6,7-Dihydro-5H-pyrido[2,3-C]pyridazine derivatives and related compounds as BCL-XL protein inhibitors and pro-apoptotic agents for treating cancer.

Abstract

The present invention discloses 6,7-dihydro-5H-pyrido[2,3-c]pyridazine, 1,2,3,4-tetrahydroquinoline, 1H-indole, 3,4-dihydro-2H-1,4-benzoxacin, 7H-pyrrolo[2,3-b]pyridin-1-yl, 5H,6H,7H,8H,9H-pyridazino[3,4-b]azepine derivatives and related compounds represented by Formula (I) as Bcl-xL protein inhibitors for use as pro-apoptotic agents for treating cancer, autoimmune diseases, or immune system disorders. Formula (I) In the description, preparations of exemplary compounds (e.g., Examples 1-221 on pages 113-354) and pharmacological studies with relevant data (e.g., Examples A-E, Tables 1-5 on pages 355-367) are disclosed. Exemplary compounds are 2-{6-[(1,3-benzothiazol-2-yl)amino]-1,2,3,4-tetrahydroquinolin-1-yl}-1,3-thiazole-4-carboxylic acid (Example 1) or, for example, 3-{1-[(adamantan-1-yl)methyl]-5-methyl-1H-pyrazol-4-yl}-6-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}pyridine-2-carboxylic acid (Example 24).

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to 6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl derivatives, pharmaceutical compositions containing them, and their use as pro-apoptotic agents. The compounds of the present invention inhibit the activity of the Bcl-xL protein and may be of interest in the treatment of cancer, immune disorders, and autoimmune diseases.

[0002] Background of the Invention Apoptosis (programmed cell death) is an evolutionarily conserved pathway essential for tissue homeostasis, development, and elimination of damaged cells. Deregulation of apoptosis contributes to human diseases, including malignancies, neurodegenerative disorders, immune system disorders, and autoimmune diseases (Hanahan and Weinberg, Cell. 2011 Mar 4;144(5):646-74; Marsden and Strasser, Annu Rev Immunol. 2003;21:71-105; Vaux and Flavell, Curr Opin Immunol. 2000 Dec;12(6):719-24). Evasion of apoptosis is recognized as a hallmark of cancer and is involved in tumor progression and persistent spread, as well as resistance to anticancer treatments (Hanahan and Weinberg, Cell. 2000 Jan 7;100(1):57-70).

[0003] The Bcl-2 protein family includes key regulators of cell survival, which can suppress (e.g., Bcl-2, Bcl-xL, Mcl-1) or promote (e.g., Bad, Bax) apoptosis (Gross et al., Genes Dev. 1999 Aug 1;13(15):1899-911; Youle and Strasser, Nat. Rev. Mol. Cell Biol. 2008 Jan;9(1):47-59). When faced with stressful stimuli, whether a cell survives or undergoes apoptosis depends on the degree of pairing between Bcl-2 family members that promote cell death with family members that promote cell survival. In most cases, these interactions involve docking of the Bcl-2 homology 3 (BH3) domain of the pro-apoptotic family member into a groove on the surface of the pro-survival member. The presence of Bcl-2 homology (BH) domains defines membership in the Bcl-2 family, which is divided into three major groups depending on the specific BH domains present in the protein: Pro-survival members, such as Bcl-2, Bcl-xL, and Mcl-1, contain BH domains 1-4, whereas Bax and Bak, pro-apoptotic effectors of mitochondrial outer membrane permeabilization during apoptosis, contain BH domains 1-3 (Youle and Strasser, Nat. Rev. Mol. Cell Biol. 2008 Jan;9(1):47-59).

[0004] Overexpression of pro-survival members of the Bcl-2 family is a hallmark of cancer, and these proteins have been shown to play important roles in tumor initiation, maintenance, and resistance to anticancer therapy (Czabotar et al., Nat. Rev. Mol. Cell Biol. 2014 Jan;15(1):49-63). Bcl-xL (also known as BCL2-like 1, or BCL2L1) is frequently amplified in cancer (Beroukhim et al., Nature 2010 Feb 18;463(7283):899-905), and its expression has been shown to inversely correlate with sensitivity to over 120 anticancer therapeutic molecules in a representative panel of cancer cell lines (NCI-60) (Amundson et al., Cancer Res. 2000 Nov 1;60(21):6101-10).

[0005] In addition, several studies using transgenic knockout mouse models and transgenic overexpression of Bcl-2 family members have highlighted the importance of these proteins in diseases of the immune system and autoimmune diseases (for review, see Merino et al., Apoptosis 2009 Apr;14(4):570-83. doi: 10.1007 / s10495-008-0308-4. PMID:19172396). Transgenic overexpression of Bcl-xL in the T cell compartment confers resistance to apoptosis induced by glucocorticoids, gamma-radiation, and CD3 cross-linking. This suggests that transgenic Bcl-xL overexpression may reduce apoptosis in resting and activated T cells (Droin et al., Biochim Biophys Acta 2004 Mar 1;1644(2-3):179-88. doi: 10.1016 / j.bbamcr.2003.10.011. PMID: 14996502). Sustained or high expression of anti-apoptotic Bcl-2 family proteins has been observed in patient samples (Pope et al., Nat Rev Immunol. 2002 Jul;2(7):527-35. doi: 10.1038 / nri846. PMID: 12094227). In particular, T cells isolated from the joints of patients with rheumatoid arthritis showed increased Bcl-xL expression and were resistant to spontaneous apoptosis (Salmon et al., J Clin Invest. 1997 Feb 1;99(3):439-46. doi: 10.1172 / JCI119178. PMID: 9022077). The use of BH3 mimetics has also shown benefit in preclinical models of immune system and autoimmune diseases. Treatment with ABT-737 (a Bcl-2, Bcl-xL, and Bcl-w inhibitor) resulted in potent inhibition of lymphocyte proliferation in vitro.Importantly, in animal models of arthritis and lupus, mice treated with ABT-737 showed a significant reduction in disease severity (Bardwell et al., J Clin Invest. 1997 Feb 1;99(3):439-46. doi: 10.1172 / JCI119178. PMID: 9022077). Additionally, ABT-737 has been shown to disrupt allogeneic T cell activation, proliferation, and cytotoxicity in vitro and inhibit allogeneic T and B cell responses after skin transplantation with high selectivity for lymphoid cells (Cippa et al., .Transpl Int. 2011 Jul;24(7):722-32. doi: 10.1111 / j.1432-2277.2011.01272.x. Epub 2011 May 25. PMID: 21615547).

[0006] These findings motivated the discovery and development of a new class of drugs called BH3 mimetics. These molecules can disrupt the interaction between pro- and anti-apoptotic members of the Bcl-2 family and are potent inducers of apoptosis. This new class of drugs includes inhibitors of Bcl-2, Bcl-xL, Bcl-w, and Mcl-1. The first BH3 mimetics described were ABT-737 and ABT-263, which target Bcl-2, Bcl-xL, and Bcl-w (Park et al., J. Med. Chem. 2008 Nov 13;51(21):6902-15; Roberts et al., J. Clin. Oncol. 2012 Feb 10;30(5):488-96). Subsequently, selective inhibitors of Bcl-2 (ABT-199 and S55746 - Souers et al., Nat Med. 2013 Feb;19(2):202-8; Casara et al., Oncotarget 2018 Apr 13;9(28):20075-20088), Bcl-xL (A-1155463 and A-1331852 - Tao et al., ACS Med Chem Lett. 2014 Aug 26;5(10):1088-93; Leverson et al., Sci Transl Med. 2015 Mar) and Bcl-xL (A-1155463 and A-1331852 - Tao et al., ACS Med Chem Lett. 2014 Aug 26;5(10):1088-93; Leverson et al., Sci Transl Med. 2015 Mar) were used. 18;7(279):279ra40) and selective inhibitors of Mcl-1 (A-1210477, S63845, S64315, AMG-176 and AZD-5991 - Leverson et al., Cell Death Dis. 2015 Jan 15;6:e1590.; Kotschy et al., Nature 2016, 538, 477-482; Maragno et al., AACR 2019, Poster #4482; Kotschy et al., WO 2015 / 097123; Caenepeel et al., Cancer Discov. 2018 Dec;8(12):1582-1597; Tron et al., Nat. Commun. 2018 Dec 17;9(1):5341) have also been discovered.The selective Bcl-2 inhibitor ABT-199 is currently approved in combination therapy for the treatment of patients with CLL and AML, while other inhibitors are still in preclinical or clinical development. In preclinical models, ABT-263 has shown activity in several hematological malignancies and solid tumors (Shoemaker et al., Clin. Cancer Res. 2008 Jun 1;14(11):3268-77; Ackler et al., Cancer Chemother. Pharmacol. 2010 Oct;66(5):869-80; Chen et al., Mol. Cancer Ther. 2011 Dec;10(12):2340-9). In clinical trials, ABT-263 has demonstrated promising antitumor activity in lymphoid malignancies (Wilson et al., Lancet Oncol. 2010 Dec;11(12):1149-59; Roberts et al., J. Clin. Oncol. 2012 Feb 10;30(5):488-96), and its activity is being explored in solid tumors in combination with several therapies. The selective Bcl-xL inhibitors A-1155463 and A-1331852 have demonstrated in vivo activity in preclinical models of T-cell acute lymphoblastic leukemia (T-ALL) and different types of solid tumors (Tao et al., ACS Med. Chem. Lett. 2014 Aug 26;5(10):1088-93; Leverson et al., Sci. Transl. Med. 2015 Mar 18;7(279):279ra40). Selective Mcl-1 inhibitors have shown promising in vivo activity in preclinical models of several types of hematological malignancies, and three of them, S64315, AMG176, and AZD5991, are currently being investigated in clinical trials (Yang et al., Eur. J. Med. Chem. 2019 May 8;177:63-75). Therefore, BH3 mimetics represent a very attractive approach for the development of novel therapeutics in the fields of oncology and immune and autoimmune diseases. In particular, there is a need for small molecules that selectively inhibit Bcl-xL proteins.The present invention fulfills this need.

[0007] Summary of the Invention The present invention provides potent, selective Bcl-xL inhibitors, represented by Formula (I), as defined below. The inventors have demonstrated that these compounds are capable of inducing apoptosis in cancer cells in vivo and tumor regression in mice. Based on their pro-apoptotic properties, the compounds of the present invention may be of interest for the treatment of pathologies involving deregulation of apoptosis, such as cancer, autoimmune diseases, and disorders of the immune system. Additionally, these compounds were well tolerated in mice, and treatment with effective doses did not result in clinically relevant weight loss. This indicates a potential therapeutic margin for the use of these Bcl-xL-targeting small molecules in the treatment of cancer. Consistent with the previously described role of Bcl-xL in regulating platelet lifespan (Zhang et al., Cell Death Differ. 2007 May;14(5):943-51; Mason et al., Cell. 2007 Mar 23;128(6):1173-86), a decrease in circulating platelet counts was observed after treatment of mice with these inhibitors, with recovery after treatment was discontinued. Given this effect on platelet survival, the Bcl-xL inhibitors of the present invention can also be used to treat diseases or conditions characterized by excessive or deregulated platelet activity, such as prothrombotic conditions. [Brief explanation of the drawings]

[0008]

Figure 1

Figure 2

[0009] Detailed Description of the Invention In a first embodiment (E1), the present invention provides a compound of formula (I): [ka] [In the formula, the Het moiety represents a fused aromatic or non-aromatic ring composed of 5 to 7 ring members which, in addition to nitrogen, may contain one further heteroatom or group selected from oxygen, sulfur and C═O; A4 and A5 each independently represent a carbon atom or a nitrogen atom, and preferably, A4 and A5 each represent a nitrogen atom; Z1 represents a bond, -N(R)- or -O-, where R represents hydrogen or linear or branched C1-C6 alkyl; R1 represents a group selected from hydrogen; linear or branched C1-C6 alkyl optionally substituted by a hydroxyl or C1-C6 alkoxy group; C3-C6 cycloalkyl; trifluoromethyl; linear or branched C1-C6 alkylene-heterocycloalkyl, wherein the heterocycloalkyl group is optionally substituted by a linear or branched C1-C6 alkyl group; R2 represents hydrogen or methyl; R3 is hydrogen; straight or branched C1-C4 alkyl; -X1-NR a R b ;-X1-N + R a R b R c ;-X1-OR c ;-X1-COOR c ;-X1-PO(OH)2;-X1-SO2(OH);-X1-N3 and [ka] represents a group selected from R a and R bare each independently hydrogen; heterocycloalkyl; -SO2-phenyl, wherein the phenyl can be substituted with a straight or branched chain C1-C6 alkyl; straight or branched chain C1-C6 alkyl optionally substituted with one or two hydroxyl groups; C1-C6 alkylene-SO2OH; C1-C6 alkylene-SO2O - ;C1-C6 alkylene-COOH;C1-C6 alkylene-PO(OH)2;C1-C6 alkylene-NR d R e C1-C6 alkylene-N + R d R e R f C1-C6 alkylene-phenyl (wherein the phenyl may be substituted by a C1-C6 alkoxy group); groups: [ka] represents a group selected from or R a and R b together with the nitrogen atom carrying them form ring B1, or R a , R b and R c together with their carrying nitrogen atom form a bridged C3-C8 heterocycloalkyl; R c , R d , R e , R f each independently represents hydrogen or a linear or branched C1-C6 alkyl group; or R d and R e together with the nitrogen atom carrying them form ring B2, or R d , R e and R f together with their carrying nitrogen atom form a bridged C3-C8 heterocycloalkyl; Het1 is: [ka] represents a group selected from Het2 is as follows: [ka] represents a group selected from A1 is -NH-, -N(C1-C3 alkyl), O, S or Se; A2 is N, CH or C(R5); G is -C(O)OR G3 , -C(O)NR G1 R G2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 R G2 , -OC(O)NR G1 R G2 , -NR G1 C(O)OR G3 , -C(=NOR G1 )NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O)NR G1 R G2 , -S(O)2R G3 , -S(O)NR G1 R G2 , -NR G1 S(O)2R G2 , -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , halogen, —NO2, and —CN; where: R G1 and R G2each occurrence independently represents hydrogen, C1-C6 alkyl optionally substituted with 1 to 3 halogen atoms, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, phenyl, and -(CH2) 1-4 -phenyl, R G3 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, phenyl, and —(CH2) 1-4 -phenyl, or R G1 and R G2 are linked together with the atom to which each is attached to form a C3-C8 heterocycloalkyl; Or alternatively, G is [ka] [In the formula, R G4 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl, optionally substituted with 1 to 3 halogen atoms. selected from the group consisting of R4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group; R5 represents a group selected from C1-C6 alkyl optionally substituted by 1 to 3 halogen atoms; C2-C6 alkenyl; C2-C6 alkynyl; halogen or -CN; R6 is hydrogen; -C2-C6 alkenyl; -X2-O-R7; [ka] ; -X2-NSO2-R7; -C=C(R9)-Y1-O-R7; C3-C6 cycloalkyl; C3-C6 heterocycloalkyl optionally substituted by a hydroxyl group; C3-C6 cycloalkylene-Y2-R7; C3-C6 heterocycloalkylene-Y2-R7 group; heteroarylene-R7 groups optionally substituted with straight or branched C1-C6 alkyl groups; represents a group selected from R7 is a straight or branched C1-C6 alkyl group; (C3-C6)cycloalkylene-R8; or [ka] [Wherein, Cy represents C3-C8 cycloalkyl] represents a group selected from R8 is hydrogen; straight or branched C1-C6 alkyl; -NR' a R' b ;-NR' a -CO-OR' c ;-NR' a -CO-R' c ;-N + R' a R' b R' c ;-O-R' c ;-NH-X'2-N + R' a R' b R' c ;-O-X'2-NR' a R' b ;-X'2-NR' a R' b ;-NR' c -X'2-N3 and [ka] represents a group selected from R9 represents a group selected from linear or branched C1-C6 alkyl, trifluoromethyl, hydroxyl, halogen, C1-C6 alkoxy; R 10represents a group selected from hydrogen, fluorine, chlorine, bromine, —CF3 and methyl, R 11 is hydrogen, halogen, C1-C3 alkylene-R8, -O-C1-C3 alkylene-R8, -CO-NR h R i and -CH=CH-C1-C4 alkylene-NR h R i , -CH=CH-CHO, C3-C8 cycloalkylene-CH2-R8, C3-C8 heterocycloalkylene-CH2-R8; R 12 and R 13 each independently represents a hydrogen atom or a methyl group; R 14 and R 15 each independently represents a hydrogen atom or a methyl group, or R 14 and R 15 together with the carbon atom carrying them form a cyclohexyl, R h and R i each independently represents hydrogen or a linear or branched C1-C6 alkyl group; X1 represents a linear or branched C1-C4 alkylene group optionally substituted by one or two groups selected from trifluoromethyl, hydroxyl, halogen, C1-C6 alkoxy; X2 represents a linear or branched C1-C6 alkylene group optionally substituted by one or two groups selected from trifluoromethyl, hydroxyl, halogen, C1-C6 alkoxy; X'2 represents a linear or branched C1-C6 alkylene; R' a and R' bare each independently hydrogen; heterocycloalkyl; -SO2-phenyl (wherein the phenyl can be substituted with a straight or branched chain C1-C6 alkyl); straight or branched chain C1-C6 alkyl optionally substituted with one or two hydroxyl or C1-C6 alkoxy groups; C1-C6 alkylene-SO2OH; C1-C6 alkylene-SO2O - ;C1-C6 alkylene-COOH;C1-C6 alkylene-PO(OH)2;C1-C6 alkylene-NR' d R' e C1-C6 alkylene-N + R d 'R' e R' f C1-C6 alkylene-O-C1-C6 alkylene-OH; C1-C6 alkylene-phenyl (wherein the phenyl may be substituted by a hydroxyl or C1-C6 alkoxy group); groups: [ka] represents a group selected from or R' a and R' b together with the nitrogen atom carrying them form ring B3, or R' a , R' b and R' c together with their carrying nitrogen atom form a bridged C3-C8 heterocycloalkyl; R' c , R' d , R' e , R' f each independently represents hydrogen or a linear or branched C1-C6 alkyl group; or R' d and R' e together with the nitrogen atom carrying them form ring B4, or R' d , R' e and R' ftogether with their carrying nitrogen atom form a bridged C3-C8 heterocycloalkyl; Y1 represents a linear or branched C1-C4 alkylene; Y2 represents a bond, -O-, -O-CH2-, -O-CO-, -O-SO2-, -CH2-, -CH2-O, -CH2-CO-, -CH2-SO2-, -C2H5-, -CO-, -CO-O-, -CO-CH2-, -CO-NH-CH2-, -SO2-, -SO2-CH2-, -NH-CO-, or -NH-SO2-; m=0, 1 or 2; p=1, 2, 3 or 4; B1, B2, B3, and B4 each independently represent a C3-C8 heterocycloalkyl group, which (i) can be a monocyclic or bicyclic group, where the bicyclic group includes fused, bridged, or spiro ring systems; (ii) can contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur, and nitrogen; and (iii) can be substituted by one or two groups selected from fluorine, bromine, chlorine, straight-chain or branched C1-C6 alkyl, hydroxyl, —NH2, oxo, or piperidinyl; Also, "Aryl" means a phenyl, naphthyl, biphenyl or indenyl group; "heteroaryl" means any monocyclic or bicyclic group consisting of 5 to 10 ring members, having at least one aromatic moiety, and containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen (including quaternary nitrogen); "Cycloalkyl" means any monocyclic or bicyclic non-aromatic carbocyclic group containing 3 to 10 ring members, which may include fused, bridged, or spiro ring systems; "Heterocycloalkyl" means any monocyclic or bicyclic non-aromatic carbocyclic group consisting of 3 to 10 ring members and containing 1 to 3 heteroatoms selected from oxygen, sulfur, SO, SO, and nitrogen, it being understood that bicyclic groups can be fused or spiro; Heteroarylene, cycloalkylene, heterocycloalkylene are understood to mean the divalent heteroaryl, cycloalkyl and heterocycloalkyl. The present invention provides compounds of the formula: embedded image and their enantiomers and diastereoisomers, as well as addition salts thereof with pharmaceutically acceptable acids or bases.

[0010] Among the pharmaceutically acceptable acids, mention may be made of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid and camphoric acid, without being meant to be limited thereto.

[0011] Among the pharmaceutically acceptable bases, mention may be made of sodium hydroxide, potassium hydroxide, triethylamine and tert-butylamine, without being meant to be limiting.

[0012] Further enumerated embodiments (E) of the present invention are described herein. It will be recognized that the features specified in each embodiment can be combined with other specified features to provide further embodiments of the present invention.

[0013] E2. Formula (IA): [ka] The compound according to E1, wherein the compound is a compound represented by the formula:

[0014] E3. The compound according to E1 or E2, wherein Z1 represents -NH- or -O-.

[0015] E4. R3 is -X1-NR a R b Preferably, the compound according to any one of E1 to E3 represents a group -C2H5-NH-CH3.

[0016] E5. the below described: [ka] The compound according to E1 or E2, selected from:

[0017] E6. Formula (IB): [ka] The compound according to E5, wherein the compound is a compound represented by the formula:

[0018] E7. The compound according to E6, wherein Z1 represents a bond and R3 represents a hydrogen atom.

[0019] E8. Formula (IC): [ka] [wherein A3 represents an oxygen atom or a sulfur atom] The compound according to E1, wherein the compound is a compound represented by the formula:

[0020] E9. The compound according to any one of E1 to E8, wherein R1 represents a hydrogen atom, a methyl or a cyclopropyl group, preferably methyl.

[0021] E10. Het1, [ka] The compound according to any one of E1 to E9, which represents:

[0022] E11. Het2, [ka] The compound according to any one of E1 to E10, which represents:

[0023] E12. Het2, [ka] The compound according to any one of E1 to E10, which represents:

[0024] E13. The compound according to E11, wherein R6 represents a -X2-O-R7 group, where X2 is a propylene group.

[0025] E14. R7 is the following group: [ka] The compound according to E13,

[0026] E15. R7 is the following group: [ka] The compound according to E13,

[0027] E16. R7 is the following group: [ka] The compound according to E13,

[0028] E17. R8 is NR' a R' b The compound according to any one of E14 to E16, which represents

[0029] E18. R8 is any of the following: dimethylamino, diethylamino, diisopropylamino, diisobutylamino, methylamino, ethylamino, ethyl(methyl)amino, 4-methyl-piperazin-1-yl, piperazin-1-yl, pyrrolidin-1-yl, azetidin-1-yl, 1-piperidyl, 4-morpholinyl, 4,4-difluoropiperidin-1-yl, 3,3-difluoropiperidin-1-yl, 3-hydroxy-1-piperidyl, (1S,5R)-3-azabicyclo[3.1.0]hexan-3-yl, 4-(1-piperidyl)-1-piperidyl, 3-oxo-2,8-diazaspiro[4.5]decan-8-yl, (1S,5R)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl aryl, 2-(dimethylamino)ethylamino, 3-piperazin-1-yl, (3R,5S)-3,5-dimethylpiperazin-1-yl, (but-3-yn-1-yl)amino, (but-3-yn-1-yl)(methyl)amino, (3-azidopropyl)amino, (3-azidopropyl)(methyl)amino(3-aminopropyl)amino, (pent-4-yn-1-yl)amino, methyl(pent-4-yn-1-yl)amino, (prop-2-yn-1-yl)amino, (hex-5-yn-1-yl)amino, 3-[(hex-5-yn-1-yl)(methyl)amino, (4-azidobutyl)amino, (4-azidobutyl)(methyl)amino, [2-(2-hydroxyethoxy)ethyl](methyl)amino, and [ka] The compound according to any one of E14 to E16, wherein the compound represents a group selected from:

[0030] E19. The compound according to any one of E14 to E16, wherein R8 represents a group selected from bis[(3S)-3,4-dihydroxybutyl]amino, amino, [(3S)-3,4-dihydroxybutyl]amino, [(3R)-3,4-dihydroxybutyl]amino, acetyl(methyl)amino, and 3-hydroxypropylamino.

[0031] E20. R7, [ka] [In the formula, R 11 is selected from 3-(dimethylamino)propyl, 3-(methylamino)propyl, aminomethyl, 2-(dimethylamino)ethyl, 4-(dimethylamino)butyl, 2-(methylamino)ethyl, 4-(methylamino)butyl, 3-(azetidin-1-yl)propyl, 3-(4-methylpiperazin-1-yl)propyl, 3-pyrrolidin-1-ylpropyl, 3-morpholinopropyl, 3-(1-piperidyl)propyl, 3-[(1R,5S)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl, and 3-(3-oxo-2,8-diazaspiro[4.5]decan-8-yl)propyl] The compound according to E13,

[0032] E21. R7, [ka] The compound according to E13, wherein the compound represents a group selected from:

[0033] E22. R6, [ka] The compound according to E12,

[0034] E23. R7, [ka] wherein R8 is -O-X'2-NR' a R' b or -X'2-NR' a R' b represents] The compound according to E22, wherein the compound represents a group selected from:

[0035] E24. R7, [ka] wherein R8 is hydrogen, 2-(methylamino)ethoxy, 2-(dimethylamino)ethoxy, 2-[(2-sulfoethyl)amino]ethoxy, 2-[methyl(2-sulfoethyl)amino]ethoxy, 4-methylpiperazin-1-yl, and [ka] represents a group selected from The compound according to E22, wherein the compound represents a group selected from:

[0036] E25. R7, [ka] [Wherein R8 is 2-pyrrolidin-1-ylethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 2-[[(3R)-3,4-dihydroxybutyl]-methyl-amino]ethoxy, 2-(4-hydroxybutylamino)ethoxy, 2-[[3-hydroxy-2-(hydroxymethyl)propyl]amino]ethoxy, 2-[bis(2-hydroxyethyl)amino]ethoxy, 2-[[2-hydroxy-1-(hydroxymethyl)ethyl yl]amino]ethoxy, 2-[2-(2-hydroxyethoxy)ethylamino]ethoxy, 2-[bis(3-hydroxypropyl)amino]ethoxy, 2-(3-hydroxypropylamino)ethoxy, 2-[bis(4-hydroxybutyl)amino]ethoxy, 2-morpholinoethoxy, 2-(1-piperidyl)ethoxy, 2-piperazin-1-ylethoxy, 2-(azepan-1-yl)ethoxy, 2-(4-isopropylpiperazin-1-yl)ethoxy, yl)ethoxy, 2-[(4-hydroxyphenyl)methylamino]ethoxy, 2-[2-hydroxyethyl(methyl)amino]ethoxy, 2-[3-methoxypropyl(methyl)amino]ethoxy, 2-[4-hydroxybutyl(methyl)amino]ethoxy, 3-pyrrolidin-1-ylpropyl, 3-(dimethylamino)propyl, 3-(4-methylpiperazin-1-yl)propyl, 3-morpholinopropyl, 3-(3-hydroxypropylamino)propyl, 3-(4-hydroxybutylamino)propyl, 3-[[(3S)-3,4-dihydroxybutyl]amino]propyl, 3-hydroxy-2-(hydroxymethyl)propyl]amino]propyl, 3-[4-hydroxybutyl(methyl)amino]propyl, 3-[3-hydroxypropyl(methyl)amino]propyl, 3-[3-[bis(3-hydroxypropyl)amino]propyl, 3-piperazin-1-ylpropyl represents a group selected from The compound according to E22, wherein the compound represents a group selected from:

[0037] E26. R3 is -X1-PO(OH)2, -X1-SO2(OH), -X1-NR a R b , -X1-N + Ra R b R c where R a Or R b or both of them are C1-C6 alkylene-SO2OH, C1-C6 alkylene-SO2O - and C1-C6 alkylene-PO(OH)2.

[0038] E27. R8 is -NR' a R' b , -N + R a 'R' b R' c , -NH-X'2-N + R' a R' b R' c where R' represents a and R' b The compound according to any one of E1, E2 and E6, wherein both of them represent a group selected from C1-C6 alkylene-SO2OH and C1-C6 alkylene-PO(OH)2.

[0039] E28. The following groups: 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[4-[3-(dimethylamino)prop-1-ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylic acid, 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}-5-(3-{2-fluoro-4-[3-(methylamino)prop-1-yn-1-yl]phenoxy}propyl)-1,3-thiazole-4-carboxylic acid, 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}-5-(3-{4-[3-(dimethylamino)propyl]-2-fluorophenoxy}propyl)-1,3-thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[2-fluoro-4-[3-(4-methylpiperazin-1-yl)but-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[2-fluoro-4-(3-pyrrolidin-1-ylprop-1-ynyl)phenoxy]propyl]thiazole-4-carboxylic acid, 5-(3-{4-[3-(azetidin-1-yl)prop-1-yn-1-yl]-2-fluorophenoxy}propyl)-2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}-1,3-thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[2-fluoro-4-[3-(4-methylpiperazin-1-yl)prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid, 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}-5-(3-{4-[3-(4,4-difluoropiperidin-1-yl)prop-1-yn-1-yl]-2-fluorophenoxy}propyl)-1,3-thiazole-4-carboxylic acid, 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}-5-(3-{4-[3-(3,3-difluoropiperidin-1-yl)prop-1-yn-1-yl]-2-fluorophenoxy}propyl)-1,3-thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[2-fluoro-4-[3-(3-oxo-2,8-diazaspiro[4.5]decan-8-yl)prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[4-[3-[(1S,5R)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl]prop-1-ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[2-fluoro-4-(3-piperazin-1-ylprop-1-ynyl)phenoxy]propyl]thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[4-[3-[(3R,5S)-3,5-dimethylpiperazin-1-yl]prop-1-ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[4-[3-(diethylamino)prop-1-ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[4-[3-(diisopropylamino)prop-1-ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylic acid, - 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[4-[3-[2-(dimethylamino)ethylamino]prop-1-ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylic acid, 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-6-[2-(methylamino)ethoxy]-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}-5-(3-{4-[3-(dimethylamino)prop-1-yn-1-yl]-2-fluorophenoxy}propyl)-1,3-thiazole-4-carboxylic acid, - 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[4-[1-[(dimethylamino)methyl]-3-bicyclo[1.1.1]pentanyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[2-fluoro-4-[3-methyl-3-(methylamino)but-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[2-fluoro-4-[3-(prop-2-ynylamino)prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid, - 6-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}-3-[1-({3-[2-(dimethylamino)ethoxy]-5,7-dimethyladamantan-1-yl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic acid, - 6-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}-3-[1-({3,5-dimethyl-7-[2-(methylamino)ethoxy]adamantan-1-yl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic acid, 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}-5-(3-{4-[3-(ethylamino)-3-methylbut-1-yn-1-yl]-2-fluorophenoxy}propyl)-1,3-thiazole-4-carboxylic acid, 3-{1-[(adamantan-1-yl)methyl]-5-methyl-1H-pyrazol-4-yl}-6-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}pyridine-2-carboxylic acid, A compound according to E1 selected from its enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.

[0040] E29. The following groups: - 6-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}-3-[1-({3-[2-(dimethylamino)ethoxy]-5,7-dimethyladamantan-1-yl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic acid, - 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3,5-dimethyl-7-(2-pyrrolidin-1-ylethoxy)-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, - 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3,5-dimethyl-7-[2-(4-methylpiperazin-1-yl)ethoxy]-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, - 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-(3-hydroxypropylamino)ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, - 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-(4-hydroxybutylamino)ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, - 6-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}-3-(1-{[3-(2-{[(3S)-3,4-dihydroxybutyl]amino}ethoxy)-5,7-dimethyladamantan-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid, - 6-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}-3-(1-{[3-(2-{[(3R)-3,4-dihydroxybutyl]amino}ethoxy)-5,7-dimethyladamantan-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid, - 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-[2-hydroxyethyl(methyl)amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, - 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-[4-hydroxybutyl(methyl)amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, - 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-[[(3R)-3,4-dihydroxybutyl]-methyl-amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, - 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3,5-dimethyl-7-(2-piperazin-1-ylethoxy)-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, - 6-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}-3-[1-({3,5-dimethyl-7-[2-(methylamino)ethoxy]adamantan-1-yl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic acid, - 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3,5-dimethyl-7-[2-(1-piperidyl)ethoxy]-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, - 3-[1-[[3-[2-(azepan-1-yl)ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]-6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]pyridine-2-carboxylic acid, - 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-(4-isopropylpiperazin-1-yl)ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, - 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3,5-dimethyl-7-(2-morpholinoethoxy)-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, - 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-[3-methoxypropyl(methyl)amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, - 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-[2-(2-hydroxyethoxy)ethylamino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, - 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, - 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-[[3-hydroxy-2-(hydroxymethyl)propyl]amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, - 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-[bis(2-hydroxyethyl)amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, - 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-[bis(3-hydroxypropyl)amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, - 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-[bis(4-hydroxybutyl)amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, - 6-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}-3-{1-[(3,5-dimethyl-7-{2-[(2-sulfoethyl)amino]ethoxy}adamantan-1-yl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic acid, - 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-[(4-hydroxyphenyl)methylamino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[4-[3-(dimethylamino)prop-1-ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[4-[3-[[(3S)-3,4-dihydroxybutyl]amino]prop-1-ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[2-fluoro-4-[3-(3-hydroxypropylamino)prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid, A compound according to E1 selected from its enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.

[0041] E30. As a starting material, a compound of formula (II): [ka] A compound represented by the formula: This compound of formula (II) is subjected to leaving group incorporation (preferably using iodination) to give a compound of formula (III): [ka] wherein LG represents a leaving group (preferably a halogen atom, more preferably iodine). to produce a compound represented by the formula The compound of formula (III) is reacted with a compound of formula (IV): [ka] [wherein G1 represents a C1-C6 alkyl group or a (4-methoxyphenyl)methyl group; [ka] represents a protecting group (preferably a tert-butoxycarbonyl group). to obtain a compound of formula (V): [ka] to produce a compound represented by the formula The amino group of the compound of formula (V) is deprotected (preferably using 1,1,1,3,3,3-hexafluoroisopropanol) to give a compound of formula (VI): [ka] to produce a compound represented by the formula The compound of formula (VI) can be reacted with a phosphine palladium complex (preferably Pd(AtaPhos)Cl), a base (preferably CsCO) and a compound of formula (VII): [ka] wherein R7 is as defined in formula (I). to a Suzuki coupling reaction in an aqueous or organic medium in the presence of a compound of formula (VIII): [ka] to produce a compound represented by the formula The compound of formula (VIII) is further subjected to an intramolecular Buchwald coupling reaction in the presence of a phosphine palladium complex (preferably Pd(AtaPhos)2Cl2) and at least one base (preferably Cs2CO3 and DIPEA) in an aqueous or organic medium to give a compound of formula (IX): [ka] to produce a compound represented by the formula The compound of formula (IX) can be reacted with a palladium catalyst (preferably Pd2(dba)3), a base (preferably DIPEA), a phosphine (preferably Xantphos) and a compound of formula (X): [ka] wherein R4 and m are as defined in formula (I). to a Buchwald reaction in an aqueous or organic medium in the presence of a compound of formula (XI): [ka] to produce a compound represented by the formula hydrolyzing the ester functionality of the compound of formula (XI) (preferably using LiOH×HO or TFA) to produce a compound of formula (I); The compound of formula (I) can be purified according to conventional separation techniques, converted into its addition salt with a pharmaceutically acceptable acid or base, which can optionally be separated into its isomers according to conventional separation techniques, It is understood that at any point in the course of the above-described processes deemed appropriate, hydroxy, amino, carboxylic acid and phosphono groups of synthetic reagents or intermediates may be protected and then deprotected according to the requirements of the synthesis. A method for producing a compound of formula (I) according to E6.

[0042] E31. The group R7 is [ka] [In the formula, R8, R 12 and R 13 is as defined in formula (I). The method of E30, wherein the method is selected from the group consisting of:

[0043] E32. As a starting material, a compound of formula (II): [ka] A compound represented by the formula: The compound of formula (II) can be reacted with triphenylphosphine in toluene, a suitable coupling reagent (preferably di-tert-butyl azodicarboxylate) and a compound of formula (XII-a) or (XII-b): [ka] [In the formula, A1, A2, and R6 are as defined in formula (I), G1 represents a C1-C6 alkyl group or a (4-methoxyphenyl)methyl group, [ka] represents a protecting group (preferably a tert-butoxycarbonyl group)] to obtain a compound of formula (XIII-a) or (XIII-b): [ka] to produce a compound represented by the formula The amino group of the compound represented by formula (XIII-a) or (XIII-b) is further deprotected to obtain a compound represented by formula (XIV-a) or (XIV-b): [ka] To produce a compound represented by (i) further subjecting the compound of formula (XIV-a) to an intramolecular coupling reaction in the presence of a base (preferably Cs2CO3) in an aqueous or organic medium to produce a compound of formula (XV-a); or or (ii) The compound of formula (XIV-b) is further subjected to an intramolecular Buchwald coupling reaction in the presence of a phosphine palladium complex (preferably Pd(AtaPhos)Cl) and at least one base (preferably CsCO and DIPEA) in an aqueous or organic medium to obtain a compound of formula (XV-b): [ka] to produce a compound represented by the formula A compound represented by formula (XV-a) or (XV-b) can be reacted with a palladium catalyst (preferably Pd2(dba)3), a base (preferably DIPEA), a phosphine (preferably Xantphos) and a compound represented by formula (X): [ka] to a Buchwald reaction in an aqueous or organic medium in the presence of a compound of formula (XVI-a) or (XVI-b): [ka] to produce a compound represented by the formula hydrolyzing the ester functionality of the compound of formula (XVI-a) or (XVI-b) (preferably using LiOH×HO or TFA) to produce a compound of formula (I); The compound of formula (I) can be purified according to conventional separation techniques, converted into its addition salt with a pharmaceutically acceptable acid or base, which can optionally be separated into its isomers according to conventional separation techniques, It is understood that at any point in the course of the above-described processes deemed appropriate, hydroxy, amino, carboxylic acid and phosphono groups of synthetic reagents or intermediates may be protected and then deprotected according to the requirements of the synthesis. A method for producing a compound of formula (I) according to E6.

[0044] E33. The following groups: [ka] wherein R7 is as defined in formula (I), and G1 represents a C1-C6 alkyl group, preferably a methyl group or a (4-methoxyphenyl)methyl group. Selected from: A synthetic intermediate according to E30 or E31.

[0045] E34. The following groups: [ka] wherein R6 is as defined in formula (I), and G1 represents a C1-C6 alkyl group, preferably a methyl group or a (4-methoxyphenyl)methyl group. Selected from: A synthetic intermediate described in E32.

[0046] E35. The compound according to E1, wherein R4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl or methoxy group.

[0047] E36. R8 is hydrogen; straight or branched C1-C6 alkyl; -NR' a R' b ;-NR' a -CO-OR' c ;-N + R' a R' b R' c ;-O-R' c ;-NH-X'2-N + R' a R' b R' c ;-O-X'2-NR' a R' b ;-NR' c -X'2-N3 and [ka] The compound according to E1, wherein the compound is a group selected from the group consisting of:

[0048] E37. R' a and R' b are each independently hydrogen; heterocycloalkyl; -SO2-phenyl (wherein the phenyl can be substituted with a straight or branched chain C1-C6 alkyl); straight or branched chain C1-C6 alkyl optionally substituted with one or two hydroxyl groups; C1-C6 alkylene-SO2OH; C1-C6 alkylene-SO2O - ;C1-C6 alkylene-COOH;C1-C6 alkylene-PO(OH)2;C1-C6 alkylene-NR'd R' e C1-C6 alkylene-N + R d 'R' e R' f C1-C6 alkylene-O-C1-C6 alkylene-OH; C1-C6 alkylene-phenyl (wherein the phenyl may be substituted by a C1-C6 alkoxy group); groups: [ka] represents a group selected from or R' a and R' b together with the nitrogen atom carrying them form ring B3, or R' a , R' b and R' c are taken together with the nitrogen atom bearing them to form a bridged C3-C8 heterocycloalkyl.

[0049] E38. The compound according to any one of E1 to E27, wherein m=1.

[0050] Pharmacological studies of the compounds of the present invention have shown that they have pro-apoptotic properties. The ability to reactivate the apoptotic process in cells is of major therapeutic interest in the treatment of cancer and immune and autoimmune diseases. In particular, the compounds of the present invention are useful in the treatment of chemotherapy- or radiotherapy-resistant cancers.

[0051] In another embodiment, the compounds of the present invention can be used to treat diseases or conditions characterized by excessive or deregulated platelet activity, particularly prothrombotic conditions.

[0052] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refer, in one embodiment, to ameliorating the disease or disorder (i.e., slowing, halting, or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treat," "treating," or "treatment" refers to alleviating or improving at least one physical parameter, including those that may not be discernible by the patient. In yet another embodiment, "treat," "treating," or "treatment" refers to modulating the disease or disorder either physically (e.g., stabilizing a discernible symptom), physiologically (e.g., stabilizing a physical parameter), or both.

[0053] Among the cancer treatments envisioned, mention may be made of, but are not limited to, the treatment of hematological malignancies and solid tumors. Hematological malignancies include myeloma, in particular multiple myeloma, lymphoma, in particular non-Hodgkin's lymphoma (NHL), especially diffuse large B-cell lymphoma (DLBCL), and leukemia, in particular chronic lymphocytic leukemia (CLL), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), and acute myeloid leukemia (AML). Solid tumors include bladder cancer, brain cancer, breast cancer, uterine cancer, esophageal cancer, liver cancer, colorectal cancer, kidney cancer, melanoma, ovarian cancer, prostate cancer, pancreatic cancer, and lung cancer, in particular non-small cell lung cancer and small cell lung cancer.

[0054] In particular, T-ALL arises from the leukemic transformation of thymocyte precursors and their arrest at a specific differentiation stage. Despite extensive recent insights into the molecular and cellular mechanisms underlying the development and progression of T-ALL, this knowledge has not yet been translated into effective targeted therapies. Current clinical treatments involve chemotherapy with or without hematopoietic stem cell transplantation, with survival rates remaining at approximately 50% and 70% in adult and pediatric cases, respectively. In both pediatric and adult cases, relapse carries a very poor prognosis, highlighting the need for the discovery of novel therapeutic options (Passaro et al., Immunol. Rev. 2016 May;271(1):156-72). Dual Bcl-2 / Bcl-xL inhibitors, such as ABT-263 and ABT-737, have shown promising activity in T-ALL patient-derived xenograft models (Van Delft et al. Cancer Cell 2006;10:389-99; Suryani et al., Clin. Cancer Res. 2014,20:4520-31). Other studies have reported different requirements for Bcl-xL or Bcl-2 for survival between mature and very immature (ETP subgroup) T-ALL (Chonghaile et al., Cancer Discov. 2014;4:1074-87). A-1331852, a previously described selective Bcl-xL inhibitor, has also been shown to have in vitro and in vivo activity in the mature T-ALL cell line xenograft model MOLT-4 (Leverson et al., Sci. Transl. Med. 2015 Mar 18;7(279):279ra40). In certain embodiments, tumor growth inhibition was also observed in the MOLT-4 xenograft model upon treatment with the Bcl-xL inhibitors of the present invention. These data support the use of the present compounds in the treatment of T-ALL.

[0055] Among the possible treatments of autoimmune diseases, mention may be made of the treatment of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), without being meant to be limiting.

[0056] The present invention also relates to pharmaceutical compositions comprising at least one compound of formula (I) as an active ingredient in combination with one or more pharmaceutically acceptable excipients, and in particular, these pharmaceutical compositions are of interest for use as pro-apoptotic and / or anti-proliferative agents, especially in the treatment of cancer and autoimmune and immune system diseases.

[0057] Excipients suitable for the present invention include diluents, lubricants, binders, disintegrants, stabilizers, preservatives, absorbents, colorants, sweeteners and flavoring agents.

[0058] As non-limiting examples, the following may be mentioned: Diluents include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and glycerol. Lubricants: silica, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol Binders include magnesium aluminum silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone. Disintegrants: agar, alginic acid and its sodium salt, effervescent mixture

[0059] Among the pharmaceutical compositions according to the invention, mention may be made especially of those suitable for oral, parenteral, nasal, transdermal, rectal, lingual, ocular or respiratory administration, in particular tablets, dragees, sublingual tablets, capsules, glossettes, capsules, lozenges, injectable or drinkable preparations, aerosols, eye or nasal drops, suppositories, creams, ointments, skin gels.

[0060] The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention can be varied to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient. The selected dosage level will depend on a variety of factors, including the activity of the particular compound of the present invention employed, the route of administration, the timing of administration, the rate of excretion or metabolism of the particular compound employed, the rate and extent of absorption, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health, and previous medical history of the patient being treated, and similar factors well known in the medical arts.

[0061] Suitable daily doses of the compounds of the present invention will depend on the factors mentioned above, and may range from 0.01 mg to 2.5 g per day, in one or more administrations.

[0062] In another aspect, the present invention also relates to combinations of compounds of formula (I) with anti-cancer agents selected from genotoxic agents, mitotic poisons, antimetabolites, proteasome inhibitors, kinase inhibitors and antibodies, as well as to pharmaceutical compositions comprising such types of combinations and their use in the manufacture of medicaments for use in the treatment of cancer.

[0063] In another embodiment, the compounds of the present invention can be used in combination with radiation therapy in the treatment of cancer.

[0064] Alternatively, the compounds of the present invention can be conjugated to monoclonal antibodies. Antibody-drug conjugates (ADCs) represent a new class of therapeutic agents formed by chemically linking a cytotoxic agent to a monoclonal antibody via a linker. The monoclonal antibody of an ADC selectively binds to a target antigen in cells (e.g., cancer cells) and releases the drug intracellularly. ADCs have therapeutic potential because they combine the specificity of an antibody with the cytotoxicity of a drug. Nevertheless, the development of ADCs as therapeutic agents has met with limited success due to various factors, such as unfavorable toxicity profiles, low efficacy, and poor pharmacological parameters. Therefore, there remains a need for novel ADCs that can overcome these problems and selectively deliver Bcl-xL to target cancer cells.

[0065] In another embodiment, the compounds of the present invention can be conjugated to fragments of monoclonal antibodies or to scaffold proteins that may or may not be related to monoclonal antibodies. Antibody fragments should be understood to be fragments of the Fv, scFv, Fab, F(ab')2, F(ab'), scFv-Fc type, or diabody type, which generally have the same binding specificity as the antibody from which they are derived. According to the present invention, antibody fragments of the present invention can be obtained starting from antibodies by methods such as digestion with enzymes, for example, pepsin or papain, and / or by cleavage of disulfide bridges by chemical reduction. Alternatively, antibody fragments encompassed by the present invention can be obtained by genetic recombination techniques also well known to those skilled in the art or by peptide synthesis, for example, by automated peptide synthesizers, such as those provided by Applied Biosystems.

[0066] Scaffold proteins, which may or may not be related to monoclonal antibodies, are understood to mean proteins that contain or do not contain an immunoglobulin fold and that produce binding abilities similar to those of monoclonal antibodies. Those skilled in the art know how to select protein scaffolds. It is known that such scaffolds are selected so that they exhibit several characteristics, such as good phylogenetic conservation, a robust structure with a known three-dimensional molecular structure (e.g., crystallography or NMR), small size, no or only little post-translational modifications, and ease of production, expression, and purification (Skerra, J. Mol. Recogn. 2000, 13, 167-187). Such protein scaffolds may be, but are not limited to, structures selected from the group consisting of fibronectin and, preferentially, the tenth fibronectin type III domain (FNfn10), lipocalins, anticalins (Skerra, J. Biotechnol. 2001, 74, 257-75), protein Z derivatives derived from domain B of staphylococcal protein A, thioredoxin A, or any protein with a repeat domain, such as ankyrin repeats (Kohl et al. PNAS 2003, 100, 1700-1705), armadillo repeats, leucine-rich repeats, or tetratricopeptide repeats. Reference may also be made to scaffold derivatives derived from toxins (such as scorpion, insect, plant, or mollusk toxins) or protein inhibitors of neuronal nitric oxide synthase (PIN).

[0067] The following examples illustrate the present invention without, however, limiting it in any way. All intermediates for preparing the examples are either commercially available or can be obtained by those skilled in the art using conventional chemistry described in the literature.

[0068] General Procedure All reagents obtained from commercial sources were used without further purification. Anhydrous solvents were obtained from commercial sources and used without further drying.

[0069] Column chromatography Automated flash column chromatography was performed on an ISCO CombiFlash® Rf 200 or CombiFlash® Rf+ Lumen™ using RediSep® Rf normal-phase silica flash columns (35-70 μm, 60 Å), RediSep® Rf Gold® Rf normal-phase silica high-performance columns (20-40 μm, 60 Å), RediSep® Rf reverse-phase C18 columns (40-63 μm, 60 Å), or RediSep® Rf Gold® reverse-phase C18 high-performance columns (20-40 μm, 100 Å).

[0070] TLC Thin layer chromatography was performed using a Merck Type 60 F 254 The experiments were carried out on silica gel-coated 5 x 10 cm plates.

[0071] Microwave Reaction Microwave heating was performed in a CEM Discover® SP or Anton Paar Monowave microwave reactor.

[0072] NMR 1 H-NMR measurements were carried out on a Bruker Avance III 500 MHz spectrometer, a Bruker Avance III 400 MHz spectrometer, or a Bruker DPX-400 spectrometer using DMSO-d6 or CDCl3 as the solvent. 1H NMR data are in the form of delta values ​​given in parts per million (ppm) using the residual solvent peaks (2.50 ppm for DMSO-d6, 7.26 ppm for CDCl3) as internal standards. Splitting patterns are designated as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), sept (septet), m (multiplet), br s (broad singlet), dd (doublet of doublets), td (triplet of doublets), dt (doublet of triplets), and ddd (doublet of doublet of doublets).

[0073] Analytical LC-MS Specific compounds of the present invention were characterized by high-performance liquid chromatography-mass spectrometry (HPLC-MS) on an Agilent HP1200 equipped with an Agilent 6140 quadrupole LC / MS operating in positive or negative ion electrospray ionization mode. The molecular weight scan range was 100-1350. Parallel UV detection was performed at 210 nm and 254 nm. Samples were delivered as 1 mM solutions in ACN or THF / HO (1:1) via a 5 μL loop injection. LCMS analysis was performed on two instruments, one operated with a basic eluent and the other with an acidic eluent.

[0074] Basic LCMS: Gemini-NX, 3 μm, C18, 50 mm x 3.00 mm ID column, 23° C., 1 mL / min flow rate using 5 mM ammonium bicarbonate (solvent A) and acetonitrile (solvent B). Gradient starting with 100% solvent A and ending with 100% solvent B over various / specified durations.

[0075] Acidic LCMS: KINATEX XB-C18-100A, 2.6 μm, 50 mm x 2.1 mm column, 40° C., 1 mL / min flow rate using 0.02% v / v formic acid in water (solvent A) and 0.02% v / v formic acid in acetonitrile (solvent B). Gradient starting at 100% solvent A and ending at 100% solvent B for various / specified durations.

[0076] Certain other compounds of the present invention were characterized by HPLC-MS using the specified named methods as follows. For all of these methods, UV detection was by a diode array detector at 230, 254, and 270 nm. The sample injection volume was 1 μL. Gradient elution was performed using HPLC-grade solvents by defining the flow rate and mixture ratio of the following mobile phases:

[0077] Solvent A: 10 mM ammonium formate solution + 0.04% (v / v) formic acid Solvent B: Acetonitrile + 5.3% (v / v) Solvent A + 0.04% (v / v) formic acid

[0078] Retention times (RT) for these named methods are reported (min). Ionization was recorded in positive, negative, or positive-negative switching mode. Specific details for each method are provided below.

[0079] LCMS-VB method An Agilent 1200 SL series instrument (LCMS-V-B1 and LCMS-V-B2) coupled to an Agilent MSD 6140 single quadrupole equipped with an ESI-APCI multimode source or an Agilent 1290 Infinity II series instrument (LCMS-V-B1) coupled to an Agilent TOF 6230 equipped with an ESI jet flow source was used; column: Thermo Accucore 2.6 μm, C18, 50 mm × 2.1 mm, 55 °C. Gradient details for LCMS-V-B1 and LCMS-V-B2 methods: [Table 1]

[0080] LCMS-VC method An Agilent 1200 SL Series instrument coupled to an Agilent MSD 6140 single quadrupole equipped with an ESI-APCI multimode source was used; column: Agilent Zorbax Eclipse plus 3.5 μm, C18(2), 30 mm x 2.1 mm, 35 °C. Gradient details for the LCMS-VC method: [Table 2]

[0081] Preparative HPLC Certain compounds of the invention were purified by high performance liquid chromatography (HPLC) on an Armen Spot liquid chromatography or Teledyne EZ system equipped with a Gemini-NX® 10 μm C18, 250 mm x 50 mm i.d. column operated at a flow rate of 118 mL / min with UV diode array detection (210-400 nm) using 25 mM aqueous NH4HCO3 and MeCN or 0.1% TFA and MeCN in water as eluents.

[0082] Certain other compounds of the present invention were purified by HPLC using the specifically named method as follows.

[0083] HPLC-VA method These were separated using a Gemini® 5 μm C18(2), 100 mm × 20 mm i.d. column (Phenomenex) at 20 cm 3 The analysis was performed on a Waters FractionLynx MS automated purification system operated at a flow rate of 1 / min with UV diode array detection (210-400 nm) and mass-directed collection. The mass spectrometer was a Waters Micromass ZQ2000 spectrometer operated in positive or negative ion electrospray ionization mode with a molecular weight scan range of 150-1000.

[0084] HPLC-V-A1 method (pH4) Solvent A: 10 mM ammonium acetate solution + 0.08% (v / v) formic acid; Solvent B: acetonitrile + 5% (v / v) solvent A + 0.08% (v / v) formic acid

[0085] HPLC-V-A2 method (pH9) Solvent A: 10 mM ammonium acetate solution + 0.08% (v / v) ammonia; Solvent B: acetonitrile + 5% (v / v) solvent A + 0.08% (v / v) ammonia

[0086] HPLC-VB method A Gemini® NX 5 μm C18(2), 150 mm × 21.2 mm i.d. column (Phenomenex) was used. 3 The analysis was performed on an AccQPrep HP125 (Teledyne ISCO) system operated at a flow rate of 1 / min with UV (214 nm and 254 nm) and ELS detection.

[0087] HPLC-V-B1 method (pH4) Solvent A: water + 0.08% (v / v) formic acid; Solvent B: acetonitrile + 0.08% (v / v) formic acid

[0088] HPLC-V-B2 method (pH9) Solvent A: Water + 0.08% (v / v) ammonia; Solvent B: Acetonitrile + 0.08% (v / v) ammonia

[0089] HPLC-V-B3 method (neutral) Solvent A: water; Solvent B: acetonitrile

[0090] Analytical GC-MS Gas chromatography coupled with low-resolution mass spectrometry (GC-MS) was performed on an Agilent 6850 gas chromatograph and Agilent 5975C mass spectrometer using a 15 m × 0.25 mm column with a 0.25 μm HP-5MS coating and helium as the carrier gas: ion source: EI+, 70 eV, 230 °C, quadrupole: 150 °C, interface: 300 °C.

[0091] High resolution MS High-resolution mass spectra were acquired on an Agilent 6230 time-of-flight mass spectrometer equipped with a Jet Stream electrospray ion source in positive ion mode. A 0.5 μl injection was directed to the mass spectrometer using an Agilent 1290 Infinity HPLC system at a flow rate of 1.5 ml / min (5 mM ammonium formate in water and acetonitrile gradient program). Jet Stream parameters: Drying gas (N2) flow and temperature: 8.0 l / min and 325 °C, respectively; Nebulizer gas (N2) pressure: 30 psi; Capillary voltage: 3000 V; Sheath gas flow and temperature: 325 °C and 10.0 l / min. TOFMS parameters: Fragmenter voltage: 100 V; Skimmer voltage: 60 V; OCT 1 RF Vpp: 750 V. Full-scan mass spectra were acquired over the m / z range of 105–1700 at an acquisition rate of 995.6 ms / spectrum and processed by Agilent MassHunter B.04.00 software.

[0092] Compound name IUPAC standard names were generated using the "Structure to Name" (s2n) function of ChemAxon within MarvinSketch or JChem for Excel (JChem versions 16.6.13-18.22.3) or by the compound naming functionality provided by Biovia® Draw 4.2.

[0093] Abbreviation Ahx 6-hexanoic acid monomer AgOTf Silver trifluoromethanesulfonate t BuOH tert-butanol cc. Concentrate CyOH Cyclohexanol dba (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one, dibenzylideneacetone DCM dichloromethane DIPA N-Isopropylpropan-2-amine, Diisopropylamine DIPEA N-Ethyl-N-isopropyl-propan-2-amine, Diisopropylethylamine DMAP 4-dimethylaminopyridine ee. Enantiomeric excess eq. equivalent amount EtOAc ethyl acetate HF×Pyr Hydrogen Fluoride Pyridine hs Homo sapiens LDA Lithium diisopropylamide MeCN acetonitrile MeOH Methanol NMP N-methyl-2-pyrrolidone Pd(AtaPhos)2Cl2 Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) rt room temperature RT Hold time (in minutes) on overnight TBAF Tetrabutylammonium Fluoride TBAOH Tetrabutylammonium hydroxide TBDPS-Cl tert-butyl-chloro-diphenyl-silane TBSCl tert-butyl-chloro-dimethyl-silane TEA N,N-Diethylethanamine TFA 2,2,2-trifluoroacetic acid pTSA 4-methylbenzenesulfonic acid THF tetrahydrofuran TMP-MgCl 2,2,6,6-Tetramethylpiperidinyl magnesium chloride lithium chloride complex solution DIAD Diisopropyl azodicarboxylate Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene BrettPhos 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl JosiPhos (2R)-1-[(1R)-1-(dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)ferrocene JosiPhos Pd G3 {(R)-1-[(Sp)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine}[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate Xantphos Pd G3 [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl rac-BINAP Pd G3 [(2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate Pd(dppf)Cl2.CH2Cl2[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)

[0094] Named general procedure Below are representative experimental procedures that are referenced by name in the preparations that follow.

[0095] General procedure for Sonogashira reaction A mixture of 1 equivalent of aryl halogenide, 2 equivalents of acetylene, 0.05 equivalents of Pd(PPh)Cl, 0.05 equivalents of CuI, and DIPA (1 mL / mmol) in THF (5 mL / mmol) was maintained at 60° C. After reaching adequate conversion, the volatiles were removed under reduced pressure and the crude intermediate was purified via flash chromatography using heptane / EtOAc as the eluent.

[0096] General procedure for deprotection with HFIP The substrate in HFIP (10 mL / mmol) was kept in a pressure bottle at 100-120° C. After reaching a suitable conversion, the volatiles were removed under reduced pressure and the crude intermediate was purified via flash chromatography using heptane / EtOAc as the eluent.

[0097] General procedure for deprotection and hydrolysis A mixture of 1 equivalent of substrate and 100 equivalents of HF×Pyr in MeCN (15 mL / mmol) was stirred at 60 °C. After reaching a suitable conversion, the volatiles were removed under reduced pressure, the residue was suspended in a 1:1 mixture of THF-water (30 mL / mmol), 150 equivalents of LiOH×HO was added, and the mixture was stirred at room temperature. After reaching a suitable conversion, the volatiles were removed under reduced pressure; the crude product was purified via flash chromatography using DCM and MeOH (containing 1.2% NH) as eluents.

[0098] General procedure for alkylation A mixture of 1 equivalent of phenol / carbamate, 1-2 equivalents of alkyl iodide / bromide, and 2-3 equivalents of CsCO in acetone (5 mL / mmol) was stirred at room temperature for phenols and at 55° C. for carbamates. After reaching adequate conversion, the volatiles were removed under reduced pressure and the crude intermediate was purified via flash chromatography using heptane / EtOAc as the eluent.

[0099] General procedure for alkylation with tosylate An oven-dried vial equipped with a PTFE-coated magnetic stir bar was charged with 1 equivalent of the tosylate and 5 equivalents of the appropriate amine and suspended in MeCN (5 mL / mmol). The reaction mixture was then warmed to 50 °C and stirred at that temperature until no further conversion was observed. The reaction mixture was diluted with DCM, which was then loaded onto a DCM-preconditioned silica gel column. It was then purified via flash chromatography using DCM and MeOH (1.2% NH) as eluents.

[0100] General procedure for alkylation of silyl-protected phenols A mixture of 1 equivalent of silyl-protected phenol, 1 equivalent of alkyl iodide, and 1.15 equivalents of TBAF (1 M in THF) in THF (2 mL / mmol) was stirred at room temperature. After reaching a suitable conversion, the volatiles were removed under reduced pressure and the crude intermediate was purified via flash chromatography using heptane / EtOAc as the eluent.

[0101] Buchwald's general procedure I A mixture of 1 equivalent of chloro substrate, 2 equivalents of 1,3-benzothiazol-2-amine, 0.1 equivalent of Pd2(dba)3, 0.2 equivalent of XantPhos, and 3 equivalents of DIPEA in CyOH (5 mL / mmol) was maintained at 140° C. After reaching adequate conversion, the reaction mixture was diluted with DCM (10 mL / mmol), loaded onto a preconditioned silica gel column, and purified via flash chromatography using heptane / EtOAc as the eluent.

[0102] Buchwald's general procedure II A mixture of the chloro compound, 2 equivalents of 1,3-benzothiazol-2-amine, 10 mol% JosiPhos Pd(G3), and 3 equivalents of DIPE suspended in 1,4-dioxane (5 mL / mmol) was stirred at reflux until no further conversion was observed. Celite was added to the reaction mixture, and volatiles were removed under reduced pressure. It was then purified via flash chromatography on a 120 g silica gel column using heptane-EtOAc or DCM-MeOH (1.2% NH) as the eluent.

[0103] Mitsunobu's general procedure To a mixture of 1 equivalent of aliphatic alcohol, 1 equivalent of carbamate / phenol, and 1 equivalent of triphenylphosphine in toluene (5 mL / mmol) was added 1 equivalent of di-tert-butyl azodicarboxylate. The mixture was stirred at 50° C. for the carbamate and at room temperature for the phenol. After reaching a suitable conversion, the volatiles were removed under reduced pressure, and the crude intermediate was purified via flash chromatography using heptane / EtOAc as the eluent.

[0104] Finkelstein's general procedure A mixture of 1 equivalent of alkyl chloride and 2 equivalents of NaI in acetone (5 mL / mmol) was kept at reflux. After reaching a suitable conversion, the volatiles were removed under reduced pressure and the crude intermediate was purified via flash chromatography using heptane / EtOAc as the eluent.

[0105] General procedure for quaternary salt formation An oven-dried vial equipped with a PTFE-coated magnetic stir bar was charged with 1 equivalent of the tosylate and 20 equivalents of the appropriate amine and suspended in CyOH (5 mL / mmol). The reaction mixture was then warmed to 140 °C and stirred at that temperature until no further conversion was observed. The reaction mixture was diluted with DCM, which was then loaded onto a DCM-preconditioned silica gel column. It was then purified via flash chromatography using DCM and MeOH (1.2% NH) as eluents.

[0106] General procedure for quaternary salt deprotection To a solution of the appropriate quaternary salt in THF (5 mL / mmol), 3 equivalents of TBAF were added, which was then stirred at room temperature until no further conversion was observed. The reaction mixture was evaporated to dryness under reduced pressure. To a suspension of 1 equivalent of the desilylated quaternary salt in dry MeCN (15 mL / mmol), 100 equivalents of HF x Pyr was added and then stirred at 60 °C. After reaching appropriate conversion, the volatiles were removed under reduced pressure, the residue was suspended in a 1:1 mixture of THF-water (30 mL / mmol), 150 equivalents of LiOH x HO was added, and the mixture was stirred at room temperature. After reaching appropriate conversion, the volatiles were removed under reduced pressure. The crude product was purified via flash column chromatography using DCM and MeOH (containing 1.2% NH) as eluents.

[0107] General procedure for the preparation of propargylic amine An oven-dried vial equipped with a PTFE-coated magnetic stir bar was charged with 2 equivalents of PPh3 and 2 equivalents of imidazole, followed by the addition of DCM (5 mL / mmol). Two equivalents of iodine were added dropwise to the resulting mixture, which was then stirred for 15 minutes at room temperature. One equivalent of the appropriate alcohol was added to the resulting mixture, dissolved in DCM, and stirred at room temperature until no further conversion was observed. Twenty equivalents of the appropriate amine were added to the resulting iodo compound, which was then stirred at room temperature for 30 minutes until complete conversion was observed. Celite was added to the reaction mixture, and the volatiles were removed under reduced pressure. It was then purified via flash chromatography using DCM and MeOH (1.2% NH3) as eluents.

[0108] General procedure for the preparation of propargylic amine using silver catalyst A 24 mL vial equipped with a stir bar was charged with 1 equivalent of 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-(4-ethynyl-2-fluoro-phenoxy)propyl]thiazole-4-carboxylic acid, 20 equivalents of paraformaldehyde / acetone, and 20 equivalents of the appropriate amine, and stirred at 80 °C in the presence of 20 mol% silver tosylate in dry ethanol (5 mL / mmol) until no further conversion was observed. Celite was added to the reaction mixture, and volatiles were removed under reduced pressure. It was then purified via flash chromatography using DCM and MeOH (1.2% NH) as eluents.

[0109] General procedure for hydrolysis The appropriate methyl ester was suspended in a 1:1 mixture of THF-water (5 mL / mmol), 10 equivalents of LiOH×HO was added, and the mixture was stirred at 50° C. After reaching a suitable conversion, the volatiles were removed under reduced pressure; the crude product was purified via flash column chromatography using DCM and MeOH (containing 1.2% NH) as eluents.

[0110] General procedure for amine substitution and hydrolysis To the product from any of Preparations 12, 13, and 14 in a 1:1 mixture of acetonitrile and N-methyl-2-pyrrolidone (10 mL / mmol), the appropriate amine (3–10 equiv.) was added, and the reaction mixture was stirred at 50°C for 2–24 h. After purification of the displacement product by column chromatography (silica gel, using DCM and MeOH as eluents), the product was dissolved in THF (10 mL / mmol), and water (2 mL / mmol) and LiOH × HO (3–5 equiv.) were added. The reaction mixture was then stirred at 20–40°C for 1–4 h. The hydrolyzed product was purified by preparative HPLC (using acetonitrile and 5 mM aqueous NH4HCO3 as eluents) to give the desired product.

[0111] Preparation The following experimental details describe the preparation of synthetic intermediates.

[0112] Preparation 1a : Methyl 2-(tert-butoxycarbonylamino)-5-[3-(2-fluoro-4-iodo-phenoxy)propyl]thiazole-4-carboxylate Step A : Methyl 2-(tert-butoxycarbonylamino)-5-iodo-thiazole-4-carboxylate 50.00 g of methyl 2-(tert-butoxycarbonylamino)thiazole-4-carboxylate (193.55 mmol, 1 equiv.) was suspended in 600 mL of dry MeCN. 52.25 g of N-iodosuccinimide (232.30 mmol) was added, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated brine, which was then extracted with EtOAc. The combined organic layers were extracted with 1 M NaSO and then again with brine. The mixture was then dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified via flash column chromatography using heptane as the eluent to give 60 g of the desired product (156 mmol, 80% yield). 1 H NMR (400 MHz, DMSO-d6): δ ppm 12.03 / 11.06 (br s), 3.78 (s, 3H), 1.47 (s, 9H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 153.8, 82.5, 77.7, 52.3, 28.3; HRMS-ESI (m / z): [M+H] + C 10 H 14 Calculated IN2O4S: 384.9713; Found 384.9708.

[0113] Step B : Methyl 2-(tert-butoxycarbonylamino)-5-(3-hydroxyprop-1-ynyl)thiazole-4-carboxylate A 500 mL oven-dried, single-necked round-bottom flask equipped with a PTFE-coated magnetic stir bar and a reflux condenser was charged with 9.6 g of the product from Step A (25 mmol, 1 equiv.), 2.80 g of prop-2-yn-1-ol (2.91 mL, 50 mmol, 2 equiv.), and 36.10 g of DIPA (50 mL, 356.8 mmol, 14.27 equiv.). 125 mL of dry THF was then added, and the system was flushed with argon. After stirring for 5 min under an inert atmosphere, 549 mg of Pd(PPh3)2Cl2 (1.25 mmol, 0.05 equiv.) and 238 mg of CuI (1.25 mmol, 0.05 equiv.) were added. The resulting mixture was then warmed to 60 °C and stirred at that temperature until no further conversion was observed. Celite was added to the reaction mixture, and the volatiles were removed under reduced pressure. It was then purified via flash chromatography using heptane and EtOAc as eluents to give 7.30 g of the desired product (23 mmol, 93% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ ppm 12.1 (br s, 1H), 5.45 (t, 1H), 4.36 (d, 2H), 3.79 (s, 3H), 1.48 (s, 9H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 12.1 (br s, 1H), 5.45 (t, 1H), 4.36 (d, 2H), 3.79 (s, 3H), 1.48 (s, 9H); HRMS-ESI (m / z): [M+H] + C 13 H 17 Calculated N2O5S value: 313.0852, found 313.0866.

[0114] Step C : Methyl 2-(tert-butoxycarbonylamino)-5-(3-hydroxypropyl)thiazole-4-carboxylate A 1 L oven-dried pressure bottle equipped with a PTFE-coated magnetic stir bar was charged with 44.75 g of the product from Step B (143.3 mmol, 1 equiv.) and 7.62 g of Pd / C (7.17 mmol, 0.05 equiv.) in 340 mL of ethanol and then placed under a nitrogen atmosphere using a hydrogenation system. It was then charged with 4 bar of H2 gas and stirred at room temperature overnight. Complete conversion was observed, but only the olefin product was formed. After filtering the catalyst through a Celite pad, the entire procedure was repeated with 5 mol% of fresh catalyst. The resulting mixture was stirred overnight to obtain complete conversion. Celite was added to the reaction mixture, and the volatiles were removed under reduced pressure. It was then purified via flash chromatography using heptane and EtOAc as eluents to give 31.9 g of the desired product (101 mmol, 70.4% yield) as pale yellow crystals. 1 H NMR (500 MHz, DMSO-d6): δ ppm 11.61 (br s, 1H), 4.54 (t, 1H), 3.76 (s, 3H), 3.43 (m, 2H), 3.09 (t, 2H), 1.74 (m, 2H), 1.46 (s, 9H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 162.8, 143.1, 135.4, 60.3, 51.9, 34.5, 28.3, 23.4; HRMS-ESI (m / z): [M+H] + C 13 H 21 Calculated for N2O5S: 317.1165, found 317.1164 (M+H).

[0115] Step D : Methyl 2-(tert-butoxycarbonylamino)-5-[3-(2-fluoro-4-iodo-phenoxy)propyl]thiazole-4-carboxylate A 250 mL oven-dried, single-necked round-bottom flask equipped with a PTFE-coated magnetic stir bar was charged with 3.40 g of 2-fluoro-4-iodo-phenol (14 mmol, 1 equiv.), 5.00 g of the product from Step C (16 mmol, 1.1 equiv.), 4.10 g of PPh3 (16 mmol, 1.1 equiv.), and 71 mL of dry toluene. After stirring for 5 minutes under a nitrogen atmosphere, 3.10 mL of DIAD (3.20 g, 16 mmol, 1.1 equiv.) was added in one portion while the reaction mixture was warming. The reaction mixture was then heated to 50 °C and stirred at that temperature for 30 minutes, at which point the reaction reached complete conversion. The reaction mixture was directly loaded onto a preconditioned silica gel column, which was then purified via flash chromatography using heptane and EtOAc as eluents. The crude product was crystallized from MeOH to give 4.64 g of the desired product (9.24 mmol, 66% yield). 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.64 (br s, 1H), 7.59 (dd, 1H), 7.45 (dd, 1H), 6.98 (t, 1H), 4.06 (t, 2H), 3.73 (s, 3H), 3.22 (t, 2H), 2.06 (m, 2H), 1.46 (s, 9H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 134, 124.9, 117.6, 68.2, 51.9, 30.5, 28.3, 23.2; HRMS-ESI (m / z): [M+H] + C 19 H 23 Calculated N2O5FSI: 537.0350; Measured 537.0348.

[0116] Preparation 1b : Methyl 2-(tert-butoxycarbonylamino)-5-[3-[4-[3-[tert-butoxycarbonyl(methyl)amino]prop-1-ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylate A 500 mL oven-dried, single-necked round-bottom flask equipped with a PTFE-coated magnetic stir bar and a reflux condenser was charged with 13.41 g of Preparation 1a (25 mmol, 1 equiv.), 8.46 g of tert-butyl N-methyl-N-prop-2-ynylcarbamate (50 mmol, 2 equiv.), and 50 mL of DIPA (36.10 g, 50 mL, 356.8 mmol, 14.27 equiv.). 125 mL of dry THF was then added, and the system was flushed with argon. After stirring for 5 minutes under an inert atmosphere, 549 mg of Pd(PPh3)2Cl2 (1.25 mmol, 0.05 equiv.) and 238 mg of CuI (1.25 mmol, 0.05 equiv.) were added. The resulting mixture was then warmed to 60 °C and stirred at that temperature until no further conversion was observed. Celite was added to the reaction mixture and the volatiles were removed under reduced pressure, which was then purified via flash chromatography using heptane and EtOAc as eluents to give 10.5 g of the desired product (18.2 mmol, 72.7% yield). 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.65 (br s, 1H), 7.31 (br d, 1H), 7.21 (br d, 1H), 7.14 (t, 1H), 4.23 (s, 2H), 4.1 (t, 2H), 3.73 (s, 3H), 3.23 (t, 2H), 2.86 (s, 3H), 2.07 (m, 2H), 1.46 / 1.41 (s, 18H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 129.1, 119.2, 115.4, 68.1, 51.9, 38.6, 33.8, 30.5, 23.2; HRMS-ESI (m / z): [M+H] + C 28 H 37 Calculated value for FN3O7S: 578.2330; found 578.2331.

[0117] Preparation 1c: Methyl 2-(tert-butoxycarbonylamino)-5-[3-[4-[3-(dimethylamino)prop-1-ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylate A 250 mL oven-dried, single-necked round-bottom flask equipped with a PTFE-coated magnetic stir bar and a reflux condenser was charged with 5.36 g of Preparation 1a (10 mmol, 1 equiv.), 1.66 g of N,N-dimethylprop-2-yn-1-amine (20 mmol, 2 equiv.), and 20 mL of DIPA (142.7 mmol, 14.27 equiv.). Dry THF (50 mL) was then added, and the system was flushed with argon. After stirring for 5 minutes under an inert atmosphere, 220 mg of Pd(PPh3)2Cl2 (0.5 mmol, 0.05 equiv.) and 95 mg of CuI (0.5 mmol, 0.05 equiv.) were added. The resulting mixture was then warmed to 60 °C and stirred at that temperature until no further conversion was observed. Celite was added to the reaction mixture, and the volatiles were removed under reduced pressure. It was then purified via flash chromatography using DCM and MeOH (1.2% NH3) as eluents to give 4.5 g of the desired product (7.8 mmol, 78% yield). 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.66 (s, 1H), 7.29 (dd, 1H), 7.19 (m, 1H), 7.12 (t, 1H), 4.09 (t, 2H), 3.73 (s, 3H), 3.44 (s, 2H), 3.23 (t, 2H), 2.24 (s, 6H), 2.07 (m, 2H), 1.45 (s, 9H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 162.8, 147.3, 129, 119.2, 115.4, 84.3, 68, 51.9, 48.1, 44.2, 30.6, 28.3, 23.2; HRMS-ESI (m / z): [M+H] + C 24 H 31 Calculated for FN3O5S: 492.1962; Found 492.1956 (M+H).

[0118] Preparation 1d : Methyl 2-{[(tert-butoxy)carbonyl]amino}-5-(3-iodopropyl)-1,3-thiazole-4-carboxylate To a solution of the product of Preparation 1a, Step C (5 g, 15.8 mmol, 1 equiv.) in diethyl ether (175 mL) and acetonitrile (35 mL) was added imidazole (1.57 mL, 23.71 mmol, 1.5 equiv.), followed by triphenylphosphine (3.73 g, 14.22 mmol, 1.5 equiv.) and iodine (6.02 g, 23.71 mmol, 1.5 equiv.). The mixture was stirred at ambient temperature for 1 h. The reaction was partitioned between ethyl acetate (150 mL) and 10% aqueous sodium thiosulfate solution (250 mL), and the organic phase was washed successively with water (200 mL) and brine (150 mL), dried (magnesium sulfate), and concentrated in vacuo. The residue was dissolved in diethyl ether and allowed to age overnight at refrigerated temperature. The resulting crystals were removed by filtration, and the filtrate was concentrated in vacuo. Purification by automated flash chromatography (Combiflash Rf, silica 80 g RediSep column) eluting with a gradient of 0-50% ethyl acetate in isoheptane gave the desired product (5.77 g, 13.53 mmol, 85%) as a white solid. LC / MS (C 13 H 19 IN2O4S) 427 [M+H] + ; Retention time 0.88 (LCMS-V-B2) 1 H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 3.79 (s, 3H), 3.29 (t, J = 6.8 Hz, 2H), 3.20 - 3.12 (m, 2H), 2.09 (dq, J = 8.7, 6.8 Hz, 2H), 1.48 (s, 9H).

[0119] Preparation 2a : 3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propan-1-ol Step A: [(pent-4-yn-1-yloxy)methyl]benzene To an oven-dried flask was added 4-pentyn-1-ol (11.1 mL, 119 mmol, 1 equiv) in THF (100 mL), and the solution was cooled to 0 °C. Sodium hydride (60% dispersion; 7.13 g, 178 mmol, 1.5 equiv) was added dropwise, and the mixture was continued stirring at 0 °C for 30 min before benzyl bromide (15.6 mL, 131 mmol, 1.1 equiv) was added dropwise. The mixture was allowed to warm to ambient temperature and stirred for 16 h, then cooled to 0 °C, quenched with saturated aqueous ammonium chloride (30 mL), and diluted with water (30 mL). The mixture was extracted with ethyl acetate (2 × 150 mL), and the combined organic extracts were washed successively with dilute aqueous ammonium hydroxide (150 mL) and brine (100 mL), dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 330g RediSep) eluted with a gradient of 0-10% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a yellow liquid (19.5 g, 112 mmol, 94%). LC / MS (C 12 H 14 O) 175 [M+H] + ; Retention time 1.28 (LCMS-V-B1) 1 H NMR (400 MHz, chloroform-d) δ 7.37 - 7.32 (m, 4H), 7.31 - 7.27 (m, 1H), 4.52 (s, 2H), 3.58 (t, J = 6.1 Hz, 2H), 2.32 (td, J = 7.1, 2.6 Hz, 2H), 1.95 (t, J = 2.7 Hz, 1H), 1.83 (tt, J = 7.1, 6.2 Hz, 2H).

[0120] Step B : [(Hex-4-yn-1-yloxy)methyl]benzene To an oven-dried flask was added the product of Step A (19.5 g, 112 mmol, 1 equiv) and tetrahydrofuran (200 mL), and the solution was cooled to −78° C. n-Butyllithium (66.9 mL, 135 mmol, 1.2 equiv) was added dropwise over 30 minutes, the reaction was stirred for 1 hour, then iodomethane (10.5 mL, 168 mmol, 1.5 equiv) was added dropwise and the mixture was allowed to warm to 0° C. over 1 hour. The reaction was quenched by the addition of saturated aqueous ammonium chloride (40 mL), diluted with water (40 mL), extracted with ethyl acetate (3×100 mL), and the combined organic extracts were washed successively with 2 M aqueous sodium thiosulfate (200 mL) and brine (200 mL), dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 330g RediSep) eluted with a gradient of 0-10% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a yellow liquid (19.2 g, 0.1 mol, 91%). LC / MS (C 13 H 16 O) 189 [M+H] + ; Retention time 1.34 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 7.41 - 7.23 (m, 5H), 4.46 (s, 2H), 3.48 (t, J = 6.3 Hz, 2H), 2.23 - 2.14 (m, 2H), 1.72 (s, 3H), 1.70 - 1.65 (m, 2H).

[0121] Step C : 4-[3-(benzyloxy)propyl]-3,6-dichloro-5-methylpyridazine A solution of 3,6-dichloro-1,2,4,5-tetrazine (5 g, 33.1 mmol, 1 equiv.) and the product of Step B (7.48 g, 39.8 mmol, 1.2 equiv.) in tetrahydrofuran (30 mL) was heated in a sealed flask at 160° C. for 19 h. The reaction was allowed to cool to ambient temperature and then concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 220 g RediSep 1000) eluted with a gradient of 0-30% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as an orange oil (7.32 g, 23.5 mmol, 71%). LC / MS (C 15 H 16 Cl2N2O) 311 [M+H] + ; Retention time 1.35 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 7.45 - 7.18 (m, 5H), 4.48 (s, 2H), 3.53 (t, J = 5.9 Hz, 2H), 2.96 - 2.83 (m, 2H), 2.42 (s, 3H), 1.88 - 1.69 (m, 2H).

[0122] Step D : 3-(3,6-dichloro-5-methylpyridazin-4-yl)propan-1-ol To a cooled solution of the product of Step C (7.32 g, 23.5 mmol, 1 equiv.) in dichloromethane (100 mL) was added dropwise boron trichloride solution (1 M in dichloromethane; 58.8 mL, 58.8 mmol, 2.5 equiv.), and the mixture was continued stirring at ambient temperature for 1 h. The reaction was quenched by the addition of methanol and concentrated in vacuo. The residue was partitioned between dichloromethane (100 mL) and saturated aqueous sodium bicarbonate (150 mL), and the organic phase was washed with brine (150 mL), dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 80 g RediSep HPLC) eluting with a gradient of 0-80% ethyl acetate in isoheptane was performed. 商標Purification by silica cartridge) gave the desired product as a yellow oil (4.19 g, 19 mmol, 81%). LC / MS (C8H 10 Cl2N2O) 221 [M+H] + ; Retention time 0.84 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 4.67 (t, J = 5.1 Hz, 1H), 3.49 (td, J = 6.0, 5.1 Hz, 2H), 2.91 - 2.80 (m, 2H), 2.43 (s, 3H), 1.72 - 1.59 (m, 2H).

[0123] Preparation 2b 2-[tert-Butyl(diphenyl)silyl]oxy-3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propan-1-ol (enantiopure, from enantiomer 2 in step A) Step A : Ethyl 3-(3,6-dichloro-5-methyl-pyridazin-4-yl)-2-hydroxy-propanoate To 3,6-dichloro-4,5-dimethyl-pyridazine (26.5 g, 150 mmol) in dry THF (375 mL) was added TMP-MgCl×LiCl (165 mL, 165 mmol, 1.1 equiv.) dropwise at −78° C., and the resulting mixture was stirred for 2 h at 0° C. The resulting Mg salt was transferred to a solution of ethyl 2-oxoacetate (45.9 g, 225 mmol, 1.5 equiv.) in dry THF (375 mL) at 0° C., which was then stirred for 30 min at 0° C. The reaction was quenched with saturated aqueous NH4Cl, and after extraction with EtOAc, the combined organic layers were dried, filtered, concentrated, and purified via flash chromatography on silica gel with heptane and EtOAc as eluents to give 11 g (26.3%) of the desired compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 5.85 (d, 1H), 4.33 (m, 1H), 4.12 (q, 2H), 3.19 (d, 2H), 2.45 (s, 3H), 1.17 (t, 3H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 172.8, 157.6, 157.2, 141.4, 139.3, 68.8, 61.2, 35.2, 17.3, 14.4. HRMS-ESI (m / z): [M+H]+ C 10 H 13 Calculated value for Cl2N2O3: 279.0303, found 279.0301.

[0124] The enantiomers of the desired product were separated on an AS-V chiral column (100*500 mm, 20 μm) using 10:90 EtOH-heptane as the eluent to give Enantiomer 1 (first eluting) with 99.6% ee and Enantiomer 2 (later eluting) with 99.1% ee.

[0125] Step B: Ethyl 2-[tert-butyl(diphenyl)silyl]oxy-3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propanoate To enantiomer 2 from step A (4500 mg, 16 mmol, imidazole (2200 mg, 2.0 equiv.) in THF (81 mL) was added TBDPS-Cl (8900 mg, 2.0 equiv.) dropwise, which was then stirred at room temperature for 18 h. The product was purified via flash chromatography using heptane and EtOAc as eluents to give the desired product (6200 mg, 74%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.52-7.27 (m, 10H), 4.46 (dd, 1H), 3.83 (m, 2H), 3.35 (dd, 1H), 3.19 (dd, 1H), 2.34 (s, 3H), 0.93 (t, 3H), 0.87 (s, 9H).

[0126] Step C : 2-[tert-butyl(diphenyl)silyl]oxy-3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propan-1-ol To the enantiopure product of step B (3600 mg, 6.95 mmol) in MeOH (35 mL) was added NaBH (2.63 g, 10 equiv.) dropwise over 5 min at 0 °C and stirred at that temperature for 30 min. The reaction was quenched with the addition of a saturated aqueous solution of NH Cl, after which it was extracted twice with EtOAc. The combined organic layers were dried, filtered, concentrated, and purified via flash chromatography on silica gel using heptane and EtOAc as eluents to give the desired product (1.6 g, 48%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.57-7.3 (m, 10H), 4.9 (brs, 1H), 4.05 (m, 1H), 3.38 / 3.32 (dd+dd, 2H), 3.13 / 3.11 (dd+dd, 2H), 2.3 (s, 3H), 0.8 (s, 9H); 13 C NMR (125 MHz, DMSO-d6) ppm 72.7, 65.5, 35.5, 26.9, 17.2; HRMS-ESI (m / z): [M+H] + C 24 H 29 Calculated value for Cl2N2O2Si: 475.1369, found 475.1362.

[0127] Preparation 2c : 2-(3,6-dichloro-5-methyl-pyridazin-4-yl)ethanol Step A : 3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propane-1,2-diol To 700 mg of the product of Preparation 2b, Step A (2.5 mmol) in 3 mL of methanol at 0° C. was added 285 mg (3 equiv.) of NaBH4, and the mixture was stirred at 0° C. for 0.5 h. After quenching the reaction with a saturated solution of NH4Cl, the crude product was purified via flash column chromatography on silica gel using DCM and MeOH (1.2% NH3) as eluents to give 500 mg (84%) of the desired compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 4.90 (bd, 1H), 4.83 (bs, 1H), 3.75 (m, 1H), 3.47 (dd, 1H), 3.38 (m, 1H), 3.00 (dd, 1H), 2.87 (dd, 1H), 2.45 (s, 3H).

[0128] Step B : 2-(3,6-dichloro-5-methyl-pyridazin-4-yl)acetaldehyde A solution of 237 mg of the product of step A (1 mmol) in 5 mL of acetone / HO (4:1) was cooled to 0° C., and then 427 mg of sodium periodate (2 mmol, 2 equiv.) was added dropwise. After stirring at room temperature for 2 h, the mixture was purified by flash chromatography using heptane-EtOAc as eluent to give 200 mg of the desired product (97%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.71 (s, 1H), 4.27 (s, 1H), 2.35 (s, 3H).

[0129] Step C : 2-(3,6-dichloro-5-methyl-pyridazin-4-yl)ethanol To a solution of 200 mg of the product of step B (0.97 mmol) in 3 mL of methanol was added 110 mg (2.92 mmol, 3 equiv.) of sodium borohydride in small portions at 0° C. After stirring for 15 min, the reaction mixture was diluted with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried, filtered, concentrated, and purified by flash chromatography using heptane-EtOAc as eluents to give 180 mg (89%) of the desired product. 1 H NMR (500 MHz, DMSO-d6) δ ppm 4.9 (t, 1H), 3.65 (m, 2H), 3 (t, 2H), 2.45 (s, 3H); 13 C NMR (125 MHz, DMSO-d) δ ppm 157.5, 157.2, 140.9, 140.7, 59.1, 34, 17.1; HRMS-ESI (m / z): [M+H]+ calculated for C7H9Cl2N2O: 207.0086, found 207.0083.

[0130] Preparation 2e : 3-(3,6-dichloro-5-methylpyridazin-4-yl)propanal To an oven-dried flask was added dimethyl sulfoxide (3.08 mL, 43.4 mmol, 2.4 equiv.) and dichloromethane (100 mL), and the solution was cooled to -78 °C. Oxalyl chloride (2 M in dichloromethane; 13.6 mL, 27.1 mmol, 1.5 equiv.) was added dropwise, and the reaction was continued to stir for 1 h. Next, a solution of the product of Preparation 2a (4 g, 18.1 mmol, 1 equiv.) in dichloromethane (20 mL) was added dropwise, and the mixture was continued to stir for 1 h. Triethylamine (15.1 mL, 109 mmol, 6 equiv.) was added, and the reaction was allowed to warm to 0 °C over 1 h. The reaction was quenched with water (50 mL) and then partitioned between saturated sodium bicarbonate (50 mL) and dichloromethane (200 mL). The aqueous phase was extracted with dichloromethane (200 mL). The combined organic extracts were washed with brine (100 mL), dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 24g RediSep) eluting with a gradient of 0-50% ethyl acetate in isoheptane was performed. 商標 Purification by silica cartridge) gave the desired product as an off-white solid (2.27 g, 10.4 mmol, 57%). LC / MS (C8H8Cl2N2O) 219 [M+H] + ; Retention time 0.87 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 3.03 (dd, J = 8.7, 7.0 Hz, 2H), 2.86 - 2.69 (m, 2H), 2.44 (s, 3H).

[0131] Preparation 3a : Methyl 2-(3-chloro-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl)-5-[3-(2-fluoro-4-iodo-phenoxy)propyl]thiazole-4-carboxylate Step A: Methyl 2-{[(tert-butoxy)carbonyl][3-(3,6-dichloro-5-methylpyridazin-4-yl)propyl]amino}-5-[3-(2-fluoro-4-iodophenoxy)propyl]-1,3-thiazole-4-carboxylate Using Mitsunobu's general procedure, starting with 4.85 g of preparation 1a (9.04 mmol, 1 equiv.) as the appropriate carbamate and 2 g of preparation 2a (9.04 mmol, 1 equiv.) as the appropriate alcohol, 4.6 g of the desired product (69% yield) was obtained. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.56 (dd, 1H), 7.44 (dm, 1H), 7.08 (m, 2H), 6.96 (t, 1H), 4.05 (t, 2H), 3.75 (s, 3H), 3.21 (t, 2H), 2.82 (m, 2H), 2.4 (s, 3H), 2.06 (m, 2H), 1.88 (m, 2H), 1.48 (s, 9H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 162.7, 157.6, 156.7, 156.5 / 153.2, 152.2, 147, 142.1, 139.8, 134, 124.9, 117.6, 84, 82.4, 68.1, 52.1, 46.1, 30.4, 28.1, 27.5, 25.8, 23.1, 16.4; HRMS-ESI (m / z): [M+H] + C 27 H 31 Calculated value for Cl2FIN4O5S: 739.0415, found 739.0395.

[0132] Step B : Methyl 2-[3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propylamino]-5-[3-(2-fluoro-4-iodo-phenoxy)propyl]thiazole-4-carboxylate Using the general procedure for deprotection with HFIPA, starting from the product of Step A as the appropriate carbamate, 3.70 g of the desired product (97% yield) was obtained. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.71 (t, 1 H), 7.59 (dd, 1 H), 7.44 (dm, 1 H), 6.96 (t, 1 H), 4.03 (t, 2 H), 3.7 (s, 3 H), 3.29 (m, 2 H), 3.11 (t, 2 H), 2.84 (m, 2 H), 2.39 (s, 3 H), 2 (m, 2 H), 1.76 (m, 2 H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 164.6, 163, 152.3, 147.1, 134.1, 124.8, 117.6, 82.4, 68.1, 51.9, 44, 30.7, 28, 26.9, 23.3, 16.4; HRMS-ESI (m / z): [M+H] + C 22 H 23 Calculated value for Cl2FIN4O3S: 638.9891, found 638.9888.

[0133] Step C : Methyl 2-(3-chloro-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl)-5-[3-(2-fluoro-4-iodo-phenoxy)propyl]thiazole-4-carboxylate A suspension of 3 g of the product of step B (4.69 mmol, 1 equiv.) and 1.81 g of cesium carbonate (9.3853 mmol, 2 equiv.) was stirred in 25 mL of dry 1,4-dioxane at 80° C. for 3 h until complete conversion was reached. The reaction mixture was evaporated directly onto Celite and then purified by flash chromatography using DCM-MeOH as eluent to give 2.67 g of the title compound (94% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.57 (dd, 1H), 7.43 (dm, 1H), 6.97 (t, 1H), 4.23 (t, 2 H), 4.08 (t, 2 H), 3.77 (s, 3 H), 3.22 (t, 2 H), 2.86 (t, 2 H), 2.29 (s, 3 H), 2.08 (m, 2 H), 2.03 (m, 2 H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 163.1, 155.4, 152.2, 151.6, 151.2, 147, 142.5, 136, 134.8, 134, 128.9, 124.9, 117.6, 82.3, 68.4, 51.9, 46.3, 30.7, 24.2, 23, 19.7, 15.7; HRMS-ESI (m / z): [M+H] + C 22 H 22 Calculated value for ClFIN4O3S: 603.0124, found 603.0108.

[0134] Preparation 3b : Methyl 5-(3-hydroxypropyl)-2-[4-methyl-3-[(Z)-[3-(2-trimethylsilylethoxymethyl)-1,3-benzothiazol-2-ylidene]amino]-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]thiazole-4-carboxylate Step A : Methyl 2-(tert-butoxycarbonylamino)-5-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]thiazole-4-carboxylate A 1 L oven-dried, single-necked round-bottom flask equipped with a PTFE-coated magnetic stir bar was charged with 20 g of Preparation 1a, Step A (52.05 mmol, 1.0 equiv.) and 17.73 g of tert-butyl-dimethyl-prop-2-ynoxy-silane (21 mL, 104.1 mmol, 2.0 equiv.) dissolved in 250 mL of dry THF / 25 mL of DIPA, then placed under a nitrogen atmosphere through a gas inlet. To this solution was then added 572 mg of Pd(PPh3)2Cl2 (1.30 mmol, 0.025 equiv.) and 247 mg of CuI (1.30 mmol, 0.025 equiv.). The reaction mixture was then warmed to reflux and stirred at that temperature until no further conversion was observed. Celite was added to the reaction mixture, and the volatiles were removed under reduced pressure. It was then purified in two parts via flash chromatography using heptane and EtOAc as eluents to give 18.00 g of the desired product (81% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.13 (br., 1H), 4.62 (s, 2H), 3.79 (s, 3H), 1.48 (s, 9H), 0.89 (s, 9H), 0.13 (s, 6H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 161.2, 52.4, 52.4, 28.3, 26.2, -4.6; HRMS-ESI (m / z): [M+H] + C 19 H 31 Calculated value of N2O5SSi: 427.1717, Measured value: 427.1711.

[0135] Step B : Methyl 2-(tert-butoxycarbonylamino)-5-[3-[tert-butyl(dimethyl)silyl]oxypropyl]thiazole-4-carboxylate 13 g of the product from Step A (30.42 mmol, 1.0 equiv.) was dissolved in 150 mL of EtOH and charged with 3.23 g of Pd / C (3.04 mmol, 0.1 equiv.). A 250 mL oven-dried autoclave equipped with a PTFE-coated magnetic stir bar was charged with the solution and then placed under a nitrogen atmosphere using a hydrogenation system. It was then charged with 10 bar H2 gas. After stirring at room temperature for 2 hours, the reaction reached complete conversion. Celite was added to the reaction mixture, and the volatiles were removed under reduced pressure. It was then purified via flash chromatography using heptane and EtOAc as eluents to give 9.95 g of the desired product (78% yield). 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.62 (br., 1H), 3.76 (s, 3H), 3.62 (t, 2H), 3.12 (t, 2H), 1.78 (quint., 2H), 1.46 (s, 9H), 0.86 (s, 9H), 0.03 (s, 6H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 162.8, 62, 51.9, 34.3, 28.3, 26.3, 23.3, -4.9; HRMS-ESI (m / z): [M+H] + C 19 H 35 Calculated value of N2O5SSi: 431.2030, measured value 431.2025.

[0136] Step C : Methyl 2-[tert-butoxycarbonyl-[3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propyl]amino]-5-[3-[tert-butyl(dimethyl)silyl]oxypropyl]thiazole-4-carboxylate Using Mitsunobu's general procedure, starting with 9.91 g of the product of Step B (23.0 mmol, 1 equiv.) as the appropriate carbamate and 5.1 g of Preparation 2a (23.0 mmol, 1 equiv.) as the appropriate alcohol, 13.02 g of the desired product (89% yield) was obtained. 1H NMR (500 MHz, DMSO-d6) δ ppm 4.09 (t, 2H), 3.77 (s, 3H), 3.61 (t, 2H), 3.12 (t, 2H), 2.82 (t, 2H), 2.41 (s, 3H), 1.88 (qn, 2H), 1.79 (qn, 2H), 1.39 (s, 9H), 0.85 (s, 9H), 0.02 (s, 6H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 162.8, 157.7, 156.3, 156.1, 152.8, 144.5, 142.1, 139.9, 135.3, 79.4, 62.1, 52.1, 46.1, 34.1, 28.6, 27.5, 26.3, 25.9, 23.2, 18.4, 16.4, -4.9; HRMS-ESI (m / z): [M+H] + C 27 H 43 Calculated value for Cl2N4O5SSi: 633.2095, found 633.2091.

[0137] Step D : Methyl 5-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-2-[3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propylamino]thiazole-4-carboxylate Using the general procedure for deprotection with HFIPA, starting from the product of Step C as the appropriate carbamate, 10.4 g of the desired product (95% yield) was obtained. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.69 (t, 1H), 3.71 (s, 3H), 3.60 (t, 2H), 3.30 (q, 2H), 3.01 (t, 2H), 2.85 (t, 2H), 2.41 (s, 3H), 1.78 (qn, 2H), 1.71 (qn, 2H), 0.86 (s, 9H), 0.02 (s, 6H); 13C NMR (125 MHz, DMSO-d6) δ ppm 164.3, 163.1, 157.7, 156.9, 142.5, 140.0, 137.6, 136.5, 62.0, 51.7, 44.1, 34.4, 28.0, 26.9, 26.3, 23.4, 18.5, 16.5, -4.9; HRMS-ESI (m / z): [M+H] + C 22 H 35 Calculated value for Cl2N4O3SSi: 533.1570, found 533.1566.

[0138] Step E : Methyl 5-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-2-(3-chloro-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl)thiazole-4-carboxylate A 250 mL oven-dried, single-necked round-bottom flask equipped with a PTFE-coated magnetic stir bar was charged with 10.4 g of the product from Step D (19.57 mmol, 1.0 equiv.), 12.75 g of CsCO (39.13 mmol, 2.0 equiv.), and 100 mL of dry 1,4-dioxane. The reaction mixture was then warmed to reflux and stirred at that temperature for 8 h. Celite was added to the reaction mixture, and the volatiles were removed under reduced pressure. It was then purified via flash chromatography using heptane and EtOAc as eluents to give 6.40 g of the desired product (66% yield). 1 H NMR (500 MHz, DMSO-d6) δ ppm 4.26 (t, 2H), 3.79 (s, 3H), 3.65 (t, 2H), 3.14 (t, 2H), 2.89 (t, 2H), 2.32 (s, 3H), 2.04 (m, 2H), 1.82 (m, 2H), 0.87 (s, 9H), 0.04 (s, 6H); 13C NMR (125 MHz, DMSO-d6) δ ppm 163.1, 155.3, 151.8, 151.3, 143.4, 136.1, 134.6, 129.0, 62.1, 52.0, 46.3, 34.4, 26.3, 24.2, 23.1, 19.7, 15.7, -4.8; HRMS-ESI (m / z): [M+H] + C 22 H 34 Calculated value for ClN4O3SSi: 497.1804, found 497.1796.

[0139] Step F : Methyl 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[tert-butyl(dimethyl)silyl]oxypropyl]thiazole-4-carboxylate A 250 mL oven-dried, single-necked round-bottom flask equipped with a PTFE-coated magnetic stir bar and a reflux condenser was charged with 6.43 g of the product from Step E (12.94 mmol, 1.0 equiv.), 3.88 g of 1,3-benzothiazol-2-amine (25.87 mmol, 2.0 equiv.), and 6.75 mL of DIPEA (38.81 mmol, 3.0 equiv.), followed by 65 mL of CyOH. The system was then flushed with argon. After stirring for 5 minutes under an inert atmosphere, 1.18 g of Pd2(dba)3 (1.29 mmol, 0.1 equiv.) and 1.49 g of XantPhos (2.587 mmol, 0.2 equiv.) were added. The resulting mixture was then warmed to 140 °C and stirred at that temperature for 1 hour until complete conversion was achieved. The reaction mixture was diluted with DCM and loaded directly onto a preconditioned silica gel column, which was then purified via flash chromatography using heptane and EtOAc as eluents to give 6.85 g of the desired product (87% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.82 (br., 1H), 7.52 (br., 1H), 7.37 (t, 1H), 7.19 (t, 1H), 4.25 (t, 2H), 3.80 (s, 3H), 3.66 (t, 2H), 3.16 (t, 2H), 2.87 (t, 2H), 2.33 (s, 3H), 2.04 (m, 2H), 1.84 (m, 2H), 0.92 (s, 9H), 0.07 (s, 6H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 163.2, 155.6, 148.8, 148.6, 142.3, 134.5, 127.6, 126.5, 122.5, 122, 62.0, 51.9, 46.3, 34.4, 26.4, 23.9, 22.9, 20.3, 12.8, -4.8; HRMS-ESI (m / z): [M+H] + C 29 H 39 Calculated value for N6O3S2Si: 611.2288, found 611.2284.

[0140] Step G : Methyl 5-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-2-[4-methyl-3-[(Z)-[3-(2-trimethylsilylethoxymethyl)-1,3-benzothiazol-2-ylidene]amino]-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]thiazole-4-carboxylate 5.00 g of the product of step F (8.18 mmol, 1.0 equiv.) was dissolved in 50 mL of dry DCM, and 50 mg of DMAP (0.41 mmol, 0.05 equiv.) and 2.85 mL of DIPEA (16.37 mmol, 2.0 equiv.) were added at 0° C. Next, 2.24 mL of 2-(chloromethoxy)ethyl-trimethyl-silane (12.69 mmol, 1.5 equiv.) was added over 5 min at 0° C., and the resulting mixture was placed in a refrigerator overnight, during which complete conversion was observed. Celite was added to the reaction mixture, and volatiles were removed under reduced pressure. It was then purified via flash chromatography using heptane and EtOAc as eluents to give 3.85 g of the desired product (63% yield). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.6-7.15 (m, 4H), 5.83 (s, 2H), 4.42 (t, 2H), 3.92 (s, 3H), 3.74 (t, 2H), 3.73 (t, 2H), 3.24 (t, 2H), 2.86 (t, 2H), 2.37 (s, 3H), 2.12 (m, 2H), 1.97 (m, 2H), 0.96 (t, 2H), 0.95 (s, 9H), 0.1 (s, 6H), -0.07 (s, 9H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 163.6, 157.7, 156.4, 154.7, 148.5, 143.7, 137.6, 134.1, 132.6, 126.1, 125.6, 73.2, 66.9, 62.5, 51.9, 46, 34.3, 26.1, 24.2, 23.4, 20.6, 18.0, 12.9, -1.4, -5.2; HRMS-ESI (m / z): [M+H] + C 35 H 53 Calculated value for N6O4S2Si2: 741.3102, found value 741.3098.

[0141] Step H: Methyl 5-(3-hydroxypropyl)-2-[4-methyl-3-[(Z)-[3-(2-trimethylsilylethoxymethyl)-1,3-benzothiazol-2-ylidene]amino]-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]thiazole-4-carboxylate 3.85 g of the product of step G (5.19 mmol, 1.0 equiv.) and 362 mg of camphorsulfonic acid (1.56 mmol, 0.3 equiv.) were dissolved in 40 mL of DCM / MeOH (2:1). The reaction mixture was then warmed to 50 °C and stirred at that temperature overnight. The reaction reached complete conversion. The reaction mixture was cooled to room temperature and quenched by the addition of saturated aqueous NaHCO3 solution, which was then extracted twice with EtOAc. Celite was added to the combined organic layers, and the volatiles were removed under reduced pressure. It was then purified via flash chromatography using heptane and EtOAc as eluents to give 2.50 g of the title compound (76% yield). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.83 (dm, 1H), 7.44 (dm, 1H), 7.42 (m, 1H), 7.23 (m, 1H), 5.84 (s, 2H), 4.57 (brs, 1H), 4.26 (t, 2H), 3.80 (s, 3H), 3.72 (m, 2H), 3.48 (t, 2H), 3.14 (m, 2H), 2.86 (t, 2H), 2.36 (s, 3H), 2.04 (m, 2H), 1.81 (m, 2H), 0.91 (m, 2H), -0.11 (s, 9H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 127.1, 123.3, 123.2, 111.9, 72.9, 66.7, 60.6, 51.9, 46.4, 35.0, 23.8, 23.2, 20.4, 17.8, 13, -1.0; HRMS-ESI (m / z): [M+H]+ C 29 H 39 Calculated value for N6O4S2Si: 627.2237, found 627.2236.

[0142] Preparation 3c 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-(4-ethynyl-2-fluoro-phenoxy)propyl]thiazole-4-carboxylic acid Step A : Methyl 2-(3-chloro-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl)-5-[3-[2-fluoro-4-(2-trimethylsilylethynyl)phenoxy]propyl]thiazole-4-carboxylate A 250 mL oven-dried, single-necked round-bottom flask equipped with a PTFE-coated magnetic stir bar and a reflux condenser was charged with 5 g of Preparation 3a (8.29 mmol, 1 equiv.), 2.34 mL of ethynyl(trimethyl)silane (16.58 mmol, 2 equiv.), and 10 mL of DIPEA. 40 mL of dry THF was then added, and the system was flushed with argon. After stirring for 5 min under an inert atmosphere, 182 mg of Pd(PPh3)2Cl2 (0.41 mmol, 0.05 equiv.) and 79 mg of Pd(PPh3)2Cl2 (0.41 mmol, 0.05 equiv.) were added. The resulting mixture was then warmed to 60 °C and stirred at that temperature for 2 h until complete conversion was achieved. Celite was added to the reaction mixture, and the volatiles were removed under reduced pressure. It was then purified via flash chromatography using heptane-EtOAc as the eluent to give 4.26 g of the desired product (89% yield). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.31 (dd, 1H), 7.23 (dn, 1H), 7.13 (t, 1H), 4.25 (t, 2H), 4.12 (t, 2H), 3.77 (s, 3H), 3.24 (t, 2H), 2.87 (t, 2H), 2.31 (s, 3H), 2.1 (m, 2H), 2.03 (m, 2H), 0.21 (s, 9H); 13C NMR (125 MHz, DMSO-d6) δ ppm 163.0, 155.3, 151.7, 151.3, 136.1, 129.4, 129.0, 119.4, 115.3, 104.6, 93.7, 68.2, 51.9, 46.3, 30.7, 24.1, 23.0, 19.7, 15.7, 0.4; HRMS-ESI (m / z): [M]+ C 27 H 30 Calculated value for ClFN4O3SSi: 572.1481, found value 572.1480.

[0143] Step B : Methyl 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[2-fluoro-4-(2-trimethylsilylethynyl)phenoxy]propyl]thiazole-4-carboxylate A 100 mL oven-dried, single-necked round-bottom flask equipped with a PTFE-coated magnetic stir bar was charged with 4.25 g of the product from Step A (7.4 mmol, 1.0 equiv.), 2.23 g of 1,3-benzothiazol-2-amine (14.8 mmol, 2.0 equiv.), and 3.87 mL of DIPEA (2.87 mg, 22.2 mmol, 3.0 equiv.). 40 mL of cyclohexanol was then added, and the system was flushed with argon. After stirring for 5 min under an inert atmosphere, 679 mg of Pd2(dba)3 (0.74 mmol, 0.10 equiv.) and 858 mg of XantPhos (1.48 mmol, 0.20 equiv.) were added. The resulting mixture was then warmed to 140 °C and stirred at that temperature for 30 min until complete conversion was achieved. The reaction mixture was diluted with DCM and directly loaded onto a preconditioned silica gel column, which was then purified via flash chromatography using heptane and EtOAc as eluents. The pure fractions were combined and concentrated under reduced pressure to give 3.90 g of the desired product (77% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.27 / 10.91 (brs, 1H), 8.1-7.1 (brm, 4H), 7.34 (dd, 1H), 7.24 (dm, 1H), 7.16 (t, 1H), 4.25 (t, 2H), 4.15 HRMS-ESI (m / z): [M+H]+ C 34 H 36 Calculated value for FN6O3S2Si: 687.2038, measured value 687.2020.

[0144] Step C 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-(4-ethynyl-2-fluoro-phenoxy)propyl]thiazole-4-carboxylic acid A 10 mL oven-dried, single-necked round-bottom flask equipped with a PTFE-coated magnetic stir bar and a reflux condenser was charged with 343 mg of the product from Step B (0.5 mmol, 1.0 equiv.) dissolved in 2.5 mL of THF / HO (4:1). Next, 105 mg of LiOH × HO (2.50 mmol, 5.0 equiv.) was added, and the resulting mixture was heated to 60 °C and stirred at this temperature for 4 h. The reaction reached complete conversion. Celite gel was added to the reaction mixture, and volatiles were removed under reduced pressure. It was then purified via flash chromatography using DCM and MeOH (1.2% NH) as eluents to give 200 mg of the title compound (66% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.88 (d, 1H), 7.49 (br., 1H), 7.37 (t, 1H), 7.36 (dd, 1H), 7.25 (dm, 1H), 7.19 (t, 1H), 7.16 (t, 1H), 4.27 (t, 2H), 4.15 (t, 2H), 4.11 (s, 1H), 3.27 (t, 2H), 2.87 (t, 2H), 2.33 (s, 3H), 2.14 (m, 2H), 2.04 (m, 2H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 164.2, 151.5, 147.9, 129.4, 126.5, 122.5, 122.3, 119.5, 115.5, 114.5, 82.9, 80.5, 68.5, 46.2, 31.0, 23.9, 23.1, 20.3, 12.9; HRMS-ESI (m / z): [M+H]+ C 30 H 26 Calculated value for FN6O3S2: 601.1486, found 601.1498.

[0145] Preparation 3d : Methyl 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[2-fluoro-4-(3-hydroxyprop-1-ynyl)phenoxy]propyl]thiazole-4-carboxylate Step A : Methyl 5-[3-[4-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]-2-fluoro-phenoxy]propyl]-2-(3-chloro-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl)thiazole-4-carboxylate Using Sonogashira's general procedure, starting with 4.00 g of preparation 3a (6.63 mmol, 1.0 equiv.) and 2.26 g of tert-butyl-dimethyl-prop-2-ynoxy-silane (13.27 mmol, 2 equiv.) as the appropriate acetylene, 2.80 g of the desired product (65% yield) was obtained. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.27 (dd, 1H), 7.19 (dd, 1H), 7.14 (t, 1H), 4.51 (s, 1H), 4.25 (m, 2H), 4.12 (t, 2H), 3.77 (s, 3H), 3.24 (t, 2H), 2.87 (t, 2H), 2.3 (s, 3H), 2.1 (quint., 2H), 2.03 (m, 2H), 0.88 (s, 9H), 0.12 (s, 6H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 163.0, 128.9, 119.1, 115.5, 68.3, 52.1, 51.9, 46.3, 30.7, 26.2, 24.2, 23.0, 19.7, 15.7, -4.6; HRMS-ESI (m / z): [M+H]+ C 31 H 39 Calculated value for ClFN4O4SSi: 645.2128, found 645.2120.

[0146] Step B : Methyl 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[4-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylate Using Buchwald's general procedure II, starting with 2.8 g of the product of Step A (4.34 mmol, 1.0 equiv) and 1.30 g of 1,3-benzothiazol-2-amine (8.67 mmol, 2.0 equiv), 2.1 g of the desired product (64% yield) was obtained. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.25 / 10.91 (brs 1H), 7.88 (br, 1H), 7.51 (br, 1H), 7.37 (t, 1H), 7.29 (dd, 1H), 7.2 (t, 1H), 7.2 (dd, 1H), 7.17 (t, 1H), 4.49 (s, 2H), 4.25 (t, 2H), 4.14 (t, 2H), 3.77 (s, 3H), 3.27 (t, 2H), 2.86 (t, 2H), 2.32 (s, 3H), 2.13 (qn, 2H), 2.04 (qn, 2H), 0.87 (s, 9H), 0.1 (s, 6H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 163.2, 155.7, 151.6, 148.5, 147.6, 141.5, 128.9, 127.6, 126.5, 122.5, 122.3, 119.1, 116.9, HRMS-ESI (m / z): [M+H]+ C 38 H 44 Calculated value for FN6O4S2Si: 759.2613, found 759.2609.

[0147] Step C : Methyl 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[2-fluoro-4-(3-hydroxyprop-1-ynyl)phenoxy]propyl]thiazole-4-carboxylate A 100 mL oven-dried, single-necked round-bottom flask equipped with a PTFE-coated magnetic stir bar and fitted with a reflux condenser was charged with 2.10 g of the product from Step B (2.76 mmol, 1.0 equiv.) dissolved in 15 mL of THF. Next, 3.32 mL of TBAF (3.32 mmol, 1.2 equiv., 1 M in THF) was added dropwise via syringe over 2 min and stirred at that temperature for 30 min. The reaction mixture was quenched with saturated NH4Cl and then evaporated directly onto Celite, which was purified via flash chromatography using heptane-EtOAc as eluent to give 1.6 g of the desired product (90% yield). 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.14 (brs, 1H), 7.83 (brd, 1H), 7.49 (brs, 1H), 7.36 (m, 1H), 7.24 (dd, 1H), 7.19 (m, 1H), 7.18 (dm, 1H), 7.15 (t, 1H), 5.08 (t, 1H), 4.28 (m, 2H), 4.27 (d, 2H), 4.17 (t, 2H), 3.8 (s, 3H), 3.29 (m, 2H), 2.89 (m, 2H), 2.35 (s, 3H), 2.15 (m, 2H), 2.07 (m, 2H); HRMS-ESI (m / z): [M+H]+ C 32 H 30 Calculated value for FN6O4S2: 645.1748, found 645.1738.

[0148] Preparation 3e : Methyl 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[2-fluoro-4-(3-hydroxypropyl)phenoxy]propyl]thiazole-4-carboxylate Step A : Methyl 2-(tert-butoxycarbonylamino)-5-[3-[4-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylate Using Sonogashira's general procedure, starting with 4.00 g of preparation 1a (7.45 mmol, 1.0 equiv.) as the appropriate acetylene and 2.54 g of tert-butyl-dimethyl-prop-2-ynoxy-silane (14.90 mmol, 2.0 equiv.), 1.70 g of the desired product (39% yield) was obtained. 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.64 (s, 1H), 7.27 (dd, 1H), 7.19 (dm, 1H), 7.14 (t, 1H), 4.51 (s, 2H), 4.1 (t, 2H), 3.73 (s, 3H), 3.23 (t, 2H), 2.07 (m, 2H), 1.46 (s, 9H), 0.89 (s, 9H), 0.12 (s, 6H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 88.2, 83.8.

[0149] Step B : Methyl 2-(tert-butoxycarbonylamino)-5-[3-[4-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylate A 50 mL oven-dried autoclave equipped with a PTFE-coated magnetic stir bar was charged with 1.70 g of the product from Step A (2.9 mmol, 1.0 equiv.), 310 mg of Pd / C (0.29 mmol, 0.10 equiv.), and 15 mL of ethanol, inertized using vacuum and nitrogen, and finally filled with 10 bar of hydrogen gas. The mixture was then stirred at room temperature for 3 hours until complete conversion was achieved. Celite was added to the reaction mixture, and volatiles were removed under reduced pressure. It was then purified via flash chromatography using heptane and EtOAc as eluents to give 1.2 g of the desired product (70% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.64 (br., 1H), 7.02 (t, 1H), 7.01 (d, 1H), 6.89 (d, 1H), 4.02 (t, 2H), 3.74 (s, 3H), 3.54 (t, 2H), 3.22 (t, 2H), 2.54 (t, 2H), 2.04 (quint., 2H), 1.70 (quint., 2H), 1.45 (s, 9H), 0.85 (s, 9H), 0 (s, 6H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 162.8, 156.2 / 153.5, 152.0, 144.7, 141.9, 135.8, 135.5, 124.6, 116.2, 115.5, 68.1, 62.0, 51.9, 34.3, 30.8, 30.8, 28.3, 26.2, 23.2, -4.9.

[0150] Step C : Methyl 2-[tert-butoxycarbonyl-[3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propyl]amino]-5-[3-[4-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylate Using Mitsunobu's general procedure, starting with 1.16 g of the product of Step B (2.0 mmol, 1.0 equiv.) as the appropriate carbamate and 484 mg of Preparation 2a (2.2 mmol, 1.1 equiv.) as the appropriate alcohol, 1.2 g of the desired product (77% yield) was obtained. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.02 (m, 1H), 6.99 (d, 1H), 6.89 (m, 1H), 4.08 (t, 2H), 4.02 (t, 2H), 3.75 (s, 3H), 3.54 (t, 2H), 3.22 (t, 2H), 2.81 (t, 2H), 2.53 (t, 2H), 2.40 (s, 3H), 2.05 (quint., 2H), 1.87 (m, 2H), 1.70 (quint., 2H), 1.48 (s, 9H), 0.85 (s, 9H), 0.00 (s, 6H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 162.7, 156.4 / 153, 152.0, 144.7, 143.6, 142 / 139.8, 141.9, 135.5, 124.6, 116.2, 115.4, 68.1, 62.0, 52.0, 46.1, 34.2, 30.8, 30.7, 28.0, 27.5, 26.2, 25.8, 23.2, 16.4, -4.9;

[0151] Step D : Methyl 5-[3-[4-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-2-fluoro-phenoxy]propyl]-2-[3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propylamino]thiazole-4-carboxylate Using the general procedure for deprotection with HFIPA, starting from 1.2 g of the product of Step C as the appropriate carbamate, 790 mg of the desired product (75% yield) was obtained.

[0152] Step E : Methyl 5-[3-[4-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-2-fluoro-phenoxy]propyl]-2-(3-chloro-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl)thiazole-4-carboxylate A 25 mL oven-dried pressure bottle equipped with a PTFE-coated magnetic stir bar was charged with 1.2 g of the product from Step D (1.75 mmol, 1.0 equiv.) and 680 mg of cesium carbonate (3.50 mmol, 2.0 equiv.) suspended in 10 mL of 1,4-dioxane. The reaction mixture was then warmed to 80 °C and stirred at that temperature for 3 h, at which time the reaction had reached complete conversion. Celite was added to the reaction mixture, and volatiles were removed under reduced pressure. It was then purified via flash chromatography using DCM and MeOH (containing 1.2% NH) as eluents to give 1.0 g of the desired product (88% yield).

[0153] Step F : Methyl 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[4-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylate Using Buchwald's general procedure II, starting with 630 mg of the product of Step E (0.97 mmol, 1.0 equiv) and 291 mg of 1,3-benzothiazol-2-amine (1.94 mmol, 2.0 equiv), 600 mg of the desired product (81%) was obtained.

[0154] Step G : Methyl 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[2-fluoro-4-(3-hydroxypropyl)phenoxy]propyl]thiazole-4-carboxylate A 250 mL oven-dried round-bottom flask equipped with a PTFE-coated magnetic stir bar was charged with 600 mg of the product from step F (0.78 mmol, 1.0 equiv.) dissolved in 10 mL of THF, followed by the dropwise addition of 936 μL of TBAF (0.963 mmol, 1.2 equiv.). After stirring for 1 h, complete conversion was observed. The reaction mixture was then quenched with saturated aqueous NH4Cl, Celite was added to the reaction mixture, and the volatiles were removed under reduced pressure. It was then purified via flash chromatography using heptane and EtOAc with MeOH (1.2% NH3) as eluents to give 450 mg of the desired product (89% yield). 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.87 (br, 1H), 7.49 (br, 1H), 7.37 (t, 1H), 7.19 (t, 1H), 7.06 (m, 1H), 7.05 (d, 1H), 6.92 (dd, 1H), 4.44 (br, 1H), 4.25 (t, 2H), 4.08 (t, 2H), 3.78 (s, 3H), 3.36 (t, 2H), 3.27 (t, 2H), 2.85 (t, 2H), 2.52 (t, 2H), 2.32 (s, 3H), 2.1 (qn, 2H), 2.04 (qn, 2H), 1.65 (qn, 2H); 13 C NMR (500 MHz, DMSO-D6) δ ppm 163.2, 155.6, 152.0, 148.5, 144.7, 141.7, 135.9, 134.8, 127.6, 126.5, 124.7, 122.5, 122.3, 116.3, 116.0, 115.6, 68.6, 60.4, 52.0, 46.4, 34.6, 31.2, 31.0, 23.9, 23.2, 20.4, 12.9.

[0155] Preparation 3f : Ethyl 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}-1,3-thiazole-4-carboxylate Step A : Ethyl 2-[(hex-4-yn-1-yl)amino]-1,3-thiazole-4-carboxylate To a solution of ethyl 2-bromo-1,3-thiazole-4-carboxylate (1.17 g, 4.97 mmol, 1 equiv.) in acetonitrile (16 mL) was added hex-4-yn-1-amine (725 mg, 7.46 mmol, 1.5 equiv.) and triethylamine (1.04 mL, 7.46 mmol, 1.5 equiv.), and the mixture was heated at 150 °C under microwave irradiation for 4 h. The reaction was partitioned between ethyl acetate and brine, and the organic phase was dried (magnesium sulfate) and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 40 g RediSep 2000) eluted with a gradient of 0-60% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a beige solid (741 mg, 2.94 mmol, 59%). LC / MS (C 12 H 16 N2O2S) 253 [M+H] + ; Retention time 2.32 (LCMS-VC)

[0156] Step B : Ethyl 2-{3-chloro-4-methyl-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}-1,3-thiazole-4-carboxylate To a solution of 3,6-dichloro-1,2,4,5-tetrazine (443 mg, 2.94 mmol, 1 equiv) in tetrahydrofuran (15 mL) was added the product of Step A (741 mg, 2.94 mmol, 1 equiv) and the mixture was heated in a sealed tube at 110° C. overnight. The reaction was concentrated in vacuo, and the residue was triturated with methanol, filtered, and dried under vacuum to give the desired product as a beige solid (607 mg, 1.79 mmol, 61%). LC / MS (C 14 H 15 ClN4O2S) 339 [M+H] + ; Retention time 2.41 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 4.38 - 4.25 (m, 4H), 2.92 (t, J = 6.3 Hz, 2H), 2.34 (s, 3H), 2.14 - 2.01(m, 2H), 1.31 (t, J = 7.1Hz, 3H).

[0157] Step C : Ethyl 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}-1,3-thiazole-4-carboxylate To an oven-dried microwave vial was added the product of Step B (607 mg, 1.79 mmol, 1 equiv), 2-aminobenzothiazole (404 mg, 2.69 mmol, 1.5 equiv), XantPhos (207 mg, 0.36 mmol, 0.2 equiv), cesium carbonate (1.17 g, 3.58 mmol, 2 equiv), and 1,4-dioxane (36 mL), the vessel was evacuated and flushed with nitrogen, then tris(dibenzylideneacetone)dipalladium(0) (164 mg, 0.18 mmol, 0.1 equiv) was added, and the mixture was sparged with nitrogen (10 min) and then heated under microwave irradiation at 150° C. for 4 h. The reaction was diluted with ethyl acetate, filtered through Celite, then washed with brine, dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 24g RediSep) eluted with a gradient of 0-100% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave a solid which was triturated with diethyl ether, filtered and dried under vacuum to give the desired product as a yellow solid (329 mg, 0.73 mmol, 41%). LC / MS (C 21 H 20 N6O2S2) 453 [M+H] + ; Retention time 2.73 (LCMS-VC) 1H NMR (400 MHz, DMSO-d6) δ 7.99 (br s + s, 2H), 7.65 (br s, 1H), 7.43 - 7.31 (m, 1H), 7.28 - 7.15 (m, 1H), 4.35 - 4.25 (m, 4H), 2.96 - 2.85 (m, 2H), 2.36 (s, 3H), 2.15 - 2.00 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H).

[0158] Preparation 3g : Ethyl 5-(3-hydroxypropyl)-2-(4-methyl-3-{[(2Z)-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1,3-benzothiazol-2-ylidene]amino}-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl)-1,3-thiazole-4-carboxylate Step A : Ethyl 2-(4-methyl-3-{[(2Z)-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1,3-benzothiazol-2-ylidene]amino}-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl)-1,3-thiazole-4-carboxylate To a solution of the product of Preparation 3f (11.7 g, 25.8 mmol, 1 equiv.) in dimethylformamide (700 mL) was added N,N-diisopropylethylamine (13.5 mL, 77.4 mmol, 3 equiv.). After 5 min, the mixture was cooled to 0 °C, and 4-(dimethylamino)pyridine (630 mg, 5.16 mmol, 0.2 equiv.) and 2-(trimethylsilyl)ethoxymethyl chloride (13.6 mL, 77.4 mmol, 3 equiv.) were added, and the mixture was stirred at ambient temperature overnight. The reaction was concentrated in vacuo, and then partitioned between dichloromethane and brine. The organic phase was dried (magnesium sulfate) and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 330 g RediSep HPLC) eluted with a gradient of 0–40% ethyl acetate in isoheptane. 商標Purification by silica cartridge) gave the desired product as a yellow solid (9.61 g, 16.5 mmol, 64%). LC / MS (C 27 H 34 N6O3SiS2) 583 [M+H] + ; Retention time 2.90 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.82 (dd, J = 7.7, 1.1 Hz, 1H), 7.49 - 7.38 (m, 2H), 7.28 - 7.19 (m, 1H), 5.86 (s, 2H), 4.38 - 4.23 (m, 4H), 3.77 - 3.67 (m, 2H), 2.89 (t, J = 6.2 Hz, 2H), 2.38 (s, 3H), 2.13 - 2.01 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H), 0.91 (dd, J = 8.5, 7.4 Hz, 2H), -0.11 (s, 9H).

[0159] Step B : Ethyl 5-bromo-2-(4-methyl-3-{[(2Z)-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1,3-benzothiazol-2-ylidene]amino}-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl)-1,3-thiazole-4-carboxylate To a solution of the product of Step A (9.61 g, 16.5 mmol, 1 equiv.) in dichloromethane (400 mL) was added N-bromosuccinimide (3.52 g, 19.8 mmol, 1.2 equiv.) and the mixture was stirred at ambient temperature overnight. The reaction was partitioned between dichloromethane and water, and the organic phase was washed with brine, dried (PTFE phase separator), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 220 g RediSep 2000) eluted with a gradient of 0-40% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a yellow solid (9.66 g, 14.6 mmol, 89%). LC / MS (C 27 H 33 BrN6O3SiS2) 663 [M+H] + ; Retention time 3.13 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 7.84 (dd, J = 7.5, 1.1 Hz, 1H), 7.59 - 7.38 (m, 2H), 7.24 (ddd, J = 8.3, 6.7, 1.7 Hz, 1H), 5.85 (s, 2H), 4.37 - 4.23 (m, 4H), 3.72 (dd, J = 8.5, 7.4 Hz, 2H), 2.87 (t, J = 6.2 Hz, 2H), 2.38 (s, 3H), 2.13 - 2.00 (m, 2H), 1.32 (t, 3H), 0.95 - 0.81 (m, 2H), -0.12 (s, 9H).

[0160] Step C Ethyl 5-[(1E)-3-[(tert-butyldimethylsilyl)oxy]prop-1-en-1-yl]-2-(4-methyl-3-{[(2Z)-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1,3-benzothiazol-2-ylidene]amino}-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl)-1,3-thiazole-4-carboxylate To an oven-dried, sealed flask was added the product of Step B (9.66 g, 14.6 mmol, 1 equiv), (£)-3-(tert-butyldimethylsilyloxy)propen-1-yl-boronic acid pinacol ester (5.74 mL, 17.5 mmol, 1.2 equiv), potassium carbonate (6.05 g, 43.8 mmol, 3 equiv), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.19 g, 1.46 mmol, 0.1 equiv), tetrahydrofuran (360 mL), and water (120 mL), and the mixture was sparged with nitrogen (10 min) and then heated at 120° C. for 2 h. The reaction was partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 220g RediSep) eluted with a gradient of 0-30% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a yellow solid (6.46 g, 8.58 mmol, 59%). LC / MS (C 36 H 52 N6O4Si2S2) 753 [M+H] + ; Retention time 1.62 (LCMS-V-B2) 1 H NMR (400 MHz, DMSO-d6) δ 7.80 (dd, J = 7.6, 1.0 Hz, 1H), 7.51 - 7.38 (m, 3H), 7.24 (ddd, J = 8.3, 6.8, 1.8 Hz, 1H), 6.28 (dt, J = 16.0, 4.3 Hz, 1H), 5.85 (s, 2H), 4.37 (dd, J = 4.4, 2.1 Hz, 2H), 4.35 - 4.25 (m, 4H), 3.72 (dd, J = 8.5, 7.4 Hz, 2H), 2.88 (t, J = 6.3 Hz, 2H), 2.37 (s, 3H), 2.09 - 1.99 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H), 0.93 (s, 9H), 0.92 - 0.83 (m, 2H), 0.11 ( (s, 6H), -0.11 (s, 9H).

[0161] Step D Ethyl 5-{3-[(tert-butyldimethylsilyl)oxy]propyl}-2-(4-methyl-3-{[(2Z)-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1,3-benzothiazol-2-ylidene]amino}-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl)-1,3-thiazole-4-carboxylate To a solution of the product of Step C (6.46 g, 8.58 mmol, 1 equiv.) in ethyl acetate (300 mL) under a nitrogen atmosphere was added platinum(IV) oxide (390 mg, 1.72 mmol, 0.2 equiv.). The vessel was evacuated and back-filled with nitrogen (×3), then evacuated, placed under an atmosphere of hydrogen, and shaken at ambient temperature for 3 days. The reaction was filtered through Celite, eluted with ethyl acetate, and concentrated in vacuo to give the desired product as a brown gum (6.72 g, 8.9 mmol, >100%). LC / MS (C 36 H 54 N6O4Si2S2) 755 [M+H] + ; Retention time 1.67 (LCMS-V-B2) 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, 1H), 7.48 - 7.35 (m, 2H), 7.24 (ddd, J = 8.2, 6.5, 1.9 Hz, 1H), 5.84 (s, 2H), 4.33 - 4.22 (m, 4H), 3.76 - 3.62 (m, 4H), 3.15 (t, J = 7.5 Hz, 2H), 2.87 (t, J = 6.4 Hz, 2H), 2.37 (s, 3H), 2.10 - 1.98 (m, 3H), 1.91 - 1.79 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H), 0.95 - 0.85 (m, 11H), 0.06 (s, 6H), -0.12 (s, 9H).

[0162] : Ethyl 5-(3-hydroxypropyl)-2-(4-methyl-3-{[(2Z)-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1,3-benzothiazol-2-ylidene]amino}-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl)-1,3-thiazole-4-carboxylate To a solution of the product of Step D (6.72 g, 8.9 mmol, 1 equiv.) in 1,4-dioxane (400 mL) was added hydrochloric acid (4 M in dioxane; 67 mL, 267 mmol, 30 equiv.), and the mixture was stirred at ambient temperature for 1 h. The reaction was cooled to 0 °C, neutralized with 1 N aqueous sodium hydroxide solution (300 mL), and then partitioned between ethyl acetate and water. The organic phase was dried (magnesium sulfate) and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 120 g RediSep HPLC) eluting with a gradient of 0-80% ethyl acetate in isoheptane was performed. 商標 Purification by silica cartridge) gave a solid which was triturated with diethyl ether, filtered and dried under vacuum to give the desired product as a white solid (3.87 g, 6.04 mmol, 68%). LC / MS (C 30 H 40 N6O4SiS2) 641 [M+H] + ; Retention time 2.80 (LCMS-VC) 1H NMR (400 MHz, DMSO-d6) δ 7.83 (dd, J = 7.6, 1.1 Hz, 1H), 7.48 - 7.37 (m, 2H), 7.23 (ddd, J = 8.3, 6.7, 1.8 Hz, 1H), 5.85 (s, 2H), 4.56 (t, J = 5.1 Hz, 1H), 4.33 - 4.22 (m, 4H), 3.72 (dd, J = 8.6, 7.3 Hz, 2H), 3.48 (td, J = 6.3, 5.1 Hz, 2H), 3.17 - 3.08 (m, 2H), 2.88 (t, J = 6.4 Hz, 2H), 2.38 (s, 3H), 2.11 - 1.99 (m, 2H), 1.87 - 1.75 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H), 0.96 - 0.86 (m, 2H), -0.11 (s, 9H).

[0163] Step E : 4-[1-[(dimethylamino)methyl]-3-bicyclo[1.1.1]pentanyl]-2-fluoro-phenol Preparation 4a : Tricyclo[1.1.1.0 1 , 3 ]Pentane A 1 L three-neck flask equipped with a stir bar was assembled with a steel head fitted with a condenser, a 250 mL collection flask fitted with a Schlenk tap, a 250 mL addition funnel, and a thermometer. All glassware was assembled hot, then connected to a Schlenk line and allowed to cool under a stream of nitrogen. A solution of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane (59.4 g, 200 mmol, 1 equiv.) in diethyl ether (200 mL) was cooled to -45 °C, and phenyllithium (1.9 M in n-butyl ether; 211 mL, 400 mmol, 2 equiv.) was added via the addition funnel over 25 min. After complete addition, the mixture was allowed to warm to 0 °C and stirred for 2 h. After this time, the receiving flask was cooled to -78 °C, and the manifold connection was temporarily closed and replaced with a vacuum pump attachment (with a pressure-equalizing inlet connected to a nitrogen manifold). Before switching on the pump, the dropping funnel and thermometer were replaced with pre-greased glass stoppers. The pump was brought to a pressure of 200 mbar and then the connections were opened. The pressure was gradually reduced to 120 mbar over 3 minutes, and then the reaction vessel was allowed to warm to ambient temperature. The pressure was then carefully reduced to 45 mbar and maintained at this pressure for 45 minutes. After this time, the vacuum was released with nitrogen and the resulting clear, colorless distillate was stored at -20°C. The concentration of the desired product was determined by 1 Determined to be 0.45M by 1 H NMR. 1 H NMR (400 MHz, chloroform-d) δ 2.04 (s, 6H).

[0164] Step A : Bromo(3-fluoro-4-methoxyphenyl)magnesium Magnesium (681 mg, 28 mmol, 1.4 equiv.) was added to a 50 mL three-neck flask equipped with a stir bar and condenser. The apparatus was heated intensely (~500 °C) with a heat gun for 5 minutes with vigorous stirring, then allowed to cool to ambient temperature under nitrogen. Diethyl ether (5 mL) was added, followed by 1,2-dibromoethane (172 μL, 2 mmol, 0.1 equiv.). The mixture was heated to reflux 4-5 times over 5 minutes, then allowed to stand for 10 minutes, after which a gentle reflux was observed. The mixture was brought to a constant reflux by hand heating, and then slow stirring was initiated. At this point, a solution of 4-bromo-2-fluoroanisole (4.1 g, 20 mmol, 1 equiv.) in diethyl ether (10 mL) was added at a rate that maintained a constant reflux, and the stirring speed was increased (300 rpm). The addition was completed after 15 minutes. The mixture was continued to stir at ambient temperature for 0.5 hours, after which a clear, two-phase system was obtained. The lower, dark straw-colored layer (10.15 mL) was transferred via syringe through a 0.2 μm PTFE filter to a dry Schlenk flask. The concentration of the solution was calculated to be 1.38 M by titration against a solution of iodine in dry tetrahydrofuran. The resulting solution was used directly in the next step without further characterization.

[0165] Step B : Ethyl 3-(3-fluoro-4-methoxyphenyl)bicyclo[1.1.1]pentane-1-carboxylate The product of Step B (1.38 M in diethyl ether; 4.83 mL, 6.67 mmol, 1 equiv.) followed by the product of Step A (0.45 M in diethyl ether; 14.8 mL, 6.67 mmol, 1 equiv.) were added to a 50 mL oven-dried ACE pressure vessel equipped with a stir bar. The vessel was sealed with a Teflon screw top fitted with a front O-ring and placed on a preheated heater block at 105 °C behind a blast shield for 3 h. The mixture was allowed to cool at ambient temperature for 20 min and then in ice water for 10 min. The Teflon screw top was replaced with a suba seal attached to a nitrogen line, and the reaction was cooled to -78 °C. Ethyl chloroformate (5.1 mL, 53.3 mmol, 4 equiv.) was added, and the mixture was allowed to warm to ambient temperature for 1.5 h. The reaction was partitioned between saturated aqueous ammonium chloride solution and diethyl ether, and the aqueous phase was extracted with ether. The combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 80g RediSep 2000) eluting with a gradient of 0-10% ethyl acetate in isoheptane was performed. 商標 Purification by automated flash column chromatography (CombiFlash Torrent, 200 g RediSep) eluting with a gradient of 0-80% dichloromethane in heptane gave the desired product as a colorless liquid, which was a mixture of the desired product and a by-product. This material was further purified by automated flash column chromatography (CombiFlash Torrent, 200 g RediSep) eluting with a gradient of 0-80% dichloromethane in heptane. 商標 Purification by silica cartridge) gave the desired product (640 mg, 3.78 mmol, 56%). 1 13C NMR (500 MHz, DMSO-D6) δ ppm 169.8, 151.8, 146.6, 133.0, 122.8, 114.2, 114.2, 60.6, 56.5, 53.2, 41.0, 36.9, 14.6. HRMS-EI (m / z): M+ calculated for C15H17F03: 264.1162, found 264.1156.

[0166] Step C : 1-(3-fluoro-4-methoxy-phenyl)bicyclo[1.1.1]pentane-3-carboxylic acid 200 mg of the product of step C (0.76 mmol, 1 equiv.) and 159 mg of LiOH×HO (3.78 mmol, 5 equiv.) were mixed in 1,4-dioxane (2 mL / mmol) and water (2 mL / mmol) and stirred at room temperature for 1 h, at which time complete conversion was observed. The reaction mixture was made basic with a 1:1 HCl solution, and the precipitate was filtered, washed with water, and then dried in vacuum overnight to isolate 170 mg (95%) of the desired product as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.41 (s, 1H), 7.09 (m, 1H), 7.09 (m, 1H), 6.97 (dm, 1H), 3.80 (s, 3H), 2.18 (s, 6H); 13 GC-MS-EI (m / z): [M] + C 13 H 13 FO3 calculated value: 236.0849, measured value 236.0840.

[0167] Step D : 1-(3-fluoro-4-methoxy-phenyl)-N,N-dimethyl-bicyclo[1.1.1]pentane-3-carboxamide 164 mg of the product of step D (1.04 mmol, 1 equiv.) and 278 mg of N,N-diethylethanamine (1.39 mmol, 2 equiv.) were mixed in EtOAc (3 mL / mmol), then 663 mg of 2,4,6-tripropyl-1,3,5,2λ^{5},4λ^{5},6λ^{5}-trioxatriphosphinane 2,4,6-trioxide (50 wt % in EtOAc, 1.04 mmol, 1.5 equiv.) was added in one portion and stirred at room temperature for 40 min. After this reaction time, 0.52 mL of N-methylmethanamine (2 M in MeOH, 1.04 mmol, 1.5 equiv.) was added and the mixture was stirred at room temperature until complete conversion was observed (60 min). The reaction mixture was diluted with DCM and then washed with concentrated NaHCO3, and the organic phase was then washed with concentrated NaCl, dried over MgSO4, filtered, concentrated, and dried in vacuo to give 187 mg (quantitative) of the desired product as a pink solid. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.14 (m, 2H), 6.86 (m, 2H), 3.72 (s, 3H), 3.08 (s, 3H), 2.81 (s, 3H), 2.26 (s, 6H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 168.9, 158.6, 132.5, 127.6, 114.1, 55.5, 54.2, 42.0, 39.0, 37.4, 35.9; HRMS-ESI (m / z): [M+H] + C 15 H 19 Calculated FNO2: 264.1394, measured 264.1389.

[0168] Step E : 1-[3-(3-fluoro-4-methoxy-phenyl)-1-bicyclo[1.1.1]pentanyl]-N,N-dimethyl-methanamine 182 mg of the product of Step E (0.69 mmol, 1 equiv.) was dissolved in THF (5 mL / mmol), then 1.38 mL of LiAlH4 (1 M in THF, 1.38 mmol, 2 equiv.) was added under a nitrogen atmosphere at ambient temperature and stirred until complete conversion was achieved (approximately 1 h). The mixture was cooled to 0 °C and then quenched with concentrated NH4Cl. After quenching with ∼5 mL of water and ∼10 mL of EtOAc, the mixture was shaken well. 2 M HCl was added, the (acidic) aqueous phase was separated, and the organic phase was extracted with additional 2 M HCl. The combined aqueous phases were made basic with 2 M NaOH and extracted with DCM. The combined organic phases were washed with brine, dried over MgSO4, concentrated, and dried in vacuo. 119 mg (69%) of the desired product was obtained as a viscous oil. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.07 (t, 1H), 7.01 (dd, 1H), 6.93 (dm, 1H), 3.79 (s, 3H), 2.35 (s, 2H), 2.16 (s, 6H), 1.90 (s, 6H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 151.8, 146.2, 134.5, 122.5, 114.1, 114.0, 60.7, 56.5, 52.9, 46.6, 41.7, 38.0; HRMS-ESI (m / z): [M+H] + C 15 H 21 Calculated FNO: 250.1602, measured 250.1596.

[0169] Step F : 4-[1-[(dimethylamino)methyl]-3-bicyclo[1.1.1]pentanyl]-2-fluoro-phenol 113 mg of the product of step F (0.45 mmol, 1 equiv.) was dissolved in DCM (5 mL / mmol), then 1.36 mL of BBr3 (1 M in DCM, 1.36 mmol, 3 equiv.) was added at 0 °C under a nitrogen atmosphere, followed by stirring at 0 °C for 15 min and at room temperature until complete conversion was achieved (approximately 45 min). DCM was added, then poured into a NaHCO3 solution and stirred for several minutes, which was then neutralized with concentrated NH4Cl. It was separated, washed with brine, dried over MgSO4, concentrated, and dried in vacuo. 47 mg (quantitative) of the desired crude product was obtained as a viscous oil. 1 H NMR (400 MHz, CDCl3) δ ppm 6.95 (t, 1H), 6.90 (dd, 1H), 6.85 (dm, 1H), 3.84 (s, 2H), 3.17 (s, 6H), 2.24 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ ppm 122.4, 117.4, 113.4, 59.5, 54.8, 46.0, 43.8, 34.8; HRMS-ESI (m / z): [M+H] + C 14 H 19 Calculated FNO: 236.1445, 236.1445.

[0170] Step G : 4-[3-(dimethylamino)prop-1-ynyl]-2-fluoro-phenol Using Sonogashira's general procedure, starting with 10.00 g of 2-fluoro-4-iodo-phenol (42.0 mmol, 1 equiv.) as the appropriate phenol and 5.24 g of N,N-dimethylprop-2-yn-1-amine (63 mmol, 1.5 equiv.) as the alkyne, 7.30 g (90%) of the desired product was obtained. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.20 (dd, 1H), 7.07 (dm, 1H), 6.91 (m, 1H), 3.39 (m, 2H), 2.21 (m, 3H); 13C NMR (125 MHz, DMSO-d6) δ ppm 150.9, 146.2, 128.9, 119.5, 118.4, 113.6, 84.5, 84.2, 48.2, 44.3; HRMS-ESI (m / z): [M+H] + C 11 H 13 Calculated FNO: 194.0976, measured 194.0981.

[0171] Preparation 4b : tert-Butyl N-[3-(3-fluoro-4-hydroxy-phenyl)prop-2-ynyl]-N-methyl-carbamate Using the general procedure of Sonogashira, starting with 10.00 g of 2-fluoro-4-iodo-phenol (42.0 mmol, 1 equiv.) as the appropriate phenol and 10.67 g of tert-butyl N-methyl-N-prop-2-ynyl-carbamate (63.1 mmol, 1.5 equiv.) as the alkyne, 10.8 g (92%) of the desired product was obtained. 1 H NMR (500 MHz, DMSO-d6) δ ppm 10.32 (s, 1H), 7.22 (brd, 1H), 7.08 (dm, 1H), 6.92 (dd, 1H), 4.21 (s, 2H), 2.85 (s, 3H), 1.41 (s, 9H); 13 C NMR (125 MHz, DMSO-d6) δ ppm 150.8, 146.4, 129.0, 119.6, 118.4, 113.2, 84.4, 82.7, 38.5, 33.8, 28.5; HRMS-ESI (m / z): [M-C4H8+H] + C 11 H 11 Calculated FNO3 value: 224.0717, measured value 224.0720.

[0172] Preparation 4c : 4-[3-(dimethylamino)propyl]-2-fluorophenol To a solution of the product of Preparation 4b (1.5 g, 7.76 mmol, 1 equiv.) in ethyl acetate (54 mL) and ethanol (18 mL) under nitrogen was added platinum(IV) oxide hydrate (353 mg, 1.55 mmol, 0.2 equiv.). The vessel was evacuated and back-filled with nitrogen (×3), then evacuated, subjected to an atmosphere of hydrogen, and shaken overnight at ambient temperature. The reaction was filtered through Celite, eluted with ethyl acetate, and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 24 g RediSep 1000) eluted with a gradient of 0-10% 1N methanolic ammonia in dichloromethane was performed. 商標 Purification by silica cartridge) gave the desired product (652 mg, 3.31 mmol, 42%) as an off-white solid. LC / MS (C 11 H 16 FNO) 198 [M+H] + ; Retention time 0.44 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 6.96 (dd, J = 12.5, 1.9 Hz, 1H), 6.88 - 6.76 (m, 2H), 2.47 (dd, J = 8.5, 6.8 Hz, 2H), 2.20 - 2.13 (m, 2H), 2.11 (s, 6H), 1.69 - 1.57 (m, 2H).

[0173] Preparation 4d : 4-[2-(dimethylamino)ethoxy]phenol Preparation 4e : 4-(methoxymethoxy)phenol To a solution of hydroquinone (0.76 mL, 9.08 mmol, 1 equiv.) in acetone (30 mL) was added potassium carbonate (2.51 g, 18.2 mmol, 2 equiv.) and chloromethyl methyl ether (0.69 mL, 9.08 mmol, 1 equiv.), and the mixture was stirred at ambient temperature overnight. The reaction was partitioned between ethyl acetate and water, and the organic phase was dried (magnesium sulfate) and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 24 g RediSep 2000) was performed, eluting with a gradient of 0-20% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a brown oil (601 mg, 3.9 mmol, 43%). 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 6.91 - 6.80 (m, 2H), 6.72 - 6.62 (m, 2H), 5.05 (s, 2H), 3.36 (s, 3H).

[0174] Step A : {2-[4-(methoxymethoxy)phenoxy]ethyl}dimethylamine To a solution of the product of Step A (400 mg, 2.59 mmol, 1 equiv.) in tetrahydrofuran (20 mL) was added N,N-dimethylethanolamine (526 μL, 5.19 mmol, 2 equiv.), di-tert-butyl azodicarboxylate (1.19 g, 5.19 mmol, 2 equiv.), and triphenylphosphine (1.36 g, 5.19 mmol, 2 equiv.), and the mixture was heated at 50 °C for 3 h. The reaction was concentrated in vacuo, partitioned between dichloromethane and saturated aqueous sodium bicarbonate, and the organic phase was separated (PTFE phase separator) and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 24 g RediSep) eluting with a gradient of 0-7% methanol in dichloromethane was performed. 商標 Purification by silica cartridge) gave the desired product as a brown oil (383 mg, 1.7 mmol, 66%). LC / MS (C 12 H 19 NO3) 226 [M+H]+ ; Retention time 0.88 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 6.99 - 6.90 (m, 2H), 6.94 - 6.82 (m, 2H), 5.10 (s, 2H), 3.98 (t, J = 5.8 Hz, 2H), 3.36 (s, 3H), 2.59 (t, J = 5.9 Hz, 2H), 2.20 (s, 6H).

[0175] Step B : 4-[2-(dimethylamino)ethoxy]phenol A solution of the product of Step B (383 mg, 1.7 mmol, 1 equiv) in hydrochloric acid (4 M in 1,4-dioxane; 5 mL, 20 mmol, 11.7 equiv) was stirred at ambient temperature for 1 h. The reaction was concentrated in vacuo, then dissolved in methanol, loaded onto a methanol-wet SCX cartridge (10 g), washed with methanol, eluted with 1.75 N methanolic ammonia, and concentrated in vacuo to give the desired product as a brown solid (249 mg, 1.37 mmol, 812%). LC / MS (C 10 H 15 NO2) 182 [M+H] + ; Retention time 0.24 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 6.79 - 6.70 (m, 2H), 6.70 - 6.62 (m, 2H), 3.92 (t, J = 5.9 Hz, 2H), 2.57 (t, J = 5.9 Hz, 2H), 2.20 (s, 6H).

[0176] Step C : 4-[2-(pyrrolidin-1-yl)ethoxy]phenol Preparation 4f : 1-{2-[4-(methoxymethoxy)phenoxy]ethyl}pyrrolidine To a solution of the product of Preparation 4e, Step A (525 mg, 3.41 mmol, 1 equiv.) in tetrahydrofuran (20 mL) was added 1-(2-hydroxyethyl)pyrrolidine (0.8 mL, 6.81 mmol, 2 equiv.), di-tert-butyl azodicarboxylate (1.57 g, 6.81 mmol, 2 equiv.), and triphenylphosphine (1.79 g, 6.81 mmol, 2 equiv.), and the mixture was heated at 50 °C overnight. The reaction was concentrated in vacuo, partitioned between dichloromethane and saturated aqueous sodium bicarbonate, and the organic phase was separated (PTFE phase separator) and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 40 g RediSep) eluting with a gradient of 0-7% methanol in dichloromethane was performed. 商標 Purification by silica cartridge) gave the desired product as a brown oil (556 mg, 2.21 mmol, 65%). LC / MS (C 14 H 21 NO3) 252 [M+H] + ; Retention time 1.09 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 6.98 - 6.91 (m, 2H), 6.91 - 6.82 (m, 2H), 5.10 (s, 2H), 4.00 (t, J = 5.9 Hz, 2H), 3.36 (d, J = 6.0 Hz, 3H), 2.75 (t, J = 6.0 Hz, 2H), 2.50 - 2.42 (m, 4H), 1.74 - 1.61 (m, 4H).

[0177] Step A : 4-[2-(pyrrolidin-1-yl)ethoxy]phenol A solution of the product of Step A (556 mg, 2.21 mmol, 1 equiv) in hydrochloric acid (4 M in 1,4-dioxane; 7 mL, 28 mmol, 12.7 equiv) was stirred at ambient temperature for 30 minutes. The reaction was concentrated in vacuo, then dissolved in methanol, loaded onto a methanol-wet SCX cartridge (10 g), washed with methanol, eluted with 1.75 N methanolic ammonia, and concentrated in vacuo to give the desired product as a brown solid (453 mg, 2.19 mmol, 99%). LC / MS (C 12 H 17 NO2) 208 [M+H] + ; Retention time 0.28 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 6.79 - 6.70 (m, 2H), 6.70 - 6.62 (m, 2H), 3.94 (t, J = 6.0 Hz, 2H), 3.17 (d, J = 4.3 Hz, 2H), 2.73 (t, J = 6.0 Hz, 2H), 2.49 (dt, J = 4.1, 1.4 Hz, 2H), 1.74 - 1.60 (m, 4H).

[0178] Step B : 4-[2-(dimethylamino)ethyl]-2-fluorophenol Preparation 4g : 2-Fluoro-1-methoxy-4-[(E)-2-nitroethenyl]benzene To a solution of 3-fluoro-4-methoxybenzaldehyde (400 mg, 2.6 mmol, 1 equiv.) and nitromethane (339 μL, 6.23 mmol, 2.4 equiv.) in methanol (50 mL) cooled to 0° C., 1 M aqueous sodium hydroxide solution (20 mL, 20 mmol, 7.71 equiv.) was added dropwise, and the resulting mixture was stirred at 0° C. for 1 h. The mixture was added dropwise to 8 M aqueous hydrochloric acid solution (12 mL, 96 mmol, 37 equiv.) cooled to 0° C., and the resulting suspension was allowed to warm to ambient temperature and stirred for 30 min. The precipitate was collected by filtration, washed with water, and dried under vacuum to give the desired product as a yellow solid (393 mg, 1.99 mmol, 76%). 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 13.6 Hz, 1H), 8.10 (dd, J = 13.5, 1.0 Hz, 1H), 7.88 (dd, J = 12.6, 2.1 Hz, 1H), 7.70 (dt, J = 8.6, 1.5 Hz, 1H), 7.29 (t, J = 8.8 Hz, 1H), 3.92 (s, 3H).

[0179] Step A : 2-(3-fluoro-4-methoxyphenyl)ethan-1-amine To a solution of the product of Step A (393 mg, 1.99 mmol, 1 equiv.) in tetrahydrofuran (12 mL) was added lithium aluminum hydride (1 M in tetrahydrofuran; 5.98 mL, 5.98 mmol, 3 equiv.) and the mixture was heated at 40° C. overnight. The reaction was quenched with water (1.2 mL) and concentrated in vacuo. The residue was dissolved in 2 N aqueous hydrochloric acid (20 mL) and washed with ethyl acetate (×2). Tartaric acid (2.1 g) was added to the aqueous phase and the pH was adjusted to pH 11 with concentrated ammonium hydroxide. The mixture was extracted with dichloromethane (×3), and the combined organic extracts were separated (PTFE phase separator) and concentrated in vacuo to give the desired product as a yellow oil (252 mg, 1.49 mmol, 75%). LC / MS (C9H 12 FNO) 170 [M+H] + ; Retention time 0.14 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 7.16 - 7.03 (m, 3H), 3.80 (s, 3H), 3.38 - 3.30 (m, 2H), 2.79 - 2.69 (m, 2H), 2.62 - 2.54 (m, 2H).

[0180] Step B : [2-(3-fluoro-4-methoxyphenyl)ethyl]dimethylamine To a solution of the product of Step B (252 mg, 1.49 mmol, 1 equiv.) in methanol (5 mL) was added formaldehyde (13.4 M in water; 123 μL, 4.47 mmol, 3 equiv.), followed by sodium triacetoxyborohydride (947 mg, 4.47 mmol, 3 equiv.) and glacial acetic acid (0.05 mL), and the mixture was stirred at ambient temperature for 1 h. The reaction was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, and the organic phase was dried (magnesium sulfate) and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 4g RediSep 1000) was performed, eluting with a gradient of 0-10% methanol in dichloromethane. 商標 Purification by silica cartridge) gave the desired product as a yellow oil (92 mg, 0.47 mmol, 31%). LC / MS (C 11 H 16 FNO) 198 [M+H] + ; Retention time 0.82 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 7.16 - 6.94 (m, 3H), 3.80 (s, 3H), 2.64 (dd, J = 8.5, 6.7 Hz, 2H), 2.41 (dd, J = 8.5, 6.7 Hz, 2H), 2.16 (s, 6H).

[0181] Step C : 4-[2-(dimethylamino)ethyl]-2-fluorophenol To a solution of the product of Step C (92 mg, 0.47 mmol, 1 equiv) in dichloromethane (3.5 mL) cooled to 0 °C, boron tribromide (1 M in dichloromethane, 1.4 mL, 1.4 mmol, 3 equiv) was added and the mixture was stirred at ambient temperature overnight. The reaction was cooled to 0 °C, quenched with methanol, and then concentrated in vacuo. The residue was dissolved in methanol, loaded onto a methanol-wet SCX cartridge (5 g), washed with methanol, eluted with 1.75 N methanolic ammonia, and concentrated in vacuo to give the desired product as a brown oil (41 mg, 0.22 mmol, 48%). LC / MS (C10 H 14 FNO) 184 [M+H] + ; Retention time 0.36 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 7.03 - 6.95 (m, 1H), 6.88 - 6.78 (m, 2H), 2.59 (dd, J = 8.7, 6.7 Hz, 2H), 2.38 (dd, J = 8.6, 6.7 Hz, 2H), 2.15 (s, 6H).

[0182] Step D : 3-[(dimethylamino)methyl]-5-fluoro-1-methyl-1H-indol-6-ol Preparation 4h : 6-(benzyloxy)-5-fluoro-1H-indole-2-carboxylic acid To a stirred solution of 6-benzyloxy-5-fluoro-1H-indole-2-carboxylic acid methyl ester (2.5 g, 8.35 mmol, 1 equiv.) in a mixture of tetrahydrofuran (25 mL) and methanol (25 mL), a solution of sodium hydroxide (4 g, 100 mmol, 12 equiv.) in water (30 mL) was added, and the mixture was stirred for 2.5 h. The reaction was cooled in ice water and acidified with stirring by the slow addition of 2 N aqueous hydrochloric acid (60 mL), resulting in a precipitate. Water (80 mL) was added, and the mixture was stirred for 45 min. The solid was then collected by filtration, washed with water, and dried under vacuum to give the desired product (2.25 g, 7.89 mmol, 94%) as an off-white solid. LC / MS (C 16 H 12 FNO3) 284 [MH] - ; Retention time 1.16 (LCMS-V-B1) 1H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 11.71 (d, J = 2.3 Hz, 1H), 7.54 - 7.39 (m, 5H), 7.39 - 7.32 (m, 1H), 7.10 (dd, J = 7.4, 0.8 Hz, 1H), 7.01 (dd, J = 2.2, 0.8 Hz, 1H), 5.19 (s, 2H).

[0183] Step A : 6-(benzyloxy)-5-fluoro-1H-indole A mixture of the product of Step A (1.25 g, 4.38 mmol, 1 equiv.) and diphenyl ether (60 mL) was heated at 290 °C (external) for 45 min. The reaction was allowed to cool to ambient temperature, then diluted with heptane (180 mL) and loaded under vacuum onto a hexane-wet prepacked silica column (80 g). Purification by automated flash chromatography (CombiFlash Rf, silica 80 g RediSep column) eluting with a gradient of 0 to 80% ethyl acetate in hexane gave the desired product (372 mg, 1.54 mmol, 35%) as a beige solid. LC / MS (C 15 H 12 FNO) 242 [M+H] + ; Retention time 1.26 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.52 - 7.45 (m, 2H), 7.49 - 7.37 (m, 2H), 7.41 - 7.30 (m, 2H), 7.25 (t, J = 2.8 Hz, 1H), 7.13 (dd, J = 7.3, 0.8 Hz, 1H), 6.34 (ddd, J = 3.0, 2.0, 0.8 Hz, 1H), 5.18 (s, 2H).

[0184] Step B : 6-(benzyloxy)-5-fluoro-1-methyl-1H-indole To a stirred solution of the product of Step B (365 mg, 1.51 mmol, 1 equiv.) in dimethylformamide (10 mL) cooled in an ice-water bath was added sodium hydride (60% dispersion; 72.6 mg, 3.03 mmol, 2 equiv.), and the mixture was stirred for 15 min. Iodomethane (0.11 mL, 1.82 mmol, 1.2 equiv.) was added, and the mixture was then allowed to warm to ambient temperature and stirred for 1 h. The reaction was cooled in ice and then quenched by the dropwise addition of saturated aqueous ammonium chloride solution and slowly poured into ice-water (40 mL) with stirring, resulting in a precipitate. Additional ice (20 mL) was added, and after stirring for 30 min, the solid was collected by filtration, washed successively with ice-cold water (2 × 30 mL) and hexane (2 × 10 mL), and dried under vacuum to give the desired product (259 mg, 1.01 mmol, 67%) as a beige solid. LC / MS (C 16 H 14 FNO) 256 [M+H] + ; Retention time 1.36 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 7.55 - 7.48 (m, 2H), 7.47 - 7.38 (m, 2H), 7.40 - 7.29 (m, 3H), 7.25 (d, J = 3.1 Hz, 1H), 6.33 (dd, J = 3.1, 0.8 Hz, 1H), 5.21 (s, 2H), 3.76 (s, 3H).

[0185] Step C {[6-(benzyloxy)-5-fluoro-1-methyl-1H-indol-3-yl]methyl}dimethylamine To a stirred mixture of 1,4-dioxane (5 mL) and glacial acetic acid (5 mL) was added aqueous formaldehyde (37 wt%; 1.18 mL, 14.54 mmol, 14.6 equiv), followed by aqueous dimethylamine (40 wt%; 1.42 mL, 12.6 mmol, 12.6 equiv). This solution (1.6 mL) was added to a stirred solution of the product of Step C (255 mg, 1 mmol, 1 equiv) in 1,4-dioxane (1 mL), and the mixture was stirred at ambient temperature for 4 h. The reaction was concentrated in vacuo, then 2N aqueous sodium hydroxide (4 mL) was added, and the resulting thick suspension was diluted with water (10 mL), stirred, and cooled in ice-water for 15 min. It was then filtered, washed with water (×3), and dried under vacuum to give the desired product (290 mg, 0.93 mmol, 93%) as a cream-colored solid. LC / MS (C 19 H 21 FN2O) 268 [M+H-NHMe2] + ; Retention time 0.99 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 7.55 - 7.47 (m, 2H), 7.47 - 7.38 (m, 2H), 7.40 - 7.31 (m, 2H), 7.28 (d, J = 7.3 Hz, 1H), 7.13 (s, 1H), 5.20 (s, 2H), 3.71 (s, 3H), 3.44 (s, 2H), 2.12 (s, 6H).

[0186] Step D : 3-[(dimethylamino)methyl]-5-fluoro-1-methyl-1H-indol-6-ol The flask was charged with 10% Pd / C (50 mg, 0.05 equiv.), then evacuated and flushed with nitrogen (×2). A solution of the product of Step D (285 mg, 0.91 mmol, 1 equiv.) in ethanol (20 mL) was added, and the flask was evacuated and flushed with nitrogen (×3), then evacuated and flushed with hydrogen (×3), then subjected to an atmosphere of hydrogen and shaken at ambient temperature for 4 h. The reaction was filtered through an HM-N cartridge, eluted with ethanol, and concentrated in vacuo. Purification by reverse-phase automated flash chromatography (CombiFlash Rf, C18 50 g Gold RediSep column) eluting with a gradient of 10–100% acetonitrile in water gave the desired product (69.8 mg, 0.27 mmol, 29%) as an off-white solid (hydrochloride salt). LC / MS (C 12 H 15 FN2O) 178 [M+H-NHMe2] + ; Retention time 0.36 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.66 (s, 1H), 7.60 (d, J = 11.8 Hz, 1H), 7.40 (s, 1H), 6.96 (d, J = 7.5 Hz, 1H), 4.29 (s, 2H), 3.71 (s, 3H), 2.66 (s, 6H), 1.23 (d, J = 6.5 Hz, 1H).

[0187] Step E : 4-[4-(dimethylamino)butyl]-2-fluorophenol Preparation 4i : [3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propyl]triphenylphosphanium bromide N-(3-Bromopropyl)phthalimide (2.75 g, 10.26 mmol, 1 equiv.) and triphenylphosphine (2.69 g, 10.3 mmol, 1 equiv.) were stirred in toluene (25 mL) and heated at reflux overnight. The reaction was allowed to cool to ambient temperature, and the solid was collected by filtration and dried under vacuum to give the desired product as a white solid (2.55 g, 4.81 mmol, 47%). 1 H NMR (400 MHz, DMSO-d6) δ 7.95 - 7.85 (m, 7H), 7.82 - 7.71 (m, 12H), 3.80 - 3.64 (m, 4H), 1.99 - 1.90 (m, 2H).

[0188] Step A : 2-[(3E)-4-(3-fluoro-4-methoxyphenyl)but-3-en-1-yl]-2,3-dihydro-1H-isoindole-1,3-dione To a solution of the product of Step A (2.55 g, 4.81 mmol, 1 equiv.) in toluene (25 mL) was added 3-fluoro-4-methoxybenzaldehyde (741 mg, 4.81 mmol, 1 equiv.), followed by 18-crown-6 (108 μL, 0.48 mmol, 0.1 equiv.), and the mixture was stirred at ambient temperature overnight. The reaction was partitioned between ethyl acetate and water, and the organic phase was dried (magnesium sulfate) and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 24 g RediSep 2000) was performed, eluting with a gradient of 0-30% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a white solid (1.48 g, 4.55 mmol, 95%). LC / MS (C 19 H 16 FNO3) 302 [OTHER]; Retention time 2.25 (LCMS-VC) 1H NMR (400 MHz, DMSO-d6) δ 7.91 - 7.79 (m, 4H), 7.13 - 6.98 (m, 3H), 6.43 - 6.33 (m, 1H), 5.61 (dt, J = 11.7, 7.4 Hz, 1H), 3.82 (s, 3H), 3.70 (t, 2H), 2.64 (qd, J = 7.2, 1.8 Hz, 2H).

[0189] Step B (3E)-4-(3-fluoro-4-methoxyphenyl)but-3-en-1-amine To a solution of the product of Step B (1.48 g, 4.55 mmol, 1 equiv.) in ethanol (60 mL) was added methylamine (2 M in methanol; 24 mL, 665 mmol, 146 equiv.) and the mixture was heated at reflux overnight. The reaction was allowed to cool to ambient temperature and concentrated in vacuo. The residue was triturated with diethyl ether, filtered, and dried under vacuum. The crude solid was dissolved in ethyl acetate and extracted with 1 N aqueous hydrochloric acid (3 × 100 mL). The combined aqueous extracts were basified with 4 M aqueous potassium hydroxide and extracted with ethyl acetate (×2), and the combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to give the desired product as a pink gum (395 mg, 2.02 mmol, 45%). LC / MS (C 11 H 14 FNO) 196 [M+H] + ; Retention time 1.25 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 7.24 - 7.04 (m, 4H), 6.44 - 6.30 (m, 1H), 5.63 (dt, J = 11.6, 7.2 Hz, 1H), 2.65 (t, 2H), 2.37 (qd, J = 7.1, 2.0Hz, 2H).

[0190] Step C : 4-(3-fluoro-4-methoxyphenyl)butan-1-amine To a solution of the product of Step C (395 mg, 2.02 mmol, 1 equiv.) in methanol (10 mL) under a nitrogen atmosphere was added platinum(IV) oxide (45.9 mg, 0.2 mmol, 0.1 equiv.). The vessel was evacuated, back-filled with nitrogen (×3), evacuated, then placed under an atmosphere of hydrogen and shaken at ambient temperature overnight. The reaction was filtered through Celite, eluted with methanol, and concentrated in vacuo. The residue was dissolved in methanol, applied to a methanol-wet SCX cartridge (5 g), eluted with 1.75 N methanolic ammonia, washed with methanol, and concentrated in vacuo to give the desired product as a pink gum (219 mg, 1.11 mmol, 55%). LC / MS (C 11 H 16 FNO) 198 [M+H] + ; Retention time 1.18 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 7.10 - 7.01 (m, 2H), 6.99 - 6.90 (m, 1H), 3.80 (s, 3H), 2.57 - 2.44 (m, 2H), 1.61 - 1.42 (m, 4H), 1.39 - 1.26 (m, 2H).

[0191] Step D : [4-(3-fluoro-4-methoxyphenyl)butyl]dimethylamine To a solution of the product of Step D (219 mg, 1.11 mmol, 1 equiv.) in methanol (5 mL) was added aqueous formaldehyde (37 wt %; 91.8 μL, 13.4 M, 3.33 mmol, 3 equiv.), sodium triacetoxyborohydride (706 mg, 3.33 mmol, 3 equiv.), and glacial acetic acid (6.36 μL, 0.11 mmol, 0.1 equiv.), and the mixture was stirred at ambient temperature overnight. The reaction was concentrated in vacuo and then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was dried (magnesium sulfate) and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 4g RediSep 1000) was performed, eluting with a gradient of 0-10% methanol in dichloromethane. 商標Purification by silica cartridge) gave the desired product as a clear oil (163 mg, 0.72 mmol, 65%). LC / MS (C 13 H 20 FNO) 226 [M+H] + ; Retention time 1.30 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 7.10 - 7.00 (m, 2H), 6.98 - 6.90 (m, 1H), 3.80 (s, 3H), 2.56 - 2.47 (m, 2H), 2.23 - 2.15 (m, 2H), 2.09 (s, 6H), 1.59 - 1.47 (m, 2H), 1.43 - 1.31 (m, 2H).

[0192] Step E : 4-[4-(dimethylamino)butyl]-2-fluorophenol To a solution of the product of Step E (163 mg, 0.72 mmol, 1 equiv.) in dichloromethane (5 mL) cooled to 0° C. was added boron tribromide (1 M in dichloromethane; 2.17 mL, 2.17 mmol, 3 equiv.) and the mixture was stirred at ambient temperature overnight. The reaction was cooled to 0° C., quenched with methanol, and concentrated in vacuo. The residue was dissolved in methanol, applied to a methanol-wet SCX cartridge (5 g), washed with methanol, eluted with 1.75 N methanolic ammonia, and concentrated in vacuo to give the desired product as a yellow oil (110 mg, 0.52 mmol, 72%). LC / MS (C 12 H 18 FNO) 212 [M+H] + ; Retention time 0.96 (LCMS-VC) 1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 6.94 (dd, J = 12.5, 2.0 Hz, 1H), 6.88 - 6.75 (m, 2H), 2.47 (t, J = 7.6 Hz, 2H), 2.21 - 2.13 (m, 2H), 2.08 (s, 6H), 1.56 - 1.44 (m, 2H), 1.42 - 1.30 (m, 2H).

[0193] Step F : tert-Butyl N-[2-(3-fluoro-4-hydroxyphenyl)ethyl]-N-methylcarbamate Preparation 4j : Ethyl N-[2-(3-fluoro-4-methoxyphenyl)ethyl]carbamate To a solution of 2-(3-fluoro-4-methoxyphenyl)ethan-1-amine (263 mg, 1.55 mmol, 1 equiv.) in dichloromethane (10 mL) was added triethylamine (315 mg, 3.11 mmol, 2 equiv.) and the mixture was cooled to 0 °C before the addition of ethyl chloroformate (149 μL, 1.55 mmol, 1 equiv.). The mixture was stirred overnight at ambient temperature. The reaction was partitioned between dichloromethane and saturated aqueous sodium bicarbonate, and the organic phase was separated (PTFE phase separator) and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 12 g RediSep 1000) eluted with a gradient of 0-1% methanol in dichloromethane. 商標 Purification by silica cartridge) gave the desired product as a white wax (245 mg, 1.02 mmol, 65%). LC / MS (C 12 H 16 FNO3) 242 [M+H] + ; Retention time 1.81 (LCMS-VC) 1H NMR (400 MHz, DMSO-d6) δ 7.13 (t, 1H), 7.11 - 7.01 (m, 2H), 6.98 - 6.92 (m, 1H), 3.96 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 3.16 (td, J = 7.3, 5.8 Hz, 2H), 2.64 (t, J = 7.3 Hz, 2H), 1.13 (t, J = 7.1 Hz, 3H).

[0194] Step A : [2-(3-fluoro-4-methoxyphenyl)ethyl](methyl)amine A solution of the product of Step A (245 mg, 1.02 mmol, 1 equiv) in tetrahydrofuran (3 mL) was cooled to 0°C. Lithium aluminum hydride (1 M in tetrahydrofuran, 2.54 mL, 2.54 mmol, 2.5 equiv) was added and the mixture was heated at reflux overnight. The reaction was cooled to 0°C and water (96 μL) was added, followed by 15% aqueous sodium hydroxide (96 μL), then water (288 μL). Further tetrahydrofuran was added to aid stirring and the mixture was stirred at ambient temperature for 30 minutes. Magnesium sulfate was added, followed by ethyl acetate, and the mixture was stirred for 15 minutes, then filtered through Celite and eluted with ethyl acetate. The solvent was removed in vacuo and purified by automated flash column chromatography (CombiFlash Rf, 4g RediSep) eluting with a gradient of 0-10% methanol in dichloromethane. 商標 Purification by silica cartridge) gave the desired product as a clear oil (89 mg, 0.49 mmol, 48%). LC / MS (C 10 H 14 FNO) 184 [M+H] + ; Retention time 0.75 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 7.15 - 7.01 (m, 2H), 6.96 (ddd, J = 8.3, 2.0, 1.0 Hz, 1H), 3.80 (s, 3H), 2.69 - 2.57 (m, 4H), 2.27 (s, 3H).

[0195] Step B : 2-fluoro-4-[2-(methylamino)ethyl]phenol To a solution of the product of Step B (89 mg, 0.49 mmol, 1 equiv) in dichloromethane (4 mL) cooled to 0 °C was added boron tribromide (1 M in dichloromethane, 1.46 mL, 1.46 mmol, 3 equiv) and the mixture was stirred at ambient temperature for 4 h. The reaction was cooled to 0 °C, quenched with methanol, and then concentrated in vacuo. The residue was dissolved in methanol, applied to a methanol-wet SCX cartridge (5 g), washed with methanol, eluted with 1.75 N methanolic ammonia, and concentrated in vacuo to give the desired product as a brown gum (62 mg, 0.37 mmol, 75%). LC / MS (C9H 12 FNO) 170 [M+H] + ; Retention time 0.24 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 7.02 - 6.93 (m, 1H), 6.88 - 6.76 (m, 2H), 2.67 - 2.53 (m, 4H), 2.27 (s, 3H).

[0196] Step C : tert-Butyl N-[2-(3-fluoro-4-hydroxyphenyl)ethyl]-N-methylcarbamate To a solution of the product of Step C (62 mg, 0.37 mmol, 1 equiv.) in dichloromethane (5 mL) was added triethylamine (153 μL, 1.1 mmol, 3 equiv.) and 4-(dimethylamino)pyridine (4.48 mg, 0.04 mmol, 0.1 equiv.), followed by di-tert-butyl dicarbonate (0.09 mL, 0.44 mmol, 1.2 equiv.), and the mixture was stirred at ambient temperature for 3 h. The reaction was partitioned between dichloromethane and saturated aqueous sodium bicarbonate, and the organic phase was dried (PTFE phase separator) and concentrated in vacuo. The resulting product was purified by automated flash column chromatography (CombiFlash Rf, 4 g RediSep HPLC) eluting with a gradient of 0–85% ethyl acetate in isoheptane.商標 Purification by silica cartridge) gave the desired product as a clear oil (48 mg, 0.18 mmol, 49%). LC / MS (C 14 H 20 FNO3) 170 [M-Boc+H] + ; retention time 2.54 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 6.95 (d, J = 12.3 Hz, 1H), 6.89 - 6.72 (m, 2H), 3.34 - 3.27 (m, 2H), 2.73 (s, 3H), 2.64 (t, J = 7.1 Hz, 2H), 1.28 (s, 9H).

[0197] Step D : tert-Butyl N-[4-(3-fluoro-4-hydroxyphenyl)butyl]-N-methylcarbamate Preparation 4k : Ethyl N-[(3E)-4-(3-fluoro-4-methoxyphenyl)but-3-en-1-yl]carbamate To a solution of the product of Preparation 4i, Step C (397 mg, 2.03 mmol, 1 equiv.) in dichloromethane (20 mL) was added triethylamine (0.57 mL, 4.07 mmol, 2 equiv.) and the mixture was cooled to 0 °C. Ethyl chloroformate (194 μL, 2.03 mmol, 1 equiv.) was added and the mixture was allowed to warm to ambient temperature and stirred overnight. The reaction was partitioned between dichloromethane and saturated aqueous sodium bicarbonate, and the organic phase was separated (PTFE phase separator) and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 12 g RediSep 1000) eluted with a gradient of 0-25% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a clear oil (310 mg, 1.16 mmol, 57%). LC / MS (C 14 H 18 FNO3) 268 [M+H] +; Retention time 2.06 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 7.24 - 7.05 (m, 3H), 6.42 - 6.33 (m, 1H), 5.57 (dt, J = 11.7, 7.2 Hz, 1H), 4.00 (dq, J = 26.6, 7.1 Hz, 2H), 3.84 (s, 3H), 3.08 (q, J = 6.8 Hz, 2H), 2.42 (qd, J = 7.1, 1.9 Hz, 2H), 1.16 (t, 3H).

[0198] Step A : Ethyl N-[4-(3-fluoro-4-methoxyphenyl)butyl]carbamate To a solution of the product of Step A (310 mg, 1.16 mmol, 1 equiv.) in methanol (12 mL) under a nitrogen atmosphere was added platinum(IV) oxide (26.3 mg, 0.12 mmol, 0.1 equiv.). The vessel was evacuated, back-filled with nitrogen (×3), evacuated, placed under an atmosphere of hydrogen, and shaken at ambient temperature overnight. The reaction was filtered through Celite, eluted with methanol, and concentrated in vacuo to give the desired product as a clear oil (275 mg, 1.02 mmol, 88%). LC / MS (C 14 H 20 FNO3) 270 [M+H] + ; Retention time 2.07 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 7.12 - 7.00 (m, 3H), 6.99 - 6.91 (m, 1H), 3.96 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 2.97 (q, J = 6.7 Hz, 2H), 2.52 - 2.45 (m, 2H), 1.51 (p, J = 7.8, 7.4 Hz, 2H), 1.37 (p, J = 7.2 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H).

[0199] Step B: [4-(3-fluoro-4-methoxyphenyl)butyl](methyl)amine To a solution of the product of Step B (417 mg, 1.55 mmol, 1 equiv) in tetrahydrofuran (5 mL) cooled to 0 °C was added lithium aluminum hydride (1 M in tetrahydrofuran; 3.87 mL, 3.87 mmol, 2.5 equiv) and the mixture was heated at reflux overnight. The reaction was cooled to 0 °C and water (150 μL) was added, followed by 15% aqueous sodium hydroxide (150 μL) and water (450 μL). The mixture was diluted with tetrahydrofuran and stirred for 30 minutes. Magnesium sulfate and ethyl acetate were added, and the mixture was filtered through Celite and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 4g RediSep) eluting with a gradient of 0-15% methanol in dichloromethane was performed. 商標 Purification by silica cartridge) gave the desired product as a clear oil (222 mg, 1.05 mmol, 68%). LC / MS (C 12 H 18 FNO) 212 [M+H] + ; retention time 1.28 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 7.09 - 6.99 (m, 2H), 6.94 (dd, 1H), 3.80 (s, 3H), 2.51 - 2.48 (m, 2H), 2.44 (t, 2H), 2.24 (s, 3H), 1.61 - 1.47 (m, 2H), 1.47 - 1.31 (m, 2H).

[0200] Step C : 2-fluoro-4-[4-(methylamino)butyl]phenol To a solution of the product of Step C (222 mg, 1.05 mmol, 1 equiv) in dichloromethane (10 mL) cooled at 0 °C, boron tribromide (1 M in dichloromethane, 3.15 mL, 3.15 mmol, 3 equiv) was added and the mixture was stirred at ambient temperature for 3 h. The reaction was cooled to 0 °C, quenched with methanol, and concentrated in vacuo. The residue was dissolved in methanol, applied to a methanol-wet SCX cartridge (5 g), washed with methanol, eluted with 1.4 N methanolic ammonia, and concentrated in vacuo to give the desired product as a brown gum (63 mg, 0.32 mmol, 30%). LC / MS (C 11 H 16 FNO) 198 [M+H] + ; Retention time 1.01 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 7.00 - 6.91 (m, 1H), 6.88 - 6.75 (m, 2H), 2.49 - 2.40 (m, 4H), 2.24 (s, 3H), 1.58 - 1.45 (m, 2H), 1.43 - 1.33 (m, 2H).

[0201] Step D : tert-Butyl N-[4-(3-fluoro-4-hydroxyphenyl)butyl]-N-methylcarbamate To a solution of the product of Step D (63 mg, 0.32 mmol, 1 equiv.) in dichloromethane (5 mL) was added triethylamine (133 μL, 0.96 mmol, 3 equiv.) and 4-(dimethylamino)pyridine (3.9 mg, 0.03 mmol, 0.1 equiv.), the mixture was cooled to 0 °C, di-tert-butyl dicarbonate (66 μL, 0.29 mmol, 0.9 equiv.) was added, and the mixture was stirred at ambient temperature for 1 h. The reaction was partitioned between dichloromethane and saturated aqueous sodium bicarbonate, and the organic phase was separated (PTFE phase separator) and concentrated in vacuo. The resulting product was purified by automated flash column chromatography (CombiFlash Rf, 4g RediSep) eluting with a gradient of 0-35% ethyl acetate in isoheptane. 商標Purification by silica cartridge) gave the desired product (33 mg, 0.11 mmol, 35%). LC / MS (C 16 H 24 FNO3) 198 [M-Boc+H] + ; Retention time 2.18 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 6.95 (dd, J = 12.4, 2.0 Hz, 1H), 6.88 - 6.74 (m, 2H), 3.21 - 3.11 (m, 2H), 2.74 (s, 3H), 2.49 - 2.41 (m, 2H), 1.53 - 1.40 (m, 4H), 1.37 (s, 9H).

[0202] Step E : 1-(1-adamantylmethyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Preparation 5a : 1-(1-adamantylmethyl)-4-iodo-pyrazole A mixture of 35.9 g of 1-adamantylmethanol (216 mmol), 73.48 g of triphenylphosphine (280 mmol, 1.3 equiv.), 54.25 g of 4-iodo-1H-pyrazole (280 mmol, 1.3 equiv.) and 64.4 g of tert-butyl N-(tert-butoxycarbonyliminomethylene)carbamate (266 mmol, 1.3 equiv.) in 1078 mL of THF was stirred at room temperature for 48 hours. After addition of an additional 10.94 g of 4-iodo-1H-pyrazole (56 mmol, 0.26 equiv), 12.81 g of tert-butyl N-(tert-butoxycarbonyliminomethylene)carbamate (53 mmol, 0.26 equiv), and 14.69 g of triphenylphosphine (56 mmol, 0.26 equiv), the reaction was stirred at room temperature for 24 h, then concentrated and purified via flash column chromatography using DCM as eluent, triturated in cold MeOH, and filtered off to give 53.6 g (73%) of the desired product as a white powder.

[0203] Step A : 1-(1-adamantylmethyl)-4-iodo-5-methyl-pyrazole To 9.8 mL of diisopropylamine (69.5 mmol, 1.1 equiv) in 180 mL of THF at −78° C. was added 33.4 mL of a 2.5 M solution of butyllithium (84 mmol, 1.3 equiv) dropwise, and the mixture was stirred at −78° C. for 0.5 h, treated with 22.0 g of the product of Step A (64.28 mmol, 1 equiv) in 90 mL of THF, stirred at −78° C. for 1 h, and treated with 4.67 mL of methyl iodide (73.3 mmol, 1.14 equiv) and stirred at −78° C. for 18 h. After quenching with concentrated NH4Cl, the reaction was extracted with EtOAc, and the combined organic phases were washed with brine, dried, concentrated, triturated in MeOH, and filtered to give 21 g (92%) of the desired product.

[0204] [[ID= : 1-(1-adamantylmethyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole To 21 g of the product of Step B (58.95 mmol, 1 equiv) in 300 mL of THF at −78° C. was added 28.3 mL of a 2.5 M solution of butyllithium (70.8 mmol, 1.2 equiv), and the mixture was stirred at −78° C. for 0.5 h, treated with 16.4 g of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (88.1 mmol, 1.5 equiv) (dropwise over 40 min) and maintained at −78° C. for 24 h. After quenching with concentrated NH4Cl at room temperature, the reaction was extracted with EtOAc, and the combined organic phases were washed with brine, dried, concentrated, triturated in MeOH, and filtered to give 19.7 g (94%) of the desired product as off-white crystals. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.45 (s, 1H), 3.69 (s, 2H), 2.36 (s, 3H), 1.91 (m, 1H), 1.64 / 1.54 (m, 6H), 1.50 (m, 6H), 1.24 (s, 12H); 13 C NMR (500 MHz, , DMSO-d6) δ ppm 146.9, 144.1, 104.6, 59.7, 40.6, 36.8, 35.4, 28.1, 25.1, 12.1; HRMS-ESI (m / z): [M+H]+ C 21 H 34 Calculated BN2O2: 357.2713, Found 357.2704.

[0205] ​ : 1-{[1-(3-methoxypropyl)cyclooctyl]methyl}-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole ​ : Methyl 1-(3-methoxypropyl)cyclooctanecarboxylate To 4.74 g (1.14 equiv.) of diisopropylamine in 90 mL of tetrahydrofuran was added 18.8 mL (1.14 equiv.) of a 2.5 M solution of butyllithium at −78° C. After 0.5 h at −78° C., 7.0 g (41.1 mmol) of methyl cyclooctanecarboxylate in 40 mL of tetrahydrofuran was added over 1 h. After 1 h at −78° C., 7.2 g (1.14 equiv.) of 1-bromo-3-methoxypropane was added, and the mixture was stirred for 18 h. After quenching the reaction with saturated NH4Cl solution, the mixture was extracted with EtOAc, and the organic phase was dried over MgSO4 and concentrated to give 8.0 g (80%) of the desired product. 1 H NMR (400 MHz, CDCl3) δ ppm 3.66 (s, 3H), 3.33 (t, 2H), 3.31 (s, 3H), 2.03-1.94 (m, 2H), 1.64-1.38 (m, 16H).

[0206] ​ : [1-(3-methoxypropyl)cyclooctyl]methanol To 9.0 g (37.13 mmol) of the product from Step A in 93 mL of diethyl ether was added dropwise 1.76 g (1.25 equiv.) of lithium aluminum hydride at 0° C. After stirring at room temperature for 2 h, the reaction was quenched by the addition of ice-cold water, followed by EtOAc and a 10% solution of NaOH. The mixture was extracted with EtOAc, dried, and concentrated to give 7.4 g (93%) of the desired product. 1 H NMR (400 MHz, CDCl3) δ ppm 3.37 (t, 2H), 3.34 (s, 3H), 3.30 (s, 2H), 1.61-1.23 (m, 18H).

[0207] ​ : 4-Iodo-1-[[1-(3-methoxypropyl)cyclooctyl]methyl]-1H-pyrazole To 1.39 g (6.5 mmol) of the product from Step B and 1.64 g (1.3 equivalents) of 4-iodo-1H-pyrazole in 33 mL of tetrahydrofuran were added 2.22 g (1.3 equivalents) of triphenylphosphine and 1.95 g (1.3 equivalents) of di-tert-butyl azodicarboxylate, and the mixture was stirred at room temperature for 67 hours. To the mixture, 278 mg of 4-iodo-1H-pyrazole, 444 mg of triphenylphosphine, and 390 mg of di-tert-butyl azodicarboxylate were added and the mixture was stirred at room temperature for 24 hours. After the addition of the reagents, stirring was repeated for 24 hours at room temperature (total stirring time: 115 hours), and the mixture was concentrated and purified via flash column chromatography (silica gel) using heptane and EtOAc as eluents to give 1.24 g (49%) of the desired product. 1 H NMR (400 MHz, CDCl3) δ ppm 7.47 (s, 1H), 7.42 (s, 1H), 3.93 (s, 2H), 3.37 (t, 2H), 3.36 (s, 3H), 1.68-1.18 (m, 18H).

[0208] ​ : 4-iodo-1-[[1-(3-methoxypropyl)cyclooctyl]methyl]-5-methyl-1H-pyrazole To 1.2 g (3.07 mmol) of the product from step C in 5 mL of tetrahydrofuran was added 3.7 mL (1.2 equiv.) of a 1 M solution of LDA at −78° C. After 0.6 h at −78° C., 0.5 mL (1.14 equiv.) of methyl iodide was added dropwise to the mixture, which was allowed to warm to room temperature over 20 h. The reaction was quenched with a saturated solution of NH4Cl and extracted with EtOAc. The combined organic phases were dried, concentrated, and purified via flash column chromatography (silica gel) using heptane and EtOAc as eluents to give 0.79 g (64%) of the desired product. 1 H NMR (400 MHz, CDCl3) δ ppm 7.43 (s, 1H), 3.85 (s, 2H), 3.38 (t, 2H), 3.35 (s, 3H), 2.29 (s, 3H), 1.69-1.24 (m, 18H).

[0209] ​ : 1-[[1-(3-methoxypropyl)cyclooctyl]methyl]-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole To a solution of 0.81 g (2 mmol) of the product from step D in 15 mL of tetrahydrofuran was added dropwise 0.96 mL (1.2 equiv.) of a 2.5 M solution of butyllithium at −78° C. After 0.5 h, 0.5 mL (1.2 equiv.) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added over 20 min, and the mixture was kept at −78° C. for 6 h and at room temperature for 6 h. The reaction was quenched with a saturated solution of NHCl and extracted with EtOAc. The combined organic phases were then washed with brine, dried, and purified via flash column chromatography (silica gel) using heptane and EtOAc as eluents to give 0.33 g (34%) of the desired product. 1H NMR (500 MHz, dmso-d6) δ ppm 7.46 (s, 1H), 3.75 (s, 2H), 3.27 (t, 2H), 3.21 (s, 3H), 2.36 (s, 3H), 1.66-1.1 (m, 14H), 1.57 (m, 2H), 1.24 (s, 12H), 1.24 (m, 2H). 13 C NMR (500 MHz, DMSO-D6) δ ppm 147.3, 144.5, 104.5, 73.2, 58.2, 54.4, 40.5, 33.2, 25.1, 23.6, 11.8. IR: 2922, 1556, 1246, 1144, 1055. HRMS-ESI (m / z): [M+H]+ C 23 H 42 Calculated N2O3B: 405.3289, Measured 405.3329.

[0210] ​ : 1-{[1-(3-methoxypropyl)cyclohexyl]methyl}-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole ​ : Methyl 1-(3-methoxypropyl)cyclohexanecarboxylate To 6.84 g (1.09 equiv.) of diisopropylamine in 130 mL of tetrahydrofuran was added 27 mL (1.09 equiv.) of a 2.5 M solution of butyllithium at −78° C. After 0.5 h at −78° C., 8.8 g of methyl cyclohexanecarboxylate in 50 mL of tetrahydrofuran was added over 1 h. After 1 h at −78° C., 10.7 g (1.13 equiv.) of 1-bromo-3-methoxypropane was added, and the mixture was stirred for 18 h. After quenching the reaction with saturated NH4Cl solution, the mixture was extracted with EtOAc, and the organic phase was dried over MgSO4 and concentrated to give 12 g (92%) of the desired product. 1H NMR (400 MHz, CDCl3) δ ppm 3.67 (s, 3H), 3.35 (d, 1H), 3.32 (d, 1H), 3.31 (s, 3H), 2.11-2.03 (m, 2H), 1.60-1.16 (m, 12H).

[0211] ​ : [1-(3-methoxypropyl)cyclohexyl]methanol To 12 g (56.41 mmol) of the product from Step A in 140 mL of diethyl ether at 0° C. was added 2.68 g (1.25 equiv.) of lithium aluminum hydride dropwise. After stirring at room temperature for 2 h, the reaction was quenched by the addition of ice-cold water, followed by EtOAc and 10% NaOH solution. The mixture was extracted with EtOAc, dried, and concentrated to give 9.37 g (89%) of the desired product. 1 H NMR (400 MHz, CDCl3) δ ppm 3.41 (s, 2H), 3.38 (t, 2H), 3.35 (s, 3H), 1.56-1.27 (m, 14H).

[0212] ​ : 4-Iodo-1-[[1-(3-methoxypropyl)cyclohexyl]methyl]pyrazole To 1.21 g (6.5 mmol) of the product from Step B and 2.58 g (2.05 equivalents) of 4-iodo-1H-pyrazole in 33 mL of tetrahydrofuran, 3.5 g (2.05 equivalents) of triphenylphosphine and 3.07 g (2.05 equivalents) of di-tert-butyl azodicarboxylate were added, and the mixture was stirred at room temperature for 2 hours. 140 mg of 4-iodo-1H-pyrazole, 230 mg of triphenylphosphine, and 200 mg of di-tert-butyl azodicarboxylate were added, and the mixture was stirred at room temperature for 24 hours. After the addition of the reagents, the 24-hour stirring at room temperature was repeated twice (total stirring time: 96 hours), and the mixture was concentrated and purified via flash column chromatography (silica gel) using heptane and EtOAc as eluents to give 1.4 g (59.5%) of the desired product. 1H NMR (400 MHz, CDCl3) δ ppm 7.47 (s, 1H), 7.41 (s, 1H), 4.00 (s, 2H), 3.36 (t, 2H), 3.35 (s, 3H), 1.62-1.21 (m, 14H).

[0213] ​ : 4-Iodo-1-[[1-(3-methoxypropyl)cyclohexyl]methyl]-5-methyl-pyrazole To 3.7 g (10.21 mmol) of the product from Step C in 15 mL of tetrahydrofuran was added 12.3 mL (1.2 equiv.) of a 1 M solution of LDA in tetrahydrofuran at −78° C. After 0.6 h at −78° C., 0.73 mL (1.14 equiv.) of methyl iodide was added dropwise to the mixture, which was allowed to warm to room temperature over 20 h. The reaction was quenched with a saturated solution of NH4Cl and extracted with EtOAc. The combined organic phases were dried, concentrated, and purified via flash column chromatography (silica gel) using heptane and EtOAc as eluents to give 2.85 g (74%) of the desired product. 1 H NMR (400 MHz, CDCl3) δ ppm 7.44 (s, 1H), 3.92 (s, 2H), 3.38 (t, 2H), 3.35 (s, 3H), 2.29 (s, 3H), 1.58-1.13 (m, 14H).

[0214] ​ : 1-[[1-(3-methoxypropyl)cyclohexyl]methyl]-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole To a solution of 5.0 g (13.3 mmol) of the product from step D in 71 mL of tetrahydrofuran was added dropwise 6.38 mL (1.2 equiv.) of a 2.5 M solution of butyllithium at −78° C. After 0.5 h, 4.1 mL (1.5 equiv.) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added over 40 min, and the mixture was maintained at −78° C. for 6 h and at room temperature for 6 h. The reaction was quenched with a saturated solution of NHCl and extracted with EtOAc. The combined organic phases were then washed with brine, dried, and purified via flash column chromatography (silica gel) using heptane and EtOAc as eluents to give 2.3 g (46%) of the desired product. 1 H NMR (500 MHz, dmso-d6) δ ppm 7.47 (s, 1H), 3.84 (s, 2H), 3.27 (t, 2H), 3.2 (s, 3H), 2.37 (s, 3H), 1.54-1.07 (m, 10H), 1.46 (m, 2H), 1.32 (m, 2H), 1.24 (s, 12H). 13 C NMR (500 MHz, DMSO-D6) δ ppm 147.3, 144.4, 104.6, 73.1, 58.2, 55.7, 37.9, 30.6, 25.1, 23.1, 12.0. IR: 2927, 1556, 1257, 1144, 1053. HRMS-ESI (m / z): [M+H]+ C 21 H 38 Calculated N2O3B: 376.2897, Measured 376.3019.

[0215] ​ : Ethyl 5-bromo-2-(4-methyl-3-{[(2Z)-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1,3-benzothiazol-2-ylidene]amino}-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl)-1,3-thiazole-4-carboxylate ​ : Ethyl 2-[(pent-3-yn-1-yl)amino]-1,3-thiazole-4-carboxylate To a solution of ethyl 2-bromo-1,3-thiazole-4-carboxylate (538 mg, 2.28 mmol, 1 equiv.) in acetonitrile (10 mL) was added pent-3-yn-1-amine hydrochloride (300 mg, 2.51 mmol, 1.1 equiv.) and triethylamine (0.7 mL, 5.02 mmol, 2.2 equiv.), and the mixture was heated at 150 °C under microwave irradiation for 3 h. The reaction was partitioned between ethyl acetate and brine, and the organic phase was dried (magnesium sulfate) and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 24 g RediSep 2000) eluted with a gradient of 0-40% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a beige solid (221 mg, 0.93 mmol, 41%). LC / MS (C 11 H 14 N2O2S) 239 [M+H] + ; Retention time 2.22 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (t, J = 5.7 Hz, 1H), 7.52 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.38 - 3.28 (m, 2H), 2.44 - 2.33 (m, 2H), 1.75 (t, J = 2.5 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0216] ​ : Ethyl 2-{3-chloro-4-methyl-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,3-thiazole-4-carboxylate To a solution of 3,6-dichloro-1,2,4,5-tetrazine (140 mg, 0.93 mmol, 1 equiv.) in tetrahydrofuran was added the product of Step A (221 mg, 0.93 mmol, 1 equiv.) and the mixture was heated at reflux overnight. The reaction was concentrated in vacuo, and the residue was triturated with dichloromethane, filtered, and dried under vacuum to give the desired product as an off-white solid (148 mg, 0.46 mmol, 49%). LC / MS (C 13 H 13 ClN4O2S) 325 [M+H] + ; Retention time 2.32 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 4.41 (dd, J = 8.8, 7.7 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 3.34 - 3.24 (m, 2H), 2.29 (d, J = 1.1 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H).

[0217] ​ : Ethyl 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,3-thiazole-4-carboxylate To an oven-dried microwave vial was added the product of Step B (148 mg, 0.46 mmol, 1 equiv), 2-aminobenzothiazole (103 mg, 0.68 mmol, 1.5 equiv), XantPhos (52.7 mg, 0.09 mmol, 0.2 equiv), cesium carbonate (297 mg, 0.91 mmol, 2 equiv), and 1,4-dioxane (20 mL), the vessel was evacuated and flushed with nitrogen, then tris(dibenzylideneacetone)dipalladium(0) (41.7 mg, 0.05 mmol, 0.1 equiv) was added and the mixture was sparged with nitrogen (10 min) and then heated under microwave irradiation at 150° C. for 2 h. The reaction was diluted with ethyl acetate, filtered through Celite, washed with brine, dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 24g RediSep) eluted with a gradient of 0-10% methanol in dichloromethane. 商標 Purification by silica cartridge) gave the desired product as a yellow solid (103 mg, 0.23 mmol, 52%). LC / MS (C 20 H 18 N6O2S2) 439 [M+H] + ; retention time 2.67 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (br s, 1H), 8.06 (s, 1H), 7.95 (br s, 1H), 7.66 (br s, 1H), 7.44 - 7.33 (m, 1H), 7.28 - 7.15 (m, 1H), 4.42 - 4.34 (m, 2H), 4.30 (q, 2H), 3.32 - 3.28 (m, 2H), 2.34 (s, 3H), 1.32 (t, J = 7.1, 2.4 Hz, 3H).

[0218] ​: Ethyl 2-(4-methyl-3-{[(2Z)-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1,3-benzothiazol-2-ylidene]amino}-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl)-1,3-thiazole-4-carboxylate To a cooled solution of the product of Step C (103 mg, 0.23 mmol, 1 equiv.) in tetrahydrofuran (15 mL) and dimethylformamide (5 mL) was added N,N-diisopropylethylamine (81.8 μL, 0.47 mmol, 2 equiv.). After 5 min, 4-dimethylaminopyridine (5.74 mg, 0.05 mmol, 0.2 equiv.) and [2-(chloromethoxy)ethyl]trimethylsilane (103 μL, 0.59 mmol, 2.5 equiv.) were added, and the mixture was stirred at ambient temperature overnight. The reaction was partitioned between ethyl acetate and water, and the organic phase was dried (magnesium sulfate) and concentrated in vacuo. The reaction was analyzed by automated flash column chromatography (CombiFlash Rf, 24 g RediSep 1000) eluting with a gradient of 0-70% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as an off-white solid (98 mg, 0.17 mmol, 73%). LC / MS (C 26 H 32 N6O3SiS2) non-ionized; retention time 3.08 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.60 - 7.51 (m, 2H), 7.39 - 7.30 (m, 1H), 5.96 (s, 2H), 4.48 (t, J = 8.1 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 3.87 - 3.78 (m, 2H), 3.48 - 3.36 (m, 2H), 2.44 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H), 1.07 - 0.98 (m, 2H), 0.00 (s, 9H).

[0219] ​ : Ethyl 5-bromo-2-(4-methyl-3-{[(2Z)-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1,3-benzothiazol-2-ylidene]amino}-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl)-1,3-thiazole-4-carboxylate To a solution of the product of Step D (98 mg, 0.17 mmol, 1 equiv.) in dichloromethane (15 mL) was added N-bromosuccinimide (39.9 mg, 0.22 mmol, 1.3 equiv.), and the mixture was stirred at ambient temperature for 3 h. Automated flash column chromatography (CombiFlash Rf, 12 g RediSep 1000) eluted with a gradient of 0 to 50% ethyl acetate in isoheptane was performed. 商標 Purification by silica cartridge) gave the desired product as an off-white solid (98 mg, 0.15 mmol, 88%). LC / MS (C 26 H 31 BrN6O3SiS2) non-ionized; retention time 3.22 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (dd, J = 7.6, 1.1 Hz, 1H), 7.50 - 7.39 (m, 2H), 7.28 - 7.21 (m, 1H), 5.85 (s, 2H), 4.40 - 4.24 (m, 4H), 3.68 - 3.58 (m, 2H), 3.27 (t, J = 8.0 Hz, 2H), 2.32 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H), 1.02 (dd, J = 8.5, 7.4 Hz, 2H), -0.12 (s, 9H).

[0220] ​ : tert-Butyl-diphenyl-[2-[[3,5-dimethyl-7-[[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methyl]-1-adamantyl]oxy]ethoxy]silane ​: 3-Bromo-5,7-dimethyladamantane-1-carboxylic acid After stirring iron (6.7 g, 120 mmol) in bromine (30.7 mL, 600 mmol, 5 equiv.) at 0° C. for 1 h, 3,5-dimethyladamantane-1-carboxylic acid (25 g, 1 equiv.) was added and the reaction mixture was stirred at room temperature for 2 days. After the addition of EtOAc, the reaction mixture was carefully treated with a saturated solution of sodium thiosulfate at 0° C. and stirred for 15 min. After filtration through a pad of Celite and rinsing with EtOAc, the organic phase was separated, washed with a saturated solution of sodium thiosulfate and brine, dried, and concentrated to give the desired product (34.28 g, 74.6%), which was used without further purification. 1 H NMR (400 MHz, DMSO-d6): δ ppm 12.33 (br., 1H), 2.21 (s, 2H), 1.96 / 1.91 (d+d, 4H), 1.50 / 1.43 (d+d, 4H), 1.21 / 1.14 (dm+dm, 2H), 0.86 (s, 6H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 176.8, 66.8, 54.0, 48.7, 48.5, 45.7, 43.3, 35.5, 29.4; HRMS-ESI (m / z): [MH]- C 13 H 18 Calculated BrO2: 285.0496; Measured 285.0498.

[0221] ​ 3-Bromo-5,7-dimethyl-1-adamantyl-methanol To the product of Step A (34.3 g, 119 mmol) in THF (77.6 mL) was slowly added a 1 M solution of BH3-THF in THF (358 mL, 3 equiv.), and the reaction mixture was stirred for 18 h. After addition of methanol and stirring for 30 min, purification by column chromatography (silica gel, heptane and MTBE as eluents) gave the desired product (16.19 g, 49.6%). 1H NMR (400 MHz, DMSO-d6): δ ppm 4.51 (t, 1H), 3.05 (d, 2H), 1.91 (s, 2H), 1.91 (s, 4H), 1.19 / 1.09 (d+d, 2H), 1.19 / 1.05 (d+d, 4H), 0.85 (s, 6H) 13 C NMR (100 MHz, DMSO-d6) δ ppm 70.4, 68.9, 54.9, 49.8, 49.3, 43.8, 41.4, 35.7, 29.7; HRMS-ESI (m / z): [M-Br]- C 13 H 21 Calculated O: 193.1598 Measured: 193.1589.

[0222] ​ : 1-[3-bromo-5,7-dimethyl-1-adamantyl]methyl]pyrazole To the product of Step B (16.19 g, 59.26 mmol) and 1H-pyrazole (4.841 g, 1.2 equiv.) in toluene (178 mL) was added cyanomethylenetributylphosphorane (18.64 mL, 1.2 equiv.) in one portion, and the reaction mixture was stirred for 2 h at 90° C. Purification by column chromatography (silica gel, heptane and MTBE as eluents) gave the desired product (17.88 g, 93%). 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.63 (d, 1H), 7.43 (d, 1H), 6.23 (t, 1H), 3.90 (s, 2H), 1.92-1.02 (m, 12H), 0.83 (s, 6H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 139.0, 131.8, 105.2, 67.7, 61.4, 54.4 / 48.8 / 44.6, 50.4, 35.7, 29.6; HRMS-ESI (m / z): [M]+ C 16 H 23 Calculated value for BrN2: 322.1045 Found value: 322.1014.

[0223] ​ 5-Methyl-1-[[-3-bromo-5,7-dimethyl-1-adamantyl]methyl]pyrazole To a solution of the product of Step C (17.88 g, 55.3 mmol) in THF (277 mL) was added butyllithium (2.5 M in THF, 66 mL, 3 equiv.) at −78° C., followed after 1 h by the addition of iodomethane (17.2 mL, 5 equiv.). After 10 min, the reaction mixture was quenched with a saturated solution of NH4Cl, extracted with EtOAc, and the combined organic layers were dried and concentrated to give the desired product (18.7 g, 100%), which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.31 (d, 1H), 6.00 (d, 1H), 3.79 (s, 2H), 2.23 (s, 3H), 2.01 (s, 2H), 1.89 / 1.85 (d+d, 4H), 1.23 / 1.15 (d+d, 4H), 1.16 / 1.05 (d+d, 2H), 0.83 (s, 6H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 139.2, 138.0, 105.2, 67.8, 57.8, 54.4, 50.6, 48.8, 44.8, 41.5, 35.7, 29.6, 11.8; HRMS-ESI (m / z): [M+H]+C 17 H 26 Calculated value for BrN2: 337.1279 Found value: 337.1289.

[0224] ​ 2-[[-3,5-dimethyl-7-[(5-methylpyrazol-1-yl)methyl]-1-adamantyl]oxy]ethanol A mixture of the product of Step D (18.7 g, 55.3 mmol), ethylene glycol (123 mL, 40 equiv.) and DIPEA (48.2 mL, 5 equiv.) was stirred for 6 h at 120° C. After the reaction mixture was diluted with water and extracted with EtOAc, the combined organic layers were dried and concentrated to give the desired product (18.5 g, 105%), which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.29 (d, 1H), 5.99 (d, 1H), 4.45 (t, 1H), 3.78 (s, 2H), 3.39 (q, 2H), 3.32 (t, 2H), 2.23 (s, 3H), 1.34 (s, 2H), 1.27 / 1.21 (d+d, 4H), 1.13 / 1.07 (d+d, 4H), 1.04 / 0.97 (d+d, 2H), 0.84 (s, 6H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 139.0, 137.8, 105.1, 74.0, 62.1, 61.5, 58.5, 50.1, 47.0, 46.1, 43.3, 39.7, 33.5, 30.2, 11.9; HRMS-ESI (m / z): [M+H]+ C 19 H 31 Calculated N2O2: 319.2386 Measured: 319.2387.

[0225] ​ : tert-Butyl-diphenyl-[2-[[-3,5-dimethyl-7-[(5-methylpyrazol-1-yl)methyl]-1-adamantyl]oxy]ethoxy]silane To a mixture of the product of Step E (17.6 g, 55.3 mmol) and imidazole (5.65 g, 1.5 equiv.) in DCM (150 mL) was added tert-butyl-chloro-diphenyl-silane (18.6 g, 1.2 equiv.), and the reaction mixture was stirred for 1 h. Purification by column chromatography (silica gel, heptane and MTBE as eluents) gave the desired product (27.0 g, 87.8%). 1H NMR (400 MHz, DMSO-d6): δ ppm 7.72-7.34 (m, 10H), 7.29 (d, 1H), 5.99 (br., 1H), 3.78 (s, 2H), 3.67 (t, 2H), 3.44 (t, 2H), 2.21 (s, 3H), 1.33 (s, 2H), 1.26 / 1.18 (d+d, 4H), 1.12 / 1.06 (d+d, 4H), 1.03 / 0.96 (d+d, 2H), 0.98 (s, 9H), 0.82 (s, 6H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 139.0, 137.8, 105.1, 74.2, 64.4, 61.7, 58.5, 50.0, 46.9, 46.0, 43.4, 39.6, 33.5, 30.1, 27.1, 19.3, 11.9; HRMS-ESI (m / z): [M+H]+ C 35 H 49 Calculated value of N2O2Si : 557.3563 Actual value: 557.3564.

[0226] ​ tert-Butyl-diphenyl-[2-[[3-[(4-iodo-5-methyl-pyrazol-1-yl)methyl]-5,7-dimethyl-1-adamantyl]oxy]ethoxy]silane To a solution of the product of step F (27.0 g, 48.56 mmol) in DMF (243 mL) was added N-iodosuccinimide (13.6 g, 1.25 equiv.) and the reaction mixture was stirred for 2 h. After dilution with water, the mixture was extracted with DCM. The combined organic layers were washed with saturated sodium thiosulfate solution and brine, dried, and concentrated to give the desired product (30.1 g, 90%). 1H NMR (400 MHz, DMSO-d6): δ ppm 7.68-7.37 (m, 10H), 7.45 (s, 1H), 3.89 (s, 2H), 3.67 (t, 2H), 3.44 (t, 2H), 2.23 (s, 3H), 1.30 (s, 2H), 1.26 / 1.17 (d+d, 4H), 1.12 / 1.05 (d+d, 4H), 1.00 / 0.96 (d+d, 2H), 0.98 (s, 9H), 0.82 (s, 6H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 142.5, 140.8, 133.7, 64.4, 61.7, 60.3, 59.9, 49.9, 46.8, 45.9, 43.2, 39.7, 33.5, 30.1, 27.1, 19.3, 12.2; HRMS-ESI (m / z): [M+H]+ C 35 H 48 Calculated value of IN2O2Si: 683.2530 Found value: 683.2533.

[0227] ​ tert-Butyl-diphenyl-[2-[[3,5-dimethyl-7-[[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methyl]-1-adamantyl]oxy]ethoxy]silane To the product of step G (17.5 g, 25.6 mmol) in THF (128 mL) was added chloro(isopropyl)magnesium-LiCl (1.3 M in THF, 24 mL, 1.2 equiv.) at 0° C. and stirred for 40 min. The mixture was treated with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (15.7 mL, 3 equiv.) and stirred for 10 min. After dilution with saturated NH4Cl solution and extraction with EtOAc, the combined organic phases were concentrated and purified by column chromatography (silica gel, heptane and MTBE as eluents) to give the desired product (15.2 g, 86.9%). 1H NMR (400 MHz, DMSO-d6): δ ppm 7.65 (dm, 4H), 7.47 (s, 1H), 7.45 (tm, 2H), 7.40 (tm, 4H), 3.80 (s, 2H), 3.66 (t, 2 H), 3.44 (t, 2H), 2.35 (s, 3H), 1.35-0.94 (m, 12H), 1.24 (s, 12H), 0.97 (s, 9H), 0.83 (s, 6H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 146.9, 144.3, 135.6, 130.2, 128.2, 104.7, 83.0, 74.2, 64.4, 61.7, 58.4, 30.1, 27.1, 25.2, 19.3, 12.0; HRMS-ESI (m / z): [M+H]+ C 41 H 60 Calculated value for BN2O4Si: 683.4415 Found value: 683.4423.

[0228] ​ tert-Butyl-[3-[3,5-dimethyl-7-[[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methyl]-1-adamantyl]propoxy]-diphenyl-silane ​ : 1-[[3-allyl-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazole To the product of Step D of Preparation 7 (15.66 g, 46.43 mmol) and AgOTf (597 mg, 0.05 equiv.) in THF (232 mL) was added a 2 M solution of allyl-Mg—Cl in THF (46.4 mL, 2 equiv.), and the reaction mixture was stirred for 0.5 h. After quenching with a saturated solution of NH Cl and extraction with EtOAc, the combined organic phases were concentrated and purified by column chromatography (silica gel, heptane and MTBE as eluents) to give the desired product (11.32 g, 81.7%). 1H NMR (400 MHz, DMSO-d6): δ ppm 7.27 (d, 1H), 5.98 (m, 1H), 5.76 (m, 1H), 5.01 / 4.96 (dm+dm, 2H), 3.73 (s, 2H), 2.22 (s, 3H), 1.83 (d, 2H), 1.15-0.93 (m, 12H), 0.78 (s, 6H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 139.0, 137.7, 135.0, 117.7, 105.0, 59.0, 47.8, 44.2, 35.0, 31.8, 30.6, 11.9; HRMS-ESI (m / z): [M+H]+ C 20 H 31 Calculated N2: 299.2487 Measured: 299.2485.

[0229] ​ 3-[3,5-dimethyl-7-[(5-methylpyrazol-1-yl)methyl]-1-adamantyl]propan-1-ol To the product of Step A (10.2 g, 34.17 mmol) in THF (85 mL) was added a 1 M solution of BH3-THF in THF (85.4 mL, 2 equiv.), and the reaction mixture was stirred for 1 h. After treatment with a 10 M solution of NaOH (24 mL, 7 equiv.) and a 33% solution of hydrogen peroxide (73 mL, 25 equiv.) at 0 °C, the reaction mixture was stirred at room temperature for 1 h. It was then quenched with aqueous HCl, extracted with EtOAc, and purified by column chromatography (silica gel, heptane and MTBE as eluents) to give the desired product (9.75 g, 90%). 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.28 (d, 1H), 5.98 (m, 1H), 4.33 (t, 1H), 3.73 (s, 2H), 3.32 (m, 2H), 2.22 (brs, 3H), 1.32 (m, 2H), 1.12-0.92 (m, 12H), 1.06 (m, 2H), 0.78 (s, 6H); 13C NMR (100 MHz, DMSO-d6) δ ppm 137.7, 105.0, 62.1, 59.1, 39.7, 30.7, 26.5, 11.9, HRMS-ESI (m / z): [M+H]+ C 20 H 33 Calculated N2O value: 317.2593 Measured value: 317.2590

[0230] ​ tert-Butyl-[3-[3,5-dimethyl-7-[(5-methylpyrazol-1-yl)methyl]-1-adamantyl]propoxy]-diphenyl-silane To the product of step B (9.75 g, 30.8 mmol) and imidazole (3.1 g, 1.5 equiv.) in DCM (92 mL) was added tert-butyl-chloro-diphenyl-silane (9.45 mL, 1.2 equiv.), and the reaction mixture was stirred for 1 h. Purification by column chromatography (silica gel, heptane and MTBE as eluents) gave the desired product (12.5 g, 73%). 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.63-7.39 (m, 10H), 7.27 (d, 1H), 5.98 (d, 1H), 3.72 (s, 2H), 3.59 (t, 2H), 2.21 (s, 3H), 1.42 (m, 2H), 1.1-0.92 (br., 12H), 1.09 (m, 2H), 0.98 (s, 9H), 0.77 (s, 6H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 137.7, 105.0, 64.8, 59.1, 39.3, 38.0, 34.2, 31.8, 30.6, 27.2, 26.1, 19.2, 11.9; HRMS-ESI (m / z): [M+H]+C 36 H 51 Calculated N2OSi value: 555.3771 Measured value: 555.3770.

[0231] ​: tert-Butyl-[3-[3-[(4-iodo-5-methyl-pyrazol-1-yl)methyl]-5,7-dimethyl-1-adamantyl]propoxy]-diphenyl-silane To the product of Step C (12.5 g, 22.54 mmol) in DMF (112 mL) was added N-iodosuccinimide (6.34 g, 1.25 equiv.) and the reaction mixture was stirred for 2 h. After quenching with a saturated solution of sodium thiosulfate and extraction with DCM, the combined organic phases were washed with saturated sodium thiosulfate and brine, dried, and evaporated to give the desired product (16.3 g, 105%). LC / MS (C 36 H 50 IN2OSi) 681 [M+H] + .

[0232] ​ tert-Butyl-[3-[3,5-dimethyl-7-[[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methyl]-1-adamantyl]propoxy]-diphenyl-silane To the product of step D (16.25 g, 23.9 mmol) in THF (119 mL) was added chloro(isopropyl)magnesium-LiCl (1.3 M in THF, 22 mL, 1.2 equiv.) at 0° C. The mixture was stirred for 40 min, treated with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (14.6 mL, 3 equiv.) and stirred for 10 min. After dilution with saturated NH4Cl solution and extraction with EtOAc, the combined organic phases were concentrated and purified by column chromatography (silica gel, heptane and MTBE as eluents) to give the desired product (11.4 g, 70%). 1H NMR (400 MHz, DMSO-d6): δ ppm 7.59 (d, 4H), 7.46 (s, 1H), 7.45 (t, 2H), 7.43 (t, 4H), 3.74 (s, 2H), 3.59 (t, 2H), 2.35 (s, 3H), 1.41 (qn, 2H), 1.24 (s, 12H), 1.09 (m, 2H), 1.08 (s, 4H), 1.05 (s, 2H), 0.98 (s, 9H), 0.98 (s, 2H), 0.94 (s, 4H), 0.78 (s, 6H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 146.9, 144.2, 135.5, 133.8, 130.3, 128.3, 104.6, 83.0, 64.7, 64.7, 59.0, 50.6, 48.2, 46.5, 44.1, 39.2, 37.9, 31.8, 30.7, 27.2, 26.1, 25.2, 19.2, 12.0; HRMS-ESI (m / z): [M+H] + C 42 H 62 Calculated value for BN2O3Si: 681.4623 Found value: 681.4631.

[0233] ​ tert-Butyl-[2-[[3-[[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methyl]-1-adamantyl]oxy]ethoxy]-diphenyl-silane ​ :(3-Bromo-1-adamantyl)methanol To 3-bromoadamantane-1-carboxylic acid (10.0 g, 38.6 mmol) in THF (25 mL) was slowly added a 1 M solution of BH-THF in THF (115 mL, 3 equiv.), and the mixture was stirred for 48 h. After addition of methanol and stirring for 30 min, purification by column chromatography (silica gel, heptane and MTBE as eluents) gave the desired product (8.37 g, 88%). 1H NMR (400 MHz, DMSO-d6): δ ppm 4.50 (t, 1H), 3.02 (d, 2H), 2.28 / 2.21 (dm+dm, 4H), 2.11 (m, 2H), 2.07 (s, 2H), 1.66 / 1.56 (dm+dm, 2H), 1.48 / 1.39 (dm+dm, 4H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 70.9, 69.3, 51.3, 49.0, 40.6, 37.3, 35.1, 32.3.

[0234] ​ 1-[(3-bromo-1-adamantyl)methyl]pyrazole To the product of Step A (8.37 g, 34.1 mmol), 1H-pyrazole (2.79 g, 1.2 equiv.) in toluene (100 mL) was added (cyanomethylene)tributylphosphorane (10.7 mL, 1.2 equiv.), and the reaction mixture was stirred for 2 h at 90° C. Purification by column chromatography (silica gel, heptane and MTBE as eluents) gave the desired product (8.50 g, 84%). 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.63 (dd, 1H), 7.43 (dd, 1H), 6.23 (t, 1H), 3.87 (s, 2H), 2.24 / 2.13 (m+m, 4H), 2.1 (m, 2H), 2.07 (s, 2H), 1.63 / 1.50 (m+m, 2H), 1.47 / 1.43 (m+m, 4H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 138.9, 131.7, 105.1, 68.0, 61.8, 51.8, 48.5, 39.8, 38.3, 34.6, 32.1; HRMS-ESI (m / z): [M+H]+ C 14 H 20 Calculated value for BrN2: 295.0810 Found value: 295.0804.

[0235] ​: 1-[(3-bromo-1-adamantyl)methyl]-5-methyl-pyrazole To the product of Step B (1.70 g, 5.76 mmol) in THF (30 mL) was added butyllithium (2.5 M in THF, 12 mL, 5 equiv.) at −78° C. After 1 h, iodomethane (7.2 mL, 5 equiv.) was added to the mixture. After 10 min, the reaction mixture was quenched with a saturated solution of NH4Cl and extracted with EtOAc, and the combined organic layers were dried and concentrated to give the desired product (2.0 g, 112%), which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.31 (d, 1H), 6.01 (d, 1H), 3.76 (s, 2H), 2.25 / 2.15 (d+d, 4H), 2.24 (s, 3H), 2.16 (s, 2H), 2.10 (m, 2H), 1.63 / 1.52 (d+d, 2H), 1.52 / 1.49 (d+d, 4H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 139.2, 138.0, 105.2, 68.2, 58.3, 52.1, 48.5, 40.5, 38.4, 34.5, 32.2, 11.8; HRMS-ESI (m / z): [M+H]+ C 15 H 22 Calculated value for BrN2: 309.0966 Found value: 309.0962.

[0236] ​ : 2-[[3-[(5-methylpyrazol-1-yl)methyl]-1-adamantyl]oxy]ethanol A mixture of the product of Step C (2.00 g, 6.47 mmol), ethylene glycol (14.4 mL, 40 equiv.), and DIPEA (5.6 mL, 5 equiv.) was stirred for 6 h at 120° C. After dilution with water and extraction with EtOAc, the combined organic phases were purified by column chromatography (silica gel, heptane and MTBE as eluents) to give the desired product (1.62 g, 86.6%). 1H NMR (400 MHz, DMSO-d6): δ ppm 7.28 (d, 1H), 5.99 (m, 1H), 4.46 (t, 1H), 3.75 (s, 2H), 3.40 (m, 2H), 3.32 (m, 2H), 2.23 (brs, 3H), 2.13 (m, 2H), 1.61 / 1.52 (m+m, 4H), 1.47 / 1.43 (m+m, 2H), 1.45 (s, 2H), 1.44-1.35 (m, 4H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 137.8, 105.1, 61.8, 61.5, 59.0, 44.6, 40.8, 39.6, 35.7, 30.0, 11.9; HRMS-ESI (m / z): [M+H]+ C 17 H 27 Calculated N2O2: 291.2073 Measured: 291.2069.

[0237] ​ tert-Butyl-[2-[[3-[(5-methylpyrazol-1-yl)methyl]-1-adamantyl]oxy]ethoxy]-diphenyl-silane To the product of step D (6.52 g, 22.5 mmol) and imidazole (2.29 g, 1.5 eq.) in DCM (67 ml) was added tert-butyl-chloro-diphenyl-silane (6.9 mL, 1.2 eq.) and the reaction mixture was stirred for 1 h. Purification by column chromatography (silica gel, heptane and MTBE as eluents) gave the desired product (11.0 g, 92.7%). LC / MS (C 33 H 45 N2O2Si) 529 [M+H] + .

[0238] ​ : tert-Butyl-[2-[[3-[(4-iodo-5-methyl-pyrazol-1-yl)methyl]-1-adamantyl]oxy]ethoxy]-diphenyl-silane To the product of Step E (11.0 g, 20.8 mmol) in DMF (105 mL) was added N-iodosuccinimide (5.85 g, 1.25 equiv.) and the reaction mixture was stirred for 3 h. The reaction mixture was diluted with water and extracted with DCM, after which the combined organic phases were washed with saturated sodium thiosulfate and brine, dried, and evaporated to give the desired product (11.0 g, 81%). 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.70-7.36 (m, 10H), 7.44 (s, 1H), 3.86 (s, 2H), 3.67 (t, 2H), 3.45 (t, 2H), 2.24 (s, 3H), 2.12 (m, 2H), 1.66-1.32 (m, 12H), 0.98 (s, 9H) 13 C NMR (100 MHz, DMSO-d6) δ ppm 142.4, 140.9, 64.4, 61.4, 60.4, 60.3, 30.0, 27.1, 12.2; HRMS-ESI (m / z): [M+H]+ C 33 H 44 Calculated value of IN2O2Si: 655.2217 Found value: 655.2217.

[0239] ​ : tert-Butyl-[2-[[3-[[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methyl]-1-adamantyl]oxy]ethoxy]-diphenyl-silane To the product of step F (11.0 g, 16.8 mmol) in THF (84 mL) was added chloro(isopropyl)magnesium-LiCl (1.3 M in THF, 17 mL, 1.2 equiv.) at 0° C. The reaction mixture was stirred for 40 min, treated with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.3 mL, 3 equiv.) and stirred for 10 min. After dilution with saturated NH4Cl solution and extraction with EtOAc, the combined organic phases were concentrated and purified by column chromatography (silica gel, heptane and MTBE as eluents) to give the desired product (9.0 g, 82%). 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.66 (d, 4H), 7.47 (s, 1H), 7.45 (t, 2H), 7.40 (t, 4H), 3.77 (s, 2H), 3.67 (t, 2H), 3.44 (t, 2H), 2.36 (s, 3H), 2.11 (br, 2H), 1.60 / 1.48 (d+d, 4H), 1.44 (d, 2H), 1.44 (s, 2H), 1.40 (d, 4H), 1.23 (s, 12H), 0.97 (s, 9H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 146.9, 144.2, 133.8, 130.2, 128.3, 125.7, 104.6, 83.0, 72.5, 64.4, 61.4, 58.9, 44.6, 40.7, 39.6, 38.7, 35.6, 30.0, 27.1, 25.2, 19.3, 12.1; HRMS-ESI (m / z): [M+H]+ C 39 H 56 Calculated value for BN2O4Si: 655.4102 Found value: 655.4108.

[0240] ​ : Methyl 3-bromo-6-[3-(3,6-dichloro-5-methyl-pyridazine-4-l)propylamino]pyridine-2-carboxylate ​ : Methyl 6-[bis(tert-butoxycarbonyl)amino]-3-bromo-pyridine-2-carboxylate To methyl 6-amino-3-bromo-pyridine-2-carboxylate (25.0 g, 108.2 mmol) and DMAP (1.3 g, 0.1 equiv.) in DCM (541 mL) was added BocO (59.0 g, 2.5 equiv.) at 0° C. and the reaction mixture was stirred for 2.5 h. After addition of a saturated solution of NaHCO and extraction with DCM, the combined organic phases were dried and concentrated to give the desired product (45.0 g, 72.3%). LC / MS (C 17 H 23 BrN2O6Na) 453 [M+Na]+ .

[0241] ​ Methyl 3-bromo-6-(tert-butoxycarbonylamino)pyridine-2-carboxylate To the product of Step A (42.7 g, 74.34 mmol) in DCM (370 mL) was added TFA (17.1 mL, 3 equiv.) at 0° C., and the reaction mixture was stirred for 18 h. After washing with a saturated solution of NaHCO and brine, the combined organic phase was dried, concentrated, and purified by column chromatography (silica gel, heptane and EtOAc as eluents) to give the desired product (28.3 g, 115.2%). 1 H NMR (400 MHz, DMSO-d6): δ ppm 10.29 (s, 1H), 8.11 (d, 1H), 7.88 (d, 1H), 3.87 (s, 3H), 1.46 (s, 9H) 13 C NMR (100 MHz, DMSO-d6) δ ppm 165.6, 153.1, 151.8 / 148.3, 143.5, 116.3, 109.2, 53.2, 28.4. 12 H 15 BrN2O4Na) 353 [M+Na] + .

[0242] ​ : Methyl 3-bromo-6-[tert-butoxycarbonyl-[3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propyl]amino]pyridine-2-carboxylate To the product of Step B (10.0 g, 30.1967 mmol) in acetone (150 mL) was added CsCO (29.5 g, 3 equiv.) and 3,6-dichloro-4-(3-iodopropyl)-5-methyl-pyridazine (9.9 g, 1 equiv.), and the reaction mixture was stirred for 18 h. After dilution with water and extraction with EtOAc, the combined organic phases were washed with brine, dried, and concentrated to give the desired product (17.5 g, 108%). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.13 (d, 1H), 7.78 (d, 1H), 3.91 (t, 2H), 3.89 (s, 3H), 2.79 (m, 2H), 2.38 (s, 3H), 1.82 (m, 2H), 1.46 (s, 9H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 165.3, 157.6, 156.6, 153.2, 152.9, 147.2, 143.1, 142.2, 139.7, 122.6, 111.8, 82.2, 53.3, 46.4, 28.1, 27.7, 26.5, 16.3; HRMS-ESI (m / z): [M+Na] + C 20 H 23 Calculated value for BrCl2N4NaO4: 555.0177 Found value: 555.0172.

[0243] ​ Methyl 3-bromo-6-[3-(3,6-dichloro-5-methyl-pyridazine-4-l)propylamino]pyridine-2-carboxylate The product of Step C (17.5 g, 32.7 mmol) in 1,1,1,3,3,3-hexafluoroisopropanol (330 mL) was stirred for 18 hours at 110° C. Purification by column chromatography (silica gel, heptane and EtOAc as eluents) gave the desired product (9.9 g, 70%). 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.63 (d, 1H), 7.22 (t, 1H), 6.57 (d, 1H), 3.83 (s, 3H), 3.30 (m, 2H), 2.83 (m, 2H), 2.37 (s, 3H), 1.74 (m, 2H) 13 C NMR (100 MHz, DMSO-d6) δ ppm 166.5, 141.5, 112.6, 52.9, 40.9, 28.0, 27.0, 16.4.

[0244] ​:(4-Methoxyphenyl)methyl 3-bromo-6-[3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propylamino]pyridine-2-carboxylate ​ 3-Bromo-6-[3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propylamino]pyridine-2-carboxylic acid A mixture of the product of Preparation 10 (35.39 g, 81.52 mmol) and LiOH×HO (13.68 g, 4 equiv.) in 1,4-dioxane (408 mL) and water (82 mL) was stirred for 1 h at 60° C. After quenching with a 1 M solution of HCl and extraction with EtOAc, the combined organic phases were dried, concentrated and purified by flash chromatography (silica gel with DCM and MeOH as eluents) to give the desired product (27.74 g, 81%). LC / MS (C 14 H 14 BrCl2N4O2) 421 [M+H] + .

[0245] ​ (4-Methoxyphenyl)methyl 3-bromo-6-[3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propylamino]pyridine-2-carboxylate To the product of Step A (27.7 g, 65.9 mmol), (4-methoxyphenyl)methanol (16.4 mL, 2 equiv.) and PPh3 (34.6 g, 2 equiv.) in toluene (660 mL) and THF (20 mL) was added diisopropyl azodicarboxylate (26 mL, 2 equiv.) dropwise and the reaction mixture was stirred for 1 h at 50° C. Purification by flash chromatography (silica gel, using heptane and EtOAc as eluents) gave the desired product (23.65 g, 66.4%). 1H NMR (500 MHz, dmso-d6) δ ppm 7.62 (d, 1H), 7.37 (dn, 2H), 7.21 (t, 1H), 6.91 (dm, 2H), 6.56 (d, 1H), 5.25 (s, 2H), 3.74 (s, 3H), 3.30 (q, 2H), 2.81 (m, 2H), 2.33 (s, 3H), 1.73 (m, 2H); 13 C NMR (500 MHz, DMSO-D6) δ ppm 165.9, 159.7, 157.6, 157.5, 156.8, 148.0, 142.7, 141.5, 139.7, 130.6, 127.8, 114.3, 112.6, 101.6, 67.0, 55.6, 40.9, 28.0, 27.1, 16.4; HRMS-ESI (m / z): [M+H]+ C 22 H 22 Calculated value for BrCl2N4O3: 539.0252, Found: 539.0246.

[0246] ​ : Methyl 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3,5-dimethyl-7-[2-(p-tolylsulfonyloxy)ethoxy]-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylate ​ : Methyl 6-[3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propylamino]-3-[5-methyl-1-[[3-[2-[tert-butyl(diphenyl)silyl]oxyethoxy]-5,7-dimethyl-1-adamantyl]methyl]pyrazol-4-yl]pyridine-2-carboxylate A mixture of the product of Preparation 10 (15.0 g, 34.55 mmol), the product of Preparation 7 (30.7 g, 1.3 equiv.), CsCO (33.8 g, 3.0 equiv.), and Pd(AtaPhos)Cl (1.53 g, 0.1 equiv.) in 1,4-dioxane (207 mL) and HO (34.5 mL) was stirred at 80° C. for 1.5 h. Purification by column chromatography (silica gel, heptane and EtOAc as eluents) gave the desired product (18.5 g, 58%). 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.69-7.37 (m, 10H), 7.32 (d, 1H), 7.23 (s, 1H), 6.98 (t, 1H), 6.63 (d, 1H), 3.82 (s, 2H), 3.67 (t, 1.27 / 1.2 (m+m, 4H), 1.15 / 1.09 (m+m, 4H), 1.05 / 0.97 (m+m, 2H), 0.97 (s, 9H), 0.84 (s, 6H); HRMS-ESI (m / z): [M+H]+ C 50 H 63 Calculated value for Cl2N6O4Si: 909.4057 Found: 909.4053.

[0247] ​ : Methyl 6-(3-chloro-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl)-3-[5-methyl-1-[[[2-[tert-butyl(diphenyl)silyl]oxyethoxy]-5,7-dimethyl-1-adamantyl]methyl]pyrazol-4-yl]pyridine-2-carboxylate A mixture of the product of Step A (18.5 g, 20.3 mmol), CsCO (13.2 g, 2 equiv.), DIPEA (7.1 mL, 2 equiv.), and Pd(Ataphos)Cl (900 mg, 0.1 equiv.) in 1,4-dioxane (102 mL) was stirred at 110° C. for 18 h. After filtration and concentration, the residue was taken up in DCM, washed with water, and purified by column chromatography (silica gel, DCM and EtOAc as eluents) to give the desired product (12.6 g, 71%). 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.85 (d, 1H), 7.69 (d, 1H), 7.66 (dm, 4H), 7.47-7.36 (m, 6H), 7.38 (s, 1H), 3.97 (t, 2H), 3.87 (s, 2H), 3.68 (t, 2H), 3.66 (s, 3H), 3.47 (t, 2H), 2.87 (t, 2H), 2.30 (s, 3H), 2.14 (s, 3H), 1.99 (br., 2H), 1.38 (s, 2H), 1.32-0.96 (br., 10H), 0.98 (s, 9H), 0.85 (s, 6H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 139.9, 137.6, 120.5, 64.4, 61.7, 58.9, 52.3, 46.0, 43.4, 30.2, 27.1, 24.6, 21.0, 15.5, 10.9; HRMS-ESI (m / z): [M+H]+ C 50 H 62 Calculated value for ClN6O4Si: 873.4290 Found: 873.4291.

[0248] ​ : Methyl 6-(3-chloro-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl)-3-[1-[[3-(2-hydroxyethoxy)-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylate To the product of step B (8.46 g, 9.68 mmol) in THF (95 mL) was added a 1 M solution of TBAF in THF (10.6 mL, 1.1 equiv.) at 0° C., and the reaction mixture was stirred for 2 h. After quenching with a saturated solution of NH4Cl and extraction with EtOAc, the combined organic phases were washed with brine, dried, and purified by column chromatography (silica gel, DCM and MeOH as eluents) to give the desired product (5.38 g, 88%). 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.86 (d, 1H), 7.71 (d, 1H), 7.38 (s, 1H), 4.46 (t, 1H), 3.97 (t, 2H), 3.87 (s, 2H), 3.70 (s, 3H), 3.40 (m, 2H), 3.35 (t, 2H), 2.87 (t, 2H), 2.30 (s, 3H), 2.15 (s, 3H), 1.99 (m, 2H), 1.42-0.95 (m, 12H), 0.87 (s, 6H); HRMS-ESI (m / z): [M+H]+ C 34 H 44 Calculated value for ClN6O4: 635.3113 Found: 635.3112.

[0249] ​ : Methyl 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-(2-hydroxyethoxy)-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylate Using Buchwald's general procedure I, starting with 3.7 g of the product of step C (5.78 mmol) and 1.74 g of 1,3-benzothiazol-2-amine (2 equivalents) at 130° C. for 1 hour, 3.1 g of the desired product (72% yield) was obtained. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.96 (d, 1H), 7.82 (br., 1H), 7.70 (d, 1H), 7.50 (br., 1H), 7.38 (s, 1H), 7.35 (t, 1H), 7.17 (t, 1H), 4.46 (br., 1H), 4.00 (t, 2H), 3.88 (s, 2H), 3.70 (s, 3H), 3.40 (brt., 2H), 3.35 (t, 2H), 2.86 (t, 2H), 2.32 (s, 3H), 2.16 (s, 3H), 2.03-1.94 (m, 2H), 1.42-0.96 (m, 12H), 0.87 (s, 6H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 139.8, 137.5, 126.4, 122.4, 122.1, 119.0, 62.1, 61.5, 59.0, 52.6, 45.4, 30.2, 24.3, 21.7, 12.6, 10.9; HRMS-ESI (m / z): [M+H]+ C 41 H 49 Calculated value for N8O4S: 749.3597 Found value: 749.3595.

[0250] ​ : Methyl 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3,5-dimethyl-7-[2-(p-tolylsulfonyloxy)ethoxy]-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylate To the product of step D (3.85 g, 5.14 mmol) and triethylamine (2.15 mL, 3 equiv.) in DCM (50 mL) was added p-tolylsulfonyl 4-methylbenzenesulfonate (2.51 g, 1.5 equiv.), and the reaction mixture was stirred for 1 h. Purification by column chromatography (silica gel, heptane and EtOAc as eluents) gave the desired product (3.2 g, 69%). 1H NMR (400 MHz, DMSO-d6): δ ppm 7.96 (d, 1H), 7.81 (br., 1H), 7.77 (d, 2H), 7.70 (d, 1H), 7.50 (br., 1H), 7.46 (d, 2H), 7.39 (s, 1H), 7.35 (t, 1H), 7.17 (t, 1H), 4.06 (t, 2H), 4.00 (t, 2H), 3.85 (s, 2H), 3.69 (s, 3H), 3.49 (t, 2H), 2.86 (t, 2H), 2.40 (s, 3H), 2.32 (s, 3H), 2.15 (s, 3H), 1.99 (m, 2H), 1.32-0.93 (m, 12H), 0.84 (s, 6H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 139.8, 137.6, 130.6, 128.1, 126.4, 122.4, 122.1, 119, 71.5, 58.8, 58.4, 52.6, 45.4, 30.1, 24.3, 21.7, 21.6, 12.6, 10.9; HRMS-ESI (m / z): [M+H]+ C 48 H 55 Calculated value for N8O6S2: 903.3686 Found value: 903.3685.

[0251] ​ (4-Methoxyphenyl)methyl 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3,5-dimethyl-7-[3-(p-tolylsulfonyloxy)propyl]-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylate ​ : (4-Methoxyphenyl)methyl 3-[1-[[3-[3-[tert-butyl(diphenyl)silyl]oxypropyl]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]-6-[3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propylamino]pyridine-2-carboxylate A mixture of the product of Preparation 11 (3.67 g, 6.79 mmol), the product of Preparation 8 (5.09 g, 1.1 equiv.), Pd(AtaPhos)Cl (301 mg, 0.1 equiv.), and CsCO (6.64 g, 3 equiv.) in 1,4-dioxane (41 mL) and HO (6.8 mL) was stirred for 18 h at 80° C. Purification by column chromatography (silica gel, heptane and EtOAc as eluents) gave the desired product (4.43 g, 64%). 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.62-7.38 (m, 10H), 7.32 (d, 1H), 7.26 (s, 1H), 7.10 (m, 2H), 6.98 (t, 1H), 6.83 (m, 2H), 6.63 (d, 1H), 4.98 (s, 2H), 3.74 (s, 2H), 3.70 (s, 3H), 3.58 (t, 2H), 3.35 (m, 2H), 2.84 (m, 2H), 2.34 (s, 3H), 2.02 (s, 3H), 1.77 (m, 2H), 1.43 (m, 2H), 1.18-0.85 (m, 12H), 1.09 (t, 2H), 0.97 (s, 9H), 0.77 (s, 6H); HRMS-ESI (m / z): [M+H]+ C 58 H 71 Calculated value for Cl2N6O4Si: 1013.4683 Found value: 1013.4683;

[0252] ​ (4-Methoxyphenyl)methyl 3-[1-[[3-[3-[tert-butyl(diphenyl)silyl]oxypropyl]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]-6-(3-chloro-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl)pyridine-2-carboxylate A mixture of the product of Step A (4.43 g, 4.37 mmol), CsCO (2.84 g, 2 equiv.), DIPEA (1.5 mL, 2 equiv.), and Pd(Ataphos)Cl (193 mg, 0.1 equiv.) in 1,4-dioxane (22 mL) was stirred at 110° C. for 18 h. After quenching with water and extraction with EtOAc, the combined organic phases were dried, concentrated, and purified by column chromatography (silica gel, DCM and EtOAc as eluents) to give the desired product (2.83 g, 66%). 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.84 (d, 1H), 7.68 (d, 1H), 7.59 (d, 4H), 7.44 (t, 2H), 7.42 (t, 4H), 7.38 (s, 1H), 7.14 (d, 2H), 6.87 (d, 2H), 5.07 (s, 2H), 3.96 (t, 2H), 3.78 (s, 2H), 3.71 (s, 3H), 3.59 (t, 2H), 2.86 (t, 2H), 2.29 (s, 3H), 2.08 (s, 3H), 1.97 (qn, 2H), 1.43 (qn, 2H), 1.12 (s, 4H), 1.10 (s, 2H), 1.09 (t, 2H), 0.97 (s, 9H), 0.95 (s, 2H), 0.94 / 0.91 (d+d, 4H), 0.78 (s, 6H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 166.9, 159.6, 156.3, 153.6, 150.8, 147.7, 140.1, 137.5, 137.3, 136.0, 135.5, 133.8, 130.3, 130.1, 129.1, 128.3, 127.6, 123.1, 120.5, 115.5, 114.3, 66.8, 64.8, 64.8, 59.6, 55.6, 50.5, 48.1, 46.4, 46.0, 44.2, 39.3, 38.1, 31.7, 30.6, 27.2, 26.1, 24.6, 21.0, 19.3, 15.5, 10.9; HRMS-ESI (m / z): [M+H]+ C 58 H70 Calculated value for ClN6O4Si: 977.4916 Found: 977.4915.

[0253] ​ (4-Methoxyphenyl)methyl 6-(3-chloro-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl)-3-[1-[[3-(3-hydroxypropyl)-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylate To the product of step B (2.83 g, 2.89 mmol) in THF (95 mL) was added a 1 M solution of TBAF in THF (3.2 mL, 1.1 equiv.) at 0° C., and the reaction mixture was stirred for 2 h. After quenching with a saturated solution of NH4Cl and extraction with EtOAc, the combined organic phases were washed with brine, dried, concentrated, and purified by column chromatography (silica gel, DCM and MeOH as eluents) to give the desired product (2.21 g, 103%). 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.85 (d, 1H), 7.70 (d, 1H), 7.39 (s, 1H), 7.17 (d, 2H), 6.90 (d, 2H), 5.09 (s, 2H), 4.34 (t, 1H), 3.96 (t, 2H), 3.79 (s, 2H), 3.74 (s, 3H), 3.32 (q, 2H), 2.86 (t, 2H), 2.29 (s, 3H), 2.09 (s, 3H), 1.98 (qn, 2H), 1.34 (qn, 2H), 1.13 (s, 2H), 1.13 (s, 4H), 1.06 (t, 2H), 0.99 / 0.95 (d+d, 4H), 0.97 (s, 2H), 0.78 (s, 6H); 13C NMR (100 MHz, DMSO-d6) δ ppm 166.9, 159.7, 156.4, 153.6, 150.8, 147.7, 140.2, 137.5, 137.3, 136.0, 130.2, 129.1, 127.6, 123.1, 120.4, 115.5, 114.3, 66.8, 66.8, 62.1, 59.7, 55.6, 50.6, 48.2, 46.5, 46.0, 44.3, 39.7, 38.1, 31.8, 30.6, 26.5, 24.6, 21.0, 15.5, 10.9; HRMS-ESI (m / z): [M+H]+ C 42 H 52 Calculated value for ClN6O4: 739.3739 Found: 739.3739.

[0254] ​ : (4-Methoxyphenyl)methyl 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-(3-hydroxypropyl)-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylate A mixture of the product of Step C (1.71 g, 2.31 mmol), 1,3-benzothiazol-2-amine (695 mg, 2 equiv.), Pd2dba3 (212 mg, 0.1 equiv.), XantPhos (268 mg, 0.2 equiv.), and DIPEA (1.2 mL, 3 equiv.) in cyclohexanol (14 mL) was stirred for 1 h at 130 °C. Purification by column chromatography (silica gel, heptane, DCM and MeCN as eluents) gave the desired product (1.25 g, 63%). 1H NMR (400 MHz, DMSO-d6): δ ppm12.08 / 10.87 (brs / brs, 1H), 7.95 (d, 1H), 7.81 (br, 1H), 7.68 (d, 1H), 7.50 (br, 1H), 7.39 (s, 1H), 7.35 (t, 1H), 7.18 (d, 2H), 7.17 (t, 1H), 6.90 (d, 2H), 5.10 (s, 2H), 4.34 (t, 1H), 3.99 (t, 2H), 3.79 (s, 2H), 3.74 (s, 3H), 3.33 (q, 2H), 2.85 (t, 2H), 2.32 (s, 3H), 2.11 (s, 3H), 1.98 (qn, 2H), 1.34 (qn, 2H), 1.14 (s, 4H), 1.14 (s, 2H), 1.07 (t, 2H), 1.00 / 0.95 (d+d, 2H), 0.99 / 0.95 (d+d, 4H), 0.79 (s, 6H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 140.0, 137.6, 130.2, 126.4, 122.4, 122.0, 119.0, 114.3, 66.7, 62.1, 59.6, 55.6, 50.6, 48.2, 46.5, 45.4, 44.3, 39.7, 30.6, 26.5, 24.3, 21.7, 12.6, 11.0; HRMS-ESI (m / z): [M+H]+ C 49 H 57 Calculated value for N8O4S: 853.4223 Found value: 853.4229.

[0255] ​ (4-Methoxyphenyl)methyl 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3,5-dimethyl-7-[3-(p-tolylsulfonyloxy)propyl]-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylate To the product of step D (1.25 g, 1.47 mmol) and triethylamine (0.61 mL, 3 equiv.) in DCM (15 mL) was added p-tolylsulfonyl 4-methylbenzenesulfonate (717 mg, 1.5 equiv.), and the reaction mixture was stirred for 1 h. Purification by column chromatography (silica gel, heptane and EtOAc as eluents) gave 800 mg (54%) of the desired product. 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.95 (d, 1H), 7.88 (brs, 1H), 7.77 (m, 2H), 7.68 (d, 1H), 7.62 (brs, 1H), 7.47 (m, 2H), 7.39 (s, 1H), 7.35 (brs, 1H), 7.17 (brs, 1H), 7.10 (m, 2H), 6.90 (m, 2H), 5.09 (s, 2H), 4.00 (m, 2H), 3.98 (t, 2H), 3.77 (s, 2H), 3.74 (s, 3H), 2.85 (t, 2H), 2.40 (s, 3H), 2.32 HRMS-ESI (m / z): [M+H]+ C 56 H 63 Calculated value for N8O6S2: 1007.4312 Found value: 1007.4318.

[0256] ​ : (4-Methoxyphenyl)methyl 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[5-methyl-1-[[3-[2-(p-tolylsulfonyloxy)ethoxy]-1-adamantyl]methyl]pyrazol-4-yl]pyridine-2-carboxylate ​: (4-Methoxyphenyl)methyl 3-[1-[[3-[2-[tert-butyl(diphenyl)silyl]oxyethoxy]-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]-6-[3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propylamino]pyridine-2-carboxylate A mixture of the product of Preparation 11 (3.67 g, 6.79 mmol), the product of Preparation 9 (4.89 g, 1.1 equiv.), Pd(AtaPhos)Cl (301 mg, 0.1 equiv.), and CsCO (6.64 g, 3 equiv.) in 1,4-dioxane (41 mL) and HO (6.8 mL) was stirred for 12 h at 80 °C. Purification by column chromatography (silica gel, heptane and EtOAc as eluents) gave the desired product (3.0 g, 45%). 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.69-7.37 (m, 10H), 7.31 (d, 1H), 7.24 (s, 1H), 7.12 (m, 2H), 6.98 (t, 1H), 6.83 (m, 2H), 6.62 (d, 1H), 4.99 (s, 2H), 3.76 (s, 2H), 3.70 (s, 3H), 3.66 (t, 2H), 3.45 (t, 2H), 3.35 (m, 2H), 2.85 (m, 2H), 2.34 (s, 3H), 2.12 (m, 2H), 2.02 (s, 3H), 1.77 (m, 2H), 1.65-1.33 (m, 12H), 0.97 (s, 9H); HRMS-ESI (m / z): [M+H]+ C 55 H 65 Calculated value for Cl2N6O5Si: 987.4163 Found: 987.4158.

[0257] ​(4-Methoxyphenyl)methyl 3-[1-[[3-[2-[tert-butyl(diphenyl)silyl]oxyethoxy]-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]-6-(3-chloro-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl)pyridine-2-carboxylate A mixture of the product of Step A (3.00 g, 3.00 mmol), CsCO (1.95 g, 2 equiv.), DIPEA (1.0 mL, 2 equiv.), and Pd(Ataphos)Cl (212 mg, 0.1 equiv.) in 1,4-dioxane (15 mL) was stirred for 18 h at 110° C. Purification by column chromatography (silica gel, DCM and MeOH as eluents) gave the desired product (1.74 g, 60%). 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.84 (d, 1H), 7.68 (d, 1H), 7.68-7.37 (m, 10H), 7.36 (s, 1H), 7.16 (m, 2H), 6.87 (m, 2H), 5.08 (s, 2H), 3.96 (m, 2H), 3.81 (s, 2H), 3.72 (s, 3H), 3.67 (t, 2H), 3.46 (t, 2H), 2.87 (t, 2H), 2.29 (s, 3H), 2.13 (m, 2H), 2.09 (s, 3H), 1.98 (m, 2H), 1.65-1.37 (m, 12H), 0.97 (s, 9H); HRMS-ESI (m / z): [M+H]+ C 55 H 64 Calculated value for ClN6O5Si: 951.4396 Found: 951.4397.

[0258] ​ : (4-Methoxyphenyl)methyl 6-(3-chloro-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl)-3-[1-[[3-(2-hydroxyethoxy)-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylate To the product of Step B (1.73 g, 1.82 mmol) in THF (20 mL) was added a 1 M solution of TBAF in THF (2.0 mL, 1.1 equiv.) at 0° C., and the reaction mixture was stirred for 2 h. Purification by column chromatography (silica gel, DCM and MeOH as eluents) gave the desired product (1.06 g, 82%). 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.85 (d, 1H), 7.71 (d, 1H), 7.36 (s, 1H), 7.19 (m, 2H), 6.90 (m, 2H), 5.10 (s, 2H), 4.47 (t, 1H), 3.96 (m, 2H), 3.81 (s, 2H), 3.75 (s, 3H), 3.40 (m, 2H), 3.34 (t, 2H), 2.87 (t, 2H), 2.29 (s, 3H), 2.14 (m, 2H), 2.10 (s, 3H), 1.98 (m, 2H), 1.67-1.36 (m, 12H); HRMS-ESI (m / z): [M+H]+ C 39 H 46 Calculated value for ClN6O5: 713.3218 Found: 713.3217.

[0259] ​ : (4-Methoxyphenyl)methyl 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-(2-hydroxyethoxy)-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylate A mixture of the product of Step C (1.00 g, 1.40 mmol), 1,3-benzothiazol-2-amine (421 mg, 2 equiv.), Pd2dba3 (128 mg, 0.1 equiv.), XantPhos (162 mg, 0.2 equiv.), and DIPEA (0.72 mL, 3 equiv.) in cyclohexanol (10 mL) was stirred for 1 h at 130° C. Purification by column chromatography (silica gel, heptane as eluent, followed by DCM and MeOH) gave the desired product (600 mg, 53%). 1 H NMR (400 MHz, DMSO-d6): δ ppm12.18 / 10.84 (brs / brs, 1H), 7.94 (d, 1H), 7.83 (br, 1H), 7.69 (d, 1H), 7.57 (br, 1H), 7.36 (s, 1H), 7.35 (brt, 1H), 7.20 (d, 2H), 7.17 (brt, 1H), 6.91 (d, 2H), 5.11 (s, 2H), 4.47 (brt, 1H), 4.00 (t, 2H), 3.81 (s, 2H), 3.75 (s, 3H), 3.41 (brq, 2H), 3.35 (t, 2H), 2.85 (t, 2H), 2.32 (s, 3H), 2.14 (m, 2H), 2.12 (s, 3H), 1.99 (qn, 2H), 1.62 / 1.53 (d+d, 4H), 1.53 (s, 2H), 1.49 / 1.44 (d+d, 2H), 1.44 (s, 4H); 13 C NMR (100 MHz, DMSO-d6) δ ppm 139.9, 137.6, 130.1, 126.4, 122.4, 122.0, 118.9, 114.2, 66.7, 61.9, 61.5, 59.5, 55.6, 45.4, 44.7, 40.8, 39.5, 35.6, 30.1, 24.3, 21.7, 12.6, 10.8; HRMS-ESI (m / z): [M+H]+ C 46 H 51 Calculated value for N8O5S: 827.3703 Found value: 827.3709.

[0260] ​ : (4-Methoxyphenyl)methyl 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[5-methyl-1-[[3-[2-(p-tolylsulfonyloxy)ethoxy]-1-adamantyl]methyl]pyrazol-4-yl]pyridine-2-carboxylate To the product of Step D (600 mg, 0.726 mmol) and N,N-diethylethanamine (0.31 mL, 3 equiv.) in dichloromethane (7 mL) was added p-tolylsulfonyl 4-methylbenzenesulfonate (357 mg, 1.5 equiv.) and the reaction mixture was stirred for 18 h. Purification by flash chromatography (silica gel using DCM and MeOH as eluents) gave 354 mg (50%) of the desired product. 1 H NMR (500 MHz, dmso-d6) δ ppm 12.22 / 10.85 (brs / brs, 1H), 7.94 (d, 1H), 7.81 (br, 1H), 7.77 (d, 2H), 7.70 (d, 1H), 7.52 (br, 1H), 7.45 (d, 2H), 7.37 (s, 1H), 7.35 (t, 1H), 7.19 (d, 2H), 7.17 (t, 1H), 6.89 (d, 2H), 5.10 (s, 2H), 4.05 (t, 2 H), 4.00 (t, 2H), 3.79 (s, 2H), 3.74 (s, 3H), 3.49 (t, 2H), 2.86 (t, 2H), 2.40 (s, 3H), 2.32 (s, 3H), 2.11 (m, 2H), 2.11 (s, 3H), 1.99 (qn, 2H), 1.55-1.36 (m, 12H); 13 C NMR (500 MHz, DMSO-D6) δ ppm 139.9, 137.6, 130.5, 130.3, 128.1, 126.4, 122.4, 122.0, 118.9, 114.2, 71.4, 66.8, 59.4, 58.2, 55.6, 45.4, 30.0, 24.2, 21.6, 21.6, 12.6, 10.9; HRMS-ESI (m / z): [M+H]+ C 53 H 57 Calculated value for N8O7S2: 981.3792 Found value: 981.3795.

[0261] ​Ethyl 2-(3-chloro-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl)-5-[3-(2-fluoro-4-iodo-phenoxy)propyl]thiazole-4-carboxylate ​ : 2-(3-chloro-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl)-5-[3-(2-fluoro-4-iodo-phenoxy)propyl]thiazole-4-carboxylic acid A mixture of the product of preparation 3a (35.39 g, 81.52 mmol) and LiOH×HO (4 equiv.) in 1,4-dioxane (408 mL) and water (82 mL) was stirred for 1 h at 60° C. After quenching with a 1 M solution of HCl and extraction with EtOAc, the combined organic phases were dried, concentrated, and purified by flash chromatography (silica gel with DCM and MeOH as eluents) to give the desired product (27.7 g, 81%). 1 H NMR (500 MHz, dmso-d6) δ ppm 7.56 (dd, 1H), 7.43 (brd., 1H), 6.96 (t, 1H), 4.18 (t, 2H), 4.05 (t, 2H), 3.28 (t, 2H), 2.84 (t, 2H), 2.29 (s, 3H), 2.07 (m, 2H), 1.97 (m, 2H); 13 C NMR (500 MHz, DMSO-D6) δ ppm 166.4, 154.8, 152.1, 151.8, 151.1, 147.1, 143.9, 135.7, 134.0, 133.8, 129.0, 124.9, 117.6, 82.3, 68.8, 46.3, 31.0, 24.0, 22.5, 19.8, 15.7; HRMS-ESI (m / z): [M+H]+ C 21 H 20 Calculated value for ClFIN4O3S: 588.9973 Found: 588.9969.

[0262] ​: Ethyl 2-(3-chloro-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl)-5-[3-(2-fluoro-4-iodo-phenoxy)propyl]thiazole-4-carboxylate To a mixture of the product of Step A (27.7 g, 65.9 mmol), ethanol (2 equivalents), and PPh3 (2 equivalents) in toluene (660 mL) and THF (20 mL) was added diisopropyl azodicarboxylate (2 equivalents) dropwise and the reaction was stirred for 1 h at 50° C. Purification by flash chromatography (silica gel, using heptane and EtOAc as eluents) gave the desired product (23.65 g, 66.4%). 1 H NMR (500 MHz, dmso-d6) δ ppm 7.59 (dd, 1H), 7.44 (dm, 1H), 6.98 (t, 1H), 4.29 (m, 2H), 4.25 (q, 2H), 4.08 (t, 2H), 3.24 (t, 2H), 2.89 (t, 2H), 2.32 (s, 3H), 2.09 (m, 2H), 2.04 (m, 2H), 1.28 (t, 3H); 13 C NMR (500 MHz, DMSO-D6) δ ppm 162.6, 155.4, 152.2, 151.7, 151.3, 147.0, 134.0, 124.9, 117.6, 82.4, 68.3, 60.7, 46.3, 30.8, 24.1, 23.1, 19.7, 15.7, 14.6; HRMS-ESI (m / z): [M+H] + C 23 H 24 Calculated value for ClFIN4O3S: 617.0286, Found: 617.0282.

[0263] ​ : 2-{6-[(1,3-benzothiazol-2-yl)amino]-1,2,3,4-tetrahydroquinolin-1-yl}-1,3-thiazole-4-carboxylic acid [ka] ​ : Ethyl 2-(6-bromo-1,2,3,4-tetrahydroquinolin-1-yl)-1,3-thiazole-4-carboxylate To a solution of benzoyl isothiocyanate (380 μL, 2.83 mmol, 1.2 equiv.) in acetone (10 mL) was added 6-bromo-1,2,3,4-tetrahydroquinoline (500 mg, 2.36 mmol, 1 equiv.), and the mixture was heated at reflux for 1 h. The mixture was poured into ice water, and the precipitate was filtered, washed with water, and dried to give a pale yellow solid. The solid was added to 1 N aqueous sodium hydroxide solution (10 mL), and the suspension was heated at 80 °C for 30 min, cooled to ambient temperature, and poured into cold 1 N aqueous hydrochloric acid solution. The pH was adjusted to pH 8 with saturated aqueous sodium carbonate, and the solid was collected by filtration and washed with water to give a yellow solid. A suspension of the solid and ethyl bromopyruvate (296 μL, 2.36 mmol, 1 equiv.) in ethanol (10 mL) was heated at reflux for 2 h. The mixture was allowed to cool to ambient temperature and then partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (3 x 50 mL) and the combined organic extracts were washed with brine (50 mL), dried (magnesium sulfate) and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 24 g RediSep 2000) eluting with a gradient of 0-10% ethyl acetate in isoheptane was performed. 商標 Purification by silica cartridge) gave the desired product as a yellow gum (232 mg, 0.63 mmol, 27%). LC / MS (C 15 H 15 BrN2O2S) 367 [M+H] + ; Retention time 1.42 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 7.99 (d, 1H), 7.87 (s, 1H), 7.53 - 7.48 (m, 1H), 7.44 - 7.38 (m, 1H), 4.27 (q, 2H), 3.83 (t, 2H), 2.83 - 2.73 (m, 2H), 2.00 - 1.90 (m, 2H), 1.29 (t, 3H).

[0264] ​ : Ethyl 2-{6-[(1,3-benzothiazol-2-yl)amino]-1,2,3,4-tetrahydroquinolin-1-yl}-1,3-thiazole-4-carboxylate To an oven-dried microwave vial was added the product of Step A (93.8 mg, 0.26 mmol, 1 equiv), 2-aminobenzothiazole (46.0 mg, 0.31 mmol, 1.2 equiv), cesium carbonate (166 mg, 0.51 mmol, 2 equiv), and 1,4-dioxane (4 mL), and the mixture was sparged with nitrogen (10 min) and heated under microwave irradiation at 120 °C for 2 h before adding BrettPhos (13.7 mg, 0.03 mmol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium(0) (23.4 mg, 0.03 mmol, 0.1 equiv). The reaction was partitioned between ethyl acetate and water, the aqueous phase was extracted with ethyl acetate (3 × 50 mL), and the combined organic extracts were washed with brine (50 mL), dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 12g RediSep) eluted with a gradient of 0-20% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a yellow gum (85.1 mg, 0.19 mmol, 76%). LC / MS (C 22 H 20 N4O2S2) 437 [M+H] + ; Retention time 1.40 (LCMS-V-B1) 1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, 1H), 7.83 - 7.78 (m, 1H), 7.69 - 7.65 (m, 1H), 7.63 - 7.57 (m, 2H), 7.36 - 7.29 (m, 1H), 7.18 - 7.13 (m, 1H), 7.03 - 6.98 (m, 1H), 4.28 (q, J = 7.08 Hz, 2H), 3.92 - 3.84 (m, 2H), 2.80 (t, J = 6.30 Hz, 2H), 2.00 - 1.89 (m, 2H), 1.30 (t, J = 7.09 Hz, 2H).

[0265] ​ : 2-{6-[(1,3-benzothiazol-2-yl)amino]-1,2,3,4-tetrahydroquinolin-1-yl}-1,3-thiazole-4-carboxylic acid To a solution of the product of Step B (85.1 mg, 0.19 mmol, 1 equiv.) in tetrahydrofuran (2 mL) and methanol (1 mL) was added 1N aqueous sodium hydroxide (0.39 mL, 0.39 mmol, 2 equiv.) and the mixture was heated at 50° C. for 3 h. The reaction was partitioned between ethyl acetate and water, the aqueous phase was extracted with ethyl acetate (3×30 mL), and the combined organic extracts were washed with brine (50 mL), dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 12 g RediSep 1000 rF, 12 g RediSep 1000 rF, 12 g RediSep 1000 rF) eluted with a gradient of 0-6% methanol in dichloromethane. 商標 Purification by silica cartridge) gave the material which was further purified by preparative HPLC (HPLC-V-A2) to give the desired product as a cream solid (1.2 mg, 1.5%). HRMS-ESI (m / z) [M+H]+ C 20 H 17 Calculated N4O2S2: 409.0793, Measured: 409.0830

[0266] ​: 2-{5-[(1,3-benzothiazol-2-yl)amino]-1H-indol-1-yl}-1,3-thiazole-4-carboxylic acid [ka] ​ : Methyl 2-(5-bromo-1H-indol-1-yl)-1,3-thiazole-4-carboxylate To a cooled solution of 5-bromoindole (150 mg, 0.77 mmol, 1 equiv.) in dimethylformamide (2 mL) was added sodium hydride (60% dispersion; 36.7 mg, 1.53 mmol, 2 equiv.) in small portions, and the mixture was stirred at 0 °C for 30 min before adding methyl 2-chloro-4-thiazolecarboxylate (272 mg, 1.53 mmol, 2 equiv.) and then allowed to warm to ambient temperature and stir overnight. The reaction was partitioned between ethyl acetate and water, the aqueous phase was extracted with ethyl acetate (3 × 30 mL), and the combined organic extracts were washed with brine (3 × 30 mL), dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 12 g RediSep 1000) eluted with a gradient of 0–20% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a yellow solid (72.8 mg, 0.22 mmol, 28%). LC / MS (C 13 H9BrN2O2S) 339 [M+H] + ; Retention time 1.35 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 8.41 - 8.38 (m, 1H), 8.37 (s, 1H), 8.02 (d, J = 3.5 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.57 (dd, J = 8.8, 2.0 Hz, 1H), 6.86 (dd, J = 3.5, 0.8 Hz, 1H), 3.89 (s, 3H).

[0267] ​: Methyl 2-{5-[(1,3-benzothiazol-2-yl)amino]-1H-indol-1-yl}-1,3-thiazole-4-carboxylate To an oven-dried microwave vial was added the product of Step A (72.8 mg, 0.22 mmol, 1 equiv), 2-aminobenzothiazole (38.9 mg, 0.26 mmol, 1.2 equiv), cesium carbonate (141 mg, 0.43 mmol, 2 equiv), and 1,4-dioxane (2 mL), and the mixture was sparged with nitrogen (10 min) and then heated under microwave irradiation at 120° C. for 2 h before adding BrettPhos (11.6 mg, 0.02 mmol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium(0) (19.8 mg, 0.02 mmol, 0.1 equiv). The reaction was partitioned between ethyl acetate and water, the aqueous phase was extracted with ethyl acetate (3×30 mL), and the combined organic extracts were washed with brine (30 mL), dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 12g RediSep) eluted with a gradient of 0-20% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a pale yellow solid (10.5 mg, 0.03 mmol, 12%). LC / MS (C 20 H 14 N4O2S2) 407 [M+H] + ; Retention time 1.35 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 8.9 Hz, 1H), 8.34 (d, J = 4.4 Hz, 1H), 7.96 (d, J = 3.6 Hz, 1H), 7.84 - 7.78 (m, 1H), 7.67 - 7.57 (m, 2H), 7.39 - 7.30 (m, 2H), 7.20 - 7.12 (m, 1H), 6.92 (d, J = 3.7 Hz, 1H), 3.90 (s, 3H).

[0268] ​: 2-{5-[(1,3-benzothiazol-2-yl)amino]-1H-indol-1-yl}-1,3-thiazole-4-carboxylic acid To a solution of the product of Step B (10.5 mg, 0 mol, 1 equiv) in tetrahydrofuran (2 mL) and methanol (1 mL) was added 1N aqueous sodium hydroxide (0.05 mL, 0.05 mmol, 2 equiv) and the mixture was heated at 50 °C for 2 h. The reaction was partitioned between ethyl acetate and water, the aqueous phase was extracted with ethyl acetate (3 × 30 mL), and the combined organic extracts were washed with brine (50 mL), dried (magnesium sulfate), and concentrated in vacuo. Purification by preparative HPLC (HPLC-V-A2) gave the desired product as a cream-colored solid (3.5 mg, 0.01 mmol, 35%). HRMS-ESI (m / z) [M+H]+ C 19 H 13 Calculated N4O2S2: 393.0480, Measured: 393.0503

[0269] ​ : 2-{5-[(1,3-benzothiazol-2-yl)amino]-2,3-dihydro-1H-indol-1-yl}-1,3-thiazole-4-carboxylic acid [ka] ​ : Ethyl 2-(5-bromo-2,3-dihydro-1H-indol-1-yl)-1,3-thiazole-4-carboxylate To a solution of benzoyl isothiocyanate (0.33 mL, 2.42 mmol, 1.2 equiv.) in acetone (10 mL) was added 5-bromoindoline (400 mg, 2.02 mmol, 1 equiv.) and the mixture was heated at reflux for 1 h. The reaction was poured into ice water, and the precipitate was filtered, washed with water, and dried to give a pale yellow solid. The solid was added to 1 N aqueous sodium hydroxide solution (10 mL), and the suspension was heated at 80 °C for 30 min, allowed to cool to ambient temperature, and poured into cold 1 N aqueous hydrochloric acid solution. The pH was adjusted to pH 8 with saturated aqueous sodium carbonate, and the solid was collected by filtration and washed with water to give a yellow solid. A suspension of the solid and ethyl bromopyruvate (253 μL, 2.02 mmol, 1 equiv.) in ethanol (10 mL) was heated at reflux for 2 h and then allowed to cool to ambient temperature. The reaction was partitioned between ethyl acetate and water, the aqueous phase extracted with ethyl acetate (3 x 50 mL), and the combined organic extracts washed with brine (50 mL), dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 24g RediSep 2000) eluting with a gradient of 0-20% ethyl acetate in isoheptane was performed. 商標 Purification by silica cartridge) gave the desired product as a yellow solid (377 mg, 1.07 mmol, 53%). LC / MS (C 14 H 13 BrN2O2S) 353 [M+H] + ; Retention time 1.39 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H), 7.57 - 7.53 (m, 1H), 7.47 - 7.44 (m, 1H), 4.30 (q, J = 7.1 Hz, 2H), 4.08 (t, 2H), 3.34 - 3.26 (m, 2H), 1.31 (t, 3H).

[0270] ​: Ethyl 2-{5-[(1,3-benzothiazol-2-yl)amino]-2,3-dihydro-1H-indol-1-yl}-1,3-thiazole-4-carboxylate To an oven-dried microwave vial was added the product of Step A (100 mg, 0.28 mmol, 1 equiv), 2-aminobenzothiazole (51.0 mg, 0.34 mmol, 1.2 equiv), cesium carbonate (129 mg, 0.4 mmol, 2 equiv), and 1,4-dioxane (2 mL), and the mixture was sparged with nitrogen (10 min) and then heated at 120 °C under microwave irradiation for 1 h before adding BrettPhos (10.6 mg, 0.02 mmol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium(0) (18.2 mg, 0.02 mmol, 0.1 equiv). The reaction was partitioned between ethyl acetate and water, the aqueous phase was extracted with ethyl acetate (3 × 50 mL), and the combined organic extracts were washed with brine (50 mL), dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 24g RediSep) eluted with a gradient of 0-40% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a brown gum (29.8 mg, 0.07 mmol, 36%). LC / MS (C 21 H 18 N4O2S2) 423 [M+H] + ; Retention time 1.38 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 8.01 (d, 1H), 7.87 (s, 1H), 7.83 - 7.78 (m, 1H), 7.61 - 7.57 (m, 1H), 7.45 (s, 1H), 7.33 - 7.28 (m, 1H), 7.18 - 7.10 (m, 1H), 7.00 (td, J = 1.24, 7.55 Hz, 1H), 4.31 (q, J = 7.12 Hz, 2H), 4.13 - 4.06 (m, 2H), 3.43 - 3.34 (m, 2H), 1.33 (t, J = 7.12 Hz, 3H).

[0271] ​ : 2-{5-[(1,3-benzothiazol-2-yl)amino]-2,3-dihydro-1H-indol-1-yl}-1,3-thiazole-4-carboxylic acid To a solution of the product of Step B (29.8 mg, 0.07 mmol, 1 equiv.) in tetrahydrofuran (2 mL) and methanol (1 mL) was added 1N aqueous sodium hydroxide (0.14 mL, 0.14 mmol, 2 equiv.) and the mixture was heated at 50° C. for 1 h. The reaction was partitioned between ethyl acetate and water, the aqueous phase was extracted with ethyl acetate (3×30 mL), and the combined organic extracts were washed with brine (50 mL), dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 4g RediSep 2000) eluted with a gradient of 0-15% methanol in dichloromethane. 商標 Purification by silica cartridge) gave the material which was further purified by preparative HPLC (HPLC-V-A2) to give the desired product as a cream solid (3.7 mg, 0.01 mmol, 13%). HRMS-ESI (m / z) [M+H]+ C 19 H 15 Calculated N4O2S2: 395.0636, Measured: 395.0659

[0272] ​ : 2-{7-[(1,3-benzothiazol-2-yl)amino]-3,4-dihydro-2H-1,4-benzoxazin-4-yl}-1,3-thiazole-4-carboxylic acid [ka] ​ : Ethyl 2-(7-bromo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)-1,3-thiazole-4-carboxylate To a solution of benzoyl isothiocyanate (301 μL, 2.24 mmol, 1.2 equiv.) in acetone (10 mL) was added 7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (400 mg, 1.87 mmol, 1 equiv.) and the mixture was heated at reflux for 1 h. The reaction was poured into ice water, and the precipitate was filtered, washed with water, and dried to give a pale yellow solid. The solid was added to 1 N sodium hydroxide (10 mL), and the suspension was heated at 80 °C for 30 min, cooled to ambient temperature, and poured into cold 1 N aqueous hydrochloric acid. The pH was adjusted to pH 8 with saturated aqueous sodium carbonate, and the solid was collected by filtration and washed with water to give a yellow solid. A suspension of the solid and ethyl bromopyruvate (235 μL, 1.87 mmol, 1 equiv.) in ethanol (10 mL) was heated at reflux for 2 h and then allowed to cool to ambient temperature. The reaction was partitioned between ethyl acetate and water, the aqueous phase extracted with ethyl acetate (3 x 50 mL), and the combined organic extracts washed with brine (50 mL), dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 24g RediSep 2000) eluted with a gradient of 0-20% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a yellow solid (264 mg, 0.71 mmol, 38%). LC / MS (C 14 H 13 BrN2O3S) 369 [M+H] + ; Retention time 1.36 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 8.76 Hz, 1H), 7.94 (s, 1H), 7.26 - 7.11 (m, 2H), 4.37 - 4.21 (m, 4H), 4.07 - 3.99 (m, 2H), 1.29 (t, 3H).

[0273] ​ : Ethyl 2-{7-[(1,3-benzothiazol-2-yl)amino]-3,4-dihydro-2H-1,4-benzoxazin-4-yl}-1,3-thiazole-4-carboxylate To an oven-dried microwave vial was added the product of Step A (173 mg, 0.47 mmol, 1 equiv), 2-aminobenzothiazole (105 mg, 0.7 mmol, 1.5 equiv), potassium tert-butoxide (105 mg, 0.94 mmol, 2 equiv), and 1,4-dioxane (5 mL), and the mixture was sparged with nitrogen (10 min) and then heated under microwave irradiation at 140 °C for 1 h before adding BrettPhos (37.7 mg, 0.07 mmol, 0.15 equiv) and tris(dibenzylideneacetone)dipalladium(0) (42.9 mg, 0.05 mmol, 0.1 equiv). The reaction was partitioned between ethyl acetate and water, the aqueous phase was extracted with ethyl acetate (3 × 50 mL), and the combined organic extracts were washed with brine (50 mL), dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 12g RediSep) eluted with a gradient of 0-30% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a pale yellow solid (91.4 mg, 0.21 mmol, 45%), which was used directly in the next step without further purification. LC / MS (C 21 H 18 N4O3S2) 439 [M+H] + ; Retention time 1.35 (LCMS-V-B1)

[0274] ​ : 2-{7-[(1,3-benzothiazol-2-yl)amino]-3,4-dihydro-2H-1,4-benzoxazin-4-yl}-1,3-thiazole-4-carboxylic acid To a solution of the product of Step B (91.4 mg, 0.21 mmol, 1 equiv.) in tetrahydrofuran (3 mL) and methanol (1 mL) was added 1 N aqueous sodium hydroxide solution (0.42 mL, 0.42 mmol, 2 equiv.), and the mixture was heated at 50° C. for 2 h. The reaction was partitioned between ethyl acetate and water, the aqueous phase was extracted with ethyl acetate (3×30 mL), and the combined organic extracts were washed with brine (50 mL), dried (magnesium sulfate), and concentrated in vacuo. Purification by preparative HPLC (HPLC-V-A1) gave the desired product as a cream-colored solid (1.5 mg, 2%). LC / MS (C 19 H 14 N4O3S2) 411 [M+H] + ; Retention time 1.18 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.02 (d, J = 8.9 Hz, 1H), 7.81 (dd, J = 7.8, 1.2 Hz, 1H), 7.69 - 7.59 (m, 3H), 7.33 (td, J = 7.7, 1.3 Hz, 1H), 7.24 (dd, J = 8.9, 2.5 Hz, 1H), 7.16 (td, J = 7.6, 1.2 Hz, 1H), 4.30 (t, J = 4.4 Hz, 2H), 4.03 (t, J = 4.5 Hz, 2H). HRMS-ESI (m / z) [M+H]+ C 19 H 15 Calculated value of N4O3S2: 411.0586, Found value: 411.0610

[0275] ​ : 6-{5-[(1,3-benzothiazol-2-yl)amino]-1H-indol-1-yl}pyridine-2-carboxylic acid [ka] ​ : 6-(5-iodo-1H-indol-1-yl)pyridine-2-carboxylic acid To a stirred solution of 5-iodoindole (170 mg, 0.7 mmol, 1 equiv.) in 1,4-dioxane (5 mL) / dimethylformamide (1 mL), sodium hydride (60% dispersion; 20.1 mg, 0.84 mmol, 1.2 equiv.) was added portionwise over 20 min. The mixture was stirred for 30 min before ethyl 6-chloropicolinate (143 mg, 0.77 mmol, 1.1 equiv.) was added and stirred at 70 °C overnight. The reaction was partitioned between ethyl acetate and water, the aqueous phase was extracted with ethyl acetate (3 × 30 mL), and the combined organic extracts were washed with brine (3 × 30 mL), dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 12 g RediSep 1000) eluted with a gradient of 0–30% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a yellow solid (38.3 mg, 0.11 mmol, 15%). LC / MS (C 14 H9IN2O2) 365 [M+H] + ; Retention time 1.22 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 13.47 (s, 1H), 8.64 (d, J = 8.8 Hz, 1H), 8.20 - 8.17 (m, 1H), 8.16 - 8.13 (m, 1H), 8.08 - 8.02 (m, 2H), 7.93 (dd, J = 7.5, 0.8 Hz, 1H), 7.59 (dd, J = 1.8 Hz, 1H), 6.78 (dd, J = 3.6, 0.7 Hz, 1H).

[0276] ​ : 6-{5-[(1,3-benzothiazol-2-yl)amino]-1H-indol-1-yl}pyridine-2-carboxylic acid To an oven-dried microwave vial was added the product of Step A (38.3 mg, 0.11 mmol, 1 equiv), 2-aminobenzothiazole (19 mg, 0.13 mmol, 1.2 equiv), sodium tert-butoxide (20.2 mg, 0.21 mmol, 2 equiv), and 1,4-dioxane (2 mL), and the mixture was sparged with nitrogen (10 min) and then heated under microwave irradiation at 140 °C for 4 h before adding BrettPhos (5.65 mg, 0.01 mmol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium(0) (9.63 mg, 0.01 mmol, 0.1 equiv). The reaction was partitioned between ethyl acetate and water, the aqueous phase was extracted with ethyl acetate (3 × 50 mL), and the combined organic extracts were washed with brine (50 mL), dried (magnesium sulfate), and concentrated in vacuo. Purification by preparative HPLC (HPLC-V-A2) gave the desired product as a cream-colored solid (0.8 mg, 2%). HRMS-ESI (m / z) [M+H]+ C 21 H 15 Calculated N4O2S: 387.0916, Measured: 387.0943

[0277] ​ : 2-{5-[(1,3-benzothiazol-2-yl)amino]-1H-pyrrolo[2,3-b]pyridin-1-yl}-1,3-thiazole-4-carboxylic acid [ka] ​ : Ethyl 2-{5-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl}-1,3-thiazole-4-carboxylate To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (250 mg, 1.27 mmol, 1 equiv.) in 1,4-dioxane (5 mL) and dimethylformamide (2 mL), sodium hydride (60% dispersion; 36.5 mg, 1.52 mmol, 1.2 equiv.) was added in portions over 20 min, and the mixture was stirred at ambient temperature for 30 min before adding ethyl 2-bromo-1,3-thiazole-4-carboxylate (449 mg, 1.9 mmol, 1.5 equiv.). The mixture was heated at reflux for 2 h, then allowed to cool to ambient temperature, and the resulting precipitate was collected by filtration and dried under vacuum to give the desired product as a cream-colored solid (300 mg, 0.85 mmol, 67%). LC / MS (C 13 H 10 BrN3O2S) 352 [M+H] + ; Retention time 1.41 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 2.2 Hz, 1H), 8.48 (d, J = 2.2 Hz, 1H), 8.38 (s, 1H), 8.33 (d, J = 3.9 Hz, 1H), 6.88 (d, J = 3.8 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H).

[0278] ​ : Ethyl 2-{5-[(1,3-benzothiazol-2-yl)amino]-1H-pyrrolo[2,3-b]pyridin-1-yl}-1,3-thiazole-4-carboxylate To an oven-dried microwave vial was added the product of Step A (200 mg, 0.57 mmol, 1 equiv), 2-aminobenzothiazole (128 mg, 0.85 mmol, 1.5 equiv), cesium carbonate (370 mg, 1.14 mmol, 2 equiv), and 1,4-dioxane (3 mL), and the mixture was sparged with nitrogen (10 min) and then heated under microwave irradiation at 120° C. for 6 h before adding tris(dibenzylideneacetone)dipalladium(0) (52 mg, 0.06 mmol, 0.1 equiv) and Xantphos (64.8 mg, 0.12 mmol, 0.2 equiv). The reaction was partitioned between ethyl acetate and water, the aqueous phase was extracted with ethyl acetate (3×30 mL), and the combined organic extracts were washed with brine (30 mL), dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 12g RediSep) eluted with a gradient of 0-70% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the crude desired product as a yellow gum which was used directly in the next step without further purification. LC / MS (C 20 H 15 N5O2S2) 422 [M+H] + ; Retention time 1.37 (LCMS-V-B1)

[0279] ​ : 2-{5-[(1,3-benzothiazol-2-yl)amino]-1H-pyrrolo[2,3-b]pyridin-1-yl}-1,3-thiazole-4-carboxylic acid To a solution of the product of Step B (61.2 mg, 0.15 mmol, 1 equiv.) in tetrahydrofuran (3 mL) and methanol (1 mL) was added 1N aqueous sodium hydroxide (0.29 mL, 0.29 mmol, 2 equiv.), and the mixture was heated at 50 °C for 2 h. The reaction was concentrated in vacuo, the residue suspended in water, and acidified to pH 6 with 1N aqueous hydrochloric acid. The mixture was partitioned between ethyl acetate and water, the aqueous phase extracted with ethyl acetate (3 × 30 mL), and the combined organic extracts washed with brine (50 mL), dried (magnesium sulfate), and concentrated in vacuo. Purification by reverse-phase automated flash chromatography (CombiFlash Rf, C18 5.5 g RediSep column) eluting with a gradient of 5–95% acetonitrile in water gave the desired product as a white solid (2.5 mg, 0.01 mmol, 4%). HRMS-ESI (m / z) [M+H]+ C 18 H 12 Calculated N5O2S2: 394.0432, Found: 394.0459

[0280] ​ 2-{5-[(1,3-benzothiazol-2-yl)amino]-1H-pyrrolo[2,3-c]pyridin-1-yl}-1,3-thiazole-4-carboxylic acid [ka] ​ : Ethyl 2-{5-chloro-1H-pyrrolo[2,3-c]pyridin-1-yl}-1,3-thiazole-4-carboxylate To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine (300 mg, 1.97 mmol, 1 equiv) in 1,4-dioxane (5 mL) and dimethylformamide (2 mL) was added sodium hydride (60% dispersion; 56.6 mg, 2.36 mmol, 1.2 equiv) in portions over 20 min, and the mixture was stirred at ambient temperature for 30 min and heated at reflux for 2 h before adding ethyl 2-bromo-1,3-thiazole-4-carboxylate (696 mg, 2.95 mmol, 1.5 equiv). The reaction was allowed to cool to ambient temperature, and the resulting precipitate was collected by filtration and dried under reduced pressure to give the desired product as a pale brown solid (518 mg, 1.68 mmol, 86%). LC / MS (C 13 H 10 ClN3O2S) 308 [M+H] + ; Retention time 1.19 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.39 (s, 1H), 8.33 (d, J = 3.5 Hz, 1H), 7.85 (d, J = 0.9 Hz, 1H), 6.93 (dd, J = 3.5, 0.8 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H).

[0281] ​ : Ethyl 2-{5-[(1,3-benzothiazol-2-yl)amino]-1H-pyrrolo[2,3-c]pyridin-1-yl}-1,3-thiazole-4-carboxylate To an oven-dried microwave vial was added the product of Step A (300 mg, 0.97 mmol, 1 equiv), 2-aminobenzothiazole (220 mg, 1.46 mmol, 1.5 equiv), cesium carbonate (635 mg, 1.95 mmol, 2 equiv), and 1,4-dioxane (7 mL), and the mixture was sparged with nitrogen (10 min) and then heated under microwave irradiation at 130° C. for 8 h before adding tris(dibenzylideneacetone)dipalladium(0) (89.3 mg, 0.1 mmol, 0.1 equiv) and Xantphos (113 mg, 0.19 mmol, 0.2 equiv). The reaction was partitioned between ethyl acetate and water, the aqueous phase was extracted with ethyl acetate (3×50 mL), and the combined organic extracts were washed with brine (30 mL), dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 12g RediSep) eluted with a gradient of 0-70% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a yellow solid (17.3 mg, 0.04 mmol, 4%). LC / MS (C 20 H 15 N5O2S2) 422 [M+H] + ; Retention time 1.34 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 9.53 (t, J = 0.9 Hz, 1H), 8.34 (s, 1H), 8.22 (d, J = 3.5 Hz, 1H), 7.87 (d, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.40 - 7.27 (m, 1H), 7.21 - 7.14 (m, 1H), 6.94 (dd, J = 3.5, 0.7 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H).

[0282] ​2-{5-[(1,3-benzothiazol-2-yl)amino]-1H-pyrrolo[2,3-c]pyridin-1-yl}-1,3-thiazole-4-carboxylic acid To a solution of the product of Step B (17.3 mg, 0.04 mmol, 1 equiv) in tetrahydrofuran (3 mL) and methanol (1 mL) was added 1 N aqueous sodium hydroxide solution (0.08 mL, 0.08 mmol, 2 equiv) and the mixture was heated at 50° C. for 2 h. The reaction was concentrated in vacuo, the residue was suspended in water, and acidified to pH 7 with 1 N aqueous hydrochloric acid. The solid was collected by filtration, washed with methanol, then diethyl ether, and dried under reduced pressure to give the desired product as a cream-colored solid (9.1 mg, 0.02 mmol, 56%). HRMS-ESI (m / z) [M+H]+ C 18 H 12 Calculated N5O2S2: 394.0432, Found: 394.0452

[0283] ​ : 2-{3-[(1,3-benzothiazol-2-yl)amino]-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,3-thiazole-4-carboxylic acid [ka] ​ : Ethyl 2-{3-chloro-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,3-thiazole-4-carboxylate To a solution of 3-chloro-7H-pyrrolo[2,3-c]pyridazine (285 mg, 1.86 mmol, 1 equiv.) in 1,4-dioxane (5 mL) and dimethylformamide (2 mL), sodium hydride (60% dispersion; 53.4 mg, 2.23 mmol, 1.2 equiv.) was added portionwise over 20 min. The mixture was stirred at ambient temperature for 30 min and heated at reflux for 2 h before ethyl 2-chlorothiazole-4-carboxylate (533 mg, 2.78 mmol, 1.5 equiv.) was added. The reaction was partitioned between ethyl acetate and water, the aqueous phase was extracted with ethyl acetate (3 × 40 mL), and the combined organic extracts were washed with brine, dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 24 g RediSep 1000) was performed, eluting with a gradient of 0–40% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a pink solid (388 mg, 1.26 mmol, 68%). LC / MS (C 12 H9ClN4O2S) 309 [M+H] + ; Retention time 1.14 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 3.8 Hz, 1H), 8.46 (s, 1H), 8.30 (s, 1H), 6.97 (d, J = 3.8 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H).

[0284] ​ : Ethyl 2-{3-[(1,3-benzothiazol-2-yl)amino]-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,3-thiazole-4-carboxylate To an oven-dried microwave vial was added the product of Step A (388 mg, 1.26 mmol, 1 equiv), 2-aminobenzothiazole (283 mg, 1.89 mmol, 1.5 equiv), cesium carbonate (819 mg, 2.51 mmol, 2 equiv), and 1,4-dioxane (10 mL), and the mixture was sparged with nitrogen (10 min) and then heated under microwave irradiation at 130° C. for 6 h before adding tris(dibenzylideneacetone)dipalladium(0) (115 mg, 0.13 mmol, 0.1 equiv) and Xantphos (145 mg, 0.25 mmol, 0.2 equiv). The reaction was partitioned between ethyl acetate and water, the aqueous phase was extracted with ethyl acetate (3×50 mL), and the combined organic extracts were washed with brine (30 mL), dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 24g RediSep) eluted with a gradient of 0-100% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a brown solid (112 mg, 0.27 mmol, 21%). LC / MS (C 19 H 14 N6O2S2) 423 [M+H] + ; Retention time 1.29 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.58 (d, J = 3.9 Hz, 1H), 8.41 (s, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.91 (s, 1H), 7.71 - 7.63 (m, 1H), 7.40 (ddd, J = 8.2, 7.2, 1.3 Hz, 1H), 7.24 (td, J = 7.6, 1.1 Hz, 1H), 6.99 (d, J = 3.9 Hz, 1H), 4.36 (q, J = 7.1 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H).

[0285] ​: 2-{3-[(1,3-benzothiazol-2-yl)amino]-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,3-thiazole-4-carboxylic acid To a solution of the product of Step B (112 mg, 0.27 mmol, 1 equiv) in tetrahydrofuran (5 mL) and methanol (1.5 mL) was added 1 N aqueous sodium hydroxide (0.53 mL, 0.53 mmol, 2 equiv) and the mixture was heated at 50 °C for 2 h. The reaction was concentrated in vacuo, the residue was suspended in water, and the solid was collected by filtration. Purification by reverse-phase automated flash chromatography (CombiFlash Rf, C18 5.5 g RediSep column) eluting with a gradient of 5 to 95% acetonitrile in water gave the desired product as a pale yellow solid (4.9 mg, 0.01 mmol, 5%). HRMS-ESI (m / z) [M+H]+ C 17 H 11 Calculated N6O2S2: 395.0385, Found: 395.0406

[0286] ​ 2-{3-[(1,3-benzothiazol-2-yl)amino]-7H-pyrrolo[2,3-c]pyridazin-7-yl}-5-[3-(2-fluorophenoxy)propyl]-1,3-thiazole-4-carboxylic acid [ka] ​ : Ethyl 5-bromo-2-acetamido-1,3-thiazole-4-carboxylate To a solution of ethyl 2-amino-5-bromothiazole-4-carboxylate (4 g, 15.9 mmol, 1 equiv.) in dichloromethane (70 mL), acetic anhydride (1.65 mL, 17.5 mmol, 1.1 equiv.) and 4-dimethylaminopyridine (2.24 g, 18.3 mmol, 1.15 equiv.) were added, and the mixture was stirred at ambient temperature overnight. The reaction was allowed to cool to ambient temperature, then washed with water followed by brine, dried (magnesium sulfate), and concentrated in vacuo. The resulting solid was triturated with diethyl ether, filtered, and dried under reduced pressure to give the desired product as an off-white solid (4.15 g, 14.15 mmol, 89%). LC / MS (C8H9BrN2O3S) 294 [M+H] + ; Retention time 0.82 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 4.28 (q, J = 7.1 Hz, 2H), 2.15 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H).

[0287] ​ : Ethyl 2-acetamido-5-(3-hydroxyprop-1-yn-1-yl)-1,3-thiazole-4-carboxylate Tetrakis(triphenylphosphine)palladium(0) (813 mg, 0.7 mmol, 0.05 equiv.) was added to a solution of the product of Step A (4.13 g, 14.1 mmol, 1 equiv.), propargyl alcohol (1.64 mL, 28.2 mmol, 2 equiv.), triethylamine (5.87 mL, 42.2 mmol, 3 equiv.), and copper(I) iodide (0.27 g, 1.41 mmol, 0.1 equiv.) in dimethylformamide (60 mL) under a nitrogen atmosphere, and the mixture was heated at 100 °C for 3 h. The reaction was concentrated in vacuo and purified by automated flash column chromatography (CombiFlash Rf, 120 g RediSep 1000 rF ... 商標 Purification by silica cartridge) gave the desired product as a cream solid (3 g, 11.2 mmol, 79%). LC / MS (C 11 H 12 N2O4S) 269 [M+H] + ; Retention time 0.63 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 5.45 (t, J = 6.0 Hz, 1H), 4.37 (d, J = 6.0 Hz, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.16 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H).

[0288] ​ : Ethyl 2-acetamido-5-(3-hydroxypropyl)-1,3-thiazole-4-carboxylate Ethyl acetate (30 mL) and methanol (30 mL) were added to a flask containing the product of Step B (3 g, 11.2 mmol, 1 equiv.) and platinum(IV) oxide hydrate (508 mg, 2.23 mmol, 0.2 equiv.) under a nitrogen atmosphere. The vessel was evacuated and back-filled with nitrogen (×3), then evacuated, placed under a hydrogen atmosphere, and shaken at ambient temperature for 24 h. The reaction was filtered through Celite (10 g), eluted with methanol, and the solvent removed in vacuo. Automated flash column chromatography (CombiFlash Rf, 80 g RediSep) eluted with a gradient of 0-10% methanol in dichloromethane. 商標 Purification by silica cartridge) gave the desired product as a brown solid (1.89 g, 6.94 mmol, 62%). LC / MS (C 11 H 16 N2O4S) 273 [M+H] + ; Retention time 0.61 (LCMS-V-B1) 1H NMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H), 4.54 (t, J = 5.1 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.44 (q, J = 6.1 Hz, 2H), 3.20 - 3.08 (m, 2H), 2.12 (s, 3H), 1.82 - 1.68 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H).

[0289] ​ : Ethyl 2-amino-5-(3-hydroxypropyl)-1,3-thiazole-4-carboxylate To a solution of the product of Step C (500 mg, 1.84 mmol, 1 equiv) in ethanol (15 mL) was added hydrochloric acid (4 M in 1,4-dioxane; 4.59 mL, 4 M, 18.4 mmol, 10 equiv) and the mixture was heated at 60 °C overnight. The reaction was allowed to cool to ambient temperature and then concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 12 g RediSep 1000 rF, 12 g RediSep 1000 rF) eluting with a gradient of 0-10% methanol in dichloromethane was performed. 商標 Purification by silica cartridge) gave the desired product as a beige solid (422 mg, 1.83 mmol, 100%). LC / MS (C9H 14 N2O3S) 231 [M+H] + ; Retention time 0.50 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 8.04 (br s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 3.44 (t, J = 6.3 Hz, 2H), 3.05 - 2.96 (m, 2H), 1.76 - 1.64 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H).

[0290] ​ : Ethyl 2-bromo-5-(3-hydroxypropyl)-1,3-thiazole-4-carboxylate Tert-Butyl nitrate (0.26 mL, 2.2 mmol, 1.2 equiv.) was added dropwise to a stirred solution of copper(II) bromide (491 mg, 2.2 mmol, 1.2 equiv.) in acetonitrile (6 mL), the mixture was heated to 60°C, and then a suspension of the product of Step D (422 mg, 1.83 mmol, 1 equiv.) in acetonitrile (8 mL) was added slowly. The mixture was maintained at 60°C for 2 hours, then allowed to cool to ambient temperature and quenched by the addition of 2N aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. The organic extract was washed with water, brine, dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 12g RediSep 1000) eluted with a gradient of 0-50% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a colorless oil (271 mg, 0.92 mmol, 50%). LC / MS (C9H 12 BrNO3S) 296 [M+H] + ; Retention time 0.76 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 4.59 (t, J = 5.1 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.44 (td, J = 6.3, 5.1 Hz, 2H), 3.24 - 3.15 (m, 2H), 1.81- 1.69 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H).

[0291] Project F : Ethyl 2-bromo-5-[3-(2-fluorophenoxy)propyl]-1,3-thiazole-4-carboxylate A solution of the product of Step E (271 mg, 0.92 mmol, 1 equiv.), 2-fluorophenol (0.12 mL, 1.38 mmol, 1.5 equiv.), and triphenylphosphine (362 mg, 1.38 mmol, 1.5 equiv.) in tetrahydrofuran (10 mL) was cooled in an ice bath, then diisopropyl azodicarboxylate (0.27 mL, 1.38 mmol, 1.5 equiv.) was slowly added, and the mixture was stirred at 0°C for 30 minutes, then at ambient temperature for 3 hours. The reaction was partitioned between ethyl acetate and water, and the organic phase was washed with brine, dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 40 g RediSep 1000) eluted with a gradient of 0-60% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as an orange oil (302 mg, 0.78 mmol, 85%). LC / MS (C 15 H 15 BrFNO3S) 390 [M+H] + ; Retention time 1.23 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 7.26 - 7.07 (m, 3H), 7.01 - 6.88 (m, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.09 (t, J = 6.1 Hz, 2H), 3.39 - 3.29 (m, 2H), 2.16 - 2.03 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H).

[0292] Project G : Ethyl 2-{3-chloro-7H-pyrrolo[2,3-c]pyridazin-7-yl}-5-[3-(2-fluorophenoxy)propyl]-1,3-thiazole-4-carboxylate To a stirred solution of 3-chloro-7H-pyrrolo[2,3-c]pyridazine (179 mg, 1.17 mmol, 1.5 equiv.) in 1,4-dioxane (10 mL) and dimethylformamide (3 mL) was added sodium hydride (60% dispersion; 22.4 mg, 0.93 mmol, 1.2 equiv.) in portions over 20 min. The mixture was stirred for 30 min, 2 h at ambient temperature, and overnight at reflux before the product of Step F (302 mg, 0.78 mmol, 1 equiv.) was added. The reaction was partitioned between ethyl acetate and water, the aqueous phase was extracted with ethyl acetate (3 x 30 mL), and the combined organic extracts were washed with brine, dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 12 g RediSep 1000) eluted with a gradient of 0-50% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a pale yellow solid (122 mg, 0.27 mmol, 34%). LC / MS (C 21 H 18 ClFN4O3S) 461 [M+H] + ; Retention time 1.41 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 3.8 Hz, 1H), 8.28 (s, 1H), 7.26 - 7.07 (m, 3H), 6.99 - 6.87 (m, 2H), 4.32 (q, J = 7.1 Hz, 2H), 4.15 (t, J = 6.1 Hz, 2H), 3.48 - 3.37 (m, 2H), 2.28 - 2.14 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H).

[0293] Project H : Ethyl 2-{3-[(1,3-benzothiazol-2-yl)amino]-7H-pyrrolo[2,3-c]pyridazin-7-yl}-5-[3-(2-fluorophenoxy)propyl]-1,3-thiazole-4-carboxylate To a microwave vial was added the product of Step G (122 mg, 0.27 mmol, 1 equiv), 2-aminobenzothiazole (59.7 mg, 0.4 mmol, 1.5 equiv), cesium carbonate (173 mg, 0.53 mmol, 2 equiv), tris(dibenzylideneacetone)dipalladium(0) (24.3 mg, 0.03 mmol, 0.1 equiv), Xantphos (15.3 mg, 0.03 mmol, 0.1 equiv), and 1,4-dioxane (7.5 mL), and the mixture was heated under microwave irradiation at 120° C. for 6 h. The mixture was partitioned between ethyl acetate and water, and the aqueous phase was extracted with ethyl acetate (3×40 mL), washed with brine, dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 12g RediSep) eluted with a gradient of 0-50% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a yellow solid (42.8 mg, 0.07 mmol, 28%). LC / MS (C 28 H 23 FN6O3S2) 575 [M+H] + ; Retention time 1.47 (LCMS-V-B1) 1 H NMR (400 MHz, DMSO-d6) δ 11.80 (br s, 1H), 8.53 (d, J = 3.8 Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.88 (s, 1H), 7.69 - 7.63 (m, 1H), 7.40 (ddd, J = 8.2, 7.3, 1.3 Hz, 1H), 7.26 - 7.16 (m, 3H), 7.15 - 7.11 (m, 1H), 6.98 - 6.91 (m, 2H), 4.32 (q, J = 7.1 Hz, 2H), 4.17 (t, J = 6.1Hz, 2H), 3.48 - 3.39 (m, 2H), 2.28 - 2.17 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H).

[0294] Project I2-{3-[(1,3-benzothiazol-2-yl)amino]-7H-pyrrolo[2,3-c]pyridazin-7-yl}-5-[3-(2-fluorophenoxy)propyl]-1,3-thiazole-4-carboxylic acid To a solution of the product of step H (42.8 mg, 0.07 mmol, 1 equiv.) in 1,4-dioxane (2 mL), 1.25 M aqueous lithium hydroxide (0.12 mL, 0.15 mmol, 2 equiv.) was added and the mixture was heated at reflux for 2 h. The reaction was concentrated in vacuo, and purification by preparative HPLC (HPLC-V-A2) gave the desired product as a yellow solid (2.3 mg, 6%). HRMS-ESI (m / z) [M+H]+ C 26 H 20 Calculated value for FN6O3S2: 547.1022, found value 547.1010.

[0295] Example 10 2-{3-[(1,3-benzothiazol-2-yl)amino]-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,3-thiazole-4-carboxylic acid [ka] Project A : tert-Butyl 3-chloro-5H,6H,7H-pyrrolo[2,3-c]pyridazine-7-carboxylate To a solution of N-(but-3-yn-1-yl)-6-chloro-1,2,4,5-tetrazin-3-amine (381 mg, 2.08 mmol, 1 equiv.) in tetrahydrofuran (15 mL) was added di-tert-butyl dicarbonate (1.36 g, 6.23 mmol, 3 equiv.) and 4-dimethylaminopyridine (12.7 mg, 0.1 mmol, 0.05 equiv.), and the mixture was stirred overnight at ambient temperature. Automated flash column chromatography (CombiFlash Rf, 24 g RediSep 1000) was performed, eluting with a gradient of 0-70% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a red solid (89 mg, 0.35 mmol, 17%). LC / MS (C 11 H 14 ClN3O2) 256 [M+H] + ; Retention time 2.06 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (t, J = 1.6 Hz, 1H), 3.97 (dd, J = 8.9, 7.9 Hz, 2H), 3.10 (ddd, J = 9.4, 7.8, 1.6 Hz, 2H), 1.51 (s, 9H).

[0296] Project B : 3-chloro-5H,6H,7H-pyrrolo[2,3-c]pyridazine To a solution of the product of Step A (89 mg, 0.35 mmol, 1 equiv) in dichloromethane (3 mL) was added trifluoroacetic acid (1.5 mL) and the mixture was stirred at ambient temperature for 1 h. The reaction was concentrated in vacuo and then loaded onto a methanol-washed SCX cartridge (5 g), washed with methanol, and then eluted with 1.4 N methanolic ammonia to give the desired product as a beige solid (51 mg, 0.33 mmol, 94%). LC / MS (C6H6ClN3) 156 [M+H] + ; Retention time 0.37 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 7.27 (br s, 1H), 7.24 - 7.20 (m, 1H), 3.55 (td, J = 8.2, 1.1 Hz, 2H), 3.06 (ddd, J = 9.7, 7.8, 1.7 Hz, 1H).

[0297] Project C : Ethyl 2-{3-chloro-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,3-thiazole-4-carboxylate To an oven-dried microwave vial was added the product of Step B (51 mg, 0.33 mmol, 1 equiv), ethyl 2-bromo-1,3-thiazole-4-carboxylate (92.9 mg, 0.39 mmol, 1.2 equiv), trans-N,N'-dimethylcyclohexane-1,2-diamine (10.3 μL, 0.07 mmol, 0.2 equiv), copper(I) iodide (6.24 mg, 0.03 mmol, 0.1 equiv), and potassium phosphate tribasic (139 mg, 0.66 mmol, 2 equiv), and 1,4-dioxane (3 mL), and the vessel was evacuated, flushed with nitrogen, and then heated under microwave irradiation at 150° C. for 1 h. The reaction was diluted with ethyl acetate, filtered through Celite, washed with brine, dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 12g RediSep) eluted with a gradient of 0-3% methanol in dichloromethane. 商標 Purification by silica cartridge) gave the crude desired product as a beige solid (19 mg, 0.06 mmol, 19%), which was used directly in the next step without further purification. LC / MS (C 12 H 11 ClN4O2S) 311 [M+H] + ; Retention time 2.24 (LCMS-VC)

[0298] Project D : Ethyl 2-{3-[(1,3-benzothiazol-2-yl)amino]-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,3-thiazole-4-carboxylate To an oven-dried microwave vial was added the product of Step C (19 mg, 0.06 mmol, 1 equiv), 2-aminobenzothiazole (13.8 mg, 0.09 mmol, 1.5 equiv), Xantphos (7.08 mg, 0.01 mmol, 0.2 equiv), cesium carbonate (39.8 mg, 0.12 mmol, 2 equiv), and 1,4-dioxane (3 mL), the vessel was evacuated and flushed with nitrogen, then tris(dibenzylideneacetone)dipalladium(0) (5.6 mg, 0.01 mmol, 0.1 equiv) was added, and the mixture was sparged with nitrogen (10 min) and then heated under microwave irradiation at 150° C. for 1 h. The reaction was diluted with ethyl acetate, filtered through Celite, washed with brine, dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 12g RediSep) eluted with a gradient of 0-10% methanol in dichloromethane. 商標 Purification by silica cartridge) gave the desired product as a brown solid (9 mg, 0.02 mmol, 35%). LC / MS (C 19 H 16 N6O2S2) 425 [M+H] + ; Retention time 2.53 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 7.95 - 7.89 (m, 1H), 7.69 - 7.58 (m, 2H), 7.41 - 7.35 (m, 1H), 7.33 - 7.29 (m, 1H), 7.25 - 7.15 (m, 1H), 4.40 - 4.26 (m, 4H), 1.33 (t, 3H).

[0299] Project E 2-{3-[(1,3-benzothiazol-2-yl)amino]-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,3-thiazole-4-carboxylic acid To a solution of the product of Step D (9 mg, 0.02 mmol, 1 equiv.) in 1,4-dioxane (2 mL) was added lithium hydroxide monohydrate (3.56 mg, 0.08 mmol, 4 equiv.) and the mixture was heated at reflux for 6 h. The reaction was concentrated in vacuo, then dissolved in methanol, loaded onto a methanol-washed PE-AX cartridge (5 g), washed with methanol, eluted with 10:1 dichloromethane / formic acid, and concentrated in vacuo. The crude material was triturated with dichloromethane, filtered, and dried under reduced pressure to give the desired product as the formate salt (2.42 mg, 0.01 mmol, 29%) as a beige solid. HRMS-ESI (m / z) [M+H]+ C 17 H 13 Calculated N6O2S2: 397.0541, Found 397.0529.

[0300] Example 11 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,3-thiazole-4-carboxylic acid [ka] Project A : 3-chloro-4-methyl-5H,6H,7H-pyrrolo[2,3-c]pyridazine To a solution of 3,6-dichloro-1,2,4,5-tetrazine (600 mg, 3.97 mmol, 1 equiv.) in tetrahydrofuran (16 mL) was added pent-3-yn-1-amine hydrochloride (475 mg, 3.97 mmol, 1 equiv.) and triethylamine (553 μL, 3.97 mmol, 1 equiv.), and the mixture was heated in a sealed tube at 110 °C for 8 h. The reaction was diluted with methanol, filtered through a pad of Celite, and the filtrate was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane, and the combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 40 g RediSep 1000 rF, 40 g RediSep 1000 rF) eluted with a gradient of 0-10% methanol in dichloromethane.商標 Purification by silica cartridge) gave the desired product as a beige solid (96 mg, 0.57 mmol, 14%). LC / MS (C7H8ClN3) 170 [M+H] + ; Retention time 0.54 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 7.12 (s, 1H), 3.56 (td, J = 8.4, 1.2 Hz, 2H), 3.04 (ddd, J = 9.2, 7.9, 1.3 Hz, 2H), 2.13 (d, J = 1.3 Hz, 3H).

[0301] Project B : Ethyl 2-{3-chloro-4-methyl-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,3-thiazole-4-carboxylate To an oven-dried microwave vial was added the product of Step A (96 mg, 0.57 mmol, 1 equiv), ethyl 2-bromo-1,3-thiazole-4-carboxylate (187 mg, 0.79 mmol, 1.4 equiv), trans-N,N'-dimethylcyclohexane-1,2-diamine (17.9 μL, 0.11 mmol, 0.2 equiv), copper(I) iodide (10.8 mg, 0.06 mmol, 0.1 equiv) tribasic, potassium phosphate (240 mg, 1.13 mmol, 2 equiv), and 1,4-dioxane (8 mL), and the vessel was evacuated, flushed with nitrogen, and then heated under microwave irradiation at 150°C for 1 h. The reaction was diluted with ethyl acetate, filtered through Celite, washed with brine, dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 12g RediSep) eluted with a gradient of 0-100% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a beige solid (18 mg, 0.06 mmol, 10%). LC / MS (C 13 H 13 ClN4O2S) 325 [M+H] +; Retention time 2.32 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 4.41 (dd, J = 8.8, 7.6 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 3.34 - 3.27 (m, 2H), 2.29 (d, J = 1.2 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H).

[0302] Project C : Ethyl 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,3-thiazole-4-carboxylate To an oven-dried microwave vial was added the product of Step B (27 mg, 0.08 mmol, 1 equiv), 2-aminobenzothiazole (18.7 mg, 0.12 mmol, 1.5 equiv), Xantphos (9.62 mg, 0.02 mmol, 0.2 equiv), cesium carbonate (54.2 mg, 0.17 mmol, 2 equiv), and 1,4-dioxane (4 mL), the vessel was evacuated and flushed with nitrogen, then tris(dibenzylideneacetone)dipalladium(0) (7.61 mg, 0.01 mmol, 0.1 equiv) was added, and the mixture was sparged with nitrogen (10 min) and then heated under microwave irradiation at 150° C. for 1 h. The reaction was diluted with ethyl acetate, filtered through Celite, then washed with brine, dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 4g RediSep) eluted with a gradient of 0-100% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a yellow solid (15 mg, 0.03 mmol, 41%). LC / MS (C 20 H 18 N6O2S2) 439 [M+H] + ; retention time 2.67 (LCMS-VC) 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.88 (s, 1H), 7.53 (br s, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 4.38 (t, J = 8.0 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 3.32 - 3.21 (m, 2H), 2.33 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H).

[0303] Project D 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,3-thiazole-4-carboxylic acid To a solution of the product of Step C (15 mg, 0.03 mmol, 1 equiv.) in 1,4-dioxane (2 mL) was added lithium hydroxide monohydrate (5.74 mg, 0.14 mmol, 4 equiv.) and the mixture was heated at reflux for 3 h. The reaction was concentrated under reduced pressure, dissolved in methanol, loaded onto a methanol-washed PE-AX cartridge (5 g), washed with methanol, eluted with 9:1 dichloromethane / formic acid, and concentrated in vacuo. The residue was triturated with dichloromethane, filtered, and dried under vacuum to give the desired product as a cream-colored solid (9.03 mg, 0.02 mmol, 64%). HRMS-ESI (m / z) [M+H]+ C 18 H 15 Calculated value of N6O2S2: 411.0698, found value 411.0701.

[0304] Example 12 : 2-{3-[(1,3-benzothiazol-2-yl)amino]-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}-1,3-thiazole-4-carboxylic acid [ka] Project A: Pent-4-yn-1-yl methanesulfonate To a solution of 4-pentyn-1-ol (3.32 mL, 35.7 mmol, 1 equiv) in dichloromethane (60 mL) was added triethylamine (6.45 mL, 46.4 mmol, 1.3 equiv), and the mixture was cooled to 0 °C before adding methanesulfonyl chloride (3.31 mL, 42.8 mmol, 1.2 equiv) dropwise and stirring at ambient temperature overnight. The reaction was partitioned between dichloromethane and water, and the organic phase was washed successively with saturated sodium bicarbonate and brine, dried (magnesium sulfate), and concentrated in vacuo to give the desired product as an amber oil (5.8 g, 35.8 mmol, 100%). 1 H NMR (400 MHz, DMSO-d6) δ 4.26 (t, J = 6.2 Hz, 2H), 3.19 (s, 3H), 2.88 (t, J = 2.7 Hz, 1H), 2.29 (td, J = 7.1, 2.7 Hz, 2H), 1.91 - 1.80 (m, 2H).

[0305] Project B : 5-Azidopent-1-yne To a solution of the product of Step A (5.8 g, 35.8 mmol, 1 equiv) in dimethylformamide (30 mL) was added sodium azide (5.81 g, 89.4 mmol, 2.5 equiv) and the mixture was heated at 70° C. for 3 h. The reaction was diluted with water, the aqueous phase was extracted with diethyl ether (×3), and the combined organics were dried (magnesium sulfate) and concentrated in vacuo to give the desired product as a yellow oil (5.65 g, 51.8 mmol, >100%). 1 H NMR (400 MHz, DMSO-d6) δ 3.42 (t, J = 6.7 Hz, 2H), 2.85 (t, J = 2.7 Hz, 1H), 2.25 (td, J = 7.0, 2.7 Hz, 2H), 1.75 - 1.64 (m, 2H).

[0306] Project C : Pent-4-yn-1-amine A solution of the product of Step B (3.9 g, 35.7 mmol, 1 equiv) in diethyl ether (40 mL) was cooled to 0 °C, triphenylphosphine (14.1 g, 53.6 mmol, 1.5 equiv) was added, and the reaction was stirred at 0 °C for 6 h. The reaction was quenched by the addition of water (5 mL) and stirred at ambient temperature overnight. The mixture was poured into 4 N aqueous hydrochloric acid (300 mL) and extracted with diethyl ether (x3). The aqueous phase was basified by the addition of sodium hydroxide in small portions and further extracted with diethyl ether (x2). The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to give the desired product as a yellow oil (1.51 g, 18.16 mmol, 51%). 1 H NMR (400 MHz, DMSO-d6) δ 2.73 (t, 1H), 2.58 (t, J = 6.7 Hz, 2H), 2.19 (td, J = 7.2, 2.7 Hz, 2H), 1.55 - 1.44 (m, 2H).

[0307] Project D : Ethyl 2-[(pent-4-yn-1-yl)amino]-1,3-thiazole-4-carboxylate To a solution of ethyl 2-bromo-1,3-thiazole-4-carboxylate (750 mg, 3.18 mmol, 1 equiv.) in acetonitrile (15 mL) was added the product of Step C (396 mg, 4.77 mmol, 1.5 equiv.) and triethylamine (0.66 mL, 4.77 mmol, 1.5 equiv.), and the mixture was heated under microwave irradiation at 150°C for 10 h. The reaction was partitioned between ethyl acetate and brine, and the organic phase was dried (MgSO4) and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 24 g RediSep 1000) eluted with a gradient of 0-50% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a colorless solid (263 mg, 1.1 mmol, 35%). LC / MS (C 11 H 14 N2O2S) 239 [M+H] +; Retention time 2.20 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 7.84 (t, J = 5.4 Hz, 1H), 7.51 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.28 (td, J = 6.9, 5.4 Hz, 2H), 2.82 (t, J = 2.6 Hz, 1H), 2.25 (td, J = 7.1, 2.7 Hz, 2H), 1.73 (p, J = 7.0 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H).

[0308] Project E : Ethyl 2-{3-chloro-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}-1,3-thiazole-4-carboxylate To a solution of 3,6-dichloro-1,2,4,5-tetrazine (103 mg, 0.68 mmol, 1 equiv.) in tetrahydrofuran (12 mL) was added the product of Step D (163 mg, 0.68 mmol, 1 equiv.), and the mixture was heated at 90 °C overnight. Automated flash column chromatography (CombiFlash Rf, 24 g RediSep 1000) eluted with a gradient of 0 to 70% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as an off-white solid (141 mg, 0.43 mmol, 64%). LC / MS (C 13 H 13 ClN4O2S) 325 [M+H] + ; retention time 2.42 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.77 - 7.71 (m, 1H), 4.40 - 4.33 (m, 2H), 4.30 (q, 2H), 2.94 (t, J = 6.1 Hz, 2H), 2.11 - 2.00 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H).

[0309] Project F : Ethyl 2-{3-[(1,3-benzothiazol-2-yl)amino]-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}-1,3-thiazole-4-carboxylate To an oven-dried microwave vial was added the product of Step E (141 mg, 0.43 mmol, 1 equiv), 2-aminobenzothiazole (97.8 mg, 0.65 mmol, 1.5 equiv), Xantphos (50.2 mg, 0.09 mmol, 0.2 equiv), cesium carbonate (283 mg, 0.87 mmol, 2 equiv), and 1,4-dioxane (15 mL), the vessel was evacuated and flushed with nitrogen, then tris(dibenzylideneacetone)dipalladium(0) (39.8 mg, 0.04 mmol, 0.1 equiv) was added, and the mixture was sparged with nitrogen (10 min) and then heated under microwave irradiation at 150° C. for 2 h. The reaction was diluted with ethyl acetate, filtered through Celite, washed with brine, dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 12g RediSep) eluted with a gradient of 0-100% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a yellow solid (29 mg, 0.07 mmol, 15%). LC / MS (C 20 H 18 N6O2S2) 439 [M+H] + ; retention time 2.64 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 8.02 (s, 1H), 7.98 (d, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.42 (dt, J = 15.0, 7.2 Hz, 1H), 7.35 (s, 1H), 7.23 (t, J = 7.5 Hz, 1H), 4.41 - 4.24 (m, 4H), 2.96 (t, 2H), 2.12 - 2.02 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H).

[0310] Project G : 2-{3-[(1,3-benzothiazol-2-yl)amino]-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}-1,3-thiazole-4-carboxylic acid To a solution of the product of Step F (29 mg, 0.07 mmol, 1 equiv.) in 1,4-dioxane (6 mL) was added lithium hydroxide monohydrate (13.9 mg, 0.33 mmol, 5 equiv.) and the mixture was heated at reflux for 5 h. The reaction was concentrated under reduced pressure, dissolved in methanol, and then loaded onto a methanol-washed PE-AX cartridge (5 g), washed with methanol, eluted with 9:1 dichloromethane / formic acid, and concentrated under reduced pressure. The residue was triturated with dichloromethane, filtered, and dried under vacuum to give the desired product as the formate salt as a cream-colored solid (9.86 mg, 0.02 mmol, 36%). HRMS-ESI (m / z) [M+H]+ C 18 H 15 Calculated N6O2S2: 411.0698, Found: 411.0722

[0311] Example 13 5-{1-[(adamantan-1-yl)methyl]-5-methyl-1H-pyrazol-4-yl}-2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,3-thiazole-4-carboxylic acid [ka] Project A Ethyl 5-{1-[(adamantan-1-yl)methyl]-5-methyl-1H-pyrazol-4-yl}-2-(4-methyl-3-{[(2Z)-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1,3-benzothiazol-2-ylidene]amino}-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl)-1,3-thiazole-4-carboxylate To an oven-dried microwave vial was added the product of Preparation 6a (98 mg, 0.15 mmol, 1 equiv.), the product of Preparation 5a (64.7 mg, 0.18 mmol, 1.2 equiv.), potassium carbonate (62.7 mg, 0.45 mmol, 3 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11.1 mg, 0.02 mmol, 0.1 equiv.), tetrahydrofuran (3 mL), and water (1 mL). The mixture was sparged with nitrogen (10 min) and then heated at 120 °C under microwave irradiation for 1 h. The reaction was partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 12 g RediSep 1000 rF ... 商標 Purification by silica cartridge) gave the desired product as a cream solid (57 mg, 0.07 mmol, 47%). 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (d, 1H), 7.56 (s, 1H), 7.48 - 7.38 (m, 2H), 7.27 - 7.20 (m, 1H), 5.85 (s, 2H), 4.37 (t, J = 8.1 Hz, 2H), 4.17 (q, J = 7.1 Hz, 2H), 3.79 (s, 2H), 3.76 - 3.67 (m, 2H), 3.45 - 3.36 (m, 2H), 2.34 (s, 3H), 2.23 (s, 3H), 2.02 - 1.90 (m, 3H), 1.73 - 1.52 (m, 12H), 1.16 (t, 3H), 0.96 - 0.87 (m, 2H), -0.11 (s, 9H).

[0312] Project B : Ethyl 5-{1-[(adamantan-1-yl)methyl]-5-methyl-1H-pyrazol-4-yl}-2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,3-thiazole-4-carboxylate To a cooled solution of the product of Step A (57 mg, 0.07 mmol, 1 equiv.) in dichloromethane (6 mL) was added trifluoroacetic acid (0.6 mL), and after 10 min the mixture was allowed to warm to ambient temperature and stirred overnight. The reaction was partitioned between dichloromethane and saturated aqueous sodium bicarbonate, dried (PTFE phase separator), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 4g RediSep 2000) eluted with a gradient of 0-100% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a yellow solid (17 mg, 0.03 mmol, 36%). LC / MS (C 35 H 38 N8O2S2) 667 [M+H] + ; Retention time 1.55 (LCMS-V-B2) 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 7.6 Hz, 1H), 7.62 - 7.44 (m, 2H), 7.42 - 7.31 (m, 1H), 7.20 (t, J = 7.6 Hz, 1H), 4.37 (t, J = 8.1 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.80 (s, 2H), 3.34 - 3.24 (m, 2H), 2.34 (d, J = 3.4 Hz, 3H), 2.24 (s, 3H), 2.02 - 1.93 (m, 3H), 1.74 - 1.51 (m, 12H), 1.18 (t, 3H).

[0313] Project C 5-{1-[(adamantan-1-yl)methyl]-5-methyl-1H-pyrazol-4-yl}-2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,3-thiazole-4-carboxylic acid To a solution of the product of Step B (17 mg, 0.03 mmol, 1 equiv.) in 1,4-dioxane (6 mL) was added lithium hydroxide monohydrate (10.7 mg, 0.25 mmol, 10 equiv.) and the mixture was heated at reflux for 5 h. The reaction was concentrated in vacuo, dissolved in methanol, loaded onto a methanol-washed PE-AX cartridge (5 g), washed with methanol, eluted with 9:1 dichloromethane / formic acid, and concentrated in vacuo. The residue was triturated with diethyl ether and acetonitrile, filtered, and dried under reduced pressure to give the desired product as a beige solid (2.4 mg, 3.7 μmol, 15%). HRMS-ESI (m / z) [M+H]+ C 33 H 35 Calculated value of N8O2S2: 639.2324, Measured value: 639.2310

[0314] Example 14 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl}-5-(1-{[1-(3-methoxypropyl)cyclooctyl]methyl}-5-methyl-1H-pyrazol-4-yl)-1,3-thiazole-4-carboxylic acid [ka] Project A Ethyl 5-(1-{[1-(3-methoxypropyl)cyclooctyl]methyl}-5-methyl-1H-pyrazol-4-yl)-2-(4-methyl-3-{[(2Z)-3-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1,3-benzothiazol-2-ylidene]amino}-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl)-1,3-thiazole-4-carboxylate To an oven-dried microwave vial was added the product of Preparation 6a (34 mg, 0.05 mmol, 1 equiv.), the product of Preparation 5b (25.5 mg, 0.06 mmol, 1.2 equiv.), potassium carbonate (21.8 mg, 0.16 mmol, 3 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.84 mg, 0.01 mmol, 0.1 equiv.), tetrahydrofuran (3 mL), and water (1 mL). The mixture was sparged with nitrogen (10 min) and then heated at 120 °C under microwave irradiation for 1 h. The reaction was partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 4g RediSep) eluting with a gradient of 0-50% ethyl acetate in isoheptane was performed. 商標 Purification by silica cartridge) gave the desired product as a white solid (29 mg, 0.03 mmol, 65%). LC / MS (C 43 H 60 N8O4SiS2) 845 [M+H] + ; Retention time 1.79 (LCMS-V-B2) 1 H NMR (400 MHz, DMSO-d6) δ 7.77 (d,1 H), 7.58 (s, 1H), 7.49 - 7.38 (m, 2H), 7.27 - 7.19 (m, 1H), 5.85 (s, 2H), 4.37 (t, J = 8.2 Hz, 2H), 4.17 (q, J = 7.1 Hz, 2H), 3.85 (s, 2H), 3.77 - 3.66 (m, 2H), 3.45 - 3.34 (m, 2H), 3.31 - 3.26 (m, 4H), 3.23 (s, 3H), 2.33 (s, 3H), 2.22 (s, 3H), 1.74 - 1.48 (m, 8H), 1.47 - 1.20 (m, 8H), 1.18 (t, 3H), 0.96 - 0.87 (m, 2H), -0.11 (s, 9H).

[0315] Project B: Ethyl 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl}-5-(1-{[1-(3-methoxypropyl)cyclooctyl]methyl}-5-methyl-1H-pyrazol-4-yl)-1,3-thiazole-4-carboxylate To a cooled solution of the product of Step A (29 mg, 0.03 mmol, 1 equiv.) in dichloromethane (5 mL) was added trifluoroacetic acid (0.9 mL), and after 10 min, the mixture was allowed to warm to ambient temperature and stirred overnight. The reaction was partitioned between dichloromethane and saturated aqueous sodium bicarbonate, dried (PTFE phase separator), and concentrated in vacuo to give the desired product as a yellow solid (13 mg, 0.02 mmol, 54%). LC / MS (C 37 H 46 N8O3S2) 715 [M+H] + ; Retention time 1.59 (LCMS-V-B2) 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.59 (br s + s, 2H), 7.37 (t, 1H), 7.20 (t, J = 7.6 Hz, 1H), 4.37 (t, J = 8.1 Hz, 2H), 4.19 (q, J = 7.0 Hz, 2H), 3.87 (s, 2H), 3.34 - 3.26 (m, 6H), 3.25 (s, 3H), 2.34 (s, 3H), 2.23 (s, 3H), 1.73 - 1.49 (m, 8H), 1.48 - 1.21 (m, 8H), 1.18 (t, 3H).

[0316] Project C 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl}-5-(1-{[1-(3-methoxypropyl)cyclooctyl]methyl}-5-methyl-1H-pyrazol-4-yl)-1,3-thiazole-4-carboxylic acid To a solution of the product of Step B (13 mg, 0.02 mmol, 1 equiv) in 1,4-dioxane (3 mL) was added lithium hydroxide monohydrate (11.5 mg, 0.27 mmol, 15 equiv) and the mixture was heated at reflux for 5 h. The reaction was concentrated under reduced pressure, and the residue was triturated with water, filtered, and dried under vacuum to give the desired product as the lithium salt (5.64 mg, 0.01 mmol, 45%) as a yellow solid. HRMS-ESI (m / z) [M+H]+ C 35 H 43 Calculated value for N8O3S2: 687.2900, Found value: 687.2932

[0317] Example 15 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}-1,3-thiazole-4-carboxylic acid [ka] Project A 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}-1,3-thiazole-4-carboxylic acid To a solution of the product of Preparation 3f (24 mg, 0.05 mmol, 1 equiv.) in 1,4-dioxane (6 mL) was added lithium hydroxide monohydrate (33.4 mg, 0.8 mmol, 15 equiv.), and the mixture was heated at reflux for 7 h. The reaction was concentrated under reduced pressure, then dissolved in methanol, loaded onto a methanol-wet PE-AX cartridge (5 g), washed with methanol, eluted with 9:1 dichloromethane / formic acid, and concentrated in vacuo. The residue was triturated with dichloromethane, filtered, and dried under vacuum to give the desired product as the formate salt as a beige solid (13.5 mg, 0.03 mmol, 60%). HRMS-ESI (m / z) [M+H]+ C 19 H 17 Calculated N6O2S2: 425.0854, Found 425.0845.

[0318] Example 16 2-{3-[(1,3-benzothiazol-2-yl)amino]-6-methyl-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,3-thiazole-4-carboxylic acid [ka] Project A : Ethyl 2-[(pent-4-yn-2-yl)amino]-1,3-thiazole-4-carboxylate To a solution of ethyl 2-bromo-1,3-thiazole-4-carboxylate (1.87 g, 7.93 mmol, 1 equiv.) in acetonitrile (18 mL) was added pent-4-yn-2-amine (989 mg, 11.9 mmol, 1.5 equiv.) and triethylamine (1.66 mL, 11.9 mmol, 1.5 equiv.), and the mixture was heated in a sealed tube at 170 °C overnight. The reaction was partitioned between ethyl acetate and brine, and the organic phase was dried (magnesium sulfate) and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 40 g RediSep 1000) eluted with a gradient of 0-50% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a yellow oil (555 mg, 2.33 mmol, 29%). LC / MS (C 11 H 14 N2O2S) 239 [M+H] + ; Retention time 2.21 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 7.4 Hz, 1H), 7.51 (s, 1H), 4.27 (q, 2H), 3.91 - 3.79 (m, 1H), 2.89 (t, J = 2.6 Hz, 1H), 2.51 - 2.45 (m, 1H), 2.44 - 2.41 (m, 1H), 1.30 - 1.21 (m, 6H).

[0319] Project B : Ethyl 2-{3-chloro-6-methyl-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,3-thiazole-4-carboxylate To a solution of 3,6-dichloro-1,2,4,5-tetrazine (352 mg, 2.33 mmol, 1 equiv.) in tetrahydrofuran (15 mL) was added the product of Step A (555 mg, 2.33 mmol, 1 equiv.) and the mixture was heated at reflux overnight. The reaction was concentrated in vacuo and purified by automated flash column chromatography (CombiFlash Rf, 24 g RediSep 2000) eluting with a gradient of 0-100% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave the desired product as a red solid (124 mg, 0.38 mmol, 16%). LC / MS (C 13 H 13 ClN4O2S) 325 [M+H] + ; Retention time 2.39 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.71 (t, J = 1.6 Hz, 1H), 5.11 - 4.97 (m, 1H), 4.31 (q, J = 7.1, 1.4 Hz, 2H), 3.65 - 3.53 (m, 1H), 3.00 - 2.88 (m, 1H), 1.50 (d, J = 6.3 Hz, 3H), 1.31 (t, 3H).

[0320] Project C : Ethyl 2-{3-[(1,3-benzothiazol-2-yl)amino]-6-methyl-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,3-thiazole-4-carboxylate To an oven-dried microwave vial was added the product of Step B (124 mg, 0.38 mmol, 1 equiv), 2-aminobenzothiazole (86 mg, 0.57 mmol, 1.5 equiv), Xantphos (44.2 mg, 0.08 mmol, 0.2 equiv), cesium carbonate (249 mg, 0.76 mmol, 2 equiv), 1,4-dioxane (4 mL), and tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.04 mmol, 0.1 equiv), and the mixture was sparged with nitrogen (10 min) and then heated under microwave irradiation at 150° C. for 2 h. The reaction was diluted with ethyl acetate, filtered through Celite, then washed with brine, dried (magnesium sulfate), and concentrated in vacuo. Automated flash column chromatography (CombiFlash Rf, 24g RediSep) eluted with a gradient of 0-100% ethyl acetate in isoheptane. 商標 Purification by silica cartridge) gave a solid which was triturated with diethyl ether, filtered and dried under reduced pressure to give the desired product as a beige solid (37 mg, 0.08 mmol, 22%). LC / MS (C 20 H 18 N6O2S2) 439 [M+H] + ; Retention time 2.62 (LCMS-VC) 1 H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.07 (s, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.44 - 7.37 (m, 1H), 7.36 (s, 1H), 7.23 (td, J = 7.6, 1.1 Hz, 1H), 5.07 - 4.95 (m, 1H), 4.31 (q, 2H), 3.65 - 3.52 (m, 1H), 3.03 - 2.93 (m, 1H), 1.49 (d, J = 6.3 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H).

[0321] Project D2-{3-[(1,3-benzothiazol-2-yl)amino]-6-methyl-5H,6H,7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,3-thiazole-4-carboxylic acid To a solution of the product of Step C (37 mg, 0.08 mmol, 1 equiv.) in 1,4-dioxane (8 mL) was added lithium hydroxide monohydrate (53.1 mg, 1.27 mmol, 15 equiv.) and the mixture was heated at reflux for 7 h. The reaction was concentrated in vacuo, dissolved in methanol, and then loaded onto a methanol-wet PE-AX cartridge (10 g), washed with methanol, eluted with 9:1 dichloromethane / formic acid, and concentrated in vacuo. The residue was triturated with dichloromethane, filtered, and dried under reduced pressure to give the desired product as the formate salt as a beige solid (24.8 mg, 0.06 mmol, 72%). HRMS-ESI (m / z) [M+H]+ ...

Claims

1. Formula (IA): 【Chemistry 1】 [In the formula, n=0, 1 or 2; --- represents a single bond or a double bond, A ４ and A ５ each independently represents a carbon atom or a nitrogen atom, Z １ represents a bond, —N(R)— or —O—, where R is hydrogen or a straight or branched chain C １ -C ６ represents alkyl, R １ is hydrogen; optionally hydroxyl or C １ -C ６ A straight or branched chain C substituted with an alkoxy group １ -C ６ Alkyl; C ３ -C ６ Cycloalkyl; trifluoromethyl; straight or branched chain C １ -C ６ alkylene-heterocycloalkyl, wherein the heterocycloalkyl group is optionally a linear or branched C １ -C ６ is substituted with an alkyl group, R ２ represents hydrogen or methyl, R ３ is hydrogen; -X １ -NR ａ R ｂ ;-X １ represents a group selected from —O—Rc R ａ and R ｂ are each independently hydrogen; heterocycloalkyl; ２ -phenyl, wherein the phenyl is a straight or branched C １ -C ６ alkyl); straight or branched chain C optionally substituted by one or two hydroxyl groups １ -C ６ Alkyl; C １ -C ６ Alkylene-SO ２ OH;C １ -C ６ Alkylene-SO ２ O － ; C １ -C ６ Alkylene-COOH; C １ -C ６ Alkylene-PO(OH) ２ ; C １ -C ６ Alkylene -NR ｄ R ｅ ; C １ -C ６ Alkylene-N ＋ R ｄ R ｅ R ｆ ; C １ -C ６ Alkylene-phenyl, wherein the phenyl is C １ -C ６ optionally substituted by an alkoxy group); 【Chemistry 2】 represents a group selected from or R ａ and R ｂ together with the nitrogen atom carrying them form ring B １ It forms or R ａ , R ｂ and R ｃ together with the nitrogen atoms carrying them form a bridged C ３ -C ８ forming a heterocycloalkyl, R ｃ , R ｄ , R ｅ , R ｆ are each independently hydrogen or a straight or branched chain C １ -C ６ represents an alkyl group, or R ｄ and R ｅ together with the nitrogen atom carrying them form ring B ２ It forms or R ｄ , R ｅ and R ｆ together with the nitrogen atoms carrying them form a bridged C ３ -C ８ forming a heterocycloalkyl, Het １ is below: 【Transformation 3】 represents a group of Het ２ is below: 【Chemistry 4】 represents a group selected from A １ is S, A ２ is CH, G is -C(O)OR Ｇ３ , —C(O)NR Ｇ１ R Ｇ２ , -C(O)R Ｇ２ , and -NR Ｇ１ C(O)R Ｇ２ selected from the group consisting of where: R Ｇ１ and R Ｇ２ each occurrence independently represents a C optionally substituted by hydrogen and 1 to 3 halogen atoms; １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, phenyl and -(CH ２ ) １－４ -phenyl, R Ｇ３ is C optionally substituted by 1 to 3 halogen atoms １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, phenyl and -(CH ２ ) １－４ -phenyl, or R Ｇ１ and R Ｇ２ together with the atoms to which they are attached, ３ -C ８ are linked to form a heterocycloalkyl; Or alternatively, G is 【Transformation 5】 [In the formula, R Ｇ４ is C optionally substituted by 1 to 3 halogen atoms １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl and C ３ -C ６ cycloalkyl] selected from the group consisting of R ４ represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, R ５ is C optionally substituted by 1 to 3 halogen atoms １ -C ６ Alkyl; C ２ -C ６ Alkenyl; C ２ -C ６ alkynyl; halogen or -CN, R ６ teeth, hydrogen; -C ２ -C ６ Alkenyl; -X ２ -O-R ７ ; 【Transformation 6】 ； -X ２ -NSO ２ -R ７ ; -C=C(R ９ )-Y １ -O-R ７ ; C ３ -C ６ cycloalkyl; C optionally substituted with a hydroxyl group ３ -C ６ heterocycloalkyl; C ３ -C ６ Cycloalkylene-Y ２ -R ７ ; C ３ -C ６ Heterocycloalkylene-Y ２ -R ７ Base; Optionally, linear or branched chain C １ -C ６ Heteroarylene-R substituted with alkyl groups ７ base represents a group selected from R ７ is a straight or branched chain C １ -C ６ Alkyl group; (C ３ -C ６ ) Cycloalkylene-R ８ ; or 【Transformation 7】 [Wherein Cy is C ３ -C ８ represents cycloalkyl] represents a group selected from R ８ is hydrogen; straight or branched chain C １ -C ６ Alkyl; —NR′ ａ R' ｂ -NR' ａ -CO-OR' ｃ -NR' ａ -CO-R' ｃ ;-N ＋ R' ａ R' ｂ R' ｃ ;-O-R' ｃ -NH-X' ２ -N ＋ R' ａ R' ｂ R' ｃ ;-O-X' ２ -NR' ａ R' ｂ ;-X' ２ -NR' ａ R' ｂ -NR' ｃ -X' ２ -N ３ and 【Transformation 8】 represents a group selected from R ９ is a linear or branched chain C １ -C ６ Alkyl, trifluoromethyl, hydroxyl, halogen, C １ -C ６ alkoxy, R １０ is hydrogen, fluorine, chlorine, bromine, -CF ３ and methyl, R １１ is hydrogen, halogen, C １ -C ３ Alkylene-R ８ , —O—C １ -C ３ Alkylene-R ８ , —CO—NR ｈ R ｉ , -CH=CH-C １ -C ４ Alkylene -NR ｈ R ｉ , -CH=CH-CHO,C ３ -C ８ Cycloalkylene -CH ２ -R ８ , C ３ -C ８ Heterocycloalkylene -CH ２ -R ８ represents a group selected from R １２ and R １３ each independently represents a hydrogen atom or a methyl group; R １４ and R １５ each independently represents a hydrogen atom or a methyl group, or R １４ and R １５ together with the carbon atom carrying them form a cyclohexyl, R ｈ and R ｉ are each independently hydrogen or a straight or branched chain C １ -C ６ represents an alkyl group, X １ is optionally selected from trifluoromethyl, hydroxyl, halogen, C １ -C ６ A straight or branched chain C substituted with one or two groups selected from alkoxy １ -C ４ represents an alkylene group, X ２ is optionally selected from trifluoromethyl, hydroxyl, halogen, C １ -C ６ A straight or branched chain C substituted with one or two groups selected from alkoxy １ -C ６ represents an alkylene group, X' ２ is a linear or branched chain C １ -C ６ represents alkylene, R' ａ and R' ｂ are each independently hydrogen; heterocycloalkyl; ２ -phenyl (wherein the phenyl is a straight or branched C １ -C ６ optionally substituted by one or two hydroxyl or C １ -C ６ A straight or branched chain C substituted with an alkoxy group １ -C ６ Alkyl; C １ -C ６ Alkylene-SO ２ OH;C １ -C ６ Alkylene-SO ２ O － ; C １ -C ６ Alkylene-COOH; C １ -C ６ Alkylene-PO(OH) ２ ; C １ -C ６ Alkylene-NR' ｄ R' ｅ ; C １ -C ６ Alkylene-N ＋ R ｄ 'R' ｅ R' ｆ ; C １ -C ６ Alkylene -O-C １ -C ６ Alkylene-OH; C １ -C ６ Alkylene-phenyl, wherein the phenyl is selected from the group consisting of hydroxyl and C １ -C ６ optionally substituted by an alkoxy group); 【Chemistry 9】 represents a group selected from or R' ａ and R' ｂ together with the nitrogen atom carrying them form ring B ３ It forms or R' ａ , R' ｂ and R' ｃ together with the nitrogen atoms carrying them form a bridged C ３ -C ８ forming a heterocycloalkyl, R' ｃ , R' ｄ , R' ｅ , R' ｆ are each independently hydrogen or a straight or branched chain C １ -C ６ represents an alkyl group, or R' ｄ and R' ｅ together with the nitrogen atom carrying them form ring B ４ It forms or R' ｄ , R' ｅ and R' ｆ together with the nitrogen atoms carrying them form a bridged C ３ -C ８ forming a heterocycloalkyl, Y １ is a linear or branched chain C １ -C ４ represents alkylene, Y ２ represents bonding, -O-, -O-CH ２ -, -O-CO-, -O-SO ２ -, -CH ２ -, -CH ２ -O-, -CH ２ -CO-, -CH ２ -SO ２ -, -C ２ H ５ -, -CO-, -CO-O-, -CO-CH ２ -, -CO-NH-CH ２ -, -SO ２ -, -SO ２ -CH ２ -, -NH-CO-, or -NH-SO ２ - and represents m=0, 1 or 2; p=1, 2, 3 or 4; B １ , B ２ , B ３ and B ４ are each independently C ３ -C ８ represents a heterocycloalkyl group, which (i) can be a monocyclic or bicyclic group, where the bicyclic group includes fused, bridged, or spiro ring systems; (ii) can contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur, and nitrogen; and (iii) can be selected from fluorine, bromine, chlorine, straight- or branched-chain C １ -C ６ Alkyl, hydroxyl, -NH ２ , oxo, or piperidinyl. a compound represented by its enantiomers or diastereoisomers, or addition salts thereof with pharmaceutically acceptable acids or bases.

2. A ４ and A ５ 2. The compound according to claim 1, wherein each represents a nitrogen atom, its enantiomers or diastereoisomers, or addition salts thereof with a pharmaceutically acceptable acid or base.

3. Z １ 3. The compound according to claim 1 or 2, wherein represents --NH-- or --O--, its enantiomers or diastereoisomers, or addition salts thereof with a pharmaceutically acceptable acid or base.

4. R ３ But, -X １ -NR ａ R ｂ 4. The compound according to any one of claims 1 to 3, its enantiomers or diastereoisomers, or addition salts thereof with a pharmaceutically acceptable acid or base, which represents:

5. R ３ is the group -C ２ H ５ -NH-CH ３ 5. The compound according to claim 4, which represents: or an enantiomer or diastereoisomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base.

6. the below described: 【Chemistry 10】 2. The compound according to claim 1, an enantiomer or diastereoisomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base, selected from:

7. Formula (IB): 【Chemistry 11】 7. The compound according to claim 6, which is a compound of the formula: or an enantiomer or diastereoisomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base.

8. R １ A compound according to any one of claims 1 to 7, wherein represents a hydrogen atom, a methyl or a cyclopropyl group, an enantiomer or diastereoisomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base.

9. R １ 9. The compound according to claim 8, wherein represents methyl, its enantiomers or diastereoisomers, or addition salts thereof with a pharmaceutically acceptable acid or base.

10. Het １ but, 【Chemistry 12】 10. The compound according to any one of claims 1 to 9, its enantiomers or diastereoisomers, or addition salts thereof with a pharmaceutically acceptable acid or base, which represents:

11. Het ２ but, 【Chemistry 13】 11. The compound according to any one of claims 1 to 10, wherein the compound represents an enantiomer or diastereoisomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base.

12. Het ２ but, 【Chemistry 14】 11. The compound according to any one of claims 1 to 10, wherein the compound represents an enantiomer or diastereoisomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base.

13. R ６ But, -X ２ -O-R ７ represents a group, where X ２ is a propylene group, its enantiomers or diastereoisomers, or addition salts thereof with a pharmaceutically acceptable acid or base.

14. R ７ is the following group: 【Chemistry 15】 14. The compound of claim 13, wherein:

15. R ７ is the following group: 【Chemistry 16】 14. The compound of claim 13, wherein:

16. R ８ dimethylamino, diethylamino, diisopropylamino, diisobutylamino, methylamino, ethylamino, ethyl(methyl)amino, 4-methyl-piperazin-1-yl, piperazin-1-yl, pyrrolidin-1-yl, azetidin-1-yl, 1-piperidyl, 4-morpholinyl, 4,4-difluoropiperidin-1-yl, 3,3-difluoropiperidin-1-yl, 3-hydroxy-1-piperidyl, (1S,5R)-3-azabicyclo[3.1.0]hexan-3-yl, 4-(1-piperidyl)-1-piperidyl, 3-oxo-2,8-diazaspiro[4.5]decan-8-yl, (1S,5R)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl, 2-(dimethylamino)ethylamino, 3-piperazin-1-yl, (3R,5S)-3,5-dimethylpiperazin-1-yl, (but-3-yn-1-yl)amino, (but-3-yn-1-yl)(methyl)amino, (3-azidopropyl)amino, (3-azidopropyl)(methyl)amino, (3-aminopropyl)amino, (pent-4-yn-1-yl)amino, methyl(pent-4-yn-1-yl)amino, (prop-2-yn-1-yl)amino, (hex-5-yn-1-yl)amino, 3-[(hex-5-yn-1-yl)(methyl)amino, (4-azidobutyl)amino, (4-azidobutyl)(methyl)amino, [2-(2-hydroxyethoxy)ethyl](methyl)amino, and 【Chemistry 17】 16. A compound according to claim 14 or 15, wherein R represents a group selected from the group consisting of:

17. R ８ represents a group selected from bis[(3S)-3,4-dihydroxybutyl]amino, amino, [(3S)-3,4-dihydroxybutyl]amino, [(3R)-3,4-dihydroxybutyl]amino, acetyl(methyl)amino, 3-hydroxypropylamino, its enantiomers or diastereoisomers, or addition salts thereof with a pharmaceutically acceptable acid or base according to claim 14 or 15.

18. R ７ but, [Chemistry 18] [In the formula, R １１ is selected from 3-(dimethylamino)propyl, 3-(methylamino)propyl, aminomethyl, 2-(dimethylamino)ethyl, 4-(dimethylamino)butyl, 2-(methylamino)ethyl, 4-(methylamino)butyl, 3-(azetidin-1-yl)propyl, 3-(4-methylpiperazin-1-yl)propyl, 3-pyrrolidin-1-ylpropyl, 3-morpholinopropyl, 3-(1-piperidyl)propyl, 3-[(1R,5S)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl, and 3-(3-oxo-2,8-diazaspiro[4.5]decan-8-yl)propyl] 14. The compound of claim 13, wherein:

19. R ７ but, 【Chemistry 19】 14. The compound of claim 13, wherein R represents a group selected from:

20. R ６ but, 【Chemistry 20】 13. The compound according to claim 12, which represents: or an enantiomer or diastereoisomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base.

21. R ７ but, 【Chemistry 21】 [In the formula, R ８ is hydrogen, 2-(methylamino)ethoxy, 2-(dimethylamino)ethoxy, 2-[(2-sulfoethyl)amino]ethoxy, 2-[methyl(2-sulfoethyl)amino]ethoxy, 4-methylpiperazin-1-yl, and 【Chemistry 22】 represents a group selected from 21. The compound of claim 20, wherein R represents a group selected from:

22. R ７ but, 【Chemistry 23】 [In the formula, R ８ 2-pyrrolidin-1-ylethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 2-[[(3R)-3,4-dihydroxybutyl]-methyl-amino]ethoxy, 2-(4-hydroxybutylamino)ethoxy, 2-[[3-hydroxy-2-(hydroxymethyl)propyl]amino]ethoxy, 2-[bis(2-hydroxyethyl)amino]ethoxy, 2-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino ]ethoxy, 2-[2-(2-hydroxyethoxy)ethylamino]ethoxy, 2-[bis(3-hydroxypropyl)amino]ethoxy, 2-(3-hydroxypropylamino)ethoxy, 2-[bis(4-hydroxybutyl)amino]ethoxy, 2-morpholinoethoxy, 2-(1-piperidyl)ethoxy, 2-piperazin-1-ylethoxy, 2-(azepan-1-yl)ethoxy, 2-(4-isopropylpiperazin-1-yl) Ethoxy, 2-[(4-hydroxyphenyl)methylamino]ethoxy, 2-[2-hydroxyethyl(methyl)amino]ethoxy, 2-[3-methoxypropyl(methyl)amino]ethoxy, 2-[4-hydroxybutyl(methyl)amino]ethoxy, 3-pyrrolidin-1-ylpropyl, 3-(dimethylamino)propyl, 3-(4-methylpiperazin-1-yl)propyl, 3-morpholinopropyl, 3-(3-hydroxypropylamino)propyl, 3-(4-hydroxybutylamino)propyl, 3-[[(3S)-3,4-dihydroxybutyl]amino]propyl, 3-hydroxy-2-(hydroxymethyl)propyl]amino]propyl, 3-[4-hydroxybutyl(methyl)amino]propyl, 3-[3-hydroxypropyl(methyl)amino]propyl, 3-[3-[bis(3-hydroxypropyl)amino]propyl, 3-piperazin-1-ylpropyl represents a group selected from 21. The compound of claim 20, wherein R represents a group selected from:

23. R ３ But, -X １ -NR ａ Rb, where R ａ Or R ｂ Or both of them are C １ -C ６ Alkylene-SO ２ OH, C １ -C ６ Alkylene-SO ２ O － and C １ -C ６ Alkylene-PO(OH) ２ 8. A compound according to any one of claims 1, 2 and 7, wherein R represents a group selected from:

24. R ８ But -NR' ａ R' ｂ , -N ＋ R ａ 'R' ｂ R' ｃ , or —NH—X′ ２ -N ＋ R' ａ R' ｂ R' ｃ where R' represents ａ and R' ｂ Or both of them are C １ -C ６ Alkylene-SO ２ OH and C １ -C ６ Alkylene-PO(OH) ２ 8. A compound according to any one of claims 1, 2 and 7, wherein R represents a group selected from:

25. The following groups: 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[4-[3-(dimethylamino)prop-1-ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylic acid, 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}-5-(3-{2-fluoro-4-[3-(methylamino)prop-1-yn-1-yl]phenoxy}propyl)-1,3-thiazole-4-carboxylic acid, 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}-5-(3-{4-[3-(dimethylamino)propyl]-2-fluorophenoxy}propyl)-1,3-thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[2-fluoro-4-[3-(4-methylpiperazin-1-yl)but-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[2-fluoro-4-(3-pyrrolidin-1-ylprop-1-ynyl)phenoxy]propyl]thiazole-4-carboxylic acid, 5-(3-{4-[3-(azetidin-1-yl)prop-1-yn-1-yl]-2-fluorophenoxy}propyl)-2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}-1,3-thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[2-fluoro-4-[3-(4-methylpiperazin-1-yl)prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid, 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}-5-(3-{4-[3-(4,4-difluoropiperidin-1-yl)prop-1-yn-1-yl]-2-fluorophenoxy}propyl)-1,3-thiazole-4-carboxylic acid, 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}-5-(3-{4-[3-(3,3-difluoropiperidin-1-yl)prop-1-yn-1-yl]-2-fluorophenoxy}propyl)-1,3-thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[2-fluoro-4-[3-(3-oxo-2,8-diazaspiro[4.5]decan-8-yl)prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[4-[3-[(1S,5R)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl]prop-1-ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[2-fluoro-4-(3-piperazin-1-ylprop-1-ynyl)phenoxy]propyl]thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[4-[3-[(3R,5S)-3,5-dimethylpiperazin-1-yl]prop-1-ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[4-[3-(diethylamino)prop-1-ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[4-[3-(diisopropylamino)prop-1-ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[4-[3-[2-(dimethylamino)ethylamino]prop-1-ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylic acid, 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-6-[2-(methylamino)ethoxy]-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}-5-(3-{4-[3-(dimethylamino)prop-1-yn-1-yl]-2-fluorophenoxy}propyl)-1,3-thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[4-[1-[(dimethylamino)methyl]-3-bicyclo[1.1.1]pentanyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[2-fluoro-4-[3-methyl-3-(methylamino)but-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[2-fluoro-4-[3-(prop-2-ynylamino)prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid, 6-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}-3-[1-({3-[2-(dimethylamino)ethoxy]-5,7-dimethyladamantan-1-yl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic acid, 6-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}-3-[1-({3,5-dimethyl-7-[2-(methylamino)ethoxy]adamantan-1-yl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic acid, 2-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}-5-(3-{4-[3-(ethylamino)-3-methylbut-1-yn-1-yl]-2-fluorophenoxy}propyl)-1,3-thiazole-4-carboxylic acid, and 3-{1-[(adamantan-1-yl)methyl]-5-methyl-1H-pyrazol-4-yl}-6-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl}pyridine-2-carboxylic acid 2. The compound according to claim 1, selected from the group consisting of: its enantiomers or diastereoisomers, or addition salts thereof with a pharmaceutically acceptable acid or base.

26. The following groups: 6-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}-3-[1-({3-[2-(dimethylamino)ethoxy]-5,7-dimethyladamantan-1-yl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic acid, 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3,5-dimethyl-7-(2-pyrrolidin-1-ylethoxy)-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3,5-dimethyl-7-[2-(4-methylpiperazin-1-yl)ethoxy]-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-(3-hydroxypropylamino)ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-(4-hydroxybutylamino)ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, 6-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}-3-(1-{[3-(2-{[(3S)-3,4-dihydroxybutyl]amino}ethoxy)-5,7-dimethyladamantan-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid, 6-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}-3-(1-{[3-(2-{[(3R)-3,4-dihydroxybutyl]amino}ethoxy)-5,7-dimethyladamantan-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid, 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-[2-hydroxyethyl(methyl)amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-[4-hydroxybutyl(methyl)amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-[[(3R)-3,4-dihydroxybutyl]-methyl-amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3,5-dimethyl-7-(2-piperazin-1-ylethoxy)-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, 6-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}-3-[1-({3,5-dimethyl-7-[2-(methylamino)ethoxy]adamantan-1-yl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic acid, 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3,5-dimethyl-7-[2-(1-piperidyl)ethoxy]-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, 3-[1-[[3-[2-(azepan-1-yl)ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]-6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]pyridine-2-carboxylic acid, 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-(4-isopropylpiperazin-1-yl)ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3,5-dimethyl-7-(2-morpholinoethoxy)-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-[3-methoxypropyl(methyl)amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-[2-(2-hydroxyethoxy)ethylamino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-[[3-hydroxy-2-(hydroxymethyl)propyl]amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-[bis(2-hydroxyethyl)amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-[bis(3-hydroxypropyl)amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-[bis(4-hydroxybutyl)amino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, 6-{3-[(1,3-benzothiazol-2-yl)amino]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}-3-{1-[(3,5-dimethyl-7-{2-[(2-sulfoethyl)amino]ethoxy}adamantan-1-yl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic acid, 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-[2-[(4-hydroxyphenyl)methylamino]ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[4-[3-(dimethylamino)prop-1-ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylic acid, 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[4-[3-[[(3S)-3,4-dihydroxybutyl]amino]prop-1-ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylic acid, and 2-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-5-[3-[2-fluoro-4-[3-(3-hydroxypropylamino)prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid 2. The compound according to claim 1, selected from the group consisting of: its enantiomers or diastereoisomers, or addition salts thereof with a pharmaceutically acceptable acid or base.

27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26, an enantiomer or diastereoisomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base.

28. 28. The pharmaceutical composition of claim 27 for use as a pro-apoptotic agent.

29. 28. A pharmaceutical composition according to claim 27 for use in the treatment of cancer, an autoimmune disease or an immune system disease.

30. 30. The pharmaceutical composition of claim 29, wherein the cancer is a hematological malignancy or a solid tumor.

31. 31. The pharmaceutical composition of claim 30, wherein the hematological malignancy is myeloma, lymphoma, or leukemia.

32. 32. The pharmaceutical composition of claim 31, wherein the myeloma is multiple myeloma; the lymphoma is non-Hodgkin's lymphoma (NHL); and the leukemia is chronic lymphocytic leukemia (CLL), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), or acute myeloid leukemia (AML).

33. 31. The pharmaceutical composition of claim 30, wherein the solid tumor is selected from bladder cancer, brain cancer, breast cancer, uterine cancer, esophageal cancer, liver cancer, colorectal cancer, kidney cancer, melanoma, ovarian cancer, prostate cancer, pancreatic cancer and lung cancer.

34. 27. A compound according to any one of claims 1 to 26, an enantiomer or diastereoisomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base, for use in the treatment of a cancer selected from myeloma, lymphoma, leukemia, bladder cancer, brain cancer, breast cancer, uterine cancer, esophageal cancer, liver cancer, colorectal cancer, kidney cancer, melanoma, ovarian cancer, prostate cancer, pancreatic cancer and lung cancer.

35. A compound according to any one of claims 1 to 26, its enantiomer or diastereoisomer, or an addition salt thereof with a pharmaceutically acceptable acid or base; an anti-cancer agent selected from a genotoxic agent, a mitotic toxin, an antimetabolite, a proteasome inhibitor, a kinase inhibitor, and an antibody; Includes a kit.

36. A compound according to any one of claims 1 to 26, its enantiomer or diastereoisomer, or an addition salt thereof with a pharmaceutically acceptable acid or base; an anti-cancer agent selected from a genotoxic agent, a mitotic poison, an antimetabolite, a proteasome inhibitor, a kinase inhibitor, and an antibody; one or more pharmaceutically acceptable excipients; A pharmaceutical composition comprising:

37. 36. The kit of claim 35 for use in treating cancer.

38. 27. A compound according to any one of claims 1 to 26, an enantiomer or diastereoisomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base, for use in the treatment of cancer requiring radiotherapy.

39. 28. A pharmaceutical composition according to claim 27 for use in the treatment of a disease or condition characterized by excessive or deregulated platelet activity.

40. 28. A pharmaceutical composition according to claim 27 for use in the treatment of a prothrombotic condition.

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