Nitrogen-linked benzisoxazole sulfonamide derivatives for the treatment of cancer

Abstract

The present invention relates to nitrogen-linked benzisoxazole sulfamide derivatives or pharmaceutically acceptable salts thereof, which act as lysine acetyltransferase (KAT) inhibitors, useful for treating abnormal cell growth, such as cancer, in a patient. Additional embodiments relate to pharmaceutical compositions containing the compounds and methods of using the compounds and the compositions to treat abnormal cell growth, such as cancer, in a patient.

Description

[0001] This application claims the benefits of U.S. Provisional Application No. 63 / 542,051, filed October 2, 2023; U.S. Provisional Application No. 63 / 546,442, filed October 30, 2023; U.S. Provisional Application No. 63 / 566,213, filed March 15, 2024; U.S. Provisional Application No. 63 / 633,660, filed April 12, 2024; U.S. Provisional Application No. 63 / 665,990, filed June 28, 2024; and U.S. Provisional Application No. 63 / 697,154, filed September 20, 2024, the contents of which are hereby incorporated by reference in their entirety.

[0002] sequence list

[0003] This application includes an electronically submitted sequence list in .XML format. The .XML file contains a sequence list titled "PC073303A_SEQListing_ST26.xml" created on September 23, 2024, and is 20 KB in size. The sequence list contained in this .XML file is part of this specification and is incorporated herein by reference in its entirety. Background of the Invention

[0005] This invention relates to novel nitrogen-linked benzisoxazole sulfonamide derivatives that act as MYST family lysine acetyltransferase (KAT) inhibitors and can be used to treat abnormal cell growth in patients, such as cancer. The invention also relates to pharmaceutical compositions containing said compounds and methods of treating abnormal cell growth in patients using said compounds and said compositions.

[0006] KAT enzymes play an important regulatory role in cancer and are therefore often targeted by mutations, translocations, and amplifications (Hu, Z. et al., Genomic characterization of genes encoding histone acetylation modulator proteins identifies therapeutic targets for cancer treatment. NatCommun. 2019 Feb 13;10(1):733). KAT6A was identified in 1996 as part of the chromosomal translocation t(8;16)(p11;p13) of CREB-binding protein (CREBBP) in a subtype of acute myeloid leukemia (AML) (Borrow, J. et al., The translocation t(8;16)(p11;p13) of acute myeloid leukemia fuses a putativeacetyltransferase to the CREB-binding protein). Nat. Genet. 1996, 14 (33-41). Subsequently, other KAT6A and KAT6B translocations were identified in more AML patients, resulting in fusions with other HATs, such as adenovirus EIA-associated protein p300 (EP300), nuclear receptor coactivator 2 (NCOA2), and NCOA3 (Huang et al.).

[0007] In human cancers, particularly breast cancer, KAT6A has been identified as part of the recurrently amplified region of 8p11-12 found in 10-15% of breast cancers (Adélaïde J. et al., Chromosome region 8p11-p21: refined mapping and molecular alterations in breast cancer. Genes Chromosomes Cancer. July 1998; 22(3):186-99). Breast cancer cell lines containing KAT6A amplification overexpress KAT6A, suggesting that KAT6A is a presumed breast cancer susceptibility gene. Turner-Ivey et al. used a genome-wide shRNA screening strategy to identify KAT6A as an important dependent factor in 8p11 amplified breast cancer cell lines containing KAT6A overexpression (Turner-Ivey B et al., KAT6A, a chromatin modifier from the 8p11-p12 amplicon is a candidate oncogene inluminal breast cancer. Neoplasia. 2014 Aug;16(8):644-55). Yu et al. subsequently confirmed that in 8p11 amplified breast cancer cells, KAT6A is localized to the estrogen receptor promoter, and shRNA-mediated KAT6A knockdown reduces ERα ESR1 mRNA and protein levels (Yu, L. et al., Identification of MYST3 as a novelepigenetic activator of ERα frequently amplified in breast cancer). Oncogene 2017, 36 (2910-2918). Furthermore, it demonstrates that the growth defects in 8p11-amplified breast cancer cells caused by KAT6A depletion can be addressed through… ESR1 The cells were partially rescued through reexpression. These findings suggest that KAT6A plays an important role in the gene regulation of ERα, which is required for the growth of ER+ breast cancer cells.

[0008] Chromosome 8p11-12 amplification and KAT6A overexpression are present in other tumor types, including ovarian cancer, cervical cancer, lung adenocarcinoma, colorectal adenocarcinoma, and medulloblastoma (Zack TI et al., Pan-cancer patterns of somatic copy number alteration. Nat Genet 2013 45:1134-1140; Northcott PA et al., Multiple recurrent genetic events converge on control of histone lysinemethylation in medulloblastoma. Nat Genet 2009 41:465-472). KAT6A dependency has been identified in other tumor types, including prostate cancer (Yu C et al., High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor celllines. Nat Biotechnol. 2016; Meyers RM et al., Computational correction of copynumber effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells. Nat Genet. 2017; and Tsherniak A et al., Defining a cancer dependency map. Cell. 2017). Overall, these data suggest that targeting KAT6A offers broad therapeutic opportunities in other tumor types.

[0009] In addition to its catalytic function mediated by the histone acetyltransferase (HAT) domain, the KAT6A protein also includes other domains such as the PHD domain, acidic domain, and serine / methionine-rich domain. It has been reported that KAT6A regulates gene expression independently of its catalytic activity (Kitabayashi, I. et al., Activation of AML1 mediated transcription by MOZ and inhibition by the MOZ-CBP fusion protein. EMBO J. 2001, 20(24): 7184-7196). Knockdown of KAT6A protein levels using RNA interference confirmed the dependence of ER+ breast cancer cells on KAT6A (Turner-Ivey B. et al. and Yu, L. et al.). However, the demand of ERα expression and ER+ breast cancer cell proliferation on KAT6A catalytic activity remains unclear.

[0010] KAT7 (HBO1 / MYST2) is a member of the MYST (MOZ, Ybf2 / Sas3, Sas2, and Tip60) family of histone lysine acetyltransferases that target histone and non-histone proteins involved in lysine acetylation (Neal, Pannuti et al., 2000; Roth, Denu et al., 2001; Yang 2004; Sapountzi and Cote 2011; Wang and Cole 2020). KAT7 exists as an enzymatic component of a four-membered protein complex containing alternative adaptor proteins (including JADE1 / 2 / 3 or BRPF1 / 2 / 3) as well as ING family proteins and MEAF6 (Doyon, Cayrou et al., 2006; Lalonde, Avvakumov et al., 2013). Post-translational modifications of histone tails are a major mechanism for regulating chromatin structure and function, and have been shown to play a crucial role in transcription, DNA damage repair, and DNA replication (Jenuwein and Allis 2001, Suganuma and Workman 2011, Allis and Jenuwein 2016). KAT7 enzymatically transfers the acetyl group of acetyl-CoA to the lysine residue CoA. -Amino group (Roth, Denu et al., 2001). KAT7 can accommodate other acyl-CoA cofactors to catalyze histone propionylation, butyrylation, and crotonylation, but not succinylation (Xiao, Li et al., 2021). The formation of KAT7 protein complexes with different backbone proteins BPRF1 / 2 / 3 or JADE1 / 2 / 3 regulates the biochemical activity and substrate presence of histone H3 or histone H4, respectively (Doyon, Cayrou et al., 2006; Foy, Song et al., 2008; Kueh, Dixon et al., 2011; Mishima, Miyagi et al., 2011; Lalonde, Avvakumov et al., 2013; Tao, Zhong et al., 2017).

[0011] Other complex subunits ING4 / ING5 and MEAF6 regulate the recruitment and function of the KAT7 complex on chromatin through interactions with modified histone proteins (Doyon, Cayrou et al., 2006; Champagne, Saksouk et al., 2008; Saksouk, Avvakumov et al., 2009; Palacios, Moreno et al., 2010; Matsuura, Tani et al., 2020; Barman, Roy et al., 2022). The combined function of protein reader domains on KAT7 interacting proteins provides specificity for locating the KAT7 complex on chromatin. These protein reader domains include the PHD domain (Doyon, Cayrou et al., 2006; Saksouk, Avvakumov et al., 2009; Klein, Muthurajan et al., 2016), the PWWP domain (Zhang, Lei et al., 2021), and the BROMO domain (Filippakopoulos and Knapp, 2012; Barman, Roy et al., 2022).

[0012] KAT7 was initially identified as a protein that binds to ORC1, the largest subunit of the initiation recognition complex involved in DNA replication (Iizuka and Stillman 1999). In cervical cancer cells, the zinc finger of KAT7 interacts with MCM2 (a key component of the pre-replication complex) (Burke, Cook et al., 2001; Doyon, Cayrou et al., 2006). KAT7 has also been reported to interact directly with CDT1, enhancing CDT1-dependent re-replication at the DNA replication origin (Miotto and Struhl 2008), indicating a crucial role for KAT7 during the initiation and elongation of DNA synthesis. Chromatin immunoprecipitation DNA sequencing (ChIP-seq) has confirmed KAT7 binding at the DNA replication origin (Feng, Vlassis et al., 2016; Xiao, Li et al., 2021). Consistent with the role of KAT7 in DNA replication, knocking down KAT7 with siRNA induces growth arrest in a large number of cancer cell lines during the S phase of the cell cycle (Doyon, Cayrou et al., 2006; Wu and Liu, 2008).

[0013] In addition to its proposed role in DNA replication, there is evidence that KAT7 participates in gene regulation through transcriptional regulation. The KAT7 complex binds to transcription start sites and gene coding regions (Saksouk, Avvakumov et al., 2009; Xiao, Li et al., 2021). When complexed with nuclear receptors, such as the progesterone receptor, the KAT7 MYST domain can act as a coactivator to increase the expression of target genes (Georgiakaki, Chabbert-Buffet et al., 2006). KAT7 also interacts with androgen receptors in a ligand-dependent manner and can induce both activation and repression of AR target gene expression, indicating that KAT7 can act as both a transcriptional activator and repressor (Sharma, Zarnegar et al., 2000; Mi, Ji et al., 2023). Expression of the N-terminal serine-rich region of KAT7 can inhibit TNFα-stimulated NF-κB activity in 293T cells through cofactor-binding chelation, indicating that the non-catalytic function of KAT7 can also affect transcriptional regulation (Contzler, Regamey et al., 2006).

[0014] During mouse development, KAT7 acts as a fundamental activator of gene expression for shaping genes during post-gastrulation embryonic development. Knockout of the KAT7 gene in mouse embryos leads to increased apoptosis, particularly affecting mesodermal structure and embryonic lethality at E10.5 (Kueh, Dixon et al., 2011). Conditional knockout of KAT7 in developing mice indicates that KAT7 functions in other tissues during development, including vascular endothelial cells (Grant, Hickey et al., 2021), bone marrow and fetal liver hematopoiesis (Mishima, Miyagi et al., 2011; Yang, Kueh et al., 2022), T cells (Newman, Voss et al., 2017), and neurons and oligodendrocytes (Kueh, Bergamasco et al., 2023). KAT7 is associated with the genus Drosophila (…). Drosophila Homologous compounds, i.e. chameau This is crucial for larval development. Heterozygous knockout of the developing embryo... chameau Alleles show defects in homeomorphic transformation mediated by desuppression of Hox gene expression (Grienenberger, Miotto et al., 2002).

[0015] Elevated KAT7 expression has been found in various cancers, including esophageal, bladder, testicular, breast, ovarian, and gastric cancers (Iizuka, Takahashi et al., 2009; Chen, Zhou et al., 2018; Wang, Chen et al., 2019; Guo, Li et al., 2022). In ER+ and HER2+ breast cancer, KAT7 has been identified as a common amplified region of the genome on chromosome 17q21 (Hu, Stern et al., 2009). KAT7 regulates estrogen receptor-dependent transcription and can directly interact with and acetylate estrogen receptor α (ERα), resulting in decreased protein stability (Iizuka, Susa et al., 2013). Inhibition of KAT7 in breast cancer cell lines leads to loss of cell proliferation and blocks progression through the S phase of the cell cycle (Hu, Stern et al., 2009). Conversely, overexpression of KAT7 leads to increased community formation of breast cancer cell lines on soft agar (Hu, Stern et al., 2009). In breast cancer, the CDK2 / cyclin E complex induces extensive KAT7 phosphorylation in stem cell-like cells in the CD44hi / CD24lo population (Duong, Akli et al., 2013). KAT7 overexpression in breast cancer increases the transcription of the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA), leading to enhanced PI3K / AKT signaling and the development of resistance to radiotherapy (Ma, Chen et al., 2023).

[0016] KAT7 acetyltransferase activity is involved in cancer pathways. KAT7 and related complex members ING4 and ING5 physically interact with p53 tumor suppressor genes (Shiseki, Nagashima et al., 2003; Iizuka, Sarmento et al., 2008). Inhibition of KAT7 leads to the downregulation of numerous genes involved in the p53 pathway, which is responsible for cell cycle control, senescence, and apoptosis (Avvakumov, Lalonde et al., 2012). KAT7 promotes bladder cancer cell proliferation by activating the Wnt / β-catenin signaling pathway (Chen, Zhou et al., 2018). In gastric cancer, KAT7 promotes the transcription and nuclear translocation of Yes-associated protein 1 (YAP1) through overexpression (Guo, Li et al., 2022).

[0017] In AML, KAT7 is overexpressed in leukemia stem cells, thereby promoting the expression of HOXA9 and HOXA10 and maintaining the functional properties of leukemia stem cells. In MLL rearranged AML, KAT7 acetylated histones recruit MLL fusion-related adaptor proteins, such as BRD4 and AF4, to gene promoters (Au, Gu et al., 2021; Takahashi, Kanai et al., 2021). In mouse models, KAT7 knockdown or small molecule inhibition reduces the leukemia burden (Sauer, Arteaga et al., 2015; MacPherson, Anokye et al., 2020; Au, Gu et al., 2021). In chronic myelomonocytic leukemia (CMML), an oncogene fusion protein, nucleoporin-98 (NUP98)-KAT7, has been identified. In mouse models, experimental overexpression of NUP98-KAT7 led to overexpression of HOXA9 and induced leukemia (Hayashi, Harada et al., 2019).

[0018] Given the established role of KAT, and especially MYST, in diseases such as cancer, there is a need for new inhibitors of these proteins. Invention Overview

[0020] This invention provides, in part, compounds of formula (I) and pharmaceutically acceptable salts thereof. Such compounds can be used to treat cancer. Pharmaceutical compositions comprising either a single compound or salt of the invention, or a combination of a compound or salt of the invention with another therapeutic agent, are also provided. The invention also provides, in part, methods for preparing such compounds, pharmaceutically acceptable salts, and compositions of the invention, as well as methods of using the foregoing. This overview is provided to introduce a series of concepts in a simplified form, which are further described in detail below. This overview is not intended to identify key or essential features of the claimed subject matter, nor is it intended solely to help determine the scope of the claimed subject matter.

[0021] According to a first embodiment of the present invention, a compound of formula (I) is provided:

[0022]

[0023] Or its pharmaceutically acceptable salt, wherein:

[0024] R 1 It can be hydrogen, methoxy, or fluorine;

[0025] R 2 It is hydrogen or methoxy.

[0026] Its prerequisite is R 1 and R 2 Not all of them are hydrogen.

[0027] Its further prerequisite is R 1 and R 2 Not all of them are methoxyl groups;

[0028] Ring A is a C4-C5 cycloalkyl, a 4-6 membered heterocycloalkyl, or a 5-10 membered heteroaryl, wherein the bonding point is at a carbon atom;

[0029] R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or one or two fluorine atoms;

[0030] R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0031] R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0032] Ring B is a C3-C6 cycloalkyl group, C6-C 10 Aryl or 5-10 heteroaryl groups;

[0033] R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0034] R 7 It is hydrogen, C1-C4 alkyl, or methoxy;

[0035] R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, or -(CHR) 11 ) n -4-8-membered heterocyclic alkyl, 5-8-membered heteroaryl, 9-10-membered heteroaryl, -C(O)NR 12 R 13 -N(CH3) (4-5 membered heterocyclic alkyl) or -O-phenyl,

[0036] The C1-C4 alkyl group is optionally substituted with one or two methoxy groups, -N(R) 14 (R) 15 (or one, two, or three fluorine atoms are substituted.)

[0037] The phenyl group is optionally substituted with a methoxy group.

[0038] Wherein -(CHR) 11 ) n The 4-8-membered heterocyclic alkyl group is optionally substituted by one, two, or three independent substituents selected from the following: oxo, one or two methyl substituents, ethyl, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, 4-6-membered heterocyclic alkyl group, and one or two fluorine atoms.

[0039] The 5-8 heteroaryl group is optionally substituted by one of the following: oxo, cyano, methyl, -[CH(R) 16 )] p [N(CH3)2] or optionally a methyl-substituted 6-membered heterocyclic alkyl group,

[0040] The 9-10 membered heteroaryl group is optionally substituted with a methyl group.

[0041] The -C(O)NR 12 R 13 Optionally substituted with one or two fluorine atoms, and

[0042] The -O-phenyl group is optionally substituted with fluorine, methyl or methoxy groups;

[0043] R 9 It is hydrogen or fluorine;

[0044] R 10 It is hydrogen or C 1-3 alkyl;

[0045] R 11 It can be hydrogen or methyl;

[0046] R 12 For hydrogen, C 1-3 Alkyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3;

[0047] R 13 It is hydrogen or C 1-2 alkyl;

[0048] Where R 12 C 1-3 Alkyl and R 13 C 1-2 When alkyl, R 12 and R 13 It can form a 4-6 membered heterocyclic alkyl ring together with the nitrogen to which it is attached, wherein the 4-6 membered heterocyclic alkyl ring is optionally substituted with one or two fluorine atoms;

[0049] Each R 14 and R 15 It can be methyl or ethyl independently;

[0050] R 16 It can be hydrogen or methyl;

[0051] n is 0 or 1; and

[0052] p is 0 or 1.

[0053] According to a second embodiment of the present invention, a compound of formula (Ia) is provided:

[0054]

[0055] (Ia)

[0056] Or its pharmaceutically acceptable salt, wherein:

[0057] R 1 It can be hydrogen, methoxy, or fluorine;

[0058] R 2 It is hydrogen or methoxy.

[0059] Its prerequisite is R 1 and R 2 Not all of them are hydrogen.

[0060] Its further prerequisite is R 1 and R 2 Not all of them are methoxyl groups;

[0061] Ring A is a C4-C5 cycloalkyl, a 4-6 membered heterocycloalkyl, or a 5-10 membered heteroaryl, wherein the bonding point is at a carbon atom;

[0062] R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or one or two fluorine atoms;

[0063] R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0064] R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0065] Ring B is a C3-C6 cycloalkyl group, C6-C 10 Aryl or 5-10 heteroaryl groups;

[0066] R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0067] R 7 It is hydrogen, C1-C4 alkyl, or methoxy;

[0068] R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, or -(CH2). n -4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, -C(O)NR 11 R 12 or -O-phenyl, wherein the C1-C4 alkyl group is optionally hydroxylated by a methoxy group, -N(R) 13 (R) 14 The phenyl group may be substituted with one, two, or three fluorine atoms, wherein the phenyl group is optionally substituted with a methoxy group, and wherein the -(CH2) group is... n -4-6-membered heterocyclic alkyl groups and the 5-6-membered heteroaryl groups are each optionally substituted with methyl groups, and the -O-phenyl groups are optionally substituted with fluorine, methyl or methoxy groups;

[0069] R 9 It is hydrogen or fluorine;

[0070] R 10 It is hydrogen or C 1-3 alkyl;

[0071] R 11 It is hydrogen, methyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3;

[0072] R 12 It can be hydrogen or methyl;

[0073] Each R 13 and R 14 Independently methyl or ethyl; and

[0074] n is 0 or 1.

[0075] According to a third embodiment of the present invention, a compound of formula (Ib) is provided:

[0076]

[0077] Or its pharmaceutically acceptable salt, wherein:

[0078] R 1 It can be hydrogen, methoxy, or fluorine;

[0079] R 2 It is hydrogen or methoxy.

[0080] Its prerequisite is R 1 and R 2 Not all of them are hydrogen.

[0081] Its further prerequisite is R 1 and R 2 Not all of them are methoxyl groups;

[0082] Ring A is a C4-C5 cycloalkyl, a 4-6 membered heterocycloalkyl, or a 5-10 membered heteroaryl, wherein the bonding point is at a carbon atom;

[0083] R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or two fluorine atoms;

[0084] R 4It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0085] R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0086] Ring B is a C3-C6 cycloalkyl group, C6-C 10 Aryl or 5-10 heteroaryl groups;

[0087] R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0088] R 7 It is hydrogen, C1-C4 alkyl, or methoxy;

[0089] R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, 4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, -C(O)NR 11 R 12 Or -O-phenyl, wherein the C1-C4 alkyl group is optionally substituted with a methoxy group or one, two or three fluorine atoms, wherein the phenyl group is optionally substituted with a methoxy group, wherein the 5-6 heteroaryl group is optionally substituted with a methyl group, and wherein the -O-phenyl group is optionally substituted with a fluorine, methyl or methoxy group;

[0090] R 9 It is hydrogen or fluorine;

[0091] R 10 It is hydrogen or C 1-3 alkyl;

[0092] R 11 It is hydrogen, methyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3; and

[0093] R 12 It can be hydrogen or methyl.

[0094] The following describes embodiments of the present invention, wherein, for convenience, embodiments 1 (E1), 2 (E2), and 3 (E3) are equivalent to the embodiments of formulas (I), (Ia), and (Ib) provided above.

[0095] It should be understood that the foregoing general description and the following detailed description are merely illustrative and explanatory, and do not limit the claimed invention. Brief description of the attached diagram

[0097] Figure 1 It displays 2,6-dimethoxy-4-[(2 S The X-ray crystal structure of 2,6-dimethoxy-4-[(2-oxacyclopent-2-yl]benzene-1-sulfonyl chloride (intermediate 140h) was obtained, showing 2,6-dimethoxy-4-[(2-]benzene-1-sulfonyl chloride. S Absolute stereochemistry of the (S) configuration of )-oxacyclopent-2-yl]benzene-1-sulfonyl chloride (intermediate 140h).

[0098] Figure 2 Display (2) R The X-ray crystal structure of 2-(4-bromo-3,5-dimethoxyphenyl)-1,4-dioxane (intermediate 145a) was observed, revealing (2 R Absolute stereochemistry of the (R) configuration of )-2-(4-bromo-3,5-dimethoxyphenyl)-1,4-dioxane (intermediate 145a).

[0099] Figure 3 show N -{6-[(5-Cyclopropyl-1- H [-pyrazole-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}-4-[(2] S The X-ray crystal structure of 1,4-dioxane-2-yl]-2,6-dimethoxybenzene-1-sulfonamide (Example 146) was shown. N -{6-[(5-Cyclopropyl-1- H [-pyrazole-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}-4-[(2] S Absolute stereochemistry of the (S) configuration of 1,4-dioxane-2-yl]-2,6-dimethoxybenzene-1-sulfonamide (Example 146).

[0100] Figure 4 show N -{6-[(5-Cyclopropyl-1- H -pyrazol-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}-2,6-dimethoxy-4-[(2 S The X-ray crystal structure of 1-methylpyrrolidone-2-yl]benzene-1-sulfonamide (Example 189) was shown. N -{6-[(5-Cyclopropyl-1- H -pyrazole-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}-2,6-dimethoxy-4-[(2 S Absolute stereochemistry of the (S) configuration of 1-methylpyrrolidone-2-yl]benzene-1-sulfonamide (Example 189). Invention Details

[0102] The invention can be more readily understood by referring to the following detailed description of embodiments of the invention and the examples included therein. It should be understood that the invention is not limited to specific synthetic preparation methods, which can, of course, be varied. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0103] E1 A compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above.

[0104] E2 A compound of formula (Ia) or a pharmaceutically acceptable salt thereof, as defined above.

[0105] E3 A compound of formula (Ib) or a pharmaceutically acceptable salt thereof, as defined above.

[0106] E4 The compound of any one of embodiments E1 to E3 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of: cyclobutyl, cyclopentyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, pyrroleyl, imidazolyl, isoxazolyl, oxazolyl, 1-oxa-2,4-diazolyl, triazolyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl, 5,6-dihydro-4 H -pyrrolo[1,2- b ]pyrazolyl, 5',6'-dihydrospiro[cyclopropane-1,4'-pyrrolo[1,2- b ]pyrazolyl] and 2,4,5,6-tetrahydropyrrolo[3,4- c ]Pyrazolyl group.

[0107] E5 is a compound of embodiment E4 or a pharmaceutically acceptable salt thereof, wherein ring A is cyclobutyl.

[0108] E6 The compound of embodiment E4 or a pharmaceutically acceptable salt thereof, wherein ring A is cyclopentyl.

[0109] E7 The compound of embodiment E4 or a pharmaceutically acceptable salt thereof, wherein ring A is an oxecyclobutyl group.

[0110] E8 The compound of embodiment E4 or its pharmaceutically acceptable salt, wherein ring A is tetrahydrofuranyl.

[0111] E9 The compound of embodiment E4 or its pharmaceutically acceptable salt, wherein ring A is a tetrahydropyranyl group.

[0112] E10 The compound of embodiment E4 or a pharmaceutically acceptable salt thereof, wherein ring A is a pyrrole group.

[0113] E11 The compound of embodiment E4 or a pharmaceutically acceptable salt thereof, wherein ring A is an imidazole group.

[0114] E12 is a compound of embodiment E4 or a pharmaceutically acceptable salt thereof, wherein ring A is an isoxazolyl group.

[0115] E13 The compound of embodiment E4 or a pharmaceutically acceptable salt thereof, wherein ring A is an oxazolyl group.

[0116] E14 The compound of embodiment E4 or a pharmaceutically acceptable salt thereof, wherein ring A is 1-oxa-2,4-diazolyl.

[0117] E15 The compound of embodiment E4 or a pharmaceutically acceptable salt thereof, wherein ring A is a triazole group.

[0118] E16 The compound of embodiment E4 or a pharmaceutically acceptable salt thereof, wherein ring A is a triazole group; R 6 It is hydrogen or C 1-3 Alkyl; and R 7 R 8 and R 9 Each of them is hydrogen.

[0119] E17 The compound of embodiment E4 or a pharmaceutically acceptable salt thereof, wherein ring A is a pyrazolyl group.

[0120] E18 The compound of embodiment E4 or a pharmaceutically acceptable salt thereof, wherein ring A is pyridyl.

[0121] E19 The compound of embodiment E4 or a pharmaceutically acceptable salt thereof, wherein ring A is pyridazinyl.

[0122] E20 is a compound of embodiment E4 or a pharmaceutically acceptable salt thereof, wherein ring A is a pyrimidinyl group.

[0123] E21 The compound of embodiment E4 or a pharmaceutically acceptable salt thereof, wherein ring A is pyrazinyl.

[0124] E22 The compound of embodiment E4 or a pharmaceutically acceptable salt thereof, wherein ring A is 5,6-dihydro-4 H -pyrrolo[1,2-b]pyrazolyl.

[0125] E23 is a compound of embodiment E4 or a pharmaceutically acceptable salt thereof, wherein ring A is 5',6'-dihydrospiro[cyclopropane-1,4'-pyrrolo[1,2-b]pyrazolyl].

[0126] E24 The compound of embodiment E4 or a pharmaceutically acceptable salt thereof, wherein ring A is 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl.

[0127] E25 A compound of formula (II):

[0128]

[0129] Or its pharmaceutically acceptable salt, wherein:

[0130] R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or one or two fluorine atoms;

[0131] R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0132] R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0133] Ring B is a C3-C6 cycloalkyl group, C6-C 10 Aryl or 5-10 heteroaryl groups;

[0134] R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0135] R 7 It is hydrogen, C1-C4 alkyl, or methoxy;

[0136] R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, or -(CHR) 11 ) n -4-8-membered heterocyclic alkyl, 5-8-membered heteroaryl, 9-10-membered heteroaryl, -C(O)NR 12 R 13 -N(CH3) (4-5 membered heterocyclic alkyl) or -O-phenyl,

[0137] The C1-C4 alkyl group is optionally substituted with one or two methoxy groups, -N(R) 14 (R) 15(or one, two, or three fluorine atoms are substituted.)

[0138] The phenyl group is optionally substituted with a methoxy group.

[0139] Wherein -(CHR) 11 ) n The 4-8-membered heterocyclic alkyl group is optionally substituted by one, two, or three independent substituents selected from the following: oxo, one or two methyl substituents, ethyl, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, 4-6-membered heterocyclic alkyl group, and one or two fluorine atoms.

[0140] The 5-8 heteroaryl group is optionally substituted by one of the following: oxo, cyano, methyl, -[CH(R) 16 )] p [N(CH3)2] or optionally a methyl-substituted 6-membered heterocyclic alkyl group,

[0141] The 9-10 membered heteroaryl group is optionally substituted with a methyl group.

[0142] The -C(O)NR 12 R 13 Optionally substituted with one or two fluorine atoms, and

[0143] The -O-phenyl group is optionally substituted with fluorine, methyl or methoxy groups;

[0144] R 9 It is hydrogen or fluorine;

[0145] R 10 It is hydrogen or C 1-3 alkyl;

[0146] R 11 It can be hydrogen or methyl;

[0147] R 12 For hydrogen, C 1-3 Alkyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3;

[0148] R 13 It is hydrogen or C 1-2 alkyl;

[0149] Where R 12 C 1-3 Alkyl and R 13 C 1-2 When alkyl, R 12 and R 13It can form a 4-6 membered heterocyclic alkyl ring together with the nitrogen to which it is attached, wherein the 4-6 membered heterocyclic alkyl ring is optionally substituted with one or two fluorine atoms;

[0150] Each R 14 and R 15 It can be methyl or ethyl independently;

[0151] R 16 It can be hydrogen or methyl;

[0152] n is 0 or 1; and

[0153] p is 0 or 1.

[0154] E26 A compound of formula (IIa):

[0155]

[0156] Or its pharmaceutically acceptable salt, wherein:

[0157] R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or one or two fluorine atoms;

[0158] R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0159] R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0160] Ring B is a C3-C6 cycloalkyl group, C6-C 10 Aryl or 5-10 heteroaryl groups;

[0161] R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0162] R 7 It is hydrogen, C1-C4 alkyl, or methoxy;

[0163] R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, or -(CH2). n-4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, -C(O)NR 11 R 12 or -O-phenyl, wherein the C1-C4 alkyl group is optionally hydroxylated by a methoxy group, -N(R) 13 (R) 14 The phenyl group may be substituted with one, two, or three fluorine atoms, wherein the phenyl group is optionally substituted with a methoxy group, and wherein the -(CH2) group is... n -4-6-membered heterocyclic alkyl groups and the 5-6-membered heteroaryl groups are each optionally substituted with methyl groups, and the -O-phenyl groups are optionally substituted with fluorine, methyl or methoxy groups;

[0164] R 9 It is hydrogen or fluorine;

[0165] R 10 It is hydrogen or C 1-3 alkyl;

[0166] R 11 It is hydrogen, methyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3;

[0167] R 12 It can be hydrogen or methyl;

[0168] Each R 13 and R 14 Independently methyl or ethyl; and

[0169] n is 0 or 1.

[0170] E27 A compound of formula (IIb):

[0171]

[0172] Or its pharmaceutically acceptable salt, wherein:

[0173] R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or two fluorine atoms;

[0174] R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0175] R 5It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0176] Ring B is a C3-C6 cycloalkyl group, C6-C 10 Aryl or 5-10 heteroaryl groups;

[0177] R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0178] R 7 It is hydrogen, C1-C4 alkyl, or methoxy;

[0179] R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, 4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, -C(O)NR 11 R 12 Or -O-phenyl, wherein the C1-C4 alkyl group is optionally substituted with a methoxy group or one, two or three fluorine atoms, wherein the phenyl group is optionally substituted with a methoxy group, wherein the 5-6 heteroaryl group is optionally substituted with a methyl group, and wherein the -O-phenyl group is optionally substituted with a fluorine, methyl or methoxy group;

[0180] R 9 It is hydrogen or fluorine;

[0181] R 10 It is hydrogen or C 1-3 alkyl;

[0182] R 11 It is hydrogen, methyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3; and

[0183] R 12 It can be hydrogen or methyl.

[0184] E28 A compound or a pharmaceutically acceptable salt thereof as described in any of embodiments E1 to E27, wherein ring B is cyclopropyl, 1,2,3,4-tetrahydronaphthyl, naphthyl, chromium, isochromthyl, 2,3-dihydrobenzo[b][1,4]dioxane-hexenyl, pyrazolyl, pyrimidinyl, quinolinyl, or indazoleyl.

[0185] E29 The compound of embodiment E28 or a pharmaceutically acceptable salt thereof, wherein ring B is cyclopropyl.

[0186] E30 The compound of embodiment E28 or a pharmaceutically acceptable salt thereof, wherein ring B is 1,2,3,4-tetrahydronaphthyl.

[0187] E31 The compound of embodiment E28 or a pharmaceutically acceptable salt thereof, wherein ring B is naphthyl.

[0188] E32 The compound of embodiment E28 or a pharmaceutically acceptable salt thereof, wherein ring B is a chromanyl group.

[0189] E33 The compound of embodiment E28 or a pharmaceutically acceptable salt thereof, wherein ring B is an isochoric methyl group.

[0190] E34 The compound of embodiment E28 or a pharmaceutically acceptable salt thereof, wherein ring B is 2,3-dihydrobenzo[b][1,4]dioxane-hexenyl.

[0191] E35 The compound of embodiment E28 or a pharmaceutically acceptable salt thereof, wherein ring B is a pyrazolyl group.

[0192] E36 The compound of embodiment E28 or a pharmaceutically acceptable salt thereof, wherein ring B is a pyrimidinyl group.

[0193] E37 The compound of embodiment E28 or a pharmaceutically acceptable salt thereof, wherein ring B is quinolinyl.

[0194] E38 The compound of embodiment E28 or a pharmaceutically acceptable salt thereof, wherein ring B is an indazole group.

[0195] E39 A compound of formula (III):

[0196]

[0197] Or its pharmaceutically acceptable salt, wherein:

[0198] R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or one or two fluorine atoms;

[0199] R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0200] R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0201] R 6It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0202] R 7 It is hydrogen, C1-C4 alkyl, or methoxy;

[0203] R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, or -(CHR) 11 ) n -4-8-membered heterocyclic alkyl, 5-8-membered heteroaryl, 9-10-membered heteroaryl, -C(O)NR 12 R 13 -N(CH3) (4-5 membered heterocyclic alkyl) or -O-phenyl,

[0204] The C1-C4 alkyl group is optionally substituted with one or two methoxy groups, -N(R) 14 (R) 15 (or one, two, or three fluorine atoms are substituted.)

[0205] The phenyl group is optionally substituted with a methoxy group.

[0206] Wherein -(CHR) 11 ) n The 4-8-membered heterocyclic alkyl group is optionally substituted by one, two, or three independent substituents selected from the following: oxo, one or two methyl substituents, ethyl, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, 4-6-membered heterocyclic alkyl group, and one or two fluorine atoms.

[0207] The 5-8 heteroaryl group is optionally substituted by one of the following: oxo, cyano, methyl, -[CH(R) 16 )] p [N(CH3)2] or optionally a methyl-substituted 6-membered heterocyclic alkyl group,

[0208] The 9-10 membered heteroaryl group is optionally substituted with a methyl group.

[0209] The -C(O)NR 12 R 13 Optionally substituted with one or two fluorine atoms, and

[0210] The -O-phenyl group is optionally substituted with fluorine, methyl or methoxy groups;

[0211] R 9 It is hydrogen or fluorine;

[0212] R 10It is hydrogen or C 1-3 alkyl;

[0213] R 11 It can be hydrogen or methyl;

[0214] R 12 For hydrogen, C 1-3 Alkyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3;

[0215] R 13 It is hydrogen or C 1-2 alkyl;

[0216] Where R 12 C 1-3 Alkyl and R 13 C 1-2 When alkyl, R 12 and R 13 It can form a 4-6 membered heterocyclic alkyl ring together with the nitrogen to which it is attached, wherein the 4-6 membered heterocyclic alkyl ring is optionally substituted with one or two fluorine atoms;

[0217] Each R 14 and R 15 It can be methyl or ethyl independently;

[0218] R 16 It can be hydrogen or methyl;

[0219] n is 0 or 1; and

[0220] p is 0 or 1.

[0221] E40 A compound of formula (IIIa):

[0222]

[0223] Or its pharmaceutically acceptable salt, wherein:

[0224] R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or one or two fluorine atoms;

[0225] R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0226] R 5It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0227] R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0228] R 7 It is hydrogen, C1-C4 alkyl, or methoxy;

[0229] R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, or -(CH2). n -4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, -C(O)NR 11 R 12 or -O-phenyl, wherein the C1-C4 alkyl group is optionally hydroxylated by a methoxy group, -N(R) 13 (R) 14 The phenyl group may be substituted with one, two, or three fluorine atoms, wherein the phenyl group is optionally substituted with a methoxy group, and wherein the -(CH2) group is... n -4-6-membered heterocyclic alkyl groups and the 5-6-membered heteroaryl groups are each optionally substituted with methyl groups, and the -O-phenyl groups are optionally substituted with fluorine, methyl or methoxy groups;

[0230] R 9 It is hydrogen or fluorine;

[0231] R 10 It is hydrogen or C 1-3 alkyl;

[0232] R 11 It is hydrogen, methyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3;

[0233] R 12 It can be hydrogen or methyl;

[0234] Each R 13 and R 14 Independently methyl or ethyl; and

[0235] n is 0 or 1.

[0236] E41 A compound of formula (IIIb):

[0237]

[0238] Or its pharmaceutically acceptable salt, wherein:

[0239] R3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or two fluorine atoms;

[0240] R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0241] R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0242] R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0243] R 7 It is hydrogen, C1-C4 alkyl, or methoxy;

[0244] R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, 4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, -C(O)NR 11 R 12 Or -O-phenyl, wherein the C1-C4 alkyl group is optionally substituted with an ethoxy or one, two or three fluorine atoms, wherein the phenyl group is optionally substituted with a methoxy, wherein the 5-6 heteroaryl group is optionally substituted with a methyl, and wherein the -O-phenyl group is optionally substituted with a fluorine, methyl or methoxy group;

[0245] R 9 It is hydrogen or fluorine;

[0246] R 10 It is hydrogen or C 1-3 alkyl;

[0247] R 11 It is hydrogen, methyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3; and

[0248] R 12 It can be hydrogen or methyl.

[0249] E42 A compound or a pharmaceutically acceptable salt thereof as described in any of embodiments E1 to E15 and E17 to E41, wherein R 6It is a methoxy group, R 7 It is a methoxy group, R 8 It is hydrogen, and R 9 It is hydrogen.

[0250] E43 A compound of formula (IV):

[0251]

[0252] Or its pharmaceutically acceptable salt, wherein:

[0253] R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or one or two fluorine atoms;

[0254] R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0255] R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0256] R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0257] R 7 It is hydrogen, C1-C4 alkyl, or methoxy;

[0258] R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, or -(CHR) 11 ) n -4-8-membered heterocyclic alkyl, 5-8-membered heteroaryl, 9-10-membered heteroaryl, -C(O)NR 12 R 13 -N(CH3) (4-5 membered heterocyclic alkyl) or -O-phenyl,

[0259] The C1-C4 alkyl group is optionally substituted with one or two methoxy groups, -N(R) 14 (R) 15 (or one, two, or three fluorine atoms are substituted.)

[0260] The phenyl group is optionally substituted with a methoxy group.

[0261] Wherein -(CHR) 11 ) n The 4-8-membered heterocyclic alkyl group is optionally substituted by one, two, or three independent substituents selected from the following: oxo, one or two methyl substituents, ethyl, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, 4-6-membered heterocyclic alkyl group, and one or two fluorine atoms.

[0262] The 5-8 heteroaryl group is optionally substituted by one of the following: oxo, cyano, methyl, -[CH(R) 16 )] p [N(CH3)2] or optionally a methyl-substituted 6-membered heterocyclic alkyl group,

[0263] The 9-10 membered heteroaryl group is optionally substituted with a methyl group.

[0264] The -C(O)NR 12 R 13 Optionally substituted with one or two fluorine atoms, and

[0265] The -O-phenyl group is optionally substituted with fluorine, methyl or methoxy groups;

[0266] R 11 It can be hydrogen or methyl;

[0267] R 12 For hydrogen, C 1-3 Alkyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3;

[0268] R 13 It is hydrogen or C 1-2 alkyl;

[0269] Where R 12 C 1-3 Alkyl and R 13 C 1-2 When alkyl, R 12 and R 13 It can form a 4-6 membered heterocyclic alkyl ring together with the nitrogen to which it is attached, wherein the 4-6 membered heterocyclic alkyl ring is optionally substituted with one or two fluorine atoms;

[0270] Each R 14 and R 15 It can be methyl or ethyl independently;

[0271] R 16 It can be hydrogen or methyl;

[0272] n is 0 or 1; and

[0273] p is 0 or 1.

[0274] E44 A compound of formula (V):

[0275]

[0276] Or its pharmaceutically acceptable salt, wherein:

[0277] R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or one or two fluorine atoms;

[0278] R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0279] R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0280] R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0281] R 7 It is hydrogen, C1-C4 alkyl, or methoxy;

[0282] R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, or -(CHR) 11 ) n -4-8-membered heterocyclic alkyl, 5-8-membered heteroaryl, 9-10-membered heteroaryl, -C(O)NR 12 R 13 -N(CH3) (4-5 membered heterocyclic alkyl) or -O-phenyl,

[0283] The C1-C4 alkyl group is optionally substituted with one or two methoxy groups, -N(R) 14 (R) 15 (or one, two, or three fluorine atoms are substituted.)

[0284] The phenyl group is optionally substituted with a methoxy group.

[0285] Wherein -(CHR) 11 )n The 4-8-membered heterocyclic alkyl group is optionally substituted by one, two, or three independent substituents selected from the following: oxo, one or two methyl substituents, ethyl, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, 4-6-membered heterocyclic alkyl group, and one or two fluorine atoms.

[0286] The 5-8 heteroaryl group is optionally substituted by one of the following: oxo, cyano, methyl, -[CH(R) 16 )] p [N(CH3)2] or optionally a methyl-substituted 6-membered heterocyclic alkyl group,

[0287] The 9-10 membered heteroaryl group is optionally substituted with a methyl group.

[0288] The -C(O)NR 12 R 13 Optionally substituted with one or two fluorine atoms, and

[0289] The -O-phenyl group is optionally substituted with fluorine, methyl or methoxy groups;

[0290] R 11 It can be hydrogen or methyl;

[0291] R 12 For hydrogen, C 1-3 Alkyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3;

[0292] R 13 It is hydrogen or C 1-2 alkyl;

[0293] Where R 12 C 1-3 Alkyl and R 13 C 1-2 When alkyl, R 12 and R 13 It can form a 4-6 membered heterocyclic alkyl ring together with the nitrogen to which it is attached, wherein the 4-6 membered heterocyclic alkyl ring is optionally substituted with one or two fluorine atoms;

[0294] Each R 14 and R 15 It can be methyl or ethyl independently;

[0295] R 16 It can be hydrogen or methyl;

[0296] n is 0 or 1; and

[0297] p is 0 or 1.

[0298] E45 Compound of Formula (VI):

[0299]

[0300] Or its pharmaceutically acceptable salt, wherein:

[0301] R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or one or two fluorine atoms;

[0302] R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0303] R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0304] R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0305] R 7 It is hydrogen, C1-C4 alkyl, or methoxy;

[0306] R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, or -(CHR) 11 ) n -4-8-membered heterocyclic alkyl, 5-8-membered heteroaryl, 9-10-membered heteroaryl, -C(O)NR 12 R 13 -N(CH3) (4-5 membered heterocyclic alkyl) or -O-phenyl,

[0307] The C1-C4 alkyl group is optionally substituted with one or two methoxy groups, -N(R) 14 (R) 15 (or one, two, or three fluorine atoms are substituted.)

[0308] The phenyl group is optionally substituted with a methoxy group.

[0309] Wherein -(CHR) 11 ) nThe 4-8-membered heterocyclic alkyl group is optionally substituted by one, two, or three independent substituents selected from the following: oxo, one or two methyl substituents, ethyl, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, 4-6-membered heterocyclic alkyl group, and one or two fluorine atoms.

[0310] The 5-8 heteroaryl group is optionally substituted by one of the following: oxo, cyano, methyl, -[CH(R) 16 )] p [N(CH3)2] or optionally a methyl-substituted 6-membered heterocyclic alkyl group,

[0311] The 9-10 membered heteroaryl group is optionally substituted with a methyl group.

[0312] The -C(O)NR 12 R 13 Optionally substituted with one or two fluorine atoms, and

[0313] The -O-phenyl group is optionally substituted with fluorine, methyl or methoxy groups;

[0314] R 11 It can be hydrogen or methyl;

[0315] R 12 For hydrogen, C 1-3 Alkyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3;

[0316] R 13 It is hydrogen or C 1-2 alkyl;

[0317] Where R 12 C 1-3 Alkyl and R 13 C 1-2 When alkyl, R 12 and R 13 It can form a 4-6 membered heterocyclic alkyl ring together with the nitrogen to which it is attached, wherein the 4-6 membered heterocyclic alkyl ring is optionally substituted with one or two fluorine atoms;

[0318] Each R 14 and R 15 It can be methyl or ethyl independently;

[0319] R 16 It can be hydrogen or methyl;

[0320] n is 0 or 1; and

[0321] p is 0 or 1.

[0322] E46 A compound of formula (VIa):

[0323]

[0324] Or its pharmaceutically acceptable salt, wherein:

[0325] R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or one or two fluorine atoms;

[0326] R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0327] R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0328] R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0329] R 7 It is hydrogen, C1-C4 alkyl, or methoxy;

[0330] R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, or -(CH2). n -4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, -C(O)NR 11 R 12 or -O-phenyl, wherein the C1-C4 alkyl group is optionally hydroxylated by a methoxy group, -N(R) 13 (R) 14 The phenyl group may be substituted with one, two, or three fluorine atoms, wherein the phenyl group is optionally substituted with a methoxy group, and wherein the -(CH2) group is... n -4-6-membered heterocyclic alkyl groups and the 5-6-membered heteroaryl groups are each optionally substituted with methyl groups, and the -O-phenyl groups are optionally substituted with fluorine, methyl or methoxy groups;

[0331] R 11 It is hydrogen, methyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3;

[0332] R12 It can be hydrogen or methyl;

[0333] Each R 13 and R 14 Independently methyl or ethyl; and

[0334] n is 0 or 1.

[0335] E47 A compound of formula (VIb):

[0336]

[0337] Or its pharmaceutically acceptable salt, wherein:

[0338] R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or two fluorine atoms;

[0339] R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0340] R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0341] R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0342] R 7 It is hydrogen, C1-C4 alkyl, or methoxy;

[0343] R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, 4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, -C(O)NR 11 R 12 Or -O-phenyl, wherein the C1-C4 alkyl group is optionally substituted with a methoxy group or one, two or three fluorine atoms, wherein the phenyl group is optionally substituted with a methoxy group, wherein the 5-6 heteroaryl group is optionally substituted with a methyl group, and wherein the -O-phenyl group is optionally substituted with a fluorine, methyl or methoxy group;

[0344] R 11It is hydrogen, methyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3; and

[0345] R 12 It can be hydrogen or methyl.

[0346] E48 A compound of formula (VII):

[0347]

[0348] Or its pharmaceutically acceptable salt, wherein:

[0349] R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or one or two fluorine atoms;

[0350] R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0351] R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0352] R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0353] R 7 It is hydrogen, C1-C4 alkyl, or methoxy;

[0354] R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, or -(CHR) 11 ) n -4-8-membered heterocyclic alkyl, 5-8-membered heteroaryl, 9-10-membered heteroaryl, -C(O)NR 12 R 13 -N(CH3) (4-5 membered heterocyclic alkyl) or -O-phenyl,

[0355] The C1-C4 alkyl group is optionally substituted with one or two methoxy groups, -N(R) 14 (R) 15 (or one, two, or three fluorine atoms are substituted.)

[0356] The phenyl group is optionally substituted with a methoxy group.

[0357] Wherein -(CHR) 11 ) n The 4-8-membered heterocyclic alkyl group is optionally substituted by one, two, or three independent substituents selected from the following: oxo, one or two methyl substituents, ethyl, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, 4-6-membered heterocyclic alkyl group, and one or two fluorine atoms.

[0358] The 5-8 heteroaryl group is optionally substituted by one of the following: oxo, cyano, methyl, -[CH(R) 16 )] p [N(CH3)2] or optionally a methyl-substituted 6-membered heterocyclic alkyl group,

[0359] The 9-10 membered heteroaryl group is optionally substituted with a methyl group.

[0360] The -C(O)NR 12 R 13 Optionally substituted with one or two fluorine atoms, and

[0361] The -O-phenyl group is optionally substituted with fluorine, methyl or methoxy groups;

[0362] R 11 It can be hydrogen or methyl;

[0363] R 12 For hydrogen, C 1-3 Alkyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3;

[0364] R 13 It is hydrogen or C 1-2 alkyl;

[0365] Where R 12 C 1-3 Alkyl and R 13 C 1-2 When alkyl, R 12 and R 13 It can form a 4-6 membered heterocyclic alkyl ring together with the nitrogen to which it is attached, wherein the 4-6 membered heterocyclic alkyl ring is optionally substituted with one or two fluorine atoms;

[0366] Each R 14 and R 15 It can be methyl or ethyl independently;

[0367] R 16 It can be hydrogen or methyl;

[0368] n is 0 or 1; and

[0369] p is 0 or 1.

[0370] E49 A compound of formula (VIIa):

[0371]

[0372] Or its pharmaceutically acceptable salt, wherein:

[0373] R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or one or two fluorine atoms;

[0374] R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0375] R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0376] R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0377] R 7 It is hydrogen, C1-C4 alkyl, or methoxy;

[0378] R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, or -(CH2). n -4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, -C(O)NR 11 R 12 or -O-phenyl, wherein the C1-C4 alkyl group is optionally hydroxylated by a methoxy group, -N(R) 13 (R) 14 The phenyl group may be substituted with one, two, or three fluorine atoms, wherein the phenyl group is optionally substituted with a methoxy group, and wherein the -(CH2) group is... n -4-6-membered heterocyclic alkyl groups and the 5-6-membered heteroaryl groups are each optionally substituted with methyl groups, and the -O-phenyl groups are optionally substituted with fluorine, methyl or methoxy groups;

[0379] R 11 It is hydrogen, methyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3;

[0380] R 12 It can be hydrogen or methyl;

[0381] Each R 13 and R 14 Independently methyl or ethyl; and

[0382] n is 0 or 1.

[0383] E50 A compound of formula (VIIb):

[0384]

[0385] Or its pharmaceutically acceptable salt, wherein:

[0386] R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or two fluorine atoms;

[0387] R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0388] R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0389] R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0390] R 7 It is hydrogen, C1-C4 alkyl, or methoxy;

[0391] R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, 4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, -C(O)NR 11 R 12Or -O-phenyl, wherein the C1-C4 alkyl group is optionally substituted with a methoxy group or one, two or three fluorine atoms, wherein the phenyl group is optionally substituted with a methoxy group, wherein the 5-6 heteroaryl group is optionally substituted with a methyl group, and wherein the -O-phenyl group is optionally substituted with a fluorine, methyl or methoxy group;

[0392] R 11 It is hydrogen, methyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3; and

[0393] R 12 It can be hydrogen or methyl.

[0394] E51 Compound of Formula (VIII):

[0395]

[0396] Or its pharmaceutically acceptable salt, wherein:

[0397] R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or one or two fluorine atoms;

[0398] R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0399] R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0400] R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0401] R 7 It is hydrogen, C1-C4 alkyl, or methoxy;

[0402] R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, or -(CHR) 11 ) n -4-8-membered heterocyclic alkyl, 5-8-membered heteroaryl, 9-10-membered heteroaryl, -C(O)NR 12 R13 -N(CH3) (4-5 membered heterocyclic alkyl) or -O-phenyl,

[0403] The C1-C4 alkyl group is optionally substituted with one or two methoxy groups, -N(R) 14 (R) 15 (or one, two, or three fluorine atoms are substituted.)

[0404] The phenyl group is optionally substituted with a methoxy group.

[0405] Wherein -(CHR) 11 ) n The 4-8-membered heterocyclic alkyl group is optionally substituted by one, two, or three independent substituents selected from the following: oxo, one or two methyl substituents, ethyl, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, 4-6-membered heterocyclic alkyl group, and one or two fluorine atoms.

[0406] The 5-8 heteroaryl group is optionally substituted by one of the following: oxo, cyano, methyl, -[CH(R) 16 )] p [N(CH3)2] or optionally a methyl-substituted 6-membered heterocyclic alkyl group,

[0407] The 9-10 membered heteroaryl group is optionally substituted with a methyl group.

[0408] The -C(O)NR 12 R 13 Optionally substituted with one or two fluorine atoms, and

[0409] The -O-phenyl group is optionally substituted with fluorine, methyl or methoxy groups;

[0410] R 11 It can be hydrogen or methyl;

[0411] R 12 For hydrogen, C 1-3 Alkyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3;

[0412] R 13 It is hydrogen or C 1-2 alkyl;

[0413] Where R 12 C 1-3 Alkyl and R 13 C 1-2 When alkyl, R 12 and R 13It can form a 4-6 membered heterocyclic alkyl ring together with the nitrogen to which it is attached, wherein the 4-6 membered heterocyclic alkyl ring is optionally substituted with one or two fluorine atoms;

[0414] Each R 14 and R 15 It can be methyl or ethyl independently;

[0415] R 16 It can be hydrogen or methyl;

[0416] n is 0 or 1; and

[0417] p is 0 or 1.

[0418] E52 A compound of formula (VIIIa):

[0419]

[0420] Or its pharmaceutically acceptable salt, wherein:

[0421] R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or one or two fluorine atoms;

[0422] R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0423] R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0424] R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0425] R 7 It is hydrogen, C1-C4 alkyl, or methoxy;

[0426] R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, or -(CH2). n -4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, -C(O)NR 11 R 12or -O-phenyl, wherein the C1-C4 alkyl group is optionally hydroxylated by a methoxy group, -N(R) 13 (R) 14 The phenyl group may be substituted with one, two, or three fluorine atoms, wherein the phenyl group is optionally substituted with a methoxy group, and wherein the -(CH2) group is... n -4-6-membered heterocyclic alkyl groups and the 5-6-membered heteroaryl groups are each optionally substituted with methyl groups, and the -O-phenyl groups are optionally substituted with fluorine, methyl or methoxy groups;

[0427] R 11 It is hydrogen, methyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3;

[0428] R 12 It can be hydrogen or methyl;

[0429] Each R 13 and R 14 Independently methyl or ethyl; and

[0430] n is 0 or 1.

[0431] E53 A compound of formula (VIIIb):

[0432]

[0433] Or its pharmaceutically acceptable salt, wherein:

[0434] R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or two fluorine atoms;

[0435] R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0436] R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0437] R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0438] R 7It is hydrogen, C1-C4 alkyl, or methoxy;

[0439] R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, 4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, -C(O)NR 11 R 12 Or -O-phenyl, wherein the C1-C4 alkyl group is optionally substituted with a methoxy group or one, two or three fluorine atoms, wherein the phenyl group is optionally substituted with a methoxy group, wherein the 5-6 heteroaryl group is optionally substituted with a methyl group, and wherein the -O-phenyl group is optionally substituted with a fluorine, methyl or methoxy group;

[0440] R 11 It is hydrogen, methyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3; and

[0441] R 12 It can be hydrogen or methyl.

[0442] E54 Compound of Formula (IX):

[0443]

[0444] Or its pharmaceutically acceptable salt, wherein:

[0445] R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or one or two fluorine atoms;

[0446] R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0447] R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0448] R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0449] R 7 It is hydrogen, C1-C4 alkyl, or methoxy;

[0450] R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, or -(CHR) 11 ) n -4-8-membered heterocyclic alkyl, 5-8-membered heteroaryl, 9-10-membered heteroaryl, -C(O)NR 12 R 13 -N(CH3) (4-5 membered heterocyclic alkyl) or -O-phenyl,

[0451] The C1-C4 alkyl group is optionally substituted with one or two methoxy groups, -N(R) 14 (R) 15 (or one, two, or three fluorine atoms are substituted.)

[0452] The phenyl group is optionally substituted with a methoxy group.

[0453] Wherein -(CHR) 11 ) n The 4-8-membered heterocyclic alkyl group is optionally substituted by one, two, or three independent substituents selected from the following: oxo, one or two methyl substituents, ethyl, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, 4-6-membered heterocyclic alkyl group, and one or two fluorine atoms.

[0454] The 5-8 heteroaryl group is optionally substituted by one of the following: oxo, cyano, methyl, -[CH(R) 16 )] p [N(CH3)2] or optionally a methyl-substituted 6-membered heterocyclic alkyl group,

[0455] The 9-10 membered heteroaryl group is optionally substituted with a methyl group.

[0456] The -C(O)NR 12 R 13 Optionally substituted with one or two fluorine atoms, and

[0457] The -O-phenyl group is optionally substituted with fluorine, methyl or methoxy groups;

[0458] R 11 It can be hydrogen or methyl;

[0459] R 12 For hydrogen, C 1-3 Alkyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3;

[0460] R 13 It is hydrogen or C 1-2 alkyl;

[0461] Where R 12 C 1-3 Alkyl and R 13 C 1-2 When alkyl, R 12 and R 13 It can form a 4-6 membered heterocyclic alkyl ring together with the nitrogen to which it is attached, wherein the 4-6 membered heterocyclic alkyl ring is optionally substituted with one or two fluorine atoms;

[0462] Each R 14 and R 15 It can be methyl or ethyl independently;

[0463] R 16 It can be hydrogen or methyl;

[0464] n is 0 or 1; and

[0465] p is 0 or 1.

[0466] E55 A compound of formula (IXa):

[0467]

[0468] Or its pharmaceutically acceptable salt, wherein:

[0469] R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or one or two fluorine atoms;

[0470] R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0471] R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0472] R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0473] R 7 It is hydrogen, C1-C4 alkyl, or methoxy;

[0474] R 8It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, or -(CH2). n -4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, -C(O)NR 11 R 12 or -O-phenyl, wherein the C1-C4 alkyl group is optionally hydroxylated by a methoxy group, -N(R) 13 (R) 14 The phenyl group may be substituted with one, two, or three fluorine atoms, wherein the phenyl group is optionally substituted with a methoxy group, and wherein the -(CH2) group is... n -4-6-membered heterocyclic alkyl groups and the 5-6-membered heteroaryl groups are each optionally substituted with methyl groups, and the -O-phenyl groups are optionally substituted with fluorine, methyl or methoxy groups;

[0475] R 11 It is hydrogen, methyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3;

[0476] R 12 It can be hydrogen or methyl;

[0477] Each R 13 and R 14 Independently methyl or ethyl; and

[0478] n is 0 or 1.

[0479] E56 A compound of formula (IXb):

[0480]

[0481] Or its pharmaceutically acceptable salt, wherein:

[0482] R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or two fluorine atoms;

[0483] R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH;

[0484] R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2;

[0485] R 6It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms;

[0486] R 7 It is hydrogen, C1-C4 alkyl, or methoxy;

[0487] R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, 4-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, -C(O)NR 11 R 12 Or -O-phenyl, wherein the C1-C4 alkyl group is optionally substituted with a methoxy group or one, two or three fluorine atoms, wherein the phenyl group is optionally substituted with a methoxy group, wherein the 5-6 heteroaryl group is optionally substituted with a methyl group, and wherein the -O-phenyl group is optionally substituted with a fluorine, methyl or methoxy group;

[0488] R 11 It is hydrogen, methyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3; and

[0489] R 12 It can be hydrogen or methyl.

[0490] E57 The compound or a pharmaceutically acceptable salt thereof as described in any of embodiments E1 to E56, wherein R 3 It is hydrogen, chlorine, C1-C4 alkyl, -CHF2, -CF3, -CF2CH3, -CH2-CF3, -CH2OCH3, methoxy, -O-CHF2, -C(O)OH, -C(O)OCH3, bicyclo[1.1.1]pent-1-yl, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH and the cyclopropyl is optionally substituted with methyl or two fluorine atoms.

[0491] E58 The compound of embodiment E57 or a pharmaceutically acceptable salt thereof, wherein R 3 It is cyclopropyl.

[0492] E59 The compound or a pharmaceutically acceptable salt thereof as described in any of embodiments E1 to E58, wherein R 4 It can be hydrogen, methyl, ethyl, or isopropyl.

[0493] E60 The compound of embodiment E59 or a pharmaceutically acceptable salt thereof, wherein R 4 It is hydrogen.

[0494] E61 The compound or a pharmaceutically acceptable salt thereof as described in any of embodiments E1 to E60, wherein R 5 It can be hydrogen, fluorine, cyano, methyl, ethyl, or -C(O)NH2.

[0495] E62 The compound of embodiment E61 or a pharmaceutically acceptable salt thereof, wherein R 5 It is hydrogen.

[0496] E63 The compound of embodiment E62 or a pharmaceutically acceptable salt thereof, wherein R 3 It is cyclopropyl, R 4 It is hydrogen, and R 5 It is hydrogen.

[0497] E64 A compound or a pharmaceutically acceptable salt thereof as described in any of embodiments E1 to E15 and E17 to E62, wherein R 6 It can be hydrogen, bromine, chlorine, fluorine, methyl, ethyl, methoxy, ethoxy, -O-isopropyl, -O-CH2CHF2, -O-CF3, -O-cyclobutyl or -O-cyclopropyl.

[0498] E65 The compound of embodiment E64 or a pharmaceutically acceptable salt thereof, wherein R 6 It is a methoxy group.

[0499] E66 A compound or a pharmaceutically acceptable salt thereof as described in any of embodiments E1 to E15 and E17 to E56, wherein R 7 It can be hydrogen, methyl, ethyl, or methoxy.

[0500] E67 The compound or its pharmaceutically acceptable salt as described in embodiment E66, wherein R 7 It is a methoxy group.

[0501] E68 The compound of embodiment E66 or a pharmaceutically acceptable salt thereof, wherein R 7 It is hydrogen.

[0502] E69 A compound or a pharmaceutically acceptable salt thereof as described in any of embodiments E1 to E15 and E17 to E68, wherein R 8It is hydrogen, chlorine, fluorine, cyano, methyl, ethyl, propyl, -CHF2, -CF3, -CH2OCH3, methoxy, phenyl, azacyclobutyl, oxacyclobutyl, tetrahydrofuranyl, pyrrolyl, tetrahydropyranyl, piperidinyl, morpholinyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridinyl, pyrazinyl, -C(O)N(CH3)2, -C(O)NH(CH2)5NH2, -C(O)NH(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3 or -O-phenyl, wherein the phenyl is optionally substituted with a methoxy group, wherein the pyrazolyl, the imidazolyl and the thiazolyl are each optionally substituted with a methyl group, and wherein the -O-phenyl is optionally substituted with a methyl, fluorine or methoxy group.

[0503] E70 A compound or a pharmaceutically acceptable salt thereof as described in any of embodiments E1 to E69, wherein R 8 It is hydrogen, chlorine, fluorine, cyano, methyl, ethyl, propyl, -CHF2, -CF3, -CH2OCH3, methoxy, phenyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridinyl, pyrazinyl, -C(O)N(CH3)2, -C(O)NH(CH2)5NH2, -C(O)NH(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3 or -O-phenyl, wherein the phenyl is optionally substituted with a methoxy group, wherein the pyrazolyl, the imidazolyl and the thiazolyl are each optionally substituted with a methyl group, and wherein the -O-phenyl is optionally substituted with a methyl, fluorine or methoxy group.

[0504] E71 The compound or its pharmaceutically acceptable salt as described in embodiment E69 or embodiment E70, wherein R 8 It is hydrogen.

[0505] E72 A compound of formula (X):

[0506]

[0507] Or its pharmaceutically acceptable salt, wherein:

[0508] R 1 It is hydrogen or fluorine;

[0509] R 3 It is hydrogen, ethyl, or cyclopropyl;

[0510] R 6 It is methoxy, ethoxy, O-cyclopropyl, or O-cyclobutyl;

[0511] R 7 It can be hydrogen, fluorine, or methoxy;

[0512] R 8 It can be hydrogen, fluorine, methyl, or -CHF2.

[0513] E73 A compound or a pharmaceutically acceptable salt thereof as described in any of embodiments E1 to E24 and E72, wherein R 1 It is fluorine, and R 2 It is a methoxy group.

[0514] E74 A compound or a pharmaceutically acceptable salt thereof as described in any of embodiments E1 to E24 and E72, wherein R 1 It is hydrogen, and R 2 It is a methoxy group.

[0515] E75 The compound or a pharmaceutically acceptable salt thereof as described in any of embodiments E72 to E74, wherein R 3 It is cyclopropyl.

[0516] E76 A compound selected from the group consisting of...

[0517]

[0518]

[0519]

[0520]

[0521] ,

[0522] Or its tautomers, or pharmaceutically acceptable salts of the compound or its tautomers.

[0523] E77 is a compound as described in embodiment E76, which is

[0524]

[0525] Or its tautomers, or pharmaceutically acceptable salts of the compound or its tautomers.

[0526] E78 is a compound as described in embodiment E76, which is

[0527]

[0528] Or its tautomers, or pharmaceutically acceptable salts of the compound or its tautomers.

[0529] E79 is a compound as described in embodiment E76, which is

[0530]

[0531] Or its tautomers, or pharmaceutically acceptable salts of the compound or its tautomers.

[0532] E80 is a compound as described in embodiment E76, which is

[0533]

[0534] Or its tautomers, or pharmaceutically acceptable salts of the compound or its tautomers.

[0535] E81 is a compound as described in embodiment E76, which is

[0536]

[0537] Or its tautomers, or pharmaceutically acceptable salts of the compound or its tautomers.

[0538] E82 is a compound as described in embodiment E76, which is

[0539]

[0540] Or its tautomers, or pharmaceutically acceptable salts of the compound or its tautomers.

[0541] E83 is a compound as described in embodiment E76, which is

[0542]

[0543] Or its tautomers, or pharmaceutically acceptable salts of the compound or its tautomers.

[0544] E84 is a compound as described in embodiment E76, which is

[0545]

[0546] Or its tautomers, or pharmaceutically acceptable salts of the compound or its tautomers.

[0547] E85 is a compound as described in embodiment E76, which is

[0548]

[0549] Or its tautomers, or pharmaceutically acceptable salts of the compound or its tautomers.

[0550] E86 is a compound as described in embodiment E76, which is

[0551]

[0552] Or its tautomers, or pharmaceutically acceptable salts of the compound or its tautomers.

[0553] E87 is a compound as described in embodiment E76, which is

[0554] ,

[0555] Or its pharmaceutically acceptable salt.

[0556] E88 is a compound as described in embodiment E76, which is

[0557]

[0558] Or its pharmaceutically acceptable salt.

[0559] E89 is a compound as described in embodiment E76, which is

[0560]

[0561] Or its pharmaceutically acceptable salt.

[0562] E90 is a compound as described in embodiment E76, which is

[0563]

[0564] Or its pharmaceutically acceptable salt.

[0565] E91 is the compound of embodiment E76, which is

[0566]

[0567] Or its pharmaceutically acceptable salt.

[0568] E92 is a compound as described in embodiment E76, which is

[0569]

[0570] Or its pharmaceutically acceptable salt.

[0571] E93 is a compound as described in embodiment E76, which is

[0572]

[0573] Or its pharmaceutically acceptable salt.

[0574] E94 is a compound as described in embodiment E76, which is

[0575]

[0576] Or its pharmaceutically acceptable salt.

[0577] E95 is a compound as described in embodiment E76, which is

[0578] ,

[0579] Or its pharmaceutically acceptable salt.

[0580] E96 A pharmaceutical composition comprising a compound according to any one of embodiments E1 to E94 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0581] E97 A method for treating cancer, comprising administering to a subject in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, as described in any one of embodiments E1 to E95.

[0582] E98 The method of implementation scheme E96, wherein the cancer is breast cancer.

[0583] E99 The method of implementation scheme E97, wherein the breast cancer is ER+ breast cancer.

[0584] E100 is the method of embodiment E98, wherein the ER+ breast cancer is ER+ HER2- breast cancer.

[0585] E101 A method for treating cancer, comprising administering to a subject in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments E1 to E99, and the method further comprising administering an additional therapeutic agent.

[0586] E102 The method of implementation scheme E100, wherein the cancer is breast cancer.

[0587] E103 is the method of implementation scheme E101, wherein the breast cancer is ER+ breast cancer.

[0588] E104 The method of embodiment E102, wherein the ER+ breast cancer is ER+ HER2- breast cancer.

[0589] E105 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments E1 to E103 is used as a medicine.

[0590] E106 A compound or a pharmaceutically acceptable salt thereof, as described in any of embodiments E1 to E104, is used to treat cancer.

[0591] E107 Use of a compound or a pharmaceutically acceptable salt thereof, as described in any of embodiments E1 to E105, for the preparation of a medicament for the treatment of cancer.

[0592] Each embodiment described herein may be combined with any other embodiment(s) described herein, and such other embodiment(s) is not contradictory to the embodiment(s) in which it is combined. Furthermore, with respect to any of the embodiments(s) described herein, any of the compounds described in the examples or a pharmaceutically acceptable salt thereof may be claimed individually or in combination with one or more other compounds of the examples or a pharmaceutically acceptable salt thereof.

[0593] Furthermore, each embodiment described herein envisions a pharmaceutically acceptable salt of the compound described herein within its scope.

[0594] definition

[0595] Unless otherwise defined herein, scientific and technical terms used in connection with this invention have the meanings commonly understood by one of ordinary skill in the art.

[0596] The invention described herein can be suitably implemented in the absence of any of the (multiple) elements not specifically disclosed herein.

[0597] As used herein, unless otherwise indicated, the singular forms “a,” “an,” and “the” include plural references. For example, a “a” substituent includes one or more substituents.

[0598] As used herein, the term “about” when used to modify a numerically defined parameter (e.g., a dose of 5 mg) means that the parameter may vary by up to 10% less or more than its specified value. For example, a dose of about 5 mg means 5 mg ± 10%, that is, it may vary between 4.5 mg and 5.5 mg.

[0599] If a substituent is described as being "independently selected" from a group, then each substituent is selected independently of the others. Therefore, each substituent can be the same as or different from the other (multiple) substituents(s).

[0600] "Optional" or "optionally" means that the event or situation described below may occur but is not required to occur, and the description includes both the possibility that the event or situation may occur and the possibility that it may not occur.

[0601] The term "optionally substituted" is used to indicate that a particular group described may not have non-hydrogen substituents (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 substituents that may be present is equal to the number of H atoms present in the unsubstituted form of the described group. In the case of optional substituents connected via double bonds, such as oxo (=O) substituents, the group occupies two possible valences, thus reducing the total number of other substituents included by two. In the case where optional substituents are independently selected from the list of alternatives, the selected groups may be the same or different. Throughout this disclosure, it should be understood that the number and nature of optional substituent groups will be limited to the extent that such substitution is chemically reasonable to a person skilled in the art.

[0602] "Halogen" or "halogen group" refers to fluorine, chlorine, bromine and iodine (F, Cl, Br, I).

[0603] "Cyano" refers to a substituent that has a carbon atom connected to a nitrogen atom via a triple bond, i.e., -C≡N.

[0604] "Hydroxy group" refers to the -OH group.

[0605] "Oxygenation" refers to oxygen (=O) bonded by a double bond.

[0606] "alkyl" refers to a saturated monovalent aliphatic hydrocarbon group having a specified number of carbon atoms, including straight-chain or branched groups. An alkyl group may contain, but is not limited to, 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, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, etc. In one embodiment, the alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. The alkyl group may optionally be substituted, may be unsubstituted, or may be substituted, as further defined herein.

[0607] “Cycloalkyl” refers to a fully saturated hydrocarbon ring system having a specified number of carbon atoms, which can be a monocyclic or bridged ring system in which carbon atoms of the cycloalkyl ring are connected to a base molecule. The cycloalkyl group may contain, but is not limited to, 3 to 6 carbon atoms (“C3-C6 cycloalkyl”), 3 to 5 carbon atoms (“C3-C5 cycloalkyl”), 4 to 5 carbon atoms (“C4-C5 cycloalkyl”), or 3 to 4 carbon atoms (“C3-C4 cycloalkyl”). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pent-1-yl, cyclohexyl, etc. In one embodiment, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or bicyclo[1.1.1]pent-1-yl. The cycloalkyl group may optionally be substituted, may be unsubstituted, or may be substituted, as further defined herein.

[0608] "Heterocyclic alkyl" refers to a fully saturated ring system containing a specified number of ring atoms and at least one heteroatom selected from nitrogen and oxygen as a ring member, wherein the heterocyclic alkyl ring is linked to a base molecule via a ring atom that can be C or N. The heterocyclic alkyl ring may contain one to two heteroatoms selected from N and O as ring members, provided that such a heterocyclic alkyl ring does not contain two consecutive nitrogen or oxygen atoms. Heterocyclic alkyl rings include rings that are spirocyclic, wherein such spirocyclic rings are saturated, provided that the connection point to the base molecule is an atom of the heterocyclic alkyl portion of the ring system. "4-8-membered heterocyclic alkyl" contains four to eight ring atoms, "4-6-membered heterocyclic alkyl" contains four to six ring atoms, "6-membered heterocyclic alkyl" contains four to six ring atoms, and "4-5-membered heterocyclic alkyl" contains four to five ring atoms. Heterocyclic alkyl rings may optionally be substituted, may be unsubstituted, or may be substituted, as further defined herein. Examples of heterocyclic alkyl groups include, but are not limited to:

[0609]

[0610] "Aryl" or "aromatic" refers to a monocyclic or bicyclic (e.g., biaryl, fused) ring system containing a specified number of ring atoms, wherein all carbon atoms in the ring are sp. 2 Hybridized, with π electrons in a conjugated state. The aryl group may contain, but is not limited to, 6 to 10 carbon atoms (“C6-C”). 10 Aryl groups can include aryl rings (e.g., phenyl rings) fused to another aryl ring. Examples include, but are not limited to, phenyl and naphthyl. As used herein, the term "aryl" also includes groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl (2,3-dihydro-1-yl ... H Aryl groups (-indene) and tetrahydronaphthyl (also known as 1,2,3,4-tetrahydronaphthyl), wherein the linking group or linking point is on the aromatic ring. The aryl group may optionally be substituted, unsubstituted, or substituted, as further defined herein.

[0611] "Heteroaryl" or "heteroaryl group" refers to a monocyclic, bicyclic (e.g., heterobiaryl, fused) or polycyclic system containing a specified number of ring atoms and including at least one heteroatom selected from N, O, and S as a ring member, wherein all carbon atoms in the ring are sp. 2 Hybridized, wherein the π electrons are in a conjugated state. Heteroaryl rings include rings that are spirocyclic, bridged, or fused with one or more other cycloalkyl or heterocyclic alkyl rings, wherein such spirocyclic, bridged, or fused rings may themselves be saturated, partially unsaturated, or aromatic, and the degree of their unsaturation or aromaticity is chemically reasonable, provided that the connection point with the base molecule is an atom of the aromatic portion of the ring system.

[0612] Heteroaryl groups may contain, but are not limited to, 5 to 10 ring atoms (“5-10-membered heteroaryl”), 5 to 8 ring atoms (“5-8-membered heteroaryl”), 9 to 10 ring atoms (“9-10-membered heteroaryl”), or 5 to 6 ring atoms (“5-6-membered heteroaryl”). The heteroaryl ring is linked to the base molecule via the ring atoms of the aromatic ring. Therefore, a 5- or 6-membered heteroaryl ring (alone or in a fused or polycyclic structure) may be linked to the base molecule via a ring C or N atom. As defined herein, the term “heteroaryl” also includes 5- or 6-membered monocyclic heteroaryl rings that may be fused with cycloalkyl or heterocycloalkyl groups to form fused or polycyclic structures. Examples of heteroaryl groups as defined herein include, but are not limited to, pyrrole (1... H -pyrroleyl), pyrazolyl (1 H -pyrazolyl), imidazoleyl (1 H -imidazolyl), isoxazolyl, oxazolyl, oxadiazolyl (1-oxa-2,4-diazolyl), thiazolyl, triazolyl (1 H -1,2,3-triazole, 1 H -1,2,4-triazole), pyridinyl, pyridinyl, pyrimidinyl, pyrazinyl, indazole (2 H -Indazole), quinolinyl, quinoxalinyl, chromanyl, isochoryl, 2,3-dihydrobenzo[b][1,4]dioxacyclohexenyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 5',6'-dihydrospiro[cyclopropane-1,4'-pyrrolo[1,2-b]pyrazolyl] or tetrahydropyrrolo[3,4-c]pyrazolyl, hexahydropyrido[3,4-d]pyrimidinyl. In a preferred embodiment, the heteroaryl group is pyrazolyl. The heteroaryl group may optionally be substituted, may be unsubstituted, or may be substituted, as further defined herein.

[0613] Illustrative examples of monocyclic heteroaryl groups include, but are not limited to, the following monovalent groups:

[0614]

[0615] Illustrative examples of fused-ring heteroaryl groups include, but are not limited to:

[0616]

[0617]

[0618]

[0619] The term “pharmaceutically acceptable” means a substance (such as the compounds described herein) and any salt thereof, or a composition containing the substance or salt of the present invention, suitable for administration to a subject or patient.

[0620] "Compounds of the present invention" includes compounds of formulas (I)-(X), (Ia)-(VIIa), (Ib)-(VIIb) and the examples used in their preparation. Those skilled in the art will understand that the compounds of the present invention and their novel intermediates include their possible conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic mixtures of such isomers, diastereomer mixtures and other mixtures, and their tautomers. Those skilled in the art will also understand that the compounds of the present invention and their novel intermediates include their solvates, hydrates, isomorphs, polymorphs, esters, salts, prodrugs, and their isotopically labeled forms (including deuterium-substituted forms).

[0621] The compounds of this invention act as KAT6 / 7 inhibitors selective for KAT5 and KAT8. The MYST family of histone lysine acetyltransferases—KAT5, KAT6A, KAT6B, KAT7, and KAT8—regulate gene transcription crucial for cellular function. These enzymes share a common MYST domain but reside in unique complexes that define their functions. According to the Cancer DepMap (https: / / depmap.org / portal), combined inhibition of KAT6A / B and KAT7, predicted by the loss of histone acetylation at H3K23, H3K14, and H4K12, could drive selective dependence in cancer cells. Conversely, KAT5 and KAT8 are classified as essential genes in DepMap, and gene knockout mouse models exhibit embryonic lethality (Thomas, Tim et al., “Mof (MYST1 or KAT8) is essential for progression of embryonic development past the blastocyst stage and required for normal chromatin architecture”). Molecular and cellular biology 28.16 (2008): 5093-5105; Hu, Yaofei et al., “Homozygous disruption of the Tip60 gene causes early embryonic lethality.” Developmental dynamics: an official publication of the American Association of Anatomists238.11 (2009): 2912-2921). KAT8, as a catalytic component of the NSL complex, is essential for cell survival and regulates the transcription of genes that are critical to cell homeostasis (Radzisheuskaya A, Shliaha PV, Grinev VV, ShlyuevaD, Damhofer H, Koche R, Gorshkov V, Kovalchuk S, Zhan Y, Rodriguez KL, Johnstone AL, Keogh MC, Hendrickson RC, Jensen ON, Helin K. Complex-dependent histone acetyltransferase activity of KAT8 determines its role intranscription and cellular homeostasis. Mol Cell. April 15, 2021; 81(8):1749-1765.e8. doi: 10.1016 / j.molcel.2021.02.012. Epub March 2, 2021. PMID:33657400; PMCID: PMC8056186).

[0622] The compounds of this invention include, but are not limited to:

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632] "Pharmaceutical composition" means a mixture of one or more of the compounds of the present invention, or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof, as an active ingredient and at least one pharmaceutically acceptable excipient.

[0633] As used in this article, the “deuterium enrichment factor” refers to the ratio between the abundance of deuterium and the natural abundance of deuterium, each relative to the abundance of hydrogen. In certain embodiments, the deuterium enrichment factor designated for the atomic positions containing deuterium is typically at least 1000 (15% deuterium doping), at least 2000 (30% deuterium doping), at least 3000 (45% deuterium doping), at least 3500 (52.5% deuterium doping), at least 3500 (52.5% deuterium doping at each designated deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3. (99.5% deuterium added).

[0634] As used herein, “excipient” refers to any ingredient other than the compounds of this invention. The selection of excipients will depend to a great extent on factors such as the method of application, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0635] As used herein, “excipient” includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonics and absorption delay agents, carriers, diluents, etc. Examples of excipients include one or more of water, saline, phosphate-buffered saline, dextran, glycerol, ethanol, etc., and combinations thereof, and may include isotonics in the composition, such as sugars, sodium chloride, or polyols, such as mannitol or sorbitol. Examples of excipients also include various organic solvents (such as hydrates and solvates). Where necessary, pharmaceutical compositions may contain additional excipients, such as flavor enhancers, binders / adhesives, lubricants, disintegrants, sweeteners or flavorings, colorants 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, alginate, and certain complex silicates) and binders (such as sucrose, gelatin, and acacia). Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. Furthermore, lubricants (such as magnesium stearate, sodium lauryl sulfate, and talc) are often used for tableting purposes. Similar types of solid compositions can also be used in the form of soft and hard-filled gelatin capsules. Therefore, non-limiting examples of excipients also include lactose or milk sugar and high molecular weight polyethylene glycol. When oral administration of aqueous suspensions or elixirs is required, the active compounds therein can be combined with various sweeteners or flavorings, colorants or dyes, and, if necessary, emulsifiers or suspending agents, as well as with other excipients (such as water, ethanol, propylene glycol, glycerin, or combinations thereof).

[0636] Examples of excipients also include pharmaceutically acceptable substances (such as wetting agents) or small amounts of auxiliary substances (such as wetting agents or emulsifiers, preservatives or buffers) that enhance the shelf life or effectiveness of the compound.

[0637] Unless otherwise indicated, as used herein, the term "treating" means reversing, alleviating, or suppressing the progression of a disease, disorder, or condition to which such term applies, or one or more symptoms of such a disease, disorder, or condition. Unless otherwise indicated, as used herein, the term "treatment" means therapeutic acts performed in accordance with the definition of "treating" just above.

[0638] As used herein, the terms “subject,” “individual,” or “patient” are used interchangeably and refer to any animal, including mammals. Mammals according to the invention include dogs, cats, cattle, goats, horses, sheep, pigs, rodents, rabbits, primates, humans, etc., and include unborn mammals. In one embodiment, humans are preferred subjects. Human subjects can be of any sex and at any developmental stage.

[0639] As used herein, the phrase “therapeutic effective amount” or “effective amount” refers to the amount of an active compound or agent that elicits a biological or medical response sought by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, individual, or human, said biological or medical response may include one or more of the following:

[0640] (1) Prevention of disease; for example, prevention of disease, condition or disorder in individuals who may be susceptible to disease, condition or disorder but have not yet experienced or shown the pathology or symptoms of disease;

[0641] (2) Suppressing disease; for example, suppressing the disease, condition, or disorder of an individual who is experiencing or exhibiting the pathology or symptoms of a disease, symptom, or disorder (i.e., curbing (or slowing down) the further development of the pathology or symptoms or both); and

[0642] (3) Improve disease; for example, improve the disease, condition or disorder of an individual who is experiencing or showing pathology or symptoms of disease, symptom or disorder (i.e., reverse the pathology or symptoms or both).

[0643] Salt

[0644] The term "pharmaceutically acceptable salt" refers to the compounds of the present invention, which are typically prepared by reacting a free base or free acid with a suitable organic or inorganic acid or a suitable organic or inorganic base, respectively, to provide a salt of the compounds of the present invention suitable for administration to a subject or patient.

[0645] Additionally, compounds of formula (I)-(X), (Ia)-(VIIa), and (Ib)-(VIIb) may also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts and may be used as intermediates for one or more of the following: 1) preparing compounds of formula (I)-(X), (Ia)-(VIIa), and (Ib)-(VIIb); 2) purifying compounds of formula (I)-(X), (Ia)-(VIIa), and (Ib)-(VIIb); 3) isolating enantiomers of compounds of formula (I)-(X), (Ia)-(VIIa), and (Ib)-(VIIb); or 4) isolating diastereomers of compounds of formula (I)-(X), (Ia)-(VIIa), and (Ib)-(VIIb).

[0646] Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include, but are not limited to, acetates, adipates, aspartates, benzoates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, borates, camphorsulfonates, citrates, cyclamates, ethanedisulfonates, ethanesulfonates, formates, fumarates, gluconate, glucuronide, glucuronide, hexafluorophosphates, phenacetin, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, hydroxyethanesulfonate, lactate, and apple salts. Salts, maleates, malonates, methanesulfonates, methyl sulfates, naphthylcarbamates, 2-naphthalenesulfonates, nicotinates, nitrates, orotates, oxalates, palmitates, dihydroxynaphthalates, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, gluconate, stearates, succinates, tannates, tartrates, toluenesulfonates, trifluoroacetates, 1,5-naphthalenedisulfonates, and xinofoate.

[0647] 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, diethanolamine, glycine, lithium, lysine, magnesium, meglumine, ethanolamine, piperazine, potassium, sodium, aminobutanetriol, and zinc salts.

[0648] It can also form half-salts of acids and bases, such as half-sulfates and half-calcium salts.

[0649] For a review of suitable salts, see Paulekun, GS et al., Trends in Active Pharmaceutical Ingredient Salt Selection Based on Analysis of the Orange Book Database, J. Med. Chem. 2007; 50(26), 6665-6672.

[0650] Pharmaceutically acceptable salts of the compounds of the present invention can be prepared by methods well known to those skilled in the art, including but not limited to the following procedures:

[0651] (i) Reacting the compound of the present invention with a desired acid or base;

[0652] (ii) Using a desired acid or base, remove the acid- or base-instantaneous protecting group from a suitable precursor of the compound of the present invention, or open the ring of a suitable cyclic precursor (e.g., a lactone or lactam); or

[0653] (iii) Converting one salt of the compounds of the present invention into another salt. This can be achieved by reacting with a suitable acid or base or by means of a suitable ion exchange procedure.

[0654] These procedures are typically carried out in solution. The resulting salt can be precipitated and collected by filtration, or it can be recovered by evaporating the solvent.

[0655] solvates

[0656] The compounds of the present invention and their pharmaceutically acceptable salts can exist in both non-solventized and solvated forms. The term "solvent" is used herein to describe molecular complexes comprising the compounds of the present invention or their pharmaceutically acceptable salts, and one or more pharmaceutically acceptable solvent molecules, such as ethanol. When the solvent is water, the term "hydrate" is used.

[0657] Additionally, compounds of formula (I)-(X), (Ia)-(VIIa), and (Ib)-(VIIb) may also include other solvates of such compounds, which are not necessarily pharmaceutically acceptable solvates and may be used as intermediates for one or more of the following: 1) preparing compounds of formula (I)-(X), (Ia)-(VIIa), and (Ib)-(VIIb); 2) purifying compounds of formula (I)-(X), (Ia)-(VIIa), and (Ib)-(VIIb); 3) isolating enantiomers of compounds of formula (I)-(X), (Ia)-(VIIa), and (Ib)-(VIIb); or 4) isolating diastereomers of compounds of formula (I)-(X), (Ia)-(VIIa), and (Ib)-(VIIb).

[0658] The currently accepted classification system for organic hydrates defines isolated site hydrates, channel hydrates, or metal ion coordination hydrates. See KR Morris. Polymorphism in Pharmaceutical Solids (HG Brittain, ed., Marcel Dekker, 1995). Isolated site hydrates are hydrates in which water molecules are separated from each other and do not directly contact each other by intercalation into organic molecules. In channel hydrates, water molecules are located in lattice channels adjacent to other water molecules. In metal ion coordination hydrates, water molecules are bonded to metal ions.

[0659] When solvent or water is tightly bound, the complex can have a well-defined stoichiometry independent of humidity. However, when solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content can depend on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

[0660] complex

[0661] The scope of this invention also includes multicomponent complexes (other than salts and solvates) in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. This type of complex includes cages (drug-host inclusion complexes) and cocrystals. The latter is generally defined as a crystalline complex of neutral molecular components bonded together by non-covalent interactions, for example, forming hydrogen-bonded complexes (cocrystals) with neutral molecules or with salts. Cocrystals can be prepared by melt crystallization, by recrystallization from an autosolvent, or by physically grinding the components together; see O. Almarsson and MJ Zaworotko, Chem Commun, 17, 1889-1896 (2004). For a general overview of multicomponent complexes, see Haleblian, J Pharm Sci, 64(8), 1269-1288 (August 1975).

[0662] solid form

[0663] The compounds of this invention can exist in a continuous solid form 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 exhibits physical properties that vary with temperature, either solid or liquid. Such materials typically do not produce distinctive X-ray diffraction patterns and, when exhibiting solid properties, are more formally described as liquids. Upon heating, a change from solid to liquid properties occurs, characterized by a change in state, typically a second-order change ("glass transition"). The term "crystalline" refers to a solid phase in which the material has a regularly ordered internal structure at the molecular level and produces a distinctive X-ray diffraction pattern with defined peaks. Such materials will also exhibit liquid properties upon sufficient heating, but the change from solid to liquid is characterized by a phase transition, typically a first-order change ("melting point").

[0664] The compounds of this invention can also exist in a mesocrystalline state (intermediate phase or liquid crystal) under suitable conditions. The mesocrystalline state lies between a truly crystalline state and a truly liquid state (melt or solution), and is composed of two-dimensional order at the molecular level. Mesocrystalline phenomena arising from temperature changes are described as "thermotropic," while those arising from the addition of a second component (such as water or another solvent) are described as "lyotropic." Compounds with the potential to form lyotropic interphases are described as "amphiphilic," and are characterized by ionicly polar head groups (such as -COO). - Na + -COO - K + or -SO3 - Na +) or nonionic polar head groups (such as -N) - N + The molecular composition of (CH3)3). For more information, see NH Hartshorne and A. Stuart, Crystals and the Polarizing Microscope, 4th edition (Edward Arnold, 1970).

[0665] Stereoisomers

[0666] The compounds of this invention can exist in two or more stereoisomers. The stereoisomers of the compounds may include cis and trans isomers (geometric isomers), optical isomers (such as... R and S Enantiomers, diastereomers, rotational isomers, rotationally blocked isomers, and conformational isomers. For example, compounds of the present invention containing one or more asymmetric carbon atoms can exist in two or more stereoisomers. Saturated rings can also exist in cis / trans isomers.

[0667] Pharmaceutically acceptable salts of the compounds of the present invention may also contain optically active counterions (e.g., d-lactate or l-lysine) or racemic counterions (e.g., dl-tartrate or dl-arginine).

[0668] Cis / trans isomers can be separated using conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0669] Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound (e.g., an alcohol, or, in the case of compounds of the present invention, a base or acid, such as 1-phenylethylamine or tartaric acid, if the compounds contain an acidic or basic moiety). The resulting diastereomeric mixture can be separated by chromatography, fractional crystallization, or by using both of the aforementioned techniques, and one or both of the diastereomeric isomers can be converted into one or both corresponding pure enantiomers in a manner well known to those skilled in the art. The chiral compounds of the present invention (and their chiral precursors) can be obtained in enantiomer-enriched form using chromatography (typically HPLC). The eluent is concentrated to obtain an enriched mixture. Chiral chromatography using subcritical and supercritical fluids can be employed. The methods for chiral chromatography used in some embodiments of the present invention are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pp. 223-249 and the references cited therein).

[0670] When any racemate crystallizes, two different types of crystals may occur. The first type is the racemic compound mentioned above (the true racemate), in which a homogeneous crystalline form containing equimolar amounts of the two enantiomers is produced. The second type is a racemic mixture or racemic stack, in which two crystalline forms each containing a single enantiomer are produced in equimolar amounts. Although the two crystalline forms present in a racemic mixture may have the same physical properties, their physical properties may differ from those of the true racemate. Racemic mixtures can be separated using conventional techniques known to those skilled in the art, see, for example, Stereochemistry of Organic Compounds, EL Eliel and SH Wilen (Wiley, 1994).

[0671] Tautomerism

[0672] Tautomerism (“tautomerism”) can occur when structural isomers can interconvert via low energy barriers. This can manifest as proton tautomerism in compounds of the present invention containing, for example, imino / amino, keto / enol, or oxime / nitroso, lactam / lactamimide, or as so-called valence tautomerism in compounds containing aromatic moieties. Therefore, a single compound can exhibit more than one type of isomerism.

[0673] It must be emphasized that, although for the sake of brevity the compounds of the present invention have been drawn in a single tautomer form herein, all possible tautomer forms are included within the scope of the present invention.

[0674] The tautomerism in the compounds of the present invention can be described as shown in the following structures.

[0675]

[0676] The dashed lines in the above structures represent tautomerisms in resonance form, which only depict the movement of electrons. Resonance is the presence of more than one form (within the same compound), which determines the actual structure of the compound.

[0677] structure:

[0678] Equivalent to and .

[0679] Having substituents

[0680] and The compounds of this invention are tautomers.

[0681] isotope

[0682] This invention includes all pharmaceutically acceptable isotopically labeled compounds of this invention, wherein one or more atoms are replaced with atoms having the same number of atoms, but with atomic masses or mass numbers different from those of the majority of atoms in nature.

[0683] Examples of isotopes suitable for inclusion in the compounds of the present invention may include isotopes of hydrogen, such as 2 H (D, deuterium) and 3 H (T, tritium); isotopes of carbon, such as 11 C 13 C and 14 C; isotopes of chlorine, such as 36 Cl; isotopes of fluorine, such as 18 F; isotopes of iodine, such as 123 I and125 I; isotopes of nitrogen, such as 13 N and 15 N; isotopes of oxygen, such as 15 O、 17 O and 18 O; isotopes of phosphorus, such as 32 P; and isotopes of sulfur, such as 35 S.

[0684] Certain isotopically labeled compounds of the present invention (e.g., compounds doped with radioactive isotopes) can be used in drug or substrate tissue distribution studies, or both. Radioactive isotopes (such as tritium and...) 14 C) It is particularly suitable for this purpose due to its ease of incorporation and simple detection method. Positron-emitting isotopes (such as...) 11 C 18 F, 15 O and 13 (N) substitution can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Deuterium substitution can yield certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dose requirement, decreased CYP450 inhibition (competitive or time-dependent), or improved therapeutic index or tolerability.

[0685] In some embodiments, this disclosure provides deuterium-labeled (or deuterated) compounds and salts, wherein the chemical formulas and variables of such compounds and salts are each independently as described herein. “Deuterated” means that at least one of the atoms in the compound is deuterium, with an abundance greater than the natural abundance of deuterium (typically about 0.015%). Those skilled in the art will recognize that in compounds containing hydrogen atoms, the hydrogen atom effectively represents a mixture of H and D, where about 0.015% is D. The deuterium concentration in the deuterium-labeled compounds and salts of the present invention can be defined by a deuterium enrichment factor. It should be understood that one or more deuterium atoms can exchange with hydrogen under physiological conditions.

[0686] In some embodiments, one or more hydrogen atoms at certain metabolic sites on the compounds of the present invention are deuterated. Certain metabolic sites on the compounds of the present invention are described below.

[0687]

[0688] In some embodiments, the deuterium compound is selected from any of the compounds shown in the examples section set forth in Tables 1-12.

[0689] Table 1

[0690]

[0691]

[0692] Table 2

[0693]

[0694]

[0695] Table 3

[0696]

[0697]

[0698] Table 4

[0699]

[0700]

[0701] Table 5

[0702]

[0703]

[0704] Table 6

[0705]

[0706]

[0707] Table 7

[0708]

[0709]

[0710] Table 8

[0711]

[0712]

[0713] Table 9

[0714]

[0715]

[0716] Table 10

[0717]

[0718]

[0719] Table 11

[0720]

[0721]

[0722] Table 12

[0723]

[0724]

[0725] Table 13

[0726]

[0727]

[0728] The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described in the accompanying examples and preparations, using appropriate isotopically labeled reagents instead of previously used unlabeled reagents.

[0729] Pharmaceutically acceptable solvates according to the invention include solvates in which the solvent in which crystallization occurs can be isotopically substituted, such as D2O, d6-acetone, d6-DMSO.

[0730] prodrug

[0731] The compounds of the present invention can be administered in prodrug form. Therefore, certain derivatives of the compounds of the present invention, which may themselves have little or no pharmacological activity, can be converted into the compounds of the present invention having the desired activity, for example, through hydrolytic cleavage, particularly hydrolytic cleavage promoted by esterases or peptidases, when administered in vivo or to the body. Such derivatives are called “prodrugs”. Further information on the use of prodrugs can be found in “The Expanding Role of Prodrugs in Contemporary Drug Design and Development”, Nature Reviews DrugDiscovery, 17, 559-587 (2018) (J. Rautio et al.).

[0732] The prodrug according to the invention can be produced, for example, by replacing suitable functional groups present in the compounds of the invention with certain portions known to those skilled in the art as “proparts” (e.g., as described in H. Bundgaard’s “Design of Prodrugs” (Elsevier, 1985)).

[0733] Therefore, the prodrug according to the present invention can be (a) an ester or amide derivative of a carboxylic acid when present in the compound of the present invention; (b) an ester, carbonate, carbamate, phosphate ester or ether derivative of a hydroxyl group when present in the compound of the present invention; or (c) an amide, imine, carbamate or amine derivative of an amino group when present in the compound of the present invention.

[0734] Some specific examples of the prodrug according to the present invention include:

[0735] (i) When the compounds of the present invention contain a carboxylic acid functional group (-COOH), their esters, such as those in which the hydrogen of the carboxylic acid functional group of the compound is substituted with a C1-C8 alkyl group (e.g., ethyl) or (C1-C8 alkyl)C(=O)OCH2- (e.g. t Compounds substituted with BuC(=O)OCH2-);

[0736] (ii) When the compounds of the present invention contain an alcohol functional group (-OH), their esters, such as compounds in which the hydrogen of the alcohol functional group of the compound is replaced by -CO (C1-C8 alkyl) (e.g., methyl carbonyl) or the alcohol is esterified by an amino acid;

[0737] (iii) When the compounds of the present invention contain an alcohol functional group (-OH), their ethers, such as compounds in which the hydrogen of the alcohol functional group of the compound is replaced by (C1-C8 alkyl)C(=O)OCH2- or -CH2OP(=O)(OH)2;

[0738] (iv) When the compounds of the present invention contain an alcohol functional group (-OH), their phosphate esters, such as those in which the hydrogen of the alcohol functional group of the compound is via -P(=O)(OH)2 or -P(=O)(O - Na + )2 or -P(=O)(O - )2Ca 2+ Displaced compounds;

[0739] (v) When the compounds of the present invention contain a primary or secondary amino functional group (-NH2 or -NHR, where R ≠ H), its amide, for example, wherein, depending on the specific case, one or both hydrogens of the amino functional group of the compound are via (C1-C2) hydroxyl groups. 10 Compounds derived from amino acids by substitution of alkyl acyl groups, -COCH2NH2 groups, or amino groups;

[0740] (vi) When the compounds of the present invention contain a primary or secondary amino functional group (-NH2 or -NHR, where R≠H), their amines, for example, are compounds in which, depending on the specific case, one or both hydrogens of the amino functional group of the compound are replaced by -CH2OP(=O)(OH)2.

[0741] Some of the compounds of this invention can themselves act as prodrugs for other compounds of this invention. Two compounds of this invention can also be combined together as prodrugs. In some cases, prodrugs of the compounds of this invention can be generated by internally linking two functional groups in the compounds of this invention, for example, by forming a lactone.

[0742] Pharmaceutical Composition

[0743] In another embodiment, the present invention comprises a pharmaceutical composition. For the purposes of a pharmaceutical composition, the compound itself or a pharmaceutically acceptable salt thereof will be simply referred to as the compound of the present invention.

[0744] The compositions of the present invention can be in a variety of forms. These forms include, for example, semi-solid and solid dosage forms, such as dispersions or suspensions, tablets, capsules, and pills. The form depends on the intended method of administration and therapeutic application.

[0745] Oral administration of solid dosage forms can be, for example, in discrete units such as hard or soft capsules, pills, sachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention. In such solid dosage forms, the compound of the present invention is typically combined with one or more excipients. Such capsules or tablets may contain controlled-release formulations. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer or may be prepared with an enteric coating.

[0746] Other excipients and administration methods known in pharmaceutical technology may also be used. The pharmaceutical compositions of the present invention can be prepared by any of the well-known pharmaceutical techniques, such as efficient formulation and administration procedures. The considerations above regarding efficient formulation and administration procedures are well known in the art and described in standard textbooks. Pharmaceutical formulations are discussed, for example, by Ansel, Howard C. et al. Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems . Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al. Remington: The Science and Practice of Pharmacy . Philadelphia: Lippincott, Williams & Wilkins, 2000; Rowe, Raymond C. Handbook of Pharmaceutical Excipients Chicago, Pharmaceutical Press, 2005; eds. Stahl, P. Heinrich and Camilli G. Wermuth. Handbook of Pharmaceutical Salts: Properties, Selection, and UseNew York: Wiley-VCH, 2011; and Brittany, Harry G., eds. Polymorphism in Pharmaceutical Solids . New York: Informa Healthcare USA, Inc., 2016.

[0747] Acceptable excipients are non-toxic to subjects at the doses and concentrations used and may contain 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 octadecyl dimethylbenzyl ammonium chloride, hexamethylammonium chloride, benzalkonium chloride, benzyl chloride, phenol, butanol, or benzyl alcohol; 5) alkyl p-hydroxybenzoates, such as methyl or propyl p-hydroxybenzoate, catechol, resorcinol, cyclohexanol, 3-pentanol, or m-cresol; 6) low molecular weight (less than about 10 residues) peptides; 7) proteins, such as serum albumin, etc. 8) Gels or immunoglobulins; 9) Hydrophilic polymers, such as polyvinylpyrrolidone; 10) Amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; 11) Monosaccharides, disaccharides, or other carbohydrates, including glucose, mannose, or dextrin; 12) Chelating agents, such as EDTA; 13) Sugars, such as sucrose, mannitol, trehalose, or sorbitol; 14) Salt-forming counterions, such as sodium, metal complexes (e.g., Zn-protein complexes); or 15) Nonionic surfactants, such as polysorbates (e.g., polysorbate 20 or polysorbate 80), poloxamer, or polyethylene glycol (PEG).

[0748] For oral administration, the composition may be provided in tablet or capsule form 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 mg of the active ingredient for symptomatic dose adjustment to the patient. The drug typically contains about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, about 1 mg to about 100 mg of the active ingredient. Dosage regimens may vary depending on the route of administration, duration of administration, use of a fixed dose, body surface area, or weight-based administration. For example, for weight-based administration, the intravenous dose may be in the range of about 0.01 to about 10 mg / kg / min during a constant rate infusion.

[0749] Liposomes containing the compounds of the present invention can be prepared by methods known in the art (see, for example, Chang, HI; Yeh, MK; Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy; Int J Nanomedicine 2012; 7; 49-60). Particularly useful liposomes can be produced by reverse-phase evaporation using a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derived phosphatidylethanolamine (PEG-PE). The liposomes are extruded through a filter with pore size defined to produce liposomes of the desired diameter.

[0750] The compounds of the present invention can also be embedded in microcapsules (e.g., hydroxymethyl cellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively) prepared by, for example, cohesive techniques or interfacial polymerization, colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th edition, Mack Publishing (2000).

[0751] Sustained-release formulations can be used. Suitable examples of sustained-release formulations include semi-permeable matrices of solid hydrophobic polymers containing the compounds of the present invention, said matrices being in the form of molded articles, such as membranes or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactic acid, copolymers of L-glutamic acid and 7-ethyl-L-glutamic acid ester, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers (such as copolymers in leuprolide acetate used in reservoir-type suspensions) (injectable microspheres composed of lactic acid-glycolic acid copolymers and leuprolide acetate), sucrose isobutyrate acetate, and poly-D-(-)-3-hydroxybutyric acid.

[0752] Pharmaceutical intermediates (DPIs) are partially processed materials that must undergo further processing steps before becoming drug substances. The compounds of the present invention can be formulated as pharmaceutical intermediates (DPIs) containing the active ingredient in a form with a higher free energy compared to its crystalline form. One reason for using DPIs is to improve oral absorption characteristics attributable to low solubility, slow dissolution, increased transport through the mucous layer adjacent to epithelial cells, and in some cases, limitations imposed by biological barriers such as metabolic and transport proteins. Other reasons may include improved solid-state stability and downstream prepareability. In one embodiment, the pharmaceutical intermediate contains the compound of the present invention, separated and stable in an amorphous form (e.g., an amorphous solid dispersion (ASD)). Many techniques for preparing ASDs are known in the art, producing materials suitable for integration into drug substances, such as spray-dried dispersions (SDDs), melt extrusions (commonly referred to as HMEs), coprecipitates, amorphous drug nanoparticles, and nanoadsorbents. In one embodiment, the amorphous solid dispersion comprises the compound of the present invention and a polymeric excipient. Other excipients and the concentrations of said excipients and the compound of the present invention are well known in the art and described in standard textbooks. See, for example, Navnit Shah et al.'s " Amorphous Solid Dispersions Theory and Practice ".

[0753] Application and administration

[0754] Typically, the compounds of the present invention are administered in amounts effective in treating the conditions described herein. The compounds of the present invention may be administered either as the compound itself or as pharmaceutically acceptable salts. For purposes of administration and delivery, the compound itself or its pharmaceutically acceptable salts will be simply referred to as the compounds of the present invention.

[0755] The compounds of the present invention are administered via any suitable route, in the form of a pharmaceutical composition suitable for such a route, and at a dose that effectively achieves the intended therapeutic effect.

[0756] The compounds of the present invention can be administered orally. Oral administration may involve swallowing, allowing the compound to enter the gastrointestinal tract, or it may be administered sublingually or by dispensing, thereby allowing the compound to enter the bloodstream directly from the mouth.

[0757] The dosing regimens of the compounds of the present invention or compositions containing said compounds are based on various factors, including patient type, age, weight, sex, and medical condition; severity of condition; route of administration; and activity of the specific compound used. Therefore, dosing regimens can vary widely. In one embodiment, the total daily dose of the compounds of the present invention is typically from about 0.01 to about 100 mg / kg (i.e., mg of the compounds of the present invention per kg of body weight) for the treatment of the specified condition discussed herein. In another embodiment, the total daily dose of the compounds of the present invention is from about 0.1 to about 50 mg / kg, and in yet another embodiment, from about 0.5 to about 30 mg / kg. It is not uncommon for the compounds of the present invention to be repeatedly administered multiple times a day (typically not exceeding four times). Where necessary, multiple daily doses can typically be used to increase the total daily dose.

[0758] Treatment methods and uses

[0759] The compounds of this invention act as inhibitors of MYST family lysine acetyltransferases (KAT) and can be used to treat abnormal cell growth, such as cancer. In particular, such compounds act as inhibitors of KAT6 and / or KAT7.

[0760] References to methods of treatment using the therapies described in this specification should be interpreted as also referring to one or more compounds, pharmaceutical compositions, and drugs of the present invention used in said methods, including drugs used in the preparation of said methods.

[0761] Unless otherwise indicated, “abnormal cell growth” or “cancer” as used herein refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes abnormal growth of: (1) tumor cells (tumors) that proliferate by expressing mutant tyrosine kinases or overexpressing receptor tyrosine kinases; (2) benign and malignant cells of other proliferative disorders with abnormal tyrosine kinase activation; (3) any tumor that proliferates by receptor tyrosine kinases; (4) any tumor that proliferates by abnormal serine / threonine kinase activation; (5) benign and malignant cells of other proliferative disorders with abnormal serine / threonine kinase activation; (6) any tumor that proliferates by abnormal signal transduction, metabolism, epigenetics, and transcriptional mechanisms; and (7) benign and malignant cells of other proliferative disorders with abnormal signal transduction, metabolism, epigenetics, and transcriptional mechanisms.

[0762] For convenience, certain well-known abbreviations may be used in this article, including: estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-), non-small cell lung cancer (NSCLC), and castration-resistant prostate cancer (CRPC).

[0763] Another implementation method relates to a method of treating cancer in a subject in need, which includes administering to the subject an amount of the compound described herein that is effective in treating cancer.

[0764] In another implementation, the cancer is selected from the group consisting of: lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, liver cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, hematologic malignancies, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) sarcoma, primary CNS lymphoma, spinal axis tumors, glioblastoma, brainstem glioma, and pituitary adenoma, or a combination of two or more of the aforementioned cancers.

[0765] In another implementation, the cancer is breast cancer, lung cancer, colon cancer, brain cancer, prostate cancer, stomach cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.

[0766] In another implementation, the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

[0767] In another implementation, the cancer is breast cancer.

[0768] In another implementation, the breast cancer is ER+ breast cancer.

[0769] In another implementation, the breast cancer is ER+ HER2- breast cancer.

[0770] In another implementation, the breast cancer is locally advanced or metastatic ER+ HER2- breast cancer.

[0771] In another implementation, the lung cancer is non-small cell lung cancer.

[0772] In another implementation, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0773] In another implementation, the prostate cancer is castration-resistant prostate cancer.

[0774] In another implementation, the prostate cancer is locally advanced or metastatic castration-resistant prostate cancer.

[0775] Other implementation methods relate to methods of treating hematologic malignancies in subjects. Some implementation methods relate to treating hematologic malignancies in subjects in need, which includes administering to the subject an amount of the compound described herein that is effective in treating the hematologic malignancy.

[0776] In another implementation, the hematologic malignancy is leukemia, lymphoma, or multiple myeloma.

[0777] In another implementation, the hematologic malignancy is leukemia or lymphoma.

[0778] Another implementation involves a method of treating a patient’s cancer, which includes administering to the patient an effective amount of the compound described herein in combination with an antitumor agent selected from the group consisting of: mitosis inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxic agents, antihormones, and antiandrogens.

[0779] Further embodiments involve pharmaceutical compositions for treating cancer in patients, comprising an amount of the compounds described herein and a pharmaceutically acceptable carrier that is effective in treating cancer.

[0780] Further embodiments relate to methods for treating angiogenesis-related disorders in patients (including humans), comprising administering to the patient an amount effective for treating the disorder of a compound as defined above, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with one or more of the antitumor agents listed above. Such barriers include cancerous tumors, such as melanoma; ocular disorders, such as age-related macular degeneration, presumed ocular histoplasmosis syndrome, and retinal neovascularization due to proliferative diabetic retinopathy; rheumatoid arthritis; bone loss disorders, such as osteoporosis, Paget's disease, humoral hypercalcemia due to malignant tumors, hypercalcemia due to tumor metastasis to bone, and osteoporosis induced by glucocorticoid therapy; coronary restenosis; and certain microbial infections, including infections associated with microbial pathogens selected from adenoviruses, hantaviruses, Borrelia burgdorferi, Yersinia spp., Bordetella pertussis, and Group A streptococci.

[0781] Some implementations relate to methods (and pharmaceutical compositions) for treating a patient’s cancer, comprising an amount of the compound described herein or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and an amount of one or more substances selected from anti-angiogenic agents, signal transduction inhibitors (e.g., inhibiting the way regulatory molecules that control essential processes of cell growth, differentiation, and survival communicate within the cell), and antiproliferative agents, said amounts together effectively treating said abnormal cell growth.

[0782] Anti-angiogenic agents, such as matrix metalloproteinase 2 (MMP-2) inhibitors, matrix metalloproteinase 9 (MMP-9) inhibitors, and cyclooxygenase II (COX-II) inhibitors, may be used in combination with the methods described herein and the compounds described herein in pharmaceutical compositions.

[0783] Tyrosine kinase inhibitors can also be combined with the compounds described herein.

[0784] VEGF inhibitors, such as sutent and axitinib, can also be combined with the compounds described herein.

[0785] ErbB2 receptor inhibitors can be administered in combination with the compounds described herein. Various other compounds, such as styrene derivatives, have also been shown to possess tyrosine kinase inhibitory properties, and some tyrosine kinase inhibitors have been identified as ErbB2 receptor inhibitors.

[0786] Epidermal growth factor receptor (EGFR) inhibitors can be administered in combination with the compounds of this invention.

[0787] PI3K inhibitors, such as PI3Kα or PI3Kβ inhibitors, can be administered in combination with the compounds of the present invention.

[0788] Mammalian target of rapamycin (mTOR) inhibitors can be administered in combination with the compounds of this invention.

[0789] c-MeT inhibitors can be administered in combination with the compounds of this invention.

[0790] CDK inhibitors can be administered in combination with the compounds of this invention.

[0791] MEK inhibitors can be administered in combination with the compounds of this invention.

[0792] PARP inhibitors can be administered in combination with the compounds of this invention.

[0793] JAK inhibitors can be administered in combination with the compounds of this invention.

[0794] Antagonists of programmed death receptor 1 (PD-1) protein can be administered in combination with the compounds of this invention.

[0795] Antagonists of programmed death receptor ligand 1 (PD-L1) can be administered in combination with the compounds of the present invention.

[0796] Other antiproliferative agents that can be used with the compounds described herein include inhibitors of enzymatic farnesyl protein transferase and receptor tyrosine kinase PDGFr.

[0797] The compounds described herein may also be used in conjunction with other agents that can be used to treat abnormal cell growth or cancer, including but not limited to agents that can enhance antitumor immune responses, such as cytotoxic lymphocyte antigen 4 (CTLA4) antibodies and other agents that can block CTLA4; and antiproliferative agents, such as other farnesyl protein transferase inhibitors, for example, farnesyl protein transferases.

[0798] The compounds described herein may be administered as a sole therapy or may involve one or more other antitumor substances, such as those selected from the following: mitosis inhibitors, alkylating agents, antimetabolites, growth factor inhibitors, cell cycle inhibitors, embedded antibiotics, enzymes, and antihormones.

[0799] The compounds described herein can be used alone or in combination with one or more of a variety of anticancer agents or supportive care agents. For example, the compounds described herein can be used with cytotoxic agents. Some embodiments also cover the use of the compounds described herein in combination with hormone therapy. Furthermore, some embodiments provide the compounds described herein alone or in combination with one or more supportive care products, such as those selected from the group consisting of: Filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or combinations thereof. Such combination therapy can be achieved by administering the individual components of the treatment simultaneously, sequentially, or separately.

[0800] The compounds described herein can be used with the following: antitumor agents, alkylating agents, antimetabolites, antibiotics, plant-derived antitumor agents, camptothecin derivatives, tyrosine kinase inhibitors, antibodies, interferons, and / or biological response modifiers. In this regard, the following is a non-limiting list of examples of second agents that can be used with the compounds described herein.

[0801] Co-application

[0802] The compounds of the present invention can be used alone or in combination with one or more other therapeutic agents. The present invention provides any of the uses, methods, or compositions as defined herein, wherein the compounds of the present invention or pharmaceutically acceptable salts thereof are used in combination with one or more other therapeutic agents discussed herein.

[0803] "Combined" administration of two or more compounds refers to the administration of all compounds at sufficiently close temporal proximity to achieve therapeutic effect on the subject. Depending on the treatment regimen, two or more compounds may be administered simultaneously or sequentially via the same or different routes of administration, with or without specific time constraints. Simultaneous administration can also be achieved by mixing the compounds prior to administration or by administering the compounds as a single dosage form at the same time point but at the same or different sites of administration. Examples of "combined" administration include, but are not limited to, "parallel administration," "co-administration," "simultaneous administration," "sequential administration," and "administered simultaneously."

[0804] The compounds of the present invention and one or more other therapeutic agents can be administered in fixed or non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of the compound of the present invention or a pharmaceutically acceptable salt thereof and one or more therapeutic agents to a subject in a single composition or dose. The term "non-fixed combination" refers to the formulation of the compound of the present invention or a pharmaceutically acceptable salt thereof and one or more therapeutic agents as a single composition or dose, such that they can be administered simultaneously or at different times at variable time intervals to a subject in need, wherein such administration provides an effective amount of two or more compounds in the subject.

[0805] These agents and the compounds of the present invention can be combined with pharmaceutically acceptable media, such as saline, Ringer's solution, dextran solution, etc. Specific dosage regimens, i.e., dosage, timing, and repetition, will be determined based on the specific individual and that individual's medical history.

[0806] Reagent test kit

[0807] 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. In addition to the compounds of the present invention or pharmaceutical compositions thereof, the kit may also comprise diagnostic or therapeutic agents. The kit may also comprise instructions for use for diagnostic or therapeutic methods. In some embodiments, the kit comprises a compound or pharmaceutical composition thereof and a diagnostic agent.

[0808] In yet another embodiment, the invention comprises a kit suitable for performing the treatment methods described herein. In one embodiment, the kit comprises a first dosage form containing one or more of the compounds of the invention in an amount sufficient to perform the methods of the invention. In another embodiment, the kit comprises one or more of the compounds of the invention in an amount sufficient to perform the methods of the invention and a container for dosing.

[0809] Synthesis method

[0810] The compounds of this invention can be synthesized via synthetic routes including methods similar to those well known in chemical techniques, particularly according to the description contained herein. Starting materials are generally available from commercial sources or can be prepared using methods well known to those skilled in the art. Many of the compounds used herein are related to or can be derived from compounds of general scientific significance or previously identified as meeting commercial needs. Therefore, such compounds can be one or more of the following: 1) commercially available; 2) reported in the literature; or 3) prepared by those skilled in the art from other generally available substances using materials reported in the literature.

[0811] For illustrative purposes, the reaction schemes described below provide possible pathways for synthesizing the compounds of the present invention and key intermediates. For a more detailed description of individual reaction steps, see the Examples section below. Those skilled in the art will understand that other synthetic routes can also be used to synthesize the compounds of the present invention. While specific starting materials and reagents are discussed below, other starting materials and reagents can be substituted to provide one or more of a variety of derivatives or reaction conditions. Furthermore, many compounds prepared by the methods described below can be further modified according to this disclosure using conventional chemical methods well known to those skilled in the art.

[0812] Those skilled in the art will understand that the experimental conditions described in the following schemes illustrate suitable conditions for achieving the illustrated transformations, and that it may be necessary or desirable to modify the precise conditions used to prepare the compounds of the present invention. It should be further understood that transformations may need to be performed in a different order than that described in the schemes, or one or more transformations may be modified, to provide the desired compounds of the present invention.

[0813] When preparing the compounds of the present invention, it should be noted that some methods suitable for preparing the compounds described herein may require protection of long-range functional groups (e.g., primary amines, secondary amines, carboxyl groups, etc., in the precursors of the compounds of the present invention). The need for such protection will vary depending on the nature of the long-range functional groups and the conditions of the preparation method. The need for such protection can be readily determined by those skilled in the art. The use of such protection / deprotection methods is also within the scope of the art. For a general description of protecting groups and their uses, see March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8th edition.

[0814] For example, if a compound contains amine or carboxylic acid functional groups, such functional groups (if not protected) may interfere with reactions at other sites on the molecule. Therefore, such functional groups can be protected with appropriate protecting groups (PGs), which can be removed in subsequent steps. Suitable protecting groups for amines and carboxylic acids include those commonly used in peptide synthesis (such as those for amines). N - tert-butoxycarbonyl (Boc), benzoxycarbonyl (Cbz), and 9-fluorenylmethoxycarbonyl (Fmoc), and lower alkyl or benzyl esters for carboxylic acids), wherein the protecting groups are generally not chemically reactive under the described reaction conditions and can generally be removed without chemically altering other functional groups in the compounds of the present invention.

[0815] General experimental details

[0816] In illustrating the invention and in the non-limiting embodiments and preparations set forth in the specification, as well as in the following general methods and approaches, reference may be made to the following abbreviations, definitions, and analytical procedures:

[0817] Unless otherwise stated, the materials were obtained from commercial suppliers and used without further purification. Removal of solvent under reduced pressure or concentration refers to the use of a B pump connected to a vacuum pump (3 mm Hg). Chi rotary evaporator distillation. The product obtained as a solid or high-boiling oil is dried under vacuum (1 mm Hg). The product is then distilled using a CombiFlash evaporator. ® (Teledyne ISCO), SP4 or Isolera TM (Biotage) purification system for silica gel chromatography. Unless otherwise indicated, all reactions are carried out under positive pressure of nitrogen or argon, or in anhydrous solvent at ambient temperature (unless otherwise specified) using a desiccator.

[0818] Analytical thin-layer chromatography was performed on glass-backed silica gel 60_F 254 plates (Analtech, 0.25 mm) with elution at an appropriate solvent ratio (v / v). The reaction was analyzed by high-performance liquid chromatography-mass spectrometry (LCMS) or thin-layer chromatography (TLC), and termination was determined by the consumption of starting materials. The TLC plates were visualized by UV, anisaldehyde, phosphomolybdic acid, or iodine staining. Microwave-assisted reactions were performed using Biotage initiator.

[0819] Recorded on a Bruker XWIN-NMR (400 MHz) spectrometer 1 1H NMR spectroscopy. Proton resonances are reported in parts per million (ppm) at the low field of tetramethylsilane (TMS). 1 H NMR data are reported as multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; quintet; sept, heptet; dd, double doublet; ddd, double doublet; dt, double triplet; td, triple doublet; tt, triple triplet; dq, double quartet; qd, quartet; bs, broad singlet). Exchangeable protons were not consistently observed. In NMR spectra, "br" indicates a broad peak, and "m" indicates a multiplet. J "" refers to the coupling constant. For spectra obtained in CDCl3, DMSO-d6, and CD3OD, residual protons (7.27, 2.50, and 3.31 ppm, respectively) were used as internal references. The progress of the reaction and the purity of the products were measured using LCMS at wavelengths of 254 and 220 nm, as well as electrospray ionization (ESI) in positive mode or atmospheric pressure chemical ionization (APCI) in positive mode.

[0820] Purification instructions

[0821] All final compounds were purified to ≥95% purity. For most compounds, purity was determined by Agilent 1200 or 1260 series HPLC with simultaneous UV (220 nm and 254 nm) and TIC detection (APCI or ESI) linked to an Agilent 6120 or 6140 Quadrupole LC / MS, or by Shimadzu LC-20 HPLC with UV 220 nm detection, or by Agilent 1260 Infinity Hybrid HPLC / SFC with an Aurora A5 SFC control module, DAD, Leap PAL autosampler, and 6120 single quadrupole MS detection. Chiral purity was analyzed using chiral SFC analysis with the Agilent 1260 Infinity Hybrid HPLC / SFC and by screening multiple chiral columns.

[0822] abbreviation

[0823] Ab is absolute;

[0824] Ac represents the acetyl group;

[0825] ACN or CH3CN is acetonitrile;

[0826] AcOH is acetic acid;

[0827] approx. means approximately;

[0828] aq is an aqueous solution;

[0829] ArX is an aryl bromide, aryl chloride, or aryl iodine;

[0830] Boc is tert-butoxycarbonyl;

[0831] BPin is pinacol borate ester;

[0832] B2Pin2 is bis(pinacol) diboron;

[0833] ℃ is degrees Celsius;

[0834] cat is a catalyst;

[0835] CDCl3 is deuterated chloroform;

[0836] CN stands for cyano group;

[0837] δ represents the chemical shift;

[0838] D2O is deuterated water;

[0839] DABSO is a 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct;

[0840] DAST stands for diethylaminosulfur trifluoride;

[0841] DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene;

[0842] DCC is N,N-dicyclohexylcarbodiimide;

[0843] DCM stands for dichloromethane; methyl chloride.

[0844] DIEA is N,N-diisopropylethylamine;

[0845] DHP is dihydrogen-2 H -pyran;

[0846] DIAD stands for diisopropyl azodicarbonate.

[0847] DIPEA is N-ethyl diisopropylamine, also known as N,N-diisopropylethylamine;

[0848] DMA is dimethylacetamide;

[0849] DMAD stands for dimethyl ethynyl dicarboxylate.

[0850] DMAP is 4-(dimethylamino)pyridine;

[0851] DMB is 2,4-dimethoxybenzyl;

[0852] DMF is N,N-dimethylformamide;

[0853] DMSO stands for dimethyl sulfoxide.

[0854] DMSO- d 6 It is deuterated dimethyl sulfoxide;

[0855] DPPA stands for diphenyl azidophosphate.

[0856] Et is ethyl;

[0857] EtOAc is ethyl acetate;

[0858] EtOH is ethanol;

[0859] F / mol is the number of Faradays per mole;

[0860] g stands for grams;

[0861] HATU is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate;

[0862] As used in the scheme, Het(Ar) and Ar(Het) refer to heteroaryl or aryl, as defined in this specification and claims;

[0863] HFIP stands for hexafluoroisopropanol;

[0864] HPLC is high-performance liquid chromatography.

[0865] HSPMB is 4-methoxy-α-toluenethiol;

[0866] hr stands for hours;

[0867] L stands for liter;

[0868] LCMS stands for Liquid Chromatography-Mass Spectrometry.

[0869] LDA is lithium diisopropylamine;

[0870] LiHMDS is lithium hexamethyldisilazide (a type of lithium bis(trimethylsilane)amino).

[0871] M is the number of moles;

[0872] mA is milliampere or one-thousandth of an ampere;

[0873] MeOH is methanol;

[0874] mg stands for milligram;

[0875] MHz stands for megahertz;

[0876] MIDA stands for N-methyliminodiacetic acid;

[0877] min stands for minutes;

[0878] mL stands for milliliters;

[0879] mmol is millimole;

[0880] mol stands for mole;

[0881] MPa is megapascal;

[0882] MS (m / z) represents the mass spectrometry peak value;

[0883] MsOH is methanesulfonic acid;

[0884] MTBE is tert-butyl methyl ether;

[0885] NaOtPn is sodium 2-methylbut-2-ol;

[0886] n BuLi is n-butyllithium;

[0887] n -Bu2Mg is di-n-butylmagnesium;

[0888] NCS is N-chlorosuccinimide;

[0889] N / D was not determined;

[0890] NMR stands for Nuclear Magnetic Resonance spectroscopy.

[0891] Pd / C is palladium / carbon;

[0892] Pd2(dba)3 is tris(diphenylmethyleneacetone)dipalladium(0);

[0893] Pd(dppf)Cl2 is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II);

[0894] Pd(OAc)2 is palladium(II) acetate;

[0895] Pd(PPh3)4 is tetra(triphenylphosphine)palladium(0);

[0896] Pet ether is a petroleum ether, specifically a petroleum fraction composed of aliphatic hydrocarbons that boils in the range of 35-60°C.

[0897] PG is a protecting group;

[0898] pH is the power of hydrogen or the potential of hydrogen.

[0899] Ph3P is triphenylphosphine;

[0900] PMB is p-methoxybenzyl or 4-methoxybenzyl;

[0901] ppm stands for parts per million.

[0902] rt is room temperature;

[0903] R f The retention factor;

[0904] R t For retention period;

[0905] sat. means saturated;

[0906] SEM image shows 2-(trimethylsilyl)ethoxymethyl;

[0907] SEM-Cl is 2-(trimethylsilyl)ethoxymethyl chloride or [2-(chloromethoxy)ethyl](trimethyl)silane;

[0908] SFC stands for supercritical fluid chromatography.

[0909] SiO2 is silicon dioxide;

[0910] SM is the starting material;

[0911] STAB is sodium triacetoxyborohydride;

[0912] t Bu is tert-butyl;

[0913] TEA is triethylamine;

[0914] TFA stands for trifluoroacetic acid;

[0915] TFAA stands for trifluoroacetic anhydride;

[0916] THF stands for tetrahydrofuran;

[0917] THP stands for tetrahydropyran;

[0918] TLC is a thin-layer chromatography method.

[0919] TMPLi is lithium tetramethylpiperidine;

[0920] TMS consists of trimethylsilyl and tetramethylsilane;

[0921] Turbo grignard is a composite solution of isopropyl magnesium chloride and lithium chloride;

[0922] µL is a microliter;

[0923] µmol is a micromolar;

[0924] Xantphos is 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran; and

[0925] XPhos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0926] The embodiments described below are intended to provide a general description of methods for preparing the compounds of the present invention. Some of the compounds of the present invention contain one or two chiral centers. In the embodiments described below, the general methods for preparing the compounds are shown in racemic or enantiomer-rich forms. It will be apparent to those skilled in the art that all synthetic transformations can be carried out in a very similar manner, regardless of whether the material is enantiomer-rich or racemic. Furthermore, the resolution of the desired optically active material can be performed at any desired point in the sequence using well-known methods such as those described herein and in the chemical literature.

[0927] General Method

[0928] Unless otherwise stated, the variables in scheme IX have the same meaning as defined herein.

[0929] Option I:

[0930]

[0931] Option II:

[0932]

[0933] Option III:

[0934]

[0935] Option IV:

[0936]

[0937] Option V:

[0938]

[0939] Option VI:

[0940]

[0941] Option VII:

[0942]

[0943] Option VIII:

[0944]

[0945] Option IX:

[0946]

[0947] Option X:

[0948]

[0949] In some cases, the compounds described in schemes I-VIII may contain protecting groups, which can be added or removed by additional steps in the synthetic sequence using conditions known in the art (March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8th edition, or...). Protecting Groups (10 Georg Thieme Verlag, 1994). The compound at each step can be purified using standard techniques such as column chromatography, crystallization, or reversed-phase SFC or HPLC. Ring A, Ring B, R 1 R 2 R 3 R4 R 5 R 6 R 7 R 8 R 9 R 10 R 13 and R 14 As defined in the embodiments, schemes, examples and claims herein.

[0950] Example

[0951] To better understand the present invention, the following embodiments are described. These embodiments are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

[0952] The compounds and intermediates described below are named according to the naming conventions provided in ACD / Spectrus Processor 2019.1.1, S05S41; 2020.2.1.1, C25H41; or 2022.2.0, C45H41 (Advanced Chemistry Development, 8 King Street East, Suite 107, Toronto, Ontario, M5C 1B5, Canada). The naming conventions provided in ACD / Spectrus Processor 2019.1.1, S05S41; 2020.2.1.1, C25H41; or 2022.2.0, C45H41 are well known to those skilled in the art and are considered to generally conform to the recommendations of the International Union for Pure and Applied Chemistry (IUPAC) on organic chemistry nomenclature and the CAS indexing rules. Unless otherwise stated, all reactants were commercially available without further purification or prepared using methods known in the literature.

[0953] Preparation of synthetic intermediates

[0954] Intermediate A: 6-bromo-4-methoxy-1,2-benzoxazole-3-amine

[0955]

[0956] 4-Bromo-2-fluoro-6-methoxybenzonitrile (A1): Sodium methoxide (65 g, 360 mmol) was added aliquots to a cooled (0°C) solution of 100 g (459 mmol) of 4-bromo-2,6-difluorobenzonitrile in 1000 mL of THF. When the addition was complete, stirring was continued at room temperature (30°C) for 16 hours. The mixture was quenched with H2O (600 mL) and extracted with EtOAc (2 × 400 mL). The combined organic extracts were concentrated under reduced pressure, and the residue was recrystallized from DCM (100 mL) and petroleum ether (300 mL) to give A1 (64.5 g, 61%) as a white solid. 1 H NMR (400 MHz, chloroform-) d ) δ 7.10-6.99 (m, 1H), 6.99-6.93 (m, 1H), 3.98 (br s, 3H).

[0957] 6-Bromo-4-methoxy-1,2-benzoxazole-3-amine (intermediate A): 4-Bromo-2-fluoro-6-methoxybenzonitrile (A1) (26.0 g, 90 mmol) was obtained by heating at 60 °C. N A mixture of 20.4 g (271 mmol) of hydroxyacetamide and 1,1,3,3-tetramethylguanidine (62.5 g, 543 mmol) in ACN (240 mL) and H₂O (30 mL) was prepared for 16 hours. After cooling to room temperature, the solvent was removed under vacuum. H₂O (50 mL) was added to the residue, resulting in the formation of a white precipitate. The precipitate was collected by filtration and dried to give intermediate A (17.0 g, 77% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ7.32 (d, J =0.9 Hz, 1H), 6.91 (s, 1H), 6.05 (s, 2H), 3.93 (s, 3H).

[0958] Intermediate B: 6-bromo-5-methoxy-1,2-benzoxazole-3-amine

[0959]

[0960] 4-Bromo-2-fluoro-5-methoxybenzamide (B1): At room temperature (15°C), DIPEA (17.1 g, 133 mmol) was added to a solution of 4-bromo-2-fluoro-5-methoxybenzamide (11.0 g, 44.2 mmol) and ammonium chloride (3.58 g, 66.9 mmol) in DMF (100 mL). Next, HATU (25.2 g, 66.3 mmol) was added sequentially, slowly enough to maintain the internal temperature below 20°C. When the addition was complete, stirring was continued at room temperature (15°C) for two hours. The reaction mixture was poured into cold H2O (200 mL) with stirring to allow precipitation. The solid was collected by filtration, washed with H2O, and dried to give B1 (9.3 g, 85%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 7.75 (br s, 2H),7.67 (d, J =9.5 Hz, 1H), 7.31 (d, J =6.2 Hz, 1H), 3.87 (s, 3H).

[0961] 4-Bromo-2-fluoro-5-methoxybenzonitrile (B2): A suspension of 4-bromo-2-fluoro-5-methoxybenzoamide (B1) (9.3 g, 37.5 mmol) and TEA (11.4 g, 112 mmol) in DCM (180 mL) was treated dropwise with TFAA (11.8 g, 56 mmol) at 15 °C. The resulting clear solution was stirred at 15 °C for two hours. The mixture was poured into H2O (200 mL), the layers were separated, and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to give B2 (10 g, >100%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d ) δ 7.48 (d, J =7.8Hz, 1H), 7.04 (d, J =5.3 Hz, 1H), 3.92 (s, 3H).

[0962] 6-Bromo-5-methoxy-1,2-benzoxazol-3-amine (Intermediate B): At room temperature (20°C), 4-bromo-2-fluoro-5-methoxybenzonitrile (B2) (6.00 g, 23 mmol) and potassium carbonate (18.8 g, 136 mmol) were suspended in DMF (140 mL) and H2O (20 mL). Addition N5.11 g (68 mmol) of hydroxyacetamide was heated at 60 °C for three hours. After cooling to room temperature, the crude reaction mixture was poured into ice water (250 mL), and the precipitate was collected by filtration. The filter cake was washed with H₂O (50 mL) and dried to give the first product. The aqueous filtrate was extracted with EtOAc (2 × 100 mL). The combined organic extracts were washed with brine (3 × 50 mL), dried over sodium sulfate, concentrated, and the residue (900 mg) was recrystallized from 20 mL of 1:4 EtOAc / petroleum ether to give the second product. The two products were combined and dried under vacuum to give intermediate B (4.7 g, 85%) as a pale yellow solid. LCMS m / z 242.8 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6)δ 7.83 (s, 1H), 7.52 (s, 1H), 6.40 (s, 2H), 3.86 (s, 3H).

[0963] Intermediate C: 6-bromo-5-fluoro-4-methoxy-1,2-benzoxazole-3-amine

[0964]

[0965] 4-Bromo-2,3,6-Trifluorobenzaldehyde (C1): TMPLi (1 M, 1422 mmol, 1.42 L) was added dropwise to a solution of 1-bromo-2,3,5-trifluorobenzene (200 g, 948 mmol, 114 mL) in THF (2000 mL) at -65 °C, and the mixture was stirred at 25 °C for one hour. Then, DMF (83.2 g, 1.14 mol, 87.5 mL) was added dropwise at 25 °C, and the crude reaction mixture was stirred at 25 °C for one hour. LC-MS showed complete consumption of the starting material and formation of the desired product. The process was repeated, and the two batches were combined. The reactants were quenched with saturated NH4Cl (2000 mL) at 0–5 °C and adjusted to pH 5 with 2 N HCl aqueous solution. The aqueous layer was extracted with EtOAc (2000 mL × 2). The combined organic layers were washed with brine (2000 mL), dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by silica gel chromatography and eluted with petroleum ether-THF (1:0~97:3) to give C1 (158 g, 34%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d ) δ 10.21 (s,1H), 7.22-7.19 (m, 1H).

[0966] 4-Bromo-2,3,6-trifluorobenzonitrile (C2): Hydroxylamine-O-sulfonic acid (66.4 g, 588 mmol) was added to a solution of 4-bromo-2,3,6-trifluorobenzaldehyde (C1) (108 g, 452 mmol) in H2O (1000 mL), and the reaction mixture was stirred at 105 °C for four hours. TLC (petroleum ether-EtOAc = 10:1, R f =0.5) indicates complete consumption of the starting material. The reactants were extracted with EtOAc (1000 mL × 2). The combined organic layers were washed with brine (1000 mL), dried over MgSO4, filtered, and the filtrate was concentrated to give the crude product. TFAA (113.1 g, 539 mmol, 74.9 mL) was added to a solution of the crude product (114 g, 449 mmol) and TEA (136.2 g, 1.4 mol, 187 mL) in THF (1200 mL) at 0–5 °C, and the reaction mixture was then stirred at 25 °C for 2 h. TLC (petroleum ether-EtOAc = 10:1, R f =0.4) indicates complete consumption of the starting material. The reactants were added to H2O (1000 mL) and the aqueous layer was extracted with EtOAc (1000 mL × 2). The combined organic layers were washed with brine (1000 mL), dried over MgSO4, filtered, and the filtrate was concentrated to give the crude product. The crude product was combined with the crude product 4-bromo-2,3,6-trifluorobenzaldehyde (C1) (50 g, 209 mmol) from the previous experiment and purified by silica gel chromatography, eluting with petroleum ether-THF (1:0~98:2) to give C2 (115 g, 74% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-) d 6) δ 8.11-8.07 (m, 1H).

[0967] 4-Bromo-3,6-difluoro-2-methoxybenzonitrile (C3): Sodium methoxide (72 g, 400 mmol) was added dropwise to a solution of 4-bromo-2,3,6-trifluorobenzonitrile (C2) (94.3 g, 400 mmol) in methanol (1000 mL) at 0–5 °C, and the reaction mixture was stirred at 0–5 °C for one hour. LC-MS showed complete consumption of the starting material. The reaction mixture was added to H2O (1000 mL), and the aqueous layer was extracted with EtOAc (1000 mL × 2). The combined organic layers were washed with brine (1000 mL), dried over MgSO4, filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel chromatography and eluted with petroleum ether-THF (1:0–99:1) to give C3 (84.3 g, 85%) as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6) δ7.78 (dd, J =8.5, 4.9 Hz, 1H), 4.16 (d, J =3.4 Hz, 3H).

[0968] 6-Bromo-5-fluoro-4-methoxy-1,2-benzoxazol-3-amine (intermediate C): to 4-bromo-3,6-difluoro-2-methoxybenzonitrile (C3) (84.3 g, 340 mmol), N 1-Hydroxyacetamide (76.5 g, 1.02 mol) was added to a solution of DMF (800 mL) and H2O (100 mL) with K2CO3 (281.8 g, 2.04 mol), and the reaction mixture was stirred at 60 °C for two hours. LCMS showed complete consumption of the starting material and formation of the desired product. The reaction mixture was added to H2O (1000 mL) and extracted with EtOAc (1000 mL × 2). The combined organic layers were washed with brine (1000 mL), dried over MgSO4, filtered, and the filtrate was concentrated to give a crude product. The crude product was milled at 25 °C with petroleum ether-EtOAc = 10:1 (250 mL) for one hour. The mixture was filtered and the filter cake was washed with petroleum ether (20 mL × 2). The filter cake was collected and concentrated under reduced pressure to give intermediate C (53.5 g, 60%) as a grayish-white solid. LCMS m / z 261 / 263 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ7.58 (d, J =4.2 Hz, 1H), 6.19 (s, 2H), 4.10 (d,J =3.8 Hz, 3H).

[0969] Intermediate D: 3-Methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonyl chloride

[0970]

[0971] 3-Methoxy-5,6,7,8-Tetrahydronaphthalene-2-sulfonyl chloride (Intermediate D): Under nitrogen atmosphere, chlorosulfonic acid (338 mg, 0.22 mL, 3.33 mmol) was added dropwise to a cooled (0°C) solution of 6-methoxy-1,2,3,4-tetrahydronaphthalene (200 mg, 1.1 mmol) in DCM (3.0 mL). The solution was stirred at 0°C for 1 hour, during which time the color changed from gray to purple. The mixture was slowly poured into ice water and extracted with DCM (2 × 30 mL). The combined organic extracts were washed with H₂O (2 × 30 mL) and brine (30 mL), dried over sodium sulfate, filtered, and concentrated to give intermediate D (230 mg, 80%) as a white solid. 1 H NMR (400 MHz, chloroform-) d ) δ 7.65 (s, 1H), 6.79 (s, 1H), 4.01 (s, 3H), 2.84 (br s, 2H), 2.75 (br s, 2H), 1.82 (td, J =3.4, 6.4 Hz, 4H).

[0972] The sulfonyl chloride intermediates in Table 14 were prepared according to the general method for intermediate D.

[0973] Table 14

[0974]

[0975] Intermediate E: 2-ethoxy-4-methylbenzene-1-sulfonyl chloride

[0976]

[0977] 5-Bromo-2-ethoxy-4-methylbenzene-1-sulfonic acid (E1): 1-Bromo-4-ethoxy-2-methylbenzene (158 g, 732 mmol) was added dropwise to an ice-bath-cooled flask containing concentrated sulfuric acid (300 mL) over 10 minutes. The resulting light brown mixture was stirred overnight, and then quenched by adding crushed ice (750 mL) to form a white precipitate. The solid was collected by filtration and dried to give E1 (180 g, 83%) as a white solid.

[0978] 2-Ethoxy-4-methylbenzene-1-sulfonic acid (E2): A suspension of 5-bromo-2-ethoxy-4-methylbenzene-1-sulfonic acid (E1) (150 g, 508 mmol) and 10% Pd / C (27 g) in ethanol (1000 mL) was reacted overnight at 60 °C under 0.4 MPa hydrogen. The mixture was filtered through a powdered cellulose pad to remove solids, and the filtrate was concentrated to dryness, leaving E2 (96.6 g, 88%) as a white solid.

[0979] 2-Ethoxy-4-methylbenzene-1-sulfonyl chloride (Intermediate E): A flask containing 2-ethoxy-4-methylbenzene-1-sulfonic acid (E2) (46.2 g, 214 mmol) was cooled in an ice bath. Thionyl chloride (240 mL, 3.3 mol) and DMF (30 drops) were added over 30 minutes. The mixture was heated under reflux for two hours, followed by stirring overnight at room temperature. The mixture was concentrated to dryness, leaving intermediate E (33.6 g, 67%) as a white solid. GCMS m / z 234 M + ; 1 H NMR (400MHz, chloroform-) d ) δ 7.81 (d, J =8.5 Hz, 1H), 6.87-6.85 (m. 2H), 4.25 (q, J =7.0 Hz,2H), 2.44 (s, 3H), 1.54 (t, J =7.0 Hz, 3H).

[0980] Intermediate F: 2-ethoxy-6-methoxybenzene-1-sulfonyl chloride

[0981]

[0982] 2-(Benzylthio)-1-methoxy-3-(methoxymethoxy)benzene (F1): Under a dry nitrogen atmosphere, n-butyllithium (2.5 M THF solution, 17.8 mL, 44.6 mmol) was added dropwise to a cooled (0°C) solution of 1-methoxy-3-(methoxymethoxy)benzene (6.00 g, 35.7 mmol) in 150 mL of dry THF. After the addition was complete, stirring was continued at 0°C for one hour, followed by the addition of diphenylmethyl disulfide (10.5 g, 42.8 mmol). Stirring was continued at 0°C for two hours, followed by overnight at room temperature. The reactants were quenched with methanol, directly adsorbed onto silica gel, and purified by silica gel chromatography (eluting with petroleum ether containing 0-50% EtOAc) to give F1 (7.7 g, 74%) as a yellow oil. 1H NMR (400MHz, chloroform-) d ) δ 7.24-7.14 (m, 6H), 6.77 (d, J =8.3 Hz, 1H), 6.60 (d, J =8.3 Hz,1H), 5.09 (s, 2H), 4.02 (s, 2H), 3.85 (s, 3H), 3.44 (s, 3H).

[0983] 2-(Benzylthio)-3-methoxyphenol (F2): A solution of 2-(Benzylthio)-1-methoxy-3-(methoxymethoxy)benzene (F1) (7.70 g, 26.5 mmol) in acetone (330 mL) was treated with sodium iodide (4.77 g, 31.8 mmol) and stirred until completely dissolved. The solution was cooled to 0 °C, and then a solution of HCl in methanol (4.0 M dioxane solution, 166 mL, 664 mmol) was added dropwise. The turbid yellow mixture was stirred at 0 °C for 10 minutes, and then poured into a saturated aqueous solution of NaHCO3 (500 mL). Solid NaHCO3 was added until pH=7. The mixture was extracted with EtOAc (300 mL). The organic layer was washed with brine (200 mL), dried over sodium sulfate, and concentrated to give crude F2 (7.0 g, 100%) as a yellow oil. 1 H NMR (400 MHz, chloroform-) d ) δ 7.30-7.15 (m, 4H), 7.15-7.08 (m, 2H), 6.74 (s,1H), 6.57 (dd, J =1.1, 8.3 Hz, 1H), 6.47 (d, J =8.3 Hz, 1H), 3.88 (s, 2H), 3.87 (s, 3H).

[0984] 2-(Benzylthio)-1-ethoxy-3-methoxybenzene (F3): A solution of 2-(Benzylthio)-3-methoxyphenol (F2) (1.0 g, 3.78 mmol), iodoethane (807 mg, 5.18 mmol), and cesium carbonate (2.81 g, 8.63 mmol) in dry DMF (20.0 mL) was stirred at 80 °C for 16 hours. The mixture was poured into brine (30 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, concentrated, and purified by silica gel chromatography (eluting with petroleum ether containing 0–50% EtOAc) to give F3 (900 mg, 86%) as a pale yellow oil. LCMS m / z 275 [M+H] + ; 1 H NMR (400 MHz, chloroform-) d ) δ 7.26-7.10 (m, 6H), 6.52 (d, J =8.4 Hz, 2H), 4.07-3.98 (m, 4H), 3.85-3.77 (m, 3H), 1.44 (t, J =6.9 Hz, 3H).

[0985] 2-Ethoxy-6-methoxybenzene-1-sulfonyl chloride (intermediate F): Add to a cooled (0°C) solution of 2-(benzylthio)-1-ethoxy-3-methoxybenzene (F3) (900 mg, 3.28 mmol) in acetic acid (27 mL) and H2O (9.0 mL). N 1,4-chlorosuccinimide (482 mg, 3.61 mmol). Stirring was continued at 0°C for several minutes, followed by the addition of a second NCS (482 mg, 3.61 mmol), and the mixture was stirred at 20°C for 30 minutes, but no further conversion was observed. A third NCS (482 mg, 3.61 mmol) was added, and stirring continued at 15°C for 2.5 hours. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 (100 mL), and solid NaHCO3 was carefully added to alkalize the solution. The mixture was extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, concentrated, and immediately purified by silica gel chromatography (eluting with petroleum ether containing 0–50% EtOAc) to give intermediate F (700 mg, 85%) as a colorless oil, which solidified upon standing. The product was stored at 0°C to delay decomposition. 1 H NMR (400 MHz, chloroform-) d ) δ 7.53 (t,J =8.5 Hz, 1H), 6.65 (d, J =8.5 Hz, 2H), 4.73 (s, 1H), 4.22 (q, J =7.0 Hz, 2H), 3.99 (s,3H), 1.54 (t, J =7.0 Hz, 3H).

[0986] According to the general method for intermediate F, the sulfonyl chloride intermediates in Table 15 are prepared by using a specified alkyl halide instead of iodoethane in the ether formation step.

[0987] Table 15

[0988]

[0989] Intermediate G: 2-(2,2-difluoroethoxy)-4-methylbenzene-1-sulfonyl chloride

[0990]

[0991] 1-Bromo-2-(2,2-difluoroethoxy)-4-methylbenzene (G1): A mixture of 2-bromo-5-methylphenol (1.0 g, 5.3 mmol), 1,1-difluoro-2-iodoethane (2.0 g, 10.7 mmol), and potassium carbonate (2.2 g, 16 mmol) in DMF (10 mL) was heated at 80 °C for 16 hours. The mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give G1 (1.4 g, quantitative) as a brown solid. TLC (1 / 4 petroleum ether / EtOAc) R f 0.3.

[0992] 2-(2,2-Difluoroethoxy)-1-{[(4-methoxyphenyl)methyl]thio}-4-methylbenzene (G2): A solution of 1-bromo-2-(2,2-difluoroethoxy)-4-methylbenzene (G1) (700 mg, 2.8 mmol), Pd2(dba)3 (102 mg, 0.11 mmol), Xantphos (129 mg, 0.22 mmol), and (4-methoxyphenyl)methanethiol (1.3 g, 8.4 mmol) in dioxane (16 mL) was degassed and purged three times with nitrogen, followed by the addition of diisopropylamine (2.4 mL, 13.9 mmol). The crude reaction mixture was heated at 105 °C for 16 hours. The crude reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography and eluted with 0–40% EtOAc-petroleum ether to give G2 (400 mg, 44%) as a white solid. TLC (1 / 4 petroleum ether / EtOAc) R f 0.2; 1 H NMR (400 MHz, chloroform-) d ) δ 7.24-7.15 (m, 3H), 6.85-6.75 (m,3H), 6.69 (s, 1H), 6.35-5.96 (m, 1H), 4.23 (dt, J =4.3, 13.1 Hz, 2H), 4.04 (s, 2H), 3.80 (s, 3H), 2.42-2.26 (m, 3H).

[0993] 2-(2,2-Difluoroethoxy)-4-methylbenzene-1-sulfonyl chloride (intermediate G): Acetic acid (0.7 mL), H₂O (0.5 mL), and 1,3-dichloro-5,5-dimethyllactone (486 mg, 2.5 mmol) were added to a solution of 2-(2,2-difluoroethoxy)-1-{[(4-methoxyphenyl)methyl]thio}-4-methylbenzene (G₂) (400 mg, 1.2 mmol) in ACN (16 mL). The latter was added partically at 0 °C. After the addition, the crude reaction mixture was stirred at 0–10 °C for 1 hour. The crude reaction mixture was diluted with EtOAc (20 mL) and washed with sodium bicarbonate aqueous solution (5 mL) and brine (5 mL), dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel chromatography elution with 0-40% EtOAc-petroleum ether to give intermediate G (250 mg, 75%) as a white solid. TLC (1 / 2 EtOAc / petroleum ether) R f 0.1 relative to the starting material R f 0.3; 1H NMR (400 MHz, chloroform-) d ) δ 7.88 (d, J =8.3 Hz, 1H), 7.01 (d, J =8.3 Hz,1H), 6.92 (s, 1H), 6.38-6.08 (m, 1H), 4.41 (dt, J =4.3, 12.4 Hz, 2H), 2.49 (s, 3H).

[0994] The sulfonyl chloride intermediates in Table 16 were prepared according to the general method for intermediate G.

[0995] Table 16

[0996]

[0997] Intermediate H: 2-(cyclopropyloxy)-6-methoxybenzene-1-sulfonyl chloride

[0998]

[0999] 2-(Benzylthio)-1-(Cyclopropyloxy)-3-methoxybenzene (H1): A mixture of 2-(Benzylthio)-3-methoxyphenol (F2) (1.50 g, 6.09 mmol), potassium cyclopropyltrifluoroborate (2.30 g, 15.5 mmol), 1,10-phenanthroline (274 mg, 1.52 mmol), copper(II) acetate (277 mg, 1.52 mmol), and potassium carbonate (1.68 g, 12.2 mmol) in toluene (12.0 mL) and H2O (4.0 mL) was purged with oxygen and then stirred under an oxygen balloon at 70 °C for 16 hours. The mixture was diluted with EtOAc (50 mL) and the aqueous layer was separated. The organic layer was concentrated and purified by silica gel chromatography (eluting with petroleum ether containing 0-10% EtOAc) to obtain H1 (700 mg, 40%), which was a yellow oil. 1 H NMR (400 MHz, chloroform-) d ) δ 7.27-7.10 (m, 6H), 6.88 (dd, J =0.9, 8.3 Hz, 1H), 6.55 (d, J =8.6 Hz,1H), 3.95 (s, 2H), 3.83 (s, 3H), 3.71 (br d, J =3.1 Hz, 1H), 0.81-0.72 (m,2H), 0.72-0.63 (m, 2H).

[1000] 2-(cyclopropyloxy)-6-methoxybenzene-1-sulfonyl chloride (intermediate H): Intermediate H (700 mg, 85%) was prepared as a colorless oil using the same method as that used to convert G2 to intermediate G, and it solidified upon standing. 1 H NMR (400 MHz, chloroform-) d ) δ 7.61-7.51 (m, 1H), 7.05 (dd, J =0.9, 8.4 Hz, 1H), 6.68 (d, J =8.6 Hz, 1H), 4.73 (s, 1H), 4.04-3.96 (m, 3H), 3.96-3.88 (m, 1H), 0.99-0.83 (m, 4H).

[1001] Intermediate I: 3-(1,1 -difluoroethyl)-1 -[(4-methoxyphenyl)methyl]-1 H pyrazole-5-amine

[1002]

[1003] Heating at 80℃ E A mixture of potassium 1-cyano-3,3-difluorobut-1-en-2-ol (171 mg, 1.0 mmol) and (4-methoxybenzyl)hydrazine hydrochloride (225 mg, 1.00 mmol) in ethanol (3.3 mL) was prepared over six hours. The crude reaction mixture was analyzed by LCMS, yielding an approximately 3:2 mixture of isomers (R... t 1.2 min and R t 1.5 min). The crude reaction mixture was concentrated to a solid and partitioned between EtOAc and H2O. The EtOAc layer was washed with brine, dried over Na2SO4, filtered, and concentrated to an oil. The crude product was purified by silica gel chromatography and eluted with 0-100% EtOAc-heptane. The two isomers were separated on silica gel, and the isomer with R was isolated. t The 1.2-minute time-released pale amber oily isomer (189 mg, 71%). LCMS m / z 268 [M+H] + ; 1 H NMR (400 MHz, chloroform-) d ) δ 7.13 (d, J =8.6 Hz, 2H), 6.88 (d, J=8.6Hz, 2H), 5.75 (s, 1H), 5.17 (s, 2H), 3.80 (s, 3H), 3.39 (br s, 2H), 2.00 (t, J =18.4 Hz, 3 H).

[1004] Intermediate J: 5-(difluoromethoxy)-1-[(4-methoxyphenyl)methyl]-1 H -Pyrazole-3-amine

[1005]

[1006] 5-Hydroxy-1-[(4-Methoxyphenyl)methyl]-1 H 3-Pyrazole-3-carboxylic acid ethyl ester (J1): At room temperature, TEA (1.1 g, 11.0 mmol, 1.5 mL) was added to a mixture of butyryldiethyl 2-acetylglucosinolate (1.70 g, 10.0 mmol) and (4-methoxybenzyl)hydrazine (1.89 g, 10.0 mmol) in ethanol (20 mL). Two days later, LCMS yielded an 86:13 mixture of isomers (R). t 1.2 min (most of the time) and R t 1.4 min (small fraction)). The crude reaction mixture was concentrated and the crude product was partitioned between EtOAc and H2O. The EtOAc layer was washed with brine, dried over Na2SO4, filtered, and concentrated into an oil. The crude product was purified by silica gel chromatography (40 g) and eluted with 0-100% EtOAc-heptane to give J1 (1.5 g, 54%) as a white solid. LCMS m / z 277 [M+H] + .

[1007] 5-(difluoromethoxy)-1-[(4-methoxyphenyl)methyl]-1 H 5-Pyrazole-3-carboxylic acid ethyl ester (J2): Heated at 60°C. HA mixture of ethyl pyrazole-3-carboxylate (J1) (276 mg, 1.0 mmol) and sodium carbonate (116 mg, 1.1 mmol) in ACN (3.3 mL) was prepared. After 20 minutes, (bromodifluoromethyl)trimethylsilane (203 mg, 1.0 mmol, 155 µL) was added, and a white precipitate formed. LCMS of the crude reaction mixture showed a 36% conversion to the product. Further addition of (bromodifluoromethyl)trimethylsilane (203 mg, 1.0 mmol, 155 µL) was made, and after 45 minutes, a 57% conversion to the product was observed. Further addition of (bromodifluoromethyl)trimethylsilane (203 mg, 1.0 mmol, 155 µL) was made. After 15 minutes, the crude reaction mixture was cooled to room temperature and stirred overnight. LCMS analysis of the crude reaction mixture revealed approximately 11% of the starting material remaining, 61% of the product, and 27% of unknown byproducts. The crude reaction mixture was diluted with EtOAc and H2O. The EtOAc layer was washed with brine, dried over Na2SO4, filtered, and concentrated into an oil. The crude product was purified by silica gel chromatography (12 g) and eluted with 0-100% EtOAc-heptane to give J2 (176 mg, 54%) as a white solid. LCMS m / z 349 [M+Na] + ; 1 HNMR (400 MHz, chloroform- d ) δ 7.23 (d, J =8.8 Hz, 2H), 6.91-6.81 (m, 2H), 6.42 (s,1H), 6.61-6.15 (m, 1H), 5.25 (s, 2H), 4.41 (q, J =7.1 Hz, 2H), 3.79 (s, 3H)1.40 (t, J =7.1 Hz, 3H).

[1008] 5-(difluoromethoxy)-1-[(4-methoxyphenyl)methyl]-1 H -Pyrazole-3-carboxylic acid (J3): At room temperature, 5-(difluoromethoxy)-1-[(4-methoxyphenyl)methyl]-1 HA mixture of ethyl pyrazole-3-carboxylate (J2) (153 mg, 0.47 mmol) and lithium hydroxide hydrate (98.5 mg, 2.34 mmol) in methanol (1.56 mL) was stirred for 20 minutes, followed by heating at 60 °C. After one hour, LC-MS yielded no starting material and mainly the product. The crude reaction mixture was concentrated to a white solid and partitioned between EtOAc and a 1 N HCl aqueous solution (3 mL). The EtOAc layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give J3 (141 mg, quantified) as a white solid. LC-MS m / z 321 [M+Na] + ; 1 H NMR (400 MHz, chloroform-) d ) δ 7.24 (d, J =8.7 Hz, 2H), 6.91-6.84 (m, 2H), 6.66-6.23 (m, 2H), 5.25 (s, 2H), 3.80 (s, 3H).

[1009] {5-(difluoromethoxy)-1-[(4-methoxyphenyl)methyl]-1 H 3-pyrazole-3-yl}tert-butyl carbamate (J4): at room temperature, to 5-(difluoromethoxy)-1-[(4-methoxyphenyl)methyl]-1 H 3-Pyrazole-3-carboxylic acid (J3) (137 mg, 0.46 mmol) was suspended in toluene (1.53 mL) and TEA (51 mg, 0.5 mmol, 70 µL) was added. A paste formed and adhered to the side of the flask. Next, DPPA (139 mg, 0.50 mmol, 109 µL) was added and the mixture was heated at 90 °C for 16 hours. LCMS yielded a 2:1 mixture of urea and product. The crude reaction mixture was diluted with EtOAc and H2O. The EtOAc layer was washed with brine, dried over Na2SO4, filtered, and concentrated to an oil. The crude product was purified by silica gel chromatography (12 g) and eluted with 0–100% EtOAc-heptane to give J4 (36 mg, 22%) as a colorless oil. LCMS m / z 370 [M+H] + ; 1 HNMR (400 MHz, chloroform- d ) δ 7.49 (br s, 1H), 7.15 (d, J =8.7 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H), 6.66-6.26 (m, 1H), 6.22 (br s, 1H), 5.04 (s, 2H), 4.57-4.13 (m,1H), 3.78 (s, 3H), 1.49 (s, 9H).

[1010] 5-(difluoromethoxy)-1-[(4-methoxyphenyl)methyl]-1 H -Pyrazole-3-amine (intermediate J): Stirred at room temperature {5-(difluoromethoxy)-1-[(4-methoxyphenyl)methyl]-1 H A mixture of tert-butyl 3-pyrazole-3-yl)carbamate (J4) (36 mg, 0.10 mmol) and TFA (445 mg, 3.90 mmol, 0.3 mL) in DCM (0.3 mL) was prepared for five hours. The crude reaction mixture was concentrated into an oil (37 mg, quantified), and ¹H NMR revealed intermediate J as a TFA salt. 1 H NMR (400 MHz, chloroform-) d ) δ 7.23 (d, J =8.6 Hz, 2H), 6.93-6.81 (m, 2H), 6.73-6.35 (m,1H), 6.26 (br s, 3H), 5.30 (s, 1H), 4.99 (s, 2H), 3.80 (s, 3H).

[1011] Intermediate K: 5-(2,2-difluorocyclopropyl)-1-[(4-methoxyphenyl)methyl]-1 H -Pyrazole-3-amine

[1012]

[1013] 2,2-Difluorocyclopropane-1-carboxylate (K1): 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 837 mg, 5.5 mmol, 0.81 mL) was added to a solution of 2,2-difluorocyclopropane-1-carboxylic acid (610 mg, 5.0 mmol) in ACN (10.0 mL) at room temperature. The mixture was cooled in an ice-water bath, followed by the addition of iodobutane (1.0 g, 5.5 mmol, 0.63 mL). After two days, the reaction mixture was concentrated to give a solid. The solid was partitioned between EtOAc and H2O, and the EtOAc layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give K1 (499 mg, 56%) as an amber oil. 1 HNMR (400 MHz, chloroform- d) δ 4.16 (t, J =6.7 Hz, 2H), 2.45-2.41 (m, 1H), 2.11-2.03(m, 1H), 1.84-1.70 (m, 1H), 1.67-1.57 (m, 2H), 1.40 (dq, J =15.0, 7.4 Hz, 2H), 0.95 (t, J =7.4 Hz, 3H).

[1014] 3-(2,2-Difluorocyclopropyl)-3-oxopropionitrile (K2): A solution of butyl 2,2-difluorocyclopropane-1-carboxylate (K1) (342 mg, 1.92 mmol) and ACN (158 mg, 3.84 mmol, 0.158 mL) in THF (0.91 mL) was cooled to -70°C in a dry ice acetone bath. LDA (452 ​​mg, 4.22 mmol, 2.11 mL, 2.0 M) was added to the solution. A dark brown solution was formed. After 30 minutes, the crude reaction mixture was warmed to room temperature. A saturated aqueous solution of NH4Cl was added to the crude reaction mixture. The aqueous layer was partitioned between EtOAc and H2O, and the EtOAc layer was washed with brine, dried over Na2SO4, filtered, and concentrated into an oil. The crude product K2 was used in the next step.

[1015] 5-(2,2-Difluorocyclopropyl)-1-[(4-methoxyphenyl)methyl]-1 H 3-Pyrazole-3-amine (Intermediate K): Crude β-ketonitrile 3-(2,2-difluorocyclopropyl)-3-oxopropionitrile (K2) was dissolved in isopropanol (2.0 mL), and (4-methoxybenzyl)hydrazine (362 mg, 1.9 mmol) was added, followed by TEA (194 mg, 1.92 mmol, 0.27 mL). The mixture was heated at 60 °C for 4 hours and cooled to room temperature. The crude reaction mixture was concentrated to a solid. The solid was suspended in DCM and loaded onto a 5 g silica gel pre-column. LCMS of the solid confirmed it to be a TEA-HCl salt and discarded. The crude product was purified by silica gel chromatography (pre-column and 12 g silica gel column in tandem) and eluted with 0-100% EtOAc-heptane to give intermediate K (76 mg, 14%) as a yellow oil. LCMS m / z 280 [M+H] + ; 1 H NMR (400 MHz, chloroform-) d ) δ 7.11 (d, J=8.6 Hz,2H), 6.90-6.84 (m, 2H), 5.42 (d,J =1.1 Hz, 1H), 5.11 (s, 2H), 3.79 (s, 3H), 3.55-3.08 (m, 2H), 2.69 (td, J =12.2, 8.0 Hz, 1H), 1.83-1.74 (m, 1H), 1.70-1.62 (m, 1H).

[1016] According to the general method for intermediate K, the aminopyrazole intermediates in Table 17 are prepared using commercially available acids or esters and excess hydrazine or (4-methoxybenzyl)hydrazine in an alcohol solvent.

[1017] Table 17

[1018]

[1019] Intermediate L: 4-methyl-5,6-dihydro-4 H -pyrrolo[1,2- b ]Pyrazole-2-amine

[1020]

[1021] 5-(4-chlorobut-2-yl)-1 H -Pyrazole-3-amine (L1): Add 3-(3-amino-1-yl)pyrazole-3-amine to a round-bottom flask H 5-pyrazol-5-yl)but-1-ol (intermediate Kb) (183 mg, 1.18 mmol) and THF (7.8 mL) were added, followed by the addition of thionyl chloride (701 mg, 5.9 mmol, 0.43 mL). The resulting milky white mixture was stirred at room temperature for two hours. LCMS yielded an approximately 1:1 mixture of L1 and intermediate L. m / z They are 174 [M+H] respectively. + And 138 [M+H] + .

[1022] 4-Methyl-5,6-dihydro-4 H -pyrrolo[1,2- b Pyrazole-2-amine (Intermediate L): The crude reaction mixture from L1 was concentrated, followed by the addition of DMF (6.6 mL) and cesium carbonate (576 mg, 1.8 mmol). The mixture was placed in a preheated hot pan at 100 °C and stirred at 100 °C for one hour. LCMS showed complete conversion to the product. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and milled with EtOAc and methanol (approximately 5:1) to give intermediate L (68 mg, 42%) as a beige solid. LCMS m / z 138 [M+H] + .

[1023] Intermediate M: 5',6'-dihydrospiro[cyclopropane-1,4'-pyrrolo[1,2- b ]pyrazole]-2'-amine

[1024]

[1025] 3-[1-(2-hydroxyethyl)cyclopropyl]-3-oxopropionitrile (M1): LDA (0.49 mL, 0.98 mmol) and anhydrous THF (1 mL) were added to a sealed, dried vial rinsed with nitrogen. The solution was degassed, backfilled with nitrogen three times, and cooled to -78 °C. A degassed and nitrogen-rinsed solution of 5-oxaspiro[2.4]hepta-4-one (42 µL, 0.45 mmol) in anhydrous THF (1.4 mL) and anhydrous ACN (47 µL, 0.89 mmol) was added dropwise to the solution of LDA in THF. The solution was stirred at -78 °C for 15 min, then the vial was warmed to room temperature and stirred for 2 h to give a pale yellow mixture. The crude reaction mixture was diluted with saturated ammonium chloride aqueous solution and the aqueous layer was extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give M1 as an orange oil. The crude product is used in the next step.

[1026] 2-[1-(3-amino-1-yl] H [-pyrazol-5-yl]cyclopropyl]ethane-1-ol (M2): 3-[1-(2-hydroxyethyl)cyclopropyl]-3-oxopropionitrile (M1) (68 mg, 0.44 mmol) and methanol (0.63 mL) were added to a vial. Hydrazine monohydrate (32 µL, 0.67 mmol) was added to the solution, and the solution was stirred overnight at 80 °C to produce a yellow solution. LC-MS yielded a product. The crude reaction mixture was cooled to room temperature and concentrated to an orange oil. The crude product was purified by silica gel chromatography (4 g) and eluted with 0–20% methanol-DCM to give M2 (26 mg, 35%) as a yellow oil. 1 H NMR (methanol-) d 4, 400 MHz) δ 5.31 (s, 1H),3.50 (t, J =7.3 Hz, 2H), 1.70 (t, J =7.3 Hz, 2H), 0.80-0.70 (m, 2H), 0.69-0.60 (m, 2H).

[1027] 5-[1-(2-chloroethyl)cyclopropyl]-1 H -Pyrazole-3-amine (M3): Add 2-[1-(3-amino-1-ylamine)] to a vial containing anhydrous THF (86 mL) and thionyl chloride (58 µL, 0.78 mmol). H[5-[1-(2-chloroethyl)cyclopropyl]ethyl-1-ol (M2) (26 mg, 0.16 mmol). The crude reaction mixture was stirred at room temperature for two hours. The yellow solution rapidly turned into a turbid mixture, and then into a concentrated yellow solution. LC-MS yielded a 2:1 ratio of 5-[1-(2-chloroethyl)cyclopropyl]-1-ol. H -Pyrazole-3-amine (M3) is more potent than 5',6'-dihydrospiro[cyclopropane-1,4'-pyrrolo[1,2-] b [Pyrazole]-2'-amine (intermediate M). After 18 hours, the LCMS trace yielded the same results as after two hours. The crude reaction mixture was concentrated to give a deep orange oil, which was used in the next step.

[1028] Intermediate M: 5',6'-dihydrospiro[cyclopropane-1,4'-pyrrolo[1,2- b ]pyrazole]-2'-amine

[1029] The crude product was dissolved in DMF (0.86 mL) and Cs₂CO₃ (76 mg, 0.23 mmol) was added. The crude reaction mixture was heated at 100 °C for one hour. LCMS of the resulting orange mixture yielded 5-[1-(2-chloroethyl)cyclopropyl]-1 H -Pyrazole-3-amine (M3) is completely converted to 5',6'-dihydrospiro[cyclopropane-1,4'-pyrrolo[1,2-] b [Pyrazole]-2'-amine (intermediate M). The crude reaction mixture was cooled to room temperature and added dropwise to H2O (75 mL). The aqueous layer was extracted three times with DCM. An emulsion was formed, which was separated by adding a spoonful of LiCl to disrupt the emulsion. LCMS of the aqueous layer showed that the product remained in the aqueous layer even after three extractions with EtOAc. Therefore, the organic and aqueous layers were combined and lyophilized for one week, which gave an orange solid. The crude product was purified by reverse-phase HPLC (5-45% ACN-H2O gradient, 25 min), which gave intermediate M (6 mg, 25%). 1 H NMR (methanol-) d 4, 400 MHz) δ 4.94 (s, 1H), 3.91 (t, J =7.2 Hz, 2H), 2.38 (dt, J =7.3,1.0 Hz, 2H), 0.86 (s, 4H).

[1030] Intermediate N: 5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1 H -Pyrazole-3-amine

[1031]

[1032] 2-(5-Cyclopropyl-1- H -pyrazole-3-yl)-1H -Isoindole-1,3(2) H )-Diketone (N1): 5-cyclopropyl-1 H A mixture of pyrazole-3-amine (10 g, 81 mmol) and 2-benzofuran-1,3-dione (12 g, 81 mmol) in acetic acid was heated at 100 °C for two hours and then at 120 °C for six hours. The crude reaction mixture was concentrated under reduced pressure and H₂O was added. A white solid (19 g, 92%) was collected by filtration. LCMS m / z 254 [M+H] + .

[1033] 2-[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1 H -pyrazole-3-yl]-1 H -Isoindole-1,3(2) H )-Diketone (N2): To 2-(5-cyclopropyl-1 H -pyrazole-3-yl)-1 H -Isoindole-1,3(2) H )-Diketone (N1) (17.9 g, 71 mmol) was added to a suspension in ACN (353 mL) containing pyridinium p-tosylate (2.7 g, 11 mmol) and dihydro-2-diketone (N1 ... H -Pyran (12 g, 141 mmol). The reaction mixture was stirred at 60 °C for 16 h. The crude reaction mixture was combined with smaller batches (using 1 g N1) and concentrated under reduced pressure. The crude product was milled with H2O (300 mL) and EtOAc (50 mL) and filtered. The solid was washed with H2O and EtOAc (50 mL × 3) and dried to give N2 (19.8 g, 83.0%) as a white solid. The filtrate was extracted with EtOAc (100 mL × 2), washed with brine (200 mL), concentrated under vacuum at 66 °C, and then concentrated under high vacuum to obtain a crude product that was a light red oil. This crude product was ground with petroleum ether:EtOAc = 3:1 (100 mL) for 2 hours, filtered, and the collected solid was washed with H2O and petroleum ether:EtOAc = 3:1 (10 mL × 3) and dried to obtain a separate grayish-white solid, N2 (2.9 g, 12%). LCMS m / z 260 [M+Na] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 7.99-7.89(m, 4H), 6.06 (s, 1H), 5.64 (dd, J=9.9, 2.3 Hz, 1H), 3.98-2.94 (m, 1H), 3.75-3.63 (m, 1H), 2.33-2.19 (m, 1H), 2.09-1.96 (m, 2H), 1.96-1.87 (m, 1H), 1.77-1.61 (m, 1H), 1.61-1.48 (m, 2H), 1.07-0.96 (m, 2H), 0.79-0.64 (m, 2H).

[1034] 5-Cyclopropyl-1-(oxacyclohexyl-2-yl)-1 H -Pyrazole-3-amine (intermediate N): 2-[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1 H -pyrazole-3-yl]-1 H -Isoindole-1,3(2) H A solution of 22.7 g (67 mmol) of diketone (N2) in THF (336 mL) was treated with hydrazine monohydrate (9.5 g, 150 mmol) and stirred at 70 °C for 4 h. After cooling to ambient temperature, the suspension was filtered. The filtrate was extracted with EtOAc (200 mL × 6), and the combined organic phases were washed with saturated sodium bicarbonate (200 mL × 2) and brine (200 mL × 2), dried over sodium sulfate, and concentrated under reduced pressure to give intermediate N (9.8 g, 70%), which was yellow and oily. The combined aqueous phases were extracted again with EtOAc (200 mL × 6). The combined organic phases were washed with saturated sodium bicarbonate (100 mL) and brine (200 mL × 2), dried over sodium sulfate, and concentrated under reduced pressure to give more intermediate N (2.84 g, 20%), which was yellow and oily. LCMS m / z 208 [M+H] + ; 1 H NMR (400 MHz, CDCl3)δ 5.35 (dd, J =2.4, 10.5 Hz, 1H), 5.28 (s, 1H), 4.15-4.04 (m, 1H), 3.92-3.20(m, 3H), 2.47-2.30 (m, 1H), 2.17-2.00 (m, 1H), 1.91-1.82 (m, 1H), 1.81-1.64(m, 3H), 1.58-1.51 (m, 1H), 0.93-0.90 (m, 2H), 0.78-0.69 (m, 1H), 0.65-0.55(m, 1H).

[1035] Example

[1036] Method A

[1037] Example 01: 2,6-Dimethoxy- N -{4-methoxy-6-[(1 H [-pyrazole-3-yl)amino]-1,2-benzox 3-ylbenzene-1-sulfonamide

[1038]

[1039] N -(6-bromo-4-methoxy-1,2-benzoxazol-3-yl)-2,6-dimethoxybenzene-1-sulfonamide (1a): A solution of 6-bromo-4-methoxy-1,2-benzoxazol-3-amine (intermediate A) (17 g, 70 mmol) and 2,6-dimethoxybenzene-1-sulfonyl chloride (24.8 g, 105 mmol) in pyridine (170 mL) was heated at 120 °C for two hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (eluting with 100% EtOAc) to give 1a (26.5 g, 85%) as a solid. LCMS m / z 443 / 445 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 9.78 (s,1H), 7.56-7.45 (m, 2H), 7.05 (d, J =1.1 Hz, 1H), 6.78 (d, J =8.4 Hz, 2H), 3.93 (s, 3H), 3.77 (s, 6H).

[1040] N -(6-bromo-4-methoxy-1,2-benzoxazol-3-yl)- N -[(2,4-dimethoxyphenyl)methyl]-2,6-dimethoxyphenyl-1-sulfonamide (1b): NA solution of (6-bromo-4-methoxy-1,2-benzoxazol-3-yl)-2,6-dimethoxybenzene-1-sulfonamide (1a) (28.0 g, 63 mmol), (2,4-dimethoxyphenyl)methanol (15.9 g, 94.8 mmol), and triphenylphosphine (41.4 g, 158 mmol) in THF (300 mL) was cooled to 0 °C, followed by dropwise addition of DIAD (25.5 g, 126 mmol). After stirring at room temperature (15 °C) for 16 hours, the pale yellow solution was concentrated under reduced pressure and purified by silica gel chromatography (eluting with petroleum ether containing 60-70% EtOAc) to give approximately 25 g of product, which was mixed with triphenylphosphine oxide. Recrystallization from methanol gave 1b (7.0 g, 19%) as a white solid. The mother liquor was concentrated and purified by reverse-phase preparative HPLC (YMC-Triart Prep C18 250×50 mm, 10 µm column, eluted with 50–70% H₂O + ACN containing 0.1% TFA). The fraction containing the product was concentrated to remove ACN, extracted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated to give a second batch of 1b (8.30 g, 22%) in solid form. 1 H NMR (400 MHz, DMSO- d 6) δ 7.64 (d, J =1.1 Hz, 1H), 7.56 (t, J =8.4 Hz, 1H), 7.22 (d, J =8.4 Hz, 1H), 7.03 (d, J =1.0 Hz, 1H), 6.77 (d, J =8.6 Hz, 2H), 6.45 (d, J =8.0 Hz, 1H), 6.39 (s, 1H), 4.78 (s, 2H), 3.70 (s, 3H), 3.65 (s, 3H), 3.52 (s, 6H), 3.39 (s, 3H).

[1041] 3-[(3-{(2,6-dimethoxyphenyl-1-sulfonyl)[(2,4-dimethoxyphenyl)methyl]amino}-4-methoxy-1,2-benzoxazol-6-yl)amino]-1 H -Pyrazole-1-carboxylic acid tert-butyl ester (1c): To N -(6-bromo-4-methoxy-1,2-benzoxazol-3-yl)- N-[(2,4-dimethoxyphenyl)methyl]-2,6-dimethoxybenzene-1-sulfonamide (1b) (100.0 mg, 0.169 mmol) and 3-amino-1 H A solution of tert-butyl pyrazole-1-carboxylate (92.6 mg, 0.506 mmol) in 1,4-dioxane (2 mL) was supplemented with cesium carbonate (165 mg, 0.506 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (Xantphos, 29.3 mg, 0.051 mmol), and tris(diphenylmethyleneacetone)dipalladium(O) (23.1 mg, 0.025 mmol). The suspension was stirred at 100 °C for 16 hours, followed by concentration under vacuum to give a brown gel-like crude 1c (150 mg, >100%), which was used in the next step without further purification. LCMS m / z 696 [M+H] + .

[1042] 2,6-Dimethoxy- N -{4-methoxy-6-[(1 H [3-pyrazole-3-yl)amino]-1,2-benzoxazole-3-yl}benzene-1-sulfonamide (Example 01): Crude 3-[(3-{(2,6-dimethoxybenzene-1-sulfonyl)[(2,4-dimethoxyphenyl)methyl]amino}-4-methoxy-1,2-benzoxazole-6-yl)amino]-1 H 1-Pyrazole-1-carboxylic acid tert-butyl ester (1c) (100 mg, maximum 0.113 mmol) was dissolved in DCM (2 mL) and TFA (2 mL) and stirred at room temperature (20 °C) for 15 hours. The resulting pink solution was concentrated to dryness, and the residue was dissolved in methanol (2 mL) and DMSO (2 mL). The solution was filtered and purified by preparative reversed-phase HPLC (YMC Triart C18, 250 × 50 mm × 7 µm column, eluted with 11-51% H2O + ACN containing 0.2% formic acid). The fraction containing the product was lyophilized to give Example 01 (40 mg, 80%) as a white solid. LCMS m / z 446.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 9.18 (s, 1H), 9.10 (s, 1H), 7.62(d, J =2.2 Hz, 1H), 7.50 (t, J=8.5 Hz, 1H), 7.25 (s, 1H), 6.78 (d, J =8.4 Hz,2H), 6.63 (s, 1H), 5.90 (d, J =2.1 Hz, 1H), 3.88 (s, 3H), 3.79 (s, 6H).

[1043] Method B

[1044] Example 02: N -{6-[(3-ethyl-1-] H [-pyrazole-5-yl)amino]-5-methoxy-1,2-benzoxazole-3- 2,6-Dimethoxybenzene-1-sulfonamide

[1045]

[1046] N -(6-bromo-5-methoxy-1,2-benzoxazol-3-yl)-2,6-dimethoxybenzene-1-sulfonamide (2a): 6-bromo-5-methoxy-1,2-benzoxazol-3-amine (intermediate B) (1.50 g, 6.17 mmol) and 2,6-dimethoxybenzene-1-sulfonyl chloride (1.75 g, 7.41 mmol) were charged into a sealable reaction vessel. A 0.05 M solution of DMSO in ACN (6.17 mL, 0.309 mmol DMSO) was added, followed by a solution of 3,5-dimethylpyridine (1.98 g, 2.11 mmol) in ACN (15.0 mL). The vessel was sealed and stirred at 23 °C for 20 hours. A solid precipitate formed during this time. According to LCMS, because unreacted intermediate B was still present, a second portion of 2,6-dimethoxybenzene-1-sulfonyl chloride (906 mg, 3.83 mmol) and 3,5-dimethylpyridine (992 mg, 9.26 mmol) was added, the container was resealed, and stirring was continued at 23°C for 20 hours. The reaction mixture was then diluted with DCM (100 mL) and washed with 2 N HCl aqueous solution (35 mL). The organic layer was washed with saturated NaHCO3 aqueous solution (50 mL), resulting in a white solid precipitate. The suspension was filtered, and the filter cake was washed with H2O (3 × 10 mL) and DCM (3 × 5 mL). The precipitate was dried under vacuum overnight, then suspended in ACN (5 mL) and H2O (30 mL) and lyophilized to dryness, leaving 2a (2.1 g, 77%) as a white solid. LCMS m / z 443 / 445 [M+H] + ; 1 HNMR (400 MHz, DMSO- d 6) δ 7.65 (s, 1H), 7.28 (s, 1H), 7.24 (t,J =8.3 Hz, 1H), 6.61 (d, J =8.4 Hz, 2H), 3.83 (s, 3H), 3.59 (s, 6H).

[1047] Alternatively, ACN (15.0 mL) containing 6-bromo-5-methoxy-1,2-benzoxazole-3-amine (intermediate B) (0.70 g, 2.88 mmol) and 2,6-dimethoxybenzene-1-sulfonyl chloride (1.02 g, 4.32 mmol) was added to the reaction vessel. The vessel was stirred at 23°C, and a 2.0 M solution of sodium tert-butoxide in THF (5.0 mL, 10.1 mmol) was added dropwise. A solid precipitate formed during this time. The reaction mixture was stirred for two hours, then diluted with EtOAc (50 mL) and washed with 1 N HCl aqueous solution (35 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, and concentrated. The solid residue was slurried in heptane, filtered under vacuum, and washed with heptane, leaving 2a (1.3 g, 99%) as a white solid. LCMS m / z 443 / 445 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 11.35 (s, 1H), 8.00 (s, 1H), 7.73 (s,1H), 7.48 (t, J =8.4 Hz, 1H), 6.74 (d, J =8.5 Hz, 2H), 3.87 (s, 3H), 3.74 (s,6H).

[1048] N -(6-bromo-5-methoxy-1,2-benzoxazol-3-yl)-2,6-dimethoxy- N -[(4-methoxyphenyl)methyl]benzene-1-sulfonamide (2b): stirred at 50°C NA mixture of 2a (2.78 g, 6.17 mmol), 4-methoxybenzyl chloride (1.06 g, 6.79 mmol), and potassium carbonate (1.02 g, 7.40 mmol) in DMF (30.0 mL) was prepared for 16 hours. The mixture was then added to H2O (100 mL) and stirred for 20 minutes. The resulting suspension was filtered, and the filter cake was washed with H2O (5 mL). The solid was dissolved in ACN (50 mL) and evaporated to dryness (three cycles) to give 2b (3.0 g, 86%) as a white solid. LCMS m / z 563 / 565 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.09 (s, 1H), 7.57 (t, J =8.4 Hz, 1H), 7.30(d, J =8.7 Hz, 2H), 7.24 (s, 1H), 6.88-6.83 (m, 2H), 6.81 (d, J =8.6 Hz, 2H), 4.98 (s, 2H), 3.78 (s, 3H), 3.72 (s, 6H), 3.69 (s, 3H).

[1049] N -{6-[(3-ethyl-1-] H [-pyrazole-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl]-2,6-dimethoxy- N -[(4-methoxyphenyl)methyl]benzene-1-sulfonamide (2c): N -(6-bromo-5-methoxy-1,2-benzoxazol-3-yl)-2,6-dimethoxy- N -[(4-methoxyphenyl)methyl]benzene-1-sulfonamide (2b) (150 mg, 0.266 mmol), 5-ethyl-1 HA yellow suspension of pyrazole-3-amine (188 mg, 1.69 mmol), cesium carbonate (260 mg, 0.799 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (Xantphos, 108 mg, 0.186 mmol), and tris(diphenylmethyleneacetone)dipalladium(0) (48.8 mg, 0.0532 mmol) in 1,4-dioxane (6.0 mL) was purged with dry argon for one minute, followed by heating the mixture at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with H₂O (30 mL) and stirred for 30 minutes. The resulting solids were collected by filtration. The filter cake was washed with H₂O (2 × 5 mL) and then suspended in DCM (100 mL) with stirring for 10 minutes. The suspension was filtered, and the solids were washed with methanol (4 × 1 mL). The filtrate was concentrated under vacuum and purified by silica gel chromatography (eluting with petroleum ether containing 0-100% EtOAc) to give 2c (130 mg, 82%), a yellow glassy substance. LCMS m / z 594 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 11.89 (s, 1H), 8.16 (d, J =12.5 Hz, 2H), 7.54 (t, J =8.4 Hz, 1H), 7.32 (d, J =8.5 Hz, 2H), 6.97 (s, 1H), 6.87 (d, J =8.8 Hz, 2H), 6.79 (d, J =8.5 Hz, 2H), 5.88 (d, J =1.8 Hz, 1H), 4.99(s, 2H), 3.77 (s, 3H), 3.75 (s, 6H), 3.70 (s, 3H), 2.56 (q, J =7.7 Hz, 2H), 1.18 (t, J =7.5 Hz 3H).

[1050] N -{6-[(3-ethyl-1-] H [-pyrazol-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl]-2,6-dimethoxybenzene-1-sulfonamide (Example 02): TFA (1 mL) was added to N -{6-[(3-ethyl-1-] H[-pyrazole-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl]-2,6-dimethoxy- N 1-[(4-methoxyphenyl)methyl]benzene-1-sulfonamide (2c) (130 mg, 0.219 mmol) was placed in a cooled (0°C) solution of DCM (4 mL). After stirring at room temperature (25°C) for five hours, the solvent was evaporated, and the residue was suspended in methanol (2 mL) and ACN (2 mL) and stirred for five minutes. The solid was collected by filtration and washed with ACN (3 × 1 mL). The filter cake was dissolved in H2O (20 mL) and DCM (20 mL), stirred for 10 minutes, and adjusted to pH 10 with a saturated aqueous solution of NaHCO3. The layers were separated, and the aqueous layer was extracted with DCM / methanol (10:1, 4 × 25 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated, and purified by reverse-phase preparative HPLC (YMC Triart C18; 250 × 50 mm, 7 µm column, eluted with 0–40% H₂O + ACN containing 0.05% NH₄OH) to obtain Example 02 (55 mg, 53%) as a white solid. LCMS m / z 474.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 11.89(s, 1H), 10.97 (br s, 1H), 8.16 (s, 1H), 8.10 (s, 1H), 7.46 (t, J =8.4 Hz,1H), 7.40 (s, 1H), 6.74 (d, J =8.6 Hz, 2H), 5.89 (s, 1H), 3.88 (s, 3H), 3.76(s, 6H), 2.57 (q, J =7.7 Hz, 2H), 1.18 (t, J =7.6 Hz, 3H).

[1051] Method C

[1052] Example 03: 2,6-Dimethoxy- N -{5-methoxy-6-[(1 H [-pyrazole-3-yl)amino]-1,2-benzox 3-ylbenzene-1-sulfonamide

[1053]

[1054] Stir at 100°C N-(6-bromo-5-methoxy-1,2-benzoxazol-3-yl)-2,6-dimethoxybenzene-1-sulfonamide (2a, as prepared in method B) (50.0 mg, 0.11 mmol), 3-amino-1 H A solution of tert-butyl pyrazole-1-carboxylate (62.0 mg, 0.338 mmol), cesium carbonate (110 mg, 0.338 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (Xantphos, 19.6 mg, 0.0338 mmol), and tris(diphenylmethyleneacetone)dipalladium(O) (15.5 mg, 0.0169 mmol) in 1,4-dioxane (2.0 mL) was prepared for 16 hours. A yellow precipitate formed. The suspension was diluted with EtOAc (10 mL), filtered to remove the solids, and the filtrate was concentrated to dryness under vacuum. The residue was purified by reverse-phase preparative HPLC (YMCTriart C18; 250 × 50 mm, 7 μm column, eluted with 17–57% H₂O + ACN containing 0.05% NH₄OH) to give Example 03 (20 mg, 40%) as a pale yellow solid. LCMS m / z 446.1 [M+H] + 468 [M+Na] + ; 1 H NMR (400 MHz, DMSO-) d 6) δ 12.17 (br s, 1H), 8.21 (s, 1H), 8.15 (br d, J =4.6 Hz, 1H), 7.59 (d, J =2.3 Hz, 1H), 7.46 (t, J =8.4 Hz, 1H), 7.41 (s, 1H), 6.74 (d, J =8.5 Hz, 2H), 6.11 (d, J =2.3 Hz, 1H), 3.89 (s, 3H), 3.76 (s, 6H).

[1055] Example 04: 2,6-Dimethoxy- N -{5-methoxy-6-[(1-methyl-1 H [-pyrazole-3-yl)amino]-1,2- Benzoxazol-3-ylbenzene-1-sulfonamide

[1056]

[1057] Stir at 100°C N-(6-bromo-5-methoxy-1,2-benzoxazol-3-yl)-2,6-dimethoxybenzene-1-sulfonamide (2a, as prepared in method B) (50.0 mg, 0.11 mmol), 1-methyl-1 H A solution of pyrazole-3-amine (32.9 mg, 0.338 mmol), cesium carbonate (110 mg, 0.338 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (Xantphos, 19.6 mg, 0.0338 mmol), and tris(diphenylmethyleneacetone)dipalladium(O) (15.5 mg, 0.0169 mmol) in 1,4-dioxane (2.0 mL) was prepared for 16 hours. After cooling to room temperature, the mixture was diluted with EtOAc (10 mL), the solid was filtered off, the filtrate was concentrated to dryness, and the residue was purified by reverse-phase preparative HPLC (YMC Triart C18; 250 × 50 mm, 7 μm column, eluted with 24–64% H2O + ACN containing 0.2% formic acid) to give Example 04 (30 mg, 52%) as a pale yellow solid. LCMS m / z 460.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 10.92 (br s,1H), 8.23 ​​(s, 1H), 8.15 (s, 1H), 7.53 (d, J =2.3 Hz, 1H), 7.47 (t, J =8.4 Hz,1H), 7.41 (s, 1H), 6.74 (d, J =8.5 Hz, 2H), 6.06 (d, J =2.4 Hz, 1H), 3.88 (s, 3H), 3.79 (s, 3H), 3.76 (s, 6H).

[1058] Example 05: 3-Methoxy- N -{5-methoxy-6-[(1 H [-pyrazole-3-yl)amino]-1,2-benzoxazole-3- 5,6,7,8-Tetrahydronaphthalene-2-sulfonamide

[1059]

[1060] N-(6-bromo-5-methoxy-1,2-benzoxazol-3-yl)-3-methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonamide (5a): 6-bromo-5-methoxy-1,2-benzoxazol-3-amine (intermediate B) (257 mg, 1.06 mmol) and 3-methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonyl chloride (intermediate D) (230 mg, 0.882 mmol) were purified by reverse-phase preparative HPLC to give 5a (165 mg, 40%) as a white solid. 1 H NMR (400MHz, chloroform-) d ) δ 7.70 (s, 1H), 7.54 (s, 1H), 7.42 (s, 1H), 6.72 (s, 1H), 3.99(d, J =1.7 Hz, 6H), 2.76 (br t, J =5.3 Hz, 2H), 2.62 (br t, J =5.0 Hz, 2H),1.83-1.68 (m, 5H).

[1061] 3-Methoxy- N -{5-methoxy-6-[(1 H [-pyrazol-3-yl)amino]-1,2-benzoxazol-3-yl}-5,6,7,8-tetrahydronaphthalene-2-sulfonamide (Example 05): By means of the same method used in the synthesis of Example 03, but using 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos) instead of Xantphos, N -(6-bromo-5-methoxy-1,2-benzoxazol-3-yl)-3-methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonamide (5a) (165 mg, 0.353 mmol) and 3-amino-1 H The reaction was carried out with tert-butyl pyrazole-1-carboxylate (129 mg, 0.706 mmol) to give Example 05 (15 mg, 9%) as a white solid. LCMS m / z 470.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ12.19 (br s, 1H), 11.19 (br s, 1H), 8.25 (s, 1H), 8.16 (br d, J =5.5 Hz, 1H), 7.59 (d,J =2.3 Hz, 1H), 7.36 (s, 1H) 7.53 (s, 1H), 6.84 (s, 1H), 6.11 (d, J =2.3 Hz, 1H), 3.90 (s, 3H), 3.76 (s, 3H), 2.76-2.65 (m, 4H), 1.70 (br s, 4H).

[1062] Method D

[1063] Example 06: 2-Methoxy- N -{5-methoxy-6-[(3-methyl-1 H [-pyrazole-5-yl)amino]-1,2-benzo[ Oxazol-3-ylbenzene-1-sulfonamide

[1064]

[1065] Step 1: 1-[(4-methoxyphenyl)methyl]-3-methyl-1 H 5-Pyrazole-5-amine (6a): A solution of 3-oxobutyronitrile (5.0 g, 60.2 mmol) and [(4-methoxyphenyl)methyl]hydrazine (11.9 g, 78.2 mmol) in ethanol (50 mL) was stirred at 50 °C for three hours. The crude reaction mixture was concentrated under reduced pressure and diluted with EtOAc (50 mL). The organic layer was washed with saturated sodium bicarbonate (10 mL), H2O (40 mL), and brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated, and the resulting residue was purified by silica gel (Combi-flash, 40 g) and eluted with 0–60% EtOAc-petroleum ether to give 6a (4 g, 49% yield) as a white solid. LCMS m / z 218 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 7.09 (d, J =8.6 Hz, 2H), 6.89-6.81 (m, 2H), 5.08 (d, J =8.1 Hz, 3H), 4.91 (s, 2H), 3.74-3.62 (m, 3H), 1.94 (s, 3H).

[1066] Step 2: 2-Fluoro-5-methoxy-4-({1-[(4-methoxyphenyl)methyl]-3-methyl-1 H 4-Bromo-2-fluoro-5-methoxybenzonitrile (B2) (100 mg, 0.4 mmol), 1-[(4-methoxyphenyl)methyl]-3-methyl-1 HA yellow suspension of pyrazole-5-amine (6a) (115 mg, 0.5 mmol) and cesium carbonate (425 mg, 1.3 mmol) in dioxane (6 mL) was degassed and purged with argon, followed by the addition of Pd2(dba)3 (40 mg, 0.04 mmol) and Xantphos (75 mg, 0.13 mmol). LCMS yielded a product after heating the mixture at 80 °C for 18 hours. The mixture was prepared using a solution containing 4-bromo-2-fluoro-5-methoxybenzonitrile (B2) (1.5 g, 6.6 mmol) and 1-[(4-methoxyphenyl)methyl]-3-methyl-1 H The procedure was repeated with pyrazole-5-amine (6a) (1.7 g, 8.0 mmol), cesium carbonate (6.5 g, 20 mmol), Pd2(dba)3 (609 mg, 0.7 mmol), and dioxane (30 mL) of Xantphos (1.1 g, 2.0 mmol). After 18 hours at 80 °C, the crude reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), and filtered. The filtrates from both reactions were combined and purified by silica gel (Combi-flash, 40 g) and eluted with 0–45% EtOAc-petroleum ether to give a yellow solid 6b (3 g, 56% purity according to LCMS). LCMS m / z 367 [M+H] + .

[1067] Step 3: 5-Methoxy- N 6 -{1-[(4-methoxyphenyl)methyl]-3-methyl-1 H ⁻pyrazol-5-yl}-1,2-benzoxazole-3,6-diamine (6c): N A solution of hydroxyacetamide (1.8 g, 25 mmol) and sodium tert-butoxide (2.8 g, 25 mmol) in DMF (75 mL) was stirred for 30 minutes. 2-fluoro-5-methoxy-4-({1-[(4-methoxyphenyl)methyl]-3-methyl-1- H A solution of pyrazol-5-yl)amino)benzonitrile (6b) (3.0 g, 8.2 mmol) in DMF (5 mL) was prepared. The mixture was stirred at 80 °C for 16 hours. LC-MS yielded the starting material and product. Another portion... N 1,8-hydroxyacetamide (1.8 g, 25 mmol) and sodium tert-butoxide (2.8 g, 25 mmol) were added to the crude reaction mixture. The resulting mixture was stirred at 80 °C for 16 hours. LC-MS showed that more product was present, but the starting material was still present. This process was repeated to add more... N1,8-hydroxyacetamide (1.8 g, 25 mmol) and sodium tert-butoxide (2.8 g, 25 mmol) were added to the crude reaction mixture, followed by heating at 80 °C for 16 hours three times. The crude reaction mixture was concentrated to remove DMF and diluted with EtOAc (250 mL). The organic layer was washed with H2O (250 mL) and the aqueous layer was extracted with EtOAc (3 × 250 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated, and the crude product was purified by silica gel (Combi-flash, 40 g) and eluted with 0–60% EtOAc-petroleum ether, giving compound 6c (2 g, 64%) as a brown oil. LCMS m / z 380 [M+H] + .

[1068] Step 4: 2-Methoxy- N -[5-methoxy-6-({1-[(4-methoxyphenyl)methyl]-3-methyl-1 H [-pyrazole-5-yl]amino)-1,2-benzoxazole-3-yl]benzene-1-sulfonamide (6d): heated at 120°C with 5-methoxy- N 6 -{1-[(4-methoxyphenyl)methyl]-3-methyl-1 H A solution of pyrazol-5-yl}-1,2-benzoxazole-3,6-diamine (6c) (200 mg, 0.5 mmol) and 2-methoxybenzene-1-sulfonyl chloride (163 mg, 0.79 mmol) in pyridine (2 mL) was prepared over six hours. The crude reaction mixture was concentrated and purified by silica gel (12 g) and eluted with 0–80% EtOAc-petroleum ether to give compound 6d (50 mg, 17%) as a brown oil. LCMS m / z 550 [M+H] + .

[1069] Step 5: 2-Methoxy- N -{5-methoxy-6-[(3-methyl-1 H [-pyrazol-5-yl]amino]-1,2-benzoxazol-3-yl]benzene-1-sulfonamide (Example 06): 2-methoxy- N -[5-methoxy-6-({1-[(4-methoxyphenyl)methyl]-3-methyl-1 HA solution of pyrazol-5-ylamino)-1,2-benzoxazol-3-ylbenzene-1-sulfonamide (6d) in TFA (2 mL) was prepared for 16 hours. The crude reaction mixture was concentrated and the residue was diluted with methanol (5 mL) and saturated sodium bicarbonate (1 mL). The mixture was concentrated and dissolved in DMSO (3 mL), and the crude product was purified by reverse-phase chromatography using a Phenomenex C18 column (75 × 30 mm; 3 μm) and eluted with ammonium hydroxide-ACN aqueous solution, yielding Example 06 (6 mg, 25%) as a white solid. LCMS m / z 430.2 [M+H] + ; 1 H NMR (400 MHz, methanol-) d 4) δ 7.89 (dd, J =1.6, 7.8 Hz, 1H), 7.65-7.52 (m, 2H), 7.26 (s, 1H), 7.13 (d, J =8.4 Hz, 1H), 7.03 (t, J =7.6 Hz, 1H), 5.88 (s, 1H), 3.97 (s, 3H), 3.87 (s, 3H), 2.27 (s, 3H).

[1070] Method E

[1071] Example 07: N -{6-[(3-Cyclopropyl-1- H [-pyrazole-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl]-2,6-dimethoxy-4-(pyridin-3-yl)benzene-1-sulfonamide

[1072]

[1073] Step 1: Synthesis N 6 -{3-Cyclopropyl-1-[(4-Methoxyphenyl)methyl]-1 H ⁻pyrazol-5-yl}-5-methoxy-1,2-benzoxazole-3,6-diamine (7a)

[1074] 7a is prepared in a similar manner to 6c, using 3-cyclopropyl-3-oxopropionitrile instead of 3-oxobutyronitrile in the first step. 1 H NMR (400 MHz, DMSO- d 6) δ ppm 0.63 - 0.68 (m, 2 H) 0.82 - 0.86 (m, 2 H)1.81 - 1.88 (m, 1 H) 3.66 - 3.70 (m, 3 H) 3.87 (s, 3 H) 5.05 (s, 2 H) 5.87 -5.92 (m, 1 H) 6.02 - 6.08 (m, 2 H) 6.39 - 6.42 (m, 1 H) 6.81 (d, J=8.63 Hz, 2H) 7.04 (d, J=8.63 Hz, 2 H) 7.26 (s, 1 H) 7.51 (s, 1 H); LCMS m / z 406.1 (M+H).

[1075] Step 2: Synthesis of 4-bromo- N -[6-({3-cyclopropyl-1-[(4-methoxyphenyl)methyl]-1 H [-pyrazole-5-yl]amino)-5-methoxy-1,2-benzoxazole-3-yl]-2,6-dimethoxybenzene-1-sulfonamide (7b)

[1076] Towards N 6 -{3-Cyclopropyl-1-[(4-Methoxyphenyl)methyl]-1 H A solution of pyrazol-5-yl}-5-methoxy-1,2-benzoxazole-3,6-diamine 7a (900 mg, 2.22 mmol) and 4-bromo-2,6-dimethoxybenzene-1-sulfonyl chloride (intermediate Db) (1.1 g, 3.6 mmol) in ACN (5 mL) was supplemented with ACN (9 mg, 0.1 mmol) containing 0.05 N DMSO and 3,5-dimethylpyridine (714 mg, 6.66 mmol). The suspension was stirred at 60 °C for 16 hours. The solvent color changed from yellow to red. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel and eluted with petroleum ether containing 0-54% EtOAc to give 7a as a pink solid (810 mg, 53% yield). LCMS m / z 685 (M+H).

[1077] Step 3: Synthesis N -[6-({3-cyclopropyl-1-[(4-methoxyphenyl)methyl]-1 H [-pyrazole-5-yl]amino)-5-methoxy-1,2-benzoxazole-3-yl]-2,6-dimethoxy-4-(pyridin-3-yl)benzene-1-sulfonamide (7c)

[1078] To 4-bromo-N -[6-({3-cyclopropyl-1-[(4-methoxyphenyl)methyl]-1 H [-pyrazol-5-yl]amino]-5-methoxy-1,2-benzoxazol-3-yl]-2,6-dimethoxybenzene-1-sulfonamide (7b) (100 mg, 0.15 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyridine (60 mg, 0.29 mmol) in a solution of dioxane (2.0 mL) and H2O (0.7 mL) were added with tripotassium phosphate (93 mg, 0.44 mmol) and Pd(dppf)Cl2 (2.4 mg, 0.003 mmol). The mixture was heated and stirred under nitrogen at 80 °C for 1 hour. LCMS showed that the reaction was complete and the desired product was observed. The crude reaction mixture was combined with a batch from another experiment (using 25 mg of aryl bromide) and diluted with H2O (10 mL). The aqueous layer was extracted with EtOAc (10 × 3 mL), and the combined organic extracts were washed with brine, dried over Na₂SO₄, filtered, and concentrated to give 7c (158 mg) as a brown solid. LCMS m / z 683 [M+H] + .

[1079] Step 4: Synthesis N -{6-[(3-Cyclopropyl-1- H [-pyrazol-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}-2,6-dimethoxy-4-(pyridin-3-yl)benzene-1-sulfonamide (Example 07)

[1080] The crude product 7c was dissolved in TFA (5 mL) and stirred at 80 °C for 18 hours. LCMS showed the consumption of starting material 7c and the desired product was observed. The crude reaction mixture was concentrated under reduced pressure and diluted with H2O. The aqueous layer was extracted with EtOAc (50 mL × 2), and the combined extracts were washed with saturated NaHCO3 aqueous solution (15 mL), brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure to give a crude product (150 mg) as a brown solid. The crude product was diluted to DMF (2 mL) and purified by reverse-phase chromatography using a Phenomenex Gemini NX column (150 × 20 mm, 5 μm) with an ammonium hydroxide buffer solution and an ACN gradient at 60 mL / min. -1 After elution, Example 07 (31 mg) was obtained as a white solid. LCMS m / z 563.3 [M+H] + ; 1H NMR (400 MHz, DMSO- d 6) δ 11.90 (br s, 1H), 11.06 (s,1H), 9.01 (s, 1H), 8.68-8.60 (m, 1H), 8.23-8.18 (m, 1H), 8.14 (s, 1H), 8.07(d, J =1.1 Hz, 1H), 7.54-7.49 (m, 1 H), 7.44 (s, 1H), 7.05 (d, J =2.0 Hz, 2H), 5.78 (s, 1H), 3.91-3.87 (m, 9H), 1.91-1.80 (m, 1H) 0.96-0.89 (m, 2H), 0.69-0.63 (m, 2H).

[1081] Method F

[1082] Example 08: N -{6-[(3-Cyclopropyl-1- H [-pyrazol-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl]-2,6-dimethoxy-4-(1,3-oxazol-2-yl)benzene-1-sulfonamide

[1083]

[1084] Step 1: N '-(6-bromo-5-methoxy-1,2-benzoxazol-3-yl)- N , N -Dimethylformamidinium (8-1a)

[1085] Intermediate B (125 g, 514.28 mmol) was... N,N The solution of 8-dimethylformamide dimethyl acetal (462.69 g, 3.88 mol, 515.82 mL) was heated to 90 °C for 30 min. H₂O (3 L) was added to the crude reactant at 15 °C–25 °C, and the mixture was stirred at 25 °C for 2 h, followed by filtration and washing with H₂O (500 mL × 6). The filter cake was dried at 50 °C for 24 h to give 8-1a (151.2 g, 98% yield) as a grayish-white solid. 1 LCMS m / z 299.8 (M+H) + .

[1086] Step 2: Synthesis N '-(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1 H [-pyrazole-3-yl]amino}-5-methoxy-1,2-benzoxazole-3-yl)- N , N -Dimethylformamidinium (8-2a)

[1087] The reaction was carried out in two batches. Under nitrogen atmosphere at 25°C, the reaction proceeded to 8-1a (80 g, 268.33 mmol). t A mixture of BuBrettPhosPd G3 (27.51 g, 32.20 mmol) and Cs2CO3 (122.40 g, 375.67 mmol) in 2-methylbut-2-ol (2.2 L) was supplemented with a solution of intermediate N (66.74 g, 322.00 mmol) in dioxane (160 mL). The reaction mixture was heated to 100 °C for 16 h, then diluted with water (3 L) and brine (1 L), followed by extraction with EtOAc (3 L × 3). The combined organic layers were washed with brine (1 L × 2), dried over MgSO4, filtered, and concentrated. The crude material was purified by column chromatography on silica gel (0-85% EtOAc / DCM) to give 8-2a (210 g, 66% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.79 (s, 1H), 7.00 - 6.88 (m, 2H), 5.69 (s, 1H), 5.37 - 5.24 (m, 1H), 3.98 - 3.86 (m, 3H), 3.70 - 3.55 (m, 2H),3.14 (s, 3H), 3.08 (s, 3H), 2.64 - 2.29 (m, 2H), 2.15 (br dd, J = 3.7, 9.6Hz, 1H), 1.79 - 1.61 (m, 4H), 0.99 - 0.90 (m, 2H), 0.81 - 0.45 (m, 2H); LCMS m / z 425.2 (M+H) + .

[1088] Step 3: Synthesis N 6-[5-Cyclopropyl-1-(oxacyclohexyl-2-yl)-1 H [-pyrazol-3-yl]-5-methoxy-1,2-benzoxazole-3,6-diamine (8a)

[1089] The reaction was carried out in two batches. Ethylene-1,2-diamine (93.17 g, 1.55 mol, 103.75 mL) was added to a solution of 8-2a (105 g, 247.35 mmol) in EtOH (2.6 L) at 25 °C. The reaction mixture was heated to 80 °C for 16 hours, then cooled to 25 °C, and a water / EtOH mixture of approximately 2:1 was added dropwise. The reaction mixture was stirred for 30 minutes, then filtered and washed with H₂O (900 mL × 2). Both batches of filter cake were dried in an oven at 50 °C for 18 hours to give crude 8a. The crude solid was purified by column chromatography on silica gel (0-85% EtOAc / DCM). The resulting material was suspended in MTBE (1.5 L) and stirred at 25 °C for 2 hours, then filtered, washed, and dried to give 8a (101.3 g, 55% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 6.94 (s, 1H), 6.74 (s, 1H), 5.68 (s, 1H), 5.48 (dd, J = 2.4, 10.0 Hz, 1H), 4.27 - 4.14 (m, 2H), 4.09 (brd, J = 11.4 Hz, 1H), 3.89 (s, 3H), 3.72 - 3.63 (m, 1H), 2.66 - 2.44 (m, 1H), 2.15 (br dd, J = 3.5, 9.1 Hz, 1H), 1.97 (br dd, J = 2.1, 13.5 Hz, 1H), 1.91 -1.83 (m, 1H), 1.82 - 1.68 (m, 2H), 1.59 (br d, J = 11.5 Hz, 1H), 0.98 (dd, J = 2.0, 8.4 Hz, 2H), 0.86 - 0.76 (m, 1H), 0.69 - 0.58 (m, 1H); LCMS m / z 370.2(M+H) + .

[1090] Step 4: Synthesis of 4-bromo- N -(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1-} H [-pyrazol-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl)-2,6-dimethoxybenzene-1-sulfonamide (8b)

[1091] Intermediate Db (41.11 g, 130.26 mmol) and DMAP (1.59 g, 12.99 mmol) were added to a solution of 8a (40 g, 108.28 mmol) in pyridine (200 mL) at 25 °C under nitrogen atmosphere. The reaction solution was stirred at 25 °C for 16 hours. The crude reaction mixture was combined with another crude reaction mixture using 4 g of 8a. Both reaction mixtures were diluted with DCM (1.6 L) and washed with 1 M AcOH (2.8 L), followed by extraction with DCM (900 mL × 3). The combined organic phases were washed with brine (500 mL × 2), dried over MgSO4, filtered, and concentrated. The crude residue was purified by column chromatography on silica gel (0-8% EtOAc / DCM) to give 8b (68.6 g, 87% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.12 (s, 1H), 8.38 - 8.08 (m, 2H), 7.53 - 7.31 (m, 1H), 6.99 (s,2H), 5.77 (d, J = 8.8 Hz, 1H), 5.50 (dd, J = 2.3, 9.7 Hz, 1H), 3.93 (br d, J = 11.0 Hz, 1H), 3.89 (s, 3H), 3.79 (s, 6H), 3.70 - 3.53 (m, 1H), 2.41 - 2.26(m, 1H), 2.10 - 2.01 (m, 1H), 1.95 - 1.89 (m, 2H), 1.80 - 1.64 (m, 1H), 1.63- 1.46 (m, 2H), 0.97 (dd, J = 2.4, 8.3 Hz, 2H), 0.77 - 0.53 (m, 2H); LCMS m / z 648.1, 650.1 (M+H) + .

[1092] Step 5: Synthesis N-(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1-} H [-pyrazol-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl)-2,6-dimethoxy-4-(1,3-oxazol-2-yl)benzene-1-sulfonamide (8c)

[1093] At 20°C under nitrogen atmosphere, to 4-bromo- N -(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1-} H A mixture of pyrazol-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl)-2,6-dimethoxybenzene-1-sulfonamide 8b (280 mg, 0.43 mmol) in dioxane (6.0 mL) was supplemented with 1,3-oxazole (60 mg, 0.86 mmol), potassium tert-butoxide (104 mg, 0.93 mmol), 2-dicyclohexylphosphino-2',4,6'-triisopropylbiphenyl (41 mg, 0.09 mmol), and tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.06 mmol). The mixture was then stirred at 100 °C under nitrogen for 10 h. LCMS of the crude reaction mixture showed the consumption of starting material and the desired product mass was observed. The crude reaction mixture was combined with another batch (using 20 mg of aryl bromide), and the mixture was filtered. The filter cake was washed with EtOAc (2 × 30 mL) and purified by combi-flash (12 g silica gel, petroleum ether / EtOAc, 0–100%, followed by 0–20% methanol / DCM) to obtain a yellow gel. N -(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1-} H [Pyrazol-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl)-2,6-dimethoxy-4-(1,3-oxazol-2-yl)benzene-1-sulfonamide 8c (140 mg). LCMS m / z 637 [M+H] + .

[1094] Step 6: Synthesis N -{6-[(3-Cyclopropyl-1- H [-pyrazole-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}-2,6-dimethoxy-4-(1,3-oxazol-2-yl)benzene-1-sulfonamide (Example 8)

[1095] A solution of 140 mg (0.22 mmol) in DCM (2.0 mL) and TFA (5.0 mL) was stirred at room temperature for 3 hours. LCMS showed the formation of the desired product. The crude reaction mixture was concentrated under reduced pressure to give a crude product (200 mg), which was dissolved in DMF (2 mL) and purified by C18 reversed-phase chromatography to give Example 08 (16 mg) as a white solid. LCMS m / z 553.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 11.91 (br s, 1H), 11.17(br s, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 8.08 (br s, 1H), 7.46 (s, 1H), 7.40(s, 1H), 7.26 (s, 2H), 5.78 (s, 1H), 3.89 (s, 3H), 3.87 (s, 6H), 1.90-1.79 (m, 1H), 0.96-0.87 (m, 2H), 0.70-0.63 (m, 2H).

[1096] The compounds in Table 18 below were prepared using intermediate AN or commercially available reagents according to method AF described above for Examples 01-08. The following examples were synthesized with non-critical changes or substitutions to exemplary procedures that will be obvious to those skilled in the art.

[1097] Table 18:

[1098]

[1099]

[1100]

[1101]

[1102]

[1103]

[1104]

[1105]

[1106]

[1107]

[1108]

[1109]

[1110]

[1111]

[1112]

[1113]

[1114]

[1115]

[1116]

[1117]

[1118]

[1119]

[1120]

[1121]

[1122]

[1123]

[1124]

[1125]

[1126]

[1127]

[1128]

[1129]

[1130]

[1131]

[1132]

[1133]

[1134]

[1135] Intermediate O: 5-Ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1 H -Pyrazole-3-amine

[1136]

[1137] N '-(5-ethyl-1 H -pyrazole-3-yl)- N , N -Dimethylformamidinium (O1): Heated at 90°C 5-ethyl-1 H A solution of pyrazole-3-amine was dissolved in DMF-DMA for 15 hours, after which the reaction mixture was cooled, concentrated, and purified by silica gel chromatography (eluting with DCM containing 0-10% methanol) to give O1 (4.2 g, 94%) as a viscous brown oil. LCMS m / z 167 [M+H] + .

[1138] N '-(5-ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1 H -pyrazole-3-yl)- N , N - Dimethylformamide (O2): Sodium hydride (3.3 g, 81.6 mmol, 60% dispersion in mineral oil) was added in part-parts at approximately 0°C. N '-(5-ethyl-1 H -pyrazole-3-yl)- N,N Dimethylformamidinium (O1) (11.3 g, 67.9 mmol) was added to a stirred solution in anhydrous THF (100 mL), and the reaction mixture was stirred for 30 min. Then, [2-(chloromethoxy)ethyl](trimethyl)silane (17.0 g, 18.0 mL, 102 mmol) was added, and the reaction mixture was stirred at room temperature for two h. LCMS indicated that most of the starting material had been consumed, and the reaction mixture was diluted with EtOAc (100 mL) and washed with a saturated aqueous solution of ammonium chloride (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated to give O2 (18.7 g, 93%) as a brown oil. LCMS m / z 297.1 [M+H] + .

[1139] 5-Ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1 H -Pyrazole-3-amine (Intermediate O): Solid NaHCO3 (17.1 g, 204 mmol) was added to a stirred solution of hydrazine hydrochloride (14.0 g, 204 mmol) in a mixture of methanol (140 mL) / H2O (10 mL), and the reaction mixture was stirred at room temperature for 10 minutes. Next, pyrazole-3-amine was added... N '-(5-ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1 H -pyrazole-3-yl)- N,N - Dimethylformamidinium (O2) (20.2 g, 68.0 mmol) and acetic acid (4.1 g, 3.9 mL, 68.0 mmol) were reacted and stirred at 50 °C for seven hours. LCMS indicated the consumption of the starting material. The reactants were concentrated, diluted with EtOAc (200 mL), and washed with saturated NaHCO3 aqueous solution (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by silica gel chromatography (eluting with petroleum ether containing 0-50% EtOAc) to give intermediate O (5.3 g, 32%) as a yellow oil. LCMS m / z 242 [M+H] + ; 1 H NMR (400 MHz, chloroform-) d ) δ 5.49 (s, 1H), 5.20 (s, 2H), 3.60-3.53 (m, 2H), 2.61 (q, J =7.4 Hz, 2H), 1.24 (t, J =7.6 Hz, 3H), 0.93-0.86(m, 2H, -0.01 (s, 9H).

[1140] Intermediate P: N 6 -(5-ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1 H -pyrazole-3-yl)- 5-Methoxy-1,2-benzoxazole-3,6-diamine

[1141]

[1142] 4-Bromo-2-fluoro-5-methoxybenzaldehyde (P1): Under a dry nitrogen atmosphere, bromine (51.8 g, 16.6 mL, 324.0 mmol) was added dropwise to a cooled (0°C) solution of 2-fluoro-5-methoxybenzaldehyde (25.0 g, 162.2 mmol) in chloroform (500 mL). After the addition was complete, the black solution was heated to room temperature and stirred for 5 days. At this point, the red solution was poured into a saturated NaHCO3 aqueous solution (200 mL) and extracted with DCM (3 × 200 mL). The combined organic layers were washed with H2O (100 mL), dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with petroleum ether containing 0-10% EtOAc) to give 24 g of solid material, which appeared as a 2:1 mixture of 4-bromo-2-fluoro-5-methoxybenzaldehyde (P1) and 2-fluoro-5-methoxybenzaldehyde. The mixture was ground with petroleum ether (50 mL) and then filtered to obtain P1 (6.40 g, 17%), which was a pale yellow solid. 1 H NMR (400 MHz, chloroform-) d ) δ 10.39 (s, 1H), 7.23-6.95 (m, 2H), 3.95 (s, 3H).

[1143] N -[( E [4-Bromo-2-fluoro-5-methoxyphenyl]hydroxylamine (P2): Hydroxylamine hydrochloride (3.8 g, 54.9 mmol) was added to a suspension of 4-bromo-2-fluoro-5-methoxybenzaldehyde (P1) (6.4 g, 27.5 mmol) and potassium acetate (5.4 g, 54.9 mmol) in acetic acid (40 mL). The reaction mixture was then refluxed at 120 °C for 4 h, after which LCMS indicated the consumption of the starting material and the detection of two new products. The reaction mixture was cooled, concentrated, and diluted with saturated aqueous NaHCO3 solution (200 mL). The mixture was extracted with EtOAc (3 × 50 mL), and the organic extract was dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with petroleum ether containing 0-10% EtOAc) to give 4-bromo-2-fluoro-5-methoxybenzonitrile (P3, 2.0 g, 32%) as a white solid (see experiments below for analytical data), followed by the more polar P2 (4.0 g, 59%), also a white solid. For P2, 1 H NMR (400 MHz, chloroform-) d ) δ 8.24 (s, 1H), 7.27 (d, J=9.1 Hz, 1H), 7.22-7.16 (m, 1H), 3.84 (s, 3H).

[1144] 4-Bromo-2-fluoro-5-methoxybenzonitrile (P3): To N -[( E [4-Bromo-2-fluoro-5-methoxyphenyl]methylene hydroxylamine (P2) (3.5 g, 14.1 mmol) was added to a solution of ACN (70 mL) with TEA (1.43 g, 14.1 mmol), followed by the addition of dimethyl ethynyl dicarboxylate (DMAD, 4.1 g, 28.2 mmol). The resulting crude reaction mixture was stirred at room temperature for 25 hours, after which TLC (petroleum ether: EtOAc 3 / 1) indicated the consumption of the starting material and the formation of a less polar product. The reactants were concentrated and purified by silica gel chromatography (eluting with petroleum ether containing 0–30% EtOAc) to give P3 (3.0 g, 81%) as a colorless solid. 1 H NMR (400 MHz, chloroform-) d ) δ 7.48 (d, J =7.9 Hz, 1H), 7.03 (d, J =5.3Hz, 1H), 3.92 (s, 3H).

[1145] 4-[(5-ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1 H [-pyrazol-3-yl)amino]-2-fluoro-5-methoxybenzonitrile (P4): Argon gas is bubbled through 4-bromo-2-fluoro-5-methoxybenzonitrile (P3) (2.0 g, 8.7 mmol) and 5-ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1 H A yellow suspension of pyrazole-3-amine (2.5 g, 10.3 mmol, intermediate O) and cesium carbonate (8.4 g, 25.8 mmol) in dioxane (40 mL) was prepared for 1 min, followed by the addition of Pd2(dba)3 (0.79 g, 0.86 mmol) and Xantphos (1.5 g, 2.6 mmol). The mixture was heated at 80 °C for 18 h, after which LCMS showed the consumption of the starting material. The reaction mixture was cooled and diluted with EtOAc (200 mL), filtered, and concentrated to give a brown gel, which was purified by silica gel chromatography (eluting with petroleum ether containing 0–10% EtOAc) to give P4 (3.5 g, 74%) as a yellow oil. LCMS m / z 391 [M+H] + .

[1146] N 6 -(5-ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1 H 3-Pyrazol-3-yl)-5-methoxy-1,2-benzoxazole-3,6-diamine (intermediate P): A solution of acetyloxyoxime acid (2.3 g, 30.1 mmol) and potassium tert-butoxide (3.4 g, 30.1 mmol) in anhydrous DMF (60 mL) was stirred under nitrogen for 30 minutes. 4-[(5-ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1 H A solution of [-pyrazol-3-yl)amino]-2-fluoro-5-methoxybenzonitrile (P4) (3.9 g, 10.0 mmol) in anhydrous DMF (20 mL) was added. Following the addition, the crude reaction mixture was stirred at 80 °C for 16 hours. LCMS indicated approximately 35% of the desired product was formed, with the starting material still present. The reaction mixture was cooled to room temperature, and then acetoxyxamic acid (2.3 g, 30.1 mmol) and potassium tert-butoxide (3.4 g, 30.1 mmol) were added again. After purging with nitrogen, the reaction mixture was stirred at 80 °C for 40 hours. LCMS indicated approximately 55% of the desired product was formed, with the starting material still present. The reaction mixture was cooled to room temperature, and then acetoxyxamic acid (2.3 g, 30.1 mmol) and potassium tert-butoxide (3.4 g, 30.1 mmol) were added again. After purging with nitrogen, the reaction mixture was stirred at 80°C for 16 hours, and LCMS indicated the formation of approximately 80% of the desired product. The reaction was stopped, cooled to room temperature, and concentrated under vacuum to remove DMF, yielding a residue which was dissolved in EtOAc (250 mL). This organic solution was washed with H2O (250 mL), and the aqueous layer was back-extracted with EtOAc (3 × 250 mL). The combined organic extracts were washed with a saturated brine solution (250 mL), dried over sodium sulfate, filtered, and concentrated to give a gel, which was purified by silica gel chromatography (eluting with petroleum ether containing 0–60% EtOAc) to give intermediate P as a solid with approximately 80% purity. The crude product was slurried in a mixture of DCM (5 mL) and petroleum ether (50 mL), stirred for 1 hour, and filtered to give intermediate P (1.2 g, 30%) as a white solid. LCMS m / z 404 [M+H] + ; 1 H NMR (400 MHz, chloroform-) d) δ 7.88 (s, 1H), 6.96 (s, 1H), 6.78 (s, 1H), 5.91 (s, 1H), 5.35 (s, 2H), 3.95 (s, 3H), 3.67-3.63 (m, 2H), 2.72 (q, J =7.4 Hz, 2H), 1.31(t, J =7.6 Hz, 3H), 0.95-0.87 (m, 2H), -0.01 (s, 9H). Note that the recovered filtrate was subjected to silica gel chromatography (eluting with petroleum ether containing 0-60% EtOAc), followed by the DCM / petroleum ether slurry (1:10) to obtain a second batch of intermediate P (1.6 g, 40%) as a yellow / orange solid.

[1147] Method G

[1148] Schemes for synthesizing library compounds

[1149]

[1150] The reactants and stock solutions were placed in a glovebox environment. For the stock solutions, intermediate P (170 mg) was dissolved in anhydrous THF (2.1 mL) to produce a clear solution. The stock solution of the base was prepared by dissolving solid LiHMDS (248 mg) in anhydrous THF (2.3 mL) to obtain a clear solution. Sulfonyl chloride monomers were purchased as needed and supplied in pure form from our stock in 1 mL glass tubes. To prepare the reactants, a solution of intermediate P (100 μL, corresponding to 20 μmol) was added to a 1 mL glass vial containing sulfonyl chloride monomer (30 μmol), followed by the addition of LiHMDS solution (100 μL, 60 μmol). The tray containing the array of glass vials was sealed, removed from the glovebox, and shaken at 60 °C (950 rpm) for 16 hours. LCMS analysis was performed at this time to check for the presence of the desired product, and the reactants were concentrated using Evaporex N2. Saturated NaHCO3 aqueous solution (200 μL) and EtOAc (300 μL) were added to each of the dried samples, followed by shaking at room temperature for 15 min. The organic layer was separated, and the aqueous solution was further extracted with EtOAc (2 × 200 μL). The combined organic matter was concentrated, and then methanesulfonic acid was added to 0.3 M solution of HFIP (200 μL, 60 μmol). The reaction mixture was shaken at room temperature for 50 min, followed by concentration. The dried sample was reconstituted in DMSO (150 μL) and purified by mass-directed reversed-phase HPLC using a Sunfire C18 10 × 50 mm, 5 μm column (5 min method: ACN / H2O (modified with 0.1% formic acid), 4 mL / min).

[1151] Table 19

[1152]

[1153]

[1154]

[1155]

[1156] Example 138: 4-({6-[(3-ethyl-1 ... H [-pyrazole-5-yl)amino]-5-methoxy-1,2-benzoxazole-3- (3-methoxy)- N -{5-[4-(6-methyl-1,2,4,5-tetraazin-3-yl)benzamido]pentyl}benzyl amide

[1157]

[1158] Methyl 4-(chlorosulfonyl)-3-methoxybenzoate (intermediate Gf)

[1159]

[1160] A mixture of methyl 4-iodo-3-methoxybenzoate (3500 mg, 11.98 mmol), 4-methoxybenzyl mercaptan (2030 mg, 13.2 mmol), DIPEA (3100 mg, 24.0 mmol), xantphos (693 mg, 1.20 mmol), and Pd2(dba)3 (549 mg, 0.599 mmol) in anhydrous dioxane (50.0 mL) was degassed six times with nitrogen, followed by stirring at 110 °C for 15 hours. After cooling, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (eluting with petroleum ether containing 0-5% EtOAc) to give methyl 3-methoxy-4-{[(4-methoxyphenyl)methyl]thio}benzoate (3500 mg, 91.7%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d ) δ 7.60 (dd, J =1.38, 8.00 Hz, 1H), 7.49 (d, J =1.00 Hz, 1H), 7.31 (d, J =8.50 Hz, 2H), 7.24(d, J =8.00 Hz, 1H), 6.86 (d, J =8.63 Hz, 2H), 4.15 (s, 2H), 3.96 (s, 3H), 3.93(s, 3H), 3.74-3.86 (m, 3H)

[1161] At 0 °C, 1,3-dichloro-5,5-dimethyllactone (1240 mg, 6.28 mmol) was added fractionally to a stirred solution of methyl 3-methoxy-4-{[(4-methoxyphenyl)methyl]thio}benzoate (1000.0 mg, 3.141 mmol) in a mixture of ACN-HOAc-water (35 mL-1.8 mL-1.3 mL). After the addition, the reaction mixture was stirred at 0–10 °C for 1 hour and then diluted with EtOAc (20 mL). The organic layer was washed with aqueous NaHCO3 solution (5 mL) and brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (eluting with petroleum ether containing 0–40% EtOAc) to give intermediate Gf (500 mg, 60.1%) as a white solid. 1 H NMR (400 MHz, chloroform-) d ) δ 8.06 (d,J =8.28 Hz, 1H), 7.80 (d, J =1.00 Hz, 1H), 7.76 (dd, J =1.51,8.28 Hz, 1H), 4.12-4.18 (m, 3H), 3.98-4.04 (m, 3H)

[1162] 4-[(6-bromo-5-methoxy-1,2-benzoxazol-3-yl)aminosulfonyl]-3-methoxybenzoate (138a)

[1163] Intermediate B (400.0 mg, 1.65 mmol), intermediate Gf (500.0 mg, 1.89 mmol), 3,5-dimethylpyridine (0.563 mL, 4.94 mmol), and DMSO (1.65 mL, 0.0823 mmol) in ACN (4 mL) were stirred at 32 °C for 16 hours. LCMS showed the desired product as the main peak with 40% of the starting material remaining. 3,5-dimethylpyridine (0.563 mL, 4.94 mmol) was added, and the reaction mixture was stirred again at 32 °C for 16 hours. The reaction mixture was diluted with EtOAc, and the organic layer was washed with 1 N citric acid, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (eluting with DCM containing 0-100% ethyl acetate) to give a yellow gel-like 138a (250 mg, 32.2%). LCMS m / z 471.0 [M+H] + .

[1164] 4-{(6-bromo-5-methoxy-1,2-benzoxazol-3-yl)[(4-methoxyphenyl)methyl]aminosulfonyl}-3-methoxybenzoate (138b)

[1165] A solution of 138a (250 mg, 0.530 mmol), 4-methoxybenzyl chloride (91.4 mg, 0.584 mmol), and K₂CO₃ (88.0 mg, 0.637 mmol) in DMF (5.0 mL) was stirred at approximately 80 °C for about 16 hours. The reaction mixture was cooled to 15 °C, poured into H₂O (100 mL), and stirred for 20 minutes. A white solid precipitate formed. EtOAc was added, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (eluting with petroleum ether containing 0–30% EtOAc) to give a gel-like 138b (220 mg, 70.1%), LC-MS. m / z 614.8 [M+H+Na] + .

[1166] 4-({6-[(5-ethyl-1-ethyl) ... 1-(5 H [-pyrazole-3-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}[(4-methoxyphenyl)methyl]aminosulfonyl)-3-methoxybenzoic acid (138c): Method B is derived from methyl 4-{(6-bromo-5-methoxy-1,2-benzoxazol-3-yl)[(4-methoxyphenyl)methyl]aminosulfonyl}-3-methoxybenzoic acid 138b and 4-ethyl-1 H 138c (100 mg, 44%) was prepared as a yellow solid by pyrazole preparation. LCMS m / z 608 [M+H] + .

[1167] {5-[4-({6-[(5-ethyl-1- H [-pyrazole-3-yl)amino]-5-methoxy-1,2-benzoxazole-3-yl}[(4-methoxyphenyl)methyl]aminosulfonyl)-3-methoxybenzamido]pentyl} tert-butyl carbamate (138d): 4-({6-[(5-ethyl-1 H [-pyrazol-3-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}[(4-methoxyphenyl)methyl]aminosulfonyl)-3-methoxybenzoic acid (138c) (100 mg, 0.165 mmol), Boc-1,5-diaminopentane (50 mg, 0.247 mmol), HATU (94 mg, 0.247 mmol) and N,N A solution of diisopropylethylamine (64 mg, 0.494 mmol) in dimethylformamide (2 mL) was stirred for 16 hours, followed by quenching with saturated sodium bicarbonate aqueous solution and partitioning between EtOAc and H2O. The H2O layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with DCM containing 0-10% methanol) to give 138d (120 mg, 92%) as a brown oil. LCMS m / z 792 [M+H] + .

[1168] 4-({6-[(3-ethyl-1-ethyl) ... 1-(3 H [-pyrazole-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl]aminosulfonyl)-3-methoxy- N-{5-[4-(6-methyl-1,2,4,5-tetraazin-3-yl)benzamido]pentyl}benzamide (Example 138): 5-[4-({6-methyl-1,2,4,5-tetraazin-3-yl)benzamido]pentyl}benzamide was stirred in DCM (4 mL) and trifluoroacetic acid (4 mL). H [-pyrazol-3-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}[(4-methoxyphenyl)methyl]aminosulfonyl)-3-methoxybenzamido]pentyl} tert-butyl carbamate (138d) (120 mg, 0.152 mmol) was added for 16 hours and concentrated. The residue was stirred in dimethylformamide (2 mL) and 4-(6-methyl-1,2,4,5-tetraazine-3-yl)benzoic acid (30 mg, 0.14 mmol), HATU (79.1 mg, 0.208 mmol) and N,N -Diisopropylethylamine (143 mg, 1.11 mmol). The mixture was stirred for 16 hours, concentrated, and purified by preparative HPLC by elution with 35-75% ACN-H2O on a Phenomenex C18 (75 × 30 mm, 3 μm) column for 9 minutes to give Example 138 (12 mg, 11%) as a solid. LCMS m / z 770 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.33 (s, 1H), 8.66-8.54 (m, 2H), 8.46 (d, J =8.4 Hz, 2H), 8.07 (s, 2H), 8.01 (d, J =8.5 Hz, 2H), 7.84 (d, J =8.1 Hz, 1H),7.49-7.40 (m, 2H), 7.27 (s, 1H), 5.81 (s, 1H), 3.82 (d, J =4.5 Hz, 6H), 3.23-3.14 (m, 4H), 2.95 (s, 3H), 2.53-2.47 (m, 2H), 1.59-1.45 (m, 4H), 1.38-1.25(m, 2H), 1.10 (t, J =1.0 Hz, 3H).

[1169] Example 139: 2-ethoxy-5-fluoro- N -{6-[(4-Fluoro-1-] H [-pyrazole-3-yl)amino]-5-methoxy-1,2- Benzoxazol-3-yl-4-methylbenzene-1-sulfonamide

[1170]

[1171] Prepare the catalyst complex solution as follows. Dissolve a bulk stock solution of 2-chloro-1,10-phenanthroline (0.21 mg) and [Pd(terpy)(ACN)][BF4]2 (0.51 mg) in 91 µL of ACN in a separate 1 dram vial; this produces a yellow solution. Add the 2-ethoxy-5-fluoro- N -{5-methoxy-6-[(1 H Selectfluor was added to a 1-daramid release vial containing pyrazol-3-yl)amino]-1,2-benzoxazol-3-yl}-4-methylbenzene-1-sulfonamide (Example 77) (1.3 mg, 2.82 µmol). ® (2.0 mg, 5.6 µmol) and ACN (94 µL) were added, followed by the addition of a catalyst complex solution (14 µL, consisting of a palladium complex (0.078 mg, 0.14 µmol, 5 mol%) and 2-chloro-phenanthroline (0.03 mg, 0.14 µmol, 5 mol%)). The crude reaction mixture (labeled as orange solution) was stirred overnight at 25 °C and purified by HPLC to give 0.03 mg of Example 139. LCMS m / z 480 [M+H] + ; 1 H NMR (600 MHz, DMSO- d 6) δ 12.40 (s, 1H), 11.38 (s, 1H), 7.88 (dd, J =4.7, 2.0 Hz, 1H), 7.62 (s, 1H), 7.56 (d, J =8.9 Hz,1H), 7.45 (s, 1H), 7.31 (s, 1H), 7.15 (d, J =5.9 Hz, 1H), 4.10 (q, J =7.0 Hz,2H), 3.90 (s, 3H), 2.27 (s, 3H), 1.22 (t, J =7.0 Hz, 4H).

[1172] Examples 140 and 141: N -{6-[(3-Cyclopropyl-1- H [-pyrazole-5-yl)amino]-5-methoxy-1,2-benzox 3-azolyl-2,6-dimethoxy-4-(oxacyclopent-2-yl)benzene-1-sulfonamide

[1173]

[1174] Step 1: Synthesis of 4-bromo- N -[6-({3-cyclopropyl-1-[(4-methoxyphenyl)methyl]-1H -pyrazole-5-yl]amino)-5-methoxy-1,2-benzoxazol-3-yl]-2,6-dimethoxy- N -[(4-methoxyphenyl)methyl]benzene-1-sulfonamide (140a)

[1175] To 4-bromo- N -[6-({3-cyclopropyl-1-[(4-methoxyphenyl)methyl]-1 H [-pyrazol-5-yl]amino)-5-methoxy-1,2-benzoxazol-3-yl]-2,6-dimethoxybenzyl-1-sulfonamide (7b) and K2CO3 (491 mg, 3.55 mmol) in DMF (11.8 mL) were added to a solution of p-methoxybenzyl chloride (185 mg, 1.18 mmol). The mixture was stirred at 80 °C for 3.5 h. The crude reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel and eluted with 0–40% EtOAc-petroleum ether, which gave 140a (680 mg, 71% yield) as a yellow solid. LCMS m / z 805 (M+H).

[1176] Step 2: Synthesis N -[6-({3-cyclopropyl-1-[(4-methoxyphenyl)methyl]-1 H [-pyrazole-5-yl]amino)-5-methoxy-1,2-benzoxazol-3-yl]-4-(4,5-dihydrofuran-2-yl)-2,6-dimethoxy- N -[(4-methoxyphenyl)methyl]benzene-1-sulfonamide (140b)

[1177] 4-bromo- N -[6-({3-cyclopropyl-1-[(4-methoxyphenyl)methyl]-1 H -pyrazole-5-yl]amino)-5-methoxy-1,2-benzoxazol-3-yl]-2,6-dimethoxy- NA mixture of 140a (580 mg, 0.72 mmol) and 2-(4,5-dihydrofuran-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (250 mg, 1.28 mmol), bis(tri-tert-butylphosphine)palladium (37 mg, 0.07 mmol), and Cs₂CO₃ (705 mg, 2.16 mmol) was prepared for one hour. This crude reaction mixture was combined with crude reaction mixtures from three other reactants (the theoretical combined yield of these three reactants was 247 mg), and the solvent was removed under reduced pressure. The crude product was purified by silica gel (0-45% EtOAc-petroleum ether) to give 400 mg of 140b as a white solid (55% purity according to LCMS). A white solid was passed through an SFC (60% ethanol and 0.1% ammonium hydroxide in CO2; 80 mL / min flow rate; Daicel Chiralpak) ® Further purification was performed using AD (250×30 mm, 10 µm) to yield 50 mg of 140b as a colorless oil (6% yield).

[1178] Step 3: Synthesis N -[6-({3-cyclopropyl-1-[(4-methoxyphenyl)methyl]-1 H -pyrazole-5-yl]amino)-5-methoxy-1,2-benzoxazol-3-yl]-2,6-dimethoxy- N -[(4-methoxyphenyl)methyl]-4-(oxacyclopent-2-yl)benzene-1-sulfonamide (140c)

[1179] Towards N -[6-({3-cyclopropyl-1-[(4-methoxyphenyl)methyl]-1 H [-pyrazole-5-yl]amino)-5-methoxy-1,2-benzoxazol-3-yl]-4-(4,5-dihydrofuran-2-yl)-2,6-dimethoxy- N 140b (50 mg, 0.06 mmol) of 1-[(4-methoxyphenyl)methyl]benzene-1-sulfonamide (140b) was prepared in a solution of TFA (1.0 mL) and DCM (1.0 mL) with the addition of triethylsilane (0.4 mL, 2.5 mmol). The crude reaction mixture was stirred for 30 minutes and the solvent was removed under reduced pressure to give 50 mg of 140c as a yellow oil.

[1180] Step 4: Synthesis N -{6-[(3-Cyclopropyl-1- H[-pyrazol-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}-2,6-dimethoxy-4-(oxacyclopent-2-yl)benzene-1-sulfonamide (140d)

[1181] Heating at 80°C N -[6-({3-cyclopropyl-1-[(4-methoxyphenyl)methyl]-1 H -pyrazole-5-yl]amino)-5-methoxy-1,2-benzoxazol-3-yl]-2,6-dimethoxy- N -[(4-methoxyphenyl)methyl]-4-(oxacyclopent-2-yl)benzene-1-sulfonamide (140c) (350 mg, 0.6 mmol) in TFA (3 mL) for 16 hours. The crude reaction mixture was concentrated under reduced pressure and purified by silica gel (12 g, 0-60% EtOAc-petroleum ether), yielding 80 mg of 140d as a yellow solid (50% purity according to LCMS). The yellow solid was combined with 20 mg of crude product from another experiment (36 mg theoretical yield) and purified by SFC (35% ethanol and 0.1% ammonium hydroxide in CO2; 80 mL / min flow rate; Daicel Chiralcel OJ 250 × 30 mm, 10 µm). The two isomers were separated (10 mg each as white solid).

[1182] N -{6-[(3-Cyclopropyl-1- H [-pyrazol-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}-2,6-dimethoxy-4-(oxacyclopent-2-yl)benzene-1-sulfonamide (Example 140)

[1183] The first elution peak was further purified using SFC (50% ethanol and 0.1% ammonium hydroxide in CO2; flow rate 80 mL / min; Daicel Chiralcel OD 250 × 30 mm, 10 µm) to give Example 140 (6.3 mg, 2% yield) as a white solid. 1 H NMR (400 MHz, chloroform-) d ) δ 7.63 (s, 1H), 7.47 (s, 1H), 7.16 (br.s,1H), 6.57 (s, 2H), 5.75 (br. s, 1H), 4.83 (t, J =7.2 Hz, 1H), 4.03-3.93 (m,1H), 3.96-3.94 (m, 4H), 3.91 (s, 6H), 2.26 (br d,J =6.1 Hz, 1H), 1.89 (br d, J =6.9 Hz, 2H), 1.82-1.76 (m, 1H), 1.69-1.62 (m, 2H), 0.98-0.88 (m, 2H), 0.72-0.66 (m, 2H); LCMS m / z 556.2 (M+H) + ; [α] D 26 = -19.3° (C 0.1, CH3OH).

[1184] N -{6-[(3-Cyclopropyl-1- H [-pyrazol-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}-2,6-dimethoxy-4-(oxacyclopent-2-yl)benzene-1-sulfonamide (Example 141)

[1185] The second elution peak was further purified using SFC (50% ethanol and 0.1% ammonium hydroxide in CO2; 150 mL / min flow rate; Daicel Chiralcel AD 250×30 mm, 10 µm) to give Example 141 (6.0 mg, 2% yield) as a white solid. 1 H NMR (400 MHz, chloroform-) d ) δ 7.66 (s, 1H), 7.47 (s, 1H), 7.11 (br.s,1H), 6.57 (s, 2H), 5.73 (br. s, 1H), 4.83 (t, J =7.2 Hz, 1H), 4.01-3.94 (m,1H), 3.98-3.94 (m, 4H), 3.91 (s, 6H), 2.37-2.30 (m, 1H), 2.02-1.94 (m, 1H),1.90-1.84 (m, 1H), 1.76-1.63 (m, 2H), 0.96-0.91 (m, 2H), 0.72-0.64 (m, 2H);LCMS m / z 556.3 (M+H) + ; [α] D 26 = +4.0° (C 0.1, CH3OH).

[1186] Example 140: Determining N -{6-[(3-Cyclopropyl-1- H [-pyrazole-5-yl)amino]-5-methoxy-1,2-benzox Azolium-3-yl}-2,6-dimethoxy-4-[(2 S The absolute stereochemical procedure of )-oxacyclopent-2-yl]benzene-1-sulfonamide

[1187]

[1188] Step 1: Synthesis of 2-(4-bromo-3,5-dimethoxyphenyl)oxacyclopentane (140e) and 2-(4-bromo-3,5-dimethoxyphenyl)oxacyclopentane (140f)

[1189] The reaction was carried out in four batches. 2-Bromo-5-iodo-1,3-dimethoxybenzene (0.89 g, 2.6 mmol) and 2-[(oxepane-2-carbonyl)oxy]-1 were added to vials. H -Isoindole-1,3(2) H 2,2'-dione (0.52 g, 2.0 mmol), nickel chloride hexahydrate (95 mg, 0.4 mmol), 2,2'-bipyridine (62 mg, 0.4 mmol), DMF (15.0 mL), and a stir bar were added. The mixture was stirred for approximately 5 minutes, followed by the addition of silver nitrate (170 mg, 1.0 mmol). The vial was sealed with an IKA ElectraSyn 2.0 vial cap with a magnesium sacrificial anode (left) and a mesh glassy carbon (RVC) cathode (right), and immediately placed on the IKA ElectraSyn 2.0 stirring plate. Electrolysis was set to 40 mA, 2.0 mmol, 4.0 F / mol. The mixture was allowed to stand for approximately 24 hours. The four batches of the resulting crude reaction mixture were combined and then added to 600 mL of saturated NaHCO3 aqueous solution and extracted with MTBE (3 × 200 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over Na₂SO₄, filtered through a silica stopper (washed with 200 mL EtOAc), and concentrated to give a beige semi-solid. 10 mL of DCM was added to the solid. The mixture was filtered and washed with DCM (2 × 10 mL). The resulting amber filtrate was concentrated and purified by column chromatography (SiO₂, eluted with heptane containing 5–30% EtOAc) to give a grayish-white solid, racemic 2-(4-bromo-3,5-dimethoxyphenyl)oxacyclopentane (1.3 g, 56%). The solid was further purified by chiral SFC (CO₂ containing 14% methanol; 100 mL / min flow rate, 120 bar; Regis...). R,R (Whelk-O1 250×21.1 mm, 10 µm) Separate enantiomers.

[1190] 2-(4-bromo-3,5-dimethoxyphenyl)oxacyclopentane (140e)

[1191] The first elution peak (575 mg, 44%) was separated out as a white solid. 1H NMR (400 MHz, DMSO- d 6) δ6.67 (s, 2H), 4.80 (t, J =7.2 Hz, 1H), 4.05-3.99 (m, 1H), 3.82-3.79 (m, 7H), 2.36-2.28 (m, 1H), 1.99-1.89 (m, 2H), 1.74-1.63 (m, 1H).; [α] D 22 = -30.1° ( c 0.2, MeOH).

[1192] 2-(4-bromo-3,5-dimethoxyphenyl)oxacyclopentane (140f)

[1193] The second elution peak (565 mg, 43%) was separated out as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ6.67 (s, 2 H), 4.80 (t, J =7.2 Hz, 1 H), 4.06-3.98 (m, 1 H), 3.85-3.79 (m, 7H), 2.36-2.28 (m, 1 H), 1.97-1.90 (m, 2 H), 1.74-1.64 (m, 1 H).; [α] D 22 = +21.9° ( c 0.2, MeOH).

[1194] Step 2: Synthesis of 2-(3,5-dimethoxy-4-{[(4-methoxyphenyl)methyl]thio}phenyl)oxacyclopentane (140g)

[1195] Add 20 mL of toluene containing 2-(4-bromo-3,5-dimethoxyphenyl)oxacyclopentane (140e) (575 mg, 2.0 mmol), CataCXium-Pd-G4 (149 mg, 0.2 mmol), 4-methoxybenzyl mercaptan (371 mg, 2.4 mmol), and sodium 2-methylbut-2-ol (1.65 g, 1.8 mL, 40% by weight, 6.01 mmol) to a vial. Seal the vial and rinse three times with nitrogen. Heat the reaction mixture at 100 °C for 18 hours to obtain a light brown / orange solution. Add 20 mL of saturated aqueous NaHCO3 solution to the stirred reaction mixture, which is then extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give a yellow oil, which was purified by column chromatography (SiO2, eluted with heptane containing 5-40% EtOAc) to give 140 g (526 mg, 73%) of a thick orange oil. 1 HNMR (400 MHz, DMSO- d 6) δ 7.12 (d, J =8.56 Hz, 2 H) 6.79 (d, J = 8.56 Hz, 2 H)6.58 (s, 2 H) 4.77 (t, J =7.21 Hz, 1 H) 4.05-3.97 (m, 1 H) 3.90 (s, 2 H) 3.85-3.79 (m, 1 H) 3.77 (s, 6 H) 3.70 (s, 3 H) 2.36-2.22 (m, 1 H) 1.97-1.88 (m, 2H) 1.73-1.61 (m, 1H).

[1196] Step 3: Synthesis of 2,6-dimethoxy-4-[(2 S [-oxacyclopent-2-yl]benzene-1-sulfonyl chloride (140 h) was subjected to small molecule X-ray diffraction to determine its stereochemistry.

[1197] NCS (578 mg, 4.33 mmol) was added to a solution of 2-(3,5-dimethoxy-4-{[(4-methoxyphenyl)methyl]thio}phenyl)oxacyclopentane (140 g) (520 mg, 1.44 mmol) in acetic acid (10.8 mL) and water (3.61 mL), and the resulting reaction mixture was stirred at room temperature for 1 hour. The crude reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic extracts were washed with water (25 mL), dried over Na2SO4, and concentrated to give an orange oil, which was purified by column chromatography (SiO2, eluted with heptane containing 5-75% EtOAc) to give compound 140h (231 mg, 52%) as a beige solid. The absolute stereochemistry of 140h was determined by single-crystal X-ray crystallography. S Crystals of the intermediate were grown from DCM / pentane over 140 h, and data were collected in a nitrogen stream at 100(2) K. See also Figure 1 .

[1198] 1 H NMR (400 MHz, DMSO- d 6) δ 6.56 (s, 2 H) 4.77 (t, J =7.09 Hz, 1 H) 4.04-3.97 (m, 1 H) 3.84-3.77 (m, 1 H) 3.71 (s, 6 H) 2.35-2.25 (m, 1 H) 1.92 (quintet, J =7.09 Hz, 2 H) 1.72-1.60 (m, 1 H).

[1199] Step 4: Synthesis N -(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1-} H -pyrazol-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl)-2,6-dimethoxy-4-[(2 S [-oxacyclopent-2-yl]benzene-1-sulfonamide (140j)

[1200] Towards N 6 -(5-Cyclopropyl-1-(Tetrahydro-2-) H -pyran-2-yl)-1 H -pyrazole-3-yl)-5-methoxybenzo[ dA solution of isoxazol-3,6-diamine (8a) (180 mg, 0.46 mmol) and DMAP (5.67 mg, 0.046 mmol) in pyridine (1.16 mL) was reacted with 2,6-dimethoxy-4-[(2S)-oxacyclopentan-2-yl]benzene-1-sulfonyl chloride (140 h) (199 mg, 0.65 mmol). The solution turned dark orange and was stirred at room temperature for 18 hours. The reactants were diluted with DCM (10 mL) and 1M AcOH (10 mL) and extracted with DCM (3 × 8 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4 and concentrated to give an orange oil, which was purified by reverse-phase HPLC (40-80% acetonitrile / water with 10 mM ammonium acetate; 25 mL / min flow rate, within 8 minutes, 120 bar; Phenomenex Gemini 5 μm NX-C18 150×21.2 mm, 5 µm) to give 140j (188 mg, 63%) as a white powder. 1 H NMR (400 MHz, DMSO- d 6) δ 10.93 (s,1 H) 8.17 (s, 1 H) 8.15 (s, 1 H) 7.42 (s, 1 H) 6.65 (s, 2 H) 5.78 (s, 1 H)5.50 (dd, J =9.69, 2.44 Hz, 1 H) 4.79 (t, J =7.13 Hz, 1 H) 4.04-3.90 (m, 2 H)3.87 (s, 3 H) 3.84-3.72 (m, 7 H) 3.70-3.59 (m, 1 H) 2.41-2.26 (m, 2 H) 2.11-2.00 (m, 1 H) 1.97-1.85 (m, 4 H) 1.77-1.49 (m, 4 H) 0.97 (dd, J =8.19, 2.44Hz, 2 H) 0.70-0.54 (m, 2 H); LCMS m / z 639.9 (M+H) + .

[1201] Step 5: Synthesis N -{6-[(3-Cyclopropyl-1- H -pyrazole-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}-2,6-dimethoxy-4-[(2 S[-oxacyclopent-2-yl]benzene-1-sulfonamide (Example 140)

[1202] To contain N -(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1-} H -pyrazol-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl)-2,6-dimethoxy-4-[(2 S [-oxacyclopent-2-yl]benzene-1-sulfonamide (140j) (183 mg, 0.29 mmol) was added to a 1.43 mL vial of DCM with hydrogen chloride (2.86 mL, 4.0 M dioxane solution, 11.4 mmol), and the reaction mixture was stirred at room temperature for 48 hours. The resulting solid was filtered and recrystallized from ACN to give compound 140 (138 mg, 87%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 10.93 (s, 1H) 8.11 (br. s, 1 H) 8.03 (s, 1 H) 7.42 (s, 1 H) 6.65 (s, 2 H) 5.82 (s, 1 H)4.78 (t, J =7.15 Hz, 1 H) 4.03-3.95 (m, 1 H) 3.88 (s, 3 H) 3.84-3.78 (m, 1 H)3.76 (s, 6 H) 2.37-2.27 (m, 1 H) 1.96-1.83 (m, 3 H) 1.65 (dq, J =12.15, 7.77Hz, 1 H) 0.99-0.89 (m, 2 H) 0.73-0.65 (m, 2 H) ); LCMS m / z 556.9 (M+H) + [α] D 22 = -14.8° ( c 0.3, MeOH). N -{6-[(3-Cyclopropyl-1- H -pyrazole-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}-2,6-dimethoxy-4-[(2 S Enantiomeric excess (ee) of 1-oxacyclopentan-2-yl]benzene-1-sulfonamide (140) was obtained via a chiral SFC (20% methanol with CO2 containing 10 mM NH3; 4 mL / min flow rate, 140 bar; Regis ( S,SThe 140-inch (Whelk-O1; 100 × 4.6 mm, 5 µm) was confirmed to be >99%. It was determined that the absolute stereochemical configuration of Example 140 was (S) because the X-ray structure of intermediate 140h (step 3) exhibited absolute stereochemistry of (S), and none of the subsequent reactions of intermediate 140h could affect the stereochemical integrity of the chiral center. See also... Figure 1 .

[1203] Example 141: N -{6-[(3-Cyclopropyl-1- H [-pyrazole-5-yl)amino]-5-methoxy-1,2-benzoxazole-3- 2,6-dimethoxy-4-[(2] R The absolute stereochemical determination of 1-oxacyclopentan-2-yl]benzene-1-sulfonamide

[1204]

[1205] Step 1: Synthesis of 2-(3,5-dimethoxy-4-{[(4-methoxyphenyl)methyl]thio}phenyl)oxacyclopentane (141a)

[1206] A vial containing 19.7 mL of toluene (140f) (565 mg, 1.97 mmol), CataCXium-Pd-G4 (146 mg, 0.19 mmol), 4-methoxybenzyl mercaptan (364 mg, 2.36 mmol), and sodium 2-methylbut-2-ol (1.63 g, 1.77 mL, 40 wt%, 5.90 mmol) was added. The vial was sealed and rinsed three times with nitrogen. The reaction mixture was heated at 100 °C for 18 hours to give a light brown / orange solution. A saturated aqueous solution of NaHCO3 (20 mL) was added to the stirred reaction mixture, which was then extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give a yellow oily substance, which was purified by column chromatography (SiO2, eluted with heptane containing 5-40% EtOAc) to give compound 141a (555 mg, 78%) as a thick orange gel. 1 H NMR (400 MHz, DMSO- d 6) δ 7.12 (d, J =8.56 Hz, 2H) 6.79 (d, J =8.56Hz, 2H) 6.58 (s, 2H) 4.77 (t, J =7.15 Hz, 1H) 4.05-3.97 -(m, 1H) 3.90 (s, 2H)3.85-3.79 (m, 1H) 3.77 (s, 6H) 3.70 (s, 3H) 2.30 (dq, J=12.47, 6.48 Hz, 1H)1.93 (quintuplet, J =7.09 Hz, 2H) 1.74-1.61 (m, 1H).

[1207] Step 2: Synthesis of 2,6-dimethoxy-4-[(2 R )-Oxycyclopentan-2-yl]benzene-1-sulfonyl chloride (141b)

[1208] NCS (611 mg, 4.58 mmol) was added to a solution of 2-(3,5-dimethoxy-4-{[(4-methoxyphenyl)methyl]thio}phenyl)oxacyclopentane (141a) (550 mg, 1.53 mmol) in acetic acid (11.4 mL) and water (3.81 mL), and the mixture was stirred at room temperature for 1 hour. The crude mixture was diluted with water (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic extracts were washed with water (25 mL) and brine (25 mL), dried over Na2SO4, and concentrated to give an orange oil, which was purified by column chromatography (SiO2, eluted with heptane containing 5-75% EtOAc) to give compound 141b (256 mg, 55%) as a pale yellow solid. It has been determined that, since 141b is the opposite enantiomer of 140h as studied by single-crystal X-ray crystallography, its absolute stereochemistry is ( R See also Figure 1 . 1 H NMR (400 MHz, DMSO- d 6) δ6.56 (s, 2H) 4.77 (br. t, J =7.09 Hz, 1H) 3.97 - 4.05 (m, 1H) 3.76 - 3.85 (m, 1H) 3.72 (s, 6H) 2.25 - 2.35 (m, 1H) 1.92 (quintet, J =7.09 Hz, 2H) 1.67 (dq, J =12.01, 7.77 Hz, 1H).

[1209] Step 3: Synthesis N -(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1-} H -pyrazol-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl)-2,6-dimethoxy-4-[(2 R [-oxacyclopent-2-yl]benzene-1-sulfonamide (141c)

[1210] TowardsN 6 -(5-Cyclopropyl-1-(Tetrahydro-2-) H -pyran-2-yl)-1 H -pyrazole-3-yl)-5-methoxybenzo[ d A solution of isoxazol-3,6-diamine (8a) (185 mg, 0.47 mmol) and DMAP (5.82 mg, 0.048 mmol) in pyridine (1.19 mL) was supplemented with 2,6-dimethoxy-4-[(2R)-oxacyclopentan-2-yl]benzene-1-sulfonyl chloride (141b) (249 mg, 0.81 mmol). The solution turned dark orange and was stirred at room temperature for 18 hours. The reactants were diluted with DCM (10 mL) and 1M AcOH (10 mL) and extracted with DCM (3 × 8 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4 and concentrated to give an orange / brown oil, which was dried under vacuum for 48 hours to give 141c (408 mg, >99% containing residual pyridine and acetic acid) as a beige solid, which was used without further purification. 1 H NMR (400MHz, DMSO- d 6) δ 10.93 (s, 1H) 8.17 (s, 1H) 8.16 (s, 1H) 7.42 (s, 1H) 6.65 (s,2H) 5.78 (s, 1H) 5.50 (dd, J =9.72, 2.38 Hz, 1H) 4.78 (t, J =7.15 Hz, 1H) 4.03-3.90 (m, 2H) 3.87 (s, 3H) 3.84-3.77 (m, 1H) 3.76 (s, 6 H) 3.70-3.60 (m, 1H)2.41-2.24 (m, 2H) 2.10-2.01 (m, 1H) 1.93-1.89 (m, 4H) 1.76-1.53 ​​(m, 4H) 0.97(dd, J =8.25, 2.38 Hz, 2H) 0.69-0.55 (m, 2H); LCMS m / z 641.0 (M+H) + .

[1211] Step 4: Synthesis N -{6-[(3-Cyclopropyl-1- H -pyrazole-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}-2,6-dimethoxy-4-[(2R [-oxacyclopent-2-yl]benzene-1-sulfonamide (Example 141)

[1212] To contain N -(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1-} H -pyrazol-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl)-2,6-dimethoxy-4-[(2 R [-oxacyclopent-2-yl]benzene-1-sulfonamide (141c) (305 mg, 0.48 mmol) was added to a vial of DCM (2.38 mL) with hydrogen chloride (4.77 mL, 4.0 M dioxane solution, 19.1 mmol), and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM (10 mL) and 1 M HCl aqueous solution (10 mL) and extracted with DCM (3 × 10 mL). The combined organic extracts were dried over Na2SO4 and concentrated to give a clear oily substance, which was purified by reverse-phase HPLC (0-90% acetonitrile / water containing 0.5% TFA; 25 mL / min flow rate, over 8 minutes, Phenomenex Gemini 5 μm NX-C18 150 × 21.2 mm, 5 µm) to give 141 (216 mg, 82%) as a white powder. 1 H NMR (400 MHz, DMSO- d 6) δ 10.91 (s, 1H) 8.08 (s, 1H) 8.04 (s,1H) 7.40 (s, 1H) 6.65 (s, 2H) 5.79 (s, 1H) 4.79 (t, J =7.15 Hz, 1H) 4.03-3.94(m, 1H) 3.87 (s, 3H) 3.84-3.78 (m, 2H) 3.76 (s, 6H) 2.36-2.26 (m, 1H) 1.97-1.81 (m, 3H) 1.65 (dq, J =12.15, 7.77 Hz, 1H) 0.97-0.88 (m, 2H) 0.71-0.62 (m,2H); LCMS m / z 556.5 (M+H) + ; [α] D 22 = +10.6° ( c 0.3, MeOH). N -{6-[(3-Cyclopropyl-1- H-pyrazole-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}-2,6-dimethoxy-4-[(2 R The ee of )-oxacyclopent-2-yl]benzene-1-sulfonamide (141) was obtained by chiral SFC (20% methanol with 10 mM NH3 in CO2; 4 mL / min flow rate, 140 bar; Regis ( S,S Whelk-O1 (100 × 4.6 mm, 5 µm) was confirmed to be approximately 99%. It was determined that intermediate 141b was a manifestation of ( S The absolute stereochemical intermediate 140h is an enantiomer of the X-ray structure of the intermediate 141b, and none of the subsequent reactions of the intermediate 141b can affect the stereochemical integrity of the chiral center. Therefore, the absolute stereochemical configuration of Example 141 is ( R See also Figure 1 .

[1213] Examples 142 and 143: N -{6-[(3-Cyclopropyl-1- H [-pyrazole-5-yl)amino]-5-methoxy-1,2-benzox 3-azolyl-2,6-dimethoxy-4-(oxacyclohexyl-2-yl)benzene-1-sulfonamide

[1214]

[1215] N -(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1-} H [-pyrazol-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl)-4-(3,4-dihydro-2-yl] H -pyran-6-yl)-2,6-dimethoxybenzene-1-sulfonamide (142a): to 4-bromo- N -(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1-} H [-pyrazol-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl)-2,6-dimethoxybenzene-1-sulfonamide (8b) (600 mg, 0.92 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,4-dihydro-2 H142a (292 mg, 1.39 mmol) was added to a solution of DMA (5 mL) with H₂O (1.1 mL) containing XPos Pd G₃ (78.3 mg, 0.09 mmol) and tripotassium phosphate (589 mg, 2.78 mmol). The mixture was degassed, purged with nitrogen, and heated at 80 °C for 3 hours. The crude reaction mixture was combined with another batch (50 mg theoretical yield), filtered, concentrated under reduced pressure, and purified by silica gel (20 g, eluted with 50–100% EtOAc-petroleum ether followed by 0–10% CH₃OH-DCM) to give 142a (673 mg, 100% yield) as a yellow oil. LCMS m / z 652.2 (M+H) + .

[1216] N -{6-[(3-Cyclopropyl-1- H [-pyrazol-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl]-2,6-dimethoxy-4-(oxacyclohex-2-yl)benzene-1-sulfonamide (Examples 142 and 143): to N -(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1-} H [-pyrazol-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl)-4-(3,4-dihydro-2-yl] H (-pyran-6-yl)-2,6-dimethoxybenzene-1-sulfonamide (142a) (730 mg, 1.12 mmol) was added to a solution of DCM (6 mL) and TFA (6 mL) with 1.5 mL of triethylsilane. After 30 minutes, the brown solution turned black. Another 6 mL of TFA was added, and the crude reaction mixture was stirred for 3 hours. The solvent was removed under reduced pressure, and the resulting black oil was purified by reversed-phase chromatography (C18 column, 150 × 40 mm, ammonium formate aqueous solution-acetonitrile mobile phase) to give the product as a white solid (125 mg, 20% yield). LCMS m / z 570.3 (M+H) + Enantiomers were separated by a chiral SFC (30% methanol and 0.1% ammonium hydroxide in CO2; 80 mL / min flow rate; Daicel Chiralcel OJ, 250 mm × 30 mm, 10 µm).

[1217] N -{6-[(3-Cyclopropyl-1- H[-pyrazol-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}-2,6-dimethoxy-4-(oxacyclohex-2-yl)benzene-1-sulfonamide (Example 142): The first elution peak (30 mg, 4.7% yield) was isolated as a white solid. 1 H NMR (400 MHz, methanol-) d 4 ) δ 7.61 (br s, 1H), 7.30 (s, 1H), 6.69 (s, 2H), 5.76 (s, 1H), 4.33 (dd, J =11.2, 1.9 Hz, 1H), 4.09-4.05 (m, 1H), 3.94 (s, 3H), 3.84 (s, 6H), 3.62-3.56 (m, 1H), 1.92-1.83 (m, 3H), 1.73-1.54(m, 3H), 1.49-1.42 (m, 1H), 1.00-0.95 (m, 2H), 0.76-0.72 (m, 2H); LCMS m / z 570.3 (M+H) + ; [α] D 25 = -17.43 o ( c (, CH3OH).

[1218] N -{6-[(3-Cyclopropyl-1- H [-pyrazol-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}-2,6-dimethoxy-4-(oxacyclohex-2-yl)benzene-1-sulfonamide (Example 143): The second elution peak (28 mg, white solid) was further purified by a chiral SFC (35% methanol and 0.1% ammonium hydroxide in CO2; 80 mL / min flow rate; Daicel Chiralcel OJ, 250 mm × 30 mm, 10 µm), which yielded a product as a white solid (15 mg, 2.3% yield). 1 H NMR (400 MHz, methanol-) d 4 ) δ 7.62 (br s, 1H), 7.30 (s, 1H), 6.69 (s, 2H), 5.76 (s,1H), 4.33 (dd, J=11.2, 1.8 Hz, 1H), 4.09-4.06 (m, 1H), 3.94 (s, 3H), 3.83 (s,6H), 3.62-3.56 (m, 1H), 1.95-1.86 (m, 3H), 1.72-1.56 (m, 3H), 1.49-1.42 (m,1H), 1.00-0.95 (m, 2H), 0.76-0.72 (m, 2H); LCMS m / z 570.3 (M+H) + ; [α] D 25 = + 12.43 o ( c = 0.19, CH3OH).

[1219] Example 144: N -{6-[(3-Cyclopropyl-1- H [-pyrazole-5-yl)amino]-5-methoxy-1,2-benzoxazole-3- 4-[(dimethylamino)methyl]-2,6-dimethoxybenzene-1-sulfonamide

[1220]

[1221] 4-Bromo- N -(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1-} H [-pyrazole-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl)-2,6-dimethoxy- N -[(4-methoxyphenyl)methyl]benzene-1-sulfonamide (144a): towards 4-bromo- N -(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1-} H [-pyrazol-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl)-2,6-dimethoxybenzyl-1-sulfonamide (8b) (930 mg, 1.43 mmol) and K2CO3 (793 mg, 5.74 mmol) in DMF (14.3 mL) were added dropwise with 4-methoxybenzyl chloride (269 mg, 1.72 mmol). The crude reaction mixture was stirred at 80 °C for 16 hours. The crude reaction mixture was added to ice water (10 mL) and a white solid was formed. The mixture was extracted with EtOAc (5 × 3 mL) and the combined organic extracts were concentrated under reduced pressure to give a dark yellow solid. The crude product was purified by silica gel (40 g) and eluted with 0–50% EtOAc-petroleum ether to give 144a (930 mg, 84% yield) as a white solid. LCMS m / z 770 (M+H) + .

[1222] 4-{(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1 H [-pyrazole-3-yl]amino}-5-methoxy-1,2-benzoxazole-3-yl)[(4-methoxyphenyl)methyl]aminosulfonyl}-3,5-dimethoxybenzoate methyl ester (144b): to 4-bromo- N -(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1-} H [-pyrazole-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl)-2,6-dimethoxy- N A mixture of 144a (930 mg, 1.21 mmol) and Pd(dppf)Cl2 (177 mg, 0.242 mmol) and triethylamine (367 mg, 3.63 mmol) in MeOH (60.5 mL) was added. The mixture was degassed and purged twice with nitrogen, followed by degassed and refilled twice with carbon monoxide. The reaction mixture was stirred at 65 °C under a carbon monoxide (50 psi) atmosphere for 16 h. The crude reaction mixture was concentrated and purified by silica gel (20 g) and eluted with 0–50% EtOAc-petroleum ether to give 144b (815 mg, 90% yield) as a yellow solid. LCMS m / z 748 (M+H) + .

[1223] 4-{(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1 H [-pyrazol-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl)[(4-methoxyphenyl)methyl]aminosulfonyl}-3,5-dimethoxybenzoic acid (144c): to 4-{(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1 HMethyl methyl 144b (144b) (815 mg, 1.09 mmol) in a mixture of pyrazol-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl)[(4-methoxyphenyl)methyl]aminosulfonyl}-3,5-dimethoxybenzoate (144b) and THF (10.9 mL) was added to a solution of 2 M LiOH-H2O (1.36 mL, 2.72 mmol). The mixture was stirred at 25 °C for 3 hours. The crude reaction mixture was diluted with H2O (10 mL) at 0 °C and then concentrated to remove THF. The resulting aqueous mixture was treated with 1 M HCl aqueous solution until the pH was about 3, and then extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried (MgSO4), filtered, and concentrated to give 144c (805 mg, 99% yield) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d ) δ 7.90 (s, 1H), 7.38 (d, J =8.6 Hz, 2H),7.23 (s, 1H), 7.08 (s, 1H), 7.02 (s, 1H), 6.75 (d, J =8.6 Hz, 2H), 5.64 (s,1H), 5.48 (dd, J =10.0, 2.4 Hz, 1H), 5.04 (s, 2H), 4.16-4.08 (m, 2H), 3.89 (s,3H), 3.82-3.61 (m, 11H), 2.60-2.50 (m, 1H), 2.16-2.13 (m, 2H), 1.99-1.84 (m,2H), 1.77-1.69 (m, 2H), 0.83-0.78 (m, 2H), 0.66-0.62 (m, 2H); LCMS m / z 734 (M+H) + .

[1224] 4-{(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1 H [-pyrazol-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl)[(4-methoxyphenyl)methyl]aminosulfonyl}-3,5-dimethoxy- N , N -Dimethylbenzamide (144d): oriented towards 4-{(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1-} HHATU (311 mg, 0.818 mmol) was added to a solution of pyrazol-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl)[(4-methoxyphenyl)methyl]aminosulfonyl}-3,5-dimethoxybenzoic acid (144c) (400 mg, 0.545 mmol), DIEA (282 mg, 2.18 mmol), and dimethylamine hydrochloride (89 mg, 1.09 mmol) in DMF (2.73 mL). The mixture was stirred at room temperature for 16 hours. The crude reaction mixture was diluted with ice water (20 mL) and then extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried (MgSO4), filtered, and concentrated. The crude residue was purified by silica gel (20 g) and eluted with 0-100% EtOAc-petroleum ether to give 144d (390 mg, 94% yield) as a light orange solid. LCMS m / z 761 (M+H) + .

[1225] N -(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1-} H [-pyrazol-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl)-4-[(dimethylamino)methyl]-2,6-dimethoxy- N -[(4-methoxyphenyl)methyl]benzene-1-sulfonamide (144e): under nitrogen atmosphere at 0 °C, to 4-{(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1- H [-pyrazol-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl)[(4-methoxyphenyl)methyl]aminosulfonyl}-3,5-dimethoxy- N,N 144e (50.0 mg, 0.066 mmol) was dissolved in THF (0.66 mL) with lithium aluminum hydride (2.74 mg, 0.0723 mmol). The crude reaction mixture was stirred at 0 °C for 50 min, then quenched with H2O (3 mL) and extracted with EtOAc (5 mL × 3). The combined organic extracts were washed with brine (10 mL), dried (MgSO4), filtered, and concentrated to give 144e (45 mg, 92% yield) as a yellow gel.

[1226] N -{6-[(3-Cyclopropyl-1- H[-pyrazol-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}-4-[(dimethylamino)methyl]-2,6-dimethoxybenzene-1-sulfonamide (Example 144): Stirred at room temperature N -(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1-} H [-pyrazol-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl)-4-[(dimethylamino)methyl]-2,6-dimethoxy- N 1-[(4-methoxyphenyl)methyl]benzene-1-sulfonamide (144e) (45 mg, 0.060 mmol) was prepared in TFA (1.0 mL) and DCM (1.0 mL) for 16 hours. The mixture was concentrated and purified by preparative HPLC (Boston Prime C18, 150 × 30 mm, 5 µm, H2O-ACN containing 0.1% ammonium hydroxide, gradient 15–35% ACN, 35 mL / min over 10 min) to give Example 144 (7.1 mg, 22% yield) as a white solid. 1 HNMR (methanol-) d 4 , 400 MHz) δ 7.54 (br s, 1H), 7.29 (s, 1H), 6.71 (s, 2H), 5.75(s, 1H), 3.95 (s, 3H), 3.79 (s, 6H), 3.57 (s, 2H), 2.31 (s, 6H), 1.93-1.86(m, 1H), 1.00-0.96 (m, 2H), 0.75-0.71 (m, 2H); LCMS m / z 543.3 (M+H) + .

[1227] Examples 145 and 146: N -{6-[(3-Cyclopropyl-1- H [-pyrazole-5-yl)amino]-5-methoxy-1,2-benzox AZol-3-yl}-4-[1,4-dioxane-2-yl]-2,6-dimethoxybenzene-1-sulfonamide

[1228]

[1229] Examples 145 and 146, in a similar manner to Examples 142 and 143, use 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2,3-dihydro-1,4-dioxane instead of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,4-dihydro-2 H-Pyran was prepared. Enantiomers were separated by chiral SFC (60% isopropanol and 0.1% ammonium hydroxide in CO2; 80 mL / min flow rate; Daicel Chiralcel OJ 250×30 mm, 10 µm).

[1230] N -{6-[(3-Cyclopropyl-1- H [-pyrazol-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}-4-[1,4-dioxane-2-yl]-2,6-dimethoxybenzene-1-sulfonamide (Example 145):

[1231] The first elution peak, which was a white solid, was separated (46 mg, 19% yield). 1 H NMR (400 MHz, chloroform-d) δ 7.78-7.71 (m, 1H), 7.47-7.42 (m, 1H), 7.06-6.98 (m, 1H), 6.62-6.54 (m,2H), 5.76-5.64 (m, 1H), 4.61-4.52 (m, 1H), 4.00-3.96 (m, 3H), 3.96-3.93 (m,1H), 3.92-3.90 (m, 6H), 3.89-3.78 (m, 3H), 3.75-3.65 (m, 1H), 3.40-3.28 (m,1H), 1.90-1.82 (m, 1H), 1.04-0.95 (m, 2H), 0.78-0.70 (m, 2H); LCMS m / z 572.3[M+H] + ; [α] D 26 = -56° ( c 0.1, MeOH). Example 145 was characterized by a chiral SFC (40% isopropanol with 0.05% DIPEA in CO2; 4 mL / min flow rate, 103 bar, 35 °C; Chiralcel OJ-3; 50 × 4.6 mm, 3 µm) and a retention time of 0.961 min (peak 1).

[1232] N -{6-[(3-Cyclopropyl-1- H [-pyrazol-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}-4-[1,4-dioxane-2-yl]-2,6-dimethoxybenzene-1-sulfonamide (Example 146):

[1233] The second elution peak, which was a white solid, was separated (39 mg, 16% yield). 1 H NMR (400 MHz, chloroform-) d ) δ 7.82-7.72 (m, 1H), 7.50-7.38 (m, 1H), 7.07-6.96 (m, 1H), 6.64-6.54 (m,2H), 5.77-5.62 (m, 1H), 4.65-4.47 (m, 1H), 4.00-3.96 (m, 3H), 3.96-3.93 (m,1H), 3.92-3.90 (m, 6H), 3.89-3.77 (m, 3H), 3.76-3.65 (m, 1H), 3.40-3.27 (m,1H), 1.89-1.82 (m, 1H), 1.04-0.95 (m, 2H), 0.79–0.68 (m, 2H); LCMS m / z 572.3[M+H] + ; [α] D 26 = +31° ( c 0.1, MeOH). Example 146 was characterized by a chiral SFC (40% isopropanol with 0.05% DIPEA in CO2; 4 mL / min flow rate, 103 bar, 35 °C; Chiralcel OJ-3; 50 × 4.6 mm, 3 µm) and a retention time of 1.931 min (peak 2).

[1234] Example 145 (Procedure for Determining Absolute Stereochemistry)

[1235]

[1236] Step 1: Synthesis (2) R )-2-(4-bromo-3,5-dimethoxyphenyl)-1,4-dioxane (145a) (small molecule X-ray diffraction to determine stereochemistry) and (2 S )-2-(4-bromo-3,5-dimethoxyphenyl)-1,4-dioxane(145b)

[1237] Add 2-bromo-5-iodo-1,3-dimethoxybenzene (0.89 g, 2.6 mmol), 1,4-dioxane-2-carboxylic acid 1,3-dioxoisoindoline-2-yl ester (0.55 g, 2.0 mmol), nickel chloride hexahydrate (95 mg, 0.4 mmol), 2,2'-bipyridine (62 mg, 0.4 mmol), DMF (15.0 mL), and a stir bar to a vial. Stir the mixture for approximately 5 minutes, then add silver nitrate (170 mg, 1.0 mmol). Seal the vial with an IKA ElectraSyn 2.0 vial cap with a magnesium sacrificial anode (left) and a mesh glassy carbon (RVC) cathode (right), and immediately place the vial on an IKA ElectraSyn 2.0 stirring plate. Set the electrolysis to 40 mA, 2.0 mmol, 4.0 F / mol. Allow the mixture to stand for approximately 24 hours. The crude reaction mixture was combined with an earlier batch of the same size, diluted with water, and extracted with MTBE (3×). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The racemic mixture was purified by column chromatography (ISCO, SiO2, eluted with heptane containing 0-100% DCM) to give a yellow solid (477 mg, 39%). 1 H NMR (400 MHz, DMSO- d 6) δ 6.74(s, 2H), 4.59 (dd, J=10.1, 2.7 Hz, 1H), 3.95-3.86 (m, 2H), 3.84 (s, 6H), 3.81-3.72 (m, 2H), 3.66-3.55 (m, 1H), 3.33-3.28 (m, 1H); LCMS m / z 303.6 (M+H) + Enantiomers were separated by chiral SFC (10% methanol with 10 mM NH3 in CO2; 4 mL / min flow rate, 160 bar, 25 °C; Lux Cell-1; 100 × 4.6 mm, 3 µm).

[1238] 145a: (2 R )-2-(4-bromo-3,5-dimethoxyphenyl)-1,4-dioxane

[1239] The first elution peak (188 mg, 31%, >95% ee) was separated as a white solid. LCMS m / z 303.6 (M+H) + ; [α] D 22 = -42.0° ( c0.1, MeOH). The absolute stereochemistry of 145a was determined by single-crystal X-ray crystallography as ( R Crystals of intermediate 145a were grown from DCM / pentane, and data were collected in a nitrogen stream at 100(2) K. See also Figure 2 .

[1240] 145b: (2 S )-2-(4-bromo-3,5-dimethoxyphenyl)-1,4-dioxane

[1241] A second elution peak (193 mg, 32%, >95% ee) was separated as a white solid. LCMS m / z 303.6 (M+H) + ; [α] D 22 = +33.5° ( c 0.1, MeOH). It has been determined that 145b is determined through single-crystal X-ray crystallography to be ( R The 145a enantiomer of ) has the absolute stereochemistry as ( S See also Figure 2 .

[1242] Step 2: Synthesize 4-[(2 R )-1,4-dioxane-2-yl]-2,6-dimethoxybenzene-1-sulfonyl chloride (145c)

[1243] Add (2) dissolved in THF (1.2 mL) to the vial. R2-(4-bromo-3,5-dimethoxyphenyl)-1,4-dioxane (145a) (60 mg, 0.20 mmol). Nitrogen gas was bubbled through the solution for 5 minutes, followed by the addition of a solution of isopropyl magnesium chloride-lithium chloride complex (69 mg, 0.37 mL, 1.3 M THF solution, 2.4 equivalents, 0.48 mmol), and the reaction mixture was stirred at 60 °C for 2.5 h. The reaction mixture was cooled to room temperature and then added dropwise at -40 °C to a degassed solution of DABSO (0.12 g, 0.49 mmol) in 1.2 mL of THF. The reaction mixture was slowly heated to room temperature over 18 h. NCS (0.13 g, 0.95 mmol) was added, and the reaction mixture was stirred at 40 °C for 20 minutes, followed by cooling to room temperature and dilution with EtOAc and water. The mixture was extracted with EtOAc (×4) and washed with brine, then dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (ISCO, SiO2, eluting with heptane containing 0-100% EtOAc) to give an oily 145c (10 mg, 16%). The crude oily residue was used.

[1244] Step 3: Synthesis N -(6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1-} H -pyrazol-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl)-4-[(2 R 1,4-Dioxacyclohex-2-yl]-2,6-dimethoxybenzene-1-sulfonamide (145d)

[1245] Add 8a (10 mg, 27 μmol), 145c (10 mg, 32 μmol), DMAP (0.33 mg, 2.7 μmol), and pyridine (34 μL) to the vial. Stir the reaction mixture at room temperature for 18 h. Dilute the crude reaction mixture with 1 M AcOH and extract with DCM (×4). Wash the combined organic layers with brine, then dry (Na₂SO₄), filter, and concentrate. Continue using the crude oil for 145 days. LCMS m / z 656.3 (M+H) + .

[1246] Step 4: N -{6-[(3-Cyclopropyl-1- H [-pyrazole-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}-4-[(2] R )-1,4-dioxane-2-yl]-2,6-dimethoxybenzene-1-sulfonamide (145)

[1247] TFA (0.21 g, 0.14 mL, 120 equivalents, 1.8 mmol) was added dropwise to a solution of 145a (10 mg, 15 μmol) in DCM (0.25 mL). The reaction mixture was sealed and stirred at room temperature for 18 hours. The crude reaction mixture was concentrated and analyzed by SFC to correlate retention time with structural partition. Chiral SFC (40% isopropanol with 0.05% DIPEA in CO2; 4 mL / min flow rate, 103 bar, 35 °C; Chiralcel OJ-3; 50 × 4.6 mm, 3 µm) yielded a retention time of 0.693 min (peak 1), corresponding to 145a. It was determined that the X-ray structure of intermediate 145a (step 1) showed ( R The absolute stereochemistry of Example 145 is such that none of the subsequent reactions of intermediate 145a affect the stereochemical integrity of the chiral center. Therefore, the absolute stereochemical configuration of Example 145 is ( R See also Figure 2 .

[1248] Example 145 (Stereospecific procedure): N -{6-[(3-Cyclopropyl-1- H [-pyrazole-5-yl)amino]-5-methoxy 1,2-benzoxazol-3-yl}-4-[(2 R 1,4-Dioxacyclohex-2-yl]-2,6-dimethoxybenzene-1-sulfonamide

[1249]

[1250] Step 1: Synthesis of 1-(4-bromo-3,5-dimethoxyphenyl)-2-(2-chloroethoxy)ethyl-1-one (145e)

[1251] A solution of 2-bromo-5-iodo-1,3-dimethoxybenzene (142.5 g, 415.51 mmol) in THF (1280 mL) was cooled in a dry ice / acetone bath and bubbled with N2 for 15 min. Under nitrogen, a solution of isopropyl magnesium chloride-lithium chloride complex (1 M THF solution, 457.06 mL) was added dropwise. After stirring at -78°C for 1 hour, THF containing 2-(2-chloroethoxy)acetonitrile (69.54 g, 581.71 mmol) (143 mL) was added dropwise and stirred for 15 min. The dry ice / acetone bath was replaced with a NaCl ice bath, and the reaction mixture was stirred for 2.5 h. Water (500 mL) was added dropwise to the mixture, and the pH was adjusted to pH 3–4 with a 1 N HCl aqueous solution while maintaining the reaction mixture in the NaCl ice bath. The aqueous phase was extracted with EtOAc (1 L × 2). The organic compound was layered and washed with brine (1 L × 2), then dried over MgSO4, filtered, and concentrated. The crude residue was purified by column chromatography (SiO2, 0–14% THF / petroleum ether). The resulting solid was slurried in MTBE (200 mL) at 25 °C for 3 hours, then filtered and the filter cake was dried under vacuum to give 145e (150 g, 53.5%) as a white solid. 1 LCMS m / z 339.0 (M+H) + .

[1252] Step 2: Synthesis (1) R )-1-(4-bromo-3,5-dimethoxyphenyl)-2-(2-chloroethoxy)ethanol-1-ol (145f)

[1253] Sodium formate (60.43 g, 888.64 mmol, 48.04 mL) and chlorine were added to a solution of 145e (150 g, 444.32 mmol) in MeOH (2.5 L). R ,2 RRuthenium(II) (4.42 g, 6.93 mmol) was obtained by cooling the mixture in an ice bath and degassing it in a three-stage vacuum-purge sequence. The resulting yellow suspension was stirred at 25 °C for 16 hours. The mixture was concentrated to approximately 1.5 L MeOH to obtain a yellow solid precipitate, which was filtered. 1.5 L H2O was added to the filtrate with stirring, followed by the addition of another 500 mL H2O to obtain a brown solid suspension. The brown solid was filtered and washed with H2O. The yellow and brown solids were combined, and then 500 mL H2O was added. The slurry was stirred at 25 °C for 1 hour, followed by filtration and washing with H2O (250 mL × 3) to obtain 145f (150 g, 99.17%) as a gray solid. 1 H NMR (400 MHz, CDCl3) δ 6.63 (s, 2H), 4.89 (dd, J =3.1, 8.8 Hz, 1H), 3.91 (s, 6H), 3.82 (dt, J =3.6, 5.5 Hz, 2H), 3.75-3.64 (m, 3H), 3.58-3.44 (m, 1H), 2.98 (br s, 1H).

[1254] Step 3: Synthesis of (2R)-2-(4-bromo-3,5-dimethoxyphenyl)-1,4-dioxane (145a)

[1255] A solution of 145f (150 g, 441.68 mmol) in DMSO (1 L) was supplemented with 500 mL of H2O containing 183.13 g, 1.33 mol of K2CO3. The mixture was heated to 80 °C for 16 hours, then cooled to 25 °C. 2 L of H2O was added and the mixture was stirred at 25 °C for 1 hour, followed by filtration and washing with 250 mL × 5 H2O to obtain a gray solid. The solid was dissolved in EtOAc (800 mL), dried over MgSO4, filtered, and concentrated to obtain 145a (100 g, 74%) as a grayish-white solid. 1 H NMR (400 MHz, CDCl3) δ 6.56-6.43 (m, 2H), 4.58-4.43 (m,1H), 3.92-3.86 (m, 2H), 3.85-3.82 (m, 6H), 3.81-3.62 (m, 3H), 3.43-3.27 (m,1H).LCMS m / z305.1 (M+H) + .

[1256] Step 4: Synthesize 4-[(2 R )-1,4-dioxane-2-yl]-2,6-dimethoxybenzene-1-sulfonyl chloride (145c)

[1257] Dibutylmagnesium (1 M heptane solution, 362.86 mL) was added to n-butyllithium (2.5 M hexane solution, 72.57 mL), and the mixture was stirred at 25 °C for 30 min. The mixture was cooled to -60 °C, and then 145a (55 g, 181.43 mmol, 1 equivalent) was added to a solution of THF (250 mL), and the mixture was stirred at -60 °C for 3 h. The resulting mixture was added to a solution of sulfonyl chloride (97.95 g, 725.72 mmol, 72.56 mL) in toluene (550 mL) at -60 °C and stirred for 30 min. The reaction mixture was quenched with H₂O (1 L) and extracted with EtOAc (250 mL × 3), followed by washing with brine (500 mL × 3) and drying (MgSO₄), filtering and concentrating. The crude residue was purified by column chromatography (SiO2, 0-25% THF / petroleum ether) to give compound 145c (43.2 g, 70%) as a grayish-white solid. 1 H NMR (400 MHz, CDCl3) δ 6.63 (s, 2H), 4.63 (dd, J =2.6, 10.1 Hz, 1H), 3.99 (s, 6H), 3.98-3.79 (m, 4H), 3.78-3.68 (m,1H), 3.39 (dd, J =10.2, 11.6 Hz, 1H).

[1258] Step 5: Sodium (6-{[5-cyclopropyl-1-(oxacyclohexyl-2-yl)-1H-pyrazol-3-yl]amino}-5-methoxy-1,2-benzoxazol-3-yl){4-[(2R)-1,4-dioxacyclohexyl-2-yl]-2,6-dimethoxybenzene-1-sulfonyl}amino(azanide) (145g)

[1259] A 4 Å molecular sieve (75 g) was added to a solution of compound 8a (25 g, 67.67 mmol) and DMAP (826.78 mg, 6.77 mmol) in pyridine (150 mL). The reaction mixture was purged with nitrogen, followed by the addition of 145c (28.4 g, 87.98 mmol) and stirring continued at room temperature for 16 hours. The reaction mixture was filtered and washed with MeOH. The resulting filtrate was concentrated and then diluted in MeOH (450 mL), and NaOH (8.12 g, 203.02 mmol) was added. A yellow solid precipitated from the solution after the addition of NaOH. The mixture was heated at 60 °C for 1 hour, cooled to 25 °C, and then cooled to 0 °C. The resulting mixture was filtered and washed with cold MeOH (100 mL × 3), and then dried to give 145 g (43 g, 94% yield) as a white solid. 1 H NMR (400 MHz, DMSO-) d 6) δ 8.05-7.97 (m, 1H), 7.80-7.71 (m, 1H), 7.09-7.02 (m, 1H), 6.67-6.56 (m, 2H), 5.78-5.70 (m, 1H), 5.53-5.44 (m, 1H), 4.57-4.46 (m, 1H), 3.95-3.82 (m, 6H), 3.78-3.68 (m, 2H), 3.61 (s, 7H), 3.31-3.24 (m, 1H), 2.41-2.27 (m, 1H), 2.09-2.02 (m, 1H), 1.96-1.87 (m, 2H), 1.78-1.65 (m,1H), 1.61-1.51 (m,2H), 1.03-0.90 (m,2H), 0.55-0.53 (m,1H), 0.70-0.52 (m,2H); LCMS m / z 656.4 (M+H-Na) + .

[1260] Step 6: N -{6-[(3-Cyclopropyl-1- H [-pyrazole-5-yl)amino]-5-methoxy-1,2-benzoxazol-3-yl}-4-[(2] R 1,4-Dioxacyclohex-2-yl]-2,6-dimethoxybenzene-1-sulfonamide (Example 145)

[1261] Triethylsilane (14.76 g, 126.90 mmol, 20.27 mL) and HCl (12 M, 317.25 mL) were added to a cooled (0–5 °C) solution of 145 g (43 g, 63.45 mmol) in EtOH (450 mL). The mixture was stirred at 25 °C for 16 hours, then concentrated and poured into a saturated NaHCO3 aqueous solution (1.5 L) to adjust the pH to approximately 7. The aqueous layer was further extracted with DCM (550 mL × 3), and the combined organic layers were dried over MgSO4, filtered, and concentrated. The resulting crude solid was dissolved in MeOH (150 mL) and heated to 70 °C for 5 hours. The mixture was filtered, and the filter cake was washed with MeOH (100 mL × 3) and then dried to give 145 g (30.3 g, 83%) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6) δ12.01-11.86 (m, 1H), 11.05-10.89 (m, 1H), 8.16-8.11 (m, 1H), 8.07-8.03 (m,1H), 7.43-7.34 (m, 1H), 6.81-6.69 (m, 2H), 5.82-5.75 (m, 1H), 4.62-4.53 (m,1H), 3.93-3.87 (m, 5H), 3.79-3.69 (m, 8H), 3.61-3.51 (m, 1H), 3.31-3.22 (m,1H), 1.95-1.77 (m, 1H), 0.97-0.84 (m, 2H), 0.73–0.61 (m, 2H); LCMS m / z 572.2(M+H) + .

[1262] The structural partition of 145 was confirmed by a chiral SFC (40% isopropanol with 0.05% DIPEA in CO2; 4 mL / min flow rate, 103 bar, 35 °C; Chiralcel OJ-3; 50 × 4.6 mm, 3 µm) and a retention time of 0.686 min (peak 1). [α] D 22 = -21.3° ( c 0.31, CH3OH).

[1263] Example 146 (Stereospecific procedure): N -{6-[(3-Cyclopropyl-1- H [-pyrazole-5-yl)amino]-5-methoxy 1,2-benzoxazol-3-yl}-4-[(2 S 1,4-Dioxacyclohex-2-yl]-2,6-dimethoxybenzene-1-sulfonamide

[1264]

[1265] Step 1: Synthesis of 1-(4-bromo-3,5-dimethoxyphenyl)-2-(2-chloroethoxy)ethyl-1-one (146a)

[1266] At -78°C, a solution of 2-bromo-5-iodo-1,3-dimethoxybenzene (40.0 g, 117 mmol) in THF (360 mL) was purged with nitrogen for 15 minutes. Under nitrogen, isopropyl magnesium chloride-lithium chloride complex (18.6 g, 128 mmol; 98.7 mL of 1.30 M solution in THF) was added dropwise to the solution. After stirring at -78°C for 1 hour, 2-(2-chloroethoxy)acetonitrile (20.9 g, 175 mmol) was added dropwise as a solution in THF (40 mL). The cooling bath was replaced with a NaCl ice bath (-4°C), under which the temperature was raised to 0°C over 3 hours. The mixture was pa...

Claims

1. A compound of formula (I): Or its pharmaceutically acceptable salt, wherein: R 1 It can be hydrogen, methoxy, or fluorine; R 2 It is hydrogen or methoxy. Its prerequisite is R 1 and R 2 Not all of them are hydrogen. Its further prerequisite is R 1 and R 2 Not all of them are methoxyl groups; Ring A is a C4-C5 cycloalkyl, a 4-6 membered heterocycloalkyl, or a 5-10 membered heteroaryl, wherein the bonding point is at a carbon atom; R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or one or two fluorine atoms; R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH; R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2; Ring B is a C3-C6 cycloalkyl group, C6-C 10 Aryl or 5-10 heteroaryl groups; R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms; R 7 It is hydrogen, C1-C4 alkyl, or methoxy; R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, or -(CHR) 11 ) n -4-8-membered heterocyclic alkyl, 5-8-membered heteroaryl, 9-10-membered heteroaryl, -C(O)NR 12 R 13 -N(CH3) (4-5 membered heterocyclic alkyl) or -O-phenyl, The C1-C4 alkyl group is optionally substituted with one or two methoxy groups, -N(R) 14 (R) 15 (or one, two, or three fluorine atoms are substituted.) The phenyl group is optionally substituted with a methoxy group. Wherein -(CHR) 11 ) n The 4-8-membered heterocyclic alkyl group is optionally substituted by one, two, or three independent substituents selected from the following: oxo, one or two methyl substituents, ethyl, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, 4-6-membered heterocyclic alkyl group, and one or two fluorine atoms. The 5-8 heteroaryl group is optionally substituted by one of the following: oxo, cyano, methyl, -[CH(R) 16 )] p [N(CH3)2] or optionally a methyl-substituted 6-membered heterocyclic alkyl group, The 9-10 membered heteroaryl group is optionally substituted with a methyl group. The -C(O)NR 12 R 13 Optionally substituted with one or two fluorine atoms, and The -O-phenyl group is optionally substituted with fluorine, methyl or methoxy groups; R 9 It is hydrogen or fluorine; R 10 It is hydrogen or C 1-3 alkyl; R 11 It can be hydrogen or methyl; R 12 For hydrogen, C 1-3 Alkyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3; R 13 It is hydrogen or C 1-2 alkyl; Where R 12 C 1-3 Alkyl and R 13 C 1-2 When alkyl, R 12 and R 13 It can form a 4-6 membered heterocyclic alkyl ring together with the nitrogen to which it is attached, wherein the 4-6 membered heterocyclic alkyl ring is optionally substituted with one or two fluorine atoms; Each R 14 and R 15 Independently methyl or ethyl; R 16 It can be hydrogen or methyl; n is 0 or 1; and p is 0 or 1.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of: cyclobutyl, cyclopentyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, pyrroleyl, imidazolyl, isoxazolyl, oxazolyl, 1-oxa-2,4-diazolyl, triazolyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl, 5,6-dihydro-4 H -pyrrolo[1,2- b ]pyrazolyl, 5',6'-dihydrospiro[cyclopropane-1,4'-pyrrolo[1,2- b ]pyrazolyl] and 2,4,5,6-tetrahydropyrrolo[3,4- c ]Pyrazolyl group.

3. A compound of formula (II): Or its pharmaceutically acceptable salt, wherein: R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or one or two fluorine atoms; R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH; R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2; Ring B is a C3-C6 cycloalkyl group, C6-C 10 Aryl or 5-10 heteroaryl groups; R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms; R 7 It is hydrogen, C1-C4 alkyl, or methoxy; R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, or -(CHR) 11 ) n -4-8-membered heterocyclic alkyl, 5-8-membered heteroaryl, 9-10-membered heteroaryl, -C(O)NR 12 R 13 -N(CH3) (4-5 membered heterocyclic alkyl) or -O-phenyl, The C1-C4 alkyl group is optionally substituted with one or two methoxy groups, -N(R) 14 (R) 15 (or one, two, or three fluorine atoms are substituted.) The phenyl group is optionally substituted with a methoxy group. Wherein -(CHR) 11 ) n The 4-8-membered heterocyclic alkyl group is optionally substituted by one, two, or three independent substituents selected from the following: oxo, one or two methyl substituents, ethyl, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, 4-6-membered heterocyclic alkyl group, and one or two fluorine atoms. The 5-8 heteroaryl group is optionally substituted by one of the following: oxo, cyano, methyl, -[CH(R) 16 )] p [N(CH3)2] or optionally a methyl-substituted 6-membered heterocyclic alkyl group, The 9-10 membered heteroaryl group is optionally substituted with a methyl group. The -C(O)NR 12 R 13 Optionally substituted with one or two fluorine atoms, and The -O-phenyl group is optionally substituted with fluorine, methyl or methoxy groups; R 9 It is hydrogen or fluorine; R 10 It is hydrogen or C 1-3 alkyl; R 11 It can be hydrogen or methyl; R 12 For hydrogen, C 1-3 Alkyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3; R 13 It is hydrogen or C 1-2 alkyl; Where R 12 C 1-3 Alkyl and R 13 C 1-2 When alkyl, R 12 and R 13 It can form a 4-6 membered heterocyclic alkyl ring together with the nitrogen to which it is attached, wherein the 4-6 membered heterocyclic alkyl ring is optionally substituted with one or two fluorine atoms; Each R 14 and R 15 Independently methyl or ethyl; R 16 It can be hydrogen or methyl; n is 0 or 1; and p is 0 or 1.

4. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of: cyclopropyl, 1,2,3,4-tetrahydronaphthyl, naphthyl, chromanyl, isochromthyl, 2,3-dihydrobenzo[b][1,4]dioxane-hexenyl, pyrazolyl, pyrimidinyl, quinolinyl, and indazoleyl.

5. The compound of claim 3 or a pharmaceutically acceptable salt thereof, having formula (III): (III) Or its pharmaceutically acceptable salt, wherein: R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or one or two fluorine atoms; R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH; R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2; R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms; R 7 It is hydrogen, C1-C4 alkyl, or methoxy; R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, or -(CHR) 11 ) n -4-8-membered heterocyclic alkyl, 5-8-membered heteroaryl, 9-10-membered heteroaryl, -C(O)NR 12 R 13 -N(CH3) (4-5 membered heterocyclic alkyl) or -O-phenyl, The C1-C4 alkyl group is optionally substituted with one or two methoxy groups, -N(R) 14 (R) 15 (or one, two, or three fluorine atoms are substituted.) The phenyl group is optionally substituted with a methoxy group. Wherein -(CHR) 11 ) n The 4-8-membered heterocyclic alkyl group is optionally substituted by one, two, or three independent substituents selected from the following: oxo, one or two methyl substituents, ethyl, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, 4-6-membered heterocyclic alkyl group, and one or two fluorine atoms. The 5-8 heteroaryl group is optionally substituted by one of the following: oxo, cyano, methyl, -[CH(R) 16 )] p [N(CH3)2] or optionally a methyl-substituted 6-membered heterocyclic alkyl group, The 9-10 membered heteroaryl group is optionally substituted with a methyl group. The -C(O)NR 12 R 13 Optionally substituted with one or two fluorine atoms, and The -O-phenyl group is optionally substituted with fluorine, methyl or methoxy groups; R 9 It is hydrogen or fluorine; R 10 It is hydrogen or C 1-3 alkyl; R 11 It can be hydrogen or methyl; R 12 For hydrogen, C 1-3 Alkyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3; R 13 It is hydrogen or C 1-2 alkyl; Where R 12 C 1-3 Alkyl and R 13 C 1-2 When alkyl, R 12 and R 13 It can form a 4-6 membered heterocyclic alkyl ring together with the nitrogen to which it is attached, wherein the 4-6 membered heterocyclic alkyl ring is optionally substituted with one or two fluorine atoms; Each R 14 and R 15 Independently methyl or ethyl; R 16 It can be hydrogen or methyl; n is 0 or 1; and p is 0 or 1.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 6 It is a methoxy group, R 7 It is a methoxy group, R 8 It is hydrogen, and R 9 It is hydrogen.

7. The compound of claim 5 or a pharmaceutically acceptable salt thereof, having formula (IV): Or its pharmaceutically acceptable salt, wherein: R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or one or two fluorine atoms; R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH; R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2; R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms; R 7 It is hydrogen, C1-C4 alkyl, or methoxy; R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, or -(CHR) 11 ) n -4-8-membered heterocyclic alkyl, 5-8-membered heteroaryl, 9-10-membered heteroaryl, -C(O)NR 12 R 13 -N(CH3) (4-5 membered heterocyclic alkyl) or -O-phenyl, The C1-C4 alkyl group is optionally substituted with one or two methoxy groups, -N(R) 14 (R) 15 (or one, two, or three fluorine atoms are substituted.) The phenyl group is optionally substituted with a methoxy group. Wherein -(CHR) 11 ) n The 4-8-membered heterocyclic alkyl group is optionally substituted by one, two, or three independent substituents selected from the following: oxo, one or two methyl substituents, ethyl, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, 4-6-membered heterocyclic alkyl group, and one or two fluorine atoms. The 5-8 heteroaryl group is optionally substituted by one of the following: oxo, cyano, methyl, -[CH(R) 16 )] p [N(CH3)2] or optionally a methyl-substituted 6-membered heterocyclic alkyl group, The 9-10 membered heteroaryl group is optionally substituted with a methyl group. The -C(O)NR 12 R 13 Optionally substituted with one or two fluorine atoms, and The -O-phenyl group is optionally substituted with fluorine, methyl or methoxy groups; R 11 It can be hydrogen or methyl; R 12 For hydrogen, C 1-3 Alkyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3; R 13 It is hydrogen or C 1-2 alkyl; Where R 12 C 1-3 Alkyl and R 13 C 1-2 When alkyl, R 12 and R 13 It can form a 4-6 membered heterocyclic alkyl ring together with the nitrogen to which it is attached, wherein the 4-6 membered heterocyclic alkyl ring is optionally substituted with one or two fluorine atoms; Each R 14 and R 15 Independently methyl or ethyl; R 16 It can be hydrogen or methyl; n is 0 or 1; and p is 0 or 1.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, having formula (V): Or its pharmaceutically acceptable salt, wherein: R 3 It is hydrogen, halogen, C1-C4 alkyl, -CH2OCH3, methoxy, -C(O)OH, -C(O)OCH3, C3-C5 cycloalkyl, 4-6 membered heterocyclic alkyl or benzyl, wherein the C1-C4 alkyl is optionally substituted with -OH or one, two or three fluorine atoms, the methoxy is optionally substituted with one, two or three fluorine atoms, and the C3-C5 cycloalkyl is optionally substituted with methyl or one or two fluorine atoms; R 4 It is hydrogen or optionally a C1-C3 alkyl group substituted with -OH; R 5 It can be hydrogen, halogen, cyano, C1-C3 alkyl, or -C(O)NH2; R 6 It is hydrogen, halogen, C1-C4 alkyl, -O-(C1-C4 alkyl) or -O-(C3-C5 cycloalkyl), wherein the -O-(C1-C4 alkyl) is optionally substituted with one, two or three fluorine atoms; R 7 It is hydrogen, C1-C4 alkyl, or methoxy; R 8 It can be hydrogen, halogen, cyano, C1-C4 alkyl, methoxy, phenyl, or -(CHR) 11 ) n -4-8-membered heterocyclic alkyl, 5-8-membered heteroaryl, 9-10-membered heteroaryl, -C(O)NR 12 R 13 -N(CH3) (4-5 membered heterocyclic alkyl) or -O-phenyl, The C1-C4 alkyl group is optionally substituted with one or two methoxy groups, -N(R) 14 (R) 15 (or one, two, or three fluorine atoms are substituted.) The phenyl group is optionally substituted with a methoxy group. Wherein -(CHR) 11 ) n The 4-8-membered heterocyclic alkyl group is optionally substituted by one, two, or three independent substituents selected from the following: oxo, one or two methyl substituents, ethyl, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, 4-6-membered heterocyclic alkyl group, and one or two fluorine atoms. The 5-8 heteroaryl group is optionally substituted by one of the following: oxo, cyano, methyl, -[CH(R) 16 )] p [N(CH3)2] or optionally a methyl-substituted 6-membered heterocyclic alkyl group, The 9-10 membered heteroaryl group is optionally substituted with a methyl group. The -C(O)NR 12 R 13 Optionally substituted with one or two fluorine atoms, and The -O-phenyl group is optionally substituted with fluorine, methyl or methoxy groups; R 11 It can be hydrogen or methyl; R 12 For hydrogen, C 1-3 Alkyl, -(CH2)5NH2 or -(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3; R 13 It is hydrogen or C 1-2 alkyl; Where R 12 C 1-3 Alkyl and R 13 C 1-2 When alkyl, R 12 and R 13 It can form a 4-6 membered heterocyclic alkyl ring together with the nitrogen to which it is attached, wherein the 4-6 membered heterocyclic alkyl ring is optionally substituted with one or two fluorine atoms; Each R 14 and R 15 Independently methyl or ethyl; R 16 It can be hydrogen or methyl; n is 0 or 1; and p is 0 or 1.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 3 It can be hydrogen, chlorine, C1-C4 alkyl, -CHF2, -CF3, -CF2CH3, -CH2-CF3, -CH2OCH3, methoxy, -O-CHF2, -C(O)OH, -C(O)OCH3, bicyclo[1.1.1]pent-1-yl, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, or benzyl. The C1-C4 alkyl group is optionally substituted with -OH, and The cyclopropyl group is optionally substituted with a methyl group or two fluorine atoms.

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R 3 It is cyclopropyl.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 4 It can be hydrogen, methyl, ethyl, or isopropyl.

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein R 4 It is hydrogen.

13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 5 It can be hydrogen, fluorine, cyano, methyl, ethyl, or -C(O)NH2.

14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein R 5 It is hydrogen.

15. The compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R 3 It is cyclopropyl, R 4 It is hydrogen, and R 5 It is hydrogen.

16. The compound of any one of claims 1 to 5 and 7 to 15, or a pharmaceutically acceptable salt thereof, wherein R 6 It can be hydrogen, bromine, chlorine, fluorine, methyl, ethyl, methoxy, ethoxy, -O-isopropyl, -O-CH2CHF2, -O-CF3, -O-cyclobutyl or -O-cyclopropyl.

17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein R 6 It is a methoxy group.

18. The compound of any one of claims 1 to 5 and 7 to 15, or a pharmaceutically acceptable salt thereof, wherein R 7 It can be hydrogen, methyl, ethyl, or methoxy.

19. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein R 7 It is a methoxy group.

20. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein R 7 It is hydrogen.

21. The compound of any one of claims 1 to 5 and 7 to 15, or a pharmaceutically acceptable salt thereof, wherein R 8 Hydrogen, chlorine, fluorine, methyl, ethyl, propyl, -CHF2, -CF3, -CH2OCH3, -CH(CH3)(OCH3), -C(CH3)2(OCH3), -CH(OCH3)(CH2OCH3), -CH2-N(CH3)2, methoxy, phenyl, aziridine, oxacyclobutyl, tetrahydrofuranyl, pyrrolyl, tetrahydropyranyl, piperidinyl, dioxacyclohexyl, morpholinyl, -CH(CH3)-aziridine, -CH2-pyrrolyl, -CH(CH3)-morpholinyl, azispiro[3.4]octyl, imidazolyl, Pyrazolyl, triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, hexahydropyrido[3,4-d]pyrimidinyl, -C(O)-azacyclobutyl, -C(O)-pyrrolidinyl, -C(O)-piperidinyl, -C(O)NH(CH2)5NH2, -C(O)NH(CH2)5NHC(O)-phenyl-(1,2,4,5-tetraazine)-CH3, -N(CH3) (oxacyclobutyl), -N(CH3) (tetrahydrofuranyl) or -O-phenyl, The phenyl group is optionally substituted with a methoxy group. The nitrogen-containing heterocyclic butyl group is optionally substituted with a methoxy group, a fluorine group, or a tetrahydrofuran group. The pyrrolidinium is optionally substituted with one substituent selected from oxo, methyl, ethyl, -CH2CHF2, methoxy, tetrahydrofuran, and fluorine, or with two or three independent substituents selected from oxo, methyl, and fluorine. The dioxane-hexyl group is optionally substituted with two methyl substituents. The piperidinyl group is optionally substituted with one substituent selected from methyl, ethyl, -CH2CHF2, -CH2CF3, oxetyl, and tetrahydrofuran, or with two or three substituents selected from methyl and one or two fluorine atoms. Piperazine is optionally substituted with methyl or two substituents selected from oxo and methyl. The morpholino group is optionally substituted with a methyl or ethyl group. The -CH2-azacyclobutyl group is optionally substituted with a methyl group or one or two fluorine atoms. The -CH(CH3)-azacyclobutyl group is optionally substituted with one fluorine atom. The -CH2-pyrrolidinyl group is optionally substituted with -CHF2, -CF3, two methyl substituents, or one or two fluorine atoms. The -CH2-piperidinyl group may optionally be substituted with a methyl, a methoxy, or one or two fluorine atoms. The pyrazolyl group is optionally substituted with a methyl group. The triazolyl group is optionally substituted with a methyl group. The imidazolyl group is optionally substituted with a methyl group. The pyridyl group is optionally substituted with one or two substituents selected from methyl and oxo groups. The pyrazinyl group is optionally substituted with methyl or -N(CH3)2. The pyrimidinyl group is optionally substituted with a methyl, cyano, -CH2[N(CH3)2], -N(CH3)2, -CH(CH3)[N(CH3)2], or a piperazine group substituted with a methyl group. The pyridazinyl group is optionally substituted with an oxo or methyl group. The hexahydropyrido[3,4-d]pyrimidinyl group is optionally substituted with a methyl group. The -C(O)-azacyclobutyl, the -C(O)-pyrrolidinyl, and the -C(O)-piperidinyl are each optionally substituted with one or two fluorine atoms independently, and The -O-phenyl group is optionally substituted with methyl or fluorine.

22. A compound selected from the group consisting of: ， Or its tautomers, or pharmaceutically acceptable salts of the compound or its tautomers.

23. The compound of claim 22, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, wherein said compound is: Or its tautomers, or pharmaceutically acceptable salts of the compound or its tautomers.

24. The compound of claim 22, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, wherein said compound is: Or its tautomers, or pharmaceutically acceptable salts of the compound or its tautomers.

25. The compound of claim 22, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, wherein said compound is: Or its tautomers, or pharmaceutically acceptable salts of the compound or its tautomers.

26. The compound of claim 22, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, wherein said compound is: Or its tautomers, or pharmaceutically acceptable salts of the compound or its tautomers.

27. The compound of claim 22, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, wherein said compound is: Or its tautomers, or pharmaceutically acceptable salts of the compound or its tautomers.

28. The compound of claim 22, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, wherein said compound is: Or its tautomers, or pharmaceutically acceptable salts of the compound or its tautomers.

29. The compound of claim 22, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, wherein said compound is: Or its tautomers, or pharmaceutically acceptable salts of the compound or its tautomers.

30. The compound of claim 22, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, wherein said compound is: Or its tautomers, or pharmaceutically acceptable salts of the compound or its tautomers.

31. The compound of claim 22, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or a tautomer thereof, wherein said compound is: Or its tautomers, or pharmaceutically acceptable salts of the compound or its tautomers.

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