Biphenyl and phenylpyridine compounds as KAT2A and / or KAT2B inhibitors

Abstract

The present invention relates to a compound of the following formula (I) and a pharmaceutically acceptable salt thereof, the use thereof in medicine; a composition containing the same; a method for preparing the same; and an intermediate used in the method. The compound of the present invention may be useful for the treatment, prevention, inhibition, and improvement of diseases, disorders, and pathological conditions such as cancer: (I).

Description

Technology Field

[0001] The present invention relates to novel biphenyl and phenylpyridine compounds. The present invention also relates to the preparation of said compounds, intermediates useful for the preparation of said compounds, compositions containing said compounds, and the use of said compounds as KAT2A and KAT2B inhibitors in the treatment of KAT2A and KAT2B-related diseases such as cancer. Background Technology

[0002] Histone lysine acetyltransferases (HATs) are a group of enzymes responsible for regulating essential cellular biological processes such as DNA repair, replication, and gene transcription (Literature [Abbas, Eman MH et al. Archiv der Pharmazie vol. 355(7) (2022)]). Lysine acetyltransferase 2A (KAT2A, also known as general control nonderepressible 5 (GCN5)) and lysine acetyltransferase 2B (KAT2B, also known as p300 / CBP associated factor (PCAF)) are part of the HAT family.

[0003] KAT enzymes perform important regulatory functions in cancer and are therefore frequently targeted by mutations, translocations, and amplification (Literature [Hu, Z., et al., Nat Commun . 10(1):733 (2019)]). KAT2A and KAT2B are two different multiprotein histone modification complexes, Spt-Ada-Gcn5-acetyltransferase (SAGA) KAT2A and KAT2B are paralogous catalytic subunits in Ada-Two-A-Containing (ATAC). KAT2A and KAT2B function as lysine acetyltransferases within these multiprotein complexes to post-translate histones as well as other non-histone proteins, and regulate their function in biological processes such as transcription co-activators.

[0004] Outside the KAT module, SAGA and ATAC differ in composition, which reflects their unique functions (Reference [Riss, A., et al., J Biol Chem [ , 290(48) (2015): 28997-9009]). SAGA and ATAC can be targeted to genomic loci through interactions with sequence-specific transcription factors and stabilized in specific regions through interactions between the "reader" domain and specific histone modifications. Due to the different subunit compositions of the two complexes, which contain proteins with unique histone reader domains, these complexes can be recruited to specific regions of the genome. Different biochemical activities driven by additional subunits of the SAGA complex (e.g., USP22 deubiquitase) suggest the potential for unique regulatory functions of the SAGA versus ATAC complexes at these recruitment sites.

[0005] In cancer, both SAGA and ATAC have been reported to alter the function of important regulators of tumorigenesis, including MYC, E2F, and p53 (Literature [Mustachio, LM, Cancer research Members of the SAGA complex are found to be upregulated in up to 50% of multiple myeloma cancers (Chen, YJ bloodKAT2A has been identified as a vulnerability in forms of acute myeloid leukemia, and high KAT2A expression has been associated with poor prognosis in breast cancer, non-small cell lung carcinoma, and colorectal cancer (Literature [Arede, L. & Pina C., Experimental hematology [ , 93 (2021): 25-37]). In computer analysis of DepMap CRISPR screening, cancer-specific dependence of KAT2A and KAT2B forms a network with components of both SAGA and ATAC complexes, which suggests the importance of the two complexes in cancer.

[0006] Many HAT inhibitors lack selectivity for members of the HAT family, and therefore, selectivity for specific enzymes, such as KAT2A, remains an unresolved issue.

[0007] Therefore, there remains a need for KAT2 inhibitors that could be useful in the treatment of cancer.

[0008] The present invention partially provides compounds of formula (I) and pharmaceutically acceptable salts thereof (collectively referred to as the compounds of the invention). These compounds may inhibit the activity of KAT2A or KAT2B and may be useful for the treatment, prevention, inhibition, and improvement of diseases such as cancer, disorders, and pathologies mediated by the inhibition of KAT2A or KAT2B, or a combination thereof.

[0009] In addition, a pharmaceutical composition comprising a compound or salt of the present invention alone or in combination with an additional anticancer agent is provided. The present invention also partially provides a method for preparing such a compound, a pharmaceutically acceptable salt, and a composition of the present invention, and a method for using the foregoing.

[0010] This summary is provided to introduce, in a simplified form, a selection of concepts that are further described below in the detailed description. This summary is not intended to identify the core or essential features of the claimed subject matter, nor is it intended to be used in isolation as an aid to determining the scope of the claimed subject matter.

[0011] According to one embodiment of the present invention, a compound of the following formula (I) or a pharmaceutically acceptable salt thereof is provided:

[0012] (I)

[0013] In the above formula,

[0014] Ring A is phenyl, or a 5 or 6-membered N-containing heteroaryl consisting of 1 or 2 N atoms and carbon atoms as ring members;

[0015] L is the chemical formula

[0016]

[0017] It is a connector of;

[0018] The asterisk * indicates the attachment point for ring A, and the dashed line is R 4 Indicates the attachment point for;

[0019] z is 0 or 1 and;

[0020] q is 0, 1, or 2, and;

[0021] Each Q is independently -OH, -CH3, or a halogen;

[0022] Ring B is a C3-C6 cycloalkyl;

[0023] R 1 and R 2 One of them is H or a halogen, and R 1 and R 2 The other one is a group of the following chemical formulas (E1-1), (E1-2), (E1-3), (E2-1), (E2-2) or (E3-1):

[0024]

[0025] In the above formula,

[0026] Each asterisk * indicates an attachment point for ring A;

[0027] m is 0 or 1 and;

[0028] R 5 and R 6 Each is independently (i) H, (ii) a halogen, (iii) a C1-C6 alkyl optionally substituted with 1 to 3 halogens and 1 to 3 -OH groups, (iv) a C1-C3 deuterinated alkyl, (v) a C2-C6 alkenyl, or (vi) a C2-C6 alkenyl;

[0029] R 5 and R 6 Together, they form a 4 to 6-membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of C3-C6 cycloalkyl, or N, O, and S;

[0030] R 7 silver,

[0031] C1-C6 alkyl optionally substituted with 1 to 3 halogens,

[0032] (i) 1 to 4 halogens, or (ii) a C3-C5 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens, and

[0033] -NR 8 R 9

[0034] Selected from a group consisting of, and R 8 and R 9 Each is independently H or C1-C6 alkyl, or R 8 and R 9 Together, they form a 4 to 6-membered N-containing heterocycloalkyl ring optionally substituted with 1 to 4 halogens;

[0035] Ring C1 is a 5- or 6-membered N-containing heteroaryl optionally substituted with one group selected from (i) C1-C3 alkyl optionally substituted with 1 to 4 halogens, (ii) C2-C3 hydroxyalkyl, and (iii) C3-C4 cycloalkyl;

[0036] Ring C2 is a 5- or 6-membered N-containing heterocyclic ring optionally substituted with one group selected from (i) C1-C3 alkyl optionally substituted with 1 to 4 halogens, (ii) C2-C3 hydroxyalkyl, and (iii) C3-C4 cycloalkyl;

[0037] n is 1, 2, or 3, and;

[0038] Each R 3 is independently selected from the group consisting of (i) halogen, (ii) C1-C6 alkyl optionally substituted with 1 to 3 halogens, (iii) C2-C6 alkenyl, (iv) C2-C6 alkynyl, and (v) C3-C6 cycloalkyl optionally substituted with 1 to 4 halogens;

[0039] R 4 Is,

[0040] halogen,

[0041] -OH,

[0042] -CN,

[0043] C1-C3 alkyl optionally substituted with 1 to 3 halogens,

[0044] (i) 1 to 3 halogens, or (ii) a spirocyclic C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens, and

[0045] A spirocyclic 3 to 6-membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O, and S, optionally substituted with (i) 1 to 3 halogens, or (ii) a C1-C3 alkyl optionally substituted with 1 to 3 halogens.

[0046] It is a 3 to 6-membered N-containing heterocycloalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of;

[0047] The attachment point for linker L is on the carbon atom.

[0048] Embodiments of the present invention are described below, and for convenience, Embodiment 1 (E1) is identical to the embodiment of the provided formula (I).

[0049] It should be understood that the foregoing general description and the following detailed description are merely illustrative and descriptive and do not limit the invention as claimed. Specific details for implementing the invention

[0050] The present invention may be more easily understood by referring to the following detailed description of embodiments of the present invention and the examples included herein. It should be understood that the present invention is not limited to specific synthetic methods of manufacture, which may vary. Furthermore, it should be understood that the terms used herein are for the purpose of describing specific embodiments only and are not intended to be limiting.

[0051] E1: A compound of the formula (I) defined above or a pharmaceutically acceptable salt thereof.

[0052] E2: In embodiment E1, a compound of the following formula (II) or a pharmaceutically acceptable salt thereof:

[0053] (II)

[0054] In the above formula,

[0055] Y is N or CH, preferably Y is CH;

[0056] n is 1, 2 or 3, and preferably n is 1 or 2.

[0057] E3: In embodiment E1 or E2, R2 is a compound that is H or a pharmaceutically acceptable salt thereof.

[0058] E4: In embodiment E1 or E2, R 1 A compound that is H or a pharmaceutically acceptable salt thereof.

[0059] E5: In any one of embodiments E1 to E4, the following compound or pharmaceutically acceptable salt thereof:

[0060] n is 1 and;

[0061] R 3 is a C1-C6 alkyl optionally substituted with 1 to 3 halogens or a C3-C6 cycloalkyl optionally substituted with 1 to 4 halogens, preferably R 3 is a C1-C3 alkyl optionally substituted with 1 to 3 halogens or a C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens, and more preferably R 3 is -CH2CH3, -CH2CF3, -CH(CH3)2, cyclopropyl, or cyclobutyl; more preferably R 3 It is cyclobutyl.

[0062] E6: In embodiment E1, a compound of the following formula (II-a1) or (II-b1) or a pharmaceutically acceptable salt thereof:

[0063] (II-a1) (II-b1).

[0064] E7: In any one of embodiments E1 to E4, the following compound or pharmaceutically acceptable salt thereof:

[0065] n is 2 and;

[0066] One R 3 is R 3ASelected from the group consisting of C1-C6 alkyl optionally substituted with 1 to 3 halogens and C3-C6 cycloalkyl optionally substituted with 1 to 4 halogens, preferably R 3A is selected from the group consisting of C1-C3 alkyl optionally substituted with 1 to 3 halogens and C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens, and more preferably R 3A is selected from the group consisting of -CH2CH3, -CH2CF3, -CH(CH3)2, cyclopropyl, and cyclobutyl, and more preferably R 3A is cyclobutyl;

[0067] Other R 3 is R 3B It is a halogen, and preferably R 3B is F.

[0068] E8: In embodiment E1, a compound of the following formula (II-a2) or (II-b2) or a pharmaceutically acceptable salt thereof:

[0069] (II-a2) (II-b2).

[0070] E9: In any one of embodiments E1 to E8, R 4 is a compound derived from the chemical formula (E4-1), (E4-2), (E4-3), (E4-4), (E4-5), (E4-6), (E5-1), (E5-2), (E5-3), (E5-4), (E5-5), (E5-6), (E5-7), (E5-8) or (E5-9) or a pharmaceutically acceptable salt thereof:

[0071]

[0072]

[0073] In the above formula,

[0074] dashed line represents the attachment point for connector L;

[0075] R 10 is a C1-C3 alkyl optionally substituted with (i) H, (ii) a halogen, (iii) -OH, (iv) -CN, or (v) 1 to 3 halogens, wherein R 10 This R 4 When adjacent to ring N, R 10 It is not OH or a halogen;

[0076] R 11 is (i) H, (ii) a C1-C3 alkyl optionally substituted with 1 to 3 halogens, (iii) a C2-C3 hydroxyalkyl, or (iv) a C1-C3 deuterinated alkyl;

[0077] R 12 and R 13 Each is a C1-C3 alkyl group independently substituted with (i) H, (ii) a halogen, or (iii) 1 to 3 halogens, wherein R 12 and R 13 Ga R 4 When adjacent to ring N, R 12 and R 13 is not a halogen or;

[0078] R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens;

[0079] R 12 and R 13 ... comprises one or more heteroatoms selected from the group consisting of N, O, and S, and forms a 3 to 6-membered heterocycloalkyl optionally substituted with (i) 1 to 3 halogens, or (ii) a C1-C3 alkyl optionally substituted with 1 to 3 halogens, wherein R 12 and R 13 This R 4When forming a 3 to 6-membered heterocycloalkyl adjacent to the ring N of, the 3 to 6-membered heterocycloalkyl is formed by R of the heteroatom 4 It is not attached to the ring.

[0080] "R 10 This R 4 When adjacent to ring N, R 10 The premise that "is not an OH or halogen" is based on R in chemical formulas (E4-1), (E4-2), (E4-3), (E5-1), (E5-2), (E5-3), and (E5-4). 10 This means that it is not OH or a halogen.

[0081] "R 12 and R 13 This R 4 When adjacent to ring N, R 12 and R 13 The premise that "is not a halogen" holds true for R in (E4-1), (E4-4), (E4-6), (E5-1), (E5-5), and (E5-8). 12 and R 13 This means it is not a halogen.

[0082] "R 12 and R 13 This R 4 When adjacent to ring N and forming a 3 to 6-membered heterocycloalkyl, the 3 to 6-membered heterocycloalkyl is formed by R of the heteroatom 4 The premise that "it is not attached to the ring" applies to R in (E4-1), (E4-4), (E4-6), (E5-1), (E5-5), and (E5-8). 12 and R 13 R by this heteroatom 4 This means that it does not form 3 to 6-membered heterocycloalkyl groups attached to the ring.

[0083] E10: In embodiment E9, R 4 is a compound derived from the following chemical formulas (E4-2), (E4-4), (E5-6) or (E5-8) or a pharmaceutically acceptable salt thereof:

[0084] R 10 is H or a halogen, preferably R 10 is H or F, but R 10 This R 4 When adjacent to ring N, R 10 It is not a halogen;

[0085] R 11 is a C1-C3 alkyl or C1-C3 deuterinated alkyl optionally substituted with H, 1 to 3 halogens, and preferably R 11 is H or C1-C3 alkyl, and more preferably R 11 is H, -CH3 or CD3;

[0086] R 12 and R 13 Each is independently a C1-C3 alkyl group optionally substituted with H, a halogen, or one to three halogens, preferably R 12 and R 13 are each C1-C3 alkyls optionally substituted with 1 to 3 halogens, and more preferably R 12 and R 13 are each -CH3, but R 12 and R 13 This R 4 When adjacent to ring N, R 12 and R 13 is not a halogen or;

[0087] R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens;

[0088] R 12 and R 13... comprises one or more heteroatoms selected from the group consisting of N, O, and S, and forms a 3 to 6-membered heterocycloalkyl optionally substituted with (i) 1 to 3 halogens, or (ii) a C1-C3 alkyl optionally substituted with 1 to 3 halogens, wherein R 12 and R 13 This R 4 When adjacent to ring N and forming a 3 to 6-membered heterocycloalkyl, the 3 to 6-membered heterocycloalkyl is formed by R of the heteroatom 4 Not attached to a ring;

[0089] Preferably R 12 and R 13 ...together, it forms a C4-C5 cycloalkyl group optionally substituted with 1 to 3 halogens, or R 12 and R 13 ...together forms a 4 to 6-membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N and O, and more preferably R 12 and R 13 ☐ forms a C4-C5 cycloalkyl group together, or R 12 and R 13 It forms a 6-membered heterocycloalkyl containing O together.

[0090] E11: In any one of embodiments E1 to E10, R 4 is a compound selected from the group consisting of the following or a pharmaceutically acceptable salt thereof:

[0091] .

[0092] E12: In any one of embodiments E1 to E10, R 4 is a compound selected from the group consisting of the following or a pharmaceutically acceptable salt thereof:

[0093] .

[0094] E13: Any one of embodiments E1 to E12, wherein L is a compound or a pharmaceutically acceptable salt thereof that is a linker selected from the group consisting of L1, L2 and L3:

[0095] (L1)

[0096] (L2)

[0097] (L3)

[0098] In the above formula,

[0099] The asterisk * indicates the attachment point for ring A, and the dashed line is R 4 Indicates the attachment point for .

[0100] E14: In embodiment E13, L is a compound or a pharmaceutically acceptable salt thereof that is a linker selected from the group consisting of L1', L2' and L3':

[0101] (L1')

[0102] (L2')

[0103] (L3').

[0104] E15: In any one of embodiments E1 to E14, the following compound or pharmaceutically acceptable salt thereof:

[0105] R 1 and R 2 One of them is H or a halogen, and R 1 and R 2 The other one is the group of the following chemical formulas (E1-1), (E1-2a), (E1-2b), (E1-3), (E2-1), (E2-2a), (E2-2b), or (E3-1a):

[0106]

[0107]

[0108] In the above formula,

[0109] Each asterisk * is R 1 and R 2 The other one indicates an attachment point connected to ring A;

[0110] m is 0 or 1 and;

[0111] R 5 and R 6 Each is independently (i) H, (ii) a halogen, (iii) a C1-C6 alkyl optionally substituted with 1 to 3 halogens and 1 to 3 -OH groups, (iv) a C2-C6 alkenyl, or (v) C 2-6 Alkynyl or;

[0112] R 5 and R 6 Together, they form a 4 to 6-membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of C3-C6 cycloalkyl, or N, O, and S;

[0113] R 7 silver

[0114] C1-C6 alkyl optionally substituted with 1 to 3 halogens,

[0115] C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens or C1-C3 alkyl optionally substituted with 1 to 3 halogens, and

[0116] -NR 8 R 9 (At this time, R 8 and R 9 Each is independently H or C1-C6 alkyl, or R 8 and R 9 (together forming a 4 to 6-membered N-containing heterocycloalkyl ring optionally substituted with 1 to 4 halogens)

[0117] Selected from a group consisting of;

[0118] R 7Ais (i) H, (ii) C1-C3 alkyl optionally substituted with 1 to 3 halogens, (iii) C2-C3 hydroxyalkyl, or (iv) C3-C4 cycloalkyl.

[0119] E16: In embodiment E15, the following compound or pharmaceutically acceptable salt thereof:

[0120] R 5 and R 6 Each is independently a C1-C6 alkyl optionally substituted with H, a halogen, or 1 to 3 halogens;

[0121] R 5 and R 6 Together, they form a C3-C5 cycloalkyl or a 4- or 5-membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O, and S, and preferably R 5 and R 6 Each is independently a C1-C3 alkyl group optionally substituted with H, a halogen, or one to three halogens, and more preferably R 5 and R 6 Each is independently H or C1-C3 alkyl, and more preferably, R 5 and R 6 Each is independently H or -CH3;

[0122] R 7 silver

[0123] C1-C3 alkyl optionally substituted with 1 to 3 halogens,

[0124] C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens or C1-C3 alkyl optionally substituted with 1 to 3 halogens, and

[0125] -NR 8 R 9 (At this time, R 8 and R 9 Each is independently H or C1-C3 alkyl, or R 8 and R9 (together forming a 4 or 5-membered N-containing heterocycloalkyl ring optionally substituted with 1 to 4 halogens)

[0126] Selected from the group consisting of, preferably R 7 C1-C3 alkyl, 1 to 4 halogens or a C3-C4 cycloalkyl optionally substituted with a C1-C3 alkyl, or -NR 8 R 9 and, more preferably R 7 -CH3, -CH2CH3, -CH(CH3)2, cyclopropyl, cyclopropyl substituted with -CH3, -NH2, -N(CH3)2, -N(CH2CH3)(CH3), or -NR 8 R 9 (At this time, R 8 and R 9 (and together form an azetidine optionally substituted with 1 to 3 halogens);

[0127] R 7A is (i) H, (ii) a C1-C3 alkyl optionally substituted with 1 to 3 halogens, (iii) a C2-C3 hydroxyalkyl, or (iv) a C3-C4 cycloalkyl, preferably R 7A is H, C1-C3 alkyl or C3-C4 cycloalkyl, and more preferably R 7A is H, -CH3, -CH2CH3, -CH(CH3)2, or cyclopropyl.

[0128] E17: In embodiment E15 or E16, R 1 and R 2 One of them is H and R 1 and R 2 The other one is a compound derived from the following chemical formulas (E1-1), (E1-2a), (E1-3), (E2-1), (E2-2b) or (E3-1) or a pharmaceutically acceptable salt thereof.

[0129] E18: In any one of embodiments E1 to E17, R 1and R 2 One of them is H and R 1 and R 2 The other one is a compound selected from the group consisting of the following or a pharmaceutically acceptable salt thereof:

[0130] .

[0131] E19: In any one of embodiments E1 to E17, R 1 and R 2 One of them is H and R 1 and R 2 The other one is a compound selected from the group consisting of the following or a pharmaceutically acceptable salt thereof:

[0132] .

[0133] E20: In any one of embodiments E1 to E17, R 1 and R 2 One of them is H and R 1 and R 2 The other one is a compound such as the following or a pharmaceutically acceptable salt thereof:

[0134] .

[0135] E21: In any one of embodiments E1 to E17, R 1 and R 2 One of them is H and R 1 and R 2 The other one is a compound selected from the group consisting of the following or a pharmaceutically acceptable salt thereof:

[0136]

[0137] .

[0138] E22: In any one of embodiments E1 to E17, R 1 and R 2 One of them is H and R 1 and R 2The other one is a compound such as the following or a pharmaceutically acceptable salt thereof:

[0139] .

[0140] E23: In any one of embodiments E1 to E17, R 1 and R 2 One of them is H and R 1 and R 2 The other one is a compound such as the following or a pharmaceutically acceptable salt thereof:

[0141] .

[0142] E24: In embodiment E1 or E2, a compound of the following formula (IA) or a pharmaceutically acceptable salt thereof:

[0143] (IA)

[0144] In the above formula,

[0145] R 1 and R 2 One of them is H and R 1 and R 2 The other one is the group of the following chemical formulas (E1-1), (E1-2a), (E1-2b), (E2-1), (E2-2b), or (E3-1a):

[0146]

[0147] In the above formula,

[0148] Each asterisk * is R 1 and R 2 Indicates the attachment point to the other ring A;

[0149] m is 0 or 1 and;

[0150] R 5 and R 6 Each is independently (i) H, (ii) a halogen, (iii) a C1-C6 alkyl optionally substituted with 1 to 3 halogens and 1 to 3 -OH groups, (iv) a C2-C6 alkenyl, or (v) C 2-6Alkynyl or;

[0151] R 5 and R 6 Together, they form a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O, and S;

[0152] R 7 silver

[0153] C1-C6 alkyl optionally substituted with 1 to 3 halogens,

[0154] C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens or C1-C3 alkyl optionally substituted with 1 to 3 halogens, and

[0155] -NR 8 R 9 (At this time, R 8 and R 9 Each is independently H or C1-C6 alkyl, or R 8 and R 9 (together forming a 4 to 6-membered N-containing heterocycloalkyl ring optionally substituted with 1 to 4 halogens)

[0156] Selected from a group consisting of;

[0157] R 7A is (i) H, (ii) a C1-C3 alkyl optionally substituted with 1 to 3 halogens, (iii) a C2-C3 hydroxyalkyl, or (iv) a C3-C4 cycloalkyl;

[0158] R 4 is a group of the chemical formula (E4-2), (E4-4), (E5-6), or (E5-8):

[0159]

[0160] In the above formula,

[0161] dashed line indicates the attachment point to connector L;

[0162] R 10is a C1-C3 alkyl optionally substituted with H, a halogen, -OH, -CN, or 1 to 3 halogens, wherein R 10 This R 4 When adjacent to ring N, R 10 It is not OH or a halogen;

[0163] R 11 is H, C1-C3 alkyl, C1-C3 alkyl optionally substituted with 1 to 3 halogens, C2-C3 hydroxyalkyl, or C1-C3 deuterinated alkyl;

[0164] R 12 and R 13 Each is a C1-C3 alkyl group independently substituted with H, a halogen, or 1 to 3 halogens, wherein R 12 and R 13 This R 4 When adjacent to ring N, R 12 and R 13 is not a halogen or;

[0165] R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens;

[0166] R 12 and R 13 ... comprises one or more heteroatoms selected from the group consisting of N, O, and S, and forms a 3 to 6-membered heterocycloalkyl optionally substituted with (i) 1 to 3 halogens, or (ii) a C1-C3 alkyl optionally substituted with 1 to 3 halogens, wherein R 12 and R 13 This R 4 When adjacent to ring N and forming a 3 to 6-membered heterocycloalkyl, the 3 to 6-membered heterocycloalkyl is formed by R of the heteroatom 4 It is not attached to the ring.

[0167] E25: In embodiment E24, a compound of the following formula (IA-1) or a pharmaceutically acceptable salt thereof:

[0168] (IA-1)

[0169] In the above formula,

[0170] m is 0 or 1 and;

[0171] n is 1 or 2 and;

[0172] Each R 3 A silver halogen, a C1-C6 alkyl optionally substituted with 1 to 3 halogens, and a C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens

[0173] Independently selected from a group consisting of;

[0174] R 5 and R 6 Each is independently a C1-C3 alkyl group optionally substituted with H, a halogen, or 1 to 3 halogens;

[0175] R 10 is H or a halogen;

[0176] R 11 is H or C1-C3 alkyl;

[0177] R 12 and R 13 Each is independently H or C1-C3 alkyl, or R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens.

[0178] E26: In embodiment E25, a compound of the following formula (IA-1a) or (IA-1b) or a pharmaceutically acceptable salt thereof:

[0179] (IA-1a)

[0180] (IA-1b)

[0181] In the above formula,

[0182] R 3A is a C1-C6 alkyl or C3-C4 cycloalkyl;

[0183] R 3B is a halogen, and preferably R 3B is F and;

[0184] R 5 and R 6 Each is independently H or C1-C3 alkyl, preferably R 5 and R 6 Each is independently H, -CH3, or -CH2CH3;

[0185] R 10 is H or a halogen, preferably R 10 is H or F;

[0186] R 11 , R 12 and R 13 Each is a C1-C3 alkyl.

[0187] E27: In embodiment E26, R 3A is cyclobutyl and R 3B is a compound of F or a pharmaceutically acceptable salt thereof.

[0188] E28: In embodiment E26, a compound of formula (IA-1a) or a pharmaceutically acceptable salt thereof.

[0189] E29: In any one of embodiments E25 to E28, R 10 and R 11 Each is a compound of H or a pharmaceutically acceptable salt thereof.

[0190] E30: In any one of embodiments E25 to E28, R 12 and R 13 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0191] E31: In embodiment E25, the following compound or pharmaceutically acceptable salt thereof:

[0192] .

[0193] E32: In embodiment E24, a compound of the following formula (IA-2) or a pharmaceutically acceptable salt thereof:

[0194] (IA-2)

[0195] In the above formula,

[0196] m is 0 or 1 and;

[0197] n is 1 or 2 and;

[0198] Each R 3 halogen,

[0199] C1-C6 alkyl optionally substituted with 1 to 3 halogens, and

[0200] C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens

[0201] Independently selected from a group consisting of;

[0202] R 5 and R 6 Each is independently a C1-C3 alkyl group optionally substituted with H, a halogen, or 1 to 3 halogens;

[0203] R 10 is H or C1-C3 alkyl;

[0204] R 11 is H or C1-C3 alkyl;

[0205] R 12 and R 13 Each is independently H or C1-C3 alkyl, or R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens.

[0206] E33: In embodiment E32, a compound of the following formula (IA-2a) or (IA-2b) or a pharmaceutically acceptable salt thereof:

[0207] (IA-2a)

[0208] (IA-2b)

[0209] In the above formula,

[0210] R 3A is a C1-C6 alkyl or C3-C4 cycloalkyl, preferably R 3A is -CH2CH3, -CH(CH3)2, or C3-C4 cycloalkyl;

[0211] R 3B is a halogen, and preferably R 3B is F and;

[0212] R 5 and R 6 Each is independently H or C1-C3 alkyl, preferably R 5 and R 6 Each is independently H, -CH3, or -CH2CH3;

[0213] R 10 is H or C1-C3 alkyl, preferably R 10 is H;

[0214] R 11 , R 12 and R 13 Each is a C1-C3 alkyl.

[0215] E34: In embodiment E33, R 3A is -CH(CH3)2 or cyclobutyl and R 3B is a compound of F or a pharmaceutically acceptable salt thereof.

[0216] E35: In embodiment E33, having the chemical formula (IA-2b), R 5 and R 6 Each is a compound of H or a pharmaceutically acceptable salt thereof.

[0217] E36: In any one of embodiments E32 to E35, R 10 A compound that is H or a pharmaceutically acceptable salt thereof.

[0218] E37: In any one of embodiments E32 to E36, R 11 , R 12 and R 13 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0219] E38: In embodiment E32, the following compound or pharmaceutically acceptable salt thereof:

[0220] .

[0221] E39: In embodiment E24, a compound of the following formula (IA-3) or (IA-3') or a pharmaceutically acceptable salt thereof:

[0222] (IA-3)

[0223] (IA-3')

[0224] In the above formula,

[0225] m is 0 or 1 and;

[0226] n is 1 or 2 and;

[0227] Each R 3 silver

[0228] halogen,

[0229] C1-C6 alkyl optionally substituted with 1 to 3 halogens, and

[0230] C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens

[0231] Independently selected from a group consisting of;

[0232] R 5 and R 6Each is independently a C1-C3 alkyl group optionally substituted with H, a halogen, or 1 to 3 halogens;

[0233] R 7 silver

[0234] C1-C3 alkyl,

[0235] C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens or C1-C3 alkyl optionally substituted with 1 to 3 halogens, and

[0236] -NR 8 R 9 (At this time, R 8 and R 9 Each is independently H or C1-C3 alkyl, or R 8 and R 9 (together forming a 4 or 5-membered N-containing heterocycloalkyl ring optionally substituted with 1 to 4 halogens)

[0237] Selected from a group consisting of;

[0238] R in the chemical formula (IA-3) 10 is H or C1-C3 alkyl, and in the chemical formula (IA-3'), R 10 is H or a halogen;

[0239] R 11 is H or C1-C3 alkyl;

[0240] R 12 and R 13 Each is independently H or C1-C3 alkyl, or R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens.

[0241] E40: In embodiment E39, a compound of the following formula (IA-3a), (IA-3b), (IA-3c) or (IA-3d) or a pharmaceutically acceptable salt thereof:

[0242]

[0243] In the above formula,

[0244] R 3A is a C1-C6 alkyl or C3-C4 cycloalkyl, preferably R 3A is -CH2CH3, -CH(CH3)2, or C3-C4 cycloalkyl;

[0245] R 3B is a halogen, and preferably R 3B is F and;

[0246] R 5 and R 6 Each is independently H or C1-C3 alkyl, preferably R 5 and R 6 Each is independently H, -CH3, or -CH2CH3;

[0247] R 10 is H or C1-C3 alkyl, preferably R 10 is H;

[0248] R 11 is H or C1-C3 alkyl;

[0249] R 12 and R 13 are each C1-C3 alkyl, or R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens.

[0250] E41: In embodiment E40, R 3A is cyclobutyl and R 3B is a compound of F or a pharmaceutically acceptable salt thereof.

[0251] E42: In embodiment E40 or E41, having the chemical formula (IA-3b) or (IA-3d), R 5 and R 6Each is a compound of H or a pharmaceutically acceptable salt thereof.

[0252] E43: In any one of embodiments E39 to E42, R 7 A compound that is -CH3, -CH2CH3, -CH(CH3)2, cyclopropyl, cyclopropyl substituted with -CH3, -NH2, -N((CH)3)2, -N(CH3)(CH2CH3), or azetidine optionally substituted with 1, 2, or 3 F, or a pharmaceutically acceptable salt thereof.

[0253] E44: In any one of embodiments E39 to E43, R 10 is H and R 11 A compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0254] E45: In any one of embodiments E39 to E44, R 12 and R 13 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0255] E46: In any one of embodiments E39 to E44, R 12 and R 13 A compound that forms a cyclopentyl together with a pharmaceutically acceptable salt thereof.

[0256] E47: In embodiment E39, the following compound or pharmaceutically acceptable salt thereof:

[0257]

[0258]

[0259] .

[0260] E48: In embodiment E24, a compound of the following formula (IA-4) or a pharmaceutically acceptable salt thereof:

[0261] (IA-4)

[0262] In the above formula,

[0263] m is 0 or 1 and;

[0264] n is 1 or 2 and;

[0265] Each R 3 silver

[0266] halogen,

[0267] C1-C6 alkyl optionally substituted with 1 to 3 halogens, and

[0268] C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens

[0269] Independently selected from a group consisting of;

[0270] R 5 and R 6 Each is independently a C1-C3 alkyl group optionally substituted with H, a halogen, or 1 to 3 halogens;

[0271] R 10 is H or a halogen;

[0272] R 11 is H or C1-C3 alkyl;

[0273] R 12 and R 13 Each is independently H or C1-C3 alkyl, or R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens.

[0274] E49: A compound of the following formula (IA-4a) or (IA-4b) or a pharmaceutically acceptable salt thereof according to embodiment E48:

[0275] (IA-4a)

[0276] (IA-4b)

[0277] In the above formula,

[0278] R3A is a C1-C6 alkyl or C3-C4 cycloalkyl, preferably R 3A is -CH2CH3, -CH(CH3)2, or C3-C4 cycloalkyl;

[0279] R 3B is a halogen, and preferably R 3B is F and;

[0280] R 5 and R 6 Each is independently H or C1-C3 alkyl, preferably R 5 and R 6 Each is independently H, -CH3, or -CH2CH3;

[0281] R 10 is H or a halogen, preferably R 10 is H or F;

[0282] R 11 is a C1-C3 alkyl;

[0283] R 12 and R 13 are each C1-C3 alkyl, or R 12 and R 13 It forms a C3-C6 cycloalkyl group optionally substituted with 1 to 3 halogens.

[0284] E50: In embodiment E49, R 3A is cyclobutyl and R 3B is a compound of F or a pharmaceutically acceptable salt thereof.

[0285] E51: In embodiment E49, having the chemical formula (IA-4b), R 5 and R 6 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0286] E52: In any one of embodiments E48 to E51, R 10 is F and R 11 A compound that is H or a pharmaceutically acceptable salt thereof.

[0287] E53: In any one of embodiments E48 to E52, R 12 and R 13 A compound that forms cyclobutyl together with or a pharmaceutically acceptable salt thereof.

[0288] E54: In embodiment E48, the following compound or pharmaceutically acceptable salt thereof:

[0289] ; .

[0290] E55: In embodiment E24, a compound of the following formula (IA-5) or a pharmaceutically acceptable salt thereof:

[0291] (IA-5)

[0292] In the above formula,

[0293] m is 0 or 1 and;

[0294] n is 1 or 2 and;

[0295] Each R 3 silver

[0296] halogen,

[0297] C1-C6 alkyl optionally substituted with 1 to 3 halogens, and

[0298] C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens

[0299] Independently selected from a group consisting of;

[0300] R 5 and R 6 Each is independently a C1-C3 alkyl group optionally substituted with H, a halogen, or 1 to 3 halogens;

[0301] R 7A is a C1-C3 alkyl or C3-C4 cycloalkyl optionally substituted with H or 1 to 3 halogens;

[0302] R 10 is H or C1-C3 alkyl;

[0303] R 11 is H or C1-C3 alkyl;

[0304] R 12 and R 13 Each is independently H or C1-C3 alkyl, or R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens.

[0305] E56: In embodiment E55, a compound of the following formula (IA-5a) or (IA-5b) or a pharmaceutically acceptable salt thereof:

[0306] (IA-5a)

[0307] (IA-5b)

[0308] In the above formula,

[0309] R 3A is a C1-C6 alkyl or C3-C4 cycloalkyl, preferably R 3A is -CH2CH3, -CH(CH3)2, or C3-C4 cycloalkyl;

[0310] R 3B is a halogen, and preferably R 3B is F and;

[0311] R 5 and R 6 Each is independently H or C1-C3 alkyl, preferably R 5 and R 6 Each is independently H, -CH3, or -CH2CH3;

[0312] R 7A is H, C1-C3 alkyl or C3-C4 cycloalkyl, preferably R 7A is H, -CH3, -CH2CH3, -CH(CH3)2, or cyclopropyl, and more preferably R 7Ais H or -CH3;

[0313] R 10 is H or C1-C3 alkyl, preferably R 10 is H;

[0314] R 11 is H or C1-C3 alkyl;

[0315] R 12 and R 13 Each forms a C1-C3 alkyl or a C3-C6 cycloalkyl optionally substituted with 1 to 3 halogens.

[0316] E57: In embodiment E56, R 3A is cyclobutyl and R 3B is a compound of F or a pharmaceutically acceptable salt thereof.

[0317] E58: In embodiment E56, having the chemical formula (IA-5b), R 5 and R 6 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0318] E59: In any one of embodiments E55 to E58, R 10 is H and R 11 A compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0319] E60: In any one of embodiments E55 to E59, R 12 and R 13 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0320] E61: In embodiment E51, the following compound or pharmaceutically acceptable salt thereof:

[0321] .

[0322] E62: In embodiment E24, a compound of the following formula (IA-6) or a pharmaceutically acceptable salt thereof:

[0323] (IA-6)

[0324] In the above formula,

[0325] m is 0 or 1 and;

[0326] n is 1 or 2 and;

[0327] Each R 3 silver

[0328] halogen,

[0329] C1-C6 alkyl optionally substituted with 1 to 3 halogens, and

[0330] C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens

[0331] Independently selected from a group consisting of;

[0332] R 5 and R 6 Each is independently a C1-C3 alkyl group optionally substituted with H, a halogen, or 1 to 3 halogens;

[0333] R 7A is a C1-C3 alkyl or C3-C4 cycloalkyl optionally substituted with H or 1 to 3 halogens;

[0334] R 10 is H or a halogen;

[0335] R 11 is H or C1-C3 alkyl;

[0336] R 12 and R 13 Each is independently H or C1-C3 alkyl, or R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens.

[0337] E63: In embodiment E62, a compound of the following formula (IA-6a) or (IA-6b) or a pharmaceutically acceptable salt thereof:

[0338] (IA-6a)

[0339] (IA-6b)

[0340] In the above formula,

[0341] R 3A is a C1-C6 alkyl or C3-C4 cycloalkyl, preferably R 3A is -CH2CH3, -CH(CH3)2, or C3-C4 cycloalkyl;

[0342] R 3B is a halogen, and preferably R 3B is F and;

[0343] R 5 and R 6 Each is independently H or C1-C3 alkyl, preferably R 5 and R 6 Each is independently H, -CH3, or -CH2CH3;

[0344] R 7A is H, C1-C3 alkyl or C3-C4 cycloalkyl, preferably H, -CH3, -CH2CH3, -CH(CH3)2, or cyclopropyl;

[0345] R 10 is H or a halogen, preferably R 10 is H or F;

[0346] R 11 is a C1-C3 alkyl;

[0347] R 12 and R 13 It forms a C3-C6 cycloalkyl group optionally substituted with 1 to 3 halogens.

[0348] E64: In embodiment E63, R 3A is cyclobutyl and R 3B is a compound of F or a pharmaceutically acceptable salt thereof.

[0349] E65: In embodiment E63 or E64, having the chemical formula (IA-6b), R 5 and R 6 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0350] E66: In embodiment E63 or E64, having the chemical formula (IA-6b), R 5 and R 6 One of them is -CH3 and R 5 and R 6 The other one is a compound that is H or a pharmaceutically acceptable salt thereof.

[0351] E67: In any one of embodiments E62 to E64, R 10 is F and R 11 A compound that is H or a pharmaceutically acceptable salt thereof.

[0352] E68: In any one of embodiments E62 to E67, R 12 and R 13 A compound that forms cyclobutyl together with or a pharmaceutically acceptable salt thereof.

[0353] E69: In embodiment E62, the following compound or pharmaceutically acceptable salt thereof:

[0354]

[0355]

[0356] .

[0357] E70: In embodiment E24, a compound of the following formula (IA-7) or a pharmaceutically acceptable salt thereof:

[0358] (IA-7)

[0359] In the above formula,

[0360] m is 0 or 1 and;

[0361] n is 1 or 2 and;

[0362] Each R 3 halogen,

[0363] C1-C6 alkyl optionally substituted with 1 to 3 halogens, and

[0364] C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens

[0365] Independently selected from a group consisting of;

[0366] R 5 and R 6 Each is independently a C1-C3 alkyl group optionally substituted with H, a halogen, or 1 to 3 halogens;

[0367] R 7A is a C1-C3 alkyl or C3-C4 cycloalkyl optionally substituted with H or 1 to 3 halogens;

[0368] R 10 is H or C1-C3 alkyl;

[0369] R 11 is H or C1-C3 alkyl;

[0370] R 12 and R 13 Each is independently H or C1-C3 alkyl, or R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens.

[0371] E71: In embodiment E70, a compound of the following formula (IA-7a) or (IA-7b) or a pharmaceutically acceptable salt thereof:

[0372] (IA-7a)

[0373] (IA-7b)

[0374] In the above formula,

[0375] R 3Ais a C1-C6 alkyl or C3-C4 cycloalkyl, preferably R 3A is -CH2CH3, -CH(CH3)2, or C3-C4 cycloalkyl;

[0376] R 3B is a halogen, and preferably R 3B is F and;

[0377] R 5 and R 6 Each is independently H or C1-C3 alkyl, preferably H, -CH3, or -CH2CH3;

[0378] R 7A is H, C1-C3 alkyl or C3-C4 cycloalkyl, preferably H, -CH3, -CH2CH3, -CH(CH3)2, or cyclopropyl;

[0379] R 10 is H or C1-C3 alkyl, preferably R 10 is H;

[0380] R 11 , R 12 and R 13 Each is a C1-C3 alkyl.

[0381] E72: In embodiment E71, R 3A is cyclobutyl and R 3B is a compound of F or a pharmaceutically acceptable salt thereof.

[0382] E73: In embodiment E71, having the chemical formula (IA-7b), R 5 and R 6 Each is a compound of H or a pharmaceutically acceptable salt thereof.

[0383] E74: In any one of embodiments E70 to E73, R 10 is H and R 11 A compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0384] E75: In any one of embodiments E70 to E74, R12 and R 13 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0385] E76: In embodiment E70, the following compound or pharmaceutically acceptable salt thereof:

[0386] ; or .

[0387] E77: In embodiment E24, a compound of the following formula (IA-8) or (IA-8') or a pharmaceutically acceptable salt thereof:

[0388] (IA-8)

[0389] (IA-8')

[0390] In the above formula,

[0391] n is 1 or 2 and;

[0392] Each R 3 halogen,

[0393] C1-C6 alkyl optionally substituted with 1 to 3 halogens, and

[0394] C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens

[0395] Independently selected from a group consisting of;

[0396] R 7 C1-C3 alkyl,

[0397] C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens or C1-C3 alkyl optionally substituted with 1 to 3 halogens, and

[0398] -NR 8 R 9 (At this time, R 8 and R 9 Each is independently H or C1-C3 alkyl, or R 8 and R 9(together forming a 4 or 5-membered N-containing heterocycloalkyl ring optionally substituted with 1 to 4 halogens)

[0399] Selected from a group consisting of;

[0400] R 7A is a C1-C3 alkyl or C3-C4 cycloalkyl optionally substituted with H or 1 to 3 halogens;

[0401] R in the chemical formula (IA-8) 10 is H or C1-C3 alkyl, preferably H, and R in formula (IA-8'). 10 is H or a halogen;

[0402] R 11 is H or C1-C3 alkyl;

[0403] R 12 and R 13 Each is independently H or C1-C3 alkyl, or R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens.

[0404] E78: In embodiment E77, a compound of the following formula (IA-8a) or (IA-8a') or a pharmaceutically acceptable salt thereof:

[0405] (IA-8a)

[0406] (IA-8a')

[0407] In the above formula,

[0408] R 3A is a C1-C6 alkyl or C3-C4 cycloalkyl, preferably R 3A is -CH2CH3, -CH(CH3)2, or C3-C4 cycloalkyl;

[0409] R 3B is a halogen, and preferably R3B is F and;

[0410] R 7 silver

[0411] C1-C3 alkyl,

[0412] A C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens or C1-C3 alkyls, and

[0413] -NR 8 R 9

[0414] Selected from the group consisting of, preferably R 7 is -CH3, -CH2CH3, -CH(CH3)2, cyclopropyl, cyclopropyl substituted with -CH3, -NH2, -N((CH)3)2, -N(CH3)(CH2CH3), or azetidine optionally substituted with 1, 2, or 3 Fs;

[0415] R 7A is H, C1-C3 alkyl or C3-C4 cycloalkyl, preferably R 7A is H, -CH3, -CH2CH3, -CH(CH3)2, or cyclopropyl;

[0416] R 10 is H, a halogen, or a C1-C3 alkyl, preferably R 10 is H or a halogen;

[0417] R 11 is H or C1-C3 alkyl;

[0418] R 12 and R 13 Each is independently H or C1-C3 alkyl, or R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens.

[0419] E79: In embodiment E78, R 3A is cyclobutyl and R 3Bis a compound of F or a pharmaceutically acceptable salt thereof.

[0420] E80: In any one of embodiments E77 to E79, R 10 is H and R 11 is -CH3 or R 10 is F and R 11 A compound that is H or a pharmaceutically acceptable salt thereof.

[0421] E81: In any one of embodiments E77 to E80, R 12 and R 13 are respectively -CH3 or R 12 and R 13 Compounds that form a C3-C6 cycloalkyl group together or pharmaceutically acceptable salts thereof.

[0422] E82: In any one of embodiments E77 to E81, R 7 and R 7A Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0423] E83: In embodiment E77, the following compound or pharmaceutically acceptable salt thereof:

[0424] ; ; or .

[0425] E84: In embodiment E24, a compound of the following formula (IA-9) or a pharmaceutically acceptable salt thereof:

[0426] (IA-9)

[0427] In the above formula,

[0428] m is 0 or 1 and;

[0429] n is 1 or 2 and;

[0430] Each R 3It is independently selected from the group consisting of a halogen, a C1-C6 alkyl optionally substituted with 1 to 3 halogens, and a C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens;

[0431] R 5 and R 6 Each is independently H, a halogen, a C1-C3 deuterinated alkyl, or a C1-C3 alkyl optionally substituted with 1 to 3 halogens;

[0432] R 10 is H or a halogen;

[0433] R 11 is H or C1-C3 alkyl;

[0434] R 12 and R 13 Each is independently H or C1-C3 alkyl, or R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens.

[0435] E85: In embodiment E84, a compound of formula (IA-9a) or (IA-9b) or a pharmaceutically acceptable salt thereof:

[0436] (IA-9a)

[0437] (IA-9b)

[0438] In the above formula,

[0439] R 3A is a C1-C6 alkyl or C3-C4 cycloalkyl, preferably R 3A is -CH2CH3, -CH(CH3)2, or C3-C4 cycloalkyl;

[0440] R 3B is a halogen, and preferably R 3B is F and;

[0441] R5 and R 6 Each is independently H or C1-C3 alkyl, preferably R 5 and R 6 Each is independently H, -CH3, or -CH2CH3;

[0442] R 10 is H or a halogen, preferably R 10 is H or F;

[0443] R 11 is H or C1-C3 alkyl;

[0444] R 12 and R 13 are each C1-C3 alkyl, or R 12 and R 13 It forms a C3-C6 cycloalkyl group optionally substituted with 1 to 3 halogens.

[0445] E86: In embodiment E85, R 3A is cyclobutyl and R 3B is a compound of F or a pharmaceutically acceptable salt thereof.

[0446] E87: In embodiment E85, having the chemical formula (IA-9b), R 5 and R 6 Each is a compound of H or a pharmaceutically acceptable salt thereof.

[0447] E88: In embodiment E85, having the chemical formula (IA-9b), R 5 and R 6 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0448] E89: In any one of embodiments E84 to E88, R 10 is F, and R 11 is H, and R 12 and R 13 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0449] E90: In any one of embodiments E84 to E88, R 10 is F, and R 11 is H, and R 12 and R 13 A compound that forms together with cyclobutyl or cyclopentyl, preferably cyclobutyl, or a pharmaceutically acceptable salt thereof.

[0450] E91: In any one of embodiments E84 to E88, R 10 is H, and R 11 , R 12 and R 13 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0451] E92: In embodiment E84, the following compound or pharmaceutically acceptable salt thereof:

[0452]

[0453]

[0454]

[0455] .

[0456] E93: In embodiment E84, the following compound or pharmaceutically acceptable salt thereof:

[0457] .

[0458] E94: In embodiment E84, the following compound or pharmaceutically acceptable salt thereof:

[0459] .

[0460] E95: In embodiment E84, the following compound or pharmaceutically acceptable salt thereof:

[0461] .

[0462] E96: In embodiment E84, the following compound or pharmaceutically acceptable salt thereof:

[0463] .

[0464] E97: In embodiment E84, the following compound or pharmaceutically acceptable salt thereof:

[0465] .

[0466] E98: In embodiment E84, the following compound or pharmaceutically acceptable salt thereof:

[0467] .

[0468] E99: In embodiment E84, the following compound or pharmaceutically acceptable salt thereof:

[0469] .

[0470] E100: In embodiment E84, the following compound or pharmaceutically acceptable salt thereof:

[0471] .

[0472] E101: In embodiment E24, a compound of the following formula (IA-10) or a pharmaceutically acceptable salt thereof:

[0473] (IA-10)

[0474] In the above formula,

[0475] m is 0 or 1 and;

[0476] n is 1 or 2 and;

[0477] Each R 3 is independently

[0478] halogen,

[0479] C1-C6 alkyl optionally substituted with 1 to 3 halogens, and

[0480] C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens

[0481] Selected from a group consisting of;

[0482] R 5 and R 6 Each is independently a C1-C3 alkyl group optionally substituted with H, a halogen, or 1 to 3 halogens;

[0483] R 10 is H or C1-C3 alkyl;

[0484] R 11 is H, C1-C3 alkyl or C1-C3 deuterinated alkyl;

[0485] R 12 and R 13 Each is independently H or C1-C3 alkyl;

[0486] R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens;

[0487] R 12 and R 13 It comprises one or more heteroatoms selected from the group consisting of N, O and S, and forms a 3 to 6-membered heterocycloalkyl optionally substituted with (i) 1 to 3 halogens, or (ii) a C1-C3 alkyl optionally substituted with 1 to 3 halogens.

[0488] E102: In Embodiment 101, a compound of formula (IA-10a), (IA-10b), (IA-10c) or (IA-10d) or a pharmaceutically acceptable salt thereof:

[0489] (IA-10a)

[0490] (IA-10b)

[0491] (IA-10c)

[0492] (IA-10d)

[0493] In the above formula,

[0494] R 3A is a C1-C6 alkyl or C3-C4 cycloalkyl, preferably R 3A is -CH2CH3, -CH(CH3)2, or C3-C4 cycloalkyl;

[0495] R 3B is a halogen, and preferably R 3B is F and;

[0496] R 5 and R 6 Each is independently H or C1-C3 alkyl, preferably R 5 and R 6 Each is independently H, -CH3, or -CH2CH3;

[0497] R 10 is H or C1-C3 alkyl, preferably R 10 is H;

[0498] R 11 is a C1-C3 alkyl or a C1-C3 deuterinated alkyl;

[0499] R 12 and R 13 are each C1-C3 alkyl or;

[0500] R 12 and R 13 It forms a C3-C6 cycloalkyl group optionally substituted with 1 to 3 halogens together;

[0501] R 12 and R 13 It comprises one or more heteroatoms selected from the group consisting of N, O, and S, and forms a 4 to 6-membered heterocycloalkyl group optionally substituted with 1 to 3 halogens.

[0502] E103: In embodiment E102, R 3A is cyclobutyl and R 3B is a compound of F or a pharmaceutically acceptable salt thereof.

[0503] E104: In embodiment E102, R 3A is -CH(CH3)2 and R 3B is a compound of F or a pharmaceutically acceptable salt thereof.

[0504] E105: In embodiment E102, having the chemical formula (IA-10b) or (IA-10d), R 5 and R 6 Each is a compound of H or a pharmaceutically acceptable salt thereof.

[0505] E106: In embodiment E102, having the chemical formula (IA-10b) or (IA-10d), R 5 and R 6 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0506] E107: In embodiment E102, having the chemical formula (IA-10b) or (IA-10d), R 5 and R 6 One of them is H and R 5 and R 6 The other one is a compound that is -CH3 or a pharmaceutically acceptable salt thereof.

[0507] E108: In any one of embodiments E101 to E107, R 10 is H and R 11 A compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0508] E109: In any one of embodiments E101 to E108, R 12 and R 13 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0509] E110: In any one of embodiments E101 to E108, R 12 and R 13 A compound that forms together with cyclobutyl or cyclopentyl, preferably cyclopentyl, or a pharmaceutically acceptable salt thereof.

[0510] E111: In any one of embodiments E101 to E108, R 12 and R 13 It forms a hexacyclic heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O, and S, and preferably R 12 and R 13 A compound that forms tetrahydropyran together with or a pharmaceutically acceptable salt thereof.

[0511] E112: In embodiment E101, the following compound or pharmaceutically acceptable salt thereof:

[0512]

[0513]

[0514] .

[0515] E113: In embodiment E101, the following compound or pharmaceutically acceptable salt thereof:

[0516] .

[0517] E114: In embodiment E101, the following compound or pharmaceutically acceptable salt thereof:

[0518] .

[0519] E115: In embodiment E101, the following compound or pharmaceutically acceptable salt thereof:

[0520] .

[0521] E116: In embodiment E101, the following compound or pharmaceutically acceptable salt thereof:

[0522] .

[0523] E117: In embodiment E24, a compound of the following formula (IA-11) or a pharmaceutically acceptable salt thereof:

[0524] (IA-11)

[0525] In the above formula,

[0526] m is 0 or 1 and;

[0527] n is 1 or 2 and;

[0528] Each R 3 halogen,

[0529] C1-C6 alkyl optionally substituted with 1 to 3 halogens, and

[0530] C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens

[0531] Independently selected from a group consisting of;

[0532] R 5 and R 6 Each is independently a C1-C3 alkyl group optionally substituted with H, a halogen, or 1 to 3 halogens;

[0533] R 7 silver

[0534] C1-C3 alkyl,

[0535] C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens or C1-C3 alkyl optionally substituted with 1 to 3 halogens, and

[0536] -NR 8 R 9 (At this time, R 8 and R 9 Each is independently H or C1-C3 alkyl, or R 8 and R 9 (together forming a 4 or 5-membered N-containing heterocycloalkyl ring optionally substituted with 1 to 4 halogens)

[0537] Selected from a group consisting of;

[0538] R 10 is H or C1-C3 alkyl;

[0539] R 11 is H, C1-C3 alkyl or C1-C3 deuterinated alkyl;

[0540] R 12 and R 13 Each is independently H or C1-C3 alkyl, or R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens.

[0541] E118: In embodiment E111, a compound of the following formula (IA-11a), (IA-11b), or (IA-11c) or a pharmaceutically acceptable salt thereof:

[0542] (IA-11a)

[0543] (IA-11b)

[0544] (IA-11c)

[0545] In the above formula,

[0546] R 3A is a C1-C3 alkyl or C3-C4 cycloalkyl optionally substituted with 1 to 3 halogens, preferably R 3A is -CH2CH3, -CH2CF3, -CH(CH3)2 or C3-C4 cycloalkyl;

[0547] R 3B is a halogen, and preferably R 3B is F and;

[0548] R 3C is a halogen, and preferably R 3C is F and;

[0549] R 5 and R 6 Each is independently H or C1-C3 alkyl, preferably H, -CH3, or -CH2CH3;

[0550] R 7silver

[0551] C1-C3 alkyl,

[0552] A C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens or C1-C3 alkyls, and

[0553] -NR 8 R 9

[0554] Selected from a group consisting of;

[0555] Preferably R 7 is -CH3, -CH2CH3, -CH(CH3)2, cyclopropyl, cyclopropyl substituted with -CH3, -NH2, -N((CH)3)2, -N(CH3)(CH2CH3), or azetidine optionally substituted with 1, 2, or 3 Fs;

[0556] R 10 is H or C1-C3 alkyl, preferably R 10 is H;

[0557] R 11 is a C1-C3 alkyl or a C1-C3 deuterinated alkyl;

[0558] R 12 and R 13 Each is a compound that is a C1-C3 alkyl or a pharmaceutically acceptable salt thereof.

[0559] E119: In embodiment E118, having the chemical formula (IA-11a), R 3A A compound that is -CH2CF3, preferably CH2CF3, or a pharmaceutically acceptable salt thereof.

[0560] E120: In embodiment E118, having the chemical formula (IA-11b) or (IA-11c), R 3A is -CH2CH3, cyclopropyl, or cyclobutyl, and R 3B is F, and R 3C is a compound of F or a pharmaceutically acceptable salt thereof.

[0561] E121: In any one of embodiments E117 to E120, R 5 and R 6 Each is a compound of H or a pharmaceutically acceptable salt thereof.

[0562] E122: In any one of embodiments E117 to E120, R 5 and R 6 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0563] E123: In any one of embodiments E117 to E120, R 5 and R 6 One of them is H and R 5 and R 6 The other one is a compound that is -CH3 or a pharmaceutically acceptable salt thereof.

[0564] E124: In any one of embodiments E117 to E123, R 10 A compound that is H or a pharmaceutically acceptable salt thereof.

[0565] E125: In any one of embodiments E117 to E124, R 11 , R 12 and R 13 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0566] E126: In any one of embodiments E117 to E124, R 11 is -CD3 and R 12 and R 13 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0567] E127: In any one of embodiments E117 to E126, R 7 A compound that is -CH3 or -N((CH)3)2 or a pharmaceutically acceptable salt thereof.

[0568] E128: In embodiment E117, the following compound or pharmaceutically acceptable salt thereof:

[0569]

[0570] .

[0571] E129: In embodiment E117, the compound or pharmaceutically acceptable salt thereof which is the following compound:

[0572] .

[0573] E130: In embodiment E117, a compound that is the following compound or a pharmaceutically acceptable salt thereof:

[0574] .

[0575] E131: In embodiment E24, a compound of the following formula (IA-12) or a pharmaceutically acceptable salt thereof:

[0576] (IA-12)

[0577] In the above formula,

[0578] m is 0 or 1 and;

[0579] n is 1 or 2 and;

[0580] Each R 3 silver

[0581] halogen,

[0582] C1-C6 alkyl optionally substituted with 1 to 3 halogens, and

[0583] C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens

[0584] Independently selected from a group consisting of;

[0585] R 5 and R 6 Each is independently a C1-C3 alkyl group optionally substituted with H, a halogen, or 1 to 3 halogens;

[0586] R 7 silver

[0587] C1-C3 alkyl,

[0588] C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens or C1-C3 alkyl optionally substituted with 1 to 3 halogens, and

[0589] -NR 8 R 9 (At this time, R 8 and R 9 Each is independently H or C1-C3 alkyl, or R 8 and R 9 (together forming a 4 or 5-membered N-containing heterocycloalkyl ring optionally substituted with 1 to 4 halogens)

[0590] Selected from a group consisting of;

[0591] R 10 is H or a halogen;

[0592] R 11 is H, C1-C3 alkyl or C1-C3 deuterinated alkyl;

[0593] R 12 and R 13 Each is independently H or C1-C3 alkyl, or R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens.

[0594] E132: In embodiment E131, a compound of the following formula (IA-12a) or (IA-12b) or a pharmaceutically acceptable salt thereof:

[0595] (IA-12a)

[0596] (IA-12b)

[0597] In the above formula,

[0598] R3A is a C1-C3 alkyl or C3-C4 cycloalkyl, preferably R 3A is -CH2CH3, -CH(CH3)2, or C3-C4 cycloalkyl;

[0599] R 3B is a halogen, and preferably R 3B is F and;

[0600] R 5 and R 6 Each is independently H or C1-C3 alkyl, preferably R 5 and R 6 Each is independently H, -CH3, or -CH2CH3;

[0601] R 7 C1-C3 alkyl,

[0602] A C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens or C1-C3 alkyls, and

[0603] -NR 8 R 9

[0604] Selected from the group consisting of, preferably R 7 is azetidine substituted with -CH3, -CH2CH3, -CH(CH3)2, -CH3, -NH2, -N((CH)3)2, -N(CH3)(CH2CH3), or 1, 2, or 3 F groups;

[0605] R 10 is H or a halogen, preferably R 10 is H or F;

[0606] R 11 is H or C1-C3 alkyl;

[0607] R 12 and R 13 are each C1-C3 alkyl, or R 12 and R 13 It forms a C3-C6 cycloalkyl group optionally substituted with 1 to 3 halogens.

[0608] E133: In embodiment E132, R 3A -CH2CH 3이고 R 3B is a compound of F or a pharmaceutically acceptable salt thereof.

[0609] E134: In embodiment E132, R 3A is cyclopropyl or cyclobutyl, preferably R 3A is cyclobutyl, and R 3B is a compound of F or a pharmaceutically acceptable salt thereof.

[0610] E135: In any one of embodiments E131 to E134, R 5 and R 6 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0611] E136: In any one of embodiments E131 to E135, R 10 A compound that is F or a pharmaceutically acceptable salt thereof.

[0612] E137: In any one of embodiments E131 to E136, R 11 A compound that is H or a pharmaceutically acceptable salt thereof.

[0613] E138: In any one of embodiments E131 to E137, R 12 and R 13 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0614] E139: In any one of embodiments E131 to E137, R 12 and R 13 A compound that forms cyclobutyl together with or a pharmaceutically acceptable salt thereof.

[0615] E140: In any one of embodiments E131 to E137, R 12 and R 13A compound that forms a cyclopentyl together with a pharmaceutically acceptable salt thereof.

[0616] E141: In embodiment E131 or E140, R 7 A compound that is -CH3, -CH2CH3, -CH(CH3)2, cyclopropyl, -CH3-substituted cyclopropyl, -N((CH)3)2, -N(CH3)(CH2CH3), or optionally substituted with 1, 2, or 3 Fs, or a pharmaceutically acceptable salt thereof.

[0617] E142: In embodiment E131, the following compound or pharmaceutically acceptable salt thereof:

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626] .

[0627] E143: In embodiment E131, the following compound or pharmaceutically acceptable salt thereof:

[0628] .

[0629] E144: In embodiment E131, the following compound or pharmaceutically acceptable salt thereof:

[0630] .

[0631] E145: In embodiment E24, a compound having the following chemical formulas (IA-13), (IA-14), (A-15), (A-16) or (IA-17) or a pharmaceutically acceptable salt thereof:

[0632] (IA-13)

[0633] (IA-14)

[0634] (IA-15)

[0635] (IA-16)

[0636] (IA-17)

[0637] In the above formula,

[0638] m is 0 or 1 and;

[0639] n is 1 or 2 and;

[0640] Each R 3 It is independently selected from the group consisting of a halogen, a C1-C6 alkyl optionally substituted with 1 to 3 halogens, and a C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens;

[0641] R 5 and R 6 Each is independently a C1-C3 alkyl group optionally substituted with (H), a halogen, or 1 to 3 halogens;

[0642] R 7 C1-C3 alkyl, C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens or C1-C3 alkyl optionally substituted with 1 to 3 halogens, and -NR 8 R 9 (At this time, R 8 and R 9 Each is independently (H) or C1-C3 alkyl, or R 8 and R 9Selected from the group consisting of (forming a 4-5-membered N-containing heterocycloalkyl ring optionally substituted with 1 to 4 halogens together);

[0643] R 10 is H or a halogen;

[0644] R 11 is H, C1-C3 alkyl or C1-C3 deuterinated alkyl;

[0645] R 12 and R 13 Each is independently (H) or C1-C3 alkyl, or R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens.

[0646] E146: In embodiment E145, a compound of the following formula (IA-13a), (IA-14a), (IA-15a), (IA-16a) or (IA-17a) or a pharmaceutically acceptable salt thereof:

[0647] (IA-13a)

[0648] (IA-14a)

[0649] (IA-15a)

[0650] (IA-16a)

[0651] (IA-17a)

[0652] In the above formula,

[0653] R 3A is a C1-C3 alkyl or C3-C4 cycloalkyl, preferably R 3A is -CH2CH3, -CH(CH3)2, or C3-C4 cycloalkyl;

[0654] R 3B is a halogen, and preferably R3B is F and;

[0655] R 5 and R 6 Each is independently (H) or C1-C3 alkyl, preferably R 5 and R 6 Each is independently (H), -CH3, or -CH2CH3;

[0656] R 7 silver

[0657] C1-C3 alkyl,

[0658] A C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens or C1-C3 alkyls, and

[0659] -NR 8 R 9

[0660] Selected from a group consisting of;

[0661] Preferably R 7 is -CH3, -CH2CH3, -CH(CH3)2, cyclopropyl, cyclopropyl substituted with -CH3, -NH2, -N((CH)3)2, -N(CH3)(CH2CH3), or azetidine optionally substituted with 1, 2, or 3 Fs;

[0662] R 10 is H or a halogen, preferably R 10 is H or F;

[0663] R 11 is H or C1-C3 alkyl;

[0664] R 12 and R 13 are each H or C1-C3 alkyl, or R 12 and R 13 It forms a C3-C6 cycloalkyl group optionally substituted with 1 to 3 halogens.

[0665] E147: In embodiment E146, R 3A is cyclobutyl and R 3Bis a compound of F or a pharmaceutically acceptable salt thereof.

[0666] E148: In any one of embodiments E145 to E147, R 5 and R 6 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0667] E149: In any one of embodiments E145 to E148, R 10 A compound that is H or a pharmaceutically acceptable salt thereof.

[0668] E150: In any one of embodiments E145 to E148, R 10 A compound that is F or a pharmaceutically acceptable salt thereof.

[0669] E151: In any one of embodiments E145 to E150, R 11 A compound that is H or a pharmaceutically acceptable salt thereof.

[0670] E152: In any one of embodiments E145 to E151, R 12 and R 13 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0671] E153: In any one of embodiments E145 to E151, R 12 and R 13 Each is a compound of H or a pharmaceutically acceptable salt thereof.

[0672] E154: In embodiment E145, the following compound or pharmaceutically acceptable salt thereof:

[0673]

[0674]

[0675]

[0676] .

[0677] E155: In embodiment E1 or E2, a compound of the following formula (IB) or a pharmaceutically acceptable salt thereof:

[0678] (IB)

[0679] In the above formula,

[0680] R 1 and R 2 One of them is H and R 1 and R 2 The other one is a group of the following chemical formula (E1-1) or (E2-1);

[0681] R 4 is a group of the chemical formula (E4-1), (E4-2), (E4-3), (E4-4), (E4-5) or (E4-6):

[0682]

[0683] In the above formula,

[0684] dashed line represents the attachment point for connector L;

[0685] R 10 is a C1-C3 alkyl optionally substituted with H, a halogen, -OH, -CN, or 1 to 3 halogens, wherein R 10 This R 4 When adjacent to ring N, R 10 It is not OH or a halogen;

[0686] R 11 is a C1-C3 alkyl, C2-C3 hydroxyalkyl, or C1-C3 deuterinated alkyl optionally substituted with H, 1 to 3 halogens;

[0687] R 12 and R 13 Each is a C1-C3 alkyl group independently substituted with H, a halogen, or 1 to 3 halogens, wherein R 12 and R 13 This R 4 When adjacent to ring N, R 12 and R 13is not a halogen or;

[0688] R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens;

[0689] R 12 and R 13 ... comprises one or more heteroatoms selected from the group consisting of N, O, and S, and forms a 3 to 6-membered heterocycloalkyl optionally substituted with (i) 1 to 3 halogens, or (ii) a C1-C3 alkyl optionally substituted with 1 to 3 halogens, wherein R 12 and R 13 This R 4 When adjacent to ring N and forming a 3 to 6-membered heterocycloalkyl, the 3 to 6-membered heterocycloalkyl is formed by R of the heteroatom 4 It is not attached to the ring.

[0690] E156: In embodiment E155, a compound of the following formula (IB-1) or (IB-2) or a pharmaceutically acceptable salt thereof:

[0691] (IB-1)

[0692] (IB-2)

[0693] In the above formula,

[0694] m is 0 or 1 and;

[0695] n is 1 or 2 and;

[0696] Each R 3 is independently

[0697] halogen,

[0698] C1-C6 alkyl optionally substituted with 1 to 3 halogens, and

[0699] C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens

[0700] Selected from a group consisting of;

[0701] R 5 and R 6 Each is independently a C1-C3 alkyl group optionally substituted with H, a halogen, or 1 to 3 halogens;

[0702] R in the chemical formula (IB-1) 10 is H or C1-C3 alkyl, and in the chemical formula (IB-2), R 10 is H or a halogen;

[0703] R 11 is H or C1-C3 alkyl;

[0704] R 12 and R 13 Each is independently H or C1-C3 alkyl, or R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens.

[0705] E157: In embodiment E156, a compound of the following formula (IB-1a) or (IB-2a) or a pharmaceutically acceptable salt thereof:

[0706] (IB-1a)

[0707] (IB-2a)

[0708] In the above formula,

[0709] R 3A is a C1-C6 alkyl or C3-C4 cycloalkyl, preferably R 3A is -CH2CH3, -CH(CH3)2, or C3-C4 cycloalkyl;

[0710] R 3B is a halogen, and preferably R 3B is F and;

[0711] R 5 and R 6 Each is independently H or C1-C3 alkyl, preferably R 5 and R 6 Each is independently H, -CH3, or -CH2CH3;

[0712] In the chemical formula (IB-1a),

[0713] R 10 is H or C1-C3 alkyl, preferably R 10 is H;

[0714] R 11 , R 12 and R 13 Each is a C1-C3 alkyl;

[0715] In the chemical formula (IB-2a),

[0716] R 10 is H or a halogen, preferably R 10 is H or F;

[0717] R 11 is H or C1-C3 alkyl;

[0718] R 12 and R 13 are each C1-C3 alkyl, or R 12 and R 13 It forms a C3-C6 cycloalkyl group optionally substituted with 1 to 3 halogens.

[0719] E158: In embodiment E157, R 3A is cyclobutyl and R 3B is a compound of F or a pharmaceutically acceptable salt thereof.

[0720] E159: In any one of embodiments E156 to E158, R 5 and R 6 Each is a compound of H or a pharmaceutically acceptable salt thereof.

[0721] E160: In any one of embodiments E156 to E159, R 10 is H and R 11 A compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0722] E161: In any one of embodiments E156 to E160, R 12 and R 13 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0723] E162: In any one of embodiments E156 to E159, having the chemical formula (IB-2a), and R 10 is F, and R 11 is H, and R 12 and R 13 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0724] E163: In any one of embodiments E156 to E159, having the chemical formula (IB-2a), and R 10 is F, and R 11 is H, and R 12 and R 13 A compound that forms cyclobutyl or cyclopentyl together, or a pharmaceutically acceptable salt thereof.

[0725] E164: In embodiment E156, the following compound or pharmaceutically acceptable salt thereof:

[0726] ; or .

[0727] E165: In embodiment E155, a compound of the following formula (IB-3) or (IB-4) or a pharmaceutically acceptable salt thereof:

[0728] (IB-3)

[0729] (IB-4)

[0730] In the above formula,

[0731] m is 0 or 1 and;

[0732] n is 1 or 2 and;

[0733] Each R 3 halogen,

[0734] C1-C6 alkyl optionally substituted with 1 to 3 halogens, and

[0735] C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens

[0736] Independently selected from a group consisting of;

[0737] R 5 and R 6 Each is independently a C1-C3 alkyl group optionally substituted with H, a halogen, or 1 to 3 halogens;

[0738] R in the chemical formula (IB-3) 10 is H or C1-C3 alkyl, and in the chemical formula (IB-4), R 10 is H or a halogen;

[0739] R 11 is H or C1-C3 alkyl;

[0740] R 12 and R 13 Each is independently H or C1-C3 alkyl, or R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens.

[0741] E166: In embodiment E165, a compound of the following formula (IB-3a), (IB-3b), (IB-3c) or (IB-4a) or a pharmaceutically acceptable salt thereof:

[0742] (IB-3a)

[0743] (IB-3b)

[0744] (IB-3c)

[0745] (IB-4a)

[0746] (IB-4b)

[0747] In the above formula,

[0748] R 3A is a C1-C6 alkyl or C3-C4 cycloalkyl, preferably R 3A is -CH2CH3, -CH(CH3)2, or C3-C4 cycloalkyl;

[0749] R 3B is a halogen, and preferably R 3B is F and;

[0750] R 5 and R 6 Each is independently H or C1-C3 alkyl, preferably R 5 and R 6 Each is independently H, -CH3, or -CH2CH3;

[0751] In chemical formulas (IB-3a), (IB-3b), and (IB-3c),

[0752] R 10 It is H or C1-C3 alkyl, preferably H;

[0753] R 11 , R 12 and R 13 Each is a C1-C3 alkyl;

[0754] In chemical formulas (IB-4a) and (IB-4b),

[0755] R 10 is H or a halogen, preferably R 10 is H or F;

[0756] R 11 is H or C1-C3 alkyl;

[0757] R 12 and R 13 are each C1-C3 alkyl, or R12 and R 13 It forms a C3-C6 cycloalkyl group optionally substituted with 1 to 3 halogens.

[0758] E167: In embodiment E166, R 3A is cyclobutyl and R 3B is a compound of F or a pharmaceutically acceptable salt thereof.

[0759] E168: In any one of embodiments E165 to E167, R 5 and R 6 Each is a compound of H or a pharmaceutically acceptable salt thereof.

[0760] E169: In any one of embodiments E165 to E167, R 5 and R 6 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0761] E170: In any one of embodiments E165 to E169, R 10 is H and R 11 A compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0762] E171: In any one of embodiments E165 to E170, R 12 and R 13 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0763] E172: In any one of embodiments E165 to E169, having the chemical formula (IB-4a) or (IB-4b), R 10 is F, and R 11 is H, and R 12 and R 13 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0764] E173: In any one of embodiments E165 to E169, having the chemical formula (IB-4a) or (IB-4b), R10 is F, and R 11 is H, and R 12 and R 13 A compound that forms together with cyclobutyl or cyclopentyl, preferably cyclobutyl, or a pharmaceutically acceptable salt thereof.

[0765] E174: In embodiment E165, the following compound or pharmaceutically acceptable salt thereof:

[0766] .

[0767] E175: In embodiment E1 or E2, a compound of the following formula (IC) or a pharmaceutically acceptable salt thereof:

[0768] (IC)

[0769] In the above formula,

[0770] R 1 is a group of the chemical formula (E1-1) or (E2-1);

[0771] R 4 is a group of the chemical formula (E4-1), (E4-2), (E4-3), (E4-4), (E4-5) or (E4-6):

[0772]

[0773] In the above formula,

[0774] dashed line represents the attachment point for connector L;

[0775] R 10 is a C1-C3 alkyl optionally substituted with H, a halogen, -OH, -CN, or 1 to 3 halogens, wherein R 10 This R 4 When adjacent to ring N, R 10 It is not -OH or a halogen;

[0776] R 11is a C1-C3 alkyl, C2-C3 hydroxyalkyl, or C1-C3 deuterinated alkyl optionally substituted with H, 1 to 3 halogens;

[0777] R 12 and R 13 Each is a C1-C3 alkyl group independently substituted with H, a halogen, or 1 to 3 halogens, wherein R 12 and R 13 This R 4 When adjacent to ring N, R 12 and R 13 is not a halogen or;

[0778] R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens;

[0779] R 12 and R 13 ... comprises one or more heteroatoms selected from the group consisting of N, O, and S, and forms a 3 to 6-membered heterocycloalkyl optionally substituted with (i) 1 to 3 halogens, or (ii) a C1-C3 alkyl optionally substituted with 1 to 3 halogens, provided that R 12 and R 13 This R 4 When forming a 3 to 6-membered heterocycloalkyl group adjacent to the ring N of, the 3 to 6-membered heterocycloalkyl group is formed by R of the heteroatom 4 It is not attached to the ring.

[0780] E176: In embodiment E175, a compound of the following formula (IC-1) or formula (IC-2) or a pharmaceutically acceptable salt thereof:

[0781] (IC-1)

[0782] (IC-2)

[0783] In the above formula,

[0784] n is 1 or 2 and;

[0785] Each R 3 halogen,

[0786] C1-C6 alkyl optionally substituted with 1 to 3 halogens, and

[0787] C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens

[0788] Independently selected from a group consisting of;

[0789] R 5 and R 6 Each is independently a C1-C3 alkyl group optionally substituted with H, a halogen, or 1 to 3 halogens;

[0790] R in the chemical formula (IC-1) 10 is H or C1-C3 alkyl, and in the chemical formula (IC-2), R 10 is H or a halogen;

[0791] R 11 is H or C1-C3 alkyl;

[0792] R 12 and R 13 Each is independently H or C1-C3 alkyl, or R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens.

[0793] E177: In embodiment E176, a compound of the following formula (IC-1a) or formula (IC-2a) or a pharmaceutically acceptable salt thereof:

[0794] (IC-1a)

[0795] (IC-2a)

[0796] In the above formula,

[0797] R 3A is a C1-C6 alkyl or C3-C4 cycloalkyl, preferably R 3A is -CH2CH3, -CH(CH3)2, or C3-C4 cycloalkyl;

[0798] R 3B is a halogen, and preferably R 3B is F and;

[0799] R 5 and R 6 Each is independently H or C1-C3 alkyl, preferably R 5 and R 6 Each is independently H, -CH3, or -CH2CH3;

[0800] R in the chemical formula (IC-1a) 10 is H or C1-C3 alkyl, preferably R in formula (IC-1a). 10 is H, and in the chemical formula (IC-2a), R 10 is H or a halogen, preferably R in the chemical formula (IC-2a). 10 is F and;

[0801] R 11 It is 1-C3 alkyl;

[0802] R 12 and R 13 are each C1-C3 alkyl, or R 12 and R 13 It forms a C3-C6 cycloalkyl group together.

[0803] E178: In embodiment E177, R 3A is cyclobutyl and R 3B is a compound of F or a pharmaceutically acceptable salt thereof.

[0804] E179: In any one of embodiments E176 to E178, R 5 and R 6 Each is a compound of H or a pharmaceutically acceptable salt thereof.

[0805] E180: In any one of embodiments E176 to E178, R 5 and R 6 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0806] E181: In any one of embodiments E176 to E180, in the chemical formula (IC-1a), R 10 is H and R 11 is -CH3, and in the chemical formula (IC-2a), R 10 is F and R 11 A compound that is H or a pharmaceutically acceptable salt thereof.

[0807] E182: In any one of embodiments E176 to E181, R 12 and R 13 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0808] E183: In embodiment E176, the following compound or pharmaceutically acceptable salt thereof:

[0809] .

[0810] E184: In embodiment (E175), a compound of the following formula (IC-3) or formula (IC-4) or a pharmaceutically acceptable salt thereof:

[0811] (IC-3)

[0812] (IC-4)

[0813] In the above formula,

[0814] n is 1 or 2 and;

[0815] Each R 3 It is independently selected from the group consisting of a halogen, a C1-C6 alkyl optionally substituted with 1 to 3 halogens, and a C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens;

[0816] R5 and R 6 Each is independently a C1-C3 alkyl group optionally substituted with (H), a halogen, or 1 to 3 halogens;

[0817] R 7 C1-C3 alkyl, C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens or C1-C3 alkyl optionally substituted with 1 to 3 halogens, and -NR 8 R 9 (At this time, R 8 and R 9 Each is independently (H) or C1-C3 alkyl, or R 8 and R9 are selected from the group consisting of (forming a 4-5-membered N-containing heterocycloalkyl ring optionally substituted with 1 to 4 halogens together);

[0818] R in the chemical formula (IC-3) 10 is H or C1-C3 alkyl, and R in chemical formula (IC-4) 10 is H or a halogen;

[0819] R 11 is H or C1-C3 alkyl;

[0820] R 12 and R 13 Each is independently (H) or C1-C3 alkyl, or R 12 and R 13 Together, they form (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens.

[0821] E185: In embodiment E184, a compound of the following formula (IC-3a) or (IC-4a) or a pharmaceutically acceptable salt thereof:

[0822] (IC-3a)

[0823] (IC-4a)

[0824] In the above formula,

[0825] R 3A is a C1-C6 alkyl or C3-C4 cycloalkyl, preferably R 3A is -CH2CH3, -CH(CH3)2, or C3-C4 cycloalkyl;

[0826] R 3B is a halogen, and preferably R 3B is F and;

[0827] R 5 and R 6 Each is independently H or C1-C3 alkyl, preferably R 5 and R 6 Each is independently H, -CH3, or -CH2CH3;

[0828] R 7 silver

[0829] C1-C3 alkyl,

[0830] A C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens or C1-C3 alkyls, and

[0831] -NR 8 R 9

[0832] Selected from the group consisting of, preferably R 7 is -CH3, -CH2CH3, -CH(CH3)2, cyclopropyl, cyclopropyl substituted with -CH3, -NH2, -N((CH)3)2, -N(CH3)(CH2CH3), or azetidine optionally substituted with 1, 2, or 3 Fs;

[0833] R in the chemical formula (IC-3a) 10 is H or C1-C3 alkyl, preferably R in formula (IC-3a). 10 is H, and in the chemical formula (IC-4a), R 10 is H or a halogen, preferably R in the chemical formula (IC-4a). 10 is F and;

[0834] R 11is H or C1-C3 alkyl;

[0835] R 12 and R 13 are each C1-C3 alkyl, or R 12 and R 13 They together form a C3-C6 cycloalkyl group.

[0836] E186: In embodiment E185, R 3A is cyclobutyl and R 3B is a compound of F or a pharmaceutically acceptable salt thereof.

[0837] E187: In any one of embodiments E184 to E178, R 5 and R 6 Each is a compound of H or a pharmaceutically acceptable salt thereof.

[0838] E188: In any one of embodiments E184 to E178, R 5 and R 6 Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0839] E189: In any one of embodiments E184 to E178, R 5 and R 6 One of them is H and R 5 and R 6 The other one is a compound that is -CH3 or a pharmaceutically acceptable salt thereof.

[0840] E190: In any one of embodiments E184 to E181, in the chemical formula (IC-3a), R 10 is H and R 11 is -CH3, and in the chemical formula (IC-4a), R 10 is F and R 11 A compound that is H or a pharmaceutically acceptable salt thereof.

[0841] E191: In any one of embodiments E184 to E182, R 12 and R 13Each is a compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0842] E192: In any one of embodiments E184 to E183, R 7 A compound having -CH3 or a pharmaceutically acceptable salt thereof.

[0843] E193: In embodiment E184, the following compound or pharmaceutically acceptable salt thereof:

[0844]

[0845] .

[0846] E194: Compound of the following chemical formula (I') or a pharmaceutically acceptable salt thereof:

[0847] (I')

[0848] In the above formula,

[0849] Ring A is phenyl, or a 5 or 6-membered N-containing heteroaryl consisting of 1 or 2 N atoms and carbon atoms as ring members;

[0850] y is 0 when ring A is a 5 or 6-membered N-containing heteroaryl consisting of 2 N atoms and carbon atoms as ring members; y is 1 when ring A is a 5 or 6-membered N-containing heteroaryl consisting of 1 N atom and carbon atoms as ring members; and y is 2 when ring A is phenyl;

[0851] L is a linker of the following chemical formula and:

[0852] ;

[0853] The asterisk * indicates the attachment point for ring A, and the dashed line is R 4 Indicates the attachment point for;

[0854] z is 0 or 1 and;

[0855] q is 0, 1, or 2, and;

[0856] Each Q is independently -D, -OH, -CH3, or a halogen;

[0857] Ring B is a C3-C6 cycloalkyl;

[0858] Each R 1' is independently H or D;

[0859] R 1 and R 2 One of them is H, D, or a halogen, and R 1 and R 2 The other one is a group of the following chemical formulas (E1-1), (E1-2), (E1-3), (E2-1), (E2-2) or (E3-1):

[0860]

[0861] In the above formula,

[0862] Each asterisk * indicates an attachment point for ring A;

[0863] m is 0 or 1 and;

[0864] R 5 and R 6 Each is independently (i) H, (ii) a halogen, (iii) a C1-C6 alkyl optionally substituted with 1 to 3 halogens and 1 to 3 -OH groups, (iv) a C1-C6 deuterated alkyl, (v) a C2-C6 alkenyl, or (iii) a C2-C6 alkynyl;

[0865] R 5 and R 6 are each D or;

[0866] R 5 and R 6 Together, they form a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O, and S;

[0867] R 7 silver

[0868] C1-C6 alkyl optionally substituted with 1 to 3 halogens,

[0869] C1-C6 deuterated alkyl optionally substituted with 1 to 3 halogens,

[0870] Optionally deuterated and (i) a C1-C3 alkyl optionally substituted with 1 to 4 halogens, (ii) a C1-C3 alkyl optionally substituted with 1 to 3 halogens, or (iii) a C3-C5 cycloalkyl optionally substituted with a C1-C3 deuterated alkyl optionally substituted with 1 to 3 halogens, and

[0871] -NR 8 R 9 (At this time, R 8 and R 9 Each is independently H, a C1-C6 alkyl or a C1-C6 deuterated alkyl, or R 8 and R 9 Selected from the group consisting of (forming a 4 to 6-membered N-containing heterocycloalkyl ring optionally substituted with 1 to 4 halogens together);

[0872] Ring C1 is a 5- or 6-membered N-containing heteroaryl optionally substituted with one group selected from (i) C1-C3 alkyl optionally substituted with 1 to 4 halogens, (ii) C2-C3 hydroxyalkyl, and (iii) C3-C4 cycloalkyl, and any substituent of ring C1 is optionally deuterated;

[0873] Ring C2 is a 5- or 6-membered N-containing heterocyclic ring optionally substituted with one group selected from (i) C1-C3 alkyl optionally substituted with 1 to 4 halogens, (ii) C2-C3 hydroxyalkyl, and (iii) C3-C4 cycloalkyl, and any substituent of ring C2 is optionally deuterated;

[0874] n is 0, 1, or 2, and n' is 3, 4, or 5, where n + n' is 5;

[0875] Each R3 is independently selected from the group consisting of (i) halogen, (ii) C1-C6 alkyl optionally substituted with 1 to 3 halogens, (iii) C1-C6 deuterated alkyl optionally substituted with 1 to 3 halogens, (iv) C2-C6 alkenyl, (v) C2-C6 alkynyl, and (vi) C3-C6 cycloalkyl optionally deuterated and optionally substituted with 1 to 4 halogens;

[0876] Each R 3' is independently H or D;

[0877] R 4 Is

[0878] -D,

[0879] halogen,

[0880] -OH,

[0881] -CN,

[0882] C1-C3 alkyl optionally substituted with 1 to 3 halogens,

[0883] C1-C3 deuterinated alkyl optionally substituted with 1 to 3 halogens,

[0884] Optionally deuterated and (i) 1 to 3 halogens, (ii) a C1-C3 alkyl optionally substituted with 1 to 3 halogens, or (iii) a spirocyclic C3-C6 cycloalkyl optionally substituted with a C1-C3 deuterated alkyl, and

[0885] A spirocyclic 3 to 6-membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O, and S (wherein the spirocyclic 3 to 6-membered heterocycloalkyl is optionally deuterated and optionally substituted with (i) 1 to 3 halogens, (ii) a C1-C3 alkyl optionally substituted with 1 to 3 halogens, or (iii) a C1-C3 deuterated alkyl).

[0886] It is a 3 to 6-membered N-containing heterocycloalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of;

[0887] The attachment point for linker L is on the carbon atom.

[0888] E195: In embodiment E194, a compound of formula (II') or a pharmaceutically acceptable salt thereof:

[0889] (II')

[0890] In the above formula,

[0891] Y is N or CR 1' and, preferably, Y is CR 1' And;

[0892] L is a connector selected from the group consisting of L1', L2' and L3', preferably L is connector L1':

[0893] (L1')

[0894] (L2')

[0895] (L3')

[0896] In the above formula,

[0897] The asterisk * indicates the attachment point for ring A, and the dashed line is R 4 Indicates the attachment point for;

[0898] R 4 is a group of the chemical formula (E4-1), (E4-2), (E4-3), (E4-4), (E4-5), (E4-6), (E5-1), (E5-2), (E5-3), (E5-4), (E5-5), (E5-6), (E5-7), (E5-8) or (E5-9):

[0899]

[0900] In the above formula,

[0901] dashed line represents the attachment point for connector L;

[0902] R 10 is (i) H, (ii) D, (iii) halogen, (iv) -OH, (v) -CN, (vi) C1-C3 alkyl optionally substituted with 1 to 3 halogens, (vii) C1-C3 deuterinated alkyl optionally substituted with 1 to 3 halogens, wherein R 10 This R 4 When adjacent to ring N, R 10 It is not OH or a halogen;

[0903] R 11 is (i) H, (ii) a C1-C3 alkyl optionally substituted with 1 to 3 halogens, (iii) a C1-C3 deuterinated alkyl, or (iv) a C2-C3 hydroxyalkyl;

[0904] R 12 and R 13 Each is independently (i) H, (ii) a halogen, (iii) a C1-C3 alkyl optionally substituted with 1 to 3 halogens, or (iv) a C1-C3 deuterinated alkyl, wherein R 12 and R 13 This R 4 When adjacent to ring N, R 12 and R 13 is not a halogen or;

[0905] R 12 and R 13 are each D or;

[0906] R 12 and R 13 ...are optionally deuterated together to form (i) 1 to 3 halogens, (ii) a C1-C3 alkyl optionally substituted with 1 to 3 halogens, or (iii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 deuterated alkyl;

[0907] R 12 and R 13... comprises one or more heteroatoms selected from the group consisting of N, O, and S, optionally deuterided to form a 3 to 6-membered heterocycloalkyl optionally substituted with (i) 1 to 3 halogens, (ii) a C1-C3 alkyl optionally substituted with 1 to 3 halogens, or (iii) a C1-C3 deuteridated alkyl optionally substituted, wherein R 12 and R 13 This R 4 When adjacent to ring N and forming a 3 to 6-membered heterocycloalkyl, the 3 to 6-membered heterocycloalkyl is formed by R of the heteroatom 4 It is not attached to the ring.

[0908] E196: In embodiment E194 or E195, the following compound or pharmaceutically acceptable salt thereof:

[0909] R 1 and R 2 One of them is H, D, or a halogen, and R 1 and R 2 The other one is a group of the following chemical formulas (E1-1), (E1-2a), (E1-2b), (E1-3), (E2-1), (E2-2a), (E2-2b) or (E3-1a):

[0910]

[0911] In the above formula,

[0912] Each asterisk * is R 1 and R 2 Indicates the attachment point for the other ring A;

[0913] m is 0 or 1 and;

[0914] R 5 and R 6 Each is independently (i) H, (ii) halogen, (iii) C1-C6 alkyl optionally substituted with 1 to 3 halogens and 1 to 3 -OH groups, (iv) C1-C3 deuterinated alkyl, (v) C2-C6 alkenyl, (vi) C2-6 Alkynyl or;

[0915] R 5 and R 6 are both D or;

[0916] R 5 and R 6 Together, they form a C3-C6 cycloalkyl or a 4 to 6-membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O, and S;

[0917] R 7 silver

[0918] C1-C3 alkyl optionally substituted with 1 to 3 halogens,

[0919] C1-C3 deuterinated alkyl optionally substituted with 1 to 3 halogens,

[0920] Optionally deuterated and (i) a C1-C3 alkyl optionally substituted with 1 to 4 halogens, (ii) a C1-C3 alkyl optionally substituted with 1 to 3 halogens, or (iii) a C3-C4 cycloalkyl optionally substituted with a C1-C3 deuterated alkyl optionally substituted with 1 to 3 halogens, and

[0921] -NR 8 R 9 (At this time, R 8 and R 9 Each is independently H, a C1-C6 alkyl or a C1-C6 deuterated alkyl, or R 8 and R 9 (together forming a 4 to 6-membered N-containing heterocycloalkyl ring optionally substituted with 1 to 4 halogens)

[0922] Selected from a group consisting of;

[0923] R 7Ais (i) H, (ii) C1-C3 alkyl optionally substituted with 1 to 3 halogens, (iii) C1-C3 deuterated alkyl, (iv) C2-C3 hydroxyalkyl, or (v) C3-C4 cycloalkyl, wherein the C3-C4 cycloalkyl is optionally deuterated.

[0924] E197: In any one of embodiments E194 to E196, the following compound or pharmaceutically acceptable salt thereof:

[0925] One or more R 3 is present and selected from (i) C1-C6 alkyl, (ii) C1-C6 deuterated alkyl optionally substituted with 1 to 3 halogens, and (iii) C3-C6 cycloalkyl optionally deuterated and optionally substituted with 1 to 4 halogens, preferably one or more R 3 The is present and is selected from (i) C1-C3 alkyl, (ii) C1-C3 deuterinated alkyl optionally substituted with 1 to 3 halogens, and (iii) C3-C4 cycloalkyl optionally deuterinated and optionally substituted with 1 to 4 halogens.

[0926] Any compound or pharmaceutically acceptable salt thereof described in any one of embodiments E31, E38, E47, E54, E61, E69, E76, E83, E92-E100, E112-E116, E128-E130, E142-E144, E154, E164, E174, E183, and E193 may be claimed individually or grouped together with one or more other compounds or pharmaceutically acceptable salts thereof of embodiments E31, E38, E47, E54, E61, E69, E76, E83, E92-E100, E112-E116, E128-E130, E142-E144, E154, E164, E174, E183, and E193.

[0927] E198: A pharmaceutical composition comprising any one of the compounds of embodiments E1 to E197 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0928] E199: A method for treating cancer, comprising the step of administering a therapeutically effective amount of any one of the compounds of embodiments E1 to E197 or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0929] E200: A method for treating cancer, comprising the step of administering a therapeutically effective amount of any one of the compounds of embodiments E1 to E197 or a pharmaceutically acceptable salt thereof as a single preparation to a subject in need thereof.

[0930] E201: A method for treating cancer, comprising the step of administering a therapeutically effective amount of any one of the compounds of embodiments E1 to E197 or a pharmaceutically acceptable salt thereof to a subject requiring the treatment, and further comprising the step of administering a therapeutically effective amount of an additional anticancer agent.

[0931] E202: A method in any one of embodiments E199 to E201, wherein the cancer is multiple myeloma, lung cancer, breast cancer, prostate cancer, or acute myeloid leukemia.

[0932] E203: In any one of embodiments E1 to E197, a compound for use as a medicine or a pharmaceutically acceptable salt thereof.

[0933] E204: Any one of embodiments E1 to E197, a compound for use in the treatment of cancer or a pharmaceutically acceptable salt thereof.

[0934] E205: A method according to embodiment E204, wherein the cancer is multiple myeloma, lung cancer, breast cancer, prostate cancer, or acute myeloid leukemia.

[0935] E206: Use of any one of the compounds in embodiments E1 to E197 or a pharmaceutically acceptable salt thereof for the manufacture of a medicine for the treatment of cancer.

[0936] E207: In embodiment E206, the cancer is multiple myeloma, lung cancer, breast cancer, prostate cancer, or acute myeloid leukemia.

[0937] E208: A method for treating a disorder mediated by inhibition of KAT2A or KAT2B in a subject, comprising the step of administering to a subject in need of the compound of any one of embodiments E1 to E197 or a pharmaceutically acceptable salt thereof in an amount effective for treating said disorder.

[0938] E209: A pharmaceutical combination comprising any one of the compounds of embodiments E1 to E197 or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents or pharmaceutically acceptable salts thereof.

[0939] E210: A pharmaceutical composition comprising the pharmaceutical combination of embodiment E209 and one or more excipients.

[0940] References to therapeutic methods in this specification are also interpreted as references to the compound(s), pharmaceutical compositions, and medicines of the present invention for use in those methods. For example, a method for treating a disorder mediated by the inhibition of KAT2A or KAT2B, such as small cell lung cancer (SCLC), neuroendocrine prostate cancer (NEPC), acute myeloid leukemia (AML), and multiple myeloma, by administering to a subject a therapeutically effective amount of any one of embodiments E1 to E179 or a pharmaceutically acceptable salt thereof, comprises: (1) a KAT2A or KAT2B inhibitory compound or a pharmaceutically acceptable salt thereof for use as a medicine; and (2) a KAT2A or KAT2B inhibitory compound or a pharmaceutically acceptable salt thereof for use in treating a disorder mediated by the inhibition of KAT2A or KAT2B in a subject. (3) use of a KAT2A or KAT2B inhibitory compound or a pharmaceutically acceptable salt thereof to treat a disorder mediated by inhibition of KAT2A or KAT2B in a subject; and / or (4) use of a KAT2A or KAT2B inhibitory compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicine to treat a disorder mediated by inhibition of KAT2A or KAT2B in a subject.

[0941] Each embodiment described herein may be combined with any other embodiment(s) described herein that are not inconsistent with the embodiment(s) to which it is combined. Additionally, any compound or pharmaceutically acceptable salt thereof described in the embodiments may be claimed individually for any embodiment(s) described herein or grouped together with one or more other compounds or pharmaceutically acceptable salts thereof of the embodiments.

[0942] Additionally, each embodiment described herein anticipates a pharmaceutically acceptable salt of the compound described herein to the extent thereof.

[0943] definition

[0944] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings commonly understood by those skilled in the art.

[0945] The invention described herein may be suitably practiced in the absence of any element(s) not specifically disclosed herein.

[0946] "Compounds of the invention" include compounds of Formula I. Those skilled in the art will understand that, where possible, the compounds of the invention include conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racems of such isomers, diastereomers and other mixtures, and tautomers thereof. Those skilled in the art will also understand that, where possible, the compounds of the invention include solvates, hydrates, isomorphs, polymorphs, esters, salt forms, prodrugs, and isotope-labeled versions thereof (including deuterium substitution).

[0947] As used herein, the singular form includes the plural designation unless otherwise indicated. For example, a substituent includes one or more substituents.

[0948] As used herein, the term “about” means that when used to modify a numerically defined parameter (e.g., a dose of 5 mg), the parameter may vary by 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg means 5% ± 10%, that is, it may vary between 4.5 mg and 5.5 mg.

[0949] When a substituent is described as being "independently selected" from the group, each substituent is selected independently of the others. Therefore, each substituent may be identical to or different from the other substituent(s).

[0950] "Optional" or "optional" means that an event or situation described thereafter may occur but is not necessarily required to occur, and the description includes examples where the event or situation occurs and examples where it does not occur.

[0951] The terms “optionally substituted” and “substituted or unsubstituted” are used interchangeably to indicate that the specific group described does not have a non-hydrogen substituent (i.e., unsubstituted) or that the group may have one or more non-hydrogen substituents (i.e., substituted). Unless otherwise specified, the total number of possible substituents is equal to the number of H atoms present on the unsubstituted form of the group described. If any substituent, such as an oxo (=O) substituent, is attached via a double bond, the group occupies two available valencies, and thus the total number of other substituents included is reduced by two. If any substituent is selected independently from a list of alternatives, the selected group may be the same or different. Throughout the disclosure, it will be understood by those skilled in the art that the number and properties of any substituents will be limited to the extent that such substitutions have chemical significance.

[0952] "D" refers to deuterium.

[0953] "Halogen" or "halo" refers to fluoro, chloro, bromo, and iodo (F, Cl, Br, I).

[0954] "Cyano" refers to a substituent having a carbon atom bonded to a nitrogen atom by a triple bond, i.e., -C≡N, and is also referred to herein as -CN.

[0955] "Hydroxy" refers to the -OH group.

[0956] "Oxo" refers to double-bonded oxygen (=O).

[0957] "Alkyl" refers to a saturated monovalent aliphatic hydrocarbon radical having a specified number of carbon atoms, including a straight-chain or branched-chain group. The alkyl group may include, but is not limited to, 1 to 6 carbon atoms ("C1-C6 alkyl"), 1 to 5 carbon atoms ("C1-C5 alkyl"), 1 to 4 carbon atoms ("C1-C4 alkyl"), 1 to 3 carbon atoms ("C1-C3 alkyl"), or 1 to 2 carbon atoms ("C1-C2 alkyl"). Examples include, but are not limited to, methyl (-CH3), ethyl (-CH2CH3), n-propyl (-CH2CH2CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2CH2CH2CH3), etc.

[0958] "Deuterated alkyl" refers to a preceding alkyl group in which a hydrogen atom is partially or completely replaced by its isotope deuterium. Examples include, but are not limited to, -CD3 (deuterated methyl), -CD2CD3 (deuterated ethyl), and -CD2CD2CD3 (deuterated propyl).

[0959] "Haloalkyl" refers to the defined alkyl group comprising a specified number of carbon atoms in which one or more hydrogen atoms are replaced by halogens. The haloalkyl group may comprise, but is not limited to, 1 to 6 carbon atoms ("C1-C6 haloalkyl"), 1 to 4 carbon atoms ("C1-C4 haloalkyl"), or 1 or 2 carbon atoms ("C1-C2 haloalkyl").

[0960] "Fluoroalkyl" refers to an alkyl group as defined herein, in which one or all of the hydrogen atoms of the alkyl group are replaced by fluoro atoms. Examples include, but are not limited to, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and tetrafluoroethyl. Examples of a fully substituted fluoroalkyl group, also referred to as a perfluoroalkyl group, include trifluoromethyl (-CF3) and pentafluoroethyl (-C2F5).

[0961] "Hydroxyalkyl" refers to an alkyl group substituted with 1, 2, or 3 hydroxy(-OH) groups as defined above.

[0962] "Alkoxy" refers to an alkyl group single-bonded to an oxygen atom as defined herein. The attachment site of the alkoxy radical to the molecule is through the oxygen atom. The alkoxy radical can be represented as alkyl-O-. The alkoxy group may include, but is not limited to, 1 to 6 carbon atoms ("C1-C6 alkoxy"), 1 to 4 carbon atoms ("C1-C4 alkoxy"), or 1 to 3 carbon atoms ("C1-C3 alkoxy"). The alkoxy group includes, but is not limited to, methoxy, ethoxy, n-propoxy, isobutoxy, etc.

[0963] "Haloalkoxy" refers to the alkoxy group defined above, comprising a specified number of carbon atoms in which one or more hydrogen atoms are replaced by halogens. The haloalkoxy group may comprise, but is not limited to, 1 to 6 carbon atoms ("C1-C6 haloalkoxy"), 1 to 4 carbon atoms ("C1-C4 haloalkoxy"), or 1 or 2 carbon atoms ("C1-C2 haloalkoxy"). More specifically, the fluorinated alkoxy group may be specifically referred to as "fluoroalkoxy."

[0964] "Alkenyl" refers to an alkyl group composed of at least two carbon atoms and one or more carbon-carbon double bonds, as defined herein. For example, as used herein, the term "C2-C6 alkenyl" means a straight-chain or branched-chain unsaturated radical of 2 to 6 carbon atoms, including but not limited to ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl.

[0965] "Alkynyl" refers to an alkyl group composed of at least two carbon atoms and one or more carbon-carbon triple bonds as defined herein. Examples include, but are not limited to, ethinyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl.

[0966] "Cycloalkyl" refers to a fully saturated hydrocarbon ring system having a specified number of carbon atoms, which may be a monocyclic, cross-linked, or fused cyclic or polycyclic ring system connected to the base molecule through carbon atoms of the cycloalkyl ring. The cycloalkyl group may comprise, but is not limited to, 3 to 6 carbon atoms ("C3-C6 cycloalkyl"), 3 to 5 carbon atoms ("C3-C5 cycloalkyl"), or 3 to 4 carbon atoms ("C3-C4 cycloalkyl"). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl group may optionally be substituted, unsubstituted, or substituted as further defined herein.

[0967] "Heterocycloalkyl" refers to a fully saturated ring system comprising a specified number of ring atoms and one or more heteroatoms selected from N, O, and S as ring members, wherein the ring S atoms are optionally substituted with one or two oxo groups (i.e., S(O) q, where q is 0, 1, or 2), the heterocycloalkyl ring is connected to the base molecule through a ring atom that can be C or N. The heterocycloalkyl ring consists of N, O, and S(O) as ring members. q It may comprise 1 to 3 heteroatoms selected from, or 1 to 2 cyclic heteroatoms, provided that such heterocycloalkyl rings do not comprise 2 adjacent oxygen or sulfur atoms. The heterocycloalkyl rings may additionally be optionally substituted, unsubstituted, or substituted as defined herein. Such substituents may be present on a heterocyclic ring attached to the base molecule, or on a spirocyclic, cross-linked, or fused ring attached thereto.

[0968] As defined herein, the heterocycloalkyl ring may comprise a 3 to 6-membered heterocyclyl group, e.g., a 3 to 6-membered heterocycloalkyl group, but is not limited thereto. Exemplary examples of the heterocycloalkyl ring include, but are not limited to, the following monovalent radicals:

[0969]

[0970] .

[0971] As used herein, "N-containing heterocycloalkyl" refers to one or more cyclic methylene groups (-CH2-) that are -NR 11 It refers to a fully saturated cycloalkyl ring system in which a cyclic methylene group is replaced by an optional additional cyclic methylene group and an additional cyclic methylene group is replaced by a heteroatom selected from oxygen and sulfur.

[0972] Non-limiting examples of N-containing heterocycloalkyls include pyrazolidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, or mopolinyl, wherein N of the heterocycloalkyl is R as defined herein. 11 It is substituted with. Non-limiting examples of such N-containing heterocycloalkyls include the following:

[0973]

[0974] In the above formula, can be attached to a heterocycloalkyl at any atom of sufficient valence, and R 4 It provides an attachment site for linker L within. Such N-containing heterocycloalkyl rings may be unsubstituted or substituted as further defined in the present invention. Such substituents may be present on a heterocyclic ring attached to the base molecule, or on a spirocyclic, cross-linked, or fused ring attached thereto.

[0975] "5 or 6-membered N-containing heteroaryls" are those in which all carbon atoms within the ring are sp 2 It refers to a cyclic ring system having five to six ring atoms having one or more nitrogen as ring members and optionally additionally nitrogen, oxygen, and sulfur as ring members in a hybridized and pi-electron-bonded ring. Such heteroaryl groups may be attached through ring carbon atoms or, if valence permits, through ring heteroatoms. Such heteroaryl groups may be unsubstituted or substituted as further defined herein.

[0976] Exemplary examples of monocyclic heteroaryl groups include, but are not limited to, the following monovalent radicals:

[0977] .

[0978] For ring C1, non-limiting examples include imidazolyl, pyrazolil, or pyrrolil, and ring carbon or ring N is as defined herein and R as illustrated below. 7A It is replaced with:

[0979]

[0980] In the above formula, the asterisk * can be attached to the heteroaryl at any atom of sufficient valence and provides an attachment point from ring C1 to ring A, and R 7A is as defined herein.

[0981] "5 or 6-membered N-containing heterocyclic ring" refers to a carbon-cyclic group in which one or more of the ring carbon atoms are replaced with nitrogen and additional ring carbons are optionally replaced with nitrogen, oxygen, or sulfur, the ring may be saturated (i.e., 5 or 6-membered N-containing heterocycloalkyl), partially unsaturated, or aromatic (i.e., 5 or 6-membered N-containing heteroaryl), and substituents may be present on any atom of sufficient valence.

[0982] "Amino" refers to the unsubstituted group -NH2. Where amino is described as substituted or optionally substituted, this term is -NR x R y Includes a form of group, and R x and R y Each is further defined as described herein. For example, "alkylamino" is a group -NR in which one of Rx and Ry is an alkyl moiety and the other is H. x R y It refers to, and "dialkylamino" is R x and R y Both refer to -NRxRy, which is an alkyl moiety, and the alkyl moiety has a specified number of carbon atoms (e.g., -NH(C1-C4alkyl) or -N(C1-C4alkyl)2).

[0983] dashed lines used in the chemical structure of the present disclosure " " or the asterisk "*" indicates the attachment point of the substituent.

[0984] As used herein, "deuterium enrichment factor" refers to the ratio between the deuterium abundance and the natural abundance of deuterium relative to the hydrogen abundance. Atomic positions specified to have deuterium are, in certain embodiments, at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least It typically has a deuterium enrichment factor of 6633.3 (99.5% deuterium incorporation).

[0985] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention as active ingredients, or pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof, and one or more pharmaceutically acceptable excipients.

[0986] The term "pharmaceuticalally acceptable" means that a substance (e.g., a compound described herein) and any salt thereof, or a composition containing the substance or salt of the invention, is suitable for administration to a subject or patient.

[0987] As used herein, "excipients" refer to any component other than the compound(s) of the invention. The selection of excipients depends to a significant extent on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0988] As used herein, “excipients” include any and all physiologically compatible solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic and absorption retardants, carriers, and diluents, etc. Examples of excipients include one or more of the following, as well as combinations thereof, such as water, saline solution, phosphate-buffered saline solution, dextrose, glycerol, ethanol, etc., and the composition may include isotonic agents such as, for example, sugars, sodium chloride, or polyalcohols such as mannitol or sorbitol. Examples of excipients also include various organic solvents (e.g., hydrates and solvates). The pharmaceutical composition may, if necessary, contain additional excipients such as flavorings, binders / binding agents, lubricants, disintegrants, sweeteners or flavorings, coloring agents or dyes, etc. For example, for oral administration, tablets containing various excipients such as citric acid may be used with various disintegrants such as starch, alginic acid, and certain complex silicates, and binders such as sucrose, gelatin, and acacia. Non-limiting examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oil, and polyethylene glycol. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often useful for tableting purposes. Similar types of solid compositions may also be used in soft and hard-filled gelatin capsules. Thus, non-limiting examples of excipients also include lactose and high molecular weight polyethylene glycol. Where an aqueous suspension or elixir is preferred for oral administration, the active compound therein may be combined with various sweeteners or flavorings, coloring agents or dyes, and, if necessary, with emulsifiers or suspending agents, and additional excipients such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

[0989] Examples of excipients also include pharmaceutically acceptable substances, e.g., wetting agents, small amounts of auxiliary substances, e.g., wetting agents or emulsifiers, preservatives, or buffers.

[0990] As used herein, the terms “treating,” “treat,” or “treatment” include both preventive, i.e., prophylactic, and palliative treatment, i.e., alleviating, reducing, or slowing the progression of the patient’s disease (or condition) or any tissue damage associated with the disease.

[0991] As used herein, the terms “to treat” or “treating” cancer mean administering a compound of the present invention to a subject having or diagnosed with cancer to achieve one or more positive therapeutic effects, such as, for example, a reduced number of cancer cells, a reduced tumor size, a reduced rate of cancer cell infiltration into peripheral organs, or a reduced rate of tumor metastasis or tumor growth; reversing, alleviating, or inhibiting the progression of the disorder or condition to which the term applies; or reversing, alleviating, or inhibiting one or more symptoms of said disorder or condition. Unless otherwise indicated, the term “treatment” as used herein refers to the act of “treating” as defined above. The term “treatment” also includes adjuvant and neoadjuvant therapy of the subject.

[0992] The term "tumor size" refers to the total size of a tumor that can be measured by its length and width. Tumor size may be determined by various methods known in the art, such as measuring the dimensions of the tumor using a caliper during removal from the subject, or using imaging techniques while the tumor is inside the body, such as bone scans, ultrasound, CR, or MRI scans.

[0993] As used herein, the interchangeable terms “subject,” “individual,” or “patient” refer to any animal, including mammals. Mammals according to the invention include canids, felines, bovines, goats, horses, sheep, pigs, rodents, lagomorphs, primates, humans, etc., and include mammals in the womb. In one embodiment, a human is a suitable subject. The human subject may be of any gender and any stage of development.

[0994] The “effective dose” or “effective amount” of a drug, compound, or pharmaceutical composition used herein is an amount sufficient to affect any one or more beneficial or desirable signs, including biochemical, histological, and / or behavioral symptoms of the disease, complications, and intermediate pathological phenotype that appear during the development of the disease.

[0995] As used herein, the phrase “therapeutic effective dose” refers to an amount of an active compound or pharmaceutical preparation sought by a researcher, veterinarian, physician, or other clinician to induce a biological or medical response in a tissue, system, animal, individual, or human, which may include one or more of the following:

[0996] (1) Preventing disease; for example, preventing disease, condition, or disorder in an individual who may be susceptible to disease, condition, or disorder but has not yet experienced or exhibited the pathology or symptomaticity of the disease;

[0997] (2) suppressing a disease; for example, suppressing a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptomaticity of a disease, condition, or disorder (i.e., preventing (or delaying) further development of the pathology or symptomaticity or both); and

[0998] (3) Improving a disease; for example, improving a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptomaticity of a disease, condition, or disorder (i.e., reversing the pathology or symptomaticity or both).

[0999] With respect to the treatment of cancer, the therapeutic dose refers to an amount having the effect of (1) reducing the size of the tumor, (2) inhibiting tumor metastasis (i.e., slowing it down to some extent, preferably stopping it), (3) inhibiting tumor growth or tumor invasiveness to some extent (i.e., slowing it down to some extent, preferably stopping it), (4) alleviating one or more signs or symptoms associated with cancer to some extent (or, preferably, eliminating them), (5) reducing the dose of other drugs required to treat the disease, and / or (6) enhancing the effect of other drugs, and / or (7) delaying the progression of the disease in the patient.

[1000] salt

[1001] The salts included in the term "pharmaceutically acceptable salts" refer to compounds of the present invention that are generally prepared by reacting a free base or a free acid with a suitable organic or inorganic acid or a suitable organic or inorganic base to provide a salt of the compound of the present invention suitable for administration to a subject or patient.

[1002] Additionally, the compound of formula (I) is not necessarily a pharmaceutically acceptable salt and may also include other salts of such compound that may be useful as intermediates for one or more of the following: 1) preparing the compound of formula (I); 2) purifying the compound of formula (I); 3) separating enantiomers of the compound of formula (I); or 4) separating diastereomers of the compound of formula (I).

[1003] Suitable acid addition salts are formed from acids that form non-toxic salts. Examples are not limited to, but include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edicilate, esylate, formate, fumarate, gluteptate, gluconate, glucuronate, hexafluorophosphate, hybenzoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, maleate, maleate, malonate, mesylate, methyl sulfate, naphthalate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, It includes saccharates, stearates, succinates, tannates, tartrates, tosylates, trifluoroacetates, 1,5-naphthalenedisulfonic acid, and zinopoate salts.

[1004] Suitable base salts are formed from bases that form non-toxic salts. Examples include, but are not limited to, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts.

[1005] Acid and base antisalts, for example, hemisulfate and hemicalcium salts, can also be formed.

[1006] For a review of suitable salts, refer to the literature [PAULEKUHN, GS, et al., "Trends in Active Pharmaceutical Ingredient Salt Selection Based on Analysis of the Orange Book Database," Journal of Medicinal Chemistry, 2007, 50(26):6665-6672].

[1007] Pharmaceutically acceptable salts of the compounds of the present invention can be prepared by methods well known to those skilled in the art, which include, but are not limited to, the following procedures:

[1008] (i) by reacting the compound of the invention with a desired acid or base;

[1009] (ii) by removing an acid- or base-unstable protecting group from a suitable precursor of the compound of the invention, or by ring-opening a suitable cyclic precursor, such as, for example, a lactone or lactam, using a desired acid or base; or

[1010] (iii) By converting one salt of the compound of the invention into another. This can be achieved by reaction with a suitable acid or base or by a suitable ion exchange procedure.

[1011] This procedure is typically performed in solution. The resulting salt can be precipitated and collected by filtration or recovered by the evaporation of the solvent.

[1012] solvate

[1013] The compounds of the present invention and pharmaceutically acceptable salts thereof may exist in non-solvent and solvated forms. The term "solvent" is used herein to describe a molecular complex comprising the compound of the invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable solvent molecules, e.g., ethanol. The term "hydrate" is used when the solvent is water.

[1014] Additionally, the compound of Formula I may also include other solvates of this compound that are useful as intermediates for one or more of the following, although not necessarily pharmaceutically acceptable solvates: 1) preparing the compound of Formula I; 2) purifying the compound of Formula I; 3) separating enantiomers of the compound of Formula I; or 4) separating diastereomers of the compound of Formula I.

[1015] The currently accepted classification system for organic hydrates defines isolated sites, channels, or metal-ion coordination hydrates, and the literature [BRITTAIN, HG Polymorphism in Pharmaceutical Solids. 2 nd Refer to Ed. CRC Press, 2009. Isolated site hydrates are those in which water molecules are isolated from each other by organic molecules interposed therein. In channel hydrates, water molecules are positioned in lattice channels next to other water molecules. In metal-ion coordination hydrates, water molecules are bonded to metal ions.

[1016] When the solvent or water is tightly bound, the complex can have a well-defined stoichiometry independent of humidity. However, when the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content may depend on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

[1017] solid form

[1018] The compounds of the present invention may exist as a continuum of solid states ranging from amorphous to crystalline. The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and may exhibit solid or liquid physical properties depending on temperature. Typically, such materials do not provide a characteristic X-ray diffraction pattern and exhibit solid properties, but are more formally described as liquid. Upon heating, a transition from solid to liquid properties occurs, which is typically characterized by a second-order ("glass transition") phase change. The term "crystalline" refers to a solid phase in which a material has a regularly aligned internal structure at the molecular level and provides a characteristic X-ray diffraction pattern with defined peaks. Such materials will also exhibit liquid properties when sufficiently heated, but the transition from solid to liquid is typically characterized by a first-order ("melting point") phase change.

[1019] The compounds of the present invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is an intermediate between a true crystalline state and a true liquid state (melt or solution) and consists of a two-dimensional order at the molecular level. Mesomorphism resulting from a change in temperature is described as 'thermotropic,' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic.' Compounds capable of forming a lyotropic mesophase are described as 'amphiphilic,' and ionic (e.g., -COO) - Na + , -COO - K + , or -SO3 - Na + ) or non-ionic (e.g., -N - N +It consists of molecules having (CH3)3) polar head groups. For additional information, refer to [HARTSHORNE, NH and STUART, A., Crystals and the Polarizing Microscope. 4]. th Refer to Ed. London, Edward Arnold, 1970.

[1020] stereoisomers

[1021] The compound of the present invention may exist as two or more stereoisomers. The stereoisomers of the compound are cis and trans isomers (geometric isomers), R and S Optical isomers such as enantiomers, diastereomers, rotational isomers, atropisomers, and conformational isomers may be included. For example, a compound of the invention comprising one or more asymmetric carbon atoms may exist as two or more stereoisomers. If the compound of the invention comprises an alkenyl group, geometric cis / trans (or Z / E) isomers are possible. Cis / trans isomers may also exist for saturated rings.

[1022] Pharmaceutically acceptable salts of the compounds of the present invention may also include optically active (e.g., d-lactate or l-lysine) or racemic (e.g., dl-tartrate or dl-arginine) counterions.

[1023] Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

[1024] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or the separation of a racemic mixture (or a racemic mixture of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC). Alternatively, the racemic mixture (or racemic precursor) may react with a suitable optically active compound, for example, an alcohol, or with a base or acid, such as 1-phenylethylamine or tartaric acid, if the compound of the present invention contains an acidic or basic moiety. The resulting mixture of diastereoisomers may be separated using chromatography, fractional crystallization, or both of the above techniques, and one or both of the diastereoisomers are converted into the corresponding pure enantiomer(s) by means well known to those skilled in the art. The chiral compounds (and their chiral precursors) of the present invention can be obtained in a mirror-image concentrated form using chromatography, and typically the concentration of the HPLC eluent provides a concentrated mixture. Chiral chromatography using subcritical and supercritical fluids may be used. Methods for chiral chromatography useful in some embodiments of the present invention are known in the art (e.g., literature [SMITH, RM, Supercritical Fluid Chromatography with Packed Columns. 1] st Ed. RSC Chromatography Monographs, 1988].

[1025] When any racemic mixture is crystallized, two different types of crystals are possible. The first type is the aforementioned racemic compound (true racemic mixture), in which a single homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is a racemic mixture or aggregate, in which two crystal forms are produced containing a single enantiomer in equimolar amounts. Both crystal forms present in a racemic mixture have identical physical properties, but may have different physical properties compared to the true racemic mixture. Racemic mixtures can be separated by conventional techniques known to those skilled in the art—for example, [ELIEL, EL and WILEN, SH, Stereochemistry of Organic Compounds. 1] st Refer to Ed. New York, Wiley, 1994.

[1026] Tautomerization

[1027] When structural isomers are interconvertible through a low energy barrier, tautomeric isomerization ('tautomeric isomerization') may occur. This may take the form of proton tautomeric isomerization in the compound of the invention containing, for example, an imidic acid / amide tautomeric isomer as described below, or the form of so-called valence tautomeric isomerization in a compound containing an aromatic moiety:

[1028] .

[1029] Therefore, a single compound can exhibit more than one type of isomerization.

[1030] For the sake of brevity, the compounds of the invention are described herein in the form of a single tautomeric isomer, but it should be emphasized that all possible tautomeric isomer forms are included within the scope of the invention.

[1031] isotopes

[1032] The present invention comprises all pharmaceutically acceptable isotope-labeled compounds of the present invention, wherein one or more atoms are replaced by atoms having the same atomic number but having an atomic mass or mass number different from that which is dominant in nature.

[1033] Examples of isotopes suitable for inclusion in the compounds of the present invention are 2 H(D, deuterium) and 3 Isotopes of hydrogen such as H(T, tritium), 11 C, 13 C and 14 Carbon, such as C 36 Chlorine, such as Cl 18 Fluorine like F, 123 I and 125 Iodine like I, 13 N and 15 Nitrogen, such as N 15 O, 17 O and 18 Oxygen such as O, and 35 It can contain sulfur such as S.

[1034] Certain isotope-labeled compounds of the present invention, for example, those introducing radioactive isotopes, are useful in studies of drug or substrate tissue distribution, or both. Tritium and 14 Radioactive isotopes such as C are particularly useful for this purpose in terms of the ease of introduction and the ease of detection.

[1035] 11 C, 18 F, 15 O and 13 Substitution with positron-emitting isotopes such as N can be useful in Positron Emission Topography (PET) studies to investigate substrate acceptor occupancy. Deuterium ( 2Substitution with H) may provide specific therapeutic benefits resulting from greater metabolic stability, e.g., increased in vivo half-life, reduced dose requirements, reduced CYP450 inhibition (competitive or time-dependent), or improvements in therapeutic index or tolerability.

[1036] In some embodiments, the disclosure provides deuterium-labeled (or deuterated) compounds and salts, the chemical formulas and variables of such compounds and salts are each independently described herein. “Deuterated” means that one or more atoms in the compound are deuterium in an abundance greater than the natural abundance of deuterium (typically about 0.015%). Those skilled in the art recognize that in chemical compounds containing hydrogen atoms, the hydrogen atoms actually represent a mixture of H and D, and that about 0.015% is D. The concentration of deuterium introduced into the deuterium-labeled compounds and salts of the present invention may be defined by a deuterium enrichment factor. It is understood that one or more deuteriums can be exchanged for hydrogen under physiological conditions.

[1037] In some embodiments, one or more hydrogen atoms at specific metabolic sites on the compound of the present invention are deuteriumized.

[1038] The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described in the attached examples and preparations, using a suitable isotope-labeled reagent instead of a previously used unlabeled reagent.

[1039] Pharmaceutically acceptable solvates according to the present invention include those in which the solvent of crystallization can be isotopicly substituted, e.g., D2O, d6-acetone, d6-DMSO.

[1040] prodrug

[1041] The compounds of the present invention may be administered in the form of prodrugs. Accordingly, certain derivatives of the compounds of the invention, which may have little or no pharmaceutical activity in themselves, may be converted into the compounds of the invention having desired activity when administered into or onto the body, for example, by hydrolytic cleavage, particularly by hydrolytic cleavage facilitated by esterase or peptidase enzymes. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs can be found in the literature [RAUTIO, J., et al., "The expanding role of prodrugs in contemporary drug design and development," Nature Reviews Drug Discovery, 2018, 17(8):559-58].

[1042] The prodrug according to the present invention can be produced by replacing a suitable functional group present in the compound of the present invention with a specific moiety known to those skilled in the art as a 'pro-moiety,' for example, as described in the literature [BUNDGAARD, H., Design of Prodrugs. New York, Elsevier, 1985].

[1043] Accordingly, when the prodrug according to the present invention is present in the compound of the invention, it may be (a) an ester or amide derivative of a carboxylic acid; (b) an ester, carbonate, carbamate, phosphate, or ether derivative of a hydroxyl group; (c) an amide, imine, carbamate, or amine derivative of an amino group; (d) a thioester, thiocarbonate, thiocarbamate, or sulfide derivative of a thiol group; or (e) an oxime or imine derivative of a carbonyl group.

[1044] Some specific examples of the prodrug according to the present invention include the following:

[1045] (i) Where the compound of the invention comprises a carboxylic acid functional group (-COOH), its ester, e.g., in which the hydrogen of the carboxylic acid functional group of the compound is C1-C8 alkyl (e.g., ethyl) or (C1-C8 alkyl)C(=O)OCH2- (e.g., t Compounds replaced with BuC(=O)OCH2-), for example:

[1046] ;

[1047] (ii) Where the compound of the invention comprises an alcohol functional group (-OH), an ester thereof, e.g., a compound in which the hydrogen of the alcohol functional group of the compound is replaced with -CO(C1-C8 alkyl) (e.g., methyl carbonyl) or the alcohol is esterified with an amino acid;

[1048] (iii) where the compound of the invention comprises an alcohol functional group (-OH), its ether, e.g., a compound in which the hydrogen of the alcohol functional group of the compound is replaced with (C1-C8alkyl)C(=O)OCH2- or -CH2OP(=O)(OH)2;

[1049] (iv) Where the compound of the invention comprises an alcohol functional group (-OH), its phosphate, e.g., where the hydrogen of the alcohol functional group of the compound is -P(=O)(OH)2 or -P(=O)(O - Na + )2 or -P(=O)(O - )2Ca 2+ Compound replaced by;

[1050] (v) Where the compound of the invention comprises a primary or secondary amino functional group (-NH2 or -NHR, wherein R ≠H), the amide thereof, for example, in some cases, has hydrogens of both of the amino functional groups of the compound (C1-C 10 )Alkanoylic, compounds replaced by -COCH2NH2 or amino groups derivatized into amino acids;

[1051] (vi) A compound in which, where the compound of the invention comprises a primary or secondary amino functional group (-NH2 or -NHR, wherein R ≠H), the amine thereof, for example, in which the hydrogens of both of the amino functional groups of the compound are replaced with -CH2OP(=O)(OH)2.

[1052] A specific compound of the present invention may itself act as a prodrug for another compound of the invention. It is also possible for two compounds of the present invention to be combined together in the form of a prodrug. Under certain circumstances, a prodrug of a compound of the present invention may be generated by internally linking two functional groups within the compound of the invention, for example, by forming a lactone.

[1053] Metabolites

[1054] In addition, the scope of the invention includes active metabolites of the compounds of the invention, namely compounds that are often formed in vivo by oxidation or dealkylation upon administration of the drug. Some examples of metabolites according to the invention include, but are not limited to, those listed below.

[1055] (i) Where the compound of the invention contains an alkyl group, its hydroxyalkyl derivative (-CH → -COH):

[1056] (ii) where the compound of the invention contains an alkoxy group, its hydroxyl derivative (-OR → -OH);

[1057] (iii) Where the compound of the invention contains a tertiary amino group, its secondary amino derivative (-NRR ' → -NHR or -NHR ' );

[1058] (iv) Where the compound of the invention contains a secondary amino group, its primary derivative (-NHR → -NH2);

[1059] (v) a phenol derivative thereof (-Ph → -PhOH) where the compound of the invention contains a phenyl moiety;

[1060] (vi) a carboxylic acid derivative thereof (-CONH2→COOH) where the compound of the invention contains an amide group; and

[1061] (vii) If the compound contains a hydroxyl or carboxylic acid group, the compound may be metabolized by conjugation to form, for example, glucuronides with glucuronic acid. Other pathways of conjugation metabolism exist. These pathways are often known as two-step metabolisms and include, for example, sulfation or acetylation. Other functional groups, such as NH groups, may also be targets of conjugation.

[1062] protein degrader

[1063] The present invention discloses a difunctional compound comprising a targeting ligand (i.e., the compound of the initiation) linked to an E3 ligase ligand or a ligand known to interact with the ubiquitin proteasome system (UPS) through a linker. The diactive compound of the disclosure has a general structure of [Degron]-[Linker]-[Targeting Ligand], the linker is covalently bonded to one or more degrons and covalently bonded to one or more targeting ligands, the degrons are compounds capable of binding to ubiquitin ligases such as E3 ubiquitin ligases (e.g., Cereblon (CRBN), von Hippel-Lindau (VHL), etc.), and the targeting ligand or compound of the disclosure can bind to the histone acetyltransferase domain of KAT2A and / or KAT2B. The diactive compound of the disclosure may be used therapeutically to treat the pathological conditions disclosed herein.

[1064] In one embodiment, the difunctional compound of the disclosure is a compound of the following formula or a pharmaceutically acceptable salt thereof:

[1065] [Degron]-[Linker]-[Compound of Chemical Formula (I)].

[1066] Degron : Degron is a compound that is highly effective at recruiting targeted proteins to ubiquitin ligases for proteasome degradation. Degron recruits targeted proteins through a linker and a targeting ligand (i.e., the compound of the initiation). In some embodiments, degron is a compound capable of binding to a ubiquitin ligase. In one embodiment, degron can bind to an E3 ubiquitin ligase such as cereblon, and degron is thalidomide, lenalidomide, pomalidomide, or iverdomide, or a newer IMiDs CRBN ligand, or an analog thereof (e.g., WO 2019 / 060693, WO 2019 / 140387, WO 2019 / 236483). In one embodiment, the degron can bind to an E3 ubiquitin ligase such as the von Hippel-Lindau ligand (e.g., WO 2020 / 092907; WO 2013106643; reference [BUCKLEY, DL, et al., "Targeting the von Hippel-Lindau E3 Ubiquitin Ligase Using Small Molecules to Disrupt the VHL / HIF-1a Interaction," Journal of the American Chemical Society, 2012, 134(10):4465-4468]; [SOARES, P., et al., "Group-Based Optimization of Potent and Cell-Active Inhibitors of the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase: Structure-Activity Relationships Leading to the Chemical Probe (2 S ,4 R )-1-(( S)-2-(1-Cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VH298)," Journal of Medicinal Chemistry, 2018, 61(2):599-618]). In further embodiments, degron can bind to E3 ubiquitin ligases, such as inhibitors of apoptosis protein ligases (IAP1, IAP2, XIAP) (e.g., ITOH, Y., et al., "Protein knockdown using methyl bestatin-ligand hybrid molecules: design and synthesis of inducers of ubiquitination-mediated degradation of cellular retinoic acid-binding proteins," Journal of the American Chemical Society, 2010, 132(16):5820-5826]; [MARES, A., et al., "Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2," Communications Biology, 2020, 3:1-13]; [TINWORTH, C., et al., "PROTAC-Mediated Degradation of Bruton's Tyrosine Kinase Is Inhibited by Covalent Binding," ACS Chemical Biology, 2019, 14(3):342-347]). In further embodiments, degron binds to ubiquitin proteasome proteins that induce degradation, such as Hsp70 / 90 chaperone complex (e.g., WO 2020 / 207395), Usp14 (e.g., WO 2019 / 238886), UchL5 (e.g., WO 2019238816) and Rpn11 (e.g., WO 2019 / 238817).In some embodiments, the degron is an amino acid moiety (e.g., ZHANG, J., et al., "Single amino acid-based PROTACs trigger degradation of the oncogenic kinase BCR-ABL in chronic myeloid leukemia (CML)," Journal of Biological Chemistry, 2023, 299(8):104994).

[1067] Linker : The linker ("L") provides a covalent attachment between the targeting ligand and the degron. The linker has two terminals, one of which is attached to the degron and the other to the targeting ligand, which is a compound of formula (I). The structure of the linker may not be important as long as it does not substantially interfere with the activity of the targeting ligand or the degron. The optimal linker length and composition may vary depending on the target and may be estimated, for example, based on 1) the X-ray structure of the original targeting ligand bound to its target; and / or 2) computational modeling of the protein target and the UPS protein. The linker length and composition may also be modified to regulate metabolic stability and pharmacokinetic (PK) and pharmacodynamic (PD) parameters. In some embodiments, the linker is designed and optimized based on the structure-activity relationship (SAR) and X-ray crystallography of the targeting ligand with respect to the site of attachment to the linker. In some embodiments, the target ligand may bind to multiple protein targets, and the selectivity of the difunctional compound disclosed herein may be achieved by varying the linker length so that the ligand may target different binding pockets, for example, deeper or shallower binding pockets than others.

[1068] In some embodiments, the linker is C 2-20It is an alkylene or polyethylene glycol (PEG) chain. In other embodiments, the linker may be an alkylene chain, a PEG chain, or a divalent alkylene chain, each of which is -O-, -S-, -N(R L )-, -C=C-, -C(O)-, -C(O)O-,-OC(O)-, -OC(O)O-, -C(NOR L )-, -C(O)N(R L )-, -C(O)N(R L )C(O)-, -C(O)N(R L )C(O)N(R L )-, -N(R L )C(O)-, -N(R L )C(O)N(R L )-, -N(R L )C(O)O-, -OC(O)N(R L )-, -C(NR L )-,-N(R L )C(NR L )-, -C(NR L )N(R L )-, -N(R L )C(NR L )N(R L )-, -OB(CH3)O-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R L )S(O)2-, -S(O)2N(R L )-, -N(R L )S(O)-, -S(O)N(R L )-, -N(R L )S(O)2N(R L )-, -N(R L )S(O)N(R L )-, C 3-12 It may be interrupted or terminated by one or more of carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene, or arylene, or any combination thereof, and R L H or C 1-6It is an alkyl. In one embodiment, and in some embodiments, the linker is C 1-10 It is alkylene-NH-, and the nitrogen is bonded to the degron. In one embodiment, the linker is -(CH2) n' C interrupted or terminated by -C(O)-NH- 1-10 It is an alkylene or 1-8 PEG unit, and n' is 0, 1, 2, 3, 4 or 5.

[1069] Non-limiting examples of linkers are -(CH2CH2-O) n" -(CH2) n' -C(O)-, (CH2) n' -C(O)-N(R L )-(CH2CH2-O) n" -(CH2) n' -C(O)-, -(CH2CH2-O) n" -(CH2) n' -N(R L )-C(O)-, -(CH2CH2-O) n" -(CH2) n' -C(O)-N(R L )-, -(CH2) n' -phenylene-N(R L )-C(O)-(CH2) n' -, -N(R L )-(CH2) n' -O-phenylene-(CH2) n" -N(R L )-(CH2) n' -, -(CH2) n' -C(O)-N(R L )-phenylene-C(O)-, -N(R L )-(CH2) n' -phenylene-(CH2) n" -heterocyclilene-, -(CH2) n' -phenylene-N(R L )-C(O)-(CH2CH2-O) n" -(CH2) n' -,-(CH2) n' -phenylene-(CH2) n" -heterocyclilene-(CH2) n" C(O)-N(R L )-(CH2)n' -, -(CH2) n' -phenylene-O-(CH2) n' -heterocyclilene- (CH2) n' -, -(CH2) n' -phenylene-(CH2) n' -heterocyclilene- (CH2) n' -O-, -(CH2) n' -heterocyclilene-(CH2) n' Includes, and R L H or C 1-6 It is alkyl; n' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and n" is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[1070] Pharmaceutical composition

[1071] In another embodiment, the present invention comprises a pharmaceutical composition. For the purposes of the pharmaceutical composition, the compound itself or a pharmaceutically acceptable salt thereof is simply referred to as the compound of the invention.

[1072] The compositions of the present invention may be in various forms. These include, for example, liquid, semi-solid, and solid dosage forms such as liquid solutions (e.g., injectable and injectable solutions), dispersions or suspensions, tablets, capsules, pills, powders, liposomes, and suppositories. The form depends on the intended mode of administration and therapeutic application.

[1073] A typical composition is in the form of an injectable or infusionable solution, such as a composition similar to that generally used for human passive immunity using antibodies. One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the compound is administered by intravenous infusion or injection. In yet another embodiment, the compound is administered by intramuscular or subcutaneous injection.

[1074] Oral administration in solid dosage forms may be provided in individual units, such as hard or soft capsules, pills, cases, lozenges, or tablets, each containing a predetermined amount of one or more compounds of the invention. In other embodiments, the oral administration may be in powder or granule form. In other embodiments, the oral dosage form is sublingual, such as a lozenge. In these solid dosage forms, the compounds of the invention are typically combined with one or more adjuvants. These capsules or tablets may contain a controlled-release agent. In the case of capsules, tablets, and pills, the dosage forms may also contain a buffer or be manufactured with an enteric coating.

[1075] In other embodiments, oral administration may be in the form of a liquid administration. Liquid administration forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing an inert diluent (e.g., water) commonly used in the art. These compositions may also include one or more adjuvants among wetting, emulsifying, suspension, flavoring (e.g., sweeteners), or flavoring agents.

[1076] In other embodiments, the present invention comprises parenteral administration forms. "Parental administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal, intramuscular injection, intrasternal injection, and infusion. Injectable formulations (i.e., sterile injectable aqueous or oily suspensions) may be formulated according to known techniques using one or more of suitable dispersants, wetting agents, or suspending agents.

[1077] In other embodiments, the present invention comprises a form of topical administration. "Topical administration" includes skin and transdermal administration, such as, for example, through a transdermal patch or an iontophoresis device, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may include compounds that enhance the absorption or penetration of an active ingredient through the skin or other affected area. When a compound of the present invention is administered by a transdermal device, administration is achieved using a reservoir and a patch of a porous membrane type or a variety of solid matrix. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical excipients include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be included, for example, see the literature [FINNIN, BC and MORGAN, TM, "Transdermal penetration enhancers: Applications, limitations, and potential," Journal of Pharmaceutical Sciences, 1999, 88(10):955-958].

[1078] Formulations suitable for topical administration to the eye include, for example, eye drops in which a compound of the present invention is dissolved or suspended in a suitable excipient. Typical formulations suitable for ocular or ear administration may be in the form of droplets of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline solution. Other formulations suitable for ocular and ear administration include ointments, biodegradable (i.e., absorbent gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses, and microparticle or vesicle systems such as niosomes or liposomes. Cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers, for example, gellan gum, may be included together with a preservative such as benzalkonium chloride. These formulations may also be delivered by iontophoresis.

[1079] For intranasal administration, the compound of the present invention is conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by a patient, or as an aerosol spray formulation from a pressurized container or nebulizer using a suitable propellant. Formulations suitable for intranasal administration are typically administered as a dry powder from a dry powder inhaler (alone, as a mixture, e.g., as a dry blend with lactose, or as mixed component particles, e.g., mixed with a phospholipid such as phosphatidylcholine), or as an aerosol spray from a pressurized container, pump, spray, nebulizer (preferably a nebulizer using electrohydrodynamics to produce a fine mist), or nebulizer with or without a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, e.g., chitosan or cyclodextrin.

[1080] In another embodiment, the present invention comprises a rectal administration form. Such a rectal administration form may be, for example, in the form of a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be appropriately used.

[1081] Other excipients and modes of administration known in pharmaceutical technology may also be used. The pharmaceutical compositions of the present invention may be prepared by any of the well-known techniques of pharmaceuticals, such as effective formulations and administration procedures. The above considerations regarding effective formulations and administration procedures are well known in the art and are described in the standards. Formulations of drugs are, for example, described in the literature [ALLEN, LV and ANSEL, HC Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. 10]. th Ed. Philadelphia, Lippincott Williams & Wilkins, 2014]; [ADEJARE, A. Remington: The Science and Practice of Pharmacy. 23 rd Ed. Philadelphia, Lippincott Williams & Wilkins, 2000]; [ROWE, RC, et al., Handbook of Pharmaceutical Excipients. 5 th Ed. Chicago, Pharmaceutical Press, 2006]; [STAHL, PH and WERMUTH, CG, Pharmaceutical Salts: Properties, Selection, and Use. 2 nd Revised Ed. New York, Wiley-VCH, 2011]; and [BRITTAIN, HG Polymorphism in Pharmaceutical Solids. 2 nd It is discussed in Ed. CRC Press, 2009.

[1082] Acceptable excipients are non-toxic to the subject at the doses and concentrations used and may include one or more of the following: 1) buffers such as phosphates, citrates, or other organic acids; 2) salts such as sodium chloride; 3) antioxidants such as ascorbic acid or methionine; 4) preservatives such as octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol; 5) alkyl parabens such as methyl or propyl parabens, catechol, resorcinol, cyclohexanol, 3-pentanol, or m-cresol; 6) low molecular weight (less than about 10 residues) polypeptides; 7) proteins such as serum albumin, gelatin, or immunoglobulin; 8) hydrophilic polymers such as polyvinylpyrrolidone; 9) amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; 10) monosaccharides, disaccharides, or other carbohydrates including glucose, mannose, or dextrin; 11) chelating agents such as EDTA; 12) sugars such as sucrose, mannitol, trehalose, or sorbitol; 13) salt-forming counterions such as sodium, metal complexes (e.g., Zn-protein complexes), or 14) nonionic surfactants such as polysorbates (e.g., polysorbate 20 or polysorbate 80), poloxamer, or polyethylene glycol (PEG).

[1083] For oral administration, the composition may be provided in the form of tablets or capsules containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250, or 500 milligrams of the active ingredient for symptomatic adjustment of the dose to the patient. The medicine typically contains about 0.01 mg to about 500 mg of the active ingredient, or in other embodiments, about 1 mg to about 100 mg of the active ingredient. The administration regimen may vary depending on the route of administration, administration schedule, and the use of fixed dose, body surface area, or body weight-based administration. For example, in the case of body weight-based administration, the intravenous dose may be in the range of about 0.01 to about 10 mg / kg / min during constant rate infusion.

[1084] The liposome-containing compounds of the present invention can be prepared by methods known in the art (e.g., see CHANG, HI and YEH, MK, "Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy," International Journal of Nanomedicine, 2012, 7:49-60). Particularly useful liposomes can be produced by reverse-phase evaporation with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derived phosphatidylethanolamine (PEG-PE). The liposomes are extruded through a filter of a defined pore size to produce liposomes having a desired diameter.

[1085] The compounds of the present invention may also be encapsulated within colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or macroemulsions, for example, by coacervation techniques or interfacial polymerization, in microcapsules prepared, for example, from hydroxymethylcellulose or gelatin-microcapsules and poly-(methyl methacrylate) microcapsules, respectively. Such techniques are described in the literature [ADEJARE, A. Remington: The Science and Practice of Pharmacy. 23 rd It is disclosed in Ed. Philadelphia, Lippincott Williams & Wilkins, 2000.

[1086] Sustained-release formulations may be used. Suitable examples of sustained-release formulations include a semipermeable matrix of a solid hydrophobic polymer containing the compound of the invention in the form of a molded article, e.g., a film, or a microcapsule. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactide, copolymers of L-glutamic acid and 7-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as those used in depot suspensions (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

[1087] Preparations to be used for intravenous administration must be sterile. This is easily achieved, for example, by filtration through a sterile filter membrane. The compounds of the present invention are generally placed in a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper that can be punctured with a subcutaneous injection needle.

[1088] Suitable emulsions may be prepared using commercially available lipid emulsions, such as lipid emulsions containing soybean oil, lipid emulsions for intravenous administration (e.g., containing safflower oil, soybean oil, egg phosphatide, and glycerin in water), emulsions containing soybean oil and medium-chain triglycerides, and lipid emulsions of cottonseed oil. The active ingredient may be dissolved in a pre-mixed emulsion composition, or alternatively, dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil, or almond oil) and mixed with a phospholipid (e.g., egg phospholipid, soybean phospholipid, or soybean lecithin) and water to form an emulsion. It will be understood that other ingredients, such as glycerol or glucose, may be added to adjust the tension of the emulsion. A suitable emulsion will typically contain up to 20% oil, for example, 5 to 20%. The fat emulsion may contain fat droplets between 0.1 and 1.0 μm, particularly between 0.1 and 0.5 μm, and may have a pH in the range of 5.5 to 8.0.

[1089] For example, the emulsion composition may be prepared by mixing the compound of the invention with a lipid emulsion containing soybean oil or its components (soybean oil, egg phospholipid, glycerol, and water).

[1090] Compositions for inhalation or airway insufflation comprise solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, compositions are administered via oral or nasal respiratory routes for local or systemic effects. Preferably, compositions in sterile pharmaceutically acceptable solvents may be atomized by the use of gas. The atomized solution may be inhaled directly from a nebulizer, or the nebulizer may be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered from a device that delivers the formulation in an appropriate manner, preferably orally or nasally.

[1091] A drug product intermediate (DPI) is a partially processed material that must undergo additional processing steps before becoming an active pharmaceutical ingredient. The compounds of the present invention can be formulated as drug product intermediate DPIs containing active ingredients in a form with higher free energy than their crystalline form. One reason for using DPIs is to improve oral absorption characteristics due to limitations caused by low solubility, slow dissolution, improved material transport through the mucous layer adjacent to epithelial cells, and, in some cases, biological barriers such as metabolism and transporters. Other reasons may include improved solid-state stability and downstream manufacturability. In one embodiment, the drug product intermediate contains the compounds of the invention isolated and stabilized in an amorphous state (e.g., amorphous solid dispersions (ASDs)). There are many techniques known in the art for producing ASDs that produce materials suitable for incorporation into active pharmaceutical ingredients, such as spray dried dispersions (SDDs), melt extrudes (often referred to as HMEs), co-precipitates, amorphous drug nanoparticles, and nano-adsorbents. In one embodiment, the amorphous solid dispersion comprises the compound of the invention and a polymer excipient. The concentrations of the excipients, as well as other excipients and the compound of the invention, are well known in the art and are described in the standards. For example, refer to the literature [SHAH, N., et al., Amorphous Solid Dispersions: Theory and Practice. New York, Springer, 2014].

[1092] Administration and Medication

[1093] Typically, the compound of the present invention is administered in an effective amount to treat a condition as described herein. The compound of the present invention may be administered as the compound itself, or alternatively, as a pharmaceutically acceptable salt. For the purposes of administration and medication, the compound itself or a pharmaceutically acceptable salt thereof is simply referred to as the compound of the invention.

[1094] The compounds of the present invention are administered by any suitable route in the form of pharmaceutical compositions suitable for such routes, and in an effective dose for the intended treatment. The compounds of the present invention may be administered orally, rectally, vaginally, parenterally, topically, nasally, or by inhalation.

[1095] The compounds of the present invention may be administered orally. Oral administration may include swallowing the compound so that it enters the gastrointestinal tract, or cheek or sublingual administration may be used so that the compound enters the bloodstream directly from the mouth.

[1096] In other embodiments, the compounds of the present invention may also be administered parenterally, for example, directly into the bloodstream, muscle, or internal organ. Suitable means for parenteral administration include intravenous, intra-arterial, intraperitoneal, intravertebral, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needleless injectors, and infusion techniques.

[1097] In another embodiment, the compound of the present invention may also be administered externally to the skin or mucous membranes, that is, by the skin or transdermally. In another embodiment, the compound of the present invention may also be administered into the nasal cavity or by inhalation. In another embodiment, the compound of the present invention may be administered into the rectum or vagina. In another embodiment, the compound of the present invention may also be administered directly to the eyes or ears.

[1098] The administration regimen for the compound of the present invention or a composition containing said compound is based on various factors including the patient's type, age, weight, sex, and medical condition; the severity of the condition; the route of administration; and the activity of the specific compound used. Accordingly, the administration regimen may vary significantly. In one embodiment, the total daily dose of the compound of the present invention for the treatment of the indicated conditions discussed herein is typically about 0.01 to about 100 mg / kg (i.e., mg of the compound of the present invention per kg body weight). In another embodiment, the total daily dose of the compound of the present invention is about 0.1 to about 50 mg / kg, and in yet another embodiment, about 0.5 to about 30 mg / kg. It is not uncommon for the administration of the compound of the present invention to be repeated several times a day (typically not exceeding four times). Multiple daily doses may typically be used to increase the total daily dose as needed.

[1099] Treatment methods and uses

[1100] The compounds of the present invention act as inhibitors of KAT2A and / or KAT2B and may be useful for the treatment, prevention, inhibition, and improvement of diseases such as cancer, disorders, and pathologies mediated by KAT2A and KAT2B, or a combination thereof.

[1101] As used herein, unless otherwise indicated, “cancer” refers to cell growth unrelated to normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the following abnormal growths: (1) tumor cells (tumors) that proliferate by expressing mutated tyrosine kinases or by overexpression of receptor tyrosine kinases; (2) benign and malignant cells of other proliferative diseases in which abnormal tyrosine kinase activation occurs; (3) any tumor proliferating by receptor tyrosine kinases; (4) any tumor proliferating by abnormal serine / threonine kinase activation; (5) benign and malignant cells of other proliferative diseases in which abnormal serine / threonine kinase activation occurs; (6) any tumor proliferating by abnormal signaling, metabolic, epigenetic, and transcriptional mechanisms; and (7) benign and malignant cells of other proliferative diseases in which abnormal signaling, metabolic, epigenetic, and transcriptional mechanisms occur.

[1102] For convenience, certain well-known abbreviations including estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-), non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and castration-resistant prostate cancer (CRPC) may be used herein.

[1103] Further embodiments relate to a method for treating cancer in a subject requiring such treatment, comprising the step of administering to the subject an amount of a compound described herein that is effective for treating cancer.

[1104] In another embodiment, cancer is from the group consisting of lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, gastric cancer, liver carcinoma, colon cancer, breast cancer, uterine cancer, carcinoma of the duct of Fallopio, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid, cancer of the parathyroid, cancer of the adrenal gland, soft tissue sarcoma, cancer of the urethra, cancer of the penis, prostate cancer, hematological malignancy, chronic or acute leukemia, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, spinal tumor, glioblastoma, brainstem glioma, and pituitary adenoma. It is selected, or a combination of two or more of the aforementioned cancers.

[1105] In another embodiment, the cancer is cancer of the breast, lung, colon, brain, prostate, stomach, pancreas, ovary, melanoma, endocrine, uterus, testis, or bladder.

[1106] In another embodiment, the cancer is the breast, lung, prostate, pancreas, or ovary.

[1107] In another embodiment, the cancer is breast cancer.

[1108] In another embodiment, the breast cancer is ER+ breast cancer.

[1109] In another embodiment, the breast cancer is ER+ HER2- breast cancer.

[1110] In another embodiment, the breast cancer is locally advanced or metastatic ER+ HER2- breast cancer.

[1111] In another embodiment, the lung cancer is non-small cell lung cancer (NSCLC). In a specific embodiment, the lung cancer is small cell lung cancer (SCLC).

[1112] In another embodiment, the lung cancer is locally advanced or metastatic NSCLC or locally advanced or metastatic SCLC.

[1113] In another embodiment, the prostate cancer is castration-resistant prostate cancer. In a specific embodiment, the prostate cancer is neuroendocrine prostate cancer (NEPC).

[1114] In another embodiment, the prostate cancer is locally advanced or metastatic castration-resistant prostate cancer.

[1115] In another embodiment, the cancer is colon cancer.

[1116] Further embodiments relate to a method for treating a hematological tumor in a subject. Some embodiments relate to the treatment of a hematological tumor, comprising the step of administering an amount of a compound described herein that is effective for treating the hematological tumor to a subject in need.

[1117] In another embodiment, the hematological tumor is leukemia, lymphoma, or multiple myeloma. In a specific embodiment, the hematological tumor is acute myeloid leukemia.

[1118] In another embodiment, the hematological tumor is multiple myeloma.

[1119] In another embodiment, the cancer is multiple myeloma, breast cancer, or prostate cancer. In another embodiment, the cancer is multiple myeloma.

[1120] Further embodiments relate to a method for treating cancer in a patient, comprising the step of administering to the patient an amount of a compound described herein that is effective for treating cancer in combination with an antitumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological reaction modifiers, antibodies, cytotoxic agents, anti-hormones, and anti-androgens.

[1121] Further embodiments relate to a pharmaceutical composition for treating a patient's cancer, comprising an amount of the compound described herein effective for treating cancer and a pharmaceutically acceptable carrier.

[1122] Further embodiments relate to a method for treating disorders related to angiogenesis in a patient, including humans, comprising the step of administering to the patient an amount of the compound described herein as defined above or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, which is effective for treating said disorders in combination with one or more antitumor agents listed above. Such disorders include cancerous tumors such as melanoma; ocular disorders such as age-related macular degeneration, presumed ocular histoplasmosis syndrome, and retinal neovascularization from proliferative diabetic retinopathy; rheumatoid arthritis; bone loss disorders such as osteoporosis, Paget's disease, humoral hypercalcemia from malignant tumors, hypercalcemia from tumors metastatic to bone, and osteoporosis induced by glucocorticoid therapy; coronary artery restenosis; and adenovirus, hantavirus, Borrelia burgdorferi ( Borrelia burgdorferi ), Yersinia( Yersinia It includes specific microbial infections associated with microbial pathogens selected from ) spp., Bordetella pertussis, and Group A Streptococcus.

[1123] Some embodiments relate to a method for treating a patient's cancer (and a pharmaceutical composition for the same), comprising, in an amount effective for treating the abnormal cell growth together, an amount of the compound described herein or a pharmaceutically acceptable salt, solvate, or hydrate thereof in combination with an amount of one or more substances selected from anti-angiogenic agents, signal transduction inhibitors (e.g., inhibiting means by which regulatory molecules governing the basic processes of cell growth, differentiation, and survival communicate within a cell), and antiproliferative agents.

[1124] Anti-angiogenic agents such as MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors may be used in combination with the compounds described herein in the methods and pharmaceutical compositions described herein.

[1125] Tyrosine kinase inhibitors may also be combined with compounds described herein.

[1126] VEGF inhibitors, for example, sutent and axitinib, may also be combined with the compounds described herein.

[1127] ErbB2 receptor inhibitors may be administered in combination with the compounds described herein. Various other compounds, such as styrene derivatives, have also been shown to have tyrosine kinase inhibitory properties, and some tyrosine kinase inhibitors have been identified as erbB2 receptor inhibitors.

[1128] Epidermal growth factor receptor (EGFR) inhibitors can be administered in combination with the compounds of the present invention.

[1129] PI3K inhibitors, such as PI3K alpha or PI3K beta inhibitors, may be administered in combination with the compounds of the present invention.

[1130] Mammalian target (mTOR) inhibitors of rapamycin can be administered in combination with the compounds of the present invention.

[1131] c-Met inhibitors can be administered in combination with the compounds of the present invention.

[1132] CDK inhibitors can be administered in combination with the compounds of the present invention.

[1133] MEK inhibitors can be administered in combination with the compounds of the present invention.

[1134] PARP inhibitors can be administered in combination with the compounds of the present invention.

[1135] JAK inhibitors can be administered in combination with the compounds of the present invention.

[1136] Antagonists of Programmed Death 1 (PD-1) can be administered in combination with the compounds of the present invention.

[1137] Antagonists of Programmed Death-Ligand 1 (PD-L1) can be administered in combination with the compounds of the present invention.

[1138] Other antiproliferative agents that can be used with the compounds described herein include inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr.

[1139] The compounds described herein may also be used in combination with other agents useful for treating abnormal cell growth or cancer, including but not limited to agents capable of enhancing an antitumor immune response, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies and other agents capable of blocking CTLA4, and bispecific antibodies capable of binding to CD3 on T-cells and B-cell maturation antigen (BCMA) on the surface of myeloma cells (e.g., ellanatab); and anti-proliferative agents such as other farnesyl protein transferase inhibitors, such as farnesyl protein transferase.

[1140] The compounds described herein may be applied as monotherapy or may include one or more other antitumor substances selected from, for example, mitotic inhibitors, alkylating agents, antimetabolites, growth factor inhibitors, cell cycle inhibitors, intercalating antibiotics, enzymes, and anti-hormones.

[1141] The compounds described herein may be used alone or in combination with one or more of various anticancer agents or adjuvant therapies. For example, the compounds described herein may be used with cytotoxic agents. Some embodiments also consider the use of the compounds described herein with hormone therapy. Additionally, some embodiments provide the compounds described herein alone or in combination with one or more adjuvant therapy products selected from the group consisting of filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or combinations thereof. Such combination therapy may be achieved by simultaneous, sequential, or separate administration of the individual components of the therapy.

[1142] The compounds described herein may be used with antitumor agents, alkylating agents, anmetatars, antibiotics, plant-derived antitumor agents, camptothecin derivatives, tyrosine kinase inhibitors, antibodies, interferons, and / or biological reaction modifiers. In this regard, the following is a non-limiting list of examples of secondary agents that may be used with the compounds described herein.

[1143] concomitant administration

[1144] The compounds of the present invention may be used alone or in combination with one or more other therapeutic agents. The present invention provides any use, method, or composition defined herein, and the compounds of the present invention or pharmaceutically acceptable salts thereof are used in combination with one or more other therapeutic agents discussed herein.

[1145] Administration of two or more compounds "in combination" means that all compounds are administered within a time sufficiently close to affect the treatment of the subject. Two or more compounds may be administered simultaneously or sequentially through the same or different routes of administration, according to the same or different administration schedules, with or without specific time limits depending on the therapeutic regimen. Additionally, simultaneous administration may be performed by mixing the compounds before administration, or by administering the compounds as separate forms of administration at the same time but at the same or different sites of administration. Examples of "in combination" include, but are not limited to, "simultaneous administration," "concomitant administration," "simultaneous administration," "sequential administration," and "administered simultaneously."

[1146] The compound of the present invention and one or more other therapeutic agents may be administered as a fixed or non-fixed combination of active ingredients. The term "fixed combination" means that the compound of the present invention or a pharmaceutically acceptable salt thereof and one or more therapeutic agents are administered simultaneously to a subject in a single composition or dose. The term "non-fixed combination" means that the compound of the present invention or a pharmaceutically acceptable salt thereof and one or more therapeutic agents are formulated in separate compositions or doses and may be administered simultaneously or at different times with variable intervening time limits to a subject requiring them, and such administration provides effective levels of two or more compounds to the subject's body.

[1147] These formulations and compounds of the present invention may be combined with pharmaceutically acceptable vehicles such as saline solution, Ringer's solution, dextrose solution, etc. Specific administration regimens, i.e., dosage, timing, and repetition, vary depending on the specific individual and their medical record.

[1148] Kit

[1149] Another aspect of the present invention provides a kit comprising a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention. The kit may comprise a diagnostic agent or a therapeutic agent in addition to the compound of the present invention or its pharmaceutical composition. The kit may also include instructions for use in a diagnostic or therapeutic method. In some embodiments, the kit comprises a compound or its pharmaceutical composition and a diagnostic agent. In other embodiments, the kit comprises a compound or its pharmaceutical composition and one or more therapeutic agents, such as an anticancer agent.

[1150] In another embodiment, the present invention comprises a kit suitable for use in carrying out the method of treatment described herein. In one embodiment, the kit comprises a first dosage form comprising one or more compounds of the present invention in an amount sufficient to carry out the method of the invention. In another embodiment, the kit comprises one or more compounds of the invention in an amount sufficient to carry out the method of the present invention, a container for the dosage, and a container for the dosage.

[1151] Synthesis method

[1152] The compounds of the present disclosure may be synthesized by routes involving processes similar to those well known in the chemical art, particularly in light of the description contained herein. Starting materials may be generally available from commercial sources or may be prepared using methods well known to those skilled in the art. Many of the compounds used herein may be related to or derived from compounds for which one or more of scientific interest or commercial needs have arisen. Accordingly, such compounds may be one or more of: 1) commercially available; 2) reported in the literature; or 3) prepared by those skilled in the art from other commonly available materials using materials reported in the literature.

[1153] For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present disclosure as well as key intermediates. For a more detailed description of individual reaction steps, refer to the Examples section below. Those skilled in the art will understand that other synthetic routes may be used to synthesize the compounds of the present invention. Although specific starting materials and reagents are discussed below, other starting materials and reagents may be substituted to provide various derivatives or one or more of the reaction conditions. Furthermore, many of the compounds prepared by the methods described below may be further modified using conventional chemistry well known to those skilled in the art in light of this disclosure.

[1154] Those skilled in the art will understand that the experimental conditions described in the reaction schemes below are examples of suitable conditions for carrying out the depicted modifications, and that it may be necessary or desirable to change the exact conditions used to prepare the compounds of the disclosure. They will also understand that it may be necessary or desirable to carry out modifications in a different order than described in the reaction schemes, or to modify one or more of the modifications to provide the desired compounds of the disclosure.

[1155] It should be noted that in the preparation of the compounds of the disclosure, some of the preparation methods useful for the preparation of the compounds described herein may require protection of remote functional groups (e.g., primary amines, secondary amines, carboxyls, etc. in the precursors of the compounds of the disclosure). The need for such protection depends on the nature of the remote functional group and the conditions of the preparation method. The need for such protection is readily determined by those skilled in the art. The use of such protection / deprotection methods is also within the skill of those skilled in the art. For a general description of protecting groups and their use, see the literature [SMITH, MB, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure. 8]. thRefer to Ed. New Jersey, Wiley, 2019.

[1156] For example, if a compound contains amine or carboxylic acid functional groups, these functional groups can interfere with reactions at other parts of the molecule if left unprotected. Therefore, these functional groups can be protected by a suitable protecting group (PG) that can be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection are protecting groups commonly used in peptide synthesis (e.g., for amines). N It includes -t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc) and lower alkyl or benzyl esters for carboxylic acids, which are generally not chemically reactive under the described reaction conditions and can typically be removed without chemically altering other functional groups in the compounds of the disclosure.

[1157] General experiment details

[1158] 1 H and 19 The F Nuclear Magnetic Resonance (NMR) spectrum was recorded on a Bruker XWIN-NMR (400 or 700 MHz) spectrometer. 1 H and 19 F resonance is reported from tetramethylsilane in the low field as a million parts sugar (ppm). 1 ¹H NMR data are reported as multiplicity (e.g., s, single; d, double; t, triple; q, quadruplet; quint, pentuplet; dd, doublet of double; dt, triplet of double; br s, broad single; m, multiple). CDCl3, DMSO- d For the spectra obtained from 6 and CD3OD, residual protons (7.27, 2.50, and 3.31 ppm, respectively) were used as internal true wh. All observed coupling constants, JIt is reported in Hertz (Hz). "δ" signifies chemical shift. Exchangeable protons are not always observed.

[1159] Optical rotation was determined on a Jasco P-2000 or Rudolph Autopol IV polarimeter. All final compounds were purified to ≥ 95% purity unless otherwise specified. Where absolute stereochemistry is known, ( R , S ) labels are used. If absolute stereochemistry is unknown, the software-generated name is modified to include a symbol (ξ) representing a single isomer with unknown stereochemistry, and the chemical structure is modified to include "or 1" at a chiral center with unknown stereochemistry. If there is an atrope isomer and absolute stereochemistry is unknown, the software-generated name is modified to include a symbol (ψ) representing a single isomer with unknown stereochemistry.

[1160] Mass spectra, MS (m / z), were recorded using electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). Unless otherwise noted and applicable, the provided m / z data are isotopes 19 F, 35 Cl, 79 Br and 127 It is about I.

[1161] The compounds and intermediates described below were named using the naming conventions provided with ACD / Labs 2022.2.0, File Version N25E41, Build 131856, 30 Jan 2025, and ACD / Labs 2023.2.0, File Version C45H41, Build 137017, 18 Jan 2024 (Advanced Chemistry Development, 8 King Street East, Suite 107, Toronto, Ontario, M5C 1B5, Canada). The nomenclature provided with ACD / Labs 2022.2.0 and ACD / Labs 2023.2.0 is well known to those skilled in the art and is generally considered to be in accordance with the IUPAC (International Union for Pure and Applied Chemistry) recommendations and CAS index rules for nomenclature in organic chemistry. Unless otherwise noted, all reactants were obtained commercially without further purification or prepared using methods known in the literature.

[1162] abbreviation

[1163] In the non-limiting examples and preparations described in the description illustrating the invention, and in the following reaction schemes, the following abbreviations, definitions, and analytical procedures may be referenced: "ACN" means acetonitrile, "AIBN" means azobisisobutyronitrile, "APCI" means atmospheric chemical ionization, "aq" means aqueous, "atm" means atmosphere, "BBr3" means borane tribromide, "BOC," "Boc," or "boc" means N-tert-butoxycarbonyl, "Boc2O" means di-tert-butyl dicarbonate, "B(pin)" means pinacollato boron ((CH3)4C2O2B-), "B2Pin2" means bis(pinacollato)diborane, "br" means broad signal, and "Bn" means benzyl. "Bu" means butyl, "nBu" means normal-butyl, "tBu" means tert-butyl, and "KO t"Bu" means potassium tert-butoxide, "c" means concentration, "°C" means temperature in degrees Celsius, "CDCl3" means deuterium chloroform, "CO2" means carbon dioxide, "Cs2CO3" means cesium carbonate, "d" means doublet, "DBU" means 1,8-diazabicyclo 5.4.0-undec-7-ene, "DCE" means dichloroethane, "DCM(CH2Cl2)" means methylene chloride, "dd" means doublet of doublet, "de" means excess diastereoisomer, "DEA" means diethylamine, "DIAD" means diisopropyl azodicarboxylate, "DIPEA" and "DIEA" mean diisopropyl ethylamine, and "DMAP" is It means 4-(dimethylamino)pyridine, "DME" means 1,2-dimethoxyethane, "DMSO-d6" means deuterated dimethyl sulfoxide, "DMF" means N,N-dimethylformamide, "DMSO" means dimethyl sulfoxide, "dt" means triplet of doubles, "EA" or "EtOAc" means ethyl acetate, "EDCI" means 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, "ESI" means electrospray ionization, "ee" means enantiomer excess, "equiv" means equivalent, "Et" means ethyl, "EtOH" means ethanol, "g" means gram, "h" means time, and "HATU" 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b ] refers to Pyridinium 3-Oxide Hexafluorophosphate, "HCl" refers to hydrochloric acid, "HOAc" or "AcOH" refers to acetic acid, and " 1 ¹H NMR is proton nuclear magnetic resonance ,It means, "H2O" means water, "HPLC" means high-pressure liquid chromatography, and "i-Pr" or " i "Pr" means isopropyl, "IPA" means isopropyl alcohol, "K2CO3" means potassium carbonate, "KOAc" means potassium acetate, "KOH" means potassium hydroxide, "L" means liter, "LAH" means lithium aluminum hydride, "LCMS" means liquid chromatography-mass spectrometry, "LDA" means lithium diisopropylamide, "LiHMDS" means lithium hexamethyldisylazide (lithium bis(trimethylsilyl)amide), "LiOH" means lithium hydroxide, "m" means multiline, "M" means molar, "Me" means methyl, "MeCN" means acetonitrile, "MeOH" means methanol, "mg" means milligram, and "MgSO4" means magnesium It means sulfate, "MHz" means megahertz, "mL" means milliliter, "min" means minute, "mm" means millimeter, "mmol" means millimole, "MS" means mass spectrometry, "MTBE" means methyl tert-butyl ether, "N" means normal, "NaHCO3" means sodium bicarbonate, "Na2SO4" means sodium sulfate, "NBS" means N-bromosuccinimide, "N / D" means undetermined, "NH3" means ammonia, "NH4Cl" means ammonium chloride, "NIS" means N-iodosuccinimide, "NMI" means 1-methylimidazole, and "PdCl2(dppf)" is [1,1'-Bis(diphenylphosphino)ferrocene] means dichloropalladium(II), "PE" means petroleum ether, "Ph" means phenyl, "ppm" means parts per million, and "PTSA" is p- refers to toluenesulfonic acid monohydrate, "q" refers to a quadruplet, "quint" refers to a pentuplet, "RT" refers to room temperature, "s" refers to a single line, "sat" refers to saturation, "SiO2" refers to silica, "sxt" refers to a hexuplet, "t" refers to a triplet, "TBAF" refers to tetrabutylammonium fluoride, "TBME" refers to tert-butyl methyl ether, and "TCFH" refers to chloro- N , N , N ', N '-It means tetramethylformamidinium hexafluorophosphate, "td" means triplet double, "TEA" means triethylamine, "TFA" means trifluoroacetic acid, "THF" means tetrahydrofuran, "TMSCN" means trimethylsilyl cyanide, "SFC" means supercritical fluid chromatography, "TLC" means thin-layer chromatography, "Rf" means retention factor, "~" means approximate, "rt" means retention time, "uL" means microliter, and "um" means micrometer.

[1164] The reaction schemes described below are intended to provide a general description of the methodology used for the preparation of the compounds of the present disclosure. Some of the compounds of the present disclosure contain a single chiral center. In the reaction schemes below, the general method for preparing the compounds is shown in a racemic or enantiomer-enriched form. It will be apparent to those skilled in the art that whether the material is enantiomer-enriched or racemic, the respective synthetic modifications can be carried out in exactly similar ways. Furthermore, the splitting into the desired optically active material can occur at any desired point in the sequence using well-known methods, such as those described herein and in the chemical literature.

[1165] General method:

[1166] Unless otherwise specified, Reaction Equation I inside XII Variables in this context have the same meaning as defined herein.

[1167] Reaction Equation I: General Method A

[1168]

[1169]

[1170] General method A is as described above, Chemical formula A It refers to the synthesis sequence for preparing the compound of phenol. MA -1 and commercially available amino alcohols MA -2 Sai's Mitsunobu reaction is ether MA -3 Provides boronate or boronic acid ester MA -4 (In this case, the Suzuki coupling of R' with (HO)2B- or (CH3)4C2O2B- (i.e., pinacolato boron "B(pin)") is under standard cross-coupling conditions MA -5 It provides. The deprotection of amines under acidic conditions is the amine MA -6 Provides amine MA -6 and acid MA -7 The amide coupling between (n = 0 or 1) is an amide MA -8 It provides. By ester hydrolysis of the ester group MA -9 After providing, the protector (Boc) is deprotected using conditions known in the art to acid Chemical formula A It provides.

[1171] MA -1 If this is not commercially available (R 5 and R 6(If this is not H and m is not 0), MA -1 silver bromide MA -10 Synthesized from through a two-step procedure including alkylation and demethylation MA-1 It provides

[1172] mountain MA -7 (n = 0 or 1) is formed through the three-step procedure described above. Acid MA -12 ester according to standard esterification conditions MA -13 It is converted to. Fluorination following α-deprotonation is MA -14 A fluoro group is introduced into it. Finally, the ester MA -14 The hydrolysis of acid MA-7 It provides

[1173] Reaction Equation II: General Method B

[1174]

[1175]

[1176] General method B is as described above Chemical formula B It refers to a synthesis sequence for preparing a compound. ester MA -5 The hydrolysis of acid MB -1 It provides. Under standard conditions, acid MB -1 class MB -2 The coupling is MB -3 It provides. Deprotection of amines under acidic conditions is amine MB -4 Provides amine MB -4 Wa San MA -7 The amide coupling between them is an amide MB-5 It provides. The deprotection of a protector (Boc) using conditions known in the relevant technical field is Chemical formula B It provides.

[1177] Reaction Equation III: General Method C

[1178]

[1179]

[1180] General method C is as described above Chemical formula C It refers to a synthetic sequence for preparing a compound. Under standard conditions, acid MA -9 and MB -2 The coupling is MB -5 It provides. By deprotecting the protector (Boc) using conditions known in the relevant technical field. Chemical formula C It provides.

[1181] Reaction Equation IV: General Method D

[1182]

[1183] General method D is as described above Chemical formula D It refers to a synthesis sequence for preparing a compound of. amine MA -6 and acid MD -1 The amide coupling between them is an amide MD -2 It provides. The ester hydrolysis of the ester group is acid Chemical formula D It provides.

[1184] MD -1 If this is not commercially available (R 12 and R 13 (if this is not methyl), MD-1 It is acidic, involving Eschweiler-Clarke methylation following Boc removal under acidic conditions. MD -3 Synthesized through a two-step procedure from MD -1 It provides

[1185] Reaction equation V: General method E

[1186]

[1187] General method E is as described above Chemical formula E Describes the synthesis sequence for preparing the compound. Under standard conditions, acid Chemical formula D and MB -2 The coupling is Chemical formula E It provides.

[1188] Reaction Equation VI: General Method F

[1189]

[1190]

[1191] General method F is as described above Chemical formula F It refers to the synthesis sequence for preparing the compound of phenol. MA -1 and commercially available amino alcohols MF-1 Sai's Mitsunobu reaction is ether MF-2 Provides boronate or boronic acid esters under standard cross-coupling conditions MA -4 The Suzuki coupling with (where R' is the (HO)2B- or B(pin) defined above) is MF-3 It provides. Deprotection of amines under acidic conditions is amine MF-4 Provides amine MF-4 Wa San MA -7 or mountain MD -1 The amide coupling between them is an amide MF-5 Provides ester hydrolysis of the ester group and, where R4 includes a protecting group, deprotection of the protecting group (Boc) using conditions known in the art is acid Chemical formula F It provides.

[1192] Reaction Equation VII: General Method G

[1193]

[1194] General method G is as described above Chemical formula G It refers to a synthesis sequence for preparing a compound. ester MF-5 The ester hydrolysis of acid MG -1 It provides. Under standard conditions, acid MG -1 class MB -2 In the case of coupling, and where R4 includes a protector, the deprotection of the protector (Boc) using conditions known in the art is Chemical formula G It provides.

[1195] Reaction Equation VIII: General Method H

[1196]

[1197] General method H is as described above Chemical formula H It refers to the synthesis sequence for preparing the compound of phenol. MH -1 and commercially available amino alcohols MA -2 Sai's Mitsunobu reaction is ether MH -2 Provides boronate or boronic acid esters under standard cross-coupling conditions MA -4 The Suzuki coupling with (where R' is the (HO)2B- or B(pin) defined above) is MH -3 It provides. Deprotection of amines under acidic conditions is amine MH -4 Provides amine MH -4 and acid MA -7 or mountain MD -1 The amide coupling between them is an amide MH-5 Provides ester hydrolysis of the ester group, and, where R4 contains a protecting group, deprotection of the protecting group (Boc) using conditions known in the art, acid Chemical formula H It provides.

[1198] MH -1 If this is not commercially available (m is not 0), MH -1 silver MH -6 It is synthesized from acid. MH -6 The reduction of alcohol MH -7 It provides, which subsequently uses thionyl chloride to produce chloride MH -8 It can be converted to chloride. MH - 8 is cyano through substitution MH -9 It transforms into. Under acidic conditions, cyano MH -9 The hydrolysis of is ester MH - 10 It provides. Finally, ester MH -10 The demethylation of phenol MH -1 It provides

[1199] Reaction Equation IX: General Method I

[1200]

[1201] General method I is as described above Chemical Formula I It refers to a synthesis sequence for preparing a compound. ester MH -5 The ester hydrolysis of acid MI -1 It provides. Mountain MI-1 under standard conditions MB -2 Coupling with, and if R4 includes a protector, deprotect the protector (Boc) using conditions known in the art. Chemical Formula I It provides

[1202] Reaction equation X: General method J

[1203]

[1204]

[1205] General method J is as described above, Chemical formula J It refers to the synthesis sequence for preparing the compound of phenol. MJ-1 and commercially available amino alcohols MA -2 Sai's Mitsunobu reaction is ether MJ-2 It provides iodide under standard cross-coupling conditions. MJ-2 and boronate or boronic acid ester MJ-3 The Suzuki coupling (where R' is the above-defined (HO)2B- or B(pin)) is MJ-4 It provides bromide under standard cross-coupling conditions. MJ-4 and boronate or boronic acid ester MA -4 The Suzuki coupling (where R' is the above-defined (HO)2B- or B(pin)) is MJ-5 It provides. Deprotection of amines under acidic conditions is amine MJ-6 Provides amine MJ-6 and acid MA -7 or mountain MD -1 The amide coupling between them is an amide MJ- 7 Provides ester hydrolysis of the ester group and, where R4 includes a protecting group, deprotection of the protecting group (Boc) using conditions known in the art is performed by acid Chemical formula J It provides.

[1206] Boronic acid ester ( MJ-3 ) is a mountain( MJ-8 It is formed in a 3-4 step sequence starting with ). Acid( MJ-8 ) is Esther ( MJ-9 It is converted to ). Alkylation is R 5 and / or R 6 It is performed in some cases to introduce pyrrole. MJ-9 The bromination of ) is bromide ( MJ-10) provides, which subsequently boronic acid ester ( MJ-3 It can be converted to ).

[1207] Reaction Equation XI: General Method K

[1208]

[1209]

[1210] General method K is as described above Chemical formula K It refers to a synthesis sequence for preparing a compound. Alcohols via benzylation ( MK - 1 Benzyl protection and subsequent hydrolysis of ) alcohol( MK - 2 Provides ). Alcohol( MK - 2 imidate formation from ) MK -3 It provides. Iodo-cyclization MK -4 It provides. The deprotection of amino alcohols and subsequent radical-mediated deiodination MK -5 It provides. Using a Boc group in the nitrogen phase MK -5 The first protection of and subsequently hemiaminal formation and debenzylation under standard conditions is alcohol ( MK - 6 It provides ).

[1211] phenol( MA - 1 ) and alcohol( MK -6 The Mitsunobu reaction between ) is ether ( MK - 7 Provides ). Bromide( MK-7 ) and boronate or boronic acid ester ( MA - 4The Suzuki coupling under standard cross-coupling conditions of )(where R' is the (HO)2B- or B(pin) defined above) is MK -8 It provides. Acid-mediated deprotection is amine ( MK - 9 Provides ). Amine( MK - 9 ) and mountain( MA -7 ) or acid( MD-1 The amide coupling between ) is amide ( MK - 10 Provides ). In the case where the ester hydrolysis of the ester group and R4 includes a protecting group, the deprotection of the protecting group (Boc) using conditions known in the art is acid Chemical formula K It provides. Also, phenol ( MH - 1 ) provides the compound chemical formula K, phenol( MA-1 It can be used instead of ).

[1212] Reaction Equation XII: General Method L

[1213]

[1214] The general method L is as described above, Chemical formula L It refers to the synthesis sequence for preparing the compound of. Phenol ( ML - 1 ) is aniline ( in a two-step procedure including methylation and nitro reduction under standard conditions) ML - 2 It is converted to ). Aniline( ML - 2 The diazotization and reduction of ) is hydrazine ( ML - 3 After providing ), cyclization with aminoacrylonitrile is aminopyrazole ( ML - 4It provides ). Demethylation is phenol( ML - 5 Provides ). Phenol( ML -5 ) and commercially available amino alcohols ( MA -2 The Mitsunobu reaction between ) is ether ( ML-6 Provides ). Bromide( ML - 6 ) and boronate or boronic acid ester ( MA -4 The Suzuki coupling under standard cross-coupling conditions of )(where R' is the (HO)2B- or B(pin) defined above) is ML -7 Provides . amine( ML - 7 sulfonamide formation from ) is sulfonamide ( ML-8 ) provides. Deprotection of Boc-protected amines under acidic conditions is amine ( ML-9 Provides ). Amine( ML - 9 ) and mountain( MA -7 ) or acid( MD -1 In the case of amide coupling between ) and where R4 includes a protecting group, deprotection of the protecting group (Boc) using conditions known in the art is performed on a sulfonamide Chemical formula L It provides

[1215] Preparation of intermediates

[1216] Preparation of Intermediate 1: Methyl 2-(3- Bromo -4- hydroxyphenyl )-2- Methylpropanoate

[1217] Step 1 : Methyl (3-bromo-4-methoxyphenyl)acetate ( 1a )

[1218]

[1219] NBS (207.4 g, 1.17 mol) was slowly added at 25°C to a solution of methyl (4-methoxyphenyl)acetate (200 g, 1.11 mol) in ACN (1.8 L). The mixture was stirred for 15 hours and then concentrated under reduced pressure. The residue was dissolved in EtOAc (1.5 L), washed with saturated NaHCO3 (2x) and brine (2x), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain methyl (3-bromo-4-methoxyphenyl)acetate as an orange oil. 1a )(280 g, 97%) was obtained. LCMS ESI (+) 259.0, 261.0 (M+H). 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 7.48 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 8.4, 2.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 3.83 (s, 3H), 3.63 (s, 2H), 3.61 (s, 3H).

[1220] Step 2 : Methyl 2-(3-bromo-4-methoxyphenyl)-2-methylpropanoate( 1b )

[1221]

[1222] Methyl (3-bromo-4-methoxyphenyl)acetate in THF (2.5 L) 1a Iodomethane (247 g, 1.74 mol) was slowly added to a solution of )(180 g, 0.695 mol) at -50°C. Subsequently, KO tBu (195 g, 1.74 mol) was added gradually while maintaining the internal temperature below -40°C. The cooling bath was removed, and the mixture was stirred for 4 hours. The mixture was quenched in ice water and then extracted with EtOAc. The organic layer was washed with brine (twice), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (THF / PE = 1 / 10) to obtain methyl 2-(3-bromo-4-methoxyphenyl)-2-methylpropanoate as a yellow oil. 1b )(160 g, 80%) was obtained. LCMS ESI (+) 287.0, 289.0 (M+H). 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 7.45 (d, J = 2.4 Hz, 1H), 7.27 (dd, J = 8.4, 2.4 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 3.83 (s, 3H), 3.58 (s, 3H), 1.48 (s, 6H).

[1223] Step 3 : Methyl 2-(3-bromo-4-hydroxyphenyl)-2-methylpropanoate( Intermediate 1 )

[1224]

[1225] Intermediate 1

[1226] Methyl 2-(3-bromo-4-methoxyphenyl)-2-methylpropanoate in DCM (1.5 L) 1b BBr3 (97 mL, 1.05 mol) was slowly added to a solution of ) (150 g, 0.522 mol) at 0°C. The cooling bath was removed, and the mixture was stirred for 12 hours. The mixture was cooled back to 0°C, methanol was added dropwise, and the mixture was quenched and neutralized with saturated NaHCO3. The solution was extracted with DCM (2x), and the combined organic matter was extracted with Na2SO4 ,It was dried on a surface, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (THF / PE = 1 / 8) to obtain methyl 2-(3-bromo-4-hydroxyphenyl)-2-methylpropanoate ( intermediate 1 )(130 g, 91%) was obtained as a yellow solid. LCMS ESI (+) 273.0, 275.0 (M+H). 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 10.20 (s, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.11 (dd, J = 8.8, 2.4 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 3.57 (s, 3H), 1.45 (s, 6H).

[1227] Preparation of Intermediate 2: 2-(2- Cyclobutyl -3- fluorophenyl )-4,4,5,5- Tetramethyl -1,3,2-dioxaborolein

[1228] Step 1 : 1-(2-fluoro-6-methoxyphenyl)cyclobutan-1-ol( 2a )

[1229]

[1230] LDA (2.0 M, 0.516 mol) was added dropwise at -65°C to a solution of 1-fluoro-3-methoxybenzene (50.5 g, 0.396 mol) in THF (600 mL). After stirring for 1 hour at -65°C, cyclobutanone (33.4 g, 0.476 mol) was added dropwise. After 1 hour, the reaction was quenched with saturated NH4Cl and water at 0°C and then extracted with EtOAc (3x). The combined organic matter was washed with brine (2x), and Na2SO4 ,It was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-17% EtOAc / PE) to obtain 1-(2-fluoro-6-methoxyphenyl)cyclobutan-1-ol as a pale yellow oil ( 2a )(45 g, 56%) was obtained. 1 ¹H NMR (400 MHz, chloroform-d) δ = 7.19 (dt, J = 6.4, 8.3 Hz, 1H), 6.73 - 6.62 (m, 2H), 3.86 (s, 3H), 2.78 - 2.65 (m, 3H), 2.51 - 2.28 (m, 3H), 1.94 - 1.79 (m, 1H).

[1231] Step 2 : 2-cyclobutyl-1-fluoro-3-methoxybenzene( 2b )

[1232]

[1233] 1-(2-fluoro-6-methoxyphenyl)cyclobutan-1-ol in DCM (650 mL) 2a Triethylsilane (80.0 g, 0.688 mol, 110 mL) was added to a solution of ) (45.0 g, 0.229 mol) at 0°C. After 30 minutes, TFA (105 g, 0.917 mol, 68.1 mL) was added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (0-10% EtOAc / PE) to obtain 2-cyclobutyl-1-fluoro-3-methoxybenzene ( 2b )(23.7 g, 57% yield) was obtained. 1 ¹H NMR (400 MHz, chloroform-d) δ = 7.00 (dt, J = 6.6, 8.3 Hz, 1H), 6.60 - 6.50 (m, 2H), 3.85 - 3.68 (m, 4H), 2.47 - 2.36 (m, 2H), 2.27 - 2.15 (m, 2H), 1.97 - 1.76 (m, 2H).

[1234] Step 3 : 2-cyclobutyl-3-fluorophenol( 2c )

[1235]

[1236] 2-cyclobutyl-1-fluoro-3-methoxybenzene in DCM (700 mL) 2b BBr3 (172 g, 66.1 mL, 0.686 mol) was added dropwise to a solution of )(41.2 g, 0.229 mol) at -65°C. After stirring the reaction at 0°C for 2 hours, it was quenched with ice water and extracted with DCM (3x). The combined organic matter was washed with brine (3x), and Na2SO4 , It was dried and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0-10% EtOAc / PE) to obtain 2-cyclobutyl-3-fluorophenol as a brown oil ( 2c )(31.5 g, 83%) was obtained. 1 ¹H NMR (400 MHz, chloroform-d) δ = 7.01 (dt, J = 6.3, 8.2 Hz, 1H), 6.62 (t, J = 9.4 Hz, 1H), 6.55 (d, J = 8.1 Hz, 1H), 4.96 (br s, 1H), 3.83 - 3.73 (m, 1H), 2.59 - 2.48 (m, 2H), 2.44 - 2.34 (m, 2H), 2.07 - 1.90 (m, 2H).

[1237] Step 4 : 2-cyclobutyl-3-fluorophenyl trifluoromethanesulfonate ( 2d )

[1238]

[1239] 2-cyclobutyl-3-fluorophenol in pyridine (350 mL) 2cTrifluoromethanesulfonic acid anhydride (63.2 g, 37.7 mL, 0.224 mol) was added dropwise at 0°C to a solution of ) (31.0 g, 0.187 mol). The reaction was stirred at room temperature for 2 hours and then quenched with EtOAc. The reaction was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0-10% EtOAc / PE) to obtain 2-cyclobutyl-3-fluorophenyl trifluoromethanesulfonate ( 2d )(38.4 g, 69%) was obtained. 1 H NMR (400 MHz, CDCl3) δ ppm 7.25 (td, J =8.36, 5.94 Hz, 1H) 7.08 (td, J =10.12, 8.80 Hz, 2H) 3.81 (quin, J =9.19 Hz, 1H) 2.40 - 2.57 (m, 4H) 1.90 - 2.16 (m, 2H).

[1240] step 5 : 2-(2-cyclobutyl-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolein( Intermediate 2 )

[1241]

[1242] Intermediate 2

[1243] 2-cyclobutyl-3-fluorophenyl trifluoromethanesulfonate in dioxane (400 mL) 2dA mixture of )(19.2 g, 0.064 mol), bis(pinacolato)diborane (22.9 g, 0.090 mol), and KOAc (19.0 g, 0.193 mol) was degassed and purged with N2 (3x). [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium (4.71 g, 6.44 mmol) was added to the mixture, and the mixture was stirred at 110°C for 24 hours. After concentrating the reaction mixture under reduced pressure, PE was added to the residue, and the mixture was stirred for 2 hours. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% EtOAc / PE) to obtain 2-(2-cyclobutyl-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolein ( intermediate 2 )(85%) was obtained as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ ppm 7.42 (dd, J =7.26, 1.10 Hz, 1H) 7.15 (td, J =7.70, 4.84 Hz, 1H) 7.03 - 7.10 (m, 1H) 4.15 (quin, J =9.19 Hz, 1H) 2.31 - 2.55 (m, 4H) 1.87 - 2.11 (m, 2H) 1.37 - 1.41 (m, 12H).

[1244] Preparation of Intermediate 3: 5-( tert - Butoxycarbonyl )-7- fluoro -5- Azaspiro[3.4]octane -7-carboxylic acid

[1245] step 1 : 5- tert -butyl 7-methyl 5-azaspiro[3,4]octane-5,7-dicarboxylate( 3a )

[1246]

[1247] 5- in DMF (91 mL) tert K2CO3 (9.5 g, 69 mmol) was added to a solution of -butoxycarbonyl)-5-azaspiro[3,4]octane-7-carboxylic acid (7.0 g, 27 mmol), followed by the addition of iodomethane (4.9 g, 2.1 mL, 34 mmol). The reaction mixture was stirred at room temperature for 4 hours and then concentrated under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was separated, washed again with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain 5- as an orange oil. tert -butyl 7-methyl 5-azaspiro[3,4]octane-5,7-dicarboxylate( 3a )(7.0 g, 95%) was obtained. LCMS APCI (+) 170.1 (M-Boc). 1 ¹H NMR (400 MHz, DMSO- d 6 , 80℃) δ ppm 3.65 (s, 3H) 3.49 - 3.57 (m, 1H) 3.38 - 3.47 (m, 1H) 2.93 - 3.02 (m, 2H) 2.75 - 2.83 (m, 1H) 2.39 (dd, J=12.57, 6.82 Hz, 1H) 2.19 (dd, J=12.38, 9.01 Hz, 1H) 1.77 - 1.89 (m, 2H) 1.58 - 1.74 (m, 2H) 1.46 (s, 9H).

[1248] step 2 : 5- tert -butyl 7-methyl 7-fluoro-5-azaspiro[3,4]octane-5,7-dicarboxylate( 3b )

[1249]

[1250] In a -78°C solution of LDA (2.0 M, 6.4 mL, 12.8 mmol) in THF (26 mL), 5- in THF (13 mL) tert-butyl 7-methyl 5-azaspiro[3,4]octane-5,7-dicarboxylate( 3a A solution of )(1.38 g, 5.12 mmol) was added via a syringe pump at a rate of 0.4 mL / min. After 1 hour at -78°C, this solution was injected dropwise via a cannula into a -78°C solution of N-fluorobenzenesulfonimide (1.04 g, 12.8 mmol) in THF (26 mL). After 1 hour at -78°C, the reaction was quenched with saturated NH4Cl under cold conditions and allowed to be heated to RT. The reaction was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% EtOAc / heptane) to obtain a clear oil, 5- tert -butyl 7-methyl 7-fluoro-5-azaspiro[3,4]octane-5,7-dicarboxylate( 3b )(950 mg, 65%) was obtained. LCMS APCI (+) 188.1 (M-Boc). 1 ¹H NMR (400 MHz, DMSO- d 6 , 80℃) δ ppm 3.78 (s, 4H) 3.68 - 3.72 (m, 1H) 3.17 (q, J=10.13 Hz, 1H) 2.67 - 2.83 (m, 2H) 2.44 (d, J=14.38 Hz, 1H) 1.89 - 2.07 (m, 2H) 1.56 - 1.78 (m, 2H) 1.47 (s, 9H).

[1251] step 3 : 5-( tert -butoxycarbonyl)-7-fluoro-5-azaspiro[3,4]octane-7-carboxylic acid ( Intermediate 3 )

[1252]

[1253] Intermediate 3

[1254] 5- in methanol (13.9 mL) tert -butyl 7-methyl 7-fluoro-5-azaspiro[3,4]octane-5,7-dicarboxylate( 3b LiOH (1 M, 5.55 mL, 5.55 mmol) was added to a solution of )(798 mg, 2.78 mmol). After stirring at RT for 2 hours, the reaction was diluted with EtOAc, washed with 1 N HCl and saline solution, dried over MgSO4, filtered, and concentrated under reduced pressure to 5-( tert -butoxycarbonyl)-7-fluoro-5-azaspiro[3,4]octane-7-carboxylic acid ( intermediate 3 )(736 mg, 97%) was obtained as a light brown waxy solid. LCMS APCI (-) 272.1 (MH). 1 ¹H NMR (400 MHz, DMSO- d 6 , 80℃) δ ppm 3.75 (s, 1H) 3.68 (s, 1H) 3.12 - 3.24 (m, 1H) 2.66 - 2.83 (m, 2H) 2.42 (d, J=14.26 Hz, 1H) 1.90 - 2.06 (m, 2H) 1.59 - 1.77 (m, 2H) 1.47 (s, 9H).

[1255]

[1256] Intermediate 3'

[1257]

[1258] Intermediate 3"

[1259] The racemic compound could be purified into enantiomers via preparative SFC (Column: Chiralpak IC SFC, 250 x 21 mm, 5 µm; Temperature: 25°C; Pressure: 120 bar; Flow rate: 70 mL / min; 10% MeOH + 10 mm NH3 in CO2). Peak 1: (7 S )-5-( tert-butoxycarbonyl)-7-fluoro-5-azaspiro[3,4]octane-7-carboxylic acid ( Intermediate 3' ) was isolated as a white solid (>99% ee). = +6.1°( c 0.1, MeOH). The absolute stereochemistry of the intermediate 3' was determined by small molecule X-ray crystallography. Peak 2: (7 R )-5-( tert -butoxycarbonyl)-7-fluoro-5-azaspiro[3,4]octane-7-carboxylic acid ( Intermediate 3" ) was isolated as a white solid (93% ee). = -11.8°( c 0.1, MeOH). Procedure for single-crystal X-ray diffraction: Crystals of (3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxyhexahydro-2H-1,3-benzodioxol-5-amium salt of intermediate 3' were grown from acetonitrile / H2O, and the structure and stereochemistry of intermediate 3' were Cu K α It was confirmed by small molecule X-ray crystallography using a Bruker SMART Pt135 CCD diffractometer equipped with radiation (λ = 1.54178 Å).

[1260] Preparation of Intermediate 4: 1-( tert - Butoxycarbonyl )-3- fluoro -5,5- Dimethylpyrrolidine -3-carboxylic acid

[1261]

[1262] Intermediate 4

[1263] Intermediate 4 is 1-( tert Starting from -butoxycarbonyl)-5,5-dimethylpyrrolidine-3-carboxylic acid Intermediate 3 It was manufactured in a similar manner to LCMS APCI (+) 162.1 (M-Boc). 1 ¹H NMR (400 MHz, DMSO- d 6) δ = 3.86 - 3.77 (m, 1H), 3.75 (s, 1H), 2.48 - 2.23 (m, 2H), 1.45 - 1.41 (m, 15H).

[1264] Preparation of Intermediate 5 : 1-( tert - Butoxycarbonyl )-3- fluoro -1- Azaspiro[4.4] Nonan -3-carboxylic acid

[1265]

[1266] Intermediate 5

[1267] Intermediate 5 is 1-( tert Starting from -butoxycarbonyl)-1-azaspiro[4,4]nonane-3-carboxylic acid Intermediate 3 It was manufactured in a similar manner to LCMS APCI (+) 188.1 (M-Boc). 1 ¹H NMR (400 MHz, DMSO- d 6) δ 3.84 - 3.71 (m, 2H), 2.50 - 2.25 (m, 3H), 2.20 - 2.05 (m, 1H), 1.84 - 1.66 (m, 3H), 1.59 - 1.47 (m, 3H), 1.44 (s, 9H).

[1268] Preparation of intermediate 6: methyl(2- Bromo -3- hydroxyphenyl )acetate

[1269] Step 1 : (2-bromo-3-methoxyphenyl)methanol( 6a )

[1270]

[1271] A solution of 2-bromo-3-methoxybenzoic acid (200 g, 866 mmol) in THF (3000 mL) was cooled in an ice bath, after which borane THF (89.3 g, 1040 mmol) was slowly added. After 30 minutes, the ice bath was removed, and the reaction mixture was stirred for 12 hours. The mixture was quenched with methanol (100 mL) until no more gas was formed. The mixture was concentrated under reduced pressure to (2-bromo-3-methoxyphenyl)methanol ( 6a )(182 g, 96.9%) was obtained as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ = 7.39 - 7.32 (m, 1H), 7.14 (d, J = 7.5 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 5.41 (t, J = 5.7 Hz, 1H), 4.51 (d, J = 5.5 Hz, 2H), 3.84 (s, 3H).

[1272] Step 2 : 2-Bromo-1-(chloromethyl)-3-methoxybenzene( 6b )

[1273]

[1274] (2-bromo-3-methoxyphenyl)methanol in DCM (300 mL) 6a Thionyl chloride (592 g, 4980 mmol) was slowly added to a solution of )(180 g, 829 mmol). After stirring the reaction for 1 hour, it was concentrated under reduced pressure. The residue was basicized with saturated Na2CO3 to pH = 8-9. After adding water, it was extracted with DCM (3x). The combined organic matter was washed with brine and concentrated under reduced pressure to obtain 2-bromo-1-(chloromethyl)-3-methoxybenzene ( 6b )(180 g, 92.2%) was obtained as a yellow solid. 1 ¹H NMR (400 MHz, DMSO-d 6 ) δ = 7.41 - 7.34 (m, 1H), 7.22 - 7.18 (m, 1H), 7.12 (dd, J = 1.1, 8.4 Hz, 1H), 4.83 (s, 2H), 3.87 (s, 3H).

[1275] Step 3: (2-bromo-3-methoxyphenyl)acetonitrile ( 6c )

[1276]

[1277] 2-bromo-1-(chloromethyl)-3-methoxybenzene in ACN (2000 mL) 6b After cooling a solution of )(180 g, 764 mmol) and TMSCN(152 g, 1530 mmol) in an ice bath, TBAF(400 g, 1530 mmol) was added. The ice bath was removed, and the reaction was stirred for 18 hours, after which it was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% EtOAc / PE) to obtain (2-bromo-3-methoxyphenyl)acetonitrile( 6c )(160 g, 92.6%) was obtained as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ = 7.44 - 7.37 (m, 1H), 7.13 (t, J = 8.3 Hz, 2H), 4.08 (s, 2H), 3.87 (s, 3H).

[1278] Step 4: Methyl (2-bromo-3-methoxyphenyl)acetate ( 6d )

[1279]

[1280] (2-bromo-3-methoxyphenyl)acetonitrile in methanol (2000 mL) 6cSaturated HCl (51.6 g, 1420 mmol) in methanol was added to a solution of )(160 g, 708 mmol). After 16 hours, the reaction was concentrated under reduced pressure. The residue was dissolved in DCM, washed with water, concentrated, and purified by silica gel chromatography (0-15% EtOAc / PE) to obtain methyl (2-bromo-3-methoxyphenyl)acetate as a yellow oil. 6d )(81.8%) was obtained. 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ = 7.35 - 7.27 (m, 1H), 7.06 - 6.97 (m, 2H), 3.86 - 3.82 (m, 5H), 3.62 (s, 3H).

[1281] Step 5: Methyl (2-bromo-3-hydroxyphenyl)acetate ( Intermediate 6 )

[1282]

[1283] Intermediate 6

[1284] Methyl (2-bromo-3-methoxyphenyl)acetate in DCM (2000 mL) 6d After cooling a solution of )(150 g, 579 mmol) in an ice bath, borane tribromide (290 g, 1160 mmol) was slowly added. After 30 minutes, the ice bath was removed, and the reaction was stirred for 16 hours. The mixture was quenched by slowly adding methanol. After adding water, it was extracted with DCM (2x). The combined organic matter was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0-50% EtOAc / PE) to obtain methyl (2-bromo-3-hydroxyphenyl)acetate ( intermediate 6 )(100 g, 70.5%) was obtained. 1 ¹H NMR (400 MHz, DMSO- d 6) δ = 10.21 (s, 1H), 7.16 - 7.08 (m, 1H), 6.88 (dd, J = 1.5, 8.1 Hz, 1H), 6.82 (dd, J = 1.5, 7.5 Hz, 1H), 3.78 (s, 2H), 3.62 (s, 3H).

[1285] Preparation of Intermediate 7: 2-[3- fluoro -2-(propane-2-yl)phenyl]-4,4,5,5- Tetramethyl -1,3,2-dioxaborolein

[1286] Step 1: 3-fluoro-2-(prop-1-en-2-yl)phenol( 7a )

[1287]

[1288] A solution of 2-bromo-3-fluorophenol (50 g, 262 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolein (66.0 g, 393 mmol), K2CO3 (72.4 g, 524 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (13.4 g, 18.3 mmol) in dioxane (500 mL) and water (100 mL) was degassed and purged with N2 (5x). After heating the reaction at 90°C for 18 hours, it was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% EtOAc / PE) (2x) to obtain 3-fluoro-2-(prop-1-en-2-yl)phenol ( 7a )(32.2 g, 80.8%) was obtained. 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.71 (s, 1H), 7.06 (dt, J =6.8, 8.2 Hz, 1H), 6.66 (d, J =8.3 Hz, 1H), 6.59 (dt, J=1.0, 8.9 Hz, 1H), 5.35 - 5.21 (m, 1H), 4.97 - 4.81 (m, 1H), 1.99 - 1.94 (m, 3H).

[1289] Step 2: 3-fluoro-2-(propane-2-yl)phenol( 7b )

[1290]

[1291] 3-fluoro-2-(prop-1-en-2-yl)phenol in THF (500 mL) 7a 10% carbon-phase palladium (33.8 g, 31.7 mmol) was added to a solution of )(32.2 g, 211.3 mmol). The reaction mixture was stirred under hydrogen (25 psi) for 20 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 3-fluoro-2-(propane-2-yl)phenol ( 7b )(29.1 g, 89.2%) was obtained as yellow oil. 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.68 (s, 1H), 7.02 - 6.91 (m, 1H), 6.61 (d, J =8.1 Hz, 1H), 6.52 (dd, J =8.7, 10.7 Hz, 1H), 3.41 - 3.34 (m, 1H), 1.24 (dd, J =0.7, 7.0 Hz, 6H).

[1292] Step 3 : 3-fluoro-2-(propane-2-yl)phenyl trifluoromethanesulfonate( 7c )

[1293]

[1294] 3-fluoro-2-(propane-2-yl)phenol in DCM (450 mL) 7bAfter cooling a solution of )(29.1 g, 189 mmol) and TEA(28.6 g, 39.5 mL, 283 mmol) in an ice bath, trifluoromethanesulfonic acid anhydride (79.9 g, 47.6 mL, 283 mmol) was added dropwise. After stirring at 0°C for 2 hours, the reaction mixture was poured into a mixture of saturated NaHCO3 and ice. The aqueous layer was extracted with DCM (3x), and the combined organic matter was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-2% EtOAc / PE) to obtain 3-fluoro-2-(propane-2-yl)phenyl trifluoromethanesulfonate ( 7c )(40.0 g, 74.0%) was obtained as yellow oil. 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.54 - 7.42 (m, 1H), 7.41 - 7.32 (m, 1H), 7.26 (d, J =8.4 Hz, 1H), 3.26 - 3.17 (m, 1H), 1.32 (dd, J =1.3, 7.0 Hz, 6H).

[1295] step 4: 2-[3-fluoro-2-(propane-2-yl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolein( Intermediate 7 )

[1296]

[1297] Intermediate 7

[1298] -fluoro-2-(propane-2-yl)phenyl trifluoromethanesulfonate in dioxane (500 mL) 7cA mixture of )(40.0 g, 140 mmol), bis(pinacollato)diborane (53.2 g, 210 mmol), KOAc (27.4 g, 279 mmol), and bis(diphenylphosphino)ferrocene]dichloropalladium (5.11 g, 6.99 mmol) was heated at 80°C for 12 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0-10% EtOAc / PE) to obtain 2-[3-fluoro-2-(propane-2-yl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolein ( intermediate 7 )(20.9 g, 56.8%) was obtained. 1H NMR (400 MHz, DMSO- d 6 ) δ = 7.36 (dd, J =1.8, 6.8 Hz, 1H), 7.26 - 7.14 (m, 2H), 3.60 (td, J =7.0, 13.6 Hz, 1H), 1.30 (s, 12H), 1.27 (d, J =1.5 Hz, 3H), 1.25 (d, J =1.5 Hz, 3H).

[1299] Preparation of intermediate 8: 2-methyl-8-oxa-2-azaspiro[4.5]decane-3-carboxylic acid

[1300]

[1301] Intermediate 8

[1302] 2- in DCM (3.5 mL) tertHCl (4 N in dioxane, 0.876 mL, 3.5 mmol) was added to a solution of 2-methyl-8-oxa-2-azspiro[4.5]decane-3-carboxylic acid (100 mg, 0.35 mmol). After 4 hours, the reaction was concentrated under vacuum. The residue was dissolved in 1:1 formic acid:formaldehyde (37% in water) and heated at 100°C overnight. After concentrating the reaction, the residue was dissolved in 1:1 methanol:DCM and loaded into an SCX-2 cartridge. Subsequently, the cartridge was rinsed with 1:1 methanol:DCM and then rinsed with 7N NH3 in methanol to 2-methyl-8-oxa-2-azspiro[4.5]decane-3-carboxylic acid ( intermediate 8 )(69 mg, 99%) was obtained. LCMS APCI (+) 200.1 (M+H).

[1303] Preparation of Intermediate 9: 2-methyl-2-azaspiro[4.4]nonane-3-carboxylic acid

[1304]

[1305] Intermediate 9

[1306] Intermediate 9 It starts from 2-azaspiro[4.4]nonane-3-carboxylic acid without Boc deprotection Intermediate 8 Manufactured in a similar manner. LCMS APCI (+) 184.1 (M+H). 1 H NMR (400MHz, MeOD) δ = 4.38 (dd, J=7.5, 9.8 Hz, 1H), 3.58 (d, J=11.5 Hz, 1H), 3.19 (d, J=11.5 Hz, 1H), 3.07 - 2.97 (m, 3H), 2.53 (dd, J=9.8, 13.4 Hz, 1H), 2.14 (dd, J=7.4, 13.4 Hz, 1H), 1.83 - 1.64 (m, 8H).

[1307] Preparation of intermediate 10: 4,4-dimethyl-1-( 2 H 3 )Methylproline

[1308] step1 : 2-Benzyl 1-( tert -butyl)(2S)-4,4-dimethylpyrrolidine-1,2-dicarboxylate( 10a )

[1309]

[1310] 1- (in acetonitrile (14 ml) at 23℃) tert Benzyl bromide (497 μl, 4.19 mmol) was added to a mixture of β-butoxycarbonyl)-4,4-dimethyl-L-proline (1.02 g, 4.18 mmol) and potassium carbonate (637 mg, 4.61 mmol). After stirring the mixture at 23°C for 23 hours, the reaction mixture was diluted with EtOAc and water. The EtOAc layer was washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (0-100% EtOAc / heptane) to obtain 2-benzyl 1-( tert -butyl)(2S)-4,4-dimethylpyrrolidine-1,2-dicarboxylate( 10a )(1.17 g, 84%) was obtained. LCMS ESI (+) 356.1 (M+Na). 1 H NMR (400 MHz, CDCl3) δ ppm 7.29 - 7.41 (m, 5H) 5.05 - 5.32 (m, 2H) 4.27 - 4.44 (m, 1H) 3.15 - 3.42 (m, 2H) 1.99 - 2.10 (m, 1H) 1.68 - 1.81 (m, 1H) 1.33 - 1.49 (m, 9H) 1.03 - 1.14 (m, 6H).

[1311] Step 2 : Benzyl 4,4-dimethyl-L-prolinate( 10b )

[1312]

[1313] 2-benzyl 1-( in DCM (9 ml) tert -butyl)(2S)-4,4-dimethylpyrrolidine-1,2-dicarboxylate( 10aA mixture of )(1.17 g, 3.52 mmol) and 4 N HCl (8.81 ml, 35.2 mmol) in 1,4-dioxane was stirred at 23°C for 1.5 hours. The reaction mixture was concentrated into oil under reduced pressure, after which EtOAc and saturated NaHCO3 (aqueous solution) were added. The EtOAc layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain benzyl 4,4-dimethyl-L-prolinate (a pale amber liquid). 10c )(825 mg, 100%) was obtained. LCMS ESI (+) 234.1 (M+H). 1 H NMR (400 MHz, CDCl3) δ ppm 7.29 - 7.46 (m, 5H) 5.09 - 5.25 (m, 2H) 3.94 (t, J =8.01 Hz, 1H) 3.61 - 3.81 (m, 1H) 2.63 - 2.88 (m, 2H) 2.47 (br s, 2H) 1.96 (dd, J =12.72, 8.80 Hz, 1H) 1.67 (dd, J =12.72, 7.21 Hz, 1H) 1.08 (s, 3H) 1.04 (s, 3H).

[1314] Step 3 : Benzyl 4,4-dimethyl-1-( 2 H3)Methyl-L-prolinate( 10d )

[1315]

[1316] Benzyl 4,4-dimethyl-L-prolinate in CD3CN (3.44 ml) 10c A mixture of )(241 mg, 1.03 mmol) and potassium carbonate (286 mg, 2.07 mmol) was sparged with dry nitrogen for 5 minutes. After cooling the mixture in an ice bath, iodomethane- d3 (51.4 μl, 0.826 mmol) was added. After 3 hours, the reaction mixture was diluted with EtOAc and water. The EtOAc layer was washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (0-100% EtOAc / heptane) to obtain benzyl 4,4-dimethyl-1-( 2 H3)Methyl-L-prolinate( 10d ) was obtained as a colorless liquid (77 mg, 30%). LCMS ESI (+) 251.2 (M+H). 1 H NMR (400 MHz, CDCl3) δ ppm 7.29 - 7.42 (m, 5H) 5.10 - 5.27 (m, 2H) 3.16 (t, J =8.38 Hz, 1H) 2.92 (d, J =9.05 Hz, 1H) 2.20 (d, J =9.05 Hz, 1H) 1.96 (dd, J =12.72, 8.93 Hz, 1H) 1.81 (dd, J =12.72, 7.83 Hz, 1H) 1.17 (s, 3H) 1.07 (s, 3H).

[1317] Step 4 : 4,4-dimethyl-1-( 2 H3)Methyl-L-proline( Intermediate 10 )

[1318]

[1319] Intermediate 10

[1320] Benzyl 4,4-dimethyl-1- in ethanol (1.0 ml) 2 A mixture of H3)methyl-L-prolinate (77 mg, 0.31 mmol) and 10% palladium on carbon (8 mg) was hydrogenated at 1 atm (balloon) and RT for 17 hours. The reaction mixture was diluted with methanol and filtered through Celite. The filtrate was concentrated under reduced pressure to form 4,4-dimethyl-1-( 2H3)Methyl-L-proline( intermediate 10 )(48 mg, 97%) was obtained. 1 H NMR (400 MHz, CDCl3) δ ppm 3.75 - 3.96 (m, 2H) 2.71 (br d, J =10.88 Hz, 1H) 2.29 (dd, J =13.39, 9.23 Hz, 1H) 2.13 (dd, J =13.45, 7.82 Hz, 1H) 1.21 (d, J =4.03 Hz, 6H).

[1321] Preparation of Intermediate 11: Methyl 2-(3-bromo-4-hydroxyphenyl)propanoate

[1322] Step 1 : Methyl-2-(3-bromo-4-methoxyphenyl)propanoate( 11a )

[1323]

[1324] Sodium hydride (60%) (810 mg, 20.3 mmol) in oil was added to a solution of methyl 2-(3-bromo-4-methoxyphenyl)acetate in THF (50 mL) at 15°C. After 30 minutes, the reaction was cooled to 0°C, and methyl iodide (2.79 g, 19.7 mmol) was added. The ice bath was removed, and the mixture was stirred for 16 hours. The reaction mixture was added to saturated aqueous NH4Cl (100 mL) at 0°C and extracted with EtOAc (3x). The combined organic matter was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (0-10% EtOAc / PE) to obtain methyl-2-(3-bromo-4-methoxyphenyl)propanoate ( 11a )(3.2 g, 60.7%) was obtained. 1 ¹H NMR (400 MHz, DMSO- d6 ) δ ppm 7.49 (d, J =2.1 Hz, 1H) 7.26 (dd, J=2.2, 8.4 Hz, 1H) 7.07 (d, J =8.5 Hz, 1H) 3.83 (s, 3H) 3.81 - 3.74 (m, 1H) 3.59 (s, 3H) 1.38 (d, J =8.0 Hz, 3H).

[1325] Step 2 : 2-(3-bromo-4-hydroxyphenyl)propanoic acid( 11b )

[1326]

[1327] HBr (12.0 mL) was added to an acetic acid (24.0 mL) solution of methyl-2-(3-bromo-4-methoxyphenyl)propanoate. The resulting solution was heated at 110°C for 24 hours. After cooling the reaction mixture to room temperature, it was extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (0-40% EtOAc / PE) to obtain 2-(3-bromo-4-hydroxyphenyl)propanoic acid ( 11b )(1.6 g, 66% yield) was obtained as a colorless oil. 1 ¹H NMR (400 MHz, DMSO- d6 ) δ ppm 12.29 (br s, 1H) 10.15 (s, 1H) 7.37 (d, J =2.0 Hz, 1H) 7.09 (dd, J =2.2, 8.4 Hz, 1H) 6.90 (d, J =8.4 Hz, 1H) 3.58 (q, J =7.0 Hz, 1H) 1.31 (d, J =7.3 Hz, 3H).

[1328] Step 3 : Methyl 2-(3-bromo-4-hydroxyphenyl)propanoate( Intermediate 11 )

[1329]

[1330] Intermediate 11

[1331] 2-(3-bromo-4-hydroxyphenyl)propanoic acid in MeOH (25.0 mL) 11b After cooling a solution of )(1.95 g, 7.95 mmol) to 0°C, thionyl chloride was slowly added. The ice bath was removed, and the reaction was stirred at rt for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in EtOAc (30 mL), washed with saturated NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain methyl 2-(3-bromo-4-hydroxyphenyl)propanoate ( Intermediate 11 )(1.67 g, 81.0% yield) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.20 (s, 1H) 7.38 (s, 1H) 7.10 (d, J =8.0 Hz, 1H) 6.91 (d, J =8.0 Hz, 1H) 3.71 (q, J =6.7 Hz, 1H) 3.58 (d, J =1.4 Hz, 3H) 1.35 (d, J =8.8 Hz, 3H) 1.34 (br d, J =7.1 Hz, 3H).

[1332] Preparation of Intermediate 12: 2-(2-ethyl-3- fluorophenyl )-4,4,5,5- Tetramethyl -1,3,2-dioxaborolein

[1333] Step 1 : 1-(2-bromo-6-fluorophenyl)ethanol-1-ol( 12a )

[1334]

[1335] CH3MgBr (8.69 mL, 3.4 M, 29.56 mmol) was added dropwise to a solution of 2-fluoro-6-bromobenzaldehyde (3.0 g, 1.8 mL, 14.78 mmol) at 0°C. The resulting mixture was stirred at 0°C for 40 minutes. The reaction was quenched with saturated NH4Cl (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography (0-20% EtOAc / heptane) to obtain 1-(2-bromo-6-fluorophenyl)ethanol-1-ol as a colorless oil ( 12a )(2.91 g, 13.3 mmol, 89.9 %) was obtained. 1 H NMR (400 MHz, CDCl3) δ 7.25 (td, J = 1.1, 7.9 Hz, 1H), 7.01 (dt, J = 6.1, 8.1 Hz, 1H), 6.97 - 6.89 (m, 1H), 5.30 - 5.21 (m, 1H), 1.52 (dd, J = 1.1, 6.7 Hz, 3H).

[1336] Step 2 : 1-Bromo-2-ethyl-3-fluorobenzene( 12b )

[1337]

[1338] After adding chlorodimethylsilane (2.6 mL, 24 mmol) to a suspension of InCl3 (0.26 g, 1.2 mmol) in 1,2-dichloroethane (50 mL), 1-(2-bromo-6-fluorophenyl)ethanol-1-ol (in 1,2-dichloroethane (10 mL) 12a)(2.6 g, 12 mmol) was added. The resulting mixture was stirred at RT for 1 hour, then heated at 80°C for 3 hours. The mixture was cooled to RT, filtered, and washed with heptane. The filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (heptane) to obtain 1-bromo-2-ethyl-3-fluorobenzene ( 12b )(1.75 g, 73%) was obtained. 1 H NMR (400 MHz, CDCl3) δ 7.45 - 7.31 (m, 1H), 7.12 - 6.91 (m, 2H), 2.85 (dq, J = 2.2, 7.5 Hz, 2H), 1.20 (t, J = 7.5 Hz, 3H).

[1339] step 3 : 2-(2-ethyl-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolein( Intermediate 12 )

[1340]

[1341] Intermediate 12

[1342] 1-bromo-2-ethyl-3-fluorobenzene in 1,4-dioxane (14.4 mL) 12b After degassing a mixture of )(586 mg, 2.89 mmol), KOAc(850 mg, 8.66 mmol), and B2Pin2(879 mg, 3.46 mmol) three times, Pd(dppf)Cl2-DCM(189 mg, 0.231 mmol) was added. The mixture was heated at 100°C for 18 hours. The reaction mixture was cooled to RT, and volatile substances were removed under reduced pressure. The crude mixture was purified by flash column chromatography (0-20% EtOAc / heptane) to obtain 2-(2-ethyl-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolein ( intermediate 12 )(541 mg, 75%) was obtained.1 H NMR (400 MHz, CDCl3) δ 7.64 - 7.47 (m, 1H), 7.19 - 7.11 (m, 1H), 7.10 - 7.02 (m, 1H), 2.96 (dq, J = 2.0, 7.5 Hz, 2H), 1.36 (s, 12H), 1.17 (t, J = 7.4 Hz, 3H).

[1343] Preparation of Intermediate 13: 2-(2- cyclopropyl -3- fluorophenyl )-4,4,5,5- Tetramethyl -1,3,2-dioxaborolein

[1344]

[1345] Intermediate 13

[1346] A mixture of 1-bromo-2-cyclopropyl-3-fluorobenzene (430 mg, 2.00 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolein) (609 mg, 2.40 mmol), PdCl2(dppf)·DCM (81.7 mg, 0.1 mmol), and potassium acetate (589 mg, 6.00 mmol) in toluene (5 ml) was sparged with dry nitrogen for 5 minutes and then heated at 95°C for 20 hours. The reaction mixture was diluted with EtOAc and water, and then filtered through a sintered glass funnel containing Celite. The clear yellow EtOAc layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% EtOAc / heptane) to obtain 2-(2-cyclopropyl-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolein ( intermediate 13 )(406 mg, 77%) was obtained as a yellow liquid. 1 H NMR (400 MHz, CDCl3) δ ppm 7.42 (d, J=7.21 Hz, 1H) 7.13 (td, J =7.67, 4.95 Hz, 1H) 7.00 (dd, J =11.43, 8.25 Hz, 1H) 2.20 (tt, J =8.67, 5.58 Hz, 1H) 1.38 (s, 12H) 0.89 - 0.99 (m, 2H) 0.77 - 0.87 (m, 2H).

[1347] Preparation of Intermediate 14: 2-(2- Cyclobutyl -3,4- difluorophenyl )-4,4,5,5- Tetramethyl -1,3,2-dioxaborolein

[1348] Step 1 : 1-(2,3-difluoro-6-methoxyphenyl)cyclobutan-1-ol( 14a )

[1349]

[1350] 1 M LDA (5.50 ml, 5.50 mmol) was added to a solution of 1,2-difluoro-4-methoxybenzene (721 mg, 5 mmol) in THF (5.00 ml) cooled in a dry ice acetone bath. After 1 hour, cyclobutanone (747 μl, 10.0 mmol) was added as is. The reaction mixture was heated to 23°C for 18 hours, then quenched with saturated NH4Cl(aq) and diluted with water and EtOAc. The EtOAc layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-100% EtOAc / heptane) to obtain 1-(2,3-difluoro-6-methoxyphenyl)cyclobutan-1-ol ( 14a )(463 mg, 39%) was obtained as a pale amber oil. LCMS ESI (+) 197.1 (MH-H2O). 1H NMR (400 MHz, chloroform-d) δ ppm 7.00 (q, J=9.17 Hz, 1H) 6.49 - 6.61 (m, 1H) 3.82 (s, 3H) 2.64 - 2.79 (m, 2H) 2.39 - 2.51 (m, 2H) 2.25 - 2.38 (m, 1H) 1.81 - 1.95 (m, 1H).

[1351] Step 2 : 2-cyclobutyl-3,4-difluoro-1-methoxybenzene( 14b )

[1352]

[1353] 1-(2,3-difluoro-6-methoxyphenyl)cyclobutan-1-ol in DCM (7 ml) cooled in an ice bath ( 14a After adding triethylsilane (1.03 ml, 6.44 mmol) to a solution of )(460 mg, 2.15 mmol), TFA(622 l, 8.59 mmol) was added. After 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (0-100% EtOAc / heptane) to obtain 2-cyclobutyl-3,4-difluoro-1-methoxybenzene ( 14b )(413 mg, 64%) was obtained as oil. 1 H NMR (400 MHz, CDCl3) δ ppm 6.91 (q, J =9.17 Hz, 1H) 6.50 (ddd, J =9.11, 3.73, 2.08 Hz, 1H) 3.80 - 3.93 (m, 1H) 3.79 (s, 3H) 2.42 - 2.59 (m, 2H) 2.23 - 2.39 (m, 2H) 1.83 - 2.12 (m, 2H) 0.95 (t, J =7.95 Hz, 3H) 0.53 (q, J =7.99 Hz, 2H).

[1354] Step 3 : 2-cyclobutyl-3,4-difluorophenol( 14c )

[1355]

[1356] 2-cyclobutyl-3,4-difluoro-1-methoxybenzene( 14b AcOH (4 ml, 70 mmol) was added to a solution of )(389 mg, 1.96 mmol), followed by the addition of 48 wt% HBr (1.6 ml, 14 mmol). The mixture was heated at 100°C for 48 hours. The reaction mixture was diluted with EtOAc, washed with water, saturated NaHCO3(aq), and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Subsequently, the residue was purified by column chromatography (0-10% EtOAc / heptane) to obtain 2-cyclobutyl-3,4-difluorophenol ( 14c )(234 mg, 64%) was obtained as orange oil. 1 H NMR (400 MHz, CDCl3) δ ppm 6.84 (q, J =9.05 Hz, 1H) 6.44 (ddd, J =9.02, 3.88, 2.14 Hz, 1H) 4.66 (br s, 1H) 3.70 - 3.82 (m, 1H) 2.46 - 2.58 (m, 2H) 2.34 - 2.43 (m, 2H) 2.06 (s, 1H) 1.89 - 1.99 (m, 1H).

[1357] step 4 : 2-cyclobutyl-3,4-difluorophenyl trifluoromethanesulfonate ( 14d )

[1358]

[1359] 2-cyclobutyl-3,4-difluorophenol( 14cPyridine (6.35 ml) was added to a flask containing )(234 mg, 1.27 mmol). After cooling the solution in an ice bath, a 1 M solution of trifluoromethanesulfonic acid anhydride in DCM (2.54 ml, 2.54 mmol) was added dropwise. After 1.5 hours, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in EtOAc, and washed with 1 N HCl(aq) and 1 N NaOH(aq). The EtOAc solution was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain 2-cyclobutyl-3,4-difluorophenyl trifluoromethanesulfonate ( 14d )(318 mg, 79%) was obtained as orange oil. 1 H NMR (400 MHz, CDCl3) δ ppm 7.08 (q, J =8.88 Hz, 1H) 6.96 - 7.02 (m, 1H) 3.73 - 3.86 (m, 1H) 2.40 - 2.54 (m, 4H) 2.03 - 2.16 (m, 1H) 1.91 - 2.01 (m, 1H).

[1360] step 5 : 2-(2-cyclobutyl-3,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolein( Intermediate 14 )

[1361]

[1362] Intermediate 14

[1363] 2-cyclobutyl-3,4-difluorophenyl trifluoromethanesulfonate ( 14d1,4-dioxane (6.7 ml) was added to a flask containing )(318 mg, 1.01 mmol), followed by the addition of bis(pinacolato)diborane (511 mg, 2.01 mmol) and potassium acetate (296 mg, 3.02 mmol). After sparging the mixture with dry nitrogen, PdCl2(dppf)·DCM (82.1 mg, 0.1 mmol) was added. The resulting mixture was heated at 100°C for 20 hours. The reaction mixture was diluted with EtOAc, water, and brine. The mixture was filtered through Celite, the EtOAc layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% EtOAc / heptane) to obtain 2-(2-cyclobutyl-3,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolein ( intermediate 14 )(260 mg, 88%) was obtained as oil. 1 H NMR (400 MHz, CDCl3) δ ppm 9.31 - 9.39 (m, 1H) 8.87 - 8.95 (m, 1H) 6.16 (quin, J =9.19 Hz, 1H) 4.38 - 4.52 (m, 2H) 4.27 - 4.37 (m, 2H) 3.84 - 4.05 (m, 2H) 3.32 (s, 12H).

[1364] Preparation of Intermediate 15: tert -butyl [( 1 R ,3 R )-3-(2- Bromo -4- Iodophenoxy )cyclopentyl]carbamate

[1365]

[1366] Intermediate 15

[1367] A solution of 2-bromo-4-iodophenol (800 mg) and PPh in THF (24.0 mL) was cooled in an ice bath. The addition was slow. The ice bath was removed, and the reaction was stirred overnight. The reaction was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0-20% EtOAc / PE) to obtain tert-butyl ((1R,3R)-3-(2-bromo-4-iodophenoxy)cyclopentyl)carbamate ( 15a )(0.97 g, 75.2% yield) was obtained. 1 H NMR (400 MHz, CDCl3) δ ppm 7.82 (d, J=2.0 Hz, 1H) 7.50 (dd, J=1.8, 8.7 Hz, 1H) 6.60 (d, J=8.6 Hz, 1H) 4.85 - 4.78 (m, 1H) 4.50 (br s, 1H) 4.30 - 4.17 (m, 1H) 2.41 - 2.20 (m, 2H) 2.19 - 2.08 (m, 1H) 1.99 - 1.86 (m, 1H) 1.84 - 1.73 (m, 1H) 1.46 (s, 10H).

[1368] Preparation of intermediate 16: methyl [1-methyl-4-(4,4,5,5- Tetramethyl -1,3,2- Dioxaboro -2-day)-1 H -pyrazol-3-yl]acetate

[1369] Step 1 : Methyl 2-(1-methyl-1H-pyrazole-3-yl)acetate( 16a )

[1370]

[1371] A solution of 2-(1-methyl-1H-pyrazole-3-yl)acetic acid (900 mg, 6.42 mmol) in methanol (20.0 mL) was cooled in an ice bath, after which thionyl chloride (1.15 g, 9.63 mmol) was added dropwise. Subsequently, the ice bath was removed, and the reaction was stirred overnight. The reaction was concentrated under reduced pressure, and the residue was dissolved in DCM and washed with saturated NaHCO3 and brine. The organic matter was concentrated under reduced pressure to obtain methyl 2-(1-methyl-1H-pyrazole-3-yl)acetate as a pale yellow oil ( 16a )(1.06 g, >99% crude yield) was obtained. 1 H NMR (400 MHz, CDCl3) δ ppm 7.30 (d, J=2.1 Hz, 1H) 6.20 (d, J=2.2 Hz, 1H) 3.87 (s, 3H) 3.74 (s, 3H) 3.68 (s, 2H).

[1372] Step 2 : Methyl 2-(4-bromo-1-methyl-1H-pyrazole-3-yl)acetate( 16b )

[1373]

[1374] NBS (1.28 g, 7.22 mmol) was added to a solution of methyl 2-(1-methyl-1H-pyrazole-3-yl)acetate in ACN (65.0 mL). The reaction was stirred overnight and then concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with saturated Na2CO3 and brine. The organic matter was dried over Na2SO4, filtered, and concentrated to obtain methyl 2-(4-bromo-1-methyl-1H-pyrazole-3-yl)acetate as a yellowish-brown oil ( 16b )(1.22 g, 76.1% yield) was obtained. LCMS APCI (+) 233.1 (M+H). 1 H NMR (400 MHz, CDCl3) δ ppm 7.37 (s, 1H) 3.87 (s, 3H) 3.74 (s, 3H) 3.71 (s, 2H).

[1375] Step 3: Methyl 2-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-3-yl)acetate( Intermediate 16 )

[1376]

[1377] Intermediate 16

[1378] Di(1-adamantyl)-n-butylphosphine (46.2 mg, 0.13 mmol) and palladium(II) acetate (14.4 mg, 0.06 mmol) were added to a solution of methyl 2-(4-bromo-1-methyl-1H-pyrazole-3-yl)acetate, bispinacollatodiborane (981 mg, 3.86 mmol), and cesium fluoride (587 mg, 3.86 mmol) in dioxane. The reaction was heated at 100°C under N2 for 16 hours. The reaction was concentrated and the residue was purified by silica gel chromatography (0-100% EtOAc / PE) to obtain methyl 2-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-3-yl)acetate as a yellow oil ( intermediate 16 )(340 mg, 94.3% yield) was obtained. LCMS APCI (+) 281.1 (M+H). 1 H NMR (400 MHz, CDCl3) δ ppm 7.60 (s, 1H) 3.87 (s, 5H) 3.72 (s, 3H) 1.28 (s, 12H).

[1379] Intermediate 17: Methyl 2-[1-methyl-4-(4,4,5,5- Tetramethyl -1,3,2- Dioxaboro -2-day)-1 H Preparation of -pyrazol-3-yl]propanoate

[1380] Step 1 : Methyl 2-(4-bromo-1-methyl-1H-pyrazole-3-yl)propanoate( 17a )

[1381]

[1382] A solution of methyl 2-(4-bromo-1-methyl-1H-pyrazole-3-yl)acetate in THF (15 mL) was cooled in an ice bath, after which sodium hydride (60% of the mineral oil phase, 126 mg, 3.15 mmol) was added. After 30 minutes, methyl iodide (435 mg, 3.06 mmol) was added. The ice bath was removed, and the reaction was stirred for 2 hours. After quenching with saturated NH4Cl, it was extracted with EtOAc (2x). The combined organic matter was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (10-35% EtOAc / PE) to obtain methyl 2-(4-bromo-1-methyl-1H-pyrazole-3-yl)propanoate ( 17a )(420 mg, 56.6%) was obtained as a yellow oil. LCMS APCI (+) 247.1 (M+H). 1 H NMR (400 MHz, CDCl3) δ ppm 7.34 (s, 1H) 3.91 - 3.88 (m, 1H) 3.86 (s, 3H) 3.72 (s, 3H) 1.55 (d, J=7.5 Hz, 3H).

[1383] Step 2 : Methyl 2-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-3-yl)propanoate( Intermediate 17 )

[1384]

[1385] Intermediate 17

[1386] A mixture of methyl 2-(4-bromo-1-methyl-1H-pyrazole-3-yl)propanoate, 4,4,5,5-tetramethyl-1,3,2-dioxaborolein (829 mg), and triethylamine (491 mg) in dioxane (10 mL) was stirred at 100°C for 15 hours under N2 protection. The reaction was diluted with ice water (15 mL) and extracted with EtOAc (2x). The combined organic matter was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (15-35% EtOAc / PE) to obtain methyl 2-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-3-yl)propanoate as a yellow oil. intermediate 17 )(350 mg, 73.5% yield) was obtained. LCMS APCI (+) 295.3 (M+H). 1 H NMR (400 MHz, CDCl3) δ ppm 7.59 (s, 1H) 4.18 - 4.16 (m, 1H) 3.85 (s, 3H) 3.68 (s, 3H) 1.55 (d, J=7.3 Hz, 3H) 1.25 (s, 12H).

[1387] Intermediate 18: Methyl 2-methyl-2-[1-methyl-4-(4,4,5,5- Tetramethyl -1,3,2- Dioxaboro -2-day)-1 H Preparation of -pyrazol-3-yl]propanoate

[1388] Step 1 : Methyl 2-(4-bromo-1-methyl-1H-pyrazole-3-yl)-2-methylpropanoate( 18a )

[1389]

[1390] A solution of methyl 2-(4-bromo-1-methyl-1H-pyrazole-3-yl)propanoate in THF (10.0 mL) was added after cooling in an ice bath. After 1.5 hours, methyl iodide (494 mg, 3.48 mmol) was added, the ice bath was removed, and the reaction was stirred for 2 hours. The reaction mixture was quenched with cold saturated NH4Cl (25 mL) and extracted with EtOAc (2x). The combined organic matter was washed with brine, dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was redissolved in THF (10.0 mL) and cooled in an ice bath. After adding LiHMDS (1.50 mL, 1.0 M THF solution), methyl iodide (200 mg) was added after 1.5 hours. The ice bath was removed, and the mixture was stirred for 2 hours. The reaction mixture was quenched with cold saturated NH4Cl (25 mL) and extracted with EtOAc (2x). The combined organic matter was washed with brine, dried with Na2SO4, filtered, and concentrated under reduced pressure to obtain methyl 2-(4-bromo-1-methyl-1H-pyrazole-3-yl)-2-methylpropanoate ( 18a )(400 mg, 88% yield) was obtained as a yellow oil. LCMS APCI (+) 261.2 (M+H). 1 H NMR (400 MHz, CDCl3) δ ppm 7.35 (s, 1H) 3.86 (s, 3H) 3.71 (s, 3H) 1.62 (s, 6H).

[1391] Step 2 : Methyl 2-methyl-2-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-3-yl)propanoate( Intermediate 18 )

[1392]

[1393] Intermediate 18

[1394] A mixture of methyl 2-(4-bromo-1-methyl-1H-pyrazole-3-yl)-2-methylpropanoate, bispinacollatodiborane (686 mg, 5.36 mmol), triethylamine (407 mg, 4.02 mmol), and Pd(dppf)Cl in dioxane (5.0 mL) was degassed with N2 and heated at 100°C for 15 hours. An additional mixture of bispinacollatodiborane (686 mg, 5.36 mmol), triethylamine (407 mg, 4.02 mmol), and Pd(dppf)Cl in dioxane (5.0 mL) was degassed with N2 and heated at 100°C for an additional 15 hours. The reaction was diluted with ice water and extracted with EtOAc (2x). The combined organic matter was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-25% EtOAc / PE) to obtain methyl 2-methyl-2-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-3-yl)propanoate as a yellow oil Intermediate 18 )(300 mg, 72.6% yield) was obtained. LCMS APCI (+) 309.3 (M+H). 1 H NMR (400 MHz, CDCl3) δ ppm 7.63 (s, 1H) 3.84 (s, 3H) 3.66 (s, 3H) 1.62 (s, 6H) 1.28 (s, 12H).

[1395] Preparation of intermediate 19: methyl 1-methyl-4-(4,4,5,5- Tetramethyl -1,3,2- Dioxaboro -2-day)-1 H - Pyrazole-3-carboxylate

[1396]

[1397] Intermediate 19

[1398] A mixture of methyl 4-bromo-1-methyl-1H-pyrazole-3-carboxylate (1), 4,4,5,5-tetramethyl-1,3,2-dioxaborolein (2.34 g, 18.3 mmol), Et, and Pd(dppf)Cl in dioxane (15.0 mL) was stirred at 100°C for 15 hours under N2 protection. The reaction mixture was poured into water (35 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (30-50% EtOAc / heptane) to obtain methyl 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-3-carboxylate ( intermediate 19 )(200 mg, 16.5% yield) was obtained as a yellow solid. LCMS APCI (+) 267.3 (M+H). 1 H NMR (400 MHz, CDCl3) δ ppm 7.62 (s, 1H) 3.96 (s, 3H) 3.93 (s, 3H), 1.36 (s, 12H).

[1399] Preparation of intermediate 20: 1-( tert - Butoxycarbonyl )-3- fluoro -5,5- dimethylpiperidine -3-carboxylic acid

[1400]

[1401] Intermediate 20

[1402] Intermediate 20 1-( tert Starting from -butoxycarbonyl)-5,5-dimethylpiperidine-3-carboxylic acid Intermediate 3 Manufactured in a similar manner to LCMS APCI (+) 220.1 (M+H-56). 1H NMR (400 MHz, CDCl3) δ ppm 4.64 - 4.36 (m, 1H) 4.04 - 3.70 (m, 1H) 3.31 - 2.94 (m, 1H) 2.75 - 2.57 (m, 2H) 1.96 - 1.88 (m, 1H) 1.48 (s, 9H) 1.08 (s, 3H) 0.97 (s, 3H).

[1403] Preparation of Intermediate 21: 6-( tert - Butoxycarbonyl )-8- fluoro -6- Azaspiro[3.5] Nonan -8-carboxylic acid

[1404]

[1405] Intermediate 21

[1406] Intermediate 21 6-( tert Starting from -butoxycarbonyl)-6-azaspiro[3.5]nonane-8-carboxylic acid Intermediate 3 It was manufactured in a similar manner to LCMS APCI (+) 188.2 (M+H-Boc). 1 H NMR (400 MHz, DMSO-d6) δ = 4.23 - 4.12 (m, 2H), 3.25 - 3.06 (m, 1H), 2.81 - 2.71 (m, 1H), 2.21 - 2.08 (m, 1H), 1.95 - 1.66 (m, 8H), 1.44 - 1.42 (m, 9H).

[1407] Preparation of Intermediate 22: tert -butyl ( 3a S ,5 R ,6a R )-5-hydroxy-2,2- dimethyltetrahydro -2 H -Cyclopenta[ d ][1,3]Oxazole-3(3a H )-carboxylate

[1408] Step 1 : (1R,4S)-4-(benzyloxy)cyclopent-2-en-1-yl acetate( 22a )

[1409]

[1410] (1 in DCM (39.1 ml) R ,4 S A mixture of )-4-hydroxycyclopent-2-en-1-yl acetate (2.78 g, 19.6 mmol), benzyl bromide (4.01 g, 23.5 mmol), and silver(I) oxide (4.99 g, 21.5 mmol) was stirred at 23°C for 19 hours. The reaction mixture was filtered through Celite and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% EtOAc / heptane) tert -butyl (3 aS ,5 R ,6 aR )-5-hydroxy-2,2-dimethyltetrahydro-2 H -Cyclopenta[ d ]Oxazol-3(3 aH )-carboxylate( 22a )(1.95 g, 43%) was obtained as a colorless oil. LCMS-ESI(+) = 255.1 (M+Na), 1 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.27 - 7.42 (m, 5H) 6.15 (dt, J =5.69, 1.56 Hz, 1H) 6.01 (dt, J =5.62, 1.59 Hz, 1H) 5.52 (ddt, J =6.02, 4.00, 0.98, 0.98 Hz, 1H) 4.54 - 4.63 (m, 2H) 4.52 (dddd, J =5.09, 4.20, 2.20, 0.86 Hz, 1H) 2.79 (dt, J =14.40, 7.29 Hz, 1H) 2.06 (s, 3H) 1.78 (dt, J =14.21, 4.39 Hz, 1H).

[1411] Step 2 : (1 R ,4 S )-4-(benzyloxy)cyclopent-2-en-1-ol( 22b )

[1412]

[1413] (1 in methanol (28.0 ml) R ,4 S )-4-(benzyloxy)cyclopent-2-en-1-yl acetate( 22a A mixture of )(1.95 g, 8.395 mmol) and potassium carbonate (1.39 g, 10.1 mmol) was stirred in an ice bath for 75 minutes. The reaction mixture was quenched with saturated NH4Cl (aqueous solution) and then concentrated under reduced pressure. The mixture was diluted with EtOAc and water. The EtOAc layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% EtOAc / heptane) to obtain a colorless oil (1 R ,4 S )-4-(benzyloxy)cyclopent-2-en-1-ol( 22b )(1.488 g, 93%) was obtained. LCMS-ESI(+) = 208.1 (M+H2O), 1 H NMR (400 MHz, CDCl3) δ ppm 7.29 - 7.41 (m, 5H) 6.05 - 6.10 (m, 2H) 4.64 - 4.70 (m, 1H) 4.54 - 4.64 (m, 2H) 4.47 (ddd, J =6.88, 4.13, 0.73 Hz, 1H) 2.69 (dt, J =14.06, 7.03 Hz, 1H) 1.70 (dt, J =14.03, 4.05 Hz, 1H), [α]= -20.1° (C 0.5, MeOH).

[1414] Step 3 : (1 R ,4 S)-4-(benzyloxy)cyclopent-2-en-1-yl 2,2,2-trichloroacetimidate( 22c )

[1415]

[1416] (1 in DCM (39.0 ml) at 23℃ R ,4 S )-4-(benzyloxy)cyclopent-2-en-1-ol( 22b DBU (117 µl, 0.781 mmol) was added to a solution of ) (1.48 g, 7.80 mmol) and 2,2,2-trichloroacetonitrile (861 µl, 8.59 mmol). The mixture was stirred for 90 minutes, then quenched with saturated NH4Cl(aq) and diluted with DCM and water. The DCM layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% EtOAc / heptane) (1 R ,4 S )-4-(benzyloxy)cyclopent-2-en-1-yl 2,2,2-trichloroacetimidate( 22c )(2.22 g, 85%) was obtained as a colorless liquid. 1 H NMR (400 MHz, CDCl3) δ ppm 8.31 (br s, 1H) 7.28 - 7.41 (m, 5H) 6.19 - 6.24 (m, 1H) 6.14 - 6.18 (m, 1H) 5.64 - 5.71 (m, 1H) 4.53 - 4.64 (m, 3H) 2.90 (dt, J =14.31, 7.27 Hz, 1H) 1.94 (dt, J =14.31, 4.52 Hz, 1H).

[1417] Step 4 : (3a R ,4 S ,5 S ,6a R )-5-(benzyloxy)-4-iodo-2-(trichloromethyl)-3a,5,6,6a-tetrahydro-4 H -Cyclopenta[d ]Joksajol( 22d )

[1418]

[1419] (1 in DCM (22.2 ml) at 23℃ R ,4 S )-4-(benzyloxy)cyclopent-2-en-1-yl 2,2,2-trichloroacetimidate( 22c NIS (1.89 g, 7.99 mmol) was added to a solution of ) (2.22 g, 6.658 mmol). The reaction mixture was stirred for 3.5 hours and then quenched with 10% aqueous Na2S2O3. After separating the layers, the aqueous layer was washed with DCM. The combined DCM extract was washed with saline, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% EtOAc / heptane) (3a R ,4 S ,5 S ,6a R )-5-(benzyloxy)-4-iodo-2-(trichloromethyl)-3a,5,6,6a-tetrahydro-4 H -Cyclopenta[ d ]Joksajol( 22d )(2.15 g, 70%) was obtained as a white solid. LCMS-ESI(+) = 459.9 / 461.9 (M+H), 1 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.28 - 7.39 (m, 5H) 5.48 (t, J =7.15 Hz, 1H) 5.19 (d, J =7.70 Hz, 1H) 4.68 (d, J =1.96 Hz, 1H) 4.41 - 4.59 (m, 2H) 4.34 (d, J =4.40 Hz, 1H) 2.75 (ddd, J =15.89, 6.48, 4.52 Hz, 1H) 2.52 (dd, J=15.96, 1.90 Hz, 1H). [α]= +13.4° (C 0.6, CHCl3).

[1420] Step 5 : (1 R ,2 R ,3 S ,4 S )-2-amino-4-(benzyloxy)-3-iodocyclopentane-1-ol hydrochloride( 22e )

[1421]

[1422] (3a in methanol (23.3 ml) R ,4 S ,5 S ,6a R )-5-(benzyloxy)-4-iodo-2-(trichloromethyl)-3a,5,6,6a-tetrahydro-4 H -Cyclopenta[d]oxazole( 22d A mixture of )(2.15 g, 4.67 mmol) and 2M HCl(aq)(6 ml, 10 mmol) was stirred at 23°C for 20 hours. The reaction mixture was concentrated into a solid and suspended in MTBE. The solid was filtered and dried under reduced pressure at 70°C (1 R ,2 R ,3 S ,4 S )-2-amino-4-(benzyloxy)-3-iodocyclopentane-1-ol hydrochloride( 22e )(1.38 g, 81%) was obtained as a white solid. LCMS-ESI(+) = 334.0 (M+H), 1 ¹H NMR (400 MHz, DMSO- d 6) δ ppm 8.25 (br s, 3H) 7.25 - 7.41 (m, 5H) 4.50 - 4.65 (m, 2H) 4.12 - 4.22 (m, 2H) 4.09 (br s, 1H) 3.48 - 3.62 (m, 1H) 2.26 - 2.39 (m, 1H) 1.64 - 1.75 (m, 1H).

[1423] Step 6 : (1R ,2 S ,4 R )-2-amino-4-(benzyloxy)cyclopentane-1-ol hydrochloride( 22f )

[1424]

[1425] (1 in a mixture of toluene (12.2 ml) and methanol (360 ul) R ,2 R ,3 S ,4 S )-2-amino-4-(benzyloxy)-3-iodocyclopentane-1-ol hydrochloride( 22e A suspension of )(1.35 g, 3.65 mmol) and AIBN(59.9 mg, 0.365 mmol) was heated to 70°C, after which (TMS)3SiH(5.63 ml, 18.2 mmol) was added. The temperature was raised to 90°C for 1 hour. The reaction mixture was concentrated to remove methanol, and the residue was diluted with EtOAc and 1N HCl (5 ml). The layers were separated, and the EtOAc layer was extracted with water. The water and HCl(aq) layers were combined, then freeze-dried (1 R ,2 S ,4 R )-2-amino-4-(benzyloxy)cyclopentane-1-ol hydrochloride salt( 22f )(1.26 g) was obtained as pale amber foam. LCMS-ESI (+) = 208.1 (M+H), 1 ¹H NMR (400 MHz, CD3OD) δ ppm 7.20 - 7.43 (m, 5H) 4.45 - 4.59 (m, 2H) 4.24 - 4.33 (m, 1H) 4.05 - 4.15 (m, 1H) 3.51 (td, J =7.06, 5.44 Hz, 1H) 2.23 - 2.40 (m, 2H) 1.87 - 2.02 (m, 2H).

[1426] Step 7 : tert -butyl ((1 S ,2R ,4 R )-4-(benzyloxy)-2-hydroxycyclopentyl)carbamate( 22g )

[1427]

[1428] (1R,2S,4R)-2-amino-4-(benzyloxy)cyclopentan-1-ol in DCM (12.2 ml) cooled in an ice bath ( 22f TEA (1.02 ml, 7.3 mmol) was added to a mixture of ) (890 mg, 3.65 mmol) and Boc anhydride (956 mg, 4.38 mmol). After heating the mixture to 23°C for 17 hours, it was purified by silica gel chromatography (0-100% EtOAc / heptane). tert -butyl ((1 S ,2 R ,4 R )-4-(benzyloxy)-2-hydroxycyclopentyl)carbamate( 22g )(837 mg, 75%) was obtained as a colorless oil. LCMS-ESI(+) = 330.1 (M+Na), 1 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.28 - 7.41 (m, 5H) 5.22 - 5.44 (m, 1H) 4.39 - 4.58 (m, 2H) 4.03 - 4.19 (m, 2H) 3.94 (br d, J =2.45 Hz, 1H) 2.50 - 2.91 (m, 1H) 2.40 (ddd, J =14.67, 8.50, 6.54 Hz, 1H) 2.02 - 2.12 (m, 2H) 1.87 - 2.00 (m, 1H) 1.76 (ddt, J=14.52, 7.18, 2.29, 2.29 Hz, 1H) 1.46 (s, 9H).

[1429] Step 8 : tert -butyl (3a S ,5 R ,6a R )-5-(benzyloxy)-2,2-dimethyltetrahydro-2H -Cyclopenta[ d ]Oxazole-3(3a H )-carboxylate( 23h )

[1430]

[1431] tert -butyl ((1 S ,2 R ,4 R )-4-(benzyloxy)-2-hydroxycyclopentyl)carbamate( 22g A mixture of )(834 mg, 2.71 mmol), 2,2-dimethoxypropane (667 µl, 5.43 mmol), and PTSA (46.7 mg, 0.271 mmol) was stirred in acetone (9.0 ml) at 23°C for 17.5 hours. The reaction mixture was quenched with saturated NaHCO3(aq) and then diluted with EtOAc and water. The EtOAc layer was washed with brine, dried over Na2SO4, filtered, and concentrated into oil. The residue was purified by silica gel chromatography (EtOAc / heptane 0-100%) as a colorless oil tert -butyl (3a S ,5 R ,6a R )-5-(benzyloxy)-2,2-dimethyltetrahydro-2 H -Cyclopenta[ d ]Oxazole-3(3a H )-carboxylate( 22h )(810 mg, 85%) was obtained. LCMS-ESI(+) = 248.2 (M-Boc+H). 1 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.28 - 7.39 (m, 5H) 4.44 - 4.61 (m, 3H) 3.96 - 4.28 (m, 2H) 2.20 - 2.38 (m, 1H) 2.10 - 2.20 (m, 1H) 1.86 - 2.10 (m, 2H) 1.59 - 1.71 (m, 3H) 1.49 (br d, J =9.29 Hz, 9H) 1.44 (br d, J=9.78 Hz, 3H).

[1432] Step 9 : tert -butyl (3a S ,5 R ,6a R )-5-hydroxy-2,2-dimethyltetrahydro-2 H -Cyclopenta[ d ]Oxazole-3(3a H )-carboxylate( Intermediate 22 )

[1433]

[1434] Intermediate 22

[1435] in ethanol (7.77 ml) tert -butyl (3a S ,5 R ,6a R )-5-(benzyloxy)-2,2-dimethyltetrahydro-2 H -Cyclopenta[ d ]Oxazole-3(3a H )-carboxylate( 22h A mixture of )(810 mg, 2.33 mmol) and 10% Pd / C(80 mg) was hydrogenated (1 atm, balloon) at 23°C for 1 hour. The reaction mixture was filtered through Celite and concentrated under reduced pressure as a pale yellowish-brown solid. tert -butyl (3a S ,5 R ,6a R )-5-hydroxy-2,2-dimethyltetrahydro-2 H -Cyclopenta[ d ]Oxazole-3(3a H )-carboxylate( intermediate 22 )(592 mg, 99%) was obtained. LCMS-ESI(+) = 158.2 (M-Boc+H), 1 ¹H NMR (400 MHz, CDCl₃) δ ppm 4.67 (t, J =4.89 Hz, 1H) 4.28 (br s, 2H) 2.86 (br dd, J=5.69, 2.14 Hz, 1H) 2.20 (br d, J =14.92 Hz, 1H) 2.00 - 2.17 (m, 2H) 1.81 (dt, J =14.95, 4.63 Hz, 1H) 1.67 (br s, 3H) 1.49 (s, 9H) 1.43 - 1.47 (m, 3H).

[1436] Preparation of Intermediate 23: tert -butyl {( 1 R ,3 R )-3-[4-(5-amino-3-methyl-1 H -pyrazol-1-yl)-2-bromophenoxy]cyclopentyl}carbamate

[1437] Step 1 : (2 E )-3-aminobut-2-enenenitrile( 23a )

[1438]

[1439] LiHMDS (1.02 g) was added to a solution of acetonitrile (500 mg) in dimethoxyethane (18.0 mL). The mixture was heated to 90°C for 18 hours and then concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc (3x). The combined organic matter was dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-60% EtOAc / PE) to obtain a yellow oil (2 E )-Aminobut-2-Enenitrile(400 mg, 80% yield)( 23a ) obtained. 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.47 (br s, 4H) 3.89 (s, 1H) 3.61 (s, 3H) 1.93 (s, 3H) 1.76 (s, 3H).

[1440] Step 2 : 2-Bromo-1-methoxy-4-nitrobenzene( 23b )

[1441]

[1442] Methyl iodide (1.95 g, 13.8 mmol) was added to a mixture of 2-bromo-4-nitrophenol (1.0 g, 4.59 mmol) and K in DMF (20 mL). The reaction was stirred at RT for 16 hours. The reaction suspension was poured into ice water, and the solid was collected by filtration to obtain 2-bromo-1-methoxy-4-nitrobenzene (1.32 g, >99% crude yield) as a white solid ( 23b ) obtained. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (d, J = 2.7 Hz, 1H) 8.29 (dd, J = 2.8, 9.2 Hz, 1H) 7.34 (d, J = 9.2 Hz, 1H) 4.01 (s, 3H).

[1443] Step 3 : 3-Bromo-4-Methoxyaniline( 23c )

[1444]

[1445] Iron (1.59 g, 28.4 mmol) was added to a solution of 2-bromo-1-methoxy-4-nitrobenzene and NH in methanol (20.0 mL). The mixture was heated at 80°C for 2 hours. The suspension was filtered. The filtrate was extracted with EtOAc (2x), and the combined organic matter was concentrated under reduced pressure to obtain 3-bromo-4-methoxyaniline as a brown solid ( 23c )(870 mg, 75.5% yield) was obtained. LCMS APCI (+) 202.1 (M+H). 1 H NMR (400 MHz, CDCl3) δ ppm 6.96 (d, J = 2.7 Hz, 1H) 6.77 (d, J = 8.6, Hz, 1H) 6.63 (dd, J = 2.8, 8.6 Hz, 1H) 3.84 (s, 3H).

[1446] Step 4 : (3-bromo-4-methoxyphenyl)hydrazine (23d )

[1447]

[1448] After cooling a solution of 3-bromo-4-methoxycyaniline in H₂ and concentrated HCl (11 mL) in an ice bath, sodium nitrite (449 mg, 6.50 mmol) was added dropwise to the solution. After 30 minutes, tin (II) chloride (1.96 g, 10.3 mmol) was added, followed by the addition of concentrated HCl (11 mL). After 2 hours, the solid was collected by filtration and washed with ethyl acetate to obtain (3-bromo-4-methoxyphenyl)hydrazine hydrochloride as a pale red solid. 23d )(670 mg, 71.7% yield) was obtained. LCMS APCI (+) 218.1 (M+H). 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.18 (br s, 3H) 7.30 (d, J = 2.6, Hz, 1H) 7.09 - 7.00 (m, 2H) 3.80 (s, 3H).

[1449] Step 5 : 1-(3-bromo-4-methoxyphenyl)-3-methyl-1H-pyrazol-5-amine( 23e )

[1450]

[1451] A solution of (3-bromo-4-methoxyphenyl)hydrazine and 3-aminobut-2-enenenitrile in concentrated HCl (5.00 mL) and H₂ was stirred at 100°C for 1 hour. After cooling the solution, saturated aqueous lithium chloride (25 mL) was added. The solid was collected by filtration and, as a yellow solid, 1-(3-bromo-4-methoxyphenyl)-3-methyl-1H-pyrazol-5-amine ( 23d )(600 mg, 83.9% yield) was obtained. LCMS APCI (+) 282.0 (M+H). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.72 (d, J = 2.4 Hz, 1H) 7.53 (dd, J = 2.4, 8.8 Hz, 1H) 7.18 (d, J = 8.9 Hz, 1H) 5.30 (s, 1H) 5.19 (br s, 2H) 3.88 (s, 3H) 2.05 (s, 3H).

[1452] Step 6 : 4-(5-amino-3-methyl-1H-pyrazole-1-yl)-2-bromophenol( 23f )

[1453]

[1454] BBr was added to a solution of 1-(3-bromo-4-methoxyphenyl)-3-methyl-1H-pyrazole-5-amine in DCM (20.0 mL) at -20°C. The resulting reaction mixture was stirred at 30°C for 3 hours. The solution was poured into H2O (40 mL), and the pH was adjusted to approximately 7 with saturated NaHCO3. It was extracted with DCM (30x) and EtOAc (2x). The combined organic matter was concentrated under reduced pressure to obtain 4-(5-amino-3-methyl-1H-pyrazole-1-yl)-2-bromophenol ( 23f )(425 mg, 89.4% yield) was obtained. LCMS APCI (+) 267.8 (M+H). 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.37 (s, 1H) 7.59 (d, J = 2.4 Hz, 1H) 7.33 (dd, J = 2.5, 8.7 Hz, 1H) 6.99 (d, J = 8.8 Hz, 1H) 5.27 (s, 1H) 5.15 (s, 2H) 2.03 (s, 3H).

[1455] Step 7 : tert -butyl {(1 R ,3 R )-3-[4-(5-amino-3-methyl-1 H -pyrazol-1-yl)-2-bromophenoxy]cyclopentyl}carbamate( Intermediate 23 )

[1456]

[1457] Intermediate 23

[1458] DIAD (641 mg, 3.17 mmol) was added dropwise to a solution of 4-(5-amino-3-methyl-1H-pyrazole-1-yl)-2-bromophenol, tert-butyl ((1R,3S)-3-hydroxycyclopentyl)carbamate (479 mg, 2.38 mmol), and triphenylphosphine (832 mg, 3.17 mmol) in THF (15.0 mL). After stirring overnight, the solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0-50% EtOAc / PE) to obtain tert-butyl ((1R,3R)-3-(4-(5-amino-3-methyl-1H-pyrazole-1-yl)-2-bromophenoxy)cyclopentyl)carbamate as a yellow solid. Intermediate 23 (1.26 g, >99% crude yield) was obtained. LCMS APCI (+) 472.9 (M+Na).

[1459] Preparation of intermediate 24: Methyl 2-(3- Bromo -4- hydroxyphenyl )-2- Methylbutanoate

[1460] Step 1 : Methyl 2-(3-bromo-4-methoxyphenyl)butanoate( 24a )

[1461]

[1462] NaH (60% in oil) (810 mg, 20.3 mmol) was added at 0°C to a solution of methyl 2-(3-bromo-4-methoxyphenyl)acetate (5 g, 19.3 mmol) in THF (50.0 mL). After stirring the mixture at 25°C for 0.5 hours, ethyl iodide (3.07 g, 19.7 mmol) was added at 0°C. After addition, the mixture was stirred at 25°C for 16 hours. The solution was quenched with ice water and extracted with EtOAc (3x). The combined organic matter was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-10% EtOAc / PE) to obtain methyl 2-(3-bromo-4-hydroxyphenyl)-2-methylbutanoate as a yellow oil ( 24a )(3.4 g, 61.4% yield) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.48 (d, J = 2.1 Hz, 1H) 7.26 (dd, J = 2.1, 8.5 Hz, 1H) 7.07 (d, J = 8.5 Hz, 1H) 3.82 (s, 3H) 3.58 (s, 3H) 3.55 - 3.48 (m, 1H) 1.98 - 1.87 (m, 1H) 1.74 - 1.58 (m, 1H) 0.89 - 0.71 (m, 3H).

[1463] Step 2: Methyl 2-(3-bromo-4-methoxyphenyl)-2-methylbutanoate( 24b )

[1464]

[1465] Methyl 2-(3-bromo-4-hydroxyphenyl)-2-methylbutanoate in THF (20.0 mL) 24aLiHMDS (2.33 g, 13.9 mmol, 13.9 mL, 1.0 M THF solution) was added to a solution of )(2.0 g, 6.97 mmol) at 0°C. After stirring the resulting solution for 0.5 hours, methyl iodide (1.98 g, 13.9 mmol) was added at approximately 10°C. The reaction mixture was stirred at 25°C for 3 hours. The reaction was quenched with saturated NH4Cl and then extracted with EtOAc (3x). The combined organic matter was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-10% EtOAc / PE) to obtain methyl 2-(3-bromo-4-methoxyphenyl)-2-methylbutanoate ( 24b )(1.6 g, 76.3% yield) was obtained.

[1466] Step 3 : 2-(3-bromo-4-hydroxyphenyl)-2-methylbutanoic acid( 24c )

[1467]

[1468] Hydrobromic acid (5.00 mL) was added to the solution in acetic acid (10.0 mL). After heating the reaction at 110°C for 16 hours, it was poured into H2O and extracted with EtOAc (3x). The combined organic matter was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (0-20% EtOAc / PE) to obtain 2-(3-bromo-4-hydroxyphenyl)-2-methylbutanoic acid (3-bromo-4-hydroxyphenyl)-2-methylbutanoic acid ( 24c )(1.24 g, 92% yield) was obtained. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.28 (br s, 1H) 10.15 (br s, 1H) 7.34 (d, J = 2.4 Hz, 1H) 7.12 (dd, J = 2.3, 8.5 Hz, 1H) 6.90 (d, J = 8.5 Hz, 1H) 1.94 - 1.87 (m, 1H) 1.85 - 1.74 (m, 1H) 1.36 (s, 3H) 0.75 (t, J = 7.3 Hz, 3H).

[1469] Step 4 : Methyl 2-(3-bromo-4-hydroxyphenyl)-2-methylbutanoate( Intermediate 24 )

[1470]

[1471] Intermediate 24

[1472] 2-(3-bromo-4-hydroxyphenyl)-2-methylbutanoic acid( 24c H2SO4 (1.5 mL) was added to a solution of )(1.33 g, 4.87 mmol) in methanol (15 mL). The reaction was refluxed at 80°C for 16 hours and then concentrated. The residue was extracted with EtOAc (3x), and the combined organic matter was saturated with NaHCO₃. 3, and washed with brine, dried over Na2SO4, and concentrated to methyl 2-(3-bromo-4-hydroxyphenyl)-2-methylbutanoate ( intermediate 24 )(1.08 g 77.2% yield) was obtained as a pale yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.19 (s, 1H) 7.30 (d, J = 2.3 Hz, 1H) 7.07 (dd, J = 2.3, 8.6 Hz, 1H) 6.90 (d, J = 8.6 Hz, 1H) 3.57 (s, 3H) 1.97 - 1.78 (m, 2H), 1.39 (s, 3H) 0.73 (t, J = 7.4 Hz, 3H).

[1473] Preparation of intermediate 25: Methyl 1-ethyl-4-(4,4,5,5- Tetramethyl-1,3,2- Dioxaboro -2-day)-1 H - Pyrazole-3-carboxylate

[1474] Step 1 : Methyl 4-bromo-1-ethyl-1H-pyrazol-3-carboxylate ( 25a )

[1475]

[1476] Iodoethane (2.28 g, 14.6 mmol) was added dropwise to a mixture of and in ACN (20.0 mL). The reaction was heated at 60°C for 16 hours. The reaction was filtered, the filtrate was concentrated, and purified by silica gel chromatography (0-50% EtOAc / PE) to obtain methyl 4-bromo-1-ethyl-1H-pyrazole-3-carboxylate ( 25a )(1.5 g, 66% yield) was provided as a pale yellow solid. LCMS APCI (+) 233.0 (M+H). 1 H NMR (400 MHz, CDCl3) δ ppm 7.52 (s, 1H) 4.25 (q, J=7.3 Hz, 2H) 3.95 (s, 3H) 1.52 (t, J=7.3 Hz, 3H).

[1477] Step 2 : Methyl 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-3-carboxylate( Intermediate 25 )

[1478]

[1479] Intermediate 25

[1480] A mixture of methyl 4-bromo-1-ethyl-1H-pyrazole-3-carboxylate, bispinacollatodiborane (2.16 g, 8.50 mmol), and Pd(dppf)Cl in dioxane (15.0 mL) was stirred at 100°C for 16 hours. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography (0-50% EtOAc / PE) to obtain methyl 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-3-carboxylate ( intermediate 25 )(1.3 g, 82% yield) was provided as a yellow oil. LCMS APCI (+) 281.1 (M+H). 1 H NMR (400 MHz, CDCl3) δ ppm 7.63 (s, 1H) 4.25 - 4.20 (m, 2H) 3.89 (s, 3H) 1.50 - 1.43 (t, J=7.3 Hz, 3H) 1.33 (s, 12H).

[1481] Preparation of intermediate 26: methyl 1-(propane-2-yl)-4-(4,4,5,5- Tetramethyl -1,3,2- Dioxaboro -2-day)-1 H - Pyrazole-3-carboxylate

[1482]

[1483] Intermediate 26 Using isopropyl iodide instead of ethyl iodide Intermediate 25 Manufactured in a similar manner to LCMS APCI (+) 295.1 (M+H). 1 H NMR (400 MHz, CDCl3) δ ppm 7.70 (s, 1H) 4.69 - 4.59 (m, 1H) 3.94 (s, 3H) 1.56 - 1.52 (m, 6H) 1.39 (s, 12H).

[1484] Preparation of Intermediate 27: Methyl 1- cyclopropyl -4-(4,4,5,5- Tetramethyl -1,3,2- Dioxaboro -2-day)-1 H - Pyrazole-3-carboxylate

[1485] Step 1 : Methyl 4-bromo-1-cyclopropyl-1H-pyrazol-3-carboxylate( 27a )

[1486]

[1487] A mixture of 2,2-bipyridine (1.68 g, 10.7 mmol) and Cu(OAc)2 (1.95 g, 10.7 mmol) in DCE (20 mL) was heated at 75°C for 25 minutes and then cooled to RT. Subsequently, a solution of methyl 4-bromo-1H-pyrazole-3-carboxylate (2.0 g, 10 mmol), cyclopropylboronic acid (1.68 g, 19.5 mmol), and Na2CO3 (2.07 g, 19.5 mmol) in DCE (20 mL) was added to the mixture. The mixture was heated under an O2 balloon at 75°C for 4 hours. The reaction mixture is filtered, the filtrate is concentrated, and purified by silica gel chromatography (0-30% EtOAc / PE) to obtain methyl 4-bromo-1-cyclopropyl-1H-pyrazole-3-carboxylate as an oil ( 27a )(1.16 g, 50% yield) was obtained. LCMS APCI (+) 244.9 (M+H). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (s, 1H) 3.88 - 3.81 (m, 1H) 3.79 (s, 3H) 1.14 - 1.06 (m, 2H) 1.05 - 0.97 (m, 2H).

[1488] Step 2 : Methyl 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-3-carboxylate( Intermediate 27 )

[1489]

[1490] ( Intermediate 27 )

[1491] A mixture of methyl 4-bromo-1-cyclopropyl-1H-pyrazole-3-carboxylate (27a) (1.06 g, 4.309 mmol), bispinacollatodiborane (1.64 g, 6.46 mmol), KOAc (1.27 g, 12.9 mmol), and Pd(dppf)Cl in dioxane (20 mL) was stirred at 100°C for 16 hours. The mixture was concentrated and purified by silica gel chromatography (0-40% EtOAc / PE) to obtain methyl 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-3-carboxylate ( intermediate 27 )(690 mg, 54.8% yield) was obtained as a yellow oil. LCMS APCI (+) 293.1 (M+H).

[1492] Preparation of intermediate 28: 1-( tert - Butoxycarbonyl )-5,5- diethyl -3- Fluoropyrrolidine -3-carboxylic acid

[1493] step 1 : 1- tert -Butyl 3-methyl 5,5-diethylpyrrolidine-1,3-dicarboxylate( 28a )

[1494]

[1495] A solution of 5,5-diethylpyrrolidine-3-carboxylic acid (620 mg, 3.6 mmol, prepared according to Org. Lett, 2019, 21, 9296-9299) in MeOH (7.70 mL) was cooled in an ice bath, and then thionyl chloride (4.31 g, 36.2 mmol) was added dropwise. After 2 hours, the reaction was concentrated, the residue was dissolved in THF (50 mL), and then concentrated again (3x) to obtain brown oil. The brown oil was dissolved in DCM (15.7 mL), TEA (733 mg, 7.24 mmol) was added, and then Boc2O (949 mg, 4.35 mmol) was added. After stirring the reaction overnight, additional TEA (733 mg, 7.24 mmol) and Boc2O (949 mg, 4.35 mmol) were added. After 4 hours, the reaction was concentrated and the residue was purified by silica gel chromatography (0-40% EtOAc / PE) to 1- tert -Butyl 3-methyl 5,5-diethylpyrrolidine-1,3-dicarboxylate( 28a )(920 mg, 89.0%) was obtained as a colorless oil. 1 ¹H NMR (400 MHz, chloroform-d) δ 3.92 - 3.75 (m, 1H), 3.70 (s, 3H), 3.50 - 3.36 (m, 1H), 3.05 - 2.92 (m, 1H), 2.20 - 1.80 (m, 4H), 1.79 - 1.53 (m, 2H), 1.45 (br d, J = 7.8 Hz, 9H), 0.90 - 0.77 (m, 6H).

[1496] step 2 : 1- tert -butyl 3-methyl 5,5-diethyl-3-fluoropyrrolidine-1,3-dicarboxylate( 28b )

[1497]

[1498] In a -78°C solution of LDA (2.0 M, 863 mmol, 8.06 mmol) in THF (16 mL), 1- in THF (8.2 mL) tert -Butyl 3-methyl 5,5-diethylpyrrolidine-1,3-dicarboxylate( 28a A solution of )(920 mg, 3.22 mmol) was slowly added. After 1 hour at -78°C, this solution was added dropwise via a cannula to a -78°C solution of N-fluorobenzenesulfonimide (2.54 g, 8.06 mmol) in THF (16 mL). After 1 hour at -78°C, the reaction was quenched with saturated NH4Cl under cold conditions and allowed to be heated to RT. The reaction was distributed between EtOAc and water. The organic layer was separated, and the aqueous substance was re-extracted with EtOAc. The organic layers were combined and concentrated. The residue was dissolved in DCM and washed with saturated aqueous citric acid solution, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc / heptane) to obtain 1- as a yellow oil tert -butyl 3-methyl 5,5-diethyl-3-fluoropyrrolidine-1,3-dicarboxylate( 28b )(630 mg, 64%) was obtained. 1 ¹H NMR (400 MHz, chloroform-d) δ 4.14 - 3.63 (m, 5H), 2.54 - 1.79 (m, 5H), 1.62 - 1.39 (m, 10H), 0.91 - 0.81 (m, 6H).

[1499] step 3 : 1-( tert -butoxycarbonyl)-5,5-diethyl-3-fluoropyrrolidine-3-carboxylic acid ( Intermediate 28 )

[1500]

[1501] ( Intermediate 28 )

[1502] LiOH·H2O (102 mg, 4.25 mmol) was added to a solution of 1-tert-butyl 3-methyl 5,5-diethyl-3-fluoropyrrolidin-1,3-dicarboxylate (28b) (430 mg, 1.42 mmol) in MeOH (4.0 mL) and water (1.5 mL). After 3 hours, the reaction solution was concentrated to remove MeOH, and the resulting aqueous solution was acidified with 1 M HCl to pH = 4–5. The aqueous phase was extracted with DCM (3x). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated to 1-( tert -butoxycarbonyl)-5,5-diethyl-3-fluoropyrrolidine-3-carboxylic acid ( intermediate 28 )(264 mg, 64.4%) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 3.96 - 3.60 (m, 3H), 2.53 - 2.27 (m, 2H), 2.12 - 1.80 (m, 3H), 1.46 (d, J = 7.3 Hz, 9H), 0.93 - 0.76 (m, 6H).

[1503] Preparation of intermediate 29: Methyl 2-(5- Bromo -6- Methoxypyridine -3-day)-2- Methylpropanoate

[1504] Step 1 : Methyl (5-bromo-6-methoxypyridine-3-yl)acetate ( 29a )

[1505]

[1506] A suspension of (5-bromo-6-methoxypyridine-3-yl)acetonitrile (488 mg, 2.15 mmol) in methanol (2.15 mL) was cooled in an ice bath, after which thionyl chloride (639 mg, 392 μL, 2.50 Eq, 5.37 mmol) was added. The ice bath was removed, and the reaction was stirred for 19 hours. The reaction mixture was concentrated to become a white solid, the solid was suspended in EtOAc, and neutralized with saturated NaHCO3(aq). Organic matter was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% EtOAc / heptane) to obtain methyl (5-bromo-6-methoxypyridine-3-yl)acetate ( 29a )(432 mg, 77%) was obtained as a colorless oil. LCMS ESI (+) 260.0 / 262.0 (M+H). 1 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.98 (d, J=1.96 Hz, 1H) 7.79 (d, J=2.08 Hz, 1H) 4.00 (s, 3H) 3.72 (s, 3H) 3.54 (s, 2H).

[1507] Step 2 : Methyl 2-(5-bromo-6-methoxypyridine-3-yl)-2-methylpropanoate( 29b )

[1508]

[1509] Methyl (5-bromo-6-methoxypyridine-3-yl)acetate in THF (5.5 mL) 29aAfter cooling a solution of )(430 mg, 1.65 mmol) in an ice bath, methyl iodide (516 mg, 227 μL, 3.64 mmol) was added, followed by the addition of potassium tert-butoxide (390 mg, 1.74 mL, 2 molar, 3.47 mmol). After 3 hours, the reaction mixture was quenched with saturated NH4Cl(aq) and diluted with EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% EtOAc / heptane) to obtain methyl 2-(5-bromo-6-methoxypyridine-3-yl)-2-methylpropanoate ( 29b )(410 mg, 86%) was obtained. LCMS ESI (+) 288.0 / 290.0 (M+H). 1 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.10 (d, J =2.32 Hz, 1H) 7.81 (d, J =2.32 Hz, 1H) 4.01 (s, 3H) 3.68 (s, 3H) 1.59 (s, 6H).

[1510] Step 3 : Methyl 2-(5-bromo-6-methoxypyridine-3-yl)-2-methylpropanoate( Intermediate 29 )

[1511]

[1512] Intermediate 29

[1513] Methyl 2-(5-bromo-6-methoxypyridine-3-yl)-2-methylpropanoate in ACN (4.72 mL) 29bTMS-Cl (385 mg, 449 μL, 3.54 mmol) was added to a mixture of ) (408 mg, 1.42 mmol) and sodium iodide (531 mg, 3.54 mmol). The reaction mixture was stirred at RT for 6 hours and then quenched with saturated NaHCO3(aq). The mixture was diluted with EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% EtOAc / heptane) to obtain methyl 2-(5-bromo-6-hydroxypyridine-3-yl)-2-methylpropanoate ( Intermediate 29 )(340 mg, 87%) was obtained. LCMS ESI(+) 274 / 276 (M+H). 1 ¹H NMR (400 MHz, CDCl₃) δ = 13.69 - 12.68 (m, 1H), 7.93 (br s, 1H), 7.45 (br s, 1H), 3.70 (br s, 3H), 1.52 (br s, 6H).

[1514] Preparation of intermediate 30: Methyl 2-(3- Bromo -4- hydroxyphenyl )-2- ( 2 H 3 )methyl( 2 H 3 )Propanoate

[1515]

[1516] Intermediate 30 Iodo instead of methyl iodide ( 2 Using H3)methane Intermediate I It was manufactured in a similar manner to. 1 H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.12 (dd, J= 2.4, 8.5 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 3.58 (s, 3H).

[1517] Examples

[1518] To better understand the present disclosure, the following examples are provided. These examples are for illustrative purposes only and should not be construed as limiting the scope of the disclosure in any way.

[1519] Preparation of the example

[1520] Example A1: 2-(2'-cyclobutyl-3'-fluoro-6-{[(1 R ,3 R )-3-{[(7 S )-7-fluoro-5-azaspiro[3,4]octane-7-carbonyl]amino}cyclopentyl]oxy}[1,1'-biphenyl]-3-yl)-2-methylpropanoic acid

[1521]

[1522] A1

[1523] Example A1 It was manufactured according to general method A.

[1524] Step 1 : Methyl 2-[3-bromo-4-({(1 R ,3 R )-3-[( tert -butoxycarbonyl)amino]cyclopentyl}oxy)phenyl]-2-methylpropanoate( A1a )

[1525]

[1526] Methyl 2-(3-bromo-4-hydroxyphenyl)-2-methylpropanoate( Intermediate 1After cooling a solution of )(2.05 g, 7.506 mmol), tert-butyl ((1R,3S)-3-hydroxycyclopentyl)carbamate (1.813 g, 9.007 mmol), and triphenylphosphine (3.937 g, 15.01 mmol) in an ice bath, diisopropyl azodicarboxylate (3.035 g, 2.919 mL, 15.01 mmol) was added dropwise to the solution. After 2 hours, the reaction was concentrated under reduced pressure and purified by silica gel chromatography (0-50% EtOAc / heptane) to obtain methyl 2-[3-bromo-4-({(1 R ,3 R )-3-[( tert -butoxycarbonyl)amino]cyclopentyl}oxy)phenyl]-2-methylpropanoate( A1a )(3.14 g, 92%) was obtained. LCMS APCI (+) 356.1, 358.1 (M-Boc). 1 H NMR (400 MHz, CDCl3) δ ppm 7.50 (d, J=2.50 Hz, 1H) 7.19 (dd, J=8.63, 2.38 Hz, 1H) 6.78 (d, J=8.63 Hz, 1H) 4.79 - 4.86 (m, 1H) 4.49 (br s, 1H) 4.24 (br d, J=6.00 Hz, 1H) 3.66 (s, 3H) 2.35 (br dd, J=14.26, 7.38 Hz, 1H) 2.22 - 2.30 (m, 1H) 2.07 - 2.17 (m, 1H) 1.88 - 1.99 (m, 1H) 1.76 (dt, J=13.91, 6.86 Hz, 1H) 1.55 (s, 6H) 1.48 - 1.53 (m, 1H) 1.45 (s, 9H).

[1527] Step 2 : Methyl 2-[6-({(1 R ,3 R )-3-[( tert -butoxycarbonyl)amino]cyclopentyl}oxy)-2'-cyclobutyl-3'-fluoro[1,1'-biphenyl]-3-yl]-2-methylpropanoate( A1b )

[1528]

[1529] Methyl 2-[3-bromo-4-({(1 ) in 5:1 dioxane:water (41.4 mL) R ,3 R )-3-[( tert -butoxycarbonyl)amino]cyclopentyl}oxy)phenyl]-2-methylpropanoate( A1a )(3.14 g, 6.88 mmol), 2-(2-cyclobutyl-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolein( intermediate 2 N2 was sparged for 15 minutes in a solution of )(2.19 g, 7.91 mol) and Cs2CO3(6.73 g, 20.6 mmol). 1,1'-bis(di-t-butylphosphino)ferrocene palladium dichloride (0.224 g, 0.344 mmol) was added, and the reaction was heated at 90°C for 4 hours. The reaction was concentrated under reduced pressure, the residue was dissolved in EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% EtOAc / heptane) to obtain methyl 2-[6-({(1) as an orange gum. R ,3 R )-3-[( tert -butoxycarbonyl)amino]cyclopentyl}oxy)-2'-cyclobutyl-3'-fluoro[1,1'-biphenyl]-3-yl]-2-methylpropanoate( A1b )(3.35 g, 92.6%) was obtained. LCMS APCI (+) 426.3 (M-Boc). 1H NMR (400 MHz, CDCl3) δ ppm 7.23 - 7.26 (m, 1H) 7.10 - 7.17 (m, 1H) 7.06 (t, J=2.31 Hz, 1H) 6.98 (ddd, J=11.57, 8.19, 1.13 Hz, 1H) 6.89 (td, J=7.41, 1.19 Hz, 1H) 6.82 (d, J=8.25 Hz, 1H) 4.68 (qt, J=6.03, 2.89 Hz, 1H) 4.29 - 4.48 (m, 1H) 3.85 - 4.03 (m, 1H) 3.66 (s, 3H) 3.39 - 3.52 (m, 1H) 2.24 - 2.36 (m, 1H) 2.07 - 2.23 (m, 2H) 1.85 - 2.06 (m, 4H) 1.64 - 1.83 (m, 4H) 1.57 (d, J=5.50 Hz, 6H) 1.43 (d, J=3.00 Hz, 9H) 1.33 - 1.41 (m, 1H).

[1530] Step 3 : Methyl 2-(6-{[(1 R ,3 R )-3-aminocyclopentyl]oxy}-2'-cyclobutyl-3'-fluoro[1,1'-biphenyl]-3-yl)-2-methylpropanoate( A1c )

[1531]

[1532] Methyl 2-[6-({(1 ) in DCM (31.9 mL) R ,3 R )-3-[( tert -butoxycarbonyl)amino]cyclopentyl}oxy)-2'-cyclobutyl-3'-fluoro[1,1'-biphenyl]-3-yl]-2-methylpropanoate( A1bHCl (4 N in dioxane, 15.9 mL, 63.7 mmol) was added to a solution of )(3.35 g, 6.37 mmol). After 4 hours, the reaction was concentrated under reduced pressure, the residue was dissolved in EtOAc, washed with 1 N NaOH and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain methyl 2-(6-{[(1 ) as an orange gum R ,3 R )-3-aminocyclopentyl]oxy}-2'-cyclobutyl-3'-fluoro[1,1'-biphenyl]-3-yl)-2-methylpropanoate( A1c )(2.66 g, 98%) was obtained. LCMS APCI (+) 426.1 (M+H). 1 H NMR (400 MHz, CDCl3) δ ppm 7.25 (br d, J=2.57 Hz, 1H) 7.09 - 7.16 (m, 1H) 7.06 (d, J=2.08 Hz, 1H) 6.98 (dd, J=11.13, 8.19 Hz, 1H) 6.85 - 6.90 (m, 1H) 6.80 - 6.85 (m, 1H) 4.75 (dt, J=5.78, 3.04 Hz, 1H) 3.66 (s, 3H) 3.39 - 3.53 (m, 2H) 2.24 - 2.36 (m, 2H) 2.12 - 2.23 (m, 2H) 1.97 - 2.05 (m, 2H) 1.84 - 1.93 (m, 2H) 1.69 - 1.81 (m, 3H) 1.58 (d, J=5.38 Hz, 6H) 1.30 - 1.40 (m, 1H).

[1533] Step 4 : tert -butyl (7 S )-7-{[(1 R ,3 R )-3-{[2'-cyclobutyl-3'-fluoro-5-(1-methoxy-2-methyl-1-oxopropane-2-yl)[1,1'-biphenyl]-2-yl]oxy}cyclopentyl]carbamoyl}-7-fluoro-5-azaspiro[3,4]octane-5-carboxylate( A1d )

[1534]

[1535] methyl 2-(6-{[(1 R ,3 R )-3-aminocyclopentyl]oxy}-2'-cyclobutyl-3'-fluoro[1,1'-biphenyl]-3-yl)-2-methylpropanoate( A1c )(356 mg, 0.837 mmol), (7 S )-5-( tert -butoxycarbonyl)-7-fluoro-5-azaspiro[3,4]octane-7-carboxylic acid ( Intermediate 3' Solutions of )(208 mg, 0.761 mmol) and 1-methylimidazole (219 mg, 0.211 mL, 2.66 mmol) were cooled in an ice water batch. Chloro- N , N , N ' , N '-tetramethylformamidinium hexafluorophosphate (256 mg, 0.913 mmol) was added, and the ice bath was removed. After 3 hours, the reaction was concentrated under reduced pressure, the residue was dissolved in EtOAc, washed with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-50% EtOAc / heptane). tert -butyl (7 S )-7-{[(1 R ,3 R )-3-{[2'-cyclobutyl-3'-fluoro-5-(1-methoxy-2-methyl-1-oxopropane-2-yl)[1,1'-biphenyl]-2-yl]oxy}cyclopentyl]carbamoyl}-7-fluoro-5-azaspiro[3,4]octane-5-carboxylate( A1d )(411 mg, 79.3%) was obtained as a foamy white solid. LCMS APCI (+) 581.2 (M-Boc). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.24 - 8.41 (m, 1H) 7.27 (dd, J=8.69, 2.56 Hz, 1H) 7.18 - 7.24 (m, 1H) 7.10 (dd, J=11.82, 7.32 Hz, 1H) 6.99 (d, J=8.76 Hz, 1H) 6.95 (dd, J=2.38, 1.50 Hz, 1H) 6.88 (ddd, J=7.57, 3.38, 1.19 Hz, 1H) 4.82 (br d, J=2.63 Hz, 1H) 3.98 - 4.16 (m, 1H) 3.62 - 3.72 (m, 1H) 3.59 (s, 4H) 3.36 - 3.50 (m, 1H) 2.59 - 3.11 (m, 3H) 1.58 - 2.22 (m, 15H) 1.38 - 1.56 (m, 17H).

[1536] Step 5 : 2-(6-{[(1 R ,3 R )-3-{[(7 S )-5-( tert -butoxycarbonyl)-7-fluoro-5-azspiro[3,4]octane-7-carbonyl]amino}cyclopentyl]oxy}-2'-cyclobutyl-3'-fluoro[1,1'-biphenyl]-3-yl)-2-methylpropanoic acid( A1e )

[1537]

[1538] in 1:1 THF:methanol (6 mL) tert -butyl (7 S )-7-{[(1 R ,3 R )-3-{[2'-cyclobutyl-3'-fluoro-5-(1-methoxy-2-methyl-1-oxopropane-2-yl)[1,1'-biphenyl]-2-yl]oxy}cyclopentyl]carbamoyl}-7-fluoro-5-azaspiro[3,4]octane-5-carboxylate( A1dLiOH (1 N, 5.29 mL, 5.29 mmol) was added to a solution of )(240 mg, 0.353 mmol). The mixture was heated overnight at 70°C. The reaction was cooled to RT, acidified with 1 N HCl, and then extracted with DCM (2x). The organic matter was combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(6-{[(1 R ,3 R )-3-{[(7 S )-5-( tert -butoxycarbonyl)-7-fluoro-5-azspiro[3,4]octane-7-carbonyl]amino}cyclopentyl]oxy}-2'-cyclobutyl-3'-fluoro[1,1'-biphenyl]-3-yl)-2-methylpropanoic acid( A1e )(250 mg, 93%) was obtained as a foamy white solid. LCMS APCI (+) 567.3 (M-Boc). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.08 - 7.93 (m, 1H), 7.32 (dd, J = 2.4, 8.6 Hz, 1H), 7.21 (dt, J = 5.6, 7.8 Hz, 1H), 7.07 (dd, J = 8.2, 11.9 Hz, 1H), 7.03 - 6.95 (m, 2H), 6.88 (dd, J = 2.1, 7.1 Hz, 1H), 4.84 - 4.75 (m, 1H), 4.15 - 4.01 (m, 1H), 3.65 - 3.57 (m, 3H), 3.52 - 3.36 (m, 1H), 3.26 - 3.11 (m, 1H), 2.84 - 2.73 (m, 1H), 2.69 - 2.56 (m, 1H), 2.28 - 2.14 (m, 1H), 2.13 - 2.06 (m, 1H), 2.00 (br d, J = 6.3 Hz, 2H), 1.95 - 1.87 (m, 3H), 1.86 - 1.78 (m, 3H), 1.75 - 1.57 (m, 4H), 1.50 - 1.43 (m, 17H).

[1539] Step 6: 2-(2'-cyclobutyl-3'-fluoro-6-{[(1 R ,3 R )-3-{[(7 S )-7-fluoro-5-azaspiro[3,4]octane-7-carbonyl]amino}cyclopentyl]oxy}[1,1'-biphenyl]-3-yl)-2-methylpropanoic acid( Examples A1 )

[1540]

[1541] A1

[1542] 2-(6-{[(1 in DCM(1.52 mL) R ,3 R )-3-{[(7 S )-5-( tert -butoxycarbonyl)-7-fluoro-5-azspiro[3,4]octane-7-carbonyl]amino}cyclopentyl]oxy}-2'-cyclobutyl-3'-fluoro[1,1'-biphenyl]-3-yl)-2-methylpropanoic acid( A1e HCl (4 N in dioxane, 1.52 mL, 6.09 mmol) was added to a solution of )(203 mg, 0.304 mmol). After stirring at RT for 2 hours, the reaction was concentrated under reduced pressure, and the residue was purified by Prep HPLC (Phenomenex Gemini NX C18 150 x 21.2 mm, 5 µm, AXIA Pack column, mobile phase A: water + 10 mM ammonium acetate, mobile phase B: acetonitrile, 20-60% B for 8.0 min, 40 mL / min) to obtain 2-(2'-cyclobutyl-3'-fluoro-6-{[(1 R ,3 R )-3-{[(7 S )-7-fluoro-5-azaspiro[3,4]octane-7-carbonyl]amino}cyclopentyl]oxy}[1,1'-biphenyl]-3-yl)-2-methylpropanoic acid( Examples A1 )(99 mg, 57%) was obtained. LCMS APCI (+) 567.3 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.82 (br s, 1H), 7.32 (dd, J = 2.5, 8.6 Hz, 1H), 7.21 (dt, J = 5.6, 7.9 Hz, 1H), 7.08 (ddd, J = 1.1, 8.3, 11.9) Hz, 1H), 7.03 - 6.96 (m, 2H), 6.92 - 6.81 (m, 1H), 4.84 - 4.75 (m, 1H), 4.18 - 3.98 (m, 1H), 3.54 - 3.40 (m, 1H), 3.30 - 3.12 (m, 3H), 2.38 - 1.96 (m, 10H), 1.91 - 1.58 (m, 7H), 1.50 (d, J = 2.4 Hz, 7H). [α]= -12.1° ( c 0.1, MeOH).

[1543] Table 1 reported in Example A2 inside A44 is something that can be realized by a person skilled in the art Examples A1 It was synthesized by a non-critical change or substitution to the exemplified procedure.

[1544] Table 1

[1545]

[1546]

[1547]

[1548]

[1549]

[1550]

[1551]

[1552]

[1553]

[1554]

[1555]

[1556]

[1557]

[1558]

[1559]

[1560]

[1561] Example B1: (7ξ)- N -{(1 R ,3 R )-3-[(2'-cyclobutyl-5-{1-[(ethanesulfonyl)amino]-2-methyl-1-oxopropane-2-yl}-3'-fluoro[1,1'-biphenyl]-2-yl)oxy]cyclopentyl}-7-fluoro-5-azaspiro[3,4]octane-7-carboxamide; and

[1562] Example B2: (7ξ)- N -{(1 R ,3 R )-3-[(2'-cyclobutyl-5-{1-[(ethanesulfonyl)amino]-2-methyl-1-oxopropane-2-yl}-3'-fluoro[1,1'-biphenyl]-2-yl)oxy]cyclopentyl}-7-fluoro-5-azaspiro[3,4]octane-7-carboxamide

[1563]

[1564] Example B1 and B2 It was manufactured according to general method B.

[1565] step 1 : 2-[6-({(1 R ,3 R )-3-[( tert -butoxycarbonyl)amino]cyclopentyl}oxy)-2'-cyclobutyl-3'-fluoro[1,1'-biphenyl]-3-yl]-2-methylpropanoic acid ( B1a )

[1566]

[1567] Methyl 2-[6-({(1 ) in MeOH (50.0 mL) R ,3 R )-3-[( tert -butoxycarbonyl)amino]cyclopentyl}oxy)-2'-cyclobutyl-3'-fluoro[1,1'-biphenyl]-3-yl]-2-methylpropanoate( A1bLiOH (1.5 N, 10.0 mL, 5.29 mmol) was added to a solution of )(3.93 g, 7.48 mmol). The reaction was stirred overnight at RT but did not complete. LiOH·H2O (941 mg, 22.4 mg) was added and heated at 40°C overnight. After removing MeOH under reduced pressure, the residue was distributed between EtOAc and 1 N HCl. The aqueous layer was extracted with EtOAc (3x), the combined organic matter was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a pale yellow gum. A minimum amount of EtOAc was added, diluted with PE, sonicated until a white precipitate formed, and collected by filtration to 2-[6-({(1 R ,3 R )-3-[( tert -butoxycarbonyl)amino]cyclopentyl}oxy)-2'-cyclobutyl-3'-fluoro[1,1'-biphenyl]-3-yl]-2-methylpropanoic acid ( B1a )(3.7 g, 97%) was obtained. LCMS (+) ESI 534.3 (M+Na). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.46 - 12.14 (m, 1H), 7.29 (dd, J = 2.4, 8.7 Hz, 1H), 7.25 - 7.17 (m, 1H), 7.14 - 7.06 (m, 1H), 7.01 - 6.94 (m, 2H), 6.91 - 6.81 (m, 2H), 4.83 - 4.70 (m, 1H), 3.84 - 3.65 (m, 1H), 3.48 - 3.39 (m, 1H), 2.24 - 2.12 (m, 1H), 2.11 - 1.92 (m, 3H), 1.89 - 1.61 (m, 6H), 1.46 (d, J = 5.3 Hz, 7H), 1.35 (d, J = 1.5 Hz, 10H).

[1568] Step 2 : tert -butyl {(1 R ,3 R)-3-[(2'-cyclobutyl-5-{1-[(ethanesulfonyl)amino]-2-methyl-1-oxopropane-2-yl}-3'-fluoro[1,1'-biphenyl]-2-yl)oxy]cyclopentyl}carbamate( B1b )

[1569]

[1570] 2-[6-({(1 in DCM(8.0 mL) R ,3 R )-3-[( tert -butoxycarbonyl)amino]cyclopentyl}oxy)-2'-cyclobutyl-3'-fluoro[1,1'-biphenyl]-3-yl]-2-methylpropanoic acid ( B1a Carbonyldiimidazole (143 mg, 0.880 mmol) was added to a solution of )(300 mg, 0.586 mmol). After stirring the reaction at 25-30°C for 1 hour, ethanesulfonamide (160 mg, 1.47 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (357 mg, 2.35 mmol) were added. After 3 hours, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0-10% MeOH / EtOAc) as an impure yellow gum used directly in the next step. tert -butyl {(1 R ,3 R )-3-[(2'-cyclobutyl-5-{1-[(ethanesulfonyl)amino]-2-methyl-1-oxopropane-2-yl}-3'-fluoro[1,1'-biphenyl]-2-yl)oxy]cyclopentyl}carbamate( B1b ) was obtained. LCMS (+) ESI 625.3 (M+Na).

[1571] step 3 : 2-(6-{[(1 R ,3 R )-3-aminocyclopentyl]oxy}-2'-cyclobutyl-3'-fluoro[1,1'-biphenyl]-3-yl)- N -(ethansulfonyl)-2-methylpropanamide( B1c )

[1572]

[1573] 2-(6-{[(1 from the previous step R ,3 R )-3-aminocyclopentyl]oxy}-2'-cyclobutyl-3'-fluoro[1,1'-biphenyl]-3-yl)- N -(ethansulfonyl)-2-methylpropanamide( B1c The DCM (5.0 mL) solution of ) was cooled in an ice bath. After adding HCl (2 N in dioxane, 4.0 mL, 8.0 mmol), the ice bath was removed. The reaction was stirred for 3 hours and then concentrated under reduced pressure to obtain 2-(6-{[(1 ) as a white solid to be used directly in the next step R ,3 R )-3-aminocyclopentyl]oxy}-2'-cyclobutyl-3'-fluoro[1,1'-biphenyl]-3-yl)- N -(ethanesulfonyl)-2-methylpropanamide hydrochloride( B1c ) was obtained. LCMS (+) APCI 503.2 (M+H).

[1574] Step (4) : tert -butyl (7ξ)-7-({(1 R ,3 R )-3-[(2'-cyclobutyl-5-{1-[(ethanesulfonyl)amino]-2-methyl-1-oxopropane-2-yl}-3'-fluoro[1,1'-biphenyl]-2-yl)oxy]cyclopentyl}carbamoyl)-7-fluoro-5-azaspiro[3,4]octane-5-carboxylate( B1d ); and

[1575] tert -butyl (7ξ)-7-({(1 R ,3 R )-3-[(2'-cyclobutyl-5-{1-[(ethanesulfonyl)amino]-2-methyl-1-oxopropane-2-yl}-3'-fluoro[1,1'-biphenyl]-2-yl)oxy]cyclopentyl}carbamoyl)-7-fluoro-5-azaspiro[3,4]octane-5-carboxylate( B1e )

[1576]

[1577] 2-(6-{[(1 in ACN(5.0 mL) R ,3 R )-3-aminocyclopentyl]oxy}-2'-cyclobutyl-3'-fluoro[1,1'-biphenyl]-3-yl)- N -(ethanesulfonyl)-2-methylpropanamide hydrochloride( B1c )(80 mg, 0.16 mmol) and 5-( tert -butoxycarbonyl)-7-fluoro-5-azaspiro[3,4]octane-7-carboxylic acid ( Intermediate (3) In a solution of )(52.2 mg, 0.191 mmol), 1-methylimidazole (45.7 mg, 0.557 mmol), chloro- N , N , N ', N '-tetramethylformamidinium hexafluorophosphate (51.4 mg, 0.183 mmol), and N , N -Diisopropylethylamine (61.7 mg, 0.0832 mL, 0.477 mmol) was added. After stirring the reaction at RT for 16 hours, additional 1-methylimidazole (19.6 mg, 0.239 mmol), chloro- N , N , N ', N '-tetramethylformamidinium hexafluorophosphate (22.3 mg, 0.0796 mmol), and N , N-Diisopropylethylamine (30.9 mg, 0.0416 mL, 0.239 mmol) was added. After stirring the reaction at RT for 16 hours, it was combined with the previous 15 mg scale reaction and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% EtOAc / PE) to obtain a mixture of diastereoisomers with LCMS (+) APCI 780.5 (M+Na), which was then preparatively analyzed using SFC (DAICEL CHIRALPAK AD column (250 x 30 mm, 10 µm particle size), temperature: 40°C, pressure: 100.0 bar, flow rate: 70 mL / min, 25% CO2). i Separated by elution with PrOH + 0.1% NH4OH as peak (1) tert -butyl (7ξ)-7-({(1 R ,3 R )-3-[(2'-cyclobutyl-5-{1-[(ethanesulfonyl)amino]-2-methyl-1-oxopropane-2-yl}-3'-fluoro[1,1'-biphenyl]-2-yl)oxy]cyclopentyl}carbamoyl)-7-fluoro-5-azaspiro[3,4]octane-5-carboxylate( B1d )(15 mg) and peak(2) as tert -butyl (7ξ)-7-({(1 R ,3 R )-3-[(2'-cyclobutyl-5-{1-[(ethanesulfonyl)amino]-2-methyl-1-oxopropane-2-yl}-3'-fluoro[1,1'-biphenyl]-2-yl)oxy]cyclopentyl}carbamoyl)-7-fluoro-5-azaspiro[3,4]octane-5-carboxylate( B1e )(15 mg) was obtained.

[1578] Step 5 : (7ξ)- N -{(1 R ,3 R )-3-[(2'-cyclobutyl-5-{1-[(ethanesulfonyl)amino]-2-methyl-1-oxopropane-2-yl}-3'-fluoro[1,1'-biphenyl]-2-yl)oxy]cyclopentyl}-7-fluoro-5-azaspiro[3,4]octane-7-carboxamide( Example B1 ); and

[1579] (7ξ)- N -{(1 R ,3 R )-3-[(2'-cyclobutyl-5-{1-[(ethanesulfonyl)amino]-2-methyl-1-oxopropane-2-yl}-3'-fluoro[1,1'-biphenyl]-2-yl)oxy]cyclopentyl}-7-fluoro-5-azaspiro[3,4]octane-7-carboxamide( Example B2 )

[1580]

[1581] in DCM (5.0 mL) tert -butyl (7ξ)-7-({(1 R ,3 R )-3-[(2'-cyclobutyl-5-{1-[(ethanesulfonyl)amino]-2-methyl-1-oxopropane-2-yl}-3'-fluoro[1,1'-biphenyl]-2-yl)oxy]cyclopentyl}carbamoyl)-7-fluoro-5-azaspiro[3,4]octane-5-carboxylate( B1d A solution of )(15 mg) was cooled in an ice bath. After adding HCl (2 N in dioxane, 4.0 mL, 8.0 mmol), the ice bath was removed. After stirring the reaction for 16 hours, it was concentrated under reduced pressure and freeze-dried to obtain (7ξ)- N -{(1 R ,3 R )-3-[(2'-cyclobutyl-5-{1-[(ethanesulfonyl)amino]-2-methyl-1-oxopropane-2-yl}-3'-fluoro[1,1'-biphenyl]-2-yl)oxy]cyclopentyl}-7-fluoro-5-azaspiro[3,4]octane-7-carboxamide( Example B1 )(8.77 mg, 64%) was obtained as a brown solid. LCMS (+) ESI 658.3 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 - 9.36 (m, 2H), 8.56 - 8.48 (m, 1H), 7.29 - 7.19 (m, 2H), 7.15 - 7.07 (m, 1H), 7.06 - 7.01 (m, 1H), 6.99 - 6.94 (m, 1H), 6.92 - 6.85 (m, 1H), 4.87 - 4.79 (m, 1H), 4.21 - 4.00 (m, 2H), 3.71 - 3.54 (m, 4H), 2.62 - 2.52 (m, 2H), 2.47 - 2.36 (m, 1H), 2.24 - 2.11 (m, 3H), 2.10 - 1.95 (m, 3H), 1.94 - 1.61 (m, 8H), 1.55 - 1.44 (m, 8H), 1.30 - 1.25 (m, 1H), 1.06 (t, J = 7.3 Hz, 3H). [α]= -28.1° ( c 0.1, MeOH). Example B2 Is B1e It was manufactured in a similar manner starting from. LCMS (+) ESI 658.3 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.24 - 9.60 (m, 2H), 8.72 - 8.38 (m, 1H), 7.28 - 7.19 (m, 2H), 7.14 - 7.07 (m, 1H), 7.05 - 7.00 (m, 1H), 6.98 - 6.95 (m, 1H), 6.90 - 6.85 (m, 1H), 4.88 - 4.78 (m, 1H), 4.15 - 4.01 (m, 1H), 3.71 - 3.52 (m, 4H), 3.29 (br s, 1H), 2.62 - 2.54 (m, 2H), 2.47 (br s, 1H), 2.23 - 2.13 (m, 3H), 2.10 - 1.96 (m, 3H), 1.93 - 1.77 (m, 6H), 1.75 - 1.63 (m, 2H), 1.53 - 1.44 (m, 8H), 1.30 - 1.25 (m, 1H), 1.06 (t, J = 7.4 Hz, 3H. [α]= -10.5° ( c 0.1, MeOH).

[1582] Table 2 reported in Example B3 inside B35 is something that can be realized by a person skilled in the art Example B1 and B2 It was synthesized by non-deterministic changes or substitutions to the exemplified procedure. In Examples B7 and B8, proline is methylated after Boc deprotection using formic acid and formaldehyde.

[1583] Table 2

[1584]

[1585]

[1586]

[1587]

[1588]

[1589]

[1590]

[1591]

[1592]

[1593]

[1594]

[1595]

[1596] Example C1 : (7 S )- N -{(1 R ,3 R )-3-[(2'-cyclobutyl-3'-fluoro-5-{1-[(methanesulfonyl)amino]-2-methyl-1-oxopropane-2-yl}[1,1'-biphenyl]-2-yl)oxy]cyclopentyl}-7-fluoro-5-azaspiro[3,4]octane-7-carboxamide

[1597]

[1598] C1

[1599] Example C1 It was manufactured according to general method C.

[1600] Step 1 : tert -butyl (7 S )-7-({(1 R ,3 R )-3-[(2'-cyclobutyl-3'-fluoro-5-{1-[(methanesulfonyl)amino]-2-methyl-1-oxopropane-2-yl}[1,1'-biphenyl]-2-yl)oxy]cyclopentyl}carbamoyl)-7-fluoro-5-azaspiro[3,4]octane-5-carboxylate( C1a )

[1601]

[1602] 2-(6-{[(1 in DCM(0.79 mL) R ,3 R )-3-{[(7 S )-5-( tert -butoxycarbonyl)-7-fluoro-5-azspiro[3,4]octane-7-carbonyl]amino}cyclopentyl]oxy}-2'-cyclobutyl-3'-fluoro[1,1'-biphenyl]-3-yl)-2-methylpropanoic acid( A1e Carbonyldiimidazole (19 mg, 0.12 mmol) was added to a solution of )(53 mg, 0.079 mmol). After heating the reaction at 40°C for 1 hour, ...

Claims

Claim 1 Compound of the following chemical formula (I) or a pharmaceutically acceptable salt thereof: (I) In the above formula, ring A is phenyl, or a 5 or 6-membered N-containing heteroaryl consisting of 1 or 2 N atoms and carbon atoms as ring members; L is a linker of the following formula: ;In the above formula, the asterisk * indicates the attachment point for ring A, and the dashed line is R 4 Indicates the attachment point for; z is 0 or 1; q is 0, 1, or 2; each Q is independently -OH, -CH3, or a halogen; ring B is a C3-C6 cycloalkyl; and R 1 and R 2 One of them is H or a halogen, and R 1 and R 2 The other one is a group of the following chemical formulas (E1-1), (E1-2), (E1-3), (E2-1), (E2-2) or (E3-1): In the above formula, each asterisk * indicates an attachment point for ring A; m is 0 or 1; and R 5 and R 6 Each is independently (i) H, (ii) halogen, (iii) C1-C6 alkyl optionally substituted with 1 to 3 halogens and 1 to 3 -OH groups, (iv) C1-C3 deuterinated alkyl, (v) C2-C6 alkenyl, or (vi) C 2-6 Alkynyl or; R 5 and R 6 ...together to form a 4 to 6-membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of C3-C6 cycloalkyl, or N, O, and S; R 7 silver, a C1-C6 alkyl optionally substituted with 1 to 3 halogens, (i) 1 to 4 halogens, or (ii) a C3-C5 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens, and -NR 8 R 9 Selected from a group consisting of, and R 8 and R 9 Each is independently H or C1-C6 alkyl, or R 8 and R 9 is formed together with 1 to 4 halogens to form a 4 to 6-membered N-containing heterocycloalkyl ring optionally substituted; ring C1 is a 5 or 6-membered N-containing heteroaryl optionally substituted with one group selected from (i) C1-C3 alkyl optionally substituted with 1 to 4 halogens, (ii) C2-C3 hydroxyalkyl, and (iii) C3-C4 cycloalkyl; ring C2 is a 5 or 6-membered N-containing heterocyclic ring optionally substituted with one group selected from (i) C1-C3 alkyl optionally substituted with 1 to 4 halogens, (ii) C2-C3 hydroxyalkyl, and (iii) C3-C4 cycloalkyl; n is 1, 2, or 3; and each R 3 is independently selected from the group consisting of (i) halogen, (ii) C1-C6 alkyl optionally substituted with 1 to 3 halogens, (iii) C2-C6 alkenyl, (iv) C2-C6 alkynyl, and (v) C3-C6 cycloalkyl optionally substituted with 1 to 4 halogens; R 4 is a halogen, -OH, -CN, C1-C3 alkyl optionally substituted with 1 to 3 halogens, (i) 1 to 3 halogens, or (ii) spirocyclic C3-C6 cycloalkyl optionally substituted with C1-C3 alkyl optionally substituted with 1 to 3 halogens, and one or more heteroatoms selected from the group consisting of N, O and S, and is a 3 to 6-membered N-containing heterocycloalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of (i) 1 to 3 halogens, or (ii) spirocyclic 3 to 6-membered heterocycloalkyl optionally substituted with C1-C3 alkyl optionally substituted with 1 to 3 halogens; and the attachment point for the linker L is on a carbon atom. Claim 2 In claim 1, a compound of the following formula (II) or a pharmaceutically acceptable salt thereof: (II) In the above formula, Y is N or CH. Claim 3 In paragraph 2, a compound or a pharmaceutically acceptable salt thereof in which Y is CH and n is 1 or 2. Claim 4 In any one of paragraphs 1 to 3, R 2 A compound or a pharmaceutically acceptable salt thereof in which H is present. Claim 5 In any one of paragraphs 1 to 3, R 1 This H, a compound or a pharmaceutically acceptable salt thereof. Claim 6 In any one of paragraphs 1 to 5, n is 1 and; R 3 A compound or a pharmaceutically acceptable salt thereof, which is a C1-C6 alkyl optionally substituted with 1 to 3 halogens or a C3-C6 cycloalkyl optionally substituted with 1 to 4 halogens. Claim 7 In claim 1, a compound of the following formula (II-a1) or (II-b1) or a pharmaceutically acceptable salt thereof: (II-a1) (II-b1) In the above formula, R 3 It is a C1-C3 alkyl optionally substituted with 1 to 3 halogens or a C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens. Claim 8 In any one of paragraphs 1 to 5, n is 2; and one R 3 This R 3A and selected from the group consisting of C1-C6 alkyl optionally substituted with 1 to 3 halogens and C3-C6 cycloalkyl optionally substituted with 1 to 4 halogen atoms; and other R 3 This R 3B and, a halogen, a compound or a pharmaceutically acceptable salt thereof. Claim 9 In claim 1, a compound of the following formula (II-a2) or (II-b2) or a pharmaceutically acceptable salt thereof: (II-a2) (II-b2) In the above formula, R 3A is selected from the group consisting of C1-C3 alkyl optionally substituted with 1 to 3 halogens and C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens; R 3B is F. Claim 10 In any one of paragraphs 1 through 9, R 4 a. Compounds or pharmaceutically acceptable salts thereof derived from the chemical formulas (E4-1), (E4-2), (E4-3), (E4-4), (E4-5), (E4-6), (E5-1), (E5-2), (E5-3), (E5-4), (E5-5), (E5-6), (E5-7), (E5-8) or (E5-9): In the above equation, each dashed line represents the attachment point for connector L; R 10 is a C1-C3 alkyl optionally substituted with H, a halogen, -OH, -CN, or 1 to 3 halogens, wherein R 10 This R 4 When adjacent to ring N, R 10 is not OH or a halogen; R 11 is H, a C1-C3 alkyl, C2-C3 hydroxyalkyl, or C1-C3 deuterinated alkyl optionally substituted with 1 to 3 halogens; R 12 and R 13 Each is a C1-C3 alkyl group independently substituted with H, a halogen, or 1 to 3 halogens, wherein R 12 and R 13 This R 4 When adjacent to ring N, R 12 and R 13 is not a halogen or;R 12 and R 13 Together, it forms (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens; R 12 and R 13 ... comprises one or more heteroatoms selected from the group consisting of N, O, and S, and forms a 3 to 6-membered heterocycloalkyl optionally substituted with (i) 1 to 3 halogens, or (ii) a C1-C3 alkyl optionally substituted with 1 to 3 halogens, wherein R 12 and R 13 This R 4 When adjacent to ring N and forming a 3 to 6-membered heterocycloalkyl, the 3 to 6-membered heterocycloalkyl is formed by R of the heteroatom 4 It is not attached to the ring. Claim 11 In Paragraph 10, R 4 is a group of the chemical formula (E4-2), (E4-4), (E5-6) or (E5-8); R 10 This is H or a halogen, but R 10 This R 4 When adjacent to ring N, R 10 It is not a halogen; R 11 This is a C1-C3 alkyl or C1-C3 deuterated alkyl optionally substituted with H, 1 to 3 halogens; R 12 and R 13 Each of these is a C1-C3 alkyl group independently substituted with H, a halogen, or 1 to 3 halogens, wherein R 12 and R 13 This R 4 When adjacent to ring N, R 12 and R 13 is not a halogen or;R 12 and R 13 Together, this forms (i) 1 to 3 halogens, or (ii) a C3-C6 cycloalkyl optionally substituted with a C1-C3 alkyl optionally substituted with 1 to 3 halogens; R 12 and R 13 This comprises one or more heteroatoms selected from the group consisting of N, O, and S, and forms a 3 to 6-membered heterocycloalkyl optionally substituted with (i) 1 to 3 halogens, or (ii) a C1-C3 alkyl optionally substituted with 1 to 3 halogens, wherein R 12 and R 13 This R 4 When adjacent to ring N and forming a 3 to 6-membered heterocycloalkyl, the 3 to 6-membered heterocycloalkyl is formed by R of the heteroatom 4 A compound that is not attached to a ring. Claim 12 In any one of paragraphs 1 through 11, R 4 go A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of Claim 13 In any one of paragraphs 1 through 11, R 4 go A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of Claim 14 In any one of paragraphs 1 through 13, L is a connector selected from the group consisting of the following L1, L2 and L3: (L1) (L2) (L3); each asterisk * indicates the attachment point to ring A; each dashed line This R 4 A compound or a pharmaceutically acceptable salt thereof that indicates an attachment site to. Claim 15 In paragraph 14, a compound or a pharmaceutically acceptable salt thereof in which L is a linker selected from the group consisting of L1', L2' and L3' below: (L1') (L2') (L3'). Claim 16 In any one of paragraphs 1 through 15, R 5 and R 6 are each independently a C1-C6 alkyl group optionally substituted with H, a halogen, or 1 to 3 halogens; R 5 and R 6 ...together forms a C3-C5 cycloalkyl or a 4- or 5-membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O, and S; R 7 silver, C1-C3 alkyl optionally substituted with 1 to 3 halogens, C3-C4 cycloalkyl optionally substituted with 1 to 4 halogens or C1-C3 alkyl optionally substituted with 1 to 3 halogens, and -NR 8 R 9 Selected from a group consisting of, and R 8 and R 9 Each is independently H or C1-C3 alkyl, or R 8 and R 9 A compound or a pharmaceutically acceptable salt thereof that forms a 4- or 5-membered N-containing heterocycloalkyl ring optionally substituted with 1 to 4 halogens. Claim 17 In any one of paragraphs 1 through 16, R 1 and R 2 One of them is H and;R 1 and R 2 The other one is a group of the following chemical formulas (E1-1), (E1-2a), (E1-2b), (E1-3), (E2-1), (E2-2a), (E2-2b) or (E3-1a): ;In chemical formulas (E1-2a), (E1-2b), (E2-2a), (E2-2b) and (E3-1a), R 7A A compound or a pharmaceutically acceptable salt thereof, wherein (i) H, (ii) a C1-C3 alkyl optionally substituted with 1 to 3 halogens, (iii) a C2-C3 hydroxyalkyl, or (iv) a C3-C4 cycloalkyl. Claim 18 In any one of paragraphs 1 through 17, R 1 and R 2 One of them is H, and R 1 and R 2 A compound or a pharmaceutically acceptable salt thereof, the other of which is selected from the group consisting of: . Claim 19 In paragraph 1, a compound selected from the group consisting of the following or a pharmaceutically acceptable salt thereof: . Claim 20 In paragraph 1, a compound selected from the group consisting of the following or a pharmaceutically acceptable salt thereof: . Claim 21 Compound of the following chemical formula (I') or a pharmaceutically acceptable salt thereof: (I') In the above formula, ring A is phenyl or a 5- or 6-membered N-containing heteroaryl consisting of 1 or 2 N atoms and carbon atoms as ring members; y is 0 when ring A is a 5- or 6-membered N-containing heteroaryl consisting of 2 N atoms and carbon atoms as ring members; y is 1 when ring A is a 5- or 6-membered N-containing heteroaryl consisting of 1 N atom and carbon atoms as ring members; y is 2 when ring A is phenyl; and L is a linker of the following formula: ; The asterisk * indicates the attachment point for ring A, and the dashed line is R 4 Indicates the attachment point for; z is 0 or 1; q is 0, 1, or 2; each Q is independently -D, -OH, -CH3, or a halogen; ring B is a C3-C6 cycloalkyl; and each R 1' is independently H or D and;R 1 and R 2 One of them is H, D, or a halogen, and R 1 and R 2 The other one is a group of the following chemical formulas (E1-1), (E1-2), (E1-3), (E2-1), (E2-2) or (E3-1): In the above formula, each asterisk * indicates an attachment point for ring A; m is 0 or 1; and R 5 and R 6 Each is independently (i) H, (ii) a halogen, (iii) a C1-C6 alkyl optionally substituted with 1 to 3 halogens and 1 to 3 -OH groups, (iv) a C1-C6 deuteriumated alkyl, (v) a C2-C6 alkenyl, or (iii) a C2-C6 alkynyl; R 5 and R 6 are respectively D or;R 5 and R 6 ...together to form a 4 to 6-membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of C3-C6 cycloalkyl, or N, O, and S; R 7 silver, a C1-C6 alkyl optionally substituted with 1 to 3 halogens, a C1-C6 deuterated alkyl optionally substituted with 1 to 3 halogens, optionally deuterated and a C3-C5 cycloalkyl optionally substituted with (i) 1 to 4 halogens, (ii) 1 to 3 halogens optionally substituted with a C1-C3 deuterated alkyl optionally substituted with 1 to 3 halogens, and -NR 8 R 9 Selected from a group consisting of, and R 8 and R 9 Each is independently H, a C1-C6 alkyl or a C1-C6 deuterated alkyl, or R 8 and R 9 ... together form a 4 to 6-membered N-containing heterocycloalkyl ring optionally substituted with 1 to 4 halogens; ring C1 is a 5 or 6-membered N-containing heteroaryl optionally substituted with one group selected from (i) C1-C3 alkyl optionally substituted with 1 to 4 halogens, (ii) C2-C3 hydroxyalkyl, and (iii) C3-C4 cycloalkyl, and any substituent of ring C1 is optionally deuterated; ring C2 is a 5 or 6-membered N-containing heterocycloalkyl ring optionally substituted with one group selected from (i) C1-C3 alkyl optionally substituted with 1 to 4 halogens, (ii) C2-C3 hydroxyalkyl, and (iii) C3-C4 cycloalkyl, and any substituent of ring C2 is optionally deuterated; n is 0, 1, or 2, n' is 3, 4, or 5, and the sum of n and n' is 5; each R 3 is independently selected from the group consisting of (i) halogen, (ii) C1-C6 alkyl optionally substituted with 1 to 3 halogens, (iii) C1-C6 deuteriumated alkyl optionally substituted with 1 to 3 halogens, (iv) C2-C6 alkenyl, (v) C2-C6 alkynyl, and (vi) C3-C6 cycloalkyl optionally deuteriumated and optionally substituted with 1 to 4 halogens; each R 3' is independently H or D and;R 4 is a C1-C3 alkyl optionally substituted with -D, halogen, -OH, -CN, 1 to 3 halogens, a C1-C3 deuterium alkyl optionally substituted with 1 to 3 halogens, optionally deuteriumized and a 3 to 6 N-containing heterocycloalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of spirocyclic 3 to 6 heterocycloalkyls comprising one or more heteroatoms selected from the group consisting of N, O, and S, wherein the spirocyclic 3 to 6 heterocycloalkyl is optionally deuteriumized and (i) (ii) 1 to 3 halogens, optionally substituted with 1 to 3 halogens, or (iii) optionally substituted with a C1-C3 deuterinated alkyl; and the attachment point to linker L is on a carbon atom. Claim 22 In paragraph 1, A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof. Claim 23 A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients. Claim 24 A method for treating cancer, comprising the step of administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22 to a subject in need thereof. Claim 25 A method for treating cancer, comprising the steps of: administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22 to a subject in need thereof; and administering an additional amount of an anticancer therapeutic agent. Claim 26 A compound for use as a medicine in any one of paragraphs 1 to 22. Claim 27 A compound for use in the treatment of cancer in any one of paragraphs 1 to 22. Claim 28 Use of a compound according to any one of paragraphs 1 to 22 for the manufacture of a medicine for the treatment of cancer.

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