Compounds targeting p53 mutants

Abstract

The present invention provides compounds of formula (I) that can bind to the mutant p53 and restore the ability of the p53 mutant to bind DNA and activate downstream effectors involved in tumor suppression. Also provided are pharmaceutical compositions comprising the compounds, methods of preparing the compounds, and methods of using the compounds to prevent or treat diseases or conditions associated with p53 mutants. # imgabs0 #

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit and priority of PCT application PCT / CN2022 / 137535, filed on December 08, 2022; the entire content of which is incorporated herein by reference in its entirety. Field of the invention

[0003] The present invention relates to compounds targeting p53 mutants, pharmaceutical compositions comprising said compounds, methods for preparing said compounds, and methods for using said compounds to prevent or treat diseases or disorders associated with p53 mutants. Background of the invention

[0005] The p53 protein, known as the "guardian of the human genome", is a tetrameric transcription factor that prevents genomic mutations by regulating the expression of a subset of target genes. Although biologically active as a homotetramer, each p53 monomer contains 393 amino acids and is divided into five key regulatory domains: the trans - activation domain (TAD), the proline - rich region (PR), the DNA - binding domain (DBD), the oligomerization domain (OD), and the C - terminus.

[0006] Under normal circumstances, the p53 protein has an "anti - cancer" effect, but p53 is unstable with a half - life in the range of 5 to 30 minutes. Activation of p53 initiates pathways involving apoptosis, DNA repair, cell - cycle arrest, anti - angiogenesis, and senescence to prevent the propagation of damaged cells. Activation of p53 occurs through a complex regulatory network that includes three key steps: (1) stabilization of p53 by phosphorylation, (2) DNA binding, and (3) target - gene activation.

[0007] p53 is the most commonly mutated protein in human cancers. For example, mutations occur 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 a worsened prognosis and patient survival rate. In addition, mutant p53 is a highly abundant and tumor-specific target as it is often overexpressed in cancers, partly because it fails to induce MDM2 gene expression to establish a negative feedback loop to control p53 expression. Due to its overexpression, mutant p53 also has toxic gain-of-function (GoF) properties that can spread and cause malfunction in other important proteins and pathways regulating the cell cycle. Given the above factors, mutant p53 represents an important pharmacological target, and over the past two decades, there has been a considerable effort to develop small molecules aimed at restoring the wild-type function of mutant p53. In particular, targeting mutant p53 means more selectively targeting cancer cells, reducing the risk of side effects and toxicity against healthy tissues. Among the small molecules that have been developed, many mechanistic strategies have been developed, including protein refolding through cysteine modification, protein stabilization, regulation of protein aggregation, and zinc chelation.

[0008] P53 is directly inactivated by mutations in 50% of human cancers (ranging from approximately 1% to 85%, depending on the type of cancer), and almost all cancers exhibit dysfunction of the p53 pathway. Over the past few decades, the frequency and aggressiveness of cancers exhibiting p53 dysfunction have driven extensive efforts in academia and the pharmaceutical industry to restore normal p53 expression and activity. Although this approach faces significant challenges, including frequent off-target mechanisms, major technological advancements in gene sequencing capabilities and the shift towards personalized medicine have brought significant hope for the development of small molecules capable of mutant-specific p53 reactivation.

[0009] P53 mutations located in or peripheral to the DNA-binding domain or DNA-binding surface of the protein result in abnormal protein folding required for DNA recognition and binding. P53 mutations can occur, for example, at amino acids Val143, His168, Arg175, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, and Arg282. P53 mutations that can abrogate p53 activity include, such as, R175H, Y220C, G245S, R248Q, R248W, R273H, and R282W. These p53 mutations can distort the structure of the DNA-binding site and can also render the folded protein thermodynamically unstable at body temperature. The wild-type function of the p53 mutant can be restored by the binding of the p53 mutant to a compound that can shift the folding-unfolding equilibrium towards the folded state, thereby reducing the unfolding rate and the rate of destabilization.

[0010] Since p53 mutations are prevalent in almost all types of cancer, reactivating wild-type p53 function in cancer cells can be an effective therapy. The P53 Y220C mutation is associated with many cancers, such as breast cancer, non-small cell lung cancer, colorectal cancer, pancreatic cancer, and ovarian cancer.

[0011] Although PC14586 has been reported as a small molecule reactivator targeting the p53 Y220C mutant developed by PMV Pharmaceuticals, there is still an urgent need in the art to develop novel small molecule reactivators targeting p53 mutants (such as the Y220C mutant) with high specificity, high activity, and low toxicity. Summary of the Invention

[0012] In one aspect, an object of the present invention is to provide a compound targeting a p53 mutant, preferably the Y220C mutant.

[0013] In one aspect, an object of the present invention is to provide a pharmaceutical composition comprising the compound targeting a p53 mutant mentioned above.

[0014] In one aspect, an object of the present invention is to provide a method for preventing or treating a disease or disorder associated with a p53 mutant protein, the method comprising administering to a subject a therapeutically effective amount of the compound or the pharmaceutical composition.

[0015] In one aspect, an object of the present invention is to provide a method for preparing the compound of the present invention.

[0016] It should be understood that each preventive or therapeutic method embodiment herein can also be clearly expressed as a corresponding use type embodiment.

[0017] The present disclosure also provides the following aspects.

[0018] 1. A compound of formula (I), or a stereoisomer, tautomer, deuterated derivative, prodrug, or pharmaceutically acceptable salt thereof:

[0019]

[0020] Y is selected from O, S, NR', S=O, -S(=O)(=NR')-, or O=S=O;

[0021] One of X1, X2, X3, and X4 is selected from N or CR2, and the other X1, X2, X3, and X4 are each independently selected from: N or CR4;

[0022] X5 is selected from N or CR1;

[0023] E is selected from alkylene, alkenylene, or alkynylene;

[0024] R1 is independently selected 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)2R’, -S(O)2N(R’)2, -NR’S(O)2R’, -NR’S(O)2N(R’)2, -PO(R’)2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl or 5-12 membered heteroaryl; said -C 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 each independently optionally substituted with one or more (such as 1, 2, 3, 4, 5 or 6) substituents selected from: deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -CN, oxo, -OR’, -SR’, -C(O)R’, -C(O)N(R’)2, -C(O)OR’, -OC(O)R’, -OC(O)N(R’)2, -N(R’)2, -NR’C(O)R’, -NR’C(O)OR’, -NR’C(O)N(R’)2, -S(O)R’, -S(O)N(R’)2, -NR’S(O)R’, -NR’S(O)N(R’)2, -S(O)2R’, -S(O)2N(R’)2, -NR’S(O)2R’, -NR’S(O)2N(R’)2, -PO(R’)2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl or 5-12 membered heteroaryl;

[0025] R2 is -NR 51 R 52 、-OR 53 or -SR 54 ;

[0026] R3 is 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)2R’, -S(O)2N(R’)2, -PO(R’)2, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 6- to 12-membered aryl, 5- to 12-membered heteroaryl; 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 12-membered aryl, and 5- to 12-membered heteroaryl are each independently optionally substituted with one or more (such as 1, 2, 3, 4, 5, or 6) R 3a substituents;

[0027] Each R 3a 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)2R’, -S(O)2N(R’)2, -S(=O)(=NR’)R’, -NR’S(O)2R’, -NR’S(O)2N(R’)2, -PO(R’)2, -P(S)(R’)2, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 6- to 12-membered aryl or 5- to 12-membered heteroaryl; 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 12-membered aryl, and 5- to 12-membered heteroaryl are each independently optionally substituted with one or more R3b Substituted by a substituent;

[0028] 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)2R’, -S(O)2N(R’)2, -S(=O)(=NR’)R’, -NR’S(O)2R’, -NR’S(O)2N(R’)2, -PO(R’)2;

[0029] Each occurrence of R4 is independently selected 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)2R’, -S(O)2N(R’)2, -NR’S(O)2R’, -NR’S(O)2N(R’)2, -PO(R’)2, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 6- to 12-membered aryl or 5- to 12-membered heteroaryl; 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 12-membered aryl, and 5- to 12-membered heteroaryl are each independently optionally substituted by one or more (such as 1, 2, 3, 4, 5, or 6) substituents selected from: deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6Alkynyl, -C 1-6 Haloalkyl, -CN, oxo, -OR', -SR', -C(O)R', -C(O)N(R')2, -C(O)OR', -OC(O)R', -OC(O)N(R')2, -N(R')2, -NR'C(O)R', -NR'C(O)OR', -NR'C(O)N(R')2, -S(O)R', -S(O)N(R')2, -NR'S(O) R', -NR'S(O)N(R')2, -S(O)2R', -S(O)2N(R')2, -S(=O)(=NR')R', -NR'S(O)2R', -NR'S(O)2N(R')2, -PO(R')2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, or 5-12 membered heteroaryl;

[0030] R 51 , R 52 , R 53 and R 54 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)2R', -S(O)2N(R')2, -PO(R')2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, 5-12 membered heteroaryl, or ... 1-6 Alkyl-C 3-12 Heterocycloalkyl; the -C 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, -C 3-12 The heterocycloalkyl, and 5-12 membered heteroaryl are each independently optionally substituted by one or more (e.g., 1, 2, 3, 4, 5 or 6) substituents selected from the group consisting of deuterium, halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Haloalkyl, -CN, oxo, =NR', -C 1-6alkyl-CH(R')2, -OR', -SR', -C(O)R', -C(O)N(R')2, -C(O)OR', -OC(O)R', -OC(O)N(R')2, -N(R')2, -NR'C(O)R', -NR'C(O)OR', -NR'C(O)N(R')2, -S(O)R', -S(O)N(R')2, -NR'S(O)R', -NR'S(O)N(R')2, -S(O)2R', -S(O)2N(R')2, -S(=O)(=NR')R', -NR'S(O)2R', -NR'S(O)2N(R')2, -PO(R')2, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heteroalkyl, 3- to 12-membered heteroalkenyl, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl;

[0031] R 11 and R 12 are independently selected from: hydrogen, deuterium, -OH, halogen, -CN, oxo, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2 or 3- to 6-membered cycloalkyl; wherein said -C 1-6 alkyl, -C 1-6 alkoxy and 3- to 6-membered cycloalkyl are each independently optionally substituted with one or more (such as 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- to 6-membered cycloalkyl; or

[0032] R 11 or R 12 and R3 together with the atoms to which they are respectively attached form a ring, for example, a monocyclic, bicyclic or polycyclic 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 6- to 12-membered aryl or 5- to 12-membered heteroaryl, which ring is independently optionally substituted with one or more R 3a substituents;

[0033] R 13 is selected from hydrogen, deuterium, -C 1-6 alkyl or 3- to 6-membered cycloalkyl; wherein said -C 1-6 alkyl and 3- to 6-membered cycloalkyl are each independently optionally substituted with one or more (such as 1, 2, 3, 4, 5 or 6) substituents selected from: deuterium, -OH, halogen, -CN, oxo, -C 1-6 alkoxy, -NH2, -NHC1-6 alkyl, or -N(C 1-4 alkyl)2; or

[0034] R3 and R 13 together with the nitrogen atom to which they are attached form a ring, for example, a monocyclic, bicyclic or polycyclic 3- to 12-membered cycloalkyl, 3- to 12-membered heterocycloalkyl, 6- to 12-membered aryl or 5- to 12-membered heteroaryl, and the ring is independently optionally substituted by one or more R 3a substituents;

[0035] each R', each occurrence independently selected from hydrogen, deuterium, halogen, -OH, -CN, oxo, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -C 1-6 alkyl, -C 1-6 alkylOC 1-6 alkyl, -C 1-6 alkyl-NHC 1-6 alkyl, -C 1-6 alkyl-N(C 1-6 alkyl)2, -C 1-6 haloalkyl, -OC 1-6 alkyl, -C(O)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; wherein the -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 independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from: deuterium, halogen, -CN, -C 1-3 alkyl, oxo, -OH, -OC 1-3 alkyl, -NH2, -NHC 1-3 alkyl, -N(C 1-3 alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-3 alkyl), -C(=O)N(C 1-3 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 alkyl), -S(=O)2C 1-3 alkyl, -S(=O)2N(C 1-3 alkyl)2, -S(=O)(=NH)C1-3 alkyl, -S(=O)(=NC 1-3 alkyl)C 1-3 alkyl, or 3- to 6-membered cycloalkyl;

[0036] Said heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain 1, 2, 3, 4, 5, or 6 heteroatoms selected from: N, O, P, or S;

[0037] m is selected from 1, 2, 3, 4, 5, or 6.

[0038] 2. The compound according to item 1, wherein E is selected from ethynylene or ethylene.

[0039] 3. The compound according to item 1 or 2, wherein,

[0040] Said formula (I) is:

[0041] In said formula (I-1), X2, X3, and X4 each independently are selected from: N or CR4;

[0042] Y is selected from O, S, S=O, or O=S=O.

[0043] 4. The compound according to item 1 or 2, wherein said formula (I) is:

[0044]

[0045] Wherein, X2 is independently selected from N or CR4.

[0046] 5. The compound according to any one of 1 to 4, wherein,

[0047] R1 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, 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, and 5- to 12-membered heteroaryl are independently optionally substituted with one or more (such as 1, 2, 3, 4, 5, or 6) substituents selected from: halogen, -OH, -C 1-6 alkyl, -C 2-6 alkenyl, -C2-6 alkynyl, -C 1-6 haloalkyl, -CN, oxo, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heteroalkyl, 3- to 12-membered heteroalkenyl, 6- to 10-membered aryl, or 5- to 12-membered heteroaryl, wherein each of the heteroalkyl, heteroalkenyl, and heteroaryl independently contains 1 or 2 heteroatoms selected from: N or S.

[0048] 6. The compound according to any one of 1 to 5, wherein R1 is independently selected from -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 heteroalkyl, 6- to 10-membered aryl, 5- to 12-membered heteroaryl, the -C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 1-3 haloalkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heteroalkyl, 6- to 10-membered aryl, and 5- to 12-membered heteroaryl are each independently optionally substituted with one or more (such as 1, 2, 3, 4, 5, or 6) substituents selected from: -F, -Cl, -OH, -C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 1-3 haloalkyl, -CN, oxo, 3- to 6-membered cycloalkyl, 3- to 6-membered heteroalkyl, 6- to 10-membered aryl, or 5- to 12-membered heteroaryl, wherein each of the heteroalkyl, heteroalkenyl, and heteroaryl independently contains 1 or 2 heteroatoms selected from: N or S.

[0049] 7. The compound according to any one of items 1 to 6, wherein R1 is independently selected from -F, -Cl, -C 1-3 alkyl, -C 1-3 haloalkyl, 3- to 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; the -C 1-3 alkyl, -C 1-3 haloalkyl, 3- to 6-membered cycloalkyl, 5-membered heteroaryl, and 6-membered heteroaryl are each independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from: -F, -OH, -C 1-3 alkyl, -OC 1-3 alkyl, -NH2, -NHC 1-3 alkyl, -N(C 1-3 alkyl)2, -CN, or 3- to 6-membered cycloalkyl.

[0050] 8. The compound according to any one of 1 to 7, wherein R1 is independently selected from -C 1-3 alkyl, -C 1-3 haloalkyl, or a 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S; and R1 is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from the following: -F, -OH, -OC 1-3 alkyl, -NH2, -NHC 1-3 alkyl, -N(C 1-3 alkyl)2, -CN or 3- to 6-membered cycloalkyl.

[0051] 9. The compound according to any one of 1-8, wherein R1 is independently selected from

[0052] 10. The compound according to any one of 1 to 9, wherein R2 is -NR 51 R 52 .

[0053] 11. The compound according to any one of 1 to 10, wherein R2 is -NHR 51 .

[0054] 12. The compound according to any one of 1 to 11, wherein R 51 is selected from -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- to 6-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, or -C 1-6 alkyl-C 3-12 heterocycloalkyl; the -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, 3- to 6-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl and -C 3-12 heterocycloalkyl are each independently optionally substituted with one or more (such as 1, 2, 3, 4, 5 or 6) substituents selected from the following: halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -CN, oxo, =NR’, -C 1-6alkyl-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- to 6-membered cycloalkyl, 3- to 6-membered heteroalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each of said heteroalkyl, heteroalkenyl, and heteroaryl independently contains 1 heteroatom selected from N, O, or S.

[0055] 13. A compound according to any one of 1 to 12, wherein R 51 is selected from -C 1-3 alkyl, cyclopentyl, cyclohexyl, -C(O)-C 3-6 heteroalkyl, -C 1-3 alkyl-C 3-6 heteroalkyl, or a 5-, 6-, or 8-membered heterocyclic group containing 1 heteroatom selected from N, O, S, S(=O), S(=O)(=NH), or S(=O)2; said -C 1-3 alkyl, cyclopentyl, cyclohexyl, C 3-6 heteroalkyl, and the 5-, 6-, or 8-membered heterocyclic group are each independently optionally substituted with 1, 2, or 3 substituents selected from: -F, -C 1-3 alkyl, -OC 1-3 alkyl, -NH2, -NHC 1-3 alkyl, oxo, =NH, -N(C 1-3 alkyl)2, -CN, or 3- to 6-membered cycloalkyl.

[0056] 14. A compound according to any one of 1 to 13, wherein R 51 is selected from 8-membered bridged heterocyclic group, -C(O)-C 3-5 heteroalkyl, or -C 1-3 alkyl-C 3-5 heteroalkyl, said 8-membered bridged heterocyclic group, -C 1-3 alkyl, or -C 3-5 heteroalkyl is optionally substituted with 1, 2, 3, 4, 5, or 6 R 5e substituents;

[0057] R 5a , R 5c and R 5d are each independently selected from: hydrogen; -C 1-6 alkyl; or -C 1-6 alkyl, which is substituted with 1, 2, 3, 4, 5, or 6 substituents selected from: -F, -C 1-3alkyl, oxo, -OC 1-3 alkyl, -NH2, -NHC 1-3 alkyl, -N(C 1-3 alkyl)2, -CN or 3- to 6-membered cycloalkyl;

[0058] R 5b and R 5e each independently selected from: -F, -C 1-6 alkyl, oxo, -OC 1-6 alkyl, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -CN or 3- to 6-membered cycloalkyl, wherein the -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, -NH2, -NHC 1-3 alkyl, -N(C 1-3 alkyl)2, -CN or 3- to 6-membered cycloalkyl.

[0059] 15. The compound according to any one of 1 to 14, wherein R 51 is selected from

[0060] 16. The compound according to any one of 1 to 15, wherein R3 is independently selected from 3- to 12-membered heteroalkenyl, 6- to 10-membered aryl, or 5- to 12-membered heteroaryl; the 3- to 12-membered heteroalkenyl, 6- to 10-membered aryl, or 5- to 12-membered heteroaryl is each independently optionally substituted, each time it appears, with one or more R 3a substituents selected from: halogen, NH2, NH-C 1-6 alkyl, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6haloalkyl, -CN, -NO2, -OR’, -SR’, -C(O)R’, oxo, -C(O)N(R’)2, -C(O)OR’, -OC(O)R’, -N(R’)2, -NR’C(O)R’, -S(O)R’, -NR’S(O)R’, -S(O)N(R’)2, -S(O)2R’, -NR’S(O)2R’, -S(O)2N(R’)2, -S(=O)(=NR’)R’, -PO(R’)2, -P(S)(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, wherein the heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain 1, 2, 3, or 4 heteroatoms selected from N, O, or S; and said R3a is independently optionally substituted with one or more substituents of R 3b substituted.

[0061] 17. The compound according to any one of 1 to 16, wherein R 3a is selected from l halogen; oxo; -C 1-3 alkyl; -OC 1-3 alkyl; -NH2; -NHC 1-3 alkyl; -N(C 1-3 alkyl)2; -C(=O)NH2, -C(=O)NH(C 1-3 alkyl); -C(=O)N(C 1-3 alkyl)2; -CN; -S(=O)2NH2; -S(=O)2NH(C 1-3 alkyl); -S(=O)2NHC(=O)C 1-3 alkyl; -S(=O)2N(C 1-3 alkyl)2; -S(=O)2C 1-3 alkyl; -S(=O)(=NH)C 1-3 alkyl; -S(=O)(=NH)C 3-6 cycloalkyl; -S(=O)(=NR’)C 2-6 heterocycloalkyl; -S(=O)(=NC 3-6 cycloalkyl)C 1-3 alkyl; -S(=O)(=NC 2-6 heterocycloalkyl)C 1-3 alkyl; -S(=O)(=NC 1-3 alkyl)C 1-3 alkyl; -S(=O)(=NCN)C 1-3 alkyl; -N(C 1-3 alkyl)S(=O)2C 1-3 alkyl; -PO(C 1-3 alkyl)2; -P(S)(C1-3 alkyl)2; 3- to 6-membered cycloalkyl; 3- to 6-membered heteroalkyl or 5- to 12-membered heteroaryl optionally containing 1, 2 or 3 heteroatoms selected from N, O, P or S; wherein said C 1-3 alkyl, OC 1-3 alkyl, 3- to 6-membered cycloalkyl, C 3-6 cycloalkyl, C 2-6 heteroalkyl, 3- to 6-membered heteroalkyl or 5- to 12-membered heteroaryl is independently optionally substituted, each occurrence, by 1, 2, 3, 4, 5 or 6 substituents selected from: deuterium, halogen, -CN, -C 1-3 alkyl, oxo, -OH, -OC 1-3 alkyl, -NH2, -NHC 1-3 alkyl, -N(C 1-3 alkyl)2, -COOH, -C(O)OC 1-3 alkyl, -C(=O)NH2, -C(=O)NH(C 1-3 alkyl), -C(=O)N(C 1-3 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 alkyl), -S(=O)2C 1-3 alkyl, -S(=O)2N(C 1-3 alkyl)2, -S(=O)(=NH)C 1-3 alkyl, -S(=O)(=NC 1-3 alkyl)C 1-3 alkyl, or 3- to 6-membered cycloalkyl.

[0062] 18. The compound according to any one of 1-17, wherein R3 is independently selected from phenyl, pyridyl, benzofuranyl, or isoindolinyl, and R3 is independently optionally substituted by one or more R 3a substituents, R 3a is independently selected from halogen, oxo, -CN, -CH3, CF3, -OCH3, -OCD3, OCH2CH3, -SCH3, -C(O)OC(CH3)3, -PO(CH3)2, -P(S)(CH3)2, -S(O)2CH3, -S(=O)(=NH)CH3, -S(=O)(=NCH3)CH3, pyrazolyl,

[0063] 19. The compound according to any one of 1 to 18, wherein R 11 or R 12 is hydrogen or oxo; or R 11 or R 12R3 and the atom to which it is attached together form a 5- to 12-membered heterocyclic group, preferably indolinyl, which is optionally substituted by one or more R 3a substituents.

[0064] 20. The compound according to any one of 1 to 19, wherein R 13 is H; or R3 and R 13 together with the nitrogen atom to which they are attached form a 5- to 12-membered heterocyclic group, preferably benzimidazolyl, which is optionally substituted by one or more R 3a substituents.

[0065] 21. The compound according to any one of 1 to 20, wherein the chemical moiety is selected from:

[0066]

[0067] 22. The compound according to any one of 1 to 21, wherein the compound of formula (I) is selected from:

[0068]

[0069] 23. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) according to any one of 1 - 22, or a stereoisomer, tautomer, deuterated derivative, prodrug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0070] 24. Use of the compound of formula (I) according to any one of 1 - 22, or a stereoisomer, tautomer, deuterated derivative, prodrug or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to 23, in the manufacture of a drug for preventing or treating a disease or disorder in a subject.

[0071] 25. The use according to item 24, wherein the disease or disorder is cancer, preferably a solid tumor, such as an advanced solid tumor.

[0072] 26. The use according to item 25, wherein the cancer cells express a p53 mutant.

[0073] 27. The use according to item 26, wherein the p53 mutant has a mutation at amino acid Val143, His168, Arg175, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, Arg282 and / or a combination thereof.

[0074] 28. Use according to item 26, wherein the p53 mutant is V157F, R175H, Y220C, G245S, R248Q, R248W, R249S, R273H, R273C, R282W, and / or a combination thereof, preferably Y220C.

[0075] 29. Use according to any one of 24 to 28, wherein the disease or disorder is selected from the group consisting of ovarian cancer, breast cancer, lung cancer, and / or a combination thereof.

[0076] 30. The compound of formula (I) according to any one of 1 - 22, or a stereoisomer, tautomer, deuterated derivative, prodrug, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to 23, for preventing or treating a disease or disorder associated with a p53 mutant protein in a subject.

[0077] 31. A method for preventing or treating a disease or disorder associated with a p53 mutant protein in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of formula (I) according to any one of 1 - 22, or a stereoisomer, tautomer, deuterated derivative, prodrug, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to 23.

[0078] 32. The method according to item 31, wherein the disease or disorder is cancer.

[0079] 33. The method according to item 32, wherein the cancer cells express a p53 mutant.

[0080] 34. The method according to item 33, wherein the p53 mutant has a mutation at amino acid Val143, His168, Arg175, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, Arg282, and / or a combination thereof.

[0081] 35. The method according to item 33, wherein the p53 mutant is V157F, R175H, Y220C, G245S, R248Q, R248W, R249S, R273H, R273C, R282W, and / or a combination thereof, preferably Y220C.

[0082] 36. The method according to any one of 31 to 35, wherein the disease or disorder is selected from the group consisting of ovarian cancer, breast cancer, lung cancer, and / or a combination thereof.

[0083] Detailed description

[0084] The present invention provides compounds, compositions, and methods for restoring the wild-type function of mutant p53. The compounds of the present invention can bind to mutant p53 and restore the ability of the p53 mutant to bind DNA. Restoration of p53 mutant activity can permit activation of downstream effectors of p53, thereby inhibiting cancer progression. The present invention further provides a method for treating a disease or disorder associated with a p53 mutant protein. A method for preparing the compounds of the present invention is also provided.

[0085] The compounds of the present invention can selectively bind to p53 mutants and can restore the 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 the p53 Y220C mutant. The Y220C mutant is a temperature-sensitive mutant that binds to DNA at lower temperatures and denatures at body temperature. The compounds of the present invention can selectively bind to p53 Y220C and stabilize the Y220C mutant to reduce the likelihood of the protein denaturing at body temperature.

[0086] To determine the ability of the compounds of the present invention to bind and stabilize mutant p53, assays can be used to detect, for example, conformational changes in the p53 mutant or activation of wild-type p53 targets. Conformational changes in p53 can be measured by, for example, differential scanning fluorimetry (DSF), isothermal titration calorimetry (ITC), nuclear magnetic resonance spectroscopy (NMR), or X-ray crystallography. In addition, wild-type-specific antibodies against the p53 mutant conformation can be used to detect conformational changes via, for example, immunoprecipitation (IP), immunofluorescence (IF), or immunoblotting. Methods for detecting the ability of p53 mutants to bind DNA can 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). To determine whether the compounds described herein can reactivate the transcriptional activity of p53, activation of downstream targets in the p53 signaling cascade can be measured. Activation of p53 effector proteins can be detected by, for example, immunohistochemistry (IHC-P), reverse transcription polymerase chain reaction (RT-PCR), and Western blotting. Activation of p53 can also be measured by inducing apoptosis via the caspase cascade and using methods including, for example, annexin V staining, TUNEL assay, caspase precursor and caspase levels, and cytochrome c levels. Another consequence of p53 activation is senescence, which can be measured using methods such as β-galactosidase staining.

[0087] The present invention is described herein using several definitions as set forth below and throughout the application.

[0088] Unless the context clearly indicates otherwise, the terms "a", "an", and "the" mean "one or more". For example, "a compound" shall be construed to mean "one or more compounds".

[0089] As used herein, the terms "about", "approximately", "substantially", and "significantly" will be 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 the use of these terms is unclear to those of ordinary skill in the art in the context in which they are used, "about" and "approximately" will mean the particular term ± 10%, and "substantially" and "significantly" will mean the particular term ± > 10%.

[0090] As used herein, the terms "include" and "including" have the same meaning as the terms "comprise" and "comprising", and these terms are "open" transitional terms that do not limit the claim to the elements recited after these transitional terms. The term "consisting of" while covered by the term "include" shall be construed as a "closed" transitional term that limits the claim to the elements recited after this transitional term. The term "consisting essentially of" while covered by the term "include" shall be construed as a "partially closed" transitional term that allows additional elements after this transitional term, provided that these additional elements do not materially affect the basic and novel characteristics of the claim.

[0091] The total number of carbon atoms present in a chemical group as defined herein is represented by a shorthand symbol before the group. For example, C 1-6 Alkyl refers to an alkyl group having a total of 1 to 6 carbon atoms as defined below; C 3-8 Cycloalkyl refers to a cycloalkyl group having a total of 3 to 8 carbon atoms as defined below; C 6-10 Aryl refers to an aryl group having a total of 6 to 10 carbon atoms as defined below. Carbon atoms that may be present in the substituents of a chemical group are not included in the total number of carbon atoms of the shorthand symbol.

[0092] Unless otherwise indicated in this specification, all combinatorial groups (i.e., groups containing two or more groups) according to the present invention are attached to the remainder of the molecule in such a way that the last-described group serves as the point of attachment. For example, "arylalkyl" means that the aryl is attached to the remainder of the molecule through an alkyl group; "alkoxy" means that an aliphatic group is attached to the remainder of the molecule through an oxygen group, and so on.

[0093] In this application, "optional" or "optionally" means that the subsequent event or circumstance may or may not occur, and this description includes instances where the event or circumstance occurs and instances where it does not occur. Additionally, the term "optionally substituted" means that any one or more hydrogen atoms on a specified atom or group may or may not be replaced by a moiety other than hydrogen. For example, "alkyl optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, or 6) halogens" means that the alkyl is unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4, 5, or 6) halogens, and this description includes both the substituted and unsubstituted alkyl cases.

[0094] The term "substituted" means that any one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents other than hydrogen, provided that the normal valence of the specified atom is not exceeded. Unless otherwise indicated, the term "substituted" refers to any level of substitution, such as mono-, di-, tri-, tetra-, or penta-substitution, provided that such substitution is permitted. The substituents are independently selected, and substitution can occur at any chemically accessible position. It should be understood that substitution on a given atom is limited by valence. It should be understood that substitution on a given atom should result in a chemically stable molecule. As used herein, the term "substituted" is intended to include all permitted substituents of organic compounds. Broadly speaking, permitted substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For suitable organic compounds, the permitted substituents can be one or more and the same or different. The phrase "optionally substituted" means unsubstituted or substituted. The term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, such as oxo, can replace two hydrogen atoms.

[0095] The term "stereoisomer" refers to compounds composed of the same atoms bonded by the same bonds but having different three-dimensional structures. 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.

[0096] The stereochemical definitions and conventions used herein generally follow 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 thus exist in different stereoisomeric forms. Many organic compounds exist in optically active forms, i.e., they 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 denote the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l or (+) and (-) are used to denote the sign of rotation of the compound of plane-polarized light, where (-) or l indicates that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is usually called a racemic mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur in the absence of stereoselectivity or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric substances without optical activity.

[0097] The term “tautomer” refers to an isomer produced by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of formula (I) of the present invention are included within the scope of the present invention.

[0098] Unless otherwise indicated, structures described herein are also intended to include all isomeric forms thereof, such as racemic mixtures, cis-trans isomers, geometric (or conformational) isomers, e.g., (Z) and (E) isomers. Compounds having double bonds or rings in this application include both E- and Z-geometric isomers unless otherwise indicated.

[0099] Unless otherwise indicated, the bonds in this application or include and

[0100] All isotopes of any specific atom or element designated are expected to be within the scope of the compounds of the present invention and their uses. Isotopes include those atoms having the same atomic number but different mass numbers. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 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 I. As a general example and not a limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of hydrogen can be represented as 1 H (hydrogen), 2 H (deuterium), and 3 H (tritium). They are also commonly represented as D for deuterium and T for tritium. In the present application, CD3 represents a methyl group in which all hydrogen atoms are deuterium. Isotopes of carbon include 13 C and 14 C. The isotopically labeled compounds of the present disclosure are equivalent to the unlabeled compounds. For example, the deuterated compounds of the present disclosure are equivalent to the non-deuterated compounds. The isotopically labeled compounds of the present invention can generally be prepared by using appropriate isotopically labeled reagents in place of the unlabeled reagents by conventional techniques known to those skilled in the art or by methods similar to those described herein.

[0101] As used herein, a "deuterated derivative" means a compound having the same chemical structure as a reference compound but with one or more hydrogen atoms replaced by deuterium atoms ("D" or " 2Compounds substituted with deuterium (i.e., “D”) in place of hydrogen (i.e., “H”) are contemplated. It will be recognized that some variation in the natural isotopic abundances will occur in the synthetic compounds, depending on the source of the chemical materials used in the synthesis. Despite such variation, the concentration of stable hydrogen isotopes at natural abundance is small and inconsequential compared to the degree of stable isotope substitution of the deuterated derivatives described herein. Thus, unless otherwise stated, when referring to a “deuterated derivative” of a compound of the present disclosure, at least one hydrogen is replaced with deuterium at a level far higher than its natural isotopic abundance (typically about 0.015%). In some embodiments, the deuterated derivatives disclosed herein have an isotope enrichment factor of at least 3500 (incorporating 52.5% deuterium at each designated deuterium), at least 4500 (incorporating 67.5% deuterium at each designated deuterium), at least 5000 (incorporating 75% deuterium at each designated deuterium), at least 5500 (incorporating 82.5% deuterium at each designated deuterium), at least 6000 (incorporating 90% deuterium at each designated deuterium), at least 6333.3 (incorporating 95% deuterium at each designated deuterium), at least 6466.7 (incorporating 97% deuterium at each designated deuterium), or at least 6600 (incorporating 99% deuterium at each designated deuterium) for each deuterium atom. As used herein, the term “isotope enrichment factor” refers to the ratio of the isotope abundance to the natural abundance of the designated isotope.

[0102] In addition to the above, as used in the specification and claims, unless otherwise indicated, the following terms have the meanings set forth below:

[0103] “Amino” refers to the —NH2 group.

[0104] “Cyano” refers to the —CN group.

[0105] “Hydroxy” refers to the —OH group

[0106] “Nitro” refers to the —NO2 group.

[0107] “Carboxy” refers to the —COOH group.

[0108] “Nitroso” refers to the —N═O group.

[0109] As used herein, unless otherwise indicated, the term “halogen” refers to fluorine, chlorine, bromine, or iodine. Preferred halogen groups include —F, —Cl, and —Br.

[0110] Unless otherwise indicated, the term “alkyl” as used herein includes saturated monovalent hydrocarbon groups having straight or branched chains. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl. Similarly, as in C 1-6 C in alkyl1-6 is defined as recognizing the group as having 1, 2, 3, 4, 5 or 6 carbon atoms in a straight-chain or branched-chain arrangement.

[0111] The term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon group containing one or more (e.g., 1, 2, 3, 4, 5 or 6) double bonds and typically having a length of 2 to 20 carbon atoms. For example, "C 2-6 alkenyl" contains 2 to 6 carbon atoms. Alkenyls include, but are not limited to, for example, vinyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl, octenyl, etc.

[0112] The term "alkynyl" includes straight-chain or branched-chain hydrocarbon groups that contain one or more (e.g., 1, 2, 3, 4, 5 or 6) triple bonds and typically have a length of 2 to 20 carbon atoms. For example, "C 2-6 alkynyl" contains 2 to 6 carbon atoms. Representative alkynyls include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, etc.

[0113] The term "alkoxy" is an oxygen ether formed from the aforementioned alkyl group.

[0114] The term "oxo" refers to the group =O or (O), or an oxygen atom attached to another atom (e.g., C, N, S or P) by a double bond.

[0115] "Cycloalkyl" refers to a completely saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic and bicyclic. Typically, unless otherwise defined, a monocyclic cycloalkyl has from about 3 to about 12 carbon atoms, more typically 3 to 8 carbon atoms. Exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Cycloalkyl includes bicyclic molecules in which one, two, three or more atoms are shared between the two rings. The term "spirocycloalkyl" refers to a bicyclic cycloalkyl in which each ring shares an adjacent atom with the other ring. The term "fused cycloalkyl" refers to a bicyclic cycloalkyl in which each ring shares two adjacent atoms with the other ring. The term "bridged cycloalkyl" refers to a cycloalkyl containing 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 "polycyclic bridged cycloalkyl" containing more than two bridgehead carbon atoms. Typical bridged cycloalkyls include, but are not limited to, adamantyl, noradamantyl, bicyclo[1.1.0]butyl, norbornyl (bicyclo[2.2.1]heptyl), norbornenyl (bicyclo[2.2.1]heptenyl), norbornadienyl (bicyclo[2.2.l]heptadienyl), tricyclo[2.2.1.0]heptyl, bicyclo[3.2.1]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.1]octadienyl, bicyclo[2.2.2]octyl, bicyclo[2.2.2]octenyl, bicyclo[2.2.2]octadienyl, bicyclo[5,2,0]nonyl, bicyclo[4.3.2]undecyl, tricyclo[5.3.1.1]dodecyl, etc.

[0116] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group, each ring system containing 1 to 4 rings and 3 to 8 carbons. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. "Cycloalkenyl" includes monocyclic, bicyclic, tricyclic or tetracyclic ring systems in which one, two, three or more atoms are shared between the two rings. The term "spirocycloalkenyl" refers to a bicyclic cycloalkenyl in which each ring shares an 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 including 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 more than two bridgehead atoms.

[0117] The term "heterocycloalkyl" refers to a fully saturated, stable 3- to 18-membered non-aromatic cyclic group that contains 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from, for example, nitrogen, oxygen, phosphorus, and sulfur. Unless otherwise specifically stated in the specification, heterocycloalkyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. The term "spiroheterocycloalkyl" or "spiroheterocyclyl" 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 that contains 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 heterocycloalkyl are optionally oxidized. In some embodiments, heterocycloalkyl is attached to the remainder of the molecule through any atom in the ring. Examples of heterocycloalkyl include, but are not limited to, dioxolanyl, thieno[1,3]dithiolanyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidoneyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithiolanyl, tetrahydropyranyl, thiomorpholinyl, thioxomorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl.

[0118] The term "heterocycloenyl" refers to the above-described heterocycloalkyl having at least one double bond. Heterocycloenyl can be monocyclic or polycyclic, where polycyclic includes "spiroheterocycloenyl", "fused heterocycloenyl", and "bridged heterocycloenyl". "Spiroheterocycloenyl" refers to a polycyclic heterocycloenyl in which two rings share one atom, "fused heterocycloenyl" refers to a polycyclic heterocycloenyl in which two rings share two adjacent atoms, and "bridged heterocycloenyl" refers to a heterocycloenyl that contains at least two bridgehead atoms and at least one bridging atom. "Bridged heterocycloenyl" includes "bicyclic bridged heterocycloenyl" containing two bridgehead atoms and "polycyclic bridged heterocycloenyl" containing more than two bridgehead atoms.

[0119] As used herein, unless otherwise indicated, the term "aryl" refers to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing carbocyclic atoms. Preferred aryls are monocyclic or bicyclic aromatic ring systems. Phenyl and naphthyl are preferred aryls.

[0120] As used herein, unless otherwise specified, the term "heteroaryl" refers to an aromatic ring system containing carbon and at least one heteroatom. Heteroaryl can be monocyclic or polycyclic, substituted or unsubstituted. Monocyclic heteroaryl can have 1 to 4 heteroatoms in the ring, while polycyclic heteroaryl can contain 1 to 10 heteroatoms. Polycyclic heteroaryl rings can include fused, spiro or bridged ring linkages. For example, bicyclic heteroaryl is a polycyclic heteroaryl. Bicyclic heteroaryl rings can contain 8 to 12 ring atoms. Monocyclic heteroaryl rings can contain 5 to 8 ring atoms (carbon atoms and heteroatoms). Examples of heteroaryl include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuryl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adeninyl, quinolinyl or isoquinolinyl.

[0121] As used herein, the term "heterocyclic group" or "heterocycle" refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic 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, the heterocyclic group has about 3 to 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 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 (e.g., 3, 4, 5, 6 or 7-membered ring). When valence requirements permit, the rings of a polyfused ring (e.g., bicyclic heterocyclic group) system can be connected to each other by fused, spiro and bridged bonds. The term "heterocyclic group" or "heterocyclic ring" or "heterocycle" includes heterocyclenyl (i.e., a heterocyclic group having at least one double bond). The heterocyclic group can be a single ring or multiple rings, where the multiple rings can be fused, bridged or spiro-connected. As used herein, the heterocyclic group has 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclic group), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclic group), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclic group), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclic group), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclic group), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclic group) or 3 to 6 ring carbon atoms (i.e., C 3-6(heterocyclic group); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom, which are independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl and morpholinyl. As used herein, the term "bridged heterocyclic group" refers to a four- to ten-membered cyclic moiety having at least one heteroatom and connected to one or more (e.g., 1 or 2) four- to ten-membered cyclic moieties at two non-adjacent atoms of the heterocyclic group, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. As used herein, "bridged heterocyclic group" includes bicyclic and tricyclic ring systems. Also as used herein, the term "spiro heterocyclic group" refers to a ring system in which a three- to ten-membered heterocyclic group has one or more additional rings, wherein the one or more additional rings are three- to ten-membered cycloalkyl or three- to ten-membered heterocyclic groups, and a single atom of the one or more additional rings is also an atom of the three- to ten-membered heterocyclic group. Examples of spiro heterocyclic groups include bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl and 6-oxa-1-azaspiro[3.3]heptyl. The heterocyclic group also includes 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 including fully aromatic ring systems. Examples include dihydroquinoline (e.g., 3,4-dihydroquinoline), dihydroisoquinoline (e.g., 1,2-dihydroisoquinoline), dihydroimidazole, tetrahydroimidazole, indoline, isoindoline, isoindolinone (e.g., isoindolin-1-one), isatin, dihydrophthalazine, quinolinone, spiro[cyclopropane-1,1'-isoindoline]-3'-one, tetrahydroisoquinoline, tetrahydronaphthalene, etc. For example, additional examples of heterocycles include 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, 3,6-diazabicyclo[3.1.1]heptyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonyl and hexahydropyrazino[2,1-c][1,4]oxazinyl. As used herein, the terms "heterocycle", "heterocyclic group" and "heterocyclic ring" are used interchangeably.

[0122] Any hydrogen atom bonded to C, N, O or S in a 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heteroalkyl, 3- to 12-membered heteroalkenyl, 3- to 12-membered heterocyclic group, 6- to 10-membered aryl or 5- to 12-membered heteroaryl may be replaced by a substituent.

[0123] As used herein, the term "composition" is intended to cover a product containing a specified amount of a specified ingredient, as well as any product directly or indirectly resulting from the combination of the specified amounts of the specified ingredients. Thus, pharmaceutical compositions containing the compounds of the present invention as active ingredients, as well as methods for preparing the compounds of the present invention, are also part of the present invention. In addition, some crystalline forms of the compounds may exist as polymorphs and are themselves intended to be included in the present invention. Further, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be covered within the scope of the present invention.

[0124] When the compounds and their pharmaceutically acceptable salts exist in solvated or polymorphic forms, the present invention includes any possible solvates and polymorphic forms. The type of solvent forming the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable. For example, water, ethanol, propanol, acetone, etc. can be used.

[0125] In many cases, the compounds of the present disclosure are capable of forming acid addition salts and / or base addition salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0126] The term "pharmaceutically acceptable salts" of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and are not otherwise undesirable in a biological or other context. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, 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, bis(substituted alkyl)amines, tris(substituted alkyl)amines, alkenylamines, dialkenylamines, trialkenylamines, substituted alkenylamines, bis(substituted alkenyl)amines, tris(substituted alkenyl)amines, mono-, di- or tricyclic alkylamines, mono-, di- or triarylamines, or mixed amines, etc. By way of example only, specific examples of suitable amines include isopropylamine, trimethylamine, diethylamine, tris(isopropyl)amine, tris(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. Pharmaceutically acceptable acid addition salts can be prepared from inorganic acids and organic acids. Salts derived from inorganic acids include salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. 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, etc. Since the compounds are for pharmaceutical use, they are preferably provided in substantially pure form, for example, at least 60% purity, more suitably at least 75% purity, particularly at least 98% purity (% by weight).

[0127] The term "prodrug" refers to a biologically inactive derivative of a drug that is converted into the biologically active parent drug in the human body according to a chemical or enzymatic pathway after administration.

[0128] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. It is contemplated for use in therapeutic compositions unless any conventional media or agent is incompatible with the active ingredient. Supplementary active ingredients can also be incorporated into the compositions.

[0129] The pharmaceutical compositions of the present invention comprise a compound (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. The compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although in any given case the most suitable route will depend on the particular host and the nature and severity of the condition for which the active ingredient is being administered. The pharmaceutical compositions may conveniently be presented in unit dosage form and prepared by any methods well known in the pharmaceutical art.

[0130] In practice, the compounds or prodrugs or metabolites or pharmaceutically acceptable salts thereof of the present invention can be combined as an active ingredient with a pharmaceutical carrier to form a tight admixture according to conventional pharmaceutical compounding techniques. The carrier can take a variety of forms, depending on the form of preparation required for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions 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. In addition, the compositions can be presented in the form of powders, granules, solutions, suspensions in aqueous liquids, non-aqueous liquids, water-in-oil emulsions, or oil-in-water liquid emulsions. In addition to the above common dosage forms, the compounds or pharmaceutically acceptable salts thereof can also be administered by controlled release means and / or delivery devices. The compositions can be prepared by any pharmaceutical method. Generally, such methods include the step of bringing the active ingredient into association with a carrier which constitutes one or more (e.g., 1, 2, 3, 4, 5, or 6) necessary ingredients. Usually, the compositions are prepared by uniformly and intimately admixing the active ingredient with a liquid carrier or a finely divided solid carrier or both. The product can then be conveniently shaped into the desired appearance.

[0131] Accordingly, the pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier and the above compound or its pharmaceutically acceptable salt. The compound or its pharmaceutically acceptable salt may also be included in the pharmaceutical composition in combination with one or more (e.g., 1, 2, 3, 4, 5 or 6) other therapeutically active compounds.

[0132] Tablets containing the composition of the present invention may be prepared by compression or molding, optionally with one or more (e.g., 1, 2, 3, 4, 5 or 6) accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules (optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersing agent). Molded tablets may be made 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 preparation intended for oral administration to humans may contain from about 0.5 mg to about 5 g of the active agent, formulated with a suitable and convenient amount of a carrier material, the amount of which may be from about 0.05% to about 95% of the total composition. Unit dosage forms will generally contain from about 0.01 mg to about 2 g of the active ingredient, typically 0.01 mg, 0.02 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

[0133] The pharmaceutical composition of the present invention suitable for parenteral administration may be prepared as a solution or suspension of the active compound in water. Suitable surfactants may be included, such as, for example, hydroxypropylcellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. In addition, preservatives may be included to prevent the detrimental growth of microorganisms.

[0134] The pharmaceutical composition of the present invention suitable for injectable use comprises a sterile aqueous solution or dispersion. In addition, the composition may be in the form of a sterile powder for the extemporaneous preparation of such a sterile injectable solution or dispersion. In all cases, the final injectable form must be sterile and must be effectively fluid to facilitate injection. The pharmaceutical composition must be stable under the conditions of production and storage; thus, it is preferably preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium, including, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils and suitable mixtures thereof.

[0135] The pharmaceutical composition of the present invention can be in a form suitable for topical use, such as, for example, aerosols, creams, ointments, lotions, dusting powders, etc. In addition, the composition can be in a form suitable for use in a transdermal device. These formulations can be prepared by conventional processing methods using the compounds of the present invention or their pharmaceutically acceptable salts. For example, creams or ointments are prepared by admixing a hydrophilic material and water with about 0.05 wt% to about 10 wt% of the compound to produce a cream or ointment having the desired consistency.

[0136] The pharmaceutical composition of the present invention can be in a form suitable for rectal administration, wherein the carrier is solid. Preferably, the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently formed by first mixing the composition with the softened or melted carrier and then cooling and shaping in a mold.

[0137] In addition to the above carrier components, the above pharmaceutical formulations can, where appropriate, include one or more (e.g., 1, 2, 3, 4, 5 or 6) additional carrier components, such as diluents, buffers, flavoring agents, binders, surfactants, thickening agents, lubricants, preservatives (including antioxidants), etc. In addition, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing the compound or its pharmaceutically acceptable salt can also be prepared in the form of powders or liquid concentrates.

[0138] Generally, a dosage level of about 0.001 mg / kg body weight to about 150 mg / kg body weight per day can be used to treat the above conditions, or alternatively, about 0.05 mg to about 7 g per patient per day. For example, inflammation, cancer, psoriasis, allergy / asthma, diseases and conditions of the immune system, diseases and conditions of the central nervous system (CNS) can be effectively treated by administering about 0.001 to 50 mg of the compound / kg body weight / day or about 0.05 mg to about 3.5 g of the compound per patient per day.

[0139] However, it should be understood that the specific dosage level for any particular patient will depend on a variety of factors, including age, body weight, general health, gender, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease being treated.

[0140] In some embodiments, a method of treating cancer is disclosed herein, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention. For example, the compounds of the invention can slow the proliferation of cancer cell lines or kill cancer cells. Non-limiting examples of cancers that can be treated by the compounds of the invention include: acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, bladder cancer, bone cancer, brain tumors (such as cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, visual pathway and hypothalamic glioma), breast cancer, central nervous system lymphoma, cerebellar astrocytoma, cervical cancer, colon cancer, gallbladder cancer, gastric cancer, head and neck cancer, heart 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 tumors, pancreatic cancer, pancreatic islet cell cancer, prostate cancer, rectal cancer, renal cell cancer, skin cancer, skin Merkel cell carcinoma, small intestine cancer, and laryngeal cancer. Example

[0141] Example 1

[0142] (4-((3-(7-(((Z)-3-Fluoro-1-methylpiperidin-4-yl)amino)-3-(perfluoroether)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (racemic) (1)

[0143] Reaction Scheme

[0144]

[0145] Experimental Details

[0146] Step 1: 2,2,2-Trifluoro-1-(7-nitrobenzo[b]thiophen-3-yl)ethan-1-one

[0147] Into a 500 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add 2,2,2-trifluoro-1-(7-nitrobenzo[b]thiophen-3-yl)ethan-1-ol (3.81 g, 13.76 mmol), Dess-Martin periodinane (11.82 g, 27.87 mmol), and DCM (80 mL). Stir the reaction mixture at room temperature for 3 h. Add the resulting solution to water (100 mL). Extract the resulting solution with DCM (2 × 100 mL). Combine the organic layers, wash with brine (100 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Load the residue onto a silica gel column and elute with EA:hexane (v:v = 3:1). Obtain 3.11 g (82.07% yield) of 2,2,2-trifluoro-1-(7-nitrobenzo[b]thiophen-3-yl)ethan-1-one as a yellow solid. LCMS: m / z = 276 [M+1] +

[0148] Step 2: 7-Nitro-3-(perfluoroethyl)benzo[b]thiophene.

[0149] Into a 100 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add 2,2,2-trifluoro-1-(7-nitrobenzo[b]thiophen-3-yl)ethan-1-one (560.00 mg, 1.83 mmol) and DCM (10 mL). Stir the mixture at 0 °C and add DAST (5.92 g, 36.77 mmol). Stir the mixture at room temperature for 13 h. Add the reaction mixture to an aqueous NaHCO3 solution (50 mL), and extract with EA (2 × 50 mL). Combine the organic layers, wash with brine (50 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Load the residue onto a silica gel column and elute with EA:hexane (v:v = 3:1). Obtain 311.00 mg (56.91% yield) of 7-nitro-3-(perfluoroethyl)benzo[b]thiophene as a yellow solid. LCMS: m / z = 298 [M+1] +

[0150] Step 3: 2-Iodo-7-nitro-3-(perfluoroethyl)benzo[b]thiophene.

[0151] Into a 50 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add 7-nitro-3-(perfluoroethyl)benzo[b]thiophene (306.00 mg, 1.02 mmol), NIS (589.00 mg, 2.61 mmol), AcOH (5 mL) and CF3SO3H (5 mL). Stir the reaction mixture at room temperature for 12 h. Add the reaction mixture to an aqueous Na2CO3 solution (50 mL) and extract with EA (2 × 50 mL). Combine the organic layers, wash with brine (50 mL), dry over anhydrous Na2SO4 and concentrate in vacuo. Load the residue onto a silica gel column and elute with EA:hexane (v:v = 3:1). Obtain 400.00 mg (yield 91.82%) of 2-iodo-7-nitro-3-(perfluoroethyl)benzo[b]thiophene as a yellow solid.

[0152] Step 4: 2-Iodo-3-(perfluoroethyl)benzo[b]thiophen-7-amine.

[0153] Into a 100 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add 2-iodo-7-nitro-3-(perfluoroethyl)benzo[b]thiophene (400.00 mg, 0.94 mmol), Fe (541.00 mg), NH4Cl (591.00 mg, 11.04 mmol), EtOH (20 ml) and H2O (5 ml). Stir the reaction mixture at 80 °C for 4 h. Filter the reaction mixture and wash the residue with EtOH (20 mL). Concentrate the filtrate in vacuo. Load the residue onto a silica gel column and elute with EA:hexane (v:v = 1:1). Obtain 370.00 mg (99.55% yield) of 2-iodo-3-(perfluoroethyl)benzo[b]thiophen-7-amine as a yellow solid. LCMS: m / z = 394 [M+1] +

[0154] Step 5: (Z)-tert-Butyl 3-fluoro-4-((2-iodo-3-(perfluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (racemic).

[0155] Into a 100 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, add 2-iodo-3-(perfluoroethyl)benzo[b]thiophen-7-amine (364.00 mg, 0.92 mmol), tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (980.00 mg, 4.51 mmol), dibutyldichlorotin (345.00 mg, 1.13 mmol), and THF (10 mL). Stir the reaction mixture at 50 °C for 1 h, then add phenylsilane (987.00 mg, 9.12 mmol). Continue stirring at 80 °C for 12 h. Then concentrate the reaction mixture in vacuo. Load the residue onto a silica gel column and elute with EA:hexane (v:v = 1:5). Obtain 450.00 mg (yield 81.76%) of (Z)-tert-butyl 3-fluoro-4-((2-iodo-3-(perfluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (racemic) as a yellow solid. LCMS: m / z = 595 [M+1] +

[0156] Step 6: (Z)-3-Fluoro-N-(2-iodo-3-(perfluoroethyl)benzo[b]thiophen-7-yl)piperidin-4-amine (racemic).

[0157] Into a 100 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, add (Z)-tert-butyl 3-fluoro-4-((2-iodo-3-(perfluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (racemic) (450.00 mg, 0.75 mmol), TFA (1 mL), and DCM (10 mL). Stir the reaction mixture at room temperature for 2 h. Add the reaction mixture to Na2CO3 (aqueous solution) (20 mL). Extract the mixture with DCM (2 × 50 mL). Combine the organic layers, wash with brine (50 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Load the residue onto a C 18 column and elute with ACN / H2O (0.01% TFA) (v:v = 1:1) at a flow rate of 80 mL / min. Obtain 350.00 mg (93.53% yield) of (Z)-3-fluoro-N-(2-iodo-3-(perfluoroethyl)benzo[b]thiophen-7-yl)piperidin-4-amine (racemic) as a yellow solid. LCMS: m / z = 495 [M+1] +

[0158] Step 7: (Z)-3-Fluoro-N-(2-iodo-3-(perfluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (racemic).

[0159] Into a 100 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add (Z)-3-fluoro-N-(2-iodo-3-(perfluoroethyl)benzo[b]thiophen-7-yl)piperidin-4-amine (racemic) (350.00 mg, 0.71 mmol), formaldehyde (30% aqueous solution, 59.00 mg, 0.59 mmol), AcOH (0.5 mL), and MeOH (10 mL). Stir the reaction mixture at room temperature for 1 h, then add sodium cyanoborohydride (100.00 mg, 1.61 mmol). Then concentrate the reaction mixture in vacuo. Load the residue onto a C 18 column and elute with ACN / H2O (0.01% TFA) (v:v = 1:1) at a flow rate of 100 mL / min. Obtain 340.00 mg (yield 94.46%) of (Z)-3-fluoro-N-(2-iodo-3-(perfluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (racemic) as a yellow solid. LCMS: m / z = 509 [M+1] +

[0160] Step 8: (4-((3-(7-(((Z)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(perfluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (racemic) (1).

[0161] Into a 50 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add (Z)-3-fluoro-N-(2-iodo-3-(perfluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (racemic) (111.00 mg, 0.21 mmol), (3-methoxy-4-(prop-2-yn-1-amino)phenyl)dimethylphosphine oxide (71.00 mg, 0.300 mmol), Pd(PPh3)2Cl2 (34.00 mg, 0.048 mol), CuI (74.00 mg, 0.39 mol), DIEA (187.00 mg, 1.45 mol), and DMSO (5 mL). Stir the reaction mixture at 50 °C for 3 h. Load the residue onto a C 18On the column, elute with ACN / H2O (0.01% TFA) (v:v = 1:1), flow rate: 80 mL / min. Concentrate the eluate in vacuo. Purify the resulting crude product by preparative HPLC (mobile phase ACN / H2O (0.1% ammonium hydroxide; flow rate: 70 mL / min; gradient: 30 - 70 - 95% B (2 - 30 - 33 min); 245 nm; RT: 37.76 - 39.52) to afford the desired product. Obtained 41.00 mg (yield 30.40%) of (4 - ((3 - (7 - (((Z) - 3 - fluoro - 1 - methylpiperidin - 4 - yl)amino) - 3 - (perfluoroethyl)benzo[b]thiophen - 2 - yl)prop - 2 - ynyl)amino) - 3 - methoxyphenyl)dimethylphosphine oxide (racemic) (1), as a white solid. LCMS: m / z = 618 [M+1] +

[0162] 1 1H NMR (600 MHz, DMSO) δ 8.55 (s, 1H), 7.25–7.20 (m, 1H), 7.14 (d, J = 11.9 Hz, 2H), 6.83–6.82 (m, 1H), 6.75 (s, 1H), 5.96 (t, J = 6.1 Hz, 1H), 5.68 (d, J = 8.4 Hz, 1H), 4.79 (d, J = 49.5 Hz, 1H), 4.24 (d, J = 6.1 Hz, 2H), 3.86 (s, 3H), 3.79–3.70 (m, 1H), 3.04 (t, J = 10.9 Hz, 1H), 2.80 (d, J = 10.5 Hz, 1H), 2.32–2.24 (m, 1H), 2.20 (s, 3H), 2.14–2.10 (m, 1H), 2.04–1.96 (m, 1H), 1.77–1.66 (m, 1H), 1.58 (d, J = 13.2 Hz, 6H).

[0163] Example 2

[0164] (7 - ((3 - (7 - (((3S,4R) - 3 - fluoro - 1 - methylpiperidin - 4 - yl)amino) - 3 - (2,2,2 - trifluoroethyl)benzo[b]thiophen - 2 - yl)prop - 2 - ynyl)amino)benzofuran - 4 - yl)dimethylphosphine oxide (2)

[0165] Reaction Scheme

[0166]

[0167] Experimental Details

[0168] Step 1: 4 - iodobenzofuran - 7 - amine.

[0169] Into a 50 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add benzofuran-7-amine (1.03 g, 7.73 mmol), CaCO3 (1.50 g, 14.69 mmol), and MeOH (5 mL). Add ammonium benzyltrimethyliodate (530.00 mg, 1.52 mmol) to the reaction mixture in portions within 30 min at room temperature. Stir the mixture at 40 °C for 12 min. Add the resulting solution to water (100 mL) and extract with EA (2 × 100 mL). Combine the organic layers, wash with brine (100 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Load the residue onto a C 18 column and elute with ACN / H2O (0.01% TFA) (v:v = 1:1) at a flow rate of 100 mL / min. Obtain 804.00 mg (yield 40.16%) of 4-iodobenzofuran-7-amine as a brown oil. LCMS: m / z = 260 [M+1] +

[0170] Step 2: (7-Aminobenzofuran-4-yl)dimethylphosphine oxide.

[0171] Into a 50 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add 4-iodobenzofuran-7-amine (738.00 mg, 2.85 mmol), palladium acetate (84.00 mg, 0.37 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (313.00 mg, 0.54 mmol), DIEA (706.00 mg, 5.46 mmol), and DMF (10 mL). Stir the mixture at 80 °C for 5 min. Then add dimethylphosphine oxide (528.00 mg, 6.76 mmol). Stir the mixture at 80 °C for 0.5 h. Filter the reaction mixture. Load the residue onto a C 18 column and elute with ACN / H2O (0.01% TFA) (v:v = 1:1) at a flow rate of 80 mL / min. Obtain 500.00 mg (yield 83.90%) of (7-aminobenzofuran-4-yl)dimethylphosphine oxide as a yellow oil. LCMS: m / z = 210 [M+1] +

[0172] Step 3: Dimethyl(7-(prop-2-yn-1-ylamino)benzofuran-4-yl)phosphine oxide.

[0173] Into a 50 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add (7-aminobenzofuran-4-yl)dimethylphosphine oxide (500.00 mg, 2.39 mmol), 3-bromopropyne (1.12 g, 9.43 mmol), DIEA (1.23 g, 9.56 mmol), and NMP (10 mL). Stir the reaction mixture at 50 °C for 12 h. Then concentrate the reaction mixture in vacuo. Load the residue onto a C 18 column and elute with ACN / H2O (0.01% TFA) (v:v = 1:1) at a flow rate of 80 mL / min. Obtain 300.00 mg (yield 50.76%) of dimethyl(7-(prop-2-yn-1-ylamino)benzofuran-4-yl)phosphine oxide as a brown solid. LCMS: m / z = 248 [M+1] +

[0174] Step 4: (7-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzofuran-4-yl)dimethylphosphine oxide (2).

[0175] Into a 50 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add (3S,4R)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (114.00 mg, 0.24 mmol), dimethyl(7-(prop-2-yn-1-ylamino)benzofuran-4-yl)phosphine oxide (130.00 mg, 0.852 mmol), Pd(PPh3)2Cl2 (29.00 mg, 0.041 mmol), CuI (42.00 mg, 0.22 mmol), DIEA (120.00 mg, 0.93 mmol), and DMSO (6 mL). Stir the reaction mixture at 50 °C for 3 h. Load the residue onto a C 18On the column, elute with ACN / H2O (0.01% TFA) (v:v = 1:1), flow rate: 80 ml / min. Concentrate the eluate in vacuo. Purify the resulting crude product by preparative HPLC with ACN / H2O (0.1% ammonium hydroxide) further, flow rate: 70 ml / min; gradient: 35 - 68 - 71% B (2 - 30 - 33 min); 268 nm; RT: 30.35 - 32.77. Obtain 70.00 mg (40.01% yield) of (7 - ((3 - (7 - (((3S,4R) - 3 - fluoro - 1 - methylpiperidin - 4 - yl)amino) - 3 - (2,2,2 - trifluoroethyl)benzo[b]thiophen - 2 - yl)prop - 2 - yn - 1 - yl)amino)benzofuran - 4 - yl)dimethylphosphine oxide (2), as a yellow solid. LCMS: m / z = 592 [M+1] +

[0176] 1 H NMR (400 MHz, DMSO - d6) δ 8.06 (s, 1H), 7.47–7.42 (m, 1H), 7.31–7.23 (m, 2H), 7.20 (d, J = 7.9 Hz, 1H), 6.89 (t, J = 6.1 Hz, 1H), 6.81–6.76 (m, 2H), 5.13 (d, J = 8.4 Hz, 1H), 4.79 (d, J = 49.4 Hz, 1H), 4.46 (d, J = 6.1 Hz, 2H), 3.82–3.74 (m, 2H), 3.64 (d, J = 28.3 Hz, 1H), 3.05–2.99 (m, 1H), 2.79 (d, J = 11.2 Hz, 1H), 2.30–2.13 (m, 4H), 2.10–2.04 (m, 1H), 1.98–1.89 (m, 1H), 1.72–1.64 (m, 7H).

[0177] Example 3

[0178] (4 - ((3 - (7 - (((3S,4R) - 3 - fluoro - 1 - methylpiperidin - 4 - yl)amino) - 3 - (2,2,2 - trifluoroethyl)benzo[b]thiophen - 2 - yl)prop - 2 - yn - 1 - yl)amino) - 3 - (1H - pyrazol - 3 - yl)phenyl)dimethylphosphine oxide (3)

[0179] Reaction Scheme

[0180]

[0181] Experimental Details

[0182] Step 1: 4 - Bromo - 2 - (1 - (tetrahydro - 2H - pyran - 2 - yl) - 1H - pyrazol - 5 - yl)aniline.

[0183] Into a 500 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add 4-bromo-2-iodoaniline (10.05 g, 33.73 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11.04 g, 39.69 mmol), Pd(dppf)Cl2 (3.03 g, 4.14 mmol), Na2CO3 (15.64 g, 147.56 mmol), 1,4-dioxane (150 mL) and H2O (30 mL). Stir the reaction mixture at 100 °C for 1.5 h. Add the resulting solution to water (300 ml). Extract the resulting solution with EA (2 × 300 ml). Combine the organic layers, wash with brine (100 ml), dry over anhydrous Na2SO4 and concentrate in vacuo. Purify the resulting crude product by silica gel column chromatography, eluting with EA:hexane (v:v = 3:1). Obtain 6.00 g (55.20% yield) of 4-bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)aniline as a brown oil. LCMS: m / z = 322 [M+1] +

[0184] Step 2: (4-Amino-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)phenyl)dimethylphosphine oxide.

[0185] Into a 250 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add 4-bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)aniline (6.11 g, 18.96 mmol), palladium acetate (1.00 mg, 4.47 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.27 g, 5.65 mmol), DIEA (12.32 g, 95.31 mmol), DMF (100 mL). Stir the mixture at 110 °C for 5 min. Then add dimethylphosphine oxide (10.34 g, 132.49 mmol). Stir the mixture at 110 °C for 3 h. Filter the reaction mixture. Load the residue onto a C 18 column and elute with ACN / H2O (0.01% TFA) (v:v = 1:1) at a flow rate of 100 ml / min. Obtain 3.5 g (57.78% yield) of (4-amino-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)phenyl)dimethylphosphine oxide as a yellow solid. LCMS: m / z = 320 [M+1] +

[0186] Step 3: (4-Amino-3-(1H-pyrazol-5-yl)phenyl)dimethylphosphine oxide.

[0187] Into a 500 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add (4-amino-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)phenyl)dimethylphosphine oxide (3.025 g, 9.47 mmol), MeOH (30 mL), and HCl(aq) (12 M, 60 mL). Stir the reaction mixture at room temperature for 12 h. Concentrate the resulting solution in vacuo. Obtain 2.50 g (97.14% yield) of (4-amino-3-(1H-pyrazol-5-yl)phenyl)dimethylphosphine oxide as a yellow solid. LCMS: m / z = 236 [M+1] +

[0188] Step 4: Dimethyl(4-(prop-2-yn-1-ylamino)-3-(1H-pyrazol-5-yl)phenyl)phosphine oxide.

[0189] Into a 250 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add (4-amino-3-(1H-pyrazol-5-yl)phenyl)dimethylphosphine oxide (1.00 g, 4.26 mmol), 3-bromopropyne (1.05 g, 8.81 mmol), DIEA (3.75 g, 29.03 mmol), and MeCN (20 mL). Stir the reaction mixture at 80 °C for 4 h. Then concentrate the reaction mixture in vacuo. Load the residue onto a C 18 column and elute with ACN / H2O (0.01% TFA) (v:v = 1:1) at a flow rate of 100 ml / min. Obtain 300.00 mg (25.74% yield) of dimethyl(4-(prop-2-yn-1-ylamino)-3-(1H-pyrazol-5-yl)phenyl)phosphine oxide as a brown solid. LCMS: m / z = 274 [M+1] +

[0190] Step 5: (4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-(1H-pyrazol-3-yl)phenyl)dimethylphosphine oxide (3).

[0191] Into a 50 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, add (3S,4R)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (228.00 mg, 0.48 mmol), dimethyl(4-(prop-2-yn-1-ylamino)-3-(1H-pyrazol-5-yl)phenyl)phosphine oxide (303.00 mg, 1.10 mmol), Pd(PPh3)2Cl2 (70.00 mg, 0.099 mmol), CuI (133.00 mg, 0.70 mmol), DIEA (457.00 mg, 3.53 mmol), DMSO (8 mL). Stir the reaction mixture at 50 °C for 3 h. Load the residue onto a 18 C column and elute with ACN / H2O (0.01% TFA) (v:v = 1:1), flow rate: 80 ml / min. Concentrate the eluate in vacuo. Further purify the resulting crude product by preparative HPLC with ACN / H2O (0.1% ammonium hydroxide), flow rate: 70 ml / min; gradient: 35 - 67 - 67% B (2 - 30 - 33 min); 268 nm; RT: 29.55 - 31.48. Obtain 74.00 mg (24.81% yield) of (4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-(1H-pyrazol-3-yl)phenyl)dimethylphosphine oxide (3) as a yellow solid. LCMS: m / z = 618 [M+1] +

[0192] 1 1H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 8.53–8.45 (m, 1H), 7.93 (d, J = 11.9 Hz, 2H), 7.89 (s, 1H), 7.59–7.50 (m, 1H), 7.30–7.20 (m, 2H), 7.07–7.02 (m, 1H), 6.87 (s, 1H), 6.78 (d, J = 7.6 Hz, 1H), 5.15 (d, J = 8.5 Hz, 1H), 4.79 (d, J = 49.8 Hz, 1H), 4.57 (d, J = 5.9 Hz, 2H), 3.90–3.80 (m, 2H), 3.65 (d, J = 29.5 Hz, 1H), 3.08–2.98 (m, 1H), 2.79 (d, J = 11.5 Hz, 1H), 2.33–2.15 (m, 4H), 2.12–2.04 (m, 1H), 2.00–1.90 (m, 1H), 1.62 (d, J = 13.2 Hz, 6H).

[0193] Example 4

[0194] (3-Methoxy-4-((3-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)thieno[2,3-c]pyridin-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide (4)

[0195] Reaction Scheme

[0196]

[0197] Experimental Details

[0198] Step 1: 3-Methylthieno[2,3-c]pyridine.

[0199] To a 500 mL three-necked flask purged and maintained under an inert nitrogen atmosphere, 3-bromothieno[2,3-c]pyridine (5.00 g, 23.35 mmol), trimethylcyclotriboroxane (26.00 g, 103.55 mmol), Pd2(dba)3 (2.31 g, 2.52 mmol), S-phos (1.25 g, 3.04 mmol), 1,4-dioxane (200 ml), and K2CO3 (40 mL) (2.0 M in H2O) were added. The reaction mixture was stirred at 100 °C for 1.5 h. The resulting solution was added to water (300 mL). The resulting solution was extracted with EA (2 × 300 ml). The organic layers were combined, washed with brine (100 ml), dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography, eluting with EA:hexane (v:v = 3:1). 2.7 g (yield 77.47%) of 3-methylthieno[2,3-c]pyridine as a yellow oil was obtained. LCMS: m / z = 150 [M+1] +

[0200] Step 2: 3-Methylthieno[2,3-c]pyridin-6-oxide.

[0201] Into a 250 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add 3-methylthieno[2,3-c]pyridine (2.70 g, 18.14 mmol) and DCM (100 mL). Stir the mixture at room temperature and add m-CPBA (8.25 g, 47.84 mmol) in portions within 30 min. Stir the mixture at room temperature for 12 h. Add the resulting solution to water (100 ml). Extract the resulting solution with DCM (3 × 100 mL). Combine the organic layers, wash with brine (100 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Obtain 3.0 g (yield 100.05%) of 3-methylthieno[2,3-c]pyridine-6-oxide as a yellow solid. LCMS: m / z = 166 [M+1] +

[0202] Step 3: 7-Chloro-3-methylthieno[2,3-c]pyridine.

[0203] Into a 250 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add 3-methylthieno[2,3-c]pyridine-6-oxide (3.00 g, 18.15 mmol), MeCN (20 mL), and POCl3 (30 mL). Stir the reaction mixture at 90 °C for 12 h. Concentrate the resulting solution in vacuo. Add the resulting solution to water (100 mL). Extract the resulting solution with DCM (3 × 100 mL). Combine the organic layers, wash with brine (100 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Purify the resulting crude product by silica gel column chromatography, eluting with EA:hexane (v:v = 3:1). Obtain 1.47 g (44.34% yield) of 7-chloro-3-methylthieno[2,3-c]pyridine as a yellow solid. LCMS: m / z = 184 [M+1] +

[0204] Step 4: 3-(Bromomethyl)-7-chlorothieno[2,3-c]pyridine.

[0205] Into a 250 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add 7-chloro-3-methylthieno[2,3-c]pyridine (1.32 g, 7.20 mmol), NBS (2.06 g, 11.60 mmol), AIBN (550.00 mg, 3.35 mmol), and EA (20 mL). Stir the reaction mixture at 80 °C for 6 h. Add the resulting solution to water (100 mL). Extract the resulting solution with EA (3 × 100 mL). Combine the organic layers, wash with brine (100 ml), dry over anhydrous Na2SO4, and concentrate in vacuo. Purify the resulting crude product by silica gel column chromatography, eluting with EA:hexane (v:v = 3:1). Obtain 1.80 g (95.17% yield) of 3-(bromomethyl)-7-chlorothieno[2,3-c]pyridine as a yellow solid. LCMS: m / z = 262 [M+1] +

[0206] Step 5: 7-Chloro-3-(2,2,2-trifluoroethyl)thieno[2,3-c]pyridine.

[0207] Into a 100 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add 3-(bromomethyl)-7-chlorothieno[2,3-c]pyridine (1.82 g, 6.96 mmol), diphenyl-(trifluoromethyl)-sulfonium triflate (5.05 g, 12.49 mmol), Cu (1.02 g, 16.09 mmol), and NMP (20 mL). Stir the reaction mixture at 60 °C for 4 h. Cool the resulting solution to room temperature and quench with H2O (100 mL). Filter the resulting solution through a pad of diatomaceous earth, and extract the filtrate with EA (2 × 100 mL). Combine the organic layers, wash with brine (50 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Purify the resulting crude product by silica gel column chromatography, eluting with EA:hexane (v:v = 1:10). Obtain 800.00 mg (82.63% yield) of 7-chloro-3-(2,2,2-trifluoroethyl)thieno[2,3-c]pyridine as a yellow oil. LCMS: m / z = 252 [M+1] +

[0208] Step 6: 7-Chloro-2-iodo-3-(2,2,2-trifluoroethyl)thieno[2,3-c]pyridine.

[0209] Into a 100 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add 7-chloro-3-(2,2,2-trifluoroethyl)thieno[2,3-c]pyridine (1.26 g, 5.01 mmol) and tetrahydrofuran (20 mL). Then add LDA (5.00 mL, 10.00 mmol) at -70 °C. Stir the reaction mixture at -70 °C for 0.5 h. Then add iodine (2.32 g, 9.13 mmol) (in 5 mL THF). Stir the reaction mixture at -70 °C for another 1 h. Quench the reaction with an aqueous solution of NH4Cl (100 mL). Extract with EA (3 × 100 mL). Combine the organic layers, wash with brine (50 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Purify the resulting crude product by silica gel column chromatography, eluting with EA:hexane (v:v = 1:10). Obtain 411.00 mg (21.70% yield) of 7-chloro-2-iodo-3-(2,2,2-trifluoroethyl)thieno[2,3-c]pyridine as a yellow oil. LCMS: m / z = 378 [M+1] +

[0210] Step 7: 2-Iodo-N-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)thieno[2,3-c]pyridin-7-amine.

[0211] Into a 50 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add 7-chloro-2-iodo-3-(2,2,2-trifluoroethyl)thieno[2,3-c]pyridine (409 mg, 1.08 mmol), NMP (20 mL), and 1-methylpiperidin-4-amine (4.36 g, 38.18 mmol). Stir the reaction mixture at 110 °C for 12 h, then cool to room temperature. Add the resulting solution to water (50 mL). Extract the resulting solution with EA (3 × 50 mL). Combine the organic layers, wash with brine (30 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Load the residue onto a C 18 column, eluting with ACN / H2O (0.01% TFA) (v:v = 1:1) at a flow rate of 80 mL / min. Concentrate the eluate in vacuo. Obtain 50 mg (yield 10.13%) of 2-iodo-N-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)thieno[2,3-c]pyridin-7-amine as a brown solid. LCMS: m / z = 456 [M+1] +

[0212] Step 8: (3-Methoxy-4-((3-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)thieno[2,3-c]pyridin-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide (4).

[0213] Into a 50 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, add 2-iodo-N-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)thieno[2,3-c]pyridin-7-amine (50.00 mg, 0.11 mmol), (3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide (111.00 mg, 0.46 mmol), Pd(PPh3)2Cl2 (23.00 mg, 0.032 mmol), CuI (23.00 mg, 0.12 mmol), DIEA (47.00 mg, 0.36 mmol), DMSO (5 mL). Stir the reaction mixture at 50 °C for 3 h. Load the residue onto a C 18 column and elute with ACN / H2O (0.01% TFA) (v:v = 1:1) at a flow rate of 80 mL / min. Concentrate the eluate in vacuo. Further purify the obtained crude product by preparative HPLC using MeOH / H2O (0.1% ammonium hydroxide) at a flow rate of 70 mL / min; gradient: 35 - 64 - 85% B (2 - 28 - 46 min); 260 nm; RT: 35.32 - 39.48. Obtain 24.00 mg (yield 38.70%) of (3-methoxy-4-((3-(7-((1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)thieno[2,3-c]pyridin-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide (4) as a yellow solid. LCMS: m / z = 564 [M+1] +

[0214] 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 5.7 Hz, 1H), 7.24–7.19 (m, 1H), 7.15 (d, J = 11.8 Hz, 1H), 7.00 (d, J = 5.7 Hz, 1H), 6.86–6.84 (m, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.09–6.06 (m, 1H), 4.35 (d, J = 6.3 Hz, 2H), 4.03–4.00 (m, 2H), 3.85 (s, 3H), 3.81–3.73 (m, 2H), 2.79 (d, J = 10.8 Hz, 2H), 2.18 (s, 3H), 2.03–1.85 (m, 5H), 1.67

[0215] –1.51 (m, 6H).

[0216] Example 5

[0217] 5-(4-((3-(7-(((3S,4R)-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)-1,2,5-thiadiazolidin-3-one-1,1-dioxide (5)

[0218] Reaction Scheme

[0219]

[0220] Experimental Details

[0221] Step 1: 2-Methoxy-4-nitro-N-(prop-2-yn-1-yl)aniline.

[0222] Into a 250 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, 2-methoxy-4-nitroaniline (6.94 g, 41.27 mmol), 3-bromopropyne (10.61 g, 89.18 mmol), DIEA (16.60 g, 128.44 mmol), and DMF (50 mL) were added. The reaction mixture was stirred at 90 °C for 12 h and then cooled to room temperature. The resulting solution was added to water (100 mL). The resulting solution was extracted with EA (2 × 100 mL). The organic layers were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography, eluting with EA:hexane (v:v = 3:1). 6.00 g (yield 70.50%) of 2-methoxy-4-nitro-N-(prop-2-yn-1-yl)aniline as a yellow solid was obtained. LCMS: m / z = 207 [M+1] +

[0223] Step 2: tert-Butyl (2-methoxy-4-nitrophenyl)(prop-2-yn-1-yl)carbamate.

[0224] Into a 250 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add 2-methoxy-4-nitro-N-(prop-2-yn-1-yl)aniline (5.57 g, 27.01 mmol), (Boc)2O (20.65 g, 94.61 mmol), DMAP (1.45 g, 11.86 mmol), DIEA (14.55 g, 112.57 mmol), and DCM (200 mL). Stir the mixture at room temperature for 12 h. Add the resulting solution to water (200 mL). Extract the resulting solution with EA (2 × 200 mL). Combine the organic layers, wash with brine (100 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Purify the resulting crude product by silica gel column chromatography, eluting with EA:hexane (v:v = 3:1). Obtain 8.00 g (96.68% yield) of tert-butyl (2-methoxy-4-nitrophenyl)(prop-2-yn-1-yl)carbamate as a yellow oil. LCMS: m / z = 307 [M+1] +

[0225] Step 3: tert-Butyl (4-amino-2-methoxyphenyl)(prop-2-yn-1-yl)carbamate.

[0226] Into a 1000 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add tert-butyl (2-methoxy-4-nitrophenyl)(prop-2-yn-1-yl)carbamate (8.00 g, 26.11 mmol), Fe (20.11 g, 360.10 mmol), NH4Cl (24.82 g, 464.00 mmol), EtOH (300 mL), and H2O (60 mL). Stir the reaction mixture at 80 °C for 2 h. Filter the reaction mixture and wash the filter cake with EtOH (200 mL). Concentrate the filtrate in vacuo. Purify the resulting crude product by silica gel column chromatography, eluting with EA:hexane (v:v = 1:1). Obtain 6.00 g (83.13% yield) of tert-butyl (4-amino-2-methoxyphenyl)(prop-2-yn-1-yl)carbamate as a brown solid. LCMS: m / z = 277 [M+1] +

[0227] Step 4: Ethyl (4-((tert-butoxycarbonyl)(prop-2-yn-1-yl)amino)-3-methoxyphenyl)glycinate.

[0228] Into a 250 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, add tert-butyl (4-amino-2-methoxyphenyl)(prop-2-yn-1-yl)carbamate (2.03 g, 7.34 mmol), ethyl 2-bromoacetate (1.58 g, 9.50 mmol), DIEA (3.03 g, 23.48 mmol), and DMF (15 mL). Stir the reaction mixture at 80 °C for 4 h. Add the resulting solution to water (100 mL). Extract the resulting solution with EA (2 × 100 mL). Combine the organic layers, wash with brine (100 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Purify the resulting crude product by silica gel column chromatography, eluting with EA:hexane (v:v = 3:1). Obtain 2.62 g (98.35% yield) of ethyl (4-((tert-butoxycarbonyl)(prop-2-yn-1-yl)amino)-3-methoxyphenyl)glycinate as a brown solid. LCMS: m / z = 363 [M+1] +

[0229] Step 5: tert-butyl (chlorosulfonyl)carbamate.

[0230] Into a 100 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, add isocyanatochlorosulfate (2.11 g, 14.92 mmol), tBuOH (1.42 g, 19.19 mmol), and DCM (15 mL). Stir the reaction mixture at room temperature for 0.5 h. Use the resulting solution directly for the next step.

[0231] Step 6: Ethyl N-(4-((tert-butoxycarbonyl)(prop-2-yn-1-yl)amino)-3-methoxyphenyl)-N-(N-(tert-butoxycarbonyl)sulfamoyl)glycinate.

[0232] To a 250 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, add ethyl (4-((tert-butoxycarbonyl)(prop-2-yn-1-yl)amino)-3-methoxyphenyl)glycinate (2.04 g, 5.62 mmol) and DCM (30 mL). Stir the mixture at 0 °C and add a solution of tert-butyl (chlorosulfonyl)carbamate (3.21 g, 14.88 mmol) in DCM (20 mL). Stir the mixture at room temperature for 3 h. Add the resulting solution to water (100 mL). Extract the resulting solution with DCM (2 × 100 mL). Combine the organic layers, wash with brine (100 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Purify the resulting crude product by silica gel column chromatography, eluting with EA:hexane (v:v = 3:1). Obtain 3.0 g (98.40% yield) of ethyl N-(4-((tert-butoxycarbonyl)(prop-2-yn-1-yl)amino)-3-methoxyphenyl)-N-(N-(tert-butoxycarbonyl)sulfamoyl)glycinate as a yellow oil. LCMS: m / z = 542 [M+1] +

[0233] Step 7: Ethyl N-(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)-N-sulfamoylglycinate.

[0234] To a 100 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, add ethyl N-(4-((tert-butoxycarbonyl)(prop-2-yn-1-yl)amino)-3-methoxyphenyl)-N-(N-(tert-butoxycarbonyl)sulfamoyl)glycinate (2.88 g, 5.31 mmol), TFA (10 mL), and DCM (30 mL). Stir the reaction mixture at room temperature for 12 h. Concentrate the resulting solution in vacuo. Load the residue onto a C 18 column and elute with ACN / H2O (0.01% TFA) (v:v = 1:1) at a flow rate of 100 mL / min. Obtain 1.70 g (94.05% yield) of ethyl N-(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)-N-sulfamoylglycinate as a brown oil. LCMS: m / z = 342 [M+1] +

[0235] Step 8: 5-(3-Methoxy-4-(prop-2-yn-1-ylamino)phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.

[0236] Into a 100 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, add N-(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)-N-sulfamoylglycine ethyl ester (1.70 g, 4.99 mmol), EtOH (30 mL), NaOH (1.19 g, 29.90 mmol) and H2O (5 mL). Stir the reaction mixture at room temperature for 4 h. Add the resulting solution to water (100 mL). Extract the resulting solution with DCM (2 × 100 mL). Combine the organic layers, wash with brine (100 mL), dry over anhydrous Na2SO4 and concentrate in vacuo. Load the residue onto a C 18 column, elute with ACN / H2O (0.01% TFA) (v:v = 1:1), flow rate: 80 mL / min. Concentrate the eluate in vacuo. Obtain 1.00 g (yield 67.76%) of 5-(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide as a brown solid. LCMS: m / z = 296 [M+1] +

[0237] Step 9: 5-(4-((3-(7-(((3S,4R)-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)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (5).

[0238] Into a 50 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, add (3S,4R)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (102.00 mg, 0.21 mmol), 5-(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (199.00 mg, 0.67 mmol), Pd(PPh3)2Cl2 (56.00 mg, 0.079 mmol), CuI (46.00 mg, 0.24 mmol), DIEA (126.00 mg, 0.97 mmol), DMSO (5 mL). Stir the reaction mixture at 50 °C for 3 h. Treat the residue with C 18On the column, elute with ACN / H2O (0.01% TFA) (v:v = 1:1), flow rate: 80 mL / min. Concentrate the eluate in vacuo. Further purify the resulting crude product by preparative HPLC using ACN / H2O (0.1% ammonium hydroxide), flow rate: 70 mL / min; gradient: 30 - 70 - 90% B (2 - 30 - 35 min); 265 nm; RT: 29.50 - 31.48. Obtain 34.00 mg (yield 24.61%) of 5-(4-((3-(7-(((3S,4R)-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)-1,2,5-thiadiazolidin-3-one-1,1-dioxide (5), as a yellow solid. LCMS: m / z = 640 [M+1] +

[0239] 1 H NMR (600 MHz, DMSO-d6) δ 9.52 (s, 1H), 7.31–7.28 (m, 1H), 7.25 (d, J = 8.0 Hz, 1H), 6.82–6.78 (m, 2H), 6.70 (d, J = 8.5 Hz, 1H), 6.60–6.58 (m, 1H), 5.57 (s, 1H), 5.21–5.16 (m, 1H), 5.07 (d, J = 47.0 Hz, 1H), 4.25 (d, J = 5.3 Hz, 2H), 3.92 (s, 3H), 3.87–3.79 (m, 3H), 3.78 (s, 3H), 3.72–3.64 (m, 1H), 3.11–2.97 (m, 1H), 2.79–2.64 (m, 3H), 2.22–2.11 (m, 2H), 2.01–1.93 (m, 1H).

[0240] Example 6

[0241] (4-((3-(7-((1-imino-1-oxohexahydro-1λ 6 -thiopyran-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (6)

[0242] Reaction Scheme

[0243]

[0244] Experimental Details

[0245] Step 1: 4-((2-Iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)tetrahydro-2H-thiopyran-1-oxide.

[0246] Into a 100 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add 2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-amine (2.01 g, 5.64 mmol), tetrahydro-4H-thiopyran-4-one-1-oxide (1.74 g, 13.17 mmol), dibutyltin dichloride (514 mg, 1.69 mmol). Stir the reaction mixture at 60 °C for 1.5 h, then add phenylsilane (2.51 g, 23.20 mmol). Stir the reaction mixture at 60 °C for 12 h. Cool the resulting solution to room temperature and add it to water (300 mL). Extract the resulting solution with EA (2 × 300 mL). Combine the organic layers, wash with brine (100 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Purify the resulting crude product by silica gel column chromatography, eluting with MeOH:DCM (v:v = 20:1). Obtain 2.00 g (yield 74.85%) of 4-((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)tetrahydro-2H-thiopyran-1-oxide as a yellow solid. LCMS: m / z = 474 [M+1] +

[0247] Step 2: tert-Butyl (2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)(1-oxotetrahydro-2H-thiopyran-4-yl)carbamate.

[0248] Into a 100 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add 4-((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)tetrahydro-2H-thiopyran-1-oxide (605.00 mg, 1.27 mmol), (Boc)2O (6.44 g, 29.52 mmol), DMAP (662.00 mg, 5.41 mmol), pyridine (1.05 g, 13.27 mmol), THF (10 mL). Stir the mixture at 80 °C for 12 h. Cool the resulting solution to room temperature and add it to water (50 mL). Extract the resulting solution with EA (2 × 50 mL). Combine the organic layers, wash with brine (30 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Load the residue onto C 18On a column, elute with ACN / H2O (0.01% TFA) (v:v = 1:1), flow rate: 100 mL / min. 300 mg (40.92% yield) of tert-butyl (2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)(1-oxotetrahydro-2H-thiopyran-4-yl)carbamate was obtained as a brown solid. LCMS: m / z = 574 [M+1] +

[0249] Step 3: tert-Butyl (1-imino-1-oxohexahydro-1λ 6 -thiopyran-4-yl)(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)carbamate.

[0250] Into a 100 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, add tert-butyl (2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)(1-oxotetrahydro-2H-thiopyran-4-yl)carbamate (300 mg, 0.52 mmol), MeOH (10 mL), PhI(OAc)2 (1.20 g, 3.72 mmol) and ammonium acetate (560 mg, 7.26 mmol). Stir the reaction mixture at room temperature for 12 h. Load the residue onto a C 18 column, elute with ACN / H2O (0.01% TFA) (v:v = 1:1), flow rate: 100 mL / min. 250.00 mg (81.20% yield) of tert-butyl (1-imino-1-oxohexahydro-1λ 6 -thiopyran-4-yl)(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)carbamate was obtained as a brown solid. LCMS: m / z = 589 [M+1] +

[0251] Step 4: tert-Butyl (2-(3-((4-(dimethylphosphoryl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)(1-imino-1-oxohexahydro-1λ 6 -thiopyran-4-yl)carbamate.

[0252] Into an 8 mL reaction flask purged and maintained with a nitrogen inert atmosphere, add (1-imino-1-oxohexahydro-1λ 6(1-Imino-1-oxohexahydro-1λ6-thiopyran-4-yl)(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)carbamic acid tert-butyl ester (80.00 mg, 0.14 mmol), (3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide (79.00 mg, 0.33 mmol), Pd(PPh3)2Cl2 (33.00 mg, 0.046 mmol), CuI (39.00 mg, 0.20 mmol), DIEA (315.00 mg, 2.43 mmol), DMSO (3 mL). The reaction mixture was stirred at 50 °C for 3 h. The residue was loaded onto a 18 C column and eluted with ACN / H2O (0.01% TFA) (v:v = 1:1) at a flow rate of 60 mL / min. 70.00 mg (73.79% yield) of (2-(3-((4-(dimethylphosphoryl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)(1-iminio-1-oxohexahydro-1λ 6 6-thiopyran-4-yl)carbamic acid tert-butyl ester was obtained as a brown solid. LCMS: m / z = 698 [M+1] +

[0253] Step 5: (4-((3-(7-((1-Imino-1-oxohexahydro-1λ 6 6-thiopyran-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (6).

[0254] To a 25 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, (2-(3-((4-(dimethylphosphoryl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)(1-iminio-1-oxohexahydro-1λ 6 6-thiopyran-4-yl)carbamic acid tert-butyl ester (70.00 mg, 0.10 mmol), DCM (5 mL), and TFA (2 mL) were added. The reaction mixture was stirred at room temperature for 3 h. Then the reaction mixture was concentrated in vacuo. The resulting crude product was further purified by preparative HPLC with ACN / H2O (0.05% ammonium hydroxide) at a flow rate of 70 mL / min; gradient: 35 - 70 - 70% B (2 - 30 - 60 min); 266 nm; RT: 19.43 - 20.51. 47.00 mg (78.39% yield) of (4-((3-(7-((1-iminio-1-oxohexahydro-1λ 6((4-(Dimethylphosphoryl)-2-methoxyphenyl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (6), is a white solid. LCMS: m / z = 598 [M+1] +

[0255] 1 H NMR (400 MHz, DMSO-d6) δ 7.28 (t, J = 7.9 Hz, 1H), 7.25–7.12 (m, 3H), 6.86–6.84 (m, 1H), 6.73 (t, J = 7.7 Hz, 1H), 6.07 (t, J = 6.4 Hz, 1H), 5.60 (d, J = 8.1 Hz, 1H), 4.34 (d, J = 6.4 Hz, 2H), 3.86 (s, 3H), 3.81–3.76 (m, 3H), 3.66 (s, 1H), 3.18–3.10 (m, 2H), 3.07–3.05 (m, 2H), 2.18–2.08 (m, 2H), 2.09–1.97 (m, 2H), 1.59 (d, J = 13.2 Hz, 6H).

[0256] Examples 7 and 10

[0257] (1S,3S,4R)-4-((2-(3-((4-(Dimethylphosphoryl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-3-fluoro-1-methylpiperidine-1-oxide (10) and (1R,3S,4R)-4-((2-(3-((4-(Dimethylphosphoryl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-3-fluoro-1-methylpiperidine-1-oxide (7)

[0258] Reaction Scheme

[0259]

[0260] Experimental Details

[0261] Step 1: (1S,3S,4R)-4-((2-(3-((4-(Dimethylphosphoryl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-3-fluoro-1-methylpiperidine-1-oxide (10) and (1R,3S,4R)-4-((2-(3-((4-(Dimethylphosphoryl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-3-fluoro-1-methylpiperidine-1-oxide (7).

[0262] Into a 40 mL reaction flask purged and maintained with an inert nitrogen atmosphere, add (4-((3-(7-(((3S,4R)-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 (229 mg, 0.39 mmol), m-CPBA (167 mg, 0.97 mmol), DCM (10 mL). Stir the reaction mixture at 25 °C for 12 h. Add the resulting solution to saturated Na2CO3 (aqueous solution) (30 mL). Extract the resulting solution with DCM (2 × 50 mL). Combine the organic layers, wash with brine (30 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. The resulting crude product is further purified by preparative HPLC, eluting with ACN / H2O (0.05% ammonium hydroxide), flow rate: 70 mL / min; gradient: 35 - 50 - 50% B (2 - 24 - 31 min); 262 nm; RT: 25.87 - 28.61 and 28.68 - 30.81. The first group of fractions is dried by rotary evaporation to obtain 89 mg (yield 33.44%) of (1S,3S,4R)-4-((2-(3-((4-(Dimethylphosphoryl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-3-fluoro-1-methylpiperidine-1-oxide (10) as a white solid. LCMS: m / z = 598 [M+1] +

[0263] 11H NMR (400 MHz, DMSO-d6) δ 7.31–7.20 (m, 3H), 7.14 (d, J = 11.9, 1H), 6.95–6.75 (m, 2H), 6.08 (t, J = 6.4 Hz, 1H), 5.43 (d, J = 8.9 Hz, 1H), 4.88 (d, J = 49.3 Hz, 1H), 4.34 (d, J = 6.3 Hz, 2H), 3.99–3.68 (m, 7H), 3.65–3.54 (m, 2H), 3.20–3.12 (m, 1H), 3.05 (s, 3H), 2.80–2.67 (m, 1H), 1.78–1.67 (m, 1H), 1.61 (t, J = 18.6 Hz, 6H).

[0264] The second fraction was evaporated to dryness to obtain 26 mg (11.05% yield) of (1R,3S,4R)-4-((2-(3-((4-(dimethylphosphoryl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-3-fluoro-1-methylpiperidine-1-oxide (7) as a white solid. LCMS: m / z = 598 [M+1] +

[0265] 1 1H NMR (400 MHz, DMSO-d6) δ 7.36–7.18 (m, 3H), 7.16–7.13 (m, 1H), 6.93–6.79 (m, 2H), 6.09 (t, J = 6.3 Hz, 1H), 5.35 (d, J = 7.9 Hz, 1H), 5.15 (d, J = 47.1 Hz, 1H), 4.34 (d, J = 6.3 Hz, 2H), 4.23 (s, 1H), 3.94–3.71 (m, 6H), 3.62–3.48 (m, 2H), 3.21–3.09 (m, 4H), 2.20 (s, 1H), 2.03 (s, 1H), 1.59 (d, J = 13.2 Hz, 6H).

[0266] Examples 8 and 9

[0267] (1S,3S,4R)-3-Fluoro-4-((2-(3-((2-methoxy-4-((R)-S-methylsulfinimidoyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-1-methylpiperidine-1-oxide (8) and (1R,3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-((R)-S-methylsulfinimidoyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-1-methylpiperidine-1-oxide (9)

[0268] Reaction Scheme

[0269]

[0270] Experimental Details

[0271] Step 1: (1S,3S,4R)-3-Fluoro-4-((2-(3-((2-methoxy-4-((R)-S-methylsulfinimidoyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-1-methylpiperidine-1-oxide (8) and (1R,3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-((R)-S-methylsulfinimidoyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-1-methylpiperidine-1-oxide (9).

[0272] To a 40 mL reaction flask purged and maintained under an inert nitrogen atmosphere, add (R)-(4-((3-(7-(((3S,4R)-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)(imino)(methyl)-λ 6-Sulfoxide (259 mg, 0.44 mmol), m-CPBA (166 mg, 0.96 mmol), DCM (10 mL). The reaction mixture was stirred at 25 °C for 12 h. The resulting solution was added to saturated Na2CO3 (aqueous solution) (30 mL). The resulting solution was extracted with DCM (2 × 50 mL). The organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting crude product was further purified by preparative HPLC, eluting with ACN / H2O (0.05% ammonium hydroxide), flow rate: 70 mL / min; gradient: 35 - 55 - 55% B (2 - 19 - 25 min); 212 nm; RT: 17.80 - 19.95 and 20.39 - 22.11. The first fraction was dried by rotary evaporation to give 43 mg (yield 18.27%) of (1S,3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-((R)-S-methylsulfinimidoyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-1-methylpiperidin-1-oxide (8), as a white solid. LCMS: m / z = 599 [M+1] +

[0273] 1 1H NMR (400 MHz, DMSO-d6) δ 7.43–7.41 (m, 1H), 7.31–7.27 (m, 2H), 7.23 (d, J = 7.9 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 7.7 Hz, 1H), 6.37 (t, J = 6.3 Hz, 1H), 5.45 (d, J = 8.8 Hz, 1H), 4.89 (d, J = 48.9 Hz, 1H), 4.38 (d, J = 6.2 Hz, 2H), 3.88 (s, 3H), 3.84–3.78 (m, 2H), 3.74–3.51 (m, 5H), 3.20–3.16 (m, 1H), 3.07 (s, 3H), 2.99 (s, 3H), 2.78–2.69 (m, 1H), 1.79–1.64 (m, 1H). The second fraction was dried by rotary evaporation to give 42 mg (15.78% yield) of (1R,3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-((R)-S-methylsulfinimido)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-1-methylpiperidin-1-oxide (9), as a white solid. LC MS: m / z = 599 [M+1] +

[0274] 11H NMR (400 MHz, DMSO-d6) δ 7.44–7.41 (m, 1H), 7.36–7.20 (m, 3H), 6.86 (d, J = 8.3 Hz, 2H), 6.37 (t, J = 6.2 Hz, 1H), 5.36 (d, J = 7.9 Hz, 1H), 5.16 (d, J = 47.1 Hz, 1H), 4.38 (d, J = 6.2 Hz, 2H), 4.23 (s, 1H), 3.99–3.67 (m, 7H), 3.60–3.48 (m, 2H), 3.12 (s, 4H), 3.00 (s, 3H), 2.19 (s, 1H), 2.04 (s, 1H).

[0275] Example 11

[0276] 5-(Dimethylphosphoryl)-2-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzonitrile (11)

[0277] Reaction Scheme

[0278]

[0279] Experimental Details

[0280] Step 1: 2-Amino-5-(dimethylphosphoryl)-3-methoxybenzonitrile

[0281] To a 50 mL three-necked flask purged and maintained under an inert nitrogen atmosphere, 2-amino-5-bromo-3-methoxybenzonitrile (2.025 g, 8.92 mmol), Pd(OAc)2 (0.355 g, 1.58 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.813 g, 1.41 mmol), DIEA (3.435 g, 26.58 mmol), and DMF (20 mL) were added. The reaction mixture was heated to 130 °C. Then dimethylphosphine oxide (2.374 g, 30.42 mmol) was added and the mixture was stirred at the same temperature for 1.0 h. LCMS showed that the reaction was complete. The residue was filtered and purified by column chromatography on C 18 column, eluting with ACN / H2O (0.05% NH4HCO3) (v / v = 1 / 10). 1.70 g (85.02% yield) of 2-amino-5-(dimethylphosphoryl)-3-methoxybenzonitrile as a yellow oil was obtained. LCMS: m / z = 225 [M+1] + .

[0282] Step 2: tert-Butyl (2-cyano-4-(dimethylphosphoryl)-6-methoxyphenyl)carbamate

[0283] Into a 50 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add 2-amino-5-(dimethylphosphoryl)-3-methoxybenzonitrile (0.702 g, 3.13 mmol), (Boc)2O (2.281 g, 10.45 mmol), DMAP (0.067 g, 548.43 μmol), and 1,4-dioxane (20 mL). Stir the reaction mixture at 110 °C for 0.5 h. LCMS shows that the reaction is complete. Concentrate the resulting solution and purify it by passing through a C 18 chromatographic column, eluting with ACN / H2O (v / v = 5 / 3). Obtain 0.620 g (61.05% yield) of tert-Butyl (2-cyano-4-(dimethylphosphoryl)-6-methoxyphenyl)carbamate as a white solid. LCMS: m / z = 325 [M+1] + .

[0284] Step 3: tert-Butyl (2-cyano-4-(dimethylphosphoryl)-6-methoxyphenyl)(prop-2-yn-1-yl)carbamate

[0285] Into a 25 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add tert-Butyl (2-cyano-4-(dimethylphosphoryl)-6-methoxyphenyl)carbamate (0.613 g, 1.89 mmol) and THF (10 mL). Stir the reaction mixture at 0 °C. Then add NaH (0.430 g, 17.92 mmol). Stir the mixture at 20 °C for 1.0 h. Then add 3-bromopropyne (1.143 g, 9.61 mmol) to the reaction at -10 °C. Stir the reaction mixture at room temperature for 2 h. Quench the reaction by adding acetic acid (10 mL). Extract the resulting solution with EA (2 × 10 mL). Combine the organic layers, wash with brine (10 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Purify the residue by passing through a C 18 chromatographic column, eluting with ACN / H2O (v / v = 1 / 1). Obtain 0.515 g (75.19% yield) of tert-Butyl (2-cyano-4-(dimethylphosphoryl)-6-methoxyphenyl)(prop-2-yn-1-yl)carbamate as a yellow oil. LCMS: m / z = 363 [M+1] + .

[0286] Step 4: tert-Butyl (2-cyano-4-(dimethylphosphoryl)-6-methoxyphenyl)(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)carbamate

[0287] Into an 8 mL flask purged and maintained with a nitrogen inert atmosphere, (3S,4R)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.108 g, 228.68 μmol), CuI (0.008 g, 42.01 μmol), tert-butyl (2-cyano-4-(dimethylphosphoryl)-6-methoxyphenyl)(prop-2-yn-1-yl)carbamate (0.125 g, 344.96 μmol), Pd(PPh3)2Cl2 (0.056 g, 79.33 μmol), TEA (0.089 g, 879.54 μmol), and DMSO (2 mL) were added. The reaction mixture was stirred at 50 °C for 16 h. LCMS showed that the reaction was complete. The residue was purified by a C 18 chromatographic column and eluted with ACN / H2O (v / v = 1 / 3). 0.214 g (132.42% yield) of crude tert-butyl (2-cyano-4-(dimethylphosphoryl)-6-methoxyphenyl)(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)carbamate was obtained as a yellow oil. LCMS: m / z = 707 [M+1] + .

[0288] Step 5: 5-(Dimethylphosphoryl)-2-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzonitrile (11)

[0289] To a 20 mL round-bottom flask purged and maintained with a nitrogen inert atmosphere, add tert-butyl (2-cyano-4-(dimethylphosphoryl)-6-methoxyphenyl)(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)carbamate (0.209 g, 295.73 μmol), EA (10 mL), and HCl (5 mL, 4 M in EA solution). Stir the reaction mixture at room temperature for 1 h. LC MS shows the reaction is complete. Quench the resulting solution with NaHCO3 solution until pH = 7 - 8 and extract with EA (2 × 10 mL). Combine the organic layers, wash with brine (10 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Purify the mixture by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: acetonitrile; flow rate: 70 mL / min; gradient: 35 - 68 - 68% B (2 - 30 - 31 min); 268 nm; RT: 29.10 - 30.23 min. Obtain 0.019 g (10.59% yield) of 5-(dimethylphosphoryl)-2-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzonitrile (11) as a white solid. LCMS: m / z = 607 [M+1] + .

[0290] 1 H NMR (500 MHz, DMSO) δ 7.51–7.44 (m, 1H), 7.37–7.31 (m, 1H), 7.30–7.25 (m, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.96 (t, J = 6.9 Hz, 1H), 6.78 (d, J = 7.7 Hz, 1H), 5.76 (s, 3H), 5.17 (d, J = 8.4 Hz, 1H), 4.85 (m, 1H), 4.69 (d, J = 7.0 Hz, 1H), 4.34 (t, J = 5.0 Hz, 1H), 3.91 (s, 2H), 3.86–3.75 (m, 2H), 3.48–3.40 (m, 2H), 3.09–2.99 (m, 1H), 2.84–2.76 (m, 1H), 2.18 (s, 2H), 2.11–2.04 (m, 1H), 1.99–1.90 (m, 1H), 1.75–1.68 (m, 1H), 1.65–1.60 (m, 3H), 1.06 (t, J = 7.0 Hz, 2H).

[0291] Example 12

[0292] 3-Chloro-5-(dimethylphosphoryl)-2-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzonitrile (12)

[0293] Reaction Scheme

[0294]

[0295] Experimental Details

[0296] Step 1: 2-Amino-3-chloro-5-(dimethylphosphoryl)benzonitrile

[0297] To a 40 mL three-necked flask purged and maintained under an inert nitrogen atmosphere, 2-amino-5-(dimethylphosphoryl)benzonitrile (3.035 g, 15.63 mmol), MeCN (20 mL), and NCS (2.288 g, 17.13 mmol) were added. The reaction mixture was stirred at 80 °C for 1 h. LCMS showed the reaction was complete. The reaction was quenched by adding a NaHSO3 solution (10 mL). The resulting solution was extracted with EA (2 × 10 mL). The organic layers were combined, washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on a C 18 column, eluting with ACN / H2O (v / v = 1 / 3). 0.58 g (16.23% yield) of 2-amino-3-chloro-5-(dimethylphosphoryl)benzonitrile as a yellow solid was obtained. LCMS: m / z = 229 [M+1] + .

[0298] Step 2: tert-Butyl (2-chloro-6-cyano-4-(dimethylphosphoryl)phenyl)carbamate

[0299] To a 25 mL three-necked flask purged and maintained under an inert nitrogen atmosphere, 2-amino-3-chloro-5-(dimethylphosphoryl)benzonitrile (0.496 g, 2.17 mmol), (Boc)2O (2.054 g, 9.41 mmol), DMAP (0.928 g, 7.60 mmol), and 1,4-dioxane (10 mL) were added. The reaction mixture was stirred at 110 °C for 1 h. LCMS showed the reaction was complete. The resulting solution was concentrated and purified by column chromatography on a C 18 column, eluting with ACN / H2O (v / v = 1 / 4). 0.338 g (47.39% yield) of tert-butyl (2-chloro-6-cyano-4-(dimethylphosphoryl)phenyl)carbamate as a white solid was obtained. LCMS: m / z = 329 [M+1] + .

[0300] Step 3: tert-Butyl (2-chloro-6-cyano-4-(dimethylphosphoryl)phenyl)(prop-2-yn-1-yl)carbamate

[0301] Into an 8 mL three-necked flask purged and maintained under an inert nitrogen atmosphere, add tert-butyl (2-chloro-6-cyano-4-(dimethylphosphoryl)phenyl)carbamate (0.153 g, 465.43 μmol) and THF (2 mL). Stir the reaction mixture at 0 °C. Then add NaH (0.125 g, 5.21 mmol). Stir the mixture at 20 °C for 1.0 h. Then add 3-bromopropyne (0.339 g, 2.85 mmol) to the reaction at -10 °C. Stir the reaction mixture at 90 °C for 2 h. Quench the reaction with H2O (10 mL). Extract the resulting solution with EA (2 × 10 mL). Combine the organic layers and wash with brine (10 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Purify the residue by C 18 chromatographic column, eluting with ACN / H2O (v / v = 1 / 1). Obtain 0.085 g (49.79% yield) of tert-butyl (2-chloro-6-cyano-4-(dimethylphosphoryl)phenyl)(prop-2-yn-1-yl)carbamate as a yellow oil. LCMS: m / z = 367 [M+1] + .

[0302] Step 4: tert-Butyl (2-chloro-6-cyano-4-(dimethylphosphoryl)phenyl)(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)carbamate

[0303] Into an 8 mL flask purged and maintained under an inert nitrogen atmosphere, add (3S,4R)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.083 g, 175.74 μmol), CuI (0.004 g, 21.00 μmol), tert-butyl (2-chloro-6-cyano-4-(dimethylphosphoryl)phenyl)(prop-2-yn-1-yl)carbamate (0.087 g, 237.20 μmol), Pd(PPh3)2Cl2 (0.021 g, 29.75 μmol), TEA (0.053 g, 523.77 μmol), and DMSO (2 mL). Stir the reaction mixture at 50 °C for 5 h. LCMS shows that the reaction is complete. Purify the residue by C 18Column purification was carried out with elution using ACN / H2O (0.05% TFA) (v / v = 1 / 1). 0.08 g (64.01% yield) of tert-butyl (2-chloro-6-cyano-4-(dimethylphosphoryl)phenyl)(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)carbamate was obtained as a yellow oil. LCMS: m / z = 712 [M+1] + .

[0304] Step 5: 3-Chloro-5-(dimethylphosphoryl)-2-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzonitrile (12)

[0305] To an 8 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere, tert-butyl (2-chloro-6-cyano-4-(dimethylphosphoryl)phenyl)(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)carbamate (0.079 g, 111.09 μmol), EA (1 mL), and HCl (1 mL, 4 M EA solution) were added. The reaction mixture was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The resulting solution was quenched with NaHCO3 until pH = 7 - 8 and extracted with EA (2 × 10 mL). The organic layers were combined, washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: acetonitrile; flow rate: 70 mL / min; gradient: 35 - 73 - 73% B (2 - 30 - 33 min); 266 nm; RT: 29.27 - 32.69 min). 0.009 g (13.26% yield) of 3-chloro-5-(dimethylphosphoryl)-2-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)benzonitrile (12) was obtained as a white solid. LCMS: m / z = 612 [M+1] + .

[0306] 11H NMR (400 MHz, DMSO) δ 8.01–7.86 (m, 2H), 7.26 (m, 3H), 6.79 (d, J = 7.8 Hz, 1H), 5.21 (d, J = 8.5 Hz, 1H), 4.82–4.71 (m, 2H), 3.83 (m, 2H), 3.08–2.98 (m, 1H), 2.86–2.77 (m, 1H), 2.19 (s, 3H), 2.13–2.04 (m, 1H), 2.01–1.92 (m, 1H), 1.72 (d, J = 12.9 Hz, 1H), 1.66 (s, 2H), 1.62 (s, 3H), 1.35 (d, J = 6.1 Hz, 1H), 1.27–1.20 (m, 3H).

[0307] Example 13

[0308] (4 - ((3 - (7 - ((4 - Fluoro - 1 - methylpyrrolidin - 3 - yl)amino)-3-(2,2,2 - trifluoroethyl)benzo[b]thiophen - 2 - yl)prop - 2 - ynyl - 1 - yl)amino)-3 - methoxyphenyl)dimethylphosphine oxide (13)

[0309] Reaction Scheme

[0310]

[0311] Experimental Details

[0312] Step 1: tert - Butyl 3 - fluoro - 4 - ((2 - iodo - 3 - (2,2,2 - trifluoroethyl)benzo[b]thiophen - 7 - yl)amino)pyrrolidine - 1 - carboxylate

[0313] To a 25 mL three - necked flask purged and maintained under an inert nitrogen atmosphere, add 2 - iodo - 3 - (2,2,2 - trifluoroethyl)benzo[b]thiophen - 7 - amine (0.497 g, 1.39 mmol), tert - butyl 3 - fluoro - 4 - oxopyrrolidine - 1 - carboxylate (0.329 g, 1.62 mmol), dibutyltin dichloride (0.029 g, 95.44 μmol), tetrahydrofuran (10 mL), and phenylsilane (0.173 g, 1.60 mmol). Stir the reaction mixture at 50 °C for 43 h. LCMS shows the reaction is complete. Concentrate the resulting solution and apply it to a silica gel column, eluting with EA / hexane (v / v = 1 / 10). Obtain 0.635 g (83.83% yield) of tert - butyl 3 - fluoro - 4 - ((2 - iodo - 3 - (2,2,2 - trifluoroethyl)benzo[b]thiophen - 7 - yl)amino)pyrrolidine - 1 - carboxylate as a yellow solid. LCMS: m / z = 545 [M + 1] + .

[0314] Step 2: 4-Fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)pyrrolidin-3-amine

[0315] To a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, 3-fluoro-4-((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (0.631 g, 1.16 mmol), EA (10 mL), and HCl (10 mL, 4 M in EA) were added. The reaction mixture was stirred at room temperature for 0.5 h. LCMS showed the reaction was complete. The resulting solution was quenched with NaHCO3 until pH = 7 - 8 and extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. 0.450 g (87.38% yield) of 4-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)pyrrolidin-3-amine was obtained as a yellow solid. LCMS: m / z = 445 [M+1] + 。

[0316] Step 3: 4-Fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpyrrolidin-3-amine

[0317] To a 25 mL three-necked flask purged and maintained under an inert nitrogen atmosphere, 4-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)pyrrolidin-3-amine (0.415 g, 934.20 μmol), formaldehyde (0.070 g, 2.33 mmol), sodium cyanoborohydride (0.197 g, 4.59 mmol), methanol (10 mL), and acetic acid (0.1 mL) were added. The mixture was stirred at 60 °C for 3.0 h. The resulting solution was concentrated in vacuo. The residue was purified by C 18 chromatography column, eluting with ACN / H2O (v / v = 1 / 1). 0.130 g (yield 30.37%) of 4-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpyrrolidin-3-amine was obtained as a yellow solid. LCMS: m / z = 459 [M+1] + 。

[0318] Step 4: (4-((3-(7-((4-Fluoro-1-methylpyrrolidin-3-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (13)

[0319] To an 8 mL flask purged and maintained with a nitrogen inert atmosphere, add 4-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpyrrolidin-3-amine (0.118 g, 257.50 μmol), (3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide (0.183 g, 771.39 μmol), Pd(PPh3)2Cl2 (0.040 g, 56.66 μmol), CuI (0.010 g, 52.51 μmol), TEA (0.366 g, 3.62 mmol), DMSO (2 mL). Stir the reaction mixture at 50 °C for 4 h. LCMS shows the reaction is complete. Purify the residue by C 18 chromatography column, eluting with ACN / H2O (v / v = 1 / 1). Obtain 3.43 mg (2.35% yield) of (4-((3-(7-((4-fluoro-1-methylpyrrolidin-3-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (13) as a white solid. LCMS: m / z = 568 [M+1] + .

[0320] 1 H NMR (400 MHz, DMSO) δ 7.31–7.12 (m, 4H), 6.87–6.80 (m, 1H), 6.09–6.04 (m, 1H), 5.47 (d, J = 8.5 Hz, 1H), 5.25 (m, 1H), 4.34 (d, J = 6.5 Hz, 2H), 3.85 (s, 1H), 3.82–3.77 (m, 1H), 2.73–2.65 (m, 2H), 2.36–2.27 (m, 3H), 2.06–1.94 (m, 2H), 1.58 (d, J = 13.2 Hz, 3H), 1.37–1.33 (m, 1H), 1.31–1.20 (m, 6H), 0.89–0.83 (m, 1H).

[0321] Example 14

[0322] tert-Butyl 6-(dimethylphosphoryl)-3-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (14)

[0323] Reaction Scheme

[0324]

[0325] Experimental details

[0326] Step 1: (4-Amino-3-nitrophenyl)dimethylphosphine oxide

[0327] Into a 50 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add 4-bromo-2-nitroaniline (2.002 g, 9.23 mmol), palladium acetate (0.312 g, 1.39 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.823 g, 1.42 mmol), N,N-diisopropylethylamine (2.487 g, 19.24 mmol), and DMF (20 mL). Heat the reaction mixture to 130 °C. Then add dimethylphosphine oxide (2.249 g, 28.82 mmol) and stir at the same temperature for 1.0 h. LCMS shows that the reaction is complete. Concentrate the resulting solution in vacuo. Purify the residue by C 18 chromatographic column, eluting with ACN / H2O (v / v = 1 / 5). Obtain 1.34 g (67.83% yield) of (4-amino-3-nitrophenyl)dimethylphosphine oxide as a yellow solid. LCMS: m / z = 215 [M+1] + .

[0328] Step 2: tert-Butyl (4-(dimethylphosphoryl)-2-nitrophenyl)carbamate

[0329] Into a 100 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add (4-amino-3-nitrophenyl)dimethylphosphine oxide (1.332 g, 6.22 mmol), (Boc)2O (4.125 g, 18.90 mmol), DMAP (0.167 g, 1.37 mmol), and 1,4-dioxane (20 mL). Stir the reaction mixture at 110 °C for 0.5 h. LCMS shows that the reaction is complete. Concentrate the resulting solution and purify by C 18 chromatographic column, eluting with ACN / H2O (v / v = 1 / 3). Obtain 0.75 g (38.37% yield) of tert-butyl (4-(dimethylphosphoryl)-2-nitrophenyl)carbamate as a yellow oil. LCMS: m / z = 315 [M+1] + .

[0330] Step 3: tert-Butyl (4-(dimethylphosphoryl)-2-nitrophenyl)(prop-2-yn-1-yl)carbamate

[0331] Into a 25 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, add tert-butyl (4-(dimethylphosphoryl)-2-nitrophenyl)carbamate (0.712 g, 2.27 mmol) and THF (10 mL). Stir the reaction mixture at 0 °C. Then add NaH (0.449 g, 18.71 mmol). Stir the mixture at 20 °C for 1.0 h. Then add 3-bromopropyne (2.826 g, 23.76 mmol) to the reaction at -10 °C. Stir the reaction mixture at 60 °C for 40 h. Quench the reaction by adding acetic acid (10 mL). Extract the resulting solution with EA (2 × 10 mL). Combine the organic layers and wash with brine (10 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Purify the residue by C 18 chromatography column, eluting with ACN / H2O (v / v = 1 / 1). Obtain 0.84 g (105.24% yield) (crude) yellow oily tert-butyl (4-(dimethylphosphoryl)-2-nitrophenyl)(prop-2-yn-1-yl)carbamate. LCMS: m / z = 353 [M+1] + .

[0332] Step 4: tert-butyl (2-amino-4-(dimethylphosphoryl)phenyl)(prop-2-yn-1-yl)carbamate

[0333] Into a 25 mL flask purged and maintained with a nitrogen inert atmosphere, add tert-butyl (4-(dimethylphosphoryl)-2-nitrophenyl)(prop-2-yn-1-yl)carbamate (0.803 g, 2.28 mmol), Fe (0.688 g, 12.32 mmol), NH4Cl (1.344 g, 25.13 mmol), MeOH (8 mL), and H2O (1 mL). Stir the reaction mixture at 60 °C for 15 h. LCMS shows the reaction is complete. Filter out the solid and purify the residue by C 18 chromatography column, eluting with ACN / H2O (v / v = 2 / 5). Obtain 0.280 g (38.11% yield) of tert-butyl (2-amino-4-(dimethylphosphoryl)phenyl)(prop-2-yn-1-yl)carbamate as a yellow solid. LCMS: m / z = 323 [M+1] + .

[0334] Step 5: tert-butyl 6-(dimethylphosphoryl)-2-oxo-3-(prop-2-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate

[0335] To a 25 mL flask purged and maintained with a nitrogen inert atmosphere, add tert-butyl (2-amino-4-(dimethylphosphoryl)phenyl)(prop-2-yn-1-yl)carbamate (0.201 g, 623.57 μmol), (Boc2)O (1.002 g, 4.59 mmol), and 1,4-dioxane (5 mL). Stir the reaction mixture at 110 °C for 4 h. LCMS shows that the reaction is complete. Then concentrate the reaction mixture in vacuo and purify it by column chromatography using C 18 chromatography column, eluting with ACN / H2O (v / v = 1 / 3). Obtain 0.138 g (yield 63.53%) of tert-butyl 6-(dimethylphosphoryl)-2-oxo-3-(prop-2-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate as a yellow oil. LCMS: m / z = 349 [M+1] + .

[0336] Step 6: tert-Butyl 6-(dimethylphosphoryl)-3-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (14)

[0337] Into an 8 mL flask purged and maintained with a nitrogen inert atmosphere, (3S,4R)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.063 g, 133.40 μmol), tert-butyl 6-(dimethylphosphoryl)-2-oxo-3-(prop-2-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (0.046 g, 132.06 μmol), Pd(PPh3)2Cl2 (0.027 g, 38.25 μmol), CuI (0.007 g, 36.76 μmol), TEA (0.060 g, 592.95 μmol), and DMSO (2 mL) were added. The reaction mixture was stirred at 50 °C for 19 h. LCMS showed that the reaction was complete. The mixture was purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: -50 - 50% B (2 - 28 - 30 min); 262 nm; RT: 21.30 - 23.55 min). 0.012 g (15.18% yield) of tert-butyl 6-(dimethylphosphoryl)-3-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (14) was obtained as a white solid. LCMS: m / z = 593 [M+1] + .

[0338] 1 1H NMR (400 MHz, DMSO) δ 11.30 (s, 1H), 7.50–7.34 (m, 3H), 7.33–7.21 (m, 2H), 6.80 (d, J = 7.5 Hz, 1H), 5.20 (d, J = 8.5 Hz, 1H), 5.08 (s, 2H), 4.88–4.72 (m, 1H), 3.94–3.82 (m, 2H), 3.65 (m, 2H), 3.09–2.99 (m, 1H), 2.84–2.76 (m, 1H), 2.18 (s, 3H), 2.12–2.04 (m, 1H), 1.95 (m, 1H), 1.72 (m, 1H), 1.65 (s, 3H), 1.61 (s, 3H).

[0339] Example 15

[0340] N-(2-(3-((4-(Dimethylphosphoryl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-3-fluoro-1-methylazetidine-3-carboxamide (15)

[0341] Reaction Scheme

[0342]

[0343] Experimental Details

[0344] Step 1: tert-Butyl 3-fluoro-3-((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)carbamoyl)azetidine-1-carboxylate

[0345] Into a 25 mL three-necked flask purged and maintained under an inert nitrogen atmosphere, 2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-amine (0.400 g, 857.53 μmol), 1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-carboxylic acid (0.502 g, 2.29 mmol), HATU (1.604 g, 4.22 mmol), DIPEA (0.522 g, 4.04 mmol), and DMF (10 mL) were added. The reaction mixture was stirred at room temperature for 2 h. LCMS showed that the reaction was complete. The resulting solution was concentrated and applied to a silica gel column, eluting with EA / hexane (v / v = 1 / 5). 0.59 g (123.23% yield) (crude) tert-butyl 3-fluoro-3-((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)carbamoyl)azetidine-1-carboxylate was obtained as a brown solid. LCMS:

[0346] m / z = 559 [M+1] + 。

[0347] Step 2: 3-Fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)azetidine-3-carboxamide

[0348] To a 25 mL round-bottom flask purged and maintained with a nitrogen inert atmosphere, add tert-butyl 3-fluoro-3-((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)carbamoyl)azetidine-1-carboxylate (0.58 g, 1.04 mmol), DCM (10 mL), and TFA (2 mL). Stir the reaction mixture at room temperature for 1 h. LCMS shows that the reaction is complete. Quench the resulting solution with NaHCO3 until pH = 7 - 8 and extract with DCM (2 × 10 mL). Combine the organic layers and concentrate in vacuo. This gives 0.51 g (yield 107.14%) (crude) 3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)azetidine-3-carboxamide as a white solid. LCMS: m / z = 459 [M+1] + 。

[0349] Step 3: 3-Fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylazetidine-3-carboxamide

[0350] To a 10 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, add formaldehyde (0.257 g, 8.56 mmol), 3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)azetidine-3-carboxamide (0.497 g, 1.08 mmol), sodium cyanoborohydride (0.114 g, 2.66 mmol), MeOH (5 mL), and acetic acid (0.1 mL). Stir the mixture at room temperature for 2.0 h. Concentrate the resulting solution in vacuo. Purify the residue by C 18 chromatography column, eluting with ACN / H2O (v / v = 1 / 3). Obtain 0.261 g (yield 50.96%) of 3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylazetidine-3-carboxamide as a white solid. LCMS: m / z = 473 [M+1] + 。

[0351] Step 4: N-(2-(3-((4-(dimethylphosphoryl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-3-fluoro-1-methylazetidine-3-carboxamide (15)

[0352] To an 8 mL flask purged and maintained with a nitrogen inert atmosphere, add 3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylazetidine-3-carboxamide (0.152 g, 321.87 μmol), (3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide (0.098 g, 413.09 μmol), Pd(PPh3)2Cl2 (0.055 g, 77.91 μmol), CuI (0.014 g, 73.51 μmol), TEA (0.048 g, 474.36 μmol), DMSO (2 mL). Stir the reaction mixture at 50 °C for 1 h. LCMS shows the reaction is complete. Purify the residue by 18 a C column, eluting with ACN / H2O (v / v = 1 / 3). Obtain 0.039 g (20.83% yield) of N-(2-(3-((4-(dimethylphosphoryl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-3-fluoro-1-methylazetidine-3-carboxamide (15) as a white solid. LCMS: m / z = 582 [M+1] + .

[0353] 1 H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.39 (d, J = 7.5 Hz, 1H), 7.26–7.12 (m, 2H), 6.88–6.83 (m, 1H), 6.09–6.03 (m, 1H), 4.35 (d, J = 6.3 Hz, 2H), 3.95–3.83 (m, 4H), 3.72–3.62 (m, 2H), 3.58–3.48 (m, 3H), 2.34 (s, 2H), 1.58 (d, J = 13.2 Hz, 4H), 1.35 (d, J = 6.2 Hz, 1H), 1.27–1.22 (m, 2H).

[0354] Example 16

[0355] (4-((3-(7-(((4-fluoro-1-methylpiperidin-4-yl)methyl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl))prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (16)

[0356] Reaction Scheme

[0357]

[0358] Experimental details

[0359] Step 1: tert-Butyl 4-fluoro-4-(((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)methyl)piperidine-1-carboxylate

[0360] Into a 100 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, 2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-amine (0.40 g, 1.12 mmol), tert-butyl 4-fluoro-4-formylpiperidine-1-carboxylate (0.46 g, 1.99 mmol), DMF (10 mL) and trimethylchlorosilane (1.30 g, 11.97 mmol) were added at -10 °C. The reaction mixture was stirred at 0 °C for 2 h. Then borane-tetrahydrofuran complex (15 mL) was added at -10 °C. The reaction mixture was stirred at 0 °C for 1 h. LCMS showed that the reaction was complete. The resulting solution was quenched with MeOH (15 mL) and concentrated. The residue was purified by column chromatography on C 18 using ACN / H2O (v / v = 3 / 5) as the eluent. 0.405 g (63.17% yield) of tert-butyl 4-fluoro-4-(((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)methyl)piperidine-1-carboxylate was obtained as a brown solid. LCMS: m / z = 573 [M+1] + .

[0361] Step 2: N-((4-Fluoropiperidin-4-yl)methyl)-2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-amine

[0362] Into a 25 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere, tert-butyl 4-fluoro-4-(((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)methyl)piperidine-1-carboxylate (0.405 g, 707.55 μmol), DCM (10 mL), and TFA (2 mL) were added. The reaction mixture was stirred at room temperature for 1 h. LCMS showed that the reaction was complete. The resulting solution was quenched with NaHCO3 until pH = 7 - 8 and extracted with DCM (2 × 10 mL). The organic layers were combined and concentrated in vacuo. 0.58 g (173.57% yield) (crude) of N-((4-fluoropiperidin-4-yl)methyl)-2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-amine was obtained as a brown solid. LCMS: m / z = 459 [M+1] + .

[0363] Step 3: N-((4-Fluoro-1-methylpiperidin-4-yl)methyl)-2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-amine

[0364] To a 10 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add N-((4-fluoropiperidin-4-yl)methyl)-2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-amine (0.530 g, 1.12 mmol), formaldehyde (0.228 g, 7.59 mmol), sodium cyanoborohydride (0.283 g, 6.60 mmol), and MeOH (5 mL). Stir the mixture at room temperature for 1.0 h. Concentrate the resulting solution in vacuo. Purify the residue by C 18 chromatography column, eluting with ACN / H2O (v / v = 2 / 5). Obtain 0.252 g (46.18% yield) of N-((4-fluoro-1-methylpiperidin-4-yl)methyl)-2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-amine as a brown solid. LCMS: m / z = 487 [M+1] + .

[0365] Step 4: (4-((3-(7-(((4-Fluoro-1-methylpiperidin-4-yl)methyl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (16)

[0366] To an 8 mL flask purged and maintained with a nitrogen inert atmosphere, add N-((4-fluoro-1-methylpiperidin-4-yl)methyl)-2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-amine (0.159 g, 326.95 μmol), (3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide (0.097 g, 408.88 μmol), Pd(PPh3)2Cl2 (0.045 g, 63.75 μmol), CuI (0.018 g, 94.51 μmol), TEA (0.056 g, 553.42 μmol), DMSO (2 mL). Stir the reaction mixture at 50 °C for 2 h. LCMS shows the reaction is complete. Purify the mixture by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: MeOH; flow rate: 40 mL / min; gradient: 35 - 75 - 100% B (2 - 30 - 60 min; 266 nm; RT: 35.016 - 37.912 min). Obtain 0.015 g (yield 7.70%) of (4-((3-(7-(((4-fluoro-1-methylpiperidin-4-yl)methyl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (16), a white solid. LCMS: m / z = 596 [M+1] + .

[0367] 1 H NMR (400 MHz, DMSO) δ 7.29–7.18 (m, 2H), 7.18–7.12 (m, 2H), 6.88–6.82 (m, 1H), 6.77 (d, J = 7.8 Hz, 1H), 6.08 (t, J = 6.3 Hz, 1H), 5.69 (t, J = 6.4 Hz, 1H), 4.34 (d, J = 6.3 Hz, 2H), 3.85 (s, 3H), 3.83–3.73 (m, 2H), 2.61 (d, J = 10.7 Hz, 2H), 2.19 (s, 3H), 2.17–2.09 (m, 2H), 1.90–1.75 (m, 4H), 1.75–1.64 (m, 2H), 1.60 (s, 3H), 1.57 (s, 3H).

[0368] Examples 17 & 18

[0369] (4-((3-(7-(((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)amino)-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (18) & (4-((3-(7-(((3R,4S)-3)-fluoro-1-methylpiperidin-4-yl)amino)-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (17)

[0370] Reaction Scheme

[0371]

[0372] Experimental Details

[0373] Step 1: 7-Nitro-3-(3,3,3-trifluoroprop-1-en-2-yl)benzo[b]thiophene

[0374] Into a 25 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, 3-bromo-7-nitrobenzo[b]thiophene (0.413 g, 1.60 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.275 g, 370.73 μmol), sodium acetate (0.508 g, 6.1926 mmol), 1,4-dioxane (10 mL), and water (2 mL) were added. Then a solution of (3,3,3-trifluoroprop-1-en-2-yl)boronic acid (0.750 g, 3.38 mmol) in 1,4-dioxane (5 mL) was added at 70 °C. The reaction mixture was stirred at 70 °C for 1.5 h. LCMS showed that the reaction was complete. The reaction was quenched by adding water (20 mL) and extracted with EA (2 × 20 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on C 18 using ACN / H2O (v / v = 1 / 3) as the eluent. 0.305 g (yield 69.76%) of 7-nitro-3-(3,3,3-trifluoroprop-1-en-2-yl)benzo[b]thiophene as a yellow solid was obtained. LCMS: m / z = 274 [M+1] + .

[0375] Step 2: 7-Nitro-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophene

[0376] Into a 25 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere, add 7-nitro-3-(3,3,3-trifluoroprop-1-en-2-yl)benzo[b]thiophene (0.528 g, 1.93 mmol), 4-methylbenzenesulfonyl hydrazide (1.087 g, 5.84 mmol), NaOAc (2.200 g, 26.82 mmol), THF (10 mL), and water (5 mL). Stir the reaction mixture at 70 °C for 4 h. LCMS shows that the reaction is complete. Quench the reaction by adding water (10 mL) and extract with EA (3 × 10 mL). Combine the organic layers, wash with brine (20 mL), dry over anhydrous Na2SO4 and concentrate in vacuo. Purify the residue by column C 18 chromatography, eluting with ACN / H2O (v / v = 3 / 5). Obtain 0.374 g (yield 70.31%) of 7-nitro-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophene as a brown solid. LCMS: m / z = 276 [M+1] + .

[0377] Step 3: 2-Iodo-7-nitro-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophene

[0378] Into a 25 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add 7-nitro-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophene (0.348 g, 1.26 mmol), NIS (0.360 g, 1.60 mmol), acetic acid (5 mL), and trifluoromethanesulfonic acid (0.2 mL). Stir the mixture at room temperature for 3.0 h. Quench the reaction by adding brine (30 mL) and extract with EA (2 × 30 mL). Combine the organic layers, dry over anhydrous Na2SO4 and concentrate in vacuo. Obtain 0.506 g (99.77% yield) of 2-iodo-7-nitro-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophene as a yellow solid. LCMS: m / z = 402 [M+1] + .

[0379] Step 4: 2-Iodo-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophen-7-amine

[0380] Into a 40 mL flask purged and maintained with a nitrogen inert atmosphere, add 2-iodo-7-nitro-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophene (0.493 g, 1.23 mmol), Fe (0.421 g, 7.54 mmol), NH4Cl (0.244 g, 4.56 mmol), EtOH (10 mL), and water (5 mL). Stir the reaction mixture at 80 °C for 1 h. LCMS shows that the reaction is complete. Filter the resulting solution and concentrate it in vacuo. Purify the residue by C 18 chromatography column, eluting with ACN / H2O (v / v = 1 / 1). Obtain 0.260 g (57.00% yield) of 2-iodo-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophen-7-amine as a yellow solid. LCMS: m / z = 372 [M+1] + .

[0381] Step 5: tert-Butyl 3-fluoro-4-((2-iodo-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate

[0382] Into a 25 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, add 2-iodo-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophen-7-amine (0.258 g, 695.12 μmol), tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (0.318 g, 1.46 mmol), dibutyltin dichloride (0.063 g, 207.34 μmol), phenylsilane (0.131 g, 1.21 mmol), and THF (10 mL). Stir the reaction mixture at 50 °C for 40 h. LCMS shows that the reaction is complete. Filter the resulting solution and concentrate it in vacuo. Purify the resulting crude product by silica gel column chromatography, eluting with EA / hexane (v / v = 1 / 10). Obtain 0.229 g (57.55% yield) of tert-butyl 3-fluoro-4-((2-iodo-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate as a yellow oil. LCMS: m / z = 573 [M+1] + .

[0383] Step 6: 3-Fluoro-N-(2-iodo-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophen-7-yl)piperidin-4-amine

[0384] To a 100 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere, add tert-butyl 3-fluoro-4-((2-iodo-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (0.229 g, 400.07 μmol), DCM (20 mL), and TFA (5 mL). Stir the reaction mixture at room temperature for 0.5 h. LCMS shows that the reaction is complete. Quench the resulting solution with NaHCO3 until pH = 7 - 8 and extract with DCM (2 × 10 mL). Combine the organic layers and concentrate in vacuo. Obtain 0.199 g (yield 105.32%) (crude) 3-fluoro-N-(2-iodo-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophen-7-yl)piperidin-4-amine as a yellow oil. LCMS: m / z = 473 [M+1] + 。

[0385] Step 7: 3-Fluoro-N-(2-iodo-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine

[0386] To an 8 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add 3-fluoro-N-(2-iodo-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophen-7-yl)piperidin-4-amine (0.198 g, 419.24 μmol), paraformaldehyde (0.034 g, 1.13 mmol), sodium cyanoborohydride (0.079 g, 1.84 mmol), MeOH (2 mL), and acetic acid (0.1 mL). Stir the mixture at room temperature for 0.5 h. Quench the reaction by adding H2O (2 mL) and extract with EA (2 × 10 mL). Combine the organic layers, dry over anhydrous Na2SO4 and concentrate in vacuo. Obtain 0.199 g (yield 97.61%) 3-fluoro-N-(2-iodo-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine as a yellow solid. LCMS: m / z = 487 [M+1] + 。

[0387] Step 8: (4-((3-(7-(((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)amino)-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (18) & (4-((3-(7-(((3R,4S)-3-Fluoro-1-methylpiperidin-4-yl)amino)-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (17)

[0388] Into a 25 mL flask purged and maintained with a nitrogen inert atmosphere, add 3-fluoro-N-(2-iodo-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.156 g, 320.78 μmol), (3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide (0.183 g, 771.39 μmol), Pd(PPh3)2Cl2 (0.042 g, 59.50 μmol), CuI (0.015 g, 78.76 μmol), TEA (0.132 g, 1.30 mmol), and DMSO (5 mL). Stir the reaction mixture at 50 °C for 2 h. LCMS shows that the reaction is complete. Purify the mixture by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: MeOH; flow rate: 70 mL / min; gradient: 35 - 70 - 70% B (2 - 30 - 60 min; 262 nm; RT: 33.657 - 40.403 min), and further purify by chiral HPLC (column: IG, mobile phase A: (HeX:DcM = 3:1)(0.1% IPA.M), mobile phase B: EtOH; flow rate: 20 mL / min; v / v = 80 / 20; 220 nm; RT: 7.441, 8.329). Obtain 0.023 g (12.04% yield) of (4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(1,1,1-trifluoropropan-2-yl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (18) as a white solid. LCMS: m / z = 596 [M+1] + 。

[0389] 11H NMR (400 MHz, DMSO) δ 7.30–7.18 (m, 3H), 7.18–7.12 (m, 1H), 6.87–6.81 (m, 1H), 6.80–6.75 (m, 1H), 6.07 (t, J = 6.4 Hz, 1H), 5.12 (d, J = 7.0 Hz, 1H), 4.89–4.72 (m, 1H), 4.34 (d, J = 6.4 Hz, 2H), 4.21 (s, 1H), 3.85 (s, 3H), 3.68–3.59 (m, 1H), 3.11–3.01 (m, 1H), 2.82 (d, J = 9.8 Hz, 1H), 2.21 (s, 3H), 2.16–2.08 (m, 1H), 2.01–1.89 (m, 1H), 1.77–1.69 (m, 1H), 1.60 (s, 3H), 1.57 (s, 3H), 1.55 (s, 1H), 1.53 (s, 1H), 1.26–1.22 (m, 2H).

[0390] and 0.029 g (15.18% yield) of (4 - ((3 - (7 - (((3R,4S)-3 - fluoro - 1 - methylpiperidin - 4 - yl)amino)-3-(1,1,1 - trifluoropropan - 2 - yl)benzo[b]thiophen - 2 - yl)prop - 2 - yn - 1 - yl)amino)-3 - methoxyphenyl)dimethylphosphine oxide (17), which was a white solid. LCMS: m / z = 596 [M + 1] + 。

[0391] 1 1H NMR (400 MHz, DMSO) δ 7.31–7.18 (m, 3H), 7.17–7.11 (m, 1H), 6.86–6.82 (m, 1H), 6.80–6.75 (m, 1H), 6.07 (t, J = 6.4 Hz, 1H), 5.12 (d, J = 6.9 Hz, 1H), 4.88–4.71 (m, 1H), 4.34 (d, J = 6.4 Hz, 2H), 4.21 (s, 1H), 3.85 (s, 3H), 3.74–3.57 (m, 1H), 3.13–3.01 (m, 1H), 2.81 (d, J = 9.7 Hz, 1H), 2.20 (s, 3H), 2.14–2.05 (m, 1H), 2.02–1.89 (m, 1H), 1.78–1.68 (m, 1H), 1.60 (s, 3H), 1.56 (d, J = 4.8 Hz, 3H), 1.55 (s, 1H), 1.53 (s, 1H), 1.23 (d, J = 3.7 Hz, 2H).

[0392] Example 19

[0393] (4-((3-(7-(((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propyl)amino)-3-methoxyphenyl)dimethylphosphine oxide (19)

[0394] Reaction Scheme

[0395]

[0396] Experimental Details

[0397] Step 1: (4-((3-(7-(((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propyl)amino)-3-methoxyphenyl)dimethylphosphine oxide (19)

[0398] Into a 10 mL three-necked flask purged and maintained under an inert nitrogen atmosphere, add (4-((3-(7-(((3S,4R)-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 (0.030 g, 51.58 μmol), Pd / C (0.015 g, 140.95 μmol), and MeOH (4 mL). Stir the reaction mixture at room temperature for 0.5 h. LCMS shows that the reaction is complete. Filter the resulting solution and concentrate it under vacuum. Purify the residue by C 18 chromatography column, eluting with ACN / H2O (v / v = 2 / 5). Obtain 0.27 g (89.38% yield) of (4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propyl)amino)-3-methoxyphenyl)dimethylphosphine oxide (19) as a white solid. LCMS: m / z = 586 [M+1] + .

[0399] 11H NMR (400 MHz, DMSO) δ 7.54–7.49 (m, 1H), 7.24–7.18 (m, 1H), 7.19–7.10 (m, 2H), 7.08 (m, 1H), 6.69 (d, J = 7.4 Hz, 1H), 6.65–6.60 (m, 1H), 5.54 (m, 1H), 4.90–4.80 (m, 2H), 4.75 (s, 1H), 3.87 (s, 1H), 3.83 (d, J = 5.1 Hz, 3H), 3.27–3.21 (m, 3H), 3.05–2.99 (m, 2H), 2.88–2.76 (m, 2H), 2.68 (s, 1H), 2.35–2.31 (m, 1H), 2.21 (s, 3H), 2.02–1.89 (m, 3H), 1.80–1.71 (m, 2H), 1.56 (d, J = 13.1 Hz, 4H).

[0400] Example 20

[0401] N-(4-(Dimethylphosphoryl)-2-methoxyphenyl)-3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propanamide (20)

[0402] Reaction Scheme

[0403]

[0404] Experimental Details

[0405] Step 1: N-(4-(Dimethylphosphoryl)-2-methoxyphenyl)-3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propanamide (20)

[0406] To an 8 mL three-necked flask purged and maintained under an inert nitrogen atmosphere, add N-(4-(dimethylphosphoryl)-2-methoxyphenyl)-3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propynamide (0.010 g, 16.79 μmol), Pd / C (0.033 g, 310.09 μmol), and methanol (2 mL). Stir the reaction mixture at room temperature for 0.5 h. LCMS shows the reaction is complete. Filter the resulting solution and concentrate it in vacuo. Purify the residue by C 18Column purification was performed and eluted with ACN / H2O (v / v = 2 / 5). 0.003 g (yield 29.80%) of N-(4-(dimethylphosphoryl)-2-methoxyphenyl)-3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)propanamide (20) was obtained as a white solid. LCMS: m / z = 600 [M+1] + 。

[0407] 1 1H NMR (400 MHz, DMSO) δ 9.44 (s, 1H), 8.19–8.12 (m, 1H), 7.37–7.26 (m, 2H), 7.24–7.15 (m, 2H), 6.70 (d, J = 7.5 Hz, 1H), 4.86 (s, 1H), 4.78–4.71 (m, 1H), 3.95–3.90 (m, 1H), 3.87 (s, 2H), 3.28–3.22 (m, 2H), 3.08–3.00 (m, 2H), 2.88 (t, J = 7.7 Hz, 2H), 2.81–2.76 (m, 1H), 2.68 (s, 1H), 2.33 (s, 1H), 2.28–2.23 (m, 1H), 2.18 (s, 2H), 2.11–2.06 (m, 1H), 1.92–1.86 (m, 1H), 1.79–1.69 (m, 2H), 1.63 (m, 4H), 1.24 (s, 2H).

[0408] Example 21

[0409] ((S)-2-((7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen)-2-yl)ethynyl)indolin-5-yl)dimethylphosphine oxide (21)

[0410] Reaction Scheme:

[0411]

[0412] Experimental Details:

[0413] Step 1: (S)-Indoline-2-carboxylic acid

[0414] Into a 100 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, add (S)-2-amino-3-(2-bromophenyl)propanoic acid (3.020 g, 12.37 mmol), CuBr (0.111 g, 773.78 μmol), K2CO3 (3.401 g, 24.60 mmol) and water (20 mL). Stir the reaction mixture at 100 °C for 16 h. Purify the reaction mixture by passing it through a 18 column, eluting with ACN / H2O (v / v = 1 / 20). Obtain 1.366 g (yield 67.66%) of (S)-indoline-2-carboxylic acid as a white solid. LCMS: m / z = 164 [M+1] + .

[0415] Step 2: (S)-indolin-2-ylmethanol

[0416] Into a 25 mL three-necked flask, add (S)-indoline-2-carboxylic acid (1.318 g, 8.07 mmol) and THF (15 mL). Stir the reaction mixture at -78 °C. Then add LiAlH4 (0.646 g, 17.02 mmol). Stir the mixture at 25 °C for 16 h. Quench the resulting solution with methanol (2 mL) at -5 °C. Filter the reaction mixture through a diatomaceous earth pad and wash the diatomaceous earth pad with EA (2 × 10 mL). Add the filtrate to water (30 mL). Extract the resulting solution with EA (3 × 50 mL). Combine the organic layers, wash with brine (50 mL), and dry over anhydrous Na2SO4. Purify the crude product by silica gel column chromatography, eluting with EA / hexane (v / v = 1 / 1). Obtain 0.916 g (yield 76.01%) of (S)-indolin-2-ylmethanol as a yellow solid. LCMS: m / z = 150 [M+1] + .

[0417] Step 3: (S)-(5-bromoindolin-2-yl)methanol

[0418] To a 25 mL three-necked flask purged and maintained with an inert atmosphere of nitrogen, (S)-indolin-2-ylmethanol (1.602 g, 10.73 mmol) and acetonitrile (20 mL) were added. The reaction mixture was stirred at -30 ° C, and then NBS (1.413 g, 7.93 mmol) was added. The reaction mixture was stirred at -30 ° C for 0.5 h. The resulting solution was added to water (20 mL). The resulting solution was extracted with EA (3×30 mL). The organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4, and then the filtrate was concentrated under reduced pressure to obtain the product. The crude product was purified by silica gel column and eluted with EA / hexane (v / v=1 / 1). 1.805 g (yield 73.69%) of (S)-(5-bromoindolin-2-yl)methanol was obtained as a yellow oil. LCMS: m / z=228[M+1] + .

[0419] Step 4: (S)-tert-butyl 5-bromo-2-(hydroxymethyl)indoline-1-carboxylate

[0420] To a 25 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, (S)-(5-bromoindolyl-2-yl)methanol (1.75 g, 7.67 mmol), di-tert-butyl dicarbonate (2.47 g, 11.31 mmol) and DCM (18 mL) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was passed through C 18 Column purification, eluting with ACN / H2O (v / v=3 / 2), filtration and vacuum concentration were performed to obtain 2.704 g (107.38% yield) of (S)-tert-butyl 5-bromo-2-(hydroxymethyl)indoline-1-carboxylate as a yellow oil. LCMS: m / z=328 [M+1] + .

[0421] Step 5: (S)-tert-Butyl 5-(dimethylphosphoryl)-2-(hydroxymethyl)indoline-1-carboxylate.

[0422] To a 25mL three-necked flask was added (S)-5-bromo-2-(hydroxymethyl)indoline-1-carboxylic acid tert-butyl ester (2.657g, 8.09mmol), palladium acetate (0.421g, 1.87g mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (0.920g, 1.59mmol), DIEA (3.129g, 24.21mmol), and DMF (30mL). The reaction was stirred at 130°C for 0.5h under a nitrogen atmosphere. Dimethylphosphine oxide (5mL) was then added at 130°C. The reaction was stirred at 130°C for 3h under a nitrogen atmosphere. The reaction mixture was passed through C 18Column purification was performed and eluted with ACN / H2O (v / v = 1 / 3). 1.014 g (yield 38.49%) of (S)-5-(dimethylphosphoryl)-2-(hydroxymethyl)indoline-1-carboxylic acid tert-butyl ester was obtained as a white solid. LCMS: m / z = 326 [M+1] + 。

[0423] Step 6: (S)-5-(dimethylphosphoryl)-2-formylindoline-1-carboxylic acid tert-butyl ester

[0424] To a 25 mL three-necked flask were added (S)-5-(dimethylphosphoryl)-2-(hydroxymethyl)indoline-1-carboxylic acid tert-butyl ester (0.308 g, 946.70 μmol) and DMF (5 mL). The reaction mixture was stirred at 0 °C. Then Dess-Martin periodinane (0.854 g, 2.01 mmol) was added. The mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered through a pad of Celite and the Celite pad was washed with EA (2 × 10 mL). The filtrate was concentrated in vacuo. 0.155 g (50.63% yield) of (S)-5-(dimethylphosphoryl)-2-formylindoline-1-carboxylic acid tert-butyl ester was obtained as a yellow solid. LCMS: m / z = 324 [M+1] +

[0425] Step 7: (S)-5-(dimethylphosphoryl)-2-ethynylindoline-1-carboxylic acid tert-butyl ester.

[0426] To a 25 mL three-necked flask were added (S)-5-(dimethylphosphoryl)-2-formylindoline-1-carboxylic acid tert-butyl ester (0.153 g, 473.21 μmol), K2CO3 (0.114 g, 824.85 μmol), and isopropanol (2 mL). The reaction mixture was stirred at 0 °C. Then dimethyl (1-diazo-2-oxopropyl)phosphonate (0.134 g, 697.52 mmol) was added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction mixture was purified by column chromatography and eluted with ACN / H2O (v / v = 2 / 3). 0.128 g (yield 84.70%) of (S)-5-(dimethylphosphoryl)-2-ethynylindoline-1-carboxylic acid tert-butyl ester was obtained as a light red solid. LCMS: m / z = 320 [M+1] 18 Column purification was performed and eluted with ACN / H2O (v / v = 2 / 3). 0.128 g (yield 84.70%) of (S)-5-(dimethylphosphoryl)-2-ethynylindoline-1-carboxylic acid tert-butyl ester was obtained as a light red solid. LCMS: m / z = 320 [M+1] + 。

[0427] Step 8: (S)-5-(dimethylphosphoryl)-2-((7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)ethynyl)indoline-1-carboxylic acid tert-butyl ester

[0428] Add (3S,4R)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.083 g, 175.74 μmol), (S)-tert-butyl 5-(dimethylphosphoryl)-2-ethynylindoline-1-carboxylate (0.096 g, 300.62 μmol), Pd(PPh3)2Cl2 (0.029 g, 41.08 μmol), CuI (0.020 g, 154.01 μmol), DIEA (0.104 g, 804.68 μmol), and dimethyl sulfoxide (2 mL) to a 10 mL round-bottom flask. Stir the reaction mixture at room temperature under a nitrogen atmosphere for 3 h. Filter the reaction mixture through a pad of diatomaceous earth and wash the diatomaceous earth pad with acetonitrile (3 × 10 mL). Purify the reaction mixture by passing it through a C 18 column, eluting with ACN / H2O (v / v = 2 / 3), filtering, and concentrating in vacuo. Obtain 0.102 g (yield 87.44%) of (S)-tert-butyl 5-(dimethylphosphoryl)-2-((7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)ethynyl)indoline-1-carboxylate as a pale yellow solid. LCMS: m / z = 664 [M+1] +

[0429] Step 9: ((S)-2-((7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)ethynyl)indolin-5-yl)dimethylphosphine oxide (21)

[0430] To a 10 mL round-bottom flask purged and maintained with a nitrogen inert atmosphere, add tert-butyl (S)-5-(dimethylphosphoryl)-2-((7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)ethynyl)indoline-1-carboxylate (0.086 g, 129.57 μmol), ethyl acetate (1 mL), and an EA solution of HCl (1 mL, 4 M). Stir the reaction mixture at room temperature for 1 h. Concentrate the mixture to obtain the crude product. Purify the crude product by preparative HPLC (mobile phase A: water (0.05% ammonium hydroxide), mobile phase B: acetonitrile; flow rate: 70 mL / min; gradient: 35 - 68 - 71% B (2 - 28 - 31 min); 260 nm; 34.960 - 37.222) to provide the desired product. Obtain 0.049 g (67.09% yield) of ((S)-2-((7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)ethynyl)indolin-5-yl)dimethylphosphine oxide (21) as a white solid. LCMS: m / z = 564 [M+1] + .

[0431] 1 H NMR (400 MHz, DMSO-d6) δ 7.56–7.53 (m, 1H), 7.34–7.15 (m, 2H), 6.91–6.73 (m, 3H), 5.20 (d, J = 8.5 Hz, 1H), 4.80 (d, J = 49.4 Hz, 1H), 4.46 (d, J = 6.2 Hz, 2H), 3.80–3.77 (m, 2H), 3.75–3.61 (m, 1H), 3.04 (t, J = 10.7 Hz, 1H), 2.81 (d, J = 10.3 Hz, 1H), 2.24 (s, 3H), 2.19 (s, 3H), 2.10 (t, J = 11.7 Hz, 1H), 2.04–1.91 (m, 2H), 1.72 (d, J = 10.2 Hz, 1H), 1.63 (d, J = 13.5 Hz, 6H).

[0432] Example 22

[0433] ((R)-2-((7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)ethynyl)indolin-5-yl)dimethylphosphine oxide (22)

[0434] Reaction Scheme:

[0435]

[0436] Experimental details:

[0437] Step 1: (R)-Indoline-2-carboxylic acid

[0438] Into a 100 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, add (R)-2-amino-3-(2-bromophenyl)propanoic acid (5.068 g, 20.76 mmol), CuBr (1.455 g, 10.14 mmol), K2CO3 (5.600 g, 40.51 mmol) and water (35 mL). Stir the reaction mixture at 100 °C for 16 h. Purify the reaction mixture by column C 18 purification, eluting with ACN / H2O (v / v = 1 / 20). Obtain 1.183 g (yield 34.91%) of (R)-indoline-2-carboxylic acid as a white solid. LCMS: m / z = 164 [M+1] + .

[0439] Step 2: (R)-Indolin-2-ylmethanol

[0440] Into a 25 mL three-necked flask, add (R)-indoline-2-carboxylic acid (1.181 g, 7.23 mmol) and THF (15 mL). Stir the reaction mixture at -78 °C. Then add LiAlH4 (0.626 g, 16.49 mmol). Stir the mixture at 25 °C for 16 h. Quench the resulting solution with methanol (2 mL). Filter the reaction mixture through a pad of diatomaceous earth and wash the diatomaceous earth pad with EA (2 × 10 mL). Add the resulting solution to water (30 mL). Extract the resulting solution with EA (3 × 50 mL). Combine the organic layers, wash with brine (50 mL), dry over anhydrous Na2SO4, and then concentrate the filtrate under reduced pressure to obtain the product. Purify the crude product by silica gel column chromatography, eluting with EA / hexane (v / v = 1 / 1). Obtain 0.653 g (yield 60.47%) of (R)-indolin-2-ylmethanol as a yellow solid. LCMS: m / z = 150 [M+1] + .

[0441] Step 3: (R)-(5-Bromoindolin-2-yl)methanol

[0442] To a 25 mL three-necked flask purged and maintained with an inert atmosphere of nitrogen, (R)-indolin-2-ylmethanol (0.615 g, 4.11 mmol) and acetonitrile (7 mL) were added. The reaction mixture was stirred at -30 ° C, and then NBS (0.615 g, 3.45 mmol) was added. The reaction mixture was stirred at -30 ° C for 0.5 h. The resulting solution was added to water (20 mL). The resulting solution was extracted with EA (3×30 mL). The organic layers were combined and washed with brine (30 mL) and dried over anhydrous Na2SO4. The filtrate was then concentrated under reduced pressure to obtain the product. The crude product was purified by silica gel column and eluted with EA / hexane (v / v=1 / 1). 0.716 g (yield 76.65%) of (R)-(5-bromoindolin-2-yl)methanol as a yellow oil was obtained. LCMS: m / z=228[M+1] + .

[0443] Step 4: (R)-tert-butyl 5-bromo-2-(hydroxymethyl)indoline-1-carboxylate

[0444] To a 25 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, (R)-(5-bromoindolyl-2-yl)methanol (0.680 g, 2.98 mmol), di-tert-butyl dicarbonate (1.043 g, 4.77 mmol) and DCM (8 mL) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was passed through C 18 Column purification, eluting with ACN / H2O (v / v=3 / 2). 0.914 g (93.41% yield) of (R)-tert-butyl 5-bromo-2-(hydroxymethyl)indoline-1-carboxylate was obtained as a yellow oil. LCMS: m / z=328 [M+1] + .

[0445] Step 5: (R)-tert-Butyl 5-(dimethylphosphoryl)-2-(hydroxymethyl)indoline-1-carboxylate.

[0446] To a 25 mL three-necked flask was added (R)-5-bromo-2-(hydroxymethyl)indoline-1-carboxylic acid tert-butyl ester (0.887 g, 2.70 mmol), palladium acetate (0.125 g, 556.77 μmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.292 g, 504.65 μmol), DIEA (1.187 g, 9.18 mmol), and DMF (10 mL). The reaction was stirred at 130 ° C for 0.5 h under a nitrogen atmosphere. Dimethylphosphine oxide (2 mL) was then added at 130 ° C. The reaction was stirred at 130 ° C for 3 h under a nitrogen atmosphere. The reaction mixture was passed through C 18Column purification was carried out, eluting with ACN / H2O (v / v = 1 / 3). 0.364 g (41.39% yield) of (R)-5-(dimethylphosphoryl)-2-(hydroxymethyl)indoline-1-carboxylic acid tert-butyl ester was obtained as a white solid. LCMS: m / z = 326 [M+1] + 。

[0447] Step 6: (R)-5-(dimethylphosphoryl)-2-formylindoline-1-carboxylic acid tert-butyl ester

[0448] To a 25 mL three-necked flask was added (R)-5-(dimethylphosphoryl)-2-(hydroxymethyl)indoline-1-carboxylic acid tert-butyl ester (0.172 g, 528.67 μmol) and DMF (2 mL). The reaction mixture was stirred at 0 °C. Then Dess-Martin periodinane (0.410 g, 966.65 μmol) was added. The mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered through a pad of Celite and the Celite pad was washed with EA (2 × 10 mL). The filtrate was concentrated in vacuo. 0.174 g (101.79% yield) of (R)-5-(dimethylphosphoryl)-2-formylindoline-1-carboxylic acid tert-butyl ester was obtained as a yellow solid. LCMS: m / z = 324 [M+1] +

[0449] Step 7: (R)-5-(dimethylphosphoryl)-2-ethynylindoline-1-carboxylic acid tert-butyl ester.

[0450] To a 25 mL three-necked flask was added (R)-5-(dimethylphosphoryl)-2-formylindoline-1-carboxylic acid tert-butyl ester (0.163 g, 504.13 μmol), K2CO3 (0.142 g, 1.02 mmol), and isopropanol (2 mL). The reaction mixture was stirred at 0 °C. Then dimethyl (1-diazo-2-oxopropyl)phosphonate (0.544 g, 2.83 mmol) was added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction mixture was purified by column chromatography, eluting with ACN / H2O (v / v = 2 / 3), filtered and concentrated in vacuo. 0.053 g (32.92% yield) of (R)-5-(dimethylphosphoryl)-2-ethynylindoline-1-carboxylic acid tert-butyl ester was obtained as a light red solid. LCMS: m / z = 320 [M+1] 18 Column purification was carried out, eluting with ACN / H2O (v / v = 2 / 3), filtering and concentrating in vacuo. 0.053 g (32.92% yield) of (R)-5-(dimethylphosphoryl)-2-ethynylindoline-1-carboxylic acid tert-butyl ester was obtained as a light red solid. LCMS: m / z = 320 [M+1] + 。

[0451] Step 8: (R)-5-(dimethylphosphoryl)-2-((7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)ethynyl)indoline-1-carboxylic acid tert-butyl ester

[0452] Add (3S,4R)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.063 g, 133.39 μmol), (R)-tert-butyl 5-(dimethylphosphoryl)-2-ethynylindoline-1-carboxylate (0.054 g, 169.10 μmol), Pd(PPh3)2Cl2 (0.024 g, 33.99 μmol), CuI (0.012 g, 63.00 μmol), DIEA (0.060 g, 464.24 μmol), and dimethyl sulfoxide (1 mL) to a 10 mL round-bottom flask. Stir the reaction mixture at room temperature for 3 h under a nitrogen atmosphere. Filter the reaction mixture through a pad of celite and wash the celite pad with acetonitrile (3 × 10 mL). Purify the reaction mixture by column chromatography using ACN / H2O (v / v = 2 / 3) as the eluent, filter, and concentrate in vacuo. Obtain 0.042 g (47.43% yield) of (R)-tert-butyl 5-(dimethylphosphoryl)-2-((7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)ethynyl)indoline-1-carboxylate as a pale yellow solid. LCMS: m / z = 664 [M+1] 18 Column purification, eluting with ACN / H2O (v / v = 2 / 3), filtering, and concentrating in vacuo. Obtain 0.042 g (47.43% yield) of (R)-tert-butyl 5-(dimethylphosphoryl)-2-((7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)ethynyl)indoline-1-carboxylate as a pale yellow solid. LCMS: m / z = 664 [M+1] +

[0453] Step 9: ((R)-2-((7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)ethynyl)indolin-5-yl)dimethylphosphine oxide (22)

[0454] To a 10 mL round-bottom flask purged and maintained with a nitrogen inert atmosphere, add tert-butyl (R)-5-(dimethylphosphoryl)-2-((7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)ethynyl)indoline-1-carboxylate (0.040 g, 60.26 μmol), ethyl acetate (1 mL), and an EA solution of hydrogen chloride (1 mL, 4 M). Stir the reaction mixture at room temperature for 1 h. Concentrate the mixture to obtain the crude product. Purify the crude product by preparative HPLC (mobile phase A: water (0.05% ammonium hydroxide), mobile phase B: acetonitrile; flow rate: 70 mL / min; gradient: 35 - 68 - 71% B (2 - 28 - 31 min); 260 nm; 34.960 - 37.222) to provide the desired product. Obtain 0.059 g (yield 61.65%) of ((R)-2-((7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)ethynyl)indolin-5-yl)dimethylphosphine oxide (22) as a white solid. LCMS: m / z = 564 [M+1] + 。

[0455] Example 23

[0456] (4-((3-(7-(((3S,4R)-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-2-(methylthio)phenyl)dimethylphosphine oxide (23)

[0457] Reaction Scheme:

[0458]

[0459] Experimental Details:

[0460] Step 1: (2-methoxy-3-nitrophenyl)(methyl)sulfane

[0461] 1-Fluoro-2-methoxy-3-nitrobenzene (2.051 g, 11.98 mmol), sodium thiomethoxide (1.082 g, 15.43 mmol), K2CO3 (2.495 g, 18.05 mmol), and DMF (30 mL) were placed in a 100 mL three-necked flask. The reactants were stirred at 100 °C for 16 h. The reaction was quenched with water (50 mL). The resulting solution was extracted with EA (3 × 100 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. 1.887 g (yield 79.02%) of (2-methoxy-3-nitrophenyl)(methyl)sulfane as a red oil was obtained. LCMS: m / z = 200 [M+1] + 。

[0462] Step 2: 2-Methoxy-3-(methylthio)aniline

[0463] (2-Methoxy-3-nitrophenyl)(methyl)sulfane (2.014 g, 10.10 mmol), iron (5.594 g, 100.17 mmol), NH4CL (5.316 g, 99.88 mmol), EtOH (20 mL), and water (4 mL) were added to a 100 mL three-necked flask. The reactants were stirred at 95 °C for 2 h. The reaction mixture was filtered through a pad of diatomaceous earth, and the pad was washed with methanol (2 × 30 mL). The filtrate was then concentrated under reduced pressure to give the product. The crude product was purified by silica gel column chromatography, eluting with EA / hexane (v / v = 1 / 8). 0.335 g (yield 19.58%) of 2-methoxy-3-(methylthio)aniline as a yellow oil was obtained. LCMS: m / z = 170 [M+1] + 。

[0464] Step 3: 4-Bromo-2-methoxy-3-(methylthio)aniline

[0465] 2-Methoxy-3-(methylthio)aniline (0.454 g, 2.68 mmol) and acetonitrile (5 mL) were added to a 25 mL three-necked flask purged and maintained under an inert nitrogen atmosphere. The reaction mixture was stirred at 0 °C, and then NBS (0.453 g, 2.54 mmol) was added. The reaction mixture was stirred at 0 °C for 1 h. The resulting solution was added to water (20 mL). The resulting solution was extracted with EA (3 × 30 mL). The organic layers were combined, washed with brine (30 mL), and dried over anhydrous Na2SO4. The filtrate was then concentrated under reduced pressure to give the product. The crude product was purified by silica gel column chromatography, eluting with EA / hexane (v / v = 1 / 9). 0.497 g (yield 74.66%) of 4-bromo-2-methoxy-3-(methylthio)aniline as a yellow oil was obtained. LCMS: m / z = 248 [M+1] + 。

[0466] Step 4: (4-Amino-3-methoxy-2-(methylthio)phenyl)dimethylphosphine oxide.

[0467] Add 4-bromo-2-methoxy-3-(methylthio)aniline (0.466 g, 1.87 mmol), palladium(II) acetate (0.083 g, 369.69 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.253 g, 437.24 μmol), DIEA (0.719 g, 5.56 μmol), and DMF (5 mL) to a 25 mL three-necked flask. Stir the reaction under a nitrogen atmosphere at 130 °C for 0.5 h. Then add dimethylphosphine oxide (2 mL) at 130 °C. Stir the reaction under a nitrogen atmosphere at 130 °C for 1 h. Purify the reaction mixture by column chromatography using C 18 column, eluting with ACN / H2O (v / v = 1 / 3). Obtain 0.155 g (33.64% yield) of (4-amino-3-methoxy-2-(methylthio)phenyl)dimethylphosphine oxide as a yellow oil. LCMS: m / z = 246 [M+1] + .

[0468] Step 5: (3-Methoxy-2-(methylthio)-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide

[0469] Place (4-amino-3-methoxy-2-(methylthio)phenyl)dimethylphosphine oxide (0.131 g, 534.08 μmol), 3-bromopropyne (0.656 g, 5.51 mmol), DIEA (0.227 g, 1.75 mmol), and DMF (2 mL) in a 25 mL three-necked flask. Stir the reaction mixture under nitrogen at 50 °C for 16 h. Filter the reaction mixture through a pad of diatomaceous earth and wash the pad with acetonitrile (3 × 20 mL). Purify the reaction mixture by column chromatography using C 18 column, eluting with ACN / H2O (v / v = 1 / 2). Obtain 0.065 g (42.95% yield) of (3-methoxy-2-(methylthio)-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide as a yellow oil. LCMS: m / z = 284 [M+1] + .

[0470] Step 6: (4-((3-(7-(((3S,4R)-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-2-(methylthio)phenyl)dimethylphosphine oxide (23)

[0471] To a 10 mL round-bottom flask was added (3S,4R)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.069 g, 146.09 μmol), (3-methoxy-2-(methylthio)-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide (0.060 g, 211.77 μmol), Pd(PPh3)2Cl2 (0.026 g, 36.83 μmol), CuI (0.015 g, 78.76 μmol), DIEA (0.062 g, 479.71 μmol), and dimethyl sulfoxide (1 mL). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 16 h. The reaction mixture was filtered through a pad of Celite and the Celite pad was washed with acetonitrile (3 × 20 mL). The filtrate was then concentrated under reduced pressure to give the crude product. 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: 35 - 70 - 95% B (2 - 30 - 60 min); 254 nm; RT: 37.056 - 39.529) to afford the desired product. 0.061 g (66.51% yield) of (4-((3-(7-(((3S,4R)-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-2-(methylthio)phenyl)dimethylphosphine oxide (23) was obtained as a white solid. LCMS: m / z = 628 [M+1] + .

[0472] 1 H NMR (600 MHz, DMSO-d6) δ 7.46 (t, J = 7.1 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 7.22–7.09 (m, 2H), 6.83–6.69 (m, 2H), 5.15 (d, J = 8.5 Hz, 1H), 4.80 (d, J = 49.5 Hz, 1H), 4.42 (d, J = 7.0 Hz, 2H), 3.80–3.58 (m, 6H), 3.04 (t, J = 11.3 Hz, 1H), 2.80 (d, J = 11.1 Hz, 1H), 2.40 (s, 3H), 2.27 (d, J = 13.1 Hz, 1H), 2.19 (s, 3H), 2.09 (t, J = 11.7 Hz, 1H), 1.95–1.93 (m, 1H), 1.69 (d, J = 13.4 Hz, 7H).

[0473] Examples 24 & 25

[0474] (S)-(4-((3-(7-(((3S,4R)-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)(imino)(tetrahydro-2H-pyran-4-yl)-λ 6 (R)-(4-((3-(7-(((3S,4R)-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)(imino)(tetrahydro-2H-pyran-4-yl)-λ 6 -sulfoxide (25)

[0475] Reaction Scheme:

[0476]

[0477] Experimental Details:

[0478] Step 1: 4-((3-Methoxy-4-nitrophenyl)thio)tetrahydro-2H-pyran

[0479] To a 50 mL three-necked flask, 3-methoxy-4-nitrobenzenethiol (0.528 g, 3.55 mmol), 4-bromotetrahydro-pyran (1.362 g, 8.25 mmol), Cs2CO3 (1.886 g, 5.78 mmol), and DMF (10 mL) were added. The reaction mixture was stirred at 80 °C for 10 h. The reaction was quenched with water (30 mL). The resulting solution was extracted with EA (3 × 30 mL), washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography, eluting with EA / hexane (v / v = 3 / 7). 0.669 g (yield 69.91%) of 4-((3-methoxy-4-nitrophenyl)thio)tetrahydro-2H-pyran as a yellow oil was obtained. LCMS: m / z = 270 [M+1] + .

[0480] Step 2: Imino(3-methoxy-4-nitrophenyl)(tetrahydro-2H-pyran-4-yl)-λ 6 -sulfoxide

[0481] In a 25 mL three-necked flask, 4-((3-methoxy-4-nitrophenyl)thio)tetrahydro-2H-pyran (0.633 g, 2.35 mmol), (diacetoxyiodo)benzene (1.339 g, 4.15 mmol), ammonium acetate (1.120 g, 14.52 mmol), and MeOH (7 mL) were added. The reaction mixture was stirred at room temperature under nitrogen for 6 h. The reaction mixture was filtered through a Celite pad and the Celite pad was washed with EA (3 × 20 mL). 0.467 g (66.15% yield) of imino(3-methoxy-4-nitrophenyl)(tetrahydro-2H-pyran-4-yl)-λ 6 -sulfoxide was obtained as a white solid. LCMS: m / z = 301 [M+1] + .

[0482] Step 3: 2,2,2-Trifluoro-N-((3-methoxy-4-nitrophenyl)(oxo)(tetrahydro-2H-pyran-4-yl)-λ 6 -sulfamoyl)acetamide

[0483] Imino(3-methoxy-4-nitrophenyl)(tetrahydro-2H-pyran-4-yl)-λ 6 -sulfoxide (0.458 g, 1.52 mmol) and THF (5 mL) were placed in a 25 mL three-necked flask. The reaction mixture was stirred at 0 °C. Then trifluoroacetic anhydride (0.538 g, 2.56 mmol) was added. The mixture was stirred at 25 °C for 0.5 h. The resulting solution was added to methanol (2 mL). Then the filtrate was concentrated under reduced pressure to obtain the product. The crude product was purified by silica gel column chromatography and eluted with EA / hexane (v / v = 2 / 3). 0.698 g (115.48% yield) of 2,2,2-trifluoro-N-((3-methoxy-4-nitrophenyl)(oxo)(tetrahydro-2H-pyran-4-yl)-λ 6 -sulfamoyl)acetamide was obtained as a yellow solid. LCMS: m / z = 397 [M+1] + .

[0484] Step 4: N-((4-Amino-3-methoxyphenyl)(oxo)(tetrahydro-2H-pyran-4-yl)-λ 6 -sulfamoyl)-2,2,2-trifluoroacetamide

[0485] 2,2,2-Trifluoro-N-((3-methoxy-4-nitrophenyl)(oxo)(tetrahydro-2H-pyran-4-yl)-λ 6-Sulfonamido)acetamide (0.641 g, 1.01 mmol), iron powder (0.990 g, 17.72 mmol), NH4Cl (0.976 g, 18.24 mmol), EtOH (5 mL), water (1 mL). The reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was filtered through a Celite pad and the Celite pad was washed with methanol (2 × 30 mL). Then the filtrate was concentrated under reduced pressure to obtain the product. The crude product was purified by silica gel column chromatography, eluting with EA / hexane (v / v = 7 / 3). 0.301 g (50.80% yield) of N-((4-Amino-3-methoxyphenyl)(oxo)(tetrahydro-2H-pyran-4-yl)-λ 6 -sulfonamido)-2,2,2-trifluoroacetamide was obtained as a yellow oil. LCMS: m / z = 367 [M+1] + .

[0486] Step 5: 2,2,2-Trifluoro-N-((3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)(oxo)(tetrahydro-2H-pyran-4-yl)-λ 6 -sulfonamido)acetamide

[0487] In a 25 mL three-necked flask, N-((4-Amino-3-methoxyphenyl)(oxo)(tetrahydro-2H-pyran-4-yl)-λ 6 -sulfonamido)-2,2,2-trifluoroacetamide (0.282 g, 769.74 μmol), 3-bromopropyne (0.568 g, 4.77 mmol), DIEA (0.211 g, 1.63 mmol), DMF (3 mL) were added. The reaction mixture was stirred at 50 °C under nitrogen for 16 h. The reaction mixture was filtered through a Celite pad and the Celite pad was washed with acetonitrile (3 × 20 mL). The reaction mixture was purified by C 18 column chromatography, eluting with ACN / H2O (v / v = 1 / 1). 0.218 g (70.03% yield) of 2,2,2-trifluoro-N-((3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)(oxo)(tetrahydro-2H-pyran-4-yl)-λ 6 -sulfonamido)acetamide was obtained as a yellow oil. LCMS: m / z = 405 [M+1] + .

[0488] Step 6: Imino(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)(tetrahydro-2H-pyran-4-yl)-λ 6 -sulfoxide

[0489] 2,2,2-Trifluoro-N-((3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)(oxo)(tetrahydro-2H-pyran-4-yl)-λ 6 -sulfonamido)acetamide (0.528 g, 3.55 mmol), K2CO3 (0.148 g, 1.07 mmol), and MeOH (2 mL) were placed in a 50 mL three-necked flask. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water (10 mL). The resulting solution was extracted with EA (3 × 30 mL), washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with EA / hexane (v / v = 1 / 20). 0.080 g (57.95% yield) of imino(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)(tetrahydro-2H-pyran-4-yl)-λ 6 -sulfoxide as a yellow oil was obtained. LCMS: m / z = 309 [M+1] +

[0490] Step 7: (4-((3-(7-(((3S,4R)-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)(imino)(tetrahydro-2H-pyran-4-yl)-λ 6 -sulfoxide

[0491] (3S,4R)-3-Fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.096 g, 201.15 μmol), imino(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)(tetrahydro-2H-pyran-4-yl)-λ 6 -sulfoxide (0.061 g, 201.04 μmol), Pd(PPh3)2Cl2 (0.028 g, 39.66 μmol), CuI (0.009 g, 47.25 μmol), DIEA (0.091 g, 704.10 μmol), and dimethyl sulfoxide (1 mL) were placed in a 10 mL round-bottom flask. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 16 h. The reaction mixture was filtered through a Celite pad and the Celite pad was washed with ACN (3 × 20 mL). Then the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by C 18Column purification, eluted with ACN / H2O (v / v = 2 / 3). 0.110 g (83.77% yield) of (4-((3-(7-(((3S,4R)-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)(imino)(tetrahydro-2H-pyran-4-yl)-λ 6 -sulfoxide, a white solid. LCMS: m / z = 653 [M+1] + .

[0492] Step 8: (S)-(4-((3-(7-(((3S,4R)-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)(imino)(tetrahydro-2H-pyran-4-yl)-λ 6 -sulfoxide (24) and (R)-(4-((3-(7-(((3S,4R)-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)(imino)(tetrahydro-2H-pyran-4-yl)-λ 6 -sulfoxide (25)

[0493] The sample (4-((3-(7-(((3S,4R)-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)(imino)(tetrahydro-2H-pyran-4-yl)-λ 6 -sulfoxide (0.107 g, 163.91 μmol) was subjected to preparative chiral separation (column: SA, mobile phase A: MTBE, mobile phase B: MeOH; flow rate: 20 mL / min; MTBE:MeOH = 90:10; 220 nm; RT: 10.692, 12.639) to provide two isomers. 0.049 g (45.79% yield) of (S)-(4-((3-(7-(((3S,4R)-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)(imino)(tetrahydro-2H-pyran-4-yl)-λ 6 -sulfoxide (24), a white solid. LCMS: m / z = 653 [M+1] + .

[0494] 11H NMR (600 MHz, DMSO-d6) δ 7.44–7.12 (m, 4H), 6.89 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 7.7 Hz, 1H), 6.42 (t, J = 6.3 Hz, 1H), 5.17 (d, J = 8.6 Hz, 1H), 4.80 (d, J = 49.4 Hz, 1H), 4.38 (d, J = 6.3 Hz, 1H), 3.96–3.78 (m, 6H), 3.65 (d, J = 29.9 Hz, 1H), 3.23–3.20 (m, 2H), 3.14–3.10 (m, 1H), 3.09–3.00 (m, 1H), 2.80 (d, J = 11.2 Hz, 1H), 2.19 (s, 3H), 2.12–2.05 (m, 1H), 1.95–1.90 (m, 1H), 1.79–1.69 (m, 2H), 1.49–1.40 (m, 2H), 1.25 (d, J = 13.8 Hz, 4H), 0.86 (t, J = 6.8 Hz, 1H).

[0495] and 0.047 g (43.92% yield) of (R)-(4-((3-(7-(((3S,4R)-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)(imino)(tetrahydro-2H-pyran-4-yl)-λ 6 -sulfoxide (25), a white solid. LCMS: m / z = 653 [M+1] + .

[0496] 1 1H NMR (600 MHz, DMSO-d6) δ 7.44–7.12 (m, 4H), 6.89 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 7.7 Hz, 1H), 6.42 (t, J = 6.3 Hz, 1H), 5.17 (d, J = 8.6 Hz, 1H), 4.80 (d, J = 49.4 Hz, 1H), 4.38 (d, J = 6.3 Hz, 1H), 3.96–3.78 (m, 6H), 3.65 (d, J = 29.9 Hz, 1H), 3.23–3.20 (m, 2H), 3.14–3.10 (m, 1H), 3.09–3.00 (m, 1H), 2.80 (d, J = 11.2 Hz, 1H), 2.19 (s, 3H), 2.12–2.05 (m, 1H), 1.95–1.90 (m, 1H), 1.79–1.69 (m, 2H), 1.49–1.40 (m, 2H), 1.25 (d, J = 13.8 Hz, 4H), 0.86 (t, J = 6.8 Hz, 1H).

[0497] Examples 26 & 27

[0498] (R)-(4-((3-(7-(((3S,4R)-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)(imino)(isopropyl)-λ 6 -sulfoxide (26) and (S)-(4-((3-(7-(((3S,4R)-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)(imino)(isopropyl)-λ 6 -sulfoxide (27)

[0499] Reaction Scheme:

[0500]

[0501] Experimental Details:

[0502] Step 1: Isopropyl (3-methoxy-4-nitrophenyl)sulfane

[0503] 3-Methoxy-4-nitrobenzenethiol (3.129 g, 16.88 mmol), 2-iodopropane (5.744 g, 33.78 mmol), Cs2CO3 (8.28 g, 26.11 mmol), and DMF (10 mL) were added to a 50 mL three-necked flask. The reaction mixture was stirred at 80 °C for 3 h. The reaction was quenched with water (30 mL). The resulting solution was extracted with EA (3 × 30 mL), washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with EA / hexane (v / v = 3 / 7). 3.253 g (yield 88.31%) of isopropyl (3-methoxy-4-nitrophenyl)sulfane was obtained as a yellow oil. LCMS: m / z = 228 [M+1] + .

[0504] Step 2: Imino(isopropyl)(3-methoxy-4-nitrophenyl)-λ 6 -sulfoxide

[0505] Add isopropyl (3-methoxy-4-nitrophenyl)sulfane (3.24 g, 14.25 mmol), (diacetoxyiodo)benzene (7.91 g, 24.55 mmol), ammonium acetate (6.83 g, 88.60 mmol), and MeOH (35 mL) to a 100 mL three-necked flask. Stir the reaction mixture under nitrogen at room temperature for 16 h. Quench the reaction with water (50 mL). Extract the resulting solution with EA (3 × 80 mL), wash with brine (80 mL), dry over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify the crude product by silica gel column chromatography, eluting with EA / hexane (v / v = 9 / 1). Obtain 3.005 g (81.61% yield) of imino(isopropyl)(3-methoxy-4-nitrophenyl)-λ 6 -sulfoxide as a white solid. LCMS: m / z = 259 [M+1] + .

[0506] Step 3: 2,2,2-Trifluoro-N-(isopropyl(3-methoxy-4-nitrophenyl)(oxo)-λ 6 -sulfonyl)acetamide

[0507] Place imino(isopropyl)(3-methoxy-4-nitrophenyl)-λ 6 -sulfoxide (2.991 g, 11.57 mmol) and THF (30 mL) in a 100 mL three-necked flask. Stir the reaction mixture at 0 °C. Then add trifluoroacetic anhydride (3.012 g, 14.34 mmol). Stir the mixture at 25 °C for 0.5 h. Add the resulting solution to methanol (5 mL). Then concentrate the filtrate under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography, eluting with EA / hexane (v / v = 2 / 3). Obtain 3.744 g (91.25% yield) of 2,2,2-trifluoro-N-(isopropyl(3-methoxy-4-nitrophenyl)(oxo)-λ 6 -sulfonyl)acetamide as a yellow solid. LCMS: m / z = 355 [M+1] + .

[0508] Step 4: N-((4-Amino-3-methoxyphenyl)(isopropyl)(oxo)-λ 6 -sulfonyl)-2,2,2-trifluoroacetamide

[0509] Place 2,2,2-trifluoro-N-(isopropyl(3-methoxy-4-nitrophenyl)(oxo)-λ 6-(sulfonyl)acetamide (2.992 g, 8.44 mmol), iron (4.908 g, 89.84 mmol), NH4Cl (0.4806 g, 87.88 mmol), EtOH (25 mL), water (5 mL). The reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was filtered through a Celite pad and the Celite pad was washed with methanol (2 × 30 mL). The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography, eluting with EA / hexane (v / v = 1 / 1). 3.171 g (115.78% yield) of N-((4-amino-3-methoxyphenyl)(isopropyl)(oxo)-λ 6 -sulfonyl)-2,2,2-trifluoroacetamide was obtained as a yellow oil. LCMS: m / z = 325 [M+1] + .

[0510] Step 5: 2,2,2-Trifluoro-N-(isopropyl(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)(oxo)-λ 6 -sulfonyl)acetamide

[0511] To a 25 mL three-necked flask was added N-((4-amino-3-methoxyphenyl)(isopropyl)(oxo)-λ 6 -sulfonyl)-2,2,2-trifluoroacetamide (0.514 g, 1.58 mmol), 3-bromopropyne (1.453 g, 12.21 mmol), DIEA (0.402 g, 3.11 mmol), DMF (6 mL). The reaction mixture was stirred at 50 °C under nitrogen for 16 h. The reaction mixture was filtered through a Celite pad and the Celite pad was washed with ACN (3 × 20 mL). The reaction mixture was purified by C 18 column chromatography, eluting with ACN / H2O (v / v = 1 / 1). 0.348 g (60.59% yield) of 2,2,2-trifluoro-N-(isopropyl(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)(oxo)-λ 6 -sulfonyl)acetamide was obtained as a yellow oil. LCMS: m / z = 363 [M+1] + .

[0512] Step 6: Imino(isopropyl)(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)-λ 6 -sulfoxide

[0513] To a 50 mL three-necked flask was added 2,2,2-trifluoro-N-(isopropyl(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)(oxo)-λ 6-(sulfonyl)acetamide (0.340 g, 938.27 μmol), K2CO3 (0.308 g, 2.21 mmol), MeOH (3.5 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water (10 mL). The resulting solution was extracted with EA (3 × 30 mL), washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction mixture was purified by column C 18 and eluted with ACN / H2O (v / v = 1 / 1). 0.187 g (yield 74.82%) of imino(isopropyl)(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)-λ 6 -sulfoxide was obtained as a yellow oil. LCMS: m / z = 267 [M+1] +

[0514] Step 7: (R)-imino(isopropyl)(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)-λ 6 -sulfoxide and (S)-imino(isopropyl)(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)-λ 6 -sulfoxide

[0515] The sample imino(isopropyl)(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)-λ 6 -sulfoxide (0.185 g, 694.55 μmol) was separated by preparative chiral chromatography (column: SC, mobile phase A: HeX, mobile phase B: ETOH; flow rate: 20 mL / min; HeX(0.1% IPA.M):ETOH = 55:45; 220 nm; RT: 9.773, 10.97) to provide two isomers. 0.076 g (yield 41.08%) of (R)-imino(isopropyl)(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)-λ 6 -sulfoxide was obtained as a white solid. LCMS: m / z = 267 [M+1] + .

[0516] And 0.075 g (40.54% yield) of (S)-imino(isopropyl)(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)-λ 6 -sulfoxide was obtained as a white solid. LCMS: m / z = 267 [M+1] + .

[0517] Step 8: (S)-(4-((3-(7-(((3S,4R)-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)(imino)(isopropyl)-λ 6 -sulfoxide (27)

[0518] Place (3S,4R)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.095 g, 201.15 μmmol), (S)-imino(isopropyl)(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)-λ 6 -sulfoxide (0.062 g, 201.04 μmol), Pd(PPh3)2Cl2 (0.028 g, 39.66 μmol), CuI (0.009 g, 47.25 μmol), DIEA (0.091 g, 704.10 μmol), and dimethyl sulfoxide (1 mL) in a 10 mL round-bottom flask. Stir the reaction mixture at room temperature under a nitrogen atmosphere for 16 h. Purify the crude product by preparative HPLC (mobile phase A: water (0.05% ammonium hydroxide), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 25 - 55 - 58% B (2 - 30 - 33 min); 240 nm; 30.59 - 32.54). Obtain 0.059 g (61.65% yield) of (S)-(4-((3-(7-(((3S,4R)-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)(imino)(isopropyl)-λ 6 -sulfoxide (27), as a white solid. LCMS: m / z = 611 [M+1] + .

[0519] 11H NMR (400 MHz, DMSO-d6) δ 7.40–7.17 (m, 4H), 6.88 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.39 (t, J = 6.3 Hz, 1H), 5.17 (d, J = 8.6 Hz, 1H), 4.80 (d, J = 49.6 Hz, 1H), 4.38 (d, J = 6.2 Hz, 2H), 3.94–3.58 (m, 7H), 3.19–2.99 (m, 2H), 2.81 (d, J = 11.0 Hz, 1H), 2.19 (s, 5H), 2.00–1.87 (m, 1H), 1.72 (d, J = 12.2 Hz, 1H), 1.12 (dd, J = 6.7, 4.5 Hz, 6H).

[0520] Step 9: (R)-(4-((3-(7-(((3S,4R)-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)(imino)(isopropyl)-λ 6 -sulfoxide (26)

[0521] Place (3S,4R)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.075 g, 158.80 μmol), (R)-imino(isopropyl)(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)-λ 6 -sulfoxide (0.044 g, 165.19 μmol), Pd(PPh3)2Cl2 (0.025 g, 35.41 μmol), CuI (0.017 g, 89.26 μmol), DIEA (0.078 g, 603.51 μmol), dimethyl sulfoxide (1 mL) into a 10 mL round-bottom flask. Stir the reaction mixture at room temperature under a nitrogen atmosphere for 16 h. Purify the crude product by preparative HPLC (mobile phase A: water (0.05% ammonium hydroxide), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 25 - 55 - 58% B (2 - 30 - 33 min); 240 nm; 30.59 - 32.54) to afford the desired product. Obtain 0.061 g (yield 62.89%) of (R)-(4-((3-(7-(((3S,4R)-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)(imino)(isopropyl)-λ 6 -sulfoxide (26), as a white solid. LCMS: m / z = 611 [M+1]+ .

[0522] 1 H NMR (400 MHz, DMSO-d6) δ 7.38–7.19 (m, 4H), 6.88 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.39 (t, J = 6.3 Hz, 1H), 5.18 (d, J = 8.6 Hz, 1H), 4.80 (d, J = 49.5 Hz, 1H), 4.38 (d, J = 6.2 Hz, 2H), 3.91–3.60 (m, 7H), 3.19–3.01 (m, 2H), 2.81 (d, J = 11.0 Hz, 1H), 2.31–2.05 (m, 5H), 2.03–1.89 (m, 1H), 1.72 (d, J = 11.9 Hz, 1H), 1.12 (dd, J = 6.8, 4.5 Hz, 6H).

[0523] Examples 28 & 29

[0524] (R)-(3-Methoxy-4-((3-(7-((1-methylpiperidin-3-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide (28) and (S)-(3-Methoxy-4-((3-(7-((1-methylpiperidin-3-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide (29)

[0525] Reaction Scheme

[0526]

[0527] Experimental Details

[0528] Step 1: (3-Methoxy-4-((3-(7-((1-methylpiperidin-3-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide.

[0529] Into an 8 mL sealed tube purged and maintained with a nitrogen inert atmosphere, add (4-((3-(7-amino-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (0.129 g, 276.55 μmol), 1-methylpiperidin-3-one hydrochloride (0.133 g, 888.92 μmol), acetic acid (0.2 mL), methanol (1 mL), DCM (1 mL). Then add sodium cyanoborohydride (0.178 g, 4.15 mmol). Stir the mixture at room temperature for 16 h. Filter the reaction mixture through a diatomaceous earth pad and wash the diatomaceous earth pad with ACN (3 × 20 mL). Then concentrate the filtrate under reduced pressure to obtain the crude product. Purify the crude product by preparative HPLC (mobile phase A: water (0.05% ammonium hydroxide), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 35 - 70 - 90% B (2 - 30 - 60 min); 262 nm; 44.428 - 48.546). Obtain 0.055 g (35.28% yield) of (3-methoxy-4-((3-(7-((1-methylpiperidin-3-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide as a yellow solid. LCMS: m / z = 564 [M+1] + .

[0530] Step 2: (R)-(3-methoxy-4-((3-(7-((1-methylpiperidin-3-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide (28) and (S)-(3-methoxy-4-((3-(7-((1-methylpiperidin-3-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide (29)

[0531] Sample (3-methoxy-4-((3-(7-((1-methylpiperidin-3-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide (0.054 g, 9.77 μmol) was separated into two isomers by preparative chiral separation (column: IG, mobile phase A: HeX, mobile phase B: DcM; flow rate: 20 mL / min; (HeX:DcM = 3:1)(0.1% IPA.M):EtOH = 50:50; 220 nm; RT: 5.392, 5.392). 5.28 mg (yield 9.77%) of (S)-(3-methoxy-4-((3-(7-((1-methylpiperidin-3-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide (29) was obtained as a white solid. LCMS: m / z = 564 [M+1]+.

[0532] And 5.04 mg (9.33% yield) of (R)-(3-methoxy-4-((3-(7-((1-methylpiperidin-3-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide (28) was obtained as a white solid. LCMS: m / z = 564 [M+1] + 。

[0533] Example 30

[0534] 6-(Dimethylphosphoryl)-3-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)picolinitrile (30)

[0535] Reaction Scheme:

[0536]

[0537] Experimental Details:

[0538] Step 1: 3-Amino-6-bromopicolinitrile.

[0539] 3-Aminopyridinecarbonitrile (0.51 g, 4.29 mmol), NBS (0.80 g, 4.51 mmol), and ACN (10 mL) were placed in a 50 mL bottom flask. The reaction mixture was stirred at 20 °C for 2 h. The crude product was purified by silica gel column chromatography and eluted with EA / hexane (v / v = 3 / 7). 0.521 g (yield 61.33%) of 3-amino-6-bromopyridinecarbonitrile as a brown solid was obtained. LCMS: m / z = 198 [M+1] + .

[0540] Step 2: 3-Amino-6-(dimethylphosphoryl)pyridinecarbonitrile.

[0541] 3-Amino-6-bromopyridinecarbonitrile (0.50 g, 2.51 mmol), palladium acetate (0.12 g, 0.53 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.33 g, 0.56 mmol), DIEA (1.04 g, 8.51 mmol), and DMF (10 mL) were placed in a 50 mL three-necked bottom flask purged and maintained with an inert nitrogen atmosphere. The reaction was heated to 130 °C and dimethylphosphine oxide (0.59 g, 7.50 mmol) was added. The mixture was stirred at 130 °C for 1 h. The residue was purified by C 18 column chromatography and eluted with ACN / water (v / v = 1 / 4). 0.608 g (crude) of 3-amino-6-(dimethylphosphoryl)pyridinecarbonitrile as an off-white solid was obtained. LCMS: m / z = 196 [M+1] + .

[0542] Step 3: tert-Butyl N-(2-cyano-6-dimethylphosphoryl-3-pyridyl)carbamate.

[0543] 3-Amino-6-(dimethylphosphoryl)pyridinecarbonitrile (0.55 g, 2.80 mmol), di-tert-butyl dicarbonate (3.06 g, 14.01 mmol), N-(4-pyridyl)dimethylamine (0.13 g, 1.08 mmol), and 1,4-dioxane (10 mL) were placed in a 500 mL round bottom flask. The reaction mixture was stirred at 110 °C for 0.5 h. The mixture was concentrated in vacuo. 0.79 g (crude) of tert-Butyl N-(2-cyano-6-dimethylphosphoryl-3-pyridyl)carbamate as a brown oil was obtained. LCMS: m / z = 396 [M+1] + .

[0544] Step 4: tert-Butyl N-(2-cyano-6-dimethylphosphoryl-3-pyridyl)carbamate.

[0545] Place N-Boc-N-(2-cyano-6-dimethylphosphoryl-3-pyridyl)carbamic acid tert-butyl ester (0.78 g, 1.98 mmol), K2CO3 (1.01 g, 7.32 mmol), and methanol (10 mL) into a 50 mL round-bottom flask. Stir the reaction mixture at 60 °C for 1 h. Concentrate the mixture in vacuo. Quench the reaction with water (500 mL) and extract with EA (50 mL). Combine the organic layers, wash with brine (2 × 50 mL), dry over anhydrous sodium sulfate, filter, and concentrate in vacuo. Obtain 0.346 g (crude product) of N-(2-cyano-6-dimethylphosphoryl-3-pyridyl)carbamic acid tert-butyl ester as a brown solid. LCMS: m / z = 296 [M+1] + 。

[0546] Step 5: tert-Butyl (2-cyano-6-(dimethylphosphoryl)pyridin-3-yl)(prop-2-yn-1-yl)carbamate.

[0547] Place N-(2-cyano-6-dimethylphosphoryl-3-pyridyl)carbamic acid tert-butyl ester (0.34 g, 1.15 mmol) and THF (20 mL) into a 50 mL round-bottom flask. Stir the reaction mixture at 0 °C. Slowly add NaH (0.21 g, 8.75 mmol) to the reaction mixture at 0 °C and stir for 0.5 h. Add 3-bromopropyne (0.80 g, 6.72 mmol) to the reaction and stir at 60 °C for 1 h. Quench the reaction with water (50 mL) and extract with EA (2 × 30 mL). Concentrate the organic layer in vacuo. Purify the mixture by flash C 18 purification, eluting with ACN / H2O (v / v = 1 / 4) to obtain the desired product. Obtain 0.238 g (yield 61.83%) of tert-butyl (2-cyano-6-(dimethylphosphoryl)pyridin-3-yl)(prop-2-yn-1-yl)carbamate as a yellow oil. LCMS: m / z = 334 [M+1] + 。

[0548] Step 6: 6-(Dimethylphosphoryl)-3-(prop-2-yn-1-ylamino)pyridinecarbonitrile.

[0549] Place tert-butyl (2-cyano-6-(dimethylphosphoryl)pyridin-3-yl)(prop-2-yn-1-yl)carbamate (0.24 g, 0.71 mmol), TFA (3 mL), and DCM (10 mL) into a 50 mL round-bottom flask. Stir the reaction mixture at room temperature for 0.5 h. Concentrate the reactant in vacuo. Purify the crude product by C 18Column purification, eluting with ACN / H2O (v / v = 1 / 9) to obtain the desired product. 0.101 g (60.66% yield) of 6-(dimethylphosphoryl)-3-(prop-2-yn-1-ylamino)picolinitrile as a brown solid was obtained. LCMS: m / z = 234 [M+1] + 。

[0550] Step 7: 6-(Dimethylphosphoryl)-3-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)picolinitrile (30).

[0551] (3S,4R)-3-Fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.12 g, 0.25 mmol), 6-(dimethylphosphoryl)-3-(prop-2-yn-1-ylamino)picolinitrile (0.09 g, 0.39 mmol), bis(triphenylphosphine)palladium(II) chloride (0.06 g, 0.08 mmol), CuI (0.01 g, 0.05 mmol), DIEA (0.09 g, 0.70 mmol), and dimethyl sulfoxide (5 mL) were placed in a 20 mL round-bottom flask. The reaction mixture was stirred at 60 °C under nitrogen for 1 h. The reaction was quenched with water (50 mL) and extracted with EA (2 × 50 mL). The organic layers were combined, washed with brine (2 × 100 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 NH4OH), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 35 - 67 - 67% B (2 - 30 - 33 min); 270 nm; RT: 28.86 - 29.72 min) to afford the desired product. 0.0124 g (8.59% yield) of 6-(dimethylphosphoryl)-3-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)picolinitrile (30) was obtained as a white solid. LCMS: m / z = 578 [M+1] + 。

[0552] 11H NMR (600 MHz, DMSO-d6) δ 8.01–7.95 (m, 1H), 7.65–7.61 (m, 1H), 7.54 (t, J = 6.1 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 7.7 Hz, 1H), 5.19 (d, J = 8.5 Hz, 1H), 4.80 (d, J = 49.5 Hz, 1H), 4.48 (d, J = 5.9 Hz, 2H), 3.89–3.80 (m, 2H), 3.66 (d, J = 29.0 Hz, 1H), 3.04 (t, J = 11.3 Hz, 1H), 2.80 (d, J = 11.2 Hz, 1H), 2.26 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.12–2.05 (m, 1H), 2.01–1.90 (m, 1H), 1.75–1.69 (m, 1H), 1.63 (s, 3H), 1.61 (s, 3H).

[0553] Examples 31, 32, 33 and 34

[0554] (4 - ((3 - (7 - (((3S,4R)-3 - fluoro - 1 - methylpiperidin - 4 - yl)amino)-3 - ((S)-2,2,2 - trifluoro - 1 - hydroxyethyl)benzo[b]thiophen - 2 - yl)prop - 2 - ynyl)amino)-3 - methoxyphenyl)dimethylphosphine oxide (31), (4 - ((3 - (7 - (((3R,4S)-3 - fluoro - 1 - methylpiperidin - 4 - yl)amino)-3 - ((S)-2,2,2 - trifluoro - 1 - hydroxyethyl)benzo[b]thiophen - 2 - yl)prop - 2 - ynyl)amino)-3 - methoxyphenyl)dimethylphosphine oxide (32), (4 - ((3 - (7 - (((3S,4R)-3 - fluoro - 1 - methylpiperidin - 4 - yl)amino)-3 - ((R)-2,2,2 - trifluoro - 1 - hydroxyethyl)benzo[b]thiophen - 2 - yl)prop - 2 - ynyl)amino)-3 - methoxyphenyl)dimethylphosphine oxide (33) and (4 - ((3 - (7 - (((3R,4S)-3 - fluoro - 1 - methylpiperidin - 4 - yl)amino)-3 - ((R)-2,2,2 - trifluoro - 1 - hydroxyethyl)benzo[b]thiophen - 2 - yl)prop - 2 - ynyl)amino)-3 - methoxyphenyl)dimethylphosphine oxide (34)

[0555] Reaction Scheme

[0556]

[0557] Experimental Details

[0558] Step 1: (4 - ((3 - (7 - (((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((S)-2,2,2-trifluoro-1-hydroxyethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (31), (4 - ((3 - (7 - (((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((S)-2,2,2-trifluoro-1-hydroxyethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (32), (4 - ((3 - (7 - (((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((R)-2,2,2-trifluoro-1-hydroxyethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (33) and (4 - ((3 - (7 - (((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((R)-2,2,2-trifluoro-1-hydroxyethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (34).

[0559] 2,2,2-Trifluoro-1-(7-((3-fluoro-1-methylpiperidin-4-yl)amino)-2-iodobenzo[b]thiophen-3-yl)ethan-1-ol (0.07 g, 0.29 mmol), (3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide (0.10 g, 0.21 mmol), bis(triphenylphosphine)palladium(II) chloride (0.03 g, 0.04 mmol), CuI (0.01 g, 0.05 mmol), DIEA (0.08 g, 0.65 mmol), and dimethyl sulfoxide (5 mL) were placed in a 20 mL round-bottom flask. The reaction mixture was stirred at 60 °C for 1 h under nitrogen. The reaction was quenched with water (50 mL) and extracted with EA (2 × 50 mL). The organic layers were combined, washed with brine (2 × 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was further purified by preparative HPLC using MeOH / H2O (0.1% ammonium hydroxide), flow rate: 25 mL / min; gradient: 50 - 85 - 100% B (2 - 30 - 60 min); 270 nm; RT: 36.800 - 38.238 / 40.647 - 42.205). The resulting product was separated by preparative chiral HPLC (column: IG, mobile phase A: hexane, mobile phase B: EtOH; flow rate: 20 mL / min; hexane:EtOH = 50:50; 220 nm; RT: 5.307, 6.573, 7.835) to afford three isomers. 0.0165 g (yield 13.35%) of (4-((3-(7-((3-fluoro-1-methylpiperidin-4-yl)amino)-3-((R)-2,2,2-trifluoro-1-hydroxyethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (racemic) was obtained as a yellow solid. LCMS: m / z = 598 [M+1] +

[0560] And 0.008 g (13.37% yield) of (4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((S)-2,2,2-trifluoro-1-hydroxyethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (31) was obtained as a white solid. LCMS: m / z = 598 [M+1] +

[0561] 11H NMR (600 MHz, DMSO-d6) δ 7.51 (d, J = 8.0 Hz, 1H), 7.25–7.20 (m, 2H), 7.17–7.12 (m, 1H), 7.10 (d, J = 5.2 Hz, 1H), 6.84–6.80 (m, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.08 (t, J = 6.4 Hz, 1H), 5.43–5.35 (m, 1H), 5.05 (d, J = 8.2 Hz, 1H), 4.80 (d, J = 49.2 Hz, 1H), 4.35 (d, J = 6.4 Hz, 2H), 3.86 (s, 3H), 3.64 (d, J = 28.8 Hz, 1H), 3.04 (t, J = 11.2 Hz, 1H), 2.80 (d, J = 11.2 Hz, 1H), 2.28 (d, J = 13.2 Hz, 1H), 2.20 (s, 3H), 2.10 (t, J = 11.6 Hz, 1H), 1.97–1.88 (m, 1H), 1.77–1.69 (m, 1H), 1.60 (s, 3H), 1.58 (s, 3H).

[0562] and 0.007 g (11.69% yield) of (4-((3-(7-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((S)-2,2,2-trifluoro-1-hydroxyethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (32). LCMS: m / z = 598 [M+1] +

[0563] 11H NMR (600 MHz, DMSO-d6) δ 7.51 (d, J = 8.0 Hz, 1H), 7.25–7.20 (m, 2H), 7.17–7.12 (m, 1H), 7.10 (d, J = 5.2 Hz, 1H), 6.84–6.80 (m, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.08 (t, J = 6.4 Hz, 1H), 5.43–5.35 (m, 1H), 5.05 (d, J = 8.2 Hz, 1H), 4.80 (d, J = 49.2 Hz, 1H), 4.35 (d, J = 6.4 Hz, 2H), 3.86 (s, 3H), 3.64 (d, J = 28.8 Hz, 1H), 3.04 (t, J = 11.2 Hz, 1H), 2.80 (d, J = 11.2 Hz, 1H), 2.28 (d, J = 13.2 Hz, 1H), 2.20 (s, 3H), 2.10 (t, J = 11.6 Hz, 1H), 1.97–1.88 (m, 1H), 1.77–1.69 (m, 1H), 1.60 (s, 3H), 1.58 (s, 3H).

[0564] The third eluate (racemate) was separated by preparative chiral HPLC (column: IG, mobile phase A: (HeX:DcM = 5:1)(0.1% IPA.M), mobile phase B: EtOH; flow rate: 20 mL / min; (HeX:DcM = 5:1)(0.1% IPA.M):EtOH = 70:30; 220 nm; RT: 6.840, 7.713) to afford two additional isomers. 0.0047 g (7.85% yield) of (4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((R)-2,2,2-trifluoro-1-hydroxyethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (33) was obtained as a white solid. LCMS: m / z = 598 [M+1] +

[0565] and 0.0049 g (7.85% yield) of (4-((3-(7-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((R)-2,2,2-trifluoro-1-hydroxyethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (34) was obtained as a white solid. LCMS: m / z = 598 [M+1] +

[0566] Examples 35 and 36

[0567] (3R,4S)-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 (35) and (3S,4R)-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 (36)

[0568] Reaction Scheme

[0569]

[0570] Step 1: (3R,4S)-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 (35) and (3S,4R)-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 (36)

[0571] 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 (0.15 g, 0.26 mmol) was further separated by Prep-HPLC-Gilson under the following conditions: column, CHIRAL ART Cellulose-SA column (2 cm × 25 cm, 5 μm); mobile phase, MTBE (0.1% DEA):MeOH = 90:10; flow rate: 20 mL / min. This gave Compound A (the first eluted isomer, retention time 4.663 min) and Compound B (the second eluted isomer, retention time 5.689 min). 0.0625 g (40.72% yield) of (3R,4S)-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 (35) was obtained as a white solid. LCMS: m / z = 584 [M+1] +11H NMR (400 MHz, DMSO-d6) δ 7.44–7.36 (m, 1H), 7.30–7.18 (m, 3H), 6.90 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.52 (d, J = 12.5 Hz, 1H), 5.18 (d, J = 8.5 Hz, 1H), 4.80 (d, J = 49.4 Hz, 1H), 4.39 (d, J = 6.3 Hz, 2H), 3.90 (s, 3H), 3.89–3.76 (m, 2H), 3.73–3.58 (m, 1H), 3.10 (s, 3H), 3.04 (d, J = 23.0 Hz, 1H), 2.80 (d, J = 11.0 Hz, 1H), 2.28 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.14–2.04 (m, 1H), 2.02–1.88 (m, 1H), 1.72 (d, J = 12.3 Hz, 1H).

[0572] And 0.0665 g (43.32% yield) of (3S,4R)-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 (36), which was a white solid. LCMS: m / z = 584 [M+1] +

[0573] 1 1H NMR (400 MHz, DMSO-d6) δ 7.44–7.36 (m, 1H), 7.30–7.18 (m, 3H), 6.90 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.52 (d, J = 12.5 Hz, 1H), 5.18 (d, J = 8.5 Hz, 1H), 4.80 (d, J = 49.4 Hz, 1H), 4.39 (d, J = 6.3 Hz, 2H), 3.90 (s, 3H), 3.89–3.76 (m, 2H), 3.73–3.58 (m, 1H), 3.10 (s, 3H), 3.04 (d, J = 23.0 Hz, 1H), 2.80 (d, J = 11.0 Hz, 1H), 2.28 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.14–2.04 (m, 1H), 2.02–1.88 (m, 1H), 1.72 (d, J = 12.3 Hz, 1H).

[0574] Example 37

[0575] (5-((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)-6-methoxypyridin-2-yl)dimethylphosphine oxide (37).

[0576] Reaction Scheme

[0577]

[0578] Experimental Details

[0579] Step 1: (5-((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)-6-methoxypyridin-2-yl)dimethylphosphine oxide (37).

[0580] (3R,4S)-3-Fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.15 g, 0.31 mmol), (6-methoxy-5-(prop-2-yn-1-ylamino)pyridin-2-yl)dimethylphosphine oxide (0.09 g, 0.36 mmol), bis(triphenylphosphine)palladium(II) chloride (0.03 g, 0.04 mmol), CuI (0.01 g, 0.05 mmol), DIEA (0.12 g, 0.95 mmol), and dimethyl sulfoxide (2 mL) were placed in an 8 mL round-bottom flask. The reaction mixture was stirred under nitrogen at 60 °C for 1 h. The reaction was quenched with water (50 mL) and extracted with EA (2 × 50 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was further purified by preparative HPLC using ACN / H2O (0.05% ammonium hydroxide), flow rate: 70 mL / min; gradient: 30 - 70 - 95% B (2 - 30 - 60 min); 265 nm; RT: 33,005 - 35,765). 0.0669 g (36.89%) of (5-((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)-6-methoxypyridin-2-yl)dimethylphosphine oxide (37) was obtained as a yellow solid. LCMS: m / z = 583 [M+1] +

[0581] 11H NMR (600 MHz, DMSO-d6) δ 7.43–7.37 (m, 1H), 7.29–7.25 (m, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.10–7.04 (m, 1H), 6.78 (d, J = 7.2 Hz, 1H), 6.41 (t, J = 6.4 Hz, 1H), 5.18 (d, J = 8.4 Hz, 1H), 4.80 (d, J = 49.2 Hz, 1H), 4.35 (d, J = 6.4 Hz, 2H), 3.94 (s, 3H), 3.86–3.77 (m, 2H), 3.65 (d, J = 29.6 Hz, 1H), 3.07–2.98 (m, 1H), 2.84–2.77 (m, 1H), 2.29–2.21 (m, 1H), 2.19 (d, J = 6.8 Hz, 3H), 2.11–2.06 (m, 1H), 1.97–1.93 (m, 1H), 1.74–1.69 (m, 1H), 1.59 (s, 3H), 1.57 (s, 3H).

[0582] Example 38

[0583] (4 - ((3 - (7 - (((3S,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)dimethylphosphine oxide (38).

[0584] Reaction Scheme:

[0585]

[0586] Experimental Details:

[0587] Step 1: (3S)-3 - fluoro - N-(2 - iodo - 3-(2,2,2 - trifluoroethyl)benzo[b]thiophen - 7 - yl)piperidin - 4 - amine.

[0588] (3S)-3-Fluoro-4-((2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (7.22 g, 12.93 mmol), DCM (15 mL), and TFA (5 mL) were placed in a 100 mL round-bottom flask. The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous NaHCO3 (100 mL) and extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. 7.10 g (crude) of (3S)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidin-4-amine was obtained as a yellow solid. LCMS: m / z = 459 [M+1] + .

[0589] Step 2: (3S,4S)-3-Fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine.

[0590] (3S)-3-Fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)piperidin-4-amine (6.86 g, 14.97 mmol), paraformaldehyde (1.32 g, 43.96 mmol), sodium cyanoborohydride (4.01 g, 64.85 mmol), EtOH (100 mL), and HOAc (2 mL) were placed in a 500 mL round-bottom flask. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NaHCO3 (100 mL) and extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with MeOH / DCM (v / v = 1 / 20). The racemate was separated by preparative chiral HPLC (column: IG, mobile phase A: HeX, mobile phase B: IPA; flow rate: 20 mL / min; HeX:IPA = 80:20; 220 nm; RT: 7.982) to afford 2.21 g (31.26% yield) of (3S,4S)-3-fluoro-N-(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] + .

[0591] Step 3: (4 - ((3 - (7 - (((3S,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)dimethylphosphine oxide (38).

[0592] Into an 8 mL sealed tube purged and maintained under an inert nitrogen atmosphere, place (3S,4S)-3 - fluoro - N-(2 - iodo - 3-(2,2,2 - trifluoroethyl)benzo[b]thiophen - 7 - yl)-1 - methylpiperidin - 4 - amine (0.10 g, 0.21 mmol), (3 - methoxy - 4-(prop - 2 - yn - 1 - ylamino)phenyl)dimethylphosphine oxide (0.08 g, 0.32 mmol), bis(triphenylphosphine)palladium(II) chloride (0.03 g, 0.04 mmol), CuI (0.01 g, 0.02 mmol), DIEA (0.10 g, 0.74 mmol), and dimethyl sulfoxide (2 mL). Stir the reaction mixture under nitrogen at 60 °C for 2 h. Quench the reaction with water (20 mL), extract with EA (30 mL), wash the combined organic layers with brine (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify the mixture 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; RT: 26.258 - 28.090 min) to afford the desired product. Obtain 0.0536 g (48.87% yield) of (4 - ((3 - (7 - (((3S,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)dimethylphosphine oxide (38) as a yellow solid. LCMS: m / z = 582 [M + 1] + 。

[0593] 11H NMR (400 MHz, DMSO-d6) δ 7.26 (d, J = 8.0 Hz, 1H), 7.23–7.19 (m, 1H), 7.16 (d, J = 1.6 Hz, 1H), 7.15–7.11 (m, 1H), 6.89–6.82 (m, 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.07 (t, J = 6.4 Hz, 1H), 5.57 (d, J = 8.8 Hz, 1H), 4.73–4.50 (m, 1H), 4.34 (d, J = 6.4 Hz, 2H), 3.86 (s, 3H), 3.77 (t, J = 11.2 Hz, 2H), 3.59 (d, J = 4.8 Hz, 1H), 3.14–3.05 (m, 1H), 2.69 (d, J = 11.6 Hz, 1H), 2.23 (s, 3H), 2.13–2.00 (m, 2H), 1.95 (d, J = 13.6 Hz, 1H), 1.60 (s, 3H), 1.57 (s, 3H), 1.52–1.48 (m, 1H).

[0594] Example 39

[0595] 3-(5-(Dimethylphosphoryl)-2-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)-1,2,4-oxadiazol-5(2H)-one (39).

[0596] Reaction Scheme

[0597]

[0598] Experimental Details

[0599] Step 1: 2-Amino-5-(dimethylphosphoryl)benzonitrile.

[0600] Into a 100 mL three-necked flask purged and maintained under an inert nitrogen atmosphere, 2-amino-5-bromobenzonitrile (4.070 g, 20.62 mmol), Pd(OAc)2 (1.872 g, 8.33 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.018 g, 3.49 mmol), DIEA (4.046 g, 31.31 mmol) and DMF (20 mL) were placed. The reaction mixture was stirred at 130 °C for 0.5 h. Then dimethylphosphine oxide (4.045 g, 51.83 mmol) was added. The reaction mixture was stirred at 130 °C for an additional 1 h. LCMS indicated completion of the reaction. The reaction mixture was passed through C 18Column purification, eluted with ACN / H2O (v / v = 2 / 8). 2,297 g (yield 57.27%) of 2-amino-5-(dimethylphosphoryl)benzonitrile was obtained as a red oil. LCMS: m / z = 195 [M+1] + 。

[0601] Step 2: 5-(Dimethylphosphoryl)-2-(prop-2-yn-1-ylamino)benzonitrile.

[0602] Place 2-amino-5-(dimethylphosphoryl)benzonitrile (2.63 g, 13.54 mmol), 3-bromopropyne (5.73 g, 48.17 mmol), DIEA (2.99 g, 23.13 mmol), KI (2.17 g, 13.07 mmol), and DMF (10 mL) into a 50 mL flask. Stir the reaction mixture at 80 °C for 16 h. LCMS indicated the completion of the reaction. Purify the reaction mixture by passing it through a C 18 column, eluted with ACN / H2O (v / v = 2 / 8). 1.019 g (yield 32.40%) of 5-(dimethylphosphoryl)-2-(prop-2-yn-1-ylamino)benzonitrile as a red solid was obtained. LCMS: m / z = 233 [M+1] + 。

[0603] Step 3: 5-(Dimethylphosphoryl)-N-hydroxy-2-(prop-2-yn-1-ylamino)benzamidine amide.

[0604] Place 5-(dimethylphosphoryl)-2-(prop-2-yn-1-ylamino)benzonitrile (0.88 g, 3.79 mmol), NH2-OH (50% aqueous solution, 10 mL), and EtOH (10 mL) into a 50 mL flask. Stir the reaction mixture at 70 °C for 3 h. LCMS indicated the completion of the reaction. Purify the reaction mixture by passing it through a C 18 column, eluted with ACN / H2O (v / v = 1 / 10). 0.982 g (yield 97.70%) of 5-(dimethylphosphoryl)-N-hydroxy-2-(prop-2-yn-1-ylamino)benzamidine amide as a red oil was obtained. LCMS: m / z = 266 [M+1] + 。

[0605] Step 4: 3-(5-(Dimethylphosphoryl)-2-(prop-2-yn-1-ylamino)phenyl)-1,2,4-oxadiazol-5(2H)-one.

[0606] Into a 100 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, 5-(dimethylphosphoryl)-N-hydroxy-2-(prop-2-yn-1-ylamino)benzamidine amide (0.269 g, 1.01 mmol), CDI (0.512 g, 3.16 mmol), DBU (0.354 g, 2.33 mmol), and DMF (3 mL) were added. The reaction mixture was stirred at 100 °C for 2 h. LCMS indicated that the reaction was complete. The reaction mixture was purified by column 18 chromatography, eluting with ACN / H2O (v / v = 1 / 10). 0.049 g (yield 16.59%) of 3-(5-(dimethylphosphoryl)-2-(prop-2-yn-1-ylamino)phenyl)-1,2,4-oxadiazol-5(2H)-one was obtained as a red solid. LCMS: m / z = 292 [M+1] + .

[0607] Step 5: 3-(5-(dimethylphosphoryl)-2-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)-1,2,4-oxadiazol-5(2H)-one (39).

[0608] Into a 50 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, place (3S,4R)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.059 g, 0.12 mmol), 3-(5-(dimethylphosphoryl)-2-(prop-2-yn-1-ylamino)phenyl)-1,2,4-oxadiazol-5(2H)-one (0.044 g, 0.15 mmol), CuI (0.070 g, 0.37 mmol), Pd(PPh3)2Cl2 (0.021 g, 0.030 mmol), DIEA (0.070 g, 0.54 mmol) and DMSO (2 mL). Stir the reaction mixture at room temperature for 1 h. LCMS indicates that the reaction is complete. Purify the mixture by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 35 - 69 - 69% B (2 - 30 - 60 min); 266 nm; RT: 6.45 - 7.91 min). Obtain 0.019 g (yield 24.00%) of 3-(5-(dimethylphosphoryl)-2-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)-1,2,4-oxadiazol-5(2H)-one (39) as an off-white solid. LCMS: m / z = 636 [M+1] + .

[0609] 1 1H NMR (600 MHz, DMSO) δ 8.01 (d, J = 12.0 Hz, 1H), 7.81 (s, 1H), 7.69 (t, J = 9.5 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.25 (d, J = 7.9 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.80 (d, J = 7.7 Hz, 1H), 5.40 (d, J = 7.0 Hz, 2H), 4.95 (d, J = 48.0 Hz, 2H), 3.92–3.73 (m, 3H), 3.11 (s, 2H), 2.49–2.45 (m, 3H), 2.14–1.98 (m, 2H), 1.86 (d, J = 12.0 Hz, 2H), 1.62 (s, 3H), 1.60 (s, 3H), 1.26 (s, 1H).

[0610] Example 40

[0611] 3-(4-((3-(7-(((3S,4R)-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)-1,2,4-oxadiazol-5(2H)-one (40).

[0612] Reaction Scheme

[0613]

[0614] Experimental Details

[0615] Step 1: 3-Methoxy-4-nitrobenzonitrile.

[0616] Place 3-fluoro-4-nitrobenzonitrile (4.97 g, 29.92 mmol), MeONa (5.49 g, 101.62 mmol), and MeOH (80 mL) into a 250 mL flask. Stir the reaction mixture at 30 °C for 16 h. LCMS indicates the completion of the reaction. Add the resulting solution to water (100 mL). Extract the resulting solution with EA (2 × 100 mL). Combine the organic layers, wash with brine (20 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Purify the crude product by silica gel column chromatography, eluting with hexane / EA (v / v = 20 / 1). Obtain 1.41 g (26.45% yield) of 3-methoxy-4-nitrobenzonitrile as a yellow solid. LCMS: m / z = 179 [M+1] + .

[0617] Step 2: 4-Amino-3-methoxybenzonitrile.

[0618] Place 3-methoxy-4-nitrobenzonitrile (1.41 g, 7.91 mmol), Fe (2.16 g, 38.68 mmol), NH4Cl (2.66 g, 49.73 mmol), EtOH (50 mL), and H2O (10 mL). Stir the reaction mixture at 80 °C for 3 h. LCMS indicates the completion of the reaction. Filter the mixture, collect the filtrate, and concentrate in vacuo. Purify the crude product by C 18 column chromatography, eluting with ACN (100%). Obtain 1.12 g (95.51% yield) of 4-amino-3-methoxybenzonitrile as a yellow solid. LCMS: m / z = 149 [M+1] + .

[0619] Step 3: 3-Methoxy-4-(prop-2-yn-1-ylamino)benzonitrile.

[0620] 4-Amino-3-methoxybenzonitrile (0.699 g, 4.72 mmol), 3-bromopropyne (2.157 g, 18.13 mmol), DIEA (2.386 g, 18.46 mmol), and DMF (5 mL) were placed in a 50 mL flask. The reaction mixture was stirred at 80 °C for 4 h. LCMS indicated that the reaction was complete. The reaction mixture was purified by passing through a C 18 column and eluted with ACN / H2O (v / v = 2 / 8). 0.581 g (yield 66.13%) of 3-methoxy-4-(prop-2-yn-1-ylamino)benzonitrile as a red solid was obtained. LCMS: m / z = 187 [M+1] + .

[0621] Step 4: N-Hydroxy-3-methoxy-4-(prop-2-yn-1-ylamino)benzamidine amide.

[0622] 3-Methoxy-4-(prop-2-yn-1-ylamino)benzonitrile (0.394 g, 2.11 mmol), NH2-OH (50% aqueous solution, 10 mL), and EtOH (10 mL) were placed in a 50 mL flask. The reaction mixture was stirred at 70 °C for 3 h. LCMS indicated that the reaction was complete. The reaction mixture was purified by passing through a C 18 column and eluted with ACN / H2O (v / v = 4 / 6). 0.376 g (81.05% yield) of N-hydroxy-3-methoxy-4-(prop-2-yn-1-ylamino)benzamidine amide as a red oil was obtained. LCMS: m / z = 220 [M+1] + .

[0623] Step 5: 3-(3-Methoxy-4-(prop-2-yn-1-ylamino)phenyl)-1,2,4-oxadiazol-5(2H)-one.

[0624] N-Hydroxy-3-methoxy-4-(prop-2-yn-1-ylamino)benzamidine amide (0.290 g, 1.56 mmol), CDI (0.592 g, 3.65 mmol), DBU (0.518 g, 3.40 mmol), and DMF (2 mL) were placed in a 50 mL flask. The reaction mixture was stirred at 100 °C for 4 h. LCMS indicated that the reaction was complete. The reaction mixture was purified by passing through a C 18 column and eluted with ACN / H2O (v / v = 1 / 1). 0.065 g (17.02% yield) of 3-(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)-1,2,4-oxadiazol-5(2H)-one, as a red oil, was obtained. LCMS: m / z = 246 [M+1] + .

[0625] Step 6: 3-(4-((3-(7-(((3S,4R)-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)-1,2,4-oxadiazol-5(2H)-one (40).

[0626] Into a 50 mL three-necked flask purged and maintained under an inert nitrogen atmosphere, place (3S,4R)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.108 g, 0.23 mmol), 3-(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)-1,2,4-oxadiazol-5(2H)-one (0.110 g, 0.45 mmol), CuI (0.018 g, 0.068 mmol), Pd(PPh3)2Cl2 (0.061 g, 0.086 mmol), DIEA (0.110 g, 0.81 mmol) and DMSO (2 mL). Stir the reaction mixture at room temperature for 1 h. LCMS indicates completion of the reaction. The mixture is purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 25 - 75 - 75% B (2 - 30 - 60 min); 266 nm; RT: 52.053 - 53.667 min). 0.018 g (13.35% yield) of 3-(4-((3-(7-(((3S,4R)-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)-1,2,4-oxadiazol-5(2H)-one (40) is obtained as an off-white solid. LCMS: m / z = 590 [M+1] + 。

[0627] 1 H NMR (600 MHz, DMSO) δ 7.57–7.11 (m, 5H), 6.87 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 7.7 Hz, 1H), 6.36 (t, J = 6.2 Hz, 1H), 5.61 (d, J = 8.0 Hz, 1H), 5.10 (d, J = 47.5 Hz, 2H), 4.38 (d, J = 6.2 Hz, 2H), 3.86 (s, 3H), 3.85–3.80 (m, 2H), 3.75 (d, J = 8.4 Hz, 1H), 3.43 (s, 2H), 3.13 (s, 1H), 2.79 (s, 3H), 2.24–2.11 (m, 1H), 1.98 (d, J = 12.4 Hz, 1H).

[0628] Example 41

[0629] (4 - ((3 - (7 - (((3S,4R)-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 - 2 - methylphenyl)dimethylphosphine oxide (41).

[0630] Reaction Scheme

[0631]

[0632] Experimental Details

[0633] Step 1: 4 - bromo - 2 - methoxy - 3 - methylaniline.

[0634] Add 2 - methoxy - 3 - methylaniline (1.192 g, 8.69 mmol) and ACN (30 mL) to a 50 mL flask. Then add NBS (1.549 g, 8.70 mmol) at - 20 °C. Stir the reaction mixture at - 20 °C for 2 h. LCMS indicates the completion of the reaction. Add the resulting solution to water (30 mL). Extract the resulting solution with EA (2 × 15 mL). Combine the organic layers, wash with brine (20 mL), dry over anhydrous Na2SO4 and concentrate in vacuo. The mixture is purified by a C 18 column, eluting with ACN / H2O (v / v = 6 / 4). 1.633 g (yield 86.97%) of 4 - bromo - 2 - methoxy - 3 - methylaniline as a red oil is obtained. LCMS: m / z = 216 [M + 1] + .

[0635] Step 2: (4 - amino - 3 - methoxy - 2 - methylphenyl)dimethylphosphine oxide.

[0636] Place 4 - bromo - 2 - methoxy - 3 - methylaniline (1.012 g, 4.68 mmol), Pd(OAc)2 (0.537 g, 2.39 mmol), 4,5 - bis(diphenylphosphino)-9,9 - dimethyloxanthrene (0.652 g, 1.12 mmol), DIEA (1.189 g, 9.20 mmol) and DMF (10 mL) into a 100 mL three - necked flask purged and maintained under an inert nitrogen atmosphere. Stir the reaction mixture at 130 °C for 0.5 h. Then add dimethylphosphine oxide (1.189 g, 15.23 mmol). Stir the resulting mixture at 130 °C for another 1 h. LCMS indicates the completion of the reaction. Pass the reaction mixture through a C 18Column purification was carried out with elution using ACN / H2O (v / v = 2 / 8). 0.235 g (23.53% yield) of (4-amino-3-methoxy-2-methylphenyl)dimethylphosphine oxide as a red oil was obtained. LCMS: m / z = 214 [M+1] + .

[0637] Step 3: (3-Methoxy-2-methyl-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide.

[0638] (4-Amino-3-methoxy-2-methylphenyl)dimethylphosphine oxide (0.213 g, 0.99 mmol), 3-bromopropyne (0.214 g, 1.80 mmol), DIEA (0.221 g, 1.71 mmol), and DMF (2 mL) were placed in a 50 mL flask. The reaction mixture was stirred at 80 °C for 4 h. LCMS indicated completion of the reaction. The reaction mixture was purified by column chromatography 18 with elution using ACN / H2O (v / v = 4 / 6). 0.060 g (23.90% yield) of (3-methoxy-2-methyl-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide as a red oil was obtained. LCMS: m / z = 252 [M+1] + .

[0639] Step 4: (4-((3-(7-(((3S,4R)-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-2-methylphenyl)dimethylphosphine oxide (41).

[0640] Into a 50 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, place (3S,4R)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.040 g, 0.085 mmol), (3-methoxy-2-methyl-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide (0.051 g, 0.21 mmol), CuI (0.007 g, 0.037 mmol), Pd(PPh3)2Cl2 (0.019 g, 0.027 mmol), DIEA (0.051 g, 0.39 mmol) and DMSO (1 mL). Stir the reaction mixture at room temperature for 1 h. LCMS indicates the completion of the reaction. The mixture is purified by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 30 - 68 - 90% B (2 - 30 - 60 min); 266 nm; RT: 33.273 - 35.573 min). Obtain 0.020 g (yield 39.66%) of (4-((3-(7-(((3S,4R)-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-2-methylphenyl)dimethylphosphine oxide (41), as an off-white solid. LCMS: m / z = 596 [M+1] + .

[0641] 1 H NMR (400 MHz, DMSO) δ 7.39–7.14 (m, 3H), 6.85–6.67 (m, 2H), 6.29 (t, J = 6.3 Hz, 1H), 5.17 (d, J = 8.6 Hz, 1H), 4.80 (d, J = 49.4 Hz, 1H), 4.34 (d, J = 6.3 Hz, 2H), 3.79 (dd, J = 21.9, 10.9 Hz, 2H), 3.64 (d, J = 7.9 Hz, 3H), 3.03 (t, J = 10.7 Hz, 1H), 2.80 (d, J = 10.6 Hz, 1H), 2.47 (s, 3H), 2.37–2.23 (m, 1H), 2.19 (s, 3H), 2.15–2.03 (m, 2H), 2.03–1.86 (m, 2H), 1.65 (s, 3H), 1.62 (s, 3H).

[0642] Example 42

[0643] (4-((3-(7-(((3S,4R)-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-2-(trifluoromethyl)phenyl)dimethylphosphine oxide (42).

[0644] Reaction Scheme

[0645]

[0646] Experimental Details

[0647] Step 1: 4-Bromo-2-methoxy-3-(trifluoromethyl)aniline.

[0648] Add 2-methoxy-3-(trifluoromethyl)aniline (0.864 g, 4.52 mmol) and ACN (5 mL) to a 50 mL flask. Then add NBS (0.639 g, 3.59 mmol) portionwise at -10 °C. Stir the reaction mixture at 20 °C for 4 h. LCMS indicates the completion of the reaction. Purify the reaction mixture by passing it through a C 18 column, eluting with ACN / H2O (v / v = 1 / 1). Obtain 0.448 g (yield 36.70%) of 4-bromo-2-methoxy-3-(trifluoromethyl)aniline as a red oil. LCMS: m / z = 270 [M+1] + .

[0649] Step 2: (4-Amino-3-methoxy-2-(trifluoromethyl)phenyl)dimethylphosphine oxide.

[0650] Place 4-bromo-2-methoxy-3-(trifluoromethyl)aniline (0.486 g, 1.80 mmol), Pd(OAc)2 (0.325 g, 1.45 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.363 g, 0.63 mmol), DIEA (0.532 g, 4.12 mmol) and DMF (2 mL) into a 100 mL three-necked flask purged and maintained with an inert nitrogen atmosphere. Stir the reaction mixture at 130 °C for 0.5 h. Then add dimethylphosphine oxide (0.532 g, 6.82 mmol). Stir the reaction mixture at 130 °C for another 1 h. LCMS indicates the completion of the reaction. Purify the reaction mixture by passing it through a C 18 column, eluting with ACN / H2O (v / v = 2 / 8). Obtain 0.099 g (20.59% yield) of (4-amino-3-methoxy-2-(trifluoromethyl)phenyl)dimethylphosphine oxide as a red oil. LCMS: m / z = 268 [M+1] + .

[0651] Step 3: (3-Methoxy-4-(prop-2-yn-1-ylamino)-2-(trifluoromethyl)phenyl)dimethylphosphine oxide.

[0652] (4-Amino-3-methoxy-2-(trifluoromethyl)phenyl)dimethylphosphine oxide (0.154 g, 0.58 mmol), 3-bromopropyne (0.089 g, 0.75 mmol), DIEA (0.108 g, 0.84 mmol), and DMF (2 mL) were placed in a 50 mL flask. The reaction mixture was stirred at 80 °C for 4 h. LCMS indicated the completion of the reaction. The reaction mixture was purified by column C 18 eluted with ACN / H2O (v / v = 2 / 8). 0.045 g (25.58% yield) of (3-methoxy-4-(prop-2-yn-1-ylamino)-2-(trifluoromethyl)phenyl)dimethylphosphine oxide as a red oil was obtained. LCMS: m / z = 306 [M+1] + .

[0653] Step 4: (4-((3-(7-(((3S,4R)-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-2-(trifluoromethyl)phenyl)dimethylphosphine oxide (42).

[0654] Into a 50 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, place (3S,4R)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.048 g, 0.11 mmol), (3-methoxy-4-(prop-2-yn-1-ylamino)-2-(trifluoromethyl)phenyl)dimethylphosphine oxide (0.046 g, 0.15 mmol), CuI (0.013 g, 0.068 mmol), Pd(PPh3)2Cl2 (0.029 g, 0.041 mmol), DIEA (0.046 g, 0.36 mmol) and DMSO (2 mL). Stir the reaction mixture at room temperature for 1 h. LCMS indicates completion of the reaction. Purify the mixture by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 25 - 75 - 75% B (2 - 30 - 60 min); 266 nm; RT: 52.053 - 53.667 min). Obtain 0.026 g (yield 39.38%) of (4-((3-(7-(((3S,4R)-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-2-(trifluoromethyl)phenyl)dimethylphosphine oxide (42) as an off-white solid. LCMS: m / z = 650 [M+1] + .

[0655] 1 H NMR (400 MHz, DMSO) δ 7.89–7.79 (m, 1H), 7.32–7.16 (m, 3H), 6.81–6.75 (m, 2H), 5.17 (d, J = 8.7 Hz, 1H), 4.86 (s, 1H), 4.42 (d, J = 6.2 Hz, 1H), 3.83 (s, 1H), 3.80 (s, 1H), 3.76 (s, 3H), 3.61 (s, 1H), 3.04 (s, 1H), 2.79 (s, 1H), 2.31 (d, J = 10.8 Hz, 1H), 2.19 (s, 3H), 2.09 (s, 1H), 2.00–1.90 (m, 1H), 1.71 (s, 3H), 1.69 (s, 3H), 1.24 (s, 2H).

[0656] Example 43

[0657] (2-Ethoxy-4-((3-(7-(((3S,4R)-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 (43).

[0658] Reaction Scheme

[0659]

[0660] Experimental Details

[0661] Step 1: 2-Chloro-1-ethoxy-3-nitrobenzene.

[0662] Place 2-chloro-3-nitrophenol (3.03 g, 17.46 mmol), Cs2CO3 (13.09 g, 40.58 mmol), iodoethane (7.22 g, 46.29 mmol), and NMP (30 mL) into a 50 mL flask. Stir the reaction mixture at 80 °C for 2 h. LCMS indicates the completion of the reaction. Add the resulting solution to water (30 mL). Extract the resulting solution with EA (2 × 15 mL). Combine the organic layers, wash with brine (20 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Purify the crude product by washing with HEX / EA (v / v = 10 / 1). Obtain 3.379 g (yield 96.00%) of 2-chloro-1-ethoxy-3-nitrobenzene as a red solid. LCMS: m / z = 202 [M+1] + .

[0663] Step 2: 1-Ethoxy-2-methoxy-3-nitrobenzene.

[0664] Place 2-chloro-1-ethoxy-3-nitrobenzene (3.89 g, 19.30 mmol), MeONa (2.00 g, 37.02 mmol), and DMF (15 mL) into a 50 mL flask. Stir the reaction mixture at 80 °C for 2 h. LCMS indicates the completion of the reaction. Add the resulting solution to water (50 mL). Extract the resulting solution with EA (2 × 25 mL). Combine the organic layers, wash with brine (20 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Purify the crude product by washing with HEX / EA (v / v = 8 / 2). Obtain 2.256 g (yield 59.29%) of 1-ethoxy-2-methoxy-3-nitrobenzene as a red oil. LCMS: m / z = 198 [M+1] + .

[0665] Step 3: 3-Ethoxy-2-methoxyaniline.

[0666] Place 1-ethoxy-2-methoxy-3-nitrobenzene (2.99 g, 15.16 mmol), iron powder (2.99 g, 53.54 mmol), NH4Cl (3.96 g, 74.03 mmol), MeOH (20 mL), and H2O (2 mL) into a 50 mL flask. Stir the reaction mixture at 50 °C for 2 h. LCMS indicates the completion of the reaction. Add the resulting solution to water (50 mL). Extract the resulting solution with EA (2 × 25 mL). Combine the organic layers, wash with brine (20 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Purify the crude product by silica gel column chromatography, eluting with hexane / EA (v / v = 8 / 2). Obtain 1.408 g (yield 55.53%) of 3-ethoxy-2-methoxyaniline as a colorless oil. LCMS: m / z = 168 [M+1] + 。

[0667] Step 4: 4-Bromo-3-ethoxy-2-methoxyaniline.

[0668] Add 3-ethoxy-2-methoxyaniline (1.063 g, 6.35 mmol) and THF (20 mL) to a 50 mL flask. Then add NBS (0.899 g, 5.05 mmol) portionwise at -60 °C. Stir the reaction mixture at -60 °C for 1 h. LCMS indicates the completion of the reaction. Add the resulting solution to water (50 mL). Extract the resulting solution with EA (2 × 25 mL). Combine the organic layers, wash with brine (20 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Purify the crude product by silica gel column chromatography, eluting with HEX / EA (v / v = 8 / 2). Obtain 1.334 g (yield 85.26%) of 4-bromo-3-ethoxy-2-methoxyaniline as a yellow oil. LCMS: m / z = 246 [M+1] + 。

[0669] Step 5: (4-Amino-2-ethoxy-3-methoxyphenyl)dimethylphosphine oxide.

[0670] Place 4-bromo-3-ethoxy-2-methoxyaniline (0.705 g, 2.86 mmol), Pd(OAc)2 (0.432 g, 1.92 mmol)), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.417 g, 0.72 mmol), DIEA (0.988 g, 7.64 mmol), and DMF (20 mL) into a 100 mL three-necked flask purged and maintained under an inert nitrogen atmosphere. Stir the reaction mixture at 130 °C for 0.5 h. Then add dimethylphosphine oxide (0.699 g, 8.56 mmol). Stir the reaction mixture at 130 °C for an additional 1 h. LCMS indicates the completion of the reaction. Pass the reaction mixture through C 18Column purification, eluted with ACN / H2O (v / v = 2 / 8). 0.377 g (54.10% yield) of (4-amino-2-ethoxy-3-methoxyphenyl)dimethylphosphine oxide as a red oil was obtained. LCMS: m / z = 244 [M+1] + .

[0671] Step 6: (2-Ethoxy-3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide.

[0672] (4-Amino-2-ethoxy-3-methoxyphenyl)dimethylphosphine oxide (0.151 g, 0.62 mmol), 3-bromopropyne (0.179 g, 1.50 mmol), DIEA (0.160 g, 1.24 mmol), and DMF (2 mL) were placed in a 50 mL flask. The reaction mixture was stirred at 80 °C for 4 h. LCMS indicated the completion of the reaction. The reaction mixture was purified by C 18 column, eluted with ACN / H2O (v / v = 4 / 6). 0.118 g (67.58% yield) of (2-ethoxy-3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide as a red oil was obtained. LCMS: m / z = 282 [M+1] + .

[0673] Step 7: (2-Ethoxy-4-((3-(7-(((3S,4R)-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 (43).

[0674] Into a 50 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, place (3S,4R)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.062 g, 0.13 mmol), (2-ethoxy-3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide (0.060 g, 0.21 mmol), CuI (0.011 g, 0.057 mmol), Pd(PPh3)2Cl2 (0.037 g, 0.052 mmol), DIEA (0.060 g, 0.46 mmol) and DMSO (2 mL). Stir the reaction mixture at room temperature for 1 h. LCMS indicates completion of the reaction. Purify the mixture by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 25 - 75 - 75% B (2 - 30 - 60 min); 266 nm; RT: 52.053 - 53.667 min). Obtain 0.008 g (yield 9.74%) of (2-ethoxy-4-((3-(7-(((3S,4R)-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 (43), as an off-white solid. LCMS: m / z = 626 [M+1] + .

[0675] 1 H NMR (400 MHz, DMSO) δ 7.34–7.17 (m, 3H), 6.78 (d, J = 7.7 Hz, 1H), 6.68 (dd, J = 8.4, 2.1 Hz, 1H), 6.35 (d, J = 6.3 Hz, 1H), 5.16 (d, J = 8.6 Hz, 1H), 4.79 (d, J = 49.6 Hz, 1H), 4.33 (d, J = 6.4 Hz, 2H), 4.17 (dd, J = 14.0, 7.0 Hz, 2H), 3.86–3.73 (m, 2H), 3.69 (s, 3H), 3.08–2.99 (m, 1H), 2.79 (d, J = 9.8 Hz, 1H), 2.17 (s, 3H), 2.13–1.91 (m, 2H), 1.71 (d, J = 14.7 Hz, 1H), 1.59 (d, J = 13.6 Hz, 6H), 1.39–1.31 (m, 3H), 1.24 (s, 2H).

[0676] Examples 44 and 45

[0677] (S)-(5-((3-(7-(((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-6-methoxypyridin-2-yl)(imino)(methyl)-λ 6 -sulfoxide (45) and (R)-(5-((3-(7-(((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-6-methoxypyridin-2-yl)(imino)(methyl)-λ 6 -sulfoxide (44).

[0678] Reaction Scheme

[0679]

[0680] Experimental Details

[0681] Step 1: 2-Methoxy-6-(methylthio)-3-nitropyridine.

[0682] Into a 100 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, 6-fluoro-2-methoxy-3-nitropyridine (2.03 g, 10.77 mmol) and ACN (20 mL) were placed. Then, NaSCH3 (2.31 g, 32.96 mmol) was added at -20 °C. The reaction mixture was stirred at 25 °C for 2 h. LCMS indicated the completion of the reaction. The mixture was quenched with water (20 mL). A large amount of solid precipitated, and the filter cake was collected by filtration. 1.93 g (yield 89.54%) of 2-methoxy-6-(methylthio)-3-nitropyridine was obtained as a white solid. LCMS: m / z = 201 [M+1] + .

[0683] Step 2: Imino(6-methoxy-5-nitropyridin-2-yl)(methyl)-λ 6 -sulfoxide.

[0684] Into a 100 mL three-necked flask, 2-methoxy-6-(methylthio)-3-nitropyridine (1.93 g, 9.63 mmol), PhI(OAc)2 (6.64 g, 20.62 mmol), NH4OAc (6.48 g, 84.07 mmol), and MeOH (20 mL) were placed. The reaction mixture was stirred at 25 °C for 4 h. The resulting solution was added to water (30 mL). The resulting solution was extracted with EA (2 × 30 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The reaction mixture was passed through C 18Column purification, eluting with ACN / H2O (v / v = 2 / 8). 1.17 g (52.49% yield) of imino(6-methoxy-5-nitropyridin-2-yl)(methyl)-λ 6 -sulfoxide was obtained as a red oil. LCMS: m / z = 232 [M+1] + .

[0685] Step 3: N-((5-Amino-6-methoxypyridin-2-yl)(methyl)(oxo)-λ 6 -sulfinyl)-2,2,2-trifluoroacetamide

[0686] Into a 50 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, imino(6-methoxy-5-nitropyridin-2-yl)(methyl)-λ 6 -sulfoxide (1.10 g, 4.76 mmol), TFAA (1.12 g, 5.33 mmol), and THF (10 mL) were placed. The reaction mixture was stirred at 25 °C for 1 h. Subsequently, Fe (1.77 g, 31.69 mmol), NH4Cl (2.59 g, 48.42 mmol), MeOH (10 mL), and H2O (5 mL) were added. The reaction mixture was stirred at 50 °C for an additional 1 h. The reaction mixture was purified by C 18 column, eluting with ACN / H2O (v / v = 1 / 1). 0.333 g (23.54% yield) of N-((5-amino-6-methoxypyridin-2-yl)(methyl)(oxo)-λ 6 -sulfinyl)-2,2,2-trifluoroacetamide was obtained as a red solid. LCMS: m / z = 298 [M+1] + .

[0687] Step 4: 2,2,2-Trifluoro-N-((6-methoxy-5-(prop-2-yn-1-ylamino)pyridin-2-yl)(methyl)(oxo)-λ 6 -sulfinyl)acetamide

[0688] Into a 50 mL flask, N-((5-amino-6-methoxypyridin-2-yl)(methyl)(oxo)-λ 6 -sulfinyl)-2,2,2-trifluoroacetamide (0.205 g, 0.69 mmol), 3-bromopropyne (0.222 g, 1.87 mmol), DIEA (0.230 g, 1.78 mmol), and DMF (5 mL) were placed. The reaction mixture was stirred at 80 °C for 4 h. LCMS indicated completion of the reaction. The reaction mixture was passed through C 18Column purification was performed, eluting with ACN / H2O (v / v = 2 / 8). 0.199 g (85.63% yield) of 2,2,2-trifluoro-N-((6-methoxy-5-(prop-2-yn-1-ylamino)pyridin-2-yl)(methyl)(oxo)-λ 6 -sulfinyl)acetamide was obtained as a red solid. LCMS: m / z = 336 [M+1] + .

[0689] Step 5: Imino(6-methoxy-5-(prop-2-yn-1-ylamino)pyridin-2-yl)(methyl)-λ 6 -sulfoxide

[0690] 2,2,2-Trifluoro-N-((6-methoxy-5-(prop-2-yn-1-ylamino)pyridin-2-yl)(methyl)(oxo)-λ 6 -sulfinyl)acetamide (0.214 g, 0.64 mmol), K2CO3 (0.213 g, 1.54 mmol), and MeOH (2 mL) were placed in a 50 mL flask. The reaction mixture was stirred at 20 °C for 1 h. LCMS indicated completion of the reaction. The reaction mixture was purified by column chromatography, eluting with ACN / H2O (v / v = 2 / 8). 0.146 g (95.60% yield) of imino(6-methoxy-5-(prop-2-yn-1-ylamino)pyridin-2-yl)(methyl)-λ 18 -sulfoxide as a red solid was obtained. LCMS: m / z = 240 [M+1] 6 . + .

[0691] Step 6: (5-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-6-methoxypyridin-2-yl)(imino)(methyl)-λ 6 -sulfoxide

[0692] (3S,4R)-3-Fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.122 g, 0.26 mmol), CuI (0.020 g, 0.11 mmol), Pd(PPh3)2Cl2 (0.065 g, 0.092 mmol), DIEA (0.125 g, 0.97 mmol), and DMF (5 mL) were placed in a 50 mL three-necked flask purged and maintained under an inert nitrogen atmosphere. Then, imino(6-methoxy-5-(prop-2-yn-1-ylamino)pyridin-2-yl)(methyl)-λ 6-sulfoxide (0.097 g, 0.35 mmol). The reaction mixture was stirred at 60 °C for 1 h. LCMS indicated the completion of the reaction. The reaction mixture was purified by a C 18 column, eluting with ACN / H2O (v / v = 1 / 1). 0.147 g (97.50% yield) of (5-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-6-methoxypyridin-2-yl)(imino)(methyl)-λ 6 -sulfoxide was obtained as an off-white solid. LCMS: m / z = 584 [M+1] + .

[0693] Step 7: (S)-(5-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-6-methoxypyridin-2-yl)(imino)(methyl)-λ 6 -sulfoxide (45) and (R)-(5-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-6-methoxypyridin-2-yl)(imino)(methyl)-λ 6 -sulfoxide (44).

[0694] The racemic sample (5-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-6-methoxypyridin-2-yl)(imino)(methyl)-λ 6 -sulfoxide (0.13 g, 0.22 mmol) was separated by preparative chiral HPLC (column: IG, mobile phase A: n-hexane, mobile phase B: EtOH; flow rate: 20 mL / min; EtOH = 50:50; 220 nm; RT: 9.677, 12.009) to separate the two isomers. 0.029 g (22.31% yield) of (S)-(5-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-6-methoxypyridin-2-yl)(imino)(methyl)-λ 6 -sulfoxide (45) was obtained as a white solid. LCMS: m / z = 584 [M+1] +

[0695] 1 1H NMR (600 MHz, DMSO) δ 7.57 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 6.65 (t, J = 6.2 Hz, 1H), 5.20 (d, J = 7.4 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.38 (d, J = 6.2 Hz, 2H), 3.98 (s, 3H), 3.68 (d, J = 28.3 Hz, 2H), 3.09 (s, 1H), 3.04 (s, 3H), 2.84 (s, 1H), 2.51 (s, 2H), 2.23 (s, 3H), 2.17 (s, 1H), 2.04–1.88 (m, 2H), 1.74 (d, J = 11.6 Hz, 1H).

[0696] and 0.031 g (23.84% yield) of (R)-(5-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-6-methoxypyridin-2-yl)(imino)(methyl)-λ 6 -sulfoxide (44), a white solid. LCMS: m / z = 584 [M+1] + .

[0697] 1 1H NMR (600 MHz, DMSO) δ 7.57 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 7.9 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.12 (t, J = 11.1 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 6.68–6.60 (m, 1H), 5.22 (d, J = 7.6 Hz, 1H), 4.83 (d, J = 49.2 Hz, 1H), 4.38 (d, J = 6.2 Hz, 2H), 3.98 (s, 3H), 3.84 (dd, J = 22.1, 11.0 Hz, 2H), 3.69 (d, J = 29.3 Hz, 1H), 3.13 (d, J = 25.0 Hz, 1H), 3.04 (s, 3H), 2.87 (s, 1H), 2.51 (s, 1H), 2.45–2.33 (m, 1H), 2.26 (s, 3H), 2.19 (d, J = 7.7 Hz, 1H), 2.03–1.93 (m, 1H), 1.75 (d, J = 12.2 Hz, 1H).

[0698] Example 47

[0699] (4-((3-(7-(((3S,4R)-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-d3)phenyl)dimethylphosphine sulfide (47)

[0700] Reaction Scheme

[0701]

[0702] Experimental Details

[0703] Step 1: (4-((3-(7-(((3S,4R)-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-d3)phenyl)dimethylphosphine sulfide (47).

[0704] Into a 50 mL three-necked flask purged and maintained under an inert nitrogen atmosphere, place (4-((3-(7-(((3S,4R)-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-d3)phenyl)dimethylphosphine oxide (0.211 g, 0.36 mmol), Lawesson's Reagent (0.421 g, 1.04 mmol), and toluene (20 mL). Stir the reaction mixture at 110 °C for 16 h. LCMS shows that the reaction is complete. Purify the mixture by preparative HPLC (mobile phase A: water (10 mmol / L ammonium hydroxide), mobile phase B: ACN; flow rate: 40 mL / min; gradient: 25 - 75 - 75% B (2 - 30 - 60 min); 266 nm; RT: 52.053 - 53.667 min). Obtain 0.014 g (6.46% yield) of (4-((3-(7-(((3S,4R)-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-d3)phenyl)dimethylphosphine sulfide (47) as an off-white solid. LCMS: m / z = 601 [M+1] + 。

[0705] 11H NMR (600 MHz, DMSO) δ 7.45 (dd, J = 13.4, 8.1 Hz, 1H), 7.36 (d, J = 13.3 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.86 (dd, J = 8.1, 2.7 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 5.64 (d, J = 7.5 Hz, 2H), 5.12 (d, J = 47.3 Hz, 2H), 4.36 (s, 2H), 4.03–3.89 (m, 2H), 3.87–3.75 (m, 3H), 2.82 (s, 3H), 2.25–2.12 (m, 2H), 2.00 (d, J = 12.9 Hz, 1H), 1.91 (s, 3H), 1.88 (s, 3H).

[0706] Examples 46 and 48

[0707] (S)-(3-Methoxy-4-((3-(7-(quinolin-3-ylamino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide (48) and (R)-(3-Methoxy-4-((3-(7-(quinolin-3-ylamino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide (46)

[0708] Reaction Scheme

[0709]

[0710] Experimental Details

[0711] Step 1: N-(2-Iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)quinolin-3-amine.

[0712] Into a 100 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, place 2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-amine (1.06 g, 2.97 mmol), quinolin-3-one (3.69 g, 29.48 mmol), Ti(OEt)4 (10 mL). Stir the reaction mixture at 120 °C for 2 h. Add EtOH (20 mL), NaBH4 (1.05 g, 27.63 mmol). Stir the reaction mixture at 80 °C for another 2 h. LCMS shows the reaction is complete. Quench the mixture with water (20 mL). A large amount of solid precipitates from the reaction, filter and collect the solid. Pass the reaction mixture through C 18Column purification, eluted with ACN / H2O (v / v = 4 / 6). 1.489 g (107.59% yield) of N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)quinuclidin-3-amine as a yellow solid was obtained. LCMS: m / z = 467 [M+1] + 。

[0713] Step 2: (3-Methoxy-4-((3-(7-(quinuclidin-3-ylamino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide.

[0714] Into a 50 mL three-necked flask purged and maintained under an inert nitrogen atmosphere, N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)quinuclidin-3-amine (0.412 g, 0.88 mmol), CuI (0.091 g, 0.51 mmol), Pd(PPh3)2Cl2 (0.198 g, 0.272 mmol), DIEA (0.318 g, 2.46 mmol) and DMF (5 mL) were placed. Then (3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide (0.427 g, 1.80 mmol) was added at 60 °C. The reaction mixture was stirred at 60 °C for 1 h. LCMS showed the reaction was complete. The reaction mixture was purified by C 18 Column purification, eluted with ACN / H2O (v / v = 1 / 1). 0.345 g (57.50% yield) of (3-methoxy-4-((3-(7-(quinuclidin-3-ylamino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide as an off-white solid was obtained. LCMS: m / z = 576 [M+1] + 。

[0715] Step 3: (S)-(3-Methoxy-4-((3-(7-(quinuclidin-3-ylamino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide (48) and (R)-(3-Methoxy-4-((3-(7-(quinuclidin-3-ylamino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide (46)

[0716] Racemic sample (3-methoxy-4-((3-(7-(quinolin-3-ylamino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide (0.345 g, 0.59 mmol) was separated by preparative chiral HPLC (column: IG, mobile phase A: n-hexane, mobile phase B: DCM; flow rate: 20 mL / min; EtOH = 70:30; 220 nm; RT: 5.596, 6.325) to provide two isomers. 0.075 g (43.48% yield) of (S)-(3-methoxy-4-((3-(7-(quinolin-3-ylamino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide (48) was obtained as a white solid. LCMS: m / z = 576 [M+1] +

[0717] 1 H NMR (400 MHz, DMSO) δ 7.31–7.11 (m, 4H), 6.91–6.79 (m, 1H), 6.60 (d, J = 7.7 Hz, 1H), 6.08 (t, J = 6.3 Hz, 1H), 5.52 (d, J = 6.2 Hz, 1H), 4.35 (d, J = 6.3 Hz, 2H), 3.86 (s, 3H), 3.82–3.65 (m, 3H), 2.95 (d, J = 8.6 Hz, 1H), 2.86–2.70 (m, 4H), 1.99 (s, 1H), 1.85 (s, 1H), 1.70–1.65 (m, 2H), 1.60 (s, 3H), 1.57 (s, 3H), 1.35–1.25 (m, 2H).

[0718] And 0.076 g (yield 43.49%) of (R)-(3-methoxy-4-((3-(7-(quinolin-3-ylamino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide (46) was obtained as a white solid. LCMS: m / z = 576 [M+1] + 。

[0719] 11H NMR (400 MHz, DMSO) δ 7.29–7.11 (m, 4H), 6.85 (dd, J = 8.0, 2.9 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 6.08 (t, J = 6.3 Hz, 1H), 5.54 (d, J = 6.1 Hz, 1H), 4.35 (d, J = 6.3 Hz, 2H), 3.87 (s, 3H), 3.82–3.68 (m, 3H), 3.02–2.94 (m, 1H), 2.90–2.73 (m, 4H), 2.00 (d, J = 2.5 Hz, 1H), 1.88 (d, J = 17.0 Hz, 1H), 1.69 (s, 2H), 1.60 (s, 3H), 1.57 (s, 3H), 1.36–1.25 (m, 2H).

[0720] Examples 49 & 50

[0721] (S)-(4-((3-(7-(((3S,4R)-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)(imino)(oxetan-3-yl)-λ 6 -sulfoxide (50) and (R)-(4-((3-(7-(((3S,4R)-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)(imino)(oxetan-3-yl)-λ 6 -sulfoxide (49)

[0722] Reaction Scheme

[0723]

[0724] Experimental Details

[0725] Step 1: 3-Methoxy-4-nitrobenzenethiol.

[0726] Into a 100 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, 4-fluoro-2-methoxy-1-nitrobenzene (3.41 g, 19.93 mmol) and DMF (20 mL) were placed. Then, Na2S (1.89 g, 24.22 mmol) was added at -20 °C. The reaction mixture was stirred at 25 °C for 2 h. LCMS showed the reaction was complete. The mixture was quenched with HCl (4 M, 200 mL). A large amount of solid precipitated during the reaction, and it was filtered to collect the filter cake. 4.212 g (yield 94.13%) of 3-methoxy-4-nitrobenzenethiol as a yellow solid was obtained. LCMS: m / z = 184 [M-1]- 。

[0727] Step 2: 3-((3-Methoxy-4-nitrophenyl)thio)oxetane.

[0728] Add 3-methoxy-4-nitrobenzenethiol (0.718 g, 3.88 mmol), 3-bromooxetane (0.990 g, 7.28 mmol), Cs2CO3 (2.185 g, 6.71 mmol), and DMF (10 mL) to a 50 mL flask. Stir the reaction mixture at 60 °C for 16 h. LCMS shows that the reaction is complete. Add the resulting solution to water (30 mL). Extract the resulting solution with EA (2 × 15 mL). Combine the organic layers, wash with brine (20 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Purify the crude product by silica gel column chromatography, eluting with hexane / EA (v / v = 8 / 2). Obtain 0.959 g (yield 92.52%) of 3-((3-methoxy-4-nitrophenyl)thio)oxetane as a yellow solid. LCMS: m / z = 242 [M+1] +

[0729] Step 3: Imino(3-methoxy-4-nitrophenyl)(oxetan-3-yl)-λ 6 -sulfoxide.

[0730] Place 3-((3-methoxy-4-nitrophenyl)thio)oxetane (0.958 g, 3.97 mmol), PhI(OAc)2 (2.133 g, 6.62 mmol), NH4OAc (1.935 g, 25.10 mmol), and MeOH (10 mL) in a 100 mL three-necked flask. Stir the reaction mixture at 25 °C for 4 h. Concentrate the reaction mixture in vacuo. Purify the crude product by crystallization (hexane / EA = 5 / 1). Obtain 0.669 g (61.88% yield) of imino(3-methoxy-4-nitrophenyl)(oxetan-3-yl)-λ 6 -sulfoxide as a red oil. LCMS: m / z = 273 [M+1] + 。

[0731] Step 4: tert-Butyl ((3-methoxy-4-nitrophenyl)(oxetan-3-yl)(oxo)-λ 6 -sulfinyl)carbamate.

[0732] Place imino(3-methoxy-4-nitrophenyl)(oxetan-3-yl)-λ 6-Sulfoxide (0.659 g, 2.42 mmol), THF (10 mL). Then NaH (1.945 g, 32.41 mmol) and Boc2O (3.084 g, 14.13 mmol) were added at -10 °C. The reaction mixture was stirred at 25 °C for 2 h. The resulting solution was added to water (30 mL). The resulting solution was extracted with EA (2 × 15 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexane / EA (v / v = 1 / 1). 0.536 g (59.47% yield) of tert-butyl ((3-methoxy-4-nitrophenyl)(oxetan-3-yl)(oxo)-λ 6 -sulfinyl)carbamate was obtained as a yellow solid. LCMS: m / z = 373 [M+1] + .

[0733] Step 5: tert-Butyl ((4-amino-3-methoxyphenyl)(oxetan-3-yl)(oxo)-λ 6 -sulfinyl)carbamate

[0734] To a 50 mL flask was added tert-butyl ((3-methoxy-4-nitrophenyl)(oxetan-3-yl)(oxo)-λ 6 -sulfinyl)carbamate (0.561 g, 1.51 mmol), Pd / C (0.571 g, 5.37 mmol), MeOH (20 mL). The reaction mixture was stirred at 25 °C for 4 h under a hydrogen atmosphere. LCMS showed completion of the reaction. The reaction mixture was filtered and the filtrate was collected. The filtrate was concentrated in vacuo to give 0.486 g (94.22% yield) of tert-butyl ((4-amino-3-methoxyphenyl)(oxetan-3-yl)(oxo)-λ 6 -sulfinyl)carbamate as a colorless oil. LCMS: m / z = 343 [M+1] + .

[0735] Step 6: tert-Butyl ((3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)(oxetan-3-yl)(oxo)-λ 6 -sulfinyl)carbamate

[0736] To a 50 mL flask was added tert-butyl ((4-amino-3-methoxyphenyl)(oxetan-3-yl)(oxo)-λ 6tert-Butyl ((3-methoxy-4-((prop-2-yn-1-yl)amino)phenyl)(oxetan-3-yl)(oxo)-λ6-sulfinyl)carbamate (0.467 g, 1.36 mmol), 3-bromopropyne (0.331 g, 2.78 mmol), DIEA (0.360 g, 2.78 mmol), DMF (5 mL). The reaction mixture was stirred at 80 °C for 4 h. LCMS showed the reaction was complete. The reaction mixture was purified by a C 18 column, eluting with ACN / H2O (v / v = 2 / 8). 0.234 g (46.83% yield) of ((3-methoxy-4-((prop-2-yn-1-yl)amino)phenyl)(oxetan-3-yl)(oxo)-λ 6 6-sulfinyl)carbamate was obtained as a red solid. LCMS: m / z = 381 [M+1] + .

[0737] Step 7: ((4-((3-(7-(((3S,4R)-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)(oxetan-3-yl)(oxo)-λ 6 6-sulfinyl)carbamate

[0738] Into a 50 mL three-necked flask purged and maintained with an inert nitrogen atmosphere, (3S,4R)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.211 g, 0.45 mmol), CuI (0.051 g, 0.21 mmol), Pd(PPh3)2Cl2 (0.131 g, 0.18 mmol), DIEA (0.214 g, 1.66 mmol) and DMF (2 mL) were placed. Then ((3-methoxy-4-((prop-2-yn-1-yl)amino)phenyl)(oxetan-3-yl)(oxo)-λ 6 6-sulfinyl)carbamate (0.214 g, 0.56 mmol) was added at 60 °C. The reaction mixture was stirred at 60 °C for 1 h. LCMS showed the reaction was complete. The reaction mixture was purified by a C 18 column, eluting with ACN / H2O (v / v = 1 / 1). 0.288 g (88.94% yield) of ((4-((3-(7-(((3S,4R)-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)(oxetan-3-yl)(oxo)-λ 6 6-sulfinyl)carbamate was obtained as an off-white solid. LCMS: m / z = 725 [M+1]+ .

[0739] Step 8: (4 - ((3 - (7 - (((3S,4R)-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)(imino)(oxetan - 3 - yl)-λ 6 -sulfoxide

[0740] Add ((4 - ((3 - (7 - (((3S,4R)-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)(oxetan - 3 - yl)(oxo)-λ 6 -sulfinyl)carbamic acid tert - butyl ester ((0.183 g, 0.25 mmol), DCM (2 mL), TFA (1 mL) into a 50 mL flask. Stir the mixture at 20 °C for 1 h. LCMS shows the reaction is complete. Add the resulting solution to an aqueous sodium carbonate solution (50 mL) and extract with EA (3 × 50 mL). Combine the organic layers, wash with brine (50 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Purify the reaction mixture by passing it through a C 18 column, eluting with ACN / H2O (v / v = 4 / 6). Obtain 0.122 g (yield 77.35%) of (4 - ((3 - (7 - (((3S,4R)-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)(imino)(oxetan - 3 - yl)-λ 6 -sulfoxide, as an off - white solid. LCMS: m / z = 625 [M + 1] + .

[0741] Step 9: (S)-(4 - ((3 - (7 - (((3S,4R)-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)(imino)(oxetan - 3 - yl)-λ 6 -sulfoxide (50) and (R)-(4 - ((3 - (7 - (((3S,4R)-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)(imino)(oxetan - 3 - yl)-λ 6 -sulfoxide (49)

[0742] Racemic sample (4-((3-(7-(((3S,4R)-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)(imino)(oxetan-3-yl)-λ 6 -sulfoxide (0.080 g, 0.13 mmol) was separated by preparative chiral HPLC (column: IG, mobile phase A: MTBE, mobile phase B: MeOH; flow rate: 20 mL / min; EtOH = 85:15; 220 nm; RT: 6.031, 7.087) to afford two isomers. 0.026 g (yield 32.50%) of (S)-(4-((3-(7-(((3S,4R)-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)(imino)(oxetan-3-yl)-λ 6 -sulfoxide (50), a white solid. LCMS: m / z = 625 [M+1] +

[0743] 1 H NMR (600 MHz, DMSO) δ 7.40 (dd, J = 8.4, 1.7 Hz, 1H), 7.31–7.20 (m, 3H), 6.88 (t, J = 6.6 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 6.46 (t, J = 6.2 Hz, 1H), 5.17 (d, J = 8.5 Hz, 1H), 4.80 (d, J = 49.3 Hz, 1H), 4.72–4.64 (m, 3H), 4.64–4.59 (m, 1H), 4.59–4.54 (m, 1H), 4.38 (d, J = 6.2 Hz, 2H), 3.88 (s, 3H), 3.82 (dd, J = 22.5, 11.5 Hz, 2H), 3.72–3.58 (m, 1H), 3.04 (t, J = 10.5 Hz, 1H), 2.81 (d, J = 10.4 Hz, 1H), 2.27 (d, J = 13.3 Hz, 1H), 2.20 (s, 3H), 2.15–2.06 (m, 1H), 2.00–1.89 (m, 1H), 1.72 (d, J = 10.5 Hz, 1H).

[0744] and 0.025 g (yield 31.25%) (R)-(4-((3-(7-(((3S,4R)-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)(imino)(oxetan-3-yl)-λ 6 -sulfoxide (49), a white solid. LCMS: m / z = 625 [M+1] + .

[0745] 1 H NMR (600 MHz, DMSO) δ 7.40 (dd, J = 8.4, 1.7 Hz, 1H), 7.33–7.19 (m, 3H), 6.88 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 6.46 (t, J = 6.2 Hz, 1H), 5.16 (d, J = 8.5 Hz, 1H), 4.80 (d, J = 49.8 Hz, 1H), 4.73–4.65 (m, 3H), 4.64–4.60 (m, 1H), 4.59–4.53 (m, 1H), 4.38 (d, J = 6.2 Hz, 2H), 3.87 (d, J = 11.4 Hz, 3H), 3.82 (dd, J = 21.1, 11.9 Hz, 2H), 3.71–3.60 (m, 1H), 3.03 (t, J = 10.9 Hz, 1H), 2.80 (d, J = 11.2 Hz, 1H), 2.26 (d, J = 12.7 Hz, 1H), 2.20 (d, J = 10.5 Hz, 3H), 2.08 (t, J = 11.3 Hz, 1H), 2.00–1.89 (m, 1H), 1.72 (d, J = 9.8 Hz, 1H).

[0746] Example 51 & 52

[0747] (R)-(difluoromethyl)(4-((3-(7-(((3S,4R)-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)(imino)-λ 6 -sulfoxide (52) and (S)-(difluoromethyl)(4-((3-(7-(((3S,4R)-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)(imino)-λ 6 -sulfoxide (51)

[0748] Reaction Scheme

[0749]

[0750] Experimental details

[0751] Step 1: (Difluoromethyl)(3-methoxy-4-nitrophenyl)sulfane.

[0752] Put 3-methoxy-4-nitrobenzenethiol (3.18 g, 17.17 mmol), sodium difluorochloroacetate (7.92 g, 51.95 mmol), K2CO3 (8.83 g, 63.89 mmol), DMF (30 mL), and H2O (3 mL) into a 50 mL flask. Stir the reaction mixture at 130 °C for 4 h. LCMS shows that the reaction is complete. Add the resulting solution to water (30 mL). Extract the resulting solution with EA (2 × 15 mL). Combine the organic layers, wash with brine (20 mL), dry over anhydrous Na2SO4, and concentrate in vacuo. Purify the crude product by silica gel column chromatography, eluting with hexane / EA (v / v = 7 / 3). Obtain 2.432 g (yield 60.22%) of (difluoromethyl)(3-methoxy-4-nitrophenyl)sulfane as a yellow oil. LCMS: m / z = 236 [M+1] + 。

[0753] Step 2: (Difluoromethyl)(imino)(3-methoxy-4-nitrophenyl)-λ 6 -sulfoxide.

[0754] Put (difluoromethyl)(3-methoxy-4-nitrophenyl)sulfane (2.34 g, 9.95 mmol), PhI(OAc)2 (7.23 g, 22.44 mmol), NH4OAc (6.23, 80.82 mmol), and methanol (20 mL) into a 100 mL three-necked flask. Stir the reaction mixture at 25 °C for 4 h. Concentrate the reaction mixture in vacuo. Purify the crude product by crystallization [hexane / EA (v / v = 1 / 1)]. Obtain 1.410 g (53.23% yield) of (difluoromethyl)(imino)(3-methoxy-4-nitrophenyl)-λ 6 -sulfoxide as a white oil. LCMS: m / z = 267 [M+1] + 。

[0755] Step 3: (4-Amino-3-methoxyphenyl)(difluoromethyl)(imino)-λ 6 -sulfoxide.

[0756] Put (difluoromethyl)(imino)(3-methoxy-4-nitrophenyl)-λ 6-Sulfoxide (0.503 g, 1.89 mmol), Fe (0.851 g, 15.24 mmol), NH4Cl (0.610 g, 11.40 mmol), MeOH (10 mL), H2O (2 mL). The reactants were stirred at 50 °C for 4 h. LCMS showed that the reaction was complete. The resulting solution was added to water (10 mL). The resulting solution was extracted with EA (2 × 15 mL). The organic layers were combined and washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. 0.455 g (91.07% yield) of (4-Amino-3-methoxyphenyl)(difluoromethyl)(imino)-λ 6 -sulfoxide as a white solid was obtained. LCMS: m / z = 237 [M+1] + .

[0757] Step 4: (Difluoromethyl)(imino)(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)-λ 6 -sulfoxide

[0758] (4-Amino-3-methoxyphenyl)(difluoromethyl)(imino)-λ 6 -sulfoxide (0.422 g, 1.79 mmol), 3-bromopropyne (0.422 g, 3.55 mmol), DIEA (0.517 g, 4.00 mmol), and DMF (5 mL) were placed in a 50 mL flask. The reaction mixture was stirred at 80 °C for 4 h. LCMS showed that the reaction was complete. The reaction mixture was purified by column C 18 and eluted with ACN / H2O (v / v = 2 / 8). 0.120 g (24.49% yield) of (Difluoromethyl)(imino)(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)-λ 6 -sulfoxide as a red oil was obtained. LCMS: m / z = 275 [M+1] + .

[0759] Step 5: (Difluoromethyl)(4-((3-(7-(((3S,4R)-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)(imino)-λ 6 -sulfoxide

[0760] Into a 50 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, place (3S,4R)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.117 g, 0.25 mmol), CuI (0.014 g, 0.073 mmol), Pd(PPh3)2Cl2 (0.057 g, 0.080 mmol), DIEA (0.115 g, 0.89 mmol) and DMF (2 mL). Then add (difluoromethyl)(imino)(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)-λ 6 -sulfoxide (0.115 g, 0.42 mmol) at 60 °C. Stir the reaction mixture at 60 °C for 1 h. LCMS shows that the reaction is complete. Purify the reaction mixture by passing it through a C 18 column, eluting with ACN / H2O (v / v = 4 / 6). Obtain 0.108 g (yield 70.47%) of (difluoromethyl)(4-((3-(7-(((3S,4R)-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)(imino)-λ 6 -sulfoxide, as an off-white solid. LCMS: m / z = 619 [M+1] + .

[0761] Step 6: (R)-(difluoromethyl)(4-((3-(7-(((3S,4R)-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)(imino)-λ 6 -sulfoxide (52) and (S)-(difluoromethyl)(4-((3-(7-(((3S,4R)-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)(imino)-λ 6 -sulfoxide (51)

[0762] The racemic sample (difluoromethyl)(4-((3-(7-(((3S,4R)-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)(imino)-λ 6-Sulfoxide (0.111 g, 0.18 mmol) was separated by preparative chiral HPLC (column: IG, mobile phase A: n-hexane, mobile phase B: DCM; flow rate: 20 mL / min; EtOH = 80:20; 220 nm; RT: 12.018, 12.922) to afford two isomers. 0.027 g (yield 32.50%) of (R)-(difluoromethyl)(4-((3-(7-(((3S,4R)-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)(imino)-λ 6 -Sulfoxide (52) was a white solid. LCMS: m / z = 619 [M+1] +

[0763] 1 H NMR (600 MHz, DMSO) δ 7.47 (dd, J = 8.5, 1.6 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.27–7.23 (m, 2H), 6.95 (d, J = 8.5 Hz, 1H), 6.84–6.79 (m, 1H), 6.76–6.71 (m, 2H), 5.47 (s, 1H), 5.16 (s, 1H), 4.99 (d, J = 48.2 Hz, 1H), 4.41 (d, J = 6.2 Hz, 2H), 3.88 (s, 3H), 3.87–3.85 (m, 1H), 3.83 (d, J = 4.4 Hz, 1H), 3.21 (s, 1H), 2.92 (s, 1H), 2.77–2.71 (m, 1H), 2.56 (s, 2H), 2.11 (d, J = 11.6 Hz, 1H), 1.90 (s, 1H), 1.24 (s, 3H). 0.026 g (32.50% yield) of (S)-(difluoromethyl)(4-((3-(7-(((3S,4R)-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)(imino)-λ 6 -Sulfoxide (51), was a white solid. LCMS: m / z = 619 [M+1] + 。

[0764] 11H NMR (600 MHz, DMSO) δ 7.47 (dd, J = 8.5, 1.6 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.27–7.23 (m, 2H), 6.95 (d, J = 8.5 Hz, 1H), 6.84–6.79 (m, 1H), 6.74 (dd, J = 7.1, 5.1 Hz, 2H), 5.47 (s, 1H), 5.16 (s, 1H), 4.99 (d, J = 48.2 Hz, 1H), 4.41 (d, J = 6.2 Hz, 2H), 3.88 (s, 3H), 3.87–3.85 (m, 1H), 3.83 (d, J = 4.4 Hz, 1H), 3.21 (s, 1H), 2.92 (s, 1H), 2.77–2.71 (m, 1H), 2.56 (s, 2H), 2.11 (d, J = 11.6 Hz, 1H), 1.90 (s, 1H), 1.24 (s, 3H).

[0765] Examples 53 & 54

[0766] (S)-Cyclopropyl(4-((3-(7-(((3S,4R)-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)(imino)-λ 6 -sulfoxide (54) and (R)-cyclopropyl(4-((3-(7-(((3S,4R)-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)(imino)-λ 6 -sulfoxide (53)

[0767] Reaction Scheme

[0768]

[0769] Experimental Details

[0770] Step 1: Cyclopropyl(3-methoxy-4-nitrophenyl)sulfane.

[0771] 3-Methoxy-4-nitrobenzenethiol (2.04 g, 11.02 mmol), tricyclopropylbismuth (3.81 g, 11.47 mmol), pyridine (2.69 g, 34.00 mmol), and DCM (30 mL) were placed in a 50 mL flask. The reaction mixture was stirred at 50 °C for 16 h. LCMS showed that the reaction was complete. The resulting solution was added to water (30 mL). The resulting solution was extracted with EA (2 × 15 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexane / EA (v / v = 2 / 1). 1.15 g (46.34% yield) of cyclopropyl(3-methoxy-4-nitrophenyl)sulfane as a yellow oil was obtained. LCMS: m / z = 226 [M+1] + .

[0772] Step 2: Cyclopropyl(imino)(3-methoxy-4-nitrophenyl)-λ 6 -sulfoxide.

[0773] Cyclopropyl(3-methoxy-4-nitrophenyl)sulfane (1.26 g, 5.59 mmol), PhI(OAc)2 (3.27 g, 10.15 mmol), NH4OAc (2.77 g, 35.94 mmol), and methanol (10 mL) were placed in a 100 mL three-necked flask. The reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was concentrated in vacuo. The crude product was purified by crystallization (Hex / EA (v / v = 5 / 1)). 1.007 g (70.25% yield) of cyclopropyl(imino)(3-methoxy-4-nitrophenyl)-λ 6 -sulfoxide was obtained. LCMS: m / z = 257 [M+1] + .

[0774] Step 3: N-(Cyclopropyl(3-methoxy-4-nitrophenyl)(oxo)-λ 6 -sulfonyl)-2,2,2-trifluoroacetamide.

[0775] To a 50 mL three-necked flask purged and maintained under an inert nitrogen atmosphere, cyclopropyl(imino)(3-methoxy-4-nitrophenyl)-λ 6-Sulfoxide (0.981 g, 3.83 mmol), THF (10 mL). Then TFAA (0.973 g, 4.63 mmol) was added at -10 °C. The reaction mixture was stirred at 25 °C for 2 h. The resulting solution was added to water (30 mL). The resulting solution was extracted with EA (2 × 15 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexane / EA (v / v = 1 / 1). 1.233 g (yield 91.43%) of N-(cyclopropyl(3-methoxy-4-nitrophenyl)(oxo)-λ 6 -sulfanylsulfonyl)-2,2,2-trifluoroacetamide was obtained as a white solid. LCMS: m / z = 353 [M+1] + .

[0776] Step 4: N-((4-Amino-3-methoxyphenyl)(cyclopropyl)(oxo)-λ 6 -sulfanylsulfonyl)-2,2,2-trifluoroacetamide

[0777] N-(cyclopropyl(3-methoxy-4-nitrophenyl)(oxo)-λ 6 -sulfanylsulfonyl)-2,2,2-trifluoroacetamide (1.01 g, 2.87 mmol), Pd / C (1.01 g, 9.49 mmol), and MeOH (20 mL) were placed in a 50 mL flask. The reaction mixture was stirred at 25 °C under a hydrogen atmosphere for 4 h. LCMS showed completion of the reaction. The reaction mixture was filtered and the filtrate was collected. The filtrate was concentrated in vacuo to give 1.084 g (94.22% yield) of N-((4-Amino-3-methoxyphenyl)(cyclopropyl)(oxo)-λ 6 -sulfanylsulfonyl)-2,2,2-trifluoroacetamide as a white solid. LCMS: m / z = 323 [M+1] + .

[0778] Step 5: N-(cyclopropyl(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)(oxo)-λ 6 -sulfanylsulfonyl)-2,2,2-trifluoroacetamide

[0779] N-((4-Amino-3-methoxyphenyl)(cyclopropyl)(oxo)-λ 6-(sulfonyl)-2,2,2-trifluoroacetamide (1.053 g, 3.27 mmol), 3-bromopropyne (1.504 g, 12.64 mmol), DIEA (1.641 g, 12.70 mmol), KI (1.054 g, 6.35 mmol), DMF (5 mL). The reaction mixture was stirred at 80 °C for 4 h. LCMS showed that the reaction was complete. The reaction mixture was purified by column C 18 and eluted with ACN / H2O (v / v = 2 / 8). 0.719 g (61.07% yield) of N-(cyclopropyl(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)(oxo)-λ 6 -sulfonyl)-2,2,2-trifluoroacetamide was obtained as a white solid. LCMS: m / z = 361 [M+1] + .

[0780] Step 6: Cyclopropyl(imino)(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)-λ 6 -sulfoxide

[0781] In a 50 mL flask, N-(cyclopropyl(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)(oxo)-λ 6 -sulfonyl)-2,2,2-trifluoroacetamide (1.32 g, 3.66 mmol), K2CO3 (1.54 g, 11.14 mmol), MeOH (5 mL) were added. The reaction mixture was stirred at 20 °C for 4 h. LCMS showed that the reaction was complete. The reaction mixture was purified by column C 18 and eluted with ACN / H2O (v / v = 4 / 6). 0.495 g (51.12% yield) of cyclopropyl(imino)(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)-λ 6 -sulfoxide was obtained as a white solid. LCMS: m / z = 265 [M+1] + .

[0782] Step 7: Cyclopropyl(4-((3-(7-(((3S,4R)-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)(imino)-λ 6 -sulfoxide

[0783] Into a 50 mL three-necked flask purged and maintained with a nitrogen inert atmosphere, add (3S,4R)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.153 g, 0.32 mmol), CuI (0.032 g, 0.17 mmol), Pd(PPh3)2Cl2 (0.075 g, 0.11 mmol), DIEA (0.165 g, 1.27 mmol) and DMF (2 mL). Then add cyclopropyl(imino)(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)-λ 6 -sulfoxide (0.108 g, 0.41 mmol) at 60 °C. Stir the reaction mixture at 60 °C for 1 h. LCMS shows that the reaction is complete. Purify the reaction mixture by column C 18 , eluting with ACN / H2O (v / v = 1 / 1). This gives 0.151 g (yield 76.574%) of cyclopropyl(4-((3-(7-(((3S,4R)-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)(imino)-λ 6 -sulfoxide, as an off-white solid. LCMS: m / z = 609 [M+1] + .

[0784] Step 8: (S)-cyclopropyl(4-((3-(7-(((3S,4R)-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)(imino)-λ 6 -sulfoxide (54) and (R)-cyclopropyl(4-((3-(7-(((3S,4R)-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)(imino)-λ 6 -sulfoxide (53)

[0785] The racemic sample cyclopropyl(4-((3-(7-(((3S,4R)-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)(imino)-λ 6-Sulfoxide (0.150 g, 0.25 mmol) was separated by preparative chiral HPLC (column: IG), mobile phase A: n-hexane, mobile phase B: EtOH; flow rate: 20 mL / min; EtOH = 50:50; 220 nm; RT: 13.233, 14.859) to provide two isomers. 0.031 g (yield 32.50%) of (S)-cyclopropyl(4-((3-(7-(((3S,4R)-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)(imino)-λ 6 -sulfoxide (54), a white solid. LCMS:

[0786] m / z = 609 [M+1] +

[0787] 1 H NMR (600 MHz, DMSO) δ 7.40 (dd, J = 8.4, 1.7 Hz, 1H), 7.31–7.20 (m, 3H), 6.88 (t, J = 6.6 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 6.46 (t, J = 6.2 Hz, 1H), 5.17 (d, J = 8.5 Hz, 1H), 4.80 (d, J = 49.3 Hz, 1H), 4.72–4.64 (m, 3H), 4.64–4.59 (m, 1H), 4.59–4.54 (m, 1H), 4.38 (d, J = 6.2 Hz, 2H), 4.21 (s, 1H), 3.88 (s, 3H), 3.82 (dd, J = 22.5, 11.5 Hz, 2H), 3.72–3.58 (m, 1H), 3.04 (t, J = 10.5 Hz, 1H), 2.81 (d, J = 10.4 Hz, 1H), 2.27 (d, J = 13.3 Hz, 1H), 2.20 (s, 3H), 2.15–2.06 (m, 1H), 2.00–1.89 (m, 1H), 1.72 (d, J = 10.5 Hz, 1H).

[0788] And 0.045 g (41.25% yield) of (R)-cyclopropyl(4-((3-(7-(((3S,4R)-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)(imino)-λ 6 -sulfoxide (53), a white solid. LCMS: m / z = 609 [M+1] + .

[0789] 1 1H NMR (600 MHz, DMSO) δ 7.40 (dd, J = 8.4, 1.7 Hz, 1H), 7.33–7.19 (m, 3H), 6.88 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 6.46 (t, J = 6.2 Hz, 1H), 5.16 (d, J = 8.5 Hz, 1H), 4.80 (d, J = 49.8 Hz, 1H), 4.73–4.65 (m, 3H), 4.64–4.60 (m, 1H), 4.59–4.53 (m, 1H), 4.38 (d, J = 6.2 Hz, 2H), 4.21 (s, 1H), 3.87 (d, J = 11.4 Hz, 3H), 3.82 (dd, J = 21.1, 11.9 Hz, 2H), 3.71–3.60 (m, 1H), 3.03 (t, J = 10.9 Hz, 1H), 2.80 (d, J = 11.2 Hz, 1H), 2.26 (d, J = 12.7 Hz, 1H), 2.20 (d, i = 10.5 Hz, 3H), 2.08 (t, J = 11.3 Hz, 1H), 2.00–1.89 (m, 1H), 1.72 (d, J = 9.8 Hz, 1H).

[0790] Example 55

[0791] 4-(Dimethylphosphoryl)-7-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)isoindolin-1-one (55)

[0792] Reaction Scheme:

[0793]

[0794] Step 1: 7-Amino-4-iodoisoindolin-1-one

[0795] 7-Aminoisoindolin-1-one (1.501 g, 10.13 mmol), 1-iodo-5-pyrrolidinedione (2.468 g, 10.97 mmol), and DMF (15 mL) were placed in a 40 mL sealed tube. The reaction mixture was stirred at room temperature for 2 h. The mixture was poured into 150 mL of Na2SO3(aq), filtered, and the filter cake was washed with water (50 mL). The filtrate was collected and concentrated in vacuo to give 2.517 g (90.72%) of 7-amino-4-iodoisoindolin-1-one as a brown solid. LCMS: m / z = 275 [M+1] +

[0796] Step 2: 7-Amino-4-(dimethylphosphoryl)isoindolin-1-one

[0797] Into a 20 mL sealed tube purged and maintained with an inert nitrogen atmosphere, place 7-amino-4-iodoisoindolin-1-one (1.048 g, 3.82 mmol), Pd(OAc)2 (0.106 g, 0.47 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.409 g, 0.71 mmol), DIEA (1.439 g, 11.13 mmol), and DMF (10 mL). Add dimethylphosphine oxide (0.558 g, 7.15 mmol) at 100 °C, and stir the reaction mixture at 130 °C for 0.5 h. Purify the mixture by C 18 column chromatography, eluting with ACN / H2O (v / v = 2 / 3) to obtain 0.661 g (77.10%) of 7-amino-4-(dimethylphosphoryl)isoindolin-1-one as a yellow oil. LCMS: m / z = 225 [M+1] +

[0798] Step 3: 4-(Dimethylphosphoryl)-7-(prop-2-yn-1-ylamino)isoindolin-1-one

[0799] Into a 20 mL sealed tube purged and maintained with an inert nitrogen atmosphere, place 7-amino-4-(dimethylphosphoryl)isoindolin-1-one (0.543 g, 2.42 mmol), 3-bromopropyne (0.347 g, 2.92 mmol), DIEA (1.017 g, 7.87 mmol), KI (0.135 g, 0.81 mmol), and DMF (5 mL). Stir the reaction mixture at 50 °C for 12 h. Filter the mixture and purify it by C 18 column chromatography, eluting with ACN / H2O (v / v = 2 / 3) to obtain 0.030 g of 4-(dimethylphosphoryl)-7-(prop-2-yn-1-ylamino)isoindolin-1-one as a yellow oil. LCMS: m / z = 263 [M+1] +

[0800] Step 4: 4-(Dimethylphosphoryl)-7-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)isoindolin-1-one (55)

[0801] Into an 8 mL sealed tube purged and maintained with a nitrogen inert atmosphere, add (3S,4R)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.050 g, 0.11 mmol), 4-(dimethylphosphoryl)-7-(prop-2-yn-1-ylamino)isoindolin-1-one (0.030 g, 0.11 mmol), Pd(PPh3)2Cl2 (0.015 g, 0.02 mmol), CuI (0.010 g, 0.05 mmol), DIEA (0.040 g, 0.31 mmol), DMSO (1 mL). Stir the reaction mixture at 50 °C for 1 h. Purify the residue by preparative HPLC, eluting with CH3CN / H2O (0.05% NH3·H2O) (v / v = 2 / 1). Obtain 0.018 g (28%) of 4-(dimethylphosphoryl)-7-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)isoindolin-1-one (55) as a white solid. LCMS: m / z = 607 [M+1] +

[0802] 1 1H NMR (400 MHz, DMSO) δ 8.49 (s, 1H), 7.67–7.57 (m, 1H), 7.54 (t, J = 6.2 Hz, 1H), 7.33–7.24 (m, 1H), 7.24–7.15 (m, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 5.20 (d, J = 8.5 Hz, 1H), 4.91–4.70 (m, 1H), 4.59–4.47 (m, 4H), 3.90–3.75 (m, 2H), 3.72–3.58 (m, 1H), 3.05 (t, J = 10.6 Hz, 1H), 2.81 (d, J = 10.7 Hz, 1H), 2.34–2.24 (m, 1H), 2.19 (s, 3H), 2.10 (t, J = 11.4 Hz, 1H), 2.04–1.86 (m, 1H), 1.72 (d, J = 10.3 Hz, 1H), 1.64 (s, 3H), 1.62 (s, 3H).

[0803] Example 56

[0804] (5-((3-(7-(((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-6-(methoxy-d3)pyridin-2-yl)dimethylphosphine oxide (56)

[0805] Reaction Scheme:

[0806]

[0807] Step 1: 2-(Methoxy-d3)-3-nitropyridine

[0808] 2-Chloro-3-nitropyridine (10.04 g, 0.86 mmol) and THF (100 mL) were placed in a 3 L three-necked round-bottom flask, degassed and purged with N2(g), then NaH (60%, 5.06 g) was added at 0 °C, and methanol-d4 (3 mL) was added dropwise at 0 °C. Then the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with ice water (200 mL) and extracted with EA (300 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / hexane (v / v = 1 / 5) to obtain 2-(methoxy-d3)-3-nitropyridine (6.98 g, 70.14% yield) as a brown solid. LCMS: m / z = 158 [M+1] +

[0809] Step 2: 2-(Methoxy-d3)pyridin-3-amine

[0810] 10% Pd / C (1.71 g) was added to a solution of 2-(methoxy-d3)-3-nitropyridine (6.76 g, 43.02 mmol) in 100 mL of MeOH. The mixture was stirred under a hydrogen atmosphere for 2 days and the catalyst was removed by filtration. The filtrate was concentrated in vacuo. 5.07 g (92.68%) of 2-(methoxy-d3)pyridin-3-amine was obtained as a colorless oil. LCMS: m / z = 128 [M+1] +

[0811] Step 3: 6-Bromo-2-(methoxy-d3)pyridin-3-amine

[0812] 2-(Methoxy-d3)pyridin-3-amine (5.00 g, 39.32 mmol), 1-bromopyrrolidine-2,5-dione (8.34 g, 46.86 mmol), and DMF (50 mL) were placed in a 500 mL three-necked round-bottom flask. The reaction mixture was stirred at room temperature for 2 h. The mixture was quenched with 150 mL of water and extracted with EA (2 × 250 mL). The combined organic layers were washed with 150 mL of NaCl(aq) and dried over Na2SO4. The organic layer was filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with EA / hexane (v / v = 1 / 2) to give 6-bromo-2-(methoxy-d3)pyridin-3-amine (5.829 g, 71.94% yield) as a brown solid. LCMS: m / z = 206 [M+1] +

[0813] Step 4: (5-Amino-6-(methoxy-d3)pyridin-2-yl)dimethylphosphine oxide

[0814] 6-Bromo-2-(methoxy-d3)pyridin-3-amine (5.79 g, 28.10 mmol), Pd(OAc)2 (0.80 g, 3.56 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.30 g, 5.70 mmol), DIEA (8.97 g, 69.40 mmol), and DMF (50 mL) were placed in a 250 mL three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. Dimethylphosphine oxide (3.34 g, 42.79 mmol) was added at 100 °C, and the reaction mixture was stirred at 130 °C for 0.5 h. The mixture was purified by C 18 column chromatography, eluting with ACN / H2O (v / v = 1 / 4) to give 5.02 g (87.92%) of (5-amino-6-(methoxy-d3)pyridin-2-yl)dimethylphosphine oxide as a brown solid. LCMS: m / z = 204 [M+1] +

[0815] Step 5: tert-Butyl N-(6-dimethylphosphoryl-2-(trideuteriomethoxy)-3-pyridinyl)carbamate

[0816] (5-Amino-6-(methoxy-d3)pyridin-2-yl)dimethylphosphine oxide (4.95 g, 24.36 mmol), di-tert-butyl dicarbonate (9.36 g, 42.89 mmol), and 1,4-dioxane (50 mL) were placed in a 250 mL round-bottom flask. The reaction mixture was stirred at 100 °C for 2 h. The mixture was filtered and concentrated in vacuo. This gave 6.5 g (66.14%) of tert-butyl N-(tert-butoxycarbonyl)-N-(6-dimethylphosphoryl-2-(trideuteriomethoxy)-3-pyridinyl)carbamate as a yellow solid. LCMS: m / z = 404 [M+1] +

[0817] Step 6: tert-Butyl (6-(dimethylphosphoryl)-2-(methoxy-d3)pyridin-3-yl)carbamate

[0818] tert-Butyl N-(tert-butoxycarbonyl)-N-[6-dimethylphosphoryl-2-(trideuteriomethoxy)-3-pyridinyl]carbamate (6.5 g, 16.11 mmol), K2CO3 (8.59 g, 62.15 mmol), and MeOH (80 mL) were placed in a 250 mL round-bottom flask. The reaction mixture was stirred at 80 °C for 6 h. The mixture was filtered and concentrated in vacuo. The crude product was purified by column chromatography using ACN / H2O (v / v = 1 / 1) as the eluent to give 2.02 g of tert-Butyl (6-(dimethylphosphoryl)-2-(methoxy-d3)pyridin-3-yl)carbamate as a yellow oil. LCMS: m / z = 304 [M+1] 18 tert-Butyl (6-(dimethylphosphoryl)-2-(methoxy-d3)pyridin-3-yl)carbamate (2.02 g, 6.66 mmol) and THF (20 mL) were placed in a 100 mL three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. Then, NaH (60%, 0.304 g) was added portionwise at 0 °C over 0.5 h. 3-Bromopropyne (1.02 g, 8.57 mmol) was added dropwise at 0 °C, and then the reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was quenched with water (100 mL) and extracted with EA (100 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using ACN / H2O (v / v = 1 / 1) as the eluent to give 2.02 g of tert-Butyl (6-(dimethylphosphoryl)-2-(methoxy-d3)pyridin-3-yl)carbamate as a yellow oil. LCMS: m / z = 304 [M+1] +

[0819] Step 7: (2,3-Dimethoxy-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide

[0820] tert-Butyl (6-(dimethylphosphoryl)-2-(methoxy-d3)pyridin-3-yl)carbamate (2.02 g, 6.66 mmol) and THF (20 mL) were placed in a 100 mL three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. Then, NaH (60%, 0.304 g) was added portionwise at 0 °C over 0.5 h. 3-Bromopropyne (1.02 g, 8.57 mmol) was added dropwise at 0 °C, and then the reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was quenched with water (100 mL) and extracted with EA (100 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using ACN / H2O (v / v = 1 / 1) as the eluent to give 2.02 g of tert-Butyl (6-(dimethylphosphoryl)-2-(methoxy-d3)pyridin-3-yl)carbamate as a yellow oil. LCMS: m / z = 304 [M+1] 18Column purification, eluted with ACN / H2O (v / v = 1 / 1), to obtain (2,3-dimethoxy-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide (1.474 g, 64.84% yield), which is a yellow oil. LCMS: m / z = 342 [M+1] +

[0821] Step 8: tert-Butyl (6-(dimethylphosphoryl)-2-(methoxy-d3)pyridin-3-yl)(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)carbamate

[0822] Into an 8 mL sealed tube purged and maintained with a nitrogen inert atmosphere, add (3S,4R)-3-fluoro-N-(2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine (0.104 g, 0.22 mmol), (2,3-dimethoxy-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide (0.092 g, 0.27 mmol), Pd(PPh3)2Cl2 (0.025 g, 0.04 mmol), CuI (0.014 g, 0.07 mmol), DIEA (0.087 g, 0.67 mmol), DMSO (1 mL). Stir the reaction mixture at 50 °C for 1 h. Purify the residue by C 18 Column purification, eluted with ACN / H2O (v / v = 1 / 1), to obtain tert-Butyl (6-(dimethylphosphoryl)-2-(methoxy-d3)pyridin-3-yl)(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)carbamate (0.120 g, 79.47% yield), which is a yellow oil. LCMS: m / z = 686 [M+1] +

[0823] Step 9: (5-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-6-(methoxy-d3)pyridin-2-yl)dimethylphosphine oxide (56)

[0824] tert-Butyl ((6-(dimethylphosphoryl)-2-(methoxy-d3)pyridin-3-yl)(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)carbamate (0.120 g, 0.17 mmol), TFA (0.2 mL), and DMF (0.8 mL) were placed in an 8 mL sealed tube. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC, eluting with CH3CN / H2O (0.05% NH3·H2O) (v / v = 2 / 1). 0.078 g (69.09%) of (5-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-6-(methoxy-d3)pyridin-2-yl)dimethylphosphine oxide (56) was obtained as a white solid. LCMS: m / z = 586 [M+1] +

[0825] 1 1H NMR (600 MHz, MeOD) δ 7.55–7.48 (m, 1H), 7.35–7.28 (m, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.12–7.07 (m, 1H), 6.80 (d, J = 7.7 Hz, 1H), 4.40 (s, 2H), 3.80–3.74 (m, 1H), 3.74–3.67 (m, 2H), 3.26–3.19 (m, 1H), 2.95 (d, J = 11.4 Hz, 1H), 2.41 (d, J = 13.4 Hz, 1H), 2.33 (s, 3H), 2.30–2.21 (m, 1H), 2.01 (d, J = 9.4 Hz, 1H), 2.00–1.93 (m, 2H), 1.77 (s, 3H), 1.74 (s, 3H).

[0826] Example 57

[0827] (4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-2,3-dimethoxyphenyl)dimethylphosphine oxide (57)

[0828] Reaction Scheme:

[0829]

[0830] Step 1: 4-Bromo-2,3-dimethoxyaniline

[0831] To a 40 mL sealed tube, add 2,3-dimethoxyaniline (2.045 g, 13.35 mmol), 1-bromopyrrolidine-2,5-dione (2.558 g, 14.37 mmol), and DMF (20 mL). Stir the reaction mixture at room temperature for 2 h. Quench the mixture with 150 mL of water and extract with EA (2 × 250 mL). Wash the combined organic layers with 150 mL of brine and dry over Na2SO4. Filter the organic layer and concentrate it in vacuo to obtain 2.416 g (77.99%) of 4-bromo-2,3-dimethoxyaniline as a yellow oil. LCMS: m / z = 232 [M+1] +

[0832] Step 2: (4-Amino-2,3-dimethoxyphenyl)dimethylphosphine oxide

[0833] To a 20 mL sealed tube purged and maintained with an inert nitrogen atmosphere, add 4-bromo-2,3-dimethoxyaniline (2.078 g, 8.61 mmol), Pd(OAc)2 (0.377 g, 1.68 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.875 g, 1.51 mmol), DIEA (3.677 g, 28.45 mmol), and DMF (20 mL). Add dimethylphosphine oxide (0.940 g, 12.04 mmol) at 100 °C and stir the reaction mixture at 130 °C for 0.5 h. Purify the mixture by C 18 column chromatography, eluting with ACN / H2O (v / v = 1 / 4) to obtain 1.025 g (51.89%) of (4-amino-2,3-dimethoxyphenyl)dimethylphosphine oxide as a yellow oil. LCMS: m / z = 230 [M+1] +

[0834] Step 3: (2,3-Dimethoxy-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide

[0835] To a 20 mL sealed tube purged and maintained with an inert nitrogen atmosphere, place (4-amino-2,3-dimethoxyphenyl)dimethylphosphine oxide (0.361 g, 1.58 mmol), 3-bromopropyne (0.139 g, 1.17 mmol), DIEA (0.514 g, 3.98 mmol), and DMF (4 mL). Stir the reaction mixture at 50 °C for 12 h. Filter the mixture and purify it by C 18 column chromatography, eluting with ACN / H2O (v / v = 1 / 3) to obtain 0.098 g of (2,3-dimethoxy-4-(prop-2-yn-1-ylamino)phenyl)dimethylphosphine oxide as a yellow oil. LCMS: m / z = 268 [M+1] +

[0836] Step 4: (4 - ((3 - (7 - (((3S,4R)-3 - fluoro - 1 - methylpiperidin - 4 - yl)amino)-3-(2,2,2 - trifluoroethyl)benzo[b]thiophen - 2 - yl)prop - 2 - yn - 1 - yl)amino)-2,3 - dimethoxyphenyl)dimethylphosphine oxide (57)

[0837] Into an 8 mL sealed tube purged and maintained with an inert nitrogen atmosphere, add (3S,4R)-3 - fluoro - N-(2 - iodo - 3-(2,2,2 - trifluoroethyl)benzo[b]thiophen - 7 - yl)-1 - methylpiperidin - 4 - amine (0.126 g, 0.27 mmol), (2,3 - dimethoxy - 4-(prop - 2 - yn - 1 - ylamino)phenyl)dimethylphosphine oxide (0.097 g, 0.36 mmol), Pd(PPh3)2Cl2 (0.020 g, 0.03 mmol), CuI (0.029 g, 0.15 mmol), DIEA (0.105 g, 0.81 mmol), DMSO (1 mL). Stir the reaction mixture at 50 °C for 1 h. Purify the residue by preparative HPLC, eluting with CH3CN / H2O (0.05% NH3·H2O) (v / v = 2 / 1). Obtain 0.084 g (51.91%) of (4 - ((3 - (7 - (((3S,4R)-3 - fluoro - 1 - methylpiperidin - 4 - yl)amino)-3-(2,2,2 - trifluoroethyl)benzo[b]thiophen - 2 - yl)prop - 2 - yn - 1 - yl)amino)-2,3 - dimethoxyphenyl)dimethylphosphine oxide (57) as a white solid. LCMS: m / z = 628 [M+1] +

[0838] 1 1H NMR (400 MHz, DMSO) δ 7.36–7.24 (m, 2H), 7.24–7.17 (m, 1H), 6.78 (d, J = 7.7 Hz, 1H), 6.74–6.66 (m, 1H), 6.39 (t, J = 6.4 Hz, 1H), 5.19 (d, J = 8.5 Hz, 1H), 4.90–4.71 (m, 1H), 4.34 (d, J = 6.3 Hz, 2H), 3.90 (s, 3H), 3.85–3.74 (m, 2H), 3.70 (s, 3H), 3.65–3.55 (m, 1H), 3.03 (t, J = 10.6 Hz, 1H), 2.80 (d, J = 11.3 Hz, 1H), 2.37–2.22 (m, 1H), 2.18 (s, 3H), 2.16–2.04 (m, 1H), 2.01–1.90 (m, 1H), 1.80–1.68 (m, 1H), 1.60 (s, 3H), 1.56 (s, 3H).

[0839] Examples 58, 59, 60 and 61

[0840] (S)-(4-((3-(7-(((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((R)-2,2,2-trifluoro-1-hydroxyethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)(imino)(methyl)-λ 6 -sulfoxide (58), (S)-(4-((3-(7-(((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((R)-2,2,2-trifluoro-1)-hydroxyethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)(imino)(methyl)-λ 6 -sulfoxide (59), (S)-(4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((R)-2,2,2-trifluoro-1-hydroxyethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)(imino)(methyl)-λ 6 -sulfoxide (60) and (S)-(4-((3-(7-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((R)-2,2,2-trifluoro-1-hydroxyethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)(imino)(methyl)-λ 6 -sulfoxide (61)

[0841] Reaction Scheme

[0842]

[0843] Experimental Details

[0844] (S)-(4-((3-(7-(((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((R)-2,2,2-trifluoro-1-hydroxyethyl)benzo[...

Claims

1. A compound of formula (I), or a stereoisomer, tautomer, deuterated derivative, prodrug or pharmaceutically acceptable salt thereof: Y is selected from O, S, NR', S=O, -S(=O)(=NR')- or O=S=O; One of X1, X2, X3 and X4 is selected from N or CR2, and the other X1, X2, X3 and X4 are each independently selected from: N or CR4; X5 is selected from N or CR1; E is selected from alkylene, alkenylene or alkynylene; R1 is independently selected 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)2R’, -S(O)2N(R’)2, -NR’S(O)2R’, -NR’S(O)2N(R’)2, -PO(R’)2, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 6- to 12-membered aryl or 5- to 12-membered heteroaryl; said -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 6- to 12-membered aryl, and 5- to 12-membered heteroaryl are each independently optionally substituted with one or more (such as 1, 2, 3, 4, 5 or 6) substituents selected from: deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -CN, oxo, -OR’, -SR’, -C(O)R’, -C(O)N(R’)2, -C(O)OR’, -OC(O)R’, -OC(O)N(R’)2, -N(R’)2, -NR’C(O)R’, -NR’C(O)OR’, -NR’C(O)N(R’)2, -S(O)R’, -S(O)N(R’)2, -NR’S(O)R’, -NR’S(O)N(R’)2, -S(O)2R’, -S(O)2N(R’)2, -NR’S(O)2R’, -NR’S(O)2N(R’)2, -PO(R’)2, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 6- to 12-membered aryl or 5- to 12-membered heteroaryl; R2 is -NR 51 R 52 , -OR 53 or -SR 54 ; R3 is 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)2R’, -S(O)2N(R’)2, -PO(R’)2, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 6- to 12-membered aryl, 5- to 12-membered heteroaryl; 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 12-membered aryl, and 5- to 12-membered heteroaryl are each independently optionally substituted with one or more (such as 1, 2, 3, 4, 5, or 6) R 3a substituents; Each R 3a is independently selected from deuterium, a halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -CN, oxo, -OR', -SR', -C(O)R', -C(O)N(R')2, -C(O)OR', -OC(O)R', -OC(O)N(R')2, -N(R')2, -NR'C(O)R', -NR'C(O)OR', -NR'C(O)N(R')2, -S(O)R', -S(O)N(R')2, -NR'S(O)R', -NR'S(O)N(R')2, -S(O)2R', -S(O)2N(R')2, -S(=O)(=NR')R', -NR'S(O)2R', -NR'S(O)2N(R')2, -PO(R')2, -P(S)(R')2, a 3-12 membered cycloalkyl, a 3-12 membered cycloalkenyl, a 3-12 membered heterocycloalkyl, a 3-12 membered heterocycloalkenyl, a 6-12 membered aryl or a 5-12 membered heteroaryl; the -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, a 3-12 membered cycloalkyl, a 3-12 membered cycloalkenyl, a 3-12 membered heterocycloalkyl, a 3-12 membered heterocycloalkenyl, a 6-12 membered aryl, and a 5-12 membered heteroaryl are each independently optionally substituted with one or more R 3b substituents; Each R 3b is independently selected from deuterium, a halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -CN, oxo, -OR', -SR', -C(O)R', -C(O)N(R')2, -C(O)OR', -OC(O)R', -OC(O)N(R')2, -N(R')2, -NR'C(O)R', -NR'C(O)OR', -NR'C(O)N(R')2, -S(O)R', -S(O)N(R')2, -NR'S(O)R', -NR'S(O)N(R')2, -S(O)2R', -S(O)2N(R')2, -S(=O)(=NR')R', -NR'S(O)2R', -NR'S(O)2N(R')2, -PO(R')2; R4, each occurrence independently selected 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)2R’, -S(O)2N(R’)2, -NR’S(O)2R’, -NR’S(O)2N(R’)2, -PO(R’)2, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 6- to 12-membered aryl or 5- to 12-membered heteroaryl; said -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 6- to 12-membered aryl, and 5- to 12-membered heteroaryl are each independently optionally substituted with one or more (such as 1, 2, 3, 4, 5 or 6) substituents selected from: deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -CN, oxo, -OR’, -SR’, -C(O)R’, -C(O)N(R’)2, -C(O)OR’, -OC(O)R’, -OC(O)N(R’)2, -N(R’)2, -NR’C(O)R’, -NR’C(O)OR’, -NR’C(O)N(R’)2, -S(O)R’, -S(O)N(R’)2, -NR’S(O)R’, -NR’S(O)N(R’)2, -S(O)2R’, -S(O)2N(R’)2, -S(=O)(=NR’)R’, -NR’S(O)2R’, -NR’S(O)2N(R’)2, -PO(R’)2, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 6- to 12-membered aryl or 5- to 12-membered heteroaryl; 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)2R', -S(O)2N(R')2, -PO(R')2, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 6- to 12-membered aryl, 5- to 12-membered heteroaryl or -C 1-6 alkyl-C 3-12 heterocycloalkyl; 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, -C 3-12 heterocycloalkyl, and 5- to 12-membered heteroaryl are each independently optionally substituted with one or more (such as 1, 2, 3, 4, 5 or 6) substituents selected from: deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -CN, oxo, =NR', -C 1-6 alkyl-CH(R')2, -OR', -SR', -C(O)R', -C(O)N(R')2, -C(O)OR', -OC(O)R', -OC(O)N(R')2, -N(R')2, -NR'C(O)R', -NR'C(O)OR', -NR'C(O)N(R')2, -S(O)R', -S(O)N(R')2, -NR'S(O)R', -NR'S(O)N(R')2, -S(O)2R', -S(O)2N(R')2, -S(=O)(=NR')R', -NR'S(O)2R', -NR'S(O)2N(R')2, -PO(R')2, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl; 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, -NH2, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)2 or 3-6 membered cycloalkyl; wherein said -C 1-6 alkyl, -C 1-6 alkoxy and 3-6 membered cycloalkyl are each independently optionally substituted with one or more (such as 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; or R 11 or R 12 R3 and the atoms to which they are respectively attached together form a ring, for example, a monocyclic, bicyclic or polycyclic 3- to 12-membered cycloalkyl group, 3- to 12-membered heterocyclic group, 6- to 12-membered aryl group or 5- to 12-membered heteroaryl group, and the ring is independently optionally substituted by one or more R 3a substituted; R 13 selected from hydrogen, deuterium, -C 1-6 alkyl or 3- to 6-membered cycloalkyl; wherein said -C 1-6 alkyl and 3- to 6-membered cycloalkyl are each independently optionally substituted with one or more (such as 1, 2, 3, 4, 5 or 6) substituents selected from: deuterium, -OH, halogen, -CN, oxo, -C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, or -N(C 1-4 alkyl)2; or R3 and R 13 together with the nitrogen atom to which they are attached form a ring, for example, a monocyclic, bicyclic or polycyclic 3- to 12-membered cycloalkyl, 3- to 12-membered heterocycloalkyl, 6- to 12-membered aryl or 5- to 12-membered heteroaryl ring, which ring is independently optionally substituted with one or more R 3a substituents; Each R’ is independently selected from hydrogen, deuterium, halogen, -OH, -CN, oxo, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -C 1-6 alkyl, -C 1-6 alkylOC 1-6 alkyl, -C 1-6 alkyl-NHC 1-6 alkyl, -C 1-6 alkyl-N(C 1-6 alkyl)2, -C 1-6 haloalkyl, -OC 1-6 alkyl, -C(O)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; wherein 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, 6-12 membered aryl, or 5-12 membered heteroaryl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from: deuterium, halogen, -CN, -C 1-3 alkyl, oxo, -OH, -OC 1-3 alkyl, -NH2, -NHC 1-3 alkyl, -N(C 1-3 alkyl)2, -C(=O)NH2, -C(=O)NH(C 1-3 alkyl), -C(=O)N(C 1-3 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 alkyl), -S(=O)2C 1-3 alkyl, -S(=O)2N(C 1-3 alkyl)2, -S(=O)(=NH)C 1-3 alkyl, -S(=O)(=NC 1-3 alkyl)C 1-3 alkyl, or 3-6 membered cycloalkyl; The heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain 1, 2, 3, 4, 5 or 6 heteroatoms selected from the following: N, O, P or S; m is selected from 1, 2, 3, 4, 5 or 6.

2. The compound according to claim 1, wherein E is selected from ethynylene or ethylene.

3. The compound according to claim 1 or 2, wherein The formula (I) is: In the formula (I-1), X2, X3, and X4 are each independently selected from: N or CR4; Y is selected from O, S, S=O, or O=S=O.

4. The compound according to claim 1 or 2, wherein the formula (I) is: Among them, X2 is independently selected from N or CR4.

5. The compound according to any one of claims 1 to 4, wherein R1 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 (such as 1, 2, 3, 4, 5, or 6) substituents selected from: halogen, -OH, -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, wherein each of the heterocycloalkyl, heterocycloalkenyl, and heteroaryl independently contains 1 or 2 heteroatoms selected from: N or S.

6. The compound according to any one of claims 1 to 5, wherein R1 is independently selected from -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, 5- to 12-membered heteroaryl, wherein the -C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 1-3 haloalkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 12-membered heteroaryl are each independently optionally substituted with one or more (such as 1, 2, 3, 4, 5, or 6) substituents selected from: -F, -Cl, -OH, -C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 1-3 haloalkyl, -CN, oxo, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 12-membered heteroaryl, wherein each of the heterocycloalkyl, heterocycloalkenyl, and heteroaryl independently contains 1 or 2 heteroatoms selected from: N or S.

7. The compound according to any one of claims 1 to 6, wherein R1 is independently selected from -F, -Cl, -C 1-3 alkyl, -C 1-3 haloalkyl, 3- to 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- to 6-membered cycloalkyl, 5-membered heteroaryl and 6-membered heteroaryl are each independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from: -F, -OH, -C 1-3 alkyl, -OC 1-3 alkyl, -NH2, -NHC 1-3 alkyl, -N(C 1-3 alkyl)2, -CN or 3- to 6-membered cycloalkyl.

8. A compound according to any one of claims 1 to 7, wherein R1 is independently selected from -C 1-3 alkyl, -C 1-3 haloalkyl, or a 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S; and R1 is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from: -F, -OH, -OC 1-3 alkyl, -NH2, -NHC 1-3 alkyl, -N(C 1-3 alkyl)2, -CN or 3-6 membered cycloalkyl.

9. The compound according to any one of claims 1-8, wherein R1 is independently selected from 10. The compound according to any one of claims 1 to 9, wherein R2 is -NR 51 R 52 .

11. The compound according to any one of claims 1 to 10, wherein R2 is -NHR 51 .

12. The compound according to any one of claims 1 to 11, wherein R 51 is selected from -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, 3-10 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, or -C 1-6 alkyl-C 3-12 heterocycloalkyl; the -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, 3-6 membered cycloalkyl, 3-10 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl and -C 3-12 heterocycloalkyl are each independently optionally substituted with one or more (such as 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, wherein, The heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain 1 heteroatom selected from N, O, or S.

13. The compound according to any one of claims 1 to 12, wherein R 51 is selected from -C 1-3 alkyl, cyclopentyl, cyclohexyl, -C(O)-C 3-6 heterocycloalkyl, -C 1-3 alkyl-C 3-6 heterocycloalkyl, or a 5-, 6-, or 8-membered heterocyclic group containing 1 heteroatom selected from N, O, S, S(=O), S(=O)(=NH), or S(=O)2; the -C 1-3 alkyl, cyclopentyl, cyclohexyl, C 3-6 heterocycloalkyl, and the 5-, 6-, or 8-membered heterocyclic group are each independently optionally substituted with 1, 2, or 3 substituents selected from: -F, -C 1-3 alkyl, -OC 1-3 alkyl, -NH2, -NHC 1-3 alkyl, oxo, =NH, -N(C 1-3 alkyl)2, -CN, or 3- to 6-membered cycloalkyl.

14. A compound according to any one of claims 1 to 13, wherein R 51 is selected from an 8-membered bridged heterocyclic group, -C(O)-C 3-5 heteroalkyl, or -C 1-3 alkyl-C 3-5 heteroalkyl, and the 8-membered bridged heterocyclic group, -C 1-3 alkyl or -C 3-5 heteroalkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 R 5e substituents; R 5a 、R 5c and R 5d each independently selected from: hydrogen; -C 1-6 alkyl; or -C 1-6 alkyl, which is substituted with 1, 2, 3, 4, 5 or 6 substituents selected from the following: -F, -C 1-3 alkyl, oxo, -OC 1-3 alkyl, -NH2, -NHC 1-3 alkyl, -N(C 1-3 alkyl)2, -CN or 3-6 membered cycloalkyl; R 5b and R 5e are each independently selected from: -F, -C 1-6 alkyl, oxo, -OC 1-6 alkyl, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -CN or 3-6 membered cycloalkyl, wherein 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, -NH2, -NHC 1-3 alkyl, -N(C 1-3 alkyl)2, -CN or 3-6 membered cycloalkyl.

15. The compound according to any one of claims 1 to 14, wherein R 51 is selected from 16. The compound according to any one of claims 1 to 15, wherein R3 is independently selected from 3- to 12-membered heteroalkenyl, 6- to 10-membered aryl, or 5- to 12-membered heteroaryl; and each occurrence of the 3- to 12-membered heteroalkenyl, 6- to 10-membered aryl, or 5- to 12-membered heteroaryl is independently optionally substituted with one or more R 3a substituents selected from: halogen, NH2, NH-C 1-6 alkyl, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -CN, -NO2, -OR’, -SR’, -C(O)R’, oxo, -C(O)N(R’)2, -C(O)OR’, -OC(O)R’, -N(R’)2, -NR’C(O)R’, -S(O)R’, -NR’S(O)R’, -S(O)N(R’)2, -S(O)2R’, -NR’S(O)2R’, -S(O)2N(R’)2, -S(=O)(=NR’)R’, -PO(R’)2, -P(S)(R’)2, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered heteroalkyl, 3- to 12-membered heteroalkenyl, 6- to 10-membered aryl, or 5- to 12-membered heteroaryl, wherein the heteroalkyl, heteroalkenyl, and heteroaryl each independently contain 1, 2, 3, or 4 heteroatoms selected from N, O, or S; and R3a is independently optionally substituted with one or more R 3b substituents.

17. The compound according to any one of claims 1 to 16, wherein R 3a is selected from l halogen; oxo; -C 1-3 alkyl; -OC 1-3 alkyl; -NH2; -NHC 1-3 alkyl; -N(C 1-3 alkyl)2; -C(=O)NH2, -C(=O)NH(C 1-3 alkyl); -C(=O)N(C 1-3 alkyl)2; -CN; -S(=O)2NH2; -S(=O)2NH(C 1-3 alkyl); -S(=O)2NHC(=O)C 1-3 alkyl; -S(=O)2N(C 1-3 alkyl)2; -S(=O)2C 1-3 alkyl; -S(=O)(=NH)C 1-3 alkyl; -S(=O)(=NH)C 3-6 cycloalkyl; -S(=O)(=NR')C 2-6 heterocycloalkyl; -S(=O)(=NC 3-6 cycloalkyl)C 1-3 alkyl; -S(=O)(=NC 2-6 heterocycloalkyl)C 1-3 alkyl; -S(=O)(=NC 1-3 alkyl)C 1-3 alkyl; -S(=O)(=NCN)C 1-3 alkyl; -N(C 1-3 alkyl)S(=O)2C 1-3 alkyl; -PO(C 1-3 alkyl)2; -P(S)(C 1-3 alkyl)2; 3-6 membered cycloalkyl; 3-6 membered heterocycloalkyl or 5-12 membered heteroaryl optionally containing 1, 2 or 3 heteroatoms selected from N, O, P or S; wherein the C 1-3 alkyl, OC 1-3 alkyl, 3-6 membered cycloalkyl, C 3-6 cycloalkyl, C 2-6 heterocycloalkyl, 3-6 membered heterocycloalkyl or 5-12 membered heteroaryl are each independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from: deuterium, halogen, -CN, -C 1-3 alkyl, oxo, -OH, -OC 1-3 alkyl, -NH2, -NHC 1-3 alkyl, -N(C 1-3 alkyl)2, -COOH, -C(O)OC 1-3 alkyl, -C(=O)NH2, -C(=O)NH(C 1-3 alkyl), -C(=O)N(C 1-3 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 alkyl), -S(=O)2C 1-3 alkyl, -S(=O)2N(C 1-3 alkyl)2, -S(=O)(=NH)C 1-3 alkyl, -S(=O)(=NC 1-3 alkyl)C 1-3 alkyl, or 3- to 6-membered cycloalkyl.

18. A compound according to any one of claims 1-17, wherein R3 is independently selected from phenyl, pyridyl, benzofuranyl, or isoindolinyl, and R3 is independently optionally substituted with one or more substituents of R 3a wherein the substituents of R 3a are independently selected from halogen, oxo, -CN, -CH3, CF3, -OCH3, -OCD3, OCH2CH3, -SCH3, -C(O)OC(CH3)3, -PO(CH3)2, -P(S)(CH3)2, -S(O)2CH3, -S(=O)(=NH)CH3, -S(=O)(=NCH3)CH3, pyrazolyl, 19. The compound according to any one of claims 1 to 18, wherein R 11 or R 12 is hydrogen or oxo; or R 11 or R 12 and R3 together with the atoms to which they are respectively attached form a 5- to 12-membered heterocyclic group, preferably indolinyl, which is optionally substituted by one or more R 3a substituents.

20. The compound according to any one of claims 1 to 19, wherein R 13 is H; or R3 and R 13 together with the nitrogen atom to which they are attached form a 5- to 12-membered heterocyclic group, preferably benzimidazolyl, which is optionally substituted by one or more R 3a substituents.

21. The compound according to any one of claims 1 to 20, wherein the chemical moiety is selected from:

22. The compound according to any one of claims 1 to 21, wherein the compound of formula (I) is selected from:

23. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1-22, or a stereoisomer, tautomer, deuterated derivative, prodrug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

24. Use of a compound of formula (I) according to any one of claims 1-22, or a stereoisomer, tautomer, deuterated derivative, prodrug or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23 in the manufacture of a drug for preventing or treating a disease or disorder in a subject.

25. The use according to claim 24, wherein the disease or disorder is cancer, preferably a solid tumor, such as an advanced solid tumor.

26. The use according to claim 25, wherein the cancer cells express a p53 mutant.

27. The use according to claim 26, wherein the p53 mutant has a mutation at amino acid Val143, His168, Arg175, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, Arg282 and / or a combination thereof.

28. The use according to claim 26, wherein the p53 mutant is V157F, R175H, Y220C, G245S, R248Q, R248W, R249S, R273H, R273C, R282W, and / or a combination thereof, preferably Y220C.

29. Use according to any one of claims 24 to 28, wherein the disease or disorder is selected from the group consisting of ovarian cancer, breast cancer, lung cancer, and / or combinations thereof.

30. A compound of formula (I) according to any one of claims 1 - 22, or a stereoisomer, tautomer, deuterated derivative, prodrug, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23 for preventing or treating a disease or disorder associated with a p53 mutant protein in a subject.

31. A method for preventing or treating a disease or disorder associated with a p53 mutant protein in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 - 22, or a stereoisomer, tautomer, deuterated derivative, prodrug, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23.

32. The method according to claim 31, wherein the disease or disorder is cancer.

33. The method according to claim 32, wherein the cancer cells express a p53 mutant.

34. The method according to claim 33, wherein the p53 mutant has a mutation at amino acid Val143, His168, Arg175, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, Arg282, and / or combinations thereof.

35. The method according to claim 33, wherein the p53 mutant is V157F, R175H, Y220C, G245S, R248Q, R248W, R249S, R273H, R273C, R282W, and / or combinations thereof, preferably Y220C.

36. The method according to any one of claims 31 to 35, wherein the disease or disorder is selected from the group consisting of ovarian cancer, breast cancer, lung cancer, and / or combinations thereof.

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