Compounds targeting the p53 variant

Abstract

The present invention provides compounds of formula (I) that can bind to p53 mutants and restore the ability of p53 mutants to bind DNA and activate downstream effectors involved in tumor suppression.Also provided are pharmaceutical compositions containing the compounds, methods for preparing the compounds, and methods for using the compounds to prevent or treat diseases or conditions associated with p53 mutants. [Formula 1] JPEG2024530952000735.jpg23170

Description

[Technical Field]

[0001] The present invention relates to compounds targeting p53 variants, pharmaceutical compositions containing such compounds, methods for preparing such compounds, and methods for using such compounds to prevent or treat diseases or conditions associated with p53 variants.

[0002] Cross-references to related applications This application claims the benefits and priority of PCT applications PCT / CN2021 / 111797 filed on 10 August 2021, PCT / CN2021 / 125725 filed on 22 October 2021, PCT / CN2021 / 132409 filed on 23 November 2021, PCT / CN2022 / 073977 filed on 26 January 2022, and PCT application PCT / CN2022 / 097840 filed on 9 June 2022, the contents of each of these applications being incorporated herein by reference in their entirety. [Background technology]

[0003] Often called the "guardian of the human genome," the p53 protein is a tetrameric transcription factor that prevents genomic mutations by regulating the expression of subgroups of target genes. While biologically active as a homotetramer, each p53 monomer consists of 393 amino acids and is divided into five major regulatory domains: the transcriptional activation domain (TAD), the proline-rich region (PR), the DNA-binding domain (DBD), the oligomerization domain (OD), and the C-terminus.

[0004] Under normal conditions, the p53 protein has a "tumor-suppressing" effect, but p53 is unstable, with a half-life of 5-30 minutes. Activation of p53 initiates pathways involved in apoptosis, cis-, DNA repair, cell cycle arrest, anti-angiogenesis, and aging, preventing the proliferation of damaged cells. Activation of p53 occurs through a complex regulatory network consisting of three key steps: (1) stabilization of p53 by phosphorylation, (2) DNA binding, and (3) activation of target genes.

[0005] P53 is the most frequently mutated protein in human cancers. For example, mutations are present in 96% of serous ovarian cancers, 87% of metastatic gastric cancers, 85% of small cell lung cancers, and 75% of pancreatic cancers, and are associated with poor prognosis and patient survival. Furthermore, mutant p53 is a very abundant and tumor-specific target because it is generally overexpressed in cancer, partly because it is unable to induce the expression of the MDM2 gene to establish a negative feedback loop that controls p53 expression. As a result of overexpression, mutant p53 also has toxic GoF properties that can propagate to other important proteins and pathways that control the cell cycle, potentially causing dysfunction. Given the above factors, mutant p53 is an important pharmacological target, and considerable effort has been made over the past 20 years to develop small molecules aimed at restoring the wild-type function of mutant p53. In particular, targeting mutant p53 means more selectively targeting cancer cells and reducing the risk of side effects and toxicity to healthy tissues. Among the small molecules developed, numerous mechanistic strategies have been explored, including protein refolding, protein stabilization, regulation of protein aggregation, and zinc chelation via cis-thein modification.

[0006] p53 is directly inactivated by mutation in 50% of human cancers (ranging from approximately 1% to 85% depending on the type of cancer), and almost all cancers exhibit dysfunction along the p53 pathway. Due to the frequency and aggressiveness of cancers exhibiting p53 dysfunction, efforts to restore normal p53 expression and activity have been widely pursued in both academia and the pharmaceutical industry over the past several decades. While this approach faces significant challenges, including frequent off-target mechanisms of action, major technological advances in gene sequencing capabilities and the shift towards personalized medicine offer great promise for the development of small molecule compounds capable of mutation-specific p53 reactivation.

[0007] Mutations in p53, located in the DNA-binding domain or the periphery of the DNA-binding surface of a protein, lead to abnormalities in the protein's folding necessary for DNA recognition and binding. Examples of p53 mutations include those in the amino acids Val143, His168, Arg175, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, and Arg282. Examples of p53 mutations that impair p53 activity include R175H, Y220C, G245S, R248Q, R248W, R273H, and R282W. These p53 mutations distort the structure of the DNA-binding site or thermodynamically destabilize the folded protein at body temperature. The wild-type function of the p53 mutant can be restored by conjugating the p53 mutant to a compound that reduces the rate of unfolding and destabilization by shifting the equilibrium between folding and unfolding to the folded state.

[0008] Because p53 mutations are common in virtually all types of cancer, reactivating wild-type p53 function in cancer cells could be an effective treatment. The p53 Y220C mutation is associated with many cancers, including breast cancer, non-small cell lung cancer, colorectal cancer, pancreatic cancer, and ovarian cancer.

[0009] PC14586 has been reported as a small molecule reactivator targeting the p53 Y220C variant, developed by PMV Pharmaceuticals. In this field, there remains a significant need for the development of new small molecule reactivators targeting p53 variants (e.g., the Y220C variant) that possess low toxicity, high specificity, and high activity. [Overview of the Initiative]

[0010] In one embodiment, the object of the present invention is to provide compounds that target mutant p53, preferably the Y220C mutant.

[0011] In one embodiment, an object of the present invention is to provide a pharmaceutical composition comprising the compound that targets mutant p53.

[0012] In one embodiment, an object of the present invention is to provide a method for preventing or treating a disease or condition associated with the p53 mutant protein, comprising administering a therapeutically effective amount of the compound or the pharmaceutical composition to a target.

[0013] In one embodiment, an object of the present invention is to provide a method for preparing the compounds of the present invention.

[0014] In a certain context, an object of the present invention is to provide an intermediate compound (e.g., formula (IN-I)) used in the preparation of the compound of the present invention (e.g., formula (I)).

[0015] It should be understood that each embodiment of a preventive or therapeutic method described herein may also be configured as an embodiment of a corresponding application type.

[0016] This disclosure further provides the following aspects:

[0017] [1] A compound of formula (I), or a stereoisomer, tautomer, deuterated derivative thereof, prodrug or pharmaceutically acceptable salt thereof: [ka] Y is selected from O, S, NR', S=O, -S(=O)(=NR')-, or O=S=O; One of X1, X2, X3, and X4 is selected from CR2, and the other X1, X2, X3, and X4 are each independently selected from N or CR4; X5 is selected from N or CR1; R1 is hydrogen, deuterium, halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6Selected independently from haloalkyl, -CN, -OR', -SR', -C(O)R', -C(O)N(R')2, -C(O)OR', -OC(O)R', -OC(O)N(R')2, -N(R')2, -NR'C(O)R', -NR'C(O)OR', -NR'C(O)N(R')2, -S(O)R', -S(O)N(R')2, -NR'S(O)R', -NR'S(O)N(R')2, -S(O)2R', -S(O)2N(R')2, -NR'S(O)2R', -NR'S(O)2N(R')2, -PO(R')2, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 6- to 12-membered aryl or 5- to 12-membered heteroaryl; said -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 6- to 12-membered aryl, and 5- to 12-membered heteroaryl are each independently optionally substituted with one or more (e.g., 1, 2, 3, 4, 5 or 6) substituents selected from deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -CN, oxo, -OR', -SR', -C(O)R', -C(O)N(R')2, -C(O)OR', -OC(O)R', -OC(O)N(R')2, -N(R')2, -NR'C(O)R', -NR'C(O)OR', -NR'C(O)N(R')2, -S(O)R', -S(O)N(R')2, -NR'S(O)R', -NR'S(O)N(R')2, -S(O)2R', -S(O)2N(R')2, -NR'S(O)2R', -NR'S(O)2N(R')2, -PO(R')2, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 6- to 12-membered aryl or 5- to 12-membered heteroaryl; R2 is -NR 51 R 52 、-OR53 or -SR 54 and; R3 is hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6 Selected from haloalkyl, -C(O)R', -C(O)N(R')2, -C(O)OR', -S(O)R', -S(O)N(R')2, -S(O)2R', -S(O)2N(R')2, -PO(R')2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, 5-12 membered heteroaryl; the -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6 Haloalkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl are R 3a It is independently and arbitrarily substituted with one or more substituents (e.g., 1, 2, 3, 4, 5, or 6); Each R 3a Deuterium, halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6 Haloalkyl, -CN, oxo, -OR', -SR', -C(O)R', -C(O)N(R')2, -C(O)OR', -OC(O)R', -OC(O)N(R')2, -N(R')2 , -NR'C(O)R', -NR'C(O)OR', -NR'C(O)N(R')2, -S(O)R', -S(O)N(R')2, -NR'S(O)R', -NR'S(O)N(R')2 Selected from -S(O)2R', -S(O)2N(R')2, -S(=O)(=NR')R', -NR'S(O)2R', -NR'S(O)2N(R')2, -PO(R')2, 3-12 member cycloalkyl, 3-12 member cycloalkenyl, 3-12 member heterocycloalkyl, 3-12 member heterocycloalkenyl, 6-12 member aryl, 5-12 member heteroaryl; the -C1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6 Haloalkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl are R 3b It is independently and arbitrarily substituted with one or more substituents (e.g., 1, 2, 3, 4, 5, or 6), Each R 3b Deuterium, halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6 Independently selected from haloalkyl, -CN, oxo, -OR', -SR', -C(O)R', -C(O)N(R')2, -C(O)OR', -OC(O)R', -OC(O)N(R')2, -N(R')2, -NR'C(O)R', -NR'C(O)OR', -NR'C(O)N(R')2, -S(O)R', -S(O)N(R')2, -NR'S(O)R', -NR'S(O)N(R')2, -S(O)2R', -S(O)2N(R')2, -S(=O)(=NR')R', -NR'S(O)2R', -NR'S(O)2N(R')2, -PO(R')2; R4, if present, is hydrogen, deuterium, halogen, and -C. 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6Haloalkyl, -CN, -OR', -SR', -C(O)R', -C(O)N(R')2, -C(O)OR', -OC(O)R', -OC(O)N(R')2, -N(R')2, -NR'C(O)R', -NR'C(O)OR', -NR'C(O)N(R')2, -S(O)R', -S(O)N(R')2, -NR'S(O)R', -NR'S(O)N(R' )2, -S(O)2R', -S(O)2N(R')2, -NR'S(O)2R', -NR'S(O)2N(R')2, -PO(R')2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl or 5-12 membered heteroaryl, independently selected from the above-mentioned -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6 Haloalkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl are derived from deuterium, halogens, and -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6 Haloalkyl, -CN, oxo, -OR', -SR', -C(O)R', -C(O)N(R')2, -C(O)OR', -OC(O)R', -OC(O)N(R')2, -N(R')2, -NR'C(O)R' , -NR'C(O)OR', -NR'C(O)N(R')2, -S(O)R', -S(O)N(R')2, -NR'S(O)R', -NR'S(O)N(R')2, -S(O)2R', -S(O)2N(R')2 Each substituent is independently and arbitrarily substituted with one or more substituents (e.g., 1, 2, 3, 4, 5, or 6) selected from -S(=O)(=NR')R', -NR'S(O)2R', -NR'S(O)2N(R')2, -PO(R')2, 3-12 member cycloalkyl, 3-12 member cycloalkenyl, 3-12 member heterocycloalkyl, 3-12 member heterocycloalkenyl, 6-12 member aryl, or 5-12 member heteroaryl; R 51 , R 52 , R53 and R 54 is hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6 Each of the following is independently selected from haloalkyl, -C(O)R', -C(O)N(R')2, -C(O)OR', -S(O)R', -S(O)N(R')2, -S(O)2R', -S(O)2N(R')2, -PO(R')2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl; the -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6 Haloalkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl are derived from deuterium, halogens, and -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6 Haloalkyl, -CN, oxo, =NR', -C 1-6 Alkyl-CH(R')2, -OR', -SR', -C(O)R', -C(O)N(R')2, -C(O)OR', -OC(O)R', -OC(O)N(R')2, -N(R')2, -NR'C(O)R', - NR'C(O)OR', -NR'C(O)N(R')2, -S(O)R', -S(O)N(R')2, -NR'S(O)R', -NR'S(O)N(R')2, -S(O)2R', -S(O)2N(R')2, Each molecule is independently and arbitrarily substituted with one or more substituents (e.g., 1, 2, 3, 4, 5, or 6) selected from -S(=O)(=NR')R', -NR'S(O)2R', -NR'S(O)2N(R')2, -PO(R')2, 3-12 member cycloalkyl, 3-12 member cycloalkenyl, 3-12 member heterocycloalkyl, 3-12 member heterocycloalkenyl, 6-12 member aryl, or 5-12 member heteroaryl; R 11 and R12 is independently selected from hydrogen, deuterium, -OH, halogen, -CN, oxo, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2 or 3-6 member cycloalkyl; said -C 1-6 alkyl, -C 1-6 alkoxy and 3-6 member cycloalkyl are each independently optionally substituted with one or more (e.g., 1, 2, 3, 4, 5 or 6) substituents selected from deuterium, -OH, halogen, -CN, oxo, -C 1-6 alkoxy, -NH-C 1-6 alkyl, -N(C 1-4 alkyl)2, or 3-6 member cycloalkyl; R 13 is selected from hydrogen, deuterium, -C 1-6 alkyl or 3-6 member cycloalkyl; said -C 1-6 alkyl and 3-6 member cycloalkyl are each independently optionally substituted with one or more (e.g., 1, 2, 3, 4, 5 or 6) substituents selected from deuterium, -OH, halogen, -CN, oxo, -C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, or -N(C 1-4 alkyl)2; Each R', when present, is hydrogen, deuterium, halogen, -OH, -CN, oxo, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -C 1-6 alkyl, -C 1-6 alkylOC 1-6 alkyl, -C 1-6 alkyl-NHC 1-6 alkyl, -C 1-6 alkyl-N(C 1-6 alkyl)2, -C 1-6 haloalkyl, -OC 1-6 alkyl, -C 3-14 cycloalkyl, -C 3-14 heterocycloalkyl, -C 2-6Alkenyl, -C 2-6 Independently selected from alkynyl, 6-12 membered aryl, or 5-12 membered heteroaryl; -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-14 Cycloalkyl, -C 3-14 Heterocycloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynnyl, 6-12 membered aryl, or 5-12 membered heteroaryl compounds are derived from deuterium, halogens, -CN, and -C. 1-3 Alkyl, oxo, -OH, -OC 1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl), -S(=O)2C 1-3 Alkyl, -S(=O)2N(C 1-3 Alkyl)2,-S(=O)(=NH)C 1-3 Alkyl, -S(=O)(=NC 1-3 Alkyl)C 1-3 Each substituent is independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from alkyl or 3-6 membered cycloalkyl groups; The heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently comprises one, two, or three heteroatoms selected from N, O, P, or S; m is selected from 1, 2, 3, 4, 5, or 6. Compounds, their stereoisomers, tautomers, deuterated derivatives, prodrugs, or pharmaceutically acceptable salts.

[0018] [2] Equation (I) is, [ka] And, In equation (I-1), X2, X3, and X4 are independently selected from N or CR4; Y is selected from O, S, S=O, or O=S=O. The compound described in [1].

[0019] [3] Equation (I) is, [ka] That is, The compound described in [1] or [2].

[0020] [4] Equation (I) is, [ka] That is, The compound described in [1] or [2].

[0021] [5] Equation (I) is, [ka] That is, The compound described in [1] or [2].

[0022] [6] Equation (I) is, [ka] That is, The compound described in [1] or [2].

[0023] [7] Equation (I) is, [ka] That is, The compound described in [1] or [2].

[0024] [8] Equation (I) is, [ka] That is, The compound described in [1] or [2].

[0025] [9] Equation (I) is, [ka] That is, The compound described in [1] or [2].

[0026]

[10] Equation (I) is, [ka] Selected from, A compound listed in any one of [1] to [3].

[0027]

[11] R1 is halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6 A haloalkyl, -CN, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-10 membered aryl, or 5-12 membered heteroaryl is independently selected from the -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6 Haloalkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-10 membered aryl, and 5-12 membered heteroaryl are halogens, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6The molecules are independently and optionally substituted with one or more substituents (e.g., 1, 2, 3, 4, 5, or 6) selected from haloalkyl, -CN, oxo, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-10 membered aryl, or 5-12 membered heteroaryl, wherein each heterocycloalkyl, heterocycloalkenyl, and heteroaryl molecule independently contains one or two heteroatoms selected from N or S. A compound listed in any one of [1] to

[10] .

[0028]

[12] R1 is -F, -Cl, -C 1-3 Alkyl, -C 2-4 Alkenyl, -C 2-4 Alkinyl, -C 1-3 Independently selected from haloalkyl, -CN, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, and 5-12 membered heteroaryl, the -C 1-3 Alkyl, -C 2-4 Alkenyl, -C 2-4 Alkinyl, -C 1-3 Haloalkyls, 3-6 membered cycloalkyls, 3-6 membered heterocycloalkyls, 6-10 membered aryls, and 5-12 membered heteroaryls are -F, -Cl, -C 1-3 Alkyl, -C 2-4 Alkenyl, -C 2-4 Alkinyl, -C 1-3 The molecules are independently and optionally substituted with one or more substituents (e.g., 1, 2, 3, 4, 5, or 6) selected from haloalkyl, -CN, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, or 5-12 membered heteroaryl, wherein each heterocycloalkyl, heterocycloalkenyl, and heteroaryl molecule independently contains one or two heteroatoms selected from N or S. A compound listed in any one of [1] to

[11] .

[0029]

[13] R1 is -F, -Cl, -C 1-3 Alkyl, -C 1-3Independently selected from haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, the -C 1-3 Alkyl, -C 1-3 Haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl are -F, -Cl, -C 1-3 Alkyl, -C 1-3 The molecules are independently and optionally substituted with one or more substituents (e.g., 1, 2, 3, 4, 5, or 6) selected from haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein the heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain one or two heteroatoms selected from N or S. A compound listed in any one of [1] to

[12] .

[0030]

[14] R1 is -F, -Cl, -C 1-3 Alkyl, -C 1-3 Independently selected from haloalkyls, 3-6 membered cycloalkyls, 5-membered heteroaryls containing 1 or 2 heteroatoms selected from N, O, or S, or 6-membered heteroaryls containing 1 or 2 heteroatoms selected from N; -C 1-3 Alkyl, -C 1-3 Haloalkyls, 3-6 membered cycloalkyls, 5-membered heteroaryls, and 6-membered heteroaryls are -F, -C 1-3 Alkyl, -OC 1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 The alkyl group is independently and optionally substituted with 1, 2, or 3 substituents selected from 2, CN, or 3-6 membered cycloalkyl groups. A compound listed in any one of [1] to

[12] .

[0031]

[15] R1 is -C 1-3 Alkyl;-C 1-3 Haloalkyl; 5-membered heteroaryl containing one or two heteroatoms selected from N, O, or S; or -F, -OC1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 -C substituted with 1, 2, or 3 substituents selected from alkyl, 2, -CN, or 3-6 membered cycloalkyl groups. 1-3 Selected independently of alkyl, A compound listed in any one of [1] to

[14] .

[0032]

[16] R1, [ka] Selected independently of A compound listed in any one of [1] to

[15] .

[0033]

[17] R2 is -NR 51 R 52 The compound described in any one of [1] to

[16] .

[0034]

[18] R2, -NHR 51 The compound described in any one of [1] to

[17] .

[0035]

[19] R 51 However, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6 Selected from haloalkyl, -C(O)R', -C(O)N(R')2, -C(O)OR', 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl; the -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6 Haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6 Haloalkyl, -CN, oxo, =NR', -C1-6 Each of the alkyl-CH(R')2, -OR', -SR', -C(O)R', -C(O)N(R')2, -C(O)OR', -OC(O)R', -OC(O)N(R')2, -N(R')2, -NR'C(O)R', -NR'C(O)OR', -NR'C(O)N(R')2, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl molecules is independently and optionally substituted with one or more substituents (e.g., 1, 2, 3, 4, 5, or 6) selected from these, wherein each of the heterocycloalkyl, heterocycloalkenyl, and heteroaryl molecules independently contains one heteroatom selected from N, O, or S. A compound listed in any one of [1] to

[18] .

[0036]

[20] R 51 However, -C 1-3 Selected from a 5-membered heterocycline containing one heteroatom selected from alkyl, cyclopentyl, cyclohexyl, N, O, S, S(=O), S(=O)(=NH), or S(=O)2, or a 6-membered heterocycline containing one heteroatom selected from N, O, S, S(=O), S(=O)(=NH), or S(=O)2; the -C 1-3 Alkyl, cyclopentyl, cyclohexyl, 5-membered heterocyclyl and 6-membered heterocyclyl are -F, -C 1-3 Alkyl, -OC 1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, oxo, =NH, -N(C) 1-3 The alkyl group is independently and optionally substituted with 1, 2, or 3 substituents selected from 2, CN, or 3-6 membered cycloalkyl groups. A compound listed in any one of [1] to

[19] .

[0037]

[21] R 51 However, -C 1-6 Selected from alkyl, 5-membered cycloalkyl, 5-membered heterocycloalkyl, 6-membered cycloalkyl, or 6-membered heterocycloalkyl;-C 1-6Alkyl, cycloalkyl, and heterocycloalkyl are -F, -Cl, -CH3, -CD3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH(OH)CH2(OH), -CH(OCH3)CH2(OH), -CH(OH)CH2(OCH3), -CH2CH(OH)(OCH3), -CH2CH(OH)(OCH2CH3), -CH2CH(OCH3)2, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -C(O)-(CH2)-NH2, -C(O)-(CH2)-NH(CH3), -C(O)-(CH2)-NH(CH2CH3), -C(O)-(CH2)-N(CH 3)2, -C(O)-(CH2CH2)-NH2, -C(O)-(CH2CH2)-NH(CH3), -C(O)-(CH2CH2)-NH(CH2CH3), -C(O)-(CH2CH2)-N(CH3)2, -NH2, -NH(CH3), -NH(CH2CH3), -N(CH3)2, -NH(CH2CH2CH3), -NH(CH(CH3)2), or -N(CH3)(CH2CH3), each independently and arbitrarily substituted with one or more substituents (e.g., 1, 2, 3, 4, 5, or 6) selected from -N(CH3)(CH2CH3), wherein the heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain one heteroatom selected from N, O, or S. A compound listed in any one of [1] to

[20] .

[0038]

[22] R 51 but, [ka] or -C 1-6 Selected from alkyl, the -C 1-6 Alkyl is R 1, 2, 3, 4, 5 or 6 5e It is arbitrarily replaced with; R 5a , R 5c and R 5d However, hydrogen;-C 1-6 Alkyl; or -F, -C 1-3 Alkyl, oxo, -OC 1-3 Alkyl, -NH2, -NHC1-3 Alkyl, -N(C 1-3 -C substituted with 1, 2, 3, 4, 5, or 6 substituents selected from alkyl)2, -CN, or 3-6 membered cycloalkyl groups. 1-6 Each alkyl group is independently selected; R 5b and R 5e However, -F, -C 1-6 Alkyl, oxo, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CN or 3-6 membered cycloalkyl, each independently selected, and the -C 1-6 Alkyl is -F, -C 1-3 Alkyl, oxo, -OC 1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Optionally substituted with 1, 2, 3, or 4 substituents selected from alkyl, 2, -CN, or 3-6 membered cycloalkyl groups. A compound listed in any one of [1] to

[21] .

[0039]

[23] R 51 but, [ka] or -C 1-3 Alkyl-N(C 1-3 Selected from alkyl)2; R 5a However, -C 1-3 Alkyl; or -F, -C 1-3 Alkyl, oxo, -OC 1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 -C substituted with 1, 2, 3, 4, 5, or 6 substituents selected from alkyl)2, -CN, or 3-6 membered cycloalkyl groups. 1-3 Selected independently of alkyl; R 5b However, -F, -C 1-3 Alkyl, oxo, -OC 1-3Alkyl, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Independently selected from alkyl)2 or -CN; R 5c and R 5d However, -C 1-3 Each alkyl is independently selected. A compound listed in any one of [1] to

[22] .

[0040]

[24] R 51 but, [ka] Alternatively, selected from -CH2CH2-N(CH3)2; R 5a However, it is independently selected from methyl, -CH2CH(OH)OCH3, or -C(=O)CH2N(CH3)2; R 5b However, it is selected independently of -F; R 5c and R 5d However, each is independently selected from methyl, A compound listed in any one of [1] to

[23] .

[0041]

[25] R 51 but, [ka] Selected from, A compound listed in any one of [1] to

[24] .

[0042]

[26] R3 is hydrogen, deuterium, halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6Independently selected from haloalkyl, -CN, -NO2, -OR', -SR', -C(O)R', -C(O)N(R')2, -C(O)OR', -OC(O)R', -N(R')2, -NR'C(O)R', -S(O)R', -NR'S(O)R', -S(O)N(R')2, -S(O)2R', -NR'S(O)2R', -S(O)2N(R')2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-10 membered aryl, or 5-12 membered heteroaryl; the -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6 If a haloalkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-10 membered aryl, or 5-12 membered heteroaryl is present, then halogen, NH2, NH-C 1-6 Alkyl, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6 Haloalkyl, -CN, -NO2, -OR', -SR', -C(O)R', oxo, -C(O)N(R')2, C(O)OR', OC(O)R', N(R')2, -NR'C(O)R', -S(O)R', -NR'S(O)R', -S(O)N(R')2, -S(O)2R', -NR'S(O)2R', -S(O)2N(R')2, -S(=O)(=NR')R', 3-12 member cyclo The molecule is independently and optionally substituted with one or more substituents selected from lykyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-10 membered aryl, or 5-12 membered heteroaryl, wherein the heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain one heteroatom selected from N, O, or S. A compound listed in any one of [1] to

[25] .

[0043]

[27] R3 is independently selected from phenyl or a 5-6 member heteroaryl comprising one or two heteroatoms selected from N, O or S; the phenyl and the 5-6 member heteroaryl are R 3c They are independently and arbitrarily substituted with 1, 2, or 3 substituents selected from; R 3c However, -F;-C 1-3 Alkyl;-OC 1-3 Alkyl;-OC 3-6 Cycloalkyl;-NH2;-NHC 1-3 Alkyl;-N(C 1-3 Alkyl)2;-C(=O)NH2,-C(=O)NH(C 1-3 Alkyl);-C(=O)N(C 1-3 Alkyl)2;-CN;-S(=O)2NH2;-S(=O)2NH(C 1-3 Alkyl);-S(=O)2NHC(=O)C 1-3 Alkyl;-S(=O)2N(C 1-3 Alkyl)2;-S(=O)2C 1-3 Alkyl;-S(=O)(=NH)C 1-3 Alkyl;-S(=O)(=NH)C 3-6 Cycloalkyl;-S(=O)(=NC 3-6 Cycloalkyl)C 1-3 Alkyl;-S(=O)(=NC 2-6 (Heterocycloalkyl)C 1-3 Alkyl;-S(=O)(=NC 1-3 Alkyl)C 1-3 Alkyl;-S(=O)(=NCN)C 1-3 Alkyl; or selected from 3-6 membered cycloalkyl; the C 1-3 Alkyl, C 3-6 Cycloalkyl, C 2-6 Heterocycloalkyl or OC 1-3 If alkyl groups are present, deuterium, -F, and -C are present. 1-3 Alkyl, oxo, -OH, -OC 1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-3Alkyl), -C(=O)N(C 1-3 Alkyl)2, -CN, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl), -S(=O)2C 1-3 Alkyl, -S(=O)2N(C 1-3 Alkyl)2,-S(=O)(=NH)C 1-3 Alkyl, -S(=O)(=NC 1-3 Alkyl)C 1-3 They are independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from alkyl or 3-6 membered cycloalkyl groups. A compound listed in any one of [1] to

[25] .

[0044]

[28] R3 is independently selected from phenyl or pyridinyl. A compound listed in any one of [1] to

[27] .

[0045]

[29] R3 is independently selected from phenyl, a 5-membered heteroaryl, or a 6-membered heteroaryl; if phenyl and heteroaryl are present, respectively, -F, -Cl, -CH3, -CD3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, -CF2CH3, -CHFCH2F, -CH2CHFCH3, -CH2CF2CH3, -CH2CH2CF3, -C(CH3)2F, -CN, -OH, -O-CH3, -O- CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -SH, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3, -S-CH(CH3)2, -CHO, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-CH2CH2CH3, - C(O)-CH(CH3)2, -C(O)NH2, -C(O)NH(CH3), -C(O)NH(CH2CH3), -C(O)N(CH3)2, -C(O)NH(CH2CH2CH3), -C(O)NH(CH(CH3)2), -C(O)N(CH3)(CH2CH3), - NH2, -NH(CH3), -NH(CH2CH3), -N(CH3)2, -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH3)(CH2CH3), -NHC(O)(CH3), -NHC(O)(CH2CH3), -NHC(O)(CH3)2, - NHC(O)(CH2CH2CH3), -NHC(O)(CH(CH3)2), -NHC(O)(CH3)(CH2CH3), -S(O)2H, -S(O)2(CH3), -S(O)2(CH2CH3), -S(O)2(CH3)2, -S(O)2(CH2CH2CH3), -S(O)2(CH(CH3)2), -S(O)2(CH3)(CH2CH3), -S(O)2NH2, -S(O)2NH(CH3), -S(O)2NH(CH2CH3), -S(O)2N(CH3)2, -S(O)2NH(CH2CH2CH3), -S(O)2NH(CH(CH3)2), -S(O)2N(CH3)(CH2CH3), -S(=O)(=NH)CH3, or -S(=O)(=NCH3)CH3 are independently and arbitrarily substituted with one or more substituents (e.g., 1, 2, 3, 4, 5, or 6) selected from -S(O)2(CH3)2, -S(O)2N(CH3)(CH2CH3), and the heterocycloalkyl,Heterocycloalkenyls and heteroaryls each independently contain one heteroatom selected from N, O, or S. A compound listed in any one of [1] to

[28] .

[0046]

[30] R3 is independently selected from phenyl, a 5-membered heteroaryl, or a 6-membered heteroaryl; if phenyl and heteroaryl are present, respectively, -F, -CH3, -CD3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2F, -CF3, -CH2CH2F, -CHFCH3, -CF2CH3, -C(CH3)2F, -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH 3, -O-CH(CH3)2, -C(O)NH2, -C(O)NH(CH3), -C(O)NH(CH2CH3), -C(O)N(CH3)2, -C(O)NH(CH2CH2CH3), -C(O)NH(CH( CH3)2), -C(O)N(CH3)(CH2CH3), -NH2, -NH(CH3), -NH(CH2CH3), -N(CH3)2, -NH(CH2CH2CH3), -NH(CH(CH3)2), -N(CH 3)(CH2CH3), -S(O)2H, -S(O)2(CH3), -S(O)2(CH2CH3), -S(O)2(CH3)2, -S(O)2(CH2CH2CH3), -S(O)2(CH(CH3)2), - S(O)2(CH3)(CH2CH3), -S(O)2NH2, -S(O)2NH(CH3), -S(O)2NH(CH2CH3), -S(O)2N(CH3)2, -S(O)2NH(CH2CH2CH3), -S The heterocycloalkyl, heterocycloalkenyl, and heteroaryl compounds are independently and arbitrarily substituted with one or more substituents (e.g., 1, 2, 3, 4, 5, or 6) selected from (O)2NH(CH(CH3)2), -S(O)2N(CH3)(CH2CH3), -S(=O)(=NH)CH3, or -S(=O)(=NCH3)CH3, wherein each heterocycloalkyl, heterocycloalkenyl, and heteroaryl compound independently contains one heteroatom selected from N, O, or S. A compound listed in any one of [1] to

[29] .

[0047]

[31] R3, [ka] Selected independently of A compound listed in any one of [1] to

[30] .

[0048]

[32] Equation (I) is, [ka] and; During the ceremony, R 51 However, -C 1-3 Selected from a 5-membered heterocycline containing one heteroatom selected from alkyl, cyclopentyl, cyclohexyl, N, O, S, S(=O), S(=O)(=NH), or S(=O)2, or a 6-membered heterocycline containing one heteroatom selected from N, O, S, S(=O), S(=O)(=NH), or S(=O)2; the -C 1-3 Alkyl, cyclopentyl, cyclohexyl, 5-membered heterocyclyl and 6-membered heterocyclyl are -F, -C 1-3 Alkyl, -OC 1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, oxo, -N(C) 1-3 Each substituent is independently and optionally substituted with 1, 2, or 3 substituents selected from alkyl)2,-CN, or 3-6 membered cycloalkyl groups; R1 is -F, -Cl, -C 1-3 Alkyl, -C 2-4 Alkenyl, -C 2-4 Alkinyl, -C 1-3 Selected from haloalkyl, -CN, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, and 5-12 membered heteroaryl, and the -C 1-3 Alkyl, -C 2-4 Alkenyl, -C 2-4 Alkinyl, -C 1-3 Haloalkyls, 3-6 membered cycloalkyls, 3-6 membered heterocycloalkyls, 6-10 membered aryls, and 5-12 membered heteroaryls are -F, -Cl, -C 1-3 Alkyl, -C 2-4Alkenyl, -C 2-4 Alkinyl, -C 1-3 The molecules are independently and optionally substituted with one or more substituents (e.g., 1, 2, 3, 4, 5, or 6) selected from haloalkyl, -CN, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, or 5-12 membered heteroaryl, wherein each heterocycloalkyl, heterocycloalkenyl, and heteroaryl molecule independently contains one or two heteroatoms selected from N or S; Each R4 is hydrogen, deuterium, -F, -Cl, -C 1-3 Alkyl, -OC 1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Independently selected from alkyl)2,-CN or 3-6 membered cycloalkyl groups; R 11 and R 12 However, hydrogen, deuterium, -F, -C 1-3 Alkyl, oxo, -OC 1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) independently selected from 2, -CN or 3-6 member cycloalkyl groups, and the -C 1-3 Alkyl is -F, -C 1-3 Alkyl, oxo, -OC 1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Each comprises independently one or two heteroatoms selected from alkyl)2,-CN, or 3-6 membered cycloalkyl groups; R 13 However, hydrogen;-C 1-3 Alkyl; or -F, -C 1-3 Alkyl, -C 1-3 Alkyl, oxo, -OC 1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 -C substituted with 1, 2, 3, 4, 5, or 6 substituents selected from alkyl)2, -CN, or 3-6 membered cycloalkyl groups. 1-3 Selected from alkyl groups; R3 is independently selected from phenyl or a 5-6 member heteroaryl containing one or two heteroatoms selected from N, O, or S; and the phenyl and 5-6 member heteroaryl are R 3c They are independently and arbitrarily substituted with 1, 2, or 3 substituents selected from; R 3c However, -F;-C 1-3 Alkyl;-OC 1-3 Alkyl;-NH2;-NHC 1-3 Alkyl;-N(C 1-3 Alkyl)2;-C(=O)NH2,-C(=O)NH(C 1-3 Alkyl);-C(=O)N(C 1-3 Alkyl)2;-CN;-S(=O)2NH2;-S(=O)2NH(C 1-3 Alkyl);-S(=O)2N(C 1-3 Alkyl) 2; 3-6 member cycloalkyl; or -F, -C 1-3 Alkyl, oxo, -OC 1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2, -CN, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl), -S(=O)2N(C 1-3 Alkyl)2,-S(=O)(=NH)C 1-3 Alkyl, -S(=O)(=NC 1-3 Alkyl)C 1-3 -C substituted with 1, 2, 3, 4, 5, or 6 substituents selected from alkyl or 3-6 membered cycloalkyl groups. 1-3 Selected from alkyl groups, A compound listed in any one of [1] to

[31] .

[0049]

[33] R 51 but, [ka] or -C 1-6Selected from alkyl, the -C 1-6 Alkyl is R 1, 2, 3, 4, 5 or 6 5e It is arbitrarily replaced with; R 5a , R 5c and R 5d However, hydrogen;-C 1-6 Alkyl; or -F, -C 1-3 Alkyl, oxo, -OC 1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 -C substituted with 1, 2, 3, 4, 5, or 6 substituents selected from alkyl)2, -CN, or 3-6 membered cycloalkyl groups. 1-6 Each alkyl group is independently selected; R 5b and R 5e However, -F, -C 1-6 Alkyl, oxo, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CN or 3-6 membered cycloalkyl, each independently selected, and the -C 1-6 Alkyl is -F, -C 1-3 Alkyl, oxo, -OC 1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Optionally substituted with 1, 2, 3, or 4 substituents selected from alkyl)2, -CN, or 3-6 membered cycloalkyl groups; R1, -C 1-3 Alkyl;-C 1-3 Haloalkyl; 5-membered heteroaryl containing one or two heteroatoms selected from N, O, or S; or -F, -OC 1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 -C substituted with 1, 2, or 3 substituents selected from alkyl, 2, -CN, or 3-6 membered cycloalkyl groups. 1-3 Selected independently of alkyl; Each R4 is hydrogen, deuterium, -F, -Cl, -C 1-3 Alkyl, -OC1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Independently selected from alkyl)2,-CN or 3-6 membered cycloalkyl groups; R 11 and R 12 However, hydrogen or -C 1-3 Selected independently of alkyl; R 13 However, hydrogen or -C 1-3 Selected from alkyl groups; R3 is selected from phenyl, and the phenyl is R 3c They are independently and arbitrarily substituted with 1, 2, or 3 substituents selected from; R 3c However, -F;-C 1-3 Alkyl;-OC 1-3 Alkyl;-NH2;-NHC 1-3 Alkyl;-N(C 1-3 Alkyl)2;-C(=O)NH2,-C(=O)NH(C 1-3 Alkyl);-C(=O)N(C 1-3 Alkyl)2;-CN;-S(=O)2NH2;-S(=O)2NH(C 1-3 Alkyl);-S(=O)2N(C 1-3 Alkyl)2;-S(=O)2C 1-3 Alkyl; selected from -S(=O)(=NH)CH3; or -S(=O)(=NCH3)CH3, The compound described in

[32] .

[0050]

[34] R 51 but, [ka] Selected from; R1 is [ka] Selected independently of; Each R4 is hydrogen; R 11 and R 12 However, it is selected independently of hydrogen; R 13 However, it was selected from hydrogen; R3 [ka] Selected from, The compound described in

[33] .

[0051]

[35] Equation (I) is, [ka] That is, A compound listed in any one of [1] to

[34] .

[0052]

[36] .R1 is -C 1-3 Haloalkyl; or -F, -CN, -OC 1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 -C 1-3 Selected independently of alkyl, The compound described in

[35] .

[0053]

[37] R1 is, [ka] Selected independently of The compounds described in

[35] or

[36] .

[0054]

[38] .R2, -NHR 51 That is, A compound listed in any one of

[35] to

[37] .

[0055]

[39] .R 51 However, -C 1-6 Alkyl, -C 1-6 Selected from haloalkyl, 3-6 membered cycloalkyl, or 3-10 membered heterocycloalkyl; the -C 1-6Alkyl, -C 1-6 Haloalkyl, 3-6 membered cycloalkyl, or 3-10 membered heterocycloalkyl, halogen, -C 1-6 Alkyl (halogen, -CN, oxo, =NH, -OH, -OC) 1-6 Alkyl, halogen, -CN, oxo, =NH, -OH, or -OC 1-6 (One or more alkyl groups are arbitrarily substituted, and one or more 5-6 member heterocycloalkyl groups are arbitrarily substituted), -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6 Haloalkyl, -CN, -OH, -NH2, oxo, =NH, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Alkyl-NHC 1-6 Alkyl, -C(O)C 1-6 Alkyl-N(C 1-6 Alkyl)2,-C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 Alkyl)2,-C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl) 2, 3-6 member cycloalkyl, or 3-12 member heterocycloalkyl (e.g., 5-12 member spiroheterocyclyl or cross-linked heterocyclyl (halogen, -CN, oxo, =NH, -OH, or -OC) 1-6 The heterocycloalkyl is independently and arbitrarily substituted with one or more substituents (e.g., 1, 2, 3, 4, 5, or 6) selected from one or more alkyl groups, and the heterocycloalkyl independently contains one or more heteroatoms selected from N, O, or S. A compound listed in any one of

[35] to

[38] .

[0056]

[40] .R 51 However, -C 1-6Selected from alkyl, 3-6 membered cycloalkyl, or 5-10 membered heterocycloalkyl (e.g., 5-10 membered spiroheterocyclyl or crosslinked heterocyclyl); -C 1-6 Alkyl, 3-6 membered cycloalkyl, or 5-10 membered heterocycloalkyl, halogen, -C 1-6 Alkyl (halogen, -CN, oxo, =NH, -OH, -OC) 1-6 alkyl, or [ka] (One or more of the above are arbitrarily substituted), -CN, -OH, NH2, oxo, =NH, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C(O)C 1-6 Alkyl-NHC 1-6 Alkyl, -C(O)C 1-6 Alkyl-N(C 1-6 Alkyl)2,-NHC 1-6 Alkyl, -N(C 1-6 Alkyl) 2, 3-5 member cycloalkyl, or 5-12 member heterocycloalkyl (e.g., 5-12 member spiroheterocyclyl or cross-linked heterocyclyl (halogen, -CN, oxo, =NH, -OH, or -OC) 1-6 The heterocycloalkyl is independently and arbitrarily substituted with one or more substituents (e.g., 1, 2, 3, 4, 5, or 6) selected from one or more alkyl groups, and the heterocycloalkyl independently contains one or more heteroatoms selected from N, O, or S. A compound listed in any one of

[35] to

[39] .

[0057]

[41] .R 51 However, -C 1-3 Selected from alkyl, cyclohexyl, or 6-8 member heterocycloalkyl (e.g., 6-8 member spiroheterocyclyl or crosslinked heterocyclyl); -C 1-3 Alkyl, cyclohexyl, or 6-8 member heterocycloalkyl groups may be halogens, -C 1-6 Alkyl (oxo, =NH, -OH, -OC) 1-6 alkyl, or [ka] (One or more of the above are arbitrarily substituted), -CN, -OH, NH2, oxo, =NH, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C(O)CH2-NHC 1-6 Alkyl, -C(O)CH2-N(C 1-6 Alkyl)2,-NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, cyclopropyl, or 5-12 member heterocycloalkyl (e.g.) [ka] The heterocycloalkyl is independently and arbitrarily substituted with one or more substituents selected from (e.g., 1, 2, 3, 4, 5, or 6), and the heterocycloalkyl independently contains one or more heteroatoms selected from N, O, or S, preferably R 51 but, [ka] That is, A compound listed in any one of

[35] to

[40] .

[0058]

[42] R2 is, [ka] Selected from TIFF0007897926000029.tif216170 A compound listed in any one of

[35] to

[41] .

[0059]

[43] . R3 is independently selected from a 5-10 membered heterocycloalkenyl containing one or two heteroatoms selected from phenyl, N, O, or S, or a 5-10 membered, preferably 5-6 membered heteroaryl containing one or two heteroatoms selected from N, O, or S; each of them is R 3a They are independently and arbitrarily substituted with 1, 2, or 3 substituents selected from; R 3a However, halogen; oxo; -C 1-3 Alkyl;-OC 1-3 Alkyl;-NH2;-NHC 1-3 Alkyl;-N(C 1-3 Alkyl)2;-C(=O)NH2,-C(=O)NH(C 1-3 Alkyl);-C(=O)N(C 1-3 Alkyl)2;-CN;-S(=O)2NH2;-S(=O)2NH(C 1-3 Alkyl);-S(=O)2NHC(=O)C 1-3 Alkyl;-S(=O)2N(C 1-3 Alkyl)2;-S(=O)2C 1-3 Alkyl;-S(=O)(=NH)C 1-3 Alkyl;-S(=O)(=NH)C 3-6 Cycloalkyl;-S(=O)(=NR')C 2-6 Heterocycloalkyl;-S(=O)(=NC 3-6 Cycloalkyl)C 1-3 Alkyl;-S(=O)(=NC 2-6 (Heterocycloalkyl)C 1-3 Alkyl;-S(=O)(=NC 1-3 Alkyl)C 1-3 Alkyl;-S(=O)(=NCN)C 1-3 Alkyl;-N(C 1-3 Alkyl)S(=O)2C 1-3 Alkyl;-PO(C 1-3 Alkyl) 2; 3-6 membered cycloalkyl; selected from 3-6 membered heterocycloalkyls, optionally containing 1, 2, or 3 heteroatoms selected from N, O, P, or S; the C 1-3 Alkyl, OC 1-3 Alkyl, 3-6 membered cycloalkyl, C 3-6 Cycloalkyl, C 2-6 If heterocycloalkyl or 3-6 member heterocycloalkyl groups are present, then deuterium, halogen, -CN, and -C are present, respectively. 1-3 Alkyl, oxo, -OH, -OC 1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, -N(C 1-3Alkyl)2,-COOH,-C(O)OC 1-3 Alkyl, -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl), -S(=O)2C 1-3 Alkyl, -S(=O)2N(C 1-3 Alkyl)2,-S(=O)(=NH)C 1-3 Alkyl, -S(=O)(=NC 1-3 Alkyl)C 1-3 They are independently and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from alkyl or 3-6 membered cycloalkyl groups. A compound listed in any one of

[35] to

[42] .

[0060]

[44] . R3 is independently selected from phenyl, pyridinyl, and 5-10 membered benzoheterocycloalkyl groups containing one or two heteroatoms selected from N, O, or S, each of which is R 3a It is optionally substituted with 1, 2, or 3 substituents selected from; R 3a However, deuterium, -F; oxo; -OC 1-3 Alkyl;-C(=O)NH2,-C(=O)NH(C 1-3 alk;-CN;-S(=O)2NH2;-S(=O)2NH(C 1-3 Alkyl);-S(=O)2NHC(=O)C 1-3 Alkyl;-S(=O)2N(C 1-3 Alkyl)2;-S(=O)2C 1-3 Alkyl;-S(=O)(=NH)C 1-3 Alkyl;-S(=O)(=NC 1-3 Alkyl)C 1-3 Alkyl;-N(C 1-3 Alkyl)S(=O)2C 1-3 Alkyl;-PO(C 1-3 A 3-6 membered heterocycloalkyl group comprising either alkyl)2 or 1, 2, or 3 heteroatoms selected from N, O, P, or S; the C1-3 Alkyl, OC 1-3 If alkyl or 3-6 member heterocycloalkyl groups are present, deuterium, -F, -CN, oxo, and -C are present, respectively. 1-3 Alkyl, -OH, -OC 1-3 Alkyl, -N(C 1-3 Alkyl)2,-C(O)OC 1-3 Alkyl, -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), or -C(=O)N(C 1-3 The alkyl group is independently and optionally substituted with substituents 1, 2, 3, 4, 5, or 6 selected from 2. The compound described in

[43] .

[0061]

[45] .R3 is phenyl, pyridinyl, [ka] Selected from, each of them is R 3a It is optionally substituted with 1, 2, or 3 substituents selected from; R 3a However, -F; oxo; -OC 1-3 Alkyl;-C(=O)NHC 1-3 Alkyl;-S(=O)2NH2;-S(=O)2NHC(=O)CH3;-S(=O)2CH3;-S(=O)(=NH)C 1-3 Alkyl;-S(=O)(=NC 1-3 Alkyl)C 1-3 Alkyl;-N(CH3)S(=O)2CH3;-PO(C 1-3 Alkyl)2; Selected from 5-6 membered heterocycloalkyls, which optionally contain 1, 2, or 3 heteroatoms selected from morpholinyl or N, O, or P; The C 1-3 Alkyl, OC 1-3 If alkyl or 5-6 member heterocycloalkyl groups are present, then deuterium, -F, -CN, oxo, -OH, -OCH3, -N(C) 1-3 The alkyl group is independently and optionally substituted with substituents 1, 2, 3, 4, 5, or 6 selected from -C(O)OCH3, or -C(=O)NH. The compounds described in

[44] .

[0062]

[46] .R3 is R 3a Independently selected from phenyls optionally substituted with 1, 2, or 3 substituents selected from; R 3a is -F, -OCH3, -OCD3, -OCH2CN, -OCH2CF3, -CH2F, -CHF2, -OCH2CH2OH, -OCH2CH2OCH3, -S(O)2NH2, -S(O)2NHCOCH3, -S(O)2CH3, -S( =O)(=NH)CH3, -S(=O)(=NCH3)CH3, -N(CH3)S(=O)2CH3, -C(O)NHCH3, -C(O)NHCH(COOCH3)CH2CH2CONH2, -PO(CH3)2, morpholinyl, or [ka] Selected from, The compound described in

[43] .

[0063]

[47] .R 11 and R 12 A compound described in any one of [1] to

[46] , wherein both are hydrogen atoms.

[0064]

[48] .R 13 A compound described in any one of [1] to

[47] , wherein H is present.

[0065]

[49] .Chemical part [ka] but, [ka] Selected from, A compound listed in any one of [1] to

[48] .

[0066]

[50] .Chemical part [ka] but, [ka] Selected from, A compound listed in any one of [1] to

[48] .

[0067]

[51] .Chemical part [ka] but, [ka] Selected from, A compound listed in any one of [1] to

[48] .

[0068]

[52] .Chemical part [ka] but, [ka] Selected from, A compound listed in any one of [1] to

[48] .

[0069]

[53] .Chemical part [ka] but, [ka] Selected from, A compound listed in any one of [1] to

[48] .

[0070]

[54] The compound of formula (I) is selected from the following, one of the compounds listed in [1] to

[53] . [Table 1] TIFF0007897926000043.tif202170TIFF0007897926000044.tif211170TIFF0007897926000045.tif213170TIFF0007897926000046.tif210170TIFF0007897926000047.tif213170TIFF0007897926000048.tif207170TIFF0007897926000049.tif213170TIFF0007897926000050.tif205170TIFF0007897926000051.tif208170TIFF0007897926000052.tif211170TIFF0007897926000053.tif213170TIFF0007897926000054.tif220170TIFF0007897926000055.tif221170TIFF0007897926000056.tif214170TIFF0007897926000057.tif214170TIFF0007897926000058.tif216170TIFF0007897926000059.tif212170TIFF0007897926000060.tif214170TIFF0007897926000061.tif212170TIFF0007897926000062.tif213170TIFF0007897926000063.tif211170TIFF0007897926000064.tif214170TIFF0007897926000065.tif215170TIFF0007897926000066.tif219170TIFF0007897926000067.tif222170TIFF0007897926000068.tif220170TIFF0007897926000069.tif210170TIFF0007897926000070.tif212170TIFF0007897926000071.tif217170TIFF0007897926000072.tif218170TIFF0007897926000073.tif212170TIFF0007897926000074.tif215170TIFF0007897926000075.tif220170TIFF0007897926000076.tif213170TIFF0007897926000077.tif214170TIFF0007897926000078.tif219170TIFF0007897926000079.tif212170TIFF0007897926000080.tif213170TIFF0007897926000081.tif221170TIFF0007897926000082.tif209170TIFF0007897926000083.tif206170TIFF0007897926000084.tif211170TIFF0007897926000085.tif214170TIFF0007897926000086.tif215170TIFF0007897926000087.tif206170TIFF0007897926000088.tif217170TIFF0007897926000089.tif213170TIFF0007897926000090.tif212170TIFF0007897926000091.tif217170TIFF0007897926000092.tif219170TIFF0007897926000093.tif210170TIFF0007897926000094.tif219170TIFF0007897926000095.tif218170TIFF0007897926000096.tif206170TIFF0007897926000097.tif211170TIFF0007897926000098.tif220170TIFF0007897926000099.tif210170TIFF0007897926000100.tif211170TIFF0007897926000101.tif210170TIFF0007897926000102.tif213170TIFF0007897926000103.tif216170TIFF0007897926000104.tif216170TIFF0007897926000105.tif221170TIFF0007897926000106.tif209170TIFF0007897926000107.tif221170TIFF0007897926000108.tif214170TIFF0007897926000109.tif220170TIFF0007897926000110.tif214170TIFF0007897926000111.tif222170TIFF0007897926000112.tif221170TIFF0007897926000113.tif214170TIFF0007897926000114.tif217170TIFF0007897926000115.tif215170TIFF0007897926000116.tif214170TIFF0007897926000117.tif220170TIFF0007897926000118.tif206170TIFF0007897926000119.tif212170TIFF0007897926000120.tif214170TIFF0007897926000121.tif220170TIFF0007897926000122.tif221170TIFF0007897926000123.tif219170TIFF0007897926000124.tif221170TIFF0007897926000125.tif216170TIFF0007897926000126.tif221170TIFF0007897926000127.tif221170TIFF0007897926000128.tif221170TIFF0007897926000129.tif222170TIFF0007897926000130.tif216170TIFF0007897926000131.tif216170TIFF0007897926000132.tif216170TIFF0007897926000133.tif214170TIFF0007897926000134.tif213170TIFF0007897926000135.tif224170TIFF0007897926000136.tif215170TIFF0007897926000137.tif223170TIFF0007897926000138.tif217170TIFF0007897926000139.tif221170TIFF0007897926000140.tif215170TIFF0007897926000141.tif221170TIFF0007897926000142.tif223170TIFF0007897926000143.tif172170.

[0071]

[55] . The compound of formula (I) [ka] TIFF0007897926000145.tif189170TIFF0007897926000146.tif195170TIFF0007897926000147.tif161170TIFF0007897926000148.tif195170TIFF 0007897926000149.tif200170TIFF0007897926000150.tif197170TIFF0007897926000151.tif205170TIFF0007897926000152.tif208170TIFF00078 97926000153.tif212170TIFF0007897926000154.tif217170TIFF0007897926000155.tif209170TIFF0007897926000156.tif221170TIFF0007897926 000157.tif218170TIFF0007897926000158.tif209170TIFF0007897926000159.tif222170TIFF0007897926000160.tif214170TIFF000789792600016 1.tif214170TIFF0007897926000162.tif221170TIFF0007897926000163.tif205170TIFF0007897926000164.tif220170TIFF0007897926000165.ti f216170TIFF0007897926000166.tif217170TIFF0007897926000167.tif221170TIFF0007897926000168.tif222170TIFF0007897926000169.tif2301 Select from 70TIFF0007897926000170.tif226170TIFF0007897926000171.tif221170TIFF0007897926000172.tif214170TIFF0007897926000173.tif223170TIFF0007897926000174.tif211170TIFF0007897926000175.tif185170TIFF0007897926000176.tif217170TIFF0007897926000177.tif153170 A compound listed in any one of the following [1] to

[53] .

[0072]

[56] . Compounds of formula (I) [ka] TIFF0007897926000179.tif215170TIFF0007897926000180.tif217170TIFF0007897926000181.tif227170TIFF0007897926000182.tif214170TIFF0007897926000183.tif225170TIFF0007897926000184.tif223170TIFF0007897926000185.tif221170TIFF0007897926000186.tif223170TIFF0007897926000187.tif215170TIFF0007897926000188.tif221170TIFF0007897926000189.tif214170TIFF0007897926000190.tif219170TIFF0007897926000191.tif213170TIFF0007897926000192.tif219170TIFF0007897926000193.tif216170TIFF0007897926000194.tif211170TIFF0007897926000195.tif207170TIFF0007897926000196.tif218170TIFF0007897926000197.tif226170TIFF0007897926000198.tif223170TIFF0007897926000199.tif211170TIFF0007897926000200.tif209170TIFF0007897926000201.tif221170TIFF0007897926000202.tif225170TIFF0007897926000203.tif211170TIFF0007897926000204.tif226170TIFF0007897926000205.tif211170TIFF0007897926000206.tif208170TIFF0007897926000207.tif208170TIFF0007897926000208.tif203170TIFF0007897926000209.tif219170TIFF0007897926000210.tif217170TIFF0007897926000211.Selected from tif210170TIFF0007897926000212.tif189170. A compound listed in any one of the following [1] to

[53] .

[0073]

[57] . Compounds of formula (I) [ka] TIFF0007897926000214.tif217170TIFF0007897926000215.tif217170TIFF0007897926000216.tif191170TIFF0007897926000 217.tif217170TIFF0007897926000218.tif215170TIFF0007897926000219.tif213170TIFF0007897926000220.tif229170TIFF Select from 0007897926000221.tif229170TIFF0007897926000222.tif224170TIFF0007897926000223.tif211170TIFF0007897926000224.tif224170TIFF0007897926000225.tif232170TIFF0007897926000226.tif223170TIFF0007897926000227.tif240170. A compound listed in any one of the following [1] to

[53] .

[0074]

[58] . Compounds of formula (I) [ka] TIFF0007897926000229.tif214170TIFF0007897926000230.tif215170TIFF0007897926000231.ti f223170TIFF0007897926000232.tif220170TIFF0007897926000233.tif216170TIFF0007897926000 234.tif217170TIFF0007897926000235.tif229170TIFF0007897926000236.tif216170TIFF000789 7926000237.tif225170TIFF0007897926000238.tif215170TIFF0007897926000239.tif191170TIFF 0007897926000240.tif183170TIFF0007897926000241.tif184170TIFF0007897926000242.tif184 170TIFF0007897926000243.tif192170TIFF0007897926000244.tif193170TIFF0007897926000245. Select from tif199170TIFF0007897926000246.tif187170TIFF0007897926000247.tif181170TIFF0007897926000248.tif184170TIFF0007897926000249.tif189170TIFF0007897926000250.tif117170 A compound listed in any one of the following [1] to

[53] .

[0075]

[59] . [ka] Select from TIFF0007897926000252.tif202170TIFF0007897926000253.tif198170TIFF0007897926000254.tif191170TIFF0007897926000255.tif203170TIFF0007897926000256.tif80170. A compound listed in any one of the following [1] to

[53] .

[0076]

[60] Compounds of formula (IN-I): [ka] A compound wherein R1, R2, or R4 is defined as in any one of claims 1 to 59, and LG is selected from leaving groups such as halogens, preferably from leaving groups such as bromine or iodine.

[0077]

[61] A method for preparing a compound of formula (I-1) described in any one of [1] to

[59] , including the following steps: [ka] (1) In the presence of an alkalizing agent, compound S1-1 as a starting material is reacted with compound S1-2 to form compound S2-1; (2) Converting compound S2-1 to compound S3-1 under acidic conditions; (3) Converting compound S3-1 to compound S4-1 in the presence of a halogenating agent; (4) Reacting compound S4-1 with reagent S4-2 in the presence of a coupling catalyst to form compound S5-1; (5) Converting compound S5-1 to the compound of formula (I-1) by one or more steps of a reaction such as a reductive amination reaction, a deprotection reaction, or a combination thereof; Here, L1, L2, and L3 independently represent leaving groups; Y is selected from O or S; X2, X3, X4, R1, R2, R 11 , R 12 , R 13 , R3, R 51 , R 52 and m are methods as defined in any one of the terms [1] to

[59] , respectively.

[0078]

[62] The method according to

[61] , wherein the alkalizing agent is K2CO3.

[0079]

[63] The method according to

[61] or

[62] , wherein the acidic conditions are polyphosphate.

[0080]

[64] The method according to

[61] or

[62] , wherein the halogenating agent is NIS.

[0081]

[65] .R2 is -NR 51 R 52 The method according to

[61] or

[62] , wherein, in this case, the group L1 of compound S5-1 is converted to -NH2, and subsequently converted to the compound of formula (I-1) via a reductive amination reaction, a deprotection reaction, or a combination thereof.

[0082]

[66] The method according to

[61] or

[62] , comprising a Pd-containing coupling catalyst such as Pd(PPh3)2Cl2 or Pd(dppf)Cl2.

[0083]

[67] The method according to

[61] or

[62] , wherein the leaving group is a halogen such as -Cl, -Br, or -I.

[0084]

[68] The method according to

[61] or

[62] , wherein L1 is selected from -Br; L2 is selected from -Br; and L3 is selected from -I.

[0085]

[69] A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) described in any one of [1] to

[59] , a stereoisomer thereof, a tautomer thereof, a deuterated derivative thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0086]

[70] . Use of a compound of formula (I), or a stereoisomer thereof, a tautomer thereof, a deuterated derivative thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described in any one of [1] to

[59] , in the manufacture of a pharmaceutical for the prevention or treatment of a disease or condition in a subject.

[0087]

[71] The use according to

[70] , wherein the disease or condition is cancer, preferably a solid cancer such as an advanced solid tumor.

[0088]

[72] . Use as described in

[71] , where cancer cells express a p53 variant.

[0089]

[73] . The use described in

[72] , wherein the p53 variant has mutations in the amino acids Val143, His168, Arg175, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, Arg282, and / or combinations thereof.

[0090]

[74] . Use as described in

[72] , where the p53 mutant is V157F, R175H, Y220C, G245S, R248Q, R248W, R249S, R273H, R273C, R282W, and / or a combination thereof, preferably Y220C.

[0091]

[75] . Use as described in any one of

[70] to

[74] , where the disease or condition is selected from the group consisting of ovarian cancer, breast cancer, lung cancer and / or a combination thereof.

[0092]

[76] A compound of formula (I) described in any one of [1] to

[59] , or a stereoisomer thereof, a tautomer thereof, a deuterated derivative thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in

[69] , for use in the prevention or treatment of a disease or condition associated with the p53 mutant protein in a subject.

[0093]

[77] A method for preventing or treating a disease or condition in a subject that is associated with a p53 mutant protein, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) according to any one of [1] to

[59] , or a stereoisomer thereof, a tautomer thereof, a deuterated derivative thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to

[69] .

[0094]

[78] . The method of

[77] in which the disease or condition is cancer.

[0095]

[79] . The method described in

[78] , wherein cancer cells express a p53 variant.

[0096]

[80] . Use as described in

[79] , where the p53 variant has mutations in the amino acids Val143, His168, Arg175, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, Arg282, and / or combinations thereof.

[0097]

[81] The method according to

[79] , wherein the p53 mutant is V157F, R175H, Y220C, G245S, R248Q, R248W, R249S, R273H, R273C, R282W, and / or a combination thereof, preferably Y220C.

[0098]

[82] . The method according to any one of

[77] to

[81] , wherein the disease or condition is selected from the group consisting of ovarian cancer, breast cancer, lung cancer and / or a combination thereof. Detailed description of the invention

[0099] This invention provides compounds, compositions, and methods for restoring the wild-type function of p53 mutants. The compounds of this invention can bind to p53 mutants and restore their DNA-binding ability. Restoration of p53 mutant activity may enable the activation of p53 downstream effectors, leading to the suppression of cancer progression. This invention further provides methods for treating diseases or conditions associated with p53 mutant proteins. Methods for preparing the compounds of this invention are also provided.

[0100] The compounds of the present invention can selectively bind to p53 mutants and may restore wild-type activity of the p53 mutants, including, for example, activation of downstream targets involved in DNA binding function and tumor suppression. In some embodiments, the compounds of the present invention selectively bind to the p53 Y220C mutant. The Y220C mutant is a temperature-sensitive mutant that binds to DNA at low temperatures and denatures at body temperature. The compounds of the present invention can selectively bind to p53 Y220C and stabilize the Y220C mutant, reducing the likelihood of protein denaturation at body temperature.

[0101] To determine the ability of the compounds of the present invention to bind to and stabilize p53 mutants, assays that detect conformational changes in p53 mutants or the activity of wild-type p53 targets can be utilized, for example. Conformational changes in p53 can be measured, for example, by differential scanning fluorescence (DSF), isothermal titration (ITC), nuclear magnetic resonance spectroscopy (NMR), or X-ray crystallography. Furthermore, conformational changes can be detected using antibodies specific to the wild-type of the mutant conformation of p53, for example, by immunoprecipitation (IP), immunofluorescence (IF), or immunoblotting. Methods used to detect the ability of p53 mutants to bind to DNA include, for example, DNA affinity immunoblotting, modified enzyme-linked immunosorbent assay (ELISA), electrophoretic mobility shift assay (EMSA), fluorescence resonance energy transfer (FRET), homogeneous time-resolved fluorescence (HTRF), and chromatin immunoprecipitation (ChIP) assays. To determine whether the compounds described herein can reactivate the transcriptional activity of p53, the activation of downstream targets in the p53 signaling cascade may be measured. Activation of p53 effector proteins can be detected, for example, by immunohistochemistry (IHC-P), reverse transcription polymerase chain reaction (room-temperature PCR), and Western blotting. p53 activation can also be measured by induction of apotho, cis- via the caspase cascade, using methods such as annexin V staining, TMNEL assay, procaspase and caspase levels, and cytochrome c levels. Another consequence of p53 activation is senescence, which can be measured using methods such as β-galactosidase staining.

[0102] The compounds that bind to DNA in vitro and are recorded in this document are 0.010 μM or less, 0.015 μM or less, 0.020 μM or less, 0.025 μM or less, 0.030 μM or less, 0.035 μM or less, 0.040 μM or less, 0.045 μM or less, 0.050 μM or less, 0.055 μM or less, 0.060 μM or less, 0.065 μM or less, 0.070 μM or less, 0.075 μM or less, 0.080 μM or less, 0.085 μM or less, 0.090 μM or less, 0.095 μM or less, 0.100 μM or less, 0.110 μM or less, 0.120 μM or less, 0.130 μM or less. Below μM, 0.140 μM, 0.150 μM, 0.160 μM, 0.170 μM, 0.180 μM, 0.190 μM, 0.200 μM, 0.250 μM, 0.300 μM, 0.400 μM, 0.500 μM, 0.600 μM, 0.800 μM, 1.000 μM, 1.500 μM, 2.000 μM, 6.000 μM, または10.000 μM or below EC 50 をshows しgets る.

[0103] The cell survival rate of cell lines containing NMgGC-3 (p53, Y220C) and other p53 Y220C variants is as follows: [List of compounds listed in this document] 0.100 μM or less, 0.110 μM or less, 0.120 μM or less, 0.130 μM or less, 0.140 μM or less, 0.150 μM or less, 0.160 μM or less, 0.170 μM or less, 0.180 μM or less, 0.190 μM or less, 0.200 μM or less, 0.250 μM or less, 0.300 μM or less, 0.350 μM or less, 0.400 μM or less, 0.450 μM or less, 0.500 μM or less. Below μM, below 0.550 μM, below 0.600 μM, below 0.650 μM, below 0.700 μM, below 0.750 μM, below 0.800 μM, below 0.850 μM, below 0.900 μM, below 0.950 μM, below 1.000 μM, below 1.500 μM, below 2.000 μM, below 2.500 μM, below 3.000 μM, below 4.000 μM, below 5.000 μM, below 6.000 μM, below 7.000 μM, below 8.000 μM, below 9.000 μM, below 15.000 μM, または25.000 μM and below no IC 50 をshows しgets る.

[0104] NMGC-4 (p53, wt) and other wild-type p53 cell lines have cell viability rates and compounds described in this specification, 1.00 μM or more, 1.30 μM or more, 1.60 μM and above, 2.00 μM and above, 2.50 μM and above, 3.00 μM and above, 3.50 μM and above, 4.00 μM and above, 4.50 μM and above, 5.00 μM and below, 5.50 μM and above, 6.00 μM and above, 6.50 μM and above, 7.00 μM and above, 7.50 μM and above, 8.00 μM and above, 8.50 μM and above, 9.00 μM and above, 9.50 μM and above, 10.00 μM and above, 10.50 μM and above, 11.00 μM and above, 11.50 μM and above, 12.00 μM and above, 12.50 μM and above, 13.00 μM and above, 13.50 μM and above, 14.00 μM and above, 15.00 μM and above, 16.00 μM and above, 17.00 μM and above, 18.00 μM and above, 19.00 μM and above, 20.00 μM and above, または21.00 μM and above no IC50 This could demonstrate that.

[0105] In some embodiments, some compounds of the present invention are p53 such as NMGC-3 (p53, Y220C). Cell lines containing the Y220C mutant exhibit at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 150, 200, or 300 times lower IC50 than cell lines containing wild-type p53 such as NMGC-4(p53, wt). 50 This could demonstrate that.

[0106] In some embodiments, some compounds of the present invention are found to be at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 times more potent in cell lines possessing p53 Y220C mutants such as NMGC-3(p53, Y220C) compared to cell lines possessing wild-type p53 such as NMGC-4(p53, wt). It may exhibit selectivity or specificity of 24x, 25x, 26x, 27x, 28x, 29x, 30x, 31x, 32x, 33x, 34x, 35x, 36x, 37x, 38x, 39x, 40x, 45x, 50x, 55x, 60x, 70x, 80x, 90x, 100x, 120x, 150x, 200x, or 300x.

[0107] In reporter gene assays, some compounds of the invention may be 0.010 μM or less, 0.015 μM or less, 0.020 μM or less, 0.025 μM or less, 0.030 μM or less, 0.035 μM or less, 0.040 μM or less, 0.045 μM or less, 0.0.050 μM or less, 0.055 μM or less, 0.060 μM or less 0.065 µM or less, 0.070 µM or less, 0.075 µM or less, 0.080 µM or less, 0.085 µM or less, 0.090 µM or less, 0.095 µM or less, 0.100 µM or less, 0.110 µM or less, 0.120 µM or less, 0.130 µM or less, 0.140 µM or less, 0.150 µM or less, 0.160 µM or less, 0.170 µM or less, 0.180 µM or less, 0.190 µM or less, 0.200 µM or less, 0.250 µM or less, 0.300 µM or less, 0.350 µM or less, 0.400 µM or less, 0.450 µM or less, 0.500 µM or less, 0.550 µM or less, 0.600 µM or less, 0.650 µM or less, 0.700 EC of less than μM, less than 0.750 μM, less than 0.800 μM, less than 0.900 μM, less than 1.000 μM, less than 5.000 μM, or less than 10.000 μM 50 This could demonstrate that.

[0108] The present invention will be described using several definitions as set forth herein and throughout this application.

[0109] Unless otherwise specified or indicated by context, the terms “a,” “an,” and “the” mean “one or more.” For example, “compound” should be interpreted as “one or more compounds.”

[0110] As used herein, “about,” “approximately,” “substantially,” and “significantly” are to be understood by those skilled in the art and vary to some extent depending on the context in which they are used. Where there are uses of these terms that are not clear to those skilled in the art from the context in which they are used, “about” and “approximately” mean less than plus or minus 10% of a given term, and “substantially” and “significantly” mean more than plus or minus 10% of a given term.

[0111] As used herein, the terms “include” and “including” have the same meaning as “comprise” and “comprising,” with the latter being an “open” transitional term that does not limit the claim to only the cited elements that follow these transitional terms. The term “consisting of” is encompassed by the term “comprising,” but should be interpreted as a “closed” transitional phrase that limits the scope of the claim to only the cited elements that follow this transitional phrase. The term “consisting essentially of” is encompassed by the term “comprising,” but should be interpreted as a “partially closed” transitional phrase that allows for additional elements following this transitional phrase, provided that such additional elements do not materially affect the basic and novel characteristics of the claim.

[0112] The total number of carbon atoms present in a chemical group as defined herein is indicated by an abbreviation preceding the group. For example, C 1-6 Alkyl refers to an alkyl group having a total of 1 to 6 carbon atoms, as defined below; C 3-8 A cycloalkyl group refers to a cycloalkyl group having a total of 3 to 8 carbon atoms, as defined below; C 6-10The term "aryl" refers to an aryl group defined below, which has a total of 6 to 10 carbon atoms. Carbon atoms that may be present in substituents of the chemical group are not included in the total number of carbon atoms in the abbreviated notation.

[0113] Unless otherwise specified herein, all bonding groups according to the present invention (i.e., groups composed of two or more groups) are bonded to the rest of the molecule in such a manner that the last group listed acts as a bonding site. Examples include: “arylalkyl” means that the aryl group is bonded to the rest of the molecule via an alkyl group; “alkoxyl” means that the aliphatic group is bonded to the rest of the molecule via an oxy group; and so on.

[0114] In this application, "optional" or "optionally" means that the event or situation described thereafter may or may not occur, and that the description includes examples of when such event or situation occurs and examples of when it does not occur. Also, the term "optionally substituted" means that one or more hydrogen atoms on the specified atom or group may or may not be substituted with a non-hydrogen part. For example, "alkyl optionally substituted with one or more halogens (e.g., 1, 2, 3, 4, 5, or 6)" means that the alkyl group is either unsubstituted or substituted with one or more halogens (e.g., 1, 2, 3, 4, 5, or 6), and this includes both substituted and unsubstituted alkyl groups.

[0115] The term "substituted" means that one or more hydrogen atoms on a specified atom or group are substituted by one or more non-hydrogen substituents, provided that the valence of the specified atom does not exceed the normal valence of the specified atom. Unless otherwise specified, "substituted" means any level of substitution, such as mono-, di-, tri-, tetra-, or penta-substitution, and such substitutions are permitted. Substituents are selected independently, and substitutions may be at any chemically accessible position. It should be understood that substitutions at a given atom are limited by their valence. It should be understood that substitutions at a given atom result in a chemically stable molecule. As used herein, the term "substituted" is intended to include all permitted substituents of an organic compound. In a broader embodiment, permitted substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. For a given organic compound, there may be one or more permitted substituents, and they may be the same or different. "Optionally substituted" means unsubstituted or substituted. "Substituting" means that a hydrogen atom has been removed and replaced with a substituent. Divalent substituents such as oxo substituents can substitute for two hydrogen atoms.

[0116] The term "stereoisomer" refers to a compound in which the same atoms are bonded together by the same bonds, but which has a different three-dimensional structure. All stereoisomers in this invention can be identified and determined by conventional X-ray single-crystal diffraction analysis. This invention envisions various stereoisomers and mixtures thereof.

[0117] The stereochemical definitions and conventions used herein generally follow SP. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company in New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds described herein may contain chiral or asymmetric centers and therefore may exist in different stereoisomers. Many organic compounds exist in optically active forms, i.e., forms that have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule with respect to the chiral center (S). The prefixes d and l, or (+) and (-), are used to indicate the sign of the rotation of plane-polarized light by the compound, where (-) or 1 means that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical to each other except that they are mirror images of one another. Certain stereoisomers are sometimes called enantiomers, and mixtures of such isomers are often referred to as enantiomer mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to equimolar mixtures of two optically inactive enantiomer species.

[0118] The term "tautomer" refers to an isomer resulting from a proton shift from one atom in a molecule to another atom in the same molecule. All tautomers of the compound of formula (I) of the present invention are included within the scope of the present invention.

[0119] Unless otherwise specified, the structures described herein include all isomeric forms of the structure, such as racemic mixtures, cis- / trans isomers, (Z) isomers, and (E) isomers, and other geometric (or conformational) isomers. Unless otherwise specified, compounds having double bonds or rings in this application include both E and Z geometric isomers.

[0120] Unless otherwise specified, [ka] or [ka] In this application, the combination of these is: [ka] and [ka] Includes.

[0121] All isotopes of a specified atom or element are assumed within the scope of the compounds of the present invention and their applications. Isotopes include atoms with the same atomic number but different mass numbers. Exemplary isotopes that can be incorporated into the compounds of the present invention include: 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I or 125 Examples of isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine. Common examples of hydrogen isotopes include deuterium and tritium, but are not limited to these. Hydrogen isotopes include,1 H (hydrogen), 2 H (deuterium) and 3 It can be represented as H (tritium). Also, deuterium is sometimes denoted as D and tritium as T. In this application, CD3 represents a methyl group in which all hydrogen atoms are deuterium. As for carbon isotopes, 13 C and 14 C is an example. The isotope-labeled compounds of this disclosure are equivalent to the unlabeled compounds; for example, the deuterated compounds of this disclosure are equivalent to the undeuterated compounds. The isotope-labeled compounds of the present invention can generally be prepared by processes known to those skilled in the art, or similar to those described herein, using a suitable isotope-labeling reagent instead of an unlabeled reagent.

[0122] As used herein, "deuterated derivative" refers to a compound having the same chemical structure as the reference compound, but with one or more hydrogen atoms replaced by deuterium atoms ("D" or " 2This refers to compounds in which hydrogen is substituted with deuterium. It will be recognized that the synthesized compounds will exhibit variations in the natural isotopic abundances depending on the origin of the chemicals used in their synthesis. Regardless of this variation, the concentrations of naturally abundant stable hydrogen isotopes are small and insignificant compared to the degree of stable isotopic substitution in the deuterated derivatives described herein. Therefore, unless otherwise specified, when we refer to a “deuterated derivative” of a compound in this disclosure, at least one hydrogen is substituted with deuterium at a level well above its natural isotopic abundance, which is typically about 0.015%. In some embodiments, the deuterated derivatives disclosed herein have an isotopic enrichment factor of at least 3500 (52.5% deuterium introduced in each designated deuterium), at least 4500 (67.5% deuterium introduced in each designated deuterium), at least 5000 (75% deuterium introduced in each designated deuterium), at least 5500 (82.5% deuterium introduced in each designated deuterium), at least 6000 (90% deuterium introduced in each designated deuterium), at least 6333.3 (95% deuterium introduced in each designated deuterium), at least 6466.7 (97% deuterium introduced in each designated deuterium), or at least 6600 (99% deuterium introduced in each designated deuterium). As used herein, the term “isotopic enrichment factor” means the ratio of the isotopic abundance to the natural abundance of the designated isotope.

[0123] In addition to the foregoing, the following terms used in this specification and in the claims have the following meanings unless otherwise specified: "Amino" refers to the -NH2 group. "Cyano" refers to the -CN group. "Hydroxy" refers to the -OH group. "Nitro" refers to the -NO2 group. "Carbonyl" refers to the -COOH group. "Nitroso" refers to the -N=O group.

[0124] As used herein, the term "halogen" means fluoro, chloro, bromo, or iodine unless otherwise specified. Preferred halogen groups include -F, -Cl, and -Br.

[0125] As used herein, the term "alkyl" includes linear or branched saturated monovalent hydrocarbon radicals unless otherwise specified. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl. Similarly, C 1-6 C in alkyl 1-6 This term is defined to identify a group having 1, 2, 3, 4, 5, or 6 carbon atoms in a linear or branched arrangement.

[0126] The term "alkenyl" refers to a linear or branched hydrocarbon radical containing one or more double bonds (1, 2, 3, 4, 5, or 6, etc.), typically containing 2 to 20 carbon atoms. For example, "C 2-6 An "alkenyl" group contains 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-butenyl-1-yl, hepetenyl, and octenyl.

[0127] The term "alkynyl" refers to a linear or branched hydrocarbon radical containing one or more (1, 2, 3, 4, 5, or 6, etc.) triple bonds, typically having a length of 2 to 20 carbon atoms. For example, "C 2-6 Alkynyl groups contain 2 to 6 carbon atoms. Typical alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, and octynyl.

[0128] The term "alkoxyl" radical refers to an oxygen ether formed from the alkyl group mentioned earlier.

[0129] The term "oxo" refers to a group = O or (O), or an oxygen atom bonded to another atom (e.g., C, N, S, P) via a double bond.

[0130] A "cycloalkyl" is a fully saturated cyclic hydrocarbon. Cycloalkyls include monocyclic and bicyclic rings. Typically, monocyclic cycloalkyls, unless otherwise defined, have 3 to about 12 carbon atoms, more typically 3 to 8 carbon atoms. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyls include bicyclic molecules in which one, two, or more atoms are shared between two rings. The term "spirocyclic cycloalkyl" refers to a bicyclic cycloalkyl in which each ring shares one adjacent atom with the other. The term "condensed cycloalkyl" refers to a bicyclic cycloalkyl in which each ring shares two adjacent atoms with the other. The term "bridged cycloalkyl" refers to a cycloalkyl containing at least two bridgehead carbon atoms and at least one bridged carbon atom. "Cross-linked cycloalkyl" includes "bicyclic cross-linked cycloalkyl" containing two bridgehead carbon atoms, and "bicyclic cross-linked cycloalkyl" containing two or more bridgehead carbon atoms. Typical cross-linked cycloalkyls include adamantyl, nordamantyl, bicyclo[1.1.0]butanyl, norboranyl (bicyclo[2.2.1]heptanyl), norbornel (bicyclo[2.2.l]heptanyl), norbornadienyl (bicyclo[2.2.l]heptadienyl), tricyclo[2.2.1.0]heptanyl, bicyclo[3.2.1]octanyl, bicyclo[3.2.1]octadinyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl, bicyclo[2.2.2]octadinyl, bicyclo[5,2,0]nonanyl, bicyclo[4.3.2]undecanyl, and tricyclo[5.3.1.1]dodecanyl.

[0131] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbon atoms per ring system. Examples of such groups include cyclobutenyl, cyclopentenyl, and cyclohexenyl. "Cycloalkenyl" includes monocyclic, bicyclic, tricyclic, or tetracyclic ring systems in which one, two, three, or more atoms are shared between two rings. The term "spirocyclic cycloalkenyl" refers to a bicyclic cycloalkenyl in which each ring shares one adjacent atom with the other. The term "condensed cycloalkenyl" refers to a polycyclic cycloalkenyl in which two rings share two adjacent atoms. The term "bridged cycloalkenyl" refers to a cycloalkenyl containing at least two bridgehead atoms and at least one bridging atom. "Bridged cycloalkenyl" includes "bicyclic bridged cycloalkenyls" containing two bridgehead atoms and "polycyclic bridged cycloalkenyls" containing two or more bridgehead atoms.

[0132] The term "heterocycloalkyl" refers to a fully saturated, stable 3-18 member non-aromatic ring radical consisting of 2-12 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, phosphorus, sulfur, etc. Unless otherwise specified herein, heterocycloalkyl radicals are monocyclic, bicyclic, tricyclic, or tetracyclic ring systems. The term "spirocyclic heterocycloalkyl" or "spiro-heterocyclyl" refers to a polycyclic heterocycloalkyl in which two rings share one atom. The term "condensed heterocycloalkyl" refers to a polycyclic heterocycloalkyl in which two rings share two adjacent atoms. The term "bridged heterocycloalkyl" or "bridged heterocyclyl" refers to a heterocycloalkyl containing at least two bridgehead atoms and at least one bridgehead atom. "Bridged heterocycloalkyl" or "bridged heterocyclyl" includes "bicyclic bridged heterocycloalkyl" containing two bridgehead atoms and "polycyclic bridged heterocycloalkyl" containing at least two bridgehead atoms. The heteroatoms in heterocycloalkyl radicals are optionally oxidized. In some embodiments, the heterocycloalkyl is bonded to the rest of the molecule via any atom of the ring. Examples of heterocycloalkyl radicals include dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 1,2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl.

[0133] The term "heterocycloalkenyl" refers to the above-mentioned heterocycloalkyl having at least one double bond. Heterocycloalkenyls may be monocyclic or polycyclic, and polycyclic heterocycloalkenyls include "spiro-ring heterocycloalkenyls," "condensed heterocycloalkenyls," and "bridged heterocycloalkenyls." A "spiro-ring heterocycloalkenyl" refers to a polycyclic heterocycloalkenyl in which two rings share one atom, a "condensed heterocycloalkenyl" refers to a polycyclic heterocycloalkenyl in which two rings share two adjacent atoms, and a "bridged heterocycloalkenyl" refers to a heterocycloalkenyl containing at least two bridgehead atoms and at least one bridged atom. Bridged heterocycloalkenyls include "bicyclic bridged heterocycloalkenyls" containing two bridgehead atoms and "polycyclic bridged heterocycloalkenyls" containing two or more bridgehead atoms.

[0134] As used herein, the term "aryl" refers to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing a carbocyclic atom, unless otherwise specified. Preferred aryls are monocyclic or bicyclic aromatic ring systems. Phenyl and naphthyl are preferred aryls.

[0135] As used herein, the term "heteroaryl" refers to an aromatic ring system comprising carbon and at least one heteroatom, unless otherwise specified. Heteroaryls may be monocyclic or polycyclic, and may be substituted or unsubstituted. Monocyclic heteroaryl groups may have 1 to 4 heteroatoms in the ring, and polycyclic heteroaryls may have 1 to 10 heteroatoms.

[0136] As used herein, the terms “heterocyclyl” or “heterocycle” refer to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic system having at least one heteroatom (e.g., at least one cyclic heteroatom selected from oxygen, nitrogen, phosphorus, and sulfur) in the ring. Unless otherwise specified, a heterocyclyl group has 3 to about 20 cyclic atoms, e.g., 3 to 12 cyclic atoms, e.g., 3 to 10 cyclic atoms, e.g., 5 to 10 cyclic atoms, or e.g., 5 to 6 cyclic atoms. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a tri, tetra, quin, hexa, or henicycle) having about 1 to 6 cyclic carbon atoms and about 1 to 3 cyclic heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. Rings in a multiple fused ring system (e.g., a bicyclic heterocyclyl) may be linked to one another via fused bonds, spirobonds, and bridging bonds, where permitted by valence requirements. The terms "heterocyclyl," "heterocyclic ring," or "heterocycle" include a heterocycloalkenyl group (i.e., a heterocyclyl group having at least one double bond). A heterocyclyl may be monocyclic or polycyclic. A polycyclic ring may be a fused ring, a bridging ring, or a spiro-ring. As used herein, a heterocyclyl has 2 to 20 ring carbon atoms (i.e., C 2-20 Heterocyclines), 2 to 12 ring carbon atoms (i.e., C 2-12 Heterocycline), 2 to 10 ring carbon atoms (i.e., C 2-10 Heterocyclyl), 2-8 ring carbon atoms (i.e., C 2-8 Heterocyclines), 3 to 12 ring carbon atoms (i.e., C 3-12 Heterocyclyl), 3-8 ring carbon atoms (i.e., C 3-8 Heterocyclyl), or ring carbon atoms with 3-6 atoms (i.e., C 3-6A heterocyclil has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclil groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. As used herein, the term "bridged heterocyclil" refers to a 4 to 10-membered cyclic moiety linked at two non-adjacent atoms of a heterocyclil to one or more (e.g., 1 or 2) 4 to 10-membered cyclic moieties having at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. As used herein, "bridged heterocyclil" includes bicyclic and tricyclic systems. Furthermore, as used herein, the term “spiroheterocyclyl” refers to a ring system in which a 3- to 10-membered heterocyclyl has one or more addition rings, where one or more addition rings are 3- to 10-membered cycloalkyls or 3- to 10-membered heterocyclyls, where one atom of the one or more addition rings is also an atom of the 3- to 10-membered heterocyclyl. Examples of spiroheterocyclyls include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Heterocyclyl groups also include partially unsaturated ring systems containing one or more double bonds, which include fused ring systems having one aromatic ring and one non-aromatic ring, but do not include fully aromatic ring systems. Examples include dihydroquinoline (e.g., 3,4-dihydroquinoline), dihydroisoquinoline (e.g., 1,2-dihydroisoquinoline), dihydroimidazole, tetrahydroimidazole, indoline, isoindoline, isoindrone (e.g., isoindrin-1-one), isatin, dihydrophthalazine, quinolinone, spiro[cyclopropane-1,1'-isoindoline]-3'-one, tetrahydroisoquinoline, and tetraline.Further examples of heterocycles include, for example, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl, and hexahydropyrazino[2,1-c][1,4]oxazinyl. As used herein, the terms “heterocycle,” “heterocyclyl,” and “heterocyclic ring” are interchangeable.

[0137] Any hydrogen atom bonded to C, N, O, or S in a 3-12 member cycloalkyl, 3-12 member cycloalkenyl, 3-12 member heterocycloalkyl, 3-12 member heterocycloalkenyl, 3-12 member heterocyclyl, 6-10 member aryl, or 5-12 member heteroaryl may be substituted with a substituent.

[0138] Any further reduction, oxidation, or other functionalization of the compounds of formula (I) of the present invention can be carried out according to methods well known to those skilled in the art. Within the scope of this description, unless otherwise indicated in the context, only easily removable groups that are not components of a particular desired final product of the compounds of the present invention are referred to as “protecting groups”. The protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are discussed in JFW McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973; TW Greene and PGM Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999; “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981; “Methoden der organischen Chemie” (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974; and H.-D. Jakubke and H. Jeschkeit, “Aminosauren, Peptide, Proteine” (Amino acids, Peptides, Proteins), Verlag Chemie. This is described in standard references such as Weinheim, Deerfield Beach, and Basel 1982. A characteristic of protecting groups is that they can be easily removed (i.e., without undesirable secondary reactions) by means of solvolysis, reduction, photolysis, or under physiological conditions (e.g., enzymatic cleavage).

[0139] As used herein, the term “leaving group” has the meaning conventionally defined in organic synthesis chemistry, namely, an atom or group that can be substituted by a nucleophile, and includes halos (chloro, bromo, iodine, etc.), alkanesulfonyloxys, arenesulfonyloxys, alkylcarbonyloxys (e.g., acetoxy), arylcarbonyloxys, mesyloxys, tosyloxys, trifluoromethanesulfonyloxys, aryloxys (e.g., 2,4-dinitrophenoxy), methoxys, N,O-dimethylhydroxylamino, and the like.

[0140] As used herein, the term “reductive amination” has the meaning commonly understood in the art and can be carried out by those skilled in the art in the presence of a reductive amination agent. In some embodiments, the reductive amination agent used in the reductive amination reaction is selected from the group consisting of organoborane complex compounds such as sodium cyanoborohydride; sodium triacetoxyborohydride; sodium borohydride; 4-(dimethylamino)pyridineborane complex, N-ethyldiisopropylamineborane complex, N-ethylmorpholineborane complex, N-methylmorpholineborane complex, N-phenylmorpholineborane complex, lutidineborane complex, triethylamineborane complex, trimethylamineborane complex, and combinations of two or more of these. Preferably, the reductive amination agent is sodium cyanoborohydride (NaBH3CN).

[0141] As used herein, the term “composition” is intended to encompass substances consisting of specified amounts of specified components, and substances resulting directly or indirectly from combinations of specified amounts of specified components. Therefore, pharmaceutical compositions containing the compounds of the present invention as active ingredients, as well as instantaneous methods for preparing the compounds, are also part of the present invention. Furthermore, some crystalline forms of the compounds may exist as polymorphs and are intended to be included in the present invention. Additionally, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be included within the scope of the present invention.

[0142] If the compounds of the present invention and their pharmaceutically acceptable salts exist in the form of solvates or polymorphs, the present invention includes all possible solvates and polymorphs. The type of solvent that forms the solvate is not particularly limited, as long as it is a pharmaceutically acceptable solvent. For example, water, ethanol, propanol, acetone, etc., may be used.

[0143] In many cases, the compounds of this disclosure can form acid addition salts and / or base addition salts in the presence of an amino group and / or a carboxyl group, or a similar group.

[0144] The term "pharmaceutically acceptable salt" of a compound means a salt that retains the biological effects and properties of the compound and is not biologically or otherwise undesirable. pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Examples of salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Examples of salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dialkenylamines, trialkenylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, mono, di, or tricycloalkylamines, mono, di, or triarylamines, or mixed amines. Specific examples of suitable amines include isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, and N-ethylpiperidine, but these are merely examples. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include those from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Salts derived from organic acids include those from acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Since the compound is for pharmaceutical use, it is preferable that it be provided in a substantially pure form, for example, with a purity of at least 60%, more preferably at least 75%, and particularly at least 98% (percentages are by weight).

[0145] A "prodrug" is a derivative of a biologically inactive drug that, when administered to the human body, is converted into a biologically active parent drug through some chemical or enzymatic pathway.

[0146] In this specification, the terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” include all solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic agents and absorption retarders, etc. The use of such media and agents with pharmaceutically active substances is well known in the art. Their use in therapeutic compositions is envisioned unless conventional media or agents are incompatible with the active ingredient. Auxiliary active ingredients may also be incorporated into compositions.

[0147] The pharmaceutical compositions of the present invention comprise a compound (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. The compositions include those suitable for oral, rectal, topical, and parenteral administration (including subcutaneous, intramuscular, and intravenous administration), although the most suitable route in any case depends on the specific host and the nature and severity of the condition to which the active ingredient is administered. The pharmaceutical compositions are presented in convenient unit dosage forms and can be prepared by any method well known in the pharmaceutical art.

[0148] In practice, the compounds of the present invention or their prodrugs, metabolites thereof, or pharmaceutically acceptable salts thereof can be formulated as active ingredients by intimate miscion with a pharmaceutical carrier according to conventional pharmaceutical formulation techniques. The carrier may be in various forms depending on the desired form of formulation for administration, such as oral or parenteral (including intravenous administration). Thus, the pharmaceutical compositions of the present invention can be presented as individual units suitable for oral administration, such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the compositions may be presented as powders, granules, solutions, suspensions in aqueous liquids, non-aqueous liquids, oil-in-water emulsions, or water-in-oil liquid emulsions. In addition to the above general dosage forms, the compounds or pharmaceutically acceptable salts thereof can also be administered by controlled release means and / or delivery devices. The compositions can be prepared by any pharmaceutical method. Generally, such methods include the step of associating the active ingredient with a carrier constituting one or more essential components (such as 1, 2, 3, 4, 5, or 6). Generally, the composition is prepared by uniformly and closely mixing the active ingredient with a liquid carrier, a finely divided solid carrier, or both. The product can then be molded into the desired shape.

[0149] Therefore, the pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier and the above-mentioned compound or a pharmaceutically acceptable salt thereof. The compound of the present invention or a pharmaceutically acceptable salt thereof may also be included in the pharmaceutical composition in combination with one or more (e.g., 1, 2, 3, 4, 5, or 6) other therapeutically active compounds.

[0150] Tablets containing the composition of the present invention can be prepared by compression or molding, and may optionally contain one or more (e.g., 1, 2, 3, 4, 5, or 6) auxiliary components or adjuvants. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form such as powder or granules using a suitable machine, and may optionally be mixed with a binder, lubricant, inert diluent, surfactant, or dispersant. Molded tablets can be produced by molding a mixture of powder compounds moistened with an inert liquid diluent using a suitable machine. Each tablet preferably contains about 0.05 mg to about 5 g of the active ingredient, and each cachet or capsule preferably contains about 0.05 mg to about 5 g of the active ingredient. For example, a formulation intended for oral administration to humans may contain about 0.5 mg to about 5 g of the active ingredient and may be compounded with an appropriate and convenient amount of carrier material that can vary from about 0.05% to about 95% of the total composition. Each unit dosage form generally contains approximately 0.01 mg to 2 g of the active ingredient, typically 0.01 mg, 0.02 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

[0151] The pharmaceutical composition of the present invention, suitable for parenteral administration, can be prepared as a solution or suspension of the active compound in water. For example, it may contain a suitable surfactant such as hydroxypropylcellulose. The dispersion can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. Furthermore, preservatives may be included to prevent harmful microbial growth.

[0152] The pharmaceutical compositions of the present invention suitable for injection use include sterile aqueous solutions or dispersions. Furthermore, the compositions may be in the form of sterile powders for the immediate preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and effectively fluid for easy injection. The pharmaceutical compositions must be stable under manufacturing and storage conditions; therefore, preferably, they should be preserved from contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0153] The pharmaceutical compositions of the present invention can be in forms suitable for topical use, such as aerosols, creams, ointments, lotions, and powders. Furthermore, the compositions of the present invention can be in forms suitable for use in transdermal devices. These formulations can be prepared by conventional processing methods using the compounds of the present invention or pharmaceutically acceptable salts thereof. As an example, a cream or ointment can be prepared by mixing a hydrophilic substance and water with about 0.05 wt% to about 10 wt% of the compound to produce a cream or ointment with the desired consistency.

[0154] The pharmaceutical composition of the present invention can be in a form suitable for rectal administration, wherein the carrier is solid. The mixture is preferably in the form of a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppository can be conveniently formed by first mixing the composition with a softened or melted carrier, then cooling and molding it in a mold.

[0155] In addition to the carrier components described above, the pharmaceutical composition may optionally contain one or more (1, 2, 3, 4, 5, or 6, etc.) further carrier components such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, and preservatives (including antioxidants). Furthermore, it may contain other adjuvants to make the formulation isotonic with the blood of the intended recipient. Compositions containing the compound or a pharmaceutically acceptable salt thereof may also be prepared in the form of a powder or liquid concentrate.

[0156] In general, dosages on the order of approximately 0.001 mg / kg to 150 mg / kg of body weight per day are useful for treating the above indications, or dosages on the order of approximately 0.05 mg to 7 g per patient per day are also useful. For example, inflammation, cancer, psoriasis, allergies / asthma, diseases and conditions of the immune system, and diseases and conditions of the central nervous system (CNS) are effectively treated with administration of the compound at a rate of approximately 0.001 mg to 50 mg per kg of body weight per day, or at a rate of approximately 0.05 mg to 3.5 g per patient per day.

[0157] However, it is understood that the specific dosage for a particular patient will vary depending on various factors such as age, weight, general health status, sex, diet, administration time, route of administration, excretion rate, drug combinations, and the severity of the specific disease being treated.

[0158] In some embodiments, disclosed herein are methods for treating cancer, the methods comprising administering a therapeutically effective amount of the compounds of the present invention to a subject in need thereof. The compounds of the present invention can, for example, slow the growth of cancer cell lines or kill cancer cells. Non-limiting examples of cancers that can be treated with the compounds of the present invention include: acute lymphoblastic leukemia; acute myeloid leukemia; adrenocortical carcinoma; AIDS-related cancers; AIDS-related lymphomas; anal cancers; bladder cancers; bone cancers; brain tumors such as cerebellar astrocytoma, cerebral astrocytoma / gliomas, ependymomas, medulloblastomas, supratentorial primordial neuroectoderm tumors, visual tract tumors, and hypothalamic gliomas; breast cancers; central nervous system lymphomas; cerebellar astrocytomas; cervical cancers; colorectal cancers; gallbladder cancers; stomach cancers; head and neck cancers; heart cancers; hepatocellular (liver) cancers; kidney cancers; liver cancers; lung cancers such as non-small cell lung cancer and small cell lung cancer; ovarian cancers; ovarian epithelial cancers; ovarian germ cell tumors; pancreatic cancers; islet cell carcinomas; prostate cancers; rectal cancers; renal cell carcinomas; skin cancers; Merkel cell carcinomas; small intestine cancers; and pharyngeal cancers. [Examples]

[0159] Preparation method The following embodiments are included to provide guidance for carrying out typical embodiments of the subject matter disclosed herein. In light of the present state of the art and the disclosure, those skilled in the art will understand that the following embodiments are intended to be illustrative only and that many changes, modifications, and alterations can be adopted without departing from the scope of the subject matter disclosed herein. The following composite descriptions and specific examples are for illustrative purposes only and should not be construed as limiting the invention in any way.

[0160] Unless otherwise specified, all parts and percentages are by weight, and temperatures are in Celsius.

[0161] The following abbreviations are used in the examples: [Table 2]

[0162] General synthesis scheme 1: [ka]

[0163] As illustrated in General Synthesis Scheme 1, the compound of formula (I-1) can be synthesized by the following steps: (1) In the presence of an alkalizing agent such as K2CO3, a compound such as S1-1 having a -YH group and an L1 group can be reacted with a compound such as S1-2 as a starting material to form a compound such as S2-1; (2) The compound of S2-1 is subjected to a cyclization reaction and aromatization reaction under acidic conditions such as polyphosphate to form the compound of S3-1; (3) Compound S4-1 can be obtained by halogenating the adjacent position of the Y atom of compound S3-1 in the presence of a halogenating reagent. For example, the adjacent position of the Y atom of compound S3-1 can be iodized in the presence of NIS. (4) Compound S5-1 can be obtained by coupling compound S4-1 with reagent S4-2 in the presence of a coupling catalyst, the catalyst preferably includes a Pd-containing catalyst such as Pd(PPh3)2Cl2 or Pd(dppf)Cl2; (5) The L1 group of compound S5-1 can be converted to the target compound of formula (I-1) by one or more reaction steps, for example, by substituting compound S5-1 with -NH2 and R2 becomes -NR 51 R 52 In this case, a compound can be produced that can be converted to the target compound by a reductive amination reaction.

[0164] X-ray single-crystal diffraction analysis All stereoisomers of the present invention can be identified and determined by X-ray single-crystal diffraction analysis.

[0165] Generally, the structure of the single crystal of the compound of the present invention is analyzed using Allex2 (version: 1.5) software, and the diffraction data is preliminaryly analyzed using the ShelXT (version: 2018 / 2) preliminary solution program (using the intrinsic phase method) to determine the space group of the single crystal. Subsequently, the ShelXL (version: 2018 / 3) refinement program is used to perform complete matrix least squares structure refinement based on F2. All atoms except hydrogen atoms are refined anisotropically. Hydrogen atoms are refined by theoretical hydrogenation (riding model).

[0166] Example 1 4-((3-(3-ethyl-7-((1-methylpiperidine-4-yl)amino)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide(1) [ka]

[0167] Step 1. Synthesis of 1-((2-bromophenyl)thio)butan-2-one To a solution of 2-bromobenzenethiol (16.58 g, 0.09 mol) dissolved in 160 ml of ACN, K2CO3 (24.42 g, 0.18 mol) and 1-bromobutan-2-one (14.60 g, 0.10 mol) were added. The mixture was stirred at room temperature for 2 hours, and the solid was removed by filtration. The filtrate was concentrated under vacuum. The residue was eluted with EA / hexane (v / v = 0%-12%) and passed through a silica gel column to obtain 19.89 g of 1-((2-bromophenyl)thio)butan-2-one as a yellow oil. LCMS: m / z = 259 [M+1] + .

[0168] Step 2. Synthesis of 7-bromo-3-ethylbenzo[b]thiophene e A mixture of polyphosphate (10 mL) and 1-((2-bromophenyl)thio)butan-2-one (1.99 g, 7.68 mmol) was slowly heated to 160°C with continued stirring. The reaction mixture was stirred at 160°C for 2 hours. The mixture was then cooled and water (30 mL) was added. The mixture was extracted with EA (90 mL × 3), dried over (Na2SO4), filtered, and concentrated under vacuum. The residue was traced on a silica gel column eluted with EA / hexane (v / v = 0%-5%). As a result, 1.334 g of 7-bromo-3-ethylbenzo[b]thiophene was obtained as a yellow oil.

[0169] Step 3. Synthesis of 7-bromo-3-ethyl-2-iodobenzo[b]thiophene To a solution of 7-bromo-3-ethylbenzo[b]thiophene (1.093 g, 4.53 mmol) in 10 mL of AcOH, NIS (1.307 g, 5.81 mmol) was partially added. The mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding water (20 mL). The resulting solution was extracted with EA (2 x 30 mL). Next, the organic layers were combined, washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was traced on a silica gel column eluted with EA / hexane (v / v = 0%-5%). As a result, 1.186 g of 7-bromo-3-ethyl-2-iodobenzo[b]thiophene was obtained as a yellow oil.

[0170] Step 4.4 - Synthesis of ((3-(7-bromo-3-ethylbenzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide In a 20 mL sealed tube purged and maintained under an inert nitrogen atmosphere, 7-bromo-3-ethyl-2-iodobenzo[b]thiophene (0.504 g, 1.37 mmol), 4-(propa-2-in-1-ylamino)benzenesulfonamide (0.335 g, 1.59 mmol), Pd(PPh3)2Cl2 (0.219 g, 0.31 mmol), CμI (0.093 g, 0.49 mmol), DIEA (0.529 g, 4.09 mmol), and DMSO (5 mL) were added. The reaction mixture was stirred at room temperature for 1 hour. The residue was applied to a silica gel column eluted with EA / hexane (v / v = 0%-35%). As a result, 0.424 g of 4-((3-(7-bromo-3-ethylbenzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide was obtained as a yellow oil. LCMS: m / z = 449 [M+1] + .

[0171] Step 5.4 - Synthesis of ((3-(7-amino-3-ethylbenzo[b]thiophen-2-yl)prop-2-in-1-yl)amino)benzenesulfonamide 4-((3-(7-bromo-3-ethylbenzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide (0.402 g, 0.89 mmol), NaN3 (0.135 g, 2.08 mmol), L-proline (0.038 g, 0.33 mmol), CμI (0.042 g, 0.22 mmol), NaI (0.145 g, 0.97 mmol), Cs2CO3 (0.586 g, 1.80 mmol), and DMSO (5 mL) were added to a 20 mL sealed tube purged under an inert nitrogen atmosphere. The residue was purified by Prep-HPLC CH3CN / H2O (0.2% HCOOH) (v / v = 0%-50%). As a result, 0.048 g of 4-((3-(7-amino-3-ethylbenzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide was obtained as a yellow solid. LCMS: m / z = 389 [M+1] + .

[0172] Step 6.4 Synthesis of ((3-(3-ethyl-7-((1-methylpiperidine-4-yl)amino)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide (1) To a solution of 4-((3-(7-amino-3-ethylbenzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide (0.040 g, 4.53 mmol) in 5 ml of MeOH, 1-methylpiperidine-4-one (0.087 g, 768.8419 μmol) was added. The mixture was stirred at room temperature for 0.5 hours. Then, NaBH3CN (0.087 g, 2.03 mmol) and AcOH (0.002 mL) were added to the system. The reaction mixture was stirred at room temperature for 3 days. The residue was purified by Prep-HPLC CH3CN / H2O (0.05% NH3H2O) (v / v = 0%-50%). As a result, 0.010 g (17%) of 4-((3-ethyl-7-((1-methylpiperidine-4-yl)amino)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide (1) was obtained as a white solid. LCMS: m / z = 483 [M+1] + . 1 H NMR (400 MHz, CD3OD) δ 7.71 - 7.65 (m, 2H), 7.22 - 7.15 (m, 1H), 7.11 - 7.03 (m, 1H), 6.84 - 6.73 (m, 2H), 6.68 - 6.59 (m, 1H), 4.29 - 4.20 (m, 2H), 3.49 - 3.40 (m, 1H), 2.84 - 2.73 (m, 4H), 2.30 (s, 3H), 2.21 - 2.13 (m, 2H), 2.03 - 1.95 (m, 2H), 1.61 - 1.51 (m, 2H), 1.14 (s, 3H).

[0173] Example 2 (Z)-3-fluoro-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (racemic mixture)(2) Reaction scheme: [ka]

[0174] Experiment details: Step 1. 2-Iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine 2-iodo-7-nitro-3-(2,2,2-trifluoroethyl)benzo[b]thiophene (0.674 g, 1.74 mmol), iron (0.605 g, 10.83 mmol), NH4Cl (0.951 g, 17.78 mmol), EtOH (8 mL), and H2O (1.5 mL) were placed in a 20 mL sealed tube. The reaction mixture was extracted with EA (100 mL x 1), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. As a result, 0.621 g (99.87%) of 2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine was obtained as a gray solid. LCMS: m / z = 358 [M+1] +

[0175] Step 2. tert-butyl(Z)-3-fluoro-4-((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (racemic mixture) 2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (0.308 g, 0.86 mmol), tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (0.455 g, 2.09 mmol), and TMSCl (1.156 g, 10.64 mmol) in DMF (5 mL) were degassed, purged with N2, and then BH3.THF (1 M, 9 mL) was added. The mixture was stirred at 0°C for 1 hour under an N2 (g) atmosphere. The reaction mixture was quenched with water (20 mL) at 0°C and extracted with EA (40 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with EA / hexane (v / v=1 / 5) to obtain tert-butyl(Z)-3-fluoro-4-((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (racemic mixture). LCMS: m / z = 559 [M+1] +

[0176] Step 3. tert-butyl(Z)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (racemic mixture) In a 20 mL sealed tube purged and maintained under an inert nitrogen atmosphere, tert-butyl(Z)-3-fluoro-4-((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (racemic) (0.306 g, 0.55 mmol), 2-methoxy-4-(methylsulfonyl)-N-(propa-2-in-1-yl)aniline (0.184 g, 0.77 mmol), Pd(dppf)Cl2 (0.103 g, 0.15 mmol), CμI (0.082 g, 0.43 mmol), DIEA (0.253 g, 1.96 mmol), and DMSO (5 mL) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (20 mL) and extracted with EA (40 mL x 2). The combined organic layers were washed with brine (20 mL), separated, and concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with EA / hexane (v / v=3 / 1) to obtain tert-butyl(Z)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (racemic) (0.338 g, yield 92.09%) as a slightly yellow solid. LCMS: m / z = 670 [M+1] +

[0177] Step 4. (Z)-3-fluoro-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidine-4-amine (racemic mixture) In a 100 mL round-bottom flask, tert-butyl(Z)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (racemic) (0.319 g, 0.48 mmol), DCM (5 mL), and TFA (1 mL) were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH=9 with NaHCO3 (aq.) and extracted with EA (100 mL × 2). The combined organic layers were washed with brine (40 mL), separated, and concentrated under vacuum. As a result, (Z)-3-fluoro-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidine-4-amine (racemic mixture) was obtained as a yellow oil (0.220 g, 81.09%). LCMS: m / z = 570 [M+1] + .

[0178] Step 5. (Z)-3-fluoro-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (racemic mixture) (2) The mixture was stirred at room temperature for 0.5 hours, after which NaBH3CN (0.032 g, 0.75 mmol) and HOAc (0.002 mL) were added. The reaction mixture was stirred at room temperature for 2 days. The residue was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: MeOH; flow rate: 60 mL / min; gradient: 50-80-100% B (2-30-60 min); 244 nm; room temperature: 35.560-37.110 min) to obtain (Z)-3-fluoro-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (racemic mixture) (2) (0.052 g, yield 50.75%) as a white solid. LCMS: m / z = 584 [M+1] + 1 H NMR (400 MHz, MeOD) δ 7.48 (d, J = 8.0 Hz, 1H), 7.36 - 7.25 (m, 2H), 7.19 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 7.2 Hz, 1H), 4.77 (s, 1H), 4.40 (s, 2H), 3.95 (s, 3H), 3.78 - 3.62 (m, 3H), 3.23 - 3.14 (m, 1H), 3.06 (s, 3H), 2.92 (d, J = 11.2 Hz, 1H), 2.39 (d, J = 13.2 Hz, 1H), 2.30 (s, 3H), 2.28 - 2.19 (m, 1H), 1.96 (d, J = 10.8 Hz, 2H).

[0179] Example 3 N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine(3) Reaction scheme: [ka]

[0180] Experiment Details Step 1. Methyl 7-nitrobenzo[b]thiophene-2-carboxylate A mixture of 2-chloro-3-nitrobenzaldehyde (10.029 g, 0.05 mol) and K2CO3 (8.235 g, 0.06 mol) in 100 mL of DMF was mixed with 2-mercaptoacetate methyl (6.193 g, 0.06 mol) at 0°C. The mixture was stirred at room temperature for 8 hours, then added to 500 mL of water. The mixture was filtered, washed with water, and the filter cake was dried in an oven. As a result, 11.91 g of 7-nitrobenzo[b]thiophene-2-carboxylate methyl was obtained as an off-white solid.

[0181] Step 2.7-Nitrobenzo[b]thiophene-2-carboxylic acid To a solution of methyl 7-nitrobenzo[b]thiophene-2-carboxylate (2.44 g, 0.01 mmol) in 20 mL of MeOH at 0°C, NaOH (2 N, 20 mL) was added. The reaction mixture was stirred at room temperature for 8 hours, and the mixture was concentrated under vacuum. The mixture was adjusted to pH 2-3 with HCl (6 N). The mixture was extracted with EA (100 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under vacuum to obtain 2.27 g of 7-nitrobenzo[b]thiophene-2-carboxylic acid as a small yellow solid.

[0182] Step 3.7-Nitrobenzo[b]thiophene 7-nitrobenzo[b]thiophene-2-carboxylic acid (2.105 g, 9.43 mmol), Cμ2O (0.335 g, 1.59 mmol), and DMF (20 mL) were placed in a 40 mL sealed tube. The reaction mixture was stirred at 120°C for 12 hours. When the mixture was added to 100 mL of water, a large precipitate formed. The mixture was filtered, the filter cake was washed with water, and dried in an oven. As a result, 1.765 g of 7-nitrobenzo[b]thiophene was obtained as a gray solid.

[0183] Step 4.7-Nitrobenzo[b]thiophene-3-carboaldehyde 7-nitrobenzo[b]thiophene (0.51 g, 2.85 mmol), dichloro(methoxy)methane (1.65 g, 14.35 mmol), TiCl4 (1.50 g, 7.91 mmol), and CHCl3 (5 mL) were placed in a 20 mL sealed tube. The reaction mixture was stirred at 60°C for 2 hours. The reaction was quenched with water (50 mL), extracted with EA (3 x 100 mL), washed with brine (100 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v = 1 / 3). As a result, 0.268 g of 7-nitrobenzo[b]thiophene-3-carbaldehyde was obtained as a yellow solid.

[0184] Step 5. (7-Nitrobenzo[b]thiophene-3-yl)methanol To a solution of methyl 7-nitrobenzo[b]thiophene-3-carbaldehyde (1.699 g, 8.20 mmol) in 20 mL of MeOH at 0°C, NaBH4 (0.656 g, 17.34 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was quenched with water (50 mL), extracted with EA (3 x 100 mL), washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. As a result, 1.197 g of (7-nitrobenzo[b]thiophene-3-yl)methanol was obtained as a pale yellow solid.

[0185] Step 6.3-(bromomethyl)-7-nitrobenzo[b]thiophene e (7-nitrobenzo[b]thiophen-3-yl)methanol (0.45 g, 2.15 mmol) and 30% HBr / HOAc (5 mL) were placed in a 20 mL sealed tube. The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (50 mL), extracted with EA (3 x 100 mL), washed with brine (100 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v=1 / 6). As a result, 0.446 g of 3-(bromomethyl)-7-nitrobenzo[b]thiophene was obtained as a yellow solid.

[0186] Step 7. 7-Nitro-3-(2,2,2-trifluoroethyl)benzo[b]thiophene e In a 20 mL sealed tube, 3-(bromomethyl)-7-nitrobenzo[b]thiophene (0.32 g, 1.18 mmol), copper (0.221 g, 3.48 mmol), diphenyl-(trifluoromethyl)-sulfonium trifluoromethanesulfonate (0.918 g, 2.27 mmol), and NMP (3 mL) were added. The reaction mixture was stirred at 60°C for 1 hour. The reaction was quenched with water (40 mL), extracted with EA (2 x 100 mL), washed with brine (100 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v = 1 / 5). As a result, 0.295 g of 7-nitro-3-(2,2,2-trifluoroethyl)benzo[b]thiophene was obtained as a yellow solid.

[0187] Step 8. 2-iodo-7-nitro-3-(2,2,2-trifluoroethyl)benzo[b]thiophene e 7-nitro-3-(2,2,2-trifluoroethyl)benzo[b]thiophene (0.293 g, 1.12 mmol), NIS (0.336 g, 1.49 mmol), trifluoromethanesulfonic acid (0.5 mL), and AcOH (4 mL) were placed in a 20 mL sealed tube. The reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with water (30 mL), extracted with EA (2 x 100 mL), washed with brine (80 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v=1 / 8). As a result, 0.389 g of 2-iodo-7-nitro-3-(2,2,2-trifluoroethyl)benzo[b]thiophene was obtained as a yellow solid.

[0188] Step 9. 2-Methoxy-4-(methylsulfonyl)-N-(3-(7-nitro-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)aniline In a 20 mL sealed tube purged and maintained under an inert nitrogen atmosphere, 2-iodo-7-nitro-3-(2,2,2-trifluoroethyl)benzo[b]thiophene (0.380 g, 0.98 mmol), 2-methoxy-4-(methylsulfonyl)-N-(propa-2-in-1-yl)aniline (0.259 g, 1.08 mmol), Pd(dppf)Cl2 (0.080 g, 0.11 mmol), CμI (0.053 g, 0.28 mmol), DIEA (0.413 g, 3.20 mmol), and DMSO (5 mL) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (100 mL), extracted with EA (100 mL x 2), washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by eluting with EA / hexane (v / v=2 / 3) using a silica gel column. As a result, 0.526 g (crude) of 2-methoxy-4-(methylsulfonyl)-N-(3-(7-nitro-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)aniline was obtained as a yellow oil.

[0189] Step 10.2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine In a 20 mL sealed tube, 2-methoxy-4-(methylsulfonyl)-N-(3-(7-nitro-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)aniline (0.518 g, 1.04 mmol), iron (0.391 g, 7.00 mmol), NH4Cl (0.430 g, 8.04 mmol), EtOH (5 mL), and H2O (1 mL) were added. The reaction mixture was extracted with EA (100 mL × 1), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. As a result, 0.282 g (57.92%) of 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine was obtained as a yellow solid.

[0190] Step 11. N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine(3) 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (0.220 g, 0.43 mmol), 1-methylpiperidine-4-amine (0.259 g, 2.29 mmol), and MeOH (4 mL) were placed in a 25 mL round-bottom flask. The mixture was stirred at room temperature for 0.5 hours, then NaBH3CN (0.177 g, 4.12 mmol) and HOAc (0.02 mL) were added, and the mixture was stirred for 48 hours. The mixture was subjected to preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 50-75-100% B (2-30-60 mins); 270 nm; room temperature: 44.886-46.470 mins) to obtain N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine(3) (0.038 g, 15.58% yield) as an off-white solid.

[0191] Example 4 4-((3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide(4) Reaction scheme: [ka]

[0192] Experiment Details Step 1. N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine. 2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (0.108 g, 302.41 μmol) and 1-methylpiperidine-4-one (0.023 g, 203.26 μmol) were placed in a 4 mL bale. The reaction mixture was heated to 130 °C and stirred for 0.5 hours, then cooled to room temperature. Sodium cyanoborohydride (0.113 g, 2.634 mmol), acetic acid (0.01 μmol), and ethanol (1 mL) were added. The reaction mixture was stirred at 50 °C for 1 hour. LC-MS indicated that the reaction was complete, and the reaction mixture was concentrated under vacuum. 18 The solution was purified by column chromatography and eluted with ACN / water (v / v=1 / 3) to obtain N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.068 g, 149.68 μmol, 49.50% yield) as an off-white solid. LCMS: m / z = 455[M+1] + .

[0193] Step 2.4-((3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide(4). N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.067 g, 147.48 μmol), 4-(propa-2-in-1-ylamino)benzenesulfonamide (0.058 g, 275.86 μmol), Pd(PPh3)2Cl2 (0.011 g, 15.58 μmol), CμI (0.007 g, 36.76 μmol), TEA (0.031 g, 306.36 μmol), and DMF (1 mL) were added and stirred overnight at room temperature. LC-MS indicated that the reaction was complete. The reaction was quenched with water (4 mL) and extracted with EA (2 mL x 2). The combined organic layers were successively washed with water (2 mL) and brine (2 mL), separated, and concentrated under vacuum. The residue was purified by prep-HPLC (mobile phase A: water (ammonium hydroxide), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 50-80-100%B (2-30-60 mins); 265 nm; room temperature: 33.245-35.153 mins) to obtain 4-((3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide (4) (0.021 g, 39.13 μmol, yield 26.53%) as an off-white solid. LCMS: m / z = 537[M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J = 8.4 Hz, 2H), 7.26 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H), 6.98 (s, 2H), 6.89 (t, J = 6.1 Hz, 1H), 6.78 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 7.8 Hz, 1H), 5.31 (d, J = 7.9 Hz, 1H), 4.33 (d, J = 6.0 Hz, 2H), 3.84 (q, J = 11.1 Hz, 2H), 2.77 (d, J = 11.0 Hz, 2H), 2.18 (s, 3H), 2.01 (t, J = 11.6 Hz, 2H), 1.88 (d, J = 11.8 Hz, 2H), 1.63 - 1.47 (m, 2H).

[0194] Example 5 4-((3-(7-(((3R,4S)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide (racemic) (5) and 4-((3-(7-(((3R,4R)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide (racemic) (5b) Reaction scheme: [ka]

[0195] Experiment details: Step 1: tert-butyl-3-fluoro-4-((2-(3-((4-sulfamoylphenyl)amino)prop-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate In a 50 mL three-necked flask, tert-butyl 3-fluoro-4-((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (0.688 g, 1.23 mmol), 4-(propa-2-in-1-ylamino)benzenesulfonamide (0.561 g, 1.51 mmol), Pd(PPh3)2Cl2 (0.184 g, 260.65 μmol), CμI (0.081 g, 425.30 μmol), DIEA (0.573 g, 4.43 mmol), and methyl sulfoxide (7 mL) were added. The reaction was stirred under a nitrogen atmosphere at room temperature for 3 hours. The reaction was quenched with water (20 mL). The resulting solution was extracted with EA (3 × 50 mL), washed with brine (50 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v = 3 / 2). As a result, 0.642 g (1.00 mmol, 81.32% yield) of tert-butyl3-fluoro-4-((2-(3-((4-sulfamoylphenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate was obtained as a yellow solid. LCMS: m / z = 641 [M+1] + .

[0196] Step 2: 4-((3-(7-((3-fluoropiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide In a 20 mL sealed tube, tert-butyl 3-fluoro-4-((2-(3-((4-sulfamoylphenyl)amino)prop-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (0.622 g, 970.79 mmol), HCl (g) in EA (2 mL, 4 N), and EA (2 mL) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum, and water (2 mL) was added to the reaction mixture. NaOH (aq, 3 N) was added until the pH was 7, and the mixture was extracted with EA (3 x 50 mL), washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. As a result, 0.530 g (980.40 μmol, 100.00% yield) of 4-((3-(7-((3-fluoropiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide was obtained as a brown solid. LCMS: m / z = 274 [M+1] + The reaction mixture was purified using a C18 column eluted with ACN / H2O (v / v = 1 / 1). As a result, 3.012 g of ethyl N-(3-bromo-5-nitro-4-(1H-pyrrole-1-yl)phenyl)-1-methylpiperidine-4-amine was obtained as a yellow solid (74% yield). LCMS: m / z = 541 [M+1] + .

[0197] Step 3 4-((3-(7-(((3R,4S)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide (racemate) (5) and 4-((3-(7-(((3R,4R)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide (racemate) (5b) In a 25 mL round-bottom flask, 4-((3-(7-((3-fluoropiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide (0.317 g, 586.38 μmol), triformol (0.043 g, 1.43 mmol), acetic acid (0.5 mL), and methyl alcohol (5 mL) were added. The reaction mixture was stirred at room temperature for 1 hour, then NaBH3CN (0.231 g, 5.38 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (20 mL). The resulting solution was extracted with EA (3 x 50 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC (mobile phase A: water (0.1% ammonium hydroxide), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 35-65-75% B (2-30-60 min); 264 nm; room temperature: 30.01-31.74) to obtain the target product. As a result, 0.055 g (99.16 μmol, yield 16.91%) of 4-((3-(7-(((3R,4S)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide (racemic mixture) (5) was obtained as a white solid. LCMS: m / z = 555 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J = 8.4 Hz, 2H), 7.31 - 7.20 (m, 2H), 6.97 (s, 2H), 6.98 - 6.92 (m, 1H), 6.78 (d, J = 8.2 Hz, 3H), 5.17 (d, J = 8.5 Hz, 1H), 4.79 (d, J = 49.5 Hz, 1H), 4.33 (d, J = 6.0 Hz, 2H), 3.88 - 3.72 (m, 2H), 3.82 - 3.61 (m, 1H)3.03 (t, J = 11.1 Hz, 1H), 2.79 (d, J = 11.1 Hz, 1H), 2.27 (d, J = 13.0 Hz, 1H), 2.18 (s, 3H), 2.08 (t, J = 11.4 Hz, 1H), 2.01 - 1.89 (m, 1H), 1.71 (d, J = 11.9 Hz, 1H).

[0198] Then, 4-((3-(7-(((3R,4R)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide (racemic mixture) (5b) was obtained as a white solid in 0.027 g (48.68 μmol, yield 8.30%). LCMS: m / z = 555 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J = 8.4 Hz, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 6.98 (s, 2H), 6.90 (t, J = 6.1 Hz, 1H), 6.77 - 6.68 (m, 3H), 5.57 (d, J = 8.5 Hz, 1H), 4.71 - 4.52 (m, 1H), 4.33 (d, J = 6.0 Hz, 2H), 3.85 - 3.79 (m, 2H), 3.59 (d, J = 4.2 Hz, 1H), 3.10 - 3.01 (m, 1H), 2.69 (d, J = 11.5 Hz, 1H), 2.23 (s, 3H), 2.04 - 3.01 (m, 1H), 1.99 - 1.88 (m, 1H), 1.59 - 1.47 (m, 1H).

[0199] Example 6 1-((Z)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-yl)-3-methoxypropan-2-ol (racemic mixture)(6) Reaction scheme: [ka]

[0200] Experiment details: Step 1.1-((Z)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-yl)-3-methoxypropan-2-ol (racemic mixture)(6). In a 4 mL vial, (Z)-3-fluoro-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidine-4-amine (racemic) (0.036 g, 63.20 μmol), 2-(methoxymethyl)oxirane (0.044 g, 499.41 μmol), and ethanol (1 mL) were added. The reaction mixture was concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: MeOH; flow rate: 70 mL / min; gradient: 50-80-100% B (2-30-60 min); 269 nm; room temperature: 33.838-34.618) to obtain the target product. As a result, 0.029 g (69.77% yield) of 1-((Z)-3-fluoro-4-((2-(3-(2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-yl)-3-methoxypropan-2-ol (racemic mixture) (6) was obtained as an off-white solid. LCMS: m / z = 659 [M+1] + . 1 H NMR (400 MHz, MeOD) δ 7.49 (d, J = 8.3 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.19 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 4.40 (s, 2H), 3.95 (s, 3H), 3.90 (s, 1H), 3.79 - 3.61 (m, 3H), 3.45 - 3.33 (m, 5H), 3.30 - 3.29 (m, 2H), 3.06 (s, 3H), 2.99 (s, 1H), 2.57 - 2.44 (m, 2H), 2.44 - 2.28 (m, 2H), 2.03 - 1.85 (m, 2H).

[0201] Example 7 N-(2-(3-((5-fluoro-2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine(7) Reaction scheme: [ka]

[0202] Experiment details: Step 1. 1,2-Difluoro-4-methoxy-5-nitrobenzene 4,5-difluoro-2-nitrophenol (4.76 g, 27.19 mmol), K2CO3 (11.33 g, 81.98 mmol), iodomethane (3 mL), and DMF (30 mL) were placed in a 100 mL flask. The reaction was stirred at 20°C for 1 hour. The reaction was quenched with water (50 mL) and extracted with EA (3 x 50 mL). The organic layers were combined and concentrated under vacuum. The residue was purified by silica gel column elution with EA / Hex (v / v = 2 / 8). As a result, 5.30 g of 1,2-difluoro-4-methoxy-5-nitrobenzene (99% yield) was obtained as a white solid. LCMS: m / z = 190 [M+1] + .

[0203] Step 2.1-Fluoro-4-methoxy-2-(methylsulfonyl)-5-nitrobenzene. In a 100 mL flask, methyl 1,2-difluoro-4-methoxy-5-nitrobenzene (2.99 g, 15.84 mmol), sodium methanesulfinate (1.90 g, 18.62 mmol), and DMA (10 mL) were added. The reaction was stirred at 85°C for 16 hours. The reaction was quenched with water (50 mL). Subsequently, a large amount of solid precipitated. The mixture was filtered, and the filter cake was recovered. This filter cake was dried at 60°C for 16 hours to obtain 3.00 g of 1-fluoro-4-methoxy-2-(methylsulfonyl)-5-nitrobenzene as a white solid (yield 76%). LCMS: m / z = 250 [M+1] +.

[0204] Step 3.5-Fluoro-2-methoxy-4-(methylsulfonyl)aniline. In a 100 mL round-bottom flask, 1-fluoro-4-methoxy-2-(methylsulfonyl)-5-nitrobenzene (4.62 g, 18.54 mmol), Pd / C (3.47 g, 32.61 mmol), and MeOH (50 mL) were added. H2 was charged into the flask. The reaction mixture was stirred at 20°C for 16 hours. The mixture was filtered, and the filtrate was collected. The filtrate was concentrated under vacuum. The residue was purified by silica gel column elution with EA / hexane (v / v = 2 / 8). As a result, 2.27 g of 5-fluoro-2-methoxy-4-(methylsulfonyl)aniline was obtained as a yellow solid (55% yield). LCMS: m / z = 220[M+1] + .

[0205] Step 4.5-Fluoro-2-methoxy-4-(methylsulfonyl)-N-(propa-2-in-1-yl)aniline. A 50 mL round-bottom flask was filled with 5-fluoro-2-methoxy-4-(methylsulfonyl)aniline (0.91 g, 4.13 mmol), 3-bromopropa-1-in (0.62 g, 5.24 mmol), K2CO3 (1.86 g, 13.42 mmol), NaI (0.10 g, 0.67 mmol), and DMF (20 mL). The reaction mixture was eluted with ACN / H2O (v / v = 1 / 1). 18 The solution was purified by column chromatography. As a result, 318 mg of 5-fluoro-2-methoxy-4-(methylsulfonyl)-N-(propa-2-in-1-yl)aniline was obtained as a pale yellow solid (29% yield). LC-MS: m / z = 258 [M+1] + .

[0206] Step 5. N-(2-(3-((5-fluoro-2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine(7). N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.066 g, 145.28 μmol), 5-fluoro-2-methoxy-4-(methylsulfonyl)-N-(propa-2-in-1-yl)aniline (0.063 g, 244.87 μmol), CμI (0.043 g, 225.78 μmol), Pd(PPh3)2Cl2 (0.051 g, 56.26 μmol), DIEA (0.041 g, 317.23 μmol), and methyl sulfoxide (2 mL) were added to a 50 mL round-bottom flask. The mixture was stirred at 25°C for 4 hours. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: ACN; flow rate: 40 mL / min; gradient: 40-80-100% B (2-30-60 min); 220 nm; room temperature: 23.767-27.715 min). As a result, 22 mg (25% yield) of N-(2-(3-((5-fluoro-2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (7) was obtained as a white solid. LCMS: m / z = 584 [M+1] + . 1H NMR (400 MHz, DMSO) δ 7.26 (t, J = 7.9 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 6.4 Hz, 1H), 6.88 (t, J = 5.7 Hz, 1H), 6.77 (d, J = 12.6 Hz, 1H), 6.67 (d, J = 7.8 Hz, 1H), 5.33 (d, J = 7.9 Hz, 1H), 4.39 (d, J = 6.2 Hz, 2H), 3.34 (s, 5H), 3.18 (s, 3H), 2.76 (d, J = 11.2 Hz, 2H), 2.17 (s, 3H), 2.00 (t, J = 10.9 Hz, 2H), 1.89 (d, J = 14.3 Hz, 2H), 1.63 - 1.46 (m, 2H), 1.23 (s, 1H).

[0207] Example 8 3-Methoxy-N-methyl-4-((3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzamide(8) Reaction scheme: [ka]

[0208] Experiment Details Step 1. 4-Amino-3-methoxy-N-methylbenzamide 4-amino-3-methoxybenzoic acid (10.01 g, 59.88 mmol), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (68.52 g, 180.2070 mmol), N,N-diisopropylethylamine (20.96 g, 162.18 mmol), methylamine hydrochloride (24.87 g, 368.35 mmol), and N,N-dimethylformamide (500 mL) were added to a 1 L flask. The reaction mixture was stirred at room temperature for 24 hours, and the reaction was quenched by adding water (10 mL). Next, saturated sodium hydroxide aqueous solution was added to the mixture until the pH was 10-11. The resulting solution was extracted with EA (2 x 200 mL). The organic layers were combined, washed with brine (200 mL), dried on anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted with EA / heptane (v / v = 9 / 1) and then filtered through a silica gel column. As a result, 8.53 g (79.05% yield) of 4-amino-3-methoxy-N-methylbenzamide was obtained as a yellow oil. LCMS: m / z = 181 [M+1] + .

[0209] Step 2.3-Methoxy-N-methyl-4-(propa-2-in-1-ylamino)benzamide 4-amino-3-methoxy-N-methylbenzamide (5.003 g, 27.76 mmol), potassium carbonate (11.775 g, 85.20 mmol), sodium iodide (4.402 g, 29.37 mmol), and N,N-dimethylformamide (200 mL) were placed in a 500 mL flask and kept under an inert nitrogen atmosphere. The reaction mixture was stirred at 85°C for 7 hours. The residue was applied to a silica gel column eluted with EA / heptane (v / v = 3 / 1). The reaction was quenched by adding water (200 mL). The resulting solution was extracted with EA (2 x 200 mL). The organic layers were combined, washed with brine (200 mL), dried on anhydrous Na2SO4, and concentrated under vacuum. The residue was applied to a silica gel column eluted with EA / heptane (v / v = 2 / 5). As a result, 2.686 g of 3-methoxy-N-methyl-4-(propa-2-in-1-ylamino)benzamide (yield 44.33%) was obtained as a yellow solid. LCMS: m / z = 219 [M+1] + .

[0210] Step 3.3-Methoxy-N-methyl-4-((3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzamide(8) In a 500 mL flask purged and maintained under an inert nitrogen atmosphere, 3-methoxy-N-methyl-4-(propa-2-in-1-ylamino)benzamide (0.029 g, 132.87 μmol), N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.054 g, 118.87 μmol), bis(triphenylphosphine)palladium(II) chloride (0.014 g, 19.83 μmol), cuprous iodide (0.008 g, 42.01 μmol), triethylamine (0.022 g, 217.41 μmol), and methyl sulfoxide (2 mL) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding water (2 mL) and extracted with EA (2 x 4 mL). The organic layers were combined, washed with brine (5 mL), and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: MeOH; flow rate: 40 mL / min; gradient: 45-75-100% B (2-30-60 min); 270 nm; room temperature: 33.580-36.570 min). This yielded 0.010 g (yield 7.42%) of 3-methoxy-N-methyl-4-((3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzamide (8) as a white solid. LCMS: m / z = 545 [M+1] + . 1H NMR (400 MHz, DMSO) δ 8.10 (s, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.35 (s, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H), 6.01 (s, 1H), 5.29 (d, J = 7.9 Hz, 1H), 4.33 (d, J = 6.6 Hz, 2H), 3.84 (s, 3H), 3.81 - 3.74 (m, 2H), 2.75 (d, J = 4.4 Hz, 4H), 2.16 (s, 3H), 1.98 (t, J = 11.3 Hz, 2H), 1.87 (d, J = 12.1 Hz, 2H), 1.53 (d, J = 11.9 Hz, 3H), 1.23 (s, 1H).

[0211] Example 9 Dimethyl(4-((3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)phenyl)phosphine oxide(9) Reaction scheme: [ka]

[0212] Experiment Details Step 1. Dimethyl(4-((3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)phenyl)phosphine oxide(9). In a 4 mL flask purged under a nitrogen atmosphere, N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.049 g, 107.86 μmol), dimethyl(4-(propa-2-in-1-ylamino)phenyl)phosphine oxide (0.068 g, 328.17 μmol), Pd(PPh3)2Cl2 (0.009 g, 12.75 μmol), CμI (0.004 g, 21.00 μmol), TEA (0.015 g, 148.24 μmol), and DMF (0.5 mL) were added and the mixture was stirred at room temperature for 1 hour. LC-MS indicated that the reaction was complete. The reaction was quenched with water (4 mL) and extracted with EA (2 mL x 2). The combined organic layers were sequentially washed with water (2 mL) and brine (2 mL), separated, and concentrated under vacuum. The residue was purified by prep-HPLC (mobile phase A: water (trifluoroacetic acid), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 25-45-45%B (2-30-60 min); 262 nm; room temperature: 27.501-29.585 min) to obtain dimethyl(4-((3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)phenyl)phosphine oxide (9) (0.010 g, 18.74 μmol, 17.38% yield) as an off-white solid. LCMS: m / z = 534[M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 7.53 - 7.46 (m, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.14 (d, J = 7.9 Hz, 1H), 6.83 - 6.78 (m, 2H), 6.72 - 6.64 (m, 2H), 5.31 (d, J = 7.9 Hz, 1H), 4.31 (d, J = 6.1 Hz, 2H), 3.80 (q, J = 10.8 Hz, 2H), 2.81 - 2.73 (m, 2H), 2.17 (s, 3H), 2.04 - 1.95 (m, 2H), 1.91 - 1.85 (m, 2H), 1.55 (d, J = 13.1 Hz, 8H).

[0213] Example 10 (4-((3-(7-(((Z)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-(fluoromethoxy)phenyl)dimethylphosphine oxide (racemic mixture) (10) Reaction scheme: [ka]

[0214] Experiment details: Step 1. 4-Bromo-2-(fluoromethoxy)-1-nitrobenzene 5-bromo-2-nitrophenol (1.16 g, 5.32 mmol), fluoroiodomethane (1.43 g, 8.94 mmol), DBM (2.28 g, 14.97 mmol), and ACN (10 mL) were placed in a 50 mL three-necked flask. The reaction mixture was stirred at 80°C for 1 hour, then quenched with water (10 mL). The resulting solution was extracted with EA (3 x 30 mL), washed with brine (30 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. As a result, 1.276 g (5.10 mmol, 95.91% yield) of 4-bromo-2-(fluoromethoxy)-1-nitrobenzene was obtained as a yellow solid. LCMS: m / z = 250 [M+1] + .

[0215] Step 2.4-Bromo-2-(fluoromethoxy)aniline 4-bromo-2-(fluoromethoxy)-1-nitrobenzene (1.332 g, 5.32 mmol), iron (2.678 g, 47.95 mmol), NH4Cl (2.610 g, 48.79 mmol), EtOH (15 mL), and water (3 mL) were placed in a 100 mL three-necked flask. The reaction mixture was filtered, and the filter cake was washed with methanol (2 x 30 mL). The filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column elution with EA / hexane (v / v = 1 / 3). As a result, 1.01 g (4.59 mmol, yield 86.15%) of 4-bromo-2-(fluoromethoxy)aniline was obtained as a yellow oil. LCMS: m / z = 220 [M+1] + .

[0216] Step 3. (4-amino-3-(fluoromethoxy)phenyl)dimethylphosphine oxide. In a 25 mL three-necked flask purged and maintained under an inert nitrogen atmosphere, 4-bromo-2-(fluoromethoxy)aniline (0.551 g, 2.50 mmol), palladium(II) acetate (0.132 g, 587.95 μmol), DIEA (0.865 g, 6.69 mmol), and DMF (5 mL) were added. Next, dimethylphosphine oxide (0.603 g, 7.72 mmol) was added at 130°C. The reaction mixture was stirred under a nitrogen atmosphere at 130°C for 1 hour. The reaction mixture was eluted with ACN / H2O (v / v = 1 / 9). 18 The solution was purified by column chromatography. As a result, 0.400 g (1.84 mmol, 73.55% yield) of (4-amino-3-(fluoromethoxy)phenyl)dimethylphosphine oxide was obtained as a brown oil. LC-MS: m / z = 218 [M+1] + .

[0217] Step 4. (3-(fluoromethoxy)-4-(propa-2-in-1-ylamino)phenyl)dimethylphosphine oxide A 25 mL three-necked flask was filled with (4-amino-3-(fluoromethoxy)phenyl)dimethylphosphine oxide (0.366 g, 1.68 mmol), 3-bromopropa-1-yne (0.295 g, 2.47 mmol), K2CO3 (0.695 g, 5.02 mmol), KI (0.384 g, 2.31 mmol), and NMP (5 mL). The reaction mixture was stirred under a nitrogen atmosphere at 80°C for 4 hours. The reaction mixture was eluted with ACN / H2O (v / v = 2 / 8). 18 The solution was purified by column chromatography. As a result, 0.066 g (258.59 μmol, 15.34% yield) of (3-(fluoromethoxy)-4-(propa-2-in-1-ylamino)phenyl)dimethylphosphine oxide was obtained as a brown oil. LC-MS: m / z = 256 [M+1] + .

[0218] Step 5. (4-((3-(7-(((Z)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-(fluoromethoxy)phenyl)dimethylphosphine oxide (racemic mixture) (10) (3-(fluoromethoxy)-4-(propa-2-in-1-ylamino)phenyl)dimethylphosphine oxide (0.071 g, 278.15 μmol), (Z)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (racemic mixture) (0.051 g, 107.98 μmol), Pd(PPh3)2Cl2 (0.030 g, 42.49 μmol), CμI (0.018 g, 94.51 μmol), DIEA (0.063 g, 487.45 μmol), and methyl sulfoxide (1 mL) were added to a 10 mL round-bottom flask maintained under a nitrogen inert atmosphere. The crude product was purified by preparative HPLC (mobile phase A: water (0.1% ammonium hydroxide), mobile phase B: MeOH; flow rate: 70 mL / min; gradient: 30-30-60-80%B (0-2-30-60 min); 262 nm; room temperature: 33.31-35.22) to obtain the target product. As a result, 1.05 mg (1.75 μmol, yield 0.62%) of (4-((3-(7-(((-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-(fluoromethoxy)phenyl)dimethylphosphine oxide (racemic mixture) (10) was obtained as a white solid. LCMS: m / z = 600 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ7.53 - 7.33 (m, 2H), 7.31 - 7.11 (m, 2H), 6.96 (s, 1H), 6.79 (s, 1H), 6.33 (s, 1H), 5.92 (s, 1H), 5.78 (s, 1H), 5.16 (s, 1H), 4.80 (d, J = 49.3 Hz, 1H), 4.37 (s, 2H), 3.81 (d, J = 11.4 Hz, 2H), 3.70 - 3.65 (m, 1H), 3.10 - 2.98 (m, 1H), 2.87 - 2.76 (m, 1H), 2.19 (s, 3H), 2.02 - 1.93 (m, 2H), 1.76 - 1.69 (m, 1H), 1.58 (d, J = 13.2 Hz, 6H), 1.50 - 1.41 (m, 1H).

[0219] Example 11 N-(2-(3-((2-(fluoromethoxy)-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine(11) Reaction scheme: [ka]

[0220] Experiment Details Step 1. 2-(fluoromethoxy)-4-(methylsulfonyl)-N-(propa-2-in-1-yl)aniline 5-(methylsulfonyl)-2-(propa-2-in-1-ylamino)phenol (0.101 g, 448.36 μmol), bromofluoromethane (0.053 g, 469.32 μmol), potassium carbonate (0.126 g, 911.69 μmol), and N,N-dimethylformamide (2 mL) were placed in an 8 mL flask. The reaction mixture was stirred at 45°C for 3 hours, and the reaction was quenched with water (2 mL) and extracted with EA (2 x 5 mL). The organic layers were combined, washed with brine (10 mL), dried on anhydrous Na2SO4, and concentrated under vacuum. The residue was traced on a silica gel column eluted with EA / heptane (v / v = 1 / 1). As a result, 0.096 g of 2-(fluoromethoxy)-4-(methylsulfonyl)-N-(propa-2-in-1-yl)aniline (yield 83.22%) was obtained as a yellow oil. LCMS: m / z = 258 [M+1] + .

[0221] Step 2. N-(2-(3-((2-(fluoromethoxy)-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine(11) In an 8 mL flask purged and maintained under an inert nitrogen atmosphere, N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.051 g, 112.26 μmol), cuprous iodide (0.007 g, 36.76 μmol), 2-(fluoromethoxy)-4-(methylsulfonyl)-N-(propa-2-in-1-yl)aniline (0.028 g, 108.83 μmol), bis(triphenylphosphine)palladium(II) chloride (0.023 g, 32.58 μmol), triethylamine (0.024 g, 237.18 μmol), and methyl sulfoxide (2 mL) were added. The reaction mixture was stirred at room temperature for 2 hours, the reaction was quenched with water (2 mL), and the mixture was extracted with EA (2 x 4 mL). The organic layers were combined, washed with brine (5 mL), dried on anhydrous Na2SO4, and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: MeOH; flow rate: 40 mL / min; gradient: 50-75-100% B (2-30-60 min); 270 nm; room temperature: 32.200-34.270 min). As a result, 0.023 g of N-(2-(3-((2-(fluoromethoxy)-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (11) was obtained as yellow oil (yield 35.10%). LCMS: m / z = 584 [M+1] + . 1H NMR (400 MHz, DMSO) δ 7.54 (d, J = 8.6 Hz, 1H), 7.49 (s, 1H), 7.25 (t, J = 7.7 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 6.4 Hz, 1H), 6.66 (d, J = 7.7 Hz, 1H), 5.97 (s, 1H), 5.84 (s, 1H), 5.30 (d, J = 7.9 Hz, 1H), 4.40 (d, J = 6.1 Hz, 2H), 3.86 - 3.76 (m, 2H), 3.11 (s, 3H), 2.75 (d, J = 11.1 Hz, 2H), 2.16 (s, 3H), 1.98 (t, J = 11.7 Hz, 2H), 1.87 (d, J = 10.5 Hz, 2H), 1.53 (d, J = 12.6 Hz, 2H), 1.23 (s, 1H).

[0222] Example 12 N-(2-(3-((2-(2,2-difluoroethoxy)-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine(12) Reaction scheme [ka]

[0223] Experiment Details Step 1. 2-(2,2-difluoroethoxy)-4-(methylsulfonyl)-N-(propa-2-in-1-yl)aniline. In a 4 mL flask purged under a nitrogen atmosphere, 5-(methylsulfonyl)-2-(propa-2-in-1-ylamino)phenol (0.101 g, 448.36 μmol), 2-bromo-1,1-difluoroethane (0.094 g, 648.52 μmol), K2CO3 (0.069 g, 499.26 μmol), and DMF (1 mL) were added. The reaction mixture was heated to 50°C and stirred for 2.5 hours. LC-MS results indicated that the reaction was complete. The reaction products were converted to C 18 The solution was purified by column chromatography and eluted with ACN / water (v / v = 1 / 3) to obtain 2-(2,2-difluoroethoxy)-4-(methylsulfonyl)-N-(propa-2-in-1-yl)aniline (0.072 g, 248.88 μmol, 55.51% yield) as a pale yellow oil. LCMS: m / z = 290[M+1] + .

[0224] Step 2. N-(2-(3-((2-(2,2-difluoroethoxy)-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine(12). In a 4 mL flask maintained under a nitrogen atmosphere, N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.048 g, 105.66 μmol), 2-(2,2-difluoroethoxy)-4-(methylsulfonyl)-N-(propa-2-in-1-yl)aniline (0.054 g, 186.66 μmol), Pd(PPh3)2Cl2 (0.013 g, 18.42 μmol), CuI (0.003 g, 15.75 μmol), TEA (0.025 g, 247.06 μmol), and DMF (0.5 mL) were added and the mixture was stirred at room temperature for 1 hour. LC-MS indicated that the reaction was complete. The reaction was quenched with water (4 mL) and extracted with EA (2 mL x 2). The combined organic layers were successively washed with water (2 mL) and brine (2 mL), separated, and concentrated under vacuum. The residue was purified by prep-HPLC (mobile phase A: water (ammonium hydroxide), mobile phase B: ACN; flow rate: 40 mL / min; gradient: 44-80-100%B (2-22-40 min); 220 nm; room temperature: 20.738-23.498 min) to obtain N-(2-(3-((2,2-difluoroethoxy)-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine(12) (0.021 g, 34.11 μmol, 18.27% yield) as an off-white solid. LCMS: m / z = 616[M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 7.44 (d, J = 8.4 Hz, 1H), 7.37 (s, 1H), 7.25 (t, J = 7.9 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 7.8 Hz, 1H), 6.58 - 6.27 (m, 2H), 5.32 (d, J = 7.9 Hz, 1H), 4.49 - 4.39 (m, 4H), 3.81 (q, J = 11.1 Hz, 2H), 3.10 (s, 3H), 2.78 (d, J = 11.2 Hz, 2H), 2.18 (s, 3H), 2.02 (t, J = 11.5 Hz, 2H), 1.93 - 1.84 (m, 2H), 1.60 - 1.48 (m, 2H).

[0225] Example 13 1-Methyl-N-(2-(3-((4-(methylsulfonyl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidine-4-amine(13) Reaction scheme: [ka]

[0226] Experiment Details Step 1. 2-Methoxy-4-(methylsulfonyl)-1-nitrobenzene In a 500 mL flask purged and maintained under an inert nitrogen atmosphere, 20.27 g, 118.45 mmol of 4-fluoro-2-methoxy-1-nitrobenzene, 12.62 g, 123.62 mmol of sodium methanesulfinate, and 200 mL of DMA were added. The reaction mixture was quenched with 400 mL of H2O, extracted with EA (1000 mL x 2), washed with NaCl (aq. 500 mL x 3), and concentrated under vacuum. Next, 200 mL of MTBE was added, the mixture was stirred at room temperature for 1 hour, and filtered. As a result, 24.96 g of 2-methoxy-4-(methylsulfonyl)-1-nitrobenzene (yield 91.13%) was obtained as a yellow solid. LCMS: m / z = 232 [M+1] + .

[0227] Step 2. 2-Methoxy-4-(methylsulfonyl)aniline In a 2 L flask purged and maintained under an inert hydrogen atmosphere, 2-(methylsulfonyl)-5-nitropyridine (24.24 g, 104.83 mmol), Pd / C (22.32 g, 209.74 mmol), and methanol (1 L) were added. The reaction mixture was stirred at room temperature for 19 hours. The catalyst was removed by filtration, and the filtrate was concentrated under vacuum. As a result, 15.79 g of 2-methoxy-4-(methylsulfonyl)aniline (74.85% yield) was obtained as a yellow solid. LCMS: m / z = 173 [M+1] + .

[0228] Step 3. 2-Methoxy-4-(methylsulfonyl)-N-(propa-2-in-1-yl)aniline In a 500 mL flask purged and maintained under an inert nitrogen atmosphere, 3-bromopropylene (6.57 g, 55.23 mmol), 2-methoxy-4-(methylsulfonyl)aniline (10.02 g, 49.79 mmol), sodium iodide (15.58 g, 103.94 mmol), potassium carbonate (21.39 g, 154.7695 mmol), and N,N-dimethylformamide (200 mL) were added, and the reaction mixture was stirred at 85°C for 3 hours. The resulting solution was extracted with EA (2 x 500 mL). The organic layers were combined, washed with brine (500 mL), dried on anhydrous Na2SO4, and concentrated under vacuum. As a result, 7.56 g of 2-methoxy-4-(methylsulfonyl)-N-(propa-2-in-1-yl)aniline (yield 63.45%) was obtained as a yellow oil. LCMS: m / z = 211 [M+1]+.

[0229] Step 4.5-(methylsulfonyl)-2-(propa-2-in-1-ylamino)phenol In a 100 mL flask purged with nitrogen to maintain an inert atmosphere, 2-methoxy-4-(methylsulfonyl)-N-(propa-2-in-1-yl)aniline (2.35 g, 9.82 mmol) and dichloromethane (20 mL) were added, and tribromoboron (20 mL) was added at -10°C. The reaction mixture was stirred at 0°C for 1 hour, and then 1 M sodium hydroxide aqueous solution was added to bring the pH to 11-12. The aqueous layer was collected, 2 M hydrochloric acid aqueous solution was added to bring the pH to 7-8, and extracted with EA (2 x 100 mL). The organic layers were combined, washed with brine (100 mL), dried on anhydrous Na2SO4, and concentrated under vacuum. The residue was traced on a silica gel column eluted with EA / hexane (v / v = 3 / 5).

[0230] As a result, 1.275 g of 5-(methylsulfonyl)-2-(propa-2-in-1-ylamino)phenol (yield 57.63%) was obtained as a yellow solid. LCMS: m / z = 226 [M+1]+.

[0231] Step 5.4-(methylsulfonyl)-N-(propa-2-in-1-yl)-2-(2,2,2-trifluoroethoxy)aniline 5-(methylsulfonyl)-2-(propa-2-in-1-ylamino)phenol (0.102 g, 452.80 μmol), 1,1,1-trifluoro-2-bromoethane (0.084 g, 515.54 μmol), potassium carbonate (0.126 g, 911.69 μmol), and N,N-dimethylformamide (2 mL) were placed in an 8 mL flask. The reaction mixture was stirred at 45°C for 3 hours, and the reaction was quenched with water (2 mL) and extracted with EA (2 x 5 mL). The organic layers were combined, washed with brine (10 mL), dried on anhydrous Na2SO4, and concentrated under vacuum. The residue was traced on a silica gel column eluted with EA / heptane (v / v = 1 / 1). As a result, 0.098 g of 4-(methylsulfonyl)-N-(propa-2-in-1-yl)-2-(2,2,2-trifluoroethoxy)aniline was obtained as a yellow oil (yield 70.43%). LCMS: m / z = 308 [M+1] + .

[0232] Step 6. 1-Methyl-N-(2-(3-((4-(methylsulfonyl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidine-4-amine(13) In an 8 mL flask maintained under a nitrogen inert atmosphere, N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.045 g, 99.06 μmol), cuprous iodide (0.009 g, 47.26 μmol), 4-(methylsulfonyl)-N-(propa-2-in-1-yl)-2-(2,2,2-trifluoroethoxy)aniline (0.036 g, 117.15 μmol), bis(triphenylphosphine)palladium(II) chloride (0.026 g, 36.83 μmol), triethylamine (0.022 g, 217.41 μmol), and methyl sulfoxide (2 mL) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding water (2 mL) and extracted with EA (2 x 4 mL). The organic layers were combined, washed with brine (5 mL), dried on anhydrous Na2SO4, and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: MeOH; flow rate: 40 mL / min; gradient: 45-80-100%B (2-30-60 min); 270 nm; room temperature: 33.274-34.355 min). As a result, 0.023 g (yield 35.10%) of 1-methyl-N-(2-(3-((4-(methylsulfonyl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidine-4-amine (13) was obtained as a yellow oil. LCMS: m / z = 634 [M+1] + . 1H NMR (400 MHz, DMSO) δ 7.69 (d, J = 13.5 Hz, 1H), 7.50 - 7.42 (m, 2H), 7.25 (t, J = 7.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.44 (t, J = 6.1 Hz, 1H), 5.31 (d, J = 7.8 Hz, 1H), 4.89 (q, J = 8.8 Hz, 2H), 4.42 (d, J = 6.0 Hz, 2H), 4.22 (t, J = 6.5 Hz, 1H), 3.81 (q, J = 11.3 Hz, 2H), 3.10 (s, 3H), 2.76 (d, J = 11.2 Hz, 2H), 2.17 (s, 3H), 1.88 (d, J = 11.9 Hz, 2H), 1.54 (d, J = 11.4 Hz, 2H), 1.37 (dd, J = 14.9, 7.5 Hz, 1H).

[0233] Example 14 N-[2-[3-[2-(2-methoxyethoxy)-4-methylsulfonylanilino]prop-1-inyl]-3-(2,2,2-trifluoroethyl)benzothiophen-7-yl]-1-methylpiperidine-4-amine(14) Reaction scheme: [ka]

[0234] Experiment details: Step 1.2-(2-methoxyethoxy)-4-methylsulfonyl-N-propa-2-inyl-l-aniline. 5-(methylsulfonyl)-2-(propa-2-in-1-ylamino)phenol (0.100 g, 443.92 μmol), 1-bromo-2-methoxyethane (0.074 g, 532.41 μmol), potassium carbonate (0.204 g, 1.48 mmol), and dimethylformamide (4 mL) were placed in a 20 mL vial. The reaction mixture was stirred overnight at 50°C. The reaction was quenched with water (50 mL) and extracted with EA (3 x 30 mL). The organic layers were combined, washed with brine (50 mL), dried on anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v = 1 / 1). As a result, 0.113 g of 2-(2-methoxyethoxy)-4-methylsulfonyl-N-prop-2-inyl-aniline (yield 89.84%) was obtained as an off-white solid. LCMS: m / z = 284 [M+1] + .

[0235] Step 2. N-[2-[3-[2-(2-methoxyethoxy)-4-methylsulfonyl-anilino]prop-1-inyl]-3-(2,2,2-trifluoroethyl)benzothiophen-7-yl]-1-methylpiperidine-4-amine(14). In an 8 mL vial, 2-(2-methoxyethoxy)-4-methylsulfonyl-N-prop-2-inyl-aniline (0.049 g, 172.94 μmol), N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl9-1-methylpiperidine-4-amine) (0.050 g, 110.06 μmol), bis(triphenylphosphine)palladium(II) chloride (0.076 g, 107.66 μmol), CuI (0.140 g, 735.10 μmol), DIEA (0.209 g, 1.62 mmol), and methyl sulfoxide (3 mL) were added. The reaction mixture was stirred under nitrogen at room temperature for 3 hours. The reaction was quenched with water (20 mL) and extracted with EA (3 x 30 mL). The organic layers were combined and brine (50 The mixture was washed with (mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L TFA), mobile phase B: ACN; flow rate: 40 mL / min; gradient: 15-40-50% B2-30-40 min); 270 nm; room temperature: 36.17-36.91 min) to obtain the target product. As a result, 0.014 g (yield 20.86) of N-[2-[3-(2-methoxyethoxy)-4-methylsulfonyl-anilino]prop-1-inyl]-3-(2,2,2-trifluoroethyl)benzothiophen-7-yl]-1-methylpiperidine-4-amine (14) was obtained as an off-white solid. LCMS: m / z = 610 [M+1] + . 1H NMR (400 MHz, MeOD) δ 7.52 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 7.29 (t, J = 7.9 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 7.2 Hz, 1H), 4.43 (s, 2H), 4.33 - 4.21 (m, 2H), 3.87 - 3.77 (m, 2H), 3.77 - 3.64 (m, 2H), 3.58 - 3.49 (m, 1H), 3.47 (s, 3H), 3.06 (d, J = 10.9 Hz, 3H), 2.95 (d, J = 11.5 Hz, 2H), 2.36 (s, 3H), 2.29 (t, J = 11.2 Hz, 2H), 2.09 (d, J = 12.5 Hz, 2H), 1.73 - 1.58 (m, 2H).

[0236] Example 15 (4-((3-(7-(((Z)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (racemic mixture) (15) Reaction scheme: [ka]

[0237] Experiment details: Step 1 (4-((3-(7-(((Z)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (racemic mixture) (15) In a 10 mL round-bottom flask, (3-methoxy-4-(propa-2-in-1-ylamino)phenyl)dimethylphosphine oxide (0.078 g, 328.78 μmol), (Z)-3-fluoro-1-methyl-N-(3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidine-4-amine (racemic mixture) (0.076 g, 160.92 μmol), Pd(PPh3)2Cl2 (0.023 g, 32.58 μmol), CuI (0.020 g, 105.01 μmol), DIEA (0.086 g, 665.41 μmol), and methyl sulfoxide (2 mL) were added. The reaction was stirred under a nitrogen atmosphere at room temperature for 6 hours. The reaction was quenched with water (5 mL). The obtained solution was extracted with EA (3 x 10 mL), washed with brine (10 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC (mobile phase A: water (0.1% ammonium hydroxide), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 35-70-70% B (2-30-60 min); 270 nm; room temperature: 25.18-26.87) to obtain the target product. As a result, 0.047 g (80.81 μmol, 24.57% yield) of (4-((3-(7-(((-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (racemic mixture) (15) was obtained as a white solid. LCMS: m / z = 582 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 7.32 - 7.17 (m, 3H), 7.15 - 7.09 (m, 1H), 6.85 - 6.79 (m, 1H), 6.78 (d, J = 7.7 Hz, 1H), 6.06 (t, J = 6.4 Hz, 1H), 5.15 (d, J = 8.5 Hz, 1H), 4.79 (d, J = 49.5 Hz, 1H), 4.34 (d, J = 6.3 Hz, 2H), 3.81 (d, J = 29.5 Hz, 5H), 3.64 (d, J = 28.8 Hz, 1H), 3.03 (t, J = 11.4 Hz, 1H), 2.79 (d, J = 11.6 Hz, 1H), 2.27 (d, J = 13.0 Hz, 1H), 2.18 (s, 3H), 2.08 (t, J = 11.4 Hz, 1H), 1.99 - 1.90 (m, 1H), 1.71 (d, J = 11.8 Hz, 1H), 1.58 (d, J = 13.1 Hz, 6H).

[0238] Example 16 N1-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-N4,N4-dimethylcyclohexane-1,4-diamine(16) Reaction scheme: [ka]

[0239] Experiment details: Step 1. N1-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-N4,N4-dimethylcyclohexane-1,4-diamine(16). In a 50 mL round-bottom flask, 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (0.083 g, 177.15 μmol), 4-(dimethylamino)cyclohexane-1-one (0.120 g, 849.80 μmol), NaCNBH3 (0.079 g, 1.84 mmol), and EtOH (5 mL) were added. The mixture was stirred at 60°C for 16 hours. The reaction was quenched with water (20 mL) and extracted with EA (50 mL x 2). The combined organic layers were successively washed with water (50 mL) and brine (50 mL), separated, and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 60-90-100% B (2-30-60 mins); 265 nm; room temperature: 33.497-37.464 mins). This yielded 47 mg (44% yield) of N1-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-N4,N4-dimethylcyclohexane-1,4-diamine(16) as a white solid. LCMS: m / z = 594 [M+1] + . 1H NMR (400 MHz, DMSO) δ 7.39 (d, J = 8.3 Hz, 1H), 7.24 (d, J = 10.9 Hz, 2H), 7.13 (t, J = 7.5 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.67 (t, J = 8.5 Hz, 1H), 6.51 (t, J = 6.1 Hz, 1H), 5.21 (dd, J = 40.1, 7.5 Hz, 1H), 4.38 (d, J = 6.1 Hz, 2H), 3.90 (s, 3H), 3.56 (s, 2H), 3.10 (s, 3H), 2.21 (s, 3H), 2.18 (s, 3H), 2.05 (d, J = 18.8 Hz, 2H), 1.76 (d, J = 7.6 Hz, 3H), 1.61 (s, 1H), 1.48 (s, 1H), 1.33 (d, J = 14.5 Hz, 2H).

[0240] Example 17 trans-N-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine(17) and cis-N-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine(17b) Reaction scheme: [ka]

[0241] Experiment Details Step 1. N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1,4-dioxaspiro[4.5]decane-8-amine In a 25 mL flask, titanium ethoxide (0.577 g, 2.53 mmol), 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (0.401 g, 855.90 μmol), toluene (10 mL), and 1,4-dioxaspiro[4.5]decan-8-one (0.437 g, 2.80 mmol) were added. The reaction mixture was stirred at 110 °C for 2 hours. The reaction mixture was concentrated under vacuum and dissolved in methanol (10 mL). Next, sodium cyanoboron anhydrous (0.226 g, 5.27 mmol) was added. The reaction mixture was stirred at room temperature for a further 15 hours. The reaction was quenched by adding water (20 mL) and extracted with EA (2 x 20 mL). The organic layers were combined, washed with brine (20 mL), dried on anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted with EA / heptane (v / v = 2 / 5) and traced on a silica gel column. This yielded 0.608 g of N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1,4-dioxaspiro[4.5]decane-8-amine as a yellow oil (yield 93.60%). LCMS: m / z = 609 [M+1] + .

[0242] Step 2.4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)cyclohexane-1-one In a 25 mL flask maintained under a nitrogen inert atmosphere, add N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2, 2-Trifluoroethyl)benzo[b]thiophen-7-yl)-1,4-dioxaspiro[4.5]decane-8-amine (0.603 g, 990.65 μmol), acetonitrile (10 mL), and 4-methylbenzenesulfonic acid hydrate (1.583 g, 8.32 mmol) in water (5 mL). The reaction mixture was stirred at room temperature for 5 hours, after which saturated sodium bicarbonate aqueous solution was added until the pH was 7-8. The resulting solution was extracted with EA (2 x 20 mL). The organic layers were combined, washed with brine (50 mL), dried on anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted with EA / heptane (v / v = 3 / 1) and traced on a silica gel column. As a result, 0.447 g (79.91% yield) of 4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)cyclohexane-1-one was obtained as a yellow oil. LCMS: m / z = 565 [M+1] + .

[0243] Step 3. trans-N-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine(17) and cis-N-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine(17b) In an 8 mL flask, 2-oxa-6-azaspiro[3.3]heptane (0.100 g, 1.01 mmol), 4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-yl)amino)cyclohexane-1-one (0.050 g, 88.55 μmol), methanol (2 mL), and acetic acid (0.1 mL) were added. The reaction mixture was stirred at room temperature for 24 hours, after which sodium cyanoboron anhydrous (0.030 g, 699.70 μmol) was added. The reaction mixture was stirred at room temperature for a further 2 hours. The reaction was quenched by adding water (10 mL) and extracted with EA (2 x 20 mL). The organic layers were combined, washed with brine (20 mL), and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: MeOH; flow rate: 70 mL / min; gradient: 40-75-100% B (2-30-60 min; 272 nm; room temperature: 33.268-34.375 min). This yielded 0.017 g (yield 29.63%) of trans-N-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (17) as a white solid. LCMS: m / z = 648 [M+1] + . 1H NMR (400 MHz, DMSO) δ 7.39 (d, J = 8.9 Hz, 1H), 7.27 - 7.21 (m, 2H), 7.11 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.63 (d, J = 7.9 Hz, 1H), 6.50 (s, 1H), 5.23 (d, J = 8.2 Hz, 1H), 4.58 (s, 4H), 4.37 (d, J = 6.5 Hz, 2H), 3.89 (s, 3H), 3.79 (d, J = 11.5 Hz, 2H), 3.21 (s, 4H), 3.09 (s, 3H), 1.92 (s, 2H), 1.69 (s, 2H), 1.25 (d, J = 14.6 Hz, 3H), 0.99 (d, J = 13.7 Hz, 3H).

[0244] Then, 0.010 g (17.43% yield) of cis-N-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (17b) was obtained as a white solid. LCMS: m / z = 648 [M+1] + . 1H NMR (400 MHz, DMSO) δ 7.39 (d, J = 8.7 Hz, 1H), 7.29 - 7.19 (m, 2H), 7.11 (d, J = 7.9 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 6.63 (d, J = 7.8 Hz, 1H), 6.51 (t, J = 6.1 Hz, 1H), 5.27 (d, J = 7.8 Hz, 1H), 4.59 (s, 4H), 4.38 (d, J = 6.1 Hz, 2H), 3.89 (s, 3H), 3.79 (q, J = 10.8 Hz, 2H), 3.20 (s, 4H), 3.09 (s, 3H), 2.09 (d, J = 15.6 Hz, 1H), 1.57 (dd, J = 31.9, 18.2 Hz, 6H), 1.39 (d, J = 10.3 Hz, 2H), 1.23 (s, 1H).

[0245] Example 18 Trans-N-(4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine(18) and cis-N-(4-(7-oxa-2-azaspiro[3.5]nonanan-2-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine(18b) Reaction scheme [ka]

[0246] Step 1. trans-N-(4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine(18) and cis-N-(4-(7-oxa-2-azaspiro[3.5]nonanan-2-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine(18b). The mixture was placed in a sealed tube and kept under an inert nitrogen atmosphere. 4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-yl)amino)cyclohexane-1-one (0.05 g, 88.55 mmol), 7-oxa-2-azaspiro[3.5]nonane (0.05 g, 393.11 mmol), acetic acid (0.03 g, 499.58 mmol), and methanol (1 mL) were added. The reaction mixture was stirred at room temperature for 3 hours. Sodium borocyanohydride (0.04 g, 636.53 mmol) was added to the reaction mixture and stirred at room temperature for 2 hours. The resulting solution was extracted with ethyl acetate (2 x 50 mL), the organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product obtained was further purified by pre-HPLC using MeOH / H2O (0.1% ammonium hydroxide), flow rate: 25 mL / min; gradient: 50-85-100% B (2-30-60 min); 270 nm; room temperature: 36.800-38.238 / 40.647-42.205. This yielded 0.008 g (yield 13.37%) of trans-N-(4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (18) as a white solid. LCMS: m / z = 676 [M+1] + 1 H NMR (400 MHz, DMSO) δ 7.39 (d, J = 8.3 Hz, 1H), 7.29 - 7.19 (m, 2H), 7.12 (d, J = 7.8 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 7.7 Hz, 1H), 6.51 (t, J = 6.2 Hz, 1H), 5.24 (d, J = 8.0 Hz, 1H), 4.38 (d, J = 6.0 Hz, 2H), 3.89 (s, 3H), 3.80 (dd, J = 22.2, 11.3 Hz, 2H), 3.47 (s, 4H), 3.10 (s, 3H), 2.91 (s, 4H), 1.95 (d, J = 11.1 Hz, 3H), 1.74 (d, J = 11.7 Hz, 2H), 1.61 (s, 4H), 1.27 (dd, J = 23.1, 11.1 Hz, 3H), 1.10 - 0.92 (m, 2H).

[0247] Then, cis-N-(4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (18b) was obtained as a white solid in an amount of 0.007 g (yield 11.69%). LCMS: m / z = 676 [M+1] + 1H NMR (400 MHz, DMSO) δ 7.39 (d, J = 8.2 Hz, 1H), 7.31 - 7.19 (m, 2H), 7.12 (d, J = 7.8 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 7.5 Hz, 1H), 6.51 (t, J = 5.8 Hz, 1H), 5.22 (d, J = 7.4 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 3.89 (s, 3H), 3.79 (dd, J = 22.2, 11.2 Hz, 2H), 3.49 (s, 4H), 3.10 (s, 3H), 2.89 (s, 4H), 2.22 (s, 1H), 1.71 - 1.51 (m, 9H), 1.40 (t, J = 15.1 Hz, 2H), 1.23 (s, 2H).

[0248] Example 19 trans-2,2'-((4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-yl)amino)cyclohexyl)azandiyl)bis(ethane-1-ol)(19) and cis-2,2'-((4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-yl)amino)cyclohexyl)azandiyl)bis(ethane-1-ol)(19b) Reaction scheme: [ka]

[0249] Experiment details: Step 1. Synthesis of trans-2,2'-((4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-yl)amino)cyclohexyl)azandiyl)bis(ethane-1-ol)(19) and cis-2,2'-((4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-yl)amino)cyclohexyl)azandiyl)bis(ethane-1-ol)(19b) To an 8 mL reaction vial, 4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-yl)amino)cyclohexane-1-one (0.033 g, 58.44 μmol), acetic acid (0.033 g, 549.52 μmol), and 2,2'-azandiylbis(ethane-1-ol) (0.554 g, 5.26 mmol) were added. The reaction mixture was stirred at 60°C for 2 hours. The reaction was quenched with aq. Na2CO3 (10 mL), extracted with DCM (30 mL x 3), and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: ACN; flow rate: 40 mL / min; gradient: 35-65-65%B (2-30-60 min); 270 nm; room temperature: 26.332-27.528 min and room temperature: 31.669-33.143 min) to obtain trans-2,2'-((4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)cyclohexyl)azandiyl)bis(ethane-1-ol) (0.005 g, 13.08% yield) as an off-white solid. LCMS: m / z = 654 [M+1] + . 1H NMR (400 MHz, DMSO) δ 7.39 (dd, J = 8.3, 1.6 Hz, 1H), 7.25 (dd, J = 8.3, 4.8 Hz, 2H), 7.12 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 7.9 Hz, 1H), 6.51 (t, J = 6.2 Hz, 1H), 5.23 (d, J = 8.0 Hz, 1H), 4.44 - 4.23 (m, 4H), 3.89 (s, 3H), 3.80 (q, J = 11.0 Hz, 2H), 3.41 - 3.33 (m, 4H), 3.10 (s, 3H), 2.54 (d, J = 6.4 Hz, 4H), 1.74 (d, J = 11.3 Hz, 2H), 1.46 - 1.17 (m, 6H).

[0250] Then, cis-2,2'-((4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)cyclohexyl)azandiyl)bis(ethane-1-ol) (0.004 g, 10.46%) was obtained as an off-white solid. LCMS: m / z = 654 [M+1] + . 1H NMR (400 MHz, DMSO) δ 7.39 (d, J = 8.3 Hz, 1H), 7.31 - 7.23 (m, 2H), 7.18 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 7.7 Hz, 1H), 6.52 (t, J = 6.1 Hz, 1H), 5.05 (d, J = 5.7 Hz, 1H), 4.38 (d, J = 6.1 Hz, 2H), 3.95 - 3.74 (m, 5H), 3.71 (s, 1H), 3.40 (t, J = 6.2 Hz, 4H), 3.10 (s, 3H), 2.62 (dd, J = 18.5, 12.6 Hz, 4H), 2.05 - 1.85 (m, 3H), 1.71 - 1.41 (m, 5H), 1.24 (s, 3H).

[0251] Example 20 N-[2-[3-(2-methoxy-4-methylsulfonylanilino)propa-1-inyl]-3-(2,2,2-trifluoroethyl)benzothiophen-7-yl]-1-(3-methoxypropyl)piperidine-4-amine(20) Reaction scheme: [ka]

[0252] Experiment details: Step 1. N-[2-[3-(2-methoxy-4-methylsulfonylanilino)prop-1-inyl]-3-(2,2,2-trifluoroethyl)benzothiophen-7-yl]-1-(3-methoxypropyl)piperidine-4-amine(20). In an 8 mL vial, 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (0.056 g, 119.53 μmol), 1-(3-methoxypropyl)piperidine-4-one (0.125 g, 729.99 μmol), titanium ethoxide (0.156 g, 683.89 μmol), and toluene (1 mL) were added. The reaction mixture was stirred at 110 °C for 1 hour and concentrated under vacuum. MeOH (1 mL) and anhydrous sodium cyanoboron (0.120 g, 2.80 mmol) were added to the crude product. The reaction mixture was stirred overnight at room temperature. The reaction was quenched with water (20 mL) and extracted with EA (30 mL x 2). The combined organic layers were sequentially washed with water (50 mL) and brine (50 mL), separated, and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: MeOH; flow rate: 70 mL / min; gradient: 45-80-100% B (2-30-60 min); 270 nm; room temperature: 40.998-42.953 min). As a result, 0.035 g (yield 46.95%) of N-[2-[3-(2-methoxy-4-methylsulfonylanilino)propa-1-inyl]-3-(2,2,2-trifluoroethyl)benzothiophen-7-yl]-1-(3-methoxypropyl)piperidine-4-amine (20) was obtained as an off-white solid. LCMS: m / z = 624 [M+1] + . 1H NMR (400 MHz, , methanol-d4) δ 7.54 - 7.47 (m, 1H), 7.36 - 7.25 (m, 2H), 7.15 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 4.42 (s, 2H), 3.97 (s, 3H), 3.76 - 3.64 (m, 2H), 3.58 - 3.49 (m, 1H), 3.45 (d, J = 6.0 Hz, 2H), 3.34 (s, 3H), 3.08 (s, 3H), 3.00 (d, J = 11.6 Hz, 2H), 2.54 - 2.46 (m, 2H), 2.23 (d, J = 23.2 Hz, 2H), 2.09 (d, J = 12.2 Hz, 2H), 1.87 - 1.76 (m, 2H), 1.71 - 1.56 (m, 2H).

[0253] Example 21 3-Methoxy-N,N-dimethyl-4-((3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide(21) Reaction scheme: [ka]

[0254] Experiment details: Step 1: 3-Methoxy-N,N-dimethyl-4-nitrobenzenesulfonamide 3-methoxy-4-nitrobenzenesulfonyl chloride (0.536 g, 2.13 mmol), dimethylamine (0.542 g, 3.96 mmol), and ACN (5 mL) were placed in a 20 mL sealed tube. The reaction mixture was purified by eluting with EA / hexane (v / v = 2 / 3) using a silica gel column. As a result, 0.554 g (2.12 mmol, 99.93% yield) of 3-methoxy-N,N-dimethyl-4-nitrobenzenesulfonamide was obtained as a pale yellow solid. LCMS: m / z = 261 [M+1] + .

[0255] Step 2: 4-amino-3-methoxy-N,N-dimethylbenzenesulfonamide In a 40 mL sealed tube, 0.566 g (2.17 mmol) of 3-methoxy-N,N-dimethyl-4-nitrobenzenesulfonamide, 1.406 g (25.17 mmol) of iron, 1.121 g (20.95 mmol) of NH4Cl, 8 mL of MeOH, and 2 mL of water were added. The reaction mixture was stirred under nitrogen at 70°C for 4 hours. The reaction mixture was filtered through a Celite pad, and the filter cake was washed with methanol (2 x 20 mL). The filtrate was concentrated under reduced pressure to obtain the product. As a result, 0.530 g (2.29 mmol, 99.93% yield) of 4-amino-3-methoxy-N,N-dimethylbenzenesulfonamide was obtained as a pale yellow solid. LCMS: m / z = 231 [M+1] + .

[0256] Step 3: 3-Methoxy-N,N-dimethyl-4-(propa-2-in-1-ylamino)benzenesulfonamide 4-amino-3-methoxy-N,N-dimethylbenzenesulfonamide (0.151 g, 655.71 μmol), 3-bromopropa-1-yin (0.102 g, 857.43 μmol), K2CO3 (0.263 g, 1.90 mmol), and NMP (2 mL) were placed in an 8 mL sealed tube. The reaction mixture was stirred under nitrogen at 80°C for 4 hours. The resulting solution was extracted with EA (3 x 20 mL), washed with brine (20 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v = 2 / 3). As a result, 0.119 g (443.48 μmol, yield 67.63%) of 3-methoxy-N,N-dimethyl-4-(propa-2-in-1-ylamino)benzenesulfonamide was obtained as a pale yellow solid. LCMS: m / z = 269 [M+1] + .

[0257] Step 4 3-Methoxy-N,N-dimethyl-4-((3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide (21) In a 10 mL round-bottom flask, 3-methoxy-N,N-dimethyl-4-(propa-2-in-1-ylamino)benzenesulfonamide (0.098 g, 365.22 μmol), N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.058 g, 127.67 μmol), Pd(PPh3)2Cl2 (0.036 g, 50.99 μmol), CuI (0.019 g, 99.76 μmol), DIEA (0.044 g, 340.44 μmol), and methyl sulfoxide (1 mL) were added. The reaction was stirred under a nitrogen atmosphere at room temperature for 1 hour. The obtained solution was extracted with EA (3 × 20 mL), washed with brine (20 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC (mobile phase A: water (0.1% ammonium hydroxide), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 50-80-95-95%B (2-30-45-60 mins); 220 nm; room temperature: 41.58-49.20) to obtain the target product. As a result, 3-methoxy-N,N-dimethyl-4-((3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide (21) was obtained as a white solid in an amount of 0.035 g (58.85 μmol, yield 40.09%). LCMS: m / z = 595 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 7.28 - 7.22 (m, 2H), 7.32 - 7.10 (m, 2H), 6.91 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 7.8 Hz, 1H), 6.49 (t, J = 6.2 Hz, 1H), 5.92 (s, 1H), 5.78 (s, 1H), 5.16 (d, J = 7.9 Hz, 1H), 4.80 (d, J = 49.3 Hz, 2H), 3.83 (d, J = 35.5 Hz, 5H), 2.79 (d, J = 11.1 Hz, 2H), 2.56 (s, 6H), 2.20 (s, 3H), 2.08 - 2.00 (m, 2H), 1.92 - 1.84 (m, 2H), 1.60 - 1.53 (m, 2H), 1.23 (s, 1H).

[0258] Example 22 N-(2-(3-((2-methoxy-4-(morpholinosulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine(22) Reaction scheme [ka]

[0259] Experiment details: Step 1: 4-((3-methoxy-4-nitrophenyl)sulfonyl)morpholin 3-methoxy-4-nitrobenzenesulfonyl chloride (0.529 g, 2.10 mmol), morpholine (0.387 g, 4.44 mmol), and ACN (5 mL) were placed in a 20 mL sealed tube. The reaction mixture was purified by eluting with EA / hexane (v / v = 2 / 3) using a silica gel column. As a result, 0.690 g (2.28 mmol, 100.00% yield) of 4-((3-methoxy-4-nitrophenyl)sulfonyl)morpholine was obtained as a slightly yellow solid. LCMS: m / z = 303 [M+1]+ .

[0260] Step 2: 2-Methoxy-4-(morpholinosulfonyl)aniline 4-((3-methoxy-4-nitrophenyl)sulfonyl)morpholine (0.669 g, 2.57 mmol), iron (1.275 g, 22.83 mmol), NH4Cl (1.220 g, 22.80 mmol), EtOH (10 mL), and water (2 mL) were placed in a 40 mL sealed tube. The reaction mixture was stirred under nitrogen at 90°C for 16 hours. The reaction mixture was filtered through a Celite pad, and the filter cake was washed with methanol (2 x 20 mL). The filtrate was concentrated under reduced pressure to obtain the product. As a result, 0.392 g (1.43 mmol, yield 56.00%) of 2-methoxy-4-(morpholinosulfonyl)aniline was obtained as a slightly yellow solid. LCMS: m / z = 273 [M+1] + .

[0261] Step 3: 2-Methoxy-4-(morpholinosulfonyl)-N-(propa-2-in-1-yl)aniline 2-methoxy-4-(morpholinosulfonyl)aniline (0.161 g, 591.21 μmol), 3-bromopropa-1-yne (0.099 g, 832.21 μmol), K2CO3 (0.251 g, 1.81 mmol), and NMP (2 mL) were placed in an 8 mL sealed tube. The reaction mixture was stirred under nitrogen at 80°C for 16 hours. The resulting solution was extracted with EA (3 x 20 mL), washed with brine (20 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v = 2 / 3). As a result, 0.138 g (444.63 μmol, yield 75.20%) of 2-methoxy-4-(morpholinosulfonyl)-N-(propa-2-yin-1-yl)aniline was obtained as a slightly yellow solid. LCMS: m / z = 311 [M+1] + .

[0262] Step 4 N-(2-(3-((2-methoxy-4-(morpholinosulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine(22) In a 10 mL round-bottom flask, 2-methoxy-4-(morpholinosulfonyl)-N-(propa-2-in-1-yl)aniline (0.072 g, 231.98 μmol), N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.128 g, 281.75 μmol), Pd(PPh3)2Cl2 (0.036 g, 50.99 μmol), CuI (0.013 g, 68.25 μmol), DIEA (0.072 g, 557.09 μmol), and methyl sulfoxide (2 mL) were added. The reaction was stirred under a nitrogen atmosphere at room temperature for 2 hours. The reaction was quenched with water (5 mL). The obtained solution was extracted with EA (3 x 20 mL), washed with brine (20 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC (mobile phase A: water (0.1% ammonium hydroxide), mobile phase B: ACN; flow rate: 40 mL / min; gradient: 40-80-80% B (2-30-60 min); 220 nm; room temperature: 24.95-29.32) to obtain the target product. As a result, 0.035 g (58.85 μmol, yield 40.09%) of N-(2-(3-((2-methoxy-4-(morpholinosulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (22) was obtained as a white solid. LCMS: m / z = 595 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 7.29 - 7.21 (m, 2H), 7.14 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 1.9 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 7.8 Hz, 1H), 6.55 (t, J = 6.2 Hz, 1H), 5.31 (d, J = 7.9 Hz, 1H), 4.39 (d, J = 6.2 Hz, 2H), 3.84 (d, J = 39.1 Hz, 5H), 3.62 (t, J = 4.5 Hz, 4H), 2.83 (t, J = 4.8 Hz, 4H), 2.78 - 2.70 (m, 2H), 2.17 (s, 3H), 1.99 - 1.89 (m, 2H), 1.93 - 1.83 (m, 2H), 1.56 - 1.49 (m, 2H), 1.23 (s, 1H).

[0263] Example 23 3-Methoxy-4-((3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide(23) Reaction scheme: [ka]

[0264] Experiment details: Step 1. Benzyl(3-methoxy-4-nitrophenyl)sulfane A mixture of 4-fluoro-2-methoxy-1-nitrobenzene (20.50 g, 119.80 mmol) and K2CO3 (125.57 g, 908.57 mol) in 200 mL of DMF was mixed with phenylmethanethiol (16.34 g, 131.77 mol) at 0°C. The mixture was stirred at room temperature for 8 hours, added to 500 mL of water, filtered, washed with water (100 mL x 2), and dried in an oven. As a result, 18.10 g (54.88%) of benzyl(3-methoxy-4-nitrophenyl)sulfan was obtained as a small yellow solid. LCMS: m / z = 276 [M+1] +

[0265] Step 2.3-Methoxy-4-nitrobenzenesulfonyl chloride Benzyl(3-methoxy-4-nitrophenyl)sulfan (14.47 g, 52.56 mmol), HOAc (90 mL), and H2O (15 mL) were placed in a 100 mL round-bottom flask. The mixture was cooled to 0°C. Next, NCS (30.45 g, 228.03 mmol) was added over 5 minutes while maintaining the internal temperature below 5°C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (150 mL) and extracted with EA (300 mL × 2). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column and eluted with EA / hexane (v / v = 1 / 1) to obtain 3-methoxy-4-nitrobenzenesulfonyl chloride (9.792 g, yield 74.04%) as a slightly yellow solid.

[0266] Step 3.3-Methoxy-4-nitrobenzenesulfonamide A mixture of 3-methoxy-4-nitrobenzenesulfonyl chloride (0.510 g, 2.03 mmol) in 10 mL of MeCN was mixed with ammonium hydroxide (1 mL) at 0°C. The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated under reduced pressure. As a result, 3-methoxy-4-nitrobenzenesulfonamide (0.491 g, crude) was obtained as an off-white solid. LCMS: m / z = 233 [M+1]+

[0267] Step 4.4-Amino-3-methoxybenzenesulfonamide To a solution of 3-methoxy-4-nitrobenzenesulfonamide (0.481 g, 2.07 mmol) in MeOH (8 mL), Pd / C (10%, 0.097 g) was added under N2. The mixture was degassed under vacuum and purged three times with H2 (g). The reaction mixture was stirred at room temperature for 2 hours. The solid was filtered, and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated under vacuum to obtain 4-amino-3-methoxybenzenesulfonamide (0.470 g, crude) as a gray solid. LCMS: m / z = 203 [M+1] +

[0268] Step 5. 3-Methoxy-4-(propa-2-in-1-ylamino)benzenesulfonamide A mixture of 4-amino-3-methoxybenzenesulfonamide (0.465 g, 2.30 mmol), 3-bromopropa-1-yin (0.595 g, 5.00 mmol), and K2CO3 (0.958 g, 6.93 mmol) in DMA (10 mL) was degassed and purged three times with N2 (g). The mixture was stirred at 50°C for 12 hours. The reaction mixture was quenched by adding water (20 mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with brine (30 mL x 4), filtered, and concentrated under reduced pressure. The residue was purified by eluting with ACN / water (v / v = 1 / 2) on a C18 column to obtain 0.152 g (27.51%) of 3-methoxy-4-(propa-2-in-1-ylamino)benzenesulfonamide as a yellow solid. LCMS: m / z = 241 [M+1] +

[0269] Step 6. 3-Methoxy-4-((3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide (23) In an 8 mL sealed tube purged and maintained under an inert nitrogen atmosphere, N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.051 g, 0.11 mmol), 3-methoxy-4-(propa-2-in-1-ylamino)benzenesulfonamide (0.048 g, 0.20 mmol), Pd(dppf)Cl2 (0.024 g, 0.04 mmol), CuI (0.018 g, 0.09 mmol), DIEA (0.057 g, 0.44 mmol), and DMSO (1 mL) were added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was extracted with H2O (20 mL), quenched, and extracted with EA (20 mL x 2). The combined organic layers were washed with brine (10 mL), separated, and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 50-85-95% B (2-30-40 min); 220 nm; room temperature: 32.686-34.791 min) to obtain 3-methoxy-4-((3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide (23) (0.024 g, 37.73% yield) as a white solid. LCMS: m / z = 567 [M+1] + 1H NMR (400 MHz, MeOD) δ 7.50 - 7.42 (m, 1H), 7.32 (t, J = 5.9 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.71 (t, J = 7.7 Hz, 1H), 4.37 (s, 2H), 3.93 (s, 3H), 3.75 - 3.59 (m, 2H), 3.58 - 3.45 (m, 1H), 2.90 (d, J = 12.0 Hz, 2H), 2.32 (d, J = 6.0 Hz, 3H), 2.22 (t, J = 11.4 Hz, 2H), 2.06 (d, J = 12.0 Hz, 2H), 1.67 - 1.53 (m, 2H).

[0270] Example 24 N-(2,3-dihydroxypropyl)-3-methoxy-4-((3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide(24) Reaction scheme: [ka]

[0271] Experiment details: Step 1. Benzyl(3-methoxy-4-nitrophenyl)sulfane To a mixture of 3-methoxy-4-nitrobenzenesulfonyl chloride (0.512 g, 2.03 mmol) in 10 mL of MeCN, 3-aminopropane-1,2-diol (0.238 g, 2.61 mmol) was added at 0°C. The resulting mixture was concentrated under reduced pressure. As a result, N-(2,3-dihydroxypropyl)-3-methoxy-4-nitrobenzenesulfonamide (1.033 g, crude) was obtained as a colorless oil. LCMS: m / z = 307 [M+1] +

[0272] Step 2.4-Amino-N-(2,3-dihydroxypropyl)-3-methoxybenzenesulfonamide To a solution of N-(2,3-dihydroxypropyl)-3-methoxy-4-nitrobenzenesulfonamide (1.031 g, 3.36 mmol) in MeOH (8 mL), Pd / C (10%, 0.219 g) was added under N2 (g). The mixture was degassed under vacuum and purged three times with H2 (g). The reaction mixture was stirred at room temperature for 2 hours. The solid was filtered off, and the filter cake was washed with MeOH (10 mL). The combined filtrate was concentrated under vacuum to obtain 4-amino-N-(2,3-dihydroxypropyl)-3-methoxybenzenesulfonamide (1.004 g, crude) as a gray solid. LCMS: m / z = 277 [M+1] +

[0273] Step 3. N-(2,3-dihydroxypropyl)-3-methoxy-4-(propa-2-in-1-ylamino)benzenesulfonamide A mixture of 4-amino-N-(2,3-dihydroxypropyl)-3-methoxybenzenesulfonamide (1.001 g, crude), 3-bromopropa-1-yin (0.467 g, 3.93 mmol), and K2CO3 (0.795 g, 5.75 mmol) in NMP (10 mL) was degassed and purged three times with N2 (g). The mixture was stirred at 80°C for 48 hours. The reaction mixture was quenched by adding water (20 mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with brine (30 mL x 4), filtered, and concentrated under reduced pressure. The residue was purified by eluting with ACN / water (v / v = 1 / 4) using a C18 column to obtain 0.078 g (6.85%) of N-(2,3-dihydroxypropyl)-3-methoxy-4-(propa-2-in-1-ylamino)benzenesulfonamide as a colorless oil. LCMS: m / z = 315 [M+1] +

[0274] Step 4. N-(2,3-dihydroxypropyl)-3-methoxy-4-((3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide (24) In an 8 mL sealed tube purged and maintained under an inert nitrogen atmosphere, N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.048 g, 0.11 mmol), N-(2,3-dihydroxypropyl)-3-methoxy-4-(propa-2-in-1-ylamino)benzenesulfonamide (0.077 g, 0.24 mmol), Pd(dppf)Cl2 (0.019 g, 0.03 mmol), CuI (0.009 g, 0.05 mmol), DIEA (0.062 g, 0.48 mmol), and DMSO (1 mL) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (20 mL) and extracted with EA (20 mL x 2). The combined organic layers were washed with brine (10 mL), separated, and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: MeOH; flow rate: 40 mL / min; gradient: 35-65-95%B (2-30-60 min); 270 nm; room temperature: 38.125-42.751 min) to obtain N-(2,3-dihydroxypropyl)-3-methoxy-4-((3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)benzenesulfonamide (24) (0.015 g, 22.14% yield) as a white solid. LCMS: m / z = 641 [M+1] + 1H NMR (400 MHz, DMSO) δ 7.32 - 7.23 (m, 2H), 7.21 (s, 1H), 7.18 - 7.10 (m, 1H), 7.11 - 7.06 (m, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 6.33 (t, J = 6.0 Hz, 1H), 5.32 (d, J = 7.6 Hz, 1H), 4.72 (s, 1H), 4.51 (s, 1H), 4.36 (d, J = 6.0 Hz, 2H), 3.88 - 3.75 (m, 4H), 3.55 - 3.42 (m, 2H), 2.85 - 2.75 (m, 3H), 2.59 - 2.52 (m, 1H), 2.20 (s, 3H), 2.12 - 1.93 (m, 3H), 1.89 (d, J = 12.4 Hz, 2H), 1.61 - 1.47 (m, 2H), 1.37 - 1.26 (m, 2H).

[0275] Example 25 N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-3-methyl-3-azabicyclo[3.2.1]octan-8-amine(25) Reaction scheme [ka]

[0276] Experiment details: Step 1: tert-butyl8-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate In a 20 mL sealed tube, 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (0.117 g, 414.07 μmol), tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate (0.561 g, 519.34 μmol), and dibutyltin dichloride (0.082 g, 269.87 μmol) were added. Next, phenylsilane (0.235 g, 2.17 mmol) was added. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by eluting with EA / hexane (v / v = 3 / 2) on a silica gel column. As a result, tert-butyl 8-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate was obtained as a yellow solid of 0.194 g (286.22 μmol, yield 69.12%). LCMS: m / z = 678 [M+1] + .

[0277] Step 2: N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-3-azabicyclo[3.2.1]octane-8-amine In an 8 mL sealed tube, tert-butyl 8-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-3-azabicyclo[3.2.1]octane-3-carboxylate (0.192 g, 283.27 μmol), HCl (g) in EA (2 mL, 4 N), and EA (2 mL) were added. The reaction mixture was stirred at room temperature for 1 hour, and the mixture was concentrated under vacuum. Water (2 mL) was added to the reaction mixture, and NaOH (aq, 3 N) was added until the pH reached 7. The mixture was extracted with EA (3 x 10 mL), washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. As a result, 0.153 g (264.85 μmol, 93.49% yield) of N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-yl)-3-azabicyclo[3.2.1]octan-8-amine was obtained as a brown solid. The reaction mixture was purified by eluting with ACN / H2O (v / v = 1 / 1) on a C18 column. LCMS: m / z = 578 [M+1] + .

[0278] Step 3 N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-3-methyl-3-azabicyclo[3.2.1]octan-8-amine(25) In an 8 mL sealed tube, N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-yl)-3-azabicyclo[3.2.1]octan-8-amine (0.152 g, 263.12 μmol), paraformaldehyde (0.054 g, 1.79 mmol), acetic acid (0.3 mL), and methanol (2 mL) were added. Then NaBH3CN (0.090 g, 2.37 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. The reaction was quenched with water (10 mL), the resulting solution was extracted with EA (3 x 20 mL), washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC (mobile phase A: water (0.1% ammonium hydroxide), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 50-80-100% B (2-30-60 mins); 270 nm; room temperature: 44.33-46.51) to obtain the target product. As a result, 0.023 g (38.87 μmol, yield 14.77%) of N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-3-methyl-3-azabicyclo[3.2.1]octan-8-amine (25) was obtained as a white solid. LCMS: m / z = 592 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 7.42 - 7.32 (m, 1H), 7.32 - 7.25 (m, 2H), 7.20 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 7.7 Hz, 1H), 6.52 (t, J = 6.2 Hz, 1H), 5.18 (d, J = 3.6 Hz, 1H), 4.39 (d, J = 6.2 Hz, 2H), 3.86 (d, J = 33.0 Hz, 5H), 3.51 - 3.42 (m, 1H), 3.10 (s, 3H), 2.43 (d, J = 10.5 Hz, 2H), 2.32 - 3.28 (m, 4H), 2.13 (s, 3H), 1.72 (d, J = 3.6 Hz, 4H).

[0279] Example 26 N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine(26) Reaction scheme: [ka]

[0280] Experiment details: Step 1. tert-butyl 3-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate. 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (0.147 g, 313.76 μmol), tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (0.442 g, 1.96 mmol), titanium ethoxide (0.498 g, 2.18 mmol), and toluene (3 mL) were added to a 20 mL vial. The reaction mixture was stirred at 110°C for 16 hours and concentrated under vacuum. MeOH (3 mL) and anhydrous sodium cyanoboron (0.159 g, 3.71 mmol) were added to the crude product. The reaction mixture was stirred overnight at room temperature. The reaction was quenched with water (50 mL) and extracted with EA (3 x 20 mL). The organic layers were combined, washed with brine (50 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column and eluted with EA / hexane (v / v = 1 / 2). As a result, 0.330 g (crude) of tert-butyl 3-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate was obtained as a yellow oil. LCMS: m / z = 678 [M+1] + .

[0281] Step 2. N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-8-azabicyclo[3.2.1]octan-3-amine. In a 50 mL flask, tert-butyl 3-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (0.330 g, 486.87 μmol) and HCl in EA (20 mL, 4.0 M) were added. The reaction mixture was adjusted to pH = 8 by KHCO3 (aq.) at 0°C. The mixture was extracted with EA (3 x 20 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column and eluted with MeOH / DCM (v / v = 1 / 9). As a result, 0.074 g (yield 26.31%) of N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-8-azabicyclo[3.2.1]octan-3-amine was obtained as a yellow solid. LCMS: m / z = 578 [M+1] + .

[0282] Step 3. N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine(26). In an 8 mL vial, N-[2-[3-(2-methoxy-4-methylsulfonylanilino)propa-1-inyl]-3-(2,2,2-trifluoroethyl)benzothiophen-7-yl]-8-azabicyclo[3.2.1]octan-3-amine (0.075 g, 129.82 μmol), polyoxymethylene (0.008 g, 266.44 μmol), anhydrous sodium cyanoboron (0.058 g, 1.35 mmol), MeOH (3 mL), and HOAc (0.1 mL) were added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with water (10 mL), extracted with EA (20 mL), washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L TFA), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 50-100-100% B (0-45-50 min); 271 nm; room temperature: 43.810-47.680 min) to obtain the target product. As a result, 0.017 g (yield 22.13%) of N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine (26) was obtained as an off-white solid. LCMS: m / z = 592 [M+1] + . 1 H NMR (400 MHz, methanol-d4) δ 7.52 - 7.45 (m, 1H), 7.34 - 7.25 (m, 2H), 7.18 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 4.40 (s, 2H), 3.95 (s, 3H), 3.82 (d, J = 12.0 Hz, 1H), 3.75 - 3.63 (m, 2H), 3.30 (s, 2H), 3.06 (s, 3H), 2.40 (s, 3H), 2.27 - 2.08 (m, 6H), 1.97 (d, J = 14.8 Hz, 2H).

[0283] Example 27 N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-2-methyl-2-azabicyclo[2.2.1]heptan-5-amine(27) Reaction scheme: [ka]

[0284] Experiment details: Step 1.1. N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-2-methyl-2-azabicyclo[2.2.1]heptan-5-amine(27). In an 8 mL reaction vial, N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-yl)-2-azabicyclo[2.2.1]heptan-5-amine (0.018 g, 31.93 μmol), paraformaldehyde (0.002 g, 66.60 μmol), acetic acid (0.015 g, 249.78 μmol), and methanol (1 mL) were added. The reaction mixture was stirred at room temperature for 12 hours, after which sodium cyanoboron anhydrous (0.037 g, 862.95 μmol) was added. The reaction was stirred at room temperature for 5 hours. The reaction was quenched with aq. Na2CO3 (10 mL), extracted with DCM (3 x 10 mL), and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: MeOH; flow rate: 40 mL / min; gradient: 50-70-90% B (2-30-60 mins); 270 nm; room temperature: 43.971-48.403 mins) to obtain N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-2-methyl-2-azabicyclo[2.2.1]heptan-5-amine (27) (0.004 g, 21.68%) as an off-white solid. LCMS: m / z = 578 [M+1] + . 1H NMR (400 MHz, DMSO) δ 7.39 (d, J = 8.3 Hz, 1H), 7.29 - 7.22 (m, 2H), 7.16 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 7.7 Hz, 1H), 6.52 (t, J = 6.2 Hz, 1H), 5.53 (d, J = 4.5 Hz, 1H), 4.38 (d, J = 6.2 Hz, 2H), 3.90 (s, 3H), 3.81 (q, J = 10.6 Hz, 2H), 3.12 (d, J = 12.6 Hz, 3H), 2.98 (s, 1H), 2.74 - 2.59 (m, 2H), 2.36 - 2.27 (m, 1H), 2.22 (d, J = 13.6 Hz, 3H), 2.01 - 1.83 (m, 1H), 1.69 (d, J = 8.8 Hz, 1H), 1.62 - 1.54 (m, 1H), 1.42 (d, J = 9.4 Hz, 1H), 1.23 (s, 1H).

[0285] Example 28 N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-2-azabicyclo[2.2.1]heptan-5-amine(28) Reaction scheme: [ka]

[0286] Experiment details: Step 1. tert-butyl 5-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-2-azabicyclo[2.2.1]heptan-2-carboxylate. In an 8 mL reaction vial, 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (0.061 g, 130.19 μmol), tert-butyl 5-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate (0.214 g, 1.01 mmol), titanium ethoxide (0.233 g, 1.021 mmol), and toluene (2 mL) were added. The reaction mixture was stirred at 100°C for 2 hours, then cooled to room temperature. The toluene was concentrated under vacuum. MeOH (3 mL) and anhydrous sodium cyanoboron (0.030 g, 699.69 μmol) were added to the residue. The reaction was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL), extracted with EA (3 x 30 mL), washed with brine (20 mL), dried on anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v = 1 / 3) to obtain tert-butyl 5-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-2-azabicyclo[2.2.1]heptan-2-carboxylate (.083 g, 96.03%) as a yellow solid. LCMS: m / z = 664 [M+1] + .

[0287] Step 2. N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-2-azabicyclo[2.2.1]heptan-5-amine(28). In an 8 mL reaction vial, tert-butyl 5-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-yl)amino)-2-azabicyclo[2.2.1]heptan-2-carboxylate (0.080 g, 120.52 μmol), DCM (3 mL), and 2,6-bis(1,1-dimethylethyl)pyridine (0.122 g, 637.70 μmol) were added. The reaction mixture was stirred at 0°C, and trimethylsilyl trifluoromethanesulfonate (0.161 g, 724.38 μmol) was added. The reaction was stirred at room temperature for 12 hours. The reaction was quenched with aq. Na2CO3 (10 mL), extracted with DCM (3 x 10 mL), and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 45-80-95-95%B (2-30-52-90 min); 270 nm; room temperature: 61.333-73.370 min) to obtain N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-2-azabicyclo[2.2.1]heptan-5-amine (28) (0.028 g, 41.21%) as an off-white solid. LCMS: m / z = 564 [M+1] + . 1H NMR (400 MHz, DMSO) δ 7.39 (d, J = 8.3 Hz, 1H), 7.30 - 7.21 (m, 2H), 7.15 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 7.7 Hz, 1H), 6.52 (t, J = 6.1 Hz, 1H), 5.61 (d, J = 6.1 Hz, 1H), 4.38 (d, J = 6.1 Hz, 2H), 3.96 - 3.73 (m, 5H), 3.10 (s, 3H), 2.69 - 2.61 (m, 1H) 2.14 - 1.95 (m, 1H), 1.57 (d, J = 23.6 Hz, 2H), 1.43 - 1.32 (m, 2H), 1.30 - 1.11 (m, 2H).

[0288] Example 29 N-(3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)-1H-indole-7-amine(29) Reaction scheme: [ka]

[0289] Experiment Details Step 1. 7-Nitro-1-(phenylsulfonyl)-1H-indole 7-nitro-1H-indole (5.04 g, 31.08 mmol) and tetrahydrofuran (200 mL) were placed in a 500 mL flask. Next, NaH (4.28 g, 178.35 mmol) was added gradually at 0°C. Then, benzenesulfonyl chloride (8.46 g, 47.89 mmol) in tetrahydrofuran (100 mL) was added. The reaction mixture was stirred at 0°C for a further 1 hour. The reaction was quenched with water (500 mL) and extracted with EA (2 x 200 mL). The organic layers were combined, washed with brine (200 mL), dried on anhydrous Na2SO4, and concentrated under vacuum. The crude product was recrystallized with heptane / EA (v / v = 20 / 1) to obtain 8.99 g (95.67%) of 7-nitro-1-(phenylsulfonyl)-1H-indole as a yellow solid. LCMS: m / z = 303 [M+1] + .

[0290] Step 2.1-(phenylsulfonyl)-1H-indole-7-amine 7-nitro-1-(phenylsulfonyl)-1H-indole (5.03 g, 16.64 mmol), methanol (80 mL), ammonium chloride (10.19 g, 190.50 mmol), and iron (4.77 g, 85.42 mmol) in water (10 mL) were placed in a 250 mL flask. The reaction mixture was stirred at 45°C for 2 hours, and the catalyst was removed by filtration. The filtrate was extracted with EA (2 x 100 mL). The organic layers were combined, washed with brine (100 mL), dried on anhydrous Na2SO4, and concentrated under vacuum. The residue was traced on a silica gel column eluted with EA / hexane (v / v = 2 / 5). As a result, 2.84 g (yield 62.68%) of 1-(phenylsulfonyl)-1H-indole-7-amine was obtained as a yellow solid. LCMS: m / z = 273 [M+1] + .

[0291] Step 3.1-(phenylsulfonyl)-N-(propa-2-in-1-yl)-1H-indole-7-amine In a nitrogen-purged 100 mL flask, 1-(phenylsulfonyl)-1H-indole-7-amine (2.002 g, 7.35 mmol), 3-bromopropylene (1.05 g, 8.83 mmol), cesium carbonate (7.313 g, 22.45 mmol), sodium iodide (3.357 g, 22.40 mmol), and N,N-dimethylformamide (50 mL) were added. The reaction mixture was stirred at 100°C for 24 hours, and then quenched with water (100 mL). The resulting solution was extracted with EA (2 x 100 mL). The organic layers were combined, washed with brine (100 mL), dried on anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by C18 chromatography column eluted with ACN / H2O (v / v = 1 / 1). As a result, 1.474 g of 1-(phenylsulfonyl)-N-(propa-2-in-1-yl)-1H-indole-7-amine was obtained as a yellow solid (yield 64.60%). LCMS: m / z = 311 [M+1] + .

[0292] Step 4. N-(prop-2-in-1-yl)-1H-indole-7-amine In a 25 mL flask purged with nitrogen and maintained in an inert atmosphere, 1-(phenylsulfonyl)-N-(propa-2-in-1-yl)-1H-indole-7-amine (0.500 g, 1.61 mmol), tetrahydrofuran (5 mL), and tetrabutylammonium fluoride (5 mL) were added. The reaction mixture was stirred at 80°C for 3 hours, and then the reaction was quenched with aqueous ammonium chloride solution (2 M, 30 mL). The resulting solution was extracted with EA (20 mL). The organic layers were combined, washed with brine (20 mL), dried on anhydrous Na2SO4, and concentrated under vacuum. The residue was traced on a silica gel column eluted with EA / hexane (v / v = 1 / 3). As a result, 0.117 g of N-(propa-2-in-1-yl)-1H-indole-7-amine was obtained as brown oil (yield 42.67%). LCMS: m / z = 171 [M+1] + .

[0293] Step 5. N-(3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)-1H-indole-7-amine(29) In a 25 mL flask purged and maintained under an inert nitrogen atmosphere, N-(propa-2-in-1-yl)-1H-indole-7-amine (0.044 g, 258.50 μmol), N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.099 g, 217.92 μmol), bis(triphenylphosphine)palladium(II) chloride (0.026 g, 36.83 μmol), cuprous iodide (0.009 g, 47.26 μmol), triethylamine (0.038 g, 375.53 μmol), and methyl sulfoxide (5 mL) were added. The reaction mixture was stirred at room temperature for 17 hours. The reaction was quenched by adding water (5 mL) and extracted with EA (2 x 5 mL). The organic layers were combined, washed with brine (10 mL), dried on anhydrous Na2SO4, and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: MeOH; flow rate: 70 mL / min; gradient: 55-90-100% B (2-30-40 min); 222 nm; room temperature: 36.225-37.590 min). As a result, 0.011 g (yield 9.10%) of N-(3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)-1H-indole-7-amine (29) was obtained as a white solid. LCMS: m / z = 497 [M+1] + . 1H NMR (400 MHz, DMSO) δ 10.64 (s, 1H), 7.29 - 7.22 (m, 2H), 7.14 (d, J = 7.5 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.86 (t, J = 7.6 Hz, 1H), 6.66 (d, J = 7.8 Hz, 1H), 6.47 (d, J = 7.6 Hz, 1H), 6.35 (s, 1H), 5.84 (s, 1H), 5.29 (d, J = 7.4 Hz, 1H), 4.43 (d, J = 5.7 Hz, 2H), 3.86 - 3.76 (m, 2H), 2.76 (d, J = 11.1 Hz, 2H), 2.17 (s, 3H), 1.99 (s, 2H), 1.88 (d, J = 13.8 Hz, 2H), 1.53 (d, J = 12.5 Hz, 2H), 1.23 (s, 1H).

[0294] Example 30 N-(3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)-3-(piperidine-4-yl)-1H-indole-7-amine(30) Reaction scheme: [ka]

[0295] Experiment details: Step 1: 3-iodo-7-nitro-1H-indole 7-nitro-1H-indole (2.09 g, 12.88 mmol), NIS (3.49 g, 15.51 mmol), and ACN (30 mL) were placed in a 100 ml three-necked flask. The reaction was stirred at 80°C for 1 hour. The reaction was quenched with Na2CO3aq (20 mL). The resulting solution was extracted with EA (3 x 50 mL), washed with brine (50 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. As a result, 2.86 g (9.92 mmol, 77.03% yield) of 3-iodo-7-nitro-1H-indole was obtained as a pale yellow solid. LCMS: m / z = 289 [M+1] + .

[0296] Step 2: 3-iodo-7-nitro-1-(phenylsulfonyl)-1H-indole 3-iodo-7-nitro-1H-indole (2.608 g, 9.05 mmol) and THF (30 mL) were placed in a 50 ml three-necked flask. The reaction mixture was cooled to 0°C. Next, NaH (0.522 g, mmol) was added while vigorously stirring at 0-5°C. Then, benzenesulfonyl chloride (2.071 g, 11.72 mmol) was added. The reaction was stirred at room temperature for about 1 hour. The reaction was quenched with water (20 mL). The resulting solution was extracted with EA (3 x 50 mL), washed with brine (50 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. As a result, 2.836 g (6.62 mmol, yield 73.14%) of 3-iodo-7-nitro-1-(phenylsulfonyl)-1H-indole was obtained as a pale yellow solid. LCMS: m / z = 429 [M+1] + .

[0297] Step 3: tert-butyl 4-(7-nitro-1-(phenylsulfonyl)-1H-indole-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate In a 100 ml three-necked flask, 3-iodo-7-nitro-1-(phenylsulfonyl)-1H-indole (2.401 g, 5.60 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.089 g, 9.90 mmol), Pd(dppf)Cl2 (0.836 g, 1.14 mmol), Na2CO3 (1.808 g, 17.05 mmol), water (4 mL), and 1,4-dioxane (20 mL) were added. The reaction mixture was stirred under nitrogen at 50°C for 5 hours. The resulting solution was extracted with EA (3 x 100 mL), washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v = 3 / 7). As a result, 1.585 g (3.27 μmol, yield 58.45%) of tert-butyl 4-(7-nitro-1-(phenylsulfonyl)-1H-indole-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate was obtained as a yellow solid. LCMS: m / z = 484 [M+1] + .

[0298] Step 4: tert-butyl 4-(7-amino-1-(phenylsulfonyl)-1H-indole-3-yl)piperidine-1-carboxylate In a 100 ml three-necked flask, tert-butyl 4-(7-nitro-1-(phenylsulfonyl)-1H-indole-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.901 g, 1.86 mmol), EA (8 mL), MeOH (2 mL), and Pd / C (0.738 g, 3.46 mmol) were added. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered through a Celite pad, and the filter cake was washed with methanol (3 x 20 mL). The filtrate was concentrated under reduced pressure to obtain the target product. As a result, tert-butyl 4-(7-amino-1-(phenylsulfonyl)-1H-indole-3-yl)piperidine-1-carboxylate was obtained as a slightly yellow solid of 0.789 g (1.73 mmol, 92.94% yield). LCMS: m / z = 456 [M+1] + .

[0299] Step 5: tert-butyl 4-(1-(phenylsulfonyl)-7-(propa-2-in-1-ylamino)-1H-indole-3-yl)piperidine-1-carboxylate In a 25 mL three-necked flask, tert-butyl 4-(7-amino-1-(phenylsulfonyl)-1H-indole-3-yl)piperidine-1-carboxylate (0.295 g, 647.54 μmol), 3-bromopropa-1-yin (0.082 g, 689.30 μmol), K2CO3 (0.266 g, 1.92 mmol), KI (0.219 g, 1.31 mmol), and NMP (5 mL) were added. The resulting solution was extracted with EA (3 x 20 mL), washed with brine (20 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v = 1 / 3). As a result, tert-butyl 4-(1-(phenylsulfonyl)-7-(propa-2-in-1-ylamino)-1H-indole-3-yl)piperidine-1-carboxylate was obtained as a yellow solid of 0.132 g (267.41 μmol, yield 41.29%). LCMS: m / z = 494 [M+1] + .

[0300] Step 6: tert-butyl 4-(7-(prop-2-in-1-ylamino)-1H-indole-3-yl)piperidine-1-carboxylate Methyl tert-butyl 4-(1-(phenylsulfonyl)-7-(propa-2-in-1-ylamino)-1H-indole-3-yl)piperidine-1-carboxylate (0.136 g, 275.51 mmol), tetrabutylammonium fluoride (72.03 g, 275.51 mmol), and THF (2 mL) were placed in a 25 mL three-necked flask. The reaction was stirred at 80°C for 0.5 hours. The reaction was quenched with NH4Cl aq (10 mL). The resulting solution was extracted with EA (3 x 20 mL), washed with brine (20 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. As a result, 0.096 g (271.60 μmol, 98.57% yield) of tert-butyl 4-(7-(propa-2-in-1-ylamino)-1H-indole-3-yl)piperidine-1-carboxylate was obtained as a yellow oil. LCMS: m / z = 354 [M+1] + .

[0301] Step 7: tert-butyl4-(7-((3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-1H-indole-3-yl)piperidine-1-carboxylate In a 25 mL three-necked flask, tert-butyl 4-(7-(propa-2-in-1-ylamino)-1H-indole-3-yl)piperidine-1-carboxylate (0.092 g, 260.28 μmol), N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.079 g, 173.89 μmol), Pd(PPh3)2Cl2 (0.038 g, 64.43 μmol), CuI (0.024 g, 128.41 μmol), DIEA (0.115 g, 892.05 μmol), and methyl sulfoxide (2 mL) were added. The reaction was stirred under a nitrogen atmosphere at room temperature for 16 hours. The reaction was quenched with water (5 mL). The resulting solution was extracted with EA (3 x 10 mL), washed with brine (10 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column elution with MeOH / DCM (v / v = 1 / 9). As a result, tert-butyl 4-(7-((3-(1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-1H-indole-3-yl)piperidine-1-carboxylate was obtained as brown oil in an amount of 0.073 g (107.37 μmol, yield 41.25%). LCMS: m / z = 680 [M+1] + .

[0302] Step 8 8 N-(3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)-3-(piperidine-4-yl)-1H-indole-7-amine(30) tert-butyl4-(7-((3-(1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-1H-indole-3-yl)piperidine-1-carboxylate (0.073 g, 107.37 μmol), TFA (1 mL), and DCM (1 mL) were placed in an 8 mL sealed tube. The mixture was purified by preparative HPLC (mobile phase A: water (0.1% ammonium hydroxide), mobile phase B: ACN; flow rate: 40 mL / min; gradient: 30-70-100-100%B (2-30-60-90 mins); 228 nm; room temperature: 36.80-39.49) to obtain the target product. As a result, 0.009 g (15.52 μmol, yield 14.45%) of N-(3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)-3-(piperidine-4-yl)-1H-indole-7-amine (30) was obtained as a white solid. LCMS: m / z = 580 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.37 - 7.21 (m, 2H), 7.14 (d, J = 8.0 Hz, 1H), 7.01 (s, 1H), 6.95 (d, J = 8.1 Hz, 1H), 6.84 (t, J = 7.7 Hz, 1H), 6.66 (d, J = 7.8 Hz, 1H), 6.47 (d, J = 7.4 Hz, 1H), 5.80 (t, J = 6.1 Hz, 1H), 5.29 (d, J = 8.0 Hz, 1H), 4.42 (d, J = 6.0 Hz, 2H), 3.82 - 3.76 (m, 2H), 3.02 (d, J = 12.0 Hz, 2H), 2.75 (d, J = 10.5 Hz, 2H), 2.69 - 2.60 (m, 3H), 2.17 (s, 3H), 1.99 (t, J = 11.5 Hz, 2H), 1.86 (d, J = 11.2 Hz, 4H), 1.54 (d, J = 11.2 Hz, 4H), 1.24 (s, 1H).

[0303] Example 31 N-(3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)-4-(methylsulfonyl)-1H-indole-7-amine(31) Reaction scheme: [ka]

[0304] Experiment details: Step 1.4 - Fluoroindoline. 4-fluoro-1H-indole (15.12 g, 111.88 mmol) and acetic acid (80 mL) were placed in a 250 mL flask. The reaction mixture was stirred at room temperature while adding sodium cyanoboron anhydrous (13.99 g, 326.29 mmol) in batches. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with H2O (200 mL), extracted with EA (3 x 100 mL), and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v = 1 / 1) to obtain 4-fluoroindoline (14.35 g, 93.51%) as a yellow solid. LCMS: m / z = 138 [M+1] + .

[0305] Step 2.1-(4-fluoroindoline-1-yl)ethane-1-one. Acetic anhydride (100 mL) was placed in a 250 mL flask. The reaction mixture was stirred at 0°C, and 4-fluoroindoline (14.41 g, 105.06 mmol) was added in a single addition. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with H2O (200 mL), extracted with EA (3 x 100 mL), and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v = 1 / 3) to obtain 1-(4-fluoroindoline-1-yl)ethane-1-one (12.16 g, 64.58%) as a yellow solid. LCMS: m / z = 180 [M+1] + .

[0306] Step 3.1-(4-fluoro-7-nitroindoline-1-yl)ethane-1-one. 1-(4-fluoroindolin-1-yl)ethane-1-one (6.07 g, 33.87 mmol) and sulfuric acid (50 mL) were placed in a 250 mL flask. The reaction mixture was stirred under a nitrogen atmosphere at -10°C, and nitric acid (3.0 g, 47.60 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with H2O (100 mL), extracted with EA (3 x 100 mL), and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v = 1 / 3) to obtain 1-(4-fluoro-7-nitroindolin-1-yl)ethane-1-one (1.67 g, 21.99%) as a yellow solid. LCMS: m / z = 225 [M+1] + .

[0307] Step 4.4-Fluoro-7-nitroindoline e. 1-(4-fluoro-7-nitroindoline-1-yl)ethane-1-one (2.146 g, 9.57 mmol) and hydrogen chloride (50 mL) were placed in a 250 mL flask. The reaction mixture was stirred at 100°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under vacuum. The reaction mixture was quenched with aq. Na2CO3 (50 mL), extracted with EA (3 x 100 mL), and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v = 1 / 1) to obtain 4-fluoro-7-nitroindoline (1.69 g, 96.98%) as a yellow solid. LCMS: m / z = 183 [M+1] + .

[0308] Step 5.4-fluoro-7-nitro-1H-indole. 4-fluoro-7-nitroindoline (1.351 g, 7.41 mmol), manganese oxide (6.319 g, 72.68 mmol), and chloroform (50 mL) were placed in a 250 mL flask. The reaction mixture was filtered, washed with EA (50 mL), and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v = 1 / 3) to obtain 4-fluoro-7-nitro-1H-indole (1.181 g, 88.39%) as a yellow solid. LCMS: m / z = 181 [M+1] + .

[0309] Step 6.4-Fluoro-7-nitro-1-(phenylsulfonyl)-1H-indole. 4-fluoro-7-nitro-1H-indole (1.184 g, 6.57 mmol) and DMF (30 mL) were placed in a 100 mL flask. The reaction mixture was stirred at 0°C under an N2 atmosphere, and NaH (0.459 g, 19.12 mmol) was added partially. The reaction mixture was stirred at room temperature for 30 minutes, and benzenesulfonyl chloride (2.541 g, 14.38 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with H2O (50 mL), extracted with EA (3 x 100 mL), and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v = 1 / 3) to obtain 4-fluoro-7-nitro-1-(phenylsulfonyl)-1H-indole (2.036 g, 96.71%) as a yellow solid. LCMS: m / z = 321 [M+1] + .

[0310] Step 7.4-(methylsulfonyl)-7-nitro-1-(phenylsulfonyl)-1H-indole. 4-fluoro-7-nitro-1-(phenylsulfonyl)-1H-indole (2.01 g, 6.27 mmol), sodium methanesulfinate (1.366 g, 13.38 mmol), and DMF (30 mL) were placed in a 100 mL flask. The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was cooled to room temperature, quenched with H2O (100 mL), extracted with EA (3 x 100 mL), and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v = 1 / 2) to obtain 4-(methylsulfonyl)-7-nitro-1-(phenylsulfonyl)-1H-indole (1.24 g, 51.94%) as a yellow solid. LCMS: m / z = 381 [M+1] + .

[0311] Step 8.4-(methylsulfonyl)-1-(phenylsulfonyl)-1H-indole-7-amine. In a 100 mL flask, 4-(methylsulfonyl)-7-nitro-1-(phenylsulfonyl)-1H-indole (1.19 g, 3.12 mmol), zinc (1.499 g, 22.92 mmol), NH4Cl (1.367 g, 25.55 mmol), ethanol (50 mL), and water (10 mL) were added. The reaction mixture was stirred at 70°C for 3 hours. The reaction mixture was filtered, washed with EA (50 mL), and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v = 1 / 3) to obtain 4-(methylsulfonyl)-1-(phenylsulfonyl)-1H-indole-7-amine (0.942 g, 85.93%) as a yellow solid. LCMS: m / z = 351 [M+1] + .

[0312] Step 9. tert-butyl(4-(methylsulfonyl)-1-(phenylsulfonyl)-1H-indole-7-yl)carbamate. In a 100 mL flask, 4-(methylsulfonyl)-1-(phenylsulfonyl)-1H-indole-7-amine (0.616 g, 1.75 mmol), di-tert-butyl dicarbonate (0.443 g, 2.02 mmol), TEA (0.659 g, 6.51 mmol), THF (10 mL), and N-(4-pyridyl)dimethylamine (0.041 g, 335.60 μmol) were added. The reaction mixture was stirred at room temperature for 2 hours, then quenched with H2O (30 mL), extracted with EA (3 x 50 mL), and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v = 1 / 2) to obtain tert-butyl N-[1-(benzenesulfonyl)-4-methylsulfonylindole-7-yl]carbamate (0.738 g, 93.18%) as a yellow solid. LCMS: m / z = 451 [M+1] + .

[0313] Step 10. tert-butyl(4-(methylsulfonyl)-1-(phenylsulfonyl)-1H-indole-7-yl)(propa-2-in-1-yl)carbamate. tert-butyl(4-(methylsulfonyl)-1-(phenylsulfonyl)-1H-indole-7-yl)carbamate (0.742 g, 1.64 mmol) and DMF (10 mL) were added to an 8 mL reaction vial. The reaction mixture was stirred at 0°C, and then NaH (0.221 g, 9.20 mmol) was partially added. The reaction mixture was stirred at room temperature for 30 minutes. 3-bromopropa-1-yin (0.888 g, 7.46 mmol) was added to the above mixture. The reaction was stirred at room temperature for 12 hours, then quenched with H2O (30 mL), extracted with EA (3 x 50 mL), and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v = 1 / 2) to obtain tert-butyl(4-(methylsulfonyl)-1-(phenylsulfonyl)-1H-indole-7-yl)(propa-2-in-1-yl)carbamate (0.533 g, 66.23%) as a yellow solid. LCMS: m / z = 489 [M+1]+.

[0314] Step 11.4-(methylsulfonyl)-1-(phenylsulfonyl)-N-(propa-2-in-1-yl)-1H-indole-7-amine. In a 50 mL flask, tert-butyl(4-(methylsulfonyl)-1-(phenylsulfonyl)-1H-indole-7-yl)(propa-2-in-1-yl)carbamate (0.456 g, 933.32 μmol), DCM (6 mL), and trifluoroacetic acid (2 mL) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with aq. Na2CO3 (20 mL), extracted with DCM (3 x 30 mL), and concentrated under vacuum. The crude product was purified by prep-TLC using DCM / MeOH (v / v = 20 / 1) to obtain 4-(methylsulfonyl)-1-(phenylsulfonyl)-N-(propa-2-in-1-yl)-1H-indole-7-amine (0.050 g, 13.79%) as a yellow solid. LCMS: m / z = 389 [M+1] + .

[0315] Step 12.4-(methylsulfonyl)-1-(phenylsulfonyl)-N-(propa-2-in-1-yl)-1H-indole-7-amine. 4-(methylsulfonyl)-1-(phenylsulfonyl)-N-(propa-2-in-1-yl)-1H-indole-7-amine (0.049 g, 126.13 μmol), TBAF (1 M in THF) (2 mL), and THF (0.5 mL) were added to an 8 mL reaction vial. The reaction mixture was stirred at 80°C for 1 hour. The reaction was quenched with H₂O (10 mL), extracted with EA (3 x 30 mL), and concentrated under vacuum. The crude product was purified by prep-TLC using DCM / MeOH (v / v = 20 / 1) to obtain 4-(methylsulfonyl)-N-(propa-2-in-1-yl)-1H-indole-7-amine (0.023 g, 73.43%) as a yellow solid. LCMS: m / z = 249 [M+1] + .

[0316] Step 13. N-(3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)-4-(methylsulfonyl)-1H-indole-7-amine(31). To an 8 mL reaction vial, N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.050 g, 110.06 μmol), 4-(methylsulfonyl)-N-(propa-2-in-1-yl)-1H-indole-7-amine (0.021 g, 84.57 μmol), bis(triphenylphosphine)palladium(II) chloride (0.018 g, 25.49 μmol), N,N-diisopropylethylamine (0.031 g, 239.85 μmol), CuI (0.015 g, 78.76 μmol), and methyl sulfoxide (2 mL) were added. The reaction was stirred at room temperature under an N2 atmosphere for 1 hour. The reaction was quenched with H2O (10 mL), extracted with EA (3 x 20 mL), and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: ACN; flow rate: 40 mL / min; gradient: 25-55-80%B (2-30-60 min); 228 nm; room temperature: 36.803-39.498 min) to obtain N-(3-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)-4-(methylsulfonyl)-1H-indole-7-amine (31) (0.007 g, 11.06%) as an off-white solid. LCMS: m / z = 575 [M+1] + . 1H NMR (400 MHz, DMSO) δ 11.30 (s, 1H), 7.52 (d, J = 3.0 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H), 6.88 (s, 1H), 6.67 (t, J = 5.8 Hz, 2H), 6.61 (d, J = 8.3 Hz, 1H), 5.31 (d, J = 8.0 Hz, 1H), 4.56 (d, J = 3.8 Hz, 2H), 3.84 (q, J = 11.1 Hz, 2H), 3.05 (s, 3H), 2.75 (d, J = 11.4 Hz, 2H), 2.53 (s, 1H), 2.18 (d, J = 13.8 Hz, 3H), 1.98 (t, J = 10.9 Hz, 2H), 1.88 (d, J = 11.4 Hz, 2H), 1.54 (dd, J = 21.3, 10.4 Hz, 2H).

[0317] Example 32 N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-3-methyl-3-azabicyclo[3.2.0]heptan-6-amine(32) Reaction scheme: [ka]

[0318] Experiment Details Step 1. tert-butyl 6-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-3-azabicyclo[3.2.0]heptan-3-carboxylate. 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (0.099 g, 211.31 μmol) and tert-butyl 6-oxo-3-azabicyclo[3.2.0]heptane-3-carboxylate (0.250 g, 1.18 mmol) were placed in a 4 mL bale. After cooling to room temperature, sodium borohydride (211 mg, 3.43 mmol), acetic acid (0.01 μmol), and ethanol (0.5 mL) were added. The reaction mixture was stirred at room temperature for 1 hour. LC-MS indicated the completion of the reaction. The reaction product was concentrated under vacuum, purified by C18 column, and eluted with ACN / water (v / v = 1 / 3) to obtain tert-butyl6-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-yl)amino)-3-azabicyclo[3.2.0]heptan-3-carboxylate (0.288 g, 433.89 μmol, 205.33% yield) as a clear oil. LC-MS: m / z = 664[M+1] + .

[0319] Step 2. N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-3-azabicyclo[3.2.0]heptan-6-amine. In a 4 mL flask, tert-butyl 6-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-yl)amino)-3-azabicyclo[3.2.0]heptan-3-carboxylate (0.208 g, 313.36 μmol) and HCl (g) in HCl (1 M, 0.5 mL) were added, and the mixture was stirred at room temperature for 1 hour. LC-MS indicated that the reaction was complete, and the reaction was quenched with sat.NaHCO3 aq. to pH 8-9 at 0°C, and extracted with EA (3 mL x 3). The combined organic layers were sequentially washed with water (3 mL) and brine (3 mL), separated, and concentrated under vacuum. The residue was purified using a C18 column and eluted with ACN / water (v / v = 1 / 2) to obtain N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-3-azabicyclo[3.2.0]heptan-6-amine. LCMS: m / z = 564[M+1] + .

[0320] Step 3. N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-3-methyl-3-azabicyclo[3.2.0]heptan-6-amine(32). In a 4 mL flask, N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-yl)-3-azabicyclo[3.0]heptan-6-amine (0.047 g, 70.81 μmol), paraformaldehyde (0.004 g, 133.22 μmol), anhydrous sodium cyanoboron (37 mg, 606.40 μmol), EtOH (0.5 mL), and glacial acetic acid (0.01 mL) were added. The reaction mixture was stirred overnight at room temperature. LC-MS indicated that the reaction was complete. The reaction was quenched with water (4 mL) and extracted with EA (2 mL x 2). The combined organic layers were successively washed with water (2 mL) and brine (2 mL), separated, and concentrated under vacuum. The residue was purified by prep-HPLC (mobile phase A: water (ammonium hydroxide), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 50-85-100% B (2-30-60 min); 270 nm; room temperature: 38.379-39.803 min) to obtain N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-3-methyl-3-azabicyclo[3.2.0]heptan-6-amine(32) (5 mg, 8.66 μmol, yield 12.22%) as an off-white solid. LCMS: m / z = 578[M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 7.41 - 7.38 (m, 1H), 7.28 - 7.23 (m, 2H), 7.19 - 7.15 (m, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.53 - 6.47 (m, 2H), 5.33 (d, J = 7.4 Hz, 1H), 4.39 (d, J = 6.2 Hz, 2H), 4.12 - 4.08 (m, 1H), 3.90 (s, 3H), 3.84 - 3.79 (m, 2H), 3.10 (s, 3H), 2.72 (d, J = 9.1Hz, 1H), 2.64 - 2.58 (m, 2H), 2.27 (s, 3H), 1.99 - 1.94 (m, 2H), 1.86 - 1.81 (m, 2H).

[0321] Example 33 N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-7-methyl-7-azaspiro[3.5]nonane-2-amine(33) Reaction scheme: [ka]

[0322] Experiment Details Step 1. tert-butyl 2-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-7-azaspiro[3.5]nonane-7-carboxylate Titanium ethoxide (0.072 g, 315.64 μmol), 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (0.061 g, 130.20 μmol), tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (0.164 g, 685.30 μmol), and toluene (2 mL) were added to an 8 mL flask. The reaction mixture was stirred at 110°C for 2 hours. The reaction mixture was concentrated under vacuum and dissolved in methanol (2 mL). Next, sodium cyanoboron anhydrous (0.034 g, 792.99 μmol) was added. The reaction mixture was stirred at room temperature for a further 15 hours. The reaction was quenched by adding water (10 mL) and extracted with EA (2 x 10 mL). The organic layers were combined, washed with brine (10 mL), dried on anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted with EA / heptane (v / v = 1 / 3) and traced on a silica gel column. As a result, 0.080 g (yield 88.82%) of tert-butyl 2-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-7-azaspiro[3.5]nonane-7-carboxylate was obtained as a yellow oil. LCMS: m / z = 692 [M+1] + .

[0323] Step 2. N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-7-azaspiro[3.5]nonane-2-amine tert-butyl 2-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-7-azaspiro[3.5]nonane-7-carboxylate (0.079 g, 114.19 μmol) and hydrogen chloride (4 M, 2 mL in EA) were added to an 8 mL flask. The reaction mixture was stirred at room temperature for 0.5 hours, after which saturated sodium bicarbonate aqueous solution was added until the pH reached 7-8. The resulting solution was extracted with EA (2 x 10 mL). The organic layers were combined, washed with brine (10 mL), dried on anhydrous Na2SO4, and concentrated under vacuum. As a result, 0.067 g of N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-7-azaspiro[3.5]nonane-2-amine was obtained as a yellow solid (yield 99.16%). LCMS: m / z = 592[M+1] + .

[0324] Step 3. N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-7-methyl-7-azaspiro[3.5]nonane-2-amine(33) In an 8 mL flask, N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-7-azaspiro[3.5]nonan-2-amine (0.066 g, 111.54 μmol), paraformaldehyde (0.007 g, 233.13 μmol), methanol (4 mL), and acetic acid (0.1 mL) were added. The reaction mixture was stirred at room temperature for 19 hours, after which sodium cyanoboron anhydrous (0.009 g, 209.91 μmol) was added. The reaction mixture was stirred at room temperature for a further 4 hours. The reaction was quenched by adding water (2 mL) and extracted with EA (2 x 5 mL). The organic layers were combined, washed with brine (10 mL), and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: MeOH; flow rate: 40 mL / min; gradient: 50-80-100% B (2-30-60 min); 278 nm; room temperature: 39.752-43.259). This yielded 0.002 g (yield 2.96%) of N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-7-methyl-7-azaspiro[3.5]nonane-2-amine (33) as a white solid. LCMS: m / z = 606 [M+1] + .

[0325] Example 34 3-Fluoro-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine(34) Reaction scheme: [ka]

[0326] Experiment details: Step 1. tert-butyl 3,3-difluoro-4-((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate 2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (0.506 g, 1.42 mmol), tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (1.053 g, 4.48 mmol), and TMSCl (1.680 g, 15.46 mmol) were degassed in DMF (10 mL), purged with N2 (g), and then BH3.THF (1 M, 15 mL) was added. The mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with water (20 mL) at 0°C and extracted with EA (60 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with EA / hexane (v / v = 1 / 2) to obtain tert-butyl 3,3-difluoro-4-((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (0.932 g, crude) as a small amount of yellow oil. LCMS: m / z = 577 [M+1] +

[0327] Step 2.3,3-Difluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidine-4-amine In a 100 mL round-bottom flask, tert-butyl 3,3-difluoro-4-((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (0.871 g, 1.51 mmol), DCM (10 mL), and TFA (2 mL) were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH = 9 with NaHCO3 (aq.) and extracted with EA (100 mL x 2). The combined organic layers were washed with brine (40 mL), separated, and concentrated under vacuum. As a result, 0.656 g (91.15%) of 3,3-difluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidine-4-amine was obtained as a yellow oil. LCMS: m / z = 477 [M+1] + .

[0328] Step 3.3-Fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine To a solution of 3,3-difluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidine-4-amine (0.628 g, 1.32 mmol) in 10 mL of MeOH, paraformaldehyde (0.082 g, 2.73 mmol) was added. The mixture was stirred at room temperature for 0.5 hours, after which NaBH3CN (0.289 g, 6.74 mmol) and HOAc (0.002 mL) were added. The reaction mixture was stirred at room temperature for 12 hours. The residue was purified by silica gel column and eluted with EA / hexane (v / v = 1 / 2) to obtain 3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.544 g, 84.15% yield) as a yellow oil. LCMS: m / z = 491 [M+1] +

[0329] Step 4.3-Fluoro-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine(34) In an 8 mL sealed tube purged and maintained under an inert nitrogen atmosphere, 3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.097 g, 0.20 mmol), 2-methoxy-4-(methylsulfonyl)-N-(propa-2-in-1-yl)aniline (0.090 g, 0.38 mmol), Pd(dppf)Cl2 (0.029 g, 0.04 mmol), CuI (0.035 g, 0.18 mmol), DIEA (0.077 g, 0.60 mmol), and DMSO (2 mL) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding water (80 mL) and extracted with EA (80 mL x 2). The combined organic layers were washed with brine (20 mL), separated, and concentrated under vacuum. The residue was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: MeOH; flow rate: 60 mL / min; gradient: 50-80-100% B (2-30-60 min); 244 nm; room temperature: 35.560-37.110 min) to obtain 3-fluoro-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (34) (0.053 g, 44.52% yield) as a white solid. LCMS: m / z = 602 [M+1] + 1H NMR (400 MHz, MeOD) δ 7.49 (d, J = 8.4 Hz, 1H), 7.33 - 7.23 (m, 2H), 7.18 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.83 (s, 1H), 4.41 (s, 2H), 3.99 (d, J = 11.2 Hz, 1H), 3.95 (s, 3H), 3.72 - 3.63 (m, 2H), 3.11 (d, J = 9.2 Hz, 1H), 3.07 (s, 3H), 2.90 (d, J = 8.0 Hz, 1H), 2.60 - 2.44 (m, 1H), 2.37 (s, 3H), 2.35 - 2.25 (m, 1H), 2.06 (d, J = 13.2 Hz, 1H), 1.98 - 1.84 (m, 1H).

[0330] Example 35 Diethyl(4-((3-(7-(((Z)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxyphenyl)phosphine oxide (racemic mixture) (35) Reaction scheme: [ka]

[0331] Experiment details: Step 1. (4-amino-3-methoxyphenyl)diethylphosphine oxide In a 20 mL sealed tube purged and maintained under an inert nitrogen atmosphere, 4-bromo-2-methoxyaniline (0.981 g, 4.86 mmol), diethylphosphine oxide (1.039 g, 9.79 mmol), Pd(OAc)2 (0.411 g, 1.83 mmol), xanthophos (0.381 g, 0.66 mmol), DIEA (1.841 g, 14.24 mmol), and DMF (10 mL) were added. The reaction mixture was stirred at 120°C for 2 hours. The reaction mixture was quenched by adding water (80 mL) and extracted with EA (80 mL x 2). The combined organic layers were washed with brine (40 mL), separated, and concentrated under vacuum. The mixture was purified by eluting with ACN / water (v / v = 1 / 8) using a C18 column to obtain 0.775 g (70.24%) of (4-amino-3-methoxyphenyl)diethylphosphine oxide as a colorless oil. LCMS: m / z = 228 [M+1] +

[0332] Step 2. Diethyl (3-methoxy-4-(propa-2-in-1-ylamino)phenyl)phosphine oxide A mixture of (4-amino-3-methoxyphenyl)diethylphosphine oxide (0.423 g, 1.86 mmol), 3-bromopropa-1-yne (0.219 g, 1.84 mmol), NaI (0.227 g, 1.51 mmol), and K2CO3 (0.578 g, 4.18 mmol) in NMP (10 mL) was degassed, purged three times with N2, and the mixture was stirred at 80°C for 48 hours. The reaction mixture was purified by eluting with ACN / water (v / v = 1 / 3) on a C18 column to obtain 0.172 g (34.83%) of diethyl(3-methoxy-4-(propa-2-in-1-ylamino)phenyl)phosphine oxide as a colorless oil. LCMS: m / z = 266 [M+1] +

[0333] Step 3. Diethyl(4-((3-(7-(((Z)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxyphenyl)phosphine oxide (racemic mixture) (35) (Z)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.098 g, 0.21 mmol), diethyl(3-methoxy-4-(propa-2-in-1-ylamino)phenyl)phosphine oxide (0.098 g, 0.37 mmol), Pd(dppf)Cl2 (0.021 g, 0.03 mmol), CuI (0.048 g, 0.25 mmol), DIEA (0.099 g, 0.77 mmol), and DMSO (1 mL) were placed in an 8 mL sealed tube and purged under an inert nitrogen atmosphere. The reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was quenched by adding water (20 mL) and extracted with EA (20 mL x 2). The combined organic layers were washed with brine (10 mL), separated, and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: MeOH; flow rate: 50 mL / min; gradient: 35-65-95% B (2-30-60 min); 236 nm; room temperature: 38.125-42.75 min) to obtain diethyl(4-((3-(7-(((Z)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxyphenyl)phosphine oxide (racemic) (35). LCMS: m / z = 610 [M+1] + 1H NMR (400 MHz, DMSO) δ 7.26 (d, J = 7.3 Hz, 1H), 7.25 - 7.12 (m, 2H), 7.08 (d, J = 10.2 Hz, 1H), 6.86 (d, J = 6.1 Hz, 1H), 6.78 (d, J = 6.7 Hz, 1H), 6.07 (s, 1H), 5.15 (d, J = 7.9 Hz, 1H), 4.80 (d, J = 49.5 Hz, 1H), 4.35 (s, 2H), 3.84 (s, 3H), 3.82 - 3.71 (m, 2H), 3.71 - 3.55 (m, 1H), 3.13 - 2.95 (m, 1H), 2.80 (d, J = 8.7 Hz, 1H), 2.27 (d, J = 12.5 Hz, 1H), 2.18 (s, 3H), 2.13 - 2.04 (m, 1H), 1.99 - 1.68 (m, 6H), 1.05 - 0.82 (m, 6H).

[0334] Example 36 1-(2-fluoroethyl)-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidine-4-amine(36) Reaction scheme [ka]

[0335] Experiment Details Step 1. 1-(2-fluoroethyl)-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidine-4-amine(36) The mixture was placed in a 4 mL sealed tube and kept under an inert nitrogen atmosphere. N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidine-4-amine (0.040 g, 72.51 μmol), 1-fluoro-2-iodoethane (0.025 g, 143.71 μmol), K2CO3 (0.063 g, 455.86 μmol), and acetonitrile (1 mL) were added. The reaction mixture was stirred at 50°C for a long time. The resulting solution was added to water (10 mL). The resulting solution was extracted with EA (2 x 10 mL), the organic layers were combined, dried on anhydrous Na2SO4, and the residue was concentrated under vacuum. The crude product was purified by pre-HPLC using MeCN / H2O (0.1% ammonium hydroxide): 70 mL / min; gradient: 40-75-100% B (2-30-60 mins); 263 nm; room temperature: 33.540-34.450 mins. As a result, 0.018 g (41.54% yield) of 1-(2-fluoroethyl)-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidine-4-amine (36) was obtained as a white solid. LCMS: m / z = 598 [M+1] + 1H NMR (400 MHz, DMSO) δ 7.40 (dd, J = 8.3, 1.6 Hz, 1H), 7.35 - 7.20 (m, 2H), 7.14 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 7.8 Hz, 1H), 6.52 (t, J = 6.2 Hz, 1H), 5.32 (d, J = 8.0 Hz, 1H), 4.59 (t, J = 4.8 Hz, 1H), 4.47 (t, J = 4.9 Hz, 1H), 4.38 (d, J = 6.2 Hz, 2H), 3.90 (s, 3H), 3.86 - 3.71 (m, 2H), 3.10 (s, 3H), 2.89 (d, J = 11.8 Hz, 2H), 2.65 (t, J = 4.9 Hz, 1H), 2.58 (t, J = 4.9 Hz, 1H), 2.14 (t, J = 11.1 Hz, 2H), 1.90 (d, J = 11.4 Hz, 2H), 1.54 (dd, J = 20.8, 11.3 Hz, 2H), 1.24 (s, 1H).

[0336] Example 37 N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-(2,2,2-trifluoroethyl)piperidine-4-amine(37) Reaction scheme [ka]

[0337] Experiment Details Step 1. N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-(2,2,2-trifluoroethyl)piperidine-4-amine(37) The mixture was placed in a sealed tube and kept under an inert nitrogen atmosphere. N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidine-4-amine (0.023 g, 41.69 μmol), 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.017 g, 73.24 μmol), Cs2CO3 (0.028 g, 85.94 μmol), and acetonitrile (1 mL) were added. The reaction mixture was stirred at room temperature for 2 hours. The resulting solution was added to water (10 mL). The resulting solution was extracted with EA (2 x 10 mL), the organic layers were combined, dried on anhydrous Na2SO4, and the residue was concentrated under vacuum. The crude product was purified by pre-HPLC using MeOH / H2O (0.1% ammonium hydroxide): 40 mL / min; gradient: 45-75-100% B (2-30-60 mins); 270 nm; room temperature: 38.379-40.311 mL / min. As a result, 0.016 g (yield 60.56%) of N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-(2,2,2-trifluoroethyl)piperidine-4-amine (37) was obtained as a white solid. LCMS: m / z = 634 [M+1] + 1H NMR (400 MHz, DMSO) δ 7.39 (d, J = 6.9 Hz, 1H), 7.25 (t, J = 7.8 Hz, 2H), 7.15 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 7.8 Hz, 1H), 6.52 (t, J = 6.0 Hz, 1H), 5.30 (d, J = 8.0 Hz, 1H), 4.38 (d, J = 6.1 Hz, 2H), 3.90 (s, 2H), 3.80 (dd, J = 21.9, 10.9 Hz, 2H), 3.64 (d, J = 12.7 Hz, 2H), 3.17 (dd, J = 20.5, 10.3 Hz, 3H), 3.10 (s, 4H), 2.93 (d, J = 11.6 Hz, 2H), 1.89 (d, J = 11.1 Hz, 2H), 1.55 (dd, J = 20.5, 11.4 Hz, 2H).

[0338] Example 38 N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidine-4-amine(38) Reaction scheme [ka]

[0339] Experiment Details Step 1. tert-butyl 4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate In a 40 mL sealed tube kept under an inert nitrogen atmosphere, 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (0.303 g, 0.65 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (0.646 g, 3.24 mmol), titanium ethoxide (0.754 g, 3.29 mmol), and toluene (4 mL) were added. The reaction mixture was stirred at 110°C for 2 hours. Sodium cyanoborohydride (0.170 g, 2.75 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum, and the residue was applied to a silica gel column eluted with EA / hexane (v / v = 1 / 1). As a result, 0.348 g of tert-butyl 4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate was obtained as a yellow solid (yield 82.56%). LCMS: m / z = 652 [M+1] +

[0340] Step 2. N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidine-4-amine(38) In a 25 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, tert-butyl 4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (0.336 g, 0.52 mmol) and EA (3 mL) were added. After stirring the reaction mixture at room temperature, hydrochloric acid (3 mL, 4 M) in the EA was added to the reactants, and the mixture was stirred at room temperature for 2 hours. The resulting solution was added to saturated sodium bicarbonate aqueous solution (20 mL). The resulting solution was extracted with EA (2 x 30 mL), the organic layers were combined, dried over anhydrous Na2SO4, and the residue was concentrated under vacuum. One-quarter of the obtained crude product was further purified by pre-HPLC in MeOH / H2O (0.1% ammonium hydroxide), flow rate: 25 mL / min; gradient: 40-70-100% B (2-30-60 mins), 220 nm; room temperature: 32.890-37.835 mins. As a result, 0.028 g (yield 49.30%) of N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidine-4-amine (38) was obtained as a yellow solid. LCMS: m / z = 552 [M+1] + 1H NMR (400 MHz, DMSO) δ 7.39 (d, J = 8.3 Hz, 1H), 7.25 (dd, J = 7.7, 4.8 Hz, 2H), 7.14 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.65 (t, J = 16.6 Hz, 1H), 6.52 (t, J = 6.3 Hz, 1H), 5.33 (d, J = 7.9 Hz, 1H), 4.38 (d, J = 6.2 Hz, 2H), 3.90 (s, 3H), 3.80 (dd, J = 22.0, 11.0 Hz, 2H), 3.42 (s, 2H), 3.10 (s, 3H), 2.97 (t, J = 16.5 Hz, 2H), 2.68 - 2.52 (m, 2H), 1.88 (d, J = 11.1 Hz, 2H), 1.39 (dd, J = 20.0, 11.3 Hz, 2H).

[0341] Example 39 cis-N-(4-(2-oxa-6-azaspiro[3.3]heptane-6-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine(39) and trans-N-((1R,4R)-4-(2-oxa-6-azaspiro[3.3]heptane-6-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine(39b) Reaction scheme [ka]

[0342] Step 1. Synthesis of 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine. In a 50 mL flask, 2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine (0.620 g, 1.82 mmol), 4-(methylsulfonyl)-N-(propa-2-in-1-yl)aniline (0.457 g, 1.90 mmol), bis(triphenylphosphine)palladium(II) chloride (0.240 g, 339.97 μmol), N,N-diisopropylethylamine (0.458 g, 3.54 mmol), CuI (0.177 g, 929.37 μmol), and methyl sulfoxide (20 mL) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with H2O (30 mL), extracted with EA (50 mL x 3), and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v = 1 / 1) to obtain 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine (0.545 g, 66.21%) as a yellow solid. LCMS: m / z = 452 [M+1] + .

[0343] Step 2.2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-N-(1,4-dioxaspiro[4.5]decane-8-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine. 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine (0.545 g, 1.20 mmol), 1,4-dioxaspiro[4.5]decan-8-one (0.574 g, 3.67 mmol), titanium ethoxide, and toluene (10 mL) were placed in a 50 mL flask. The reaction mixture was stirred at 100°C for 2 hours, then cooled to room temperature. The reaction mixture was concentrated under vacuum. EtOH (5 mL) and anhydrous sodium cyanoboron (0.392 g, 9.1427 mmol) were added to the residue. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with H2O (10 mL), extracted with EA (3 x 30 mL), and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v = 1 / 1) to obtain 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-N-(1,4-dioxaspiro[4.5]decane-8-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine (0.626 g, 87.64%) as a yellow solid. LCMS: m / z = 592 [M+1] + .

[0344] Step 3.4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-in-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-yl)amino)cyclohexane-1-one. In a 50 mL flask, 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-N-(1,4-dioxaspiro[4.5]decane-8-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine (0.731 g, 1.23 mmol), 4-methylbenzenesulfonic acid hydrate (2.002 g, 10.52 mmol), acetonitrile (10 mL), and water (5 mL) were added. The reaction mixture was stirred at room temperature under an N2 atmosphere for 1 hour. The reaction was quenched with H2O (30 mL), extracted with EA (3 x 50 mL), and concentrated under vacuum. The crude product was purified by silica gel column elution with EA / hexane (v / v = 3 / 1) to obtain 4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-yl)amino)cyclohexane-1-one (0.402 g, 59.41%) as a yellow solid. LCMS: m / z = 548 [M+1] + .

[0345] Step 4. cis-N-(4-(2-oxa-6-azaspiro[3.3]heptane-6-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine(39) and trans-N-(4-(2-oxa-6-azaspiro[3.3]heptane-6-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine(39b). In a 25 mL flask, 4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-yl)amino)cyclohexane-1-one (0.219 g, 399.93 μmol), 2-oxa-6-azaspiro[3.3]heptane (0.145 g, 1.4627 mmol), acetic acid (0.264 g, 4.39 mmol), and MeOH (5 mL) were added. The reaction mixture was stirred at room temperature for 12 hours, and sodium cyanoboron anhydrous (0.392 g, 9.1427 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with H2O (10 mL), extracted with EA (3 x 30 mL), and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: CAN; flow rate: 70 mL / min; gradient: 30-60-60% B (2-32-60 min), 248 nm; room temperature: 30.513-32.468 and room temperature: 34.848-36.835 min) to obtain cis-N-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine(39) (0.027 g, 10.70%) as an off-white solid. LCMS: m / z = 631 [M+1] + . 1H NMR (400 MHz, DMSO) δ 7.38 (d, J = 8.3 Hz, 1H), 7.25 (s, 1H), 7.06 (s, 1H), 6.98 (t, J = 7.9 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H), 6.49 (t, J = 6.0 Hz, 1H), 6.12 (d, J = 7.8 Hz, 1H), 5.44 (d, J = 8.0 Hz, 1H), 4.91 (q, J = 8.8 Hz, 2H), 4.58 (s, 4H), 4.35 (d, J = 6.1 Hz, 2H), 3.89 (s, 3H), 3.21 (s, 5H), 3.09 (s, 3H), 1.96 (d, J = 11.1 Hz, 2H), 1.86 (t, J = 10.5 Hz, 1H), 1.71 (d, J = 11.3 Hz, 2H), 1.19 (dd, J = 24.1, 11.5 Hz, 2H), 0.99 (dd, J = 23.4, 10.9 Hz, 2H).

[0346] Then, trans-N-(4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine(39b) (0.023 g, 9.11%) was obtained as an off-white solid. LCMS: m / z = 631 [M+1] + . 1H NMR (400 MHz, DMSO) δ 7.38 (d, J = 8.2 Hz, 1H), 7.25 (s, 1H), 7.12 (s, 1H), 6.97 (t, J = 7.9 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 8.1 Hz, 1H), 6.49 (t, J = 6.0 Hz, 1H), 6.12 (d, J = 7.8 Hz, 1H), 5.48 (d, J = 8.0 Hz, 1H), 4.90 (q, J = 8.9 Hz, 2H), 4.59 (s, 4H), 4.35 (d, J = 6.0 Hz, 2H), 3.89 (s, 3H), 3.20 (s, 4H), 3.09 (s, 3H), 2.09 (d, J = 12.5 Hz, 1H), 1.69 - 1.46 (m, 6H), 1.39 (s, 2H), 1.23 (s, 1H).

[0347] Example 40 4-((3-(7-(((Z)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxybenzenesulfonamide (racemic mixture) (40) Reaction scheme: [ka]

[0348] Experiment Details Step 1. (Z)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidine-4-amine (racemic mixture). In a 500 mL round-bottom flask, tert-butyl(Z)-3-fluoro-4-((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (racemic mixture) (16.02 g, 28.69 mmol), DCM (150 mL), and TFA (50 mL) were added. The reaction was quenched with saturated aqueous solution of NaHCO3 (100 mL) and extracted with EA (3 x 100 mL). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. As a result, 14.04 g (crude) of (Z)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidine-4-amine (racemic mixture) was obtained as an off-white solid. LCMS: m / z = 459 [M+1] + .

[0349] Step 2. (Z)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (racemic mixture). In a 500 mL round-bottom flask, (Z)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidine-4-amine (racemic) (13.962 g, 30.47 mmol), polyoxymethylene (1.575 g, 52.45 mmol), anhydrous sodium cyanoboron (11.745 g, 189.94 mmol), MeOH (150 mL), and HOAc (30 mL) were added. The reaction mixture was stirred overnight at room temperature. The reaction was quenched with saturated aqueous NaHCO3 (100 mL), extracted with EA (3 x 100 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column elution with MeOH / DCM (v / v = 1 / 20). As a result, (Z)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (racemic mixture) was obtained as an off-white solid in an amount of 8.513 g (yield 59.43%). LCMS: m / z = 473 [M+1] + .

[0350] Step 3.4-((3-(7-(((Z)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxybenzenesulfonamide (racemic mixture) (40). In a 25 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, (Z)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (racemic) (0.119 g, 251.97 μmol), 3-methoxy-4-(propa-2-in-1-ylamino)benzenesulfonamide (0.094 g, 391.21 μmol), bis(triphenylphosphine)palladium(II) chloride (0.051 g, 72.25 μmol), CuI (0.044 g, 231.03 μmol), DIEA (0.159 g, 1.23 mmol), and methyl sulfoxide (5 mL) were added. The mixture was stirred at 60°C for 2 hours under a nitrogen atmosphere. The reaction was quenched with water (20 mL) and extracted with EA (30 mL). The combined organic layer was washed with brine (30 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: MeOH; flow rate: 70 mL / min; gradient: 50-90-100% B (2-30-40 min); 270 nm; room temperature: 26.258-28.090 min) to obtain the target product. As a result, 0.072 g (48.88% yield) of 4-((3-(7-(((Z)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxybenzenesulfonamide (racemic mixture) (40) was obtained as a yellow solid. LCMS: m / z = 585 [M+1] + . 1H NMR (400 MHz, methanol-d4) δ 7.50 - 7.43 (m, 1H), 7.36 - 7.26 (m, 2H), 7.20 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 4.38 (s, 2H), 3.93 (s, 3H), 3.80 - 3.63 (m, 3H), 3.22 (d, J = 23.6 Hz, 2H), 2.95 (d, J = 11.6 Hz, 1H), 2.33 - 2.12 (m, 5H), 2.02 - 1.90 (m, 2H).

[0351] Example 41 4-((3-(7-(((3R,4S)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxy-N-methylbenzamide (racemic mixture) (41) Reaction scheme: [ka]

[0352] Experiment Details Step 1.4-((3-(7-(((3R,4S)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxy-N-methylbenzamide (racemic mixture) (41) In an 8 mL vial purged and maintained under an inert nitrogen atmosphere, (3R,4S)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (racemic) (0.137 g, 290.08 μmol), cuprous iodide (0.015 g, 78.76 μmol), 3-methoxy-N-methyl-4-(propa-2-in-1-ylamino)benzamide (0.119 g, 545.24 μmol), bis(triphenylphosphine)palladium(II) chloride (0.023 g, 32.5813 μmol), triethylamine (0.119 g, 1.18 mmol), and methyl sulfoxide (4 mL) were added. The reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched by adding water (10 mL) and extracted with EA (3 x 10 mL). The organic layers were combined, washed with brine (10 mL), dried on anhydrous Na2SO4, and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 35-65-90%B (2-30-60 min); 269 nm; room temperature: 32.043-33.407 min). As a result, 0.075 g (45.95% yield) of 4-((3-(7-(((3R,4S)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxy-N-methylbenzamide (racemic mixture) (41) was obtained as a white solid. LCMS: m / z = 563 [M+1] + . 1H NMR (400 MHz, DMSO) δ 8.11 (s, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.35 (s, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 6.76 (t, J = 7.9 Hz, 2H), 6.01 (s, 1H), 5.22 - 5.14 (m, 1H), 4.90 - 4.84 (m, 1H), 4.80 - 4.70 (m, 1H), 4.33 (d, J = 6.2 Hz, 2H), 3.89 - 3.74 (m, 5H), 2.75 (d, J = 4.2 Hz, 3H), 2.20 (s, 3H), 1.91 (s, 3H), 1.73 (s, 2H), 1.23 (s, 1H).

[0353] Example 42 (Z)-3-fluoro-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-N,1-dimethylpiperidine-4-amine (racemic mixture) (42) Reaction scheme: [ka]

[0354] Experiment details: Step 1. (Z)-3-fluoro-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-N,1-dimethylpiperidine-4-amine (racemic mixture) (42). In a 40 mL vial, 2-methoxy-4-(methylsulfonyl)-N-(propa-2-in-1-yl)aniline (0.296 g, 1.24 mmol), (Z)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-N,1-dimethylpiperidine-4-amine (racemic mixture) (0.281 g, 578.19 μmol), bis(triphenylphosphine)palladium(II) chloride (0.157 g, 222.40 μmol), CuI (0.145 g, 761.35 μmol), DIEA (0.745 g, 5.76 mmol), and methyl sulfoxide (20 mL) were added. The reaction mixture was stirred under a nitrogen atmosphere at 60°C for 3 hours. The reaction was quenched with water (30 mL) and extracted with EA (3 x 20 mL). The organic layers were combined, washed with brine (50 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: MeOH; flow rate: 70 mL / min; gradient: 55-80-100% B (2-30-60 min); 269 nm; room temperature: 36.753-38.278 min) to obtain the target product. As a result, (Z)-3-fluoro-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-N,1-dimethylpiperidine-4-amine (racemic mixture) (42) was obtained as an off-white solid in a yield of 0.015 g (4.35% yield). LCMS: m / z = 598 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J = 8.0 Hz, 1H), 7.47 - 7.37 (m, 2H), 7.29 - 7.21 (m, 2H), 6.89 (d, J = 8.4 Hz, 1H), 6.50 (t, J = 6.4 Hz, 1H), 4.84 (d, J = 50.0 Hz, 1H), 4.39 (d, J = 6.4 Hz, 2H), 3.94 - 3.79 (m, 5H), 3.28 - 3.20 (m, 1H), 3.09 (s, 3H), 2.96 (t, J = 12.4 Hz, 1H), 2.83 (s, 4H), 2.10 (d, J = 21.2 Hz, 4H), 2.06 - 1.89 (m, 2H), 1.52 (d, J = 12.0 Hz, 1H).

[0355] Example 43 (4-((3-(7-((3,3-difluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (43) Reaction scheme: [ka]

[0356] Experiment details: Step 1: 4-Bromo-2-methoxyaniline 4-bromo-2-methoxy-1-nitrobenzene (15.75 g, 67.87 mmol), iron (28.61 g, 512.31 mmol), NH4Cl (28.40 g, 530.92 mmol), EtOH (150 mL), and water (15 mL) were placed in a 500 mL three-necked flask. The reaction mixture was filtered through a Celite pad, and the filter cake was washed with methanol (2 x 200 mL). The filtrate was concentrated under reduced pressure to obtain the product. The crude product was purified by silica gel column elution with EA / hexane (v / v = 1 / 2). As a result, 13.82 g (68.39 mmol, yield 100.00%) of 4-bromo-2-methoxyaniline was obtained as a yellow oil. LCMS: m / z = 202 [M+1] + .

[0357] Step 2 (4-amino-3-methoxyphenyl)dimethylphosphine oxide 4-bromo-2-methoxyaniline (5.055 g, 25.01 mmol), palladium(II) acetate (0.868 g, 3.87 mmol), dimethylbisdiphenylphosphinoxanthene (2.143 g, 3.70 mmol), and DIEA (6.442 g, 49.84 mmol) were added to a 250 mL three-necked flask and stirred at 130°C for 0.5 hours under a nitrogen atmosphere. The reaction mixture was purified by eluting with ACN / H2O (v / v = 1 / 9) on a C18 column, filtered, and concentrated under vacuum. As a result, 4.798 g (24.08 mmol, 96.27% yield) of (4-amino-3-methoxyphenyl)dimethylphosphine oxide was obtained as a brown oil. LCMS: m / z = 200 [M+1] + .

[0358] Step 3 (3-Methoxy-4-(propa-2-in-1-ylamino)phenyl)dimethylphosphine oxide In a 250 mL three-necked flask, (4-amino-3-methoxyphenyl)dimethylphosphine oxide (2.059 g, 10.33 mmol), 3-bromopropa-1-yin (1.693 g, 14.23 mmol), K2CO3 (3.305 g, 23.91 mmol), and KI (1.877 g, 11.30 mmol) NMP (25 mL) were added. The reaction mixture was stirred under nitrogen at 80°C for 4 hours. The reaction mixture was purified by eluting with ACN / H2O (v / v = 2 / 8) on a C18 column, filtered, and concentrated under vacuum. As a result, 1.351 g (5.69 mmol, yield 55.09%) of (3-methoxy-4-(propa-2-yin-1-ylamino)phenyl)dimethylphosphine oxide was obtained as a brown oil. LCMS: m / z = 238 [M+1] + .

[0359] Step 4 (4-((3-(7-((3,3-difluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (43) In a 10 mL round-bottom flask, (3-methoxy-4-(propa-2-in-1-ylamino)phenyl)dimethylphosphine oxide (0.102 g, 429.95 μmol), 3,3-difluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.089 g, 181.53 μmol), Pd(PPh3)2Cl2 (0.034 g, 48.16 μmol), CuI (0.022 g, 115.51 μmol), DIEA (0.105 g, 812.42 μmol), and methyl sulfoxide (2 mL) were added. The reaction was stirred under a nitrogen atmosphere at room temperature for 16 hours. The reaction was quenched with water (5 mL). The obtained solution was extracted with EA (3 x 10 mL), washed with brine (10 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC (mobile phase A: water (0.1% ammonium hydroxide), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 55-85-100% B (2-32-50 min); 225 nm; room temperature: 30.53-31.56) to obtain the target product. As a result, 0.010 g (16.67 μmol, 9.18% yield) of (4-((3-((3,3-difluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (43) was obtained as a white solid. LCMS: m / z = 600 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 7.28 - 7.12 (m, 4H), 6.85 (d, J = 7.8 Hz, 2H), 6.06 (t, J = 6.3 Hz, 1H), 5.38 (d, J = 8.9 Hz, 1H), 4.34 (d, J = 6.4 Hz, 2H), 3.85 (s, 3H), 3.79 (d, J = 11.0 Hz, 2H), 2.78 (d, J = 11.6 Hz, 2H), 2.25 (s, 3H), 2.17 (s, 1H), 1.95 - 1.82 (m, 3H), 1.58 (d, J = 13.2 Hz, 6H), 1.24 (s, 1H).

[0360] Examples 44 and 45 (R)-4-((4-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)buta-3-in-2-yl)amino)benzenesulfonamide and (S)-4-((4-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)buta-3-in-2-yl)amino)benzenesulfonamide (44 and 45) Reaction scheme: [ka]

[0361] Experiment details: Step 1. Buta-3-in-2-yl methanesulfonate In a 100 mL flask, bu-3-in-2-ol (2.30 g, 32.82 mmol), DCM (20 mL), TEA (2 mL), and MsCl (3 mL) were added. The reaction was stirred at 20°C for 4 hours. The reaction was quenched with H2O (20 mL) and extracted with DCM (3 x 20 mL). The organic layers were combined and concentrated under vacuum. As a result, 1.99 g (crude) of bu-3-in-2-ol methanesulfonic acid was obtained as a red oil. LCMS: m / z = 149 [M+1] +.

[0362] Step 2.4-(buta-3-in-2-ylamino)benzenesulfonamide. In a 100 mL flask, 1.83 g, 12.35 mmol of buta-3-in-2-yl methanesulfonate, 1.53 g, 9.06 mmol of 4-aminobenzenesulfonamide, 2.87 g, 8.81 mmol of Cs2CO3, and 3 mL of DMF were added. The reaction mixture was purified by eluting with ACN / H2O (0.15% TFA) (v / v = 1 / 3) using a C18 chromatography column. As a result, 0.38 g of 4-(buta-3-in-2-ylamino)benzenesulfonamide was obtained as a yellow solid (yield 13%). LCMS: m / z = 225 [M+1] + .

[0363] Step 3.4-((4-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)buta-3-in-2-yl)amino)benzenesulfonamide. 4-(buta-3-in-2-ylamino)benzenesulfonamide (0.058 g, 258.61 μmol), N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.082 g, 180.50 μmol), CuI (0.047 g, 246.78 μmol), Pd(PPh3)2Cl2 (0.081 g, 99.68 μmol), DIEA (0.050 g, 386.87 μmol), and methyl sulfoxide (2 mL) were added to a 100 mL flask. The mixture was stirred at 25°C for 4 hours. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 50-70-90% B (2-30-60 mins); 220 nm; room temperature: 33.580-36.110 mins). This yielded 53 mg (34% yield) of 4-((4-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)buta-3-in-2-yl)amino)benzenesulfonamide (racemic mixture) as a white solid. LCMS: m / z = 551 [M+1] + .

[0364] Step 4. (R)-4-((4-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)buta-3-in-2-yl)amino)benzenesulfonamide and (S)-4-((4-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)buta-3-in-2-yl)amino)benzenesulfonamide (44 and 45). 4-((4-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)buta-3-in-2-yl)amino)benzenesulfonamide (racemic mixture) was subjected to chiral separation to obtain 8 mg (18% yield) of (R)-4-((4-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)buta-3-in-2-yl)amino)benzenesulfonamide as a white solid. LCMS: m / z = 551 [M+1] + . 1 H NMR (400 MHz, DMSO) δ 7.58 (d, J = 8.6 Hz, 2H), 7.25 (t, J = 7.8 Hz, 1H), 7.14 (d, J = 7.9 Hz, 1H), 6.98 (s, 2H), 6.79 (t, J = 7.8 Hz, 3H), 6.66 (d, J = 7.8 Hz, 1H), 5.28 (d, J = 8.1 Hz, 1H), 4.73 - 4.63 (m, 1H), 3.89 - 3.76 (m, 2H), 2.76 (d, J = 11.5 Hz, 2H), 2.17 (s, 3H), 2.00 (t, J = 11.4 Hz, 2H), 1.88 (d, J = 12.3 Hz, 2H), 1.58 (d, J = 6.7 Hz, 3H), 1.25 (d, J = 9.4 Hz, 3H).

[0365] Then, 4-((4-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)buta-3-in-2-yl)amino)benzenesulfonamide was subjected to chiral separation, and 10 mg (22% yield) of (S)-4-((4-(7-((1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)buta-3-in-2-yl)amino)benzenesulfonamide was obtained as a white solid. LCMS: m / z = 551 [M+1] + . 1H NMR (400 MHz, DMSO) δ 7.58 (d, J = 8.6 Hz, 2H), 7.25 (t, J = 7.8 Hz, 1H), 7.14 (d, J = 7.9 Hz, 1H), 6.98 (s, 2H), 6.79 (t, J = 7.8 Hz, 3H), 6.66 (d, J = 7.7 Hz, 1H), 5.29 (d, J = 7.8 Hz, 1H), 4.66 (dd, J = 14.0, 6.9 Hz, 1H), 3.92 - 3.74 (m, 2H), 2.77 (d, J = 11.3 Hz, 2H), 2.18 (s, 3H), 2.01 (t, J = 11.2 Hz, 2H), 1.88 (d, J = 12.0 Hz, 2H), 1.41 - 1.25 (m, 3H), 1.23 (s, 3H).

[0366] Example 46 4-((3-(7-(((Z)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxybenzamide (racemic mixture) (46) Reaction scheme: [ka]

[0367] Experiment details: Step 1. Methyl 4-amino-3-methoxybenzoate 4-amino-3-methoxybenzoic acid (15.06 g, 90.09 mmol), MeOH (200 mL), and sulfuric acid (15 mL) were placed in a 500 mL flask. The reaction was stirred at 65°C for 16 hours. The reaction was quenched with NaOH (2 N, 500 mL) at 10°C. A precipitate then appeared. The mixture was filtered, and the filter cake was collected. The filter cake was dried at 60°C for 16 hours. As a result, 14.35 g of methyl 4-amino-3-methoxybenzoate (yield 87.91%) was obtained as a white solid. LCMS: m / z = 182 [M+1]+ .

[0368] Step 2. Methyl 3-methoxy-4-(propa-2-in-1-ylamino)benzoate. In a 100 mL flask, methyl 4-amino-3-methoxybenzoate (4.15 g, 22.90 mmol), Cs2CO3 (3.73 g, 11.45 mmol), 3-bromopropa-1-yin (8.89 g, 74.73 mmol), KI (2.77 g, 16.69 mmol), and DMF (20 mL) were added. The reaction mixture was purified by eluting with ACN / H2O (v / v = 1 / 1) using a C18 column. As a result, 1.40 g of methyl 3-methoxy-4-(propa-2-in-1-ylamino)benzoate (yield 27%) was obtained as a pale yellow solid. LCMS: m / z = 220 [M+1] + .

[0369] Step 3. 3-Methoxy-4-(propa-2-in-1-ylamino)benzoic acid. In a 25 mL round-bottom flask, methyl 3-methoxy-4-(propa-2-in-1-ylamino)benzoate (0.82 g, 3.73 mmol), MeOH (4 mL), THF (4 mL), H2O (4 mL), and LiOH (0.81 g, 33.95 mmol) were added. The reaction mixture was stirred at 50°C for 3 hours, and the reaction product was diluted with water (50 mL). Then, Na2CO3 (aq, 100 mL) was added until the pH > 8. The mixture was filtered, and the filter cake was collected. The filter cake was dried at 60°C for 16 hours. As a result, 0.75 g of 3-methoxy-4-(propa-2-in-1-ylamino)benzoic acid (97% yield) was obtained as a yellow solid. LCMS: m / z = 206[M+1] + .

[0370] Step 4.3-Methoxy-4-(propa-2-in-1-ylamino)benzamide. In a 50 mL round-bottom flask, 3-methoxy-4-(propa-2-in-1-ylamino)benzoic acid (0.137 g, 667.61 μmol), NH4Cl (0.324 g, 6.06 mmol), HATU (0.455 g, 1.20 mmol), DIEA (1.919 g, 14.85 mmol), and DMF (5 mL) were added. The mixture was stirred at 20°C for 3 hours. The reaction mixture was purified by eluting with ACN / H2O (v / v = 1 / 1) using a C18 column. As a result, 83 mg of 3-methoxy-4-(propa-2-in-1-ylamino)benzamide (60% yield) was obtained as a pale yellow solid. LCMS: m / z = 205 [M+1] + .

[0371] Step 5.4-((3-(7-(((Z)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxybenzamide (racemic mixture) (46). 3-methoxy-4-(propa-2-in-1-ylamino)benzamide (0.069 g, 337.86 μmol), (Z)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (racemic mixture) (0.106 g, 224.44 μmol), CuI (0.014 g, 73.51 μmol), Pd(PPh3)2Cl2 (0.037 g, 52.41 μmol), DIEA (0.058 g, 448.77 μmol), and methyl sulfoxide (2 mL) were added to a 50 mL round-bottom flask. The mixture was stirred at 25°C for 4 hours. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 50-80-100% B (2-32-60 min); 269 nm; room temperature: 33.448-35.501 min). As a result, 43 mg (34% yield) of 4-(3-(7-(((Z)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxybenzamide (racemic mixture) (46) was obtained as a white solid. LCMS: m / z = 549 [M+1] + . 1H NMR (400 MHz, DMSO) δ 7.69 (s, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.39 (s, 1H), 7.30 - 7.17 (m, 2H), 6.98 (s, 1H), 6.81 - 6.69 (m, 2H), 6.05 (t, J = 6.2 Hz, 1H), 5.17 (d, J = 8.5 Hz, 1H), 4.79 (d, J = 49.7 Hz, 1H), 4.34 (d, J = 6.1 Hz, 2H), 3.84 (s, 3H), 3.80 (s, 1H), 3.64 (d, J = 30.1 Hz, 2H), 3.02 (t, J = 10.9 Hz, 1H), 2.79 (d, J = 11.1 Hz, 1H), 2.32 - 2.21 (m, 1H), 2.17 (d, J = 9.7 Hz, 3H), 2.07 (t, J = 11.1 Hz, 1H), 2.01 - 1.86 (m, 1H), 1.71 (d, J = 9.8 Hz, 1H).

[0372] Example 47 4-((3-(7-((3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxy-N-(1-methylpiperidine-4-yl)benzamide (racemic mixture) (47) Reaction scheme: [ka]

[0373] Experiment Details Step 1. 3-Methoxy-N-(1-methylpiperidine-4-yl)-4-(propa-2-in-1-ylamino)benzamide. To a 4 mL bale, 3-methoxy-4-(propa-2-in-1-ylamino)benzoic acid (0.049 g, 238.78 μmol), 1-methylpiperidine-4-amine (0.044 g, 385.33 μmol), ECDI (0.049 g, 315.64 μmol), HOBT (0.043 g, 318.23 μmol), DMAP (0.003 g, 24.56 μmol), TEA (0.042 g, 415.06 μmol), and DMF (0.5 mL) were added. The reaction mixture was stirred at 40°C for 3 hours. LC-MS indicated that the reaction was complete. The reaction product was purified using a C18 column and eluted with ACN / water (v / v = 1 / 3) to obtain 3-methoxy-N-(1-methylpiperidine-4-yl)-4-(propa-2-in-1-ylamino)benzamide (0.050 g, 165.90 μmol, 69.48% yield) as a clear oil. LC-MS: m / z = 302[M+1] + .

[0374] Step 2.4-((3-(7-((3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxy-N-(1-methylpiperidine-4-yl)benzamide (racemic mixture) (47). In a 4 mL flask maintained under a nitrogen atmosphere, 3-methoxy-N-(1-methylpiperidine-4-yl)-4-(propa-2-in-1-ylamino)benzamide (0.049 g, 162.58 μmol), (Z)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (racemic mixture) (0.049 g, 103.75 μmol), Pd(PPh3)2Cl2 (0.009 g, 12.75 μmol), CuI (0.003 g, 15.75 μmol), TEA (0.035 g, 345.89 μmol), and DMF (0.5 mL) were added and the mixture was stirred overnight at room temperature. LC-MS indicated that the reaction was complete. The reaction was quenched with water (4 mL) and extracted with EA (2 mL x 2). The combined organic layers were successively washed with water (2 mL) and brine (2 mL), separated, and concentrated under vacuum. The residue was purified by prep-HPLC (mobile phase A: water (ammonium hydroxide), mobile phase B: ACN; flow rate: 50 mL / min; gradient: 55-80-100% B (2-30-60 mins); 248 nm; room temperature: 33.450-36.020 mins) to obtain 4-((3-(7-(3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxy-N-(1-methylpiperidine-4-yl)benzamide (racemic) (47) (42 mg, 65.04 μmol, 40.00% yield) as an off-white solid. LCMS: m / z = 646[M+1] + 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.36 (s, 1H), 7.32 - 7.16 (m, 2H), 6.77 (dd, J = 10.9, 7.9 Hz, 2H), 6.02 (t, J = 6.5 Hz, 1H), 5.15 (d, J = 8.5 Hz, 1H), 4.79 (d, J = 49.0 Hz, 1H), 4.34 (d, J = 6.3 Hz, 2H), 3.95 - 3.77 (m, 5H), 3.76 - 3.55 (m, 2H), 3.03 (t, J = 11.3 Hz, 1H), 2.77 (d, J = 11.3 Hz, 3H), 2.27 (d, J = 13.2 Hz, 1H), 2.17 (d, J = 9.2 Hz, 6H), 2.10 - 1.88 (m, 4H), 1.80 - 1.66 (m, 3H), 1.63 - 1.52 (m, 2H).

[0375] Example 48 (1,1-Dioxidethiomorpholino)(4-((3-(7-(((3R,4S)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxyphenyl)methanone (racemic mixture)(48) Reaction scheme: [ka]

[0376] Experiment Details Step 1. (1,1-Dioxidethiomorpholino)(3-Methoxy-4-(Propa-2-in-1-ylamino)phenyl)methanone In an 8 mL flask purged and maintained under an inert nitrogen atmosphere, 3-methoxy-4-(propa-2-in-1-ylamino)benzoic acid (0.053 g, 258.27 μmol), 4-thiomorpholine 1,1-dione hydrochloride (0.139 g, 809.81 μmol), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.366 g, 962.58 μmol), N,N-diisopropylethylamine (0.119 g, 920.75 μmol), and N,N-dimethylformamide (2 mL) were added. The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched by adding water (2 mL) and extracted with EA (2 x 2 mL). The organic layers were combined, washed with 15% potassium carbonate aqueous solution (2 x 2 mL) and brine (5 mL), dried on anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by C18 chromatography column eluted with ACN / H2O (v / v = 3 / 1). As a result, 0.092 g (yield 110.50%) of (1,1-dioxidethiomorpholino)(3-methoxy-4-(propa-2-in-1-ylamino) Crude phenyl(methanone) was obtained as a white solid. LC-MS: m / z = 323 [M+1] + .

[0377] Step 2. (1,1-Dioxidethiomorpholino)(4-((3-(7-(((3R,4S)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxyphenyl)methanone (racemic mixture) (48) In a 100 mL flask purged and maintained under an inert nitrogen atmosphere, (3R,4S)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (racemic) (0.103 g, 218.09 μmol), cuprous iodide (0.008 g, 42.01 μmol), (1,1-dioxidethiomorpholino)(3-methoxy-4-(propa-2-in-1-ylamino)phenyl)methanone (0.084 g, 260.5629 μmol), bis(triphenylphosphine)palladium(II) chloride (0.021 g, 29.75 μmol), triethylamine (0.153 g, 1.51 mmol), and methyl sulfoxide (1 mL) were added. The reaction mixture was stirred at room temperature for 5 hours. The reaction was quenched by adding water (2 mL) and extracted with EA (2 x 2 mL). The organic layers were combined, washed with brine (5 mL), dried on anhydrous Na2SO4, and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: MeOH; flow rate: 70 mL / min; gradient: 55-80-100% B (2-32-60 min); 269 nm; room temperature: 30.797-31.863 min). As a result, 0.026 g (17.88% yield) of (1,1-dioxide thiomorpholino)(4-((3-(7-(((3R,4S)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxyphenyl)methanone (racemic mixture) (48) was obtained as a white solid. LCMS: m / z = 667 [M+1] + . 1H NMR (400 MHz, DMSO) δ 7.31 - 7.19 (m, 2H), 7.02 (dd, J = 10.5, 2.5 Hz, 2H), 6.82 - 6.74 (m, 2H), 6.02 (t, J = 6.3 Hz, 1H), 5.16 (d, J = 8.6 Hz, 1H), 4.80 (d, J = 49.6 Hz, 1H), 4.34 (d, J = 6.3 Hz, 2H), 3.90 (s, 4H), 3.86 - 3.76 (m, 5H), 3.74 - 3.55 (m, 1H), 3.25 (d, J = 4.4 Hz, 4H), 3.03 (t, J = 10.8 Hz, 1H), 2.80 (d, J = 12.0 Hz, 1H), 2.25 (t, J = 13.1 Hz, 1H), 2.18 (s, 3H), 2.08 (t, J = 11.1 Hz, 1H), 2.02 - 1.89 (m, 1H), 1.72 (d, J = 9.8 Hz, 1H).

[0378] Example 49 (4-((3-(7-(((Z)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxyphenyl)(4-methylpiperazine-1-yl)methanone (racemic mixture) (49) Reaction scheme: [ka]

[0379] Experiment details: Step 1. (3-Methoxy-4-(propa-2-in-1-ylamino)phenyl)(4-methylpiperazine-1-yl)methanone. In a 4 mL sealed tube, 3-methoxy-4-(propa-2-in-1-ylamino)benzoic acid (0.101 g, 492.18 μmol), 1-methylpiperazine (0.107 g, 1.07 mmol), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.324 g, 852.12 μmol), N,N-diisopropylethylamine (0.205 g, 1.59 mmol), and N,N-dimethylformamide (2 mL) were added. The reaction mixture was stirred overnight at room temperature. The reaction was quenched with water (50 mL) and extracted with EA (20 mL x 2). The combined organic layers were successively washed with water (20 mL) and brine (30 mL x 2), separated, and concentrated under vacuum. The crude product was purified by eluting with MeOH / DCM (v / v = 1 / 9) using a silica gel column. As a result, 0.19 g (crude) of (3-methoxy-4-(propa-2-in-1-ylamino)phenyl)(4-methylpiperazine-1-yl)methanone was obtained as a brownish-yellow oil. LCMS: m / z = 288 [M+1] + .

[0380] Step 2. (4-((3-(7-(((Z)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxyphenyl)(4-methylpiperazine-1-yl)methanone (racemic mixture) (49). (3-methoxy-4-(propa-2-in-1-ylamino)phenyl)(4-methylpiperazine-1-yl)methanone (0.167 g, 581.16 μmol), (Z)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (racemic mixture) (0.100 g, 211.74 μmol), bis(triphenylphosphine)palladium(II) chloride (0.043 g, 60.91 μmol), CuI (0.036 g, 189.03 mmol), DIEA (0.164 g, 1.27 mmol), and methyl sulfoxide (5 mL) were added to a 25 mL round-bottom flask. The mixture was stirred at 60°C for 2 hours under a nitrogen atmosphere. The reaction was quenched with water (20 mL) and extracted with EA (20 mL x 2). The combined organic layers were successively washed with water (30 mL) and brine (30 mL), separated, and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: MeOH; flow rate: 70 mL / min; gradient: 45-80-100%B (2-32-60 min); 269 nm; room temperature: 39.863-41.317 min) to obtain the target product. As a result, 0.061 g (45.60% yield) of (4-((3-(((Z)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxyphenyl)(4-methylpiperazine-1-yl)methanone (racemic mixture) (49) was obtained as an off-white solid. LCMS: m / z = 632 [M+1] + . 1H NMR (400 MHz, MeOD) δ 7.29 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.96 (s, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 4.96 - 4.89 (m, 1.5H), 4.83 - 4.73 (m, 0.5H), 4.35 (s, 2H), 3.89 (s, 3H), 3.77 - 3.62 (m, 6H), 3.25 - 3.15 (m, 1H), 2.98 - 2.88 (m, 1H), 2.56 - 2.42 (m, 4H), 2.42 - 2.36 (m, 1H), 2.30 (d, J = 7.1 Hz, 6H), 2.27 - 2.20 (m, 1H), 2.01 - 1.91 (m, 2H).

[0381] Example 50 (4-((3-(7-(((Z)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxyphenyl)(morpholino)methanone (racemic mixture) (50) Reaction scheme: [ka]

[0382] Experiment details: Step 1. (3-Methoxy-4-(propa-2-in-1-ylamino)phenyl)(morpholino)methanone. 3-methoxy-4-(propa-2-in-1-ylamino)benzoic acid (0.065 g, 316.74 μmol), morpholin (0.125 g, 1.43 mmol), HATU (0.280 g, 0.74 mmol), DIEA (0.296 g, 2.29 mmol), and DMF (5 mL) were placed in a 50 mL round-bottom flask. The mixture was stirred at 20°C for 3 hours. The reaction mixture was purified by eluting with ACN / H2O (v / v = 1 / 1) on a C18 column. As a result, 94 mg (98% yield) of (3-methoxy-4-(propa-2-in-1-ylamino)phenyl)(morpholino)methanone was obtained as a pale yellow solid. LCMS: m / z = 275 [M+1] + .

[0383] Step 2. (4-((3-(7-(((Z)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxyphenyl)(morpholino)methanone (racemic mixture) (50) (3-methoxy-4-(propa-2-in-1-ylamino)phenyl)(morpholino)methanone (0.069 g, 251.54 μmol), (Z)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.106 g, 224.44 μmol), CuI (0.014 g, 73.51 μmol), Pd(PPh3)2Cl2 (0.037 g, 52.41 μmol), DIEA (0.058 g, 448.77 μmol), and methyl sulfoxide (2 mL) were added to a 50 mL round-bottom flask. The mixture was stirred at 25°C for 4 hours. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 55-80-100% B (2-32-60 mins); 269 nm; room temperature: 37.007-38.908 mins). As a result, 41 mg (yield 29%) of (4-((3-(7-(((Z)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-3-methoxyphenyl)(morpholino)methanone (racemic) (50) was obtained as a white solid. LCMS: m / z = 619 [M+1] + . 1H NMR (400 MHz, DMSO) δ 7.34 - 7.15 (m, 2H), 7.02 - 6.88 (m, 2H), 6.77 (m, 2H), 5.98 (t, J = 6.3 Hz, 1H), 5.16 (d, J = 8.6 Hz, 1H), 4.79 (d, J = 49.3 Hz, 1H), 4.33 (d, J = 6.3 Hz, 2H), 3.86 - 3.82 (mii, 3H), 3.82 - 3.75 (m, 2H), 3.73 - 3.65 (m, 1H), 3.59 (d, J = 3.9 Hz, 4H), 3.52 (d, J = 3.8 Hz, 4H), 3.03 (t, J = 10.7 Hz, 1H), 2.79 (d, J = 11.0 Hz, 1H), 2.36 - 2.21 (m, 1H), 2.17 (d, J = 10.6 Hz, 3H), 2.07 (t, J = 11.2 Hz, 1H), 2.01 - 1.88 (m, 1H), 1.71 (d, J = 9.7 Hz, 1H)

[0384] Example 51 N-(4-fluoro-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine(51) Reaction scheme: [ka]

[0385] Experiment details: Step 1. N-(4-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine In a 20 mL sealed tube purged and maintained under an inert nitrogen atmosphere, N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.408 g, 0.90 mmol), SelectFluor (0.375 g, 1.06 mmol), and MeCN (10 mL) were added. The mixture was purified by silica gel column chromatography and eluted with EA / hexane (v / v = 1 / 4) to obtain 0.304 g (71.67%) of N-(4-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine as a yellow oil. LCMS: m / z = 473 [M+1] +

[0386] Step 2. N-(4-fluoro-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine(51) In a 20 mL sealed tube purged and maintained under an inert nitrogen atmosphere, the following were added: N-(4-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (0.268 g, 0.57 mmol), 2-methoxy-4-(methylsulfonyl)-N-(propa-2-in-1-yl)aniline (0.271 g, 1.13 mmol), Pd(dppf)Cl2 (0.098 g, 0.14 mmol), CuI (0.164 g, 0.86 mmol), DIEA (0.314 g, 2.43 mmol), and DMSO (5 mL). The reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was quenched by adding water (20 mL) and extracted with EA (20 mL x 2). The combined organic layers were washed with brine (10 mL), separated, and concentrated under vacuum. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 50-75-95%B (2-30-55 min); 242 nm; room temperature: 34.125-36.751 min) to obtain N-(4-fluoro-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)propa-1-in-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (51) (0.092 g, yield 27.78%) as a white solid. LCMS: m / z = 584 [M+1] + 1H NMR (400 MHz, MeOD) δ 7.52 - 7.46 (m, 1H), 7.32 - 7.23 (m, 2H), 7.23 - 7.13 (m, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.40 (s, 2H), 3.95 (s, 3H), 3.74 - 3.63 (m, 2H), 3.51 (d, J = 22.0 Hz, 1H), 3.06 (s, 3H), 2.86 (d, J = 11.8 Hz, 2H), 2.29 (s, 3H), 2.14 (t, J = 11.2 Hz, 2H), 1.92 (d, J = 12.4 Hz, 2H), 1.67 - 1.51 (m, 2H).

[0387] Example 52 (2-fluoro-4-((3-(7-(((Z)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-5-methoxyphenyl)dimethylphosphine oxide (racemic mixture) (52) Reaction scheme: [ka]

[0388] Experiment Details Step 1. Synthesis of (4-amino-2-fluoro-5-methoxyphenyl)dimethylphosphine oxide In a 40 mL vial, 4-bromo-5-fluoro-2-methoxyaniline (1.084 g, 4.93 mmol), dimethylphosphine oxide (0.508 g, 6.51 mmol), palladium(II) acetate (0.150 g, 668.13 μmol), dimethylbisdiphenylphosphine oxanthene (0.652 g, 1.13 mmol), N,N-diisopropylethylamine (1.495 g, 11.57 mmol), and DMF (10 mL) were added. The mixture was stirred overnight at 130°C under a nitrogen atmosphere. The resulting reaction product was purified by eluting with ACN / water (v / v = 1 / 6) on a C18 chromatography column. As a result, 0.955 g (yield 89.26%) of (4-amino-2-fluoro-5-methoxyphenyl)dimethylphosphine oxide was obtained. LCMS: m / z = 218 [M+1] + .

[0389] Step 2. Synthesis of (2-fluoro-5-methoxy-4-(propa-2-in-1-ylamino)phenyl)dimethylphosphine oxide (4-amino-2-fluoro-5-methoxyphenyl)dimethylphosphine oxide (0.654 g, 3.01 mmol), DMA (15 mL), cesium carbonate (3.149 g, 9.67 mmol), sodium iodide (0.413 g, 2.76 mmol), N-(4-pyridyl)dimethylamine (0.083 g, 679.40 μmol), and 3-bromopropa-1-yin (0.746 g, 6.27 mmol) were added to a 40 mL vial. The mixture was then stirred overnight at 90°C. The resulting reaction product was purified by eluting with ACN / water (v / v = 1 / 3) on a C18 chromatography column. As a result, 0.255 g (yield 33.18%) of (2-fluoro-5-methoxy-4-(propa-2-yin-1-ylamino)phenyl)dimethylphosphine oxide was obtained. LCMS: m / z = 256 [M+1] + .

[0390] Step 3. Synthesis of (2-fluoro-4-((3-(7-(((Z)-3-fluoro-1-methylpiperidine-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propa-2-in-1-yl)amino)-5-methoxyphenyl)dimethylphosphine oxide (racemic mixture) (52) In a 40 mL vial, (2-fluoro-5-methoxy-4-(propa-2-in-1-ylamino)phenyl)dimethylphosphine oxide (0.251 g, 983.45 μmol), (Z)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl(benzo[b]thiophen-7-yl)-1-methylpiperidine-4-amine (racemic) (0.470 g, 995.17 μmol), bis(triphenylphosphine)palladium(II) chloride (0.070 g, 99.16 μmol), copper(I) iodide (0.034 g, 178.52 μmol), N,N-diisopropylethylamine (0.437 g, 3.38 mmol), and methyl sulfoxide (10 mL) were added. The mixture was stirred at 40°C for 4 hours. The resulting reaction product was dissolved in water (30 The reaction was diluted with EA (10 mL x 3) and extracted. The organic phase ...

Claims

1. A compound selected from the group consisting of the following compounds, or a stereoisomer thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 【Chemistry 2】

2. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in claim 1, a stereoisomer thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

3. A pharmaceutical composition according to claim 2 for use in the prevention or treatment of a disease or condition in a subject, wherein the disease or condition is cancer.

4. A pharmaceutical composition for use according to claim 3, wherein cancer cells express a p53 variant at the amino acid Tyr220.

5. A pharmaceutical composition for use according to claim 4, wherein the p53 mutant is Y220C.

6. A pharmaceutical composition for use according to claim 3, wherein the disease or condition is selected from the group consisting of ovarian cancer, breast cancer, lung cancer and / or a combination thereof.

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