Macrocyclic compound as well as pharmaceutical composition and application thereof

Abstract

The invention discloses a macrocyclic compound as well as a pharmaceutical composition and application thereof. The present invention provides a compound represented by formula (I), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of the pharmaceutically acceptable salt thereof. The compounds of the present disclosure are useful as inhibitors of TNF [alpha] and are useful in the treatment of inflammation and autoimmune diseases.

Description

[0001] This application claims priority to PCT / CN2024 / 141170 filed December 20, 2024 and CN2025103733553 filed March 26, 2025, the entire contents of which are incorporated herein. TECHNICAL FIELD

[0002] The present application relates to macrocyclic compounds, pharmaceutical compositions thereof, and uses thereof. PRIOR ART

[0003] Tumor necrosis factor alpha (TNFa) is a homotrimeric protein composed of 157 amino acids. TNFa is initially expressed as a trimeric type II transmembrane protein, which can be cleaved by the metalloprotease TNF-converting enzyme to form soluble extracellular TNF. Both the transmembrane and soluble forms of TNFa can form biologically active trimeric complexes and transmit signals through TNF receptor 1 and TNF receptor 2. Binding of TNF to TNFR1 or TNFR2 can ultimately activate the transcription factor nuclear factor-kappa B (NF-kB), but there are significant differences in the signaling cascades mediated by each receptor to activate NF-kB. These complexities are compounded by multiple regulatory mechanisms of TNF expression itself, which allow cells to produce finely tuned, cell type-specific responses to TNF. Inappropriate or excessive activation of TNFa signaling is associated with chronic inflammation and ultimately leads to the development of pathological complications such as autoimmune diseases. (Brenner D., et al., Nat. Rev. Immunol., 2015, 15, 362-374; Kalliolias, G.D., et al., Nat. Rev. Rheumatol., 2016, 12, 49-62.).

[0004] As TNFa is an important regulator of inflammatory responses, a variety of TNFa modulators have been developed, including adalimumab, golimumab, certolizumab pegol, infliximab, and etanercept. Infliximab is a chimeric antibody whose Fab region contains a mouse amino acid sequence. Adalimumab and golimumab contain a human amino acid sequence. Certolizumab pegol is a humanized Fab fragment chemically coupled to polyethylene glycol. Etanercept is a fusion protein composed of the extracellular domain of a TNF receptor combined with the Fc fragment of human IgG1. (Jang, D.I., et al., Int. J. Mol. Sci., 2021, 22, 1-16; Willrich, M.A., et al., Transl. Res., 2015, 165, 270-282).

[0005] The disclosed compounds are modulators of human TNFα activity, which are beneficial for treating and / or preventing a variety of human diseases. Among them are inflammatory and autoimmune diseases, neurological and neurodegenerative diseases, pain and nociceptive sensory disorders, cardiovascular diseases, metabolic diseases, ocular diseases, and neoplastic diseases. As small molecules, they can have advantages over biologies. There is still a need for small molecule compounds with good biological activity. SUMMARY

[0006] The present invention relates to macrocyclic compounds, pharmaceutical compositions thereof, and uses thereof. The compounds of the present disclosure are useful as TNFα inhibitors and can be used in the treatment of inflammatory and autoimmune diseases.

[0007] The present disclosure provides a compound represented by Formula (I), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof;

[0008]

[0009] wherein:

[0010] L is -(CR a R b ) n1 -, c R d ) n2 -Y1-(CR e R f ) n3 -, c R d ) n4 -Y2-(CR e R f ) n5 - or -(CR c R d ) n6 -Y3-(CR e R f ) n7 -;

[0011] “*” indicates the position of L connected to the benzene ring;

[0012] R a and R b are each independently H, deuterium, halogen, -OH, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 haloalkoxy;

[0013] n1 is 3, 4, or 5;

[0014] 0 or 1 -CR a R b - is replaced with -Y-;

[0015] -Y- is m1 is 1, 2, 3, or 4, R y independently deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl, p1 is 0, 1, 2, 3, or 4; R ya and R yb each independently H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl;

[0016] n2 is 0, 1, 2, or 3;

[0017] n3 is 0, 1, 2, or 3;

[0018] n2 + n3 = 1, 2, or 3;

[0019] -Y1- is -CR a1 =CR a2 - or

[0020] R a1 and R a2 each independently H, halogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl;

[0021] m2 is 0, 1, 2, 3, or 4;

[0022] R y1 independently deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, -CN, or C 1-6 alkyl substituted with 1, 2, or 3 deuterium;

[0023] Ring A is C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

[0024] n4 is 0, 1, or 2;

[0025] n5 is 0, 1, or 2;

[0026] n4 + n5 = 0, 1, or 2;

[0027] -Y2- is

[0028] "**" indicates the point of attachment of -Y2- to -(CR e R f ) n5 -;

[0029] m3 is independently 0, 1, 2, or 3;

[0030] R y2 is independently halogen, deuterium, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl;

[0031] -Y3- is

[0032] "***" indicates the point of attachment of -Y3- to -(CR e R f ) n7 -;

[0033] n6 is 0 or 1;

[0034] n7 is 0 or 1;

[0035] n6 + n7 = 0 or 1;

[0036] R y3 is independently halogen, deuterium, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl;

[0037] m4 is independently 0, 1, 2, or 3;

[0038] R c and R d are each independently H, deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, or C e alkyl;

[0039] R f and R 1-6 are each independently H, deuterium, halogen, -OH, C 1-6 alkyl, C 1-6haloalkyl, C 1-6 alkyl;

[0040] X 1 and X 2 are each independently N or -CR X1 ;

[0041] R X1 is independently H, deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl;

[0042] is a single or double bond;

[0043] when is a single bond, X 3 is -C(O)-; X 4 is N or CH;

[0044] when is a double bond, X 3 is N; X 4 is C;

[0045] R 1 and R 2 are each independently H, deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -R 3 -R 4 , 5-12 membered heteroaryl, or 5-12 membered heteroaryl substituted with 1, 2, or 3 R 2-1 ;

[0046] R 2-1 is independently -OH, =O, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -(CR 2a R 2b ) 0-3 NR 2c R 2d or -CONR 2c R 2d ;

[0047] R 2a , R 2b , R 2c , and R 2d are each independently H or C1-6 alkyl;

[0048] -R 3 independently a bond, 5-6 membered heteroarylene, or 5-6 membered heteroarylene substituted with 1, 2, or 3 R 3-1 substituted 5-6 membered heteroarylene;

[0049] R 4 independently C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 5-12 membered heterocycloalkenyl, 5-12 membered heteroaryl, C 6-10 aryl, -C 1-6 alkylene-C 3-12 cycloalkyl, -C 1-6 alkylene-3-12 membered heterocycloalkyl, -C 1-6 alkylene-5-12 membered heterocycloalkenyl, -C 1-6 alkylene-5-12 membered heteroaryl, -C 1-6 alkylene-C 6-10 aryl, -M-C 3-12 cycloalkyl, -M-3-12 membered heterocycloalkyl, -M-5-12 membered heterocycloalkenyl, -M-5-12 membered heteroaryl, -M-C 6-10 aryl, substituted with 1, 2, or 3 R 4-1 C 3-12 cycloalkyl, substituted with 1, 2, or 3 R 4-2 3-12 membered heterocycloalkyl, substituted with 1, 2, or 3 R 4-3 5-12 membered heterocycloalkenyl, substituted with 1, 2, or 3 R 4-4 C 1-6 alkylene-C 3-12 cycloalkyl, substituted with 1, 2, or 3 R 4-5 C 1-6 alkylene-3-12 membered heterocycloalkyl, substituted with 1, 2, or 3 R 4-6 C 1-6 alkylene-5-12 membered heterocycloalkenyl, substituted with 1, 2, or 3 R 4-1 5-12 membered heteroaryl, substituted with 1, 2, or 3 R 4-1 C 6-10 aryl, substituted with 1, 2, or 3 R 4-1 C 1-6 alkylene-5-12 membered heteroaryl, substituted with 1, 2, or 3 R 4-1 C 1-6 alkylene-C 6-10 aryl, substituted with 1, 2, or 3 R 4-1 M-C 3-12 cycloalkyl, substituted with 1, 2, or 3 R 4-1substituted -M-3-12 membered heterocycloalkyl, 1, 2 or 3 R 4-1 substituted -M-5-12 membered heterocycloalkenyl, 1, 2 or 3 R 4-1 substituted -M-5-12 membered heteroaryl, 1, 2 or 3 R 4-1 substituted -M-C 6-10 aryl or

[0050] M is -O-, -S- or -NR 2c -;

[0051] R 3-1 independently -OH, -CN, halogen, -NR 3a R 3b , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 haloalkyl;

[0052] R 31 and R 32 each independently C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 haloalkyl;

[0053] or, is wherein Z 1 , Z 2 and Z 3 each independently -CH2-, -NH-, -O- or -S-; R 33 independently halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 haloalkyl; t is 0, 1, 2 or 3;

[0054] R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-5 and R 4-6 each independently -OH, -CN, halogen, -NR 3a R 3b , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 3-12 membered heterocycloalkyl, =0, -CO-NR3a R 3b , -NR 3a -CO-R 3e -COOR 3f , by 1, 2 or 3 R 3g Replacement C 1-6 alkyl;

[0055] R 3a and R 3b Independent of H, deuterium, and C 1-6 Alkyl groups or those with 1, 2, or 3 R groups 3a-1 Replacement C 1-6 Alkyl, wherein R 3a-1 Independently -NH2, -COOH, or -CONH2;

[0056] R 3c Independent of H, deuterium or C 1-6 alkyl;

[0057] R 3d Independently H, deuterium, -NH2 or C 1-6 alkyl;

[0058] R 3e For 1, 2 or 3 R 3e-1 Replacement C 1-6 Alkyl, wherein R 3e-1 Independently -NH2, -COOH, or -CONH2;

[0059] R 3f H, deuterium, or C 1-6 alkyl;

[0060] R 3g Independently D, -OH, -NR 2c R 2d C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0061] R 3h Independently H, halogen, deuterium or C 1-6 alkyl;

[0062] R 5 Independently for C 1-6 Alkyl, deuterium, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups or halogens;

[0063] Or, two adjacent R 5 Together with the carbon atom it is attached to, they form C 3-6cycloalkyl, 3-6 membered heterocycloalkyl, substituted by 1, 2, or 3 R 5-1 substituted C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, substituted by 1, 2, or 3 R 5-1 substituted 3-6 membered heterocycloalkyl;

[0064] R 5-1 independently C 1-6 alkyl, deuterium, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or halogen;

[0065] R 6a and R 6b each independently H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 haloalkyl;

[0066] u is 0, 1, 2, or 3;

[0067] each of said heterocycloalkyl independently refers to a heterocycloalkyl having 1, 2, 3, or 4 number of heteroatoms, wherein each heteroatom is independently N, O, or S;

[0068] each of said heteroarylene independently refers to a heteroarylene having 1, 2, 3, or 4 number of heteroatoms, wherein each heteroatom is independently N, O, or S;

[0069] each of said heterocyclenyl independently refers to a heterocyclenyl having 1, 2, 3, or 4 number of heteroatoms, wherein each heteroatom is independently N, O, or S;

[0070] each of said heteroaryl independently refers to a heteroaryl having 1, 2, 3, or 4 number of heteroatoms, wherein each heteroatom is independently N, O, or S.

[0071] The present disclosure provides a compound represented by Formula (I), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof;

[0072]

[0073] wherein:

[0074] L is -(CR a R b ) n1 -, -(CR c R d ) n2 -Y1-(CR e R f ) n3*, -(CR c R d ) n4 -Y2-(CR e R f ) n5 * or -(CR c R d ) n6 -Y3-(CR e R f ) n7 * ;

[0075] " " indicates the position of the L connection with the benzene;

[0076] R a and R b are each independently H, deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 haloalkoxy;

[0077] n1 is 3, 4, or 5;

[0078] 0 or 1 -CR a R b - is replaced with -Y-;

[0079] -Y- is m1 is 1, 2, 3, or 4, R y are independently deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl, p1 is 0, 1, 2, 3, or 4; R ya and R yb are each independently H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl;

[0080] n2 is 0, 1, 2, or 3;

[0081] n3 is 0, 1, 2, or 3;

[0082] n2 + n3 = 1, 2, or 3;

[0083] -Y1- is -CR a1 =CR a2 - or

[0084] R a1 and Ra2 Each is independently H, halogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 1-6 Halogenated alkyl groups;

[0085] m2 can be 0, 1, 2, 3 or 4;

[0086] R y1 Independently deuterium, halogen, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkyl, -CN, or C substituted with 1, 2 or 3 deuteriums 1-6 alkyl;

[0087] Ring A is C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

[0088] n4 is 0, 1, or 2;

[0089] n5 is 0, 1, or 2;

[0090] n4 + n5 = 0, 1, or 2;

[0091] -Y2- is

[0092] "**" represents -Y2- and -(CR e R f ) n5 - Connection position;

[0093] m3 can be 0, 1, 2 or 3 independently;

[0094] R y2 Independently halogen, deuterium, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 1-6 Halogenated alkyl groups;

[0095] -Y3- is

[0096] “***” represents -Y3- and -(CR e R f ) n7 - Connection position;

[0097] n6 is either 0 or 1;

[0098] n7 is either 0 or 1;

[0099] n6 + n7 = 0 or 1;

[0100] R y3 independently halogen, deuterium, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl;

[0101] m4is independently 0, 1, 2, or 3; R c and R d each independently H, deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, or C 1-6 alkyl;

[0102] R e and R f each independently H, deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, or C 1-6 alkyl;

[0103] X 1 and X 2 each independently N or -CR X1 ;

[0104] R X1 independently H, deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl;

[0105] is a single or double bond;

[0106] when is a single bond, X 3 is -C(O)-; X 4 is N or CH;

[0107] when is a double bond, X 3 is N; X 4 is C;

[0108] R 1 and R 2 each independently H, deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or -R3 -R 4 ;

[0109] -R 3 independently a bond, 5-6 membered heteroarylene, or 5-6 membered heteroarylene substituted with 1, 2, or 3 R 3-1 substituted with 1, 2, or 3 R

[0110] R 4 independently C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 5-12 membered heterocycloalkenyl, -C 1-6 alkylene-C 3-12 cycloalkyl, -C 1-6 alkylene-3-12 membered heterocycloalkyl, -C 1-6 alkylene-5-12 membered heterocycloalkenyl, C 4-1 substituted with 1, 2, or 3 R 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 5-12 membered heterocycloalkenyl, C 4-2 substituted with 1, 2, or 3 R 4-3 substituted with 1, 2, or 3 R 4-4 substituted with 1, 2, or 3 R 1-6 alkylene-C 3-12 cycloalkyl, C 4-5 substituted with 1, 2, or 3 R 1-6 alkylene-3-12 membered heterocycloalkyl, or C 4-6 substituted with 1, 2, or 3 R 1-6 alkylene-5-12 membered heterocycloalkenyl, or

[0111] R 3-1 independently -OH, -CN, halogen, -NR 3a R 3b , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl;

[0112] R 31 and R 32 are each independently C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl;

[0113] or, is wherein Z 1 , Z 2 , and Z 3each independently -CH2-, -NH-, -O-, or -S-; R 33 independently halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl; t is 0, 1, 2, or 3;

[0114] R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-5 , and R 4-6 each independently -OH, -CN, halogen, -NR 3a R 3b , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, =0, -CO-NR 3a R 3b , -NR 3a -CO-R 3e , -COOR 3f , C 3g alkyl substituted with 1, 2, or 3 R 1-6 ;

[0115] R 3a and R 3b are independently H, deuterium, C 1-6 alkyl, or C 3a-1 alkyl substituted with 1, 2, or 3 R 1-6 , wherein R 3a-1 is independently -NH2, -COOH, or -CONH2;

[0116] R 3c is independently H, deuterium, or C 1-6 alkyl;

[0117] R 3d is independently H, deuterium, -NH2, or C 1-6 alkyl;

[0118] R 3e is C 3e-1 alkyl substituted with 1, 2, or 3 R 1-6 , wherein R 3e-1 is independently -NH2, -COOH, or -CONH2;

[0119] R 3f is H, deuterium, or C 1-6 alkyl;

[0120] R 3g Independently D or -OH;

[0121] R 5 Independently for C 1-6 Alkyl, deuterium, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups or halogens;

[0122] R 6a and R 6b Each is independently H, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 1-6 Halogenated alkyl groups;

[0123] u can be 0, 1, 2, or 3;

[0124] Each of the heterocyclic alkyl groups refers independently to a heterocyclic alkyl group having 1, 2, 3 or 4 heteroatoms, wherein each heteroatom is independently N, O or S;

[0125] Each of the aforementioned heteroarylene groups independently refers to a heteroarylene group having 1, 2, 3, or 4 heteroatoms, wherein each heteroatom is independently N, O, or S;

[0126] Each heterocyclic alkenyl group independently refers to a heterocyclic alkenyl group with 1, 2, 3 or 4 heteroatoms, wherein each heteroatom is independently N, O or S.

[0127] This disclosure provides compounds of formula (I), solvates thereof, pharmaceutically acceptable salts thereof, or solvates of pharmaceutically acceptable salts thereof;

[0128]

[0129] in:

[0130] L is -(CR) a R b ) n1 -、-(CR c R d ) n2 -Y1-(CR e R f ) n3 -*、-(CR c R d ) n4 -Y2-(CR e R f ) n5 -* or -(CR c Rd ) n6 -Y3-(CR e R f ) n7 -*;

[0131] “*” indicates the position of attachment of L to the phenyl group;

[0132] R a and R b each independently H, deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 haloalkoxy;

[0133] n1 is 3, 4, or 5;

[0134] 0 or 1 -CR a R b - is replaced with -Y-;

[0135] -Y- is m1 is 1, 2, 3, or 4, R y independently deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl, p1 is 0, 1, 2, 3, or 4; R ya and R yb each independently H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl;

[0136] n2 is 0, 1, 2, or 3;

[0137] n3 is 0, 1, 2, or 3;

[0138] n2 + n3 = 1, 2, or 3;

[0139] -Y1- is -CR a1 =CR a2 - or

[0140] R a1 and R a2 each independently H, halogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl;

[0141] m2 is 0, 1, 2, 3, or 4;

[0142] R y1 independently deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl;

[0143] Ring A is C 3-6 cycloalkyl, or 3-6 membered heterocycloalkyl;

[0144] n4 is 0, 1, or 2;

[0145] n5 is 0, 1, or 2;

[0146] n4 + n5 = 0, 1, or 2;

[0147] -Y2- is

[0148] “**” indicates the attachment position of -Y2- to -(CR e R f ) n5 -;

[0149] m3 is independently 0, 1, 2, or 3;

[0150] R y2 independently halogen, deuterium, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl;

[0151] -Y3- is

[0152] “***” indicates the attachment position of -Y3- to -(CR e R f ) n7 -;

[0153] n6 is 0 or 1;

[0154] n7 is 0 or 1;

[0155] n6 + n7 = 0 or 1;

[0156] R y3 independently halogen, deuterium, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl;

[0157] m4 is independently 0, 1, 2, or 3; R c and R d each independently H, deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, or C 1-6 alkyl;

[0158] R e and R f each independently H, deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, or C 1-6 alkyl;

[0159] X 1 and X 2 each independently N or -CR X1 ;

[0160] R X1 is independently H, deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 haloalkoxy;

[0161] is a single or double bond;

[0162] when is a single bond, X 3 is -C(O)-; X 4 is N or CH;

[0163] when is a double bond, X 3 is N; X 4 is C;

[0164] R 1 and R 2 each independently H, deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, or C 3 haloalkoxy; 4 ;

[0165] -R 3 - is independently a bond, 5-6 membered heteroarylene, or 5-6 membered heteroarylene substituted with 1, 2, or 3 R 3-1 ;

[0166] R 4 independently C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 5-12 membered heterocycloalkenyl, -C 1-6 alkylene-C 3-12 cycloalkyl, -C 1-6 alkylene-3-12 membered heterocycloalkyl, -C 1-6 alkylene-5-12 membered heterocycloalkenyl, substituted with 1, 2, or 3 R 4-1 substituted C 3-12 cycloalkyl, substituted with 1, 2, or 3 R 4-2 substituted 3-12 membered heterocycloalkyl, substituted with 1, 2, or 3 R 4-3 substituted 5-12 membered heterocycloalkenyl, substituted with 1, 2, or 3 R 4-4 substituted -C 1-6 alkylene-C 3-12 cycloalkyl, substituted with 1, 2, or 3 R 4-5 substituted -C 1-6 alkylene-3-12 membered heterocycloalkyl, substituted with 1, 2, or 3 R 4-6 substituted -C 1-6 alkylene-5-12 membered heterocycloalkenyl;

[0167] R 3-1 independently -OH, -CN, halogen, -NR 3a R 3b , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl;

[0168] R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-5 and R 4-6 each independently -OH, -CN, halogen, -NR 3a R 3b , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or =O;

[0169] R 3a and R 3b each independently H, deuterium, or C 1-6 alkyl;

[0170] R 5 independently C 1-6 alkyl, deuterium, C 1-6haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;

[0171] R 6a and R 6b each independently H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 haloalkyl;

[0172] u is 0, 1, 2 or 3;

[0173] each of said heterocycloalkyl group independently refers to a heterocycloalkyl group having 1, 2, 3 or 4 number of heteroatoms, each of which is independently N, O or S;

[0174] each of said heteroarylene group independently refers to a heteroarylene group having 1, 2, 3 or 4 number of heteroatoms, each of which is independently N, O or S;

[0175] each of said heterocycloalkenyl group independently refers to a heterocycloalkenyl group having 1, 2, 3 or 4 number of heteroatoms, each of which is independently N, O or S.

[0176] In some preferred embodiments of the present application, certain groups in the compound of formula (I), solvate thereof, pharmaceutically acceptable salt thereof or solvate of the pharmaceutically acceptable salt thereof are defined as follows, and the definition of groups not mentioned is as described in any embodiments of the present application (referred to as “in certain embodiments”).

[0177] In certain embodiments, R a and R b each independently H or C 1-6 alkyl.

[0178] In certain embodiments, n1 is 3 or 4.

[0179] In certain embodiments, m1 is 1.

[0180] In certain embodiments, R y independently halogen.

[0181] In certain embodiments, p1 is 2.

[0182] In certain embodiments, R ya and R yb each independently H.

[0183] In certain embodiments, n3 is 0, 1 or 2.

[0184] In certain embodiments, R a1and R a2 is H.

[0185] In certain embodiments, m2 is 0, 1, 2, or 3, preferably, m2 is 0, 1, or 2.

[0186] In certain embodiments, R y1 is independently deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -CN, or C 1-6 alkyl substituted with 1, 2, or 3 deuterium, preferably, R y1 is independently halogen or C 1-6 alkyl.

[0187] In certain embodiments, ring A is C 3-6 cycloalkyl.

[0188] In certain embodiments, n4 is 0.

[0189] In certain embodiments, n5 is 0.

[0190] In certain embodiments, -Y2- is

[0191] In certain embodiments, m3 is 0.

[0192] In certain embodiments, -Y3- is

[0193] In certain embodiments, n6 is 0.

[0194] In certain embodiments, n7 is 0.

[0195] In certain embodiments, m4 is 0.

[0196] In certain embodiments, R c and R d are each independently H, deuterium, halogen, -OH, or C 1-6 alkyl, preferably, R c and R d are each independently H, halogen, -OH, or C 1-6 alkyl.

[0197] In certain embodiments, R e and R f are each independently H, halogen, -OH, or C 1-6 alkyl.

[0198] In certain embodiments, R X1 is independently H or halogen.

[0199] In certain embodiments, R 1H, halogen, C 1-6 alkyl or -R 3 -R 4 , preferably R 1 is independently H, halogen or C 1-6 alkyl.

[0200] In certain embodiments, R 2 is H, halogen or -R 3 -R 4 .

[0201] In certain embodiments, -R 3 is independently a bond or 5-6 membered heteroarylene.

[0202] In certain embodiments, R 4 is independently 3-12 membered heterocycloalkyl, C 4-1 cycloalkyl substituted with 1, 2, or 3 R 3-12 , 3-12 membered heterocycloalkyl substituted with 1, 2, or 3 R 4-2 , or 5-12 membered heterocycloalkenyl substituted with 1, 2, or 3 R 4-3 , preferably R 4 is independently or, preferably R 4 is independently 3-12 membered heterocycloalkyl, C 4-1 cycloalkyl substituted with 1, 2, or 3 R 3-12 , or 5-12 membered heterocycloalkenyl substituted with 1, 2, or 3 R 4-3 .

[0203] In certain embodiments, -R 3 -R 4 is independently -R 4 ,

[0204] In certain embodiments, R 4-1 and R 4-3 are each independently -NR 3a R 3b , C 1-6 alkyl or =0.

[0205] In certain embodiments, R 3a and R 3b are each independently H.

[0206] In certain embodiments, R 5 is independently C 1-6 alkyl, C 1-6 haloalkoxy or halogen, preferably R 5 is independently C 1-6 alkyl or C 1-6haloalkoxy.

[0207] In certain embodiments, R 6a is H or deuterium, preferably, R 6a is H.

[0208] In certain embodiments, R 6b is H or C 1-6 alkyl, preferably, R 6b is H. In certain embodiments, R 31 and R 32 are each independently C 1-6 alkyl.

[0209] In certain embodiments, u is 0, 1, 2.

[0210] In certain embodiments, L is -(CR a R b ) n1 -;

[0211] n1 is 3 or 4;

[0212] R a and R b are each independently H or C 1-6 alkyl;

[0213] 0 or 1 -CR a R b - is replaced with -Y-;

[0214] -Y- is m1 is 1, R y is independently halogen, p1 is 2, and

[0215] R ya and R yb are independently H.

[0216] In certain embodiments, L is -(CR c R d ) n2 -Y1-(CR e R f ) n3 -,

[0217] " " indicates the position of L attached to the phenyl;

[0218] n2 is 0, 1, 2 or 3;

[0219] n3 is 0, 1 or 2;

[0220] n2 + n3 = 1, 2 or 3;

[0221] -Y1- is -CR a1=CR a2 -OR

[0222] R a1 and R a2 is H;

[0223] m2 is 0, 1, 2;

[0224] R y1 is independently halogen;

[0225] Ring A is C 3-6 cycloalkyl;

[0226] R c and R d are each independently H, halogen, -OH, or C 1-6 alkyl; and

[0227] R e and R f are each independently H, halogen, -OH, or C 1-6 alkyl.

[0228] In certain embodiments, n2 is 1.

[0229] In certain embodiments, n3 is 0.

[0230] In certain embodiments, n3 is 1.

[0231] In certain embodiments, m2 is 1.

[0232] In certain embodiments, -Y1- is

[0233] In certain embodiments, Ring A is cyclopropyl.

[0234] In certain embodiments, R y1 is independently C 1-6 alkyl, preferably R y1 is methyl.

[0235] In certain embodiments, R c and R d are H.

[0236] In certain embodiments, R e and R f are H.

[0237] In certain embodiments, R 2 is -R 3 -R 4 , 5-12 membered heteroaryl, or 5-12 membered heteroaryl substituted with 1, 2, or 3 R 2-1 .

[0238] In certain embodiments, R 2-1 independently -OH, =0, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, -(CR 2a R 2b ) 0-3 NR 2c R 2d or -CONR 2c R 2d .

[0239] In certain embodiments, M is -O- or -NH-.

[0240] In certain embodiments, R 5 is C 1-6 haloalkoxy.

[0241] In certain embodiments, u is 1.

[0242] In certain embodiments, each halo is independently F, CI, Br, or I, preferably each halo is F.

[0243] In certain embodiments, each C 1-6 alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, preferably each C 1-6 alkyl is methyl.

[0244] In certain embodiments, each C 3-6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, preferably each C 3-6 cycloalkyl is cyclopropyl or cyclobutyl.

[0245] In certain embodiments, R 3 the 5-6 membered heteroarylene in R 3 the 5-6 membered heteroarylene in R

[0246] In certain embodiments, R 4 the 3-12 membered heterocycloalkyl in R 4 the 3-12 membered heterocycloalkyl in R 4 the 3-12 membered heterocycloalkyl in R

[0247] In certain embodiments, R 4The 3-12 membered heterocyclic alkyl group is a 3-12 membered heterocyclic alkyl group containing one or two heteroatoms, each of which is independently selected from N and O.

[0248] In some embodiments, R 4 The 3-12 membered heterocyclic alkyl groups are monocyclic systems, fused ring systems, bridged ring systems, or spirocyclic systems.

[0249] In some embodiments, R 4 The 3-12 membered heterocyclic alkyl group is

[0250] In some embodiments, R 4 The 5-12 membered heterocyclic alkenyl group is a 5-6 membered heterocyclic alkenyl group, preferably, the 5-12 membered heterocyclic alkenyl group is More preferably, R 4 The 5-12 membered heterocyclic alkenyl group is

[0251] In some embodiments, R 4 In for

[0252] In some embodiments, R 4 In for

[0253] In some embodiments, R 1 and R 2 The 5-12 heteroaryl groups are each independently formed by the following structures: phenyl fused with a 5-6 heterocyclic alkyl group, phenyl fused with a 5-6 heteroaryl group, 6 heteroaryl fused with a 5-6 heterocyclic alkyl group, 6 heteroaryl fused with a 5-6 heterocyclic alkenyl group, or 6 heteroaryl fused with a 5-6 heteroaryl group.

[0254] More preferably, R 1 and R 2 The 5-12 heteroaryl groups are each independently...

[0255] In some embodiments, R 4 The 5-12 heteroaryl group is a 5-6 heteroaryl group.

[0256] In some embodiments, R 4 The 5-12-membered heteroaryl group in R4 is a 5-12-membered heteroaryl group containing 1, 2, or 3 heteroatoms, each of which is independently selected from N. Preferably, the 5-12-membered heteroaryl group in R4 is...

[0257] In certain embodiments, R 4 The 5-12 membered heterocyclenyl group in -R

[0258] In certain embodiments, -R 3 -R 4 is wherein Q1is independently CH or N, and Q2is independently CH2, NH or O.

[0259] In certain embodiments, the compound is represented by formula (I-1), (I-2) or (I-3):

[0260]

[0261] wherein, R 1 and R 2 are each independently H, halogen or C 1-6 alkyl, R 3 , R 4 , R 5 , R 6a , R 6b , X 1 , X 2 , X 4 and u are as defined in any embodiment herein; “*a” indicates that when the carbon atom with “*a” label is a chiral carbon atom, its configuration is R configuration, S configuration or a mixture thereof.

[0262] In certain embodiments, the compound represented by formula (I-2) is a compound represented by formula (I-2-1), (I-2-2), (I-2-3), (I-2-4), (I-2-5), (I-2-6) or (I-2-7):

[0263]

[0264] wherein, R 1 is independently H, halogen or C 1-6 alkyl, R 3 , R 4 , R 5 , R 6a , R 6b , X 1 , X 2 , X 4 and u are as defined in any embodiment herein;

[0265] “*a” indicates that when the carbon atom with “*a” label is a chiral carbon atom, its configuration is R configuration, S configuration or a mixture thereof.

[0266] "*b" indicates that when the carbon atom bearing the "*b" designation is a chiral carbon atom, it is (independently) of the R configuration, the S configuration, or a mixture thereof;

[0267] "*c" indicates that when the carbon atom bearing the "*c" designation is a chiral carbon atom, it is (independently) of the R configuration, the S configuration, or a mixture thereof;

[0268] "*d" indicates that when the carbon atom bearing the "*d" designation is a chiral carbon atom, it is of the R configuration, the S configuration, or a mixture thereof; and,

[0269] "*e" indicates that when the carbon atom bearing the "*e" designation is a chiral carbon atom, it is of the R configuration, the S configuration, or a mixture thereof.

[0270] In certain embodiments, the compound is represented by formula (I-1-a), (I-1-b), or (I-1-c):

[0271]

[0272] wherein R 1 , R 5 , R a , R b , R 6a , R 6b , X 1 , X 2 and u are as described in any embodiment herein; and the definitions of "*a", "*b", "*c", "*d", and "*e" are as described herein.

[0273] In certain embodiments, the compound is represented by formula (I-2-a), (I-2-b), or (I-2-c):

[0274]

[0275] wherein R 1 , R 5 , R c , R d , R e , R f , R 6a , R 6b , X 1 , X 2 , u, R y1 and m2 are as described in any embodiment herein; and the definitions of "*a", "*b", and "*c" are as described herein.

[0276] In certain embodiments, the compound is represented by formula (I-3-a):

[0277] In certain embodiments, the compound is represented by formula (I-3-a):

[0278] wherein R 1 , R 5 , R c , R d , R e , R f , R 6a , R 6b , X 1 , X 2 , u, R y2 and m3 are as defined in any embodiment herein; and “*a” and “*b” are as described herein.

[0279] In certain embodiments, the compound is represented by any of the following formulae:

[0280]

[0281]

[0282] wherein R 1 , R 3 , R 4 , R 5 , R c , R d , R e , R f , R 6a , R 6b and u are as defined in any embodiment herein; and “*a” is as described herein.

[0283] In certain embodiments, the compound is represented by any of the following formulae:

[0284]

[0285] wherein R 1 , R 3 , R 4 , R 5 , R c , R d , R e , R f , R 6a , R 6b and u are as defined in any embodiment herein; and “*a” is as described herein.

[0286] In certain embodiments, the compound is represented by any of the following formulae:

[0287]

[0288] wherein R1 , R 2 , R 4 , R 5 , R c , R d , R e , R f , R 6a , R 6b and the definition of "a" is as described herein.

[0289] In certain embodiments, X 1 is CH, CF, or N, preferably, X 1 is CH.

[0290] In certain embodiments, X 2 is CH, CF, or N, preferably, X 2 is CH.

[0291] In certain embodiments, is a double bond, X 3 is N; X 4 is C.

[0292] In certain embodiments, R 1 is H, F, -CH3, preferably, R 1 is H.

[0293] In certain embodiments, R 2-1 is independently -OH, -CH3, -NH2, =0, -CF3, -OCH3, or -CONH2.

[0294] In certain embodiments, R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-5 , and R 4-6 are each independently -CH3, =0, -CN, -NH2, -CO-NH2, -OH, -CF3, -COOH, F, -CONHCH3, -CON(CH3)2, -CH2OCH3, -CH2OH, preferably, R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-5 , and R 4-6each independently -CH3, =0, -CN, -NH2, -CO-NH2, -OH, -CF3, -COOH,

[0295] In certain embodiments, -R 3 is In certain embodiments, -R 3 is “*4” indicates the position of attachment of -R 3 to -R 4 .

[0296] In certain embodiments, R 4 is In certain embodiments, R 4 is

[0297] In certain embodiments, R 2 is H, Cl, In certain embodiments, R 2 is H, Cl, More preferably, R 2 is H, Cl,

[0298] In certain embodiments, R 5 is CH3or F, preferably R 5 is or CH3.

[0299] In certain embodiments, the moiety is In certain embodiments, the moiety is More preferably, the moiety is “*” indicates the position of attachment of L to the phenyl.

[0300] In certain embodiments, L is Preferably, L is More preferably, L is “*” indicates the position of attachment of L to the phenyl group.

[0301] In certain embodiments, the compound represented by formula (I) is any one of the following:

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320] The present disclosure also provides a compound represented by formula (II),

[0321]

[0322] wherein R 1 , R 5 , R 6a , R 6b , X 1 , X 2 , X 3 , X 4 , u, L and “*a” are as defined in any embodiment herein; PG1is an amino protecting group.

[0323] The present disclosure also provides a compound represented by Formula (II-A),

[0324]

[0325] wherein R 1 , R 6a , R 6b , X 1 , X 2 and “*a” are as defined in any embodiment herein; PG1is an amino protecting group; R 5a is halogen; t1is 1, 2 or 3.

[0326] The present disclosure also provides a compound represented by Formula (II-B),

[0327]

[0328] wherein R 1 , R 6a , R 6b , X 1 , X 2 , n2, n3and “*a” are as defined in any embodiment herein; R 2a is halogen or PG1is an amino protecting group.

[0329] The present disclosure also provides a compound represented by Formula (II-C),

[0330]

[0331] wherein R 1 , R 6a , R 6b , X 1 , X 2 and “*a” are as defined in any embodiment herein; PG1is an amino protecting group; R 5a is halogen; t4is 1, 2 or 3.

[0332] The present disclosure also provides a compound represented by Formula (II-D),

[0333]

[0334] wherein R 1 , R 6a , R 6b , X 1 , X 2 , “a”, ring A, R y1 , and m2 are as defined in any embodiment herein; PG1 is an amino protecting group; R 5a is halogen; t5 is 1, 2, or 3.

[0335] The present disclosure also provides a compound represented by Formula (II-E) or Formula (II-F),

[0336]

[0337]

[0338] wherein R 1 , R 6a , R 6b , X 1 , X 2 , “a”, ring A, R y1 , m2, n2, and n3 are as defined in any embodiment herein; PG1 is an amino protecting group; R 5a is halogen.

[0339] In certain embodiments, PG1 is Boc.

[0340] In certain embodiments, R 5a is Br.

[0341] In certain embodiments, R 2a is Br.

[0342] The present disclosure also provides a compound represented by Formula (III),

[0343]

[0344] wherein R 1 , R 5 , R 6a , R 6b , X 1 , X 2 , X 3 , X 4 , u, L, and “a” are as defined in any embodiment herein; R 2X is halogen,

[0345] In certain embodiments, the compound represented by Formula (III) is represented by any one of the following formulas:

[0346]

[0347]

[0348] R 2X independently halogen,

[0349] In certain embodiments, R 2X is Cl, The present disclosure also provides a compound selected from the group consisting of:

[0350]

[0351]

[0352]

[0353] The present disclosure also provides a pharmaceutical composition comprising a compound represented by Formula (I), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0354] The present disclosure also provides use of a compound represented by Formula (I), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, in the preparation of a TNFα inhibitor.

[0355] The present disclosure also provides use of a compound represented by Formula (I), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating and / or preventing inflammatory and autoimmune diseases.

[0356] The present disclosure also provides a method for treating and / or preventing inflammatory and autoimmune diseases in a subject in need thereof, comprising: administering to the subject an effective amount of a compound represented by Formula (I), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0357] Unless otherwise indicated, the terms in this application are defined as follows.

[0358] The term "pharmaceutically acceptable" means relatively non-toxic, safe and suitable for a patient.

[0359] The term "pharmaceuticalally acceptable salt" refers to the salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting it with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting it with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, please refer to *Handbook of Pharmaceutical Sales: Properties, Selection, and Use* (P. Heinrich Stahl, Camille, G. Wermuth, 2011, 2nd revised edition).

[0360] The term "solvent" refers to a substance formed by the combination of a compound and a solvent. Solvents can be classified into stoichiometric solvates and non-stoichiometric solvates.

[0361] The term "solvent of a pharmaceutically acceptable salt" refers to a substance formed by the combination of a compound with a pharmaceutically acceptable acid or base and a solvent. The amount of solvent can be stoichiometric or non-stoichiometric.

[0362] The term "halogen" refers to F, Cl, Br, or I.

[0363] The term "alkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon group having a specific number of carbon atoms (e.g., C1 to C6). For example, "C 1-6 "Alkyl" refers to a straight-chain saturated monovalent hydrocarbon group with 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group with 3 to 6 carbon atoms. C 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomers such as n-propyl and isopropyl), butyl (including all isomers such as n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl (including all isomers such as n-pentyl, isopentyl, sec-pentyl, neopentyl and tert-pentyl) and hexyl (including all isomers such as n-hexyl, isohexyl and sec-hexyl).

[0364] The term "haloalkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon group having a specific number of carbon atoms (e.g., C1–C6) and being substituted with 1, 2, 3, 4, or more halogens. For example, the term "C1"... 1-6 "Haloalkyl" refers to a straight-chain saturated monovalent hydrocarbon group with 1 to 6 carbon atoms substituted by 1, 2, 3, 4 or more halogens, or a branched saturated monovalent hydrocarbon group with 3 to 6 carbon atoms, wherein C 1-6 The alkyl group in haloalkyl is defined as described in this article, C 1-6 The definition of halogens in haloalkyl groups is as described in this article.

[0365] The term "alkylene" refers to a straight-chain saturated divalent hydrocarbon group having a specific number of carbon atoms (e.g., C1–C6). For example, the term "C…" 1-6 "Alkylene" refers to a straight-chain saturated divalent hydrocarbon group with 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon group with 3 to 6 carbon atoms.

[0366] The term "alkoxy" refers to -O-alkyl, where the alkyl group in an alkoxy group is defined as described herein. For example, the term "C 1-6 "Alkoxy" refers to -OC 1-6 Alkyl group. C 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and tert-butoxy.

[0367] The term "haloalkoxy" refers to an alkoxy group substituted with one, two, three, four, or more halogens, wherein the alkyl group and the halogen are defined as described herein. For example, the term "C 1-6 "Haloalkoxy" refers to a carbon atom substituted with one, two, three, four or more halogens. 1-6 Alkyl group.

[0368] The term "cycloalkyl" refers to a alkyl group having a specific number of carbon atoms (e.g., C3-C4). 12 A cyclic saturated monovalent hydrocarbon group, which can be monocyclic or bicyclic. For example, the term "C 3-12 "Cycloalkyl" refers to C 3-12 Cyclic hydrocarbon group. C 3-12 Examples of cycloalkyl groups include, but are not limited to, C10. 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0369] The term "heterocyclic alkyl" refers to a saturated monovalent group having a specific number of heteroatoms (e.g., 1, 2, 3, 4, or 5), a specific number of ring atoms (e.g., 3-12, 5-6, or 8-10), and a specific type of heteroatom (one or more independently selected from the N, O, and S groups), which can be monocyclic or polycyclic. Heterocyclic alkyl groups are attached to the rest of the molecule by carbon atoms or heteroatoms.

[0370] The term "heterocyclic alkenyl" refers to an unsaturated monovalent group having a specific number of heteroatoms (e.g., 1, 2, 3, 4 or 5), a specific number of ring atoms (e.g., 5-12, 5-6 or 8-10), and a specific type of heteroatoms (one or more independently selected from the N, O and S groups), which is monocyclic or polycyclic, non-aromatic, and has one or more (e.g., 1, 2 or 3) carbon-carbon sp2 double bonds.

[0371] The term "heteroaryl" refers to a divalent unsaturated aromatic group having a specific number of heteroatoms (e.g., 1, 2, 3, 4 or 5), a specific number of ring atoms (5-6 members), and a specific type of heteroatoms (one or more independently selected from the N, O and S groups).

[0372] The term "heteroaryl" refers to an aromatic cyclic monovalent group having a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), a specified number of ring atoms (5-12 membered or 5-6 membered), and a specified type of heteroatom (one or more each independently selected from the group of N, O, and S).

[0373] The term "aryl" refers to a group of conjugated hydrocarbon rings that satisfy the 4n+2 rule and are composed of carbon atoms (e.g., 6 to 10 carbon atoms).

[0374] The absolute configuration of a chiral center is represented by a wedge-shaped solid bond and a wedge-shaped dashed bond The absolute configuration of a chiral center is represented by a wedge-shaped solid bond or a wedge-shaped dashed bond or a mixture thereof.

[0375] For example, the term "cis" refers to or a mixture thereof. The term "trans" refers to or a mixture thereof.

[0376] When a compound is labeled as a racemate, it means that it is a mixture of two enantiomers. For clarity, only the structure of one enantiomer may be shown.

[0377] The term "treatment" refers to eliminating the cause or alleviating the symptoms.

[0378] The term "prevention" refers to reducing the risk of disease.

[0379] The term "pharmaceutically acceptable carrier" refers to all substances in a pharmaceutical preparation other than the active pharmaceutical ingredient, usually divided into excipients and additives. For details, please refer to the "People's Republic of China Pharmacopoeia" (2020 edition) and "Handbook of Pharmaceutical Exceptions" (Paul J sheskey, Bruno C Hancock, Gary P moss, David J Goldfarb, 2020, 9th edition).

[0380] The term "effective amount" refers to the amount administered to a patient sufficient to effectively treat the disease. The effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, and other factors, but can be appropriately adjusted by those skilled in the art.

[0381] Unless otherwise specified, the term "Ex" has the same meaning as "Example".

[0382] ​​Unless otherwise stated, the term "peak 1" refers to the isomer that elutes first in a chromatographic separation, and the term "peak 2" refers to the other isomer that elutes later. BRIEF DESCRIPTION OF DRAWINGS

[0383] Figure 1 NMR data for EX01.

[0384] Figure 2 NMR data for 48F.

[0385] Figure 3 NMR data for 48L.

[0386] Figure 4 NMR data for 68C.

[0387] Figure 5 NMR data for 68D.

[0388] Figure 6 Crystal structure for EX69-A.

[0389] Figure 7 NMR data for 106G.

[0390] Figure 8 NMR data for 109E.

[0391] Figure 9 NMR data for 112J.

[0392] Figure 10 Crystal structure for EX106-A.

[0393] Figure 11 Crystal structure for EX110-A.

[0394] DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0395] The following examples further illustrate the application but do not limit it.

[0396] The preferred embodiments of the present application are provided below in conjunction with the accompanying drawings, to give a detailed explanation of the technical solutions of the present application.

[0397] Abbreviations

[0398] AcOH: acetic acid

[0399] Aq.: aqueous solution

[0400] Brine: saturated aqueous sodium chloride solution

[0401] DCM: dichloromethane

[0402] DIBAL-H: diisobutylaluminum hydride

[0403] DIEA: N,N-diisopropylethylamine

[0404] DMF: N,N-dimethylformamide

[0405] DMSO: dimethyl sulfoxide

[0406] dppf: 1,1'-bis(diphenylphosphino)ferrocene

[0407] Et: ethyl

[0408] EtOAc: ethyl acetate

[0409] h: hour(s)

[0410] HATU: N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine-1-yliden]-N- ethylmethanaminium hexafluorophosphate-N-oxide

[0411] HPLC: high performance liquid chromatography

[0412] LC / MS: liquid chromatography mass spectrometry

[0413] M: molar concentration

[0414] Me: methyl

[0415] MeOH: methanol

[0416] min: minute(s)

[0417] PE: petroleum ether

[0418] r.t.: room temperature

[0419] TBAF: tetrabutylammonium fluoride

[0420] TEA: triethylamine

[0421] Tert-: tertiary

[0422] TFA: trifluoroacetic acid

[0423] THF: tetrahydrofuran

[0424] Analytical conditions

[0425] NMR:

[0426] Bruker 400 MHz NMR spectrometer using solvent as internal standard 1 H NMR spectra, chemical shifts in parts per million (ppm).

[0427] LCMS:

[0428] LCMS data were obtained using one of the following instruments: an Agilent 1260 series HPLC system equipped with DAD and SQ mass spectrometers, ESI positive / negative mode, scan range of 100–1200 amu; or a Waters ARC HPLC system equipped with TUV and SQ mass spectrometers, ESI positive / negative mode, scan range of 50–1250 amu.

[0429] The samples were analyzed using the following chromatographic columns under the following conditions: Sepax GP-C18 column, 3 μm, 50 mm × 3 mm; gradient elution of solvent B from 5% to 95% over 2 minutes; Solvent A: H2O / 0.05% formic acid; Solvent B: acetonitrile / 0.05% formic acid; flow rate: 1.5 mL / min; temperature: 40 °C; or Waters Xbrige-C18 column, 3 μm, 50 mm × 4.6 mm; gradient elution of solvent B from 5% to 95% over 3.5 minutes; Solvent A: H2O / 0.05% NH3H2O; Solvent B: acetonitrile / 0.05% NH3H2O; flow rate: 1.5 mL / min; temperature: 40 °C.

[0430] Preparative HPLC:

[0431] Unless otherwise specified, all reversed-phase chromatographic analyses were performed using a Waters 3767 / QDA system with a SunFire C18 column (10 μm, 30 mm × 75 mm), mobile phase A: 0.1% formic acid / H2O, mobile phase B: acetonitrile; flow rate: 20 mL / min.

[0432] Example 1

[0433] Example 01, Example 02, Example 03

[0434]

[0435] To a mixture of (S)-2-methylpropane-2-sulfmamide (26.01 g, 0.214 mol) and cyclobutanone (1A) (15.04 g, 0.214 mol) in THF (400 mL) was added Ti(OEt)4(73.37 g, 0.32 mol) and the mixture was stirred at 60 °C for 12 h. The reaction was quenched with saturated NaHC03solution to form a white solid. Water (100 mL) was added and the combined aqueous phase was extracted with EtOAc (300 mL x 3) and the combined organic layer was washed with water (300 mL x 3) and brine (300 mL x 3). The organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE:EtOAc = 5: 1) to give (S)-N-cyclobutylidene-2-methyl-propane-2-sulfmamide (1B) (17.31 g, yield: 45.73%) as a light yellow oil. LCMS (ESI) m / z: [M+H] + 118.0.

[0436]

[0437] To a solution of 5-bromo-2-iodo-pyrimidine (1C) (85.16 g, 0.30 mol) in DCM (800 mL) was added butyllithium (110 mL, 0.28 mol) dropwise at -70 °C under nitrogen. The mixture was stirred at -70 °C for 2 h. Then a solution of (S)-N-cyclobutylidene-2-methyl-propane-2-sulfmamide (1B) (37.00 g, 0.21 mol) in DCM (30 mL) was added. The temperature was kept at -60 °C to -70 °C for 2 h stirring, then warmed to 25 °C. The mixture was stirred for 16 h and quenched with water (500 mL). The combined aqueous layer was extracted with DCM (500 mL x 3) and the combined organic layer was washed with water (500 mL x 3) and brine (500 mL x 3). The organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE:EtOAc = 1: 1) to give (S)-N-[l-(5-bromopyrimidin-2-yl)cyclobutyl]-2-methyl-propane-2-sulfmamide (1D) (18 g, yield: 25.37%) as a yellow oil. LCMS (ESI) m / z: [M+H] + 332.29.

[0438]

[0439] To a solution of (S)-N-[1-(5-bromopyrimidin-2-yl)cyclobutyl]-2-methyl- propanesulfmide (1D) (7.700 g, 23 mmol) in MeOH (20 mL) was added HC1 solution (4.0 M, 845 mg, 23 mmol). After the mixture was stirred at 25 °C for 16 h, it was concentrated under reduced pressure. Then 2-methoxy-2-methyl-propane (180 mL) and MeOH (20 mL) were added, and the mixture was stirred at 25 °C for 16 h. Filtration and washing of the solid with DCM (50 mL) gave [1-(5-bromopyrimidin-2-yl)cyclobutyl]ammonium (1E) (4.681 g, 20 mmol, yield: 88.15%) as a white solid. LCMS (ESI) m / z: [M+H] + 228.24.

[0440]

[0441] To a solution of [1-(5-bromopyrimidin-2-yl)cyclobutyl]ammonium (1E) (4.682 g, 20 mmol) in DCM (50 mL) was added TEA (6.200 g, 61 mmol, 8.5 mL) and tert-butyloxycarbonyl tert-butyl carbonate (4.900 g, 22 mmol, 5.2 mL). The mixture was heated to 25 °C for 16 h. Water (100 mL) was added, and the combined aqueous layers were extracted with DCM (200 mL x 3), and the combined organic layers were washed with water (100 mL x 3) and brine (200 mL x 3). The organic layer was dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give tert-butyl N-[1-(5-bromopyrimidin-2-yl)cyclobutyl]carbamate (1F) (5.951 g, yield: 88.75%) as a light yellow solid. LCMS (ESI) m / z: [M-100] + 272.21.

[0442]

[0443] To a solution of tert-butyl-N-[l-(5-bromopyrimidin-2-yl)cyclobutyl]carbamate (1F) (5.955 g, 18 mmol) in dioxane (60 mL) was added Pd(dppf)Cl2(1.336 g, 2 mmol) and KOAc (5.343 g, 54 mmol, 3.4 mL) under nitrogen. The mixture was heated to 90 °C for 16 h. After cooling, water (100 mL) was added, and the combined aqueous layers were extracted with EtOAc (100 mL x 3), and the combined organic layers were washed with water (100 mL x 3) and brine (100 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE:EtOAc = 3:1) to give tert-butyl-N-[l-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]cyclobutyl]carbamate (1G) (5.706 g, yield: 83.78%) as a white solid. LCMS (ESI) m / z: [M+H] + 376.0, [M+H-82] + 294.1. 1 H NMR (400 MHz, DMSO) δ 8.89 (s, 2H), 7.85 (s, 1H), 2.64-2.57 (m, 2H), 2.37-2.30 (m, 2H), 2.03-1.87 (m, 2H), 1.33 (s, 19H), 1.17 (d, J = 4 Hz, 1H), 1.07 (s, 1H).

[0444]

[0445] To a mixture of tert-butyl-N-[l-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrimidin-2-yl]cyclobutyl]carbamate (1G) (2.35 g, 5.00 mmol), 4-bromo-2- fluoro-l-nitro-benzene (1H) (1.00 g, 4.55 mmol) and K2CO3(3.14 g, 22.7 mmol) in water (2.4 mL) and dioxane (12 mL) was added Pd(dppf)Cl2(333 mg, 455 μmol) under nitrogen. The mixture was stirred at 100 °C for 4 h under nitrogen. The reaction mixture was cooled to room temperature, quenched with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography (18% ethyl acetate in petroleum ether) to afford tert-butyl-N-[l-[5-(3-fluoro-4-nitrophenyl)pyrimidin-2- yl]cyclobutyl]carbamate (1I) (1.53 g, 99%, 3.90 mmol, yield: 87%) as an orange solid. LCMS (ESI) m / z: 389.34 [M+H] + .

[0446]

[0447] A mixture of 2-bromo-6-hydroxybenzaldehyde (1J) (10.0 g, 50.0 mmol) and potassium hydroxide (55.8 g, 994.0 mmol) in acetonitrile (240 mL) and H2O (248 mL) was cooled to -25 °C. Diethyl(bromodifluoromethyl)phosphonate (14.2 mL, 80.0 mmol) was added dropwise to the reaction mixture. After about 15 min at -20 °C or below, the bath temperature was slowly increased to 20 °C and stirring was continued for 1 h. The reaction was diluted with EtOAc (400 mL), washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated, and purified by silica gel chromatography (5-10% ethyl acetate in petroleum ether) to afford 2-bromo-6-(difluoromethoxy)benzaldehyde (1K) (7.40 g, yield: 59%) as a white solid. LC-MS: m / z = 251.0 [M+H] + .

[0448]

[0449] 2-bromo-6-(difluoromethoxy)benzaldehyde (1K) (6.7 g, 26.7 mmol), tert-butyl carbamate (9.4 g, 80.07 mmol) were taken in DCM (20 mL) and acetonitrile (60 mL) to make a mixture. Then to the reaction mixture was added triethylsilane (12.9 mL, 80.1 mmol) and TFA (4 mL, 53.4 mmol) slowly drop wise at 25 °C. The resulting mixture was stirred at room temperature for 16 h and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5-10% ethyl acetate in petroleum ether) to afford tert-butyl-(2-bromo-6-(difluoromethoxy)benzyl)carbamate (1L) (5.0 g, yield: 53%) as a white solid. LC-MS: m / z = 352.0 [M+H] + .

[0450]

[0451] To a solution of tert-butyl-(2-bromo-6-(difluoromethoxy)benzyl)carbamate (1L) (2.2 g, 6.27 mmol) in DCM (30 mL) was added TFA (10 mL) drop wise at room temperature with stirring. The resulting mixture was stirred at room temperature for 2 h, concentrated under reduced pressure to afford crude (1M) which was used as such in the next step without further purification. LC-MS: m / z = 252.0 [M+H] + .

[0452]

[0453] A mixture of (2-bromo-6-(difluoromethoxy)phenyl)methanamine (1M) (1.50 g, 5.98 mmol), tert-butyl-N-[1-[5-(3-fluoro-4-nitrophenyl)pyrimidin-2-yl]cyclobutyl]carbamate (1I) (2.78 g, 7.17 mmol) and diisopropylethylamine (7.72 g, 59.8 mmol) in EtOH (40 mL) was stirred at 80 °C for 12 h. After cooling, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% ethyl acetate in petroleum ether) to afford tert-butyl-(1-(5-(3-((2-bromo-6-(difluoromethoxy)benzyl)amino)-4-nitrophenyl)pyrimidin-2-yl)cyclobutyl)carbamate (1N) (2.7 g, yield: 73%). LC-MS: m / z = 620.0 [M+H] + .

[0454]

[0455] A mixture of tert-butyl-(l-(5-(3-((2-bromo-6-(difluoromethoxy)benzyl)amino)-4- nitrophenyl)pyrimidin-2-yl)cyclobutyl)carbamate (2.70 g, 4.36 mmol) (1N) and iron powder (1.22 g, 21.8 mmol) in saturated aqueous ammonium chloride (10 mL) and EtOH (40 mL) was stirred at 70 °C for 8 h. After cooling, the resulting mixture was filtered. The filter cake was washed with MeOH (5 x 100 mL). The combined filtrates were concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (0-50% ethyl acetate in petroleum ether) to give tert-butyl-(l-(5-(4-amino-3-((2-bromo-6- (difluoromethoxy)benzyl)amino)phenyl)pyrimidin-2-yl)cyclobutyl)carbamate (10) (1.7 g, 66.2%). LC-MS m / z = 590.0 [M+H] + .

[0456]

[0457] A mixture of tert-butyl-(l-(5-(4-amino-3-((2-bromo-6-(difluoromethoxy)benzyl)amino)phenyl)pyrimidin-2-yl)cyclobutyl)carbamate (10) (800 mg, 1.36 mmol), pent-4-enoic acid (40.0 mg, 0.21 mmol), HATU (150 mg, 1.50 mmol) and DIEA (527 mg, 4.08 mmol) in DMF (20 mL) was stirred at room temperature for 12 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-50% ethyl acetate in petroleum ether) to give tert-butyl-(l-(5-(3-((2-bromo-6-(difluoromethoxy)benzyl)amino)-4-(pent-4- enoylamino)phenyl)pyrimidin-2-yl)cyclobutyl)carbamate (1P) (800 mg, yield: 87.8%) as a white solid. LC-MS: m / z = 672.1 [M+H] + .

[0458]

[0459] A solution of tert-butyl-(l-(5-(3-((2-bromo-6-(difluoromethoxy)benzyl)amino)-4- (pent-4-enoylamino)phenyl)pyrimidin-2-yl)cyclobutyl)carbamate (1P) (800 mg, 1.19 mmol) in AcOH (15 mL) was stirred at 60 °C for 12 h. The reaction mixture was diluted with water (50 mL) and the pH was adjusted to 8 with saturated aqueous sodium carbonate solution. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried and concentrated. The residue was purified by silica gel chromatography (30% to 60% ethyl acetate in petroleum ether) to give 1Q (600 mg, 77.1%) as a white solid. LC-MS: m / z = 654.0 [M+H] + .

[0460]

[0461] A mixture of tert-butyl-(l-(5-(l-(2-bromo-6-(difluoromethoxy)benzyl)-2-(3- buten- 1 -yl)- 1 H-benzo [d] imidazol-5-yl)pyrimidin-2-yl)cyclobutyl)carbamate (1Q) (100 mg, 0.15 mmol), Pd(dppf)Cl2(11.0 mg, 0.015 mmol) and K2CO3(62.19 mg, 0.45 mmol) in dioxane (1.5 mL) and water (0.4 mL) was stirred at 110 °C for 2 h under argon. After cooling, the resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (C18 column chromatography eluting with acetonitrile: water (0.1% formic acid) = 25% to 65%) to give tert-butyl-(l-(5-(l-(difluoromethoxy)-5-methylene-5,6,7,14- tetrahydrobenzo[f]benzo[4,5]imidazo[l,2-a]azocin-11-yl)pyrimidin-2-yl)cyclobutyl)carbamate (1T) (10.0 mg, yield: 17.1%) as a white solid. LC-MS: m / z = 574.4 [M+H] + ; and tert-butyl-(Z)-(l-(5-(l-(difluoromethoxy)-5,15-dihydro-8H- benzo[g]benzo[4,5]imidazo[l,2-a]azanonan-12-yl)pyrimidin-2-yl)cyclobutyl)carbamate (1U) (15.0 mg, 17.1%) as a white solid. LC-MS: m / z = 574.4 [M+H] +; and tert-butyl-(E)-(1-(5-(1-(difluoromethoxy)-7,15-dihydro-8H-benzo[g]benzo[4,5]imidazo[1,2-a]azanon-12-yl)pyrimidin-2-yl)cyclobutyl)carbamate (1V) (12.0 mg, yield: 13.7%), as a white solid. LC-MS: m / z = 574.4 [M+H] + .

[0462] Example 01

[0463]

[0464] TFA (0.3 mL) was added to a 1.0 mL solution of tert-butyl-(1-(5-(1-(difluoromethoxy)-5-methylene-5,6,7,14-tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azaoct-11-yl)pyrimidin-2-yl)cyclobutyl)carbamate (1T) (15.0 mg, 0.026 mmol) in DCM. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure. The crude product was purified by preparative HPLC (C18 column chromatography, eluting with acetonitrile:water (0.1% formic acid) = 25%–65%) to give EX 01 (3.17 mg, 25.6%) as a white solid. LC-MS: m / z = 474.1 [M+H] + . 1 H NMR (400MHz, MeOD-d4): δ 9.28 (s, 2H), 8.52 (s, 1H), 7.97 (d, J = 10.0Hz, 1H), 7.90 (d, J = 8.4Hz, 1H), 7.45 (t, J = 8.0Hz, 1H), 7.32–7.00 (m, 3H), 5.80 (s, 2H), 5.62 (s, 1H), 5.30 (s, 1H), 3.62 (t, J = 5.6Hz, 2H), 3.04 (s, 2H), 2.96–2.89 (m, 2H), 2.67–2.59 (m, 2H), 2.47–2.26 (m, 2H). NMR data for EX01 are as follows... Figure 1 As shown.

[0465] Example 02

[0466]

[0467] Under stirring, 0.3 mL of trifluoroacetic acid was added to a 1 mL solution of tert-butyl-(Z)-(1-(5-(1-(difluoromethoxy)-5,15-dihydro-8H-benzo[g]benzo[4,5]imidazo[1,2-a]azanon-12-yl)pyrimidin-2-yl)cyclobutyl)carbamate (1 U) (15.0 mg, 0.026 mmol). The resulting mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The crude product was purified by preparative HPLC (C18 column chromatography, eluting with acetonitrile:water (0.1% formic acid) = 35%–75%) to give tert-butyl-(Z)-(1-(5-(1-(difluoromethoxy)-5,15-dihydro-8H-benzo[g]benzo[4,5]imidazo[1,2-a]azanon-12-yl)pyrimidin-2-yl)cyclobutyl)carbamate EX 02 (2.81 mg, 25.6%), as a white solid. LC-MS: m / z = 474.1 [M+H] + . 1 H NMR (400MHz, MeOD-d4): δ9.20(s,2H), 8.21(s,1H), 7.94(d,J=1.6Hz,2H), 7.45(t,J=8.0Hz,1H), 7.22~7.19(m,2H), 6.91(t,J=73.4Hz,1H), 6.09~6.00(m,1H), 5.82~5.72(m,1H), 5.95(s,2H), 3.73(m,2H), 3.52~ 3.47(m,2H), 2.96~2.86(m,2H), 2.67~2.57(m,2H), 2.46~2.25(m,2H).

[0468] The NMR data for Ex02 are shown in Tables 1 and 2 below:

[0469]

[0470] Table 1. Ex02 1 H NMR data

[0471]

[0472]

[0473] Table 2. Ex02 13 C NMR data

[0474]

[0475] Example 03

[0476]

[0477] To a solution of tert-butyl-(E)-(l-(5-(l-(difluoromethoxy)-7,15-dihydro-8H- benzo[g]benzo[4,5]imidazo[l,2-a]azanon-12-yl)pyrimidin-2-yl)cyclobutyl)carbamate (IV) (12.0 mg, 0.021 mmol) in DCM (1.0 mL) was added TFA (0.3 mL) with stirring. The resulting mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The crude product was purified by preparative HPLC (C18 column chromatography eluted with acetonitrile: water (0.1% formic acid) = 35% ~ 75%) to give (E)-l-(5-(l-(difluoromethoxy)-7,15-dihydro-8H-benzo[g]benzo[4,5]imidazo[l,2-a]azanon-12-yl)pyrimidin-2-yl)cyclobutane-l-amine (2.74 mg, yield: 27.7%) EX 03 as a white solid. LC-MS: m / z = 474.0 [M+H] + . 1 H NMR (400 MHz, MeOD-d4): δ 8.90 (s, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.55 ~ 7.48 (m, 1H), 7.36 ~ 6.95 (m, 5H), 6.17 ~ 6.09 (m, 1H), 5.65 (m, 2H), 5.40 (d, J = 16.4 Hz, 1H), 3.42 (m, 1H), 3.17 (m, 1H), 2.88 ~ 2.78 (m, 3H), 2.48 ~ 2.36 (m, 3H), 2.24 ~ 2.16 (m, 2H).

[0478] NMR data of Ex03 are shown in Table 3 and Table 4 below:

[0479]

[0480] Table 3. NMR data of Ex03 1 H NMR data

[0481]

[0482] Table 4. NMR data of Ex03 13 C NMR data

[0483]

[0484]

[0485] Example 04 and Example 05

[0486]

[0487] To a solution of 4B (200 mg, 796 pmol) in dioxane (10.0 mL) and water (2.0 mL) was added tert-butyl-N-[l-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2- yl]cyclobutyl]carbamate (1G) (299 mg, 796 pmol), K2CO3 (330 mg, 2.39 mmol) and Pd(dppf)Cl2 (58.3 mg, 79.6 pmol). The reaction mixture was stirred at 100 °C under nitrogen for 16 h. The mixture was concentrated and purified by silica gel chromatography (PE:EtOAc = 1:1) to give the target compound tert-butyl-(l-(5-(2-(but-3-en-l-yl)-lH-benzo[d]imidazol-6-yl)pyrimidin-2-yl)cyclobutyl)carbamate (4C) (300 mg, 0.72 mmol, yield: 89%) as a white solid. LCMS (ESI) m / z: 420.4 [M+H] + .

[0488]

[0489] To a solution of 4B (200 mg, 796 pmol) in dioxane (10.0 mL) and water (2.0 mL) was added tert-butyl-N-[l-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2- yl]cyclobutyl]carbamate (1G) (299 mg, 796 pmol), K2CO3 (330 mg, 2.39 mmol) and Pd(dppf)Cl2 (58.3 mg, 79.6 pmol). The reaction mixture was stirred at 100 °C under nitrogen for 16 h. The mixture was concentrated and purified by silica gel chromatography (PE:EtOAc = 1:1) to give the target compound tert-butyl-(l-(5-(2-(but-3-en-l-yl)-lH-benzo[d]imidazol-6-yl)pyrimidin-2-yl)cyclobutyl)carbamate (4C) (300 mg, 0.72 mmol, yield: 89%) as a white solid. LCMS (ESI) m / z: 420.4 [M+H] + .

[0490]

[0491] To a mixture of 4C (100 mg, 238 pmol) in acetonitrile (10 mL) was added l-(bromomethyl)-2-vinyl-benzene (4D) (94.0 mg, 477 pmol) and K2CO3 (98.8 mg, 715 pmol). The reaction was then stirred at 60 °C for 16 h. The mixture was poured into water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography (PE:EtOAc = 5: 1) to give a mixture of compounds 4E and 4F (120 mg, 0.22 mmol, yield: 94%) as a white solid. LCMS (ESI) m / z: 536.4 [M+H] + .

[0492]

[0493] To a solution of the mixture of 4E and 4F (100 mg, 187 pmol) in DCM was added p-toluenesulfonic acid monohydrate (39.1 mg, 205 pmol) and Grubbs second generation catalyst (15.9 mg, 18.7 pmol) and stirred at 50 °C for 16 h. The mixture was concentrated to give a residue, which was purified by preparative HPLC to give a mixture of 4G and 4H (25 mg, 0.049 mmol, yield: 26%) as a yellow solid. LCMS (ESI) m / z: 508.4 [M+H] + .

[0494]

[0495] To a solution of the mixture of 4G and 4H (10.0 mg, 19.7 pmol) in DCM (3.0 mL) was added TFA (1.0 mL). The reaction mixture was stirred at room temperature for 2 h, then concentrated to give a residue, which was purified by preparative HPLC to give the target compounds (Z)-l-(5-(7, 15-dihydro-8H-benzo[g]benzo[4,5]imidazo[l,2-a]azanonan-12-yl)pyrimidin-2-yl)cyclobutane-l- amine EX 04 (1.0 mg, 2.48 pmol, yield: 12.0%) and EX 05 (0.95 mg, 2.33 pmol, yield: 11%) as white solids.

[0496] EX 04: LCMS (ESI) m / z: 408.43 [M+H]+. 1H NMR (400 MHz, CDC13) δ 9.02 (s, 2H), 7.79 (d, J = 8.0 Hz, 1H), 7.64 - 7.72 (m, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.24 - 7.21 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.55 (d, J = 12 Hz, 1H), 6.08 - 5.96 (m, 1H), 5.36 (s, 2H), 3.35 - 3.19 (m, 2H), 2.94 - 2.81 (m, 4H), 2.50 - 2.37 (m, 2H), 2.31 - 2.17 (m, 2H).

[0497] EX 05: LCMS (ESI) m / z: 408.41 [M+H]+. 1 H NMR (400 MHz, CDC13) δ 8.92 (s, 2H), 7.99 (s, 1H), 7.83 - 7.73 (m, 1H), 7.61 (d, J = 12 Hz, 2H), 7.37 - 7.31 (m, 2H), 7.18 (d, J = 8.0 Hz, 1H), 6.57 (d, J = 12 Hz, 1H), 6.06 - 5.99 (m, 1H), 5.54 (s, 2H), 3.61 - 3.47 (m, 2H), 2.88 (t, J = 7.6 Hz, 4H), 2.57 - 2.48 (m, 2H), 2.39 - 2.31 (m, 2H).

[0498] Example 06

[0499]

[0500] To a mixture of 3-bromo-2-methyl-phenol (6A) (8.00 g, 42.8 mmol) in DMF (50 mL) was added (2-chloro-2,2-difluoro-acetyl)oxy sodium (6.52 g, 42.8 mmol) and K2CO3 (11.8 g, 85.6 mmol). Then the mixture was stirred at 100 °C under nitrogen for 16 hours. The mixture was concentrated and purified by silica gel chromatography (PE:EtOAc = 10:1) to give the target compound 1-bromo-3-(difluoromethoxy)-2-methylbenzene (6B) (4.4 g, 18.56 mmol, yield: 43%) as a colorless liquid. 1 H NMR (400 MHz, CDC13) δ 7.44 - 7.37 (m, 1H), 7.04 (d, J = 4.0 Hz, 2H), 6.46 (t, J = 73.6 Hz, 1H), 2.36 (s, 3H).

[0501]

[0502] To a mixture of 1-bromo-3-(difluoromethoxy)-2-methylbenzene (6B) (500 mg, 2.11 mmol) in CCI4(10 mL) was added NBS (412 mg, 2.30 mmol) and AIBN (69.3 mg, 422 pmol). The mixture was stirred at 90 °C under nitrogen for 16 h. The mixture was concentrated and purified by silica gel chromatography (PE) to give the target compound 6C (524 mg, 2.21 mmol, yield: 78%) as colorless oil. 1 H NMR (400 MHz, CDC13) δ 7.58 ~ 7.53 (m, 1.2H), 7.41 ~ 7.35 (m, 1.5H), 7.29 (d, J = 8.0 Hz, 1H), 7.17 (s, 0.3H), 4.49 (s, 2H).

[0503]

[0504] To a solution of tert-butyl-N-[1-[5-(2-(3-butenyl)-3H-benzimidazol-5-yl)pyrimidin-2- yl]cyclobutyl]carbamate (4C) (270 mg, 644 pmol) in DMF (10 mL) was added 1-bromo- 2-(bromomethyl)-3-(difluoromethoxy)benzene (6C) (305 mg, 965 pmol) and Cs2CO3(419 mg, 1.29 mmol). The mixture was stirred at room temperature for 2 h, concentrated and purified by silica gel chromatography (PE: EtOAc = 1: 1) to give a mixture of the target compound 6D and its regioisomer 6E (300 mg, 458.33 pmol, yield: 71%) as white solid. LCMS (ESI) m / z: 653.9 [M+H] + .

[0505]

[0506] To a solution of 6D and 6E (250 mg, 50.4 pmol) in dioxane (16 mL) and H2O (4 mL) was added potassium trifluoro(vinyl)borate (51.2 mg, 382 pmol), K2CO3(158 mg, 1.15 mmol) and Pd(dppf)Cl2(27.9 mg, 38.2 pmol). The mixture was stirred at 110 °C under nitrogen for 16 h, concentrated and purified by silica gel chromatography (PE: EtOAc = 1: 1) to give 6F and 6G (108 mg, 179.50 pmol, yield: 47%) as yellow oil. LCMS (ESI) m / z: 602.6 [M+H] + .

[0507]

[0508] To a solution of 6F and 6G (80.0 mg, 133 pmol) in DCM (20 mL) was added p-toluenesulfonic acid monohydrate (25.2 mg, 132 pmol) and Grubbs second generation catalyst (56.4 mg, 66.5 pmol). The mixture was stirred at 50 °C for 16 h, concentrated, purified by prep-HPLC to give a mixture of the target compound 6H and its isomer 6I (60 mg, 104.60 pmol, yield: 78%) as a yellow solid. 1 H NMR (400 MHz, CDC13) d 8.99 (m, 2H), 8.11 - 7.74 (m, 2H), 7.53 - 7.42 (m, 1H), 7.38 - 7.28 (m, 1H), 7.06 (dt, J = 11.6, 8.0 Hz, 2H), 6.89 - 6.50 (m, 1H), 5.98 (s, 1H), 5.48 - 5.43 (m, 2H), 5.16 (d, J = 2.4 Hz, 1H), 3.44 (s, 2H), 2.76 (br s, 4H), 2.24 - 2.11 (m, 2H), 1.85 (s, 2H), 1.55 - 1.31 (m, 9H).

[0509]

[0510] To a solution of 6H and 6I (60 mg, 104.60 pmol) in DCM (3.0 mL) was added TFA (1.0 mL). The reaction mixture was stirred at 0 °C for 2 h. The mixture was concentrated, purified by prep-HPLC to give the target compound (Z)-1-(5-(1-(difluoromethoxy)-7,15-dihydro-8H-benzo[g]benzo[4,5]imidazo[1,2-a]azene-12-yl)pyrimidin-2-yl)cyclobutane-1-amine (EX 06) (10.29 mg, 0.022 mmol, yield: 21%) as a white solid. LCMS (ESI) m / z: 474.39 [M+H] + ; Rt = 2.269 min. 1H NMR (400 MHz, CDC13) δ 8.99 (s, 2H), 7.93 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 1.2 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.32 (s, 1H), 7.05 (t, J = 8.0 Hz, 2H), 6.72 (t, J = 72 Hz, 1H), 5.50 (s, 1H), 5.44 (s, 2H), 5.18 (s, 1H), 3.47 (s, 2H), 2.97-2.80 (m, 4H), 2.60-2.55 (m, 2H), 2.34-2.32 (m, 2H), 2.18-2.16 (m, 2H).

[0511] Examples 07 and 08

[0512]

[0513] A mixture of tert-butyl (2-bromo-6-(difluoromethoxy)benzyl)carbamate (IL) (5.0 g, 14.3 mmol), 2-allyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (3.6 g, 21.4 mmol), Pd(dppf)Cl2(1.04 g, 1.43 mmol) and K2CO3(5.90 g, 42.7 mmol) in dioxane (16 mL) and water (4.0 mL) was stirred at 90 °C under argon for 12 h. The reaction mixture was cooled, concentrated and purified by silica gel column chromatography (5% to 10% EtOAc / PE solution) to give tert-butyl (2-allyl-6-(difluoromethoxy)benzyl)carbamate (7A) (4.0 g, yield: 90%) as a white solid. LC-MS: m / z = 314.2 [M+H] + .

[0514]

[0515] To a solution of tert-butyl (2-allyl-6-(difluoromethoxy)benzyl)carbamate (7A) (4.0 g, 12.8 mmol) in DCM (9.0 mL) was added TFA (3.0 mL) with stirring. The mixture was stirred at room temperature for 2 h and concentrated. The crude product was used directly in the next step reaction without further purification. LC-MS: m / z = 214.3 [M+H] + .

[0516]

[0517] A mixture of (2-allyl-6-(difluoromethoxy)phenyl)methanamine (7B) (2.72 g, 12.8 mmol), 4-bromo-2-fluoro-l-nitrobenzene (3.37 g, 15.3 mmol), DIEA (4.9 g, 38.34 mmol) in EtOH (15 mL) was stirred at 80 °C for 12 h. The resulting mixture was cooled, concentrated, and purified by silica gel column chromatography (5% to 10% EtOAc / PE solution) to give N-(2-allyl-6-(difluoromethoxy)benzyl)-5-bromo-2-nitroaniline (4.9 g, 93%) as a white solid. LC-MS: m / z = 413.2 [M+H] + .

[0518]

[0519] A mixture of N-(2-allyl-6-(difluoromethoxy)benzyl)-5-bromo-2-nitroaniline (7C) (4.90 g, 11.9 mmol) and iron powder (3.30 g, 59.3 mmol) in saturated ammonium chloride solution (4.0 mL) and ethanol (16.0 mL) was stirred at 70 °C for 4 h. The resulting mixture was cooled and filtered. The filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated and washed with DCM (3 x 10 mL) to give N1-(2-allyl-6-(difluoromethoxy)benzyl)-5-bromobenzene-l,2-diamine (7D) (4.2 g, 93%) as a white solid. LC-MS: m / z = 383.3 [M+H] + .

[0520]

[0521] To a mixture of 7D (4.2 g, 11.0 mmol) and triethylamine (3.3 g, 33.0 mmol) in DCM (20 mL) was added a solution of acryloyl chloride (995 mg, 11.0 mmol) in DCM (2.0 mL) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 h, concentrated under reduced pressure, and purified by silica gel column chromatography (5% to 10% EtOAc / PE solution) to give N-(2-((2-allyl-6-(difluoromethoxy)benzyl)amino)-4-bromophenyl)acrylamide (4 g, yield 84%) as a white solid. LC-MS: m / z = 437.0 [M+H] + .

[0522]

[0523] A mixture of 7E (2.0 g, 4.59 mmol) in AcOH (15 mL) was stirred at 120 °C for 12 h. The resulting mixture was cooled, concentrated, adjusted to pH = 8 with saturated aqueous sodium carbonate solution. The resulting mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried, concentrated, and purified by silica gel column chromatography (10% to 50% EtOAc / PE solution) to give 1-(2-allyl-6-(difluoromethoxy)benzyl)-6-bromo-2-vinyl-1H- benzo[d]imidazole (7F) (900 mg, 48% yield) as a white solid. LC-MS: m / z = 419.2 [M+H] + .

[0524]

[0525] A solution of 7F (300 mg, 0.72 mmol) and Grubbs second generation catalyst (122 mg, 0.14 mmol) in DCM (15 mL) was stirred at 40 °C for 12 h under argon. The mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% to 60% EtOAc / PE solution) to give 11-bromo-1-(difluoromethoxy)-5,14-dihydrobenzo[f]benzo[4,5]imidazo[1,2-a]azepine (110 mg, 39% yield, mixture of cis and trans isomers) as a white solid. LC-MS: m / z = 390.9 [M+H] + .

[0526]

[0527] A mixture of 11-bromo-1-(difluoromethoxy)-5,14-dihydrobenzo[f]benzo[4,5]imidazo[1,2- a]azocine (40 mg, 0.10 mmol), tert-butyl (1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrimidin-2-yl)cyclobutyl)carbamate (60 mg, 0.21 mmol), Pd(dppf)Cl2(7.5 mg, 0.01 mmol) and K2CO3(28 mg, 0.21 mmol) in dioxane (2 mL) and water (0.5 mL) was stirred at 100 °C under argon for 12 h. After cooling, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-60% EtOAc / PE solution) to give tert-butyl-(1-(5-(1-(difluoromethoxy)-5,14-dihydrobenzo[f]benzo[4,5]imidazo[1,2- a]azocin-11-yl)pyrimidin-2-yl)cyclobutyl)carbamate (35 mg, 61% yield, mixture of cis and trans isomers) as a white solid. LC-MS: m / z = 560.3 [M+H] + .

[0528]

[0529] To a solution of 7H (35 mg, 0.06 mmol) in DCM (3.0 mL) was added TFA (0.3 mL) dropwise at room temperature with stirring for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by preparative HPLC (C18 column eluted with ACN:H2O (0.1% FA) = 5% to 95%) to give EX07 (3.25 mg, 11.31% yield) and EX08 (0.57 mg, 2%).

[0530] EX07: LC-MS: m / z = 460.0 [M+H] + . 1 H NMR (400 MHz, MeOD-d4): δ 9.15 (s, 2H), 8.09 (s, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.50 (t, J = 8.8 Hz, 1H), 7.26-7.19 (m, 3H), 6.89 (t, J = 8.8 Hz, 1H), 6.23 (dt, J = 10 Hz, 7.6 Hz, 1H), 5.42 (s, 2H), 3.48 (d, J = 8.8 Hz, 2H), 2.85-2.78 (m, 2H), 2.36-2.28 (m, 2H), 2.17-2.06 (m, 2H).

[0531] EX08: LC-MS: m / z = 460.0 [M+H] + . 1 H NMR (400 MHz, MeOD-d4) δ 9.23 (s, 2H), 8.14 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.35 (t, J = 8.8 Hz, 1H), 7.19 - 6.65 (m, 4H), 6.66 (d, J = 13.2 Hz, 1H), 6.51 (dt, J = 13.2 Hz, 7.2 Hz, 1H), 5.80 (s, 2H), 3.96 (d, J = 6.0 Hz, 2H), 2.93 - 2.84 (m, 2H), 2.55 - 2.45 (m, 2H), 2.30 - 2.18 (m, 2H).

[0532] Example 09 and Example 10

[0533]

[0534] A mixture of 5-bromo-2-iodo-pyrimidine (9A) (7.00 g, 24.6 mmol), morpholine (4.28 g, 49.1 mmol, 4.30 mL), DIEA (6.35 g, 49.1 mmol, 8.56 mL) in ACN (50 mL) was stirred at room temperature for 16 h. The reaction mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (15% EtOAc / PE solution) to give 4-(5-bromopyrimidin-2-yl)morpholine (9B) (5.80 g, 96% purity, 23.7 mmol, 96% yield) as a gray solid. LCMS (ESI) m / z: 244.13 [M+H] + .

[0535]

[0536] To a solution of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (1.1 g, 96% purity, 4.5 mmol) and 4-(5-bromopyrimidin-2-yl)morpholine (9B) (1.0 g, 4.1 mmol) in dioxane (5 mL) was added Pd(dppf)Cl2(449 mg, 0.614 mmol) and potassium acetate (1.21 g, 12.2 mmol). The reaction mixture was purged with N2and stirred at 85 °C for 16 h. Water (30 mL) was added, the mixture was extracted with EtOAc (3 x 100 mL), the combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated and purified by silica gel column chromatography (25% EtOAc / PE solution) to give 4-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]morpholine (9C) (1.0 g, 80% purity, 3.4 mmol, 84% yield) as a yellow solid. LCMS (ESI) m / z: 295.2 [M+H] @ 1.9 min. + 292.1.

[0537]

[0538] To a solution of 9C (268 mg, 90% purity, 923 pmol) and 6-bromo-2-but-3-enyl-l-[[2- (difluoromethoxy)-6-ethenyl-phenyl]methyl]benzimidazole (9D) (400 mg, 80% purity, 923 pmol) in dioxane (5.0 mL) and water (1.0 mL) was added K2CO3(382 mg, 2.77 mmol) and Pd(dppf)Cl2(101 mg, 138 pmol). The mixture was stirred at 100 °C under N2for 16 h. Water was added, the mixture was extracted with EtOAc (30 mL x 3), the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated and purified by silica gel column chromatography (40% to 50% EtOAc / PE solution) to give 4-[5-[2-but-3-enyl-3-[[2-(difluoromethoxy)-6-ethenyl- phenyl]methyl]benzimidazol-5-yl]pyrimidin-2-yl]morpholine (9E) (350 mg, 96% purity, 676 pmol, 73% yield) as a white solid. LCMS (ESI) m / z: 518.46 [M+H] @ 2.1 min. + .

[0539]

[0540] To a solution of 9C (190 mg, 90% purity, 456 pmol) and 5-bromo-2-but-3-enyl-1-[[2-(difluoromethoxy)-6-ethenyl-phenyl]methyl]benzoimidazole (9F) (210 mg, 80% purity, 460 pmol) in dioxane (5.0 mL) and water (1.0 mL) was added K2CO3 (190 mg, 1.37 mmol) and Pd(dppf)Cl2 (50 mg, 68 pmol). The mixture was stirred at 100 °C under N2for 16 h. Water was added, and the mixture was extracted with EtOAc (30 mL x 3), and the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (40% to 50% EtOAc / PE solution) to give 4-[5-[2-but-3-enyl-1-[[2-(difluoromethoxy)-6-ethenyl-phenyl]methyl]benzoimidazol-5-yl]pyrimidin-2-yl]morpholine (9G) (160 mg, 89% purity, 293 pmol, 63% yield) as a white solid. LCMS (ESI) m / z: 518.5 [M+H] + .

[0541]

[0542] To a solution of 9E (95 mg, 96% purity, 183 pmol) and 4-methylbenzenesulfonic acid (31.6 mg, 183 mol) in DCM (40 mL) was added Grubbs second generation catalyst (77.9 mg, 91.7 pmol) under N2protection at 50 °C for 30 min, then cooled to room temperature. The mixture was stirred at 50 °C under N2for 16 h. The mixture was concentrated, and sodium bicarbonate solution was added and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and purified by prep-HPLC (column: Waters Xbridge 250*30 mm, 5 pm; mobile phase A: H2O (+0.1% NH4Cl), mobile phase B: ACN; gradient: 20-55% B; flow rate: 30 mL / min; wavelength: 214 nm / 254 nm) to give (Z)-4-(5-(1-(difluoromethoxy)-7,15-dihydro-8H-benzo[g]benzo[4,5]imidazo[1,2-a]azetidin-12-yl)pyrimidin-2-yl)morpholine (EX09) (6.7 mg, 100% purity, 13 pmol, 7% yield) as a white solid. LCMS (ESI) m / z: [M+H] + 490.3. 1H NMR (400 MHz, CDCI3) δ 8.66-8.57 (m, 2H), 7.77-7.73 (m, 1H), 7.39-7.31 (m, 2H), 7.20-7.12 (m, 1H), 7.09-7.02 (m, 2H), 6.68-6.47 (m, 1H), 6.35-6.29 (m, 1H), 6.24-5.82 (m, 1H), 5.58-5.26 (m, 2H), 3.89-3.78 (m, 8H), 3.54-3.29 (m, 2H), 2.71 (s, 1H), 1.72 (s, 1H).

[0543]

[0544] To a solution of 9G (150 mg, 89% purity, 275 μmol) and 4-methylbenzenesulfonic acid (48 mg, 278 μmol) in DCM (60 mL) was added Grubbs second generation catalyst (114 mg, 134 μmol) at 50 °C under N2protection for 30 min, then cooled to room temperature. The mixture solution was stirred at 50 °C for 16 h under N2. The mixture was concentrated, added with NaHC03solution, extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2S04, filtered. The filtrate was concentrated and purified by prep-HPLC (column: Waters Xbridge 250*30 mm, 5 μm; mobile phase A: H20 (+0.1% NH4CI), mobile phase B: ACN; gradient: 15-55% B; flow rate: 30 mL / min; wavelength: 214 nm / 254 nm) to give (Z)-4-(5-(1-(difluoromethoxy)-7,15-dihydro-8H-benzo[g]benzo[4,5]imidazo[1,2-a]azepin-11 -yl)pyrimidin-2-yl)morpholine (EX10) (6.0 mg, 100% purity, 12 μmol, 4% yield) as a white solid. LCMS (ESI) m / z: [M+H] + 490.41. 1 H NMR (400 MHz, CDCI3) δ 8.63-8.59 (m, 2H), 7.83 (s, 1H), 7.52-7.43 (m, 1H), 7.39-7.34 (m, 2H), 7.23-7.04 (m, 2H), 6.71-6.50 (m, 1H), 6.38-6.31 (m, 1H), 6.23-5.85 (m, 1H), 5.59-5.26 (m, 2H), 3.87-3.79 (m, 8H), 3.38 (s, 1H), 2.72 (s, 1H), 1.63 (s, 2H).

[0545] Example 11 and Example 12

[0546]

[0547] A mixture of tert-butyl (2-bromo-6-(difluoromethoxy)benzyl)carbamate (1L) (2.0 g, 5.70 mmol), but-3-en-1-ylboronic acid (855 mg, 8.55 mmol), Pd(dppf)Cl2(417 mg, 0.57 mmol) and K2CO3(2.36 g, 42.7 mmol) in dioxane (16 mL) and water (4 mL) was stirred at 90 °C under argon for 12 h. The resulting mixture was cooled and concentrated. The residue was purified by column chromatography on silica gel (5% to 15% EtOAc / PE solution) to give tert-butyl (2-(but-3-en-1-yl)-6-(difluoromethoxy)benzyl)carbamate (11A) (760 mg, 41% yield) as a white solid. LC-MS: m / z = 328.0 [M+H] + .

[0548]

[0549] To a solution of tert-butyl (2-(but-3-en-1-yl)-6-(difluoromethoxy)benzyl)carbamate (11A) (760 mg, 2.32 mmol) in DCM (3.0 mL) was added TFA (1.0 mL) with stirring. The mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure to give crude product 11B, which was used directly in the next step without further purification. LC-MS: m / z = 228.0 [M+H] + .

[0550]

[0551] A mixture of (2-(but-3-en-1-yl)-6-(difluoromethoxy)phenyl)methanamine (11B) (511 mg, 2.25 mmol), 4-bromo-2-fluoro-1-nitrobenzene (594 mg, 2.70 mmol), DIEA (871 mg, 6.75 mmol) in EtOH (5 mL) was stirred at 80 °C for 12 h. The resulting mixture was cooled, concentrated under reduced pressure, and purified by column chromatography on silica gel (5% to 10% EtOAc / PE solution) to give 5-bromo-N-(2-(but-3-en-1-yl)-6-(difluoromethoxy)benzyl)-2-nitroaniline (11C) (820 mg, 86%) as a white solid. LC-MS: m / z = 427.0 [M+H] + .

[0552]

[0553] A mixture of 5-bromo-N-(2-(but-3-en-1-yl)-6-(difluoromethoxy)benzyl)-2-nitroaniline (11C) (820 mg, 1.92 mmol) and iron powder (538 mg, 9.60 mmol) in saturated ammonium chloride solution (1.0 mL) and EtOH (4.0 mL) was stirred at 70 °C for 4 h. The resulting mixture was cooled, filtered, and the filter cake was washed with methanol (3 x 10 mL). The filtrate was concentrated to dryness under reduced pressure. The residue was washed with DCM (3 x 10 mL) to give 11D (600 mg, 79%) as a white solid. LC-MS: m / z = 397.2 [M+H] + .

[0554]

[0555] A mixture of 5-bromo-N-(2-(but-3-en-1-yl)-6-(difluoromethoxy)benzyl)-2-nitroaniline (11C) (820 mg, 1.92 mmol) and iron powder (538 mg, 9.60 mmol) in saturated ammonium chloride solution (1.0 mL) and EtOH (4.0 mL) was stirred at 70 °C for 4 h. The resulting mixture was cooled, filtered, and the filter cake was washed with methanol (3 x 10 mL). The filtrate was concentrated to dryness under reduced pressure. The residue was washed with DCM (3 x 10 mL) to give 11D (600 mg, 79%) as a white solid. LC-MS: m / z = 397.2 [M+H] + .

[0556]

[0557] A mixture of 5-bromo-N-(2-(but-3-en-1-yl)-6-(difluoromethoxy)benzyl)-2-nitroaniline (11C) (820 mg, 1.92 mmol) and iron powder (538 mg, 9.60 mmol) in saturated ammonium chloride solution (1.0 mL) and EtOH (4.0 mL) was stirred at 70 °C for 4 h. The resulting mixture was cooled, filtered, and the filter cake was washed with methanol (3 x 10 mL). The filtrate was concentrated to dryness under reduced pressure. The residue was washed with DCM (3 x 10 mL) to give 11D (600 mg, 79%) as a white solid. LC-MS: m / z = 397.2 [M+H] + .

[0558]

[0559] A mixture of 6-bromo-l-(2-(but-3-en-l-yl)-6-(difluoromethoxy)benzyl)-2- ethyl ene-lH-benzo[d]imidazole (11F) (80 mg, 0.19 mmol) and Grubbs second generation catalyst (33 mg, 0.038 mmol) in DCM (2.0 mL) was stirred at 40 °C under argon for 12 h. The mixture was cooled, concentrated and purified by silica gel column chromatography (10-60% EtOAc / PE solution) to give 11G (a mixture of trans and cis isomers) (40 mg, 51% yield) as a white solid. LC-MS: m / z = 390.9 [M+H] + .

[0560]

[0561] A mixture of 11G (40 mg, 0.10 mmol), tert-butyl (l-(5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrimidin-2-yl)cyclobutyl)carbamate (1G) (60 mg, 0.21 mmol), Pd(dppf)Cl2(7.5 mg, 0.01 mmol) and K2CO3(28 mg, 0.21 mmol) in dioxane (2.0 mL) and water (0.5 mL) was stirred at 100 °C under argon for 12 h. The resulting mixture was concentrated and purified by silica gel column chromatography (10-60% EtOAc / PE solution) to give 11H (a mixture of trans and cis isomers) (26.5 mg, 47% yield) as a white solid. LC-MS: m / z = 574.2 [M+H] + .

[0562]

[0563] To a solution of 11H (26.5 mg, 0.046 mmol) in DCM (3.0 mL) was added TFA (0.30 mL) with stirring. The mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The crude product was purified by preparative HPLC (C18 column chromatography eluted with acetonitrile-water (0.1% formic acid) = 5-95%) to give two isomers: EX11 (1.80 mg, 8% yield) and EX11 (2.46 mg, 11% yield) as white solids.

[0564] EX11: LC-MS: m / z = 474.0 [M+H] + . 1H NMR (400 MHz, MeOD-d4) δ 9.29 (m, 2H), 8.47 (m, 1H), 7.98 - 7.86 (m, 2H), 7.63 - 7.56 (m, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.89 (t, J = 73.6 Hz, 1H), 6.31 - 6.11 (m, 1H), 5.90 (m, 1H), 4.94 (s, 2H), 3.91 - 3.74 (m, 1H), 3.26 - 3.15 (m, 1H), 3.01 - 2.85 (m, 3H), 2.72 - 2.59 (m, 3H), 2.47 - 2.31 (m, 3H).

[0565] EX12: LC-MS: m / z = 474.1 [M+H] + . 1 H NMR (400 MHz, MeOD-d4) δ 9.29 (s, 2H), 7.79 (s, 2H), 7.49 - 7.41 (m, 1H), 7.34 - 7.27 (m, 1H), 7.18 - 6.78 (m, 2H), 6.55 (d, J = 14.0 Hz, 1H), 6.46 - 6.39 (m, 1H), 5.96 (m, 3H), 3.45 - 3.42 (m, 1H), 3.00 - 2.86 (m, 2H), 2.68 - 2.56 (m, 2H), 2.48 - 2.26 (m, 2H), 1.68 (s, 3H).

[0566] Example 13

[0567]

[0568] A mixture of 4-bromobenzene-1,2-diamine (13A) (3.0 g, 16 mmol) and hex-5-enoic acid (3.6 g, 32 mmol) in HCl solution (5.0 M, 5.0 mL in water) was stirred at 100 °C for 16 hours. Then the pH was adjusted to 7.0 with saturated sodium bicarbonate, the combined aqueous layers were extracted with EtOAc (2 x 200 mL), the combined organic layers were washed with brine (3 x 200 mL), dried over Na2S04and filtered. The filtrate was concentrated and purified by silica gel column chromatography (25% EtOAc / PE solution) to give 6-bromo-2-pent-4-enyl-1H-benzimidazole (13B) (2.0 g, 95% purity, 7.5 mmol, 47% yield) as a white solid. LCMS (ESI) m / z: [M+H] + 264.9.

[0569]

[0570] A mixture of 6-bromo-2-but-3-enyl-lH-benzimidazole (13B) (2.10 g, 95% purity, 7.80 mmol), [2-(difluoromethoxy)-6-vinyl-phenyl]methanol (1.56 g, 95% purity, 7.80 mmol) and 2-(tributyl-phosphoranylidene)acetonitrile (2.26 g, 9.36 mmol) in toluene (15 mL) was stirred at 120 °C for 3 h under N2protection. The mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (35% EtOAc / PE solution) to give 6-bromo-2-but-3-enyl-l-[[2-(difluoromethoxy)-6-vinyl-phenyl]methyl]- benzimidazole (13C) (880 mg, 92% purity, 1.85 mmol, 23% yield) as a white solid. LCMS (ESI) m / z: [M+H] + 446.9.

[0571]

[0572] To a solution of 6-bromo-2-but-3-enyl-l-[[2-(difluoromethoxy)-6-vinyl-phenyl]methyl]- benzimidazole (13C) (200 mg, 92% purity, 443 μmol) and tert-butyl N-[l-[5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]cyclobutyl]carbamate (1G) (166 mg, 80% purity, 443 μmol) in dioxane (5.0 mL) and water (1.0 mL) was added Pd(dppf)Cl2(48 mg, 66 μmol) and K2CO3(183 mg, 1.33 mmol). The mixture was stirred at 100 °C for 16 h under N2protection. The reaction mixture was cooled to room temperature, quenched with water (50 mL), and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (40-50% EtOAc / PE solution) to give tert-butyl N-[l-[5-[3-[[2-(difluoromethoxy)-6-vinyl-phenyl]methyl]-2-pent-4-enyl- benzimidazol-5-yl]pyrimidin-2-yl]cyclobutyl]carbamate (13D) (270 mg, 95% purity, 438 μmol, 95% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] + 616.5.

[0573]

[0574] A mixture of 13D (120 mg, 95% purity, 194 pmol) and 4-methylbenzenesulfonic acid (33.0 mg, 194 pmol) in DCM (60 mL) was stirred at 50 °C under N2for 30 min, cooled to room temperature, and Grubbs second generation catalyst (15 mg, 20 pmol) was added. The reaction mixture was stirred at 50 °C under N2for 16 h. The mixture was concentrated, sodium bicarbonate solution (40 mL) was added, and the mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated, and the resulting residue was purified by preparative thin-layer chromatography (TLC) (EtOAc:PE = 3: 1) to give 13E (15 mg, 77% purity, 25 pmol, 13% yield) as a white solid. LCMS (ESI) m / z: [M+H] + 588.4.

[0575]

[0576] To a solution of 13E in DCM (5.0 mL) was added TFA (1.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. The mixture was concentrated and purified by preparative HPLC (column: Waters Xbridge 250*30 mm, 5 pm; mobile phase A: H2O (+0.1% NH4OH), mobile phase B: ACN; gradient: 20-60% B; flow rate: 30 mL / min; wavelength: 214 nm / 254 nm) to give 1-[5-[(9Z)-4-(difluoromethoxy)-1,15-diazatetracyclo[12.7.0.03,8.016,21]heneicos-3,5,7,9,14,16,18,20-octaen-19-yl]pyrimidin-2-yl]cyclobutaneamine (EX13) (3.5 mg, 98% purity, 35% yield) as a white solid. LCMS (ESI) m / z: [M+H] + 488.43; Rt = 2.331 min. 1H NMR (400 MHz, CDC13) δ 8.86 - 8.81 (m, 2H), 7.81 - 7.71 (m, 1H), 7.44 - 7.35 (m, 1H), 7.28 - 7.24 (m, 1H), 7.19 - 7.10 (m, 1H), 7.02 (d, J = 1.6 Hz, 1H), 6.94 (t, J = 3.6 Hz, 1H), 6.76 - 6.74 (m, 1H), 5.64 - 5.55 (m, 2H), 5.38 - 5.28 (m, 1H), 4.98 - 4.92 m, 1H), 2.88 - 2.73 (m, 2H), 2.25 - 2.14 (m, 4H), 2.04 - 1.95 (m, 6H).

[0577] Example 14

[0578]

[0579] To a solution of 4-bromo-benzene-l,2-diamine (14A) (3.00 g, 16.0 mmol) in POCl3(30 mL) was added 2-methyl-4-pentenoic acid (3.66 g, 32.1 mmol). The mixture was stirred at 110 °C for 16 h. The solvent was removed and the reaction mixture was quenched by adding aqueous solution. Dried with NaHCO3at 0 °C, extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated and purified by silica gel column chromatography (PE solution of EtOAc) to give 6-bromo-2-(pent-4-en-2-yl)-lH-benzo[d]imidazole (14B) (3.00 g, 96% purity, 11.3 mmol, 70.5% yield) as a light brown solid. LCMS (ESI) m / z: 264.9 [M+H] + .

[0580]

[0581] To a mixture of 6-bromo-2-(1-methylbut-3-enyl)-1H-benzimidazole (14B) (2.70 g, purity 96%, 10.2 mmol), [2-(difluoromethoxy)-6-vinyl-phenyl]methanol (2.04 g, 10.2 mmol) in toluene (7 mL) was added cyanomethylidene tributylphosphonium (2.95 g, 12.2 mmol). The mixture was placed in a microwave reactor and stirred at 120 °C for 3 hours. The mixture was diluted with EtOAc, washed with water and brine. The organic layer was dried, concentrated, and purified by preparative TLC (PE:EtOAc = 4:1) to give 6-bromo-1-[[2-(difluoromethoxy)-6-vinyl-phenyl]methyl]-2-(1-methylbut-3-enyl)benzimidazole (14C) (850 mg, 1.90 mmol, 18.66% yield) as a yellow oil, and 5-bromo-3-[[2-(difluoromethoxy)-6-vinyl-phenyl]methyl]-2-(1-methylbut-3-enyl)-1,2-dihydrobenzoimidazole (14D) (630 mg, 1.40 mmol, 13.8% yield) as a yellow oil.

[0582]

[0583] To a mixture of 6-bromo-2-(1-methylbut-3-enyl)-1H-benzimidazole (14B) (2.70 g, purity 96%, 10.2 mmol), [2-(difluoromethoxy)-6-vinyl-phenyl]methanol (2.04 g, 10.2 mmol) in toluene (7 mL) was added cyanomethylidene tributylphosphonium (2.95 g, 12.2 mmol). The mixture was placed in a microwave reactor and stirred at 120 °C for 3 hours. The mixture was diluted with EtOAc, washed with water and brine. The organic layer was dried, concentrated, and purified by preparative TLC (PE:EtOAc = 4:1) to give 6-bromo-1-[[2-(difluoromethoxy)-6-vinyl-phenyl]methyl]-2-(1-methylbut-3-enyl)benzimidazole (14C) (850 mg, 1.90 mmol, 18.66% yield) as a yellow oil, and 5-bromo-3-[[2-(difluoromethoxy)-6-vinyl-phenyl]methyl]-2-(1-methylbut-3-enyl)-1,2-dihydrobenzoimidazole (14D) (630 mg, 1.40 mmol, 13.8% yield) as a yellow oil. + .

[0584]

[0585] To a solution of tert-butyl (Z)-(1-(5-(1-(2-(difluoromethoxy)-6-ethenylbenzyl)-2-(pent-4-en-2-yl)-1H- benzo[d]imidazol-6-yl)pyrimidin-2-yl)cyclobutyl)carbamate (14E) (250 mg, 85% purity, 406 pmol) in DCE (125 mL) was added Grubbs second generation catalyst (172 mg, 203 pmol) and TsOH.H2O (77.2 mg, 406 pmol). The mixture was stirred at 65 °C for 4 h. The reaction mixture was quenched with aqueous NaHC03solution at 0 °C, then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure, purified on a silica gel column (40-50% EtOAc / PE solution) to give tert-butyl (Z)-(1-(5-(1-(difluoromethoxy)-8-methyl-7,15-dihydro-8H- benzo[g]benzo[4,5]imidazo[1,2-a]azene-12-yl)pyrimidin-2-yl)cyclobutyl)carbamate (14F) (16.0 mg, 83% purity, 26.1 pmol, 6.44% yield) as a yellow solid. LCMS (ESI) m / z: 588.55 [M+H] + .

[0586]

[0587] To a solution of tert-butyl (Z)-(1-(5-(1-(difluoromethoxy)-8-methyl-7,15-dihydro-8H- benzo[g]benzo[4,5]imidazo[1,2-a]azene-12-yl)pyrimidin-2-yl)cyclobutyl)carbamate (14F) (15.0 mg, 83% purity, 24.3 pmol) in DCM (10.0 mL) was added TFA (149 mg, 1.31 mmol, 0.10 mL). The mixture was stirred at 0 °C for 1 h. The solvent was removed, and the residue was purified by prep-HPLC (column: Waters Xbridge 250*30 mm, 5 pm; mobile phase A: H20 (+0.1% FA), mobile phase B: ACN; gradient: 30-80% B; flow rate: 40 mL / min; wavelength: 214 nm / 254 nm) to give (Z)-1-(5-(1-(difluoromethoxy)-8-methyl-7,15-dihydro-8H- benzo[g]benzo[4,5]imidazo[1,2-a]azepin-12-yl)pyrimidin-2-yl)cyclobutane-1-amine (EX14) (racemic mixture, 6.10 mg, 100% purity, 12.5 pmol, 51.6% yield) as a white solid. LCMS (ESI) m / z: 488.4 [M+H] + .1 H NMR (400 MHz, Chloroform-d) d 8.86 (s, 2H), 7.81 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.69 (t, J = 73.2 Hz, 1H), 6.10 (d, J = 11.6 Hz, 1H), 5.68 (d, J = 13.6 Hz, 3H), 3.74 (q, J = 6.8 Hz, 1H), 2.94 (s, 9H), 2.80 (s, 3H), 2.43 (s, 2H), 2.16 (d, J = 56.0 Hz, 2H), 1.71 (d, J = 7.2 Hz, 3H).

[0588] Example 15

[0589]

[0590] A mixture of 5-bromo-3-fluoro-benzene-1,2-diamine (15A) (5.00 g, 24.4 mmol), pent-4-enoic acid (2.44 g, 24.4 mmol, 2.5 mL) and HCl solution (5.0 M, 200 mL) was stirred at 100 °C for 16 h. The reaction mixture was quenched with saturated NaHCO3solution at 0 °C, then the mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (0-50% EtOAc / PE solution) to give 6-bromo-2-but-3-enyl-4-fluoro-1H-benzimidazole (15B) (3.10 g, 95% purity, 11.5 mmol, 47.2% yield) as a yellow solid. LCMS (ESI) m / z: 269.11 [M+H] + .

[0591]

[0592] A mixture of 15B (1.08 g, 95% purity, 4.00 mmol), tert-butyl (1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)cyclobutyl)carbamate (1G) (1.50 g, 96% purity, 4.00 mmol), K2CO3 (1.66 g, 12.0 mmol) and Pd(dppf)Cl2 (293 mg, 0.40 mmol) in dioxane (40 mL) and water (8.0 mL) was stirred at 110 °C for 5 h under N2protection. The reaction mixture was diluted with water, then extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (0-50% EtOAc / PE) to give tert-butyl (1-(5-(2-(but-3-en-1-yl)-4-fluoro-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)cyclobutyl)carbamate (15C) (700 mg, 95% purity, 1.52 mmol, 38.0% yield) as a yellow oil. LCMS (ESI) m / z: 438.42 [M+H] + . 1 H NMR (400 MHz, CDCl3) d 8.81 (s, 2H), 7.56 (s, 1H), 7.05 (s, 1H), 5.98-5.83 (m, 2H), 5.14 (d, J = 16.0 Hz, 1H), 5.07 (d, J = 12.0 Hz, 1H), 3.19 (t, J = 7.2 Hz, 2H), 2.83-2.60 (m, 4H), 2.59-2.55 (m, 2H), 2.20-2.07 (m, 2H), 1.45 (s, 9H).

[0593]

[0594] A mixture of tert-butyl (1-(5-(2-(but-3-en-1-yl)-4-fluoro-1H-benzo[d]imidazol-6- yl)pyrimidin-2-yl)cyclobutyl)carbamate 15C (500 mg, 95% purity, 1.09 mmol), 1- bromo-2-(bromomethyl)-3-(difluoromethoxy)benzene (515 mg, 1.63 mmol) and Cs2CO3(706 mg, 2.17 mmol) in DMF (5.0 mL) was stirred at room temperature for 0.5 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated and purified by silica gel column chromatography (0-50% EtOAc / PE solution) to give tert-butyl (1-(5-(1-(2-bromo-6-(difluoromethoxy)benzyl)-2-(but-3-en-1-yl)-4-fluoro-1H- benzo[d]imidazol-6-yl)pyrimidin-2-yl)cyclobutyl)carbamate 15D (264 mg, 98% purity, 385 µmol, 35.4% yield) as a white solid.

[0595] LCMS (ESI) m / z: 672.40 [M+H] + . 1 H NMR (400 MHz, CDCl3) d 8.82 (s, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.14-7.07 (m, 3H), 6.32 (t, J = 72.4 Hz, 1H), 5.99-5.79 (m, 2H), 5.58 (s, 2H), 5.09 (dd, J = 27.2, 13.2 Hz, 2H), 3.13 (t, J = 8.0 Hz, 1H), 2.79-2.63 (m, 6H), 2.22-2.09 (m, 2H), 1.43 (s, 9H).

[0596]

[0597] A mixture of tert-butyl (1-(5-(1-(2-bromo-6-(difluoromethoxy)benzyl)-2-(but-3-en-1-yl)-4-fluoro-1H- benzo[d]imidazol-6-yl)pyrimidin-2-yl)cyclobutyl)carbamate (15D) (120 mg, 98% purity, 175 pmol), Pd(dppf)Cl2(12.8 mg, 17.5 pmol), K2CO3(72.5 mg, 524 pmol) in dioxane (4.0 mL) and water (1.0 mL) was stirred at 100 °C for 5 h under N2protection. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated and purified by prep-TLC (5% MeOH in DCM) and prep-HPLC (Waters XBridge Prep C18 5 pm 19*250 mm, A H2O 0.1% NH3H2O, B MeCN 61%~68%) to give tert-butyl (Z)-(1-(5-(1-(difluoromethoxy)-10-fluoro-7,15-dihydro-8H- benzo[g]benzo[4,5]imidazo[1,2-a]azetidin-12-yl)pyrimidin-2-yl)cyclobutyl)carbamate (15F) (4.00 mg, 95% purity, 6.49 pmol, 3.7% yield) as a white solid, LCMS (ESI) m / z: 592.44 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.838 (s, 2H), 7.294-7.157 (m, 4H), 7.080-6.962 (m, 3H), 6.638-6.262 (m, 2H), 5.809-5.787 (m, 2H), 5.516 (s, 2H), 3.225 (s, 2H), 2.666 (s, 6H), 2.089-2.037 (m, 2H), 1.356 (s, 9H), 1.192 (s, 2H); and tert-butyl [1-(5-(1-(difluoromethoxy)-9-fluoro-5-methylene-5,6,7,14-tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azepin-11-yl)pyrimidin-2-yl)cyclobutyl]carbamate (15G) (12 mg, 19.9 pmol, 11.4% yield, 98% purity) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.99 (s, 2H), 7.83 (s, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.15 (d, J = 10.8 Hz, 1H), 7.05 (dd, J = 15.2, 8.0 Hz, 2H), 6.67 (t, J = 73.6 Hz, 1H), 5.96 (s, 1H), 5.45 (d, J = 25.2 Hz, 3H), 5.17 (s, 1H), 3.51 - 3.36 (m, 2H), 2.90 - 2.63 (m, 6H), 2.20 - 2.16 (m, 2H), 1.60 (s, 9H), 1.44 (s, 2H).

[0598]

[0599] A mixture of tert-butyl (1-(5-(1-(difluoromethoxy)-9-fluoro-5-methylene-5,6,7,14- tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azocine-11-yl)pyrimidin-2-yl)cyclobutyl)carbamate (15G) (10.0 mg, 98% purity, 16.6 μmol) and a solution of HCl in dioxane (4.0 M, 0.5 mL) in DCM (1.0 mL) was stirred at room temperature for 0.5 h. The reaction mixture was concentrated to give a residue and EtOAc (3.0 mL) was added. After the mixture was stirred at room temperature for 1 h, it was filtered to give 1-(5-(1-(difluoromethoxy)-9-fluoro-5-methylene-5,6,7,14- tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azocine-11-yl)pyrimidin-2-yl)cyclobutane-1-amine (EX15) (5.00 mg, 97.6% purity, 9.24 μmol, 55.8% yield, HC1 salt) as a gray solid. LCMS (ESI) m / z: 492.35 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 2H), 8.93 (s, 3H), 8.05 (s, 1H), 7.65 (d, J = 11.2 Hz, 1H), 7.47 - 7.39 (m, 2H), 7.18 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 5.55 (s, 2H), 5.48 (s, 1H), 5.14 (s, 1H), 3.40 (d, J = 7.6 Hz, 2H), 2.84 - 2.72 (m, 4H), 2.67 - 2.61 (m, 2H), 2.25 - 2.17 (m, 2H).

[0600] Example 16

[0601]

[0602] A mixture of 4-chloro-2-fluoro-l-nitro-benzene (16A) (1.50 g, 8.54 mmol), [2-bromo-6-(difluoromethoxy)phenyl]methanamine (1 M) (2.39 g, 8.54 mmol) and DIEA (8.83 g, 68.4 mmol) in EtOH (60 mL) was stirred at reflux for 16 h. The mixture was cooled to room temperature, then concentrated. The residue was quenched with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with water (150 mL x 3) and brine (150 mL), dried over Na2S04and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EtOAc = 10: 1) to give the title compound N-[[2-bromo-6-(difluoromethoxy)phenyl]methyl]-5-chloro-2-nitro-aniline (16B) (2.7 g, 93% purity, 6.18 mmol, 73% yield) as a yellow solid. LCMS (ESI) m / z: 407.10 [M+H] + .

[0603]

[0604] A mixture of N-[[2-bromo-6-(difluoromethoxy)phenyl]methyl]-5-chloro-2-nitro-aniline (16B) (3.0 g, 93% purity, 6.8 mmol), iron powder (2.47 g, 44.2 mmol) and NH4CI (3.94 g, 73.6 mmol) in EtOH (60 mL) and water (12 mL) was stirred at 85 °C for 2.5 h. The reaction mixture was cooled to room temperature, filtered and the filter cake was washed with EtOAc (200 mL). The combined organic layers were washed with water (200 mL) and brine (200 mL), dried over Na2S04and filtered. The filtrate was concentrated, purified by silica gel chromatography (PE:EtOAc = 5: 1) to give N1-(2-bromo-6-(difluoromethoxy)benzyl)-5-chlorobenzene-l,2-diamine (16C) (2.5 g, 91% purity, 6.05 mmol, 89% yield) as a yellow oil. LCMS (ESI) m / z: 377.13 [M+H] + .

[0605]

[0606] A mixture of pent-4-enoic acid (327 mg, 3.27 mmol), HATU (1.43 g, 3.77 mmol) and DIEA (975 mg, 7.55 mmol) in DMF (20 mL) was stirred at room temperature for 5 min. Then N2-[[2-bromo-6-(difluoromethoxy)phenyl]methyl]-4-chloro-benzene-1,2-diamine (16C) (1.0 g, 91% purity, 2.4 mmol) was added portionwise to the mixture, which was stirred at room temperature for 3 h. The reaction mixture was quenched with water (150 mL) and extracted with EtOAc (100 mL x 2), the combined organic layers were washed with water (150 mL x 3) and brine (100 mL). The organic layer was dried over Na2SO4and filtered. The filtrate was concentrated and purified by silica gel chromatography (PE:EtOAc = 3:1) to give the title compound N-[2-[[2-bromo-6-(difluoromethoxy)phenyl]methylamino]-4-chlorophenyl]pent-4- enoic amide (16D) (1.01 g, 91% purity, 2.09 mmol, 84% yield) as a white solid. LCMS (ESI) m / z: 459.20 [M+H] + .

[0607]

[0608] A solution of N-[2-[[2-bromo-6-(difluoromethoxy)phenyl]methylamino]-4-chlorophenyl]pent-4- enoic amide (16D) (1.01 g, 91% purity, 2.09 mmol) in AcOH (20 mL) was stirred at 60 °C for 12 h, then at 80 °C for 5 h. The reaction mixture was concentrated, the residue was dissolved in EtOAc (150 mL). The organic layer was washed with saturated aqueous Na2CO3solution (150 mL) and brine (150 mL), dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (PE:EtOAc = 3:1) to give the title compound 1-(2-bromo-6-(difluoromethoxy)benzyl)-2-(but-3-en-1-yl)-6-chloro-1H-benzo[d]imidazole (16E) (910 mg, 90% purity, 1.86 mmol, 85% yield) as a grey solid. LCMS (ESI) m / z: 441.21 [M+H] + .

[0609]

[0610] A mixture of 1-[[2-bromo-6-(difluoromethoxy)phenyl]methyl]-2-but-3-enyl-6- chlorobenzimidazole (16E) (240 mg, 90% purity, 490 pmol), Pd(dppf)Cl2(36 mg, 49 pmol) and K2CO3(203, 1.47 mmol) in dioxane (5 mL) and water (1.0 mL) was stirred at 100 °C under N2protection for 16 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (PE:EtOAc = 1:1) to give P1 (mixture, 65 mg) and P2 (mixture, 67 mg). Both P1 and P2 were purified by preparative HPLC (column: Waters Xbridge 250*30 mm, 5 pm; mobile phase A: H2O (+0.1% NH4HCO3), mobile phase B: ACN; gradient: 30-75% B; flow rate: 38 mL / min; wavelength: 214 nm / 254 nm) to give 11-chloro-1-(difluoromethoxy)-5-methylene-5,6,7,14-tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azepine (EX16), 7.8 mg, 97% purity, 22 pmol, 4% yield), both as white solids. LCMS (ESI) m / z: 361.26 [M+H] + ; Rt = 5.423 min. 1 H NMR (400 MHz, CDC13) δ 7.79 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.30-7.26 (m, 1H), 7.20-7.18 (m, 1H), 7.03 (d, J = 7.6 Hz, 2H), 6.70 (t, J = 73.2 Hz, 1H), 5.45 (s, 1H), 5.32 (s, 2H), 5.14 (s, 1H), 3.38 (s, 2H), 2.79 (s, 2H).

[0611] Example 17

[0612]

[0613] To a solution of 1-[5-[4-(difluoromethoxy)-9-methylene-1,13-diazatetracyclo[10.7.0.03,8.014,19]nonadeca-3,5,7,12,14,16,18-heptaen-17-yl]pyrimidin-2-yl]cyclobutane- amine (EX01) (10 mg, 21 pmol) in MeOH (4.0 mL) was added Pd / C (10% on carbon, 10 mg) and the mixture was stirred at room temperature under hydrogen for 3 hours. The mixture was filtered and purified by preparative HPLC (column: Waters Xbridge 250*30 mm, 5 pm; mobile phase A: H20 (+0.1% NH4HCO3), mobile phase B: ACN; gradient: 25-85% B; flow rate: 39 mL / min; wavelength: 214 nm / 254 nm) to give 1-(5-(1-(difluoromethoxy)-5-methyl-5,6,7,14-tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azocin-11-yl)pyrimidin-2-yl)cyclobutane-1-amine (EX17) (racemic mixture, 2.0 mg, 97.61% purity, 4.21 pmol, 20% yield) as a white solid. LCMS (ESI) m / z: [M-18+H] 476.29. + 476.29. 1 H NMR (400 MHz, CDC13) δ 8.98 (s, 2H), 7.76 - 7.67 (m, 2H), 7.40 - 7.32 (m, 2H), 7.18 - 7.16 (m, 2H), 6.99 (d, J = 8.0 Hz, 1H), 6.49 (t, J = 73.2 Hz, 1H), 5.72 (d, J = 14.4 Hz, 1H), 5.09 (d, J = 14.4 Hz, 1H), 3.03 - 2.94 (m, 1H), 2.87 - 2.76 (m, 1H), 2.67 - 2.54 (m, 2H), 2.37 - 2.07 (m, 4H), 1.42 (d, J = 6.4 Hz, 3H).

[0614] Example 18 and Example 19

[0615]

[0616] A mixture of 1-bromo-5-fluoro-2-methyl-4-nitrobenzene (18A) (1.0 g, 4.27 mmol), tert-butyl (1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2- yl)cyclobutyl)carbamate (1.60 g, 4.27 mmol), Pd(dppf)Cl2(625 mg, 854 µmol), Cs2CO3(2.78 g, 8.55 mmol) in dioxane (10 mL) was degassed and purged with nitrogen for 3 times, then the mixture was stirred at 90 °C under nitrogen for 2 hours. After cooling to room temperature, the mixture was concentrated to give a residue, which was purified by silica gel column chromatography (40%~50% EtOAc / PE solution) to give tert-butyl (1-(5-(5-fluoro-2-methyl-4-nitrophenyl)pyrimidin-2- yl)cyclobutyl)carbamate (1.94 g, 4.39 mmol, 92% yield, 91% purity) as a yellow solid. LCMS (ESI) m / z: 347.2 [M+H] + .

[0617]

[0618] To a solution of tert-butyl N-[1-[5-(5-fluoro-2-methyl-4-nitro-phenyl)pyrimidin-2- yl]cyclobutyl]carbamate (18B) (500 mg, 1.13 mmol) in EtOH (10 mL) was added DIEA (730 mg, 5.65 mmol, 984 µL). The mixture was stirred at 80 °C for 16 hours. After cooling to room temperature, the mixture was concentrated and purified by silica gel column chromatography (40%~50% EtOAc / PE solution) to give tert-butyl [1-(5-(5-((2-bromo-6-(difluoromethoxy)benzyl)amino)-2-methyl-4-nitrophenyl)pyrimidin-2- yl)cyclobutyl]carbamate (18C) (686 mg, 864 µmol, 76.5% yield, 80% purity) as a yellow solid. LCMS (ESI) m / z: 634.4 [M+H] + .

[0619]

[0620] To a solution of tert-butyl N-[1-[5-[5-[[2-bromo-6-(difluoromethoxy)phenyl]methylamino]-2-methyl-4-nitrophenyl]pyrimidin-2-yl]cyclobutyl]carbamate (18C) (1.05 g, 1.32 mmol) in EtOH (20.0 mL) was added iron powder (369 mg, 6.62 mmol, 47.0 μL) and NH4Cl (212 mg, 3.97 mmol, 138 μL). The mixture was stirred at 80 °C for 16 hours. After cooling to room temperature, the mixture was concentrated and purified by column chromatography on silica gel (40%~50% EtOAc / PE solution) to give tert-butyl N-[1-[5-[4-amino-5-[[2-bromo-6-(difluoromethoxy)phenyl]methylamino]-2-methyl-phenyl]pyrimidin-2-yl]cyclobutyl]carbamate (18D) (970 mg, 1.28 mmol, 96.9% yield, 80% purity) as a yellow solid. LCMS (ESI) m / z: 604.4 [M+H] + .

[0621]

[0622] A mixture of pent-4-enoic acid (197 mg, 1.97 mmol, 200 μL), DIEA (508 mg, 3.94 mmol, 685 μL), HATU (748 mg, 1.97 mmol) in DMF (10.2 mL) was degassed and purged with nitrogen for 3 times, then the mixture was stirred at 25 °C under nitrogen for 30 minutes. tert-Butyl N-[1-[5-[6-amino-5-[[2-bromo-6-(difluoromethoxy)phenyl]methylamino]-3-pyridyl]pyrimidin-2-yl]cyclobutyl]carbamate (970 mg, 1.31 mmol) was added to the mixture and stirred at 25 °C for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography on silica gel (40%~50% EtOAc / PE solution) to give tert-butyl (1-(5-(5-((2-bromo-6-(difluoromethoxy)benzyl)amino)-6-(pent-4-enoylamino)pyridin-3-yl)pyrimidin-2-yl)cyclobutyl)carbamate (18E) (774 mg, 1.10 mmol, 84.0% yield, 96% purity) as a light yellow solid. LCMS (ESI) m / z: 686.4 [M+H] + .

[0623]

[0624] tert-Butyl (1-(5-(5-((2-bromo-6-(difluoromethoxy)benzyl)amino)-2-methyl-4- (pent-4-enoylamino)phenyl)pyrimidin-2-yl)cyclobutyl)carbamate (18E) (774 mg, 1.08 mmol) was dissolved in AcOH (25 mL). The mixture was stirred at 60 °C for 16 h. After cooling to room temperature, the mixture was concentrated and purified by silica gel column chromatography (PE solution of EtOAc) to give tert-butyl (1-(5-(1-(2-bromo-6-(difluoromethoxy)benzyl)-2-(but-3-en-1-yl)-5- methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)cyclobutyl)carbamate (18F) (700 mg, 984 µmol, 90.9% yield, 94% purity) as a light yellow solid. LCMS (ESI) m / z: 668.5 [M+H] + .

[0625]

[0626] tert-Butyl N-[1-[5-[3-[[2-bromo-6-(difluoromethoxy)phenyl]methyl]-2-but-3-enyl-6- methyl-benzoimidazol-5-yl]pyrimidin-2-yl]cyclobutyl]carbamate (18F) (700 mg, 963 µmol), Pd(dppf)Cl2 (141 mg, 192 µmol) and K2CO3 (399 mg, 2.89 mmol) were dissolved in a mixture of dioxane (20 mL) and water (4.0 mL). After cooling to room temperature, the mixture was concentrated and purified by silica gel column chromatography (PE solution of EtOAc) to give tert-butyl (1-(5-(1-(difluoromethoxy)-10-methyl-5-methylene-5,6,7,14- tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azepin-11-yl)pyrimidin-2-yl)cyclobutyl)carbamate (500 mg, 595.58 µmol, 61.83% yield, 70% purity) as a light yellow solid. The product was further purified by preparative HPLC (column: Waters Xbridge 250*30 mm, 5 µm; mobile phase A: H2O (+0.1% FA), mobile phase B: ACN; gradient: 5-95% B; flow rate: 40 mL / min; wavelength: 214 nm / 254 nm) to give title compounds 18G (15 mg) and 18H (15 mg) as white solids.

[0627]

[0628] To a solution of 18G (15 mg, 25.0 μmol) was added HC1 solution in 1,4-dioxane (4.0 M, 0.5 mL). The mixture was stirred at 25 °C for 0.5 h. The solid was collected by filtration to give the product (Z)-1-(5-(1-(difluoromethoxy)-11-methyl-5,15-dihydro-8H- benzo[g]benzo[4,5]imidazo[1,2-a]azomethine-12-yl)pyrimidin-2-yl)cyclobutan-1-amine (EX18) (8.5 mg, 17.0 μmol, 68.3% yield, 98% purity) as a white solid. LCMS (ESI) m / z: 488.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.94 (s, 2H), 7.83 (d, J = 18.8 Hz, 2H), 7.46 (t, J = 8.0 Hz, 1H), 7.21 (t, J = 8.4 Hz, 2H), 7.08 - 6.66 (m, 1H), 6.07 (dd, J = 12.4, 6.8 Hz, 1H), 5.90 (s, 2H), 5.76 (t, J = 6.0 Hz, 1H), 3.73 (t, J = 5.2 Hz, 2H), 3.66 (s, 5H), 3.61 - 3.52 (m, 3H), 2.93 (ddd, J = 14.4, 8.8, 5.2 Hz, 3H), 2.66 (td, J = 12.8, 11.2, 7.2 Hz, 3H), 2.47 (s, 3H), 2.46 - 2.27 (m, 2H).

[0629]

[0630] To a solution of 18H (15 mg, 25.0 μmol) was added HC1 solution in 1,4-dioxane (4.0 M, 0.5 mL). The mixture was stirred at 25 °C for 0.5 h. The solid was collected to give 1-(5-(1-(difluoromethoxy)-10-methyl-5-methylene-5,6,7,14-tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azomethine-11-yl)pyrimidin-2-yl)cyclobutan-1-amine (EX19) (8.5 mg, 17.0 μmol, 68.3% yield, 98% purity) as a white solid. LCMS (ESI) m / z: 488.4 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 9.00 (s, 2H), 8.09 (s, 1H), 7.76 (s, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.29 - 6.86 (m, 3H), 5.74 (s, 2H), 5.62 (s, 1H), 5.30 (s, 1H), 3.78 - 3.56 (m, 4H), 3.04 (s, 2H), 2.99 - 2.89 (m, 2H), 2.67 (ddd, J = 12.8, 9.6, 6.8 Hz, 2H), 2.46 (s, 4H).

[0631] Example 20

[0632]

[0633] To a solution of 2,5-dibromopyridine (20A) (10.0 g, 42.2 mmol) in DCM (10 mL) was added butyllithium (2.73 g, 42.6 mmol) at -78 °C. The mixture was stirred at -78 °C for 10 min, then to the mixture was added a solution of (S)-N-cyclobutylidene-2-methyl-propane-2-sulfmamide (6.65 g, 38.4 mmol) in DCM at -78 °C. The mixture was stirred at -78 °C for 1 h, then stirred at room temperature for 1 h. To the mixture was added aqueous NH4Cl solution, and the mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (3 x 150 mL) and brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated, and purified by silica gel column chromatography (PE solution of EtOAc) to give (R)-N-[1-(5-bromo-2-pyridyl)cyclobutyl]-2-methyl-propane-2-sulfmamide (20B) (6.0 g, 90% purity, 18.1 mmol, 47% yield) as an orange oil. LCMS (ESI) m / z: [M+H] + 330.9.

[0634]

[0635] To a solution of (R)-N-[l-(5-bromo-2-pyridyl)cyclobutyl]-2-methyl-propane-2- sulfonamide (20B) (2.0 g, 90% purity, 6.0 mmol) in dioxane (20 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2- dioxaborolane (1.69 g, 6.64 mmol), KOAc (1.78 g, 18.1 mmol) and Pd(dppf)Cl2 (662 mg, 905 μmol), the mixture was stirred at 85 °C under N2for 16 h. The mixture was filtered, the filtrate was concentrated to give (R)-2-methyl-N-[l-[5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2-pyridyl]cyclobutyl]propane-2-sulfonamide (20C) (4.0 g, crude, 70% purity) as a black oil. LCMS (ESI) m / z: [M+H] + 297.3.

[0636]

[0637] A mixture of (R)-2-methyl-N-[l-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-2-pyridyl]cyclobutyl]propane-2-sulfonamide (20C) (5.30 g, 54% purity, 7.56 mmol), 4-bromo-2-fluoro-l-nitro-benzene (1.66 g, 7.53 mmol), K2CO3(3.14 g, 22.7 mmol) and Pd(dppf)Cl2(277 mg, 378 μmol) in dioxane (100 mL) and H2O (25 mL) was stirred at 100 °C under argon for 3 h. The mixture was concentrated and purified by silica gel column chromatography (PE:EtOAc = 1:9) to give (S)-N-[l-[5-(3-fluoro-4-nitro-phenyl)-2-pyridyl]cyclobutyl]-2-methyl- propane-2-sulfonamide (20D) (2.52 g, 95% purity, 6.12 mmol, 81% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] + 392.33.

[0638]

[0639] A mixture of (S)-N-[l-[5-(3-fluoro-4-nitrophenyl)-2-pyridyl]cyclobutyl]-2- methyl-propane-2-sulfinamide (20D) (2.52 g, 95% purity, 6.12 mmol), [2-bromo-6- (difluoromethoxy)phenyl]methanamine (1 M) (2.32 g, 7.35 mmol) and DIEA (7.90 g, 61.16 mmol, 10.65 mL) in EtOH (50 mL) was stirred at 90 °C for 20 h. The resulting mixture was cooled, concentrated in vacuo and purified by silica gel column chromatography (EtOAc:PE = 7:3) to give (S)-N-[l-[5-[3-[[2-bromo-6- (difluoromethoxy)phenyl]methylamino]-4-nitro-phenyl]-2-pyridyl]cyclobutyl]-2-methyl- propane-2-sulfinamide (20E) (3.84 g, 94% purity, 5.79 mmol, 95% yield) as a yellow oil. LCMS (ESI) m / z: [M+H] + 624.26.

[0640]

[0641] To a solution of (S)-N-[l-[5-[3-[[2-bromo-6-(difluoromethoxy)phenyl]methylamino]-4- nitrophenyl]-2-pyridyl]cyclobutyl]-2-methyl-propane-2-sulfinamide (20E) (1.00 g, 94% purity, 1.51 mmol) in AcOH (10 mL) and MeOH (3 mL) was added Zn (986 mg, 15.1 mmol) and the mixture was stirred at room temperature for 3 h. It was filtered, the filtrate was adjusted to pH 7-8 with saturated Na2CO3 solution and extracted with EtOAc. The combined organic layers were concentrated and purified by silica gel column chromatography (PE:EtOAc = 30:70) to give (S)-N-[l-[5-[4-amino-3-[[2-bromo-6- (difluoromethoxy)phenyl]methylamino]phenyl]-2-pyridyl]cyclobutyl]-2-methyl-propane-2- sulfinamide (20F) (934 mg, 94% purity, 1.48 mmol, 98% yield) as a yellow oil. LCMS (ESI) m / z: [M+H] + 594.23.

[0642]

[0643] A mixture of 20F (430 mg, 94% purity, 681 pmol), pent-4-enoic acid (82 mg, 817 pmol) and DIEA (264 mg, 2.05 mmol) in DMF (5 mL) was stirred at room temperature for 10 min, then HATU (516 mg, 1.36 mmol) was added. After the mixture was stirred at room temperature for 2 h, it was diluted with EtOAc, washed with saturated Na2CO3solution and brine. The organic layer was concentrated and purified by silica gel column chromatography (PE:EtOAc = 4:6) to give N-[2-[[2-bromo-6-(difluoromethoxy)phenyl]methylamino]-4-[6-[1-[[(S)-tert- butylsulfinyl]amino]cyclobutyl]-3-pyridyl]phenyl]pent-4-enoic amide (20G) (540 mg, crude, 96% purity, 767 pmol, 113% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] + 676.35.

[0644]

[0645] N-[2-[[2-bromo-6-(difluoromethoxy)phenyl]methylamino]-4-[6-[1-[[(S)-tert- butylsulfinyl]amino]cyclobutyl]-3-pyridyl]phenyl]pent-4-enoic amide (20G) (540 mg, 96% purity, 767 pmol) was dissolved in AcOH (6 mL) and stirred at 60 °C overnight. The mixture was concentrated and basified to pH = 8 with Na2CO3(aq). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH in DCM 8-11%) to give (S)-N-[1-[5-[3-[[2-bromo-6-(difluoromethoxy)phenyl]methyl]-2-but-3-enyl- benzimidazol-5-yl]-2-pyridyl]cyclobutyl]-2-methyl-propane-2-sulfmamide (20H) (200 mg, 61% purity, 186 pmol, 24% yield) LCMS (ESI) m / z: [M+H] + 596.32 and N-[1-[5-[3-[[2-bromo-6-(difluoromethoxy)phenyl]methyl]-2-but-3-enyl- benzimidazol-5-yl]-2-pyridyl]cyclobutyl]acetamide (20I) (200 mg, 34% purity, 114 pmol, 15% yield) as a mixture of yellow oil.[M+H] + 658.32.

[0646]

[0647] (S)-N-[1-[5-[3-[[2-bromo-6-(difluoromethoxy)phenyl]methyl]-2-but-3-enyl- benzimidazol-5-yl]-2-pyridyl]cyclobutyl]-2-methyl-propane-2-sulfmamide (20H) (200 mg, 61% purity, 186 pmol) and N-[1-[5-[3-[[2-bromo-6- (difluoromethoxy)phenyl]methyl]-2-but-3-enyl-benzimidazol-5-yl]-2-pyridyl] cyclobutyl]acetamide (20I) (200 mg, 34% purity, 114 pmol), Pd(dppf)Cl2(27 mg, 36.9 pmol) and K2CO3(77 mg, 558 pmol) were dissolved in dioxane (4 mL) and H2O (1 mL) and stirred at 100 °C under argon for 24 h. The mixture was concentrated and purified by silica gel column chromatography as a mixture of (S)-N-(1-(5-(1-(difluoromethoxy)-5-methylene-5,6,7,14- tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azepin-11-yl)pyridin-2-yl)cyclobutyl)-2- methylpropane-2-sulfmamide (20J) (150 mg, 59% purity, 153.46 pmol, 83% yield) as a yellow oil and N-(1-(5-(1-(difluoromethoxy)-5-methylene-5,6,7,14- tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azepin-11-yl)pyridin-2-yl)cyclobutyl)acetamide (20K) (150 mg, 30% purity, 87.45 pmol, 47% yield) as a yellow oil. LCMS (ESI) m / z: [M+H] + 577.33. + 515.32.

[0648]

[0649] A mixture of 20J (135 mg, 59% purity, 138 pmol), 20K (135 mg, 30% purity, 78.7 pmol), and HC1 solution (4.0 M in 1,4-dioxane, 5.0 mL) and H20 (5.0 mL) was stirred at 80 °C for 7 h. The mixture was concentrated and purified by prep-HPLC (column: Waters Xbridge 250*30 mm, 5 pm; mobile phase A: H20 (+0.1% NH4HC03), mobile phase B: ACN; gradient: 35-85% B; flow rate: 39 mL / min; wavelength: 214 nm / 254 nm) to give 1-(5-(1-(difluoromethoxy)-5-methylene-5,6,7,14-tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azosin-11-yl)pyridin-2-yl)cyclobutan-1-amine (EX20) (16 mg, 98.92% purity, 33.86 pmol, 25% yield) as a white solid. LCMS (ESI) m / z: [M+H] + 473.31. 1 H NMR (400 MHz, CDC13) d 8.91 (d, J = 1.6 Hz, 1H), 8.06 - 7.98 (m, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.10 - 7.02 (m, 2H), 6.70 (t, J = 73.6 Hz, 1H), 5.53 - 5.34 (m, 3H), 5.17 (s, 1H), 3.43 (s, 2H), 3.43 (s, 2H), 2.97 - 2.68 (m, 4H), 2.37 - 2.29 (m, 2H), 2.27 - 2.18 (m, 4H). 19 F NMR (376 MHz, CDC13) d -80.21.

[0650] Example 21

[0651]

[0652] A mixture of tert-butyl (1-(5-(4-amino-3-((2-bromo-6-(difluoromethoxy)benzyl)amino)phenyl)pyrimidin-2- yl)cyclobutyl)carbamate (10) (400 mg, 0.68 mmol), 3-methylpent-4-enoic acid (93 mg, 0.82 mmol), HATU (388 mg, 1.02 mmol) and DIEA (263 mg, 2.04 mmol) in DMF (10 mL) was stirred at room temperature for 12 h. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10-50% EtOAc / PE solution) to give tert-butyl (1-(5-(3-((2-bromo-6-(difluoromethoxy)benzyl)amino)-4-(3-methylpent-4- enoylamino)phenyl)pyrimidin-2-yl)cyclobutyl)carbamate (21A) (400 mg, 86.0%) as a white solid. LC-MS: m / z = 683.9 [M-H].

[0653]

[0654] A solution of 21A (400.0 mg, 0.60 mmol) in AcOH (15 mL) was stirred at 60 °C for 12 h. The mixture was adjusted to pH = 8 with aqueous Na2CO3 solution and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (25-70% EtOAc / PE solution) to give tert-butyl [1-(5-(1-(2-bromo-6-(difluoromethoxy)benzyl)-2-(2-methylbut-3-en-1-yl)-1H- benzo[d]imidazol-5-yl)pyrimidin-2-yl)cyclobutyl]carbamate (21B) (300 mg, 77.1%) as a white solid. LC-MS: m / z = 668.4 [M+H] + .

[0655]

[0656] A mixture of 21B (300 mg, 0.45 mmol), Pd(dppf)Cl2(32.9 mg, 0.045 mmol) and K2CO3(186.6 mg, 1.35 mmol) in dioxane (4 mL) and water (1 mL) was stirred at 110 °C under argon for 2 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (25% - 70% EtOAc / PE solution) to give tert-butyl [1-(5-(1-(difluoromethoxy)-6-methyl-5-methylene-5,6,7,14-tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azepine-11-yl)pyrimidin-2-yl)cyclobutyl)carbamate (21C) (50.0 mg, 18.9%) as a white solid. LC-MS: m / z = 588.4 [M+H] + .

[0657]

[0658] To a solution of 21C (30.0 mg, 0.051 mmol) in DCM (1 mL) was added TFA (0.3 mL) with stirring. The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The crude product was purified by preparative HPLC (C18 column chromatography eluted with acetonitrile-water (0.1% formic acid) = 30% - 75%) to give 1-(5-(1-(difluoromethoxy)-6-methyl-5-methylene-5,6,7,14-tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azepine-11-yl)pyrimidin-2-yl)cyclobutane-1-amine (EX21) (3.56 mg, yield 14.3%) as a white solid. LC-MS: m / z = 488.1 [M+H] + . 1 H NMR (400 MHz, MeOD-d4): δ 9.24 (s, 2H), 8.29 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.63 (m, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.29 - 6.92 (m, 3H), 5.75 (s, 1H), 5.58 (s, 1H), 5.32 (s, 1H), 5.06 (s, 1H), 3.61 - 3.43 (m, 2H), 2.97 - 2.89 (m, 2H), 2.65 - 2.58 (m, 2H), 2.42 - 2.24 (m, 2H), 0.72 (s, 3H).

[0659] Example 22

[0660]

[0661] A reaction mixture of 5-bromo-3-fluoro-2-nitro-pyridine (22A) (1.00 g, 100% purity, 4.53 mmol), [2-[1-(tert-butoxycarbonylamino)cyclobutyl]pyrimidin-5-yl]boronic acid (1G) (1.78 g, 82% purity, 4.98 mmol), Pd(dppf)Cl2(662 mg, 905 µmol) and Cs2CO3(2.95 g, 9.05 mmol) in dioxane (5 mL) and water (1 mL) was stirred at 90 °C for 2 h. The reaction was quenched with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated and purified by silica gel column chromatography (PE:EtOAc) to give tert-butyl N-[1-[5-(5-fluoro-6-nitro-3-pyridyl)pyrimidin-2-yl]cyclobutyl]carbamate (22B) (1.4 g, 57% purity, 1.54 mmol, 79% yield) as a light yellow solid. LCMS (ESI) m / z: 334.25 [M+H] + .

[0662]

[0663] To a solution of 22B (1.4 g, 57% purity, 1.54 mmol) in EtOH (20 mL) was added DIEA (2.46 g, 19.0 mmol, 3.31 mL) and 1M (1.80 g, 84% purity, 5.71 mmol). The mixture was stirred at 80 °C for 16 h. The mixture was cooled to rt, concentrated and purified by silica gel column chromatography (PE:EtOAc) to give tert-butyl (1-(5-(5-((2-bromo-6-(difluoromethoxy)benzyl)amino)-6-nitropyridin-3-yl)pyrimidin-2-yl)cyclobutyl)carbamate (22C) (2.15 g, 98% purity, 3.36 mmol, 88.1% yield) as a yellow solid. LCMS (ESI) m / z: 621.4 [M+H] + .

[0664]

[0665] To a solution of 22C (500 mg, 98% purity, 764 pmol) in EtOH (10 mL) and water (2.5 mL) was added iron powder (213 mg, 3.82 mmol) and NH4CI (122 mg, 2.29 mmol). The mixture was stirred at 80 °C for 1 h. The mixture was cooled to room temperature, concentrated, and purified by column chromatography on silica gel (EtOAc in PE) to give tert-butyl N-[1-[5-[6-amino-5-[[2-bromo-6-(difluoromethoxy)phenyl]methylamino]-3-pyridyl]pyrimidin-2-yl]cyclobutyl]carbamate (22D) (281 mg, 82% purity, 427 pmol, 56% yield) as a yellow solid. LCMS (ESI) m / z: 591.4 [M+H] + .

[0666]

[0667] To a solution of 22D (528 mg, 82% purity, 803 pmol) in DMF (10 mL) was added HATU (458 mg, 1.21 mmol) and DIEA (311 mg, 2.41 mmol, 419 pL). The mixture was stirred at 50 °C for 24 h. The mixture was cooled to room temperature, concentrated, and purified by column chromatography on silica gel (EtOAc in PE) to give tert-butyl (1-(5-(5-((2-bromo-6-(difluoromethoxy)benzyl)amino)-6-(pent-4-enamido)pyridin-3-yl)pyrimidin-2-yl)cyclobutyl)carbamate (22E) (375 mg, 97% purity, 545 pmol, 67.9% yield) as a yellow solid. LCMS (ESI) m / z: 673.4 [M+H] + .

[0668]

[0669] A solution of 22E (375 mg, 97% purity, 523 pmol) in AcOH (10 mL) was stirred at 60 °C for 16 h. The mixture was cooled to room temperature, concentrated, and purified by column chromatography on silica gel (EtOAc in PE) to give tert-butyl (1-(5-(1-(2-bromo-6-(difluoromethoxy)benzyl)-2-(but-3-en-1-yl)-1H-imidazo[4,5-b]pyridin-6-yl)pyrimidin-2-yl)cyclobutyl)carbamate (22F) (311 mg, 89% purity, 426 pmol, 81.5% yield) as a yellow solid. LCMS (ESI) m / z: 655.5 [M+H] + .

[0670]

[0671] To a solution of 22F (311 mg, 89% purity, 445 pmol) in dioxane (10 mL) was added Pd(dppf)Cl2(65 mg, 89 pmol) and K2CO3(185 mg, 1.34 mmol). The mixture was stirred at 60 °C for 16 h. The mixture was cooled to room temperature, concentrated, and purified by column chromatography on silica gel (PE solution of EtOAc) to give tert-butyl (1-(5-(1-(difluoromethoxy)-5-methylene-5,6,7,14-tetrahydrobenzo[f]pyrido[2',3':4,5]imidazo[1,2-a]azepine-11-yl)pyrimidin-2-yl)cyclobutyl)carbamate (22G) (400 mg, 58% purity, 487 pmol, 85% yield) as a yellow solid. LCMS (ESI) m / z: 575.6 [M+H] + .

[0672]

[0673] To a solution of 22G (35 mg, 58% purity, 25.5 pmol) in dioxane (3 mL) was added HC1 (0.5 mL). The mixture was stirred at 25 °C for 0.5 h. The mixture was cooled to room temperature, concentrated, and purified by prep-HPLC (column: Waters Xbridge 250*30 mm, 5 pm; mobile phase A: H2O (+0.1% FA), mobile phase B: ACN; gradient: 30-80% B; flow rate: 40 mL / min; wavelength: 214 nm / 254 nm) to give 1-(5-(1-(difluoromethoxy)-5-methylene-5,6,7,14-tetrahydrobenzo[f]pyrido[2',3':4,5]imidazo[1,2-a]azepine-11-yl)pyrimidin-2-yl)cyclobutane-1-amine (EX22) (9 mg, 98% purity, 18.5 pmol, 72.6% yield) as a white solid. LCMS (ESI) m / z: 475.4 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 9.35 (s, 2H), 9.06 (d, J = 1.6 Hz, 1H), 9.00 (d, J = 1.6 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.37 - 6.98 (m, 3H), 5.80 (s, 2H), 5.66 (s, 1H), 5.33 (d, J = 1.2 Hz, 1H), 3.69 - 3.62 (m, 2H), 3.02 (s, 2H), 2.94 (ddd, J = 14.8, 9.2, 5.6 Hz, 2H), 2.66 (ddd, J = 13.2, 10.0, 7.2 Hz, 2H), 2.49 - 2.28 (m, 1H).

[0674] Example 23 and Example 24

[0675]

[0676]

[0677] A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (1.98 g, 8.40 mmol), 1-bromo-2,5-difluoro-4-nitro-benzene (23A) (2.00 g, 8.40 mmol), Pd(dppf)Cl2(614 mg, 840.38 μmol), Na2CO3(2.67 g, 25.21 mmol, 1.06 mL) in H2O (8 mL) and dioxane (20 mL) was stirred at 100 °C for 16 h under N2protection. It was diluted with EtOAc and washed with brine. The organic layer was collected and purified by silica gel column chromatography (5% MeOH in DCM) to give 5-(2,5-difluoro-4-nitro-phenyl)-l-methyl-pyridin-2-one (23B) (1.4 g, 80% purity, 50% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] 273.0. + 267.1.

[0678]

[0679] A mixture of 23B (550 mg, 80% purity, 1.92 mmol), [2-bromo-6- (difluoromethoxy)phenyl]methanamine (1 M) (645 mg, 2.31 mmol), DIEA (1.99 g, 15.37 mmol, 2.68 mL) in EtOH (10 mL) was stirred at 100 °C for 24 h. The reaction mixture was concentrated and purified by silica gel column chromatography (80% EtOAc / PE solution) to give 5-[5-[[2-bromo-6- (difluoromethoxy)phenyl]methylamino]-2-fluoro-4-nitro-phenyl]-1-methyl- pyridin-2-one (24C) (802 mg, 85% purity, 71% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] + 498.2.

[0680]

[0681] A mixture of 24C (100 mg, 200.70 pmol), Zn (131 mg, 2.01 mmol), NH4Cl (107 mg, 2.01 mmol, 70.17 pL) in H2O (1 mL) and MeOH (4 mL) was stirred at room temperature for 2 h. The reaction mixture was filtered and diluted with EtOAc and washed with brine. The organic layer was collected and purified by silica gel column chromatography (6% MeOH in DCM) to give 5-[4-amino-5-[[2-bromo-6- (difluoromethoxy)phenyl]methylamino]-2-fluoro-phenyl]-1-methyl-pyridin-2-one (24D) (647 mg, 70% purity, 70% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] + 466.18.

[0682]

[0683] A mixture of HATU (415 mg, 1.09 mmol), DIEA (282 mg, 2.18 mmol, 380.30 pL), pent-4-enoic acid (109 mg, 1.09 mmol, 111.41 pL) in DMF (10 mL) was stirred at room temperature for 30 min. Compound 24D (480 mg, 70% purity, 727.79 pmol) was added. The resulting mixture was stirred at room temperature for 5 h, then diluted with EtOAc and washed with brine. The organic layer was collected and purified by silica gel column chromatography (6% MeOH in DCM) to give N-[2-[[2-bromo-6-(difluoromethoxy)phenyl]methylamino]-5-fluoro-4-(l-methyl-6-oxo-3- pyridyl)phenyl]pent-4-enoic amide (24E) (440 mg, 76% purity, 83% yield) as a white solid. LCMS (ESI) m / z: [M+H] + 634.26.

[0684]

[0685] A solution of 24E (440 mg, 76% purity, 607 pmol) in AcOH (10 mL) was stirred at 60 °C for 6 h. The reaction mixture was concentrated and diluted with EtOAc and washed with aqueous Na2CO3solution. The organic layer was collected and purified by silica gel column chromatography (6% MeOH in DCM) to give 5-[3-[[2-bromo-6-(difluoromethoxy)phenyl]methyl]-2-but-3-enyl-6-fluoro- benzimidazol-5-yl]-l-methyl-pyridin-2-one (24F) (370 mg, 81% purity, 562 pmol, 92% yield) as a white solid. LCMS (ESI) m / z: [M+H] + 532.17.

[0686]

[0687] A mixture of 24F (345 mg, 525.97 pmol, 81% purity), Pd(dppf)Cl2(153 mg, 210.39 pmol), K2CO3(218 mg, 1.58 mmol) in H2O (0.25 mL) and dioxane (1.0 mL) was stirred at 100 °C for 8 h. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was collected and purified by prep-HPLC (column: Waters Xbridge 250*30 mm, 5 pm; mobile phase A: H2O (+0.1% NH4HCO3), mobile phase B: ACN; gradient: 25%~85% B; flow rate: 39 mL / min; wavelength: 214 nm / 254 nm) to give (E)-5-(1-(difluoromethoxy)-11-fluoro-7,15-dihydro-8H- benzo[g]benzo[4,5]imidazo[1,2-a]azocine-12-yl)-1-methylpyridin-2(1H)-one (EX23) (4.7 mg, 96% purity, 21.93 pmol, 4% yield) as a white solid. LCMS (ESI) m / z: [M+H]+452.26. 1 H NMR (400 MHz, CDC13) d 7.67 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 5.2 Hz, 1H), 7.41 (d, J = 9.2 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.69 (s, 1H), 6.61 (d, J = 9.2 Hz, 1H), 6.51 (s, 1H), 6.33 (s, 1H), 5.87 (s, 1H), 5.73 (d, J = 11.2 Hz, 1H), 5.66 (s, 1H), 3.96 (s, 1H), 3.53 (d, J = 16.4 Hz, 2H), 3.24 (s, 1H).

[0688] and (E)-5-(1-(difluoromethoxy)-10-fluoro-5-methylene-5,6,7,14-tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azocin-11-yl)-1-methylpyridin-2(1H)-one (EX24) (5.3 mg, 99% purity, 21.93 pmol, 4% yield) as a white solid. LCMS (ESI) m / z: [M+H]+452.26. 1H NMR (400 MHz, CDC13) δ 7.98 (d, J = 5.6 Hz, 1H), 7.66 (s, 3H), 7.44 (t, J = 7.2 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.76 (s, 1H), 6.75 (d, J = 2.4 Hz, 2H), 5.62 (s, 1H), 5.50 (s, 2H), 5.29 (s, 1H), 3.75 (s, 2H), 3.68 (s, 4H), 2.91 (s, 2H).

[0689] Example 25, Example 26 and Example 27

[0690]

[0691] A mixture of tert-butyl N-[1-[5-[4-amino-3-[[2-bromo-6- (difluoromethoxy)phenyl]methylamino]phenyl]pyrimidin-2-yl]cyclobutyl] carbamate (380 mg, 92% purity, 592 pmol), 2-methylpent-4-enoic acid (111 mg, 972 pmol), HATU (270 mg, 710 pmol) and DIEA (250 mg, 1.93 mmol) in DMF (5.4 mL) was stirred at room temperature for 16 h. LCMS showed most of the starting material was consumed and the target product was formed. After cooling to room temperature, the reaction mixture was quenched with water (60 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2S04, and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (50% EtOAc / PE solution) to give tert-butyl N-[1-[5-[3-[[2-bromo-6-(difluoromethoxy)phenyl]methylamino]-4-(2- methylpent-4-enoylamino)phenyl]pyrimidin-2-yl]cyclobutyl]carbamate (25A) (403 mg, 528.3 pmol, 89.22% yield, 90% purity) as an orange solid. LCMS (ESI) m / z: 686.30 [M+H] + .

[0692]

[0693] A mixture of tert-butyl N-[1-[5-[3-[[2-bromo-6-(difluoromethoxy)phenyl]methylamino]-4-(2-methylpent-4- enoylamino)phenyl]pyrimidin-2-yl]cyclobutyl]carbamate (410 mg, 90% purity, 537 pmol) in AcOH (8 mL) was stirred at 60 °C for 16 h. The mixture was basified to pH = 8 with aqueous Na2CO3solution. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (40% EtOAc / PE solution) to give tert-butyl N-[1-[5-[3-[[2-bromo-6-(difluoromethoxy)phenyl]methyl]-2-(1- methylbut-3-enyl)benzoimidazol-5-yl]pyrimidin-2-yl]cyclobutyl]carbamate (320 mg, 88% purity, 421 pmol, 78% yield) as a yellow solid. LCMS (ESI) m / z: 668.40 [M+H] + .

[0694]

[0695] A mixture of 25B (220 mg, 88% purity, 290 pmol) and K2CO3(125 mg, 904 pmol) was added to dioxane (4 mL) and water (1 mL) under N2protection, and Pd(dppf)Cl2(44 mg, 60 pmol) was added. The mixture was stirred at 100 °C for 16 h under N2. After cooling, the resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 250*30 mm, 5 um; mobile phase A: H2O (+0.1% NH4CO3), mobile phase B: ACN; gradient: 35-85% B; flow rate: 38 mL / min; wavelength: 214 nm / 254 nm) to give (endo-trans)-tert-butyl (E)-(1-(5-(1-(difluoromethoxy)-8-methyl-7,15-dihydro-8H-benzo[g]benzo[4,5]imidazo[1,2-a]azepin-12- yl)pyrimidin-2-yl)cyclobutyl)carbamate (25C) (5.6 mg, 100% purity, 10 pmol, 3% yield) LCMS (ESI) m / z: 588.41 [M+H] +, and tert-butyl (1 -(5-(1 -(difluoromethoxy)-7-methyl-5-methylene-5, 6, 7, 14- tetrahydrobenzo [f]benzo [4, 5] imidazo [1, 2-a] azocin-11 -yl)pyrimidin-2-yl)cyclobutyl) carbamate (25D) (5.6 mg, 100% purity, 9.5 pmol, 3% yield) LCMS (ESI) m / z: 588.41 [M+H] + ; and tert-butyl (1 -(5-(1 -(difluoromethoxy)-8-methyl-5, 15-dihydro-8H- benzo[g]benzo[4,5]imidazo[1,2-a]azepin-12-yl)pyrimidin-2-yl)cyclobutyl)carbamate (25E) (9.0 mg, 100% purity, 15 pmol, 5% yield). LCMS (ESI) m / z: 588.41 [M+H] + .

[0696]

[0697] EX27 (7.0 mg, 12.69 pmol, 82.87% yield) as a yellow solid. LCMS (ESI) m / z: 488.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) d 9.23 (s, 2H), 8.32 (s, 1H), 8.01 (d, J = 5.2 Hz, 2H), 7.47 (t, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 6.91 (t, J = 73.6 Hz, 1H), 6.22 (d, J = 15.6 Hz, 1H), 6.07 - 5.99 (m, 1H), 5.81 (d, J = 15.2 Hz, 1H), 5.60 - 5.46 (m, 2H), 4.14 - 4.04 (m, 1H), 3.76 - 3.64 (m, 2H), 3.54 - 3.46 (m, 1H), 2.95 - 2.88 (m, 2H), 2.70 - 2.60 (m, 3H), 2.45 - 2.28 (m, 3H), 1.61 (d, J = 6.8 Hz, 3H).

[0698] EX25 was also obtained from 25C similarly to EX27.

[0699] EX25 (5.0 mg, 96% yield). LCMS (ESI) m / z: 488.4 [M+H] + ; Rt = 0.736 min.1 H NMR (400 MHz, CD3OD) δ 9.01 (s, 2H), 8.04 - 7.93 (m, 2H), 7.58 (s, 1H), 7.47 - 7.40 (m, 1.25H), 7.37 - 7.33 (m, 1H), 7.26 (d, J = 3.2 Hz, 0.5H), 7.09 - 7.01 (m, 1.25H), 6.34 - 6.22 (m, 1H), 5.94 (s, 2H), 5.64 (d, J = 16.8 Hz, 1H), 3.93 (s, 1H), 2.98 (d, J = 11.6 Hz, 1H), 2.91 - 2.83 (m, 2H), 2.69 - 2.57 (m, 2H), 2.45 - 2.24 (m, 4H), 1.84 (d, J = 6.0 Hz, 3H).

[0700] EX26 was obtained from 25D, similar to EX27. LCMS (ESI) m / z: 588.41 [M+H] + ; Rt = 0.740 min. 1 H NMR (400 MHz, CD3OD) δ 9.26 (s, 2H), 8.03 - 7.94 (m, 2H), 7.43 (t, J = 8.0 Hz, 1H), 7.38 (s, 0.25H), 7.24 (d, J = 8.0 Hz, 1H), 7.20 - 7.15 (m, 1.5H), 7.01 (s, 0.25H), 6.02 (s, 1H), 5.54 (s, 2H), 5.25 (s, 1H), 4.04 (s, 1H), 2.96 - 2.87 (m, 2H), 2.70 - 2.61 (m, 2H), 2.45 - 2.28 (m, 2H), 1.81 (d, J = 5.2 Hz, 3H).

[0701] Example 28 and Example 29

[0702]

[0703] A mixture of 1-bromo-2,5-difluoro-4-nitro-benzene (28A) (1.50 g, 6.30 mmol), 1G (2.60 g, 6.93 mmol) and K2CO3(4.36 g, 31.51 mmol) was added to dioxane (15 mL) and water (5 mL) under N2protection, Pd(dppf)Cl2(462, 631 μmol) was added. The mixture was stirred at 100 °C for 4 h under nitrogen. After cooling to room temperature, the reaction mixture was quenched with water (100 mL), extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (20% EtOAc / PE solution) to give tert-butyl N-[1-[5-(2,5-difluoro-4-nitrophenyl)pyrimidin-2- yl]cyclobutyl]carbamate (28B) (2.3 g, 96% purity, 5.4 mmol, 86% yield) as an orange solid. LCMS (ESI) m / z: 407.27 [M+H] + .

[0704]

[0705] A mixture of tert-butyl N-[1-[5-(2,5-difluoro-4-nitrophenyl)pyrimidin-2- yl]cyclobutyl]carbamate (1.30 g, 96% purity, 3.01 mmol), [2-bromo-6- (difluoromethoxy)phenyl]methanamine (986 mg, 90% purity, 3.52 mmol) and DIEA (1.65 g, 12.80 mmol) in EtOH (20 mL) was stirred at 80 °C for 16 h. After cooling, the resulting mixture was concentrated and purified by silica gel flash chromatography (25% EtOAc / PE solution) to give tert-butyl N-[1-[5-[5-[[2-bromo-6- (difluoromethoxy)phenyl]methylamino]-2-fluoro-4-nitrophenyl]pyrimidin-2- yl]cyclobutyl]carbamate (28C) (2.1 g, 92% purity, 3.03 mmol, 91% yield) as an orange solid. LCMS (ESI) m / z: 638.20 [M+H] + .

[0706]

[0707] A mixture of tert-butyl 28C (1.00 g, 92% purity, 1.44 mmol), iron powder (410 mg, 7.34 mmol) and NH4Cl (780 mg, 14.6 mmol) in water (5 mL) and EtOH (20 mL) was stirred at 80 °C for 3 h. After cooling, the resulting mixture was filtered, and the filter cake was washed with MeOH (5 x 50 mL). The filtrate was concentrated and purified by silica gel column chromatography (40% EtOAc / PE solution) to give tert-butyl N-[1-[5-[4-amino-5-[[2-bromo-6- (difluoromethoxy)phenyl]methylamino]-2-fluorophenyl]pyrimidin-2-yl]cyclobutyl]carbamate (28D) (650 mg, 58% purity, 620 µmol, 43% yield) as a yellow solid. LCMS (ESI) m / z: 608.25 [M+H] + .

[0708]

[0709] A mixture of 28D (650 mg, 58% purity, 620 µmol), pent-4-enoic acid (114 mg, 1.14 mmol), HATU (316 mg, 831.08 µmol) and DIEA (294 mg, 2.27 mmol) in DMF (10 mL) was stirred at room temperature for 16 h. After cooling to room temperature, the reaction mixture was quenched with water (60 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (50% EtOAc / PE solution) to give tert-butyl N-[1-[5-[5-[[2-bromo-6-(difluoromethoxy)phenyl]methylamino]-2-fluoro-4-(pent-4- enoylamino)phenyl]pyrimidin-2-yl]cyclobutyl]carbamate (28E) (380 mg, 100% purity, 550 µmol, 89% yield) as an orange solid. LCMS (ESI) m / z: 690.28 [M+H] + .

[0710]

[0711] A mixture of 28E (360 mg, 100% purity, 521 μmol) in AcOH (7 mL) was stirred at 60 °C for 16 h. The mixture was basified to pH = 8 with aqueous Na2CO3solution. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and purified by silica gel flash chromatography (40% EtOAc / PE solution) to give tert-butyl N-[1-[5-[3-[[2-bromo-6-(difluoromethoxy)phenyl]methyl]-2-but-3-enyl-6-fluoro- benzoimidazol-5-yl]pyrimidin-2-yl]cyclobutyl]carbamate (28F) (280 mg, 100% purity, 416 μmol, 80% yield) as a yellow solid. LCMS (ESI) m / z: 672.26 [M+H] + .

[0712]

[0713] A mixture of tert-butyl N-[1-[5-[3-[[2-bromo-6-(difluoromethoxy)phenyl]methyl]-2-but-3-enyl-6-fluoro- benzoimidazol-5-yl]pyrimidin-2-yl]cyclobutyl]carbamate (260 mg, 100% purity, 386.60 μmol) and K2CO3 (169.00 mg, 1.22 mmol) under N2protection was added to Pd(dppf)Cl2 (65 mg, 89 μmol). The mixture was stirred at 100 °C under N2for 16 h. After cooling, the resulting mixture was concentrated and purified by preparative HPLC (column: Waters Xbridge 250*30 mm, 5 μm; mobile phase A: H2O (+0.1% NH4CO3), mobile phase B: ACN; gradient: 35-85% B; flow rate: 38 mL / min; wavelength: 214 nm / 254 nm) to give (endo-cis) tert-butyl (Z)-(1-(5-(1-(difluoromethoxy)-11-fluoro-7,15-dihydro-8H- benzo[g]benzo[4,5]imidazo[1,2-a]azepin-12-yl)pyrimidin-2-yl)cyclobutyl)carbamate (28G) (7.0 mg, 11.83 μmol, 100% purity, 3.06% yield). LCMS (ESI) m / z: 592.37 [M+H] +tert-Butyl (1-(5-(1-(difluoromethoxy)-10-fluoro-5-methylene-5,6,7,14-tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azepine-11-yl)pyrimidin-2-yl)cyclobutyl)carbamate (28H) (7.5 mg, 12.68 µmol, 100% purity, 3.28% yield). LCMS (ESI) m / z: 592.37 [M+H] + .

[0714]

[0715] A mixture of 28H (7.0 mg, 11.83 µmol) in HCl solution (4.0 M in 1,4-dioxane, 12.0 mmol, 3.0 mL) and MeOH (1 mL) was stirred at room temperature for 0.5 h. Then the mixture was concentrated and lyophilized to give EX29 (6.0 mg, 10.91 µmol, 92.21% yield, 96% HPLC purity) as a white solid.

[0716] EX29: LCMS (ESI) m / z: 588.41 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 9.20 (s, 2H), 8.42 (d, J = 5.6 Hz, 1H), 7.77 (d, J = 9.6 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.31 (s, 0.25H), 7.22 – 7.15 (m, 2H), 7.12 (s, 0.5H), 6.94 (s, 0.25H), 5.79 (s, 2H), 5.64 (s, 1H), 5.31 (s, 1H), 3.68 – 3.58 (m, 5H), 3.04 (s, 2H), 2.98 – 2.89 (m, 2H), 2.70 – 2.60 (m, 2H), 2.48 – 2.27 (m, 2H).

[0717] Similarly, EX28 was obtained from 28G (6.0 mg, 11 µmol, 89% yield). EX28: LCMS (ESI) m / z: 488.33 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 9.15 (s, 2H), 8.23 (d, J = 6.0 Hz, 1H), 7.79 (d, J = 9.6 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.21 - 7.14 (m, 2H), 6.95 (t, J = 73.6 Hz, 1H), 6.59 (d, J = 12.0 Hz, 1H), 6.10 - 6.00 (m, 1H), 5.95 (s, 2H), 3.42 (s, 2H), 2.96 - 2.81 (m, 4H), 2.70 - 2.59 (m, 2H), 2.47 - 2.26 (m, 2H).

[0718] Example 30

[0719]

[0720] A mixture of EX01 (88 mg, 0.20 mmol), osmium(VIII) oxide (7.37 mg, 0.02 mmol) and sodium periodate (171 mg, 0.80 mmol) in acetonitrile (6.0 mL) and water (1.0 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by prep-HPLC (C18 column chromatography eluted with acetonitrile-water (0.1% formic acid) = 20%~70%) to give 11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-5-yl)-1-(difluoromethoxy)-6,7-dihydrobenzo[f]benzo[4,5]imidazo[1,2-a]azocine-5(14H)-one (EX30) (20 mg, 21.1%) as a white solid. 1 H NMR (400 MHz, MeOD-d4) δ 9.08 (m, 2H), 7.94 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.41 (m, 2H), 7.11 (t, J = 73.6 Hz, 1H), 5.84 (s, 2H), 3.49 (s, 2H), 3.45 (d, J = 6.8 Hz, 2H), 2.79 (s, 2H), 2.41 - 2.24 (m, 2H), 2.09 (d, J = 8.0 Hz, 2H). LC-MS: m / z = 476.1 [M+H] + .

[0721] EX31, EX32, EX33 and EX34,

[0722]

[0723] At 0 °C, oxaloyl chloride (31.5 g, 248 mmol) was added dropwise to a DCM (250 mL) suspension of 4-chloro-2-nitrobenzoic acid (31A) (20 g, 99 mmol), followed by DMF (72.5 mg, 992 μmol). The mixture was stirred for 4 hours at room temperature under nitrogen, and then concentrated to give 4-chloro-2-nitrobenzoyl chloride (31B) (21 g, 93% purity, 86 mmol, 86% yield), a yellow oil that was used directly in the next reaction step without further purification. LCMS (ESI) m / z: 189.10 [M+H] + .

[0724]

[0725] At room temperature, a solution of 31B (21 g, 93% purity, 86 mmol) in ACN (100 mL) was added dropwise to a mixture of 3-buten-1-amine (6.1 g, 56 mmol) and TEA (30.4 g, 300 mmol, 41.9 mL) in ACN (150 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, water (150 mL) was added, and the mixture was extracted with EtOAc (200 mL × 2). The combined organic layers were washed with water (300 mL) and brine (300 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue solid was purified by silica gel column chromatography (PE:EtOAc = 3:1) to give a gray solid 31C (20.5 g, 96% purity, 76.5 mmol, yield 89%). LCMS (ESI) m / z: 255.20 [M+H] + .

[0726]

[0727] Under nitrogen atmosphere, at 0 °C, NaOH (1.0 M solution in MeOH, 40 mL) was added dropwise to a mixture of 31C (1.0 g, 96% purity, 3.7 mmol) and tetrahydroxydiboron (1.67 g, 18.7 mmol) in MeOH (20 mL), and the mixture was stirred at 40 °C for 16 hours. The reaction mixture was cooled to room temperature, concentrated, and the residue was purified by silica gel column chromatography (MeOH:DCM = 1:3) to give 31D (230 mg, 83% purity, 857 μmol, yield 23%) as a yellow oil. LCMS (ESI) m / z: 223.20 [M+H] + .

[0728]

[0729] A mixture of 31D (100 mg, 83% purity, 413 pmol), 31E (2.20 g, 6.61 mmol) and K2CO3 (2.74 g, 19.8 mmol) in DMF (20 mL) was stirred at room temperature for 1 h. The reaction mixture was quenched with water and diluted with EtOAc (150 mL). The combined organic layers were washed with water (150 mL x 3) and brine (150 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give 31F (3.3 g, 80% purity, 6.5 mmol, 88% yield) as a colorless oil. LCMS (ESI) m / z: 457.20 [M+H] + .

[0730]

[0731] A mixture of 31F (150 mg, 80% purity, 298 pmol), Pd(dppf)Cl2 (494 mg, 676 pmol) and K2CO3 (1.4 g, 10 mmol) in dioxane (40 mL) and water (8 mL) was stirred at 100 °C under nitrogen for 16 h. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with EtOAc (30 mL). The combined filtrate was concentrated and purified by silica gel column chromatography (PE:EtOAc = 3:1) to give a mixture of 31G, 31H, 31I and 31J (670 mg, 87% purity, 1.55 mmol, 46% yield) as a colorless oil. LCMS (ESI) m / z: 377.20 [M+H] + .

[0732]

[0733] A mixture of 31G, 31H, 31I and 31J (670 mg, 87% purity, 1.55 mmol), 1G (774 mg, 1.86 mmol), XPhosPd G2 (182 mg, 232 pmol) and Na2CO3 (328 mg, 3.09 mmol) in dioxane (20 mL) and water (4 mL) was stirred at 110 °C under nitrogen for 2 h. The reaction mixture was cooled to room temperature, filtered. The filtrate was concentrated and purified by silica gel column chromatography (MeOH:DCM = 1:33) to give a mixture of 31K, 31L, 31M and 31N (82 mg, 75% purity, 10 pmol, 8% yield) as a yellow oil. LCMS (ESI) m / z: 590.50 [M+H] + .

[0734]

[0735] To a solution of 31K, 31L, 31M and 31N (82 mg, 75% purity, 10 pmol) in MeOH (1.0 mL) was added HC1 solution (4.0 M solution in 1,4-dioxane, 5 mL) dropwise at room temperature and stirred at room temperature for 3 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (column: Waters Xbridge 250 x 30 mm, 5 pm; mobile phase A: H2O (+0.1% HC1), mobile phase B: ACN; gradient: 30%~55% B; flow rate: 30 mL / min; wavelength: 214 nm / 254 nm) to give EX31, (33 mg, HPLC purity 98%, 67 pmol, 63% yield), EX32 (7.8 mg, HPLC purity 97%, 16 pmol, 14% yield), EX33 (1.9 mg, HPLC purity 98%, 3.9 pmol, 4% yield) and EX34 (1.8 mg, HPLC purity 92%, 3.4 pmol, 3% yield) as white solids.

[0736] EX31: LCMS (ESI) m / z: 490.26 [M+H]+. 1 H NMR (400 MHz, MeOD) d 9.31 (s, 2H), 8.11 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.58-7.56 (m, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.03-6.58 (m, 3H), 5.54 (s, 1H), 5.28 (s, 2H), 5.03 (d, J = 1.6 Hz, 1H), 4.24-4.21 (m, 2H), 2.95-2.82 (m, 4H), 2.69-2.61 (m, 2H), 2.47-2.28 (m, 2H).

[0737] EX32: LCMS (ESI) m / z: 490.27 [M+H]+. 1 H NMR (400 MHz, MeOD) d 9.14 (s, 2H), 8.44 (s, 1H), 7.84-7.77 (m, 2H), 7.49-7.46 (m, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.00-6.90 (m, 2H), 6.72-6.53 (m, 2H), 6.07-6.01 (m, 1H), 5.10 (s, 2H), 3.78-3.75 (m, 2H), 2.81-2.78 (m, 2H), 2.51-2.43 (m, 4H), 2.31-2.12 (m, 2H).

[0738] EX33: LCMS (ESI) m / z: 490.25 [M+H]+. 1 H NMR (400 MHz, MeOD) δ 9.16 (d, J = 5.6 Hz, 2H), 7.86 - 7.73 (m, 2H), 7.53 - 7.48 (m, 1H), 7.28 - 7.24 (m, 1H), 7.13 - 7.03 (m, 2H), 7.00 - 6.61 (m, 1H), 6.03 - 5.58 (m, 1H), 5.48 - 5.47 (m, 1H), 5.31 - 5.21 (m, 1H), 5.10 - 4.76 (m, 3H), 4.55 - 4.50 (m, 1H), 4.21 - 4.13 (m, 1H), 3.59 - 3.54 (m, 1H), 3.38 - 3.31 (m, 1H), 2.86 - 2.80 (m, 2H), 2.59 - 2.51 (m, 2H), 2.32 - 2.20 (m, 2H).

[0739] EX34: LCMS (ESI) m / z: 490.26 [M+H]+. 1 H NMR (400 MHz, MeOD) δ 9.14 (d, J = 14.8 Hz, 2H), 7.83 - 7.78 (m, 2H), 7.45 (d, J = 8.0 Hz, 1H), 7.24 - 7.20 (m, 1H), 7.07 - 6.65 (m, 4H), 5.67 - 5.57 (m, 1H), 5.18 (s, 1H), 4.86 - 4.76 (m, 2H), 4.04 - 4.00 (m, 2H), 2.83 - 2.76 (m, 2H), 2.57 - 2.50 (m, 2H), 2.35 - 2.14 (m, 4H).

[0740] Example 35

[0741]

[0742] A mixture of tert-butyl (1-(5-(1-(difluoromethoxy)-5-methylene-5,6,7,14- tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azocine-11-yl)pyrimidin-2-yl)cyclobutyl) carbamate (1T) (30 mg, 0.0524 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (101 mg, 0.524 mmol), potassium iodide (483 mg, 0.524 mmol) in acetonitrile (2 mL) was stirred at 50 °C under nitrogen for 1 h. The reaction was diluted with EtOAc (30 mL), washed with water (30 mL) and brine (30 mL), dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3% MeOH in DCM) to give tert-butyl (1-(5-(1-(difluoromethoxy)-2',2'-difluoro-6,7-dihydro-14H- spiro[benzo[f]benzo[4,5]imidazo[1,2-a]azocine-5,1'-cyclopropyl]-11-yl)pyrimidin-2- yl)cyclobutyl)carbamate (35A) (15 mg, 46% yield) as a yellow oil. LC-MS: m / z = 624.1 [M+H] + ;

[0743]

[0744] To a solution of 35A (15.0 mg, 0.024 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) with stirring. The mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The crude product was purified by preparative HPLC (C18 column chromatography eluted with acetonitrile: water (0.1% formic acid) = 5% to 95%) to give 1-(5-(1-(difluoromethoxy)-2',2'-difluoro-6,7-dihydro-14H- spiro[benzo[f]benzo[4,5]imidazo[1,2-a]azocine-5,1'-cyclopropyl]-11-yl)pyrimidin-2- yl)cyclobutane-1 -amine (EX35) (5 mg, 40% yield) as a white solid. 1 HNMR (400 MHz, MeOD-d4) δ 9.31 (s, 2H), 8.65 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.15 (m, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.34 - 6.95 (m, 4H), 5.96 (s, 2H), 5.61 (s, 1H), 5.32 (s, 1H), 3.87 (m, 1H), 3.15 (s, 2H), 3.00 - 2.85 (m, 3H), 2.72 - 2.59 (m, 2H), 2.52 - 2.25 (m, 2H). LC-MS: m / z = 524.0 [M+H] + .

[0745] Example 36 and Example 37

[0746]

[0747] A mixture of 6-bromo-2-fluoro-3-nitropyridine (1.0 g, 4.53 mmol), tert-butyl N-[1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl] cyclobutyl]carbamate (1.89 g, 98% purity, 4.53 mmol), Pd(dppf)Cl2(331 mg, 452 µmol) and K3PO4(2.40 g, 11.3 mmol) in water (2 mL) and dioxane (20 mL) was stirred at 60 °C under nitrogen for 1 h. After TLC and LCMS showed the reaction was completed, the mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue solid was purified by silica gel flash chromatography (PE:EtOAc = 3:1) to give the title compound tert-butyl N-[1-[5-(6-fluoro-5-nitro-2-pyridyl)pyrimidin-2-yl]cyclobutyl]carbamate (36B) (1.55 g, 80% purity, 3.18 mmol, 64% yield) as a gray solid. LCMS (ESI) m / z: 390.30 [M+H] + .

[0748]

[0749] A mixture of tert-butyl N-[1-[5-(6-fluoro-5-nitro-2-pyridyl)pyrimidin-2-yl]cyclobutyl]carbamate (1.55 g, 80% purity, 3.18 mmol), [2-bromo-6-(difluoromethoxy)phenyl]methanamine (1.28 g, 100% purity, 4.57 mmol) and DIEA (3.63 g, 28.1 mmol) in EtOH (20 mL) was stirred at 82 °C for 2 h. The reaction mixture was concentrated, and the resulting residue was dissolved in EtOAc (200 mL). The organic layer was washed with water (200 mL x 3) and brine (200 mL), dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EtOAc = 3:1) to give the title compound tert-butyl N-[1-[5-[6-[[2-bromo-6-(difluoromethoxy)phenyl]methylamino]-5-nitro-2-pyridyl]pyrimidin-2-yl]cyclobutyl]carbamate (36C) (1.85 g, 92% purity, 2.68 mmol, 76% yield) as a yellow solid. LCMS (ESI) m / z: 621.40 [M+H] + .

[0750]

[0751] A mixture of tert-butyl N-[1-[5-[6-[[2-bromo-6-(difluoromethoxy)phenyl]methylamino]-5-nitro-2-pyridyl]pyrimidin-2-yl]cyclobutyl]carbamate (1.85 g, 92% purity, 2.68 mmol), iron powder (873 mg, 15.6 mmol) and NH4Cl (1.39 g, 26.0 mmol) in EtOH (30 mL) and water (6 mL) was stirred at 84 °C for 2.5 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and diluted with EtOAc (150 mL). The organic layer was washed with water (150 mL x 3) and brine (150 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EtOAc = 3:1) to give the title compound tert-butyl N-[1-[5-[5-amino-6-[[2-bromo-6-(difluoromethoxy)phenyl]methylamino]-2-pyridyl]pyrimidin-2-yl]cyclobutyl]carbamate (36D) (1.45 g, 94% purity, 2.31 mmol, 85% yield) as a gray solid. LCMS (ESI) m / z: 591.32 [M+H] + .

[0752]

[0753] A mixture of tert-butyl N-[1-[5-[5-amino-6-[[2-bromo-6-(difluoromethoxy)phenyl]methylamino]-2-pyridyl]pyrimidin-2-yl]cyclobutyl]carbamate (1.45 g, 94% purity, 2.31 mmol), 4-pentenoic acid (342 mg, 3.42 mmol), HATU (1.30 g, 3.42 mmol) and DIEA (885 mg, 6.85 mmol) in DMF (20 mL) was stirred at room temperature for 5 h. The reaction mixture was quenched with water (100 mL), extracted with EtOAc (100 mL x 2), and washed with water (200 mL x 3) and brine (200 mL). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc = 3:2) to give tert-butyl N-[1-[5-[6-[[2-bromo-6-(difluoromethoxy)phenyl]methylamino]-5-(pent-4-enoylamino)-2-pyridyl]pyrimidin-2-yl]cyclobutyl]carbamate (36E) (1.3 g, 92% purity, 1.78 mmol, 76% yield) as a gray solid. LCMS (ESI) m / z: 673.50 [M+H] + .

[0754]

[0755] A solution of tert-butyl N-[1-[5-[6-[[2-bromo-6-(difluoromethoxy)phenyl]methylamino]-5-(pent-4- enoylamino)-2-pyridyl]pyrimidin-2-yl]cyclobutyl]carbamate (1.0 g, 92% purity, 1.3 mmol) in POCl3(15 mL) was stirred at 80 °C for 10 h. The reaction mixture was concentrated, dissolved in EtOAc (150 mL), and adjusted to pH = 10 with saturated aqueous NaHCO3solution in an ice bath. The combined organic layers were washed with brine (150 mL), dried over Na2SO4, and filtered. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (MeOH:DCM = 1:5) to give 1-[5-[3-[[2-bromo-6-(difluoromethoxy)phenyl]methyl]-2-but-3-enyl- imidazo[4,5-b]pyridin-5-yl]pyrimidin-2-yl]cyclobutanimine (36F) (510 mg, 91% purity, 826 pmol, 61.85% yield) as a gray solid. LCMS (ESI) m / z: 555.21 [M+H] + .

[0756]

[0757] A mixture of 1-[5-[3-[[2-bromo-6-(difluoromethoxy)phenyl]methyl]-2-but-3-enyl- imidazo[4,5-b]pyridin-5-yl]pyrimidin-2-yl]cyclobutanimine (510 mg, 91% purity, 826 pmol), Boc20 (228 mg, 1.05 mmol), and TEA (264 mg, 2.61 mmol) in DCM (20 mL) was stirred at room temperature for 5 h. The reaction mixture was concentrated and dissolved in EtOAc (100 mL). The organic layer was washed with water (100 mL x 2) and brine (100 mL), dried over anhydrous Na2CO3, and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl N-[1-[5-[3-[[2-bromo-6-(difluoromethoxy)phenyl]methyl]-2-but-3-enyl- imidazo[4,5-b]pyridin-5-yl]pyrimidin-2-yl]cyclobutyl]carbamate (36G) (749 mg, 90% purity, 914 pmol, 95% yield) as a yellow solid. LCMS (ESI) m / z: 655.50 [M+H] + .

[0758]

[0759] A mixture of N-[1-[5-[3-[[2-bromo-6-(difluoromethoxy)phenyl]methyl]-2-but-3-enyl- imidazo[4,5-b]pyridin-5-yl]pyrimidin-2-yl]cyclobutyl]carbamic acid tert-butyl ester (580 mg, 90% purity, 708 pmol), Pd(dppf)Cl2(103 mg, 141 pmol) and K2CO3(293 mg, 2.12 mmol) in dioxane (25 mL) and water (5 mL) was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature, concentrated, purified by silica gel column chromatography (PE:EtOAc = 1:5) to give a mixture of 36H and 36I (56 mg, 86% purity, 6.5 pmol, 14% yield) as a white solid. LCMS (ESI) m / z: 575.50 [M+H] + .

[0760]

[0761] To a solution of 36H and 36I (56 mg, 86% purity, 6.5 pmol) in MeOH (1 mL) was added HCl (4.0 M solution in 1,4-dioxane, 4 mL) dropwise at room temperature, then stirred at room temperature for 3 h. The reaction mixture was concentrated, purified by preparative HPLC (column: Waters Xbridge 250 x 30 mm, 5 pm; mobile phase A: H2O (+0.1% HC1), mobile phase B: ACN; gradient: 30%~65% B; flow rate: 34 mL / min; wavelength: 214 nm / 254 nm) to give the target compound (Z)-1-(5-(1-(difluoromethoxy)-5,15-dihydro-8H-benzo[g]pyrido[3',2':4,5]imidazo[1,2-a]azanon-12- yl)pyrimidin-2-yl)cyclobutane-1 -amine (EX36) (3.2 mg, HPLC purity 96%, 26 pmol, 8% yield) and 1-(5-(1-(difluoromethoxy)-5-methylene-5,6,7,14-tetrahydrobenzo[f]pyrido[3',2':4,5]imidazo[1,2-a]azaoct-11- yl)pyrimidin-2-yl)cyclobutane-1 -amine (EX 37) (12.8 mg, HPLC purity 99%, 26.8 pmol, 32% yield) as white solids.

[0762] EX36: LCMS (ESI) m / z: 475.40 [M+H]+. 1H NMR (400 MHz, MeOD) δ 9.36 (s, 2H), 8.25 (d, J = 49.6 Hz, 2H), 7.27 - 7.20 (m, 2H), 7.01 - 6.83 (m, 2H), 6.22 - 6.04 (m, 2H), 5.71 (s, 2H), 3.56 - 3.55 (m, 4H), 2.86 - 2.73 (m, 2H), 2.57 - 2.45 (m, 2H), 2.34 - 2.21 (m, 2H).

[0763] EX37: LCMS (ESI) m / z: 475.25 [M+H]+. 1 H NMR (400 MHz, MeOD) δ 9.71 (s, 2H), 8.33 (q, J = 8.8 Hz, 2H), 7.47 (t, J = 8.0 Hz, 1H), 7.25 - 7.18 (m, 2H), 7.00 (t, J = 74.0 Hz, 1H), 6.03 (s, 2H), 5.53 (s, 1H), 5.31 (s, 1H), 3.61 - 3.58 (m, 2H), 3.23 - 3.20 (m, 2H), 2.98 - 2.91 (m, 2H), 2.70 - 2.63 (m, 2H), 2.50 - 2.28 (m, 2H).

[0764] Example 38

[0765]

[0766] To a solution of tert-butyl acetate (38A) (10.0 g, 86.1 mmol, 11.6 mL) in THF (100 mL) was added LDA (2M solution in THF, 94.70 mmol, 47.35 mL) dropwise at -78 °C under argon. After 1 h, 2,3-dibromoprop-1-ene (38B) (17.2 g, 86.1 mmol, 8.90 mL) was added dropwise and the mixture was allowed to warm to room temperature over 16 h. The mixture was quenched with saturated aqueous NH4Cl, concentrated at 25 °C, diluted with DCM and washed with water and brine. The organic layer was concentrated at 25 °C, purified by column chromatography on silica gel (PE:EtOAc = 95:5) to give tert-butyl 4-bromopent-4-enoate (38C) (10.05 g, 98% purity, 41.89 mmol, 49% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 5.60 (d, J = 1.2 Hz, 1H), 5.40 (d, J = 1.6 Hz, 1H), 2.68 (t, J = 7.2 Hz, 2H), 2.46 (t, J = 7.6 Hz, 2H), 1.42 (s, 9H).

[0767]

[0768] A mixture of 38C (3.25 g, 98% purity, 13.6 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.13 g, 16.3 mmol), Pd(dppf)Cl2(494 mg, 675 µmol) and KOAc (3.99 g, 40.6 mmol) in dioxane (40 mL) was stirred at 60 °C under argon for 16 h. The mixture was concentrated and purified by silica gel column chromatography (PE:EtOAc = 97:3) to give tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-enoate (38D) (4.26 g, 85% purity, 12.8 mmol, 95% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 5.72 (d, J = 3.2 Hz, 1H), 5.57 (s, 1H), 2.40–2.34 (m, 2H), 2.30 (d, J = 7.6 Hz, 2H), 1.36 (s, 9H), 1.20 (s, 12H).

[0769]

[0770] A solution of 38D (4.66 g, 95% yield, 14.9 mmol) in TFA (3 mL) and DCM (9 mL) was stirred at 40 °C for 16 h. The mixture was concentrated to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-enoic acid (38E) (3.91 g, 85% purity, 14.7 mmol, 99% yield) as a colorless oil. LCMS (ESI) m / z: [M-H]- - 225.18. 1 H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 5.68 (d, J = 3.4 Hz, 1H), 5.61 (d, J = 3.2 Hz, 1H), 2.30 (s, 4H), 1.21 (s, 12H).

[0771]

[0772] To a mixture of 2-bromo-6-fluoro-3-methylbenzaldehyde (38F) (10.0 g, 46.1 mmol) in MeOH (70 mL) was added MeONa (10.0 g, 185 mmol) and the mixture was stirred at 60 °C under nitrogen for 6 hours. The reaction mixture was quenched with water (150 mL) and adjusted to pH = 2 with aqueous HC1 (2.0 M). After removal of MeOH in vacuo, the mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (150 mL x 2) and brine (150 mL), dried over anhydrous Na2S04, and then filtered. The filtrate was concentrated and purified by column chromatography on silica gel (15% EtOAc in PE) to give 2-bromo-6-methoxy-3-methylbenzaldehyde (38G) (7.40 g, 88% purity, 30.7 mmol, 67% yield) as olive solid. LCMS (ESI) m / z: [M+H] + 228.04.

[0773]

[0774] To a mixture of 38G (526 mg, 88% purity, 2.18 mmol) in DCM (8 mL) was added BBr3 (2.0 M solution in DCM, 2.20 mL) dropwise at -78 °C under nitrogen. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water and extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (100 mL x 2) and brine (150 mL), dried over anhydrous Na2S04, and then filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (20% EtOAc in PE) to give 2-bromo-6-hydroxy-3-methylbenzaldehyde (38H) (400 mg, 93% purity, 1.77 mmol, 81% yield) as olive solid. LCMS (ESI) m / z: [M+H] + 214.09.

[0775]

[0776] To a mixture of KOH (1.98 g, 35.3 mmol) in water (10 mL) was added 38H (400 mg, 93% purity, 1.77 mmol) in ACN (10 mL). The mixture was stirred at -10 °C for 10 min, then 1-[[bromo(difluoro)methyl]- ethoxyphosphoryl]oxoethane (755 mg, 2.83 mmol) was added dropwise. The mixture was stirred at -10 °C for 1 h, then quenched with NaHCO3 and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give an olive solid, which was purified by column chromatography on silica gel (15% to 20% EtOAc in PE) to give 2-bromo-6-(difluoromethoxy)-3-methylbenzaldehyde (38I) (400 mg, 100% purity, 1.51 mmol, 85% yield) as an olive solid. LCMS (ESI) m / z: [M+H] 279.0, 281.0. + 264.10.

[0777]

[0778] To a mixture of 38I (400 mg, 93% purity, 1.43 mmol) in ACN (9 mL) was added BocNH2 (490 mg, 4.30 mmol). The mixture was stirred at room temperature for 5 h. Et3SiH (500 mg, 4.30 mmol) was added dropwise to the mixture, and the mixture was stirred at room temperature for 43 h. The reaction mixture was quenched with water and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl N-[[2-bromo-6-(difluoromethoxy)-3-methylphenyl]methyl]carbamate (38J) (400 mg, 83% purity, 881 µmol, 84% yield) as a yellow oil. LCMS (ESI) m / z: [M+H] 323.0, 325.0. + 310.05.

[0779]

[0780] To a mixture of 38J (2.6 g, 83% purity, 7.1 mmol) in DCM (20 mL) was added TFA (7.0 mL), and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated, diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL) and brine (100 mL), dried over anhydrous Na2S04and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (30-40% EtOAc in PE) to give [2-bromo-6-(difluoromethoxy)-3-methylphenyl]methanamine (38K) (1.3 g, 76% purity, 3.4 mmol, 48% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] + 266.07.

[0781]

[0782] To a solution of 1I (1.80 g, 72% purity, 4.63 mmol) and 38L (1.23 g, 76% purity, 4.63 mmol) in EtOH (30 mL) was added DIEA (4.79 g, 37.1 mmol). The mixture was stirred at 80 °C under nitrogen for 16 h. The reaction mixture was concentrated, the residue was diluted with EtOAc (150 mL), washed with water (2 x 100 mL) and brine (100 mL), dried over anhydrous Na2S04and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (40-50% EtOAc in PE) to give tert-butyl N-[1-[5-[3-[[2-bromo-6-(difluoromethoxy)-3-methylphenyl]methylamino]-4-nitrophenyl]pyrimidin-2-yl]cyclobutyl]carbamate (38L) (2.0 g, 75% purity, 2.2 mmol, 47% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] + 634.24.

[0783]

[0784] To a mixture of 38L (1.3 g, 75% purity, 1.4 mmol) in EtOH (20 mL) and water (6.0 mL) was added iron powder (800 mg, 14.0 mmol) and NH4Cl (767 mg, 14.0 mmol). The mixture was stirred at 80 °C under nitrogen for 6 h. The reaction mixture was filtered. The filtrate was diluted with EtOAc (150 mL), washed with water (2 x 100 mL) and brine (100 mL), dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated and purified by column chromatography on silica gel (50-60% EtOAc in PE) to give tert-butyl N-[1-[5-[4-amino-3-[[2-bromo-6-(difluoromethoxy)-3-methylphenyl]methylamino]phenyl]pyrimidin-2-yl]cyclobutyl]carbamate (38M) (1.1 g, 64% purity, 1.3 mmol, 88% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] + 604.27.

[0785]

[0786] To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-enoic acid (38E) (78 mg, 345 µmol) in DMF (4.0 mL) was added DIEA (121 mg, 942 µmol) and HATU (179 mg, 471 µmol). The mixture was stirred at room temperature for 30 min, then 38M (200 mg, 64% purity, 314 µmol) was added. The mixture was stirred at room temperature for 30 min. The reaction mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL) and brine (100 mL), dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated and purified by column chromatography on silica gel (60-70% EtOAc in PE) to give tert-butyl N-[1-[5-[3-[[2-bromo-6-(difluoromethoxy)-3-methylphenyl]methylamino]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-enoylamino]phenyl]pyrimidin-2-yl]cyclobutyl]carbamate (38N) (120 mg, 68% purity, 140 µmol, 44% yield) as an olive solid. LCMS (ESI) m / z: [M+H] + 812.41.

[0787]

[0788] A mixture of 38N (100 mg, 68% purity, 123 pmol) in AcOH (2.0 mL) was stirred at 60 °C for 16 h. The reaction mixture was concentrated and the residue was diluted with EtOAc (50 mL), washed with water (3 x 50 mL) and brine (50 mL), dried over anhydrous Na2S04, then filtered. The filtrate was concentrated and purified by column chromatography on silica gel (70%~80% EtOAc in PE) to give tert-butyl N-[1-[5-[3-[[2-bromo-6-(difluoromethoxy)-3-methylphenyl]methyl]-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyl]benzoimidazol-5-yl]pyrimidin-2-yl]cyclobutyl]carbamate (38O) (80 mg, 78% purity, 96 pmol, 78% yield) as olive solid. LCMS (ESI) m / z: [M+H] + 694.22.

[0789]

[0790] To a mixture of 38O (60 mg, 78% purity, 72 pmol) in dioxane (2.0 mL) and water (0.4 mL) was added K2C03(29.74 mg, 215.22 pmol) and Pd(dppf)C12(5 mg, 7 pmol). The mixture was stirred at 100 °C under nitrogen for 4 h. The reaction mixture was quenched with water and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2S04, then filtered. The filtrate was concentrated and purified by column chromatography on silica gel (100% EtOAc) to give tert-butyl (1-(5-(1-(difluoromethoxy)-4-methyl-5-methylene-5,6,7,14-tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azepin-11-yl)pyrimidin-2-yl)cyclobutyl)carbamate (30 mg, 94% purity, 49 pmol, 67% yield) (38P) as a yellow solid. LCMS (ESI) m / z: [M+H] + 588.34.

[0791]

[0792] To a mixture of 38P (25 mg, 94% purity, 42 pmol) in MeOH (1.0 mL) was added HC1 solution (4.0 M solution in 1,4-dioxane, 2.0 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by preparative HPLC (column: Waters Xbridge 250 x 30 mm, 5 pm; mobile phase A: H20 (+0.1% NH4OH), mobile phase B: ACN; gradient: 15% to 85% B; flow rate: 35 mL / min; wavelength: 214 nm / 254 nm) to give 1-(5-(1-(difluoromethoxy)-4-methyl-5-methylene-5,6,7,14-tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azepin-11-yl)pyrimidin-2-yl)cyclobutan-1-amine (EX38) (6.0 mg, 97% HPLC purity, 12 pmol, 28% yield) as a white solid. LCMS (ESI) m / z: [M+H] 480.3. + 488.28. 1 H NMR (400 MHz, DMSO-d6) d 9.14 (s, 2H), 8.18 (d, J = 1.6 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.39 (s, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 5.68 - 5.61 (m, 2H), 5.24 (d, J = 15.2 Hz, 1H), 5.04 (d, J = 1.6 Hz, 1H), 3.43 - 3.40 (m, 1H), 3.32 - 3.23 (m, 1H), 3.17 - 3.12 (m, 1H), 2.68 - 2.61 (m, 1H), 2.57 (s, 2H), 2.17 (s, 3H), 2.14 - 2.09 (m, 3H), 2.04 - 1.94 (m, 1H), 1.88 - 1.79 (m, 1H).

[0793] Example 39

[0794] A mixture of 1-bromo-2,3-difluoro-4-nitrobenzene (39A) (2.0 g, 8.4 mmol), tert-butyl N-[1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl] cyclobutyl]carbamate (1G) (3.47 g, 95% yield, 9.24 mmol), K2CO3(3.48 g, 25.2 mmol) and Pd(dppf)Cl2(360 mg, 492 µmol) in dioxane (20 mL) and H2O (4 mL) was stirred at 70 °C under argon for 2 h. The mixture was concentrated and purified by silica gel column chromatography (PE:EtOAc = 17:83) to give tert-butyl N-[1-[5-(2,3-difluoro-4-nitrophenyl)pyrimidin-2-yl]cyclobutyl]carbamate crude product (38B) (3.54 g, 97% purity, 8.45 mmol) as a yellow solid. LCMS (ESI) m / z: [M+H] + 351.14.

[0795]

[0796] A mixture of 39B (3.54 g, 97% purity, 8.45 mmol), 1M (2.93 g, 95% purity, 9.29 mmol) and DIEA (6.01 g, 46.5 mmol, 8.09 mL) in EtOH (35 mL) was stirred at 90 °C for 20 h. The mixture was cooled and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-50% EtOAc in PE) to give tert-butyl N-[1-[5-[3-[[2-bromo-6-(difluoromethoxy)phenyl]methylamino]-2-fluoro-4-nitrophenyl]pyrimidin-2-yl]cyclobutyl]carbamate (39C) (3.63 g, 97% purity, 5.52 mmol, 65% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] + 638.18.

[0797]

[0798] A mixture of 39C (1.00 g, 97% purity, 1.57 mmol), Zn (1.02 g, 15.7 mmol) and NH4Cl (837 mg, 15.7 mmol) in 75% EtOH (10 mL) was stirred at 60 °C for 50 min. The mixture was filtered, concentrated, purified by column chromatography on silica gel (DCM:MeOH = 95:5) to give tert-butyl N-[1-[5-[4-amino-3-[[2-bromo-6- (difluoromethoxy)phenyl]methylamino]-2-fluorophenyl]pyrimidin-2-yl]cyclobutyl]carbamate (39D) (820 mg, 91% purity, 1.23 mmol, 78% yield) as an orange solid. LCMS (ESI) m / z: [M+H] + 609.18.

[0799]

[0800] A mixture of 39D (780 mg, 91% purity, 1.17 mmol), 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pent-4-enoic acid (467 mg, 85% purity, 1.17 mmol) and NMI (335 mg, 4.08 mmol) in ACN (8 mL) was stirred for 10 min, then TCFH (687 mg, 2.45 mmol) was added, and the mixture was stirred at 50 °C for 16 h. The mixture was diluted with EtOAc and washed with brine. The organic layer was concentrated and purified by column chromatography on silica gel (PE:EtOAc = 38:62) to give tert-butyl N-[1-[5-[3-[[2-bromo-6-(difluoromethoxy)phenyl]methylamino]-2-fluoro-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-enoylamino]phenyl]pyrimidin-2-yl]cyclobutyl]carbamate (39E) (630 mg, 66% purity, 509 µmol, 44% yield) as a dark red solid. LCMS (ESI) m / z: [M+H] + 817.37.

[0801]

[0802] A solution of 39E (610 mg, 493.07 µmol) in AcOH (6 mL) was stirred at 60 °C for 4 h. The mixture was concentrated and purified by column chromatography on silica gel (MeOH:DCM = 4:96) to give tert-butyl N-[1-[5-[3-[[2-bromo-6-(difluoromethoxy)phenyl]methyl]-4-fluoro-2-[3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)but-3-enyl]benzoimidazol-5-yl]pyrimidin-2-yl]cyclobutyl]carbamate (39F) (390 mg, purity 42%, 204.57 µmol, 41% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] + 798.36.

[0803]

[0804] A mixture of 39F (135 mg, purity 42%, 71 µmol), Pd(dppf)Cl2 (15 mg, 21 µmol) and K2CO3 (30 mg, 217 µmol) in dioxane (3 mL) and H2O (0.6 mL) was stirred at 90 °C under argon for 2 h. The mixture was concentrated and purified by column chromatography on silica gel (MeOH:DCM = 5:95) to give tert-butyl (1-(5-(1-(difluoromethoxy)-12-fluoro-5-methylene-5,6,7,14-tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azocin-11-yl)pyrimidin-2-yl)cyclobutyl)carbamate (39G) (80 mg, purity 94%, quantitative, 127 µmol) as a yellow oil. LCMS (ESI) m / z: [M+H] + 592.39.

[0805]

[0806] To a solution of 39G (80 mg, 135 μmol) in DCM (5.0 mL) was added HC1 (4 M, 8.00 mmol, 2 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated, diluted with ACN, purified by prep-HPLC (column: Waters Xbridge 250 x 30 mm, 5 μm; mobile phase A: H20 (+0.1% NH4HCO3), mobile phase B: ACN; gradient: 35%~85% B; flow rate: 39 mL / min; wavelength: 214 nm / 254 nm) to give 1-(5-(1-(difluoromethoxy)-12-fluoro-5-methylene-5,6,7,14-tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azepin-11-yl)pyrimidin-2-yl)cyclobutan-1-amine (EX39) (13.5 mg, 100% purity, 27 μmol, 20% yield) as a white solid.

[0807] LCMS (ESI) m / z: [M+H]+ + 492.27. 1 H NMR (400 MHz, CDCl3) δ 8.96 (s, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.25-7.18 (m, 2H), 7.12 (t, J = 7.2 Hz, 1H), 5.71 (s, 1H), 5.35 (s, 1H), 5.22 (s, 1H), 3.37-3.28 (m, 1H), 3.09-3.01 (m, 1H), 2.87 (dt, J = 12.0, 9.2 Hz, 1H), 2.43 (dd, J = 17.1, 10.4 Hz, 1H), 2.33-2.22 (m, 1H), 2.18-2.05 (m, 1H). 19 F NMR (376 MHz, CDCl3) δ -76.03, -81.01.

[0808] Example 40

[0809]

[0810] A mixture of 1I (1.56 g, 95% purity, 4.02 mmol), [2-bromo-5- (fluoromethoxy)phenyl]methanamine (940 mg, 100% purity, 4.02 mmol), DIEA (4.2 g, 32 mmol) in EtOH (20 mL) was stirred at 80 °C for 16 h. The reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel (PE:EtOAc = 5:1) to give tert-butyl N-[1-[5-[3-[[2-bromo-5-(difluoromethoxy)phenyl]methyl]-4- nitrophenyl]pyrimidin-2-yl]cyclobutyl]carbamate (40A) (2.14 g, 86% purity, 3.04 mmol, 75% yield) as a yellow solid. LCMS (ESI) m / z: 620.21 [M+H] + .

[0811]

[0812] A mixture of 40A (2.0 g, 86% purity, 2.77 mmol), Zn (1.8 g, 28 mmol), NH4Cl (1.48 g, 27.7 mmol) in EtOH (40 mL) was stirred at 60 °C for 2 h. The reaction mixture was cooled to room temperature, filtered and diluted with EtOAc (200 mL). The combined organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated, and the resulting residue solid was purified by column chromatography on silica gel (PE:EtOAc = 1:1) to give tert-butyl N-[1-[5-[4-amino-3-[[2-bromo-5-(difluoromethoxy)phenyl]methylamino]phenyl]pyrimidin-2- yl]cyclobutyl]carbamate (40B) (1.0 g, 70% purity, 1.2 mmol, 42% yield) as a yellow solid. LCMS (ESI) m / z: 590.19 [M+H] + .

[0813]

[0814] A mixture of 38E (440 mg, 100% purity, 1.37 mmol), HATU (741 mg, 1.95 mmol), DIPEA (461 mg, 3.57 mmol) in DMF (10 mL) was stirred at 50 °C for 40 min. Then 40B (900 mg, 70% purity, 1.08 mmol) was added to the reaction mixture, which was stirred at 50 °C for another 3 h. The reaction mixture was cooled to room temperature, quenched with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with water (150 mL x 3) and brine (150 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated and purified by silica gel chromatography (PE:EtOAc = 2:3) to give tert-butyl N-[1-[5-[3-[[2-bromo-5-(difluoromethoxy)phenyl]methylamino]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-enoylamino]phenyl]pyrimidin-2-yl]cyclobutyl]carbamate (40C) (780 mg, 79% purity, 937 µmol, 78% yield) as a yellow solid. LCMS (ESI) m / z: 798.40 [M+H]+.

[0815]

[0816] A solution of 40C (210 mg, 79% purity, 252 µmol) in POCl3(3 mL) was stirred at 80 °C for 3 h. The reaction mixture was concentrated, and the residue was dissolved in DCM (20 mL). K2CO3(200 mg) was added to the mixture and stirred at room temperature for 15 min, then filtered. The filtrate was concentrated and purified by silica gel column chromatography (MeOH in DCM, 1:10 to 10:1) to give [3-[6-[2-(1-aminocyclobutyl)pyrimidin-5-yl]-1-[[2-bromo-5-(difluoromethoxy)phenyl]methyl]benzo[d]imidazol-2-yl]-1-methylene-propyl]boronic acid (40D) (65 mg, 90% purity, 92.35 µmol, 50% yield) as a yellow solid. LCMS (ESI) m / z: 598.25 [M+H]+. + .

[0817]

[0818] A mixture of 40D (65 mg, 90% purity, 92.35 pmol), Pd(dppf)Cl2(15 mg, 20 pmol) and K2CO3(69.0 mg, 497 pmol) in dioxane (4 mL) and water (0.9 mL) was stirred at 100 °C under nitrogen for 16 h. The reaction mixture was cooled to room temperature and concentrated. The residue solid was purified by prep-HPLC (column: Waters Xbridge 250x30 mm, 5 pm; mobile phase A: H2O (+0.1% FA), mobile phase B: ACN; gradient: 35%~73% B; flow rate: 35 mL / min; wavelength: 214 nm / 254 nm) to give the target compound 1-(5-(2-(difluoromethoxy)-5-methylene-5,6,7,14-tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azocin-11-yl)pyrimidin-2-yl)cyclobutane-1-amine FA salt (EX40) (2.5 mg, yield 7%, purity 100%). LCMS (ESI) m / z: 474.28 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 2H), 8.38-8.33 (m, 2H), 7.79 (d, J = 2.0 Hz, 1H), 7.63-7.57 (m, 2H), 7.38-7.01 (m, 3H), 5.46-5.43 (m, 3H), 5.08 (d, J = 1.6 Hz, 1H), 3.55-3.48 (m, 2H), 2.70-2.63 (m, 2H), 2.22-2.15 (m, 2H), 2.08-1.84 (m, 2H).

[0819] Examples 41 and 42

[0820]

[0821] A mixture of ((2-bromo-6-(difluoromethoxy)benzyl)oxy)(tert-butyl)dimethylsilane (41A) (20.0 g, 54.6 mmol), (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylic acid ethyl ester (41B) (14.8 g, 65.5 mmol), Pd(dppf)Cl2(4.00 g, 5.46 mmol) and K2CO3(22.6 g, 163.8 mmol) in dioxane (200 mL) and H2O (50 mL) was stirred at 90 °C for 3 h. The mixture was cooled and concentrated in vacuo. The residue was purified by silica gel column chromatography (0~15% EtOAc in PE) to give 41C (16.0 g, yield 75.9%). 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 16.0 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.38 - 6.96 (m, 3H), 6.51 (d, J = 16.0 Hz, 1H), 4.74 (s, 2H), 4.12 (q, J = 7.2 Hz, 2H), 1.19 (t, J = 7.2 Hz, 3H), 0.77 (s, 9H), 0.00 (s, 6H).

[0822]

[0823] A mixture of 41C (16.0 g, 41.5 mmol) and LiOH H2O (8.72 g, 207.5 mmol) in MeOH (50 mL), THF (50 mL) and H2O (50 mL) was stirred at room temperature for 2 h. The resulting mixture was diluted with aqueous HC1 (1.0 M, 100 mL). The resulting mixture was extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo and the residue was used in the next step reaction without further purification. LC-MS: m / z = 357.0 [M-H].

[0824]

[0825] A mixture of 41D (4.9 g, 50.3 mmol), HATU (19.1 g, 50.3 mmol) and DIEA (21.6 g, 167.5 mmol) in DMF (150 mL) was stirred at room temperature overnight. The resulting mixture was diluted with H2O (200 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (0-50% EtOAc in PE) to give the target product 41F (10.0 g, yield 74.4%). LC-MS: m / z = 402.1 [M+H] + .

[0826]

[0827] To a solution of Me3SOI (10.97 g, 49.88 mmol) in DMSO was added NaH (2.0 g, 49.88 mmol, 60%) portion wise at 10 °C with stirring. The resulting mixture was stirred at 10 °C for 1 h. To the above mixture was added 41F (10.0 g, 24.94 mmol) drop wise at 10 °C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with aqueous NH4Cl (50 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-40% EtOAc in PE) to give the target product 41G (3.2 g, yield 30.9%). LC-MS: m / z = 416.1 [M+H] + .

[0828]

[0829] To a solution of 41G (3.2 g, 7.71 mmol) in THF (50 mL) was added DIBAL-H (11.56 mL, 1.0 mol in hexane) drop wise at -78 °C under argon and stirring. The resulting mixture was stirred at -78 °C under argon for 3 h. The reaction was quenched with aqueous NH4Cl (100 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-40% EtOAc in PE) to give the target product (2.4 g, yield 87.4%). 1 H NMR (400 MHz, MeOD-d4) δ 9.20 (d, J = 4.8 Hz, 1H), 7.19 (t, J = 8.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 6.68 (t, J = 74.4 Hz, 1H), 4.76 (d, J = 4.8 Hz, 2H), 2.92-2.87 (m, 1H), 2.05-1.99 (m, 1H), 1.65-1.61 (m, 1H), 1.55-1.50 (m, 1H), 0.79 (s, 9H), 0.00 (d, J = 4.8 Hz, 6H).

[0830]

[0831] A mixture of 41H (2.0 g, 5.62 mmol) and ethyl 2-(triphenyl-5-phosphono)acetate (2.93 g, 8.43 mmol) in DCM (20 mL) was stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (0-10% EtOAc in PE) to give the target product 41I (2.0 g, yield 83.6%). 1 H NMR (400 MHz, MeOD-d4) δ 7.18 (t, J = 8.0 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.87-6.48 (m, 3H), 5.87 (d, J = 15.2 Hz, 1H), 4.84-4.74 (m, 2H), 4.08 (q, J = 7.2 Hz, 2H), 2.49-2.44 (m, 1H), 1.72-1.65 (m, 1H), 1.50-1.45 (m, 1H), 1.26-1.21 (m, 1H), 1.20 (t, J = 7.2 Hz, 3H), 0.79 (s, 9H), 0.00 (d, J = 3.2 Hz, 6H).

[0832]

[0833] A mixture of 41I (2.0 g, 4.69 mmol) and Pd / C (300 mg, 10%) in TFEA (20 mL) was stirred at room temperature under H2(1 atm) for 3 hours. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 20 mL). The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (0-10% EtOAc in PE) to give 41J (1.5 g, yield 74.3%). 1 H NMR (400 MHz, MeOD-d4) δ 7.18 (t, J = 8.0 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.87-6.48 (m, 3H), 5.87 (d, J = 15.2 Hz, 1H), 4.84-4.74 (m, 2H), 4.08 (q, J = 7.2 Hz, 2H), 2.49-2.44 (m, 1H), 1.72-1.65 (m, 1H), 1.50-1.45 (m, 1H), 1.26-1.21 (m, 1H), 1.20 (t, J = 7.2 Hz, 3H), 0.79 (s, 9H), 0.00 (d, J = 3.2 Hz, 6H).

[0834]

[0835] A mixture of 41 J (1.5 g, 3.49 mmol) and NaOH (700 mg, 17.45 mmol) in MeOH (5.0 mL), THF (5.0 mL), and H₂O (5.0 mL) was stirred at room temperature for 2 hours. The resulting mixture was diluted with an aqueous HCl solution (1.0 M, 20 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The crude product was used directly in the next reaction step without further purification. LC-MS: m / z = 401.1 [MH]⁻.

[0836]

[0837] A mixture of 41K (1.0 g, 2.49 mmol), 41L (1.15 g, 3.24 mmol), HATU (1.42 g, 3.74 mmol), and DIEA (964 mg, 7.47 mmol) in DMF (10.0 mL) was stirred overnight at room temperature. The residue was purified by preparative HPLC (C18 column, eluting with CH3CN:H2O (0.1% NH3.H2O) = 5%–95%) to give the target product 41M (600 mg, yield 32.6%). LC-MS: m / z = 740.6 [M+H] + .

[0838]

[0839] A 5.0 mL solution of 41 M AcOH (500 mg, 0.68 mmol) was stirred overnight at 80 °C. The mixture was alkalized to a final Na₂CO₃ solution with an aqueous Na₂CO₃ solution. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (25%–75% EtOAc in PE solution) to give the target product 41N (300 mg, yield 61.5%). LC-MS: m / z = 722.3 [M + H] + .

[0840]

[0841] To a solution of 41N (300 mg, 0.416 mmol) in THF (5.0 mL) was added TBAF (0.624 mL, 1.0 M in THF) dropwise at room temperature with stirring. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with aqueous NH4Cl (20 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-10% MeOH in DCM) to give 41Q (150 mg, 59.4% yield). LC-MS: m / z = 608.6 [M+H] + .

[0842]

[0843] A mixture of 41O (100 mg, 0.165 mmol) and 2-(tributyl-5-phosphono)acetonitrile (119 mg, 0.49 mmol) in toluene (2.0 mL) was heated at 110 °C under argon and microwave irradiation for 3 h. The resulting mixture was cooled and concentrated in vacuo. The residue was purified by preparative HPLC (C18 column eluted with CH3CN:H2O (0.1% FA) = 5%-95%) to give the target product 41P (20 mg, 20.6% yield). LC-MS: m / z = 590.3 [M+H] + ; and 41Q (22 mg, 22.7% yield). LC-MS: m / z = 590.3 [M+H] + .

[0844]

[0845] To a solution of 41P (20.0 mg, 0.034 mmol) in DCM (1.0 mL) was added TFA (0.30 mL) dropwise at room temperature with stirring. The resulting mixture was stirred at room temperature for 1 h. The residue was purified by preparative HPLC (C18 column eluted with CH3CN:H2O (0.1% FA) = 5%-95%) to give EX 41 (1.42 mg, 8.55% yield).

[0846] LC-MS: m / z = 490.2 [M+H] + ; 1H NMR (400 MHz, MeOD-d4): d 9.29-9.21 (m, 2H), 8.55 (s, 1H), 7.90-7.82 (m, 2H), 7.48 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.15-6.78 (m, 2H), 6.04-5.86 (m, 2H), 3.68 (s, 1H), 3.11-3.00 (m, 1H), 2.98-2.87 (m, 2H), 2.67-2.60 (m, 2H), 2.47-2.26 (m, 2H), 2.16-2.04 (m, 1H), 1.91-1.86 (m, 1H), 1.81-1.62 (m, 1H), 1.47 (d, J = 6.4 Hz, 3H), 1.41-1.14 (m, 2H).

[0847]

[0848] To a solution of 41Q (22.0 mg, 0.037 mmol) in DCM (1.0 mL) was added TFA (0.30 mL) dropwise at room temperature with stirring. The resulting mixture was stirred at room temperature for 1 h. The residue was purified by prep-HPLC (C18 column, eluted with CH3CN:H2O (0.1% FA) = 5% ~ 95%) to give EX 42 (2.01 mg, yield 11.0%). LC-MS: m / z = 490.1 [M+H] + ; 1 H NMR (400 MHz, MeOD-d4): d 9.20-9.18 (m, 2H), 8.09 (s, 1H), 7.95 (s, 1H), 7.79-7.70 (m, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.16-7.11 (m, 1H), 7.01-6.92 (m, 1H), 5.87-5.75 (m, 2H), 3.58-3.39 (m, 1H), 3.12-2.99 (m, 2H), 2.93-2.86 (m, 2H), 2.68-2.57 (m, 2H), 2.45-2.35 (m, 1H), 2.32-2.26 (m, 1H), 2.03-1.97 (m, 1H), 1.88-1.78 (m, 1H), 1.74-1.65 (m, 1H), 1.42 (d, J = 6.8 Hz, 3H), 1.34-1.26 (m, 1H).

[0849] Example 43

[0850]

[0851] To a mixture of 1I (640 mg, 83% purity, 980 pmol) in EtOH (20 mL) and water (4 mL) was added NH4CI (525 mg, 9.81 mmol) and iron (274 mg, 4.91 mmol). The mixture was stirred at 80 °C for 6 h. Water (50 mL) was added, and the mixture was filtered, concentrated, and then extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2S04, and then filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography on silica gel (30-35% EtOAc in PE) to give tert-butyl N-[1-[5-[4-amino-3-[[2-bromo-6- (difluoromethoxy)phenyl]methylamino]phenyl]pyrimidin-2-yl]cyclobutyl]carbamate (43A) (430 mg, 100% purity, 692 pmol, 71% yield) as a white solid. LCMS (ESI) m / z: 590.35 [M+H] + .

[0852]

[0853] To a mixture of 43B (83.7 mg, 100% purity, 209 pmol) in DMF (2.0 mL) was added DIEA (62 mg, 483 pmol) and HATU (92.0 mg, 241 pmol). The mixture was stirred at room temperature for 30 min, and then 43A (100 mg, 100% purity, 161 pmol) was added. The mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2S04, and then filtered. The filtrate was concentrated and purified by column chromatography on silica gel (40-50% EtOAc in PE) to give tert-butyl [1-(5-(3-((2-bromo-6-(difluoromethoxy)benzyl)amino)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hex-5-enamido)phenyl)pyrimidin-2-yl)cyclobutyl]carbamate (43C) (120 mg, 92% purity, 125 pmol, 78% yield) as an olive solid. LCMS (ESI) m / z: 812.45 [M+H] + .

[0854]

[0855] A mixture of 43C (100 mg, 92% purity, 117 pmol) in AcOH (2 mL) was stirred at 60 °C for 16 h. The reaction mixture was concentrated and purified by column chromatography on silica gel (75-80% EtOAc in PE) to give tert-butyl N-[1-[5-[3-[[2-bromo-6-(difluoromethoxy)phenyl]methyl]-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-enyl]benzoimidazol-5-yl]pyrimidin-2-yl]cyclobutyl]carbamate (43D) (80 mg, 85% purity, 95 pmol, 81% yield) as olive solid. LCMS (ESI) m / z: 794.36 [M+H] + .

[0856]

[0857] To a solution of 43D (74 mg, 85% purity, 88 pmol) in dioxane (1.0 mL) was added K2CO3 (36 mg, 264 pmol) and Pd(dppf)Cl2 (6.0 mg, 9 pmol). The mixture was stirred at 100 °C under nitrogen for 4 h. The reaction mixture was quenched with water and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (10% MeOH in DCM) to give tert-butyl (1-(5-(1-(difluoromethoxy)-5-methylene-5,7,8,15-tetrahydro-6H- benzo[g]benzo[4,5]imidazo[1,2-a]azanon-12-yl)pyrimidin-2-yl)cyclobutyl)carbamate (40 mg, 54% purity, 40 pmol, 45% yield) as a brown solid. LCMS (ESI) m / z: 588.33 [M+H] + .

[0858]

[0859] To a mixture of 43E (18 mg, 54% purity, 18 pmol) in MeOH (0.5 mL) was added HC1 (4.0 M solution in 1,4-dioxane, 2.0 mL). The reaction mixture was stirred at room temperature for 1 h and concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge 250 x 30 mm, 5 pm; mobile phase A: H20 (+0.1% FA), mobile phase B: ACN; gradient: 30%~55% B; flow rate: 30 mL / min; wavelength: 214 nm / 254 nm) to give 1-(5-(1-(difluoromethoxy)-5-methylene-5,7,8,15-tetrahydro-6H- benzo[g]benzo[4,5]imidazo[1,2-a]azanonin-12-yl)pyrimidin-2-yl)cyclobutan-1-amine (EX 43) (3.0 mg, 6 pmol, 33% yield, 100% purity). LCMS (ESI) m / z: 488.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.95 (s, 2H), 8.39 (s, 2H), 7.69 - 7.51 (m, 3H), 7.41 - 7.28 (m, 3H), 6.83 (dd, J = 7.2, 1.2 Hz, 1H), 5.70 (s, 2H), 4.73 (s, 1H), 4.23 (s, 1H), 3.17 (t, J = 6.0 Hz, 2H), 2.67 - 2.62 (m, 3H), 2.39 - 2.32 (m, 1H), 2.13 - 1.99 (m, 5H), 1.83 - 1.82 (m, 1H).

[0860] Example 44

[0861]

[0862] A mixture of 1-(2-bromo-6-hydroxyphenyl)ethan-1-one (44A) (10.0 g, 46.7 mmol) and potassium hydroxide (55.8 g, 994 mmol) in acetonitrile (240 mL) and H20 (248 mL) was cooled to -25 °C. (Bromodifluoromethyl)diethyl phosphate (14.2 mL, 80 mmol) was added dropwise to the reaction mixture. After maintaining at -20 °C or below for about 15 min, the bath temperature was slowly increased to 20 °C and stirring was continued for 1 h. The reaction was diluted with EtOAc (400 mL), washed with brine (100 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0~15% EtOAc in PE) to give 44B (8.70 g, 71% yield). 1HNMR (400 MHz, CDC13) δ 7.45 (dd, J = 8.0, 0.8 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.17 (dd, J = 8.0, 0.8 Hz, 1H), 6.48 (t, J = 72.8 Hz, 1H), 2.56 (s, 3H).

[0863]

[0864] A mixture of 44B (4.7 g, 17.8 mmol) and sodium borohydride (2.7 g, 71.2 mmol) in MeOH (10.0 mL) was stirred at room temperature for 16 hours. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2S04. After filtration, the filtrate was concentrated and purified by silica gel column chromatography (PE solution of EtOAc, 5% to 20%) to give 1-(2-bromo-6-(difluoromethoxy)phenyl)ethan-1-ol (44C) (4.2 g, yield 89%). LC-MS: m / z = 267.0 [M+H] + .

[0865]

[0866] A mixture of 44C (4.2 g, 15.8 mmol), carbon tetrabromide (7.86 g, 23.7 mmol) and triphenylphosphine (6.23 g, 23.7 mmol) in DCM (15.0 mL) was stirred at room temperature for 16 hours. The resulting mixture was concentrated and purified by silica gel column chromatography (0 to 20% EtOAc in PE) to give 1-bromo-2-(1-bromoethyl)-3-(difluoromethoxy)benzene (44D) (4.0 g, yield 77%). LC-MS: m / z = 331.0 [M+H] + .

[0867]

[0868] To a solution of 44D (4.0 g, 12.2 mmol) in MeOH (10.0 mL) was added ammonia at room temperature with stirring for 16 hours. The resulting mixture was concentrated and purified by silica gel column chromatography (5% to 30% EtOAc in PE) to give 1-(2-bromo-6-(difluoromethoxy)phenyl)ethan-1-amine (44E) (1.6 g, yield 50%). LC-MS: m / z = 266.0 [M+H]+.

[0869]

[0870] A mixture of 44E (1.6 g, 6.04 mmol), tert-butyl (1-(5-(3-fluoro-4- nitrophenyl)pyrimidin-2-yl)cyclobutyl)carbamate (2.58 g, 6.64 mmol), DIEA (2.3 g, 18.12 mmol) in EtOH (15 mL) was stirred at 80 °C overnight. The resulting mixture was cooled, concentrated in vacuo, and purified by silica gel column chromatography (PE solution of EtOAc, 0-20%) to give tert-butyl (1-(5-(3-((1-(2-bromo-6-(difluoromethoxy)phenyl)ethyl)amino)-4- nitrophenyl)pyrimidin-2-yl)cyclobutyl)carbamate (44F) (2.5 g, 65%). LC-MS: m / z = 634.0 [M+H]+.

[0871]

[0872] A mixture of 44F (2.5 g, 3.95 mmol) and Fe (1.1 g, 19.75 mmol) in saturated ammonium chloride solution (4.0 mL) and EtOH (16.0 mL) was stirred at 70 °C for 5 h. The resulting mixture was cooled and filtered. The filter cake was washed with MeOH and the filtrate was concentrated. The residue was washed with DCM, concentrated, and purified by silica gel column chromatography (5-20% EtOAc in PE) to give tert-butyl (1-(5-(4-amino-3-((1-(2-bromo-6-(difluoromethoxy)phenyl)ethyl)amino)phenyl)pyrimidin-2- yl)cyclobutyl)carbamate (44G) (1.62 g, 68%). LC-MS: m / z = 604.0 [M+H]+. + .

[0873]

[0874] A mixture of 44G (1.62 g, 2.69 mmol), 38E (911 mg, 4.03 mmol), HATU (1.53 g, 4.03 mmol), and DIEA (1.04 g, 8.06 mmol) in DMF (5.0 mL) was stirred at 50 °C for 1 h. After cooling, water was added and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo and purified by silica gel column chromatography (PE solution of EtOAc, 5-20%) to give tert-butyl (1-(5-(3-((1-(2-bromo-6-(difluoromethoxy)phenyl)ethyl)amino)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-enamido)phenyl)pyrimidin-2- yl)cyclobutyl)carbamate (44H) (1.14 g, 52% yield). LC-MS: m / z = 812.0 [M+H]+. + .

[0875]

[0876] A mixture of 44H (650 mg, 0.80 mmol) in AcOH (5.0 mL) was stirred at 90 °C for 16 h. The resulting mixture was cooled, concentrated in vacuo, and purified by prep-HPLC (C18 column, eluted with ACN:H2O (0.1% FA) = 50%~95%, MeOH (100%)) to give (4-(6-(2-(1- aminocyclobutyl)pyrimidin-5-yl)-1-(1-(2-bromo-6-(difluoromethoxy)phenyl)ethyl)-1H- benzo[d]imidazol-2-yl)but-1-en-2-yl)boronic acid (44I) (245 mg, 50% yield). LC-MS: m / z = 612.0 [M+H] + .

[0877]

[0878] A mixture of 44I (245 mg, 0.40 mmol), Boc2O (175 mg, 0.80 mmol), triethylamine (121 mg, 1.20 mmol) and 4-dimethylaminopyridine (5 mg, 0.04 mmol) in THF (5.0 mL) was stirred at 50 °C for 16 h. The resulting mixture was cooled, concentrated in vacuo, and purified by silica gel column chromatography (10%~60% EtOAc in PE) to give (4-(1-(1-(2-bromo-6-(difluoromethoxy)phenyl)ethyl)-6-(2-(1-((tert- butoxycarbonyl)amino)cyclobutyl)pyrimidin-5-yl)-1H-benzo[d]imidazol-2-yl)but-1-en-2- yl)boronic acid (44J) (130 mg, 46% yield). LC-MS: m / z = 712.0 [M+H] + .

[0879]

[0880] A mixture of 44J (130 mg, 0.18 mmol), Pd(dppf)Cl2(27 mg, 0.04 mmol) and K2CO3(76 mg, 0.55 mmol) in dioxane (4.0 mL) and water (1.0 mL) was stirred at 90 °C under argon for 2 h. The resulting mixture was cooled, concentrated in vacuo, and purified by silica gel column chromatography (10% to 50% EtOAc in PE) to give [1-(5-(1-(difluoromethoxy)-14-methyl-5-methylene-5,6,7,14-tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azocin-11-yl)pyrimidin-2-yl)cyclobutyl)carbamic acid tert-butyl ester (44K) (32 mg, 30%). LC-MS: m / z = 588.2 [M+H] + .

[0881]

[0882] To a solution of 44K (32 mg, 0.05 mmol) in DCM (3.0 mL) was added TFA (0.3 mL) dropwise at room temperature with stirring and stirred for 2 h. The resulting mixture was concentrated in vacuo and purified by preparative HPLC (C18 column eluted with ACN:H2O (0.1% FA) = 5% to 95%) to give 1-(5-(1-(difluoromethoxy)-14-methyl-5-methylene-5,6,7,14-tetrahydrobenzo[f]benzo[4,5]imidazo[1,2-a]azocin-11-yl)pyrimidin-2-yl)cyclobutane-1-amine (EX 44) (3.2 mg, yield 12%). LC-MS: m / z = 488.0 [M+H] + ; 1 H NMR (400 MHz, MeOD-d4) δ 9.11 (s, 2H), 8.14 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 8.4 Hz, 1H), 7.27 - 6.87 (m, 3H), 6.47 (s, 1H), 5.40 (s, 1H), 5.10 (s, 1H), 3.48 (s, 1H), 3.10 - 2.87 (m, 2H), 2.84 - 2.76 (m, 2H), 2.35 - 2.26 (m, 2H), 2.26 - 1.97 (m, 6H).

[0883] Example 45

[0884]

[0885] To a mixture of 4-chloro-2-fluoro-1-nitrobenzene (45A) (3.00 g, 17.1 mmol) and [2-bromo-6-(difluoromethoxy)phenyl]methanamine (1 M) (4.31 g, 17.1 mmol, purity 98%) in EtOH (90 mL) was added DIEA (6.63 g, 51.3 mmol). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in EtOAc (200 mL), washed with water (3 x 200 mL) and brine (200 mL), dried over anhydrous Na2SO4, then filtered. The filtrate was concentrated and purified by silica gel column chromatography (25% EtOAc in PE) to give N-[[2-bromo-6-(difluoromethoxy)phenyl]methyl]-5-chloro-2-nitroaniline (45B) (3.60 g, purity 91%, 8.39 mmol, 49% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] + 407.05.

[0886]

[0887] To a mixture of 45B (3.37 g, purity 91%, 7.85 mmol) in EtOH (45 mL) and water (15 mL) was added iron powder (4.38 g, 78.5 mmol) and NH4Cl (4.20 g, 78.5 mmol). The reaction mixture was stirred at 80 °C under nitrogen for 4 h. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with EtOAc (50 mL). The filtrate was diluted with water (150 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, then filtered. The filtrate was concentrated and purified by silica gel column chromatography (40% EtOAc in PE) to give N2-[[2-bromo-6-(difluoromethoxy)phenyl]methyl]-4-chloro-benzene-1,2-diamine (45C) (2.80 g, purity 78%, 7.04 mmol, 89% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] + 377.03.

[0888]

[0889] To a mixture of 45C (2.2 g, 78% purity, 5.5 mmol) and tert-butyl 3- formylpyrrolidine-1-carboxylate (1.1 g, 5.5 mmol) in DMSO (20 mL) was added Na2S2O5 (2.5 g, 13 mmol). The mixture was stirred at 60 °C for 4 h. After cooling to room temperature, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated and purified by column chromatography on silica gel (60% EtOAc in PE) to give tert-butyl 3-[1-[[2-bromo-6-(difluoromethoxy)phenyl]methyl]-6-chloro- benzoimidazol-2-yl]pyrrolidine-1-carboxylate (45D) (2.8 g, 99% purity, 4.8 mmol, 86% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] + 556.11.

[0890]

[0891] To a mixture of 45D (2.8 g, 99% purity, 4.8 mmol) in MeOH (5 mL) was added HCl solution (4.0 M solution in 1,4-dioxane, 20 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to give 1-[[2-bromo-6-(difluoromethoxy)phenyl]methyl]-6-chloro-2-pyrrolidin-3-yl- benzoimidazole (45E) (21 g, 99% purity, 44 mmol, 91% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] + 456.06.

[0892]

[0893] A mixture of 45E (1.2 g, 99% purity, 2.5 mmol), Pd(OAc)2 (200 mg, 890 µmol), BINAP (468 mg, 755 µmol) and Cs2CO3 (4.1 g, 12 mmol) in dioxane (30 mL) was stirred at 80 °C under nitrogen for 16 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and purified by prep-HPLC (80 g, 60% ACN in water) to give 12-chloro-1-(difluoromethoxy)-7,8-dihydro-6H,15H-5,8- methanoben[b]benzo[4,5]imidazo[1,2-e][1,5]diazepine (45F) (330 mg, 95% purity, 834 µmol, 33% yield) as a white solid. LCMS (ESI) m / z: [M+H]+ 376.13.

[0894]

[0895] A mixture of 1G (100 mg, 95% purity, 268 pmol), 45F (85.0 mg, 223 pmol), XPhos PdG2 (35 mg, 45 pmol) and Na2CO3 (59.0 mg, 559 pmol) in dioxane (3 mL) and water (0.6 mL) was stirred at 120 °C under nitrogen for 2 h. The reaction mixture was cooled to room temperature, filtered, concentrated and purified by silica gel column chromatography (MeOH:DCM = 1:20) to give tert-butyl (1-(5-(1-(difluoromethoxy)-7,8-dihydro-6H,15H-5,8- methanobenzo[b]benzo[4,5]imidazo[1,2-e][1,5]diazepin-12-yl)pyrimidin-2-yl)cyclobutyl)carbamate (45G) (65 mg, 83% purity, 91.65 pmol, 41% yield) as a white solid. LCMS (ESI) m / z: [M+H] + 589.34.

[0896]

[0897] To a solution of 45G (65 mg, 83% purity, 92 pmol) in MeOH (1 mL) was added HCl solution (4.0 M in 1,4-dioxane, 3 mL) dropwise at room temperature, and then stirred at room temperature for 3 h. The reaction mixture was concentrated, and the residue was purified by prep-HPLC (column: Waters Xbridge 250 x 30 mm, 5 pm; mobile phase A: H2O (+0.1% FA), mobile phase B: ACN; gradient: 25%~45% B; flow rate: 35 mL / min; wavelength: 214 nm / 254 nm) to give 1-(5-(1-(difluoromethoxy)-7,8-dihydro-6H,15H-5,8- methanobenzo[b]benzo[4,5]imidazo[1,2-e][1,5]diazepin-12-yl)pyrimidin-2-yl)cyclobutane-1-amine (EX 45) (38 mg, 100% purity, 78 pmol, 84% yield) as a white solid. LCMS (ESI) m / z: [M+H] + 489.26. 1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 2H), 8.29 (s, 2H), 7.83 (s, 1H), 7.68 - 7.23 (m, 4H), 6.92 - 6.79 (m, 2H), 5.84 (s, 2H), 5.09 (s, 1H), 3.91 - 3.63 (m, 4H), 2.71 - 2.64 (m, 3H), 2.51 - 2.46 (s, 2H), 2.33 - 2.23 (m, 2H), 2.08 - 1.88 (m, 2H).

[0898] Example 46

[0899]

[0900]

[0901] To a solution of (E)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)but-3-en-l-yl)oxy)silane (46A) (2 g, 6.40 mmol) in DCM (30 mL) was added diethylzinc (32.0 mL, 32.0 mmol) at 0 °C under nitrogen. After the mixture was stirred at 0 °C for 0.5 h, diiodomethane (8.57 g, 32.0 mmol) and TFA (3.65 g, 32.0 mmol) were added to the reaction mixture by syringe. The mixture was stirred at room temperature for 2 h and quenched with water (30 mL). The solid was filtered off and the filtrate was separated. The aqueous phase was extracted with DCM (30 mL x 2). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give tert-butyldimethyl(2-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl)ethoxy)silane (46B) (a pair of trans isomers, 2.1 g, yield 100%) as a yellow oil. The compound was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 3.62 (td, J = 6.7, 1.9 Hz, 2H), 1.42 (dt, J = 13.0, 4.3 Hz, 2H), 1.16 (s, 12H), 0.93 (m, 1H), 0.84 (s, 9H), 0.62 (m, 1H), 0.37 (m, 1H), -0.00 (s, 6H), -0.45 (dt, J = 9.4, 5.8 Hz, 1H).

[0902]

[0903] To tert-butyldimethyl(2-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)cyclopropyl)ethoxy)silane (2.1 g, 6.43 mmol) was added TBAF in THF (1.0 M, 19.3 mL, 19.3 mmol). The solution was stirred at room temperature for 16 hours. The mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were dried over Na2S04and concentrated to give yellow oil (1.6 g), which was used in the next step reaction without further purification. 1 H NMR (400 MHz, CDC13) δ 3.72 (t, J = 6.5 Hz, 2H), 1.45 (m, 2H), 1.21 (s, 12H), 0.99 - 0.95 (m, 1H), 0.75 - 0.68 (m, 1H), 0.49 - 0.42 (m, 1H), -0.35 (dt, J = 9.5, 5.8 Hz, 1H).

[0904]

[0905] To a mixture of 2-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl)ethan-l-ol (1.6 g, 7.55 mmol) and sodium bicarbonate (3.17 g, 37.8 mmol) in DCM (16 mL) was added Dess-Martin periodinane (3.52 g, 8.31 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was quenched with water (30 mL). The solid was filtered off and the filtrate was separated. The aqueous phase was extracted with DCM (30 mL x 2). The combined organic phases were dried over anhydrous Na2S04, filtered, concentrated under reduced pressure and purified on a silica gel column (30% EtOAc in PE) to give 2-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl)acetaldehyde (0.40 g, 31% yield over two steps) as a yellow oil. 1 H NMR (400 MHz, CDC13) δ 9.78 (t, J = 2.2 Hz, 1H), 2.43 (ddd, J = 16.8, 6.5, 2.1 Hz, 1H), 2.24 (ddd, J = 16.8, 7.5, 2.2 Hz, 1H), 1.22 (s, 13H), 0.84 (m, 1H), 0.52 (m, 1H), -0.26 (dt, J = 9.6, 5.9 Hz, 1H).

[0906]

[0907] A mixture of 2-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl)acetaldehyde (187 mg, 0.889 mmol) and tert-butyl (l-(5-(4-amino-3-((2-bromo-6- (difluoromethoxy)benzyl)amino)phenyl)pyrimidin-2-yl)cyclobutyl)carbamate (500 mg, 0.847 mmol) in DMF (5.0 mL) was stirred at 90 °C for 2 h. The solvent was removed under reduced pressure to give a yellow oil (700 mg), which was used directly in the next step. LC-MS: m / z = 780.0, 782.0 [M+H] + .

[0908]

[0909] A mixture of tert-butyl (l-(5-(l-(2-bromo-6-(difluoromethoxy)benzyl)-2-((2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl)methyl)-lH-benzo[d]imidazol-5-yl)pyrimidin- 2-yl)cyclobutyl)carbamate (100 mg, 0.128 mmol), Pd(dppf)Cl2(9.36 mg, 0.0128 mmol) and K2CO3(35.3 mg, 0.256 mmol) in dioxane (2.5 mL) and water (0.5 mL) was stirred at 90 °C under nitrogen for 1 h. The mixture was cooled, concentrated and purified by silica gel column chromatography (5% MeOH in DCM) to give tert-butyl (l-(5-((laR,13aS)-5-(difluoromethoxy)-la,6,13,13a- tetrahydro-lH-benzo[f]benzo[4,5]imidazo[l,2-a]cyclopropyl[d]azocin-9-yl)pyrimidin-2- yl)cyclobutyl)carbamate (60 mg, 81% yield). LC-MS: m / z = 574.2 [M+H] + .

[0910]

[0911] To a solution of tert-butyl (l-(5-((laR,13aS)-5-(difluoromethoxy)-la,6,13,13a- tetrahydro-lH-benzo[f]benzo[4,5]imidazo[l,2-a]cyclopropyl[d]azocin-9-yl)pyrimidin-2- yl)cyclobutyl)carbamate (60 mg, 0.105 mmol) in DCM (2.5 mL) was added TFA (0.5 mL) dropwise with stirring at room temperature, and the reaction was allowed to proceed for 16 h. The resulting mixture was concentrated to dryness in vacuo and purified by preparative HPLC (C18 column, eluted with ACN:H20 (0.1% FA) = 5% ~ 95%) to give EX 46 (a pair of trans isomers, 22.5 mg, 45% yield). LC-MS: m / z = 474.2 [M+H] + ; 1 H NMR (400 MHz, MeOD-d4) δ 9.10 (m, 2H), 8.40 (s, 1H), 7.80 - 7.64 (m, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.35 (m, 1H), 7.22 - 6.94 (m, 3H), 6.09 - 5.60 (m, 2H), 4.03 - 3.68 (m, 1H), 3.03 (m, 1H), 2.80 (m, 2H), 2.30 (m, 3H), 2.20 - 1.99 (m, 2H), 1.65 (m, 1H), 1.37 (m, 2H), 1.09 (s, 1H), 0.24 (s, 1H).

[0912] Example 47

[0913]

[0914] A mixture of 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (5.0 g, 39.1 mmol), (but-3-yn-l-yloxy)(tert-butyl)dimethylsilane (47A) (8.64 g, 46.9 mmol), [Rh(cod)Cl]2(289 mg, 0.59 mmol), PCy3(660 mg, 2.34 mmol) and TEA (3.95 g, 39.1 mmol) in hexane (100 mL) was stirred at room temperature under argon for 3 h. The resulting mixture was concentrated in vacuo and purified by silica gel column chromatography (0-5% EtOAc in PE) to give (Z)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)but-3-en-l- yl)oxy)silane (47B) (5.0 g, 41.0% yield).

[0915]

[0916] To a solution of 47B (3.0 g, 9.61 mmol) in DCM (60 mL) was added diethylzinc (48 mL, 1 mol in hexane) dropwise at 0 °C under argon with stirring. The resulting mixture was stirred at 0 °C under argon for 1 h. To the above mixture was added CH2I2(12.9 g, 48 mmol) and TFA (5.47 g, 48 mmol) dropwise at 0 °C under argon. The resulting mixture was stirred at room temperature for another 3 h. The reaction was quenched with NH4CI (aq) (60 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated in vacuo to give tert-butyldimethyl(2-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl)ethoxy)silane (47C) as a pair of cis isomers which was used directly in the next step reaction without further purification. 1 H NMR (400 MHz, CDC13) δ 3.65-3.58 (m, 2H), 1.58 (q, J = 6.8 Hz, 2H), 1.17 (d, J = 6.8 Hz, 12H), 1.10-1.05 (m, 1H), 0.84 (s, 9H), 0.75-0.70 (m, 1H), 0.36-0.32 (m, 1H), 0.00 (s, 6H), -0.12 -0.18 (m, 1H).

[0917]

[0918] A mixture of 47C (3.0 g, 9.20 mmol) and TBAF solution in THF (1.0 M, 20 mL) was stirred at 40 °C overnight. The resulting mixture was cooled, diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated in vacuo to give 2-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl)ethan-l-ol (47D) as a crude product which was used directly in the next step reaction without further purification.

[0919]

[0920] A mixture of crude 47D (1500 mg, 7.07 mmol), Dess-Martin periodinane (3598.5 mg, 8.48 mmol) and NaHC03(3234 mg, 38.5 mmol) in DCM (50 mL) was stirred at room temperature for 4 h. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 50 mL). The filtrate was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (0-15% EtOAc in PE) to give 2-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl)acetaldehyde (30 mg, 2.0% yield). 1 H NMR (400 MHz, CDC13) δ 9.71-9.66 (m, 1H), 1.46 (s, 2H), 1.11 (s, 12H), 0.79 (s, 1H), 0.73 (q, J = 2.0 Hz, 1H), 0.30 (q, J = 2.0 Hz, 1H), -0.05 (s, 1H).

[0921]

[0922] A mixture of 47E (20 mg, 0.095 mmol) and 10 (61.7 mg, 0.10 mmol) in DMF (2.0 mL) was stirred at 70 °C for 1 h. The resulting mixture was cooled, diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (0-10% MeOH in DCM) to give tert-butyl (l-(5-(l-(2-bromo-6-(difluoromethoxy)benzyl)-2-((2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl)methyl)-lH-benzo[d]imidazol-5-yl)pyrimidin-2-yl)cyclobutyl)carbamate (47F) (30 mg, 40.4% yield). LC-MS: m / z = 780.4 [M+H] + .

[0923]

[0924] A mixture of 47F (30 mg, 0.038 mmol), Pd(dppf)Cl2(2.78 mg, 0.0038 mmol) and K2CO3(15.76 mg, 0.11 mmol) in dioxane (0.8 mL) and H2O (0.2 mL) was stirred at 90 °C under argon for 1 h. The resulting mixture was cooled, diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (0-10% MeOH in DCM) to give tert-butyl (1-(5-((1aS,13aS)-5-(difluoromethoxy)-1a,6,13,13a-tetrahydro-1H- benzo[f]benzo[4,5]imidazo[1,2-a]cyclopropyl[d]azocin-9-yl)pyrimidin-2-yl)cyclobutyl)carbamate (47G) (15 mg, 68.0%). LC-MS: m / z = 574.3 [M+H] + .

[0925]

[0926] To a solution of 47G (15 mg, 0.026 mmol) in DCM (1.0 mL) was added TFA (0.30 mL) dropwise with stirring at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo and the residue was purified by preparative HPLC (C18 column eluted with CH3CN:H2O (0.1% FA) = 5%-95%) to give 1-(5-((1aS,13aS)-5-(difluoromethoxy)-1a,6,13,13a-tetrahydro-1H- benzo[f]benzo[4,5]imidazo[1,2-a]cyclopropyl[d]azocin-9-yl)pyrimidin-2-yl)cyclobutane-1- amine (EX 47) (1.26 mg, 10.2%, one pair of cis isomers). LC-MS: m / z = 474.0 [M+H] + . 1 H NMR (400 MHz, MeOD): δ 9.20 (s, 2H), 8.04 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.43 - 7.36 (m, 2H), 7.16 (d, J = 8.0 Hz, 1H), 6.88 (t, J = 74.0 Hz, 1H), 5.84 (s, 2H), 3.34 (s, 2H), 2.94 - 2.83 (m, 2H), 2.55-2.42 (m, 2H), 2.31 - 2.17 (m, 2H), 1.35-1.24 (m, 3H), 0.94-0.81 (m, 1H).

[0927] Example 48 and Example 53

[0928]

[0929] A mixture of tert-butyl (l-(5-(3-((2-bromo-6-(difluoromethoxy)benzyl)amino)-4- nitrophenyl)pyrimidin-2-yl)cyclobutyl)carbamate (48A) (4.4 g, 7.09 mmol), cesium fluoride (2.15 g, 14.18 mmol), tricyclohexylphosphine (398 mg, 1.42 mmol), bis(dibenzylideneacetone)palladium (408 mg, 0.71 mmol) and allyltributylstannane (3.5 g, 10.63 mmol) in dioxane (10 mL) was stirred at 90 °C under argon for 16 h. After cooling, the resulting mixture was concentrated to dryness in vacuo and purified by silica gel column chromatography (8% to 25% EtOAc in PE) to give 48B (1.6 g, 39%). LCMS: m / z = 582.4 [M+H]+.

[0930]

[0931] To a mixture of 48B (1.6 g, 2.75 mmol), copper iodide (26 mg, 0.14 mmol) and 1,1,1,3,3,3-hexafluoropropan-2-ol (10.0 mL) was added ethyl diazoacetate (1.25 g, 11.00 mmol) portion wise at 0 °C. The mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated in vacuo and purified by silica gel column chromatography (5% to 20% EtOAc in PE) to give the target product (1R,2R)-ethyl 2-(2-(((5-(2-(l-((tert-butoxycarbonyl)amino)cyclobutyl)pyrimidin-5-yl)-2- nitrophenyl)amino)methyl)-3-(difluoromethoxy)benzyl)cyclopropane-l-carboxylate (48C) (270 mg, yield 15%, one pair of trans isomers) and (1S,2R)-ethyl 2-(2-(((5-(2-(l-((tert- butoxycarbonyl)amino)cyclobutyl)pyrimidin-5-yl)-2-nitrophenyl)amino)methyl)-3- (difluoromethoxy)benzyl)cyclopropane-l-carboxylate (48D) (220 mg, yield 12%, one pair of cis isomers) and 48B (1.1 g) was recovered. LCMS: m / z = 668.2 [M+H]+.

[0932]

[0933] A mixture of (1S,2R)-2-(2-(((5-(2-(1-((tert-butoxycarbonyl)amino)cyclobutyl)pyrimidin-5-yl)-2- nitrophenyl)amino)methyl)-3-(difluoromethoxy)benzyl)cyclopropane-1-carboxylic acid ethyl ester (270 mg, 0.40 mmol, trans isomer) and sodium hydroxide (81 mg, 2.02 mmol) in MeOH (1.0 mL), THF (1.0 mL) and water (1.0 mL) was stirred at room temperature for 16 h. The resulting mixture was diluted with water, extracted with EtOAc and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo to give the crude product (48E) (233 mg, yield 90%) which was used directly in the next step reaction without further purification. LCMS: m / z = 640.2 [M+H]+.

[0934]

[0935] A mixture of 48E (233 mg, 0.36 mmol), N, O-dimethylhydroxylamine hydrochloride (53 mg, 0.55 mmol), HATU (209 mg, 0.55 mmol) and DIEA (141 mg, 1.09 mmol) in DMF (3.0 mL) was stirred at room temperature for 16 h. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated in vacuo. The residue was purified by silica gel column chromatography (18%~25% EtOAc in PE) to give 48F (199 mg, yield 80%). LCMS: m / z = 683.2 [M+H]+. + . 1 H NMR (400 MHz, MeOD-d4) δ 9.08 (s, 2H), 8.28-8.22 (m, 1H), 7.44 (s, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.05-7.00 (m, 1H), 6.89 (t, J = 74.0 Hz, 1H), 4.73 (s, 2H), 3.56 (s, 3H), 3.12 (s, 3H), 3.00 (dd, J = 15.2, 6.4 Hz, 1H), 2.86-2.75 (m, 3H), 2.55-2.41 (m, 2H), 2.18-2.02 (m, 3H), 1.61-1.51 (m, 1H), 1.47-1.19 (m, 9H), 1.17-1.11 (m, 1H), 0.93-0.84 (m, 1H), NMR data of 48F are shown as Figure 2

[0936] with Figure 2 ​The relevant instrument parameters are shown in Table 5 below:

[0937] Name: IDSUT11_01-YB_B-045-4-P1; EXP NO: 4; PROC NO: 1

[0938] Table 5. Instrument parameters

[0939]

[0940]

[0941]

[0942] To a mixture of 48F (199 mg, 0.29 mmol) in THF (2.0 mL) was added DIBAL-H (0.58 mL, 0.58 mmol) dropwise at -78 °C under argon and stirred at -78 °C for 3 h. The resulting mixture was quenched with saturated ammonium chloride, diluted with water, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and purified by silica gel column chromatography (15% to 35% ethyl acetate in petroleum ether) to give 48G (94 mg, yield 52%). LCMS: m / z = 624.2 [M+H] + .

[0943]

[0944] To a mixture of (methoxymethyl)triphenylphosphonium bromide (116 mg, 0.30 mmol) in THF (2.0 mL) was added lithium bis(trimethylsilyl)amide (0.30 mL, 0.30 mmol) dropwise at 0 °C under argon. The resulting mixture was stirred at 0 °C for 1 h under argon. To a solution of 48G (94 mg, 0.15 mmol) in THF (2.0 mL) was added the mixture dropwise at 0 °C under argon and stirred at 0 °C for 16 h. The resulting mixture was quenched with saturated ammonium chloride, diluted with water, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and purified by silica gel column chromatography (15% to 35% ethyl acetate in petroleum ether) to give 48H (49 mg, yield 50%). LCMS: m / z = 652.2 [M+H] + .

[0945]

[0946] A mixture of 48H (49 mg, 0.08 mmol) and hydrochloric acid (1.5 M, 0.5 mL) in THF (2.0 mL) was stirred at 60 °C for 1 h. After cooling, the resulting mixture was concentrated, which was used directly for the next step reaction without further purification. LCMS: m / z = 638.2 [M+H]+.

[0947]

[0948] A mixture of 48I (48 mg, 0.08 mmol) and iron powder (21 mg, 0.38 mmol) in saturated ammonium chloride solution (1.0 mL) and ethanol (4.0 mL) was stirred at 70 °C for 1 h. After cooling, the resulting mixture was filtered, and the filter cake was washed with MeOH. The filtrate was concentrated in vacuo, and the residue was washed with DCM. The filtrate was concentrated, which was used directly for the next step reaction without further purification. LCMS: m / z = 588.4 [M+H]+. + .

[0949]

[0950] To a solution of 48J (44 mg, 0.07 mmol) in DCM (3.0 mL) was added TFA (0.3 mL) dropwise at room temperature with stirring, and the mixture was stirred for 2 h. The resulting mixture was concentrated and purified by prep-HPLC (C18 column eluted with acetonitrile: water (0.1% FA) = 5% ~ 95%) to give EX 53 (2.91 mg, yield 8%, one pair of trans isomers). LCMS: m / z = 488.1 [M+H]+. + . 1 H NMR (400 MHz, MeOD-d4) δ 9.28 (s, 2H), 8.54 (s, 1H), 7.90 - 7.78 (m, 2H), 7.30 (t, J = 7.6 Hz, 1H), 7.14 - 6.52 (m, 3H), 6.10 (d, J = 16.0 Hz, 1H), 5.89 (d, J = 16.0 Hz, 1H), 3.89 - 3.85 (m, 2H), 2.96 - 2.86 (m, 2H), 2.76 - 2.56 (m, 4H), 2.48 - 2.24 (m, 2H), 1.65 - 1.25 (m, 1H), 1.09 - 0.98 (m, 1H), 0.97 - 0.83 (m, 1H), 0.74 - 0.34 (m, 1H).

[0951] Example 48

[0952]

[0953] Analogous procedure to EX53 was employed, using 48D (220 mg, a pair of cis isomers) as starting material, NMR data of 48L is shown below, to give EX 48 (1.12 mg, yield 4%, a pair of cis isomers). LCMS: m / z = 488.0 [M+H] Figure 3 + . 1 HNMR (400 MHz, MeOD - d4) δ 9.24 (s, 2H), 8.63 (d, J = 1.2 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.62 (dd, J = 8.0, 1.6 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.31 (dd, J = 8.0, 1.2 Hz, 1H), 7.22 - 6.82 (m, 2H), 5.67 (q, J = 15.6 Hz, 2H), 3.54 - 3.46 (m, 1H), 3.16 - 3.12 (m, 1H), 3.11 - 3.03 (m, 1H), 2.98 - 2.88 (m, 2H), 2.66 - 2.57 (m, 2H), 2.45 - 2.36 (m, 1H), 2.35 - 2.23 (m, 1H), 1.36 - 1.25 (m, 2H), 1.20 - 1.08 (m, 1H), 1.02 - 0.94 (m, 1H), 0.41 - 0.35 (m, 1H).

[0954] Instrument parameters related to Figure 3 are shown in Table 6 below:

[0955] Name: IDSUT11_01-YT_B-044-4-P1; EXP NO: 4; PROC NO: 1

[0956] Table 6. Instrument parameters

[0957]

[0958]

[0959] Example 49

[0960]

[0961] ​A mixture of ethyl pent-4-ynoate (49A) (5.0 g, 39.64 mmol), Schwartz reagent (260 mg, 0.025 mmol), TEA (400 mg, 3.96 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.07 g, 39.64 mmol) was stirred at 40 °C for 16 h. The resulting mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and purified by silica gel column chromatography (0-5% ethyl acetate in petroleum ether) to give 49B (3.5 g, 34.75% yield). LC-MS: m / z = 254.8 [M+H] + .

[0962]

[0963] A mixture of 49B ethyl (1000 mg, 3.93 mmol) and sodium hydroxide (786 mg, 19.65 mmol) in THF (3.0 mL) and water (3.0 mL) was stirred at 40 °C for 2 h. The pH value of the mixture was adjusted to 1-2 with HC1 (1.0 M) and the resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The crude product was used directly in the next step without further purification. LC-MS: m / z = 227.1 [M+H] + .

[0964]

[0965] A mixture of 1O (500 mg, 0.85 mmol), HATU (480 mg, 1.27 mmol), DIEA (330 mg, 2.55 mmol) and 49C (0.29 g, 1.27 mmol) in DMF (5.0 mL) was stirred at 50 °C for 2 h. The resulting mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and purified by silica gel column chromatography (0-4% MeOH in DCM) to give tert-butyl (E)-(1-(5-(3-((2-bromo-6-(difluoromethoxy)benzyl)amino)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-enoylamino)phenyl)pyrimidin-2-yl)cyclobutyl)carbamate (49D) (650 mg, 96.13%). LC-MS: m / z = 798.2 [M+H] + .

[0966]

[0967] A solution of 49D (650 mg, 0.81 mmol) in acetic acid (3.0 mL) was stirred at 60 °C for 16 h. The resulting mixture was diluted with Na2CO3. The resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-5% MeOH in DCM) to give tert-butyl (E)-(1-(5-(1-(2-bromo-6-(difluoromethoxy)benzyl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)cyclobutyl)carbamate (49E) (320 mg, 50.37%). LC-MS: m / z = 780.4 [M+H] + .

[0968]

[0969] A mixture of 49E (100 mg, 0.13 mmol), K2CO3 (54 mg, 0.39 mmol) and Pd(dppf)Cl2 (9.5 mg, 0.013 mmol) in 1,4-dioxane (1.6 mL) and water (0.4 mL) was stirred at 90 °C under argon for 1 h. The resulting mixture was cooled, concentrated and purified by column chromatography on silica gel (0-5% MeOH in DCM) to give tert-butyl (E)-(1-(5-(1-(difluoromethoxy)-7,15-dihydro-8H-benzo[g]benzo[4,5]imidazo[1,2-a]azanonan-12-yl)pyrimidin-2-yl)cyclobutyl)carbamate (49F) (14 mg, 19.05%). LC-MS: m / z = 574.6 [M+H] + .

[0970]

[0971] To a mixture of 49F (30 mg, 0.052 mmol) and Pd(OAc)2(1.17 mg, 0.0052 mmol) in THF (1 mL) was added diazomethane (21.86 mg, 0.52 mmol) dropwise at room temperature under argon with stirring. The resulting mixture was stirred at room temperature under argon overnight. The resulting mixture was concentrated in vacuo and purified by silica gel column chromatography (0%~5% MeOH in DCM) to give tert-butyl (1-(5-((4bR,5aR)-1-(difluoromethoxy)-4b,5,5a,6,7,14-hexahydrobenzo[g]benzo[4,5]imidazo[1,2-a]cycloprop[e]azanonyl-11-yl)pyrimidin-2-yl)cyclobutyl)carbamate (49G) (25 mg, 81.4%, a pair of trans isomers). LC-MS: m / z = 588.2 [M+H] + .

[0972]

[0973] To a solution of 49G (25 mg, 0.043 mmol) in DCM (3.0 mL) was added TFA (1.0 mL) dropwise at room temperature with stirring. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated and purified by prep-HPLC (C18 column eluted with acetonitrile: water (0.1% NH3H2O) = 5%~95%) to give EX 49 (1.0 mg, 4.73%, a pair of trans isomers). LC-MS: m / z = 488.0 [M+H] + ; 1 H NMR (400 MHz, MeOD-d4): d 8.96 (s, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 9.6 Hz, 1H), 7.42 (s, 1H), 7.30 (t, J = 10.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.15-6.96 (m, 2H), 5.83 (dd, J = 54.0, 16.0 Hz, 2H), 2.94-2.82 (m, 2H), 2.73-2.64 (m, 1H), 2.61-2.51 (m, 2H), 2.40-2.23 (m, 2H), 1.37-1.22 (m, 2H), 1.21-1.12 (m, 1H), 1.08-0.98 (m, 1H), 0.96-0.84 (m, 2H), 0.72-0.59 (m, 1H).

[0974] Example 50

[0975]

[0976] A mixture of 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (5.0 g, 39.1 mmol), tert- butyldimethyl(penta-4-yn-l-yloxy)silane (50A) (9.29 g, 46.9 mmol), [Rh(cod)Cl]2(289 mg, 0.59 mmol), PCy3(660 mg, 2.34 mmol) and TEA (3.95 g, 39.1 mmol) in hexane (100 mL) was stirred at room temperature under argon for 2 h. The resulting mixture was concentrated and purified by silica gel column chromatography (0% to 5% ethyl acetate in petroleum ether) to give 50B (5.0 g, yield 39.3%). 1 H NMR (400 MHz, CDC13) δ 6.48 - 6.32 (m, 1H), 5.28 (d, J = 12.8 Hz, 1H), 3.58 (t, J = 6.8 Hz, 2H), 2.42 - 2.33 (m, 2H), 1.60 - 1.54 (m, 2H), 1.21 (s, 12H), 0.85 (s, 9H), 0.00 (s, 6H).

[0977]

[0978] To a solution of 50B (5.0 g, 15.33 mmol) in DCM (100 mL) was added diethylzinc (1.0 M solution in hexane, 77 mL) dropwise at 0 °C under argon and stirring. The resulting mixture was stirred at 0 °C under argon for 1 h. To the above mixture was added DCM (20.5 g, 76.6 mmol) and TFA (8.74 g, 76.6 mmol) dropwise at 0 °C under argon. The resulting mixture was stirred at room temperature for another 3 h. The reaction was quenched with NH4CI (aqueous solution) (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated to give the crude product as a pair of cis isomers, which was used directly in the next step reaction without further purification. 1 H NMR (400 MHz, CDC13) δ 6.48 - 6.32 (m, 1H), 5.28 (d, J = 12.8 Hz, 1H), 3.58 (t, J = 6.8 Hz, 2H), 2.42 - 2.33 (m, 2H), 1.60 - 1.54 (m, 2H), 1.21 (s, 12H), 0.85 (s, 9H), 0.00 (s, 6H).

[0979]

[0980] A mixture of 50C (5.0 g, 14.69 mmol) and TBAF solution in THF (1.0 M, 50 mL) was stirred at 40 °C overnight. The resulting mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2S04and filtered. The filtrate was concentrated and purified by silica gel column chromatography (0-5% ethyl acetate in petroleum ether) to give 50D (500 mg, yield 15.0%) as a pair of cis isomers. 1 H NMR (400 MHz, DMSO-d6) δ 4.54 (t, J = 5.2 Hz, 1H), 3.63 - 3.56 (m, 2H), 1.72 - 1.63 (m, 3H), 1.49 - 1.41 (m, 1H), 1.37 (d, J = 9.2 Hz, 12H), 1.26-1.16 (m, 1H), 0.96-0.90 (m, 1H), 0.51 - 0.39 (m, 1H), 0.04--0.05 (m, 1H).

[0981]

[0982] A mixture of 50D (500 mg, 2.21 mmol), Dess-Martin periodinane (1124.8 mg, 2.65 mmol) and NaHC03(928.2 mg, 11.05 mmol) in DCM (10 mL) was stirred at room temperature for 4 h. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 50 mL). The filtrate was concentrated and purified by silica gel column chromatography (0-30% ethyl acetate in petroleum ether) to give 50E (300 mg, yield 60.5%) as a pair of cis isomers. 1 H NMR (400 MHz, MeOD-d4) δ 9.72 (t, J = 2.0 Hz, 1H), 1.73 - 1.49 (m, 3H), 1.43 - 1.35 (m, 1H), 1.22 (d, J = 6.0 Hz, 12H), 1.10 - 1.00 (m, 1H), 0.84 - 0.74 (m, 1H), 0.39 - 0.31 (m, 1H), -0.08--0.19 (m, 1H).

[0983]

[0984] A mixture of 50E (100 mg, 0.45 mmol) and 1O (262.9 mg, 0.45 mmol) in DCM (5.0 mL) was stirred at 70 °C for 1 h. The resulting mixture was cooled, diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and purified by silica gel column chromatography (0%~10% MeOH in DCM) to give 50F (80 mg, 22.6% yield) as a pair of cis isomers. LC-MS: m / z = 794.0 [M+H] + .

[0985]

[0986] A mixture of 50F (80 mg, 0.10 mmol), Pd(dppf)Cl2(7.37 mg, 0.01 mmol) and K2CO3(69.0 mg, 0.50 mmol) in dioxane (1.6 mL) and water (0.4 mL) was stirred at 90 °C under argon for 1 h. The resulting mixture was cooled, diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated to give the crude product as a pair of cis isomers, which was used directly in the next step without further purification. LC-MS: m / z = 588.3 [M+H] + .

[0987]

[0988] To a solution of 50G (50 mg, 0.085 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) dropwise at room temperature with stirring. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC (C18 column eluted with acetonitrile: water (0.1% FA) = 5%~95%) to give EX 50 as a pair of cis isomers (30 mg, 72.3%). LC-MS: m / z = 488.0 [M+H] + ; 1H NMR (400 MHz, MeOD) δ 9.23 (s, 2H), 8.07 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.65 (dd, Ji = 8.4 Hz, J2= 1.2 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.86 (t, J = 73.6 Hz, 1H), 5.82 (q, J = 14.8 Hz, 2H), 2.93 - 2.83 (m, 2H), 2.80 - 2.72 (m, 1H), 2.61 - 2.45 (m, 3H), 2.41 - 2.15 (m, 4H), 1.17 - 1.05 (m, 2H), 0.93 - 0.81 (m, 2H).

[0989] Example 51

[0990]

[0991] A solution of tribromoborane (1.0 M in DCM, 30 mmol, 30 mL) in DCM (30 mL) was cooled to -78 °C under nitrogen. A solution of but-3-yn-1-ol (51A) (1.0 g, 14 mmol, 1.1 mL) in DCM (30 mL) was then added dropwise to the mixture, the reaction mixture was stirred at -78 °C for 3 h. A solution of 2,3-dimethylbutane-2,3-diol (3.4 g, 28 mmol) and DIEA (9.3 g, 71 mmol, 12 mL) in DCM (40 mL) was added dropwise to the mixture at -78 °C, slowly warmed to room temperature, and stirred at room temperature for 2 h. The reaction mixture was quenched with brine (150 mL) and extracted with DCM (150 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4and filtered. The filtrate was concentrated and purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to give 51B (2.0 g, 92% purity, 6.5 mmol, 46% yield) as a yellow oil. LCMS (ESI) m / z: [M+H] + 277.20.

[0992]

[0993] To a solution of ZnCl2(1.0 M solution in THF, 42 mL) in THF (28 mL) was added methylmagnesium bromide (3 M solution in ether, 14 mL) dropwise at room temperature, then stirred at room temperature for 45 min. To the reaction mixture was added a solution of 51B (2.0 g, 92% purity, 6.5 mmol) in THF (15 mL) and bis(tri-tert-butylphosphine)palladium(0) (306 mg, 599 μmol) at room temperature under nitrogen, then stirred at room temperature for 16 h. The reaction mixture was quenched with a solution of HC1 (2.0 M, 20 mL). Water (150 mL) was added, and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (18% ethyl acetate in petroleum ether) to give 51C (1.1 g, 4.9 mmol, 74% yield, 95% purity) as a yellow oil. LCMS (ESI) m / z: [M+H] + 213.30.

[0994]

[0995] A mixture of 51C (780 mg, 95% purity, 3.49 mmol), TBDPSCl (1.25 g, 4.56 mmol), imidazole (333 mg, 4.89 mmol), and DMAP (34.0 mg, 279 μmol) in DCM (25 mL) was stirred at room temperature for 16 h. The reaction mixture was quenched with water, diluted with DCM (100 mL), and washed with water (100 mL x 3) and brine (100 mL x 3). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (6% ethyl acetate in petroleum ether) to give 51D (1.40 g, 2.95 mmol, 84% yield) as a yellow oil. 1 H NMR (400 MHz, CDC13) δ 7.59-7.57 (m, 4H), 7.33-7.27 (m, 6H), 5.01 (s, 1H), 3.70 (t, J = 7.2 Hz, 2H), 2.30 (t, J = 7.2 Hz, 2H), 1.86 (s, 3H), 1.17 (s, 12H), 0.96 (s, 9H).

[0996]

[0997] To a solution of 51D (1.0 g, 95% purity, 2.1 mmol) in DCM (20 mL) was added diethylzinc (12 mL, 12 mmol) at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 0.5 h, then diiodomethane (2.82 g, 10.5 mmol) and TFA (1.20 g, 10.5 mmol, 806 μί) were added by syringe. After addition, the mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water (50 mL). The solid was filtered off and the filtrate was separated. The aqueous phase was extracted with DCM (50 mL x 2). The combined organic layers were dried over anhydrous Na2S04and filtered. The filtrate was concentrated under reduced pressure to give 51E (a pair of trans isomers, 885 mg, 90% purity, 1.71 mmol, 81% yield) as a yellow oil. 1 H NMR (400 MHz, CDC13) δ 7.61-7.58 (m, 4H), 7.36-7.27 (m, 6H), 3.69 (t, J = 7.6 Hz, 2H), 1.60-1.54 (m, 1H), 1.43-1.36 (m, 1H), 1.22-1.12 (m, 12H), 1.02-0.96 (m, 12H), 0.55-0.46 (m, 2H).

[0998]

[0999] To a solution of 51E (885 mg, 90% purity, 1.71 mmol) in THF (10 mL) was added TBAF (1.0 M in THF, 15 mL) dropwise, then stirred at room temperature for 16 h. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (60 mL x 2), the combined organic layers were washed with water (100 mL x 2) and brine (100 mL), dried over anhydrous Na2S04and filtered. The filtrate was concentrated to give 51F (550 mg, 65% purity, 1.58 mmol, 92% yield) as a yellow oil, which was used in the next step reaction without further purification. 1 H NMR (400 MHz, CDC13) δ 7.61-7.58 (m, 4H), 7.36-7.27 (m, 6H), 3.69 (t, J = 7.6 Hz, 2H), 1.60-1.54 (m, 1H), 1.43-1.36 (m, 1H), 1.22-1.12 (m, 12H), 1.02-0.96 (m, 12H), 0.55-0.46 (m, 2H).

[1000]

[1001] To a mixture of 51F (320 mg, 65% purity, 920 pmol) in DCM (15 mL) was added Dess-Martin periodinane (468 mg, 1.10 mmol) portionwise at 0 °C and stirred at room temperature for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with saturated aqueous NaHC03solution (100 mL) and brine, dried over Na2S04and filtered. The filtrate was concentrated and purified by silica gel column chromatography (15% ethyl acetate in petroleum ether) to give 51G (85.0 mg, 90% purity, 341 pmol, 37% yield) as a yellow oil. 1 H NMR (400 MHz, CDC13) δ 9.85 (t, J = 2.8 Hz, 1H), 2.41 - 2.24 (m, 2H), 1.46 - 1.26 (m, 12H), 1.02 - 0.79 (m, 6H).

[1002]

[1003] A mixture of 51G (85.0 mg, 90% purity, 341 pmol), 10 (214 mg, 341 pmol) and Na2S205 (327 mg, 1.72 mmol) in DMSO (3.0 mL) was stirred at 80 °C for 8 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2S04and filtered. The filtrate was concentrated and purified by silica gel column chromatography (45% ethyl acetate in petroleum ether) to give 51H (140 mg, 85% purity, 153 pmol, 45% yield) as a yellow oil. LCMS (ESI) m / z: [M+H] + 794.37.

[1004]

[1005] A mixture of 51H (140 mg, 85% purity, 153 pmol), Pd(dppf)Cl2(22 mg, 30 pmol) and K2C03(106 mg, 766 pmol) in dioxane (5 mL) and water (1.0 mL) was stirred at 90 °C under nitrogen for 1 h. It was concentrated and purified by silica gel column chromatography (5% MeOH in DCM) to give 51I (85.0 mg, 66% purity, 101 pmol, 64% yield) as a yellow oil. LCMS (ESI) m / z: [M+H] + 588.35.

[1006]

[1007] To a solution of 51I (85.0 mg, 66% purity, 101 pmol) in DCM (2.0 mL) was added TFA (0.5 mL) dropwise at room temperature, and stirred at room temperature for 16 h. The reaction mixture was concentrated, and the resulting residue was dissolved in ethyl acetate (100 mL). The organic layer was washed with aqueous NaHC03solution (100 mL) and brine (100 mL), dried over anhydrous Na2C03and filtered. The filtrate was concentrated, and the resulting residue was purified by prep-HPLC (column: Waters Xbridge 250*30 mm, 5 pm; mobile phase A: water (+0.1% FA), mobile phase B: acetonitrile; gradient: 30%~55% B; flow rate: 35 mL / min; wavelength: 214 nm / 254 nm) to give EX 51 (as a pair of trans isomers, 33 mg, 98% purity, 67 pmol, 66% yield) as a white solid. LCMS (ESI) m / z: [M+H] + 488.28; Rt = 4.354 min. 1 H NMR (400 MHz, DMSO-d6) d 9.18 (s, 2H), 8.37 (s, 1H), 8.26 (s, 1H), 7.70-7.52 (m, 3H), 7.42-7.33 (m, 1H), 7.10 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 5.73-5.64 (m, 2H), 3.60-3.56 (m, 1H), 3.16 (d, J = 14.0 Hz, 1H), 2.71-2.65 (m, 3H), 2.25-2.17 (m, 2H), 2.10-1.84 (m, 2H), 1.48-1.45 (m, 2H), 0.00 (s, 3H).

[1008] Example 52

[1009]

[1010] CuCl (49.0 mg, 499 mmol) was added to a Schlenk tube under argon followed by PPh3 (157 mg, 599 mmol) and tBuOK (224 mg, 2.00 mmol). This was dissolved in anhydrous THF (5 mL) and stirred at room temperature for 0.5 h. A solution of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.79 g, 11.0 mmol) in anhydrous THF (6.0 mL) was added and the reaction stirred for 10 min. The reaction was cooled to 0 °C and a solution of pent-3-yn-1-ol (51A) (840 mg, 9.99 mmol, 0.92 mL) in MeOH (640 mg, 20.0 mmol, 0.8 mL) and anhydrous THF (3 mL) was added. The reaction was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was filtered through celite, washed with methyl-tert-butyl ether (MTBE) and purified by column chromatography on silica gel (40% MTBE in petroleum ether) to give 52B (2.80 g, 66% purity, 6.60 mmol, 50% yield) as a colourless, clear oil. 1 H NMR (400 MHz, CDC13) δ 6.25 (dd, J = 6.8, 5.2 Hz, 1H), 3.83 (t, J = 6.8 Hz, 2H), 2.40-2.33 (m, 2H), 1.64 (m, 3H), 1.18 (s, 12H).

[1011]

[1012] To a solution of 52B (2.80 g, 50% purity, 6.60 mmol), imidazole (629 mg, 9.24 mmol) and DMAP (8 mg, 66.01 pmol) in anhydrous DCM (20 mL) was added TBSC1 (1.29 g, 8.58 mmol) under nitrogen and the reaction stirred at room temperature for 16 h. The reaction was quenched with saturated aqueous NH4C1 (5 mL) and extracted with MTBE (3 x 10 mL). The combined organic extracts were washed successively with water (5 mL) and brine (5 mL), dried over Na2S04, filtered and concentrated in vacuo. This was purified by column chromatography on silica gel (2-5% MTBE in petroleum ether) to give 52C (1.61 g, 90% purity, 4.44 mmol, 67% yield) as a colourless, clear oil. 1H NMR (400 MHz, CDC13) δ 6.23 (dd, J = 7.2, 5.6 Hz, 1H), 3.61 (t, J = 7.2 Hz, 2H), 2.33 (q, J = 7.2 Hz, 2H), 1.65 (s, 3H), 1.20 (s, 12H), 0.84 (s, 9H), 0.00 (s, 6H).

[1013]

[1014] To a solution of 52C (630 mg, 1.74 mmol) in DCM (8 mL) was added diethylzinc (1 M, 8.69 mmol, 8.69 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 0.5 h. Then diiodomethane (2.33 g, 8.69 mmol, 700 μί) and TFA (990 mg, 8.68 mmol, 664 μί) were added to the reaction mixture by syringe. After the addition, the mixture was stirred at room temperature for 2 h. The reaction was quenched with water (30 mL). The solid was filtered off and the filtrate was separated. The aqueous phase was extracted with DCM (20 mL) twice. The combined organic phase was dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give 52D (580 mg, 1.62 mmol, 95% purity, 93% yield) as a yellow oil, which was used directly in the next step without further purification. 1 H NMR (400 MHz, CDC13) δ 3.68 - 3.56 (m, 2H), 1.60 - 1.44 (m, 2H), 1.14 (s, 9H), 0.97 (s, 3H), 0.90 - 0.77 (m, 14H), 0.00 (s, 6H).

[1015]

[1016] A mixture of 52D (610 mg, 1.78 mmol, 95% purity) and TBAF solution (1.0 M solution in THF, 4 mL) was stirred at room temperature for 2 h. The mixture was diluted with DCM, washed with water and brine, and the organic layer was concentrated to give 52E (310 mg, 1.10 mmol, 75% purity, 62% yield) as a yellow oil. 1 H NMR (400 MHz, CDC13) δ 3.64 (t, J = 6.8 Hz, 2H), 1.73 - 1.62 (m, 1H), 1.47 - 1.33 (m, 4H), 1.11 (s, 12H), 0.94 (s, 3H).

[1017]

[1018] To a mixture of 52E (310 mg, 75% purity, 1.10 mmol) and NaHC03(432 mg, 5.50 mmol) in DCM (6 mL) was added Dess-Martin periodinane (479 mg, 1.13 mmol). The mixture was stirred at room temperature for 6 h. The reaction was quenched with water (30 mL). The solid was filtered off and the filtrate was separated. The aqueous phase was extracted with DCM (30 mL x 2). The combined organic phase was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate: petroleum ether = 3:7) to give 52F (63 mg, 253.01 μmol, 90% purity, 24% yield) as a yellow oil. 1 H NMR (400 MHz, CDC13) δ 9.72 (t, J = 2.0 Hz, 1H), 2.41 (ddd, J = 17.2, 6.8, 2.0 Hz, 1H), 2.24 (ddd, J = 17.2, 8.0, 2.0 Hz, 1H), 1.11 (s, 12H), 0.96-0.91 (m, 4H), 0.79 (dd, J = 13.2, 4.2 Hz, 2H).

[1019]

[1020] A mixture of 52G (60 mg, 74% purity, 71 μmol), Pd(dppf)Cl2(10.39 mg, 14.20 μmol) and K2C03(29 mg, 213 μmol) in dioxane (4 mL) and water (1 mL) was stirred at 90 °C under argon for 6 h. The mixture was diluted with EtOAc, washed with water and brine. The organic layer was concentrated and purified by column chromatography on silica gel (ethyl acetate: petroleum ether = 44:56) to give 52H (9 mg, 15.32 μmol, 88% purity, 22% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] + 795.35.

[1021]

[1022] A mixture of 52G (60 mg, 74% purity, 71 μmol), Pd(dppf)Cl2(10.39 mg, 14.20 μmol) and K2C03(29 mg, 213 μmol) in dioxane (4 mL) and water (1 mL) was stirred at 90 °C under argon for 6 h. The mixture was diluted with EtOAc, washed with water and brine. The organic layer was concentrated and purified by column chromatography on silica gel (ethyl acetate: petroleum ether = 44:56) to give 52H (9 mg, 15.32 μmol, 88% purity, 22% yield) as a yellow solid. LCMS (ESI) m / z: [M+H] +588.34.

[1023]

[1024] To a solution of 52H (9.0 mg, 15 pmol, 88% purity) in DCM (2 mL) was added HC1 (4 M, 8.00 mmol, 2 mL). The mixture was stirred at room temperature for 1 h. The mixture was concentrated and purified by prep-HPLC (column: Waters Xbridge 250*30 mm, 5 um; mobile phase A: water (+0.1% NH4HCO3), mobile phase B: ACN; gradient: 35%~85% B; flow rate: 39 mL / min; wavelength: 214 nm / 254 nm) to give EX 52 (2.53 mg, 5.04 pmol, 97% purity, 33% yield, one pair of trans isomers) as a white solid. LCMS (ESI) m / z: [M+H] + 488.29. 1 H NMR (400 MHz, CD3OD) d 9.09 (s, 2H), 7.82 (s, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.61 (dd, J = 8.4, 1.6 Hz, 1H), 7.44 - 6.97 (m, 4H), 6.08 (d, J = 17.6 Hz, 1H), 5.85 (d, J = 17.2 Hz, 1H), 3.94 (dd, J = 17.6, 8.2 Hz, 1H), 3.19 (dd, J = 17.6, 10.8 Hz, 1H), 2.87 - 2.75 (m, 2H), 2.38 - 2.26 (m, 2H), 2.21 - 1.98 (m, 3H), 1.50 (dd, J = 9.2, 4.8 Hz, 1H), 1.14 - 1.07 (m, 1H), 0.50 (s, 3H).

[1025] Example 54-A and Example 54-B

[1026]

[1027] A solution of 16C (3.00 g, 7.98 mmol) and 46D (2.01 g, 9.57 mmol) in DMF (15.0 mL) was stirred at 70 °C for 16 hours. The reaction mixture was diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (3:1), to give 1-(2-bromo-6-(difluoromethoxy)benzyl)-6-chloro-2-((2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)cyclopropyl)methyl)-1H-benzo[d]imidazolium (54A) (1.50 g, yield 33.3%), as a yellow solid. LCMS (ESI): m / z = 567.9 [M+H] + .

[1028]

[1029] Under stirring and argon atmosphere at room temperature, Pd(dppf)Cl2 (193.88 mg, 0.26 mmol) and K2CO3 (1.10 g, 7.95 mmol) were added to a mixture of 54A (1.50 g, 2.65 mmol) in dioxane (40 mL) and water (10 mL). The resulting mixture was stirred at 100 °C for 16 hours. The reaction mixture was diluted with water (30.0 mL). The resulting mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1:1), to give a crude product (racemic mixture) (260.0 mg, yield 27.2%) as a yellow solid. The racemic mixture (260.00 mg, 0.72 mmol) was separated by preparative SFC (column: IC, 250*25mm 10pm; mobile phase A: CO2, mobile phase B: ethanol; flow rate: 70 mL / min; gradient: isocratic, 30% B; wavelength: 214 nm; retention time 1 : 4.450 min; retention time 2: 4.974 min), to give (1aR,13aS)-9-chloro-5-(difluoromethoxy)-1a,6,13,13a-tetrahydro-1H- benzo[f]benzo[4,5]imidazo[1,2-a]cycloprop[d]azocine (54B) (retention time 1 : 4.450 min, 130.00 mg, yield 13.6% as a yellow solid) and (1aS,13aR)-9-chloro-5- (difluoromethoxy)-1a,6,13,13a-tetrahydro-1H-benzo[f]benzo[4,5]imidazo[1,2-a]cycloprop[d] azocine (54C) (retention time 2: 4.974 min, 130.00 mg, yield 13.6% as a yellow solid). LCMS (ESI): m / z = 361.0 [M+H] + .

[1030]

[1031] To a mixture of 54B (15.00 mg, 0.04 mmol), (2-(dimethylphosphoryl)pyrimidin-5- yl)boronic acid (20.83 mg, 0.10 mmol) in dioxane (2 mL) and water (0.5 mL) was added Xphos PdG2 (3.14 mg, 0.004 mmol) and K2CO3 (17.25 mg, 0.12 mmol) at room temperature under argon and stirring. The resulting mixture was stirred at 110 °C for 1 h. The reaction mixture was diluted with water (5.0 mL). The resulting mixture was extracted with ethyl acetate (5 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting mixture was purified by prep-HPLC eluted with acetonitrile: water (0.1% FA) = 5-95% to give (5-((1aR,13aS)-5-(difluoromethoxy)-1a,6,13,13a-tetrahydro-1H- benzo[f]benzo[4,5]imidazo[1,2-a]cycloprop[d]azocin-9-yl)pyrimidin-2-yl)dimethyl phosphine oxide (EX54-A) (5.00 mg, yield 25.0%) as a white solid. LCMS (ESI): m / z = 481.4 [M+H] + . 1H NMR (400 MHz, MeOD-d4) δ 9.40 - 9.20 (m, 2H), 7.89 - 6.91 (m, 7H), 6.10 - 5.67 (m, 2H), 4.01 - 3.70 (m, 1H), 3.11 - 3.00 (m, 1H), 2.39 - 2.28 (m, 1H), 1.97 (d, J = 13.6 Hz, 6H), 1.78 - 1.55 (m, 1H), 1.50 - 1.30 (m, 1H), 1.14 - 1.00 (m, 1H), 0.33 - 0.17 (m, 1H).

[1032]

[1033] To a mixture of 54C (15.00 mg, 0.04 mmol), (2-(dimethylphosphoryl)pyrimidin-5- yl)boronic acid (20.83 mg, 0.10 mmol) in dioxane (2 mL) and water (0.5 mL) was added Xphos PdG2 (3.14 mg, 0.004 mmol) and K2CO3 (17.25 mg, 0.12 mmol) at room temperature under argon with stirring. The resulting mixture was stirred at 110 °C for 1 h. The reaction mixture was diluted with water (5.0 mL). The resulting mixture was extracted with ethyl acetate (5 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting mixture was purified by prep-HPLC eluted with acetonitrile: water (0.1% FA) = 5-95% to give (5-((1aS,13aR)-5-(difluoromethoxy)-1a,6,13,13a-tetrahydro-1H- benzo[f]benzo[4,5]imidazo[1,2-a]cycloprop[d]azin-9-yl)pyrimidin-2-yl)dimethyl phosphine oxide (EX54-B) (5.00 mg, yield 25.0%) as a white solid. LCMS (ESI): m / z = 481.4 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 9.38 - 9.17 (m, 2H), 8.28 - 6.91 (m, 7H), 6.09 - 5.65 (m, 2H), 4.04 - 3.70 (m, 1H), 3.10 - 3.00 (m, 1H), 2.37 - 2.25 (m, 1H), 1.97 (d, J = 13.6 Hz, 6H), 1.80 - 1.58 (m, 1H), 1.54 - 1.34 (m, 1H), 1.15 - 1.03 (m, 1H), 0.30 - 0.20 (m, 1H).

[1034] Example 55

[1035]

[1036] A mixture of (laR,13aS)-9-chloro-5-(difluoromethoxy)-la,6,13,13a-tetrahydro-lH- benzo[f]benzo[4,5]imidazo[l,2-a]cycloprop[d]azocine (54B) (150 mg, 0.33 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (167.60 mg, 0.66 mmol), potassium acetate (74.49 mg, 0.76 mmol), XPhos (15.73 mg, 0.033 mmol), XPhos Pd G2 (25.96 mg, 0.033 mmol) and Pd2(dba)3 (9.49 mg, 0.017 mmol) in 1,4-dioxane (2.0 mL) was purged with argon and stirred at 110 °C for 1 h under argon. The resulting mixture was diluted with water (2.0 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5.0 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate / petroleum ether (30%~85%) to give the product 55A (68.0 mg, yield 45.21%) as a yellow solid. LC-MS: m / z = 453.3 [M+H] + .

[1037]

[1038] A mixture of 5-bromo-2-chloropyrimidine (55B) (1.00 g, 5.21 mmol), 3-oxa-8- azabicyclo[3.2.1]octane (1.30 g, 11.5 mmol) and DIEA (3.47 g, 26.84 mmol) in DMF (10 mL) was stirred at room temperature for 16 h. The reaction was quenched with water (300 mL) and extracted with DCM (200 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH / DCM (1:10) to give the target product 55C (1.1 g, yield 78%). LC-MS: m / z = 269.7 [M+H]; 271.7 [M+H+2] + ; 271.7 [M+H+2] + .

[1039]

[1040] A mixture of (laR,13aS)-5-(difluoromethoxy)-9-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-la,6,13,13a-tetrahydro-lH-benzo[f]benzo[4,5]imidazo[l,2- a]cycloprop[d]azocine (55A) (15.00 mg, 0.03 mmol), 8-(5-bromopyrimidin-2-yl)-3- oxabicyclo[3.2.1]octane (55C) (20.2 mg, 0.08 mmol), XPhos Pd G2 (2.6 mg, 0.003 mmol) and K2CO3 (14.0 mg, 0.10 mmol) in dioxane (1.6 mL) and water (0.4 mL) was stirred at 90 °C under argon for 1 h. After cooling, the resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep-HPLC with acetonitrile: water (0.1% FA) = 5% ~ 95% elution to give the target product EX55 (3.22 mg, 18.8%). LC-MS: m / z = 516.5 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.75 & 8.67 (s, 2H), 8.45 & 8.12 (br s, 1H), 7.68 - 6.99 (m, 6H), 5.75 - 5.61 (m, 2H), 4.06 - 3.88 (m, 1H), 3.68 - 3.60 (m, 5H), 3.14 - 2.82 (m, 2H), 2.39 (s, 1H), 2.06 - 1.87 (m, 4H), 1.82 - 1.24 (m, 3H), 1.01 (s, 1H), 0.15 (s, 1H).

[1041] EX56, 57, 58, 59, 60 and 61 were prepared using similar procedures as EX55 as shown in Table 7.

[1042] Table 7

[1043]

[1044]

[1045]

[1046] Example 62

[1047]

[1048] To a solution of (E)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)but-3-en-1-yl)oxy)silane (46A) (3.5 g, 11.2 mmol) in DCM (35 mL) was added diethylzinc (56.1 mL, 1 mol / L in hexane) dropwise at 0 °C under argon with stirring. The resulting mixture was stirred at 0 °C under argon for 0.5 h. To the above mixture was added di-deuterated (diiodo)methane (12.10 g, 44.8 mmol) and TFA (6.39 g, 56.0 mmol) dropwise at 0 °C under argon. The resulting mixture was stirred at 25 °C under argon for another 3 h. The reaction was quenched with aqueous NH4Cl solution (100 mL). The resulting mixture was extracted with ethyl acetate (200 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product (62A), which was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ 3.63-3.59 (m, 2H), 1.44-1.38 (m, 2H), 1.16 (s, 12H), 0.94-0.90 (m, 1H), 0.84 (s, 9H), 0.00 (s, 6H), -0.46 (d, J = 5.6 Hz, 1H).

[1049]

[1050] A solution of tert-butyldimethyl(2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)cyclopropyl-3,3-d2)ethoxy)silane (62A) (3200 mg, 9.75 mmol) in TBAF solution (32 mL, 1.0 M solution in THF) was stirred at 40 °C overnight. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0% to 25% ethyl acetate in petroleum ether to give the target product 62B (1100 mg, yield 52.7%). 1 H NMR (400 MHz, CDCl3): δ 3.63-3.59 (m, 2H), 1.44-1.38 (m, 2H), 1.16 (s, 12H), 0.94-0.90 (m, 1H), 0.84 (s, 9H), 0.00 (s, 6H), -0.46 (d, J = 5.6 Hz, 1H).

[1051]

[1052] To a mixture of 2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl-3,3-d2)ethan-1-ol (62B) (1100 mg, 5.14 mmol) in DCM (20 mL) was added Dess-Martin periodinane (2616.1 mg, 6.17 mmol) and NaHCO3(2159.1 mg, 25.7 mmol). The resulting mixture was stirred at 25 °C for 2 h. The reaction was quenched with water (30 mL). The solid was filtered off and the filtrate was separated. The aqueous phase was extracted with DCM (30 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0%~20% ethyl acetate in petroleum ether to give 62C (700 mg, yield 64.2%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 9.78 (t, J = 2.0 Hz, 1H), 2.46-2.39 (m, 1H), 2.27-2.20 (m, 1H), 1.53 (br s, 1H), 1.22 (s, 12H), -0.27 (d, J = 5.6 Hz, 1H).

[1053]

[1054] A mixture of 2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl-3,3-d2)acetaldehyde (62C) (722 mg, 3.40 mmol) and N1-(2-bromo-6-(difluoromethoxy)benzyl)-5-chlorobenzene-1,2-diamine (16C) (1412.2 mg, 3.74 mmol) in DMF (10 mL) was stirred at 70 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with acetonitrile / 0.1% aqueous TFA (5%~95%) to give 62D (700 mg, yield 36.1%) as a white solid. LC-MS: m / z = 569.2 [M+H] + .

[1055]

[1056] To a mixture of 1-(2-bromo-6-(difluoromethoxy)benzyl)-6-chloro-2-((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl-3,3-d2)methyl)-1H- benzo[d]imidazole (62D) (700 mg, 1.44 mmol) and K2CO3 (597.0 mg, 4.32 mmol) in dioxane (14 mL) and water (3.5 mL) was added Pd(dppf)Cl2 (105.3 mg, 0.14 mmol) with stirring. The resulting mixture was stirred at 90 °C under argon for 5 h. After cooling, the resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0%~5% MeOH in DCM to give 1-(2-bromo-6-(difluoromethoxy)benzyl)-6-chloro-2-((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl-3,3-d2)methyl)-1H- benzo[d]imidazole (200 mg, yield 38.3%) as a pair of racemic mixture. The racemic mixture was separated by preparative SFC to give 62E (70 mg). Its retention time was similar to the non-deuterated compound. LC-MS: m / z = 363.0 [M+H] + .

[1057]

[1058] To a mixture of 2,5-dibromo-3-fluoropyridine (62F) (1.0 g, 3.95 mmol) and dimethyl phosphine oxide (339 mg, 4.35 mmol) in dioxane (10 mL) was added Pd2dba3 (366 mg, 0.40 mmol), Xantphos (231.2 mg, 0.40 mmol) and TEA (1.2 g, 11.85 mmol) with stirring. The resulting mixture was stirred at 90 °C under argon overnight. After cooling, the resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0%~100% ethyl acetate in petroleum ether to give 62G (490 mg, yield 49.4%). LC-MS: m / z = 252.0 [M+H] + .

[1059]

[1060] To a mixture of (5-bromo-3-fluoropyridin-2-yl)dimethylphosphine oxide (62G) (490 mg, 1.95 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (991.7 mg, 3.90 mmol) in dioxane (10 mL) was added Pd(dppf)Cl2(146 mg, 0.20 mmol) and KOAc (573.3 mg, 5.85 mmol) with stirring. The resulting mixture was stirred at 80 °C under argon overnight. After cooling, the resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0% to 100% ethyl acetate in petroleum ether to give 62H (100 mg, yield 23.6%) as a white solid. LC-MS: m / z = 217.8 [M+H] + .

[1061]

[1062] To a mixture of (6-(dimethylphosphoryl)-5-fluoropyridin-3-yl)boronic acid (62H) (100 mg, 0.46 mmol) and (laR,13aS)-9-chloro-5-(difluoromethoxy)-la,6,13,13a-tetrahydro-lH- benzo[f]benzo[4,5]imidazo[l,2-a]cyclopropa[d]azocine-l,l-d2(62E) (166.52 mg, 0.46 mmol) in dioxane (2 mL) and water (0.5 mL) was added Pd(dppf)Cl2(33.6 mg, 0.046 mmol) and K2CO3(190 mg, 1.38 mmol) with stirring. The resulting mixture was stirred at 100 °C under argon for 2 h. After cooling, the resulting mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with acetonitrile / 0.1% aqueous TFA (5% to 95%) to give (5-((laR,13aS)-5-(difluoromethoxy)-la,6,13,13a-tetrahydro-lH- benzo[f]benzo[4,5]imidazo[l,2-a]cyclopropa[d]azocin-9-yl-l,l-d2)-3-fluoropyridin-2- yl)dimethylphosphine oxide (EX62) (0.79 mg, yield 0.34%) as a white solid. LC-MS: m / z = 500.0 [M+H] + ; 1H NMR (400 MHz, MeOD-d4): δ 8.96 (br s, 1H), 8.45 (s, 1H), 8.06 - 7.99 (m, 1H), 7.78 - 7.65 (m, 2H), 7.35 - 7.02 (m, 4H), 5.99 - 5.67 (m, 2H), 3.93 - 3.72 (m, 1H), 3.03 - 3.00 (m, 1H), 2.27 - 2.19 (m, 1H), 2.00 (s, 3H), 1.97 (s, 3H), 1.69 - 1.61 (m, 1H).

[1063] Example 63

[1064]

[1065] To a mixture of 2,5-dibromo-3-fluoropyridine (63A) (1.0 g, 4.22 mmol) and dimethyl phosphine oxide (365 mg, 4.68 mmol) in dioxane (10 mL) was added Pd2dba3(393 mg, 0.43 mmol), Xantphos (248.5 mmol, 0.43 mmol) and TEA (1.29 g, 12.8 mmol) under stirring. The resulting mixture was stirred at 90 °C under argon overnight. After cooling, the resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0% to 100% ethyl acetate in petroleum ether to give 63B (900 mg, yield 90.8%). LC-MS: m / z = 235.8 [M+H+2] + .

[1066]

[1067] To a mixture of (5-bromopyridin-2-yl)dimethylphosphine oxide (63B) (500 mg, 2.15 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.09 g, 4.29 mmol) in dioxane (10 mL) was added Pd(dppf)Cl2(161 mg, 0.22 mmol) and KOAc (1.26 g, 12.9 mmol) with stirring. The resulting mixture was stirred at 80 °C under argon overnight. After cooling, the resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0% to 100% ethyl acetate in petroleum ether to give 63C (30 mg, 7.03% yield) as a white solid. LC-MS: m / z = 199.9 [M+H] + .

[1068]

[1069] To a mixture of (6-(dimethylphosphoryl)pyridin-3-yl)boronic acid (63C) (30 mg, 0.15 mmol) and (laR,13aS)-9-chloro-5-(difluoromethoxy)-la,6,13,13a-tetrahydro-lH- benzo[f]benzo[4,5]imidazo[l,2-a]cycloprop[d]azocin-l,l-d2(54.6 mg, 0.15 mmol) in dioxane (2 mL) and water (0.5 mL) was added Pd(dppf)Cl2(11 mg, 0.015 mmol) and K2CO3(62.1 mg, 0.45 mmol) with stirring. The resulting mixture was stirred at 100 °C under argon for 2 h. After cooling, the resulting mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with acetonitrile / 0.1% aqueous TFA (5% to 95%) to give (5-((laR,13aS)-5-(difluoromethoxy)-la,6,13,13a-tetrahydro-lH- benzo[f]benzo[4,5]imidazo[l,2-a]cycloprop[d]azocin-9-yl-l,l-d2)pyridin-2- yl)dimethylphosphine oxide (EX63) (4.62 mg, 6.37% yield) as a white solid. LC-MS: m / z = 482.0 [M+H] + ; 1H NMR (400 MHz, MeOD-d4): δ 9.16 & 9.04 (br s, 1H), 8.44 (s, 1H), 8.32-8.21 (m, 1H), 8.11 (s, 1H), 7.77-7.55 (m, 2H), 7.37-6.94 (m, 4H), 6.07-5.63 (m, 2H), 3.99-3.73 (m, 1H), 3.07-3.01 (m, 1H), 2.31-2.16 (m, 1H), 1.87 (d, J = 13.6 Hz, 6H), 1.69-1.55 (m, 1H).

[1070] Example 64

[1071]

[1072] To a solution of 64A (7.00 g, 66.0 mmol) in THF (70 mL) was added LAH (2.5 M, 58.1 mL) dropwise at 0 °C. The solution was stirred at 70 °C for 12 h. The reaction was quenched with water (5.7 mL), 15% NaOH (5.7 mL), and water (17.1 mL). The mixture was filtered, and the filtrate was concentrated in vacuo to give 64B (3.4 g, yield 66%) as a colorless oil. 1 H NMR: (400 MHz, CDC13) δ ppm 3.89 (s, 4H).

[1073]

[1074] To a solution of 2,2-dideuteropropane-l,3-diol (64B) (3.40 g, 43.5 mmol) in THF (50 mL) was added NaH (2.09 g, 52.2 mmol, 60% purity) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 0.5 h, and BnBr (5.96 g, 34.8 mmol, 4.14 mL) was added. The reaction mixture was stirred at 25 °C under nitrogen for 11.5 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: 0%~30% ethyl acetate / petroleum ether, gradient elution, rate: 40 mL / min) to give 64C (1.8 g, yield 25%, yellow oil) and (3-benzyloxy-2,2-dideuteropropoxy)methylbenzene (3.0 g, yield 27%, yellow oil). 40g silica gel flash column, eluent: 0%~30% ethyl acetate / petroleum ether, gradient elution, rate: 40 mL / min) to give 64C (1.8 g, yield 25%, yellow oil) and (3-benzyloxy-2,2-dideuteropropoxy)methylbenzene (3.0 g, yield 27%, yellow oil). 1H NMR δ ppm 7.36-7.30 (m, 5H), 4.54 (s, 2H), 3.80 - 3.79 (m, 2H), 3.67 (s, 2H), 2.25 (t, 1H).

[1075]

[1076] To a solution of 64C (1.80 g, 10.7 mmol) and CBr4(4.51 g, 13.6 mmol) in DCM (203 mL) was added PPh3(5.05 g, 19.3 mmol) portion wise at 0 °C. The resulting mixture was stirred at 25 °C for 12 h. TLC (petroleum ether: ethyl acetate = 1 : 1) showed the reaction was complete. The solution was diluted with DCM (30.0 mL) and washed with water (30.0 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: 0% to 15% ethyl acetate / petroleum ether, gradient elution, rate 18 mL / min) to give 64D (2.24 g, yield 91%) as a colorless oil. 20.0 g Flash column chromatography on silica gel (eluent: 0% to 15% ethyl acetate / petroleum ether, gradient elution, rate 18 mL / min) to give 64D (2.24 g, yield 91%) as a colorless oil. 1 H NMR: (400 MHz, CDC13) δ ppm 7.37-7.30 (m, 5H), 4.53 (s, 2H), 3.61 (s, 2H), 3.53 (s, 2H).

[1077]

[1078] To a solution of 64D (2.24 g, 9.69 mmol) in toluene (30 mL) was added PPh3(3.05 g, 11.63 mmol). The mixture was stirred at 110 °C for 12 h. The mixture was concentrated in vacuo. To the residue was added ethyl acetate (10 mL), filtered and the filter cake was concentrated in vacuo to give 64E (4.47 g, yield 93%) as a white solid. 1 H NMR: (400 MHz, CDC13) δ ppm 7.89-7.69 (m, 8H), 7.36-7.31 (m, 12H), 4.54-4.53 (m, 2H), 4.11-3.87 (m, 2H), 3.68 - 3.55 (m, 2H).

[1079]

[1080] A mixture of (3-(benzyloxy)propyl-2,2-d2)triphenylphosphonium bromide (64E) (3.98 g, 8.07 mmol), NaH (359 mg, 8.96 mmol, purity 60%) in THF (30.0 mL) was degassed and purged with nitrogen for 3 times, then the mixture was stirred at 0 °C under nitrogen for 0.5 h. Then compound 1K (1.5 g, 5.98 mmol) was added. The reaction mixture was purged with nitrogen for 3 times, and stirred at 25 °C under nitrogen for 11.5 h. The reaction mixture was quenched with aqueous NH4Cl solution at 0 °C (50.0 mL), then diluted with ethyl acetate (50.0 mL), and extracted with ethyl acetate (50.0 mL x 2). The combined organic layer was washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give yellow oil. The residue was purified by flash silica gel column chromatography (0%~30% ethyl acetate / petroleum ether, gradient elution, rate 35 mL / min) and SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; B%: 20%, isocratic elution mode) to give 1-[(Z)-4-benzyloxy-3,3-dideuterio-but-1-enyl]-2-bromo-3-(difluoromethoxy)benzene (650 mg, yield 28%) and 64F (230 mg, yield 9.9%) as yellow oil. 20.0 g Silica gel flash column, eluent 0%~30% ethyl acetate / petroleum ether, gradient elution, rate 35 mL / min) and SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; B%: 20%, isocratic elution mode) purification to give 1-[(Z)-4-benzyloxy-3,3-dideuterio-but-1-enyl]-2-bromo-3-(difluoromethoxy)benzene (650 mg, yield 28%) and 64F (230 mg, yield 9.9%) as yellow oil. 1 H NMR: (400 MHz, DMSO-d6) δ ppm 7.60-7.50 (m, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.35-7.33 (m, 3H), 7.30-7.26 (m, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 15.6 Hz, 1H), 6.36 (d, J = 16.0 Hz, 1H), 4.50 (s, 2H), 3.57 (s, 2H).

[1081]

[1082] A solution of TFA (266 mg, 2.34 mmol, 174 μL) in DCM (1.50 mL) was added to a solution of diethylzinc (1.0 M, 2.34 mL) in DCM (1.50 mL) under nitrogen. The solution was stirred at 0 °C for 30 min, then a solution of diiodomethane (626 mg, 2.34 mmol, 188 μL) in DCM (1.50 mL) was added to the mixture. The solution was stirred at 0 °C for 30 min. Then a solution of 64F (180 mg, 467 μmol) in DCM (1.50 mL) was added to the mixture. The resulting mixture was stirred at 25 °C under nitrogen for 12 h. The reaction mixture was quenched with aqueous NH4Cl (50.0 mL) at 0 °C, then diluted with ethyl acetate (50.0 mL) and extracted with ethyl acetate (50.0 mL x 2). The combined organic layers were washed with brine (30.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil. The residue was purified by flash column chromatography on silica gel (eluent: 0%~20% ethyl acetate / petroleum ether, gradient elution, rate: 20 mL / min) to give 64G (150 mg, yield 80%) as a yellow oil. 4.00 g Flash column chromatography on silica gel (eluent: 0%~20% ethyl acetate / petroleum ether, gradient elution, rate: 20 mL / min) to give 64G (150 mg, yield 80%) as a yellow oil. 1 H NMR:(400MHz,CDCl3)δppm 7.34-7.27 (m, 5H), 7.19 (br t, J=8.0 Hz, 1H), 7.03 (br d, J=8.0 Hz, 1H), 6.80 (br d, J=7.6 Hz, 1H), 6.72-6.31 (m, 1H), 4.54 (s, 2H), 3.69-3.55 (m, 2H), 2.03-1.96 (m, 1H), 1.17-1.10 (m, 1H), 0.96-0.88 (m, 2H). 19 F NMR:(376MHz,CDCl3)δppm -81.102 (s, 2F).

[1083]

[1084] A mixture of 1-[2-(2-benzyloxy-1,1-dideuterioethyl)cyclopropyl]-2-bromo-3- (difluoromethoxy)benzene (64G) (180 mg, 451 pmol), potassium (((tert- butoxycarbonyl)amino)methyl)trifluoroborate (160 mg, 676 pmol), Cs2CO3(294 mg, 902 pmol), [2-(2-aminophenyl)phenyl]-chloro-palladium; bis(1- adamantyl)-butylphosphine (30.1 mg, 45.1 pmol) in dioxane (2.00 mL) and water (0.400 mL) was degassed and purged with nitrogen 3 times, then the mixture was stirred at 90 °C under nitrogen for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (FA condition; column: Welch Xtimate C18 150*30mm*5pm; mobile phase: [water (FA)-acetonitrile]; gradient: 70%~100%B, 9 minutes) to give 64H (100 mg, 49% yield) as a yellow oil. LCMS: m / z = 450.1 (M+H) + . 1 HNMR: (400 MHz, DMSO-d6) δ ppm 7.33-7.04 (m, 7H), 6.97-6.92 (m, 1H), 6.90-6.85 (m, 1H), 6.79 (d, J = 7.6 Hz, 1H), 4.47 (s, 2H), 4.33 (d, J = 5.2 Hz, 2H), 3.57-3.48 (m, 2H), 1.94-1.82 (m, 1H), 1.37 (s, 9H), 1.11-1.05 (m, 1H), 0.91-0.85 (m, 1H), 0.83-0.76 (m, 1H). 19 F NMR: (376 MHz, DMSO-d6) δ ppm -80.114 (s, 2F).

[1085]

[1086] To a solution of 64H (75.0 mg, 0.166 mmol) in DCM (4.0 mL) was added FeCl3(135.0 mg, 0.834 mmol) at 0 °C. The mixture was stirred at 20 °C under nitrogen for 2 hours. The resulting mixture was concentrated to dryness under vacuum. The residue was purified by silica gel column chromatography eluted with 3%~10% MeOH in DCM to give 64I (30 mg, 69%) as a yellow oil. LCMS (ESI): m / z = 260.0 [M+H] + .

[1087]

[1088] A solution of 64I (30.0 mg, 0.115 mmol), 4-chloro-2-fluoro-l-nitrobenzene (16A) (40.6 mg, 0.23 mmol) and DIEA (59.0 mg, 0.456 mmol) in EtOH (2.0 mL) was stirred at 70 °C for 3 h. The resulting mixture was concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 0% to 30% ethyl acetate in petroleum ether to give 64J (30.0 mg, 63%) as a yellow solid. LCMS (ESI): m / z = 414.9 [M+H] + .

[1089]

[1090] To a solution of 64J (30.0 mg, 0.072 mmol) in DCM (2.0 mL) was added Dess-Martin periodinane (46.0 mg, 0.108 mmol) at 0 °C. The mixture was stirred at 20 °C for 3 h. The resulting mixture was concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 0% to 30% ethyl acetate in petroleum ether to give 64K (18.0 mg, 60%) as a yellow solid. LCMS (ESI): m / z = 413.2 [M+H] + .

[1091]

[1092] A mixture of 64K (18.0 mg, 0.044 mmol) and iron powder (21.0 mg, 0.38 mmol) in NH4Cl solution (1.0 mL) and ethanol (4.0 mL) was stirred at 70 °C for 1 h. After cooling, the resulting mixture was filtered, and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 0% to 20% ethyl acetate in petroleum ether to give 64L (9.0 mg, 57%) as a white solid. LCMS (ESI): m / z = 362.9 [M+H] + .

[1093]

[1094] To a mixture of 64L (9.00 mg, 0.025 mmol), (2-(dimethylphosphoryl)pyrimidin-5- yl)boronic acid (20.0 mg, 0.10 mmol) in 1,4-dioxane (1.0 mL) and water (0.2 mL) was added K2CO3 (11.00 mg, 0.08 mmol) and Xphos Pd G2 (2.0 mg, 0.0026 mmol) at 25 °C under nitrogen and stirring. The resulting mixture was stirred at 110 °C under nitrogen for 1 h. The reaction mixture was diluted with water (1.0 mL). The resulting mixture was extracted with ethyl acetate (5 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase column eluted with acetonitrile / 0.1% aqueous FA solution (0%~70%) to give (5-((1aR,13aS)-5-(difluoromethoxy)-1a,6,13,13a-tetrahydro-1H- benzo[f]benzo[4,5]imidazo[1,2-a]cycloprop[d]azin-9-yl-13,13-d2)pyrimidin-2-yl)dimethyl phosphine oxide (EX64) (2.0 mg, yield 17%) as a white solid. LCMS (ESI): m / z = 483.0 [M+H] + ; 1 H NMR (400 MHz, MeOD-d4) δ 9.33 & 9.22 (s, 2H), 8.47 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.37–7.33 (m, 1H), 7.16–7.03 (m, 3H), 5.81 (d, J = 16.0 Hz, 1H), 5.83 (d, J = 16.0 Hz, 1H), 3.61–3.57 (m, 1H), 2.31–2.26 (m, 1H), 1.99 (s, 3H), 1.96 (s, 3H), 1.61–1.53 (m, 1H), 0.98–0.92 (m, 1H).

[1095] Example 65

[1096]

[1097] A mixture of 2-bromo-6-(difluoromethoxy)benzonitrile (65A) (3.00 g, 12.10 mmol), (E)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)but-3-en-l- yl)oxy)silane (46A) (3.02 g, 9.67 mmol), Pd(dppf)Cl2(88 mg, 0.12 mmol) and K2CO3(5.01 g, 36.29 mmol) in dioxane (40 mL) and water (10 mL) was stirred at 90 °C under nitrogen for 16 h. After cooling, the resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (silica gel 100 mesh, petroleum ether: ethyl acetate, 0%~10%) to give 65B (3.50 g, yield 82%) as a yellow solid. 1 H NMR (400 MHz, MeOD-d4) δ 7.63 - 7.55 (m, 2H), 7.23 - 6.83 (m, 2H), 6.76 (d, J = 16.0 Hz, 1H), 6.66 - 6.59 (m, 1H), 3.83 - 3.80 (m, 2H), 2.53 - 2.48 (m, 2H), 0.90 (s, 9H), 0.08 (s, 6H).

[1098]

[1099] To a mixture of sodium 2-chloro-2,2-difluoroacetate (15.10 g, 99.01 mmol) in diethylene glycol dimethyl ether (200 mL) was added a solution of (E)-2-(4-((tert- butyldimethylsilyl)oxy)but-l-en-l-yl)-6-(difluoromethoxy)benzonitrile (65B) (3.5 g, 9.90 mmol) in diethylene glycol dimethyl ether (35 mL) dropwise. The resulting mixture was stirred at 180 °C for 1 h. The mixture was cooled to room temperature. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC ((Waters 3767 / QDA) column: Sunfire Sunfire C18, 19*250mm*10pm; flow rate: 20 mL / min; mobile phase A: 0.05% TFA / water, B: acetonitrile; gradient: 87%~95%; retention time: 8.9~9.7 min, total 17 min) to give 65C (400 mg, yield 10%) as a white solid. LCMS (ESI): m / z = 404.2 [M+H] + .

[1100]

[1101] To a solution of 2-(3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2,2- difluorocyclopropyl)-6-(difluoromethoxy)benzonitrile (65C) (400 mg, 0.99 mmol) and nickel dichloride (128 mg, 0.99 mmol) in MeOH (10 mL) was added sodium borohydride (375 mg, 9.91 mmol) in portions at 0 °C with stirring. The resulting mixture was stirred at 50 °C for 16 h. The mixture was cooled to room temperature. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The residue was purified by C18 column with acetonitrile / water (0.1% TFA) = 5%~95% elution to give 65D (120 mg, yield 41%) as a white solid. LCMS (ESI): m / z = 294.2 [M+H] + .

[1102]

[1103] A solution of 65D (120 mg, 0.41 mmol), tert-butyl (1-(5-(3-fluoro-4- nitrophenyl)pyrimidin-2-yl)cyclobutyl)carbamate (II) (191 mg, 0.49 mmol) and DIEA (159 mg, 1.23 mmol) in DMSO (2 mL) was stirred at 120 °C for 2 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC with acetonitrile: water (0.1% TFA) = 5%~95% elution to give 65E (120 mg, yield 44%) as a white solid. LCMS (ESI): m / z = 662.4 [M+H] + .

[1104]

[1105] To a mixture of 65E (120 mg, 0.18 mmol) and sodium bicarbonate (45.71 mg, 0.54 mmol) in DCM (2.0 mL) was added Dess-Martin periodinane (115 mg, 0.27 mmol). The mixture was stirred at 25 °C for 1 h. The resulting mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluted with petroleum ether: ethyl acetate (0%~30%) to give 65F (60 mg, yield 50%) as a yellow oil. LCMS (ESI): m / z = 660.4 [M+H] + .

[1106]

[1107] A mixture of 65F (60 mg, 0.09 mmol) and iron powder (50.94 mg, 0.91 mmol) in NH4Cl solution (0.5 mL) and ethanol (2.0 mL) was stirred at 70 °C for 1 h. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluted with petroleum ether: ethyl acetate (0%~50%) to give 65G (30 mg, yield 54%) as a yellow solid. LCMS (ESI): m / z = 610.4 [M+H] + .

[1108]

[1109] To a solution of 65G (30 mg, 0.05 mmol) in DCM (1.0 mL) was added TFA (0.2 mL) under stirring. The mixture was stirred at 25 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC ((Waters 3767 / QDA, Column: XBridge, Xbridge C18 19*250mm*10μm; Flow rate: 20 mL / min; Mobile phase: A: 0.05% NH3H2O / H2, B: Acetonitrile; Gradient: 47%~57%; Retention time: 6.8~7.7 min, Total time 17 min)) to give the target product (EX65) (3.96 mg, yield 16%) as a white solid. LCMS: m / z = 510.1 [M+H] + . 1H NMR (400 MHz, MeOD) δ 9.16 - 9.04 (m, 2H), 7.74 - 7.16 (m, 6H), 6.08 - 5.34 (m, 2H), 3.95 - 3.91 (m, 1H), 3.44 - 3.38 (m, 1H), 2.87 - 2.74 (m, 2H), 2.62 - 2.60 (m, 1H), 2.38 - 2.24 (m, 2H), 2.29 - 2.10 (m, 2H), 1.88 - 1.86 (m, 1H), 1.60 - 0.88 (m, 1H).

[1110] Example 66

[1111]

[1112] To a solution of compound 46A (2.0 g, 4.42 mmol) and di-tert-butyl (2-bromo-6- (difluoromethoxy)benzyl) iminodicarbonate (1.66 g, 5.31 mmol) in dioxane (20.0 mL) and water (4.00 mL) was added Pd(dppf)Cl2(323.56 mg, 442.20 μmol) and Cs2CO3(4.32 g, 13.27 mmol). The mixture was stirred at 90 °C under nitrogen for 2 hours. The reaction was extracted with ethyl acetate (30 mL x 3) and water (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel fast column, eluent of 0%~5% ethyl acetate / petroleum ether, gradient elution, rate of 30 mL / min) to give compound 66A (2.4 g, yield 97.3%) as a yellow solid. 40g silica gel fast column, eluent of 0%~5% ethyl acetate / petroleum ether, gradient elution, rate of 30 mL / min) to give compound 66A (2.4 g, yield 97.3%) as a yellow solid. 1 H NMR (400 MHz, CDCl3-d) δ ppm 7.16-7.26 (m, 2H), 7.00 (d, J=7.15 Hz, 1H), 6.78 (d, J=15.62 Hz, 1H), 6.29-6.70 (m, 1H), 6.04 (dt, J=15.59, 7.11 Hz, 1H), 4.93 (s, 2H), 3.69-3.80 (m, 2H), 2.43 (qd, J=6.83, 1.31 Hz, 2H), 1.40 (s, 18H), 0.91 (s, 9H), 0.06-0.13 (m, 6H). LCMS: m / z = 558.3 (M+H) + .

[1113]

[1114] To a solution of compound 66A (2.40 g, 4.30 mmol) and TEBAC (127.42 mg, 559.40 μmol) in chloroform (294.86 g, 2.47 mol, 198.69 mL) was added NaOH solution (4.30 mmol, 100 mL). The mixture was stirred at 25 °C for 2 hours. The reaction was extracted with DCM (100 mL x 3) and water (200 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel fast column, eluent: 0%~10% ethyl acetate / petroleum ether, gradient elution, speed: 50 mL / min) to give compound 66B (2.4 g, yield 97.31%) as a yellow oil. 80g silica gel fast column, eluent: 0%~20% ethyl acetate / petroleum ether, gradient elution, speed: 60 mL / min) to give compound 66C (1.5 g, yield 85.36%, purity 98.19%) as a yellow oil. LCMS: m / z = 526.3 (M+H) 1 HNMR: (400 MHz, CHLOROFORM-d) δ ppm 7.21 (d, J = 7.78 Hz, 1H), 7.09 (d, J = 8.03 Hz, 1H), 7.01 (d, J = 7.78 Hz, 1H), 6.27-6.73 (m, 1H), 5.28 (d, J = 15.06 Hz, 1H), 4.75 (d, J = 15.06 Hz, 1H), 3.77-3.95 (m, 2H), 2.95 (d, J = 8.03 Hz, 1H), 2.08 (br dd, J = 6.15, 3.89 Hz, 2H), 1.82-1.93 (m, 1H), 1.45 (s, 18H), 0.93 (s, 9H) 0.10 (d, J = 3.01 Hz, 6H). LCMS: m / z = 662.2 (M+Na) + .

[1115]

[1116] To a solution of compound 66B (2.10 g, 3.28 mmol) in DCM (30.0 mL) was added TBAF (1.0 M, 9.83 mL). The mixture was stirred at 25 °C for 2 hours. The reaction was extracted with ethyl acetate (90 mL x 3) and water (100 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel fast column, eluent: 0%~20% ethyl acetate / petroleum ether, gradient elution, speed: 60 mL / min) to give compound 66C (1.5 g, yield 85.36%, purity 98.19%) as a yellow oil. LCMS: m / z = 526.3 (M+H) 80g silica gel fast column, eluent: 0%~20% ethyl acetate / petroleum ether, gradient elution, speed: 60 mL / min) to give compound 66C (1.5 g, yield 85.36%, purity 98.19%) as a yellow oil. LCMS: m / z = 526.3 (M+H) + ; 1H NMR: (400 MHz, CDCI3-d) δ ppm 7.20-7.26 (m, 1 H), 7.10 (d, J = 7.99 Hz, 1 H), 6.99 (d, J = 7.75 Hz, 1 H), 6.30-6.71 (m, 1 H), 5.28 (d, J = 15.14 Hz, 1 H), 4.75 (d, J = 15.02 Hz, 1 H), 3.83-4.01 (m, 2 H), 3.00 (d, J = 8.11 Hz, 1 H), 2.06-2.21 (m, 2 H), 1.90-2.01 (m, 1 H), 1.45 (s, 18 H).

[1117]

[1118] To a mixture of 66C (220 mg, 0.42 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuum to give crude 66D (200 mg), which was used directly in the next step reaction without further purification. LC-MS: m / z = 326.0 [M+H] + .

[1119]

[1120] A mixture of 66D (200 mg, crude), (5-(3-fluoro-4-nitrophenyl)pyrimidin-2-yl)dimethyl phosphine oxide (120 mg, 0.41 mmol) and DIPEA (517 mg, 4.0 mmol) in ethanol (4 mL) was stirred at 70 °C for 4 hours. The reaction was quenched with water (20 mL) and extracted with DCM (30 mL x 3). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / CH3OH (10:1) to give 66E (140 mg, 55.6% yield over two steps). LC-MS: m / z = 601.2; 603.2 [M+H] + .

[1121]

[1122] To a mixture of 66E (140 mg, 0.23 mmol) in DCM (3 mL) was added Dess-Martin periodinane (292.7 mg, 0.69 mmol) at 0 °C with stirring. The mixture was stirred at 25 °C for 4 hours. The reaction was quenched with water (200 mL) and extracted with DCM (30 mL x 3). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude 66F (140 mg) was used directly in the next step reaction without further purification.

[1123]

[1124] A mixture of 66F (140 mg, crude), Fe (64.23 mg, 1.15 mmol) and NH4CI (123.03 mg, 2.30 mmol) in ethanol (10.0 mL) and water (1.0 mL) was stirred at 75 °C for 20 min. The reaction was quenched with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude product was further purified by prep-HPLC (acetonitrile (0.1% FA) / water (0.1% FA) = 5%~75%) to give the target product (EX66) (30 mg, 23.5% yield over two steps). LC-MS: m / z = 548.8 [M+H] + ; 1 H NMR (400 MHz, MeOD-d4) δ 9.24 (s, 2H), 7.93 - 7.78 (m, 3H), 7.49 (t, J = 8.0 Hz, 1H), 7.43 - 7.04 (m, 3H), 6.15 (d, J = 17.6 Hz, 1H), 5.85 (d, J = 17.2 Hz, 1H) 4.29 - 4.18 (m, 1H), 3.56 - 3.48 (m, 1H), 2.89 - 2.79 (m, 1H), 2.16 - 2.09 (m, 1H), 1.98 (s, 3H), 1.94 (s, 3H).

[1125] Example 67-A and Example 67-B

[1126]

[1127] To a solution of but-3-yn-1-ol (67A) (140.00 g, 2.0 mol) in DCM (1.50 L) was added imidazole (204.0 g, 3.0 mol) and TBDPSC1 (659 g, 2.4 mol) at 0 °C with stirring. The resulting mixture was stirred at room temperature for 16 h. The mixture was diluted with water (1.00 L) and extracted with DCM (1.00 L x 3). The combined organic phase was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0% ethyl acetate in petroleum ether to give (but-3-yn-1-yloxy)(tert-butyl)diphenylsilane (67B) (580.0 g, 94% yield) as a colorless oil. 1H NMR (400 MHz, CDC13) δ 7.70 - 7.65 (m, 4H), 7.46 - 7.35 (m, 6H), 3.78 (t, J = 7.2 Hz, 2H), 2.47 - 2.43 (m, 2H), 1.94 (t, J = 2.8 Hz, 1H), 1.06 (s, 9H).

[1128]

[1129] To a mixture of 67B (580.0 g, 1882.1 mmol) in THF (4350 mL) was added n-BuLi (2.5 M in hexane, 1885 mL, 4705 mmol) at -78 °C under nitrogen and stirring. After the mixture was stirred at -78 °C for 1 h, MeI (580.00 mL, 9411.00 mmol) was added to the reaction mixture by syringe. The mixture was stirred at -78 °C to room temperature for 16 h. The reaction was quenched with saturated NH4Cl solution (1000 mL). The aqueous phase was extracted with ethyl acetate (1000 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified by silica gel column chromatography eluted with petroleum ether to give tert-butyl(penta-3-yn-1-yloxy)diphenylsilane (67C) (600.0 g, yield 98%) as colorless oil. 1 H NMR (400 MHz, CDC13) δ 7.70 - 7.65 (m, 4H), 7.46 - 7.35 (m, 6H), 3.78 (t, J = 7.2 Hz, 2H), 2.47 - 2.43 (m, 2H), 1.94 (t, J = 2.8 Hz, 1H), 1.06 (s, 9H).

[1130]

[1131] A mixture of CuCl (9.22 g, 93.17 mmol), PPh3(29.29 g, 111.80 mmol) and t-BuOK (41.74 g, 372.67 mmol) in THF (900 mL) was stirred at room temperature under nitrogen for 0.5 h. Then a solution of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (946.58 g, 3726.70 mmol) in THF (1800.0 mL) was added to the reaction mixture by syringe under nitrogen. The resulting mixture was stirred at room temperature for 0.5 h, then a solution of 67C (600.0 g, 1863.35 mmol) in MeOH (151 mL) and THF (900 mL) was added to the reaction mixture by syringe under nitrogen. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with saturated NH4Cl solution (1000 mL) and extracted with ethyl acetate (1000 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0% to 5% ethyl acetate in petroleum ether to give (Z)-tert-butyldiphenyl((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pent-3-en-l- yl)oxy)silane (67D) (600 g, yield 72%) as a colorless oily product. 1 H NMR (400 MHz, CDC13) δ 7.68 - 7.64 (m, 4H), 7.39 - 7.32 (m, 6H), 6.28 (t, J = 7.2 Hz, 1H), 3.76 - 3.59 (m, 2H), 2.50 - 2.38 (m, 2H), 1.65 (s, 3H), 1.28 (s, 12H), 1.04 (s, 9H).

[1132]

[1133] To a solution of 67D (600.0 g, 1332.50 mmol) in DCM (7500 mL) was added diethylzinc (6662.50 mL, 6662.50 mmol) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 0.5 h, and diiodomethane (540.00 mL, 6662.50 mmol) and trifluoroacetic acid (510.0 mL, 6662.50 mmol) were added to the reaction mixture by syringe. The mixture was stirred at room temperature for 2 h. The reaction was quenched with water (1000 mL). The solid was filtered off and the filtrate was separated. The aqueous phase was extracted with DCM (1000 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude tert-butyl (2-(2-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)ethoxy)diphenylsilane (67E) (one pair of racemic mixture, 500.0 g) as a yellow oil. The crude product was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.69-7.65 (m, 4H), 7.44-7.32 (m, 6H), 3.79-3.68 (m, 2H), 1.74-1.51 (m, 2H), 1.23-1.08 (m, 12H), 1.05 (s, 9H), 1.00-0.94 (m, 4H), 0.82-0.78 (m, 1H), -0.01--0.05 (m, 1H).

[1134]

[1135] To a solution of TBAF in THF (1.0 M, 1077 mL, 1077 mmol) was added 67E (500.0 g, 1076.91 mmol). The mixture was stirred at 40 °C for 16 h. The mixture was diluted with water (1000 mL) and extracted with ethyl acetate (1000 mL x 3). The combined organic layers were dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with petroleum ether / ethyl acetate (7 / 1) to give the product 2-(2-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)ethan-1-ol (67F) (130.00 g, yield 53.4%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 3.78-3.71 (m, 2H), 1.81-1.74 (m, 1H), 1.53-1.44 (m, 1H), 1.21 (s, 12H), 1.04 (s, 3H), 0.94-0.88 (m, 2H), 0.09-0.04 (m, 1H).

[1136]

[1137] To a mixture of 67F (130.0 g, 574.79 mmol) and sodium bicarbonate (241.41 g, 2873.94 mmol) in DCM (1500 mL) was added Dess-Martin periodinane (365.6 g, 862.18 mmol) under stirring. The mixture was stirred at room temperature for 16 h. The reaction was quenched with water (500.0 mL). The solid was filtered off and the filtrate was separated. The aqueous phase was extracted with DCM (500 mL x 3). The combined organic phase was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with petroleum ether / ethyl acetate (10 / 1) to give 2-(2-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl)acetaldehyde (67G) (100.00 g, yield 77.6%) as a yellow oil. 1 H NMR (400 MHz, CDC13) δ 9.82 (t, J = 2.0 Hz, 1H), 2.54 - 2.27 (m, 2H), 1.23 (s, 12H), 1.08 - 0.96 (m, 5H), 0.17 - 0.11 (m, 1H).

[1138]

[1139] A mixture of 16C (100.0 g, 265.97 mmol) and 2-(2-methyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)cyclopropyl)acetaldehyde (67G) (100.00 g, 446.11 mmol) in DMF (50.0 mL) was stirred at 70 °C for 16 h. The reaction mixture was diluted with water (500 mL). The mixture was extracted with ethyl acetate (500 mL x 3). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with petroleum ether / ethyl acetate (3 / 1) to give l-(2-bromo-6-(difluoromethoxy)benzyl)-6-chloro-2-((2-methyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)cyclopropyl)methyl)-lH-benzo[d]imidazole (67H) (54.00 g, yield 35.0%) as a yellow solid. LCMS (ESI): m / z = 583.2 [M+H+2] + .

[1140]

[1141] To a mixture of 67H (54.0 g, 93.09 mmol) in a mixture of dioxane (2160 mL) and water (540 mL) was added CataCXium APd G3 (6779.2 mg, 9.31 mmol) and Cs2C03(91.04 g, 279.26 mmol) at room temperature with stirring. The resulting mixture was stirred at 90 °C for 16 h under argon. The reaction mixture was diluted with water (500 mL). The mixture was extracted with ethyl acetate (500 mL x 3). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with petroleum ether / ethyl acetate (1 / 1) to give racemic 9-chloro-5-(difluoromethoxy)-1a-methyl-1a,6,13,13a-tetrahydro-1H- benzo[f]benzo[4,5]imidazo[1,2-a]cycloprop[d]azepine (67I) (racemic mixture, 13.30 g, yield 38.2%) as a yellow solid. The racemic mixture was separated by SFC (column: OD, 250*40 mm 10 pm; mobile phase A: C02, mobile phase B: MeOH (methanol containing 0.1% 7.0 mol / L ammonia water); flow rate: 140 mL / min; gradient: 20% mobile phase B isocratic elution; wavelength: 214 nm) to give (1aR,13aS)-9-chloro-5-(difluoromethoxy)-1a-methyl-1a,6,13,13a-tetrahydro-1H- benzo[f]benzo[4,5]imidazo[1,2-a]cycloprop[d]azine (67J) (peak 1, retention time 2.168 min, 4600 mg) and (1aS,13aR)-9-chloro-5-(difluoromethoxy)-1a-methyl-1a,6,13,13a-tetrahydro-1H- benzo[f]benzo[4,5]imidazo[1,2-a]cycloprop[d]azine (67K) (peak 2, retention time 2.838 min, 5500.0 mg), both as yellow solids.

[1142]

[1143] A mixture of 67J (20 mg, 0.05 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bis(l,3,2-dioxaborinane) (27.10 mg, 0.11 mmol), Xphos (4.77 mg, 0.01 mmol), Pd2(dba)3(4.89 mg, 0.005 mmol), Xphos Pd G2 (8.39 mg, 0.01 mmol), KOAc (15.71 mg, 0.16 mmol) in 1,4-dioxane (1 mL) was stirred at 110 °C for 2 h under argon. The reaction was quenched with water (10 mL) and extracted with DCM (6 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1 / 1) to give the product 67L (20.0 mg, 80.2% yield). LC-MS: m / z = 467.1 [M+H] + .

[1144]

[1145] A mixture of 67J (20.00 mg, 0.05 mmol), (2-(dimethylphosphoryl)pyrimidin-5- yl)boronic acid (27.00 mg, 0.13 mmol), Xphos PdG2 (4.00 mg, 0.005 mmol) and K2CO3 (22.00 mg, 0.15 mmol) in dioxane (1.6 mL) and water (0.4 mL) was stirred at 90 °C for 1 h under argon. After cooling, the resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. The resulting mixture was concentrated under vacuum. The residue was purified by C18 column eluting with acetonitrile: water (containing 0.1% formic acid) = 5% ~ 95% to give the target product EX67-A (8.0 mg, 30.3% yield) as a white solid. LC-MS: m / z = 495.3 [M+H]+; 1 H NMR (400 MHz, MeOD-d4) δ 9.24 (s, 2H), 7.86 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.24 - 7.00 (m, 4H), 6.09 - 5.81 (m, 2H), 3.95 - 3.89 (m, 1H), 3.21 - 3.14 (m, 1H), 1.97 (s, 3H), 1.93 (s, 3H) 1.49 - 1.46 (m, 1H), 1.08 (t, J = 4 Hz, 1H), 0.46 (s, 2H), 0.00 (s, 3H).

[1146]

[1147] A mixture of 67K (20.00 mg, 0.05 mmol), (2-(dimethylphosphoryl)pyrimidin-5- yl)boronic acid (27.00 mg, 0.13 mmol), Xphos Pd G2 (4.00 mg, 0.005 mmol) and K2CO3 (22.00 mg, 0.15 mmol) in dioxane (1.6 mL) and water (0.4 mL) was stirred at 90 °C under argon for 1 h. After cooling, the resulting mixture was diluted with water (5 mL). The resulting mixture was extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4. The resulting mixture was concentrated in vacuum. The residue was purified by C18 column eluted with acetonitrile: water (containing 0.1% formic acid) = 5% ~ 95% to give the target product (EX67-B) (8 mg, yield 30.3%) as a white solid. LC-MS: m / z = 495.3 [M+H] + . 1 H NMR (400 MHz, MeOD) d 9.24 (s, 2H), 7.87 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.41 - 6.98 (m, 4H), 6.08 (d, J = 16.4 Hz, 1H), 5.85 (d, J = 17.2 Hz, 1H), 3.96 - 3.89 (m, 1H), 3.21 - 3.14 (m, 1H), 1.97 (s, 3H) 1.93 (s, 3H) 1.49 - 1.46 (m, 1H), 1.14 - 1.04 (m, 1H), 0.46 (s, 3H).

[1148] Example 68

[1149]

[1150] To a solution of 1 -methyl-3-oxocyclobutane-1 -carbonitrile (68A) (12 g, 109.96 mmol) in THF (700 mL) was added (R)-2-methylpropane-2-sulfinamide (13.33 g, 109.96 mmol) followed by Ti(OEt)4(1.8 mL, 8.7 mmol). The reaction mixture was stirred at 75 °C for 16 h under nitrogen. The reaction mixture was cooled to room temperature. The reaction was quenched by the addition of saturated aqueous NaHC03solution (1000 mL). The resulting mixture was filtered through celite. The filtrate was extracted with ethyl acetate (500 mL x 3). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (silica gel 100 mesh, petroleum ether: ethyl acetate, 0% to 20%) to give (R)-N-(3-cyano-3-methylcyclobutylidene)-2-methylpropane-2-sulfinamide (68B) (15 g, yield 64%) as a white solid. LCMS: m / z = 212.9 [M+H] + .

[1151]

[1152] To a solution of 5-bromo-2-iodopyrimidine (11.27 g, 39.56 mmol) in DCM (300 mL) was added dropwise n-butyllithium (15.8 mL, 2.5 M) at -78 °C under argon. The mixture was stirred at -78 °C for 30 min and a solution of 68B (7.0 g, 32.97 mmol) in DCM (70 mL) was added. The reaction mixture was stirred at -78 °C for 1 h, then allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with aqueous NH4CI solution (500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 100 mesh, petroleum ether: ethyl acetate, 0% to 50%) to give the product (trans / cis mixture, 840 mg, yield 6.86%) as a yellow solid. The trans / cis mixture was separated by prep-SFC (Chiralpak® IC column: AD, 250*30 mm 10 pm; mobile phase A: supercritical CO2, mobile phase B: ethanol (ethanol containing 0.1% 7.0 mol / L ammonia water); flow rate: 120 ml / min; gradient: 15% mobile phase B isocratic elution; wavelength: 214 nm; RT1 : 1.37 min; RT2: 2.46 min) to give (R)-N-((1s,3S)-1-(5-bromopyrimidin-2-yl)-3-cyano-3- methylcyclobutyl)-2-methylpropane-2-sulfmide (68C) (peak 1, 550 mg) and (R)-N-((1r,3R)-1-(5-bromopyrimidin-2-yl)-3-cyano-3-methylcyclobutyl)-2- methylpropane-2-sulfmide (68D) (peak 2, 200 mg) as white solids.

[1153] 68C (cis): 1 H NMR (400 MHz, MeOD-d4) d 8.88 (s, 2H), 3.13 (d, J = 12.8 Hz, 1H), 3.08 - 2.96 (m, 2H), 2.81 - 2.75 (m, 1H), 1.48 (s, 3H), 1.27 (s, 9H). NMR data for 68C as shown. Figure 4

[1154] 68D (trans): 1 H NMR (400 MHz, MeOD-d4) d 8.94 (d, J = 5.2 Hz, 2H), 3.56 - 3.50 (m, 1H), 3.41 - 3.34 (m, 1H), 2.75 - 2.66 (m, 2H), 1.65 (s, 3H), 1.19 (s, 9H). NMR data for 68D as shown. Figure 5

[1155]

[1156] ​​A mixture of 67L (20.0 mg, 0.04 mmol), (R)-N-((1s,3S)-1-(5-bromopyrimidin-2-yl)-3- cyano-3-methylcyclobutyl)-2-methylpropane-2-sulfmide (68C) (19.1 mg, 0.05 mmol), Xphos Pd G2 (6.8 mg, 0.008 mmol) and K2CO3 (17.8 mg, 0.13 mmol) in 1,4-dioxane (1 mL) and water (0.2 mL) was stirred at 110 °C for 2 h under argon. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC ((Waters 3767 / QDA) Column: Agilent C18, 19*250mm*10μm; Flow rate: 20 mL / min. Mobile phase A: 0.1% formic acid / water, B: acetonitrile; Gradient: 42%~52%; Retention time: 8.0~9.5 min, 17 min) to give the target product EX68 (16 mg, yield 59.2%); LC-MS: m / z = 631.0 [M+H] + ; 1 H NMR (400 MHz, MeOD-d4) δ 9.07 (s, 2H), 7.80 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.60 (dd, J = 8.4, 1.2 Hz, 1H), 7.41 - 6.97 (m, 4H), 6.04 (d, J = 17.2 Hz, 1H), 5.83 (d, 17.2 Hz, 1H), 3.97 - 3.87 (m, 1H), 3.21 - 3.02 (m, 4H), 2.90 (d, J = 13.2 Hz, 1H), 2.00 (s, 1H), 1.51 (s, 3H), 1.50 - 1.45 (m, 1H), 1.29 (s, 9H), 1.10 - 1.05 (m, 1H), 0.45 (s, 3H).

[1157] Example 69-A

[1158]

[1159] A solution of EX68 (50.00 mg, 79.27 μmol) in hydrochloric acid / dioxane (1.0 mL) was stirred at room temperature for 5 min. The resulting mixture was concentrated to dryness in vacuo and purified by prep-HPLC eluted with acetonitrile: water (containing 0.1% formic acid) = 5%~95% to give EX69-A (25.30 mg, yield 60.6%) as a white solid. LC-MS: m / z = 527.1 [M+H] + ; 1H NMR (400 MHz, MeOD-d4) δ 9.09 (s, 2H), 7.80 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.41 - 7.35 (m, 1H), 7....

Claims

1. A compound represented by Formula (I), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof; wherein: "*" indicates the position of attachment of L to the phenyl group; nl is 3, 4, or 5; n2 is 0, 1, 2, or 3; n3 is 0, 1, 2, or 3; n2 + n3 = 1, 2, or 3; m2 is 0, 1, 2, 3, or 4; n4 is 0, 1, or 2; n5 is 0, 1, or 2; n4 + n5 = 0, 1, or 2; m3 is independently 0, 1, 2, or 3; n6 is 0 or 1; n7 is 0 or 1; n6 + n7 = 0 or 1; m4 is independently 0, 1, 2, or 3; u is 0, 1, 2, or 3; each of the heterocycloalkyl groups, independently of one another, denotes a heterocycloalkyl group having 1, 2, 3, or 4 heteroatoms, each independently of one another N, O, or S; each of the heteroarylenes, independently of one another, denotes a heteroarylene group having 1, 2, 3, or 4 heteroatoms, each independently of one another N, O, or S; each of the heterocycloalkenyl groups, independently of one another, denotes a heterocycloalkenyl group having 1, 2, 3, or 4 heteroatoms, each independently of one another N, O, or S; and each of the heteroaryl groups, independently of one another, denotes a heteroaryl group having 1, 2, 3, or 4 heteroatoms, each independently of one another N, O, or S.

2. The compound represented by Formula (I) of claim 1, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof; wherein: "*" indicates the position of attachment of L to the phenyl group; nl is 3, 4, or 5; n2 is 0, 1, 2, or 3; n3 is 0, 1, 2, or 3; n2 + n3 = 1, 2, or 3; m2 is 0, 1, 2, 3, or 4; n4 is 0, 1, or 2; n5 is 0, 1, or 2; n4 + n5 = 0, 1, or 2; m3 is independently 0, 1, 2, or 3; n6 is 0 or 1; n7 is 0 or 1; n6 + n7 = 0 or 1; u is 0, 1, 2, or 3; each of the heterocycloalkyl groups, independently of one another, denotes a heterocycloalkyl group having 1, 2, 3, or 4 heteroatoms, each independently of one another N, O, or S; each of the heteroarylenes, independently of one another, denotes a heteroarylene group having 1, 2, 3, or 4 heteroatoms, each independently of one another N, O, or S; each of the heterocycloalkenyl groups, independently of one another, denotes a heterocycloalkenyl group having 1, 2, 3, or 4 heteroatoms, each independently of one another N, O, or S. L is -(CR a R b ) n1 -, -(CR c R d ) n2 -Y1-(CR e R f ) n3 -*, -(CR c R d ) n4 -Y2-(CR e R f ) n5 -* or -(CR c R d ) n6 -Y3-(CR e R f ) n7 -* ; 3. The compound represented by Formula (I) of claim 1, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof; wherein: "*" indicates the position of attachment of L to the phenyl group; nl is 3, 4, or 5; n2 is 0, 1, 2, or 3; n3 is 0, 1, 2, or 3; n2 + n3 = 1, 2, or 3; m2 is 0, 1, 2, 3, or 4; n4 is 0, 1, or 2; n5 is 0, 1, or 2; n4 + n5 = 0, 1, or 2; m3 is independently 0, 1, 2, or 3; n6 is 0 or 1; n7 is 0 or 1; n6 + n7 = 0 or 1; m4 is independently 0, 1, 2, or 3; u is 0, 1, 2, or 3; R a and R b each independently H, deuterium, halogen, -OH, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 haloalkoxy; ​ 0 or 1 -CR a R b - replaced by -Y-; -Y- is m1 is 1, 2, 3, or 4, R y independently deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl, p1 is 0, 1, 2, 3, or 4; R ya and R yb each independently H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl; ​ ​ ​ - Y1- is -CR a1 =CR a2 - or R a1 and R a2 each independently H, halogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 haloalkyl; ​ Ry 1 independently deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, -CN, or C 1-6 alkyl substituted with 1, 2, or 3 deuterium; Ring A is C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; ​ ​ ​ - Y2- is "**" indicates the position of attachment of -Y2- to -(CR e R f ) n5 - of -Y2- to -(CR ​ R y2 independently halogen, deuterium, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl; - Y3- is *** indicates the position of attachment of -Y3- to -(CR e R f ) n7 - of -Y2-; and *** indicates the position of attachment of -Y3- to -(CR e R f ) ​ ​ ​ Ry 3 independently halogen, deuterium, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 haloalkyl; ​ R c and R d each independently is H, deuterium, halogen, -OH, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkyl; R e and R f each independently H, deuterium, halogen, -OH, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkyl; X 1 and X 2 each independently is N or -CR X1 ; R X1 independently H, deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl; is a single or double bond; When X is -C(O)-; X 3 is -C(O)-; X 4 is N or CH; When X is N; X 3 is N; X 4 is C; R 1 and R 2 each independently H, deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -R 3 -R 4 , 5-12 membered heteroaryl or 5-12 membered heteroaryl substituted with 1, 2, or 3 R 2-1 substituents. R 2-1 independently -OH, =0, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -(CR 2a R 2b ) 0-3 NR 2c R 2d or -CONR 2c R 2d ; R 2a , R 2b , R 2c and R 2d are each independently H or C 1-6 alkyl; -R 3 independently are a bond, 5-6 membered heteroarylene or 5-6 membered heteroarylene substituted with 1, 2, or 3 R 3-1 substituted 5-6 membered heteroarylene; R 4 independently C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 5-12 membered heterocycloalkenyl, 5-12 membered heteroaryl, C 6-10 aryl, -C 1-6 alkylene-C 3-12 cycloalkyl, -C 1-6 alkylene-3-12 membered heterocycloalkyl, -C 1-6 alkylene-5-12 membered heterocycloalkenyl, -C 1-6 alkylene-5-12 membered heteroaryl, -C 1-6 alkylene-C 6-10 aryl, -M-C 3-12 cycloalkyl, -M-3-12 membered heterocycloalkyl, -M-5-12 membered heterocycloalkenyl, -M-5-12 membered heteroaryl, -M-C 6-10 aryl, C 3-12 cycloalkyl is substituted with 1, 2, or 3 R 4-1 3-12 membered heterocycloalkyl is substituted with 1, 2, or 3 R 4-2 5-12 membered heterocycloalkenyl is substituted with 1, 2, or 3 R 4-3 -C 1-6 alkylene-C 3-12 cycloalkyl is substituted with 1, 2, or 3 R 4-4 C 1-6 alkylene-3-12 membered heterocycloalkyl is substituted with 1, 2, or 3 R 4-5 -C 1-6 alkylene-5-12 membered heterocycloalkenyl is substituted with 1, 2, or 3 R 4-6 5-12 membered heteroaryl is substituted with 1, 2, or 3 R 4-1 C 6-10 aryl is substituted with 1, 2, or 3 R 4-1 -C 1-6 alkylene-5-12 membered heteroaryl is substituted with 1, 2, or 3 R 4-1 -C 1-6 alkylene-C 6-10 aryl is substituted with 1, 2, or 3 R 4-1 -M-C 3-12 cycloalkyl is substituted with 1, 2, or 3 R 4-1 -M-3-12 membered heterocycloalkyl is substituted with 1, 2, or 3 R 4-1 -M-5-12 membered heterocycloalkenyl is substituted with 1, 2, or 3 R 4-1 -M-5-12 membered heteroaryl is substituted with 1, 2, or 3 R 4-1 -M-C 6-10 aryl is substituted with 1, 2, or 3 R 4-1 or substituted; M is -0-, -S- or -NR 2c -; R 3-1 independently -OH, -CN, halogen, -NR 3a R 3b , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 haloalkyl; R 31 and R 32 each independently is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 haloalkyl; or for wherein Z 1 , Z 2 and Z 3 are each independently -CH2-, -NH-, -O- or -S-; R 33 are each independently halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 haloalkyl; t is 0, 1, 2 or 3; R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-5 , and R 4-6 are independently -OH, -CN, halogen, -NR 3a R 3b , C 1-6 1-6 alkyl, C 1-6 1-6 haloalkyl, C 1-6 1-6 alkoxy, C 1-6 1-6 haloalkoxy, C 3-6 3-12 cycloalkyl, 3-12 heterocycloalkyl, =0, -CO-NR 3a R 3b , -NR 3a -CO-R 3e , -COOR 3f , C 1-6 1-6 alkyl substituted with 1, 2, or 3 R 3 g; R 3a and R 3b Independent of H, deuterium, and C 1-6 Alkyl groups or those with 1, 2, or 3 R groups 3a-1 Replacement C 1-6 Alkyl, wherein R 3a-1 Independently -NH2, -COOH, or -CONH2; R 3c independently H, deuterium, or C 1-6 alkyl; R 3d independently H, deuterium, -NH2, or C 1-6 alkyl; R 3e R is independently -NH2, -COOH or -CONH2; and 3e-1 R is independently -NH2, -COOH or -CONH2; and 1-6 R is independently -NH2, -COOH or -CONH2; and 3e-1 R is independently -NH2, -COOH or -CONH2; and R 3f H, deuterium or C 1-6 alkyl; R 3 g is independently D, -OH, -NR 2c R 2d , C 1-6 alkyl, C 3-6 alkoxy or C 3-6 cycloalkyl; R 3h independently H, halogen, deuterium, or C 1-6 alkyl; R 5 independently C 1-6 alkyl, deuterium, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or halogen; or two adjacent R 5 and the carbon atom to which they are attached join to form a C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 5-1 substituted C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl substituted with 1, 2, or 3 R 5-1 substituted C R 5-1 independently C 1-6 alkyl, deuterium, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or halogen; R 6a and R 6b each independently is H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 haloalkyl; ​ ​ ​ ​ ​ ​ ​ L is -(CR a R b ) n1 - -(CR c R d ) n2 - Y1-(CR e R f ) n3 - -(CR c R d ) n4 - Y2-(CR e R f ) n5 - -(CR c R d ) n6 - Y3-(CR e R f ) n7 - ; ​ R a and R b each independently is H, deuterium, halogen, -OH, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 haloalkoxy; ​ 0 or 1 -CR a R b - replaced by -Y-; -Y- is m1 is 1, 2, 3, or 4, R y independently deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl, p1 is 0, 1, 2, 3, or 4; R ya and R yb each independently H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl; ​ ​ ​ - Y1- is -CR a1 =CR a2 - or R a1 and R a2 each independently H, halogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 haloalkyl; ​ Ry 1 independently deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, -CN, or C 1-6 alkyl substituted with 1, 2, or 3 deuterium; Ring A is C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; ​ ​ ​ - Y2- is "**" indicates the position of attachment of -Y2- to -(CR e R f ) n5 - ​ R y2 independently halogen, deuterium, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl; - Y3- is *** indicates the position of attachment of -Y3- to -(CR e R f ) n7 - ​ ​ ​ R y3 independently halogen, deuterium, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl; m4 is independently 0, 1, 2, or 3; R c and R d each independently H, deuterium, halogen, -OH, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, or C 1-6 alkyl; R e and R f each independently H, deuterium, halogen, -OH, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkyl; X 1 and X 2 each independently is N or -CR X1 ; R X1 independently H, deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl; is a single or double bond; When X is -C(O)-; X 3 is -C(O)-; X 4 is N or CH; When X is N; X 3 is N; X 4 is C; R 1 and R 2 each independently H, deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or -R 3 -R 4 ; -R 3 independently are a bond, 5-6 membered heteroarylene or 5-6 membered heteroarylene substituted with 1, 2, or 3 R 3-1 substituted 5-6 membered heteroarylene; R 4 independently C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 5-12 membered heterocycloalkenyl, -C 1-6 alkylene-C 3-12 cycloalkyl, -C 1-6 alkylene-3-12 membered heterocycloalkyl, -C 1-6 alkylene-5-12 membered heterocycloalkenyl, C 3-12 cycloalkyl is substituted with 1, 2, or 3 R 4-1 3-12 membered heterocycloalkyl is substituted with 1, 2, or 3 R 4-2 5-12 membered heterocycloalkenyl is substituted with 1, 2, or 3 R 4-3 -C 1-6 alkylene-C 3-12 cycloalkyl is substituted with 1, 2, or 3 R 4-4 -C 1-6 alkylene-3-12 membered heterocycloalkyl is substituted with 1, 2, or 3 R 4-5 -C 1-6 alkylene-5-12 membered heterocycloalkenyl is substituted with 1, 2, or 3 R 4-6 or substituted; R 3-1 independently -OH, -CN, halogen, -NR 3a R 3b , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 haloalkyl; R 31 and R 32 each independently is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 haloalkyl; or for wherein Z 1 , Z 2 and Z 3 are each independently -CH2-, -NH-, -O- or -S-; R 33 is independently halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 haloalkyl; t is 0, 1, 2 or 3; R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-5 and R 4-6 are each independently -OH, -CN, halogen, -NR 3a R 3b , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, =0, -CO-NR 3a R 3b , -NR 3a -CO-R 3e , -COOR 3f , C 1-6 alkyl is substituted by 1, 2 or 3 R 3 g; R 3a and R 3b are independently H, deuterium, C 1-6 alkyl or C 3a-1 alkyl substituted with 1, 2, or 3 R 1-6 , wherein R 3a-1 is independently -NH2, -COOH, or -CONH2; R 3c independently H, deuterium, or C 1-6 alkyl; R 3d independently H, deuterium, -NH2, or C 1-6 alkyl; R 3e R is substituted by 1, 2 or 3 R 3e-1 C 1-6 alkyl, wherein R 3e-1 independently -NH2, -COOH or -CONH2; R 3f H, deuterium or C 1-6 alkyl; R 3 g is independently D or -OH; R 5 independently C 1-6 alkyl, deuterium, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or halogen; R 6a and R 6b each independently is H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 haloalkyl; ​ ​ ​ ​ ​ ​ L is -(CR a R b ) n1 -, -(CR c R d ) n2 -Y1-(CR e R f ) n3 -, -(CR c R d ) n4 -Y2-(CR e R f ) n5 -, -(CR c R d ) n6 -Y3-(CR e R f ) n7 - ; ​ R a and R b each independently H, deuterium, halogen, -OH, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 haloalkoxy; ​ 0 or 1 -CR a R b - replaced by -Y-; -Y- is m1 is 1, 2, 3, or 4, R y independently deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl, p1 is 0, 1, 2, 3, or 4; R ya and R yb each independently H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl; ​ ​ ​ - Y1- is -CR a1 =CR a2 - or R a1 and R a2 each independently H, halogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 haloalkyl; ​ R y1 independently deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl; Ring A is C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; ​ ​ ​ - Y2- is "**" indicates the position of attachment of -Y2- to -(CR e R f ) n5 - of -Y2- to -(CR ​ Ry 2 independently halogen, deuterium, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 haloalkyl; - Y3- is *** indicates the position of attachment of -Y3- to -(CR e R f ) n7 - of -Y2-; ​ ​ ​ Ry 3 independently halogen, deuterium, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 haloalkyl; ​ R c and R d each independently H, deuterium, halogen, -OH, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkyl; R e and R f each independently H, deuterium, halogen, -OH, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkyl; X 1 and X 2 each independently is N or -CR X1 ; R X1 independently H, deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 haloalkyl; is a single or double bond; When X is -C(O)-; X 3 is -C(O)-; X 4 is N or CH; When X is N; X 3 is N; X 4 is C; R 1 and R 2 each independently is H, deuterium, halogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or -R 3 -R 4 ; -R 3 independently are a bond, 5-6 membered heteroarylene or 5-6 membered heteroarylene substituted with 1, 2, or 3 R 3-1 substituted 5-6 membered heteroarylene; R 4 independently C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 5-12 membered heterocycloalkenyl, -C 1-6 alkylene-C 3-12 cycloalkyl, -C 1-6 alkylene-3-12 membered heterocycloalkyl, -C 1-6 alkylene-5-12 membered heterocycloalkenyl substituted with 1, 2, or 3 R 4-1 substituted C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 5-12 membered heterocycloalkenyl, -C 4-2 substituted 3-12 membered heterocycloalkyl, -C 4-3 substituted 5-12 membered heterocycloalkenyl, -C 4-4 substituted -C 1-6 alkylene-C 3-12 cycloalkyl, -C 4-5 substituted -C 1-6 alkylene-3-12 membered heterocycloalkyl, or -C 4-6 substituted -C 1-6 alkylene-5-12 membered heterocycloalkenyl; R 3-1 independently -OH, -CN, halogen, -NR 3a R 3b , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 haloalkyl; R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-5 and R 4-6 are each independently -OH, -CN, halogen, -NR 3a R 3b , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or =0; R 3a and R 3b each independently is H, deuterium, or C 1-6 alkyl; R 5 independently C 1-6 alkyl, deuterium, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; R 6a and R 6b each independently H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 haloalkyl; ​ each of said heteroaryloxy groups independently denotes a heteroaryl group having 1, 2, 3 or 4 heteroatoms each independently being N, O or S, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents each independently being halo, haloalkyl, alkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -CN, -ORa, -NRbRc, -C(=O)Ra, -C(=O)ORa, -C(=O)NRbRc, -NRdC(=O)Ra, -NRdC(=O)ORa, -NRdC(=O)NRbRc, -S(O)mRa, -S(O)mORa, -S(O)mNRbRc, -NRS(O)mRa, -NRS(O)mNRbRc, -NRS(O)mORa, -P(=O)(ORa)2, -OP(=O)(ORa)2, -Si(Ra)3, -N3, =O or =S; each of said heteroaryloxy groups independently denotes a heteroaryl group having 1, 2, 3 or 4 heteroatoms each independently being N, O or S, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents each independently being halo, haloalkyl, alkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -CN, -ORa, -NRbRc, -C(=O)Ra, -C(=O)ORa, -C(=O)NRbRc, -NRdC(=O)Ra, -NRdC(=O)ORa, -NRdC(=O)NRbRc, -S(O)mRa, -S(O)mORa, -S(O)mNRbRc, -NRS(O)mRa, -NRS(O)mNRbRc, -NRS(O)mORa, -P(=O)(ORa)2, -OP(=O)(ORa)2, -Si(Ra)3, -N3, =O or =S; each of said heteroaryloxy groups independently denotes a heteroaryl group having 1, 2, 3 or 4 heteroatoms each independently being N, O or S, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents each independently being halo, haloalkyl, alkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -CN, -ORa, -NRbRc, -C(=O)Ra, -C(=O)ORa, -C(=O)NRbRc, -NRdC(=O)Ra, -NRdC(=O)ORa, -NRdC(=O)NRbRc, -S(O)mRa, -S(O)mORa, -S(O)mNRbRc, -NRS(O)mRa, -NRS(O)mNRbRc, -NRS(O)mORa, -P(=O)(ORa)2, -OP(=O)(ORa)2, -Si(Ra)3, -N3, =O or =S; 4. The compound of any one of claims 1-3, represented by Formula (I), solvate, pharmaceutically acceptable salt, or solvate of a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (I). R a and R b each independently H or C 1-6 alkyl; (II). n1 is 3 or 4; (III). m1 is 1; (IV). R y independently halogen; (V). p1 is 2; (VI).R ya and R yb each independently H; (VII). n3 is 0, 1 or 2; (VIII).R a1 and R a2 is H; (IX). m2 is 0, 1 or 2; (X). R y1 halogen, or C 1-6 alkyl; (XI). Ring A is C 3-6 Cycloalkyl; (XII). n4 is 0; (XIII). n5 is 0; (XIV). -Y2- is (XV). m3 is 0; (XVI). - Y3- is (XVII). n6 is 0; (XVIII). n7 is 0; (XIX). m4 is 0; (XX). R c and R d each independently H, halogen, -OH, or C 1-6 alkyl; (XXI).R e and R f each independently H, halogen, -OH, or C 1-6 alkyl; (XXII).R X1 H, or halogen; (XXIII). R 1 H, halogen, C 1-6 alkyl, or -R 3 -R 4 ; preferably, R 1 independently H, halogen or C 1-6 alkyl; (XXIV). R 2 H, halogen or -R 3 -R 4 ; (XXV).-R 3 independently a bond, or 5-6 membered heteroarylene; (XXVI). R 4 independently 3-12 membered heterocycloalkyl, C 3-12 cycloalkyl is substituted by 1, 2 or 3 R 4-1 heteroaryl is substituted by 1, 2 or 3 R 4-3 preferably -R 3 -R 4 is -R 4 , (XXVII).R 4-1 and R 4-3 each independently is -NR 3a R 3b , C 1-6 alkyl or =0; (XXVIII).R 3a and R 3b each independently H; (XXIX). R 5 independently C 1-6 alkyl or C 1-6 haloalkoxy; (XXX). R 6a is H; (XXXI). R 6b H or C 1-6 alkyl; and (XXXII). u is 0, 1, 2.

5. The compound of claim 1 or 2, represented by Formula (I), solvate, pharmaceutically acceptable salt, or solvate of a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (I). m2 is 0, 1, 2 or 3; (II). R y1 independently deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -CN, or C 1-6 alkyl is substituted with 1, 2, or 3 deuterium; (III). R c and R d independently H, deuterium, halogen, -OH, or C 1-6 alkyl; (IV). R 4 independently 3-12 membered heterocycloalkyl, C 3-12 cycloalkyl is substituted by 1, 2 or 3 R 4-1 substituted, 3-12 membered heterocycloalkyl is substituted by 1, 2 or 3 R 4-2 substituted, 5-12 membered heterocycloalkenyl is substituted by 1, 2 or 3 R 4-3 substituted, preferably R 4 is or (V).R 5 independently C 1-6 alkyl, C 1-6 haloalkoxy or halogen; (VI).R 6a H or deuterium; (VII).R 6b is H; and (VIII).R 31 and R 32 each independently is C 1-6 alkyl.

6. The compound of claim 1, represented by Formula (I), solvate, pharmaceutically acceptable salt, or solvate of a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (I). n2 is 1; (II). n3 is 0; (III). n3 is 1; (IV). m2 is 1; (V). - Y1- is (VI). A ring is cyclopropyl; (VII).R y1 independently C 1-6 alkyl, preferably R y1 is methyl; (VIII).R c and R d is H; (IX). R e and R f is H; (X). R 2 R is -R 3 R is -R 4 , 5-12 membered heteroaryl, or 5-12 membered heteroaryl substituted with 1, 2, or 3 R 2-1 substituents; (XI). R 2-1 independently -OH, =0, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, -(CR 2a R 2b ) 0-3 NR 2c R 2d or -CONR 2c R 2d ; (XII). M is -O-, or -NH-; (XIII). R 5 is C 1-6 haloalkoxy; and (XIV). u is 1.

7. The compound of any one of claims 1-3, represented by Formula (I), solvate, pharmaceutically acceptable salt, or solvate of a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (I). each halo is independently F, Cl, Br or I, preferably each halo is F; (II). each C 1-6 alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, preferably each C 1-6 alkyl is methyl; (III). each C 3-6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably each C 3-6 cycloalkyl is cyclopropyl or cyclobutyl; (IV). R 3 5-6 membered heteroaryl is a 5-6 membered aromatic ring containing carbon atoms and 1, 2, 3, or 4 heteroatoms selected from N, O, and S, wherein the N and S are independently selected from NH, S, and oxo; (V).R 4 3-12 membered heterocycloalkyl as described in the definition of R 4 3-12 membered heterocycloalkyl as described in the definition of R 3-12 membered heterocycloalkyl as described in the definition of R (VI). Preferably R 4 3-12 membered heterocycloalkyl in R1is 3-12 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N and O; (VII).R 4 5-12 membered heterocycloalkenyl in (VII) is 5-6 membered heterocycloalkenyl; and (VIII).R 4 5-12 membered heterocycloalkenyl in (VIII) is a 5-12 membered heterocycloalkenyl having 1 or 2 heteroatoms independently selected from N.

8. The compound of claim 1 or 2, represented by Formula (I), solvate, pharmaceutically acceptable salt, or solvate of a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (I). R 3 5-6 membered heteroaryl is pyridyl or pyrimidinyl; (II). R 4 3-12 membered heterocycloalkyl in R1is (III). R 4 5-12 membered heterocycloalkenyl in (III) is (IV). In R 4 egarding (V). In R 4 egularly 9. The compound of claim 1, represented by Formula (I), solvate, pharmaceutically acceptable salt, or solvate of a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (I). R 4 3-12 membered heterocycloalkyl as described in the definition of R 4 3-12 membered heterocycloalkyl as described in the definition of R (II).R 4 5-12 membered heterocycloalkenyl in (III). R 1 and the 5-12 membered heteroaryl in R 2 1 2 ​​​ (IV). R 4 5-12 membered heteroaryl in (IV) is 5-6 membered heteroaryl; (V). R 4 5-12 membered heteroaryl in R 4 5-12 membered heteroaryl in R and (VI). -R 3 -R 4 is wherein Q1is independently CH or N, and Q2is independently CH2, NH or O.

10. The compound of any one of claims 1-3, represented by Formula (I), solvate, pharmaceutically acceptable salt, or solvate of a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (I).X 1 is CH, CF or N; (II).X 2 is CH, CF or N; (III). is a double bond, X 3 is N; X 4 is C; (IV). R 1 H, F, -CH3, (V). R 2 H, Cl, (VI).R 5 is or CH3, preferably said moiety is more preferably said moiety is "*" represents the position of attachment of L to the phenyl; and (VII). L is " " represents the position of the attachment of L to the phenyl group.

11. The compound of claim 1 or 2, represented by Formula (I), solvate, pharmaceutically acceptable salt, or solvate of a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (I). R 1 is H; (II).X 1 is CH; (III).X 2 is CH; (IV). R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-5 and R 4-6 are each independently -CH3, =0, -CN, -NH2, -CO-NH2, -OH, -CF3, -COOH, (V).-R 3 - is "*4" represents -R 3 - and -R 4 attached at position (VI).R 5 For CH3or F; (VII). L is Preferably one or more of the following conditions are met: (I). R 4 To (II). the portion to be More preferably, R 2 H, Cl, 12. The compound of Formula (I) according to claim 1, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (I). R 2-1 independently -OH, -CH3, -NH2, =0, -CF3, -OCH3, or -CONH2; (II). R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-5 and R 4-6 are each independently -CH3=0, -CN, -NH2, -CO-NH2, -OH, -CF3, -COOH, F, -CONHCH3, -CON(CH3)2, -CH2OCH3, -CH2OH, (III). -R 3 - is (IV). L is Preferably R 4 To More preferably, R 2 is H, Cl, 13. The compound of Formula (I) according to any one of claims 1-3, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof wherein, said compound is represented by Formula (I-1), (I-2), or (I-3): wherein R 1 and R 2 each independently is H, halogen or C 1-6 alkyl; R 3 , R 4 , R 5 , R 6a , R 6b , X 1 , X 2 , X 4 and u are as defined in any one of claims 1 to 12; and "*"a" indicates that when the carbon atom bearing "*"a" is a chiral carbon atom, it is in the R configuration, the S configuration or a mixture thereof.

14. The compound of Formula (I) according to claim 13, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein, the compound of Formula (I-2) is a compound of Formula (I-2-1), (I-2-2), (I-2-3), (I-2-4), (I-2-5), (I-2-6), or (I-2-7): wherein R 1 independently H, halogen or C 1-6 alkyl, R 3 , R 4 , R 5 , R 6a , R 6b , X 1 , X 2 , X 4 and u are as defined in any one of claims 1-12; "*a" represents, when the carbon atom bearing the "*a" mark is a chiral carbon atom, the configuration thereof is R configuration, S configuration, or a mixture thereof; "*b" represents, when the carbon atom bearing the "*b" mark is a chiral carbon atom, the (independently) R configuration, S configuration, or a mixture thereof; "*c" represents, when the carbon atom bearing the "*c" mark is a chiral carbon atom, the (independently) R configuration, S configuration, or a mixture thereof; "*d" represents, when the carbon atom bearing the "*d" mark is a chiral carbon atom, the configuration thereof is R configuration, S configuration, or a mixture thereof; and, "*e" represents, when the carbon atom bearing the "*e" mark is a chiral carbon atom, the configuration thereof is R configuration, S configuration, or a mixture thereof.

15. The compound of Formula (I) according to any one of claims 1-3, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof wherein, said compound is a compound of Formula (I-1-a), (I-1-b), (I-1-c), (I-2-a), (I-2-b), (I-2-c), or (I-3-a): wherein R 1 , R 5 , R a , R b , R c , R d , R e , R f , R 6a , R 6b , X 1 , X 2 , Ry 1 , Ry 2 , m2, m3 and u are as defined in any one of claims 1 to 12; and "*a", "*b", "*c", "*d" and "*e" are as defined in claim 14.

16. The compound of Formula (I) according to claim 14, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, said compound is represented by any one of the following formulas: wherein R 1 , R 3 , R 4 , R 5 , R c , R d , R e , R f , R 6a , R 6b and u are as defined in any one of claims 1-12; and "a" is as defined in claim 14.

17. The compound of Formula (I) according to claim 14, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, said compound is represented by any one of the following formulas: wherein, R 1 , R 3 , R 4 , R 5 , R c , R d , R e , R f , R 6a , R 6b and u are as defined in any one of claims 1-12; and "a" is as defined in claim 14.

18. The compound of Formula (I) according to claim 1, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof said compound is represented by any one of the following formulas: wherein, R 1 , R 2 , R 4 , R 5 , R c , R d , R e , R f , R 6a , R 6b and u are as defined in any one of claims 1 to 12, and "a" is as defined in claim 13.

19. The compound of Formula (I) according to claim 1, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof wherein, said compound of Formula (I) is any one of the following compounds:

20. A compound of Formula (II), Formula (II-A), Formula (II-B), Formula (II-C), Formula (II-D), Formula (II-E), or Formula (II-F) In formula (II), wherein, R 1 , R 5 , R 6a , R 6b , X 1 , X 2 , X 3 , X 4 , u, L and "*a" are as defined in any one of claims 1 to 19; PG1is an amino protecting group; In formula (II-A), wherein R 1 , R 6a , R 6b , X 1 , X 2 and the definition of "a" are as described in any one of claims 1-19; PG1is an amino protecting group; R 5a is halogen; t1is 1, 2 or 3; In formula (II-B), wherein R 1 , R 6a , R 6b , X 1 , X 2 , n2, n3 and the definition of "a" are as described in any one of claims 1 to 19; R 2a is halogen or PG1is an amino protecting group; t2is 0, 1, 2 or 3; t3is 0, 1, 2 or 3, and t2+t3= 1, 2 or 3; In formula (II-C), wherein R 1 , R 6a , R 6b , X 1 , X 2 and the definition of "a" are as described in any one of claims 1-19; PG1is an amino protecting group; R 5a is halogen; t4is 1, 2 or 3; In formula (II-D), wherein R 1 , R 6a , R 6b , X 1 , X 2 , "a", A ring, R 1 , m2 are as defined in any one of claims 1-19; PG1 is an amino protecting group; R 5a is halogen; t5 is 1, 2 or 3; and In formula (II-E), wherein, R 1 , R 6a , R 6b , X 1 , X 2 , "a", A ring, R 1 , m2, n2 and n3 are as defined in any one of claims 1-19; PG1 is an amino protecting group; R 5a is halogen.

21. A compound represented by formula (III), wherein, R 1 , R 5 , R 6a , R 6b , X 1 , X 2 , X 3 , X 4 , u, L and "*a" are as defined in any one of claims 1 to 19; R 2X is halogen, preferably, the compound of Formula (III) is represented by any one of the following formulas: R 2X halogen, More preferably, R 2X Cl, 22. The compound of formula (II), formula (II-A), formula (II-B), formula (II-C), formula (II-D), or formula (II-E) according to claim 20, which satisfies one or more of the following conditions: (I) PG1is Boc; (II) R 5a is Br; and (III) R 2a is Br; Preferably, the compound of formula (II), formula (III), formula (II-A), formula (II-B), formula (II-C), formula (II-D), or formula (II-E) is selected from 23. A pharmaceutical composition comprising a compound of formula (I), solvate thereof, pharmaceutically acceptable salt thereof, or solvate of a pharmaceutically acceptable salt thereof, as defined in any one of claims 1-19, and a pharmaceutically acceptable carrier.

24. Use of a compound of formula (I), solvate thereof, pharmaceutically acceptable salt thereof, or solvate of a pharmaceutically acceptable salt thereof, as defined in any one of claims 1-19, for the manufacture of a TNFα inhibitor.

25. Use of a compound of formula (I), solvate thereof, pharmaceutically acceptable salt thereof, or solvate of a pharmaceutically acceptable salt thereof, as defined in any one of claims 1-19, for the manufacture of a medicament for the treatment and / or prevention of inflammatory and autoimmune diseases.

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