Biaryl derivatives as inhibitors of YAP / TAZ-TEAD protein-protein interaction

Abstract

The invention relates to a biaryl derivative serving as a YAP / TAZ-TEAD protein-protein interaction inhibitor, and particularly provides a compound with a formula (I) or a pharmaceutically acceptable salt thereof. A method for preparing said compounds and its therapeutic use. The invention further provides a combination of pharmacologically active agents and a pharmaceutical composition comprising the compound. # imgabs0 #

Description

[0001] This application is a divisional application of the international application filed on March 15, 2021, with application number PCT / IB2021 / 052136 and the invention title "Biaryl Derivative as a Protein-Protein Interaction Inhibitor of YAP / TAZ-TEAD". The international application entered the Chinese national phase on September 14, 2022, with application number 202180021187.1. Technical Field

[0002] The present invention provides a biaryl derivative compound, its use in inhibiting YAP / TAZ-TEAD protein-protein interaction (PPI), and a method of treating diseases using said compound. Background Technology

[0003] Normal tissue growth, repair, and remodeling all require specific control of transcriptional activity and regulation of its balance. Transcriptional output is coordinated through several key signaling modules, one of which is the Hippopathway. Genetic studies in Drosophila and mammals have defined a conserved core signaling cassette composed of MST1 / 2 and LATS1 / 2 kinases that inhibit the transcriptional coactivators YAP and TAZ (official gene name: WWTR1).

[0004] Activation of the hippocampal pathway leads to phosphorylation of YAP and TAZ and their chelation / degradation in the cytoplasm. Following inactivation of the hippocampal pathway, YAP and TAZ translocate to the nucleus and bind to transcription factors (i.e., members of the TEAD family (TEAD1-4)). The YAP / TAZ-TEAD complex further promotes the transcription of downstream genes involved in cell proliferation, death, and differentiation. Although YAP and TAZ can also interact with many other factors, TEAD is generally considered a key mediator of YAP and TAZ's growth-promoting and tumorigenic potential (pathway reviews in: Yu et al., 2015; Holden and Cunningham, 2018).

[0005] Therefore, overactivation of YAP and / or TAZ (and subsequently, overactivation of the YAP / TAZ-TEAD transcriptional complex) is commonly observed in several human cancers. This is evidenced by elevated YAP / TAZ levels and nuclear localization in many tumors, including breast cancer, lung cancer (e.g., non-small cell lung cancer, NSCLC), ovarian cancer, colorectal cancer, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer, and bone cancer (sarcoma) (Steinhardt et al., 2008; Harvey et al., 2013; Moroishi et al., 2015; extensively reviewed in Zanconato et al., 2016, and references therein).

[0006] Although genetic alterations in the core hippocampal pathway have been detected at a limited frequency in major samples to date, the most prominent cancerous malignancy associated with inactivation mutations in NF2 or LATS1 / 2 and associated YAP / TEAD overactivation is malignant pleural mesothelioma (MPM) (reviewed in Sekido, 2018). Similarly, many human tumors are characterized by YAP amplification at the 11q22.1 locus (e.g., hepatocellular carcinoma, medulloblastoma, esophageal squamous cell carcinoma), TAZ (WWTR1) amplification at the 3q25.1 locus (e.g., rhabdomyosarcoma, triple-negative breast cancer), or gene fusions involving YAP or TAZ (epithelial hemangioendothelioma, ependymal tumors) (reviewed in Yu et al., 2015, and references therein). Like MPM, these tumors are expected to depend on their elevated YAP / TAZ-TEAD activity.

[0007] Disrupting the YAP / TAZ-TEAD protein-protein interaction (PPI) (as the most distal effector node in the hippocampal pathway) holds promise for eliminating the carcinogenic potential of this complex. Designing and optimizing the compounds of this invention to bind to TEAD and selectively disrupt their interactions with YAP and TAZ is considered potentially yielding drugs for treating the aforementioned cancers. In particular, these cancers are characterized by (but not limited to) certain described aberrations.

[0008] Notably, tumor cells with activated YAP / TAZ-TEAD exhibit resistance to chemotherapy, which may be related to the YAP / TAZ that confers stem cell-like characteristics to cancer. Furthermore, YAP / TAZ-TEAD also confers resistance to molecularly targeted therapies (e.g., BRAF, MEK, or EGFR inhibitors), as reported by various genetic and pharmacological screenings (Kapoor et al., 2014; Shao et al., 2014; Lin et al., 2015). This, in turn, suggests that inhibiting YAP / TAZ-TEAD activity (in parallel or sequentially with other cancer treatments) could provide beneficial therapeutic effects by reducing the growth of tumors resistant to other therapies.

[0009] Inhibition of YAP / TAZ-TEAD activity following PPI disruption with the aforementioned LMW compounds may also reduce tumor evasion of immune surveillance. This is evidenced, for example, by reported data showing that YAP promotes the expression of the chemokine CXCL5, leading to the recruitment of myeloid cells, which suppressor T cells (Wang et al., 2016). YAP in Tregs (regulatory T cells) has also been shown to support FOXP3 expression via activin signaling and Treg function. Therefore, YAP deficiency leads to Treg dysfunction, thus failing to suppress antitumor immunity. Thus, selective inhibition of YAP / TEAD activity by preventing Treg function may help enhance antitumor immunity (Ni et al., 2018). Recent literature also shows that YAP upregulates PD-L1 expression and directly mediates the escape of cytotoxic T cell immune responses (e.g., in BRAF inhibitor-resistant melanoma cells) through this mechanism (Kim et al., 2018).

[0010] See, for example:

[0011] Yu, FX., Zhao, B. and Guan, K.-L. (2015). Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell, 163, 811-828.

[0012] Holden, JK and Cunningham, CN (2018). Targeting the Hippo pathway and cancer through the TEAD family of transcription factors. Cancers (Basel), 10, E81.

[0013] Steinhardt, AA, Gayyed, MF, Klein, AP, Dong, J., Maitra, A., Pan, D., Montgomery, EA, Anders, RA (2008). Expression of Yes-associated protein incommon solid tumors. Hum. Pathol., 39, 1582-1589.

[0014] Harvey,K.F.,Zhang,X.,and Thomas,D.M.(2013).The Hippo pathway andhuman cancer.Nat.Rev.Cancer,13,246-257.

[0015] Moroishi,T.,Hansen,C.G.,and Guan,K.-L.(2015).Nat.Rev.Cancer,15,73-79.

[0016] Zanconato,F.,Cordenonsi,M.,and Piccolo,S.(2016).YAP / TAZ at the rootsof cancer.Cancer Cell,29,783-803.

[0017] Sekido,Y.(2018).Cancers(Basel),10,E90.

[0018] Kapoor,A.,Yao,W.,Ying,H.,Hua,S.,Liewen,A.,Wang,Q.,Zhong,Y.,Wu,C.J.,Sadanandam,A.,Hu,B.et al.(2014).Yap1 activation enables bypass of oncogenicKras addiction in pancreatic cancer.Cell,158,185-197.

[0019] Shao,D.D.,Xue,W.,Krall,E.B.,Bhutkar,A.,Piccioni,F.,Wang,X.,Schinzel,A.C.,Sood,S.,Rosenbluh,J.,Kim,J.W.,et al.(2014).KRAS and YAP1 converge toregulate EMT and tumor survival.Cell,158,171-184.

[0020] Lin, L., Sabnis, AJ, Chan, E., Olivas, V., Cade, L., Pazarentzos, E., Asthana, S., Neel, D., Yan, JJ, Lu,

[0021] Wang, G., Lu,

[0022] Ni,

[0023] Kim, MH, Kim, CG, Kim, SK, Shin, SJ, Choe, EA, Park, SH, Shin, EC, and Kim, J. (2018). Cancer Immunol Res., 6, 255-266. Summary of the Invention

[0024] There is an ongoing need to develop novel YAP / TAZ-TEAD protein-protein interaction (PPI) inhibitors, which are promising candidates. These candidates are particularly valuable for cancer treatment, especially mesothelioma (including malignant pleural mesothelioma), pancreatic cancer, sarcoma, and non-small cell lung cancer (e.g., NF2-mutant NSCLC).

[0025] This invention provides compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof, which are YAP / TAZ-TEAD protein-protein interaction inhibitors. The invention further provides methods for treating, preventing, or alleviating cancer, comprising administering an effective amount of a YAP / TAZ-TEAD PPI inhibitor to a subject in need. For therapeutic purposes, the YAP / TAZ-TEAD PPI compounds of this invention can be used in combination with cancer immunotherapy agents such as immune checkpoint inhibitors (e.g., anti-PD-1 antibodies).

[0026] This document describes various embodiments of the present invention.

[0027] In some respects, this article provides compounds having formula (I) or pharmaceutically acceptable salts thereof:

[0028]

[0029] A, Q, W, X, Y, Z, R2, R3, R4, R5, and R6 are as defined in this paper.

[0030] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound as defined by formula (I) or a pharmaceutically acceptable salt thereof or a sub-formula (Ia), (Ia*), (Ia-1), (Ib), (Ic), (Id) as defined herein, and one or more pharmaceutically acceptable carriers.

[0031] In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound as defined by formula (I) or a pharmaceutically acceptable salt thereof or a subformula of formula (Ia), (Ia*), (Ia-1), (Ib), (Ic), (Id), and optionally one or more pharmaceutically acceptable carriers.

[0032] In another embodiment, the present invention provides a combination, particularly a pharmaceutical combination, comprising a compound as defined by formula (I) or a pharmaceutically acceptable salt thereof or a subformula of formula (Ia), (Ia*), (Ia-1), (Ib), (Ic), (Id), and one or more therapeutically active agents.

[0033] In another embodiment, the present invention relates to a method for inhibiting the protein-protein interaction activity of YAP / TAZ-TEAD in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound having formula (I) or its sub-formulas (Ia), (Ia*), (Ia-1), (Ib), (Ic), (Id) as defined herein, or a pharmaceutically acceptable salt thereof.

[0034] In yet another embodiment, the present invention relates to a method for treating a disorder or disease in a subject in need, wherein the disorder or disease is selected from the following cancers or tumors: mesothelioma (including pleural mesothelioma, malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, and tunica vaginalis mesothelioma), carcinoma (including cervical squamous cell carcinoma, endometrial carcinoma, esophageal squamous cell carcinoma, esophageal adenocarcinoma, bladder urothelial carcinoma, and cutaneous squamous cell carcinoma), poroma (benign poroma), porocarcinoma (including malignant porocarcinoma), supratentorial ependymoma (including pediatric supratentorial ependymoma), epithelioid hemangioendothelioma (EHE), ependymal tumor, solid tumor, breast cancer (including triple-negative breast cancer), lung cancer (including non-small cell lung cancer), ovarian cancer, colorectal cancer (including colon cancer), melanoma, pancreatic cancer (including pancreatic adenocarcinoma), prostate cancer, gastric cancer, Esophageal cancer, liver cancer (including hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma), neuroblastoma, schwannoma, renal cancer, sarcoma (including rhabdomyosarcoma, embryonal rhabdomyosarcoma (ERMS), osteosarcoma, undifferentiated pleomorphic sarcoma (UPS), Kaposi's sarcoma, soft tissue sarcoma, and rare soft tissue sarcoma), bone cancer, brain cancer, medulloblastoma, glioma, meningioma, and head and neck cancer (including squamous cell carcinoma of the head and neck), more particularly, breast cancer, lung cancer, ovarian cancer, colorectal cancer, malignant pleural mesothelioma, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer, and bone cancer, wherein the method comprises administering to the subject a therapeutically effective amount of a compound having formula (I) or its sub-formulas (Ia), (Ia*), (Ia-1), (Ib), (Ic), (Id) as defined herein, or a pharmaceutically acceptable salt thereof.

[0035] In another embodiment, the present invention relates to a method for inhibiting the formation of a YAP / TAZ-TEAD complex in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound having formula (I) or its sub-formulas (Ia), (Ia*), (Ia-1), (Ib), (Ic), (Id) as defined herein, or a pharmaceutically acceptable salt thereof.

[0036] In another embodiment, the present invention relates to a method for inhibiting the formation of a YAP / TAZ-TEAD complex in a subject, wherein the method comprises administering to the subject a compound having formula (I) or its sub-formulas (Ia), (Ia*), (Ia-1), (Ib), (Ic), (Id) as defined herein, or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION

[0037] In a first aspect, the present invention provides a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0038]

[0039] in

[0040] W is selected from O; and CH-R w ;

[0041] X is selected from CH; and N;

[0042] Y is selected from CH; and N;

[0043] Z is selected from CH2; O; and NH;

[0044] When Y is N, W is CH-R. w And Z is O;

[0045] A is selected from

[0046] (i) Phenyl, wherein the phenyl is optionally substituted by: halogenation; or halogenation of C1-C3 alkoxy;

[0047] (ii) a 5- or 6-membered aromatic heterocycle comprising at least one heteroatom selected from N, O, and S, preferably N and S, wherein the aromatic heterocycle is optionally substituted with: a hydroxyl group; a C1-C3 alkoxy group; or an oxo group; and

[0048] (iii) A halobenzodioxane moiety having the following formula:

[0049] R w Selected from: (i) hydrogen; (ii) hydroxyl; (iii) C1-C3 alkoxy; (iv) hydroxy-C1-C3 alkyl; (v) C1-C3 alkyl; and (vi) C1-C3 alkoxy-C1-C3 alkyl;

[0050] Q is selected from

[0051] (i)-C(R 7 )2-N(R 8 -R1;

[0052] (ii) a 9- or 10-membered partially saturated heteroaryl group containing at least one N heteroatom; and

[0053] (iii) A 4-, 5-, or 6-membered saturated heterocycle comprising at least one heteroatom or heteroatom group selected from N, O, S, -S(=O) and -S(=O)2, wherein at least one N heteroatom is present, wherein the heterocycle is unsubstituted or substituted by one or more substituents independently selected from hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, halogen and C1-C3 alkylene, which form a bridge between the two ring atoms of the saturated heterocycle, thereby forming a bridged bicyclic structure;

[0054] R1 is selected from: (i) hydrogen; (ii) C1-C6 alkyl (wherein the alkyl group is optionally deuterated in one embodiment, for example, fully deuterated); and (iii) (CH2). 0-2 R 1a ;

[0055] R 1a Selected from

[0056] (i) Hydroxyl C1-C4 alkyl;

[0057] (ii) C1-C3 alkoxy groups;

[0058] (iii) A 5- or 6-membered saturated heterocycle comprising at least one heteroatom selected from N and O, wherein the saturated heterocycle is optionally independently substituted once or more by: C1-C3 alkyl; (CH2) 0-1 C(O)bis(C1-C3 alkyl)amino; SO2C1-C3 alkyl; C(O)C1-C3 alkyl; or oxo;

[0059] (iv) C3-C6 cycloalkyl, optionally independently substituted once or more by: hydroxyl; hydroxyl C1-C4 alkyl; C1-C6 alkoxy (preferably C1-C4 alkoxy); C(O)OC1-C3 alkyl; CO2H; SO2C1-C3 alkyl; halo-C1-C3 alkyl; NHR 1b (CH2) 0-1 C(O)NR 1c R 1d (Preferred C(O)NR) 1c R 1d C1-C6 alkyl; halogenated C1-C3 alkoxy-C1-C3 alkyl; halogenated; a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from N, O, and S; or two R 1e Group,

[0060] Two R atoms attached to the same carbon atom 1e Together with the carbon atoms to which they are attached, they form a 5-membered saturated heterocycle or a C3-C6 cycloalkyl group containing at least one heteroatom selected from N (preferably) and O, wherein the saturated heterocycle or cycloalkyl group is optionally substituted with hydroxyl or oxo.

[0061] R 1b Selected from: (i) C(O)C1-C3 alkyl; and (ii) SO2C1-C3 alkyl;

[0062] R 1c and R 1d Each is independently selected from: (i) hydrogen; (ii) C1-C3 alkyl; and (iii) hydroxy C1-C4 alkyl, preferably selected from: (i) hydrogen and (ii) C1-C3 alkyl;

[0063] R2 is selected from: (i) hydrogen; and (ii) halogenated;

[0064] R3 is selected from: (i) halogenated; (ii) halogenated C1-C3 alkyl, especially selected from halogenated and monohalogenated methyl, dihalogenated methyl or preferably trihalogenated methyl; and (iii) cyano;

[0065] R4 is selected from: (i) hydrogen; (ii) halogenated; and (iii) C1-C3 alkyl, especially selected from hydrogen, halogenated, and methyl;

[0066] R5 is selected from

[0067] (i)Hydrogen;

[0068] (ii) C1-C6 alkoxy, which is optionally substituted by: C3-C6 cycloalkyl; CO2H; SO2C1-C3 alkyl; a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom; or a 5- or 6-membered saturated heterocycle containing at least one heteroatom selected from N and O, wherein the ring is optionally substituted by C(O)C1-C3 alkyl;

[0069] (iii) Halogenation;

[0070] (iv) Hydroxyl C1-C6 alkoxy group (wherein the alkoxy group is optionally deuterated in one embodiment, for example, fully deuterated);

[0071] (v) Halogenated C1-C6 alkoxy groups optionally substituted with hydroxyl groups;

[0072] (vi) S-halogenated C1-C3 alkyl groups optionally substituted with hydroxyl groups;

[0073] (vii)C1-C3 alkoxy group;

[0074] (viii)NR 5a R 5b ;

[0075] (ix)C1-C3 alkyl;

[0076] (x) comprises at least one heteroatom selected from N, O, and S, preferably a 5- or 6-membered aromatic heterocycle with at least one N heteroatom; and

[0077] (xi) hydroxyl group

[0078] R 5a and R 5b Each is independently selected from: (i) hydrogen; and (ii) C1-C3 alkyl;

[0079] or

[0080] R 5a and R 5b Together with the nitrogen atoms to which they are attached, they form 5- or 6-membered saturated heterocycles, which optionally also carry hydroxyl groups;

[0081] R6 is selected from: (i) hydrogen; (ii) cyano; (iii) C(O)NHR 6a (iv) NHR 6b ; and (v) C1-C3 alkoxy groups substituted with NH2 or hydroxyl groups;

[0082] R 6a Selected from: (i) hydrogen; (ii) C1-C3 alkyl; (iii) C3-C6 cycloalkyl; (iv) a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom, wherein the aromatic heterocycle is optionally substituted with: C1-C3 alkyl;

[0083] R 6b It is a C1-C3 alkyl group substituted with NH2 or hydroxyl groups;

[0084] R 7 Each is independently selected from hydrogen and C1-C3 alkyl groups; and

[0085] R 8 It is hydrogen or C1-C3-alkyl, especially hydrogen or methyl.

[0086] When R2 is halogenated, R2 is preferably fluorine. When R3 is halogenated, R3 is preferably chlorine. When R4 is halogenated, R4 is preferably fluorine. In a preferred embodiment, R3 is chlorine and R4 is fluorine. In a more preferred embodiment, R2 is hydrogen or fluorine, R3 is chlorine and R4 is fluorine.

[0087] In one embodiment of the first aspect of the invention, a compound having formula (I) is provided, wherein Y is CH.

[0088] In another embodiment of the first aspect of the invention, a compound having formula (I) is provided, wherein Y is CH and W is CH-R. W .

[0089] In another embodiment of the first aspect of the invention, a compound having formula (I) is provided, wherein Y is CH and W is CH-R. W And Z is O.

[0090] In a second aspect, the present invention provides a compound having formula (I) as shown above, or a pharmaceutically acceptable salt thereof, wherein

[0091] W is CH-R w ;

[0092] X is selected from CH and N;

[0093] Y is CH;

[0094] Z is selected from O and NH;

[0095] A is selected from: (i) phenyl, wherein the phenyl is optionally substituted by: halogenation; or halogenated C1-C3 alkoxy;

[0096] (ii) a 5- or 6-membered aromatic heterocycle comprising at least one heteroatom selected from N, O, and S, preferably N and S, wherein the aromatic heterocycle is optionally substituted with: a hydroxyl group; a C1-C3 alkoxy group; or an oxo group; and

[0097] (iii) A halobenzodioxane moiety having the following formula:

[0098]

[0099] R w Selected from: (i) hydrogen; (ii) hydroxyl; (iii) C1-C3 alkoxy; (iv) hydroxy-C1-C3 alkyl; (v) C1-C3 alkyl; and (vi) C1-C3 alkoxy-C1-C3 alkyl;

[0100] Q is selected from: (i)-C(R) 7 )2-N(R 8 )-R 1 (ii) a 9- or 10-membered partially saturated heteroaryl group containing at least one N heteroatom, preferably wherein the N is present at the α position of the atom that bonds Q to the remainder of the molecule; and (iii) a 4-, 5-, or 6-membered saturated heterocycle containing at least one heteroatom selected from N, O, and S, provided that at least one N heteroatom is present, preferably wherein the N is present at the α position of the atom that bonds Q to the remainder of the molecule, and wherein the heterocycle is unsubstituted or substituted by one or more substituents independently selected from: hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, halogen, and methylene (-CH2-), which form a bridge between the two ring atoms of the saturated heterocycle, thereby forming a bridged bicyclic structure;

[0101] R1 is selected from: hydrogen; C1-C6 alkyl; and (CH2). 0-2 R 1a ,in

[0102] R 1aSelected from: (i) C1-C3 alkoxy; (ii) C3-C6 cycloalkyl, which may optionally be independently substituted once or more with: hydroxyl; hydroxyl C1-C4 alkyl; C1-C4 alkoxy; C(O)OC1-C3 alkyl; CO2H; C(O)NR 1c R 1d C1-C6 alkyl; halogenated; halogenated C1-C3 alkoxy-C1-C3 alkyl; SO2C1-C3 alkyl; halogenated C1-C3 alkyl; NHR 1b ;C(O)NR 1c R 1d ; a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from N, O, and S; or two R 1e Groups; of which the two R groups 1e Groups are attached to the same carbon atom and together with the carbon atom to which they are attached form a 5-membered saturated heterocycle or a C3-C6 cycloalkyl ring containing at least one heteroatom selected from N (preferably) and O, wherein the saturated heterocycle or cycloalkyl ring is optionally substituted with hydroxyl or oxo groups; and (iii) a 5- or 6-membered saturated heterocycle containing at least one heteroatom selected from N and O, wherein the saturated heterocycle is optionally independently substituted once or more with C1-C3 alkyl groups; (CH2) 0-1 C(O)bis(C1-C3 alkyl)amino; SO2C1-C3 alkyl; C(O)C1-C3 alkyl; or oxo;

[0103] R 1b Selected from C(O)C1-C3 alkyl groups; and SO2C1-C3 alkyl groups;

[0104] R 1c and R 1d Each is independently selected from: (i) hydrogen; (ii) C1-C3 alkyl; and (iii) hydroxy C1-C4 alkyl.

[0105] R2 is hydrogen or preferably halogenated.

[0106] R3 is a halogenated group; a halogenated C1-C3 alkyl group, especially a monohalogenated methyl group, a dihalogenated methyl group, or particularly a trihalogenated methyl group; or a cyano group.

[0107] R4 is selected from: hydrogen; halogenated; and C1-C3 alkyl (especially methyl).

[0108] R5 is selected from: (i) hydrogen; (ii) a halo-C1-C6 alkoxy group optionally substituted with a hydroxyl group; (iii) an S-halo-C1-C3 alkyl group optionally substituted with a hydroxyl group; (iv) a C1-C3 alkoxy group; (v) a C1-C6 alkoxy group optionally substituted with: SO2C1-C3 alkyl, C3-C6 cycloalkyl, CO2H, or a 5- or 6-membered saturated heterocycle containing at least one heteroatom selected from N and O, said ring optionally substituted with C(O)C1-C3 alkyl; (vi) a C1-C3 alkyl group; (vii) a hydroxyl C1-C6 alkoxy group; (viii) a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom; and (ix) a hydroxyl group.

[0109] R6 is a cyano group; C(O)NHR 6a NHR 6b ; or C1-C3 alkoxy groups substituted with NH2 or hydroxyl groups,

[0110] R 6a Selected from: (i) hydrogen; (ii) C1-C3 alkyl; (iii) C3-C6 cycloalkyl; and (iv) a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom, wherein the aromatic heterocycle is optionally substituted with: C1-C3 alkyl;

[0111] R 6b It is a C1-C3 alkyl group substituted with NH2 or hydroxyl groups;

[0112] R 7 Each is independently selected from hydrogen or C1-C3 alkyl groups; and

[0113] R 8 It is hydrogen or C1-C3-alkyl, especially hydrogen or methyl.

[0114] A third aspect of the invention relates to a compound having formula (I) as given above, or a pharmaceutically acceptable salt thereof.

[0115] in

[0116] W is CH-R w ;

[0117] X is selected from CH; and N;

[0118] Y is CH;

[0119] Z is selected from O and NH;

[0120] A is a phenyl group, which is optionally substituted by: halogenation; or halogenation of C1-C3 alkoxy groups;

[0121] Rw Selected from: (i) hydrogen; (ii) C1-C3 alkoxy; (iii) hydroxy-C1-C3 alkyl; (iv) C1-C3 alkyl; and (v) C1-C3 alkoxy-C1-C3 alkyl;

[0122] Q is selected from: (i)-C(R) 7 (ii) 2-NH-R1; and (iii) comprising a 4-, 5-, or 6-membered saturated heterocycle comprising one or two heteroatoms independently selected from N, O, and S, provided that at least one N heteroatom is present, preferably wherein the N is present at the α position of the atom that bonds Q to the rest of the molecule, and wherein the heterocycle is unsubstituted or substituted by one or more substituents independently selected from hydroxyl, C1-C3 alkyl, and halogenated.

[0123] R1 is selected from: (i) C1-C6 alkyl groups; and (ii) R 1a ;in

[0124] R 1a Selected from C3-C6 cycloalkyl groups, which may optionally be independently substituted once or multiple times with: hydroxyl; C1-C6 alkyl; or halogenated;

[0125] R2 is hydrogen or preferably halogenated;

[0126] R3 is halogenated;

[0127] R4 is selected from: (i) hydrogen; and (ii) halogenated;

[0128] R5 is selected from: halogenated-C1-C6 alkoxy, hydroxyl, C1-C6 alkoxy; and hydroxy-C1-C6 alkoxy;

[0129] R6 is C(O)NHR 6a ;

[0130] R 6a Selected from: (i) hydrogen; and (ii) C1-C3 alkyl;

[0131] and

[0132] R 7 Each is independently selected from hydrogen or C1-C3 alkyl groups.

[0133] For the second and third aspects of the present invention, the following embodiments are particularly preferred:

[0134] When R2 is halogenated, R2 is preferably fluorine. When R3 is halogenated, R3 is preferably chlorine. When R4 is halogenated, R4 is preferably fluorine. In a preferred embodiment, R3 is chlorine and R4 is fluorine. In a more preferred embodiment, R2 is hydrogen or fluorine, R3 is chlorine and R4 is fluorine.

[0135] In one embodiment of the second and third aspects of the invention, a compound having formula (I) is provided, wherein Y is CH.

[0136] In further embodiments of the second and third aspects of the invention, a compound having formula (I) is provided, wherein Y is CH and W is CH-R. W .

[0137] In further embodiments of the second and third aspects of the invention, a compound having formula (I) is provided, wherein Y is CH and W is CH-R. W And Z is O.

[0138] In a fourth aspect, the present invention provides a compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0139] W is CH-R w ;

[0140] X is selected from CH; and N;

[0141] Y is CH;

[0142] Z is selected from O; and NH;

[0143] A is a phenyl group, which is optionally substituted by: halogenation; or (ii) halogenation of C1-C3 alkoxy groups, especially unsubstituted phenyl groups;

[0144] R w Selected from: (i) hydrogen; (ii) C1-C3 alkyl; and (iii) hydroxy-C1-C3 alkyl;

[0145] Q is selected from: (i)-C(R) 7 (ii) 2-NH-R1; and (iii) comprising a 4-, 5-, or 6-membered saturated heterocycle comprising one or two heteroatoms independently selected from N and O, provided that at least one N heteroatom is present and said N heteroatom is located at the α position of a carbon atom that bonds Q to the remainder of the molecule, wherein said heterocycle is unsubstituted or substituted by one or more substituents independently selected from: hydroxyl, C1-C3 alkyl, and halogenated;

[0146] R1 is selected from: (i) C1-C6 alkyl groups; and (ii) R 1a ;in

[0147] R 1a It is a C3-C6 cycloalkyl group, which may optionally be independently substituted once or multiple times with: hydroxyl; C1-C6 alkyl; or halogenated;

[0148] R2 is halogenated, especially fluorine;

[0149] R3 is halogenated, especially chlorinated;

[0150] R4 is halogenated, especially fluorinated;

[0151] R5 is selected from: C1-C6 alkoxy; and hydroxyC1-C6 alkoxy;

[0152] R6 is C(O)NHR 6a ;

[0153] R 6a Selected from: (i) hydrogen; and (ii) C1-C3 alkyl;

[0154] and

[0155] Each R 7 It is hydrogen.

[0156] Unless otherwise stated herein, the terms “compound of the present invention” or “compound of the present invention” or “compound having formula (I)” refer to compounds having formulas (I), (Ia), (Ia*), (Ia-1), (Ib), (Ic), (Id) and their salts (both preferably pharmaceutically acceptable), as well as all stereoisomers (including diastereomers and enantiomers), transisomers, rotational isomers, tautomers, and isotopically labeled compounds (including deuterium-substituted compounds), and the inherently formed moieties.

[0157] In particular, compounds having formulas (Ic) and (Id) are stereo-oriented transisomers. Compounds having formulas (I), (Ia), (Ia*), (Ia-1), and (Ib) include all stereoisomers, including diastereomers, transisomers, enantiomers, mixtures thereof, and racemic mixtures.

[0158] The presence of diastereomers can be identified by those skilled in the art using tools such as NMR. The separation of diastereomers can be performed by those skilled in the art using chromatographic methods such as HPLC (High Performance Liquid Chromatography), thin-layer chromatography, SFC (Supercritical Fluid Chromatography), GC (Gas Chromatography), or recrystallization. The separation of enantiomers can be performed by those skilled in the art using tools such as chiral HPLC, chiral SFC, and chiral GC.

[0159] The compounds of the present invention, particularly the ortho-substituted biaryl compounds, can exhibit rotational isomerism, referred to herein as transisomerism (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., pp. 1142-55). In some cases, depending on the substituents R4 and R6, the biaryl compounds of the present invention exhibit transisomerism.

[0160] Therefore, compounds having formula (I) and sub-formulas (Ia), (Ia*), (Ia-1), (Ib), (Ic), (Id), and mixtures of their isomers (including diastereomer mixtures, enantiomer mixtures, and racemic mixtures) also constitute a part of this invention.

[0161] definition

[0162] As used herein, the term "C1-C6 alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without any unsaturation, having one to six carbon atoms, and attached to the rest of the molecule by a single bond. The terms "C1-C3 alkyl" and "C1-C4 alkyl" should be interpreted accordingly. Examples of C1-C6 alkyl include, but are not limited to: methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), and hexyl.

[0163] Generally, unless otherwise indicated herein or clearly contradicted by the context, for substituents comprising two or more subunits, the last mentioned group is the group attachment point, for example, "alkylaryl" means a monovalent group having the formula alkyl-aryl-, while "arylalkyl" means a monovalent group having the formula aryl-alkyl-.

[0164] As used herein, the term "hydroxy C1-C4 alkyl" refers to formula -R a -OH groups, where R a It is a C1-C4 alkyl group as defined above. Examples of hydroxy C1-C4 alkyl groups include, but are not limited to: hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, and 3-hydroxy-propyl.

[0165] As used herein, the term "hydroxy C1-C3 alkyl" refers to formula -R a -OH groups, where R a It is a C1-C3 alkyl group as defined above. Examples of hydroxy C1-C3 alkyl groups include, but are not limited to: hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, and 3-hydroxy-propyl.

[0166] As used herein, the term "C3-C6 cycloalkyl" refers to a saturated monocyclic hydrocarbon group with 3 to 6 carbon atoms. Examples of C3-C6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0167] As used herein, the term "C1-C6 alkoxy" refers to an alkoxy group having the formula -OR a The group, wherein R a These are C1-C6 alkyl groups as generally defined above. The terms “C1-C3 alkoxy” and “C1-C4 alkoxy” should be interpreted accordingly. Examples of C1-C6 alkoxy groups include, but are not limited to: methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy.

[0168] As used herein, the term “C1-C3-alkoxy-C1-C3 alkyl” refers to a C1-C3-alkyl group as defined above, wherein one hydrogen atom in the C1-C3-alkyl group is replaced by a C1-C3-alkoxy group.

[0169] "Halogen" or "halogenated" refers to fluorine, chlorine, bromine, or iodine. Preferably, the halogenated element is fluorine, chlorine, or bromine. More preferably, the halogenated element is fluorine or chlorine.

[0170] The term "oxo" refers to the =O group.

[0171] The term "sulfonyl" refers to the group —S(═O)2—.

[0172] The term "amino" refers to the group —NH2.

[0173] The term "NHR" 1b "Refers to the group —N(H)R 1b Similarly, for example, "NR" 5a R 5b The term "" refers to the group -N(R) 5a )R 5b .

[0174] As used herein, the terms "halogenated C1-C3 alkyl" or "halogenated C1-C3 alkyl" refer to a C1-C3 alkyl group as defined above that is substituted with one or more halogenated groups as defined above. Examples of halogenated C1-C3 alkyl groups include, but are not limited to: trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-fluoropropyl, 3,3-difluoropropyl, and 1-fluoromethyl-2-fluoroethyl.

[0175] As used herein, the term "halogenated C1-C6 alkoxy" refers to a C1-C6 alkoxy group as defined above, wherein at least one hydrogen atom in the C1-C6 alkoxy group is substituted by a halogenated group as defined above. The term "halogenated C1-C3 alkoxy" should be interpreted accordingly. Examples of halogenated C1-C6 alkoxy groups include, but are not limited to: trifluoromethoxy, difluoromethoxy, trifluoroethoxy, 2-fluoropropoxy, and 3,3-difluoropropoxy.

[0176] As used herein, the term "hydroxyC1-C6 alkoxy" refers to a C1-C6 alkoxy group as defined above, wherein at least one hydrogen atom in the C1-C6 alkoxy group is replaced by OH. The term "hydroxyC1-C3 alkoxy" should be interpreted accordingly. Examples of hydroxyC1-C6 alkoxy groups include, but are not limited to: hydroxymethoxy, hydroxyethoxy, and 2-hydroxypropoxy.

[0177] As used herein, the term "C1-C3alkoxy" refers to a C1-C3 alkoxy group as defined above, wherein one hydrogen atom in the C1-C3 alkoxy group is replaced by an -O-C1-C3 alkyl group. Examples of C1-C3 alkoxy groups include, but are not limited to, 2-methoxyethoxy.

[0178] As used herein, the term "halogenated C1-C3 alkoxy-C1-C3 alkyl" refers to a C1-C3 alkyl group as defined above, wherein one hydrogen atom of the C1-C3 alkyl group is replaced by a halo-C1-C3 alkoxy group as defined above. Examples of halo-C1-C3 alkoxy-C1-C3 alkyl groups include, but are not limited to, (difluoromethoxy)methyl (i.e., CHF2-O-CH2-).

[0179] As used in this article, the term "C(O)NR" 1c R 1d " refers to having the formula -R a1 -N(R a2 )2 groups, wherein R a1 It is a carbonyl group, and each R a2 R can be the same or different as defined in this article. 1c or R 1d Group.

[0180] As used herein, the term "C(O)di(C1-C3 alkyl)amino" refers to a compound having the formula -R a1 -N(R a2 )2 groups, wherein R a1 It is a carbonyl group, and each R a2 These are C1-C3 alkyl groups that can be the same or different as defined herein.

[0181] As used herein, the term "C(O)C1-C3 alkyl" refers to an alkyl group having the formula -R a1 -C1-C3 alkyl groups, wherein R a1 It is a carbonyl group, and the C1-C3 alkyl group is as defined above.

[0182] As used in this article, the term "C(O)NHR" 6a " refers to having the formula -R a1 -N(H)-R 6a The group, wherein R a1 It is a carbonyl group, and R 6a It is as defined in this article.

[0183] As used herein, the term "S-halogenated C1-C3 alkyl" refers to a group having the formula -S-halogenated C1-C3 alkyl, wherein the halogenated C1-C3 alkyl is as defined above.

[0184] As used herein, the term "C(O)OC1-C3 alkyl" refers to an alkyl group having the formula -R a1 -O-C1-C3 alkyl groups, wherein R a1 It is a carbonyl group, and the C1-C3 alkyl group is as defined above.

[0185] As used herein, the term "SO2C1-C3 alkyl" refers to an alkyl group having the formula -S(=O)2-R a2 The group, wherein R a2 It is a C1-C3 alkyl group as defined above.

[0186] As used herein, the term "C1-C3 alkylene" refers to a straight-chain or branched divalent hydrocarbon group consisting only of carbon and hydrogen atoms, without unsaturation, and having one to three carbon atoms. In embodiments where a 4-, 5-, or 6-membered saturated heterocycle of Q (or Q1) is replaced by a C1-C3 alkylene to form a bridge between the two ring atoms of the saturated heterocycle, thereby forming a bridged bicyclic structure, the C1-C3 alkylene is preferably propylene (-CH2-CH2-CH2-), ethylene (-CH2-CH2-), or methylene (-CH2-).

[0187] The term "(CH2)" 0-2 R 1a "This refers to the formula -(CH2) 0-2 R 1a The group, namely the group R 1a It is attached to the rest of the molecule via bonds, methylene joints, or ethylene joints.

[0188] The term "(CH2)" 0-1 "C(O)di(C1-C3 alkyl)amino" refers to a compound with the formula -(CH2). 0-1 -Ra3 The group, and R a3 It is a C(O)di(C1-C3 alkyl)amino group as defined above.

[0189] Term (CH2) 0-1 C(O)NR 1c R 1d It refers to having the formula -(CH2). 0-1 C(O)NR 1c R 1d . group.

[0190] As used herein, the term "a 5- or 6-membered saturated heterocycle comprising at least one heteroatom selected from N and O" refers to a monocyclic ring and includes, but is not limited to, piperazine, piperidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, dioxyl, and morpholinyl. Preferably, the term includes piperidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, and morpholinyl. The terms "a 5-membered saturated heterocycle comprising at least one heteroatom selected from N and O" and "a 6-membered saturated heterocycle comprising at least one heteroatom selected from N and O" should be interpreted accordingly.

[0191] As used herein, the term "a 4-, 5-, or 6-membered saturated heterocycle comprising at least one heteroatom or heteroatom group selected from N, O, S, -S(=O), and -S(=O)2" refers to a monocyclic ring and includes, but is not limited to: nitrogen-containing heterocyclic butyl, pyrrolidinyl, piperidinyl, piperazineyl, morpholinyl, thiomorpholinyl, S-oxo-thiomorpholinyl, or S,S-dioxothiomorpholinyl. For the avoidance of doubt, in some embodiments where N is present at the α position of the atom that bonds Q to the remainder of the molecule, this may be represented by the following formula:

[0192]

[0193] As used herein, the term "a 5- or 6-membered aromatic heterocycle comprising at least one heteroatom selected from N, O, or S, preferably N or S" refers to a monocyclic aromatic ring. Examples of this term include, but are not limited to, oxazolyl, isoxazolyl, pyrimidinyl, pyridazinyl, tetrazolyl, pyrazinyl, triazolyl, imidazoleyl, pyrazolyl, pyridinyl, and thiazolyl.

[0194] As used herein, the term "a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from N, O, and S" refers to an aromatic monocycle, and includes, but is not limited to: pyrimidinyl, pyridazinyl, tetrazolyl, pyrazinyl, triazolyl, imidazoleyl, pyrazolyl, pyridinyl, oxazolyl, and thiazolyl. The attachment site to the imidazole ring is preferably attached to the nitrogen atom of the imidazole ring.

[0195] As used herein, the term "a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from N and S" refers to a monocyclic aromatic ring, and includes, but is not limited to: pyrimidinyl, pyridazinyl, tetrazolyl, pyrazinyl, triazolyl, imidazoleyl, pyrazolyl, pyridinyl, and thiazolyl.

[0196] As used herein, the term "a 6-membered aromatic heterocycle containing at least one N heteroatom" refers to a monocyclic aromatic ring, and includes, but is not limited to, pyrimidinyl, pyridazinyl, pyrazinyl, and pyridinyl groups.

[0197] As used herein, the term "a 5-membered aromatic heterocycle containing at least one N heteroatom" (where N may also be NH) refers to a monocyclic aromatic ring, and includes, but is not limited to, tetrazolyl, triazolyl, imidazole, and pyrazolyl groups.

[0198] As used herein, the term "5- or 6-membered aromatic heterocycle containing at least one N heteroatom" refers to a monocyclic aromatic ring, and includes, but is not limited to: pyrimidinyl, pyridazinyl, tetrazolyl, pyrazinyl, triazolyl, imidazoleyl, pyrazolyl, and pyridinyl.

[0199] As used herein, an aromatic heterocycle in a substituent defined as “a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from N, O, or S, preferably N or S” may optionally be substituted with: hydroxyl; C1-C3 alkoxy; or oxo.

[0200] It will be understood that the substitution of the aromatic heterocycle with an oxygen is intended to include (e.g., in the 1H-pyridin-2-one system) a 5- or 6-membered ring having an aromatic tautomer (see, for example, Example 92).

[0201] As used in this article, the term "5- or 6-membered saturated heterocycle" refers to the cyclic ring R in which R... 5a and R 5b Examples of rings formed together with the N atoms to which they are attached (where N may also be NH) include, for example, but not limited to: a nitrogen-containing heterocyclic butyl ring, a pyrrolidine ring, or a piperidine ring.

[0202] As used herein, the term "9- or 10-membered partially saturated heteroaryl containing at least one N heteroatom" refers to a partially saturated aromatic bicyclic heterocyclic system in which a 5- or 6-membered heterocycle containing one N heteroatom is fused to a benzene ring or a heteroaromatic ring. In some embodiments, where N is present at the α position of the atom that bonds Q to the remainder of the molecule, this can be represented by the following formula: The dashed ring represents a benzo[a] ring or a heteroaryl ring. Representative examples are dihydroindolyl, isoindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. Preferably, it is...

[0203] As used herein, the term “optionally replaced by” includes both unreplaced and replaced.

[0204] As used herein, the term "multiple times" includes 2, 3, 4, 5, or 6 times. Preferably, it includes 2 or 3 times.

[0205] As used herein, the term "more than one" includes 2, 3, 4, 5, or 6. Preferably, it includes 2 or 3.

[0206] As used herein, the term "at least one heteroatom" includes 1, 2, 3, 4 or 5, preferably 1, 2, 3 or 4, more preferably 1 or 2 heteroatoms.

[0207] The use of any and all instances or exemplary language (such as "as" or "preferred") provided herein is intended only to better illustrate the invention and not to limit the scope of the invention as otherwise claimed.

[0208] As used herein, the term nitrogen protecting group (PG) in compounds having formula (IV) and its subforms refers to a group that is intended to protect the relevant functional group from undesirable secondary reactions (e.g., acylation, etherification, esterification, oxidation, solvent decomposition, and similar reactions). It can be removed under deprotection conditions. Depending on the protecting group used, those skilled in the art will know how to remove the protecting group to obtain the free amine NH2 group by referring to known procedures. These include references to organic chemistry textbooks and literature programs, such as J.F.W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973; T.W. Greene and P.G. W. Uts, “Greene’s Protective Groups in Organic Synthesis”, 4th edition, Wiley, New York 2007; “The Peptides”, Volume 3 (edited by E. Gross and J. Meienhofer), Academic Press, London and New York 1981; and “Methoden der organischen Chemie”, Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974, and subsequent editions.

[0209] Preferred nitrogen protecting groups typically include: C1-C6 alkyl (e.g., tert-butyl), preferably C1-C4 alkyl, more preferably C1-C2 alkyl, and most preferably C1 alkyl, which is mono, di, or trisubstituted with trialkylsilyl-C1-C7 alkoxy (e.g., trimethylsilylethoxy);

[0210] Aryl, preferably phenyl, or heterocyclic group (e.g., benzyl, cumyl, diphenylmethyl, pyrrolyl, triphenylmethyl, pyrrolylmethyl, 1-methyl-1,1-dimethylbenzyl, (phenyl)methylbenzyl), wherein the aryl ring or heterocyclic group is unsubstituted or substituted by one or more (e.g., two or three) residues selected from the group consisting of: C1-C7 alkyl, hydroxyl, C1-C7 alkoxy (e.g., p-methoxybenzyl (PMB)), C2-C8-alkanoyl-oxy, halogen, nitro, cyano, and CF3;

[0211] aryl-C1-C2-alkoxycarbonyl (preferably phenyl-C1-C2-alkoxycarbonyl (e.g., benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), neopentyloxymethyl (POM)), C1-C 10 -Alkenyloxycarbonyl, C1-C6 alkylcarbonyl (e.g., acetyl or neopentanoyl), C6-C 10 -Arylcarbonyl; C1-C6-alkoxycarbonyl (e.g., tert-butoxycarbonyl (Boc), methylcarbonyl, trichloroethoxycarbonyl (Troc), neopentanoyl (Piv), allyloxycarbonyl), C6-C 10 -aryl C1-C6-alkoxycarbonyl (e.g., 9-fluorenylmethyloxycarbonyl (Fmoc)), allyl or cinnamyl, sulfonyl or sulfinyl, succinimide group, silyl group (e.g., triarylsilyl, trialkylsilyl, triethylsilyl (TES), trimethylsilylethoxymethyl (SEM), trimethylsilyl (TMS), triisopropylsilyl or tert-butyldimethylsilyl).

[0212] According to this disclosure, the preferred protecting group (PG) may be selected from the group consisting of: tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), p-methoxybenzyl (PMB), methyloxycarbonyl, and benzyl. The protecting group (PG) is preferably tert-butyloxycarbonyl (Boc).

[0213] The term "phenyl" refers to a group having the formula -C6H5.

[0214] The term "halogenated benzodioxane" refers to a 1,3-benzodioxane group having the following formula:

[0215]

[0216] The halogenation is as defined above. Preferably, both halogenated groups are fluorine.

[0217] The term "stereoisomer" refers to compounds that have the same chemical composition but different spatial arrangements of atoms or groups.

[0218] The term "diastereoisomer" or "diastereomer" refers to a stereoisomer that is independent of its mirror image. Diastereoisomers are characterized by differences in physical properties and some differences in chemical behavior. Mixtures of diastereomers can be separated using analytical procedures such as chromatography or crystallization.

[0219] The term "enantiomer" refers to one of a pair of molecular entities that are mirror images of each other and cannot be overlapped.

[0220] The term "enantiomer mixture" refers to an enantiomer-enriched mixture, a composition of an enantiomer of the present invention comprising a larger proportion or percentage of one enantiomer or racemate than another enantiomer or racemate.

[0221] The term "diastereomer mixture" refers to a mixture enriched with diastereomers or a mixture of diastereomers in equal proportions.

[0222] The term "diastere-enriched" refers to a composition containing a larger proportion or percentage of the compound of the present invention relative to one or more other diastereomers.

[0223] The term "restricted rotation isomer" refers to a stereoisomer resulting from restricted rotation around a single bond, where the rotational barrier is high enough to allow for the separation of the isomers. Typically, rotation around the single bond in the molecule is restricted or significantly slowed down due to spatial interactions with other parts of the molecule and the asymmetry of the substituents at both ends of the single bond, resulting in the formation of a stereo unit called a "chiral axis".

[0224] As used in this article, the term "YAP" refers to the associated protein, also known as YAP1 or YAP65.

[0225] Whenever YAP is mentioned in this article, it can also refer to the YAP / TAZ complex.

[0226] As used in this article, the term “YAP / TAZ-TEAD” refers to the complex of YAP / TAZ and TEAD transcription factors.

[0227] As used herein, the term “NF2 / LATS1 / LATS2” means “NF2”, “LATS1”, or “LATS2” or any combination thereof.

[0228] As used herein, the term "pharmaceutically acceptable carrier" includes any one or more of the following: all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antimicrobial agents, antifungal agents), isotonic agents, absorption delay agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, and combinations thereof, as known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Printing Company, 1990, pp. 1289-1329). Except where any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions should be considered.

[0229] The term "therapeuticly effective amount" for compounds of the present invention refers to an amount of the compound of the present invention that will cause a biological or medical response in a subject (e.g., a reduction or inhibition of enzyme or protein activity) or improve symptoms, alleviate symptoms, slow or delay disease progression, or prevent disease, etc. In one non-limiting embodiment, the term "therapeuticly effective amount" refers to an amount of the compound of the present invention that, when administered to a subject, is effective in: (1) at least partially alleviating, inhibiting, preventing, and / or improving (I) symptoms or disorders or diseases mediated by YAP / TAZ-TEAD protein-protein interactions (PPIs), or (ii) related to YAP / TAZ-TEAD PPI activity, or (iii) characterized by YAP / TAZ-TEAD PPI activity; or (2) reducing or inhibiting YAP / TAZ-TEAD PPI activity; or (3) reducing or inhibiting the expression of YAP / TAZ-TEAD. In another non-limiting embodiment, the term "therapeutic effective amount" refers to an amount of the compound of the present invention that, when applied to cells, tissues, noncellular biological materials, or media, effectively at least partially reduces or inhibits the activity of YAP / TAZ-TEAD PPI.

[0230] As used herein, the term "subject" refers to an animal. Typically, an animal is a mammal. A subject also refers to, for example, primates (e.g., humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the subject is a primate. In still other embodiments, the subject is a human.

[0231] As used herein, the term “inhibit (inhibition or inhibiting)” means the reduction or suppression of a given condition, symptom or disorder, or disease, or a significant reduction in baseline activity of a biological activity or process.

[0232] As used herein, the term "treat, treating, or treatment" for any disease or disorder, in one embodiment, means improving the disease or disorder (i.e., slowing down or stopping or reducing the development of the disease or at least one of its clinical symptoms). In another embodiment, "treat, treating, or treatment" means reducing or improving at least one bodily parameter, including those that cannot be identified by the patient. In yet another embodiment, "treat, treating, or treatment" means regulating the disease or disorder physically (e.g., stabilization of identifiable symptoms), physiologically (e.g., stabilization of bodily parameters), or both. In yet another embodiment, "treat, treating, or treatment" means preventing or delaying the onset, development, or progression of the disease or disorder.

[0233] As used in this article, subjects who will benefit from the treatment biologically, medically, or in terms of quality of life are considered to "need" the treatment.

[0234] As used herein, the terms “a”, “the”, and similar terms used in the context of this invention (especially in the context of the claims) should be interpreted to cover both the singular and the plural, unless otherwise indicated or clearly contradicted by the context.

[0235] If a compound name is marked with an asterisk (*) next to its stereochemical configuration, such as the name N1-(2-((2S*,4S*)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenyl)ethane-1,2-diamine (Example 2a), this refers to a racemic mixture of two enantiomers (i.e., N1-(2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenyl)ethane-1,2-diamine and N1-(2-((2R,4R)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenyl)ethane-1,2-diamine). Name: N1-(2-((2S*,4R*)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenyl)ethane-1,2-diamine (Example 2b) should be explained accordingly.

[0236] If the structure of a compound is drawn with indeterminate absolute stereochemistry, such as in Example 2a:

[0237]

[0238] (Without wedges), which means a racemic mixture of single diastereomers with indicative relative stereochemistry.

[0239] To avoid ambiguity, if compounds are drawn using wedge-shaped bonds, such as in Example 2a-1, this means a single diastereomer with absolute stereochemistry as indicated by its chemical structure. Therefore, the compound of Example 2a-1 has the structure shown below:

[0240]

[0241] It is the compound N1-(2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenyl)ethane-1,2-diamine.

[0242] The compounds of this invention can also be named using the Cahn-Ingold-Prelog (CIP) helical rule, with stereotypes (P) or (M) (Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names, 2013, Cambridge, UK: Royal Soc. of Chem., 2014). https: / / doi.org / 10.1039 / 9781849733069 See Chapter 9, “Specification of Configuration and Conformation”, https: / / doi.org / 10.1039 / 9781849733069-01156.

[0243] The stereolabels “cis” and “trans” can be used to describe the relative configurations of substituents having a disubstituted 1,4-cyclohexyl or 1,3-cyclobutyl moiety on the cycloalkyl ring of the compounds exemplified herein. The stereolabels “cis” or “trans” describe the relative arrangement of the substituent with the highest CIP priority at the two substitution positions on the cycloalkyl ring. For example, in the case of Example 114a, the stereolabel “trans” means that the hydroxyl and amine groups on the cyclohexyl ring are on opposite sides of the cyclohexyl ring plane; while in the case of Example 114b, the stereolabel “cis” means that the hydroxyl and amine groups are on the same side of the cyclohexyl ring plane.

[0244] Example 114a: 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide.

[0245]

[0246] Example 114b: 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide

[0247]

[0248] Alternatively, the following names of the compounds of Examples 114a and 114b may be used:

[0249] Example 114a: (2P)-2-[(2S,3S)-5-chloro-6-fluoro-2-({[(1r,4S)-4-hydroxy-4-methylcyclohexyl]amino}methyl)-3-methyl-2-phenyl-2,3-dihydro-1-benzofuran-4-yl]-3-fluoro-4-[(2S)-2-hydroxypropoxy]benzamide

[0250] Example 114b: (2P)-2-[(2S,3S)-5-chloro-6-fluoro-2-({[(1s,4R)-4-hydroxy-4-methylcyclohexyl]amino}methyl)-3-methyl-2-phenyl-2,3-dihydro-1-benzofuran-4-yl]-3-fluoro-4-[(2S)-2-hydroxypropoxy]benzamide

[0251] The stereo center at the 2-position on the dihydrobenzofuran ring of the compounds of the present invention is shown below (i.e., using wedge bonds):

[0252]

[0253] This can also be expressed as:

[0254]

[0255] Therefore, it will be understood that, where applicable, the stereochemistry of the compounds of the present invention at this position can be drawn by connecting the "A" or "Q" substituents with plain bonds or by connecting the "A" or "Q" substituents with wedge bonds.

[0256] In embodiments of the first, second, third, or fourth aspect of the present invention, a compound having formula (Ia) or a pharmaceutically acceptable salt thereof is provided.

[0257]

[0258] The substituents are defined as described above in the first, second, third, or fourth embodiments of the present invention.

[0259] In a preferred embodiment, A is a phenyl ring.

[0260] In other embodiments of the first, second, third, or fourth aspect of the invention, a compound having formula (Ia*) or a pharmaceutically acceptable salt thereof is provided.

[0261]

[0262] The substituents are defined as described above in the first, second, third, or fourth embodiments of the present invention.

[0263] When R2 is halogenated, R2 is preferably fluorine. When R3 is halogenated, R3 is preferably chlorine. When R4 is halogenated, R4 is preferably fluorine. In a preferred embodiment, R3 is chlorine and R4 is fluorine. In a more preferred embodiment, R2 is fluorine, R3 is chlorine, and R4 is fluorine.

[0264] In a preferred embodiment, A is a phenyl ring.

[0265] In another embodiment of the first, second, third, or fourth aspect of the invention, a compound having formula (Ia-1) or a pharmaceutically acceptable salt thereof is provided.

[0266]

[0267] The substituents are defined as described above in the first, second, third, or fourth embodiments of the present invention.

[0268] In another embodiment of the first, second, third, or fourth aspect of the invention, a compound having formula (Ia-1) or a pharmaceutically acceptable salt thereof is provided.

[0269]

[0270] The substituents are defined as described above in the first, second, third, or fourth embodiments of the present invention.

[0271] When R2 is halogenated, R2 is preferably fluorine. When R3 is halogenated, R3 is preferably chlorine. In a preferred embodiment, R3 is chlorine. In a more preferred embodiment, R2 is fluorine and R3 is chlorine.

[0272] In another embodiment of the first, second, third, or fourth aspect of the invention, a compound having formula (Ib) or a pharmaceutically acceptable salt thereof is provided.

[0273]

[0274] The substituents are defined as described above in the first, second, third, or fourth embodiments of the present invention.

[0275] In a preferred embodiment, A is a phenyl ring.

[0276] In other embodiments of the first, second, third, or fourth aspect of the invention, a compound having formula (Ic) or a pharmaceutically acceptable salt thereof is provided.

[0277]

[0278] The substituents are defined as above in the first, second, third or fourth embodiments of the present invention, and preferably, R3 and R4 have meanings other than hydrogen, as disclosed with respect to the various aspects of the invention.

[0279] In a preferred embodiment, A is a phenyl ring.

[0280] In another embodiment, A is a phenyl ring, and X is CH.

[0281] In another embodiment, A is a phenyl ring and X is N.

[0282] In other embodiments of the first, second, third, or fourth aspect of the invention, a compound having formula (Id) or a pharmaceutically acceptable salt thereof is provided.

[0283]

[0284] The substituents are defined as above in the first, second, third or fourth embodiments of the present invention, and preferably, R3 and R4 have meanings other than hydrogen, as disclosed with respect to the various aspects of the invention.

[0285] In a preferred embodiment, A is a phenyl ring.

[0286] In another embodiment, A is a phenyl ring, and X is CH.

[0287] In another embodiment, A is a phenyl ring and X is N.

[0288] This document describes various enumerated embodiments of the invention. It should be understood that the features specified in each embodiment may be combined with one, more than one, or all other specified features to provide further embodiments of the invention.

[0289] Example 1. A compound having formula (I) or a pharmaceutically acceptable salt thereof,

[0290]

[0291] in

[0292] W is selected from O; and CH-R w ;

[0293] X is selected from CH; and N;

[0294] Y is selected from CH; and N;

[0295] Z is selected from CH2; O; and NH;

[0296] When Y is N, W is CH-R. w And Z is O;

[0297] A is selected from

[0298] (i) Phenyl, wherein the phenyl is optionally substituted by: halogenation; or halogenation of C1-C3 alkoxy;

[0299] (ii) a 5- or 6-membered aromatic heterocycle comprising at least one heteroatom selected from N, O, and S, preferably N and S, wherein the aromatic heterocycle is optionally substituted with: a hydroxyl group; a C1-C3 alkoxy group; or an oxo group; and

[0300] (iii) A halobenzodioxane moiety having the following formula:

[0301]

[0302] R w Selected from: (i) hydrogen; (ii) hydroxyl; (iii) C1-C3 alkoxy; (iv) hydroxy-C1-C3 alkyl; (v) C1-C3 alkyl; and (vi) C1-C3 alkoxy-C1-C3 alkyl;

[0303] Q is selected from: (i)-C(R) 7 )2-N(R 8 (ii) a 9- or 10-membered partially saturated heteroaryl group containing at least one N heteroatom; and (iii) a 4-, 5-, or 6-membered saturated heterocycle containing at least one heteroatom or heteroatom group selected from N, O, S, -S(=O) and -S(=O)2, provided that at least one N heteroatom is present, wherein the heterocycle is unsubstituted or substituted by one or more substituents independently selected from: hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, halogenated, and C1-C3 alkylene, which form a bridge between the two ring atoms of the saturated heterocycle, thereby forming a bridged bicyclic structure;

[0304] R1 is selected from: (i) hydrogen; (ii) C1-C6 alkyl (wherein the alkyl group is optionally deuterated in one embodiment, for example, fully deuterated); and (iii) (CH2). 0-2 R 1a ;

[0305] R 1a Selected from: (i) hydroxyl C1-C4 alkyl; (ii) C1-C3 alkoxy; (iii) a 5- or 6-membered saturated heterocycle containing at least one heteroatom selected from N and O, said saturated heterocycle optionally independently substituted once or more by: C1-C3 alkyl; (CH2) 0-1 C(O) di(C1-C3 alkyl)amino; SO2C1-C3 alkyl; C(O)C1-C3 alkyl; or oxo; (iv) C3-C6 cycloalkyl, which is optionally independently substituted once or more by: hydroxyl; hydroxy C1-C4 alkyl; C1-C6 alkoxy, preferably C1-C4 alkoxy; C(O)OC1-C3 alkyl; CO2H; SO2C1-C3 alkyl; haloC1-C3 alkyl; NHR 1b (CH2) 0-1 C(O)NR 1c R 1d C(O)NR is preferred 1c R 1d C1-C6 alkyl; halo-C1-C3 alkoxy-C1-C3 alkyl; halo; a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from N, O, and S; or two R 1e Group,

[0306] Two R atoms attached to the same carbon atom 1e Together with the carbon atoms to which they are attached, they form a 5-membered saturated heterocycle or a C3-C6 cycloalkyl group containing at least one heteroatom selected from N (preferably) and O, wherein the saturated heterocycle or cycloalkyl group is optionally substituted with hydroxyl or oxo.

[0307] R 1b Selected from: (i) C(O)C1-C3 alkyl; and (ii) SO2C1-C3 alkyl;

[0308] R 1c and R 1d Each is independently selected from: (i) hydrogen; (ii) C1-C3 alkyl; and (iii) hydroxy C1-C4 alkyl, preferably selected from: (i) hydrogen and (ii) C1-C3 alkyl;

[0309] R2 is selected from: (i) hydrogen; and (ii) halogenated;

[0310] R3 is selected from: (i) halogenated; (ii) halogenated C1-C3 alkyl, especially selected from halogenated and monohalogenated methyl, dihalogenated methyl or preferably trihalogenated methyl; and (iii) cyano;

[0311] R4 is selected from: (i) hydrogen; (ii) halogenated; and (iii) C1-C3 alkyl, especially selected from hydrogen, halogenated, and methyl;

[0312] R5 is selected from: (i) hydrogen; (ii) C1-C6 alkoxy, which is optionally substituted with: C3-C6 cycloalkyl; CO2H; SO2C1-C3 alkyl; a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom; or a 5- or 6-membered saturated heterocycle containing at least one heteroatom selected from N and O, wherein the ring is optionally substituted with C(O)C1-C3 alkyl;

[0313] (iii) Halogenated; (iv) Hydroxyl C1-C6 alkoxy (wherein the alkoxy moiety is optionally deuterated in one embodiment, for example, fully deuterated); (v) Halogenated C1-C6 alkoxy optionally substituted with a hydroxyl group; (vi) S-halogenated C1-C3 alkyl optionally substituted with a hydroxyl group; (vii) C1-C3 alkoxy; (viii) NR 5a R 5b (ix) C1-C3 alkyl; (x) a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom; and (xi) hydroxyl group.

[0314] R 5a and R 5b Each is independently selected from: (i) hydrogen; and (ii) C1-C3 alkyl;

[0315] or

[0316] R 5a and R 5b Together with the nitrogen atoms to which they are attached, they form 5- or 6-membered saturated heterocycles, which optionally also carry hydroxyl groups;

[0317] R6 is selected from: (i) hydrogen; (ii) cyano; (iii) C(O)NHR 6a (iv) NHR 6b ; and (v) C1-C3 alkoxy groups substituted with NH2 or hydroxyl groups;

[0318] R 6aSelected from: (i) hydrogen; (ii) C1-C3 alkyl; (iii) C3-C6 cycloalkyl; (iv) a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom, wherein the aromatic heterocycle is optionally substituted with: C1-C3 alkyl;

[0319] R 6b It is a C1-C3 alkyl group substituted with NH2 or hydroxyl groups;

[0320] R 7 Each is independently selected from hydrogen and C1-C3 alkyl groups; and

[0321] R 8 It is hydrogen or C1-C3-alkyl, especially hydrogen or methyl.

[0322] Example 2. A compound having formula (I) according to Example 1, or a pharmaceutically acceptable salt thereof,

[0323] W is CH-R w ;

[0324] X is selected from CH; and N;

[0325] Y is CH;

[0326] Z is selected from O, and NH;

[0327] A is selected from

[0328] (i) Phenyl, wherein the phenyl is optionally substituted by: halogenation; or halogenation of C1-C3 alkoxy;

[0329] (ii) a 5- or 6-membered aromatic heterocycle comprising at least one heteroatom selected from N, O, and S, preferably N and S, wherein the aromatic heterocycle is optionally substituted with: a hydroxyl group; a C1-C3 alkoxy group; or an oxo group; and

[0330] (iii) A halobenzodioxane moiety having the following formula:

[0331]

[0332] R w Selected from: (i) hydrogen; (ii) hydroxyl; (iii) C1-C3 alkoxy; (iv) hydroxy-C1-C3 alkyl; (v) C1-C3 alkyl; and (vi) C1-C3 alkoxy-C1-C3 alkyl;

[0333] Q is selected from: (i)-C(R) 7 )2-N(R 8 )-R 1(ii) a 9- or 10-membered partially saturated heteroaryl group containing at least one N heteroatom, preferably wherein the N is present at the α position of the atom that bonds Q to the remainder of the molecule; and (iii) a 4-, 5-, or 6-membered saturated heterocycle containing at least one heteroatom selected from N, O, and S, provided that at least one N heteroatom is present, preferably wherein the N is present at the α position of the atom that bonds Q to the remainder of the molecule, and wherein the heterocycle is unsubstituted or substituted by one or more substituents independently selected from: hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, and halogenated;

[0334] R1 is selected from: hydrogen; C1-C6 alkyl; and (CH2). 0-2 R 1a ,in

[0335] R 1a Selected from: (i) C1-C3 alkoxy; (ii) C3-C6 cycloalkyl, which may optionally be independently substituted once or more with: hydroxyl; hydroxyl C1-C4 alkyl; C1-C4 alkoxy; C(O)OC1-C3 alkyl; CO2H; C(O)NR 1c R 1d C1-C6 alkyl; halogenated; halogenated C1-C3 alkoxy-C1-C3 alkyl; SO2C1-C3 alkyl; halogenated C1-C3 alkyl; NHR 1b ;C(O)NR 1c R 1d ; a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from N, O, and S; or two R 1e (iii) A 5- or 6-membered saturated heterocycle comprising at least one heteroatom selected from N and O, wherein the saturated heterocycle is optionally independently substituted once or more by: C1-C3 alkyl; (CH2) 0-1 C(O)bis(C1-C3 alkyl)amino; SO2C1-C3 alkyl; C(O)C1-C3 alkyl; or oxo;

[0336] R 1b Selected from C(O)C1-C3 alkyl groups; and SO2C1-C3 alkyl groups;

[0337] R 1c and R 1d Each is independently selected from: (i) hydrogen; (ii) C1-C3 alkyl; and (iii) hydroxy C1-C4 alkyl.

[0338] Two R atoms attached to the same carbon atom 1eTogether with the carbon atoms to which they are attached, they form a 5-membered saturated heterocycle or a C3-C6 cycloalkyl group containing at least one heteroatom selected from N (preferably) and O, wherein the saturated heterocycle or cycloalkyl group is optionally substituted with hydroxyl or oxo.

[0339] R2 is hydrogen or preferably halogenated.

[0340] R3 is a halogenated group; a C1-C3 alkyl halogen, especially a monohalomethyl, dihalomethyl, or preferably a trihalomethyl group; or a cyano group.

[0341] R4 is selected from: hydrogen; halogenated; and C1-C3 alkyl (especially methyl).

[0342] R5 is selected from: (i) hydrogen; (ii) a halo-C1-C6 alkoxy group optionally substituted with a hydroxyl group; (iii) an S-halo-C1-C3 alkyl group optionally substituted with a hydroxyl group; (iv) a C1-C3 alkoxy group; (v) a C1-C6 alkoxy group optionally substituted with: SO2C1-C3 alkyl, C3-C6 cycloalkyl, CO2H, or a 5- or 6-membered saturated heterocycle containing at least one heteroatom selected from N and O, said ring optionally substituted with C(O)C1-C3 alkyl; (vi) a C1-C3 alkyl group; (vii) a hydroxyl C1-C6 alkoxy group; (viii) a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom; and (ix) a hydroxyl group.

[0343] R6 is a cyano group; C(O)NHR 6a NHR 6b ; or C1-C3 alkoxy groups substituted with NH2 or hydroxyl groups,

[0344] R 6a Selected from: (i) hydrogen; (ii) C1-C3 alkyl; (iii) C3-C6 cycloalkyl; and (iv) a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom, wherein the aromatic heterocycle is optionally substituted with: C1-C3 alkyl;

[0345] R 6b It is a C1-C3 alkyl group substituted with NH2 or hydroxyl groups;

[0346] R 7 Each is independently selected from hydrogen or C1-C3 alkyl groups; and

[0347] R 8 It is hydrogen or C1-C3-alkyl, especially methyl.

[0348] Example 3. The compound or a pharmaceutically acceptable salt thereof as described in Example 1,

[0349] in

[0350] W is CH-R w ;

[0351] X is selected from CH; and N;

[0352] Y is CH;

[0353] Z is selected from O and NH;

[0354] A is a phenyl group, which is optionally substituted by: halogenation; or halogenation of C1-C3 alkoxy groups;

[0355] R w Selected from: (i) hydrogen; (ii) C1-C3 alkoxy; (iii) hydroxy-C1-C3 alkyl; (iv) C1-C3 alkyl; and (v) C1-C3 alkoxy-C1-C3 alkyl;

[0356] Q is selected from: (i)-C(R) 7 (ii) 2-NH-R1; and (iii) comprising a 4-, 5-, or 6-membered saturated heterocycle comprising one or two heteroatoms independently selected from N, O, and S, provided that at least one N heteroatom is present, preferably wherein the N is present at the α position of the atom that bonds Q to the rest of the molecule, and wherein the heterocycle is unsubstituted or substituted by one or more substituents independently selected from hydroxyl, C1-C3 alkyl, and halogenated.

[0357] R1 is selected from: (i) C1-C6 alkyl groups; (ii) R 1a ;in

[0358] R 1a Selected from C3-C6 cycloalkyl groups, which may optionally be independently substituted once or multiple times with: hydroxyl; C1-C6 alkyl; or halogenated;

[0359] R2 is hydrogen or preferably halogenated;

[0360] R3 is halogenated;

[0361] R4 is selected from: (i) hydrogen; and (ii) halogenated;

[0362] R5 is selected from: hydroxyl, C1-C6 alkoxy; and hydroxyC1-C6 alkoxy;

[0363] R6 is C(O)NHR 6a ;

[0364] R 6a Selected from: (i) hydrogen; and (ii) C1-C3 alkyl;

[0365] and

[0366] R 7 Each is independently selected from hydrogen or C1-C3 alkyl groups.

[0367] Example 4. A compound having Formula I according to any one of Examples 1 to 3,

[0368] in

[0369] W is CH-R w ;

[0370] X is selected from CH; and N;

[0371] Y is CH;

[0372] Z is selected from O and NH;

[0373] A is a phenyl group, which is optionally substituted by: halogenation; or halogenation of C1-C3 alkoxy groups, especially unsubstituted phenyl groups;

[0374] R w Selected from: (i) hydrogen; and (ii) C1-C3 alkyl, or hydroxy-C1-C3 alkyl;

[0375] Q is selected from: (i)-C(R) 7 (ii) 2-NH-R1; and (iii) comprising a 4-, 5-, or 6-membered saturated heterocycle comprising one or two heteroatoms independently selected from N and O, provided that at least one N heteroatom is present and said N heteroatom is located at the α position of a carbon atom that bonds Q to the remainder of the molecule, wherein said heterocycle is unsubstituted or substituted by one or more substituents independently selected from: hydroxyl, C1-C3 alkyl, and halogenated;

[0376] R1 is selected from: (i) C1-C6 alkyl groups; (ii) R 1a ;in

[0377] R 1a Selected from C3-C6 cycloalkyl groups, which may optionally be independently substituted once or multiple times with: hydroxyl; C1-C6 alkyl; or halogenated;

[0378] R2 is halogenated, especially fluorine;

[0379] R3 is halogenated, especially chlorinated;

[0380] R4 is halogenated, especially fluorinated;

[0381] R5 is selected from: C1-C6 alkoxy; and hydroxyC1-C6 alkoxy;

[0382] R6 is C(O)NHR 6a ;

[0383] R 6aSelected from: (i) hydrogen; and (ii) C1-C3 alkyl;

[0384] and

[0385] Each R 7 It is hydrogen.

[0386] Example 5. The compound or a pharmaceutically acceptable salt thereof according to Examples 1, 2, 3 or 4, wherein the compound has formula (Ia):

[0387]

[0388] Example 6. The compound or a pharmaceutically acceptable salt thereof according to Examples 1, 2, 3, 4 or 5, wherein the compound has the formula (Ia-1):

[0389]

[0390] Example 7. The compound or a pharmaceutically acceptable salt thereof according to Examples 1, 2, 3, 4 or 5, wherein the compound has the formula (Ib):

[0391]

[0392] Example 8. The compound or a pharmaceutically acceptable salt thereof according to Examples 1, 2, 3, 4 or 5, wherein the compound has the formula (Ic):

[0393]

[0394] Example 9. The compound or a pharmaceutically acceptable salt thereof according to Examples 1, 2, 3, 4 or 5, wherein the compound has the formula (Id):

[0395]

[0396] Example 10. The compound or a pharmaceutically acceptable salt thereof according to Example 1, 2, 3 or 4, wherein Y is CH.

[0397] Example 11. A compound or a pharmaceutically acceptable salt thereof according to Examples 1, 2, 3 or 4, wherein Y is CH and W is CH-R. W .

[0398] Example 12. A compound or a pharmaceutically acceptable salt thereof according to Examples 1, 2, 3 or 4, wherein Y is CH and W is CH-R. W And Z is O.

[0399] Example 13. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 5, 7 to 12, wherein A is a phenyl ring that is unsubstituted.

[0400] Example 14. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 13, wherein R3 is chlorine.

[0401] Example 15. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 5, 7 to 14, wherein R4 is fluorine.

[0402] Example 16. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 15, wherein R2 is fluorine.

[0403] Example 17. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 5, 8 to 16, wherein X is CH.

[0404] Example 18. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 5, 8 to 16, wherein X is N.

[0405] Example 19. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 18, wherein R5 is selected from: (i) C1-C6 alkoxy, optionally substituted with: C3-C6 cycloalkyl; CO2H; SO2C1-C3 alkyl; a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from N, O, and S; or a 5- or 6-membered saturated heterocycle containing at least one heteroatom selected from N and O, said ring optionally substituted with C(O)C1-C3 alkyl; (ii) hydroxyl C1-C6 alkoxy; (iii) halogenated C1-C6 alkoxy optionally substituted with hydroxyl; (iv) C1-C3 alkoxy C1-C3 alkoxy.

[0406] Example 20. The compound of Example 19 or a pharmaceutically acceptable salt thereof, wherein R5 is selected from: (i) C1-C6 alkoxy, optionally substituted with: C3-C6 cycloalkyl; CO2H; SO2C1-C3 alkyl; a 6-membered aromatic heterocycle containing at least one N heteroatom; or a 5- or 6-membered saturated heterocycle containing at least one heteroatom selected from N and O, said ring optionally substituted with C(O)C1-C3 alkyl; (ii) hydroxy C1-C6 alkoxy; (iii) halogenated C1-C6 alkoxy optionally substituted with hydroxyl; (iv) C1-C3 alkoxy C1-C3 alkoxy.

[0407] Example 21. A compound according to any one of Examples 1 to 20 or a pharmaceutically acceptable salt thereof, wherein R5 is selected from: (i) C1-C6 alkoxy; (ii) hydroxy C1-C6 alkoxy; (iii) halogenated C1-C6 alkoxy optionally substituted with a hydroxyl group; (iv) C1-C3 alkoxy C1-C3 alkoxy.

[0408] Example 22. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 21, wherein R5 is a hydroxyC1-C6 alkoxy or a C1-C6 alkoxy, preferably wherein R5 is a hydroxyC1-C6 alkoxy.

[0409] Example 23. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 22, wherein R6 is selected from: (i) cyano; (ii) C(O)NHR 6a Preferably, R6 is C(O)NHR 6a .

[0410] Example 24. The compound or a pharmaceutically acceptable salt thereof according to Example 23, wherein R 6a Selected from: (i) hydrogen; (ii) C1-C3 alkyl; (iii) C3-C6 cycloalkyl; (iv) a 5- or 6-membered aromatic heterocycle containing at least one N heteroatom, wherein the aromatic heterocycle is optionally substituted with: C1-C3 alkyl.

[0411] Example 25. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 24, wherein R 6a It is hydrogen or C1-C3 alkyl.

[0412] Example 26. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 25, wherein R 6a It is a C1-C3 alkyl group.

[0413] Example 27. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 26, wherein R 6a It is a methyl group.

[0414] Example 28. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 27, wherein Q is (I)-C(R) 7 )2-N(R8)-R1, preferably Q is -C(R 7(ii) a 9- or 10-membered partially saturated heteroaryl group containing at least one N heteroatom; and (iii) a 4-, 5-, or 6-membered saturated heterocycle containing at least one heteroatom selected from N, O, and S, provided that at least one N heteroatom is present, wherein the heterocycle is unsubstituted or substituted by one or more substituents independently selected from hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, halogen, and C1-C3 alkylene, which form a bridge between the two ring atoms of the saturated heterocycle, thereby forming a bridged bicyclic structure.

[0415] Example 29. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 28, wherein Q is -C(R 7 )2-N(R8)-R1, preferably Q is -C(R 7 )2-NH-R1, or choose from the following groups:

[0416]

[0417] Example 30. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 29, wherein Q is -C(R 7 )2-N(R8)-R1, preferably Q is -C(R 7 )2-NH-R1, or choose from the following groups:

[0418]

[0419] Example 31. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 30, wherein Q is -C(R 7 )2-N(R8)-R1, preferably Q is -C(R 7 )2-NH-R1, or choose from the following groups:

[0420]

[0421] Example 32. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 31, wherein Q is

[0422]

[0423] Example 33. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 31, wherein R1 is selected from: (i) hydrogen; (ii) C1-C6 alkyl; (iii) (CH2). 0-2 R 1a ;

[0424] in

[0425] R1a Selected from: (i) hydroxy C1-C4 alkyl; (ii) C1-C3 alkoxy; (iii) a 5- or 6-membered saturated heterocycle containing at least one heteroatom selected from N and O, said saturated heterocycle optionally being independently substituted once or more by: C1-C3 alkyl; (CH2)C(O)di(C1-C3 alkyl)amino; SO2C1-C3 alkyl; C(O)C1-C3 alkyl; or oxo;

[0426] (iv) C3-C6 cycloalkyl, optionally independently substituted once or more by: hydroxyl; hydroxyl C1-C4 alkyl; C1-C6 alkoxy, preferably C1-C4 alkoxy; C(O)OC1-C3 alkyl; CO2H; SO2C1-C3 alkyl; halo-C1-C3 alkyl; NHR 1b ;C(O)NR 1c R 1d C1-C6 alkyl; halogenated C1-C3 alkoxy-C1-C3 alkyl; halogenated; a 5-membered aromatic heterocycle containing at least one N heteroatom; or two R atoms 1e ,

[0427] Among these two R 1e The groups are attached to the same carbon atom and together with the carbon atom to which they are attached, form a 5-membered saturated heterocycle or a C3-C6 cycloalkyl group containing at least one N heteroatom, wherein the saturated heterocycle or cycloalkyl group is optionally substituted with a hydroxyl group or an oxo group.

[0428] Example 34. The compound according to Example 33 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from: (i) C1-C6 alkyl; (ii) (CH2) 0-2 R 1a ;

[0429] in

[0430] R 1a Selected from: (i) hydroxy C1-C4 alkyl; (ii) C3-C6 cycloalkyl, preferably cyclohexyl, optionally independently substituted once or more by: hydroxyl; hydroxy C1-C4 alkyl; C1-C6 alkoxy, preferably C1-C4 alkoxy; C(O)OC1-C3 alkyl; CO2H; SO2C1-C3 alkyl; halo-C1-C3 alkyl; NHR 1b ;C(O)NR 1c R 1d C1-C6 alkyl; halogenated C1-C3 alkoxy-C1-C3 alkyl; halogenated; 5-membered aromatic heterocycle containing at least one N heteroatom; or R 1e ,

[0431] Among these two R 1eThe groups are attached to the same carbon atom and together with the carbon atom to which they are attached, form a 5-membered saturated heterocycle or a C3-C6 cycloalkyl group containing at least one N heteroatom, wherein the saturated heterocycle is substituted with an oxygen and the cycloalkyl group is substituted with a hydroxyl group.

[0432] Example 35. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 31, 33 or 34, wherein R1 is selected from: (i) C1-C6 alkyl; (ii) (CH2)OR 1a ;

[0433] in

[0434] R 1a It is a C3-C6 cycloalkyl group, preferably cyclohexyl, which is optionally independently substituted once or more by: hydroxyl; hydroxyl C1-C4 alkyl; C1-C6 alkoxy, preferably C1-C4 alkoxy; C(O)OC1-C3 alkyl; CO2H; SO2C1-C3 alkyl; halo-C1-C3 alkyl; NHR 1b ;C(O)NR 1c R 1d C1-C6 alkyl; halogenated C1-C3 alkoxy-C1-C3 alkyl; or halogenated.

[0435] Example 36. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 31, 33 to 35, wherein R1 is selected from: (i) C1-C6 alkyl; (ii) (CH2)OR 1a ;

[0436] in

[0437] R 1a It is a C3-C6 cycloalkyl, preferably cyclohexyl, which is optionally independently substituted once or more by: hydroxyl; hydroxyl C1-C4 alkyl; C1-C6 alkoxy, preferably C1-C4 alkoxy; C(O)OC1-C3 alkyl; halo-C1-C3 alkyl; C1-C6 alkyl; or halogenated.

[0438] Example 37. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 31, 33 to 36, wherein R1 is (CH2)OR 1a ,in

[0439] R 1a It is a cyclohexyl group, which is independently substituted once or multiple times by: hydroxyl; hydroxyl C1-C4 alkyl; C1-C6 alkoxy, preferably C1-C4 alkoxy; C(O)OC1-C3 alkyl; halo-C1-C3 alkyl; C1-C6 alkyl; or halogenated.

[0440] Example 38. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 31, 33 to 37, wherein R1 is (CH2)OR 1a ,in

[0441] R 1a It is a cyclohexyl group, which is independently substituted twice by the following: hydroxyl; hydroxy C1-C4 alkyl; C1-C4 alkoxy; halo C1-C3 alkyl; C1-C6 alkyl; or halogenated.

[0442] Example 39. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 31, 33 to 38, wherein R1 is (CH2)OR 1a ,in

[0443] R 1a It is a cyclohexyl group, which is independently substituted twice by the following: hydroxyl and C1-C6 alkyl groups.

[0444] Example 40. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 31, 33 to 39, wherein R1 is

[0445]

[0446] Example 41. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 31, 33 to 40, wherein R1 is

[0447]

[0448] Example 42. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 31, 33 to 41, wherein R 7 Each is independently selected from hydrogen and C1-C3 alkyl groups.

[0449] Example 43. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 31, 33 to 42, wherein two R 7 All the radicals are hydrogen.

[0450] Example 44. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 31, 33 to 42, wherein one of R 7 One is hydrogen, and the other is a C1-C3 alkyl group.

[0451] Example 45. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 31, 33 to 42, 44, wherein R 7 One is hydrogen, and the other is methyl.

[0452] Example 46. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 31, 33 to 43, wherein Q is -CH2-NH-R1, and R1 is as defined in any one of Examples 33 to 41.

[0453] Example 47. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 31, 33 to 43, 46, wherein Q is

[0454]

[0455] Example 48. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 31, 33 to 43, 46, and 47, wherein Q is

[0456]

[0457] Example 49. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 31, 33 to 36, 42, 43, 46, wherein Q is a -CH2-NH-C1-C6 alkyl group.

[0458] Example 50. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 31, 33 to 36, 42, 43, 46, 49, wherein Q is -CH2-NH-CH3.

[0459] Example 51. The compound or a pharmaceutically acceptable salt thereof according to Example 1, wherein the compound is selected from the compounds of the examples or the compounds listed in claim 8.

[0460] Example 52. The compound according to Example 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0461] N1-(2-((2S*,4S*)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenyl)ethane-1,2-diamine;

[0462] N1-(2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenyl)ethane-1,2-diamine;

[0463] 2-((2S*,4S*)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide;

[0464] 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide;

[0465] 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0466] 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-chloro-3-fluorobenzamide;

[0467] 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3,4-difluorobenzamide;

[0468] 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

[0469] 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0470] 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-methoxyethoxy)benzamide;

[0471] 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide;

[0472] 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((R)-2-hydroxypropoxy)benzamide;

[0473] 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((R)-2-fluoropropoxy)benzamide;

[0474] 2-(3-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-carbamoyl-2-fluorophenoxy)acetic acid trifluoroacetate;

[0475] 4-(((R)-4-acetylmorpholin-2-yl)methoxy)-2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide;

[0476] 4-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-methoxynicotinamide;

[0477] 4-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-6-(difluoromethoxy)-5-fluoronicotinamide;

[0478] 2-((2S,4S)-5-chloro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0479] 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxy-N-methylbenzamide;

[0480] 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-N-cyclopropyl-3-fluoro-4-methoxybenzamide;

[0481] 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3,4-difluoro-N-(1-methyl-1H-pyrazol-5-yl)benzamide;

[0482] 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxy-N-(pyridin-3-yl)benzamide;

[0483] 2-((2S,4S)-5-chloro-2-(((trans-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0484] 2-((2S,4S)-5-chloro-2-(((cis-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0485] (trans)-4-((((2S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexanecarboxylic acid;

[0486] (cis)-4-((((2S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexanecarboxylic acid;

[0487] 2-((2R,4S)-2-(aminomethyl)-5-chloro-2-(thiazolyl-4-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0488] 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-(2-fluorophenyl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0489] 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0490] 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(cyclopropylmethoxy)-3-fluorobenzamide;

[0491] 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0492] 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(1,1-difluoro-2-hydroxyethoxy)-3-fluorobenzamide;

[0493] 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-methoxyethoxy)benzamide;

[0494] 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

[0495] 4-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-methoxynicotinamide;

[0496] 4-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinamide;

[0497] 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide;

[0498] 4-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide;

[0499] 2-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0500] 4-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-methoxyethoxy)nicotinamide;

[0501] 2-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

[0502] 4-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinamide;

[0503] 2-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide;

[0504] 2-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide;

[0505] 4-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide;

[0506] 2-((2S,4S)-5-chloro-6-fluoro-2-((((trans)-4-(methylsulfonyl)cyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0507] 2-((2S,4S)-5-chloro-6-fluoro-2-(((4-(fluoromethyl)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0508] 2-((2S,4S)-2-(((4-acetamidocyclohexyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0509] 2-((2S,4S)-5-chloro-6-fluoro-2-(((4-(methylsulfonamido)cyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0510] 2-((2S,4S)-5-chloro-2-(((4-(dimethylcarbamoyl)cyclohexyl)amino)methyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0511] 2-((2S,4S)-5-chloro-6-fluoro-2-(((2-oxo-1-azaspiro[4.5]decane-8-yl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0512] 2-((2S,4S)-5-chloro-2-(((1-(2-(dimethylamino)-2-oxoethyl)piperidin-4-yl)amino)methyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0513] 2-((2S,4S)-5-chloro-6-fluoro-2-(((4-(hydroxymethyl)cyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0514] 2-((2S,4S)-5-chloro-6-fluoro-2-(((3-(2-hydroxypropyl-2-yl)cyclobutyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0515] 2-((2S,4S)-5-chloro-6-fluoro-2-((((trans)-3-(hydroxymethyl)cyclobutyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

[0516] 2-((2S,4S)-5-chloro-6-fluoro-2-((((cis)-3-(hydroxymethyl)cyclobutyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

[0517] 2-((2S,4S)-5-chloro-2-((((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)amino)methyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

[0518] 4-((2S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-methoxynicotinamide;

[0519] 4-((2S,4S)-5-chloro-6-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-methoxynicotinamide;

[0520] 2-((2S,4S)-5-chloro-6-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(((R)-tetrahydrofuran-2-yl)methoxy)benzamide;

[0521] 2-((2S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(((R)-tetrahydrofuran-2-yl)methoxy)benzamide;

[0522] 2-((2S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-ethyl-3-fluorobenzamide;

[0523] 2-((2S,4S)-5-chloro-6-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-ethyl-3-fluorobenzamide;

[0524] 2-((2S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(1H-imidazol-1-yl)benzamide;

[0525] 2-((2S,4S)-5-chloro-6-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(1H-imidazol-1-yl)benzamide;

[0526] 2-((2S,4S)-2-(((1-acetylpiperidin-4-yl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0527] 2-((2S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(pyrimidin-2-ylmethoxy)benzamide;

[0528] 2-((2S,4S)-5-chloro-6-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(pyrimidin-2-ylmethoxy)benzamide;

[0529] 2-((2S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0530] 2-((2S,4S)-2-((tert-butylamino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0531] 2-((2S,4S)-2-((((trans)-4-(1H-tetrazol-1-yl)cyclohexyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0532] 2-((2S,4S)-5-chloro-2-(((trans-3-((difluoromethoxy)methyl)cyclobutyl)amino)methyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0533] 2-((2S,4S)-5-chloro-6-fluoro-2-(((6-hydroxyspiro[3.3]heptane-2-yl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0534] 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0535] 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-methoxyethoxy)benzamide;

[0536] 2-((2R,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0537] 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-(2-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0538] 2-((2S,3S,4S)-5-chloro-3-hydroxy-2-((((trans)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0539] 2-((2S,3S,4S)-5-chloro-3-hydroxy-2-((((cis)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0540] 2-((2R,3S,4S)-5-chloro-3-hydroxy-2-((((trans)-4-hydroxycyclohexyl)amino)methyl)-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0541] 2-((2R,3S,4S)-5-chloro-3-hydroxy-2-((((cis)-4-hydroxycyclohexyl)amino)methyl)-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0542] 2-((2S,3S,4S)-5-chloro-2-((cyclobutylamino)methyl)-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0543] 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0544] 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

[0545] 2-((2S,3S,4S)-5-chloro-2-((cyclobutylamino)methyl)-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

[0546] 2-((2S,3S,4S)-5-chloro-6-fluoro-3-hydroxy-2-((((trans)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0547] 2-((2S,3S,4S)-5-chloro-6-fluoro-3-hydroxy-2-((((cis)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0548] 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

[0549] 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxycyclohexyl)amino)methyl)-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0550] 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((cis)-4-hydroxycyclohexyl)amino)methyl)-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0551] 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0552] 2-((2S,3S,4S)-5-chloro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0553] 2-((2S,3S,4S)-5-chloro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0554] 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0555] 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-methoxyethoxy)benzamide;

[0556] 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

[0557] 4-((2S,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-methoxyethoxy)nicotinamide;

[0558] 2-((2R,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0559] 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

[0560] 2-((2R,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-methoxyethoxy)benzamide;

[0561] 2-((2R,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

[0562] 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide;

[0563] 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide;

[0564] 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide;

[0565] 2-((2S,3S,4S)-5-chloro-6-fluoro-2-(((trans-4-hydroxycyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0566] 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((cis)-4-hydroxycyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0567] 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-methoxyethoxy)benzamide;

[0568] 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-methoxyethoxy)benzamide;

[0569] 2-((2S,3S,4S)-5-chloro-6-fluoro-2-(((trans-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

[0570] 2-((2S,3S,4S)-5-chloro-6-fluoro-2-(((cis-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

[0571] 2-((2S,3S,4S)-5-chloro-2-((cyclobutylamino)methyl)-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

[0572] 4-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinamide;

[0573] 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzylnitrile;

[0574] 2-((2S,3S,4S)-5-chloro-6-fluoro-2-(((trans-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide;

[0575] 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide;

[0576] 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide;

[0577] 2-(2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3,4-difluorophenoxy)ethane-1-ol;

[0578] 2-((2R,3S,4S)-5-chloro-6-fluoro-2-(6-hydroxypyridin-2-yl)-3-methyl-2-((methylamino)methyl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0579] 2-((2R,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-methoxyethoxy)benzamide;

[0580] 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-(pyridin-3-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0581] 2-((2S,4S)-5-chloro-2-((cyclohexylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0582] 2-((2S,3S,4S)-5-chloro-6-fluoro-3-hydroxy-2-((((cis)-4-methoxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0583] 2-((2S,3S,4S)-5-chloro-6-fluoro-3-hydroxy-2-((((trans)-4-methoxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0584] Methyl(cis)-4-((((2S,4S)-4-(6-carbamoyl-2,3-difluorophenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexane-1-carboxylate;

[0585] Methyl(trans)-4-((((2S,4S)-4-(6-carbamoyl-2,3-difluorophenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexane-1-carboxylate;

[0586] 2-((2S,4S)-2-((((trans)-4-carbamoylcyclohexyl)amino)methyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide;

[0587] 2-((2S,4S)-2-((((cis)-4-carbamoylcyclohexyl)amino)methyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide;

[0588] 2-((2S,4S)-5-chloro-2-((((trans)-4-(methylcarbamoyl)cyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide;

[0589] 2-((2S,4S)-5-chloro-2-((((cis)-4-(methylcarbamoyl)cyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide;

[0590] 2-((2S,4S)-5-chloro-2-((((cis)-3-(difluoromethyl)cyclobutyl)amino)methyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

[0591] 2-((2S,4S)-5-chloro-2-((((trans)-3-(difluoromethyl)cyclobutyl)amino)methyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

[0592] 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy-1,1,2,2-d4)-N-methylbenzamide;

[0593] 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0594] 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidine-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide;

[0595] 2-((2S,4S)-5-chloro-6-fluoro-2-(((methyl-d3)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; and

[0596] 2-((2S,4S)-5-chloro-6-fluoro-2-(((methyl-d3)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy-1,1,2,2-d4)benzamide.

[0597] Example 53. The compound or a pharmaceutically acceptable salt thereof according to Example 1, wherein the compound is selected from the group consisting of:

[0598] 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0599] 4-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide; 2-((2S,3R,4S)-5-chloro-6-fluoro-3-(methoxymethyl)-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0600] 2-((2S,3R,4S)-5-chloro-6-fluoro-3-(hydroxymethyl)-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0601] 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxy-2-methylpropoxy)benzamide;

[0602] 2-((2S,4S)-2-(azacyclobutan-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide;

[0603] 2-((2S,3S,4S)-2-(azacyclobutan-2-yl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide;

[0604] 2-((2S,3S,4S)-2-(azacyclobutan-2-yl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide;

[0605] (2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolid-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

[0606] 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidine-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide;

[0607] 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidine-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide;

[0608] 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidone-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide;

[0609] 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidine-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide;

[0610] 2-((4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidine-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-5-(methylcarbamoyl)pyridin-2-yl)oxy)acetic acid;

[0611] 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidine-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-hydroxy-N-methylnicotinamide;

[0612] 2-((2S,4S)-5-chloro-6-fluoro-2-(4-hydroxypyrrolidone-2-yl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

[0613] 2-((2S,4S)-5-chloro-6-fluoro-2-(4-hydroxy-4-methylpyrrolidone-2-yl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide;

[0614] (2S,4R)-2-((S)-5-chloro-6-fluoro-2,4-diphenyl-2,3-dihydrobenzofuran-2-yl)-4-fluoropyrrolidine;

[0615] 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-piperidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide;

[0616] (3-((S)-5-chloro-6-fluoro-2,4-diphenyl-2,3-dihydrobenzofuran-2-yl)morpholine;

[0617] 2-((2S,4S)-5-chloro-6-fluoro-2-(morpholin-3-yl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0618] 2-((2S,3S,4S)-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2-(pyrrolidone-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0619] 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methoxy-2-phenyl-2-(pyrrolidone-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0620] 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methoxy-2-phenyl-2-(pyrrolidone-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

[0621] 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-phenyl-2-(pyrrolidone-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide;

[0622] 2-((2S,4S)-2-(1-aminoethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0623] 2-((2S,3S,4S)-2-(1-aminoethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-methoxyethoxy)benzamide;

[0624] 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidine-2-yl)indoline-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

[0625] 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidine-2-yl)indoline-4-yl)-3-fluoro-4-methoxybenzamide;

[0626] 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidine-2-yl)indoline-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide;

[0627] 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidine-2-yl)indoline-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide;

[0628] 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidine-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0629] 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidine-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxy-N-methylbenzamide; and

[0630] 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide.

[0631] Example 54. The compound according to Example 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0632] 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide;

[0633] 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide;

[0634] 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

[0635] 4-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide;

[0636] 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidine-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide; and

[0637] 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidine-2-yl)indoline-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide.

[0638] Example 55. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 54.

[0639] Example 56. A combination comprising a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 54, and one or more therapeutically active agents.

[0640] Example 57. The combination according to Example 56, wherein one or more therapeutic agents are selected from anticancer agents.

[0641] Example 58. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 54, combined simultaneously or sequentially with an anticancer therapeutic agent.

[0642] Example 59. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 54 is used as a medicine.

[0643] Example 60. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 54, for use in inhibiting YAP / TAZ-TEAD protein-protein interaction activity in a subject.

[0644] Example 61. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 54, for use in treating a disorder or disease by inhibiting the YAP / TAZ-TEAD protein-protein interaction in a subject, preferably wherein the disorder or disease is cancer.

[0645] Example 62. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 54, for use in treating a disorder or disease, said disorder or disease being cancer or tumor.

[0646] Example 63. A compound or a pharmaceutically acceptable salt thereof used according to Example 62, wherein the cancer or tumor is a cancer or tumor carrying: (i) one or more YAP / TAZ fusions; (ii) one or more truncated mutations or deletions of NF2 / LATS1 / LATS2; or (iii) one or more functional YAP / TAZ fusions.

[0647] Example 64. A compound or a pharmaceutically acceptable salt thereof used according to Example 62 or 63, wherein the cancer or tumor is selected from: mesothelioma (including pleural mesothelioma, malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, and tunica vaginalis mesothelioma), carcinoma (including cervical squamous cell carcinoma, endometrial carcinoma, esophageal squamous cell carcinoma, esophageal adenocarcinoma, bladder urothelial carcinoma, and skin squamous cell carcinoma), poroma (benign poroma), porocarcinoma (including malignant porocarcinoma), supratentorial ependymoma (including pediatric supratentorial ependymoma), epithelioid hemangioendothelioma (EHE), ependymal tumor, solid tumor, breast cancer. (Including triple-negative breast cancer), lung cancer (including non-small cell lung cancer), ovarian cancer, colorectal cancer (including colon cancer), melanoma, pancreatic cancer (including pancreatic adenocarcinoma), prostate cancer, gastric cancer, esophageal cancer, liver cancer (including hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma), neuroblastoma, schwannoma, renal cancer, sarcoma (including rhabdomyosarcoma, embryonal rhabdomyosarcoma (ERMS), osteosarcoma, undifferentiated pleomorphic sarcoma (UPS), Kaposi's sarcoma, soft tissue sarcoma, and rare soft tissue sarcoma), bone cancer, brain cancer, medulloblastoma, glioma, meningioma, and head and neck cancer (including squamous cell carcinoma of the head and neck).

[0648] Example 65. A compound or a pharmaceutically acceptable salt thereof used according to any one of Examples 61 to 64, wherein the disease or cancer is selected from breast cancer, lung cancer (including non-small cell lung cancer), ovarian cancer, colorectal cancer, malignant pleural mesothelioma, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer, sarcoma, and bone cancer, preferably wherein the cancer is malignant pleural mesothelioma or epithelioid hemangioendothelioma (EHE).

[0649] Example 66. A method for inhibiting the protein-protein interaction activity of YAP / TAZ-TEAD in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 54.

[0650] Example 67. A method for modulating the YAP / TAZ-TEAD protein-protein interaction activity in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 54.

[0651] Example 68. A method for inhibiting, reducing, or eliminating YAP / TAZ-TEAD protein-protein interactions, the method comprising administering to a subject a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 54.

[0652] Example 69. A method for treating a disease or disorder affected by the regulation of YAP / TAZ-TEAD protein-protein interaction activity, the method comprising administering to a patient in need a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 54.

[0653] Example 70. A method for treating a disease or disorder affected by suppressed, reduced, or eliminated YAP / TAZ-TEAD protein-protein interactions in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 54.

[0654] Example 71. The method according to Example 69 or 70, wherein the disease or obstacle is cancer or tumor.

[0655] Example 72. A method of treating a subject with cancer or tumor, wherein the method comprises administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 54.

[0656] Example 73. The method according to any one of Examples 71 or 72, wherein the cancer or tumor is selected from: mesothelioma (including pleural mesothelioma, malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, and tunica vaginalis mesothelioma), carcinoma (including cervical squamous cell carcinoma, endometrial carcinoma, esophageal squamous cell carcinoma, esophageal adenocarcinoma, bladder urothelial carcinoma, and skin squamous cell carcinoma), poroma (benign poroma), porocarcinoma (including malignant porocarcinoma), supratentorial ependymoma (including pediatric supratentorial ependymoma), epithelioid hemangioendothelioma (EHE), ependymal tumor, solid tumor, breast cancer (including triple-negative breast cancer). Breast cancer, lung cancer (including non-small cell lung cancer), ovarian cancer, colorectal cancer (including colon cancer), melanoma, pancreatic cancer (including pancreatic adenocarcinoma), prostate cancer, gastric cancer, esophageal cancer, liver cancer (including hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma), neuroblastoma, schwannoma, renal cancer, sarcoma (including rhabdomyosarcoma, embryonal rhabdomyosarcoma (ERMS), osteosarcoma, undifferentiated pleomorphic sarcoma (UPS), Kaposi's sarcoma, soft tissue sarcoma, and rare soft tissue sarcoma), bone cancer, brain cancer, medulloblastoma, glioma, meningioma, and head and neck cancer (including squamous cell carcinoma of the head and neck).

[0657] Example 74. The method according to any one of Examples 71 to 73, wherein the cancer is breast cancer, lung cancer (including non-small cell lung cancer), ovarian cancer, colorectal cancer, malignant pleural mesothelioma, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer, sarcoma, and bone cancer, preferably wherein the cancer is malignant pleural mesothelioma or epithelioid hemangioendothelioma (EHE).

[0658] Example 75. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 54 is used to prepare a medicine, preferably for the treatment of diseases, cancers or tumors as described herein (e.g., as defined in any one of Examples 73 or 74).

[0659] In the compounds according to any one of the listed Examples 1 to 50, A is preferably an unsubstituted phenyl ring.

[0660] Pharmaceutically acceptable salts

[0661] Depending on the choice of starting materials and procedures, compounds may exist in possible isomeric forms or as mixtures thereof (e.g., as pure optical isomers or as mixtures of isomers, such as racemic and diastereomeric mixtures), depending on the number of asymmetric centers. This invention is intended to include all such possible isomers, including racemic mixtures, enantiomer-enriched mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a disubstituted or trisubstituted cycloalkyl group, the one or more cycloalkyl substituents may have cis or trans configurations. This invention includes cis and trans configurations of substituted cycloalkyl groups and mixtures thereof. All tautomeric forms are also included. In particular, when the heteroaryl ring containing N as a ring atom is a 2-pyridinone, for example, tautomers in which the carbonyl group is depicted as a hydroxyl group are included (e.g., 2-hydroxypyridine).

[0662] As used herein, the term "salt" (or salts) refers to an acid addition salt or a base addition salt of the compounds of the present invention. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salt" means that the compounds of the present invention retain their biological efficacy and properties and are typically not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid salts and / or base salts due to the presence of amino and / or carboxyl groups or similar groups.

[0663] Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and trifluoroacetic acid.

[0664] Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases.

[0665] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I through XII of the periodic table. In some embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0666] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; and basic ion exchange resins. Some organic amines include isopropylamine, benzylamine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0667] In another aspect, the present invention provides compounds in the form of: acetates, ascorbic acid salts, adipates, aspartates, benzoates, benzenesulfonates, bromides / hydrobromates, bicarbonates / carbonates, bisulfates / sulfates, camphorsulfonates, decanoates, chlorides / hydrochlorides, chlortheophyllonates, citrates, ethanedisulfonates, fumarates, glucohepanoates, glucuronates, glucuronates, glutamates, glutamates, glycolic acid, hippurate, and hydroiodates / iodides. Hydroxyethyl sulfonate, lactate, lacturonate, dodecyl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methyl sulfate, mucilage, naphthate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, dihydroxynaphthalate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebate, stearate, succinate, sulfosalicylate, sulfate, tartrate, toluenesulfonate, trifluoromethanesulfonate, trifluoroacetate, or sine in the form of naphthate.

[0668] Isotope-labeled compounds

[0669] Any formulas given herein are intended to represent both the unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures described by the formulas given herein, except that one or more atoms are replaced by atoms having a chosen atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, […]. 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 17 O、 18 O、 18 F, 35 S, 36 Cl、 123 I, 124 I,125 I. This invention includes various isotope-labeled compounds as defined herein, such as those containing a radioactive isotope (e.g., 3 H and 14 Those compounds in C), or those containing non-radioactive isotopes (such as...) 2 H and 13 C). Compounds labeled with this type of isotope can be used for metabolic studies (using...) 14 C) Reaction kinetic studies (e.g., using...) 2 H or 3 H) Detection or imaging techniques, including those for determining drug or substrate tissue distribution (e.g., positron emission tomography (PET) or single-photon emission computed tomography (SPECT), or those applicable to the patient's radiation therapy. In particular, 18 Compound F may be particularly ideal for PET or SPECT studies. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples, using an appropriate isotopically labeled reagent instead of an unlabeled previously used reagent.

[0670] In addition, heavier isotopes, especially deuterium (i.e., 2 H or D substitution can provide certain therapeutic advantages arising from greater metabolic stability (e.g., prolonged in vivo half-life, reduced dose requirement, or improved therapeutic index). It should be understood that, in this context, deuterium is considered a substituent in compounds having formula (I). The concentration of such heavier isotopes (particularly deuterium) can be defined by an isotope enrichment factor. As used herein, the term "isotope enrichment factor" refers to the ratio between the isotope abundance and the native abundance of a given isotope. If the substituent in the compound of the present invention specifies deuterium, such a compound has an isotopic enrichment factor for each specified deuterium atom of at least 3500 (52.5% deuterium doping on each specified deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping).

[0671] The present invention also relates to compounds as described in any of the above embodiments, wherein one or more hydrogen atoms in one or more substituents are replaced by deuterium, for example, all hydrogen atoms in one or more alkyl substituents are replaced by deuterium (and then the corresponding one or more portions are fully deuterated).

[0672] Pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent can be substituted with an isotope, such as D2O, d6-acetone, and d6-DMSO.

[0673] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by the context. Any and all instances or exemplary language (e.g., “as”) used herein are intended only to better illustrate the invention and not to limit the scope of the invention as otherwise claimed.

[0674] Any asymmetric center in the compounds of the present invention may exist in the form of a racemic mixture or a mixture of enantiomers or an enantiomer enrichment. In some embodiments, for example, as a mixture of enantiomers, each asymmetric center exists in an enantiomer excess of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%. In some embodiments, for example, in the form of enantiomer enrichment, each asymmetric center is present with an enantiomer excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%.

[0675] Therefore, the compounds of the present invention as used herein may be in the form of one of the possible isomers, enantiomers, transisomers, diastereomers, tautomers or mixtures thereof, for example as substantially pure diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0676] Any resulting mixture of isomers can be separated into pure or substantially pure optical isomers, diastereomers, or racemates based on the physicochemical differences of the components, for example by chromatography and / or fractional crystallization.

[0677] Racemic derivatives of any resulting end product or intermediate can be resolved into optical enantiomers by known methods, for example, by separating their diastereomers obtained with optically active acids or bases and releasing optically active acidic or basic compounds. In particular, the basic moiety can thus be used to resolve the compounds of the present invention into their optical enantiomers, for example, by fractional crystallization with salts formed from optically active acids (e.g., tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid). Racemic products can also be resolved by chiral chromatography (e.g., high-performance liquid chromatography (HPLC) using chiral adsorbents).

[0678] Furthermore, the compounds of the present invention (including their salts) can also be obtained in their hydrated form, or include other solvents for their crystallization. The compounds of the present invention can inherently or by design form solvates having pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to encompass both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including its pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical field and are known to be harmless to the recipient, such as water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0679] Those skilled in the art can use tools (such as NMR) to identify the presence of solvates.

[0680] The compounds of the present invention (including their salts, hydrates and solvates) can be inherently or by design to form polymorphs.

[0681] Preparation method

[0682] Typically, compounds having formula (I) can be prepared according to the schemes provided below.

[0683] The schemes provided below are intended to represent individual diastereomers / enantiomers and mixtures of their isomers. Separation of diastereomers / enantiomers can be performed according to the techniques described herein. Unless otherwise defined, in the general schemes described below, R2, R3, R4, R5, R7, R... w A, Q, W, X, Y, and Z are as defined in this document. Specifically, R2, R3, R4, R5, R7, and R... w A, Q, W, X, Y, and Z are as defined in any of the listed Examples 1 to 50. The amine protecting group is also referred to herein as a nitrogen protecting group or PG.

[0684] Option 1: General synthesis of compounds having formula (I)

[0685]

[0686] Step 1: Using a suitable catalyst (e.g., a Pd catalyst) and a base, a compound having formula (IV) is cross-coupled with a compound having formula (V). a It can be boric acid or borate ester, while R c It is a halide, such as a bromide or iodide. Alternatively, R a It can be a halide (such as a bromide or iodide), while R c It is boric acid or borate ester. When R4 and / or R6' are non-hydrogen, compounds having formula (III) are usually composed of a mixture of diastereomers.

[0687] R6 ’ It can be any functional group that can be converted into R6, where R6 is as defined herein. In particular, R6 is defined according to any one of the listed embodiments 1 to 49.

[0688] Step 2: After cross-coupling (step 1), functional group R6' can be transformed into functional group R6.

[0689] Step 3: Compounds having formula (I) can be obtained by converting group Q1 to Q under deprotection conditions (e.g., when Q1 contains a nitrogen-protected amine).

[0690] The synthesis of compounds having formula (I) is described in further detail below.

[0691] Option 2: General synthesis of compounds having formula (I)

[0692]

[0693] Step 1: Using a suitable Pd catalyst (e.g., N-XantPhos-Pd-G3) and a base (e.g., potassium phosphate), compounds having formula (IV) are cross-coupled with aryl halides having formula (V). In R4 and / or R... 6’ In the case of non-hydrogen, compounds having formula (III) are typically composed of a mixture of diastereomers.

[0694] Step 2:Following cross-coupling (step 1), a catalyst in EtOH and water can be used to hydrogenate (dimethyltrivalent phosphonic acid-kP)[hydrobis(dimethylphosphonic acid-kP)]platinum (II), converting functional group R6' to functional group R6 (e.g., R6' = nitrile can be converted to R6 = amide group; or R6' = ester can be converted to R6 = substituted amide) to obtain a compound having formula (II).

[0695] Step 3: When Q1 contains a nitrogen-protected amine, the amine protecting group of the compound having formula (II) is cleaved to obtain a compound having formula (I) with a free amine. For example, the Boc group can be cleaved under acidic conditions, and the benzyl group can be removed by hydrogenation in the presence of a metal such as palladium.

[0696] In Q=C(R) 7 In the case of )2-NH2, the NH2 group of a compound having formula (I) can be further functionalized according to the procedures described herein and the schemes provided below, as well as according to methods commonly known to those skilled in the art.

[0697] Option 3: Compounds having formula (I), wherein an alkyl group is attached to an amine group.

[0698]

[0699] Step 1 and Step 2: Using similar conditions as outlined in step 1 of scheme 2, a compound having formula (IV-a) is cross-coupled with a compound having formula (V) to obtain a compound having formula (III-a). The compound having formula (III-a) is then alkylated to give a compound having formula (III-b).

[0700] Step 1' and Step 2' Using similar conditions as outlined in step 1 of scheme 2, the compound having formula (IV-a) is alkylated to obtain the compound having formula (IV-b), which is then converted into the compound having formula (III-b) by cross-coupling with the compound having formula (V).

[0701] Typical reaction conditions for alkylation include a base (such as sodium hydride) and an alkyl halide (such as methyl iodide).

[0702] Steps 3 and 4: As outlined in step 3 of scheme 2, a compound having formula (III-b) can be converted into a compound having formula (II-a) by interconverting functional groups such as R6' into functional groups such as R6 (step 3, see scheme 2 and specific examples outlined therein), and then cleaving the protecting group (step 4).

[0703] Option 4: Compounds having formula (I), wherein R1 = unsubstituted or substituted cycloalkyl

[0704]

[0705] Compounds having formula (I) can be synthesized by reductive amination with a suitable ketone, such as a cyclohexanone derivative having formula (R9-I). This reaction involves a suitable reducing agent, such as sodium triacetoxyborohydride.

[0706] Option 5: Compounds having formula (I) - dihydrobenzofuran (an alternative to scheme 4)

[0707]

[0708] Step 1: Compounds having formula (III-c) can be synthesized by cross-coupling a borate having formula (IV-c) with an aromatic halide having formula (Va) using similar reaction conditions as outlined in step 1 of scheme 2.

[0709] Step 2: Oxidation of alcohols having formula (III-c) yields aldehydes having formula (III-d). Typical reaction conditions are oxalyl chloride / DMSO / triethylamine in dichloromethane (Swern oxidation conditions).

[0710] Step 3: Compounds having formula (III-e) can be obtained by reductive amination of aldehydes having formula (III-d) with amines (e.g., cyclohexylamine having formula (R9-II)) using similar reaction conditions as outlined in Scheme 4.

[0711] Step 4: As outlined in step 2 of scheme 2, functional group R6' is converted into functional group R6 to obtain a compound having the formula (IcI).

[0712] Option 6: Compounds having formula (I) - dihydrobenzofuran (alternatives to schemes 4 and 5)

[0713]

[0714] Step 1 Aldehydes having formula (IV-e) can be obtained by oxidizing alcohols having formula (IV-d) using similar reaction conditions as shown in step 2 of scheme 5.

[0715] Step 2Using similar reaction conditions as outlined in Scheme 4, an aldehyde having formula (IV-e) is reductively amination with cyclohexylamine having formula (R9-II) to give a compound having formula (IV-f).

[0716] Step 3 Compounds having formula (IV-f) can be converted into corresponding borate esters having formula (IV-g) using suitable palladium catalysts such as PdCl2(dppf)-CH2Cl2 adducts, bis(pinacolyl)diboron, and bases (such as potassium acetate).

[0717] Steps 4 and 5: These steps can be performed as outlined in the above scheme.

[0718] Option 7: Compounds having formula IV

[0719]

[0720] Step 1 : Sulfinamides having formula (IV-h) can be obtained by reacting an aldehyde having formula (IV-e) with 2-methylpropane-2-sulfinamide.

[0721] Step 2 Azacyclopropanes having formula (IV-i) can be formed by reacting sulfinamides having formula (IV-h) with trimethyl sulfoxide and sodium hydride (Corey Chaykovsky reaction).

[0722] Step 3 The oxidation of a compound having formula (IV-i) to a corresponding sulfonamide having formula (IV-j) can be achieved by using an oxidizing agent (such as m-CPBA).

[0723] Step 4 Compounds having formula (IV-k) can be obtained by reacting compounds having formula (IV-j) with trimethyl sulfoxide and sodium hydride (Kori-Tchaikovsky reaction).

[0724] Step 5: As outlined in step 3 of scheme 6, boronic esters having formula (IV-l) can be synthesized from compounds having formula (IV-k) by cleaving sulfone groups (e.g., by using trifluoromethanesulfonic acid), then reprotecting the amine (e.g., with a Boc group), and converting bromine into the corresponding boronic ester.

[0725] Option 8: Compounds having formula IV

[0726]

[0727] Step 1 Weinreb amides having formula (IV-n) can be obtained by reacting an acid having formula (IV-m) with N,O-dimethylhydroxylamine using standard peptide coupling.

[0728] Step 2 Dihydro-2H-pyrrole with formula (IV-o) can be synthesized by adding the corresponding Mg species of 1-(3-bromopropyl)-2,2,5,5-tetramethyl-1,2,5-azadisilazane to a Weinreb amide with formula (IV-n) via Grignard addition, followed by the formation of an intramolecular imine.

[0729] Step 3: Dihydro-2H-pyrrole having the formula (IV-o) can be reduced using, for example, sodium borohydride, followed by protection of the pyrrole nitrogen with a suitable protecting group (e.g., a Boc group) to obtain a compound having the formula (IV-p).

[0730] Step 4 Compounds having formula (IV-q) can be obtained from compounds having formula (IV-p) using similar reaction conditions as shown in step 3 of scheme 6.

[0731] Option 9: Compounds having formula IV

[0732]

[0733] Step 1 Amino alcohols having the formula (IV-r) can be synthesized by Grignard addition of the corresponding Mg species of 1-(3-bromopropyl)-2,2,5,5-tetramethyl-1,2,5-azadisilazane to an aldehyde having the formula (IV-e).

[0734] Step 2 Ketones having formula (IV-s) can be synthesized from compounds having formula (IV-r) by Boc-protection followed by oxidation of alcohols using, for example, Sven oxidation conditions (oxalyl chloride / DMSO / TEA).

[0735] Steps 3 and 4: Compounds having formula (IV-p) can be obtained from compounds having formula (IV-s) by removing the Boc group, then cyclizing them under the conditions outlined in steps 2 and 3 of scheme 8, and reprotecting the pyrrolidine with, for example, the Boc group. Boron esters having formula (IV-q) can be synthesized as outlined in step 3 of scheme 6.

[0736] Option 10: Compounds having formula IV

[0737]

[0738] Step 1 Suitable organometallic species can be generated by treating (IV-t) with reagents (e.g., organolithium or organomagnesium compounds (optionally in the presence of transition metal salts (e.g., CuI) to form organocuprate reagents), organozinc, organocuprate, or organocerium reagents), and alcohols (IV-v) can be synthesized by epoxide ring-opening of compounds having formula (IV-u) with these organometallic species. For example, the reagents can be alkyllithium (t-BuLi), Grignard reagents, dialkylzinc reagents, dialkylcuprates, or trialkylcerium reagents. Suitable organometallic species can also be converted to another suitable organometallic species by transition metallization reactions with magnesium halides, zinc halides, copper halides, or cerium halides. Preferably, the reagent is a Grignard reagent, such as iPrMgCl. 1 and Hal 2 Each can be I, Cl, or Br, provided that Hal is present. 1 Halides are more than Hal 2 Halides of [a substance] carry less negative charge (and are therefore more reactive to organometallic reagents). For example, if Hal... 1 If it is I, then Hal 2 It must be Cl or Br. If Hal 2 If it is Cl, then Hal 1 It must be Br or I. Preferably, Hal. 1 It is I and Hal 2 It is Br.

[0739] Step 2 The oxidation of an alcohol having formula (IV-v) to a ketone having formula (IV-w) can be achieved, for example, by using a suitable secondary alcohol oxidation method with Des Martin periodoyl alkane.

[0740] Step 3 Suitable organometallic species can be generated by treating compounds having the formula AX (where X = Cl, Br, I) with alkyllithium, Grignard reagents, or trialkylcerium reagents, and compounds having the formula (IV-x) can be obtained by adding these organometallic species. For example, compounds having the formula (IV-x) can be obtained by Grignard addition of a Grignard reagent having the formula AMgX (where X = Cl, Br, I, such as AMgBr, where A is as described herein) to a ketone having the formula (IV-w). For example, the Grignard reagent can be PhMgBr.

[0741] Step 4: Dihydrobenzofurans of formula (IV-y) can be obtained by intramolecular cyclization of formula (IV-x) using a suitable base (e.g., KOtBu).

[0742] Step 5 Chlorination with N-chlorosuccinimide (IV-y) yields a compound having the formula (IV-p”).

[0743] Step 6 Compounds having formula (IV-q) can be obtained from compounds having formula (IV-p”) using similar reaction conditions as shown in step 3 of scheme 6.

[0744] Preferably, a compound having formula (IV) is prepared according to scheme 10a.

[0745] Option 10a: Compounds having formula IV

[0746]

[0747] Step 1 Magnesium species were generated by treating iodide (IV-t)-a with iPrMgCl in the presence of CuI, and then the compound having formula (IV-u)-a was subjected to epoxide ring-opening with the magnesium species to obtain an alcohol having formula (IV-v)-a.

[0748] Step 2 The oxidation of an alcohol having the formula (IV-v)-a to a ketone having the formula (IV-w)-a can be achieved, for example, by using Des Martin periodoyl alkane.

[0749] Step 3 Compounds having the formula (IV-x)-a can be obtained by Grignard addition of a Grignard reagent having the formula AMgBr (where A is as described herein) to a ketone having the formula (IV-w)-a. For example, the Grignard reagent can be PhMgBr.

[0750] Step 4: Dihydrobenzofurans having the formula (IV-y)-a can be obtained from alcohols having the formula (IV-x)-a by intramolecular cyclization using a suitable base (e.g., KOtBu).

[0751] Step 5 Chlorination of (IV-y)-a with N-chlorosuccinimide yields a compound having the formula (IV-p)-a.

[0752] Step 5 Compounds having formula (IV-q)-a can be obtained from compounds having formula (IV-p)-a using similar reaction conditions as shown in step 3 of scheme 6.

[0753] Option 11: Compounds having formula IV

[0754]

[0755] Step 1 Compounds having formula (IV-ab) can be obtained from aldehydes having formula (IV-e) by reacting with allylamine followed by Grignard addition of allyl magnesium bromide.

[0756] Step 2 The ring-closing metathesis of dielyl compounds having formula (IV-ab) can be achieved, for example, by using a second-generation Grubb catalyst to obtain tetrahydropyridine compounds having formula (IV-ac).

[0757] Steps 3 and 4: The tetrahydropyridine is hydrogenated and the piperidine nitrogen is protected with a suitable group (PG) such as Boc to obtain a compound having the formula (IV-ad), which can be converted into a borate ester having the formula (IV-ae) using the conditions described in step 3 of scheme 6.

[0758] Option 12: Compounds having formula IV

[0759]

[0760] Step 1 Compounds having formula (IV-af) can be obtained from aldehydes having formula (IV-e) by reacting with SnAP M reagent = 2-[(tributyltinyl)methoxy]-ethylamine.

[0761] Steps 2 and 3: Protecting the morpholine nitrogen with a suitable group (e.g., like Boc) yields a compound having the formula (IV-ag), which can be converted into a borate ester having the formula (IV-ah) using the conditions described in step 3 of scheme 6.

[0762] Option 13: Compounds having formula IV

[0763]

[0764] Step 1 Compounds having formula (IV-ai) can be obtained from sulfinamides having formula (IV-h) by reacting with Grignard reagents.

[0765] Steps 2 and 3: The sulfinamide is cleaved and then reprotected with a suitable protecting group (e.g., Boc) to give a compound having the formula (IV-aj), which can be converted into a borate ester having the formula (IV-ak) using the conditions described in step 3 of scheme 6.

[0766] In the embodiments, a compound having formula (IV) or a salt thereof is provided.

[0767]

[0768] in

[0769] R a Selected from: (i) halides, such as bromides or iodides (preferably bromides); and (ii) B(R' a )2, where each R' a It is a hydroxyl group, or two R's. a The groups, together with the boron to which they are attached, form a pinacol borate moiety having the following formula:

[0770]

[0771] Q1 is selected from: (i)-C(R) 7 )2-R b (ii) a 9- or 10-membered partially saturated heteroaryl group containing at least one N heteroatom; and (iii) a 4-, 5-, or 6-membered saturated heterocycle containing at least one heteroatom or heteroatom group selected from N, O, S, -S(=O) and -S(=O)2, provided that at least one N heteroatom is present, said N heteroatom is optionally substituted by a protecting group, said heterocycle is unsubstituted or substituted by one or more substituents independently selected from: hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, halogen and C1-C3 alkylene, which form a bridge between the two ring atoms of said saturated heterocycle, thereby forming a bridged bicyclic structure;

[0772] R b Selected from: (i) hydroxyl group; (ii) N(R) 8 )-R b ’ (iii) Azide group,

[0773] R b ’ Selected from: (i) nitrogen-protecting groups; (ii) C3-C6 cycloalkyl groups, which are optionally independently substituted once or more by: hydroxyl; hydroxyl C1-C4 alkyl; C1-C6 alkoxy, preferably C1-C4 alkoxy; C(O)OC1-C3 alkyl; CO2H; SO2C1-C3 alkyl; halo-C1-C3 alkyl; NHR 1b (CH2) 0-1 C(O)NR 1c R 1d C1-C6 alkyl; halo-C1-C3 alkoxy-C1-C3 alkyl; halo; a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from N, O, and S; or two R1 atoms. e Group,

[0774] Among these two R1e Groups are attached to the same carbon atom and together with the carbon atom to which they are attached form a 5-membered saturated heterocycle or a C3-C6 cycloalkyl group containing at least one heteroatom selected from N and O, wherein the saturated heterocycle or cycloalkyl group is optionally substituted with hydroxyl or oxo.

[0775] R 1b Selected from: (i) C(O)C1-C3 alkyl; and (ii) SO2C1-C3 alkyl;

[0776] R 1c and R 1d Each is independently selected from: (i) hydrogen; (ii) C1-C3 alkyl; and (iii) hydroxy C1-C4 alkyl;

[0777] R2, R3, R 7 、R 8 A, W, Y and Z are defined as in any of the listed embodiments 1 to 50.

[0778] In the embodiments, a compound having formula (IV-I) or a salt thereof is provided.

[0779]

[0780] where R a Selected from: (i) bromine; (ii) B(R') a )2, where each R' a It is a hydroxyl group, or two R's. a The groups, together with the boron to which they are attached, form a pinacol borate moiety having the following formula:

[0781]

[0782] Q1 is selected from: (i)-C(R) 7 )2-R b (ii) a 9- or 10-membered partially saturated heteroaryl group containing at least one N heteroatom; and (iii) a 4-, 5-, or 6-membered saturated heterocycle containing at least one heteroatom or heteroatom group selected from N, O, S, -S(=O) and -S(=O)2, provided that at least one N heteroatom is present, said N heteroatom optionally being substituted by a protecting group, said heterocycle being unsubstituted or substituted by one or more substituents independently selected from: hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, halogen and C1-C3 alkylene, which form a bridge between the two ring atoms of said saturated heterocycle, thereby forming a bridged bicyclic structure;

[0783] R b Selected from: (i) hydroxyl group; (ii) N(R) 8 )-R b’ (iii) Azide group,

[0784] R b ’ Selected from: (i) nitrogen-protecting groups; (ii) C3-C6 cycloalkyl groups, which are optionally independently substituted once or more by: hydroxyl; hydroxyl C1-C4 alkyl; C1-C6 alkoxy, preferably C1-C4 alkoxy; C(O)OC1-C3 alkyl; CO2H; SO2C1-C3 alkyl; halo-C1-C3 alkyl; NHR 1b (CH2) 0-1 C(O)NR 1c R 1d C1-C6 alkyl; halo-C1-C3 alkoxy-C1-C3 alkyl; halo; a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from N, O, and S; or two R1 atoms. e Group,

[0785] Among these two R 1e Groups are attached to the same carbon atom and together with the carbon atom to which they are attached form a 5-membered saturated heterocycle or a C3-C6 cycloalkyl group containing at least one heteroatom selected from N and O, wherein the saturated heterocycle or cycloalkyl group is optionally substituted with hydroxyl or oxo.

[0786] R 1b Selected from: (i) C(O)C1-C3 alkyl; and (ii) SO2C1-C3 alkyl;

[0787] R 1c and R 1d Each is independently selected from: (i) hydrogen; (ii) C1-C3 alkyl; and (iii) hydroxy C1-C4 alkyl;

[0788] R2, R3, R 7 、R 8 A, W, Y and Z are defined as in any of the listed embodiments 1 to 50.

[0789] In the embodiments, a compound having formula (IV-II) or a salt thereof is provided.

[0790]

[0791] in

[0792] Each R' a It is a hydroxyl group, or two R's. a The groups, together with the boron to which they are attached, form a pinacol borate moiety having the following formula:

[0793]

[0794] Q1 is selected from: (i)-C(R) 7 )2-R b (ii) a 9- or 10-membered partially saturated heteroaryl group containing at least one N heteroatom; and (iii) a 4-, 5-, or 6-membered saturated heterocycle containing at least one heteroatom or heteroatom group selected from N, O, S, -S(=O) and -S(=O)2, provided that at least one N heteroatom is present, said N heteroatom optionally being substituted by a protecting group, said heterocycle being unsubstituted or substituted by one or more substituents independently selected from: hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, halogen and C1-C3 alkylene, which form a bridge between the two ring atoms of said saturated heterocycle, thereby forming a bridged bicyclic structure;

[0795] R b Selected from: (i) hydroxyl group; (ii) N(R) 8 )-R b ’ (iii) Azide group,

[0796] R b ’ Selected from: (i) nitrogen-protecting groups; (ii) C3-C6 cycloalkyl groups, which are optionally independently substituted once or more by: hydroxyl; hydroxyl C1-C4 alkyl; C1-C6 alkoxy, preferably C1-C4 alkoxy; C(O)OC1-C3 alkyl; CO2H; SO2C1-C3 alkyl; halo-C1-C3 alkyl; NHR 1b (CH2) 0-1 C(O)NR 1c R 1d C1-C6 alkyl; halo-C1-C3 alkoxy-C1-C3 alkyl; halo; a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from N, O, and S; or two R1 atoms. e Group,

[0797] Among these two R 1e Groups are attached to the same carbon atom and together with the carbon atom to which they are attached form a 5-membered saturated heterocycle or a C3-C6 cycloalkyl group containing at least one heteroatom selected from N and O, wherein the saturated heterocycle or cycloalkyl group is optionally substituted with hydroxyl or oxo.

[0798] R 1b Selected from: (i) C(O)C1-C3 alkyl; and (ii) SO2C1-C3 alkyl;

[0799] R 1c and R 1d Each is independently selected from: (i) hydrogen; (ii) C1-C3 alkyl; and (iii) hydroxy C1-C4 alkyl;

[0800] R2, R3, R 7 、R 8 A, W, Y and Z are defined as in any of the listed embodiments 1 to 49.

[0801] In the embodiments, a compound having formula (IV-III) or a salt thereof is provided.

[0802]

[0803] in

[0804] Each R' a It is a hydroxyl group, or two R's. a The groups, together with the boron to which they are attached, form a pinacol borate moiety having the following formula:

[0805]

[0806] Q1 is selected from: (i)-C(R) 7 )2-R b (ii) a 9- or 10-membered partially saturated heteroaryl group containing at least one N heteroatom; and (iii) a 4-, 5-, or 6-membered saturated heterocycle containing at least one heteroatom or heteroatom group selected from N, O, S, -S(=O) and -S(=O)2, provided that at least one N heteroatom is present, said N heteroatom optionally being substituted by a protecting group, said heterocycle being unsubstituted or substituted by one or more substituents independently selected from: hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, halogen and C1-C3 alkylene, which form a bridge between the two ring atoms of said saturated heterocycle, thereby forming a bridged bicyclic structure;

[0807] R b Selected from: (i) hydroxyl group; (ii) N(R) 8 )-R b ’ (iii) Azide group,

[0808] R b ’ Selected from: (i) nitrogen-protecting groups; (ii) C3-C6 cycloalkyl groups, which are optionally independently substituted once or more by: hydroxyl; hydroxyl C1-C4 alkyl; C1-C6 alkoxy, preferably C1-C4 alkoxy; C(O)OC1-C3 alkyl; CO2H; SO2C1-C3 alkyl; halo-C1-C3 alkyl; NHR 1b (CH2) 0-1 C(O)NR 1c R 1dC1-C6 alkyl; halo-C1-C3 alkoxy-C1-C3 alkyl; halo; a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from N, O, and S; or two R1 atoms. e Group,

[0809] Among these two R 1e Groups are attached to the same carbon atom and together with the carbon atom to which they are attached form a 5-membered saturated heterocycle or a C3-C6 cycloalkyl group containing at least one heteroatom selected from N and O, wherein the saturated heterocycle or cycloalkyl group is optionally substituted with hydroxyl or oxo.

[0810] R 1b Selected from: (i) C(O)C1-C3 alkyl; and (ii) SO2C1-C3 alkyl;

[0811] R 1c and R 1d Each is independently selected from: (i) hydrogen; (ii) C1-C3 alkyl; and (iii) hydroxy C1-C4 alkyl;

[0812] R2, R3, R 7 、R 8 A, W, Y and Z are defined as in any of the listed embodiments 1 to 50.

[0813] In another embodiment, compounds selected from the group consisting of:

[0814] tert-butyl(S)-((5-chloro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate;

[0815] tert-butyl((5-chloro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate;

[0816] tert-butyl ((5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2-(thiazo-4-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate;

[0817] tert-butyl-((5-chloro-2-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate;

[0818] tert-butyl(S)-((5-chloro-2-(2-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate;

[0819] tert-butyl(((2S,3S)-5-chloro-3-hydroxy-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate;

[0820] tert-butyl(((2R*,3S*)-5-chloro-3-hydroxy-2-(pyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate;

[0821] tert-butyl(((2S*,3S*)-5-chloro-3-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2-(2-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate;

[0822] tert-butyl (((2R*,3S*)-5-chloro-3-hydroxy-2-(6-methoxypyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate;

[0823] ((2S*,3S*)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-3-hydroxy-2-(2-methoxypyridin-3-yl)-2,3-dihydrobenzofuran-4-yl)boronic acid;

[0824] tert-butyl (((2S,3S)-5-chloro-3-methyl-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate;

[0825] tert-butyl(S)-((5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate;

[0826] (S)-(5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methanol;

[0827] tert-butyl(((2S,3S)-5-chloro-6-fluoro-3-hydroxy-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate;

[0828] tert-butyl(((2S,3S)-5-chloro-6-fluoro-3-methoxy-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate;

[0829] tert-butyl(((2S,3S)-5-chloro-6-fluoro-3-methyl-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate;

[0830] ((2S,3S)-5-chloro-6-fluoro-3-methyl-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methanol;

[0831] tert-butyl (((2R,3S)-5-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate;

[0832] ((2S,3S)-2-(6-(benzyloxy)pyridin-2-yl)-5-chloro-6-fluoro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methanol;

[0833] (trans)-4-((((2R,3S)-5-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)amino)-1-methylcyclohexane-1-ol;

[0834] (trans)-4-((((2S,3S)-5-chloro-6-fluoro-3-methyl-2-(pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)amino)-1-methylcyclohexane-1-ol;

[0835] tert-butyl(S)-((2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-5-(trifluoromethyl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate;

[0836] (S)-2-(hydroxymethyl)-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-5-carboxynitrile;

[0837] (S)-4-bromo-2-((((trans)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-5-carboxynitrile;

[0838] tert-butyl(S)-((4-bromo-5-chloro-2-phenyl-2,3-dihydrofurano[2,3-b]pyridin-2-yl)methyl)carbamate

[0839] tert-butyl ((6-chloro-2-phenyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate;

[0840] tert-butyl ((4-bromo-5-chloro-2-phenylbenzo[d][1,3]dioxacyclopenten-2-yl)methyl)carbamate

[0841] (S)-2-(azidomethyl)-4-bromo-5-chloro-6-fluoro-2-phenylindoline;

[0842] tert-butyl(((2S,3S)-5-chloro-6-fluoro-3-methyl-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate;

[0843] tert-butyl(((2S,3R)-5-chloro-6-fluoro-3-(methoxymethyl)-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate;

[0844] tert-butyl(((2S,3R)-3-((benzyloxy)methyl)-5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate;

[0845] tert-butyl 2-((S)-5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)azacyclobutane-1-carboxylate;

[0846] tert-butyl 2-((2S,3S)-5-chloro-6-fluoro-3-methyl-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)azacyclobutane-1-carboxylate;

[0847] tert-butyl(S)-2-((S)-5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate;

[0848] (S)-2-((S)-5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)pyrrolidine;

[0849] tert-butyl 2-((S)-5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)-4-hydroxypyrrolidine-1-carboxylate;

[0850] tert-butyl 2-((S)-5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)-4-hydroxy-4-methylpyrrolidine-1-carboxylate;

[0851] tert-butyl(2S,4R)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-fluoropyrrolidine-1-carboxylate;

[0852] tert-butyl 2-((2S,3S)-5-chloro-6-fluoro-3-hydroxy-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate;

[0853] tert-butyl 2-((2S,3S)-5-chloro-6-fluoro-3-methoxy-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate;

[0854] tert-butyl 2-((2S,3S)-5-chloro-6-fluoro-3-methyl-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate;

[0855] tert-butyl(S)-2-((S)-5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)piperidine-1-carboxylate;

[0856] tert-butyl 3-((S)-5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)morpholine-4-carboxylate;

[0857] tert-butyl(1-((S)-5-chloro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)ethyl)carbamate;

[0858] tert-butyl (1-((2S,3S)-5-chloro-6-fluoro-3-methyl-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)ethyl)carbamate; and

[0859] tert-Butyl(S)-2-((S)-1-(tert-Butoxycarbonyl)pyrrolidine-2-yl)-5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)indoline-1-carboxylate.

[0860] In another aspect, the present invention relates to a method for preparing a compound of formula (I) in free form or in pharmaceutically acceptable salt form, the method comprising the steps of:

[0861] a) A compound having formula (IV), (IV-I), (IV-II) or (IV-III) as defined herein is coupled with a suitable cross-coupling partner (e.g., a suitable aryl halide or arylboronic acid or ester) in the presence of a suitable catalyst (e.g., a Pd catalyst) to give a compound having general formula (III) as defined in Schemes 1 and 2 or a compound having its sub-formula as defined in any of Schemes 3, 5 and 6.

[0862] Therefore, the present invention relates to a method for preparing compounds having formula (I), (Ia), (Ic) or (Id) or pharmaceutically acceptable salts thereof, the method comprising the following steps:

[0863] a) Coupling a compound having formula (IV) as defined herein with a compound having formula (V) in the presence of a suitable catalyst, such as a Pd catalyst.

[0864]

[0865] To give compounds having general formula (III)

[0866]

[0867] in

[0868] A, W, X, Y, Z, R2, R3, R4, and R5 are as defined in this article;

[0869] Where R a When it is a halide such as a bromide or iodide, R c It is B(R') a )2, where each R' a It is a hydroxyl group, or two R's. a The groups, together with the boron to which they are attached, form a pinacol borate moiety having the following formula:

[0870]

[0871] Where R a It is B(R') a )2, where each R' a It is a hydroxyl group, or two R's. a When the groups together with the boron to which they are attached form a pinacol boronic acid ester moiety having the following formula:

[0872] R c These are halides, such as bromides or iodides;

[0873] Q1 is as defined in this article; and

[0874] R6' is a functional group that can be converted to R6, such as -CN or C(O)OC1-C6 alkyl, where R6 is as defined herein.

[0875] In another aspect, the present invention relates to a method for preparing a compound of formula (I) in free form or in pharmaceutically acceptable salt form, the method comprising the steps of:

[0876] a) Couple a compound having formula (IV) as defined herein with a compound having formula (V) as defined herein in the presence of a suitable catalyst to give a compound having formula (III) as defined herein.

[0877] b) Under suitable hydrolysis conditions, the compound having formula (III) as defined herein obtained in step a) is transformed to give a compound having formula (II) as defined herein.

[0878] c) Deprotect the compound of formula (II) obtained in step b) as defined herein to give a compound of formula (I) as defined herein;

[0879] d) Optionally, further functionalize the amine group of the compound having formula (I);

[0880] e) Recover compounds of formula (I) that are available therefrom in free form or in pharmaceutically acceptable salt form.

[0881] In another aspect, the present invention provides a method for preparing a compound having formula (IV-v) or a salt thereof, the method comprising the steps of: (i) treating a compound having formula (IV-t) with an organometallic reagent, and (ii) reacting the resulting mixture with an epoxide having formula (IV-u).

[0882]

[0883] Where R2 is as defined in this paper; PG is a nitrogen protecting group;

[0884] When Hal 1 When it is I, Hal 2 It is Cl or Br, and when Hal 2 When it is Cl, Hal 1 It is Br or I.

[0885] In another aspect, the present invention provides a method for preparing a compound having formula (IV-q) from compounds having formula (IV-v) and compounds having formula (IV-u) according to the following synthetic scheme:

[0886]

[0887] Among them, R2, PG, Hal 1 and Hal 2 It is as defined in this article, and R3 is chlorine.

[0888] The invention further includes any variations of the method of the invention, wherein an intermediate product available at any stage is used as a starting material and the remaining steps are carried out, or wherein the starting material is formed in situ under reaction conditions, or wherein the reaction component is used in the form of its salt or an optically pure substance.

[0889] The compounds and intermediates of the present invention can also be converted into each other according to methods commonly known to those skilled in the art.

[0890] Pharmaceutical composition

[0891] Compounds having formulas (V), (IV), (III), and (II) as defined herein can be used to prepare the compounds of the present invention, such as compounds having formula (I). Therefore, in one aspect, the present invention relates to a compound having formula (V), (IV), (III), or (II), or a salt thereof. In another aspect, the present invention relates to the use of compounds having formulas (V), (IV), (III), or (II), or salts thereof, in the manufacture of compounds having formula (I).

[0892] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In further embodiments, the composition comprises at least two pharmaceutically acceptable carriers (e.g., those described herein). For the purposes of this invention, solvates and hydrates are generally considered to be part of the composition unless otherwise specified. Preferably, the pharmaceutically acceptable carrier is sterile. The pharmaceutical composition can be formulated for a specific route of administration, such as oral, parenteral, and rectal administration. Furthermore, the pharmaceutical compositions of the present invention can be formulated in solid form (including but not limited to capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including but not limited to solutions, suspensions, or emulsions). The pharmaceutical composition can be subjected to conventional pharmaceutical processes, such as sterilization, and / or can contain conventional inert diluents, lubricants, or buffers, as well as excipients (such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers).

[0893] Typically, a pharmaceutical composition is a tablet or gelatin capsule containing an active ingredient and one or more of the following:

[0894] a) Diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0895] b) Lubricants, such as silica, talc, stearic acid, their magnesium or calcium salts and / or polyethylene glycol;

[0896] c) Adhesives, such as magnesium aluminum silicate, starch paste, gelatin, astragalus gum, methylcellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone;

[0897] d) Disintegrants, such as starch, agar, alginate or its sodium salt, or effervescent mixtures; and

[0898] e) Adsorbents, colorants, flavoring agents and sweeteners.

[0899] In the examples, the pharmaceutical composition is a capsule containing only the active ingredient.

[0900] Tablets may be coated with film or enteric coating according to methods known in the art.

[0901] Suitable compositions for oral administration include effective amounts of the compounds of the present invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs, solutions, or solid dispersions. Compositions intended for oral use are prepared according to any method known in the art for manufacturing pharmaceutical compositions, and in order to provide a pharmaceutically refined and palatable formulation, such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives. Tablets may contain the active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for manufacturing tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets are uncoated or coated by known techniques to delay breakdown and absorption in the gastrointestinal tract and thereby provide a prolonged duration of action. For example, time-delayed materials such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oil-based medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0902] Some injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fat emulsions or suspensions. The compositions may be sterile and / or contain excipients (e.g., preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts and / or buffers for adjusting osmotic pressure). Additionally, they may contain other substances of therapeutic value. The compositions are prepared according to conventional mixing, granulation, or coating methods and contain about 0.1%–75%, or about 1%–50%, of the active ingredient.

[0903] Suitable compositions for transdermal applications include an effective amount of the compound of the present invention and a suitable carrier. Suitable carriers for transdermal delivery include absorbable, pharmacologically acceptable solvents that facilitate passage through the host skin. For example, a transdermal device may be in the form of a bandage comprising a liner, a reservoir containing the compound and optionally a carrier, a rate-controlled barrier optionally delivering the compound to the host skin at a controlled and predetermined rate over an extended period of time, and an apparatus for securing the device to the skin.

[0904] Compositions suitable for topical applications (e.g., application to skin and eyes) include aqueous solutions, suspensions, ointments, creams, gels, or aerosol formulations, for example, for delivery via aerosols, etc. Such topical delivery systems are particularly suitable for dermal applications, such as for the treatment of skin cancer, and for preventative uses, such as in sunscreens, lotions, sprays, etc. Therefore, it is particularly suitable for topical applications, including cosmetics and formulations well known in the art. Such systems may contain solubilizers, stabilizers, tension enhancers, buffers, and preservatives.

[0905] As used herein, topical applications may also involve inhalation or intranasal application. They can be conveniently delivered, with or without a suitable propellant, from a dry powder inhaler in the form of dry powder (alone as a mixture, such as a dry blend with lactose, or mixed component particles, such as component particles mixed with phospholipids) or from a pressurized container, pump, spray, nebulizer, or nebulizer in the form of an aerosol spray.

[0906] Compounds of formula (I) that are in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, such as YAP / TAZ-TEAD modulatory properties; for example, YAP / TAZ-TEAD inhibitory properties (e.g., as indicated in in vitro tests provided in the examples), and thus indicate their use in therapy or as research chemicals, such as as tool compounds.

[0907] Diseases and disabilities and methods of use

[0908] Of particular interest are the compounds of the present invention, which exhibit good potency in the bioassays described herein. On the other hand, they should have a favorable safety profile. On the other hand, they should have favorable pharmacokinetic properties. Furthermore, ideally, the candidate drug will be in a stable, non-hygroscopic, and easily reconstituted form.

[0909] In view of its activity as a YAP / TAZ-TEAD PPI inhibitor, compounds of formula (I), in free form or in pharmaceutically acceptable salt form, may be used to treat conditions mediated by YAP or TAZ amplification, and / or dysregulation of the hippocampal pathway, and / or elevated YAP / TEAD or TAZ / TEAD activity (e.g., cancer), and / or conditions that respond to inhibition of YAP / TAZ-TEAD interactions (especially in a therapeutically beneficial manner), most particularly the diseases or disorders mentioned below.

[0910] The compounds of this invention can be used to treat cancer or tumors. Specifically, the compounds of this invention can be used to treat cancers or tumors selected from the following: mesothelioma (including pleural mesothelioma, malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, and tunica vaginalis mesothelioma), carcinoma (including cervical squamous cell carcinoma, endometrial carcinoma, esophageal squamous cell carcinoma, esophageal adenocarcinoma, bladder urothelial carcinoma, and cutaneous squamous cell carcinoma), porioma (benign porioma), poriocarcinoma (including malignant poriocarcinoma), supratentorial ependymoma (including pediatric supratentorial ependymoma), epithelioid hemangioendothelioma (EHE), ependymal tumors, solid tumors, and breast cancer (including triple-negative breast cancer). Lung cancer (including non-small cell lung cancer), ovarian cancer, colorectal cancer (including colon cancer), melanoma, pancreatic cancer (including pancreatic adenocarcinoma), prostate cancer, gastric cancer, esophageal cancer, liver cancer (including hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma), neuroblastoma, schwannoma, renal cancer, sarcoma (including rhabdomyosarcoma, embryonal rhabdomyosarcoma (ERMS), osteosarcoma, undifferentiated pleomorphic sarcoma (UPS), Kaposi's sarcoma, soft tissue sarcoma, and rare soft tissue sarcoma), bone cancer, brain cancer, medulloblastoma, glioma, meningioma, and head and neck cancer (including squamous cell carcinoma of the head and neck).

[0911] The compounds of this invention can also be used to treat solid malignancies characterized by YAP overexpression.

[0912] The compounds of the present invention can also be used to treat solid malignancies characterized by dysregulated YAP / TAZ-TEAD interactions.

[0913] The compounds of this invention can also be used to treat solid malignant tumors characterized by YAP amplification.

[0914] The compounds of the present invention can also be used to treat tumors or cancers that are cancers or tumors carrying the following: (i) one or more YAP / TAZ fusions; (ii) one or more truncated mutations or deletions of NF2 / LATS1 / LATS2; and / or (iii) one or more functional YAP / TAZ fusions.

[0915] The compounds of the present invention can be used to treat NF2-mutant cancers, particularly NF2-mutant NSCLC.

[0916] As mentioned above, any positive expression in YAP can be evaluated using methods known to the technician (e.g., immunohistochemistry, qRT-PCR, RNASeq, or similar methods).

[0917] Therefore, as another embodiment, the present invention provides the use of compounds having formula (I) or pharmaceutically acceptable salts thereof in a therapeutic manner. In a preferred embodiment, the therapeutic is selected from diseases that can be treated by inhibiting the YAP / TAZ-TEAD interaction. In a more preferred embodiment, the disease is selected from the above list, suitably malignant pleural mesothelioma.

[0918] Therefore, as another embodiment, the present invention provides compounds having formula (I) or pharmaceutically acceptable salts thereof for use in therapies. In a preferred embodiment, the therapy is for a disease that can be treated by inhibiting the YAP / TAZ-TEAD interaction. In a more preferred embodiment, the disease is selected from the above list, suitably malignant pleural mesothelioma.

[0919] In another embodiment, the present invention provides a method for treating a disease in a subject of need by inhibiting the YAP / TAZ-TEAD interaction, the method comprising administering to the subject a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the disease is selected from the above list, suitably malignant pleural mesothelioma.

[0920] Therefore, as another embodiment, the present invention provides the use of compounds having formula (I) or its sub-formulas, or pharmaceutically acceptable salts thereof, for the manufacture of medicaments. In a preferred embodiment, the medicament is used to treat diseases that can be treated by inhibiting the YAP / TAZ-TEAD interaction. In a more preferred embodiment, the disease is selected from the above list, suitably malignant pleural mesothelioma.

[0921] In one embodiment of the invention, 2-((2S,4S)-5-chloro-2-(((trans-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide or a pharmaceutically acceptable salt thereof is provided for use in the treatment of malignant pleural mesothelioma. In another embodiment of the invention, 2-((2S,4S)-5-chloro-2-(((trans-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide or a pharmaceutically acceptable salt thereof is provided for use in the treatment of solid malignancies characterized by YAP or TAZ overexpression and / or YAP or TAZ amplification and / or TEAD amplification and / or YAP / TAZ-TEAD (over) activation.

[0922] In one embodiment of the present invention, a method is provided.

[0923] 2-((2S,4S)-5-chloro-6-fluoro-2-(((trans-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide

[0924] Or a pharmaceutically acceptable salt thereof, for use in the treatment of malignant pleural mesothelioma. In another embodiment of the invention, provided...

[0925] 2-((2S,4S)-5-chloro-6-fluoro-2-(((trans-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide or a pharmaceutically acceptable salt thereof, for use in the treatment of solid malignancies characterized by YAP or TAZ overexpression and / or YAP or TAZ amplification and / or TEAD amplification and / or YAP / TAZ-TEAD (over) activation.

[0926] In one embodiment of the invention, 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide or a pharmaceutically acceptable salt thereof is provided for use in the treatment of malignant pleural mesothelioma. In another embodiment of the invention, 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide or a pharmaceutically acceptable salt thereof is provided for use in the treatment of solid malignancies characterized by YAP or TAZ overexpression and / or YAP or TAZ amplification and / or TEAD amplification and / or YAP / TAZ-TEAD (over) activation.

[0927] In one embodiment of the invention, 2-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide or a pharmaceutically acceptable salt thereof is provided for use in the treatment of malignant pleural mesothelioma. In another embodiment of the invention, 2-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide or a pharmaceutically acceptable salt thereof is provided for use in the treatment of solid malignancies characterized by YAP or TAZ overexpression and / or YAP or TAZ amplification and / or TEAD amplification and / or YAP / TAZ-TEAD (over) activation.

[0928] In one embodiment of the invention, 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide or a pharmaceutically acceptable salt thereof is provided for use in the treatment of malignant pleural mesothelioma. In another embodiment of the invention, 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide or a pharmaceutically acceptable salt thereof is provided for use in the treatment of solid malignancies characterized by YAP or TAZ overexpression and / or YAP or TAZ amplification and / or TEAD amplification and / or YAP / TAZ-TEAD (over) activation.

[0929] In one embodiment of the invention, 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzyl nitrile or a pharmaceutically acceptable salt thereof is provided for use in the treatment of malignant pleural mesothelioma. In another embodiment of the invention, 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzyl nitrile or a pharmaceutically acceptable salt thereof is provided for use in the treatment of solid malignancies characterized by YAP or TAZ overexpression and / or YAP or TAZ amplification and / or TEAD amplification and / or YAP / TAZ-TEAD (over) activation.

[0930] In one embodiment of the invention, 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide or a pharmaceutically acceptable salt thereof is provided for use in the treatment of malignant pleural mesothelioma. In another embodiment of the invention, 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide or a pharmaceutically acceptable salt thereof is provided for use in the treatment of solid malignancies characterized by YAP or TAZ overexpression and / or YAP or TAZ amplification and / or TEAD amplification and / or YAP / TAZ-TEAD (over) activation.

[0931] In one embodiment of the invention, 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide or a pharmaceutically acceptable salt thereof is provided for use in the treatment of malignant pleural mesothelioma. In another embodiment of the invention, 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide or a pharmaceutically acceptable salt thereof is provided for use in the treatment of solid malignancies characterized by YAP or TAZ overexpression and / or YAP or TAZ amplification and / or TEAD amplification and / or YAP / TAZ-TEAD (over) activation.

[0932] In one embodiment of the invention, 2-((2S,3S,4S)-5-chloro-6-fluoro-3-hydroxy-2-((((trans)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide or a pharmaceutically acceptable salt thereof is provided for use in the treatment of malignant pleural mesothelioma. In another embodiment of the invention, 2-((2S,3S,4S)-5-chloro-6-fluoro-3-hydroxy-2-((((trans)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide or a pharmaceutically acceptable salt thereof is provided for use in the treatment of solid malignancies characterized by YAP or TAZ overexpression and / or YAP or TAZ amplification and / or TEAD amplification and / or YAP / TAZ-TEAD (over) activation.

[0933] In one embodiment of the invention, 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide or a pharmaceutically acceptable salt thereof is provided for use in the treatment of malignant pleural mesothelioma. In another embodiment of the invention, 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide or a pharmaceutically acceptable salt thereof is provided for use in the treatment of solid malignancies characterized by YAP or TAZ overexpression and / or YAP or TAZ amplification and / or TEAD amplification and / or YAP / TAZ-TEAD (over) activation.

[0934] In one embodiment of the invention, 4-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide or a pharmaceutically acceptable salt thereof is provided for use in the treatment of malignant pleural mesothelioma. In another embodiment of the invention, 4-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide or a pharmaceutically acceptable salt thereof is provided for use in the treatment of solid malignancies characterized by YAP or TAZ overexpression and / or YAP or TAZ amplification and / or TEAD amplification and / or YAP / TAZ-TEAD (over) activation.

[0935] In one embodiment of the invention, 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidone-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide or a pharmaceutically acceptable salt thereof is provided for use in the treatment of malignant pleural mesothelioma. In another embodiment of the invention, 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidone-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide or a pharmaceutically acceptable salt thereof is provided for use in the treatment of solid malignancies characterized by YAP or TAZ overexpression and / or YAP or TAZ amplification and / or TEAD amplification and / or YAP / TAZ-TEAD (over) activation.

[0936] In one embodiment of the invention, 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidone-2-yl)indoline-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide or a pharmaceutically acceptable salt thereof is provided for use in the treatment of malignant pleural mesothelioma. In another embodiment of the invention, 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidone-2-yl)indoline-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide or a pharmaceutically acceptable salt thereof is provided for use in the treatment of solid malignancies characterized by YAP or TAZ overexpression and / or YAP or TAZ amplification and / or TEAD amplification and / or YAP / TAZ-TEAD (over) activation.

[0937] dose

[0938] For subjects weighing approximately 50-70 kg, the pharmaceutical compositions or combinations of the present invention may be in units of about 1-1000 mg of one or more active ingredients, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of active ingredient. The therapeutically effective dose of the compound, pharmaceutical composition, or combination thereof depends on the species, weight, age, and individual condition, disorder, or disease being treated, or its severity. A physician, clinician, or veterinarian with general skills can readily determine the effective amount of each active ingredient necessary for the prevention, treatment, or inhibition of the progression of a disorder or disease.

[0939] The above-described dosage characteristics can be demonstrated in in vitro and in vivo tests using advantageous mammals (e.g., mice, rats, dogs, monkeys) or their isolated organs, tissues, and articles thereof. The compounds of the invention can be applied in vitro in solution (e.g., aqueous solution) and in vivo, for example, in suspension or aqueous solution, either enterically, parenterally (advantageously, intravenously). In vitro doses can be approximately 10... -3 mole and 10 -9 The effective therapeutic dose in vivo can be between approximately 0.1-500 mg / kg or approximately 1-100 mg / kg, depending on the route of administration.

[0940] The activity of the compounds according to the invention can be evaluated using the in vitro methods described in the examples.

[0941] Combination therapy

[0942] The compounds of the present invention can be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of the present invention can be administered separately via the same or different routes of administration as other pharmaceutical agents, or together in the same pharmaceutical composition. Therapeutic agents are, for example, chemical compounds, peptides, antibodies, antibody fragments, or nucleic acids that, when administered to a patient in combination with the compounds of the present invention, have therapeutic activity or enhance therapeutic activity. Therefore, in one embodiment, the present invention provides a combination comprising a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents.

[0943] In one embodiment, the present invention provides a product comprising a compound having formula (I) and at least one other therapeutic agent, as a combination formulation for simultaneous, separate, or sequential use in a therapy. In one embodiment, the therapy is for treating a disease or condition mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction. The product provided as a combination formulation comprises a composition comprising a compound having formula (I) and other therapeutic agents together in the same pharmaceutical composition, or comprises a compound having formula (I) and other therapeutic agents in a separate form (e.g., a kit form).

[0944] In certain circumstances, the compounds of the present invention can be combined with other therapeutic agents, such as other anticancer agents, anti-allergy agents, antiemetics (or antiemetics), analgesics, cell protectants, and combinations thereof.

[0945] Particularly interesting anticancer agents that can be combined with the compounds of the present invention include: B-RAF inhibitors; mitogen-activated protein kinase (MEK) inhibitors; epidermal growth factor receptor (EGFR) inhibitors; and inhibitors of immune checkpoint molecules (e.g., one or more PD-1 or PD-L1 inhibitors).

[0946] The compounds of the present invention can be used, together or separately, in combination with the treatment of another cancer (particularly malignant pleural mesothelioma) (e.g., surgery, chemotherapy (including cisplatin, carboplatin, alimta (pemetrexed), gemcitabine, and doxorubicin), and radiation). For example, combination therapy with one or more agents selected from pemetrexed, cisplatin, bevacizumab, nivoluab, gemcitabine, vinorelbine, nivolumab, and ipilimumab may be particularly useful, especially for the treatment of pleural mesothelioma (particularly malignant pleural mesothelioma).

[0947] Some patients may experience allergic reactions to the compounds of this invention and / or one or more other anticancer agents during or after administration; therefore, antihistamines are usually administered to minimize the risk of allergic reactions. Suitable antihistamines include corticosteroids, antihistamines, and bronchodilators.

[0948] Some patients may experience nausea during and after administration of the compounds of the present invention and / or one or more other anticancer agents; therefore, antiemetics are used to prevent nausea (regurgitation) and vomiting.

[0949] Medication is usually prescribed to relieve pain experienced during treatment and to make the patient more comfortable.

[0950] To protect normal cells from therapeutic toxicity and limit organ toxicity, cell protectants (such as neuroprotectants, free radical scavengers, cardioprotectants, anthracycline extravasation neutralizers, nutrients, etc.) can be used as adjunctive therapy.

[0951] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound having formula (I) and one or more additional therapeutic agents. Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable carrier as described above.

[0952] In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, wherein at least one pharmaceutical composition contains a compound having formula (I). In one embodiment, the kit includes means (e.g., containers, separate bottles, or separate foil packs) for separately retaining the compositions. An example of such a kit is blister packaging, as typically used for packaging tablets, capsules, etc.

[0953] The kits of the present invention can be used to administer different dosage forms (e.g., oral and parenteral), to administer individual compositions at different dose intervals, or to titrate individual compositions relative to each other. To aid compliance, the kits of the present invention typically include instructions for use for administration.

[0954] In the combination therapy of the present invention, the compounds of the present invention and other therapeutic agents may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compounds of the present invention and other therapeutic agents may be combined to form a combination therapy in the following ways: (i) before the combination product is dispensed to a physician (e.g., in a kit that includes the compounds of the present invention and other therapeutic agents); (ii) shortly before administration, by the physician himself (or under the guidance of a physician); (iii) in the patient himself, for example, during the sequential administration of the compounds of the present invention and other therapeutic agents.

[0955] Therefore, the present invention provides the use of a compound having formula (I) for treating diseases or conditions mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction, wherein the preparation of the medicament is for administration in combination with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating diseases or conditions mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction, wherein the medicament is administered in combination with a compound having formula (I).

[0956] The present invention also provides a compound having formula (I) for use in a method of treating a disease or condition mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction, wherein the compound having formula (I) is prepared for administration in combination with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction, wherein the other therapeutic agent is prepared for administration in combination with a compound having formula (I). The present invention also provides a compound having formula (I) for use in a method of treating a disease or condition mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction, wherein the compound having formula (I) is administered in combination with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction, wherein the other therapeutic agent is administered together with a compound having formula (I).

[0957] The present invention also provides the use of a compound having formula (I) for treating diseases or conditions mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction, wherein the patient has previously (e.g., within 24 hours) received treatment with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating diseases or conditions mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction, wherein the patient has previously (e.g., within 24 hours) received treatment with a compound having formula (I).

[0958] In one embodiment, the other therapeutic agent is selected from anticancer agents.

[0959] Preparation of compounds

[0960] The following examples are intended to illustrate the invention and should not be construed as limiting it. Temperatures are given in degrees Celsius. Unless otherwise specified, all evaporation was carried out under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (=20–133 mbar). The structures of the end products, intermediates, and starting materials were confirmed by standard analytical methods (e.g., spectroscopic features such as MS, IR, NMR). Stereochemistry was assigned by single-crystal X-ray structural analysis of several intermediates and examples (indicated below), and by the eutectic structures of several examples bound to the YAP-binding domains of TEAD3 or TEAD4. All other stereochemical assignments were similar and based on the relative affinity determined for the YAP-binding domains of TEAD, for example, the IC50 of diastereomer X determined in YAP-TEAD TR-FRET determinations. 50 Significantly higher than the diastereomer Y. The abbreviations used are those commonly used in this field.

[0961] All starting materials, structural units, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of this invention are commercially available or can be prepared by organic synthesis methods known to those skilled in the art. Furthermore, the compounds of this invention can be produced by organic synthesis methods known to those skilled in the art, as illustrated in the following examples.

[0962] abbreviation:

[0963]

[0964]

[0965]

[0966] General conditions:

[0967] Mass spectra were acquired on an LC-MS system using electrospray ionization methods from a range of instruments with the following configurations: Waters Acquity UPLC with a Waters SQ detector; [M+H] + It refers to the protonated molecular ion of a chemical species.

[0968] NMR spectroscopy was performed using a Bruker Ultrashield. TM 400(400MHz) and Bruker Ultrashield TMSpectrometer operation was performed at 600 MHz, with or without trimethylsilane as an internal standard. Chemical shifts (d-values) were reported in low-field ppm for tetramethylsilane. Spectral splitting modes were specified as single signal (s), double signal (d), triple signal (t), quadruple signal (q), multiple signal, unresolved or more overlapping signals (m), and broad signal (br). Solvents are given in parentheses.

[0969] Instrumental method

[0970] Microwave: Unless otherwise stated, all microwave reactions were carried out in a Biotage initiator, irradiated at 0-400W from a magnetron at 2.45GHz with the processing power of Robot Eight / Robot Sixty.

[0971] UPLC-MS method: Using Waters Acquity UPLC with Waters SQ detector.

[0972] Method UPLC-MS 1: UPLC-MS instrument: Waters Acquity UPLC with Waters SQ detector; Column: Acquity UPLC HSS T3, 1.8 μm, 2.1 x 50 mm, column temperature: 60 °C; Eluent: A: water + 0.05% formic acid + 3.75 mM ammonium acetate (pH 3.8), B: acetonitrile + 0.04% formic acid; Flow rate: 1.0 mL / min; Gradient: 5% to 98% B over 1.40 min, 98% B for 0.40 min.

[0973] Method UPLC-MS 2: UPLC-MS instrument: Waters Acquity UPLC with Waters SQ detector; Column: Acquity UPLC HSS T3, 1.8 μm, 2.1 x 100 mm, column temperature: 60 °C; Eluent: A: water + 0.05% formic acid + 3.75 mM ammonium acetate (pH 3.8), B: acetonitrile + 0.04% formic acid; Flow rate: 0.8 mL / min; Gradient: 5% to 98% B over 9.40 min, 98% B for 0.40 min.

[0974] Method UPLC-MS 3:UPLC-MS instrument: Waters Acquity UPLC with Waters SQ detector; Column: Acquity UPLC BEH C18, 1.7 μm, 2.1 x 50 mm, column temperature: 80 °C; Eluent: A: water + 4.76% isopropanol + 0.05% formic acid + 3.75 mM ammonium acetate, B: isopropanol + 0.05% formic acid; Flow rate: 0.6 mL / min; Gradient: 1% to 98% B over 1.70 min, 98% B for 0.10 min.

[0975] Method UPLC-MS 4: UPLC-MS instrument: Waters Acquity UPLC with Waters SQ detector; Column: CORTECS C18+, 2.7 μm, 2.1 x 50 mm, column temperature: 80 °C; Eluent: A: water + 4.76% isopropanol + 0.05% formic acid + 3.75 mM ammonium acetate, B: isopropanol + 0.05% formic acid; Flow rate: 1.0 mL / min; Gradient: 1% to 50% B over 1.40 min, 50% to 98% B over 0.30 min.

[0976] Method UPLC-MS5: UPLC-MS instrument: Waters Acquity UPLC with Waters Q-TOF detector; Column: Waters BEH C18, 1.7 μm, 2.1 x 100 mm, column temperature: 40 °C; Eluent: A: water + 0.1% formic acid, B: acetonitrile + 0.1% formic acid; Flow rate: 0.5 mL / min; Gradient: 5% B for 0.5 min, 5% to 95% B over 5.5 min, 95% B for 2.0 min, 95% to 5% B over 0.1 min, 5% B for 1.9 min.

[0977] intermediates

[0978] Intermediates used in the Suzuki cross-coupling reaction of borate ester structural units:

[0979] Synthesis of tert-butyl (2-((2-bromo-3-fluorophenyl)amino)ethyl)carbamate (NI)

[0980]

[0981] Sodium triacetoxyborohydride (12.68 g, 59.8 mmol) was added to a stirred solution of 2-bromo-3-fluoroaniline (3.79 g, 20 mmol) and tert-butyl(2-oxoethyl)carbamate (3.65 g, 23 mmol) in DCM (30 mL) under RT, and stirring was continued at RT for 1 day. DCM was added, followed by a saturated solution of NaHCO3. The organic phase was separated, and the aqueous phase was extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by rapid chromatography (silica, heptane / EtOAc, gradient: 0% to 30% EtOAc) to give the title compound (2.30 g). UPLC-MS 1: m / z 333.1 [M+H] + .t R =1.19min. 1 H NMR (400MHz, DMSO-d6) δ7.23-7.10(m,1H),7.00(t,J=5.7Hz,1H),6.60-6.42(m,2H),5.56(d,J=5.6Hz,1H),3.15(dt,J=16.8,6.0Hz,4H),1.37(s,9H).

[0982] Synthesis of 2-(2-bromo-3,4-difluorophenoxy)ethane-1-ol (N-II)

[0983]

[0984] Step 1: (2-(2-bromo-3,4-difluorophenoxy)ethoxy)(tert-butyl)dimethylsilane(N-II-a)

[0985] K₂CO₃ (2.26 g, 16.3 mmol) and KI (0.135 g, 0.81 mmol) were added to a solution of 2-bromo-3,4-difluorophenol (CAS 1376335-05-5) (1.7 g, 8.13 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (CAS 86864-60-0) (1.946 g, 8.13 mmol) in DMF (27 mL). The reaction mixture was heated at 80 °C for 3.5 h. More K₂CO₃ (2.25 g, 16.3 mmol) and KI (0.135 g, 0.81 mmol) were added, and stirring was continued at 80 °C for 1 h. The reaction mixture was quenched with water and extracted with EtOAc. The aqueous layer was extracted again with EtOAc, and the combined organic layers were dried (in a phase separator box) and concentrated. The residue was purified by rapid chromatography (silica, cyclohexane / EtOAc, gradient: 0% to 10% EtOAc) to give the title compound (1.00 g) as a colorless oil. UPLC-MS 1: m / z 384.1 / 386.3 [M+NH4] + .t R =1.57min.

[0986] Step 4: 2-(2-Bromo-3,4-difluorophenoxy)ethanol (N-II)

[0987] TBAF trihydrate (515 mg, 1.63 mmol) was added to a solution of 2-(2-bromo-3,4-difluorophenoxy)ethoxy)(tert-butyl)dimethylsilane (N-II-a) (500 mg, 1.361 mmol) in THF (14 mL), and the reaction mixture was stirred at RT for 1.5 h. The reaction mixture was concentrated, and the residue was purified by rapid chromatography (silica, cyclohexane / EtOAc, gradient: 0% to 100% EtOAc) to give the title compound (344 mg) as a colorless liquid. 1 H NMR (400MHz, DMSO-d6) δ 7.43-7.36 (m, 1H), 7.20-7.15 (m, 1H), 4.85 (t, J = 5.4Hz, 1H), 4.13 (td, J = 4.9, 1.0Hz, 2H), 3.72 (q, J = 5.4Hz, 2H).

[0988] Synthesis of tert-butyl(2-(3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenoxy)ethyl)carbamate (N-III)

[0989]

[0990] Step 1: tert-butyl (2-(2-bromo-3-fluorophenoxy)ethyl)carbamate (N-III-a)

[0991] At RT, tert-butyl(2-bromoethyl)carbamate (2.29 g, 10.2 mmol) was added to a solution of 2-bromo-3-fluorophenol (1.5 g, 7.9 mmol) and K₂CO₃ (1.63 g, 11.8 mmol) in DMF (10 mL), and the reaction mixture was stirred at RT for 18 h. Water was added, and the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by rapid chromatography (silica, hexane / EtOAc, gradient: 0% to 50% EtOAc) to give the title compound (2.6 g) as a colorless foam. UPLC-MS 1: m / z 334.0 / 336.0 [M+H] + ,t R =1.18min.

[0992] Step 2: tert-Butyl(2-(3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenoxy)ethyl)carbamate (N-III).

[0993] At 100 °C, the PdCl2(dppf).CH2Cl2 adduct (0.39 g, 0.48 mmol) was added to a stirred suspension of tert-butyl (2-(2-bromo-3-fluorophenoxy)ethyl)carbamate (N-III-a) (1.6 g, 4.8 mmol), bis(pinacolyl)diboron (2.43 g, 9.6 mmol), and KOAc (1.41 g, 14.4 mmol) in dioxane (10 mL), and the reaction mixture was stirred at 100 °C for 5 h. After filtration through a diatomaceous earth pad and concentration under reduced pressure, the residue was purified by rapid chromatography (silica, hexane / EtOAc, gradient: 0% to 40% EtOAc) to give the title compound (927 mg) as a yellow oil. UPLC-MS 1: m / z 382.2 [M+H] + ,t R =1.32min

[0994] Synthesis of 2-bromo-3-fluoro-4-methoxybenzyl nitrile (N-IV)

[0995]

[0996] Sodium methoxide (6.29 mL, 27.5 mmol, 25% in MeOH) was added to a stirred solution of 2-bromo-3,4-difluorobenzyl nitrile (4 g, 18.35 mmol) in MeOH (50 mL). The reaction mixture was then stirred at RT for 16 h. The reaction mixture was quenched with a saturated solution of NaHCO3 and extracted with EtOAc. The organic layers were combined, washed with a saturated solution of NaHCO3, dried over Na2SO4, and concentrated. The residue was purified by normal-phase chromatography (silica, hexane / EtOAc; gradient: 0% to 80% EtOAc) to give the title compound (4.17 g). 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.87-7.67 (m, 1H), 7.44-7.20 (m, 1H), 3.95 (s, 3H).

[0997] Synthesis of 2-bromo-4-(difluoromethoxy)-3-fluorobenzyl nitrile (NV)

[0998]

[0999] Step 1: 2-Bromo-3-fluoro-4-hydroxybenzonitrile (NVa)

[1000] Under Ar conditions and at 0 °C, NaH (3.48 g, 138 mmol, 95%) was added to a stirred solution of 2-bromo-3,4-difluorobenzyl nitrile (10 g, 45.9 mmol) and 2-hydroxyethylmethyl sulfone (6.26 g, 50.5 mmol) in DMF (100 mL), and stirring was continued at RT for 2 h. The reaction mixture was quenched with 0.1 N HCl and extracted with EtOAc. The organic layers were combined, washed with 0.1 N HCl, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by rapid chromatography (silica, hexane / EtOAc gradient: 0% to 80% EtOAc) to give the desired product (8.97 g). UPLC-MS 1: m / z 215.9 [M+H] + ,t R =0.80min.

[1001] Step 2: 2-Bromo-4-(difluoromethoxy)-3-fluorobenzylnitrile (NV)

[1002] At 0 °C, a solution of KOH (46.6 g, 831 mmol) in H₂O (150 mL) and subsequently diethyl (bromodifluoromethyl)phosphonate (14.75 mL, 83 mmol) were added to a stirred solution of 2-bromo-3-fluoro-4-hydroxybenzonitrile (NVa) (8.97 g, 41.5 mmol) in ACN (150 mL). Stirring was continued at RT for 2 h. The reaction mixture was quenched with a saturated solution of NaHCO₃ and extracted with EtOAc. The organic layers were combined, washed with a saturated solution of NaHCO₃, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by rapid chromatography (silica, hexane / EtOAc; gradient: 0% to 40% EtOAc) to give the title compound (10.45 g). 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.94-7.87 (m, 1H), 7.62-7.57 (m, 1H), 7.57-7.20 (m, 1H).

[1003] Synthesis of 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzyl nitrile (N-VI)

[1004]

[1005] Under Ar conditions and at 0 °C, NaH (0.477 g, 11.9 mmol, 60% in mineral oil) was added in portions to a stirred solution of 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (1.34 g, 9.17 mmol) in DMF (40 mL). After 5 min, 2-bromo-3,4-difluorobenzyl nitrile (2 g, 9.17 mmol) was added, and the reaction mixture was stirred at 0 °C for 1.5 h. The reaction mixture was quenched with a saturated solution of NH4Cl and then extracted with EtOAc. The organic layers were combined, washed with a saturated solution of NH4Cl, dried over Na2SO4, and concentrated. The residue was purified by rapid chromatography (silica, hexane / EtOAc 2:1) to give the title compound (1.93 g). 1 H NMR(400MHz,DMSO-d6)δ(ppm):7.87-7.74(m,1H),7.53-7.29(m,1H),4.73-4.57(m,1H),4.4 7-4.28(m,2H),4.04-3.90(m,1H),3.87-3.63(m,2H),3.55-3.35(m,1H),1.88-1.24(m,6H).

[1006] Synthesis of 2-bromo-3-fluoro-4-(2-hydroxyethoxy)benzyl nitrile (N-VII)

[1007]

[1008] A solution of 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzyl nitrile (N-VI) (2.47 g, 7.2 mmol) and p-TsOH (0.55 g, 2.9 mmol) in EtOH (35 mL) was stirred for 24 h at RT. A saturated solution of NaHCO3 was added, and the mixture was extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4 and concentrated to give the title compound (1.48 g) as a colorless powder. UPLC-MS 1 m / z 304.0 [M+ formate ester] - .

[1009] Synthesis of (R)-2-bromo-3-fluoro-4-(2-fluoropropoxy)benzyl nitrile (N-VIII)

[1010]

[1011] Similar to 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzyl nitrile (N-VI), the title compound was synthesized from 2-bromo-3,4-difluorobenzyl nitrile and (R)-2-fluoroprop-1-ol. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.80 (dd, J = 8.6, 2.0Hz, 1H), 7.40 (t, J = 8.2Hz, 1H), 5.14-4.95 (m, 1H), 4.43-4.23 (m, 2H), 1.36 (dd, J = 23.8, 6.6Hz, 3H).

[1012] Synthesis of 2-bromo-3-fluoro-4-(2-methoxyethoxy)benzyl nitrile (N-IX)

[1013]

[1014] Sodium (79 mg, 3.44 mmol) was added to a stirred solution of 2-methoxyethanol (10 mL) under an Ar atmosphere. After 1 h, 2-bromo-3,4-difluorobenzyl nitrile (500 mg, 2.294 mmol) was added under RT and stirring was continued for 1 h. The reaction mixture was quenched with a saturated solution of NaHCO3 and extracted with DCM. The organic layers were combined, washed with a saturated solution of NaHCO3, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (silica, hexane / EtOAc; gradient 0% to 85% EtOAc) to yield the desired product (593 mg). 1H NMR (400MHz, DMSO-d6) δ (ppm) 7.84-7.70 (m, 1H), 7.39 (t, J = 8.4Hz, 1H), 4.35-4.25 (m, 2H), 3.74-3.61 (m, 2H), 3.29 (s, 3H).

[1015] Synthesis of 2-bromo-4-(cyclopropylmethoxy)-3-fluorobenzyl nitrile (NX)

[1016]

[1017] Under Ar and RT conditions, NaH (0.413 g, 10.3 mmol, 60% in mineral oil) was added to a stirred solution of cyclopropylmethanol (0.744 g, 10.32 mmol) in THF (15 mL). The suspension was stirred at RT for 1 h, and then 2-bromo-3,4-difluorobenzyl nitrile (1.5 g, 6.88 mmol) was added. The resulting viscous suspension was diluted in THF (10 mL) and stirred further at RT for 1.5 h. A saturated solution of NaHCO3 was added, and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by rapid chromatography (silica, hexane / EtOAc 9:1) to give the title compound (1.6 g). 1 H NMR (600MHz, DMSO-d6) δ (ppm) 7.77 (d, J = 8.7 Hz, 1H), 7.34 (t, J = 8.3 Hz, 1H), 4. 03(d,J=7.2Hz,2H),1.29-1.21(m,1H),0.63-0.56(m,2H),0.38-0.31(m,2H).

[1018] Synthesis of 4-chloro-5-fluoro-6-(2-methoxyethoxy)nicotinonitrile (N-XI)

[1019]

[1020] Step 1: 4-Chloro-5,6-difluoronicotinamide (N-XI-a)

[1021] At RT, DMF (2 mL) was added to a solution of 4-chloro-5,6-difluoronicotinic acid (3.00 g, 15.55 mmol) in SOCl2 (20 mL), and stirring was continued at 80 °C for 16 h. The reaction mixture was concentrated, and the resulting residue was suspended in DCM (50 mL). At 0 °C, NH4Cl (0.914 g, 17.10 mmol) and NET3 (10.8 mL, 77.73 mmol) were added, and the reaction mixture was stirred at this temperature for another 3 h. A saturated solution of NaHCO3 and NaCl was added, and the mixture was extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by rapid chromatography (silica, hexane / EtOAc; gradient 0% to 60% EtOAc) to give the title compound (1.70 g) as a colorless powder. UPLC-MS m / z 192.8 [M+H] + .

[1022] Step 2: 4-Chloro-5-fluoro-6-(2-methoxyethoxy)nicotinamide (N-XI-b)

[1023] At 0 °C, NaH (0.21 g, 5.2 mmol, 60% in mineral oil) was added in portions to a stirred solution of 2-methoxyethanol (0.41 mL, 5.2 mmol) in THF (30 mL). After 5 min, 4-chloro-5,6-difluoronicotinamide (N-XI-a) (1.00 g, 5.2 mmol) was added, and the reaction mixture was stirred at 0 °C for 10 min. Water was added, and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The crude product was purified by rapid chromatography (silica, hexane / EtOAc; gradient 0% to 65% EtOAc) to give the title compound (0.80 g) as a colorless powder. UPLC-MS m / z 248.9 [M+H] + .

[1024] Step 3: 4-Chloro-5-fluoro-6-(2-methoxyethoxy)nicotinonitrile (N-XI)

[1025] CuCl (0.016 g, 0.16 mmol) and subsequently 2,2,2-trifluoro-N-methyl-N-(trimethylsilyl)acetamide (3.851 g, 19.4 mmol) were added to a stirred solution of 4-chloro-5-fluoro-6-(2-methoxyethoxy)nicotinamide (N-XI-b) (1.60 g, 6.5 mmol) in toluene (20 mL), and the resulting reaction mixture was stirred at 100 °C for 24 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by rapid chromatography (silica, hexane / EtOAc; gradient 0% to 15% EtOAc) to give the title compound (1.20 g) as a colorless powder. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.63 (d, J = 08Hz, 1H), 4.60-4.57 (m, 2H), 3.72-3.70 (m, 2H), 3.30 (s, 3H). UPLC-MS m / z 230.9[M+H] + .

[1026] Synthesis of 5-fluoro-4-iodo-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinonitrile (N-XII)

[1027]

[1028] Step 1: 5-Bromo-3-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine(N-XII-a)

[1029] At 0 °C, NaH (0.21 g, 5.2 mmol, 60% in mineral oil) was added in portions to a stirred solution of 2-((tetrahydro-2H-pyran-2-yl)oxy)ethane-1-ol (1.2 mL, 7.8 mmol) in THF (20 mL). After 5 min, 5-bromo-2,3-difluoropyridine (1.00 g, 5.2 mmol) was added, and the reaction mixture was stirred at 0 °C for 45 min. NH4Cl solution (50 mL) was added, and the mixture was stirred for 5 min and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (silica, hexane / EtOAc; gradient 0% to 10% EtOAc) to give the title compound (1.00 g) as a colorless powder. UPLC-MS m / z 322.2 [M+H] + .

[1030] Step 2:5-Fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinonitrile(N-XII-b)

[1031] A mixture of 5-bromo-3-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine (N-XII-a) (0.50 g, 1.6 mmol), zinc cyanide (0.36 g, 3.1 mmol), and tetra(triphenylphosphine)palladium (0) (0.180 g, 0.16 mmol) in DMF (8 mL) was heated at 100 °C under MW radiation for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by rapid chromatography (silica, hexane / EtOAc; gradient 0% to 14% EtOAc) to give the title compound (0.35 g) as a colorless oil. 1 H NMR(400MHz, DMSO-d6)δ(ppm)8.53(d,J=2.0Hz,1H),8.31(dd,J=10.8,2.0Hz,1H),4.66-4.64(m,1H),4.63- 4.53(m,2H),3.98-3.93(m,1H),3.79-3.72(m,2H),3.45-3.40(m,1H),1.69-1.57(m,2H),1.49-1.44(m,4H).

[1032] Step 3: 5-Fluoro-4-iodo-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinonitrile (N-XII)

[1033] At -78 °C, LDA (4.0 mL, 7.90 mmol) was added dropwise to a stirred solution of 5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinonitrile (N-XII-b) (0.70 g, 2.6 mmol) in THF (20 mL). After 10 min, I2 (0.67 g, 5.3 mmol) was added at -78 °C, and the reaction mixture was heated to RT and stirred for another 16 h. Ice water was added, and the mixture was stirred for 5 min, then extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (silica, hexane / EtOAc; gradient 0% to 14% EtOAc) to give the title compound (0.70 g) as a colorless oil. 1H NMR(400MHz,DMSO-d6)δ(ppm)8.44(s,1H),4.65-4.63(m,1H),4.63-4.52(m,2H),3.97-3 .92(m,1H),3.78-3.72(m,2H),3.45-3.41(m,1H),1.69-1.51(m,2H),1.46-1.44(m,4H).

[1034] Synthesis of 2-bromo-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzyl nitrile (N-XIII)

[1035]

[1036] Step 1: (2S)-Ethyl 2-((tetrahydro-2H-pyran-2-yl)oxy)propionate (N-XIII-a)

[1037] At 0 °C and under Ar, 3,4-dihydro-2H-pyran (13.16 mL, 144 mmol) and pyridinium toluene-4-sulfonate (1.064 g, 4.23 mmol) were added to a stirred solution of (-)-ethyl L-lactic acid ester (9.67 mL, 85 mmol) in DCM (100 mL). Stirring was continued at RT for 16 h. The reaction mixture was quenched with water and then extracted with DCM. The organic layers were combined, washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (silica, hexane / EtOAc, gradient: 0% to 30% EtOAc) to give the title compound (16.3 g). 1 H NMR(400MHz,DMSO-d6)δ(ppm)4.71-4.65(m,1H),4.64-4.55(m,1H),4.15-4.00(m,4H),3.83-3.64(m,2H),3.4 9-3.30(m,2H),1.76-1.54(m,5H),1.52-1.34(m,9H),1.32-1.28(m,3H),1.27-1.21(m,3H),1.20-1.14(m,6H)

[1038] Step 2: (2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-ol(N-XIII-b)

[1039] At 0 °C, lithium aluminum hydride (23.03 mL, 81 mmol, 18% in toluene) was added dropwise over 6 min to a solution of (2S)-ethyl 2-((tetrahydro-2H-pyran-2-yl)oxy)propionate (N-XIII-a) (16.3 g, 81 mmol) in Et₂O (800 mL). The resulting reaction mixture was stirred at 0 °C for 1.5 h, and then carefully quenched with a saturated solution of NH₄Cl. The precipitate was filtered off, and the mother liquor was extracted with Et₂O. The organic layers were combined, washed with brine, dried over anhydrous Na₂SO₄, and concentrated to give the title compound (10.12 g). 1 H NMR(400MHz,DMSO-d6)δ(ppm)4.75-4.69(m,1H),4.68-4.62(m,1H),3.89-3.74(m,2H),3.7 3-3.62(m,2H),3.49-3.19(m,6H),1.80-1.54(m,4H),1.52-1.36(m,8H),1.10-0.99(m,6H).

[1040] Step 3: 2-Bromo-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzyl nitrile (N-XIII)

[1041] At 0 °C, NaH (2.03 g, 50.7 mmol, 60% in mineral oil) was added in portions over 4 min to a stirred solution of (2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-ol (N-XIII-b) (7.50 g, 46.8 mmol) in DMF (140 mL). Then, 2-bromo-3,4-difluorobenzyl nitrile (8.50 g, 39.0 mmol) was added, and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with a saturated solution of NH4Cl and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, and concentrated. The resulting crude product was purified by rapid chromatography (silica, hexane / EtOAc 2:1) to give the title product (14.68 g). UPLC-MS 1: m / z 375.2 [M+NH4] + ,t R =1.22min.

[1042] Synthesis of (S)-2-bromo-3-fluoro-4-(2-hydroxypropoxy)benzyl nitrile (N-XIV)

[1043]

[1044] p-TsOH (158 mg, 0.83 mmol) was added to a solution of 2-bromo-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzyl nitrile (N-XIII) (746 mg, 2.08 mmol) in EtOH (10 mL), and the resulting reaction mixture was stirred at RT for 16 h. For post-treatment, a saturated solution of NaHCO3 was added, followed by extraction with EtOAc. The combined organic extracts were washed with a saturated solution of NaHCO3 and dried over anhydrous Na2SO4. Concentration was used to give a crude product, which was purified by rapid chromatography (silica, hexane / EtOAc, gradient: 0% to 100% EtOAc) to give the title compound (528 mg) as a colorless powder. UPLC-MS 1: m / z 317.9 [M+ formate] - ,t R =0.84min.

[1045] Synthesis of (R)-2-bromo-3-fluoro-4-(2-hydroxypropoxy)benzyl nitrile (N-XV)

[1046]

[1047] Similar to (S)-2-bromo-3-fluoro-4-(2-hydroxypropoxy)benzyl nitrile (N-XIV), the title compound was synthesized from 2-bromo-3,4-difluorobenzyl nitrile and (+)-ethyl-D-lactate. UPLC-MS 1: m / z 318.1 [M+ formate] - ,t R =0.87min.

[1048] Synthesis of ethyl 2-(3-bromo-4-cyano-2-fluorophenoxy)acetate (N-XVI)

[1049]

[1050] A solution of ethyl-2-hydroxyacetic acid ester (215 mg, 2.1 mmol) and KOtBu (170 mg, 1.5 mmol) in THF (5 mL) was slowly added to a solution of 2-bromo-3,4-difluorobenzyl nitrile (300 mg, 1–4 mmol) in THF (5 mL) cooled to 0 °C. The reaction mixture was heated to RT and stirred for another 40 min. The reaction mixture was concentrated under reduced pressure, and the residue was treated with a saturated solution of NH4Cl followed by extraction with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The crude product was purified by rapid chromatography (silica, cyclohexane / EtOAc, gradient: 0% to 20% EtOAc) to give the title compound (280 mg) as a colorless powder. 1H NMR (400MHz, DMSO-d6) δ (ppm) 7.78 (dd, J = 9.0, 2.0Hz, 1H), 7.35 (t, J = 8.2Hz, 1H), 5.06 (s, 2H), 4.17 (q, J = 7.0Hz, 2H), 1.20 (t, J = 7.0Hz, 3H).

[1051] Synthesis of (R)-4-((4-acetylmorpholin-2-yl)methoxy)-2-bromo-3-fluorobenzyl nitrile (N-XVII)

[1052]

[1053] The title compound was synthesized from 2-bromo-3,4-difluorobenzyl nitrile and (R)-morpholino-2-ylmethanol (CAS1664380-75-9), similar to ethyl 2-(3-bromo-4-cyano-2-fluorophenoxy)acetate (N-XVI). UPLC-MS 1: m / z 357.1 / 359.1 [M+H] + ,t R =0.84min

[1054] Synthesis of (R)-2-bromo-3-fluoro-4-((tetrahydrofuran-2-yl)methoxy)benzyl nitrile (N-XVIII)

[1055]

[1056] At 0 °C, a solution containing (R)-(tetrahydrofuran-2-yl)methanol (211 mg, 2.06 mmol) in THF (2.5 mL) and KOtBu (170 mg, 1.51 mmol) was added dropwise to a stirred solution of 2-bromo-3,4-difluorobenzyl nitrile (300 mg, 1.37 mmol) in THF (7.5 mL). The reaction mixture was stirred at 0 °C for 40 min. The reaction mixture was then partitioned between EtOAc and 10% citric acid solution. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude product was purified by rapid chromatography (silica, EtOAc / cyclohexane, gradient: 0% to 33% EtOAc) to give the desired product (330 mg). 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.77 (dd, J=8.7, 1.9Hz, 1H), 7.39 (t, J=8.7Hz, 1H), 4.25-4.08 (m, 3H ),3.79-3.72(m,1H),3.70-3.62(m,1H),2.05-1.92(m,1H),1.91-1.76(m,2H),1.73-1.50(m,1H).

[1057] Synthesis of 2-bromo-4-ethyl-3-fluorobenzyl nitrile (N-XIX)

[1058]

[1059] Step 1: 3-Fluoro-4-vinylbenzylnitrile (N-XIX-a)

[1060] Under Ar conditions, vinylboric anhydride pyridine complex (600 mg, 2.50 mmol), Pd(tBu3P)2 (128 mg, 0.25 mmol), and K2CO3 (1.04 g, 7.50 mmol) were added to a stirred solution of 4-bromo-3-fluorobenzyl nitrile (1.00 g, 32.26 mmol) in dioxane / water (20 mL, 3:1). The reaction mixture was stirred at 100 °C for 1 h and then cooled to RT. The reaction mixture was partitioned between a saturated solution of NaHCO3 and EtOAc. The organic layer was washed with a saturated solution of NaHCO3, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by rapid chromatography (silica, cyclohexane / EtOAc, gradient: 0% to 8% EtOAc) to give the desired product (616 mg). 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.93-7.75 (m, 2H), 7.67 (dd, J = 8.1, 1.7Hz, 1H), 6.85(dd,J=17.8,11.3Hz,1H), 6.10(d,J=17.8Hz,1H), 5.61(d,J=11.3Hz,1H).

[1061] Step 2: 4-Ethyl-3-fluorobenzylnitrile (N-XIX-b)

[1062] A solution of 3-fluoro-4-vinylbenzylnitrile (N-XIX-a) (200 mg, 1.40 mmol) in THF (10 mL) was treated with 10% Pd / C (145 mg) and hydrogenated in a shake flask at RT for 10 min under a superpressure of 0.1 bar. The reaction mixture was filtered and concentrated. The crude product was purified by rapid chromatography (silica, cyclohexane / EtOAc, gradient: 0% to 10% EtOAc) to give the title compound (169 mg). 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.75 (dd, J = 10.0, 1.7Hz, 1H), 7.62 (dd, J = 7.8, 1.6Hz, 1H), 7.51 (t, J = 7.8Hz, 1H), 2.67 (q, J = 7.5Hz, 2H), 1.16 (t, J = 7.5Hz, 2H).

[1063] Step 3: 2-Bromo-4-ethyl-3-fluorobenzylnitrile (N-XIX)

[1064] Under Ar conditions, at -78 °C, LDA (0.608 mL, 1.217 mmol, 2 M in THF / heptane / ethylbenzene) was added to a stirred solution of 4-ethyl-3-fluorobenzyl nitrile (N-XIX-b) (165 mg, 1.10 mmol) in THF (10 mL). The reaction mixture was stirred at -78 °C for 1 h, and then 1,2-dibromotetrachloroethane (720 mg, 2.21 mmol) was added. Stirring was continued at -78 °C for 1 h. The reaction mixture was then quenched with a saturated solution of NaHCO3 and extracted with EtOAc. The combined organic layers were washed with a saturated solution of NaHCO3, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by rapid chromatography (silica, cyclohexane / EtOAc, gradient: 0% to 7% EtOAc) to give the title compound (206 mg). 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.73 (dd, J = 7.9, 1.2Hz, 1H), 7.57-7.48 (m, 1H), 2.72 (qd, J = 7.5, 1.5Hz, 2H), 1.17 (t, J = 7.5Hz, 3H).

[1065] Synthesis of 2-bromo-3-fluoro-4-(1H-imidazol-1-yl)benzyl nitrile (N-XX)

[1066]

[1067] A solution of imidazole (94 mg, 1.37 mmol) in THF (2 mL) was treated with solid NaH (34 mg, 1.38 mmol, 95%), and the resulting suspension was stirred at RT for 30 min. Then, a solution of 2-bromo-3,4-difluorobenzyl nitrile (200 mg, 0.92 mmol) in THF (4 mL) was slowly added, and the reaction mixture was stirred at RT for 2 h. The reaction mixture was then quenched with a saturated solution of NaHCO3 and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated. The crude product was purified by rapid chromatography (silica, DCM / MeOH, gradient: 0% to 3% MeOH) to give the title compound (121 mg) as a colorless powder. UPLC-MS 1: m / z 266.0 / 268.0 [M+H] + ;t R =0.71min.

[1068] Synthesis of 2-bromo-3-fluoro-4-(pyrimidin-2-ylmethoxy)benzyl nitrile (N-XXI)

[1069]

[1070] A solution of pyrimidin-2-ylmethanol (227 mg, 2.06 mmol) in THF (2.5 mL) was treated with solid KOtBu (170 mg, 1.51 mmol), and the resulting suspension was stirred at RT for 30 min. This mixture was then added to a solution of 2-bromo-3,4-difluorobenzyl nitrile (300 mg, 1.38 mmol) in THF cooled to 0 °C (7.5 mL). The reaction mixture was stirred at RT for 2 h, followed by quenching with citric acid solution. The resulting solid was collected by filtration to give the title compound (350 mg). UPLC-MS 1: m / z 308.0 [M+H] + ;t R =0.87min.

[1071] Synthesis of 2-bromo-4-(1,1-difluoro-2-hydroxyethoxy)-3-fluorobenzyl nitrile (N-XXII)

[1072]

[1073] Reaction scheme N-XXII:

[1074]

[1075] Step 1: 2-Bromo-4-((1,1-difluoroallyl)oxy)-3-fluorobenzyl nitrile (N-XXII-a)

[1076] To a stirred solution of 2-bromo-3-fluoro-4-hydroxybenzonitrile (NVa) (1.4 g, 6.42 mmol) in THF (50 mL), NaH (0.257 g, 6.42 mmol, 60%), Pd(OAc)₂ (14 mg, 0.06 mmol), triphenylphosphine (67 mg, 0.26 mmol), and 3-bromo-3,3-difluoroprop-1-ene (1.0 g, 6.4 mmol) were added. The reaction mixture was stirred overnight at RT. A saturated solution of NaHCO₃ was added, and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The crude product was purified by rapid chromatography (silica, cyclohexane / EtOAc, gradient: 0% to 10% EtOAc) to give the title compound (1.3 g). 1H NMR (600MHz, DMSO-d6) δ7.92 (d, J = 8.6 Hz, 1H), 7.67 (t, J = 8.1 Hz, 1H), 6.33 (dq, J = 17.7, 8.2 Hz, 1H), 6.01 (d, J = 17.2 Hz, 1H), 5.85 (d, J = 10.9 Hz, 1H).

[1077] Step 2: 2-Bromo-4-(1,1-difluoro-2,3-dihydroxypropoxy)-3-fluorobenzyl nitrile (N-XXII-b)

[1078] Osmium tetroxide (0.3 mL, 0.048 mmol, 4% in water) and N-methylmorpholine-N-oxide (0.3 g, 2.64 mmol) were added to a suspension of 2-bromo-4-((1,1-difluoroallyl)oxy)-3-fluorobenzyl nitrile (N-XXII-a) (0.7 g, 2.40 mmol) in dioxane (16 mL) and water (5 mL) at RT. The reaction mixture was stirred at RT for 3 days. A saturated solution of NaHCO3 was added, and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by rapid chromatography (silica, cyclohexane / EtOAc, gradient: 20% to 90% EtOAc) to give the title compound (590 mg). 1 H NMR (600MHz, DMSO-d6) δ7.90(dd,J=8.7,1.7Hz,1H),7.63(t,J=7.9Hz,1H),6.20(d,J=6.5Hz,1H),4.98(t,J=5. 9Hz, 1H), 3.98 (ddt, J = 13.6, 10.1, 5.0Hz, 1H), 3.72 (dt, J = 11.7, 3.9Hz, 1H), 3.52 (ddd, J = 11.5, 7.3, 3.8Hz, 1H).

[1079] Step 3 2-Bromo-4-(1,1-difluoro-2,2-dihydroxyethoxy)-3-fluorobenzylnitrile (N-XXII-c)

[1080] Sodium periodate (2.95 g, 13.8 mmol) was added to a suspension of 2-bromo-4-(1,1-difluoro-2,3-dihydroxypropoxy)-3-fluorobenzyl nitrile (N-XXII-b) (0.45 g, 1.38 mmol) in dioxane (16 mL) and water (5 mL) under RT. The reaction mixture was stirred at RT for 2 days. A saturated solution of NaHCO3 was added, and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give the title compound, which was used directly in the next step without purification. UPLC-MS 1: t R =0.75min.

[1081] Step 4 2-Bromo-4-(1,1-difluoro-2-hydroxyethoxy)-3-fluorobenzylnitrile (N-XXII)

[1082] At RT, NaBH4 (546 mg, 14.4 mmol) was added to a solution of 2-bromo-4-(1,1-difluoro-2,2-dihydroxyethoxy)-3-fluorobenzyl nitrile (N-XXII-c) (450 mg, 1.44 mmol) in THF (14.4 mL). The reaction mixture was stirred at RT for 1 h. A saturated solution of NaHCO3 was added, and the reaction mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (silica, cyclohexane / EtOAc, gradient: 20% to 80% EtOAc) to give the title compound (130 mg). 1 H NMR (600MHz, DMSO-d6) δ7.90 (dd, J = 8.6, 1.7Hz, 1H), 7.74-7.48 (m, 1H), 6.06 (t, J = 6.7Hz, 1H), 3.94 (td, J = 10.4, 6.7Hz, 2H).

[1083] Synthesis of 2-bromo-4-((1,1-difluoro-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)thio)benzyl nitrile (N-XXIII)

[1084]

[1085] Step 1 2-Bromo-4-mercaptobenzylnitrile (N-XXIII-a)

[1086] A solution of 2-bromo-3,4-difluorobenzyl nitrile (5.0 g, 25.0 mmol) in DMF (25 mL) was treated with Na₂S (2.14 g, 27.5 mmol) and stirred at RT for 1 h. The reaction mixture was cooled to 0 °C, quenched with 1 N NaOH, and extracted with DCM. The aqueous layer was acidified with 6 N HCl and back-extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The resulting crude product was dissolved in 10% HCl (100 mL), cooled to 0 °C, and zinc powder (10 g) was added. The reaction mixture was stirred for 1 h, diluted with EtOAc (250 mL), and stirred again for 30 min. The separated organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated to give the title compound (2.5 g), which was used for the next step without further purification. UPLC-MS m / z 214.1 [M+H] + .

[1087] Step 2: 2-Bromo-4-((1,1-difluoro-2-hydroxyethyl)thio)benzyl nitrile (N-XXIII-b)

[1088] At 0 °C, NaH (0.040 g, 0.935 mmol, 60% in mineral oil) was added in portions to a stirred solution of 2-bromo-4-mercaptobenzyl nitrile (N-XXIII-a) (0.2 g, 0.94 mmol) in DMSO (5 mL). The suspension was stirred for 30 min, and then 2-bromo-2,2-difluoroacetate (0.208 g, 1.03 mmol) was added. The reaction mixture was stirred at RT for 16 h, then quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The crude material (0.17 g) was then dissolved in MeOH (11 mL). Sodium borohydride (0.038 g, 1.012 mmol) was added in portions at RT. The reaction mixture was stirred at RT for 30 min, then quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give the title compound (0.16 g), which was used for the next step without further purification.

[1089] Step 3: 2-Bromo-4-((1,1-Difluoro-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)thio)benzyl nitrile (N-XXIII)

[1090] At 0 °C, 3,4-dihydro-2H-pyran (0.092 g, 1.09 mmol) and pyridinium p-toluenesulfonate (0.007 g, 0.027 mmol) were continuously added to a solution of crude 2-bromo-4-((1,1-difluoro-2-hydroxyethyl)thio)benzyl nitrile (N-XXIII-b) (0.16 g, 0.55 mmol) in DCM (10 mL). The reaction mixture was stirred at RT for 2 h, then quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The crude product was purified by rapid chromatography (silica, hexane / EtOAc 85:15) to give the title compound (0.13 g). 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.10 (br.s, 1H), 8.03 (d, J = 8.3Hz, 1H), 7.80 (dd, J = 1.7Hz, J = 8.3Hz, 1H), 4.75 (br s,1H),3.75-3.69(m,1H),3.55-3.43(m,1H),1.73-1.62(m,3H),1.55-1.45(m,5H).

[1091] Synthesis of 2-bromo-3-fluoro-4-((methanesulfonyl)methoxy)benzyl nitrile (N-XXIV)

[1092]

[1093] Under Ar conditions, NaH (46 mg, 1.83 mmol, 95%) was added to a stirred solution of 2-bromo-3-fluoro-4-hydroxybenzonitrile (NVa) (283 mg, 1.31 mmol) in DMF (2.2 mL). The suspension was stirred at RT for 30 min, then (chloromethyl)(methyl)thione (132 μl, 1.572 mmol) was added, and the reaction mixture was stirred at RT overnight. Water was added, and the reaction mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated. The crude product was dissolved in DCM (2.2 mL). At 0 °C, mCPBA (734 mg, 3.28 mmol, 77%) was added. The reaction mixture was stirred at RT for 1 h. To complete the reaction, more mCPBA (734 mg, 3.28 mmol, 77%) was added, and the reaction mixture was stirred at RT for 1 h. Water was added, and the pH was adjusted to 6–7 with 1 N NaOH. The reaction mixture was extracted with DCM, and the combined organic layers were dried (in a phase separator box) and concentrated. The crude product was purified by rapid chromatography (silica, hexane / EtOAc, gradient: 0% to 40% EtOAc) to give the title compound (240 mg). 1¹H NMR (400MHz, DMSO-d⁶) δ 7.86 (d, J = 8.7Hz, 1H), 7.65 (t, J = 8.4Hz, 1H), 5.59 (s, 2H), 3.09 (s, 3H). UPLC-MS 1: m / z 352.1 / 354.1 [M+formate ester] - ,t R =0.79min.

[1094] Synthesis of 2-bromo-4-(3,3-difluoropropoxy)-3-fluorobenzyl nitrile (N-XXV)

[1095]

[1096] Step 1: 2-Bromo-4-(3,3-diethoxypropoxy)-3-fluorobenzylnitrile (N-XXV-a)

[1097] At 0 °C, a solution of KOtBu (260 mg, 2.32 mmol) in THF was added dropwise to a solution of 2-bromo-3,4-difluorobenzyl nitrile (460 mg, 2.110 mmol) and 3,3-diethoxyprop-1-ol (0.85 mL, 5.4 mmol) in THF (3 mL). The reaction mixture was stirred at RT for 30 min and then diluted with EtOAc. The organic phase was washed successively with a saturated solution of NH4Cl, water, and brine. The organic layer was dried over anhydrous MgSO4 and concentrated to give the title compound, which was used as crude material for the next step without purification. UPLC-MS 1: m / z 390.2 / 392.2 [M+ formate ester] - ,t R =1.21min.

[1098] Step 2: 2-Bromo-3-fluoro-4-(3-oxopropoxy)benzylnitrile (N-XXV-b)

[1099] The crude material N-XXV-a (700 mg) from the previous step was treated with a mixture of HCl (5 mL, 4 N in dioxane) and water (5 mL). The reaction mixture was stirred at RT for 6 h. DCM was added, and the organic layer was washed with 1 N HCl and brine, dried over anhydrous MgSO4, and concentrated to give the title compound, which was used as crude material for the next step without purification. UPLC-MS 1: t R =0.87 / 0.90min.

[1100] Step 3: 2-Bromo-4-(3,3-difluoropropoxy)-3-fluorobenzylnitrile (N-XXV)

[1101] At 0 °C, diethylaminosulfur trifluoride (0.36 mL, 2.8 mmol) was added dropwise to a solution of crude 2-bromo-3-fluoro-4-(3-oxopropoxy)benzyl nitrile (N-XXV-b) (500 mg, 1.84 mmol) from the previous step in DCM (4 mL). The reaction mixture was stirred at RT for 2 h. DCM and water were added, the organic layers were separated, and the aqueous layer was extracted with DCM. The combined organic phases were dried over anhydrous MgSO4 and concentrated. The residue was purified by rapid chromatography (silica, heptane / EtOAc, gradient: 10% to 70% EtOAc) to give the title compound (50 mg). 1 H NMR (600MHz, DMSO-d6) δ7.82 (d, J = 8.8 Hz, 1H), 7.44 (t, J = 8.3 Hz, 1H), 6.24 (tt, J = 56.3, 4.5 Hz, 1H), 4.35 (t, J = 6.1 Hz, 2H), 2.44-2.33 (m, 2H).

[1102] Synthesis of methyl 2-bromo-3-fluoro-4-methoxybenzoate (N-XXVI)

[1103]

[1104] DBU (0.50 mL, 3.3 mmol) was added to a solution of methyl 2-bromo-3,4-difluorobenzoate (550 mg, 2.2 mmol) in MeOH (10 mL) at RT, and the reaction mixture was stirred at 50 °C for 22 h. A saturated solution of NaHCO3 was added, and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4 and concentrated. The crude product was purified by rapid chromatography (silica, cyclohexane / EtOAc; gradient: 0% to 20% EtOAc) to give the title compound (390 mg) as a colorless powder. UPLC-MS 1: m / z 263.1 [M+H] + ,t R =1.00min.

[1105] Synthesis of methyl 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate (N-XXVII)

[1106]

[1107] Step 1: Methyl 2-bromo-3-fluoro-4-hydroxybenzoate (N-XXVII-a)

[1108] At 0 °C, a solution of 2-(methanesulfonyl)ethanol (59.7 g, 482.1 mmol) in DMF (100 mL) was added dropwise to a stirred suspension of NaH (35.2 g, 876 mmol, 60% in mineral oil) in DMF (800 mL). After 15 min, a solution of methyl 2-bromo-3,4-difluorobenzoate (110 g, 438.2 mmol) in DMF (100 mL) was added dropwise, and the reaction mixture was stirred at 0 °C for 20 min. The reaction mixture was quenched with a saturated solution of NH4Cl and extracted with EtOAc. The organic layers were combined, washed with water and brine, dried over anhydrous Na2SO4, and concentrated to give the title compound. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.17 (s, 1H), 2.00 (dd, J = 8.68, 1.80 Hz, 1H), 7.03 (t, J = 8.60 Hz, 1H), 3.82 (s, 3H).

[1109] Step 2: Methyl 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate (N-XXVII)

[1110] At 0 °C, a solution of triphenylphosphine (63.4 g, 241.9 mmol) followed by DIAD (48.8 g, 241.9 mol) in THF (100 mL) was added dropwise to a stirred solution of methyl 2-bromo-3-fluoro-4-hydroxybenzoate (N-XXVII-a) (50 g, 201.6 mmol) and 2-((tetrahydro-2H-pyran-2-yl)oxy)ethanol (32.4 g, 221.7 mmol) in THF (500 mL). After addition, the reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layers were combined, washed with a saturated solution of NaHCO3 and brine, dried over Na2SO4, and concentrated. The resulting residue was ground in PE / EtOAc (95:5), the mother liquor was concentrated, and the crude product was purified by rapid chromatography (silica, PE / EtOAc 9:1) to give the title compound. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.69 (q, J = 1.4Hz, 1H), 7.33 (t, J = 8.5Hz, 1H), 4.66 (d, J = 3.3Hz, 1H), 4.33 (d, J = 2.2Hz, 2H ),3.97-3.92(m,1H),3.83(s,3H),3.77-3.72(m,2H),3.43(q,J=6.2Hz,1H),1.68-1.58(m,2H),1.46(t,J=9.0Hz,4H).

[1111] Synthesis of methyl 2-bromo-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzoate (N-XXVIII)

[1112]

[1113] At 0 °C, NaH (0.704 g, 17.6 mmol, 60% in mineral oil) was added in portions to a stirred solution of (2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-ol (N-XIII-b) (2.60 g, 16.25 mmol) in DMF (50 mL). Then, methyl 2-bromo-3,4-difluorobenzoate (3.4 g, 13.5 mmol) was added, and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with a saturated solution of NH4Cl and extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (silica, hexane / EtOAc 2:1) to give the title compound (3.27 g) as a beige oil. UPLC-MS 1: m / z 408.2 / 410.2 [M+NH4] + ,t R =1.24min.

[1114] Synthesis of methyl 4-chloro-5-fluoro-6-methoxynicotinic acid ester (N-XXIX)

[1115]

[1116] Conc H2SO4 (0.551 mL, 10.33 mmol) was added to a stirred solution of 4-chloro-5,6-difluoronicotinic acid (200 mg, 1.033 mmol) in MeOH (10 mL), and the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was quenched by adding a saturated solution of NaHCO3 and extracted with DCM. The organic layers were combined, washed with a saturated solution of NaHCO3, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by rapid chromatography (silica, hexane / EtOAc; gradient: 0% to 10% EtOAc) to give the title compound (143 mg) as a colorless powder. UPLC-MS 1: m / z 220.0 [M+H] + ,t R =1.02min.

[1117] Synthesis of methyl 4-chloro-6-(difluoromethoxy)-5-fluoronicotinate (N-XXX)

[1118]

[1119] Step 1: Methyl 4-chloro-5,6-difluoronicotinic acid ester (N-XXX-a)

[1120] Under RT, TMS-diazomethane (11.37 mL, 22.7 mmol, 2 M in Et₂O) was slowly added to a solution of 4-chloro-5,6-difluoronicotinic acid (4.00 g, 20.7 mmol) in MeOH (69 mL). Over the next 24 h, more TMS-diazomethane was added in four fractions (total: 34.2 mL, 68.3 mmol, 2 M in Et₂O) until the starting material was completely consumed. Water was added, and the organic solvent was removed under reduced pressure. The residue was extracted with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated to give the title compound (3.92 g) as a pale yellow oil. UPLC-MS 1: m / z 208.1 [M+H] + ,t R =0.93min.

[1121] Step 2: Methyl 4-chloro-5-fluoro-6-hydroxynicotinic acid ester (N-XXX-b)

[1122] At 0 °C, NaH (1.36 g, 34 mmol, 60% in mineral oil) was added to a solution of methyl 4-chloro-5,6-difluoronicotinic acid ester (N-XXX-a) (2.90 g, 11.3 mmol) and 2-(methylsulfonyl)ethanol (1.55 g, 12.45 mmol) in DMF (49 mL), and stirring was continued at this temperature for 30 min. Water was added, and the pH was adjusted to approximately 5 using 1 N HCl. The organic solvent was removed under reduced pressure. More water was added, and the mixture was filtered. The aqueous phase was extracted with EtOAc, dried over anhydrous Na₂SO₄, and concentrated to give the title compound (2.50 g) as a colorless powder. UPLC-MS 1: m / z 204.0 [MH] - ,t R =0.57min.

[1123] Step 3: 4-Chloro-6-(difluoromethoxy)-5-fluoronicotinic acid (N-XXX-c)

[1124] At 0 °C, a solution of KOH (1.82 g, 32.3 mmol) in water (6 mL) and subsequently diethyl (bromodifluoromethyl)phosphonate (0.58 mL, 3.2 mmol) in a stirred solution of methyl 4-chloro-5-fluoro-6-hydroxynicotinic acid ester (N-XXX-b) (350 mg) in ACN (6 mL) were added. The reaction mixture was stirred at RT for 1.5 h. The pH of the reaction mixture was adjusted to 3 by adding 2N HCl, and the organic solvent was removed under reduced pressure. MeOH was added, and the solids were removed by filtration. The organic phase was concentrated to yield the title compound (170 mg). UPLC-MS 1: m / z 240.1 [MH] - ,t R =0.66min.

[1125] Step 4: Methyl 4-chloro-6-(difluoromethoxy)-5-fluoronicotinic acid ester (N-XXX)

[1126] Thionyl chloride (0.077 mL, 1.06 mmol) and subsequently one drop of DMF were added to a solution of 4-chloro-6-(difluoromethoxy)-5-fluoronicotinic acid (N-XXX-c) (170 mg, 0.70 mmol) in DCM (4.7 mL). The reaction mixture was stirred at RT for 45 min. More thionyl chloride (0.205 mL, 2.8 mmol) was added and stirring was continued for 15 min. Then, MeOH (20 mL) was added, and the reaction mixture was stirred at RT overnight. A saturated solution of NaHCO3 was added, and the organic solvent was removed under reduced pressure. The residue was extracted with DCM, and the combined organic layers were dried over anhydrous Na2SO4 and concentrated to give the title compound (102 mg). UPLC-MS 1: The product is non-ionizable, t R =1.05min.

[1127] Synthesis of methyl 4-chloro-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinic acid ester (N-XXXI)

[1128]

[1129] At 0 °C, NaH (0.31 g, 7.7 mmol) was added in portions to a stirred solution of 2-((tetrahydro-2H-pyran-2-yl)oxy)ethane-1-ol (0.78 mL, 7.7 mmol) in THF (10 mL). After 5 min, methyl 4-chloro-5,6-difluoronicotinic acid ester (N-XXX-a) (1.60 g, 7.7 mmol) was added and stirring continued at 0 °C for 1 h. The reaction mixture was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (silica, hexane / EtOAc; gradient: 0% to 10% EtOAc) to give the title compound (1.20 g) as a colorless powder. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.53 (d, J = 1.2Hz, 1H), 4.66-4.65 (m, 1H), 4.64-4.58 (m, 2H), 3.98-3. 94(m,1H),3.87(s,3H),3.80-3.75(m,2H),3.44-3.42(m,1H),1.66-1.61(m,2H),1.49-1.45(m,4H).

[1130] Alternative synthesis of methyl 4-chloro-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinic acid ester (N-XXXI):

[1131] Reaction scheme N-XXXI:

[1132]

[1133] Step 1: 3-Fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine(N-XXXi-a)

[1134] t-BuOK (7.80 kg, 69.51 mol) and THF (20 L) were charged into a reactor, and the mixture was cooled to -5°C to 0°C. 2-((tetrahydro-2H-pyran-2-yl)oxy)ethane-1-ol (6.60 kg, 45.15 mol) was added dropwise over 1 h, and the resulting mixture was stirred at -5°C to 0°C for 1 h. 2,3-Difluoropyridine (4.0 kg, 34.76 mol) was added dropwise. The mixture was stirred for another 30 min, quenched with water (20 L), and extracted with ethyl acetate (2 x 20 L). The organic phase was washed with brine (20 L), dried over anhydrous Na₂SO₄, and concentrated. The crude product was purified by rapid chromatography (silica, heptane / ethyl acetate 10:1) to give the title compound (7.46 kg) as a yellow oil. 1H NMR (400MHz, CDCl3) δ7.89(dd,J=5.0,1.6Hz,1H),7.32(ddd,J=10.3,7.8,1.6Hz,1H),6.84(ddd,J=8.0,5.0,3.2Hz,1H),4.72(t,J=3.6Hz, 1H),4.64-4.53(m,2H),4.16-4.04(m,1H),3.96-3.81(m,2H),3.58-3 .46(m,1H),1.91-1.78(m,1H),1.77-1.67(m,1H),1.67-1.47(m,4H). UPLC-MS 5: HRMS m / z for C 12 H 17 FNO3[M+H] + The calculated value is 242.1187, and the measured value is 242.1182.

[1135] Step 2: 4-Chloro-3-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine(N-XXXI-b)

[1136] Compound 3-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine (N-XXXi-a) (3.60 kg, 14.92 mol) and THF (18 L) were charged into a reactor. The solution was cooled to -78 °C. n-BuLi (7.79 L, 19.40 mol, 2.5 M in hexane) was added dropwise, and the reaction was stirred at -78 °C for 4 h. C2Cl6 (4.59 kg, 19.40 mol) was added at -78 °C. The mixture was stirred for 30 min, quenched by adding water (18 L), stirred for another 2 h, and extracted with ethyl acetate (2 x 18 L). The organic phase was washed with brine (18 L), dried over anhydrous Na2SO4, and concentrated. The crude product was purified by rapid chromatography (silica, heptane / ethyl acetate 10:1) to give the title compound (3.74 kg) as a pale yellow oil. 1H NMR (400MHz, CDCl3) δ7.79 (dd, J=5.5, 1.0Hz, 1H), 6.91 (dd, J=5.4, 4.4Hz, 1H), 4.72 (t, J=3.6Hz, 1H), 4.58 (dt, J=6.0, 3.7Hz, 2H), 4.08 (dd d,J=11.5,5.6,3.9Hz,1H),3.94-3.80(m,2H),3.52(ddd,J=10.6,6.0,4.2Hz,1H),1.90-1.77(m,1H),1.77-1.67(m,1H),1.66-1.47(m,4H). UPLC-MS 5: HRMS m / z for C 12 H 15 ClFNNaO3[M+Na] + The calculated value is 298.0617, and the measured value is 298.0657.

[1137] Step 3: 4-Chloro-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinic acid (N-XXXI-c)

[1138] Diisopropylamine (1.91 kg, 18.88 mol) and THF (20 L) were charged into the reactor. n-BuLi (7.56 L, 18.88 mol, 2.5 M in hexane) was added dropwise at -78 °C. The mixture was stirred for 30 min, and 4-chloro-3-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine (N-XXXI-b) (4.00 kg, 14.51 mol) was added dropwise. The reaction was stirred for 3 h and poured into dry ice (12.8 kg). The mixture was stirred for 2 h. Water (16 L) was added, and the mixture was extracted with MTBE (20 L). The organic phase was washed with brine (4 L), and the combined aqueous phases were added to a mixture of ethyl acetate (40 L) and citric acid solution (3.77 kg citric acid dissolved in 22 L water). The mixture was stirred for 30 min, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (40 L). The combined organic phases were washed with brine (16 L), dried over anhydrous Na2SO4, and concentrated to give the title compound (3.68 kg) as a grayish-white solid. 1H NMR (400MHz, CDCl3) δ8.64(d,J=1.3Hz,1H),8.02(brs,1H),4.77(t,J=3.4Hz,1H),4.68(ddd,J=5.9,4.0,1.8Hz,2H ), 4.11(ddd,J=11.6,5.4,4.0Hz,1H),3.97-3.84(m,2H),3.62-3.53(m,1H),1.90-1.70(m,2H),1.68-1.49(m,4H). UPLC-MS 5: HRMS m / z for C 13 H 14 ClFNO5[MH] - The calculated value is 318.0550, and the measured value is 318.0482.

[1139] Step 4: 4-Chloro-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinic acid ester (N-XXXI)

[1140] K₂CO₃ (4.32 kg, 31.3 mol) and MeI (2.67 kg, 18.8 mol) were added to a solution of 4-chloro-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinic acid (N-XXXI-c) (4.00 kg, 12.5 mol) in DMF (20 L). The mixture was stirred overnight at RT. MTBE (40 L) and water (40 L) were added. The mixture was stirred for 10 min and the phases were separated. The organic phase was washed twice with water (40 L), dried over anhydrous Na₂SO₄, and concentrated. The crude product was purified by slurrying with n-heptane (4 L) to give the title compound (3.37 kg) as a colorless solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.51 (d, J = 1.2Hz, 1H), 4.64 (t, J = 2.9, 1H), 4.63–4.52 (m, 2H), 3.99–3.92 (m, 1H), 3.86 (s, 3H), 3.81–3.71 (m, 2H), 3.46–3.38 (m, 1H), 1.75–1.56 (m, 2H), 1.52–1.37 (m, 4H). UPLC-MS 5: HRMS m / z for C 14 H 18 ClFNO5[M+H] + The calculated value is 334.0852, and the measured value is 334.0823.

[1141] Synthesis of methyl 4-chloro-5-fluoro-6-(2-methoxyethoxy)nicotinate (N-XXXII)

[1142]

[1143] DEAD (2.54 g, 14.598 mmol) was added at 0 °C to a stirred solution of methyl 4-chloro-5-fluoro-6-hydroxynicotinic acid ester (N-XXX-b) (2.0 g, 9.7 mmol), 2-methoxyethane-1-ol (815 mg, 1.07 mmol), and triphenylphosphine (3.31 g, 12.7 mmol) in THF (40 mL), and stirring was continued at this temperature for 3 h. The reaction mixture was quenched with a saturated solution of NH4Cl and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (silica, hexane / EtOAc; gradient: 10% to 20% EtOAc) to give the title compound (3.0 g). 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.50 (d, J = 1.2Hz, 1H), 4.56-4.54 (m, 2H), 3.85 (s, 3H), 3.70-3.67 (m, 2H), 3.32 (s, 3H). (UPLC-MS m / z 264.3[M+H] + .

[1144] Synthesis of methyl(S)-2-bromo-3-fluoro-4-(2-hydroxypropoxy)benzoate (N-XXXIII)

[1145]

[1146] Pyridinium p-toluenesulfonate (10.28 g, 40.9 mmol) was added to a solution of methyl 2-bromo-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzoate (N-XXVIII) (8.0 g, 20.45 mmol) in EtOH (124 mL), and stirring was continued at RT for 16 h. The reaction mixture was quenched by adding a saturated solution of NaHCO3 and extracted with EtOAc. The combined organic layers were washed with a saturated solution of NaHCO3 (200 mL), dried over anhydrous Na2SO4, and concentrated. The crude product was purified by rapid chromatography (silica, cyclohexane / EtOAc; gradient: 5% to 40EtOAc) to give the title compound (5.50 g). 1H NMR (600MHz, DMSO-d6) δ7.69 (d, J = 8.7 Hz, 1H), 7.31 (t, J = 8.4 Hz, 1H), 4.99 (d, J = 3.8 Hz, 1H), 4.07-3.93 (m, 3H), 3.83 (s, 3H), 1.15 (d, J = 5-0 Hz, 3H).

[1147] Synthesis of methyl 2-bromo-3-fluoro-4-(2-hydroxyethoxy)benzoate (N-XXXIV)

[1148]

[1149] A solution of methyl 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate (N-XXVII) (1.00 g, 2.65 mmol) in HCl (6.63 mL, 26.5 mmol, 4 M in dioxane) was stirred at RT for 1 h. The reaction mixture was quenched by adding a saturated solution of NaHCO3 (100 mL) and extracted twice with EtOAc. The combined organic layers were washed with a saturated solution of NaHCO3 (100 mL), dried over anhydrous Na2SO4, and concentrated. The crude product was purified by rapid chromatography (silica, cyclohexane / EtOAc; gradient: 0% to 84% EtOAc) to give the title compound (694 mg) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ7.69 (d, J = 8.9 Hz, 1H), 7.32 (t, J = 8.5 Hz, 1H), 4.97 (t, J = 5.4 Hz, 1H), 4.18 (t, J = 4.9 Hz, 2H), 3.84 (s, 3H), 3.75 (q, J = 5.1 Hz, 2H).

[1150] Synthesis of methyl 4-chloro-5-fluoro-6-(2-hydroxyethoxy)nicotinate (N-XXXV)

[1151]

[1152] Under Ar and RT conditions, pyridinium p-toluenesulfonate (11.52 g, 45.8 mmol) was added to a solution of methyl 4-chloro-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate (N-XXXI) (7.65 g, 22.9 mmol) in EtOH (150 mL), and stirring was continued at RT for 16 h. The reaction mixture was quenched by adding a saturated solution of NaHCO3 (100 mL) and extracted twice with EtOAc. The combined organic layers were washed with a saturated solution of NaHCO3 (200 mL), dried over anhydrous Na2SO4, and concentrated. The crude product was purified by rapid chromatography (silica, cyclohexane / EtOAc; gradient: 0% to 76% EtOAc) to give the title compound (4.91 g) as a colorless powder. 1 H NMR (400MHz, DMSO-d6) δ8.52 (d, J = 1.3Hz, 1H), 4.94 (t, J = 5.5Hz, 1H), 4.51-4.42 (m, 2H), 3.87 (s, 3H), 3.76 (q, J = 5.3Hz, 2H). UPLC-MS1: m / z 250.3[MH] - ,t R =0.77min.

[1153] Intermediates used for the reductive amination of primary amines:

[1154] Synthesis of 4-(fluoromethyl)-4-hydroxycyclohexane-1-one (SI)

[1155]

[1156] Step 1: 8-(fluoromethyl)-1,4-dioxaspiro[4.5]decane-8-ol (SIa)

[1157] Under RT, towards 1,7,10-trioxadispiro[2.2.4] 6 .2 3 Dodecane (CAS 83365-44-0) (5.00 g, 29.40 mmol) was added to a stirred solution of toluene (200 mL) with TBAF (294 mL, 294 mmol, 1 M in THF), and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated and redissolved in EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated to give the title compound (3.00 g), which was used for the next step without further purification. 1H NMR (400MHz, DMSO-d6) δ (ppm) 4.59 (s, 1H), 4.12 (d, J = 48Hz, 2H), 3.84 (s, 4H), 1.76-1.72 (m, 2H), 1.55-1.46 (m, 6H).

[1158] Step 2: 4-(fluoromethyl)-4-hydroxycyclohexane-1-one (SI)

[1159] p-TsOH (0.815 g, 4.73 mmol) was added to a stirred solution of 8-(fluoromethyl)-1,4-dioxaspiro[4.5]decane-8-ol (SIa.) (3.00 g, 15.78 mmol) in acetone / H2O (2:1, 18 mL) under RT, and the reaction mixture was stirred under RT for 16 h. The reaction mixture was concentrated and redissolved in EtOAc. The organic layer was washed with a saturated solution of NaHCO3, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (silica, hexane / EtOAc 1:1) to give the title compound (1.30 g). 1 H NMR (400MHz, DMSO-d6) δ (ppm) 5.05 (s, 1H), 4.25 (d, J = 47.8Hz, 2H), 2.61-2.49 (m, 2H), 2.12-2.07 (m, 2H), 1.83-1.80 (m, 2H), 1.79-1.72 (m, 2H).

[1160] Synthesis of trans-4-(1H-tetrazol-1-yl)cyclohexylamine (S-II)

[1161]

[1162] Step 1: Benzyl (trans-4-(1H-tetrazole-1-yl)cyclohexyl)carbamate (S-II-a)

[1163] Under a nitrogen atmosphere, a suspension of benzyl (trans-4-aminocyclohexyl) carbamate (1500 mg, 5.27 mmol), triethyl orthocarbamate (25 mL, 5.27 mmol), Et3N (0.77 mL, 5.53 mmol), and acetic acid (1.96 mL, 34.2 mmol) was stirred for 45 min at 100 °C. Sodium azide (1.54 g, 23.7 mmol) was added dropwise at 50 °C, and stirring was continued at 100 °C for 20 h. The reaction mixture was quenched by adding a saturated solution of NaHCO3, and the resulting solid was collected by filtration and subsequently ground in Et2O / pentane (1:1) to give the title compound (1050 mg). UPLC-MS 1: m / z 302.3 [M+H] + ,t R =0.82min.

[1164] Step 2: trans-4-(1H-tetrazol-1-yl)cyclohexylamine (S-II)

[1165] Palladium (0.1 g, 10% palladium on activated carbon) was added to a solution of benzyl (trans-4-(1H-tetrazol-1-yl)cyclohexyl)carbamate (S-II-a) (1 g, 3.32 mmol) in MeOH (5 mL) under RT. The flask was evacuated and purged with hydrogen. The mixture was stirred at RT for 30 min. The solid was removed by filtration, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to give the desired product (540 mg). UPLC-MS 1: m / z 168.1 [M+H] + ,t R =0.18min.

[1166] Synthesis of trans-3-((difluoromethoxy)methyl)cyclobutamine (S-III)

[1167]

[1168] Step 1: tert-butyl (trans-3-(hydroxymethyl)cyclobutyl)carbamate (S-III-a)

[1169] At RT, a borane-methyl sulfide complex (1.16 mL, 2.323 mmol, 2 M in THF) was added to a stirred solution of trans-3-((tert-butoxycarbonyl)amino)cyclobutanecarboxylic acid (500 mg, 2.32 mmol) in 10 mL of THF, and the reaction mixture was stirred overnight under Ar. The reaction mixture was quenched with a saturated solution of NH4Cl and then extracted with TBME. The organic layers were combined, washed with a saturated solution of NaHCO3, dried over anhydrous Na2SO4, and concentrated to give the title compound (460 mg) as a colorless powder. MS: m / z 202.2.

[1170] Step 2: tert-butyl (trans-3-((difluoromethoxy)methyl)cyclobutyl)carbamate (S-III-b)

[1171] At RT, 2,2-difluoro-2-(fluorosulfonyl)acetic acid (0.077 mL, 0.745 mmol) was added to a suspension of tert-butyl (trans-3-(hydroxymethyl)cyclobutyl)carbamate (S-III-a) (100 mg, 0.497 mmol) and CuI (47.3 mg, 0.248 mmol) in ACN (2.5 mL), and the reaction mixture was stirred for 4 h. The reaction mixture was quenched with a saturated solution of NaHCO3 and extracted with EtOAc. The organic layers were combined, washed with a saturated solution of NaHCO3, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by rapid chromatography (silica, hexane / EtOAc, gradient: 0% to 30% EtOAc) to give the title compound (38 mg) as a colorless powder. 1 ¹H NMR (400MHz, chloroform-d) δ 6.21 (t, J = 74.8 Hz, 1H), 4.71 (s, 1H), 4.31–4.10 (m, 1H), 3.87 (d, J = 7.0 Hz, 2H), 2.61–2.36 (m, 1H), 2.29–2.14 (m, 2H), 2.10–1.94 (m, 2H), 1.43 (s, 9H).

[1172] Step 3: trans-3-((difluoromethoxy)methyl)cyclobutylamine (S-III)

[1173] At RT, HCl (2.5 mL, 9.85 mmol, 4 M in dioxane) was added to a solution of tert-butyl (trans-3-((difluoromethoxy)methyl)cyclobutyl)carbamate (S-III-b) (165 mg, 0.66 mmol) in 1,4-dioxane (2 mL), and the reaction mixture was stirred for 1 h. The reaction mixture was quenched with a saturated solution of NaHCO3 and extracted with TBME. The organic layers were combined, washed with a saturated solution of NaHCO3, dried over anhydrous Na2SO4, and concentrated to give the title compound (25 mg).

[1174] Synthesis of (1R,2R,4S)-4-amino-2-fluorocyclohexanol (S-IV)

[1175]

[1176] Step 1: Benzyl(1S,3S,6R)-7-oxabicyclo[4.1.0]heptane-3-ylcarbamate (S-IV-a1) and benzyl(1R,3R,6S)-7-oxabicyclo[4.1.0]heptane-3-ylcarbamate (S-IV-a2)

[1177] The racemic benzyl(1S*,3S*,6R*)-7-oxabicyclo[4.1.0]heptane-3-ylcarbamate (13.84 g) (Tetrahedron [tetrahedron] 2005, 61, 1207) was chirally separated (ChiralPak AY, 50×250 mm I.D., 10 μm hexane / IPA 80:20, 35 °C, flow rate: 30 mL / min) to obtain two enantiomers, benzyl(1S,3S,6R)-7-oxabicyclo[4.1.0]heptane-3-ylcarbamate (S-IV-a1) and benzyl(1R,3R,6S)-7-oxabicyclo[4.1.0]heptane-3-ylcarbamate (S-IV-a2), each having an enantiomer excess of >99%.

[1178] Benzyl(1S,3S,6R)-7-oxabicyclo[4.1.0]heptane-3-ylcarbamate (S-IV-a1) (6.03 g): Chiral SFC: (Chiralpak AY-H 150 x 4.6 mm ID, 5 μm, hexane / IPA 7:3, flow rate: 1 mL / min), t R =5.88min; UPLC-MS1: m / z 248.1[M+H] + ,t R =0.90min.

[1179] Benzyl(1R,3R,6S)-7-oxabicyclo[4.1.0]heptane-3-ylcarbamate (S-IV-a2) (6.20 g): Chiral SFC: (Chiralpak AY-H 150 x 4.6 mm ID, 5 μm, hexane / IPA 7:3, flow rate: 1 mL / min), t R =9.08min; UPLC-MS1: m / z 248.1[M+H] + ,t R =0.90min.

[1180] Step 2: Benzyl ((1S,3R,4R)-3-fluoro-4-hydroxycyclohexyl)carbamate (S-IV-b)

[1181] Triethylamine trihydrofluoride (1.65 mL, 10.1 mmol) was added to benzyl(1S,3S,6R)-7-oxabicyclo[4.1.0]heptane-3-ylcarbamate (S-IV-a1) (500 mg, 2.0 mmol) at RT, and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was quenched with a saturated solution of NaHCO3 and then extracted with DCM. The organic layers were combined, washed with a saturated solution of NaHCO3, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by SFC to give the title compound (364 mg) as a colorless oil. UPLC-MS 1: m / z 268.3 [M+H] + ,t R =0.82min.

[1182] Step 3: (1R,2R,4S)-4-amino-2-fluorocyclohexanol (S-IV)

[1183] Palladium (71.7 mg, 0.07 mmol, 10% palladium on activated carbon) was added to a solution of benzyl ((1S,3R,4R)-3-fluoro-4-hydroxycyclohexyl)carbamate (S-IV-b1) (360 mg, 1.35 mmol) in EtOH (19 mL) under RT. The flask was evacuated and purged with hydrogen. The mixture was stirred under RT for 20 h. The solid was filtered off, and the filter cake was washed with EtOH. The filtrate was concentrated under vacuum to give the desired product (190 mg). 1 H NMR (600MHz, DMSO-d6) δ4.96 (d, J = 3.3Hz, 1H), 4.68-4.48 (m, 1H), 3.53 (br s, 1H), 2.98 (br s, 1H), 1.93-1.52 (m, 6H), 1.48-1.35 (m, 2H).

[1184] Synthesis of (1S,2S,4R)-4-amino-2-fluorocyclohexanol (SV)

[1185]

[1186] The title compound was prepared from benzyl(1R,3R,6S)-7-oxabicyclo[4.1.0]heptane-3-ylcarbamate (S-IV-a2) in a manner similar to (1R,2R,4S)-4-amino-2-fluorocyclohexanol (S-IV). 1 H NMR(600MHz,DMSO-d6)δ5.09-4.90(m,1H),4.67-4.49(m,1H),3.70-3.48(m,1H),3.35(s,1H),2.98(br s,1H),1.77-1.52(m,5H),1.48-1.30(m,2H).

[1187] Intermediates used in the Suzuki cross-coupling reaction:

[1188] Synthesis of tert-butyl (S)-((5-chloro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (CI):

[1189]

[1190] Reaction scheme CI:

[1191]

[1192] Step 1: 2-(benzyloxy)-6-bromobenzaldehyde (CIa)

[1193] A solution of 2-bromo-6-fluorobenzaldehyde (CAS360575-28-6) (1500 g, 7.39 mol) in DMF (11.25 L), benzyl alcohol (1042 g, 9.64 mol), and Cs₂CO₃ (4840 g, 14.81 mol) in DMF was placed in a 20-L, 4-necked, round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred overnight at 80 °C. The reaction mixture was cooled to RT in a water bath and diluted with water. The solution was extracted with EtOAc, and the organic layers were combined. The resulting mixture was washed with brine, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was purified by rapid chromatography (silica, PE / EtOAc 40:1) to give the title compound (2150 g) as a colorless powder. 1H-NMR (400MHz, DMSO-d6) δ (ppm) 10.31 (s, 1H), 7.50-7.44 (m, 3H), 7.43-7.35 (m, 2H), 7.35-7.28, (m, 3H), 5.25 (s, 2H). UPLC-MS1: m / z291.2 / 293.1[M+H] +

[1194] Step 2 6-(benzyloxy)-2-bromo-3-chlorobenzaldehyde (CIb)

[1195] A solution of 2-(benzyloxy)-6-bromobenzaldehyde (CIa) (1004 g, 3.45 mol) in ACN (10 L), p-TsOH (658 g, 3.46 mol), and N-chlorosuccinimide (598 g, 4.5 mol) in ACN (10 L) was added to a 20 L 4-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred overnight at RT. The reaction mixture was then quenched by adding water / ice. The solids were collected by filtration. The filter cake was washed with water and PE to give the desired product (1786 g) as a pale yellow oil. 1 H-NMR (400MHz, DMSO-d6) δ (ppm) 10.24 (s, 1H), 7.80 (d, J = 8.8Hz, 1H), 7.54-7.23 (m, 6H), 5.26 (s, 2H). UPLC-MS1: m / z 325.0[M+H] +

[1196] Step 3 (6-(benzyloxy)-2-bromo-3-chlorophenyl)methanol (CIc)

[1197] A solution of 6-(benzyloxy)-2-bromo-3-chlorobenzaldehyde (CIb) (893 g, 2.74 mol) in THF (8 L) was placed in a 20 L 4-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. NaBH4 (105 g, 2.78 mol) was added in portions at 0 °C. The resulting solution was stirred at RT for 3 h. The reaction was repeated once. The reaction mixture was then quenched by adding acetone. The solution was diluted with water. The resulting solution was extracted with EtOAc, and the organic layers were combined. The mixture was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by rapid chromatography (silica, PE / EtOAc 20:1) to give the title compound (1496 g) as a colorless powder. 1H-NMR(400MHz,DMSO-d6)δ(ppm):7.50(dd,1H),7.48-7.43(m,2H),7.42-7.35(m, 2H),7.35-7.27(m,1H),7.12(d,1H),5.16(s,2H),4.94-4.86(m,1H),4.67(d,2H). UPLC-MS1: m / z 324.7[MH] -

[1198] Step 4 1-(benzyloxy)-3-bromo-2-(bromomethyl)-4-chlorobenzene (CId)

[1199] A solution of [6-(benzyloxy)-2-bromo-3-chlorophenyl]methanol (CIc) (1469 g, 4.48 mol) in DCM (12 L) and tetrabromomethane (2217 g, 6.69 mol) was added dropwise to a 20 L 4-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. Then, a solution of triphenylphosphine (1770 g, 6.75 mol) in DCM (3 L) was added dropwise with stirring at 0 °C. The resulting solution was stirred overnight at RT. The reaction mixture was diluted with EtOAc. The solids were removed by filtration, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure, and the crude product was purified by rapid chromatography (silica, PE / EtOAc 10:1) to give the desired product (1201 mg) as a colorless powder. 1 H-NMR (400MHz, DMSO-d6) δ (ppm) 7.59 (d, 1H), 7.51-7.46 (m, 2H), 7.43-7.29 (m, 3H), 7.19 (d, 1H), 5.25 (s, 2H), 4.77 (s, 2H).

[1200] Step 5 Methyl 3-(6-(benzyloxy)-2-bromo-3-chlorophenyl)-2-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propionate (CIf)

[1201] A solution of (CIe) (CAS 33973-12-5, according to Du, Wu; Hagmann, William K.; He, Shuwen; Lai, Zhong; Shah, Shrenik K.; Truong, Quang T. PCT International Application (2010), WO 2010083136 A1, of methyl mandelate and dihydropyran (774 g, 3.09 mol) in THF (9 L) was added dropwise at -78 °C, and the resulting reaction mixture was stirred at -70 °C for 1.5 h. A solution of 1-(benzyloxy)-3-bromo-2-(bromomethyl)-4-chlorobenzene (CId) (1201 g, 3.08 mol) in THF (3 L) was added dropwise at -78 °C. The reaction mixture was heated to RT and stirred for 3 h. The reaction was then quenched by adding an aqueous NH4Cl solution at -10 °C. The resulting solution was extracted with EtOAc, the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the title compound (1870 g) as a brown oil. UPLC-MS 1: m / z 557.2 / 559.2 [MH] - .

[1202] Step 6 : Methyl 3-(6-(benzyloxy)-2-bromo-3-chlorophenyl)-2-hydroxy-2-phenyl-propionate (CIg)

[1203] A solution of methyl 3-(6-(benzyloxy)-2-bromo-3-chlorophenyl)-2-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propionate (CIf) (935 g, 1.67 mol) in ACN (9 L) was placed in a 20 L 4-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. Hydrogen chloride (6 L, 2 N) was then added dropwise under RT. The resulting solution was stirred under RT for 3 h. The solid was collected by filtration, and the filter cake was washed with water and PE / EtOAc (8:1) to give the title compound (1100 g) as a pale yellow powder. 1 H-NMR (400MHz, DMSO-d6) δ (ppm) 7.52-7.18 (m, 11H), 6.95 (d, 1H), 5.60 (s, 1H), 5.07-4.84 (m, 2H), 3.94 (d, 1H), 3.65 (d, 1H), 3.46 (s, 3H). UPLC-MS1: m / z 475.1[M+H] + .

[1204] Step 7:Methyl 3-(2-bromo-3-chloro-6-hydroxyphenyl)-2-hydroxy-2-phenylpropionate (CIh)

[1205] A solution of methyl 3-[6-(benzyloxy)-2-bromo-3-chlorophenyl]-2-hydroxy-2-phenylpropionate (CIg) (100 g, 210.2 mmol) in MeOH / THF (5:1) (2 L) and Raney nickel (30 g) were added to a 3 L, four-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. The flask was evacuated and purged three times with nitrogen, followed by purging with hydrogen. The mixture was stirred at RT for 5 h. The reaction was repeated ten times. The solid was filtered off, and the filter cake was washed with MeOH. The filtrate was concentrated under vacuum to give the desired product (930 g) as a yellow oil. 1 H-NMR (400MHz, DMSO-d6) δ (ppm) 7.56-7.45 (m, 2H), 7.37-7.19 (m, 4H), 6.77 (d, 1H), 3.84 (d, 1H), 3.67-3.48 (m, 4H). UPLC-MS1: m / z383.1 / 385.1[MH] - .

[1206] Step 8: Methyl 4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (CIi)

[1207] A solution of methyl 3-(2-bromo-3-chloro-6-hydroxyphenyl)-2-hydroxy-2-phenylpropionate (CIh) (930 g, 2.41 mol) in THF (9 L) and triphenylphosphine (761 g, 2.90 mol) was placed in a 20-L 4-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. Then, DIAD (587 g, 2.91 mol) was added dropwise at 0 °C. The reaction solution was stirred for 3 h at RT. The solution was diluted with EtOAc and washed with brine. The organic phase was dried over anhydrous Na₂SO₄ and concentrated. The resulting crude product was purified by rapid chromatography (silica, PE / EtOAc, gradient: 0% to 5% EtOAc) to give the title compound (582 g) as a colorless powder. 1 H-NMR (300MHz, CDCl3) δ (ppm) 7.55-7.58 (m, 2H), 7.40-7.43 (m, 3H), 7.25-7.37 (m,1H),6.88-6.91(m,1H),4.18-4.23(m,1H),3.77(s,3H),3.53-3.59(m,1H). UPLC-MS1: m / z365.1 / 367.0[MH] - .

[1208] Step 9: 4-Bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylic acid (CIj)

[1209] At RT, NaOH (3.5 L, 2 N) was added to a solution of methyl 4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (CIi) (520 g, 1.414 mol) in MeOH / THF (1:1, 6 L). The clarified solution was stirred at RT for 15 min. The reaction mixture was concentrated under reduced pressure, and the resulting residue was partitioned between DCM (4 L) and water (2 L). The aqueous phase was adjusted to pH 2 with 2 N HCl and extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (474 ​​g) as a colorless powder. 1 H-NMR (400MHz, DMSO-d6) δ (ppm) 7.61-7.49 (m, 2H), 7.49-7.31 (m, 4H), 7.03 (d, 1H), 4.05 (d, 1H), 3.55 (d, 1H). UPLC-MS1: m / z 351.0 / 353.0[MH] - ,t R =1.09min.

[1210] Step 10: (1R,2R)-2-amino-1-(4-nitrophenyl)propane-1,3-diol (S)-4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (CIk) and (R)-4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran carboxylic acid (CIl)

[1211] 4-Bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylic acid (CIj) (470 g, 1.33 mol) and (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (Aldrich Nr: A7,070-4) (282 g, 1.33 mol) were suspended in MeOH (5.310 L) and heated to 80 °C. After 30 min, the clear solution was slowly cooled to RT. The resulting white suspension was stirred overnight at RT. The solid was collected by filtration, washed with mother liquor (500 mL), and dried under vacuum at 30 °C to give the salt (1R,2R)-2-amino-1-(4-nitrophenyl)propane-1,3-diol(S)-4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (CIk) (340 g), which had an enantiomer excess of >99%. UPLC-MS 1: m / z 351.0 / 353.0 [MH] - ,t R = 1.10 min and 213.1 [M+H] + ,t R =0.33 min. Chiral HPLC: (Chiralpak AD-H, heptane / EtOH / MeOH 90 / 6 / 4 + 0.05% TFA, flow rate 1 mL / min), t R =13.00 min. The opposite enantiomer (R)-4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylic acid (CIl) was retained in the mother liquor. Chiral HPLC: (Chiralpak AD-H, heptane / EtOH / MeOH 90 / 6 / 4 + 0.05% TFA, flow rate: 1 mL / min), t R =10.03min.

[1212] Step 11: (S)-4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylic acid (CIm)

[1213] (1R,2R)-2-amino-1-(4-nitrophenyl)propane-1,3-diol(S)-4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (CIk) (340 g, 601 mmol) was suspended in EtOAc (4.5 L) and stirred at RT. 2 NHCl (750 mL) and water were added. The layers were separated. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give the title compound (202 g). UPLC-MS 1: m / z 351.1 / 353.1 [MH] - ,t R= 1.10 min. The absolute configuration (S) is determined by the X-ray crystal structure.

[1214] Step 12: (S)-4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxamide (CIn)

[1215] A solution of (S)-4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylic acid (CIm) (180 g, 499 mmol) in DCM (2 L) was cooled to 0 °C. The clear yellow solution was treated with DMF (1 mL). Oxaloyl chloride (56.2 mL, 655 mmol) was added via a dropping funnel over a period of 10 min. The resulting mixture was heated to RT and stirred at RT for 4.5 h. The solution was then added to a 25% ammonia solution via a dropping funnel at 0 °C for 45 min. The resulting emulsion reaction mixture was heated to RT with stirring. The organic phase was separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with water and dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (168 g). 1 H-NMR (400MHz, DMSO-d6) δ (ppm) 7.81 (s, 1H), 7.63-7.48 (m, 3H), 7.48-7.28 (m, 4H), 6.99 (d, 1H), 4.04 (d, 1H), 3.42 (d, 1H). UPLC-MS1: m / z352.0 / 353.9[M+H] + ,t R =1.15min.

[1216] Step 13: (S)-(4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methylamine (CIo)

[1217] (S)-4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxamide (CIn) (163 g, 462 mmol) was dissolved in THF (2.6 L) at RT. Borane dimethyl sulfide complex (925 mL, 1849 mmol, 2 M in THF) was added via a dropping funnel at RT for 45 min. The reaction mixture was stirred for another 60 min and then heated to gentle reflux for 3 h. The reaction mixture was cooled to RT and stirred overnight. MeOH was added dropwise at RT for 60 min, and stirring continued at RT for 45 min. Then, 1 N HCl was added dropwise, followed by stirring at RT for another 3.5 h. Finally, 1 N NaOH was carefully added, followed by a saturated NaHCO3 solution. The reaction mixture was diluted with DCM, and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (154 g). 1 H-NMR (400MHz, DMSO-d6) δ (ppm) 7.52-7.19 (m, 6H), 6.92 (d, 1H), 3.80 (d, 1H), 3.16 (d, 1H), 2.96 (s, 2H), 1.65 (s, 2H). UPLC-MS1: m / z 338.0 / 340.0[M+H] + ,t R =0.83min.

[1218] Step 14 (S)-tert-butyl((4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (CIp)

[1219] (S)-(4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methylamine (CIo) (133 g, 255 mmol) was dissolved in DCM (1.2 L). The solution was cooled to 0 °C, and Boc₂O (58.5 g, 268 mmol) in DCM (200 mL) was added via a dropping funnel over 25 min. The reaction mixture was stirred at RT for another 3 h, then concentrated to ca. 300 mL and diluted with EtOAc. The organic layer was extracted with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by rapid chromatography (silica, cyclohexane / EtOAc 9:1) to give the title compound (113 g) as a colorless solid. 1H-NMR (400MHz, DMSO-d6) δ (ppm) 7.49-7.26 (m, 6H), 7.12 (t, 1H), 6.90 (d, 1H), 3.73 (d, 1H), 3.58-3.31 (m, 2H), 3.23 (d, 1H), 1.27 (s, 9H). UPLC-MS1: m / z 436.0 / 438.2[MH] - ,t R = 1.45min.

[1220] Step 15: (S)-tert-butyl((5-chloro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (CI)

[1221] Under Ar conditions, (S)-tert-butyl((4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (CIp) (29 g, 66 mmol), bis(pinacol)diboron (25 g, 99 mmol), and KOAc (19.5 g, 198 mmol) were dissolved in toluene (116 mL). The reaction mixture was heated to 80 °C, and then PdCl2(dppf)*CH2Cl2 (5.4 g, 6.6 mmol) was added and heating was continued overnight at 110 °C. The reaction mixture was cooled to RT, filtered through Hyflo, and concentrated. The crude product was purified by rapid chromatography (silica, cyclohexane / EtOAc, gradient 0% to 20% EtOAc) to give the title compound (25.1 g). 1 H-NMR (400MHz, DMSO-d6) δ (ppm) 7.42-7.31 (m, 4H), 7.29-7.23 (m, 1H), 7.11 (d, J = 8.6Hz, 1H), 7.08-7.01 (m, 1H), 6.90 (d, J = 8.2Hz, 1H), 3.66 (d, J = 17.2Hz, 1H), 3.56-3.47 (m, 1H), 3.38-3.30 (m, 1H), 3.61-3.30 (m, 2H), 3.18 (d, J = 16.4Hz, 1H), 1.30-1.24 (m, 21H). UPLC-MS1: m / z 486.2[M+H] + ,t R =1.49min.

[1222] Synthesis of tert-butyl ((5-chloro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-II):

[1223]

[1224] The racemic title compound was prepared in a manner similar to tert-butyl(S)-((5-chloro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (CI) without enantiomeric resolution. 1 H-NMR(600MHz,DMSO-d6)δ(ppm)7.44-7.37(m,4H),7.33-7.29(m,1H),7.17-7.12(m,2H),6.94(d,J=8.4Hz,1 H), 3.70 (d, J = 16.5Hz, 1H), 3.58-3.53 (m, 1H), 3.39-3.35 (m, 1H), 3.22 (d, J = 16.9Hz, 1H), 1.34-1.28 (m, 21H). UPLC-MS1: m / z486.2[M+H] + ,t R =1.52min.

[1225] Synthesis of tert-butyl ((5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2-(thiazo-4-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-III):

[1226]

[1227] Reaction scheme C-III:

[1228]

[1229] Step 1: 3-Bromo-2-(bromomethyl)-4-chlorophenol (C-III-a)

[1230] BBr3 (56.3 mL, 56.3 mmol) was added to a stirred solution of 1-(benzyloxy)-3-bromo-2-(bromomethyl)-4-chlorobenzene (CId) (20 g, 51.2 mmol) in DCM (200 mL) at -78 °C under Ar conditions. The reaction mixture was stirred at -78 °C for 2 h. The reaction mixture was quenched with MeOH (20 mL) and concentrated. The crude product was purified by rapid chromatography (silica, heptane / EtOAc, gradient: 0% to 30% EtOAc) to give the title compound (14.64 g) as a brown powder. 1HNMR (400MHz, CDCl3) δ7.30 (t, J = 8.6 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 5.45 (s, 1H), 4.77 (s, 2H).

[1231] Step 2: Methyl 2-acetyl-4-bromo-5-chloro-2,3-dihydrobenzofuran-2-carboxylate (C-III-b)

[1232] Methyl 2-chloroacetoacetate (4.06 mL, 33.3 mmol) and TEA (9.74 mL, 70 mmol) were added to a stirred solution of 3-bromo-2-(bromomethyl)-4-chlorophenol (C-III-a) (10 g, 33.3 mmol) in ACN (100 mL) under RT and Ar conditions. The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with a saturated solution of NaHCO3 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (silica; cyclohexane / EtOAc; gradient 0% to 30% EtOAc) to give the title compound (8.26 g) as a colorless powder. UPLC-MS 1: t R =1.17min.

[1233] Step 3: Methyl 4-bromo-2-(2-bromoacetyl)-5-chloro-2,3-dihydrobenzofuran-2-carboxylate (C-III-c)

[1234] Under RT and Ar conditions, Br2 (1.403 mL, 27.2 mmol) was added to a solution of methyl 2-acetyl-4-bromo-5-chloro-2,3-dihydrobenzofuran-2-carboxylate (C-III-b) (8.26 g, 24.76 mmol) in CHCl3 (75 mL). The reaction mixture was stirred for 5 h, then diluted with a saturated solution of NaHCO3 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (silica; cyclohexane / EtOAc; gradient 0% to 20% EtOAc) to give the title compound (9.26 g) as a colorless powder. UPLC-MS 1: t R =1.21.

[1235] Step 4: Methyl 4-bromo-5-chloro-2-(thiazo-4-yl)-2,3-dihydrobenzofuran-2-carboxylate (C-III-d)

[1236] Under Ar conditions, phosphorus pentasulfide (1.846 g, 8.31 mmol) was added to a solution of methyl 4-bromo-2-(2-bromoacetyl)-5-chloro-2,3-dihydrobenzofuran-2-carboxylate (C-III-c) (9.26 g, 22.45 mmol) and formamide (1.790 mL, 44.9 mmol) in dioxane (50 mL). The reaction mixture was stirred at 100 °C for 60 min. The reaction mixture was diluted with a saturated solution of NaHCO3 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (silica; cyclohexane / EtOAc; gradient 0% to 80% EtOAc) to give the title compound (6.98 g) as a yellow powder. UPLC-MS 1: m / z 375.9 [M+H] + ,t R =1.14min.

[1237] Step 5: (4-Bromo-5-chloro-2-(thiazo-4-yl)-2,3-dihydrobenzofuran-2-yl)methanol(C-III-e)

[1238] Under Ar conditions and at 0 °C, LiBH4 (0.812 g, 37.3 mmol) was added fractionally to a stirred solution of methyl 4-bromo-5-chloro-2-(thiazolyl-4-yl)-2,3-dihydrobenzofuran-2-carboxylate (C-III-d) (6.98 g, 18.6 mmol) in a mixture of THF (70 mL) and MeOH (3.0 mL, 74.5 mmol). The resulting suspension was stirred at RT for 10 min. The reaction mixture was diluted with a saturated solution of NH4Cl and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (silica; cyclohexane / EtOAc; gradient 0% to 85% EtOAc) to give the title compound (6.08 g) as a colorless powder. UPLC-MS 1: m / z 348.0 [M+H] + ,t R =1.01min.

[1239] Step 6: (4-Bromo-5-chloro-2-(thiazo-4-yl)-2,3-dihydrobenzofuran-2-yl)methylmethanesulfonate (C-III-f)

[1240] At 0 °C and under Ar, methanesulfonic anhydride (2.412 g, 13.85 mmol) and TEA (4.83 mL, 34.6 mmol) were added fractionally to a stirred solution of (4-bromo-5-chloro-2-(thiazolyl-4-yl)-2,3-dihydrobenzofuran-2-yl)methanol (C-III-e) (2.40 g, 6.92 mmol) in DCM (50 mL). The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with brine and extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (silica; cyclohexane / EtOAc; gradient 0% to 93% EtOAc) to give the title compound (2.85 g). UPLC-MS 1: m / z 426.0 [M+H] + ,t R =1.12min.

[1241] Step 7: 4-(2-(azidomethyl)-4-bromo-5-chloro-2,3-dihydrobenzofuran-2-yl)thiazole (C-III-g)

[1242] Sodium azide (2.181 g, 33.6 mmol) was added to a stirred solution of (4-bromo-5-chloro-2-(thiazolyl-4-yl)-2,3-dihydrobenzofuran-2-yl)methylmethanesulfonate (C-III-f) (2.85 g, 6.71 mmol) in DMF (50 mL) under Ar conditions. The reaction mixture was stirred at 130 °C for 20 h. The reaction mixture was diluted with a saturated solution of NaHCO3 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (silica; cyclohexane / EtOAc; gradient 0% to 30% EtOAc) to give the title compound (1.90 g) as a colorless powder. UPLC-MS 1: m / z 373.1 [M+H] + ,t R =1.28min.

[1243] Step 8: (4-Bromo-5-chloro-2-(thiazo-4-yl)-2,3-dihydrobenzofuran-2-yl)methylamine (C-III-h)

[1244] Under Ar conditions and at 0 °C, NaBH4 (1.934 g, 51.1 mmol) was added in portions to a stirred solution of 4-(2-(azidomethyl)-4-bromo-5-chloro-2,3-dihydrobenzofuran-2-yl)thiazole (C-III-g) (1.9 g, 5.11 mmol) in a mixture of THF (40 mL) and MeOH (4.1 mL, 102 mmol). The resulting suspension was stirred at 70 °C for 16 h. The reaction mixture was diluted with a saturated solution of NaHCO3 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (silica; DCM / MeOH; gradient: 0% to 10% MeOH) to give the title compound (1.30 g) as a colorless oil. UPLC-MS 1: m / z 347.0 [M+H] + ,t R =0.66min.

[1245] Step 9: tert-butyl ((4-bromo-5-chloro-2-(thiazo-4-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-III-i)

[1246] Boc-anhydride (0.961 mL, 4.14 mmol) was added to a stirred solution of (4-bromo-5-chloro-2-(thiazolyl-4-yl)-2,3-dihydrobenzofuran-2-yl)methylamine (C-III-h) (1.3 g, 3.76 mmol) in DCM (40 mL) at RT, and stirring was continued at RT for 2 h. The reaction mixture was diluted with brine and extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (silica; cyclohexane / EtOAc; gradient 0% to 70% EtOAc) to give the title compound (1.36 g) as a colorless powder. UPLC-MS 1: m / z 447.1 [M+H] + ,t R =1.29min.

[1247] Step 10: tert-butyl ((5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2-(thiazo-4-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-III)

[1248] A deoxygenated suspension of tert-butyl ((4-bromo-5-chloro-2-(thiazolyl-4-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-III-i) (1.36 g, 3.05 mmol), bis(pinacol)diboron (1.55 g, 6.1 mmol), KOAc (0.898 g, 9.15 mmol), and PdCl2(dppf).CH2Cl2 adduct (0.249 g, 0.305 mmol) in DMSO (400 mL) was stirred at 120 °C under an Ar atmosphere for 16 h. The reaction mixture was diluted with a saturated solution of NaHCO3 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (silica; cyclohexane / EtOAc; gradient 0% to 70% EtOAc) to give the racemic title compound (1.02 g) as a colorless powder. UPLC-MS 1: m / z 493.3 [M+H] + ,t R =1.37min.

[1249] Synthesis of tert-butyl ((5-chloro-2-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-IV):

[1250]

[1251] The racemic title compound was prepared in a manner similar to tert-butyl(S)-((5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XII) from 2-bromo-3-chloro-6-hydroxybenzaldehyde (C-VI-a) and 2-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)acetonitrile (synthesized as follows: reduction of 2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-carboxaldehyde to the corresponding alcohol, followed by benzylchloroconversion to the corresponding nitrile), without enantiomeric resolution. UPLC-MS 1: m / z 610.4 [M+carbamate] - ,t R =1.56min.

[1252] Synthesis of tert-butyl (S)-((5-chloro-2-(2-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (CV):

[1253]

[1254] CV of the reaction scheme:

[1255]

[1256] Similar to C-XVII-c (synthetic intermediate C-XVII step 3), (2R,5R)-5-(6-(benzyloxy)-2-bromo-3-chlorobenzyl)-2-(tert-butyl)-5-(2-fluorophenyl)-1,3-dioxolane-4-one (CVa) was synthesized from 1-(benzyloxy)-3-bromo-2-(bromomethyl)-4-chlorobenzyl)-2-(tert-butyl)-5-(2-fluorophenyl)-1,3-dioxolane-4-one (CVa) using LDA instead of NaH as the base.

[1257] Step 1 (2R,5R)-5-(2-bromo-3-chloro-6-hydroxybenzyl)-2-(tert-butyl)-5-(2-fluorophenyl)-1,3-dioxolane-4-one (CVb)

[1258] Ra-Ni (2.66 g, 31.1 mmol) was added to a solution of (2R,5R)-5-(6-(benzyloxy)-2-bromo-3-chlorobenzyl)-2-(tert-butyl)-5-(2-fluorophenyl)-1,3-dioxolane-4-one (CVa) (15.49 g, 28.3 mmol) in MeOH (225 mL) and THF (45 mL), and stirred for 43 h under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated. The residue was purified by rapid chromatography (silica, hexane / EtOAc 9:1) to give the title compound (11.47 g). UPLC-MS 1: m / z 455.0 / 457.0 [MH] - ,t R =1.37min.

[1259] Step 2 : Methyl(R)-3-(2-bromo-3-chloro-6-hydroxyphenyl)-2-(2-fluorophenyl)-2-hydroxypropionate (CVc)

[1260] Sodium methoxide (5.70 mL, 24.9 mmol, 25% in MeOH) was added to a solution of (2R,5R)-5-(2-bromo-3-chloro-6-hydroxybenzyl)-2-(tert-butyl)-5-(2-fluorophenyl)-1,3-dioxolane-4-one (CVb) (11.4 g, 24.9 mmol) in MeOH (60 mL), and stirring was continued at this temperature for 2 h. A saturated solution of NH4Cl was added, and the mixture was extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4 and concentrated, and the residue was purified by rapid chromatography (silica, hexane / EtOAc 2:1) to give the title compound (9.06 g). UPLC-MS 1: m / z 401.0 / 402.9 [MH] - ,t R =1.14min.

[1261] Step 3 Methyl(S)-4-bromo-5-chloro-2-(2-fluorophenyl)-2,3-dihydrobenzofuran-2-carboxylate (CVd)

[1262] At 0 °C, PPh3 (7.06 g, 26.9 mmol) and subsequently DIAD (5.23 mL, 26.9 mmol) were added to a solution of methyl(R)-3-(2-bromo-3-chloro-6-hydroxyphenyl)-2-(2-fluorophenyl)-2-hydroxypropionate (CVc) (9.06 g, 22.4 mmol) in THF (215 mL). The cooling bath was removed, and the reaction mixture was stirred at RT for 22 h. The reaction mixture was concentrated, and the residue was purified by rapid chromatography (silica, hexane / EtOAc 95:5) to give the title compound (7.76 g). UPLC-MS 1: m / z 383.0 / 385.0 [MH] - ,t R =1.37min.

[1263] (S)-((5-chloro-2-(2-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)- 2,3-Dihydrobenzofuran-2-yl)methyl)carbamate (CV):

[1264] The title compound was synthesized from methyl(S)-4-bromo-5-chloro-2-(2-fluorophenyl)-2,3-dihydrobenzofuran-2-carboxylate (CVd) according to the procedure described for the synthesis of intermediate C-XXV. The borate ester was synthesized in the final step, as described for intermediate CI. 1H-NMR(600MHz,DMSO-d6)δ(ppm)7.51(t,J=7.7Hz,1H),7.43-7.33(m,1H),7.27-7.21(m,1H),7.20-7.13(m,2H),7.13-7.08(m,1H),6.94(d,J=8.4H z,1H),3.70(d,J=17.1Hz,1H),3.60(dd,J=14.3,6.3Hz,1H),3.39(dd,J=1 4.5, 6.5Hz, 1H), 3.28 (d, J = 17.3Hz, 1H), 1.34-1.19 (m, 12H), 1.15 (s, 9H). UPLC-MS1: m / z 504.2[M+H] + ,t R =1.52min.

[1265] Synthesis of tert-butyl (((2S,3S)-5-chloro-3-hydroxy-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-VI):

[1266]

[1267] Reaction scheme C-VI:

[1268]

[1269] Step 1: 2-Bromo-3-chloro-6-hydroxybenzaldehyde (C-VI-a)

[1270] Thionyl chloride (101.2 g, 0.75 mol) was added to a solution of 2-bromo-6-hydroxybenzaldehyde (CAS22532-61-2) (100 g, 0.5 mol) in ACN (500 mL) at 0 °C, and stirring was continued overnight at 0 °C. The solid was collected by filtration, washed with a saturated solution of NaHCO3, and dried at HV to give the title compound (200 g). UPLC-MS 1: m / z 232.9 / 234.9 [MH] - .t R =1.09min.

[1271] Step 2: (2S*,3S*)-4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carboxynitrile (C-VI-b) and (2R*,3S*)-4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carboxynitrile (C-VI-c)

[1272] At RT, DIPEA (8.34 mL, 47.8 mmol) was added to a stirred solution of 2-bromo-3-chloro-6-hydroxybenzaldehyde (C-VI-a) (7.5 g, 31.9 mmol) and 2-bromo-2-phenylacetonitrile (CAS 5798-79-8) (6.24 g, 31.9 mmol) in DCM (159 mL), and the reaction mixture was stirred at RT for 2 days to obtain a brown solution. The reaction mixture was diluted with DCM and water, extracted twice with DCM, and the combined organic extracts were washed with water and brine, dried (using a phase separator), and concentrated. The racemic diastereomers (2S*,3S*)-4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carboxynitrile (C-VI-b) (6.4 g) and (2R*,3S*)-4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carboxynitrile (C-VI-c) (1.1 g) with cis and trans configurations were separated by rapid chromatography (silica, cyclohexane / EtOAc; gradient 0% to 20% EtOAc).

[1273] (2S*,3S*)-4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carboxynitrile (C-VI-b): 1 H-NMR (400MHz, DMSO-d6) δ7.65 (d, J = 8.8 Hz, 1H), 7.58-7.40 (m, 6H), 7.24 (d, J = 8.9 Hz, 1H), 5.27 (d, J = 7.7 Hz, 1H). UPLC-MS1: m / z 348.0 / 350.0[MH] - .t R =1.14min.

[1274] (2R*,3S*)-4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carboxynitrile (C-VI-c): 1 H-NMR (400MHz, DMSO-d6) δ7.69 (d, J = 8.6 Hz, 1H), 7.65-7.44 (m, 5H), 7.29 (d, J = 8.6 Hz, 1H), 6.46 (d, J = 8.6 Hz, 1H), 5.50 (d, J = 8.5 Hz, 1H). UPLC-MS1: m / z 348.0 / 350.0[MH] - ,t R =1.14min.

[1275] Step 3:(2S,3S)-4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carboxynitrile (C-VI-d) and (2R,3R)-4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carboxynitrile (C-VI-e)

[1276] The racemic mixture (2S*,3S*)-4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carboxynitrile (C-VI-b) (21.9 g) was separated by chiral SFC (Sepiatec Prep SFC 100 and Jasco Prep SFC, column: Chiralpak OJ-H 5 μm, 250 x 30 mm, 40 °C, 3 mL / injection, 170 injections, CO2 / IPA). (9:1, flow rate: 80 mL / min, circulation time: 15 min) to obtain (2S,3S)-4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carboxynitrile (C-VI-d) (9.35 g) and (2R,3R)-4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carboxynitrile (C-VI-e) (9.30 g), each having an enantiomer excess of >98%.

[1277] (2S,3S)-4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carboxynitrile (C-VI-d):

[1278] Chiral SFC: (Chiralpak OJ-H 5μm 100x 4.6mm, CO2 / IPA 8:2, flow rate: 3mL / min), t R =2.38 min; UPLC-MS1: m / z 394.1 / 396.1 [M+ formate] - ,t R =1.14min.

[1279] (2R,3R)-4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carboxynitrile (C-VI-e):

[1280] Chiral SFC: (Chiralpak OJ-H 5μm 100x 4.6mm, CO2 / IPA 8:2, flow rate: 3mL / min), t R =1.82 min; UPLC-MS1: m / z 394.1 / 396.1 [M+ formate] - ,t R =1.14min.

[1281] The absolute configuration of the intermediate (2R,3R) was confirmed by X-ray crystal structure of (2R,3R)-2-(aminomethyl)-5-chloro-2,4-diphenyl-2,3-dihydrobenzofuran-3-ol (which was synthesized from (2R,3R)-4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carboxynitrile (C-VI-e) by reducing the nitrile to an amine (using...

Claims

1. A compound having formula (IV) or a salt thereof in R a is selected from: (i) a halide, such as a bromide or an iodide (preferably a bromide); and (ii) B(R' a )2, where each R' a is a hydroxyl group, or two R' a The groups together with the boron to which they are attached form a pinacol borate moiety having the formula: Q1 is selected from: (i) -C(R 7 )2-R b and (ii) a 9- or 10-membered partially saturated heteroaryl group containing at least one N heteroatom; and (iii) a 4-, 5- or 6-membered saturated heterocycle containing at least one heteroatom or heteroatom group selected from N, O, S, -S(=O) and -S(=O)2, provided that at least one N heteroatom is present, the N heteroatom is optionally substituted with a protecting group, wherein the heterocycle is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy, C1-C3 alkyl, C1-C3 alkoxy, halo and C1-C3 alkylene, which form a bridge between two ring atoms of the saturated heterocycle, thereby forming a bridged bicyclic structure; R b Selected from: (i) hydroxyl; (ii) N(R 8 )-R b ’ ; (iii) an azido group, R b ’ Selected from: (i) nitrogen protecting groups; (ii) C3-C6 cycloalkyl, which is optionally substituted one or more times independently by: hydroxy; hydroxy C1-C4 alkyl; C1-C6 alkoxy (preferably C1-C4 alkoxy); C(O)OC1-C3 alkyl; CO2H; SO2C1-C3 alkyl; halogenated C1-C3 alkyl; NHR 1b ; (CH2) 0-1 C(O)NR 1c R 1d ; C1-C6 alkyl; halo C1-C3 alkoxy-C1-C3 alkyl; halo; a 5-membered or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O, and S; or 2 R 1e Group, These two R 1e The groups are attached to the same carbon atom and together with the carbon atom to which they are attached form a 5-membered saturated heterocyclic ring containing at least one heteroatom selected from N and O, or a C3-C6 cycloalkyl group, said saturated heterocyclic ring or cycloalkyl group being optionally substituted by: hydroxy or oxo; R 1b Selected from: (i) C(O)C1-C3 alkyl; and (ii) SO2C1-C3 alkyl; R 1c and R 1d Each independently selected from: (i) hydrogen; (ii) C1-C3 alkyl; and (iii) hydroxy C1-C4 alkyl; R2 is selected from: (i) hydrogen; and (ii) halo; R3 is selected from: (i) halo; (ii) halo C1-C3 alkyl; and (iii) cyano; R 7 Each independently selected from hydrogen and C1-C3 alkyl; R 8 is hydrogen or C1-C3-alkyl; A is selected from (i) phenyl, said phenyl being optionally substituted by: halo; or halo C1-C3 alkoxy; (ii) a 5- or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O, and S, the aromatic heterocyclic ring being optionally substituted by: hydroxy; C1-C3 alkoxy; or oxo; and (iii) a halogenated benzodioxole moiety having the formula: W is selected from O; and CH-R w ; R w Selected from: (i) hydrogen; (ii) hydroxy; (iii) C1-C3 alkoxy; (iv) hydroxy-C1-C3 alkyl; (v) C1-C3 alkyl; and (vi) C1-C3 alkoxy-C1-C3 alkyl; Y is selected from CH; and N; and Z is selected from CH2; O; and NH.

2. The compound of formula (IV) or a salt thereof according to claim 1, wherein the compound has formula (IV-I) Among them, R2, R3, R a , A, W, Y, Z and Q1 are as defined in claim 1.

3. The compound of formula (IV) or a salt thereof according to claim 1, wherein the compound has formula (IV-II): Among them, R2, R3, R w , A and Q1 as defined in claim 1; Each R' a is a hydroxyl group, or two R' a The groups together with the boron to which they are attached form a pinacol borate moiety having the formula:

4. The compound of formula (IV) or a salt thereof according to claim 1, wherein the compound has formula (IV-III): Among them, R2, R3, R w , A and Q1 as defined in claim 1; Each R' a is a hydroxyl group, or two R' a The groups together with the boron to which they are attached form a pinacol borate moiety having the formula 5. The compound of formula (IV) according to claim 1 or a salt thereof, selected from the group consisting of: tert-Butyl (S)-((5-chloro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate; tert-Butyl ((5-chloro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate; tert-Butyl ((5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(thiazol-4-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate; tert-Butyl-((5-chloro-2-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate; tert-Butyl (S)-((5-chloro-2-(2-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate; tert-Butyl (((2S,3S)-5-chloro-3-hydroxy-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate; tert-Butyl (((2R*,3S*)-5-chloro-3-hydroxy-2-(pyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate; tert-Butyl (((2S*,3S*)-5-chloro-3-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate; tert-Butyl (((2R*,3S*)-5-chloro-3-hydroxy-2-(6-methoxypyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate; ((2S*,3S*)-2-(((tert-Butyloxycarbonyl)amino)methyl)-5-chloro-3-hydroxy-2-(2-methoxypyridin-3-yl)-2,3-dihydrobenzofuran-4-yl)boronic acid; tert-Butyl (((2S,3S)-5-chloro-3-methyl-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate; tert-Butyl (S)-((5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate; (S)-(5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methanol; tert-Butyl (((2S,3S)-5-chloro-6-fluoro-3-hydroxy-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate; tert-Butyl (((2S,3S)-5-chloro-6-fluoro-3-methoxy-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate; tert-Butyl (((2S,3S)-5-chloro-6-fluoro-3-methyl-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate; ((2S,3S)-5-chloro-6-fluoro-3-methyl-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methanol; tert-Butyl (((2R,3S)-5-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate; ((2S,3S)-2-(6-(Benzyloxy)pyridin-2-yl)-5-chloro-6-fluoro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methanol; (trans)-4-((((2R,3S)-5-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)amino)-1-methylcyclohexane-1-ol; (trans)-4-((((2S,3S)-5-chloro-6-fluoro-3-methyl-2-(pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)amino)-1-methylcyclohexane-1-ol; tert-Butyl (S)-((2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate; (S)-2-(Hydroxymethyl)-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-5-carbonitrile; (S)-4-bromo-2-((((trans)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-5-carbonitrile; Tert-butyl (S)-((4-bromo-5-chloro-2-phenyl-2,3-dihydrofuro[2,3-b]pyridin-2-yl)methyl)carbamate tert-Butyl ((6-chloro-2-phenyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate; tert-Butyl ((4-bromo-5-chloro-2-phenylbenzo[d][1,3]dioxol-2-yl)methyl)carbamate (S)-2-(Azidomethyl)-4-bromo-5-chloro-6-fluoro-2-phenylindoline; tert-Butyl (((2S,3S)-5-chloro-6-fluoro-3-methyl-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate; tert-Butyl (((2S,3R)-5-chloro-6-fluoro-3-(methoxymethyl)-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate; tert-Butyl (((2S,3R)-3-((benzyloxy)methyl)-5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate; tert-Butyl 2-((S)-5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)azetidine-1-carboxylate; tert-Butyl 2-((2S,3S)-5-chloro-6-fluoro-3-methyl-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)azetidine-1-carboxylate; tert-Butyl (S)-2-((S)-5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate; (S)-2-((S)-5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)pyrrolidine; tert-Butyl 2-((S)-5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)-4-hydroxypyrrolidine-1-carboxylate; tert-Butyl 2-((S)-5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)-4-hydroxy-4-methylpyrrolidine-1-carboxylate; tert-Butyl (2S,4R)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-fluoropyrrolidine-1-carboxylate; tert-Butyl 2-((2S,3S)-5-chloro-6-fluoro-3-hydroxy-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate; tert-Butyl 2-((2S,3S)-5-chloro-6-fluoro-3-methoxy-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate; tert-Butyl 2-((2S,3S)-5-chloro-6-fluoro-3-methyl-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate; tert-Butyl (S)-2-((S)-5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)piperidine-1-carboxylate; tert-Butyl 3-((S)-5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)morpholine-4-carboxylate; tert-Butyl (1-((S)-5-chloro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)ethyl)carbamate; tert-Butyl (1-((2S,3S)-5-chloro-6-fluoro-3-methyl-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)ethyl)carbamate; and Tert-butyl (S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline-1-carboxylate.

6. A method for preparing a compound of formula (I), (Ia), (Ic) or (Id) or a pharmaceutically acceptable salt thereof, The method comprises the following steps: a) a compound of formula (IV), (IV-I), (IV-II) or (IV-III) as defined in claims 1 to 4 with a compound of formula (V) The coupling is carried out in the presence of a suitable catalyst, such as a Pd catalyst, to give a compound of the general formula (III) in W is selected from O; and CH-R w ; X is selected from CH; and N; Y is selected from CH; and N; Z is selected from CH2; O; and NH; When Y is N, W is CH-R w and Z is O; A is selected from (i) phenyl, said phenyl being optionally substituted by: halo; or halo C1-C3 alkoxy; (ii) a 5-membered or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O, and S, the aromatic heterocyclic ring being optionally substituted by: hydroxy; C1-C3 alkoxy; or oxo; and (iii) a halogenated benzodioxole moiety having the formula: R w Selected from: (i) hydrogen; (ii) hydroxy; (iii) C1-C3 alkoxy; (iv) hydroxy-C1-C3 alkyl; (v) C1-C3 alkyl; and (vi) C1-C3 alkoxy-C1-C3 alkyl; Q is selected from: (i) -C(R 7 )2-N(R 8 )-R1; (ii) a 9- or 10-membered partially saturated heteroaryl containing at least one N heteroatom; and (iii) a 4-, 5- or 6-membered saturated heterocyclic ring containing at least one heteroatom or heteroatom group selected from N, O, S, -S(=O) and -S(=O)2, provided that at least one N heteroatom is present, wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy, C1-C3 alkyl, C1-C3 alkoxy, halo and C1-C3 alkylene, which form a bridge between two ring atoms of the saturated heterocyclic ring, thereby forming a bridged bicyclic structure; R1 is selected from: (i) hydrogen; (ii) C1-C6 alkyl, which is optionally deuterated; and (iii) (CH2) 0-2 R 1a ; R 1a is selected from: (i) hydroxy C1-C4 alkyl; (ii) C1-C3 alkoxy; (iii) a 5-membered or 6-membered saturated heterocyclic ring containing at least one heteroatom selected from N and O, the saturated heterocyclic ring being optionally substituted one or more times independently by: C1-C3 alkyl; (CH2) 0-1 C(O)di(C1-C3 alkyl)amino; SO2C1-C3 alkyl; C(O)C1-C3 alkyl; or oxo; (iv) C3-C6 cycloalkyl, which is optionally substituted one or more times independently by: hydroxy; hydroxyC1-C4 alkyl; C1-C6 alkoxy; C(O)OC1-C3 alkyl; CO2H; SO2C1-C3 alkyl; haloC1-C3 alkyl; NHR 1b ; (CH2) 0-1 C(O)NR 1c R 1d ; C1-C6 alkyl; halo C1-C3 alkoxy-C1-C3 alkyl; halo; a 5-membered or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O, and S; or two R 1e Group, The two R attached to the same carbon atom 1e Together with the carbon atoms to which they are attached, they form a 5-membered saturated heterocyclic ring containing at least one heteroatom selected from N and O, or a C3-C6 cycloalkyl group, which is optionally substituted by: hydroxy or oxo; R 1b Selected from: (i) C(O)C1-C3 alkyl; and (ii) SO2C1-C3 alkyl; R 1c and R 1d Each independently selected from: (i) hydrogen; (ii) C1-C3 alkyl; and (iii) hydroxy C1-C4 alkyl; R2 is selected from: (i) hydrogen; and (ii) halo; R3 is selected from: (i) halo; (ii) halo C1-C3 alkyl; and (iii) cyano; R4 is selected from: (i) hydrogen; (ii) halo; and (iii) C1-C3 alkyl; R5 is selected from: (i) hydrogen; (ii) C1-C6 alkoxy, which is optionally substituted by: C3-C6 cycloalkyl; CO2H; SO2C1-C3 alkyl; a 5-membered or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O, and S; or a 5-membered or 6-membered saturated heterocyclic ring containing at least one heteroatom selected from N and O, which is optionally substituted by C(O)C1-C3 alkyl; (iii) halo; (iv) hydroxy C1-C6 alkoxy, wherein the alkoxy is optionally deuterated; (v) halo C1-C6 alkoxy optionally substituted with hydroxy; (vi) S-halo C1-C3 alkyl optionally substituted with hydroxy; (vii) C1-C3 alkoxy C1-C3 alkoxy; (viii) NR 5a R 5b ; (ix) C1-C3 alkyl; (x) a 5-membered or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O, and S; and (xi) a hydroxyl group; R 5a and R 5b Each is independently selected from: (i) hydrogen; and (ii) C1-C3 alkyl; or R 5a and R 5b together with the nitrogen atom to which they are attached, form a 5- or 6-membered saturated heterocyclic ring which optionally additionally carries a hydroxyl group; R6 is selected from: (i) hydrogen; (ii) cyano; (iii) C(O)NHR 6a (iv) NHR 6b ; and (v) C1-C3 alkoxy substituted by NH2 or hydroxy; R 6a Selected from: (i) hydrogen; (ii) C1-C3 alkyl; (iii) C3-C6 cycloalkyl; (iv) a 5-membered or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O, and S, the aromatic heterocyclic ring being optionally substituted by: C1-C3 alkyl; R 6b is a C1-C3 alkyl group substituted by NH2 or hydroxyl; R 7 are each independently selected from hydrogen and C1-C3 alkyl; and R 8 is hydrogen or C1-C3-alkyl. Q1 is selected from: (i) -C(R 7 )2-R b and (ii) a 9- or 10-membered partially saturated heteroaryl group containing at least one N heteroatom; and (iii) a 4-, 5- or 6-membered saturated heterocycle containing at least one heteroatom or heteroatom group selected from N, O, S, -S(=O) and -S(=O)2, provided that at least one N heteroatom is present, the N heteroatom is optionally substituted with a protecting group, wherein the heterocycle is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy, C1-C3 alkyl, C1-C3 alkoxy, halo and C1-C3 alkylene, which form a bridge between two ring atoms of the saturated heterocycle, thereby forming a bridged bicyclic structure; Wherein when R in the compound of formula (IV) a When it is a halide such as bromide or iodide, R c is B(R' a )2, where each R' a is a hydroxyl group, or two R' a The groups together with the boron to which they are attached form a pinacol borate moiety having the formula: Wherein when R in the compound of formula (IV) a is B(R' a )2, where each R' a is a hydroxyl group, or two R' a When the groups are taken together with the boron to which they are attached to form a pinacol borate moiety having the formula R c is a halide, such as bromide or iodide; and R6' is a functional group that can be converted into R6, such as -CN or C(O)OC1-C6 alkyl.

7. The method according to claim 6, comprising the steps of: a) coupling a compound of formula (IV) with a compound of formula (V) in the presence of a suitable catalyst to give a compound of formula (III); b) converting the compound of formula (III) obtained in step a) under suitable hydrolysis conditions to give a compound of formula (II); c) deprotecting the compound of formula (II) obtained in step b) to give a compound of formula (I); Among them, R2, R3, R4, R5, R6, R 6’ , R a , R c , A, W, X, Y, Z, Q and Q1 are defined as in Claim 1 and Claim 6.

8. The method according to claim 7, further comprising the steps of: d) optionally further functionalizing the amine group of the compound having formula (I); e) recovering the compound of formula (I) thus obtainable in free form or in the form of a pharmaceutically acceptable salt.

9. The method according to any one of claims 6 to 8, wherein X is selected from CH; and N; A is selected from (i) phenyl, said phenyl being optionally substituted by: halo; or halo C1-C3 alkoxy; (ii) a 5- or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O, and S, preferably selected from N and S, which is optionally substituted by: hydroxy; C1-C3 alkoxy; or oxo; and (iii) a halogenated benzodioxole moiety having the formula: R w Selected from: (i) hydrogen; (ii) hydroxy; (iii) C1-C3 alkoxy; (iv) hydroxy-C1-C3 alkyl; (v) C1-C3 alkyl; and (vi) C1-C3 alkoxy-C1-C3 alkyl; Q is selected from: (i) -C(R 7 )2-N(R 8 )-R 1 (ii) a 9- or 10-membered partially saturated heteroaryl group containing at least one N heteroatom; and (iii) a 4-, 5- or 6-membered saturated heterocyclic ring containing at least one heteroatom selected from N, O and S, provided that at least one N heteroatom is present, and wherein the N is optionally present in the alpha position to the atom that binds Q to the rest of the molecule, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy, C1-C3 alkyl, C1-C3 alkoxy, halo and methylene, which form a bridge between two ring atoms of the saturated heterocyclic ring, thereby forming a bridged bicyclic structure; R1 is selected from: hydrogen; C1-C6 alkyl; and (CH2) 0-2 R 1a ,in R 1a is selected from: (i) C1-C3 alkoxy; (ii) C3-C6 cycloalkyl, which is optionally substituted one or more times independently by: hydroxy; hydroxy C1-C4 alkyl; C1-C4 alkoxy; C(O)OC1-C3 alkyl; CO2H; C(O)NR 1c R 1d ; C1-C6 alkyl; halo; halo C1-C3 alkoxy-C1-C3 alkyl; SO2C1-C3 alkyl; halo C1-C3 alkyl; NHR 1b ; C(O)NR 1c R 1d ; A 5-membered or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O, and S; or two R 1e A group in which both R 1e The groups are attached to the same carbon atom and together with the carbon atom to which they are attached form a 5-membered saturated heterocyclic ring containing at least one heteroatom selected from N and O, or a C3-C6 cycloalkyl group, said saturated heterocyclic ring or cycloalkyl group being optionally substituted by: hydroxy or oxo; (iii) a 5-membered or 6-membered saturated heterocyclic ring containing at least one heteroatom selected from N and O, said saturated heterocyclic ring being optionally substituted one or more times independently by: C1-C3 alkyl; (CH2) 0-1 C(O)di(C1-C3 alkyl)amino; SO2C1-C3 alkyl; C(O)C1-C3 alkyl; or oxo; R 1b Selected from C(O)C1-C3 alkyl; and SO2C1-C3 alkyl; R 1c and R 1d are each independently selected from: (i) hydrogen; (ii) C1-C3 alkyl; and (iii) hydroxy C1-C4 alkyl, R2 is hydrogen or halogen, R3 is halo; halo C1-C3 alkyl; or cyano, R4 is selected from: hydrogen; halo; and C1-C3 alkyl, R5 is selected from: (i) hydrogen; (ii) halo-C1-C6 alkoxy optionally substituted by hydroxy; (iii) S-halo-C1-C3 alkyl optionally substituted by hydroxy; (iv) C1-C3 alkoxy C1-C3 alkoxy; (v) C1-C6 alkoxy, which is optionally substituted by: SO2C1-C3 alkyl, C3-C6 cycloalkyl, CO2H, or a 5- or 6-membered saturated heterocyclic ring containing at least one heteroatom selected from N and O, which is optionally substituted by C(O)C1-C3 alkyl; (vi) C1-C3 alkyl; (vii) hydroxy C1-C6 alkoxy; (viii) a 5- or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom; and (ix) hydroxy, R6 is cyano; C(O)NHR 6a ; NHR 6b ; or a C1-C3 alkoxy group substituted by NH2 or hydroxyl, R 6a is selected from: (i) hydrogen; (ii) C1-C3 alkyl; (iii) C3-C6 cycloalkyl; and (iv) a 5- or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom, the aromatic heterocyclic ring being optionally substituted by: C1-C3 alkyl; R 6b is a C1-C3 alkyl group substituted by NH2 or hydroxyl; R 7 are each independently selected from hydrogen and C1-C3 alkyl, and R 8 It is hydrogen or C1-C3 alkyl.

10. The method according to any one of claims 6 to 8, wherein X is selected from CH; and N; A is phenyl, which is optionally substituted by: halo; or halo C1-C3 alkoxy; R w Selected from: (i) hydrogen; (ii) C1-C3 alkoxy; (iii) hydroxy-C1-C3 alkyl; (iv) C1-C3 alkyl; and (v) C1-C3 alkoxy-C1-C3 alkyl; Q is selected from: (i) -C(R 7 )2-NH-R1; and (ii) a 4-, 5- or 6-membered saturated heterocyclic ring containing one or two heteroatoms independently selected from N, O and S, provided that at least one N heteroatom is present, wherein the N is present in the alpha position to the atom that binds Q to the rest of the molecule, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy, C1-C3 alkyl and halo; R1 is selected from: (i) C1-C6 alkyl; and (ii) R 1a ;in R 1a Selected from C3-C6 cycloalkyl, which is optionally substituted one or more times independently by: hydroxy; C1-C6 alkyl; or halo; R2 is hydrogen or halogen; R3 is halogenated; R4 is selected from: (i) hydrogen; and (ii) halo; R5 is selected from: halo-C1-C6 alkoxy, hydroxy, C1-C6 alkoxy; and hydroxy C1-C6 alkoxy; R6 is C(O)NHR 6a ; R 6a Selected from: (i) hydrogen; and (ii) C1-C3 alkyl; and R 7 Each is independently selected from hydrogen and C1-C3 alkyl.

11. The method according to any one of claims 6 to 8, wherein X is selected from CH; and N; A is phenyl, which is optionally substituted by: halo; or halo C1-C3 alkoxy, especially unsubstituted phenyl; R w is selected from: (i) hydrogen; and (ii) C1-C3 alkyl, Q is selected from: (i) -C(R 7 )2-NH-R1; and (ii) a 4-, 5- or 6-membered saturated heterocyclic ring containing one or two heteroatoms independently selected from N and O, provided that at least one N heteroatom is present and that the N heteroatom is alpha to the carbon atom that binds Q to the rest of the molecule, wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy, C1-C3 alkyl and halo; R1 is selected from: (i) C1-C6 alkyl; and (ii) R 1a ;in R 1a is C3-C6 cycloalkyl, which is optionally substituted one or more times independently by: hydroxy; C1-C6 alkyl; or halo; R2 is halo, especially fluorine; R3 is halo, especially chlorine; R4 is halo, especially fluorine; R5 is selected from: C1-C6 alkoxy; and hydroxy C1-C6 alkoxy; R6 is C(O)NHR 6a ; R 6a Selected from: (i) hydrogen; and (ii) C1-C3 alkyl; and Each R 7 It's hydrogen.

12. A method for preparing a compound of formula (IV-v) or a salt thereof, the method comprising the following steps: (i) treating a compound of formula (IV-t) with an organometallic reagent, and (ii) reacting the resulting mixture with an epoxide of formula (IV-u) wherein R2 is selected from: (i) hydrogen; and (ii) halo; PG is a nitrogen protecting group; Hal 1 is Br or I; Hal 2 is Cl or Br; And when Hal 1 When it is I, Hal 2 is Cl or Br, and when Hal 2 When it is Cl, Hal 1 is Br or I.

13. A method for preparing a compound of formula (IV-q) from a compound of formula (IV-v) and a compound of formula (IV-u) according to the following synthetic scheme: in A is selected from (i) phenyl, said phenyl being optionally substituted by: halo; or halo C1-C3 alkoxy; (ii) a 5- or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O, and S, the aromatic heterocyclic ring being optionally substituted by: hydroxy; C1-C3 alkoxy; or oxo; and (iii) a halogenated benzodioxole moiety having the formula: R2 is selected from: (i) hydrogen; and (ii) halo; R3 is selected from: (i) halo; (ii) halo C1-C3 alkyl; and (iii) cyano; PG is a nitrogen protecting group; Hal 1 is Br or I; Hal 2 is Cl or Br; When Hal 1 When it is I, Hal 2 is Cl or Br; and when Hal 2 When it is Cl, Hal 1 is Br or I; and R3 is chlorine.

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