Compounds that target p53 mutants

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 that target p53 mutants, pharmaceutical compositions containing the compounds, methods for preparing the compounds, and methods of using the compounds to prevent or treat diseases or conditions associated with p53 mutants.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to PCT application PCT / CN2021 / 111797 filed on August 10, 2021, PCT application PCT / CN2021 / 125725 filed on October 22, 2021, PCT application PCT / CN2021 / 132409 filed on November 23, 2021, PCT application PCT / CN2022 / 073977 filed on January 26, 2022, and PCT application PCT / CN2022 / 097840 filed on June 09, 2022, the contents of each of which are incorporated herein by reference in their entirety. [Background technology]

[0003] The p53 protein, referred to as the "guardian of the human genome," is a tetrameric transcription factor that prevents genomic mutations by controlling the expression of a subgroup of target genes. Although biologically active as a homotetramer, each p53 monomer consists of 393 amino acids and is divided into five major regulatory domains: the transcription 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 suppressor" effect, but p53 is unstable and its half-life is 5-30 minutes. Activation of p53 initiates pathways involved in apoptosis, cis-, DNA repair, cell cycle arrest, anti-angiogenesis, and senescence, avoiding 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) target gene activation.

[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 also associated with poor prognosis and patient survival. Moreover, mutant p53 is commonly overexpressed in cancers, making it a highly abundant and tumor-specific target, in part due to the inability to induce MDM2 gene expression 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 and cause dysfunction in other important proteins and pathways that control the cell cycle. Considering the aforementioned factors, mutant p53 is an important pharmacological target, and in the past two decades, considerable efforts have been made to develop small molecules aimed at restoring wild-type function of mutant p53. In particular, targeting mutant p53 means more selective targeting of cancer cells and reducing the risk of side effects and toxicity to healthy tissues. Among the small molecules developed, numerous mechanistic strategies have been developed, including protein refolding through cis-tein modifications, protein stabilization, modulation of protein aggregation, and zinc chelation.

[0006] p53 is directly inactivated by mutation in 50% of human cancers (ranging from approximately 1% to 85% depending on cancer type), and almost all cancers display dysfunction along the p53 pathway. Due to the frequency and aggressiveness of cancers that display p53 dysfunction, efforts to restore normal p53 expression and activity have been widespread in both academia and the pharmaceutical industry over the past decades. Although this approach faces significant challenges, including frequent off-target mechanisms of action, major technological advances in gene sequencing capabilities and a shift toward personalized medicine hold 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 around the DNA-binding surface of the protein result in defects in the folding of the protein required for DNA recognition and binding. Mutations in p53 can occur, for example, at amino acids Val143, His168, Arg175, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, and Arg282. P53 mutations that impair p53 activity include, for example, 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. Wild-type function of mutant p53 can be restored by binding the mutant p53 to a compound that shifts the folding / unfolding equilibrium towards the folded state, thereby decreasing the rate of unfolding and destabilization.

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

[0009] PC14586 has been reported to be a small molecule reactivator targeting p53 Y220C mutant developed by PMV Pharmaceuticals, Inc., and there remains a significant need in the art for the development of new small molecule reactivators targeting p53 mutants (e.g., Y220C mutant) with high specificity and activity in addition to low toxicity. Summary of the Invention

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

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

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

[0013] In one aspect, it is an object of the present invention to provide methods for preparing the compounds of the present invention.

[0014] In one aspect, it is an object of the present invention to provide intermediate compounds (eg, formula (IN-I)) used in the preparation of compounds of the present invention (eg, formula (I)).

[0015] It should be understood that each embodiment of the prophylactic or therapeutic methods herein may also be configured as an embodiment of the corresponding application type.

[0016] The present disclosure further provides the following aspects.

[0017] [1] A compound of formula (I) or a stereoisomer, tautomer, deuterated derivative, prodrug, or pharma- ceutically acceptable salt thereof, wherein: [ka] Y is selected from O, S, NR', S=O, -S(=O)(=NR')- or O=S=O; X 1 , X 2 , X 3 and X 4 One of them is CR 2 Selected from and other X 1 , X 2 , X 3 and X 4 are each independently N or CR 4 Selected from; X 5 is N or CR1 Selected from; R 1 is hydrogen, deuterium, halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 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) 2 R', -S(O) 2 N(R') 2 , -NR'S(O) 2 R', -NR'S(O) 2 N(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; 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -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 substituted with 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) 2 R', -S(O) 2 N(R') 2 , -NR'S(O) 2 R', -NR'S(O) 2 N(R') 2 , -PO(R') 2 , each independently optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents selected from 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; R 2 -NR 51 R 52 , -OR 53 or -SR 54 and; R 3 is hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Haloalkyl, -C(O)R', -C(O)N(R') 2 , -C(O)OR', -S(O)R', -S(O)N(R') 2 , -S(O) 2 R', -S(O) 2 N(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; 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6Haloalkyl, 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 each independently optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents; Each R 3a 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) 2 R', -S(O) 2 N(R') 2 , -S(=O)(=NR')R', -NR'S(O) 2 R', -NR'S(O) 2 N(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; 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -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 each independently optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents; Each R 3b 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) 2 R', -S(O) 2 N(R') 2 , -S(=O)(=NR')R', -NR'S(O) 2 R', -NR'S(O) 2 N(R') 2 , -PO(R') 2 are independently selected from; R 4 are hydrogen, deuterium, halogen, and -C, respectively, when present. 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 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) 2 R', -S(O) 2 N(R') 2 , -NR'S(O) 2 R', -NR'S(O) 2 N(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; 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -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 substituted with 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) 2 R', -S(O) 2 N(R') 2 , -S(=O)(=NR')R', -NR'S(O) 2 R', -NR'S(O) 2 N(R') 2 , -PO(R') 2 , each independently optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents selected from 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; R 51 , R 52 , R 53 and R 54 is hydrogen, deuterium, -C1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Haloalkyl, -C(O)R', -C(O)N(R') 2 , -C(O)OR', -S(O)R', -S(O)N(R') 2 , -S(O) 2 R', -S(O) 2 N(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; 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -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 substituted with deuterium, halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -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) 2 R', -S(O) 2 N(R') 2 , -S(=O)(=NR')R', -NR'S(O) 2 R', -NR'S(O) 2 N(R')2 , -PO(R') 2 , each independently optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents selected from 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; R 11 and R 12 is hydrogen, deuterium, -OH, halogen, -CN, oxo, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Alkoxy, -NH 2 , -NHC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 or 3- to 6-membered cycloalkyl; 1-6 Alkyl, -C 1-6 Alkoxy and 3-6 membered cycloalkyl are substituted with deuterium, -OH, halogen, -CN, oxo, -C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -N(C 1-4 Alkyl) 2 or 3- to 6-membered cycloalkyl; R 13 is hydrogen, deuterium, -C 1-6 alkyl or 3- to 6-membered cycloalkyl; 1-6 Alkyl and 3-6 membered cycloalkyl are substituted with deuterium, -OH, halogen, -CN, oxo, -C 1-6 Alkoxy, -NH 2 , -NHC 1-6 Alkyl, or -N(C 1-4 Alkyl) 2 each independently optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents selected from: Each R', when present, is hydrogen, deuterium, halogen, -OH, -CN, oxo, -NH 2 , -NHC 1-6Alkyl, -N(C 1-6 Alkyl) 2 , -C 1-6 Alkyl, -C 1-6 Alkyl OC 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 2-6 Alkenyl, -C 2-6 alkynyl, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl; 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-14 Cycloalkyl, -C 3-14 Heterocycloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 6-12 membered aryl, or 5-12 membered heteroaryl may be substituted with deuterium, halogen, -CN, -C 1-3 Alkyl, oxo, -OH, -OC 1-3 Alkyl, -NH 2 , -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 , -C(=O)NH 2 , -C(=O)NH(C 1-3 alkyl), -C(=O)N(C 1-3 Alkyl) 2 , -S(=O) 2 NH 2 , -S(=O) 2 NH(C 1-3 Alkyl), -S(=O) 2 C 1-3 Alkyl, -S(=O) 2 N(C 1-3 Alkyl) 2 , -S(=O)(=NH)C 1-3 Alkyl, -S(=O)(=NC 1-3 Alkyl)C 1-3optionally substituted with 1, 2, 3, 4, 5, or 6 substituents each independently selected from alkyl, alkyl, or 3- to 6-membered cycloalkyl; said heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain 1, 2, or 3 heteroatoms selected from N, O, P, or S; m is selected from 1, 2, 3, 4, 5 or 6; The compound, or a stereoisomer, tautomer, deuterated derivative, prodrug or pharma- ceutically acceptable salt thereof.

[0018] [2] The compound represented by formula (I): [ka] and X in formula (I-1) 2 , X 3 , and X 4 is N or CR 4 are each independently selected from Y is selected from O, S, S=O, or O=S=O; The compound according to [1].

[0019] [3] The compound represented by formula (I): [ka] That is, The compound according to [1] or [2].

[0020] [4] The compound of formula (I), [ka] That is, The compound according to [1] or [2].

[0021] [5] The compound of formula (I), [ka] That is, The compound according to [1] or [2].

[0022] [6] The compound of formula (I), [ka] That is, The compound according to [1] or [2].

[0023] [7] The compound of formula (I), [ka] That is, The compound according to [1] or [2].

[0024] [8] The compound of formula (I), [ka] That is, The compound according to [1] or [2].

[0025] [9] The compound of formula (I), [ka] That is, The compound according to [1] or [2].

[0026]

[10] The compound of formula (I), [ka] Selected from: The compound according to any one of [1] to [3].

[0027]

[11] R 1 But halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6haloalkyl, -CN, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 6- to 10-membered aryl, or 5- to 12-membered heteroaryl; 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -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 selected from the group consisting of halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 and optionally substituted independently with one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents 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 said heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain 1 or 2 heteroatoms selected from N or S; The compound according to any one of [1] to

[10] .

[0028]

[12] R 1 -F, -Cl, -C 1-3 Alkyl, -C 2-4 Alkenyl, -C 2-4 Alkynyl, -C 1-3 haloalkyl, -CN, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 12-membered heteroaryl; 1-3 Alkyl, -C 2-4 Alkenyl, -C 2-4 Alkynyl, -C 1-3 Haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, and 5-12 membered heteroaryl are selected from the group consisting of -F, -Cl, -C 1-3Alkyl, -C 2-4 Alkenyl, -C 2-4 Alkynyl, -C 1-3 and optionally substituted independently with one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents selected from haloalkyl, -CN, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, or 5-12 membered heteroaryl, wherein said heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain 1 or 2 heteroatoms selected from N or S; The compound according to any one of [1] to

[11] .

[0029]

[13] R 1 -F, -Cl, -C 1-3 Alkyl, -C 1-3 haloalkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; 1-3 Alkyl, -C 1-3 Haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl is -F, -Cl, -C 1-3 Alkyl, -C 1-3 and optionally substituted independently with one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents selected from haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain 1 or 2 heteroatoms selected from N or S; The compound according to any one of [1] to

[12] .

[0030]

[14] R 1 -F, -Cl, -C 1-3 Alkyl, -C 1-3 haloalkyl, 3-6 membered cycloalkyl, 5 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S, or 6 membered heteroaryl containing 1 or 2 heteroatoms selected from N;1-3 Alkyl, -C 1-3 Haloalkyl, 3-6 membered cycloalkyl, 5 membered heteroaryl and 6 membered heteroaryl are -F, -C 1-3 Alkyl, -OC 1-3 Alkyl, -NH 2 , -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 , -CN or 3- to 6-membered cycloalkyl; The compound according to any one of [1] to

[12] .

[0031]

[15] R 1 But -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, -NH 2 , -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 , -C substituted with 1, 2 or 3 substituents selected from -CN or 3- to 6-membered cycloalkyl 1-3 independently selected from alkyl, The compound according to any one of [1] to

[14] .

[0032]

[16] R 1 but, [ka] are independently selected from The compound according to any one of [1] to

[15] .

[0033]

[17] R 2 But -NR 51 R 52 The compound according to any one of [1] to

[16] ,

[0034]

[18] R 2 But -NHR51 The compound according to any one of [1] to

[17] ,

[0035]

[19] R 51 But -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 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; 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl are halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -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 , 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, each of which independently contains one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents selected from, and each of which independently contains one heteroatom selected from, N, O, or S; The compound according to any one of [1] to

[18] .

[0036]

[20] R 51 But -C 1-3Alkyl, cyclopentyl, cyclohexyl, N, O, S, S(=O), S(=O)(=NH) or S(=O) 2 or N, O, S, S(=O), S(=O)(=NH) or S(=O) 2 6-membered heterocyclyl containing one heteroatom selected from the group consisting of -C 1-3 Alkyl, cyclopentyl, cyclohexyl, 5-membered heterocyclyl and 6-membered heterocyclyl are -F, -C 1-3 Alkyl, -OC 1-3 Alkyl, -NH 2 , -NHC 1-3 Alkyl, oxo, =NH, -N(C 1-3 Alkyl) 2 , -CN or 3- to 6-membered cycloalkyl; The compound according to any one of [1] to

[19] .

[0037]

[21] R 51 But -C 1-6 alkyl, 5-membered cycloalkyl, 5-membered heterocycloalkyl, 6-membered cycloalkyl, or 6-membered heterocycloalkyl; 1-6 Alkyl, cycloalkyl, and heterocycloalkyl are -F, -Cl, -CH 3 , -CD 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH(OH)CH 2 (OH), -CH(OCH 3 )CH 2 (OH), -CH(OH)CH 2 (OCH 3 ), -CH 2 CH(OH)(OCH 3 ), -CH 2 CH(OH)(OCH 2 CH 3 ), -CH2 CH(OCH 3 ) 2 、-OH、-O-CH 3 、-O-CH 2 CH 3 、-O-CH 2 CH 2 CH 3 、-O-CH(CH 3 ) 2 、-C(O)-(CH 2 )-NH 2 、-C(O)-(CH 2 )-NH(CH 3 )、-C(O)-(CH 2 )-NH(CH 2 CH 3 )、-C(O)-(CH 2 )-N(CH 3 ) 2 、-C(O)-(CH 2 CH 2 )-NH 2 、-C(O)-(CH 2 CH 2 )-NH(CH 3 )、-C(O)-(CH 2 CH 2 )-NH(CH 2 CH 3 )、-C(O)-(CH 2 CH 2 )-N(CH 3 ) 2 、-NH 2 、-NH(CH 3 )、-NH(CH 2 CH 3 )、-N(CH 3 ) 2 、-NH(CH 2 CH 2 CH 3 )、-NH(CH(CH 3 ) 2 )、または-N(CH 3 )(CH 2 CH 3), wherein said heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain one heteroatom selected from N, O, or S; The compound according to any one of [1] to

[20] .

[0038]

[22] R 51 but, [ka] or -C 1-6 alkyl, 1-6 R alkyl is 1, 2, 3, 4, 5 or 6 5e is optionally substituted with; R 5a , R 5c and R 5d But hydrogen;-C 1-6 Alkyl; or -F, -C 1-3 Alkyl, oxo, -OC 1-3 Alkyl, -NH 2 , -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 , -C substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -CN or 3- to 6-membered cycloalkyl 1-6 each independently selected from alkyl; R 5b and R 5e But, -F, -C 1-6 Alkyl, oxo, -OC 1-6 Alkyl, -NH 2 , -NHC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -CN, or 3- to 6-membered cycloalkyl; 1-6 Alkyl is -F, -C 1-3 Alkyl, oxo, -OC 1-3 Alkyl, -NH 2 , -NHC 1-3 Alkyl, -N(C 1-3Alkyl) 2 , -CN or 3- to 6-membered cycloalkyl; The compound according to any one of [1] to

[21] .

[0039]

[23] R 51 but, [ka] or -C 1-3 Alkyl-N(C 1-3 Alkyl) 2 Selected from; R 5a But -C 1-3 Alkyl; or -F, -C 1-3 Alkyl, oxo, -OC 1-3 Alkyl, -NH 2 , -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 , -C substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -CN or 3- to 6-membered cycloalkyl 1-3 independently selected from alkyl; R 5b But, -F, -C 1-3 Alkyl, oxo, -OC 1-3 Alkyl, -NH 2 , -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 or -CN; R 5c and R 5d But -C 1-3 each independently selected from alkyl, The compound according to any one of [1] to

[22] .

[0040]

[24] R 51 but, [ka] or -CH 2 CH 2-N(CH 3 ) 2 Selected from; R 5a Methyl, -CH 2 CH(OH)OCH 3 or -C(=O)CH 2 N(CH 3 ) 2 are independently selected from; R 5b is independently selected from -F; R 5c and R 5d are each independently selected from methyl; The compound according to any one of [1] to

[23] .

[0041]

[25] R 51 but, [ka] Selected from: The compound according to any one of [1] to

[24] .

[0042]

[26] R 3 However, hydrogen, deuterium, halogens, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Haloalkyl, -CN, -NO 2 , -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) 2 R', -NR'S(O) 2 R', -S(O) 2 N(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; 1-6Alkyl, -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 10-membered aryl, or 5- to 12-membered heteroaryl, each when present, are selected from halogen, NH 2 , N.H.-C. 1-6 Alkyl, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Haloalkyl, -CN, -NO 2 , -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) 2 R', -NR'S(O) 2 R', -S(O) 2 N(R') 2 , -S(=O)(=NR')R', 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 said heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain one heteroatom selected from N, O, or S; The compound according to any one of [1] to

[25] .

[0043]

[27] R 3 is independently selected from phenyl, or a 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, or S; said phenyl and 5-6 membered heteroaryl are independently selected from R 3c is optionally substituted with 1, 2, 3 substituents independently selected from R 3c But -F;-C1-3 Alkyl; -OC 1-3 Alkyl; -OC 3-6 Cycloalkyl; -NH 2 ;-NHC 1-3 Alkyl; -N(C 1-3 Alkyl) 2 ;-C(=O)NH 2 , -C(=O)NH(C 1-3 alkyl);-C(=O)N(C 1-3 Alkyl) 2 ;-CN;-S(=O) 2 NH 2 ;-S(=O) 2 NH(C 1-3 alkyl);-S(=O) 2 NHC(=O)C 1-3 Alkyl; -S(=O) 2 N(C 1-3 Alkyl) 2 ;-S(=O) 2 C 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 or 3- to 6-membered cycloalkyl; 1-3 Alkyl, C 3-6 Cycloalkyl, C 2-6 Heterocycloalkyl or OC 1-3 Alkyl, when present, is deuterium, -F, -C 1-3 Alkyl, oxo, -OH, -OC 1-3 Alkyl, -NH 2 , -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 , -C(=O)NH 2 , -C(=O)NH(C 1-3alkyl), -C(=O)N(C 1-3 Alkyl) 2 , -CN, -S(=O) 2 NH 2 , -S(=O) 2 NH(C 1-3 Alkyl), -S(=O) 2 C 1-3 Alkyl, -S(=O) 2 N(C 1-3 Alkyl) 2 , -S(=O)(=NH)C 1-3 Alkyl, -S(=O)(=NC 1-3 Alkyl)C 1-3 optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from alkyl, alkyl, or 3- to 6-membered cycloalkyl; The compound according to any one of [1] to

[25] .

[0044]

[28] R 3 is independently selected from phenyl or pyridinyl; The compound according to any one of [1] to

[27] .

[0045]

[29] R 3 is independently selected from phenyl, 5-membered heteroaryl, or 6-membered heteroaryl; said phenyl and heteroaryl, each present, are selected from -F, -Cl, -CH 3 , -CD 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CHFCH 3 , -CF 2 CH 3 , -CHFCH2 F、-CH 2 CHFCH 3 、-CH 2 CF 2 CH 3 、-CH 2 CH 2 CF 3 、-C(CH 3 ) 2 F、-CN、-OH、-O-CH 3 、-O-CH 2 CH 3 、-O-CH 2 CH 2 CH 3 、-O-CH(CH 3 ) 2 、-SH、-S-CH 3 、-S-CH 2 CH 3 、-S-CH 2 CH 2 CH 3 、-S-CH(CH 3 ) 2 、-CHO、-C(O)-CH 3 、-C(O)-CH 2 CH 3 、-C(O)-CH 2 CH 2 CH 3 、-C(O)-CH(CH 3 ) 2 、-C(O)NH 2 、-C(O)NH(CH 3 )、-C(O)NH(CH 2 CH 3 )、-C(O)N(CH 3 ) 2 、-C(O)NH(CH 2 CH 2 CH 3 )、-C(O)NH(CH(CH 3 ) 2 )、-C(O)N(CH 3 )(CH 2 CH 3 )、-NH 2 、-NH(CH 3 )、-NH(CH 2 CH 3 )、-N(CH 3 ) 2、-NH(CH 2 CH 2 CH 3 )、-NH(CH(CH 3 ) 2 )、-N(CH 3 )(CH 2 CH 3 )、-NHC(O)(CH 3 )、-NHC(O)(CH 2 CH 3 )、-NHC(O)(CH 3 ) 2 、-NHC(O)(CH 2 CH 2 CH 3 )、-NHC(O)(CH(CH 3 ) 2 )、-NHC(O)(CH 3 )(CH 2 CH 3 )、-S(O) 2 H、-S(O) 2 (CH 3 )、-S(O) 2 (CH 2 CH 3 )、-S(O) 2 (CH 3 ) 2 、-S(O) 2 (CH 2 CH 2 CH 3 )、-S(O) 2 (CH(CH 3 ) 2 )、-S(O) 2 (CH 3 )(CH 2 CH 3 )、-S(O) 2 NH 2 、-S(O) 2 NH(CH 3 )、-S(O) 2 NH(CH 2 CH 3 )、-S(O) 2 N(CH 3 ) 2 、-S(O) 2 NH(CH 2 CH 2 CH 3 )、-S(O) 2NH(CH(CH 3 ) 2 ), -S(O) 2 N(CH 3 )(CH 2 CH 3 ), -S(=O)(=NH)CH 3 , or -S(=O)(=NCH 3 )CH 3 wherein said heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain one heteroatom selected from N, O, or S; The compound according to any one of [1] to

[28] .

[0046]

[30] R 3 is independently selected from phenyl, 5-membered heteroaryl, or 6-membered heteroaryl; said phenyl and heteroaryl, each present, are selected from -F, -CH 3 , -CD 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 F, -CF 3 , -CH 2 CH 2 F, -CHFCH 3 , -CF 2 CH 3 , -C(CH 3 ) 2 F, -OH, -O-CH 3 , -O-CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , -O-CH(CH 3 ) 2 , -C(O)NH 2 , -C(O)NH(CH 3 ), -C(O)NH(CH 2 CH 3 ), -C(O)N(CH3 ) 2 、-C(O)NH(CH 2 CH 2 CH 3 )、-C(O)NH(CH(CH 3 ) 2 )、-C(O)N(CH 3 )(CH 2 CH 3 )、-NH 2 、-NH(CH 3 )、-NH(CH 2 CH 3 )、-N(CH 3 ) 2 、-NH(CH 2 CH 2 CH 3 )、-NH(CH(CH 3 ) 2 )、-N(CH 3 )(CH 2 CH 3 )、-S(O) 2 H、-S(O) 2 (CH 3 )、-S(O) 2 (CH 2 CH 3 )、-S(O) 2 (CH 3 ) 2 、-S(O) 2 (CH 2 CH 2 CH 3 )、-S(O) 2 (CH(CH 3 ) 2 )、-S(O) 2 (CH 3 )(CH 2 CH 3 )、-S(O) 2 NH 2 、-S(O) 2 NH(CH 3 )、-S(O) 2 NH(CH 2 CH 3 )、-S(O) 2 N(CH 3 ) 2 、-S(O) 2 NH(CH 2 CH 2 CH3 ), -S(O) 2 NH(CH(CH 3 ) 2 ), -S(O) 2 N(CH 3 )(CH 2 CH 3 ), -S(=O)(=NH)CH 3 , or -S(=O)(=NCH 3 )CH 3 wherein said heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain one heteroatom selected from N, O, or S; The compound according to any one of [1] to

[29] .

[0047]

[31] R 3 but, [ka] are independently selected from The compound according to any one of [1] to

[30] .

[0048]

[32] The compound of formula (I), [ka] and; During the ceremony, R 51 But -C 1-3 Alkyl, cyclopentyl, cyclohexyl, N, O, S, S(=O), S(=O)(=NH) or S(=O) 2 or N, O, S, S(=O), S(=O)(=NH) or S(=O) 2 6-membered heterocyclyl containing one heteroatom selected from the group consisting of -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 Alkyl) 2 , -CN, or 3- to 6-membered cycloalkyl; R 1 -F, -Cl, -C 1-3 Alkyl, -C 2-4 Alkenyl, -C 2-4 Alkynyl, -C 1-3 haloalkyl, -CN, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 12-membered heteroaryl; 1-3 Alkyl, -C 2-4 Alkenyl, -C 2-4 Alkynyl, -C 1-3 Haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, and 5-12 membered heteroaryl are selected from the group consisting of -F, -Cl, -C 1-3 Alkyl, -C 2-4 Alkenyl, -C 2-4 Alkynyl, -C 1-3 optionally substituted independently with one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents selected from haloalkyl, -CN, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, or 5-12 membered heteroaryl, wherein said heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain 1 or 2 heteroatoms selected from N or S; Each R 4 But hydrogen, deuterium, -F, -Cl, -C 1-3 Alkyl, -OC 1-3 Alkyl, -NH 2 , -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 , —CN, or 3-6 membered cycloalkyl; R 11 and R 12 But hydrogen, deuterium, -F, -C 1-3 Alkyl, oxo, -OC1-3 Alkyl, -NH 2 , -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 , -CN, or 3- to 6-membered cycloalkyl; 1-3 Alkyl is -F, -C 1-3 Alkyl, oxo, -OC 1-3 Alkyl, -NH 2 , -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 , —CN, or 3- to 6-membered cycloalkyl; R 13 But hydrogen;-C 1-3 Alkyl; or -F, -C 1-3 Alkyl, -C 1-3 Alkyl, oxo, -OC 1-3 Alkyl, -NH 2 , -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 , -C substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -CN or 3- to 6-membered cycloalkyl 1-3 alkyl; R 3 is independently selected from phenyl, or a 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, or S; said phenyl and 5-6 membered heteroaryl are independently selected from R 3c and optionally substituted with 1, 2, or 3 substituents independently selected from: R 3c But -F;-C 1-3 Alkyl; -OC 1-3 Alkyl; -NH 2 ;-NHC 1-3 Alkyl; -N(C 1-3 Alkyl) 2 ;-C(=O)NH 2 , -C(=O)NH(C 1-3 alkyl);-C(=O)N(C 1-3 Alkyl) 2 ;-CN;-S(=O)2 NH 2 ;-S(=O) 2 NH(C 1-3 alkyl);-S(=O) 2 N(C 1-3 Alkyl) 2 ; 3-6 membered cycloalkyl; or -F, -C 1-3 Alkyl, oxo, -OC 1-3 Alkyl, -NH 2 , -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 , -C(=O)NH 2 , -C(=O)NH(C 1-3 alkyl), -C(=O)N(C 1-3 Alkyl) 2 , -CN, -S(=O) 2 NH 2 , -S(=O) 2 NH(C 1-3 Alkyl), -S(=O) 2 N(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- to 6-membered cycloalkyl 1-3 selected from alkyl, The compound according to any one of [1] to

[31] .

[0049]

[33] R 51 but, [ka] or -C 1-6 alkyl, 1-6 R with 1, 2, 3, 4, 5, or 6 alkyl 5e is optionally substituted with; R 5a , R 5c and R 5d But hydrogen;-C 1-6 Alkyl; or -F, -C 1-3Alkyl, oxo, -OC 1-3 Alkyl, -NH 2 , -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 , -C substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -CN or 3- to 6-membered cycloalkyl 1-6 each independently selected from alkyl; R 5b and R 5e But, -F, -C 1-6 Alkyl, oxo, -OC 1-6 Alkyl, -NH 2 , -NHC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -CN, or 3- to 6-membered cycloalkyl; 1-6 Alkyl is -F, -C 1-3 Alkyl, oxo, -OC 1-3 Alkyl, -NH 2 , -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 , -CN or 3-6 membered cycloalkyl; R 1 But -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, -NH 2 , -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 , -C substituted with 1, 2 or 3 substituents selected from -CN or 3- to 6-membered cycloalkyl 1-3 independently selected from alkyl; Each R 4 But hydrogen, deuterium, -F, -Cl, -C 1-3 Alkyl, -OC 1-3 Alkyl, -NH 2 , -NHC 1-3 Alkyl, -N(C1-3 Alkyl) 2 , —CN, or 3-6 membered cycloalkyl; R 11 and R 12 is hydrogen or -C 1-3 independently selected from alkyl; R 13 is hydrogen or -C 1-3 alkyl; R 3 is selected from phenyl, said phenyl being R 3c and optionally substituted with 1, 2, or 3 substituents independently selected from: R 3c But -F;-C 1-3 Alkyl; -OC 1-3 Alkyl; -NH 2 ;-NHC 1-3 Alkyl; -N(C 1-3 Alkyl) 2 ;-C(=O)NH 2 , -C(=O)NH(C 1-3 alkyl);-C(=O)N(C 1-3 Alkyl) 2 ;-CN;-S(=O) 2 NH 2 ;-S(=O) 2 NH(C 1-3 alkyl);-S(=O) 2 N(C 1-3 Alkyl) 2 ;-S(=O) 2 C 1-3 Alkyl; -S(=O)(=NH)CH 3 ; or -S(=O)(=NCH 3 )CH 3 Selected from: The compound according to

[32] .

[0050]

[34] R 51 but, [ka] Selected from; R 1 but, [ka] are independently selected from; Each R 4 is hydrogen; R 11 and R 12 is independently selected from hydrogen; R 13 is selected from hydrogen; R 3 but, [ka] Selected from: The compound described in

[33] .

[0051]

[35] . The compound of formula (I) [ka] That is, The compound according to any one of [1] to

[34] .

[0052]

[36] .R 1 But -C 1-3 Haloalkyl; or -F, -CN, -OC 1-3 Alkyl, -NH 2 , -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 or 3- to 6-membered cycloalkyl (e.g., cyclopropyl), 1-3 independently selected from alkyl, The compound described in

[35] .

[0053]

[37] .R 1 but, [ka] are independently selected from The compound according to

[35] or

[36] .

[0054]

[38] .R 2But -NHR 51 That is, The compound according to any one of

[35] to

[37] .

[0055]

[39] .R 51 But -C 1-6 Alkyl, -C 1-6 haloalkyl, 3-6 membered cycloalkyl, or 3-10 membered heterocycloalkyl; 1-6 Alkyl, -C 1-6 haloalkyl, 3- to 6-membered cycloalkyl, or 3- to 10-membered heterocycloalkyl is selected from the group consisting of halogen, -C 1-6 Alkyl (halogen, -CN, oxo, =NH, -OH, -OC 1-6 Alkyl, or halogen, -CN, oxo, =NH, -OH, or -OC 1-6 Optionally substituted with one or more 5-6 membered heterocycloalkyl optionally substituted with one or more alkyl; 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Haloalkyl, -CN, -OH, -NH 2 , 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 membered cycloalkyl, or 3-12 membered heterocycloalkyl (e.g., 5-12 membered spiroheterocyclyl or bridged heterocyclyl (halogen, -CN, oxo, =NH, -OH, or -OC 1-6each independently optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents selected from: The compound according to any one of

[35] to

[38] .

[0056]

[40] .R 51 But -C 1-6 alkyl, 3- to 6-membered cycloalkyl, or 5- to 10-membered heterocycloalkyl (e.g., 5- to 10-membered spiroheterocyclyl or bridged heterocyclyl); 1-6 Alkyl, 3- to 6-membered cycloalkyl, or 5- to 10-membered heterocycloalkyl is selected from the group consisting of halogen, -C 1-6 Alkyl (halogen, -CN, oxo, =NH, -OH, -OC 1-6 Alkyl, or [ka] Optionally substituted with one or more of -CN, -OH, NH 2 , 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 membered cycloalkyl, or 5-12 membered heterocycloalkyl (e.g., 5-12 membered spiroheterocyclyl or bridged heterocyclyl (halogen, -CN, oxo, =NH, -OH, or -OC 1-6 each independently optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents selected from: The compound according to any one of

[35] to

[39] .

[0057]

[41] .R 51 But -C 1-3 alkyl, cyclohexyl, or 6-8 membered heterocycloalkyl (e.g., 6-8 membered spiroheterocyclyl or bridged heterocyclyl); 1-3 Alkyl, cyclohexyl, or 6-8 membered heterocycloalkyl is halogen, -C 1-6 Alkyl (oxo, =NH, -OH, -OC 1-6 Alkyl, or [ka] Optionally substituted with one or more of -CN, -OH, NH 2 , oxo, =NH, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C(O)CH 2 -NHC 1-6 Alkyl, -C(O)CH 2 -N(C 1-6 Alkyl) 2 , -NHC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , cyclopropyl, or 5-12 membered heterocycloalkyl (e.g. [ka] and wherein the heterocycloalkyl independently contains one or more heteroatoms selected from N, O, or S, and preferably R 51 but, [ka] That is, The compound according to any one of

[35] to

[40] .

[0058]

[42] .R 2 but, [ka] Selected from TIFF2024530952000030.tif216170, The compound according to any one of

[35] to

[41] .

[0059]

[43] .R 3 is independently selected from phenyl, a 5-10 membered heterocycloalkenyl containing 1 or 2 heteroatoms selected from N, O, or S, or a 5-10 membered, preferably 5-6 membered, heteroaryl containing 1 or 2 heteroatoms selected from N, O, or S; each of which is selected from R 3a and optionally substituted with 1, 2, or 3 substituents independently selected from: R 3a But halogen; oxo; -C 1-3 Alkyl; -OC 1-3 Alkyl; -NH 2 ;-NHC 1-3 Alkyl; -N(C 1-3 Alkyl) 2 ;-C(=O)NH 2 , -C(=O)NH(C 1-3 alkyl);-C(=O)N(C 1-3 Alkyl) 2 ;-CN;-S(=O) 2 NH 2 ;-S(=O) 2 NH(C 1-3 alkyl);-S(=O) 2 NHC(=O)C 1-3 Alkyl; -S(=O) 2 N(C 1-3 Alkyl) 2 ;-S(=O) 2 C 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)(=NC2-6 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) 2 C 1-3 Alkyl; -PO(C 1-3 Alkyl) 2 3-6 membered cycloalkyl; 3-6 membered heterocycloalkyl optionally containing 1, 2 or 3 heteroatoms selected from N, O, P or S; 1-3 Alkyl, OC 1-3 Alkyl, 3-6 membered cycloalkyl, C 3-6 Cycloalkyl, C 2-6 Heterocycloalkyl or 3-6 membered heterocycloalkyl, when present, are each selected from deuterium, halogen, -CN, -C 1-3 Alkyl, oxo, -OH, -OC 1-3 Alkyl, -NH 2 , -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 , -COOH, -C(O)OC 1-3 Alkyl, -C(=O)NH 2 , -C(=O)NH(C 1-3 alkyl), -C(=O)N(C 1-3 Alkyl) 2 , -S(=O) 2 NH 2 , -S(=O) 2 NH(C 1-3 Alkyl), -S(=O) 2 C 1-3 Alkyl, -S(=O) 2 N(C 1-3 Alkyl) 2 , -S(=O)(=NH)C 1-3 Alkyl, -S(=O)(=NC 1-3 Alkyl)C 1-3 optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from alkyl, alkyl, or 3- to 6-membered cycloalkyl; The compound according to any one of

[35] to

[42] .

[0060]

[44] .R 3 is independently selected from phenyl, pyridinyl, and 5-10 membered benzoheterocycloalkyl containing 1 or 2 heteroatoms selected from N, O, or S, each of which is selected from R 3a optionally substituted with 1, 2, or 3 substituents selected from; R 3a Deuterium, -F; oxo; -OC 1-3 Alkyl; -C(=O)NH 2 , -C(=O)NH(C 1-3 alk(yl);-CN;-S(=O) 2 NH 2 ;-S(=O) 2 NH(C 1-3 alkyl);-S(=O) 2 NHC(=O)C 1-3 Alkyl; -S(=O) 2 N(C 1-3 Alkyl) 2 ;-S(=O) 2 C 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) 2 C 1-3 Alkyl; -PO(C 1-3 Alkyl) 2 or a 3-6 membered heterocycloalkyl optionally containing 1, 2 or 3 heteroatoms selected from N, O, P or S; 1-3 Alkyl, OC 1-3 Alkyl or 3-6 membered heterocycloalkyl, when present, are each selected from deuterium, -F, -CN, oxo, -C 1-3 Alkyl, -OH, -OC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 , -C(O)OC 1-3 Alkyl, -C(=O)NH 2 , -C(=O)NH(C1-3 alkyl), or -C(=O)N(C 1-3 Alkyl) 2 and optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from The compound described in

[43] .

[0061]

[45] .R 3 However, phenyl, pyridinyl, [ka] each of which is selected from R 3a optionally substituted with 1, 2, 3 substituents selected from; R 3a -F; oxo; -OC 1-3 Alkyl; -C(=O)NHC 1-3 Alkyl; -S(=O) 2 NH 2 ;-S(=O) 2 NHC(=O)CH 3 ;-S(=O) 2 CH 3 ;-S(=O)(=NH)C 1-3 Alkyl; -S(=O)(=NC 1-3 Alkyl)C 1-3 Alkyl; -N(CH 3 )S(=O) 2 CH 3 ;-PO(C 1-3 Alkyl) 2 morpholinyl or a 5-6 membered heterocycloalkyl optionally containing 1, 2 or 3 heteroatoms selected from N, O, or P; 1-3 Alkyl, OC 1-3 Alkyl or 5-6 membered heterocycloalkyl, when present, are each selected from deuterium, -F, -CN, oxo, -OH, -OCH 3 , -N(C 1-3 Alkyl) 2 , -C(O)OCH 3 or -C(=O)NH; The compound described in

[44] .

[0062]

[46] .R 3 But R 3a phenyl optionally substituted with 1, 2, or 3 substituents selected from R 3a But, -F, -OCH 3 , -OCD 3 , -OCH 2 CN, -OCH 2 CF 3 , -CH 2 F, -CHF 2 , -OCH 2 CH 2 OH, -OCH 2 CH 2 OCH 3 , -S(O) 2 NH 2 , -S(O) 2 NHCOCH 3 , -S(O) 2 CH 3 , -S(=O)(=NH)CH 3 , -S(=O)(=NCH 3 )CH 3 , -N(CH 3 )S(=O) 2 CH 3 , -C(O)NHCH 3 , -C(O)NHCH(COOCH 3 )CH 2 CH 2 CONH 2 , -PO(CH 3 ) 2 , morpholinyl, or [ka] Selected from: The compound described in

[43] .

[0063]

[47] .R 11 and R 12 and both are hydrogen.

[0064]

[48] .R 13The compound according to any one of [1] to

[47] , wherein is H.

[0065]

[49] .Chemical part [ka] but, [ka] Selected from: The compound according to any one of [1] to

[48] .

[0066]

[50] .Chemical part [ka] but, [ka] Selected from: The compound according to any one of [1] to

[48] .

[0067]

[51] .Chemical part [ka] but, [ka] Selected from: The compound according to any one of [1] to

[48] .

[0068]

[52] .Chemical part [ka] but, [ka] Selected from: The compound according to any one of [1] to

[48] .

[0069]

[53] .Chemical part [ka] but, [ka] Selected from: The compound according to any one of [1] to

[48] .

[0070]

[54] The compound according to any one of [1] to

[53] , wherein the compound of formula (I) is selected from the following: [Table 1] TIFF2024530952000044.tif202170TIFF2024530952000045.tif211170TIFF2024530952000046.tif213170TIFF2024530952000047.tif210170TIFF2024530952000048.tif213170TIFF2024530952000049.tif207170TIFF2024530952000050.tif213170TIFF2024530952000051.tif205170TIFF2024530952000052.tif208170TIFF2024530952000053.tif211170TIFF2024530952000054.tif213170TIFF2024530952000055.tif220170TIFF2024530952000056.tif221170TIFF2024530952000057.tif214170TIFF2024530952000058.tif214170TIFF2024530952000059.tif216170TIFF2024530952000060.tif212170TIFF2024530952000061.tif214170TIFF2024530952000062.tif212170TIFF2024530952000063.tif213170TIFF2024530952000064.tif211170TIFF2024530952000065.tif214170TIFF2024530952000066.tif215170TIFF2024530952000067.tif219170TIFF2024530952000068.tif222170TIFF2024530952000069.tif220170TIFF2024530952000070.tif210170TIFF2024530952000071.tif212170TIFF2024530952000072.tif217170TIFF2024530952000073.tif218170TIFF2024530952000074.tif212170TIFF2024530952000075.tif215170TIFF2024530952000076.tif220170TIFF2024530952000077.tif213170TIFF2024530952000078.tif214170TIFF2024530952000079.tif219170TIFF2024530952000080.tif212170TIFF2024530952000081.tif213170TIFF2024530952000082.tif221170TIFF2024530952000083.tif209170TIFF2024530952000084.tif206170TIFF2024530952000085.tif211170TIFF2024530952000086.tif214170TIFF2024530952000087.tif215170TIFF2024530952000088.tif206170TIFF2024530952000089.tif217170TIFF2024530952000090.tif213170TIFF2024530952000091.tif212170TIFF2024530952000092.tif217170TIFF2024530952000093.tif219170TIFF2024530952000094.tif210170TIFF2024530952000095.tif219170TIFF2024530952000096.tif218170TIFF2024530952000097.tif206170TIFF2024530952000098.tif211170TIFF2024530952000099.tif220170TIFF2024530952000100.tif210170TIFF2024530952000101.tif211170TIFF2024530952000102.tif210170TIFF2024530952000103.tif213170TIFF2024530952000104.tif216170TIFF2024530952000105.tif216170TIFF2024530952000106.tif221170TIFF2024530952000107.tif209170TIFF2024530952000108.tif221170TIFF2024530952000109.tif214170TIFF2024530952000110.tif220170TIFF2024530952000111.tif214170TIFF2024530952000112.tif222170TIFF2024530952000113.tif221170TIFF2024530952000114.tif214170TIFF2024530952000115.tif217170TIFF2024530952000116.tif215170TIFF2024530952000117.tif214170TIFF2024530952000118.tif220170TIFF2024530952000119.tif206170TIFF2024530952000120.tif212170TIFF2024530952000121.tif214170TIFF2024530952000122.tif220170TIFF2024530952000123.tif221170TIFF2024530952000124.tif219170TIFF2024530952000125.tif221170TIFF2024530952000126.tif216170TIFF2024530952000127.tif221170TIFF2024530952000128.tif221170TIFF2024530952000129.tif221170TIFF2024530952000130.tif222170TIFF2024530952000131.tif216170TIFF2024530952000132.tif216170TIFF2024530952000133.tif216170TIFF2024530952000134.tif214170TIFF2024530952000135.tif213170TIFF2024530952000136.tif224170TIFF2024530952000137.tif215170TIFF2024530952000138.tif223170TIFF2024530952000139.tif217170TIFF2024530952000140.tif221170TIFF2024530952000141.tif215170TIFF2024530952000142.tif221170TIFF2024530952000143.tif223170TIFF2024530952000144.tif172170.

[0071]

[55] . The compound of formula (I), [ka] TIFF2024530952000146.tif189170TIFF2024530952000147.tif195170TIFF2024530952000148.tif161170TIFF2024530952000149.tif195170TIFF 2024530952000150.tif200170TIFF2024530952000151.tif197170TIFF2024530952000152.tif205170TIFF2024530952000153.tif208170TIFF20245 30952000154.tif212170TIFF2024530952000155.tif217170TIFF2024530952000156.tif209170TIFF2024530952000157.tif221170TIFF2024530952 000158.tif218170TIFF2024530952000159.tif209170TIFF2024530952000160.tif222170TIFF2024530952000161.tif214170TIFF202453095200016 2.tif214170TIFF2024530952000163.tif221170TIFF2024530952000164.tif205170TIFF2024530952000165.tif220170TIFF2024530952000166.ti f216170TIFF2024530952000167.tif217170TIFF2024530952000168.tif221170TIFF2024530952000169.tif222170TIFF2024530952000170.tif2301 70TIFF2024530952000171.tif226170TIFF2024530952000172.tif221170TIFF2024530952000173.tif214170TIFF2024530952000174.tif223170TIFF2024530952000175.tif211170TIFF2024530952000176.tif185170TIFF2024530952000177.tif217170TIFF2024530952000178.tif153170 The compound according to any one of [1] to

[53] .

[0072]

[56] . The compound of formula (I), [ka] TIFF2024530952000180.tif215170TIFF2024530952000181.tif217170TIFF2024530952000182.tif227170TIFF2024530952000183.tif214170TIFF2024530952000184.tif225170TIFF2024530952000185.tif223170TIFF2024530952000186.tif221170TIFF2024530952000187.tif223170TIFF2024530952000188.tif215170TIFF2024530952000189.tif221170TIFF2024530952000190.tif214170TIFF2024530952000191.tif219170TIFF2024530952000192.tif213170TIFF2024530952000193.tif219170TIFF2024530952000194.tif216170TIFF2024530952000195.tif211170TIFF2024530952000196.tif207170TIFF2024530952000197.tif218170TIFF2024530952000198.tif226170TIFF2024530952000199.tif223170TIFF2024530952000200.tif211170TIFF2024530952000201.tif209170TIFF2024530952000202.tif221170TIFF2024530952000203.tif225170TIFF2024530952000204.tif211170TIFF2024530952000205.tif226170TIFF2024530952000206.tif211170TIFF2024530952000207.tif208170TIFF2024530952000208.tif208170TIFF2024530952000209.tif203170TIFF2024530952000210.tif219170TIFF2024530952000211.tif217170TIFF2024530952000212.Selected from .tif210170TIFF2024530952000213.tif189170, . The compound according to any one of [1] to

[53] .

[0073]

[57] . The compound of formula (I), [ka] TIFF2024530952000215.tif217170TIFF2024530952000216.tif217170TIFF2024530952000217.tif191170TIFF2024530952000 218.tif217170TIFF2024530952000219.tif215170TIFF2024530952000220.tif213170TIFF2024530952000221.tif229170TIFF 2024530952000222.tif229170TIFF2024530952000223.tif224170TIFF2024530952000224.tif211170TIFF2024530952000225.tif224170TIFF2024530952000226.tif232170TIFF2024530952000227.tif223170TIFF2024530952000228.tif240170, The compound according to any one of [1] to

[53] .

[0074]

[58] . The compound of formula (I), [ka] TIFF2024530952000230.tif214170TIFF2024530952000231.tif215170TIFF2024530952000232.ti f223170TIFF2024530952000233.tif220170TIFF2024530952000234.tif216170TIFF2024530952000 235.tif217170TIFF2024530952000236.tif229170TIFF2024530952000237.tif216170TIFF202453 0952000238.tif225170TIFF2024530952000239.tif215170TIFF2024530952000240.tif191170TIFF 2024530952000241.tif183170TIFF2024530952000242.tif184170TIFF2024530952000243.tif184 170TIFF2024530952000244.tif192170TIFF2024530952000245.tif193170TIFF2024530952000246. Selected from tif199170TIFF2024530952000247.tif187170TIFF2024530952000248.tif181170TIFF2024530952000249.tif184170TIFF2024530952000250.tif189170TIFF2024530952000251.tif117170 The compound according to any one of [1] to

[53] .

[0075]

[59] . [ka] TIFF2024530952000253.tif202170TIFF2024530952000254.tif198170TIFF2024530952000255.tif191170TIFF2024530952000256.tif203170TIFF2024530952000257.tif80170 The compound according to any one of [1] to

[53] .

[0076]

[60] . A compound of formula (IN-I): [ka] In the formula, R 1 , R 2 or R 4 is defined as in any one of claims 1 to 59, and LG is selected from leaving groups such as halogen, preferably from leaving groups such as bromine or iodine.

[0077]

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

[59] , comprising the steps of: [ka] (1) reacting a compound S1-1 as a starting material with a compound S1-2 in the presence of an alkalizing agent to form a 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 a compound of formula (I-1) by one or more steps of reactions such as reductive amination reaction, deprotection reaction, or a combination thereof; Here, L 1 , L 2 and L 3 each independently represents a leaving group; Y is selected from O or S; X 2 , X 3 , X 4 , R 1 , R 2 , R 11 , R 12 , R 13 , R 3 , R51 , R 52 and m are each as defined in any one of [1] to

[59] .

[0078]

[62] . The alkalizing agent is K 2 CO 3 The method according to

[61] ,

[0079]

[63] The method according to

[61] or

[62] , wherein the acidic condition is polyphosphoric acid.

[0080]

[64] The method according to

[61] or

[62] , wherein the halogenating agent is NIS.

[0081]

[65] .R 2 Ga-NR 51 R 52 When the group L of compound S5-1 is 1 But -NH 2 and subsequently converted to a compound of formula (I-1) via a reductive amination reaction, a deprotection reaction or a combination thereof.

[0082]

[66] . The coupling catalyst is Pd(PPh 3 ) 2 Cl 2 or Pd(dppf)Cl 2 The method according to

[61] or

[62] , comprising a Pd-containing coupling catalyst such as

[0083]

[67] The method of

[61] or

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

[0084]

[68] .L 1 is selected from -Br; L 2 is selected from -Br; and L 3 The method according to

[61] or

[62] , wherein -I is selected from the group consisting of -I and -I.

[0085]

[69] . A pharmaceutical composition comprising 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 pharma- ceutically acceptable salt thereof, and a pharma-ceutically acceptable carrier, diluent, or excipient.

[0086]

[70] Use 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 pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to

[69] , in the manufacture of a medicament 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 cancer.

[0088]

[72] . The use according to

[71] , wherein the cancer cells express a p53 mutant.

[0089]

[73] . The use of

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

[0090]

[74] . The use according to

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

[0091]

[75] . The use according to any one of

[70] to

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

[0092]

[76] . 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 pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to

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

[0093]

[77] . A method for preventing or treating a disease or condition associated with a mutant p53 protein in a subject, comprising administering to the subject a therapeutically effective amount of 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 pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described in

[69] .

[0094]

[78] The method according to

[77] , wherein the disease or condition is cancer.

[0095]

[79] . The method according to

[78] , wherein the cancer cells express mutant p53.

[0096]

[80] . The use of

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

[0097]

[81] The method of

[79] , wherein the p53 mutation is V157F, R175H, Y220C, G245S, R248Q, R248W, R249S, R273H, R273C, R282W, and / or combinations 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.

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

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

[0101] To determine the ability of the compounds of the present invention to bind and stabilize p53 mutants, assays can be used to detect, for example, the conformational change of p53 mutants or the activity of wild-type p53 targets. The conformational change of p53 can be measured, for example, by differential scanning fluorometry (DSF), isothermal titration calorimetry (ITC), nuclear magnetic resonance spectroscopy (NMR), or X-ray crystallography. In addition, conformational change can be detected, for example, by immunoprecipitation (IP), immunofluorescence (IF), or immunoblotting, using an antibody specific to the wild-type of mutant conformation of p53. Methods used to detect the ability of p53 mutants to bind 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, 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 (RT-PCR), and Western blotting. Activation of p53 can also be measured by induction of apoptosis, cis-, via the caspase cascade, using methods such as Annexin V staining, TNMEL assay, procaspase and caspase levels, cytochrome c levels, etc. Another consequence of p53 activation is senescence, which can be measured using methods such as β-galactosidase staining.

[0102] In an in vitro DNA binding assay, some of the compounds described herein show an EC of 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, 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, 0.400 μM or less, 0.500 μM or less, 0.600 μM or less, 0.800 μM or less, 1.000 μM or less, 1.500 μM or less, 2.000 μM or less, 6.000 μM or less, or 10.000 μM or less. 50 It may indicate.

[0103] In the cell viability assay of cell lines carrying p53 Y220C mutants such as NΜGC-3 (p53, Y220C), some of the compounds described herein have an IC 50 that can be shown.

[0104] In the cell viability assay of cell lines having wild-type p53 such as NΜGC-4 (p53, wt), some of the compounds described herein have an IC of 1.00 μM or more, 1.30 μM or more, 1.60 μM or more, 2.00 μM or more, 2.50 μM or more, 3.00 μM or more, 3.50 μM or more, 4.00 μM or more, 4.50 μM or more, 5.00 μM or less, 5.50 μM or more, 6.00 μM or more, 6.50 μM or more, 7.00 μM or more, 7.50 μM or more, 8.00 μM or more, 8.50 μM or more, 9.00 μM or more, 9.50 μM or more, 10.00 μM or more, 10.50 μM or more, 11.00 μM or more, 11.50 μM or more, 12.00 μM or more, 12.50 μM or more, 13.00 μM or more, 13.50 μM or more, 14.00 μM or more, 15.00 μM or more, 16.00 μM or more, 17.00 μM or more, 18.00 μM or more, 19.00 μM or more, 20.00 μM or more, or 21.00 μM or more.50 It can be shown that

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

[0106] In some embodiments, some compounds of the invention 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, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 120, 121, 132, 133, 142, 143, 144, 145, 146, 147, 148, 150, 151, 152, 153, 164, 165, 170, 171, It may exhibit 24-fold, 25-fold, 26-fold, 27-fold, 28-fold, 29-fold, 30-fold, 31-fold, 32-fold, 33-fold, 34-fold, 35-fold, 36-fold, 37-fold, 38-fold, 39-fold, 40-fold, 45-fold, 50-fold, 55-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 120-fold, 150-fold, 200-fold, or 300-fold selectivity or specificity.

[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; 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 ≤μM, ≤0.750 μM, ≤0.800 μM, ≤0.900 μM, ≤1.000 μM, ≤5.000 μM, or ≤10.000 μM 50 It can be shown that

[0108] The present invention is described using several definitions herein and throughout the application, as set forth below.

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

[0110] As used herein, "about," "approximately," "substantially," and "significantly" are understood by those of ordinary skill in the art and will vary to some extent depending on the context in which they are used. If there are applications of these terms that are not clear to those of ordinary skill in the art from the context in which they are used, "about" and "approximately" mean plus or minus less than 10% of the particular term, and "substantially" and "significantly" mean plus or minus more than 10% of the particular term.

[0111] As used herein, the words "include" and "including" have the same meaning as "comprise" and "comprising," the latter terms being "open" transitional terms that do not limit the claims to only the recited elements following these transitional terms. The word "consisting of," although included in the word "comprising," should be interpreted as a "closed" transitional phrase that limits the claims to only the recited elements following this transitional phrase. The word "consisting essentially of," although included in the word "comprising," should be interpreted as a "partially closed" transitional phrase that allows additional elements following this transitional phrase, but only if the 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 defined herein is represented by an abbreviation preceding the group. For example, C 1-6 Alkyl means an alkyl group as defined below having a total of 1 to 6 carbon atoms; 3-8 Cycloalkyl means a cycloalkyl group as defined below having a total of 3 to 8 carbon atoms; 6-10By aryl is meant an aryl group as defined below having a total of 6 to 10 carbon atoms. Carbon atoms that may be present in substituents of a chemical group are not included in the total number of carbon atoms in the shorthand notation.

[0113] Unless otherwise indicated herein, all linking groups (i.e., groups comprised of two or more groups) according to the present invention are attached to the remainder of the molecule in such a way that the last listed group acts as the point of attachment. For example, "arylalkyl" means that an aryl group is attached to the remainder of the molecule through an alkyl group; "alkoxyl" means that an aliphatic group is attached to the remainder of the molecule through an oxy group; and the like.

[0114] In this application, "optional" or "optionally" means that the event or circumstance described thereafter may or may not occur, and includes examples in which the event or circumstance occurs and 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 replaced with a moiety other than hydrogen. For example, "alkyl optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) halogens" means that the alkyl group is unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) halogens, including both substituted and unsubstituted alkyl groups.

[0115] The term "substituted" means that one or more hydrogen atoms on a specified atom or group are replaced with one or more substituents other than hydrogen, provided that the normal valence of the specified atom is not exceeded. The term "substituted" means any level of substitution, such as mono-, di-, tri-, tetra-, or penta-substitution, unless otherwise specified, and such substitution is permitted. The substituents are independently selected, and the substitution may be at any chemically accessible position. It is understood that substitution at a given atom is limited by valence. It is understood that substitution at a given atom results in a chemically stable molecule. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents may be one or more and the same or different for appropriate organic compounds. "Optionally substituted" means unsubstituted or substituted. "Substituted" means that a hydrogen atom has been removed and replaced with a substituent. A divalent substituent such as oxo can replace two hydrogen atoms.

[0116] The term "stereoisomers" refers to compounds in which the same atoms are bonded by the same bonds but which differ in three-dimensional structure. All stereoisomers of the present invention can be identified and determined by conventional X-ray single crystal diffraction analysis. The present invention contemplates various stereoisomers and mixtures thereof.

[0117] Stereochemical definitions and conventions used herein generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Compounds described herein may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. 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 about its chiral center (S). The prefixes d and l, or (+) and (-), are used to indicate the sign of rotation of plane polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. Compounds with a (+) or d prefix are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be called an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, and can occur when there is no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species that is devoid of optical activity.

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

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

[0120] Unless otherwise specified, [ka] or [ka] In the present application, the bond [ka] and [ka] Includes.

[0121] All isotopes of a particular atom or element designated are contemplated within the scope of the compounds of the invention and their uses. Isotopes include atoms having the same atomic number but different mass numbers. Exemplary isotopes that can be incorporated into the compounds of the 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 Common examples include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as I. Common examples include, but are not limited to, isotopes of hydrogen, such as deuterium and tritium.1 H (hydrogen), 2 H (deuterium) and 3 H (tritium). Deuterium is sometimes written as D and tritium as T. In this application, CD 3 represents a methyl group in which all hydrogen atoms are deuterium. The carbon isotopes are: 13 C and 14 C. The isotopically labeled compounds of the present disclosure are equivalent to non-labeled compounds, for example, the deuterated compounds of the present disclosure are equivalent to non-deuterated compounds. The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described herein, using suitable isotopically labeled reagents instead of non-labeled reagents.

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

[0123] In addition to those mentioned above, the following terms used in the specification and claims have the following meanings unless otherwise specified: "Amino" is -NH 2 Refers to the base. "Cyano" refers to the radical -CN. "Hydroxy" refers to the group --OH. "Nitro" is -NO 2 Refers to the base. "Carbonyl" refers to the group -COOH. "Nitroso" refers to the group --N.dbd.O.

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

[0125] The term "alkyl," as used herein, unless otherwise specified, includes saturated monovalent hydrocarbon radicals having straight or branched chains. 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 is defined to identify groups having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.

[0126] The term "alkenyl" refers to a straight or branched chain hydrocarbon radical containing one or more (e.g., 1, 2, 3, 4, 5, or 6) double bonds and typically containing 2 to 20 carbon atoms in length. 2-6 Alkenyl" contains 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hepetenyl, octenyl, and the like.

[0127] The term "alkynyl" includes straight or branched chain hydrocarbon radicals containing one or more (e.g., 1, 2, 3, 4, 5, or 6) triple bonds and typically containing 2 to 20 carbon atoms in length. For example, "C 2-6 Alkynyl" contains 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0128] The term "alkoxyl" radical is an oxygen ether formed from an alkyl group as defined above.

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

[0130] A "cycloalkyl" is a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl will have 3 to about 12 carbon atoms, more typically 3 to 8 carbon atoms, unless otherwise defined, and exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Cycloalkyl includes bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "spirocyclic cycloalkyl" refers to a bicyclic cycloalkyl in which each ring shares one adjacent atom with the other ring. The term "fused cycloalkyl" refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The term "bridged cycloalkyl" refers to a cycloalkyl that includes at least two bridgehead carbon atoms and at least one bridging carbon atom. "Bridged cycloalkyl" includes "bicyclic bridged cycloalkyl" containing two bridgehead carbon atoms, and "bicyclic bridged cycloalkyl" containing two or more bridgehead carbon atoms. Exemplary bridged cycloalkyls include adamantyl, nordamantyl, bicyclo[1.1.0]butanyl, norboranyl (bicyclo[2.2.1]heptanyl), norbornenyl (bicyclo[2.2.1]heptanyl), norbornadienyl (bicyclo[2.2.1]heptadienyl), tricyclo[2.2.1.0]heptanyl, bicyclo[3.2.1]octanyl, bicyclo[3.2.1]octadienyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl, bicyclo[2.2.2]octadienyl, bicyclo[5.2.0]nonanyl, bicyclo[4.3.2]undecanyl, tricyclo[5.3.1.1]dodecanyl, and the like.

[0131] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing one to four rings and three to eight carbons per ring system. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like. "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 of the rings shares one adjacent atom with the other ring. The term "fused 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 cycloalkenyl" containing two bridgehead atoms and "polycyclic bridged cycloalkenyl" containing two or more bridgehead atoms.

[0132] The term "heterocycloalkyl" refers to a fully saturated, stable, 3- to 18-membered, non-aromatic ring radical consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. Unless otherwise specified herein, a heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. The term "spirocyclic heterocycloalkyl" or "spiro-heterocyclyl" refers to a polycyclic heterocycloalkyl in which two rings share one atom. The term "fused 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 bridging 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 the heterocycloalkyl radical are optionally oxidized. In some embodiments, the heterocycloalkyl is bonded to the rest of the molecule through 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 heterocycloalkyl having at least one double bond. Heterocycloalkenyl may be monocyclic or polycyclic, and polycyclic includes "spirocyclic heterocycloalkenyl", "fused heterocycloalkenyl", and "bridged heterocycloalkenyl". "Spirocyclic heterocycloalkenyl" refers to a polycyclic heterocycloalkenyl in which two rings share one atom, "fused heterocycloalkenyl" refers to a polycyclic heterocycloalkenyl in which two rings share two adjacent atoms, and "bridged heterocycloalkenyl" refers to a heterocycloalkenyl containing at least two bridgehead atoms and at least one bridge atom. "Bridged heterocycloalkenyl" includes "bicyclic bridged heterocycloalkenyl" containing two bridgehead atoms and "polycyclic bridged heterocycloalkenyl" containing two or more bridgehead atoms.

[0134] The term "aryl" as used herein, unless otherwise specified, refers to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing carbon ring atoms. Preferred aryls are monocyclic or bicyclic aromatic ring systems. Phenyl and naphthyl are preferred aryls.

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

[0136] The term "heterocyclyl" or "heterocycle" as used herein refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic multiple ring system having at least one heteroatom in the ring (e.g., at least one ring heteroatom selected from oxygen, nitrogen, phosphorus, and sulfur). Unless otherwise specified, a heterocyclyl group has 3 to about 20 ring atoms, such as 3 to 12 ring atoms, such as 3 to 10 ring atoms, such as 5 to 10 ring atoms, or such as 5 to 6 ring atoms. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a three-, four-, five-, six-, or seven-membered ring) having about 1 to 6 ring carbon atoms and about 1 to 3 ring heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. The rings of a multiple fused ring (e.g., bicyclic heterocyclyl) system can be connected to each other through fused bonds, spiro bonds, and bridged bonds, if permitted by valence requirements. The term "heterocyclyl" or "heterocyclic ring" or "heterocycle" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond). A heterocyclyl may be monocyclic or polycyclic. Polycyclic rings may be fused, bridged, or spirocyclic. As used herein, a heterocyclyl is a ring system having 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C 3-6Heterocyclyl) having 1-5 ring heteroatoms, 1-4 ring heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms, or one ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. As used herein, the term "bridged heterocyclyl" refers to a 4-10 membered ring moiety connected to one or more (e.g., 1 or 2) 4-10 membered ring moieties having at least one heteroatom independently selected from nitrogen, oxygen, and sulfur at two non-adjacent atoms of the heterocyclyl. As used herein, "bridged heterocyclyl" includes bicyclic and tricyclic ring systems. Also, as used herein, the term "spiroheterocyclyl" refers to a ring system in which a 3- to 10-membered heterocyclyl has one or more additional rings, where one or more of the additional rings is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclyl, where one atom of the one or more additional rings is also an atom of the 3- to 10-membered heterocyclyl. Examples of spiroheterocyclyl include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, 6-oxa-1-azaspiro[3.3]heptanyl, and the like. Heterocyclyl groups also include partially unsaturated ring systems containing one or more double bonds, including fused ring systems having one aromatic ring and one non-aromatic ring, but not fully aromatic ring systems. Examples include dihydroquinoline (e.g., 3,4-dihydroquinoline), dihydroisoquinoline (e.g., 1,2-dihydroisoquinoline), dihydroimidazole, tetrahydroimidazole, indoline, isoindoline, isoindolone (e.g., isoindolin-1-one), isatin, dihydrophthalazine, quinolinone, spiro[cyclopropane-1,1'-isoindolin]-3'-one, tetrahydroisoquinoline, and tetralin.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 used interchangeably.

[0137] Any hydrogen atom bonded to C, N, O or S in the 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl or 5- to 12-membered 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, only those readily removable groups that are not constituents of a particular desired end product of the compounds of the present invention are referred to as "protecting groups", unless the context indicates otherwise. The protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described in J. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999, in “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in “Methoden der organischen Chemie” (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974, and in H.-D. Jakubke and H. Jeschkeit, “Aminosauren, Peptide, Proteine” (Amino acids, Peptides, Proteins), Verlag Chemie, Protecting groups are described in standard references such as Weinheim, Deerfield Beach, and Basel 1982. A characteristic of a protecting group is that it is readily removable (i.e., without undesired secondary reactions), for example, by solvolysis, reduction, photolysis, or under physiological conditions (e.g., enzymatic cleavage).

[0139] The term "leaving group" as used herein has the meaning conventionally defined in synthetic organic chemistry, i.e., an atom or group capable of being displaced by a nucleophile, including halo (chloro, bromo, iodo, etc.), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy, trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy), methoxy, N,O-dimethylhydroxylamino, and the like.

[0140] The term "reductive amination reaction" as used herein has the meaning commonly understood in the art and may be carried out by one 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 sodium cyanoborohydride; sodium triacetoxyborohydride; sodium borohydride; organoborane complex compounds such as 4-(dimethylamino)pyridine borane complex, N-ethyldiisopropylamine borane complex, N-ethylmorpholine borane complex, N-methylmorpholine borane complex, N-phenylmorpholine borane complex, lutidine borane complex, triethylamine borane complex, trimethylamine borane complex, and combinations of two or more thereof. Preferably, the reductive amination agent is sodium cyanoborohydride (NaBH 3 CN).

[0141] The term "composition" as used herein is intended to include those consisting of a specified amount of a specified component, and those resulting directly or indirectly from the combination of a specified amount of a specified component.Thus, pharmaceutical compositions containing the compounds of the present invention as active ingredients, as well as methods for preparing instant compounds, are also part of the present invention.In addition, some of the crystalline forms of the compounds may exist as polymorphs, which are intended to be included in the present invention.In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be included in the scope of the present invention.

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

[0143] In many cases, the compounds of the disclosure are capable of forming acid and / or base addition salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0144] The term "pharmaceutically acceptable salt" of a compound refers to a salt that retains the biological effectiveness and properties of a compound and is not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, for example, sodium, potassium, lithium, ammonium, calcium and magnesium salts. 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, but are not limited to, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include salts of 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, salicylic acid, and the like. As the compounds are for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60% pure, more preferably at least 75% pure, especially at least 98% pure (% by weight).

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

[0146] In this specification, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any solvent, dispersion medium, coating, antibacterial and antifungal agents, isotonicity and absorption delaying agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Except in the case where a conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is anticipated. Supplementary active ingredients can also be incorporated into the composition.

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

[0148] In practice, the compound of the present invention or its prodrug or metabolite or its pharma- ceutically acceptable salt can be formulated as an active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can be in a variety of forms, depending on the form of preparation desired for administration, such as oral or parenteral (including intravenous administration). Thus, the pharmaceutical composition of the present invention can be presented as discrete units suitable for oral administration, such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the composition can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion. In addition to the common dosage forms described above, the compound or its pharma- ceutically acceptable salt can also be administered by controlled release means and / or delivery devices. The composition can be prepared by any of the methods of pharmacy. In general, such methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more (such as 1, 2, 3, 4, 5 or 6) necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, after which the product can be shaped into the desired presentation.

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

[0150] Tablets containing the compositions of the present invention can be prepared by compression or molding, optionally with one or more (such as 1, 2, 3, 4, 5 or 6) accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active agent or dispersing agent. Molded tablets can be produced by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient, and each cachet or capsule preferably contains from about 0.05 mg to about 5 g of the active ingredient. For example, a formulation intended for oral administration to humans contains from about 0.5 mg to about 5 g of the active ingredient, which can be compounded with a suitable and convenient amount of carrier material, which can vary from about 0.05% to about 95% of the total composition. A unit dosage form generally contains from about 0.01 mg to about 2 g, 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 of active ingredient.

[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, suitable surfactants such as hydroxypropylcellulose can be included.Dispersion can also be prepared in glycerol, liquid polyethylene glycol, and their mixture in oil.In addition, preservatives can be included to prevent harmful growth of microorganisms.

[0152] The pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders for the extemporaneous 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 the conditions of manufacture and storage; thus, they should preferably be preserved against the contaminating action of microorganisms such as bacteria and fungi.The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0153] The pharmaceutical composition of the present invention can be in a form suitable for topical use, such as, for example, an aerosol, cream, ointment, lotion, powder, etc. Additionally, the composition of the present invention can be in a form suitable for use in a transdermal device. These formulations can be prepared by conventional processing methods utilizing the compound of the present invention or a pharma- ceutically acceptable salt thereof. As an example, a cream or ointment is prepared by mixing a hydrophilic material and water with about 0.05 wt% to about 10 wt% of the compound to produce a cream or ointment having a desired consistency.

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

[0155] In addition to the carrier components, the pharmaceutical compositions may optionally include one or more (such as 1, 2, 3, 4, 5 or 6) additional carrier components such as diluents, buffers, flavorings, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants). Additionally, other adjuvants may be included to make the formulation isotonic with the blood of the intended recipient. The compositions containing the compound or its pharma-ceutically acceptable salts may also be prepared in powder or liquid concentrate form.

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

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

[0158] In some embodiments, disclosed herein are methods of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention, which can, for example, slow the growth of a cancer cell line or kill a cancer cell. Non-limiting examples of cancers that may be treated by the compounds of the present invention include: acute lymphoblastic leukemia; acute myeloid leukemia; adrenal cortical carcinoma; AIDS-related cancer; AIDS-related lymphoma; anal cancer; bladder cancer; bone cancer; brain tumors such as cerebellar astrocytoma, brain astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, visual pathway, and hypothalamic glioma; breast cancer; central nervous system lymphoma; cerebellar astrocytoma; cervical cancer; colorectal cancer; gallbladder cancer; gastric cancer; head and neck cancer; cardiac cancer; hepatocellular (liver) cancer; kidney cancer; liver cancer; lung cancer, such as non-small cell lung cancer and small cell lung cancer; ovarian cancer; ovarian epithelial cancer; ovarian germ cell tumor; pancreatic cancer; pancreatic islet cell carcinoma; prostate cancer; rectal cancer; renal cell carcinoma; skin cancer; Merkel cell skin cancer; small intestine cancer; and pharyngeal cancer. EXAMPLES

[0159] Preparation method The following examples are included to provide those skilled in the art with guidance for carrying out representative embodiments of the subject matter disclosed herein. In light of this disclosure and the general state of the art, those skilled in the art will appreciate that the following examples are intended to be illustrative only, and that many changes, modifications and alterations can be made without departing from the scope of the subject matter disclosed herein. The synthetic descriptions and specific examples that follow are intended for illustrative purposes only, and are not to be construed as limiting the invention in any manner.

[0160] All parts and percentages are by weight and temperatures are in degrees Celsius unless otherwise noted.

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

[0162] General synthetic scheme 1: [ka]

[0163] As illustrated in General Synthetic Scheme 1, compounds of formula (I-1) can be synthesized by the following steps: (1) K 2 CO 3 A compound such as S1-1 having a -YH group and an L1 group can be reacted as a starting material with a compound such as S1-2 in the presence of an alkalizing agent such as S2-1 to form a compound such as S2-2; (2) Compound S2-1 is cyclized and aromatized under acidic conditions such as polyphosphoric acid to form compound S3-1; (3) In the presence of a halogenating agent, the position adjacent to the Y atom of compound S3-1 can be halogenated to obtain compound S4-1. For example, in the presence of NIS, the position adjacent to the Y atom of compound S3-1 can be iodized. (4) Compound S4-1 can be coupled with reagent S4-2 in the presence of a coupling catalyst to provide compound S5-1, preferably Pd(PPh3)2Cl. 2 or Pd(dppf)Cl 2 Such Pd-containing catalysts include; (5) The L1 group of compound S5-1 can be converted into the target compound of formula (I-1) by one or more reaction steps, for example, by converting compound S5-1 into -NH 2 Replace with R 2 Ga-NR 51 R 52 can produce a compound which 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 may be identified and determined by X-ray single crystal diffraction analysis.

[0165] In general, the structure of a single crystal of the compound of the present invention is solved by Allex2 (version: 1.5) software, and the diffraction data can be preliminarily solved by the preliminary solution program (using the eigenphase method) of ShelXT (version: 2018 / 2) to determine the space group of the single crystal. Then, full matrix least squares structure refinement based on F2 is performed using the refinement program of ShelXL (version: 2018 / 3). All atoms other than hydrogen atoms are anisotropically refined. Hydrogen atoms are refined by theoretical hydrogenation (riding model).

[0166] Example 1 4-((3-(3-ethyl-7-((1-methylpiperidin-4-yl)amino)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide (1) [ka]

[0167] Step 1. Synthesis of 1-((2-bromophenyl)thio)butan-2-one 2-Bromobenzenethiol (16.58 g, 0.09 mol) was dissolved in 160 ml of ACN and the solution was diluted with K 2 CO 3 (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 h and the solid was removed by filtration. The filtrate was concentrated under vacuum. The residue was applied to a silica gel column eluted with EA / Hexane (v / v = 0%-12%) to give 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 polyphosphoric acid (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 h. Then, the mixture was cooled and water (30 mL) was added. The mixture was extracted with EA (90 mL×3) and (Na 2 SO 4 The mixture was dried over hexanes, filtered and concentrated in vacuum. The residue was applied to 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 AcOH was added NIS (1.307 g, 5.81 mmol) in portions. The mixture was stirred at room temperature for 2 h. The reaction was quenched by the addition of water (20 mL). The resulting solution was extracted with EA (2 x 30 mL). The organic layers were then combined, washed with brine (15 mL) and concentrated under anhydrous Na 2 SO 4 The mixture was dried over 100 ml and concentrated in vacuum. The residue was applied to a silica gel column eluted with EA / Hexane (v / v = 0%-5%) to give 1.186 g of 7-bromo-3-ethyl-2-iodobenzo[b]thiophene as a yellow oil.

[0170] Step 4. Synthesis of 4-((3-(7-bromo-3-ethylbenzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide In a 20 mL sealed tube, purged and maintained under an inert atmosphere of nitrogen, was added 7-bromo-3-ethyl-2-iodobenzo[b]thiophene (0.504 g, 1.37 mmol), 4-(prop-2-yn-1-ylamino)benzenesulfonamide (0.335 g, 1.59 mmol), Pd(PPh3)2Cl 2(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 h. 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)prop-2-yn-1-yl)amino)benzenesulfonamide was obtained as a yellow oil. LCMS: m / z =449 [M+1] + .

[0171] Step 5. Synthesis of 4-((3-(7-amino-3-ethylbenzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide In a 20 mL sealed tube, purged and maintained under an inert atmosphere of nitrogen, was added 4-((3-(7-bromo-3-ethylbenzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide (0.402 g, 0.89 mmol), NaN 3 (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), Cs 2 CO 3 (0.586 g, 1.80 mmol) and DMSO (5 mL) were added. The residue was purified by Prep-HPLC CH 3 CN / H 2 2HCOOH (0.2% HCOOH) (v / v = 0%-50%). As a result, 0.048 g of 4-((3-(7-amino-3-ethylbenzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide was obtained as a yellow solid. LCMS: m / z =389 [M+1] + .

[0172] Step 6. Synthesis of 4-((3-(3-ethyl-7-((1-methylpiperidin-4-yl)amino)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide (1) To a solution of 4-((3-(7-amino-3-ethylbenzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide (0.040 g, 4.53 mmol) in 5 ml of MeOH was added 1-methylpiperidin-4-one (0.087 g, 768.8419 μmol). The mixture was stirred at room temperature for 0.5 h. Then, NaBH 3 CN (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 CH 3 CN / H 2 O(0.05%NH 3 H 2 3O) (v / v = 0%-50%). As a result, 4-((3-ethyl-7-((1-methylpiperidin-4-yl)amino)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide (1) was obtained as a white solid in 0.010 g (17%). LCMS: m / z = 483 [M+1] + . 1 H NMR (400 MHz, CD 3 OD) 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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (racemic) (2) Reaction Scheme: [ka]

[0174] Test Details: Step 1. 2-Iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine In a 20 mL sealed tube, add 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), and NH 4 Cl (0.951 g, 17.78 mmol), EtOH (8 mL) and H 2 0 (1.5 mL) was added. The reaction mixture was extracted with EA (100 mL x 1), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.621 g (99.87%) of 2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-amine as a grey 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) 2-Iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-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 and purified with N2 After purging with BH 3 THF (1 M, 9 mL) was added. The mixture was diluted with N 2 (g) The mixture was stirred at 0° C. for 1 h. 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 on a silica gel column and eluted with EA / hexane (v / v=1 / 5) to give tert-butyl (Z)-3-fluoro-4-((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (racemic). 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-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (racemic) Into a 20 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was added 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-(prop-2-yn-1-yl)aniline (0.184 g, 0.77 mmol), Pd(dppf)Cl 2(0.103 g, 0.15 mmol), CμI (0.082 g, 0.43 mmol), DIEA (0.253 g, 1.96 mmol), DMSO (5 mL) were added. The reaction mixture was stirred at room temperature for 1 h. 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 in vacuo. The residue was purified on a silica gel column and eluted with EA / hexane (v / v=3 / 1) to give tert-butyl (Z)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (racemic) (0.338 g, 92.09% yield) 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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidin-4-amine (racemic) To a 100 mL round bottom flask was added tert-butyl (Z)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-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) and the reaction mixture was stirred at room temperature for 1 h. The reaction was cooled to room temperature with NaHCO 3(aq.) to pH=9 and extracted with EA (100 mL×2). The combined organic layers were washed with brine (40 mL), separated and concentrated in vacuo. This resulted in (Z)-3-fluoro-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidin-4-amine (racemic) 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-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (racemic) (2) The mixture was stirred at room temperature for 0.5 h, and then NaBH 3 CN (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 give (Z)-3-fluoro-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (racemic) (2) (0.052 g, 50.75% yield) as a white solid. LCMS: m / z =584 [M+1] + 1H 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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (3) Reaction Scheme: [ka]

[0180] Experiment details Step 1. Methyl 7-nitrobenzo[b]thiophene-2-carboxylate 2-Chloro-3-nitrobenzaldehyde (10.029 g, 0.05 mol) in 100 mL DMF and K 2 CO 3 (8.235 g, 0.06 mol) was added with methyl 2-mercaptoacetate (6.193 g, 0.06 mol) at 0° C. The mixture was stirred at room temperature for 8 h, the mixture was 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 methyl 7-nitrobenzo[b]thiophene-2-carboxylate was obtained as an off-white solid.

[0181] Step 2. 7-Nitrobenzo[b]thiophene-2-carboxylic acid To a 0 °C solution of methyl 7-nitrobenzo[b]thiophene-2-carboxylate (2.44 g, 0.01 mmol) in 20 mL of MeOH was added NaOH (2 N, 20 mL). The reaction mixture was stirred at room temperature for 8 h and the mixture was concentrated in vacuo. 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 and washed with MgSO 4 The mixture was dried over ice, filtered, and concentrated in vacuo to give 2.27 g of 7-nitrobenzo[b]thiophene-2-carboxylic acid as a small yellow solid.

[0182] Step 3. 7-Nitrobenzo[b]thiophene e In a 40 mL sealed tube, add 7-nitrobenzo[b]thiophene-2-carboxylic acid (2.105 g, 9.43 mmol), Cμ 2 0 (0.335 g, 1.59 mmol), and DMF (20 mL). The reaction mixture was stirred at 120 °C for 12 h. The mixture was added to 100 mL of water, which resulted in a large amount of precipitates. The mixture was filtered, and 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 grey solid.

[0183] Step 4. 7-Nitrobenzo[b]thiophene-3-carbaldehyde A 20 mL sealed tube was charged with 7-nitrobenzo[b]thiophene (0.51 g, 2.85 mmol), dichloro(methoxy)methane (1.65 g, 14.35 mmol), and TiCl 4 (1.50 g, 7.91 mmol), CHCl 3(5 mL). The reaction mixture was stirred at 60° C. for 2 h. The reaction 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. The crude was purified on a silica gel column eluted 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]thiophen-3-yl)methanol A solution of methyl 7-nitrobenzo[b]thiophene-3-carbaldehyde (1.699 g, 8.20 mmol) in 20 mL MeOH at 0 °C was diluted with NaBH 4 (0.656 g, 17.34 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h. The reaction 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 in vacuo. This resulted in 1.197 g of (7-nitrobenzo[b]thiophen-3-yl)methanol as a pale yellow solid.

[0185] Step 6. 3-(Bromomethyl)-7-nitrobenzo[b]thiophene A 20 mL sealed tube was charged with (7-nitrobenzo[b]thiophen-3-yl)methanol (0.45 g, 2.15 mmol) and 30%HBr / HOAc (5 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction 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. The crude was purified on a silica gel column eluted 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 A 20 mL sealed tube was charged with 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). The reaction mixture was stirred at 60 °C for 1 h. The reaction was quenched with water (40 mL), extracted with EA (2 x 100 mL), washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude was purified on a silica gel column eluted with EA / hexane (v / v = 1 / 5). This resulted in 0.295 g of 7-nitro-3-(2,2,2-trifluoroethyl)benzo[b]thiophene as a yellow solid.

[0187] Step 8. 2-Iodo-7-nitro-3-(2,2,2-trifluoroethyl)benzo[b]thiophene A 20 mL sealed tube was charged with 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). The reaction mixture was stirred at room temperature for 3 h. The reaction was quenched with water (30 mL), extracted with EA (2 x 100 mL), washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude was purified on a silica gel column eluted 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)prop-2-yn-1-yl)aniline Into a 20 mL sealed tube, purged and maintained under an inert atmosphere of nitrogen, was added 2-iodo-7-nitro-3-(2,2,2-trifluoroethyl)benzo[b]thiophene (0.380 g, 0.98 mmol), 2-methoxy-4-(methylsulfonyl)-N-(prop-2-yn-1-yl)aniline (0.259 g, 1.08 mmol), Pd(dppf)Cl 2 (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 h. 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 was purified on a silica gel column eluted with EA / hexane (v / v=2 / 3). 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)prop-2-yn-1-yl)aniline was obtained as a yellow oil.

[0189] Step 10. 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-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)prop-2-yn-1-yl)aniline (0.518 g, 1.04 mmol), iron (0.391 g, 7.00 mmol), NH 4 Cl (0.430 g, 8.04 mmol), EtOH (5 mL) and H 2O (1 mL) was added. The reaction mixture was extracted with EA (100 mL×1), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 0.282 g (57.92%) of 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine as a yellow solid.

[0190] Step 11. N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (3) A 25 mL round-bottom flask was charged with 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (0.220 g, 0.43 mmol), 1-methylpiperidin-4-amine (0.259 g, 2.29 mmol), and MeOH (4 mL). The mixture was stirred at room temperature for 0.5 h and then diluted with NaBH 3 CN (0.177 g, 4.12 mmol) and HOAc (0.02 mL) were added and stirred for 48 h. The mixture was purified using 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 min); 270 nm; room temperature: 44.886-46.470 min) to give N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (3) (0.038 g, 15.58% yield) as an off-white solid.

[0191] Example 4 4-((3-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-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-methylpiperidin-4-amine. A 4 mL jar was charged with 2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (0.108 g, 302.41 μmol), 1-methylpiperidin-4-one (0.023 g, 203.26 μmol). The reaction was warmed to 130° C. and stirred for 0.5 h, then cooled to room temperature and sodium cyanoborohydride (0.113 g, 2.634 mmol), acetic acid (0.01 μmol), and ethanol (1 mL) were added. The reaction was stirred at 50° C. for 1 h. LCMS showed the reaction was complete and the reaction was concentrated in vacuo and C 18 Purification by column elution with ACN / water (v / v=1 / 3) gave N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide (4). N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.067 g, 147.48 μmol), 4-(prop-2-yn-1-ylamino)benzenesulfonamide (0.058 g, 275.86 μmol), Pd(PPh 3 )2Cl 2 (0.011 g, 15.58 μmol), CμI (0.007 g, 36.76 μmol), TEA (0.031 g, 306.36 μmol), DMF (1 mL) were added and stirred at room temperature overnight. LCMS showed 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 washed successively with water (2 mL) and brine (2 mL), separated and concentrated in vacuo. 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 min); 265 nm; room temperature: 33.245-35.153 min) to give 4-((3-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide (4) (0.021 g, 39.13 μmol, 26.53% yield) as an off-white solid. LCMS: m / z = 537[M+1] + . 1 H NMR (400 MHz, DMSO-d 6) 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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide (racemic) (5) and 4-((3-(7-(((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide (racemic) (5b) Reaction Scheme: [ka]

[0195] Test Details: Step 1 tert-Butyl-3-fluoro-4-((2-(3-((4-sulfamoylphenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate In a 50 mL 3-neck 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-(prop-2-yn-1-ylamino)benzenesulfonamide (0.561 g, 1.51 mmol), Pd(PPh 3 )2Cl 2 (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 at room temperature under nitrogen atmosphere for 3 h. The reaction was quenched with water (20 mL). The resulting solution was extracted with EA (3×50 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude was purified on a silica gel column eluted with EA / hexane (v / v = 3 / 2). As a result, 0.642 g (1.00 mmol, 81.32% yield) of tert-butyl 3-fluoro-4-((2-(3-((4-sulfamoylphenyl)amino)prop-1-yn-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-fluoropiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide In a 20 mL sealed tube was added tert-butyl 3-fluoro-4-((2-(3-((4-sulfamoylphenyl)amino)prop-1-yn-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), EA (2 mL). The reaction was stirred at room temperature for 1 h. The reaction was concentrated under vacuum and water (2 mL) was added to the reaction. NaOH (aq, 3 N) was added until PH=7, 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-fluoropiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide was obtained as a brown solid. LCMS: m / z=274[M+1] + The reaction mixture was diluted with ACN / H 2 The mixture was purified on a C18 column eluted with O (v / v = 1 / 1). As a result, ethyl N-(3-bromo-5-nitro-4-(1H-pyrrol-1-yl)phenyl)-1-methylpiperidin-4-amine was obtained as a yellow solid in 3.012 g (74% yield). LCMS: m / z = 541 [M+1] + .

[0197] Step 3: 4-((3-(7-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide (racemic) (5) and 4-((3-(7-(((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide (racemic) (5b) In a 25 mL round-bottom flask, 4-((3-(7-((3-fluoropiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-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 to a 25 mL round-bottom flask. The reaction mixture was stirred at room temperature for 1 h and then diluted with NaBH 3 CN (0.231 g, 5.38 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. 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 in vacuo. 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 give the desired product. This resulted in 0.055 g (99.16 μmol, 16.91% yield) of 4-((3-(7-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide (racemic) (5) as a white solid. LCMS: m / z =555 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6) 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] And 4-((3-(7-(((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide (racemic) (5b) was obtained as a white solid in 0.027 g (48.68 μmol, 8.30% yield). LCMS: m / z =555 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6) 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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidin-1-yl)-3-methoxypropan-2-ol (racemic) (6) Reaction Scheme: [ka]

[0200] Test Details: Step 1. 1-((Z)-3-Fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidin-1-yl)-3-methoxypropan-2-ol (racemic) (6). To a 4 mL vial was added (Z)-3-fluoro-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidin-4-amine (racemic) (0.036 g, 63.20 μmol), 2-(methoxymethyl)oxirane (0.044 g, 499.41 μmol), and ethanol (1 mL). The reaction 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 give the desired product. As a result, 1-((Z)-3-fluoro-4-((2-(3-(2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidin-1-yl)-3-methoxypropan-2-ol (racemic form) (6) was obtained as an off-white solid in 0.029 g (69.77% yield). 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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (7) Reaction Scheme: [ka]

[0202] Test Details: Step 1. 1,2-Difluoro-4-methoxy-5-nitrobenzene In a 100 mL flask, add 4,5-difluoro-2-nitrophenol (4.76 g, 27.19 mmol), K 2 CO 3 (11.33 g, 81.98 mmol), iodomethane (3 mL), and DMF (30 mL) were added. The reaction was stirred at 20° C. for 1 h. 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 on a silica gel column eluted with EA / Hex (v / v = 2 / 8). This resulted in 5.30 g (99% yield) of 1,2-difluoro-4-methoxy-5-nitrobenzene as a white solid. LCMS: m / z = 190 [M+1] + .

[0203] Step 2. 1-Fluoro-4-methoxy-2-(methylsulfonyl)-5-nitrobenzene. A 100 mL flask was charged with 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). The reaction was stirred at 85° C. for 16 hours. The reaction was quenched with water (50 mL). A large amount of solid precipitated out after that. The mixture was filtered and the filter cake was collected. The filter cake was dried at 60° C. for 16 hours to give 1-fluoro-4-methoxy-2-(methylsulfonyl)-5-nitrobenzene as a white solid, 3.00 g (76% yield). LCMS: m / z = 250 [M+1] + .

[0204] Step 3. 5-Fluoro-2-methoxy-4-(methylsulfonyl)aniline. A 100 mL round-bottom flask was charged with 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). 2 was charged. The reaction mixture was stirred at 20° C. for 16 h. The mixture was filtered and the filtrate was collected. The filtrate was concentrated under vacuum. The residue was purified on a silica gel column eluted with EA / Hexane (v / v = 2 / 8). As a result, 5-fluoro-2-methoxy-4-(methylsulfonyl)aniline was obtained as a yellow solid in 2.27 g (yield 55%). LCMS: m / z = 220[M+1] + .

[0205] Step 4. 5-Fluoro-2-methoxy-4-(methylsulfonyl)-N-(prop-2-yn-1-yl)aniline. In a 50 mL round-bottom flask, add 5-fluoro-2-methoxy-4-(methylsulfonyl)aniline (0.91 g, 4.13 mmol), 3-bromoprop-1-yne (0.62 g, 5.24 mmol), K 2 CO 3(1.86 g, 13.42 mmol), NaI (0.10 g, 0.67 mmol), and DMF (20 mL) were added to the reaction mixture. 2 C eluted with O (v / v = 1 / 1) 18 The product was purified by column chromatography. As a result, 5-fluoro-2-methoxy-4-(methylsulfonyl)-N-(prop-2-yn-1-yl)aniline was obtained as a pale yellow solid in an amount of 318 mg (yield 29%). LCMS: m / z = 258 [M+1] + .

[0206] Step 5. N-(2-(3-((5-fluoro-2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (7). In a 50 mL round-bottom flask, add N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.066 g, 145.28 μmol), 5-fluoro-2-methoxy-4-(methylsulfonyl)-N-(prop-2-yn-1-yl)aniline (0.063 g, 244.87 μmol), CμI (0.043 g, 225.78 μmol), Pd(PPh 3 )2Cl 2(0.051 g, 56.26 μmol), DIEA (0.041 g, 317.23 μmol) and methyl sulfoxide (2 mL) were added. The mixture was stirred at 25° C. for 4 h. 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). This resulted in 22 mg (25% yield) of N-(2-(3-((5-fluoro-2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (7) as a white solid. LCMS: m / z =584 [M+1] + . 1 H 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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzamide (8) Reaction Scheme: [ka]

[0208] Experiment details Step 1. 4-Amino-3-methoxy-N-methylbenzamide A 1 L flask was charged with 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). The reaction mixture was stirred at room temperature for 24 h, and water (10 mL) was added to quench the reaction. Then, saturated aqueous sodium hydroxide solution was added to the mixture until pH = 10-11. The resulting solution was extracted with EA (2 x 200 mL). The organic layers were combined, washed with brine (200 mL), and diluted with anhydrous NaCl. 2 SO 4 The mixture was dried over hexane and concentrated under vacuum. The residue was applied to a silica gel column eluted with EA / heptane (v / v = 9 / 1). 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-(prop-2-yn-1-ylamino)benzamide A 500 mL flask was charged with 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), N,N-dimethylformamide (200 mL) and kept under an inert atmosphere of nitrogen. The reaction mixture was stirred at 85 °C for 7 h. The residue was applied to a silica gel column eluted with EA / heptane (v / v = 3 / 1). The reaction was quenched by the addition of 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 over 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 (44.33% yield) of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide was obtained as a yellow solid. LCMS: m / z = 219 [M+1] + .

[0210] Step 3. 3-Methoxy-N-methyl-4-((3-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzamide (8) A 500 mL flask maintained under an inert purged atmosphere of nitrogen was charged with 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (0.029 g, 132.87 μmol), N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-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). The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched by the addition of 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 afforded 3-methoxy-N-methyl-4-((3-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzamide (8) as a white solid in 0.010 g (7.42% yield). 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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)phosphine oxide (9) Reaction Scheme: [ka]

[0212] Experiment details Step 1. Dimethyl(4-((3-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)phosphine oxide (9). Into a 4 mL flask purged with nitrogen and maintained was added N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.049 g, 107.86 μmol), dimethyl(4-(prop-2-yn-1-ylamino)phenyl)phosphine oxide (0.068 g, 328.17 μmol), Pd(PPh3)2Cl 2 (0.009 g, 12.75 μmol), CμI (0.004 g, 21.00 μmol), TEA (0.015 g, 148.24 μmol), DMF (0.5 mL) were added and stirred at room temperature for 1 h. LCMS showed 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 washed successively with water (2 mL) and brine (2 mL), separated and concentrated in vacuo. 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 give dimethyl(4-((3-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-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] + . 1 H NMR (400 MHz, DMSO-d 6) 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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-(fluoromethoxy)phenyl)dimethylphosphine oxide (racemic) (10) Reaction Scheme: [ka]

[0214] Test Details: Step 1. 4-Bromo-2-(fluoromethoxy)-1-nitrobenzene A 50 mL 3-neck flask was charged with 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). The reaction was stirred at 80 °C for 1 h and then quenched with water (10 mL). The resulting solution was extracted with EA (3 x 30 mL), washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 1.276 g (5.10 mmol, 95.91% yield) of 4-bromo-2-(fluoromethoxy)-1-nitrobenzene as a yellow solid. LCMS: m / z = 250 [M+1]+ .

[0215] Step 2. 4-Bromo-2-(fluoromethoxy)aniline A 100 mL three-neck flask was charged with 4-bromo-2-(fluoromethoxy)-1-nitrobenzene (1.332 g, 5.32 mmol), iron (2.678 g, 47.95 mmol), and NH 4 Cl (2.610 g, 48.79 mmol), EtOH (15 mL), and water (3 mL) were added. The reaction mixture was filtered and the filter cake was washed with MeOH (2 x 30 mL). The filtrate was concentrated under vacuum to give the crude product. The crude product was purified on a silica gel column eluted with EA / Hexane (v / v = 1 / 3). As a result, 1.01 g (4.59 mmol, 86.15% yield) 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. A 25 mL 3-neck flask purged and maintained with an inert atmosphere of nitrogen was charged with 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). Dimethylphosphine oxide (0.603 g, 7.72 mmol) was then added at 130° C. The reaction was stirred at 130° C. for 1 h under a nitrogen atmosphere. The reaction mixture was diluted with ACN / H 2 C eluted with O (v / v = 1 / 9) 18 The product 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. LCMS: m / z = 218 [M+1] + .

[0217] Step 4. (3-(fluoromethoxy)-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide In a 25 mL three-neck flask, add (4-amino-3-(fluoromethoxy)phenyl)dimethylphosphine oxide (0.366 g, 1.68 mmol), 3-bromoprop-1-yne (0.295 g, 2.47 mmol), K 2 CO 3 (0.695 g, 5.02 mmol), KI (0.384 g, 2.31 mmol), and NMP (5 mL) were added. The reaction mixture was stirred at 80° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was diluted with ACN / H 2 C eluted with O (v / v = 2 / 8) 18 The mixture was purified by column chromatography. As a result, 0.066 g (258.59 μmol, 15.34% yield) of (3-(fluoromethoxy)-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide was obtained as a brown oil. LCMS: m / z = 256 [M+1] + .

[0218] Step 5. (4-((3-(7-(((Z)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-(fluoromethoxy)phenyl)dimethylphosphine oxide (racemic) (10) Into a 10 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was added (3-(fluoromethoxy)-4-(prop-2-yn-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-methylpiperidin-4-amine (racemic) (0.051 g, 107.98 μmol), Pd(PPh3)2Cl 2(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. 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 give the desired product. This resulted in 1.05 mg (1.75 μmol, 0.62% yield) of (4-((3-(7-(((-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-(fluoromethoxy)phenyl)dimethylphosphine oxide (racemic) (10) as a white solid. LCMS: m / z =600 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6 ) 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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (11) Reaction Scheme: [ka]

[0220] Experiment details Step 1. 2-(Fluoromethoxy)-4-(methylsulfonyl)-N-(prop-2-yn-1-yl)aniline An 8 mL flask was charged with 5-(methylsulfonyl)-2-(prop-2-yn-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). The reaction mixture was stirred at 45 °C for 3 h, 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 diluted with anhydrous Na 2 SO 4 The mixture was dried over hexane and concentrated under vacuum. The residue was applied to a silica gel column eluted with EA / heptane (v / v = 1 / 1). As a result, 0.096 g (83.22% yield) of 2-(fluoromethoxy)-4-(methylsulfonyl)-N-(prop-2-yn-1-yl)aniline was obtained as a yellow oil. LCMS: m / z = 258 [M+1] + .

[0221] Step 2. N-(2-(3-((2-(fluoromethoxy)-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (11) Into an 8 mL flask maintained under an inert purged atmosphere of nitrogen was added N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.051 g, 112.26 μmol), cuprous iodide (0.007 g, 36.76 μmol), 2-(fluoromethoxy)-4-(methylsulfonyl)-N-(prop-2-yn-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). The reaction mixture was stirred at room temperature for 2 h, quenched by addition of water (2 mL), and extracted with EA (2 x 4 mL). The organic layers were combined, washed with brine (5 mL) and then soaked in anhydrous Na 2 It was dried over SO4 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). This resulted in N-(2-(3-((2-(fluoromethoxy)-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (11) in 0.023 g (35.10% yield) as a yellow oil. 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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (12) Reaction scheme [ka]

[0223] Experiment details Step 1. 2-(2,2-Difluoroethoxy)-4-(methylsulfonyl)-N-(prop-2-yn-1-yl)aniline. A 4 mL flask maintained under a purged nitrogen atmosphere was charged with 5-(methylsulfonyl)-2-(prop-2-yn-1-ylamino)phenol (0.101 g, 448.36 μmol), 2-bromo-1,1-difluoroethane (0.094 g, 648.52 μmol), K 2 CO 3(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. The reaction was complete according to LCMS. 18 Purification by column elution with ACN / water (v / v = 1 / 3) gave 2-(2,2-difluoroethoxy)-4-(methylsulfonyl)-N-(prop-2-yn-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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (12). A 4 mL flask purged with nitrogen and maintained was charged with N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.048 g, 105.66 μmol), 2-(2,2-difluoroethoxy)-4-(methylsulfonyl)-N-(prop-2-yn-1-yl)aniline (0.054 g, 186.66 μmol), Pd(PPh 3 )2Cl 2(0.013 g, 18.42 μmol), CuI (0.003 g, 15.75 μmol), TEA (0.025 g, 247.06 μmol), DMF (0.5 mL) were added and stirred at room temperature for 1 h. LCMS showed 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 washed successively with water (2 mL) and brine (2 mL), separated and concentrated in vacuo. 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 give N-(2-(3-((2,2-difluoroethoxy)-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (12) (0.021 g, 34.11 μmol, 18.27% yield) as an off-white solid. LCMS: m / z = 616[M+1] + . 1 H NMR (400 MHz, DMSO-d 6 ) 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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidin-4-amine (13) Reaction Scheme: [ka]

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

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

[0228] Step 3. 2-Methoxy-4-(methylsulfonyl)-N-(prop-2-yn-1-yl)aniline In a 500 mL flask purged and maintained with an inert atmosphere of nitrogen, 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), N,N-dimethylformamide (200 mL) were added and the reaction mixture was stirred at 85 °C for 3 h. The resulting solution was extracted with EA (2 x 500 mL). The organic layers were combined, washed with brine (500 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 7.56 g (63.45% yield) of 2-methoxy-4-(methylsulfonyl)-N-(prop-2-yn-1-yl)aniline as a yellow oil. LCMS: m / z = 211 [M+1]+.

[0229] Step 4. 5-(Methylsulfonyl)-2-(prop-2-yn-1-ylamino)phenol A 100 mL flask purged with nitrogen and kept under inert atmosphere was charged with 2-methoxy-4-(methylsulfonyl)-N-(prop-2-yn-1-yl)aniline (2.35 g, 9.82 mmol), dichloromethane (20 mL), and tribromoboron (20 mL) at -10 °C. The reaction mixture was stirred at 0 °C for 1 h, and then 1 M aqueous sodium hydroxide was added until pH = 11-12. The aqueous layer was collected, and 2 M aqueous hydrochloric acid was added until pH = 7-8, and extracted with EA (2 x 100 mL). The organic layers were combined, washed with brine (100 mL), and diluted with anhydrous NaCl. 2 It was dried over SO4 and concentrated in vacuum, and the residue was applied to a silica gel column eluted with EA / Hexane (v / v = 3 / 5).

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

[0231] Step 5. 4-(Methylsulfonyl)-N-(prop-2-yn-1-yl)-2-(2,2,2-trifluoroethoxy)aniline An 8 mL flask was charged with 5-(methylsulfonyl)-2-(prop-2-yn-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). The reaction mixture was stirred at 45 °C for 3 h, 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 diluted with anhydrous Na 2 It was dried over SO4 and concentrated under vacuum. The residue was applied to a silica gel column eluted with EA / heptane (v / v = 1 / 1). As a result, 4-(methylsulfonyl)-N-(prop-2-yn-1-yl)-2-(2,2,2-trifluoroethoxy)aniline was obtained as a yellow oil in 0.098 g (70.43% yield). LCMS: m / z = 308 [M+1] + .

[0232] Step 6. 1-Methyl-N-(2-(3-((4-(methylsulfonyl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidin-4-amine (13) To an 8 mL flask maintained under an inert purged atmosphere of nitrogen was added N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.045 g, 99.06 μmol), cuprous iodide (0.009 g, 47.26 μmol), 4-(methylsulfonyl)-N-(prop-2-yn-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). The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched by the addition of water (2 mL) and extracted with EA (2 x 4 mL). The organic layers were combined, washed with brine (5 mL) and extracted with anhydrous Na 2 It was dried over SO4 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). This resulted in 0.023 g (35.10% yield) of 1-methyl-N-(2-(3-((4-(methylsulfonyl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidin-4-amine (13) 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-methylsulfonyl-anilino]prop-1-ynyl]-3-(2,2,2-trifluoroethyl)benzothiophen-7-yl]-1-methylpiperidin-4-amine (14) Reaction Scheme: [ka]

[0234] Test Details: Step 1. 2-(2-Methoxyethoxy)-4-methylsulfonyl-N-prop-2-ynyl l-aniline. A 20 mL vial was charged with 5-(methylsulfonyl)-2-(prop-2-yn-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). The reaction was stirred at 50 °C overnight. 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 over anhydrous sodium sulfate, and concentrated under vacuum. The crude was purified on a silica gel column eluted with EA / Hexane (v / v = 1 / 1). This resulted in 0.113 g (89.84% yield) of 2-(2-methoxyethoxy)-4-methylsulfonyl-N-prop-2-ynyl-aniline 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-ynyl]-3-(2,2,2-trifluoroethyl)benzothiophen-7-yl]-1-methylpiperidin-4-amine (14). To an 8 mL vial was added 2-(2-methoxyethoxy)-4-methylsulfonyl-N-prop-2-ynyl-aniline (0.049 g, 172.94 μmol), N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl 9-1-methylpiperidin-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). The reaction was stirred under nitrogen at room temperature for 3 h. The reaction was quenched with water (20 mL) and extracted with EA (3 x 30 mL). The organic layers were combined and washed with brine (50 The mixture was washed with 10 mL of ethyl acetate, 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: 40 mL / min; Gradient: 15-40-50% B2-30-40 min; 270 nm; Room temperature: 36.17-36.91 min) to give the desired product. This resulted in N-[2-[3-(2-methoxyethoxy)-4-methylsulfonyl-anilino]prop-1-ynyl]-3-(2,2,2-trifluoroethyl)benzothiophen-7-yl]-1-methyl-piperidin-4-amine (14) as an off-white solid in 0.014 g (20.86 yield). 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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (racemic) (15) Reaction Scheme: [ka]

[0237] Test Details: Step 1 (4-((3-(7-(((Z)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (racemic) (15) In a 10 mL round-bottom flask, (3-methoxy-4-(prop-2-yn-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)piperidin-4-amine (racemic) (0.076 g, 160.92 μmol), Pd(PPh 3 ) 2 Cl 2 (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 at room temperature under nitrogen for 6 h. 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 over anhydrous sodium sulfate, filtered, and concentrated in vacuo. 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 give the desired product. This resulted in 0.047 g (80.81 μmol, 24.57% yield) of (4-((3-(7-(((-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (racemic) (15) as a white solid. LCMS: m / z = 582 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6) 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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-N4,N4-dimethylcyclohexane-1,4-diamine (16) Reaction Scheme: [ka]

[0239] Test Details: Step 1. N1-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-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, add 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-amine (0.083 g, 177.15 μmol), 4-(dimethylamino)cyclohexan-1-one (0.120 g, 849.80 μmol), NaCNBH 3 (0.079 g, 1.84 mmol) and EtOH (5 mL) were added. The mixture was stirred at 60° C. for 16 h. The reaction was quenched with water (20 mL) and extracted with EA (50 mL x 2). The combined organic layers were washed successively with water (50 mL) and brine (50 mL), separated and concentrated in vacuo. 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 min); 265 nm; room temperature: 33.497-37.464 min). This gave N1-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-N4,N4-dimethylcyclohexane-1,4-diamine (16) as a white solid, 47 mg (44% yield). 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)prop-1-yn-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)prop-1-yn-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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1,4-dioxaspiro[4.5]decan-8-amine To a 25 mL flask was added titanium ethoxide (0.577 g, 2.53 mmol), 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-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). The reaction mixture was stirred at 110 °C for 2 h. The reaction was concentrated under vacuum and dissolved in methanol (10 mL). Sodium cyanoborate anhydrous (0.226 g, 5.27 mmol) was then added. The reaction mixture was stirred at room temperature for an additional 15 h. The reaction was quenched by the addition of water (20 mL) and extracted with EA (2 x 20 mL). The organic layers were combined, washed with brine (20 mL), dried over 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, 0.608 g (93.60% yield) of N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1,4-dioxaspiro[4.5]decan-8-amine was obtained as a yellow oil. LCMS: m / z = 609 [M+1] + .

[0242] Step 2. 4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)cyclohexan-1-one Into a 25 mL flask maintained under an inert purged atmosphere of nitrogen was added N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-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), 4-methylbenzenesulfonic acid hydrate (1.583 g, 8.32 mmol) in water (5 mL). The reaction mixture was stirred at room temperature for 5 h, after which saturated aqueous sodium bicarbonate was added until pH = 7-8. The resulting solution was extracted with EA (2 x 20 mL). The organic layers were combined, washed with brine (50 mL), and purified by anhydrous Na 2 SO 4 The mixture was dried over hexane and concentrated under vacuum. The residue was applied to a silica gel column eluted with EA / heptane (v / v = 3 / 1). As a result, 0.447 g (79.91% yield) of 4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)cyclohexan-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)prop-1-yn-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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (17b) An 8 mL flask was charged with 2-oxa-6-azaspiro[3.3]heptane (0.100 g, 1.01 mmol), 4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)cyclohexan-1-one (0.050 g, 88.55 μmol), methanol (2 mL), and acetic acid (0.1 mL). The reaction mixture was stirred at room temperature for 24 h, after which sodium cyanoborate (0.030 g, 699.70 μmol) was added. The reaction mixture was stirred at room temperature for an additional 2 h. The reaction was quenched by the addition of water (10 mL) and extracted with EA (2 x 20 mL). The organic layers were combined, washed with brine (20 mL), and concentrated in vacuo. 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 afforded trans-N-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (17) in 0.017 g (29.63% yield) 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] And 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)prop-1-yn-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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (18) and cis-N-(4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (18) and cis-N-(4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (18b). The mixture was placed in a 10 mL sealed tube and kept under an inert atmosphere of nitrogen and 4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)cyclohexan-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 cyanoborohydride (0.04 g, 636.53 mmol) was added to the reaction 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 and washed with anhydrous Na 2 SO 4 The resulting crude product was extracted with MeOH / H 2Further purification was performed by pre-HPLC using 2H2O (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 afforded 0.008 g (13.37% yield) of trans-N-(4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-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] And cis-N-(4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophene-7-amine (18b) was obtained as a white solid in 0.007 g (yield 11.69%). LCMS: m / z = 676 [M+1] + 1 H 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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)cyclohexyl)azanediyl)bis(ethan-1-ol) (19) and cis-2,2'-((4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)cyclohexyl)azanediyl)bis(ethan-1-ol) (19b) Reaction Scheme: [ka]

[0249] Test Details: Step 1. Synthesis of trans-2,2'-((4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)cyclohexyl)azanediyl)bis(ethan-1-ol) (19) and cis-2,2'-((4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)cyclohexyl)azanediyl)bis(ethan-1-ol) (19b) To an 8 mL reaction vial was added 4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)cyclohexan-1-one (0.033 g, 58.44 μmol), acetic acid, (0.033 g, 549.52 μmol), and 2,2'-azanediylbis(ethan-1-ol) (0.554 g, 5.26 mmol). The reaction mixture was stirred at 60 °C for 2 h. The reaction was diluted with aq. NaCl and cooled to 30 °C. 2 CO 3(10 mL), extracted with DCM (30 mL x 3) and concentrated in vacuo. 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 give trans-2,2'-((4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)cyclohexyl)azanediyl)bis(ethan-1-ol) (0.005 g, 13.08% yield) as an off-white solid. LCMS: m / z =654 [M+1] + . 1 H 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] And cis-2,2'-((4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)cyclohexyl)azanediyl)bis(ethan-1-ol) (0.004 g, 10.46%) was obtained as an off-white solid. LCMS: m / z =654 [M+1] + . 1 H 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-methylsulfonyl-anilino)prop-1-ynyl]-3-(2,2,2-trifluoroethyl)benzothiophen-7-yl]-1-(3-methoxypropyl)piperidin-4-amine (20) Reaction Scheme: [ka]

[0252] Test Details: Step 1. N-[2-[3-(2-methoxy-4-methylsulfonyl-anilino)prop-1-ynyl]-3-(2,2,2-trifluoroethyl)benzothiophen-7-yl]-1-(3-methoxypropyl)piperidin-4-amine (20). To an 8 mL vial was added 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-amine (0.056 g, 119.53 μmol), 1-(3-methoxypropyl)piperidin-4-one (0.125 g, 729.99 μmol), titanium ethoxide (0.156 g, 683.89 μmol), and toluene (1 mL). The reaction was stirred at 110 °C for 1 h and concentrated in vacuo. To the crude was added MeOH (1 mL) and anhydrous sodium cyanoborate (0.120 g, 2.80 mmol). The reaction 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 washed successively 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). This resulted in 0.035 g (46.95% yield) of N-[2-[3-(2-methoxy-4-methylsulfonyl-anilino)prop-1-ynyl]-3-(2,2,2-trifluoroethyl)benzothiophen-7-yl]-1-(3-methoxypropyl)piperidin-4-amine (20) as an off-white solid. LCMS: m / z =624 [M+1] + . 1 H NMR (400 MHz, , methanol-d 4) 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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide (21) Reaction Scheme: [ka]

[0254] Test Details: Step 1: 3-Methoxy-N,N-dimethyl-4-nitrobenzenesulfonamide In a 20 mL sealed tube, 3-methoxy-4-nitrobenzenesulfonyl chloride (0.536g, 2.13 mmol), dimethylamine (0.542g, 3.96 mmol), and ACN (5 mL) were added. The reaction mixture was purified on a silica gel column eluted with EA / Hexane (v / v = 2 / 3). 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 A 40 mL sealed tube was charged with 3-methoxy-N,N-dimethyl-4-nitrobenzenesulfonamide (0.566 g, 2.17 mmol), iron (1.406 g, 25.17 mmol), NH4Cl (1.121 g, 20.95 mmol), MeOH (8 mL), and water (2 mL). The reaction mixture was stirred at 70 °C under nitrogen for 4 h. The reaction mixture was filtered through a pad of Celite and the filter cake was washed with methanol (2 x 20 mL). The filtrate was concentrated under reduced pressure to give 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-(prop-2-yn-1-ylamino)benzenesulfonamide In an 8 mL sealed tube, add 4-amino-3-methoxy-N,N-dimethylbenzenesulfonamide (0.151 g, 655.71 μmol), 3-bromoprop-1-yne (0.102 g, 857.43 μmol), K 2 CO 3 (0.263 g, 1.90 mmol) and NMP (2 mL) were added. The reaction mixture was stirred under nitrogen at 80° C. for 4 h. 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 on a silica gel column eluted with EA / hexane (v / v = 2 / 3). As a result, 0.119 g (443.48 μmol, 67.63% yield) of 3-methoxy-N,N-dimethyl-4-(prop-2-yn-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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide (21) In a 10 mL round-bottom flask, 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzenesulfonamide (0.098 g, 365.22 μmol), N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.058 g, 127.67 μmol), Pd(PPh 3 ) 2 Cl 2 (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 at room temperature under nitrogen for 1 h. The resulting solution was extracted with EA (3×20 mL), washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. 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 min); 220 nm; room temperature: 41.58-49.20) to give the desired product. This resulted in the production of 3-methoxy-N,N-dimethyl-4-((3-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide (21) in 0.035 g (58.85 μmol, 40.09% yield) as a white solid. LCMS: m / z =595 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6) 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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (22) Reaction scheme [ka]

[0259] Test Details: Step 1 4-((3-methoxy-4-nitrophenyl)sulfonyl)morpholine A 20 mL sealed tube was charged with 3-methoxy-4-nitrobenzenesulfonyl chloride (0.529 g, 2.10 mmol), morpholine (0.387 g, 4.44 mmol), and ACN (5 mL). The reaction mixture was purified on a silica gel column eluted with EA / Hexane (v / v = 2 / 3). As a result, 0.690 g (2.28 mmol, 100.00% yield) of 4-((3-methoxy-4-nitrophenyl)sulfonyl)morpholine was obtained as a pale yellow solid. LCMS: m / z = 303 [M+1] + .

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

[0261] Step 3: 2-Methoxy-4-(morpholinosulfonyl)-N-(prop-2-yn-1-yl)aniline In an 8 mL sealed tube, add 2-methoxy-4-(morpholinosulfonyl)aniline (0.161 g, 591.21 μmol), 3-bromoprop-1-yne (0.099 g, 832.21 μmol), K 2 CO 3 (0.251 g, 1.81 mmol) and NMP (2 mL) were added. The reaction mixture was stirred under nitrogen at 80° C. for 16 h. 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 on a silica gel column eluted with EA / hexane (v / v = 2 / 3). As a result, 2-methoxy-4-(morpholinosulfonyl)-N-(prop-2-yn-1-yl)aniline 0.138 g (444.63 μmol, 75.20% yield) was obtained as a pale yellow solid. LCMS: m / z = 311 [M+1] + .

[0262] Step 4 N-(2-(3-((2-methoxy-4-(morpholinosulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (22) In a 10 mL round-bottom flask, 2-methoxy-4-(morpholinosulfonyl)-N-(prop-2-yn-1-yl)aniline (0.072 g, 231.98 μmol), N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.128 g, 281.75 μmol), Pd(PPh 3 ) 2 Cl 2 (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 at room temperature under nitrogen for 2 h. The reaction was quenched with water (5 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 in vacuo. 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 give the desired product. This resulted in the production of N-(2-(3-((2-methoxy-4-(morpholinosulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (22) in 0.035 g (58.85 μmol, 40.09% yield) as a white solid. LCMS: m / z =595 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6) 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 = 4.8Hz, 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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide (23) Reaction Scheme: [ka]

[0264] Test Details: Step 1. Benzyl(3-methoxy-4-nitrophenyl)sulfane 4-Fluoro-2-methoxy-1-nitrobenzene (20.50 g, 119.80 mmol) and K in 200 mL DMF 2 CO 3(125.57 g, 908.57 mol) was added with phenylmethanethiol (16.34 g, 131.77 mol) at 0° C. The mixture was stirred at room temperature for 8 hours, the mixture was added to 500 mL of water, the mixture was 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)sulfane was obtained as a small yellow solid. LCMS: m / z = 276 [M+1] +

[0265] Step 2. 3-Methoxy-4-nitrobenzenesulfonyl chloride In a 100 mL round-bottom flask, add benzyl(3-methoxy-4-nitrophenyl)sulfane (14.47 g, 52.56 mmol), HOAc (90 mL), and H 2 O (15 mL) was added. The mixture was cooled to 0 °C. Then NCS (30.45 g, 228.03 mmol) was added over 5 min while maintaining the internal temperature below 5 °C. The mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water (150 mL) and extracted with EA (300 mL × 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column eluted with EA / hexane (v / v = 1 / 1) to give 3-methoxy-4-nitrobenzenesulfonyl chloride (9.792 g, 74.04% yield) as a pale yellow solid.

[0266] Step 3. 3-Methoxy-4-nitrobenzenesulfonamide To a mixture of 3-methoxy-4-nitrobenzenesulfonyl chloride (0.510 g, 2.03 mmol) in 10 mL of MeCN was added ammonium hydroxide (1 mL) at 0° C. The mixture was stirred at room temperature for 0.5 h. 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 A solution of 3-methoxy-4-nitrobenzenesulfonamide (0.481 g, 2.07 mmol) in MeOH (8 mL) was diluted with Pd / C (10%, 0.097 g) 2 The mixture was degassed under vacuum and H 2 (g) three times. The reaction mixture was stirred at room temperature for 2 h. The solid was filtered and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated in vacuo to give 4-amino-3-methoxybenzenesulfonamide (0.470 g, crude) as a grey solid. LCMS: m / z = 203 [M+1] +

[0268] Step 5. 3-Methoxy-4-(prop-2-yn-1-ylamino)benzenesulfonamide 4-Amino-3-methoxybenzenesulfonamide (0.465 g, 2.30 mmol), 3-bromoprop-1-yne (0.595 g, 5.00 mmol) and K in DMA (10 mL) 2 CO 3 (0.958 g, 6.93 mmol) was degassed and diluted with N 2 (g) three times. The mixture was stirred at 50° C. for 12 h. The reaction mixture was quenched by the addition of water (20 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (30 mL x 4), filtered and concentrated under reduced pressure. The residue was purified on a C18 column eluted with ACN / water (v / v = 1 / 2) to give 0.152 g (27.51%) of 3-methoxy-4-(prop-2-yn-1-ylamino)benzenesulfonamide as a yellow solid. LCMS: m / z = 241 [M+1] +

[0269] Step 6. 3-Methoxy-4-((3-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide (23) Into an 8 mL sealed tube, purged and maintained under an inert atmosphere of nitrogen, was added N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.051 g, 0.11 mmol), 3-methoxy-4-(prop-2-yn-1-ylamino)benzenesulfonamide (0.048 g, 0.20 mmol), Pd(dppf)Cl 2 (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 h. The mixture was diluted with H 2 The mixture was quenched by extraction with O (20 mL) and extracted with EA (20 mL x 2). The combined organic layers were washed with brine (10 mL), separated and concentrated in vacuo. 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 give 3-methoxy-4-((3-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide (24) Reaction Scheme: [ka]

[0271] Test 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 was added 3-aminopropane-1,2-diol (0.238 g, 2.61 mmol) 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), 2 Pd / C (10%, 0.219 g) was added under vacuum. The mixture was degassed under H 2 (g) three times. The reaction mixture was stirred at room temperature for 2 h. The solid was filtered off and the filter cake was washed with MeOH (10 mL). The combined filtrate was concentrated in vacuo to give 4-amino-N-(2,3-dihydroxypropyl)-3-methoxybenzenesulfonamide (1.004 g, crude) as a grey solid. LCMS: m / z = 277 [M+1] +

[0273] Step 3. N-(2,3-dihydroxypropyl)-3-methoxy-4-(prop-2-yn-1-ylamino)benzenesulfonamide 4-Amino-N-(2,3-dihydroxypropyl)-3-methoxybenzenesulfonamide (1.001 g, crude), 3-bromoprop-1-yne (0.467 g, 3.93 mmol) and K in NMP (10 mL). 2 CO 3 A mixture of (0.795 g, 5.75 mmol) was degassed and filled with N 2 (g) three times. The mixture was stirred at 80° C. for 48 h. The reaction mixture was quenched by the addition of water (20 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (30 mL x 4), filtered and concentrated under reduced pressure. The residue was purified on a C18 column eluted with ACN / water (v / v = 1 / 4) to give 0.078 g (6.85%) of N-(2,3-dihydroxypropyl)-3-methoxy-4-(prop-2-yn-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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzenesulfonamide (24) Into an 8 mL sealed tube, purged and maintained under an inert atmosphere of nitrogen, was added N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.048 g, 0.11 mmol), N-(2,3-dihydroxypropyl)-3-methoxy-4-(prop-2-yn-1-ylamino)benzenesulfonamide (0.077 g, 0.24 mmol), Pd(dppf)Cl 2 (0.019 g, 0.03 mmol), CuI (0.009 g, 0.05 mmol), DIEA (0.062 g, 0.48 mmol), DMSO (1 mL) were added. The reaction mixture was stirred at room temperature for 1 h. 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 in vacuo. 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 give N-(2,3-dihydroxypropyl)-3-methoxy-4-((3-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-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)prop-1-yn-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] Test Details: Step 1 tert-Butyl 8-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-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. Phenylsilane (0.235 g, 2.17 mmol) was then added. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified on a silica gel column eluted with EA / Hexane (v / v = 3 / 2). As a result, 0.194 g (286.22 μmol, 69.12% yield) of tert-butyl 8-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-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. LCMS: m / z = 678 [M+1] + .

[0277] Step 2: N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-3-azabicyclo[3.2.1]octan-8-amine In an 8 mL sealed tube was added tert-butyl 8-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-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), EA (2 mL). The reaction was stirred at room temperature for 1 h and the reaction was concentrated under vacuum. Water (2 mL) was added to the reaction and NaOH (aq, 3 N) was added until PH=7. 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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-3-azabicyclo[3.2.1]octan-8-amine was obtained as a brown solid. The reaction mixture was diluted with ACN / H 2 Purified on a C18 column eluted with O (v / v = 1 / 1). LCMS: m / z = 578 [M+1] + .

[0278] Step 3: N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-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, add N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-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). Then add NaBH 3CN (0.090 g, 2.37 mmol) was added. The reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with water (10 mL) and the resulting solution was extracted with EA (3 x 20 mL), washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 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 min); 270 nm; room temperature: 44.33-46.51) to give the desired product. This resulted in the production of N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-3-methyl-3-azabicyclo[3.2.1]octan-8-amine (25) in 0.023 g (38.87 μmol, 14.77% yield) as a white solid. LCMS: m / z =592 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6 ) 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)prop-1-yn-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] Test Details: Step 1. tert-Butyl 3-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate. To a 20 mL vial was added 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-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). The reaction was stirred at 110 °C for 16 h and concentrated in vacuo. To the crude was added MeOH (3 mL) and anhydrous sodium cyanoborate (0.159 g, 3.71 mmol). The reaction was stirred at room temperature overnight. 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 over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude was purified on a silica gel column and eluted with EA / Hexane (v / v = 1 / 2). The result was 0.330 g (crude) of tert-butyl 3-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate as a yellow oil. LCMS: m / z = 678 [M+1] + .

[0281] Step 2. N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-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-yn-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), HCl in EA (20 mL, 4.0 M). The reaction mixture was cooled to 0 °C with KHCO 3 (aq.) to adjust PH = 8. 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 was purified on a silica gel column and eluted with MeOH / DCM (v / v = 1 / 9). The result was 0.074 g (26.31% yield) of N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-8-azabicyclo[3.2.1]octan-3-amine as a yellow solid. LCMS: m / z = 578 [M+1] + .

[0282] Step 3. N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-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-methylsulfonyl-anilino)prop-1-ynyl]-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 cyanoborate (0.058 g, 1.35 mmol), MeOH (3 mL), and HOAc (0.1 mL) were added. The reaction mixture was stirred at room temperature overnight. The reaction 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 give the desired product. This resulted in 0.017 g (22.13% yield) of N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine (26) as an off-white solid. LCMS: m / z =592 [M+1] + . 1 H NMR (400 MHz, methanol-d 4 ) 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)prop-1-yn-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] Test Details: Step 1.1. N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-2-methyl-2-azabicyclo[2.2.1]heptan-5-amine (27). Into an 8 mL reaction vial was added N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-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). The reaction was stirred at room temperature for 12 hours, after which sodium cyanoborate (0.037 g, 862.95 μmol) was added. The reaction was stirred at room temperature for 5 hours. The reaction was diluted with aq.Na 2 CO 3(10 mL), extracted with DCM (3 x 10 mL) and concentrated in vacuo. 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 min); 270 nm; room temperature: 43.971-48.403 min) to give N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-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] + . 1 H 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)prop-1-yn-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] Test Details: Step 1. tert-Butyl 5-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-2-azabicyclo[2.2.1]heptane-2-carboxylate. To an 8 mL reaction vial was added 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-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). The reaction was stirred at 100 °C for 2 h and then cooled to room temperature. The toluene was concentrated under vacuum. To the residue was added MeOH (3 mL) and anhydrous sodium cyanoborate (0.030 g, 699.69 μmol). The reaction was stirred at room temperature for 2 h. The reaction mixture was quenched by the addition of water (10 mL), extracted with EA (3 x 30 mL), washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude was purified on a silica gel column eluted with EA / Hexane (v / v = 1 / 3) to give tert-butyl 5-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-2-azabicyclo[2.2.1]heptane-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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-2-azabicyclo[2.2.1]heptan-5-amine (28). Into an 8 mL reaction vial was added tert-butyl 5-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-2-azabicyclo[2.2.1]heptane-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). 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 diluted with aq.Na 2 CO 3 (10 mL), extracted with DCM (3 x 10 mL) and concentrated in vacuo. 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 give N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)-1H-indol-7-amine (29) Reaction Scheme: [ka]

[0289] Experiment details Step 1. 7-Nitro-1-(phenylsulfonyl)-1H-indole A 500 mL flask was charged with 7-nitro-1H-indole (5.04 g, 31.08 mmol), tetrahydrofuran (200 mL). Then NaH (4.28 g, 178.35 mmol) was added portionwise 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 another 1 h. 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 over anhydrous Na2SO4 and concentrated under vacuum. The crude was recrystallized with heptane / EA (v / v = 20 / 1) to give 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-indol-7-amine A 250 mL flask was charged with 7-nitro-1-(phenylsulfonyl)-1H-indole (5.03 g, 16.64 mmol), methanol (80 mL), ammonium chloride (10.19 g, 190.50 mmol) in water (10 mL), and iron (4.77 g, 85.42 mmol). The reaction mixture was stirred at 45 °C for 2 h, and then 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), and concentrated under reduced pressure using anhydrous NaCl. 2 SO 4 The mixture was dried over hexane and concentrated under vacuum. The residue was applied to 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-indol-7-amine was obtained as a yellow solid. LCMS: m / z = 273 [M+1] + .

[0291] Step 3. 1-(Phenylsulfonyl)-N-(prop-2-yn-1-yl)-1H-indol-7-amine A nitrogen purged 100 mL flask was charged with 1-(phenylsulfonyl)-1H-indol-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). The reaction mixture was stirred at 100° C. for 24 h, after which water (100 mL) was added to quench the reaction. The resulting solution was extracted with EA (2 x 100 mL). The organic layers were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was dissolved in 10 mL of ACN / H2SO4 to give 100%. 2 The mixture was purified by C18 chromatography column eluted with O (v / v = 1 / 1). As a result, 1-(phenylsulfonyl)-N-(prop-2-yn-1-yl)-1H-indol-7-amine was obtained as a yellow solid in 1.474 g (64.60% yield). LCMS: m / z = 311 [M+1] + .

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

[0293] Step 5. N-(3-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)-1H-indol-7-amine (29) A 25 mL flask maintained under an inert purged atmosphere of nitrogen was charged with N-(prop-2-yn-1-yl)-1H-indol-7-amine (0.044 g, 258.50 μmol), N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-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). The reaction mixture was stirred at room temperature for 17 h. The reaction was quenched by the addition of water (5 mL) and extracted with EA (2 x 5 mL). The organic layers were combined, washed with brine (10 mL) and anhydrous Na 2 SO 4 The mixture was dried over 100 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: 55-90-100% B (2-30-40 min); 222 nm; Room temperature: 36.225-37.590 min). This resulted in N-(3-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)-1H-indol-7-amine (29) in 0.011 g (9.10% yield) 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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)-3-(piperidin-4-yl)-1H-indol-7-amine (30) Reaction Scheme: [ka]

[0295] Test Details: Step 1 3-iodo-7-nitro-1H-indole A 100 ml 3-neck flask was charged with 7-nitro-1H-indole (2.09 g, 12.88 mmol), NIS (3.49 g, 15.51 mmol), and ACN (30 mL). The reaction was stirred at 80° C. for 1 h. The reaction was then cooled to 100° C. with 5% NaCl. 2 CO 3aq (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 in vacuo to give 2.86 g (9.92 mmol, 77.03% yield) of 3-iodo-7-nitro-1H-indole as a pale yellow solid. LCMS: m / z = 289 [M+1] + .

[0296] Step 2: 3-iodo-7-nitro-1-(phenylsulfonyl)-1H-indole A 50 ml 3-neck flask was charged with 3-iodo-7-nitro-1H-indole (2.608 g, 9.05 mmol) and THF (30 mL). The reaction was cooled to 0° C. NaH (0.522 g, mmol) was then added with vigorous stirring at 0-5° C. Benzenesulfonyl chloride (2.071 g, 11.72 mmol) was then added. The reaction was stirred at room temperature for about 1 h. 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. As a result, 3-iodo-7-nitro-1-(phenylsulfonyl)-1H-indole was obtained as a pale yellow solid, 2.836 g (6.62 mmol, 73.14% yield). LCMS: m / z = 429 [M+1] + .

[0297] Step 3 tert-Butyl 4-(7-nitro-1-(phenylsulfonyl)-1H-indol-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate In a 100 ml three-neck 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)Cl 2 (0.836 g, 1.14 mmol), Na2 CO 3 (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 h. 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 on a silica gel column eluted with EA / hexane (v / v = 3 / 7). As a result, tert-butyl 4-(7-nitro-1-(phenylsulfonyl)-1H-indol-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate 1.585 g (3.27 μmol, 58.45% yield) was obtained as a yellow solid. LCMS: m / z = 484 [M+1] + .

[0298] Step 4 tert-Butyl 4-(7-amino-1-(phenylsulfonyl)-1H-indol-3-yl)piperidine-1-carboxylate In a 100 ml three-neck flask, tert-butyl 4-(7-nitro-1-(phenylsulfonyl)-1H-indol-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 placed. The reaction mixture was stirred under hydrogen atmosphere at room temperature for 2 h. 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 give the product. As a result, 0.789 g (1.73 mmol, 92.94% yield) of tert-butyl 4-(7-amino-1-(phenylsulfonyl)-1H-indol-3-yl)piperidine-1-carboxylate was obtained as a pale yellow solid. LCMS: m / z = 456 [M+1] + .

[0299] Step 5 tert-Butyl 4-(1-(phenylsulfonyl)-7-(prop-2-yn-1-ylamino)-1H-indol-3-yl)piperidine-1-carboxylate In a 25 mL three-neck flask, tert-butyl 4-(7-amino-1-(phenylsulfonyl)-1H-indol-3-yl)piperidine-1-carboxylate (0.295 g, 647.54 μmol), 3-bromoprop-1-yne (0.082 g, 689.30 μmol), K 2 CO 3 (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 over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified on a silica gel column eluted with EA / hexane (v / v = 1 / 3). As a result, 0.132 g (267.41 μmol, 41.29% yield) of tert-butyl 4-(1-(phenylsulfonyl)-7-(prop-2-yn-1-ylamino)-1H-indol-3-yl)piperidine-1-carboxylate was obtained as a yellow solid. LCMS: m / z = 494 [M+1] + .

[0300] Step 6 tert-Butyl 4-(7-(prop-2-yn-1-ylamino)-1H-indol-3-yl)piperidine-1-carboxylate A 25 mL 3-neck flask was charged with methyl tert-butyl 4-(1-(phenylsulfonyl)-7-(prop-2-yn-1-ylamino)-1H-indol-3-yl)piperidine-1-carboxylate (0.136 g, 275.51 mmol), tetrabutylammonium fluoride (72.03 g, 275.51 mmol), and THF (2 mL). The reaction was stirred at 80 °C for 0.5 h. The reaction was then diluted with NH 4Quenched with Cl aq (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 in vacuo to give 0.096 g (271.60 μmol, 98.57% yield) of tert-butyl 4-(7-(prop-2-yn-1-ylamino)-1H-indol-3-yl)piperidine-1-carboxylate as a yellow oil. LCMS: m / z = 354 [M+1] + .

[0301] Step 7 tert-Butyl 4-(7-((3-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-1H-indol-3-yl)piperidine-1-carboxylate A 25 mL three-neck flask was charged with tert-butyl 4-(7-(prop-2-yn-1-ylamino)-1H-indol-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-methylpiperidin-4-amine (0.079 g, 173.89 μmol), Pd(PPh 3 ) 2 Cl 2(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 at room temperature under nitrogen atmosphere for 16 h. 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 over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude was purified on a silica gel column eluted with MeOH / DCM (v / v = 1 / 9). As a result, tert-butyl 4-(7-((3-(1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-1H-indol-3-yl)piperidine-1-carboxylate was obtained as a brown oil in 0.073 g (107.37 μmol, 41.25% yield). LCMS: m / z = 680 [M+1] + .

[0302] Step 8 8 N-(3-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)-3-(piperidin-4-yl)-1H-indol-7-amine (30) In an 8 mL sealed tube, tert-butyl 4-(7-((3-(1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-1H-indol-3-yl)piperidine-1-carboxylate (0.073 g, 107.37 μmol), TFA (1 mL), and DCM (1 mL) were added. 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 min); 228 nm; room temperature: 36.80-39.49) to give the desired product. This resulted in the production of N-(3-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)-3-(piperidin-4-yl)-1H-indol-7-amine (30) in 0.009 g (15.52 μmol, 14.45% yield) as a white solid. LCMS: m / z =580 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6) 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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)-1H-indol-7-amine (31) Reaction Scheme: [ka]

[0304] Test Details: Step 1. 4-Fluoroindoline. A 250 mL flask was charged with 4-fluoro-1H-indole (15.12 g, 111.88 mmol) and acetic acid (80 mL). The reaction was stirred at room temperature while anhydrous sodium cyanoborate (13.99 g, 326.29 mmol) was added in batches. The reaction was stirred at room temperature for 2 hours. The reaction was cooled to room temperature and cooled to room temperature. 2Quenched with O (200 mL), extracted with EA (3 x 100 mL) and concentrated in vacuo. The crude was purified on a silica gel column eluted with EA / Hexane (v / v = 1 / 1) to give 4-fluoroindoline (14.35 g, 93.51%) as a yellow solid. LCMS: m / z = 138 [M+1] + .

[0305] Step 2. 1-(4-Fluoroindolin-1-yl)ethan-1-one. A 250 mL flask was charged with acetic anhydride (100 mL). The reaction was stirred at 0 °C and 4-fluoroindoline (14.41 g, 105.06 mmol) was added in one portion. The reaction was stirred at room temperature for 2 h. The reaction was quenched with H2O (200 mL), extracted with EA (3 x 100 mL) and concentrated in vacuo. The crude was purified on a silica gel column eluted with EA / Hexanes (v / v = 1 / 3) to give 1-(4-fluoroindolin-1-yl)ethan-1-one (12.16 g, 64.58%) as a yellow solid. LCMS: m / z = 180 [M+1] + .

[0306] Step 3. 1-(4-Fluoro-7-nitroindolin-1-yl)ethan-1-one. A 250 mL flask was charged with 1-(4-fluoroindolin-1-yl)ethan-1-one (6.07 g, 33.87 mmol) and sulfuric acid (50 mL). The reaction mixture was stirred under nitrogen at -10°C and nitric acid (3.0 g, 47.60 mmol) was added dropwise. The reaction was stirred at room temperature for 1 h. The reaction was then cooled to 5°C for 1 h. 2 Quenched with O (100 mL), extracted with EA (3 x 100 mL) and concentrated in vacuo. The crude was purified on a silica gel column eluted with EA / Hexane (v / v = 1 / 3) to give 1-(4-fluoro-7-nitroindolin-1-yl)ethan-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. A 250 mL flask was charged with 1-(4-fluoro-7-nitroindolin-1-yl)ethan-1-one (2.146 g, 9.57 mmol) and hydrogen chloride (50 mL). The reaction mixture was stirred at 100° C. for 1 h. The reaction was cooled to room temperature and concentrated in vacuo. The reaction was diluted with aq.Na 2 CO 3 (50 mL), extracted with EA (3 x 100 mL) and concentrated in vacuo. The crude was purified on a silica gel column eluted with EA / Hexane (v / v = 1 / 1) to give 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. A 250 mL flask was charged with 4-fluoro-7-nitroindoline (1.351 g, 7.41 mmol), manganese oxide (6.319 g, 72.68 mmol), and chloroform (50 mL). The reaction mixture was filtered, washed with EA (50 mL), and concentrated in vacuo. The crude product was purified on a silica gel column eluted with EA / hexane (v / v = 1 / 3) to give 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. A 100 mL flask was charged with 4-fluoro-7-nitro-1H-indole (1.184 g, 6.57 mmol) and DMF (30 mL). The reaction mixture was heated to 100° C. for 2 h. 2 The reaction was stirred at 0° C. under atmospheric pressure and NaH (0.459 g, 19.12 mmol) was added in portions. The reaction was stirred at room temperature for 30 min and benzenesulfonyl chloride (2.541 g, 14.38 mmol) was added dropwise. The reaction was stirred at room temperature for 2 h. The reaction was cooled to 10° C. for 2 h. 2Quenched with O (50 mL), extracted with EA (3 x 100 mL) and concentrated in vacuo. The crude was purified on a silica gel column eluted with EA / Hexane (v / v = 1 / 3) to give 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. A 100 mL flask was charged with 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). The reaction was stirred at 80° C. for 12 hours. The reaction was cooled to room temperature and diluted with H 2 The mixture was quenched with O (100 mL), extracted with EA (3 x 100 mL) and concentrated in vacuo. The crude was purified on a silica gel column eluted with EA / Hexane (v / v = 1 / 2) to give 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-indol-7-amine. In a 100 mL flask, add 4-(methylsulfonyl)-7-nitro-1-(phenylsulfonyl)-1H-indole (1.19 g, 3.12 mmol), zinc (1.499 g, 22.92 mmol), and NH 4Cl (1.367 g, 25.55 mmol), ethanol (50 mL), and water (10 mL) were charged. The reaction was stirred at 70° C. for 3 h. The reaction mixture was filtered, washed with EA (50 mL), and concentrated in vacuo. The crude was purified on a silica gel column eluted with EA / Hexanes (v / v = 1 / 3) to give 4-(methylsulfonyl)-1-(phenylsulfonyl)-1H-indol-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-indol-7-yl)carbamate. A 100 mL flask was charged with 4-(methylsulfonyl)-1-(phenylsulfonyl)-1H-indol-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). The reaction mixture was stirred at room temperature for 2 h, and then the mixture was dissolved in H 2 The mixture was quenched with O (30 mL), extracted with EA (3 x 50 mL) and concentrated in vacuo. The crude was purified on a silica gel column eluted with EA / Hexane (v / v = 1 / 2) to give tert-butyl N-[1-(benzenesulfonyl)-4-methylsulfonyl-indol-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-indol-7-yl)(prop-2-yn-1-yl)carbamate. An 8 mL reaction vial was charged with tert-butyl (4-(methylsulfonyl)-1-(phenylsulfonyl)-1H-indol-7-yl)carbamate (0.742 g, 1.64 mmol), DMF (10 mL). The reaction mixture was stirred at 0° C., then NaH (0.221 g, 9.20 mmol) was added in portions. The reaction was stirred at room temperature for 30 minutes. 3-Bromoprop-1-yne (0.888 g, 7.46 mmol) was added to the above mixture. The reaction was stirred at room temperature for 12 hours, then H 2 Quenched with O (30 mL), extracted with EA (3 x 50 mL) and concentrated in vacuo. The crude was purified on a silica gel column eluted with EA / Hexane (v / v = 1 / 2) to give tert-butyl (4-(methylsulfonyl)-1-(phenylsulfonyl)-1H-indol-7-yl)(prop-2-yn-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-(prop-2-yn-1-yl)-1H-indol-7-amine. A 50 mL flask was charged with tert-butyl (4-(methylsulfonyl)-1-(phenylsulfonyl)-1H-indol-7-yl)(prop-2-yn-1-yl)carbamate (0.456 g, 933.32 μmol), DCM (6 mL), and trifluoroacetic acid (2 mL). The reaction was stirred at room temperature for 1 h. The reaction was diluted with aq.Na 2 CO 3 (20 mL), extracted with DCM (3 x 30 mL) and concentrated in vacuo. The crude was purified by prep-TLC using DCM / MeOH (v / v = 20 / 1) to give 4-(methylsulfonyl)-1-(phenylsulfonyl)-N-(prop-2-yn-1-yl)-1H-indol-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-(prop-2-yn-1-yl)-1H-indol-7-amine. An 8 mL reaction vial was charged with 4-(methylsulfonyl)-1-(phenylsulfonyl)-N-(prop-2-yn-1-yl)-1H-indol-7-amine (0.049 g, 126.13 μmol), TBAF (1 M in THF) (2 mL), and THF (0.5 mL). The reaction was stirred at 80° C. for 1 h. The reaction was then cooled to 5° C. for 1 h. 2 The mixture was quenched with O (10 mL), extracted with EA (3 x 30 mL) and concentrated in vacuo. The crude was purified by prep-TLC using DCM / MeOH (v / v = 20 / 1) to give 4-(methylsulfonyl)-N-(prop-2-yn-1-yl)-1H-indol-7-amine (0.023 g, 73.43%) as a yellow solid. LCMS: m / z = 249 [M+1] + .

[0316] Step 13. N-(3-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)-1H-indol-7-amine (31). To an 8 mL reaction vial was added N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.050 g, 110.06 μmol), 4-(methylsulfonyl)-N-(prop-2-yn-1-yl)-1H-indol-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 methylsulfoxide (2 mL). The reaction was then cooled to RT. 2 The reaction was stirred at room temperature for 1 hour under atmospheric pressure. 2Quenched with O (10 mL), extracted with EA (3 x 20 mL) and concentrated in vacuo. 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 give N-(3-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)-1H-indol-7-amine (31) (0.007 g, 11.06%) as an off-white solid. LCMS: m / z =575 [M+1] + . 1 H 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)prop-1-yn-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-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-3-azabicyclo[3.2.0]heptane-3-carboxylate. A 4 mL jar was charged with 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-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). Cooled to room temperature and added sodium cyanoborohydride (211 mg, 3.43 mmol), acetic acid (0.01 μmol), and ethanol (0.5 mL). The reaction was stirred at room temperature for 1 h. LCMS showed the reaction was complete, the reaction was concentrated under vacuum and purified on a C18 column, eluted with ACN / water (v / v = 1 / 3) to give tert-butyl 6-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-3-azabicyclo[3.2.0]heptane-3-carboxylate (0.288 g, 433.89 μmol, 205.33% yield) as a clear oil. LCMS: m / z = 664[M+1] + .

[0319] Step 2. N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-3-azabicyclo[3.2.0]heptane-3-carboxylate (0.208 g, 313.36 μmol), HCl(g) in EtOAc (1 M, 0.5 mL) were added and stirred at room temperature for 1 h. LCMS showed the reaction was complete and the reaction was diluted with sat.NaHCO to pH 8-9 at 0 °C. 3 aq. and extracted with EA (3 mL x 3). The combined organic layers were washed successively with water (3 mL) and brine (3 mL), separated and concentrated in vacuo. The residue was purified on a C18 column and eluted with ACN / water (v / v = 1 / 2) to give N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-3-methyl-3-azabicyclo[3.2.0]heptan-6-amine (32). A 4 mL flask was charged with N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-3-azabicyclo[3.0]heptan-6-amine (0.047 g, 70.81 μmol), paraformaldehyde (0.004 g, 133.22 μmol), anhydrous sodium cyanoborate (37 mg, 606.40 μmol), EtOH (0.5 mL), and glacial acetic acid (0.01 mL). The reaction was stirred at room temperature overnight. LCMS showed 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 washed successively with water (2 mL) and brine (2 mL), separated and concentrated in vacuo. 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 give N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-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, 12.22% yield) as an off-white solid. LCMS: m / z = 578[M+1] + . 1 H NMR (400 MHz, DMSO-d 6) 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 = 9.1 Hz, 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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-7-methyl-7-azaspiro[3.5]nonan-2-amine (33) Reaction Scheme: [ka]

[0322] Experiment details Step 1. tert-Butyl 2-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-7-azaspiro[3.5]nonane-7-carboxylate To an 8 mL flask was added titanium ethoxide (0.072 g, 315.64 μmol), 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-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). The reaction mixture was stirred at 110° C. for 2 hours. The reaction was concentrated under vacuum and dissolved in methanol (2 mL). Sodium cyanoborate anhydrous (0.034 g, 792.99 μmol) was then added. The reaction mixture was stirred at room temperature for an additional 15 hours. The reaction was quenched by the addition of water (10 mL) and extracted with EA (2 x 10 mL). The organic layers were combined, washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied to a silica gel column eluted with EA / heptane (v / v = 1 / 3). This resulted in 0.080 g (88.82% yield) of tert-butyl 2-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-7-azaspiro[3.5]nonane-7-carboxylate as a yellow oil. LCMS: m / z = 692 [M+1] + .

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

[0324] Step 3. N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-7-methyl-7-azaspiro[3.5]nonan-2-amine (33) A 8 mL flask was charged with N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-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). The reaction mixture was stirred at room temperature for 19 h, after which sodium cyanoborohydride (0.009 g, 209.91 μmol) was added. The reaction mixture was stirred at room temperature for an additional 4 h. The reaction was quenched by the addition of water (2 mL) and extracted with EA (2 x 5 mL). The organic layers were combined, washed with brine (10 mL), and concentrated in vacuo. 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 afforded N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-7-methyl-7-azaspiro[3.5]nonan-2-amine (33) in 0.002 g (2.96% yield) as a white solid. LCMS: m / z = 606 [M+1] + .

[0325] Example 34 3-Fluoro-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (34) Reaction Scheme: [ka]

[0326] Test 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]thiophen-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) and purified with N 2 After purging with (g), BH 3 THF (1 M, 15 mL) was added. The mixture was stirred at 0° C. for 1 h. 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 on a silica gel column eluted with EA / Hexane (v / v = 1 / 2) to give 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)piperidin-4-amine In a 100 mL round bottom flask was added 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) and the reaction mixture was stirred at room temperature for 1 h. The reaction was cooled to room temperature and cooled to 37° C. for 1 h. 3(aq.) to pH = 9 and extracted with EA (100 mL x 2). The combined organic layers were washed with brine (40 mL), separated and concentrated in vacuo. 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)piperidin-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-methylpiperidin-4-amine To a solution of 3,3-difluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidin-4-amine (0.628 g, 1.32 mmol) in 10 mL of MeOH was added paraformaldehyde (0.082 g, 2.73 mmol). The mixture was stirred at room temperature for 0.5 h, and then diluted with NaBH 3 CN (0.289 g, 6.74 mmol) and HOAc (0.002 mL) were added. The reaction mixture was stirred at room temperature for 12 h. The residue was purified on a silica gel column and eluted with EA / Hexane (v / v = 1 / 2) to give 3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (34) Into an 8 mL sealed tube, purged and maintained under an inert atmosphere of nitrogen, was added 3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.097 g, 0.20 mmol), 2-methoxy-4-(methylsulfonyl)-N-(prop-2-yn-1-yl)aniline (0.090 g, 0.38 mmol), Pd(dppf)Cl 2 (0.029 g, 0.04 mmol), CuI (0.035 g, 0.18 mmol), DIEA (0.077 g, 0.60 mmol), DMSO (2 mL) were added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by addition of water (80 mL) and extracted with EA (80 mL x 2). The combined organic layers were washed with brine (20 mL), separated and concentrated in vacuo. 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 give 3-fluoro-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)phosphine oxide (racemic) (35) Reaction Scheme: [ka]

[0331] Test Details: Step 1. (4-Amino-3-methoxyphenyl)diethylphosphine oxide Into a 20 mL sealed tube, purged and maintained under an inert atmosphere of nitrogen, was added 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), Xantphos (0.381 g, 0.66 mmol), DIEA (1.841 g, 14.24 mmol), DMF (10 mL). The reaction mixture was stirred at 120° C. for 2 h. The reaction mixture was quenched by addition of 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 on a C18 column eluted with ACN / water (v / v = 1 / 8) to give 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-(prop-2-yn-1-ylamino)phenyl)phosphine oxide (4-amino-3-methoxyphenyl)diethylphosphine oxide (0.423 g, 1.86 mmol), 3-bromoprop-1-yne (0.219 g, 1.84 mmol), NaI (0.227 g, 1.51 mmol) and K in NMP (10 mL). 2 CO 3 A mixture of (0.578 g, 4.18 mmol) was degassed and filled with N 2 The mixture was purged with 3× and stirred at 80° C. for 48 h. The reaction mixture was purified on a C18 column eluted with ACN / water (v / v = 1 / 3) to give 0.172 g (34.83%) of diethyl (3-methoxy-4-(prop-2-yn-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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)phosphine oxide (racemic) (35) (Z)-3-Fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.098 g, 0.21 mmol), diethyl(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)phosphine oxide (0.098 g, 0.37 mmol), Pd(dppf)Cl 2 (0.021 g, 0.03 mmol), CuI (0.048 g, 0.25 mmol), DIEA (0.099 g, 0.77 mmol), DMSO (1 mL) were placed in an 8 mL sealed tube and kept purged with an inert atmosphere of nitrogen. The reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was quenched by addition of water (20 mL) and extracted with EA (20 mL x 2). The combined organic layers were washed with brine (10 mL), separated and concentrated in vacuo. 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: 38.125-42.751 min) to give diethyl(4-((3-(7-(((Z)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-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-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidin-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-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidin-4-amine (36) Place in a 4 mL sealed tube, kept under an inert atmosphere of nitrogen, and mix with N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidin-4-amine (0.040 g, 72.51 μmol), 1-fluoro-2-iodoethane (0.025 g, 143.71 μmol), K 2 CO 3 (0.063 g, 455.86 μmol) and acetonitrile (1 mL) were added. The reaction mixture was stirred at 50° C. for an extended period of 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 over anhydrous Na2SO4, and the residue was concentrated in vacuo. The crude product was purified by elution with MeCN / H 2 Purification by pre-HPLC using 2H2O (0.1% ammonium hydroxide): 70 mL / min; gradient: 40-75-100%B (2-30-60 min); 263 nm; room temperature: 33.540-34.450 min. This resulted in 1-(2-fluoroethyl)-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidin-4-amine (36) in 0.018 g (41.54% yield) 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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-(2,2,2-trifluoroethyl)piperidin-4-amine (37) Reaction scheme [ka]

[0337] Experiment details Step 1. N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-(2,2,2-trifluoroethyl)piperidin-4-amine (37) Place in a 100 mL sealed tube, kept under an inert atmosphere of nitrogen, and mix with N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidin-4-amine (0.023 g, 41.69 μmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.017 g, 73.24 μmol), Cs 2 CO 3 (0.028 g, 85.94 μmol) and acetonitrile (1 mL) were added. The reaction mixture was stirred at room temperature for 2 h. 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 and washed with anhydrous Na 2 SO 4 The residue was concentrated in vacuo and the crude product was extracted with MeOH / H 2 Purification by pre-HPLC with 2H2O (0.1% ammonium hydroxide): 40 mL / min; gradient: 45-75-100%B (2-30-60 min); 270 nm; room temperature: 38.379-40.311 / min. This gave N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-(2,2,2-trifluoroethyl)piperidin-4-amine (37) as a white solid in 0.016 g (60.56% yield). 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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidin-4-amine (38) Reaction scheme [ka]

[0339] Experiment details Step 1. tert-Butyl 4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate Into a 40 mL sealed tube kept under an inert atmosphere of nitrogen was added 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-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). The reaction mixture was stirred at 110 °C for 2 h. Sodium cyanoborohydride (0.170 g, 2.75 mmol) was added to the reaction and stirred at room temperature for 3 h. The reaction 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 (yield 82.56%) of tert-butyl 4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-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 = 652 [M+1] +

[0340] Step 2. N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidin-4-amine (38) A 25 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with tert-butyl 4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-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). After the reaction mixture was stirred at room temperature, hydrochloric acid in EA (3 mL, 4 M) was added to the reaction and stirred at room temperature for 2 h. The resulting solution was added to saturated aqueous sodium bicarbonate (20 mL). The resulting solution was extracted with EA (2 x 30 mL) and the organic layers were combined and washed with anhydrous Na 2 SO 4 The residue was concentrated in vacuo and one-fourth of the crude product was diluted with MeOH / H 2 Further purification by pre-HPLC: 20H2O (0.1% ammonium hydroxide), flow rate: 25 mL / min; gradient: 40-70-100%B (2-30-60 min), 220 nm; room temperature: 32.890-37.835 min. This resulted in 0.028 g (49.30% yield) of N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidin-4-amine (38) 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]heptan-6-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine (39) and trans-N-((1R,4R)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine (39b) Reaction scheme [ka]

[0342] Step 1. Synthesis of 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine. A 50 mL flask was charged with 2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine (0.620 g, 1.82 mmol), 4-(methylsulfonyl)-N-(prop-2-yn-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 methylsulfoxide (20 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction was then subjected to H 2 Quenched with O (30 mL), extracted with EA (50 mL x 3) and concentrated in vacuo. The crude was purified on a silica gel column eluted with EA / Hexane (v / v = 1 / 1) to give 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-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)prop-1-yn-1-yl)-N-(1,4-dioxaspiro[4.5]decan-8-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine. A 50 mL flask was charged with 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-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). The reaction was stirred at 100° C. for 2 h and then cooled to room temperature. The reaction mixture was concentrated in vacuo. To the residue was added EtOH (5 mL), sodium cyanoborate (0.392 g, 9.1427 mmol). The reaction was stirred at room temperature for 2 h. The reaction was quenched with H2 Quenched with O (10 mL), extracted with EA (3 x 30 mL) and concentrated in vacuo. The crude was purified on a silica gel column eluted with EA / Hexane (v / v = 1 / 1) to give 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-N-(1,4-dioxaspiro[4.5]decan-8-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-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-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)cyclohexan-1-one. A 50 mL flask was charged with 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-N-(1,4-dioxaspiro[4.5]decan-8-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-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). The reaction was quenched with N 2 The reaction was stirred at room temperature for 1 hour under atmospheric pressure. 2 The mixture was quenched with O (30 mL), extracted with EA (3 x 50 mL) and concentrated in vacuo. The crude was purified on a silica gel column eluted with EA / Hexane (v / v = 3 / 1) to give 4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)cyclohexan-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]heptan-6-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine (39) and trans-N-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine (39b). A 25 mL flask was charged with 4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)cyclohexan-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). The reaction was stirred at room temperature for 12 hours and sodium cyanoborate (0.392 g, 9.1427 mmol) was added to the above mixture. The reaction was stirred at room temperature for 2 hours. The reaction was cooled to room temperature and cooled to room temperature. 2 It was quenched with O (10 mL), extracted with EA (3 x 30 mL) and concentrated in vacuo. 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 give cis-N-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine (39) (0.027 g, 10.70%) as an off-white solid. LCMS: m / z =631 [M+1] + . 1 H 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] and trans-N-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzenesulfonamide (racemic) (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)piperidin-4-amine (racemic). A 500 mL round bottom flask was charged with tert-butyl (Z)-3-fluoro-4-((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (racemic) (16.02 g, 28.69 mmol, DCM (150 mL), TFA (50 mL). The reaction was quenched with a saturated aqueous solution of NaHCO3 (100 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 14.04 g (crude) of (Z)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidin-4-amine (racemic) 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-methylpiperidin-4-amine (racemic). A 500 mL round bottom flask was charged with (Z)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidin-4-amine (racemic) (13.962 g, 30.47 mmol), polyoxymethylene (1.575 g, 52.45 mmol), anhydrous sodium cyanoborate (11.745 g, 189.94 mmol), MeOH (150 mL), and HOAc (30 mL). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO 3Quenched with aqueous solution (100 mL) and extracted with EA (3 x 100 mL), the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude was purified on a silica gel column eluted with MeOH / DCM (v / v = 1 / 20). The result was (Z)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (racemic) in 8.513 g (59.43% yield) as an off-white solid. LCMS: m / z = 473 [M+1] + .

[0350] Step 3. 4-((3-(7-(((Z)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzenesulfonamide (racemic) (40). A 25 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with (Z)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (racemic) (0.119 g, 251.97 μmol), 3-methoxy-4-(prop-2-yn-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). The mixture was stirred at 60° C. for 2 h under a nitrogen atmosphere. The reaction was quenched with water (20 mL) and extracted with EA (30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 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 give the desired product. This resulted in 0.072 g (48.88% yield) of 4-((3-(7-(((Z)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzenesulfonamide (racemic) (40) as a yellow solid. LCMS: m / z =585 [M+1] + . 1 H NMR (400 MHz, methanol-d 4) 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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (racemic) (41) Reaction Scheme: [ka]

[0352] Experiment details Step 1. 4-((3-(7-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (racemic) (41) Into an 8 mL vial purged and maintained under an inert atmosphere of nitrogen was added (3R,4S)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (racemic) (0.137 g, 290.08 μmol), cuprous iodide (0.015 g, 78.76 μmol), 3-methoxy-N-methyl-4-(prop-2-yn-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). The reaction mixture was stirred at room temperature for 3 h. The reaction was quenched by the addition of water (10 mL) and extracted with EA (3 x 10 mL). The organic layers were combined, washed with brine (10 mL) and extracted with anhydrous Na 2 SO 4 The mixture was dried over 100 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: 35-65-90% B (2-30-60 min); 269 nm; room temperature: 32.043-33.407 min). This gave 0.075 g (45.95% yield) of 4-((3-(7-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (racemic) (41) 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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-N,1-dimethylpiperidin-4-amine (racemic) (42) Reaction Scheme: [ka]

[0354] Test Details: Step 1. (Z)-3-Fluoro-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-N,1-dimethylpiperidin-4-amine (racemic) (42). To a 40 mL vial was added 2-methoxy-4-(methylsulfonyl)-N-(prop-2-yn-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-dimethylpiperidin-4-amine (racemic) (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 methylsulfoxide (20 mL). The reaction was stirred at 60 °C under nitrogen for 3 h. 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 over anhydrous sodium sulfate, filtered and concentrated in vacuo. 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 give the desired product. This resulted in the production of (Z)-3-fluoro-N-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-N,1-dimethylpiperidin-4-amine (racemic) (42) in 0.015 g (4.35% yield) as an off-white solid. LCMS: m / z =598 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6) 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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (43) Reaction Scheme: [ka]

[0356] Test Details: Step 1 4-Bromo-2-methoxyaniline A 500 mL three-neck flask was charged with 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). The reaction mixture was filtered through a pad of Celite, and the filter cake was washed with methanol (2 x 200 mL). The filtrate was concentrated under reduced pressure to give the product. The crude product was purified on a silica gel column eluted 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-neck flask and stirred at 130° C. for 0.5 hours under a nitrogen atmosphere. The reaction mixture was diluted with ACN / H 2 The mixture was purified on a C18 column eluted with O (v / v = 1 / 9), filtered, and concentrated under vacuum to give 4.798 g, (24.08 mmol, 96.27% yield) of (4-amino-3-methoxyphenyl)dimethylphosphine oxide as a brown oil. LCMS: m / z = 200 [M+1] + .

[0358] Step 3 (3-Methoxy-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide In a 250 mL three-neck flask, add (4-amino-3-methoxyphenyl)dimethylphosphine oxide (2.059 g, 10.33 mmol), 3-bromoprop-1-yne (1.693 g, 14.23 mmol), K2 CO 3 (3.305 g, 23.91 mmol), KI (1.877 g, 11.30 mmol) and NMP (25 mL) were added. The reaction mixture was stirred under nitrogen at 80° C. for 4 h. The reaction mixture was diluted with ACN / H 2 The mixture was purified on a C18 column eluted with O (v / v = 2 / 8), filtered, and concentrated under vacuum to give 1.351 g (5.69 mmol, 55.09% yield) of (3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide as a brown oil. LCMS: m / z = 238 [M+1] + .

[0359] Step 4 (4-((3-(7-((3,3-difluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (43) In a 10 mL round-bottom flask, (3-methoxy-4-(prop-2-yn-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-methylpiperidin-4-amine (0.089 g, 181.53 μmol), Pd(PPh 3 ) 2 Cl 2(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 at room temperature under nitrogen for 16 h. 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 over anhydrous sodium sulfate, filtered, and concentrated in vacuo. 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 give the desired product. This resulted in 0.010 g (16.67 μmol, 9.18% yield) of (4-((3-((3,3-difluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (43) as a white solid. LCMS: m / z =600 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6 ) 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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)but-3-yn-2-yl)amino)benzenesulfonamide and (S)-4-((4-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)but-3-yn-2-yl)amino)benzenesulfonamide (44 and 45) Reaction Scheme: [ka]

[0361] Test Details: Step 1. But-3-yn-2-yl methanesulfonate A 100 mL flask was charged with but-3-yn-2-ol (2.30 g, 32.82 mmol), DCM (20 mL), TEA (2 mL), and MsCl (3 mL). The reaction was stirred at 20° C. for 4 h. The reaction was then cooled to 5° C. for 1 h. 2 The mixture was quenched with 0 (20 mL) and extracted with DCM (3 x 20 mL). The organic layers were combined and concentrated in vacuo to give 1.99 g (crude) of bu-3-yn-2-yl methanesulfonate as a red oil. LCMS: m / z = 149 [M+1] + .

[0362] Step 2. 4-(But-3-yn-2-ylamino)benzenesulfonamide . In a 100 mL flask, add but-3-yn-2-yl methanesulfonate (1.83 g, 12.35 mmol), 4-aminobenzenesulfonamide (1.53 g, 9.06 mmol), and Cs 2 CO 3 (2.87 g, 8.81 mmol) and DMF (3 mL) were added. The reaction mixture was diluted with ACN / H 2The mixture was purified on a C18 chromatography column eluted with 0 (0.15% TFA) (v / v = 1 / 3). As a result, 0.38 g (13% yield) of 4-(but-3-yn-2-ylamino)benzenesulfonamide was obtained as a yellow solid. LCMS: m / z = 225 [M+1] + .

[0363] Step 3. 4-((4-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)but-3-yn-2-yl)amino)benzenesulfonamide. In a 100 mL flask, add 4-(but-3-yn-2-ylamino)benzenesulfonamide (0.058 g, 258.61 μmol), N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.082 g, 180.50 μmol), CuI (0.047 g, 246.78 μmol), Pd(PPh 3 ) 2 Cl 2 (0.081 g, 99.68 μmol), DIEA (0.050 g, 386.87 μmol) and methyl sulfoxide (2 mL) were added. The mixture was stirred at 25° C. for 4 h. 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 min); 220 nm; Room temperature: 33.580-36.110 min). This resulted in 53 mg (34% yield) of 4-((4-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)but-3-yn-2-yl)amino)benzenesulfonamide (racemic) as a white solid. LCMS: m / z =551 [M+1] + .

[0364] Step 4. (R)-4-((4-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)but-3-yn-2-yl)amino)benzenesulfonamide and (S)-4-((4-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)but-3-yn-2-yl)amino)benzenesulfonamide (44 and 45). 4-((4-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)but-3-yn-2-yl)amino)benzenesulfonamide (racemic mixture) was separated by chiral separation to obtain (R)-4-((4-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)but-3-yn-2-yl)amino)benzenesulfonamide (8 mg, 18% yield) 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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)but-3-yn-2-yl)amino)benzenesulfonamide was chiral separated to obtain 10 mg (yield 22%) of (S)-4-((4-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)but-3-yn-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 = 7.7 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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzamide (racemic) (46) Reaction Scheme: [ka]

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

[0368] Step 2. Methyl 3-methoxy-4-(prop-2-yn-1-ylamino)benzoate. In a 100 mL flask, add methyl 4-amino-3-methoxybenzoate (4.15 g, 22.90 mmol), Cs 2 CO 3 (3.73 g, 11.45 mmol), 3-bromoprop-1-yne (8.89 g, 74.73 mmol), KI (2.77 g, 16.69 mmol), and DMF (20 mL) were added to the reaction mixture. 2 The mixture was purified on a C18 column eluted with O (v / v = 1 / 1). As a result, 1.40 g (27% yield) of methyl 3-methoxy-4-(prop-2-yn-1-ylamino)benzoate was obtained as a pale yellow solid. LCMS: m / z = 220 [M+1] + .

[0369] Step 3. 3-Methoxy-4-(prop-2-yn-1-ylamino)benzoic acid. In a 25 mL round-bottom flask, add methyl 3-methoxy-4-(prop-2-yn-1-ylamino)benzoate (0.82 g, 3.73 mmol), MeOH (4 mL), THF (4 mL), and H 2 The reaction mixture was stirred at 50° C. for 3 h, and the reaction mixture was diluted with water (50 mL).2 CO 3 (aq, 100 mL) was added until the pH was >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 (97% yield) of 3-methoxy-4-(prop-2-yn-1-ylamino)benzoic acid was obtained as a yellow solid. LCMS: m / z = 206[M+1] + .

[0370] Step 4. 3-Methoxy-4-(prop-2-yn-1-ylamino)benzamide. In a 50 mL round-bottom flask, add 3-methoxy-4-(prop-2-yn-1-ylamino)benzoic acid (0.137 g, 667.61 μmol), NH 4 Cl (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 h. The reaction mixture was diluted with ACN / H 2 The mixture was purified on a C18 column eluted with O (v / v = 1 / 1). As a result, 83 mg (60% yield) of 3-methoxy-4-(prop-2-yn-1-ylamino)benzamide was obtained as a pale yellow solid. LCMS: m / z = 205 [M+1] + .

[0371] Step 5. 4-((3-(7-(((Z)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzamide (racemic) (46). In a 50 mL round-bottom flask, 3-methoxy-4-(prop-2-yn-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-methylpiperidin-4-amine (racemic) (0.106 g, 224.44 μmol), CuI (0.014 g, 73.51 μmol), Pd(PPh3 ) 2 Cl 2 (0.037 g, 52.41 μmol), DIEA (0.058 g, 448.77 μmol) and methyl sulfoxide (2 mL) were added. The mixture was stirred at 25° C. for 4 h. 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). This resulted in 43 mg (34% yield) of 4-(3-(7-(((Z)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzamide (racemic) (46) as a white solid. LCMS: m / z =549 [M+1] + . 1 H 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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (racemic) (47) Reaction Scheme: [ka]

[0373] Experiment details Step 1. 3-Methoxy-N-(1-methylpiperidin-4-yl)-4-(prop-2-yn-1-ylamino)benzamide. To a 4 mL jar was added 3-methoxy-4-(prop-2-yn-1-ylamino)benzoic acid (0.049 g, 238.78 μmol), 1-methylpiperidin-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). The reaction was stirred at 40° C. for 3 h. LCMS showed the reaction was complete and the reaction was purified on a C18 column and eluted with ACN / water (v / v = 1 / 3) to give 3-methoxy-N-(1-methylpiperidin-4-yl)-4-(prop-2-yn-1-ylamino)benzamide (0.050 g, 165.90 μmol, 69.48% yield) as a clear oil. LCMS: m / z = 302[M+1] + .

[0374] Step 2. 4-((3-(7-((3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (racemic) (47). Into a 4 mL flask purged with nitrogen and maintained was added 3-methoxy-N-(1-methylpiperidin-4-yl)-4-(prop-2-yn-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-methylpiperidin-4-amine (racemic) (0.049 g, 103.75 μmol), Pd(PPh 3 ) 2 Cl 2 (0.009 g, 12.75 μmol), CuI (0.003 g, 15.75 μmol), TEA (0.035 g, 345.89 μmol), DMF (0.5 mL) were added and stirred at room temperature overnight. LCMS showed 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 washed successively with water (2 mL) and brine (2 mL), separated and concentrated in vacuo. 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 min); 248 nm; room temperature: 33.450-36.020 min) to give 4-((3-(7-(3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (racemic) (47) (42 mg, 65.04 μmol, 40.00% yield) as an off-white solid. LCMS: m / z = 646[M+1] + 1 H NMR (400 MHz, DMSO-d 6) 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-Dioxidothiomorpholino)(4-((3-(7-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)methanone (racemic) (48) Reaction Scheme: [ka]

[0376] Experiment details Step 1. (1,1-dioxidethiomorpholino)(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)methanone To an 8 mL flask maintained under an inert purged atmosphere of nitrogen was added 3-methoxy-4-(prop-2-yn-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). The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched by the addition of water (2 mL) and extracted with EA (2 x 2 mL). The organic layers were combined, washed with 15% aqueous potassium carbonate (2 x 2 mL) and brine (5 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by elution with ACN / H 2 The product was purified on a C18 chromatography column eluted with 2,4-dichloro-3,5-dihydro-1,2,3,4-tetramethyl-2,4-tetramethyl ... Phenyl)methanone (crude) was obtained as a white solid. LCMS: m / z = 323 [M+1] + .

[0377] Step 2. (1,1-Dioxidothiomorpholino)(4-((3-(7-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)methanone (racemic) (48) Into a 100 mL flask purged and maintained with an inert atmosphere of nitrogen was added (3R,4S)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (racemic) (0.103 g, 218.09 μmol), cuprous iodide (0.008 g, 42.01 μmol), (1,1-dioxidothiomorpholino)(3-methoxy-4-(prop-2-yn-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). The reaction mixture was stirred at room temperature for 5 h. The reaction was quenched by the addition of water (2 mL) and extracted with EA (2 x 2 mL). The organic layers were combined, washed with brine (5 mL) and extracted with anhydrous Na 2 SO 4 The mixture was dried over 100 ml and concentrated in vacuo. 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). This gave 0.026 g (17.88% yield) of (1,1-dioxidothiomorpholino)(4-((3-(7-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)methanone (racemic) (48) 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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (racemic) (49) Reaction Scheme: [ka]

[0379] Test Details: Step 1. (3-Methoxy-4-(prop-2-yn-1-ylamino)phenyl)(4-methylpiperazin-1-yl)methanone. In a 4 mL sealed tube was added 3-methoxy-4-(prop-2-yn-1-ylamino)benzoic acid (0.101g, 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). The reaction was stirred at room temperature overnight. The reaction was quenched with water (50 mL) and extracted with EA (20 mL x 2). The combined organic layers were washed successively with water (20 mL) and brine (30 mL x 2), separated, and concentrated in vacuo. The crude was purified on a silica gel column eluted with MeOH / DCM (v / v = 1 / 9). As a result, 0.19 g (crude) of (3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)(4-methylpiperazin-1-yl)methanone was obtained as a brown-yellow oil. LCMS: m / z = 288 [M+1] + .

[0380] Step 2. (4-((3-(7-(((Z)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (racemic) (49). In a 25 mL round bottom flask, (3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)(4-methylpiperazin-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-methylpiperidin-4-amine (racemic) (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. The mixture was stirred at 60° C. for 2 hours under nitrogen atmosphere. The reaction was quenched with water (20 mL) and extracted with EA (20 mL x 2). The combined organic layers were washed successively with water (30 mL) and brine (30 mL), separated and concentrated in vacuo. 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 give the desired product. This resulted in 0.061 g (45.60% yield) of (4-((3-(((Z)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (racemic) (49) 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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)(morpholino)methanone (racemic) (50) Reaction Scheme: [ka]

[0382] Test Details: Step 1. (3-Methoxy-4-(prop-2-yn-1-ylamino)phenyl)(morpholino)methanone. A 50 mL round bottom flask was charged with 3-methoxy-4-(prop-2-yn-1-ylamino)benzoic acid (0.065 g, 316.74 μmol), morpholine (0.125 g, 1.43 mmol), HATU (0.280 g, 0.74 mmol), DIEA (0.296 g, 2.29 mmol), and DMF (5 mL). The mixture was stirred at 20 °C for 3 h. The reaction mixture was purified on a C18 column eluted with ACN / H2O (v / v = 1 / 1). As a result, 94 mg (98% yield) of (3-methoxy-4-(prop-2-yn-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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)(morpholino)methanone (racemic) (50) In a 50 mL round-bottom flask, add (3-methoxy-4-(prop-2-yn-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-methylpiperidin-4-amine (0.106 g, 224.44 μmol), CuI (0.014 g, 73.51 μmol), Pd(PPh 3 ) 2 Cl 2(0.037 g, 52.41 μmol), DIEA (0.058 g, 448.77 μmol) and methyl sulfoxide (2 mL) were added. The mixture was stirred at 25° C. for 4 h. 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 min); 269 nm; room temperature: 37.007-38.908 min). This resulted in 41 mg (29% yield) of (4-((3-(7-(((Z)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)(morpholino)methanone (racemic) (50) as a white solid. LCMS: m / z = 619 [M+1] + . 1 H 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)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (51) Reaction Scheme: [ka]

[0385] Test Details: Step 1. N-(4-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine In a 20 mL sealed tube purged and maintained under an inert atmosphere of nitrogen, N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-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 on a silica gel column and eluted with EA / Hexane (v / v = 1 / 4) to give 0.304 g (71.67%) of N-(4-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-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-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (51) In a 20 mL sealed tube, purged and maintained with an inert atmosphere of nitrogen, was added N-(4-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0. 268 g, 0.57 mmol), 2-methoxy-4-(methylsulfonyl)-N-(prop-2-yn-1-yl)aniline (0.271 g, 1.13 mmol), Pd(dppf)Cl 2 (0.098 g, 0.14 mmol), CuI (0.164 g, 0.86 mmol), DIEA (0.314 g, 2.43 mmol), DMSO (5 mL). The reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was quenched by addition of water (20 mL) and extracted with EA (20 mL x 2). The combined organic layers were washed with brine (10 mL), separated and concentrated in vacuo. 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 give N-(4-fluoro-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (51) (0.092 g, 27.78% yield) 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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-5-methoxyphenyl)dimethylphosphine oxide (racemic) (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 nitrogen atmosphere. The resulting reaction was purified on a C18 chromatography column eluted with ACN / water (v / v = 1 / 6). The result was 0.955 g (89.26% yield) of (4-amino-2-fluoro-5-methoxyphenyl)dimethylphosphine oxide. LCMS: m / z = 218 [M+1] + .

[0389] Step 2. Synthesis of (2-fluoro-5-methoxy-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide In a 40 mL vial, (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-bromoprop-1-yne (0.746 g, 6.27 mmol) were added. The mixture was then stirred at 90 °C overnight. The resulting reaction was purified on a C18 chromatography column eluted with ACN / water (v / v = 1 / 3). As a result, 0.255 g (33.18% yield) of (2-fluoro-5-methoxy-4-(prop-2-yn-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-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-5-methoxyphenyl)dimethylphosphine oxide (racemic) (52) In a 40 mL vial, (2-fluoro-5-methoxy-4-(prop-2-yn-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-methylpiperidin-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 h. The resulting reaction was dissolved in water (30 The organic phase was diluted with EA (10 mL x 3). 2 SO 4 The mixture was dried over 100 ml and concentrated under vacuum. The resulting reaction was purified on a C18 chromatography column eluted with ACN / water (0.1% ammonium bicarbonate) (v / v = 1 / 1) to give the crude product. The crude product was then concentrated and purified on a C18 chromatography column eluted with ACN / water (0.1% formic acid) (v / v = 1 / 1) to give the product. This resulted in (2-fluoro-4-((3-(7-(((Z)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-5-methoxyphenyl)dimethylphosphine oxide (racemic) (52) (HCOOH salt) 0.100 g (16.96% yield) as a white solid. LCMS: m / z = 600 [M+1] + . 1 H NMR (400 MHz, DMSO-d6 ) δ 8.15 (s, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.02 (dd, J = 12.3, 5.8 Hz, 1H), 6.78 (d, J = 7.7 Hz, 1H), 6.65 (dd, J = 11.9, 5.0 Hz, 1H), 6.45 (t, J = 6.4 Hz, 1H), 5.18 (d, J = 8.5 Hz, 1H), 4.74 (s, 1H), 4.35 (d, J = 6.2 Hz, 2H), 3.82 (s, 3H), 3.79 (d, J = 11.0 Hz, 1H), 3.69 (s, 1H), 3.62 (s, 1H), 3.04 (t, J = 11.1 Hz, 1H), 2.80 (d, J = 11.0 Hz, 1H), 2.33 - 2.67 (m, 1H), 2.19 (s, 3H), 2.12 - 2.06 (m, 1H), 1.99 - 1.90 (m, 1H), 1.76 - 1.68 (m, 1H), 1.62 (d, J = 13.5 Hz, 6H).

[0391] Intermediates In-1a and In-1b [ka]

[0392] Test Details: tert-Butyl (3R,4S)-3-fluoro-4-((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (In-1a) and tert-butyl (3S,4R)-3-fluoro-4-((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (In-1b) The racemic product In-1 (7.987 g, 14.30 mmol) was separated by Prep-HPLC-Gilson under the following conditions: column, CHIRALART Cellulose-IG column (2 cm x 25 cm, 5 μm); mobile phase, Hexane : EtOH (V / V = 75:25); flow rate: 18 ml / min. This resulted in (2.48 g, 4.44 mmol) tert-butyl (3R,4S)-3-fluoro-4-((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (In-1a) (first eluting isomer, retention time 5.804 min). LCMS: m / z = 559 [M+1] + 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.27 - 7.18 (m, 2H), 6.76 - 6.71 (m, 1H), 5.33 (d, J = 8.6 Hz, 1H), 4.83 (d, J = 48.8 Hz, 1H), 4.24 (s, 1H), 4.13 - 3.98 (m, 1H), 3.92 - 3.78 (m, 3H), 3.25 - 2.75 (...

Claims

1. A compound of formula (I), or a stereoisomer, tautomer, deuterated derivative, prodrug or pharmaceutically acceptable salt thereof, wherein: 【Chemical 1】 Y is selected from O, S, NR', S=O, -S(=O)(=NR')- or O=S=O; X 1 , X 2 , X 3 and X 4 One of them is selected from CR 2 and the other X 1 , X 2 , X 3 and X 4 are each independently selected from N or CR 4 ; X 5 is selected from N or CR 1 ; and R 1 is selected independently from hydrogen, deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 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) 2 R', -S(O) 2 N(R') 2 , -NR'S(O) 2 R', -NR'S(O) 2 N(R') 2 , -PO(R') 2 , and is independently selected from 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 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) 2 R', -S(O) 2 N(R') 2 、 -NR'S(O) 2 R', -NR'S(O) 2 N(R') 2 、 -PO(R') 2 、 optionally and independently substituted with one or more (e.g., 1, 2, 3, 4, 5 or 6) substituents selected from 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; R 2 is -NR 51 R 52 -OR 53 or -SR 54 and; R 3 is hydrogen, deuterium, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -C(O)R', -C(O)N(R') 2 , -C(O)OR', -S(O)R', -S(O)N(R') 2 , -S(O) 2 R', -S(O) 2 N(R') 2 , -PO(R') 2 , selected from 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; 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 of R 3a ; Each R 3a is 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) 2 R', -S(O) 2 N(R') 2 , -S(=O)(=NR')R', -NR'S(O) 2 R', -NR'S(O) 2 N(R') 2 , -PO(R') 2 , selected from 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; 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 of R 3b , and Each R 3b is independently 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) 2 R', -S(O) 2 N(R') 2 , -S(=O)(=NR')R', -NR’S(O) 2 R', -NR’S(O) 2 N(R') 2 , -PO(R') 2 and is independently selected from; R 4 is, when each is present, hydrogen, deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 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) 2 R', -S(O) 2 N(R') 2 , -NR'S(O) 2 R', -NR'S(O) 2 N(R') 2 , -PO(R') 2 , and is independently selected from 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 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) 2 R', -S(O) 2 N(R') 2 , -S(=O)(=NR')R', -NR'S(O) 2 R', -NR'S(O) 2 N(R') 2 , -PO(R') 2 , optionally and each independently substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents selected from 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; R 51 、R 52 、R 53 and R 54 are each independently selected from hydrogen, deuterium, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -C(O)R', -C(O)N(R') 2 、-C(O)OR', -S(O)R', -S(O)N(R') 2 、-S(O) 2 R', -S(O) 2 N(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, 5- to 12-membered heteroaryl; wherein 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 deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -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) 2 R', -S(O) 2 N(R') 2 、 -S(=O)(=NR')R', -NR'S(O) 2 R', -NR'S(O) 2 N(R') 2 、 -PO(R') 2 、 optionally and independently substituted with one or more (e.g., 1, 2, 3, 4, 5 or 6) substituents selected from 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; R 11 and R 12 are each independently selected from hydrogen, deuterium, -OH, halogen, -CN, oxo, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 or 3-6 membered cycloalkyl; said -C 1-6 alkyl, -C 1-6 alkoxy and 3-6 membered 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 membered cycloalkyl; R 13 is selected from hydrogen, deuterium, -C 1-6 alkyl or 3- to 6-membered cycloalkyl; said -C 1-6 alkyl and 3- to 6-membered 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 2 , -NHC 1-6 alkyl, or -N(C 1-4 alkyl) 2 ; and 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 Each R', when present, is independently selected from hydrogen, deuterium, halogen, -OH, -CN, oxo, -NH 2 , -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 2-6 alkenyl, -C 2-6 alkynyl, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl; said -C 1-6 alkyl, -OC 1-6 alkyl, -C 3-14 cycloalkyl, -C 3-14 heterocycloalkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl is deuterium, halogen, -CN, -C 1-3 alkyl, oxo, -OH, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , -C(=O)NH 2 , -C(=O)NH(C 1-3 alkyl), -C(=O)N(C 1-3 alkyl) 2 , -S(=O) 2 NH 2 , -S(=O) 2 NH(C 1-3 alkyl), -S(=O) 2 C 1-3 alkyl, -S(=O) 2 N(C 1-3 alkyl) 2 , -S(=O)(=NH)C 1-3 alkyl, -S(=O)(=NC 1-3 alkyl)C 1-3 alkyl, or is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from 3- to 6-membered cycloalkyl; Said heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain 1, 2 or 3 heteroatoms selected from N, O, P or S; m is selected from 1, 2, 3, 4, 5 or 6, a compound, or a stereoisomer, tautomer, deuterated derivative, prodrug or pharmaceutically acceptable salt thereof.

2. Formula (I) is 【Chemical 2】 where X in formula (I-1) 2 , X 3 , and X 4 are each independently selected from N or CR 4 ; Y is selected from O, S, S=O, or O=S=O; or Formula (I) is 【Chemical Formula 3】 where; or Formula (I) is 【Chemical 4】 where; or Formula (I) is 【Chemical Formula 5】 where; or Formula (I) is ​ where; or Formula (I) is [Chemical Formula 7] where; or Formula (I) is 【Chemical Formula 8】 where; or Formula (I) is 【Chemical Formula 9】 where; or Formula (I) is 【Chemical 10】 selected from the compound according to claim 1.

3. R 1 is independently selected from halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -CN, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 6- to 10-membered aryl, or 5- to 12-membered heteroaryl, wherein the -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 10-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 halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -CN, oxo, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 6- to 10-membered aryl, or 5- to 12-membered heteroaryl, and the heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain 1 or 2 heteroatoms selected from N or S; Preferably, R 1 is independently selected from -F, -Cl, -C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 1-3 haloalkyl, -CN, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, wherein said -C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 1-3 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, and 5-12 membered heteroaryl are each independently optionally substituted with one or more (e.g., 1, 2, 3, 4, 5 or 6) substituents selected from -F, -Cl, -C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 1-3 haloalkyl, -CN, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, or 5-12 membered heteroaryl, and said heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain 1 or 2 heteroatoms selected from N or S; Preferably, R 1 is independently selected from -F, -Cl, -C 1-3 alkyl, -C 1-3 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said -C 1-3 alkyl, -C 1-3 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl is independently optionally substituted with one or more (e.g., 1, 2, 3, 4, 5 or 6) substituents selected from -F, -Cl, -C 1-3 alkyl, -C 1-3 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, and said heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain 1 or 2 heteroatoms selected from N or S; Preferably, R 1 is independently selected from -F, -Cl, -C 1-3 alkyl, -C 1-3 haloalkyl, 3-6 membered cycloalkyl, 5 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S, or 6 membered heteroaryl containing 1 or 2 heteroatoms selected from N; said -C 1-3 alkyl, -C 1-3 haloalkyl, 3-6 membered cycloalkyl, 5 membered heteroaryl and 6 membered heteroaryl are each independently optionally substituted with 1, 2 or 3 substituents selected from -F, -C 1-3 alkyl, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , -CN or 3-6 membered cycloalkyl; Preferably, R 1 is, -C 1-3 alkyl; -C 1-3 haloalkyl; 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S; or -F, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , -CN or -C 1-3 alkyl substituted with 1, 2 or 3 substituents independently selected from 3-6 membered cycloalkyl; Preferably, R 1 is 【Chemical 11】 independently selected from the compound according to claim 1.

4. R 2 is -NR 51 R 52 ; preferably, R 2 is -NHR 51 The compound according to claim 1.

5. R 51 is -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 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; said -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl is independently optionally substituted with one or more (e.g., 1, 2, 3, 4, 5 or 6) substituents selected from halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -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 , 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, and said heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain one heteroatom selected from N, O, or S; Preferably, R 51 is selected from -C 1-3 alkyl, cyclopentyl, cyclohexyl, a 5-membered heterocyclyl containing one heteroatom selected from N, O, S, S(=O), S(=O)(=NH) or S(=O) 2 or a 6-membered heterocyclyl containing one heteroatom selected from N, O, S, S(=O), S(=O)(=NH) or S(=O) 2 ; wherein said -C 1-3 alkyl, cyclopentyl, cyclohexyl, 5-membered heterocyclyl and 6-membered heterocyclyl are each independently optionally substituted with one, two or three substituents selected from -F, -C 1-3 alkyl, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 alkyl, oxo, =NH, -N(C 1-3 alkyl) 2 , -CN or 3-6 membered cycloalkyl; Preferably, R 51 is selected from -C 1-6 alkyl, 5-membered cycloalkyl, 5-membered heterocycloalkyl, 6-membered cycloalkyl, or 6-membered heterocycloalkyl; -C 1-6 alkyl, cycloalkyl, and heterocycloalkyl are -F, -Cl, -CH 3 , -CD 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH(OH)CH 2 (OH), -CH(OCH 3 )CH 2 (OH), -CH(OH)CH 2 (OCH 3 ), -CH 2 CH(OH)(OCH 3 ), -CH 2 CH(OH)(OCH 2 CH 3 ), -CH 2 CH(OCH 3 ) 2 , -OH, -O-CH 3 , -O-CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , -O-CH(CH 3 ) 2 , -C(O)-(CH 2 )-NH 2 , -C(O)-(CH 2 )-NH(CH 3 ), -C(O)-(CH 2 )-NH(CH 2 CH 3 ), -C(O)-(CH 2 )-N(CH 3 ) 2 , -C(O)-(CH 2 CH 2 )-NH 2 , -C(O)-(CH 2 CH 2 )-NH(CH 3 )、 -C(O)-(CH 2 CH 2 )-NH(CH 2 CH 3 )、 -C(O)-(CH 2 CH 2 )-N(CH 3 ) 2 、 -NH 2 、 -NH(CH 3 )、 -NH(CH 2 CH 3 )、 -N(CH 3 ) 2 、 -NH(CH 2 CH 2 CH 3 )、 -NH(CH(CH 3 ) 2 )、 or -N(CH 3 )(CH 2 CH 3 ) and is independently optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents selected from; wherein said heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain one heteroatom selected from N, O, or S; Preferably, R 51 is 【Chemical Formula 12】 or -C 1-6 is selected from alkyl, and said -C 1-6 alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 Rs 5e ; and R 5a 、R 5c and R 5d are each independently selected from hydrogen; -C 1-6 alkyl; or -F, -C 1-3 alkyl, oxo, -OC 1-3 alkyl, -NH 2 -, -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 -, -CN or -C 1-6 alkyl substituted with 1, 2, 3, 4, 5 or 6 substituents each independently selected from 3-6 membered cycloalkyl; R 5b and R 5e are each independently selected from -F, -C 1-6 alkyl, oxo, -OC 1-6 alkyl, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -CN or 3-6 membered cycloalkyl, and said -C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from -F, -C 1-3 alkyl, oxo, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , -CN or 3-6 membered cycloalkyl; Preferably, R 51 is 【Chemical Formula 13】 or -C 1-3 alkyl-N(C 1-3 alkyl) 2 selected from; R 5a is -C 1-3 alkyl; or -F, -C 1-3 alkyl, oxo, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , -CN or -C 1-3 alkyl substituted with 1, 2, 3, 4, 5 or 6 substituents independently selected from alkyl; R 5b is selected independently from -F, -C 1-3 alkyl, oxo, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 or -CN; R 5c and R 5d are each independently selected from -C 1-3 alkyl; Preferably, R 51 is 【Chemical Formula 14】 or -CH 2 CH 2 -N(CH 3 ) 2 is selected from; R 5a is methyl, -CH 2 CH(OH)OCH 3 or -C(=O)CH 2 N(CH 3 ) 2 and is independently selected from; R 5b is selected independently of -F; R 5c and R 5d are each independently selected from methyl; Preferably, R 51 is 【Chemical Formula 15】 selected from the compound according to claim 1.

6. R 3 is hydrogen, deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -CN, -NO 2 , -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) 2 R', -NR'S(O) 2 , -S(O) 2 N(R') 2 , 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 6- to 10-membered aryl, or 5- to 12-membered heteroaryl, independently selected; provided that when each of 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 10-membered aryl, or 5- to 12-membered heteroaryl is present, it is halogen, NH 2 , NH-C 1-6 alkyl, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -CN, -NO 2 , -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) 2 R', -NR'S(O) 2 , -S(O) 2 N(R') 2 , -S(=O)(=NR')R', 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 6- to 10-membered aryl, or 5- to 12-membered heteroaryl, each independently optionally substituted with one or more substituents selected therefrom, wherein said heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain one heteroatom selected from N, O, or S; Preferably, R 3 is independently selected from phenyl or 5- to 6-membered heteroaryl containing one or two heteroatoms selected from N, O or S; said phenyl and 5- to 6-membered heteroaryl are each independently optionally substituted with one, two or three substituents selected from R 3c ; R 3c is -F; -C 1-3 alkyl; -OC 1-3 alkyl; -OC 3-6 cycloalkyl; -NH 2 ; -NHC 1-3 alkyl; -N(C 1-3 alkyl) 2 ; -C(=O)NH 2 、-C(=O)NH(C 1-3 alkyl); -C(=O)N(C 1-3 alkyl) 2 ; -CN; -S(=O) 2 NH 2 ; -S(=O) 2 NH(C 1-3 alkyl); -S(=O) 2 NHC(=O)C 1-3 alkyl; -S(=O) 2 N(C 1-3 alkyl) 2 ; -S(=O) 2 C 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; said C 1-3 alkyl, C 3-6 cycloalkyl, C 2-6 heterocycloalkyl or OC 1-3 alkyl, when each is present, is deuterium, -F, -C 1-3 alkyl, oxo, -OH, -OC 1-3 alkyl, -NH 2 、-NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 、-C(=O)NH 2 、-C(=O)NH(C 1-3 (alkyl), -C(=O)N(C 1-3 (alkyl) 2 , -CN, -S(=O) 2 NH 2 , -S(=O) 2 NH(C 1-3 (alkyl), -S(=O) 2 C 1-3 (alkyl), -S(=O) 2 N(C 1-3 (alkyl) 2 , -S(=O)(=NH)C 1-3 (alkyl), -S(=O)(=NC 1-3 (alkyl)C 1-3 is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from (alkyl), or 3-6 membered cycloalkyl; Preferably, R 3 is independently selected from phenyl, 5-membered heteroaryl, or 6-membered heteroaryl; when said phenyl and heteroaryl each exist, -F, -Cl, -CH 3 , -CD 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CHFCH 3 , -CF 2 CH 3 , -CHFCH 2 F, -CH 2 CHFCH 3 , -CH 2 CF 2 CH 3 , -CH 2 CH 2 CF 3 , -C(CH 3 ) 2 F, -CN, -OH, -O-CH 3 , -O-CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , -O-CH(CH 3 ) 2 , -SH, -S-CH 3 , -S-CH 2 CH 3 , -S-CH 2 CH 2 CH 3 , -S-CH(CH 3 ) 2 , -CHO, -C(O)-CH 3 , -C(O)-CH 2 CH 3 , -C(O)-CH 2 CH 2 CH 3 、 -C(O)-CH(CH 3 ) 2 、 -C(O)NH 2 、 -C(O)NH(CH 3 )、 -C(O)NH(CH 2 CH 3 )、 -C(O)N(CH 3 ) 2 、 -C(O)NH(CH 2 CH 2 CH 3 )、 -C(O)NH(CH(CH 3 ) 2 )、 -C(O)N(CH 3 )(CH 2 CH 3 )、 -NH 2 、 -NH(CH 3 )、 -NH(CH 2 CH 3 )、 -N(CH 3 ) 2 、 -NH(CH 2 CH 2 CH 3 )、 -NH(CH(CH 3 ) 2 )、 -N(CH 3 )(CH 2 CH 3 )、 -NHC(O)(CH 3 )、 -NHC(O)(CH 2 CH 3 )、 -NHC(O)(CH 3 ) 2 、 -NHC(O)(CH 2 CH 2 CH 3 )、 -NHC(O)(CH(CH 3 ) 2 )、 -NHC(O)(CH 3 )(CH 2 CH 3 )、 -S(O) 2 H、 -S(O) 2 (CH 3 )、 -S(O) 2 (CH 2 CH 3 )、 -S(O) 2 (CH 3 ) 2 、 -S(O) 2 (CH 2 CH 2 CH 3 )、 -S(O) 2 (CH(CH 3 ) 2 )、 -S(O) 2 (CH 3 )(CH 2 CH 3 )、 -S(O) 2 NH 2 、 -S(O) 2 NH(CH 3 )、 -S(O) 2 NH(CH 2 CH 3 )、 -S(O) 2 N(CH 3 ) 2 、 -S(O) 2 NH(CH 2 CH 2 CH 3 )、 -S(O) 2 NH(CH(CH 3 ) 2 )、 -S(O) 2 N(CH 3 )(CH 2 CH 3 )、 -S(=O)(=NH)CH 3 、 or -S(=O)(=NCH 3 )CH 3 is independently optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents selected from; and said heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain one heteroatom selected from N, O, or S; Preferably, R 3 is independently selected from phenyl, 5-membered heteroaryl, or 6-membered heteroaryl; when each of said phenyl and heteroaryl is present, -F, -CH 3 , -CD 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 F, -CF 3 , -CH 2 CH 2 F, -CHFCH 3 , -CF 2 CH 3 , -C(CH 3 ) 2 F, -OH, -O-CH 3 , -O-CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , -O-CH(CH 3 ) 2 , -C(O)NH 2 , -C(O)NH(CH 3 ), -C(O)NH(CH 2 CH 3 ), -C(O)N(CH 3 ) 2 , -C(O)NH(CH 2 CH 2 CH 3 ), -C(O)NH(CH(CH 3 )) 2 , -C(O)N(CH 3 )(CH 2 CH 3 ), -NH 2 , -NH(CH 3 ), -NH(CH 2 CH 3 ), -N(CH 3 ) 2 , -NH(CH 2 CH 2 CH 3 ), -NH(CH(CH 3 )) 2 ), -N(CH 3 )(CH 2 CH 3 ), -S(O) 2 H, -S(O) 2 (CH 3 ), -S(O) 2 (CH 2 CH 3 ), -S(O) 2 (CH 3 ) 2 , -S(O) 2 (CH 2 CH 2 CH 3 ), -S(O) 2 (CH(CH 3 )) 2 ), -S(O) 2 (CH 3 )(CH 2 CH 3 ), -S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ), -S(O) 2 NH(CH 2 CH 3 ), -S(O) 2 N(CH 3 ) 2 , -S(O) 2 NH(CH 2 CH 2 CH 3 ), -S(O) 2 NH(CH(CH 3 )) 2 ), -S(O) 2 N(CH 3 )(CH 2 CH 3 ), -S(=O)(=NH)CH 3 , or -S(=O)(=NCH 3 )CH 3 and is independently optionally substituted with one or more (such as 1, 2, 3, 4, 5 or 6) substituents selected from; wherein said heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain one heteroatom selected from N, O, or S; Preferably, R 3 is 【Chemical 16】 independently selected from; preferably R3 is independently selected from phenyl or pyridinyl, the compound according to claim 1.

7. Formula (I) is 【Chemical 17】 where; wherein R 51 is -C 1-3 alkyl, cyclopentyl, cyclohexyl, a 5-membered heterocyclyl containing one heteroatom selected from N, O, S, S(=O), S(=O)(=NH) or S(=O) 2 or a 6-membered heterocyclyl containing one heteroatom selected from N, O, S, S(=O), S(=O)(=NH) or S(=O) 2 selected; said -C 1-3 alkyl, cyclopentyl, cyclohexyl, 5-membered heterocyclyl and 6-membered heterocyclyl are each independently optionally substituted with one, two or three substituents selected from -F, -C 1-3 alkyl, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 alkyl, oxo, -N(C 1-3 alkyl) 2 , -CN or 3-6 membered cycloalkyl; R 1 is selected from -F, -Cl, -C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 1-3 haloalkyl, -CN, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, and said -C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 1-3 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, and 5-12 membered heteroaryl are each independently optionally substituted with one or more (e.g., 1, 2, 3, 4, 5 or 6) substituents selected from -F, -Cl, -C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 1-3 haloalkyl, -CN, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, or 5-12 membered heteroaryl, and said heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain 1 or 2 heteroatoms selected from N or S; Each R 4 is independently selected from hydrogen, deuterium, -F, -Cl, -C 1-3 alkyl, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , -CN or 3-6 membered cycloalkyl; R 11 and R 12 are each independently selected from hydrogen, deuterium, -F, -C 1-3 alkyl, oxo, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , -CN or 3-6 membered cycloalkyl, and said -C 1-3 alkyl contains 1 or 2 heteroatoms each independently selected from -F, -C 1-3 alkyl, oxo, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , -CN or 3-6 membered cycloalkyl; R 13 is hydrogen; -C 1-3 alkyl; or -F, -C 1-3 alkyl, -C 1-3 alkyl, oxo, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , -CN or -C 1-3 alkyl substituted with 1, 2, 3, 4, 5 or 6 substituents selected from alkyl; R 3 is independently selected from phenyl or 5- to 6-membered heteroaryl containing one or two heteroatoms selected from N, O or S; said phenyl and 5- to 6-membered heteroaryl are independently optionally substituted with one, two, or three substituents selected from R 3c ; R 3c is -F; -C 1-3 alkyl; -OC 1-3 alkyl; -NH 2 ; -NHC 1-3 alkyl; -N(C 1-3 alkyl) 2 ; -C(=O)NH 2 , -C(=O)NH(C 1-3 alkyl); -C(=O)N(C 1-3 alkyl) 2 ; -CN; -S(=O) 2 NH 2 ; -S(=O) 2 NH(C 1-3 alkyl); -S(=O) 2 N(C 1-3 alkyl) 2 ; 3- to 6-membered cycloalkyl; or -F, -C 1-3 alkyl, oxo, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , -C(=O)NH 2 , -C(=O)NH(C 1-3 alkyl), -C(=O)N(C 1-3 alkyl) 2 , -CN, -S(=O) 2 NH 2 , -S(=O) 2 NH(C 1-3 alkyl), -S(=O) 2 N(C 1-3 alkyl) 2 , -S(=O)(=NH)C 1-3 alkyl, -S(=O)(=NC 1-3 alkyl)C 1-3 alkyl, or -C 1-3 alkyl substituted with 1, 2, 3, 4, 5 or 6 substituents selected from; Preferably, R 51 is 【Chemical Formula 18】 or -C 1-6 is selected from alkyl, said -C 1-6 alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 R 5e ; and is optionally substituted R 5a 、 R 5c and R 5d are each independently selected from hydrogen; -C 1-6 alkyl; or a -F, -C 1-3 alkyl, oxo, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , -CN or -C 1-6 alkyl substituted with 1, 2, 3, 4, 5 or 6 substituents each independently selected from 3-6 membered cycloalkyl; R 5b and R 5e are each independently selected from -F, -C 1-6 alkyl, oxo, -OC 1-6 alkyl, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -CN or 3-6 membered cycloalkyl, and said -C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from -F, -C 1-3 alkyl, oxo, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , -CN or 3-6 membered cycloalkyl; R 1 is -C 1-3 alkyl; -C 1-3 haloalkyl; 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S; or -F, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , -CN or -C 1-3 alkyl substituted with 1, 2 or 3 substituents independently selected from 3-6 membered cycloalkyl; Each R 4 is independently selected from hydrogen, deuterium, -F, -Cl, -C 1-3 alkyl, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , -CN or 3-6 membered cycloalkyl; R 11 and R 12 are each independently selected from hydrogen or -C 1-3 alkyl; R 13 is selected from hydrogen or -C 1-3 alkyl; R 3 is selected from phenyl, said phenyl being optionally and independently substituted with one, two or three substituents selected from R 3c ; R 3c is -F; -C 1-3 alkyl; -OC 1-3 alkyl; -NH 2 ; -NHC 1-3 alkyl; -N(C 1-3 alkyl) 2 ; -C(=O)NH 2 , -C(=O)NH(C 1-3 alkyl); -C(=O)N(C 1-3 alkyl) 2 ; -CN; -S(=O) 2 NH 2 ; -S(=O) 2 NH(C 1-3 alkyl); -S(=O) 2 N(C 1-3 alkyl) 2 ; -S(=O) 2 C 1-3 alkyl; -S(=O)(=NH)CH 3 ; or -S(=O)(=NCH 3 )CH 3 selected from; Preferably, R 51 is 【Chemical Formula 19】 selected from R 1 is 【Chemical 20】 independently selected from Each R 4 is hydrogen; R 11 and R 12 are independently selected from hydrogen; R 13 is selected from hydrogen; R 3 is 【Chemical Formula 21】 selected from the compound according to claim 1.

8. Formula (I) is 【Chemical 22】 where; R 1 is -C 1-3 haloalkyl; or -F, -CN, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 optionally substituted with one, two or three substituents independently selected from 3-6 membered cycloalkyl (e.g. cyclopropyl)-C 1-3 alkyl; and Preferably, R 1 is 【Chemical 23】 independently selected from the compound according to claim 1.

9. R 2 is -NHR 51 and R 51 is -C 1-6 alkyl, -C 1-6 haloalkyl, 3-6 membered cycloalkyl, or 3-10 membered heterocycloalkyl; said -C 1-6 alkyl, -C 1-6 haloalkyl, 3-6 membered cycloalkyl, or 3-10 membered heterocycloalkyl is optionally substituted with one or more of halogen, -C 1-6 alkyl (halogen, -CN, oxo, =NH, -OH, -OC 1-6 alkyl, or halogen, -CN, oxo, =NH, -OH, or -OC 1-6 alkyl which is optionally substituted with one or more of 5-6 membered heterocycloalkyl which is optionally substituted with one or more of halogen, -CN, oxo, =NH, -OH, or -OC 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -CN, -OH, -NH 2 , 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 membered cycloalkyl, or 3-12 membered heterocycloalkyl (e.g., 5-12 membered spiroheterocyclyl or bridged heterocyclyl (optionally substituted with one or more of halogen, -CN, oxo, =NH, -OH, or -OC 1-6 alkyl)) and is independently optionally substituted with one or more (e.g., 1, 2, 3, 4, 5 or 6) substituents selected therefrom; said heterocycloalkyl independently contains one or more heteroatoms selected from N, O, or S; Preferably, R 51 is selected from -C 1-6 alkyl, 3-6 membered cycloalkyl, or 5-10 membered heterocycloalkyl (e.g., 5-10 membered spiroheterocyclyl or bridged heterocyclyl); said -C 1-6 alkyl, 3-6 membered cycloalkyl, or 5-10 membered heterocycloalkyl is halogen, -C 1-6 alkyl (halogen, -CN, oxo, =NH, -OH, -OC 1-6 alkyl, or 【Chemical 24】 optionally substituted with one or more of), -CN, -OH, NH 2 , 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- to 5-membered cycloalkyl, or 5- to 12-membered heterocycloalkyl (e.g., 5- to 12-membered spiroheterocyclyl or bridged heterocyclyl (optionally substituted with one or more of halogen, -CN, oxo, =NH, -OH, or -OC 1-6 alkyl) and is independently optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents selected from the group consisting of; said heterocycloalkyl independently contains one or more heteroatoms selected from N, O, or S; Preferably, R 51 is -C 1-3 alkyl, cyclohexyl, or 6-8 membered heterocycloalkyl (e.g., 6-8 membered spiroheterocyclyl or bridged heterocyclyl); said -C 1-3 alkyl, cyclohexyl, or 6-8 membered heterocycloalkyl is halogen, -C 1-6 alkyl (oxo, =NH, -OH, -OC 1-6 alkyl, or 【Chemical Formula 25】 optionally replaced by one or more of), -CN, -OH, NH 2 , oxo, =NH, -OC 1-6 alkyl, -SC 1-6 alkyl, -C(O)CH 2 -NHC 1-6 alkyl, -C(O)CH 2 -N(C 1-6 alkyl) 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , cyclopropyl, or 5- to 12-membered heterocycloalkyl (e.g., ​ optionally and independently substituted with one or more (e.g., 1, 2, 3, 4, 5 or 6) substituents selected from, said heterocycloalkyl independently containing one or more heteroatoms selected from N, O, or S, preferably R 51 is 【Chemical 27】 is the compound according to claim 8.

10. R 2 is 【Chemical Formula 28】 [Chemical] selected from the compound according to claim 8.

11. R 3 is independently selected from 5- to 10-membered heterocycloalkenyl containing one or two heteroatoms selected from phenyl, N, O or S, or 5- to 10-membered, preferably 5- to 6-membered heteroaryl containing one or two heteroatoms selected from N, O or S; each of them being optionally and independently substituted with one, two, or three substituents selected from 3a R; R 3a is halogen; oxo; -C 1-3 alkyl; -OC 1-3 alkyl; -NH 2 ; -NHC 1-3 alkyl; -N(C 1-3 alkyl) 2 ; -C(=O)NH 2 、-C(=O)NH(C 1-3 alkyl); -C(=O)N(C 1-3 alkyl) 2 ; -CN; -S(=O) 2 NH 2 ; -S(=O) 2 NH(C 1-3 alkyl); -S(=O) 2 NHC(=O)C 1-3 alkyl; -S(=O) 2 N(C 1-3 alkyl) 2 ; -S(=O) 2 C 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) 2 C 1-3 alkyl; -PO(C 1-3 alkyl) 2 ; 3-6 membered cycloalkyl; selected from 3-6 membered heterocycloalkyl optionally containing 1, 2 or 3 heteroatoms selected from N, O, P or S; said C 1-3 alkyl, OC 1-3 alkyl, 3-6 membered cycloalkyl, C 3-6 cycloalkyl, C 2-6 When heterocycloalkyl or 3- to 6-membered heterocycloalkyl is present, each is independently optionally substituted with one, two, three, four, five or six substituents selected from deuterium, halogen, -CN, -C 1-3 alkyl, oxo, -OH, -OC 1-3 alkyl, -NH 2 -, -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 -, -COOH, -C(O)OC 1-3 alkyl, -C(=O)NH 2 -, -C(=O)NH(C 1-3 alkyl), -C(=O)N(C 1-3 alkyl) 2 -, -S(=O) 2 NH 2 -, -S(=O) 2 NH(C 1-3 alkyl), -S(=O) 2 C 1-3 alkyl, -S(=O) 2 N(C 1-3 alkyl) 2 -, -S(=O)(=NH)C 1-3 alkyl, -S(=O)(=NC 1-3 alkyl)C 1-3 alkyl, or is independently optionally substituted with 3- to 6-membered cycloalkyl; Preferably, R 3 is independently selected from phenyl, pyridinyl, and 5-10 membered benzoheterocycloalkyl containing one or two heteroatoms selected from N, O or S, each of which is optionally substituted with one, two, or three substituents selected from R 3a ; and is optionally substituted with one, two, or three substituents selected from; R 3a is deuterium, -F; oxo; -OC 1-3 alkyl; -C(=O)NH 2 、-C(=O)NH(C 1-3 alk yl); -CN; -S(=O) 2 NH 2 ; -S(=O) 2 NH(C 1-3 alkyl); -S(=O) 2 NHC(=O)C 1-3 alkyl; -S(=O) 2 N(C 1-3 alkyl) 2 ; -S(=O) 2 C 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) 2 C 1-3 alkyl; -PO(C 1-3 alkyl) 2 ; or selected from 3-6 membered heterocycloalkyl optionally containing 1, 2 or 3 heteroatoms selected from N, O, P or S; said C 1-3 alkyl, OC 1-3 alkyl or 3-6 membered heterocycloalkyl, when each is present, deuterium, -F, -CN, oxo, -C 1-3 alkyl, -OH, -OC 1-3 alkyl, -N(C 1-3 alkyl) 2 、-C(O)OC 1-3 alkyl, -C(=O)NH 2 、-C(=O)NH(C 1-3 alkyl), or -C(=O)N(C 1-3 alkyl) 2 and is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from; Preferably, R 3 is phenyl, pyridinyl, 【Chemical 29】 selected from, each of them being optionally substituted with substituents 1, 2, 3 selected from R 3a and being optionally substituted with substituents 1, 2, 3 selected from R 3a is -F; oxo; -OC 1-3 alkyl; -C(=O)NHC 1-3 alkyl; -S(=O) 2 NH 2 ; -S(=O) 2 NHC(=O)CH 3 ; -S(=O) 2 CH 3 ; -S(=O)(=NH)C 1-3 alkyl; -S(=O)(=NC 1-3 alkyl)C 1-3 alkyl; -N(CH 3 )S(=O) 2 CH 3 ; -PO(C 1-3 alkyl) 2 ; selected from morpholinyl or 5-6 membered heterocycloalkyl optionally containing 1, 2 or 3 heteroatoms selected from N, O, or P; said C 1-3 alkyl, OC 1-3 alkyl or 5-6 membered heterocycloalkyl, when each is present, is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from deuterium, -F, -CN, oxo, -OH, -OCH 3 , -N(C 1-3 alkyl) 2 , -C(O)OCH 3 , or -C(=O)NH; Preferably, R 3 is independently selected from phenyl optionally substituted with 1, 2, or 3 substituents selected from R 3a ; R 3a is -F, -OCH 3 , -OCD 3 , -OCH 2 CN, -OCH 2 CF 3 , -CH 2 F, -CHF 2 , -OCH 2 CH 2 OH, -OCH 2 CH 2 OCH 3 , -S(O) 2 NH 2 , -S(O) 2 NHCOCH 3 , -S(O) 2 CH 3 , -S(=O)(=NH)CH 3 , -S(=O)(=NCH 3 )CH 3 , -N(CH 3 )S(=O) 2 CH 3 , -C(O)NHCH 3 , -C(O)NHCH(COOCH 3 )CH 2 CH 2 CONH 2 , -PO(CH 3 ) 2 , morpholinyl, or 【Chemical 30】 selected from the compound according to claim 8.

12. R 11 and R 12 are both hydrogen; R 13 The compound according to claim 8, wherein R is H.

13. Chemical moiety 【Chemical 31】 is 【Chemical 32】 selected from preferably, chemical moiety 【Chemical 33】 is 【Chemical 34】 selected from preferably, chemical moiety 【Chemical 35】 is 【Chemical 36】 selected from preferably, chemical moiety 【Chemical 37】 is 【Chemical 38】 selected from preferably, chemical moiety 【Chemical Formula 39】 is 【Chemical 40】 selected from the compound according to claim 8.

14. The compound of formula (I) is selected from the following; 【Table 1】 [Chemical] [Chemical] [Chemical] 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 [Chemical] 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 [Chemical] [Chemical] 【Chem.】 [Chemical] 【Chem.】 【Chem.】 [Chemical] [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 or, the compound of formula (I) is 【Chemical 41】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 selected from or, the compound of formula (I) is 【Chemical Formula 42】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 selected from or, the compound of formula (I) is 【Chemical 43】 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 selected from or, the compound of formula (I) is 【Chemical Formula 44】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 selected from or, the compound of formula (I) is 【Chemical 45】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 selected from the compound according to claim 1.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 14, or a stereoisomer, a tautomer, a deuterated derivative, a prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

16. The pharmaceutical composition according to claim 15 for use in the prevention or treatment of a disease or condition in a subject, wherein the disease or condition is preferably cancer, preferably solid cancer such as advanced solid cancer; preferably, cancer cells express a p53 variant; preferably, the p53 variant has mutations at amino acids Val143, His168, Arg175, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, Arg282, and / or combinations thereof; or the p53 variant is V157F, R175H, Y220C, G245S, R248Q, R248W, R249S, R273H, R273C, R282W, and / or combinations thereof, preferably Y220C.

17. The pharmaceutical composition for use according to claim 16, wherein the disease or condition is selected from the group consisting of ovarian cancer, breast cancer, lung cancer and / or combinations thereof.

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