Bifunctional degrading agents for interleukin-1 receptor-related kinases and their therapeutic use

Abstract

To provide methods for treating diseases. [Solution] This disclosure provides a bifunctional compound as an IRAK4 degradation agent via the ubiquitin-proteasome pathway, and a method for treating diseases regulated by IRAK4. Surprisingly, remarkable effects are achieved according to the present invention, as described in detail and demonstrated herein, such remarkable effects could not be readily predicted by those skilled in the art from the prior art.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Patent Application No. 63 / 234,606, filed on 18 August 2021, which is incorporated herein by reference in its entirety.

[0002] (Field of invention) The present invention provides a novel bifunctional compound for proteolytic degradation of interleukin-1 receptor-related kinase 4 (IRAK4), and a method for treating diseases regulated by IRAK4. [Background technology]

[0003] Explanation of related technologies Interleukin-1 receptor-associated kinase-4 (IRAK4) is a serine / threonine kinase that plays a crucial role in mediating Toll-like receptor (TLR) and interleukin-1 receptor (IL1R) signaling in immune cells, leading to the production of inflammatory cytokines. IRAK4 functions as part of the midosome, a large multi-protein complex that assembles at the plasma membrane upon ligand binding to TLR and IL1R receptors. The first step in midosome assembly is the recruitment of the scaffolding protein MyD88, followed by IRAK4 binding to MyD88 via homotyped death domain (DD) interactions. IRAK4 then undergoes self-activation and subsequently phosphorylates downstream kinases IRAK1 and IRAK2. As the most upstream kinase in this complex, IRAK4 is considered a “master regulator” of midosome signaling. The importance of IRAK4 kinase function has been demonstrated in IRAK-4 kinase dead mice, which are resistant to TLR-induced septic shock due to their inability to produce pro-inflammatory cytokines.

[0004] IRAK4 has also been reported to possess kinase-independent scaffolding function. For example, macrophages derived from IRAK4 kinase-dead mice can still activate NF-κB signaling via IL1, TLR2, TLR4, and TLR7 stimulation. Similar scaffolding function has been demonstrated in human fibroblasts, where kinase-dead IRAK4 can restore IL-1-induced NF-κB signaling to levels comparable to that of WT IRAK4.

[0005] Therefore, IRAK4 can be targeted for degradation, thereby providing therapeutic opportunities in treating autoimmune diseases, inflammatory diseases, and neoplastic diseases. Specific degradation of IRAK4 can be achieved by using heterobifunctional small molecules to recruit IRAK4 to ubiquitin ligases, thereby promoting ubiquitination and proteasomal degradation of IRAK4. For example, thalidomide derivatives such as lenalidomide or pomalidomide have been reported to recruit potential protein substrates to cereblon (CRBN), a component of the ubiquitin ligase complex. See, for example, International Publication 2019 / 099926, International Publication 2020 / 023851, International Application US2021 / 018710, and U.S. Patent Application Publication 2019 / 0192668. Further development of therapeutic agents targeting IRAK4 is necessary. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] International Publication No. 2019 / 099926 [Non-Patent Document 2] International Publication No. 2020 / 023851 [Non-Patent Document 3] International Application No. US2021 / 018710 [Non-Patent Document 4] U.S. Patent Application Publication No. 2019 / 0192668 [Overview of the project]

[0007] The present disclosure provides a bifunctional compound represented by formula (I)

[0008]

Chemical formula

[0009] In this specification, difunctional compounds represented by formula (I)

[0010] [ka] Alternatively, pharmaceutically acceptable salts, isotopic forms, isolated stereoisomers, or mixtures of stereoisomers thereof are also provided, in the formula, R 1 This is 1 to 3 R a C arbitrarily replaced by 1~10 Alkyl, 1-3 R a C arbitrarily replaced by 3~10 Cycloalkyl, or 1-3 R a A 4-12 member heterocycline arbitrarily substituted, L is -L1-L2-L3-L4-, and each L1, L2, L3 and L4 is independent of the others. a) 1 to 3 R b C arbitrarily replaced by 3~12 Cycloalkyl, b) 1 to 3 R b C arbitrarily replaced by 6~12 Ariel, c) 1 to 3 R b A 4-12 member heterocycline arbitrarily substituted, d) 1 to 3 R b 5-12 member heteroaryls arbitrarily substituted, e) direct binding; f) 1 to 3 R d C arbitrarily replaced by 1~12 Alkylene chain, g) 1 to 3 R d C arbitrarily replaced by 2~12 Alkenylene chain, h) 1 to 3 R d C arbitrarily replaced by 2~12 Alkynylene chain, i) 1 to 6 ethylene glycol units, j) 1 to 6 propylene glycol units, or k)-C(O)-, -C(O)O-, -O- 、 -N(Rc )-, -S-, -C(S)-, -C(S)-O-, -S(O)2-, -S(O)=N-, -S(O)2NH-, -C(O)-N(R c )-, -C=N-, -OC(O)-N(R c )-, or -OC(O)-O-, Each R a These are independently: Halo, -CN, and 1-3 R d C arbitrarily replaced by 1~3 Alkyl, 1-3 R d C arbitrarily replaced by 3~6 Cycloalkyl, or -OR c And, Each R b These are independently oxo, imino, sulfoxyimino, halo, nitro, -CN, and C. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Aryl, 5-12 member heteroaryl, 4-12 member heterocyclyl, -OR c , -C(O)-R c , -C(O)OR c -C(O)-N(R c )(R c ), -N(R c )(R c ), -N(R c )C(O)-R c , -N(R c )C(O)OR c , -N(R c )C(O)N(R c )(R c ), -N(R c )S(O)2(R c ), -NR c S(O)2N(R c )(R c ), -N(R c )S(O)2O(R c ), -OC(O)R c -OC(O)-N(R c )(R c ), -Si(R c)3, -SR c ,-S(O)R c -S(O)(NH)R c -S(O)2R c , or -S(O)2N(R c )(R c )(wherein, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Each of the aryl, 5-12 membered heteroaryl, and 4-12 membered heterocyclyl has 1-3 R d (This may be arbitrarily replaced by) Each R c These are independently hydrogen or C 1~6 It is alkyl, Each R d These are independently halo, oxo, -CN, -OH, and C, which are optionally substituted with 1 to 3 fluorocarbons. 1~6 Alkyl, or C 3~8 -OC, optionally substituted with cycloalkyl or 1-3 fluoropolymers. 1~6 It is alkyl, W is -C(R g )- or -N-, Ring B is C 6~12 They are aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, each containing 1 to 3 R j It is arbitrarily replaced with, Each R j These are independently hydrogen, oxo, imino, sulfoxyimino, halo, nitro, -CN, and C. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Aryl, 5-12 member heteroaryl, 4-12 member heterocyclyl, -OR g , -C(O)-R g , -C(O)OR g -C(O)-N(R g )(R g ), -N(Rg )(R g ), -N(R g )C(O)-R g , -N(R g )C(O)OR g , -N(R g )C(O)N(R g )(R g ), -N(R g )S(O)2(R g ), -NR g S(O)2N(R g )(R g ), -N(R g )S(O)2O(R g ), -OC(O)R g -OC(O)-N(R g )(R g ), -Si(R g )3, -SR g ,-S(O)R g -S(O)(NH)R g -S(O)2R g , or -S(O)2N(R g )(R g )(wherein, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Each of the aryl, 5-12 membered heteroaryl, and 4-12 membered heterocyclyl has 1-3 R k (This may be arbitrarily replaced by) R g is hydrogen or C 1~6 It is alkyl, Each R k These are independently halo, oxo, -CN, -OH, and C, which are optionally substituted with 1 to 3 fluorocarbons. 1~6 Alkyl, or C 3~8 -OC, optionally substituted with cycloalkyl or 1-3 fluoropolymers. 1~6 It is alkyl.

[0011] especially,

[0012] [ka] The component is a ligase harness (LHM) that specifically targets CRBN ligase, which is utilized by a bifunctional compound to induce ubiquitination of IRAK4 and subsequent proteasomal degradation.

[0013] In a more specific embodiment, the B ring of LHM has one of the following structures:

[0014] [ka] In a more specific embodiment, the bifunctional compounds are those described in Examples 1 to 147.

[0015] Further embodiments provide a pharmaceutical composition comprising one of the compounds of formula (I) or its substructures and a pharmaceutically acceptable carrier.

[0016] In some embodiments, the compound of formula (I) or a pharmaceutical composition thereof is useful as a therapeutic agent for treating cancers such as lymphoma, leukemia, acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS).

[0017] In other embodiments, the compound of formula (I) or a pharmaceutical composition thereof is useful as a therapeutic agent for treating metabolic disorders such as diabetes mellitus (type 1 and type 2 diabetes mellitus), metabolic syndrome, dyslipidemia, obesity, impaired glucose tolerance, hypertension, elevated serum cholesterol, and elevated triglycerides.

[0018] In other embodiments, the compound of formula (I) or the pharmaceutical composition thereof is used to treat inflammatory disorders, such as rheumatoid arthritis (RA), inflammatory colitis (IBD), Crohn's disease, ulcerative colitis, necrotizing enterocolitis, gout, Lyme disease, arthritis, psoriasis, pelvic inflammatory disease, systemic lupus erythematosus (SLE), Sjögren's syndrome, and Clostridioides difficile. It is useful as a therapeutic agent for treating inflammation associated with gastrointestinal infections, viral myocarditis, acute and chronic tissue injury, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, and renal diseases, including chronic kidney disease and diabetic kidney disease. [Modes for carrying out the invention]

[0019] Disclosed are bifunctional compounds capable of recruiting IRAK4 to E3 ubiquitin ligases for degradation, as well as methods for preparing and using the same. In particular, the bifunctional compounds typically comprise an IRAK4 binder covalently bound via a linker to a ligase harness portion for targeting the ubiquitin ligase. Advantageously, targeted degradation of IRAK4 provides effective treatment or improvement of disease conditions in which IRAK4 function is involved.

[0020] Therefore, in this specification, difunctional compounds represented by formula (I)

[0021] [ka] Or a pharmaceutically acceptable salt thereof, isotopic form, isolated stereoisomer, or mixture of stereoisomers is provided, in the formula, R 1 This is 1 to 3 R a C arbitrarily replaced by 1~10 Alkyl, 1-3 R a C arbitrarily replaced by 3~10 Cycloalkyl, or 1-3 R a A 4-12 member heterocycline optionally substituted with, or 1-3 R a It is a 5-12 member heteroaryl that is arbitrarily substituted with, L is -L1-L2-L3-L4-, and each L1, L2, L3 and L4 is independent of the others. a) 1 to 3 R b C arbitrarily replaced by 3~12 Cycloalkyl, b) 1 to 3 R b C arbitrarily replaced by 6~12 Ariel, c) 1 to 3 R b A 4-12 member heterocycline arbitrarily substituted, d) 1 to 3 R b 5-12 member heteroaryls arbitrarily substituted, e) direct binding; f) 1 to 3 R d C arbitrarily replaced by 1~12 Alkylene chain, g) 1 to 3 R d C arbitrarily replaced by 2~12 Alkenylene chain, h) 1 to 3 R d C arbitrarily replaced by 2~12 Alkynylene chain, i) 1 to 6 ethylene glycol units, j) 1 to 6 propylene glycol units, or k)-C(O)-, -C(O)O-, -O- 、 -N(R c )-, -S-, -C(S)-, -C(S)-O-, -S(O)2-, -S(O)=N-, -S(O)2NH-, -C(O)-N(R c )-, -C=N-, -OC(O)-N(R c )-, or -OC(O)-O-, Each R a These are independently: Halo, -CN, and 1-3 R d C arbitrarily replaced by 1~3 Alkyl, 1-3 R d C arbitrarily replaced by 3~6 Cycloalkyl, or -OR c And, Each R b These are independently oxo, imino, sulfoxyimino, halo, nitro, -CN, and C. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Aryl, 5-12 member heteroaryl, 4-12 member heterocyclyl, -OR c , -C(O)-R c , -C(O)ORc -C(O)-N(R c )(R c ), -N(R c )(R c ), -N(R c )C(O)-R c , -N(R c )C(O)OR c , -N(R c )C(O)N(R c )(R c ), -N(R c )S(O)2(R c ), -NR c S(O)2N(R c )(R c ), -N(R c )S(O)2O(R c ), -OC(O)R c -OC(O)-N(R c )(R c ), -Si(R c )3, -SR c ,-S(O)R c -S(O)(NH)R c -S(O)2R c , or -S(O)2N(R c )(R c )(wherein, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Each of the aryl, 5-12 membered heteroaryl, and 4-12 membered heterocyclyl has 1-3 R d (This may be arbitrarily replaced by) Each R c These are independently hydrogen or C 1~6 It is alkyl, Each R d These are independently halo, oxo, -CN, -OH, and C, which are optionally substituted with 1 to 3 fluorocarbons. 1~6 Alkyl, or C 3~8 -OC, optionally substituted with cycloalkyl or 1-3 fluoropolymers. 1~6 It is alkyl, W is -C(Rg )- or -N-, Ring B is C 6~12 They are aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, each containing 1 to 3 R j It is arbitrarily replaced with, Each R j These are independently hydrogen, oxo, imino, sulfoxyimino, halo, nitro, -CN, and C. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Aryl, 5-12 member heteroaryl, 4-12 member heterocyclyl, -OR g , -C(O)-R g , -C(O)OR g -C(O)-N(R g )(R g ), -N(R g )(R g ), -N(R g )C(O)-R g , -N(R g )C(O)OR g , -N(R g )C(O)N(R g )(R g ), -N(R g )S(O)2(R g ), -NR g S(O)2N(R g )(R g ), -N(R g )S(O)2O(R g ), -OC(O)R g -OC(O)-N(R g )(R g ), -Si(R g )3, -SR g ,-S(O)R g -S(O)(NH)R g -S(O)2R g , or -S(O)2N(R g )(R g )(wherein, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6Alkinyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Each of the aryl, 5-12 membered heteroaryl, and 4-12 membered heterocyclyl has 1-3 R k (This may be arbitrarily replaced by) R g is hydrogen or C 1~6 It is alkyl, Each R k These are independently halo, oxo, -CN, -OH, and C, which are optionally substituted with 1 to 3 fluorocarbons. 1~6 Alkyl, or C 3~8 -OC, optionally substituted with cycloalkyl or 1-3 fluoropolymers. 1~6 It is alkyl.

[0022] One particular embodiment is a bifunctional compound of formula (I).

[0023] [ka] Or provides a pharmaceutically acceptable salt, isotopic form, isolated stereoisomer, or mixture of stereoisomers thereof, in the formula, R 1 This is 1 to 3 R a C arbitrarily replaced by 1~10 Alkyl, 1-3 R a C arbitrarily replaced by 3~10 Cycloalkyl, or 1-3 R a It is a 4-12 member heterocycline that is arbitrarily substituted with, L is -L1-L2-L3-L4-, and each L1, L2, L3 and L4 is independent of the others. a) 1 to 3 R b C arbitrarily replaced by 3~12 Cycloalkyl, b) 1 to 3 R b C arbitrarily replaced by 6~12 Ariel, c) 1 to 3 R b A 4-12 member heterocycline arbitrarily substituted, d) 1 to 3 R b5-12 member heteroaryls arbitrarily substituted, e) direct binding; f) 1 to 3 R d C arbitrarily replaced by 1~12 Alkylene chain, g) 1 to 3 R d C arbitrarily replaced by 2~12 Alkenylene chain, h) 1 to 3 R d C arbitrarily replaced by 2~12 Alkynylene chain, i) 1 to 6 ethylene glycol units, j) 1 to 6 propylene glycol units, or k)-C(O)-, -C(O)O-, -O- 、 -N(R c )-, -S-, -C(S)-, -C(S)-O-, -S(O)2-, -S(O)=N-, -S(O)2NH-, -C(O)-N(R c )-, -C=N-, - OC(O)-N(R c )-, or -OC(O)-O-, Each R a These are independently: Halo, -CN, and 1-3 R d C arbitrarily replaced by 1~3 Alkyl, 1-3 R d C arbitrarily replaced by 3~6 Cycloalkyl, or -OR c And, Each R b These are independently oxo, imino, sulfoxyimino, halo, nitro, -CN, and C. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Aryl, 5-12 member heteroaryl, 4-12 member heterocyclyl, -OR c , -C(O)-R c , -C(O)OR c -C(O)-N(R c )(R c ), -N(Rc )(R c ), -N(R c )C(O)-R c , -N(R c )C(O)OR c , -N(R c )C(O)N(R c )(R c ), -N(R c )S(O)2(R c ), -NR c S(O)2N(R c )(R c ), -N(R c )S(O)2O(R c ), -OC(O)R c -OC(O)-N(R c )(R c ), -Si(R c )3, -SR c ,-S(O)R c -S(O)(NH)R c -S(O)2R c , or -S(O)2N(R c )(R c )(wherein, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Each of the aryl, 5-12 membered heteroaryl, and 4-12 membered heterocyclyl has 1-3 R d (This may be arbitrarily replaced by) Each R c These are independently hydrogen or C 1~6 It is alkyl, Each R d These are independently halo, oxo, -CN, -OH, and C, which are optionally substituted with 1 to 3 fluorocarbons. 1~6 Alkyl, or C 3~8 Cycloalkyl or optionally substituted with 1-3 fluoropolymers 1~6 It is alkyl, W is -C(R g )- or -N-, Ring B is C 6~12They are aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, each containing 1 to 3 R j It is arbitrarily replaced with, Each R j These are independently hydrogen, oxo, imino, sulfoxyimino, halo, nitro, -CN, and C. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Aryl, 5-12 member heteroaryl, 4-12 member heterocyclyl, -OR g , -C(O)-R g , -C(O)OR g -C(O)-N(R g )(R g ), -N(R g )(R g ), -N(R g )C(O)-R g , -N(R g )C(O)OR g , -N(R g )C(O)N(R g )(R g ), -N(R g )S(O)2(R g ), -NR g S(O)2N(R g )(R g ), -N(R g )S(O)2O(R g ), -OC(O)R g -OC(O)-N(R g )(R g ), -Si(R g )3, -SR g ,-S(O)R g -S(O)(NH)R g -S(O)2R g , or -S(O)2N(R g )(R g )(wherein, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C6~12 Each of the aryl, 5-12 membered heteroaryl, and 4-12 membered heterocyclyl has 1-3 R k (This may be arbitrarily replaced by) R g is hydrogen or C 1~6 It is alkyl, Each R k These are independently halo, oxo, -CN, -OH, and C, which are optionally substituted with 1 to 3 fluorocarbons. 1~6 Alkyl, or C 3~8 -OC, optionally substituted with cycloalkyl or 1-3 fluoropolymers. 1~6 It is alkyl.

[0024] IRAK4 Binder The IRAK4 binder portion of the bifunctional compound of formula (I) has the following structure, where the wavy line indicates a bond attached to the remainder of the compound of formula (I).

[0025] [ka] In the formula, R 1 This is 1 to 3 R a C arbitrarily replaced by 1~10 Alkyl, 1-3 R a C arbitrarily replaced by 3~10 Cycloalkyl, 1-3 R a A 4-12 member heterocycline optionally substituted with, or 1-3 R a It is a 5-12 member heteroaryl with arbitrary substitutions.

[0026] In a more specific embodiment, R 1 teeth, a) Halo, -OH, -OC 1~4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and -CN. 1~5 Alkyl, b) Hello, C 1~5 alkyl, -OH, -OC 1~4 A 4-8 membered heterocycline optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and -CN, c) Hello, C 1~5 alkyl, -OH, -OC 1~4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and -CN. 3~10 Cycloalkyl, d) Hello, C 1~5 alkyl, -OH, -OC 1~4 It is a 5-6 membered heteroaryl molecule that is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and -CN.

[0027] In a more specific embodiment, R 1 teeth, a) C optionally substituted with halo, -OH, or -CN 1~5 Alkyl, b) Hello, C 1~5 4-8 membered heterocyclyls optionally substituted with alkyl, -OH, or -CN, or c) Hello, C 1~5 C optionally substituted with alkyl, -OH, or -CN 3~10 It is a cycloalkyl group.

[0028] In a more specific embodiment, R 1 These are oxetane, tetrahydrofuran, or tetrahydropyran, each being F, C 1~3 It may be optionally substituted with alkyl, -OH, or -CN.

[0029] In some embodiments, R 1 This includes cyclobutyl, cyclohexyl, cyclopropyl, isoxazolyl, or C 1~4 They are alkyl groups, and each is F, C 1~3 It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, -OH, -OCH3, or -CN.

[0030] In other, more specific embodiments,

[0031] [ka] The part has one of the following structures (the wavy line indicates a bond attached to the thiadiazole portion):

[0032] [ka]

[0033] In a further embodiment,

[0034] [ka] The part has one of the following structures (the wavy line indicates a bond attached to the thiadiazole portion):

[0035] [ka]

[0036] Ligauze harness portion (LHM) targeting Cereblon The cereblon (CRBN) protein is a substrate-recognizing subunit of two ubiquitously expressed and biologically important karin RING E3 ubiquitin ligase complexes. The LHM of the compound of formula (I) is utilized by a bifunctional compound to target CRBN, an E3 ligase that induces IRAK4 ubiquitination and subsequent proteasomal degradation.

[0037] One embodiment provides a CRBN-targeted LHM having the following structure (the dashed line indicates the bond attached to the remainder of the compound of formula (I)):

[0038] [ka] (In the formula, W is -C(R g )- or -N-, Ring B is C 6~12 They are aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, each containing 1 to 3 R jIt is arbitrarily replaced with, Each R j These are independently hydrogen, oxo, imino, sulfoxyimino, halo, nitro, -CN, and C. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~15 Cycloal Kill, C 1~8 Haloalkyl, C 6~12 Aryl, 5-12 member heteroaryl, 4-12 member heterocyclyl, -OR g , -C(O)-R g , -C(O)OR g -C(O)-N(R g )(R g ), -N(R g )(R g ), -N(R g )C(O)-R g , -N(R g )C(O)OR g , -N(R g )C(O)N(R g )(R g ), -N(R g )S(O)2(R g ), -NR g S(O)2N(R g )(R g ), -N(R g )S(O)2O(R g ), -OC(O)R g -OC(O)-N(R g )(R g ), -Si(R g )3, -SR g ,-S(O)R g -S(O)(NH)R g -S(O)2R g , or -S(O)2N(R g )(R g )(wherein, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12Each of the aryl, 5-12 membered heteroaryl, and 4-12 membered heterocyclyl has 1-3 R k (This may be arbitrarily replaced by) R g is hydrogen or C 1~6 It is alkyl, Each R k These are independently halo, oxo, -CN, -OH, and C, which are optionally substituted with 1 to 3 fluorocarbons. 1~6 Alkyl, or C 3~8 -OC, optionally substituted with cycloalkyl or 1-3 fluoropolymers. 1~6 It is alkyl.

[0039] In a particular embodiment, ring B has one of the following structures:

[0040] [ka]

[0041] In a preferred embodiment, W is -CH-.

[0042] In a more specific embodiment, W is -CH-, and the CRBN-targeted LHM has one of the following structures:

[0043] [ka]

[0044] In a more specific embodiment, R j is either hydrogen or a halo (e.g., fluorocarbon).

[0045] In other embodiments, W is -N-.

[0046] In a more specific embodiment, W is -N-, and the CRBN-targeted LHM has the following structure:

[0047] [ka]

[0048] In a more specific embodiment, W is -N-, and the CRBN-targeted LHM has the following structure:

[0049] [ka]

[0050] Linker The bifunctional compound of formula (I) includes a linker portion that couples the IRAK4 binder to LHM. The structure of the linker portion (e.g., length or stiffness) can affect the efficiency or selectivity of the decomposition process. Typically, the linker portion includes multiple segments that contribute to the length and stiffness of the linker, in addition to providing the respective bonding sites to the IRAK4 binder and LHM.

[0051] In a particular embodiment, the linker portion (L) of formula (I) has up to four linker segments (L s (where s is 1, 2, 3 or 4), each L1, L2, L3 and L4 is independent, a) 1 to 3 R b C arbitrarily replaced by 3~12 Cycloalkyl, b) 1 to 3 R b Aryls arbitrarily replaced by, c) 1 to 3 R b A 4-12 member heterocycline arbitrarily substituted, d) 1 to 3 R b 5-12 member heteroaryls arbitrarily substituted, e) direct binding; f) 1 to 3 R d C arbitrarily replaced by 1~12 Alkylene chain, g) 1 to 3 R d C arbitrarily replaced by 2~12 Alkenylene chain, h) 1 to 3 R d C arbitrarily replaced by 2~12Alkynylene chain, i) 1 to 6 ethylene glycol units, j) 1 to 6 propylene glycol units, and k)-C(O)-, -C(O)O-, -O- 、 -N(R c )-, -S-, -C(S)-, -C(S)-O-, -S(O)2-, -S(O)=N-, -S(O)2NH-, -C(O)-N(R c )-, -C=N-, -OC(O)-N(R c )-, or -OC(O)-O- The bivalent part selected from, In the formula, each R b These are independently oxo, imino, sulfoxyimino, halo, nitro, -CN, and C. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Aryl, 5-12 member heteroaryl, 4-12 member heterocyclyl, -OR c , -C(O)-R c , -C(O)OR c -C(O)-N(R c )(R c ), -N(R c )(R c ), -N(R c )C(O)-R c , -N(R c )C(O)OR c , -N(R c )C(O)N(R c )(R c ), -N(R c )S(O)2(R c ), -NR c S(O)2N(R c )(R c ), -N(R c )S(O)2O(R c ), -OC(O)R c -OC(O)-N(R c )(R c ), -Si(R c)3, -SR c ,-S(O)R c -S(O)(NH)R c -S(O)2R c , or -S(O) 2N(R c )(R c )(wherein, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~12 Each of the aryl, 5-12 membered heteroaryl, and 4-12 membered heterocyclyl has 1-3 R d (This may be arbitrarily replaced by) Each R c These are independently hydrogen or C 1~6 It is alkyl, and Each R d These are independently halo, oxo, -CN, -OH, and C, which are optionally substituted with 1 to 3 fluorocarbons. 1~6 C optionally substituted with alkyl or 1-3 fluorocarbons 3~8 It is a cycloalkyl group.

[0052] In a more specific embodiment, each L1, L2, L3, and L4 is independently, a) 1 to 3 R b C arbitrarily replaced by 4~12 Cycloalkyl, b) 1 to 3 R b C arbitrarily replaced by 6~12 Ariel, c) 1 to 3 R b A 4-12 member heterocycline arbitrarily substituted, d) 1 to 3 R b 5-12 member heteroaryls arbitrarily substituted, e) direct binding; f) 1 to 3 R d C arbitrarily replaced by 1~12 Alkylene chain, or g)C(O)-, -O-, -N(R) c )- or -C(O)-N(R c)-is.

[0053] Unless otherwise specified, the divalent portion described herein (for example, L or L) is provided that the valence is satisfied. s It should be understood that these are not limited to the direction in which they are expressed. For example, for a given linker segment, e.g., -C(O)-NH-, the way in which it is linked to the rest of the molecule can be in either direction: i.e., -C(O)-NH- or -NH-C(O)-, provided that the linkage does not violate the rules of valence.

[0054] On the other hand, L is a series of L s When expressed by this, the directionality is in a manner consistent with the structure of formula (I), and is specific to L s This can be established by the position. For example, linker segment L1 should be understood as directly coupled to the IRAK4 binder portion. Linker segment L4 should be understood as directly coupled to the LHM.

[0055] One or more linker segments may be directly coupled. For example, in -L2-L3-L4-, if L3 is directly coupled, then L2 and L4 are directly coupled to each other, so it effectively does not exist.

[0056] In various specific embodiments, L1 is C 3~12 A ring selected from cycloalkyl, 6-15 membered aryl, 3-15 membered heterocyclyl, and 5-15 membered heteroaryl rings, each of which has up to 3 R d It may be further replaced by (as defined herein). In a more specific embodiment, L1 is C 4~12 A ring selected from cycloalkyl, 6-12 membered aryl, 4-12 membered heterocyclyl, and 5-12 membered heteroaryl rings, each of which has up to 3 R d It may be further replaced with (as defined herein).

[0057] In various specific embodiments, L1 may be one of the following ring portions:

[0058] [ka]

[0059] In other specific embodiments, L1 is

[0060] [ka] It is possible.

[0061] In a particular embodiment, -L2-L3-L4- is one of the following structures: -C(O)-, -(CH2) m -,

[0062] [ka] It has, In the formula, m is 1, 2, or 3, and R c H or C 1~3 It is alkyl.

[0063] In a further specific embodiment, -L2-L3-L4- has one of the following structures:

[0064] [ka]

[0065] In a more specific embodiment, L is one of the following structures:

[0066] [ka] It has, In the formula, R c H or C 1~3 It is an alkyl group, and m is 1, 2, or 3.

[0067] In other, more specific embodiments, L has one of the following structures:

[0068] [ka]

[0069] Construction of the compound of formula (I) The synthesis or construction of the compound of formula (I) can typically be carried out in a series of steps, including separately preparing the components of the IRAK4 binder and the LHM moiety, and then joining the respective components via covalent bond formation. Generally speaking, one or both of the components are one or more linker precursors (L x The linker precursor can be prepared using one or more linker segments (L s ) contains and has terminal reactive groups for further coupling. The two components are ultimately coupled ( L A compound of formula (I) can be obtained (through the formation of segments).

[0070] The following scheme illustrates a general approach to preparing the components. Examples 1-147 are specific examples of formula (I) that have been synthesized and characterized by their respective physiological and chemical properties.

[0071] A. Preparation of IRAK4 binder components Several general schemes for preparing IRAK4 binder components are described herein.

[0072] [ka]

[0073] The compound of formula 1.5 can be obtained according to the method shown in scheme 1. Using a suitable catalyst (e.g., HCl) and a suitable solvent (e.g., EtOH), 1-aminopyrrole 1.1 can be condensed with a suitable coupling partner to produce substituted pyrrolo[1,2-b]pyridazine 1.2. Halogenation at the indicated position using a known halogenating reagent (e.g., NBS) can form intermediate 1.3, which can be further substituted with a suitable reagent (e.g., SelectFluor) via either CH activation or electrophilic aromatic substitution to produce intermediate 1.4. Halogen metal exchange from -X to -M can be achieved using a suitable reagent (e.g., n-BuLi) or transition metal coupling using a palladium catalyst and metal source (e.g., B2Pin2, Me6Sn2) to obtain intermediate 1.5.

[0074] [ka]

[0075] The compound of formula 2.3 can be obtained according to the method shown in Scheme 2. Acid 2.1 can be converted to the corresponding acylhydrazine using a coupling reagent (e.g., HATU) in the presence of a base (e.g., DIPEA). Compound 2.3 can be obtained by achieving cyclization of compound 2.2 by heating in the presence of a thiolation reagent (e.g., Lawson's reagent).

[0076] [ka]

[0077] Compounds of formula 3.6 can be obtained according to the method shown in scheme 3. Dihalopyridine 3.1 can be converted to compound 3.2 via substitution of one of the halogen groups (e.g., nucleophilic aromatic substitution). Compound 3.2 can be further functionalized using a metal-containing heterocyclic species (e.g., compound 1.5) with a suitable catalyst such as a palladium catalyst to obtain compound 3.3. Halogenation at the indicated position using a known halogenating agent (e.g., NBS) can form intermediate 3.4, which can be further substituted by a cross-coupling reaction using a suitable catalyst such as a palladium catalyst to obtain compound 3.5.

[0078] [ka]

[0079] The compound of formula 4.2 can be prepared according to scheme A4. Compound 2.3 can be obtained by substituting the halogen group of halothiadianazole 4.1 with a nucleophile (e.g., an amine) (e.g., nucleophilic aromatic substitution). Intermediate 4.2 can be formed by halogenation at the indicated position using a known halogenating reagent (e.g., NBS).

[0080] [ka]

[0081] The compound of formula 3.5 can also be prepared according to scheme A5. Intermediate 5.1 can be obtained by performing a halogen metal exchange from -X to -M using a suitable reagent (e.g., n-BuLi) or by using transition metal coupling with a palladium catalyst and metal source (e.g., B2Pin2, Me6Sn2). Compound 3.5 can be obtained by performing a cross-coupling reaction with compound 4.2 using a suitable catalyst such as a palladium catalyst to functionalize compound 5.1.

[0082] Under Scheme A5, Lx This can be a ring having a reactive moiety, which can then be coupled to another linker segment. For example, BOC-protected L x teeth,

[0083] [ka] It may also be, and compound 4.2 is

[0084] [ka] The resulting compound 3.5 is an L1 precursor, i.e., an IRAK4 binder component having a piperazine ring, which can be further coupled to another linker segment via a reactive secondary amine of piperazine.

[0085] [ka]

[0086] Another method for accessing compound 3.5 is shown in scheme A6. Starting from nicotinic acid 6.1, the corresponding acylhydrazine can be prepared using a coupling reagent (e.g., HATU) in the presence of a base (e.g., DIPEA). By heating in the presence of a thiolation reagent (e.g., Lawson's reagent), cyclization of compound 6.3 can be achieved to obtain compound 6.4. Compound 6.4 can be further functionalized using a metal-containing heterocyclic species (e.g., compound 1.5) with a suitable catalyst such as a palladium catalyst to obtain compound 3.5.

[0087] In scheme A6, L x The ring may have a reactive moiety, which can then be coupled to another linker segment. For example, L x teeth,

[0088] [ka] It may also be (optionally in BOC-protected form during synthesis), and the resulting compound 3.5 is an L1 precursor, i.e., another IRAK4 binder component having a bicyclo[2.2.2]octane ring, which can be further coupled to another linker segment via a reactive primary amine.

[0089] Specific examples of preparing IRAK4 binder components, which are intermediates further coupled to LHM, are described in more detail below.

[0090] Intermediate A: 7-(5-(5-(piperazin-1-yl)-1,3,4-thiadiazole-2-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0091] [ka]

[0092] Step 1: To a solution of 2-bromo-4-fluoropyridine (30.0 g, 170 mmol, 1.00 equivalent) in NMP (300 mL), DIEA (33.1 g, 255 mmol, 44.5 mL, 1.50 equivalent) and tetrahydro-2H-pyran-4-amine (20.7 g, 204 mmol, 1.20 equivalent) were added, and the mixture was stirred at 110°C for 1.5 hours. The reaction mixture was poured into H2O (500 mL) and extracted with methyl tert-butyl ether (500 mL). * 4) Combine the organic layers and add saturated brine (500 mL). * Washed in step 6), the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 2-bromo-N-(tetrahydro-2H-pyran-4-yl)pyridine-4-amine. The residue was used in the next step without further purification (46 g). LCMS: m / z = 257.2 (M + H) +

[0093] Step 2: The product from Step 1 (30.0 g, 101 mmol, 1.00 equivalent) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (35.5 g, 132 mmol, 1.30 equivalents) were added to DME (300 mL) with K3PO4 (2.00 M, 102 mL, 2.00 equivalents) and Pd(dppf)Cl2·CH2Cl2 (8.29 g, 10.2 mmol, 0.100 equivalents) under N2. The mixture was stirred under N2 at 100°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue, which was then mixed with MPLC (SiO2, petroleum ether / ethyl acetate = 10 / 1~0 / 1, R f Purified by (=0.10). 7-(4-((tetrahydro-2H-pyran-4-yl)amino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (30.0 g, 93.5 mmol, yield 92.1%) was obtained as a yellow solid. LCMS: m / z = 320.2(M+H) +

[0094] Step 3: To a solution of 7-(4-((tetrahydro-2H-pyran-4-yl)amino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (36.0 g, 106 mmol, 1.00 equivalent) in MeCN (758 mL) and DCM (758 mL), a solution of NBS (16.7 g, 93.6 mmol, 0.880 equivalent) in MeCN (127 mL) and DCM (127 mL) was added at 0°C, and the mixture was stirred at 0°C for 0.5 hours. The reaction mixture was filtered, the filter cake was collected, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was converted to MPLC (SiO2, petroleum ether / ethyl acetate = 10 / 1~1 / 1, R f The solution was purified by LCMS (=0.60). The filtered cake and the yellow solid MPLC residue were combined to obtain 7-(5-bromo-4-((tetrahydro-2H-pyran-4-yl)amino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (34.9 g, 85.8 mmol, yield 80.6%). LCMS: m / z = 397.9 (M + H) +

[0095] Step 4: To a solution of 7-(5-bromo-4-((tetrahydro-2H-pyran-4-yl)amino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (34.9 g, 85.7 mmol, 1.00 equivalent) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (43.5 g, 171 mmol, 2.00 equivalent) in DMF (175 mL) and dioxane (350 mL), KOAc (25.2 g, 257 mmol, 3.00 equivalent) and Pd(PPh3)2Cl2 (9.02 g, 12.9 mmol, 0.150 equivalent) were added under N2 conditions, and the mixture was stirred under N2 conditions at 120°C for 3 hours. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure to obtain the residue. The crude product was purified by reverse-phase HPLC (TFA conditions). The desired product (13.3 g, 25.5 mmol, yield 29.8%, TFA) was obtained as a yellow solid. LCMS: Product: m / z = 364.0 (M + H) +

[0096] Step 5: To a solution of 2,5-dibromo-1,3,4-thiadiazole (20.0 g, 82.0 mmol, 1.00 equivalent) and tert-butylpiperazine-1-carboxylate (18.3 g, 98.4 mmol, 1.20 equivalent) in dioxane (200 mL), DIEA (21.2 g, 164 mmol, 28.5 mL, 2.00 equivalent) was added, and the mixture was stirred at 110 °C for 2 hours. The mixture was cooled to 25 °C, filtered, and the filtered cake was put into ethyl acetate (50.0 mL). * 2) Wash and rinse with brine (200 mL) * The solution was washed (2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was used in the next step without further purification. Tert-butyl 4-(5-bromo-1,3,4-thiadiazole-2-yl)piperazine-1-carboxylate (31.8 g, crude product) was obtained as a red solid. LCMS: m / z = 294.8 (M + H) +

[0097] Step 6: To a solution of (6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridine-3-yl)boronic acid (6.00 g, 11.5 mmol, 1.00 equivalent, TFA) and tert-butyl 4-(5-bromo-1,3,4-thiadiazole-2-yl)piperazine-1-carboxylate (4.23 g, 12.1 mmol, 1.05 equivalents) in dioxane (315 mL), Pd(OAc)2 (518 mg, 2.3 mmol, 0.200 equivalents), xanthophos (2.67 g, 4.6 mmol, 0.400 equivalents) and Cs2CO3 (9.39 g, 28.8 mmol, 2.50 equivalents) were added under N2 conditions. The mixture was stirred under N2 at 120°C for 5 hours. The reaction mixture was filtered, and the filtered cake was hydrated with ethyl acetate (200 mL). * 3) Washed and collected. Filter the filtrate, collect the filter cake, and rinse the filtrate with water (500 mL). * Washed in step 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain tert-butyl4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl)piperazine-1-carboxylate (6.00 g, 8.7 mmol, yield 75%) as a yellow solid, which was used in the next step without further purification. Desirable.

[0098] Step 7: A mixture of tert-butyl 4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl)piperazine-1-carboxylate (6.00 g, 8.7 mmol, 1.00 equivalent) in HCl / siRNA (4.00 M, 52.4 mL, 24.2 equivalents) and siRNA (20.0 mL) was stirred at 25°C for 2.5 hours. The reaction mixture was filtered, the resulting filter cake was collected, and concentrated under reduced pressure to obtain the HCl salt of the title product (4.06 g, 7.2 mmol, yield 82.6%) as a yellow solid. LCMS: m / z = 488.4 (M + H) + . 1H NMR:(400MHz,D2O)δ8.52(s,2H),8.19(s,1H),7.87(d,J=4.8Hz,1H),7.25(s,1H),7.14(d,J=5.2Hz,1H),3. 99-4.03(m,2H),3.91-3.95(m,4H),3.74(t,J=20.0Hz,2H),3.48-3.52(m,4H),2.12(d,J=11.2Hz,2H),1.66-1.78(m,2H).

[0099] Intermediate B: 7-(4-(isopropylamino-5-(5-(piperazin-1-yl)-1,3,4-thiadiazole-2-yl)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0100] [ka]

[0101] Intermediate B was prepared in the same manner as intermediate A, but in step 1, tetrahydro-2H-pyran-4-amine was used instead of isopropylamine to obtain the HCl salt of the title product as a yellow solid. LCMS: m / z = 446.2 (M + H) + . 1 H NMR:(400MHz,MeOD)δ8.77(d,J=2.0Hz,1H),8.69(d,J=2.4Hz,1H),8.56(s,1H),8.10(d,J=5.2Hz,1H),7.90(s,1H),7.2 4(d,J=4.8Hz,1H),4.32-4.29(m,1H),3.97-3.94(d,J=10.4Hz,4H),3.48-3.44(d,J=14.4Hz,4H),1.48(d,J=6.4Hz,6H).

[0102] Intermediate B: Alternative route:

[0103] [ka]

[0104] Step 1: To a solution of 2-bromo-1,3,4-thiadiazole (7.29 g, 42.4 mmol, 1.0 equivalent) and tert-butylpiperazine-1-carboxylate (19.75 g, 106 mmol, 2.5 equivalents) in n-butanol (83 mL, 0.51 M), N,N-diisopropylethylamine (29.56 mL, 16968 mmol, 4.0 equivalents) was added. The reaction mixture was stirred at 120°C for 1 hour. The reaction mixture was cooled and concentrated under vacuum. The resulting crude product was purified by chromatography using elution with ethyl acetate in hexane (0-70% gradient) to obtain tert-butyl 4-(1,3,4-thiadiazole- 2-yl)piperazine-1-carboxylate was obtained as a pale red solid (9.93 g, yield 86%). LCMS:ESI(+)[M-tBu] + = 215.26. 1 H NMR (300MHz, DMSO-d6) δ8.84 (s, 1H), 3.46 (m, 8H), 1.42 (s, 9H).

[0105] Step 2: 7-{5-bromo-4-[(propan-2-yl)amino]pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitride (5.50g, 15.4mmol, 1.0 equivalent), tert-butyl-4-(1,3,4-thiadiazole-2-yl)piperazine-1-carboxylate (3.95g, 13.9mmol, 0.9 equivalent), palladium(II) acetate (0.173g, 0 0.8 mmol, 0.05 equivalents) CuI (0.294 g, 1.5 mmol, 0.10 equivalents), xanthophos (0.893 g, 1.54 mmol, 0.1 equivalent) and Cs2CO3 (10.06 g, 30.88 mmol, 2.0 equivalents) were placed in a pressure vessel equipped with a magnetic stirrer, followed by the addition of dimethoxyethane (250 mL, 0.061 M). The vessel was degassed under vacuum and refilled with argon (5 times). The reaction mixture was stirred at 105°C for 24 hours. After cooling, the reaction mixture was filtered through a Celite pad and concentrated under vacuum. The crude product was purified by FC elution with DCM / siRNA (gradient 0-30%), followed by recrystallization from 96% EtOH to obtain tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(propan-2-yl)amino]pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate as a yellow solid (2.271 g, yield 27%). LCMS:ESI(+)[M+H] + = 546.70. 1 H NMR(300MHz,CDCl3)δ8.76(s,1H),8.51(s,1H),8.36(s,1H),8.21(d,J=2.1Hz,1H),8.18(s,1H),8.02 (s,1H),7.02(d,J=4.8Hz,1H),3.99(h,J=6.4Hz,1H),3.63(s,8H),1.51(s,9H),1.43(d,J=6.4Hz,6H).

[0106] Step 3: tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(propan-2-yl)amino]pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (2.27 g, 4.2 mmol, 1.0 equivalent) and 1,1,1,3,3,3-hexafluoro-2-propanol (6.57 mL, 62.4 mmol, 15 equivalents) were placed in a microwave reactor and stirred at 140°C for 3 hours. The solvent was then evaporated under vacuum. The resulting residue was purified by chromatography using MeOH / DCM to obtain the title compound as a yellow solid (1.615 g, yield 87%). LCMS: ESI(+)[M+H] + = 446.03. 1 H NMR(300MHz,DMSO-d6)δ8.83(d,J=2.3Hz,1H),8.72(d,J=2.2Hz,1H),8.55(d,J=7.1Hz,1H),8.47(s,1H),8.19(s,1H),7.83 (d,J=4.8Hz,1H),7.11(d,J=4.8Hz,1H),3.92(h,J=6.4Hz,1H),3.51-3.41(m,4H),2.88-2.79(m,4H),1.35(d,J=6.3Hz,6H).

[0107] Intermediate C: 7-(4-(methylamino)-5-(5-(piperazin-1-yl)-1,3,4-thiadiazole-2-yl)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0108] [ka]

[0109] Step 1: To a solution of 2-bromo-4-fluoropyridine (30.0 g, 170 mmol, 1.00 equivalent) in NMP (300 mL), methaneamine hydrochloride (13.8 g, 204 mmol, 1.20 equivalent) and DIEA (66.1 g, 511 mmol, 89.1 mL, 3.00 equivalent) were added. The reaction mixture was then stirred at 110°C for 2 hours. The reaction mixture was poured into H2O (600 mL) and DCM (200 mL) * 5) Extracted. The organic layer was then placed in a saturated NaCl solution (200 mL). * 6) was washed. The organic layer was then dried over Na2SO4, filtered, and concentrated under vacuum to obtain 2-bromo-N-methylpyridine-4-amine (29.2 g, crude) as a yellow liquid, which was used in the next step without purification. LCMS: m / z = 188.9 (M + H) +

[0110] Step 2: To a solution of 2-bromo-N-methylpyridine-4-amine (19.2 g, 102 mmol, 1.00 equivalent) in DME (250 mL), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (31.7 g, 118 mmol, 1.15 equivalent), XPhos Pd G3 (9.60 g, 11.3 mmol, 0.110 equivalent), and K3PO4 (2.00 M, 102 mL, 2.00 equivalent) were added. The reaction mixture was stirred in N2 at 100°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (DCM / MeOH = 50 / 1 to 10 / 1) to obtain 7-(4-(methylamino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (16.9 g, 67.5 mmol, yield 65.7%) as a yellow solid. LCMS: m / z = 250.0 (M+H) +

[0111] Step 3: To a solution of 7-(4-(methylamino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (16.9 g, 67.5 mmol, 1.00 equivalent) in DCM (355 mL) and ACN (355 mL), a solution of NBS (10.6 g, 59.4 mmol, 0.88 equivalent) in DCM (177 mL) and ACN (177 mL) was added. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure. The resulting residue was triturated with petroleum ether (30.0 mL) at 25°C for 30 minutes. 7-(5-bromo-4-(methylamino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (28.4 g, 75.0 mmol) was obtained as a yellow solid. LC-MS: m / z = 329.9 (M + H) +

[0112] Step 4: To a solution of 7-(5-bromo-4-(methylamino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (24.2 g, 63.9 mmol, 1.00 equivalent) in dioxane (242 mL) and DMF (121 mL), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (32.5 g, 127 mmol, 2.00 equivalent), KOAc (18.8 g, 191 mmol, 3.00 equivalent), and Pd(PPh3)2Cl2 (6.71 g, 9.6 mmol, 0.150 equivalent) were added under N2. The reaction mixture was stirred at 120°C for 1 hour. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum to obtain the residue. The residue was purified by reverse-phase HPLC (under 0.1% TFA conditions) to obtain (6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(methylamino)pyridine-3-yl)boronic acid (12.93 g, 29.7 mmol, yield 46.4%, TFA) as a yellow solid. LCMS: m / z = 293.9 (M + H) +

[0113] Step 5: To a solution of (6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(methylamino)pyridine-3-yl)boronic acid (4.00 g, 9.2 mmol, 1.00 equivalent, TFA) in dioxane (210 mL), tert-butyl 4-(5-bromo-1,3,4-thiadiazole-2-yl)piperazine-1-carboxylate (3.39 g, 9.6 mmol, 1.05 equivalent), Cs2CO3 (7.47 g, 22.9 mmol, 2.50 equivalent), xanthophos (2.12 g, 3.67 mmol, 0.40 equivalent), and Pd(OAc)2 (412 mg, 1.8 mmol, 0.20 equivalent) were added under N2 conditions. The reaction mixture was stirred at 120°C for 2 hours. The reaction mixture was filtered directly at 120°C, the filter cake was washed with DCM (30.0 mL), and the filtrate was concentrated under vacuum to obtain the residue. The residue was triturated with ELISA (30.0 mL) at 25°C for 30 minutes to obtain tert-butyl 4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(methylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl)piperazine-1-carboxylate (5.60 g, crude) as a yellow solid. LCMS: m / z = 518.1 (M + H) + . 1 H NMR:(400MHz,CDCl3)δ8.53(s,1H),8.35(d,J=2.4Hz,1H),8.19(d,J=2.0Hz,1H),8.10(s,1H), 7.92(d,J=4.8Hz,1H),6.99(s,1H),3.62(d,J=1.6Hz,8H),3.12(d,J=4.8Hz,3H),1.49(s,9H).

[0114] Step 6: To a solution of tert-butyl 4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(methylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl)piperazine-1-carboxylate (5.60 g, 10.8 mmol, 1.00 equivalent) in HCl / siRNA (4.00 M, 28.0 mL, 10.3 equivalents) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered, the filter cake was washed with DCM (50.0 mL), and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (basic conditions) to obtain 7-(4-(methylamino)-5-(5-(piperazin-1-yl)-1,3,4-thiadiazole-2-yl)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.13 g, 2.6 mmol, yield 24.2%) as a yellow solid. LCMS: m / z = 418.0 (M + H) + . 1 H NMR(400MHz,DMSO-d6)δ8.83(d,J=2.0Hz,1H),8.72(d,J=2.0Hz,1H),8.51-8.47(m,2H ),8.14(s,1H),7.85(d,J=5.2Hz,1H),7.12(d,J=4.4Hz,1H),3.45(t,J=4.8Hz,4H),3. 06(d,J=4.8Hz,3H),2.83(t,J=5.2Hz,4H).

[0115] Intermediate C: Alternative route

[0116] [ka]

[0117] Step 1: To a mixture of 2-bromo-4-fluoropyridine (25.0 g, 0.142 mol, 1.0 equivalent), methylamine in methanol (9.8 M) (142 mL, 1.42 mol, 10 equivalents) was added, and the resulting mixture was heated overnight at 80°C. After completion, the reaction mixture was cooled, all volatiles were evaporated under vacuum, dissolved in ethyl acetate, and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain 2-bromo-N-methylpyridine-4-amine (25 g, 89% yield). 1 H NMR (300MHz, DMSO-d6), δ:7.77(d,J=5.8Hz,1H),6.98-6.78(m,1H),6.59(m,1H),6.48(m,1H),2.69(d,J=4.9Hz,3H). LCMS:ESI(+)[M+H] + = 188.94.

[0118] Step 2: To a solution of 2-bromo-N-methylpyridine-4-amine (6.0 g, 32.1 mmol, 1.0 equivalent), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (12.09 g, 44.9 mmol, 1.4 equivalent), and Xphos G3 (2.17 g, 2.6 mmol, 0.08 equivalent) in anhydrous dimethoxyethane (80 mL, 0.4 M), an aqueous solution of 2 M K3PO4 (32.1 mL, 64.2 mmol, 2.0 equivalent) was added. The solution was degassed with argon for 15 minutes, and then heated overnight at 120°C with vigorous stirring. The reaction mixture was filtered through a Celite pad and evaporated to dryness under reduced pressure. The resulting crude residue was purified by chromatography using methanol (0-10%) in dichloromethane to obtain 7-[4-(methylamino)-2-pyridyl]pyrrolo[1,2-b]pyridazine-3-carbonitrile as a yellow solid (6.1 g, yield 76%). 1H NMR(300MHz,DMSO-d6),δ:8.79(d,J=2.2Hz,1H,),8.64(d,J=2.2Hz,1H,),8.19(d,J=5.6,1H,),7.87 (d,J=2.3,1H,),7.76(d,J=4.7Hz,1H,),7.08(d,J=4.7,1H,),6.80(d,J=5.0,1H,),6.45(m,1H,),2.7 7(d,J=4.8Hz,3H). LCMS:ESI(+)[M+H] + = 250.36.

[0119] Step 3: 7-[4-(methylamino)-2-pyridyl]pyrrolo[1,2-b]pyridazine-3-carbonitrile (5.3 g, 20.1 mmol, 1.0 equivalent) was dissolved in acetonitrile (65 mL, 0.3 M) and dichloromethane (20 mL, 0.7 M), and N-bromosuccinimide (3.57 g, 20.1 mmol, 1.0 equivalent) was added all at once at room temperature. The reaction mixture was stirred under ambient conditions for 30 minutes. The progress of the reaction was monitored by LC-MS. After completion, the mixture was evaporated under reduced pressure, and the resulting residue was purified by chromatography using 0-5% ethyl acetate in dichloromethane to obtain 7-(5-bromo-4-(methylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile as a yellow solid (5.95 g, yield 88%). 1 H NMR(300MHz,DMSO-d6),δ:8.80(d,J=2.2Hz,1H),8.67(d,J=2.2Hz,1H),8.36(s,1H),7.94(s,1 H),7.76(d,J=4.8Hz,1H),7.08(d,J=4.8Hz,1H),6.45(q,J=4.3Hz,1H),2.90(d,J=4.7Hz,3H). LCMS:ESI(+)[M+H] + = 330.16.

[0120] Step 4: Tert-butyl 4-(1,3,4-thiadiazole-2-yl)piperazine-1-carboxylate was prepared in the same manner as in Step 1 for intermediate B (alternative route). 1H NMR (300MHz, DMSO-d6), δ: 8.84 (s, 1H), 3.46 (s, 8H), 1.42 (s, 9H). LCMS:ESI(+)[M+2H] + = 272.16.

[0121] Step 5: 7-[5-bromo-4-(methylamino)pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.5g, 1.52 mmol, 1.0 equivalent), palladium(II) acetate (0.051g, 0.23 mmol, 0.15 equivalents), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (0.26g, 0.5 mmol, 0.3 equivalents), cesium carbonate 0.1 g, 3.1 mmol, 2.0 equivalents of thiacin (0.1 g, 3.1 mmol, 2.0 equivalents) and cuprous iodide (0.087 g, 0.5 mmol, 0.3 equivalents) were placed in an oven-dried screw-cap vial, and tert-butyl-4-(1,3,4-thiadiazole-2-yl)piperazine-1-carboxylate (0.434 g, 1.5 mmol, 1 equivalent) and anhydrous dioxane (25.39 mL, 0.06 M) were added to it. The reaction tube was evacuated with argon for 20 minutes, refilled, sealed, and stirred overnight at 105°C. After the reaction was complete (confirmed by ULC), all volatiles were evaporated under vacuum, and the resulting residue was purified by chromatography (0-31% ethyl acetate in dichloromethane) to obtain tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)-pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate as a yellow crystalline solid (0.57 g, yield 61%). 1 H NMR(300MHz,DMSO-d6),δ:8.83(s,1H),8.73(s,1H),8.48(m,2H),8.14(s,1H),7. 86(s,1H),7.12(d,J=4.8Hz,1H),3.54(s,8H),3.06(d,J=4.9Hz,3H),1.44(s,9H). LCMS:ESI(+)[M+H] + = 518.64.

[0122] Step 6: A solution of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)-pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (0.25 g, 0.5 mmol, 1 equivalent) in 0.769 mL, 7.3 mmol, 15 equivalents of 1,1,1,3,3,3-hexafluoro-2-propanol was heated at 140°C for 3 hours using a MW. Subsequently, all volatile substances were evaporated under reduced pressure, and the remaining residue was purified by chromatography (0-7% methanol in dichloromethane) to obtain the title product as a yellow solid (0.15 g, 73% yield). LCMS:ESI(+)[M+H] + = 418.06. 1 H NMR(300MHz,DMSO-d6),δ:8.83(d,J=2.2Hz,1H),8.72(s,1H),8.54-8.42(m,2H),8.13(s,1H),7.85( d,J=4.8Hz,1H),7.11(d,J=4.8Hz,1H),3.46(s,4H),3.06(d,J=4.9Hz,3H),2.84(s,4H),2.61(m,1H).

[0123] Intermediate D: 7-[5-(5-{4-formylbicyclo[2.2.2]octan-1-yl}-1,3,4-thiadiazole-2-yl)-4-[(oxan-4-yl)amino]pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0124] [ka]

[0125] Step 1: A solution of methyl 4-(5-{6-chloro-4-[(oxan-4-yl)amino]pyridine-3-yl}-1,3,4-thiadiazole-2-yl)bicyclo[2.2.2]octane-1-carboxylate (6 g, 13 mmol, 1 equivalent) in anhydrous THF (324.5 mL, 0.04 M) was cooled to -15°C under an argon atmosphere and treated with DIBAL-H (38.96 mL, 39 mmol, 3 equivalents of a 1.0 M solution in THF). After 30 minutes, the cooling bath was removed, the mixture was warmed to room temperature, and stirred for 3 hours. The reaction was quenched by adding MeOH (40 mL), stirred vigorously for 20 minutes, and then a saturated aqueous solution of Rochelle salt was added. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (0-10%, acetone / DCM) to obtain [4-(5-{6-chloro-4-[(oxan-4-yl)amino]pyridine-3-yl}-1,3,4-thiadiazole-2-yl)bicyclo[2.2.2]-octan-1-yl]methanol as an off-white solid (3.65 g, yield 65%). LCMS:ESI(+)[M+H] + = 435.54. 1 H NMR(300MHz,DMSO-d6),δ:8.91(d,J=7.7Hz,1H),8.42(s,1H),7.05(s,1H),4.46(t,J=5.4Hz,1H),3.8 6(m,3H),3.52(t,J=11.0Hz,2H),3.14(dd,J=20.1,5.3Hz,2H),2.00-1.87(m,8H),1.55-1.39(m,8H).

[0126] Step 2: To a solution of [4-(5-{6-chloro-4-[(oxan-4-yl)amino]pyridine-3-yl}-1,3,4-thiadiazole-2-yl)bicyclo[2.2.2]-octan-1-yl]methanol (3.78 g, 8.3 mmol, 1.0 equivalent), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (2.70 g, 9.9 mmol, 1.2 equivalents), and Pd(dppf)Cl2·CH2Cl2 (1.69 g, 2.1 mmol, 0.25 equivalents) in anhydrous dioxane (212 mL, 0.04 M), 8.5 mL, 16.6 mmol, 2.0 equivalents was added. Decontaminated the mixture with argon for 30 minutes. The mixture was then stirred overnight at 120°C. The reaction mixture was diluted with DCM, filtered through a Celite pad, washed with DCM / MeOH (1:1), and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography (DCM / acetone) to obtain [4-(5-{6-chloro-4-[(oxan-4-yl)amino]pyridine-3-yl}-1,3,4-thiadiazole-2-yl)bicyclo[2.2.2]octan-1-yl]methanol (3.3 g, 73% yield). LCMS:ESI(+)[M+H] + = 542.67. 1 H NMR(300MHz,DMSO-d6),δ:8.84(m,3H),8.69(s,1H),8.32(s,1H),7.86(d,J=4.8Hz,1H),7.12(d,J=4.8Hz,1H),4.46(t ,J=5.4Hz,1H),3.94(d,J=15.3Hz,3H),3.60(t,J=10.2Hz,2H),3.11(d,J=5.4Hz,2H),2.11-1.88(m,9H),1.49(s,8H).

[0127] Step 3: To a solution of [4-(5-{6-chloro-4-[(oxan-4-yl)amino]pyridine-3-yl}-1,3,4-thiadiazole-2-yl)bicyclo[2.2.2]octan-1-yl]methanol (3.3 g, 6.1 mmol, 1 equivalent) in DCM (609 mL, 0.01 M), Des-Martin periodinane (3.36 g, 8.0 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at room temperature for 2 hours, and then quenched with 20% Na2S2O3 aqueous solution and saturated NaHCO3 aqueous solution. The resulting mixture was stirred until the aqueous layer was clear. The latter was then extracted with DCM. The combined organic layers were washed with saturated NaHCO3 aqueous solution, water and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was triturated with Et2O, filtered, and washed on the filter with a mixture of DCM / Et2O (1:1), Et2O, and pentane to obtain the title compound (2.8 g, 84% yield). LCMS:ESI(+)[M+H] + = 540.20. 1 H NMR(300MHz,DMSO-d6),δ:9.49(s,1H),8.90-8.73(m,3H),8.70(s,1H),8.32(s,1H),7.86(d,J=4.8Hz,1H),7.12(d,J=4.8Hz) ,1H),3.95(d,J=11.7Hz,3H),3.60(t,J=10.3Hz,2H),2.18-1.96(m,8H),1.78(d,J=8.1Hz,6H),1.60(q,J=11.9,9.9Hz,2H).

[0128] Intermediate E: 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(oxan-4-yl)amino]pyridine-3-yl)-1,3,4-thiadiazole-2-yl]bicyclo[2.2.2]octane-1-carboxylic acid.

[0129] [ka]

[0130] Step 1: Add DIPEA (220 mL, 1.26 mol, 2.6 equivalents) to ACN (486 The mixture was added to a cooled, stirred solution of methyl 4,6-dichloronicotinate (100 g, 485 mmol, 1.0 equivalent) in 1 mL (1 M). Tetrahydro-2H-pyran-4-amine (65 mL, 631 mmol, 1.3 equivalents) was added dropwise, and the mixture was stirred at 70°C for 36 hours. The mixture was cooled, the solid was filtered off, and the filtrate was concentrated under vacuum. The residue was partitioned into ethyl acetate and water. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The resulting residue was recrystallized from hexane to obtain methyl 6-chloro-4-[(oxan-4-yl)amino]pyridine-3-carboxylate (124.8 g, 92% yield). LCMS:ESI(+)[M+H] + = 272.25. 1 H NMR(300MHz,DMSO-d6)δ:8.54(s,1H),8.06(d,J=7.9Hz,1H),7.00(s,1H),3.84(s,6H) ),3.48(td,J=11.4,2.0Hz,2H),1.90(d,J=10.7Hz,2H),1.46(qd,J=11.1,4.5Hz,2H).

[0131] Step 2: To a solution of methyl 6-chloro-4-[(oxan-4-yl)amino]pyridine-3-carboxylate (40 g, 147.7 mmol, 1.0 equivalent) in EtOH (246 mL), 65% by weight of hydrazine monohydrate (88 mL, 1.18 mol, 8.0 equivalent) was added, and the mixture was stirred at 80°C for 2 hours. The volatiles were evaporated, and then the mixture was co-evaporated several times with toluene. The residue was dried overnight at 50°C and 5 mBar to obtain 6-chloro-4-[(oxan-4-yl)amino]pyridine-3-carbohazide (37.6 g, yield 89%). LCMS: ESI(+)[M+H] + =272.05. 1 H NMR(300MHz,DMSO-d6)δ:9.87(s,1H),8.40(d,J=7.8Hz,1H),8.27(s,1H),6.84(s,1H),4.49(s,2H),3.91 -3.78(m,2H),3.77-3.64(m,1H),3.58-3.39(m,2H),1.89(d,J=12.1Hz,2H),1.39(qd,J=10.7,4.2Hz,2H).

[0132] Step 3: To a solution of monomethyl-1,4-cyclohexanedicarboxylate (31 g, 146 mmol, 1.1 equivalents) in DMF (460 mL), DIPEA (70 mL, 399 mmol, 3.0 equivalents) and HATU (60.7 g, 159.6 mmol, 1.2 equivalents) were added, followed by the gradual addition of 6-chloro-4-[(oxan-4-yl)amino]pyridine-3-carbohydrazide (37.6 g, 133 mmol, 1.00 equivalent). The mixture was stirred at 25°C for 1.5 hours. The reaction product was quenched with water and ice (600 mL) and extracted with ethyl acetate. The organic layer was washed with aqueous NaHCO3, aqueous KHSO4, water, and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with DCM / MeOH (0-10%) to obtain methyl 4-(N'-{6-chloro-4-[(oxan-4-yl)amino]pyridine-3-carbonyl}hydrazinecarbonyl)bicyclo[2.2.2]octane-1-carboxylate (45 g, yield 72%). LCMS:ESI(+)[M+H] + = 465.5. 1 H NMR(300MHz,DMSO-d6)δ:10.30(s,1H),9.51(s,1H),8.39(s,1H),8.29(d,J=7.9Hz,1H),6.90(s,1H),4.10(d,J=4.8Hz,1H),3.90-3.78(m ,2H),3.78-3.66(m,1H),3.59(s,3H),3.55-3.38(m,2H),3.17(d,J=4.0Hz,2H),1.88(d,J=10.8Hz,2H),1.76(s,12H),1.49-1.30(m,2H).

[0133] Step 4: To a solution of methyl 4-(N'-{6-chloro-4-[(oxan-4-yl)amino]pyridine-3-carbonyl}hydrazinecarbonyl)bicyclo[2.2.2]octane-1-carboxylate (45 g, 1 equivalent) in anhydrous THF (0.06 M), Lawson's reagent (1.5 equivalents) was gradually added while vigorously stirring at 40°C. The resulting suspension was stirred at 75°C for 2 hours. Upon completion, volatile substances were evaporated, and the residue was dissolved in DCM. The prepared solution was washed with an aqueous K2CO3 solution and concentrated under reduced pressure. The crude product was purified by chromatography (0-10% ethyl phosphate in DCM) to obtain methyl 4-(5-{6-chloro-4-[(oxan-4-yl)amino]pyridine-3-yl}-1,3,4-thiadiazole-2-yl)bicyclo[2.2.2]octane-1-carboxylate (15.6 g, yield 35%). LCMS:ESI(+)[M+H] + = 463.6. 1 H NMR(300MHz,DMSO-d6)δ:8.89(d,J=7.8Hz,1H),8.44(s,1H),7.06(s,1H),3.98-3.71 (m,3H),3.62(s,3H),3.52(t,J=10.1Hz,2H),2.09-1.77(m,14H),1.58-1.38(m,2H).

[0134] Step 5: Methyl 4-(5-{6-chloro-4-[(oxan-4-yl)amino]pyridine-3-yl}-1,3,4-thiadiazole-2-yl)bicyclo[2.2.2]octane-1-carboxylate (5 g, 10.8 mmol, 1.0 equivalent), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (3.78 g, 14 mmol, 1.3 equivalents), and CsOAc (6.4 g, 32.4 mmol, 3 equivalents) were dissolved in anhydrous THF (216 mL, 0.05 M). The solution was degassed with argon for 15 minutes, and the [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (2.22 g, 2.7 mmol, 0.25 equivalents) was added. The pressure vessel was sealed and stirred overnight to 90°C. The reaction product was filtered through a Celite pad and washed with DCM and MeOH. The solvent was concentrated under reduced pressure, and the residue was purified by column chromatography (5-50%, DCM in ACN) to obtain methyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(oxan-4-yl)amino]pyridine-3-yl)-1,3,4-thiadiazole-2-yl]bicyclo[2.2.2]octane-1-carboxylate (5.1 g, 80% yield). LCMS:ESI(+)[M+H] + = 570.69. 1 H NMR(300MHz,DMSO-d6)δ:8.86(d,J=2.2Hz,1H),8.81(d,J=7.1Hz,1H),8.79(d,J=2.2Hz,1H),8.71(s,1H),8.34(s,1H),7.86(d,J=4. 9Hz,1H),7.13(d,J=4.8Hz,1H),4.04-3.81(m,3H),3.67-3.45(m,5H),2.21-2.08(m,2H),2.07-1.80(m,12H),1.60(q,J=10.1Hz,2H).

[0135] Step 6: To a solution of methyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(oxan-4-yl)amino]pyridin-3-yl)-1,3,4-thiadiazole-2-yl]bicyclo[2.2.2]octane-1-carboxylate (4.1 g, 7.2 mmol, 1 equivalent) in pyridine (72 mL, 0.1 M), lithium iodide (9.73 g, 72 mmol, 10 equivalents) was added, and the resulting mixture was stirred at 150 °C for 20 hours. The reaction mixture was concentrated under vacuum and acidified with equimolar dilute HCl. The resulting residue was purified by column chromatography (0-15%, IPA / DCM) to obtain the title compound (1.25 g, yield 30%). LCMS: ESI(+)[M+H] + = 556.20. 1 H NMR(300MHz,DMSO-d6)δ:12.22(s,1H),9.51(s,1H),8.96(d,J=2.1Hz,1H),8.86(d,J=2.2Hz,1H),8.77(s,1H),8.16(s,1H),8.03(d, J=5.0Hz,1H),7.22(d,J=4.9Hz,1H),4.08(s,1H),4.01-3.89(m,2H),3.60(t,J=10.2Hz,2H),2.16-1.78(m,14H),1.75-1.56(m,2H).

[0136] Intermediate F: 7-[5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazole-2-yl)-4-(oxan-4-ylamino)pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0137] [ka]

[0138] The marked compound was synthesized following the same procedure as described for intermediate T, except that tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate was used as the starting material instead of tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate. LCMS C 26 H 27 N9OS theoretical value: 513.2, measured value: m / z = 514.3 [M+H] + .

[0139] Intermediate G: 7-[5-(5-{2,7-diazaspiro[3.5]nonanane-2-yl}-1,3,4-thiadiazole-2-yl)-4-(methylamino)pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0140] [ka]

[0141] Step 1: A suspension of 2,5-dibromo-1,3,4-thiadiazole (970 mg, 4.0 mmol, 1.0 equivalent), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (990 mg, 4.4 mmol, 1.1 equivalent), and DIPEA (1.038 mL, 4.6 mmol, 1.5 equivalent) in dioxane (15 mL, 0.21 M) was stirred at 120°C for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL). The crude product was purified by flash chromatography eluting with hexane / siRNA to obtain the desired compound as a yellow oil (1.54 g, 96% yield). LCMS: ESI(+)[M+H] + =391.3 1 1H NMR (300MHz, DMS) O-d6)δ3.83(s,4H),3.31-3.21(m,4H),1.75-1.62(m,4H),1.39(s,9H).

[0142] Step 2: 7-[5-bromo-4-(methylamino)pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carboxylic acid nitrile (1.5 g, 4.6 mmol, 1.0 equivalent) was dissolved in dioxane (25 mL) in a pressure vessel, followed by the addition of bis(pinacorato)diboron (1.39 g, 5.49 mmol, 1.2 equivalents) and KOAc (0.89 g, 9.14 mmol, 2.0 equivalents). The solution was sparged with argon for 7 minutes, and Pd(dppf)Cl2·DCM (0.375 g, 0.46 mmol, 0.1 equivalent) was added, followed by further sparging. The reaction mixture was then transferred to a preheated oil bath and stirred overnight at 90°C. UPLC showed the formation of the product. The reaction mixture was filtered through a Celite cake and evaporated to dryness. The crude product was used in the next step without further purification. LCMS:ESI(+)[M+H] + = 294.2.

[0143] Step 3: To a solution of tert-butyl 2-(5-bromo-1,3,4-thiadiazole-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (1.377 g, 2.57 mmol, 1.0 equivalent) and 7-[4-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.0 g, 2.0 mmol, 1.0 equivalent) in dioxane (13 mL, 0.2 M) in a pressure vessel, cesium carbonate (2.09 g, 6.42 mmol, 2.5 equivalents) and palladium(II) acetate (0.115 g, 0.51 mmol, 0.2 equivalents) were added. The reaction mixture was sparged with argon for 7 minutes, followed by the addition of xanthophos (0.59 g, 1.03 mmol, 0.4 equivalents). The solution was degassed with argon for a further 3 minutes, and then stirred overnight at 120°C. LC-MS showed product formation. The reaction mixture was filtered through a Celite cake and evaporated to dryness. The crude product was purified by column chromatography eluting with DCM / MeOH (0-10%) to obtain 0.415 g (29% yield) of the desired product. LC-MS: ESI(+)[M+H] + = 558.8. 1H NMR(300MHz,DMSO-d6)δ8.83(d,J=2.2Hz,1H),8.73(d,J=2.2Hz,1H),8.48(s,2H),8.14(s,1H),7.85(d,J= 4.8Hz,1H), 7.12(d,J=4.8Hz,1H),3.91(s,4H),3.06(d,J=4.8Hz,3H),1.75(t,J=5.6Hz,4H),1.40(s,9H).

[0144] Step 4: Tert-butyl 2-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (0.2 g, 0.36 mmol, 1.0 equivalent) was dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (1.13 mL, 30 equivalents) in a sealed reactor and left in microwave at 150°C for 2 hours. UPLC showed complete deprotection of the starting material. The solvent was evaporated to dryness, and the solid was triturated with Et2O to obtain 146 mg (87% yield) of the desired product as a yellow solid. LCMS: ESI(+)[M+H] + = 458.08. 1 H NMR(300MHz,DMSO-d6)δ8.83(d,J=2.2Hz,1H),8.72(d,J=2.2Hz,1H),8.47(s,2H),8.13(s,1H),7.85(d,J=4. 8Hz,1H), 7.12(d,J=4.8Hz,1H),3.86(s,4H),3.06(d,J=4.8Hz,3H),2.63(t,J=5.4Hz,4H),1.87-1.60(m,4H).

[0145] Intermediate H: 7-(5-(5-([4,4'-bipiperidine]-1-yl)-1,3,4-thiadiazole-2-yl)-4-(methylamino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0146] [ka]

[0147] The marked compound was synthesized following the same procedure as described for intermediate T, except that tert-butyl[4,4'-bipiperidine]-1-carboxylate was used as the starting material instead of tert-butyl4,7-diazaspiro[2.5]octane-4-carboxylate. LCMS C 26 H 29 N9S theoretical value: 499.2, measured value: m / z = 500.4 [M+H] + .

[0148] Intermediate I: 7-[4-(methylamino)-5-{5-[(1r,4r)-4-(methylamino)cyclohexyl]-1,3,4-thiadiazole-2-yl}pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0149] [ka]

[0150] Step 1: Methyl trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylate (3.0 g, 11.66 mmol, 1.0 equivalent) was dissolved in DMF (20 mL, 0.6 M) and cooled to 0°C. Then, NaH (0.536 g, 13.99 mmol, 1.2 equivalents) was added, and the reaction mixture was stirred at 0°C for 30 minutes. Methyl iodide (1.09 mL, 17.49 mmol, 1.5 equivalents) was added, then the cooling bath was removed, and the reaction mixture was stirred overnight at room temperature. TLC showed the formation of new spots, and the mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The crude product was purified with hexane:SiO to obtain 1.4 g (44% yield) of the desired product. 1 H NMR(300MHz,DMSO-d6)δ3.58(s,3H),2.64(s,3H),2.25(tt,J=11.7,3.6Hz,1 H),1.94(dt,J=12.3,2.6Hz,2H),1.60-1.41(m,4H),1.38(d,J=1.6Hz,12H).

[0151] Step 2: Methyl(1r,4r)-4-{[(tert-butoxy)carbonyl](methyl)amino}cyclohexane-1-carboxylate (1.3g, 4.79mmol, 1 Dissolve 0.0 equivalent in THF (18 mL, 0.27 M), then add a solution of LiOH (4.8 mL, 4.79 mmol, 2.0 equivalents) and stir at room temperature for 5 hours. Next, add another LiOH (2.4 mL, 2.39 mmol, 1.0 equivalent) and stir the reaction mixture overnight. The reaction mixture was then quenched to pH < 5 with a saturated solution of KHSO4 and extracted by DCM to obtain 1.18 g (96% yield) of the desired product as free acid. 1 H NMR (300MHz, DMSO-d6) δ3.90-3.52(m,1H)2.65(s,3H),2.13(tt,J=11.7,3.6Hz,1H),2.02-1.91(m,2H),1.66-1.45(m,4H),1.39(d,J=1.2Hz,11H).

[0152] Step 3: To a solution of 6-chloro-4-(methylamino)pyridine-3-carbohydrazide (0.84 g, 0.7975 mmol, 1.0 equivalent) and (1r,4r)-4-{[(tert-butoxy)carbonyl]amino}cyclohexane-1-carboxylic acid (1.19 g, 4.61 mmol, 1.1 equivalent) in DMF (10 mL), DIPEA (2.2 mL, 12.56 mmol, 3.0 equivalent) and HATU (1.91 g, 5.02 mmol, 1.2 equivalent) were added. This mixture was stirred at 25°C for 1 hour. UPLC showed a mass of the desired product. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over Na2SO4, concentrated, and the crude product was obtained. The crude product was purified by column chromatography eluted with DCM:MeOH (0-10%) to obtain 1.18 g (64% yield) of the desired product. LCMS:ESI(+)[M+H] + = 440.6. 1H NMR(300MHz,DMSO-d6)δ10.30(s,1H),9.78(s,1H),8.33(s,1H),8.11(s,1H),6.66(s,1H),2.82(d,3H), 2.65(s,3H),2.13(tt,J=11.7,3.6Hz,1H),2.02-1.91(m,2H),1.66-1.45(m,4H),1.39(d,J=1.2Hz,12H).

[0153] Step 4: To a suspension of tert-butyl N-methyl-N-[(1r,4r)-4-{N'-[6-chloro-4-(methylamino)pyridine-3-carbonyl]hydrazinecarbonyl}cyclohexyl]carbamate (1.18 g, 2.68 mmol, 1.0 equivalent) in dry toluene (50 mL, 0.05 M), Lawson's reagent (1.20 g, 2.95 mmol, 1.1 equivalent) was added. The reaction mixture was stirred under reflux for 1.5 hours, then quenched with water, washed with a saturated solution of NaHCO3, extracted by DCM, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM / MeOH) to obtain 0.7 g (60% yield) of the desired product as a white solid. LCMS: ESI(+)[M+H] + = 438.6. 1 H NMR(300MHz,DMSO-d6)δ8.66(d,J=5.0Hz,1H),8.40(s,1H),6.83(s,1H),3.25-3.09(m,1H),2 .98(d,J=4.9Hz,3H),2.71(s,3H),2.21(d,J=10.3Hz,2H),1.69(d,J=7.4Hz,6H),1.41(s,9H).

[0154] Step 5: To a solution of tert-butyl N-methyl-N-[(1r,4r)-4-{5-[6-chloro-4-(methylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}cyclohexyl]carbamate (0.7g, 1.6 mmol, 1.0 equivalent), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.6g, 2.23 mmol, 1.4 equivalent), and Pd(dppf)Cl2·CH2Cl2 (0.328g, 0.4 mmol, 0.25 equivalent), 2M K2CO3 (1.6mL, 3.2 mmol, 2.0 equivalent) was added in anhydrous dioxane (30mL). The solution was degassed with argon for 2-3 minutes, then heated to 120°C and stirred overnight. UPLC showed complete conversion of the starting material. The resulting solution was diluted with MeOH, filtered through a Celite pad, and concentrated to dryness. The crude product was purified by chromatography eluted with DCM:MeOH (0-10%) to obtain 0.7 The desired product was obtained in g (80% yield). LC-MS:ESI(+)[M+H] + = 546.1. 1 H NMR(300MHz,DMSO-d6)δ8.85(d,J=2.2Hz,1H),8.74(d,J=2.2Hz,1H),8.71-8.58(m,2H),8.19(s,1H),7.88(d,J=4.8Hz,1H),7. 13(d,J=4.8Hz,1H),3.24-3.15(m,1H),3.09(d,J=4.9Hz,3H),2.71(s,3H),2.30-2.12(m,2H),1.76-1.53(m,6H),1.42(s,9H).

[0155] Step 6: tert-butyl N-methyl-N-[(1r,4r)-4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]cyclohexyl]carbamate (0.67 g, 1.23 mmol, 1.0 equivalent) was dissolved in hexafluoro-2-propanol (4.0 mL, 30.0 equivalents) in a sealed cup reactor and microwaved at 150°C for 2 hours. UPLC showed complete deprotection of the starting material. The solvent was evaporated to dryness to obtain 0.54 g (99% yield) of the desired product as a yellow solid. LCMS: ESI(+)[M+H] + = 444.97. 1 H NMR(300MHz,DMSO-d6)δ8.84(d,J=2.3Hz,1H),8.73(d,J=2.2Hz,1H),8.68-8.47(m,2H),8.18(s,1H),7.88(d,J=4.8Hz,1H),7.13(d,J=4.8Hz, 1H),3.20-3.10(m,1H),3.09(d,J=4.8Hz,3H),2.36-2.26(m,4H),2.20 -2.08(m,2H),2.07-1.96(m,2H),1.70-1.49(m,3H),1.33-1.11(m,2H).

[0156] Intermediate J:7-[4-(methylamino)-5-{5-[4-(piperazine-1-yl)piperidine-1-yl]-1,3,4-thiadiazole-2-yl}pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0157] [ka]

[0158] The title compound was synthesized following the same procedure as described for intermediate T, except that tert-butyl 4-(piperidine-4-yl)piperazine-1-carboxylate was used as the starting material instead of tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate. LCMS C 25 H 28N 10 S-value: Theoretical value: 500.2, Measured value: m / z = 501.4 [M+H] + .

[0159] Intermediate K: 7-(5-(5-(4-aminobicyclo[2.2.2]octan-1-yl)-1,3,4-thiadiazole-2-yl)-4-(methylamino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0160] [ka]

[0161] Step 1: To a solution of methyl 4,6-dichloronicotinate (95.0 g, 461 mmol, 1.00 equivalent) in ACN (1000 mL), methylamine (288 g, 2.32 mol, 25% purity, 5.03 equivalents) was slowly added at 0°C. The mixture was stirred at 0°C for 0.5 hours, and then stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate (500 mL). * 3) Extract the combined organic layer and prepare it as brine (500 mL * 2) Washed, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (SiO2, petroleum ether:ethyl acetate = 20:1-10:1, R f The solution was purified by LCMS (=30). The desired product (39.0 g, 184 mmol, 40.0% yield) was obtained as a white solid. LCMS: m / z = 201.1 (M + H) + .

[0162] Step 2: To a solution of methyl 6-chloro-4-(methylamino)nicotinate (39.0 g, 184 mmol, 1.00 equivalent) in EtOH (300 mL), NH2NH2.H2O (86.6 g, 1.47 mol, 84.1 mL, 7.97 equivalents) was added, and the mixture was stirred at 80°C for 3 hours. The reaction mixture was concentrated and ethyl acetate (500 mL) was added. * 4) Extracted. Combined organic layer was brined (500 mL). *4) The product was washed, dried over Na2SO4, and concentrated to obtain the crude product. The crude product was triturated with petroleum ether / ethyl acetate = 15:1 (600 mL). The desired product (27.0 g, 120 mmol, yield 65.2%) was obtained as a white solid. LCMS: m / z = 201.2 (M + H) +

[0163] Step 3: To a solution of 6-chloro-4-(methylamino)nicotinohydrazide (8.00 g, 35.6 mmol, 1.00 equivalent) and 4-(((l1-methyl)(l1-oxidanyl)boraneil)amino)bicyclo[2.2.2]octane-1-carboxylic acid (10.5 g, 39.2 mmol, 1.10 equivalent) in DMF (100 mL), DIEA (13.8 g, 107 mmol, 18.6 mL, 3.00 equivalent) and HATU (16.2 g, 42.8 mmol, 1.20 equivalent) were added at 25°C, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was poured into water (100 mL) and ethyl acetate (100 mL) was added. * 3) Extract the combined organic layer and add water (100 mL * 3) The solution was washed with brine (200 mL), dried, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC. The desired product (15.0 g, 32.0 mmol, yield 89.7%) was obtained as a white solid. LCMS: m / z = 452.4 (M + H) +

[0164] Step 4: To a solution of N'-(4-(((l1-methyl)(l1-oxideanyl)boraneil)amino)bicyclo[2.2.2]octane-1-carbonyl)-6-chloro-4-(methylamino)nicotinohydrazide (15.0 g, 32.0 mmol, 1.00 equivalent) in THF (300 mL), Lawson's reagent (14.2 g, 35.2 mmol, 1.10 equivalent) was added, and the mixture was stirred at 90°C for 2 hours. The reaction mixture was concentrated to obtain the crude product. The crude product was purified by preparative HPLC. The desired product (4.30 g, 9.33 mmol, yield 29.1%) was obtained as an off-white solid. LCMS: m / z = 450.3 (M + H) +

[0165] Step 5: To a solution of tert-butyl(4-(5-(6-chloro-4-(methylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl)bicyclo[2.2.2]octan-1-yl) carbamate (3.80 g, 8.44 mmol, 1.00 equivalent), (3-cyanopyrrolo[1,2-b]pyridazine-7-yl)boronic acid (2.37 g, 12.67 mmol, 1.50 equivalent), and K3PO4 (2 M, 8.44 mL, 2.00 equivalent) in DME (4.00 mL), Pd(dppf)Cl2·CH2Cl2 (689 mg, 844 μmol, 0.10 equivalent) was added under N2 conditions. The resulting mixture was stirred at 110°C for 12 hours. The reaction mixture was filtered, and the filtrate was added to DCM (80.0 mL). * Extraction was performed using method 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to DCM / ethyl acetate = 1 / 1) to obtain the residue. The residue and HCl / dioxane (4M, 4.00 mL, 4.53 equivalents) in dioxane (20 mL) were stirred at 25°C for 12 hours. The mixture was concentrated under vacuum. The residue in ethyl acetate (20.0 mL) was heated at 90°C for 30 minutes and filtered three times to obtain 7-(5-(5-(4-aminobicyclo[2.2.2]octan-1-yl)-1,3,4-thiadiazole-2-yl)-4-(methylamino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.67 g, 3.22 mmol, yield 33.7%, HCl) as a brown solid. LCMS: m / z = 557.2

[0166] Intermediate L:7-[5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazole-2-yl)-4-(methylamino)pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0167] [ka]

[0168] Step 1: A stirred suspension of 2,5-dibromo-1,3,4-thiadiazole (1.05 g, 4.31 mmol, 1.0 equivalent), 8-Boc-3,8-diazabicyclo[3.2.1]octane (1.005 g, 4.73 mmol, 1.1 equivalent), and N,N-diisopropylethylamine (1.125 mL, 6.46 mmol, 1.5 equivalent) in anhydrous dioxane (21.53 mL, 0.2 M) was heated at 120°C for 1 hour. The reaction mixture was diluted with water, extracted with DCM, and the organic phase was concentrated on silica gel. The crude product was purified by flash chromatography using an toluene / hexane gradient to obtain 7-[5-bromo-4-(methylamino)pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile as a yellow oil (0.819 g, 2.18 mmol, 71%). LCMS:ESI(+)[M+H] + = 337.3. 1 H NMR (300MHz, CDCl3) δ4.37(s,2H),3.72-3.26(m,4H),2.03(m,2H),1.82(m,2H),1.50(d,J=0.8Hz,9H).

[0169] Step 2: 7-[5-bromo-4-(methylamino)pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.5 g, 4.57 mmol, 1.0 equivalent) was dissolved in dioxane (25 mL, 0.18 M) in a pressurized reactor, followed by the addition of bis(pinacorato)diboron (1.39 g, 5.49 mmol, 1.2 equivalents) and KOAc (1.39 g, 14.17 mmol, 3.1 equivalents). The solution was sparged with argon for several minutes, and Pd(dppf)Cl2·DCM (0.373 g, 0.46 mmol, 0.1 equivalent) was added, followed by repeated sparging. The reaction mixture was then transferred to a preheated oil bath and stirred overnight at 90°C. The reaction mixture was filtered through a Celite pad and evaporated to dryness. The crude product was used in the next step without further purification.

[0170] Step 3: To a solution of 7-[4-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitride (0.58 g, 1.55 mmol, 1.0 equivalent) and tert-butyl 3-(5-bromo-1,3,4-thiadiazole-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.638 g, 1.70 mmol, 1.1 equivalents) in dioxane (40 mL, 0.04 M), Cs2CO3 (1.26 g, 3.86 mmol, 2.5 equivalents) and xanthophos (0.358 g, 0.62 mmol, 0.4 equivalents) were added. The reaction mixture was sparged with argon for several minutes, followed by the addition of Pd(OAc)2 (0.069 g, 0.31 mmol, 0.2 equivalents). The solution was degassed with argon for 2-3 minutes and then stirred overnight at 120°C. The reaction mixture was filtered through a Celite pad and evaporated to dryness. The crude product was purified by FC elution with DCM / MeOH (0-10%). The main fraction was re-purified by pTLC elution with DCM / MeOH (0-10%) and finally triturated with Et2O to obtain 0.190 g (23% yield) of the desired product. LCMS:ESI(+)[M+H] + = 544.77. 1 H NMR(300MHz,DMSO-d6)δ:8.83(d,J=2.2Hz,1H),8.72(d,J=2.3Hz,1H),8.51-8.43(m,2H),8.14(s,1H),7.85(d,J=4.8Hz,1H),7.12(d,J=4.8 Hz,1H),4.28(s,2H),3.67(d,J=11.8Hz,2H),3.37(d,2H),3.06(d,J=4.9Hz,3H),1.91(d,J=6.3Hz,2H),1.75(d,J=7.4Hz,2H),1.44(s,9H).

[0171] Step 4: tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.120 g, 0.22 mmol, 1.0 equivalent) was mixed with 1,1,1,3,3,3-hexafluoro-2-propanol (0.7 mL, 30 equivalents) in a pressure vessel and heated in a microwave at 150°C for 2.5 hours. The solvent was evaporated to dryness and the mixture was dried in Et2O. Trituration was performed to obtain 0.080 g (82% yield) of the title compound. LC-MS: ESI(+)[M+H] + = 444.05. 1 H NMR(300MHz,DMSO-d6)δ:8.83(d,J=2.3Hz,1H),8.72(d,J=2.2Hz,1H),8.52-8.44(m,2H),8.13(s,1H),7.85(d, J=4.8Hz,1H),7.12(d,J=4.8Hz,1H),3.61-3.46(m,4H),3.29(s,3H),3.06(m,3H),1.70(dd,J=9.8,6.7Hz,4H).

[0172] Intermediate M: 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]cyclohexane-1-carboxylate hydrochloride.

[0173] [ka]

[0174] Step 1: To a solution of 6-chloro-4-(methylamino)pyridine-3-carbohydrazide (10.0 g, 49.84 mmol, 1.0 equivalent) and 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (11.63 g, 54.83 mmol, 1.1 equivalents) in DMF (175 mL, 0.285 M), DIPEA (149.53 mmol, 26 mL, 3.0 equivalents) and HATU (22.74 g, 59.81 mmol, 1.2 equivalents) were added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with a water / ice mixture (600 mL) and extracted with ethyl acetate. The combined organic layers were washed with aqueous NaHCO3, aqueous KHSO4, water, and brine, and dried over Na2SO4. After evaporation of volatile substances, the crude product was purified by column chromatography (DCM / MeOH) to obtain methyl 4-{N'-[6-chloro-4-(methylamino)pyridine-3-carbonyl]hydrazinecarbonyl}bicyclo-[2.2.2]octane-1-carboxylate as a white solid (15.6 g, yield 79%). LCMS:ESI(+)[M+H] + = 395.62. 1 H NMR(300MHz,DMSO-d6),δ:10.23(1H,s),9.48(1H,s),8.35(1H,s),8.14(1 H,br.q,J5.1),6.66(1H,s),3.59(3H,s),2.82(3H,d,J4.9),1.76(12H,m).

[0175] Step 2: Methyl 4-{N'-[6-chloro-4-(methylamino)pyridine-3-carbonyl]hydrazinecarbonyl}bicyclo-[2.2.2]octane-1-carboxylate (5.0 g, 12.66 mmol, 1 equivalent) was dissolved in THF (250 mL, 0.05 M) under argon. The solution was heated to 40°C, and P2S5 (4.22 g, 18.99 mmol, 1.5 equivalents) was added little by little while vigorously stirring. Next, the resulting suspension was refluxed. The mixture was stirred under controlled conditions (by ULC) for 2 hours. After completion, volatiles were evaporated. The residue was dissolved in DCM and washed with saturated K2CO3 solution. The aqueous layer was removed using a separatory funnel, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by FC(DCM / EA) to obtain 4-{5-[6-chloro-4-(methylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}cyclohexane-1-carboxylate (2.66 g, yield 53%). LCMS:ESI(+)[M+H] + =393.4. 1 H NMR (300MHz, DMSO-d6), δ:8.66(1H,br.q,J5.2),8.38(1H,s),6.82(1H,s),3.61(3H,s),2.97(3H,d,J4.9),2.05-1.94(6H,m),1.94-1.82(6H,m).

[0176] Step 3: 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitride (4.401 g, 16.35 mmol, 1.5 equivalents) was added to an argon flash flask containing methyl 4-{5-[6-chloro-4-(methylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}cyclohexane-1-carboxylate (4.04 g, 10.9 mmol, 1.0 equivalent), cesium acetate (5.2 g, 27.2 mmol, 2.5 equivalents), and Pd(dppf)Cl2·DCM (1.74 g, 2.2 mmol, 0.2 equivalents) in THF (218 mL, 0.05 M). The mixture was filtered through a Celite pad, concentrated under vacuum, redissolved in dichloromethane, and deposited on silica gel. The resulting solid was purified by flash chromatography (0-10% gradient of acetonitrile in DCM) to obtain methyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]cyclohexane-1-carboxylate as a yellow crystalline solid (2.9 g, 56% yield). LCMS:ESI(+)[M+H] + = 474.60.1 H NMR(300MHz,DMSO-d6),δ:8.83(d,J=2.2Hz,1H),8.72(d,J=2.2Hz,1H),8.62 (d,J=6.0Hz,2H),8.22-8.12(m,1H),7.87(d,J=4.8Hz,1H),7.11(d,J=4.8Hz, 1H),3.62(s,3H),3.19(s,1H),3.08(d,J=4.9Hz,3H),2.42(d,J=11.7Hz,1H), 2.19(d,J=10.3Hz,2H),2.03(d,J=10.7Hz,2H),1.59(q,J=12.3,11.2Hz,4H).

[0177] Step 4: To a solution of methyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]cyclohexane-1-carboxylate (2.9 g, 6.1 mmol, 1.0 equivalent) in dried pyridine (61.2 mL, 0.1 M), lithium iodide (8.3 g, 61.2 mmol, 10 equivalents) was added, and the resulting mixture was stirred at 150 °C until complete (using ULC control, 24-48 hours). Next, the resulting mixture was acidified with equimolar dilute HCl. The resulting solid was purified by column chromatography (0-20% gradient of 2-propanol in DCM) to obtain the target compound as a yellow solid (3.1 g, 95% yield). LCMS:ESI(+)[M+H] + = 460.23. 1 H NMR(300MHz,DMSO-d6),δ:12.17(s,1H),9.59(d,J=4.2Hz,1H),8.99(d,J=2.0Hz,1H),8.86(d,J=2.0Hz,1H),8.69(s,1H),8.15(d,J=4.9Hz,1H),7 .95(s,1H),7.24(d,J=5.0Hz,1H),3.32(m,1H),3.22(d,J=4.8Hz,3H),2. 40-2.28(m,1H),2.21(d,J=11.8Hz,2H),2.04(s,2H),1.72-1.46(m,4H).

[0178] Intermediate N:7-[4-(methylamino)-5-{5-[(1r,4r)-4-formylcyclohexyl]-1,3,4-thiadiazole-2-yl}pyridine-2-yl]pyro [1,2-b]pyridazine-3-carbonitride.

[0179] [ka]

[0180] Step 1: To a solution of methyl 4,6-dichloronicotinate (99.0 g, 481 mmol, 1.0 equivalent) in acetonitrile (990 mL, 0.49 M), 40% by weight of methylamine (208 mL, 2403 mmol, 5.0 equivalents) was slowly added at -5°C, and the mixture was stirred at 0°C for 30 minutes, then at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane / ÃO, 0-50%) to obtain methyl 6-chloro-4-(methylamino)pyridine-3-carboxylate as a white solid (65.3 g, yield 68%). LCMS:ESI(+)[M+H] + =202.2. 1 H NMR (300MHz, DMSO-d6)δ:8.50(s,1H),8.04(d,J=5.5Hz,1H),6.74(s,1H),3.83(3H,s),2.88(d,J=5.0Hz,3H).

[0181] Step 2: To a solution of methyl 6-chloro-4-(methylamino)pyridine-3-carboxylate (43 g, 0.21 mol, 1 equivalent) in EtOH (358 mL, 0.6 M), hydrazine hydrate (129 mL, 1.68 mol, 8.0 equivalents) was added, and the resulting mixture was stirred at 80°C for 4 hours (UPLC control was applied). The reaction mixture was then cooled to room temperature and extracted multiple times by DCM. The combined organic layer was dried over Na2SO4, and the solvent was concentrated under vacuum to obtain 6-chloro-4-(methylamino)pyridine-3-carbohdrazide as a white crystalline solid (34.4 g, yield 79%). LCMS: ESI(+)[M+H] + = 200.95. 1 H NMR (300MHz, DMSO-d6) δ: 9.81 (s, 1H), 8.21 (s, 1H), 8.11 (s, 1H), 6.62 (s, 1H), 4.46 (s, 2H), 2.82 (d, J = 5.0Hz, 3H).

[0182] Step 3: To a solution of 6-chloro-4-(methylamino)pyridine-3-carbohydrazide (12.0 g, 59.81 mmol, 1.0 equivalent) and monomethyltrans-1,4-cyclohexanedicarboxylate (12.25 g, 65.79 mmol, 1.1 equivalents) in DMF (150 mL), DIPEA (179.43 mmol, 32 mL, 3.0 equivalents) and HATU (27.29 g, 71.77 mmol, 1.2 equivalents) were added. The mixture was stirred at 25°C for 1 hour, then quenched with water, brine was added, and the mixture was extracted with SiO2. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum. Residual The substance was purified by column chromatography using DCM / MeOH (0-10%) to obtain methyl(1r,4r)-4-{N'-[6-chloro-4-(methylamino)pyridine-3-carbonyl]hydrazinecarbonyl}cyclohexane-1-carboxylate (15.5 g, 70% yield). LCMS:ESI(+)[M+H] + = 367.46. 1H NMR(300MHz,DMSO-d6)δ:10.31(s,1H),9.81(s,1H),8.34(s,1H),8.12(q,J=4.9Hz,1H),6.66(s,1H),3.60(s,3H), 3.33(s,2H),2.82(d,J=4.9Hz,3H),2.40-2.16(m,2H),2.02-1.91(m,2H),1.82(t,J=7.2Hz,2H),1.55-1.25(m,4H).

[0183] Step 4: To a solution of methyl(1r,4r)-4-{N'-[6-chloro-4-(methylamino)pyridine-3-carbonyl]hydrazinecarbonyl}cyclohexane-1-carboxylate (11.35 g, 30.77 mmol, 1 equivalent) in anhydrous THF (1000 mL, 0.03 M), phosphorus pentasulfide (8.9 g, 40.01 mmol, 1.3 equivalents) was added at 20°C. The resulting mixture was stirred at 50°C for 3 hours. The reaction product was filtered, washed with THF, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane / EA) to obtain methyl(1r,4r)-4-{5-[6-chloro-4-(methylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}cyclohexane-1-carboxylate (4.46 g, 40%). LCMS:ESI(+)[M+H] + = 367.48. 1 H NMR(300MHz,DMSO-d6)δ:8.65(d,J=5.2Hz,1H),8.39(s,1H),6.82(s,1H),3.62(s,3H),3.21(td,J= 11.4Hz, 3.5Hz, 1H), 2.98 (d, J=4.9Hz, 3H), 2.48-2.37 (m, 1H), 2.22-1.96 (m, 4H), 1.72-1.45 (m, 4H).

[0184] Step 5: A solution of methyl(1r,4r)-4-{5-[6-chloro-4-(methylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}cyclohexane-1-carboxylate (4.26 g, 11.61 mmol, 1 equivalent) in anhydrous THF (180.0 mL, 0.06 M) was cooled to -15°C under an argon atmosphere and treated with DIBAL-H (35 mL, 34.8 mmol, 3.0 equivalents of a 1.0 M solution in THF). After 30 minutes, the cooling bath was removed, the mixture was warmed to room temperature, and stirred for 1 hour. The reaction was then quenched by adding MeOH (30 mL), stirred vigorously for 20 minutes, and then a saturated aqueous solution of Rochelle salt was added. The resulting mixture was extracted with DCM. The combined organic layers were washed with a diluted solution of KHSO4, water, and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / ACN) to obtain [(1r,4r)-4-{5-[6-chloro-4-(methylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}cyclohexyl]methanol (3.0 g, 8.85 mmol, 1.0 equivalent) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (3.19 g, yield 81%). LCMS:ESI(+)[M+H] + =339.48. 1 H NMR(300MHz,DMSO-d6)δ:8.66(d,J=4.6Hz,1H),8.38(s,1H),6.82(s,1H),4.46(t,J=5.3Hz,1H),3.26(t,J=5.8Hz,2H),3.14( tt,J=11.9Hz,3.6Hz,1H),2.97(d,J=4.9Hz,3H),2.22-2.10(m,2H),1.92-1.80(m,2H),1.64-1.36(m,3H),1.26-1.00(m,2H).

[0185] Step 6: [(1r,4r)-4-{5-[6-chloro-4-(methylamino)pyridine-3-yl]-1,3,4-thiadiazo in anhydrous dioxane (130 mL, 0.07 M) To a solution of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (3.4 g, 12.4 mmol, 1.4 equivalents) and Pd(dppf)Cl2·CH2Cl2 (1.82 g, 2.21 mmol, 0.25 equivalents), 9 mL of 2 M K2CO3 aqueous solution (17.71 mmol, 2.0 equivalents) was added. The mixture was degassed with argon for 30 minutes, then stirred at 120°C for 25 hours. The reaction product was diluted with DCM, filtered through a Celite pad, washed with DCM / MeOH (1:1), and concentrated under vacuum. The residue was purified twice by column chromatography (DCM / ACN and DCM / IPA, respectively) to obtain 7-[4-(methylamino)-5-{5-[(1r,4r)-4-(hydroxymethyl)cyclohexyl]-1,3,4-thiadiazole-2-yl}pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile (2.35 g, 60% yield). LCMS:ESI(+)[M+H] + = 446.38. 1 H NMR(300MHz,DMSO-d6)δ:8.84(d,J=2.2Hz,1H),8.73(d,J=2.2Hz,1H),8.64(d, J=9.7Hz,2H),8.17(s,1H),7.87(d,J=4.8Hz,1H),7.12(d,J=4.8Hz,1H),4.47( t,J=5.3Hz,1H),3.27(t,J=5.8Hz,2H),3.22-3.11(m,1H),3.09(d,J=4.9Hz,3H ),2.23-2.13(m,2H),1.93-1.83(m,2H),1.66-1.39(m,3H),1.26-1.00(m,4H).

[0186] Step 7: To a solution of 7-[4-(methylamino)-5-{5-[(1r,4r)-4-(hydroxymethyl)cyclohexyl]-1,3,4-thiadiazole-2-yl}pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile (2.35 g, 5.27 mmol, 1 equivalent) in DCM (1.3 L, 0.004 M), des-martin periodinane (2.91 g, 6.86 mmol, 1.3 equivalents) was added. The mixture was stirred overnight at room temperature. The reaction was quenched with 20% aqueous Na2S2O3 and saturated aqueous NaHCO3, and stirred until the aqueous layer became clear. The latter was extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by trituration with DCM / Et2O (1:1) to obtain the title compound (1.83 g, 78% yield). LCMS:ESI(+)[M+H] + = 444.22. 1 H NMR(300MHz,DMSO-d6)δ:9.63(br.d,J=1.1Hz,1H),8.84(d,J=2.3Hz,1H),8.74(d,J=2.2Hz, 1H),8.66(s,1H),8.65(q,J=2.7Hz,1H),8.17(s,1H),7.88(d,J=4.8Hz,1H),7.12(d,J=4.8Hz ,1H),3.19(ddt,J=11.7Hz,7.0Hz,3.6Hz,1H),3.09(d,J=4.9Hz,3H),2.41(ddt,J=12.2Hz,7. 3Hz, 3.7Hz, 1H), 2.29-2.18 (m, 2H), 2.14-2.02 (m, 2H), 1.75-1.55 (m, 2H), 1.51-1.31 (m, 2H).

[0187] Intermediate O:4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]cyclohexane-1-carboxylic acid.

[0188] [ka]

[0189] Step 1: 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitride (4 g, 16.35 mmol, 1.5 equivalents) was added to an argon flash flask containing methyl 4-{5-[6-chloro-4-(methylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}cyclohexane-1-carboxylate (4 g, 10.9 mmol, 1 equivalent), CsOAc (5.3 g, 27.3 mmol, 2.5 equivalents), and Pd(dppf)Cl2·DCM (1.74 g, 2.18 mmol, 0.2 equivalents) in THF (218 mL, 0.05 M). The mixture was stirred overnight at 85°C. The reaction product was filtered, concentrated under vacuum, dissolved in DCM, and adsorbed onto silica gel. This solid was purified by flash chromatography (0-10% ACN in DCM) to obtain the desired compound as a yellow crystalline solid (2.9 g, 56% yield). LCMS:ESI(+)[M+H] + = 474.60. 1 H NMR(300MHz,DMSO-d6),δ:8.83(d,J=2.2Hz,1H),8.72(d,J=2.2Hz,1H),8.62 (d,J=6.0Hz,2H),8.22-8.12(m,1H),7.87(d,J=4.8Hz,1H),7.11(d,J=4.8Hz, 1H),3.62(s,3H),3.19(s,1H),3.08(d,J=4.9Hz,3H),2.42(d,J=11.7Hz,1H), 2.19(d,J=10.3Hz,2H),2.03(d,J=10.7Hz,2H),1.59(q,J=12.3,11.2Hz,4H).

[0190] Step 2: To a solution of methyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]cyclohexane-1-carboxylate (2.9 g, 6.12 mmol, 1 equivalent) in dried pyridine (61 mL, 0.1 M), lithium iodide (8.27 g, 61.18 mmol, 10 equivalents) was added, and the resulting mixture was stirred at 150 °C for 24 hours. The resulting mixture was acidified with equimolar dilute HCl. The resulting solid was filtered and purified by flash chromatography (0-20% 2-propanol in DCM) to obtain the desired compound as a yellow solid (2.5 g, yield 89%). LCMS: ESI(+)[M+H] + = 460.23. 1 H NMR(300MHz,DMSO-d6),δ:12.17(s,1H),9.59(d,J=4.2Hz,1H),8.99(d,J=2.0Hz,1H),8.86(d,J=2.0Hz,1H),8.69(s,1H),8.15(d,J=4.9Hz,1H),7 .95(s,1H),7.24(d,J=5.0Hz,1H),3.32(m,1H),3.22(d,J=4.8Hz,3H),2. 40-2.28(m,1H),2.21(d,J=11.8Hz,2H),2.04(s,2H),1.72-1.46(m,4H).

[0191] Intermediate P: 7-[4-(methylamino)-5-{5-[(1r,4r)-4-(ethylamino)cyclohexyl]-1,3,4-thiadiazole-2-yl}pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0192] [ka]

[0193] Step 1: To a solution of methyl trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylate (2.0 g, 7.8 mmol, 1.0 equivalent) in DMF (25 mL, 0.46 M) cooled to 0°C, NaH (0.357 g, 9.32 mmol, 1.2 equivalents) was added, and the resulting mixture was stirred at 0°C for 30 minutes. Then, ethyl iodide (0.937 mL, 11.66 mmol, 1.5 equivalents) was added, and the reaction mixture was stirred at room temperature overnight. Next, the DMF was azeotropically removed by evaporation with PhMe (3 × 100 mL). 50 mL of saturated aqueous solution of NH4Cl was added to the remaining solid. The resulting mixture was transferred to a separatory funnel and extracted with Et2O (4 × 50 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography (hexane / siRNA, gradient 0%~20%) to obtain methyl(1r,4r)-4-{[(tert-butoxy)carbonyl](ethyl)amino}cyclohexane-1-carboxylate as a yellowish viscous oil (1.883 g, yield 85%). 1 H NMR(300MHz,DMSO-d6)δ3.63(s,3H),3.07(q,J=7.1Hz,2H),2.26(t,J=11.9Hz,1H),1.94 (d,J=12.5Hz,2H),1.55(d,J=27.9Hz,4H),1.39(d,J=1.7Hz,12H),1.02(t,J=6.8Hz,3H).

[0194] Step 2: Add LiOH to methyl(1r,4r)-4-{[(tert-butoxy)carbonyl](ethyl)amino}cyclohexane-1-carboxylate (1.88 g, 6.6 mmol, 1.0 equivalent) in a mixture of THF (15 mL, 0.44 M) and water (3.0 mL, 2.41 M). *H2O (0.57 g, 13.2 mmol, 2.0 equivalents) was added, and the reaction mixture was stirred overnight at room temperature. After NMR showed complete substrate consumption, THF was then removed under vacuum, and the resulting aqueous solution was acidified to pH 5 with a 10 wt% solution of NaHSO4. The resulting suspension was then extracted with SiO4 (4 × 25 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain (1r,4r)-4-{[(tert-butoxy)carbonyl](ethyl)amino}cyclohexane-1-carboxylic acid as a white solid (1.566 g, yield 87%). 1 H NMR(300MHz,DMSO-d6)δ12.08(s,1H),3.07(d,J=7.3Hz,2H),2.13(tt,J=11.9,3.4Hz,1H),1.93(dt,J=9.2, 2.8Hz,2H),1.52(dd,J=28.7,16.5Hz,4H),1.39(s,9H),1.33(dd,J=12.4,3.8Hz,1H),1.02(t,J=6.8Hz,3H) .

[0195] Step 3: To a solution of (1r,4r)-4-{[(tert-butoxy)carbonyl](ethyl)amino}cyclohexane-1-carboxylic acid (1.57 g, 5.77 mmol, 1.00 equivalent) in anhydrous DMF (15 mL, 0.38 M), DIPEA (3.0 mL, 17.3 mmol, 3.00 equivalent) and HATU (3.29 g, 8.65 mmol, 1.5 equivalent) were added. The mixture was stirred at 25°C for 30 minutes, and 6-chloro-4-(methylamino)pyridine-3-carbohydrazide (1.216 g, 6.06 mmol, 1.05 equivalent) was added. After 2 hours at room temperature, the reaction product was quenched with brine and extracted with siRNA (5 × 50 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. The resulting crude product was purified by column chromatography (DCM / MeOH, gradient 0-3%) to obtain the desired product as a light brown solid (1.87 g, yield 71%). LCMS:ESI(+)[M+H] + = 454.4. 1H NMR(300MHz,DMSO-d6)δ10.31(s,1H),9.82(s,1H),8.35(s,1H),8.12(d,J=5.3Hz,1H),6.67(s,1H),3.13-3.06(m,2H),2.83( d,J=4.9Hz,3H),2.23(dd,J=14.7,4.0Hz,1H),1.85(d,J=11.3Hz,2H),1.69-1.46(m,5H),1.41(s,9H),1.04(t,J=6.8Hz,3H).

[0196] Step 4: To a solution of tert-butyl N-ethyl-N-[(1r,4r)-4-{N'-[6-chloro-4-(methylamino)pyridine-3-carbonyl]hydrazinecarbonyl}cyclohexyl]carbamate (1.87 g, 4.11 mmol, 1.0 equivalent) in anhydrous THF (100 mL, 0.04 M), Lawson's reagent (1.83 g, 4.52 mmol, 1.1 equivalent) was added. The reaction mixture was stirred at 90°C for 2 hours. Volatile substances were removed under vacuum, and the residue was dissolved in 50 mL of DCM and washed with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with DCM (3 × 50 mL). The organic layers were combined, dried over Na2SO4, and concentrated under vacuum. The crude product was purified by double column chromatography (DCM / MeOH, gradient 0-4% and hexane / siRNA, gradient 0-40%) to obtain tert-butyl N-ethyl-N-[(1r,4r)-4-{5-[6-chloro-4-(methylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}cyclohexyl]carbamate as a white foamy solid (0.794 g, yield 43%). LCMS:ESI(+)[M+H] + = 452.5. 1 H NMR(300MHz,DMSO-d6)δ8.66(d,J=5.9Hz,1H),8.39(d,J=1.6Hz,1H),6.82(d,J=1.7Hz,1H),3.16(t,J=12.0Hz, 3H), 2.98(d,J=4.9Hz,3H),2.24-2.14(m,2H),1.69(d,J=20.3Hz,7H),1.41(d,J=2.0Hz,9H),1.12-1.01(m,3H).

[0197] Step 5: Tert-butyl N-ethyl-N-[(1r,4r)-4-{5-[6-chloro-4-(methylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}cyclohexyl]carbamate (0.794g, 1.76 mmol, 1.0 equivalent), 7-(4,4,5,5-tetramethyl-1,3,2) in anhydrous dioxane (25 mL, 0.07 M). A suspension of (-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-3-carbonitrile (0.662 g, 2.46 mmol, 1.4 equivalents), Pd(dppf)Cl2·CH2Cl2 (0.36 g, 0.44 mmol, 0.25 equivalents), and K2CO3 (0.485 g, 3.5 mmol, 2.0 equivalents) was degassed with argon for 2-3 minutes and stirred overnight at 120°C. After the starting materials were completely converted, the reaction mixture was diluted with MeOH, filtered through a Celite pad, and concentrated under vacuum. The crude product was purified by FC (DCM / ACN, gradient 0-40%) to tert-butyl N-ethyl-N-[(1r,4r)-4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methyl Amino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]cyclohexyl]carbamate was obtained as a yellow solid (0.676 g, yield 69%). LCMS:ESI(+)[M+H] + = 559.85. 1 H NMR(300MHz,DMSO-d6)δ8.85(d,J=2.2Hz,1H),8.74(d,J=2.3Hz,1H),8.67(s,1H),8.63(d,J=5.0Hz,1H),8.19(s,1H),7.88(d,J=4.8Hz,1H) ,7.13(d,J=4.8Hz,1H),3.26-3.12(m,3H),3.09(d,J=4.9Hz,3H),2.21(d,J=11.2Hz,2H),1.83-1.57(m,6H),1.42(s,9H),1.12-1.02(m,3H).

[0198] Step 6: Tert-butyl N-ethyl-N-[(1r,4r)-4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]cyclohexyl]carbamate (0.676 g, 1.21 mmol, 1.0 equivalent) was dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (3.185 mL, 25 equivalents) and stirred at 150°C for 8 hours. After the starting material was completely consumed, the reaction mixture was co-evaporated several times using DCM to remove trace amounts of HFIP. The crude product was purified by column chromatography (DCM / MeOH, gradient 0-30%) to obtain the title compound as a dark yellow solid (0.350 g, yield 63%). LCMS: ESI(+)[M+H] + = 459.03. 1 H NMR(300MHz,DMSO-d6)δ8.84(s,1H),8.74(s,1H),8.65(s,2H),8.17(d,J=3.1Hz,1 H),7.87(d,J=4.8Hz,1H),7.12(d,J=4.7Hz,1H),4.10(s,1H),3.17(s,2H),3.09(d, J=4.7Hz,3H),2.71-2.56(m,3H),2.16(d,J=12.8Hz,2H),2.04(t,J=11.7Hz,2H),1 .60(q,J=12.4Hz,3H),1.32-1.13(m,5H),1.04(t,J=6.8Hz,3H),0.82-0.71(m,1H).

[0199] Intermediate Q: 7-[5-(5-{3,9-diazaspiro[5.5]undecane-3-yl}-1,3,4-thiadiazole-2-yl)-4-(oxan-4-ylamino)pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0200] [ka]

[0201] The synthesis was carried out using the same procedure as described for intermediate T, except that tert-butyl 3,9-diazaspiro[2.5]undecane-3-carboxylate was used as the starting material instead of tert-butyl 4,7-diazaspiro[5.5]octane-4-carboxylate. LCMS C 29 H 33 N9OS theoretical value: 555.3, measured value: m / z = 556.3 [M+H] + .

[0202] Intermediate R: 7-[5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazole-2-yl)-4-[(propan-2-yl)amino]pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0203] [ka]

[0204] The marked compound was synthesized following the same procedure as described for intermediate L, except that 7-{5-bromo-4-[(propan-2-yl)amino]pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitri was used as the starting material instead of 7-{5-bromo-4-[(methylamino]pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitri. LCMS:ESI(+)[M+H] + = 472.20. 1 H NMR(300MHz,DMSO-d6)δ:8.82(d,J=2.2Hz,1H),8.71(d,J=2.2Hz,1H),8.56(d,J=7.1Hz,1H),8.46(s,1H),8.18(s,1H),7.83(d,J=4.8Hz,1 H),7.11(d,J=4.8Hz,1H),3.91(h,J=6.5Hz,1H),3.60-3.44(m,4H),3.32-3.24(m,3H),1.69(dd,J=10.0,6.9Hz,4H),1.34(d,J=6.3Hz,6H).

[0205] Intermediate S: 7-(4-((4,4-difluorocyclohexyl)amino)-5-(5-(piperazine-1-yl)-1,3,4-thiadiazole-2-yl)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0206] [ka]

[0207] Step 1: 2-bromo-N-(4,4-difluorocyclohexyl)pyridine-4-amine (6.00 g, 20.6 mmol, 1.00 equivalent) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo in DME (60.0 mL) To a solution of [1,2-b]pyridazine-3-carbonitride (6.66 g, 24.7 mmol, 1.20 equivalents), K3PO4 (2.00 M, 20.6 mL, 2.00 equivalents) and Pd(dppf)Cl2·CH2Cl2 (1.68 g, 2.06 mmol, 0.10 equivalents) were added under N2 conditions, and the mixture was stirred under N2 conditions at 100°C for 2 hours. The reaction mixture was poured into water (50.0 mL), then filtered, and ethyl acetate (100 mL) was added. * 4) Washed, the filtration cake (4.0g) was collected and concentrated under vacuum. The filtrate was then mixed with ethyl acetate (100mL). * 3) Extraction was performed, followed by concentration under vacuum to obtain the residue (2.00 g). The residue (2.00 g) was subjected to column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to dichloromethane / methanol = 20 / 1, R f The product was purified by LCMS (=0.20). The isolated product was combined with the filtered product by column chromatography to obtain the desired product (5.00 g, 14.1 mmol, 68.6% yield) as a yellow solid. LCMS: m / z = 354.3 (M+H) + .

[0208] Step 2: To a solution of 7-(4-((4,4-difluorocyclohexyl)amino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (5.50 g, 15.5 mmol, 1.00 equivalent) in MeCN (230 mL) and DCM (230 mL), a solution of NBS (2.49 g, 14.0 mmol, 0.90 equivalent) in MeCN (45.0 mL) and DCM (45.0 mL) was added at 0°C, and the mixture was stirred at 0°C for 0.5 hours. The reaction mixture was concentrated under vacuum. The crude product was triturated with ethyl acetate (20.0 mL) at 25°C for 30 minutes to obtain the desired product (6.00 g, 13.8 mmol, yield 89.1%) as a yellow solid, which was confirmed by LC-MS. LC-MS: m / z = 432.2 (M + H) + .

[0209] Step 3: To a solution of 7-(5-bromo-4-((4,4-difluorocyclohexyl)amino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (480 mg, 1.11 mmol, 1.00 equivalent) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (563 mg, 2.22 mmol, 2.00 equivalent) in dioxane (10.0 mL) and DMF (5.00 mL), KOAc (326 mg, 3.33 mmol, 3.00 equivalent) and Pd(PPh3)2Cl2 (116 mg, 166 μmol, 0.15 equivalent) were added under N2 conditions, and the mixture was then stirred at 80°C for 2 hours. The crude material was filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (FA conditions) and then concentrated by lyophilization to obtain the desired product (1.40 g, 2.87 mmol, yield 23.5%) as a yellow solid. LCMS: m / z = 398.2 (M + H) + .

[0210] Step 4: To a solution of (6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((4,4-difluorocyclohexyl)amino)pyridine-3-yl)boronic acid (700 mg, 1.43 mmol, 1.00 equivalent, FA) and tert-butyl 4-(5-bromo-1,3,4-thiadiazole-2-yl)piperazine-1-carboxylate (525 mg, 1.51 mmol, 1.05 equivalents) in DME (15.0 mL), XPhos Pd G3 (121 mg, 143 μmol, 0.10 equivalents) and K3PO4 (2.00 M, 1.79 mL, 2.50 equivalents) were added under N2. The mixture was stirred under N2 at 100°C for 1 hour. Pour the reaction mixture into water (20.0 mL), then filter, and add ethyl acetate (10.0 mL). * 4) Wash and the filtrate is ethyl acetate (20.0 mL) * 3) The solution was extracted and then concentrated under vacuum to obtain the residue. The residue was then examined by HPLC, purified by preparative HPLC, and concentrated by lyophilization to obtain the desired product (600 mg, 965 μmol, yield 33.6%) as a yellow solid. LCMS: m / z = 622.2 (M + H) + .

[0211] Step 5: tert-butyl 4-(5-(6-(3-Sy) in ethyl(2.00 mL) To a solution of anopyrrolo[1,2-b]pyridazin-7-yl)-4-((4,4-difluorocyclohexyl)amino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl)piperazine-1-carboxylate (600 mg, 965 μmol, 1.00 equivalent), HCl / siRNA (4 M, 2.57 mL, 10.6 equivalents) was added, and the mixture was stirred at 25°C for 15 minutes. The resulting mixture was concentrated under vacuum. The crude product was triturated with ethyl acetate (1.00 mL) at 25°C for 15 minutes, then filtered. The filtered cake was concentrated under vacuum to obtain 7-(4-((4,4-difluorocyclohexyl)amino)-5-(5-(piperazin-1-yl)-1,3,4-thiadiazole-2-yl)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (310 mg, 511 μmol, yield 52.9%, HCl) as a yellow solid, which was confirmed by LC-MS. LC-MS: m / z = 522.1 (M + H) + . 1 H NMR:400MHz,DMSO-d6.δ9.78(d,J=7.2Hz,1H),9.57(s,2H),9.01(d,J=2.0Hz,1H),8.92(d,J=2.0Hz,1H),8.55(s,1H),8.30(d,J=5.2 Hz,1H),8.16(s,1H),7.26(d,J=4.8Hz,1H),4.24-4.17(m,2H),3.72-3.69(m,5H),3.23(s,2H),2.17-2.10(m,6H),1.76-1.73(m,2H).

[0212] Intermediate T:7-[5-(5-{4,7-diazaspiro[2.5]octan-7-yl}-1,3,4-thiadiazole-2-yl)-4-(isopropylamino)pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0213] [ka]

[0214] Step 1: Dibromothiadiazole (500 mg, 2.05 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (435 mg, 1 equivalent) were dissolved in DIEA (0.6 mL, 1.75 equivalents) and dioxane (0.15 M), and subsequently heated to 110°C in a sealed vial. The reaction mixture was stirred for 1.5 hours, then cooled and concentrated on silica gel. The desired product (0.105 g, 14%) was obtained by silica gel column chromatography (0-5% methanol in DCM). LCMS C 13 H 19 N4BrO2S theoretical value: 374.0, measured value: m / z = 320.9 [M-tert-butyl] + .

[0215] Step 2: 6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(isopropylamino)pyridine-3-ylboronic acid (90 mg, 0.28 mmol), cesium carbonate (0.2 g, 2.2 equivalents), xanthophos (0.06 g, 0.4 equivalents), palladium acetate (13 mg, 0.2 equivalents), and tert-butyl 7-(5-bromo-1,3,4-thiadiazole-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (105 mg, 1 equivalent) were combined in a microwave vial, followed by the addition of dioxane (8 mL). The reaction mixture was then purged with nitrogen for 1 minute and stirred in a microwave reactor at 145°C for 30 minutes. The reaction mixture was then filtered through Celite and concentrated on silica gel. The desired intermediate was obtained by chromatography (0-10% methanol in DCM). The material was dissolved in DCM:TFA (5:1 ratio DCM to TFA, 0.1M) at room temperature. The mixture was stirred for 3 hours. The reaction product was concentrated and purified by reverse-phase chromatography on a C18 column (0-100% ACN in water, 0.1% TFA), followed by lyophilization overnight to obtain the desired product (28 mg, 21% yield).

[0216] LCMS C 24 H 25 N9S theoretical value: 471.2, measured value: m / z = 472.3 [M+H] + .

[0217] Intermediate U:[5-(5-{4-formylbicyclo[2.2.2]octan-1-yl}-1,3,4-thiadiazole-2-yl)-4-(methylamino)pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0218] [ka]

[0219] Step 1: A solution of methyl 4-{5-[6-chloro-4-(methylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}bicyclo[2.2.2]octane-1-carboxylate (3.8 g, 9.67 mmol, 1 equivalent) in anhydrous THF (270 mL, 0.036 M) was cooled to -15°C under an argon atmosphere and treated with DIBAL-H (29 mL, 1.0 M solution in THF, 29.02 mmol, 3 equivalents). After 30 minutes, the cooling bath was removed, the reaction mixture was warmed to room temperature, and stirred for 1 hour. The mixture was then quenched by adding MeOH (30 mL), stirred vigorously for 20 minutes, and then a saturated aqueous solution of Rochelle salt was added. The resulting mixture was extracted with DCM, the combined organic layers were washed with saturated NH4Cl solution, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (elution with DCM / ACN) to obtain 3.25 g of (4-{5-[6-chloro-4-(methylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}bicyclo[2.2.2]octan-1-yl)methanol (yield 92%). LCMS:ESI(+)[M+H] + = 365.46. 1 H NMR(300MHz,DMSO-d6)δ:8.68(q,J=5.2Hz,1H),8.38(s,1H),6.81(s,1H),4.46(t,J=5.4H) z,1H),3.10(d,J=5.0Hz,2H),2.97(d,J=4.9Hz,3H),2.00-1.89(m,6H),1.56-1.45(m,6H).

[0220] Step 2: (4-{5-[6-chloro-4-(methylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}bicyclo[2.2.2]octan-1-yl)methanol (1.8g, 4.93 mmol, 1.0 equivalent), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.59g, 5.92 mmol, 1.2 equivalents) and Pd(dppf)Cl2·CH2Cl2 (1.01g, To a solution of 1.23 mmol, 0.25 equivalents, 2 M aqueous solution of K2CO3 (5 mL, 9.87 mmol, 2.0 equivalents) was added. The reaction mixture was degassed with argon for 30 minutes, then stirred at 120°C for 25 hours. The reaction mixture was diluted with DCM, filtered through a Celite pad, washed with DCM / MeOH (1:1), and concentrated under reduced pressure. The crude product was purified twice by column chromatography (DCM / acetone and DCM / IPA) to obtain 7-(5-{5-[4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl]-1,3,4-thiadiazole-2-yl}-4-(methylamino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.46 g, 63% yield). LCMS:ESI(+)[M+H] + = 472.40. 1 H NMR(300MHz,DMSO-d6)δ:8.83(d,J=2.2Hz,1H),8.72(d,J=2.3Hz,1H),8.65(br.q,J=4.9Hz,1H),8.63(s,1H),8.16(s,1H),7.87(d,J=4.8 Hz,1H),7.11(d,J=4.8Hz,1H),4.46(t,J=5.4Hz,1H),3.11(d,J=5.4Hz,2H),3.07(d,J=4.8Hz,3H),2.01-1.90(m,6H),1.57-1.46(m,6H).

[0221] Step 3: To a solution of 7-(5-{5-[4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl]-1,3,4-thiadiazole-2-yl}-4-(methylamino)pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.46 g, 3.10 mmol, 1 equivalent) in DCM (900 mL, 3.44 mM), Des-Martin periodinane (1.71 g, 4.02 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at room temperature for 2 hours, then quenched with 20% Na2S2O3 aqueous solution and saturated NaHCO3 aqueous solution. The mixture was stirred until the aqueous layer was clear. The aqueous layer was extracted with DCM. The combined organic layers were washed with saturated NaHCO3 solution, water and brine. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The obtained crude product was triturated with Et2O, filtered, and the filtered solid was washed with a mixture of DCM / Et2O (1:1), Et2O, and pentane to obtain the title compound (1.28 g, 88% yield). LCMS:ESI(+)[M+H] + = 470.15. 1 H NMR(300MHz,DMSO-d6)δ:9.49(s,1H),8.85(d,J=2.2Hz,1H),8.75(d,J=2.2Hz,1H),8.67(s,1H),8.64(q,J=5.1Hz,1H), 8.19(s,1H),7.88(d,J=4.8Hz,1H),7.13(d,J=4.8Hz,1H),3.09(d,J=4.9Hz,3H),2.09-1.98(m,6H),1.82-1.71(m,6H).

[0222] Intermediate V: 7-[4-(methylamino)-5-{5-[4-(piperidine-4-yl)piperazine-1-yl]-1,3,4-thiadiazole-2-yl}pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0223] [ka]

[0224] The same procedure as shown for intermediate T was followed, except that tert-butyl 4-piperazine-1-ylpiperidine-1-carboxylate was used as the starting material instead of tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate. Success. LCMS C 25 H 28 N 10 S-value: Theoretical value: 500.2, Measured value: m / z = 501.5 [M+H] + .

[0225] Intermediate W: 7-{4-[(3-methyloxetane-3-yl)amino]-5-[5-(piperazine-1-yl)-1,3,4-thiadiazole-2-yl]pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0226] [ka]

[0227] Step 1: DIPEA (17.96 mL, 138.98 mmol, 3.5 equivalents) was added to a stirred solution of 3-methyl-3-oxetanamine-HCl (4.9 g, 39.7 mmol, 1 equivalent) in DMF (39.7 mL, 1 M). Then, 2-chloro-4-fluoropyridine (7.4 mL, 79.4 mmol, 2 equivalents) was added, and the mixture was heated in a sealed tube at 100°C for 32 hours. Excess reagents and DMF were removed by evaporation using a rotary evaporator. The residue (16.25 g) was diluted with DCM and the pH was adjusted to 8 with saturated NaHCO3 aqueous solution. The layers were separated, and the organic layer was extracted four times with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated using a rotary evaporator. The crude product was purified by FC (hexane / ethyl acetate) to obtain 5.17 g (54% yield) of 2-chloro-N-(3-methyloxetan-3-yl)pyridine-4-amine. [M+H] + = 199.50 m / z. 1H NMR (300MHz, DMSO-d6) δ7.86(d,J=5.8Hz,1H),7.41(s,1H),6.36-6.25(m,2H),4.60(d,J=6.1Hz,2H),4.51(d,J=6.2Hz,2H),1.56(s,3H).

[0228] Step 2: To a solution of 2-chloro-N-(3-methyloxetan-3-yl)pyridine-4-amine (5.904 g, 24.668 mmol, 1.0 equivalent) in dimethoxyethane (123.33 mL, 0.2 M) in a 400 mL glass reactor, 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (9.293 g, 34.532 mmol, 1.4 equivalents) and tribasic potassium phosphate (10.686 g, 49.335 mmol, 2.0 equivalents) were added. The mixture was degassed by exhausting the reactor and refilling with argon (3 times). Xphos Pd G3 (1.491 g, 1.726 mmol, 0.07 equivalents) was added, and the exhaust-refill procedure was repeated three times. The reactor was sealed, and the mixture was stirred overnight at 120°C. The mixture was diluted with DCM and concentrated. The residue was purified by silica gel FC (DCM / EA 100:0~0:100) to obtain 4.83 g (55% yield) of 7-{4-[(3-methyl oxidase Tan-3-yl)amino]pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile was obtained as a yellow solid. [M+H] + = 306.46 m / z. 1 H NMR(300MHz,DMSO-d6)δ8.80(d,J=2.2Hz,1H),8.68(d,J=2.2Hz,1H),8.19(d,J=5.7Hz,1H),7.81-7.71(m,2H),7.28( s,1H),7.09(d,J=4.8Hz,1H),6.29(dd,J=5.7,2.3Hz,1H),4.69(d,J=6.0Hz,2H),4.55(d,J=6.0Hz,2H),1.64(s,3H).

[0229] Step 3: To a solution of 7-{4-[(3-methyloxetan-3-yl)amino]pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (3.944 g, 11.625 mmol, 1.0 equivalent) in anhydrous acetonitrile (136.78 mL, 0.085 M) and anhydrous dimethylformamide (35.23 mL, 0.33 M), a solution of N-bromosuccinimide (1.966 g, 11.046 mmol, 0.95 equivalent) in anhydrous acetonitrile (14.53 mL, 0.8 M) was added all at once at 0°C. The mixture was stirred at 0°C for 45 minutes. The formed precipitate was filtered and dried to obtain 7-{5-bromo-4-[(3-methyloxetan-3-yl)amino]pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (2.1 g, 5.465 mmol, 47%). The filtrate was concentrated and purified by FC (silica gel, DCM~DCM / EA 7:3) to obtain 1.57 g (yield 35%) of 7-{5-bromo-4-[(3-methyloxetan-3-yl)amino]pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile. [M+H] + = 386.26 m / z. 1 H NMR(300MHz,DMSO-d6)δ8.82(d,J=2.2Hz,1H),8.80(d,J=2.2Hz,1H),8.43(s,1H),7.79(d,J=4.8Hz,1H),7 .64(s,1H),7.09(d,J=4.8Hz,1H),6.78(s,1H),4.79(d,J=6.3Hz,2H),4.58(d,J=6.4Hz,2H),1.71(s,3H).

[0230] Step 4: In a glass pressure reactor, tert-butyl 4-(1,3,4-thiadiazole-2-yl)piperazine-1-carboxylate (2.594 g, 9.499 mmol, 1.0 equivalent) was added to a solution of 7-{5-bromo-4-[(3-methyloxetane-3-yl)amino]pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitride (3.65 g, 9.499 mmol, 1.0 equivalent) in anhydrous dioxane (279.39 mL, 0.034 M). The reactor was evacuated and filled with argon three times. Palladium(II) acetate (0.213 g, 0.949 mmol, 0.1 equivalent), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (1.099 g, 1.899 mmol, 0.2 equivalent), cesium carbonate (12.38 g, 37.997 mmol, 4.0 equivalent), and copper(I) iodide (0.362 g, 1.901 mmol, 0.2 equivalent) were added, and the reactor was sealed. The mixture was stirred at 105°C for 3 hours. UPLC showed partial conversion of SM. Palladium(II) acetate (0.107 g, 0.477 mmol, 0.05 equivalents), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (0.55 g, 0.951 mmol, 0.1 equivalent), cesium carbonate (6.19 g, 18.998 mmol, 2.0 equivalents), and copper(I) iodide (0.181 g, 0.95 mmol, 0.1 equivalent) were added, the reactor was evacuated, and argon was packed three times. The reactor was resealed, and the mixture was stirred overnight at 105°C. The additional palladium(II) acetate (0.107 g, 0.477 mmol, 0.05 equivalents), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (0.55 g, 0.951 mmol, 0.1 equivalent), cesium carbonate (6.19 g, 18.998 mmol, 2.0 equivalents), and copper(I) iodide (0.181 g, 0.95 mmol, 0.1 equivalent) were added, and after exhausting, refilling with argon, and sealing, the mixture was stirred at 105°C for 4 hours. The mixture was filtered through a Celite pad and washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by FC (silica gel, DCM~DCM / ethyl acetate 1:1). 1.11 g (20% yield) of the title compound was obtained. Two further impure fractions (F2-0.97 g and F4-0.73 g) were re-purified by FC (silica, DCM-DCM / ethyl acetate 1:1), combined, and re-purified again (silica, DCM-DCM / ACN 6:4) to obtain 0.31 g (6% yield) of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(3-methyloxetan-3-yl)amino]pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate. [M+H] + = 573.92 m / z. 1 H NMR(300MHz,DMSO-d6)δ8.92(s,1H),8.84(t,J=1.8Hz,2H),8.55(s,1H),7.89-7.84(m,2H),7.12(d,J=4 .8Hz,1H),4.78(d,J=6.4Hz,2H),4.71(d,J=6.2Hz,2H),3.54(q,J=5.5Hz,8H),1.79(s,3H),1.44(s,9H).

[0231] Step 5: To a solution of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(3-methyloxetane-3-yl)amino]pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (1.134 g, 1.917 mmol, 1.0 equivalent) in anhydrous dichloromethane (35.2 mL, 32.0 vol), trifluoroacetic acid (1.477 mL, 19.171 mmol, 9.998 equivalents) was added. The mixture was stirred at room temperature for 90 minutes. UPLC showed no conversion. Trifluoroacetic acid (0.739 mL, 9.592 mmol, 5.003 equivalents) was added and stirring was continued for 90 minutes. UPLC showed complete conversion. The mixture was concentrated and evaporated three times with DCM. The residue was triturated with diethyl ether (150 mL). The resulting solid (TFA salt) was subjected to RP FC (C18 silica, water-water / ACN). Purified by a 1:1 ratio (containing 0.1% FA), 0.545 g (59% yield) of 7-{4-[(3-methyloxetan-3-yl)amino]-5-[5-(piperazin-1-yl)-1,3,4-thiadiazole-2-yl]pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile was obtained as the TFA salt. LCMS:ESI(+)[M+H] + = 474.32. 1 H NMR(300MHz,DMSO-d6)δ8.92(s,3H),8.86(q,J=2.2Hz,2H),8.58(s,1H),7.87(d,J=4.9Hz,2H),7.13(d, J=4.8Hz,1H),4.78(d,J=6.3Hz,2H),4.73(d,J=6.2Hz,2H),3.83-3.72(m,4H),3.32(s,4H),1.79(s,3H).

[0232] Intermediate X: 7-{4-[(cyanomethyl)amino]-5-[5-(piperazin-1-yl)-1,3,4-thiadiazole-2-yl]pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitride; trifluoroacetate.

[0233] [ka]

[0234] Procedure 1: DIPEA (23.4 mL, 133.6 mmol, 3 eq) was added to a stirred solution of 2-bromo-4-fluoropyridine (7.84 g, 44.55 mmol, 1 eq) in NMP (63 mL, 0.71 M). Aminoacetonitrile-HCl (6.31 g, 66.82 mmol, 1.5 eq) was added portionwise and the mixture was heated to 120 °C in a pressure vial. After 12 h, additional aminoacetonitrile-HCl (3 g, 31.77 mmol, 0.7 eq) and DIPEA (16 mL, 91.35 mmol, 2 eq) were added. The reaction was stirred at 120 °C for 12 h. The reaction was diluted with water and extracted with EA. The EA was washed with water, brine and dried over Na2SO4. The crude was purified by FC hexane / EA (0-95%) to afford 6.0 g (64% yield) of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile. [M+H] + = 214.1 m / z. 1 H NMR (300 MHz, DMSO-d6) 7.94 (1H, d, J = 5.7 Hz), 7.43 (1H, t, J = 6.4 Hz), 6.88 (1H, d, J = 2.2 Hz), 6.70 (1H, dd, J = 5.7, 2.2 Hz), 4.41 (2H, d, J = 6.4 Hz).

[0235] Step 2: A solution of 2-[(2-bromopyridine-4-yl)amino]acetonitrile (6.5 g, 30.65 mmol, 1.0 equivalent), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (11.55 g, 42.91 mmol, 1.4 equivalents), and Xphos Pd G3 (1.3 g, 1.53 mmol, 0.05 equivalents) in DME (153 mL, 0.2 M) was mixed with 2 M K3PO4 solution (31 mL, 61.31 mmol, 2.0 equivalents). The solution was degassed with argon for 2-3 minutes and then heated at 120°C for 5 hours. UPLC showed complete conversion of the starting materials. The resulting solution was diluted with DCM and concentrated to dryness. The crude product was purified by FC elution with EA:DCM (0-85%) to obtain 4.29 g (47% yield) of 7-{4-[(cyanomethyl)amino]pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile. [M+H] + = 275.38 m / z. 1 H NMR(300MHz,DMSO-d6)8.82(1H,d,J=2.2Hz),8.65(1H,d,J=2.3Hz),8.36(1H,d,J=5.6Hz),8.03(1H,d,J=2.3Hz),7. 79(1H,d,J=4.7Hz),7.40(1H,t,J=6.4Hz),7.10(1H,d,J=4.8Hz),6.69(1H,dd,J=5.7,2.4Hz),4.42(2H,d,J=6.3Hz).

[0236] Step 3: Dissolve 7-{4-[(cyanomethyl)amino]pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitriel (4.81 g, 17.54 mmol, 1 equivalent) in an ACN / DCM / DMF (10:5:1) mixture (1.5 L, 0.011 M), and add N-bromosuccinimide (2.81 g, 15.78 mmol, 0.9 equivalents) all at once at room temperature. Stir the reaction mixture at room temperature for 30 minutes. After completion, evaporate the mixture, and purify the crude product by elution with DCM / siRNA using FC to obtain 2.0 g (yield 35%) of 7-{5-bromo-4-[(cyanomethyl)amino]pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitriel. [M+H]+ = 355.18 m / z. 1 H NMR(300MHz,DMSO-d6)8.84(1H,d,J=2.3Hz),8.64(1H,d,J=2.2Hz),8.52(1H,s),8.14(1H,s ),7.79(1H,d,J=4.8Hz),7.12(1H,d,J=4.8Hz),7.00(1H,t,J=6.2Hz),4.47(2H,d,J=6.2Hz).

[0237] Step 4: Dissolve 7-{5-bromo-4-[(cyanomethyl)amino]pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.04 g, 2.83 mmol, 1.0 equivalent) in dioxane (30 mL, 0.1 M) and DMF (10 mL, 0.3 M) in a pressure-resistant vial, followed by bis(pinacorato)diboron (1.44 g, 5.66 ( mmol, 2.0 equivalents) and KOAc (0.86 g, 8.789 mmol, 3.1 equivalents) were added. The solution was degassed with argon for several minutes, and Pd(PPh3)2Cl2 (0.2 g, 0.283 mmol, 0.1 equivalents) was added, followed by repeated degassing. The reaction mixture was stirred at 80°C for 24 hours. UPLC showed complete conversion. The reaction mixture was diluted with siRNA, washed with H2O and brine, and dried over Na2SO4. The crude product was triturated with hexane to remove excess bis(pinacorato)diboron, filtered, dried, and used in the next step without further purification.

[0238] Step 5: In a glass reactor, tert-butyl 4-(5-bromo-1,3,4-thiadiazole-2-yl)piperazine-1-carboxylate (2.77 g, 7.93 mmol, 1.0 equivalent) was added to a solution of 7-{4-[(cyanomethyl)amino]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitride (3.17 g, 7.93 mmol, 1.0 equivalent) in anhydrous dioxane (140 mL, 0.06 M). The reactor was evacuated and filled with argon three times. Tri-tert-butylphosphonium tetrafluoroborate (0.23 g, 0.793 mmol, 0.1 equivalent), tris(dibenzylideneacetone)dipalladium(0) (0.363 g, 0.397 mmol, 0.05 equivalent), and cesium fluoride (3.61 g, 23.79 mmol, 3.0 equivalent) were added. The reactor was evacuated and refilled three times, sealed, and the mixture was stirred at 70°C for 12 hours. Additional amounts of tri-tert-butylphosphonium tetrafluoroborate (0.23 g, 0.793 mmol, 0.1 equivalent), tris(dibenzylideneacetone)dipalladium(0) (0.363 g, 0.397 mmol, 0.05 equivalent), and cesium fluoride (3.61 g, 23.79 mmol, 3.0 equivalent) were added. The reactor was evacuated and refilled three times, sealed, and the mixture was stirred at 70°C for 12 hours. The mixture was cooled to room temperature, diluted with DCM (200 mL), and filtered. The residue was purified twice by FC (DCM / i-PrOH and DCM / acetone) to obtain 0.108 g (3% yield) of tert-butyl 4-(5-{4-[(cyanomethyl)amino]-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridine-3-yl}-1,3,4-thiadiazole-2-yl)piperazine-1-carboxylate. [M+H] + = 543.65 m / z. 11H NMR (300 MHz, DMSO-d6) δ 8.91 - 8.83 (2H, m), 8.68 (1H, d, J = 2.3 Hz), 8.61 (1H, s), 8.30 (1H, s), 7.88 (1H, d, J = 4.8 Hz), 7.15 (1H, d, J = 4.9 Hz), 4.70 (2H, d, J = 6.1 Hz), 3.64 - 3.48 (9H, m), 1.44 (9H, s).

[0239] Step 6: To a solution of tert-butyl 4-(5-{4-[(cyanomethyl)amino]-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl}-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (108 mg, 0.199 mmol, 1.0 eq) in anhydrous dichloromethane (5 mL, 0.4 M) was added trifluoroacetic acid (5 mL, 65.68 mmol, 330 eq). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated and co-evaporated with DCM three times. The residue was triturated with diethyl ether, filtered and washed with diethyl ether. The resulting solid was purified by RP FC (C18 silica, ACN / H2O containing 0.1% FA) to afford 66.5 mg (yield 58%) of 7-{4-[(cyanomethyl)amino]-5-[5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyridin-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile; trifluoroacetate as a yellow solid (N-51). LCMS: ESI(+) [M+H] + = 443.21. 1 1H NMR (300 MHz, DMSO-d6) δ 9.08 (2H, br.s), 8.87 (1H, d, J = 2.3 Hz), 8.83 (1H, t, J = 6.2 Hz, overlaped), 8.68 (1H, d, J = 2.2 Hz), 8.62 (1H, s), 8.30 (1H, s), 7.88 (1H, d, J = 4.8 Hz), 7.15 (1H, d, J = 4.8 Hz) , 4.71 (2H, d, J = 6.1 Hz), 3.86 - 3.68 (4H, m), 3.35 - 3.27 (4H, m).

[0240] Intermediate Y:7-{4-[(oxetane-3-yl)amino]-5-[5-(piperazine-1-yl)-1,3,4-thiadiazole-2-yl]pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0241] [ka]

[0242] Step 1: DIPEA (27 mL, 156 mmol, 3.5 equivalents) was added to a chilled, stirred solution of oxetane-3-amine-HCl (4.89 mg, 44.6 mmol, 1 equivalent) in DMF (45 mL, 1 M). Then, 2-chloro-4-fluoropyridine (8.3 mL, 90 mmol, 2 equivalents) was added, and the mixture was heated to 90°C in a sealed tube. Upon completion, the solvent was removed under reduced pressure. The residue was partitioned into RINKAN and water. The organic extract was washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by FC (acetone / DCM 10-50%) to obtain 2-chloroN-(oxetane-3-yl)pyridine-4-amine (3.2 g, yield 38%). LCMS: ESI(+)[M+H] + = 185.10. 1 H NMR(300MHz,DMSO-d6)7.85(d,J=5.8Hz,1H),7.63(d,J=6.3Hz,1H),6.55-6.33(m ,2H),4.85(t,J=6.6Hz,2H),4.65(dt,J=12.8,6.3Hz,1H),4.41(t,J=6.1Hz,2H).

[0243] Step 2: To a solution of 2-chloro-N-(oxetan-3-yl)pyridine-4-amine (2.59 g, 13.9 mmol, 1.0 equivalent) in DME (200 mL, 0.07 M), K3PO4 (6.09 g, 27.8 mmol, 2 equivalents) was added. The solution was degassed with argon for 20 minutes, and then 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (5.24 g, 19.5 mmol, 1.4 equivalents) and XPhos Pd G3 (841 mg, 0.97 mmol, 0.07 equivalents) were added. The pressure vessel was sealed and heated overnight to 120°C. The reaction product was filtered through a Celite pad. The latter was washed with DCM and MeOH. The mother liquor was evaporated under reduced pressure, and the residue was purified by FC (5-50% ACN in DCM) to obtain 7-{4-[(oxetan-3-yl)amino]pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.9 g, yield 46%). LCMS:ESI(+)[M+H] + = 292.37. 1 1H NMR (300 MHz, DMSO-d6) δ8.8 0(d,J=2.2Hz,1H),8.67(d,J=2.2Hz,1H),8.21(d,J=5.7Hz,1H),7.85(d,J=2.1Hz,1H),7.76(d,J=4.8Hz,1H),7.52(d,J=5.9Hz,1 H),7.08(d,J=4.8Hz,1H),6.40(dd,J=5.7,2.3Hz,1H),4.89(t,J=6.5Hz,2H),4.68(dt,J=12.6,6.1Hz,1H),4.50(t,J=6.1Hz,2H).

[0244] Step 3: A solution of 7-{4-[(oxetan-3-yl)amino]pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.9 g, 6.52 mmol, 1 equivalent) in a 4:1 mixture of ACN / DMF (75 mL, 0.086 M) was cooled to 0°C. N-bromosuccinimide (1.1 g, 6.2 mmol, 0.95 equivalents) was dissolved in ACN (5 mL) and added all at once. The solution was stirred at 0°C for 4 minutes until complete and monitored by TLC (AcOEt / Hex 1:1). A precipitate formed. The precipitate was collected by filtration, and the solid was thoroughly dried to remove residual DMF and ACN to obtain 2-bromo-1,3,4-thiadiazole (1.35 g, yield 56%). LCMS:ESI(+)[M+H] + = 370.20. 1 H NMR(300MHz,DMSO-d6)δ8.82(d,J=2.2Hz,1H),8.79(d,J=2.2Hz,1H),8.45(s,1H),7.78(d,J=4.8Hz,1H ),7.75(s,1H),7.09(d,J=4.8Hz,1H),6.87(d,J=3.1Hz,1H),4.94(d,J=3.2Hz,2H),4.76-4.66(m,3H).

[0245] Step 4: To a solution of 2-bromo-1,3,4-thiadiazole (5 g, 30.3 mmol, 1.0 equivalent) and tert-butylpiperazine-1-carboxylate (14.4 g, 75.75 mmol, 2.5 equivalents) in n-butanol (63 mL, 0.48 M), DIPEA (22 mL, 121.2 mmol, 4.0 equivalents) was added. The reaction mixture was heated in an oil bath at 120 °C for 1 hour. The reaction mixture was cooled and concentrated under vacuum to obtain the crude product. This was diluted with 50 mL of AcOEt and 100 mL of H2O and extracted with AcOEt (5 × 50 mL). The combined organic layer was dried over Na2SO4 and evaporated under vacuum to obtain the crude product as a deep red crystalline solid. The compound was purified by FC (Hex / AcOEt 0-100%) to obtain 7-{5-bromo-4-[(oxetan-3-yl)amino]pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (5.73 g, yield 69%). LCMS:ESI(+)[M+H]+ =271.20, 1 H NMR (300MHz, DMSO-d6) δ: 8.85 (s, 1H), 3.47 (s, 8H), 1.43 (s, 9H).

[0246] Step 5: 7-{5-bromo-4-[(oxetan-3-yl)amino]pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitride (1.3g, 3.51 mmol, 1 equivalent) in anhydrous dioxane (104 mL, 0.03 M), tert-butyl 4-(1,3,4-thiadiazole-2-yl)piperazine-1-carboxylate ( A suspension of 1.05 mg, 3.86 mmol, 1.1 equivalents of 1.05 mg, 0.7 mmol, 0.2 equivalents of CuI, 406 mg, 0.7 mmol, 0.2 equivalents of xanthophos, and 4.58 mg, 14 mmol, 4.0 equivalents of Cs2CO3 was degassed with argon for 15 minutes, and Pd(OAc)2 (80 mg, 0.35 mmol, 0.1 equivalents) was added. The pressure vessel was sealed and heated overnight at 105°C. The reaction mixture was filtered through Celite, washed with AcOEt, and the solvent was evaporated under vacuum. The crude product was purified by FC (320 g column with 20 g silica dry loading, ACN / DCM gradient 0-100% in 25 CV). The residue was triturated with Et2O (ultrasonic treatment for 15 minutes) and filtered to obtain 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(oxetan-3-yl)amino]pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (692 mg, yield 35%). LCMS: ESI(+)[M+H] + = 560.58. 1H NMR(300MHz,DMSO-d6)δ8.94(d,J=4.8Hz,1H),8.85(d,J=2.3Hz,1H),8.82( d,J=2.2Hz,1H),8.56(s,1H),7.91(s,1H),7.86(d,J=4.9Hz,1H),7.12(d,J =4.9Hz,1H),5.07(t,J=6.6Hz,2H),4.88(dd,J=11.4,5.9Hz,1H),4.59(t,J =6.2Hz,2H),3.55(d,J=5.6Hz,7H),3.47(s,5H),1.44(s,7H),1.43(s,6H).

[0247] Step 6: A solution of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(oxetan-3-yl)amino]pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (692 mg, 1.24 mmol, 1.0 equivalent) in HFIP (4.0 mL) was heated in a microwave reactor at 140 °C for 1 hour. The reaction mixture was purified by preparative HPLC to obtain the title compound (64 mg, yield 18%). LCMS: ESI(+)[M+H] + = 459.96. 1 H NMR(300MHz,DMSO-d6)δ8.94(d,J=4.6Hz,1H),8.84(d,J=2.3Hz,1H),8.81(d,J=2.2Hz,1H),8.55(s,1H),7.90(s,1H),7.85(d,J=4.8 Hz,1H),7.12(d,J=4.9Hz,1H),5.06(t,J=6.7Hz,2H),4.93-4.82(m,1H),4.59(t,J=6.2Hz,2H),3.56-3.48(m,4H),2.98-2.83(m,4H).

[0248] Intermediate Z: 7-[4-(cyclopropylamino)-5-[5-(piperazin-1-yl)-1,3,4-thiadiazole-2-yl]pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0249] [ka]

[0250] Step 1: To a stirred solution of tert-butylpiperazine-1-carboxylate (8 g, 42.9 mmol, 1.0 equivalent) in anhydrous THF (150 mL, 0.3 M), TEA (19 mL, 129 mmol, 3.0 equivalents) and 1,1'-thiocarbonyldiimidazole (11.5 g, 51.54 mmol, 1.2 equivalents) were added, and the reaction mixture was stirred at room temperature for 2 hours. Next, the solution was transferred dropwise to a solution of hydrazine monohydrate (9.6 mL, 129 mmol, 3 equivalents) in THF (50 mL). The completion of the reaction was monitored by TLC. The mixture was diluted with water (500 mL), and the aqueous layer was extracted with SiO (2 × 500 mL). The combined organic layers were washed with brine (500 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was recrystallized from AcOEt / Hex (1:2) to obtain tert-butyl 4-(aminocarbamotioil)piperazine-1-carboxylate (10.09 g, yield 89%). ESI(-)[MH] + = 259.38. 1 H NMR (300MHz, DMSO-d6)d9.13(s,1H),4.76(s,2H),3.79-3.62(m,4H),3.42-3.25(m,4H),1.41(s,9H).

[0251] Step 2: To a solution of starting 4,6-dichloronicotinic acid (5.645 g, 29.11 mmol, 1.1 equivalents) in dry DCM (90 mL, 0.3 M), Et3N (4.4 mL, 1.2 equivalents) was added under argon, and the solution was cooled to -15°C. While maintaining the temperature at -15°C, isobutyl chloroformate (3.85 mL, 1.1 equivalents) was added dropwise. The solution was then held at -15°C for 1 hour. Next, tert-butyl 4-(aminocarbamotioil)piperazine-1-carboxylate (6.89 g, 26.2 mmol, 1.0 equivalent) was added little by little, and the reaction mixture was stirred overnight at room temperature. Upon completion, the solution was treated with NaHCO3 and extracted with DCM (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness. The crude residue was triturated with Et2O and filtered to obtain tert-butyl 4-{[(4,6-dichloropyridine-3-yl)formohydrazide]methane oil}piperazine-1-carboxylate (8.2 g, yield 70%). ESI(-)[MH] + = 434.00. 1 H NMR (300MHz, DMSO-d6) δ10.68(s,1H),9.94(s,1H),8.71(s,1H),7.97(s,1H),3.99-3.80(m,4H),3.47-3.37(m,4H),1.42(s,9H).

[0252] Step 3a: A solution of tert-butyl 4-{[(4,6-dichloropyridine-3-yl)formohydrazide]methane oil}piperazine-1-carboxylate (4.211 g, 9.21 mmol, 1.0 equivalent) in sulfuric acid (31 mL, 552.6 mmol, 60 equivalents) was stirred overnight at room temperature. The reaction mixture was poured onto ice (approximately 200 mL) with vigorous stirring. K2CO3 was then carefully added little by little until the pH > 9. K2SO4 was filtered off and washed several times with DCM. The product was extracted from the aqueous phase by DCM (3 × 200 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure to obtain 1-[5-(4,6-dichloropyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine (2.276 g, 77% yield). ESI(+)[M+H] += 316.28. 1 H NMR (300MHz, DMSO-d6) δ 8.94 (s, 1H), 8.02 (s, 1H), 3.50-3.45 (m, 4H), 2.87-2.78 (m, 4H).

[0253] Step 3b: To a solution of 1-[5-(4,6-dichloropyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine (2.276 g, 7.2 mmol, 1.0 equivalent) in DCM (14 mL, 0.5 M), TEA (1.2 mL, 8.6 mmol, 1.2 equivalents) was added, and the reaction mixture was stirred for 5 minutes. Boc2O (1.9 g, 8.6 mmol, 1.2 equivalents) was added. The reaction mixture was stirred at room temperature for 1 hour. Upon completion, the solution was evaporated to dryness under reduced pressure. The crude solid was suspended in hexane and filtered to obtain tert-butyl 4-[5-(4,6-dichloropyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (2.8 g, 93% yield). ESI(+)[M+H] + = 360.34. 1 H NMR (300MHz, DMSO-d6) δ 8.94 (s, 1H), 8.04 (s, 1H), 3.63-3.46 (m, 8H), 1.43 (s, 9H).

[0254] Step 4: tert-butyl 4-[5-(4,6-dichloropyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (1.4 g, 3.4 mmol) in a 1:3 mixture of t-butanol / THF (45 mL, 0.075 M) To a 1.0 equivalent solution, cyclopropylamine (2.4 mL, 33.6 mmol, 10 equivalents) was added, and the reaction mixture was heated at 90°C for 24 hours. Upon completion, the solution was evaporated under reduced pressure, diluted with water (100 mL), and extracted with DCM (20 mL x 3). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain tert-butyl 4-{5-[6-chloro-4-(cyclopropylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}piperazine-1-carboxylate (1.33 g, 81%). ESI(+)[M+H] + = 437.70.1 H NMR(300MHz,DMSO-d6)δ8.73(s,1H),8.23(s,1H),7.05(s,1H),3.52(s,8H), 2.73-2.59(m,1H),1.43(s,9H),0.90(q,J=6.6Hz,2H),0.57(p,J=4.8Hz,2H).

[0255] Step 5: To a solution of tert-butyl 4-{5-[6-chloro-4-(cyclopropylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}piperazine-1-carboxylate (1.33 g, 3 mmol, 1.0 equivalent) in DME (40 mL, 0.07 M), K3PO4 (1.332 g, 6 mmol, 2.0 equivalent) was added, and the mixture was degassed with argon for 10 minutes. 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.147 g, 4.262 mmol, 1.4 equivalent) and XPhos Pd G3 (0.184 g, 0.213 mmol, 0.07 equivalent) were added, and the pressure vessel was sealed. The mixture was stirred overnight at 120°C. The solvent was evaporated under reduced pressure. The crude product was purified by FC (0-10% i-PrOH / DCM at 25CV) to obtain tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(cyclopropylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (120 mg, 20% yield). ESI(+)[M+H] + = 544.48. 1 H NMR(300MHz,DMSO-d6)δ9.36(s,2H),9.12(s,1H),8.92(s,1H),8.84(s,1H),8.60(s,1H),8.52(s,1H),8 .05(s,1H),7.19(s,1H),3.80(s,4H),3.30(s,4H),2.83(s,1H),1.41(s,9H),1.06(s,2H),0.70(s,2H).

[0256] Step 6: A solution of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(cyclopropylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (120 mg, 0.22 mmol, 1.0 equivalent) in DCM (1 mL, 0.3 M) was cooled to 0°C. Next, TFA (0.17 mL, 2.2 mmol, 10 equivalents) was added dropwise, and the mixture was stirred at room temperature for 3 hours. Upon completion, the mixture was evaporated to dryness. The crude product was suspended in Et2O and sonicated for 30 minutes. The suspension was filtered to obtain 95 mg (45% yield) of the title compound (TFA salt) as a yellow solid. LCMS: ESI(+)[M+H] + = 444.48. 1 H NMR(300MHz,DMSO-d6)δ9.36(s,2H),9.12(s,1H),8.92(s,1H),8.84(s,1H),8.60(s,1H),8.52(s ,1H),8.05(s,1H),7.19(s,1H),3.80(s,4H),3.30(s,4H),2.83(s,1H),1.06(s,2H),0.70(s,2H).

[0257] Intermediate AA: 7-[4-(ethylamino)-5-[5-(piperazin-1-yl)-1,3,4-thiadiazole-2-yl]pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0258] [ka]

[0259] Step 1: A mixture of tert-butyl 4-[5-(4,6-dichloropyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (1.4 g, 3.36 mmol, 1.0 equivalent) in tert-butanol (22 mL, 0.15 M) and a 2 M ethylamine solution in THF (2 mL, 7.1 mmol, 20.0 equivalents) was heated overnight at 90°C. All volatiles were then evaporated under reduced pressure, the residue was dissolved in dichloromethane, washed with water, dried, and the solvent was evaporated. The crude product was triturated with hexane to obtain 1.35 g (94% yield) of tert-butyl 4-{5-[6-chloro-4-(ethylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}piperazine-1-carboxylate. ESI(+)[M+H] + = 425.64. 1 H NMR (300MHz, DMSO-d6), d:8.59(t,J=5.0Hz,1H),8.20(s,1H),6.81(s,1H),3.52(m,8H),3.32(brq,2H),1.43(s,9H),1.23(t,J=7.2Hz,3H).

[0260] Step 2: Tert-butyl 4-{5-[6-chloro-4-(ethylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}piperazine-1-carboxylate (1.6 g, 3.77 mmol, 1.0 equivalent), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.42 g, 5.27 mmol, 1.4 equivalent), K3PO4 (1.648 g, 7.531 mmol, 2.0 equivalent), and XPhos Pd G3 (0.228 g, 0.264 mmol, 0.07 equivalent) were suspended in dimethoxymethane (54 mL, 0.07 M). The mixture was degassed with argon for 20 minutes and stirred overnight at 120°C. The crude product was purified by FC (silica gel, dichloromethane / acetonitrile 1:1) to obtain 1.2 g (60% yield) of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(ethylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate as a yellow solid. ESI(+)[M+H] + = 533.0. 1 H NMR(300MHz,DMSO-d6),δ:8.84(d,J=2.2Hz,1H),8.72(d,J=2.2Hz,1H),8.48(m,1H),8.16(s,1H), 7.85(d,J=4.8Hz,1H),7.12(d,J=4.8Hz,1H),3.54(brm,10H),1.44(s,9H),1.34(t,J=7.1Hz,3H).

[0261] Step 3: Dissolve tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(ethylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (1.2 g, 2.25 mmol, 1.0 equivalent) in acetic acid (15 mL, 0.15 M), add HCl in diethyl ether (6 g, 22.57 mmol, 10 equivalents), and stir the reaction mixture at room temperature for 2 hours. UPLC monitoring was applied. Then, all volatiles were evaporated, and the crude residue was triturated with a mixture of 2-propanol and diethyl ether to obtain 0.5 g (50% yield) of the title compound as a yellow solid. LCMS: ESI(+)[M+H] + = 432.21. 1 H NMR(300MHz,DMSO-d6),δ:8.83(s,1H),8. 71(s,1H),8.49(d,J=13.2Hz,2H),8.15(s,1H),7.84(d,J=4.7Hz,1H),7.11(d,J=4.6H z,1H),4.12(brm,1H),3.50(m,4H),3.44(brq,2H),2.90(m,4H),1.34(t,J=7.1Hz,3H).

[0262] Intermediate AB: 7-[4-(ethylamino)-5-[5-(piperazin-1-yl)-1,3,4-oxadiazole-2-yl]pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitride tetrahydrochloride.

[0263] [ka]

[0264] Step 1: A solution of tert-butyl 4-{[(4,6-dichloropyridine-3-yl)formohydrazide]methane oil}piperazine-1-carboxylate (0.11 g, 0.25 mmol, 1.0 equivalent) and p-toluenesulfonyl chloride (0.082 g, 0.43 mmol, 1.7 equivalents) in dried pyridine (1.3 mL, 0.2 M) was heated at 75°C for 1.5 hours with stirring. Then, all volatiles were evaporated under low pressure, and the crude material was purified by flash chromatography (silica gel, DCM / 2-PrOH, 9:1) to obtain 0.06 g (52% yield) of tert-butyl 4-[5-(4,6-dichloropyridine-3-yl)-1,3,4-oxadiazole-2-yl]piperazine-1-carboxylate as an off-white crystalline product. ESI(+)[M+H] + = 418.8. 1 H NMR (300MHz, DMSO-d6), d: 8.93 (s, 1H), 8.05 (s, 1H), 3.51 (s, 8H), 1.43 (s, 9H).

[0265] Step 2: Dissolve tert-butyl 4-[5-(4,6-dichloropyridine-3-yl)-1,3,4-oxadiazole-2-yl]piperazine-1-carboxylate (0.36 g, 0.865 mmol, 1.0 equivalent) in tert-butanol (6 mL, 0.15 M), and add 10% ethylamine in THF (2.0 mL, 4.32 mmol, 5 equivalents). The resulting mixture was heated overnight at 80°C, cooled to room temperature, dissolved in dichloromethane, washed with water, the organic phase was dried over Na2SO4, filtered, and evaporated to dryness under reduced pressure to obtain 0.32 g (77% yield) of tert-butyl 4-{5-[6-chloro-4-(ethylamino)pyridine-3-yl]-1,3,4-oxadiazole-2-yl}piperazine-1-carboxylate as an off-white solid. ESI(+)[M+H] + = 409.63. 1 H NMR (300MHz, DMSO-d6), δ:8.46(s,1H),7.83(d,J=5.2Hz,1H),6.85(s,1H),3.51(s,8H),3.39(s,2H),1.43(s,9H),1.23(t,J=7.1Hz,3H).

[0266] Step 3: tert-butyl 4-{5-[6-chloro-4-(ethylamino)pyridine-3-yl]-1,3,4-oxadiazole-2-yl}piperazine-1-carboxylate (0.3g, 0.74mmol, 1 equivalent), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carboxylate Bonitrile (0.28 g, 1.03 mmol, 1.4 equivalents), K3PO4 (0.35 g, 1.47 mmol, 2 equivalents), and XPhos Pd G3 (0.05 g, 0.052 mmol, 0.07 equivalents) were suspended in dimethoxyethane (11 mL, 0.07 M). The mixture was degassed with argon for 20 minutes and stirred overnight at 120°C. The crude product was purified by flash chromatography (silica gel, dichloromethane / 2-propanol) to obtain 0.2 g (51% yield) of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(ethylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate as a yellow solid. ESI(+)[M+H] + = 516.71. 1 H NMR(300MHz,DMSO-d6),δ:8.85(d,J=2.2Hz,1H),8.77(s,1H),8.74(d,J=2.2Hz,1H),8.19(s,1H),7.87(d,J=4. 8Hz,1H), 7.74(t,J=5.3Hz,1H),7.12(d,J=4.8Hz,1H),3.58-3.41(m,10H),1.44(s,9H),1.34(t,J=7.1Hz,3H).

[0267] Step 4: A solution of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(ethylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (0.2 g, 0.38 mmol, 1 equivalent) was dissolved in glacial acetic acid (2.51 mL, 0.15 M), and 1 M HCl (0.915 g, 3.76 mmol, 10 equivalents) in diethyl ether was added. The resulting mixture was stirred for 2 hours. Then, all volatiles were evaporated under reduced pressure. The residue was triturated with dry diethyl ether to obtain 0.18 g (yield 81%) of the title compound as a yellow crystalline solid. LCMS: ESI(+)[M+H] + = 416.25.

[0268] 1 H NMR(300MHz,DMSO-d6),δ:9.53(s,2H),9.00(d,J=2.1Hz,1H),8.86(d,J=2.2Hz,1H),8.75(s,2H),8.28(d,J=5.0Hz, 1H),8.12(s,1H),7.24(d,J=5.0Hz,1H),3.86(s,4H),3.65(d,J=12.8Hz,2H),3.29(brm,4H),1.35(t,J=7.1Hz,3H).

[0269] Intermediate AC: 7-(4-{[(1R)-1-cyanoethyl]amino}-5-[5-(piperazin-1-yl)-1,3,4-thiadiazole-2-yl]pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0270] [ka]

[0271] Step 1: To a solution of tert-butyl 4-[5-(4,6-dichloropyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (10.0 g, 24.02 mmol, 1.0 equivalent) in anhydrous dimethyl sulfoxide (80 mL, 0.3 M), potassium fluoride (1.61 g, 27.623 mmol, 1.15 equivalents) and 18-crown-6 (3.18 g, 12.01 mmol, 0.5 equivalents) were added. The reaction mixture was stirred at 105°C for 24 hours. After the reaction was complete, it was diluted with water (100 mL), and the aqueous layer was extracted with DCM (3 × 500 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was triturated with hexane and then purified by silica gel flash chromatography eluted with 0-50% siRNA in hexane to obtain 6.7 g (70% yield) of tert-butyl 4-[5-(6-chloro-4-fluoropyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate as an off-white solid. LCMS:[C 16 H 19 ClFN5O2S], desired mass 399.1, measured mass = 399.9[M+H + ]. 1 H NMR (300MHz, CDCl3) δ9.21(d,J=9.8Hz,1H),7.22(d,J=9.8Hz,1H),3.62(s,8H),1.49(s,9H).

[0272] Step 2: Tert-butyl 4-[5-(6-chloro-4-fluoropyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (6.7 g, 16.76 mmol, 1.0 equivalent), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (5.41 g, 20.10 mmol, 1.2 equivalents), tribasic potassium phosphate (7.11 g, 33.51 mmol, 2.0 equivalents), and XPhos Pd G3 (0.99 g, 1.17 mmol, 0.07 equivalents) were suspended in dimethoxyethane (240 mL, 0.07 M). The mixture was degassed with argon for 20 minutes and warmed overnight to 120°C. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM (5 CV), 0-30% ACN in DCM (15 CV), and 30% ACN in DCM, followed by trituration with Et2O to 950 ml. g (11% yield) of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-fluoropyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate was obtained as a yellow solid. LCMS:[C 24 H 23 [FN8O2S], desired mass 506.1, actual mass = 507.0 [M+H + ]. 1 H NMR(300MHz,CDCl3)δ9.50(d,J=10.2Hz,1H),8.69(d,J=12.7Hz,1H),8.36(s,1H),8 .22(s,1H),8.04(d,J=4.6Hz,1H),7.02(d,J=4.8Hz,1H),3.64(s,8H),1.50(s,9H).

[0273] Step 3: To a solution of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-fluoropyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (5.4 g, 8.00 mmol) in anhydrous DMSO (80.0 mL, 0.1 M), D-alaninamide hydrochloride (9.96 g, 80.0 mmol) and sodium bicarbonate (10.1 g, 120 mmol) were added. The reaction mixture was stirred at 120 °C for 1 hour. The product was precipitated by adding ice. The suspension was stirred at room temperature for 15 minutes. The solid was collected by filtration and washed with water until the filtrate was colorless. The solid was dried in a vacuum. The residue was purified by silica gel flash chromatography eluting with 0-6% MeOH in DCM to obtain 1.36 g (30% yield) of tert-butyl 4-[5-(4-{[(1R-1-carbamoylethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate as a yellow solid. LCMS:C 27 H 30 N 10 Theoretical value of O3S: 574.2, measured value: m / z = 575.2 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ8.85(d,J=2.3Hz,1H),8.64(d,J=2.3Hz,1H),8.52(s,1H),8.13(s,1H),7.83(d,J=4.8Hz,1H),7.77(s ,1H),7.23(s,1H),7.13(d,J=4.9Hz,1H),6.87(s,1H),4.27(s,1H),3.54(d,J=6.8Hz,8H),1.50(d,J=6.8Hz,3H),1.44(s,9H).

[0274] Step 4: To a solution of tert-butyl 4-[5-(4-{[(1R-1-carbamoylethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (1.36 g, 2.37 mmol) in anhydrous DCM (23.7 mL, 0.1 M), anhydrous trifluoroacetic acid (1.49 g, 7.1 mmol) and anhydrous pyridine (1.53 mL, 18.9 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 0.5 hours. Since the reaction was incomplete, anhydrous trifluoroacetic acid (0.049 g, 0.24 mmol) and anhydrous pyridine were added. Zin (0.05 mL, 0.63 mmol) was added, and the mixture was stirred under argon at room temperature for 30 minutes. A saturated aqueous solution of NaHCO3 was poured over the mixture, and the mixture was extracted with DCM to obtain 671 mg of crude product. The crude product was purified by silica gel flash chromatography eluting with 0-4% MeOH in DCM to obtain 0.33 g (yield 24%) of tert-butyl 4-[5-(4-{[(1R)-1-cyanoethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate as an orange solid. LCMS:C 27 H 28 N 10 Theoretical O2S value: 556.2, Measured value: m / z = 557.2 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ8.88(d,J=2.3Hz,1H),8.83(d,J=6.9Hz,1H),8.68(d,J=2.3Hz,1H),8.64(s,1H),8.37(s,1H),7.8 8(d,J=4.8Hz,1H),7.15(d,J=4.8Hz,1H),5.04(t,J=6.9Hz,1H),3.55(d,J=7.5Hz,8H),1.78(d,J=6.9Hz,3H),1.44(s,9H).

[0275] Step 5: To a solution of tert-butyl 4-[5-(4-{[(1R)-1-cyanoethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridin-3-yl)-1,3,4-thiadiazol-2-yl]piperazine-1-carboxylate (0.97 g, 1.7 mmol) in anhydrous dichloromethane (34.8 mL, 0.05 M) was added trifluoroacetic acid (8 mL, 105 mmol) and anisole (0.381 mL, 3.48 mmol). The reaction mixture was stirred at room temperature for 1 h. The volatiles were evaporated and the residue was triturated 4 times with diethyl ether to afford 790 mg of 7-(4-{[(1R)-1-cyanoethyl]amino}-5-[5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile as the TFA salt. The salt was dissolved in a mixture of 20 mL of DCM / MeOH (9:1, v / v) and washed with 7% aqueous NaHCO3 (30 mL). The aqueous layer was extracted twice with 10% MeOH in DCM, the combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford 0.562 g (63% yield) of the title compound as a yellow powder. LCMS:C 22 H 20 N 10 S, desired mass = 456.2, found m / z = 457.1 [M+H] + , 1 H NMR (300 MHz, DMSO-d6) δ 8.90 - 8.80 (m, 2H), 8.68 (d J = 2.3 Hz, 1H), 8.64 (s, 1H), 8.37 (s, 1H), 7.88 (d J = 4.8 Hz, 1H), 7.15 (d J = 4.8 Hz, 1H), 5.04 (t J = 7.0 Hz, 1H), 3.53 (d J = 5.2 Hz, 4H), 2.89 (m, 4H), 1.78 (d J = 6.9 Hz, 3H).

[0276] Intermediate AD: 7-[4-(methylamino)-5-[5-(piperidin-4-yl)-1,3,4-thiadiazol-2-yl]pyridin-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0277] [Chemical Structure]

[0278] Step 1: To a solution of 6-chloro-4-(methylamino)pyridine-3-carbohydrazide (3.55 g, 17.69 mmol, 1 equivalent) and monomethyl 1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid (4.46 g, 19.46 mmol, 1.1 equivalents) in DMF (60 mL, 0.3 M), DIPEA (9.3 mL, 53.08 mmol, 3 equivalents) and HATU (8.1 g, 21.23 mmol, 1.2 equivalents) were added. The mixture was stirred overnight at 25°C. The reaction mixture was quenched with ice / water (600 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by FC (DCM / MeOH, 0-10%) to obtain 6.44 g of tert-butyl 4-{N'-[6-chloro-4-(methylamino)pyridine-3-carbonyl]hydrazinecarbonyl}piperidine-1-carboxylate compound (yield 85%). LCMS:ESI(+)[MH] - = 410.40. 1 ¹H NMR (300MHz, chloroform-d) δ 10.33 (s, 1H), 9.89 (s, 1H), 8.34 (s, 1H), 8.10 (d, J=5.1Hz, 1H), 6.66 (s, 1H), 3.95 (d, J=13.2Hz, 2H), 2.82 (d, J=5.0Hz, 5H), 2.47-2.36 (m, 1H), 1.71 (d, J=12.5Hz, 2H), 1.51-1.40 (m, 11H).

[0279] Step 2: Tert-butyl 4-{N'-[6-chloro-4-(methylamino)pyridine-3-carbonyl]hydrazinecarbonyl}piperidine-1-carboxylate (3.4 g, 8.25 mmol, 1 equivalent) was dissolved in anhydrous THF (275 mL, 0.03 M) under argon. The solution was heated to 40°C, and P2S5 (2.75 mg, 12.38 mmol, 1.5 equivalents) was gradually added while vigorously stirring. The resulting suspension was stirred under reflux for 1 hour. After completion, volatiles were evaporated under reduced pressure. The residue was dissolved in DCM (100 mL) and vigorously stirred with aqueous K2CO3. The aqueous layer was removed using a separatory funnel, the organic solvent was dried over Na2SO4, and the solution was concentrated under reduced pressure. The crude residue was purified by FC (0-50% gradient of ethyl acetate in DCM) to obtain 1.82 g of tert-butyl 4-{5-[6-chloro-4-(methylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}piperidine-1-carboxylate (yield 51%). LCMS:ESI(+)[M+H] + = 410.4. 1 H NMR(300MHz,DMSO-d6)δ8.66(d,J=4.7Hz,1H),8.40(s,1H),6.84(s,1H),4.01(d,J=13.1Hz,2H),3.53- 3.36(m,1H),2.98(d,J=5.0Hz,5H),2.09(d,J=10.9Hz,2H),1.64(tt,J=12.0,6.5Hz,2H),1.42(s,9H).

[0280] Step 3: Potassium carbonate (0.87 g, 6.295 mmol, 3 equivalents) dissolved in H2O (0.35 mL, 6.0 M) was added to a solution of tert-butyl 4-{5-[6-chloro-4-(methylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}piperidine-1-carboxylate (0.860 g, 2.097 mmol, 1.0 equivalent) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.79 g, 2.936 mmol, 1.4 equivalents) in anhydrous dioxane (7 mL, 0.3 M). The solution was degassed with argon for 15 minutes, and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.43 g, 0.524 mmol, 0.25 equivalents) combined with dichloromethane was added. The tube was sealed and stirred overnight at 120°C. The reaction mixture was filtered through a Celite pad and washed with DCM and MeOH. The solvent was evaporated under reduced pressure, and the residue was purified by FC (5-50% ACN in DCM) to obtain 363 mg of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperidine-1-carboxylate (36% yield). LCMS:ESI(+)[M+H] + = 517.44. 1 H NMR(300MHz,DMSO-d6)δ8.86(d,J=1.9Hz,1H),8.75(d,J=1.9Hz,1H),8.68(s,1H),8.65(s,1H),8.21(s,1H),7.89(d,J=4.8Hz,1H),7.13( d,J=4.8Hz,1H),4.03(d,J=12.2Hz,2H),3.10(d,J=4.9Hz,3H),3.06-2.86(m,2H),2.11(d,J=11.5Hz,2H),1.76-1.56(m,2H),1.43(s,9H).

[0281] Step 4: A solution of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(methylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperidine-1-carboxylate (650 mg, 1.26 mmol) in HFIP (26 mL, 0.06 M) was stirred at 140 °C for 4 hours under MW irradiation. The volatiles were evaporated, and the residue was evaporated three times with DCM. The crude product was subjected to short silica gel flash chromatography (5-30% MeOH in DCM) to obtain 474 mg (85% yield) of the title compound. LCMS: ESI(+)[M+H] + = 417.21. 1 H NMR(300MHz,DMSO-d6)δ8.86(d,J=2.2Hz,1H),8.76(d,J=2.2Hz,1H),8.70(s,1H),8.65(q,J=4.3Hz,1H),8.21(s,1H),7.89(d,J=4.8Hz ,1H),7.14(d,J=4.8Hz,1H),3.10(d,J=4.9Hz,3H),3.08-2.98(m,2H),2.71-2.58(m,2H),2.09-1.97(m,2H),1.66(qd,J=12.2,3.6Hz,2H).

[0282] Intermediate AE: 7-(5-(5-((1r,4r)-4-(methylamino)cyclohexyl)-1,3,4-thiadiazole-2-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonilicate hydrochloride.

[0283] [ka]

[0284] Step 1: To a solution of methyl 4,6-dichloronicotinate (71.6 g, 347 mmol, 1.00 equivalent) and tetrahydro-2H-pyran-4-amine (87.9 g, 869 mmol, 2.50 equivalents) in i-PrOH (700 mL), DIEA (157 g, 1.22 mol, 212 mL, 3.50 equivalents) was added. The reaction mixture was maintained under N2 at 30°C for 12 hours. The reaction mixture was poured into H2O (1.00 L) and then extracted with ethyl acetate (1.00 L). * 3) Combine the organic layers and add brine (1.00 L * 2) Washed, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate, gradient: 20 / 1~10 / 1~3 / 1) to obtain methyl 6-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinate (43.0 g, 157 mmol, yield 45.4%, purity 99.4%) as a white solid. TLC R f =0.30 (3:1 petroleum ether / ethyl acetate). LCMS: m / z = 271.1 (M + H) + . 1 H NMR(400MHz,CDCl3)δ8.68(s,1H),8.27(d,J=8.0Hz,1H),6.56(s,1H),4.01(t,J=3.8,12.0H z,2H),3.89(s,3H),3.63-3.53(m,3H),2.04-1.98(m,2H),1.64(m,J=4.2,10.2,13.8Hz,2H)

[0285] Step 2: To a solution of methyl 6-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinate (49.0 g, 179 mmol, purity 99.4%, 1.00 equivalent) in EtOH (300 mL), NH2NH2·H2O (85.6 g, 1.45 mol, 83.2 mL, purity 85.0%, 8.03 equivalents) was added. The reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was poured into H2O (300 mL), and then ethyl acetate (300 mL) was added. * 3) Extracted. Combined organic layer was brined (600 mL). *2) Wash, dry with Na2SO4, filter, concentrate to obtain 6-chloro-4-((tetrahydro-2H-pyra (4-yl)amino)nicotinohydrazide (45.0 g, 166 mmol, yield 92.4%, purity 100%) was obtained as a white solid. LC-MS: m / z = 271.1 (M + H) + . 1 H NMR(400MHz,DMSO)δ9.86(s,1H),8.39(d,J=7.8Hz,1H),8.26(s,1H),6.84(s,1H),4.49(brs,2H),3.82(td,J= 3.6,11.6Hz,2H),3.78-3.65(m,1H),3.47(dt,J=2.2,11.2Hz,2H),1.88(brd,J=11.6Hz,2H),1.48-1.27(m,2H)

[0286] Step 3: To a solution of 6-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinohydrazide (15.0 g, 55.4 mmol, 100% purity, 1.00 equivalent) and (1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexane-1-carboxylic acid (15.6 g, 60.9 mmol, 1.10 equivalent) in DMF (150 mL), HOBT (8.98 g, 66.4 mmol, 1.2 equivalent), EDCI (12.7 g, 66.4 mmol, 1.20 equivalent), and DIEA (21.4 g, 166 mmol, 28.9 mL, 3.00 equivalent) were added. The mixed reaction was stirred under N2 at 25°C for 2 hours. The reaction mixture was poured into H2O (200 mL), and then ethyl acetate (200 mL) was added. * 3) Extracted. Combined organic layer was brined (600 mL). * 2) Washed, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1~5 / 1) to obtain tert-butyl((1r,4r)-4-(2-(6-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinoyl)hydrazine-1-carbonyl)cyclohexyl)(methyl)carbamate (10.0 g, 17.3 mmol, yield 31.3%, purity 88.4%) as a yellow solid. TLC Rf =0.30 (petroleum ether / ethyl acetate = 0 / 1). LCMS: m / z = 510.1 (M + H) + . 1 H NMR(400MHz,DMSO)δ10.37(s,1H),9.85(s,1H),8.39(s,1H),8.27(brd,J=7.8Hz,1H),6.90(s,1H),3.91-3.67(m,4H ),3.52-3.40(m,2H),2.67(s,3H),2.18(brs,1H),1.93-1.80(m,4H),1.71-1.44(m,6H),1.40(s,9H),1.38(brs,2H)

[0287] Step 4: To a solution of tert-butyl((1r,4r)-4-(2-(6-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinoyl)hydrazine-1-carbonyl)cyclohexyl)(methyl)carbamate (10.0 g, 17.3 mmol, purity 88.4%, 1.00 equivalent) in THF (100 mL), P2S5 (5.78 g, 26.0 mmol, 2.76 mL, 1.50 equivalent) was added at 30°C, and the mixture was then stirred at 70°C for 2 hours. After the reaction was complete, the volatiles were evaporated. The crude residue was dissolved in DCM (150 mL) and washed by vigorously stirring with 15% K2CO3 aqueous solution (150 mL). The organic layer was washed with water (200 mL) and brine (400 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1~25 / 1~10 / 1) to obtain tert-butyl((1r,4r)-4-(5-(6-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl)cyclohexyl)(methyl)carbamate (6.00 g, 8.82 mmol, yield 50.9%, purity 74.7%) as a yellow solid. TLC R f =0.20 (petroleum ether / ethyl acetate = 1 / 1). LCMS: m / z = 508.2 (M + H) + . 1H NMR(400MHz,CDCl3)δ9.08(brd,J=7.4Hz,1H),8.35(s,1H),6.65(s,1H),4.03(td,J=3.8,12.0Hz,2H),3.75-3.64(m,1H), 3.63-3.55(m,2H),3.09(tt,J=3.6,11.8Hz,1H),2.78(s,3H),2.37-2.27(m,2H),2.11-2.01(m,2H),1.89(brdd,J=2.4,12. 2Hz, 2H), 1.82-1.62 (m, 7H), 1.48 (s, 9H)

[0288] Step 5: In a solution of tert-butyl((1r,4r)-4-(5-(6-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl)cyclohexyl)(methyl)carbamate (6.00 g, 11.8 mmol, 1.00 equivalent) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (4.13 g, 15.3 mmol, 1.30 equivalents) in DME (60.0 mL), add K3PO4 (2.00 M, 11.8 mL, 2.00 equivalent) and XPhos Pd G3 (999 mg, 1.18 mmol, 0.100 equivalents) was added under N2 conditions, and the mixture was stirred under N2 conditions at 100°C for 2 hours. The reaction mixture was poured into H2O (100 mL) and then extracted with ethyl acetate (100 mL). * 3) Combine the organic layers and add brine (200 mL) * 2) Washed, dried over Na2SO, filtered, and concentrated. The crude product was separated by preparative HPLC (column: Welch Ultimate XB-SiOH 250). * 70 *LCMS: 10 μm; mobile phase: [hexane-EtOH (0.1% NH3, H2O)]; B%: 1%~40%, 20 min), followed by concentration by lyophilization to obtain tert-butyl((1r,4r)-4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl)cyclohexyl)(methyl)carbamate (2.00 g, 1.96 mmol, yield 16.7%, purity 60.6%) as a yellow solid. LCMS: m / z = 615.2 (M + H) +

[0289] Step 6: To a solution of tert-butyl((1r,4r)-4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl)cyclohexyl)(methyl)carbamate (2.00 g, 1.96 mmol, purity 60.6%, 1.00 equivalent) in HCl / siRNA (4.00 M, 489 μL, 1.00 equivalent) was maintained at 25°C under N2 for 15 minutes. The reaction mixture was concentrated under vacuum. The residue was treated with siRNA (10.0 mL) at 25°C for 1 hour, then filtered, and the filtered cake was concentrated under vacuum. 7-(5-(5-((1r,4r)-4-(methylamino)cyclohexyl)-1,3,4-thiadiazole-2-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (1.01 g, 1.67 mmol, yield 85.3%, purity 91.1%, HCl) was obtained as a yellow solid. LCMS: m / z = 515.1 (M + H) + . 1H NMR:(400MHz,MeOD)δ8.80-8.76(m,2H),8.71(d,J=2.0Hz,1H),8.16(d,J=5.2Hz,1H),8.0 0(s,1H),7.25(d,J=5.2Hz,1H),4.42-4.26(m,1H),4.04(td,J=3.8,12.0Hz,2H),3.78-3.6 9(m,2H),3.43-3.32(m,2H),3.20(tt,J=3.6,11.8Hz,1H),2.75(s,3H),2.49-2.40(m,2H) ,2.34(brd,J=10.4Hz,2H),2.20(brd,J=12.2Hz,2H),1.88-1.77(m,4H),1.71-1.62(m,2H)

[0290] Intermediate AF: 7-(5-(5-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazole-2-yl)-4-(((S)-tetrahydrofuran-3-yl)amino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0291] [ka]

[0292] Step 1: To a stirred solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (29.4 g, 138.49 mmol, 1.0 equivalent) in THF (462 mL, 0.3 M), TEA (57.9 mL, 3.0 equivalents) and 1,1'-thiocarbonyldiimidazole (29.61 g, 1.2 equivalents) were added at room temperature, and the reaction mixture was stirred for 2 hours. The solution was then transferred dropwise to a solution of hydrazine monohydrate (20.80 g, 3 equivalents) in THF (130 mL). The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (500 mL), and the aqueous layer was extracted with SiO2 (2 × 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was resuspended in water (600 mL) and filtered off. It was then washed with water to remove imidazole byproducts, yielding 35 g (88%) of tert-butyl 3-(aminocarbamotioil)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a light pink solid. LCMS:[C 12 H 22 [N4O2S], Desired mass = 286.4, Measured mass = 287.3 [M+H + ]. 1 H NMR (300MHz, DMSO-d6): δ9.05(s,1H),4.76(s,2H),4.40-3.98(m,4H),3.08-2.84(m,2H),1.91-1.70(m,2H),1.57(d,J=7.2Hz,2H),1.41(s,9H).

[0293] Step 2: In a dry atmosphere, TEA (17.35 mL, 124.45 mmol, 1.2 equivalents) was added to a solution of starting 4,6-dichloronicotinic acid (23.89 g, 124.45 mmol, 1.2 equivalents) in dry DCM (345 mL, 0.3 M), and the solution was cooled to -15°C. Isobutyl chloroformate (17.0 g, 124.45 mmol, 1.2 equivalents) was added dropwise while maintaining the temperature at -15°C. The solution was maintained at -15°C for 1 hour. Then, at this temperature, tert-butyl 3-(aminocarbamotioil)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30.0 g, 103.71 mmol, 1 equivalent) was added little by little, and the reaction mixture was allowed to return to 25°C overnight. After completion, the solution was treated with solid NaHCO3 (pH=8.0) and extracted with 3 × 500 mL of DCM. The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness. The crude residue was triturated three times with hexane to obtain 37.5 g (79%) of tert-butyl 3-{[(4,6-dichloropyridine-3-yl)formohydrazide]methane oil}-3,8-diazabi Cyclo[3.2.1]octane-8-carboxylate was obtained as a pale yellow solid and used without further purification. LCMS:[C 18 H 23 [Cl2N5O3S], Desired mass = 460.34, Measured mass = 459.9 [MH] - ]. 1 H NMR (300MHz, CDCl3): δ10.63(s,1H),8.88(s,1H),8.68(d,J=19.5Hz,1H),7.51(s,1H),4.38 (s,4H),3.47-3.27(m,2H),2.13-1.93(m,2H),1.81(t,J=6.9Hz,2H),1.50(d,J=3.4Hz,9H).

[0294] Step 3: Dissolve tert-butyl 3-{[(4,6-dichloropyridine-3-yl)formohydrazide]methane oil}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (37.5 g, 81.46 mmol, 1 equivalent) in H2SO4 (272 mL, 0.3 M) and stir the solution overnight at room temperature. Pour the mixture over ice while stirring and add K2CO3 until the pH is approximately 10. Filter off the K2SO4 and rinse with DCM. Separate the layers and further extract the aqueous layer with DCM (3 × 500 mL). The combined organic layers were washed with brine (1 × 500 mL), dried over Na₂SO₄, filtered, and evaporated under reduced pressure to obtain the crude product. This was then triturated with hexane to obtain 19.6 g (70%) of 3-[5-(4,6-dichloropyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane as a pale yellow solid. LCMS:[C 13 H 13 Cl2N5S], Desired mass = 341.0, Measured mass = 341.8 [M+H + ]. 1 H NMR (300MHz, CDCl3): δ9.14(s,1H),7.49(s,1H),3.72(dd,J=9.1,3.1Hz,4H),3.47(dd,J=12.2,2.8Hz,2H),1.91(d,J=2.1Hz,5H).

[0295] Step 4: A solution of 3-[5-(4,6-dichloropyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane (19.6 g, 57.27 mmol, 1 equivalent) was dissolved in DCM (115 mL, 0.5 M), and TEA (9.58 mL, 68.72 mmol, 1.2 equivalents) was added. The mixture was stirred for 5 minutes. Then, Boc2O (15 g, 68.72 mmol, 1.2 equivalents) was added, and the solution was stirred until complete (2 hours). The solution was evaporated to dryness under reduced pressure. Next, the crude product was triturated with hexane (3 × 300 mL) to obtain 21 g (83% yield) of tert-butyl 3-[5-(4,6-dichloropyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a pale yellow solid. LCMS:[C 18 H 21 Cl2N5O2S], desired mass = 441.0, measured mass = 441.9[M+H + ]. 1 H NMR (300MHz, CDCl3): δ9.14(s,1H),7.50(s,1H),4.42(s,2H),3.54(s,4H),2.16-2.00(m,2H),1.87(d,J=7.4Hz,2H),1.52(s,9H).

[0296] Step 5: The solutions of tert-butyl 3-[5-(4,6-dichloropyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.3 g, 2.94 mmol, 1.0 equivalent), (S)-3-aminotetrahydrofuran hydrochloride (2.18 g, 17.63 mmol, 6.0 equivalents), anhydrous potassium carbonate (3.24 g, 23.51 mmol, 8.0 equivalents), and DIPEA (2.56 mL, 14.69 mmol, 5.0 equivalents) in anhydrous ACN (30 mL, 0.1 M) and DMF (3 mL, 1 M) were stirred overnight at 80°C. Next, all volatiles were removed under reduced pressure, and the crude product was purified by silica gel flash chromatography eluted with dichloromethane / acetonitrile to obtain 1.0 g (62% yield) of tert-butyl 3-(5-(6-chloro-4-(((S)-tetrahydrofuran-3-yl)amino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as an off-white crystalline product. ES I(+)[M+H] + = 494.0. 1 H NMR(300MHz,DMSO-d6)d:8.87(d,J=7.0Hz,1H),8.22(s,1H),6.90(s,1H),4.38(m,1H),4.27(m,2H),3.94 -3.72(m,3H),3.64(m,3H),3.34(m,2H),2.41-2.26(m,1H),1.91(m,2H),1.86-1.68(m,3H),1.43(s,9H).

[0297] Step 6: tert-butyl3-(5-(6-chloro-4-(((S)-tetrahydrofuran-3-yl)amino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.0 g, 1.82 mmol, 1.0 equivalent), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo-[1,2-b]pyridazine-3-carbonitrile (0.709 g, 2.556 mmol, 1.4 equivalent), K3PO4 (0.775 g, 3.651 mmol, 2.0 equivalent), and XPhos Pd G3 (0.155 g, 0.18 mmol, 0.1 equivalent) was suspended in 1,2-dimethoxyethane (26.08 mL, 0.07 M). The mixture was degassed with argon for 20 minutes and stirred overnight at 120°C. The crude product was purified by silica gel flash chromatography eluted with dichloromethane / 2-propanol to obtain 0.7 g (56% yield) of tert-butyl3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((S)-tetrahydrofuran-3-yl)amino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. ESI(+)[M+H] + = 600.47. 1 H NMR(300MHz,DMSO-d6)δ:8.82(d,J=2.2Hz,1H),8.76-8.68(m,2H),8.49(s ,1H),8.18(s,1H),7.83(d,J=4.8Hz,1H),7.11(d,J=4.8Hz,1H),4.30(d,J= 11.2Hz,3H),4.08-3.99(m,1H),3.93-3.78(m,2H),3.70(t,J=11.8Hz,3H) ,2.49-2.38(m,3H),1.98-1.85(m,3H),1.75(d,J=7.3Hz,2H),1.44(s,9H).

[0298] Step 7: To a solution of tert-butyl 3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((S)-tetrahydrofuran-3-yl)amino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.7 g, 1.0 mmol, 1.0 equivalent) in anhydrous dichloromethane (3.5 mL, 0.3 M), trifluoroacetic acid (1.5 mL, 20.5 mmol, 20 equivalents) was added, and the resulting mixture was stirred at room temperature for 3 hours. The product was concentrated under reduced pressure and converted to free amines. The crude product was then purified by silica gel flash chromatography eluted with dichloromethane / methanol to obtain 0.34 g (62% yield) of 7-(5-(5-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazole-2-yl)-4-(((S)-tetrahydrofuran-3-yl)amino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile as a yellow solid.

[0299] LCMS:ESI(+)[M+H] + =500.18. 1 H NMR(300MHz,DMSO-d6)δ:8.83(d,J=2.2Hz,1H),8.74(d,J=2.3Hz,2H),8.49(s,1H),8.19(s,1H),7.84(d,J=4.8Hz,1H),7.11(d,J=4.8Hz,1H),4. 35(m,1H),4.06(m,1H),3.95-3.79(m,2H),3.72(m,1H),3.55(m,3H),3.3 1-3.27(m,2H),2.49-2.38(m,2H),1.99-1.87(m,1H),1.80-1.65(m,4H).

[0300] Intermediate AG: 7-[5-(5-{2,7-diazaspiro[3.5]nonan-2-yl} -1,3,4-thiadiazole-2-yl)-4-(oxan-4-ylamino)pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0301] [ka]

[0302] The synthesis was carried out according to the same procedure as for intermediate T, except that tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate was used. LCMS:ESI(+)[M+H] + = 528.5. 1 H NMR (500MHz, methanol-d4) δ8.78(d,J=2.4Hz,1H),8.70(d,J=2.3Hz,1H),8.56(d,J=2.3Hz,1H),8.13(t,J=3.3Hz,1H),7.94(s,1H),7.30-7.09(m,2H) ),4.31(s,1H),4.13(d,J=2.2Hz,4H),4.11-3.97(m,3H),3.74(t,J=11.1 Hz,2H),3.26(s,5H),2.19(q,J=9.8,6.5Hz,6H),1.78(d,J=11.5Hz,2H).

[0303] Intermediate AH:7-[5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazole-2-yl)-4-(ethylamino)pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0304] [ka]

[0305] Step 1: A solution of tert-butyl 3-[5-(4,6-dichloropyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octa-ne-8-carboxylate (0.44 g, 0.10 mmol, 1.0 equivalent) and ethylamine solution (5 mL, 1.0 mmol, 10.0 equivalent) in anhydrous acetonitrile (23 mL, 0.1 M) and DMF (2.5 mL, 1 M) was stirred at 80°C for 21 hours. Next, all volatiles were removed under reduced pressure, and the crude material was purified by silica gel flash chromatography eluted with dichloromethane / acetonitrile to obtain 0.44 g (98% yield) of tert-butyl 3-{5-[6-chloro-4-(ethylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as an off-white crystalline product. ESI(+)[M+H] + = 451.9. 1 H NMR(300MHz,DMSO-d6),d:8.59(t,J=5.4Hz,1H),8.19(s,1H),6.80(s,1H),4.27(s, 2H), 3.65 (m, 2H), 3.30 (m, 4H), 1.91 (m, 2H), 1.73 (m, 2H), 1.43 (s, 9H), 1.25 (t, 3H).

[0306] Step 2: tert-butyl 3-{5-[6-chloro-4-(ethylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.44 g, 0.98 mmol, 1.0 equivalent), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.387 g, 1.4 mmol, 1.4 equivalent), K3PO4 (0.414 g, 1.951 mmol, 2.0 equivalent), and XPhos Pd G3 (0.083 g, 0.1 mmol, 0.1 equivalent) were suspended in 1,2-dimethoxyethane (13.94 mL, 0.07 M). The mixture was degassed with argon for 20 minutes and stirred overnight at 120°C. The crude material was purified by silica gel flash chromatography eluted with dichloromethane / 2-propanol (9:1) to obtain 0.31 g (51% yield) of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(ethylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. ESI(+)[M+H] + = 559.0. 1 H NMR(300MHz,DMSO-d6),δ:8.83(d,J=2.2Hz,1H),8.72(d,J=2.2Hz,1H),8.49(t,J=10.2Hz,2H),8.16(s,1H),7.85(d,J=4.8Hz,1H),7.11(d,J =4.8Hz,1H),4.29(s,2H),3.68(d,J=11.2Hz,2H),3.50-3.37(m,4H),1.93(s,2H),1.76(d,J=7.4Hz,2H),1.45(s,9H),1.34(t,J=7.1Hz,3H).

[0307] Step 3: To a solution of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(ethylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.31 g, 0.5 mmol, 1.0 equivalent) in anhydrous dichloromethane (5.0 mL, 0.1 M), trifluoroacetic acid (0.8 mL, 10.0 mmol, 20.0 equivalents) was added, and the resulting mixture was stirred at room temperature for 1 hour. After evaporating all volatiles, the crude residue was triturated with anhydrous diethyl ether to obtain 0.21 g (89% yield) of 7-[5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazole-2-yl)-4-(ethylamino)pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile as a yellow solid. LCMS:ESI(+)[M+H] + = 458.09. 1 H NMR(300MHz,DMSO-d6)δ:9.19(m,3H),8.95(d,J=2.2Hz,1H),8.82(d,J=2.2Hz,1H),8.57(s,1H),8.11-7.95(m,2H),7 .21(d,J=5.0Hz,1H),4.23(m,2H),3.95-3.82(m,2H),3.65-3.60(brm,4H),2.10-1.91(m,4H),1.34(t,J=7.1Hz,3H).

[0308] Intermediate AI: 7-(4-{[(3S)-oxolan-3-yl]amino}-5-[5-(piperazine-1-yl)-1,3,4-thiadiazole-2-yl]pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0309] [ka]

[0310] Step 1: To a solution of tert-butyl 4-[5-(4,6-dichloropyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (1.4 g, 1 equivalent) in DMF (3.3 mL, 1 M) and t-BuOH (11 mL, 0.3 M), DIPEA (8.7 mL, 15 equivalents) and (S)-3-aminotetrahydrofuran hydrochloride (4.12 g, 10 equivalents) were added. The pressure vessel was sealed and the mixture was stirred overnight at 100°C. The solvent was evaporated under reduced pressure. Next, the crude product was dissolved in DCM and washed with H2O, NaHCO3, and brine. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 420 mg (24% yield) of tert-butyl 4-[5-(6-chloro-4-{[(3S)-oxolan-3-yl]amino}pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate. ESI(+)[M+H] + = 467.26.

[0311] 1 H NMR(300MHz,DMSO-d6)δ8.86(d,J=6.9Hz,1H),8.22(s,1H),6.91(s,1H),4.46-4.31(m,1H),3.96-3.69(m,3H) ,3.64(dd,J=9.3,2.5Hz,1H),3.59-3.44(m,8H),2.45-2.25(m,1H),1.81(dd,J=8.0,5.0Hz,1H),1.43(s,9H).

[0312] Step 2: tert-butyl 4-[5-(6-chloro-4-{[(3S)-oxolan-3-yl]amino}pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (420 mg, 0.9 mmol, 1 equivalent), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.267 g, 1.26 mmol, 1.4 equivalents), K3PO4 (0.382 g, 1.8 mmol, 2 equivalents), and XPhos Pd G3 (3.36 g, 0.0.063 mmol, 0.07 equivalents) were suspended in DME (13 mL, 0.07 M). The mixture was degassed with argon for 20 minutes and stirred overnight at 120°C. The crude product was purified by silica gel flash chromatography eluting with DCM / acetonitrile and DCM / i-PrOH to obtain 225 mg (53% yield) of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-{[(3S)-oxolan-3-yl]amino}pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate as a yellow solid. ESI(+)[M+H] + = 575.42. 1 H NMR(300MHz,DMSO-d6)δ8.85(s,1H),8.80-8.69(m,2H),8.52(s,1H),8.22(s,1H),7.85(d,J=5.0Hz,1H),7.12(d,J=4.6Hz,1H), 4.43-4.27(m,1H),4.10-4.00(m,1H),4.00-3.79(m,2H),3.79-3.70(m,1H),3.59-3.48(m,8H),2.01-1.87(m,1H),1.44(s,9H).

[0313] Step 3: To a solution of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-{[(3S)-oxolan-3-yl]amino}pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (225 mg, 0.384 mmol, 1 equivalent) in DCM (3 mL), TFA (2 mL) was added and the mixture was stirred at room temperature. After 1.5 hours, the solvent was evaporated under reduced pressure. The crude product was suspended in Et2O and sonicated for 30 minutes. The solid was filtered to obtain 160 mg (81% yield) of 7-(4-{[(3S)-oxolan-3-yl]amino}-5-[5-(piperazine-1-yl)-1,3,4-thiadiazole-2-yl]pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (TFA salt) as a yellow solid. LCMS:ESI(+)[M+H] + = 473.98. 1 H NMR(300MHz,DMSO-d6)δ9.28(s,1H),9.03-8.88(m,3H),8.84(d,J=1.9Hz,1H),8.61(s,1H),8.14(s,1H),7.99(d,J=4.8Hz ,1H),7.20(d,J=4.9Hz,1H),4.53(s,1H),4.04(dd,J=9.5,5.4Hz,2H),3.93-3.80(m,7H),3.32(s,4H),2.02-1.89(s,1H).

[0314] Intermediate AJ: 7-(4-{[(3R)-oxolan-3-yl]amino}-5-[5-(piperazine-1-yl)-1,3,4-thiadiazole-2-yl]pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0315] [ka]

[0316] Step 1: A solution of tert-butyl 4-[5-(4,6-dichloropyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (1.74 g, 4.18 mmol, 1 equivalent) was dissolved in DMF (4 mL, 1 M) and t-BuOH (14 mL, 0.3 M). Then, DIPEA (9 mL, 15 equivalents) and (R)-3-aminotetrahydrofuran (3.6 g, 10 equivalents) were added. The pressure vessel was sealed and the mixture was stirred overnight at 100°C. The solvent was evaporated under reduced pressure. Next, the crude product was dissolved in DCM, washed with H2O, NaHCO3, and brine, the organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure to obtain 1.7 g (79% yield) of tert-butyl 4-[5-(6-chloro-4-{[(3R)-oxolan-3-yl]amino}pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate. LCMS:ESI(+)[M+H] + = 467.27. 1 H NMR(300MHz,DMSO-d6)δ8.86(d,J=6.9Hz,1H),8.22(s,1H),6.91(s,1H),4.46-4.31(m,1H),3.96-3.69(m,3H) ,3.64(dd,J=9.3,2.5Hz,1H),3.59-3.44(m,8H),2.45-2.25(m,1H),1.81(dd,J=8.0,5.0Hz,1H),1.43(s,9H).

[0317] Step 2: tert-butyl 4-[5-(6-chloro-4-{[(3R)-oxolane- [3-yl]amino}pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (1.7 g, 3.3 mmol, 1 equivalent), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitride (1.36 g, 5.04 mmol, 1.4 equivalents), K3PO4 (1.53 g, 7.2 mmol, 2 equivalents), and XPhos Pd G3 (0.213 g, 0.252 mmol, 0.07 equivalents) were suspended in DME (52 mL, 0.07 M). The mixture was degassed with argon for 20 minutes and stirred overnight at 120°C. The crude product was purified by silica gel flash chromatography eluted with DCM / acetonitrile and DCM / i-PrOH to obtain 670 mg (33% yield) of tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-{[(3R)-oxolan-3-yl]amino}pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate as a yellow solid. ESI(+)[M+H] + = 574.42. 1 H NMR(300MHz,DMSO-d6)δ8.84(d,J=2.2Hz,1H),8.76(d,J=2.1Hz,1H),8.51(s,1H),8.21(s,1H),7.85(d,J=4. 8Hz, 1H), 7.12 (d, J=4.8Hz, 1H), 4.35 (s, 2H), 4.12-3.71 (m, 6H), 3.61-3.42 (m, 8H), 1.93 (s, 1H), 1.44 (s, 9H).

[0318] Step 3: Dissolve tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-{[(3R)-oxolan-3-yl]amino}pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (670 mg, 1.11 mmol, 1.0 equivalent) in DCM (10 mL, 0.3 M) and cool the solution to 0°C. Next, add TFA (7.6 g, 10 equivalents) dropwise and stir the mixture at room temperature for 3 hours. Upon completion, evaporate the mixture to dryness. The crude product was suspended in Et2O and sonicated for 30 minutes. The solid was filtered to obtain 380 mg (65% yield) of 7-(4-{[(3R)-oxolan-3-yl]amino}-5-[5-(piperazine-1-yl)-1,3,4-thiadiazole-2-yl]pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile

[0319] (TFA salt) was obtained as a yellow solid. LCMS:ESI(+)[M+H] + = 474.43. 1 H NMR(300MHz,DMSO-d6):δ8.96-8.83(m,4H),8.80(d,J=2.1Hz,1H),8.58(s,1H),8.22(s,1H),7.90(d,J=4.8Hz,1H),7. 16(d,J=4.9Hz,1H),4.43(s,1H),4.06(dd,J=9.3,5.3Hz,1H),3.95-3.72(m,8H),3.35-3.21(m,4H),2.01-1.86(m,1H).

[0320] Intermediate AK: 7-(5-(5-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazole-2-yl)-4-(((R)-tetrahydrofuran-3-yl)amino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0321] [ka]

[0322] Step 1: The solutions of tert-butyl 3-[5-(4,6-dichloropyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octa-ne-8-carboxylate (1.0 g, 2.26 mmol, 1.0 equivalent), (R)-3-aminotetrahydrofuran (1.38 g, 15.83 mmol, 7 equivalents), anhydrous potassium carbonate (2.5 g, 18.08 mmol, 8.0 equivalents), and DIPEA (1.5 mL, 11.30 mmol, 8.0 equivalents) in anhydrous acetonitrile (23 mL, 0.1 M) and DMF (2.5 mL, 1 M) were stirred overnight at 80°C. Next, all volatiles were evaporated under reduced pressure, and the crude material was purified by silica gel flash chromatography eluted with dichloromethane / acetonitrile to obtain 1.1 g (94% yield) of tert-butyl 3-(5-(6-chloro-4-(((R)-tetrahydrofuran-3-yl)amino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as an off-white crystalline product. LCMS:ESI(+)[M+H] + = 493.9. 1 H NMR(300MHz,DMSO-d6),d:8.87(d,J=7.0Hz,1H),8.22(s,1H),6.90(s,1H),4.37(m,1H),4.27(m,2H) ),3.87(m,3H),3.65(m,3H),3.34(m,2H),2.39-2.26(m,1H),1.91(m,2H),1.77(m,3H),1.43(s,9H).

[0323] Step 2: tert-butyl3-(5-(6-chloro-4-(((R)-tetrahydrofuran-3-yl)amino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.1g, 2.12mmol, 1.0 equivalent), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.35g, 5.27mmol, 1.4 equivalent), K3PO4 (1.0g, 5.1mmol, 2.0 equivalent), and XPhos Pd G3 (0.220 g, 0.25 mmol, 0.1 equivalent) was suspended in 1,2-dimethoxyethane (36 mL, 0.07 M). The mixture was degassed with argon for 20 minutes and stirred overnight at 120°C. The crude product was purified by silica gel flash chromatography eluted with DCM / 2-propanol to obtain 0.65 g (46% yield) of tert-butyl3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((R)-tetrahydrofuran-3-yl)amino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. LCMS:ESI(+)[M+H] + =574.42. H NMR(300MHz,DMSO-d6)δ8.84(d,J=2.2Hz,1H),8.76(d,J=2.1Hz,1H),8.51(s,1H),8.21(s,1H),7.85(d,J=4. 8Hz, 1H), 7.12 (d, J=4.8Hz, 1H), 4.35 (s, 2H), 4.12-3.71 (m, 6H), 3.61-3.42 (m, 8H), 1.93 (s, 1H), 1.44 (s, 9H).

[0324] Step 3: To a solution of tert-butyl 3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((R)-tetrahydrofuran-3-yl)amino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.64 g, 0.96 mmol, 1.0 equivalent) in dichloromethane (3.5 mL, 0.3 M), trifluoroacetic acid (1.47 mL, 19.21 mmol, 20.0 equivalents) was added, and the resulting mixture was stirred at room temperature for 3 hours. All volatiles were evaporated under reduced pressure to convert them to free amines, and the crude product was purified by silica gel flash chromatography eluting with dichloromethane / methanol to obtain 0.1 g (19% yield) of 7-(5-(5-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazole-2-yl)-4-(((R)- Tetrahydrofuran-3-yl)amino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile was obtained as a yellow solid. LCMS:ESI(+)[M+H] + = 500.13. 1 H NMR(300MHz,DMSO-d6)δ:8.83(d,J=2.2Hz,1H),8.81-8.71(m,2H),8.49(s,1H),8.19(s,1H),7.84(d,J=4.8Hz,1H),7.11(d,J=4.8Hz,1H),4.34(s,1 H),4.10-4.02(m,1H),3.95-3.79(m,2H),3.72(m,1H),3.52(d,J=9.5Hz,4 H),3.42(s,1H),2.42(s,2H),1.93(d,J=8.3Hz,1H),1.71(d,J=5.7Hz,4H).

[0325] Intermediate AL:7-[4-(cyclopropylamino)-5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazole-2-yl)pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitride bis(trifluoroacetate)

[0326] [ka]

[0327] Step 1: A solution of tert-butyl 3-[5-(4,6-dichloropyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octa-ne-8 carboxylate (1.0 g, 2.24 mmol, 1.0 equivalent) and cyclopropylamine (1.0 g, 17.514 mmol, 7.83 equivalents) in anhydrous acetonitrile (8 mL, 0.3 M) was stirred overnight at 80°C. UPLC control was applied. Next, all volatiles were removed under reduced pressure, and the crude product was purified by silica gel flash chromatography eluted with dichloromethane / acetonitrile to obtain 1.0 g (87% yield) of tert-butyl 3-{5-[6-chloro-4-(cyclopropylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as an off-white crystalline product. LCMS:ESI(+)[M+H] + = 463.9. 1 H NMR(300MHz,DMSO-d6)d:8.73(m,1H),8.22(s,1H),7.05(s,1H),4.27(m,2H),3.65(d,J=11.4Hz, 2H), 2.68 (s, 1H), 2.58 (s, 2H), 1.92 (m, 2H), 1.73 (m, 2H), 1.44 (s, 9H), 0.90 (m, 2H), 0.58 (m, 2H).

[0328] Step 2: Tert-butyl 3-{5-[6-chloro-4-(cyclopropylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}-3,8-diazabicyclo-[3.2.1]-octane-8-carboxylate (1.0 g, 1.9 mmol, 1.0 equivalent), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.77 g, 2.72 mmol, 1.4 equivalent), K3PO4 (0.825 g, 3.89 mmol, 2.0 equivalent), and XPhos Pd G3 (0.165 g, 0.194 mmol, 0.1 equivalent) were suspended in 1,2-dimethoxyethane (28 mL, 0.07 M). The mixture was degassed with argon for 20 minutes and stirred overnight at 115°C. The crude product was purified by silica gel flash chromatography eluting with dichloromethane / 2-propanol (9:1) to obtain 0.31 g. (Yield 51%) tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(cyclopropylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was obtained as a yellow solid. ESI(+)[M+H] + = 571.1. 1 H NMR(300MHz,DMSO-d6)δ:8.84(d,J=2.2Hz,1H),8.76(d,J=2.2Hz,1H),8.66(d,J=4.0Hz,2H),8.49(s,1H),7.87(d,J=4.8Hz,1H),7.13(d,J= 4.8Hz,1H),4.28(s,2H),3.67(d,J=11.5Hz,2H),3.37(m,2H),2.74(m, 1H),1.93(m,2H),1.74(m,2H),1.44(s,9H),1.00(m,2H),0.64(m,2H).

[0329] Step 3: To a solution of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(cyclopropylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.6 g, 0.85 mmol, 1.0 equivalent) in anhydrous dichloromethane (8.5 mL, 0.1 M), trifluoroacetic acid (1.3 mL, 17 mmol, 20.0 equivalents) was added, and the resulting mixture was stirred at room temperature for 1 hour. UPLC control was applied. After evaporating all volatiles, the crude residue was triturated with anhydrous diethyl ether to obtain 0.6 g (99% yield) of 7-[4-(cyclopropylamino)-5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazole-2-yl)pyridine-2-yl]pyrrole[1,2-b]pyridazine-3-carbonitrile bis(trifluoroacetate) as a yellow solid. LCMS:ESI(+)[M+H] + = 470.194. 1 H NMR(300MHz,DMSO-d6)δ:9.36(m,2H),9.17(s,1H),8.94(s,1H),8.85(s,1H),8.59(d,J=6.9Hz,2H),8.00(d,J=4.9Hz,1H),7.21(d,J =4.9Hz,1H),4.24(s,2H),3.87(d,J=12.1Hz,2H),3.63(d,J=12.1Hz,2H),2.86(s,1H),2.13-1.83(m,4H),1.07(m,2H),0.72(m,2H).

[0330] Intermediate AM: 7-[4-(cyclobutylamino)-5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazole-2-yl)pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitride trifluoroacetate.

[0331] [ka]

[0332] Step 1: A solution of tert-butyl 3-[5-(4,6-dichloropyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octa-ne-8-carboxylate (1.1 g, 2.5 mmol, 1.0 equivalent) and cyclobutylamine (1.751 g, 24.618 mmol, 10.0 equivalent) in dry acetonitrile (8 mL, 0.3 M) was heated overnight at 80°C. All volatiles were removed under low pressure, and the crude product was purified by silica gel flash chromatography eluted with dichloromethane / acetonitrile to obtain 1.05 g (yield 81%) of tert-butyl 3-{5-[6 Chloro-4-(cyclobutylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was obtained as an off-white crystalline product. ESI(+)[M+H] + = 479.0. 1 H NMR(300MHz,DMSO-d6)d:8.82(d,J=6.2Hz,1H),8.20(s,1H),6.68(s,1H),4.27(m,2H),4.1 5(m,1H),3.66(d,J=11.1Hz,2H),2.44(s,3H),1.90(s,4H),1.85-1.66(m,5H),1.43(s,9H).

[0333] Step 2: Tert-butyl 3-{5-[6-chloro-4-(cyclobutylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}-3,8-diazabicyclo[3.2.1]-octane-8-carboxylate (1.0 g, 1.992 mmol, 1.0 equivalent), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.79 g, 2.788 mmol, 1.4 equivalent), K3PO4 (0.845 g, 3.983 mmol, 2.0 equivalent), and XPhos Pd G3 (0.169 g, 0.199 mmol, 0.1 equivalent) were suspended in 1,2-dimethoxyethane (8 mL, 0.07 M). The mixture was degassed with argon for 20 minutes and stirred overnight at 117°C. The crude product was purified by silica gel flash chromatography eluted with dichloromethane / 2-propanol to obtain 0.47 g (38% yield) of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(cyclobutylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. ESI(+)[M+H] + = 584.65. 1 H NMR(300MHz,DMSO-d6)δ:8.83(d,J=2.2Hz,1H),8.78(d,J=2.2Hz,1H),8.68(d,J=5.2Hz,1H),8.48(s,1H),8.10(s,1H),7.84(d,J=4.8Hz,1H),7.11( d,J=4.8Hz,1H),4.28(s,2H),4.22-4.10(m,1H),3.68(d,J=11.3Hz,2H),2 .68-2.52(m,5H),2.05-1.84(m,6H),1.76(d,J=11.3Hz,2H),1.44(s,9H).

[0334] Step 3: To a solution of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(cyclobutylamino)-pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.47 g, 0.76 mmol, 1.0 equivalent) in anhydrous dichloromethane (8.5 mL, 0.1 M), trifluoroacetic acid (1.7 mL, 15 mmol, 20.0 equivalents) was added, and the resulting mixture was stirred at room temperature for 1 hour. All volatiles were evaporated, and the crude residue was triturated with anhydrous diethyl ether to obtain 0.35 g (91% yield) of 7-[4-(cyclobutylamino)-5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazole-2-yl)pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile trifluoroacetate as a yellow solid. LCMS:ESI(+)[M+H] + = 484.24. 1 H NMR(300MHz,DMSO-d6)δ:9.27(brm,3H),8.94(d,J=2.2Hz,1H),8.86(d,J=2.2Hz,1H),8.59(s,1H),7.99(d,J=5.8Hz,2H),7.20( d,J=4.9Hz,1H),4.32(m,2H),4.23(s,2H),3.88(d,J=12.9Hz,2H),3.69-3.58(m,2H),2.61(d,J=5.3Hz,2H),2.14-1.82(m,8H).

[0335] Intermediate AN:7-{4-[(1-cyanocyclopropyl)amino]-5-{5-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,4 -thiadiazole-2-yl}pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonilicate.

[0336] [ka]

[0337] Step 1: Tert-butyl 3-[5-(4,6-dichloropyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.0 g, 11.30 mmol, 1 equivalent), KF (755 mg, 12.99 mmol, 1.15 equivalents), and 18-crown-6 ether (1.49 g, 5.65 mmol, 0.5 equivalents) were dissolved in dimethyl sulfoxide anhydride (41 mL), and the reaction mixture was stirred overnight at 105 °C. The reaction mixture was then diluted with water (50 mL) and extracted with DCM (3 × 100 mL). The DCM layer was washed twice with water, and then with brine. The organic layer was dried over Na₂SO₄ and filtered. The solvent was then removed under vacuum. 8.3 g of the crude product was purified by FC using a gradient of 0-100% toluene in hexane to obtain 4.1 g of tert-butyl 3-[5-(6-chloro-4-fluoropyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid. LCMS:[C 18 H 21 ClFN5O2S], desired mass=425.9, measured mass=425.9[M+H + ]. 1 ¹H NMR (300MHz, DMSO-d6): δ 9.04 (d, J=10.0Hz, 1H), 7.90 (d, J=10.4Hz, 1H), 4.28 (s, 2H), 3.77-3.60 (m, 2H), 3.36-3.33 (m, 1H, combined with solvent residual peak), 3.39 (d, J=2.3Hz, 1H), 1.91 (d, J=7.1Hz, 2H), 1.74 (d, J=7.4Hz, 2H), 1.44 (s, 9H).

[0338] Step 2: To a solution of tert-butyl 3-[5-(6-chloro-4-fluoropyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.4 g, 12.68 mmol, 1.0 equivalent) in dimethoxyethane (181 mL, 0.07 M) in a glass reactor, 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (4.09 g, 15.21 mmol, 1.2 equivalents) was added. The reactor was evacuated and argon was packed three times. Xphos Pd G3 (751 mg, 0.89 mmol, 0.07 equivalents) and tribasic potassium phosphate (5.38 g, 25.357 mmol, 2.0 equivalents) were added. The reactor was evacuated and refilled three times, sealed, and the mixture was stirred overnight at 120°C. After the reaction was complete, it was cooled to room temperature and 200 mL of DCM was added. The solution was diluted and concentrated. The residue was purified by FC using a gradient of ACN in DCM (0-100%) to obtain 4.15 g (62% yield) of tert-butyl3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-fluoropyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a pale yellow solid. LCMS:[C 26 H25FN8O2S], desired mass=532.6, measured mass=533.1[M+H + ].

[0339] 1 H NMR (300MHz, CDCl3): δ9.52(d,J=10.2Hz,1H),8.71(d,J=12.9Hz,1H),8.39(d,J=2.2Hz,1H),8.25(d,J=2.3Hz,1H),8.06(d,J=4.9 Hz,1H),7.04(d,J=4.9Hz,1H),4.43(s,2H),3.64(d,J=56.8Hz,4H),2.06(q,J=8.4,6.9Hz,2H),1.88(d,J=7.4Hz,2H),1.52(s,9H).

[0340] Step 3: To a solution of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-fluoropyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.50 g, 0.76 mmol) and 1-aminocyclopropane-1-carbonitride hydrochloride (2.5 g, 21 mmol) in DMSO anhydrous (10 mL, 0.1 M), DIPEA anhydrous (10 mL, 57 mmol) was added. The reaction mixture was stirred overnight at 130 °C under an Ar atmosphere. The reaction mixture was cooled to room temperature and diluted with CH2Cl2. The organic layer was washed with brine (3 times). The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with CH3CN / CH2Cl2 (a gradient of CH3CN from 0% to 30%) to obtain 164 mg (yield 36%) of tert-butyl3-(5-{4-[(1-cyanocyclopropyl)amino]-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridine-3-yl}-1,3,4-thiadiazole-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. LCMS:[C 30 H 30 N 10 O2S], measured mass=594.70[M+H + ]. 1 H NMR(300MHz,DMSO-d6):δ9.03(s,1H),8.90-8.87(m,1H),8.86-8.83(m,2H),8.62(s,1H),7.92(d,J=4.8Hz,1H),7.16(d,J=4.8Hz,1 H),4.36-4.24(m,2H),3.78-3.60(m,2H),3.43-3.35(m,2H),1.96-1.81(m,4H),1.80-1.70(m,2H),1.58-1.47(m,2H),1.44(s,9H).

[0341] Step 4: To a solution of tert-butyl 3-(5-{4-[(1-cyanocyclopropyl)amino]-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridine-3-yl}-1,3,4-thiadiazole-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (164 mg, 0.28 mmol) in anhydrous CH2Cl2 (2.8 mL, 0.1 M), TFA (0.40 mL, 5.6 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. Volatile substances were removed under reduced pressure. The residue was triturated with anhydrous Et2O to obtain 149 mg (quantitative yield) of 7-{4-[(1-cyanocyclopropyl)amino]-5-{5-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,4-thiadiazole-2-yl}pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (TFA salt) as a yellow solid. LCMS:ESI(+)[M+H] + = 495.16. 1 H NMR(300MHz,DMSO-d6):δ9.30-9.02(m,3H),8.92(d,J=2.3Hz,1H),8.88(d,J=2.3Hz,1H),8.86(s,1H),8.67(s,1H),7.95(d,J=4.8Hz,1H),7.19(d,J =4.8Hz,1H),4.30-4.15(m,2H),3.93-3.80(m,2H),3.68-3.53(m,2H),2.10-1.94(m,4H),1.95-1.83(m,2H),1.56-1.49(m,2H).

[0342] Intermediate AO: 7-{4-[(cyanomethyl)amino]-5-{5-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,4-thiadiazole-2-yl}pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0343] [ka]

[0344] Step 1: DIPEA (2.6 mL, 15 mmol) was added to a solution of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-fluoropyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 0.62 mmol) and 2-aminoacetonitrile hydrochloride (918 mg, 9.9 mmol) in DMA / CH3CN (6.5:1) (23 mL, 0.1 M). The reaction mixture was stirred overnight at 110 °C under an Ar atmosphere. The reaction mixture was cooled to room temperature, and volatiles were removed under reduced pressure. The residue was purified by silica gel flash chromatography eluting with CH3CN / CH2Cl2 (a gradient of CH3CN from 0% to 20%) to obtain 250 mg (63% yield) of tert-butyl 3-(5-{4-[(cyanomethyl)amino]-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridine-3-yl}-1,3,4-thiadiazole-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. LCMS:[C 28 H 28 N 10 O2S], measured mass=569.10[M+H + ]. 1 H NMR(300MHz,DMSO-d6):δ8.90-8.78(m,2H),8.68(d,J=2.3Hz,1H),8.60(s,1H),8.30(s,1H),7.87(d,J=4.8Hz,1H),7.15(d,J=4.8Hz,1 H),4.69(d,J=6.1Hz,2H),4.34-4.22(m,2H),3.75-3.64(m,2H),3.43-3.35(m,2H),1.96-1.87(m,2H),1.81-1.65(m,2H),1.44(s,9H).

[0345] Step 2: To a solution of tert-butyl 3-(5-{4-[(cyanomethyl)amino]-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridine-3-yl}-1,3,4-thiadiazole-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.25 g, 0.44 mmol) in anhydrous CH2Cl2 (4.4 mL, 0.1 M), TFA (0.67 mL, 8.8 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under vacuum. The residue was purified by preparative HPLC (CH3CN / H2O + 0.1% HCOOH) to obtain 164 mg (75% yield) of 7-{4-[(cyanomethyl)amino]-5-{5-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,4-thiadiazole-2-yl}pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (TFA salt) as a yellow solid. LCMS:ESI(+)[M+H] + = 469.39. 1 H NMR (300MHz, DMSO-d6): δ8.88(d,J=2.3Hz,1H),8.82(t,J=6.2Hz,1H),8.68(d,J=2.3Hz,1H),8.63(s,1H),8.31(s,1H),7.87(d,J=4 .8Hz,1H),7.15(d,J=4.8Hz,1H),4.70(d,J=6.2Hz,2H),4.08-3.98(m,2H),3.83-3.71(m,2H),3.59-3.46(m,2H),2.02-1.82(m,4H).

[0346] Intermediate AP: 7-[4-(cyclobutylamino)-5-[5-(piperazine-1-yl)-1,3,4-thiadiazole-2-yl]pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0347] [ka]

[0348] Step 1: In a pressure vessel, tert-butyl 4-(5-(4,6-dichloropyridine-3-yl)-1,3,4-thiadiazole-2-yl)piperazine-1-carboxylate (1.2 g, 1 equivalent) was dissolved in DMF (3 mL, 1 M) and t-BuOH (9.5 mL, 0.3 M). Next, DIPEA (7.4 mL, 15 equivalents) and cyclobutylamine (1.4 g, 7 equivalents) were added. The pressure vessel was sealed and the mixture was heated to 80°C overnight. The solvent was evaporated under reduced pressure, the crude material was then dissolved in DCM, washed with H2O, NaHCO3 and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure to obtain tert-butyl 4-{5-[6-chloro-4-(cyclobutylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}piperazine-1-carboxylate (750 mg, 58%). LCMS:ESI(+)[M+H] + = 451.30. 1 H NMR(300MHz,DMSO-d6)δ8.82(d,J=6.2Hz,1H),8.21(s,1H),6.69(s,1H),4.15(h,J=8.6 ,8.1Hz,1H),3.52(d,J=3.9Hz,8H),2.48-2.41(m,2H),1.99-1.72(m,4H),1.43(s,9H).

[0349] Step 2: Tert-butyl 4-{5-[6-chloro-4-(cyclobutylamino)pyridine-3-yl]-1,3,4-thiadiazole-2-yl}piperazine-1-carboxylate (750 mg, 1.63 mmol, 1 equivalent), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (630 mg, 1.4 equivalents), K3PO4 (709 mg, 2 equivalents), and XPhos Pd G3 (101.6 mg, 0.07 equivalents) were suspended in DME (25 mL, 0.07 M). The mixture was degassed with argon for 20 minutes and incubated overnight at 120°C. The crude material was purified by FC (DCM / IPA 0-10%) to obtain tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(cyclobutylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate as a yellow solid (444 mg, 48%). LCMS:ESI(+)[M+H] + = 558.44. 1 1H NMR (300MHz, DMSO-d6) δ8. 83(d,J=2.3Hz,1H),8.78(d,J=2.3Hz,1H),8.68(d,J=5.1Hz,1H),8.49(s,1H),8.11(s,1H),7.84(d,J=4.8Hz,1H),7 .11(d,J=4.9Hz,1H),4.24-4.09(m,1H),3.60-3.46(m,8H),2.60(d,J=10.2Hz,2H),2.10-1.82(m,4H),1.44(s,9H).

[0350] Step 3: Dissolve tert-butyl 4-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-(cyclobutylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl]piperazine-1-carboxylate (444 mg, 1 equivalent) in DCM (5 mL), then add TFA (2 mL), and stir the solution for 1.5 hours. Upon completion, evaporate the mixture to dryness, suspend it in Et2O, and sonicate for 30 minutes. Filter the suspension to obtain 7-[4-(cyclobutylamino)-5-[5-(piperazine-1-yl)-1,3,4-thiadiazole-2-yl]pyridin-2-yl]pyrrolo[1,2-b]pyridazin-3-carbonitriel as the TFA salt (477 mg, 87%). LCMS: ESI(+)[M+H] + = 458.09. 1 H NMR(300MHz,DMSO-d6)δ9.17(s,1H),9.01(s,2H),8.92(d,J=2.2Hz,1H),8.85(d,J=2.2Hz,1H),8.58(s,1H),8.03(s,1H),7.96(d,J=4.9Hz,1H),7.1 8(d,J=4.9Hz,1H),4.30(dq,J=14.2,7.0Hz,1H),3.86-3.75(m,4H),3.33( s,4H),2.68-2.54(m,2H),2.15-1.97(m,2H),1.91(dt,J=9.6,5.5Hz,2H).

[0351] Intermediate AQ: 7-[5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazole-2-yl)-4-{[(2R)-1-methoxypropane-2-yl]amino}pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitride. TFA salt

[0352] [ka]

[0353] Step 1: In a solution of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-fluoropyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (660 mg, 1.24 mmol, 1 equivalent), (R)-1-methoxypropan-2-amine (2.21 g, 24.78 mmol, 20 equivalents) was suspended in anhydrous DMSO (12.4 mL, 0.1 M). Anhydrous DIPEA (12.1 mL, 68.16 mmol, 55 equivalents) was added. The reaction mixture was heated at 120 °C overnight. The reaction mixture was cooled to room temperature and quenched by adding water (100 mL). The solid was filtered off and washed with water (until the washings were colorless). The obtained solid was dissolved in ethyl acetate. This ethyl acetate layer was dried over Na2SO4 to remove trace amounts of water, filtered, and evaporated to obtain 650 mg of crude product. The crude product was purified by FC using 0-100% ACN in DCM to obtain 296 mg of semi-pure product. Trituration using MTBE and ACN was attempted to remove impurities (m / z=656; likely double-substituted Suzuki product), but was unsuccessful. Therefore, the semi-pure product was re-purified by RPFC using 5% to 95% ACN in water to obtain 250 mg (32% yield) of tert-butyl3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-{[(2R-1-methoxypropan-2-yl]amino}pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. LCMS:[C 30 H 35 [N9O3S], Desired mass = 601.2, Measured mass = 602.2 [M+H + ]. 1H NMR(300MHz,DMSO-d6):δ8.84(d,J=2.2Hz,1H),8.73-8.63(m,2H),8.49(s,1 H),8.24(s,1H),7.84(d,J=4.8Hz,1H),7.12(d,J=4.8Hz,1H),4.28(s,2H),4 .09-3.94(m,1H),3.74-3.62(m,2H),3.58-3.47(m,2H),3.39(s,1H),3.36(s ,4H),1.91(s,2H),1.76(d,J=7.5Hz,2H),1.44(s,9H),1.32(d,J=6.5Hz,3H).

[0354] Step 2: To a solution of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-{[(2R)-1-methoxypropan-2-yl]amino}pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (254 mg, 0.41 mmol, 1.0 equivalent) in anhydrous DCM (3.6 mL, 0.23 M), TFA (0.83 mL, 7.28 mmol, 20 equivalents) was added, and the resulting mixture was maintained at room temperature for 1 hour. Volatile substances were removed by evaporation. The crude product was triturated with Et2O (4 × 10 mL) to obtain 251 mg (98%) of 7-[5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazole-2-yl)-4-{[(2R)-1-methoxypropan-2-yl]amino}pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile (as TFA salt) as a pale yellow solid. LCMS:[C 25 H 27 N9OS], Desired mass = 501.2, Measured mass = 502.2 [M+H + ]. 1H NMR (300MHz, DMSO-d6): δ9.35(s,2H),9.25(s,1H),8.94(d,J=2.2Hz,1H),8.80(d,J=2.2Hz,1H),8.59(s,1H),8.12(s,1H),8.00(d,J=4.9Hz,1 H),7.20(d,J=4.9Hz,1H),4.23(s,3H),3.94-3.81(m,2H),3.69-3.51(m,4H),3.36(s,3H),1.98(dd,J=11.8,8.3Hz,4H),1.33(d,J=6.5Hz,3H).

[0355] Intermediate AR: 7-[4-(tert-butylamino)-5-[5-(piperazine 1-yl)-1,3,4-thiadiazole-2-yl]pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0356] [ka]

[0357] Step 1: Dimethyl sulfoxide (35.31 mL, 0.1 M) contains tert-butyl 4-[5-(4,6-dichloropyridine-3-yl)-1,3,4-thiadiazole-2- To a suspension of [yl]piperazine-1-carboxylate (1.5 g, 3.531 mmol), tert-butylamine (7.45 mL, 70.89 mmol) and N,N-diisopropylethylamine (29.0 mL, 166.487 mmol) were added. The reaction mixture was stirred at 110°C for 24 hours. After the reaction was complete, it was cooled to room temperature and quenched by adding ice. The formed precipitate was filtered off and dried under reduced pressure. The crude product was purified by silica gel flash chromatography using 0-100% RINKAN in hexane to obtain 810 mg (51% yield) of tert-butyl 4-{5-[4-(tert-butylamino)-6-chloropyridine-3-yl]-1,3,4-thiadiazole-2-yl}piperazine 1-carboxylate as a white solid. LCMS:[C 20 H 29[ClN6O2S], Desired mass = 452.2, Measured mass = 453.6 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ9.02 (s, 1H), 8.20 (s, 1H), 6.86 (s, 1H), 3.57-3.45 (m, 8H), 1.43 (d, J = 1.9Hz, 18H).

[0358] Step 2: Tert-butyl 4-{5-[4-(tert-butylamino)-6-chloropyridine-3-yl]-1,3,4-thiadiazole-2-yl}piperazine-1-carboxylate (0.88 g, 1.94 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.732 g, 2.72 mmol), tribasic potassium phosphate (0.825 g, 3.89 mmol), and XPhos Pd G3 (0.2 g, 0.236 mmol, 0.122 equivalents) were suspended in dimethoxyethane (27.8 mL, 0.07 M). The mixture was degassed with argon for 20 minutes and stirred overnight at 120°C. After the reaction was complete, it was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using 0-100% ACN in DCM to obtain 532.9 mg (49% yield) of tert-butyl 4-{5-[4-(tert-butylamino)-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridine-3-yl]-1,3,4-thiadiazole-2-yl}piperazine-1-carboxylate as a yellow solid. LCMS:[C 28 H 33 [N9O2S], desired mass 559.3, actual mass = 560.2 [M+H + ]. 1 H NMR(300MHz,DMSO-d6)δ8.84(d,J=2.4Hz,2H),8.76(d,J=2.3Hz,1H),8.56(s,1H),8.49(s,1H) ,7.85(d,J=4.8Hz,1H),7.12(d,J=4.9Hz,1H),3.53(d,J=6.5Hz,8H),1.55(s,9H),1.43(s,9H).

[0359] Step 3: To a solution of tert-butyl 4-{5-[4-(tert-butylamino)-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridine-3-yl]-1,3,4-thiadiazole-2-yl}piperazine-1-carboxylate (483 mg, 0.86 mmol) in anhydrous dichloromethane (8.6 mL, 0.1 M), trifluoroacetic acid (1.3 mL, 17.25 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was then evaporated to dryness. The residue was triturated with diethyl ether. The product was recovered by filtration to obtain 600 mg (100% yield) of 7-[4-tert-butylamino)-5-[5-(piperazin-1-yl)-1,3,4-thiadiazole-2-yl]pyridine2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile (bis-TFA salt) as a yellow solid. LCMS:[C 23 H 25 N9S], desired mass=459.2, measured mass=460.0[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ9.34(s,1H),9.04(s,2H),8.92(d,J=2.2Hz,1H),8.83(d,J=2.2Hz,1H),8.56(s,1H) ),8.51(s,1H),7.93(d,J=4.9Hz,1H),7.18(d,J=4.9Hz,1H),3.83-3.75(m,4H),3.31(s,4H),1.57(s,9H).

[0360] Intermediate AS: tert-butyl8-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(oxan-4-yl)amino]pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate.

[0361] [ka]

[0362] Step 1: To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.5 g, 2.36 mmol) and 2-bromo-1,3,4-thiadiazole (0.972 g, 5.89 mmol) in n-butanol (4.71 mL, 0.5 M), N,N-diisopropylethylamine (1.611 mL, 9.42 mmol) was added. The reaction mixture was stirred overnight at 120 °C. After the reaction was complete, it was cooled to room temperature. Volatiles were removed under vacuum, and the residue was transferred to a separatory funnel using a mixture of ELISA (20 mL) and H₂O (40 mL). The layers were separated, and the aqueous layer was extracted with ELISA (3 × 20 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. The obtained crude product was purified by silica gel flash chromatography eluting with 0-50% MeCN in DCM to obtain 271 mg (yield 39%) of tert-butyl 8-(1,3,4-thiadiazole-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as a red oil. LCMS:C 13 H 20 Theoretical value of N4O2S: 296.1, measured value: m / z = 296.9 [M+H] + . 1 H NMR(300MHz,chloroform-d)δ8.53(s,1H),4.29(d,J=25.9Hz,2H),3.85(dd,J=48.5,13.1Hz,2H),3 .31(dd,J=38.2,13.1Hz,2H),2.11(dt,J=6.7,3.8Hz,2H),1.90(d,J=17.8Hz,2H),1.43(s,9H).

[0363] Step 2: A suspension of 7-{5-bromo-4-[(oxan-4-yl)amino]pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.148 g, 0.37 mmol), tert-butyl 8-(1,3,4-thiadiazole-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.1 g, 0.34 mmol), copper(I) iodide (0.013 g, 0.067 mmol), xanthophos (0.039 g, 0.067 mmol), and cesium carbonate (0.44 g, 1.35 mmol) in anhydrous dioxane (11.25 mL, 0.03 M) was degassed with argon for 15 minutes, and palladium(II) acetate (8 mg, 0.034 mmol) was added. The pressure vessel was sealed and heated overnight at 105°C. After the reaction was complete, the volatiles were evaporated under vacuum. The residue was purified by silica gel flash chromatography, eluting with 0-100% MeCN in DCM followed by 0-10% IPA in DCM, to obtain a semi-pure product. This was further triturated with diethyl ether (4 × 10 mL) to obtain 80 mg (34% yield) of tert-butyl 8-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(oxan-4-yl)amino]pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as a bright yellow powder. LCMS:C 31 H 35 Theoretical value of N9O3S: 613.2, measured value: m / z = 614.1 [M+H] + . 1 1H NMR (300MHz, DMSO) -d6)δ8.85(d,J=2.3Hz,1H),8.78(d,J=2.3Hz,1H),8.67(d,J=7.0Hz,1H),8.52(s,1H),8.31(s,1H),7.85(d,J=4.8Hz,1H),7.13(d,J=4.8H) z,1H),4.35(s,2H),4.01-3.81(m,5H),3.61(s,3H),2.14(s,2H),2.03(s,2H),1.75(d,J=7.4Hz,3H),1.58(d,J=10.8Hz,3H),1.42(s,9H).

[0364] Step 3: To a solution of tert-butyl 8-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(oxan-4-yl)amino]pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.08 g, 0.12 mmol) in anhydrous dichloromethane (11.5 mL, 0.01 M), trifluoroacetic acid (0.785 g, 6.88 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the volatiles were evaporated under vacuum, and the residue was triturated with diethyl ether (4 × 10 mL). The residue was completely dried to obtain 47 mg (77% yield) of 7-[5-(5-{3,8-diazabicyclo[3.2.1]octan-8-yl}-1,3,4-thiadiazole-2-yl)-4-[(oxan-4-yl)amino]pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile as a yellow solid. LCMS:C 26 H 27 N9OS theoretical value: 513.2, measured value: m / z = 514.1 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ9.13(s,2H),8.92(d,J=2.2Hz,1H),8.83(d,J=2.2Hz,1H),8.59(s,1H),8.24(s,1H),7.94(d,J=4.9Hz,1H),7.18(d,J=4.9H) z,1H),4.50(s,3H),3.94(d,J=11.7Hz,4H),3.39(q,J=6.9Hz,4H),3.25( d,J=12.5Hz,3H),2.55(s,2H),2.18-2.05(m,4H),1.59(d,J=10.5Hz,3H).

[0365] Intermediate AT: 7-[5-(5-{3,9-diazabicyclo[3.3.1]nonane-3-yl}-1,3,4-thiadiazole-2-yl)-4-[(oxan-4-yl)amino]pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0366] [ka]

[0367] Step 1: To a solution of tert-butyl 3,9-diazabicyclo[3.3.1]nonane-9-carboxylate (0.55 g, 2.41 mmol) in n-butanol (4.82 mL, 0.5 M), 2-bromo-1,3,4-thiadiazole (1.00 g, 6.08 mmol) and DIPEA (1.66 mL, 9.72 mmol) were added. The reaction mixture was stirred at 120 °C for 2 hours. Volatiles were removed under vacuum, and the residue was transferred to a separatory funnel using a mixture of ethyl acetate (50 mL) and H2O (100 mL), and then extracted with ethyl acetate (5 × 50 mL). The combined organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with 0-70% MeCN in DCM to obtain 0.506 g (yield 67%) of tert-butyl 3-(1,3,4) -Thiadianazole-2-yl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate was obtained as a red oily substance. LCMS:C 13 H 20 Theoretical value of N4O3S: 310.2, measured value: m / z = 311.3 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ8.80(s,1H),4.18(d,J=12.3Hz,2H),3.81(dd,J=12.2,4.4Hz,2H),3.3 8(d,J=4.3Hz,2H),1.92(dt,J=11.8,5.7Hz,1H),1.84-1.61(m,4H),1.51(s,1H),1.44(m,9H).

[0368] Step 2: 7-{5-bromo-4-[(oxan-4-yl)amino]pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.208 g, 0.522 mmol), tert-butyl3-(1,3,4-thiadiazole-2-yl)-3,9-diazabicyclo[3.3.1] in anhydrous dioxane (15.83 mL, 0.03 M), A suspension of nonane-9-carboxylate (0.152 g, 0.475 mmol), CuI (0.018 g, 0.095 mmol), xanthophos (0.055 g, 0.095 mmol), and Cs2CO3 (0.619 g, 1.9 mmol) was degassed with argon for 15 minutes, and Pd(OAc)2 (0.011 g, 0.047 mmol, 0.1 equivalent) was added. The reaction mixture was stirred in an MW reactor at 130°C for 2 hours. Since the reaction was incomplete, additional xanthophos (0.055 g, 0.095 mmol), Cs2CO3 (0.619 g, 1.9 mmol), CuI (0.018 g, 0.095 mmol), and Pd(OAc)2 (0.011 g, 0.047 mmol) were added, and the reaction mixture was degassed by a vacuum / argon cycle. The reaction mixture was heated further at 130°C for 2 hours while being irradiated with MW. After the reaction was complete, the reaction mixture was cooled to room temperature, and volatiles were evaporated in a vacuum. The crude product was purified by silica gel flash chromatography, eluting with 0-100% ACN in DCM followed by 0-10% IPA in DCM, to obtain 0.056 g (19% yield) of tert-butyl3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(oxan-4-yl)amino]pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate as a yellow solid. LCMS:C 32 H 37 Theoretical value of N9O3S: 627.3, measured value: m / z = 628.2 [M+H] + . 1H NMR(300MHz,DMSO-d6)δ8.85(d,J=2.3Hz,1H),8.77(d,J=2.3Hz,1H),8.71(d,J=7.1Hz, 1H),8.52(s,1H),8.29(s,1H),7.85(d,J=4.8Hz,1H),7.13(d,J=4.8Hz,1H),4.23(d,J=1 2.6Hz,2H),3.98-3.81(m,5H),3.61(t,J=10.7Hz,2H),3.48(d,J=10.5Hz,2H),2.12(d,J =13.4Hz,2H),1.97(s,1H),1.76(d,J=25.0Hz,4H),1.58(d,J=11.3Hz,3H),1.45(s,9H).

[0369] Step 3: To a solution of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(oxan-4-yl)amino]pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate (0.056 g, 0.09 mmol) in DCM (0.9 mL, 0.1 M), a solution of 4 M HCl in dioxane (0.707 mL, 2.83 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. After completion, the solid residue from the reaction mixture was filtered off and washed with DCM. The solid was recovered and dried under vacuum to obtain 0.038 g (75% yield) of 7-[5-(5-{3,9-diazabicyclo[3.3.1]nonane-3-yl}-1,3,4-thiadiazole-2-yl)-4-[(oxan-4-yl)amino]pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitrile (2×HCl salt) as a yellow solid. LCMS:C 27 H 29 N9OS theoretical value: 527.2, measured value: m / z = 528.2 [M+H] + , 1 H NMR (300MHz, DMSO-d). d6)δ9.68-9.32(m,3H),8.98(d,J=2.3Hz,1H ),8.87(d,J=2.2Hz,1H),8.57(s,1H),8.16(s,1H),8.10(s,1H),7.23(d,J=5.0Hz,1H),4.11(d,J=13.1H) z,3H),3.88(dd,J=33.2,15.8Hz,6H),3.61(t,J=10.8Hz,3H),2.17-1.94(m,6H),1.62(d,J=11.5Hz,4H).

[0370] Intermediate AU:7-(4-{[(1R-1-cyanoethyl]amino}-5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazole-2-yl)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0371] [ka]

[0372] Step 1: Tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-fluoropyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.5 g, 0.94 mmol, 1.0 equivalent) was dissolved in dimethyl sulfoxide anhydride (9.39 mL, 0.1 M). D-alaninamide hydrochloride (1.169 g, 9.4 mmol, 10.0 equivalents) and sodium bicarbonate (1.183 g, 14.08 mmol, 15.0 equivalents) were added. The resulting mixture was stirred at 120°C for 1 hour. After the reaction was complete, it was cooled to room temperature and injected directly into the column. Purification was performed using water in 0-60% ACN as the mobile phase to obtain 0.3 g (53% yield) of tert-butyl 3-[5-(4-{[(1R-1-carbamoylethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. LCMS:[C 29 H 32 N 10O3S], desired mass=600.7, measured mass=601.2[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ8.90-8.81(m,2H),8.64(d,J=2.3Hz,1H),8.51(s,1H),8.12(s,1H),7.83(d,J=4.8Hz,1H),7.79(s,1H),7.23(s,1H),7.1 3(d,J=4.8Hz,1H),4.38-4.19(m,3H),3.79-3.63(m,2H),3.44-3.35(m, 2H), 1.93 (s, 2H), 1.86-1.69 (m, 3H), 1.50 (d, J=6.8Hz, 3H), 1.45 (s, 9H).

[0373] Step 2: tert-butyl3-[5-(4-{[(1R-1-carbamoylethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridine-3- [0.3 g, 0.499 mmol, 1.0 equivalent]-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was suspended in dichloromethane anhydride (9.99 mL, 0.05 M), followed by the addition of pyridine anhydride (0.322 mL, 3.995 mmol, 8.0 equivalents). Trifluoroacetic anhydride (0.315 g, 1.498 mmol, 3.0 equivalents) was added to the resulting suspension, and the reaction mixture was stirred at room temperature for 30 minutes. The formation of a clear solution was observed. The reaction mixture was then concentrated under vacuum, dissolved in the minimum amount of DCM, and injected into a column. The crude product was purified by flash chromatography using 0-10% DCM-IPA as the mobile phase to obtain 0.182 g (62% yield) of tert-butyl3-[5-(4-{[(1R-1-cyanoethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. LCMS:[C 29 H 30 N 10 O2S], desired mass=582.6, measured mass=583.8[M+H] + .1 H NMR(300MHz,DMSO-d6)δ8.87(d,J=2.3Hz,1H),8.84(d,J=6.9Hz,1H),8.68(d,J=2.3Hz,1H),8.63(s,1H),8.36(s,1H),7.88(d,J=4.8Hz,1H),7.15 (d,J=4.8Hz,1H),5.11-4.97(m,1H),4.40-4.22(m,2H),3.76-3.64(m,2H ),3.42-3.37(m,2H),2.04-1.86(m,2H),1.84-1.69(m,5H),1.44(s,9H).

[0374] Step 3: tert-butyl 3-[5-(4-{[(1R)-1-cyanoethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.182 g, 0.312 mmol, 1.0 equivalent) was dissolved in anhydrous DCM (6.25 mL, 0.05 M). TFA (0.712 g, 6.247 mmol, 20.0 equivalents) was added to this. The resulting mixture was stirred at room temperature for 4 hours. After the reaction was complete, it was concentrated under vacuum. The residue was triturated and sonicated with diethyl ether to obtain a yellow precipitate, which was collected by filtration and dried overnight in vacuum to obtain 0.288 g (92% yield) of 7-(4-{[(1R-1-cyanoethyl]amino}-5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazole-2-yl)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile as a yellow solid. LCMS:[C 28 H 24 F6N 10 [O4S], Desired mass = 482.5, Measured mass = 483.8 [M+H] + . 1H NMR(300MHz,DMSO-d6)δ9.13(s,1H),9.05(s,1H),8.89(d,J=2.2Hz,1H),8.84 (d,J=6.9Hz,1H),8.70(d,J=2.3Hz,1H),8.67(s,1H),8.37(s,1H),7.90(d,J= 4.8Hz,1H),7.17(d,J=4.8Hz,1H),5.08(p,J=6.8Hz,1H),4.28-4.19(m,2H),3 .92-3.83(m,2H),3.64-3.58(m,2H),2.12-1.93(m,4H),1.78(d,J=6.9Hz,3H).

[0375] Intermediate AV: 7-(5-(5-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazole-2-yl)-4-(isoxazole-4-ylamino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0376] [ka]

[0377] Step 1: To a solution of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-fluoropyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.94 mmol) in AcOH (9.5 mL, 0.1 M), 1,2-oxazole-4-amine (789 mg, 9.4 mmol) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the acetic acid was evaporated, and the residue was partitioned between saturated NaHCO3 (50 mL) and DCM (100 mL). The layers were separated, and the aqueous layer was further washed with DCM (2 × 100 mL). The combined organic layers were washed with brine (1 × 100 mL). The DCM layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 900 mg of crude product. The crude product was combined with the trial reaction and purified by silica gel flash chromatography using 0-10% IPA in DCM to obtain 600 mg of semi-pure product. The RPFC was then re-purified using ACN / water containing 0.1% FA, and then washed from the column with 95% THF, 0.1% TFA, and 4.9% water to obtain 305 mg (54% yield) of tert-butyl3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isoxazole-4-ylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a pale yellow solid. LCMS: [C29H28N10O3S], desired mass = 596.2, measured mass = 597.1 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ10.12(s,1H),9.28(s,1H),9.02(s,1H),8.70-8.63(m,2H),8.41(s,1H),8.19(d,J=5.8Hz,1H),7.87(d,J=4.8Hz,1H), 7.13(d,J=4.9Hz,1H),4.31(s,2H),3.71(d,J=11.6Hz,2H),3.41(d,J=11.1Hz,2H),1.89(d,J=24.9Hz,2H),1.77(d,J=7.5Hz,2H),1.45(s,9H).

[0378] Step 2: To a solution of tert-butyl 3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isoxazole-4-ylamino)pyridine-3-yl)-1,3,4-thiadiazole-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (305 mg, 0.511 mmol) in anhydrous DCM (3.8 mL, 0.2 M), TFA (1.72 g, 15.11 mmol) was added, and the resulting mixture was maintained at room temperature for 1 hour. Volatile substances were removed by evaporation. The crude product was triturated with Et2O (4 × 10 mL) to obtain 315 mg (100% yield) of 7-(5-(5-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazole-2-yl)-4-(isoxazole-4-ylamino)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile as a pale yellow solid. LCMS: [C24H20N10OS], desired mass = 496.15, measured mass = 497.2 [M + H] + . 1 H NMR(300MHz,DMSO-d6)δ10.12(s,1H),9.29(s,3H),9.01(s,1H),8.85(d,J=2.2H z,1H),8.69(d,J=1.6Hz,2H),8.38(s,1H),7.87(d,J=4.9Hz,1H),7.13(d,J=4.8Hz, 1H),4.24(s,2H),3.88(d,J=12.7Hz,2H),3.63(d,J=12.8Hz,2H),2.09-1.92(m,4H).

[0379] Intermediate AW: 7-(4-{[(1S)-1-cyanoethyl]amino}-5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazole-2-yl)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0380] [ka]

[0381] Step 1: To a solution of tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-fluoropyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.471 mg, 0.88 mmol) in N-methylpyrrolidone (5.9 mL, 0.15 M), L-alaninamide hydrochloride (0.33 g, 2.65 mmol) and N,N-diisopropylethylamine (0.79 mL, 4.42 mmol) were added at room temperature. The reaction mixture was stirred overnight at 120 °C. After the reaction was complete, the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0-6% MeOH in DCM to obtain 0.332 g (62% yield) of tert-butyl 3-[5-(4-{[(1S-1-carbamoylethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow gum. LCMS:[C 29 H 32 N 10 O3S], desired mass=600.2, measured mass=601.3[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ8.85(q,J=2.3,1.6Hz,2H),8.63(d,J=2.2Hz,1H),8.5 1(s,1H),8.11(s,1H),7.82(d,J=4.8Hz,1H),7.76(s,1H),7.22(s,1H),7.12(d ,J=4.8Hz,1H),4.27(d,J=7.1Hz,3H),3.70(d,J=11.8Hz,2H),3.37(d,J=11.8H z,3H),1.91(s,2H),1.76(d,J=7.4Hz,2H),1.50(d,J=6.7Hz,3H),1.44(s,9H).

[0382] Step 2: To an ice-cold solution of tert-butyl 3-[5-(4-{[(1S)-1-carbamoylethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (332 mg, 0.55 mmol) in anhydrous dichloromethane (42.5 mL, 0.01 M), trifluoroacetic anhydride (0.23 mL, 1.66 mmol) and pyridine anhydride (0.36 mL, 4.42 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0-5% MeOH in DCM to obtain 0.195 g (63% yield) of tert-butyl3-[5-(4-{[(1S-1-cyanoethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridine-3-yl)-1,3,4-thiadiazole-2-yl ]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was obtained as a yellow solid. LCMS:[C 29 H 30 N 10 O2S], desired mass=582.2, measured mass=583.1[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ8.91-8.79(m,2H),8.68(d,J=2.3Hz,1H),8.63(s,1H),8.37(s,1H),7.88(d,J=4.8Hz,1H),7.15(d,J=4.9Hz,1H), 5.04(t,J=6.8Hz,1H),4.29(s,2H),3.70(d,J=11.8Hz,2H),3.39(d,J=11.7Hz,2H),1.98-1.89(m,2H),1.77(t,J=6.7Hz,5H),1.45(s,9H).

[0383] Step 3: Trifluoroacetic acid (0.54 mL, 7.00 mmol) was added to a solution of tert-butyl 3-[5-(4-{[(1S-1-cyanoethyl]amino}-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.195 g, 0.35 mmol) in anhydrous dichloromethane (1.75 mL, 0.2 M) at room temperature. The reaction mixture was then heated to room temperature. The mixture was stirred at warm temperature for 1 hour. After the reaction was complete, the solvent was removed under reduced pressure. The residue was purified by trituration with diethyl ether (3 × 20 mL) to obtain 227.8 mg (96% yield) of 7-(4-{[(1S)-1-cyanoethyl]amino}-5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazole-2-yl)pyridine-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile as a yellow solid. LCMS:[C 24 H 22 N 10 S], desired mass=482.2, measured mass=483.0[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ9.19-9.07(m,1H),9.10-8.98(m,1H),8.89(d,J=2.3Hz,1 H),8.86(d,J=8.1Hz,1H),8.70(d,J=2.3Hz,1H),8.67(s,1H),8.35(s,1H),7.90(d ,J=4.7Hz,1H),7.16(d,J=4.9Hz,1H),5.08(t,J=6.9Hz,1H),4.22(s,2H),3.87(d ,J=13.1Hz,2H),3.60(d,J=12.7Hz,2H),2.04-1.92(m,4H),1.77(d,J=6.9Hz,3H).

[0384] Intermediate AX: 7-{4-[(1-cyano-1-methylethyl)amino]-5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazole-2-yl)pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0385] [ka]

[0386] Step 1: Dissolve tert-butyl 3-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-fluoropyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.5 g, 0.939 mmol, 1.0 equivalent) in dimethyl sulfoxide anhydride (9.39 mL, 0.1 M), then add 2-amino-2-methylpropanamide hydrochloride (1.301 g, 9.388 mmol, 10.0 equivalents) and sodium bicarbonate (1.183 g, 14.082 mmol, 15.0 equivalents), and stir the resulting mixture overnight at 120°C. DMSO was removed under vacuum, and the residue was mixed with water. The resulting precipitate was collected by filtration and dried under vacuum to obtain 0.6 g (59% yield) of crude tert-butyl3-(5-{4-[(1-carbamoyl-1-methylethyl)amino]-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridine-3-yl}-1,3,4-thiadiazole-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. LCMS:[C 30 H 34 N 10 O3S], desired mass=614.7, measured mass=615.8[M+H] + .

[0387] Step 2: Crude tert-butyl 3-(5-{4-[(1-carbamoyl-1-methylethyl)amino]-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridine-3-yl}-1,3,4-thiadiazole-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.6 g, 0.56 mmol, 1.0 equivalent) was suspended in anhydrous dichloromethane (11.13 mL, 0.05 M), followed by the addition of anhydrous pyridine (0.359 mL, 4.451 mmol, 8.0 equivalents). Anhydrous trifluoroacetic acid (0.351 g, 1.67 mmol, 3.0 equivalents) was added to the resulting suspension, and the reaction mixture was stirred at room temperature for 30 minutes. Next, the reaction mixture was concentrated under vacuum and dissolved in a minimum amount of DCM. Two FC purifications were performed using 0-7% DCM-IPA as the mobile phase, followed by 0-30% DCM-ACN as the mobile phase, to obtain 0.31 g (93% yield) of tert-butyl3-(5-{4-[(1-cyano-1-methylethyl)amino]-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridine-3-yl}-1,3,4-thiadiazole-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. LCMS:[C 30 H 32 N 10 O2S], desired mass=596.7, measured mass=597.9[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.88(d,J=2.2Hz,1H),8.71(d,J=2.2Hz,1H),8.69(s,1H),8.65(s,1H),7.90(d,J=4.8Hz,1H), 7.16(d,J=4.8Hz,1H),4.29(s,2H),3.71(d,J=11.9Hz,2H),3.39(d,J=11.3Hz,2H),1.92(s,6H),1.75(d,J=7.4Hz,4H),1.45(s,9H).

[0388] Step 3: tert-butyl 3-(5-{4-[(1-cyano-1-methylethyl)amino]-6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}pyridine-3-yl}-1,3,4-thiadiazole-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.31 g, 0.52 mmol, 1.0 equivalent) was dissolved in anhydrous DCM (5.2 mL, 0.1 M), followed by TFA (1.185 g, 10.39 mmol, 20.0 equivalents). The resulting mixture was stirred at room temperature for 4 hours and then concentrated under vacuum. The residue was triturated and sonicated with diethyl ether to obtain a yellow precipitate, which was collected by filtration and dried overnight in vacuum to obtain 0.255 g (76% yield) of 7-{4-[(1-cyano-1-methylethyl)amino]-5-(5-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,3,4-thiadiazole-2-yl)pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile as a yellow solid. LCMS:[C 25 H 24 N 10 S], desired mass=496.6, measured mass=497.8[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.27-9.09(m,2H),9.08(s,1H),8.90(d,J=2.2Hz,1H),8.73(d,J=2.2Hz,1H),8.70(s,1H),8.69(s,1H),7.9 1(d,J=4.8Hz,1H),7.17(d,J=4.8Hz,1H),4.25-4.18(m,2H),3.93-3.80(m,2H),3.67-3.57(m,2H),2.07-1.95(m,4H),1.93(s,6H).

[0389] Intermediate AY:7-[5-(5-{3-oxa-7,9-diazabicyclo[3.3.1] Nonane-7-yl)-1,3,4-thiadiazole-2-yl)-4-[(oxan-4-yl)amino]pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitride; 2×trifluoroacetate

[0390] [ka]

[0391] Step 1: To a solution of tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (0.55 g, 2.41 mmol) in n-butanol (4.82 mL, 0.5 M), 2-bromo-1,3,4-thiadiazole (0.99 g, 6.02 mmol) and DIPEA (1.65 mL, 9.64 mmol) were added. The reaction mixture was stirred at 120 °C for 1 hour. Volatiles were removed under vacuum, and the residue was transferred to a separatory funnel using a mixture of ethyl acetate (50 mL) and H₂O (100 mL), and then extracted with ethyl acetate (5 × 50 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel flash chromatography using 0-80% ACN in DCM to obtain 0.467 g (62% yield) of tert-butyl 7-(1,3,4-thiadiazole-2-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate as a red solid. LCMS:C 13 H 20 Theoretical value of N4O3S: 312.4, measured value: m / z = 313.0 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ8.75(s,1H),4.01(d,J=9.6Hz,2H),3.97-3.84(m,4H),3.62(dt,J=11.5,2.5Hz,2H),3.44(d,J=12.9Hz,2H),1.44(s,9H).

[0392] Step 2: To a suspension of 7-{5-bromo-4-[(oxan-4-yl)amino]pyridine-2-yl}pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.42 g, 1.06 mmol) in dioxane (32.0 mL, 0.03 M), tert-butyl 7-(1,3,4-thiadiazole-2-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (0.312 g, 0.959 mmol), CuI (0.037 g, 0.19 mmol), xanthophos (0.111 g, 0.19 mmol), and Cs2CO3 (1.25 g, 3.84 mmol) were added. The reaction mixture was degassed with argon for 15 minutes, and then Pd(OAc)2 (0.022 g, 0.096 mmol) was added. The reaction mixture was stirred at 130°C for 2 hours using microwave heating. Next, it was cooled to room temperature, and additional xanthophos (0.111 g, 0.19 mmol), Cs2CO3 (1.25 g, 3.84 mmol), CuI (0.037 g, 0.19 mmol), and Pd(OAc)2 (0.022 g, 0.096 mmol) were added. The mixture was stirred at 130°C for a further 2 hours using microwave heating. The volatiles were evaporated under vacuum. The residue was purified by silica gel flash chromatography eluted with 0-100% MeCN in DCM. The resulting semi-pure product was re-purified by reverse-phase flash chromatography using MeCN in water (5-75% MeCN) to obtain 0.09 g (15% yield) of tert-butyl7-[5-(6-{3-cyanopyrrolo[1,2-b]pyridadyl [(oxan-4-yl)amino]pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate was obtained as a yellow solid. LCMS:C 31 H 35 Theoretical value of N9O4S: 629.7, measured value: m / z = 630.2 [M+H] + . 1H NMR(300MHz,DMSO-d6)δ8.85(d,J=2.3Hz,1H),8.77(d,J=2.3Hz,1H),8.70(s,1H),8.51(s,1H),8.29(s,1H),7.84(d,J=4.8Hz, 1H),7.13(d,J=4.8Hz,1H),4.13-3.75(m,11H),3.60(dt,J=20.0,10.5Hz,8H),2.12(d,J=15.5Hz,3H),1.58(d,J=10.0Hz,3H).

[0393] Step 3: Trifluoroacetic acid (0.978 g, 8.58 mmol) was added to a solution of tert-butyl 7-[5-(6-{3-cyanopyrrolo[1,2-b]pyridazin-7-yl}-4-[(oxan-4-yl)amino]pyridine-3-yl)-1,3,4-thiadiazole-2-yl]-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (0.09 g, 0.143 mmol) in DCM (14.3 mL, 0.01 M). The reaction mixture was stirred overnight at room temperature. Volatile substances were removed under vacuum. The obtained crude product was triturated with Et2O (4 × 20 mL) and dried to obtain 0.08 g (83% yield) of 7-[5-(5-{3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-yl}-1,3,4-thiadiazole-2-yl)-4-[(oxan-4-yl)amino]pyridine-2-yl]pyrrolo[1,2-b]pyridazine-3-carbonitride;2x trifluoroacetate as a yellow solid. LCMS:C 26 H 27 Theoretical value of N9O2S: 529.2, measured value: m / z = 530.3 [M+H] + , Method: LCMS2-036-5-80-80-7-1-25-UV-Rot, RT=2.81 min, Purity: 95.71% (254 nm). 1H NMR(300MHz,DMSO-d6)δ8.99(d,J=2.2Hz,1H),8.87(d,J=2.2Hz,1H),8.62(s,1H),8.14-8.04(m,2H),7.25(d,J=5.0Hz,1H),4.32(d,J=13 .9Hz,2H),4.12(d,J=12.5Hz,3H),4.03-3.83(m,6H),3.67-3.54(m,2H),2.57(d,J=5.5Hz,4H),2.10(t,J=6.8Hz,2H),1.72-1.57(m,2H).

[0394] B.LHM component synthesis HA-1: 1-(5-(2,6-dioxopiperidine-3-yl)pyridine-2-yl)piperidine-4-carbaldehyde

[0395] [ka]

[0396] Step 1: Under an inert nitrogen atmosphere, 2,6-dichloropyridine (150.00 g, 1013.58 mmol, 1.00 equivalent), dimethylformamide (3 L), and NaH (272.00 g, 11334 mmol, 11.18 equivalents, 65%) were added to a 5 L four-necked round-bottom flask. Subsequently, BnOH (329.50 g, 3050 mmol, 3.01 equivalents) was added dropwise while stirring at 0°C. The resulting solution was stirred at 80°C for 4 hours. The reaction mixture was cooled. The reaction was then quenched by adding 7 L of water / ice. The solid was recovered by filtration and concentrated. This yielded 276 g (93.46%) of 2,6-bis(benzyloxy)pyridine as a gray solid. LCMS:(ES,m / z):[M+1] + =292;T=1.48 minutes.

[0397] Step 2: Under an inert atmosphere of nitrogen gas, 2,6-bis(benzyloxy)pyridine (276.00 g, 947.3 mmol, 1.00 equivalent), CH3CN (2.76 L), and K2CO3 (445.00 g, 3196.54 mmol, 3.37 equivalents) were added to a 3 L four-necked round-bottom flask. Subsequently, Br2 (151.70 g, 949.26 mmol, 1.00 equivalent) was added dropwise at 0°C. The resulting solution was stirred at room temperature for 4 hours. The resulting reaction mixture was concentrated. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (10%). This yielded 253 g (72.13%) of 2,6-bis(benzyloxy)-3-bromopyridine as a white solid. LCMS: [M+1] + =370.

[0398] Step 3: In a 3 L four-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere, 2,6-bis(benzyloxy)-3-bromopyridine (253.00 g, 683.32 mmol, 1.00 equivalent), dioxane (2.53 L), bis(pinacolato)diboron (261.00 g, 1027.80 mmol, 1.50 equivalent), potassium acetate (134.00 g, 1365.36 mmol, 2.00 equivalent), and Pd(dppf)Cl2 (25.10 g, 34.29 mmol, 0.05 equivalent) were added. The resulting solution was stirred overnight at 100°C. The reaction mixture was cooled. The resulting mixture was concentrated and loaded onto a silica gel column using ethyl acetate / petroleum ether (15%). This yielded 200 g (70.14%) of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as a white solid.

[0399] Step 4: In a 3 L four-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere, 2-fluoro-5-iodopyridine (200.00 g, 896.90 mmol, 1.00 equivalent), DMSO (2.00 L), piperidine-4-ylmethanol (128.90 g, 1119.15 mmol, 1.25 equivalent), and DIEA (347.00 g, 2684.86 mmol, 3.00 equivalent) were added. The resulting solution was stirred at 90°C for 3 days. The reaction mixture was cooled. 2 × 2 L of EA was added to the resulting mixture, and the organic layers were combined. The resulting mixture was washed with 3 × 2 L of brine. The resulting mixture was concentrated. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (35%). This yielded 182 g (63.78%) of [1-(5-iodopyridine-2-yl)piperidine-4-yl]methanol as a yellow oily substance. LCMS:[M+1] + =319.

[0400] Step 5: In a 3L four-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere, add [1-(5-iodopyridine-2-yl)piperidine-4-yl]methanol (182.00g, 572.04 mmol, 1.00 equivalent), tetrahydrofuran (1.82L), water (364.00mL), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (298.40g, 715.05 mmol, 1.25 equivalent), K2CO3 (157.90g, 1134.23 mmol, 1.98 equivalent), tetrakis(triphenylphosphine)palladium (0) (66. (00g, 57.11 mmol, 0.10 equivalents) was added. The resulting solution was stirred overnight at 90°C. The reaction mixture was cooled. The resulting mixture was extracted with 2 × 3 L of EA, and the organic layer was washed with 3 × 3 L of brine. The combined organic layers were concentrated. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (85%). This yielded 140 g (50.82%) of [1-[2',6'-bis(benzyloxy)-[3,3'-bipyridine]-6-yl]piperidine-4-yl]methanol as a green solid. LCMS:[M+1] + =482;

[0401] Step 6: In a 2 L round-bottom flask, [1-[2',6'-bis(benzyloxy)-[3,3'-bipyridine]-6-yl]piperidine-4-yl]methanol (35.00 g, 72.67 mmol, 1.00 equivalent), tetrahydrofuran (120 mL), and Pd / C (10.00 g, 10%) were added. The resulting solution was stirred overnight under a hydrogen atmosphere (4 atm). Then, the Pd / C was filtered off, followed by the addition of another 10 g of Pd / C (10%), and the mixture was stirred again overnight. The filtration / addition procedure was repeated three times. The solid was filtered off. The resulting filtrate was concentrated and washed with 3 × 100 mL of EA. This yielded 64 g of crude product. 8 g of the crude product was used directly in the next step, and the remaining 56 g of the crude product was further purified by flash chromatography. This yielded 45 g of 6'-[4-(hydroxymethyl)piperidine-1-yl]-1,3-dihydro-[3,3'-bipyridine]-2,6-dione as a yellow solid.

[0402] LCMS:[M+1] + =304. 1 H-NMR:(300MHZ,DMSO-d6,ppm):δ10.79(s,1H),7.93(d,J=2.3Hz,1H),7.35(dd,J=8.8,2.5Hz,1 H),6.79(d,J=8.8Hz,1H),4.45(t,J=5.1Hz,1H),4.27(d,J=12.9Hz,2H),3.72(dd,J=12.0,4.9Hz ,1H),3.27(t,J=5.1Hz,2H),2.82-2.59(m,3H),2.58-2.43(m,1H),2.17(qd,J=12.5,4.4Hz,1H), 1.98(dq,J=8.5,4.7Hz,1H),1.71(d,J=13.3Hz,2H),1.60(br,1H),1.11(qd,J=11.9,3.8Hz,2H).

[0403] Step 7: In a 1 L three-necked round-bottom flask under a nitrogen atmosphere, 3-[6-[4-(hydroxymethyl)piperidine-1-yl]pyridine-3-yl]piperidine-2,6-dione (8.00 g, 26.37 mmol, 1.00 equivalent) and DCM (400.00 mL) were added. Subsequently, Des-Martin periodinane (12.30 g, 31.59 mmol, 1.20 equivalent) was added at 0°C. The resulting solution was stirred at 0°C for 2 hours. The reaction mixture was filtered, the filtrate was washed with brine (200 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel column using DCM / EA (3:2). The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (15%). This yielded 5 g (62.92%) of 1-[5-(2,6-dioxopiperidine-3-yl)pyridine-2-yl]piperidine-4-carbaldehyde (HA-1) as a gray solid. LCMS:(ES,m / z):[M+1] + =302. 1 H-NMR:(300MHZ,DMSO-d6,ppm):δ10.80(s,1H),9.62(s,1H),7.95(d,J=2.5Hz,1H),7.3 9(dd,J=8.9,2.5Hz,1H),6.83(d,J=8.8Hz,1H),4.12(dd,J=13.1,4.2Hz,2H),3.73(dd, J=12.0,4.9Hz,1H),3.10-2.95(m,2H),2.64(tdd,J=24.6,11.1,4.8Hz,2H),2.18(qd,J =12.4,4.4Hz,1H),2.03-1.93(m,1H),1.89(dd,J=13.2,3.6Hz,3H),1.57-1.39(m,2H).

[0404] HA-2:rac-(R)-3-(6-(piperidine-4-yl)pyridine-3-yl ) piperidine-2,6-dione

[0405] [ka]

[0406] Step 1: To a mixture of 1,4-dioxane (100 mL) and 2,5-dibromopyridine (10 g, 42.21 mmol, 1 equivalent), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (14.36 g, 46.43 mmol, 1.10 equivalents), Na2CO3 (6.71 g, 63.32 mmol, 1.5 equivalents), and Pd(PPh3)4 (1.46 g, 1.27 mmol, 0.03 equivalents) in H2O (10 mL) were added. The resulting mixture was stirred overnight at 100°C under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA(2 / 1) to obtain tert-butyl 5-bromo-3',6'-dihydro-2'H-[2,4'-bipyridine]-1'-carboxylate (10 g, 69.83%) as a yellow solid. LCMS(ESI)(C 15 H 21 BrN2O2)[M+1] + Calculated value: 339.1; Measured value: 339.1.

[0407] Step 2: To a mixture of tert-butyl 4-(5-bromopyridine-2-yl)piperidine-1-carboxylate (1 g, 2.93 mmol, 1 equivalent) in THF (9 mL), 2,6-bis(benzyloxy)pyridine-3-ylboric acid (1.18 g, 3.52 mmol, 1.2 equivalents), K2CO3 (0.81 g, 5.86 mmol, 2 equivalents), and Pd(PPh3)4 (0.34 g, 0.29 mmol, 0.1 equivalent) in H2O (3 mL) were added. The resulting mixture was stirred overnight at 110°C under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA(5 / 1) to obtain tert-butyl 5-[2,6-bis(benzyloxy)pyridine-3-yl]-3',6'-dihydro-2'H-[2,4'-bipyridine]-1'-carboxylate (1.3 g, 80.71%) as a white solid. LCMS(ESI)(C 34 H 35 N3O4)[M+1] +Calculated value: 550.3; Measured value: 550.3.

[0408] Step 3: Pd / C (1 g) was added to a mixture of tert-butyl 5-[2,6-bis(benzyloxy)pyridine-3-yl]-3',6'-dihydro-2'H-[2,4'-bipyridine]-1'-carboxylate (1.3 g, 2.37 mmol, 1 equivalent) in THF (15 mL). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The reaction mixture was filtered and then concentrated under reduced pressure. The resulting residue was purified by C18 reversed-phase column chromatography using CH3CN / H2O (1 / 1) to obtain tert-butyl 4-[5-(2,6-dioxopiperidine-3-yl)pyridine-2-yl]piperidine-1- Carboxylate (0.35 g, 39.63%) was obtained as a brown solid. LC-MS(ESI)(C 20 H 27 N3O4)[M+1] + Calculated value: 374.2; Measured value: 374.0.

[0409] Step 4: A mixture of tert-butyl 4-[5-(2,6-dioxopiperidine-3-yl)pyridine-2-yl]piperidine-1-carboxylate (350 mg, 0.94 mmol, 1 equivalent) in HCl / dioxane (15 mL, 4 M) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. This yielded rac-(3R)-3-[6-(piperidine-4-yl)pyridine-3-yl]piperidine-2,6-dione hydrochloride (HA-2) (290 mg, 99.88%) as a pink solid. LCMS(ESI)(C 15 H 19 N3O2)[M+1] + Calculated value: 274.2; Measured value: 274.1. 1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),9.19(s,1H),9.09(s,1H),8.68-8.63(m,1 H),8.22-8.15(m,1H),7.73-7.66(m,1H),4.20-4.12(m,1H),3.44-3.36(m,2H), 3.32(s,1H),3.09-3.02(m,1H),3.02-2.96(m,1H),2.80-2.67(m,1H),2.64-2.5 5(m,1H),2.43-2.27(m,1H),2.18-2.11(m,2H),2.06(s,2H),2.11-1.96(m,1H).

[0410] HA-3: 1-(4-(2,6-dioxopiperidine-3-yl)-2-fluorophenyl)piperidine-4-carboaldehyde

[0411] [ka]

[0412] Step 1: To a solution of 2-fluoro-4-bromoiodobenzene (42.1 g, 365 mmol, 1.10 equivalents) and piperidine-4-ylmethanol (100 g, 332 mmol, 1.00 equivalent) in DMSO (1000 mL), L-proline (17.4 g, 132 mmol, 0.400 equivalents), K2CO3 (91.8 g, 664 mmol, 2.00 equivalents), and CuI (12.6 g, 66.4 mmol, 0.200 equivalents) were added under N2 conditions. The reaction mixture was stirred at 90°C for 12 hours. The reaction mixture was cooled to 20°C and poured into a saturated NH4Cl solution (1000 mL). The product was then sterilized with ethyl acetate (1000 mL). * 3) The combined organic layers were extracted, washed with brine (1000 mL), dried over Na2SO4, filtered, and concentrated. The residue was subjected to column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1, R f The solution was purified by (=0.55). The desired product (10.7 g, 35.6 mmol, yield 10.7%) was obtained as a yellow solid. LC-MS: m / z = 290.0 (M + H) + .

[0413] Step 2: Dioxane (116 mL) and H2O (23 mL) containing (1-(4-bromo-2-fluorophenyl)piperidine-4-yl)methanol (11.6 g, 38.6 mmol, 1.00 equivalent), 2,6-bis(benzyloxy)-3-(4,4,5-trimethicone) To a solution of 17.7 g, 42.4 mmol, 1.10 equivalents of ru-1,3,2-dioxaborolan-2-yl)pyridine and 16.0 g, 115 mmol, 3.00 equivalents of K2CO3, Pd(dppf)Cl2·CH2Cl2 (3.15 g, 3.86 mmol, 0.100 equivalents) was added under N2 conditions. The reaction mixture was then stirred at 110°C for 12 hours. The mixture was cooled to 25°C. The reaction mixture was then poured into H2O (300 mL) and extracted with siRNA (200 mL). * 3) The organic layer was washed with brine (200 mL), dried over Na2SO4, and concentrated. The crude product was converted to MPLC (SiO2, petroleum ether / ethyl acetate = 100 / 1~5 / 1) (petroleum ether / ethyl acetate = 1 / 1, R f The compound was purified using LCMS (=0.5). Compound 11 (10.7g, 20.5 mmol, yield 53.2%) was obtained as a pale yellow solid. LCMS: m / z = 499.4 (M + H) + .

[0414] Step 3: To a solution of (1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)-2-fluorophenyl)piperidine-4-yl)methanol (11.6 g, 23.2 mmol, 1.00 equivalent) in THF (120 mL) and EtOH (120 mL), AcOH (4.19 g, 69.8 mmol, 3.99 mL, 3.00 equivalent), Pd / C (2.90 g, 10% purity) and Pd(OH)2 (3.01 g, 4.29 mmol, 20% purity) were added under N2. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred under H2 (50 psi) at 80°C for 12 hours. The reaction product was cooled to 20°C and filtered. The filtrate was concentrated. The crude product was used in the next step without purification. The desired product (8.40 g, crude) was obtained as a yellow solid. LC-MS: m / z = 321.2 (M + H) + .

[0415] Step 4: To a solution of 3-(3-fluoro-4-(4-(hydroxymethyl)piperidine-1-yl)phenyl)piperidine-2,6-dione (8.40 g, 26.2 mmol, 1.00 equivalent) in DMSO (90.0 mL), DMP (22.2 g, 52.4 mmol, 16.2 mL, 2.00 equivalent) was gradually added. The reaction mixture was stirred at 25°C for 12 hours. The pH of the reaction mixture was adjusted to pH=10 with saturated Na2CO3 aqueous solution, and the aqueous layer was converted to ethyl acetate (400 mL) * 4) Extracted. Combined organic layers were mixed in a Na2S2O3 solution (500 mL). * 2) The product was washed with brine (1000 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was triturated with ethyl acetate (100 mL) at 25°C for 12 hours. HA-3 (2.50 g, 7.60 mmol, yield 28.9%) was obtained as a yellow solid. LCMS: m / z = 317.1 (MH) + . 1 H NMR(400MHz,DMSO-d6)δ10.8(s,1H),9.64(s,1H),7.06-6.90(s,3H),3.83-3.76(m,1H),3.29-3.24(m,2H),2.76( t,J=10.0Hz,2H),2.69-2.60(m,1H),2.48-2.41(m,2H),2.24-2.13(m,1H),2.04-1.91(m,3H),1.71-1.58(m,2H).

[0416] HA-4: 1-(4-(2,6-dioxopiperidine-3-yl)-3-fluorophenyl)piperidine-4-carboaldehyde

[0417] [ka]

[0418] HA-4 was synthesized following the same procedure as HA-3, by substituting 4-bromo-2-fluoro-1-iodobenzene with 1-bromo-2-fluoro-4-iodobenzene in step 1, to obtain the title compound. LCMS::m / z=317.1(MH) +. 1 H NMR:(400MHz,DMSO-d6)δ10.79(s,1H),9.62(s,1H) ,7.07(t,J=8.8Hz,1H),6.77-6.69(m,2H),3.91-3.84(m,1H),3.67-3.59(m,2H),2.91-2.81(m,2H),2.76-2 .65(m,1H),2.56-2.52(m,1H),2.49-2.45(m,1H),2.20-2.07(m,1H),1.97-1.86(m,3H),1.61-1.49(m,2H).

[0419] HA-5:rac-(R)-3-(1,2,3,4-tetrahydroisoquinoline-6-yl)piperidine-2,6-dione

[0420] [ka]

[0421] Step 1: Add tert-butyl6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (1000.00 mg, 3.20 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1470.31 mg, 3.52 mmol), tripotassium phosphate (2.04 g, 9.61 mmol), Pd(dppf)Cl2·DCM (0.26 g, 0.32 mmol), dioxane (7.00 mL), and water (2.50 mL) to a 40 mL vial. Reaction mixture The mixture was degassed under nitrogen for 15 minutes, then stirred at 90°C for 16 hours. The reaction mixture was then diluted with water and toluene, and filtered through Celite. The product was extracted with toluene (3×), dried over MgSO4, and then concentrated. The resulting residue was purified by column chromatography (80 g silica, 0-25% toluene / hexane) to obtain tert-butyl 6-[2,6-bis(benzyloxy)pyridine-3-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate as a colorless oil (1.48 g, 88%). LCMS C 33 H34 Theoretical value for N2O4: 522.3, Measured value: m / z = 523.3 [M + H] + .

[0422] Step 2: In a 40 mL vial, tert-butyl 6-[2,6-bis(benzyloxy)pyridine-3-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (1480.00 mg, 2.83 mmol), Pd / C (700.00 mg), THF (10.00 mL), and EtOH (10.00 mL) were added. The reaction mixture was sparged with hydrogen for 5 minutes, and then the reaction was stirred under a hydrogen atmosphere (balloon) for 16 hours. The reaction mixture was filtered through Celite and then concentrated. The resulting residue was purified by column chromatography (40 g silica, 0-10% MeOH / DCM) to obtain rac-tert-butyl 6-[(3R)-2,6-dioxopiperidine-3-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate as a white solid (852 mg, 87%). LCMS C 19 H 24 Theoretical value for N2O4: 344.2, Measured value: m / z = 345.2 [M + H] + .

[0423] Step 3: Add rac-tert-butyl6-[(3R)-2,6-dioxopiperidine-3-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (852.00 mg, 2.47 mmol) and DCM (2.00 mL) to a 40 mL vial. To the reaction mixture, 4M hydrogen chloride in dioxane (6.18 mL, 0.90 g, 24.74 mmol) was added dropwise. After 1 hour, the reaction mixture was concentrated to obtain the title compound as a white solid (707 mg, quantitative yield). LCMS C 14 H 16 Theoretical value of N2O2: 244.1, measured value: m / z = 245.0 [M + H] + .

[0424] HA-6:1-{4-[4-({4-[2-(6,6-dimethyl-1,4,5,7-tetrahydroindazole-3-yl)-1H-indole-5-carbonyl]piperazine-1-yl}methyl)piperidine-1-yl]-2-fluorophenyl}-1,3-diadinane-2,4-dione

[0425] [ka]

[0426] Step 1: Acrylic acid (22.75 g, 315.77 mmol, 3 equivalents) was added at room temperature to a mixture of 4-bromo-2-fluoroaniline (20 g, 105.26 mmol, 1 equivalent) in AcOH (80 mL) and H2SO4 (1 mL). The resulting mixture was stirred at 100 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography using ACN / H2O(1 / 4). This yielded 3-[(4-bromo-2-fluorophenyl)amino]propanoic acid (13 g, 42.41%) as an off-white solid. LCMS(ESI)(C9H9BrFNO2)[M+1] + Calculated value: 262.0; Measured value: 262.0.

[0427] Step 2: To a mixture of 3-[(4-bromo-2-fluorophenyl)amino]propanoic acid (13 g, 49.6 mmol, 1 equivalent) in MeOH (30 mL), SOCl2 (54 mL) was added at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. This yielded methyl 3-[(4-bromo-2-fluorophenyl)amino]propanoate (9 g, crude) as a brown oily substance. LCMS(ESI)(C 10 H 11 BrFNO2)[M+1] + Calculated value: 276.0; Measured value: 276.0.

[0428] Step 3: Potassium cyanate (7.93 g, 97.79 mmol, 3 equivalents) was added at room temperature to a mixture of methyl 3-[(4-bromo-2-fluorophenyl)amino]propanoate (9 g, 32.6 mmol, 1 equivalent) in AcOH (40 mL) and DCM (40 mL). The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was extracted with RINKAN (3 × 30 mL). The combined organic layers were washed with water (3 × 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography using ACN / H₂O (3 / 7). This yielded methyl 3-[(4-bromo-2-fluorophenyl)(carbamoyl)amino]propanoate (3.5 g, 30.28%) as a white solid. LCMS(ESI)(C 11 H 12 BrFN2O3)[M+1] + Calculated value: 319.0; Measured value: 319.0.

[0429] Step 4: Add potassium trimethylsilanolate (3.52 g, 27.42 mmol, 2.5) to a mixture of methyl 3-[(4-bromo-2-fluorophenyl)(carbamoyl)amino]propanoate (3.5 g, 10.97 mmol, 1 equivalent) in THF (20 mL). An equivalent amount was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was extracted with SiO2 (3 × 20 mL). The combined organic layers were washed with water (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain 1-(4-bromo-2-fluorophenyl)-1,3-diadinane-2,4-dione (2 g, crude) as a white solid. LCMS(ESI)(C 10 H8BrFN2O2)[M+1] + Calculated value: 287.0; Measured value: 287.0.

[0430] Step 5: To a mixture of 1-(4-bromo-2-fluorophenyl)-1,3-diadinane-2,4-dione (2.7 g, 9.41 mmol, 1 equivalent) in 25 mL of dioxane, piperidine-4-ylmethanol (2.29 g, 19.85 mmol, 3 equivalents), Pd(OAc)2 (0.21 g, 0.94 mmol, 0.1 equivalent), Cs2CO3 (9.19 g, 28.22 mmol, 3 equivalents), and t-BuXPhos (0.80 g, 1.88 mmol, 0.2 equivalents) were added. The resulting mixture was stirred overnight at 90°C under a nitrogen atmosphere. The residue was purified by C18 reverse-phase column chromatography using ACN / H2O(1 / 2) to obtain 1-{2-fluoro-4-[4-(hydroxymethyl)piperidine-1-yl]phenyl}-1,3-diadinane-2,4-dione (324 mg, 10.58%) as a gray solid. LMS(ESI)(C 16 H 20 FN3O3)[M+1] + Calculated value: 322.1; Measured value: 322.2. 1 H NMR(400MHz,DMSO-d6)δ7.93(s,1H),7.22-7.13(m,1H),6.84-6.72(m,1H),6.01(s,2H),3.79-3.72(m,2H), 3.66-3.58(m,2H),3.28(s,2H),2.75-2.65(m,4H),1.76-1.69(m,2H),1.56-1.52(m,1H),1.31-1.03(m,2H).

[0431] Step 6: Dess-Martin (197 mg, 0.47 mmol, 1.5 equivalents) was gradually added at 0°C to a mixture of 1-{2-fluoro-4-[4-(hydroxymethyl)piperidine-1-yl]phenyl}-1,3-diadinane-2,4-dione (100 mg, 0.31 mmol, 1 equivalent) in DCM (5 mL). The resulting mixture was stirred at 0°C for 2 hours. The resulting mixture was concentrated under reduced pressure. The resulting mixture was purified by C18 reverse-phase column chromatography using ACN / H2O(1 / 2). This yielded the title compound as a brown solid (36 mg, 37.3%). LCMS(ESI)(C 16 H 18 FN3O3)[M+1] +Calculated value: 320.1; Measured value: 320.2.

[0432] HA-7: 1-(4-(2,6-dioxopiperidine-3-yl)phenyl)piperidine-4-carbaldehyde

[0433] [ka]

[0434] Step 1: Add piperidine-4-ylmethanol (2) to a solution of compound 1-bromo-4-iodobenzene (50.0 g, 176 mmol, 1.00 equivalent) in DMSO (250 mL). 6.4g (229 mmol, 1.30 equivalents), K3PO4 (75.0g, 353 mmol, 2.00 equivalents), CuI (6.73g, 35.3 mmol, 0.200 equivalents), and L-proline (4.64g, 35.3 mmol, 0.200 equivalents) were added under N2 at 20°C. The reaction mixture was stirred under N2 at 80°C for 12 hours. The mixture was cooled to 20°C and poured into water (1.00 L). The mixture was stirred for 0.5 hours. The mixture was then mixed with ethyl acetate (500 mL). * 3) Extracted. Organic layer: NH3·H2O in H2O (100 mL of NH3·H2O in 700 mL of H2O) (250 mL * 3) Washed. The combined organic layers were washed with brine (1000 mL), dried over Na2SO4, filtered, and concentrated. The residue was subjected to column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1~2 / 1, R f The solution was purified by LC-MS (=0.30). The desired product (31.0 g, 87.0 mmol, 49.2% yield) was obtained as a yellow solid. LC-MS: m / z = 270.0 (M + H) + .

[0435] Step 2: To a solution of (1-(4-bromophenyl)piperidine-4-yl)methanol (30.0 g, 84.2 mmol, 1.00 equivalent) and 2,6-bis(benzyloxy)-3-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)pyridine (35.1 g, 84.2 mmol, 1.00 equivalent) in dioxane (300 mL) and H2O (60.0 mL), K2CO3 (34.9 g, 252 mmol, 3.00 equivalent) and Pd(dppf)Cl2·CH2Cl2 (6.88 g, 8.43 mmol, 0.100 equivalent) were added under N2 at 20°C. The reaction mixture was stirred under N2 at 110°C for 12 hours. The reaction mixture was cooled to 20°C and filtered. The filtrate was concentrated. The crude product was purified by recrystallization in MeOH (100 mL) at 20°C for 30 minutes. The mixture was filtered, and the filtered cake was subjected to column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1, R f The solution was purified by (=0.30). The desired product (22.5 g, 44.8 mmol, 53.2% yield) was obtained as a yellow solid. LC-MS: m / z = 481.2 (M + H) + .

[0436] Step 3: To a solution of (1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)phenyl)piperidine-4-yl)methanol (20.0 g, 39.8 mmol, 1.00 equivalent) and AcOH (7.18 g, 119 mmol, 6.84 mL, 3.00 equivalent) in THF (200 mL) and EtOH (200 mL), Pd / C (5.00 g, 39.8 mmol, 10% purity, 1.00 equivalent) and Pd(OH)2 (4.79 g, 34.1 mmol, 8.56 e-1 equivalent) were added under N2. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 80°C for 12 hours under H2 (50 psi). The mixture was cooled to 20°C and filtered. The filtrate was concentrated. The crude product was triturated with petroleum ether / ethyl acetate = 5 / 1 (200 mL) at 20°C for 30 minutes. The desired product (8.00 g, 24.2 mmol, 60.7% yield) was obtained as a white solid. LC-MS: m / z = 303.2 (M + H) + .

[0437] Step 4: To a solution of 3-(4-(4-(hydroxymethyl)piperidine-1-yl)phenyl)piperidine-2,6-dione (8.60 g, 28.4 mmol, 1.00 equivalent) in DMSO (90.0 mL), des-martin periodinane (24.1 g, 56.8 mmol, 17.6 mL, 2.00 equivalent) was slowly added at 20°C. The reaction mixture was stirred at 20°C for 12 hours. The mixture was adjusted with saturated Na2CO3 aqueous solution until the pH was 10, and the aqueous layer was converted to ethyl acetate (350 mL). * Extraction was performed as described in 3). The combined organic layers were washed with Na2S2O3 solution (500 mL) and brine (500 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was triturated with ethyl acetate (100 mL) at 20°C for 30 minutes. HA-7 (7.18 g, 22.8 mmol, yield 48.1%) was obtained as an off-white solid. LC-MS: m / z = 299.1 (MH) + . 1 H NMR:(400MHz,DMSO-d6)δ11.00-10.57(m,1H),9.80-9.35(m,1H),7.09-6.98 (m,2H),6.95-6.83(m,2H),3.79-3.66(m,1H),3.63-3.49(m,2H),2.89-2.72( m, 2H), 2.70-2.59 (m, 1H), 2.48-2.38 (m, 2H), 2.17-1.89 (m, 4H), 1.65-1.47 (m, 2H).

[0438] HA-8:rac-(R)-2-(1-(5-(2,6-dioxopiperidine-3-yl)pyridine-2-yl)piperidine-4-yl)acetic acid

[0439] [ka]

[0440] Step 1: In a 40 mL vial, rac-(3R)-3-(6-fluoropyridine-3-yl)piperidine-2,6-dione (1.00 g, 4.80 mmol), tert-butyl 2-(piperidine-4-yl) acetate (1.01 g, 5.04 mmol), DMSO (7.00 mL), and N,N-diisopropylethylamine (3.18 mL, 2.48 g, 19.21 mmol) were added. The reaction mixture was stirred at 130 °C for 16 hours. The reaction mixture was then diluted with ethyl acetate and brine. The product was extracted with ethyl acetate (2 ×). The combined organic layers were washed with brine (3 ×), dried over MgSO4, and then concentrated. The resulting residue was purified by column chromatography (80g silica, 0-100% siRNA / DCM) to obtain rac-tert-butyl 2-(1-{5-[(3R)-2,6-dioxopiperidine-3-yl]pyridine-2-yl}piperidine-4-yl) acetate as a brown solid (456mg, 25%). LCMS C 17 H 21 N3O4 theoretical value: 387.2, measured value: 388.2 [M+H] + .

[0441] Step 2: Rac-tert-butyl 2-(1-{5-[(3R)-2,6-dioxopiperidine-3-yl]pyridine-2-yl}piperidine-4-yl) acetate (456.00 mg, 1.18 mmol) and DCM (5.00 mL) were added to a 40 mL vial. Trifluoroacetic acid (5.00 mL, 7.45 g, 65.34 mmol) was added dropwise to the reaction mixture. After 30 minutes, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by chromatography (100 g C18 silica, 0-20% MeCN / H2O) to obtain the title compound as a white solid (1.04 g, 100%). LCMS C 21 H 29 Theoretical value for N3O4: 331.2, Measured value: m / z = 332.2 [M + H] + .

[0442] HA-9:rac-1-[5-[(3R)-2,6-dioxopiperidine-3-yl]pyridine-2-yl]piperidine-4-carboxylic acid.

[0443] [ka]

[0444] Step 1: To a mixture of 5-bromo-2-fluoropyridine (6.64 g, 37.73 mmol, 1 equivalent) in DMF (50 mL), tert-butylpiperidine-4-carboxylate (8.39 g, 45.28 mmol, 1.2 equivalents) and K2CO3 (10.43 g, 75.46 mmol, 2 equivalents) were added. The resulting mixture was stirred overnight at 90°C. The resulting mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with water (3 × 50 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / ethyl acetate (1 / 1). This yielded tert-butyl 1-(5-bromopyridine-2-yl)piperidine-4-carboxylate as a bright yellow solid (10 g, yield 46.60%). LCMS(ESI)(C 15 H 21 BrN2O2)[M+H] + Calculated value: 341.2; Measured value: 341.2.

[0445] Step 2: Pd(PPh3)4 (0.5g, 0.43 mmol, 0.1 equivalent) was added to a mixture of tert-butyl 1-(5-bromopyridine-2-yl)piperidine-4-carboxylate (2.40g, 7.04 mmol, 1.6 equivalents), 2,6-bis(benzyloxy)pyridine-3-ylboric acid (1.47g, 4.39 mmol, 1.00 equivalent), and K2CO3 (1.2g, 8.70 mmol, 2 equivalents) in THF (10mL) and H2O (10mL). The resulting mixture was stirred at 110°C for 40 minutes under a nitrogen atmosphere using microwaves. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE / siRNA(1 / 1). This yielded tert-butyl 1-[2,6-bis(benzyloxy)-[3,3-bipyridine]-6-yl]piperidine-4-carboxylate as a white solid (1.2 g, yield 49.36%). LCMS(ESI)(C 33 H 35 N3O4)[M+H] + Calculated value: 552.3; Measured value: 552.0.

[0446] Step 3: To a mixture of tert-butyl 1-[2,6-bis(benzyloxy)-[3,3-bipyridine]-6-yl]piperidine-4-carboxylate (1.8 g, 3.26 mmol, 1 equivalent) in EtOH (50 mL) and THF (50 mL), Pd / C (0.9 g) was added. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography using CH3CN / H2O (2 / 1). This yielded tert-butyl 1-[5-(2,6-dioxopiperidine-3-yl)pyridine-2-yl]piperidine-4-carboxylate as a yellow solid (390 mg, yield 28.81%). LCMS(ESI)(C 20 H 27 N3O4)[M+H] + Calculated value: 374.2; Measured value: 374.2.

[0447] Step 4: To a mixture of tert-butyl 1-[5-(2,6-dioxopiperidine-3-yl)pyridine-2-yl]piperidine-4-carboxylate (650 mg, 1.74 mmol, 1 equivalent) in DCM (100 mL), TFA (10 mL) was added dropwise at 0°C. The resulting mixture was stirred at 0°C for 2 hours. The resulting mixture was concentrated under vacuum. The residue was purified by C18 reversed-phase column chromatography using CH3CN / H2O (1 / 1). This yielded rac-1-[5-[(3R)-2,6-dioxopiperidine-3-yl]pyridine-2-yl]piperidine-4-carboxylic acid as a purple solid (540.8 mg, yield 96.08%). LCMS(ESI)(C 16 H 19 N3O4)[M+H] + Calculated value: 318.2; Measured value: 318.2. 1 H NMR(300MHz,DMSO-d6)δ10.91(s,1H),7.97-7.73(m,2H),7.30(d,J=9.3Hz,1H),4.14-4.02(m,2H),3.95-3 .84(m,1H),3.29-3.14(m,2H),2.76-2.48(m,3H),2.36-2.16(m,1H),2.02-1.88(m,3H),1.70-1.51(m,2H).

[0448] HA-10:rac-(R)-3-(6-(piperazin-1-yl)pyridine-3-yl)piperidine-2,6-dione

[0449] [ka]

[0450] Step 1: tert-butylpiperazine-1-carboxylate (0.895 g, 4.8 mmol) and 3-(6-fluoropyridine-3-yl)piperidine-2,6-dione (0.5 mg, 2.40 mmol) were combined in DMSO (0.15 M), followed by the addition of N,N-diisopropylethylamine (1.68 mL, 9.61 mmol). The vial was capped and stirred overnight at 110°C. The reaction mixture was then cooled to room temperature, concentrated on silica gel, and purified by column chromatography (0-100% ethyl acetate in hexane) to obtain rac-tert-butyl(R)-4-(5-(2,6-dioxopiperidine-3-yl)pyridine-2-yl)piperazine-1-carboxylate (0.6 g, 67%). LCMS:C 19 H 26 N4O4 theoretical value: 374.1, measured value: m / z = 375.1 [M + H] + .

[0451] Step 2: rac-tert-butyl(R)-4-(5-(2,6-dioxopiperidine-3-yl)pyridine-2-yl)piperazine-1-carboxylate was treated with 0.6 mL of TFA in HFIP (10 mL) and stirred at room temperature for 5 hours. LC-MS showed complete conversion of the starting material. The reaction mixture was concentrated and purified by C18 reverse-phase chromatography to obtain rac-(R)-3-(6-(piperazine-1-yl)pyridine-3-yl)piperidine-2,6-dione as a pale white solid (0.31 g, 71%). 1 H NMR(500MHz,DMSO)δ10.85(s,1H),8.03(d,J=2.4Hz,1H),7.56(dq,J=8.9,2.1Hz,1 H),6.98(dt,J=9.1,2.1Hz,1H),3.82(dd,J=12.4,4.9Hz,1H),3.72(t,J=5.2Hz,4H) ,3.2(t,J=5.2Hz,4H),2.70(ddd,J=17.6,13.3,5.3Hz,1H),2.56(q,J=2.8,1.9Hz, 1H),2.23(qd,J=12.6,4.2Hz,1H),2.08(s,1H),1.98(dtd,J=13.3,5.2,3.2Hz,1H). LCMS:C1 4H 18Theoretical value for N4O2: 274.32, Measured value: m / z = 275.1 [M + H] + .

[0452] HA-11:3-[(3RS)-1-[5-[(3RS&)-2,6-Dioxopiperidine-3-yl]pyridine-2-yl]pyrrolidine-3-yl]propanoic acid

[0453] [ka]

[0454] Step 1: Benzyl 2-(dimethoxyphosphoryl)acetate (28.51 g, 110.4 mmol, 1.10 equivalents) was added to a mixture of NaH (2.65 g, 110.4 mmol, 1.1 equivalents) in THF (500 mL) under a nitrogen atmosphere at 0°C. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 30 minutes. Tert-butyl 3-formylpyrrolidine-1-carboxylate (20 g, 100.4 mmol, 1 equivalent) was added to the above mixture at 0°C. The resulting mixture was stirred overnight under a nitrogen atmosphere at room temperature. The aqueous layer was extracted with ELISA (3 × 500 mL). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE / SiO(1 / 1) to obtain tert-butyl 3-[(1E)-3-(benzyloxy)-3-oxopropa-1-en-1-yl]pyrrolidine-1-carboxylate (31.6 g, 77.89% yield) as a colorless oil. LCMS(ESI)(C 19 H 25 NO4)[M+H] + Calculated value: 332.1; Measured value: 332.1.

[0455] Step 2: To a mixture of tert-butyl 3-[(1E)-3-(benzyloxy)-3-oxopropa-1-en-1-yl]pyrrolidine-1-carboxylate (12.70 g, 38.32 mmol, 1 equivalent) in THF (200 mL), Pd / C (2.04 g) was added at room temperature. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. This yielded 3-[1-(tert-butoxycarbonyl)pyrrolidine-3-yl]propanoic acid (3) as an off-white solid (9 g, crude). The crude product was used directly in the next step without further purification. LCMS(ESI)(C 12 H 21 NO4)[M+1] + Calculated value: 244.1; Measured value: 244.1.

[0456] Step 3: A mixture of 3-[1-(tert-butoxycarbonyl)pyrrolidine-3-yl]propanoic acid (9 g, crude) in HCl / dioxane (4 mol / L, 100 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. This yielded 3-(pyrrolidine-3-yl)propanoic acid as a pink solid (5.88 g, crude). LC MS(ESI)(C7H 13 N1O2)[M+1] + Calculated value: 144.0; Measured value: 144.2.

[0457] Step 4: To a mixture of 3-(pyrrolidine-3-yl)propanoic acid (5.88 g, 41.07 mmol, 1 equivalent) and 5-bromo-2-fluoropyridine (7.23 g, 41.08 mmol, 1 equivalent) in DMF (30 mL), K2CO3 (8.5 g, 61.6 mmol, 1.5 equivalents) was added at room temperature. The resulting mixture was stirred overnight at 80°C. The resulting mixture was extracted with RINKAN (3 × 100 mL). The combined organic layers were washed with water (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column using CH3CN / H2O(1 / 2). This yielded 3-[1-(5-bromopyridine-2-yl)pyrrolidine-3-yl]propanoic acid as a crude brown oil (5) (12 g, yield 89.67%). LCMS(ESI)(C 12 H 15 BrN2O2)[M+1] + Calculated value: 299.0; Measured value: 299.0.

[0458] Step 5: To a mixture of 3-[1-(5-bromopyridine-2-yl)pyrrolidine-3-yl]propanoic acid (12 g, 40.11 mmol, 1 equivalent) in DCM (100 mL), (Z)-N,N-diisopropyl tert-butoxymethaneimidamide (24.11 g, 120.4 mmol, 3 equivalents) was added at 0°C. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE / ELISA (1 / 1) to obtain tert-butyl 3-[1-(5-bromopyridine-2-yl)pyrrolidine-3-yl]propanoate (4.2 g, 28.0% yield) as a brown oil. LCMS(ESI)(C 16 H 23 BrN2O2)[M+H] + Calculated value: 355.1; Measured value: 355.0.

[0459] Step 6: To a mixture of tert-butyl 3-[1-(5-bromopyridine-2-yl)pyrrolidine-3-yl]propanoate (3 g, 8.44 mmol, 1 equivalent), 2,6-bis(benzyloxy)pyridine-3-ylboronic acid (4.25 g, 12.7 mmol, 1.5 equivalents), and K2CO3 (2.33 g, 16.89 mmol, 2 equivalents) in THF (30 mL) and H2O (10 mL), Pd(PPh3)4 (0.98 g, 0.84 mmol, 0.1 equivalent) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 110°C for 40 minutes under a nitrogen atmosphere using a microwave. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE / SiO(1 / 1) to obtain tert-butyl 3-[1-[2,6-bis(benzyloxy)-[3,3-bipyridine]-6-yl]pyrrolidine-3-yl]propanoate (7) (2.6 g, 53.34% yield) as a colorless oil. LCMS(ESI)(C 35 H 39 N3O4)[M+H] + Calculated value: 566.3; Measured value: 566.2.

[0460] Step 7: To a mixture of tert-butyl 3-[1-[2',6'-bis(benzyloxy)-[3,3'-bipyridine]-6-yl]pyrrolidine-3-yl]propanoate (2.10 g, 3.71 mmol, 1 equivalent) in THF (6 mL) and EtOH (6 mL), Pd / C (1.70 g) was added. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The resulting mixture was filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / siRNA (1 / 2) to obtain tert-butyl 3-[1-[5-(2,6-dioxopiperidine-3-yl)pyridine-2-yl]pyrrolidine-3-yl]propanoate (400 mg, 26.42% yield) as a colorless solid. MS(ESI)(C 21 H 29 N3O4)[M+1] + Calculated value: 388.2; Measured value: 388.3.

[0461] Step 8: tert-butyl 3-[1-[5- A mixture of (2,6-dioxopiperidine-3-yl)pyridine-2-yl]pyrrolidine-3-yl]propanoate (490 mg, 1.27 mmol, 1 equivalent) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. This yielded 3-[(3RS)-1-[5-[(3RS)-2,6-dioxopiperidine-3-yl]pyridine-2-yl]pyrrolidine-3-yl]propanoate HCl (HA-11) (379.1 mg, 81.56%) as a white solid. LCMS(ESI)(C 17 H 21 N3O4)[M+H] + Calculated value: 332.2; Measured value: 332.1. 1 H NMR(300MHz,DMSO-d6)δ13.61(s,1H),10.93(s,1H),7.95-7.85(m,1H),7 .82(d,J=2.1Hz,1H),7.11-7.01(m,1H),4.02-3.90(m,1H),3.80-3.69(m, 2H),3.69-3.61(m,1H),3.21-3.09(m,1H),2.77-2.48(m,1H),2.47-2.37( m, 1H), 2.36-2.19 (m, 3H), 2.17 (s, 1H), 2-1.89 (m, 1H), 1.87-1.59 (m, 4H).

[0462] HA-12:rac-(R)-1-(5-((R)-2,6-dioxopiperidine-3-yl)pyridine-2-yl)pyrrolidine-3-carbaldehyde

[0463] [ka]

[0464] Step 1: rac-(3R)-3-(6-fluoropyridine-3-yl)piperidine-2,6-dione (1000.00 mg, 4.80 mmol), rac-(3R)-pyrrolidine-3-ylmethanol (485.84 mg, 4.80 mmol), N,N-diisopropylethylamine (3.36 mL, 2.48 g, 19.21 mmol), and DMSO (7.00 mL) were added to a 40 mL vial. The reaction mixture was stirred at 115°C for 16 hours. The reaction mixture was then concentrated under reduced pressure and purified by reverse-phase column chromatography (415 g C18 silica, 0-10% MeCN / water + 0.1% TFA) to obtain (3RS&)-3-{6-[(3RS)-3-(hydroxymethyl)pyrrolidine-1-yl]pyridine-3-yl}piperidine-2,6-dione;trifluoroacetic acid as an amorphous solid (954 mg, 69%). LCMS C 15 H 19 Theoretical value of N3O3: 289.1, Measured value: m / z = 290.1 ​​[M + H] + .

[0465] Step 2: To 200 mL of RBF, (3RS&)-3-{6-[(3RS)-3-(hydroxymethyl)pyrrolidine-1-yl]pyridine-3-yl}piperidine-2,6-dione;trifluoroacetic acid (954.00 mg, 2.37 mmol), sodium bicarbonate (0.99 g, 11.83 mmol), and DCM (50.00 mL) were added. The reaction mixture was cooled to 0°C, and then 1,1-bis(acetyloxy)-3-oxo-1-lambda5,2-benzoiodooxol-1-yl acetate (1.10 g, 2.60 mmol) was added all at once. The reaction mixture was stirred for 3 hours while being warmed to room temperature. The crude reaction mixture was adsorbed onto silica and purified by FC (40g silica, 50-100% siRNA / DCM + 1% TEA) to obtain the title compound as a white solid (177mg, 26%). LCMS C 15 H 17 Theoretical value of N3O3: 287.1, Measured value: m / z = 288.0 [M + H] + .

[0466] HA-13: 1-(5-(2,6-dioxopiperidine-3-yl)pyridine-3-yl)piperidine-4-carbaldehyde

[0467] [ka]

[0468] Step 1: To a solution of piperidine-4-ylmethanol (24.3 g, 211 mmol, 1.00 equivalent) and 3,5-dibromopyridine (50.0 g, 211 mmol, 1.00 equivalent) in DMSO (400 mL), K3PO4 (89.6 g, 422 mmol, 2.00 equivalent), CuI (8.04 g, 42.2 mmol, 0.200 equivalent), and L-proline (5.54 g, 42.2 mmol, 0.200 equivalent) were added under N2 at 20°C. The mixture was stirred under N2 at 80°C for 12 hours. The mixture was cooled to 20°C and poured into water (1.00 L). The mixture was stirred at 20°C for 0.5 hours. The mixture was then added to ethyl acetate (500 mL) * 3) Extraction was performed. The organic layer was washed with brine (1.00 L), dried over Na2SO4, filtered, and concentrated. The residue was subjected to column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1~0 / 1, R f The solution was purified by (=0.35). The desired product (33.0 g, 119 mmol, 56.5% yield) was obtained as an orange solid. LC-MS: m / z = 270.8 (M + H) + 。

[0469] Step 2: To a solution of (1-(5-bromopyridine-3-yl)piperidine-4-yl)methanol (20.0 g, 72.3 mmol, 1.00 equivalent) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (30.2 g, 72.3 mmol, 1.00 equivalent) in dioxane (250 mL) and H2O (50.0 mL), Pd(dppf)Cl2·CH2Cl2 (5.91 g, 7.24 mmol, 0.100 equivalent) and K2CO3 (30.0 g, 217 mmol, 3.00 equivalent) were added under N2 at 20°C. The mixture was degassed and then stirred under N2 at 100°C for 12 hours. The reaction mixture was cooled to 20°C and concentrated. Pour the residue into water (500 mL) and add ethyl acetate (500 mL) * 4) Extraction was performed. The combined organic layers were washed with brine (1000 mL), dried over Na2SO4, filtered, and concentrated. The residue was subjected to column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1~1 / 3, R f The solution was purified by (=0.30). The desired product (25.0 g, 51.3 mmol, 70.9% yield) was obtained as a yellow solid. LC-MS: m / z = 482.1 (M + H) + .

[0470] Step 3: To a solution of the compound (1-(2',6'-bis(benzyloxy)-[3,3'-bipyridine]-5-yl)piperidine-4-yl) methanol (24.0 g, 49.2 mmol, 1.00 equivalent) and AcOH (8.88 g, 147 mmol, 8.46 mL, 3.00 equivalent) in THF (120 mL) and EtOH (120 mL), 10 wt% Pd / C (6.00 g, 49.2 mmol, 1.00 equivalent) and 20 wt% Pd(OH)2 (5.93 g, 8.45 mmol, 0.17 equivalent) were added under N2. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 80°C for 12 hours under H2 (50 psi). The mixture was cooled to 20°C and filtered. The filtrate was concentrated. The residue was adjusted with a saturated Na2CO3 aqueous solution until the pH reached 10, and the aqueous layer was converted to ethyl acetate:THF (1:1, 1000m). L *Extraction was performed using method 5). The combined organic layers were washed with brine (1000 mL), dried over Na2SO4, and concentrated under vacuum. The desired product (9.91 g, 24.1 mmol, 48.9% yield) was obtained as a pink solid without further purification. LCMS: m / z = 304.2 (M + H) + .

[0471] Step 4: To a solution of 3-(5-(4-(hydroxymethyl)piperidine-1-yl)pyridine-3-yl)piperidine-2,6-dione (9.91 g, 24.1 mmol, 1.00 equivalent) in DMSO (100 mL), DMP (20.4 g, 48.2 mmol, 14.93 mL, 2.00 equivalent) was gradually added at 20°C. The reaction mixture was stirred at 20°C for 1 hour. The mixture was poured into water (100 mL) and ethyl acetate (100 mL). The mixture was adjusted to pH=10 with saturated Na2CO3 aqueous solution, and the aqueous layer was poured into ethyl acetate (1000 mL). * 5) and THF:MeOH (1:1, 1000 mL) * Extraction was performed using method 5). The combined organic layers were washed with Na2S2O3 solution (1000 mL) and brine (1000 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was triturated with ethyl acetate (100 mL) at 20°C for 30 minutes. HA-13 (4.92 g, 16.0 mmol, yield 66.5%) was obtained as an off-white solid. LC-MS: m / z = 300.1 (MH) + . 1 H NMR:(400MHz,CDCl3)δ9.72(s,1H),8.34-8.21(m,2H),7.99(d,J=1.8Hz,1H),7.02(t,J=2.2Hz,1H),3.77-3.72(m,1H),3.68-3.61(m,2H) ),3.00-2.92(m,2H),2.84-2.76(m,1H),2.75-2.65(m,1H),2.50-2.41(m,1H),2.34-2.24(m,2H),2.11-2.04(m,2H),1.82-1.74(m,2H).

[0472] HA-14:rac-(R)-2-(1-(5-(2,6-dioxopiperidine-3-yl)pyridine-2-yl)piperidine-4-yl)acetaldehyde

[0473] [ka]

[0474] Step 1: Add rac-(3R)-3-(6-fluoropyridine-3-yl)piperidine-2,6-dione (1500.00 mg, 7.20 mmol), 4-piperidineethanol (977.44 mg, 7.57 mmol), N,N-diisopropylethylamine (5.03 mL, 3.72 g, 28.82 mmol), and DMSO (10.00 mL) to a 40 mL vial. Stir at 130 °C for 16 hours. The reaction mixture was concentrated, and the resulting residue was purified by reverse-phase column chromatography (415 g C18 silica, 5-50% MeCN / H2O + 0.1% TFA) to obtain rac-(3R)-3-{6-[4-(2-hydroxyethyl)piperidine-1-yl]pyridine-3-yl}piperidine-2,6-dione;trifluoroacetic acid as an amorphous solid (2.10 g, yield 92%). LCMS C 17 H 23 N3O3 theoretical value: 317.2, measured value: 318.2 [M+H] + .

[0475] Step 2: Add rac-(3R)-3-{6-[4-(2-hydroxyethyl)piperidine-1-yl]pyridine-3-yl}piperidine-2,6-dione; trifluoroacetic acid (1600.00 mg, 3.71 mmol) and DCM (30.00 mL) to a 40 mL vial. Cool the reaction mixture to 0°C, then add 1,1-bis(acetyloxy)-3-oxo-1-lambda5,2-benzoiodooxol-1-yl acetate (1.73 g, 4.08 mmol) all at once. After 10 minutes, remove the ice bath and warm the reaction mixture to room temperature. The mixture was stirred for 1 hour. 3 mL of TEA was added to the reaction mixture, and the crude reaction mixture was adsorbed onto silica. The mixture was then purified by column chromatography (80 g silica, 20-100% siRNA + 1% TEA / DCM) to obtain the title compound as a white solid (278 mg, yield 47%). LCMS C 17 H 21 Theoretical value for N3O3: 315.2, Measured value: m / z = 316.2 [M + H] + .

[0476] HA-15:rac-(R)-2-(4-(4-(2,6-dioxopiperidine-3-yl)pyridine-2-yl)piperazine-1-yl)acetic acid

[0477] [ka]

[0478] Step 1: In a 40 mL vial, rac-(3R)-3-(2-fluoropyridine-4-yl)piperidine-2,6-dione (1000.00 mg, 4.80 mmol), tert-butyl 2-(piperazin-1-yl) acetate (1443.01 mg, 7.20 mmol), DMSO (7.00 mL), and N,N-diisopropylethylamine (3.36 mL, 2.48 g, 19.21 mmol) were added. The reaction mixture was stirred at 120 °C for 3 hours. The reaction mixture was diluted with brine and ethylethanol. The product was extracted with ethylethanol (2×), the combined organic layers were washed with brine (4×), dried over MgSO4, and then concentrated. The resulting residue was purified by column chromatography (80g silica, 30-100% ethyl alcohol / DCM + 1% TEA) to obtain rac-tert-butyl 2-(4-{4-[(3R)-2,6-dioxopiperidine-3-yl]pyridine-2-yl}piperazine-1-yl) acetate as an off-white solid (1.454g, yield 78%). LCMS C 20 H 28 N4O4 theoretical value: 388.2, measured value: m / z = 389.2 [M + H] + .

[0479] Step 2: Rac-tert-butyl 2-(4-{4-[(3R)-2,6-dioxopiperidine-3-yl]pyridine-2-yl}piperazine-1-yl) acetate (1454.30 mg, 3.74 mmol), HFIP (5.00 mL), and trifluoroacetic acid (2.85 mL, 4.27 g, 37.44 mmol) were added to a 40 mL vial. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated. The resulting residue was purified by RP-FC (100 g C18 silica, 0-10% MeCN / H2O) to obtain the title compound as a white solid (813 mg, yield 65%). LCMS C 16 H 20 N4O4 theoretical value: 332.1, measured value: m / z = 333.1 [M + H] + .

[0480] HA-16:rac-(R)-1-(4-(2,6-dioxopiperidine-3-yl)pyridine-2-yl)piperidine-4-carboxylic acid

[0481] [ka]

[0482] Step 1: In a 40 mL vial, add rac-(3R)-3-(2-fluoropyridine-4-yl)piperidine-2,6-dione (1000 mg, 4.80 mmol), tert- Tylpiperidine-4-carboxylate (978.87 mg, 5.28 mmol), N,N-diisopropylethylamine (3.36 mL, 2.48 g, 19.21 mmol), and DMSO (7.00 mL) were added. The reaction mixture was stirred at 120°C for 16 hours. The reaction mixture was diluted with siRNA and brine. The product was extracted with siRNA (2×). The combined organic layers were washed with brine (4×), dried over MgSO4, and then concentrated. The resulting residue was purified by column chromatography (80 g silica, 0-70% siRNA / DCM) to obtain rac-tert-butyl 1-{4-[(3R)-2,6-dioxopiperidine-3-yl]pyridine-2-yl}piperidine-4-carboxylate as an off-white solid (1.235 g, yield 69%). LCMS C 20 H 27 Theoretical value for N3O4: 373.2, Measured value: m / z = 374.2 [M + H] + .

[0483] Step 2: Rac-tert-butyl 1-{4-[(3R)-2,6-dioxopiperidine-3-yl]pyridine-2-yl}piperidine-4-carboxylate (630.00 mg, 1.69 mmol) and HFIP (4.00 mL) were added to a 40 mL vial. Trifluoroacetic acid (1.28 mL, 1.92 g, 16.87 mmol) was added dropwise to the reaction mixture. After 2 hours, the reaction mixture was concentrated. The resulting residue was purified by reverse-phase column chromatography (100 g C18 silica, 0-15% MeCN / H2O) to obtain the title compound as a white solid (408 mg, yield 76%). LCMS C 16 H 19 Theoretical value for N3O4: 317.1, Measured value: m / z = 318.1 [M + H] + .

[0484] HA-17:rac-(R)-1-(5-((R)-2,6-dioxopiperidine-3-yl)pyridine-2-yl)pyrrolidine-3-carboxylic acid

[0485] [ka]

[0486] Step 1: In a 40 mL vial, rac-(3R)-3-(6-fluoropyridine-3-yl)piperidine-2,6-dione (1000.00 mg, 4.80 mmol), rac-tert-butyl(3R)-pyrrolidine-3-carboxylate (822.51 mg, 4.80 mmol), N,N-diisopropylethylamine (3.36 mL, 2.48 g, 19.21 mmol), and DMSO (7.00 mL) were added. The mixture was stirred at 115°C for 16 hours. The reaction mixture was then diluted with siRNA and brine. The product was extracted with toluene (2×), the combined organic layer was washed with brine (4×), dried over MgSO4, and then purified by column chromatography (80g silica, 10-100% toluene / DCM) to obtain tert-butyl(3RS)-1-{5-[(3RS&)-2,6-dioxopiperidine-3-yl]pyrrolidine-2-yl}pyrrolidine-3-carboxylate as a white solid (779.1 mg, yield 45%). LCMS C 19 H 25 Theoretical value for N3O4: 359.2, Measured value: m / z = 360.2 [M + H] + .

[0487] Step 2: In a 40 mL vial, tert-butyl(3RS)-1-{5-[(3RS&)-2,6-dioxopiperidine-3-yl]pyridine-2-yl}pyrrolidine-3-carboxylate (779.10 mg, 2.17 mmol), HFIP (4.00 mL), and trifluoroacetic acid (1.65 mL, 2.47 g, 21.68 mmol) were added. The reaction mixture was stirred for 4 hours and then concentrated. The resulting residue was purified by reverse-phase chromatography (100 g C18 silica, 0-10% MeCN / water) to obtain the title compound as a white solid (589 mg, 90% yield). LCMS C 15 H 17 N3O4 theory Theoretical value: 303.1, Measured value: m / z = 304.0 [M + H] + .

[0488] HA-18:rac-(R)-3-(6-(piperidine-4-yloxy)pyridine-3-yl)piperidine-2,6-dione

[0489] [ka]

[0490] Step 1: Dissolve tert-butyl 4-hydroxypiperidine-1-carboxylate (1.14 g, 5.68 mmol) in NMP (10 mL) and cool the reaction mixture to 0°C. Add sodium hydride (0.27 g, 11.36 mmol) and stir the reaction mixture for 5 minutes, then add 5-bromo-2-fluoropyridine (0.58 mL, 1.00 g, 5.68 mmol). Heat the reaction mixture to 60°C for 4 hours. The product was purified by reverse-phase flash column chromatography (0-100% acetonitrile in water) by direct injection to obtain tert-butyl 4-[(5-bromopyridine-2-yl)oxy]piperidine-1-carboxylate (0.751 g, yield 37%). LCMS:C 15 H 21 Theoretical value for BrN2O3: 357.25, Measured value: m / z = 358.10 [M + H] + .

[0491] Step 2: tert-butyl 4-[(5-bromopyridine-2-yl)oxy]piperidine-1-carboxylate (0.750 g, 2.10 mmol), Pd(dppf)Cl2·DCM (0.342 g, 0.42 mmol), cesium carbonate 1N solution (5.25 mL, 1.71 g, 5.25 mmol), 2,6-bis(benzyloxy)pyridine-3-ylboric acid (0.703 g, 2.10 mmol), and dioxane (5.00 mL) were combined in a sealed vial. The vial was purged with nitrogen gas and stirred at 100°C for 60 minutes. The reaction mixture was poured into brine, extracted with ethyl acetate, filtered, and concentrated on silica gel. The reaction product was purified by flash column chromatography (0-100% ethyl acetate in hexane) to obtain tert-butyl 4-{[2',6'-bis(benzyloxy)-[3,3'-bipyridine]-6-yl]oxy}piperidine-1-carboxylate (1.05 g, yield 88%). LCMS:C 34 H 37 Theoretical value for N3O5: 567.69, measured value: m / z = 568.70 [M + H] + .

[0492] Step 3: tert-butyl 4-{[2',6'-bis(benzyloxy)-[3,3'-bipyridine]-6-yl]oxy}piperidine-1-carboxylate (1.05 g, 1.8 mmol) was dissolved in EtOH (20.00 mL). 10% palladium carbon (0.20 g, 0.18 mmol) was added, and the reaction mixture was stirred under hydrogen balloon for 12 hours. The reaction mixture was filtered through Celite and concentrated to obtain tert-butyl 4-({5-[(3R)-2,6-dioxopiperidine-3-yl]pyridine-2-yl}oxy)piperidine-1-carboxylate (0.647 g, 95%). LCMS:C 20 H 27 Theoretical value for N3O5: 389.45, Measured value: m / z = 390.20 [M+H] + .

[0493] Step 4: tert-butyl 4-({5-[(3R)-2,6-dioxopiperidine-3 (3R)-3-[6-(piperidine-4-yloxy)pyridine-3-yl]piperidine-2,6-dione (0.427 g, 92% yield) was obtained by dissolving [-yl]pyridine-2-yl}oxy)piperidine-1-carboxylate (0.647 g, 1.66 mmol) in DCM (10 mL). 4M HCl (3 mL) was added to dioxane, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated on silica gel and purified by reverse-phase flash column chromatography (0-100% acetonitrile in water) to obtain (3R)-3-[6-(piperidine-4-yloxy)pyridine-3-yl]piperidine-2,6-dione (0.427 g, 92% yield). LCMS:C 15 H 19 Theoretical value of N3O3: 289.34, measured value: m / z = 290.20 [M+H] + .

[0494] HA-19:1-[5-(2,4-dioxo-1,3-diadinane-1-yl)pyridine-2-yl]piperidine-4-carbaldehyde

[0495] [ka]

[0496] Step 1: A mixture of 2-fluoro-4-nitropyridine (20 g, 0.140 mol, 1 equivalent), piperidine-4-yl methanol (24.318 g, 0.211 mol, 1.5 equivalents), and DIPEA (27.29 mL, 0.211 mol, 1.5 equivalents) in anhydrous DMSO (50 mL, 2.82 M) was stirred overnight at 90°C. The reaction mixture was slowly poured into ice water. The resulting precipitate was filtered and purified by FC(DCM / MeOH-9 / 1) to obtain 33.37 g of [1-(5-nitropyridine-2-yl)piperidine-4-yl]methanol (47% yield) as a yellow solid. LCMS: (M+H) + =237.7 1H NMR(300MHz,CDCl3)δ9.05(d,J=2.8Hz,1H),8.20(dd,J=9.6,2.8Hz,1H),6.60(d,J=9.6Hz,1H),4.59(d,J=13 .4Hz,2H),3.57(d,J=5.9Hz,2H),3.11-2.95(m,2H),1.98-1.84(m,3H),1.31(tdd,J=14.3,11.8,4.2Hz,2H).

[0497] Step 2: Dissolve [1-(5-nitropyridine-2-yl)piperidine-4-yl]methanol (15.5 g, 0.065 mol, 1 equivalent) in an EtOH / MeOH-1 / 1 mixture (250 mL, 0.26 M), degas, and pack with Pd / C (50% wet, 2.32 g, 15% by weight). Evacuate the reaction mixture, repack with H2, and stir overnight (balloon, 1 atm). Filter through a Celite pad, concentrate to obtain 5.85 g of [1-(5-aminopyridine-2-yl)piperidine-4-yl]methanol (45% yield) as a pale yellow oil, which was used in the next step without further purification. LCMS(M+H) + =208.25 1 H NMR(300MHz,DMSO-d6)δ7.59(dd,J=2.9,0.7Hz,1H),6.89(dd,J=8.8,2.9Hz,1H),6.61(dd,J=8.9,0.8Hz,1H),4.56-4.39(m,3H), 4.02-3.89(m,2H),3.26(dd,J=6.3,5.3Hz,2H),2.60-2.52(m,2H),1.76-1.62(m,2H),1.49(s,1H),1.12(dd,J=12.2,4.0Hz,2H).

[0498] Step 3: In a pressure vessel, [1-( 1,4-dioxane (58 mL, 0.5 M) dissolved in 1,4-dioxane ( 5-aminopyridine-2-yl)piperidine-4-yl]methanol (5.8 g, 27.9 mmol, 1 equivalent) and acrylic acid (1.9 mL, 27.9 mmol, 1 equivalent) were added. The resulting reaction mixture was stirred at 90°C. After 16 hours, 25% of the starting amine was still present. An additional 0.25 equivalents of acrylic acid were added, and the reaction mixture was stirred at 90°C for another 16 hours. The mixture was then concentrated, the resulting residue was diluted with ethyl acetate, refluxed, and the solution was decanted. The residue (black gum) was redissolved in MeOH and evaporated to obtain 6.4 g of 3-({6-[4-(hydroxymethyl)piperidine-1-yl]pyridine-3-yl}amino)propanoic acid (yield 78%). LCMS(M+H) + = 280.25. (MH) - = 278.025. 1 H NMR(300MHz,DMSO-d6)δ7.59(d,J=2.9Hz,1H),6.93(dd,J=8.9,3.0Hz,1H),6.68(d,J=8.9Hz,1H),4.00(dt,J=12.8,3.3Hz,2H) ,3.39(t,J=7.1Hz,1H),3.26(d,J=6.3Hz,3H),2.63-2.53(m,2H),2.47-2.29(m,3H),1.67(s,2H),1.13(dd,J=12.2,4.0Hz,2H).

[0499] Steps 4 and 5: 3-({6-[4-(hydroxymethyl)piperidine-1-yl]pyridine-3-yl}amino)propanoic acid (6.4 g, 21.76 mmol, 1.0 equivalent) and urea (2.614 g, 43.53 mmol, 2.0 equivalents) were dissolved in glacial acetic acid (64 mL, 10 vol) and stirred at 90°C for 48 hours. The reaction mixture was concentrated, the resulting residue was dissolved in EtOH (100 mL), and then H2SO4 (0.012 mL, 0.022 mmol, 0.01 equivalent) was added and stirred at room temperature for 48 hours. The pH of the reaction mixture was adjusted to pH=10-11 with KHSO4, concentrated, and purified by chromatography (DCM / MeOH-9 / 1). The obtained substance was further triturated by DCM to obtain 1.28 g of 1-{6-[4-(hydroxymethyl)piperidine-1-yl]pyridine-3-yl}-1,3-diadinane-2,4-dione (yield 18%). LCMS(M+H) + = 305.05. 1 H NMR(300MHz,DMSO-d6)δ10.34(s,1H),8.04(d,J=2.7Hz,1H),7.47(dd,J=9.0,2.8Hz,1H),6.84(d,J=9.1Hz,1H),4.47(t,J=5.3Hz, 1H),4.29(d,J=13.0Hz,2H),3.70(t,J=6.7Hz,2H),3.27(t,J=5.7Hz,2H),2.83-2.65(m,4H),1.77-1.54(m,3H),1.18-1.03(m,2H).

[0500] Step 6: To a solution of 1-{6-[4-(hydroxymethyl)piperidine-1-yl]pyridine-3-yl}-1,3-diadinane-2,4-dione (0.715 g, 2.3 mmol, 1 equivalent) dissolved in anhydrous DCM (0.3 M), a solution of des-martin periodinane (1.073 g, 2.53 mmol, 1.1 equivalent) in anhydrous DCM (0.15 M) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 1 hour (controlled by TLC and LCMS). The reaction mixture was diluted with saturated Na2S2O3 aqueous solution, the organic layer was separated, and washed with saturated NaHCO3. The aqueous layers were combined and back-extracted several times with DCM. The combined organic phase was dried over Na2SO4 and concentrated to obtain 0.56 g of 1-[5-(2,4-dioxo-1,3-diadinane-1-yl)pyridine-2-yl]piperidine-4-carbaldehyde (HA-19) (77% yield), a beige solid. The product tends to form a stable hydrate. 1 H NMR(300MHz,DMSO-d6)δ10.35(s,1H),9.63(d,J=0.9Hz,1H),8.08-8.03(m,1H),7.50(dd,J=9.0,2.8Hz,1H),6.88(d,J=9.1Hz,1H),4.13(dt,J=13. 2,4.1Hz,2H),3.70(t,J=6.7Hz,2H),3.11-2.99(m,2H),2.71(d,J=6.7Hz ,2H),2.66-2.55(m,1H),1.90(dd,J=13.3,3.9Hz,2H),1.55-1.42(m,2H). LCMSESI(+)[M+H] + = 305.11.

[0501] HA-20:rac-(R)-1-(4-(2,6-dioxopiperidine-3-yl)pyridine-2-yl)piperidine-4-carbaldehyde

[0502] [ka]

[0503] Step 1: In a 40 mL vial, rac-(3R)-3-(2-fluoropyridine-4-yl)piperidine-2,6-dione (1.0 g, 4.80 mmol), piperidine-4-yl methanol (0.59 g, 5.04 mmol), N,N-diisopropylethylamine (3.36 mL, 2.48 g, 19.21 mmol), and DMSO (7.00 mL) were added. The reaction mixture was stirred at 120 °C for 16 hours. The reaction mixture was then concentrated and purified by RP-FC (415 g C18 silica, 5-20% MeCN / H2O + 0.1% TFA) to obtain rac-(3R)-3-{2-[4-(hydroxymethyl)piperidine-1-yl]pyridine-4-yl}piperidine-2,6-dione;trifluoroacetic acid as a white solid (1.73 g, quantitative yield). LCMS.C 16 H 21 Theoretical value of N3O3: 303.2, Measured value: m / z = 304.5 [M + H] + .

[0504] Step 2: In a 200 mL flask, rac-(3R)-3-{2-[4-(hydroxymethyl)piperidine-1-yl]pyridine-4-yl}piperidine-2,6-dione;trifluoroacetic acid (1.71 g, 4.10 mmol), DCM (50.00 mL), and MeCN (10.00 mL) were added. The reaction mixture was cooled to 0°C, and 1,1-bis(acetyloxy)-3-oxo-1-lambda-5,2-benzoiodooxol-1-yl acetate (1.91 g, 4.51 mmol) was added all at once. After stirring at 0°C for 10 minutes, the reaction mixture was stirred for 3 hours while warming to room temperature. 3 mL of TEA was added to the reaction mixture, the crude mixture was then adsorbed onto silica, and the mixture was purified by column chromatography (120 g silica, 10-100% Â1 / DCM) to obtain the title compound as a white solid (233 mg, 18%). LCMS C 16 H 19 Theoretical value of N3O3: 301.1, Measured value: m / z = 302.1 [M + H] + .

[0505] HA-21: 1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)phenyl)piperidine-4-carbaldehyde

[0506] [ka]

[0507] Step 1: 1-(4-bromophenyl)-1,3-diadinane-2,4-dione (6.40 g, 24 mmol), cesium carbonate (9.30 g, 28.5 mmol), and DMF (60.00 mL) were added to a 40 mL vial. 4-methoxybenzyl chloride (4.17 mL, 4.84 g, 30.9 mmol) was added to the reaction mixture. The reaction mixture was stirred overnight and then quenched with water. The product was extracted with DCM (3×), dried over Na2SO4, and then concentrated. The resulting residue was purified by FC (330 g silica, 0-50% siRNA / DCM). The purified residue was concentrated under reduced pressure to obtain an amorphous solid. The mixture was then triturated with hexane to obtain 1-(4-bromophenyl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione as a white solid (9.26 g, quantitative yield). LCMS:C 18 H 17 Theoretical value for BrN2O3: 388.0, Measured value: m / z = 389.2 [M + H] + .

[0508] Step 2: 1-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diadinane-2,4-dione (550 mg, 1.41 mmol), 4-(1,3-dioxolan-2-yl)piperidine (666 mg, 4.24 mmol), di-tert-butyl({2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl})phosphane (240 mg, 0.57 mmol), palladium(II) acetate (63 mg, 0.28 mmol), cesium carbonate (1.38 g, 4.24 mmol), and dioxane (5.00 mL) were added to a 2-drum vial. The reaction mixture was sparged with N2 for 10 minutes and then stirred overnight at 95°C. The crude reaction mixture was diluted with DCM and water and then filtered through Celite. The product was extracted with DCM (3×), dried over MgSO4, and concentrated. The resulting residue was purified by FC (40g silica, 0-100% ELISA / hex) to obtain 1-(4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)phenyl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione as a white solid (395mg, 60%). LCMS:C 26 H 31 Theoretical value for N3O5: 465.2, Measured value: m / z = 466.4 [M + H] + .

[0509] Step 3: 1-{4-[4-(1,3-dioxolan-2-yl)piperidine-1-yl]phenyl}-3-[(4-methoxyphenyl)methyl]-1,3-diadinane-2,4-dione (395 mg, 0.85 mmol) and TFA (5.00 mL) were added to a 20 mL vial. Trifluoromethanesulfonic acid (374 μL, 636 mg, 4.24 mmol) was added to the reaction mixture. Complete conversion occurred after 10 minutes. The reaction mixture was diluted with a minimum amount of water and then purified by RP-FC (415 g C18 silica, 0-50% MeCN / water + 0.1% TFA) to obtain 1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)phenyl)piperidine-4-carbaldehyde as a white solid (40 mg, 16%). LCMS:C 16 H 21Theoretical value of N3O3: 301.1, Measured value: m / z = 302.2 [M + H] + .

[0510] HA-22: 1-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-fluorobenzoyl)piperidine-4-carbaldehy...

Claims

1. Compound of formula (I): 【Chemistry 267】 (In the formula, R1 is a C1-10 alkyl group optionally substituted with 1-3 Ra groups, a C3-10 cycloalkyl group optionally substituted with 1-3 Ra groups, a 4-12 member heterocyclyl group optionally substituted with 1-3 Ra groups, or a 5-12 member heteroaryl group optionally substituted with 1-3 Ra groups. L is -L1 -L2 -L3 -L4 -, and each L1, L2, L3 and L4 is independent of the others. a) C3-12 cycloalkyl groups optionally substituted with 1-3 Rb groups, b) C 6-12 Aryl, c) 4-12 member heterocyclines arbitrarily substituted with 1-3 R b, d) 5-12 member heteroaryl compounds arbitrarily substituted with 1-3 Rb groups, e) direct binding; f) C1-12 alkylene chains arbitrarily substituted with 1-3 Rd, g) C2-12 alkenylene chains arbitrarily substituted with 1-3 Rd, h) C2-12 alkynylene chains arbitrarily substituted with 1-3 Rd, i) 1 to 6 ethylene glycol units, j) 1 to 6 propylene glycol units, or k) -C(O)-, -C(O)O-, -O-, -N(R c )-, -S-, -C(S)-, -C(S)-O-, -S(O) 2 -, -S(O)=N-, -S(O) 2 NH-, -C(O)-N(R c )-, -C=N-, -O-C(O)-N(R c )-, or -O-C(O)-O- And, Each R a is independently a halo, -CN, a C1-3 alkyl group optionally substituted with 1-3 Rd groups, a C3-6 cycloalkyl group optionally substituted with 1-3 Rd groups, or -ORc. Each R b is independently an oxo, imino, sulfoxyimino, halo, nitro, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-12 aryl, 5-12 member heteroaryl, 4-12 member heterocyclyl, -O-Rc, -C(O)-Rc, -C(O)O-Rc, -C(O)-N(Rc)(Rc), -N(Rc)(Rc), -N(Rc)C(O)-Rc, -N(Rc)C (O)O-Rc, -N(Rc)C(O)N(Rc)(Rc), -N(Rc)S(O)2(Rc), -NRcS(O)2N(Rc)(Rc), -N(Rc)S(O)2O(Rc), -OC(O)Rc, -OC(O)-N(Rc)(Rc), -Si(Rc)3, -S-Rc, -S(O)Rc, -S(O)(NH)Rc, -S(O)2Rc, or -S(O)2N(Rc)(Rc) (wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C Each of the 3-15 cycloalkyl, C1-8 haloalkyl, C6-12 aryl, 5-12 member heteroaryl, and 4-12 member heterocyclil may be optionally substituted with 1-3 Rd groups. Each R c is independently hydrogen or C1-6 alkyl. Each R d is independently a C1-6 alkyl group optionally substituted with halo, oxo, -CN, -OH, 1-3 fluoro groups, or C3-8 cycloalkyl group, or an -O-C1-6 alkyl group optionally substituted with 1-3 fluoro groups. W is C(R g) or N, The B ring is a C6-12 aryl, which is optionally substituted with 1-3 Rj atoms. Each Rj can independently be hydrogen, oxo, imino, sulfoxyimino, halo, nitro, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-12 aryl, 5-12 member heteroaryl, 4-12 member heterocyclyl, -O-Rg, -C(O)-Rg, -C(O)O-Rg, -C(O)-N(Rg)(Rg), -N(Rg)(Rg), -N(Rg)C(O)-Rg, -N(Rg)C(O)O-Rg, -N(Rg)C(O)N(Rg)(Rg), -N(Rg)S(O)2 (R g), -NR g S(O) 2 N(R g)(R g), -N(R g)S(O) 2 O(R g), -OC(O)R g, -OC(O)-N(R g)(R g), -Si(R g) 3, -S-R g, -S(O)R g, -S(O)(NH)R g, -S(O) 2 R g, or -S(O) 2 N(R g)(R g) (wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-12 Each of the aryl, 5-12 membered heteroaryl, and 4-12 membered heterocyclyl may be optionally substituted with 1 to 3 R k groups. R g is hydrogen or C1-6 alkyl, Each R k is independently a halo, oxo, -CN, -OH, C1-6 alkyl or C3-8 cycloalkyl or -O-C1-6 alkyl or C3-3 alkyl), or a pharmaceutically acceptable salt thereof, isotopic form, isolated stereoisomer, or mixture of stereoisomers.

2. The B ring has the following structure: 【Chemistry 2】 Having one of the following, Each of L1, L2, L3, and L4 is independent of the others. a) C3-12 cycloalkyl groups optionally substituted with 1-3 Rb groups, b) C 6-12 Aryl, c) 4-12 member heterocyclines arbitrarily substituted with 1-3 R b, d) 5-12 member heteroaryl compounds arbitrarily substituted with 1-3 Rb groups, e) direct binding; f) C1-12 alkylene chains arbitrarily substituted with 1-3 Rd, or g) -C(O)-, -O-, -N(R c )-, or -C(O)-N(R c )- The compound according to claim 1.

3. The compound according to claim 2, wherein Rj is hydrogen or fluoro.

4. The compound according to claim 1, wherein W is CH.

5. The compound according to claim 1, wherein W is N.

6. L1 is, 【Chemistry 270】 And, -L2 -L3 -L4 - has the following structure: -C(O)-, -(CH 2 ) m -, 【Chemistry 271】 The compound according to claim 1, wherein m is 1, 2, or 3, and R c is H or C 1-3 alkyl.

7. L1 is, 【Chemistry 272】 And, -L2 -L3 -L4 - has the following structure: 【Chemistry 273】 One of them is The compound according to claim 1.

8. L1 is, 【Chemistry 274】 And -L2-L3-L4- has the following structure: -C(O)-, -(CH 2 ) m -, 【Chemistry 275】 The compound according to claim 1, wherein m is 1, 2, or 3, and R c is H or C 1-3 alkyl.

9. L has the following structure: 【Chemistry 276】 The compound according to claim 1, having one of the following.

10. L has the following structure: 【Chemistry 277】 The compound according to claim 1, having one of the following.

11. R1 is, a) C1-5 alkyl, which is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, -OH, -OC1-4 alkyl and -CN. b) A 4-8 membered heterocycline optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, C1-5 alkyl, -OH, -OC1-4 alkyl, and -CN, c) C3-10 cycloalkyls optionally substituted with 1-3 substituents independently selected from the group consisting of halo, C1-5 alkyl, -OH, -OC1-4 alkyl, and -CN, or d) 5-6 membered heteroaryl compounds optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, C1-5 alkyl, -OH, -OC1-4 alkyl, and -CN. The compound according to claim 1.

12. R1 is, a) C1-5 alkyl groups optionally substituted with halo, -OH, or -CN b) A 4-8 membered heterocycline optionally substituted with a halo, C1-5 alkyl, -OH, or -CN, or c) C3-10 cycloalkyl groups optionally substituted with halo, C1-5 alkyl, -OH, or -CN. The compound according to claim 1.

13. The compound according to claim 1, wherein R1 is oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, cyclobutyl, cyclohexyl, cyclopropyl, isoxazolyl, or C1-4 alkyl, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of F, C1-3 alkyl, -OH, -OCH3, or -CN.

14. The compound according to claim 1, wherein R1 is tetrahydrofuranyl, cyclohexyl, or C1-3 alkyl, each of which is optionally substituted with one or more substituents selected from the group consisting of F, C1-3 alkyl, -OH, -OCH3, or -CN. 【Request Item 15】 【Chemistry 278】 The structure of the part is as follows: 【Chemistry 279】 【Chemistry 280】 The compound according to claim 1, having one of the following.

16. The following 【Chemistry 16-1】 【Chemistry 16-2】 【Chemistry 16-3】 【Chemistry 16-4】 【Chemistry 16-5】 【Chemistry 16-6】 【Chemistry 16-7】 【Chemistry 16-8】 【Chemistry 16-9】 【Chemistry 16-10】 【Chemistry 16-11】 A compound having the structure.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, isotopic form, isolated stereoisomer, or mixture of stereoisomers, and a pharmaceutically acceptable carrier.

18. A pharmaceutical composition for treating cancer, comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, an isotopic form, an isolated stereoisomer, or a mixture of stereoisomers.

19. The pharmaceutical composition according to claim 18, wherein the cancer is selected from lymphoma, leukemia, acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS).

20. A pharmaceutical composition for treating metabolic disorders, comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, an isotopic form, an isolated stereoisomer, or a mixture of stereoisomers.

21. The pharmaceutical composition according to claim 20, wherein the metabolic disorder is selected from type 1 diabetes, type 2 diabetes, metabolic syndrome, dyslipidemia, obesity, impaired glucose tolerance, hypertension, elevated serum cholesterol, and elevated triglycerides.

22. A pharmaceutical composition for treating inflammatory disorders, comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, an isotopic form, an isolated stereoisomer, or a mixture of stereoisomers.

23. The pharmaceutical composition according to claim 22, wherein the inflammatory disorder is selected from rheumatoid arthritis (RA), inflammatory colitis (IBD), Crohn's disease, ulcerative colitis, necrotizing enterocolitis, gout, Lyme disease, arthritis, psoriasis, pelvic inflammatory disease, systemic lupus erythematosus (SLE), Sjögren's syndrome, inflammation associated with gastrointestinal infection, inflammation associated with Clostridioides difficile infection, viral myocarditis, acute tissue injury, chronic tissue injury, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, kidney disease, chronic kidney disease, and diabetic kidney disease.

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