Bicyclic compounds, compositions containing the same, and uses thereof

Abstract

Compounds of formula (I) are provided, as well as pharmaceutical compositions containing them and their uses. The compounds can be used for treating, preventing or ameliorating diseases or disorders such as cancer.

Description

Technical Field

[0001] The present invention relates to novel compounds of formula (I). The present invention also relates to pharmaceutical compositions comprising such compounds and methods of using said compounds for the treatment and prevention of diseases, in particular cancer, pre-cancerous syndromes, congenital diseases and hyperproliferative diseases. Background Art

[0002] Under normal circumstances, the dynamic balance between cell proliferation and apoptosis maintains the normal size of tissues and organs and the stability of the internal environment. When the proliferation or apoptosis of cells gets out of control, cell malignant transformation occurs. The Hippo signaling pathway is a cell growth inhibitory pathway, which consists of a variety of tumor suppressor factors and regulates the balance between cell proliferation and apoptosis through a series of kinase cascades. The Hippo signaling pathway plays a key role in early embryonic development, organ size and regeneration, etc.

[0003] The Hippo pathway was initially discovered in Drosophila and is an important developmental pathway that controls organ size. Subsequently, it was also found in mammals. In mammals, the Hippo pathway can be divided into three categories: upstream regulatory elements (Merlin / NF2, GPCRS, etc.), core kinase cascades (MST1 / 2, LATS1 / 2 and regulatory proteins SAV1 and MOB), and downstream effector molecules (YAP / TAZ). The tumor suppressor protein neurofibromin 2 type antigen (NF2 / merlin) or other upstream regulatory signals activate the MST1 / 2 kinase and the scaffold protein SAV1. The activated MST1 / 2 promotes the phosphorylation of LATS1 / 2 and MOB. Then, phosphorylated LATS1 / 2 can further phosphorylate YAP / TAZ to achieve the regulation of the Hippo signaling pathway. Phosphorylated YAP / TAZ is finally degraded by binding to 14-3-3, which mediates cytoplasmic retention, and β-TrCP, which mediates proteasomal degradation.

[0004] Unphosphorylated YAP / TAZ in the cytoplasm crosses the nuclear membrane and enters the nucleus and acts as a transcriptional co-activator of TEAD1-4. Various cytokines, including connective tissue growth factor (CTGF), cysteine-rich angiogenic inducer 61 (CYR61), ankyrin repeat domain 1 (ANKRD1), baculoviral IAP repeat-containing protein 5 (BIRC5), brain-derived neurotrophic factor and fibroblast growth factor 1, are downstream substrates stimulated by YAP / TAZ. As a direct target gene of YAP / TAZ, CTGF can promote cell proliferation and support cell independent growth.

[0005] The human YAP gene is located on chromosome 11q13 and is widely expressed in various tissues except peripheral blood cells. YAP contains multiple domains and specific amino acid sequences, including a TEAD-binding region, two WW domains, a proline-rich N-terminal domain, a C-terminal PDZ-binding motif, an SH3-binding motif, a coiled-coil domain, and a transcriptional activation domain. YAP has two isoforms: YAP1 and YAP2. YAP1 contains 1 WW domain, and YAP2 contains 2 WW domains. The WW domain specifically recognizes the PPXY motif to mediate the formation of transcriptional complexes. YAP2 is the main isoform of YAP and has stronger transcriptional regulatory activity than YAP1. Additionally, TAZ is homologous to YAP, has domains and functions similar to YAP, but lacks the proline-rich domain and the second WW domain.

[0006] The TEAD family is the most important transcription factor for YAP and TAZ. Point mutations at key positions in TEAD, especially those related to the YAP and TEAD binding domains, significantly inhibit the expression and function of YAP-induced genes. The human TEAD family of transcription factors includes four members, TEAD1 / 2 / 3 / 4, which have high homology. TEADs contain a TEA-binding domain at the N-terminus, which serves as the site for binding to DNA transcriptional promoters, and a YAP / TAZ-binding domain at the C-terminus. The N-terminal domain of YAP / TAZ wraps around the C-terminal domain of TEAD to form a spherical structure. The binding region between YAP / TAZ and TEAD is divided into three interfaces. Interface 1 is mediated by seven intermolecular hydrogen bonds between the peptide backbones of YAPβ1 and TEADβ7, forming an antiparallel β-sheet. Interface 2 is generated by the YAPα1 helix near the groove formed by TEADα3 and α4. In Interface 3, the Ω-loop of YAP interacts with the deep pocket formed by β4, β11, β12, α1, and α4 of TEAD.

[0007] Normally, YAP / TAZ is only induced in specific tissues and under specific conditions (such as development, wound healing, etc.). The expression level is low in other tissues. Mutations in the Hippo pathway components trigger the overactivation of YAP / TAZ, leading to the proliferation of normal cells. Studies have shown that after the dysregulation of the Hippo pathway, the overactivation of YAP / TAZ is common in cancers such as lung cancer, liver cancer, pancreatic cancer, breast cancer, etc.

[0008] In cancer stem cells of various solid tumors, YAP / TAZ can promote the survival of cancer stem cells, and is closely related to cancer cell metastasis and drug resistance, promoting the occurrence and development of various tumors. During chemotherapy drug treatment, anti-microtubule drugs, anti-metabolic drugs, DNA-damaging agents, etc. can affect the Hippo signaling pathway, leading to the activation and transcription of YAP / TAZ, thereby generating drug resistance. The over-activation of YAP / TAZ will cause the high expression of various drug transporters, which can transfer drugs to the extracellular space, resulting in the up-regulation of anti-apoptotic proteins such as Bcl and survivin, thereby inhibiting apoptosis. Many studies have shown that PD-L1 is a direct transcriptional target of YAP / TAZ. Activated YAP / TAZ can increase the expression of PD-L1. At the same time, it can also induce the expression of cytokines such as IL-6, CSF1-3, TNFA, IL-3, CXCL1 / 2, CCL2, etc. to promote the recruitment and polarization of myeloid-derived suppressor cells (MDSC), inactivate T cells or induce T cell apoptosis. More studies have shown that the de-repression of the Hippo pathway leading to the activation of YAP / TAZ is also the main mechanism of various targeted drug resistances. The transcription activated by YAP / TAZ can overcome EGFR drug resistance through multiple mechanisms. For example, the high expression of AXL mediates the resistance of NSCLC to EGFR inhibitors; the inhibition of the pro-apoptotic protein BMF mediates the resistance to EGFR / MEK inhibitors; the activation of the PI3K / AKT signaling pathway to escape targeted therapy. The transcription activated by YAP can also mediate resistance to BRAF, KRAS and MAPK inhibitors. The activation of YAP / TAZ is not only related to drug resistance, and studies have shown that YAP gene amplification is associated with the recurrence of colon cancer and pancreatic cancer.

[0009] Therefore, the Hippo pathway plays an important role in controlling the morphology of tissues and organs. It is related to many aspects of tumorigenesis, including cell proliferation, differentiation, apoptosis, competition, tissue regeneration, cancer metastasis and cancer therapy resistance. The de-repression of the Hippo pathway can lead to the high expression and activation of YAP / TAZ in the cytoplasm and nucleus, thereby inducing tumor development and metastasis and even generating drug resistance. The disruption of the YAP / TAZ-TEAD interaction can eliminate the oncogenic properties of YAP / TAZ. Therefore, the protein-protein interaction inhibitors of YAP / TAZ and TEAD provide a theoretical basis for the treatment of these cancers. Summary of the Invention

[0010] The present invention relates to a compound of formula (I), or its stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes or solvates,

[0011]

[0012] wherein,

[0013] is a single bond or a double bond;

[0014] A1 and A2 are each independently selected from C or N;

[0015] Ring B is selected from C 5-6 aryl, C 5-6 cycloalkyl, 5- or 6-membered heterocyclic group, and 5- or 6-membered heteroaryl group, where the 5- or 6-membered heterocyclic group and the 5- or 6-membered heteroaryl group contain 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O;

[0016] Ring A is selected from C 5-6 aryl, 5- or 6-membered heteroaryl group, 5- or 6-membered heterocyclic group, the 5- or 6-membered heteroaryl group and the 5- or 6-membered heterocyclic group contain 1-4 heteroatoms independently selected from N, S, and O, where C 5-6 aryl, 5- or 6-membered heteroaryl group, and 5- or 6-membered heterocyclic group may each optionally be substituted with 0-3 substituents independently selected from oxo group, ═NH, hydroxyl group, halogen, CN, -NH(C 1-6 alkyl), -NH(C 1-6 alkyl), -N-(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -OC(═O)R a , -C(═O)NR a R b , -C(═O)OR a , -C(═O)R c , -S(═O)R b , -S(═O)2R b , -S(═O)NR a R b , -S(═O)2NR a R b ;

[0017] L1 is a bond, -O-, -S-, -NR a -, -(CH2) t -, -(CH2) t -NR a -, -NR a -(CH2) t -, -(CH2) t -O-, -O-(CH2) t -, -C(═O)-, -C(═O)NR a - or -NR a -C(═O)-;

[0018] Ring E is C 5-6 aryl, 5- to 10-membered heteroaryl, C 3-8 cycloalkyl or 4- to 8-membered heterocyclic group, wherein the 5- to 10-membered heteroaryl or 4- to 8-membered heterocyclic group contains 1 to 4 heteroatoms independently selected from N, S and O;

[0019] L2 is a bond, -O-, -S-, -NH-, -(CH2) t -O-, -O-(CH2) t -, -C(=O)-, -C 1-4 alkylene, -C 2-4 alkenylene, or -C 2-4 alkynylene;

[0020] Ring D is C 5-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl or 4- to 10-membered heterocyclic group, wherein the 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclic group contains 1, 2, 3 or 4 heteroatoms independently selected from N, S and O;

[0021] R1 is H, oxo group, hydroxy group, halogen, CN, -NO2, -NR d R e , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, -C(=O)NR a R b , -C(=O)OR a , -C(=O)R c , -S(=O)R b , -S(=O)2R b , -S(=O)NR a R b , -S(=O)2NR a R b , -O-(C=O)-R a , -O-(C=O)-NR a R b , C 1-6 haloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 5-6 aryl or 5- to 6-membered heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-6 Aryl and 5-6 membered heteroaryl may each independently be optionally substituted with 0-3 substituents selected from OH, CN, halogen, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -NR a R b , -C(=O)NR a R b , -OC(=O)R a , -C(=O)OR a , -C(=O)R a , -S(=O)R b , -S(=O)2R b , -S(=O)NR a R b , -S(=O)2NR a R b , -NR a C(=O)R b , C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-6 Aryl and 5-6 membered heteroaryl are substituted with the substituents; wherein the 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl and 3-6 membered heterocyclic group optionally contain 1, 2 or 3 heteroatoms independently selected from N, S and O;

[0022] R2 is H, hydroxy, halogen, CN, -NO2, -NR a R b , oxo group, -C(=O)NR a R b , -C(=O)OR a , -C(=O)R a , -S(=O)R b , -S(=O)2R b , -S(=O)NR a R b , -S(=O)2NR a R b , -NR a C(=O)R b , SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-6A cycloalkyl group or a 3-6 membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, S and O; wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each optionally substituted by 0-3 substituents independently selected from -OR a , halogen, CN, C 1-4 alkyl, C 1-6 haloalkyl, -NR a R b , oxo group, -OC(=O)R a , -C(=O)NR a R b , -C(=O)OR a , -C(=O)R a , -S(=O)R b , -S(=O)2R b , -S(=O)NR a R b , -S(=O)2NR a R b and -NR a C(=O)R b ;

[0023] R3 is H, oxo group, halogen, -OR a , CN, -NO2, -NR a R b , -NR a C(=O)R b , -C 1-4 alkylene-NR a R b , -C 1-4 alkylene-NR a C(=O)R b , -C(=O)R b , -OC(=O)R a , -C(=O)OR a , -C(=O)NR a R b , -S(=O)R b , -S(=O)2R b , -S(=O)NR a R b , -S(=O)2NR a R b , -C 1-4 alkylene-C(=O)NR a R b, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, 3- to 6-membered heterocyclic group, C 3-6 cycloalkyl, C 5-6 aryl or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl and the 3- to 6-membered heterocyclic group optionally contain 1, 2 or 3 heteroatoms independently selected from N, S and O; wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 5-6 aryl and 5- to 6-membered heteroaryl are each optionally substituted by 0-3 substituents independently selected from oxo group, hydroxy group, halogen, CN, -NO2, C 1-6 alkyl, -C 1-4 alkylene-OH, C 1-6 haloalkyl, C 1-6 alkoxy, -S(=O)R b , -S(=O)2R b , -NR a R b , -C(=O)R b , -OC(=O)R a , -C(=O)OR a , -NR a C(=O)R b , -C(=O)NR a R b , -NR a C(=O)R b , -C 1-4 alkylene-NR a R b , -C 1-4 alkylene-NR a C(=O)R b , C 1-4 alkylene-C(=O)NR a R b , -C 1-4 alkylene-OH, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 5-6 substituted by the substituents of aryl and 5- to 6-membered heteroaryl;

[0024] R4 is

[0025] L3 is a key, -NR a -, -(CH2)t-NR a -, -C 4-6 heterocyclic group or -C 4-6 cycloalkyl-NR a -;

[0026] R5, R6, R7 and R8 are each independently selected from H, halogen, -OR a , CN, -NR a R b , -C 1-6 alkylene-NR a R b , -C 1-6 alkylene-R c , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 5-6 aryl and 5- to 6-membered heteroaryl, where C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 5-6 aryl and 5- to 6-membered heteroaryl are each optionally substituted with 0 to 4 substituents independently selected from OH, CN, halogen, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, -NR a R b , C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 5-6 aryl and 5- to 6-membered heteroaryl, where the 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclic group optionally contain 1, 2 or 3 heteroatoms independently selected from N, S and O;

[0027] R a and R b are each independently selected from H, CN, hydroxy, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkoxy, C3-6 Cycloalkyl, 3- to 6-membered heteroalkyl, C 5-6 Aryl and 5- to 6-membered heteroaryl, wherein C 1-6 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heteroalkyl, C 5-6 Aryl and 5- to 6-membered heteroaryl are each optionally substituted with 0 to 4 substituents independently selected from halogen, CN, -OH, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenoalkyl, C 1-3 Alkoxy, C 1-3 Halogenoalkoxy and C 5-6 Aryl; wherein the 5- to 6-membered heteroaryl and 3- to 6-membered heteroalkyl optionally contain 1, 2 or 3 heteroatoms independently selected from N, S and O;

[0028] R c is a 3- to 6-membered heterocyclic group optionally substituted with 0 to 4 substituents independently selected from halogen, CN, -OH, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenoalkyl, C 1-3 Alkoxy and C 1-3 Halogenoalkoxy;

[0029] R d and R e are each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenoalkyl, C 1-6 Alkoxy, -C(=O)NR f R f ,-C(=O)OR f ,-O-C(=O)R f ,-C(=O)R f ,-S(=O)R f ,-S(=O)2R f ,-S(=O)NR f R f ,-S(=O)2NR f R f ,-C 1-4 Alkylene-NR f R f ,-C 1-4 Alkylene-NR f C(=O)R f ,-C 1-4Alkylene-C(=O)NR f R f ;

[0030] R f is H, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkoxy;

[0031] t is 1, 2, 3 or 4;

[0032] x, y and m are each independently selected from 0, 1, 2, 3, 4 or 5.

[0033] In some embodiments, the compound of formula (I-1), or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof,

[0034]

[0035] wherein,

[0036] is a single bond or a double bond;

[0037] A1 and A2 are each independently selected from C or N;

[0038] Ring B is selected from C 5-6 aryl, 5- to 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from N, S and O;

[0039] Ring A is selected from C 5-6 aryl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl and 5- to 6-membered heterocyclic group contain 1-4 heteroatoms independently selected from N, S and O, and the 5- to 6-membered heterocyclic group and 5- to 6-membered heteroaryl are each independently optionally substituted by one or more and / or substituents;

[0040] L1 is a bond, -O-, -S-, -NH-, -(CH2) t -, -(CH2) t -O-, -O-(CH2) t -, -C(=O)-, -C(=O)NH- or

[0041] -NH-C(=O)-;

[0042] Ring E is C 5-6 aryl, 5- to 10-membered heteroaryl, C 3-8A cycloalkyl group or a 4- to 8-membered heterocyclic group, wherein the 5- to 10-membered heteroaryl group and the 4- to 8-membered heterocyclic group contain 1 to 4 heteroatoms independently selected from N, S, and O;

[0043] L2 is a bond, -O-, -S-, -NH-, -(CH2) t -O-, -O-(CH2) t -, -C(=O)-, -C 1-4 an alkylene group, -C 2-4 an alkenylene group, or -C 2-4 an alkynylene group;

[0044] Ring D is C 5-10 an aryl group, a 5- to 10-membered heteroaryl group, C 3-10 a cycloalkyl group or a 4- to 10-membered heterocyclic group, wherein the 5- to 10-membered heteroaryl group or the 4- to 10-membered heterocyclic group contains 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O;

[0045] R1 is H, an oxo group, a hydroxyl group, a halogen, CN, -NH(C 1-6 alkyl), -N-(C 1-6 alkyl)2, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, -C(=O)NR a R b , -C(=O)OR a , -OC(=O)R a , -C(=O)R c , -S(=O)R b , -S(=O)2R b , -S(=O)NR a R b , -S(=O)2NR a R b , C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 5-6 aryl or 5- to 6-membered heteroaryl, wherein C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 5-6 the aryl group and the 5- to 6-membered heteroaryl group may each optionally be substituted with 0 to 3 substituents independently selected from OH, CN, halogen, C 1-6 alkyl, C2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -NR a R b , -C(=O)NR a R b , -S(=O)R b , -S(=O)2R b , -S(=O)NR a R b , -S(=O)2NR a R b , -NR a C(=O)R b , C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heteroalkyl, C 5-6 Substituted by substituents of aryl and 5- to 6-membered heteroaryl; wherein the 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclic group optionally contain 1, 2 or 3 heteroatoms independently selected from N, S and O;

[0046] R2 is H, hydroxy, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 3- to 6-membered heteroalkyl containing 1, 2 or 3 heteroatoms independently selected from N, S and O; wherein C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 3- to 6-membered heteroalkyl are each optionally substituted by 0-3 substituents independently selected from hydroxy, halogen, CN and C 1-4 Alkyl;

[0047] R3 is H, oxo, halogen, CN, -NO2, -NR a R b , -NR a C(=O)R b , -C 1-4 Alkylene-NR a R b , -C 1-4 Alkylene-NR a C(=O)R b , -C(=O)R b , -OC(=O)R a , -C(=O)OR a, -C(=O)NR a R b , -S(=O)R b , -S(=O)₂R b , -S(=O)NR a R b , -S(=O)₂NR a R b , -C 1-4 alkylene-C(=O)NR a R b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-4 haloalkoxy, 3- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl, C 5-6 aryl or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl and the 3- to 6-membered heterocycloalkyl optionally contain 1, 2 or 3 heteroatoms independently selected from N, S and O; wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 5-6 aryl and 5- to 6-membered heteroaryl are each optionally substituted with 0-3 substituents independently selected from oxo, hydroxy, halogen, CN, -NO₂, C 1-6 alkyl, -C 1-4 alkylene-OH, C 1-6 haloalkyl, C 1-6 alkoxy, -S(=O)R b , -S(=O)₂R b , -NR a R b , -C(=O)R b , -OC(=O)R a , -C(=O)OR a , -NR a C(=O)R b , -C(=O)NR a R b , -NR a C(=O)R b , -C 1-4 alkylene-NR a R b , -C 1-4 alkylene-NRa C(=O)R b ,C 1-4 alkylene-C(=O)NR a R b ,-C 1-4 alkylene-OH,C 3-6 cycloalkyl,3-6-membered heterocycloalkyl,C 5-6 substituted by substituents of aryl and 5-6-membered heteroaryl;

[0048] R4 is

[0049] L3 is a bond, -NH-, -(CH2) t -NH-, -C 4-6 heterocyclic group or -C 4-6 cycloalkyl-NH-;

[0050] R5, R6, R7 and R8 are each independently selected from H, halogen, CN, -NR a R b ,-C 1-6 alkylene-NR a R b ,-C 1-6 alkylene-R c ,C 1-4 alkyl,C 2-4 alkenyl,C 2-4 alkynyl,C 1-4 alkoxy,C 3-6 cycloalkyl,3-6-membered heterocycloalkyl,C 5-6 aryl and 5-6-membered heteroaryl, where C 1-6 alkyl,C 2-4 alkenyl,C 2-4 alkynyl,C 1-4 haloalkyl,C 1-4 alkoxy,C 1-4 haloalkoxy,C 3-6 cycloalkyl,3-6-membered heterocycloalkyl,C 5-6 aryl and 5-6-membered heteroaryl are each optionally substituted by 0-4 substituents independently selected from OH, CN, halogen, C 1-6 alkyl,C 2-4 alkenyl,C 2-4 alkynyl,C 1-4 haloalkyl,C 1-4 alkoxy,-NR a R b ,C 3-6 cycloalkyl,3-6-membered heterocycloalkyl,C 5-6 aryl and 5-6-membered heteroaryl, where the 5-6-membered heteroaryl and 3-6-membered heterocycloalkyl optionally contain 1, 2 or 3 heteroatoms independently selected from N, S and O;

[0051] R a and R b are each independently selected from H, CN, hydroxy, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3- to 6-membered heteroalkyl, C 5-6 aryl, and 5- to 6-membered heteroaryl, where C 1-6 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3- to 6-membered heteroalkyl, C 5-6 aryl, and 5- to 6-membered heteroaryl are each optionally substituted with 0 to 4 substituents independently selected from halogen, CN, -OH, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, and C 5-6 aryl; where the 5- to 6-membered heteroaryl and the 3- to 6-membered heteroalkyl optionally contain 1, 2, or 3 heteroatoms independently selected from N, S, and O;

[0052] R c is a 3- to 6-membered heteroalkyl, which may optionally be substituted with 0 to 4 substituents independently selected from halogen, CN, -OH, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy substituents;

[0053] t is 1, 2, 3, or 4;

[0054] x, y, and m are each independently selected from 0, 1, 2, 3, 4, or 5.

[0055] In some embodiments, ring B is selected from C 5-6 aryl, C 5-6 cycloalkyl, 5- to 6-membered heteroaryl containing 1, 2, 3, or 4 N heteroatoms, or 5- to 6-membered heterocyclic group containing 1, 2, 3, or 4 heteroatoms independently selected from N, S, O.

[0056] In some embodiments, ring B is selected from C 5-6 aryl, C 5-6A cycloalkyl group, a 5- or 6-membered heteroaryl group containing 1 or 2 N heteroatoms, or a 5- or 6-membered heterocyclic group containing 1 or 2 O heteroatoms, wherein the 5- or 6-membered heteroaryl group and the 5- or 6-membered heterocyclic group are each independently optionally substituted by one or more substituents.

[0057] In some embodiments, ring B is selected from a phenyl group, a cyclohexyl group, a 6-membered heteroaryl group containing 1 or 2 N heteroatoms, or a 6-membered heterocyclic group containing 1 or 2 O heteroatoms.

[0058] In some embodiments, ring B is a C 5-6 aryl group, a 5- or 6-membered heteroaryl group which is optionally substituted with an oxo group, and the 5- or 6-membered heteroaryl group contains 1, 2, 3 or 4 N heteroatoms.

[0059] In some embodiments, ring B is a C 5-6 aryl group, a 5- or 6-membered heteroaryl group which is optionally substituted with an oxo group, and the 5- or 6-membered heteroaryl group contains 1 or 2 N heteroatoms.

[0060] In some embodiments, ring B is a phenyl group or a 6-membered heteroaryl group containing 1 or 2 N atoms.

[0061] In some embodiments, ring B is a phenyl group or a 6-membered heteroaryl group containing 1 or 2 N atoms, and the 6-membered heteroaryl group is optionally substituted by one or more substituents.

[0062] In some embodiments, ring A is selected from C 5-6 aryl group, 5- or 6-membered heteroaryl group, 5- or 6-membered heterocyclic group, and the 5- or 6-membered heteroaryl group and the 5- or 6-membered heterocyclic group contain 1-4 heteroatoms independently selected from N, S and O, wherein the 5- or 6-membered heterocyclic group and the 5- or 6-membered heteroaryl group are each independently optionally substituted by one or more or substituents.

[0063] In some embodiments, ring A is a C 5-6 aryl group, 5- or 6-membered heteroaryl group or 5- or 6-membered heterocyclic group, wherein the 5- or 6-membered heteroaryl group and the 5- or 6-membered heterocyclic group contain 1, 2 or 3 N heteroatoms, and the 5- or 6-membered heteroaryl group and the 5- or 6-membered heterocyclic group are each independently optionally substituted by one or more substituents.

[0064] In some embodiments, ring A is a C 5-6 aryl group, 5- or 6-membered heteroaryl group or 5- or 6-membered heterocyclic group, the 5- or 6-membered heteroaryl group and the 5- or 6-membered heterocyclic group contain 1 or 2 N heteroatoms, and the 5- or 6-membered heteroaryl group and the 5- or 6-membered heterocyclic group are each independently optionally substituted by one or more substituents.

[0065] In some embodiments, ring A is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclic group, wherein the 5- or 6-membered heteroaryl and 5- or 6-membered heterocyclic group contain 1, 2 or 3 N heteroatoms, and the 5- or 6-membered heteroaryl and 5- or 6-membered heterocyclic group are each independently optionally substituted with one or more substituents.

[0066] In some embodiments, ring A is phenyl or 5- or 6-membered heteroaryl containing 1, 2 or 3 N heteroatoms, and the 5- or 6-membered heteroaryl is optionally substituted with one or more substituents.

[0067] In some embodiments, ring A is phenyl or 5- or 6-membered heteroaryl containing 1 or 2 N heteroatoms, and the 5- or 6-membered heteroaryl is optionally substituted with one or more substituents.

[0068] In some embodiments, ring A is C6 phenyl or 5- or 6-membered heteroaryl containing 1 or 2 N heteroatoms.

[0069] In some embodiments, ring E is C 5-6 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl or 4- to 8-membered heterocyclic group, wherein the 5- or 6-membered heteroaryl and 4- to 8-membered heterocyclic group contain 1, 2 or 3 heteroatoms independently selected from N, S and O.

[0070] In some embodiments, ring E is C 3-8 cycloalkyl, C 5-6 aryl or 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, S and O.

[0071] In some embodiments, ring E is C 3-6 cycloalkyl, phenyl or 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, S and O.

[0072] In some embodiments, ring E is C 3-6 cycloalkyl, phenyl or 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N and S.

[0073] In some embodiments, both L1 and L2 are connected to ring A.

[0074] In some embodiments, L1 is a bond, -O-, -S-, -NR a -, -(CH2) t -, -(CH2) t -O-, -O-(CH2) t -, -C(=O)-, -C(=O)NR a - or -NR a-C(=O)-。

[0075] In some embodiments, L1 is a bond, -O-, -S-, -NH-, -(CH2) t -, -(CH2) t -O-, -C(=O)- or -C(=O)NH-.

[0076] In some embodiments, L1 is a bond, -NH-, -O-, -S-, -N-C 1-3 alkylene-, -(CH2) t - or -C(=O)-.

[0077] In some embodiments, L1 is a bond, -NH-, -N-C 1-3 alkylene-, -(CH2) t - or -C(=O)-.

[0078] In some embodiments, L1 is a bond, -NH-, -(CH2) t - or -C(=O)-.

[0079] In some embodiments, L1 is a bond, -NH-, -N-C 1-3 alkylene-, -CH2- or -C(=O)-.

[0080] In some embodiments, L1 is a bond, -NH-, -CH2- or -C(=O)-.

[0081] In some embodiments, L1 is a bond, -NH- or -C(=O)-.

[0082] Preferably, L1 is a bond.

[0083] In some embodiments, L2 is a bond, -O-, -S-, -NH-, -C(=O)-, -C 2-4 alkenylene, or -C 2-4 alkynylene.

[0084] In some embodiments, L2 is a bond, -O-, C 2-4 alkenylene, or C 2-4 alkynylene.

[0085] In some embodiments, L2 is a bond, C 2-4 alkenylene or C 2-4 alkynylene.

[0086] In some embodiments, L2 is a bond or -O-.

[0087] In some embodiments, L2 is C 2-4 alkenylene or C 2-4 alkynylene.

[0088] In some embodiments, when ring E is phenyl or a 5- or 6-membered heteroaryl containing 1 or 2 N heteroatoms, L2 is a bond, C 2-4 alkenylene, C 2-4 alkynylene; when ring E is C 3-6 cycloalkyl, L2 is C 2-4 alkenylene or C 2-4 alkynylene.

[0089] In some embodiments, when ring E is phenyl or a 6-membered heteroaryl containing 1 or 2 N heteroatoms, L2 is a bond, C 2-4 alkenylene, C 2-4 alkynylene; when ring E is C 3-6 cycloalkyl or a 5-membered heteroaryl independently selected from N, S, and O containing 1 or 2 N heteroatoms, L2 is C 2-4 alkenylene or C 2-4 alkynylene.

[0090] In some embodiments, L2 is a bond.

[0091] In some embodiments, ring D is C 5-6 aryl, C 5-10 heteroaryl, C 4-6 cycloalkyl or C 4-10 heterocyclic group, wherein C 5-10 heteroaryl and C 4-10 heterocyclic group optionally contains 1, 2, or 3 heteroatoms independently selected from N, S, or O.

[0092] In some embodiments, ring D is C 5-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl or 4- to 10-membered heterocyclic group, wherein the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclic group contain 1, 2, or 3 heteroatoms independently selected from N and O.

[0093] In some embodiments, ring D is C 5-6 aryl, 5- to 6-membered heteroaryl, 3- to 6-membered monocyclic alkyl, 4- to 6-membered monocyclic heterocyclic group, 6- to 10-membered fused or spiro bicyclic heteroaryl, 6- to 10-membered fused or spiro bicyclic heterocyclic group, wherein the 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclic group, 6- to 10-membered heteroaryl, 6- to 10-membered heterocyclic group contain 1, 2, or 3 heteroatoms independently selected from N and O.

[0094] In some embodiments, ring D is C 5-6 aryl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group, wherein the 5- to 6-membered heteroaryl and 4- to 6-membered heterocyclic group contain 1, 2, or 3 heteroatoms independently selected from N, S, and O.

[0095] In some embodiments, ring D is phenyl, C 3-6 cycloalkyl or a 4- to 6-membered heterocyclic group containing 1 or 2 heteroatoms independently selected from N and O.

[0096] In some embodiments, ring D is phenyl or a 4- to 5-membered heterocyclic group containing 1 or 2 N heteroatoms.

[0097] In some embodiments, R1 is H, oxo, hydroxy, halogen, CN, -NO2, -NR d R e , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, -C(=O)NR a R b , -C(=O)OR a , -C(=O)R c , -S(=O)R b , -S(=O)2R b , -S(=O)NR a R b , -S(=O)2NR a R b , -O-(C=O)-R a , -O-(C=O)-NR a R b , C 1-6 haloalkoxy, C 3-5 cycloalkyl, a 3- to 5-membered heterocyclic group, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-5 cycloalkyl, a 3- to 5-membered heterocyclic group may each be optionally substituted with 0-3 independently selected from OH, CN, halogen, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, -NR a R b , -C(=O)NR a R b , -C(=O)OR a , -OC(=O)R a , -C(=O)R a , -S(=O)R b,-S(=O)2R b ,-S(=O)NR a R b ,-S(=O)2NR a R b ,-NR a C(=O)R b ,C 1-4 substituted by a substituent of a haloalkoxy group.

[0098] In some embodiments, R1 is H, an oxo group, a hydroxyl group, a halogen, CN, -NR a R b ,-NR a C(=O)R b ,-NO2, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, -C(=O)NR a R b ,-S(=O)R b ,-S(=O)2R b ,-S(=O)NR a R b ,-S(=O)2NR a R b ,C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 5-6 aryl or C 5-6 heteroaryl, wherein C 5-6 heteroaryl and C 3-6 heterocycloalkyl optionally contains 1, 2 or 3 heteroatoms independently selected from N, S, or O; C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 5-6 aryl and C 5-6 heteroaryl are each optionally substituted by one or more independently selected from OH, CN, halogen, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, -NR a R b, -C(=O)NR a R b , -S(=O)R b , -S(=O)₂R b , -S(=O)NR a R b , -S(=O)₂NR a R b , -NR a C(=O)R b , C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 5-6 aryl or C 5-6 substituted by a substituent of heteroaryl, wherein C 5-6 heteroaryl and C 3-6 The heterocycloalkyl optionally contains 1, 2 or 3 heteroatoms independently selected from N, S, or O.

[0099] In some embodiments, R₁ is H, oxo, hydroxy, halogen, CN, -NO₂, -NR d R e , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, -C(=O)NR a R b , -C(=O)OR a , -C(=O)R c , -S(=O)R b , -S(=O)₂R b , -S(=O)NR a R b , -S(=O)₂NR a R b , -O-(C=O)-R a , -O-(C=O)-NR a R b , C 1-6 haloalkoxy, C 3-5 cycloalkyl, a 3- to 5-membered heterocycloalkyl containing 1 or 2 N heteroatoms independently selected from N, S, and O.

[0100] In some embodiments, R₁ is H, oxo, hydroxy, halogen, CN, -NR d R e , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, -C(=O)NRa R b , -C(=O)OR a , -C(=O)R c , -S(=O)₂NR a R b 。

[0101] In some embodiments, R¹ is H, an oxo group, a hydroxyl group, a halogen, CN, -N-(C 1-6 alkyl)₂, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, -C(=O)NR a R b , -C(=O)OR a or -C(=O)R c 。

[0102] In some embodiments, R¹ is H, an oxo group, a halogen, CN, -N-(C 1-6 alkyl)₂, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, -C(=O)O-C 1-4 alkyl, or -C(=O)R c 。

[0103] In some embodiments, R¹ is H, an oxo group, a halogen, -N-(C 1-3 alkyl)₂, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, -C(=O)O-C 1-4 alkyl, or -C(=O)R c 。

[0104] In some embodiments, R¹ is H, an oxo group, a halogen, -N-(CH₃)₂, C 1-6 alkyl, C 1-4 haloalkyl, or C 1-4 alkoxy.

[0105] In some embodiments, R¹ is H, an oxo group, a halogen, -NR a R b or C 1-6 alkyl, where R a is H or C 1-6 alkyl, R b is C 1-6 alkyl.

[0106] In some embodiments, R¹ is H, an oxo group, C 1-6 alkyl.

[0107] In some embodiments, R1 is H, an oxo group, C 1-3 alkyl.

[0108] In some embodiments, R2 is H, a hydroxyl group, a halogen, CN, -NO2, -NR a R b , an oxo group, -C(=O)NR a R b , -C(=O)OR a , -C(=O)R a , -S(=O)R b , -S(=O)2R b , -S(=O)NR a R b , -S(=O)2NR a R b , -NR a C(=O)R b , -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl; wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-6 cycloalkyl is optionally substituted with 0 - 3 substituents independently selected from -OR a , -NH2, a halogen, CN, C 1-4 alkyl, C 1-6 haloalkyl, -NR a R b , an oxo group, -C(=O)NR a R b , -C(=O)OR a , -OC(=O)R a , -C(=O)R a , -S(=O)R b , -S(=O)2R b , -S(=O)NR a R b , -S(=O)2NR a R b and -NR a C(=O)R b .

[0109] In some embodiments, R2 is H, a hydroxyl group, a halogen, CN, -NR a R b, -NO2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, or C 3-6 Heterocycloalkyl, wherein C 3-6 Heterocycloalkyl optionally contains 1, 2 or 3 heteroatoms independently selected from N, S, or O; wherein C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and C 3-6 Heterocycloalkyl are each optionally substituted by one or more substituents independently selected from hydroxyl, halogen, CN, -NH2 or C 1-4 alkyl.

[0110] In some embodiments, R2 is H, hydroxyl, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -SF5, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 alkoxy are each optionally substituted by 0 - 3 substituents independently selected from -OR a , halogen, CN, C 1-4 alkyl, C 1-6 haloalkyl, -NR a R b , oxo group, -C(=O)NR a R b , -C(=O)OR a , -OC(=O)R a , -C(=O)R a , -S(=O)R b , -S(=O)2R b , -S(=O)NR a R b , -S(=O)2NR a R b and -NR a C(=O)R b .

[0111] In some embodiments, R2 is hydroxyl, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -SF5, wherein C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 alkoxy are each independently optionally substituted with 0 - 3 substituents independently selected from OR a , halogen, CN, C 1-4 alkyl, C 1-6 haloalkyl, -NR a R b , oxo, -C(=O)NR a R b , -C(=O)OR a , -C(=O)R a , -S(=O)R b , -S(=O)2R b , -S(=O)NR a R b , -S(=O)2NR a R b and -NR a C(=O)R b ; where R a and R b are each independently selected from H, CN, hydroxy, halogen, C 1-6 alkyl.

[0112] In some embodiments, R2 is H, hydroxy, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl; where C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy are each independently optionally substituted with 0 - 3 substituents independently selected from hydroxy, halogen, CN and C 1-4 alkyl.

[0113] In some embodiments, R2 is H, CN, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy.

[0114] In some embodiments, R2 is H, CN, halogen, C 1-6 alkyl, C 1-6 haloalkyl.

[0115] In some embodiments, R2 is H, CN, halogen, C 1-3 alkyl, C 1-3 haloalkyl.

[0116] In some embodiments, R2 is H, halogen, C 1-4 alkyl, C 1-4 haloalkyl.

[0117] In some embodiments, R2 is H, C 1-3 haloalkyl.

[0118] Preferably, R2 is H or -CF3.

[0119] Preferably, R2 is H.

[0120] In some embodiments, R3 is H, halogen, -OR a , CN, -NR a R b , -C 1-4 alkylene-NR a R b , -C 1-4 alkylene-NR a C(=O)R b , -C(=O)R b , -OC(=O)R a , -C(=O)OR a , -C(=O)NR a R b , -S(=O)R b , -S(=O)2R b , -S(=O)NR a R b , -S(=O)2NR a R b , -C 1-4 alkylene-C(=O)NR a R b , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, 3-6 membered heterocyclic group, C 3-6 cycloalkyl, C 5-6 aryl or 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl and the 3-6 membered heterocyclic group optionally contain 1, 2 or 3 heteroatoms independently selected from N, S and O; wherein C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 5-6 aryl and 5-6 membered heteroaryl are each optionally substituted with 0-3 substituents independently selected from oxo group, hydroxy group, halogen, CN, C 1-6alkyl, -C(=O)R b , -NR a R b , -C(=O)R b , -C(=O)OR a , -C(=O)NR a R b is substituted with a substituent.

[0121] In some embodiments, R3 is H, oxo, halogen, -OR a , CN, -NO2, -NR a R b , -NR a C(=O)R b , -C 1-4 alkylene-NR a R b , -C 1-4 alkylene-NR a C(=O)R b , -C(=O)R b , -C(=O)OR a , -C(=O)NR a R b , -S(=O)R b , -S(=O)2R b , -S(=O)NR a R b , -S(=O)2NR a R b , -C 1-4 alkylene-C(=O)NR a R b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 heterocycloalkyl, C 3-6 cycloalkyl, C 5-6 aryl or C 5-6 heteroaryl, wherein C 5-6 heteroaryl and C 3-6 heterocycloalkyl optionally contains 1, 2 or 3 heteroatoms independently selected from N, S, or O; wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6Cycloalkyl, C 3-6 Heterocycloalkyl, C 5-6 Aryl and C 5-6 Heteroaryl are each optionally substituted by one or more substituents independently selected from oxo, hydroxy, halogen, CN, -NO2, C 1-6 Alkyl, -C 1-4 Alkylene-OH, C 1-4 Halogenoalkyl, C 1-4 Alkoxy, -S(=O)2R b , -C(=O)R b , -NR a R b , -C(=O)R b , -C(=O)OR a , -NR a C(=O)R b , -C(=O)NR a R b , -NR a C(=O)R b , -C 1-4 Alkylene-NR a R b , -C 1-4 Alkylene-NR a C(=O)R b , C 1-4 Alkylene-C(=O)NR a R b , -C 1-4 Alkylene-OH, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 5-6 Aryl or C 5-6 Heteroaryl substituents.

[0122] In some embodiments, R3 is H, halogen, -OR a , CN, -C 1-4 Alkylene-NR a R b , -C 1-4 Alkylene-C(=O)NR a R b , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenoalkyl, C 1-6 Halogenoalkoxy, 3- to 6-membered heterocyclic group, C 3-6 Cycloalkyl, C 5-6 Aryl or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl and the 3- to 6-membered heterocyclic group optionally contain 1, 2 or 3 heteroatoms independently selected from N, S and O; wherein C 1-6 Alkyl, C3-6 Cycloalkyl, 3- to 6-membered heterocyclic group, C 5-6 Aryl and 5- to 6-membered heteroaryl are each optionally substituted with 0 to 3 substituents independently selected from halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -NR a R b , -C(=O)OR a , -C(=O)NR a R b and are substituted with substituents of.

[0123] In some embodiments, R3 is H, halogen, -OR a , CN, -C 1-4 Alkylene-NR a R b , -C 1-4 Alkylene-C(=O)NR a R b , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, 3- to 6-membered heterocyclic group, C 3-6 Cycloalkyl or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclic group optionally contain 1, 2 or 3 heteroatoms independently selected from N, S and O; wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group and 5- to 6-membered heteroaryl are each optionally substituted with 0 to 3 substituents independently selected from halogen, CN, C 1-6 Alkyl, -NR a R b , -C(=O)OR a , -C(=O)NR a R b and are substituted with substituents of.

[0124] In some embodiments, R3 is H, halogen, -OR a , CN, -C 1-4 Alkylene-NR a R b , -C 1-4 Alkylene-C(=O)NR a R b , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, 3- to 6-membered heterocyclic group, C 3-6 Cycloalkyl or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclic group optionally contain 1, 2 or 3 heteroatoms independently selected from N, S and O; wherein C 1-6 Alkyl, C3-6 The cycloalkyl group, 3- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl group are each optionally substituted with 0 to 3 substituents independently selected from halogen, CN, C 1-6 alkyl, -NR a R b , -C(=O)OR a , -C(=O)NR a R b ; wherein R a and R b are each independently selected from H and C 1-6 alkyl.

[0125] In some embodiments, R3 is H, halogen, CN, -OR a , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl and 3- to 6-membered heterocycloalkyl optionally contain 1, 2 or 3 heteroatoms independently selected from N and O; wherein C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted with the following substituents: C 1-6 alkyl, C 1-4 haloalkyl or halogen.

[0126] In some embodiments, R3 is H, halogen, CN, -OR a , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl and 3- to 6-membered heterocycloalkyl optionally contain 1, 2 or 3 heteroatoms independently selected from N and O; wherein C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted with C 1-6 alkyl, C 1-4 haloalkyl or halogen; wherein R a and R b are each independently selected from H and C 1-6 alkyl.

[0127] In some embodiments, R3 is H, halogen, CN, C 1-6 alkyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-4 haloalkyl, -NR a R b , C 3-6 heterocycloalkyl, C3-6 Cycloalkyl or C 5-6 heteroaryl; wherein C 3-6 cycloalkyl, C 3-6 heterocycloalkyl and C 5-6 heteroaryl are each optionally substituted with one or more substituents independently selected from H, halogen or C 1-6 alkyl.

[0128] In some embodiments, R3 is H, halogen, CN, -O-C 1-3 alkyl, C 1-3 alkyl, C 1-3 haloalkyl, C 3-5 cycloalkyl, 5- to 6-membered heteroaryl or 4- to 6-membered heterocycloalkyl, wherein the 5- to 6-membered heteroaryl and the 4- to 6-membered heterocycloalkyl are each optionally substituted with C 1-6 alkyl or halogen.

[0129] Preferably, R3 is H, halogen, CN, C 1-3 alkyl, -OR a .

[0130] Preferably, R3 is H.

[0131] In some embodiments, L3 is a bond, -NH-, -N-C 1-3 alkyl-, -(CH2) t -NH-, -C 4-6 heterocyclic group.

[0132] In some embodiments, L3 is a bond or -NH-.

[0133] In some embodiments, R5, R6 and R7 are each independently selected from H, halogen, -OR a , CN, -NR a R b , -C 1-6 alkylene-NR a R b , -C 1-6 alkylene-R c , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, wherein C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group are each optionally substituted with 0 to 4 substituents independently selected from CN, halogen, C 1-6 alkyl, C 1-4 haloalkyl, -NR a R b , C 3-6Substituted with a cycloalkyl group and a substituent of a 3-6 membered heterocyclic group, wherein the 5-6 membered heteroaryl group and the 3-6 membered heterocyclic group optionally contain 1, 2 or 3 heteroatoms independently selected from N, S and O.

[0134] In some embodiments, R5, R6 and R7 are each independently selected from H, halogen, CN, -C 1-6 alkylene-NR a R b , -C 1-6 alkylene-R c , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, a 3-6 membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, S and O.

[0135] In some embodiments, R5, R6 and R7 are each independently selected from H, halogen, CN, -C 1-6 alkylene-NR a R b , -C 1-6 alkylene-R c , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, a 3-6 membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, S and O; wherein R a and R b are each independently selected from H and C 1-6 alkyl.

[0136] In some embodiments, R5, R6 and R7 are each independently selected from H, halogen, CN, C 1-6 alkyl, -C 1-6 alkylene-NR a R b , and -C 1-6 alkylene-R c .

[0137] In some embodiments, R5, R6 and R7 are each independently selected from H, halogen, CN, C 1-6 alkyl, -C 1-6 alkylene-NR a R b , and -C 1-6 alkylene-R c ; wherein R a and R b are each independently selected from H and C 1-6 alkyl.

[0138] In some embodiments, R5, R6 and R7 are each independently selected from H, halogen, CN, C 1-4Alkyl, and -C 1-4 Alkylene -NR a R b 。

[0139] In some embodiments, wherein,

[0140] R5 is H, CN, C 1-4 alkyl or halogen;

[0141] One of R6 and R7 is H, and the other is H, halogen, C 1-4 alkyl or -C 1-4 alkylene -N(C 1-3 alkyl)2.

[0142] R5 is H, C 1-4 alkyl or halogen;

[0143] One of R6 and R7 is H, and the other is H, halogen, C 1-4 alkyl or -C 1-4 alkylene -N(C 1-3 alkyl)2.

[0144] In some embodiments, wherein,

[0145] R5 is H, C 1-4 alkyl or halogen;

[0146] One of R6 and R7 is H, and the other is H, C 1-4 alkyl or halogen.

[0147] In some embodiments, R8 is H, halogen, CN, C 1-4 alkyl or -C 1-4 alkylene -NR a R b 。

[0148] In some embodiments, R8 is H, halogen or C 1-4 alkyl.

[0149] In some embodiments, R8 is H or C 1-4 alkyl.

[0150] In some embodiments, R8 is halogen.

[0151] In some embodiments, R8 is C 1-4 alkyl.

[0152] In some embodiments, R a and R b are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 3 - 6 membered heterocycloalkyl, C5-6 Aryl and 5- or 6-membered heteroaryl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 5-6 The aryl and 5- or 6-membered heteroaryl may optionally be substituted with halogen, C 1-6 Halogenated alkyl or C 5-6 Aryl, wherein the 5- or 6-membered heteroaryl and 3- to 6-membered heterocycloalkyl optionally contain 1, 2 or 3 heteroatoms independently selected from N, S and O.

[0153] In some embodiments, R a Is selected from H, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or C 3-6 Heterocyclic group.

[0154] In some embodiments, R a Is H or C 1-6 Alkyl.

[0155] In some embodiments, R b Is H, hydroxy, halogen, CN, C 1-6 Alkyl, -O-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-4 Cycloalkyl, C 3-4 Heterocycloalkyl, C 5-6 Aryl or C 5-6 Heteroaryl.

[0156] In some embodiments, R b Is selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen-substituted C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group and halogen or C 1-4 Halogenated alkyl-substituted 3- to 6-membered heterocyclic group.

[0157] In some embodiments, R b Is H, C 1-6 Alkyl or C 3-6 Heterocyclic group.

[0158] In some embodiments, R a And R b Are each independently selected from H and C 1-6 Alkyl.

[0159] In some embodiments, R d is H, C 1-6 alkyl

[0160] In some embodiments, R e is C 1-6 alkyl, -C(=O)R c , S(=O)2R b .

[0161] In some embodiments, R c is a 3- to 6-membered heteroalkyl group that can be substituted by halogen or C 1-6 haloalkyl

[0162] In some embodiments, t is 1

[0163] In some embodiments, y is 1 or 2

[0164] In some embodiments, m is 1 or 2

[0165] In some embodiments, x is 1

[0166] In some embodiments, ring A is selected from

[0167] In some embodiments, ring B is selected from

[0168] In some embodiments, ring B is selected from

[0169] In some embodiments, ring is selected from

[0170] In some embodiments, ring is selected from

[0171]

[0172] wherein represents the attachment site to L1 or L2

[0173] In some embodiments, ring is selected from

[0174] wherein represents the connection site with L1 or L2.

[0175] In some embodiments, the ring is selected from

[0176] said represents the site connected to L1 or L2.

[0177] In some embodiments, the ring D is selected from

[0178] wherein represents the connection site with L1.

[0179] In some embodiments, the ring D is selected from

[0180] wherein represents the connection site with L1.

[0181] In some embodiments, the ring E is selected from

[0182] In some embodiments, the compound represented by formula (II-1) or formula (II-2),

[0183]

[0184] or its stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes or solvates, wherein,

[0185] A1, A2, A4 and A6 are each independently C or N;

[0186] A3 is absent, CH, CH2, C=O or N;

[0187] A5 is CH, CH2, C=O, C=NH or N;

[0188] B1, B2, B3 and B4 are each independently selected from C, CH, CH2, C=O, NH or N;

[0189] Ring E, ring D, L1, L2, R1, R2, R3, R4, m, y and x are defined in the classes and subclasses of the examples.

[0190] In some embodiments, the compound of formula (III),

[0191]

[0192] or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein,

[0193] A1, A2, A4 and A6 are each C or N;

[0194] A5 is CH, CH2, N, C=O or C=NH;

[0195] B1, B2, B3 and B4 are each independently selected from C, CH, CH2, C=O, NH or N;

[0196] Ring E, ring D, L1, L2, R1, R2, R3, R4, m, y and x are each as defined in the classes and subclasses of the examples herein.

[0197] In some embodiments of formula (III), at least one of A1, A2, A4, A5 and A6 is N.

[0198] In some embodiments, the compound of formula (IV-1) or formula (IV-2),

[0199]

[0200] or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein,

[0201] A1, A2, A4 and A6 are each C or N;

[0202] A3 is absent, CH2, CH, C=O or N;

[0203] A5 is CH, CH2, C=O, C=NH or N;

[0204] B1, B2, B3 and B4 are each independently selected from C, CH, CH2, C=O, NH or N;

[0205] M1, M2, M3, M4, M5 and M6 are each independently selected from C, CH or N;

[0206] Ring D, L1, R1, R2, R3, R4, m, y and x are each as defined in the classes and subclasses of the examples herein.

[0207] In some embodiments, the compound of formula (VI),

[0208]

[0209] or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein,

[0210] A1, A2, A3, A4, A5, A6, B1, B2, B3, B4, M1, M2, M3, M4, M5, M6, Ring D, L1, R1, R2, R3, R4, m, y and x are respectively defined in the classes and subclasses of the examples herein.

[0211] In some embodiments, the compound of formula V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof,

[0212]

[0213] wherein,

[0214] is a single bond or a double bond;

[0215] A3 is CR 11 or NR 11 ;

[0216] A1, A2, A4 and A6 are each independently selected from C or N;

[0217] A5 is CR 15 or NR 15 ;

[0218] B1, B2, B3 and B4 are each independently selected from C or N;

[0219] M1, M2, M3, M4, M5 and M6 are each independently selected from C or N;

[0220] k is 0 or 1; when k is 0, at least one of A1, A2, A4, A5 or A6 is N;

[0221] R 11 is absent, H, oxo, hydroxy, halogen, CN, -NH2, -NO2, =NH, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy;

[0222] R 15 is absent, H, oxo, hydroxy, halogen, CN, -NO2, -NH2, =NH, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3Halogenoalkyl, C 1-3 Alkoxy, C 1-3 Halogenoalkoxy, C 3-4 Cycloalkyl or C 3-4 Heterocycloalkyl;

[0223] R 10 is halogen, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 halogenocycloalkyl, or C 5-6 aryl; wherein C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and C 5-6 aryl are each optionally substituted by halogen;

[0224] R 14 is -NR a C(=O)R z , -C 1-4 alkylene-NR a C(=O)R z , -C(=O)R z , C 1-4 alkylene-C(=O)R z , C 3-6 heterocycloalkyl-C(=O)R z , C 3-6 heterocycloalkyl-NR a C(=O)R z , C 3-6 cycloalkyl-NR a C(=O)R z , C 5-6 aryl-NR a C(=O)R z or C 5-6 heteroaryl-NR a C(=O)R z or C 3-6 cycloalkyl-C(=O)R z , wherein C 5-6 heteroaryl and C 3-6 heterocycloalkyl each optionally contain 1, 2 or 3 heteroatoms independently selected from N, S, or O; wherein C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 5-6 aryl and C 5-6 heteroaryl are each optionally substituted by one or more independently selected from oxo, hydroxy, halogen, CN, -NO2, C 1-6 alkyl, C2-6 alkenyl, C 2-6 alkynyl, -C 1-4 alkylene-OH, C 1-4 haloalkyl, C 1-4 alkoxy, -S(=O)2R b , -NR a R b , -C(=O)OR a , -C(=O)NR a R b , -C 1-4 alkylene-NR a R b , -C 1-4 alkylene-NR a C(=O)R b , C 1-4 alkylene-C(=O)NR a R b , C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 5-6 aryl or C 5-6 substituted by substituents of heteroaryl;

[0225] R z is C 2-6 alkenyl or C 2-6 alkynyl, wherein C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted by one or more independently selected from H, oxo group, CN, halogen, -ORa, -NO2, -NR a R b , -S(=O)R b , -S(=O)2R b , -S(=O)NR a R b , -S(=O)2NR a R b , C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 5-6 aryl or C 5-6 substituted by substituents of heteroaryl;

[0226] t and n are each independently selected from 1, 2, 3 or 4;

[0227] y, m and x are each independently selected from 0, 1, 2, 3, 4 or 5; and

[0228] provided that, is not

[0229] Ring D, L1, R1, R2, and R3 are defined respectively as in the examples, classes, and subclasses of the present disclosure.

[0230] In some embodiments, when A3 is absent, at least one of A1, A2, A4, A5, and A6 is N.

[0231] In some embodiments, R 14 is -NR a C(=O)R z , -C 1-4 alkylene-NR a C(=O)R z , -C(=O)R z or C 3-6 heterocycloalkyl-C(=O)R z , wherein C 3-6 heterocycloalkyl optionally contains 1, 2, or 3 heteroatoms independently selected from N, S, or O.

[0232] In some embodiments, R 15 is absent, H, oxo, or =NH.

[0233] In some embodiments, R z is C 2-6 alkenyl or C 2-6 alkynyl, wherein C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted with one or more substituents independently selected from H, CN, halogen, -OR a , C 3-6 cycloalkyl, or -NR a R b .

[0234] In some embodiments, R z is C 2-6 alkenyl or C 2-6 alkynyl, wherein C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted with one or more substituents independently selected from H, halogen, or -NR a R b .

[0235] In some embodiments, R z is C 2-6 alkenyl or C 2-6 alkynyl, wherein C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted with -NR a R b .

[0236] In some embodiments, R 10 is C 1-3 haloalkyl.

[0237] In some embodiments, R 10 is -CF3.

[0238] In some embodiments, R 11 is H, oxo, C 1-3 alkyl.

[0239] In some embodiments, R 11 is H.

[0240] In some embodiments, the compound represented by formula (VI),

[0241]

[0242] or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate, wherein,

[0243] A1, A2, A4, A5, A6, B1, B2, B3, B4, M1, M2, M3, M4, M5, M6, ring D, L1, R1, R2, R3, R 10 , R 14 , m, y and x are respectively defined as in the examples and classes and subclasses herein.

[0244] In some embodiments, the compound represented by the following general formula:

[0245]

[0246] or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate, wherein ring A, ring B, ring E, ring D, L1, L2, L3, R1, R2, R3, R5, R6, R7, R8, m, y and x are respectively defined as in the classes and subclasses of the examples herein.

[0247] In some embodiments, the compound represented by the following general formula:

[0248]

[0249] or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate, wherein ring A, ring B, ring D, L1, L2, L3, R1, R2, R3, R5, R6, R7, y and x are respectively defined as in the examples and classes and subclasses herein.

[0250] In some embodiments, the compound represented by the following general formula:

[0251]

[0252] or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein ring A, ring B, ring D, L1, L2, L3, R1, R2, R3, R8, y and x are as defined respectively in the examples and classes and subclasses herein.

[0253] In some embodiments, a compound represented by the following general formula:

[0254]

[0255] or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein ring A, ring B, ring E, ring D, L1, L3, R1, R2, R3, R5, R6, R7, R8, m, y and x are as defined respectively in the examples and classes and subclasses herein.

[0256]

[0257] or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein ring A, ring B, ring D, L1, L3, R1, R2, R3, R5, R6, R7, R8, m, y and x are as defined respectively in the examples and classes and subclasses herein.

[0258] In some embodiments, a compound represented by the following general formula:

[0259]

[0260] or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein ring A, ring B, ring D, L1, L3, R1, R2, R3, R5, R6, R7, R8, m, y and x are as defined respectively in the examples and classes and subclasses herein.

[0261] In some embodiments, a compound represented by the following general formula:

[0262]

[0263] or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof,

[0264] wherein J1 is 1, 2, 3 or 4, and ring A, ring B, ring D, L1, L3, R1, R2, R3, R5, R6, R7, R8, m, y and x are respectively defined as in the examples, classes and subclasses herein.

[0265] In some embodiments, a compound represented by the following general formula:

[0266]

[0267] or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof,

[0268] wherein J2 and J3 are each independently 1 or 2, and ring A, ring B, ring E, L1, L2, R1, R2, R3, R5, R6, R7, R8, m, y and x are respectively defined as in the classes and subclasses of the examples herein.

[0269] In some embodiments, a compound represented by the following general formula:

[0270]

[0271] or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein,

[0272] J2 and J3 are each independently 1 or 2;

[0273] E1, E2, E3 and E4 are each independently CH or N, and at least one or two of them are N;

[0274] ring A, ring B, L1, L2, R1, R2, R3, R5, R6, R7, R8, m, y and x are respectively defined as in the classes and subclasses of the examples herein.

[0275] In some embodiments, a compound represented by the following general formula:

[0276]

[0277]

[0278]

[0279] or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein ring B, ring E, ring D, L1, L2, L3, R1, R2, R3, R5, R6, R7, m, y and x are respectively defined as in the classes and subclasses of the examples herein.

[0280] In some embodiments, compounds of the following general formula:

[0281]

[0282]

[0283]

[0284] or their stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes or solvates, wherein ring B, ring E, ring D, L1, L2, L3, R1, R2, R3, R8, m, y and x are respectively defined as in the examples, classes and subclasses herein.

[0285] In some embodiments, compounds of the following general formula:

[0286]

[0287]

[0288] or their stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes or solvates, wherein ring B, L1, L2, R1, R2, R3, R5, R6, R7, R8, m, y and x are respectively defined as in the examples, classes and subclasses herein..

[0289] In some embodiments of formula (I), wherein the compound is:

[0290] 1) 1-(1-Acrylpyrrolidin-3-yl)-3-(4-cyclohexylphenyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

[0291] 2) 1-(1-Acrylpyrrolidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine

[0292] -7-one;

[0293] 3) 1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0294] 4) 1-(3-(1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0295] 5) 2-Fluoro-1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0296] 6) 2-Fluoro-1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0297] 7) 1-(1-Acryloylpyrrolidin-3-yl)-6-methyl-3-(4-(trifluoromethyl)phenyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

[0298] 8) 2-Fluoro-1-(3-methyl-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0299] 9) 2-Fluoro-1-(2-methyl-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0300] 10) 2-Fluoro-N-(2-methyl-5-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl)acrylamide;

[0301] 11) 2-Fluoro-1-(3-(6-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0302] 12) 2-Fluoro-1-(2-hydroxy-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0303] 13) N-(1-(3-(4-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridin-1-yl)azetidin-3-yl)acrylamide;

[0304] 14) N-(1-(1-Acryloylazetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-7-yl)methanesulfonamide;

[0305] 15) N-(1-(1-Acryloylazetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-7-yl)acetamide;

[0306] 16) 1-(3-(4-Amino-3-(4-cyclohexylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0307] 17) 1-(3-(3-(4-Cyclohexylphenyl)-4-hydroxy-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0308] 18) 1-(3-(3-(4-(Trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0309] 19) 1-(3-(3-(4-(Trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0310] 20) 1-(3-(6-Chloro-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0311] 21) 1-(3-(3-(4-(Trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0312] 22) 1-(3-(3-(4-(Trifluoromethyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0313] 23) 1-(3-(3-(4-(Trifluoromethyl)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0314] 24) 1-(3,3-Difluoro-4-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0315] 25) 1-((3R,4S)-3-Fluoro-4-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0316] 26) 1-(3-(3-(4-(Trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0317] 27) 1-(3-(3-(5-(Trifluoromethyl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0318] 28) N-(1-(1-(4-(Trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyrrolidin-3-yl)but-2-enamide;

[0319] 29) 1-(3-(3-(2-Fluoro-4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0320] 30) 1-(3-(3-(4-(Trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0321] 31) 1-(3-(3-(4-(Trifluoromethyl)phenoxy)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0322] 32) 1-(3-(3-(4-(Trifluoromethyl)phenoxy)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0323] 33) 1-(3-(3-(4-(Trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one;

[0324] 34) 1-(3-((3-(4-(Trifluoromethyl)phenyl)-1H-indazol-1-yl)methyl)pyrrolidin-1-yl)prop-2-en-1-one;

[0325] 35) N-(1-(1-(4-(Trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyrrolidin-3-yl)acrylamide;

[0326] 36) (E)-N-(1-(1-(4-(Trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyrrolidin-3-yl)but-2-enamide;

[0327] 37) N-(3-(3-(4-(Trifluoromethyl)phenyl)-1H-indazol-1-yl)cyclopentyl)acrylamide;

[0328] 38) 1-(3-((3-(4-Cyclohexylphenyl)-1H-indazol-1-yl)methyl)pyrrolidin-1-yl)prop-2-en-1-one;

[0329] 39) 1-(3-(7-Methyl-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0330] 40) (E)-4-(Dimethylamino)-1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)pyrrolidin-1-yl)but-2-en-1-one;

[0331] 41) (E)-4-(Dimethylamino)-N-(1-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyrrolidin-3-yl)but-2-enamide;

[0332] 42) 1-(1-Acryloylpyrrolidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-indazole-7-carboxamide;

[0333] 43) 1-(4-(1-(4-(trifluoromethyl)phenyl)-1H-indazole-3-carbonyl)piperazin-1-yl)prop-2-en-1-one;

[0334] 44) 1-(3-(7-Methoxy-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0335] 45) 1-(3-(7-Chloro-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0336] 46) 1-(3-(7-(Trifluoromethyl)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0337] 47) 1-(3-(6-Methyl-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0338] 48) 1-(1-Acryloylpyrrolidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-indazole-7-carbonitrile;

[0339] 49) 1-(7-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-2-azaspiro[4.4]nonan-2-yl)

[0340] prop-2-en-1-one;

[0341] 50) 1-(3-(6-Fluoro-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0342] 51) 1-(3-(5,6-Difluoro-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0343] 52) 1-(3-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0344] 53) N-(1-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolidin-3-yl)acrylamide;

[0345] 54) 1-(3-(6-Methoxy-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0346] 55) 1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)pyrrolidin-1-yl)but-2-yn-1-one;

[0347] 56) (E)-1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)pyrrolidin-1-yl)but-2-en-1-one;

[0348] 57) 1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)pyrrolidin-1-yl)prop-2-yn-1-one;

[0349] 58) 1-(3-(3-(5-(trifluoromethyl)pyridin-2-yl)-1H-indazol-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0350] 59) 1-(3-(3-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazol-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0351] 60) 1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)piperidin-1-yl)prop-2-en-1-one;

[0352] 61) 1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0353] 62) N-(4-(3-(4-(Trifluoromethyl)phenyl)-1H-indazol-1-yl)tetrahydrofuran-3-yl)acrylamide;

[0354] 63) N-((5-(3-(4-(Trifluoromethyl)phenyl)-1H-indazol-1-yl)-1,3,4-oxadiazol-2-yl)methyl)acrylamide;

[0355] 64) N-(1-(1-(4-(Trifluoromethyl)phenyl)-1H-indazole-3-carbonyl)pyrrolidin-3-yl)acrylamide;

[0356] 65) 1-(3-(1-(4-(Trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0357] 66) N-(1-(5-Methoxy-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyrrolidin-3-yl)acrylamide;

[0358] 67) 1-(3-(5-(3-(4-(Trifluoromethyl)phenyl)-1H-indazol-1-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-1-yl)prop

[0359] -2-en-1-one;

[0360] 68) N-(4-(3-(4-(Trifluoromethyl)phenyl)-1H-indazol-1-yl)tetrahydro-2H-pyran-3-yl)acrylamide;

[0361] 69) N-(1-(5-Cyano-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyrrolidin-3-yl)acrylamide;

[0362] 70) 1-(3-(7-Fluoro-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0363] 71) 2-Fluoro-1-(3-(3-(4-(Trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0364] 72) N-(1-(5-Cyano-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolidin-3-yl)acrylamide;

[0365] 73) 2-Methyl-1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)

[0366] prop-2-en-1-one;

[0367] 74) N-(1-(5-Methoxy-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolidin-3-yl)acrylamide;

[0368] 75) N-(1-(5-Methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyrrolidin-3-yl)acrylamide;

[0369] 76) 5-Methyl-2-(3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidine-1-carbonyl)hexanedinitrile;

[0370] 77) 1-(1-(2-Fluoropropenoyl)pyrrolidin-3-yl)-6-methyl-3-(4-(trifluoromethyl)phenyl)-1,6-dihydro-7H-pyrazolo

[0371] [4,3-d]pyrimidin-7-one;

[0372] 78) Methyl 1-(1-propenoylpyrrolidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-indazole-7-carboxylate;

[0373] 79) 1-(1-Propenoylazetidin-3-yl)-6-methyl-3-(4-(trifluoromethyl)phenyl)-1,6-dihydro-7H-pyrazolo

[0374] [4,3-d]pyrimidin-7-one;

[0375] 80) 1-(1-(2-Fluoropropenoyl)azetidin-3-yl)-6-methyl-3-(4-(trifluoromethyl)phenyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

[0376] 81) N-(1-(6-Methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyrrolidin-3-yl)acrylamide;

[0377] 82) 1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0378] 83) N-(1-(5-Methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolidin-3-yl)acrylamide;

[0379] 84) N-(1-(5-Chloro-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyrrolidin-3-yl)acrylamide;

[0380] 85) N-(1-(5-Chloro-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolidin-3-yl)acrylamide;

[0381] 86) N-(1-(6-Chloro-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolidin-3-yl)acrylamide;

[0382] 87) 2-Methyl-1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidin-1-yl)

[0383] prop-2-en-1-one;

[0384] 88) 4-Methyl-4-morpholine-2-(3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetid

[0385] ane-1-carbonyl)glutaronitrile;

[0386] 89) 1-(3-(5-Methoxy-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0387] 90) N-(1-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolidin-3-yl)acrylamide;

[0388] 91) N-(1-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyrrolidin-3-yl)propiram;

[0389] 92) N-(1-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolidin-3-yl)propiram;

[0390] 93) 1-(1-Acrylpyrrolidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine-5-carbonitrile;

[0391] 94) 1-(3-(5-Methoxy-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0392] 95) 2-Fluoro-1-(3-(5-methoxy-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)pyrrolidin-1-

[0393] yl)prop-2-en-1-one;

[0394] 96) 1-(3-(5-Methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0395] 97) N-(3-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)acrylamide;

[0396] 98) 1-(1-Acrylpyrrolidin-3-yl)-N-isopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-7-carboxamide;

[0397] 99) N-(1-(3-(4-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridin-1-yl)pyrrolidin-3-yl)acrylamide;

[0398] 100) 1-(1-Acrylpyrrolidin-3-yl)-N-cyclopropyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-7-carboxamide;

[0399] 101) 1-(1-Acrylpyrrolidin-3-yl)-N-(oxetan-3-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-7-carboxamide;

[0400] 102) 1-(1-Acrylpyrrolidin-3-yl)-N-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-7-carboxamide;

[0401] 103) 1-(1-Acrylpyrrolidin-3-yl)-N,N-dimethyl-3-(4-(trifluoromethyl)phenyl)-1H-indazole-7-carboxamide;

[0402] 104) 1-(1-Acrylpyrrolidin-3-yl)-N-(3,3-difluorocyclobutyl)-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-7-carboxamide;

[0403] 105) 1-(3-(1-(4-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridin-3-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0404] 106) N-(1-(6-(4-(trifluoromethyl)phenyl)imidazo[1,5-a]pyrimidin-8-yl)pyrrolidin-3-yl)acrylamide;

[0405] 107) 1-(1-acrylpyrrolidin-3-yl)-N-phenyl-3-(4-(trifluoromethyl)phenyl)-1H-indazole-7-carboxamide;

[0406] 108) 1-(3-(5-chloro-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0407] 109) 1-(3-(8-(4-(trifluoromethyl)phenyl)imidazo[1,5-a]pyrimidin-6-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0408] 110) 1-(3-(3-(4-(trifluoromethyl)phenyl)-7-(4-(trifluoromethyl)piperidine-1-carbonyl)-1H-indazol-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0409] 111) 1-(1-acrylpyrrolidin-3-yl)-N-(4,4-difluorocyclohexyl)-3-(4-(trifluoromethyl)phenyl)-1H-indazole-7-carboxamide;

[0410] 112) 1-(3-(7-(3,3-difluoropyrrolidine-1-carbonyl)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0411] 113) 1-(1-acrylpyrrolidin-3-yl)-N-(3,3-difluorocyclopentyl)-3-(4-(trifluoromethyl)phenyl)-1H-indazole-7-carboxamide;

[0412] 114) 1-(1-acrylpyrrolidin-3-yl)-N-(4-(trifluoromethyl)cyclohexyl)-3-(4-(trifluoromethyl)phenyl)-1H-indazole-7-carboxamide;

[0413] 115) 1-(1-acrylpyrrolidin-3-yl)-N-benzyl-3-(4-(trifluoromethyl)phenyl)-1H-indazole-7-carboxamide;

[0414] 116) 1-(1-Acryloxypyrrolidin-3-yl)-N-(tert-butyl)-3-(4-(trifluoromethyl)phenyl)-1H-indazole-7-carboxamide;

[0415] 117) 1-(3-Methyl-4-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0416] 118) 1-(7-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-5-azaspiro[2.4]heptan-5-yl)prop-2-en-1-one;

[0417] 119) N-(2-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)cyclopentyl)acrylamide;

[0418] 120) 1-(3-(3-(4-Cyclopropylphenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0419] 121) 1-(3-(6-(Dimethylamino)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0420] 122) 1-(3-(6-(Dimethylamino)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one;

[0421] 123) 1-(3-(3-(6-(Trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0422] 124) 2-Fluoro-1-(3-(3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0423] 125) 1-(7-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-2-azaspiro[4.4]nonan-2-yl)

[0424] prop-2-en-1-one;

[0425] 126) 2-Fluoro-1-(7-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-2-azaspiro[4.4]nonan-2-yl)prop-2-en-1-one;

[0426] 127) 1-(3-(3-(2-Fluoro-4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0427] 128) 2-Fluoro-1-(3-(3-(2-Fluoro-4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0428] 129) 1-(3-(3-(2-Fluoro-4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0429] 130) 2-Fluoro-1-(3-(3-(2-Fluoro-4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0430] 131) 1-(3-(3-(6-(Trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0431] 132) 2-Fluoro-1-(3-(3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0432] 133) N-(3-(4-(Trifluoromethyl)phenyl)-1'H-[1,6'-diindazol]-4'-yl)acrylamide;

[0433] 134) N-(6-(3-(4-(Trifluoromethyl)phenyl)-1H-indazol-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)acrylamide;

[0434] 135) N-(3-(3-(4-(Trifluoromethyl)phenyl)-1H-indazol-1-yl)phenyl)acrylamide;

[0435] 136) N-(3-Methyl-5-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)phenyl)acrylamide;

[0436] 137) N-(3-Methoxy-5-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)phenyl)acrylamide;

[0437] 138) N-(3-Chloro-5-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)phenyl)acrylamide;

[0438] 139) 1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidin-1-yl)prop-2-yn-1-one;

[0439] 140) 1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-yn-1-one;

[0440] 141) (E)-2-(3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carbonyl)

[0441] but-2-enenitrile;

[0442] 142) 1-(1-Acrylpyrrolidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile;

[0443] 143) 1-(3-(5-Methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0444] 144) 1-(3-(6-Methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0445] 145) 1-(1-Acrylpyrrolidin-3-yl)-N-(pyridin-2-yl)-3-(4-(trifluoromethyl)phenyl)-1H-indazole-7-carboxamide;

[0446] 146) 1-(3-(5-Chloro-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0447] 147) 1-(3-(6-Chloro-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0448] 148) 1-(1-Acryloylpyrrolidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)-1H-indazole-7-carboxamide;

[0449] 149) 1-Acryloyl-4-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)pyrrolidine-3-carbonitrile;

[0450] 150) 1-(3-(5-Methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0451] 151) N-(3-Cyano-5-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)phenyl)acrylamide;

[0452] 152) N-(3-Cyano-5-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)phenyl)acrylamide;

[0453] 153) N-(3-Cyclopropyl-5-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)phenyl)acrylamide;

[0454] 154) N-(3-(3,3-Difluoroazetidin-1-yl)-5-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)phenyl)acrylamide;

[0455] 155) N-(3-(3-Methylpyridin-2-yl)-5-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)phenyl)acrylamide;

[0456] 156) N-(3-(3-Chloropyridin-2-yl)-5-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)phenyl)acrylamide;

[0457] 157) N-(3-(1H-Pyrazol-1-yl)-5-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)phenyl)acrylamide;

[0458] 158) N-(3-Morpholino-5-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)phenyl)acrylamide;

[0459] 159) N-(3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl)acrylamide;

[0460] 160) 2-Fluoro-1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0461] 161) 1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0462] 162) 2-Fluoro-1-(3-fluoro-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0463] 163) 2-Fluoro-1-(2-fluoro-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0464] 164) 2-Fluoro-1-(3-hydroxy-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0465] 165) 1-(1-(2-Fluoropropionyl)azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine 7-oxide;

[0466] 166) Ethyl 2-(1-(2-fluoropropionyl)-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-3-yl)acetate;

[0467] 167) 2-(1-(2-Fluoropropionyl)-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-3-yl)acetonitrile;

[0468] 168) 2-Fluoro-1-(3-(fluoromethyl)-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0469] 169) 2-(1-(2-Fluoropropionyl)-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-3-yl)acetamide;

[0470] 170) 1-(2-Fluoropropenoyl)-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidine-3-carbonitrile;

[0471] 171) 2-Fluoro-1-(3-(3-(4-isopropylphenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0472] 172) 2-Fluoro-1-(3-(3-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)

[0473] prop-2-en-1-one;

[0474] 173) 2-Fluoro-1-(3-(3-(4-(pentafluoro-λ6-thioalkyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0475] 174) 2-Methyl-1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)

[0476] prop-2-en-1-one;

[0477] 175) (E)-1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)but-2-en-1-one;

[0478] 176) 2-Fluoro-1-(3-(3-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0479] 177) 5-(1-(1-(2-Fluoropropenoyl)azetidin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-(trifluoromethyl)

[0480] benzonitrile;

[0481] 178) 4-(1-(1-(2-Fluoropropenoyl)azetidin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-(trifluoromethyl)

[0482] benzonitrile;

[0483] 179) 2-Fluoro-1-(3-(3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0484] 180) 2-Fluoro-1-(3-(3-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0485] 181) 2-Fluoro-1-(3-(3-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0486] 182) 2-Fluoro-1-(3-(3-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0487] 183) 2-Fluoro-1-(3-(3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0488] 184) 2-Fluoro-1-(3-(3-(5-fluoro-6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0489] 185) 2-Fluoro-1-(3-(3-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0490] 186) 2-Fluoro-1-(3-(6-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin

[0491] -1-yl)prop-2-en-1-one;

[0492] 187) 1-(3-(6-chloro-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one;

[0493] 188) 2-Fluoro-N-(2-methoxy-5-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl)acrylamide;

[0494] 189) N-(2-Chloro-5-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl)acrylamide;

[0495] 190) N-(2,4-Difluoro-5-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl)-2-fluoroacrylamide;

[0496] 191) 2-Fluoro-N-(4-fluoro-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl)acrylamide;

[0497] 192) N-(2,4-Dichloro-5-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl)-2-fluoroacrylamide;

[0498] 193) 2-Fluoro-1-(6-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)indolin-1-yl)prop-2-en-1-one;

[0499] 194) N-(4-((Dimethylamino)methyl)-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl)-2-fluoroacrylamide;

[0500] 195) N-(2,4-Difluoro-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl)-2-fluoroacrylamide;

[0501] 196) 2-Fluoro-1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0502] 197) 2-Fluoro-1-(3-(3-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazol-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0503] 198) 2-Fluoro-1-(3-(3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)azetidin-1-

[0504] yl)prop-2-en-1-one;

[0505] 199) 2-Fluoro-1-(3-(6-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0506] 200) 1-(1-(2-Fluoroprop-2-enoyl)azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine

[0507] -6-carbonitrile;

[0508] 201) 1-(1-(2-Fluoroprop-2-enoyl)azetidin-3-yl)-N-methyl-3-(4-(trifluoromethyl)phenyl)-1H-indazole-7-sulfonamide;

[0509] 202) 2-Fluoro-1-(3-(5-fluoro-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0510] 203) 2-Fluoro-1-(3-(6-fluoro-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0511] 204) 2-Fluoro-1-(3-(6-fluoro-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0512] 205) 1-(3-(6-(Difluoromethyl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one;

[0513] 206) 1-(3-(6-Chloro-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one;

[0514] 207) 2-Fluoro-1-(3-(3-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0515] 208) 2-Fluoro-1-(3-(3-(4-(trifluoromethyl)phenyl)-6,7-dihydropyrano[4,3-c]pyrazol-1(4H)-yl)azetidin-1-yl)prop-2-en-1-one;

[0516] 2-Fluoro-1-(3-(3-(4-(trifluoromethyl)phenyl)-6,7-dihydropyrano[4,3-c]pyrazol-2(4H)-yl)azetidin-1-yl)prop-2-en-1-one;

[0517] 210) 1-(3-(4,4-Difluoro-3-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)azetidin-1-

[0518] yl)-2-fluoroprop-2-en-1-one;

[0519] 211) 1-(3-(5-(Difluoromethyl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one;

[0520] 212) 1-(3-(5-(Difluoromethyl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one;

[0521] 213) 2-Fluoro-1-(3-(5-Methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0522] 214) 2-Fluoro-1-(3-(5-Methoxy-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0523] 215) 2-Fluoro-1-(3-(5-(Trifluoromethyl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0524] 216) 2-Fluoro-1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0525] 217) 2-Fluoro-1-(3-(3-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0526] 218) 6-Ethyl-1-(1-(2-fluoropropanoyl)azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

[0527] 219) 1-(1-(2-fluoropropanoyl)azetidin-3-yl)-7-methyl-3-(4-(trifluoromethyl)phenyl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one;

[0528] 220) 1-(1-(2-fluoropropanoyl)azetidin-3-yl)-6-methyl-3-(4-(trifluoromethyl)phenyl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one;

[0529] 221) 2-Fluoro-1-(3-(6-methoxy-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0530] 222) 2-Fluoro-1-(3-(7-methoxy-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0531] 223) 2-Fluoro-1-(3-(6-methoxy-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0532] 224) 1-(1-(2-fluoropropanoyl)azetidin-3-yl)-7-methyl-3-(4-(trifluoromethyl)phenyl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyrazin-6-one;

[0533] 225) 1-(1-(2-fluoropropanoyl)azetidin-3-yl)-5,6-dimethyl-3-(4-(trifluoromethyl)phenyl)-1,6-dihydro

[0534] -7H-pyrazolo[4,3-d]pyrimidin-7-one;

[0535] 226) 2-Fluoro-1-(3-(7-methoxy-5-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0536] 227) 2-Fluoro-1-(3-(7-methoxy-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0537] 228) 1-(3-(5-Bromo-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one;

[0538] 229) 1-(1-(2-Fluoropropionyl)azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;

[0539] 230) 2-Fluoro-1-(3-(4-(4-(trifluoromethyl)phenyl)quinazolin-2-yl)azetidin-1-yl)prop-2-en-1-one;

[0540] 231) 1-(3-(2-Imino-3-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0541] 232) N-((5-(2-Oxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1,3,4-

[0542] oxadiazol-2-yl)methyl)acrylamide;

[0543] 233) 1-(1-Acrylpyrrolidin-3-yl)-3-(4-cyclohexylphenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;

[0544] 234) 1-(1-Acrylpyrrolidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;

[0545] 235) 1-(3-(2-Imino-3-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyrrolidin-1-

[0546] yl)prop-2-en-1-one;

[0547] 236) 1-(1-Acrylazetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazo

[0548] l-2-one;

[0549] 237) 1-(1-(2-Fluoropropenoyl)-3-methylazetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;

[0550] 238) 3-(1-(2-Fluoropropenoyl)-3-methylazetidin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

[0551] 239) 1-(1-(2-Fluoropropenoyl)azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo

[0552] [4,5-b]pyridin-2-one;

[0553] 240) 1-(1-(2-Fluoropropenoyl)azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo

[0554] [4,5-b]pyrazin-2-one;

[0555] 241) 1-(1-(2-Fluoropropenoyl)azetidin-3-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one;

[0556] 242) 3-(1-(2-Fluoropropenoyl)azetidin-3-yl)-5-methyl-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

[0557] 243) 3-(1-(2-Fluoropropenoyl)azetidin-3-yl)-5-methyl-1-(6-(trifluoromethyl)pyridin-3-yl)-1,3-dihydro

[0558] -2H-imidazo[4,5-b]pyridin-2-one;

[0559] 244) 3-(1-(2-Fluoropropenoyl)azetidin-3-yl)-6-methyl-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

[0560] 245) 3-(1-(2-Fluoropropenoyl)azetidin-3-yl)-6-(trifluoromethyl)-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

[0561] 246) 3-(1-(2-Fluoropropenoyl)azetidin-3-yl)-6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

[0562] 247) 1-(1-(2-Fluoropropenoyl)azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo

[0563] [4,5-c]pyridin-2-one;

[0564] 248) 3-(1-(2-Fluoropropenoyl)azetidin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo

[0565] [4,5-c]pyridin-2-one;

[0566] 249) 6-Chloro-3-(1-(2-Fluoropropenoyl)azetidin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

[0567] 250) 9-(1-(2-Fluoropropenoyl)azetidin-3-yl)-7-(4-(trifluoromethyl)phenyl)-7,9-dihydro-8H-purin-8-one;

[0568] 251) 3-(1-(2-Fluoropropenoyl)azetidin-3-yl)-5-methoxy-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

[0569] 252) 5-Chloro-3-(1-(2-Fluoropropenoyl)azetidin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

[0570] 253) 6-Fluoro-3-(1-(2-Fluoropropenoyl)azetidin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

[0571] 254) N-(1-(2-(4-(Trifluoromethyl)phenyl)quinazolin-4-yl)pyrrolidin-3-yl)acrylamide;

[0572] 255) 2-Fluoro-1-(3-((2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)amino)azetidin-1-yl)prop-2-en-1-one;

[0573] 256) 2-Fluoro-1-(3-(2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)azetidin-1-yl)prop-2-en-1-one;

[0574] 257) 2-Fluoro-1-(3-(4-(4-(trifluoromethyl)phenyl)quinazolin-2-yl)azetidin-1-yl)prop-2-en-1-one;

[0575] 258) N-(1-(1-(4-(trifluoromethyl)phenyl)isoquinolin-3-yl)pyrrolidin-3-yl)acrylamide;

[0576] 259) N-(3-(1-(4-(trifluoromethyl)phenyl)isoquinolin-3-yl)phenyl)acrylamide;

[0577] 260) 1-(3-(4-(4-(trifluoromethyl)phenyl)quinolin-2-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0578] 261) 1-(3-(4-(4-(trifluoromethyl)phenyl)quinazolin-2-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0579] 262) 3-(1-Acrylpyrrolidin-3-yl)-1-(4-(trifluoromethyl)phenyl)quinazoline-2,4(1H,3H)-dione;

[0580] 263) 2-(1-Acrylpyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenyl)phthalazin-1(2H)-one;

[0581] 264) 2-(1-Acrylpiperidin-3-yl)-4-(4-(trifluoromethyl)phenyl)phthalazin-1(2H)-one;

[0582] 265) 3-(1-Acrylpyrrolidin-3-yl)-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-2(1H)-one;

[0583] 266) 3-(5-(1-Acrylpyrrolidin-3-yl)-1,3,4-oxadiazol-2-yl)-1-(4-(trifluoromethyl)phenyl)quinolin-2(1H)-one;

[0584] 267) 1-(3-(5-(4-(4-(trifluoromethyl)phenyl)quinazolin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0585] 268) N-(1-(2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)azetidin-3-yl)acrylamide;

[0586] 269) 2-Fluoro-N-(1-(2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)azetidin-3-yl)acrylamide;

[0587] 270) 2-Fluoro-N-(1-(2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)pyrrolidin-3-yl)acrylamide;

[0588] 271) N-(1-(2-(4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)acrylamide;

[0589] 272) N-(1-(2-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-3-yl)acrylamide;

[0590] 273) 1-(4-(2-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one;

[0591] 274) N-(5-Methyl-1-(2-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-3-yl)acrylamide;

[0592] 275) N-(1-(2-(4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyrimidin-4-yl)azetidin-3-yl)acrylamide;

[0593] 276) 2-Fluoro-N-(1-(2-(4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyrimidin-4-yl)azetidin-3-yl)acrylamide;

[0594] 277) 2-Fluoro-N-(1-(2-(4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)acrylamide;

[0595] 278) 2-Fluoro-N-(1-(2-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-3-yl)acrylamide;

[0596] 279) N-(1-(2-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4-yl)azetidin-3-yl)acrylamide;

[0597] 280) 2-Fluoro-N-(1-(2-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4-yl)azetidin-3-yl)acrylamide;

[0598] 281) N-(1-(2-(4-(Trifluoromethyl)phenyl)pyrido[3,2-d]pyrimidin-4-yl)azetidin-3-yl)acrylamide;

[0599] 282) 2-Fluoro-N-(1-(2-(4-(trifluoromethyl)phenyl)pyrido[3,2-d]pyrimidin-4-yl)azetidin-3-yl)acrylamide;

[0600] 283) 1-(3-((2-(4-(Trifluoromethyl)phenyl)quinazolin-4-yl)amino)azetidin-1-yl)prop-2-en-1-one;

[0601] 284) N-(3-(4-(4-(Trifluoromethyl)phenoxy)naphthalen-2-yl)phenyl)acrylamide;

[0602] 285) 1-(3-(2-(4-(Trifluoromethyl)phenyl)quinolin-4-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0603] 286) 1-(3-(6-(4-(Trifluoromethyl)phenyl)quinolin-8-yl)pyrrolidin-1-yl)prop-2-en-1-one;

[0604] 287) N-(1-(2-(4-(Trifluoromethyl)phenyl)pyrido[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl)acrylamide;

[0605] 288) 2-Fluoro-N-(1-(2-(4-(trifluoromethyl)phenyl)pyrido[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl)acrylamide;

[0606] 289) 3-(1-Acrylpyrrolidin-3-yl)-1-(4-(trifluoromethyl)phenyl)-4a,8a-dihydroquinolin-2(1H)-one;

[0607] 290) 2-(1-Acrylpyrrolidin-3-yl)-4-(4-(trifluoromethyl)phenyl)-4a,8a-dihydroisoquinolin-1(2H)-one;

[0608] 291) 2-(1-Acrylazetidin-3-yl)-4-(4-(trifluoromethyl)phenyl)phthalazin-1(2H)-one;

[0609] 292) 3-(1-Acrylazetidin-3-yl)-1-(4-(trifluoromethyl)phenyl)quinazoline-2,4(1H,3H)-dione;

[0610] 293) 2-(1-Acrylazetidin-3-yl)-4-(4-(trifluoromethyl)phenyl)isoquinolin-1(2H)-one;

[0611] 294) 1-(3-(4-(4-(Trifluoromethyl)phenyl)quinazolin-2-yl)azetidin-1-yl)prop-2-en-1-one;

[0612] 295) 2-Fluoro-N-(1-(3-(4-(trifluoromethyl)phenyl)naphthalen-1-yl)azetidin-3-yl)acrylamide;

[0613] 296) 2-Fluoro-N-(1-(6-(4-(trifluoromethyl)phenyl)quinolin-8-yl)azetidin-3-yl)acrylamide;

[0614] 297) 1-(1-(2-Fluoropropionyl)azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)quinolin-2(1H)-one;

[0615] 298) 1-(1-(2-Fluoropropionyl)azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,8-naphthyridin-2(1H)-one;

[0616] 299) 1-(1-(2-Fluoropropionyl)azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)quinoxalin-2(1H)-one;

[0617] 300) 4-(1-(2-Fluoropropionyl)azetidin-3-yl)-2-(4-(trifluoromethyl)phenyl)pyrido[2,3-b]pyrazine

[0618] -3(4H)-one;

[0619] 301) 2-Fluoro-N-(1-(2-(4-(trifluoromethyl)phenyl)pteridin-4-yl)azetidin-3-yl)acrylamide;

[0620] 302) 2-Fluoro-N-methyl-N-(1-(2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)azetidin-3-yl)acrylamide;

[0621] 303) 2-Fluoro-N-(1-(7-Methoxy-2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)azetidin-3-yl)acrylamide;

[0622] 304) 2-Fluoro-N-(1-(5-(Trifluoromethyl)-2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)azetidin-3-yl)prop

[0623] enamide;

[0624] 305) 2-Fluoro-N-(1-(2-(4-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin-4-yl)azetidin-3-yl)acrylamide

[0625] Amide;

[0626] 306) 2-Fluoro-N-(1-(2-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,2-d]pyrimidin-4-yl)azetidin-3-yl)acrylamide

[0627] Acrylamide;

[0628] 307) 2-Fluoro-1-(3-(3-(phenylethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one

[0629] -1-one;

[0630] 308) (E)-2-Fluoro-1-(3-(3-styryl-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0631] 309) 1-(3-(3-((3,3-difluorocyclobutyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one

[0632] Prop-2-en-1-one;

[0633] 310) N-(3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl)acrylamide;

[0634] 311) 1-(3-(3-(cyclopentylethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0635] 312) 1-(3-(3-(cyclopentylethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one;

[0636] 313) 1-(3-(3-(pyrimidin-2-ylethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0637] 314) 2-Fluoro-1-(3-(3-(pyrimidin-2-ylethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0638] 315) 1-(3-(3-(Cyclopropylethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0639] 316) 1-(3-(3-(Thiophen-3-ylethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0640] 317) 2-Fluoro-1-(3-(3-(Thiophen-3-ylethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0641] 318) 1-(3-(3-((1-Methyl-1H-imidazol-5-yl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0642] 319) 1-(3-(3-(Phenylethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0643] 320) 1-(3-(3-(Cyclobutylethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0644] 321) 1-(3-(3-(Cyclobutylethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one;

[0645] 322) 1-(3-(3-(Cyclopropylethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one;

[0646] 323) 2-Fluoro-1-(3-(3-((1-Methyl-1H-imidazol-5-yl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0647] 324) 1-(3-(3-(Cyclohexylethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0648] 325) 1-(3-(3-(Cyclohexylethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one;

[0649] 326) 1-(3-(3-((3,3-difluorocyclobutyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-

[0650] yl)-2-fluoroprop-2-en-1-one;

[0651] 327) (E)-1-(3-(3-styryl-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0652] 328) 1-(3-(3-((3,3-difluorocyclopentyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-

[0653] yl)prop-2-en-1-one;

[0654] 329) 1-(3-(3-((3,3-difluorocyclopentyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-

[0655] yl)-2-fluoroprop-2-en-1-one;

[0656] 330) (E)-1-(3-(3-(2-cyclohexylethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0657] 331) (E)-1-(3-(3-(2-cyclohexylethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one;

[0658] 332) (E)-1-(3-(3-(2-cyclopropylethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0659] 333) (E)-1-(3-(3-(2-cyclopropylethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one;

[0660] 334) 2-fluoro-1-(3-(3-((4-fluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0661] 335) 2-Fluoro-1-(3-(3-((3-fluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0662] 336) 2-Fluoro-1-(3-(3-((2-fluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0663] 337) 1-(3-(3-((3-chlorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one;

[0664] 338) 1-(3-(3-((3-((difluoro-l3-methyl)-l2-fluoroalkyl)phenyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)

[0665] azetidin-1-yl)-2-fluoroprop-2-en-1-one;

[0666] 339) (E)-2-Fluoro-1-(3-(3-(4-fluorostyryl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0667] 340) (E)-2-Fluoro-1-(3-(3-(3-fluorostyryl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0668] 341) (E)-2-Fluoro-1-(3-(3-(2-fluorostyryl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0669] 342) (E)-1-(3-(3-(4-chlorostyryl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one;

[0670] 343) (E)-2-Fluoro-1-(3-(3-(4-(trifluoromethyl)styryl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0671] 344) (E)-4-(2-(1-(1-(2-fluoropropenoyl)azetidin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)vinyl)

[0672] benzonitrile;

[0673] 345)(E)-2-Fluoro-1-(3-(3-(3-(trifluoromethyl)styryl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one;

[0674] 346)1-(3-(3-((2,3-difluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)-2-fluoroprop-2-en-1-one;

[0675] 347)2-Fluoro-1-(3-(3-((2-fluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop

[0676] -2-en-1-one;

[0677] 348)1-(3-(3-((2-chlorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)-2-fluoroprop

[0678] -2-en-1-one; or

[0679] 349)2-Fluoro-1-(3-(3-((2-(trifluoromethyl)phenyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin

[0680] -1-yl)prop-2-en-1-one.

[0681] The present invention also provides a pharmaceutical composition, which comprises any compound of the present invention and a pharmaceutically acceptable excipient, for example, hydroxypropyl methylcellulose. In the composition, the weight ratio of the compound to the excipient is between about 0.0001 and about 10.

[0682] The present invention also provides the use of the pharmaceutical composition of formula I in the preparation of a drug for treating a disease of a subject.

[0683] The present invention also provides some preferred technical solutions regarding the above use.

[0684] In some embodiments, the drug prepared by this method can be used for treating or preventing, or for delaying or preventing cancer, cancer metastasis. The cancer is colon cancer, gastric cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, multiple melanoma, brain cancer, kidney cancer, liver cancer, squamous cell carcinoma, gastrointestinal cancer, mesothelioma, prostate cancer, ovarian cancer or breast cancer.

[0685] The present invention also provides a method for treating a disease in a subject, the method comprising administering to a subject in need an effective amount of a compound of the present invention or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the disease is colon cancer, gastric cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, multiple melanoma, brain cancer, kidney cancer, liver cancer, squamous cell carcinoma, gastrointestinal cancer, mesothelioma, prostate cancer, ovarian cancer or breast cancer.

[0686] The present invention also provides the use of a compound of the present invention or a pharmaceutical composition thereof for the preparation of a drug.

[0687] In some embodiments, the drug is used for treating, preventing cancer or a proliferative disease.

[0688] In some embodiments, the cancer is colon cancer, gastric cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, multiple melanoma, brain cancer, kidney cancer, liver cancer, squamous cell carcinoma, gastrointestinal cancer, mesothelioma, prostate cancer, ovarian cancer or breast cancer.

[0689] In some embodiments, the drug can be used as an inhibitor of YAP / TAZ-TEAD interaction.

[0690] The general chemical terms used in the above structural formula have their usual meanings. For example, unless otherwise specified, the term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine. Preferred halogen groups include F, Cl and Br.

[0691] As used herein, unless otherwise specified, alkyl includes saturated monovalent hydrocarbon groups having straight-chain, branched-chain or cyclic moieties. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. Similarly, as in C 1-4 C in alkyl 1-4 , is defined to identify a group having 1, 2, 3 or 4 carbon atoms in a straight-chain or branched-chain arrangement.

[0692] Alkenyl and alkynyl include straight-chain, branched-chain or cyclic olefins and alkynes. Similarly, "C 2-8 alkenyl" and "C 2-8 alkynyl" refer to alkenyl or alkynyl having a linear or branched arrangement of 2, 3, 4, 5, 6, 7 or 8 carbon atoms.

[0693] Alkoxy is an oxygen ether formed from the aforementioned straight-chain, branched-chain or cyclic alkyl.

[0694] Unless otherwise specified, the term "aryl" as used herein refers to an unsubstituted or substituted monocyclic or polycyclic system containing carbocyclic atoms. Preferred aryls are monocyclic or bicyclic 6- to 10-membered aromatic ring systems. Phenyl and naphthyl are preferred aryls. The most preferred aryl is phenyl.

[0695] Unless otherwise specified, the term "heterocyclic group" represents an unsubstituted or substituted stable 3- to 10-membered saturated monocyclic, spiro, bridged bicyclic or fused bicyclic system composed of carbon atoms and 1 to 3 heteroatoms selected from N, O and S. The N or S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom, thereby producing a stable structure. Examples of such heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyridazinyl, pyridazinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thioxomorpholine sulfoxide, thioxomorpholine sulfone and oxadiazolyl.

[0696] Unless otherwise specified, the term "heteroaryl" as used herein represents an unsubstituted or substituted stable five- or six-membered monocyclic aromatic ring system or an unsubstituted or substituted eight- to ten-membered benzo-fused heteroaromatic ring system or bicyclic heteroaromatic ring system composed of carbon atoms and 1-4 heteroatoms selected from N, O or S, wherein the N or S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized. The heteroaryl may be attached to any heteroatom or carbon atom, thereby producing a stable structure. Examples of heteroaryls 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, benzotriazolyl adeninyl, quinolinyl or isoquinolinyl.

[0697] The term "alkenyloxy" refers to the group -O-alkenyl, wherein alkenyl is defined as above.

[0698] The term "alkynyloxy" refers to the group -O-alkynyl, wherein alkynyl is defined as above.

[0699] The term "cycloalkyl" refers to a cyclic saturated alkyl group having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclobutyl, cyclobutyl.

[0700] The term "heterocycloalkyl" refers to a saturated cycloalkyl group containing carbon atoms and 1 to 3 heteroatoms selected from N, O, or S, where the N or S heteroatoms may optionally be oxidized and the N heteroatom may optionally be quaternized. Examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxazepinyl.

[0701] The term "substituted" means that one or more hydrogen atoms in a group are each replaced by the same or different substituents. Common substituents include, but are not limited to, halogen (F, Cl, Br, or I), C 1-8 alkyl, C 3-12 cycloalkyl, -OR 1 、SR 1 、=O、=S、-C(O)R 1 、-C(S)R 1 、=NR 1 、-C(O)OR 1 、-C(S)OR 1 、-NR 1 R 2 、-C(O)NR 1 R 2 、cyano, nitro, -S(O)2R 1 、-OS(O2)OR 1 、-OS(O)2R 1 、-OP(O)(OR 1 )(OR 2 );wherein, R 1 and R 2 are independently selected from -H, lower alkyl, lower haloalkyl. In some embodiments, the substituents are independently selected from -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH3, -SC2H5, formyl group, -C(OCH3), cyano, nitro, CF3, -OCF3, amino, dimethylamino, methylthio, sulfonyl, and acetyl.

[0702] represents the attachment position of L1 or L2.

[0703] represents the attachment position to ring A.

[0704] As used herein, the term "composition" is intended to include a product containing a specific amount of a specific ingredient, as well as a product directly or indirectly produced by the combination of a specific amount of specific ingredients. Accordingly, a pharmaceutical composition containing the compound of the present invention as an active ingredient and a method for preparing the compound of the present invention are also part of the present invention. In addition, some crystalline forms of the compound may exist as polymorphs, and such polymorphs are 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 within the scope of the present invention.

[0705] Examples of substituted alkyls include, but are not limited to, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl, and piperazinylmethyl.

[0706] Examples of substituted alkoxys include, but are not limited to, carbamoylmethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, and 3-hydroxypropoxy.

[0707] The compounds of the present invention may also exist in the form of pharmaceutically acceptable salts. For pharmaceutical use, salts of the compounds of the present invention refer to non-toxic "pharmaceutically acceptable salts". Forms of pharmaceutically acceptable salts include pharmaceutically acceptable acid / anion or base / cation salts. Pharmaceutically acceptable acid / anion salts generally exist in the form of protonation of basic nitrogen with inorganic or organic acids. Typical organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, oxalic acid, polyamic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfonic acid, salicylic acid, saccharic acid, or trifluoroacetic acid. Pharmaceutically acceptable base / cation salts include, but are not limited to, aluminum salts, calcium salts, chloroprocaine salts, choline, diethanolamine salts, ethylenediamine, lithium salts, magnesium salts, potassium salts, sodium salts, and zinc salts.

[0708] Prodrugs of the compounds of the present invention are included within the scope of the present invention. Generally, the prodrug refers to a functional derivative that is readily convertible in vivo into the desired compound. Accordingly, the term "administering" in the methods of treatment provided by the present invention refers to the administration of a compound disclosed in the present invention that can treat different diseases, or a compound that, although not explicitly disclosed, can be converted in vivo into a compound disclosed in the present invention after administration to a subject. Conventional methods for the selection and preparation of suitable prodrug derivatives are described, for example, in books such as Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

[0709] The definition of any substituent or variable at a specific position in the molecule is independent of the definitions at other positions in the molecule. It should be understood that those skilled in the art can select the substituents or substitution forms of the compounds in the present invention by means of the prior art and the methods described in the present invention to obtain compounds that are chemically stable and easy to synthesize.

[0710] The compounds described in the present invention may contain one or more asymmetric centers and may thus give rise to diastereoisomers and optical isomers. The present invention includes all possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts.

[0711] The above formula I does not precisely define the stereostructure at a certain position of the compound. The present invention includes all stereoisomers of the compounds represented by formula I and their pharmaceutically acceptable salts. Further, mixtures of stereoisomers and isolated specific stereoisomers are also included in the present invention. During the synthesis of such compounds, or during the racemization or epimerization processes well-known to those skilled in the art, the products obtained may be mixtures of stereoisomers.

[0712] When the compounds represented by formula I exist as tautomers, unless otherwise stated, the present invention includes any possible tautomers and their pharmaceutically acceptable salts, and mixtures thereof.

[0713] When the compounds represented by formula I and their pharmaceutically acceptable salts exist as solvates or polymorphs, the present invention includes any possible solvates and polymorphs. There is no particular limitation on the type of solvent forming the solvate, as long as the solvent is pharmaceutically acceptable. For example, solvents such as water, ethanol, propanol, acetone, and the like can be used.

[0714] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compounds provided by the present invention are acids, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include salts such as aluminum, ammonium, calcium, copper (higher and lower valences), ferric, ferrous, lithium, magnesium, manganese (higher and lower valences), potassium, sodium, zinc, etc. Salts of ammonium, calcium, magnesium, potassium, and sodium are particularly preferred. Pharmaceutically acceptable non-toxic organic bases capable of forming salts include primary amines, secondary amines, and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts include ion exchange resins, as well as arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, harmine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0715] When the compounds provided by the present invention are bases, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid, etc. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. More preferably, formic acid and hydrochloric acid. Since the compounds represented by formula (I) will be used as drugs, preferably, a certain purity is used, for example, at least 60% purity, a more suitable purity is at least 75%, and a particularly suitable purity is at least 98% (% is by weight).

[0716] The pharmaceutical compositions provided by the present invention include the compounds represented by formula (I) (or their pharmaceutically acceptable salts) as active ingredients, a pharmaceutically acceptable excipient, and other optional therapeutic components or adjuvants. The pharmaceutical compositions of the present invention include pharmaceutical compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous administration, intramuscular injection, intravenous administration) administration, although in any given case, the most suitable mode of administration of the active ingredient depends on the specific subject receiving the administration, the nature of the subject, and the severity of the condition. The pharmaceutical compositions of the present invention can conveniently exist in unit dosage forms well-known in the art and can be prepared by any preparation methods well-known in the pharmaceutical field.

[0717] In practice, according to conventional drug mixing techniques, the compound shown in formula (I) of the present invention, or a prodrug, or a metabolite, or a pharmaceutically acceptable salt thereof, can be used as an active ingredient and intimately mixed with a pharmaceutical carrier into a pharmaceutical composition according to conventional drug mixing techniques. The pharmaceutical carrier can take various forms, depending on the desired mode of administration, for example, oral or injection (including intravenous injection). Therefore, the pharmaceutical composition of the present invention can be in the form of unit dosage forms suitable for oral administration, such as capsules, cachets or tablets containing a predetermined dose of the active ingredient. Further, the pharmaceutical composition of the present invention can be in the form of powders, granules, solutions, aqueous suspensions, non-aqueous liquids, oil-in-water emulsions, or water-in-oil emulsions. Additionally, in addition to the common dosage forms mentioned above, the compound shown in formula I or its pharmaceutically acceptable salt can also be administered by means of controlled release and / or delivery devices. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, such a method includes the step of associating the active ingredient with a carrier constituting one or more essential ingredients. Generally, the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of both. Additionally, the product can be conveniently prepared into the desired appearance.

[0718] Therefore, the pharmaceutical composition of the present invention can include a pharmaceutically acceptable carrier and the compound shown in formula I or its pharmaceutically acceptable salt. The combined use of the compound shown in formula I or its pharmaceutically acceptable salt with one or more other therapeutically active compounds is also included in the pharmaceutical composition of the present invention.

[0719] The pharmaceutical carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gas carrier. Solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid. Liquid carriers include syrups, peanut oil, olive oil and water. Gas carriers include carbon dioxide and nitrogen. When preparing oral pharmaceutical preparations, any pharmaceutically convenient medium can be used. For example, water, ethylene glycol, oils, alcohols, flavoring agents, preservatives, coloring agents, etc. can be used in oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. can be used in oral solid preparations such as powders, capsules and tablets. Considering ease of administration, tablets and capsules are preferred for oral preparations, and solid pharmaceutical carriers are used herein. Optionally, tablet coating can be carried out using standard aqueous or non-aqueous formulation techniques.

[0720] Tablets containing the compounds or pharmaceutical compositions of the present invention can be formed by compression molding or molding, and optionally, tablets can be made together with one or more auxiliary components or excipients. The active ingredient in a free-flowing form such as powder or granules is mixed with a binder, a lubricant, an inert diluent, a surfactant or a dispersant, and in a suitable machine, compressed tablets can be prepared by compression. The powdered compound or pharmaceutical composition is moistened with an inert liquid diluent and then, in a suitable machine, molded tablets can be prepared by molding. Preferably, each tablet contains from about 0.05 mg to 5 g of the active ingredient, and each cachet or capsule contains from about 0.05 mg to 5 g of the active ingredient. For example, a formulation intended for oral administration to humans contains from about 0.5 mg to about 5 g of the active ingredient, compounded with suitable and conveniently metered auxiliary materials, which auxiliary materials account for about 5% to 95% of the total amount of the pharmaceutical composition. The unit dosage form generally contains from about 1 mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

[0721] The pharmaceutical compositions provided by the present invention suitable for parenteral administration can be prepared by adding the active ingredient to water to form an aqueous solution or suspension. Appropriate surfactants such as hydroxypropyl cellulose can be included. Dispersed systems can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oils. Further, preservatives can also be included in the pharmaceutical compositions of the present invention to prevent the growth of harmful microorganisms.

[0722] The present invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersed systems. Further, the above pharmaceutical compositions can be prepared in the form of sterile powders for immediate preparation of sterile injection solutions or dispersions. In any case, the final injection form must be sterile and must be easily flowable for easy injection. In addition, the pharmaceutical compositions must be stable during preparation and storage. Therefore, preferably, the pharmaceutical compositions are stored under conditions resistant to microbial contamination such as bacteria and fungi. The carrier can be a solvent or a dispersion medium, for example, water, ethanol, polyols (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oils and suitable mixtures thereof.

[0723] The pharmaceutical compositions provided by the present invention can be in a form suitable for topical administration, for example, aerosols, emulsions, ointments, lotions, powders or other similar dosage forms. Further, the pharmaceutical compositions provided by the present invention can be in a form suitable for use in transdermal drug delivery devices. Using the compounds of formula (I) of the present invention, or pharmaceutically acceptable salts thereof, these preparations can be prepared by conventional processing methods. As an example, an emulsion or an ointment is prepared by adding about 5 wt% to 10 wt% of a hydrophilic material and water to obtain an emulsion or an ointment with the desired consistency.

[0724] The pharmaceutical composition provided by the present invention can use a solid as a carrier and is suitable for the form of rectal administration. The suppository of a unit dose is the most typical and common dosage form. Suitable excipients include cocoa butter and other materials commonly used in the art. The suppository can be conveniently prepared by first mixing the pharmaceutical composition with the softened or melted excipient and then cooling and molding with a mold.

[0725] In addition to the above-mentioned excipient components, the above preparation formulation may further include, appropriately, one or more additional excipient components, such as diluents, buffers, flavoring agents, binders, surfactants, thickening agents, lubricants, and preservatives (including antioxidants), etc. Further, other adjuvants may also include permeation promoters for adjusting the osmotic pressure of the drug with the blood of the intended recipient. The pharmaceutical composition containing the compound shown in formula (I) or its pharmaceutically acceptable salt can be prepared in the form of a powder or a concentrate.

[0726] Generally, for treating the conditions or discomforts shown above, the dosage level of the drug is about 0.01 mg / kg body weight to 150 mg / kg body weight per day, or 0.5 mg to 7 g per patient per day. For example, for colon cancer, rectal cancer, mantle cell lymphoma, multiple myeloma, breast cancer, prostate cancer, glioblastoma, squamous cell esophageal cancer, liposarcoma, T-cell lymphoma melanoma, pancreatic cancer, malignant glioma, or lung cancer, the dosage level of the drug for effective treatment is 0.01 mg / kg body weight to 50 mg / kg body weight per day, or 0.5 mg to 3.5 g per patient per day.

[0727] However, it can be understood that lower or higher doses than those mentioned above may be required. The specific dosage level and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health status, gender, diet, time of administration, route of administration, excretion rate, drug combination, and the severity of the specific disease being treated.

[0728] These and other aspects will become apparent from the following written description of the present invention.

[0729] The following examples are provided to better illustrate the present invention. Unless otherwise clearly stated, all parts and percentages are by weight, and all temperatures are in degrees Celsius.

[0730] The present invention will be described in more detail by way of specific embodiments. The following embodiments are provided for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will readily recognize various non-critical parameters that can be changed or modified to produce substantially the same results. According to at least one of the assay methods described herein, it was found that the exemplified compounds can inhibit the transcriptional activity of the YAP / TAZ and TEAD protein / protein interactions. BRIEF DESCRIPTION OF THE DRAWINGS

[0731] Figure 1 : Inhibition curve of compound 5 on NCI-H226 cell line in Brdu assay.

[0732] Figure 2 : Inhibition curve of compound 6 on NCI-H226 cell line in Brdu assay.

[0733] Figure 3 : Inhibition curve of compound 30 on NCI-H226 cell line in Brdu assay.

[0734] Figure 4 : Inhibition curve of compound 73 on NCI-H226 cell line in Brdu assay.

[0735] Figure 5 : Inhibition curve of compound 80 on NCI-H226 cell line in Brdu assay.

[0736] Figure 6 : Inhibition curve of compound 124 on NCI-H226 cell line in Brdu assay.

[0737] Figure 7 : Inhibition curve of compound 132 on NCI-H226 cell line in Brdu assay.

[0738] Figure 8 : Tumor growth curve of different treatment groups of Balb / c nude mice bearing NCI-H226 tumors.

[0739] Figure 9 : Percentage change in body weight of Balb / c nude mice bearing NCI-H226 tumors in different treatment groups. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0740] EXAMPLES

[0741] The compounds described herein are commercially available or can be synthesized using commercially available starting materials and reagents by conventional methods as shown below. The following abbreviations were used in the examples:

[0742] BOP: Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate;

[0743] Cu(OAc)2: Copper acetate;

[0744] DMA: Dimethylacetamide;

[0745] DMF: N,N-Dimethylformamide;

[0746] DIAD: Diisopropyl azodicarboxylate;

[0747] DEAD: Diethyl azodicarboxylate;

[0748] DIEA or DIPEA: N,N-Diisopropylethylamine;

[0749] DMSO: Dimethyl sulfoxide;

[0750] DCM: Dichloromethane;

[0751] EA: Ethyl acetate;

[0752] EDTA: Ethylenediaminetetraacetic acid;

[0753] HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate;

[0754] TMB: 3,3',5,5'-Tetramethylbenzidine;

[0755] TBAF: Tetrabutylammonium fluoride;

[0756] TBDPSCl: tert-Butyldiphenylchlorosilane;

[0757] THF: Tetrahydrofuran;

[0758] TFA: Trifluoroacetic acid;

[0759] TEA: Triethylamine;

[0760] Mscl: Methanesulfonyl chloride;

[0761] NIS: N-Iodosuccinimide;

[0762] NMP: N-Methylpyrrolidone;

[0763] PBS: Phosphate buffered saline;

[0764] HRP: Horseradish peroxidase;

[0765] h or hrs: Hour;

[0766] Hex: Hexane;

[0767] HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate;

[0768] LCMS: Liquid Chromatography Mass Spectrometry;

[0769] MeOH: Methanol;

[0770] min: Minute;

[0771] NIS: N-Iodosuccinimide;

[0772] Pd / C: Palladium on carbon;

[0773] PE: Petroleum ether;

[0774] PPh3: Triphenylphosphine;

[0775] Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium(0);

[0776] Pd(dppf)Cl2.CH2Cl2: Dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane complex;

[0777] Rt or r.t or RT: Room temperature.

[0778] Synthesis of Compound 1 (1-(1-Acryloylpyrrolidin-3-yl)-3-(4-cyclohexylphenyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one) in Example 1

[0779]

[0780] Step 1: Preparation of 3-Iodo-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0781] To a mixture of 1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (1.00 g, 7.35 mmol) in DMF (20 mL) was added NIS (2.48 g, 11.02 mmol). The mixture was stirred at room temperature for 1 hour and then at 60 °C for 4 hours. After cooling to room temperature, the mixture was poured into ice water, stirred and filtered. The filter cake was suspended in toluene and concentrated in vacuo to give the title compound 1-1 (1.90 g). LCMS [M+H] + = 262.94.

[0782] Step 2: Preparation of tert-Butyl 3-(3-Iodo-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate

[0783] To a mixture of Compound 1-1 (250 mg, 954.17 μmol) and tert-butyl 3-hydroxypyrrolidine-1-carboxylate (250 mg, 1.34 mmol) in THF (5 mL) was added PPh3 (501 mg, 1.91 mmol), and then DIAD (386 mg, 1.91 mmol) was added dropwise at 0 °C. The mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was concentrated in vacuo to give a residue, which was further purified by silica gel column (Hex:EA = 0%-50%) to give the title compound 1-2 (450 mg). LCMS [M+H] + = 432.05.

[0784] Step 3: Preparation of tert-butyl 3-(3-(4-cyclohexylphenyl)-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate

[0785] To a mixture of Compound 1-2 (450 mg, 1.04 mmol) and 2-(4-cyclohexylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (213 mg, 1.04 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added Pd(dppf)Cl2·CH2Cl2 (76 mg, 103 μmol), K2CO3 (432 mg, 3.13 mmol). The reaction mixture was stirred at 100 °C for 6 h under nitrogen. The reaction mixture was concentrated in vacuo to give a residue, which was purified by silica gel column (Hex:EA = 0%-50%) to give the title compound 1-3 (450 mg). LCMS [M+H]+ = 464.26.

[0786] Step 4: Preparation of 3-(4-cyclohexylphenyl)-1-(pyrrolidin-3-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one The mixture of Compound 1-3 (340 mg, 733 μmol) in HCl / 1,4-dioxane (4.0 N, 10 ml) was stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo to give the title compound 1-4 (400 mg), which was used directly in the next step without purification. LCMS [M+H] + = 400.18.

[0787] Step 5: Preparation of 1-(1-acrylpyrrolidin-3-yl)-3-(4-cyclohexylphenyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Compound 1)

[0788] To a mixture of Compound 1-4 (200 mg, 550 μmol) in THF / H2O (v:v = 1:1, 10 mL) was added NaHCO3 (139 mg, 1.65 mmol), and then acryloyl chloride (50 mg, 552 μmol) was added dropwise under nitrogen protection at 0 °C. The mixture was stirred at 0 °C for 0.5 h, then diluted with EA, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. The residue was purified by silica gel column (DCM:MeOH = 20:1) to give the title compound 1 (31.9 mg). LCMS [M+H] + = 418.22.

[0789] Synthesis of Compound 2 (1-(1-acryloylpyrrolidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one) in Example 2

[0790]

[0791] Step 1: Preparation of tert-butyl 3-(7-oxo-3-(4-(trifluoromethyl)phenyl)-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate

[0792] To a mixture of Pd(dppf)Cl2·CH2Cl2 (60 mg, 81 μmol) and K2CO3 (336 mg, 2.43 mmol) in 1,4-dioxane (10 mL) and water (1 mL) were added Compound 1-2 (350 mg, 811 μmol) and 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (231 mg, 1.22 mmol). The reaction mixture was stirred under nitrogen at 100 °C for 6 h, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column (Hex:EA = 0%-50%) to give the title compound 2-1 (350 mg). LCMS [M+H] + = 450.17.

[0793] Step 2: Preparation of 1-(pyrrolidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0794] The mixture of Compound 2-1 (350 mg, 733 μmol) in HCl / 1,4-dioxane (4.0 N, 10 ml) was stirred overnight at room temperature, and concentrated under reduced pressure to give Compound 2-2 (400 mg). LCMS [M+H] + = 400.18.

[0795] Step 3: Preparation of 1-(1-Acryloylpyrrolidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0796] To a mixture of compound 2-2 (200 mg, 518 μmol) in THF / H2O (v:v = 1:1, 10 mL) was added NaHCO3 (130 mg, 1.56 mmol), and then acryloyl chloride (47 mg, 518 μmol) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 0.5 h. It was diluted with EA, then washed with water, dried over MgSO4 and concentrated in vacuo to obtain a residue. The residue was purified by preparative thin-layer chromatography (DCM:MeOH = 20:1) to obtain compound 2 (10 mg). LCMS [M+H] + = 404.13.

[0797] Synthesis of Example 3 Compound 3 (1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)pyrrolidin-1-yl)prop-2-en-1-one)

[0798]

[0799] Step 1 Preparation of tert-butyl 3-(3-iodo-1H-indazol-1-yl)pyrrolidine-1-carboxylate

[0800] Methanesulfonyl chloride (140 mg, 1.23 mmol) was added dropwise to a mixture of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (184 mg, 0.98 mmol), TEA (248 mg, 0.34 mL) and DCM (5.00 mL) with stirring under nitrogen at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched by adding water, extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain intermediate 1 (200 mg).

[0801] NaH (19.67 mg) was added portionwise to a solution of 3-iodo-1H-indazole (200 mg, 819 μmol) in DMF (5.00 mL) under nitrogen at 0 °C. After stirring the mixture at room temperature for 30 min, the above intermediate 1 was added to the reaction mixture, and the mixture was stirred at 60 °C overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, dried, and concentrated in vacuo to obtain a residue. The residue was purified by silica gel column (Hex:EA = 1:1) to obtain compound 3-1 (100 mg). LCMS [M+H] + = 414.06.

[0802] Step 2: Preparation of tert-butyl 3-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)pyrrolidine-1-carboxylate

[0803] Under nitrogen atmosphere, a mixture of compound 3-1 (100 mg, 0.24 mmol), 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (45 mg, 0.24 mmol), potassium carbonate (100 mg, 0.73 mmol), Pd(dppf)Cl2·CH2Cl2 (17 mg, 0.024 mmol), 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 100 °C for 6 h. The mixture was concentrated in vacuo to give a residue, which was purified by silica gel column (Hex:EA = 0%-50%) to afford compound 3-2 (120 mg). LCMS [M+H] + = 432.18

[0804] Step 3: Preparation of 1-(pyrrolidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-indazole

[0805] A mixture of compound 3-2 (100 mg, 231 μmol) in HCl / 1,4-dioxane (4.0 N, 10 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give the title compound 3-3 (100 mg), which was used in the next step without further purification. LCMS [M+H] + = 332.13

[0806] Step 4: Preparation of 1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)pyrrolidin-1-yl)prop-2-en-1-one

[0807] To a mixture of compound 3-3 (300 mg, 905 μmol) in THF / H2O (v:v = 1:1, 20 mL) was added NaHCO3 (130 mg, 1.56 mmol), and then acryloyl chloride (81 mg, 905 μmol) was added dropwise under nitrogen protection at 0 °C. The reaction mixture was stirred at 0 °C for 10 min, diluted with EA, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue. The residue was purified by silica gel column (DCM:MeOH = 30:1) to afford compound 3 (44.1 mg).

[0808] LCMS [M+H] + = 386.14

[0809] 11H NMR (500 MHz, DMSO-d6) δ 8.21 (d, J = 3.2 Hz, 1H), 8.19 (d, J = 3.2 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 3.4 Hz, 1H), 7.87 (s, 1H), 7.86 (d, J = 3.7 Hz, 1H), 7.53 (dd, J = 8.4, 6.8 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 6.65 (ddd, J = 38.9, 16.8, 10.3 Hz, 1H), 6.18 (ddd, J = 16.7, 5.7, 2.4 Hz, 1H), 5.75–5.51 (m, 2H), 4.21–3.95 (m, 2H), 3.91–3.83 (m, 1H), 3.81–3.58 (m, 1H), 2.56 (dt, J = 13.4, 6.5 Hz, 1H), 2.46 (q, J = 6.9 Hz, 1H).

[0810] Synthesis of Compound 4 (1-(3-(1-(4-(Trifluoromethyl)phenyl)-1H-indazol-3-yl)pyrrolidin-1-yl)prop-2-en-1-one) in Example 4

[0811]

[0812] Step 1: Preparation of tert-Butyl 3-(1H-indazol-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate

[0813] Under nitrogen protection, a mixture of 3-iodo-1H-indazole (200 mg, 0.82 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (290 mg, 0.98 mmol), Pd(dppf)Cl2·CH2Cl2 (67 mg, 0.082 mmol), potassium carbonate (339 mg, 2.46 mmol), 1,4-dioxane (10 mL) and water (1 mL) was stirred at 90 °C for 6 h. The reaction was monitored by LCMS. The reaction mixture was cooled to room temperature. The mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column (DCM:MeOH = 20:1) to obtain the title compound 4-1 (210 mg). LCMS [M+H] + = 286.15.

[0814] Step 2: Preparation of tert-Butyl 3-(1H-indazol-3-yl)pyrrolidine-1-carboxylate

[0815] A mixture of compound 4-1 (210 mg, 0.74 mmol), Pd / C (10 mg) and methanol (20 mL) was stirred at room temperature for 6 h under hydrogen. The reaction was monitored by LCMS. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give the title compound 4-2 (200 mg). LCMS [M+H] + = 288.16.

[0816] Step 3: Preparation of tert-butyl 3-(1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)pyrrolidine-1-carboxylate

[0817] A mixture of compound 4-2 (200 mg, 0.70 mmol), 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (132 mg, 0.70 mmol), TEA (211 mg, 2.09 mmol), Cu(OAc)2 (63 mg, 0.35 mmol) and dichloromethane (20 mL) was stirred at room temperature for 14 h. The reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column (DCM:MeOH = 30:1) to give the title compound 4-3 (210 mg). LCMS [M+H] + = 432.18.

[0818] Step 4: Preparation of 3-(pyrrolidin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indazole hydrochloride

[0819] A mixture of compound 4-3 (210 mg, 0.49 mmol) and HCl / 1,4-dioxane was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under vacuum to give compound 4-4 (200 mg), which was used directly in the next step without further purification. LCMS [M+H] + = 332.13.

[0820] Step 5: Preparation of 1-(3-(1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)pyrrolidin-1-yl)prop-2-en-1-one Under nitrogen at 0 °C, acryloyl chloride (35 mg, 0.37 mmol) was added dropwise to a mixture of compound 4-4 (100 mg, 0.30 mmol), sodium bicarbonate (76 mg, 0.90 mmol), THF (10 mL) and water (5 mL) with stirring. The mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column (DCM:MeOH = 20:1) to give the title compound 4 (33 mg). LCMS [M+H]+ = 386.14.

[0821] 1 H NMR (500 MHz, DMSO-d6) δ 8.04 (s, 1H), 8.04–7.96 (m, 3H), 7.93 (dd, J = 8.8, 2.2 Hz, 2H), 7.66–7.54 (m, 1H), 7.34 (t, J = 7.5 Hz, 1H), 6.66 (ddd, J = 16.5, 10.3, 5.9 Hz, 1H), 6.17 (dt, J = 16.8, 2.7 Hz, 1H), 5.69 (ddd, J = 12.4, 10.4, 2.4 Hz, 1H), 4.24–3.98 (m, 2H), 3.98–3.75 (m, 2H), 3.72 (ddd, J = 11.9, 8.5, 3.9 Hz, 1H), 2.48–2.20 (m, 2H).

[0822] Synthesis of Compound 5 (2-Fluoro-1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one) in Example 5

[0823]

[0824] Step 1: Preparation of tert-Butyl 3-(3-iodo-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidine-1-carboxylate

[0825] DEAD (8.53 g, 48.98 mmol) was added dropwise to a mixture containing 3-iodo-1H-pyrazolo[3,4-b]pyridine (4.00 g, 16.33 mmol), tert-butyl 3-hydroxyazetidine-1-carboxylate (4.24 g, 24.49 mmol), triphenylphosphine (12.85 g, 48.98 mmol) and anhydrous THF (80 mL) with stirring at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes and then warmed to room temperature. The reaction was stirred overnight. The reaction was monitored by LCMS. The residue obtained by concentrating the reaction mixture under vacuum was purified by silica gel column (PE:EA = 3:1) to give the title compound (7.83 g). LCMS [M+H] + = 401.04.

[0826] Step 2: Preparation of tert-Butyl 3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidine-1-carboxylate

[0827] Under nitrogen atmosphere, a mixture of tert-butyl 3-(3-iodo-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidine-1-carboxylate (4.00 g, 10 mmol), (4-(trifluoromethyl)phenyl)boronic acid (2.85 g, 15 mmol), Cs2CO3 (9.77 g, 30 mmol), Pd(dppf)Cl2·CH2Cl2 (0.82 g, 1 mmol), 1,4-dioxane (40 mL) and water (8 mL) was stirred at 100 °C for 6 h. The mixture was concentrated under vacuum. The residue was eluted through a silica gel column with DCM to give the title compound (4.62 g). LCMS [M+H] + = 419.16.

[0828] Step 3: Preparation of 1-(azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine

[0829] A mixture of tert-butyl 3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidine-1-carboxylate (4.62 g, 11.04 mmol), TFA (15 mL) and DCM (20 mL) was stirred at room temperature for 1 h. After concentrating the mixture under vacuum, the title compound (3.18 g) was obtained as a pale yellow solid and could be used in the next step without purification. LCMS [M+H] + = 319.11.

[0830] Step 4: Preparation of 2-fluoro-1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one

[0831] A mixture of 1-(azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine (3.18 g, 10 mmol), 2-fluoroacrylic acid (1.35 g, 15 mmol), HATU (7.60 g, 20 mmol), DIEA (8.07 mL, 50 mmol), DCM (100 mL) and DMF (2 mL) was stirred at room temperature for 5 h. The reaction mixture was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was dried under vacuum. The residue was purified by elution through a silica gel column (Hex:EA = 1.5:1) to give the title compound (0.94 g) as a pale yellow solid. LCMS [M+H] + = 391.11.

[0832] 11H NMR (500 MHz, CDCl3) δ 8.58 (d, J = 3.4 Hz, 1H), 8.36 (dd, J = 8.05, 0.9 Hz, 1H), 8.11 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.2 Hz, 2H), 7.28 (dd, J = 8.1, 4.5 Hz, 1H), 6.07–5.97 (m, 1H), 5.71 (dd, J = 46.65, 3.0 Hz, 1H), 5.15 (dd, J = 15.65, 3.0 Hz, 1H), 5.09 - 5.02 (m,

[0833] 1H), 5.00–4.92 (m, 1H), 4.83–4.75 (m, 1H), 4.73–4.64 (m, 1H).

[0834] Synthesis of Compound 6 (2-Fluoro-1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one) in Example 6

[0835]

[0836] Step 1: Preparation of tert-Butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate

[0837] Methanesulfonyl chloride (7.94 g, 69.28 mmol) was added to a mixture containing tert-butyl 3-hydroxyazetidine-1-carboxylate (10.00 g, 57.73 mmol), TEA (16.05 mL, 115.47 mmol) and DCM (30 mL) with stirring at 0 °C. The mixture was stirred at 0 °C for 1.5 h. Water was added to the reaction mixture to quench the reaction, and it was extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was dried under vacuum to obtain the title compound (14.67 g), which could be used in the next step without purification.

[0838] Step 2: Preparation of tert-Butyl 3-(3-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate

[0839] At 0 °C under nitrogen atmosphere, NaH (60% suspension in mineral oil, 0.97 g, 24.24 mmol) was added portionwise to a mixture of 3-bromo-1H-pyrazolo[4,3-b]pyridine (1.60 g, 8.08 mmol) in DMF (20 mL). After stirring the mixture at room temperature for 30 minutes, tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (6.09 g, 24.24 mmol) was added to the reaction mixture. The reaction was stirred at 90 °C overnight. After the reaction mixture was cooled to room temperature, it was diluted with DCM, washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through a silica gel column (DCM:CH3OH = 30:1) to obtain the title compound (3.17 g) as a pale yellow solid. LCMS [M+H] + = 353.05.

[0840] Step 3: Preparation of tert-butyl 3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate

[0841] Under nitrogen atmosphere, a mixture containing tert-butyl 3-(3-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (2.85 g, 8.07 mmol), (4-(trifluoromethyl)phenyl)boronic acid (2.30 g, 12.10 mmol), Cs2CO3 (7.89 g, 24.21 mmol), Pd(dppf)Cl2CH2Cl2 (0.66 g, 0.81 mmol), 1,4-dioxane (30 mL) and water (6 mL) was stirred at 120 °C for 4 hours. The mixture was concentrated under vacuum. The residue was purified by elution through a silica gel column with DCM to obtain the title compound (1.80 g) as a pale yellow solid. LCMS [M+H] + = 419.16.

[0842] Step 4: Preparation of 1-(azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine

[0843] A mixture containing tert-butyl 3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidine-1-carboxylate (1.80 g, 4.30 mmol), TFA (10 mL) and DCM (20 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum to obtain the title compound, which could be used in the next step without purification. LCMS [M+H] + = 319.11.

[0844] Step 5: Preparation of 2-Fluoro-1-(3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one

[0845] A mixture of 1-(azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine (1.22 g, 3.83 mmol), 2-fluoroacrylic acid (0.52 g, 5.75 mmol), HATU (2.91 g, 7.67 mmol), DIEA (3.16 mL, 19.15 mmol), DCM (100 mL) and DMF (2 mL) was stirred at room temperature for 1 h. The reaction mixture was washed with water and brine, filtered after drying over anhydrous sodium sulfate. The filtrate was concentrated under vacuum. The residue was purified by elution on a silica gel column with Hex:EA = 1.5:1 to give the title compound (0.60 g) as an off-white solid.

[0846] LCMS [M+H] + = 391.11.

[0847] 1 H NMR (500 MHz, CDCl3) δ 8.73 (d, J = 3.4 Hz, 1H), 8.70 (d, J = 8.1 Hz, 2H), 7.81 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.3 Hz, 2H), 7.39 (dd, J = 8.6, 4.3 Hz, 1H), 5.73 (dd, J = 46.7, 3.0 Hz, 1H), 5.58–5.47 (m, 1H), 5.18 (dd, J = 15.6, 3.0 Hz, 1H), 5.10–5.01 (m, 1H), 5.00–4.90 (m, 1H), 4.84–4.75 (m, 1H), 4.73–4.65 (m, 1H).

[0848] Synthesis of Compound 7 (1-(1-Acryloxypyrrolidin-3-yl)-6-methyl-3-(4-(trifluoromethyl)phenyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one) in Example 7

[0849]

[0850] Step 1: Preparation of 3-Iodo-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0851] A mixture of 1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2.00 g, 14.69 mmol), DMF (20 mL) and N-iodosuccinimide (4.96 g, 22.04 mmol) was stirred at room temperature for 1 hour and then at 60 °C for 4 hours. The reaction was monitored by LCMS. The reaction was cooled to room temperature and poured into ice water. The resulting mixture was filtered and washed with EA. The filter cake was suspended in toluene and then concentrated under vacuum to give the title compound (2.75 g) as an off-white solid. LCMS [M+H] + = 262.94.

[0852] Step 2: Preparation of tert-butyl 3-(3-iodo-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate

[0853] Sodium hydride (60% suspended in mineral oil, 330 mg, 13.74 mmol) was added portionwise to a mixture containing 3-iodo-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (1.20 g, 4.58 mmol) and DMF (10 mL) under nitrogen protection at 0 °C. The reaction was allowed to warm to room temperature and stirred for 1 hour. tert-Butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (2.43 g, 9.16 mmol) was added to the reaction mixture at room temperature, and then the mixture was stirred at 60 °C for 16 hours. The reaction was monitored by LCMS. The reaction was cooled to room temperature, diluted with ethyl acetate and poured into ice water. The organic layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was washed with n-hexane (20 ml × 3) and filtered. The filter cake was concentrated under vacuum to give the title compound (1.52 g) as an off-white solid. LCMS [M+H] + = 376.23.

[0854] Step 3: Preparation of tert-butyl 3-(7-oxo-3-(4-(trifluoromethyl)phenyl)-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate

[0855] Under nitrogen, a mixture of tert-butyl 3-(3-iodo-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (1.20 g, 2.78 mmol), (4-(trifluoromethyl)phenyl)boronic acid (0.79 g, 4.17 mmol), Pd(dppf)Cl2·CH2Cl2 (227 mg, 0.28 mmol), potassium carbonate (1.15 g, 8.35 mmol), 1,4-dioxane (20 mL) and water (2.0 mL) was stirred at 100 °C for 6 hours. The reaction was monitored by LCMS. After the reaction was cooled to room temperature, the mixture was concentrated under vacuum. The residue was purified by elution through a silica gel column (Hex:EA = 0%-40%) to obtain the title compound (1.52 g) as a pale yellow solid. LCMS [M+H] + = 394.42.

[0856] Step 4: Preparation of tert-butyl 3-(6-methyl-7-oxo-3-(4-(trifluoromethyl)phenyl)-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate

[0857] At 0 °C, methyl iodide (0.24 g, 1.67 mmol) was added to a mixture containing tert-butyl 3-(7-oxo-3-(4-(trifluoromethyl)phenyl)-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (0.50 g, 1.11 mmol), cesium carbonate (1.09 g, 3.34 mmol) and DMF (5 mL). After the reaction was warmed to room temperature, it was stirred for 2 hours. The reaction was monitored by LCMS. The reaction was diluted with ethyl acetate and poured into ice water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under vacuum to obtain the title compound (0.42 g) as a yellow solid, which could be used in the next step without purification. LCMS [M+H] + = 408.45.

[0858] Step 5: Preparation of 6-methyl-1-(pyrrolidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one hydrochloride

[0859] A mixture of tert-butyl 3-(6-methyl-7-oxo-3-(4-(trifluoromethyl)phenyl)-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (420 mg, 0.91 mmol) and HCl / 1,4-dioxane (4.0 M, 10 mL) was stirred at room temperature for 4 h. The reaction was monitored by LCMS. The reaction mixture was concentrated under vacuum to give the title compound (290 mg) as a yellow oil, which was used in the next step without purification. LCMS [M+H] + = 364.35.

[0860] Step 6: Preparation of 1-(1-acryloylpyrrolidin-3-yl)-6-methyl-3-(4-(trifluoromethyl)phenyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0861] Acryloyl chloride (99 mg, 1.09 mmol) was added to a stirred mixture of 6-methyl-1-(pyrrolidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one hydrochloride (290 mg, 0.73 mmol), sodium bicarbonate (310 mg, 3.69 mmol), DCM (20 mL) and water (10 mL) under nitrogen at 0 °C. The mixture was stirred at 0 °C for 30 min. The reaction was monitored by LCMS. Diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through a silica column (DCM:MeOH = 95:5) to give the title compound (148 mg) as a white solid.

[0862] LCMS [M+H] + = 418.22.

[0863] 1 H NMR (500 MHz, DMSO-d6) δ 8.48–8.41 (m, 2H), 8.37 (d, J = 3.6 Hz, 1H), 7.87 (dd, J = 8.5, 3.9 Hz, 2H), 6.63 (ddd, J = 51.4, 16.7, 10.3 Hz, 1H), 6.17 (ddd, J = 16.8, 7.9, 2.4 Hz, 1H), 5.90 (dp, J = 30.5, 5.2, 4.5 Hz, 1H), 5.69 (ddd, J = 27.3, 10.4, 2.4 Hz, 1H), 4.16–3.99 (m, 1H), 3.97–3.81 (m, 2H), 3.81–3.60 (m, 1H), 3.56 (s, 3H), 2.55 (d, J = 5.6 Hz, 1H), 2.44 (dd, J = 7.7, 5.7 Hz, 1H).

[0864] Synthesis of Compound 8 (2-Fluoro-1-(3-methyl-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one) in Example 8

[0865]

[0866] Step 1: Preparation of tert-butyl 3-methyl-3-((methylsulfonyl)methoxy)azetidine-1-carboxylate

[0867] Methanesulfonyl chloride (0.99 mL, 12.82 mmol) was added dropwise to a mixture containing tert-butyl 3-hydroxy-3-methylazetidine-1-carboxylate (2.00 g, 10.68 mmol), TEA (2.97 mL, 21.36 mmol), and dichloromethane (25 mL) under nitrogen at 0 °C. The reaction was allowed to warm to room temperature naturally and then stirred for 2 hours. The reaction was quenched by adding water to the mixture, and the mixture was extracted with dichloromethane. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain the title compound (2.81 g) as a yellow oily liquid, which could be directly used for the next step without purification.

[0868] Step 2: Preparation of tert-butyl 3-(3-bromo-1H-pyrazolo[3,4-b]pyridin-1-yl)-3-methylazetidine-1-carboxylate

[0869] A mixture of tert-butyl 3-methyl-3-((methylsulfonyl)methoxy)azetidine-1-carboxylate (2.81 g, 10.61 mmol), 3-bromo-1H-pyrazolo[3,4-b]pyridine (0.3 g, 1.51 mmol), cesium carbonate (2.47 g, 7.58 mmol), and DMF (20 mL) was stirred at 125 °C for 12 hours. After the reaction mixture was cooled to room temperature, it was poured into ice water, and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through a silica gel column (EA:Hex = 0%-30%) to obtain the title compound (0.2 g) as a pale yellow solid. LCMS [M+H] + = 367.07.

[0870] Step 3: Preparation of tert-butyl 3-methyl-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidine-1-carboxylate

[0871] Under nitrogen atmosphere, a mixture of tert-butyl 3-(3-bromo-1H-pyrazolo[3,4-b]pyridin-1-yl)-3-methylazetidine-1-carboxylate (0.2 g, 0.54 mmol), (4-(trifluoromethyl)phenyl)boronic acid (0.15 g, 0.82 mmol), potassium carbonate (0.15 g, 1.09 mmol), [PdCl2(dppf)]CH2Cl2 (0.04 g, 0.05 mmol), 1,4-dioxane (10 mL) and water (2 mL) was stirred at 100 °C for 4 h. After the reaction mixture was cooled to room temperature, it was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through a silica gel column (EA:Hex = 0%-10%) to give the title compound (0.15 g) as an off-white solid. LCMS [M+H] +

[0872] = 433.18.

[0873] Step 4: Preparation of 1-(3-methylazetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine

[0874] A mixture of tert-butyl 3-methyl-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidine-1-carboxylate (0.15 g, 0.35 mmol), dichloromethane (10 mL), and hydrochloric acid in 1,4-dioxane (1.77 mL, 4 M, 7.08 mmol) was stirred at room temperature for 1 h. The mixture was concentrated under vacuum. The residue was suspended in water and the pH was adjusted to 8-9 using saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (0.10 g) as a pale yellow solid, which was used directly in the next step without purification. LCMS [M+H] + = 333.12.

[0875] Step 5: Preparation of 2-fluoro-1-(3-methyl-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one

[0876] A mixture of 2-fluoroacrylic acid (0.03 g, 0.37 mmol), DMF (5.00 mL), DIEA (0.15 mL, 0.93 mmol), HATU (0.17 g, 0.46 mmol), and 1-(3-methylazetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine (0.1 g, 0.31 mmol) was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through a silica gel column (EA:Hex = 0%-10%) to give the title compound (20 mg) as a white solid.

[0877] LCMS[M+H] + = 405.13.

[0878] 1 H NMR (500 MHz, DMSO) δ 8.68 (dd, J = 12.7, 6.0 Hz, 1H), 8.28 (d, J = 7.9 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.43 (dd, J = 8.0, 4.5 Hz, 1H), 5.53 (dd, J = 48.4, 3.2 Hz, 1H), 5.39–5.20 (m, 1H), 4.95 (d, J = 10.6 Hz, 1H), 4.78 (d, J = 6.8 Hz, 1H), 4.39 (d, J = 10.5 Hz, 1H), 1.88 (s, 1H).

[0879] Synthesis of Compound 9 (2-fluoro-1-(2-methyl-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one) of Example 9

[0880]

[0881] Step 1: Preparation of tert-butyl 3-hydroxy-2-methylazetidine-1-carboxylate

[0882] Sodium borohydride (0.28 g, 7.29 mmol) was added portionwise to a solution of tert-butyl 2-methyl-3-oxoazetidine-1-carboxylate (0.90 g, 4.86 mmol) and methanol (20 mL) under nitrogen at 0 °C. The reaction was allowed to warm to room temperature naturally and then stirred for 3 h. Water was added to the reaction mixture to quench the reaction, and then concentrated under vacuum to remove methanol. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to give the title compound (0.80 g) as a white solid, which was used directly in the next step without purification. LCMS [M+H] + = 188.12.

[0883] Step 2: Preparation of methyl 3-((methylsulfonyl)methoxy)azetidine-1-carboxylate

[0884] Methanesulfonyl chloride (0.73 g, 6.41 mmol) was added dropwise to a mixture of tert-butyl 3-hydroxy-2-methylazetidine-1-carboxylate (0.80 g, 4.27 mmol), TEA (1.2 mL), and dichloromethane (20 mL) under nitrogen at 0 °C. The mixture was stirred at the same temperature for 2 h. Water was added to the reaction to quench the reaction at 0 °C, and then extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to give the title compound (1.00 g) as a white solid, which was used directly in the next step without purification.

[0885] Step 3: Preparation of tert-butyl 3-(3-bromo-1H-pyrazolo[3,4-b]pyridin-1-yl)-2-methylazetidine-1-carboxylate

[0886] A mixture of tert-butyl 2-methyl-3-((methylsulfonyl)methoxy)azetidine-1-carboxylate (1.0 g, 3.78 mmol), 3-bromo-1H-pyrazolo[3,4-b]pyridine (0.60 g, 3.03 mmol), cesium carbonate (1.97 g, 6.06 mmol), and DMF (20 mL) was stirred at 100 °C for 3 h. The reaction was cooled to room temperature and diluted with water. The mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column (EA:Hex = 0%-20%) to give the title compound (0.38 g) as a yellow solid. LCMS [M+H] + = 367.07.

[0887] Step 4: Preparation of tert-butyl 2-methyl-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidine-1-carboxylate

[0888] Under nitrogen atmosphere, a mixture of tert-butyl 3-(3-bromo-1H-pyrazolo[3,4-b]pyridin-1-yl)-2-methylazetidine-1-carboxylate (0.36 g, 0.98 mmol), (4-(trifluoromethyl)phenyl)boronic acid (0.23 g, 1.17 mmol), potassium carbonate (0.41 g, 2.93 mmol), Pd(dppf)Cl2CH2Cl2 (0.072 g, 0.10 mmol), 1,4-dioxane (20 mL) and water (4 mL) was stirred at 90 °C overnight. The mixture was cooled to room temperature and diluted with water. The mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through silica gel chromatography (EA:Hex = 0%-50%) to give the title compound (0.35 g) as a yellow solid. LCMS [M+H] + = 433.18.

[0889] Step 5: Preparation of 1-(2-methylazetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine

[0890] A mixture of tert-butyl 2-methyl-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidine-1-carboxylate (0.35 g, 0.69 mmol), dichloromethane (20 mL), and trifluoroacetic acid (0.77 mL) was stirred at room temperature for 2 h. The pH of the reaction mixture was adjusted with saturated sodium bicarbonate solution (50 mL). The mixture was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under vacuum to give the title compound (0.20 g) as a yellow solid, which was used directly in the next step without purification. LCMS [M+H] + = 333.12.

[0891] Step 6: Preparation of 2-fluoro-1-(2-methyl-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one

[0892] A mixture of 2-fluoroacrylic acid (0.11 g, 1.26 mmol), DMF (5.00 mL), DIEA (0.42 mL, 2.52 mmol), HATU (0.48 g, 1.26 mmol), and 1-(2-methylazetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine (0.20 g, 0.84 mmol) was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through silica gel chromatography (MeOH:DCM = 0%-3%) to give the title compound (0.18 g) as a white solid.

[0893] LCMS[M+H] + = 405.13.

[0894] 1 1H NMR (500 MHz, CDCl3-d3) δ 8.59–8.58 (m, 1H), 8.37–8.35 (m, 1H), 8.12–8.10 (m, 2H), 7.78–7.77 (m, 2H), 7.28–7.26 (m, 1H), 5.75–5.65 (m, 1H), 5.53–5.52 (m, 1H), 5.16–5.13 (m, 2H), 2.81 (s, 2H), 1.73–1.72 (m, 3H).

[0895] Synthesis of Compound 10 in Example 10 (2-Fluoro-N-(2-methyl-5-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl)acrylamide)

[0896]

[0897] Step 1: Preparation of 3-Bromo-1-(4-methyl-3-nitrophenyl)-1H-pyrazolo[3,4-b]pyridine

[0898] A mixture of 3-bromo-1H-pyrazolo[3,4-b]pyridine (0.50 g, 2.52 mmol), (4-methyl-3-nitro-phenyl)boronic acid (685.36 mg, 3.79 mmol), pyridine (0.50 g, 2.52 mmol), Cu(OAc)2 (0.92 g, 5.05 mmol), and DMF (20 mL) was stirred at 80 °C for 8 h under nitrogen. The mixture was diluted with ethyl acetate and filtered through diatomaceous earth. The filtrate was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by elution through silica gel chromatography (EA:Hex = 0%-20%) to give the title compound (0.65 g) as a white solid. LCMS[M+H]+ = 332.99.

[0899] Step 2: Preparation of 1-(4-methyl-3-nitrophenyl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine

[0900] Under nitrogen, 3-bromo-1-(4-methyl-3-nitrophenyl)-1H-pyrazolo[3,4-b]pyridine (0.35 g, 1.05 mmol), (4-(trifluoromethyl)phenyl)boronic acid (0.30 g, 1.58 mmol), potassium carbonate (0.44 g, 3.15 mmol), Pd(dppf)Cl2CH2Cl2 (0.085 g, 0.11 mmol), 1,4-dioxane (20 mL), and water (4 mL) were stirred at 90 °C for 4 h. After the mixture was cooled to room temperature, it was diluted with water and the mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through silica gel chromatography (EA:Hex = 0%-50%) to give the title compound (0.26 g) as a yellow solid. LCMS [M+H] + = 399.10.

[0901] Step 3: Preparation of 2-methyl-5-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)aniline A mixture of 1-(4-methyl-3-nitrophenyl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine (0.26 g, 0.88 mmol), EtOH (30 mL), H2O (10 mL), ammonium chloride (0.47 g, 8.79 mmol), and iron powder (0.25 g, 4.39 mmol) was stirred at 75 °C for 2 h. After the reaction mixture was cooled to room temperature, it was filtered through diatomaceous earth. The filtrate was concentrated under vacuum. The residue was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to give the title compound (0.20 g) as a brown solid, which could be directly used in the next step without purification. LCMS [M+H] + = 369.12.

[0902] Step 4: Preparation of 2-fluoro-N-(2-methyl-5-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl)acrylamide

[0903] A mixture of 2-fluoroacrylic acid (0.058 g, 0.65 mmol), DMF (20 mL), DIEA (0.27 mL, 1.63 mmol), HATU (0.27 g, 0.71 mmol), and 2-methyl-5-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)aniline (0.20 g, 0.54 mmol) was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through silica gel chromatography (MeOH:DCM = 0%-3%) to give the title compound (0.10 g) as a white solid.

[0904] LCMS[M+H] + = 441.13.

[0905] 1 H NMR (500 MHz, CDCl3-d3) δ 8.99–8.98 (m, 1H), 8.71–8.70 (m, 1H), 8.42–8.40 (m, 1H), 8.18–8.17 (m, 2H), 8.13–8.11 (m, 1H), 7.97 (s, 1H), 7.80–7.78 (m, 2H), 7.41–7.39 (m, 1H), 7.33–7.31 (m, 1H), 5.93–5.83 (m, 1H), 5.32–5.28 (m, 1H), 2.38 (s, 3H).

[0906] Synthesis of Compound 11 (2-fluoro-1-(3-(6-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one) of Example 11

[0907]

[0908] Step 1: Preparation of tert-butyl 3-(3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidine-1-carboxylate

[0909] A mixture of 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine (0.4 g, 1.54 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (0.7 g, 2.47 mmol), cesium carbonate (1.1 g, 3.4 mmol), and DMSO (20 ml) was stirred at 80 °C for 2 h. After the reaction mixture was cooled to room temperature, it was poured into ice water and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (EA:Hex = 0%-15%) elution to give the title compound (0.57 g) as a white solid. LCMS [M+H] + = 415.06.

[0910] Step 2: Preparation of tert-butyl 3-(6-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidine-1-carboxylate

[0911] A mixture of tert-butyl 3-(3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidine-1-carboxylate (0.25 g, 0.6 mmol), 4-(trifluoromethyl)aniline (0.29 g, 1.8 mmol), potassium phosphate (0.38 g, 1.8 mmol), XpHos (0.057 g, 0.12 mmol), Pd2dba3 (0.055 g, 0.06 mmol), and 1,4-dioxane (20 mL) was stirred at 100 °C for 8 h under nitrogen. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel chromatography (EA:Hex = 0%-30%) elution to give the title compound (0.19 g) as a white solid. LCMS [M+H] + = 448.46.

[0912] Step 3: Preparation of 1-(azetidin-3-yl)-6-methyl-N-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0913] A mixture of tert-butyl 3-(6-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidine-1-carboxylate (0.19 g, 0.43 mmol), dichloromethane (10 mL), and trifluoroacetic acid (0.3 mL, 4.29 mmol) was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum, saturated sodium carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to give the title compound (0.15 g) as a yellow solid, which was used directly in the next step without purification. LCMS [M+H] + = 348.14.

[0914] Step 4: Preparation of 2-fluoro-1-(3-(6-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one

[0915] A mixture of 2-fluoroacrylic acid (0.05 g, 0.56 mmol), DMF (10 mL), DIEA (0.21 mL, 1.3 mmol), HATU (0.24 g, 0.65 mmol), and 1-(azetidin-3-yl)-6-methyl-N-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-amine (0.15 g, 0.43 mmol) was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through silica gel chromatography (EA:Hex = 0%-20%) to give the title compound (10 mg) as a white solid.

[0916] LCMS [M+H] + = 420.14.

[0917] 1 H NMR (500 MHz, DMSO) δ 9.75 (s, 1H), 8.29 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 8.2 Hz, 1H), 5.80 (s, 1H), 5.56 (dd, J = 48.4, 3.5 Hz, 1H), 5.37 (dd, J = 16.5, 3.5 Hz, 1H), 4.89 (d, J = 7.5 Hz, 1H), 4.76 (d, J = 4.7 Hz, 1H), 4.54 (s, 1H), 4.45 (d, J = 5.2 Hz, 1H), 2.59 (s, 3H).

[0918] Synthesis of Compound 12 (2-Fluoro-1-(2-hydroxy-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one) in Example 12

[0919]

[0920] Step 1: tert-Butyl (3-((tert-butyldiphenylsilyl)methoxy)-2-hydroxypropyl)carbamate

[0921] At room temperature, tert-butyldiphenylsilyl chloride (1.58 g, 5.75 mmol) was added to a mixture containing tert-butyl (2,3-dihydroxypropyl)carbamate (1.00 g, 5.23 mmol) and imidazole (0.78 g, 11.50 mmol) in DMF (30 mL). The reaction was stirred overnight at room temperature. The reaction was monitored by LCMS. The reaction solution was quenched by adding water. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through silica gel chromatography (EA:Hex = 0%-30%) to obtain the title compound (2.1 g, 93%). LCMS [M+H] + = 430.23.

[0922] Step 2: Preparation of tert-Butyl (3-((tert-butyldiphenylsilyl)methoxy)-2-(3-iodo-1H-pyrazolo[3,4-b]pyridin-1-yl)propyl)carbamate

[0923] At 0 °C under nitrogen, DEAD (2.56 g, 14.69 mmol) was added dropwise to a mixture containing tert-butyl (3-((tert-butyldiphenylsilyl)methoxy)-2-hydroxypropyl)carbamate (2.1 g, 4.9 mmol), PPh3 (3.85 g, 14.69 mmol), 3-iodo-1H-pyrazolo[3,4-b]pyridine (1.20 g, 4.90 mmol), and THF (20 mL). After the reaction mixture was warmed to room temperature, it was stirred overnight. The reaction was monitored by LCMS. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The crude product was purified by elution through silica gel chromatography (EA:Hex = 0-30%) to obtain the title compound (2.22 g, 69%) as a red oil. LCMS [M+H] + = 657.17.

[0924] Preparation of tert-Butyl (3-((tert-Butyldiphenylsilyl)methoxy)-2-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)propyl)Carbamate

[0925] Under nitrogen atmosphere, a mixture of tert-Butyl (3-((tert-Butyldiphenylsilyl)methoxy)-2-(3-iodo-1H-pyrazolo[3,4-b]pyridin-1-yl)propyl)Carbamate (1 g, 1.52 mmol), (4-(trifluoromethyl)phenyl)boronic acid (0.40 g, 2.13 mmol), K2CO3 (0.63 g, 4.57 mmol), Pd(dppf)Cl2 (0.1 g, 0.23 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was stirred at 90 °C for 6 h. The mixture was concentrated under vacuum. The residue was further purified by elution with silica gel chromatography (EA:Hex = 0 - 20%) to obtain the title compound (0.65 g, 63%). LCMS [M+H] + = 675.29

[0926] Preparation of 3-((tert-Butyldiphenylsilyl)methoxy)-2-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)propan-1-amine

[0927] A mixture of tert-Butyl (3-((tert-Butyldiphenylsilyl)methoxy)-2-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)propyl)Carbamate (651 mg, 0.96 mmol), DCM (10 mL), and TFA (1 mL, 13.51 mmol) was stirred at room temperature for 4 h. The reaction was monitored by LCMS. The mixture was concentrated under vacuum. The residue was diluted with dichloromethane and the pH of the solution was adjusted to 10 with potassium carbonate solution. The mixture was extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain the title compound (542 mg, 98%), which could be directly used for the next step without purification. LCMS [M+H] + = 575.24

[0928] Preparation of N-(3-((tert-Butyldiphenylsilyl)methoxy)-2-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)propyl)-2-fluoropropenamide

[0929] A mixture of 2-fluoroacrylic acid (115 mg, 1.27 mmol), DIEA (0.42 mL, 2.55 mmol), HATU (387 mg, 1.02 mmol), DCM (20 mL), DMF (4 mL), and 3-((tert-butyldiphenylsilyl)methoxy)-2-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)propan-1-amine (488 mg, 0.85 mmol) was stirred at room temperature for 3 h. The reaction mixture was quenched with water. The mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through silica gel chromatography (EA:Hex = 0-20%) to give the title compound (300 mg). LCMS [M+H] + = 647.24.

[0930] Step 6: Preparation of 2-fluoro-N-(3-hydroxy-2-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)propyl)acrylamide

[0931] To a stirred solution of N-(3-((tert-butyldiphenylsilyl)methoxy)-2-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)propyl)-2-fluoroacrylamide (300 mg, 0.46 mmol) in THF (8 mL) was added TBAF (0.7 mL, 1 M in THF). The reaction was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The reaction mixture was poured into ice water and extracted with ethyl acetate, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through silica gel chromatography (EA:Hex = 0%-100%) to give the title compound (162 mg, 86%) as a white solid.

[0932] LCMS [M+H] + = 409.12.

[0933] 1 H NMR (500 MHz, DMSO) δ 8.70–8.58 (m, 3H), 8.27 (d, J = 6.0 Hz, 2H), 7.89 (d, J = 6.0 Hz, 2H), 7.35 (m, 1H), 5.49–5.33 (m, 1H), 5.32–5.23 (m, 1H), 5.15 (m, 1H), 5.04–4.91 (m, 1H), 4.05–3.97 (m, 1H), 3.96–3.88 (m, 1H), 3.84–3.76 (m, 1H), 3.71–3.62 (m, 1H).

[0934] Step 7: Preparation of 2-fluoro-1-(2-hydroxy-3-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one

[0935] To a stirred solution of 2-fluoro-N-(3-hydroxy-2-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)propyl)acrylamide (40 mg, 0.10 mmol) in DCM (10 mL) was added Dess-Martin periodinane (54 mg, 0.13 mmol). The reaction was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The reaction was quenched with sodium bicarbonate and sodium thiosulfate solution. The mixture was extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under vacuum. The residue was purified by preparative thin layer chromatography (Hex:EA = 1:1) to give the title compound (28 mg, 70%).

[0936] LCMS [M+H] + = 407.11.

[0937] 1 H NMR (500 MHz, DMSO) δ 8.65–8.54 (m, 2H), 8.39 (m, 1H), 8.26 (d, J = 8.1 Hz, 2H), 7.90 (m, 2H), 7.34 (m, 1H), 5.37–5.24 (m, 1H), 5.16 (m, 1H), 5.07 (dd, J = 15.7, 3.3 Hz, 1H), 4.09 (q, J = 5.2 Hz, 1H), 3.96–3.84 (m, 2H).

[0938] Synthesis of Compound 13 of Example 13 (N-(1-(3-(4-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridin-1-yl)azetidin-3-yl)acrylamide)

[0939]

[0940] Step 1: Preparation of 7-bromo-9-[4-(trifluoromethyl)phenyl]-1,8-diazabicyclo[4.3.0]non-2,4,6,8-tetraene

[0941] Under nitrogen, a mixture of 7,9-dibromo-1,8-diazabicyclo[4.3.0]non-2,4,6,8-tetraene (0.70 g, 2.54 mmol), [4-(trifluoromethyl)phenyl]boronic acid (0.48 g, 2.54 mmol), Pd(PPh₃)₄ (0.15 g, 0.13 mmol), K₂CO₃ (0.70 g, 5.07 mmol), 1,4-dioxane (4 mL), and water (1 mL) was stirred at 85 °C for 2 h. The reaction was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through silica gel chromatography (n-hexane / ethyl acetate = 5 / 1) to give the title compound (0.50 g, 57.78%) as a brown solid. LCMS [M+H] + = 342.13.

[0942] Step 2: Preparation of tert-butyl N-[1-[9-[4-(trifluoromethyl)phenyl]-1,8-diazabicyclo[4.3.0]non-2,4,6,8-tetraen-7-yl]azetidin-3-yl]carbamate

[0943] A mixture of 7-bromo-9-[4-(trifluoromethyl)phenyl]-1,8-diazabicyclo[4.3.0]non-2,4,6,8-tetraene (0.50 g, 1.47 mmol), tert-butyl N-(azetidin-3-yl)carbamate (0.25 g, 1.47 mmol), XantPhos (0.08 g, 0.15 mmol), Pd₂(dba)₃ (0.13 g, 0.15 mmol), and Cs₂CO₃ (0.96 g, 2.93 mmol) in 1,4-dioxane (5.00 mL) was degassed with nitrogen and stirred at 80 °C overnight. After completion, the reaction was cooled to room temperature and extracted 3 times with EA. The organic phase was concentrated under reduced pressure. The residue was purified by elution through silica gel chromatography (hexane / EA = 10 / 1) to give the title compound (0.40 g, 63.11%) as a yellow solid.

[0944] LCMS [M+H] + = 433.45.

[0945] Step 3: Preparation of 1-[9-[4-(trifluoromethyl)phenyl]-1,8-diazabicyclo[4.3.0]non-2,4,6,8-tetraen-7-yl]azetidin-3-amine

[0946] To a solution of tert-butyl N-[1-[9-[4-(trifluoromethyl)phenyl]-1,8-diazabicyclo[4.3.0]non-2,4,6,8-tetraen-7-yl]azetidin-3-yl]carbamate (0.20 g, 0.46 mmol) in DCM (2.00 mL) was added dropwise TFA (0.03 mL, 0.46 mmol) and the mixture was stirred at room temperature for 2 hours. After completion, the pH of the reaction was adjusted to 7 and extracted with DCM, then concentrated. The residue was used directly for the next step without purification. LCMS [M+H] + = 333.33.

[0947] Step 4: Preparation of N-[1-[9-[4-(trifluoromethyl)phenyl]-1,8-diazabicyclo[4.3.0]non-2,4,6,8-tetraen-7-yl]azetidin-3-yl]prop-2-enamide

[0948] To a solution of 1-[9-[4-(trifluoromethyl)phenyl]-1,8-diazabicyclo[4.3.0]non-2,4,6,8-tetraen-7-yl]azetidin-3-amine (0.10 g, 0.30 mmol) and TEA (0.08 mL, 0.60 mmol) in DCM (3 mL) at 0 °C was added prop-2-enoyl chloride (0.03 g, 0.30 mmol) and the mixture was stirred at room temperature for 0.5 hour. After completion, the reaction was quenched with water and extracted with DCM. The combined organic phases were concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography to give the title compound (10 mg, 8.6%) as an off-white solid.

[0949] LCMS [M+H] + = 387.38.

[0950] Synthesis of Compound 14 of Example 14 (N-(1-(1-acryloylazetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-7-yl)methanesulfonamide)

[0951]

[0952] Step 1: Preparation of 3-iodo-7-nitro-1H-indazole

[0953] A mixture of 7-nitro-1H-indazole (2.00 g, 12.26 mmol), KOH (2.75 g, 49.04 mmol) and I2 (1.56 g, 12.26 mmol) in DMF (10.00 mL) was stirred at room temperature overnight. After completion, the reaction mixture was diluted with water and extracted 3 times with EA. The combined organic phases were concentrated. The residue was purified by elution through silica gel chromatography to give the title compound (2.50 g, 70.55%) as a brown solid. LCMS [M+H]+ = 290.03.

[0954] Step 2: Preparation of tert-butyl 3-(3-iodo-7-nitro-1H-indazol-1-yl)azetidine-1-acetate

[0955] A mixture of 3-iodo-7-nitro-1H-indazole (1.00 g, 3.46 mmol), tert-butyl 3-bromoazetidine-1-acetate (0.98 g, 4.15 mmol), and Cs2CO3 (2.25 g, 6.92 mmol) in DMF (10.00 mL) was stirred at 100 °C for 3 hours. After completion, the reaction was cooled to room temperature, diluted with water, and extracted 3 times with EA. The organic phase was concentrated under reduced pressure. The residue was purified by elution through silica gel chromatography (hexane / EA = 10 / 1) to give the title compound (1.00 g, 65.07%) as a brown solid. LCMS [M+H] + = 445.23.

[0956] Step 3: Preparation of tert-butyl 3-(7-nitro-3-(4-(trifluoromethyl)phenyl)-1H-indazol-1-yl)azetidine-1-acetate

[0957] A mixture of tert-butyl 3-(3-iodo-7-nitro-indazol-1-yl)azetidine-1-acetate (1.00 g, 2.25 mmol), [4-(trifluoromethyl)phenyl]boronic acid (0.43 g, 2.25 mmol), Pd(PPh3)4 (0.13 g, 0.11 mmol), and K2CO3 (0.62 g, 4.50 mmol) in dioxane (5.00 mL) and water (1.00 mL) was degassed with nitrogen and stirred at 80 °C overnight. After completion of the reaction, the reaction was cooled to room temperature and extracted 3 times with EA. The organic phase was concentrated under reduced pressure. The residue was purified by elution through silica gel chromatography (hexane / EA = 3 / 1) to give the title compound (0.40 g, 38.42%) as a yellow solid. LCMS [M+H] + = 463.43.

[0958] Step 4: Preparation of 1-(azetidin-3-yl)-7-nitro-3-[4-(trifluoromethyl)phenyl]indazole

[0959] TFA (0.32 mL, 4.33 mmol) was added to a solution of tert-butyl 3-[7-nitro-3-[4-(trifluoromethyl)phenyl]indazol-1-yl]azetidine-1-acetate in DCM (4.00 mL), and the mixture was stirred at room temperature for 2 hours. After completion, the pH of the reaction mixture was adjusted to 7, and the mixture was extracted with DCM and concentrated. The residue (0.25 g, 79.77%) was used directly in the next step without purification. LCMS [M+H] += 363.31.

[0960] Step 5: Preparation of 1-[3-[7-nitro-3-[4-(trifluoromethyl)phenyl]indazol-1-yl]azetidin-1-yl]prop-2-en-1-one

[0961] At 0 °C, prop-2-enoyl chloride (0.07 g, 0.76 mmol) was added dropwise to a solution of 1-(azetidin-3-yl)-7-nitro-3-[4-(trifluoromethyl)phenyl]indazole (0.25 g, 0.69 mmol) and TEA (0.19 mL, 1.38 mmol) in DCM (4 mL), and the mixture was stirred at room temperature for 0.5 h. After completion, the reaction was quenched with water and extracted with DCM. The combined organic phases were concentrated under reduced pressure. The residue could be used for the next step without purification. LCMS [M+H] + = 417.36.

[0962] Step 6: Preparation of 1-[3-[7-amino-3-[4-(trifluoromethyl)phenyl]indazol-1-yl]azetidin-1-yl]prop-2-en-1-one

[0963] A mixture of 1-[3-[7-nitro-3-[4-(trifluoromethyl)phenyl]indazol-1-yl]azetidin-1-yl]prop-2-en-1-one (0.20 g, 0.48 mmol), Fe (0.08 g, 1.44 mmol), and NH4Cl (0.03 g, 0.58 mmol) in EtOH / H2O (4 / 1 mL) was stirred at 80 °C for 1 h. After completion, the reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by elution with silica gel chromatography (PE / EA = 3 / 1) to obtain the title product (0.17 g, 91.59%) as a brown solid. LCMS [M+H] + = 387.38.

[0964] Step 7: Preparation of N-(1-(1-acryloylazetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-7-yl)methanesulfonamide

[0965] Methanesulfonyl chloride (0.02 g, 0.17 mmol) was added to a solution of 1-[3-[7-amino-3-[4-(trifluoromethyl)phenyl]indazol-1-yl]azetidin-1-yl]prop-2-en-1-one (0.05 g, 0.13 mmol) and TEA (0.06 g, 0.26 mmol) in DCM (3 mL), and the mixture was stirred for 1 h. After completion, water was added to the reaction mixture, and the organic phase was separated and concentrated. The residue was purified by preparative thin-layer chromatography to obtain the title product (5.8 mg, 9%) as a solid. LCMS [M+H] + = 465.46.

[0966] Synthesis of Compound 15 in Example 15 (N-(1-(1-Acryloylazetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-7-yl)acetamide)

[0967]

[0968] Step 1: Preparation of N-(1-(1-Acryloylazetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1H-indazol-7-yl)acetamide

[0969] A mixture of 1-[3-[7-Amino-3-[4-(trifluoromethyl)phenyl]indazol-1-yl]azetidin-1-yl]prop-2-en-1-one (170.00 mg, 0.44 mmol) and Ac2O (0.04 mL, 0.44 mmol) in DCM (2.00 mL) was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the organic phase was separated and concentrated. The residue was purified by preparative thin-layer chromatography to obtain the title product (3.00 mg, 1.59%) as a white solid. LCMS [M+H] + = 429.42.

[0970] The compounds in Table 1 were prepared by a method similar to that of Examples 1-15 using different reaction starting materials and appropriate reagents.

[0971] Table 1

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997]

[0998] Synthesis of Example 229 Compound 229 (1-(1-(2-Fluoropropenoyl)azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one)

[0999]

[1000] Step 1: Preparation of tert-Butyl 3-((2-Nitrophenyl)amino)azetidine-1-acetate

[1001] A mixture of 1-Fluoro-2-nitrobenzene (10.0 g, 70.87 mmol), tert-Butyl 3-aminoazetidine-1-acetate (24.41 g, 141.74 mmol), Potassium carbonate (29.39 g, 212.62 mmol), and DMF (200 mL) was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. The reaction mixture was poured into ice water. The mixture was filtered. The filter cake was washed with water and dried under vacuum to give the title compound (18.12 g) as a yellow solid, which was used directly in the next step without further purification. LCMS [M+H] +

[1002] = 238.32.

[1003] Step 2: Preparation of tert-butyl 3-((2-aminophenyl)amino)azetidine-1-acetate

[1004] A mixture of tert-butyl 3-((2-nitrophenyl)amino)azetidine-1-acetate (8.00 g, 27.27 mmol), Pd / C (1.0 g, 10%), and MeOH (100 mL) was stirred overnight at room temperature under hydrogen. The reaction was monitored by LCMS. The mixture was filtered. The filtrate was concentrated under vacuum to give the title compound (10.50 g) as an off-white solid, which was used directly in the next step without further purification. LCMS [M+H] + = 264.42.

[1005] Step 3: Preparation of tert-butyl 3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)azetidine-1-acetate

[1006] A mixture of tert-butyl 3-((2-aminophenyl)amino)azetidine-1-acetate (10.00 g, 37.97 mmol), DMF (50 mL), and 1,1'-carbonyldiimidazole (12.31 g, 75.95 mmol) was stirred at 100 °C for 2 h. The reaction was monitored by LCMS. The reaction was cooled to room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through silica gel chromatography (hexane:ethyl acetate = 2:1) to give the title compound (6.10 g) as an off-white solid. LCMS [M+H] + = 234.34.

[1007] Step 4: Preparation of tert-butyl 3-(2-oxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)azetidine-1-acetate

[1008] Under an oxygen atmosphere, a mixture of tert-butyl 3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)azetidine-1-acetate (6.00 g, 20.74 mmol), (4-(trifluoromethyl)phenyl)boronic acid (5.91 g, 31.11 mmol), DIPEA (8.04 g, 62.21 mmol), Cu(OAc)2 (3.77 g, 20.74 mmol), and DCM (60 mL) was stirred at room temperature for 8 h. The reaction was monitored by LCMS. The mixture was filtered through celite. The filtrate was washed with brine, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under vacuum. The residue was purified by elution with silica gel chromatography (hexane:ethyl acetate = 3:1) to give the title compound (7.65 g) as a blue oil. LCMS [M+H] + = 378.42.

[1009] Step 5: Preparation of 1-(azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1010] A mixture of tert-butyl 3-(2-oxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)azetidine-1-acetate (7.65 g, 17.65 mmol), TFA (38.0 mL), and DCM (75 mL) was stirred at room temperature for 8 h. The reaction was monitored by LCMS. The reaction mixture was concentrated under vacuum. The residue was diluted with dichloromethane and the pH was adjusted to 10 with saturated sodium carbonate solution. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to give the title compound (4.25 g) as an off-white solid, which was used directly in the next step without further purification. LCMS [M+H] + = 334.31.

[1011] Step 6: Preparation of 1-(1-(2-fluoropropanoyl)azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1012] 1-(azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (2.80 g, 8.40 mmol), DIPEA (3.26 g, 25.20 mmol), DCM (20 mL), 2-fluoroacrylic acid (1.13 g, 12.60 mmol), and HATU (3.19 g, 8.40 mmol) were stirred at room temperature for 2 h. The reaction was monitored by LCMS. The mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under vacuum. The residue was purified by elution with silica gel chromatography (n-hexane:ethyl acetate = 2:1) to give the title compound (1.32 g) as a white solid.

[1013] LCMS[M+H] + = 406.46.

[1014] 1 1H NMR (500 MHz, DMSO-d6) δ 7.96 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 7.8 Hz, 1H), 7.27–7.18 (m, 2H), 7.14 (td, J = 7.7, 1.1 Hz, 1H), 5.55 (dd, J = 48.4, 3.5 Hz, 1H), 5.43 (tt, J = 8.7, 5.7 Hz, 1H), 5.36 (dd, J = 16.5, 3.5 Hz, 1H), 5.03–4.69 (m, 2H), 4.65–4.40 (m, 2H).

[1015] Synthesis of Compound 230 (2-fluoro-1-(3-(4-(4-(trifluoromethyl)phenyl)quinazolin-2-yl)azetidin-1-yl)prop-2-en-1-one) of Example 230

[1016]

[1017] Step 1: Preparation of tert-butyl 3-((3-nitropyridin-2-yl)amino)azetidine-1-acetate

[1018] tert-Butyl 3-aminoazetidine-1-acetate (5.45 g, 31.76 mmol), 2-fluoro-3-nitropyridine (3.0 g, 21.11 mmol), potassium carbonate (8.75 g, 63.34 mmol), and DMF (20 mL) were stirred at 20 °C for 2 h. The reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under vacuum to give the title compound (9.25 g) as a yellow oily liquid, which was used directly in the next step without further purification. LCMS[M+H] += 239.42.

[1019] Step 2: Preparation of tert-butyl 3-((3-aminopyridin-2-yl)amino)azetidine-1-acetate

[1020] A mixture of tert-butyl 3-((3-nitropyridin-2-yl)amino)azetidine-1-acetate (9.25 g, 31.43 mmol), Pd / C (1.50 g, 10%), and MeOH (100 mL) was stirred overnight at room temperature under hydrogen. The reaction was monitored by LCMS. After filtering the mixture, the filtrate was concentrated under vacuum to give the title compound (6.50 g) as a brown solid, which was used directly in the next step without further purification. LCMS [M+H] + = 265.42.

[1021] Step 3: Preparation of tert-butyl 3-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)azetidine-1-acetate

[1022] A mixture of tert-butyl 3-((3-aminopyridin-2-yl)amino)azetidine-1-acetate (5.20 g, 19.67 mmol), DMF (25 mL), and 1,1'-carbonyldiimidazole (9.57 g, 59.02 mmol) was stirred overnight at 65 °C. The reaction was monitored by LCMS. The reaction was cooled to room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through silica gel chromatography (hexane:ethyl acetate = 2:1) to give the title compound (4.25 g) as a brown foam. LCMS [M+H] + = 235.34.

[1023] Step 4: Preparation of tert-butyl 3-(2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)azetidine-1-acetate

[1024] Under oxygen conditions, tert-butyl 3-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)azetidine-1-acetate (3.52 g, 12.12 mmol), (4-(trifluoromethyl)phenyl)boronic acid (4.61 g, 24.25 mmol), TEA (6.13 g, 60.62 mmol), Cu(OAc)2 (2.20 g, 12.12 mmol), 4A powdered molecular sieve (7.0 g) and DCM (40 mL) were stirred at room temperature for 8 hours. The reaction was monitored by LCMS. The mixture was filtered through diatomaceous earth and the cake was washed with DCM. The filtrate was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by elution with silica gel chromatography (hexane:ethyl acetate = 2:1) to obtain the title compound (5.50 g) as a yellow solid. LCMS [M+H] + = 379.42.

[1025] Step 5: Preparation of 3-(azetidin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[1026] A mixture of tert-butyl 3-(2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)azetidine-1-acetate (5.50, 12.66 mmol), TFA (28.0 mL) and DCM (60 mL) was stirred at room temperature for 8 hours. The reaction was monitored using LCMS. The reaction mixture was concentrated under vacuum. The residue was dissolved in dichloromethane and the pH was adjusted to 10 with saturated sodium carbonate solution. The mixture was extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain the title compound (4.50 g) as a yellow solid, which could be used directly in the next step without further purification. LCMS [M+H] + = 335.31.

[1027] Step 6: Preparation of 3-(1-(2-fluoropropenoyl)azetidin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[1028] A mixture of 2-fluoroacrylic acid (1.82 g, 20.19 mmol), DCM (45 mL), DIPEA (5.22 g, 40.38 mmol), HATU (4.50 g, 40.38 mmol), and 3-(azetidin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (4.50 g, 13.46 mmol) was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through silica gel chromatography (hexane:ethyl acetate = 2:1) to give the title compound (3.40 g) as a white solid.

[1029] LCMS[M+H] + = 407.46.

[1030] 1 1H NMR (500 MHz, DMSO-d6) δ 8.13 (dd, J = 5.2, 1.4 Hz, 1H), 7.96 (d, J = 8.7 Hz, 2H), 7.86 (d, J = 8.3 Hz, 2H), 7.58 (dd, J = 7.8, 1.4 Hz, 1H), 7.21–7.11 (m, 1H), 5.62–5.43 (m, 2H), 5.34 (dd, J = 16.5, 3.4 Hz, 1H), 5.10–5.01 (m, 1H), 4.83–4.67 (m, 2H), 4.47–4.35 (m, 1H).

[1031] Synthesis of Compound 231 (1-(3-(2-imino-3-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)azetidin-1-yl)prop-2-en-1-one) in Example 231

[1032]

[1033] Step 1: Preparation of 1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-imine

[1034] A mixture of 3H-benzoimidazo[1,2-a]pyridin-2-amine (1.00 g, 7.51 mmol), 4-[4-(trifluoromethyl)phenyl]boronic acid (1.71 g, 9.01 mmol), Cu(OAc)2 (0.27 g, 1.50 mmol), and TEA (3.13 mL, 22.53 mmol) in DCM (10 mL) was stirred at room temperature for 4 h. The reaction mixture was filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography eluting with a hexane solution of ethyl acetate (0%-50%) to give the title product (1.50 g, 72%) as a brown solid. LCMS [M+H] + = 278.25.

[1035] Step 2: Preparation of tert-butyl 3-(2-imino-3-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazo[1,1-a]pyridin-1-yl)azetidine-1-acetate

[1036] A mixture of 1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazo[1,2-a]pyridin-2-imine (0.10 g, 0.36 mmol), tert-butyl 3-iodoazetidine-1-acetate (0.12 g, 0.43 mmol), and Cs2CO3 (0.23 g, 0.72 mmol) in DMF (3 mL) was stirred at 100 °C for 4 h. The reaction was cooled to room temperature and quenched by the addition of water. The mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography eluting with a hexane solution of ethyl acetate (0%-30%) to give the title compound (80 mg, 51%) as a brown solid. LCMS [M+H] + = 433.45.

[1037] Step 3: Preparation of 1-(azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazo[1,2-a]pyridin-2-imine

[1038] A mixture of tert-butyl 3-(2-imino-3-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazo[1,1-a]pyridin-1-yl)azetidine-1-acetate (80 mg, 0.18 mmol), DCM (5 mL), and TFA (0.14 mL, 1.85 mmol) was stirred at room temperature for 1 h. The pH was adjusted with aqueous sodium carbonate, and the mixture was extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to give the title compound (50 mg) as a yellow solid, which was used directly in the next step without further purification. LCMS [M+H] + = 333.33.

[1039] Step 4: Preparation of 1-(3-(2-imino-3-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)azetidin-1-yl)prop-2-en-1-one

[1040] At 0 °C under nitrogen, acryloyl chloride (16.30 mg, 0.18 mmol) was added dropwise to a solution containing 1-(azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-imine (50.00 mg, 0.15 mmol), TEA (0.04 mL, 0.30 mmol), and DCM (4 mL). The reaction mixture was stirred at room temperature for 0.5 h. The reaction was quenched by adding water. The mixture was extracted with dichloromethane. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by preparative thin layer chromatography (hexane / EA = 2 / 1) to give the title product (3.00 mg, 5%) as an off-white solid. LCMS [M+H] + = 387.38

[1041] The compounds in Table 2 were prepared by a method similar to that of Examples 1-235 using different reaction starting materials and appropriate reagents.

[1042] Table 2

[1043]

[1044]

[1045]

[1046]

[1047] Synthesis of Compound 254 of Example 254 (N-(1-(2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)pyrrolidin-3-yl)acrylamide)

[1048]

[1049] Step 1: Preparation of tert-butyl (1-(2-chloroquinazolin-4-yl)pyrrolidin-3-yl)carbamate

[1050] A mixture of 2,4-dichloroquinazoline (1.00 g, 5.02 mmol), tert-butyl 3-aminoazetidine-1-carboxylate (0.65 g, 3.77 mmol), carbonate (1.40 g, 7.54 mmol) and DMF (10 mL) was stirred at 45 °C for 3 hours. The reaction was monitored by LCMS. The reaction mixture was diluted with ethyl acetate and poured into ice water. The organic layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound (1.30 g) as a yellow solid. LCMS [M+H] + = 293.12.

[1051] Step 2: Preparation of tert-butyl (1-(2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)pyrrolidin-3-yl)carbamate

[1052] A mixture of tert-butyl (1-(2-chloroquinazolin-4-yl)pyrrolidin-3-yl)carbamate (1.30 g, 3.73 mmol), (4-(trifluoromethyl)phenyl)boronic acid (1.06 g, 5.59 mmol), Pd(dppf)Cl2·CH2Cl2 (303 mg, 0.37 mmol), cesium carbonate (3.64 g, 11.18 mmol), 1,4-dioxane (20 mL) and water (2.0 mL) was stirred at 100 °C for 6 hours under nitrogen. The reaction was monitored by LCMS. The reaction was cooled to room temperature. The mixture was concentrated in vacuo. The residue was purified by elution through a silica gel column (Hex:EA = 0%-30%) to give the title compound (1.30 g) as an off-white solid. LCMS [M+H] + = 403.42.

[1053] Step 3: Preparation of 1-(2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)pyrrolidin-3-amine

[1054] A mixture of tert-butyl (1-(2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)pyrrolidin-3-yl)carbamate (500 mg, 1.09 mmol), TFA (5 mL) and DCM (20 mL) was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. The reaction mixture was concentrated in vacuo to give the title compound (600 mg) as an off-white solid, which could be used in the next step without further purification. LCMS [M+H] + = 359.26.

[1055] Step 4: Preparation of N-(1-(2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)pyrrolidin-3-yl)acrylamide

[1056] At 0 °C under nitrogen atmosphere, acryloyl chloride (76 mg, 0.83 mmol) was added to a mixture containing 1-(2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)pyrrolidin-3-amine (300 mg, 0.83 mmol), sodium bicarbonate (350 mg, 4.19 mmol), DCM (20 mL) and water (10 mL) with stirring. The mixture was stirred at 0 °C for 30 minutes. The reaction was monitored by LCMS. The reaction mixture was washed with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through a silica gel column (n-hexane:ethyl acetate = 2:1) to obtain the title compound (113 mg) as an off-white solid.

[1057] LCMS[M+H] + = 413.33.

[1058] 1 H NMR (500 MHz, DMSO-d6) δ 8.68 (d, J = 8.1 Hz, 2H), 8.50 (d, J = 6.6 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.90–7.84 (m, 3H), 7.81 (t, J = 7.6 Hz, 1H), 7.51 (ddd, J = 8.5, 6.7, 1.6 Hz, 1H), 6.23 (dd, J = 17.1, 9.9 Hz, 1H), 6.13 (dd, J = 17.1, 2.4 Hz, 1H), 5.62 (dd, J = 10.0, 2.5 Hz, 1H), 4.52 (p, J = 5.5 Hz, 1H), 4.26 (dd, J = 11.8, 6.0 Hz, 1H), 4.15 (q, J = 7.7, 5.8 Hz, 1H), 4.12–4.03 (m, 1H), 3.89 (dd, J = 11.6, 4.0 Hz, 1H), 2.27 (pd, J = 9.2, 8.4, 5.5 Hz, 1H), 2.06 (dq, J = 11.8, 5.5 Hz, 1H).

[1059] Synthesis of Compound 255 (2-Fluoro-1-(3-((2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)amino)azetidin-1-yl)prop-2-en-1-one), Example 255

[1060]

[1061] Step 1: Preparation of tert-Butyl 3-((2-chloroquinazolin-4-yl)amino)azetidine-1-carboxylate

[1062] A mixture of 2,4-dichloroquinazoline (500 mg, 2.51 mmol), tert-butyl pyrrolidin-3-ylcarbamate (4.91 g, 15.07 mmol), potassium carbonate (1.04 g, 7.54 mmol) and DMF (10 mL) was stirred at room temperature for 3 h. The reaction was monitored by LCMS. After the reaction was washed with ethyl acetate, it was poured into ice water. The organic phase was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (0.80 g) as a yellow solid. LCMS [M+H] + = 335.54.

[1063] Step 2: Preparation of tert-butyl 3-((2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)amino)azetidine-1-carboxylate

[1064] Under nitrogen, a mixture of tert-butyl 3-((2-chloroquinazolin-4-yl)amino)azetidine-1-carboxylate (0.80 g, 2.39 mmol), (4-(trifluoromethyl)phenyl)boronic acid (0.68 g, 3.58 mmol), Pd(dppf)Cl2·CH2Cl2 (0.20 mg, 0.24 mmol), potassium carbonate (0.99 g, 7.17 mmol), 1,4-dioxane (20 mL) and water (2.0 mL) was stirred at 100 °C for 6 h. The reaction was monitored by LCMS. The reaction was cooled to room temperature. The mixture was concentrated under vacuum. The residue was purified by elution through a silica gel column (Hex:EA = 0%-30%) to give the title compound (0.75 g) as an off-white solid. LCMS [M+H] + = 445.43.

[1065] Step 3: Preparation of N-(azetidin-3-yl)-2-(4-(trifluoromethyl)phenyl)quinazolin-4-amine

[1066] A mixture of tert-butyl 3-((2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)amino)azetidine-1-carboxylate (750 mg, 1.69 mmol), TFA (5 mL) and DCM (20 mL) was stirred at room temperature for 4 h. The reaction was monitored by LCMS. The reaction mixture was concentrated under vacuum to give the title compound (600 mg) as a yellow oil, which was used directly in the next step without further purification. LCMS [M+H] + = 345.35.

[1067] Step 4: Preparation of 2-fluoro-1-(3-((2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)amino)azetidin-1-yl)prop-2-en-1-one

[1068] To a mixture of N-(azetidin-3-yl)-2-(4-(trifluoromethyl)phenyl)quinazolin-4-amine (300 mg, 0.87 mmol), N,N-diisopropylethylamine (563 mg, 4.36 mmol), 2-fluoroacrylic acid (118 mg, 1.31 mmol) and DMF (5 mL) was added HATU (663 mg, 1.74 mmol) with stirring, and the reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through a silica gel column (n-hexane:ethyl acetate = 1.5:1) to give the title compound (57 mg) as an off-white solid.

[1069] LCMS[M+H] + = 417.43.

[1070] 1 H NMR (500 MHz, CDCl3) δ 8.62 (d, J = 8.1 Hz, 2H), 7.98–7.96 (m, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.82–7.79 (m, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.52 (t, J = 7.6 Hz, 1H), 6.62 (m, 1H), 5.71–5.41 (m, 1H), 5.22–5.10 (m, 1H), 5.00–4.86 (m, 1H), 4.69–4.45 (m, 2H), 4.31–3.97 (m, 1H), 3.67–3.31 (m, 1H).

[1071] Synthesis of Compound 256 (2-fluoro-1-(3-(2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)azetidin-1-yl)prop-2-en-1-one), Example 256

[1072]

[1073] Step 1: Preparation of tert-butyl 3-(hydroxy(2-nitrophenyl)methyl)azetidine-1-acetate

[1074] At -60 °C under nitrogen, pHMgCl (7.23 mL, 2.00 mol / L, 14.46 mmol) was added dropwise to a solution of 1-iodo-2-nitrobenzene (3.00 g, 12.05 mmol) in THF (50 mL). The reaction was stirred at -60 °C for 30 minutes. Then a solution of tert-butyl 3-formylazetidine-1-carboxylate (2.68 g, 14.46 mmol) in THF (6 mL) was added to the reaction. The mixture was warmed to room temperature and stirred for an additional 1 hour. The reaction was monitored by LCMS. Saturated NH4Cl solution was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through silica gel chromatography (EA:Hex = 0-50%) to give the title compound (3.65 g, 98%) as a yellow solid. LCMS [M+H] + = 309.14.

[1075] Step 2: Preparation of tert-butyl 3-(2-nitrobenzoyl)azetidine-1-carboxylate

[1076] At 0 °C under nitrogen, Dess-Martin reagent (6.62 g, 15.60 mmol) was added to a stirred solution of tert-butyl 3-(hydroxy(2-nitrophenyl)methyl)azetidine-1-carboxylate (3.7 g, 12.00 mmol) in DCM (50 mL). The reaction was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. Saturated aqueous sodium bicarbonate and saturated aqueous sodium thiosulfate were added to quench the reaction. The mixture was extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through silica gel chromatography (EA:Hex = 0-30%) to give the title compound (3.4 g, 92.5%) as a yellow oil. LCMS [M+H] + = 307.12.

[1077] Step 3: Preparation of tert-butyl 3-(2-aminoaminobenzoyl)azetidine-1-carboxylate

[1078] A mixture of tert-butyl 3-(2-nitrobenzoyl)azetidine-1-carboxylate (3.40 g, 11.10 mmol), iron powder (3.10 g, 55.50 mmol), and NH4Cl (2.97 g, 55.50 mmol) in EtOH (20 mL) and water (5 mL) was stirred at 80 °C for 3 hours. The reaction was monitored by LCMS. The reaction mixture was cooled to room temperature and filtered through a pad of diatomaceous earth. The filtrate was concentrated under vacuum. The residue was purified by elution through silica gel column chromatography (EA:Hex = 0-70%) to give the title compound (2.2 g, 72%) as a yellow oil. LCMS [M+H] += 277.15.

[1079] Step 4: Preparation of tert-Butyl 3-(2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)azetidine-1-carboxylate

[1080] A mixture of tert-butyl 3-(2-aminobenzyl)azetidine-1-carboxylate (600 mg, 2.17 mmol), 2-amino-2-(4-(trifluoromethyl)phenyl)acetic acid (714 mg, 3.26 mmol), I2 (138 mg, 1.09 mmol), and 2-hydroperoxy-2-methylpropane (TBHP) (391 mg, 4.34 mmol) in DMA (15 mL) was stirred at 80 °C for 14 h. The reaction was monitored by LCMS. The reaction was quenched by adding water and ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through silica gel chromatography (EA:Hex = 0 - 30%) to give the title compound (610 mg, 65%) as a yellow oil. LCMS [M+H] + = 430.17.

[1081] Step 5: Preparation of 4-(Azetidin-3-yl)-2-(4-(trifluoromethyl)phenyl)quinazoline

[1082] A mixture of tert-butyl 3-(2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)azetidine-1-carboxylate (610 mg, 1.42 mmol), dichloromethane (5 mL), and TFA (1 mL, 14.21 mmol) was stirred at room temperature for 6 h. The mixture was concentrated under vacuum. The residue was dissolved in dichloromethane. The pH of the solution was adjusted to 10 with aqueous potassium carbonate solution. The mixture was extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (460 mg) as a yellow solid, which could be used directly in the next step without purification. LCMS [M+H]+ = 330.11.

[1083] Step 6: Preparation of 2-Fluoro-1-(3-(2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)azetidin-1-yl)prop-2-en-1-one

[1084] A mixture of 4-(azetidin-3-yl)-2-(4-(trifluoromethyl)phenyl)quinazoline (460 mg, 1.40 mmol), 2-fluoroacrylic acid (377 mg, 4.19 mmol), DIEA (1.39 mL, 8.38 mmol), dichloromethane (10 mL), DMF (2 mL), and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (BOP) (741 mg, 1.68 mmol) was stirred at room temperature for 3 h. The reaction was monitored by LCMS. The reaction was quenched by adding water and ethyl acetate to the reaction solution. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through silica gel chromatography (EA:Hex = 0–100%) to give the title compound (124 mg, 22%) as a white solid.

[1085] LCMS[M+H] + = 402.12.

[1086] 1 1H NMR (500 MHz, DMSO-d6) δ 8.80 (d, J = 8.0 Hz, 2H), 8.15 (d, J = 9.7 Hz, 2H), 8.07 (t, J = 7.6 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.79 (t, J = 7.6 Hz, 1H), 5.53 (dd, J = 48.5, 3.5 Hz, 1H), 5.34 (dd, J = 16.6, 3.5 Hz, 1H), 5.03–4.95 (m, 2H), 4.87 (s, 1H), 4.68–4.51 (m, 2H).

[1087] Synthesis of Compound 257 (2-fluoro-1-(3-(4-(4-(trifluoromethyl)phenyl)quinazolin-2-yl)azetidin-1-yl)prop-2-en-1-one), Example 257

[1088]

[1089] Step 1: Preparation of tert-butyl 3-((2-carbamoylphenyl)carbamoyl)azetidine-1-carboxylate

[1090] To a mixture of 2-aminobenzamide (4.05 g, 33.05 mmol), DIPEA (8.54 g, 66.10 mmol), 1-(tert-butylmethoxycarbonyl)azetidine-3-carboxylic acid (4.66 g, 23.14 mmol), and DCM (20 mL) at 10 °C, HATU (12.57 g, 33.05 mmol) was added with stirring. The mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The reaction solution was diluted with dichloromethane, poured into ice water to separate the organic phase, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by elution with silica gel chromatography (hexane:EA = 3:1) to obtain the title compound (7.82 g) as a white solid. LCMS [M+H] + = 320.45.

[1091] Step 2: Preparation of tert-butyl 3-(4-oxo-3,4-dihydroquinazolin-2-yl)azetidine-1-carboxylate

[1092] Under nitrogen, a mixture of tert-butyl 3-((2-carbamoylphenyl)carbamoyl)azetidine-1-carboxylate (3.00 g, 9.39 mmol), potassium carbonate (12.98 g, 93.94 mmol), and EtOH (20 mL) was stirred at 60 °C for 6 h. The reaction was monitored by LCMS. The reaction was cooled to room temperature. The mixture was concentrated under vacuum. Ice water was added to the residue, and the pH was adjusted to 4 - 5 with dilute hydrochloric acid, and then filtered. The filter cake was washed with water and dried under vacuum to obtain the title compound (2.32 g) as a white solid, which could be directly used for the next step without further purification. LCMS [M+H] + = 246.42.

[1093] Step 3: Preparation of tert-butyl 3-(4-(((trifluoromethyl)sulfonyl)methoxy)quinazolin-2-yl)azetidine-1-carboxylate

[1094] At 0 °C under nitrogen, to a mixture of tert-butyl 3-(4-oxo-3,4-dihydroquinazolin-2-yl)azetidine-1-carboxylate (1.50 g, 4.98 mmol), potassium carbonate (1.93 g, 14.93 mmol), and NMP (5.0 mL), 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.67 g, 7.74 mmol) was added with stirring. The mixture was stirred at room temperature for 2 h. The reaction was monitored using LCMS. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by elution with silica gel chromatography (hexane:EA = 4:1) to obtain the title compound (1.60 g) as a yellow oil. LCMS [M+H] += 378.26.

[1095] Step 4: Preparation of tert-butyl 3-(4-(4-(trifluoromethyl)phenyl)quinazolin-2-yl)azetidine-1-carboxylate

[1096] A mixture of tert-butyl 3-(4-(((trifluoromethyl)sulfonyl)methoxy)quinazolin-2-yl)azetidine-1-carboxylate (1.60 g, 3.69 mmol), (4-(trifluoromethyl)phenyl)boronic acid (1.05 g, 5.54 mmol), Pd(dppf)Cl2·CH2Cl2 (300 mg, 0.37 mmol), potassium carbonate (1.53 g, 11.08 mmol), 1,4-dioxane (20 mL), and water (2.0 mL) was stirred at 100 °C under nitrogen for 6 h. The reaction was monitored by LCMS. The reaction was cooled to room temperature. The mixture was concentrated under vacuum. The residue was purified by elution through silica gel chromatography (n-hexane:EA = 3:1) to give the title compound (1.40 g) as a colorless oil. LCMS [M+H] + = 374.44.

[1097] Step 5: Preparation of 2-(azetidin-3-yl)-4-(4-(trifluoromethyl)phenyl)quinazoline

[1098] A mixture of tert-butyl 3-(4-(4-(trifluoromethyl)phenyl)quinazolin-2-yl)azetidine-1-carboxylate (1.40 g, 3.26 mmol), TFA (7.0 mL), and DCM (28 mL) was stirred at room temperature for 8 h. The reaction was monitored using LCMS. The reaction mixture was concentrated under vacuum. The residue was dissolved in dichloromethane and the pH of the solution was adjusted to 10 with saturated aqueous sodium carbonate. The mixture was extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to give the title compound (0.92 g) as a colorless oil, which could be used directly in the next step without further purification. LCMS [M+H] + = 330.23.

[1099] Step 6: Preparation of 2-fluoro-1-(3-(4-(4-(trifluoromethyl)phenyl)quinazolin-2-yl)azetidin-1-yl)prop-2-en-1-one

[1100] A mixture of 2-(azetidin-3-yl)-4-(4-(trifluoromethyl)phenyl)quinazoline (900 mg, 2.73 mmol), DIPEA (1.06 g, 8.20 mmol), DCM (20 mL), 2-fluoroacrylic acid (370 mg, 4.10 mmol), and HATU (1.04 g, 2.73 mmol) was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (Hex:EA = 2:1) to give the title compound (55 mg) as a white solid.

[1101] LCMS[M+H] + = 402.43.

[1102] 1 1H NMR (500 MHz, DMSO-d6) δ 8.27–7.86 (m, 7H), 7.75 (ddd, J = 8.3, 6.7, 1.4 Hz, 1H), 5.50 (dd, J = 48.5, 3.5 Hz, 1H), 5.32 (dd, J = 16.6, 3.5 Hz, 1H), 4.86 (td, J = 8.9, 8.5, 4.0 Hz, 1H), 4.81–4.69 (m, 1H), 4.47 (t, J = 9.3 Hz, 1H), 4.44–4.29 (m, 2H).

[1103] The compounds in Table 3 were prepared by a method similar to that of Examples 1-257 using different reaction starting materials and appropriate reagents.

[1104] Table 3

[1105]

[1106]

[1107]

[1108]

[1109]

[1110]

[1111]

[1112] Synthesis of Compound 307 (2-Fluoro-1-(3-(3-(phenylethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one) of Example 307

[1113]

[1114] Step 1: Preparation of tert-butyl 3-(3-(phenylethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidine-1-carboxylate

[1115] Under nitrogen, a mixture of tert-butyl 3-(3-iodo-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidine-1-carboxylate (0.40 g, 1 mmol), phenylacetylene (0.20 g, 2 mmol), DIEA (0.50 mL, 3 mmol), Pd(PPh3)4 (0.12 g, 0.1 mmol), CuI (0.08 g, 0.4 mmol), and 1,4-dioxane (40 mL) was stirred at 100 °C for 4 h. The mixture was concentrated under vacuum to give a residue, which was washed with water three times and with brine once, and the organic phase was concentrated under vacuum. The residue was purified by elution through a silica gel column (DCM:MeOH = 30:1) to give the title compound (0.50 g) as a pale yellow solid. LCMS [M+H] + = 375.17.

[1116] Step 2: Preparation of 1-(azetidin-3-yl)-3-(phenylethynyl)-1H-pyrazolo[3,4-b]pyridine

[1117] A mixture of tert-butyl 3-(3-(phenylethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidine-1-carboxylate (0.37 g, 1 mmol), TFA (5 mL), and DCM (10 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum to give the title compound, which was used directly in the next step without further purification. LCMS [M+H] + = 275.12.

[1118] Step 3: Preparation of 2-fluoro-1-(3-(3-(phenylethynyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one

[1119] A mixture of 1-(azetidin-3-yl)-3-(phenylethynyl)-1H-pyrazolo[3,4-b]pyridine (0.18 g, 0.66 mmol), 2-fluoroacrylic acid (0.09 g, 1 mmol), HATU (0.50 g, 1.32 mmol), DIEA (0.55 mL, 3.3 mmol), DCM (20 mL) and DMF (1 mL) was stirred at room temperature overnight. The reaction mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column eluting with ethyl acetate to give the title compound (0.08 g) as an off-white solid.

[1120] LCMS[M+H] + = 347.12.

[1121] 1 H NMR (500 MHz, CDCl3) δ 8.58 (dd, J = 4.5, 1.5 Hz, 1H), 8.22 (dd, J = 8.0, 1.5 Hz, 1H), 7.68–7.62 (m, 2H), 7.43–7.36 (m, 3H), 7.27 (dd, J = 8.0, 4.5 Hz, 1H), 6.04–5.95 (m, 1H), 5.69 (dd, J = 46.7, 3.1 Hz, 1H), 5.13 (dd, J = 15.6, 3.1 Hz, 1H), 5.10–5.03 (m, 1H), 4.97–4.88 (m, 1H), 4.76 - 4.70 (m, 1H), 4.70–4.63 (m, 1H).

[1122] Synthesis of Compound 308 ((E)-2-fluoro-1-(3-(3-styryl-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one), Example 308

[1123]

[1124] Step 1: Preparation of tert-butyl (E)-3-(3-styryl-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidine-1-carboxylate

[1125] Under nitrogen, a mixture of tert-butyl 3-(3-iodo-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidine-1-carboxylate (0.50 g, 1.25 mmol), (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (0.43 g, 1.87 mmol), Cs2CO3 (1.22 g, 3.75 mmol), Pd(dppf)Cl2CH2Cl2 (0.10 g, 0.12 mmol), 1,4-dioxane (20 mL) and water (4 mL) was stirred at 100 °C overnight. The mixture was concentrated under vacuum. The residue was purified by elution through a silica gel column (DCM:MeOH = 30:1) to give the title compound (0.50 g). LCMS [M+H] + = 377.19.

[1126] Step 2: Preparation of (E)-1-(azetidin-3-yl)-3-styryl-1H-pyrazolo[3,4-b]pyridine

[1127] A mixture of tert-butyl (E)-3-(3-styryl-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidine-1-carboxylate (0.50 g, 1.33 mmol), TFA (5 mL) and DCM (10 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum to give the title compound, which was used directly in the next step without further purification. LCMS [M+H] + = 277.14.

[1128] Step 3: Preparation of (E)-2-fluoro-1-(3-(3-styryl-1H-pyrazolo[3,4-b]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one

[1129] A mixture of (E)-1-(azetidin-3-yl)-3-styryl-1H-pyrazolo[3,4-b]pyridine (0.18 g, 0.66 mmol), 2-fluoroacrylic acid (0.09 g, 1 mmol), HATU (0.50 g, 1.32 mmol), DIEA (0.55 mL, 3.3 mmol), DCM (20 mL) and DMF (1 mL) was stirred at room temperature overnight. The reaction mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under vacuum. The residue was purified by elution through a silica gel column with ethyl acetate to give the title compound (0.12 g) as an off-white solid.

[1130] LCMS [M+H] + = 349.14.

[1131] 11H NMR (500 MHz, CDCl3) δ 8.55 (dd, J = 4.5, 1.4 Hz, 1H), 8.37 (dd, J = 8.1, 1.4 Hz, 1H), 7.60 (d, J = 7.3 Hz, 2H), 7.50 (d, J = 16.7 Hz, 1H), 7.45–7.38 (m, 3H), 7.32 (t, J = 7.3 Hz, 1H), 7.24 (dd, J = 8.0, 4.5 Hz, 1H), 6.01–5.93 (m, 1H), 5.70 (dd, J = 46.6, 3.0 Hz, 1H), 5.15 (dd, J = 15.6, 3.0 Hz, 1H), 5.08–5.00 (m, 1H), 4.97–4.89 (m, 1H), 4.78–4.71 (m, 1H), 4.69–4.62 (m, 1H).

[1132] The compounds in Table 4 were prepared by a method similar to that of Examples 1 - 308 using different starting materials for the reaction and appropriate reagents.

[1133] Table 4

[1134]

[1135]

[1136]

[1137]

[1138]

[1139] The 1 1H NMR data of the compounds are as follows:

[1140] 1 1H NMR (500 MHz, CDCl3) δ 8.59 (dd, J = 4.5, 1.3 Hz, 1H), 8.37 (dd, J = 8.1, 1.3 Hz, 1H), 8.11 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.1 Hz, 2H), 7.28 (dd, J = 8.1, 4.5 Hz, 1H), 6.43 (dd, J = 17.0, 1.7 Hz, 1H), 6.30 (dd, J = 17.0, 10.3 Hz, 1H), 6.06–5.98 (m, 1H), 5.76 (dd, J = 10.3, 1.7 Hz, 1H), 4.96–4.88 (m, 1H), 4.83–4.75 (m, 2H), 4.72–4.65 (m, 1H). (Compound 30)

[1141] 11H NMR (500 MHz, DMSO-d6) δ 8.33 (d, J = 9.2 Hz, 1H), 8.23 (dt, J = 8.2, 1.4 Hz, 1H), 8.17 (d, J = 8.1 Hz, 2H), 8.00–7.80 (m, 3H), 7.60 (dd, J = 7.1, 2.8 Hz, 1H), 7.35 (ddd, J = 8.5, 7.0, 1.6 Hz, 1H), 6.62 (ddd, J = 41.2, 16.8, 10.3 Hz, 1H), 6.16 (dt, J = 16.8, 2.7 Hz, 1H), 5.71–5.65 (m, 1H), 4.17–4.03 (m, 1H), 3.98–3.76 (m, 2H), 3.74–3.51 (m, 1H), 3.21–2.83 (m, 1H), 2.61 (dd, J = 8.5, 4.2 Hz, 1H), 2.45–2.34 (m, 1H). (Compound 42)

[1142] 1 1H NMR (500 MHz, DMSO-d6) δ 8.16 (dd, J = 8.4, 4.1 Hz, 2H), 7.99 (dd, J = 8.9, 1.4 Hz, 1H), 7.84 (dd, J = 8.4, 3.8 Hz, 2H), 7.35 (dd, J = 12.3, 2.2 Hz, 1H), 6.93 (dd, J = 8.9, 2.2 Hz, 1H), 6.18 (ddd, J = 16.7, 5.3, 2.5 Hz, 1H), 5.70 (ddd, J = 28.7, 10.3, 2.5 Hz, 1H), 5.57 (dq, J = 38.1, 6.2 Hz, 1H), 4.20–3.99 (m, 1H), 3.99–3.93 (m, 1H), 3.90 (s, 3H), 3.86–3.78 (m, 2H), 3.75–3.54 (m, 1H), 2.54 (d, J = 7.1 Hz, 1H), 2.45 (qd, J = 6.7, 1.9 Hz, 1H). (Compound 54)

[1143] 1 1H NMR (500 MHz, CDCl3) δ 8.58 (dd, J = 4.5, 1.4 Hz, 1H), 8.36 (dd, J = 8.1, 1.4 Hz, 1H), 8.12 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.2 Hz, 2H), 7.27 (dd, J = 8.1, 4.5 Hz, 1H), 6.00–5.92 (m, 1H), 5.49–5.42 (m, 2H), 4.95–4.59 (m, 4H), 2.01 (s, 3H). (Compound 73)

[1144] 1 1H NMR (500 MHz, DMSO) δ 8.52 (d, J = 8.1 Hz, 2H), 8.38 (s, 1H), 7.89 (d, J = 8.3 Hz, 2H), 6.08 (m, 1H), 5.55 (dd, J = 48.4, 3.5 Hz, 1H), 5.36 (dd, J = 16.6, 3.5 Hz, 1H), 4.97–4.76 (m, 2H), 4.60–4.43 (m, 2H), 3.55 (s, 3H). (Compound 80)

[1145] 1 1H NMR (500 MHz, CDCl3) δ 8.73 (dd, J = 4.3, 1.2 Hz, 1H), 8.69 (d, J = 8.1 Hz, 2H), 7.82 (dd, J = 8.6, 1.2 Hz, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.39 (dd, J = 8.6, 4.3 Hz, 1H), 6.45 (dd, J = 17.0, 1.8 Hz, 1H), 6.30 (dd, J = 17.0, 10.3 Hz, 1H), 5.78 (dd, J = 10.3, 1.8 Hz, 1H), 5.56 - 5.49 (m, 1H), 4.96–4.86 (m, 1H), 4.83–4.72 (m, 2H), 4.72–4.64 (m, 1H). (Compound 82)

[1146] 1 1H NMR (500 MHz, CDCl3) δ 8.73 (dd, J = 4.3, 1.1 Hz, 1H), 8.69 (d, J = 8.1 Hz, 2H), 7.82 (dd, J = 8.6, 1.0 Hz, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.39 (dd, J = 8.6, 4.3 Hz, 1H), 5.53–5.44 (m, 3H), 4.97–4.83 (m, 1H), 4.82–4.60 (m, 3H), 2.02 (s, 3H). (Compound 87)

[1147] 11H NMR (500 MHz, DMSO-d6) δ 9.13 (dd, J = 13.9, 7.0 Hz, 1H), 8.26 (dd, J = 8.3, 2.3 Hz, 1H), 8.22–8.05 (m, 2H), 7.88 (dd, J = 8.5, 2.6 Hz, 2H), 7.56 (dd, J = 7.0, 3.8 Hz, 1H), 7.37 (ddd, J = 8.5, 7.1, 1.8 Hz, 1H), 6.61 (ddd, J = 42.4, 16.8, 10.3 Hz, 1H), 6.15 (dt, J = 16.8, 3.0 Hz, 1H), 5.68 (ddd, J = 12.4, 10.2, 2.4 Hz, 1H), 5.58–5.40 (m, 1H), 4.25–4.02 (m, 3H), 3.96–3.75 (m, 2H), 3.75–3.52 (m, 2H), 2.59 (td, J = 16.9, 14.5, 7.5 Hz, 2H), 2.43–2.31 (m, 2H), 2.26–2.15 (m, 2H). (Compound 113)

[1148] 1 1H NMR (500 MHz, CDCl3) δ 8.67 (dd, J = 4.3, 1.3 Hz, 1H), 8.65 (d, J = 8.1 Hz, 2H), 8.17 (dd, J = 8.6, 1.3 Hz, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.34 (dd, J = 8.6, 4.3 Hz, 1H), 6.29 (dd, J = 16.9, 1.2 Hz, 1H), 6.05 (dd, J = 16.9, 10.3 Hz, 1H), 5.66 (dd, J = 10.3, 1.2 Hz, 1H), 5.62 (d, J = 5.4 Hz, 1H), 5.34–5.27 (m, 1H), 4.45–4.35 (m, 1H), 2.64–2.53 (m, 1H), 2.40–2.20 (m, 3H), 2.08–1.96 (m, 1H), 1.95–1.83 (m, 1H). (Compound 119)

[1149] 11H NMR (500 MHz, CDCl3) δ 8.69 (dd, J = 4.3, 1.3 Hz, 1H), 8.40 (d, J = 8.3 Hz, 2H), 7.77 (dd, J = 8.6, 1.3 Hz, 1H), 7.34 (dd, J = 8.5, 4.4 Hz, 1H), 7.21 (d, J = 8.3 Hz, 2H), 6.44 (dd, J = 17.0, 1.8 Hz, 1H), 6.29 (dd, J = 17.0, 10.3 Hz, 1H), 5.76 (dd, J = 10.3, 1.8 Hz, 1H), 5.53–5.45 (m, 1H), 4.98–4.87 (m, 1H), 4.80–4.71 (m, 2H), 4.69–4.62 (m, 1H), 2.00–1.93 (m, 1H), 1.04–0.98 (m, 2H), 0.80–0.74 (m, 2H). (Compound 120)

[1150] 1 1H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 8.1 Hz, 2H), 8.00 (d, J = 9.0 Hz, 1H), 7.72 (d, J = 8.2 Hz, 2H), 6.58 (d, J = 9.0 Hz, 1H), 6.40 (dd, J = 17.0, 2.0 Hz, 1H), 6.29 (dd, J = 17.0, 10.2 Hz, 1H), 5.79–5.73 (m, 1H), 5.72 (dd, J = 10.2, 1.9 Hz, 1H), 4.99–4.92 (m, 1H), 4.85–4.78 (m, 1H), 4.74–4.67 (m, 1H), 4.64–4.57 (m, 1H), 3.19 (s, 6H). (Compound 121)

[1151] 1 1H NMR (500 MHz, CDCl3) δ 9.34 (d, J = 1.3 Hz, 1H), 8.63 (dd, J = 4.5, 1.4 Hz, 1H), 8.52 (dd, J = 8.1, 1.5 Hz, 1H), 8.36 (dd, J = 8.2, 1.4 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.33 (dd, J = 8.2, 4.5 Hz, 1H), 6.44 (dd, J = 17.0, 1.8 Hz, 1H), 6.30 (dd, J = 17.0, 10.3 Hz, 1H), 6.07–5.99 (m, 1H), 5.76 (dd, J = 10.3, 1.8 Hz, 1H), 4.95–4.85 (m, 1H), 4.84–4.73 (m, 2H), 4.72–4.65 (m, 1H).

[1152] (Compound 123)

[1153] 1 H NMR(500MHz,CDCl3)δ8.58(dd,J=4.5,1.4Hz,1H),8.26(ddd,J=8.2,3.6,1.5Hz,1H),8.10(t,J=7.6Hz,1H),7.57(d,J=8.1Hz,1H),7.52(d,J=10.5Hz,1H),7.28–7.24(m,1H),6.42(dd,J=17.0,1.9Hz,1H),6.29(dd,J=17.0,10.3Hz,1H),6.03(dq,J=8.2,5.7Hz,1H),5.74(dd,J=10.3,1.9Hz,1H),4.93–4.87(m,1H),4.82–4.73(m,2H),4.71–4.64(m,1H).(Compound 127)

[1154] 1 H NMR(500MHz,CDCl3)δ8.73(dd,J=4.3,1.1Hz,1H),8.41(t,J=7.5Hz,1H),7.87(dd,J=8.6,1.1Hz,1H),7.59(d,J=8.1Hz,1H),7.52(d,J=10.1Hz,1H),7.41(dd,J=8.6,4.3Hz,1H),6.43(dd,J=17.0,1.8Hz,1H),6.29(dd,J=17.0,10.3Hz,1H),5.77(dd,J=10.3,1.8Hz,1H),5.61–5.53(m,1H),5.00–4.89(m,1H),4.84–4.76(m,1H),4.75–4.65(m,2H).(Compound 129)

[1155] 1 H NMR(500MHz,CDCl3)δ8.72(d,J=4.0Hz,1H),8.40(t,J=7.5Hz,1H),7.86(d,J=8.4Hz,1H),7.59(d,J=8.0Hz,1H),7.52(d,J=10.1Hz,1H),7.42(dd,J=8.5,4.3Hz,1H),5.71(dd,J=46.7,3.1Hz,1H),5.62–5.52(m,1H),5.17(dd,J=15.6,3.1Hz,1H),5.12–5.04(m,1H),5.03–4.93(m,1H),4.81–4.65(m,2H).(Compound 130)

[1156] 1 1H NMR (500 MHz, CDCl3) δ 9.85 (d, J = 1.6 Hz, 1H), 9.06 (dd, J = 8.2, 1.5 Hz, 1H), 8.74 (dd, J = 4.3, 1.0 Hz, 1H), 7.85 (dd, J = 8.6, 0.9 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.42 (dd, J = 8.6, 4.3 Hz, 1H), 6.45 (dd, J = 17.0, 1.8 Hz, 1H), 6.30 (dd, J = 17.0, 10.3 Hz, 1H), 5.79 (dd, J = 10.3, 1.8 Hz, 1H), 5.59–5.50 (m, 1H), 4.97–4.87 (m, 1H), 4.86–4.77 (m, 1H), 4.75–4.65 (m, 2H).

[1157] (Compound 131)

[1158] 1 1H NMR (500 MHz, CDCl3) δ 9.86 (d, J = 1.4 Hz, 1H), 9.07 (dd, J = 8.2, 1.4 Hz, 1H), 8.74 (dd, J = 4.3, 0.9 Hz, 1H), 7.87–7.78 (m, 2H), 7.42 (dd, J = 8.6, 4.3 Hz, 1H), 5.74 (dd, J = 46.7, 3.1 Hz, 1H), 5.61–5.50 (m, 1H), 5.19 (dd, J = 15.6, 3.1 Hz, 1H), 5.10–4.94 (m, 2H), 4.81–4.66 (m, 2H). (Compound 132)

[1159] 1 1H NMR (500 MHz, DMSO-d6) δ 8.84 (d, J = 2.2 Hz, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.65 (d, J = 8.0 Hz, 2H), 7.93 (d, J = 8.1 Hz, 2H), 6.45 (dd, J = 16.9, 10.3 Hz, 1H), 6.21 (dd, J = 17.0, 2.3 Hz, 1H), 5.96 (ddd, J = 13.6, 8.2, 5.5 Hz, 1H), 5.76 (dd, J = 10.3, 2.3 Hz, 1H), 5.00–4.65 (m, 2H), 4.64–4.37 (m, 2H). (Compound 161)

[1160] 1H NMR (500 MHz, DMSO-d6) δ 8.78–8.56 (m, 2H), 8.27 (d, J = 8.1 Hz, 2H), 7.89 (d, J = 8.2 Hz, 2H), 7.43 (dd, J = 8.2, 4.4 Hz, 2H), 6.88 (d, J = 2.3 Hz, 1H), 5.51 (dd, J = 48.5, 3.6 Hz, 1H), 5.36–5.21 (m, 2H), 5.11–4.83 (m, 2H), 4.63 (d, J = 11.0 Hz, 1H), 3.20 (d, J = 3.9 Hz, 2H). (Compound 169)

[1161] 1 1H NMR (500 MHz, DMSO-d6) δ 8.67–8.55 (m, 2H), 8.00–7.91 (m, 2H), 7.45–7.39 (m, 2H), 7.36 (dd, J = 8.1, 4.4 Hz, 1H), 5.99 (tt, J = 8.2, 5.5 Hz, 1H), 5.57 (dd, J = 48.4, 3.5 Hz, 1H), 5.37 (dd, J = 16.6, 3.5 Hz, 1H), 5.02–4.80 (m, 2H), 4.72–4.41 (m, 2H), 3.05–2.81 (m, 1H), 1.26 (d, J = 6.9 Hz, 6H). (Compound 171)

[1162] 1H NMR (500 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.72–8.55 (m, 2H), 8.22–8.17 (m, 1H), 7.63–7.46 (m, 2H), 7.40 (dd, J = 8.0, 4.6 Hz, 1H), 6.01 (tt, J = 8.3, 5.5 Hz, 1H), 5.57 (dd, J = 48.4, 3.5 Hz, 1H), 5.37 (dd, J = 16.6, 3.5 Hz, 1H), 5.02–4.81 (m, 2H), 4.70–4.43 (m, 2H). (Compound 172)

[1163] 1H NMR (500 MHz, DMSO-d6) δ 8.75–8.59 (m, 2H), 8.31 (d, J = 8.4 Hz, 2H), 8.20–8.00 (m, 2H), 7.45 (dd, J = 8.0, 4.5 Hz, 1H), 6.07–6.00 (m, 1H), 5.57 (dd, J = 48.4, 3.5 Hz, 1H), 5.37 (dd, J = 16.6, 3.6 Hz, 1H), 4.93 (d, J = 49.3 Hz, 2H), 4.68–4.47 (m, 2H). (Compound 173)

[1164] 1H NMR (500 MHz, DMSO-d6) δ 8.69–8.53 (m, 2H), 8.43–8.24 (m, 2H), 7.90–7.69 (m, 2H), 7.41 (dd, J = 8.1, 4.5 Hz, 1H), 4.70–4.32 (m, 4H), 4.07 (dq, J = 26.8, 7.1 Hz, 3H). (Compound 176)

[1165] 1 1H NMR (500 MHz, DMSO-d6) δ 8.74 (dd, J = 8.3, 1.6 Hz, 1H), 8.70 (dd, J = 4.5, 1.5 Hz, 1H), 8.59 (dd, J = 8.1, 1.8 Hz, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.33 (d, J = 8.1 Hz, 1H), 7.47 (ddd, J = 8.5, 4.6, 1.4 Hz, 1H), 6.04 (tt, J = 8.4, 5.5 Hz, 1H), 5.57 (dd, J = 48.4, 3.6 Hz, 1H), 5.37 (dd, J = 16.4, 3.6 Hz, 1H), 5.08–4.80 (m, 2H), 4.69–4.48 (m, 2H). (Compound 177)

[1166] 1 1H NMR (500 MHz, DMSO-d6) δ 8.85–8.74 (m, 2H), 8.69 (dd, J = 4.5, 1.6 Hz, 1H), 8.59 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.45 (m 1.5 Hz, 1H), 6.04 (tt, J = 8.5, 5.4 Hz, 1H), 5.58 (m, 1.4 Hz, 1H), 5.38 (m, 1.4 Hz, 1H), 5.08–4.77 (m, 2H), 4.77–4.44 (m, 2H). (Compound 178)

[1167] 1 1H NMR (500 MHz, DMSO-d6) δ 9.21 (d, J = 2.0 Hz, 1H), 8.79 (dd, J = 8.2, 1.5 Hz, 1H), 8.68 (dd, J = 4.4, 1.5 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 7.43 (dd, J = 8.2, 4.5 Hz, 1H), 5.97 (tt, J = 8.2, 5.6 Hz, 1H), 4.75–4.33 (m, 4H), 4.10 (q, J = 7.0 Hz, 2H), 1.22 (t, J = 7.0 Hz, 3H). (Compound 181)

[1168] 1 1H NMR (500 MHz, DMSO) δ 8.69 (d, J = 3.9 Hz, 1H), 8.35 (dd, J = 24.0, 8.0 Hz, 2H), 7.90 (d, J = 7.9 Hz, 1H), 7.40 (dd, J = 7.8, 4.5 Hz, 1H), 6.04 (s, 1H), 5.55 (d, J = 48.3 Hz, 1H), 5.36 (dd, J = 16.5, 2.9 Hz, 1H), 5.00 (s, 1H), 4.84 (s, 1H), 4.64 (t, J = 9.4 Hz, 1H), 4.51 (s, 1H), 2.73 (s, 3H). (Compound 182)

[1169] 1 1H NMR (500 MHz, CDCl3-d3) δ 9.13 (s, 1H), 8.65–8.64 (m, 1H), 8.36–8.35 (m, 1H), 8.27–8.25 (m, 1H), 7.36–7.34 (m, 1H), 6.07–6.01 (m, 1H), 5.77 - 5.67 (m, 1H), 5.19–5.15 (m, 1H), 5.06–5.50 (m, 2H), 4.78–4.68 (m, 2H). (Compound 184)

[1170] 1 1H NMR (500 MHz, CDCl3-d3) δ 8.22–8.21 (m, 1H), 8.11–8.10 (m, 2H), 7.77–7.76 (m, 2H), 7.14–7.13 (m, 1H), 6.04–5.98 (m, 1H), 5.76–5.66 (m, 1H), 5.17–5.13 (m, 1H), 5.06–5.02 (m, 1H), 4.96–4.92 (m, 1H), 4.79–4.76 (m, 1H), 4.70–4.66 (m, 1H), 2.70 (s, 3H). (Compound 186)

[1171] 1 1H NMR (500 MHz, DMSO) δ 9.49 (d, J = 2.2 Hz, 1H), 8.75 (ddd, J = 14.9, 9.3, 2.0 Hz, 3H), 8.35 (d, J = 8.2 Hz, 2H), 8.16 (dd, J = 8.9, 2.7 Hz, 1H), 7.95 (t, J = 14.2 Hz, 2H), 7.55–7.46 (m, 1H), 7.34 (d, J = 9.0 Hz, 1H), 5.89–5.66 (m, 1H), 5.49 (dd, J = 15.8, 3.8 Hz, 1H), 3.94 (s, 3H).

[1172] (Compound 188)

[1173] 1 H NMR(500MHz, DMSO-d6) δ 9.96(s, 1H), 8.88–8.87(m, 1H), 8.79–8.78(m, 2H), 8.37–8.35(m, 2H), 8.32–8.30(m, 1H), 7.95–7.94(m, 2H), 7.77–7.75(m, 1H), 7.55–7.52(m, 1H), 6.72–6.66(m, 1H), 6.35 - 6.32(m, 1H), 5.86–5.84(m, 1H). (Compound 189)

[1174] 1 H NMR(500MHz, DMSO) δ 9.75(s, 1H), 9.02(d, J = 8.3Hz, 1H), 8.89(d, J = 2.2Hz, 1H), 8.80(d, J = 2.2Hz, 1H), 8.13(d, J = 8.2Hz, 1H), 6.00(dq, J = 8.2, 5.5Hz, 1H), 5.58(dd, J = 48.4, 3.5Hz, 1H), 5.38(dd, J = 16.6, 3.5Hz, 1H), 5.08–4.87(m, 2H), 4.70–4.54(m, 2H).

[1175] (Compound 298)

[1176] 1 H NMR(500MHz, DMSO) δ 9.44(s, 1H), 8.71(d, J = 8.2Hz, 1H), 8.62(d, J = 8.3Hz, 1H), 8.04(d, J = 8.2Hz, 1H), 7.33(d, J = 8.3Hz, 1H), 6.12–5.92(m, 1H), 5.57(dd, J = 48.4, 3.4Hz, 1H), 5.37(dd, J = 16.5, 3.4Hz, 1H), 4.98(s, 1H), 4.86(s, 1H), 4.62(t, J = 9.5Hz, 1H), 4.51(dd, J = 10.5, 5.2Hz, 1H), 2.66(s, 3H). (Compound 199)

[1177] 11H NMR (500 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.66–8.64 (m, 1H), 8.31–8.30 (m, 2H), 7.90–7.88 (m, 2H), 6.02–6.00 (m, 1H), 5.62–5.51 (m, 1H), 5.39–5.35 (m, 1H), 5.00–4.86 (m, 2H), 4.64–4.51 (m, 2H). (Compound 202)

[1178] 1 1H NMR (500 MHz, DMSO-d6) δ 7.79 (q, J = 8.4 Hz, 4H), 5.55 (d, J = 45 Hz, 1H), 5.37 (d, J = 15 Hz, 1H), 5.32–5.25 (m, 1H), 4.86–4.79 (m, 3H), 4.71 (q, J = 6.1, 5.4 Hz, 1H), 4.48 (t, J = 9.4 Hz, 1H), 4.37 (dd, J = 10.7, 5.3 Hz, 1H), 3.88 (t, J = 5.5 Hz, 2H), 2.78 (dt, J = 7.0, 3.3 Hz, 2H). (Compound 208)

[1179] 1 1H NMR (500 MHz, DMSO-d6) δ 9.09 (d, J = 2.0 Hz, 1H), 9.05 (d, J = 2.0 Hz, 1H), 8.37 (d, J = 8.1 Hz, 2H), 7.92 (d, J = 8.2 Hz, 2H), 6.06 (tt, J = 8.3, 5.4 Hz, 1H), 5.58 (d, J = 45 Hz, 1H), 5.38 (dd, J = 16.6, 3.5 Hz, 1H), 5.00 (td, J = 9.5, 9.0, 4.2 Hz, 1H), 4.90 (q, J = 8.1, 6.0 Hz, 1H), 4.64 (t, J = 9.6 Hz, 1H), 4.56 (dd, J = 10.9, 5.4 Hz, 1H). (Compound 215)

[1180] 1 1H NMR (500 MHz, DMSO) δ 8.54 (m, 2H), 8.42 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 6.11 (m, 1H), 5.55 (dd, J = 48.4, 3.5 Hz, 1H), 5.36 (dd, J = 16.6, 3.5 Hz, 1H), 4.88 (m, 2H), 4.52 (m, 2H), 4.08 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). (Compound 218)

[1181] 1 1H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J = 8.2 Hz, 2H), 8.42 (s, 1H), 7.90 (d, J = 8.2 Hz, 2H), 5.77 (ddd, J = 8.1, 5.3, 2.9 Hz, 1H), 5.57 (dd, J = 48.4, 3.6 Hz, 1H), 5.38 (dd, J = 16.6, 3.5 Hz, 1H), 4.93 (ddt, J = 40.9, 9.7, 5.3 Hz, 2H), 4.67–4.48 (m, 2H), 4.03 (s, 3H). (Compound 223)

[1182] 1 1H NMR (500 MHz, DMSO-d6) δ 8.53 (d, J = 8.1 Hz, 2H), 7.88 (d, J = 8.2 Hz, 2H), 6.07 (ddd, J = 8.1, 5.3, 2.8 Hz, 1H), 5.55 (dd, J = 48.4, 3.5 Hz, 1H), 5.35 (dd, J = 16.6, 3.6 Hz, 1H), 4.99–4.72 (m, 2H), 4.64–4.40 (m, 2H), 3.56 (s, 3H), 2.64 (s, 3H). (Compound 225)

[1183] 1 1H NMR (400 MHz, CDCl3) δ 7.83-7.81 (m, 2H), 7.70-7.68 (m, 2H), 7.32 (d, J = 6 MHz, 1H), 7.23-7.20 (m, 1H), 7.17-7.16 (m, 2H), 6.47 (dd, J = 1.4 MHz, J = 13.5 MHz, 1H), 6.33-6.27 (m, 1H), 5.78 (dd, J = 1.4 MHz, J = 8.3 MHz, 1H), 5.54-5.48 (m, 1H), 4.87-4.83 (m, 1H), 4.71-4.68 (m, 2H), 4.62-4.59 (m, 1H). (Compound 236)

[1184] 1H NMR (500 MHz, CDCl3) δ 8.11 - 8.09 (dd, J = 1.0 MHz, J = 4.2 MHz, 1H), 7.83 - 7.81 (m, 2H), 7.71 - 7.69 (m, 2H), 7.37 (dd, J = 1.0 MHz, J = 6.3 MHz, 1H), 7.07 - 7.04 (m, 1H), 5.69 - 5.60 (m, 1H), 5.27 - 5.25 (m, 1H), 5.13 (dd, J = 4.0 MHz, J = 12.0 MHz, 1H), 4.98 - 4.96 (m, 1H), 4.66 - 4.63 (m, 1H), 4.41 - 4.38 (m, 1H), 1.86 (s, 3H). (Compound 238)

[1185] 1 1H NMR (500 MHz, DMSO) δ 8.16–8.11 (m, 1H), 8.05 (d, J = 3.2 Hz, 1H), 7.99 (q, J = 8.7 Hz, 4H), 5.54 (dd, J = 48.5, 3.5 Hz, 1H), 5.45 (dq, J = 8.7, 5.8 Hz, 1H), 5.35 (dd, J = 16.6, 3.5 Hz, 1H), 5.05 - 4.97 (m, 1H), 4.79 (td, J = 9.3, 4.2 Hz, 1H), 4.67 (dd, J = 10.6, 5.8 Hz, 1H), 4.43 (t, J = 9.7 Hz, 1H). (Compound 240)

[1186] 1 1H NMR (500 MHz, DMSO) δ 9.20 (d, J = 2.2 Hz, 1H), 8.50 (dd, J = 8.5, 2.3 Hz, 1H), 8.12 - 8.15 (m, 2H), 8.09 (d, J = 3.3 Hz, 1H), 5.55 (dd, J = 48.5, 3.5 Hz, 1H), 5.48 - 5.42 (m, 1H), 5.36 (dd, J = 16.6, 3.5 Hz, 1H), 5.01 (d, J = 3.6 Hz, 1H), 4.81 (td, J = 9.2, 4.2 Hz, 1H), 4.67 (dd, J = 10.7, 5.8 Hz, 1H), 4.45 (t, J = 9.7 Hz, 1H). (Compound 241)

[1187] 11H NMR (500 MHz, DMSO) δ 8.01–7.93 (m, 3H), 7.85 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 1.7 Hz, 1H), 5.53 (dd, J = 48.5, 3.5 Hz, 1H), 5.43 (ddd, J = 14.7, 7.3, 4.4 Hz, 1H), 5.34 (dd, J = 16.6, 3.5 Hz, 1H), 5.08–4.99 (m, 1H), 4.76 (td, J = 9.3, 4.2 Hz, 1H), 4.68 (dd, J = 10.6, 6.0 Hz, 1H), 4.43–4.36 (m, 1H), 2.31 (s, 3H). (Compound 244)

[1188] 1 1H NMR (500 MHz, DMSO-d6) δ 8.55 (dd, J = 1.9, 1.0 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.3 Hz, 2H), 7.82 (d, J = 1.9 Hz, 1H), 5.59–5.48 (m, 2H), 5.35 (dd, J = 16.5, 3.5 Hz, 1H), 5.05 (td, J = 10.6, 9.2, 6.0 Hz, 1H), 4.79 (td, J = 9.4, 4.2 Hz, 1H), 4.70 (dd, J = 10.7, 5.9 Hz, 1H), 4.47–4.40 (m, 1H). (Compound 245)

[1189] 1 1H NMR (500 MHz, DMSO-d6) δ 7.97 (d, J = 8.7 Hz, 2H), 7.84 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 8.1 Hz, 1H), 7.22 (dd, J = 8.1, 1.3 Hz, 1H), 5.53 (d, J = 75 Hz, 1H), 5.41 (tt, J = 8.8, 5.7 Hz, 1H), 5.34 (d, J = 20 Hz, 1H), 5.00 (dt, J = 9.6, 4.2 Hz, 1H), 4.77 (td, J = 9.3, 3.9 Hz, 1H), 4.65 (dd, J = 10.8, 5.8 Hz, 1H), 4.45–4.37 (m, 1H). (Compound 252)

[1190] 11H NMR (500 MHz, DMSO-d6) δ 8.32–8.11 (m, 1H), 8.11–7.95 (m, 4H), 7.87–7.67 (m, 2H), 7.57–7.41 (m, 1H), 6.40 (dt, J = 16.9, 10.9 Hz, 1H), 6.15 (ddd, J = 16.8, 13.9, 2.2 Hz, 1H), 5.71 (ddd, J = 12.8, 10.3, 2.3 Hz, 1H), 4.80–4.53 (m, 2H), 4.50–4.26 (m, 3H). (Compound 294 - 310)

[1191] 1 1H NMR (500 MHz, CDCl3) δ 8.56 (dd, J = 4.5, 1.4 Hz, 1H), 8.12 (dd, J = 8.0, 1.4 Hz, 1H), 7.24 (dd, J = 8.1, 4.5 Hz, 1H), 6.39 (dd, J = 17.0, 1.8 Hz, 1H), 6.25 (dd, J = 17.0, 10.3 Hz, 1H), 5.98–5.89 (m, 1H), 5.72 (dd, J = 10.3, 1.7 Hz, 1H), 4.90–4.84 (m, 1H), 4.75–4.68 (m, 1H), 4.66–4.59 (m, 2H), 3.29–3.19 (m, 1H), 3.09–2.97 (m, 2H), 2.95–2.80 (m, 2H). (Compound 309)

[1192] 1 1H NMR (500 MHz, CDCl3) δ 8.52 (dd, J = 4.5, 1.5 Hz, 1H), 8.11 (dd, J = 8.0, 1.5 Hz, 1H), 7.20 (dd, J = 8.0, 4.5 Hz, 1H), 6.38 (dd, J = 17.0, 1.8 Hz, 1H), 6.24 (dd, J = 17.0, 10.3 Hz, 1H), 5.96–5.87 (m, 1H), 5.71 (dd, J = 10.3, 1.8 Hz, 1H), 4.90–4.82 (m, 1H), 4.73–4.66 (m, 1H), 4.66–4.55 (m, 2H), 1.60–1.52 (m, 1H), 0.99–0.90 (m, 4H). (Compound 315)

[1193] 11H NMR (500 MHz, CDCl3) δ 8.59 (dd, J = 4.5, 1.5 Hz, 1H), 8.18 (dd, J = 8.0, 1.5 Hz, 1H), 7.61 (s, 1H), 7.53 (s, 1H), 7.28 (dd, J = 8.1, 4.5 Hz, 1H), 6.41 (dd, J = 17.0, 1.8 Hz, 1H), 6.27 (dd, J = 17.0, 10.3 Hz, 1H), 6.03–5.94 (m, 1H), 5.74 (dd, J = 10.3, 1.8 Hz, 1H), 4.94–4.84 (m, 1H), 4.79–4.72 (m, 1H), 4.71 4.61 (m, 2H), 3.83 (s, 3H). (Compound 318)

[1194] 1 1H NMR (500 MHz, CDCl3) δ 8.58 (dd, J = 4.5, 1.4 Hz, 1H), 8.22 (dd, J = 8.0, 1.4 Hz, 1H), 7.69–7.60 (m, 2H), 7.45–7.35 (m, 3H), 7.27 (dd, J = 8.0, 4.5 Hz, 1H), 6.40 (dd, J = 17.0, 1.7 Hz, 1H), 6.27 (dd, J = 17.0, 10.3 Hz, 1H), 6.03–5.92 (m, 1H), 5.73 (dd, J = 10.3, 1.7 Hz, 1H), 4.96–4.87 (m, 1H), 4.79–4.72 (m, 1H), 4.71–4.59 (m, 2H). (Compound 319)

[1195] 1 1H NMR (500 MHz, CDCl3) δ 8.53 (dd, J = 4.5, 1.5 Hz, 1H), 8.13 (dd, J = 8.0, 1.5 Hz, 1H), 7.21 (dd, J = 8.0, 4.5 Hz, 1H), 5.98 - 5.91 (m, 1H), 5.67 (dd, J = 46.6, 3.1 Hz, 1H), 5.12 (dd, J = 15.6, 3.1 Hz, 1H), 5.06–4.99 (m, 1H), 4.93–4.82 (m, 1H), 4.71–4.57 (m, 2H), 3.41–3.30 (m, 1H), 2.46–2.28 (m, 4H), 2.08–1.92 (m, 2H). (Compound 321)

[1196] 11H NMR (500 MHz, CDCl3) δ 8.52 (dd, J = 4.5, 1.4 Hz, 1H), 8.11 (dd, J = 8.0, 1.3 Hz, 1H), 7.20 (dd, J = 8.0, 4.5 Hz, 1H), 5.98–5.88 (m, 1H), 5.66 (dd, J = 46.6, 3.0 Hz, 1H), 5.12 (dd, J = 15.6, 3.0 Hz, 1H), 5.06–4.96 (m, 1H), 4.93–4.83 (m, 1H), 4.70–4.56 (m, 2H), 1.61–1.52 (m, 1H), 1.00–0.91 (m, 4H). (Compound 322)

[1197] 1 1H NMR (500 MHz, CDCl3) δ 8.59 (dd, J = 4.5, 1.5 Hz, 1H), 8.17 (dd, J = 8.0, 1.5 Hz, 1H), 7.65 (s, 1H), 7.53 (s, 1H), 7.28 (dd, J = 8.1, 4.5 Hz, 1H), 6.03–5.95 (m, 1H), 5.69 (dd, J = 46.7, 3.1 Hz, 1H), 5.14 (dd, J = 15.6, 3.1 Hz, 1H), 5.08–5.00 (m, 1H), 4.98–4.88 (m, 1H), 4.75–4.60 (m, 2H), 3.83 (s, 3H). (Compound 323)

[1198] 1 1H NMR (500 MHz, CDCl3) δ 8.53 (dd, J = 4.5, 1.5 Hz, 1H), 8.11 (dd, J = 8.0, 1.5 Hz, 1H), 7.21 (dd, J = 8.0, 4.5 Hz, 1H), 5.98–5.90 (m, 1H), 5.67 (dd, J = 46.6, 3.1 Hz, 1H), 5.12 (dd, J = 15.6, 3.1 Hz, 1H), 5.07–4.99 (m, 1H), 4.92–4.84 (m, 1H), 4.72–4.65 (m, 1H), 4.65–4.58 (m, 1H), 2.76–2.67 (m, 1H), 2.01–1.91 (m, 2H), 1.86–1.74 (m, 2H), 1.68–1.53 (m, 4H), 1.45–1.34 (m, 2H). (Compound 325)

[1199] 11H NMR (500 MHz, CDCl3) δ 8.56 (dd, J = 4.5, 1.5 Hz, 1H), 8.12 (dd, J = 8.0, 1.5 Hz, 1H), 7.24 (dd, J = 8.0, 4.5 Hz, 1H), 6.00–5.92 (m, 1H), 5.68 (dd, J = 46.7, 3.1 Hz, 1H), 5.13 (dd, J = 15.6, 3.1 Hz, 1H), 5.06–4.98 (m, 1H), 4.94–4.85 (m, 1H), 4.70–4.60 (m, 2H), 3.30–3.19 (m, 1H), 3.10–2.98 (m, 2H), 2.96–2.81 (m, 2H). (Compound 326)

[1200] 1 1H NMR (500 MHz, CDCl3) δ 8.55 (dd, J = 4.5, 1.3 Hz, 1H), 8.37 (dd, J = 8.0, 1.3 Hz, 1H), 7.60 (d, J = 7.4 Hz, 2H), 7.50 (d, J = 16.7 Hz, 1H), 7.44–7.35 (m, 3H), 7.32 (t, J = 7.3 Hz, 1H), 7.24 (dd, J = 8.0, 4.5 Hz, 1H), 6.42 (dd, J = 17.0, 1.8 Hz, 1H), 6.30 (dd, J = 17.0, 10.3 Hz, 1H), 6.00–5.90 (m, 1H), 5.74 (dd, J = 10.3, 1.8 Hz, 1H), 4.93–4.84 (m, 1H), 4.78–4.68 (m, 2H), 4.67–4.60 (m, 1H). (Compound 327)

[1201] 1 1H NMR (500 MHz, CDCl3) δ 8.55 (dd, J = 4.5, 1.5 Hz, 1H), 8.10 (dd, J = 8.0, 1.5 Hz, 1H), 7.23 (dd, J = 8.0, 4.5 Hz, 1H), 6.39 (dd, J = 17.0, 1.8 Hz, 1H), 6.25 (dd, J = 17.0, 10.3 Hz, 1H), 5.98–5.89 (m, 1H), 5.72 (dd, J = 10.3, 1.8 Hz, 1H), 4.92–4.83 (m, 1H), 4.76–4.68 (m, 1H), 4.67–4.56 (m, 2H), 3.30–3.20 (m, 1H), 2.64–2.52 (m, 1H), 2.43–2.23 (m, 3H), 2.23–2.04 (m, 2H). (Compound 328)

[1202] 11H NMR (500 MHz, CDCl3) δ 8.55 (dd, J = 4.5, 1.5 Hz, 1H), 8.10 (dd, J = 8.0, 1.5 Hz, 1H), 7.23 (dd, J = 8.0, 4.5 Hz, 1H), 5.99 - 5.91 (m, 1H), 5.68 (dd, J = 46.7, 3.1 Hz, 1H), 5.13 (dd, J = 15.6, 3.1 Hz, 1H), 5.05–4.98 (m, 1H), 4.93–4.85 (m, 1H), 4.70–4.59 (m, 2H), 3.30–3.21 (m, 1H), 2.64–2.52 (m, 1H), 2.42–2.25 (m, 3H), 2.22–2.03 (m, 2H). (Compound 329)

[1203] 1 1H NMR (500 MHz, CDCl3) δ 8.50 (dd, J = 4.5, 1.4 Hz, 1H), 8.23 (dd, J = 8.1, 1.4 Hz, 1H), 7.16 (dd, J = 8.0, 4.5 Hz, 1H), 6.69–6.62 (m, 1H), 6.58 (dd, J = 16.4, 6.4 Hz, 1H), 6.40 (dd, J = 17.0, 1.9 Hz, 1H), 6.27 (dd, J = 17.0, 10.3 Hz, 1H), 5.93–5.85 (m, 1H), 5.72 (dd, J = 10.3, 1.9 Hz, 1H), 4.87–4.79 (m, 1H), 4.74–4.55 (m, 3H), 2.28–2.18 (m, 1H), 1.92–1.85 (m, 2H), 1.84–1.76 (m, 2H), 1.75–1.67 (m, 1H), 1.43–1.30 (m, 2H), 1.29–1.19 (m, 3H). (Compound 330)

[1204] 11H NMR (500 MHz, CDCl3) δ 8.49 (dd, J = 4.5, 1.4 Hz, 1H), 8.22 (dd, J = 8.0, 1.4 Hz, 1H), 7.16 (dd, J = 8.0, 4.5 Hz, 1H), 6.66 (dd, J = 16.5, 0.7 Hz, 1H), 6.58 (dd, J = 16.4, 6.4 Hz, 1H), 5.96–5.87 (m, 1H), 5.68 (dd, J = 46.6, 3.0 Hz, 1H), 5.12 (dd, J = 15.6, 3.0 Hz, 1H), 5.04–4.95 (m, 1H), 4.93–4.79 (m, 1H), 4.74–4.66 (m, 1H), 4.65–4.55 (m, 1H), 2.29–2.18 (m, 1H), 1.94–1.85 (m, 2H), 1.84–1.76 (m, 2H), 1.75–1.67 (m, 1H), 1.42–1.31 (m, 2H), 1.30–1.18 (m, 3H). (Compound 331)

[1205] 1 1H NMR (500 MHz, CDCl3) δ 8.49 (dd, J = 4.5, 1.3 Hz, 1H), 8.15 (dd, J = 8.0, 1.3 Hz, 1H), 7.14 (dd, J = 8.0, 4.5 Hz, 1H), 6.75 (d, J = 16.1 Hz, 1H), 6.40 (dd, J = 17.0, 1.8 Hz, 1H), 6.27 (dd, J = 17.0, 10.3 Hz, 1H), 6.17 (dd, J = 16.1, 9.0 Hz, 1H), 5.92–5.84 (m, 1H), 5.72 (dd, J = 10.3, 1.8 Hz, 1H), 4.86–4.80 (m, 1H), 4.73–4.63 (m, 2H), 4.63–4.56 (m, 1H), 1.71 - 1.62 (m, 1H), 0.95–0.88 (m, 2H), 0.66–0.59 (m, 2H). (Compound 332)

[1206] 11H NMR (500 MHz, CDCl3) δ 8.48 (dd, J = 4.5, 1.5 Hz, 1H), 8.15 (dd, J = 8.1, 1.5 Hz, 1H), 7.14 (dd, J = 8.0, 4.5 Hz, 1H), 6.76 (d, J = 16.1 Hz, 1H), 6.18 (dd, J = 16.1, 9.1 Hz, 1H), 5.94–5.86 (m, 1H), 5.68 (dd, J = 46.6, 3.0 Hz, 1H), 5.12 (dd, J = 15.6, 3.0 Hz, 1H), 5.02–4.94 (m, 1H), 4.92–4.82 (m, 1H), 4.73–4.65 (m, 1H), 4.65–4.57 (m, 1H), 1.74–1.59 (m, 1H), 0.95–0.88 (m, 2H), 0.65–0.59 (m, 2H). (Compound 333)

[1207] 1 1H NMR (500 MHz, CDCl3) δ 8.58 (dd, J = 4.5, 1.4 Hz, 1H), 8.21 (dd, J = 8.0, 1.3 Hz, 1H), 7.66–7.60 (m, 2H), 7.29–7.24 (m, 1H), 7.13–7.06 (m, 2H), 6.04–5.95 (m, 1H), 5.69 (dd, J = 46.7, 3.1 Hz, 1H), 5.13 (dd, J = 15.6, 3.1 Hz, 1H), 5.10–5.02 (m, 1H), 4.97–4.88 (m, 1H), 4.76–4.62 (m, 2H). (Compound 334)

[1208] 1 1H NMR (500 MHz, CDCl3) δ 8.59 (dd, J = 4.5, 1.5 Hz, 1H), 8.21 (dd, J = 8.0, 1.5 Hz, 1H), 7.46–7.41 (m, 1H), 7.40–7.32 (m, 2H), 7.28 (dd, J = 8.0, 4.5 Hz, 1H), 7.15–7.09 (m, 1H), 6.04–5.96 (m, 1H), 5.69 (dd, J = 46.7, 3.1 Hz, 1H), 5.14 (dd, J = 15.6, 3.1 Hz, 1H), 5.10–5.03 (m, 1H), 4.97–4.89 (m, 1H), 4.75–4.63 (m, 2H). (Compound 335)

[1209] 11H NMR (500 MHz, CDCl3) δ 8.59 (dd, J = 4.5, 1.4 Hz, 1H), 8.21 (dd, J = 8.0, 1.4 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.28 (dd, J = 8.0, 4.5 Hz, 1H), 6.05–5.95 (m, 1H), 5.69 (dd, J = 46.7, 3.1 Hz, 1H), 5.14 (dd, J = 15.6, 3.0 Hz, 1H), 5.10–5.02 (m, 1H), 4.97–4.89 (m, 1H), 4.75–4.62 (m, 2H). (Compound 337)

[1210] 1 1H NMR (500 MHz, CDCl3) δ 8.59 (dd, J = 4.5, 1.5 Hz, 1H), 8.23 (dd, J = 8.0, 1.5 Hz, 1H), 7.91 (s, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.29 (dd, J = 8.0, 4.5 Hz, 1H), 6.00 (dq, J = 8.2, 5.8 Hz, 1H), 5.69 (dd, J = 46.7, 3.1 Hz, 1H), 5.14 (dd, J = 15.6, 3.1 Hz, 1H), 5.10–5.02 (m, 1H), 4.98–4.88 (m, 1H), 4.76–4.62 (m, 2H). (Compound 338)

[1211] 1 1H NMR (500 MHz, CDCl3) δ 8.55 (dd, J = 4.5, 1.4 Hz, 1H), 8.34 (dd, J = 8.1, 1.3 Hz, 1H), 7.57 (dd, J = 8.6, 5.4 Hz, 2H), 7.46 (d, J = 16.6 Hz, 1H), 7.31 (d, J = 16.6 Hz, 1H), 7.23 (dd, J = 8.0, 4.5 Hz, 1H), 7.10 (t, J = 8.6 Hz, 2H), 5.96 (dq, J = 8.3, 5.8 Hz, 1H), 5.70 (dd, J = 46.6, 3.0 Hz, 1H), 5.15 (dd, J = 15.6, 3.0 Hz, 1H), 5.06–4.98 (d, J = 4.5 Hz, 1H), 4.96–4.88 (m, 1H), 4.77–4.70 (m, 1H), 4.69–4.62 (m, 1H). (Compound 339)

[1212] 1 1H NMR (500 MHz, CDCl3) δ 8.55 (dd, J = 4.5, 1.5 Hz, 1H), 8.34 (dd, J = 8.1, 1.5 Hz, 1H), 7.50–7.43 (m, 1H), 7.42–7.32 (m, 3H), 7.31–7.27 (m, 1H), 7.24 (dd, J = 8.1, 4.5 Hz, 1H), 7.04–6.97 (m, 1H), 5.96 (tt, J = 8.3, 5.8 Hz, 1H), 5.70 (dd, J = 46.6, 3.0 Hz, 1H), 5.14 (dd, J = 15.6, 3.1 Hz, 1H), 5.07–4.99 (m, 1H), 4.96–4.87 (m, 1H), 4.78–4.70 (m, 1H), 4.69–4.61 (m, 1H).

[1213] (Compound 340)

[1214] 1 1H NMR (500 MHz, CDCl3) δ 8.54 (dd, J = 4.5, 1.4 Hz, 1H), 8.37 (dd, J = 8.1, 1.4 Hz, 1H), 7.68 (td, J = 7.7, 1.4 Hz, 1H), 7.64 (d, J = 16.9 Hz, 1H), 7.47 (d, J = 16.8 Hz, 1H), 7.31–7.26 (m, 1H), 7.24 (dd, J = 8.1, 4.5 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 7.14–7.08 (m, 1H), 5.96 (tt, J = 8.3, 5.8 Hz, 1H), 5.69 (dd, J = 46.6, 3.0 Hz, 1H), 5.14 (dd, J = 15.6, 3.0 Hz, 1H), 5.06–4.98 (m, 1H), 4.96–4.86 (m, 1H), 4.78–4.70 (m, 1H), 4.69–4.63 (m, 1H). (Compound 341)

[1215] 1H NMR (500 MHz, DMSO-d6) δ 8.82 (dd, J = 8.1, 1.6 Hz, 1H), 8.64 (dd, J = 4.5, 1.5 Hz, 1H), 8.04–7.92 (m, 2H), 7.90–7.75 (m, 3H), 7.71 (d, J = 16.8 Hz, 1H), 7.41 (dd, J = 8.0, 4.5 Hz, 1H), 5.98 (tt, J = 8.5, 5.3 Hz, 1H), 5.57 (dd, J = 48.5, 3.5 Hz, 1H), 5.46–5.23 (m, 1H), 5.07–4.72 (m, 2H), 4.70–4.34 (m, 2H). (Compound 344)

[1216] 1 1H NMR (500 MHz, DMSO-d6) δ 8.85 (dd, J = 8.1, 1.7 Hz, 1H), 8.64 (dd, J = 4.3, 1.6 Hz, 1H), 8.24–8.11 (m, 2H), 7.86–7.71 (m, 2H), 7.65 (d, J = 6.3 Hz, 2H), 7.40 (dd, J = 8.1, 4.5 Hz, 1H), 5.98 (tt, J = 8.3, 5.3 Hz, 1H), 5.65–5.49 (m, 1H), 5.38 (dd, J = 16.6, 3.5 Hz, 1H), 5.01–4.73 (m, 2H), 4.66–4.41 (m, 2H). (Compound 345)

[1217] 1 1H NMR (500 MHz, DMSO-d6) δ 8.70 (dd, J = 4.5, 1.5 Hz, 1H), 8.38 (dd, J = 8.1, 1.5 Hz, 1H), 7.81 (td, J = 7.5, 1.8 Hz, 1H), 7.64–7.50 (m, 1H), 7.50–7.28 (m, 3H), 6.00 (tt, J = 8.2, 5.2 Hz, 1H), 5.56 (dd, J = 48.4, 3.6 Hz, 1H), 5.37 (dd, J = 16.5, 3.6 Hz, 1H), 5.02–4.69 (m, 2H), 4.69–4.28 (m, 2H). (Compound 347)

[1218] 11H NMR (500 MHz, DMSO-d6) δ 8.70 (dd, J = 4.5, 1.5 Hz, 1H), 8.38 (dd, J = 8.1, 1.4 Hz, 1H), 7.85 (dd, J = 7.6, 1.8 Hz, 1H), 7.67 (dd, J = 7.9, 1.3 Hz, 1H), 7.60–7.29 (m, 3H), 6.01 (tt, J = 8.3, 5.3 Hz, 1H), 5.57 (dd, J = 48.4, 3.6 Hz, 1H), 5.37 (dd, J = 16.5, 3.5 Hz, 1H), 5.06–4.66 (m, 2H), 4.53 (ddd, J = 74.3, 10.9, 7.4 Hz, 2H). (Compound 348)

[1219] 1 1H NMR (500 MHz, DMSO-d6) δ 8.71 (dt, J = 4.6, 1.5 Hz, 1H), 8.28 (dd, J = 8.0, 1.5 Hz, 1H), 8.00 (d, J = 7.7 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.75–7.61 (m, 1H), 7.48 (ddd, J = 8.1, 4.6, 1.2 Hz, 1H), 6.01 (tt, J = 8.3, 5.3 Hz, 1H), 5.64–5.45 (m, 1H), 5.44–5.29 (m, 1H), 5.04–4.74 (m, 2H), 4.53 (ddd, J = 70.5, 10.8, 7.5 Hz, 2H). (Compound 349)

[1220] Comparative Example

[1221] The following Comparative Examples (as shown in Table 5) were prepared by a method similar to Examples 1 - 349 using different reaction starting materials and appropriate reagents.

[1222] Table 5

[1223]

[1224]

[1225] Example A CTGF Detection (ELISA Method)

[1226] Detection of CTGF expression level can evaluate the activity of YAP / TAZ-TEAD transcription complex. The human-derived SimpleStep kit (Abcam, ab261851) was used to quantitatively detect the CTGF expression level.

[1227] NCI-H2052 cells (purchased from ATCC) were cultured in RPMI 1640 complete medium (containing 10% FBS, 1% penicillin-streptomycin solution and 1 mM sodium pyruvate). One day before treatment with the compound, the cultured cells were washed with FBS and digested with trypsin, and then collected by centrifugation. The supernatant was removed, and the cells were resuspended in fresh complete medium. After cell counting, the cells were seeded in a 96-well plate at 6500 cells / well. Then the cells were cultured overnight in an incubator (37 °C, 5% CO2).

[1228] After culturing the cells overnight, the culture supernatant was discarded, and the cells were washed with PBS solution. 200 μl of medium containing the compound was added to each well to culture the cells. The initial concentration was 10 μM, and serial dilutions were performed in DMSO and medium, with the final DMSO concentration being 0.5% (the final compound concentrations were 10000, 2500, 625, 156, 39.1, 9.77, 2.44, 0.61 nM, 0 nM (0.5% DMSO)), and then the cells were cultured in an incubator (37 °C, 5% CO2). After culturing for 24 hours, the cells were centrifuged at 1500 RPM for 5 minutes at 4 °C, and then 50 μl of the culture supernatant was taken for CTGF ELISA detection.

[1229] The human CTGF ELISA kit (Abcam, ab261851) uses a capture antibody labeled with an affinity tag and a detection antibody conjugated with a reporter gene, and can immuno-capture the sample analyte in the solution. The whole complex (capture antibody / analyte / detector antibody) is sequentially immobilized by the immunoaffinity of the anti-tag antibody in the coated wells. During detection, the sample or standard is added to the wells, and then an antibody mixture (capture antibody / detection antibody) is added and incubated. After incubation, the wells of the washing plate are washed to remove the un-fixed materials in each sample well. During the incubation catalyzed by HRP, the addition of TMB developing solution results in a blue color. Then the reaction is terminated by adding a stop solution, and the solution changes from blue to yellow. The absorption intensity is measured at 450 nm, and the generation of its signal value is proportional to the amount of the bound analyte. First, prepare all the reagents, samples and controls according to the instructions. Add 50 μl of the standard or the cell supernatant sample to be tested to the wells of the detection plate. Then add 50 μl of the antibody Cocktail to each well. Seal the plate and incubate on a plate shaker at room temperature for 1 hour. Wash each well 3 times with the washing buffer. Add 100 μl of the TMB developing solution to each well and incubate in the dark on a shaker for 10 minutes. Then add 100 μl of the stop solution to each well. Shake on a plate shaker for 1 minute to mix well. Record the OD value at 450 nm. Determine the concentration of the target CTGF protein in the sample through the standard curve.

[1230] EC 50Values were calculated by fitting the concentration-response curves using GraphPad Prism software. The inhibitory activity of the compounds of the present invention against the transcriptional regulatory function of TEAD-YAP / TAZ was tested by the CTGF concentration-response curves of the compounds.

[1231] Data for the example compounds obtained using the above CTGF ELISA assay are provided in Table 6.

[1232] Table 6

[1233]

[1234]

[1235]

[1236]

[1237]

[1238] Example B BRDU assay

[1239] Using the Cell Proliferation Kit from PerkinElmer (PerkinElmer, Cat: AD0200), the inhibition of the proliferation of NCI-H226 cells (ATCC, CRL-5826) by the compounds was detected.

[1240] a) Seed NCI-H226 cells at a density of 1500 cells / well in a 96-well plate.

[1241] b) After 24 hours, add the compounds and medium containing 1% FBS to each well. The final test concentrations of the compounds to be tested were 20000, 6666.667, 2222.222, 740.741, 246.914, 82.305, 27.435, 9.145, 3.048, 0.102 nM, respectively.

[1242] c) Incubate the NCI-H226 cells with the compounds in an incubator for 72 hours.

[1243] d) Add 2 μL of BrdU labeling reagent diluted 100-fold with medium to each well, and then culture the NCI-H226 cells in a 5% CO2 incubator at 37 °C for 24 hours.

[1244] e) Add the detection reagent according to the BrdU kit without removal, and finally read the luminescence signal values of each well on a multi-functional microplate reader Envision.

[1245] Data analysis:

[1246] The IC was calculated using GraphPad Prism 6 software 50 and the dose - effect curve of the compound was plotted.

[1247] Y = Bottom+(Top - Bottom) / (1 + 10^((LogIC 50 -X)×HillSlope)).

[1248] Y is the inhibition rate %,

[1249] X is the logarithm of the compound concentration.

[1250] Inhibition rate %=(Signal value HC - Signal value comp ) / (Signal value HC - Signal value LC );

[1251] HC (high control) is the DMSO group,

[1252] LC (low control) is the 10 μM Staurosporine group,

[1253] Comp is the administration group.

[1254] The IC 50 values of the obtained example compounds are shown in Table 7, and the inhibition curves in NCI - H226 cells are as Figures 1-7 shown, where the X - axis is the compound concentration (nm) and the Y - axis is the inhibition rate %.

[1255] Table 7: Proliferation inhibition ability (IC 50 ) of the compound in NCI - H226 cells

[1256]

[1257]

[1258] Pharmacokinetic study of the compound in mouse plasma after PO administration of Example C Cassette

[1259] Adult Balb / C female mice (6 - 7 weeks old, Vital River) were administered the test compound in a cassette, which contained 10 - 20% DMSO, 10% Solutol (KollipHor HS15, Beijing Fengli Jingqiu Pharmaceutical Co., Ltd.), and 80 - 70% water as excipients. The mice (n = 3) were orally administered (gavage) at a dose of 5 mg / kg. Blood sampling times: 30 min, 2 h, 4 h. Approximately 0.1 mL of whole blood was collected from the retro - orbital venous plexus and placed in a tube containing EDTA anticoagulant. The samples were centrifuged at 4000 rpm for 10 min at 4°C. Before analysis, the plasma was transferred to a centrifuge tube and stored at - 20°C. The concentration of the test compound in the plasma samples was analyzed by liquid chromatography - tandem mass spectrometry (LC - MS / MS). The plasma concentration - time data of individual animals were analyzed using Microsoft Excel 2010. A non - compartmental model was introduced in the concentration analysis. WinNonlin (version 4.1; pHarsight) software was used to calculate the pharmacokinetic parameters of the test compound. As shown in Table 8, the test compound showed good pharmacokinetic characteristics.

[1260] Table 8

[1261]

[1262]

[1263] Example D In Vivo Pharmacodynamics and Efficacy Studies

[1264] In vivo pharmacodynamics and efficacy studies of Compound 5, Compound 6, and Compound 124 in a BALB / c nude mouse subcutaneous NCI - H226 human lung squamous cell carcinoma xenograft model.

[1265] Methods:

[1266] Each mouse (D000521 BALB / c - Nu, Jicuiyaokang) was subcutaneously inoculated with NCI - H226 tumor cells (ATCC, CRL - 5826) (1x10 7 ) on the right side. The cells were dissolved in 0.2 mL of PBS (Corning, 356234) containing 50% matrigel matrix gel. Treatment was started when the average tumor size reached approximately 100 - 150 mm 3 . From the day of grouping, the test article was orally administered to the mice once a day for 28 days (QD×28 days). The body weight changes of the animals were regularly monitored as an indicator of drug safety. The tumor volume was measured twice a week in two dimensions using calipers, and the volume was in mm 3It is shown that the formula "V=(L×W²) / 2" is used, where V is the tumor volume, L is the tumor length (the longest tumor dimension), and W is the tumor width (the longest tumor dimension perpendicular to L). The therapeutic effect was evaluated by tumor growth inhibition TGI (%). TGI (%) = [1-(Ti-T0) / (Vi-V0)]×100; Ti is the average tumor volume of a certain treatment group on a certain day, T0 is the average tumor volume of the treatment group on day 0, Vi is the average tumor volume of the vehicle control group on the same day as Ti, and V0 is the average tumor volume of the excipient group on day 0. The results are shown in Table 9, Figure 8 and Figure 9 . The results are shown in Table 9, Figure 8 and Figure 9 as follows.

[1267] Table 9 Calculation of tumor growth inhibition in the NCI-H226 xenograft model based on tumor volume on day 28

[1268]

[1269] Results

[1270] On the 28th day after treatment, significant anti-tumor activities were observed in the groups of Compound 5 (2 mg / kg), Compound 5 (10 mg / kg), Compound 5 (50 mg / kg), Compound 6 (2 mg / kg), Compound 6 (10 mg / kg), and Compound 124 (2 mg / kg) compared with the excipient group in terms of tumor volume. The p-values were 0.0111, 0.0011, 0.0007, 0.007, 0.0026, and 0.0284, respectively. The TGI (%) values were 76.9%, 101.3%, 105.9%, 77.1%, 88.6%, and 67.3%, respectively. In this model, as Figure 9 shown, no significant weight loss was observed during the treatment with Compound 5, Compound 6, and Compound 124 administered daily.

Claims

1. A compound as shown below, or a pharmaceutically acceptable salt thereof, wherein, is a single bond or a double bond; L1 is a bond; Ring B is phenyl or a 6-membered heteroaryl containing 1 or 2 N atoms; Ring E is phenyl or a 6-membered heteroaryl, and the 6-membered heteroaryl contains 1 or 2 N heteroatoms; L2 is a bond; Ring D is a 4- to 5-membered N-containing heterocyclic group, and the 4- to 5-membered N-containing heterocyclic group contains 1 or 2 N heteroatoms; R1 is H, halogen, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy; R2 is H or C 1-6 haloalkyl; R3 is H or C 1-6 alkyl; L3 is a bond; R5, R6 and R7 are each independently selected from H and halogen; x and m are independently selected from 0 or 1.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is H or C 1-4 haloalkyl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1 is H, halogen, C 1-6 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1 is H, halogen or C 1-6 alkyl.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Ring D is a 4- to 5-membered N-containing heterocyclic group containing 1 N heteroatom.

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R3 is H or C 1-3 alkyl.

7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R3 is H or methyl.

8. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein selected from wherein represents a linkage site with L1 or L2.

9. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring D is selected from wherein represents the attachment site to L1.

10. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring D is selected from wherein represents the attachment site to L1.

11. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring E is selected from 12. A compound as described below, or a pharmaceutically acceptable salt thereof, wherein, The compound is: 1) 1-(1-(2-Fluoropropenoyl)azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 2) 2-Fluoro-1-(3-(4-(4-(trifluoromethyl)phenyl)quinazolin-2-yl)azetidin-1-yl)prop-2-en-1-one; 3) 1-(1-Acrylpyrrolidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 4) 1-(1-Acrylazetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 5) 1-(1-(2-Fluoropropenoyl)-3-methylazetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 6) 3-(1-(2-Fluoropropenoyl)-3-methylazetidin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; 7) 1-(1-(2-Fluoropropenoyl)azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; 8) 1-(1-(2-Fluoropropenoyl)azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one; 9) 1-(1-(2-Fluoropropenoyl)azetidin-3-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one; 10) 3-(1-(2-Fluoropropenoyl)azetidin-3-yl)-5-methyl-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; 11) 3-(1-(2-Fluoropropenoyl)azetidin-3-yl)-5-methyl-1-(6-(trifluoromethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; 12) 3-(1-(2-Fluoropropenoyl)azetidin-3-yl)-6-methyl-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; 13) 3-(1-(2-Fluoropropenoyl)azetidin-3-yl)-6-(trifluoromethyl)-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro -2H-imidazo[4,5-b]pyridin-2-one; 14) 3-(1-(2-Fluoropropenoyl)azetidin-3-yl)-6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; 15) 1-(1-(2-Fluoropropenoyl)azetidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one; 16) 3-(1-(2-Fluoropropenoyl)azetidin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one; 17) 6-Chloro-3-(1-(2-Fluoropropenoyl)azetidin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; 18) 9-(1-(2-Fluoropropenoyl)azetidin-3-yl)-7-(4-(trifluoromethyl)phenyl)-7,9-dihydro-8H-purin-8-one; 19) 3-(1-(2-Fluoropropenoyl)azetidin-3-yl)-5-methoxy-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; 20) 5-Chloro-3-(1-(2-Fluoropropenoyl)azetidin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; or 21) 6-Fluoro-3-(1-(2-Fluoropropenoyl)azetidin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one.

13. A pharmaceutical composition comprising the compound according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

14. A pharmaceutical composition comprising the compound according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

15. Use of the composition according to claim 13 or 14, or the compound according to any one of claims 1-12, in the manufacture of a medicament for the prevention and / or treatment of diseases mediated by YAP / TAZ-TEAD.

16. Use according to claim 15, wherein the medicament is for the treatment and prevention of cancer.

17. The use according to claim 16, wherein the cancer is thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, brain cancer, kidney cancer, liver cancer, squamous cell carcinoma, gastrointestinal cancer, mesothelioma, prostate cancer, ovarian cancer or breast cancer.

18. The use according to claim 17, wherein the melanoma is multiple melanoma.

19. The use according to claim 17, wherein the gastrointestinal cancer is gastric cancer or colon cancer.

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