cGAS inhibitors

Abstract

To provide novel cGAS inhibitor compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds and compositions to treat certain pathological conditions such as immune-mediated diseases.SOLUTION: The present invention provides a cGAS inhibitor compound having the formula below.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to novel cGAS inhibitor compounds, pharmaceutical compositions containing the compounds, and methods of using the compounds and compositions to treat certain pathological conditions, such as immune-mediated diseases. [Background technology]

[0002] Cyclic GAMP-AMP synthase (cGAS) is a key cytosolic DNA sensor that catalyzes the formation of 2'3'-cyclic GMP-AMP (cGAMP), a second messenger that binds to Stimulator of interferon genes (STING) and triggers downstream signaling, resulting in the production of proinflammatory cytokines and type I interferons (Ablasser, A. et al. Nature, 2013, 498, 380-384; Sun, L. et al. Science, 2013, 339, 786-791). cGAS recognizes dsDNA and retroviral DNA intermediates (Gao, D. et al. Science, 2013, 341, 903-906) in a non-sequence-specific manner, dimerizes, and activates its nucleotidyl transferase function (Civril, F. et al. Nature, 2013, 498, 332-337), triggering potent antiviral effector functions through interferon signature genes induced by type I interferons. Failure to degrade cytosolic DNA and mitochondrial DNA leakage from cellular stress has also been implicated in pathogenic cGAS activation in diseases such as Aicardi-Goutières syndrome (Gray, E. E. et al. J Immunol, 2015, 195, 1939-1943) and systemic lupus erythematosus (SLE) (Caielli, S. et al. Cell, 2021, 184, 4464-4479). cGAS deficiency rescues the autoimmune phenotype and lethality of TREX1 knockout mice that accumulate DNA in the cytosol, mimicking features of Aicardi-Goutières syndrome (Xiao, N. et al. J Autoimmun, 2019, 100, 84-94). SLE is a heterogeneous disease characterized by widespread loss of tolerance to nuclear antigens such as anti-dsDNA antibodies and a high interferon gene signature.Reduction of interferon gene signatures in clinical trials correlates with symptom improvement, and interferon signature gene panels have been used as both biomarkers and pharmacodynamic markers in SLE clinical trials (Furie, R, et al., J Clin Invest, 2019, 129, 1359-1371; Smith, MA, et al., Sci Rep, 2020, 10, 4462; Tanaka, T. et al., Mod Rheumatol, 2022, 00, 1-11). UV light exposure of the skin has been shown to activate cGAS (Skopelja-Gardner, S. et al. Sci Rep, 2020, 10, 7908), and elevated cGAMP has been reported to be elevated in SLE (An, J. et al. Arthritis Rheumatol, 2017, 69, 800-807). In addition, mitochondrial dysfunction in SLE also promotes cGAS activation (Caielli, S. et al. Cell, 2021, 184, 4464-4479).

[0003] WO 2019 / 153002 discloses 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole inhibitors of cGAS for treating autoinflammatory diseases. WO 2022 / 137085 discloses 2-heteroaryl-1H-indole compounds for treating cGAS-related diseases. However, various preclinical scaffolds have been shown to face barriers such as poor cellular activity, insufficient potency, and / or unfavorable pharmacokinetic properties. Currently, there are no cGAS inhibitors on the market that have been approved as FDA-approved drugs. Ventus Therapeutics announced a cGAS inhibitor development candidate, VENT-03, in January 2023. Despite this, VENT-03 does not appear to have yet entered the clinic at this time. Thus, there remains a need for novel, oral, selective, and / or potent cGAS inhibitors for the treatment of immune-mediated diseases, including cGAS-mediated immune disorders, such as cGAS-mediated aspects of SLE. The present invention provides novel cGAS inhibitors and compositions thereof for use in the treatment of such diseases. Summary of the Invention

[0004] In some embodiments, the present invention provides a compound of formula IIa,

[0005] [ka] During the ceremony, X and R 4 But independently, it is a halo, R 1 , R 7 , R 8 , and R 9 But independently, R b and R 6 is H or F, R 3 But -NH-R bb -OR b , -NHC(O)-R bb -OR b , -NHC(O)-C(O)-NH2 , -NH-R c , -NH-C(O)-R c , -OR c , -OR bb -C(O)NH 2 , -OR bb -OR b , -OR bb -OC(O)-R b , -OR bb -H, -OR bb -CN, -NH-R bb -H, -R bb -OH, -R bb -CN, -NH-R e , -NH-CH 2 -R e or a 5- or 6-membered heteroaryl having 2 or 3 heteroatoms, respectively, wherein the heteroaryl is -NH 2 , -R bb -H or -R bb is optionally substituted with -OH; R 5 But, H, -R bb H, -R bb C(O)OR b , -R bb C(O)N(R b ) 2 , -R bb N(R b ) 2 , -R bb N(R b )(R bb CF 3 ), -R bb OR b or

[0006] [ka] or Or R 1 and R 5 together with the atoms to which they are attached form a five-membered heterocyclic ring, R b each occurrence is independently H or -R bb H, R bb each occurrence independently represents C optionally substituted with fluoro or methyl 1~3 is alkylene, R c Each occurrence of 4~6 a carbocyclic or oxygen 4- to 6-membered heterocyclic ring; R e Each occurrence of

[0007] [ka] A compound, or a pharma- ceutically acceptable salt thereof.

[0008] In some embodiments, provided herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, together with one or more pharma- ceutically acceptable carriers, diluents, or excipients.

[0009] In some embodiments, provided herein are methods of treating immune-mediated diseases in a patient, such as systemic lupus erythematosus, lupus nephritis, dermatomyositis, and Aicardi-Goutières syndrome, comprising administering to a patient in need of such treatment an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0010] In some embodiments, provided herein is a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, for use in therapy. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] In some embodiments, the present invention provides a compound of formula IIa,

[0012] [ka] During the ceremony, X and R4 But independently, it is a halo, R 1 , R 7 , R 8 , and R 9 But independently, R b and R 6 is H or F, R 3 But -NH-R bb -OR b , -NHC(O)-R bb -OR b , -NHC(O)-C(O)-NH 2 , -NH-R c , -NH-C(O)-R c , -OR c , -OR bb -C(O)NH 2 , -OR bb -OR b , -OR bb -OC(O)-R b , -OR bb -H, -OR bb -CN, -NH-R bb -H, -R bb -OH, -R bb -CN, -NH-R e , -NH-CH 2 -R e or a 5- or 6-membered heteroaryl having 2 or 3 heteroatoms, respectively, wherein the heteroaryl is -NH 2 , -R bb -H or -R bb is optionally substituted with -OH; R 5 But, H, -R bb H, -R bb C(O)OR b , -R bb C(O)N(R b ) 2 , -R bb N(R b ) 2 , -R bb N(R b )(R bb CF 3 ), -Rbb OR b or

[0013] [ka] or Or R 1 and R 5 together with the atoms to which they are attached form a five-membered heterocyclic ring, R b each occurrence is independently H or -R bb H, R bb each occurrence independently represents C optionally substituted with fluoro or methyl 1~3 is alkylene, R c Each occurrence of 4~6 a carbocyclic or oxygen 4- to 6-membered heterocyclic ring; R e is a 5-membered heteroaryl containing N, or a pharma- ceutically acceptable salt thereof.

[0014] In some embodiments, R e teeth,

[0015] [ka] It is.

[0016] In some embodiments, the present invention provides a compound of formula IIb:

[0017] [ka] or a pharma- ceutically acceptable salt thereof, wherein each variable is as defined for formula IIa above.

[0018] In some embodiments, R 5 ,H,-R bb H, -R bbC(O)OR b , -R bb C(O)N(R b ) 2 , -R bb N(R b ) 2 , -R bb N(R b )(R bb CF 3 ), -R bb -OR b or

[0019] [ka] It is.

[0020] In some embodiments, R 5 -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 ,

[0021] [ka] It is.

[0022] In some embodiments, R 5 -R bb H, -R bb C(O)OR b , -R bb C(O)N(R b ) 2 , -R bb N(R b ) 2 , -R bb N(R b )(R bb CF 3 ), -R bb -OR b or

[0023] [ka] and

[0024] [ka] It is.

[0025] In some embodiments, R 5 -R bb H, -R bb C(O)OR b , -R bb C(O)N(R b ) 2 , -R bb N(R b ) 2 , -R bb N(R b )(R bb CF 3 ), -R bb -OR b or

[0026] [ka] and

[0027] [ka] It is.

[0028] In some embodiments, the invention provides a compound of formula IVa:

[0029] [ka]

[0030] In some embodiments, R 5 is H.

[0031] In some embodiments, R 7 is H.

[0032] In some embodiments, R 7 -R bb H,

[0033] [ka] It is.

[0034] In some embodiments, R 7 -R bb H,

[0035] [ka] It is.

[0036] In some embodiments, the invention provides a compound of formula IVb:

[0037] [ka]

[0038] In some embodiments, R 7 is methyl.

[0039] In some embodiments, R 3 is -NH-R bb -OR b , -NHC(O)-R bb -OR b , -NHC(O)-C(O)-NH 2 , -OR bb -C(O)NH 2 , -OR bb -OR b , -OR bb -OC(O)-R b , -OR bb -H, -OR bb -CN, -NH-R bb -H, -R bb -OH or -R bb -CN.

[0040] In some embodiments, R 3 is -NH-R c , -NH-C(O)-R c -OR c It is.

[0041] In some embodiments, R 3 teeth,

[0042] [ka] is selected from.

[0043] In some embodiments, R 3 is -NH-(CH 22 -OH, -NH-(CH 2 ) 2 -O(CH 3 ), -NH-(CH 2 )((CH)(CH 3 ))-OH, -NHC(O)-CH 2 -OH, -NHC(O)-CH 2 -O(CH 3 ), -NHC(O)-CH(CH 3 )-OH, -NH-(CH 2 )(CF 2 )(CH 2 )-OH, -NH-(CH 2 )-CHF 2 , -NH-(CH 2 ) 2 -CHF 2 , -O-CH 2 -C(O)NH 2 , -O-(CH 2 )(CH(CH 3 ))-OH, -O(CH 2 ) 3 -OH, -O(CH 2 ) 2 -O(CH 3 ), -O-(CH 2 )(CF 2 )(CH 2)-OH, -NH-(CH 2 )(CF 2 )(CH 2 )-OH, -O(CH 2 )CH 2 F, -O(CH 2 ) 2 CH 2 F, -O-CH 2 -CN, -NH(CH 2 ) 3 , -(CH 2 ) 3 OH and -CH 2 -CN.

[0044] In some embodiments, R 8 is H.

[0045] In some embodiments, R 8 is methyl.

[0046] In some embodiments, R 1 is H.

[0047] In some embodiments, R 1 is methyl.

[0048] In some embodiments, R 1 is C substituted with one or more fluoro groups 1~3 It is an alkyl.

[0049] In some embodiments, R 1 is trifluoroethyl.

[0050] In some embodiments, R 1 is -CH 2 CF 3 It is.

[0051] In some embodiments, the compound has the formula IIc:

[0052] [ka] During the ceremony, R 1 H, -CH 3 , or -CHF 2 and R 5 H, -CH 3 , C.H. 2 CH 3 , or -CH 2 CH 2 CH 3 and R 7 H, -CH 3 , C.H. 2 CH 3 , or -CH 2 CH 2 CH 3 and R 3 is -NH-(CH 2 ) 2 -OH, -NH-(CH 2 ) 2 -O(CH 3 ), -NH-(CH 2 )((CH)(CH 3 ))-OH, -NHC(O)-CH 2 -OH, -NHC(O)-CH 2 -O(CH 3 ), -NHC(O)-CH(CH 3 )-OH, -NH-(CH 2 )(CF 2 )(CH 2 )-OH, -NH-(CH 2 )-CHF 2 , -NH-(CH 2 ) 2 -CHF 2 , -O-CH 2 -C(O)NH 2 , -O-(CH 2 )(CH(CH 3 ))-OH, -O(CH 2 ) 3 -OH, -O(CH 2 ) 2 -O(CH 3 ), -O-(CH 2 )(CF 2 )(CH 2 )-OH, -NH-(CH 2 )(CF 2 )(CH 2 )-OH, -O(CH 2 )CH 2 F, -O(CH 2 ) 2 CH 2 F, -O-CH 2 -CN, -NH(CH 2 ) 3 , -(CH 2 ) 3 OH, -CH 2 -CN,

[0053] [ka] It is.

[0054] In some embodiments, the compound has the formula IId:

[0055] [ka] In the formula, R 1 , R 5 , and R 7 are each independently H or -CHF 2 and R 3 But -NHC(O)-CH 2 -OH, -O-(CH 2 ) 2 -O-(CH 3 ), -NH-C(O)-CH(CH 3 )-OH, or

[0056] [ka] It is.

[0057] In some embodiments, the compound is selected from the group consisting of:

[0058] [ka]

[0059] [ka]

[0060] [ka]

[0061] In some embodiments, the compound is selected from the group consisting of:

[0062] [ka]

[0063] [ka]

[0064] [ka]

[0065] [ka]

[0066] [ka]

[0067] In some embodiments, the compound is

[0068] [ka] is selected from.

[0069] In some embodiments, provided herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, together with one or more pharma- ceutically acceptable carriers, diluents, or excipients.

[0070] In some embodiments, provided herein is a method of treating an immune-mediated disease in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0071] In some embodiments, the immune-mediated disease is selected from systemic lupus erythematosus, lupus nephritis, dermatomyositis, and Aicardi-Goutières syndrome.

[0072] In some embodiments, provided herein is a method of treating a disease associated with cGAS activation in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0073] In some embodiments, provided herein is a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, for use in therapy.

[0074] In some embodiments, provided herein is a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment of a disease selected from systemic lupus erythematosus, lupus nephritis, dermatomyositis, and Aicardi-Goutières syndrome.

[0075] In some embodiments, the present invention provides a compound of formula Ia:

[0076] [ka] During the ceremony, X and R 4 are each independently halo; R 1 and R 7 Each independently, R b and R 3 But -NH-R bb -OH, -NHC(O)-R bb -OH, -OR bb -C(O)NH 2 , -OR bb -OH, -OR bb -OC(O)-R b , -OR bb -H, -OR bb -CN, -NH-R bb -H, -R bb -CN or a 5-membered heteroaryl having 2 or 3 heteroatoms, the 5-membered heteroaryl being -R bb -H or -R bb is optionally substituted with -OH; R 5 But, H, -R bb C(O)Q 1 R b , or -R bb OH, Q 1 is O or NR b and R b each occurrence is independently H or -R bb H, R bb Each occurrence of is independently a substituted or unsubstituted C 1~3 The compound, or a pharma- ceutically acceptable salt thereof.

[0077] In some embodiments, X in the compound of formula Ia is chloro.

[0078] In some embodiments, R of the compound of any of the above embodiments is 4 is chloro.

[0079] In some embodiments, R of the compound of any of the above embodiments is 1 is H, where R 3 -OR bb In some embodiments, R of the compound of any of the above embodiments is not —CN. 1 is methyl, and the R 3 -OR bb -CN.

[0080] In some embodiments, R of the compound of any of the above embodiments is 5 , R 5 is H, where R 3 is not a 5-membered heteroaryl.

[0081] In some embodiments, R of the compound of any of the above embodiments is 5 is -CH 2 C(O)NHCH 3 , -CH 2 C(O)N(CH 3 ) 2 , -CH 2 C(O)OCH 2 CH 3 , or -CH 2 C(O)OH.

[0082] In some embodiments, R of the compound of any of the above embodiments is 5 is -CH 2 CH 2 It is OH.

[0083] In some embodiments, R of the compound of any of the above embodiments is 3 is a 5-membered heteroaryl.

[0084] In some embodiments, R of the compound of any of the above embodiments is 3 is a 5-membered heteroaryl having 3 heteroatoms.

[0085] In some embodiments, R of the compound of any of the above embodiments is 3teeth,

[0086] [ka] is selected from.

[0087] In some embodiments, R of the compound of any of the above embodiments is 3 is -NH-R bb -OH, -NHC(O)-R bb -OH, -OR bb -C(O)NH 2 , -OR bb -OH, -OR bb -OC(O)-R b , -OR bb -H, -OR bb -CN, -NH-R bb -H and -R bb In some embodiments, R of the compound of any of the above embodiments is selected from -CN. 3 is -NHC(O)-R bb -OH, -OR bb -C(O)NH 2 , and -OR bb -H.

[0088] In some embodiments, R of the compound of any of the above embodiments is bb is CH 2 It is.

[0089] In some embodiments, the compound of formula Ia is

[0090] [ka] or selected from the group consisting of

[0091] or a pharma- ceutically acceptable salt thereof, wherein each substituent is as defined above for formula Ia, and n is 0, 1, or 2.

[0092] In some embodiments, the compound of formula Ia is

[0093] [ka]

[0094] [ka] or selected from the group consisting of

[0095] or a pharma- ceutically acceptable salt thereof.

[0096] In some embodiments, the present invention provides a compound of formula Ib:

[0097] [ka] or a pharma- ceutically acceptable salt thereof, wherein each variable is as defined above for formula Ia.

[0098] In some embodiments, the compound of formula Ia is

[0099] [ka] or selected from the group consisting of or a pharma- ceutically acceptable salt thereof.

[0100] In some embodiments, the compound of formula Ia is of formula Ia-1:

[0101] [ka]

[0102] In some embodiments, the compound of formula Ia is of formula Ia-2:

[0103] [ka] In some embodiments, the compounds provided herein are

[0104] [ka] or selected from the group consisting of or a pharma- ceutically acceptable salt thereof.

[0105] In some embodiments, provided herein is a pharmaceutical composition comprising a compound according to any one of the above embodiments, or a pharma- ceutically acceptable salt thereof, together with one or more pharma- ceutically acceptable carriers, diluents, or excipients.

[0106] In some embodiments, provided herein is a method of treating an immune-mediated disease in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of the above embodiments or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described above.

[0107] In some embodiments, provided herein is a method of treating systemic lupus erythematosus in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound described in any one of the above embodiments or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described above.

[0108] In some embodiments, provided herein is a method of treating lupus nephritis in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of the above embodiments or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described above.

[0109] In some embodiments, provided herein is a method of treating dermatomyositis in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound described in any one of the above embodiments, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0110] In some embodiments, provided herein is a method of treating Aicardi-Goutières syndrome in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of the above embodiments or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described above.

[0111] In some embodiments, provided herein is a method of treating a disease associated with cGAS activation in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of the above embodiments or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described above.

[0112] In some embodiments, provided herein is a compound according to any one of the above embodiments, or a pharma- ceutically acceptable salt thereof, for use in therapy.

[0113] In some embodiments, the present invention provides a method for the treatment of a cancer, comprising administering to a patient a therapeutic agent comprising:

[0114] [ka] A compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof is provided.

[0115] In some embodiments, provided herein is a compound according to any one of the above embodiments, or a pharma- ceutically acceptable salt thereof, for use in treating an immune-mediated disease, in some embodiments, the immune-mediated disease is selected from the group consisting of systemic lupus erythematosus, lupus nephritis, dermatomyositis, and Aicardi-Goutières syndrome.

[0116] In some embodiments, provided herein is a method for treating an immune-mediated disease, comprising administering to said patient:

[0117] [ka] A compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof. In some embodiments, the immune-mediated disease is selected from the group consisting of systemic lupus erythematosus, lupus nephritis, dermatomyositis, and Aicardi-Goutières syndrome.

[0118] In some embodiments, provided herein is a compound according to any one of the above embodiments, or a pharma- ceutically acceptable salt thereof, for use in the treatment of systemic lupus erythematosus.

[0119] In some embodiments, provided herein is a compound according to any one of the above embodiments, or a pharma- ceutically acceptable salt thereof, for use in treating lupus nephritis.

[0120] In some embodiments, provided herein is a compound according to any one of the above embodiments, or a pharma- ceutically acceptable salt thereof, for use in the treatment of dermatomyositis.

[0121] In some embodiments, provided herein is a compound according to any one of the above embodiments, or a pharma- ceutically acceptable salt thereof, for use in the treatment of Aicardi-Goutières syndrome.

[0122] In some embodiments, provided herein is a method of treating a disease associated with cGAS activation in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound provided herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described in any of the above embodiments.

[0123] The present application further provides the following additional embodiments.

[0124] Embodiment 1. A compound of formula IIIa,

[0125] [ka] During the ceremony, X and R 4 But independently, it is a halo, R 1 , R 7 , R 8 , and R 9 But independently, R b and R 6 is H or F, R 3 But -NH-R bb -OR b , -NHC(O)-R bb -OR b , -NHC(O)-C(O)-NH 2 , -NH-R c , -NH-C(O)-R c , -OR c , -OR bb -C(O)NH 2 , -OR bb -OR b , -OR bb -OC(O)-R b , -OR bb -H, -OR bb -CN, -NH-R bb -H, -R bb -OH, -R bb-CN, -NH-R e , -NH-CH 2 -R e or a 5- or 6-membered heteroaryl having 2 or 3 heteroatoms, respectively, wherein the heteroaryl is -NH 2 , -R bb -H, or -R bb is optionally substituted with -OH; R 5 But, H, -R bb H, -R bb C(O)OR b , -R bb C(O)N(R b ) 2 , -R bb N(R b ) 2 , -R bb N(R b )(R bb CF 3 ), -R bb OR b or

[0126] [ka] or Or R 1 and R 5 together with the atoms to which they are attached form a five-membered heterocyclic ring, R b each occurrence is independently H or -R bb H, R bb each occurrence independently represents C optionally substituted with fluoro or methyl 1~3 is alkylene, R c Each occurrence of 4~6 a carbocyclic or oxygen 4- to 6-membered heterocyclic ring; R e Each occurrence of

[0127] [ka] A compound, or a pharma- ceutically acceptable salt thereof.

[0128] Embodiment 2. A compound of formula IIIb,

[0129] [ka] During the ceremony, X and R 4 But independently, it is a halo, R 1 , R 7 , R 8 , and R 9 But independently, R b and R 3 But -NH-R bb -OR b , -NHC(O)-R bb -OR b , -NHC(O)-C(O)-NH 2 , -NH-R c , -NH-C(O)-R c , -OR c , -OR bb -C(O)NH 2 , -OR bb -OR b , -OR bb -OC(O)-R b , -OR bb -H, -OR bb -CN, -NH-R bb -H, -R bb -OH, -R bb -CN, -NH-R e , -NH-CH 2 -R e or a 5- or 6-membered heteroaryl having 2 or 3 heteroatoms, respectively, wherein the heteroaryl is -NH 2 , -R bb -H, or -R bb is optionally substituted with -OH; R 5 But, H, -Rbb H, -R bb C(O)OR b , -R bb C(O)N(R b ) 2 , -R bb N(R b ) 2 , -R bb N(R b )(R bb CF 3 ), -R bb OR b or

[0130] [ka] or Or R 1 and R 5 together with the atoms to which they are attached form a five-membered heterocyclic ring, R b each occurrence is independently H or -R bb H, R bb each occurrence independently represents C optionally substituted with fluoro or methyl 1~3 is alkylene, R c Each occurrence of 4~6 a carbocyclic or oxygen 4- to 6-membered heterocyclic ring; R e Each occurrence of

[0131] [ka] A compound, or a pharma- ceutically acceptable salt thereof.

[0132] Embodiment 3. A compound according to embodiment 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein X is Cl.

[0133] Embodiment 4.R 4The compound according to any one of embodiments 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein is Cl.

[0134] Embodiment 5. A compound of formula IIIc,

[0135] [ka] During the ceremony, R 1 , R 7 , R 8 , and R 9 But independently, R b and R 3 But -NH-R bb -OR b , -NHC(O)-R bb -OR b , -NHC(O)-C(O)-NH 2 , -NH-R c , -NH-C(O)-R c , -OR c , -OR bb -C(O)NH 2 , -OR bb -OR b , -OR bb -OC(O)-R b , -OR bb -H, -OR bb -CN, -NH-R bb -H, -R bb -OH, -R bb -CN, -NH-R e , -NH-CH 2 -R e or a 5- or 6-membered heteroaryl having 2 or 3 heteroatoms, respectively, wherein the heteroaryl is -NH 2 , -R bb -H or -R bb is optionally substituted with -OH; R 5 But, H, -R bb H, -R bb C(O)OR b , -R bbC(O)N(R b ) 2 , -R bb N(R b ) 2 , -R bb N(R b )(R bb CF 3 ), -R bb OR b or

[0136] [ka] or Or R 1 and R 5 together with the atoms to which they are attached form a five-membered heterocyclic ring, R b each occurrence is independently H or -R bb H, R bb each occurrence independently represents C optionally substituted with fluoro or methyl 1~3 is alkylene, R c Each occurrence of 4~6 a carbocyclic or oxygen 4- to 6-membered heterocyclic ring; R e Each occurrence of

[0137] [ka] A compound, or a pharma- ceutically acceptable salt thereof.

[0138] Embodiment 6.R 9 is H or methyl; or a pharma- ceutically acceptable salt thereof.

[0139] Embodiment 7.R 9 is methyl; or a pharma- ceutically acceptable salt thereof.

[0140] Embodiment 8. A compound of formula IIId,

[0141] [ka] During the ceremony, R 1 , R 7 , and R 8 But independently, R b and R 3 But -NH-R bb -OR b , -NHC(O)-R bb -OR b , -NHC(O)-C(O)-NH 2 , -NH-R c , -NH-C(O)-R c , -OR c , -OR bb -C(O)NH 2 , -OR bb -OR b , -OR bb -OC(O)-R b , -OR bb -H, -OR bb -CN, -NH-R bb -H, -R bb -OH, -R bb -CN, -NH-R e , -NH-CH 2 -R e or a 5- or 6-membered heteroaryl having 2 or 3 heteroatoms, respectively, wherein the heteroaryl is -NH 2 , -R bb -H or -R bb is optionally substituted with -OH; R 5 But, H, -R bb H, -R bb C(O)OR b , -R bb C(O)N(R b ) 2 , -R bb N(R b ) 2 , -R bbN(R b )(R bb CF 3 ), -R bb OR b or

[0142] [ka] or Or R 1 and R 5 together with the atoms to which they are attached form a five-membered heterocyclic ring, R b each occurrence is independently H or -R bb H, R bb each occurrence independently represents C optionally substituted with fluoro or methyl 1~3 is alkylene, R c Each occurrence of 4~6 a carbocyclic or oxygen 4- to 6-membered heterocyclic ring; R e Each occurrence of

[0143] [ka] A compound, or a pharma- ceutically acceptable salt thereof.

[0144] Embodiment 9.R 5 But, H, -R bb H, -R bb C(O)OR b , -R bb C(O)N(R b ) 2 , -R bb N(R b ) 2 , -R bb N(R b )(R bb CF 3 ), -R bb -OR b or

[0145] [ka] The compound according to any one of embodiments 1 to 8, or a pharma- ceutically acceptable salt thereof.

[0146] Embodiment 10.R 5 But, H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 ,

[0147] [ka] The compound according to any one of embodiments 1 to 8, or a pharma- ceutically acceptable salt thereof.

[0148] Embodiment 11.R 5 is H, methyl, ethyl, n-propyl, or isopropyl; or a pharma- ceutically acceptable salt thereof.

[0149] Embodiment 12.R 5 is other than H,

[0150] [ka] 12. The compound according to any one of embodiments 1 to 11, wherein:

[0151] Embodiment 13.R 5 is H, or a pharma- ceutically acceptable salt thereof.

[0152] Embodiment 14.R 1 and R 5together with the atoms to which they are attached form a 5-membered heterocycle; or a pharma- ceutically acceptable salt thereof.

[0153] EMBODIMENT 15.

[0154] [ka] 9. The compound of any one of embodiments 1 to 8, wherein:

[0155] Embodiment 16.R 7 is H; or a pharma- ceutically acceptable salt thereof.

[0156] Embodiment 17.R 7 But -R bb H,

[0157] [ka] 15. The compound of any one of embodiments 1 to 14, wherein:

[0158] Embodiment 18.R 7 is methyl, ethyl, or propyl; or a pharma- ceutically acceptable salt thereof.

[0159] Embodiment 19.R 7 is methyl; or a pharma- ceutically acceptable salt thereof.

[0160] Embodiment 20.R 3 but, -NH-R bb -OR b 20. The compound of any one of embodiments 1-19, wherein:

[0161] Embodiment 21.R 3 but, -NHC(O)-R bb -OR b 20. The compound of any one of embodiments 1-19, wherein:

[0162] Embodiment 22.R 3 but, -NHC(O)-C(O)-NH 2 20. The compound of any one of embodiments 1-19, wherein:

[0163] Embodiment 23.R 3 but, -NH-R c 20. The compound of any one of embodiments 1-19, wherein:

[0164] Embodiment 24.R 3 but, -NH-C(O)-R c 20. The compound of any one of embodiments 1-19, wherein:

[0165] Embodiment 25.R 3 but, -OR c 20. The compound of any one of embodiments 1-19, wherein:

[0166] Embodiment 26.R c is an oxygen 4- or 5-membered heterocycle; or a pharma- ceutically acceptable salt thereof.

[0167] Embodiment 27.R c But hydroxy-substituted C 4~6 26. The compound of any one of embodiments 23-25, or a pharma- ceutically acceptable salt thereof, which is carbocyclic.

[0168] Embodiment 28.R 3 but,

[0169] [ka] 20. The compound of any one of embodiments 1-19, wherein:

[0170] Embodiment 29.R 3 but,

[0171] [ka] 20. The compound of any one of embodiments 1-19, wherein:

[0172] Embodiment 30.R 3 but,

[0173] [ka] 20. The compound of any one of embodiments 1-19, wherein:

[0174] Embodiment 31.R 3 But -OR bb -OR b 20. The compound of any one of embodiments 1-19, wherein:

[0175] Embodiment 32.R 3 But -OR bb -OC(O)-R b 20. The compound of any one of embodiments 1-19, wherein:

[0176] Embodiment 33.R 3 but, -OR bb 20. The compound of any one of embodiments 1-19, wherein R is —H, or a pharma- ceutically acceptable salt thereof.

[0177] Embodiment 34.R 3 but, -OR bb20. The compound of any one of embodiments 1-19, wherein R is -CN, or a pharma- ceutically acceptable salt thereof.

[0178] Embodiment 35.R 3 but, -NH-R bb 20. The compound of any one of embodiments 1-19, wherein R is —H, or a pharma- ceutically acceptable salt thereof.

[0179] Embodiment 36.R 3 but, -R bb 20. The compound of any one of embodiments 1-19, wherein R is -OH, or a pharma- ceutically acceptable salt thereof.

[0180] Embodiment 37.R 3 but, -R bb 20. The compound of any one of embodiments 1-19, wherein R is -CN, or a pharma- ceutically acceptable salt thereof.

[0181] Embodiment 38.R 3 but, -NH-R e 20. The compound of any one of embodiments 1-19, wherein:

[0182] Embodiment 39.R 3 but, -NH-CH 2 -R e 20. The compound of any one of embodiments 1-19, wherein:

[0183] Embodiment 40.R 3 But -NH 2 or a pharma- ceutically acceptable salt thereof.

[0184] Embodiment 41.R 3 But -R bbThe compound according to any one of embodiments 1 to 19, wherein R is a 5-membered heteroaryl having 2 or 3 heteroatoms optionally substituted with -H; or a pharma- ceutically acceptable salt thereof.

[0185] Embodiment 42.R 3 But -R bb The compound according to any one of embodiments 1 to 19, wherein the aryl is a 5-membered heteroaryl having 2 or 3 heteroatoms optionally substituted with -OH; or a pharma- ceutically acceptable salt thereof.

[0186] Embodiment 43.R 3 but,

[0187] [ka] 20. The compound according to any one of embodiments 1 to 19, selected from:

[0188] Embodiment 44.R 3 is 6-membered heteroaryl having 2 or 3 heteroatoms; or a pharma- ceutically acceptable salt thereof.

[0189] Embodiment 45.R 3 but,

[0190] [ka] 20. The compound of any one of embodiments 1-19, wherein:

[0191] Embodiment 46.R 3 but,

[0192] [ka] 20. The compound according to any one of embodiments 1 to 19, selected from:

[0193] Embodiment 47.R 3 But -NH-R bb -OH, -NHC(O)-R bb -OH, -OR bb -C(O)NH 2 , -OR bb -OH, -OR bb -OC(O)-R b , -OR bb -H, -OR bb -CN, -NH-R bb -H and -R bb 20. The compound according to any one of embodiments 1-19, or a pharma- ceutically acceptable salt thereof, selected from:

[0194] Embodiment 48.R 3 But, OR bb -C(O)NH 2 or a pharma- ceutically acceptable salt thereof.

[0195] Embodiment 49.R 3 But -NH-(CH 2 ) 2 -OH, -NH-(CH 2 ) 2 -O(CH 3 ), -NH-(CH 2 )(CH(CH 3 ))-OH, -NHC(O)-CH 2 -OH, -NHC(O)-CH 2 -O(CH 3 ), -NHC(O)-CH(CH 3 )-OH, -NH-(CH 2 )(CF 2 )(CH 2 )-OH, -NH-(CH 2 )-CHF 2 , -NH-(CH 2 ) 2 -CHF 2 , -O-CH 2 -C(O)NH 2 , -O-(CH 2 )(CH(CH3 ))-OH, -O(CH 2 ) 3 -OH, -O(CH 2 ) 2 -O(CH 3 ), -O-(CH 2 )(CF 2 )(CH 2 )-OH, -NH-(CH 2 )(CF 2 )(CH 2 )-OH, -O(CH 2 )CH 2 F, -O(CH 2 ) 2 CH 2 F, -O-CH 2 -CN, -NH(CH 2 ) 3 , -(CH 2 ) 3 OH and -CH 2 20. The compound according to any one of embodiments 1-19, or a pharma- ceutically acceptable salt thereof, selected from:

[0196] Embodiment 49A.R 3 but, -NH-CO-CH(CH 3 20. The compound of any one of embodiments 1-19, wherein R is —OH. In some embodiments, R 3 teeth,

[0197] [ka] It is.

[0198] Embodiment 50.R 8 is H; or a pharma- ceutically acceptable salt thereof.

[0199] Embodiment 51.R 8 is methyl; or a pharma- ceutically acceptable salt thereof.

[0200] Embodiment 52.R1 is H; or a pharma- ceutically acceptable salt thereof.

[0201] Embodiment 53.R 1 is methyl; or a pharma- ceutically acceptable salt thereof.

[0202] Embodiment 54.R 1 But -CHF 2 52. The compound of any one of embodiments 1-51, wherein:

[0203] Embodiment 55. A compound of Formula IIIe,

[0204] [ka] During the ceremony, R 1 H, -CH 3 , or -CHF 2 and R 5 H, -CH 3 , C.H. 2 CH 3 , or -CH 2 CH 2 CH 3 and R 7 H, -CH 3 , C.H. 2 CH 3 , or -CH 2 CH 2 CH 3 and R 3 is -NH-(CH 2 ) 2 -OH, -NH-(CH 2 ) 2 -O(CH 3 ), -NH-(CH 2 )((CH)(CH 3 ))-OH, -NHC(O)-CH 2 -OH, -NHC(O)-CH2 -O(CH 3 ), -NHC(O)-CH(CH 3 )-OH, -NH-(CH 2 )(CF 2 )(CH 2 )-OH, -NH-(CH 2 )-CHF 2 , -NH-(CH 2 ) 2 -CHF 2 , -O-CH 2 -C(O)NH 2 , -O-(CH 2 )(CH(CH 3 ))-OH, -O(CH 2 ) 3 -OH, -O(CH 2 ) 2 -O(CH 3 ), -O-(CH 2 )(CF 2 )(CH 2 )-OH, -NH-(CH 2 )(CF 2 )(CH 2 )-OH, -O(CH 2 )CH 2 F, -O(CH 2 ) 2 CH 2 F, -O-CH 2 -CN, -NH(CH 2 ) 3 , -(CH 2 ) 3 OH, -CH 2 -CN,

[0205] [ka] A compound, or a pharma- ceutically acceptable salt thereof.

[0206] Embodiment 56. A compound of formula IIIf,

[0207] [ka] In the formula, R 1 , R 5 , and R 7 are each independently H or -CHF 2 and R 3 But -NHC(O)-CH 2 -OH, -O-(CH 2 ) 2 -O-(CH 3 ), -NH-C(O)-CH(CH 3 )-OH, or

[0208] [ka] A compound, or a pharma- ceutically acceptable salt thereof.

[0209] Embodiment 57. The compound is

[0210] [ka]

[0211] [ka]

[0212] [ka]

[0213] [ka] The compound of embodiment 1, selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

[0214] Embodiment 58. The compound is

[0215] [ka]

[0216] [ka]

[0217] [ka]

[0218] [ka]

[0219] [ka]

[0220] [ka] The compound of embodiment 1, selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

[0221] EMBODIMENT 59.

[0222] [ka] A compound selected from:

[0223] Embodiment 60. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 59, or a pharma- ceutically acceptable salt thereof, together with one or more pharma- ceutically acceptable carriers, diluents, or excipients.

[0224] Embodiment 61. A method for treating an immune-mediated disease in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound described in any one of embodiments 1 to 59 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 60.

[0225] Embodiment 62. A method for treating systemic lupus erythematosus in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of embodiments 1 to 59 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 60.

[0226] Embodiment 63. A method for treating lupus nephritis in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of embodiments 1 to 59 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 60.

[0227] Embodiment 64. A method for treating dermatomyositis in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound described in any one of embodiments 1 to 59 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 60.

[0228] Embodiment 65. A method for treating Aicardi-Goutières syndrome in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of embodiments 1 to 59 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 60.

[0229] Embodiment 66. A method for treating a disease associated with cGAS activation in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of embodiments 1 to 59 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 60.

[0230] Embodiment 67. A compound according to any one of embodiments 1 to 59, or a pharma- ceutically acceptable salt thereof, for use in therapy.

[0231] Embodiment 68. A compound according to any one of embodiments 1 to 59, or a pharma- ceutically acceptable salt thereof, for use in the treatment of an immune-mediated disease.

[0232] Embodiment 69. A compound according to any one of embodiments 1 to 59, or a pharma- ceutically acceptable salt thereof, for use in the treatment of systemic lupus erythematosus.

[0233] Embodiment 70. A compound according to any one of embodiments 1 to 59, or a pharma- ceutically acceptable salt thereof, for use in treating lupus nephritis.

[0234] Embodiment 71. A compound according to any one of embodiments 1 to 59, or a pharma- ceutically acceptable salt thereof, for use in the treatment of dermatomyositis.

[0235] Embodiment 72. A compound according to any one of embodiments 1 to 59, or a pharma- ceutically acceptable salt thereof, for use in the treatment of Aicardi-Goutières syndrome.

[0236] Embodiment 73. Use of a compound according to any one of embodiments 1 to 59 for the manufacture of a medicament for treating an immune-mediated disease in a patient in need thereof.

[0237] Embodiment 74. Use of a compound according to any one of embodiments 1 to 59 for the manufacture of a medicament for treating systemic lupus erythematosus in a patient in need thereof.

[0238] Embodiment 75. Use of a compound according to any one of embodiments 1 to 59 for the manufacture of a medicament for treating lupus nephritis in a patient in need thereof.

[0239] Embodiment 76. Use of a compound according to any one of embodiments 1 to 59 for the manufacture of a medicament for treating dermatomyositis in a patient in need thereof.

[0240] Embodiment 77. Use of a compound according to any one of embodiments 1 to 59 for the manufacture of a medicament for treating Aicardi-Goutières syndrome in a patient in need thereof.

[0241] Embodiment 78. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 59, or a pharma- ceutically acceptable salt thereof, for use in treating an immune-mediated disease in a patient in need thereof.

[0242] Embodiment 79. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 59, or a pharma- ceutically acceptable salt thereof, for use in the treatment of systemic lupus erythematosus in a patient in need thereof.

[0243] Embodiment 80. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 59, or a pharma- ceutically acceptable salt thereof, for use in treating lupus nephritis in a patient in need thereof.

[0244] Embodiment 81. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 59, or a pharma- ceutically acceptable salt thereof, for use in treating dermatomyositis in a patient in need thereof.

[0245] Embodiment 82. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 59, or a pharma- ceutically acceptable salt thereof, for use in the treatment of Aicardi-Goutières syndrome in a patient in need of such treatment.

[0246] Embodiment A1. A compound of the formula:

[0247] [ka] During the ceremony, X and R 4 But independently, it is a halo, R 1and R 7 But independently, R b and R 3 But -NH-R bb -OH, -NHC(O)-R bb -OH, -OR bb -C(O)NH 2 , -OR bb -OH, -OR bb -OC(O)-R b , -OR bb -H, -OR bb -CN, -NH-R bb -H, -R bb -CN or a 5-membered heteroaryl having 2 or 3 heteroatoms, the 5-membered heteroaryl being -R bb -H or -R bb is optionally substituted with -OH; R 5 But, H, -R bb C(O)Q 1 R b , or -R bb OH, Q 1 is O or NR b and R b each occurrence is independently H or -R bb H, R bb Each occurrence of is independently a substituted or unsubstituted C 1~3 The compound, or a pharma- ceutically acceptable salt thereof.

[0248] Embodiment A2. A compound according to embodiment A1 wherein X is chloro.

[0249] Embodiment A3.R 4 A compound according to embodiment A1 or A2, wherein is chloro.

[0250] Embodiment A4.R 1 is H, except that R 3 But -OR bbThe compound of any one of the preceding Embodiments A1-A3, which is not -CN.

[0251] Embodiment A5.R 1 is methyl, and R 3 But -OR bb The compound according to embodiment A1, wherein:

[0252] Embodiment A6.R 5 is H, except that R 3 The compound according to any one of the preceding Embodiments A1-A5, wherein is not a 5-membered heteroaryl.

[0253] Embodiment A7.R 5 But -CH 2 C(O)NHCH 3 , -CH 2 C(O)N(CH 3 ) 2 , -CH 2 C(O)OCH 2 CH 3 , or -CH 2 The compound of any one of the preceding embodiments A1-A6, wherein C(O)OH.

[0254] Embodiment A8.R 5 But -CH 2 CH 2 The compound according to any one of embodiments A1 to A6, wherein R is OH.

[0255] Embodiment A9.R 3 The compound of any one of the preceding Embodiments A1 through A8, wherein is 5-membered heteroaryl.

[0256] Embodiment A10.R 3 but,

[0257] [ka] The compound of any one of the preceding embodiments A1-A9, selected from:

[0258] Embodiment A11.R 3 But -NH-R bb -OH, -NHC(O)-R bb -OH, -OR bb -C(O)NH 2 , -OR bb -OH, -OR bb -OC(O)-R b , -OR bb -H, -OR bb -CN, -NH-R bb -H and -R bb The compound of any one of the preceding Embodiments A1-A10, wherein the compound is selected from:

[0259] Embodiment A12. The compound is

[0260] [ka]

[0261] [ka] A compound according to embodiment A1, selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

[0262] Embodiment A13. The compound is

[0263] [ka] A compound according to embodiment A1, selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

[0264] Embodiment A14. A pharmaceutical composition comprising a compound according to any one of embodiments A1-A13, or a pharma- ceutically acceptable salt thereof, together with one or more pharma- ceutically acceptable carriers, diluents, or excipients.

[0265] Embodiment A15. A method of treating an immune-mediated disease in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of embodiments A1-A13 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment A14.

[0266] Embodiment A16. A method of treating systemic lupus erythematosus in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of embodiments A1 to A13 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment A14.

[0267] Embodiment A17. A method of treating lupus nephritis in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of embodiments A1 to A13 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment A14.

[0268] Embodiment A18. A method of treating dermatomyositis in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of embodiments A1-A13 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment A14.

[0269] Embodiment A19. A method of treating Aicardi-Goutières syndrome in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of embodiments A1 to A13 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment A14.

[0270] Embodiment A20. A method of treating a disease associated with cGAS activation in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of embodiments A1-A13 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment A14.

[0271] Embodiment A21. A compound according to any one of embodiments A1 to A13, or a pharma- ceutically acceptable salt thereof, for use in therapy.

[0272] Embodiment A22. A compound according to any one of embodiments A1 to A13, or a pharma- ceutically acceptable salt thereof, for use in the treatment of an immune-mediated disease.

[0273] Embodiment A23. A compound according to any one of embodiments A1 to A13, or a pharma- ceutically acceptable salt thereof, for use in the treatment of systemic lupus erythematosus.

[0274] Embodiment A24. A compound according to any one of embodiments A1 to A13, or a pharma- ceutically acceptable salt thereof, for use in the treatment of lupus nephritis.

[0275] Embodiment A25. A compound according to any one of embodiments A1-A13, or a pharma- ceutically acceptable salt thereof, for use in the treatment of dermatomyositis.

[0276] Embodiment A26. A compound according to any one of embodiments A1 to A13, or a pharma- ceutically acceptable salt thereof, for use in the treatment of Aicardi-Goutières syndrome.

[0277] Embodiment B1. A compound of Formula IVa,

[0278] [ka] During the ceremony, X and R 4 But independently, it is a halo, R 1 , R 7 , R 8 , and R 9 But independently, R b and R 6 is H or F, R 3 But -NH-Rbb -OR b , -NHC(O)-R bb -OR b , -NHC(O)-C(O)-NH 2 , -NH-R c , -NH-C(O)-R c , -OR c , -O-CH 2 -R c , -OR bb -C(O)NH 2 , -OR bb -OR b , -OR bb -OC(O)-R b , -OR bb -H, -OR bb -CN, -NH-R bb -H, -R bb -OH, -R bb -CN, -NH-R e , -O-CH 2 -R e , -NH-CH 2 -R e or a 5- or 6-membered heteroaryl having 2 or 3 heteroatoms, respectively, wherein the heteroaryl is -NH 2 , -R bb -H, or -R bb is optionally substituted with -OH; R 5 But, H, -R bb H, -R bb C(O)OR b , -R bb C(O)N(R b ) 2 , -R bb N(R b ) 2 , -R bb N(R b )(R bb CF 3 ), -R bb OR b or

[0279] [ka] or Or R 1 and R 5 together with the atoms to which they are attached form a five-membered heterocyclic ring, R b each occurrence is independently H or -R bb H, R bb each occurrence independently represents C optionally substituted with fluoro or methyl 1~3 is alkylene, R c Each occurrence of 4~6 a carbocyclic or oxygen 4- to 6-membered heterocyclic ring; R e Each occurrence of

[0280] [ka] A compound, or a pharma- ceutically acceptable salt thereof.

[0281] Embodiment B2. A compound of formula IVb,

[0282] [ka] During the ceremony, X and R 4 But independently, it is a halo, R 1 , R 7 , R 8 , and R 9 But independently, R b and R 3 But -NH-R bb -OR b , -NHC(O)-R bb -OR b , -NHC(O)-C(O)-NH 2 , -NH-R c , -NH-C(O)-R c , -ORc , -O-CH 2 -R c , -OR bb -C(O)NH 2 , -OR bb -OR b , -OR bb -OC(O)-R b , -OR bb -H, -OR bb -CN, -NH-R bb -H, -R bb -OH, -R bb -CN, -O-CH 2 -R e , -NH-R e , -NH-CH 2 -R e or a 5- or 6-membered heteroaryl having 2 or 3 heteroatoms, respectively, wherein the heteroaryl is -NH 2 , -R bb -H or -R bb is optionally substituted with -OH; R 5 But, H, -R bb H, -R bb C(O)OR b , -R bb C(O)N(R b ) 2 , -R bb N(R b ) 2 , -R bb N(R b )(R bb CF 3 ), -R bb OR b or

[0283] [ka] or Or R 1 and R 5 together with the atoms to which they are attached form a five-membered heterocyclic ring, R b each occurrence is independently H or -Rbb H, R bb each occurrence independently represents C optionally substituted with fluoro or methyl 1~3 is alkylene, R c Each occurrence of 4~6 a carbocyclic or oxygen 4- to 6-membered heterocyclic ring; R e Each occurrence of

[0284] [ka] A compound, or a pharma- ceutically acceptable salt thereof.

[0285] Embodiment B5. A compound of Formula IVc,

[0286] [ka] During the ceremony, R 1 , R 7 , R 8 , and R 9 But independently, R b and R 3 But -NH-R bb -OR b , -NHC(O)-R bb -OR b , -NHC(O)-C(O)-NH 2 , -NH-R c , -NH-C(O)-R c , -OR c , -O-CH 2 -R c , -OR bb -C(O)NH 2 , -OR bb -OR b , -OR bb -OC(O)-R b , -OR bb -H, -OR bb -CN, -NH-R bb -H, -R bb -OH, -R bb -CN, -O-CH 2 -R e , -NH-R e , -NH-CH 2 -R e or a 5- or 6-membered heteroaryl having 2 or 3 heteroatoms, respectively, wherein the heteroaryl is -NH 2 , -R bb -H or -R bb is optionally substituted with -OH; R 5 But, H, -R bb H, -R bb C(O)OR b , -R bb C(O)N(R b ) 2 , -R bb N(R b ) 2 , -R bb N(R b )(R bb CF 3 ), -R bb OR b or

[0287] [ka] or Or R 1 and R 5 together with the atoms to which they are attached form a five-membered heterocyclic ring, R b each occurrence is independently H or -R bb H, R bb each occurrence independently represents C optionally substituted with fluoro or methyl 1~3 is alkylene, R c Each occurrence of 4~6 a carbocyclic or oxygen 4- to 6-membered heterocyclic ring; R e Each occurrence of

[0288] [ka] A compound, or a pharma- ceutically acceptable salt thereof.

[0289] Embodiment B8. A compound of formula IVd,

[0290] [ka] During the ceremony, R 1 , R 7 , and R 8 But independently, R b and R 3 But -NH-R bb -OR b , -NHC(O)-R bb -OR b , -NHC(O)-C(O)-NH 2 , -NH-R c , -NH-C(O)-R c , -OR c , -O-CH 2 -R c , -OR bb -C(O)NH 2 , -OR bb -OR b , -OR bb -OC(O)-R b , -OR bb -H, -OR bb -CN, -NH-R bb -H, -R bb -OH, -R bb -CN, -O-CH 2 -R e , -NH-R e , -NH-CH 2 -R e or a 5- or 6-membered heteroaryl having 2 or 3 heteroatoms, respectively, wherein the heteroaryl is -NH 2 , -R bb-H or -R bb is optionally substituted with -OH; R 5 But, H, -R bb H, -R bb C(O)OR b , -R bb C(O)N(R b ) 2 , -R bb N(R b ) 2 , -R bb N(R b )(R bb CF 3 ), -R bb OR b or

[0291] [ka] or Or R 1 and R 5 together with the atoms to which they are attached form a five-membered heterocyclic ring, R b each occurrence is independently H or -R bb H, R bb each occurrence independently represents C optionally substituted with fluoro or methyl 1~3 is alkylene, R c Each occurrence of 4~6 a carbocyclic or oxygen 4- to 6-membered heterocyclic ring; R e Each occurrence of

[0292] [ka] A compound, or a pharma- ceutically acceptable salt thereof.

[0293] Embodiments B3, B4, B6, B7, and B9 to B19 are according to embodiments 3, 4, 6, 7, and 9 to 19 above, respectively, except that references to embodiments 1, 2, 5, and 8 are replaced by references to embodiments B1, B2, B5, and B8, respectively.

[0294] Embodiment B20.R 3 but,

[0295] [ka] The compound according to any of embodiments B1 to B19, wherein:

[0296] Embodiment B21.R 3 but, -O-CH 2 -R c The compound according to any of embodiments B1 to B19, wherein:

[0297] Embodiment B22.R 3 but,

[0298] [ka] The compound according to any of embodiments B1 to B19, wherein:

[0299] Embodiment B23.R 3 But -O-(CH 2 ) 2 -OCH 3 The compound according to any of embodiments B1 to B19, wherein:

[0300] Embodiment B24.R 3 But -O-CH 2 -R e The compound according to any of embodiments B1 to B19, selected from:

[0301] Embodiment B25.R3 but,

[0302] [ka] The compound according to any of embodiments B1 to B19, wherein:

[0303] Embodiment B26.R 3 -NH-CO-CH(CH 3 ) —OH.

[0304] Embodiment B27.R 3 but,

[0305] [ka] The compound according to any of embodiments B1 to B19, wherein:

[0306] Embodiment B28.R 8 A compound according to any of embodiments B1-B27, wherein is H; or a pharma- ceutically acceptable salt thereof.

[0307] Embodiment B29.R 8 A compound according to any one of embodiments B1 to B27, or a pharma- ceutically acceptable salt thereof, wherein is methyl.

[0308] Embodiment B30.R 1 is H; or a pharma- ceutically acceptable salt thereof.

[0309] Embodiment B31.R 1 The compound according to any of embodiments 1-B29, or a pharma- ceutically acceptable salt thereof, wherein is methyl.

[0310] Embodiment B32.R 1 is substituted with one or more fluoro groups 1~3The compound according to any one of embodiments 1-B29, wherein is alkyl.

[0311] Embodiment B33.R 1 But -CHF 2 or a pharma- ceutically acceptable salt thereof.

[0312] Embodiment B34.R 1 The compound according to any of embodiments 1-B29, wherein is trifluoroethyl.

[0313] Embodiment B35.R 1 But -CH 2 CF 3 The compound according to any of embodiments 1-B29, wherein

[0314] Embodiment B36. A compound of Formula IVe,

[0315] [ka] During the ceremony, R 1 is H or C optionally substituted with one or more fluoro 1~3 is alkyl, R 5 H, -CH 3 , C.H. 2 CH 3 , or -CH 2 CH 2 CH 3 and R 7 H, -CH 3 , C.H. 2 CH 3 , or -CH 2 CH 2 CH 3 and R 3 But -NH-(CH 2 ) 2 -OH, -NH-(CH 2 ) 2 -O(CH 3 ), -NH-(CH2 )((CH)(CH 3 ))-OH, -NHC(O)-CH 2 -OH, -NHC(O)-CH 2 -O(CH 3 ), -NHC(O)-CH(CH 3 )-OH, -NH-(CH 2 )(CF 2 )(CH 2 )-OH, -NH-(CH 2 )-CHF 2 , -NH-(CH 2 ) 2 -CHF 2 , -O-CH 2 -C(O)NH 2 , -O-(CH 2 )(CH(CH 3 ))-OH, -O(CH 2 ) 3 -OH, -O(CH 2 ) 2 -O(CH 3 ), -O-(CH 2 )(CF 2 )(CH 2 )-OH, -NH-(CH 2 )(CF 2 )(CH 2 )-OH, -O(CH 2 )CH 2 F, -O(CH 2 ) 2 CH 2 F, -O-CH 2 -CN, -NH(CH 2 ) 3 , -(CH 2 ) 3 OH, -CH 2 -CN,

[0316] [ka] A compound, or a pharma- ceutically acceptable salt thereof.

[0317] Embodiment B37. A compound of Formula IVf,

[0318] [ka] In the formula, R 1 , R 5 , and R 7 each independently represents H, -CH 2 CF 3 , or -CHF 2 and R 3 but, -NHC(O)-CH 2 -OH, -O-(CH 2 ) 2 -O-(CH 3 ), -NH-C(O)-CH(CH 3 )-OH, or

[0319] [ka] A compound, or a pharma- ceutically acceptable salt thereof.

[0320] Embodiment B38. The compound is

[0321] [ka] The compound according to embodiment B1, selected from: or a pharma- ceutically acceptable salt thereof.

[0322] Embodiment B39.

[0323] [ka]

[0324] [ka]

[0325] [ka] A compound selected from or a pharma- ceutically acceptable salt thereof.

[0326] Embodiment B40. A pharmaceutical composition comprising a compound according to any one of embodiments B1-B39, or a pharma- ceutically acceptable salt thereof, together with one or more pharma- ceutically acceptable carriers, diluents, or excipients.

[0327] Embodiments B41 to B59 are omitted. Embodiments B61 to B82 follow embodiments 60 to 82, respectively, except that references to embodiments 1 to 59 are replaced with references to embodiments B1 to B39, and references to embodiment 60 are replaced with references to embodiment B40.

[0328] As used herein, the term "alkyl," used alone or as part of a larger moiety, refers to a saturated, straight or branched chain hydrocarbon group containing one or more carbon atoms. Alkyl is generally monovalent. For example, "ethyl" is CH 3 CH 2 The term "alkylene" refers to a divalent saturated, straight or branched chain hydrocarbon group that can be considered to be derived from alkyl by removing a terminal atom. For example, "ethylene" is represented by ·CH 2 CH 2 · and can be considered to be derived from ethyl by removing a hydrogen atom from the end of the ethyl group. As used herein, the term "propyl" includes n-propyl and isopropyl. Similarly, the term "propylene" includes n-propylene (·CH 2 CH 2 CH 2 ) and isopropylene (·CH 2 CH(CH 3 )·) are included.

[0329] The terms "alkyl" and "alkylene" may begin with a designation of the number of carbon atoms in the main carbon chain of the moiety. For example, "C 1~3 "Alkyl" refers to an alkyl having 1 to 3 carbon atoms in the main chain. 1~3 "Alkylene" refers to an alkylene having 1 to 3 carbon atoms on the backbone between two radicals or dangling bonds. That is, the designation of the number of carbon atoms does not take into account substituents. Thus, "substituted" C 1~3 Alkylene may contain more carbon atoms when the substitution is alkyl. For example, methyl substituted C 3 An alkylene R group contains a total of 4 carbon atoms in the R group.

[0330] As used herein, the term "halo" refers to a halogen as a substituent, specifically chloro, fluoro, bromo, or iodo.

[0331] As used herein, unless otherwise specified, the term "heteroaryl" refers to a group having 5 to 10 ring atoms, preferably 5, 6, 9, or 10 ring atoms, and having 6, 10, or 14 pi electrons shared in a cyclic arrangement, and having a heteroatom. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes oxidized forms of nitrogen or sulfur, and the quaternized form of a basic nitrogen.

[0332] As used herein, the term "heterocyclic ring" or "heterocycle" refers to an optionally substituted saturated ring system containing at least two carbon atoms and at least one heteroatom. Exemplary heteroatoms are oxygen, nitrogen, and sulfur. Exemplary heterocyclic rings or heterocycles include oxirane, aziridine, oxetane, oxolane, pyrrolidine, piperidine, and morpholine. As used herein, the phrase "heterocycle of" following the name of a heteroatom refers to a heterocycle that contains only that particular heteroatom and no other heteroatoms. In other words, the ring system contains carbon atoms and at least one particular heteroatom, but no other ring atoms. For example, "heterocycle of oxygen" includes, among others, oxirane, oxolane, dioxolane, but does not include oxathiolane, morpholine, thiomorpholine, etc.

[0333] As used herein, the term "solvate" refers to a type of compound that contains solvent molecules bound by non-covalent intermolecular forces. The solvate may be a solvate of the disclosed compound or a pharma- ceutically acceptable salt thereof. The solvate is a "hydrate" when the solvent molecule is water. The solvate may be stoichiometric or non-stoichiometric. Pharmaceutically acceptable solvates may contain from 1 to about 10, or from 1 to 2, 3, or 4 solvent molecules.

[0334] As used herein, the term "stereoisomer" refers to isomers that are composed of the same atoms linked by the same bonds, but have different, non-exchangeable structures in three-dimensional space. The term stereoisomer includes "enantiomers," which refer to two stereoisomers that are mirror images of each other and are not superimposable on one another. A one-to-one mixture of a pair of enantiomers is called a "racemic" mixture. The term stereoisomer also includes "diastereoisomers" (or "diastereomers"), which refer to two stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry of stereoisomers can be specified according to the Cahn-Ingold Prelog RS system, where the stereochemistry at each chiral center is designated as either R or S. When stereoisomers are resolved but their absolute configuration is unknown, their stereocenters are designated as (+) or (-) depending on the direction (dextrorotatory or levorotatory) that they rotate the plane of polarized light at the wavelength of the sodium D line. In structural diagrams, solid lines

[0335] [ka] indicates a bond approximately in the plane of the drawing. Bonds to atoms above the plane are indicated by a bold wedge shape.

[0336] [ka] The bonds to atoms below the plane are denoted by a hash of short parallel lines, starting with an atom in the plane of the drawing at the narrow end of the wedge.

[0337] [ka] The hash begins with an atom in the plane of the drawing that is at the narrow end of the wedge. All bonds connected to the stereocenter are structurally solid.

[0338] [ka] When compounds have a stereocenter represented by, or when compounds are represented by chemical nomenclature without designation of stereoisomers, unless otherwise specifically stated, they are to be construed to mean any of the possible stereoisomers, a racemic mixture thereof, or a mixture having one or more stereoisomers enriched relative to the other. In other words, for any compound disclosed herein that contains a stereocenter with all bonds connected shown with solid lines, the present disclosure contemplates all possible stereoisomers thereof, and any mixtures of those stereoisomers.

[0339] The term stereoisomer also includes "geometric isomers" such as "cis-trans isomers". These are isomers that differ from each other in the arrangement of groups around a double bond or ring despite the same molecular formula. The term stereoisomer may further include "rotational isomers" or "rotamers", which are defined as stereoisomers resulting from hindered rotation of a single bond. For simplicity, the term "stereoisomer" is used interchangeably with the term "isomer" herein. Unless otherwise specified (such as by reference to retention time for a specified separation condition), "isomer 1" refers to the stereoisomer that elutes first from the column during a separation (e.g., chiral separation of a racemic mixture or separation of a pair of cis-trans isomers) under the specified separation conditions. "Isomer 2" refers to the stereoisomer that elutes second during the same separation. An asterisk ( * ) are used to indicate the chiral centers (stereocenters) in the structures of "Isomer 1" and "Isomer 2". In addition, the bold wedge

[0340] [ka] or hash wedge

[0341] [ka] When an asterisk is used at a stereocenter to which is also bonded, the solid wedge and hashed wedge represent only relative stereochemistry, not absolute stereochemistry. Such designations can be used to convey that the absolute stereochemistry at the indicated stereocenter is unknown, or that the pair of enantiomers based on the indicated stereocenter is not separated (i.e., represents a racemic mixture of enantiomers).

[0342] As used herein, the term "patient" refers to a human.

[0343] As used herein, the term "treating" includes limiting, slowing, stopping, or reversing the progression or severity of an existing condition or disorder.

[0344] As used herein, the term "effective amount" refers to an amount or dosage of a compound of the present invention or a pharma- ceutically acceptable salt thereof that, when administered to a patient in a single or multiple doses, provides the desired effect in the patient being diagnosed or treated. An effective amount can be determined by one of skill in the art using known techniques. In determining the effective amount for a patient, several factors are considered, including, but not limited to, the species of the patient; its size, age, and general health; the particular disease or disorder involved, the extent or involvement or severity of the disease or disorder; the response of the individual patient, the particular compound administered, the mode of administration, the bioavailability characteristics of the formulation administered, the administration regimen selected, the use of concomitant drugs; and other relevant circumstances. The compounds of the present invention are generally effective over a wide dosage range. For example, the daily dosage is usually within the range of about 0.1 to about 15 mg / kg body weight.

[0345] As used herein, the term "immune-mediated disease" encompasses a group of autoimmune or inflammatory disorders in which immune pathways play an important etiological and / or pathogenic role. Such diseases are sometimes characterized by alterations in cellular homeostasis. Immune-mediated diseases can be caused by environmental factors, dietary habits, infectious agents, and genetic predisposition. Some immune-mediated diseases can be associated with cGAS activation. Immune-mediated diseases include, for example, systemic lupus erythematosus, lupus nephritis, dermatomyositis, and Aicardi-Goutières syndrome. Immune-mediated diseases can also include interferonopathies.

[0346] The compound of the present invention is preferably formulated as a pharmaceutical composition that is administered by any route that makes the compound bioavailable, including oral and transdermal routes.More preferably, such compositions are for oral administration.Such pharmaceutical compositions and the process for preparing them are well known in the art (see, for example, Remington: The Science and Practice of Pharmacy, A. Adejare, Editor, 23rd Edition, Elsevier Academic Press, 2020).

[0347] The compounds of the present invention or pharma- ceutically acceptable salts thereof can be prepared according to the following preparations and examples by methods well known and understood in the art. Suitable reaction conditions for the steps of these preparations and examples are well known in the art, and appropriate substitution of solvents and co-reagents is within the skill of the art. Similarly, those skilled in the art will appreciate that synthetic intermediates can be isolated and / or purified by various well-known techniques as necessary or desired, and in many cases, various intermediates can be used directly in subsequent synthetic steps with little or no purification. By way of example, the compounds of the preparations and examples can be isolated, for example, by silica gel purification, or directly by filtration or crystallization. Furthermore, those skilled in the art will appreciate that under some circumstances, the order in which the moieties are introduced is not critical. The particular order of steps required to prepare the compounds of the present invention depends on the particular compound being synthesized, the starting compound, and the relative disadvantages of the substituting moieties, and is well understood by the skilled chemist. All substituents are as previously defined unless otherwise indicated, and all reagents are well known and understood in the art. Abbreviations used throughout this disclosure, unless commonly understood, are provided in Table 1 below.

[0348] [Table 1]

[0349] Scheme 1. General scheme for the preparation of boronic acid pinacol esters 2

[0350] [ka] Scheme 1 shows a general scheme for the synthesis of boronic acid pinacol esters. The synthesis of boronic acid pinacol ester compound 2 can be carried out by reacting bis(pinacolato)diboron with aryl bromo compound 1 under suitable conditions (e.g., 1,4-dioxane as a solvent and potassium acetate as a base) with a catalyst (e.g., Pd(dppf)Cl as a catalyst).2 The reaction is carried out via a cross-coupling reaction using a 2-methylpyrrolidone (e.g., 2-methylpyrrolidone). The mixture is then stirred at a suitable temperature (e.g., 60-105° C.) for several minutes until the reaction is complete. The progress of the reaction can be monitored, for example, by thin layer chromatography (TLC) or other suitable methods. The reaction mixture is concentrated and purified (e.g., by silica gel chromatography) to provide the pinacol ester compound 2.

[0351] Scheme 2. General scheme for preparing compound 4

[0352] [ka] Scheme 2 shows a scheme for the synthesis of intermediate compound 4. The synthesis of 4 is initiated by treating 1,4-dioxaspiro[4.5]decan-8-one (3) with a base such as LDA in a suitable solvent (e.g., THF) at low temperature and reacting the resulting intermediate (e.g., enolate) with a suitable reagent (e.g., ethyl bromoacetate). The mixture is then stirred for several minutes until the reaction is complete. The progress of the reaction can be monitored, for example, by thin layer chromatography (TLC) or other suitable methods. The reaction mixture is concentrated and purified (e.g., by silica gel chromatography) to give intermediate compound 4.

[0353] Scheme 3. General scheme for the synthesis of compounds of formula 1s

[0354] [ka] Scheme 3 shows a general scheme for the synthesis of compounds of formula 1s and intermediates thereof. In step 1, a fluorine-containing compound 5 is contacted with hydrazine under conditions sufficient to provide intermediate compound 6. For example, N 2A solution of compound 5 below is heated with hydrazine hydrate at a suitable temperature (e.g., 70-80° C.) for several hours until the reaction is complete. The reaction is quenched (e.g., with water), extracted with a suitable solvent (e.g., EtOAc), dried (e.g., over anhydrous sodium sulfate), concentrated under reduced pressure, and purified (e.g., by silica gel chromatography) to give intermediate compound 6.

[0355] In step 2, compound 6 is contacted with 1,4-dioxaspiro[4.5]decan-8-one under conditions sufficient to provide compound 7. For example, a solution of compound 6 in a suitable solvent (e.g., toluene) and a suitable catalyst (e.g., zinc chloride) is heated to a suitable temperature (e.g., 110-130° C.) for several hours and then cooled to ambient temperature. The reaction is extracted with a suitable solvent (e.g., EtOAc), dried (e.g., over anhydrous sodium sulfate), concentrated under reduced pressure, and purified (e.g., by silica gel chromatography) to provide compound 7.

[0356] In step 3, compound 7 is converted under conditions sufficient to provide compound 8. For example, compound 7 is dissolved in a suitable solvent (e.g., acetone), treated with a suitable acid (e.g., TFA), and heated at a suitable temperature (e.g., 60-80° C.) for several hours until the reaction is complete. The reaction mixture is triturated from a suitable solvent (e.g., MTBE / EtOAc) and concentrated under reduced pressure to provide intermediate compound 8.

[0357] In step 4, compound 8 is contacted with an azide compound under conditions sufficient to obtain compound 9 (e.g., Schmidt reaction conditions). For example, compound 8 is cooled, dissolved in a suitable solvent (e.g., methanesulfonic acid), treated with an azide (e.g., sodium azide), and warmed to ambient temperature for several minutes. The reaction mixture is quenched by adding it to a suitable aqueous base (e.g., aqueous sodium bicarbonate). The solid is collected by suction filtration, washed, dried, and purified (e.g., by silica gel chromatography) to obtain compound 9. Alternatively, the quenched reaction is extracted with a suitable solvent (e.g., EtOAc), dried (e.g., over anhydrous sodium sulfate), concentrated under reduced pressure, and purified (e.g., by silica gel chromatography) to obtain compound 9.

[0358] In step 5, compound 9 is converted under sufficient reaction conditions to provide boronic acid pinacol ester compound 9a. For example, aryl bromide compound 9 is reacted with bis(pinacolato)diboron (e.g., Pd(dppf)Cl) under suitable conditions to give boronic acid pinacol ester compound 9a. 2 Heating at a suitable temperature (eg, 60-105° C.) for several hours with a catalyst, a solvent such as 1,4-dioxane or DMF, and a suitable base such as potassium acetate provides intermediate compound 9a.

[0359] In step 6, compound 9a is contacted with a protected triazole compound under conditions sufficient to provide compound 9b. For example, compound 9a can be reacted with 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole in a suitable solvent, such as 1,4-dioxane and water, to afford compound 9b. 2 and a suitable base (such as potassium carbonate or sodium carbonate) at a suitable temperature (e.g., 60-105° C.) for several hours until completion. The reaction mixture is cooled to ambient temperature, filtered, and rinsed through silica. The filtrate is concentrated under reduced pressure and purified (e.g., by silica gel flash chromatography) to provide intermediate compound 9b.

[0360] In step 7, compound 9b is deprotected under conditions sufficient to provide a compound of formula 1s (eg, using an acid such as TFA in a solvent such as DCM at ambient temperature).

[0361] Scheme 3'. General scheme for the synthesis of compounds of formula 9'

[0362] [ka] Scheme 3' shows a general scheme for the synthesis of compounds of formula 9' and intermediates thereto. In step 2a, compound 6 is reacted with compound 3b, R 2 under conditions sufficient to give compound 7'. 5 and / or R 9 For example, a solution of compound 6 in a suitable solvent (e.g., toluene or xylene) and a suitable catalyst (e.g., zinc chloride) is heated to a suitable temperature (e.g., 110-130° C.) for several hours and then cooled to ambient temperature. The reaction is extracted with a suitable solvent (e.g., EtOAc), dried (e.g., over anhydrous sodium sulfate), concentrated under reduced pressure, and purified (e.g., by silica gel chromatography) to obtain compound 7′. Steps 3a and 4a are carried out according to Scheme 3 above to obtain a compound of formula 9′.

[0363] Scheme 3'a. General scheme for the synthesis of compounds of formula 8

[0364] [ka] Scheme 3'a shows a general scheme for the synthesis of compounds of formula 8 and intermediates thereof. In step 2b, compound 6 is reacted with compound 3b, R 5Compound 7b' is contacted with 1,4-dioxaspiro[4.5]decan-8-one substituted with 1,4-dioxaspiro[4.5]decan-8-one and an alkyl carboxylate under conditions sufficient to obtain compound 7b'. For example, a solution of compound 6 in a suitable solvent (e.g., MeOH) and acetic acid is heated to reflux for several hours to obtain a hydrazone compound. The hydrazone compound is then contacted with a suitable catalyst (e.g., zinc chloride) to obtain compound 7b'. In step 3b, compound 7b' is hydrolyzed under sufficient conditions, such as in the presence of sodium hydroxide, followed by acidification to form a carboxylic acid compound. The carboxylic acid compound is contacted with a suitable acid (e.g., acetic acid) and heated under conditions sufficient to obtain compound 8.

[0365] Scheme 3''. General scheme for the synthesis of compounds of formula 1s''

[0366] [ka] Scheme 3'' shows a general scheme for the synthesis of compounds of formula 1s'' and intermediates thereof. In step 1, compound 9'' is converted under sufficient reaction conditions to give boronic acid pinacol ester compound 9a''. For example, an aryl bromide is reacted with bis(pinacolato)diboron under suitable conditions (e.g., Pd(dppf)Cl 2 Heating under a suitable temperature (eg, 60-105° C.) for several hours with a catalyst, a solvent such as 1,4-dioxane, and a suitable base such as potassium acetate forms the pinacol ester 9a′.

[0367] In step 2, a Suzuki reaction is depicted in which compound 9a' is contacted with a protected triazole compound under conditions sufficient to provide compound 9b'. For example, compound 9a' can be reacted with 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole in a suitable solvent (e.g., 1,4-dioxane and water) using Pd(dppf)Cl 2and a suitable base (e.g., potassium carbonate or sodium carbonate) at a suitable temperature (e.g., 60-105° C.) for several hours until completion. The reaction mixture is cooled to ambient temperature, filtered, and rinsed through silica. The filtrate is concentrated under reduced pressure and purified (e.g., by silica gel flash chromatography) to provide intermediate compound 9b′.

[0368] In step 3, compound 9b' is deprotected under conditions sufficient to provide a compound of formula 1s' (eg, using an acid such as TFA in a solvent such as DCM at ambient temperature).

[0369] Scheme 4. General scheme for the synthesis of compounds of formula 1b-1d

[0370] [ka] Scheme 4 shows a general scheme for the synthesis of compounds of formula 1a, 1b, 1c and 1d.

[0371] In step 1, the compound of formula 1a is hydrolyzed under conditions sufficient to obtain a compound of formula 1c. For example, a solution of the compound of formula 1a in a suitable solvent (e.g., a mixture of THF and MeOH) is treated with a suitable base (e.g., NaOH). The mixture is stirred at ambient temperature and a suitable acid (e.g., HCl) is added. The reaction mixture is diluted with a suitable solvent and the organic layer is extracted. The organic layer is dried (e.g., over sodium sulfate), filtered, and concentrated under reduced pressure. The residue is dissolved in a solvent (e.g., DCM) and dried under reduced pressure to obtain a compound of formula 1c.

[0372] In step 2, the compound of formula 1c is contacted with a suitable amine under conditions sufficient to obtain a compound of formula 1d. For example, the compound of formula 1c is mixed with an amide coupling reagent (e.g., 2,4,6-triisopropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide in EtOAc) and an amine (e.g., methylamine or di-methylamine) in a suitable solvent (e.g., DMF) and stirred at ambient temperature for several hours. The reaction mixture is diluted with saturated aqueous sodium bicarbonate and the layers are separated. The organic layer is washed with water, then saturated aqueous NaCl, dried (e.g., over anhydrous sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by silica gel flash chromatography) to obtain a compound of formula 1d.

[0373] Alternatively, in step 1a, the solution of the compound of formula 1a is contacted with a suitable reducing agent to obtain the compound of formula 1b. For example, the compound of formula 1a is cooled in a suitable solvent (e.g., DCM). A reducing agent (e.g., DIBAL-H) ​​is added, and the reaction mixture is warmed to ambient temperature. The mixture is then cooled and quenched with a suitable solvent (e.g., EtOAc). The mixture is warmed to ambient temperature and diluted with a suitable solvent. The layers are separated, the aqueous layer is extracted with a suitable solvent (e.g., DCM), and the combined organic layers are dried (e.g., over anhydrous sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by silica gel flash chromatography) to obtain the compound of formula 1b.

[0374] Scheme 4'. General scheme for the synthesis of compounds of formula 1a, 1b, 1b-i, 1c, 1c-i, 1c-ii, 1c-iii, and 1d.

[0375] [ka] Scheme 4' shows R 12 and R 18 1 shows a general scheme for the synthesis of compounds of formula 1b-i, 1c-i, 1c-ii, and 1c-iii, each of which is methyl or H.

[0376] Steps 1 and 2 are carried out according to Scheme 4 above. Step 3 depicts the Weinreb amide forming reaction in which a compound of formula 1c is reacted with N,O-dimethylhydroxylamine hydrochloride in the presence of a coupling reagent such as HATU, a solvent such as DMF, and a base such as DIPEA at a suitable temperature such as about 25° C. to give a compound of formula 1c-i.

[0377] Step 4 depicts the Weinreb ketone synthesis reaction in which a compound of formula 1c-i is reacted with an organomagnesium such as MeMgBr in the presence of a solvent such as THF at a suitable temperature to give a compound of formula 1c-ii.

[0378] Step 5 involves reacting a compound of formula 1c-ii with NaBH in the presence of a solvent such as MeOH at a suitable temperature such as about 20° C. 4 to give compounds of formula 1c-iii.

[0379] Step 1a can be carried out according to Scheme 4 above. Step 1b shows the cyclization of formula 1b in a Mitsunobu reaction to give compounds of formula 1b-i. This reaction is carried out in the presence of a reagent such as diisopropyl azodicarboxylate, a catalyst such as triphenylphosphine, in the presence of a solvent such as THF at a suitable temperature, preferably 0° C.

[0380] Scheme 5. General scheme for the synthesis of compound 12 and compounds of formula 1e

[0381] [ka] Scheme 5 shows a general scheme for the synthesis of compounds 12 and compounds of formula 1e, as well as intermediates thereto.

[0382] In step 1, compound 9 is contacted with NBS or NIS under conditions sufficient to provide compound 10. For example, a solution of compound 9 in a suitable solvent (e.g., DMF) is treated with a suitable base (e.g., cesium carbonate). The mixture is then cooled, NBS or NIS is added, and the reaction is allowed to warm to ambient temperature. The reaction mixture is quenched (e.g., with aqueous LiCl), filtered, and washed with water to provide compound 10.

[0383] In step 2, compound 10 is contacted with a suitable Grignard reagent under conditions sufficient to provide compound 11. For example, compound 10 is treated with an alkyl magnesium bromide in a suitable solvent (e.g., THF). The reaction mixture is quenched with water and a suitable acid (e.g., HCl). The reaction is extracted with a suitable solvent (e.g., EtOAc), dried (e.g., over magnesium sulfate), concentrated under reduced pressure, and purified (e.g., by silica gel chromatography) to provide compound 11.

[0384] In step 3, compound 11 is contacted with 2-hydroxyacetamide under conditions sufficient to provide a compound of formula 1e. For example, a solution of compound 11 in a suitable solvent (e.g., 1,4-dioxane) can be reacted with a suitable catalyst (e.g., Pd 2 (dba) 3 The mixture is heated to reflux for several minutes, cooled to ambient temperature, and partitioned between water and EtOAc. The combined organic layers are dried (e.g., over sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by silica gel chromatography) to provide a compound of formula 1e.

[0385] Alternatively, in step 3a, compound 11 is converted to compound 12 under sufficient conditions. For example, compound 11 is dissolved in a suitable solvent, and then a base (e.g., sodium tert-butoxide) and a catalyst (e.g., tert-BuBrettPhos-Pd-G3) are added. The reaction mixture is heated to a suitable temperature, such as about 65° C., for several hours, cooled to ambient temperature, and quenched with a suitable acid (e.g., HCl). The reaction is then extracted with a suitable solvent (e.g., EtOAc), dried (e.g., over magnesium sulfate), concentrated under reduced pressure, and purified (e.g., by silica gel chromatography) to obtain compound 12.

[0386] Scheme 5'. General scheme for the synthesis of compounds of formula 1e and 1e-i

[0387] [ka] Scheme 5' shows a general scheme for the synthesis of compound 12', compounds of formula 1e', and compounds of formula 1e-i, and intermediates thereof. Steps 1, 2, and 3a are carried out according to Scheme 5 above from compound 9'. In some embodiments, the alkyl magnesium bromide used in step 2 is methyl magnesium bromide.

[0388] In step 3, compound 11 is contacted with 2-hydroxyacetamide under conditions sufficient to provide a compound of formula 1e. For example, a solution of compound 11' in a suitable solvent (e.g., 1,4-dioxane) can be reacted with a suitable catalyst (e.g., Pd 2 (dba) 3 ) and ligand (Xantphos) or tert-BuBrettPhos-Pd-G 3The mixture is heated to reflux for several minutes, cooled to ambient temperature, and partitioned between water and EtOAc. The combined organic layers are dried (e.g., over sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by silica gel chromatography) to provide a compound of formula 1e'. One of skill in the art will recognize that there are many combinations of catalysts, ligands, bases, and solvents that can be used to effect this transformation.

[0389] Alternatively, in step 3a, compound 11' is converted to compound 12' under sufficient conditions by a hydroxylation reaction. For example, compound 11' is dissolved in a suitable solvent (e.g., 1,4-dioxane and water), and then a base (e.g., sodium tert-butoxide) and a catalyst (e.g., tert-BuBrettPhos-Pd-G3) are added. The reaction mixture is heated to a suitable temperature, such as about 65°C, for several hours, cooled to ambient temperature, and quenched with a suitable acid (e.g., HCl). The reaction is then extracted with a suitable solvent (e.g., EtOAc), dried (e.g., over magnesium sulfate), concentrated under reduced pressure, and purified (e.g., by silica gel chromatography) to obtain compound 12'. Those skilled in the art will recognize that there are many combinations of catalysts, ligands, bases, and solvents that can be used to carry out this transformation.

[0390] In step 3b, the phenol in compound 12' is alkylated to give compound 1e-i by reacting compound 12' with an alkylating agent such as chloroacetonitrile or bromoacetonitrile in the presence of a base such as potassium carbonate and a solvent such as DMF at a suitable temperature, for example ambient temperature.

[0391] Scheme 5A. General scheme for the synthesis of compounds of formula 1e-ii

[0392] [ka] Scheme 5A illustrates the synthesis of compounds of formula 1e-ii via intermediate 12a.

[0393] In step 1, compound 11' is reacted with Pd 2 (dba) 3 and a ligand such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, a solvent such as 1,4-dioxane, and a base such as cesium carbonate at a suitable temperature, for example about 100-115° C., to give compound 12a.

[0394] In step 2, compound 12a is fluorinated by reaction with 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate in the presence of a solvent such as ACN at ambient temperature. Addition of HCl to the reaction allows for deprotection of the tert-butyldimethylsilyl to give the fluorinated compound of formula 1e-ii.

[0395] Scheme 6. General scheme for the synthesis of compounds of formula 1f, 1g, 1h and 1i

[0396] [ka] Scheme 6 shows a general scheme for the synthesis of compounds of formula 1f, 1g, 1h, and 1i as well as intermediates therefor. PG is a suitable protecting group and R g is methyl or ethyl.

[0397] In step 1, compound 12 is contacted with an alkyl bromide under conditions sufficient to provide compound 14. For example, compound 12 can be dissolved in a suitable solvent (e.g., DMF) followed by addition of a suitable base (e.g., K 2 CO 3) and an alkyl bromide (e.g., 3-bromopropyl acetate or 2-(2-bromoethoxy)tetrahydro-2H-pyran). The mixture is then stirred at ambient temperature, followed by the addition of a suitable catalyst (e.g., NaI). Stirring is continued for several hours. The reaction is cooled to ambient temperature and diluted with a suitable solvent (e.g., EtOAc). Diatomaceous earth is added, followed by filtration and then rinsing with EtOAc. The filtrate is washed (e.g., with saturated aqueous sodium bicarbonate and saturated aqueous NaCl), dried (e.g., over anhydrous sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by silica gel flash chromatography) to provide compound 14.

[0398] In step 2, compound 14 is deprotected under conditions sufficient to provide a compound of formula 1g, for example, using an acid (such as HCl) and a suitable solvent (such as 1,4-dioxane) or a base (such as LiOH) in a solvent (such as MeOH).

[0399] Alternatively, in step 1a, compound 12 is contacted with a haloacetonitrile reagent to obtain a compound of formula 1h. For example, compound 12 is dissolved in a suitable solvent (e.g., DMF) and cooled to 0° C. A suitable base (e.g., potassium carbonate) is added, followed by bromoacetonitrile, and the reaction is stirred at ambient temperature. The mixture is poured into saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer is washed (e.g., with saturated aqueous NaCl), dried (e.g., over anhydrous sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by silica gel flash chromatography) to obtain a compound of formula 1h.

[0400] In step 2a, the compound of formula 1h is hydrolyzed under conditions sufficient to provide a compound of formula 1i. For example, the compound of formula 1h is dissolved in a suitable solvent (e.g., DMSO). 2 O 2and a base (e.g., potassium carbonate) is added. The reaction is stirred for an appropriate time and quenched with aqueous sodium thiosulfate, followed by the addition of water and EtOAc. The organic layer is washed (e.g., with saturated aqueous NaCl), dried (e.g., over anhydrous sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by silica gel flash chromatography) to provide a compound of formula 1i.

[0401] Alternatively, in step 1b, compound 12 is contacted with a suitable alkylating agent under conditions sufficient to obtain a compound of formula 1f. For example, compound 12 and a suitable base (such as potassium carbonate) are stirred in a suitable solvent (e.g., DMSO). An alkyl halide (e.g., iodoethane or iodomethane) is added and stirred at a suitable temperature (e.g., about 50°C). The reaction is then cooled to ambient temperature, washed (e.g., with saturated aqueous NaCl), dried (e.g., over anhydrous magnesium sulfate), filtered, concentrated onto diatomaceous earth, and purified (e.g., by silica gel flash chromatography) to obtain a compound of formula 1f.

[0402] Scheme 6'. General scheme for the synthesis of compounds of formula 1f', 1g', 1h' and 1i'

[0403] [ka] Scheme 6' shows a general scheme for the synthesis of compounds of formula 1f', 1g', 1h', and 1i' as well as intermediates thereof. PG is a suitable protecting group. R g is methyl or ethyl.

[0404] In step 1, compound 12' is contacted with a reagent under conditions sufficient to provide compound 14'. For example, compound 12 is dissolved in a suitable solvent (e.g., DMF) followed by addition of a suitable base (e.g., K 2 CO 3) and an alkyl halide (e.g., 3-bromopropyl acetate or 2-(2-bromoethoxy)tetrahydro-2H-pyran). The mixture is then stirred at ambient temperature, and then a suitable catalyst (e.g., NaI) is added. Stirring is continued for several hours. The reaction is cooled to ambient temperature and diluted with a suitable solvent (e.g., EtOAc). Diatomaceous earth is added, followed by filtration and then rinsing with EtOAc. The filtrate is washed (e.g., with saturated aqueous sodium bicarbonate and saturated aqueous NaCl), dried (e.g., over anhydrous sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by silica gel flash chromatography) to obtain compound 14'. Step 1, step 1a, step 1b, step 2, and step 2a are carried out according to Scheme 6 above to obtain compounds of formula 1f', formula 1g', formula 1h', and formula 1i'.

[0405] Scheme 7. General scheme for the synthesis of compounds of formula 1j and 1k

[0406] [ka] Scheme 7 shows a general scheme for the synthesis of compounds of formula 1j, formula 1k and their intermediates. In step 1, compound 9 is contacted with a suitable reagent to obtain compound 15 with indole nitrogen protection. For example, compound 9 is dissolved in a suitable solvent such as THF. A protecting group reagent such as SEM-Cl and a base (such as sodium hydride) are added and stirred at a suitable temperature for several hours. The reaction is quenched with saturated aqueous sodium bicarbonate, washed (e.g., with saturated aqueous sodium bicarbonate and extracted into EtOAc), dried (e.g., over anhydrous sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by silica gel flash chromatography) to obtain compound 15.

[0407] In step 2, compound 15 is contacted with an aqueous base under conditions sufficient to form compound 16. For example, compound 15 is dissolved in a solvent such as 1,4-dioxane and water. A base (such as t-BuONa) and a catalyst (such as tert-BuBrettPhos-Pd-G) are added to the reaction mixture. 3A 2-chloro-3-(2-methyl-1,2-diphenyl-2-propanediol) is added and the mixture is heated to an appropriate temperature. The mixture is cooled to ambient temperature and an acid (such as aqueous HCl) is added. The reaction mixture is diluted with EtOAc, washed (e.g., with saturated aqueous NaCl), dried (e.g., over anhydrous sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by silica gel flash chromatography) to provide compound 16.

[0408] In step 3, compound 16 is contacted with an alkyl bromide under conditions sufficient to provide compound 17. For example, compound 16 is dissolved in a suitable solvent (e.g., DMF) and cooled to 0° C. A suitable base (e.g., potassium carbonate) is added, followed by bromoacetonitrile, and the reaction is stirred at ambient temperature until completion. The mixture is poured into saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer is washed (e.g., with saturated aqueous NaCl), dried (e.g., over anhydrous sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by silica gel flash chromatography) to provide compound 17.

[0409] In step 4, compound 17 is deprotected under conditions sufficient to provide compound 18. For example, compound 17 is dissolved in a suitable solvent such as DCM, and a suitable acid such as TFA is added. The mixture is concentrated, diluted with a suitable solvent such as THF, diluted with aqueous ammonia, and stirred at ambient temperature for several hours. The reaction is diluted with EtOAc, washed (e.g., with saturated aqueous NaCl), dried (e.g., over anhydrous sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by silica gel flash chromatography) to provide compound 18.

[0410] In step 5, compound 18 is indole alkylated under sufficient conditions to give a compound of formula 1j. For example, compound 18 and a base (e.g., cesium carbonate) are stirred in a suitable solvent (e.g., DMF). A haloalkane (e.g., iodomethane or iodoethane) is added and the mixture is stirred at a suitable temperature for several hours. The mixture is diluted with water, extracted with EtOAc, concentrated under reduced pressure, and purified (e.g., by preparative HPLC) to give a compound of formula 1j.

[0411] Alternatively, in step 4a, compound 17 is converted to compound 19 under sufficient conditions. For example, compound 17 is dissolved in a suitable solvent (e.g., DMSO) and then diluted with H 2 O 2 and a base (e.g., potassium carbonate) is added. The reaction is stirred for a sufficient period of time and then diluted with an appropriate solvent (e.g., EtOAc), washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The reaction is then triturated with an appropriate solvent, such as ACN, to provide intermediate 19.

[0412] In step 5a, compound 19 is deprotected under conditions sufficient to obtain compound of formula 1k. For example, compound 19 is dissolved in a suitable solvent such as DCM. A suitable acid (such as TFA) is added, and the mixture is stirred at ambient temperature for several hours until completion. The mixture is then concentrated with a suitable solvent such as THF, diluted with aqueous ammonia, and stirred at a suitable temperature for several hours. The reaction is diluted with EtOAc, washed (e.g., with saturated aqueous NaCl), dried (e.g., over anhydrous sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by preparative HPLC) to obtain compound of formula 1k.

[0413] Scheme 7'. General scheme for the synthesis of compounds of formula 1j' and formula 1k'

[0414] [ka] Scheme 7' shows a general scheme for the synthesis of compounds of formula 1j', formula 1k' and intermediates thereof. Steps 1, 2, 3, 4 and 5 are carried out according to Scheme 7 above using suitable starting materials to obtain compounds of formula 1j'. In step 4a, compound 17' is converted to compound 19' under sufficient conditions. For example, compound 17' is dissolved in a suitable solvent (e.g., DMSO) and then subjected to H 2 O 2and a base (e.g., potassium carbonate) is added. The reaction is stirred, then diluted with a suitable solvent (e.g., EtOAc), washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The reaction is then triturated with a suitable solvent, such as ACN, to obtain intermediate 19'. In step 5a, compound 19' is deprotected under conditions sufficient to obtain formula 1k'. For example, compound 19' is dissolved in a suitable solvent, such as DCM. A suitable acid (e.g., TFA) is added, and the mixture is stirred at ambient temperature for several hours until completion. The mixture is then concentrated with a suitable solvent, such as THF, diluted with aqueous ammonia, and stirred at a suitable temperature for several hours. The reaction is diluted with EtOAc, washed (e.g., with saturated aqueous NaCl), dried (e.g., over anhydrous sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by preparative HPLC) to obtain compound of formula 1k'.

[0415] Scheme 8. General scheme for the synthesis of formula 1l

[0416] [ka] Scheme 8 illustrates the synthesis of compounds of formula 1l and intermediates thereto. In step 1, a halide-containing compound 9 is contacted with a tert-butyl carbamate compound under conditions sufficient to provide compound 20. For example, compound 9 is dissolved in a suitable solvent (such as 1,4-dioxane) and a suitable base (such as cesium carbonate) is added. The tert-butyl carbamate is then reacted with a catalyst (such as Xantphos-Pd-G 2 etc.) The mixture is stirred at an appropriate temperature for several hours until complete. The reaction is concentrated under reduced pressure and purified (e.g., by silica gel flash chromatography) to provide compound 20.

[0417] In step 2, compound 20 is deprotected under conditions sufficient to provide compound 21. For example, compound 20 is contacted with an acid (such as HCl in EtOH) and then concentrated under reduced pressure and triturated with a solvent such as EtOAc to provide compound 21.

[0418] In step 3, compound 21 is contacted with a suitable aldehyde under sufficient conditions (e.g., reductive amination conditions) to obtain compound 22. For example, compound 21 is dissolved in a suitable solvent, such as MeOH, and acetic acid, along with a base, such as DIPEA. An aldehyde (such as 3-[tertbutyl(dimethyl)silyl]oxypropanal) and a reducing agent (such as sodium cyanoborohydride) are added to the solution. The mixture is stirred at a suitable temperature (such as ambient temperature) for several hours until completion. The reaction is quenched with a suitable solvent (such as water) and extracted with EtOAc. The organics are dried (e.g., over anhydrous sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by silica gel flash chromatography) to obtain compound 22.

[0419] In step 4, compound 22 is contacted with an acid under conditions sufficient to provide a compound of formula 11. For example, compound 22 is suspended and stirred in an acid and solvent system, such as HCl / MeOH, at a suitable temperature. Upon completion, the reaction mixture is concentrated under reduced pressure, purified (e.g., by preparative HPLC), and lyophilized to provide a compound of formula 11.

[0420] Scheme 8'. General scheme for the synthesis of formula 1l'

[0421] [ka] Scheme 8' illustrates the synthesis of compounds of formula 1l' and intermediates thereof. Steps 1, 2, 3 and 4 are carried out from compounds of formula 9' according to Scheme 8 above.

[0422] Scheme 9. General scheme for the synthesis of compounds of formula 1m and formula 1n

[0423] [ka] Scheme 9 illustrates the synthesis of compounds of formula 1m, formula 1n, and intermediates thereof. In step 1, compound 21 is contacted with acetoxyacetyl chloride under conditions sufficient to provide compound 23. For example, compound 21 is reacted with a suitable base (such as Et 3 N) at ambient temperature. The reaction is then quenched using an appropriate solvent, dried (e.g., over anhydrous sodium sulfate), filtered, and concentrated under reduced pressure to provide compound 23.

[0424] In step 2, compound 23 is contacted with a base to obtain a compound of formula 1m. For example, compound 23 is dissolved in a suitable solvent (such as THF and water) and a base (such as lithium hydroxide monohydrate) is added. The mixture is stirred at a suitable temperature for several minutes until the reaction is complete. The reaction is then diluted with water, extracted, dried (e.g., over anhydrous sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by preparative HPLC) to obtain a compound of formula 1m.

[0425] Alternatively, in step 1a, compound 21 is contacted with an aldehyde under conditions sufficient to obtain a compound of formula 1n. For example, compound 21 is dissolved in a suitable solvent (such as MeOH) and an acid (such as acetic acid) is added to adjust the pH. Acetaldehyde is added along with a reducing agent (such as sodium cyanoborohydride). The mixture is stirred at ambient temperature for several hours. The reaction is then diluted, washed (e.g., with saturated aqueous sodium bicarbonate and saturated aqueous NaCl), dried (e.g., over sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by silica gel flash chromatography and preparative HPLC) to obtain a compound of formula 1n.

[0426] Scheme 9'. General scheme for the synthesis of compounds of formula 1m' and formula 1n'

[0427] [ka] Scheme 9' illustrates the synthesis of compounds of formula 1m', formula 1n' and intermediates thereof. Steps 1, 2, 3 and 4 are carried out from a compound of formula 21' according to Scheme 9 above.

[0428] Scheme 10. General scheme for the synthesis of compounds of formula 1o and 1p

[0429] [ka] Scheme 10 illustrates the synthesis of compounds of formula 1o, formula 1p, and intermediates thereof. In step 1, halide-containing compound 9 is converted under sufficient conditions (e.g., a palladium-catalyzed carbonylation reaction) to provide ester-containing compound 24. For example, compound 9 is dissolved in a suitable solvent, such as MeOH and DMF, in the presence of a suitable catalyst (Pd(dppf)Cl 2 etc.) and bases (Et 3 The reaction is suspended in a hexanes solution (such as N). The reaction is sparged with CO and stirred under a CO atmosphere at an appropriate temperature and pressure for several hours, then diluted with a solvent (such as EtOAc). The reaction is washed sequentially with water and saturated aqueous NaCl, dried (e.g., over sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by silica gel flash chromatography) to provide compound 24.

[0430] In step 2, compound 24 is hydrolyzed under conditions sufficient to provide carboxylic acid compound 25. For example, compound 24 is taken up in a suitable organic solvent (e.g., THF, water or a mixture thereof), treated with a base (e.g., lithium hydroxide monohydrate), and stirred at ambient temperature for several hours until complete. The pH of the solution is adjusted to about 4, and the resulting solid is filtered and washed (e.g., with water) to provide compound 25.

[0431] In step 3, compound 25 is contacted with N'-hydroxyacetimidamide under conditions sufficient to provide compound 26. For example, compound 25 is suspended in a solvent (such as DMF) containing a base (such as DIPEA) with a coupling agent (such as TBTU). N'-hydroxyacetimidamide and catalytic DMAP are added to the mixture and stirred at an appropriate temperature for several hours until completion. The reaction is then diluted with EtOAc, washed successively with water and saturated aqueous NaCl, dried (e.g., over sodium sulfate), filtered, and concentrated under reduced pressure to provide intermediate compound 26.

[0432] In step 4, compound 26 is contacted with a fluoride source under conditions sufficient to provide a compound of formula 1o (e.g., ring-closing conditions). For example, compound 26 is dissolved in a suitable solvent (e.g., 1,4-dioxane) and KF is added. The mixture is heated at a suitable temperature (e.g., 100-120° C.) for several hours with N 2 O until the reaction is complete. 2 The reaction is then cooled to ambient temperature and the precipitate is filtered and triturated to provide the compound of formula 1o.

[0433] Alternatively, in step 3a, compound 25 is contacted with ethyl (N'-hydroxycarbamimidoyl)formate under conditions (e.g., amide coupling conditions) sufficient to provide compound 27. The coupling process is similar to that described above for step 3.

[0434] In step 4a, compound 27 is contacted with a fluoride source under conditions sufficient to provide compound 28 (eg, ring-closing conditions), eg, in a process similar to that described above for step 4.

[0435] In step 5a, compound 28 is contacted with a reducing agent under conditions sufficient to provide a compound of formula 1p. For example, compound 28 is dissolved in a suitable solvent (such as THF) and lithium borohydride is added. The mixture is stirred for several minutes and then saturated NH 4Quench with aqueous Cl and dilute with DCM and water. The organic layer is dried (e.g., over sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by preparative HPLC) to provide a compound of formula 1p.

[0436] Scheme 10'. General scheme for the synthesis of compounds of formula 1o' and formula 1p'

[0437] [ka] Scheme 10' illustrates the synthesis of compounds of formula 1o', formula 1p' and intermediates thereof. Steps 1, 2, 3, 4, 3a, 4a, and 5a are carried out according to Scheme 10 above from the starting material of compound of formula 9'.

[0438] Scheme 11. General scheme for the synthesis of formula 1q

[0439] [ka] Scheme 11 illustrates the synthesis of compounds of formula 1q and intermediates thereto. In step 1, aryl bromide compound 9 is contacted with vinyl trifluoroborate salt under conditions sufficient to provide compound 29 (e.g., a palladium-catalyzed cross-coupling reaction). For example, compound 9 can be reacted with potassium vinyl trifluoroborate and Pd(dppf)Cl in a solvent (e.g., 1,4-dioxane and water) in the presence of a base (e.g., sodium carbonate) to give compound 29. 2 The mixture is suspended in N 2 The mixture is sparged with and stirred at a suitable temperature (e.g., 90° C.) for several hours until complete. The mixture is filtered, washed with a solvent (such as 1,4-dioxane), concentrated under reduced pressure, and purified (e.g., by silica gel flash chromatography) to provide intermediate compound 29.

[0440] In step 2, compound 29 is contacted with a suitable dihydroxylation reagent under conditions sufficient to provide diol compound 30. For example, compound 29 is dissolved in a solvent (such as THF and water) along with an oxidant (such as NMO). A dihydroxylation catalyst, such as potassium osmate dihydrate, is added, and the mixture is stirred for several hours until the reaction is complete. The reaction is diluted with EtOAc, washed (e.g., with saturated aqueous sodium bicarbonate and saturated aqueous NaCl), dried (e.g., over sodium sulfate), filtered, and concentrated under reduced pressure to provide intermediate compound 30.

[0441] In step 3, compound 30 is contacted with an oxidizing agent under conditions sufficient to provide intermediate compound 31 (e.g., oxidative cleavage conditions). For example, compound 30 is suspended in a suitable solvent (such as water and acetone) along with sodium periodate. The mixture is stirred at ambient temperature until the reaction is complete. The reaction mixture is then filtered and concentrated under reduced pressure to provide compound 31.

[0442] In step 4, compound 31 is contacted with TosMIC under conditions sufficient to provide a compound of formula 1q. For example, compound 31 is dissolved in a suitable solvent (such as MeOH) along with a base (such as potassium carbonate). TosMIC is added and the mixture is stirred at a suitable temperature (e.g., 65-80° C.) for several hours until completion. The reaction is then cooled to ambient temperature, diluted with EtOAc, washed (e.g., with saturated aqueous NaCl), dried (e.g., over sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by preparative HPLC) to provide a compound of formula 1q.

[0443] Scheme 11'. General scheme for the synthesis of formula 1q'

[0444] [ka] Scheme 11' illustrates the synthesis of compounds of formula 1q' and intermediates thereof. Steps 1, 2, 3, and 4 are carried out according to Scheme 11 above from the starting material of a compound of formula 9'.

[0445] Scheme 12. General scheme for the synthesis of formula 1r

[0446] [ka] Scheme 12 illustrates the synthesis of compounds of formula 1r and intermediates thereof. In step 1, compound 9 is contacted with 4-isoxazoleboronic acid pinacol ester under conditions (e.g., Suzuki reaction conditions) sufficient to provide compound 32. For example, 4-isoxazoleboronic acid pinacol ester is reacted with a suitable base (e.g., KF) and Pd(dppf)Cl in a suitable solvent (e.g., DMSO and water) to afford compound 32. 2 The mixture is added to compound 9 along with the catalyst. 2 The mixture is sparged with ethyl acetate and stirred at a suitable temperature (e.g., 100-130° C.) for several hours. The reaction is diluted with water, extracted with EtOAc, dried (e.g., over anhydrous sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by silica gel chromatography) to provide compound 32 (or its ring-open isomer).

[0447] In step 2, compound 32 is contacted with a fluoride source under conditions sufficient to provide a compound of formula 1r. Compound 32 is dissolved in a suitable solvent system (such as DMF and water) along with KF and stirred at a suitable temperature (e.g., 100-120° C.) for several hours until the reaction is complete. The reaction is concentrated under reduced pressure to remove water and purified (e.g., by preparative HPLC) to provide a compound of formula 1r.

[0448] Scheme 12'. General scheme for the synthesis of formula 1r'

[0449] [ka] Scheme 12' illustrates the synthesis of compounds of formula 1r' and intermediate 32' (or its ring-open isomer). Steps 1 and 2 are carried out from compound 9' starting material according to Scheme 12 above.

[0450] Scheme 13. General scheme for the synthesis of compounds of formula 1s-a

[0451] [ka] Scheme 13 illustrates the synthesis of compounds of formula 1t via intermediates 33 and 34.

[0452] In step 1, compound 25 is reacted with tert-butyl N-carbamimidoyl carbamate in the presence of a coupling agent such as ((1H-benzo[d][1,2,3]triazol-1-yl)oxy)tri(pyrrolidin-1-yl)phosphonium, a base such as 4-methylmorpholine, and a solvent such as DMF at a suitable temperature, for example ambient temperature, to give compound 33.

[0453] In step 2, compound 33 is reacted with (diacetoxyiodo)benzene in the presence of a solvent such as DMF at ambient temperature to give compound 34 via intramolecular cyclization.

[0454] In step 3, compound 34 is Boc deprotected in the presence of an acid such as TFA, a solvent such as DCM at ambient temperature to give compound of formula 1t.

[0455] Scheme 14. General scheme for the synthesis of compounds of formula 1u

[0456] [ka] Scheme 14 illustrates the synthesis of compounds of formula 1u and formula 1v and intermediates thereto.

[0457] Step 1 depicts the difluoromethylation of indole by reacting compound 11′ with a difluoromethylating reagent such as ethyl-2-bromo-2,2-difluoroacetate in the presence of a base such as sodium hydride, a solvent such as DMF at a suitable temperature, for example 60° C., to give compound 35′.

[0458] Step 2 is the coupling of compound 35' with a suitable coupling partner (primary amide or amine), such as 2-methoxyethan-1-amine, via Pd 2 (dba) 3 and a Buchwald amination or amidation reaction using a suitable catalyst such as Xantphos, a solvent such as 1,4-dioxane, and a base such as cesium carbonate. The reaction may be carried out under an inert atmosphere at elevated temperature (RT reflux).

[0459] Step 1a depicts the methylation of the indole in compound 11 to give compound 37 by reacting compound 11′ with a methylating reagent such as MeI in the presence of a base such as cesium carbonate and a solvent such as DMF at a suitable temperature, for example ambient temperature.

[0460] In step 2a, compound 37' is contacted with a base under conditions sufficient to form compound 38'. For example, compound 37' is dissolved in a solvent such as 1,4-dioxane and water. A base (such as t-BuONa) and a catalyst (such as tert-BuBrettPhos-Pd-G 3 An aqueous solution such as HCl is added and the mixture is heated to an appropriate temperature. The mixture is cooled to ambient temperature and an acid (such as aqueous HCl) is added. The reaction mixture is diluted with EtOAc, washed (e.g., with saturated aqueous NaCl), dried (e.g., over anhydrous sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by silica gel flash chromatography) to provide compound 38'.

[0461] In step 3a, compound 38' is contacted with a haloacetonitrile reagent under conditions sufficient to provide compound formula 1v. For example, compound 38' is dissolved in a suitable solvent (e.g., DMF) and cooled to 0° C. A suitable base (e.g., potassium carbonate) is added, followed by bromoacetonitrile, and the reaction is stirred at ambient temperature until completion. The mixture is poured into saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer is washed (e.g., with saturated aqueous NaCl), dried (e.g., over anhydrous sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by silica gel flash chromatography) to provide compound formula 1v.

[0462] Scheme 14'. General scheme for the synthesis of compounds of formula 1x

[0463] [ka] Scheme 14' illustrates the synthesis of compounds of formula 1x and intermediates thereof. h is -C(O)-R bb -OR b or -CH 2 -R bb -OR b where R bb and R b is as defined above for embodiment 1.

[0464] Step 1 is carried out according to Scheme 14 above. Step 2 is the coupling of compound 35' with a suitable coupling partner (primary amide or amine), such as 2-methoxyethan-1-amine, via Pd 2 (dba) 3 and a Buchwald amination or amidation reaction using a suitable catalyst such as Xantphos, a solvent such as 1,4-dioxane, and a base such as cesium carbonate. The reaction may be carried out under an inert atmosphere at elevated temperature (RT reflux).

[0465] Scheme 15. General scheme for the synthesis of formula 1w

[0466] [ka] Scheme 15 illustrates the synthesis of a compound of formula 1w. Compound 11' is contacted with a boronic acid pinacol ester 2 under conditions sufficient to provide a compound of formula 1w (e.g., Suzuki reaction conditions). For example, boronic acid pinacol ester 2 is reacted with a suitable base (e.g., sodium carbonate or potassium carbonate) and Pd(dppf)Cl in a suitable solvent (e.g., 1,4-dioxane and water) to afford a compound of formula 1w. 2 The mixture is added to compound 11' along with the catalyst. 2 Sparge with ethyl acetate and stir at a suitable temperature (e.g., 90-120° C.) for several hours. The reaction is diluted with water, extracted with EtOAc, dried (e.g., over anhydrous sodium sulfate), filtered, concentrated under reduced pressure, and purified (e.g., by silica gel chromatography) to provide a compound of formula 1w.

[0467] Scheme 15'. General scheme for the synthesis of formula 1w'

[0468] [ka] Scheme 15 illustrates the synthesis of compounds of formula 1w' and intermediates thereof. In step 1, compound 11' is converted under sufficient reaction conditions to provide boronic acid pinacol ester compound 39. For example, aryl bromide compound 11' is reacted with bis(pinacolato)diboron under suitable conditions (e.g., Pd(dppf)Cl 2 Upon heating under a suitable temperature (eg, 90° C.) for several hours, the crude boronic acid pinacol ester intermediate 39 is formed.

[0469] Step 2 depicts a Suzuki reaction in which compound 39 is contacted with an appropriate aryl bromide or aryl iodide under conditions sufficient to provide a compound of formula 1w'. For example, crude compound 39 is reacted with an appropriate aryl bromide in a suitable solvent (e.g., 1,4 dioxane) using Pd(dppf)Cl2 and a suitable base (e.g., potassium acetate or sodium carbonate) at a suitable temperature (e.g., 60-105° C.) for several hours until completion. The reaction mixture is cooled to ambient temperature, filtered, and rinsed through silica. The filtrate is concentrated under reduced pressure and purified (e.g., by silica gel flash chromatography) to provide a compound of formula 1w'.

[0470] The present disclosure provides compounds that can be prepared as racemic mixtures or as single enantiomers. Single enantiomers may be separated by supercritical fluid chromatography. Exemplary separation conditions are as follows: Column: Chiralpak AD-H, 21×150mm; Mobile phase: 30%MeOH:70%CO 2 , or 25% MeOH:75% CO 2 Flow rate: 80mL / min; Column temperature: 40°C; Detection: 225nM.

[0471] These separation conditions, with any suitable modifications as deemed appropriate by the skilled artisan, may be applied to separate enantiomers from their respective racemic mixtures, even if specific separation conditions are not provided below.

[0472] The following disclosure provides methods of preparation for exemplary compounds and their test results. For clarity, the following specific examples that contain a stereocenter but do not specify a particular stereoisomer are to be construed as a racemic mixture of the relevant stereoisomers.

[0473] Intermediate 1 (5-Bromo-3-chloro-2-fluorophenyl)hydrazine

[0474] [ka] Hydrazine hydrate (4.85 g, 48.44 mmol, 50% by weight) was added to a solution of 5-bromo-1-chloro-2,3-difluoro-benzene (10 g, 44 mmol) in DMSO (50 mL) under nitrogen. Stirred at 75° C. for 4 h. The reaction mixture was poured into ice-cold water and stirred at ambient temperature for 15 min. Diluted with EtOAc and the layers were separated. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (5-bromo-3-chloro-2-fluorophenyl)hydrazine (8.0 g, 76%) as an off-white solid. 1 H NMR (DMSO-d6):7.38(br s,1H),7.21(dd,J=7.2,2.4Hz,1H),6.86(dd,J=5.7,2.4Hz,1H),4.22(d,J=1.6Hz,2H).

[0475] Intermediate 2 5-Bromo-7-chloro-8-fluoro-1,2,4,9-tetrahydrospiro[carbazole-3,2'-[1,3]dioxolane]

[0476] [ka] Combine (5-bromo-3-chloro-2-fluorophenyl)hydrazine (8.0 g, 33.2 mmol), 1,4-dioxaspiro[4.5]decan-8-one (5.62 g, 36.05 mmol), and toluene (160 mL). Heat to 120° C. with stirring for 3 h. Then cool to ambient temperature. Add zinc chloride (5.9 g, 42.2 mmol) and heat to 120° C. with stirring for 3 days. Concentrate under reduced pressure. Dilute with EtOAc, wash with water, then saturated aqueous NaCl, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purification by silica gel flash chromatography eluting with hexanes / EtOAc gave 5-bromo-7-chloro-8-fluoro-1,2,4,9-tetrahydrospiro[carbazole-3,2′-[1,3]dioxolane] (5.5 g, 45%) as an off-white solid. 1H NMR(DMSO-d6):11.84(s,1H),7.23(d,J=5.9Hz,1H),4.02-3.91(m,4H),3.12(s,2H),2.81(t,J=6.4Hz,2H),1.93(t,J=6.4Hz,2H).

[0477] Intermediate 3 5-Bromo-7-chloro-8-fluoro-1,2,4,9-tetrahydro-3H-carbazol-3-one

[0478] [ka] A mixture of 5-bromo-7-chloro-8-fluoro-1,2,4,9-tetrahydrospiro[carbazole-3,2'-[1,3]dioxolane] (8.0 g, 22.3 mmol) and ACN (80 mL) was cooled to 0° C. TFA (8.0 mL) was added at 0° C. Stirred at 70° C. for 16 h. Concentrated under reduced pressure. Triturated from 1:1 EtOAc / MTBE, solid collected by suction filtration, washed twice with MTBE, and dried under reduced pressure to give 5-bromo-7-chloro-8-fluoro-1,2,4,9-tetrahydro-3H-carbazol-3-one (4.5 g, 64%) as a light brown solid. 1 H NMR(DMSO-d6):12.06(s,1H),7.27(d,J=6.0Hz,1H),3.78(s,2H),3.09(t,J=7.2Hz,2H),2.70(t,J=7.2Hz,2H).

[0479] Intermediate 4 10-Bromo-8-chloro-7-fluoro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0480] [ka] A mixture of 5-bromo-7-chloro-8-fluoro-1,2,4,9-tetrahydro-3H-carbazol-3-one (5.7 g, 18.0 mmol) in methanesulfonic acid (28.0 mL) was cooled to -15°C. Sodium azide (1.4 g, 21.6 mmol) was added, warmed to ambient temperature, and stirred for 30 min. The reaction mixture was poured into ice-cold water, diluted with more water, and stirred at ambient temperature for 15 min. The mixture was added slowly to saturated aqueous sodium bicarbonate. Stirred at ambient temperature for 20 min. The solid was collected by suction filtration, washed with water, and dried under reduced pressure. Purification by silica gel flash chromatography eluting with DCM / MeOH afforded 10-bromo-8-chloro-7-fluoro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (0.98 g, 16%) as a brown solid. ES / MS(m / z):328.8 / 330.8 / 332.8(MH). 1 H NMR (DMSO-d6):11.99(br s,1H),7.74(t,J=6.3Hz,1H),7.29(d,J=6.0Hz,1H),4.14(s,2H),3.58-3.48(m,2H),2.95-2.86(m,2H).

[0481] Example 1 8-Chloro-7-fluoro-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0482] [ka] 4-Bromo-2-methyl-triazole (145 mg, 0.909 mmol), 1,4-dioxane (10 mL), bis(pinacolato)diboron (307 mg, 1.21 mmol), potassium acetate (118 mg, 1.21 mmol) were combined and purged with argon for 5 min. Pd(dppf)Cl 2Added DCM (9.9 mg, 0.0121 mmol) and purged again with argon. Heated to 60 °C for 30 min. Added 10-Bromo-8-chloro-7-fluoro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (200 mg, 0.606 mmol) and heated at 100 °C for 16 h. Cooled to ambient temperature, filtered through diatomaceous earth and rinsed with EtOAc. The filtrate was washed with water, then saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by reverse phase chromatography followed by SFC chromatography gave 8-chloro-7-fluoro-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (50 mg, 0.15 mmol, 26%) as an off-white solid. ES / MS (m / z): 333.8 / 335.8 (M+H). 1 H NMR(DMSO-d6):11.83(br s,1H),7.93(s,1H),7.67(t,J=6.4Hz,1H),7.03(d,J=6.5Hz,1H),4.23(s,3H),3.54-3.46(m,2H),2.96-2.88(m,2H).

[0483] Intermediate 5 (5-Bromo-2,3-dichlorophenyl)hydrazine

[0484] [ka] Hydrazine hydrate (13.0 mL, 135 mmol, 51% by weight) was dissolved in N 2To a solution of 5-bromo-1,2-dichloro-3-fluoro-benzene (16.5 g, 64.3 mmol) in DMSO (64 mL) was added under reduced pressure. Stirred at 75° C. for 3 h. Cooled to ambient temperature and added approximately 150 mL of water. Stirred at ambient temperature for 30 min and poured into 200 mL of water. The solid was collected, washed three times with water and dried under vacuum at 60° C. to give (5-bromo-2,3-dichlorophenyl)hydrazine (16.73 g, 99+%) as a white solid. ES / MS (m / z): 252.6 / 254.6 / 256.6 (MH).

[0485] Intermediate 6 5-Bromo-7,8-dichloro-1,2,4,9-tetrahydrospiro[carbazole-3,2'-[1,3]dioxolane]

[0486] [ka] Combine (5-bromo-2,3-dichlorophenyl)hydrazine (5.00 g, 19.5 mmol), 1,4-dioxaspiro[4.5]decan-8-one (3.15 g, 19.6 mmol, 97% by weight), and toluene (126 mL). Reflux for 30 min and cool to ambient temperature. Add zinc chloride (3.20 g, 23.5 mmol). Reflux for 3 days. Add zinc chloride (3.20 g, 23.5 mmol) and reflux for 2 days. Cool to ambient temperature and dilute with EtOAc and 1N aqueous sodium hydroxide. Separate layers. Add 5N aqueous HCl to the aqueous layer until pH 7. Extract aqueous layer with EtOAc (3x). Wash combined organic layers with saturated aqueous NaCl, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Dissolve residue in hot EtOAc and slowly cool to ambient temperature. The solid was collected by suction filtration and washed twice with EtOAc to give 5-bromo-7,8-dichloro-1,2,4,9-tetrahydrospiro[carbazole-3,2'-[1,3]dioxolane] (3.56 g, 8.97 mmol, 95% by weight, 46% yield) as a brown solid.

[0487] The filtrate was concentrated and the residue was purified by silica gel flash chromatography eluting with hexanes / EtOAc and dried under reduced pressure to give additional 5-bromo-7,8-dichloro-1,2,4,9-tetrahydrospiro[carbazole-3,2'-[1,3]dioxolane] (950 mg, 13%) as a pale yellow solid. ES / MS (m / z): 376.0 / 378.0 / 380.0 (M+H).

[0488] Intermediate 7 5-Bromo-7,8-dichloro-1,2,4,9-tetrahydro-3H-carbazol-3-one

[0489] [ka] 5-Bromo-7,8-dichloro-1,2,4,9-tetrahydrospiro[carbazole-3,2'-[1,3]dioxolane] (2.22 g, 5.77 mmol, 98% by weight) and acetone (29 mL) were combined. 2 Purge with 50 mL of ethyl acetate and add TFA (0.92 mL, 12 mmol). Stir at reflux for 4 days. Cool to ambient temperature, concentrate and dry under reduced pressure. Combine the residue and acetone (29 mL). 2 The mixture was purged with ethyl acetate and TFA (0.92 mL, 12 mmol) was added. The mixture was stirred at reflux for 20 h. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in Et 2 The solid was collected by suction filtration and diluted with Et 2 Washing twice with O gave 5-bromo-7,8-dichloro-1,2,4,9-tetrahydro-3H-carbazol-3-one (1.32 g, 65%) as a yellow solid.

[0490] The filtrate was concentrated and the residue was extracted with Et 2 The solid was collected and suspended in EtO and allowed to stand overnight. 2 Washing twice with O gave additional 5-bromo-7,8-dichloro-1,2,4,9-tetrahydro-3H-carbazol-3-one (109 mg, 5%) as a light brown solid. ES / MS (m / z): 329.8 / 331.8 / 333.8 (MH).

[0491] Intermediate 8 10-Bromo-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0492] [ka] A suspension of 5-bromo-7,8-dichloro-1,2,4,9-tetrahydro-3H-carbazol-3-one (1.32 g, 3.77 mmol, 95% by weight) in methanesulfonic acid (25 mL) was cooled in an ice-water bath until the solvent nearly froze. Sodium azide (321 mg, 4.89 mmol) was added slowly and stirred at 0° C. The reaction was allowed to slowly warm to ambient temperature with stirring overnight. The reaction mixture was added dropwise to a stirred mixture of ice and 2M aqueous potassium carbonate. The solid was collected and washed twice with water. The solid was triturated with EtOAc. The solid was collected and washed twice with EtOAc. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel eluting with DCM / MeOH. Pure fractions were combined with the solid from the trituration with EtOAc. The product was dissolved in DCM and concentrated under reduced pressure. Drying under reduced pressure gave 10-bromo-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (601 mg, 44%) as a brown solid. ES / MS (m / z): 344.8 / 346.8 / 348.8 (MH).

[0493] Example 2 7,8-Dichloro-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0494] [ka] 4-Bromo-2-methyl-triazole (205 mg, 1.20 mmol, 95% by weight), bis(pinacolato)diboron (374 mg, 1.44 mmol), potassium acetate (238 mg, 2.40 mmol), Pd(dppf)Cl 2 (72 mg, 0.096 mmol) and DMF (6.0 mL) were dissolved in N 2 Combined below. N 2 Purge with hexanes and heat to 100° C. for 5 h. Cool to ambient temperature and dilute with EtOAc. Wash with water, then twice with saturated aqueous NaCl, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Dissolve in DCM and concentrate twice under reduced pressure. Purify by flash chromatography on silica gel eluting with hexanes / EtOAc to give impure 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazole. N 2 In the following, 10-bromo-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (50 mg, 0.14 mmol, 97% by mass), sodium carbonate (44 mg, 0.42 mmol), Pd(dppf)Cl 2 (16 mg, 0.021 mmol), 1,4-dioxane (1.0 mL) and water (0.2 mL). 2 The mixture was purged with 0.5% CO and heated to 100 °C for 2 h. It was cooled to ambient temperature and Pd(dppf)Cl 2 (16 mg, 0.021 mmol) was added. 2 The mixture was purged with 0.5 ml of ethyl acetate and heated to 100° C. for 1.5 h, then cooled to ambient temperature. The mixture was filtered through a plug of silica gel and rinsed through the silica with 9:1 DCM / MeOH. The filtrate was concentrated under reduced pressure. Purification was performed by flash chromatography on silica gel eluting with DCM / MeOH. Further purification by HPLC afforded 7,8-dichloro-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (10 mg, 20%) as an off-white solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 350.0 / 352.0 (M+H).1 H NMR(DMSO-d6):11.63(s,1H),7.97(s,1H),7.67(t,J=6.4Hz,1H),7.16(s,1H),4.24(s,3H),3.55-3.46(m,2H),2.99-2.91(m,2H).

[0495] Example 3 7,8-Dichloro-10-(1-methyl-1H-pyrazol-3-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0496] [ka] N 2 The mixture was mixed with 10-bromo-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (150 mg, 0.418 mmol, 97% by mass), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (155 mg, 0.730 mmol, 98% by mass), sodium carbonate (133 mg, 1.25 mmol), Pd(dppf)Cl 2 (47 mg, 0.063 mmol), 1,4-dioxane (2.8 mL) and water (0.56 mL) were combined. 2 The mixture was purged with ethyl acetate and heated to 120° C. for 2 h. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc. It was washed twice with water, then saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. It was purified by silica gel flash chromatography eluting with DCM / MeOH and dried under reduced pressure at 60° C. to give 7,8-dichloro-10-(1-methyl-1H-pyrazol-3-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (62 mg, 42%) as a light brown solid. ES / MS (m / z): 35 Cl / 37 Cl) 348.6 / 350.6 (M+H). 1H NMR(DMSO-d6):11.49(s,1H),7.80(d,J=2.2Hz,1H),7.62(t,J=6.3Hz,1H),7.08(s,1H) ,6.42(d,J=2.2Hz,1H),3.92(s,3H),3.54-3.47(m,2H),3.43(s,2H),2.96-2.90(m,2H).

[0497] Intermediate 9 2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazole

[0498] [ka] N 2 Below, 4-bromo-2-methyl-triazole (400 mg, 2.40 mmol, 97% by weight), bis(pinacolato)diboron (683 mg, 2.64 mmol, 98% by weight), potassium acetate (712 mg, 7.18 mmol), Pd(dppf)Cl 2 (197 mg, 0.264 mmol), and 1,4-dioxane (12.0 mL) were combined. 2 The mixture was purged with hexanes and heated to 100° C. for 1.5 h, then cooled to ambient temperature. The reaction was repeated twice on the same scale and all three reaction mixtures were combined. The mixture was filtered through a plug of silica gel, rinsing through the silica with EtOAc. The filtrate was concentrated under reduced pressure. Purified by silica gel flash chromatography eluting with hexanes / EtOAc. The product was dissolved in DCM, concentrated and dried under reduced pressure to give 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazole (1.22 g, 80%) as a light brown solid. ES / MS (m / z): 209.8 (M+H). 1 H NMR (CDCl 3 ):7.89(s,1H),4.25(s,3H),1.36(s,12H).

[0499] Intermediate 10 Ethyl 2-(8-oxo-1,4-dioxaspiro[4.5]decan-7-yl)acetate

[0500] [ka] 1,4-Dioxaspiro[4.5]decan-8-one (7.00 g, 43.5 mmol, 97% by weight) was dissolved in THF (145 mL) and cooled to -78°C. LDA (25 mL, 50 mmol, 2.0 M in THF / heptane / ethylbenzene) was added dropwise over 20 min. The solution was stirred at -78°C for 30 min. Ethyl bromoacetate (5.66 mL, 50.0 mmol, 98% by weight) was added dropwise over 10 min. The solution was stirred at -78°C for 1 h, warmed to ambient temperature and stirred for 1 h. Saturated NH 4 The mixture was quenched with aqueous Cl. Diluted with EtOAc and water and the layers were separated. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The reaction was repeated using an identical procedure except using 1,4-dioxaspiro[4.5]decan-8-one (4.90 g, 30.4 mmol, 97 wt%), LDA (17 mL, 34 mmol, 2.0 M in THF / heptane / ethylbenzene) and ethyl bromoacetate (3.96 mL, 35.0 mmol, 98 wt%) in THF (100 mL) and then the crude products were combined. Approximately half of the crude product was purified by silica gel flash chromatography eluting with hexane / EtOAc. The mixed fractions were combined with the remaining half of the crude product and purified by silica gel flash chromatography (DCM / EtOAc). The nearly pure fractions from each chromatography run were combined, concentrated under reduced pressure and the residue was crystallized from EtOAc / hexane. The solid was collected, washed three times with hexane, and dried under reduced pressure to give racemic ethyl 2-(8-oxo-1,4-dioxaspiro[4.5]decan-7-yl)acetate (4.81 g, 26% yield) as a white solid.

[0501] The filtrate from the crystallization was concentrated under reduced pressure. Purification was achieved by flash chromatography on silica gel eluting with DCM / EtOAc. Mostly pure fractions were combined and concentrated under reduced pressure, and the residue was crystallized from EtOAc / hexanes. The solid was collected, washed three times with hexanes, and dried under reduced pressure to give additional racemic ethyl 2-(8-oxo-1,4-dioxaspiro[4.5]decan-7-yl)acetate (1.00 g, 5%) as a white solid. ES / MS (m / z): 243.0 (M+H). 1 H NMR (CDCl 3 ):4.18-4.08(m,2H),4.08-3.98(m,4H),3.20(sextet,J=6.5Hz,1H),2.77-2.66(m,2H),2.40(ddd,J=14.4,5. 0,2.8Hz,1H),2.19(dd,J=6.1,16.6Hz,1H),2.15-1.93(m,3H),1.81(t,J=13.3Hz,1H),1.25(t,J=7.1Hz,3H).

[0502] Intermediate 11 Ethyl 2-(5-bromo-7,8-dichloro-1,2,4,9-tetrahydrospiro[carbazole-3,2'-[1,3]dioxolan]-1-yl)acetate

[0503] [ka] Combine (5-bromo-2,3-dichlorophenyl)hydrazine (4.93 g, 18.9 mmol, 98% by weight), racemic ethyl 2-(8-oxo-1,4-dioxaspiro[4.5]decan-7-yl)acetate (4.81 g, 18.9 mmol) and toluene (126 mL). Reflux for 22 hours and cool to ambient temperature to produce a crude hydrazone solution. Charge a separate flask with zinc chloride (3.09 g, 22.7 mmol) and heat the contents under reduced pressure until zinc chloride becomes a free-flowing solid. Cool to ambient temperature and add the contents of the flask containing the hydrazone solution and evaporate under reduced pressure. 2Purged with EtOAc. Refluxed for 6 days and cooled to ambient temperature. Diluted with EtOAc and saturated aqueous sodium bicarbonate. 5N aqueous HCl was added until pH 7. Separate layers and extract aqueous layer with EtOAc. Combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purified by silica gel flash chromatography eluting with hexanes / EtOAc and dried under reduced pressure to give racemic ethyl 2-(5-bromo-7,8-dichloro-1,2,4,9-tetrahydrospiro[carbazol-3,2'-[1,3]dioxolan]-1-yl)acetate (1.82 g, 21%). ES / MS (m / z): 462.0 / 464.0 / 466.0 (M+H).

[0504] Intermediate 12 Ethyl 2-(5-bromo-7,8-dichloro-3-oxo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)acetate

[0505] [ka] Ethyl 2-(5-bromo-7,8-dichloro-1,2,4,9-tetrahydrospiro[carbazole-3,2'-[1,3]dioxolan]-1-yl)acetate (1.82 g, 3.89 mmol, 99% by weight) and acetone (19.4 mL) were combined. 2 The mixture was purged with ethyl acetate and TFA (0.62 mL, 8.2 mmol) was added. The mixture was heated to 85° C. for 4 h. It was cooled to ambient temperature, concentrated, and dried under reduced pressure. The residue and acetone (19.4 mL) were combined. 2 The mixture was purged with ethyl acetate and TFA (0.62 mL) was added. The mixture was heated to 85° C. for 20 h, cooled to ambient temperature, and concentrated under reduced pressure. The residue was extracted with Et 2 The solid was collected by suction filtration and diluted with Et 2Washing twice with O gave racemic ethyl 2-(5-bromo-7,8-dichloro-3-oxo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)acetate (1.19 g, 69%) as a pale yellow solid. ES / MS (m / z): 417.8 / 419.8 / 421.8 (M+H).

[0506] Intermediate 13 Ethyl 2-(10-bromo-7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-5-yl)acetate

[0507] [ka] A suspension of ethyl 2-(5-bromo-7,8-dichloro-3-oxo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)acetate (1.19 g, 2.70 mmol, 95% by weight) in methanesulfonic acid (18 mL) was cooled in an ice-water bath until the solvent was nearly frozen. Sodium azide (230 mg, 3.50 mmol) was added slowly and stirred at 0° C. for 4 h. The reaction was allowed to warm to ambient temperature with stirring overnight. The reaction mixture was added dropwise to a stirred mixture of ice and 2 M aqueous potassium carbonate. Diluted with EtOAc and the layers separated. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Triturated with DCM and then EtOAc. The filtrate was concentrated and the residue was purified by silica gel flash chromatography eluting with DCM / EtOAc and dried under reduced pressure to give racemic ethyl 2-(10-bromo-7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-5-yl)acetate (442 mg, 0.927 mmol, 91% by mass, 34% yield) as a pale yellow solid.

[0508] The mixed fractions were combined with the solid from trituration with DCM. The filtrate was concentrated and the residue was purified by silica gel flash chromatography eluting with DCM / EtOAc. The product was dissolved in DCM and concentrated under reduced pressure. The residue was purified by reverse phase chromatography to give additional racemic ethyl 2-(10-bromo-7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-5-yl)acetate (94 mg, 8%) as an off-white solid. ES / MS (m / z): 433.0 / 435.0 / 437.0 (M+H). 1 H NMR(DMSO-d6):11.74(s,1H),7.86-7.78(m,1H),7.43(s,1H),4.23(d,J=15.7Hz,1H),4.19-4.06(m,2H),4.06(d,J=15.7Hz,1 H),3.73-3.62(m,1H),3.48-3.38(m,2H),2.93(dd,J=17.1,1.5Hz,1H),2.64(dd,J=17.1,10.1Hz,1H),1.22(t,J=7.1Hz,3H).

[0509] Example 4 Ethyl 2-(7,8-dichloro-10-(2-methyl-2H-1,2,3-triazol-4-yl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-5-yl)acetate

[0510] [ka] N 2 The mixture was cooled to room temperature and cooled to 37°C for 10 min. in a 10-mL flask. In the following, ethyl 2-(10-bromo-7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-5-yl)acetate (242 mg, 0.507 mmol, 91% by mass), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazole (166 mg, 0.762 mmol, 96% by mass), sodium carbonate (161 mg, 1.52 mmol), Pd(dppf)Cl 2(57 mg, 0.076 mmol), 1,4-dioxane (3.4 mL) and water (0.68 mL) were combined. 2 The mixture was purged with EtOAc and heated to 100° C. for 2.5 h. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc. The solution was filtered through a plug of silica gel, rinsing through the silica with 9:1 EtOAc / MeOH. The filtrate was concentrated under reduced pressure. Purification was performed by silica gel flash chromatography eluting with EtOAc / MeOH. The product was dissolved in DCM, concentrated, and dried under reduced pressure at 60° C. to give racemic ethyl 2-(7,8-dichloro-10-(2-methyl-2H-1,2,3-triazol-4-yl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-5-yl)acetate (176 mg, 76%) as a cream solid. ES / MS (m / z): 35 Cl / 37 Cl) 436.0 / 438.0 (M+H). 1 H NMR(DMSO-d6):11.62(s,1H),7.96(s,1H),7.78-7.75(m,1H),7.17(s,1H),4.24(s,3H),4.20-4.06(m,2H),3.69-3.60(m,1H),3.43(d,J=1 5.8Hz,1H),3.49-3.37(m,2H),3.24(d,J=15.8Hz,1H),2.99(dd,J=17.2,1.8Hz,1H),2.61(dd,J=17.2,10.4Hz,1H),1.22(t,J=7.1Hz,3H).

[0511] Example 5 2-(7,8-Dichloro-10-(2-methyl-2H-1,2,3-triazol-4-yl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-5-yl)acetic acid

[0512] [ka] Ethyl 2-(7,8-dichloro-10-(2-methyl-2H-1,2,3-triazol-4-yl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-5-yl)acetate (124 mg, 0.276 mmol, 97% by weight), THF (1.4 mL), MeOH (1.4 mL) and 5N aqueous NaOH (0.11 mL) were combined. Stirred at ambient temperature for 6 h. Added 5N aqueous HCl until pH 2. Diluted with EtOAc and saturated aqueous NaCl. Separated layers and extracted aqueous layer with EtOAc (5 times). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated, and dried under reduced pressure at 70° C. to give racemic 2-(7,8-dichloro-10-(2-methyl-2H-1,2,3-triazol-4-yl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-5-yl)acetic acid (71 mg, 61%) as a cream-colored solid. The aqueous layer was extracted with 9:1 DCM / iPrOH (3 times). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated, and dried under reduced pressure at 70° C. The residue was dissolved in DCM, concentrated (twice) and dried under reduced pressure at 70° C. to give a second crop of racemic 2-(7,8-dichloro-10-(2-methyl-2H-1,2,3-triazol-4-yl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-5-yl)acetic acid (6 mg, 5%) as an off-white solid. ES / MS (m / z): 35 Cl / 37 Cl) 408.0 / 410.0 (M+H). 1 H NMR(DMSO-d6):12.37(s,1H),11.62(s,1H),7.96(s,1H),7.78(t,J=6.3Hz,1H),7.16(s,1H),4.24(s,3H),3.70-3.60(m,1H) ),3.43(d,J=15.8Hz,1H),3.47-3.37(m,2H),3.24(d,J=15.8Hz,1H),2.92(d,J=18.3Hz,1H),2.53(dd,J=17.6,10.1Hz,1H).

[0513] Example 6 2-(7,8-dichloro-10-(2-methyl-2H-1,2,3-triazol-4-yl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-5-yl)-N-methylacetamide

[0514] [ka] 2-(7,8-dichloro-10-(2-methyl-2H-1,2,3-triazol-4-yl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-5-yl)acetic acid (30 mg, 0.071 mmol), DMF (0.7 mL), methylamine (0.18 mL, 0.36 mmol, 2.0 M in THF) and 2,4,6-triisopropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (86 μL, 50% in EtOAc) were combined and stirred at ambient temperature for 3 h. Methylamine (0.18 mL, 0.36 mmol, 2.0 M in THF) and 2,4,6-triisopropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (86 μL, 50% in EtOAc) were added and stirred at ambient temperature for 1.5 h. Diluted with EtOAc, saturated aqueous sodium bicarbonate, water and saturated aqueous NaCl. The layers were separated and the aqueous layer was extracted with EtOAc (3 times) and 9:1 DCM / iPrOH (3 times). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purified by flash chromatography on silica gel eluting with DCM / MeOH. The product was dissolved in DCM, then concentrated and dried under reduced pressure at 70° C. to give 2-(7,8-dichloro-10-(2-methyl-2H-1,2,3-triazol-4-yl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-5-yl)-N-methylacetamide (16 mg, 51%) as an off-white solid. ES / MS (m / z): 35 Cl / 37 Cl) 421.0 / 423.0 (M+H). 1H NMR(DMSO-d6):11.68(s,1H),7.97(s,1H),7.89(q,J=4.5Hz,1H),7.71(t,J=6.3Hz,1H),7.16(s,1H),4.24(s,3H),3.63-3.54(m,1H),3.48-3 .33(m,2H),3.39(d,J=16.1Hz,1H),3.28(d,J=16.1Hz,1H),2.77(dd,J=15.3,3.7Hz,1H),2.64(d,J=4.5Hz,3H),2.38(dd,J=15.3,9.7Hz,1H).

[0515] Example 7 2-(7,8-dichloro-10-(2-methyl-2H-1,2,3-triazol-4-yl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-5-yl)-N,N-dimethylacetamide

[0516] [ka] 2-(7,8-Dichloro-10-(2-methyl-2H-1,2,3-triazol-4-yl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-5-yl)acetic acid (30 mg, 0.071 mmol), DMF (0.7 mL), dimethylamine (0.18 mL, 0.36 mmol, 2.0 M in THF) and 2,4,6-triisopropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (86 μL, 50% in EtOAc) were combined. Stirred at ambient temperature for 3 h. Diluted with EtOAc and saturated aqueous sodium bicarbonate and separated layers. The organic layer was washed with water and then saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purified by silica gel flash chromatography eluting with DCM / MeOH. The product was dissolved in DCM, then concentrated and dried under reduced pressure at 70° C. to give 2-(7,8-dichloro-10-(2-methyl-2H-1,2,3-triazol-4-yl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-5-yl)-N,N-dimethylacetamide (18 mg, 57%) as a cream solid. ES / MS (m / z): 35 Cl / 37 Cl) 435.0 / 437.0 (M+H). 1 H NMR(DMSO-d6):11.58(s,1H),7.96(s,1H),7.72(t,J=6.4Hz,1H),7.16(s,1H) ,4.24(s,3H),3.66(ddd,J=14.5,6.4,2.9Hz,1H),3.55-3.47(m,1H),3.47(d, J=15.9Hz,1H),3.36(dt,J=14.5,6.4Hz,1H),3.22(d,J=15.9Hz,1H),2.97(s, 3H),2.90(s,3H),2.82(dd,J=16.9,3.2Hz,1H),2.67(dd,J=16.9,9.5Hz,1H).

[0517] Example 8 7,8-Dichloro-5-(2-hydroxyethyl)-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0518] [ka] A solution of ethyl 2-(7,8-dichloro-10-(2-methyl-2H-1,2,3-triazol-4-yl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-5-yl)acetate (60 mg, 0.13 mmol) in DCM (1.9 mL) was diluted with N 2 The mixture was cooled to -78°C under reduced pressure. DIBAL-H (0.54 mL, 0.65 mmol, 1.2 M in toluene) was added dropwise. The reaction mixture was warmed to ambient temperature, stirred for 10 min, cooled to -78°C and quenched with EtOAc. Warmed to ambient temperature, diluted with DCM and saturated aqueous potassium sodium tartrate. Stirred for 15 min and the layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purified by flash chromatography on silica gel eluting with DCM / MeOH. Drying under reduced pressure at 70° C. gave 7,8-dichloro-5-(2-hydroxyethyl)-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (19 mg, 0.047 mmol, 36%) as an off-white solid. ES / MS (m / z): 35 Cl / 37 Cl) 394.0 / 396.0 (M+H). 1H NMR(DMSO-d6):11.55(s,1H),7.96(s,1H),7.69(t,J=6.4Hz,1H),7.15(s,1H),4.66(t,J=4.7Hz,1H),4.24(s,3H),3.65-3.55(m, 3H),3.41(d,J=15.9Hz,1H),3.43-3.35(m,1H),3.24(d,J=15.9Hz,1H),3.16-3.08(m,1H),2.10-1.99(m,1H),1.78-1.67(m,1H).

[0519] Example 8A (R)-7,8-dichloro-5-(2-hydroxyethyl)-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (S)-7,8-dichloro-5-(2-hydroxyethyl)-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1) and Example 8B (R)-7,8-dichloro-5-(2-hydroxyethyl)-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (S)-7,8-dichloro-5-(2-hydroxyethyl)-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 2)

[0520] [ka] Racemic 7,8-dichloro-5-(2-hydroxyethyl)-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (67 mg, 0.17 mmol) was purified by supercritical fluid chromatography to give the title compound (Isomer 1 - Rt = 1.31 min (97% ee), 28 mg, 41%; Isomer 2 - Rt = 2.40 min (97% ee), 24 mg, 36%). Column: Chiralpak AD-H, 21 x 150 mm Mobile phase: 30% MeOH: 70% CO 2 ;Flow rate: 80mL / min;Column temperature: 40℃;Detection: 225nM. ES / MS(m / z):( 35 Cl / 37 Cl) 394.0 / 396.0 (M+H). 1 H NMR(DMSO-d6):11.55(s,1H),7.96(s,1H),7.69(t,J=6.4Hz,1H),7.15(s,1H),4.66(t,J=4.7Hz,1H),4.24(s,3H),3.65-3.55(m, 3H),3.41(d,J=15.9Hz,1H),3.43-3.35(m,1H),3.24(d,J=15.9Hz,1H),3.16-3.08(m,1H),2.10-1.99(m,1H),1.78-1.67(m,1H).

[0521] Intermediate 14 1-(10-Bromo-7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-1-yl)pyrrolidine-2,5-dione

[0522] [ka] 10-Bromo-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (1.72 g, 4.94 mmol) was dissolved in DMF (50 mL) and cesium carbonate (2 g, 6 mmol) was added. Cooled to 0° C. NBS (1.8 g, 10 mmol) was added and warmed to ambient temperature over 18 h. Quenched with 10% aqueous LiCl and stirred for 30 min. The reaction was filtered and the solid was washed with water to give 1-(10-Bromo-7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-1-yl)pyrrolidine-2,5-dione as a brown solid. (1.45 g, 66%). ES / MS(m / z):344.8 / 347.0 / 348.8(M+H-succinimide).

[0523] Intermediate 15 10-Bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0524] [ka] Et 2 A solution of 3M methylmagnesium bromide in 20 (6 mL, 18 mmol) was dissolved in THF (20 mL) and cooled to 0° C. A solution of 1-(10-bromo-7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-1-yl)pyrrolidine-2,5-dione (1.45 g, 3.26 mmol) in THF (10 mL) was added dropwise. After the addition was complete, the reaction was quenched with water and 1N HCl. Extracted with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with DCM / MeOH to give 10-bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one as a tan solid. (800mg, 68%). ES / MS(m / z):360.8 / 363.0 / 364.8(M+H).

[0525] Intermediate 16 7,8-Dichloro-10-hydroxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0526] [ka] 10-Bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (521 mg, 1.44 mmol) was dissolved in 1,4-dioxane (30 mL) and sparged with nitrogen for 5 minutes. tert-BuBrettPhos-Pd-G3 (61 mg, 0.071 mmol), sodium t-butoxide (346 mg, 3.6 mmol) and water (6 mL) were added. Heat to 65° C. for 2 hours. Cool to ambient temperature and quench with 1N HCl. Extract with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography eluting with DCM / MeOH gave 7,8-dichloro-10-hydroxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one as a brown powder (246 mg, 57%). ES / MS (m / z): 35 Cl / 37 Cl) 299.0 / 301.0 (M+H).

[0527] Intermediate 17 10-Bromo-7,8-dichloro-1-ethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0528] [ka] Et 2A 3M solution of ethylmagnesium bromide in 0 (0.75 mL, 2.3 mmol) was dissolved in THF (4 mL) and cooled to 0° C. A solution of 1-(10-bromo-7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-1-yl)pyrrolidine-2,5-dione (200 mg, 0.449 mmol) in THF (2 mL) was added dropwise. After the addition was complete, the reaction was quenched with water and 1N HCl. Extraction was performed with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH / DCM to give 10-bromo-7,8-dichloro-1-ethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one as a yellow solid. (138.1 mg, 82%). ES / MS(m / z):374.8 / 376.8 / 378.8(M+H).

[0529] Example 9 7,8-Dichloro-1-methyl-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0530] [ka] 10-Bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (180 mg, 0.398 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazole (366 mg, 0.875 mmol), Pd(dppf)Cl 2 (53 mg, 0.072 mmol) and sodium carbonate (170 mg, 1.60 mmol) were dissolved in 1,4-dioxane (6 mL) and water (1.5 mL). 2The mixture was sparged with ethyl acetate and stirred at 90° C. overnight. It was concentrated under reduced pressure and purified by silica gel chromatography eluting with DCM / MeOH. Purification by preparative HPLC afforded 7,8-dichloro-1-methyl-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (29 mg, 20%) as a yellow solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 364.2 / 366.2 (M+H). 1 H NMR(DMSO-d6):11.57(s,1H),7.95(s,1H),7.67(t,J=5.7Hz,1H),7.08(s,1H),4.2 4(s,3H),3.69-3.61(m,2H),3.25(m,1H),3.08-2.88(m,2H),1.19(d,J=7.5Hz,3H).

[0531] Example 10 7,8-Dichloro-10-methoxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0532] [ka] 7,8-Dichloro-10-hydroxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (25 mg, 84 μmol) was dissolved in DMSO (1 mL) and potassium carbonate (35 mg, 0.25 mmol) was added followed by iodomethane (23 mg, 0.16 mmol). Heat to 50° C. under nitrogen for 1 h. Cool and quench with saturated aqueous ammonium chloride. Extract with EtOAc, dry the organics over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purification by reverse phase flash chromatography gave 7,8-dichloro-10-methoxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (14 mg, 55%). ES-MS (m / z): ( 35 Cl / 37Cl)313.2 / 315.2(M+H).1H NMR(DMSO-d6):11.28(s,1H),7.72-7.68(m,1H),6.68(s,1H),4.29-4.26(q,J=7.5Hz,1H),3.89(s,3H) ),3.69-3.61(m,1H),3.29-3.24(m,1H),2.97-2.93(m,1H),2.87-2.78(m,1H),1.49(d,J=7.5Hz,3H).

[0533] Example 11 N-(7,8-dichloro-1-ethyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxyacetamide

[0534] [ka] 10-Bromo-7,8-dichloro-1-ethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (50 mg, 0.133 mmol) was dissolved in 1,4-dioxane (1.5 mL). Cesium carbonate (130 mg, 0.4 mmol) and 2-hydroxyacetamide (30 mg, 0.4 mmol) were added and the mixture was cooled to 10° C. 2 The mixture was sparged with Pd for 5 minutes. 2 (dba) 3 (12 mg, 0.013 mmol) and Xantphos (15 mg, 0.026 mmol) were added and heated to reflux for 90 min. Cooled to ambient temperature and partitioned between water and EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel reverse phase chromatography to give N-(7,8-dichloro-1-ethyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxyacetamide as a yellow solid. (7 mg, 14%). ES / MS (m / z):( 35 Cl / 37 Cl) 370.0 / 372.0 (M+H). 1H NMR(DMSO-d6):11.45(br s,1H),9.01(br s,1H),7.74(t,J=6.0Hz,1H),7.40(s,1H),6.05(br s,1H),4.09-4.00(m,2H),3.95(dd,J=5.8,11.2Hz,1H),3.74-3.62(m,1H),3.28-3.20(m, 1H),3.01(d,J=17.7Hz,1H),2.91-2.82(m,1H),1.94-1.80(m,2H),1.02(t,J=7.3Hz,3H).

[0535] Example 12 N-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxyacetamide

[0536] [ka] 10-Bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (370 mg, 1.02 mmol) was dissolved in 1,4-dioxane (5 mL). Cesium carbonate (1 g, 3 mmol) and 2-hydroxyacetamide (230 mg, 3.06 mmol) were added and the mixture was cooled to 10° C. 2 The mixture was sparged with Pd for 5 minutes. 2 (dba) 3 (94 mg, 0.103 mmol) and Xantphos (120 mg, 0.207 mmol) were added and heated to 90° C. for 90 min. The reaction was cooled to ambient temperature and partitioned between water and EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with DCM / MeOH to give N-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxyacetamide as a yellow solid. (38.2 mg, 10% yield). ES / MS (m / z): 35 Cl / 37 Cl) 355.9 / 357.8 (M+H).

[0537] Example 12A (S)-N-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxyacetamide or (R)-N-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxyacetamide (isomer 1) and Example 12B (S)-N-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxyacetamide or (R)-N-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxyacetamide (isomer 2)

[0538] [ka] N-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxyacetamide (38 mg, 0.107 mmol) was purified by chiral chromatography (Chiralpak AD-H, 20 × 150, 25% MeOH / CO 2 , flow rate: 80 mL / min, column temperature: 40° C.) to give N-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxyacetamide as separated enantiomers. (Isomer 1: 8.7 mg, 23%, Rt: 1.92 min, 98% ee; Isomer 2: 7.5 mg, 20%, Rt: 2.38 min, 96% ee). ES / MS (m / z): ( 35 Cl / 37 Cl) 355.9 / 357.8 (M+H).

[0539] Example 13 3-((7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)propyl acetate

[0540] [ka] 7,8-Dichloro-10-hydroxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (100 mg, 0.33 mmol) was dissolved in DMF (4.0 mL). 2 CO 3 (50 mg, 0.36 mmol) was added with stirring. Cooled to 0° C. and 3-bromopropyl acetate (47 μL, 0.37 mmol) was added. Stirring was continued at ambient temperature. NaI (5.0 mg, 0.033 mmol) was added and stirred at 60° C. for 24 h. Cooled to ambient temperature and diluted with EtOAc. Diatomaceous earth was added, filtered, and the diatomaceous earth was rinsed with EtOAc (3×). The combined EtOAc was washed with saturated aqueous sodium bicarbonate and saturated aqueous NaCl. The organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with DCM / MeOH afforded 3-((7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)propyl acetate as a racemic mixture (65 mg, 49%). ES / MS(m / z):( 35 Cl / 37 Cl) 398.8 / 400.8 (M+H). 1 H NMR(DMSO-d6):11.28(s,1H),7.72(t,J=5.8Hz,1H),6.69(s,1H),4.30-4.23(m,5H),3.30(s ,2H),2.98-2.92(m,1H),2.88-2.78(m,1H).2.11(m,2H),2.04(s,3H),1.51(d,J=7.4Hz,3H).

[0541] Example 14 7,8-Dichloro-10-(3-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (racemic)

[0542] [ka] 3-((7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)propyl acetate (55 mg, 0.14 mmol), 1,4-dioxane (1.4 mL), lithium hydroxide (0.21 g, 0.092 mmol, H 2 1.0M in 2H2O and MeOH (1.0 mL) were added at ambient temperature and stirred for 30 min. 5N HCl (55 μL, 0.28 mmol) was added and diluted with EtOAc. Poured into 1:1 water / saturated aqueous NaCl. The organic layer was extracted, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Dried overnight at 40° C. under reduced pressure to give 7,8-dichloro-10-(3-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (48 mg, 98%). ES / MS (m / z): ( 35 Cl / 37 Cl) 356.8 / 358.8 (M+H).

[0543] Example 14A (S)-7,8-dichloro-10-(3-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (R)-7,8-dichloro-10-(3-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1) and Example 14B (S)-7,8-dichloro-10-(3-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (R)-7,8-dichloro-10-(3-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 2)

[0544] [ka] 7,8-Dichloro-10-(3-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (0.046 g, 0.13 mmol) was purified by supercritical fluid chromatography to give 7,8-dichloro-10-(3-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one as separated enantiomers (isomer 1: 11 mg, 24%, Rt = 1.62 min, 96% ee; isomer 2: 15 mg, 33%, Rt = 2.35 min, 96% ee). Column: Chiralpak AD-H, 21 x 150 mm; mobile phase: 30% EtOH: 70% CO 2 ;Flow rate: 80mL / min;Column temperature: 40℃;ES / MS(m / z):( 35 Cl / 37 Cl) 356.8 / 358.8 (M+H). 1 H NMR(DMSO-d6):11.26(s,1H),7.71(t,J=5.7Hz,1H),6.66(s,1H),4.62(t,J=5.2Hz,1H),4.32-4.26(m,1H),4.15-4. 10(m,2H),3.63(m,3H),3.30-3.32(m,1H),2.95(m,1H),2.87-2.79(m,1H),1.96-1.90(m,2H),1.51(d,J=7.4Hz,3H).

[0545] Example 15 7,8-Dichloro-10-ethoxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0546] [ka] 7,8-Dichloro-10-hydroxy-1-methyl-3,4,5,6-tetrahydro-1H-azepino[4,5-b]indol-2-one (77 mg, 0.26 mmol) and potassium carbonate (76 mg, 0.77 mmol) were dissolved in DMSO (2.5 mL, 35 mmol). Iodoethane (80 μL, 0.51 mmol) was added and stirred at 50° C. for 1 h. The reaction was cooled to ambient temperature and diluted with EtOAc. It was washed with water and saturated aqueous NaCl. It was dried over anhydrous magnesium sulfate, filtered, and concentrated onto diatomaceous earth. Purification by silica gel flash chromatography eluting with DCM / MeOH gave 7,8-dichloro-10-ethoxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (43 mg, 51%). ES / MS (m / z): ( 35 Cl / 37 Cl) 327.0 / 329.0 (M+H).

[0547] Example 15A (S)-7,8-dichloro-10-ethoxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (R)-7,8-dichloro-10-ethoxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1) and Example 15B (S)-7,8-dichloro-10-ethoxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (R)-7,8-dichloro-10-ethoxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 2)

[0548] [ka] 7,8-Dichloro-10-ethoxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (0.043 g, 0.13 mmol) was purified by supercritical fluid chromatography to give 8-dichloro-10-ethoxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one as separated enantiomers (isomer 1 - Rt = 1.52 min (97% ee), 13.9 mg, 32%; isomer 2 - Rt = 2.20 min (97% ee), 14.4 mg, 34%). Column: Chiralpak AD-H, 21 x 150 mm; mobile phase: 30% EtOH:70% CO 2 ;Flow rate: 80mL / min;Column temperature: 40℃. ES / MS(m / z):( 35 Cl / 37 Cl) 327.0 / 329.0 (M+H). 1 H NMR(DMSO-d6):11.25(s,1H),7.72-7.69(m,1H),6.66(s,1H),4.33-4.27(m,2H),4.19-4.10(m,2H ),3.69-3.64(m,1H),3.30(s,0H),2.97-2.82(m,2H),1.51(d,J=7.4Hz,3H),1.40(t,J=7.0Hz,3H).

[0549] Example 16 2-((7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile

[0550] [ka] 7,8-Dichloro-10-hydroxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (322 mg, 1.076 mmol) was dissolved in DMF (11 mL) and cooled to 0° C. Potassium carbonate (71 mg, 0.51 mmol) was added followed by bromoacetonitrile (90 μL, 1.29 mmol). The reaction was stirred and allowed to warm slowly to ambient temperature. It was poured into saturated aqueous sodium bicarbonate and extracted with EtOAc (3×). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with 1:1 THF:DCM / MeOH gave 2-((7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (210 mg, 58%). ES / MS (m / z): 35 Cl / 37 Cl) 338.0 / 340.0 (M+H).

[0551] Example 16A (S)-2-((7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile or (R)-2-((7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (isomer 1) and Example 16B (S)-2-((7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile or (R)-2-((7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (isomer 2)

[0552] [ka] 2-((7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (0.210 g, 0.62 mmol) was purified by supercritical fluid chromatography to give 2-((7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile as separated enantiomers (isomer 1 - Rt = 1.35 min (98% ee), 43 mg, 20%; isomer 2 - Rt = 2.29 (98% ee), 53 mg, 25%). Column: Chiralpak AD-H, 21 × 150 mm; mobile phase: 30% MeOH:70% CO 2 ;Flow rate: 80mL / min;Column temperature: 40℃. ES / MS(m / z):( 35 Cl / 37 Cl) 338.0 / 340.0 (M+H). 1 H NMR (acetone): 10.52 (s, 1H), 7.12-6.96 (m, 1H), 6.92 (s, 1H), 5.35 (s, 2H), 3.93-3.84 (m, 1H), 3.54-3.47 (m, 2H), 3.12-3.02 (m, 2H), 1.65-1.62 (m, 3H).

[0553] Example 17 2-((7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetamide

[0554] [ka] 2-[(7,8-dichloro-1-methyl-2-oxo-3,4,5,6-tetrahydro-1H-azepino[4,5-b]indol-10-yl)oxy]acetonitrile (49 mg, 0.145 mmol) and potassium carbonate (36 mg, 0.26 mmol) were dissolved in DMSO (1.0 mL). 2 O 2(30% by weight in water) (68 μL, 0.67 mmol) was added dropwise and stirred for 2.5 h. Quenched with saturated sodium thiosulfate, water and extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl (2×), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-((7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetamide (52 mg, 99+%). ES / MS (m / z): 35 Cl / 37 Cl) 356.2 / 358.2 (M+H).

[0555] Example 17A (S)-2-((7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetamide or (R)-2-((7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetamide (isomer 1) and Example 17B (S)-2-((7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetamide or (R)-2-((7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetamide (isomer 2)

[0556] [ka] 2-((7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetamide (0.200 g, 0.561 mmol) was purified by supercritical fluid chromatography to give 2-((7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetamide as separated enantiomers (isomer 1 - Rt = 2.15 min (98% ee), 52 mg, 26%; isomer 2 - Rt = 2.84 min (94% ee), 55 mg, 27%). Column: Chiralpak AD-H, 21 x 150 mm; mobile phase: 25% MeOH:75% CO 2 ;Flow rate: 80mL / min;Column temperature: 40℃. ES / MS(m / z):( 35 Cl / 37 Cl) 356.0 / 358.0 (M+H). 1 H NMR(DMSO-d6):11.30(s,1H),7.72-7.69(m,1H),7.40-7.36(m,2H),6.57(s,1H),4.64-4. 56(m,2H),4.36-4.29(m,2H),3.70-3.66(m,1H),3.00-2.84(m,2H),1.53(d,J=7.4Hz,3H).

[0557] Intermediate 21 7,8-Dichloro-1-methyl-10-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0558] [ka] 7,8-Dichloro-10-hydroxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (50 mg, 0.167 mmol) was dissolved in DMF (2.0 mL) and then potassium carbonate (25 mg, 0.18 mmol) was added. Cooled to 0° C. and then 2-(2-bromoethoxy)tetrahydro-2H-pyran (27 μL, 0.19 mmol) was added. Stirred at ambient temperature. Sodium iodide (5.0 mg, 0.033 mmol) was added and stirred at 60° C. for 6 h. Cooled to ambient temperature and diluted with EtOAc. Extracted with saturated aqueous sodium bicarbonate (2×). Material was filtered and the filtrate was washed with saturated aqueous NaCl. Organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with DCM / MeOH gave 7,8-dichloro-1-methyl-10-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (8.0 mg, 11%). ES / MS (m / z): 35 Cl / 37 Cl) 448.8.8 / 450.8 (M+Na).

[0559] Example 18 7,8-Dichloro-10-(2-hydroxyethoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0560] [ka] 7,8-Dichloro-1-methyl-10-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (8.0 mg, 0.019 mmol) was dissolved in MeOH (1.0 mL). Hydrochloric acid (4N in 1,4-dioxane) (1.0 mL, 4.0 mmol) was added at ambient temperature and stirred for 1 h. The reaction was immersed in N 2After drying under vacuum, the crude material was diluted with EtOAc. It was washed with water (2 times) and saturated aqueous NaCl. It was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 7,8-dichloro-10-(2-hydroxyethoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (6.5 mg, 91%). ES / MS (m / z): ( 35 Cl / 37 Cl) 342.8 / 344.8 (M+H). 1 H NMR(DMSO-d6):11.25(s,1H),7.70-7.65(m,1H),6.68(s,1H),4.86(t,J=5.1Hz,1H),4.35-4.30(m,2H) ,4.15-4.06(m,2H),3.79(q,J=5.1Hz,2H),3.73-3.71(m,1H),2.97-2.85(m,2H),1.52(d,J=7.4Hz,3H).

[0561] Example 19 7,8-Dichloro-10-(1H-pyrazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0562] [ka] 10-Bromo-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (50 mg, 0.14 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (63 mg, 0.22 mmol), Pd(dppf) 2 Cl 2 (12 mg, 0.014 mmol), and sodium carbonate (30 mg, 0.287 mmol) were added together. 1,4-Dioxane (2.0 mL) and water (0.2 mL) were added. The reaction mixture was cooled to 5° C. for 1 hour and then cooled to 5° C. for 1 hour. 2The mixture was then flushed with 500 ml of ethyl acetate for 10 min and stirred at 90° C. for 1 h. The reaction was cooled to ambient temperature, filtered, and concentrated under reduced pressure. The crude residue was dissolved in DCM (1.5 mL) and TFA (1.5 mL) was added. The mixture was stirred at ambient temperature for 2 h and concentrated under reduced pressure. Purification by silica gel reverse phase chromatography afforded 7,8-dichloro-10-(1H-pyrazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (21 mg, 44%). ES / MS (m / z): 35 Cl / 37 Cl) 335.0 / 337.0 (M+H). 1 H NMR(DMSO-d6):13.12-13.10(m,1H),11.47(s,1H),7.98-7.93(m,1H),7.66-7.61(m,2H),6.97(s,1H),3.53-3.46(m,4H),2.94-2.92(m,2H).

[0563] Intermediate 22 10-Bromo-7,8-dichloro-6-((2-(trimethylsilyl)ethoxy)methyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0564] [ka] 10-Bromo-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (3.00 g, 7.76 mmol) was dissolved in THF (50 mL). Sodium hydride (750 mg, 18.6 mmol, 60% in mineral oil) was added portionwise at 0° C. and stirred for 1 h. SEM-Cl (2.80 mL, 16.0 mmol) was added dropwise at 0° C. and stirred for 3 h. Quenched with saturated aqueous sodium bicarbonate. EtOAc was added, washed successively with water and saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (hexanes / EtOAc) afforded 10-bromo-7,8-dichloro-6-((2-(trimethylsilyl)ethoxy)methyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (3.30 g, 76%) as a yellow solid. ES / MS (m / z): 476.9 / 478.8 / 480.8 (M+H).

[0565] Intermediate 23 7,8-Dichloro-10-hydroxy-6-((2-(trimethylsilyl)ethoxy)methyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0566] [ka] 10-Bromo-7,8-dichloro-6-((2-(trimethylsilyl)ethoxy)methyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (1.00 g, 1.78 mmol), tert-BuBrettPhos-Pd-G 3 (175 mg, 0.200 mmol) and t-BuONa (585 mg, 5.97 mmol) were dissolved in 1,4-dioxane (12.0 mL) and water (3.0 mL). 2The mixture was sparged with 0.5% CO and heated at 65° C. for 5 h. It was cooled to ambient temperature, acidified with 1N aqueous HCl, diluted with EtOAc, washed with saturated aqueous NaCl, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with DCM / MeOH afforded 7,8-dichloro-10-hydroxy-6-((2-(trimethylsilyl)ethoxy)methyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (700 mg, 66%) as a brown solid. ES / MS (m / z): 35 Cl / 37 Cl) 415.1 / 417.1 (M+H).

[0567] Intermediate 24 2-((7,8-dichloro-2-oxo-6-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile

[0568] [ka] 10-Bromo-7,8-dichloro-6-((2-(trimethylsilyl)ethoxy)methyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (250 mg, 0.421 mmol) and potassium carbonate (175 mg, 1.27 mmol) were suspended in DMF (3 mL). Bromoacetonitrile (160 mg, 1.29 mmol) was added at 0° C. and stirred at ambient temperature for 5 h. Diluted with EtOAc, washed with saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with DCM / MeOH afforded 2-((7,8-dichloro-2-oxo-6-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (220 mg, 86%) as a yellow solid. ES / MS (m / z): 35 Cl / 37Cl) 454.1 / 456.0 (M+H).

[0569] Intermediate 25 2-((7,8-dichloro-2-oxo-6-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetamide

[0570] [ka] 2-((7,8-dichloro-2-oxo-6-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (220 mg, 0.363 mmol) and potassium carbonate (300 mg, 2.17 mmol) were suspended in DMSO (3 mL). 2 O 2 Aqueous solution (510 mg, 4.49 mmol) was added dropwise at 0° C. and stirred at ambient temperature for 2 h. Diluted with EtOAc, washed with saturated aqueous NaCl, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Trituration with ACN (2 mL) afforded 2-((7,8-dichloro-2-oxo-6-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetamide (150 mg, 78%) as a pale yellow solid. ES / MS (m / z):( 35 Cl / 37 Cl) 472.1 / 474.0 (M+H).

[0571] Example 20 2-((7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetamide

[0572] [ka] 2-((7,8-Dichloro-2-oxo-6-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetamide (130 mg, 0.248 mmol) was dissolved in DCM (2 mL) and TFA (1 mL) was added at 0° C., followed by stirring at ambient temperature for 2 h. Concentrated, diluted with THF (3 mL) and diluted with 28% NH 3 H 2 Aqueous 2H2O (1 mL) was added and stirred at ambient temperature for 1 h. Diluted with water and extracted with EtOAc, the organic layer was washed with saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by preparative HPLC afforded 2-((7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetamide (20.51 mg, 24%) as a white solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 342.2 / 344.2 (M+H). 1 H NMR(DMSO-d6):11.43-11.41(m,1H),7.73-7.70(m,1H),7.48-7.47(m,2H), 6.61-6.55(m,1H),4.63-4.55(m,2H),4.04-4.02(m,2H),3.00-2.98(m,2H)

[0573] Intermediate 26 2-((7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile

[0574] [ka] 2-((7,8-Dichloro-2-oxo-6-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (65 mg, 0.14 mmol) was dissolved in DCM (2 mL). TFA (1 mL) was added and stirred at ambient temperature for 2 h. Concentrated, diluted with THF (3 mL) and then diluted with 28% NH 3 H 2 Aqueous 2H2O (1 mL) was added. Stirred at ambient temperature for 1.5 h. Diluted with water (25 mL), extracted with EtOAc, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by preparative HPLC afforded 2-((7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (30 mg, 64%) as a white solid. ES / MS (m / z):( 35 Cl / 37 Cl) 324.2 / 326.2 (M+H).

[0575] Example 21 2-((7,8-dichloro-6-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile

[0576] [ka] Cesium carbonate (74 mg, 0.23 mmol) and iodomethane (32 mg, 0.23 mmol) were added to 2-((7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (25 mg, 0.076 mmol) in DMF (1 mL). Stirred at ambient temperature for 2 h. Diluted with water (20 mL), extracted with EtOAc, and concentrated the organics under reduced pressure. Purification by preparative HPLC afforded 2-((7,8-dichloro-6-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (6.7 mg, 26%) as a white solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 338.2 / 340.2 (M+H). 1 H NMR (DMSO-d6):7.72(t,J=6.3Hz,1H),6.95(s,1H),5.34(s,2H),3.98(s,2H),3.94(s,3H),3.58-3.53(m,2H),2.89-2.86(m,2H).

[0577] Intermediate 27 tert-Butyl (7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)carbamate

[0578] [ka] 10-Bromo-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (500 mg, 1.36 mmol) was dissolved in 1,4-dioxane (9 mL). Cesium carbonate (1 g, 3 mmol), Xantphos-Pd-G 2 (140 mg, 0.141 mmol) and tert-butyl carbamate (330 mg, 2.76 mmol) were added at ambient temperature. 2The mixture was sparged with ethyl acetate and stirred at 100° C. overnight. It was concentrated under reduced pressure and purified by silica gel flash chromatography eluting with petroleum ether / EtOAc to give tert-butyl (7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)carbamate (290 mg, 33%) as a brown solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 328.0 / 329.9 (M+H-tBu) and 384.0 / 386.0 (M+H).

[0579] Intermediate 28 10-Amino-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one hydrochloride

[0580] [ka] A mixture of tert-butyl (7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)carbamate (290 mg, 0.457 mmol, 61% purity) and 10-amino-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one hydrochloride (290 mg, 0.232 mmol, 23% purity) in 4N HCl / EtOH (4 mL) was dissolved and stirred at ambient temperature for 1 h. Concentration under reduced pressure and trituration with EtOAc gave 10-amino-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one hydrochloride (246 mg, 0.621 mmol, 90%) as a yellow oil. ES / MS (m / z): 35 Cl / 37 Cl) 284.0 / 286.0 (M+H).

[0581] Intermediate 29 10-(3-((tert-butyldimethylsilyl)oxy)propyl)amino)-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0582] [ka] 10-Amino-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one hydrochloride (100 mg, 0.285 mmol) was dissolved in MeOH (3 mL). DIPEA was added to adjust pH to 8. Stirred at ambient temperature for 30 min. Acetic acid (40 mg, 0.67 mmol) was added to the mixture and stirred at ambient temperature for 30 min. 3-[tert-Butyl(dimethyl)silyl]oxypropanal (140 mg, 0.743 mmol) was added to the mixture and stirred at ambient temperature for 30 min. Sodium cyanoborohydride (60 mg, 0.91 mmol) was added and stirred at ambient temperature overnight. Quenched with water, extracted with EtOAc, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with DCM / MeOH gave 10-((3-((tert-butyldimethylsilyl)oxy)propyl)amino)-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (160 mg, 99%) as a yellow solid. ES / MS (m / z): 35 Cl / 37 Cl) 456.0 / 458.0 (M+H)

[0583] Example 22 7,8-Dichloro-10-((3-hydroxypropyl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0584] [ka] 10-((3-((tert-butyldimethylsilyl)oxy)propyl)amino)-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (160 mg, 0.283 mmol) was suspended in 4N HCl in MeOH (4 mL) and stirred at ambient temperature for 1 h. Concentrated under reduced pressure and purified by preparative HPLC. Lyophilization afforded 7,8-dichloro-10-((3-hydroxypropyl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (20 mg, 20%) as a grey solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 342.2 / 344.2 (M+H). 1 H NMR(DMSO-d6):11.07-11.05(m,1H),7.73-7.68(m,1H),6.21(s,1H),5.47-5.43(m,1H),4.70(t,J=4.9Hz,1H),3 .94-3.90(m,2H),3.63-3.61(m,2H),3.51-3.45(m,2H),3.18-3.15(m,2H),2.92-2.90(m,2H),1.83-1.77(m,2H).

[0585] Intermediate 30 10-(3-((tert-butyldimethylsilyl)oxy)propoxy)-7,8-dichloro-6-((2-(trimethylsilyl)ethoxy)methyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0586] [ka] 7,8-Dichloro-10-hydroxy-6-((2-(trimethylsilyl)ethoxy)methyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (50 mg, 0.11 mmol) was dissolved in DMF (2 mL). Potassium carbonate (20 mg, 0.14 mmol) and 3-bromopropoxy-tert-butyl-dimethyl-silane (55 mg, 0.22 mmol) were added at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 2 h. Quenched with water, extracted with EtOAc, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 10-(3-((tert-butyldimethylsilyl)oxy)propoxy)-7,8-dichloro-6-((2-(trimethylsilyl)ethoxy)methyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (80 mg, 75%) as a yellow gum. ES / MS (m / z): 35 Cl / 37 Cl) 587.2 / 589.2 (M+H).

[0587] Example 23 7,8-Dichloro-10-(3-hydroxypropoxy)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0588] [ka] 10-(3-((tert-butyldimethylsilyl)oxy)propoxy)-7,8-dichloro-6-((2-(trimethylsilyl)ethoxy)methyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (80 mg, 0.081 mmol) was dissolved in DCM (2 mL). TFA (2 mL) was added and then stirred at ambient temperature for 1.5 h. Concentrated and dissolved in THF (1 mL). 2N aqueous LiOH (1 mL) was added. Stirred at ambient temperature for 1 h. Quenched with water, extracted with EtOAc, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by preparative HPLC gave 7,8-dichloro-10-(3-hydroxypropoxy)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (7.7 mg, 26%) as a white solid. ES / MS (m / z): 35 Cl / 37 Cl) 343.2 / 345.2 (M+H). 1 H NMR(DMSO-d6):11.32(s,1H),7.66(t,J=6.2Hz,1H),6.67(s,1H),4.62(t,J=5.1Hz,1H),4.12(t,J=6.0Hz ,2H),3.96(s,2H),3.64-3.60(m,2H),3.56-3.50(m,2H),2.91-2.86(m,2H),1.93(quintet,J=6.0Hz,2H).

[0589] Intermediate 31 2-((7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)amino)-2-oxoethyl acetate

[0590] [ka] 10-Amino-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one hydrochloride (200 mg, 0.498 mmol) was dissolved in DCM (4 mL) and then diluted with Et 3N (0.5 mL, 4 mmol) was added and stirred at ambient temperature for 0.5 h. Acetoxyacetyl chloride (270 mg, 1.98 mmol) was added and stirred at ambient temperature overnight. Quenched with water, extracted with EtOAc, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-((7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)amino)-2-oxoethyl acetate (157 mg, 37%) as a yellow solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 383.9 / 385.9 (M+H).

[0591] Example 24 N-(7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxyacetamide

[0592] [ka] 2-((7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)amino)-2-oxoethyl acetate (176 mg, 0.206 mmol) was dissolved in THF (5 mL) and water (1 mL). Lithium hydroxide monohydrate (100 mg, 2.38 mmol) was added and stirred at ambient temperature for 1 h. Diluted with water, extracted with EtOAc, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by preparative HPLC afforded N-(7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxyacetamide (27 mg, 38%) as a white solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 342.2 / 344.1 (M+H). 1H NMR(DMSO-d6):11.07-11.05(m,1H),7.73-7.68(m,1H),6.21(s,1H),5.47-5.43(m,1H),4.70(t,J=4.9Hz,1H),3 .94-3.90(m,2H),3.63-3.61(m,2H),3.51-3.45(m,2H),3.18-3.15(m,2H),2.92-2.90(m,2H),1.83-1.77(m,2H).

[0593] Intermediate 32 Methyl 7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-10-carboxylate

[0594] [ka] 10-Bromo-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (1.00 g, 2.73 mmol), Pd(dppf)Cl 2 (303 mg, 0.410 mmol) and Et 3 N (1.20 mL, 8.60 mmol) was suspended in MeOH (9 mL) and DMF (3 mL). After sparging with CO, the mixture was stirred at 70° C. under CO (50 psi) overnight. It was diluted with EtOAc, washed successively with water and saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography eluting with DCM / MeOH afforded methyl 7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-10-carboxylate (567 mg, 57%) as a brown solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 327.0 / 329.0 (M+H).

[0595] Intermediate 33 7,8-Dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-10-carboxylic acid

[0596] [ka] Methyl 7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-10-carboxylate (642 mg, 1.77 mmol) was dissolved in THF (4 mL) and water (2 mL). Lithium hydroxide monohydrate (408 mg, 9.72 mmol) was added and stirred at ambient temperature for 1 h. 1N aqueous HCl was added to pH=4 and filtered to give 7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-10-carboxylic acid (680 mg, 98%) as a brown solid. ES / MS (m / z): ( 35 Cl / 37 Cl)313.2 / 315.2(M+H).

[0597] Intermediate 34 7,8-Dichloro-N-(1-(hydroxyimino)ethyl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-10-carboxamide

[0598] [ka] 7,8-Dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-10-carboxylic acid (200 mg, 0.511 mmol), N'-hydroxyacetimidamide (40 mg, 0.51 mmol), TBTU (185 mg, 0.565 mmol) and DIPEA (0.27 mL, 1.50 mmol) were suspended in DMF (2 mL). Stirred at 20° C. for 45 min. N'-hydroxyacetimidamide (40 mg, 0.51 mmol) and DMAP (7 mg, 0.06 mmol) were added. Stirred at 20° C. overnight. Dilution with EtOAc, washing successively with water and saturated aqueous NaCl, drying over sodium sulfate, filtering, and concentrating under reduced pressure gave 7,8-dichloro-N-(1-(hydroxyimino)ethyl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-10-carboxamide (227 mg, 99%) as a brown oil. ES / MS (m / z): 35 Cl / 37 Cl) 369.0 / 371.0 (M+H).

[0599] Example 25 7,8-Dichloro-10-(3-methyl-1,2,4-oxadiazol-5-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0600] [ka] 7,8-Dichloro-N-(1-(hydroxyimino)ethyl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-10-carboxamide (227 mg, 0.504 mmol) was suspended in 1,4-dioxane (3 mL). KF (86 mg, 1.5 mmol) was added and stirred at 110° C. for 5 days. Filtered and concentrated under reduced pressure. Purification by preparative HPLC gave 7,8-dichloro-10-(3-methyl-1,2,4-oxadiazol-5-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (14.88 mg, 8%) as a white solid. ES / MS (m / z): (35 Cl / 37 Cl) 351.2 / 353.2 (M+H). 1 H NMR(DMSO-d6):12.03(s,1H),7.77-7.72(m,1H),7.65(s,1H),3.58-3.53(m,4H),3.01-2.98(m,2H),2.48(s,3H).

[0601] Intermediate 35 Ethyl 2-(((7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-10-carbonyl)oxy)amino)-2-iminoacetate

[0602] [ka] 7,8-Dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-10-carboxylic acid (488 mg, 1.29 mmol) was dissolved in DMF (4 mL). TBTU (470 mg, 1.43 mmol) and DIEA (0.700 mL, 4.00 mmol) were added. Stirred at ambient temperature for 0.75 h, then added ethyl (N'-hydroxycarbamimidoyl)formate (200 mg, 1.44 mmol) and DMAP (16 mg, 0.13 mmol). Stirred at ambient temperature for 3 h. Filtered and the precipitate was triturated with ACN (10 mL) at ambient temperature for 1 h. Ethyl 2-(((7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-10-carbonyl)oxy)amino)-2-iminoacetate (360 mg, 61%) was obtained as a brown solid. ES / MS (m / z): 35 Cl / 37 Cl) 427.0 / 429.0 (M+H).

[0603] Intermediate 36 Ethyl 5-(7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-1,2,4-oxadiazole-3-carboxylate

[0604] [ka] Ethyl 2-(((7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-10-carbonyl)oxy)amino)-2-iminoacetate (360 mg, 0.800 mmol) was dissolved in 1,4-dioxane (9 mL). KF (470 mg, 8.08 mmol) was added and N 2 The mixture was sparged with N and stirred at 115 °C overnight. KF (700 mg, 12.0 mmol) was added and N 2 The mixture was sparged with N and stirred again at 115 °C overnight. KF (690 mg, 11.9 mmol) was added and N 2 The mixture was sparged with hexane and stirred at 115° C. for 5 hours until the reaction was complete. After cooling to ambient temperature, the reaction mixture was poured into water (30 mL). The precipitate was filtered and triturated with ACN to give ethyl 5-(7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-1,2,4-oxadiazole-3-carboxylate (230 mg, 69%) as an off-white solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 408.8 / 410.8 (M+H).

[0605] Example 26 7,8-Dichloro-10-(3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0606] [ka] Ethyl 5-(7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-1,2,4-oxadiazole-3-carboxylate (185 mg, 0.445 mmol) was dissolved in THF (8 mL). Lithium borohydride (30 mg, 1.4 mmol) was added at 0° C. and stirred for 30 min. Saturated NH 4 The mixture was quenched with aqueous Cl (10 mL) and diluted with DCM (50 mL) and water (40 mL). The solids were removed by filtration and the filtrate was extracted with DCM. The organic layer was extracted with Na 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure. Purification by preparative HPLC afforded 7,8-dichloro-10-(3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (35 mg, 21%) as a white solid. ES-MS (m / z): ( 35 Cl / 37 Cl) 367.2 / 369.2 (M+H). 1 H NMR(DMSO):12.08-12.07(m,1H),7.75(t,J=6.5Hz,1H),7.67(s,1H),5.83(t ,J=6.2Hz,1H),4.69(d,J=6.3Hz,2H),3.58-3.54(m,4H),3.01-2.99(m,2H).

[0607] Intermediate 37 7,8-Dichloro-10-vinyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0608] [ka] 10-Bromo-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (500 mg, 1.39 mmol), potassium vinyltrifluoroborate (290 mg, 2.10 mmol), Pd(dppf)Cl 2(105 mg, 0.142 mmol) and sodium carbonate (445 mg, 4.20 mmol) were suspended in 1,4-dioxane (4 mL) and water (1 mL). 2 The mixture was sparged with 1,4-dioxane and stirred at 90° C. overnight. It was filtered, the solids were washed with 1,4-dioxane, and the filtrate was then concentrated under reduced pressure. Purification by silica gel flash column chromatography eluting with DCM / MeOH afforded 7,8-dichloro-10-vinyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (275 mg, 62%) as a yellow solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 295.0 / 297.0 (M+H).

[0609] Intermediate 38 7,8-Dichloro-10-(1,2-dihydroxyethyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0610] [ka] 7,8-Dichloro-10-vinyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (275 mg, 0.866 mmol) and NMO (314 mg, 2.60 mmol) were dissolved in THF (4 mL) and water (1 mL). Potassium osmate dihydrate (87 mg, 0.26 mmol) was added and stirred at ambient temperature overnight. Diluted with EtOAc and washed successively with saturated aqueous sodium bicarbonate and saturated aqueous NaCl. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 7,8-dichloro-10-(1,2-dihydroxyethyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (153 mg, 27%) as a dark green solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 310.9.0 / 312.9 (M+H, -H 2 O).

[0611] Intermediate 39 7,8-Dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-10-carbaldehyde

[0612] [ka] 7,8-Dichloro-10-(1,2-dihydroxyethyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (153 mg, 0.237 mmol) and sodium periodate (103 mg, 0.481 mmol) were suspended in acetone (3 mL) and water (1.5 mL). The reaction was stirred at ambient temperature for 1 h until completion. Filtration and concentration under reduced pressure gave 7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-10-carbaldehyde (120 mg, crude) as a yellow solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 297.0 / 299.0 (M+H).

[0613] Example 27 7,8-Dichloro-10-(oxazol-5-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0614] [ka] 7,8-Dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-10-carbaldehyde (120 mg, 0.263 mmol) was suspended in MeOH (3 mL). TosMIC (63 mg, 0.32 mmol) and potassium carbonate (73 mg, 0.53 mmol) were added and stirred at 70° C. for 2 h. Cooled to ambient temperature, diluted with EtOAc, washed with saturated aqueous NaCl, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by preparative HPLC afforded 7,8-dichloro-10-(oxazol-5-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (15 mg, 16%) as a white solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 336.2 / 338.2 (M+H). 1 H NMR(DMSO-d6):11.79(s,1H),8.53(s,1H),7.70(t,J=6.3Hz,1H),7.45(s,1H),7.26(s,1H),3.38-3.35(m,2H),2.97-2.94(m,2H).

[0615] Intermediate 40 7,8-Dichloro-10-(isoxazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0616] [ka] 10-Bromo-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (100 mg, 0.260 mmol), 4-isoxazoleboronic acid pinacol ester (60 mg, 0.30 mmol), potassium fluoride (45 mg, 0.78 mmol) and Pd(dppf)Cl 2 (20 mg, 0.030 mmol) was suspended in DMSO (8 mL) and water (2 mL). 2The mixture was sparged with 0.5% water and then stirred at 130° C. for 2 hours. Filtration and concentration under reduced pressure gave 7,8-dichloro-10-(isoxazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or the ring-opened isomer (80 mg, crude) as a brown gum. ES / MS (m / z): ( 35 Cl / 37 Cl) 335.8 / 337.8 (M+H).

[0617] Example 28 2-(7,8-Dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)acetonitrile

[0618] [ka] 7,8-Dichloro-10-(isoxazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (80 mg, 0.21 mmol) and potassium fluoride (80 mg, 1.38 mmol) were dissolved in DMF (3 mL) and water (3 mL). Stirred at 100° C. overnight. Filtered and concentrated under reduced pressure. Purification by preparative HPLC gave 2-(7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)acetonitrile (20 mg, 30%) as a white solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 308.2 / 310.2 (M+H). 1 H NMR(DMSO-d6):11.66-11.64(m,1H),7.79(t,J=6.2Hz,1H),7.18(s,1H),4.35(s,2H),3.87(s,2H),3.56-3.48(m,2H),2.97-2.93(m,2H).

[0619] Intermediate 41 7,8-Dichloro-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0620] [ka] 10-Bromo-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (600 mg, 1.67 mmol), bis(pinacolato)diboron (900 mg, 3.37 mmol), potassium acetate (500 mg, 5.04 mmol) and Pd(dppf)Cl 2 (100 mg, 0.135 mmol) was suspended in 1,4-dioxane (10 mL) and THF (5 mL). 2 The mixture was sparged with hexane and heated at 90° C. overnight. It was cooled to room temperature and used directly in subsequent transformations (crude recovery: 3.30 g, approximately 20% by weight).

[0621] Intermediate 42 7,8-Dichloro-10-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0622] [ka] 7,8-Dichloro-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (2.20 g, crude), 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (CAS 1260599-41-4, 400 mg, 1.15 mmol), Pd(dppf)Cl 2 (85 mg, 0.12 mmol) and K 2 CO 3(500 mg, 3.44 mmol) was suspended in 1,4-dioxane (16 mL) and water (4 mL). 2 The mixture was sparged with ethyl acetate and stirred at 100° C. overnight. It was cooled to ambient temperature and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with DCM / MeOH afforded 7,8-dichloro-10-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (220 mg, 24%) as a brown solid. ES / MS (m / z): 35 Cl / 37 Cl) 465.8 / 467.9 (M+H).

[0623] Example 29 7,8-Dichloro-10-(4H-1,2,4-triazol-3-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0624] [ka] 7,8-Dichloro-10-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (200 mg, 0.240 mmol) was dissolved in DCM (4 mL) and TFA (2 mL) was added. Stirred at ambient temperature for 2 h and concentrated under reduced pressure. Purification by preparative HPLC afforded 7,8-dichloro-10-(4H-1,2,4-triazol-3-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (48 mg, 58%) as a white solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 336.2 / 338.2 (M+H). 1H NMR(DMSO-d6):14.35-14.28(m,1H),11.67(d,J=70.5Hz,1H),8.72-8.13(m ,1H),7.69-7.61(m,1H),7.31(d,J=12.1Hz,1H),3.51(s,4H),2.96(s,2H).

[0625] Example 30 7,8-Dichloro-10-(ethylamino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0626] [ka] 10-Amino-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one hydrochloride (150 mg, 0.459 mmol) was dissolved in MeOH (15 mL) and acetic acid was added to adjust the pH to 5. Stirred at ambient temperature for 30 min. Acetaldehyde (30 mg, 0.68 mmol) was added and stirred at ambient temperature for 30 min. Sodium cyanoborohydride (91 mg, 1.38 mmol) was added and stirred at ambient temperature for 5 h. Diluted with EtOAc, washed successively with saturated aqueous sodium bicarbonate and saturated aqueous NaCl, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with DCM / MeOH followed by preparative HPLC afforded 7,8-dichloro-10-(ethylamino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (18 mg, 12%) as a white solid. ES / MS (m / z): 35 Cl / 37 Cl)312.2 / 314.2(M+H). 1 H NMR(DMSO-d6):11.07-11.05(m,1H),7.74-7.70(m,1H),6.21(s,1H),5.36-5.21(m,1H), 3.93(s,2H),3.51-3.49(m,2H),3.14-3.10(m,2H),2.90-2.88(m,2H),1.24-1.20(m,3H).

[0627] Intermediate 43 7,8-Dichloro-10-(isoxazol-4-yl)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0628] [ka] 7,8-Dichloro-10-hydroxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (200 mg, 0.359 mmol), 4-isoxazoleboronic acid pinacol ester (150 mg, 0.754 mmol), KF (150 mg, 2.58 mmol), and Pd(dppf)Cl 2 (50 mg, 0.068 mmol) was dissolved in DMSO (5 mL) and water (1.25 mL). 2 The mixture was purged with 0.5% CO and stirred at 100° C. for 1 h. Diluted with water (20 mL), extracted with EtOAc, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography eluting with DCM / MeOH afforded 7,8-dichloro-10-(isoxazol-4-yl)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (130 mg, 68%) as a brown solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 349.8 / 351.8 (M+H).

[0629] Example 31 2-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)acetonitrile

[0630] [ka] 7,8-Dichloro-10-(isoxazol-4-yl)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (130 mg, 0.245 mmol), KF (120 mg, 2.07 mmol) were dissolved in DMF (3 mL) and water (3 mL). Stirred at 100° C. overnight. Concentrated under reduced pressure to remove water. Purified by preparative HPLC to give 2-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)acetonitrile (26 mg, 32%) as a yellow solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 322.2 / 324.2 (M+H). 1 H NMR(DMSO-d6):11.60(s,1H),7.83-7.79(m,1H),7.21(s,1H),4.35-4.23(m,2H),4.05-4. 00(m,1H),3.75-3.73(m,1H),3.28-3.25(m,1H),3.07-2.92(m,2H),1.58(d,J=7.5Hz,3H).

[0631] Example 32 N 1 -(7,8-Dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxalamide

[0632] [ka] 10-Amino-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (100 mg, 0.282 mmol, 80% by weight), oxamic acid (76 mg, 0.853 mmol) and DIPEA (0.25 mL, 0.853 mmol) were combined in DMF (3 mL). 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (220 mg, 0.567 mmol) was added. Stirred at 20° C. for 2 h. Quenched with water (30 mL) and extracted with EtOAc (20 mL, 3 times). The combined organic layers were washed with saturated aqueous NaCl (50 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with MeOH in DCM and concentrated under reduced pressure. The residue was further purified by preparative HPLC to give N 1 -(7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxalamide (12 mg, 11%) was obtained as a yellow solid. ES / MS (m / z): 35 Cl / 37 Cl) 355.0 / 356.9 (M+H).

[0633] Intermediate 44 tert-Butyl N-[N-(7,8-dichloro-2-oxo-3,4,5,6-tetrahydro-1H-azepino[4,5-b]indole-10-carbonyl)carbamimidoyl]carbamate

[0634] [ka] 7,8-Dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-10-carboxylic acid (400 mg, 0.894 mmol, 70% by weight), ((1H-benzo[d][1,2,3]triazol-1-yl)oxy)tri(pyrrolidin-1-yl)phosphonium (560 mg, 1.076 mmol) and 4-methylmorpholine (460 mg, 4.50 mmol) were combined in DMF (10 mL). Stirred at ambient temperature for 15 min. tert-Butyl N-carbamimidoylcarbamate (285 mg, 1.79 mmol) was added. Stirred at ambient temperature overnight. Quenched with water (20 mL) and extracted with EtOAc (30 mL). The organic layer was washed successively with water (10 mL x 5) and saturated aqueous NaCl solution (20 mL x 2), and then with Na 2 SO 4 The mixture was dried over ice, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with MeOH in DCM afforded tert-butyl N-[N-(7,8-dichloro-2-oxo-3,4,5,6-tetrahydro-1H-azepino[4,5-b]indole-10-carbonyl)carbamimidoyl]carbamate (400 mg, 82% by mass, 81%) as a yellow solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 453.8 / 455.8 (M+H).

[0635] Intermediate 45 tert-Butyl (5-(7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-1,2,4-oxadiazol-3-yl)carbamate

[0636] [ka] tert-Butyl N-[N-(7,8-dichloro-2-oxo-3,4,5,6-tetrahydro-1H-azepino[4,5-b]indole-10-carbonyl)carbamimidoyl]carbamate (200 mg, 0.361 mmol, 82% by weight) was dissolved in DMF (5 mL). (Diacetoxyiodo)benzene was added at 0° C. Stirred overnight at ambient temperature. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL) (3 times). The organic layer was washed with saturated aqueous sodium bicarbonate (10 mL). The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried over ice, filtered, and concentrated under reduced pressure. Purification by flash silica gel chromatography eluting with MeOH in DCM afforded tert-butyl (5-(7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-1,2,4-oxadiazol-3-yl)carbamate (140 mg, 53%) as a yellow solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 452.1 / 454.0 (M+H) and 396.0 / 397.9 (M+H-tBu).

[0637] Example 33 10-(3-amino-1,2,4-oxadiazol-5-yl)-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0638] [ka] TFA (1 mL, 12.9 mmol) was added to tert-butyl (5-(7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-1,2,4-oxadiazol-3-yl)carbamate (140 mg, 0.192 mmol, 62% by weight) in DCM (3 mL). Stirred at ambient temperature for 1 h. Concentrated under reduced pressure and purified by preparative HPLC to give 10-(3-amino-1,2,4-oxadiazol-5-yl)-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (32 mg, 47%) as a yellow solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 352.0 / 354.0 (M+H).

[0639] Example 34 10-(6-aminopyrazin-2-yl)-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0640] [ka] 7,8-Dichloro-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (350 mg, 0.656 mmol, 74% by weight), 6-bromopyrazin-2-amine (116 mg, 0.656 mmol), Pd(dppf)Cl 2 (49 mg, 0.066 mmol) and Na 2 CO 3 (175 mg, 1.64 mmol) in 1,4-dioxane (4 mL) and H 2 Combine in 200 mL of N 2 The mixture was stirred at 90° C. under atmospheric pressure for 3 hours. It was concentrated under reduced pressure, and the residue was diluted with water and extracted with EtOAc (3 times). The organic layers were combined and washed with anhydrous Na 2 SO 4The mixture was dried over ice, filtered and concentrated under reduced pressure. Purification was performed by flash chromatography on silica gel eluting with MeOH in DCM. Concentration under reduced pressure, trituration with ACN and stirring at 20° C. for 1 h afforded 10-(6-aminopyrazin-2-yl)-7,8-dichloro-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (54.76 mg, 22%) as a white solid. ES-MS (m / z): ( 35 Cl / 37 Cl) 362.0 / 364.0 (M+H).

[0641] Intermediate 46 7,8-Dichloro-1-ethyl-10-hydroxy-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0642] [ka] 10-Bromo-7,8-dichloro-1-ethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (500 mg, 0.651 mmol, 49% by mass), cesium hydroxide monohydrate (115 mg, 0.651 mmol), tert-BuBrettPhos-Pd-G 3 (59 mg, 0.065 mmol) in 1,4-dioxane (10 mL) and H 2 Combine in O (2.5 mL). Degas and add N 2 The mixture was purged three times with N 2 Stirred and heated at 65° C. under atmosphere for 2 h. Cooled to ambient temperature. Concentrated under reduced pressure. Purified by silica gel flash chromatography eluting with MeOH in DCM and concentrated under reduced pressure to give 7,8-dichloro-1-ethyl-10-hydroxy-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (200 mg, 66%) as a pale yellow oil. ES / MS (m / z): ( 35 Cl / 37 Cl)312.9 / 314.8(M+H).

[0643] Intermediate 47 2-((7,8-dichloro-1-ethyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile

[0644] [ka] 7,8-Dichloro-1-ethyl-10-hydroxy-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (200 mg, 0.428 mmol, 67% by weight) and K 2 CO 3 (91 mg, 0.64 mmol) was combined in DMF (5 mL) and 2-chloroacetonitrile (66 mg, 0.86 mmol) was added. Stirred at ambient temperature for 16 h. Diluted with water and extracted with EtOAc (2x). The organic layers were combined, washed with saturated aqueous NaCl (2x) and anhydrous Na 2 SO 4 The mixture was dried over ice, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with EtOAc in PE and concentrated under reduced pressure gave racemic 2-((7,8-dichloro-1-ethyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (65 mg, 32%) as a pale yellow oil. ES / MS (m / z): ( 35 Cl / 37 Cl) 351.8 / 353.8 (M+H).

[0645] Example 35 (R)-2-((7,8-dichloro-1-ethyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile or (S)-2-((7,8-dichloro-1-ethyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (isomer 1) and Example 36 (R)-2-((7,8-dichloro-1-ethyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile or (S)-2-((7,8-dichloro-1-ethyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (isomer 2)

[0646] [ka] Racemic 2-((7,8-dichloro-1-ethyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (65 mg, 0.14 mmol, 75% by weight) was purified by SFC to give the title compounds (Isomer 1 - Rt = 1.572 min (100% ee), 16 mg, 32% as an off-white solid; Isomer 2 - Rt = 1.718 min (99.6% ee), 15 mg, 32% as an off-white solid). Mobile phase: 40% EtOH (0.1% NH 3 H 2 O2): 60% CO 2 ;Column: DAICEL CHIRALCEL OJ (30×250mm, 10μm);Flow rate: 80mL / min. ES / MS(m / z)( 35 Cl / 37 Cl):352.1 / 354.0(M+H).

[0647] Example 37 (R)-7,8-dichloro-1-methyl-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (S)-7,8-dichloro-1-methyl-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1) and Example 38 (R)-7,8-dichloro-1-methyl-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (S)-7,8-dichloro-1-methyl-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 2)

[0648] [ka] Racemic 7,8-dichloro-1-methyl-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (26.5 mg, 0.073 mmol) was purified by SFC to give the title compounds (Isomer 1 - Rt = 1.61 min (100% ee), 9.9 mg, 37%; Isomer 2 - Rt = 2.22 min (94% ee), 9.6 mg, 36%). Column: Chiralpak AD-H, 21 x 150 mm; Mobile phase: 25% MeOH:75% CO 2 ;Flow rate: 80mL / min;Column temperature: 40℃;Detection: 225nM. ES / MS(m / z):( 35 Cl / 37 Cl) 364.0 / 366.0 (M+H).

[0649] Example 39 N-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-methoxyacetamide

[0650] [ka] 10-Bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (150 mg, 0.302 mmol, 73% by mass), 2-methoxyacetamide (59 mg, 0.67 mmol), Pd 2 (dba) 3(28 mg, 0.030 mmol), Xantphos (35 mg, 0.061 mmol) and cesium carbonate (345 mg, 1.06 mmol) were combined in 1,4-dioxane (10 mL) and THF (1 mL). 2 The mixture was degassed and purged with N (3 times). 2 The mixture was stirred at 110° C. under atmospheric pressure for 16 hours. The mixture was filtered, water was added to the filtrate, and the mixture was extracted with EtOAc. The organic layers were combined, washed with a saturated aqueous solution of NaCl, and then washed with anhydrous Na 2 SO 4 The mixture was dried over ice, filtered, and concentrated under reduced pressure. Purification by flash silica gel chromatography eluting with MeOH in DCM, concentrated under reduced pressure, and further purified by preparative HPLC to give N-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-methoxyacetamide (55.37 mg, 48%) as a yellow solid. ES / MS (m / z): 35 Cl / 37 Cl) 370.0 / 371.9 (M+H).

[0651] Example 40 (R)-N-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-methoxyacetamide or (S)-N-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-methoxyacetamide (isomer 1) and Example 41 (R)-N-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-methoxyacetamide or (S)-N-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-methoxyacetamide (isomer 2)

[0652] [ka] Racemic N-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-methoxyacetamide (151.6 mg, 0.409 mmol) was purified by SFC to give the title compounds (isomer 1 - Rt = 1.29 min (98% ee), 55.2 mg, 36%; isomer 2 - Rt = 2.38 min (100% ee), 49.0 mg, 32%). Column: Chiralpak AD-H, 21 × 150 mm; Mobile phase: 25% EtOH with 0.5% DMEA: 75% CO 2 ;Flow rate: 80mL / min;Column temperature: 40℃;Detection: 254nM. ES / MS(m / z):( 35 Cl / 37 Cl) 370.2 / 372.2 (M+H).

[0653] Example 42 (S)-N-((R-7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxypropanamide or (S)-N-((S-7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxypropanamide (isomer 1) and Example 43 (S)-N-((R-7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxypropanamide or (S)-N-((S-7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxypropanamide (isomer 2)

[0654] [ka] 10-Bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (270 mg, 0.664 mmol, 89% by mass), (S)-2-hydroxypropanamide (124 mg, 1.33 mmol), Xantphos-Pd-G 2 (62 mg, 0.066 mmol) and cesium carbonate (683 mg, 1.99 mmol) were combined in 1,4-dioxane (10 mL) and THF (1 mL). 2 The mixture was degassed and purged with N (3 times). 2 The mixture was stirred at 80° C. under atmospheric pressure for 2 hours. The mixture was cooled to ambient temperature. The mixture was diluted with water and extracted with EtOAc (×2). The combined organic layers were washed with saturated aqueous NaCl (×2) and anhydrous Na 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure. Purified by silica gel flash chromatography eluting with MeOH in DCM and concentrated under reduced pressure. Then further purified by preparative HPLC to give the title compounds (Isomer 1 - Rt = 1.475 min (98% de), 68 mg, 27% as a white solid; Isomer 2 - Rt = 1.547 min (97.3% de), 33 mg, 13% as a white solid). ES / MS (m / z): ( 35 Cl / 37 Cl) 370.0 / 372.0 (M+H).

[0655] Intermediate 47A 10-Amino-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0656] [ka] 10-Bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (240 mg, 663 μmol), tris(dibenzylideneacetone)dipalladium(0) (60.7 mg, 66.3 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (76.7 mg, 133 μmol), tert-butyl carbamate (155 mg, 1.33 mmol) were combined and then 1,4-dioxane (5 mL) was added. 2 Cesium carbonate (756 mg, 2.32 mmol) was added and N 2 Bubble in for an additional 2 min, then seal and heat to 100° C. overnight. Cool to ambient temperature, add EtOAc, wash with water. Wash with saturated sodium bicarbonate, saturated aqueous NaCl, dry over sodium sulfate, filter and concentrate. Redissolve in DCM (3 mL). Add 2 drops of anisole (50 mg, 50 μL, 0.46 mmol) followed by TFA (1.5 g, 1.0 mL, 13 mmol). Stir at ambient temperature for 1 h. Quench with saturated aqueous sodium bicarbonate and add EtOAc. Extraction, followed by washing with saturated aqueous sodium bicarbonate, saturated aqueous NaCl, drying over sodium sulfate, filtration, concentration under reduced pressure, and purification by normal phase silica gel column chromatography eluting with MeOH in DCM gave 10-amino-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (0.13 g, 66%) as an orange foam. ES / MS (m / z): ( 35 Cl / 37 Cl) 297.8 / 299.8 (M+H).

[0657] Example 44 N-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxetane-2-carboxamide

[0658] [ka] 10-Amino-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (50 mg, 0.17 mmol) was dissolved in DMF (2 mL) and DIPEA (73 μL, 0.42 mmol) and rac-oxetane-2-carboxylic acid (26 mg, 0.25 mmol) were added. Propylphosphonic anhydride (50% in DMF) (0.12 mL, 0.20 mmol) was added and then stirred at ambient temperature overnight. Additional DIPEA (73 μL, 0.42 mmol) was added followed by propylphosphonic anhydride (50% in DMF) (0.15 g, 0.14 mL, 0.25 mmol). Dilute with EtOAc and wash with 0.1 N HCl, saturated aqueous sodium bicarbonate (2 times) and saturated aqueous NaCl. The organics were washed with Na 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure. Purification by flash chromatography eluting with MeOH in DCM gave N-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxetane-2-carboxamide (35 mg, 55%). ES / MS (m / z): ( 35 Cl / 37 Cl) 381.9 / 383.9 (M+H).

[0659] Example 45 7,8-Dichloro-1-methyl-10-(propylamino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0660] [ka] 10-Bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (120 mg, 0.298 mmol, 90% by mass), propan-1-amine (93 mg, 1.5 mmol), Pd 2 (dba) 3(37 mg, 0.039 mmol), Xantphos (45 mg, 0.075 mmol) and cesium carbonate (245 mg, 0.746 mmol) were combined in 1,4-dioxane (4 mL) and THF (0.2 mL). 2 The mixture was stirred at 105° C. for 16 hours under atmospheric pressure. The mixture was concentrated under reduced pressure, diluted with water, and extracted with EtOAc (3 times). The organic layers were combined and washed with anhydrous Na 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure. It was purified by preparative TLC eluting with MeOH in DCM and then further purified by preparative HPLC. It was concentrated under reduced pressure and lyophilized to give 7,8-dichloro-1-methyl-10-(propylamino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (33 mg, 32%) as a grey solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 340.0 / 342.0 (M+H).

[0661] Example 46 7,8-Dichloro-10-((2-methoxyethyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0662] [ka] 10-Bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (80 mg, 0.22 mmol), 2-methoxyethan-1-amine (33 mg, 0.44 mmol), Xantphos-Pd-G2 (39 mg, 0.044 mmol), potassium phosphate tribasic monohydrate (0.20 g, 0.88 mmol) in 1,4-dioxane (2 mL) were added to a screw-cap vial under nitrogen. The vial was sealed and heated at 100° C. overnight. 0.5 mL of saturated aqueous NaCl was added. Extracted with 1 mL of EtOAc. The organic layer was separated, dried over a diatomaceous earth cartridge, and washed with additional EtOAc. The organic layer was washed with N 2Concentration under reflux gave racemic 7,8-dichloro-10-((2-methoxyethyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (30 mg, 37%). ES / MS (m / z): 35 Cl / 37 Cl) 356.0 / 358.0 (M+H).

[0663] Example 47 (R)-7,8-dichloro-10-((2-methoxyethyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (S)-7,8-dichloro-10-((2-methoxyethyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1) and Example 48 (R)-7,8-dichloro-10-((2-methoxyethyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (S)-7,8-dichloro-10-((2-methoxyethyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 2)

[0664] [ka] Racemic 7,8-dichloro-10-((2-methoxyethyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (32.9 mg, 0.092 mmol) was purified by SFC to give the title compounds (Isomer 1 - Rt = 0.95 min (100% ee), 14.8 mg, 45%; Isomer 2 - Rt = 2.18 min (100% ee), 16.2 mg, 49%). Column: Chiralpak AS-H, 21 x 150 mm; Mobile phase: 30% MeOH with 0.5% DMEA: 70% CO 2 ;Flow rate: 80mL / min;Column temperature: 40℃;Detection: 225nM. ES / MS(m / z):( 35 Cl / 37 Cl) 355.8 / 357.8 (M+H).

[0665] Intermediate 48 10-(2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0666] [ka] A solution of 10-bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (100 mg, 0.1851 mmol, 67% by weight), 2-(tert-butyldimethylsiloxy)ethanamine (80 mg, 0.407 mmol), Pd 2 (dba) 3 (20 mg, 0.0185 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (25 mg, 0.0370 mmol) and cesium carbonate (210 mg, 0.644 mmol) were combined. 2 The mixture was purged with 0.5% CO and heated to 110° C. overnight. The mixture was cooled to ambient temperature. The reaction was repeated on a 0.5x scale and the crude products were combined. Concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with EtOAc in PE afforded racemic 10-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (150 mg, 71% by weight, 83%) as a yellow solid. ES / MS (m / z): 35 Cl / 37 Cl) 455.9 / 457.9 (M+H).

[0667] Intermediate 49 (R)-10-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (S)-10-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1) and Intermediate 50 (R)-10-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (S)-10-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 2)

[0668] [ka] Racemic 10-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (1.40 g, 87% by mass, 2.67 mmol) was purified by SFC to give the title compounds (Isomer 1 - Rt = 2.3 min (98% ee), 546 mg, 44%; Isomer 2 - Rt = 2.6 min (>98% ee), 564 mg, 60% by mass, 44%). Column: Chiralpak IG, 20 x 250 mm, 5 μm; Mobile phase: 30% MeOH (0.5% DMEA): 70% CO 2 Flow rate: 80 mL / min; Column temperature: 40 °C; Outlet pressure: 100 bar; Detection: 220 nm. ES / MS (m / z): ( 35 Cl / 37 Cl) 456.2 / 458.2 (M+H).

[0669] Example 49 7,8-Dichloro-10-((2-hydroxyethyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0670] [ka] 10-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (90 mg, 0.140 mmol, 71% by weight) was dissolved in THF (2 mL). TBAF (1.0 M in THF) (0.6 mL) was added and stirred for 2 h. The reaction was diluted with EtOAc (50 mL) and washed with saturated aqueous ammonium chloride (30 mL, 3 times). The organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. Purification by preparative HPLC afforded racemic 7,8-dichloro-10-((2-hydroxyethyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (22.82 mg, 46%) as a grey solid. ES / MS (m / z): 35 Cl / 37 Cl) 342.1 / 344.0 (M+H).

[0671] Example 50 7,8-Dichloro-10-((2-hydroxyethyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1)

[0672] [ka] A single isomer of 10-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1, 400 mg, 876 μmol) and THF (9 mL) were combined with stirring. Sparged with nitrogen for 5 min, then TBAF (1 M in THF) (3.50 mL, 3.50 mmol) was added. Stirred under nitrogen atmosphere at ambient temperature for 2 h. Collected solid by filtration and washed with THF (1 mL, 2 times). Partitioned solid between water (10 mL) and EtOAc (15 mL), separated phases, and extracted aqueous phase with EtOAc (5 mL). Combined organic phases were washed with saturated aqueous NaCl, dried over magnesium sulfate, filtered, and concentrated under reduced pressure at 50° C. to give a white solid. The solid was dried at 10 mbar and 40° C. for 16 h. The solid was reslurried in water (25 mL) then filtered and washed with water (2×5 mL). The solid was dried at 10 mbar and 40° C. for 16 h to give 7,8-dichloro-10-((2-hydroxyethyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1) (199 mg (>98% ee as isomer 1), 97% by weight, 64%) as a white solid. ES / MS (m / z): 35 Cl / 37 Cl) 456.2 / 458.2 (M+H).

[0673] Example 51 7,8-Dichloro-10-((2-hydroxyethyl)amino)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H-one (isomer 1)

[0674] [ka] Combine single isomer 10-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1, 50 mg, 0.11 mmol), cesium carbonate (61 mg, 0.19 mmol) and DMF (1 mL) with stirring. Add methyl iodide (7.5 μL, 0.12 mmol), cap and stir at ambient temperature for 66 h. Add additional methyl iodide (1.0 μL, 16 μmol) and stir at ambient temperature for 2 h. Add tetra-n-butylammonium fluoride (1M in THF, 0.55 mL, 0.55 mmol) and stir at ambient temperature for 1 h. Dilute with water (6 mL) and extract with EtOAc (4×3 mL). The organic phases were combined and concentrated under a stream of nitrogen at 40° C. The residue was dissolved in 1:1 DCM:EtOAc, added together with further material from a test reaction (44 μmol scale) and purified by flash chromatography on silica using EtOH in EtOAc. Fractions containing the title compound were concentrated under reduced pressure and the residue was dried at 10 mbar and 50° C. for 20 hours to give 7,8-dichloro-10-((2-hydroxyethyl)amino)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1) (38 mg, 99+%). ES / MS (m / z): ( 35 Cl / 37 Cl) 356.0 / 358.0 (M+H).

[0675] Example 52 7,8-Dichloro-9-fluoro-10-((2-hydroxyethyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0676] [ka] 1-Fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (156 mg, 687 μmol) was added to a suspension of racemic 10-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (300 mg, 624 μmol) in ACN (12.5 mL) under nitrogen gas atmosphere. Stirred overnight at ambient temperature. 1-Fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (156 mg, 687 μmol) was added and stirred overnight. Volatiles were removed, HCl (1M) was added, the solid was filtered and washed with water. Passed through an SCX cartridge and washed with MeOH, then 2M MeOH / NH 3 The basic fraction was concentrated to dryness under reduced pressure. The impure compound was purified by silica gel flash chromatography eluting with MeOH in DCM and dried under reduced pressure. SFC (column: Luna Hilic, 5 μm 30 × 150 mm; mobile phase: 20-40% CO 2 / MeOH(10mM NH 4 HCO 3 , pH 8); flow rate: 100 mL / min) to give racemic 7,8-dichloro-9-fluoro-10-((2-hydroxyethyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (11 mg, 5%). ES / MS (m / z): 35 Cl / 37 Cl) 360.0 / 362.0 (M+H).

[0677] Intermediate 51 10-(3-((tert-butyldimethylsilyl)oxy)propyl)amino)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0678] [ka] 10-Bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (220 mg, 0.492 mmol, 81% by mass), 3-(tert-butyldimethylsilyloxypropan-1-amine (210 mg, 1.087 mmol), Pd 2 (dba) 3 (50 mg, 0.053 mmol), Xantphos (60 mg, 0.104 mmol) and cesium carbonate (560 mg, 1.72 mmol) were combined in 1,4-dioxane (40 mL) and THF (2 mL). 2 The mixture was purged with 500 rpm (3 times) and stirred at 110 °C for 14-18 hours. The reaction was repeated on a 0.136-fold scale and the crude products were combined. Concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with EtOAc in PE afforded racemic 10-((3-((tert-butyldimethylsilyl)oxy)propyl)amino)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (200 mg, 62%) as a yellow solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 470.0 / 471.9 (M+H).

[0679] Example 53 (R)-7,8-dichloro-10-((3-hydroxypropyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (S)-7,8-dichloro-10-((3-hydroxypropyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1) and Example 54 (R)-7,8-dichloro-10-((3-hydroxypropyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (S)-7,8-dichloro-10-((3-hydroxypropyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 2)

[0680] [ka] Racemic 10-((3-((tert-butyldimethylsilyl)oxy)propyl)amino)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (200 mg, 0.344 mmol) was dissolved in THF (4 mL). TBAF (1M in THF) (1.4 mL, 1.4 mmol) was added at ambient temperature. Stirred for 2 h. Diluted with EtOAc and washed with saturated aqueous ammonium chloride (2 times) and saturated aqueous NaCl. The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure. Trituration with ACN and purification by SFC afforded the title compounds (Isomer 1 - Rt = 1.55 min (99% ee), 21 mg, 16%, Isomer 2 - Rt = 1.95 min (>99% ee), 48 mg, 37%. Column: DAICEL CHIRALCEL OD (250 x 30 mm, 10 μm); Mobile phase: 40% EtOH (0.1% NH 3 H 2 O2); 60% CO 2 ;Flow rate: 80mL / min. ES / MS(m / z):( 35 Cl / 37 Cl) 356.0 / 357.9 (M+H).

[0681] Intermediate 52 7,8-Dichloro-10-((R)-2-hydroxypropyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0682] [ka] Racemic 10-bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (100 mg, 71% by weight, 196 μmol), (2R)-(-)-1-aminopropan-2-ol (29 mg, 0.39 mmol), Xantphos-Pd-G2 (26 mg, 27 μmol), potassium phosphate tripotassium (162 mg, 763 μmol) and 1,4-dioxane (4.0 mL) were combined in a glass tube with stirring. Sparged with nitrogen for 5 minutes and then heating was started with a set point of 100° C. (block). The sparge needle was removed after 5 minutes. Heating was continued for approximately 17 hours. Removed from heat, diluted with water (15 mL) and adjusted to pH 1 with 10% aqueous hydrochloric acid. Loaded onto an SCX-2 cartridge and eluted successively with water, MeOH and 2N ammonia in MeOH (3× bed volume each). The basic fractions were concentrated under reduced pressure at 50° C. and the residue was combined with material from two similar reactions. Purification by reverse phase column chromatography afforded 7,8-dichloro-10-(((R-2-hydroxypropyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (86 mg, 37%) as a beige solid. ES / MS (m / z): 35 Cl / 37 Cl) 356.0 / 358.0 (M+H).

[0683] Example 55 7,8-Dichloro-10-(((R)-2-hydroxypropyl)amino)-1-(R)-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H-one or 7,8-Dichloro-10-(((R)-2-hydroxypropyl)amino)-1-(S)-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1) and Example 56 7,8-Dichloro-10-(((R)-2-hydroxypropyl)amino)-1-(R)-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or 7,8-Dichloro-10-(((R)-2-hydroxypropyl)amino)-1-(S)-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 2)

[0684] [ka] 7,8-Dichloro-10-(((R)-2-hydroxypropyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (86 mg, 0.22 mmol) was purified as a mixture of diastereomers by SFC to give the title compound as a light brown solid (isomer 1 - Rt = 2.19 min (>98% de), 31.8 mg, 41%; isomer 2 - Rt = 4.03 min (>98% de), 35.4 mg, 45%). Column: Chiralpak AD, 20 × 250 mm, 5 μm; Mobile phase: 35% MeOH (0.5% DMEA): 65% CO 2 Flow rate: 80 mL / min; Column temperature: 40°C; Detection: 220 nm. ES / MS (m / z): ( 35 Cl / 37 Cl) 356.0 / 358.0 (M+H).

[0685] Example 57 7,8-Dichloro-1-methyl-10-((oxazol-4-ylmethyl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0686] [ka] In 1,4-dioxane (15 mL) and THF (1.5 mL), 10-bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (150 mg, 0.414 mmol), oxazol-4-ylmethanamine hydrochloride (176 mg, 1.24 mmol), Pd 2 (dba) 3 (38 mg, 0.041 mmol), Xantphos (49 mg, 0.083 mmol) and cesium carbonate (473 mg, 1.45 mmol). 2 The mixture was degassed and purged with N (3 times). 2 The mixture was stirred at 110° C. under atmospheric pressure for 16 hours. It was concentrated under reduced pressure and purified by flash silica gel chromatography eluting with MeOH in DCM and further purified by preparative HPLC. It was concentrated under reduced pressure and lyophilized to give 7,8-dichloro-1-methyl-10-((oxazol-4-ylmethyl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (74 mg, 47%) as a white solid. ES / MS (m / z): ( 35 Cl / 37 Cl)379.1 / 381.1(M+H).

[0687] Example 58 (S)-7,8-dichloro-1-methyl-10-((oxazol-4-ylmethyl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (R)-7,8-dichloro-1-methyl-10-((oxazol-4-ylmethyl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1) and Example 59 (S)-7,8-dichloro-1-methyl-10-((oxazol-4-ylmethyl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (R)-7,8-dichloro-1-methyl-10-((oxazol-4-ylmethyl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 2)

[0688] [ka] Racemic 7,8-dichloro-1-methyl-10-((oxazol-4-ylmethyl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (60 mg, 0.16 mmol) was purified by SFC to give the title compounds (Isomer 1 - Rt = 0.735 min (100% ee), 27 mg, 45%; Isomer 2 - Rt = 1.739 min (100% ee), 27 mg, 45%). Column: Chiralpak AS-H, 21 x 150 mm, 5 μm; Mobile phase: 40% MeOH:60% CO 2 ;Flow rate: 80mL / min. ES / MS(m / z):( 35 Cl / 37 Cl) 379.0 / 381.0 (M+H).

[0689] Example 60 7,8-Dichloro-1-methyl-10-(oxetan-3-ylamino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0690] [ka] 10-Bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (100 mg, 0.185 mmol, 67% by weight), 3-oxetanamine (30 mg, 0.407 mmol), Pd in ​​1,4-dioxane (20 mL) and THF (1 mL). 2 (dba) 3(20 mg, 0.0185 mmol), Xantphos (22 mg, 0.0370 mmol) and cesium carbonate (215 mg, 0.660 mmol) were combined. 2 The mixture was purged with 0.3% CO and stirred at 110° C. overnight. The reaction was repeated on a 0.3x scale and the crude products were combined. Concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography eluting with MeOH in DCM to give racemic 7,8-dichloro-1-methyl-10-(oxetan-3-ylamino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (23 mg, 25%) as a yellow solid. ES / MS (m / z): 35 Cl / 37 Cl) 354.0 / 355.8 (M+H).

[0691] Example 61 7,8-Dichloro-1-methyl-10-(((S)-tetrahydrofuran-3-yl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0692] [ka] In 1,4-dioxane (10 mL) and THF (1 mL), 10-bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (200 mg, 0.403 mmol, 73% by weight), (S)-tetrahydrofuran-3-amine (77 mg, 0.887 mmol), Pd 2 (dba) 3 (37 mg, 0.040 mmol), Xantphos (47 mg, 0.081 mmol) and cesium carbonate (460 mg, 1.41 mmol) were combined. 2 The mixture was degassed and purged with N (3 times). 2 The mixture was stirred at 110° C. under atmospheric pressure for 16 hours. The mixture was cooled to ambient temperature, filtered, and water was added to the filtrate, which was then extracted with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl, and diluted with anhydrous Na 2 SO 4The mixture was dried over ice, filtered and concentrated under reduced pressure. Purification by flash silica gel chromatography eluting with MeOH in DCM and concentrated under reduced pressure. Further purification by preparative HPLC afforded the mixture of diastereomers 7,8-dichloro-1-methyl-10-(((S)-tetrahydrofuran-3-yl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (58 mg, 39%) as a brown solid. ES / MS (m / z): 35 Cl / 37 Cl) 368.1 / 370.0 (M+H).

[0693] Example 62 (S)-7,8-dichloro-1-methyl-10-(((S)-tetrahydrofuran-3-yl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (R)-7,8-dichloro-1-methyl-10-(((S)-tetrahydrofuran-3-yl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1) and Example 63 (S)-7,8-dichloro-1-methyl-10-(((S)-tetrahydrofuran-3-yl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (R)-7,8-dichloro-1-methyl-10-(((S)-tetrahydrofuran-3-yl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 2)

[0694] [ka] A mixture of (S)-7,8-dichloro-1-methyl-10-(((S)-tetrahydrofuran-3-yl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one and (R)-7,8-dichloro-1-methyl-10-(((S)-tetrahydrofuran-3-yl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (55 mg, 0.15 mmol) was purified by SFC to give the title compounds (isomer 1 - RT = 0.88 min (100% de), 26 mg, 47%; isomer 2 - RT = 2.97 min (100% de), 17 mg, 31%). Column: Chiralpak AS-H, 21 x 150 mm; Mobile phase: 35% MeOH (0.5% DMEA): 65% CO 2 ;Flow rate: 80mL / min;Column temperature: 40℃;Detection: 225nM. ES / MS(m / z):( 35 Cl / 37 Cl) 368.0 / 370.0 (M+H).

[0695] Intermediate 53 7,8-Dichloro-1-methyl-10-(((R)-tetrahydrofuran-3-yl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0696] [ka] Combine 10-bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (500 mg, 1.38 mmol), (3R)-oxolan-3-amine (241 mg, 2.76 mmol), Xantphos-Pd-G2 (123 mg, 138 μmol), Xantphos (79.9 mg, 138 μmol), potassium phosphate tripotassium monohydrate (1.27 g, 5.52 mmol) and 1,4-dioxane (10 mL). Sealed and heated to 100° C. for 18 h. (3R-Oxolan-3-amine (241 mg, 2.76 mmol), Xantphos-Pd-G2 (123 mg, 138 μmol), and Xantphos (79.9 mg, 138 μmol) were added. Sealed and heated to 100° C. overnight. The reaction was cooled to ambient temperature. The reaction mixture was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with MeOH in DCM to give 7,8-dichloro-1-methyl-10-(((R)-tetrahydrofuran-3-yl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one as a brown solid (229.7 mg, 45%). ES / MS (m / z): 35 Cl / 37 Cl) 368.0 / 370.0 (M+H).

[0697] Example 64 (R)-7,8-dichloro-1-methyl-10-((R-tetrahydrofuran-3-yl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (S)-7,8-dichloro-1-methyl-10-(((R-tetrahydrofuran-3-yl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one and Example 65 (R)-7,8-dichloro-1-methyl-10-((R-tetrahydrofuran-3-yl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (S)-7,8-dichloro-1-methyl-10-(((R-tetrahydrofuran-3-yl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0698] [ka] The mixture of diastereomers 7,8-dichloro-1-methyl-10-(((R)-tetrahydrofuran-3-yl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (229.7 mg, 0.624 mmol) was purified by SFC to give the title compounds (isomer 1 - Rt = 1.16 min (100% de), 42.9 mg, 19%; isomer 2 - Rt = 2.34 min (100% de), 47.4 mg, 21%). Column: Chiralpak AS-H, 21 x 150 mm; mobile phase: 30% MeOH with 0.5% DMEA: 70% CO 2 ;Flow rate: 80mL / min;Column temperature: 40℃;Detection: 225nM. ES / MS(m / z):( 35 Cl / 37 Cl) 368.2 / 370.2 (M+H).

[0699] Example 66 7,8-Dichloro-1-methyl-10-(((R)-tetrahydrofuran-3-yl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0700] [ka] 10-Bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (80 mg, 0.22 mmol), (R)-tetrahydrofuran-3-amine (0.44 mmol), Xantphos-Pd-G2 (39 mg, 0.044 mmol), potassium phosphate tribasic monohydrate (0.20 g, 0.88 mmol) in 1,4-dioxane (2 mL) was dissolved in N 2 The solution was added to a screw cap vial under reduced pressure. It was sealed and heated at 100° C. overnight. 0.5 mL of saturated NaCl solution was added. Extracted with 1 mL of EtOAc. The organic layer was separated, dried through a diatomaceous earth cartridge, and washed with additional EtOAc. The organic layer was then rinsed with N 2 Concentration under reflux gave 7,8-dichloro-1-methyl-10-(((R)-tetrahydrofuran-3-yl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (1.7 mg, 2%). ES / MS (m / z): 35 Cl / 37 Cl) 368.2 / 370.0 (M+H).

[0701] Intermediate 54 4-Methylisoxazol-3-amine

[0702] [ka] To a solution of methacrylonitrile (5.00 g, 74.5 mmol) in MeOH (70 mL) was added bromine (14.3 g, 4.61 mL, 89.4 mmol) at 0° C. and stirred at 35° C. for 2 h. Then, a solution of NaOH (8.94 g, 224 mmol) and hydroxyurea (7.37 g, 96.9 mmol) in H 2 A solution of MeOH in 12 mL was added to the above reaction mixture at 0° C. Stirred at 90° C. for 4 h. Concentrated under reduced pressure to remove MeOH, diluted with water and extracted with DCM. The organic layers were combined, washed with water, saturated aqueous NaCl and anhydrous Na 2 SO 4It was dried over, filtered and concentrated under reduced pressure. Purification by flash silica gel chromatography eluting with EtOAc in PE and concentrated under reduced pressure gave 4-methylisoxazol-3-amine (1.40 g, 17%) as a yellow solid. 1 H NMR(DMSO-d6):8.08(s,1H),5.42(brs,2H),1.81(s,3H).

[0703] Example 67 7,8-Dichloro-1-methyl-10-((4-methylisoxazol-3-yl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0704] [ka] 10-Bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (300 mg, 0.704 mmol, 85% by mass), 4-methylisoxazol-3-amine (230 mg, 2.11 mmol, 90% by mass), (t-Bu 3 P) 2 Pd (72 mg, 0.14 mmol) and cesium carbonate (803 mg, 2.47 mmol) were combined in 1,4-dioxane (10 mL) and THF (1 mL). 2 The mixture was degassed and purged with N (3 times). 2 The mixture was stirred at 110° C. under atmospheric pressure for 16 h. It was concentrated under reduced pressure and purified by flash silica gel chromatography eluting with MeOH in DCM and further purified by preparative HPLC and SFC separation. Column: DAICEL CHIRALPAK IC, 30×250 mm, 10 μm; Mobile phase: 30% EtOH (0.1% NH 3. H 2 O2); 70% CO 2Flow rate: 80 mL / min. Concentration under reduced pressure and lyophilization afforded 7,8-dichloro-1-methyl-10-((4-methylisoxazol-3-yl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (14 mg, 5%) as a yellow solid. ES / MS (m / z): 35 Cl / 37 Cl) 379.1 / 381.0 (M+H).

[0705] Intermediate 55 7,8-Dichloro-10-((2,2-difluoro-3-hydroxypropyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0706] [ka] In 1,4-dioxane (5 mL) and DMF (0.25 mL), 10-bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (150 mg, 0.365 mmol, 88% by weight), 3-amino-2,2-difluoropropan-1-ol (128 mg, 1.09 mmol), Pd 2 (dba) 3 (34 mg, 0.037 mmol), Xantphos (43 mg, 0.073 mmol) and cesium carbonate (420 mg, 1.28 mmol). 2 Degassed and purged at 40° C. (3 times). Stirred at 110° C. for 16 h. Concentrated under reduced pressure and purified by silica gel flash chromatography eluting with MeOH in DCM, then further purified by preparative HPLC. Concentrated under reduced pressure and lyophilized to give racemic 7,8-dichloro-10-((2,2-difluoro-3-hydroxypropyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (54 mg, 34%). ES / MS (m / z): 35 Cl / 37 Cl) 392.0 / 393.9 (M+H).

[0707] Example 68 (R)-7,8-dichloro-10-((2.2-difluoro-3-hydroxypropyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (S)-7,8-dichloro-10-((2.2-difluoro-3-hydroxypropyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1) and Example 69 (R)-7,8-dichloro-10-((2.2-difluoro-3-hydroxypropyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (S)-7,8-dichloro-10-((2.2-difluoro-3-hydroxypropyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 2)

[0708] [ka] Racemic 7,8-dichloro-10-((2,2-difluoro-3-hydroxypropyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (54 mg, 0.12 mmol) was purified by SFC to give isomer 1 - Rt = 1.94 min (97.4% ee), 20.10 mg, 40% as an off-white solid. The second peak was purified by trituration with ACN to give isomer 2 - Rt = 2.28 min (95.9% ee), 16.12 mg, 32% as a white solid). Column: DAICEL CHIRALPAK AD, 30 x 250 mm, 10 μm; Mobile phase: 40% MeOH:60% CO 2 ;Flow rate: 80mL / min;Column temperature: 40℃. ES / MS(m / z):( 35 Cl / 37 Cl) 392.0 / 394.0 (M+H).

[0709] Example 70 7,8-Dichloro-10-((2.2-difluoroethyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0710] [ka] 10-Bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (150 mg, 0.367 mmol, 89% by mass), 2,2-difluoroethan-1-amine (94 mg, 1.1 mmol), Pd 2 (dba) 3 (34 mg, 0.037 mmol), Xantphos (43 mg, 0.074 mmol) and cesium carbonate (299 mg, 0.919 mmol) were combined in 1,4-dioxane (2 mL) and THF (0.17 mL). 2 The mixture was stirred at 100° C. under atmospheric pressure for 12 hours. It was concentrated under reduced pressure and purified by silica gel flash chromatography eluting with EtOAc in PE and further purified by preparative HPLC. It was concentrated under reduced pressure and lyophilized to give 7,8-dichloro-10-((2,2-difluoroethyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (44.08 mg, 33%) as a brown solid. ES / MS (m / z): ( 35 Cl / 37 Cl)362.1 / 364.1(M+H).

[0711] Example 71 7,8-Dichloro-10-((3.3-difluoropropyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0712] [ka] 10-Bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (100 mg, 0.243 mmol, 88% by weight), 3,3-difluoropropan-1-amine hydrochloride (96 mg, 0.73 mmol), Pd 2 (dba) 3 (23 mg, 0.024 mmol), Xantphos (28 mg, 0.049 mmol) and cesium carbonate (400 mg, 1.22 mmol) were combined. 2 The mixture was degassed and purged (3 times) at 120° C. for 2 hours. It was concentrated under reduced pressure and purified by silica gel flash chromatography eluting with MeOH in DCM and further purified by preparative HPLC. It was concentrated under reduced pressure and lyophilized to give 7,8-dichloro-10-((3,3-difluoropropyl)amino)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (40.64 mg, 44%) as a yellow solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 375.9 / 378.0 (M+H).

[0713] Intermediate 56 3-((tert-butyldimethylsilyl)oxy)-2,2-difluoropropan-1-ol

[0714] [ka] 2,2-Difluoropropane-1,3-diol (1.00 g, 8.92 mmol) and imidazole (911 mg, 13.4 mmol) were combined in DCM (15 mL) at 0° C. Stirred at 0° C. for 0.5 h. tert-Butyldimethylsilyl chloride (1.34 g, 8.92 mmol) was added at 0° C. Stirred at ambient temperature for 2 h. Diluted with water and extracted with EtOAc. Washed with saturated aqueous NaCl and concentrated to dryness. 2 SO 4The residue was dried over ice, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with EtOAc in PE and concentrated under reduced pressure gave 3-((tert-butyldimethylsilyl)oxy)-2,2-difluoropropan-1-ol (550 mg, 22%). 1 H NMR (DMSO-d6):5.44(t,J=6.0Hz,1H),3.81(t,J=13.2Hz,2H),3.61(td,J=13.6,6.0Hz,2H),0.87(s,9H),0.07(s,6H).

[0715] Intermediate 57 3-((tert-butyldimethylsilyl)oxy)-2,2-difluoropropyl trifluoromethanesulfonate

[0716] [ka] 3-((tert-butyldimethylsilyl)oxy)-2,2-difluoropropan-1-ol (500 mg, 1.77 mmol 80% by weight), pyridine (280 mg, 3.53 mmol) were combined in DCM (10 mL). Trifluoromethanesulfonic anhydride (748 mg, 2.65 mmol) was added at 0° C. Stirred at ambient temperature for 2 h. Dilute with water and extract with DCM. Wash with saturated aqueous NaCl and add Na 2 SO 4 The residue was dried over ice, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with EtOAc in PE and concentrated under reduced pressure gave 3-((tert-butyldimethylsilyl)oxy)-2,2-difluoropropyl trifluoromethanesulfonate (450 mg, 64%). 1 H NMR(DMSO-d6):5.08(t,J=13.6Hz,2H),3.97(t,J=13.0Hz,2H),0.87(s,9H),0.09(s,6H).

[0717] Intermediate 58 10-(3-((tert-butyldimethylsilyl)oxy)-2,2-difluoropropoxy)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0718] [ka] In DMF (3 mL), 7,8-dichloro-10-hydroxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (140 mg, 0.328 mmol, 70% by weight) and K 2 CO 3 (136 mg, 0.983 mmol). 3-((tert-butyldimethylsilyl)oxy)-2,2-difluoropropyl trifluoromethanesulfonate (391 mg, 0.983 mmol 90% by weight) was added. Stirred at 50° C. for 16 hours. Dilute with water and extract with EtOAc. Wash with saturated aqueous NaCl and add Na 2 SO 4 The mixture was dried over ice, filtered, and concentrated under reduced pressure to give 10-(3-((tert(butyldimethylsilyl)oxy)-2,2-difluoropropoxy)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (180 mg, 65%). ES / MS (m / z): 35 Cl / 37 Cl) 507.0 / 509.0 (M+H).

[0719] Example 72 7,8-Dichloro-10-(2,2-difluoro-3-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0720] [ka] 2M aqueous HCl (1 mL) was added to 10-(3-((tert-butyldimethylsilyl)oxy)-2,2-difluoropropoxy)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (180 mg, 0.213 mmol, 60% by weight) in THF (4 mL). Stirred at ambient temperature for 2 h. Diluted with water and extracted with EtOAc. Washed with saturated aqueous NaCl and concentrated to 100%. 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure. Purification by preparative HPLC afforded 7,8-dichloro-10-(2,2-difluoro-3-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (51.76 mg, 61%) as a pink solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 393.0 / 395.0 (M+H).

[0721] Example 73 (S)-7,8-dichloro-10-(2,2-difluoro-3-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (R)-7,8-dichloro-10-(2,2-difluoro-3-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1) and Example 74 (S)-7,8-dichloro-10-(2,2-difluoro-3-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (R)-7,8-dichloro-10-(2,2-difluoro-3-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 2)

[0722] [ka] Racemic 7,8-dichloro-10-(2,2-difluoro-3-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H-one) (49 mg, 0.12 mmol) was purified by SFC to give the title compounds (Isomer 1 - RT = 0.74 min (100% ee), 17 mg, 35%; Isomer 2 - RT = 3.35 min (100% ee), 18 mg, 36%). Column: Chiralpak AS-H, 21 × 150 mm; Mobile phase: 30% MeOH:70% CO 2 ;Flow rate: 80mL / min;Column temperature: 40℃;Detection: 225nM. ES / MS(m / z):( 35 Cl / 37 Cl) 393.0 / 395.0 (M+H).

[0723] Example 75 7,8-Dichloro-10-(2-fluoroethoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0724] [ka] 7,8-dichloro-10-hydroxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (200 mg, 0.468 mmol, 70% by weight), 1-bromo-2-fluoroethane (1.78 g, 14.0 mmol) and K 2 CO 3 (194 mg, 1.40 mmol) were combined in ACN (4 mL). 2 The mixture was degassed and purged with N (3 times). 2 The mixture was stirred at ambient temperature for 64 hours under atmospheric pressure, diluted with water, extracted with EtOAc, washed with saturated aqueous NaCl, and washed with anhydrous Na 2 SO 4The mixture was dried over ice, filtered and concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with MeOH in DCM, concentrated under reduced pressure and further purified by preparative HPLC to give 7,8-dichloro-10-(2-fluoroethoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (55.31 mg, 34%) as a white solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 345.0 / 346.9 (M+H).

[0725] Example 76 7,8-Dichloro-10-(2,2-difluoroethoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0726] [ka] In anhydrous DMF (0.67 mL), racemic 7,8-dichloro-10-hydroxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (50 mg, 0.17 mmol) and cesium carbonate (55 mg, 0.17 mmol) were dissolved in N 2 Combine under reduced pressure. Stir at ambient temperature for 20 minutes. Add 2-bromo-1,1-difluoroethane (15 μL, 0.18 mmol) and stir overnight. Add water and filter the solid and dry under vacuum. Purify by silica gel flash chromatography eluting with MeOH in DCM and dry under reduced pressure to give racemic 7,8-dichloro-10-(2,2-difluoroethoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (14 mg, 22%) as a white solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 363.0 / 365.0 (M+H).

[0727] Intermediate 59 10-(3-((tert-butyldimethylsilyl)oxy)propoxy)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0728] [ka] 7,8-Dichloro-10-hydroxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (100 mg, 0.207 mmol, 62% by weight), (3-iodopropoxy)(tert-butyl)dimethylsilane (124 mg, 0.415 mmol), and K 2 CO 3 (86 mg, 0.622 mmol) in DMF (2 mL). Stirred at 25° C. for 16 h. 2 The mixture was diluted with O and extracted with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl, and diluted with anhydrous Na 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with MeOH in DCM and concentration gave 10-(3-((tert-butyldimethylsilyl)oxy)propoxy)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one 80 mg, 61%). ES / MS (m / z): 471.0 / 473.0 (M+H).

[0729] Intermediate 60 10-(3-((tert-butyldimethylsilyl)oxy)propoxy)-7,8-dichloro-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0730] [ka] To a stirred solution of 10-(3-((tert-butyldimethylsilyl)oxy)propoxy)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (80 mg, 0.13 mmol, 75% by weight) in DMF (2 mL) was added cesium carbonate (0.15 g, 0.45 mmol) and iodomethane (22 mg, 0.15 mmol). Stirred at 25° C. for 2 h. 2 The mixture was diluted with O and extracted with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl, and diluted with anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give 10-(3-((tert-butyldimethylsilyl)oxy)propoxy)-7,8-dichloro-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (70 mg, 93%). ES / MS (m / z): 35 Cl / 37 Cl) 485.0 / 487.0 (M+H).

[0731] Example 77 7,8-Dichloro-10-(3-hydroxypropoxy)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0732] [ka] To a solution of 10-(3-((tert-butyldimethylsilyl)oxy)propoxy)-7,8-dichloro-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (70 mg, 0.12 mmol, 82% by weight) in THF (2 mL) was added TBAF (0.47 mL, 0.47 mmol, 1 M in THF). Stirred at 25° C. for 2 h. Dilute with EtOAc and wash with saturated NH 4 Wash with aqueous Cl solution, saturated aqueous NaCl solution, and anhydrous Na 2 SO 4The mixture was dried over ice, filtered and concentrated under reduced pressure. The reaction was repeated on a 0.47x scale and the crude products were combined. Purification by reverse phase preparative HPLC afforded 7,8-dichloro-10-(3-hydroxypropoxy)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (28 mg, 42%) as a white solid. ES / MS (m / z): 35 Cl / 37 Cl) 371.0 / 373.0 (M+H).

[0733] Intermediate 61 2-((7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile

[0734] [ka] A solution of 7,8-dichloro-10-hydroxy-1-methyl-3,4,5,6-tetrahydro-1H-azepino[4,5-b]indol-2-one (80 mg, 0.15 mmol, 56% by weight) in DMF (2 mL) was added with bromoacetonitrile (40 mg, 0.33 mmol) and K 2 CO 3 (30 mg, 0.22 mmol) was added at ambient temperature. Stirred at ambient temperature for 2 h. Dilute with water and extract with EtOAc (3 times). Combine the organic layers, wash with saturated aqueous NaCl, and add anhydrous Na 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure. Purification by flash silica gel chromatography eluting with MeOH in DCM and concentration afforded 2-((7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (60 mg, 100%) as a yellow gum. ES / MS (m / z): 35 Cl / 37 Cl) 337.9 / 339.9 (M+H).

[0735] Example 78 2-((7,8-dichloro-1,6-dimethyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile

[0736] [ka] 2-((7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (60 mg, 0.15 mmol, 84% by weight) and cesium carbonate (170 mg, 0.522 mmol) in DMF (2 mL) were combined and MeI (30 mg, 0.21 mmol) was added at 0° C. Stirred at ambient temperature for 2 h. Quenched with water and extracted with EtOAc (3×). The organic layers were combined, washed with saturated aqueous NaCl, and diluted with anhydrous Na 2 SO 4 The mixture was dried over ice and concentrated under reduced pressure. It was purified by preparative HPLC. It was concentrated under reduced pressure and lyophilized to give 2-((7,8-dichloro-1,6-dimethyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (27.15 mg, 50%) as a white solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 352.0 / 353.9 (M+H).

[0737] Example 79 7,8-Dichloro-10-(2-methoxyethoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0738] [ka] 7,8-Dichloro-10-hydroxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (70.0 mg, 0.183 mmol, 78% by mass), 1-iodo-2-methoxyethane (102 mg, 0.548 mmol), and K2 CO 3 (75.7 mg, 0.548 mmol) were combined in DMF (2 mL). Stirred at 60° C. for 3 h. The reaction was repeated on a 0.71x scale and both crude lots were combined. Diluted with water and extracted with EtOAc (3x). The organic layers were combined, washed with saturated aqueous NaCl (3x) and diluted with Na 2 SO 4 The mixture was dried over ice, filtered and concentrated. Purification by preparative HPLC gave impure product as a yellow solid. The reaction and purification were repeated on a 1.20-fold scale, increasing the reaction time to 16 hours, and both impure product lots were combined. Further purification by preparative TLC eluting with MeOH in DCM (1 / 10, V / V), concentrated under reduced pressure, added water and lyophilized to give 7,8-dichloro-10-(2-methoxyethoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (49.6 mg, 21%) as a white solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 357.0 / 359.0 (M+H).

[0739] Example 80 (S)-7,8-dichloro-10-(2-methoxyethoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (R)-7,8-dichloro-10-(2-methoxyethoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1) and Example 81 (S)-7,8-dichloro-10-(2-methoxyethoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (R)-7,8-dichloro-10-(2-methoxyethoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 2)

[0740] [ka] Racemic 7,8-dichloro-10-(2-methoxyethoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (150 mg, 85.5% mass, 0.359 mmol) was purified by SFC to give the title compounds (Isomer 1 - Rt = 1.407 min (100% ee), 52.8 mg, 40%; Isomer 2 - Rt = 1.626 min (99.7% ee), 51.85 mg, 39%). Column: DAICEL CHIRALPAK AD, 250 x 30 mm, 10 μm; Mobile phase: 40% EtOH (0.1% NH 3 H 2 O2); 60% CO 2 ;Flow rate: 80mL / min. ES / MS(m / z):( 35 Cl / 37 Cl)357.1 / 359.1(M+H).

[0741] Intermediate 62 7,8-Dichloro-10-(R)-2-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0742] [ka] 10-Bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (260 mg, 0.589 mmol, 82% by mass), (R)-propane-1,2-diol (10 mL, 140 mmol), tert-BuBrettPhos-Pd-G 3 (79 mg, 0.088 mmol) and t-BuONa (179 mg, 1.77 mmol) were combined in 1,4-dioxane (10 mL). 2 The mixture was degassed and purged with N (3 times). 2 Stirred at 65° C. under ambient conditions for 80 minutes. Cooled to ambient temperature. Repeated the reaction on a 0.06-fold scale and combined reaction mixtures. Diluted with water and extracted with EtOAc (×2). Combined organic layers were washed with saturated aqueous NaCl (×2) and anhydrous Na 2 SO 4The mixture was dried over ice, filtered and concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with MeOH in DCM, concentrated under reduced pressure and further purified by preparative HPLC to give 7,8-dichloro-10-((R)-2-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (90 mg, 42%) as a mixture of diastereomers. ES / MS (m / z):( 35 Cl / 37 Cl) 356.9 / 358.9 (M+H).

[0743] Example 82 (S)-7,8-dichloro-10-((R)-2-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (R)-7,8-dichloro-10-((R)-2-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1) and Example 83 (S)-7,8-dichloro-10-((R)-2-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (R)-7,8-dichloro-10-((R)-2-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 2)

[0744] [ka] The diastereomeric mixture 7,8-dichloro-10-((R)-2-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (90 mg, 0.25 mmol, 97% by weight) was purified by SFC to give the title compounds (Isomer 1 - Rt = 1.570 min (99.1% de), 37.02 mg, 42% as a white solid; Isomer 2 - Rt = 2.211 min (99.6% de), 33.08 mg, 38% as a white solid). Column: DAICEL CHIRALPAK AD, 30 x 250 mm, 10 μm; Mobile phase: 40% MeOH (0.1% NH 3 H 2 O2): 60% CO 2 ;Flow rate: 80mL / min. ES / MS(m / z):( 35 Cl / 37 Cl) 357.1 / 359.0 (M+H).

[0745] Intermediate 63 7,8-Dichloro-10-((S)-2-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0746] [ka] 10-Bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (180 mg, 0.423 mmol, 85% by mass), (S)-propane-1,2-diol (12 mL, 160 mmol), tert-BuBrettPhos-Pd-G 3 (57 mg, 0.063 mmol) and t-BuONa (128 mg, 1.27 mmol) were combined in 1,4-dioxane (12 mL). 2 The mixture was degassed and purged with N (3 times). 2 Stirred at 65° C. under ambient conditions for 80 minutes. Cooled to ambient temperature. Repeated the reaction on a 0.11-fold scale and combined reaction mixtures. Diluted with water and extracted with EtOAc (×2). Combined organic layers were washed with saturated aqueous NaCl (×2) and anhydrous Na 2SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with MeOH in DCM, concentrated under reduced pressure and further purified by preparative HPLC to give 7,8-dichloro-10-((S))-2-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (80 mg, 52%) as a mixture of diastereomers. ES / MS (m / z): ( 35 Cl / 37 Cl) 356.9 / 358.9 (M+H).

[0747] Example 84 (S)-7,8-dichloro-10-((S)-2-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (R)-7,8-dichloro-10-((S)-2-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1) and Example 85 (S)-7,8-dichloro-10-((S)-2-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (R)-7,8-dichloro-10-((S)-2-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 2)

[0748] [ka] 7,8-Dichloro-10-((S)-2-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (80 mg, 0.22 mmol) was purified by SFC to give the title compounds (Isomer 1 - Rt = 1.710 min (99.6% de), 28.62 mg, 36% as a white solid; Isomer 2 - Rt = 2.085 min (97.4% de), 32.40 mg, 40% as a white solid). Column: DAICEL CHIRALPAK AD, 30 x 250 mm, 10 μm; Mobile phase: 35% MeOH (0.1% NH 3 H 2 O2): 65% CO 2 ;Flow rate: 80mL / min. ES / MS(m / z):( 35 Cl / 37 Cl) 357.0 / 359.0 (M+H).

[0749] Example 86 7,8-Dichloro-1-methyl-10-((tetrahydrofuran-3-yl)oxy)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0750] [ka] 7,8-Dichloro-10-hydroxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (320 mg, 0.749 mmol, 70% by weight), 3-iodotetrahydrofuran (445 mg, 2.25 mmol), and K 2 CO 3 (517 mg, 3.74 mmol) was combined in DMF (8 mL). 2 The mixture was purged three times with N 2 The mixture was stirred at 60° C. under atmospheric pressure for 3 hours. The mixture was cooled to ambient temperature, diluted with water, and extracted with EtOAc. The mixture was washed with saturated aqueous NaCl solution and diluted with anhydrous Na 2 SO 4The mixture was dried over ice, filtered and concentrated under reduced pressure. Purification was performed by flash chromatography on silica gel eluting with MeOH in DCM and concentrated under reduced pressure. Purification by preparative HPLC afforded 7,8-dichloro-1-methyl-10-((tetrahydrofuran-3-yl)oxy)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (52 mg, 19%) as a white solid mixture of diastereomers. ES / MS (m / z): ( 35 Cl / 37 Cl) 369.0 / 371.0 (M+H).

[0751] Intermediate 64 7,8-Dichloro-10-(2-oxopropoxy)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0752] [ka] 7,8-Dichloro-10-hydroxy-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (200 mg, 0.449 mmol, 64% by weight), potassium iodide (85 mg, 0.512 mmol) and potassium carbonate (220 mg, 1.59 mmol) were dissolved in acetone (5 mL). Chloroacetone (170 mg, 1.84 mmol) was added. Stirred at 65° C. for 3 h. Quenched with saturated aqueous sodium bicarbonate (1 mL) and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with MeOH in DCM to give 7,8-dichloro-10-(2-oxopropoxy)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (75 mg, 44%) as a brown solid. ES / MS(m / z):( 35 Cl / 37 Cl) 340.9 / 342.9 (M+H).

[0753] Example 87 7,8-Dichloro-10-(2-hydroxypropoxy)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0754] [ka] 7,8-Dichloro-10-(2-oxopropoxy)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (75 mg, 0.198 mmol) was dissolved in MeOH (6 mL). Sodium borohydride (60 mg, 1.59 mmol) was added at 0° C. Stirred at 0° C. for 0.5 h. The reaction was quenched at 0° C. with 1M aqueous HCl (2 mL) and diluted with water (10 mL). The mixture was extracted with EtOAc (10 mL, 2 times). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure. Purification by preparative HPLC afforded 7,8-dichloro-10-(2-hydroxypropoxy)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (29.54 mg, 43%) as a white solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 343.0 / 344.9 (M+H).

[0755] Intermediate 65 10-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0756] [ka] 10-Bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (350 mg, 0.822 mmol, 85% by weight), tert-butyldimethyl(prop-2-yn-1-yloxy)silane (420 mg, 2.47 mmol), Pd(dppf)Cl 2(61 mg, 0.082 mmol), copper(I) iodide (32 mg, 0.16 mmol) and Et 3 N (840 mg, 8.22 mmol) was combined in DMF (8 mL). 2 The mixture was degassed and purged with 500 cc (3 times). The mixture was stirred at 80° C. for 16 h. The mixture was diluted with water at 0° C. and extracted with EtOAc (3 times). The organic layers were combined, washed with saturated aqueous NaCl (2 times) and diluted with anhydrous Na 2 SO 4 The mixture was dried over ice, filtered, and concentrated under reduced pressure. It was purified by silica gel flash chromatography eluting with EtOAc in PE and concentrated under reduced pressure to give 10-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (75 mg, 19%). 1 H NMR (CD 3 OD):7.17(s,1H),4.76(q,J=7.4Hz,1H),3.94-3.85(m,1H),3.45(dt,J=14.9,3 .5Hz,1H),3.10-2.99(m,2H),1.69(d,J=7.4Hz,3H),0.96(s,9H),0.19(s,6H).

[0757] Example 88 7,8-Dichloro-10-(3-hydroxypropyl)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0758] [ka] 10-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (75 mg, 0.16 mmol, 95% by weight) and wet carbon-supported Pd(OH) in THF (2.5 mL) and MeOH (2.5 mL). 2 (25 mg, 20% by weight) was combined. 2The mixture was stirred at 20° C. under (30 psi) for 24 hours. The mixture was filtered and the filtrate was concentrated. It was purified by preparative HPLC. It was concentrated under reduced pressure and lyophilized to give 7,8-dichloro-10-(3-hydroxypropyl)-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (12 mg, 22%) as a white solid. ES / MS (m / z): ( 35 Cl / 37 Cl)341.1 / 343.1(M+H).

[0759] Example 89 (R)-2-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)acetonitrile or (S)-2-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)acetonitrile (isomer 1) and Example 90 (R)-2-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)acetonitrile or (S)-2-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)acetonitrile (isomer 2)

[0760] [ka] Racemic 2-(7,8-dichloro-1-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)acetonitrile (20.82 mg, 0.0646 mmol) was purified by SFC to give the title compounds (Isomer 1 - Rt = 2.244 min (95.2% ee), 8.81 mg, 42%; Isomer 2 - Rt = 2.918 min (90.6% ee) 8.67 mg, 42%). Column: Chiralpak AD-H, 20 x 150 mm; Mobile phase: 25% MeOH:75% CO 2;Flow rate: 80mL / min;Column temperature: 40℃;Detection: 225nM. ES / MS(m / z):( 35 Cl / 37 Cl) 322.0 / 324.0 (M+H) 1 H NMR(DMSO-d6):11.59(s,1H),7.80(t,J=5.9Hz,1H),7.22(s,1H),4.35-4.24(m,2H),4.11-4. 06(m,1H),4.04-4.01(m,1H),3.75-3.67(m,1H),3.18(d,J=4.7Hz,2H),1.59(d,J=7.4Hz,3H).

[0761] Intermediate 66 10-Bromo-7,8-dichloro-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0762] [ka] 10-Bromo-7,8-dichloro-1-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (300 mg, 0.746 mmol, 90% by weight) and cesium carbonate (868 mg, 2.61 mmol) were combined in DMF (10 mL). Iodomethane (130 mg, 0.895 mmol) was added at 0° C. Stirred at ambient temperature for 2 h. Diluted with water and extracted with EtOAc (2×). The organic layers were combined, washed with saturated aqueous NaCl (2×) and diluted with anhydrous Na 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with MeOH in DCM and concentrated under reduced pressure gave 10-bromo-7,8-dichloro-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (300 mg, 94%) as a pale yellow oil. ES / MS (m / z): 374.7 / 376.8 / 378.7 (M+H).

[0763] Intermediate 67 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbonitrile

[0764] [ka] To a stirred solution of 1H-imidazole-5-carbonitrile (2.00 g, 21.1 mmol) in ACN (40 mL) was added K 2 CO 3 (5.82 g, 42.1 mmol) was added at 0° C., followed by dropwise addition of SEM-Cl (4.30 g, 25.3 mmol). Stirred at 90° C. for 6 h. Filtered and washed the cake with EtOAc. The filtrate was concentrated under reduced pressure, then diluted with water and extracted with EtOAc (3 times). The organic layers were combined and washed with anhydrous Na 2 SO 4 It was dried over ice, filtered and concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with MeOH in DCM gave 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbonitrile (3.30 g, 67%) as a pale yellow oil. ES / MS (m / z): 224.2 (M+H). 1 H NMR(DMSO-d6):8.29(d,J=0.8Hz,1H),8.06(d,J=0.8Hz,1H),5.40(s,2H),3.49(dd,J=8.4,7.7Hz,2H),0.84(dd,J=8.4,7.7Hz,2H),-0.04(s,9H).

[0765] Intermediate 68 (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanamine

[0766] [ka] To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbonitrile (2.00 g, 8.51 mmol, 95 wt%) in THF (20 mL) was added LiAlH 4 (646 mg, 17.0 mmol) was added in portions at 0° C.2 The mixture was stirred under atmospheric conditions at 0° C. for 2 hours. Water (0.6 mL) was added at 0° C. to quench the reaction, followed by the addition of 15% NaOH aqueous solution (0.6 mL) and water (1.8 mL). The mixture was diluted with THF (15 mL) and diluted with anhydrous Na 2 SO 4 Dry at rt. Stir at ambient temperature for 30 min, filter, and concentrate under reduced pressure. Purification by silica gel flash chromatography eluting with MeOH in DCM gave (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanamine (970 mg, 46%) as a yellow oil. ES / MS (m / z): 228.1 (M+H).

[0767] Intermediate 69 7,8-Dichloro-1,6-dimethyl-10-(((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0768] [ka] 10-Bromo-7,8-dichloro-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (200 mg, 0.500 mmol, 94% by mass), (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanamine (250 mg, 1.00 mmol, 91% by mass), Pd 2 (dba) 3 (56 mg, 0.060 mmol), Xantphos (70 mg, 0.12 mmol) and cesium carbonate (489 mg, 1.50 mmol) were combined in 1,4-dioxane (10 mL) and THF (1 mL). 2The mixture was degassed and purged at rt (3 times). The mixture was stirred at 100° C. for 16 h. It was concentrated under reduced pressure and purified by silica gel flash chromatography eluting with MeOH in DCM to give 7,8-dichloro-1,6-dimethyl-10-(((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (220 mg, 67%) as a yellow oil. ES / MS (m / z): 35 Cl / 37 Cl) 522.0 / 524.0 (M+H).

[0769] Example 91 10-(((1H-imidazol-5-yl)methyl)amino)-7,8-dichloro-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0770] [ka] To a solution of 7,8-dichloro-1,6-dimethyl-10-(((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)amino)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (190 mg, 0.287 mmol, 79% by weight) in THF (4 mL) was added 1,2-diaminoethane (352 mg, 5.74 mmol) and TBAF (5.7 mL, 5.7 mmol, 1 M in THF) dropwise. 2 The mixture was stirred at 60° C. under atmospheric pressure for 16 hours. The reaction was repeated on a 0.05-fold scale and the reaction mixtures were combined. The mixture was diluted with EtOAc and saturated NH 4 Wash with Cl solution (10x) and anhydrous Na 2 SO 4 The mixture was dried over hexane, filtered and concentrated under reduced pressure. It was purified twice by preparative HPLC. It was further purified by SFC (column: DAICEL CHIRALPAK AD (250×30 mm, 10 μm); mobile phase: 55% EtOH (0.1% NH 3 H 2O2); 45% CO 2 ; flow rate: 80 mL / min) to give 10-(((1H-imidazol-5-yl)methyl)amino)-7,8-dichloro-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (12.88 mg, 11%) as a yellow solid. ES / MS (m / z): 35 Cl / 37 Cl) 392.1 / 394.1 (M+H).

[0771] Example 92 (S)-N-(7,8-dichloro-1,6-dimethyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxyacetamide or (R)-N-(7,8-dichloro-1,6-dimethyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxyacetamide (isomer 1) and Example 93 (S)-N-(7,8-dichloro-1,6-dimethyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxyacetamide or (R)-N-(7,8-dichloro-1,6-dimethyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxyacetamide (isomer 2)

[0772] [ka] In 1,4-dioxane (60 mL) and THF (3 mL), 10-bromo-7,8-dichloro-1,6-dimethyl-1,3,4,5-tetrahydroazepino[4,5-b]indol-2-one (270 mg, 0.517 mmol, 72% by weight), 2-hydroxyacetamide (90 mg, 1.175 mmol), Pd 2 (dba) 3(50 mg, 0.0530 mmol), Xantphos (60 mg, 0.104 mmol) and cesium carbonate (600 mg, 1.84 mmol) were combined. The mixture was degassed and N 2 The mixture was purged with 5 mL of MeOH in DCM (3 times) and stirred at 110 °C for 14-18 h. The reaction was concentrated under reduced pressure and purified by silica flash column chromatography eluting with MeOH in DCM. The resulting residue was triturated with 5 mL of MeOH in DCM (5 / 1) and further purified by SFC to give the title compounds (Isomer 1 - Rt = 2.297 min (100% ee), 47.64 mg, 24% as a white solid; Isomer 2 - Rt = 2.804 min (100% ee), 51.07 mg, 26% as a white solid). Purification conditions: Column: DAICEL CHIRALPAK AD (30 x 250 mm, 10 μm); Mobile phase: 50% EtOH (0.1% NH 3 H 2 O2): 50% CO 2 ;Flow rate: 80mL / min. ES / MS(m / z):( 35 Cl / 37 Cl) 392.0 / 393.9 (M+Na). (Chiral analysis used - column: Chiralpak IC-3, 50×4.6 mm, 3 μm; mobile phase: 20-40% EtOH (0.05% DEA): 80-60% CO 2 ;Flow rate: 4mL / min).

[0773] Intermediate 70 (2S)-N-(7,8-dichloro-1,6-dimethyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxypropanamide

[0774] [ka] Racemic 10-bromo-7,8-dichloro-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (300 mg, 0.702 mmol, 88% by weight), (S)-2-hydroxypropanamide (197 mg, 2.11 mmol), Pd 2(dba) 3 (66 mg, 0.070 mmol), Xantphos (83 mg, 0.14 mmol) and cesium carbonate (817 mg, 2.46 mmol). 2 The mixture was degassed and purged with N (3 times). 2 Stirred at 110° C. under ambient atmosphere for 16 h. Cooled to ambient temperature. Concentrated under reduced pressure. Purified by silica gel flash chromatography eluting with MeOH in DCM and concentrated under reduced pressure to give (2S)-N-(7,8-dichloro-1,6-dimethyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxypropanamide (170 mg, 60%) as a mixture of diastereomers as an off-white solid. ES / MS (m / z): ( 35 Cl / 37 Cl)384.0 / 385.7(M+H);383.8 / 385.7(M+H).

[0775] Example 94 (2S)-N-((S)-7,8-dichloro-1,6-dimethyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxypropanamide or (2S)-N-((R)-7,8-dichloro-1,6-dimethyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxypropanamide (isomer 1) and Example 95 (2S)-N-((S)-7,8-dichloro-1,6-dimethyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxypropanamide or (2S)-N-((R)-7,8-dichloro-1,6-dimethyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxypropanamide (isomer 2)

[0776] [ka] The diastereomeric mixture (2S)-N-(7,8-dichloro-1,6-dimethyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-hydroxypropanamide (170 mg, 0.420 mmol, 95% by weight) was purified by SFC to give the title compounds (Isomer 1 - Rt = 1.342 min (100% de), 71.17 mg, 43% as a white solid; Isomer 2 - Rt = 2.589 min (100% de), 61.85 mg, 38% as a white solid). Column: DAICEL CHIRALPAK IG (30 × 250 mm (10 μm); Mobile phase: 60% EtOH (w / 0.1% NH 3 H 2 O2): 40% CO 2 ;Flow rate: 80mL / min. ES / MS(m / z):( 35 Cl / 37 Cl) 384.1 / 386.1 (M+H).

[0777] Example 96 7,8-Dichloro-10-((2-hydroxyethyl)amino)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0778] [ka] In 1,4-dioxane (8 mL) and THF (0.8 mL), 10-bromo-7,8-dichloro-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (150 mg, 0.383 mmol, 96% by weight), 2-methoxyethan-1-amine (74 mg, 0.96 mmol), Pd 2 (dba) 3 (36 mg, 0.038 mmol), Xantphos (45 mg, 0.077 mmol) and cesium carbonate (378 mg, 1.15 mmol). 2Degassed and purged at 40° C. (3 times). Stirred at 100° C. for 16 h. Concentrated under reduced pressure and purified by silica gel flash chromatography eluting with MeOH in DCM and further purified by preparative HPLC. Concentrated under reduced pressure and lyophilized to give 7,8-dichloro-10-((2-methoxyethyl)amino)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (50.74 mg, 35%) as a white solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 370.2 / 372.1 (M+H).

[0779] Example 97 7,8-Dichloro-10-(2-methoxyethoxy)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0780] [ka] 10-Bromo-7,8-dichloro-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (200 mg, 0.441 mmol, 83% by weight), sodium tert-butoxide (134 mg, 1.32 mmol), 2-methoxyethan-1-ol (1.93 g, 24.1 mmol) and t-BuBrettPhos-Pd-G 3 (40 mg, 0.044 mmol) in 1,4-dioxane (2 mL). 2 The mixture was degassed and purged with N (3 times). 2 The mixture was stirred at 65° C. for 1 hour under atmospheric pressure. The mixture was diluted with water, extracted with EtOAc, washed with a saturated aqueous NaCl solution, and then washed with anhydrous Na 2 SO 4The mixture was dried over ice, filtered and concentrated under reduced pressure. It was purified by silica gel flash chromatography eluting with MeOH in DCM, concentrated under reduced pressure and further purified by reverse phase preparative HPLC. It was concentrated under reduced pressure and lyophilized to give 7,8-dichloro-10-(2-methoxyethoxy)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (45.35 mg, 27%) as a yellow solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 370.9 / 372.9 (M+H).

[0781] Intermediate 71 7,8-Dichloro-10-(((R)-2-hydroxypropyl)amino)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0782] [ka] 10-Bromo-7,8-dichloro-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (300 mg, 0.750 mmol, 94% by mass), (R)-1-aminopropan-2-ol (178 mg, 2.25 mmol), Pd 2 (dba) 3 (69 mg, 0.075 mmol), Xantphos (90 mg, 0.15 mmol) and cesium carbonate (611 mg, 1.87 mmol) were combined in 1,4-dioxane (10 mL) and THF (0.8 mL). 2 The mixture was stirred at 110° C. under atmospheric pressure for 16 hours. The mixture was concentrated under reduced pressure and purified by silica gel flash chromatography eluting with MeOH in DCM and concentrated under reduced pressure to give 7,8-dichloro-10-(((R)-2-hydroxypropyl)amino)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (165 mg, 52%) as a mixture of diastereomers. ES / MS (m / z): ( 35 Cl / 37Cl) 370.1 / 372.0 (M+H).

[0783] Example 98 (R)-7,8-dichloro-10-(((R)-2-hydroxypropyl)amino)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (S)-7,8-dichloro-10-(((R)-2-hydroxypropyl)amino)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1) and Example 99 (R)-7,8-dichloro-10-(((R)-2-hydroxypropyl)amino)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (S)-7,8-dichloro-10-(((R)-2-hydroxypropyl)amino)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 2)

[0784] [ka] The diastereomeric mixture 7,8-dichloro-10-(((R)-2-hydroxypropyl)amino)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (165 mg, 0.392 mmol, 88% by weight) was purified by SFC to give the title compounds (Isomer 1 - Rt = 1.661 min (100% de), 51.39 mg, 35% as an off-white solid; Isomer 2 - Rt = 2.139 min (100% de), 50.23 mg, 34% as an off-white solid). Purification conditions: Column: DAICEL CHIRALPAK AD (30 x 250 mm, 10 μm); Mobile phase: 55% iPrOH (w / 0.1% NH 3 H 2 O2): 45% CO 2; Flow rate: 80 mL / min. (Chiral analysis used - column: ChiralPak IG, 50 × 4.6 mm, 3 μm; mobile phase: 40% EtOH (0.05% DEA): 60% CO 2 Flow rate: 4 mL / min; Column temperature: 35°C). ES / MS(m / z):( 35 Cl / 37 Cl) 370.1 / 372.1 (M+H).

[0785] Intermediate 72 7,8-Dichloro-10-(((R)-2-hydroxypropyl)amino)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0786] [ka] 10-Bromo-7,8-dichloro-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (200 mg, 0.511 mmol, 96% by mass), (S)-1-aminopropan-2-ol (98 mg, 1.3 mmol), Pd 2 (dba) 3 (48 mg, 0.051 mmol), Xantphos (60 mg, 0.10 mmol) and cesium carbonate (504 mg, 1.53 mmol) were combined in 1,4-dioxane (10 mL) and THF (1 mL). 2 Degassed and purged at rt (3 times). Stirred at 100° C. for 16 h. Concentrated under reduced pressure and purified by silica gel flash chromatography eluting with MeOH in DCM. Concentrated under reduced pressure and further purified by preparative HPLC. Concentrated under reduced pressure and lyophilized to give the diastereomeric mixture 7,8-dichloro-10-(((R)-2-hydroxypropyl)amino)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (100 mg, 49%) as a yellow solid. ES / MS (m / z): 35 Cl / 37 Cl) 369.9 / 371.9 (M+H).

[0787] Example 100 (R)-7,8-dichloro-10-(((R)-2-hydroxypropyl)amino)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (S)-7,8-dichloro-10-(((R)-2-hydroxypropyl)amino)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1) and Example 101 (R)-7,8-dichloro-10-(((R)-2-hydroxypropyl)amino)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (S)-7,8-dichloro-10-(((R)-2-hydroxypropyl)amino)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 2)

[0788] [ka] The diastereomeric mixture 7,8-dichloro-10-(((R)-2-hydroxypropyl)amino)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (100 mg, 0.251 mmol, 93% by weight) was purified by SFC. Column: DAICEL CHIRALPAK AD (250 × 30 mm, 10 μm); Mobile phase: 60% EtOH (w / 0.1% NH 3 H 2 O2): 40% CO 2 ; flow rate: 80 mL / min). Another patch of 7,8-dichloro-10-(((R)-2-hydroxypropyl)amino)-1,6-dimethyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (190 mg, 0.458 mmol, 89% by weight) was purified by SFC. Column: DAICEL CHIRALPAK IC, 30 x 250 mm (10 μm); mobile phase: 50% EtOH (w / 0.1% NH 3 H 2O2): 50% CO 2 ; flow rate: 80 mL / min). The first eluting product fractions from both SFC purifications were combined and lyophilized to give isomer 1 - Rt = 1.752 min (100% de), 61.67 mg, 23% as a yellow solid. The second eluting product fractions from both SFC purifications were combined and lyophilized to give isomer 2 - Rt = 2.378 min (98.9% de), 63.06 mg, 23% as a yellow solid. (Chiral analytical column used: Chiralpak AD-3, 50 × 4.6 mm, 3 μm; mobile phase: 5–40% EtOH (0.05% DEA) / CO 2 ;Flow rate: 4mL / min). ES / MS m / z:( 35 Cl / 37 Cl) 370.1 / 372.1 (M+H).

[0789] Intermediate 73 10-Bromo-7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0790] [ka] To a solution of ethyl 2-(10-bromo-7,8-dichloro-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-5-yl)acetate (200 mg, 0.392 mmol, 85 wt%) in THF (6 mL) was added MeMgBr (0.65 mL, 1.96 mmol, Et 2 3M in 0) was added at 0° C. Stirred at 0° C. for 2 h. The reaction was repeated on a 0.25-fold scale and the reaction mixtures were combined. Saturated NH 4 Quench with aqueous Cl and H 2 The mixture was diluted with O and extracted with EtOAc. The organic layers were combined and washed with saturated NH 4 Wash with aqueous Cl solution, saturated aqueous NaCl solution, and anhydrous Na 2 SO 4The mixture was dried over ice, filtered and concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with MeOH in DCM and concentrated under reduced pressure gave 10-bromo-7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one 200 mg, 57%). ES / MS (m / z): 418.8 / 420.8 / 422.8 (M+H).

[0791] Example 102 7,8-Dichloro-5-(2-hydroxy-2-methylpropyl)-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0792] [ka] 10-Bromo-7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (150 mg, 0.207 mmol, 58% by mass), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazole (173 mg, 0.414 mmol), Pd(dppf)Cl 2 (15 mg, 0.021 mmol), Na 2 CO 3 (66 mg, 0.62 mmol) in 1,4-dioxane (12 mL) and H 2 Combine in O (3 mL). 2The mixture was degassed and purged at 50° C. (3 times). Stirred at 90° C. for 2 hours. The reaction was repeated on a 0.33x scale and the reaction mixtures were combined and concentrated under reduced pressure. Purified by silica gel flash chromatography eluting with MeOH in DCM, concentrated under reduced pressure, and further purified by reverse phase preparative HPLC to give 7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (76.42 mg, 65%) as a white solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 422.0 / 423.8 (M+H).

[0793] Example 103 (R)-7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (S)-7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 1) and Example 104 (R)-7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one or (S)-7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (isomer 2)

[0794] [ka] Racemic 7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (21 mg, 0.050 mmol) was purified by SFC to give the title compound (isomer 1 - RT = 1.79 min (100% ee), 8 mg, 40%; isomer 2 - RT = 3.06 min (100% ee), 7 mg, 30%). Column: Chiralpak AD-H, 21 x 150 mm; mobile phase: 20% MeOH:80% CO 2 ;Flow rate: 80mL / min;Column temperature: 40℃;Detection: 225nM. ES / MS(m / z):( 35 Cl / 37 Cl) 422.2 / 424.2 (M+H).

[0795] Example 105 7,8-Dichloro-5-(2-hydroxy-2-methylpropyl)-6-methyl-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0796] [ka] To a stirred solution of 7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-6-methyl-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (40 mg, 0.093 mmol, 98% by weight) in DMF (2 mL) was added cesium carbonate (106 mg, 0.326 mmol) and iodomethane (13 mg, 0.093 mmol). Stirred at 25° C. for 2 hours. The reaction was repeated on a 0.25x scale and the reaction mixtures were combined. H 2 The mixture was quenched with O and extracted with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl and anhydrous Na 2 SO 4The mixture was dried over ice, filtered, and concentrated under reduced pressure. Purification by reverse phase preparative HPLC afforded 7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-6-methyl-10-(2-methyl-2H-1,2,3-triazol-4-yl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (26 mg, 49%) as a white solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 436.1 / 438.0 (M+H).

[0797] Example 106 (R)-2-(7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)acetonitrile or (S)-2-(7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)acetonitrile (Isomer 1) and Example 107 (R)-2-(7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)acetonitrile or (S)-2-(7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)acetonitrile (Isomer 2)

[0798] [ka] 10-Bromo-7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (310 mg, 0.568 mmol, 77% by mass), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-isoxazole (133 mg, 0.682 mmol), Pd(dppf)Cl 2 (42 mg, 0.057 mmol) and KF (99 mg, 1.7 mmol) were dissolved in DMSO (12 mL) and H 2 Combine in O (3 mL). 2 The mixture was degassed and purged with N (3 times). 2 The mixture was stirred at 100°C for 1 hour under atmospheric conditions. 2 The mixture was quenched with O and extracted with EtOAc (3x). The organic layers were combined, washed with saturated aqueous NaCl, and 2 SO 4 The residue was dissolved in DMF (3 mL) and KF (205 mg, 3.53 mmol) in H2SO4 (2 mL), dried over 1000 cc, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with MeOH in DCM and concentrated under reduced pressure. 2 Combine in 20O (3 mL). Stir at 100° C. for 16 h. 2 The mixture was diluted with O and extracted with EtOAc (3x). The organic layers were combined, washed with saturated aqueous NaCl, and washed with anhydrous Na 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure. Purification by reverse phase preparative HPLC and further purification by SFC afforded the title compounds (Isomer 1 - Rt = 1.308 min (99.6% ee), 29.26 mg, 17% as a white solid; Isomer 2 - Rt = 1.386 min (99.2% ee), 29.42 mg, 18% as a white solid). Column: DAICEL CHIRALPAK AD (30 x 2 50 mm, 10 μm); Method: 45% EtOH (0.1% NH 3 H 2 O2): 55% CO 2 ; Flow rate: 80 mL / min. (Chiral analysis used - column: ChiralPak AD, 50 × 4.6 mm, 3 μm; mobile phase: 5-40% EtOH (0.05% DEA) / CO 2;Flow rate: 4mL / min). ES / MS(m / z):( 35 Cl / 37 Cl)380.0 / 382.0(M+H)..

[0799] Intermediate 74 7,8-Dichloro-10-hydroxy-5-(2-hydroxy-2-methylpropyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0800] [ka] 1,4-Dioxane (15 mL) and H 2 10-Bromo-7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (470 mg, 0.839 mmol, 75% by weight), t-BuBrettPhos-Pd-G 3 (72 mg, 0.084 mmol) and t-BuONa (202 mg, 2.10 mmol) were combined. 2 The mixture was degassed and purged with N (3 times). 2 The mixture was stirred at 65° C. under atmospheric pressure for 2 hours. 1N HCl aqueous solution was added to adjust the pH to 5, and the mixture was extracted with EtOAc (3 times). The organic layers were combined, washed with saturated NaCl aqueous solution, and diluted with anhydrous Na 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure. Purification by trituration with EtOAc afforded 7,8-dichloro-10-hydroxy-5-(2-hydroxy-2-methylpropyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one 300 mg, 76%) as a brown solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 356.9 / 358.8 (M+H).

[0801] Intermediate 75 2-((7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile

[0802] [ka] In DMF (8 mL), 7,8-dichloro-10-hydroxy-5-(2-hydroxy-2-methylpropyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (270 mg, 0.574 mmol, 76% by weight), K 2 CO 3 (238 mg, 1.72 mmol) and KI (95 mg, 0.57 mmol) were combined and 2-chloroacetonitrile (87 mg, 1.2 mmol) was added at 0° C. The mixture was stirred at 25° C. for 6 hours. 2 The mixture was diluted with O and extracted with EtOAc (3x). The organic layers were combined, washed with saturated aqueous NaCl, and washed with anhydrous Na 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure. Purification by reverse phase preparative HPLC afforded 2-((7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (150 mg, 63%) as a yellow solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 396.0 / 398.0 (M+H).

[0803] Example 108 (R)-2-((7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile or (S)-2-((7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (isomer 1) and Example 109 (R)-2-((7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile or (S)-2-((7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (isomer 2)

[0804] [ka] Racemic 2-((7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (150 mg, 0.363 mmol, 96% by weight) was purified by SFC to give the title compounds (Isomer 1 - Rt = 1.505 min (99.4% ee), 63.48 mg, 43% as an off-white solid; Isomer 2 - Rt = 1.711 min (99.1% ee), 68.42 mg, 47% as an off-white solid). Column: REGIS(S,S)WHELK-O1 (30 x 250 mm, 5 μm); Mobile phase: 45% iPrOH (0.1% NH 3 H 2 O2): 55% CO 2 . ES / MS(m / z):( 35 Cl / 37 Cl) 396.0 / 398.0 (M+H).

[0805] Intermediate 77 7,8-Dichloro-10-hydroxy-5-(2-hydroxy-2-methylpropyl)-6-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0806] [ka] 10-Bromo-7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-6-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (500 mg, 1.09 mmol, 95% by mass), t-BuONa (263 mg, 2.74 mmol), t-BuBrettphos-Pd-G 3 (94 mg, 0.11 mmol) in 1,4-dioxane (6 mL) and H 2 Combine in O (2 mL). 2 Degas and purge with N (3 times). 2 The mixture was stirred at 65° C. under atmospheric pressure for 3 hours. The mixture was diluted with water, acidified with 2N HCl aqueous solution until pH=5, and then extracted with EtOAc. The organic layers were combined, washed with saturated NaCl aqueous solution, and washed with anhydrous Na 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure. Trituration with EtOAc afforded 7,8-dichloro-10-hydroxy-5-(2-hydroxy-2-methylpropyl)-6-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (200 mg, 35%) as a brown solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 371.0 / 373.0 (M+H).

[0807] Intermediate 78 2-((7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-6-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile

[0808] [ka] In DMF (3 mL), 7,8-dichloro-10-hydroxy-5-(2-hydroxy-2-methylpropyl)-6-methyl-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (180 mg, 0.349 mmol, 72% by weight), K 2 CO 3(145 mg, 1.05 mmol) and KI (58 mg, 0.35 mmol) were combined and 2-chloroacetonitrile (53 mg, 0.70 mmol) was added at 0° C. The mixture was stirred at 25° C. for 3 h. The mixture was diluted with water and extracted with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl, and then with anhydrous Na 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure. Purification by preparative HPLC afforded racemic 2-((7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-6-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (77 mg, 49%) as a white solid. ES / MS (m / z): ( 35 Cl / 37 Cl) 410.0 / 412.0 (M+H).

[0809] Example 110 (R)-2-((7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-6-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile or (S)-2-((7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-6-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (isomer 1) and Example 111 (R)-2-((7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-6-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile or (S)-2-((7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-6-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (isomer 2)

[0810] [ka] Racemic 2-((7,8-dichloro-5-(2-hydroxy-2-methylpropyl)-6-methyl-2-oxo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)oxy)acetonitrile (77 mg, 0.17 mmol) was purified by SFC to give the title compounds (isomer - Rt = 1.617 min (100% ee), 26 mg, 36% as an off-white solid; isomer 2 - Rt = 1.991 min (99.7% ee), 22 mg, 32% as an off-white solid). Column: DAICEL CHIRALPAK IC-3, 30 x 250 mm, 10 μm; Mobile phase: 60% EtOH (0.1% NH 3 H 2 O); 40% CO 2 ;Flow rate: 80mL / min. ES / MS(m / z):( 35 Cl / 37 Cl) 410.0 / 411.8 (M+H).

[0811] Intermediate 78 10-Bromo-7,8-dichloro-5-(2-((2,2,2-trifluoroethyl)amino)ethyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0812] [ka] 10-Bromo-7,8-dichloro-5-(2-hydroxyethyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (500 mg, 0.778 mmol, 61% by weight) in DMF (10 mL), Et 3 To a solution of N (249 mg, 2.33 mmol) and DMAP (10 mg, 0.078 mmol), methanesulfonic anhydride (419 mg, 2.33 mmol) was added to N 2 The addition was carried out at 0°C under atmospheric conditions. 2 The mixture was stirred at 25° C. for 2 hours under atmospheric pressure. Then, 2,2,2-trifluoroethan-1-amine (10 mL, 120 mmol) was added to the above mixture at 25° C. The mixture was stirred at 60° C. for 16 hours. 2The mixture was diluted with O and extracted with EtOAc (2x). The organic layers were combined, washed with saturated aqueous NaCl, and washed with anhydrous Na 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with MeOH in DCM and concentrated under reduced pressure gave 10-bromo-7,8-dichloro-5-(2-((2,2,2-trifluoroethyl)amino)ethyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (330 mg, 82%) as a white solid. ES / MS (m / z): 471.8 / 473.7 / 475.6 (M+H).

[0813] Example 112 7,8-Dichloro-10-(2-methyl-2H-1,2,3-triazol-4-yl)-5-(2-((2,2,2-trifluoroethyl)amino)ethyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one

[0814] [ka] 10-Bromo-7,8-dichloro-5-(2-((2,2,2-trifluoroethyl)amino)ethyl)-3,4,5,6-tetrahydroazepino[4,5-b]indol-2(1H)-one (330 mg, 0.635 mmol, 91% by mass), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazole (199 mg, 0.952 mmol), Pd(dppf)Cl 2 (49 mg, 0.064 mmol) and Na 2 CO 3 (212 mg, 1.90 mmol) in 1,4-dioxane (1...

Claims

1. 1. A compound of the formula: 【Chemistry 1】 During the ceremony, X and R ４ But independently, it is a halo, R １ , R ７ , R ８ , and R ９ But independently, R ｂ and R ６ is H or F, R ３ But -NH-R ｂｂ -OR ｂ , -NHC(O)-R ｂｂ -OR ｂ , -NHC(O)-C(O)-NH ２ , -NH-R ｃ , -NH-C(O)-R ｃ , -O-R ｃ , —O—CH ２ -R ｃ , -O-R ｂｂ -C(O)NH ２ , -O-R ｂｂ -OR ｂ , -O-R ｂｂ -O-C(O)-R ｂ , -O-R ｂｂ -H, -O-R ｂｂ -CN, -NH-R ｂｂ -H, -R ｂｂ -OH, -R ｂｂ -CN, -NH-R ｅ , —O—CH ２ -R ｅ , —NH—CH ２ -R ｅ or a 5- or 6-membered heteroaryl having 2 or 3 heteroatoms, respectively, said heteroaryl being -NH ２ , -R ｂｂ -H or -R ｂｂ is optionally substituted with -OH; R ５ But, H, -R ｂｂ H, -R ｂｂ C(O)OR ｂ , -R ｂｂ C(O)N(R ｂ ) ２ , -R ｂｂ N (R ｂ ) ２ , -R ｂｂ N (R ｂ ) (R ｂｂ CF ３ ), -R ｂｂ OR ｂ or 【Chemistry 2】 or Or, R １ and R ５ together with the atoms to which they are attached form an unsubstituted 5-membered heterocyclic ring; R ｂ Each occurrence of is independently H or -R ｂｂ H, R ｂｂ Each occurrence of is independently C optionally substituted with fluoro or methyl. １～３ is alkylene, R ｃ Each occurrence of ４～６ a carbocycle or an unsubstituted 4- to 6-membered oxygen-containing heterocycle; R ｅ is an N-containing 5-membered heteroaryl, or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1 having the formula: 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof.

3. R ５ But, H, -R ｂｂ H, -R ｂｂ C(O)OR ｂ , -R ｂｂ C(O)N(R ｂ ) ２ , -R ｂｂ N (R ｂ ) ２ , -R ｂｂ N (R ｂ ) (R ｂｂ CF ３ ), -R ｂｂ -OR ｂ or 【Chemistry 4】 2. The compound of claim 1, wherein:

4. R ５ が、H、-CH ３ 、-CH ２ CH ３ 、-CH ２ CH ２ CH ３ 、 【Chemistry 5】 2. The compound of claim 1, wherein:

5. R ５ But, -R ｂｂ H, -R ｂｂ C(O)OR ｂ , -R ｂｂ C(O)N(R ｂ ) ２ , -R ｂｂ N (R ｂ ) ２ , -R ｂｂ N (R ｂ ) (R ｂｂ CF ３ ), -R ｂｂ -OR ｂ or 【Chemistry 6】 2. The compound of claim 1, wherein:

6. R ５ is H, or a pharma- ceutically acceptable salt thereof.

7. R ７ is H, or a pharma- ceutically acceptable salt thereof.

8. R ７ But, -R ｂｂ H, 【Chemistry 7】 2. The compound of claim 1, wherein:

9. R ７ The compound of claim 1 , or a pharma- ceutically acceptable salt thereof, wherein:

10. R ３ But -NH-R ｂｂ -OR ｂ , -NHC(O)-R ｂｂ -OR ｂ , -NHC(O)-C(O)-NH ２ , -O-R ｂｂ -C(O)NH ２ , -O-R ｂｂ -OR ｂ , -O-R ｂｂ -O-C(O)-R ｂ , -O-R ｂｂ -H, -O-R ｂｂ -CN, -NH-R ｂｂ -H, -R ｂｂ -OH or -R ｂｂ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein:

11. R ３ But -NH-R ｃ , -NH-C(O)-R ｃ , or -O-R ｃ 2. The compound of claim 1, wherein:

12. R ３ but, 【Chemistry 8】 2. The compound of claim 1, selected from:

13. R ３ is -NH-(CH ２ ) ２ -OH, -NH-(CH ２ ) ２ -O(CH ３ ), -NH-(CH ２ ) ((CH) (CH ３ )) -OH, -NHC(O)-CH ２ -OH, -NHC(O)-CH ２ -O(CH ３ ), -NHC(O)-CH(CH ３ )-OH, -NH-(CH ２ ) (CF ２ ) (CH ２ )-OH, -NH-(CH ２ )-CHF ２ , -NH-(CH ２ ) ２ -CHF ２ , —O—CH ２ -C(O)NH ２ , —O—(CH ２ ) (CH (CH ３ )) -OH, -O(CH ２ ) ３ -OH, -O(CH ２ ) ２ -O(CH ３ ), —O—(CH ２ ) (CF ２ ) (CH ２ )-OH, -NH-(CH ２ ) (CF ２ ) (CH ２ )-OH, -O(CH ２ ) CH ２ F, -O(CH ２ ) ２ CH ２ F, —O—CH ２ -CN, -NH(CH ２ ) ３ , -(CH ２ ) ３ OH and -CH ２ 2. The compound of claim 1, wherein the compound is selected from -CN, or a pharma- ceutically acceptable salt thereof.

14. R ８ is H, or a pharma- ceutically acceptable salt thereof.

15. R ８ The compound of claim 1 , or a pharma- ceutically acceptable salt thereof, wherein:

16. R １ is H, or a pharma- ceutically acceptable salt thereof.

17. R １ The compound of claim 1 , or a pharma- ceutically acceptable salt thereof, wherein:

18. having the formula 【Chemistry 9】 During the ceremony, R １ is H, -CH ３ , or -CHF ２ and R ５ is H, -CH ３ , C.H. ２ CH ３ , or -CH ２ CH ２ CH ３ and R ７ is H, -CH ３ , C.H. ２ CH ３ , or -CH ２ CH ２ CH ３ and R ３ が、-NH-(CH ２ ) ２ -OH、-NH-(CH ２ ) ２ -O(CH ３ )、-NH-(CH ２ )((CH)(CH ３ ))-OH、-NHC(O)-CH ２ -OH、-NHC(O)-CH ２ -O(CH ３ )、-NHC(O)-CH(CH ３ )-OH、-NH-(CH ２ )(CF ２ )(CH ２ )-OH、-NH-(CH ２ )-CHF ２ 、-NH-(CH ２ ) ２ -CHF ２ 、-O-CH ２ -C(O)NH ２ 、-O-(CH ２ )(CH(CH ３ ))-OH、-O(CH ２ ) ３ -OH、-O(CH ２ ) ２ -O(CH ３ )、-O-(CH ２ )(CF ２ )(CH ２ )-OH、-NH-(CH ２ )(CF ２ )(CH ２ )-OH、-O(CH ２ )CH ２ F、-O(CH ２ ) ２ CH ２ F、-O-CH ２ -CN、-NH(CH ２ ) ３ 、-(CH ２ ) ３ OH、-CH ２ -CN、 【Chemistry 10】 2. The compound of claim 1, wherein:

19. having the formula 【Chemistry 11】 In the formula, R １ , R ５ , and R ７ are each independently H or -CHF ２ and R ３ is -NHC(O)-CH ２ -OH, -O-(CH ２ ) ２ -O-(CH ３ ), -NH-C(O)-CH(CH ３ ) —OH, or 【Chemistry 12】 2. The compound of claim 1, wherein:

20. The formula: 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 or a pharma- ceutically acceptable salt thereof.

21. The compound is 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 【Chemistry 23】 【Chemistry 24】 2. The compound of claim 1, selected from:

22.

25. or a pharma- ceutically acceptable salt thereof.

23. 23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22, or a pharma- ceutically acceptable salt thereof, together with one or more pharma- ceutically acceptable carriers, diluents, or excipients.

24. 23. A method for treating an immune-mediated disease in a patient, comprising administering to the patient a compound according to claim 1, or a pharma- ceutically acceptable salt thereof.

25. The method of claim 24, wherein the immune-mediated disease is selected from systemic lupus erythematosus, lupus nephritis, dermatomyositis, and Aicardi-Goutieres syndrome.

26. 23. A method for treating a disease associated with cGAS activation in a patient, comprising administering to the patient a compound according to claim 1 or a pharma- ceutically acceptable salt thereof.

27. 23. Use of a compound according to any one of claims 1 to 22, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease selected from systemic lupus erythematosus, lupus nephritis, dermatomyositis, and Aicardi-Goutières syndrome.

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