RU2830596C1 - Biaryl derivatives as inhibitors of protein-protein interaction yap/taz-tead - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

where X is selected from CH; and N; A is phenyl; R_w is selected from (i) hydrogen; and (ii) C₁-C₃ alkyl; Q is selected from (i) -C(R⁷)₂-NH-R₁; and (ii) 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 it is in the α-position with respect to the carbon atom binding Q to the rest of the molecule, where the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from hydroxy, C₁-C₃alkyl and halogen; R₁ is selected from (i) C₁-C₆alkyl and (ii) R_1a; where R_1a is C₃-C₆cycloalkyl, optionally independently substituted once or more than once with hydroxy, C₁-C₆alkyl or halogen; R₂ is halogen; R₃ is halogen; R₄ is halogen; R₅ is selected from C₁-C₆alkoxy and hydroxyC₁-C₆alkoxy; R₆ is C(O)NHR^6a; R^6a is selected from (i) hydrogen and (ii) C₁-C₃alkyl; and each R⁷ is hydrogen, as well as pharmaceutical compositions based thereon.

EFFECT: obtaining novel compounds which have YAP/TAZ-TEAD protein-protein interaction (PPI) inhibitory activity and can be used to treat diseases mediated by said activity, for example, cancer or tumor.

18 cl, 176 ex, 2 tbl

Description

Field of technology to which the invention relates

The present invention provides biaryl derivatives of the compound, their use for inhibiting the YAP/TAZ-TEAD protein-protein interaction (PPI), and methods of treating a disease using said compounds.

Prerequisites for the creation of an invention

Normal tissue growth, repair, and remodeling require specific control and a regulated balance of transcriptional activity. Transcriptional output is coordinated through a number of key signaling modules, one of which is the Hippo pathway. Genetic studies in Drosophila and mammals have identified a conserved core signaling cassette consisting of the kinases MST1/2 and LATS1/2, which repress the transcriptional coactivators YAP and TAZ (official gene name: WWTR1).

Activated Hippo pathway results in phosphorylation and sequestration/degradation of YAP and TAZ in the cytoplasm. Upon Hippo pathway inactivation, YAP and TAZ translocate to the nucleus and associate with transcription factors, namely members of the TEAD family (TEAD1-4). In turn, YAP/TAZ-TEAD complexes promote the transcription of downstream genes involved in cell proliferation, death, and differentiation. Although YAP and TAZ can also interact with a number of other factors, TEADs are generally considered key mediators of the growth-promoting and oncogenic potential of YAP and TAZ (pathway reviewed in Yu et al., 2015; Holden and Cunningham, 2018).

Accordingly, hyperactivation of YAP and/or TAZ (and subsequent hyperactivity of the YAP/TAZ-TEAD transcriptional complex) has been commonly observed in several human cancers. This is evidenced by the levels and nuclear localization of YAP/TAZ, which are elevated in a variety of tumors, including breast, lung (e.g., non-small cell lung cancer; NSCLC), ovary, colorectal, pancreatic, prostate, gastric, esophageal, liver, and bone (sarcomas) (Steinhardt et al., 2008; Harvey et al., 2013; Moroishi et al., 2015; reviewed in detail in Zanconato et al., 2016 and references therein).

While genetic alterations in core components of the Hippo pathway have so far been detected with limited frequency in primary samples, the most common cancer malignancy associated with inactivating mutations in NF2 or LATS1/2 and associated YAP/TEAD hyperactivity is malignant pleural mesothelioma (MPM) (reviewed in Sekido, 2018). Similarly, a number of human tumors are characterized by amplification of YAP at 11q22.1 (e.g., hepatocellular carcinomas, medulloblastomas, esophageal squamous cell carcinomas), TAZ (WWTR1) at 3q25.1 (e.g., rhabdomyosarcomas, triple-negative breast cancer), or gene fusions involving YAP or TAZ (epithelioid hemangioendotheliomas, ependymal tumors) (reviewed in Yu et al., 2015 and references therein). As with MPM, such tumors are also expected to be affected by their elevated YAP/TAZ-TEAD activity.

Disruption of the YAP/TAZ-TEAD protein-protein interaction (PPI) as the most distal effector node of the Hippo pathway is expected to abolish the oncogenic potential of this complex. The compounds of the present invention are designed and optimized to bind to TEAD and selectively disrupt its interaction with YAP and TAZ, which presumably leads to the production of drugs useful in the treatment of the above-mentioned cancers. In particular, such cancers may be characterized (but not limited to) by some of the described aberrations.

Notably, tumor cells with activated YAP/TAZ-TEAD exhibit resistance to chemotherapeutic drugs, possibly due to YAP/TAZ conferring cancer stem cell characteristics. Moreover, YAP/TAZ-TEAD activation also confers resistance to molecularly targeted therapeutics such as BRAF, MEK, or EGFR inhibitors, as demonstrated by various genetic and pharmacological screens (Kapoor et al., 2014; Shao et al., 2014; Lin et al., 2015). This in turn suggests that inhibition of YAP/TAZ-TEAD activity, either in parallel or sequentially with other cancer therapies, may have beneficial therapeutic effects by reducing the growth of tumors resistant to other treatments.

Suppression of YAP/TAZ-TEAD activity upon disruption of PPI by the above LMW compounds may also hinder tumor immune evasion. This is supported, for example, by published data showing that YAP promotes the expression of the chemokine CXCL5, which leads to the recruitment of myeloid cells that suppress T cells (Wang et al., 2016). It has also been demonstrated that YAP in Tregs maintains FOXP3 expression through activin signaling and Treg function. Accordingly, YAP deficiency results in dysfunctional Tregs that are no longer able to suppress antitumor immunity. Therefore, selective suppression of YAP/TEAD activity may contribute to enhancing antitumor immunity by preventing Treg function (Ni et al., 2018). Current literature data also suggest that YAP activates PD-L1 expression and through this mechanism directly mediates evasion of T cell-mediated cytotoxic immune responses, such as in BRAF inhibitor-resistant melanoma cells (Kim et al., 2018).

See, for example,

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

Holden, J. K. and Cunningham, C. N. (2018). Targeting the Hippo pathway and cancer through the TEAD family of transcription factors. Cancers (Basel), 10 , E81.

Steinhardt, A. A., Gayyed, M. F., Klein, A. P., Dong, J., Maitra, A., Pan, D., Montgomery, E. A., Anders, R. A. (2008). Expression of Yes-associated protein in common solid tumors. Hum. Pathol., 39 , 1582–1589.

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

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

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

Sekido, Y. (2018). Cancers (Basel), 10 , E90.

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 oncogenic Kras addiction in pancreatic cancer. Cell, 158 , 185-197.

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 to regulate EMT and tumor survival. Cell, 158 , 171-184.

Lin, L., Sabnis, A. J., Chan, E., Olivas, V., Cade, L., Pazarentzos, E., Asthana, S., Neel, D., Yan, J. J., Lu, X. et al. (2015). The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat. Genet., 47 , 250-256.

Wang, G., Lu, X., Dey, P., Deng, P., Wu, C. C., Jiang, S., Fang, Z., Zhao, K., Konaprathi, R., Hua, S., et al. (2016). Cancer Discov., 6 , 80-95.

Ni, X., Tao, J., Barbi, J., Chen, Q., Park B.V., Li, Z., Zhang, N., Lebid, A., Ramaswamy, A., Wei, P., et al . (2018). YAP is essential for Treg-mediated suppression of antitumor immunity. Cancer Discov., 8 , 1026-1043.

Kim, M. H., Kim, C. G., Kim, S. K., Shin, S. J., Choe, E. A., Park, S. H., Shin, E. C., and Kim, J. (2018). Cancer Immunol Res., 6, 255-266.

The essence of the invention

There is a continuing need to develop new YAP/TAZ-TEAD protein-protein interaction (PPI) inhibitors that are good drug candidates. Such candidates may have applications inter alia in the treatment of cancer, particularly in the treatment of mesothelioma (including malignant pleural mesothelioma), pancreatic cancer, sarcoma, and non-small cell lung cancer (e.g. NF2-mutated NSCLC).

The present invention provides compounds, their pharmaceutically acceptable salts, their pharmaceutical compositions and combinations thereof, wherein the compounds are inhibitors of the YAP/TAZ-TEAD protein-protein interaction. The present invention further provides methods for treating, preventing or reducing the severity of cancers, comprising administering to a subject in need thereof an effective amount of a YAP/TAZ-TEAD PPI inhibitor. For treatment, the YAP/TAZ-TEAD PPI compounds of the present invention can be used in combination with cancer immunotherapy drugs, such as immune checkpoint inhibitors (e.g., anti-PD-1 antibodies).

Various embodiments of the present invention are described herein.

In certain aspects, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof:

where A, Q, W, X, Y, Z, _R2 , _R3 , _R4 , _R5 and _R6 are as defined herein.

In another embodiment, the present invention provides a pharmaceutical composition comprising a compound according to the definition of formula (I) or subformulas (Ia), (Ia*), (Ia-1), (Ib), (Ic), (Id) thereof, or a pharmaceutically acceptable salt thereof, as defined herein, and one or more pharmaceutically acceptable carriers.

In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the definition of formula (I) or its subformulas (Ia), (Ia*), (Ia-1), (Ib), (Ic), (Id), or a pharmaceutically acceptable salt thereof and, optionally, one or more pharmaceutically acceptable carriers.

In another embodiment, the present invention provides a combination, in particular a pharmaceutical combination, comprising a compound according to the definition of formula (I) or its subformulas (Ia), (Ia*), (Ia-1), (Ib), (Ic), (Id), or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents.

In a further embodiment, the present invention relates to a method for inhibiting the activity of a YAP/TAZ-TEAD protein-protein interaction in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or subformulas (Ia), (Ia*), (Ia-1), (Ib), (Ic), (Id) thereof, as defined herein, or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention relates to a method of treating a disorder or disease in a subject in need thereof, wherein the disorder or disease is a cancer or tumor that 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), poromoma (benign poroma), porocarcinoma (including malignant porocarcinoma), supratentorial ependymoma (including childhood 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 colorectal carcinoma), melanoma, pancreatic cancer (including pancreatic adenocarcinoma), prostate cancer, gastric cancer, esophageal cancer, liver cancer (including hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma), neuroblastoma, schwannoma, renal cell carcinoma, sarcomas (including rhabdomyosarcoma, embryonal rhabdomyosarcoma (ERMS), osteosarcoma, undifferentiated pleomorphic sarcomas (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), and wherein the method comprises administering to the subject a therapeutically effective amount of a compound of formula (I) as defined herein, or subformulas (Ia), (Ia*), (Ia-1), (Ib), (Ic), (Id) thereof, or a pharmaceutically acceptable salt thereof.

In a further embodiment, the present invention relates to a method of inhibiting the formation of a YAP/TAZ-TEAD complex in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or subformulas (Ia), (Ia*), (Ia-1), (Ib), (Ic), (Id) thereof, as defined herein, or a pharmaceutically acceptable salt thereof.

In a further embodiment, the present invention relates to a method of inhibiting the formation of a YAP/TAZ-TEAD complex in a subject, the method comprising administering to the subject a compound of formula (I) or subformulas (Ia), (Ia*), (Ia-1), (Ib), (Ic), (Id) thereof, as defined herein, or a pharmaceutically acceptable salt thereof.

Detailed description of the invention

In a first aspect of the present invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof,

Where

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;

where if Y is N, W is CH-R _w , and Z is O;

A is selected from

(i) phenyl, wherein phenyl is optionally substituted with halogen or halogenC ₁ -C ₃ alkoxy;

(ii) a 5- or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O and S, preferably from N and S, wherein the aromatic heterocyclic ring is optionally substituted with hydroxy, C ₁ -C ₃ alkoxy or oxo; and

(iii) a halogen benzodioxol fragment of the formula

R _w is selected from (i) hydrogen, (ii) hydroxy, (iii) C ₁ -C ₃ alkoxy, (iv) hydroxyC ₁ -C ₃ alkyl, (v) C ₁ -C ₃ alkyl, and (vi) C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl;

Q is selected from

(i) -C(R ⁷ ) ₂ -N(R ⁸ )-R ₁ ;

(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 heteroatomic 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 hydroxy, _C1 - _C3 alkyl, _C1 - _C3 alkoxy, halogen and _C1 - _C3 alkylene, to form a bridge between two ring atoms of the saturated heterocyclic ring, thereby forming a bridged bicyclic structure;

R ₁ is selected from (i) hydrogen, (ii) C ₁ -C ₆ alkyl (wherein the alkyl in one embodiment is optionally deuterated, such as perdeuterated) and (iii) (CH ₂ ) _0-2 R _1a ;

R _1a is selected from

(i) hydroxyC ₁ -C ₄ alkyl;

(ii) C ₁ -C ₃ alkoxy;

(iii) a 5- or 6-membered saturated heterocyclic ring containing at least one heteroatom selected from N and O, wherein the saturated heterocyclic ring is optionally independently substituted once or more than once with _C1 - _C3 alkyl, ( _CH2 ) _0-1C (O)di( _C1 - _C3 alkyl)amino, _SO2C1 - _{C3 alkyl} , C(O) _C1 - _C3 alkyl or oxo;

(iv) _C3 - _C6 cycloalkyl optionally independently substituted once or more than once with hydroxy, hydroxyC1 _{- C4} alkyl, _C1 - _C6 alkoxy (preferably _C1 - _C4 alkoxy), C(O) _OC1 - _C3 alkyl, _CO2H ; SO ₂ C ₁ -C ₃ alkyl, halogen _{C 1} -C ₃ alkyl, NHR ^1b , (CH ₂ ) _0-1 C(O)NR ^1c R ^1d (preferably C(O)NR ^1c R ^1d ), C ₁ -C ₆ alkyl, halogen C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, halogen, a 5- or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O, and S, or two R ^1e groups,

wherein two R ^1e , attached at the same carbon atom, 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 (which is preferred) and O, or C ₃ -C ₆ cycloalkyl, the saturated heterocyclic ring or cycloalkyl being optionally substituted with hydroxy or oxo;

R ^1b is selected from (i) C(O)C ₁ -C ₃ alkyl and (ii) SO ₂ C ₁ -C ₃ alkyl;

each of R ^1c and R ^1d is independently selected from (i) hydrogen, (ii) C ₁ -C ₃ alkyl and (iii) hydroxyC ₁ -C ₄ alkyl, preferably from (i) hydrogen and (ii) C ₁ -C ₃ alkyl;

R ₂ is selected from (i) hydrogen and (ii) halogen;

R ₃ is selected from (i) halogen, (ii) haloC ₁ -C ₃ alkyl, in particular from halogen and mono-, di- or preferably trihalomethyl and (iii) cyano;

R ₄ is selected from (i) hydrogen, (ii) halogen and (iii) C ₁ -C ₃ alkyl, in particular from hydrogen, halogen and methyl;

R ₅ is selected from

(i) hydrogen;

(ii) _C1 - _C6 alkoxy optionally substituted with _C3 - _C6 cycloalkyl, _CO2H ; _SO2C1 - _C3 alkyl, _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, or a 5- or 6-membered saturated heterocyclic ring containing at least one heteroatom selected from N and O, the ring being optionally substituted with C(O) _C1 - _C3 alkyl;

(iii) halogen;

(iv) hydroxyC ₁ -C ₆ alkoxy (wherein the alkoxy moiety in one embodiment is optionally deuterated, such as perdeuterated);

(v) halogenC ₁ -C ₆ alkoxy optionally substituted with hydroxy;

(vi) S-haloC ₁ -C ₃ alkyl optionally substituted with hydroxy;

(vii) C ₁ -C ₃ alkoxyC ₁ -C ₃ alkoxy;

(viii) NR ^5a R ^5b ;

(ix) C ₁ -C ₃ alkyl;

(x) 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

(xi) hydroxy;

each of R ^5a and R ^5b is independently selected from (i) hydrogen and (ii) C ₁ -C ₃ 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, the saturated heterocyclic ring optionally further bearing a hydroxyl group;

R ₆ is selected from (i) hydrogen, (ii) cyano, (iii) C(O)NHR ^6a , (iv) NHR ^6b and (v) C ₁ -C ₃ alkoxy substituted with NH ₂ or hydroxy;

R ^6a is selected from (i) hydrogen, (ii) C ₁ -C ₃ alkyl, (iii) C ₃ -C ₆ cycloalkyl, (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, wherein the aromatic heterocyclic ring is optionally substituted with C ₁ -C ₃ alkyl;

R ^6b is C ₁ -C ₃ alkyl substituted with NH ₂ or hydroxy;

each R ⁷ is independently selected from hydrogen and C ₁ -C ₃ alkyl; and

R ⁸ represents hydrogen or C ₁ -C ₃ -alkyl, in particular hydrogen or methyl.

If R ₂ is halogen, R ₂ is preferably fluorine. If R ₃ is halogen, R ₃ is preferably chlorine. If R ₄ is halogen, R ₄ is preferably fluorine. In a preferred embodiment, R ₃ is chlorine and R ₄ is fluorine. In a more preferred embodiment, R ₂ is hydrogen or fluorine, R ₃ is chlorine and R ₄ is fluorine.

In one embodiment of the first aspect of the present invention, there is provided a compound of formula (I) wherein Y is CH.

In a further embodiment of the first aspect of the present invention, there is provided a compound of formula (I) wherein Y is CH and W is CH-R _w .

In a further embodiment of the first aspect of the present invention, there is provided a compound of formula (I) wherein Y is CH, W is CH-R _w , and Z is O.

In a second aspect of the present invention there is provided a compound of formula (I) as shown above or a pharmaceutically acceptable salt thereof, wherein

W is CH-R _w ;

X is selected from CH and N;

Y represents CH;

Z is selected from O and NH;

A is selected from (i) phenyl, wherein phenyl is optionally substituted with halogen or halogenC ₁ -C ₃ alkoxy;

(ii) a 5- or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O and S, preferably from N and S, wherein the aromatic heterocyclic ring is optionally substituted with hydroxy, C ₁ -C ₃ alkoxy or oxo; and

(iii) a halogen benzodioxol fragment of the formula

R _w is selected from (i) hydrogen, (ii) hydroxy, (iii) C ₁ -C ₃ alkoxy, (iv) hydroxy-C ₁ -C ₃ alkyl, (v) C ₁ -C ₃ alkyl and (vi) C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl;

Q is selected from (i) -C(R ⁷ ) ₂ -N(R ⁸ )-R ¹ , (ii) a 9- or 10-membered partially saturated heteroaryl containing at least one N heteroatom, preferably wherein N is present in the α-position with respect to the atom linking Q to the rest of the molecule, 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, preferably wherein N is present in the α-position with respect to the atom linking Q to the rest of the molecule, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen and methylene (-CH ₂ -), to form a bridge between two atoms of the saturated ring heterocyclic ring, thereby forming a bridged bicyclic structure;

R ₁ is selected from hydrogen, C ₁ -C ₆ alkyl and (CH ₂ ) _0-2 R _1a , where

R _1a is selected from (i) C ₁ -C ₃ alkoxy, (ii) C ₃ -C ₆ cycloalkyl optionally independently substituted once or more than once with hydroxy, hydroxyC ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C(O)OC ₁ -C ₃ alkyl, CO ₂ H, C(O)NR ^1c R ^1d , C ₁ -C ₆ alkyl, halogen, haloC ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, SO ₂ C ₁ -C ₃ alkyl, haloC ₁ -C ₃ alkyl, NHR ^1b , C(O)NR ^1c R ^1d , a 5- or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O and S, or two groups R ^1e , wherein two R ^1e groups are attached at the same carbon atom and form, together with the carbon atom to which they are attached, a 5-membered saturated heterocyclic ring containing at least one heteroatom selected from N (preferably) and O, or C ₃ -C ₆ cycloalkyl, wherein the saturated heterocyclic ring or cycloalkyl is optionally substituted with hydroxy or oxo, and (iii) a 5- or 6-membered saturated heterocyclic ring containing at least one heteroatom selected from N and O, wherein the saturated heterocyclic ring is optionally independently substituted once or more than once with C ₁ -C ₃ alkyl, (CH ₂ ) _0-1 C(O)di(C ₁ -C ₃ alkyl)amino, SO ₂ C ₁ -C ₃ alkyl, C(O)C ₁ -C ₃ alkyl or oxo;

R ^1b is selected from C(O)C ₁ -C ₃ alkyl and SO ₂ C ₁ -C ₃ alkyl;

each of R ^1c and R ^1d is independently selected from (i) hydrogen, (ii) C ₁ -C ₃ alkyl and (iii) hydroxyC ₁ -C ₄ alkyl;

R ₂ represents hydrogen or preferably halogen;

R ₃ is halogen, haloC ₁ -C ₃ alkyl, in particular mono-, di- or in particular trihalomethyl, or cyano;

R ₄ is selected from hydrogen, halogen and C ₁ -C ₃ alkyl (the latter being, in particular, methyl);

R ₅ is selected from (i) hydrogen, (ii) haloC ₁ -C ₆ alkoxy optionally substituted with hydroxy, (iii) S-haloC ₁ -C ₃ alkyl optionally substituted with hydroxy, (iv) C ₁ -C ₃ alkoxyC ₁ - _{C 3} alkoxy, (v) C ₁ -C ₆ alkoxy optionally substituted with SO ₂ C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, CO ₂ H, or a 5- or 6-membered saturated heterocyclic ring containing at least one heteroatom selected from N and O, the ring being optionally substituted with C(O)C ₁ -C ₃ alkyl, (vi) C ₁ -C ₃ alkyl, (vii) hydroxyC ₁ -C ₆ alkoxy, (viii) 5- or 6-membered aromatic a heterocyclic ring containing at least one heteroatom selected from N, O and S, preferably at least one N heteroatom, and (ix) hydroxy;

R ₆ is cyano, C(O)NHR ^6a , NHR ^6b or C ₁ -C ₃ alkoxy substituted with NH ₂ or hydroxy;

R ^6a is selected from (i) hydrogen, (ii) C ₁ -C ₃ alkyl, (iii) C ₃ -C ₆ 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, wherein the aromatic heterocyclic ring is optionally substituted with C ₁ -C ₃ alkyl;

R ^6b is C ₁ -C ₃ alkyl substituted with NH ₂ or hydroxy;

each R ⁷ is independently selected from hydrogen or C ₁ -C ₃ alkyl; and

R ⁸ represents hydrogen or C ₁ -C ₃ -alkyl, in particular hydrogen or methyl.

The third aspect of the present invention relates to a compound of formula (I) as set forth above, or a pharmaceutically acceptable salt thereof,

Where

W is CH-R _w ;

X is selected from CH and N;

Y represents CH;

Z is selected from O and NH;

A represents phenyl, wherein phenyl is optionally substituted with halogen or halogenC ₁ -C ₃ alkoxy;

R _w is selected from (i) hydrogen, (ii) C ₁ -C ₃ alkoxy, (iii) hydroxy-C ₁ -C ₃ alkyl, (iv) C ₁ -C ₃ alkyl and (v) C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl;

Q is selected from (i) -C(R ⁷ ) ₂ -NH-R ₁ 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, preferably where N is present in the α-position with respect to the atom linking Q to the rest of the molecule, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from hydroxy, C ₁ -C ₃ alkyl and halogen;

R ₁ is selected from (i) C ₁ -C ₆ alkyl and (ii) R _1a; , where

R _1a is selected from C ₃ -C ₆ cycloalkyl optionally independently substituted once or more than once with hydroxy, C ₁ -C ₆ alkyl or halogen;

R ₂ represents hydrogen or preferably halogen;

R ₃ is halogen;

R ₄ is selected from (i) hydrogen and (ii) halogen;

R ₅ is selected from halo-C ₁ -C ₆ alkoxy, hydroxy, C ₁ -C ₆ alkoxy and hydroxyC ₁ -C ₆ alkoxy;

R ₆ is C(O)NHR ^6a ;

R ^6a is selected from (i) hydrogen and (ii) C ₁ -C ₃ alkyl;

And

each R ⁷ is independently selected from hydrogen or C ₁ -C ₃ alkyl.

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

If R ₂ is halogen, R ₂ is preferably fluorine. If R ₃ is halogen, R ₃ is preferably chlorine. If R ₄ is halogen, R ₄ is preferably fluorine. In a preferred embodiment, R ₃ is chlorine and R ₄ is fluorine. In a more preferred embodiment, R ₂ is hydrogen or fluorine, R ₃ is chlorine and R ₄ is fluorine.

In one embodiment of the second or third aspect of the present invention, there is provided a compound of formula (I) wherein Y is CH.

In a further embodiment of the second or third aspect of the present invention, there is provided a compound of formula (I) wherein Y is CH and W is CH-R _W .

In a further embodiment of the second or third aspect of the present invention, there is provided a compound of formula (I) wherein Y is CH, W is CH-R _W , and Z is O.

In a fourth aspect of the present invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

W is CH-R _w ;

X is selected from CH and N;

Y represents CH;

Z is selected from O and NH;

A represents phenyl, wherein phenyl is optionally substituted with halogen or (ii) halogenC ₁ -C ₃ alkoxy, in particular unsubstituted phenyl;

R _w is selected from (i) hydrogen, (ii) C ₁ -C ₃ alkyl and (iii) hydroxy-C ₁ -C ₃ alkyl;

Q is selected from (i) -C(R ⁷ ) ₂ -NH-R ₁ 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 is in the α-position with respect to the carbon atom linking Q to the rest of the molecule, wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from hydroxy, C ₁ -C ₃ alkyl and halogen;

R ₁ is selected from (i) C ₁ -C ₆ alkyl and (ii) R _1a; , where

R _1a is C ₃ -C ₆ cycloalkyl optionally independently substituted once or more than once with hydroxy, C ₁ -C ₆ alkyl or halogen;

R ₂ is a halogen, in particular fluorine;

R ₃ is a halogen, in particular chlorine;

R ₄ represents a halogen, in particular fluorine;

R ₅ is selected from C ₁ -C ₆ alkoxy and hydroxyC ₁ -C ₆ alkoxy;

R ₆ is C(O)NHR ^6a ;

R ^6a is selected from (i) hydrogen and (ii) C ₁ -C ₃ alkyl;

And

each R ⁷ is a hydrogen.

Unless otherwise specified, the terms "compounds of the present invention" or "compounds of the present invention" or "compounds of formula (I)" refer to compounds of formula (I), (Ia), (Ia*), (Ia-1), (Ib), (Ic), (Id) and their salts (all of which are preferably pharmaceutically acceptable), as well as all stereoisomers (including diastereoisomers and enantiomers), atropisomers, rotamers, tautomers and isotopically labeled compounds (including deuterium substitutions), as well as the originally formed fragments.

In particular, the compounds of formula (Ic) and (Id) are stereospecific atropisomers. The compounds of formula (I), (Ia), (Ia*), (Ia-1), (Ib) include all their stereoisomers, including diastereoisomers, atropisomers, enantiomers, mixtures and racemic mixtures.

A person skilled in the art can detect the presence of diastereoisomers using instrumental methods such as NMR. A person skilled in the art can separate diastereoisomers using chromatographic methods such as HPLC (high performance liquid chromatography), thin layer chromatography, SFC (supercritical fluid chromatography), GC (gas chromatography) or a recrystallization technique. A person skilled in the art can separate enantiomers using instrumental methods such as chiral HPLC, chiral SFC, chiral GC.

The compounds of the present invention, particularly the ortho-substituted biaryl compounds, may exhibit conformational rotational isomerism, referred to herein as atropisomerism (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds , John Wiley & Sons, Inc., pp.1142-55). In some cases, depending on the R ₄ and R ₆ substituents, such biaryl compounds of the present invention exhibit atropisomerism.

Thus, compounds of formula (I) and its subformulas (Ia), (Ia*), (Ia-1), (Ib), (Ic), (Id) and their isomeric mixtures (including diastereomeric mixtures, enantiomeric mixtures and racemic mixtures) also form part of the present invention.

Definitions

As used herein, the term "C ₁ -C ₆ alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, containing from one to six carbon atoms, and which is attached to the remainder of the molecule by a single bond. The terms "C ₁ -C ₃ alkyl" and "C ₁ -C ₄ alkyl" are to be construed accordingly. Examples of C ₁ -C ₆ 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.

In general, unless otherwise indicated herein or clearly contradicted by context, for substituents containing two or more subgroups, the last named group represents the point of attachment of the radical, e.g., "alkylaryl" means a monovalent radical of the formula alkyl-aryl-, whereas "arylalkyl" means a monovalent radical of the formula aryl-alkyl-.

As used herein, the term "hydroxyC ₁ -C ₄ alkyl" refers to a radical of the formula -R _a -OH, wherein R _a is C ₁ -C ₄ alkyl as defined above. Examples of hydroxyC ₁ -C ₄ alkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, and 3-hydroxypropyl.

As used herein, the term "hydroxyC ₁ -C ₃ alkyl" refers to a radical of the formula -R _a -OH, wherein R _a is C ₁ -C ₃ alkyl as defined above. Examples of hydroxyC ₁ -C ₃ alkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, and 3-hydroxypropyl.

As used herein, the term " _C3 - _C6 cycloalkyl" refers to a saturated monocyclic hydrocarbon group of 3 to 6 carbon atoms. Examples of _C3 - _C6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, the term " _C1 - _C6 alkoxy" refers to a radical of the formula _-ORa , wherein _Ra is a _C1 - _C6 alkyl radical, as generally defined above. The terms " _C1 - _C3 alkoxy" and " _C1 - _C4 alkoxy" should be construed accordingly. Examples of _C1 - _C6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy.

As used herein, the term " _C1 - _C3- alkoxy-C1- _{C3 -} alkyl" refers to a _C1 - _C3 -alkyl radical as defined above, wherein one of the hydrogen atoms of the _C1 - _C3- alkyl radical is replaced by _C1 - _C3 -alkoxy.

"Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine. Preferably, the halogen is fluorine, chlorine or bromine. More preferably, the halogen is fluorine or chlorine.

The term "oxo" refers to the radical =O.

The term "sulfonyl" refers to the radical -S(═O) ₂ -.

The term "amino" refers to the radical -NH ₂ .

The term "NHR ^1b " refers to the radical -N(H)R ^1b . Similarly, a term such as "NR ^5a R ^5b " refers to the radical -N(R ^5a )R ^5b .

As used herein, the term "haloC ₁ -C ₃ alkyl" or "haloC ₁ -C ₃ alkyl" refers to a C ₁ -C ₃ alkyl radical, as defined above, substituted with one or more halogen radicals, as defined above. Examples of haloC ₁ -C ₃ alkyl 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.

As used herein, the term "haloC ₁ -C ₆ alkoxy" refers to C ₁ -C ₆ alkoxy as defined above, wherein at least one of the hydrogen atoms of the C ₁ -C ₆ alkoxy radical is replaced by a halogen radical as defined above. The term "haloC ₁ -C ₃ alkoxy" should be construed accordingly. Examples of halogenC ₁ -C ₆ alkoxy include, but are not limited to, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, 2-fluoropropoxy, 3,3-difluoropropoxy.

As used herein, the term "hydroxyC ₁ -C ₆ alkoxy" refers to a C ₁ -C ₆ alkoxy radical as defined above, wherein at least one of the hydrogen atoms of the C ₁ -C ₆ alkoxy radical is replaced by OH. The term "hydroxyC ₁ -C ₃ alkoxy" should be construed accordingly. Examples of hydroxyC ₁ -C ₆ alkoxy include, but are not limited to, hydroxymethoxy, hydroxyethoxy, 2-hydroxypropoxy groups.

As used herein, the term " _C1 - _C3 alkoxyC1 _{- C3} alkoxy" refers to a _C1 - _C3 alkoxy radical as defined above, wherein one of the hydrogen atoms of the _C1 - _C3 alkoxy radical is replaced by -OC1 _{- C3} alkyl. An example of C1 _{- C3} alkoxyC1- _C3 alkoxy includes _, but is not limited to, 2-methoxyethoxy.

As used herein, the term "haloC1 _{- C3} alkoxy- _C1 - _C3 alkyl" refers to a _C1 - _C3 alkyl radical, as defined above, wherein one of the hydrogen atoms of the _C1 - _C3 alkyl radical is replaced by a haloC1- _C3 alkoxy, as defined above. Examples of _haloC1 - _C3 alkoxy- _C1 - _C3 alkyl include _, but are not limited to, (difluoromethoxy)methyl (i.e., _CHF2 -O- _CH2- ).

As used herein, the term "C(O)NR ^1c R ^1d " refers to a radical of the formula -R _a1 -N(R _a2 ) ₂ , wherein R _a1 is a carbonyl radical and each R _a2 is an R ^1c or R ^1d radical, each of which may be the same or different, as defined herein.

As used herein, the term "C(O)di( _C1 - _C3 alkyl)amino" refers to a radical of the formula -R _a1 -N(R _a2 ) ₂ , wherein R _a1 is a carbonyl radical and each R _a2 is _C1 - _C3 alkyl as defined herein, and each may be the same or different.

As used herein, the term "C(O)C ₁ -C ₃ alkyl" refers to a radical of the formula -R _a1 -C ₁ -C ₃ alkyl, where R _a1 is a carbonyl radical and C ₁ -C ₃ alkyl is as defined above.

The term "C(O)NHR" as used in this document^6a" refers to the radical of the formula -R_a1-N(H)-R^6a, where R_a1represents a carbonyl radical, and R^6a is as defined in this document.

As used herein, the term "S-haloC ₁ -C ₃ alkyl" refers to a radical of the formula -S-haloC ₁ -C ₃ alkyl, wherein haloC ₁ -C ₃ alkyl is as defined above.

As used herein, the term "C(O) _OC1 - _C3 alkyl" refers to a radical of the formula -R _a1 -OC1 _{- C3} alkyl, where R _a1 is a carbonyl radical and _C1 - _C3 alkyl is as defined above.

As used herein, the term " _SO2C1 - _C3 alkyl" refers to a radical of the formula -S(=O) ₂ -R _a2 , where _{R a2} is _C1 - _C3 alkyl as defined above.

The term " _C1 - _C3 alkylene" as used herein refers to a bivalent straight or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, containing no unsaturation and containing from one to three carbon atoms. In embodiments in which a 4-, 5- or 6-membered saturated heterocyclic ring Q (or _Q1 ) is substituted with a _C1 - _C3 alkylene forming a bridge between two ring atoms of the saturated heterocyclic ring, thereby forming a bridged bicyclic structure, the _C1 - _C3 alkylene is preferably propylene ( _-CH2 - _CH2 - _CH2- ), ethylene ( _-CH2 - _CH2- ) or methylene ( _-CH2- ).

The term "(CH ₂ ) _0-2 R _1a " refers to a radical of the formula -(CH ₂ ) _0-2 R _1a , i.e., the radical R _1a is attached to the rest of the molecule through a bond, a methylene linker, or an ethylene linker.

The term "( _CH2 ) _0-1C (O)di( _C1 - _C3 alkyl)amino" refers to a radical of the formula -( _CH2 ) _0-1 -R _a3 and R _a3 is a C(O)di( _C1 - _C3 alkyl)amine radical as defined above.

The term (CH ₂ ) _0-1 C(O)NR ^1c R ^1d refers to a radical of the formula -(CH ₂ ) _0-1 C(O)NR ^1c R ^1d .

As used herein, the term "5- or 6-membered saturated heterocyclic ring containing at least one heteroatom selected from N and O" refers to a monocyclic ring and includes, but is not limited to, piperazinyl, piperidyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, dioxanyl and morpholinyl. Preferably, the term includes piperidyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl and morpholinyl. The terms "5-membered saturated heterocyclic ring containing at least one heteroatom selected from N and O" and "6-membered saturated heterocyclic ring containing at least one heteroatom selected from N and O" should be construed accordingly.

As used herein, the term "4-, 5-, or 6-membered saturated heterocyclic ring containing at least one heteroatom or heteroatomic group selected from N, O, S, -S(=O) and -S(=O) ₂ " refers to a monocyclic ring and includes, but is not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, S-oxothiomorpholinyl or S,S-dioxothiomorpholinyl. For the avoidance of doubt, in some embodiments where N is present in the α-position relative to the atom linking Q to the remainder of the molecule, this may be represented by the following formula

.

As used herein, the term "5- or 6-membered aromatic heterocyclic ring containing 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, isosaolyl, pyrimidinyl, pyridazinyl, tetrazolyl, pyrazinyl, triazolyl, imidazolyl, pyrazolyl, pyridinyl and thiazolyl.

As used herein, the term "5- or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O, and S" refers to an aromatic monocyclic ring and includes, but is not limited to, pyrimidinyl, pyridazinyl, tetrazolyl, pyrazinyl, triazolyl, imidazolyl, pyrazolyl, pyridinyl, oxazolyl, and thiazolyl. The point of attachment to the imidazolyl ring is preferably at the nitrogen atom of the imidazolyl ring.

As used herein, the term "5- or 6-membered aromatic heterocyclic ring 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, imidazolyl, pyrazolyl, pyridinyl, and thiazolyl.

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

As used herein, the term "5-membered aromatic heterocyclic ring containing at least one N heteroatom" (wherein N may also be NH) refers to a monocyclic aromatic ring and includes, but is not limited to, tetrazolyl, triazolyl, imidazolyl, pyrazolyl.

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

As used herein, an aromatic heterocyclic ring in a substituent defined as "a 5- or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O, or S, preferably from N or S" may be optionally substituted with hydroxy, C ₁ -C ₃ alkoxy, or oxo.

It should be understood that the substitution of the said aromatic heterocycle by oxo implies the inclusion of 5- or 6-membered rings in which the aromatic tautomer exists, as, for example, in the 1H-pyridin-2-one system (see, for example, Example 92).

As used herein, the term "5- or 6-membered saturated heterocyclic ring" in relation to embodiments wherein R ^5a and R ^5b together with the N atom (wherein N may also be NH) to which they are attached form said ring includes, by way of example and without limitation, an azetidinyl ring, a pyrrolidine ring, or a piperidine ring.

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 ring system whereby a 5- or 6-membered heterocyclic ring containing one N heteroatom is fused to a benzene ring or a heteroaromatic ring. In some embodiments where N is present in the α-position relative to the atom linking Q to the rest of the molecule, this may be represented by the following formula or , in which the dotted ring is a benzo or heteroaryl ring. Illustrative examples are indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. Preferably, it is or .

As used herein, the term "optionally substituted" includes the meanings unsubstituted or substituted.

As used herein, the term "more than once" includes 2, 3, 4, 5 or 6 times. Preferably, it includes 2 or 3 times.

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

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.

The use of all possible examples or exemplary language (e.g., "such as" or "preferably") herein is intended only to better explain the present invention and is not intended to limit the scope of the present invention otherwise claimed.

As used herein, the term nitrogen protecting group (PG) in a compound of formula (IV) or its subformulas refers to a group which is intended to protect the corresponding functional groups from undesired secondary reactions such as acylation, etherification, esterification, oxidation, solvolysis and the like. It can be removed under deprotection conditions. Depending on the protecting group used, one skilled in the art will know how to remove the protecting group to obtain the free amine group _NH2 following known procedures. These include references to organic chemistry textbooks and literature procedures such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; T. W. Greene and P. G. M. Wuts, "Greene's Protective Groups in Organic Synthesis", Fourth Edition, Wiley, New York 2007; in "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981 and in "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, ^4th edition, Volume 15/I, Georg Thieme Verlag, Stuttgart 1974 and its later editions.

Preferred nitrogen protecting groups generally include: _C1 - _C6 alkyl (e.g. tert -butyl), preferably _C1 - _C4 alkyl, more preferably _C1 - _C2 alkyl, most preferably _C1 alkyl which is mono-, di- or tri-substituted with trialkylsilyl- _C1 - _C7 alkoxy (e.g. trimethylsilylethoxy),

aryl, preferably phenyl or a heterocyclic group (e.g. benzyl, cumyl, benzhydryl, pyrrolidinyl, trityl, pyrrolidinylmethyl, 1-methyl-1,1-dimethylbenzyl, (phenyl)methylbenzene), wherein the aryl ring or heterocyclic group is unsubstituted or substituted by one or more, such as two or three, residues, such as those selected from the group consisting of C₁-C₇alkyl, hydroxy, C₁-C₇alkoxy (eg para-methoxybenzyl (PMB)), C₂-C₈-alkanoyloxy, halogen, nitro, cyano and CF₃,

aryl-C₁-C₂-alkoxycarbonyl (preferably phenyl-C₁-C₂-alkoxycarbonyl (for example, benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), pivaloyloxymethyl (POM)), C₁-C₁₀-alkenyloxycarbonyl, C₁-C₆alkylcarbonyl (eg acetyl or pivaloyl), C₆-C₁₀-arylcarbonyl, C₁-C₆-alkoxycarbonyl (for example,third-butoxycarbonyl (Boc), methylcarbonyl, trichloroethoxycarbonyl (Troc), pivaloyl (Piv), allyloxycarbonyl), C₆-C₁₀-arylC₁-C₆-alkoxycarbonyl (for example, 9-fluorenylmethyloxycarbonyl (Fmoc)), allyl or cinnamyl, sulfonyl or sulfenyl, succinimidyl group, silyl groups (e.g. triarylsilyl, trialkylsilyl, triethylsilyl (TES), trimethylsilylethoxymethyl (SEM), trimethylsilyl (TMS), triisopropylsilyl orrubs-butyldimethylsilyl).

According to the present invention, a preferred protecting group (PG) can be selected from the group consisting of tert -butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), para-methoxybenzyl (PMB), methyloxycarbonyl and benzyl. Preferably, the protecting group (PG) is tert- butyloxycarbonyl (Boc).

The term "phenyl" refers to a radical of the formula -C ₆ H ₅ .

The term "halobenzodioxole" refers to the 1,3-benzodioxole radical of the formula

wherein halogen is as defined above. Preferably both halogen groups are fluorine.

The term "stereoisomer" or "stereoisomers" refers to compounds that have identical chemical composition but differ in the arrangement of atoms or groups in space.

The term "diastereoisomer" or "diastereomer" refers to stereoisomers that are not mirror images of each other. Diastereoisomers are characterized by different physical properties and some differences in chemical behavior. Mixtures of diastereomers can be separated using analytical techniques such as chromatography or crystallization.

The term "enantiomer" refers to one molecule of a pair of molecular entities that are mirror images of each other and cannot be superimposed.

The term "enantiomeric mixture" refers to a mixture enriched in one enantiomer, a composition that contains a greater proportion or increased percentage of one of the enantiomers of the compounds of the present invention compared to the other enantiomer, or a racemate.

The term "diastereomeric mixture" refers to a mixture enriched in a diastereomer or to a mixture of diastereoisomers in equal proportions.

The term "diastereomer-enriched" refers to a composition that contains a greater proportion or increased percentage of one of the diastereomers of the compounds of the present invention compared to the other diastereoisomer(s).

The term "atropisomer" refers to a stereoisomer resulting from hindered rotation about single bonds, where the barrier to rotation is high enough to allow isolation of individual isomers. Typically, rotation about a single bond in a molecule is prevented or greatly slowed by steric interactions with other parts of the molecule, and the substituents at either end of the single bond are asymmetric, leading to the concept of mirror-rotational symmetry called the "chiral axis".

As used in this document, the term "YAP" refers to yes-associated protein, also known as YAP1 or YAP65.

Whenever YAP is referred to in this document, it also refers to the YAP/TAZ complex.

As used herein, the term "YAP/TAZ-TEAD" refers to the YAP/TAZ complex with the transcription factor TEAD.

As used herein, the term "NF2/LATS1/LATS2" refers to "NF2", "LATS1" or "LATS2" or any combination thereof.

As used herein, the term "pharmaceutically acceptable carrier" includes any one or more substances selected from all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, coloring agents, and the like, and combinations thereof, which will be known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, ^18th Ed. Mack Printing Company, 1990, pp.1289-1329). Except where a conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical formulations is contemplated.

The term "therapeutically effective amount" of a compound of the present invention means an amount of a compound of the present invention that will elicit a biological or medical response in a subject, such as reducing or inhibiting the activity of an enzyme or protein, or ameliorating symptoms, alleviating conditions, slowing or delaying the progression of a disease, or preventing a disease, etc. In one non-limiting embodiment, the term "therapeutically effective amount" means an amount of a compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent, and/or ameliorate a condition or disorder or disease (i) mediated by a YAP/TAZ-TEAD protein-protein interaction (PPI), or (ii) associated with YAP/TAZ-TEAD PPI activity, or (iii) characterized by YAP/TAZ-TEAD PPI activity, or (2) reduce or inhibit YAP/TAZ-TEAD PPI activity, or (3) reduce or inhibit YAP/TAZ-TEAD expression. In another non-limiting embodiment, the term "therapeutically effective amount" means an amount of a compound of the present invention that, when administered to a cell or tissue or non-cellular biological material or environment, is effective in at least partially reducing or inhibiting the activity of YAP/TAZ-TEAD PPI.

As used herein, the term "subject" refers to an animal. Typically, the animal is a mammal. The subject also refers to, for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In still other embodiments, the subject is a human.

As used herein, the terms "suppress," "suppression," or "suppressing" mean a reduction in the severity or suppression of the condition, symptom, disorder, or disease in question, or a significant reduction from the baseline level of activity with respect to a biological activity or process.

As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refer in one embodiment to reducing the severity of the disease or disorder (i.e., slowing or halting or reducing the progression of the disease or at least one of its clinical symptoms). In another embodiment, the terms "treat," "treating," or "treating" refer to alleviating or reducing the severity of at least one physical parameter, including those that may not be perceived by the patient. In yet another embodiment, "treat," "treating," or "treating" means modulating the disease or disorder either physically (e.g., stabilizing a significant symptom), physiologically (e.g., stabilizing a physical parameter), or both. In yet another embodiment, "treat," "treating," or "treating" refers to preventing or delaying the onset or development or progression of the disease or disorder.

As used in this document, a subject "needs" treatment if the subject would benefit biologically, medically, or improve his or her quality of life as a result of such treatment.

As used herein, the singular and similar terms used in the context of the present invention (in particular, in the context of the claims) are to be construed as covering both the singular and the plural forms, unless otherwise indicated herein or clearly contradicted by context.

When names of compounds have the symbol * next to the stereochemical configuration, for example in 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), then it refers to a racemic mixture of both 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, respectively. The 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 interpreted accordingly.

If the structures of a compound are depicted with undefined absolute stereochemistry, such as in Example 2a

(no wedge bonds), this means the presence of a racemic mixture of a single diastereoisomer with the indicated relative stereochemistry.

To avoid ambiguity, when compounds are depicted with a wedge bond, such as in Example 2a-1, this indicates the presence of a single diastereomer with the absolute stereochemistry as indicated in the chemical structure. Thus, the compound of Example 2a-1 with the structure shown below,

is a compound N1-(2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenyl)ethane-1,2-diamine.

The compounds of the present invention may also be named using the Cahn-Ingold-Prelog (CIP) chirality rule, using the stereochemical notations ( P ) or ( M ) Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013 (the IUPAC "Blue Book"), Cambridge, UK: Royal Soc. of Chem., 2014, https://doi.org/10.1039/9781849733069, Chapter P-9, "Specification of Configuration and Conformation", https://doi.org/10.1039/9781849733069-01156).

The stereochemical designations "cis" and "trans" may be used to describe the relative configuration of the substituents on the cycloalkyl ring of the compounds exemplified herein that bear a disubstituted 1,4-cyclohexyl or 1,3-cyclobutyl moiety. The stereochemical designations "cis" or "trans" describe the relative grouping of the substituents with the highest CIP priority at each of the two substituted positions on the cycloalkyl ring. For example, in the case of Example 114a, the stereochemical designation "trans" means that the hydroxyl and amino groups on the cyclohexyl ring are located on opposite sides of the plane of the cyclohexyl ring; while in the case of Example 114b, the stereochemical designation "cis" means that the hydroxyl and amino groups are located on the same side of the plane of the cyclohexyl ring.

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.

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

Alternatively, the following names of the compounds from Example 114a and Example 114b may be used:

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

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

If the stereocenter at position 2 on the dihydrobenzofuran ring of the compounds of the present invention is drawn as shown below (i.e. with wedge bonds)

,

then this can also be represented as

or how

.

Thus, it will be understood that, where applicable, the stereochemistry at this position of a compound of the present invention may be depicted as either a conventional bond with substituent "A" or "Q" or as a wedge bond with substituent "A" or substituent "Q".

In one embodiment of the first, second, third or fourth aspect of the present invention, there is provided a compound of formula (Ia) or a pharmaceutically acceptable salt thereof,

wherein the substituents are defined as above in the first, second, third or fourth embodiments of the present invention.

In a preferred embodiment, A is a phenyl ring.

In a further embodiment of the first, second, third or fourth aspect of the present invention, there is provided a compound of formula (Ia*) or a pharmaceutically acceptable salt thereof,

wherein the substituents are defined as above in the first, second, third or fourth embodiments of the present invention.

If R ₂ is halogen, R ₂ is preferably fluorine. If R ₃ is halogen, R ₃ is preferably chlorine. If R ₄ is halogen, R ₄ is preferably fluorine. In a preferred embodiment, R ₃ is chlorine and R ₄ is fluorine. In a more preferred embodiment, R ₂ is fluorine, R ₃ is chlorine and R ₄ is fluorine.

In a preferred embodiment, A is a phenyl ring.

In another embodiment of the first, second, third or fourth aspect of the present invention, there is provided a compound of formula (Ia-1) or a pharmaceutically acceptable salt thereof,

wherein the substituents are defined as above in the first, second, third or fourth embodiments of the present invention.

In another embodiment of the first, second, third or fourth aspect of the present invention, there is provided a compound of formula (Ia-1) or a pharmaceutically acceptable salt thereof,

wherein the substituents are defined as above in the first, second, third or fourth embodiments of the present invention.

If R ₂ is halogen, R ₂ is preferably fluorine. If R ₃ is halogen, R ₃ is preferably chlorine. In a preferred embodiment, R ₃ is chlorine. In a more preferred embodiment, R ₂ is fluorine and R ₃ is chlorine.

In another embodiment of the first, second, third or fourth aspect of the present invention, there is provided a compound of formula (Ib) or a pharmaceutically acceptable salt thereof,

wherein the substituents are defined as above in the first, second, third or fourth embodiments of the present invention.

In a preferred embodiment, A is a phenyl ring.

In a further embodiment of the first, second, third or fourth aspect of the present invention, there is provided a compound of formula (Ic) or a pharmaceutically acceptable salt thereof,

wherein the substituents are defined as above in the first, second, third or fourth embodiments of the present invention, and preferably R ₃ and R ₄ have a meaning other than hydrogen, as disclosed for the corresponding aspect of the invention.

In a preferred embodiment, A is a phenyl ring.

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

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

In a further embodiment of the first, second, third or fourth aspect of the present invention, there is provided a compound of formula (Id) or a pharmaceutically acceptable salt thereof,

wherein the substituents are defined as above in the first, second, third or fourth embodiments of the present invention, and preferably R ₃ and R ₄ have a meaning other than hydrogen, as disclosed for the corresponding aspect of the invention.

In a preferred embodiment, A is a phenyl ring.

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

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

Various numbered embodiments of the present invention are described herein. It should be understood that the features recited in each embodiment may be combined with one, more than one, or all of the other features recited to produce additional embodiments of the present invention.

Embodiment 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,

Where

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;

where if Y is N, W is CH-R _w , and Z is O;

A is selected from

(i) phenyl, wherein phenyl is optionally substituted with halogen or halogenC ₁ -C ₃ alkoxy;

(ii) a 5- or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O and S, preferably from N and S, wherein the aromatic heterocyclic ring is optionally substituted with hydroxy, C ₁ -C ₃ alkoxy or oxo; and

(iii) a halogen benzodioxol fragment of the formula

R _w is selected from (i) hydrogen, (ii) hydroxy, (iii) C ₁ -C ₃ alkoxy, (iv) hydroxy-C ₁ -C ₃ alkyl, (v) C ₁ -C ₃ alkyl and (vi) C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl;

Q is selected from (i) -C(R ⁷ ) ₂ -N(R ⁸ ) -R ₁ , (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 heteroatomic group selected from N, O, S, -S(=O) and -S(=O) ₂ , with the proviso that at least one N heteroatom is present, wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen and C ₁ -C ₃ alkylene, to form a bridge between two ring atoms of the saturated heterocyclic ring, thereby forming a bridged bicyclic structure;

R ₁ is selected from (i) hydrogen, (ii) C ₁ -C ₆ alkyl (wherein the alkyl in one embodiment is optionally deuterated, such as perdeuterated) and (iii) (CH ₂ ) _0-2 R _1a ;

R _1a is selected from (i) hydroxyC ₁ -C ₄ alkyl, (ii) C ₁ -C ₃ alkoxy, (iii) a 5- or 6-membered saturated heterocyclic ring containing at least one heteroatom selected from N and O, wherein the saturated heterocyclic ring is optionally independently substituted once or more than once with C ₁ -C ₃ alkyl, (CH ₂ ) _0-1 C(O)di(C ₁ -C ₃ alkyl)amino, SO ₂ C ₁ -C ₃ alkyl, C(O)C ₁ -C ₃ alkyl or oxo, (iv) C ₃ -C ₆ cycloalkyl optionally independently substituted once or more than once with hydroxy, hydroxyC ₁ -C ₄ alkyl, C ₁ -C ₆ alkoxy, preferably C ₁ -C ₄ alkoxy, C(O)OC _{1 - C3} alkyl, _{CO2H , SO2C1} -C3 alkyl, _halogenC1 -C3 ^alkyl , ^NHR1b , ( _CH2 ) _0-1C (O) ^NR1cR1d , preferably _{C(O)NR1cR1d, C1-C6 alkyl, halogenC1-C3 alkoxy-C1-C3} ^alkyl _{, halogen , a 5-} ^or ₆ -membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O and S, or two ^R1e groups,

wherein two R ^1e , attached at the same carbon atom, 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 (which is preferred) and O, or C ₃ -C ₆ cycloalkyl, the saturated heterocyclic ring or cycloalkyl being optionally substituted with hydroxy or oxo;

R ^1b is selected from (i) C(O)C ₁ -C ₃ alkyl and (ii) SO ₂ C ₁ -C ₃ alkyl;

each of R ^1c and R ^1d is independently selected from (i) hydrogen, (ii) C ₁ -C ₃ alkyl and (iii) hydroxyC ₁ -C ₄ alkyl, preferably from (i) hydrogen and (ii) C ₁ -C ₃ alkyl;

R ₂ is selected from (i) hydrogen and (ii) halogen;

R ₃ is selected from (i) halogen, (ii) haloC ₁ -C ₃ alkyl, in particular from halogen and mono-, di- or preferably trihalomethyl and (iii) cyano;

R ₄ is selected from (i) hydrogen, (ii) halogen and (iii) C ₁ -C ₃ alkyl, in particular from hydrogen, halogen and methyl;

R ₅ is selected from (i) hydrogen, (ii) C ₁ -C ₆ alkoxy optionally substituted with C ₃ -C ₆ cycloalkyl, CO ₂ H, SO ₂ C ₁ -C ₃ alkyl, 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, or a 5- or 6-membered saturated heterocyclic ring containing at least one heteroatom selected from N and O, wherein the ring is optionally substituted with C(O)C ₁ -C ₃ alkyl;

(iii) halogen, (iv) hydroxyC ₁ -C ₆ alkoxy (wherein the alkoxy portion in one embodiment is optionally deuterated, such as perdeuterated), (v) halogenC ₁ -C ₆ alkoxy optionally substituted with hydroxy, (vi) S-halogenC ₁ -C ₃ alkyl optionally substituted with hydroxy, (vii) C ₁ -C ₃ alkoxyC ₁ -C ₃ alkoxy, (viii) NR ^5a R ^5b , (ix) C ₁ -C ₃ alkyl, (x) 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 (xi) hydroxy;

each of R ^5a and R ^5b is independently selected from (i) hydrogen and (ii) C ₁ -C ₃ 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, the saturated heterocyclic ring optionally further bearing a hydroxyl group;

R ₆ is selected from (i) hydrogen, (ii) cyano, (iii) C(O)NHR ^6a , (iv) NHR ^6b and (v) C ₁ -C ₃ alkoxy substituted with NH ₂ or hydroxy;

R ^6a is selected from (i) hydrogen, (ii) C ₁ -C ₃ alkyl, (iii) C ₃ -C ₆ cycloalkyl, (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, wherein the aromatic heterocyclic ring is optionally substituted with C ₁ -C ₃ alkyl;

R ^6b is C ₁ -C ₃ alkyl substituted with NH ₂ or hydroxy;

each R ⁷ is independently selected from hydrogen and C ₁ -C ₃ alkyl; and

R ⁸ represents hydrogen or C ₁ -C ₃ -alkyl, in particular hydrogen or methyl.

Embodiment 2. A compound of formula (I) according to embodiment 1 or a pharmaceutically acceptable salt thereof,

W is CH-R _w ;

X is selected from CH and N;

Y represents CH;

Z is selected from O and NH;

A is selected from

(i) phenyl, wherein phenyl is optionally substituted with halogen or halogenC ₁ -C ₃ alkoxy;

(ii) a 5- or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O and S, preferably from N and S, wherein the aromatic heterocyclic ring is optionally substituted with hydroxy, C ₁ -C ₃ alkoxy or oxo; and

(iii) a halogen benzodioxol fragment of the formula

R _w is selected from (i) hydrogen, (ii) hydroxy, (iii) C ₁ -C ₃ alkoxy, (iv) hydroxy-C ₁ -C ₃ alkyl, (v) C ₁ -C ₃ alkyl and (vi) C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl;

Q is selected from (i) -C(R ⁷ ) ₂ -N(R ⁸ )-R ¹ , (ii) a 9- or 10-membered partially saturated heteroaryl containing at least one N heteroatom, preferably wherein N is present in the α-position with respect to the atom linking Q to the rest of the molecule, 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, preferably wherein N is present in the α-position with respect to the atom linking Q to the rest of the molecule, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy and halogen;

R ₁ is selected from hydrogen, C ₁ -C ₆ alkyl and (CH ₂ ) _0-2 R _1a , where

R _1a is selected from (i) C ₁ -C ₃ alkoxy, (ii) C ₃ -C ₆ cycloalkyl optionally independently substituted once or more than once with hydroxy, hydroxyC ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C(O)OC ₁ -C ₃ alkyl, CO ₂ H, C(O)NR ^1c R ^1d , C ₁ -C ₆ alkyl, halogen, haloC ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, SO ₂ C ₁ -C ₃ alkyl, haloC ₁ -C ₃ alkyl, NHR ^1b , C(O)NR ^1c R ^1d , a 5- or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O and S, or two R ^1e ; (iii) a 5- or 6-membered saturated heterocyclic ring containing at least one heteroatom selected from N and O, wherein the saturated heterocyclic ring is optionally independently substituted once or more than once with _C1 - _C3 alkyl, ( _CH2 ) _0-1C (O)di( _C1 - _C3 alkyl)amino, _{SO2C1 -C3 alkyl} , C(O) _C1 - _C3 alkyl or oxo;

R ^1b is selected from C(O)C ₁ -C ₃ alkyl and SO ₂ C ₁ -C ₃ alkyl;

each of R ^1c and R ^1d is independently selected from (i) hydrogen, (ii) C ₁ -C ₃ alkyl and (iii) hydroxyC ₁ -C ₄ alkyl,

wherein two R ^1e , attached at the same carbon atom, 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 (preferably) and O, or C ₃ -C ₆ cycloalkyl, the saturated heterocyclic ring or cycloalkyl being optionally substituted with hydroxy or oxo;

R ₂ represents hydrogen or preferably halogen;

R ₃ is halogen, haloC ₁ -C ₃ alkyl, in particular mono-, di- or preferably trihalomethyl, or cyano;

R ₄ is selected from hydrogen, halogen and C ₁ -C ₃ alkyl (in particular methyl);

R ₅ is selected from (i) hydrogen, (ii) haloC ₁ -C ₆ alkoxy optionally substituted with hydroxy, (iii) S-haloC ₁ -C ₃ alkyl optionally substituted with hydroxy, (iv) C ₁ -C ₃ alkoxyC ₁ - _{C 3} alkoxy, (v) C ₁ -C ₆ alkoxy optionally substituted with SO ₂ C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, CO ₂ H, or a 5- or 6-membered saturated heterocyclic ring containing at least one heteroatom selected from N and O, the ring being optionally substituted with C(O)C ₁ -C ₃ alkyl, (vi) C ₁ -C ₃ alkyl, (vii) hydroxyC ₁ -C ₆ alkoxy, (viii) 5- or 6-membered aromatic a heterocyclic ring containing at least one heteroatom selected from N, O and S, preferably at least one N heteroatom, and (ix) hydroxy;

R ₆ is cyano, C(O)NHR ^6a , NHR ^6b or C ₁ -C ₃ alkoxy substituted with NH ₂ or hydroxy;

R ^6a is selected from (i) hydrogen, (ii) C ₁ -C ₃ alkyl, (iii) C ₃ -C ₆ 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, wherein the aromatic heterocyclic ring is optionally substituted with C ₁ -C ₃ alkyl;

R ^6b is C ₁ -C ₃ alkyl substituted with NH ₂ or hydroxy;

each R ⁷ is independently selected from hydrogen or C ₁ -C ₃ alkyl; and

R ⁸ represents hydrogen or C ₁ -C ₃ -alkyl, in particular methyl.

Embodiment 3. The compound according to Embodiment 1 or a pharmaceutically acceptable salt thereof,

Where

W is CH-R _w ;

X is selected from CH and N;

Y represents CH;

Z is selected from O and NH;

A represents phenyl, wherein phenyl is optionally substituted with halogen or halogenC ₁ -C ₃ alkoxy;

R _w is selected from (i) hydrogen, (ii) C ₁ -C ₃ alkoxy, (iii) hydroxy-C ₁ -C ₃ alkyl, (iv) C ₁ -C ₃ alkyl and (v) C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl;

Q is selected from (i) -C(R ⁷ ) ₂ -NH-R ₁ 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, preferably where N is present in the α-position with respect to the atom linking Q to the rest of the molecule, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from hydroxy, C ₁ -C ₃ alkyl and halogen;

R ₁ is selected from (i) C ₁ -C ₆ alkyl, (ii) R _1a; , where

R _1a is selected from C ₃ -C ₆ cycloalkyl optionally independently substituted once or more than once with hydroxy, C ₁ -C ₆ alkyl or halogen;

R ₂ represents hydrogen or preferably halogen;

R ₃ is halogen;

R ₄ is selected from (i) hydrogen and (ii) halogen;

R ₅ is selected from hydroxy, C ₁ -C ₆ alkoxy and hydroxyC ₁ -C ₆ alkoxy;

R ₆ is C(O)NHR ^6a ;

R ^6a is selected from (i) hydrogen and (ii) C ₁ -C ₃ alkyl;

And

each R ⁷ is independently selected from hydrogen or C ₁ -C ₃ alkyl.

Embodiment 4. A compound of formula I according to any one of embodiments 1 to 3,

Where

W is CH-R _w ;

X is selected from CH and N;

Y represents CH;

Z is selected from O and NH;

A represents phenyl, wherein phenyl is optionally substituted by halogen or halogenC ₁ -C ₃ alkoxy, in particular unsubstituted phenyl;

R _w is selected from (i) hydrogen and (ii) C ₁ -C ₃ alkyl or is hydroxy-C ₁ -C ₃ alkyl;

Q is selected from (i) -C(R ⁷ ) ₂ -NH-R ₁ 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 is in the α-position with respect to the carbon atom linking Q to the rest of the molecule, wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from hydroxy, C ₁ -C ₃ alkyl and halogen;

R ₁ is selected from (i) C ₁ -C ₆ alkyl, (ii) R _1a; , where

R _1a is selected from C ₃ -C ₆ cycloalkyl optionally independently substituted once or more than once with hydroxy, C ₁ -C ₆ alkyl or halogen;

R ₂ is a halogen, in particular fluorine;

R ₃ is a halogen, in particular chlorine;

R ₄ represents a halogen, in particular fluorine;

R ₅ is selected from C ₁ -C ₆ alkoxy and hydroxyC ₁ -C ₆ alkoxy;

R ₆ is C(O)NHR ^6a ;

R ^6a is selected from (i) hydrogen and (ii) C ₁ -C ₃ alkyl;

And

each R ⁷ is a hydrogen.

Embodiment 5. A compound according to embodiments 1, 2, 3 or 4 of formula (Ia) or a pharmaceutically acceptable salt thereof,

Embodiment 6. A compound according to embodiments 1, 2, 3, 4 or 5 of formula (Ia-1) or a pharmaceutically acceptable salt thereof,

Embodiment 7. A compound according to embodiments 1, 2, 3, 4 or 5 of formula (Ib) or a pharmaceutically acceptable salt thereof,

Embodiment 8. A compound according to embodiments 1, 2, 3, 4 or 5 of formula (Ic) or a pharmaceutically acceptable salt thereof,

Embodiment 9. A compound according to embodiments 1, 2, 3, 4 or 5 of formula (Id) or a pharmaceutically acceptable salt thereof,

Embodiment 10. A compound according to embodiments 1, 2, 3 or 4, or a pharmaceutically acceptable salt thereof, wherein Y is CH.

Embodiment 11. A compound according to embodiments 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof, wherein Y is CH and W is CH-R _W .

Embodiment 12. A compound according to embodiments 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof, wherein Y is CH, W is CH-R _W , and Z is O.

Embodiment 13. A compound according to any one of embodiments 1-5, 7-12, or a pharmaceutically acceptable salt thereof, wherein A is a phenyl ring, wherein the phenyl ring is unsubstituted.

Embodiment 14. A compound according to any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein R ₃ is chlorine.

Embodiment 15. A compound according to any one of embodiments 1-5, 7-14, or a pharmaceutically acceptable salt thereof, wherein R ₄ is fluoro.

Embodiment 16. A compound according to any one of embodiments 1-15, or a pharmaceutically acceptable salt thereof, wherein R ₂ is fluoro.

Embodiment 17. A compound according to any one of embodiments 1-5, 8-16, or a pharmaceutically acceptable salt thereof, wherein X is CH.

Embodiment 18. A compound according to any one of embodiments 1-5, 8-16, or a pharmaceutically acceptable salt thereof, wherein X is N.

Embodiment 19. A compound according to any one of Embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein R ₅ is selected from (i) C ₁ -C ₆ alkoxy optionally substituted with C ₃ -C ₆ cycloalkyl, CO ₂ H; SO ₂ C ₁ -C ₃ alkyl, a 5- or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O, and S, or a 5- or 6-membered saturated heterocyclic ring containing at least one heteroatom selected from N and O, wherein the ring is optionally substituted with C(O)C ₁ -C ₃ alkyl, (ii) hydroxyC ₁ -C ₆ alkoxy, (iii) halogenC ₁ -C ₆ alkoxy optionally substituted with hydroxy, (iv) C ₁ -C ₃ alkoxyC ₁ -C ₃ alkoxy.

Embodiment 20. A compound according to Embodiment 19, or a pharmaceutically acceptable salt thereof, wherein R ₅ is selected from (i) C ₁ -C ₆ alkoxy optionally substituted with C ₃ -C ₆ cycloalkyl, CO ₂ H, SO ₂ C ₁ -C ₃ alkyl, a 6-membered aromatic heterocyclic ring containing at least one N heteroatom, or a 5- or 6-membered saturated heterocyclic ring containing at least one heteroatom selected from N and O, wherein the ring is optionally substituted with C(O)C ₁ -C ₃ alkyl;

(ii) hydroxyC ₁ -C ₆ alkoxy, (iii) halogenC ₁ -C ₆ alkoxy optionally substituted with hydroxy; (iv) C ₁ -C ₃ alkoxyC ₁ -C ₃ alkoxy.

Embodiment 21. A compound according to any one of Embodiments 1-20, or a pharmaceutically acceptable salt thereof, wherein R ₅ is selected from (i) C ₁ -C ₆ alkoxy, (ii) hydroxyC ₁ -C ₆ alkoxy, (iii) haloC ₁ -C ₆ alkoxy optionally substituted with hydroxy; (iv) C ₁ -C ₃ alkoxyC ₁ -C ₃ alkoxy.

Embodiment 22. A compound according to any one of embodiments 1-21, or a pharmaceutically acceptable salt thereof, wherein R ₅ is hydroxyC ₁ -C ₆ alkoxy or C ₁ -C ₆ alkoxy, preferably wherein R ₅ is hydroxyC ₁ -C ₆ alkoxy.

Embodiment 23. A compound according to any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, wherein R ₆ is selected from (i) cyano, (ii) C(O)NHR ^6a , preferably R ₆ is C(O)NHR ^6a .

Embodiment 24. A compound according to embodiment 23 or a pharmaceutically acceptable salt thereof, wherein R ^6a is selected from (i) hydrogen, (ii) C ₁ -C ₃ alkyl, (iii) C ₃ -C ₆ cycloalkyl, (iv) a 5- or 6-membered aromatic heterocyclic ring containing at least one N heteroatom, wherein the aromatic heterocyclic ring is optionally substituted with C ₁ -C ₃ alkyl.

Embodiment 25. A compound according to any one of Embodiments 1-24, or a pharmaceutically acceptable salt thereof, wherein R ^6a is hydrogen or C ₁ -C ₃ alkyl.

Embodiment 26. A compound according to any one of Embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein R ^6a is C ₁ -C ₃ alkyl.

Embodiment 27. A compound according to any one of Embodiments 1-26, or a pharmaceutically acceptable salt thereof, wherein R ^6a is methyl.

Embodiment 28. A compound according to any one of Embodiments 1 to 27, or a pharmaceutically acceptable salt thereof, wherein Q is (i) -C(R ⁷ ) ₂ -N(R ₈ )-R ₁ , preferably Q is -C(R ⁷ ) ₂ -NH-R ₁ , (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 selected from N, O and S, 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 hydroxy, _C1 - _C3 alkyl, _C1 - _C3 alkoxy, halogen and _C1 - _C3 alkylene, to form a bridge between two ring atoms of the saturated heterocyclic ring, thereby forming a bridged bicyclic structure.

Embodiment 29. A compound according to any one of embodiments 1-28, or a pharmaceutically acceptable salt thereof, wherein Q is -C(R ⁷ ) ₂ -N(R ₈ )-R ₁ , preferably Q is -C(R ⁷ ) ₂ -NH-R ₁ or is selected from the group consisting of:

Embodiment 30. A compound according to any one of embodiments 1-29, or a pharmaceutically acceptable salt thereof, wherein Q is -C(R ⁷ ) ₂ -N(R ₈ )-R ₁ , preferably Q is -C(R ⁷ ) ₂ -NH-R ₁ or is selected from the group consisting of:

, And .

Embodiment 31. A compound according to any one of embodiments 1-30, or a pharmaceutically acceptable salt thereof, wherein Q is -C(R ⁷ ) ₂ -N(R ₈ )-R ₁ , preferably Q is -C(R ⁷ ) ₂ -NH-R ₁ or is selected from the group consisting of:

Embodiment 32. A compound according to any one of Embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein Q is

Embodiment 33. A compound according to any one of Embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from (i) hydrogen, (ii) C ₁ -C ₆ alkyl, (iii) (CH ₂ ) _0-2 R _1a ;

Where

R _1a is selected from (i) hydroxyC ₁ -C ₄ alkyl, (ii) C ₁ -C ₃ alkoxy, (iii) a 5- or 6-membered saturated heterocyclic ring containing at least one heteroatom selected from N and O, wherein the saturated heterocyclic ring is optionally independently substituted once or more than once with C ₁ -C ₃ alkyl, (CH ₂ )C(O)di(C ₁ -C ₃ alkyl)amino, SO ₂ C ₁ -C ₃ alkyl, C(O)C ₁ -C ₃ alkyl or oxo;

(iv) _C3 - _C6 cycloalkyl optionally independently substituted once or more than once with hydroxy, hydroxyC1 _{- C4} alkyl, _C1 - _C6 alkoxy, preferably _C1 - _C4 alkoxy, C(O) _OC1 - _{C3 alkyl} , _CO2H , SO2C1- _C3 alkyl, haloC1- _C3 alkyl, _NHR1b , C(O ^{)NR1cR1d ,} _{C1 - C6} alkyl, ^haloC1 - _C3 alkoxy- _C1 - _C3 alkyl, halogen, a 5-membered aromatic heterocyclic ring containing at least one N heteroatom, or _two ^R1e ,

wherein 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 heterocyclic ring containing at least one N or C ₃ -C ₆ cycloalkyl heteroatom, the saturated heterocyclic ring or cycloalkyl being optionally substituted with hydroxy or oxo.

Embodiment 34. A compound according to Embodiment 33 or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from (i) C ₁ -C ₆ alkyl, (ii) (CH ₂ ) _0-2 R _1a ;

Where

R _1a is selected from (i) hydroxyC ₁ -C ₄ alkyl, (ii) C ₃ -C ₆ cycloalkyl, preferably cyclohexyl, optionally independently substituted once or more than once with hydroxy, hydroxyC ₁ -C ₄ alkyl, C ₁ -C ₆ alkoxy, preferably C ₁ -C ₄ alkoxy, C(O)OC ₁ -C ₃ alkyl, CO ₂ H, SO ₂ C ₁ -C ₃ alkyl, haloC ₁ - _{C 3} alkyl, NHR ^1b , C(O)NR ^1c R ^1d , C ₁ -C ₆ alkyl, haloC ₁ - _{C 3} alkoxy-C ₁ -C ₃ alkyl, halogen, a 5-membered aromatic heterocyclic ring containing at least one N heteroatom, or R ^1e ,

wherein 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 heterocyclic ring containing at least one N heteroatom, wherein the saturated heterocyclic ring is substituted with oxo, or C ₃ -C ₆ cycloalkyl, wherein the cycloalkyl is substituted with hydroxy.

Embodiment 35. A compound according to any one of Embodiments 1-31, 33 or 34, or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from (i) C ₁ -C ₆ alkyl, (ii) (CH ₂ ) ₀ R _1a ;

Where

R _1a is C ₃ -C ₆ cycloalkyl, preferably cyclohexyl, optionally independently substituted once or more than once with hydroxy, hydroxyC ₁ -C ₄ alkyl, C ₁ -C ₆ alkoxy, preferably C ₁ -C ₄ alkoxy, C(O)OC ₁ -C ₃ alkyl, CO ₂ H; SO ₂ C ₁ -C ₃ alkyl, haloC ₁ -C ₃ alkyl, NHR ^1b , C(O)NR ^1c R ^1d , C ₁ -C ₆ alkyl, haloC ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl or halogen.

Embodiment 36. A compound according to any one of Embodiments 1-31, 33-35, or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from (i) C ₁ -C ₆ alkyl, (ii) (CH ₂ ) ₀ R _1a ;

Where

R _1a is C ₃ -C ₆ cycloalkyl, preferably cyclohexyl, optionally independently substituted once or more than once with hydroxy, hydroxyC ₁ -C ₄ alkyl, C ₁ -C ₆ alkoxy, preferably C ₁ -C ₄ alkoxy, C(O)OC ₁ -C ₃ alkyl, haloC ₁ -C ₃ alkyl, C ₁ -C ₆ alkyl or halogen.

Embodiment 37. A compound according to any one of Embodiments 1-31, 33-36, or a pharmaceutically acceptable salt thereof, wherein R ₁ is (CH ₂ ) ₀ R _1a , wherein

R _1a is cyclohexyl, optionally independently substituted once or more than once with hydroxy, hydroxyC ₁ -C ₄ alkyl, C ₁ -C ₆ alkoxy, preferably C ₁ -C ₄ alkoxy, C(O)OC ₁ -C ₃ alkyl, haloC ₁ -C ₃ alkyl, C ₁ -C ₆ alkyl or halogen.

Embodiment 38. A compound according to any one of Embodiments 1-31, 33-37, or a pharmaceutically acceptable salt thereof, wherein R ₁ is (CH ₂ ) ₀ R _1a , wherein

R _1a is cyclohexyl independently substituted twice with hydroxy; hydroxyC ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogenC ₁ -C ₃ alkyl, C ₁ -C ₆ alkyl or halogen.

Embodiment 39. A compound according to any one of Embodiments 1-31, 33-38, or a pharmaceutically acceptable salt thereof, wherein R ₁ is (CH ₂ ) ₀ R _1a , wherein

R _1a is cyclohexyl independently substituted twice with hydroxy and C ₁ -C ₆ alkyl.

Embodiment 40. A compound according to any one of Embodiments 1-31, 33-39, or a pharmaceutically acceptable salt thereof, wherein R ₁ is

.

Embodiment 41. A compound according to any one of Embodiments 1-31, 33-40, or a pharmaceutically acceptable salt thereof, wherein R ₁ is

.

Embodiment 42. A compound according to any one of Embodiments 1-31, 33-41, or a pharmaceutically acceptable salt thereof, wherein each R ⁷ is independently selected from hydrogen and C ₁ -C ₃ alkyl.

Embodiment 43. A compound according to any one of embodiments 1-31, 33-42, or a pharmaceutically acceptable salt thereof, wherein both R ⁷ groups are hydrogen.

Embodiment 44. A compound according to any one of embodiments 1-31, 33-42, or a pharmaceutically acceptable salt thereof, wherein one R ⁷ is hydrogen and the other is C ₁ -C ₃ alkyl.

Embodiment 45. A compound according to any one of embodiments 1-31, 33-42, 44, or a pharmaceutically acceptable salt thereof, wherein one R ⁷ is hydrogen and the other is methyl.

Embodiment 46. A compound according to any one of Embodiments 1-31, 33-43, or a pharmaceutically acceptable salt thereof, wherein Q is _-CH2- NH- _R1 , wherein _R1 is as defined in any one of Embodiments 33-41.

Embodiment 47. A compound according to any one of Embodiments 1-31, 33-43, 46, or a pharmaceutically acceptable salt thereof, wherein Q is

.

Embodiment 48. A compound according to any one of Embodiments 1-31, 33-43, 46, 47, or a pharmaceutically acceptable salt thereof, wherein Q is

.

Embodiment 49. A compound according to any one of embodiments 1-31, 33-36, 42, 43, 46, or a pharmaceutically acceptable salt thereof, wherein Q is -CH ₂ -NH-C ₁ -C ₆ alkyl.

Embodiment 50. A compound according to any one of embodiments 1-31, 33-36, 42, 43, 46, 49, or a pharmaceutically acceptable salt thereof, wherein Q is -CH ₂ -NH-CH ₃ .

Embodiment 51. A compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the examples of compounds or from the compounds listed in claim 8.

Embodiment 52. A compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein said compound is selected from:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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;

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

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

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

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

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

2-((2R,4S)-2-(aminomethyl)-5-chloro-2-(thiazol-4-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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;

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

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;

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;

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

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

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

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

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;

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

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

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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

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

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;

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;

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

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

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

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

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

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;

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;

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;

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;

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

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

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;

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;

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;

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;

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;

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;

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;

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

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;

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;

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

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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)benzonitrile;

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;

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;

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;

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

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;

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;

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;

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

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;

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;

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;

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;

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

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

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

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

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;

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;

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;

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

4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide;

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

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.

Embodiment 53. A compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:

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

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;

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

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;

2-((2S,4S)-2-(azetidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide;

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

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

(2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide;

2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide;

2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide;

4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide;

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

4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-hydroxy-N-methylnicotinamide;

2-((2S,4S)-5-chloro-6-fluoro-2-(4-hydroxypyrrolidin-2-yl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;

2-((2S,4S)-5-chloro-6-fluoro-2-(4-hydroxy-4-methylpyrrolidin-2-yl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide;

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

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;

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

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

2-((2S,3S,4S)-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2-(pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

2-((2S,3S,4S)-5-chloro-6-fluoro-3-methoxy-2-phenyl-2-(pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

2-((2S,3S,4S)-5-chloro-6-fluoro-3-methoxy-2-phenyl-2-(pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-phenyl-2-(pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide;

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

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;

2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)indolin-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;

2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)indolin-4-yl)-3-fluoro-4-methoxybenzamide;

2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)indolin-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide;

4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)indolin-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide;

2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;

2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro- 4-methoxy-N-methylbenzamide; And

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

Embodiment 54. A compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, selected from:

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;

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;

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

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;

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

2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)indolin-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide.

Embodiment 55. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1-54.

Embodiment 56. A combination comprising a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-54 and one or more therapeutically active agents.

Embodiment 57. The combination according to embodiment 56, wherein one or more therapeutically active agents are selected from an anticancer agent.

Embodiment 58. A compound according to any one of embodiments 1-54, or a pharmaceutically acceptable salt thereof, in co- or sequential combination with an anticancer therapeutic agent.

Embodiment 59. A compound or pharmaceutically acceptable salt thereof according to any one of Embodiments 1-54 for use as a medicine.

Embodiment 60. A compound or pharmaceutically acceptable salt thereof according to any one of embodiments 1-54 for use in suppressing YAP/TAZ-TEAD protein-protein interaction activity in a subject.

Embodiment 61. A compound or pharmaceutically acceptable salt thereof according to any one of embodiments 1-54 for use in the treatment of a disorder or disease that is treated by inhibiting the YAP/TAZ-TEAD protein-protein interaction in a subject, wherein preferably the disorder or disease is cancer.

Embodiment 62. A compound or pharmaceutically acceptable salt thereof according to any one of embodiments 1-54 for use in the treatment of a disorder or disease that is cancer or a tumor.

Embodiment 63. A compound or pharmaceutically acceptable salt thereof for use according to Embodiment 62, wherein the cancer or tumor is a cancer or tumor harboring (i) one or more YAP/TAZ fusions; (ii) one or more NF2/LATS1/LATS2 truncating or deletion mutations; or (iii) one or more functional YAP/TAZ fusions.

Embodiment 64. The compound or pharmaceutically acceptable salt thereof for use according to Embodiment 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 squamous cell carcinoma of the cervix, endometrial carcinoma, squamous cell carcinoma of the esophagus, adenocarcinoma of the esophagus, urothelial carcinoma of the bladder, and squamous cell carcinoma of the skin), poromoma (benign poromoma), porocarcinoma (including malignant porocarcinoma), supratentorial ependymoma (including supratentorial ependymoma in children), 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 colorectal carcinoma), melanoma, pancreatic cancer (including pancreatic adenocarcinoma), prostate cancer, gastric cancer, esophageal cancer, liver cancer (including hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma), neuroblastoma, schwannoma, renal cell carcinoma, sarcomas (including rhabdomyosarcoma, embryonal rhabdomyosarcoma (ERMS), osteosarcoma, undifferentiated pleomorphic sarcomas (UPS), Kaposi 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).

Embodiment 65. A compound or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 61-64, 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).

Embodiment 66. A method for inhibiting YAP/TAZ-TEAD protein-protein interaction activity in a subject, 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 embodiments 1-54.

Embodiment 67. A method for modulating the activity of a YAP/TAZ-TEAD protein-protein interaction in a subject in need thereof, 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 embodiments 1-54.

Embodiment 68. A method for suppressing, reducing, or eliminating a YAP/TAZ-TEAD protein-protein interaction, the method comprising administering to the subject a compound according to any one of embodiments 1-54, or a pharmaceutically acceptable salt thereof.

Embodiment 69. A method of treating a disease or disorder affected by modulation of YAP/TAZ-TEAD protein-protein interaction activity, comprising administering to a patient in need thereof a compound according to any one of embodiments 1-54, or a pharmaceutically acceptable salt thereof.

Embodiment 70. A method of treating a disease or disorder affected by suppression, reduction, or elimination of a YAP/TAZ-TEAD protein-protein interaction in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-54, or a pharmaceutically acceptable salt thereof.

Embodiment 71. The method of embodiment 69 or 70, wherein the disease or disorder is cancer or a tumor.

Embodiment 72. A method of treating cancer or a tumor in a subject in need thereof, 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 embodiments 1-54.

Embodiment 73. The method of any one of embodiments 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 squamous cell carcinoma of the cervix, endometrial carcinoma, squamous cell carcinoma of the esophagus, adenocarcinoma of the esophagus, urothelial carcinoma of the bladder, and squamous cell carcinoma of the skin), poromoma (benign poroma), porocarcinoma (including malignant porocarcinoma), supratentorial ependymoma (including supratentorial ependymoma in children), 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 colorectal carcinoma), melanoma, pancreatic cancer (including pancreatic adenocarcinoma), prostate cancer, gastric cancer, esophageal cancer, liver cancer (including hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma), neuroblastoma, schwannoma, renal cell carcinoma, sarcomas (including rhabdomyosarcoma, embryonal rhabdomyosarcoma (ERMS), osteosarcoma, undifferentiated pleomorphic sarcomas (UPS), Kaposi's sarcoma, soft tissue sarcoma, and rare soft tissue sarcoma), bone cancer, brain cancer, medulloblastoma, glioma, meningiomas, and head and neck cancer (including squamous cell carcinoma of the head and neck).

Embodiment 74. The method according to any one of embodiments 71-73, 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).

Embodiment 75. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-54 for the preparation of a medicament, preferably for the treatment of a disease or cancer or tumor as described herein (e.g. as defined in any one of embodiments 73 or 74).

In the compounds according to any of the listed embodiments, 1-50 A preferably represents an unsubstituted phenyl ring.

Pharmaceutically acceptable salts

Depending on the choice of starting materials and procedures, the compounds may exist in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as mixtures of isomers such as racemates and mixtures of diastereomers, depending on the number of asymmetric centers. It is intended that the present invention embrace all such possible isomers, including racemic mixtures, enantiomerically enriched mixtures, diastereomeric mixtures and optically pure forms. Optically active ( R )- and ( S )-isomers can be prepared using chiral synthons or chiral reagents or isolated using conventional techniques. In case the compound contains a disubstituted or trisubstituted cycloalkyl, the cycloalkyl substituent can have a cis- or trans -configuration. The present invention embraces the cis- and trans- configurations of the substituents in cycloalkyl groups, as well as mixtures thereof. All tautomeric forms are also within the scope of the invention. In particular, when the heteroaryl ring containing N as a ring atom is, for example, 2-pyridone, then the scope of the invention covers tautomers in which the carbonyl is depicted as a hydroxy group (for example, 2-hydroxypyridine).

As used herein, the terms "salt" or "salts" refer to an acid addition salt or a base addition salt of a compound of the present invention. "Salts" include, in particular, "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention and that are generally not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and/or base salts due to the presence of amino and/or carboxyl groups or similar groups.

Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be obtained include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids with which such salts can be obtained 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, trifluoroacetic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be prepared include, for example, ammonium salts and salts of metals from groups I-XII of the periodic table of elements. In certain embodiments, salts are prepared using sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; in particular, suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be prepared include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Specific organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

In another aspect, the present invention provides compounds in the form of a salt which is acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride, chlorotheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelic acid salt, mesylate, methyl sulfate, mucic acid salt, naphthoic acid salt, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenate, trifluoroacetate or xinafoate.

Isotopically labeled compounds

Any formula provided herein also includes the presence of unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds are characterized by the structures depicted by the formulae provided herein, except that one or more atoms are replaced by an atom characterized by a selected atomic mass or mass number. Examples of isotopes that can be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 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, respectively. The present invention includes various isotopically labeled compounds as defined herein, such as compounds in which radioactive isotopes such as ³ H and ¹⁴ C are present, or compounds in which non-radioactive isotopes such as ² H and ¹³ C are present. Such isotopically labeled compounds are useful in metabolism studies (using ¹⁴ C), reaction kinetic studies (using, for example, ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radioisotope treatment of patients. In particular, a compound labeled with ¹⁸ F may be particularly useful 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 analogous to those described in the accompanying examples, using suitable isotopically labeled reagents in place of the unlabeled reagents previously used.

In addition, substitution with heavier isotopes, in particular deuterium (i.e. ² H or D), may provide certain therapeutic advantages due to higher metabolic stability, such as an increase in half-life in vivo, or a decrease in dosage requirements, or an improvement in the therapeutic index. It should be understood that deuterium in this context is considered as a substituent of the compound of formula (I). The concentration of such a heavier isotope, in particular deuterium, can be determined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio of the abundance of an isotope to the abundance in nature of said isotope. In case the substituent in the compound of the present invention is said deuterium, such compound is characterized by an isotopic enrichment factor for each designated deuterium atom of at least 3500 (incorporation of 52.5% deuterium at each designated deuterium atom), at least 4000 (incorporation of 60% deuterium), at least 4500 (incorporation of 67.5% deuterium), at least 5000 (incorporation of 75% deuterium), at least 5500 (incorporation of 82.5% deuterium), at least 6000 (incorporation of 90% deuterium), at least 6333.3 (incorporation of 95% deuterium), at least 6466.7 (incorporation of 97% deuterium), at least 6600 (incorporation of 99% deuterium) or at least 6633.3 (introduction of 99.5% deuterium).

The invention also relates to compounds of 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 (the corresponding moiety/moieties are then perdeuterated).

Pharmaceutically acceptable solvates according to the present invention include those wherein the solvent for crystallization may be isotopically substituted, for example, D₂O, d₆-acetone, d₆-DMSO.

All methods described herein may be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or introductory words before examples (e.g., "such as") provided herein is intended solely to better explain the present invention and does not limit the scope of the present invention as otherwise claimed.

Any asymmetric center in the compounds of the present invention may exist as a racemic mixture, or as a mixture of enantiomers, or in enantiomerically enriched form. In some embodiments, for example, if a mixture of enantiomers is present, each asymmetric center is present in an enantiomeric excess of at least 10%, an enantiomeric excess of at least 20%, an enantiomeric excess of at least 30%, an enantiomeric excess of at least 40%, an enantiomeric excess of at least 50%, an enantiomeric excess of at least 60%, an enantiomeric excess of at least 70%, an enantiomeric excess of at least 80%, an enantiomeric excess of at least 90%, an enantiomeric excess of at least 95%, or an enantiomeric excess of at least 99%. In some embodiments, for example, if an enantiomerically enriched form is present, then each asymmetric center is present in an enantiomeric excess of at least 50%, an enantiomeric excess of at least 60%, an enantiomeric excess of at least 70%, an enantiomeric excess of at least 80%, an enantiomeric excess of at least 90%, an enantiomeric excess of at least 95%, or an enantiomeric excess of at least 99%.

Accordingly, the compound of the present invention used herein may be in the form of one of the possible isomers, enantiomers, atropisomers, diastereoisomers, tautomers or mixtures thereof, for example, in the form of substantially pure diastereoisomers, optical isomers (enantiomers), racemates or mixtures thereof.

Any resulting mixtures of isomers may be separated on the basis of physicochemical differences of the constituents into pure or essentially pure optical isomers, diastereoisomers, racemates, for example, by chromatography and/or fractional crystallization.

Any resulting racemates of the final products or intermediates can be separated into their optical enantiomers by known methods, for example by separating their diastereomeric salts obtained with an optically active acid or base and releasing the optically active acidic or basic compound. In particular, a basic moiety can be used in this way to separate the compounds according to the present invention into their optical enantiomers, for example by fractional crystallization of a salt obtained using an optically active acid, for example tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be separated by chiral chromatography, for example high-pressure liquid chromatography (HPLC) using a chiral adsorbent.

In addition, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates or include other solvents used for their crystallization. The compounds of the present invention can, by their nature or by design, form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to cover 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 solvent molecules widely used in the pharmaceutical field, which are known to be harmless to the recipient, for example, water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water.

One skilled in the art can detect the presence of solvates using instrumental techniques such as NMR.

The compounds of the present invention, including their salts, hydrates and solvates, may, by nature or by design, form polymorphs.

Methods of obtaining

In general, compounds of formula (I) can be prepared according to the schemes presented below.

Presented below The diagrams are intended to represent individual diastereomers/enantiomers as well as their isomeric mixtures. Separation of diastereomers/enantiomers can be carried out according to the procedures described in this document. Unless otherwise specified, in the general diagrams described below, R₂, R₃, R₄, R₅, R₇, R_w, A, Q, W, X, Y and Z are as defined herein. In particular, R₂, R₃, R₄, R₅, R₇, R_w, A, Q, W, X, Y and Z are as defined in any one of enumerated embodiments 1-50. An amine protecting group is also referred to herein as a nitrogen protecting group or PG.

Scheme 1. General synthesis of compounds of formula (I)

Step 1. A compound of formula (IV) is cross-coupled with a compound of formula (V) using a suitable catalyst, such as a Pd catalyst and a base. R _a may be a boronic acid or boronate ester, while R _c is a halide ion, such as bromide or iodide. Alternatively, R _a may be a halide ion, such as bromide or iodide, while R _c is a boronic acid or boronate ester. Compounds of formula (III) typically consist of a mixture of diastereoisomers when R ₄ and/or R ₆ ' are other than hydrogen.

R ₆ ' may be any functional group capable of being converted to R ₆ , wherein R ₆ is as defined herein. In particular, R ₆ is defined according to any one of enumerated embodiments 1-49.

Step 2: After cross-coupling (step 1), the R ₆ ' functional groups can be converted into R ₆ functional groups.

Step 3. A compound of formula (I) can be prepared by converting a group Q ₁ to Q, for example when Q ₁ contains a nitrogen-protected amine, under deprotection conditions.

The synthesis of compounds of formula (I) is described in more detail. below.

Scheme 2. General synthesis of compounds of formula (I)

Step 1. The compound of formula (IV) is cross-coupled with an aryl halide of formula (V) using a suitable Pd catalyst such as N-XantPhos-Pd-G3 and a base such as potassium phosphate. Compounds of formula (III) typically consist of a mixture of diastereoisomers when R ₄ and/or R ⁶ ' are other than hydrogen.

Step 2. After cross-coupling (step 1), the R ₆ ' functional groups can be converted to R ₆ functional groups (e.g., R ₆ '=nitrile can be converted to R ₆ =amide group using hydrido(dimethylphosphinic acid-kP)[hydrogenbis(dimethylphosphinito-kP)]platinum(II) catalyst in EtOH and water; or R ₆ '=ester can be converted to R ₆ =substituted amides) to give compounds of formula (II).

Step 3. If Q ₁ contains a nitrogen-protected amine, the amine protecting group of the compounds of formula (II) is cleaved to give compounds of formula (I) with a free amine. For example, the Boc group can be cleaved under acidic conditions, benzyl groups can be removed by hydrogenation in the presence of a metal such as palladium.

In case Q=C(R⁷)₂-NH₂, NH group₂compounds of formula (I) can then be further functionalized according to the procedures described herein and the schemes presented below, as well as in accordance with methods generally known to those skilled in the art.

Scheme 3. Compounds of formula (I) with an alkyl group attached to an amino group

Step 1 and Step 2: The compound of formula (IV-a) is cross-coupled with a compound of formula (V) to give a compound of formula (III-a) using conditions similar to those in Scheme 2, Step 1. The compound of formula (III-a) is then alkylated to give a compound of formula (III-b).

Step 1 ' and Step 2 '. The compound of formula (IV-a) is alkylated to give a compound of formula (IV-b), which is converted to a compound of formula (III-b) by cross-coupling with a compound of formula (V) using conditions similar to those in Scheme 2, Step 1.

Typical reaction conditions for alkylation involve a base such as sodium hydride and an alkyl halide such as methyl iodide.

Step 3 and Step 4. A compound of formula (III-b) can be converted to a compound of formula (II-a) by interconversion of a functional group such as R ₆ ' to a functional group R ₆ (Step 3, referred to in Scheme 2 and the specific examples given therein) followed by cleavage of the protecting group (Step 4), as indicated in Scheme 2, Step 3.

Scheme 4. Compounds of formula (I), where R ₁ = unsubstituted or substituted cycloalkyl

Compounds of formula (I) can be synthesized by reductive amination with suitable ketones such as, for example, cyclohexanone derivatives of formula (R ₉ -I). This reaction requires a suitable reducing agent such as sodium triacetoxyborohydride.

Scheme 5. Compounds of formula (I) - dihydrobenzofurans (alternative to scheme 4)

Step 1. Compounds of formula (III-c) can be synthesized by cross-coupling a boronate of formula (IV-c) with an aromatic halide of formula (Va) using reaction conditions similar to those shown in Scheme 2, Step 1.

Step 2: Oxidation of the alcohol of formula (III-c) yields the aldehyde of formula (III-d). Typical reaction conditions are oxalyl chloride/DMSO/triethylamine in dichloromethane (Swern oxidation conditions).

Step 3. Compounds of formula (III-e) can be prepared by reductive amination of an aldehyde of formula (III-d) with an amine, such as, for example, cyclohexylamine of formula (R ₉ -II), using reaction conditions similar to those indicated in Scheme 4.

Step 4. Conversion of the R ₆ ' functional groups to R ₆ functional groups, as indicated in Scheme 2, Step 2, provides the compound of formula (IcI).

Scheme 6. Compounds of formula (I) - dihydrobenzofurans (an alternative to schemes 4 and 5)

Step 1 : An aldehyde of formula (IV-e) can be prepared by oxidizing an alcohol of formula (IV-d) using reaction conditions similar to those shown in Scheme 5, Step 2.

Step 2. Reductive amination of an aldehyde of formula (IV-e) with a cyclohexylamine of formula (R ₉ -II) using reaction conditions similar to those shown in Scheme 4 provides a compound of formula (IV-f).

Step 3. The compound of formula (IV-f) can be converted to the corresponding boronate of formula (IV-g) using a suitable palladium catalyst, such as, for example, the adduct PdCl ₂ (dppf)-CH ₂ Cl ₂ , bis(pinacolato)diboron, and a base, such as, for example, potassium acetate.

Stage 4 and Stage 5: These stages can be performed as shown in the diagrams above.

Scheme 7. Compounds of formula IV

Step 1 : The sulfinamide of formula (IV-h) can be prepared by reacting the aldehyde of formula (IV-e) with 2-methylpropane-2-sulfinamide.

Step 2. An aziridine of formula (IV-i) can be formed by reacting a sulfinamide of formula (IV-h) with trimethylsulfoxonium iodide and sodium hydride (Corey-Chaikovsky reaction).

Step 3 : Oxidation of the compound of formula (IV-i) to the corresponding sulfonamide of formula (IV-j) can be achieved using an oxidizing reagent such as, for example, m-CPBA.

Step 4 : The compound of formula (IV-k) can be prepared by reacting the compound of formula (IV-j) with trimethylsulfoxonium iodide and sodium hydride (Corey-Chaikovsky reaction).

Step 5. The boronate of formula (IV-l) can be synthesized from the compound of formula (IV-k) by cleavage of the sulfone group (e.g., by using trifluoromethanesulfonic acid) followed by reprotection of the amine (e.g., with a Boc group) and conversion of the bromine to the corresponding boronate as shown in Scheme 6, Step 3.

Scheme 8. Compounds of formula IV

Step 1 : The Weinreb amide of formula (IV-n) can be prepared by reacting the acid of formula (IV-m) with N,O-dimethylhydroxylamine using standard peptide coupling.

Step 2. Dihydro-2H-pyrrole of formula (IV-o) can be synthesized by Grignard addition of the appropriate species of Mg 1-(3-bromopropyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine to the Weinreb amide of formula (IV-n) followed by formation of the intramolecular imine.

Step 3. The dihydro-2H-pyrrole of formula (IV-o) can be reduced using, for example, sodium borohydride, followed by protection of the nitrogen in the pyrrolidine with a suitable protecting group, such as, for example, a Boc group, to obtain a compound of formula (IV-p).

Step 4 : A compound of formula (IV-q) can be prepared from a compound of formula (IV-p) using reaction conditions similar to those shown in Scheme 6, Step 3.

Scheme 9. Compounds of formula IV

Step 1. The amino alcohol of formula (IV-r) can be synthesized by Grignard addition of the appropriate species of Mg 1-(3-bromopropyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine to the aldehyde of formula (IV-e).

Step 2 : A ketone of formula (IV-s) can be synthesized from a compound of formula (IV-r) via Boc protection followed by oxidation of the alcohol using, for example, Swern oxidation conditions (oxalyl chloride/DMSO/TEA).

Step 3 and Step 4. The compound of formula (IV-p) can be prepared from the compound of formula (IV-s) by removal of the Boc group followed by cyclization using conditions as outlined in Scheme 8, Steps 2 and 3, and reprotection of the pyrrolidine with, for example, a Boc group. The boronate of formula (IV-q) can be synthesized as outlined in Scheme 6, Step 3.

Scheme 10. Compounds of formula IV

Step 1. The synthesis of alcohol (IV-v) can be achieved by opening the epoxide ring of the compound of formula (IV-u) to provide suitable organometallic species by treating (IV-t) with a reagent such as an organolithium or organomagnesium reagent (optionally in the presence of a transition metal salt such as CuI to form an organocuprate reagent), an organozinc, an organocuprate or an organocerium reagent. For example, the reagent can be an alkyl lithium (t-BuLi), a Grignard reagent, a dialkyl zinc reagent, a dialkyl cuprate or a trialkyl cerium reagent. Suitable organometallic species can also be converted to other suitable organometallic species by transmetallation with magnesium halides, zinc halides, copper halides and cerium halides. Preferably, the reagent is a Grignard reagent, such as i PrMgCl. Each of Hal ¹ and Hal ² may be I, Cl, or Br, provided that the halide ion of Hal ¹ is less electronegative (and therefore more reactive toward the organometallic reagent) than the halide ion of Hal ^2. For example, if Hal ¹ is I, then Hal ² must be Cl or Br. If Hal ² is Cl, then Hal ¹ must be Br or I. Preferably, Hal ¹ is I and Hal ² is Br.

Step 2. Oxidation of the alcohol of formula (IV-v) to the ketone of formula (IV-w) can be achieved by a suitable method for oxidation of secondary alcohols, for example, using Dess-Martin periodinane.

Step 3. A compound of formula (IV-x) can be prepared by adding a suitable organometallic species prepared by treating a compound of formula AX (where X=Cl, Br, I) with an alkyl lithium, a Grignard reagent, or a trialkyl cerium reagent. For example, a compound of formula (IV-x) can be prepared by Grignard addition of a Grignard reagent of formula AMgX (where X=Cl, Br, I), such as AMgBr, where A is as described herein, to a ketone of formula (IV-w). For example, the Grignard reagent can be PhMgBr.

Step 4: Dihydrobenzofuran of formula (IV-y) can be prepared by intramolecular cyclization of (IV-x) using a suitable base such as KOtBu.

Step 5. Chlorination of (IV-y) using N-chlorosuccinimide provides a compound of formula (IV-p").

Step 6. A compound of formula (IV-q) can be prepared from a compound of formula (IV-p") using reaction conditions similar to those shown in Scheme 6, Step 3.

Preferably, compounds of formula (IV) are prepared according to scheme 10a.

Scheme 10a. Compounds of formula IV

Step 1. Epoxy opening of the compound of formula (IV-u)-a with magnesium particles obtained by treating iodide (IV-t)-a with i PrMgCl in the presence of CuI provides an alcohol of formula (IV-v)-a.

Step 2. Oxidation of an alcohol of formula (IV-v) to a ketone of formula (IV-w) can be achieved, for example, using Dess-Martin periodinane.

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

Step 4. A dihydrobenzofuran of formula (IV-y)-a can be prepared from an alcohol of formula (IV-x)-a by intramolecular cyclization using a suitable base such as KOtBu.

Step 5 : Chlorination of (IV-y)-a using N-chlorosuccinimide yields a compound of formula (IV-p)-a.

Step 5. A compound of formula (IV-q)-a can be prepared from a compound of formula (IV-p)-a using reaction conditions similar to those shown in Scheme 6, Step 3.

Scheme 11. Compounds of formula IV

Step 1 : A compound of formula (IV-ab) can be prepared from an aldehyde of formula (IV-e) by reaction with an allylamine followed by Grignard addition of allyl magnesium bromide.

Step 2 : Ring-closing metathesis of the bis-allyl compound of formula (IV-ab) can be accomplished, for example, using a ^2nd generation Grubb catalyst to yield a tetrahydropyridine compound of formula (IV-ac).

Step 3 and Step 4: Hydrogenation of the tetrahydropyridine and protection of the nitrogen in the piperidine with a suitable group (PG) such as Boc provides a compound of formula (IV-ad), which can be converted to the boronate of formula (IV-ae) using the conditions described in Scheme 6, Step 3.

Scheme 12. Compounds of formula IV

Step 1 : A compound of formula (IV-af) can be prepared from an aldehyde of formula (IV-e) by reaction with the reagent SnAP M=2-[(tributylstannyl)methoxy]ethanamine.

Step 2 and Step 3: Protection of the nitrogen in the morpholine with a suitable group, such as, for example, Boc, provides a compound of formula (IV-ag), which can be converted to the boronate of formula (IV-ah) using the conditions described in Scheme 6, Step 3.

Scheme 13. Compounds of formula IV

Step 1 : A compound of formula (IV-ai) can be prepared from a sulfinamide of formula (IV-h) by reaction with a Grignard reagent.

Step 2 and Step 3: Cleavage of the sulfinamide followed by reprotection with a suitable protecting group such as, for example, Boc provides a compound of formula (IV-aj), which can be converted to the boronate of formula (IV-ak) using the conditions described in Scheme 6, Step 3.

In one embodiment, a compound of formula (IV) or a salt thereof is provided,

Where

R _a is selected from (i) a halide ion such as bromine or iodide (preferably bromine), and (ii) B(R' _a ) ₂ , where each R' _a is hydroxy, or two R' _a groups together with the boron to which they are attached form a pinacol boronate moiety of the formula

;

Q ₁ is selected from (i) -C(R ⁷ ) ₂ - R _b and (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 heteroatomic group selected from N, O, S, -S(=O) and -S(=O) ₂ , with the proviso that at least one N heteroatom is present, wherein the N heteroatom is optionally substituted with a protecting group, wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen and C ₁ -C ₃ alkylene, to form a bridge between two ring atoms of the saturated heterocyclic ring, thereby forming a bridged bicyclic structure;

R _b is selected from (i) hydroxy, (ii) N(R ⁸ )-R _b ', (iii) azido;

R _b ' is selected from (i) a nitrogen protecting group, (ii) C ₃ -C ₆ cycloalkyl optionally independently substituted mono- or more than mono-fold with hydroxy, hydroxyC ₁ -C ₄ alkyl, C ₁ -C ₆ alkoxy, preferably C ₁ -C ₄ alkoxy, C(O)OC ₁ -C ₃ alkyl, CO ₂ H, SO ₂ C ₁ -C ₃ alkyl, haloC ₁ -C ₃ alkyl, NHR ^1b , (CH ₂ ) _0-1 C(O)NR ^1c R ^1d , C ₁ -C ₆ alkyl, haloC ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, halogen, a 5- or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O and S; or 2 groups R1 ^e ,

wherein 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 heterocyclic ring containing at least one heteroatom selected from N and O, or C ₃ -C ₆ cycloalkyl, the saturated heterocyclic ring or cycloalkyl being optionally substituted with hydroxy or oxo;

R ^1b is selected from (i) C(O)C ₁ -C ₃ alkyl and (ii) SO ₂ C ₁ -C ₃ alkyl;

each of R ^1c and R ^1d is independently selected from (i) hydrogen, (ii) C ₁ -C ₃ alkyl and (iii) hydroxyC ₁ -C ₄ alkyl;

R ₂ , R _3, R ⁷ , R ⁸ , A, W, Y and Z are as defined in any one of embodiments 1-50 listed.

In one embodiment, a compound of formula (IV-I) or a salt thereof is provided,

where R _a is selected from (i) bromine, (ii) B(R' _a ) ₂ , where each R' _a is hydroxy, or two R' _a groups together with the boron to which they are attached form a pinacol boronate moiety of the formula

;

Q ₁ is selected from (i) -C(R ⁷ ) ₂ - R _b , (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 heteroatomic group selected from N, O, S, -S(=O) and -S(=O) ₂ , with the proviso that at least one N heteroatom is present, wherein the N heteroatom is optionally substituted with a protecting group, wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen and C ₁ -C ₃ alkylene, to form a bridge between two ring atoms of the saturated heterocyclic ring, thereby forming a bridged bicyclic structure;

R _b is selected from (i) hydroxy, (ii) N(R ⁸ )-R _b ', (iii) azido;

R _b ' is selected from (i) a nitrogen protecting group, (ii) C ₃ -C ₆ cycloalkyl optionally independently substituted mono- or more than mono-fold with hydroxy, hydroxyC ₁ -C ₄ alkyl, C ₁ -C ₆ alkoxy, preferably C ₁ -C ₄ alkoxy, C(O)OC ₁ -C ₃ alkyl, CO ₂ H, SO ₂ C ₁ -C ₃ alkyl, haloC ₁ -C ₃ alkyl, NHR ^1b , (CH ₂ ) _0-1 C(O)NR ^1c R ^1d , C ₁ -C ₆ alkyl, haloC ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, halogen, a 5- or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O and S; or 2 groups R1 ^e ,

wherein 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 heterocyclic ring containing at least one heteroatom selected from N and O, or C ₃ -C ₆ cycloalkyl, the saturated heterocyclic ring or cycloalkyl being optionally substituted with hydroxy or oxo;

R ^1b is selected from (i) C(O)C ₁ -C ₃ alkyl and (ii) SO ₂ C ₁ -C ₃ alkyl;

each of R ^1c and R ^1d is independently selected from (i) hydrogen, (ii) C ₁ -C ₃ alkyl and (iii) hydroxyC ₁ -C ₄ alkyl;

R ₂ , R _3, R ⁷ , R ⁸ , A, W, Y and Z are as defined in any one of embodiments 1-50 listed.

In one embodiment, a compound of formula (IV-II) or a salt thereof is provided,

Where

each R' _a is hydroxy, or two R' _a groups together with the boron to which they are attached form a pinacol boronate moiety of the formula

;

Q ₁ is selected from (i) -C(R ⁷ ) ₂ - R _b , (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 heteroatomic group selected from N, O, S, -S(=O) and -S(=O) ₂ , with the proviso that at least one N heteroatom is present, wherein the N heteroatom is optionally substituted with a protecting group, wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen and C ₁ -C ₃ alkylene, to form a bridge between two ring atoms of the saturated heterocyclic ring, thereby forming a bridged bicyclic structure;

R _b is selected from (i) hydroxy, (ii) N(R ⁸ )-R _b ', (iii) azido;

R _b ' is selected from (i) a nitrogen protecting group, (ii) C ₃ -C ₆ cycloalkyl optionally independently substituted mono- or more than mono-fold with hydroxy, hydroxyC ₁ -C ₄ alkyl, C ₁ -C ₆ alkoxy, preferably C ₁ -C ₄ alkoxy, C(O)OC ₁ -C ₃ alkyl, CO ₂ H, SO ₂ C ₁ -C ₃ alkyl, haloC ₁ -C ₃ alkyl, NHR ^1b , (CH ₂ ) _0-1 C(O)NR ^1c R ^1d , C ₁ -C ₆ alkyl, haloC ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, halogen, a 5- or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O and S; or 2 groups R1 ^e ,

wherein 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 heterocyclic ring containing at least one heteroatom selected from N and O, or C ₃ -C ₆ cycloalkyl, the saturated heterocyclic ring or cycloalkyl being optionally substituted with hydroxy or oxo;

R ^1b is selected from (i) C(O)C ₁ -C ₃ alkyl and (ii) SO ₂ C ₁ -C ₃ alkyl;

each of R ^1c and R ^1d is independently selected from (i) hydrogen, (ii) C ₁ -C ₃ alkyl and (iii) hydroxyC ₁ -C ₄ alkyl;

R ₂ , R _3, R ⁷ , R ⁸ , A, W, Y and Z are as defined in any one of embodiments 1-49 listed.

In one embodiment, a compound of formula (IV-III) or a salt thereof is provided,

Where

each R' _a is hydroxy, or two R' _a groups together with the boron to which they are attached form a pinacol boronate moiety of the formula

;

Q ₁ is selected from (i) -C(R ⁷ ) ₂ - R _b , (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 heteroatomic group selected from N, O, S, -S(=O) and -S(=O) ₂ , with the proviso that at least one N heteroatom is present, wherein the N heteroatom is optionally substituted with a protecting group, wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen and C ₁ -C ₃ alkylene, to form a bridge between two ring atoms of the saturated heterocyclic ring, thereby forming a bridged bicyclic structure;

R _b is selected from (i) hydroxy, (ii) N(R ⁸ )-R _b ', (iii) azido;

R _b ' is selected from (i) a nitrogen protecting group, (ii) C ₃ -C ₆ cycloalkyl optionally independently substituted mono- or more than mono-fold with hydroxy, hydroxyC ₁ -C ₄ alkyl, C ₁ -C ₆ alkoxy, preferably C ₁ -C ₄ alkoxy, C(O)OC ₁ -C ₃ alkyl, CO ₂ H, SO ₂ C ₁ -C ₃ alkyl, haloC ₁ -C ₃ alkyl, NHR ^1b , (CH ₂ ) _0-1 C(O)NR ^1c R ^1d , C ₁ -C ₆ alkyl, haloC ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, halogen, a 5- or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from N, O and S; or 2 groups R1 ^e ,

wherein 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 heterocyclic ring containing at least one heteroatom selected from N and O, or C ₃ -C ₆ cycloalkyl, the saturated heterocyclic ring or cycloalkyl being optionally substituted with hydroxy or oxo;

R ^1b is selected from (i) C(O)C ₁ -C ₃ alkyl and (ii) SO ₂ C ₁ -C ₃ alkyl;

each of R ^1c and R ^1d is independently selected from (i) hydrogen, (ii) C ₁ -C ₃ alkyl and (iii) hydroxyC ₁ -C ₄ alkyl;

R ₂ , R _3, R ⁷ , R ⁸ , A, W, Y and Z are as defined in any one of embodiments 1-50 listed.

In a further embodiment, a compound or salt thereof is provided 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 -butoxycarbonyl)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-methylcyclohexan-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-methylcyclohexan-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-dioxaborolane -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)indolin-1-carboxylate.

In a further aspect, the present invention relates to a process for the preparation of a compound of formula (I) in free form or in the form of a pharmaceutically acceptable salt, comprising the step of:

a) coupling a compound of formula (IV), (IV-I), (IV-II) or (IV-III) as defined herein with a suitable cross-coupling partner such as a suitable aryl halide, aryl boronic acid or ester, in the presence of a suitable catalyst such as a Pd based catalyst to yield a compound of general formula (III) as defined in Schemes 1 and 2, or subformulas thereof as defined in any of Schemes 3, 5 and 6.

Therefore, the present invention relates to a process for preparing a compound of formula (I), (Ia), (Ic) or (Id) or a pharmaceutically acceptable salt thereof, comprising the step of:

a) performing a coupling reaction of a compound of formula (IV), as defined herein, with a compound of formula (V),

in the presence of a suitable catalyst, such as a Pd-based catalyst, to obtain a compound of general formula (III),

Where

A, W, X, Y, Z, _R2 , _R3 , _R4 , _R5 are as defined herein;

where if R _a is a halide ion such as bromide or iodide, R _c is B(R' _a ) ₂ , where each R' _a is hydroxy, or two R' _a groups together with the boron to which they are attached form a pinacol boronate moiety of the formula

;

where if R _a is B(R' _a ) ₂ , where each R' _a is hydroxy, or two R' _a groups together with the boron to which they are attached form a pinacol boronate moiety of the formula

; R _c is a halide ion such as bromide or iodide;

Q ₁ is as defined in this document; and

R ₆ ' is a functional group capable of being converted to R ₆ , such as -CN or C(O)OC ₁ -C ₆ alkyl, where R ₆ is as defined herein.

In a further aspect, the present invention relates to a process for preparing a compound of formula (I) in free form or in the form of a pharmaceutically acceptable salt, comprising the steps of:

a) carrying out a coupling reaction of a compound of formula (IV) as defined herein with a compound of formula (V) as defined herein in the presence of a suitable catalyst to obtain a compound of formula (III) as defined herein;

b) converting the compound of formula (III) as defined herein obtained in step a) under suitable hydrolysis conditions to obtain the compound of formula (II) as defined herein;

c) removing the protecting group from the compound of formula (II) as defined herein obtained in step b) to obtain the compound of formula (I) as defined herein;

d) optional further functionalization of the amino group of the compound of formula (I);

e) isolating the thus obtained compound of formula (I) in free form or in the form of a pharmaceutically acceptable salt.

In a further aspect, the present invention provides a process for preparing a compound of formula (IV-v) or a salt thereof, comprising the steps of (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),

where _R2 is as defined herein, PG is a nitrogen protecting group;

if Hal ¹ is I, Hal ² is Cl or Br, and if Hal ² is Cl, Hal ¹ is Br or I.

In a further aspect, the present invention provides a process 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 synthesis scheme given below:

where R₂, PG, Hal¹and Hal² are as defined in this document, and R₃is chlorine.

The present invention further includes any embodiment of the processes of the present invention in which an intermediate product obtained in any step thereof is used as a starting material and the remaining steps are carried out, or in which the starting materials are obtained in situ under the reaction conditions, or in which the components of the reaction mixture are used in the form of their salts or optically pure material.

The compounds of the present invention and the intermediate compounds can also be converted into each other according to methods generally known to those skilled in the art.

Pharmaceutical compositions

Compounds of formula (V), (IV), (III) and (II) as defined herein are useful in the preparation of compounds of the present invention, for example compounds of formula (I). Thus, in one aspect, the present invention relates to a compound of formula (V), (IV), (III) or (II) or salts thereof. In another aspect, the present invention relates to the use of a compound of formula (V), (IV), (III) or (II) or salts thereof in the preparation of a compound of formula (I).

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 a further embodiment, the composition comprises at least two such pharmaceutically acceptable carriers as described herein. For the purposes of the present invention, unless otherwise indicated, solvates and hydrates generally refer to the compositions. Preferably, the pharmaceutically acceptable carriers are sterile. The pharmaceutical composition can be formulated for specific routes of administration, such as oral administration, parenteral administration, rectal administration, etc. Furthermore, the pharmaceutical compositions of the present invention can be prepared 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 compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricants or buffering agents, as well as auxiliary agents such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.

Typically, pharmaceutical compositions are tablets or gelatin capsules containing the active ingredient together with one or more of:

a) thinners, for example with lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;

b) lubricants, such as silicon dioxide, talc, stearic acid, its magnesium or calcium salt and/or

c) binding agents, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone;

d) leavening agents, such as with types of starch, agar, alginic acid or its sodium salt or effervescent mixtures; and

e) absorbents, colorants, flavorings and sweeteners.

In one embodiment, the pharmaceutical compositions are capsules containing only the active ingredient.

The tablets may be either film-coated or enteric-coated according to methods known in the art.

Suitable compositions for oral administration comprise an effective amount of a compound 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 the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives, in order to obtain preparations that are pharmaceutically aesthetic and palatable. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable auxiliary substances that are suitable for the manufacture of tablets. Such auxiliary substances are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period. For example, a material such as glyceryl monostearate or glyceryl distearate can be used to provide delayed action. Formulations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium, such as peanut oil, liquid paraffin or olive oil.

Certain injection compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions can be sterilized and/or can contain auxiliary agents such as preservatives, stabilizing, wetting or emulsifying agents, dissolution accelerators, salts for regulating osmotic pressure and/or buffers. In addition, they can also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulation or coating methods, respectively, and they contain about 0.1-75% or contain about 1-50% of the active ingredient.

Suitable compositions for transdermal use comprise an effective amount of a compound of the present invention with a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to facilitate passage through the patient's skin. For example, transdermal devices are in the form of a dressing comprising a support element, a reservoir containing the compound, optionally together with carriers, optionally a rate-controlling barrier element for delivering the compound through the patient's skin at a controlled and predetermined rate over a prolonged period of time, and a means for attaching the device to the skin.

Suitable compositions for topical application, such as in relation to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or sprays, such as, for delivery by aerosol or the like. Such systems for local delivery will be particularly suitable for cutaneous application, e.g. for the treatment of skin cancer, for example for prophylactic use in sunscreens, lotions, aerosols, etc. They are therefore particularly suitable for use in topical formulations, including cosmetic formulations, well known in the art. These may contain solubilizers, stabilizers, tonicity enhancers, buffers and preservatives.

As used herein, topical administration may also refer to inhalation or intranasal administration. For convenience, they may be delivered in the form of a dry powder (either alone, as a mixture, such as a dry mixture with lactose, or particles of mixed components, such as with phospholipids) from a dry powder inhaler or as a spray aerosol from a pressurized container, pump dispenser, atomizer, nebulizer or nebulizer, with or without a suitable propellant.

The compounds of formula (I) in free form or in the form of a pharmaceutically acceptable salt exhibit valuable pharmacological properties, such as YAP/TAZ-TEAD modulating properties, such as YAP/TAZ-TEAD suppressing properties, such as demonstrated by in vitro tests, as shown in the examples, and are therefore indicated for therapy or for use as research chemicals, i.e. as pharmacologically active compounds.

Diseases and Disorders and Methods of Use

Compounds of particular interest according to the present invention exhibit good activity in the biological assays described herein. In another aspect, they should have a favorable safety profile. In another aspect, they should have favorable pharmacokinetic properties. In addition, the ideal drug candidate will be in a form that is stable, non-hygroscopic, and easy to formulate.

In view of their activity as YAP/TAZ-TEAD inhibitors, the PPI compounds of formula (I) in free form or in pharmaceutically acceptable salt form are useful in the treatment of conditions that are mediated by YAP or TAZ amplifications and/or Hippo pathway dysregulation and/or increased YAP/TEAD or TAZ/TEAD activity, such as cancer, and/or that are susceptible (particularly meant in a therapeutically beneficial way) to inhibition of the YAP/TAZ-TEAD interaction, particularly preferably diseases or disorders as defined herein below.

The compounds of the present invention may be useful in the treatment of cancer or tumor. In particular, the compounds of the present invention may be useful in the treatment of a cancer or tumor selected from mesothelioma (including pleural mesothelioma, malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, and tunica vaginalis mesothelioma), carcinoma (including squamous cell carcinoma of the cervix, endometrial carcinoma, squamous cell carcinoma of the esophagus, adenocarcinoma of the esophagus, urothelial carcinoma of the bladder, and squamous cell carcinoma of the skin), poromoma (benign poromoma), porocarcinoma (including malignant porocarcinoma), supratentorial ependymoma (including supratentorial ependymoma in children), epithelioid hemangioendothelioma (EHE), ependymal tumor, solid tumor, breast cancer (including triple-negative breast cancer), cancer), lung cancer (including non-small cell lung cancer), ovarian cancer, colorectal cancer (including colorectal carcinoma), melanoma, pancreatic cancer (including pancreatic adenocarcinoma), prostate cancer, gastric cancer, esophageal cancer, liver cancer (including hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma), neuroblastoma, schwannomas, renal cell carcinoma, sarcomas (including rhabdomyosarcoma, embryonal rhabdomyosarcoma (ERMS), osteosarcoma, undifferentiated pleomorphic sarcomas (UPS), Kaposi sarcoma, soft tissue sarcoma, and rare soft tissue sarcoma), bone cancer, brain cancer, medulloblastoma, glioma, meningiomas, and head and neck cancer (including squamous cell carcinoma of the head and neck).

The compounds of the present invention may also be useful in the treatment of solid malignant tumors characterized by overexpression of YAP.

The compounds of the present invention may also be useful in the treatment of solid malignancies characterized by dysregulation of the YAP/TAZ-TEAD interaction.

The compounds of the present invention may also be useful in the treatment of solid malignant tumors characterized by YAP amplification.

The compounds of the present invention may also be useful in the treatment of a tumor or cancer, wherein the cancer or tumor is a cancer or tumor harboring (i) one or more YAP/TAZ fusions; (ii) one or more NF2/LATS1/LATS2 truncation or deletion mutations; or (iii) one or more functional YAP/TAZ fusions.

The compounds of the present invention may also be useful in the treatment of NF2-mutated cancer, particularly NF2-mutated NSCLC.

Any positive expression in YAP, as described above, can be assessed by methods known to those skilled in the art, such as, for example, immunohistochemistry, qRT-PCR, RNASeq, or the like.

Thus, as a further embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in therapeutic agents. In a preferred embodiment, the therapeutic agents are directed to a disease 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-mentioned list, in particular malignant pleural mesothelioma.

Thus, as a further embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapeutic agents. In a preferred embodiment, the therapeutic agents are directed to 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, in particular malignant pleural mesothelioma.

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

Thus, as a further embodiment, the present invention provides the use of a compound of formula (I), its subformulas or a pharmaceutically acceptable salt thereof for the manufacture of a medicinal product. In a preferred embodiment, the medicinal product is intended for the treatment of 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-mentioned list, in particular malignant pleural mesothelioma.

In one embodiment, the present invention provides 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 for use in the treatment of malignant pleural mesothelioma. In another embodiment of the present invention, there is provided 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 for use in the treatment of solid malignancies characterized by overexpression of YAP or TAZ and/or amplification of YAP or TAZ and/or amplification of TEAD and/or (hyper)activation of YAP/TAZ-TEAD.

In one embodiment of the present invention, there is provided

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 malignant pleural mesothelioma. In another embodiment of the present invention, there is provided

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 malignant tumors characterized by overexpression of YAP or TAZ, and/or amplification of YAP or TAZ, and/or amplification of TEAD, and/or (hyper)activation of YAP/TAZ-TEAD.

In one embodiment, the present invention provides 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 for use in the treatment of malignant pleural mesothelioma. In another embodiment of the present invention, there is provided 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 for use in the treatment of solid malignancies characterized by overexpression of YAP or TAZ and/or amplification of YAP or TAZ and/or amplification of TEAD and/or (hyper)activation of YAP/TAZ-TEAD.

In one embodiment, the present invention provides 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 for use in the treatment of malignant pleural mesothelioma. In another embodiment of the present invention, there is provided 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 for use in the treatment of solid malignancies characterized by overexpression of YAP or TAZ and/or amplification of YAP or TAZ and/or amplification of TEAD and/or (hyper)activation of YAP/TAZ-TEAD.

In one embodiment, the present invention provides 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 for use in the treatment of malignant pleural mesothelioma. In another embodiment of the present invention there is provided 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 for use in the treatment of solid malignancies characterized by overexpression of YAP or TAZ and/or amplification of YAP or TAZ and/or amplification of TEAD and/or (hyper)activation of YAP/TAZ-TEAD.

In one embodiment, the present invention provides 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)benzonitrile or a pharmaceutically acceptable salt thereof for use in the treatment of malignant pleural mesothelioma. In another embodiment of the present invention, there is provided 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)benzonitrile or a pharmaceutically acceptable salt thereof for use in the treatment of solid malignancies characterized by overexpression of YAP or TAZ and/or amplification of YAP or TAZ and/or amplification of TEAD and/or (hyper)activation of YAP/TAZ-TEAD.

In one embodiment, the present invention provides 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 for use in the treatment of malignant pleural mesothelioma. In another embodiment of the present invention, there is provided 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 for use in the treatment of solid malignancies characterized by overexpression of YAP or TAZ and/or amplification of YAP or TAZ and/or amplification of TEAD and/or (hyper)activation of YAP/TAZ-TEAD.

In one embodiment, the present invention provides 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 for use in the treatment of malignant pleural mesothelioma. In another embodiment of the present invention, there is provided 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 for use in the treatment of solid malignancies characterized by overexpression of YAP or TAZ and/or amplification of YAP or TAZ and/or amplification of TEAD and/or (hyper)activation of YAP/TAZ-TEAD.

In one embodiment, the present invention provides 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 for use in the treatment of malignant pleural mesothelioma. In another embodiment of the present invention, there is provided 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 for use in the treatment of solid malignancies characterized by overexpression of YAP or TAZ and/or amplification of YAP or TAZ and/or amplification of TEAD and/or (hyper)activation of YAP/TAZ-TEAD.

In one embodiment, the present invention provides 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 for use in the treatment of malignant pleural mesothelioma. In another embodiment of the present invention there is provided 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 for use in the treatment of solid malignancies characterized by overexpression of YAP or TAZ and/or amplification of YAP or TAZ and/or amplification of TEAD and/or (hyper)activation of YAP/TAZ-TEAD.

In one embodiment, the present invention provides 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 for use in the treatment of malignant pleural mesothelioma. In another embodiment of the present invention, there is provided 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 for use in the treatment of solid malignancies characterized by overexpression of YAP or TAZ and/or amplification of YAP or TAZ and/or amplification of TEAD and/or (hyper)activation of YAP/TAZ-TEAD.

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

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

Dose

The pharmaceutical composition or combination of the present invention can be presented in a single dosage of about 1-1000 mg of the active ingredient(s) for a subject weighing about 50-70 kg, 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 the active ingredients. The therapeutically effective dosage of the compound, pharmaceutical composition or combinations thereof depends on the type of subject, body weight, age, as well as the individual condition, disorder or disease being treated or its severity. An attending physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients required to prevent, treat or suppress the progression of a disorder or disease.

The above mentioned dosage parameters are evident in in vitro and in vivo tests using preferably mammals, for example mice, rats, dogs, monkeys, or isolated organs, tissues and preparations thereof. The compounds of the present invention can be used in vitro in the form of solutions, for example aqueous solutions, and in vivo either enterally or parenterally, preferably intravenously, for example as a suspension or an aqueous solution. The in vitro dosage can be in the concentration range of about 10 ^-3 mol/l to 10 ^-9 mol/l. Depending on the route of administration, the therapeutically effective amount in vivo can be in the range of about 0.1 to 500 mg/kg or about 1 to 100 mg/kg.

The activity of the compound of the present invention can be assessed by the in vitro methods described in the examples.

Combination therapy

The compound of the present invention may be administered simultaneously with one or more other therapeutic agents, or before or after them. The compound of the present invention may be administered separately from the other agents by the same or a different route of administration, or together with them in a single pharmaceutical composition. The therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid that is therapeutically active or enhances therapeutic activity when administered to a patient in combination with a compound of the present invention. Thus, in one embodiment of the present invention, there is provided a combination comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more therapeutically active agents.

In one embodiment, the present invention provides a product comprising a compound of formula (I) and at least one other therapeutic agent as a combination preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or condition mediated by YAP overexpression and/or YAP amplification and/or YAP/TAZ-TEAD interaction. Products provided as a combination preparation include a composition comprising a compound of formula (I) and the other therapeutic agent(s) together in the same pharmaceutical composition, or a compound of formula (I) and the other therapeutic agent(s) in a separate form, such as in a kit form.

In certain cases, the compounds of the present invention may be combined with other therapeutic agents such as other anticancer agents, antiallergic agents, antinausea agents (or antiemetics), analgesics, cytoprotective agents, and combinations thereof.

Anticancer agents of particular interest for combination with the compounds of the present invention include B-RAF inhibitors; mitogen-activated protein kinase (MEK) inhibitors; epidermal growth factor receptor (EGFR) inhibitors; immune checkpoint molecule inhibitors (e.g. one or more PD-1, PD-L1 inhibitors).

The compounds of the present invention may be used together or alone in combination with another type of cancer treatment, in particular malignant pleural mesothelioma, such as surgery, chemotherapy (including cisplatin, carboplatin, alimta (pemetrexed), gemcitabine and doxorubicin) and radiation therapy. For example, combination therapy with one or more agents selected from pemetrexed, cisplatin, bevacizumab, nivolumab, gemcitabine, vinorelbine, nivolumab and ipilimumab may be particularly useful especially for the treatment of pleural mesothelioma (in particular malignant pleural mesothelioma).

Some patients may develop allergic reactions to the compounds of the present invention and/or other anticancer agent(s) during or after administration; therefore, antiallergic agents are often administered to minimize the risk of an allergic reaction. Suitable antiallergic agents include corticosteroids, antihistamines, and bronchodilators.

Some patients may experience nausea during and after administration of a compound of the present invention and/or other anticancer agent(s); therefore, antiemetics are used to prevent nausea (upper stomach) and vomiting.

Medicines to relieve pain experienced during treatment are often prescribed to help ease the patient's condition.

In order to protect normal cells from treatment-induced toxicity and limit organ toxicity, cytoprotective agents (such as neuroprotectors, free radical scavengers, cardioprotectors, anthracycline neutralizers, nutrients, etc.) can be used as adjuvant therapy.

In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and other therapeutic agent(s). Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable carrier as described above.

In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of formula (I). In one embodiment, the kit comprises means for separately containing said compositions, such as a container, a divided bottle, or a divided foil pouch. An example of such a kit is a blister pack, commonly used for packaging tablets, capsules, etc.

The kit of the present invention can be used to administer different dosage forms, such as oral and parenteral, to administer individual compositions at different dosing intervals, or to adjust the doses of individual compositions relative to each other. To facilitate compliance, the kit of the present invention typically includes instructions for administration.

In the combination therapies of the present invention, the compound of the present invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Furthermore, the compound of the present invention and the other therapeutic agent may be combined into a combination therapy (i) prior to dispensing the combination product to physicians (e.g., in the case of a kit containing a compound of the present invention and another therapeutic agent); (ii) by the physicians themselves (or under the guidance of a physician) shortly before administration; (iii) in the patient's body itself, for example, during sequential administration of a compound of the present invention and another therapeutic agent.

Accordingly, the present invention provides the use of a compound of formula (I) for the treatment of a disease or condition mediated by YAP overexpression and/or YAP amplification and/or YAP/TAZ-TEAD interaction, wherein the medicament is prepared for administration with another therapeutic agent. The present invention also provides the use of another therapeutic agent for the treatment of a disease or condition mediated by YAP overexpression and/or YAP amplification and/or YAP/TAZ-TEAD interaction , wherein the medicament is administered with a compound of formula (I).

The present invention also provides a compound of formula (I) for use in a method of treating a disease or condition mediated by YAP overexpression and/or YAP amplification and/or a YAP/TAZ-TEAD interaction, wherein the compound of formula (I) is prepared for administration 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 a YAP/TAZ-TEAD interaction, wherein the other therapeutic agent is prepared for administration with a compound of formula (I). The present invention also provides a compound of formula (I) for use in a method of treating a disease or condition mediated by YAP overexpression and/or YAP amplification and/or a YAP/TAZ-TEAD interaction, wherein the compound of formula (I) is administered 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 with a compound of formula (I).

The present invention also provides the use of a compound of formula (I) for the treatment of a disease or condition mediated by YAP overexpression and/or YAP amplification and/or YAP/TAZ-TEAD interaction, wherein the patient has previously (e.g., within 24 hours) has been treated with another therapeutic agent. The present invention also provides for the use of another therapeutic agent for the treatment of a disease or condition mediated by YAP overexpression and/or YAP amplification and/or YAP/TAZ-TEAD interaction, wherein the patient has previously (e.g., within 24 hours) was treated with a compound of formula (I).

In one embodiment, the other therapeutic agent is selected from an anticancer agent.

Getting connections

The following examples are intended to illustrate the present invention and should not be construed as limiting it. Temperatures are in degrees Celsius. Unless otherwise stated, all evaporation operations were carried out under reduced pressure, typically from about 15 mmHg to 100 mmHg (=20-133 mbar). The structure of the final products, intermediates and starting materials was confirmed by standard analytical methods, for example, by determining spectroscopic characteristics, e.g. by MS, IR, NMR. Stereochemistry was determined by single crystal X-ray analysis for several intermediates and examples as indicated below and cocrystal structures of several examples bound to the YAP-binding domain of TEAD3 or TEAD4. All other stereochemistry assignments are analogous and based on the relative affinities determined for the YAP-binding domain of TEAD, e.g. IC₅₀, determined in the YAP-TEAD TR-FRET analysis for diastereoisomer X, was found to be significantly higher than for diastereoisomer Y. The abbreviations used are those generally accepted in the art.

All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts used to synthesize the compounds of the present invention are commercially available or can be prepared using organic synthesis methods known to a person skilled in the art. Also, the compounds of the present invention can be prepared by carrying out organic synthesis methods known to a person of ordinary skill in the art, as shown in the following examples.

Abbreviations

Abbreviation Description ACN acetonitrile aq. water Ar Argon BPR Back pressure brine Saturated aqueous sodium chloride calc. calculated CH2CL2 _{CH2Cl2 ​} conc. concentrated DAST (diethylamino)sulfur trifluoride dba Dibenzylideneacetone DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE 1,2-Dichloroethane DCM Dichloromethane DEA Diethylamine DEAD Diethyl azodicarboxylate DIAD Diisopropyl azodicarboxylate DIPEA N,N -diisopropylethylamine, N -ethyl- N -isopropylpropan-2-amine DMA N,N -dimethylacetamide DMAP 4-Dimethylaminopyridine DMF N,N -dimethylformamide DMSO Dimethyl sulfoxide DMSO-d ₆ or DMSO-d6 Hexadeuterodimethylsulfoxide dppf 1,1'-bis(diphenylphosphino)ferrocene DSC Differential scanning calorimetry ee enantiomeric excess ESI-MS Electrospray ionization mass spectroscopy EtOAc Ethyl acetate EtOH Ethanol _Et2O Diethyl ether h. hour HPLC High performance liquid chromatography HV High vacuum IPA 2-propanol l/ml/µl liter/milliliter/microliter LDA Lithium diisopropylamide LC-MS liquid chromatography and mass spectroscopy LHMDS Lithium hexamethyldisilazide M mol/l mCPBA meta-chloroperoxybenzoic acid MeOH methanol min. minutes mp melting point MW, mw microwave radiation mass/charge mass to charge ratio NaOtBu sodium tert-butoxide NBS N-Bromosuccinimide n-Buli n-butyllithium _NEt3 , _Et3N Triethylamine NMP N- methylpyrrolidinone NMR Nuclear magnetic resonance 1H-NMR, ¹ H-NMR ¹ H-Nuclear Magnetic Resonance org. organic P.E. Petroleum ether p-TsOH para-toluenesulfonic acid RM or rm Reaction mixture RP reversed phase Ph.D. Room temperature sat. saturated TBAF tetrabutylammonium fluoride TBME 2-methoxy-2-methylpropane TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran t _R Retention time (if not specified, in minutes) UPLC Ultra Performance Liquid Chromatography

General conditions

Mass spectra were obtained on LC-MS systems using electrospray ionization techniques using a variety of instruments configured as follows: Waters Acquity UPLC with a Waters SQ detector, [M+H] ⁺ refers to the protonated molecular ion of chemical compounds.

NMR spectra were obtained on Bruker Ultrashield™400 (400 MHz) and Bruker Ultrashield™600 (600 MHz) spectrometers, both with and without trimethylsilane as an internal standard. Chemical shifts (d-values) are given in ppm, measured from tetramethylsilane, with spectra in the splitting scheme designated as singlet (s), doublet (d), triplet (t), quartet (q), multiplet, unseparated or largely overlapping signals (m), broad signal (br). Solvents are given in parentheses.

Equipment

Microwave equipment: All microwave reactions were performed in a Biotage Initiator reactor with a magnetron output of 0-400 W at 2.45 GHz and processed using Robot Eight/Robot Sixty unless otherwise noted.

UPLC-MS methods : A Waters Acquity UPLC with a Waters SQ detector was used.

UPLC-MS Method 1. UPLC-MS Instrument: Waters Acquity UPLC with Waters SQ Detector; Column: Acquity UPLC HSS T3, 1.8 μm, 2.1×50 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 in 1.40 min, 98% B in 0.40 min.

UPLC-MS Method 2. UPLC-MS Instrument: Waters Acquity UPLC with Waters SQ Detector; Column: Acquity UPLC HSS T3, 1.8 μm, 2.1×100 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 in 9.40 min, 98% B in 0.40 min.

UPLC-MS Method 3. UPLC-MS Instrument: Waters Acquity UPLC with Waters SQ Detector; Column: Acquity UPLC BEH C18, 1.7 μm, 2.1×50 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 in 1.70 min, 98% B in 0.10 min.

UPLC-MS Method 4. UPLC-MS Instrument: Waters Acquity UPLC with Waters SQ Detector; Column: CORTECS C18+, 2.7 μm, 2.1×50 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 in 1.40 min, 50 to 98% B in 0.30 min.

UPLC-MS Method 5. UPLC-MS Instrument: Waters Acquity UPLC with Waters Q-TOF Detector; Column: Waters BEH C18, 1.7 μm, 2.1×100 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 over 0.5 min, 5 to 95% B over 5.5 min, 95% B over 2.0 min, 95 to 5% B over 0.1 min, 5% B over 1.9 min.

Intermediate connections

Intermediates for Suzuki cross-coupling reactions with boronate building blocks:

Synthesis of tert-butyl (2-((2-bromo-3-fluorophenyl)amino)ethyl)carbamate (N-I)

At rt, 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) was added sodium triacetoxyborohydride (12.68 g, 59.8 mmol) and stirring at rt was continued for 1 day. DCM was added followed by _saturated NaHCO3 solution. 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 flash 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 = 1.19 min. ¹ H NMR (400 MHz, DMSO-d6) δ 7.23-7.10 (m, 1H), 7.00 (t, J=5.7 Hz, 1H), 6.60-6.42 (m, 2H), 5.56 (d, J=5.6 Hz, 1H), 3.15 (dt, J=16.8, 6.0 Hz, 4H), 1.37 (s, 9H).

Synthesis of 2-(2-bromo-3,4-difluorophenoxy)ethan-1-ol (N-II)

Step 1. (2-(2-Bromo-3,4-difluorophenoxy)ethoxy)(tert-butyl)dimethylsilane (N-II-a)

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) were added K ₂ CO ₃ (2.26 g, 16.3 mmol) and KI (0.135 g, 0.81 mmol). The reaction mixture was heated at 80 °C for 3.5 h. Additional K ₂ CO ₃ (2.25 g, 16.3 mmol) and KI (0.135 g, 0.81 mmol) were added and stirring at 80 °C was continued for 1 h. The reaction mixture was quenched with water and extracted with EtOAc. The aqueous layer was re-extracted with EtOAc, then the combined organic layers were dried (phase separation cartridge) and concentrated. The residue was purified by flash 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+NH ₄ ] ⁺ . t _R =1.57 min.

Step 4. 2-(2-Bromo-3,4-difluorophenoxy)ethanol (N-II)

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) was added TBAF trihydrate (515 mg, 1.63 mmol) and the reaction mixture was stirred at rt for 1.5 h. The reaction mixture was concentrated and the residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 100% EtOAc) to give the title compound (344 mg) as a colorless liquid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.43-7.36 (m, 1H), 7.20-7.15 (m, 1H), 4.85 (t, J=5.4 Hz, 1H), 4.13 (td, J=4.9, 1.0 Hz, 2H), 3.72 (q, J=5.4 Hz, 2H).

Synthesis of tert-butyl (2-(3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)carbamate (N-III)

Step 1. tert-Butyl (2-(2-bromo-3-fluorophenoxy)ethyl)carbamate (N-III-a)

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 ) at rt was added tert-butyl (2-bromoethyl)carbamate (2.29 g, 10.2 mmol) 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 and washed with brine, dried over _{anhydrous Na2SO4} and concentrated. The residue was purified by flash chromatography (silica, hexane/EtOAc, gradient 0% to 50% EtOAc) to give the title compound (2.6 g) as a colorless foam. UPLC-MS 1: mass/charge 334.0/336.0 [M+H] ⁺ , t _R =1.18 min.

Step 2. tert-Butyl (2-(3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)carbamate (N-III).

To a stirred suspension of tert-butyl (2-(2-bromo-3-fluorophenoxy)ethyl)carbamate (N-III-a) (1.6 g, 4.8 mmol), bis(pinacolato)diboron (2.43 g, 9.6 mmol) and KOAc (1.41 g, 14.4 mmol) in dioxane (10 mL) at 100 °C was added the adduct PdCl ₂ (dppf).CH ₂ Cl ₂ (0.39 g, 0.48 mmol) and the reaction mixture was stirred at 100 °C for 5 h. After filtration through a pad of celite and concentration under reduced pressure, the residue was purified by flash chromatography (silica, hexane/EtOAc, gradient from 0% to 40% EtOAc) to give the title compound (927 mg) in as a yellow oil. UPLC-MS 1: mass/charge 382.2 [M+H] ⁺ , t _R =1.32 min.

Synthesis of 2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV)

To a stirred solution of 2-bromo-3,4-difluorobenzonitrile (4 g, 18.35 mmol) in MeOH (50 mL) under Ar was added sodium methoxide (6.29 mL, 27.5 mmol, 25% in MeOH). The reaction mixture was then stirred for 16 h at rt. The reaction mixture was quenched with saturated NaHCO ₃ solution and extracted with EtOAc. The organic layers were combined and washed with saturated NaHCO ₃ solution, dried over Na ₂ SO ₄ 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 (400 MHz, DMSO- d ₆ ) δ (ppm) 7.87-7.67 (m, 1H), 7.44-7.20 (m, 1H), 3.95 (s, 3H).

Synthesis of 2-bromo-4-(difluoromethoxy)-3-fluorobenzonitrile (N-V)

Step 1. 2-Bromo-3-fluoro-4-hydroxybenzonitrile (NVa)

Under Ar atmosphere, to a stirred solution of 2-bromo-3,4-difluorobenzonitrile (10 g, 45.9 mmol) and 2-hydroxyethylmethylsulfone (6.26 g, 50.5 mmol) in DMF (100 mL) at 0 °C was added NaH (3.48 g, 138 mmol, 95%) and stirring at rt was continued for additional 2 h. The reaction mixture was quenched with 0.1 N HCl and extracted with EtOAc. The organic layers were combined and washed with 0.1 N HCl, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, hexane/EtOAc gradient: 0% to 80% EtOAc) to afford the desired product (8.97 g). UPLC-MS 1: m/z 215.9 [M+H] ⁺ , t _R = 0.80 min.

Step 2. 2-Bromo-4-(difluoromethoxy)-3-fluorobenzonitrile (NV)

At 0 °C, to a stirred solution of 2-bromo-3-fluoro-4-hydroxybenzonitrile (NVa) (8.97 g, 41.5 mmol) in ACN (150 mL) was added a solution of KOH (46.6 g, 831 mmol) in H ₂ O (150 mL), followed by diethyl (bromodifluoromethyl)phosphonate (14.75 mL, 83 mmol). Stirring at rt was continued for 2 h. The reaction mixture was quenched with saturated NaHCO ₃ solution and extracted with EtOAc. The organic layers were combined and washed with saturated NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, hexane/EtOAc; gradient: 0% to 40% EtOAc) to give the title compound (10.45 g). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ (ppm) 7.94-7.87 (m, 1H), 7.62-7.57 (m, 1H), 7.57-7.20 (m, 1H).

Synthesis of 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzonitrile (N-VI)

At 0 °C, to a stirred solution of 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (1.34 g, 9.17 mmol) in DMF (40 mL) under Ar was added portionwise NaH (0.477 g, 11.9 mmol, 60% in mineral oil). After 5 min, 2-bromo-3,4-difluorobenzonitrile (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 saturated NH ₄ Cl solution, then extracted with EtOAc. The organic layers were combined and washed with saturated NH ₄ Cl solution, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, hexane/EtOAc 2:1) to give the title compound (1.93 g). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.87-7.74 (m, 1H), 7.53-7.29 (m, 1H), 4.73-4.57 (m, 1H), 4.47-4.28 (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).

Synthesis of 2-bromo-3-fluoro-4-(2-hydroxyethoxy)benzonitrile (N-VII)

A solution of 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzonitrile (N-VI) (2.47 g, 7.2 mmol) and p-TsOH (0.55 g, 2.9 mmol) in EtOH (35 mL) was stirred at rt for 24 h. Saturated _NaHCO3 solution 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 w/z 304.0 [M+formate] ^- .

Synthesis of (R)-2-bromo-3-fluoro-4-(2-fluoropropoxy)benzonitrile (N-VIII)

The title compound was synthesized by analogy with 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzonitrile (N-VI) from 2-bromo-3,4-difluorobenzonitrile and (R)-2-fluoropropan-1-ol. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.80 (dd, J=8.6, 2.0 Hz, 1H), 7.40 (t, J=8.2 Hz, 1H), 5.14-4.95 (m, 1H), 4.43-4.23 (m, 2H), 1.36 (dd, J=23.8, 6.6 Hz, 3H).

Synthesis of 2-bromo-3-fluoro-4-(2-methoxyethoxy)benzonitrile (N-IX)

Under Ar, sodium (79 mg, 3.44 mmol) was added to a stirred solution of 2-methoxyethanol (10 mL). After 1 h at rt, 2-bromo-3,4-difluorobenzonitrile (500 mg, 2.294 mmol) was added and stirring was continued for 1 h. The reaction mixture was quenched with saturated NaHCO ₃ solution and extracted with DCM. The organic layers were combined and washed with saturated NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, hexane/EtOAc, gradient 0% to 85% EtOAc) to afford the desired product (593 mg). ^1H NMR (400 MHz, DMSO - _d6 ) δ (ppm) 7.84-7.70 (m, 1H), 7.39 (t, J =8.4 Hz, 1H), 4.35-4.25 (m, 2H), 3.74-3.61 (m, 2H), 3.29 (s, 3H).

Synthesis of 2-bromo-4-(cyclopropylmethoxy)-3-fluorobenzonitrile (N-X)

Under Ar atmosphere, NaH (0.413 g, 10.3 mmol, 60% in mineral oil) was added to a stirred solution of cyclopropyl carbinol (0.744 g, 10.32 mmol) in THF (15 mL) at rt. The suspension was stirred at rt for 1 h, then 2-bromo-3,4-difluorobenzonitrile (1.5 g, 6.88 mmol) was added. The resulting thick suspension was diluted in THF (10 mL) and stirred for an additional 1.5 h at rt. Saturated NaHCO ₃ solution was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc 9:1) to give the title compound (1.6 g). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ (ppm) 7.77 (d, J=8.7 Hz, 1H), 7.34 (t, J=8.3 Hz, 1H), 4.03 (d, J=7.2 Hz, 2H), 1.29-1.21 (m, 1H), 0.63-0.56 (m, 2H), 0.38-0.31 (m, 2H).

Synthesis of 4-chloro-5-fluoro-6-(2-methoxyethoxy)nicotinonitrile (N-XI)

Step 1. 4-Chloro-5,6-difluoronicotinamide (N-XI-a)

At rt, DMF (2 mL) was added to a solution of 4-chloro-5,6-difluoronicotinic acid (3.00 g, 15.55 mmol) in SOCl ₂ (20 mL) and stirring at 80 °C was continued for 16 h. The reaction mixture was concentrated and the resulting residue was suspended in DCM (50 mL). NH ₄ Cl (0.914 g, 17.10 mmol) and NEt ₃ (10.8 mL, 77.73 mmol) were added at 0 °C and the reaction mixture was allowed to stir at this temperature for additional 3 h. Saturated NaHCO ₃ and NaCl were added and the mixture was extracted with DCM. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash 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] ⁺ .

Step 2. 4-Chloro-5-fluoro-6-(2-methoxyethoxy)nicotinamide (N-XI-b)

At 0 °C, NaH (0.21 g, 5.2 mmol, 60% in mineral oil) was added portionwise 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 Na ₂ SO ₄ and concentrated. The crude product was purified by flash 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] ⁺ .

Step 3. 4-Chloro-5-fluoro-6-(2-methoxyethoxy)nicotinonitrile (N-XI)

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) was added CuCl (0.016 g, 0.16 mmol) followed by 2,2,2-trifluoro-N-methyl-N-(trimethylsilyl)acetamide (3.851 g, 19.4 mmol) 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 Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, hexane/EtOAc; gradient 0% to 15% EtOAc) to give the title compound (1.20 g) as a colorless powder. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.63 (d, J=08 Hz, 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] ⁺ .

Synthesis of 5-fluoro-4-iodo-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinonitrile (N-XII)

Step 1. 5-Bromo-3-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine (N-XII-a)

At 0 °C, to a stirred solution of 2-((tetrahydro-2H-pyran-2-yl)oxy)ethan-1-ol (1.2 mL, 7.8 mmol) in THF (20 mL) was added portionwise NaH (0.21 g, 5.2 mmol, 60% in mineral oil). 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. NH ₄ Cl solution (50 mL) was added and the mixture was stirred for 5 min before it was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash 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] ⁺ .

Step 2. 5-Fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinonitrile (N-XII-b)

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 tetrakis(triphenylphosphine)palladium(0) (0.180 g, 0.16 mmol) in DMF (8 mL) was heated at 100 °C under MW irradiation for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient 0% to 14% EtOAc) to give the title compound (0.35 g) as a colorless oil. ^1H NMR (400 MHz, DMSO - _d6 ) δ (ppm) 8.53 (d, J=2.0 Hz, 1H), 8.31 (dd, J=10.8, 2.0 Hz, 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).

Step 3. 5-Fluoro-4-iodo-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinonitrile (N-XII)

At -78 °C, 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) was added dropwise LDA (4.0 mL, 7.90 mmol). After 10 min at -78 °C, I ₂ (0.67 g, 5.3 mmol) was added and the reaction mixture was allowed to warm to rt and stirred for a further 16 h. Ice water was added and the mixture was stirred for 5 min before it was extracted with EtOAc, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, hexane/EtOAc; gradient 0% to 14% EtOAc) to give the title compound (0.70 g) as a colorless oil. ¹ H NMR (400 MHz, DMSO -d ₆ ) 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).

Synthesis of 2-bromo-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile (N-XIII)

Step 1. (2S)-Ethyl 2-((tetrahydro-2H-pyran-2-yl)oxy)propanoate (N-XIII-a)

Under Ar atmosphere, to a stirred solution of (-)-ethyl L-lactate (9.67 mg, 85 mmol) in DCM (100 mL) at 0 °C were added 3,4-dihydro-2H-pyran (13.16 mL, 144 mmol) and toluene-4-pyridinium sulfonate (1.064 g, 4.23 mmol). Stirring at rt was continued for 16 h. The reaction mixture was quenched with water then extracted with DCM. The organic layers were combined and washed with water, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 30% EtOAc) to give the title compound (16.3 g). ^1H NMR (400 MHz, 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), 3.49-3.30 (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)

Step 2. (2S)-2-((Tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol (N-XIII-b)

At 0 °C, to a solution of (2S)-ethyl 2-((tetrahydro-2H-pyran-2-yl)oxy)propanoate (N-XIII-a) (16.3 g, 81 mmol) in Et ₂ O (800 mL) was added lithium aluminum hydride (23.03 mL, 81 mmol, 18% in toluene) dropwise over 6 min. The resulting reaction mixture was stirred at 0 °C for 1.5 h before it was carefully quenched with saturated NH ₄ Cl solution. The precipitate was filtered off and the original solution was extracted with Et ₂ O. The organic layers were combined and washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give the title compound (10.12 g). ^1H NMR (400 MHz, DMSO - _d6 ) δ (ppm) 4.75-4.69 (m, 1H), 4.68-4.62 (m, 1H), 3.89-3.74 (m, 2H), 3.73-3.62 (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).

Step 3. 2-Bromo-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile (N-XIII)

At 0 °C, to a stirred solution of (2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol (N-XIII-b) (7.50 g, 46.8 mmol) in DMF (140 mL) was added NaH (2.03 g, 50.7 mmol, 60% in mineral oil) portionwise over 4 min. 2-Bromo-3,4-difluorobenzonitrile (8.50 g, 39.0 mmol) was then added and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with saturated NH ₄ Cl solution and extracted with EtOAc. The organic layers were combined and washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting crude product was purified by flash chromatography (silica, hexane/EtOAc 2:1) to afford the title product (14.68 g). UPLC-MS 1: m/z 375.2 [M+NH ₄ ] ⁺ , t _R = 1.22 min.

Synthesis of (S)-2-bromo-3-fluoro-4-(2-hydroxypropoxy)benzonitrile (N-XIV)

To a solution of 2-bromo-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile (N-XIII) (746 mg, 2.08 mmol) in EtOH (10 mL) was added p-TsOH (158 mg, 0.83 mmol) and the resulting reaction mixture was stirred at rt for 16 h. For work-up, a saturated NaHCO ₃ solution was added, followed by extraction with EtOAc. The combined organic extracts were washed with a saturated NaHCO ₃ solution and dried over anhydrous Na ₂ SO ₄ . Concentration afforded the crude product, which was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 100% EtOAc) to afford the title compound (528 mg) as a colourless powder. UPLC-MS 1: m/z 317.9 [M+formate] ^- , t _R = 0.84 min.

Synthesis of (R)-2-bromo-3-fluoro-4-(2-hydroxypropoxy)benzonitrile (N-XV)

The title compound was synthesized in analogy to (S)-2-bromo-3-fluoro-4-(2-hydroxypropoxy)benzonitrile (N-XIV) from 2-bromo-3,4-difluorobenzonitrile and (+)-ethyl-D-lactate. UPLC-MS 1: m/z 318.1 [M+formate] ^- , t _R = 0.87 min.

Synthesis of ethyl 2-(3-bromo-4-cyano-2-fluorophenoxy)acetate (N-XVI)

A solution of ethyl 2-hydroxyacetate (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-difluorobenzonitrile (300 mg, 1-4 mmol) in THF (5 mL) cooled to 0 °C. The reaction mixture was allowed to warm to rt and stirred for an additional 40 min. The reaction mixture was concentrated under reduced pressure and the residue was treated with saturated NH ₄ Cl solution followed by extraction with EtOAc. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. Purification of the crude product by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 20% EtOAc) gave the title compound (280 mg) as a colorless powder. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.78 (dd, J=9.0, 2.0 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 5.06 (s, 2H), 4.17 (q, J=7.0 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H).

Synthesis of (R)-4-((4-acetylmorpholin-2-yl)methoxy)-2-bromo-3-fluorobenzonitrile (N-XVII)

The title compound was synthesized in analogy to ethyl 2-(3-bromo-4-cyano-2-fluorophenoxy)acetate (N-XVI) from 2-bromo-3,4-difluorobenzonitrile and (R)-morpholin-2-ylmethanol (CAS 1664380-75-9). UPLC-MS 1: m/z 357.1/359.1 [M+H] ⁺ , t _R = 0.84 min.

Synthesis of (R)-2-bromo-3-fluoro-4-((tetrahydrofuran-2-yl)methoxy)benzonitrile (N-XVIII)

A solution of (R)-(tetrahydrofuran-2-yl)methanol (211 mg, 2.06 mmol) and KOtBu (170 mg, 1.51 mmol) in THF (2.5 mL) was added dropwise to a stirred solution of 2-bromo-3,4-difluorobenzonitrile (300 mg, 1.37 mmol) in THF (7.5 mL) at 0 °C. 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 Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, EtOAc/cyclohexane, gradient: 0% to 33% EtOAc) to afford the desired product (330 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.77 (dd, J = 8.7, 1.9 Hz, 1H), 7.39 (t, J = 8.7 Hz, 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).

Synthesis of 2-bromo-4-ethyl-3-fluorobenzonitrile (N-XIX)

Step 1. 3-Fluoro-4-vinylbenzonitrile (N-XIX-a)

To a stirred solution of 4-bromo-3-fluorobenzonitrile (1.00 g, 32.26 mmol) in dioxane/water (20 mL, 3:1) was added vinylboronic anhydride complex (600 mg, 2.50 mmol), Pd( _tBu3P ) ₂ (128 mg, 0.25 mmol), and _K2CO3 (1.04 g, 7.50 mmol) under Ar. The reaction mixture was stirred at 100 °C for 1 _h and then cooled to rt. The reaction mixture was partitioned between saturated _NaHCO3 solution and EtOAc. The organic layer was washed with saturated _NaHCO3 solution, dried over anhydrous _{Na2SO4 ,} and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 8% EtOAc) to afford the desired product (616 mg). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ (ppm) 7.93-7.75 (m, 2H), 7.67 (dd, J=8.1, 1.7 Hz, 1H), 6.85 (dd, J=17.8, 11.3 Hz, 1H), 6.10 (d, J=17.8 Hz, 1H), 5.61 (d, J=11.3 Hz, 1H).

Stage 2. 4-Ethyl-3-fluorobenzonitrile (N-XIX-b)

A solution of 3-fluoro-4-vinylbenzonitrile (N-XIX-a) (200 mg, 1.40 mmol) in THF (10 mL) was treated with 10% Pd/C (145 mg) and hydrogenated at 0.1 bar overpressure in a shake flask at rt for 10 min. The reaction mixture was filtered and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 10% EtOAc) to afford the title compound (169 mg). ¹ H NMR (400 MHz, DMSO - _d6 ) δ (ppm) 7.75 (dd, J=10.0, 1.7 Hz, 1H), 7.62 (dd, J=7.8, 1.6 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 2.67 (q, J=7.5 Hz, 2H), 1.16 (t, J=7.5 Hz, 2H).

Step 3. 2-Bromo-4-ethyl-3-fluorobenzonitrile (N-XIX)

At -78 °C, to a stirred solution of 4-ethyl-3-fluorobenzonitrile (N-XIX-b) (165 mg, 1.10 mmol) in THF (10 mL) under Ar was added LDA (0.608 mL, 1.217 mmol, 2 M in THF/heptane/ethylbenzene). The reaction mixture was stirred for 1 h at -78 °C before 1,2-dibromotetrachloroethane (720 mg, 2.21 mmol) was added. Stirring at -78 °C was continued for 1 h. The reaction mixture was then quenched with saturated NaHCO ₃ solution and extracted with EtOAc. The combined organic layers were washed with saturated NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 7% EtOAc) to give the title compound (206 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.73 (dd, J=7.9, 1.2 Hz, 1H), 7.57-7.48 (m, 1H), 2.72 (qd, J=7.5, 1.5 Hz, 2H), 1.17 (t, J=7.5 Hz, 3H).

Synthesis of 2-bromo-3-fluoro-4-(1H-imidazol-1-yl)benzonitrile (N-XX)

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. A solution of 2-bromo-3,4-difluorobenzonitrile (200 mg, 0.92 mmol) in THF (4 mL) was then slowly added and the reaction mixture was stirred at rt for 2 h. The reaction mixture was then quenched with saturated NaHCO ₃ solution and extracted with EtOAc. The organic layer was dried over anhydrous MgSO ₄ and concentrated. The crude product was purified by flash chromatography (silica, DCM/MeOH, gradient: 0% to 3% MeOH) to give the title compound (121 mg) as a colourless powder. UPLC-MS 1: m/z 266.0/268.0 [M+H] ⁺ ; t _{R =} 0.71 min.

Synthesis of 2-bromo-3-fluoro-4-(pyrimidin-2-ylmethoxy)benzonitrile (N-XXI)

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-difluorobenzonitrile (300 mg, 1.38 mmol) in THF (7.5 mL) cooled to 0 °C. The reaction mixture was stirred at rt for 2 h before it was quenched 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 =} 0.87 min.

Synthesis of 2-bromo-4-(1,1-difluoro-2-hydroxyethoxy)-3-fluorobenzonitrile (N-XXII)

Reaction scheme N-XXII:

Step 1. 2-Bromo-4-((1,1-difluoroallyl)oxy)-3-fluorobenzonitrile (N-XXII-a)

To a stirred solution of 2-bromo-3-fluoro-4-hydroxybenzonitrile (NVa) (1.4 g, 6.42 mmol) in THF (50 mL) were added 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). The reaction mixture was stirred at rt overnight. Saturated _NaHCO3 solution 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 flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 10% EtOAc) to give the title compound (1.3 g). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.92 (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).

Step 2. 2-Bromo-4-(1,1-difluoro-2,3-dihydroxypropoxy)-3-fluorobenzonitrile (N-XXII-b)

At rt, to a suspension of 2-bromo-4-((1,1-difluoroallyl)oxy)-3-fluorobenzonitrile (N-XXII-a) (0.7 g, 2.40 mmol) in dioxane (16 mL) and water (5 mL) were added osmium tetroxide (0.3 mL, 0.048 mmol, 4% in water) and N-methylmorpholine-N-oxide (0.3 g, 2.64 mmol). The reaction mixture was stirred at rt for 3 days. Saturated NaHCO ₃ solution was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 20 to 90% EtOAc) to give the title compound (590 mg). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.90 (dd, J=8.7, 1.7 Hz, 1H), 7.63 (t, J=7.9 Hz, 1H), 6.20 (d, J=6.5 Hz, 1H), 4.98 (t, J=5.9 Hz, 1H), 3.98 (ddt, J=13.6, 10.1, 5.0 Hz, 1H), 3.72 (dt, J=11.7, 3.9 Hz, 1H), 3.52 (ddd, J=11.5, 7.3, 3.8 Hz, 1H).

Step 3. 2-Bromo-4-(1,1-difluoro-2,2-dihydroxyethoxy)-3-fluorobenzonitrile (N-XXII-c)

At rt, to a suspension of 2-bromo-4-(1,1-difluoro-2,3-dihydroxypropoxy)-3-fluorobenzonitrile (N-XXII-b) (0.45 g, 1.38 mmol) in dioxane (16 mL) and water (5 mL) was added sodium periodate (2.95 g, 13.8 mmol). The reaction mixture was stirred at rt for 2 days. Saturated _NaHCO3 solution 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 used directly in the next step without purification. UPLC-MS 1: _{t R =} 0.75 min.

Step 4. 2-Bromo-4-(1,1-difluoro-2-hydroxyethoxy)-3-fluorobenzonitrile (N-XXII)

At rt, to a solution of 2-bromo-4-(1,1-difluoro-2,2-dihydroxyethoxy)-3-fluorobenzonitrile (N-XXII-c) (450 mg, 1.44 mmol) in THF (14.4 mL) was added NaBH ₄ (546 mg, 14.4 mmol). The reaction mixture was stirred at rt for 1 h. Saturated NaHCO ₃ solution was added and the reaction mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 20 to 80% EtOAc) to give the title compound (130 mg). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.90 (dd, J=8.6, 1.7 Hz, 1H), 7.74-7.48 (m, 1H), 6.06 (t, J=6.7 Hz, 1H), 3.94 (td, J=10.4, 6.7 Hz, 2H).

Synthesis of 2-bromo-4-((1,1-difluoro-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)thio)benzonitrile (N-XXIII)

Step 1 . 2-Bromo-4-mercaptobenzonitrile (N-XXIII-a)

A solution of 2-bromo-3,4-difluorobenzonitrile (5.0 g, 25.0 mmol) in DMF (25 mL) was treated with Na ₂ S (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 Na ₂ SO ₄ and concentrated. The resulting crude product was dissolved in 10% HCl (100 mL) cooled to 0 °C and zinc dust (10 g) was added. The reaction mixture was stirred for 1 h, then diluted with EtOAc (250 mL ₎ and stirred for an additional 30 min. The separated organic layer was washed with water and brine, dried over anhydrous _Na2SO4 and concentrated to give the title compound (2.5 g), which was used in the next step without further purification. UPLC-MS m/z 214.1 [M+H] ⁺ .

Step 2. 2-Bromo-4-((1,1-difluoro-2-hydroxyethyl)thio)benzonitrile (N-XXIII-b)

To a stirred solution of 2-bromo-4-mercaptobenzonitrile (N-XXIII-a) (0.2 g, 0.94 mmol) in DMSO (5 mL) at 0 °C was added NaH (0.040 g, 0.935 mmol, 60% in mineral oil) portionwise. The suspension was stirred for 30 min before 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 Na ₂ SO ₄ 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 portionwise 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 in the next step without further purification.

Step 3. 2-Bromo-4-((1,1-difluoro-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)thio)benzonitrile (N-XXIII)

To a solution of crude 2-bromo-4-((1,1-difluoro-2-hydroxyethyl)thio)benzonitrile (N-XXIII-b) (0.16 g, 0.55 mmol) in DCM (10 mL) were added sequentially 3,4-dihydro-2H-pyran (0.092 g, 1.09 mmol) and pyridinium p-toluenesulfonate (0.007 g, 0.027 mmol) at 0 °C. 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 Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc 85:15) to give the title compound (0.13 g). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 8.10 (br s, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.80 (dd, J=1.7 Hz, J=8.3 Hz, 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).

Synthesis of 2-bromo-3-fluoro-4-((methylsulfonyl)methoxy)benzonitrile (N-XXIV)

Under Ar atmosphere, 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)sulfane (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). mCPBA (734 mg, 3.28 mmol, 77%) was added at 0 °C. The reaction mixture was stirred at rt for 1 h. To quench 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, the combined organic layers were dried (phase separation cartridge) and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 40% EtOAc) to give the title compound (240 mg). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.86 (d, J =8.7 Hz, 1H), 7.65 (t, J =8.4 Hz, 1H), 5.59 (s, 2H), 3.09 (s, 3H). UPLC-MS 1: mass/charge 352.1/354.1 [M+formate] ^- , t _R =0.79 min.

Synthesis of 2-bromo-4-(3,3-difluoropropoxy)-3-fluorobenzonitrile (N-XXV)

Step 1. 2-Bromo-4-(3,3-diethoxypropoxy)-3-fluorobenzonitrile (N-XXV-a)

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-difluorobenzonitrile (460 mg, 2.110 mmol) and 3,3-diethoxypropan-1-ol (0.85 mL, 5.4 mmol) in THF (3 mL). The reaction mixture was stirred at rt for 30 min, then diluted with EtOAc. The organic phase was washed successively with sat. NH ₄ Cl solution, water, and brine. The organic layer was dried over anhydrous MgSO ₄ and concentrated to give the title compound, which was used as crude material in the next step without purification. UPLC-MS 1: mass/charge 390.2/392.2 [M+formate] ^- , t _R =1.21 min.

Step 2. 2-Bromo-3-fluoro-4-(3-oxopropoxy)benzonitrile (N-XXV-b)

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 MgSO ₄ and concentrated to give the title compound, which was used as crude material in the next step without purification. UPLC-MS 1: t _R = 0.87/0.90 min.

Step 3. 2-Bromo-4-(3,3-difluoropropoxy)-3-fluorobenzonitrile (N-XXV)

To a solution of crude 2-bromo-3-fluoro-4-(3-oxopropoxy)benzonitrile (N-XXV-b) from the previous step (500 mg, 1.84 mmol) in DCM (4 mL) was added diethylaminosulfur trifluoride (0.36 mL, 2.8 mmol) dropwise at 0 °C. The reaction mixture was stirred at rt for 2 h. DCM and water were added, the organic layer was separated and the aqueous layer was extracted with DCM. The combined organic phases were dried over anhydrous MgSO₄and concentrated. The residue was purified by flash chromatography (silica, heptane/EtOAc, gradient: 10% to 70% EtOAc) to give the title compound (50 mg).¹H NMR (600 MHz, DMSO-d₆) δ 7.82 (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).

Synthesis of methyl 2-bromo-3-fluoro-4-methoxybenzoate (N-XXVI)

At rt, 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) and the reaction mixture was stirred at 50 °C for 22 h. Saturated NaHCO ₃ solution was added and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO ₄ and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 20% EtOAc) to afford the title compound (390 mg) as a colorless powder. UPLC-MS 1: m/z 263.1 [M+H] ⁺ , t _R = 1.00 min.

Synthesis of methyl 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate (N-XXVII)

Step 1. Methyl 2-bromo-3-fluoro-4-hydroxybenzoate (N-XXVII-a)

At 0°C, a solution of 2-(methylsulfonyl)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 sat. NH₄Cl and extracted with EtOAc. The organic layers were combined and washed with water and brine, dried over anhydrous Na₂SO₄and concentrated to give the title compound.¹H NMR (400 MHz, 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).

Step 2. Methyl 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate (N-XXVII)

At 0°C, 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) were added dropwise to triphenylphosphine (63.4 g, 241.9 mmol), followed by a solution of DIAD (48.8 g, 241.9 mol) in THF (100 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 and washed with sat. NaHCO₃and saline solution, dried over Na₂SO₄and concentrated. The resulting residue was triturated in PE/EtOAc (95:5), the crude solution was concentrated and the crude product was purified by flash chromatography (silica, PE/EtOAc 9:1) to afford the title compound.¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 7.69 (q,J=1.4 Hz, 1H), 7.33 (t,J=8.5 Hz, 1H), 4.66 (d,J=3.3 Hz, 1H), 4.33 (d,J=2.2 Hz, 2H), 3.97-3.92 (m, 1H), 3.83 (s, 3H), 3.77-3.72 (m, 2H), 3.43 (q, J=6.2 Hz, 1H), 1.68-1.58 (m, 2H), 1.46 (t, J=9.0 Hz, 4H).

Synthesis of methyl 2-bromo-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzoate (N-XXVIII)

At 0 °C, NaH (0.704 g, 17.6 mmol, 60% in mineral oil) was added portionwise to a stirred solution of (2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol (N-XIII-b) (2.60 g, 16.25 mmol) in DMF (50 mL). Methyl 2-bromo-3,4-difluorobenzoate (3.4 g, 13.5 mmol) was then added and the reaction mixture was stirred for 2 h at 0 °C. The reaction mixture was quenched with saturated NH ₄ Cl solution and extracted with EtOAc. The organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash 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+NH ₄ ] ⁺ , t _R = 1.24 min.

Synthesis of methyl 4-chloro-5-fluoro-6-methoxynicotinate (N-XXIX)

To a stirred solution of 4-chloro-5,6-difluoronicotinic acid (200 mg, 1.033 mmol) in MeOH (10 mL) was added conc. _H2SO4 ( _0.551 mL, 10.33 mmol) and the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was quenched by addition of _{saturated NaHCO3} solution and extracted with DCM. The organic layers were combined and washed with saturated _NaHCO3 solution, dried over _{anhydrous Na2SO4} and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 10% EtOAc) to give the title compound (143 mg) as a colorless powder. UPLC-MS 1: mass/charge 220.0 [M+H] ⁺ , t _R =1.02 min.

Synthesis of methyl 4-chloro-6-(difluoromethoxy)-5-fluoronicotinate (N-XXX)

Stage 1. Methyl 4-chloro-5,6-difluoronicotinate (N-XXX-a)

At 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 (total: 34.2 mL, 68.3 mmol, 2 M in _Et2O ) was added in 4 portions until the starting material was completely consumed. Water was added and the organic solvents were 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 light yellow oil. UPLC-MS 1: mass/charge 208.1 [M+H] ⁺ , t _R =0.93 min.

Step 2. Methyl 4-chloro-5-fluoro-6-hydroxynicotinate (N-XXX-b)

At 0 °C, NaH (1.36 g, 34 mmol, 60% in mineral oil) was added to a solution of methyl 4-chloro-5,6-difluoronicotinate (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 about 5 with 1 N HCl. The organic solvents were removed under reduced pressure. More water was added and the mixture was filtered. The aqueous phase was extracted with EtOAc, dried over anhydrous Na ₂ SO ₄ and concentrated to give the title compound (2.50 g) as a colorless powder. UPLC-MS 1: mass/charge 204.0 [MH] ^- , t _R = 0.57 min.

Step 3. 4-Chloro-6-(difluoromethoxy)-5-fluoronicotinic acid (N-XXX-c)

At 0 °C, to a stirred solution of methyl 4-chloro-5-fluoro-6-hydroxynicotinate (N-XXX-b) (350 mg) in ACN (6 mL) was added a solution of KOH (1.82 g, 32.3 mmol) in water (6 mL), followed by diethyl (bromodifluoromethyl)phosphonate (0.58 mL, 3.2 mmol). The reaction mixture was stirred at rt for 1.5 h. The pH of the reaction mixture was adjusted to 3 by adding 2 N HCl and the organic solvents were removed under reduced pressure. MeOH was added and the solids were removed by filtration. The organic phase was concentrated to give the title compound (170 mg). UPLC-MS 1: m/z 240.1 [MH] ^- , t _R = 0.66 min.

Step 4. Methyl 4-chloro-6-(difluoromethoxy)-5-fluoronicotinate (N-XXX)

To a solution of 4-chloro-6-(difluoromethoxy)-5-fluoronicotinic acid (N-XXX-c) (170 mg, 0.70 mmol) in DCM (4.7 mL) was added thionyl chloride (0.077 mL, 1.06 mmol), followed by one drop of DMF. 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. Saturated _NaHCO3 solution was added and the organic solvents were removed under reduced pressure. The residue was extracted with DCM, _the combined organic layers were dried over anhydrous _Na2SO4 and concentrated to give the title compound (102 mg). UPLC-MS 1: product not capable of ionization, t _R = 1.05 min.

Synthesis of methyl 4-chloro-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate (N-XXXI)

At 0 °C, NaH (0.31 g, 7.7 mmol) was added portionwise to a stirred solution of 2-((tetrahydro-2H-pyran-2-yl)oxy)ethan-1-ol (0.78 mL, 7.7 mmol) in THF (10 mL). After 5 min, methyl 4-chloro-5,6-difluoronicotinate (N-XXX-a) (1.60 g, 7.7 mmol) was added and stirring was continued for 1 h at 0 °C. The reaction mixture was diluted with water, extracted with EtOAc, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, hexane/EtOAc; gradient: 0% to 10% EtOAc) to give the title compound (1.20 g) as a colorless powder. ^1H NMR (400 MHz, DMSO - _d6 ) δ (ppm) 8.53 (d, J=1.2 Hz, 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).

Alternative synthesis methyl 4-chloro-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate (N-XXXI):

Reaction scheme N-XXXI:

Step 1. 3-Fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine (N-XXXi-a)

The reactor was charged with t -BuOK (7.80 kg, 69.51 mol) and THF (20 L) and the mixture was cooled to -5-0 °C. 2-((tetrahydro-2H-pyran-2-yl)oxy)ethan-1-ol (6.60 kg, 45.15 mol) was added dropwise over 1 h and the resulting mixture was stirred for 1 h at -5-0 °C. 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 Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, heptane/ethyl acetate 10:1) to give the title compound (7.46 kg) as a yellow oil. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.89 (dd, J =5.0, 1.6 Hz, 1H), 7.32 (ddd, J =10.3, 7.8, 1.6 Hz, 1H), 6.84 (ddd, J =8.0, 5.0, 3.2 Hz, 1H), 4.72 (t, J =3.6 Hz, 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 mass/charge calcd for C ₁₂ H ₁₇ FNO ₃ [M+H] ⁺ 242.1187, found value 242.1182.

Step 2. 4-Chloro-3-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine (N-XXXI-b)

The reactor was charged with 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). The solution was cooled to -78°C. Added dropwisen-BuLi (7.79 L, 19.40 mol, 2.5 M in hexanes) and the reaction mixture was stirred for 4 h at -78°C. 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 an additional 2 h, and extracted with ethyl acetate (2×18 L). The organic phase was washed with brine (18 L), dried over anhydrous Na₂SO₄and concentrated. The crude product was purified by flash chromatography (silica, heptane/ethyl acetate 10:1) to give the title compound (3.74 kg) as a light yellow oil.¹H NMR (400 MHz, CDCl₃) δ 7.79 (dd,J=5.5, 1.0 Hz, 1H), 6.91 (dd, J=5.4, 4.4 Hz, 1H), 4.72 (t, J=3.6 Hz, 1H), 4.58 (dt,J=6.0, 3.7 Hz, 2H), 4.08 (ddd,J=11.5, 5.6, 3.9 Hz, 1H), 3.94-3.80 (m, 2H), 3.52 (ddd, J=10.6, 6.0, 4.2 Hz, 1H), 1.90-1.77 (m, 1H), 1.77-1.67 (m, 1H), 1.66-1.47 (m, 4H). UPLC-MS 5: HRMS mass/charge calc for C₁₂H₁₅ClFNNaO₃[M+Na]⁺298.0617, found value 298.0657.

Step 3. 4-Chloro-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinic acid (N-XXXI-c)

Diisopropylamine (1.91 kg, 18.88 mol) and THF (20 L) were charged into the reactor and added dropwisen-BuLi (7.56 L, 18.88 mol, 2.5 M in hexanes) 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 mixture was stirred for 3 h and poured onto 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) then 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 Na₂SO₄and concentrated to give the title compound (3.68 kg) as an off-white solid.¹H NMR (400 MHz, CDCl₃) δ 8.64 (d,J=1.3 Hz, 1H), 8.02 (brs, 1H), 4.77 (t, J=3.4 Hz, 1H), 4.68 (ddd,J=5.9, 4.0, 1.8 Hz, 2H), 4.11 (ddd,J=11.6, 5.4, 4.0 Hz, 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 mass/charge calc for C₁₃H₁₄ClFNO₅[M-H]^-318.0550, found value 318.0482.

Step 4. 4-Chloro-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate (N-XXXI)

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) were added K ₂ CO ₃ (4.32 kg, 31.3 mol) and MeI (2.67 kg, 18.8 mol). 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 Na ₂ SO ₄ and concentrated. The crude product was purified by slurrying with n -heptane (4 L) to give the title compound (3.37 kg) as a colourless solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.51 (d, J = 1.2 Hz, 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 calcd. for C ₁₄ H ₁₈ ClFNO ₅ [M+H] ⁺ 334.0852, the found value is 334.0823.

Synthesis of methyl 4-chloro-5-fluoro-6-(2-methoxyethoxy)nicotinate (N-XXXII)

At 0 °C, to a stirred solution of methyl 4-chloro-5-fluoro-6-hydroxynicotinate (N-XXX-b) (2.0 g, 9.7 mmol), 2-methoxyethan-1-ol (815 mg, 1.07 mmol) and triphenylphosphine (3.31 g, 12.7 mmol) in THF (40 mL) was added DEAD (2.54 g, 14.598 mmol) and stirring was continued at this temperature for 3 h. The reaction mixture was quenched with saturated NH ₄ Cl solution and extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, hexane/EtOAc; gradient: 10% to 20% EtOAc) to give the title compound (3.0 g). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 8.50 (d, J=1.2 Hz, 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] ⁺ .

Synthesis of methyl (S)-2-bromo-3-fluoro-4-(2-hydroxypropoxy)benzoate (N-XXXIII)

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) was added pyridinium p-toluenesulfonate (10.28 g, 40.9 mmol) and stirring at rt was continued for 16 h. The reaction mixture was quenched by addition of saturated _NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with saturated _NaHCO3 solution (200 mL), dried over _{anhydrous Na2SO4} and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 5 to 40% EtOAc) to give the title compound (5.50 g). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.69 (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).

Synthesis of methyl 2-bromo-3-fluoro-4-(2-hydroxyethoxy)benzoate (N-XXXIV)

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 sat. _NaHCO3 (100 mL) and extracted twice with EtOAc. The combined organic layers were washed with sat. _NaHCO3 (100 mL), dried over anhydrous _{Na2SO4 ,} and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 84% EtOAc) to give the title compound (694 mg) as a colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.69 (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).

Synthesis of methyl 4-chloro-5-fluoro-6-(2-hydroxyethoxy)nicotinate (N-XXXV)

Under Ar atmosphere, 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 at rt was continued for 16 h at rt. The reaction mixture was quenched by addition of sat. _NaHCO3 solution (100 mL) and extracted twice with EtOAc. The combined organic layers were washed with sat. _NaHCO3 solution (200 mL), dried over _{anhydrous Na2SO4} and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 76% EtOAc) to give the title compound (4.91 g) as a colorless powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.52 (d, J = 1.3 Hz, 1H), 4.94 (t, J = 5.5 Hz, 1H), 4.51-4.42 (m, 2H), 3.87 (s, 3H), 3.76 (q, J = 5.3 Hz, 2H). UPLC-MS 1: m/z 250.3 [MH] ^- , t _R = 0.77 min.

Intermediates for reductive amination with primary amines:

Synthesis of 4-(fluoromethyl)-4-hydroxycyclohexan-1-one (S-I)

Step 1. 8-(Fluoromethyl)-1,4-dioxaspiro[4.5]decan-8-ol (SIa)

To a stirred solution of 1,7,10-trioxadispiro[2.2.4 ⁶ .2 ³ ]dodecane (CAS 83365-44-0) (5.00 g, 29.40 mmol) in toluene (200 mL) was added TBAF (294 mL, 294 mmol, 1 M in THF) at rt 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 Na ₂ SO ₄ and concentrated to give the title compound (3.00 g), which was used without further purification in the next step. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 4.59 (s, 1H), 4.12 (d, J=48 Hz, 2H), 3.84 (s, 4H), 1.76-1.72 (m, 2H), 1.55-1.46 (m, 6H).

Step 2. 4-(Fluoromethyl)-4-hydroxycyclohexan-1-one (SI)

At rt, to a stirred solution of 8-(fluoromethyl)-1,4-dioxaspiro[4.5]decan-8-ol (SIa) (3.00 g, 15.78 mmol) in acetone/ _H2O (2:1, 18 mL) was added p-TsOH (0.815 g, 4.73 mmol) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated and redissolved in EtOAc. The organic layer was washed with saturated _NaHCO3 solution, dried over anhydrous _Na2SO4 and concentrated. The residue was purified by flash chromatography (silica, _hexane /EtOAc 1:1) to give the title compound (1.30 g). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 5.05 (s, 1H), 4.25 (d, J=47.8 Hz, 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).

Synthesis of trans-4-(1H-tetrazol-1-yl)cyclohexanamine (S-II)

Step 1. Benzyl(trans-4-(1H-tetrazol-1-yl)cyclohexyl)carbamate (S-II-a)

Under nitrogen atmosphere, a suspension of benzyl (trans-4-aminocyclohexyl)carbamate (1500 mg, 5.27 mmol), triethyl orthoformate (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 at 100 °C was continued for 20 h. The reaction mixture was quenched by addition of saturated NaHCO ₃ solution and the resulting solid was collected by filtration followed by trituration with Et ₂ O/pentane (1:1) to give the title compound (1050 mg). UPLC-MS 1: mass/charge 302.3 [M+H] ⁺ , t _R =0.82 min.

Step 2. Trans-4-(1H-tetrazol-1-yl)cyclohexanamine (S-II)

At rt, palladium (0.1 g, 10% 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). The flask was evacuated and purged with hydrogen. The mixture was stirred at rt for 30 min. The solids were 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 = 0.18 min.

Synthesis of trans-3-((difluoromethoxy)methyl)cyclobutanamine (S-III)

Step 1. tert-Butyl (trans-3-(hydroxymethyl)cyclobutyl)carbamate (S-III-a)

At rt, to a stirred solution of trans-3-((tert-butoxycarbonyl)amino)cyclobutanecarboxylic acid (500 mg, 2.32 mmol) in THF (10 mL) was added borane-methyl sulfide complex (1.16 mL, 2.323 mmol, 2 M in THF) and the reaction mixture was stirred overnight under Ar. The reaction mixture was quenched with sat. _NH4Cl solution then extracted with TBME. The organic layers were combined and washed with sat. _NaHCO3 solution, dried over anhydrous _Na2SO4 and concentrated to give the title compound (460 mg) as a colorless powder. MS: m/ _z 202.2.

Step 2. tert-Butyl (trans-3-((difluoromethoxy)methyl)cyclobutyl)carbamate (S-III-b)

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 saturated NaHCO ₃ solution and extracted with EtOAc. The organic layers were combined and washed with saturated NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient 0% to 30% EtOAc) to give the title compound (38 mg) as a colorless powder. ¹ H NMR (400 MHz, 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).

Step 3. Trans-3-((difluoromethoxy)methyl)cyclobutanamine (S-III)

At rt, 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) was added HCl (2.5 mL, 9.85 mmol, 4 M in dioxane) and the reaction mixture was stirred for 1 h. The reaction mixture was quenched with saturated NaHCO ₃ solution and extracted with TBME. The organic layers were combined and washed with saturated NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated to give the title compound (25 mg).

Synthesis of (1R,2R,4S)-4-amino-2-fluorocyclohexanol (S-IV)

Step 1. Benzyl (1S,3S,6R)-7-oxabicyclo[4.1.0]heptan-3-ylcarbamate (S-IV-a1) and benzyl (1R,3R,6S)-7-oxabicyclo[4.1.0]heptan-3-ylcarbamate (S-IV-a2)

The racemate of benzyl (1S*,3S*,6R*)-7-oxabicyclo[4.1.0]heptan-3-ylcarbamate (13.84 g) (Tetrahedron 2005, 61 , 1207) was subjected to chiral resolution (ChiralPak AY, 50 × 250 mm i.d., 10 μm hexane/IPA 80:20, 35°C, flow rate: 30 mL/min) to give two enantiomers of benzyl (1S,3S,6R)-7-oxabicyclo[4.1.0]heptan-3-ylcarbamate (S-IV-a1) and benzyl (1R,3R,6S)-7-oxabicyclo[4.1.0]heptan-3-ylcarbamate (S-IV-a2) with an enantiomeric excess of >99%, respectively.

Benzyl-(1S,3S,6R)-7-oxabicyclo[4.1.0]heptan-3-ylcarbamate (S-IV-a1) (6.03 g): Chiral SFC: (Chiralpak AY-H 150×4.6 mm i.d., 5 µm, hexane/IPA 7:3, flow rate: 1 ml/min.) t _R =5.88 min; UPLC-MS 1: mass/charge 248.1[M+H] ⁺ , t _R =0.90 min.

Benzyl-(1R,3R,6S)-7-oxabicyclo[4.1.0]heptan-3-ylcarbamate (S-IV-a2) (6.20 g): Chiral SFC: (Chiralpak AY-H 150×4.6 mm i.d., 5 µm, hexane/IPA 7:3, flow rate: 1 ml/min) t _R =9.08 min; UPLC-MS 1: mass/charge 248.1[M+H] ⁺ , t _R =0.90 min.

Step 2. Benzyl ((1S,3R,4R)-3-fluoro-4-hydroxycyclohexyl)carbamate (S-IV-b)

At rt, triethylamine trihydrofluoride (1.65 mL, 10.1 mmol) was added to benzyl (1S,3S,6R)-7-oxabicyclo[4.1.0]heptan-3-ylcarbamate (S-IV-a1) (500 mg, 2.0 mmol) and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was quenched with saturated NaHCO ₃ solution then extracted with DCM. The organic layers were combined and washed with saturated NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by SFC to give the title compound (364 mg) as a colorless oil. UPLC-MS 1: mass/charge 268.3 [M+H] ⁺ , t _R =0.82 min.

Step 3. (1R,2R,4S)-4-amino-2-fluorocyclohexanol (S-IV)

At rt, palladium (71.7 mg, 0.07 mmol, 10% 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). The flask was evacuated and purged with hydrogen. The mixture was stirred at rt for 20 h. The solids were filtered and the filter cake was washed with EtOH. The filtrate was concentrated in vacuo to give the desired product (190 mg). ^1H NMR (600 MHz, DMSO -d6 ) δ 4.96 (d, J=3.3 Hz, 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).

Synthesis of (1S,2S,4R)-4-amino-2-fluorocyclohexanol (S-V)

The title compound was prepared in a manner analogous to that for (1R,2R,4S)-4-amino-2-fluorocyclohexanol (S-IV) from benzyl (1R,3R,6S)-7-oxabicyclo[4.1.0]heptan-3-ylcarbamate (S-IV-a2), ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 5.09-4.90 (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).

Intermediates for Suzuki cross-coupling reactions:

Synthesis 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 (C-I):

Reaction scheme C-I:

Step 1. 2-(Benzyloxy)-6-bromobenzaldehyde (CIa)

A 20 L four-neck round bottom flask, purged and maintained under an inert atmosphere of nitrogen, was charged with a solution of 2-bromo-6-fluorobenzaldehyde (CAS 360575-28-6) (1500 g, 7.39 mol) in DMF (11.25 L), _benzyl alcohol (1042 g, 9.64 mol) and _Cs2CO3 (4840 g, 14.81 mol). The resulting solution was stirred overnight at 80 °C. The reaction mixture was cooled to rt with 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 in vacuo. The residue was purified by flash chromatography (silica, PE/EtOAc 40:1) to give the title compound (2150 g) as a colourless powder. ¹ H-NMR (400 MHz, DMSO- d ₆ ) 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-MS 1: m/z 291.2/293.1 [M+H] ⁺

Step 2 . 6-(Benzyloxy)-2-bromo-3-chlorobenzaldehyde (CIb)

A 20 L four-neck round bottom flask, purged and maintained under an inert atmosphere of nitrogen, was charged with 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). 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 light yellow oil. ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 10.24 (s, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.54-7.23 (m, 6H), 5.26 (s, 2H). UPLC-MS 1: m/z 325.0 [M+H] ⁺

Step 3 . (6-(Benzyloxy)-2-bromo-3-chlorophenyl)methanol (CIc)

A 20 L four-neck round bottom flask, purged and maintained under an inert atmosphere of nitrogen, was charged with a solution of 6-(benzyloxy)-2-bromo-3-chlorobenzaldehyde (CIb) (893 g, 2.74 mol) in THF (8 L). NaBH ₄ (105 g, 2.78 mol) was added in several portions at 0 °C. The resulting solution was stirred at rt for 3 h. This reaction was repeated once. Then the reaction mixture was 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 Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, PE/EtOAc 20:1) to afford the title compound (1496 g) as a colourless powder. ¹ H NMR (400 MHz, DMSO- d ₆ ) 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-MS 1: m/z 324.7 [MH] ^-

Stage 4 . 1-(Benzyloxy)-3-bromo-2-(bromomethyl)-4-chlorobenzene (CId)

In a 20 L four-neck round-bottomed flask, purged and maintained under an inert atmosphere of nitrogen, was placed 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). 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 flash chromatography (silica, PE/EtOAc 10:1) to afford the desired product (1201 g) as a colorless powder. ¹ H-NMR (400 MHz, DMSO -d ₆ ) 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).

Stage 5 . Methyl 3-(6-(benzyloxy)-2-bromo-3-chlorophenyl)-2-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propanoate (CIf)

A 20 L four-neck round bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with a solution of (CIe) (CAS 33973-12-5, prepared from methyl mandelate and dihydropyran according to Du, Wu; Hagmann, William K.; He, Shuwen; Lai, Zhong; Shah, Shrenik K.; Truong, Quang T. PCT Int. Appl. (2010), WO 2010083136 A1) (774 g, 3.09 mol) in THF (9 L). At -78 °C, LDA (1934 mL, 2 M in THF) was added dropwise 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 allowed to warm to rt and stirring was continued for an additional 3 h. The reaction mixture was then quenched by adding aqueous NH ₄ Cl solution at -10 °C. The resulting solution was extracted with EtOAc, the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (1870 g) as a brown oil. UPLC-MS 1: mass/charge 557.2/559.2 [MH] ^- .

Step 6. Methyl 3-(6-(benzyloxy)-2-bromo-3-chlorophenyl)-2-hydroxy-2-phenylpropanoate (CIg)

In a 20 L four-neck round bottom flask, purged and maintained under an inert atmosphere of nitrogen, was placed a solution of methyl 3-(6-(benzyloxy)-2-bromo-3-chlorophenyl)-2-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propanoate (CIf) (935 g, 1.67 mol) in ACN (9 L). This was followed by the dropwise addition of hydrogen chloride (6 L, 2 N) at rt. The resulting solution was stirred at rt for 3 h. The solids were 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 light yellow powder. ^1H -NMR (400 MHz, 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-MS 1: mass/charge 475.1 [M+H] ⁺ .

Step 7. Methyl 3-(2-bromo-3-chloro-6-hydroxyphenyl)-2-hydroxy-2-phenylpropanoate (CIh)

A 3 L four-necked round-bottomed flask, purged and maintained under nitrogen, was charged with a solution of methyl 3-[6-(benzyloxy)-2-bromo-3-chlorophenyl]-2-hydroxy-2-phenylpropanoate (CIg) (100 g, 210.2 mmol) in MeOH/THF (5:1) (2 L) and Raney Ni (30 g). The flask was evacuated and purged with nitrogen three times, followed by a hydrogen purge. The mixture was stirred at rt for 5 h. This reaction was repeated ten times. The solids were filtered and the filter cake was washed with MeOH. The filtrate was concentrated in vacuo to give the desired product (930 g) as a yellow oil. ¹ H-NMR (400 MHz, DMSO- d ₆ ) 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-MS 1: m/z 383.1/385.1 [MH] ^- .

Step 8. Methyl 4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (CIi)

A 20 L four-neck round-bottomed flask, purged and maintained under an inert atmosphere of nitrogen, was charged with a solution of methyl 3-(2-bromo-3-chloro-6-hydroxyphenyl)-2-hydroxy-2-phenylpropanoate (CIh) (930 g, 2.41 mol) in THF (9 L) and triphenylphosphine (761 g, 2.90 mol). Then DIAD (587 g, 2.91 mol) was added dropwise at 0 °C. Stirring of the reaction solution was continued for 3 h at rt. The solution was diluted with EtOAc and washed with brine. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting crude product was purified by flash chromatography (silica, PE/EtOAc, gradient 0% to 5% EtOAc) to afford the title compound (582 g) as a colorless powder. ¹ H NMR (300 MHz, CDCl ₃ ) 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-MS 1: m/z 365.1/367.0 [MH] ^- .

Step 9. 4-Bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylic acid (CIj)

At rt, 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) was added NaOH (3.5 L, 2 N). The clear 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 (400 MHz, DMSO- d ₆ ) 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-MS 1: m/z 351.0/353.0 [MH] ^- , t _R = 1.09 min.

Step 10. (1 R ,2 R )-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-dihydrobenzofurancarboxylic acid (CIl)

4-Bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylic acid (CIj) (470 g, 1.33 mol) and (1 R ,2 R )-(-)-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 allowed to cool slowly to rt. The resulting white suspension was stirred at rt overnight. The solids were collected by filtration, washed with the original solution (500 mL), and dried in vacuo at 30 °C to give the salt (1 R ,2 R )-2-amino-1-(4-nitrophenyl)propane-1,3-diol(S)-4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (CIk) (340 g) with an enantiomeric 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) remained in the original solution. Chiral HPLC: (Chiralpak AD-H, heptane/EtOH/MeOH 90/6/4+0.05% TFA, flow rate: 1 mL/min) t _R = 10.03 min.

Step 11. ( S )-4-Bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylic acid (CIm)

(1 R ,2 R )-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 then stirred at rt. 2 N HCl (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) was determined by X-ray diffraction analysis.

Step 12. (S)-4-Bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxamide (CIn)

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 yellow clear solution was treated with DMF (1 mL). Oxalyl chloride (56.2 mL, 655 mmol) was added via addition funnel over 10 min. The resulting mixture was allowed to warm to rt and stirred for an additional 4.5 h at rt. This solution was then added to 25% aqueous ammonia solution via addition funnel over 45 min at 0 °C. The resulting milky white reaction mixture was allowed to warm 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 (400 MHz, 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-MS 1: m/z 352.0/353.9 [M+H] ⁺ , t _R = 1.15 min.

Step 13. ( S )-(4-Bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine (CIo)

( S )-4-Bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxamide (CI n) (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 an addition funnel at rt over 45 min. The reaction mixture was stirred for an additional 60 min and then slowly heated to reflux for 3 h. The reaction mixture was cooled to rt and stirred overnight. MeOH was added dropwise with cooling over 60 min and stirring at rt was continued for an additional 45 min. 1 N HCl was then added dropwise followed by stirring at rt. for another 3.5 h. Finally, 1 N NaOH was carefully added, followed by 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 and dried over _{anhydrous Na2SO4} , filtered and concentrated to give the title compound (154 g). ¹ H NMR (400 MHz, 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-MS 1: mass/charge 338.0/340.0 [M+H] ⁺ , t _R =0.83 min.

Step 14. (S)-tert-Butyl ((4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (CIp)

( S )-(4-Bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine (ClO) (133 g, 255 mmol) was dissolved in DCM (1.2 L). The solution was cooled to 0 °C and a solution of Boc ₂ O (58.5 g, 268 mmol) in DCM (200 mL) was added via an addition funnel over 25 min. The reaction mixture was stirred at rt for a further 3 h before it was concentrated to ca. 300 mL and diluted with EtOAc. The organic layer was extracted with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc 9:1) to give the title compound (113 g) as a colourless solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) 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-MS 1: m/z 436.0/438.2 [MH] ^- , t _R = 1.45 min.

Step 15. ( S )-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 (CI)

( S )-tert-Butyl ((4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (CIp) (29 g, 66 mmol), bis(pinacolato)diboron (25 g, 99 mmol) and KOAc (19.5 g, 198 mmol) were dissolved in toluene (116 mL) under Ar. The reaction mixture was heated at 80 °C before PdCl ₂ (dppf)*CH ₂ Cl ₂ (5.4 g, 6.6 mmol) was added and heating at 110 °C was continued overnight. The reaction mixture was cooled to rt, filtered over Hyflo and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient 0% to 20% EtOAc) to give the title compound (25.1 g). ¹ H-NMR (400 MHz, DMSO - _d6 ) δ (ppm) 7.42-7.31 (m, 4H), 7.29-7.23 (m, 1H), 7.11 (d, J=8.6 Hz, 1H), 7.08-7.01 (m, 1H), 6.90 (d, J=8.2 Hz, 1H), 3.66 (d, J=17.2 Hz, 1H), 3.56-3.47 (m, 1H), 3.38-3.30 (m, 1H), 3.61-3.30 (m, 2H), 3.18 (d, J=16.4 Hz, 1H), 1.30-1.24 (m, 21H). UPLC-MS 1: mass/charge 486.2 [M+H] ⁺ , t _R =1.49 min.

Synthesis of 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 (C-II):

The title racemic compound was prepared in a manner analogous to that for 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 (CI) without separation of the enantiomers. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ (ppm) 7.44-7.37 (m, 4H), 7.33-7.29 (m, 1H), 7.17-7.12 (m, 2H), 6.94 (d, J=8.4 Hz, 1H), 3.70 (d, J=16.5 Hz, 1H), 3.58-3.53 (m, 1H), 3.39-3.35 (m, 1H), 3.22 (d, J=16.9 Hz, 1H), 1.34-1.28 (m, 21H). UPLC-MS 1: m/z 486.2 [M+H] ⁺ , t _R =1.52 min.

Synthesis of 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 (C-III):

Reaction scheme C-III:

Step 1. 3-Bromo-2-(bromomethyl)-4-chlorophenol (C-III-a)

At -78 °C, to a stirred solution of 1-(benzyloxy)-3-bromo-2-(bromomethyl)-4-chlorobenzene (Cld) (20 g, 51.2 mmol) in DCM (200 mL) under Ar was added _BBr3 (56.3 mL, 56.3 mmol). The reaction mixture was stirred for 2 h at -78 °C. The reaction mixture was quenched with MeOH (20 mL) and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient: 0% to 30% EtOAc) to give the title compound (14.64 g) as a brown powder. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.30 (t, J =8.6 Hz, 1H), 6.75 (d, J =8.6 Hz, 1H), 5.45 (s, 1H), 4.77 (s, 2H).

Step 2. Methyl 2-acetyl-4-bromo-5-chloro-2,3-dihydrobenzofuran-2-carboxylate (C-III-b)

At rt, to a stirred solution of 3-bromo-2-(bromomethyl)-4-chlorophenol (C-III-a) (10 g, 33.3 mmol) in ACN (100 mL) under Ar were added methyl 2-chloroacetoacetate (4.06 mL, 33.3 mmol) and TEA (9.74 mL, 70 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with saturated NaHCO ₃ solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient 0% to 30% EtOAc) to give the title compound (8.26 g) as a colourless powder. UPLC-MS 1: t _R = 1.17 min.

Step 3. Methyl 4-bromo-2-(2-bromoacetyl)-5-chloro-2,3-dihydrobenzofuran-2-carboxylate

(C-III-c)

At rt, 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 CHCl ₃ (75 mL) was added Br ₂ (1.403 mL, 27.2 mmol) under Ar. The reaction mixture was stirred for 5 h before it was diluted with saturated NaHCO ₃ and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient 0% to 20% EtOAc) to give the title compound (9.26 g) as a colourless powder. UPLC-MS 1: t _R = 1.21.

Step 4. Methyl 4-bromo-5-chloro-2-(thiazol-4-yl)-2,3-dihydrobenzofuran-2-carboxylate (C-III-d)

Under Ar atmosphere, 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 for 60 min at 100 °C. The reaction mixture was diluted with saturated NaHCO ₃ solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash 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 = 1.14 min.

Step 5. (4-Bromo-5-chloro-2-(thiazol-4-yl)-2,3-dihydrobenzofuran-2-yl)methanol (C-III-e)

At 0 °C, to a stirred solution of methyl 4-bromo-5-chloro-2-(thiazol-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) was added portionwise LiBH ₄ (0.812 g, 37.3 mmol) under Ar. The resulting suspension was stirred for 10 min at rt. The reaction mixture was diluted with saturated NH ₄ Cl solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient 0% to 85% EtOAc) to give the title compound (6.08 g) as a colourless powder. UPLC-MS 1: m/z 348.0 [M+H] ⁺ , t _R = 1.01 min.

Step 6. (4-Bromo-5-chloro-2-(thiazol-4-yl)-2,3-dihydrobenzofuran-2-yl)methyl methanesulfonate (C-III-f)

At 0 °C, to a stirred solution of (4-bromo-5-chloro-2-(thiazol-4-yl)-2,3-dihydrobenzofuran-2-yl)methanol (C-III-e) (2.40 g, 6.92 mmol) in DCM (50 mL) were added methanesulfonic anhydride (2.412 g, 13.85 mmol) and TEA (4.83 mL, 34.6 mmol) portionwise under Ar. The reaction mixture was stirred for 2 h at rt. The reaction mixture was diluted with brine and extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash 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 = 1.12 min.

Step 7. 4-(2-(Azidomethyl)-4-bromo-5-chloro-2,3-dihydrobenzofuran-2-yl)thiazole (C-III-g)

Under Ar atmosphere, sodium azide (2.181 g, 33.6 mmol) was added to a stirred solution of (4-bromo-5-chloro-2-(thiazol-4-yl)-2,3-dihydrobenzofuran-2-yl)methyl methanesulfonate (C-III-f) (2.85 g, 6.71 mmol) in DMF (50 mL). The reaction mixture was stirred for 20 h at 130 °C. The reaction mixture was diluted with saturated NaHCO ₃ solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient 0% to 30% EtOAc) to give the title compound (1.90 g) as a colourless powder. UPLC-MS 1: m/z 373.1 [M+H] ⁺ , t _R = 1.28 min.

Step 8. (4-Bromo-5-chloro-2-(thiazol-4-yl)-2,3-dihydrobenzofuran-2-yl)methanamine (C-III-h)

At 0 °C, 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) under Ar was added portionwise NaBH ₄ (1.934 g, 51.1 mmol). The resulting suspension was stirred for 16 h at 70 °C. The reaction mixture was diluted with saturated NaHCO ₃ solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, DCM/MeOH, gradient: 0% to 10% MeOH) to give the title compound (1.30 g) as a colourless oil. UPLC-MS 1: m/z 347.0 [M+H] ⁺ , t _R = 0.66 min.

Step 9. tert-Butyl ((4-bromo-5-chloro-2-(thiazol-4-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-III-i)

At rt, to a stirred solution of (4-bromo-5-chloro-2-(thiazol-4-yl)-2,3-dihydrobenzofuran-2-yl)methanamine (C-III-h) (1.3 g, 3.76 mmol) in DCM (40 mL) was added Boc-anhydride (0.961 mL, 4.14 mmol) and stirring at rt was continued 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 flash chromatography (silica, cyclohexane/EtOAc, gradient 0% to 70% EtOAc) to give the title compound (1.36 g) as a colourless powder. UPLC-MS 1: m/z 447.1 [M+H] ⁺ , t _R = 1.29 min.

Step 10. 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 (C-III)

A deoxygenated suspension of tert-butyl ((4-bromo-5-chloro-2-(thiazol-4-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-III-i) (1.36 g, 3.05 mmol), bis(pinacolato)diboron (1.55 g, 6.1 mmol), KOAc (0.898 g, 9.15 mmol) and PdCl adduct₂(dppf).CH₂Cl₂(0.249 g, 0.305 mmol) in DMSO (400 mL) was stirred at 120°C for 16 h under Ar atmosphere. The reaction mixture was diluted with a saturated solution of NaHCO₃and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄and concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient 0% to 70% EtOAc) to give the title compound (1.02 g) as a colorless powder. UPLC-MS 1: m/z 493.3 [M+H]⁺, t_R=1.37 min.

Synthesis of 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 (C-IV):

The title racemic compound was prepared in a manner analogous to that for 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 (C-XII) from 2-bromo-3-chloro-6-hydroxybenzaldehyde (C-VI-a) and 2-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)acetonitrile (synthesized as follows: reduction of 2,2-difluorobenzo[d][1,3]dioxol-4-carbaldehyde to the corresponding alcohol, followed by formation of benzyl chloride and conversion to the corresponding nitrile) without separation of the enantiomers. UPLC-MS 1: mass/charge 610.4 [M+formate] ^- , t _R =1.56 min.

Synthesis of 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 (C-V):

C-V reaction scheme:

(2R,5R)-5-(6-(benzyloxy)-2-bromo-3-chlorobenzyl)-2-(tert-butyl)-5-(2-fluorophenyl)-1,3-dioxolan-4-one (C-V-a) was synthesized in analogy to C-XVII-c (synthesis of intermediate C-XVII in step 3) from 1-(benzyloxy)-3-bromo-2-(bromomethyl)-4-chlorobenzene (C-I-d) and (2R,5R)-2-(tert-butyl)-5-(2-fluorophenyl)-1,3-dioxolan-4-one using LDA instead of NaH as a base.

Step 1. (2R,5R)-5-(2-Bromo-3-chloro-6-hydroxybenzyl)-2-(tert-butyl)-5-(2-fluorophenyl)-1,3-dioxolan-4-one (CVb)

To a solution of (2R,5R)-5-(6-(benzyloxy)-2-bromo-3-chlorobenzyl)-2-(tert-butyl)-5-(2-fluorophenyl)-1,3-dioxolan-4-one (CVa) (15.49 g, 28.3 mmol) in MeOH (225 mL) and THF (45 mL) was added Ra-Ni (2.66 g, 31.1 mmol) and stirred under hydrogen atmosphere for 43 h. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by flash chromatography (silica, hexane/EtOAc 9:1) to give the title compound (11.47 g). UPLC-MS 1: mass/charge 455.0/457.0 [MH] ^- , t _R =1.37 min.

Step 2. Methyl (R)-3-(2-bromo-3-chloro-6-hydroxyphenyl)-2-(2-fluorophenyl)-2-hydroxypropanoate (CVc)

At 0 °C, to a solution of (2R,5R)-5-(2-bromo-3-chloro-6-hydroxybenzyl)-2-(tert-butyl)-5-(2-fluorophenyl)-1,3-dioxolan-4-one (CVb) (11.4 g, 24.9 mmol) in MeOH (60 mL) was added sodium methoxide (5.70 mL, 24.9 mmol, 25% in MeOH) and stirring was continued at this temperature for 2 h. Saturated NH ₄ Cl solution was added and the mixture was extracted with EtOAc. The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , concentrated and the residue was purified by flash chromatography (silica, hexane/EtOAc 2:1) to give the title compound (9.06 g). UPLC-MS 1: mass/charge 401.0/402.9 [MH] ^- , t _R =1.14 min.

Step 3. Methyl (S)-4-bromo-5-chloro-2-(2-fluorophenyl)-2,3-dihydrobenzofuran-2-carboxylate (CVd)

At 0 °C, to a solution of methyl (R)-3-(2-bromo-3-chloro-6-hydroxyphenyl)-2-(2-fluorophenyl)-2-hydroxypropanoate (CVc) (9.06 g, 22.4 mmol) in THF (215 mL) was added _PPh3 (7.06 g, 26.9 mmol) followed by DIAD (5.23 mL, 26.9 mmol). 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 flash chromatography (silica, hexane/EtOAc 95:5) to give the title compound (7.76 g). UPLC-MS 1: mass/charge 383.0/385.0 [MH] ^- , t _R =1.37 min.

(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 (C-V):

The title compound was synthesized from methyl (S)-4-bromo-5-chloro-2-(2-fluorophenyl)-2,3-dihydrobenzofuran-2-carboxylate (C-V-d) according to the procedures described for the synthesis of intermediate C-XXV. The boronate was synthesized in the final step as described for intermediate C-I.¹H-NMR (600 MHz, DMSO-d ₆ ) δ (ppm) 7.51 (t,J=7.7 Hz, 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=8.4 Hz, 1H), 3.70 (d,J=17.1 Hz, 1H), 3.60 (dd,J=14.3, 6.3 Hz, 1H), 3.39 (dd, J=14.5, 6.5 Hz, 1H), 3.28 (d, J=17.3 Hz, 1H), 1.34-1.19 (m, 12H), 1.15 (s, 9H). UPLC-MS 1: mass/charge 504.2 [M+H]⁺, t_R=1.52 min.

Synthesis of 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 (C-VI):

Reaction scheme C-VI:

Step 1. 2-Bromo-3-chloro-6-hydroxybenzaldehyde (C-VI-a)

At 0°C, sulfuryl chloride (101.2 g, 0.75 mol) was added to a solution of 2-bromo-6-hydroxybenzaldehyde (CAS 22532-61-2) (100 g, 0.5 mol) in ACN (500 mL) and stirring at 0°C was continued overnight. The solids were collected by filtration, washed with sat. _NaHCO3 solution and dried at HV to give the title compound (200 g). UPLC-MS 1: m/z 232.9/234.9 [MH] ^- . t _R = 1.09 min.

Stage 2. ( 2S *, 3S *) - 4-Bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-VI-b) and ( 2R *, 3S *) - 4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-VI-c)

At rt, 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) was added DIPEA (8.34 mL, 47.8 mmol) and the reaction mixture was stirred at rt for 2 days to give 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 (phase separation cartridge), and concentrated. The cis- and trans-configured racemic diastereoisomers ( 2S *, 3S *) - 4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-VI-b) (6.4 g) and ( 2R *, 3S *) - 4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-VI-c) (1.1 g) were separated by flash chromatography (silica, cyclohexane/EtOAc; gradient from 0% to 20% EtOAc).

( 2S *, 3S *) - 4-Bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-VI-b): ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 7.65 (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-MS 1: m/z 348.0/350.0 [MH] ^- . t _R = 1.14 min.

( 2R *, 3S *) - 4-Bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-VI-c):

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 7.69 (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-MS 1: m/z 348.0/350.0 [MH] ^- , t _R = 1.14 min.

Step 3. (2 S ,3 S )-4-Bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-VI-d) and (2 R ,3 R )-4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-VI-e)

The racemate ( 2S *, 3S *) - 4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-VI-b) (21.9 g) was separated by chiral SFC (Sepiatec Prep SFC 100 & Jasco Prep SFC, column: Chiralpak OJ-H 5 μm, 250×30 mm, 40°C, 3 ml/injection, 170 injections, _CO2 /IPA 9:1, flow rate: 80 ml/min, cycle time: 15 min) to afford ( 2S , 3S )-4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-VI-d) (9.35 g) and (2 R ,3 R )-4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-VI-e) (9.30 g) with an enantiomeric excess of >98%, respectively.

(2 S ,3 S )-4-Bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-VI-d):

Chiral SFC: (Chiralpak OJ-H 5 μm, 100×4.6 mm, _CO2 /IPA 8:2, flow rate: 3 mL/min.) t _R =2.38 min; UPLC-MS 1: m/z 394.1/396.1 [M+formate] ^- , t _R =1.14 min.

(2 R ,3 R )-4-Bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-VI-e):

Chiral SFC: (Chiralpak OJ-H 5 µm, 100×4.6 mm, _CO2 /IPA 8:2, flow rate: 3 mL/min.) t _R =1.82 min; UPLC-MS 1: m/z 394.1/396.1 [M+formate] ^- , t _R =1.14 min.

The absolute configuration (2R,3R) of this intermediate was confirmed by X-ray diffraction analysis 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-carbonitrile (C-VI-e) via reduction of the nitrile to the amine (using reaction conditions similar to those shown in Step 4 below) followed by Suzuki cross-coupling with phenylboronic acid.

Step 4. (2 S ,3 S )-2-(Aminomethyl)-4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-3-ol (C-VI-f)

To a stirred solution of ( 2S , 3S )-4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-VI-d) (2 g, 5.70 mmol) in THF (38 mL) was added borane-methyl sulfide complex (14.26 mL, 28.5 mmol, 2 M in THF) at rt and the reaction mixture was stirred at 65 °C for 1 h. After cooling to rt, the reaction mixture was quenched by careful addition of MeOH followed by 1 N HCl. Saturated NaHCO ₃ solution was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried (phase separation cartridge) and concentrated to give the title compound. UPLC-MS 1: mass/charge 354.1/356.1 [M+H] ⁺ . t _R =0.72 min.

Step 5. tert-Butyl (((2 S ,3 S )-4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-VI-g)

At rt, to a stirred solution of ( 2S , 3S )-2-(aminomethyl)-4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-3-ol (C-VI-f) (2.31 g, 4.18 mmol) in DCM (21 mL) were added Boc-anhydride (1.067 mL, 4.59 mmol) and TEA (0.582 mL, 4.18 mmol). The reaction mixture was stirred at rt for 2 h. For work-up, saturated _NaHCO3 solution was added and the mixture was extracted with DCM. The combined organic extracts were washed with water and brine, dried (phase separation cartridge), and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 30% EtOAc) to give the desired product (1.57 g). UPLC-MS 1: m/z 498.2/500.2 [M+formate] ^- . t _R = 1.28 min.

Step 6. tert-Butyl (((2 S ,3 S )-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 (C-VI)

At 80 °C, to a stirred suspension of tert-butyl (((2 S ,3 S )-4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (CVg) (1.65 g, 3.1 mmol), bis(pinacolato)diboron (1.02 g, 4.0 mmol) and potassium acetate (0.908 g, 9.3 mmol) in toluene (21 mL) was added the adduct PdCl ₂ (dppf).CH ₂ Cl ₂ (0.252 g, 0.308 mmol) and the reaction mixture was stirred vigorously at 100 °C for 17 h. The reaction mixture was filtered through celite and concentrated to give the crude product, which was purified by flash chromatography (silica, eluent cyclohexane/EtOAc, gradient: 0% to 40% EtOAc) to give the desired product (1.03 g). ¹ H-NMR (400 MHz, DMSO - _d6 ) δ (ppm) 7.42-7.36 (m, 2H), 7.33 (t, J=7.5 Hz, 2H), 7.28-7.21 (m, 2H), 7.00 (d, J=8.6 Hz, 1H), 6.25 (t, J=6.1 Hz, 1H), 6.09 (d, J=7.0 Hz, 1H), 5.18 (d, J=6.9 Hz, 1H), 3.80 (dd, J=14.2, 7.3 Hz, 1H), 3.55 (dd, J=14.3, 5.0 Hz, 1H), 1.31-1.20 (m, 21H). UPLC MS 1: mass/charge 502.3 [M+H] ⁺ . t _R =1.40 min.

Synthesis of 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 (C-VII):

The title racemic compound was prepared in a manner analogous to that for 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 (C-VI) from 2-bromo-3-chloro-6-hydroxybenzaldehyde (C-VI-a) and 2-bromo-2-(pyridin-2-yl)acetonitrile (prepared by bromination of 2-pyridylacetonitrile with NBS) without separation of the enantiomers. UPLC-MS 1: m/z 503.2 [M+H] ⁺ , t _R = 1.28 min.

Synthesis of 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 (C-VIII):

The title racemic compound was prepared analogously to 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 (C-VI) from 2-bromo-3-chloro-6-hydroxybenzaldehyde (C-VI-a) and 2-bromo-2-(2-(trifluoromethoxy)phenyl)acetonitrile (prepared by bromination of 2-trifluoromethoxy)phenylacetonitrile with Br ₂ ) without separation of enantiomers. UPLC-MS 1: m/z 584.2 [MH] ^- , t _R = 1.49 min.

Synthesis of 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 (C-IX):

The title racemic compound was prepared analogously to 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 (C-VI) from 2-bromo-3-chloro-6-hydroxybenzaldehyde (C-VI-a) and 2-bromo-2-(6-methoxypyridin-2-yl)acetonitrile (prepared by bromination of 2-(6-methoxypyridin-2-yl)acetonitrile with NBS) without separation of enantiomers. UPLC-MS 1: m/z 577.3 [MH] ^- , t _R = 1.36 min.

Synthesis of ((2S*,3S*)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-3-hydroxy-2-(2-methoxypyridin-3-yl)-2,3-dihydrobenzofuran- 4-yl)boronic acid (C-X):

The title racemic compound was prepared analogously to 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 (C-VI) from 2-bromo-3-chloro-6-hydroxybenzaldehyde (C-VI-a) and 2-bromo-2-(2-methoxypyridin-3-yl)acetonitrile (prepared by bromination of 2-(2-methoxypyridin-3-yl)acetonitrile with NBS) without separation of the enantiomers. During the final purification, the pinacol group was largely cleaved to give the corresponding boronic acid containing approximately 30% of pinacol boronate. UPLC-MS 1: mass/charge 451.2 [M+H] ⁺ , t _R =0.95 min.

Synthesis of 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 (C-XI) :

Reaction scheme C-XI:

Step 1. 4-Bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XI-a)

To a stirred solution of 2-bromo-3-chloro-6-hydroxybenzaldehyde (C-VI-a) (10 g, 42.5 mmol) and 2-bromo-2-phenylacetonitrile (9.16 g, 46.7 mmol) in ACN (100 mL) was added DIPEA (11.13 mL, 63.7 mmol) at rt and stirring was continued for 4 h. The reaction mixture was _concentrated , diluted in DCM/water and extracted with DCM. The combined organic extracts were washed with water and brine, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 25% EtOAc) to give the title compound (11.39 g, colorless foam) as a diastereomeric mixture. UPLC-MS 1: m/z 348.0/350.0 [M+H] ⁺ , t _R = 1.11 min.

Step 2. 4-Bromo-5-chloro-3-oxo-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XI-b)

At 0 °C, to a stirred solution of 4-bromo-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XI-a) (11.39 g, 32.5 mmol) in DCM (200 mL) was added Dess-Martin periodinane (27.6 g, 65.0 mmol) and the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with a mixture of DCM, saturated NaHCO ₃ solution and 10% sodium thiosulfate solution and extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient: 20% to 40% EtOAc) to give the title compound (10.86 g) as a colorless powder. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.12 (d, J=9.1 Hz, 1H), 7.61 (d, J=9.1 Hz, 1H), 7.55-7.47 (m, 5H).

Step 3. 4-Bromo-5-chloro-3-hydroxy-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XI-c)

At -78 °C, to a stirred solution of 4-bromo-5-chloro-3-oxo-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XI-b) (10.86 g, 31.2 mmol) in THF (250 mL) was added methylmagnesium bromide (15.58 mL, 46.7 mmol, 3 M in Et ₂ O) and the reaction mixture was stirred at this temperature for an additional 1.5 h. The reaction mixture was quenched at -30 °C with saturated ammonium chloride solution, diluted with EtOAc and saturated ammonium chloride solution, and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over anhydrous Na ₂ SO ₄ , and concentrated. The residue was purified by flash chromatography (silica, heptane/EtOAc, gradient: 0% to 30% EtOAc) to give the title product (10.15 g, colorless powder) as a diastereomeric mixture. UPLC-MS 1: m/z 362.0/364.0 [M+H]+, t _R = 1.21 min and 1.22 min.

Step 4. 2-(Aminomethyl)-4-bromo-5-chloro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-3-ol (C-XI-d)

At rt, to a stirred solution of 4-bromo-5-chloro-3-hydroxy-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XI-c) (10.15 g, 27.8 mmol) in THF (200 mL) was added borane-dimethyl sulfide complex (55.7 mL, 111 mmol, 2 M in THF) and the reaction mixture was stirred at 65 °C for 30 min. The reaction mixture was then quenched by adding 40 mL MeOH at 0 °C and stirring at rt was continued for 16 h. The reaction mixture was concentrated, diluted in DCM and saturated NaHCO ₃ solution. The organic phase was separated and the aqueous phase was extracted with DCM. _The combined organic extracts were dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, DCM/(7N ammonia in MeOH); gradient: 0% to 6% (7N ammonia in MeOH)) to afford the title compound (8.69 g, colorless powder) as a diastereomeric mixture. UPLC-MS 1: m/z 368.1/370.1 [M+H]+, t _R = 0.62 min and 0.77 min.

Step 5. (4-Bromo-5-chloro-3-methylene-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine (C-XI-e)

To a stirred solution of 2-(aminomethyl)-4-bromo-5-chloro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-3-ol (C-XI-d) (5.81 g, 15.76 mmol) in DCM (60 mL) was added TFA (20 mL, 260 mmol) at 0 °C and the reaction mixture was stirred at rt for 5 h. The reaction mixture was diluted in DCM and added dropwise to a stirred mixture of saturated NaHCO ₃ solution and DCM at 0 °C. The organic phase was separated and the aqueous layer was extracted with DCM. The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated to give the title compound (5.18 g) as a yellow oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.50 (d, J = 8.7 Hz, 1H), 7.44-7.41 (m, 2H), 7.36-7.23 (m, 3H), 7.08 (d, J = 8.7 Hz, 1H), 6.40 (s, 1H), 5.33 (s, 1H), 3.20 (s, 2H), 1.36 (s, 2H). UPLC-MS 1: m/z 349.9/352.0 [M+H]+, t _R = 0.83 min.

Step 6. (4-Bromo-5-chloro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine (C-XI-f)

At rt, to a stirred solution of (4-bromo-5-chloro-3-methylene-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine (C-XI-e) (5.18 g, 14.76 mmol) in EtOH (60 mL) was added hydrazine hydrate (5.79 mL, 118 mmol). The reaction mixture was cooled to 0 °C and O ₂ was bubbled into the solution for 5 min. The reaction mixture was stirred at reflux under O ₂ for 3 days. The reaction mixture was concentrated, diluted in EtOAc/water and the organic phase was separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, DCM/(7N ammonia in MeOH); gradient: 0% to 5% (7N ammonia in MeOH)) to give the title compound (3.00 g, yellow oil) as a diastereomeric mixture (12:1 ratio). UPLC-MS 1: m/z 352.0/354.0 [M+H]+, t _{R =} 0.85 min and 0.92 min.

Step 7. tert-Butyl (((2S*,3S*)-4-bromo-5-chloro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XI-g) and tert-butyl (((2R*,3S*)-4-bromo-5-chloro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XI-h)

At rt, to a stirred solution of (4-bromo-5-chloro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine (C-XI-f) (3 g, 8.51 mmol) in DCM (30 mL) was added TEA (2.371 mL, 17.01 mmol) followed by Boc-anhydride (2.37 mL, 10.21 mmol) and the reaction mixture was stirred at rt for 30 min. The reaction mixture was diluted in DCM/water and _the organic phase was separated. The aqueous phase was extracted with DCM and the combined organic extracts were washed with brine, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient: 0% to 10% EtOAc) to give, after trituration with hexane,

(((2S*,3S*)-4-bromo-5-chloro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XI-g) (3.3 g, colorless powder): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.53-7.13 (m, 6H), 6.98 (d, J=8.5 Hz, 1H), 6.49 (t, J=6.2 Hz, 1H), 3.90-3.71 (m, 1H), 3.67-3.49 (m, 2H), 1.37 (d, J=7.0 Hz, 3H), 1.18 (s, 9H). UPLC-MS 1: m/z 352.0/354.0 [M-Boc]+, t _R =1.43 min.

The filtrate was repurified by flash chromatography (silica, heptane/EtOAc; gradient: 0% to 18% EtOAc) to give (((2R*,3S*)-4-bromo-5-chloro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XI-h) (230 mg): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.54-7.23 (m, 6H), 6.89 (d, J=8.5 Hz, 1H), 6.68 (t, J=6.4 Hz, 1H), 3.67 (q, J=7.0 Hz, 1H), 3.53 (dd, J=14.4, 6.2 Hz, 1H), 3.41 (dd, J=14.3, 6.5 Hz, 1H), 1.22 (s, 9H), 0.69 (d, J=7.0 Hz, 3H). UPLC-MS 1: mass/charge 352.0/354.0 [M-Boc]+, t _R =1.46 min.

Step 8. tert-Butyl (((2R,3R)-4-bromo-5-chloro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XI-i) and tert-butyl (((2S,3S)-4-bromo-5-chloro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XI-j)

The racemate of (((2S*,3S*)-4-bromo-5-chloro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XI-g) (3.3 g, 7.3 mmol) was subjected to chiral preparative HPLC (Chiralpak lA 5 μm 2.5×25 cm, injection volume: 80×0.5 mL, mobile phase: heptane:EtOH 98:2, flow rate: 15 mL/min, UV: 220 nm)) to afford enantiomerically pure title compounds with enantiomeric excess >99%, respectively:

tert-Butyl (((2R,3R)-4-bromo-5-chloro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XI-i) (1.66 g, colorless powder): Chiral analytical HPLC (Agilent 1200, HPLC system, injection volume: 10 μL, mobile phase: heptane:EtOH 97:3, flow rate: 1 mL/min, column: Chiralpak lA 5 μm 4.6×250 mm, UV detection: 220 nm) t _R = 5.75 min. ^1H NMR (400 MHz, DMSO -d6 ) δ (ppm): 7.42-7.40 (m, 2H), 7.36 (d, J=7.1 Hz, 1H) _, 7.28-7.19 (m, 3H), 6.98 (d, J=7.1 Hz, 1H), 6.63-6.38 (m, 1H) 3.85-3.75 (m, 1H), 3.63-3.53 (m, 2H), 1.37 (d, J=7.0 Hz, 3H), 1.17 (s, 9H).

tert-Butyl (((2S,3S)-4-bromo-5-chloro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XI-j) (1.62 g, colorless powder): Chiral analytical HPLC (Agilent 1200, HPLC system, injection volume: 10 µl, mobile phase: Hep:EtOH 97:3, flow rate: 1 ml/min, column: Chiralpak lA 5 µm 4.6×250 mm, UV detection: 220 nm) t_R=7.59 min.¹H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.42-7.40 (m, 2H), 7.36 (d, J=7.1 Hz, 1H), 7.28-7.16 (m, 3H) 6.98 (d, J=7.1 Hz, 1H), 6.51-6.47 (m, 1H), 3.83-3.78 (m, 1H), 3.62-3.53 (m, 2H), 1.37 (d, J=7.0 Hz, 3H), 1.17 (s, 9H).

Step 9. 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 (C-XI)

A suspension of tert-butyl (((2S,3S)-4-bromo-5-chloro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XI-j) (1.38 g, 3.05 mmol), bis(pinacolato)diboron (1.16 g, 4.57 mmol), KOtBu (0.479 g, 4.27 mmol) and _PdCl2 (dppf) _-CH2Cl2 adduct (0.249 g, 0.305 mmol) in toluene (15 mL) was stirred at 100°C for ₅ h. The reaction mixture was filtered through a pad of celite and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient: 0% to 25% EtOAc) to give the title compound (1.20 g) as a colorless foam. ^1H NMR (400 MHz, DMSO -d6 ) δ: 7.39-7.35 (m, 2H), 7.17-7.28 (m, 3H), 7.12 (d, J=8.5 Hz, 1H) _, 6.95 (d, J=8.5 Hz, 1H), 6.42-6.39 (m, 1H), 3.77-3.72(m, 1H), 3.58-3.53 (m, 2H), 1.29-1.26 (m, 15H), 1.15 (s, 9H). UPLC-MS 1: mass/charge 400.3 [M-Boc+H] ⁺ , t _R= 1.49 min.

Synthesis of 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 (C-XII):

Reaction scheme C-XII:

Step 1. (4-Bromo-2,6-difluorophenyl)trimethylsilane (C-XII-a)

At -78 °C, diisopropylamine (555 mL, 3.9 mol, 2.5 M in hexane) was added dropwise to a solution of n-butyl lithium (1560 mL, 3.9 mol, 2.5 M in hexane) in THF (3000 mL) over 10 min. After 10 min, 1-bromo-3,5-difluorobenzene (500 g, 2.6 mol) was added dropwise to the freshly prepared LDA solution. The reaction mixture was stirred at -78 °C for 2 h before chlorotrimethylsilane (488 mL, 3.9 mol) was added dropwise at -78 °C over 10 min. The resulting solution was stirred at -78 °C for 1 h. After evaporation of the solvents, the resulting crude material was distilled to give the title compound (470 g) as a colorless oil. UPLC-MS 1: m/z 282.4 [M+NH ₄ ] ⁺ , t _R = 1.53 min. ¹ HNMR (300 MHz, CDCl ₃ ): δ 7.01 (s, (1 Η), 6.99 (s, 1 Η), 0.37 (s, 9 Η).

Step 2. 6-Bromo-2,4-difluoro-3-(trimethylsilyl)benzaldehyde (C-XII-b)

At -78 °C, redistilled diisopropylamine (186 mL, 1.13 mol) was added dropwise to a solution of n-butyl lithium in hexane (453 mL, 1.13 mol) in THF (1000 mL) cooled at -78 °C over 10 min and stirring was continued for 1 h. The freshly prepared LDA solution was then added dropwise to a solution of (4-bromo-2,6-difluorophenyl)trimethylsilane (C-XII-a) (200 g, 0.754 mol) in THF (1000 mL) cooled to -78 °C. The yellow solution was stirred for 1 h at -78 °C before DMF (104 mL, 1.36 mol) was added dropwise over 5 min. The resulting yellow reaction mixture was stirred at -78 °C for 1 h. Then acetic acid solution (188 mL) and water (800 mL) were added. The yellow suspension was stirred at rt for another 1.5 h. The two phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title product (176 g). UPLC-MS 1: m/z 293.0/295.0 [M+H] ⁺ , t _R = 1.25/1.38 min. ¹ H-NMR (600 MHz, DMSO -d6 ) δ ppm 10.13 (s, 1H), 7.61 (d, J=8.3 Hz, 1H) _, 0.35 (s, 9H).

Step 3 . 2-(Benzyloxy)-6-bromo-4-fluorobenzaldehyde (C-XII-c)

At rt, a solution of sodium benzyl oxide (1020 mL, 1.02 mol, freshly prepared: 23.46 g Na in 1020 mL benzyl alcohol) was added dropwise to a solution of 6-bromo-2,4-difluoro-3-(trimethylsilyl)benzaldehyde (C-XII-b) (300 g, 1.02 mol) in benzyl alcohol (500 mL) over 30 min. The light yellow reaction mixture was stirred at 40 °C for 15 min. The resulting suspension was diluted with EtOAc, then extracted successively with saturated NH ₄ Cl solution and brine. The separated aqueous phase was back-extracted with EtOAc. The combined organic phases were dried over anhydrous _{Na2SO4 ,} filtered and concentrated under reduced pressure to give the crude product which was purified by flash chromatography (silica, PE) to give the title compound (90 g) as a light beige solid. UPLC-MS 1: m/z 309.0/ _311.0 [M+H] ⁺ , t _R = 1.24 min. ¹ H NMR (600 MHz, DMSO- d6 ) δ ppm 10.24 (s, 1H), 7.48 (d, J=7.5 Hz, 2H), 7.41 (t, J=7.5 Hz, 2H), 7.37-7.28 (m, 3H), 5.27 (s, 2H).

Step 4. 6-(Benzyloxy)-2-bromo-3-chloro-4-fluorobenzaldehyde (C-XII-d)

To a solution of 2-(benzyloxy)-6-bromo-4-fluorobenzaldehyde (C-XII-c) (240 g, 777 mmol) in ACN (3000 mL) were added N-chlorosuccinimide (134 g, 1010 mmol) and p-TsOH monohydrate (221 g, 1165 mmol) at rt. The light yellow solution was stirred for 24 h at rt. The reaction mixture was diluted with EtOAc and extracted with sat. NaHCO ₃ solution and brine. The combined aqueous phases were back extracted with EtOAc. _The combined organic phases were dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure to give the crude product which was suspended in a mixture of MTBE and PE (ratio 1:8). The crystallized material was filtered, washed with PE and dried under HV at 50 °C overnight to give the title product (186 g) as a colorless powder. UPLC-MS 1: m/z 342.8/344.8 [M+H] ⁺ , t _R = 1.31 min. ¹ HNMR (300 MHz, _CDCl3 ): δ 10.37 (s, (1H), 7.43- 7.37 (m, 5 H), 6.91 (d, J=10.2 Hz, 1 H), 5.18 (s, 2 H).

Step 5. 2-Bromo-3-chloro-4-fluoro-6-hydroxybenzaldehyde (C-XII-e)

To a suspension of 6-(benzyloxy)-2-bromo-3-chloro-4-fluorobenzaldehyde (C-XII-d) (300 g, 873 mmol) in DCM (3 L) placed under nitrogen and cooled to -78 °C was added a solution of boron tribromide (960 mL, 960 mmol, 1 M in DCM) over 5 min. The resulting brown solution was stirred at -78 °C for 1.5 h. The reaction mixture was slowly quenched with MeOH and the solvents were removed under reduced pressure. The crude material was redissolved in MeOH and concentrated again under reduced pressure. The crude product was purified by flash chromatography (silica, PE/EtOAc, gradient 0% to 10% EtOAc) to afford the title compound (180 g) as a beige powder. UPLC-MS 1: m/z 251.0/252.9 [M-1] ^- , t _R = 1.12 min. ¹ H-NMR (600 MHz, DMSO- d ₆ ) δ ppm 12.05 (s, 1H), 10.19 (s, 1H), 7.18 (d, J = 10.6 Hz, 1H).

Step 6 . 4-Bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XII-f)

At rt, to a solution of 2-bromo-3-chloro-4-fluoro-6-hydroxybenzaldehyde (C-XII-e) (230 g, 910 mmol) in DCM (4.5 L) was added 2-bromo-2-phenylacetonitrile (196 g, 1 mol) followed by DIPEA (238 mL, 1.4 mol) and stirring was continued for 5 h at rt. For work-up, the reaction mixture was diluted with DCM and washed with water. The aqueous layer was back-extracted with DCM. _The combined organic phases were dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica, heptane/EtOAc then DCM) to give the title compound as a diastereomeric mixture (230 g). UPLC-MS 1: m/z 366.0/368.0 [MH] ^- , t _R = 1.20 min (both diastereoisomers co-elute).

Step 7. 2-(Aminomethyl)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-3-ol (C-XII-g)

At rt, to a solution of 4-bromo-5-chloro-6-fluoro-3-hydroxy-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XII-f) (240 g, 0.65 mol) in THF (2.4 L) was added a solution of borane-methyl sulfide complex (1.6 L, 3.25 mol, 2 M in THF). The reaction mixture was stirred at 65 °C for 2 h. The solution was cooled to rt and MeOH (5 L) was carefully added dropwise over 3 min. After 30 min at rt, 1 N HCl was added and stirring at rt was continued for 18 h. The reaction solution was quenched by addition of saturated NaHCO ₃ solution and extracted with DCM. The combined organic phases were washed with water, dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure to give the title compound as a diastereomeric mixture (175 g) as a yellow foam. UPLC-MS 1: m/z 372.1/374.1 [M+1]+, t _R = 0.65 min and 0.78 min.

Step 8. (S)-(4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine (C-XII-h) and (R)-(4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine (C-XII-i)

At rt, to a solution of 2-(aminomethyl)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-3-ol (C-XII-g) (250 g, 671 mmol) in DCM (3 L) was added triethylsilane (930 mL, 5.8 mol) followed by boron trifluoride diethyl etherate (244 mL, 2 mol). The reaction solution was stirred at rt overnight before it was quenched by addition of saturated NaHCO ₃ solution (sat) and extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica, DCM/MeOH/NH ₃ 100:1:0.5) to give racemic (4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine (115 g). UPLC-MS 1: m/z 356.0/358.0 [M+H] ⁺ , t _R = 0.89 min.

The racemate (4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine was subjected to chiral SFC (ChiralPak IC, 300 × 50 mm i.d., 10 μm, _CO2 /IPA (0.1% ammonia) 7:3, 40°C, flow rate: 200 mL/min, 7 mL/injection, cycle time 7 min) to afford the two enantiomers (S)-(4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine (C-XII-h) and (R)-(4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine (C-XII-i) with enantiomeric excess >98%, respectively.

(S)-(4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine (C-XII-h):

Chiral SFC: (Chiralpak IC 150×4.6 mm i.d., 3 μm, _CO2 /IPA (0.05% DEA) 8:2, flow rate: 2.4 mL/min.) t _R = 5.64 min; UPLC-MS 1: m/z 356.0/358.0 [M+H] ⁺ , t _R = 0.89 min. ¹ H NMR (600 MHz, DMSO - _d6 ) δ 7.46 (d, J =7.6 Hz, 2H), 7.40 (t, J =7.6 Hz, 2H), 7.32 (t, J =7.3 Hz, 1H), 7.16 (d, J =9.6 Hz, 1H), 3.81 (dd, J =16.2, 1.8 Hz, 1H), 3.19 (d, J =16.2 Hz, 1H), 3.01 (s, 2H).

X-ray diffraction analysis of (S)-(4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine (C-XII-h) as a besylate salt confirmed the absolute configuration of (S):

(R)-(4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine C-XII-i):

Chiral SFC: (Chiralpak IC 150×4.6 mm i.d., 3 μm, _CO2 /IPA (0.05% DEA) 8:2, flow rate: 2.4 mL/min) t _R = 6.55 min; UPLC-MS 1: m/z 356.0/358.0 [M+H] ⁺ , t _R = 0.89 min.

Step 9. tert-Butyl (S)-((4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XII-j)

To a solution of (S)-(4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine (C-XII-h) (72.00 g, 201.9 mmol) in DCM (1500 mL) was added Boc ₂ O (46.27 g, 212.00 mmol, 48.71 mL) portionwise. The reaction mixture was stirred at rt for 16 h. After removal of the solvents under reduced pressure, the crude product was purified by flash chromatography (silica, PE/EtOAc, gradient from 0% to 15% EtOAc) to give the title compound (102 g) as a colorless oil. UPLC-MS 1: mass/charge 458.1/460.0 [M+H] ⁺ , t _R =1.48 min. ¹ H NMR (600 MHz, DMSO - _d6 ) δ 7.46 (d, J=7.6 Hz, 2H), 7.41 (t, J=7.7 Hz, 2H), 7.33 (t, J=7.3 Hz, 1H), 7.21 (t, J=6.2 Hz, 1H), 7.12 (d, J=9.5 Hz, 1H), 3.75 (d, J=16.4 Hz, 1H), 3.54 (dd, J=14.5, 6.5 Hz, 1H), 3.38 (dd, J=14.6, 6.1 Hz, 1H), 3.25 (d, J=16.6 Hz, 1H), 1.30 (s, 9H).

Step 10. 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 (C-XII)

At 100°C, to a stirred solution of tert-butyl (S)-((4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XII-j) (20 g, 43.8 mmol), bis(pinacolato)diboron (16.68 g, 65.7 mmol) and KOAc (12.89 g, 131 mmol) in dioxane (100 mL) was added the PdCl adduct₂(dppf).CH₂Cl₂(3.58 g, 4.38 mmol) under Ar atmosphere and stirring at 100°C was continued for 16 h. The reaction mixture was filtered through celite and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 25% EtOAc) to give the title compound (15.1 g) as a colorless powder.¹H NMR (600 MHz, DMSO-d ₆) δ 7.44-7.38 (m, 4H), 7.34-7.31 (m, 1H), 7.17 (d, J=6.2 Hz, 1H), 7.08 (d, J=9.9 Hz, 1H), 3.70 (d, J=16.5 Hz, 1H), 3.56 (dd, J=14.7, 6.8 Hz, 1H), 3.37 (dd, J=14.5, 5.9 Hz, 1H), 3.22 (d, J=16.9 Hz, 1H), 1.32 (s, 9H), 1.31 (s, 6H), 1.30 (s, 6H). UPLC-MS 1: mass/charge 521.3/523.3 [M+17]⁺, t_R=1.52 min.

Synthesis of (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 (C-XIII):

Reaction scheme C-XIII:

Step 1. Methyl 4-bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (C-XIII-a)

To a solution of 2-bromo-3-chloro-4-fluoro-6-hydroxybenzaldehyde (C-XII-e) (500 g, 1.97 mol) in ACN (2.3 L) were added methyl 2-bromo-2-phenylacetate (542 g, 2.37 mol) and DIEA (381.2 g, 2.96 mol). The reaction mixture was heated under reflux for 16 h. After removal of the solvents under reduced pressure, MTBE was added and the organic phase was washed with brine. The organic phase was dried over _{anhydrous Na2SO4} and concentrated in vacuo. The resulting crude material was purified by flash chromatography to afford the title compound as a diastereomeric mixture (608 g) as a colorless powder. ^1H NMR (300 MHz, DMSO -d6 ) δ ppm: 7.44 (d, 1H, J =6 Hz), 7.43-7.41 ₍ d, 1H, J =4.4 Hz), 7.39-7.36 (m, 4H), 6.90-6.88 (d, 0.5H, J =7.2 Hz), 6.10-6.08 (d, 0.4H, J =8.8 Hz), 5.60-5.58 (d, 0.47H, J =8.4 Hz), 5.42-5.41 (d, 0.52H, J =7.2 Hz), 3.72-3.64 (m.3H).

Step 2. Methyl (S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (C-XIII-b) and methyl (R)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (C-XIII-c)

At 0°C and in N atmosphere₂To a solution of methyl 4-bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (C-XIII-a) (607 g, 1.51 mol) in DCM (6 L) was added dropwise Et₃SiH (878 g, 7.55 mol) and BF₃.Et₂O (643 g, 3.06 mol). The reaction mixture was stirred for 24 h at rt. A saturated solution of NaHCO was added.₃to adjust the pH to 8~9. The organic layer was separated, washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography (silica, hexane/EtOAc) to give racemic methyl 4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (362 g).¹H NMR (300 MHz, CDCl₃) δ ppm: 7.56 (d, 2H,J=6.9 Hz), 7.44-7.37 (m, 3H), 6.84 (d, 1H,J=8.7 Hz), 4.19 (d, 1H,J=15.9 Hz), 3.79 (s, 3H), 3.55 (d, 1H,J=16.2 Hz).

The racemate of methyl 4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate was subjected to chiral SFC (ChiralPak AD, 300 × 50 mm i.d., 10 μm, CO ₂ /IPA 8:2, 38 °C, flow rate: 200 mL/min, 5 mL/injection, cycle time 3.7 min) to afford methyl (S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (C-XIII-b) and methyl (R)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (C-XIII-c) as pure enantiomers with enantiomeric excess >98%, respectively.

Methyl (S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (C-XIII-b):

Chiral SFC: (Chiralpak AD 150×4.6 mm i.d., 3 µm, _CO2 /IPA (0.05% DEA) 95/5 to 60/40, flow rate: 2.5 mL/min), t _R = 3.02 min; UPLC-MS 1: no ionization, t _R = 1.38 min.

Methyl (R)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (C-XIII-c):

Chiral SFC: (Chiralpak AD 150×4.6 mm i.d., 3 µm, _CO2 /IPA (0.05% DEA) 95/5 to 60/40, flow rate: 2.5 mL/min), t _R = 2.75 min; UPLC-MS 1: no ionization, t _R = 1.38 min.

Step 3. (S)-(4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XIII-d)

Under Ar atmosphere, to a stirred solution of methyl (S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (C-XIII-b) (40 g, 104 mmol) in a mixture of THF (400 mL) and MeOH (17 mL) was added LiBH ₄ (4.52 g, 207 mmol) portionwise at 0 °C and stirring at rt was continued for 30 min. The reaction mixture was quenched by addition of saturated NaHCO ₃ solution and extracted with EtOAc. The combined organic layers were washed with saturated NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica, hexane/EtOAc; gradient 0% to 40% EtOAc) to afford the title product (39 g) as a colourless oil. UPLC-MS 1: m/z 401.2/403.2/405.1 [M+formate] ^- , t _R = 1.24 min.

Step 4. (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 (C-XIII)

A deoxygenated suspension of (S)-(4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XIII-d) (18.50 g, 51.7 mmol), bis(pinacolato)diboron (19.71 g, 78 mmol), KOAc (15.23 g, 155 mmol) and PdCl adduct₂(dppf).CH₂Cl₂(4.22 g, 5.17 mmol) in dioxane (200 mL) was stirred at 100°C for 16 h under Ar atmosphere. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, hexane/EtOAc; gradient: 0% to 50%) to give the title product (19.7 g) as a yellow oil.¹H NMR (400 MHz, DMSO-d ₆) δ 7.45-7.40 (m, 2H), 7.40-7.33 (m, 2H), 7.31-7.26 (m, 1H), 7.07 (d, J=9 ,9 Hz, 1H), 5.34-5.27 (m, 1H), 3.73 (d, J=16.5 Hz, 1H), 3.69-3.64 (m, 2H), 3.18 (d, J=16.4 Hz, 1H), 1.30 (s, 12H). UPLC-MS 1: mass/charge 449.1 [M+formate]^-, t_R=1.32 min.

Synthesis of tert-butyl-(((2S,3S)-5-chloro-6-fluoro-3-hydroxy-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XIV):

Reaction scheme C-XIV:

Step 1. (2S*,3S*)-4-Bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XIV-a) and (2R*,3S*)-4-bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XIV-b)

At rt, 2-bromo-2-phenylacetonitrile (648.5 g, 2.845 mol) and DIPEA (734.2 g, 5.69 mol) were added to a solution of 2-bromo-3-chloro-4-fluoro-6-hydroxybenzaldehyde (C-XII-e) (500 g, 1.973 mol) in dichloromethane (6 L). The resulting brown solution was stirred at rt for 21 h. The solution was then diluted with DCM and washed with water. The aqueous layer was back-extracted with DCM. _The combined organic phases were washed with water, brine, dried over anhydrous _Na2SO4 and concentrated under reduced pressure to give a diastereomeric cis/trans mixture of 4-bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile. The racemic cis- and trans-configured title compounds were separated by two consecutive flash chromatographies (silica, heptane/EtOAc; gradient: 2% to 20% EtOAc):

(2S*,3S*)-4-bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XIV-a): ¹ HNMR (600MHz, DMSO- d ₆ ) δ 7.55-7.48 (m, 7H), 5.27 (d, J=7.7 Hz, 1H). UPLC-MS 1: m/z 412.0/414.0 [M+formate] ^- , t _R =1.17 min.

(2R*,3S*)-4-Bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XIV-b): ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 7.60-7.55 (m, 3H), 7.55-7.47 (m, 3H), 6.50 (d, J=8.6 Hz, 1H), 5.54 (d, J=8.5 Hz, 1H). UPLC-MS 1: m/z 412.0/414.0 [M+formate] ^- , t _R =1.17 min.

Step 2. (2S,3S)-4-Bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XIV-c) and (2R,3R)-4-bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XIV-d)

The racemate of (2S*,3S*)-4-bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XIV-a) (504 g, 1.37 mol) was subjected to chiral SFC (ChiralPak AD, 300 × 50 mm i.d., 10 μm, _CO2 /IPA 8:2, 38°C, flow rate: 200 mL/min, 6 mL/injection, cycle time 12 min) to afford (2S,3S)-4-bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XVI-c) (228 g) and (2R,3R)-4-bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XIV-d) (232 g) as pure enantiomers with an enantiomeric excess of >98%, respectively.

(2S,3S)-4-Bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XIV-c): Chiral SFC: (Chiralpak AD 150×4.6 mm i.d., 3 μm, _CO2 /IPA (0.05% DEA) 95/5 to 60/40, flow rate: 2.5 mL/min) t _R = 3.68 min; ¹ H NMR (600 MHz, _{DMSO- d6} ) δ 7.59-7.44 (m, 7H), 5.30 (d, J = 7.0 Hz, 1H); UPLC-MS 1: mass/charge 385.1/387.0 [M+NH ₄ ] ⁺ , t _R =1.20 min.

The absolute configuration (2S,3S) was confirmed by X-ray structural analysis:

(2R,3R)-4-bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XIV-d): Chiral SFC: (Chiralpak AD 150×4.6 mm i.d., 3 μm, CO ₂ /IPA (0.05% DEA) 95/5 to 60/40, flow rate: 2.5 mL/min), t _R = 4.18 min; UPLC-MS 1: m/z 385.1/387.2 [M+NH ₄ ] ⁺ , t _R = 1.20 min.

The absolute configuration (2R,3R) was confirmed by X-ray structural analysis:

Step 3. (2S,3S)-2-(Aminomethyl)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-3-ol (C-XIV-e)

At rt, to a stirred solution of (2S,3S)-4-bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XIV-c) (20.5 g, 55.6 mmol) in THF (309 mL) was added borane-methyl sulfide complex (139 mL, 278 mmol, 2 M in THF) and the yellow solution was stirred at 65 °C for 3.25 h. While cooling in an ice bath, the reaction mixture was quenched very slowly with MeOH (100 mL) and stirred for 30 min, then 1 N HCl (200 mL) was added and stirring was continued overnight. Saturated NaHCO ₃ solution was added and the reaction mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated to give the title compound (22 g), which was used in the next step without further purification. UPLC-MS 1: m/z 372.0/374.0 [M+H] ⁺ , t _R = 0.74 min.

Step 4. tert-Butyl (((2S,3S)-4-bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XIV-f)

At rt, to a stirred solution of (2S,3S)-2-(aminomethyl)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-3-ol (C-XIV-e) (21.93 g, 58.9 mmol) in DCM (294 mL) was added Boc-anhydride (15.03 mL, 64.7 mmol). The reaction mixture was stirred at rt for 26 h before sat. _NaHCO3 was added for work-up. The mixture was extracted with DCM and the combined organic extracts were washed with water and brine and concentrated to give the title compound (33.2 g). UPLC-MS 1: mass/charge 516.2/518.2 [M+formate] ^- , t _R =1.30 min.

Stage 5 . tert-Butyl-(((2S,3S)-5-chloro-6-fluoro-3-hydroxy-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XIV)

The adduct PdCl ₂ (dppf).CH ₂ Cl ₂ (2.5 g, 3.01 mmol) was added at 80 °C to a stirred suspension of tert-butyl (((2S,3S)-4-bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XIV-f) (16.2 g, 30.1 mmol), bis(pinacolato)diboron (11.5 g, 45.2 mmol) and potassium acetate (8.9 g, 90 mmol) in 1,4-dioxane (75 mL). The reaction mixture was stirred at 100 °C for 28 h. After completion of the reaction, the mixture was filtered through celite, which was carefully rinsed with toluene. Concentration of the filtrate afforded the crude product which was purified by flash chromatography (silica, cyclohexane/EtOAc; gradient: 0% to 30% EtOAc) to afford the title product (8.2 g) as a colourless powder. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.42-7.36 (m, 2H), 7.36-7.30 (m, 2H), 7.29-7.22 (m, 1H), 7.13 (d, J=9.4 Hz, 1H), 6.30-6.25 (m, 1H). 6.13 (d, J=6.7 Hz, 1H), 5.16 (d, J=6.5 Hz, 1H), 3.80 (dd, J=14.4, 7.1 Hz, 1H), 3.56 (dd, J=14.6, 5.0 Hz, 1H), 1.31 (s, 6H), 1.27 (s, 6H), 1.22(s,9H). UPLC-MS 1: mass/charge 518.3 [MH] ^- , t _R =1.43 min.

Synthesis of 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 (C-XV):

Reaction scheme C-XV:

Step 1. (2S,3S)-4-Bromo-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XV-a)

At 0 °C, to a solution of (2S,3S)-4-bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XIV-c) (2.0 g, 5.43 mmol) in THF (20 mL) and DMF (5 mL) was slowly added NaH (0.206 g, 8.14 mmol, 95%). After 1 h, methyl iodide (1.02 mL, 16.3 mmol) was slowly added and the reaction mixture was stirred at rt for 15 min. Saturated NaHCO ₃ solution was added and the mixture was extracted with ethyl acetate. Drying of the combined organic layers over anhydrous MgSO ₄ and concentration provided the title compound (2.35 g). UPLC-MS 1: product not capable of ionization, t _R = 1.34 min.

Step 2. ((2S,3S)-4-Bromo-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine (C-XV-b)

To a stirred solution of (2S,3S)-4-bromo-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XV-a) (2.22 g, 5.8 mmol) in THF (40 mL) was added borane-methyl sulfide complex (14.5 mL, 29.0 mmol, 2 M in THF) and the reaction mixture was stirred at 60 °C for 3 h. The reaction mixture was cooled to rt, MeOH and 1 N HCl were carefully added and the mixture was stirred vigorously at rt for 3 h. Saturated NaHCO ₃ solution was added and the mixture was extracted with EtOAc. The combined extracts were dried ( _MgSO4 ) and concentrated to give the crude product, which was purified by flash chromatography (silica, DCM/MeOH, gradient: 0% to 10% MeOH) to give the title compound (1.27 g) as a colourless foam. UPLC-MS 1: m/z 386.1 [M+H] ⁺ , t _R = 0.85 min.

Step 3. tert-Butyl (((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XV-c)

A solution of ((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine (C-XV-b) (615 mg, 1.6 mmol) and Boc-anhydride (0.406 mL, 1.750 mmol) in DCM (18 mL) was stirred at rt for 2 h. Saturated _NaHCO3 was added and the mixture was extracted with EtOAc. The combined extracts were dried ( _MgSO4 ) and concentrated to give the title compound (766 mg, 1.6 mmol) as a colorless powder. UPLC-MS 1: m/z 530.3 [M+formate] ^- , t _R = 1.45 min.

Step 4. 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 (C-XV)

A solution of tert-butyl (((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XV-c) (1.20 g, 2.5 mmol), bis ₍ pinacolato)diboron (0.88 g, 3.5 mmol), _PdCl2 (dppf) _-CH2Cl2 adduct (0.201 g, 0.25 mmol) and KOtBu (0.415 g, 3.7 mmol) was stirred at 100 °C for 20 min. The reaction mixture was cooled to rt and filtered through celite. The filter cake was washed thoroughly with toluene. The organic phase was concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: EtOAc from 0% to 20%) to give the title compound (687 mg) as a slightly pink powder. UPLC-MS 1: m/z 578.4 [M+formate] ^- , t _R = 1.49 min.

Synthesis of tert-butyl-(((2 S ,3 S )-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 (C-XVI):

Reaction scheme C-XVI:

Step 1. ( S )-4-Bromo-5-chloro-6-fluoro-3-oxo-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (1) (C-XVI-a)

To a stirred solution of ( 2S , 3S )-4-bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XIV-c) (12 g, 32.6 mmol) in DCM (200 mL) was added Dess-Martin periodinane (16.57 g, 39.1 mmol) at 0 °C. The ice bath was removed and the reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with 10% sodium thiosulfate solution and saturated NaHCO ₃ solution and extracted with DCM. The organic phase was washed with water and brine, dried and concentrated. The crude product was purified by flash chromatography (silica, eluent: DCM/EtOAc; gradient: 0% to 100% EtOAc) to afford the desired product (11.79 g). UPLC-MS 1: m/z 363.9 [MH] ^- , t _R = 1.26 min.

Step 2. (2 S )-4-Bromo-5-chloro-6-fluoro-3-hydroxy-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XVI-b)

To a stirred solution of ( S )-4-bromo-5-chloro-6-fluoro-3-oxo-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XVI-a) (24.17 g, 65.9 mmol) in THF (500 mL) was added methylmagnesium bromide (30.8 mL, 92 mmol, 3 M in _Et2O ) at -50 °C and the reaction mixture was allowed to warm to -30 °C over 1.5 h. The reaction mixture was quenched at -30 °C with saturated ammonium chloride solution. The mixture was washed with saturated ammonium chloride solution, extracted with EtOAc _and the combined organic extracts were washed with water and brine, dried ( _Na2SO4 ) and concentrated. The crude product was triturated with DCM and filtered to afford the desired product. More product was isolated by concentrating the filtrate and purifying the residue by flash chromatography (silica, heptane/EtOAc; gradient: 0% to 30% EtOAc). Both fractions of product were combined to afford the title compound (24.53 g) as a mixture of diastereoisomers. UPLC-MS 1: m/z 380.0 [MH] ^- , t _R = 1.20 min (diastereoisomers co-elute).

Step 3. (2 S )-2-(Aminomethyl)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-3-ol (C-XVI-c)

At rt, borane-methyl sulfide complex (100 mL, 200 mmol, 2 M in THF) was added to a stirred solution of ( 2S )-4-bromo-5-chloro-6-fluoro-3-hydroxy-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XVI-b) (25.5 g, 66.6 mmol) in THF (400 mL) and stirring at 80 °C was continued for 2 h. The reaction mixture was quenched by careful addition of MeOH at 0 °C and stirred overnight at rt. THF and MeOH were evaporated under reduced pressure. EtOAc and saturated NaHCO _{3 solution were added,} the organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried ( _Na2SO4 ) and concentrated. The crude product was triturated with DCM and filtered to afford the desired product. The concentrated filtrate was purified by flash chromatography (silica, DCM/( _7N ammonia in MeOH), gradient 0% to 10% (7N ammonia in MeOH)) to afford additional product. Both fractions of product were combined to afford the title compound (18.7 g) as mixtures of diastereoisomers. UPLC-MS 1: m/z 386.0 [M+H] ⁺ , t _R = 0.64 min and 0.78 min.

Step 4. ( R )-(4-Bromo-5-chloro-6-fluoro-3-methylene-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine (C-XVI-d)

To a stirred solution of ( 2S )-2-(aminomethyl)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-3-ol (C-XVI-c) (18.73 g, 48.4 mmol) in DCM (200 mL) was added _BF3.OEt2 (12.3 mL, 97 mmol) at 0 °C and stirring at rt was continued for 6 _h . The reaction mixture was quenched with saturated _NaHCO3 solution and extracted with DCM. The combined organic extracts were washed with brine, dried ( _{Na2SO4 ) and concentrated to give the title compound. UPLC-MS 1: product not ionizable; t R =} 0.84 min.

Step 5. ( R )-tert-Butyl ((4-bromo-5-chloro-6-fluoro-3-methylene-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XVI-e)

At 0 °C, to a stirred solution of ( R )-(4-bromo-5-chloro-6-fluoro-3-methylene-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine (C-XVI-d) (17.86 g, 48.4 mmol) in DCM (250 mL) was added TEA (13.5 mL, 97 mmol) followed by Boc-anhydride (16.9 mL, 72.7 mmol) and stirring at rt was continued for 2.5 h. The reaction mixture was diluted with DCM and water, the organic phase was separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient 0% to 20% EtOAc) to give the title product (20.17 g) as a colorless foam. UPLC-MS 1: non-ionizable product; t _R = 1.46 min; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.53-7.22 (m, 6H), 6.97 (t, J = 6.2 Hz, 1H), 6.38 (s, 1H), 5.33 (d, J = 1.4 Hz, 1H), 3.79 (t, J = 6.1 Hz, 2H), 1.30 (s, 9H).

Step 6. tert-Butyl (((2 S ,3 S )-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XVI-f)

To a stirred solution of ( R )-tert-butyl ((4-bromo-5-chloro-6-fluoro-3-methylene-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XVI-e) (20.17 g, 38.7 mmol) in DCE (400 mL) were added TEA (30 mL, 215 mmol) and 3-nitrobenzenesulfonylhydrazine (18.7 g, 86 mmol) and the reaction mixture was stirred at 60 °C for 18 h. Over a further 72 h, more TEA (total: 78 mL, 559 mmol) and 3-nitrobenzenesulfonylhydrazine (total: 48.6 g, 222 mmol) were added in 3 portions until the reaction was complete. Water and brine were added and the organic phase was separated. The aqueous phase was back _- extracted with DCM. The combined organic phases were dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by two successive flash chromatographies (silica, heptane/DCM, gradient: 0% to 100% DCM) and (silica, heptane/EtOAC, gradient: 0% to 15% EtOAc) to afford the title product (15.7 g) as a colorless powder. UPLC-MS 1: m/z 370.1/372.1 [M+H-Boc] ⁺ , t _R = 1.46 min; ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 7.55-7.11 (m, 6H), 6.56 (t, J =6.2 Hz, 1H), 3.83 (dd, J =14.2, 6.7 Hz, 1H), 3.70-3.52 (m, 2H), 1.39 (d, J =7.0 Hz, 3H), 1.19 (s, 9H). Only one diastereoisomer was isolated and the presence of the indicated absolute stereochemistry was determined by comparing its ¹ H NMR spectrum with the ¹ H NMR spectra of structurally related intermediates C-XI-g and C-XI-h.

Step 7. tert-Butyl (((2 S ,3 S )-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 (C-XVI)

A suspension of tert-butyl (((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XVI-f) (6.8 g, 14.44 mmol), bis(pinacolato)diboron (5.50 g, 21.7 mmol), KOtBu (2.269 g, 20.22 mmol) and PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (1.180 g, 1.444 mmol) in toluene (72 mL) was stirred at 105 °C for 6 h. The reaction mixture was filtered through celite and concentrated. The crude product was purified by flash chromatography (silica, eluent cyclohexane/EtOAc, EtOAc gradient from 0% to 20%) to give the desired product (4.47 g). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.43-7.38 (m, 2H), 7.32-7.27 (m, 2H), 7.25-7.20 (m, 1H), 7.11 (d, J=9.8 Hz, 1H), 6.46-6.41 (m, 1H). 3.76 (dd, J=13.7, 6.1 Hz, 1H), 3.63-3.55 (m, 2H), 1.33-1.30 (m, 15H), 1.21 (s, 9H). UPLC-MS 1: mass/charge 518.3 [M+H] ⁺ , t _R =1.49 min.

Synthesis of ((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 (C-XVII):

Reaction scheme CXVII:

Step 1 . 1-(2-Bromo-4,6-difluorophenyl)ethan-1-ol (C-XVII-a)

Two reactions were carried out in parallel as follows. To a stirred solution of 1-bromo-3,5-difluoro-2-iodobenzene (500 g, 1.57 mol) in 2-methyltetrahydrofuran (5000 mL) was added dropwise lithium chloro(isopropyl)magnesium chloride (1.3 M, 1.89 mol, 1.45 L) at -65 °C under N ₂ . The reaction mixture was stirred for 30 min at -65 °C before acetaldehyde (138.15 g, 3.14 mol) was added dropwise. Stirring of the reaction mixture at -65 °C was continued for 30 min. Saturated NH ₄ Cl solution was added for work-up, followed by extraction with MTBE. The combined organic layers were washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure to give the racemic title compound (800 g) as a colourless oil which was used in the next step without further purification. ¹ HNMR (400 MHz, DMSO -d6 ) 7.43 (td, J=2.0, 8.0 Hz, 1H), 7.30 (ddd, J ₌ 2.4, 9.2, 11.6 Hz, 1H), 5.42 (d, J=4.4 Hz, 1H), 5.21-5.10 (m, 1H), 1.41 (d, J=6.4 Hz, 3H).

Step 2 . 1-Bromo-2-(1-bromoethyl)-3,5-difluorobenzene (C-XVII-b)

Five reactions were carried out in parallel as follows. To a stirred solution of 1-(2-bromo-4,6-difluorophenyl)ethan-1-ol (C-XVII-a) (220.0 g, 928.11 mmol) in DCM (4000 mL) were added CBr ₄ (461.68 g, 1.39 mol) and PPh ₃ (365.15 g, 1.39 mol) under N ₂ at 0 °C and stirring was continued for 30 min. The reaction mixture was quenched by addition of saturated NaHCO ₃ solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Five batches of crude product were combined and purified by flash chromatography (silica, PE) followed by distillation at 100°C to give the title product (1.10 kg) as a racemate. ¹ H NMR (400 MHz, DMSO- d ₆ ) 7.52 (td, J = 2.0, 8.0 Hz, 1H), 7.41 (ddd, J = 2.4, 9.2, 11.6 Hz, 1H), 5.71-5.52 (m, 1H), 2.03 (dd, J = 2.0, 7.2 Hz, 3H).

Step 3. (2S,5S)-5-(1-(2-Bromo-4,6-difluorophenyl)ethyl)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one (C-XVII-c)

Six reactions were carried out in parallel as follows. To a stirred suspension of 1-bromo-2-(1-bromoethyl)-3,5-difluorobenzene (C-XVII-b) (185 g, 616.8 mmol) and (2S,5S)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one (CAS 81036-97-7) (203.79 g, 925.2 mmol) in DMF (2500 mL) was added NaH (37.0 g, 925.2 mmol, 60% in mineral oil) under N ₂ at 0 °C. The reaction mixture was stirred for 30 min at 0 °C. For work-up, the mixture was quenched with saturated NaHCO ₃ solution and extracted with MTBE. The combined organic layers were washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica, PE/EtOAc, gradient: 0% to 5% EtOAc) to give the title compound (810 g) as a mixture of diastereoisomers as a light yellow oil.

Step 4. Methyl (2S,3S)-3-(2-bromo-4,6-difluorophenyl)-2-hydroxy-2-phenylbutanoate (C-XVII-e)

Four reactions were carried out in parallel as follows. To a stirred solution of (2S,5S)-5-(1-(2-bromo-4,6-difluorophenyl)ethyl)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one (C-XVII-c) (202 g, 459.8 mmol) in MeOH (2800 mL) was added sodium methanolate (331.23 g, 708 mL, 1.84 mol, 30% in MeOH) at rt and stirring at 60 °C was continued for 1 h. The reaction mixture was cooled to rt, quenched by addition of saturated NaHCO₃and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give the crude product. Four batches of crude product were combined and purified by flash chromatography (silica, PE/EtOAc, gradient: 0% to 5% EtOAc) to give the title product. (60 g) in the form of a colorless oil with an enantiomeric excess of 82%: Chiral SFC: Chiralcel OD-3, 150×4.6 mm i.d., 3 µm, CO₂/ethanol (0.05% DEA), gradient: from 95/5 to 60/40 in 5.5 min and hold at 60/40 for 3 min, then 95/5 for 1.5 min; column temperature 40°C, flow rate: 2.5 ml/min, t_R=1.94 min; UPLC-MS 1: non-ionizable, t_R=1.24 min. (another diastereoisomer methyl (2S,3R)-3-(2-bromo-4,6-difluorophenyl)-2-hydroxy-2-phenylbutanoate: UPLC-MS 1: non-ionizable, t_R=1.31 min).

In addition, the pH of the combined aqueous layers was adjusted to pH=3~4 with 1 N HCl and back extracted with EtOAc. _The combined organic extracts were dried over anhydrous _Na2SO4 , filtered and concentrated to afford the crude carboxylic acid by-product (2S,3S)-3-(2-bromo-4,6-difluorophenyl)-2-hydroxy-2-phenylbutanoic acid (C-XVII-d) (460 g) as a colorless powder: ¹ H NMR (400 MHz, DMSO -d6 ) 7.38-7.28 (m, 2H), 7.21-7.03 (m, 5H), 6.04 ₍ s, 1H), 4.43-4.25 (m, 1H), 3.78 (s, 3H), 1.38 (dd, J =1.6, 6.8 Hz, 3H). UPLC-MS 1: non-ionizable, t _R = 1.04 min. (another diastereoisomer (2S,3R)-3-(2-bromo-4,6-difluorophenyl)-2-hydroxy-2-phenylbutanoic acid: UPLC-MS 1: non-ionizable, t _R = 1.13 min).

A suspension of (2S,3S)-3-(2-bromo-4,6-difluorophenyl)-2-hydroxy-2-phenylbutanoic acid (C-XVII- _d ) (460.0 g, 1.24 mol), _CH3I (209.4 g, 91.85 mL, 1.48 mol), and _K2CO3 (256.9 g, 1.86 mol) in acetone (4600 mL) was stirred at rt for 6 h. The mixture was quenched by addition of water and extracted with EtOAc. _The combined organic layers were washed with brine, dried over anhydrous _Na2SO4 , filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (silica, PE/EtOAc, gradient: 0% to 2% EtOAc) to afford additional title product (67 g, 80% enantiomeric excess). ¹ H NMR (400 MHz, DMSO- d ₆ ) 7.38-7.28 (m, 2H), 7.21-7.03 (m, 5H), 6.04 (s, 1H), 4.43-4.25 (m, 1H), 3.78 (s, 3H), 1.38 (dd, J= 6.8, 1.6 Hz, 3H).

Step 5. Methyl (2S,3S)-4-bromo-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (C-XVII-f)

At 0 °C, to a stirred solution of methyl (2S,3S)-3-(2-bromo-4,6-difluorophenyl)-2-hydroxy-2-phenylbutanoate (C-XVII-e) (67 g, 173.94 mmol) in DMF (644 mL) was added NaH (7.65 g, 191.33 mmol, 60% in mineral oil) under N ₂ . The resulting reaction mixture was stirred at 0 °C for 1 h before it was quenched with saturated NaHCO ₃ solution and extracted with MTBE. The combined organic layers were washed with saturated NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude product was suspended in n-hexane and stirred for 30 min. The solid was collected by filtration and dried in HV to give the title compound (54 g) as a colourless powder with an enantiomeric excess of 90%. Chiral SFC: ChiralPak-AD-3, 150 x 4.6 mm i.d., 3 μm, _CO2 /ethanol (0.05% DEA), gradient: 95/5 to 60/40 over 5.5 min and hold at 60/40 for 3 min, then 95/5 for 1.5 min; column temperature 40°C, flow rate: 2.5 mL/min, t _R = 1.71 min. ^1H NMR (400 MHz, DMSO _-d6 ) 7.62 (d, J =7.2 Hz, 2H), 7.43-7.30 (m, 3H), 7.07 (br d, J =9.2 Hz, 1H), 7.03 (br d, J =9.2 Hz, 1H), 3.92 (q, J =6.8 Hz, 1H), 3.74 (s, 3H), 1.31 (d, J =6.8 Hz, 3H).

Step 6. Methyl (2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (C-XVII-g)

To a stirred solution of methyl (2S,3S)-4-bromo-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (C-XVII-f) (54 g, 147.87 mmol) in ACN (920 mL) were added N-chlorosuccinimide (19.75 g, 147.87 mmol) and 4-methylbenzenesulfonic acid hydrate (42.2 g, 221.80 mmol) under N ₂ . The resulting reaction mixture was stirred at 60 °C for 12 h before it was quenched with saturated NaHCO ₃ solution and extracted with EtOAc. The same reaction conditions were used for the second crop of methyl (2S,3S)-4-bromo-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (C-XVII-f) (51 g). The combined organic layers were washed with sat. _NaHCO3 solution, dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure. The crude product thus obtained was suspended in n- _hexane and stirred for 30 min. The solid was collected by filtration and dried under HV to give the title product (115 g) as a colorless powder with an enantiomeric excess of 82%. Chiral SFC: Chiralpak AD-3, 150 x 4.6 mm i.d. dia., 3 μm, CO ₂ /IPA (0.05% DEA), gradient: from 95/5 to 60/40 in 5.5 min and hold at 60/40 for 3 min, then 95/5 for 1.5 min; column temperature 40°C, flow rate: 2.5 mL/min, t _R = 2.55 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) 7.75-7.55 (m, 2H), 7.45-7.26 (m, 4H), 4.01-3.91 (m, 1H), 3.75 (s, 3H), 1.32 (d, J = 6.8 Hz, 3H).

Step 7. ((2S,3S)-4-Bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XVII-h)

Three reactions were carried out in parallel as follows. To a stirred solution of methyl (2S,3S)-4-bromo-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (C-XVII-g) (46.0 g, 115.1 mmol) in a mixture of THF (620 mL) and MeOH (14.75 g, 18.63 mL, 460.4 mmol) was added LiBH ₄ (5.01 g, 230.21 mmol) portionwise under N ₂ . The resulting suspension was stirred for 60 min at 10 °C. The reaction mixture was quenched by addition of sat. NaHCO ₃ solution and extracted with EtOAc. The combined organic layers were washed with sat. NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was dissolved in MeOH and purified by chiral SFC (Cellulose-2, 300 mm × 50 mm i.d., 10 μm, _CO2 /EtOH (0.1% ammonia); 7:3, 38°C, flow rate: 200 mL/min, 2.5 mL/injection, cycle time 2.5 min) to afford the title product (110 g) as a light yellow oil with an enantiomeric excess of 99% (chiral SFC: Lux Cellulose-2, 150 mm × 4.6 mm i.d., 3 μm, _CO2 /EtOH (0.05% DEA), gradient: 95/5 to 60/40 over 5.5 min and hold at 60/40 for 3 min, then 95/5 for 1.5 min; column temperature 40°C; flow rate: 2.5 ml/min, t _R =4.24 min). ¹ H NMR (400 MHz, DMSO - _d6 ) 7.50-7.41 (m, 2H), 7.32 (t, J =7.2 Hz, 2H), 7.28-7.18 (m, 2H), 5.08 (t, J =5.2 Hz, 1H), 3.95 (dq, J =5.8, 13.6 Hz, 2H), 3.56 (q, J =6.8 Hz, 1H), 1.44 (d, J =6.8 Hz, 3H).

Stage 8 . ((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 (C-XVII)

At 60 °C, to a stirred suspension of ((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XVII-h) (20 g, 53.8 mmol), bis(pinacolato)diboron (20.50 g, 81 mmol) and potassium hydroxide (6.04 g, 108 mmol) in toluene (200 mL) was added the adduct PdCl ₂ (dppf).CH ₂ Cl ₂ (4.39 g, 5.38 mmol). The reaction mixture was stirred at 100 °C for 3 h before it was filtered through celite and concentrated under reduced pressure. The resulting crude material was purified twice by flash chromatography (silica, heptane/EtOAc, gradient: 0% to 30% EtOAc) to give the title product (16.7 g) as a colorless foam. ¹ H NMR (400 MHz, DMSO _-d6 ) δ 7.45-7.40 (m, 2H), 7.33 (t, J= 7.5 Hz, 2H), 7.28-7.22 (m, 1H), 7.12 (d, J= 9.5 Hz, 1H), 4.98 (t, J= 5.1 Hz, 1H), 3.95 (dd, J = 11.7, 5.6 Hz, 1H), 3.87 (dd, J= 11.7, 5.4 Hz, 1H), 3.55 (q, J= 7.0 Hz, 1H), 1.37 (d, J= 7.1 Hz, 3H), 1.32 (s, 6H), 1.30(s, 6H). UPLC-MS 1: mass/charge 463.3 [M+formate] ^- , t _R =1.30 min.

An alternative procedure for converting C-XVII-c to C-XVII-f:

Step 1. Methyl (2S,3S)-3-(2-bromo-4,6-difluorophenyl)-2-hydroxy-2-phenylbutanoate (C-XVII-e)

Two reactions were carried out in parallel as follows. To a stirred solution of (2S,5S)-5-(1-(2-bromo-4,6-difluorophenyl)ethyl)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one (C-XVII-c) (425 g, 967 mmol) in MeOH (4500 mL) was added sodium methanolate (261 g, 1.45 mol, 30% in MeOH) at rt and stirring at 60 °C was continued for 3 h. The reaction mixture was concentrated and the residue was poured into a solution of NH ₄ Cl (200 g) and citric acid (40 g) in water (2.5 L). The organic layer was separated and washed with brine (1 L), dried and filtered. The filtrate was concentrated under reduced pressure to give the title product (800 g) as a mixture of diastereoisomers and was used in the next step without any further purification.

Step 2. Methyl (2S,3S)-4-bromo-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (C-XVII-f)

Three reactions were carried out in parallel as follows. At 15 °C, to a stirred solution of methyl (2S,3S)-3-(2-bromo-4,6-difluorophenyl)-2-hydroxy-2-phenylbutanoate (C-XVII-e) (430 g, 1.12 mol) in NMP (2.6 L) was added NaH (40.2 g, 1.00 mol, 60% in mineral oil) under N ₂ . The resulting reaction mixture was stirred at 15 °C for 15 min. The reaction mixture was poured into saturated NH ₄ Cl (5 L) and extracted three times with TBME (2 L) before it was quenched by adding saturated NaHCO ₃ and extracted three times with MTBE (2 L). The combined organic layers were washed with brine (3 L), dried, filtered and concentrated. The crude product was purified by flash chromatography (silica, PE/EtOAc, gradient: 2% to 20% EtOAc) to give a yellow solid (360 g). The solid was recrystallized from PE/ethyl acetate (1.8 L, heated to 70 °C with stirring to dissolve all the solid and allowed to cool to 10 °C, with the solid collected by filtration). The title product (260 g) was isolated as a colorless solid with an enantiomeric excess of >99%. Chiral SFC: ChiralPak AD-3, 150 x 4.6 mm i.d. diameter, 3 µm, _CO2 /ethanol (0.05% DEA), gradient: from 95/5 to 60/40 in 5.5 min and hold at 60/40 for 3 min, then 95/5 for 1.5 min; column temperature 40°C, flow rate: 2.5 ml/min, t _R = 1.72 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) 7.62 (d, J = 7.2 Hz, 2H), 7.43-7.30 (m, 3H), 7.07 (br d, J = 9.2 Hz, 1H), 7.03 (br d, J = 9.2 Hz, 1H), 3.92 (q, J = 6.8 Hz, 1H), 3.74 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H). A second batch of the title compound (100 g) was also isolated with 70% purity.

Synthesis of 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 (C-XVIII):

Reaction scheme C-XVIII:

2-(Aminomethyl)-4-bromo-5-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-3-ol (C-XVIII-a) as a diastereomeric mixture was prepared from 2-bromo-3-chloro-4-fluoro-6-hydroxybenzaldehyde (C-XII-e) and 2-bromo-2-(pyridin-2-yl)acetonitrile according to the procedures reported in the syntheses of intermediates (C-XIV) and (C-XVI).

Step 1. 2-(((2R*,3R*)-4-Bromo-5-chloro-6-fluoro-3-hydroxy-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)isoindolin-1,3-dione (C-XVIII-b) and 2-(((2R*,3S*)-4-bromo-5-chloro-6-fluoro-3-hydroxy-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)isoindolin-1,3-dione (C-XVIII-c)

To a stirred solution of 2-(aminomethyl)-4-bromo-5-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-3-ol (C-XVIII-a) (7.43 g, 17.4 mmol) in toluene (100 mL) was added phthalic anhydride (2.84 g, 19.2 mmol) at rt and the reaction mixture was stirred at 105 °C for 2 h. The reaction mixture was concentrated and saturated NaHCO ₃ solution and EtOAc were added. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, DCM/EtOAc, gradient 0% to 60% EtOAc) to afford the title compounds as colorless powders:

2-(((2R*,3R*)-4-bromo-5-chloro-6-fluoro-3-hydroxy-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)isoindolin-1,3-dione (C-XVIII-b) (1.44 g). UPLC-MS 1: m/z 517.0/519.0 [M+H] ⁺ , t _R =1.15 min.

2-(((2R*,3S*)-4-bromo-5-chloro-6-fluoro-3-hydroxy-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)isoindolin-1,3-dione (C-XVIII-c) (5.82 g): UPLC-MS 1: m/z 517.0/519.0 [M+H] ⁺ , t _R = 1.22 min.

Step 2. 2-((4-Bromo-5-chloro-6-fluoro-3-methylene-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)isoindoline-1,3 -dione (C-XVIII-d)

A solution of 2-(((2R*,3R*)-4-bromo-5-chloro-6-fluoro-3-hydroxy-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)isoindolin-1,3-dione (C-XVIII-b) (5.47 g, 6.8 mmol) and TFA (25 mL, 324 mmol) in DCM (25 mL) was stirred at rt for 18 h. The reaction mixture was added to _{saturated NaHCO3} solution and extracted with DCM. _The combined organic extracts were washed with water and brine, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, DCM/EtOAc, gradient 0% to 30% EtOAc) to give the title compound (3.15 g) as a colorless powder. UPLC-MS 1: m/z 499.0/501.0 [M+H] ⁺ , t _R = 1.35 min. ^1H NMR (600 MHz, DMSO -d6 ) δ 8.75 (dt, J=4.8, 1.4 Hz, 1H), 7.87-7.77 (m, 5H) _, 7.48-7.41 (m, 2H), 7.33 (d, J=9.2 Hz, 1H), 6.39 (s, 1H), 5.74 (s, 1H), 4.66 (d, J=14.7 Hz, 1H), 4.41 (d, J=14.7 Hz, 1H).

The same reaction was repeated with 2-(((2R*,3S*)-4-bromo-5-chloro-6-fluoro-3-hydroxy-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)isoindolin-1,3-dione (C-XVIII-c) (3.8 g, 7.3 mmol) to give the title compound (2.06 g). The reaction was stopped after 5 days and unreacted starting material still remained.

Step 3. ((2R*,3S*)-4-Bromo-5-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methanamine (C-XVIII-e)

At k.t. To a stirred solution of 2-((4-bromo-5-chloro-6-fluoro-3-methylene-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)isoindolin-1,3-dione (C-XVIII-d) (5.2 g, 10.1 mmol) in DCE (100 mL) was added TEA (2.81 mL, 20.19 mmol) followed by 3-nitrobenzenesulfonylhydrazine (4.38 g, 20.2 mmol) and the reaction mixture was stirred at 75 °C for 14 h. More TEA (1.4 mL, 10.1 mmol) and 3-nitrobenzenesulfonylhydrazine (2.2 g, 10.1 mmol) were added and stirring at 75 °C was continued for 8 h. DCM and water were added. The organic phase was separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed with water and brine, dried over _{anhydrous Na2SO4} and concentrated. The crude intermediate was dissolved in EtOH (125 mL), hydrazine hydrate (1.22 mL, 25.2 mmol) was added and the reaction mixture was stirred at 75 °C for 2 h. The reaction mixture was concentrated then taken up in EtOAc and water. The organic layer was separated and the aqueous layer was extracted with EtOAc. _The combined organic extracts were washed with brine, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, DCM/(7N ammonia in MeOH), gradient 0% to 10% (7N ammonia in MeOH)) to give the title compound (7.43 g) as a colorless powder. UPLC-MS 1: m/z 371.0/373.1 [M+H] ⁺ , t _R = 0.74 min.

^1H NMR (400 MHz, DMSO- d6 ) δ 8.61 (dt, J=4.7, 1.5 Hz, 1H) _, 7.76 (td, J=7.8, 1.8 Hz, 1H), 7.46 (dt, J=8.1, 1.2 Hz, 1H), 7.33-7.28 (m, 1H), 7.23 (d, J=9.5 Hz, 1H), 3.92 (q, J=7.1 Hz, 1H), 3.27 (d, J=3.0 Hz, 2H) , 1.38 (d, J=7.1 Hz, 3H), 1.15 (s, 2H).

Step 4. ((2S,3R)-4-Bromo-5-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methanamine (C-XVIII-f) and ((2R,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methanamine (C-XVIII-g)

Racemic ((2R*,3S*)-4-bromo-5-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methanamine (C-XVIII-e) (4.63 g, 12.46 mmol) was subjected to chiral preparative SFC (ChiralPak AD-H 250×30 mm i.d., 5 μm, _CO2 /IPA (+1% isopropylamine) 3:1, flow rate: 80 mL/min, column temperature 40°C) to afford the title compounds as single enantiomers in >99% enantiomeric excess, respectively.

((2S,3R)-4-Bromo-5-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methanamine (2.47 g) (C-XVIII-f): chiral SFC (ChiralPak AD-H 250×4.6 mm i.d., 5 μm, _CO2 /IPA (+1% isopropylamine) 7:3, flow rate: 3 mL/min.) t _R = 3.06 min.

((2R,3S)-4-Bromo-5-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methanamine (2.32 g) (C-XVIII-g): chiral SFC (ChiralPak AD-H 250×4.6 mm i.d., 5 μm, _CO2 /IPA (+1% isopropylamine) 7:3, flow rate: 3 mL/min.) t _R = 4.05 min.

Step 5. tert-Butyl (((2R,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XVIII-h)

((2R,3S)-4-Bromo-5-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methanamine (C-XVII-g) (2.25 g, 6.1 mmol) was converted to the title compound (2.86 g) following reaction conditions similar to those for the synthesis of intermediate CIp (step 14 of intermediate CI). UPLC-MS 1: m/z 471.2/473.2 [M+H] ⁺ , t _R = 1.41 min.

Step 6. 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 (C-XVIII)

tert-Butyl (((2R,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XVII-h) (2.88 g, 6.1 mmol) was converted to the title compound following reaction conditions similar to those for the synthesis of intermediate C-XVI (step 7 of intermediate C-XVI). UPLC-MS 1: m/z 519.4 [M+H] ⁺ , t _R = 1.43 min. ¹ H NMR (400 MHz, DMSO _-d6 ) δ 8.53 (d, J=4.6 Hz, 1H), 7.68 (t, J=7.8 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.23 (t, J=6.2 Hz, 1H), 7.11 (d, J=9.6 Hz, 1H), 6.61-6.48 (m, 1H), 3.79-3.67 (m, 1H), 3.64-3.52 (m, 1H), 3.39-3.22 (m, 1H), 1.33-1.12 (m, 24H).

Synthesis of ((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 (C-XIX):

Reaction scheme C-XIX:

Step 1 . 1-(6-(Benzyloxy)-2-bromo-3-chloro-4-fluorophenyl)ethanol (C-XIX-a)

At -30 °C, to a solution of 6-(benzyloxy)-2-bromo-3-chloro-4-fluorobenzaldehyde (C-XII-d) (50.0 g, 146 mmol) in THF (570 mL) was added methylmagnesium bromide (67.9 mL, 204 mmol, 3 M in Et ₂ O). The reaction mixture was allowed to warm to 0 °C over 2 h. The reaction mixture was quenched by addition of saturated NH ₄ Cl solution and extracted with EtOAc. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated to give the title compound (51.8 g) as a colorless solid. UPLC-MS 1: m/z 357.1 [MH] ^- , t _R = 1.28 min.

Step 2 . 1-(6-(Benzyloxy)-2-bromo-3-chloro-4-fluorophenyl)ethanone (C-XIX-b)

At 0 °C, to a solution of 1-(6-(benzyloxy)-2-bromo-3-chloro-4-fluorophenyl)ethanol (C-XIXI-a) (51.1 g, 136 mmol) in DCM (640 mL) was added Dess-Martin periodinane (69.4 g, 164 mmol) and the reaction mixture was allowed to warm to rt. Stirring at rt was continued for 12 h before a saturated solution of NaHCO ₃ /10% sodium thiosulfate (800 mL) was added. The organic phase was separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was triturated with Et ₂ O/heptane 4:1 (300 mL), collected by filtration and dried in HV. The isolated product was dissolved in DCM, re-extracted with _NaHCO3 /10% sodium thiosulfate (800 mL) and triturated with _Et2O /heptane 4:1 (250 mL) to give the title compound (56.0 g) as a colorless solid. UPLC-MS 1: m/z 373.9 [M+ _NH4 ] ⁺ , t _R = 1.29 min.

Step 3 . 1-(2-Bromo-3-chloro-4-fluoro-6-hydroxyphenyl)ethanone (C-XIX-c)

A mixture of 1-(6-(benzyloxy)-2-bromo-3-chloro-4-fluorophenyl)ethanone (C-XIX-b) (41.0 g, 115 mmol) and PtO ₂ (6.51 g, 28.7 mmol) in THF (460 mL) in a duck-shaped shake flask was stirred under 0.1 bar H ₂ for 17 h. The solids were removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (32.2 g). UPLC-MS 1: m/z 265.0 [MH] ^- , t _R = 0.95 min.

Stage 4 . Ethyl 2-(6-(benzyloxy)pyridin-2-yl)-2-oxoacetate (C-XIX-d)

At -78 °C, to a stirred solution of 2-benzyloxy-6-bromopyridine (20 g, 76 mmol) in THF (120 mL) was added n-BuLi (36.3 mL, 91 mmol, 2.5 M in hexane) and stirring was continued for 30 min at -78 °C. This solution was added dropwise via cannula to a stirred solution of diethyl oxalate (12.4 mL, 91 mmol) in THF (200 mL) at -78 °C. After 15 min of complete addition, the reaction mixture was quenched with saturated NH ₄ Cl solution and extracted with EtOAc. The organic extract was washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient: 0% to 25% EtOAc) to give the title compound (16.5 g) as a yellow oil. UPLC-MS 1: m/z 286.1 [M+-H] ⁺ , t _R = 1.18 min.

Step 5. Ethyl 2-(6-(benzyloxy)pyridin-2-yl)-2-hydroxyacetate (C-XIX-e)

At rt, to a stirred solution of ethyl 2-(6-(benzyloxy)pyridin-2-yl)-2-oxoacetate (C-XIX-d) (16.5 g, 57.8 mmol) in EtOH (102 mL), water (34 mL) and AcOH (17 mL) was added sodium triacetoxyborohydride (24.52 g, 116 mmol) and the reaction mixture was stirred at rt for 1 h. Saturated NaHCO ₃ solution was added and the mixture was extracted with EtOAc, the combined organic extracts were washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, heptane/EtOAc, gradient: 0% to 40% EtOAc) to give the title compound (11.8 g) as a yellow oil. UPLC-MS 1: m/z 288.0 [M+-H] ⁺ , t _R = 1.00 min.

Step 6. Ethyl 2-(6-(benzyloxy)pyridin-2-yl)-2-((methylsulfonyl)oxy)acetate (C-XIX-f)

At 0 °C, to a stirred solution of ethyl 2-(6-(benzyloxy)pyridin-2-yl)-2-hydroxyacetate (C-XIX-e) (13.1 g, 41.0 mmol) and TEA (17.2 mL, 123 mmol) in DCM (120 mL) was added methanesulfonic anhydride (10.72 g, 61.6 mmol) and the reaction mixture was stirred at 0 °C for 2 h. Water was added and the mixture was extracted with DCM. The combined organic extracts were washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient: 0% to 40% EtOAc) to give the title compound (16.2 g) as a colorless oil. UPLC-MS 1: m/z 366.5 [M+H] ⁺ , t _R = 1.12 min.

Step 7. Ethyl 2-(6-(benzyloxy)pyridin-2-yl)-4-bromo-5-chloro-6-fluoro-3-hydroxy-3-methyl-2,3-dihydrobenzofuran-2-carboxylate (C-XIX-g)

At rt, to a stirred solution of 1-(2-bromo-3-chloro-4-fluoro-6-hydroxyphenyl)ethanone (C-XIX-c) (9.50 g, 35.5 mmol) and K ₂ CO ₃ (7.36 g, 53.3 mmol) in DMF (100 mL) was added ethyl 2-(6-(benzyloxy)pyridin-2-yl)-2-((methylsulfonyl)oxy)acetate (C-XIX-f) (15.88 g, 40.8 mmol). After stirring at rt for 40 h, water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient: 0% to 100% EtOAc) to give the title compound (17.29 g) as a mixture of diastereoisomers. UPLC-MS 1: m/z 536.0 [M+-H] ⁺ , t _R = 1.37 and 1.39 min.

Step 8. Ethyl 2-(6-(benzyloxy)pyridin-2-yl)-4-bromo-5-chloro-6-fluoro-3-methylene-2,3-dihydrobenzofuran-2-carboxylate (C-XIX-h)

At rt, to a stirred solution of ethyl 2-(6-(benzyloxy)pyridin-2-yl)-4-bromo-5-chloro-6-fluoro-3-hydroxy-3-methyl-2,3-dihydrobenzofuran-2-carboxylate (C-XIX-g) (17.29 g, 26.7 mmol) in DCM (200 mL) was added triethylamine (18.6 mL, 134 mmol), followed by methanesulfonic anhydride (9.31 g, 53.5 mmol). After 4 h, water was added and the mixture was extracted with DCM. The combined organic extracts were washed with water and brine, dried over anhydrous _{Na2SO4 ,} and concentrated. The residue was purified by flash chromatography (silica, heptane/EtOAc, gradient: 0% to 20% EtOAc) to give the title compound (14.83 g) as a colorless oil. UPLC-MS 1: m/z 518.0 [M+-H] ⁺ , t _R = 1.52 min.

Step 9. (2-(6-(Benzyloxy)pyridin-2-yl)-4-bromo-5-chloro-6-fluoro-3-methylene-2,3-dihydrobenzofuran-2-yl)methanol (C-XIX-i)

At 0 °C, sodium borohydride (1.46 g, 38.6 mmol) was added to a stirred solution of 2-(6-(benzyloxy)pyridin-2-yl)-4-bromo-5-chloro-6-fluoro-3-methylene-2,3-dihydrobenzofuran-2-carboxylate (C-XIX-h) (14.83 g, 25.7 mmol) in MeOH (200 mL) and the reaction mixture was allowed to warm to rt. After 1 h, more sodium borohydride (1.460 g, 38.6 mmol) was added. Three more portions of sodium borohydride (1.460 g, 38.6 mmol) were added over 12 h. Acetone was added for workup and the reaction mixture was concentrated and diluted in EtOAc/water. The organic phase was separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over _{anhydrous Na2SO4} and concentrated. The residue was purified by flash chromatography (silica, heptane/EtOAc, gradient: 0% to 40% EtOAc) to give the title compound (7.80 g). UPLC-MS 1: m/z 476.1 [M+-H] ⁺ , t _R = 1.42 min.

Step 10. ((2S*,3S*)-2-(6-(Benzyloxy)pyridin-2-yl)-4-bromo-5-chloro-6-fluoro-3-methyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XIX-j) and ((2S*,3R*)-2-(6-(benzyloxy)pyridin-2-yl)-4-bromo-5-chloro-6-fluoro-3-methyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XIX-k)

At k.t. To a stirred solution of (2-(6-(benzyloxy)pyridin-2-yl)-4-bromo-5-chloro-6-fluoro-3-methylene-2,3-dihydrobenzofuran-2-yl)methanol (C-XIX-i) (11.88 g, 24.9 mmol) in DCE (250 mL) were added 3-nitrobenzenesulfonylhydrazine (10.8 g, 49.8 mmol) and TEA (17.4 mL, 125 mmol) and the reaction mixture was stirred at 70 °C for 5 h. More 3-nitrobenzenesulfonylhydrazine (5.4 g, 24.9 mmol) and TEA (8.7 mL, 62.3 mmol) were added and stirring at 70 °C was continued for 16 h. Water was added, the organic phase was separated and the aqueous phase extracted with DCM. The combined organic extracts were washed with water and brine, dried over anhydrous _Na2SO4 and concentrated. The two title compounds were isolated by two successive flash chromatographies (silica, heptane/EtOAc, gradient: 0% to 30% _EtOAc and gradient: 0% to 20% EtOAc):

((2S*,3S*)-2-(6-(benzyloxy)pyridin-2-yl)-4-bromo-5-chloro-6-fluoro-3-methyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XIX-j) (9.11 g, colorless powder): UPLC-MS 1: m/z 478.0 [M+-H] ⁺ , t _R = 1.41 min.

((2S*,3R*)-2-(6-(benzyloxy)pyridin-2-yl)-4-bromo-5-chloro-6-fluoro-3-methyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XIX-k) (1.56 g, colorless powder): UPLC-MS 1: m/z 478.0 [M+-H] ⁺ , t _R =1.45 min.

Step 11. ((2S,3S)-2-(6-(Benzyloxy)pyridin-2-yl)-4-bromo-5-chloro-6-fluoro-3-methyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XIX-l) and ((2R,3R)-2-(6-(benzyloxy)pyridin-2-yl)-4-bromo-5-chloro-6-fluoro-3-methyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XIX-m)

The racemate of ((2S*,3S*)-2-(6-(benzyloxy)pyridin-2-yl)-4-bromo-5-chloro-6-fluoro-3-methyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XIX-j) (8.8 g) was subjected to chiral SFC (ChiralCel OJ, 250 × 30 mm i.d., 5 μm, CO ₂ /MeOH (0.1% ammonia) 7:3, temperature 38 °C, flow rate: 65 mL/min, cycle time 4 min) to afford two enantiomers of ((2S,3S)-2-(6-(benzyloxy)pyridin-2-yl)-4-bromo-5-chloro-6-fluoro-3-methyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XIX-l) (4.02 g) and ((2R,3R)-2-(6-(benzyloxy)pyridin-2-yl)-4-bromo-5-chloro-6-fluoro-3-methyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XIX-m) (3.91 g) with an enantiomeric excess of >98%, respectively.

((2S,3S)-2-(6-(Benzyloxy)pyridin-2-yl)-4-bromo-5-chloro-6-fluoro-3-methyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XIX-l): Chiral SFC: (ChiralCel OJ 150×4.6 mm i.d., 3 μm, _CO2 /MeOH (0.05% DEA) 5 to 40%, flow rate: 2.5 mL/min, column temperature 35°C) t _R = 5.01 min; UPLC-MS 1: m/z 478.0 [M+H] ⁺ , t _R = 1.40 min.

((2R,3R)-2-(6-(Benzyloxy)pyridin-2-yl)-4-bromo-5-chloro-6-fluoro-3-methyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XIX-m): Chiral SFC: (ChiralCel OJ 150×4.6 mm i.d., 3 μm, _CO2 /MeOH (0.05% DEA) 5 to 40%, flow rate: 2.5 mL/min, column temperature 35°C) t _R = 4.61 min; UPLC-MS 1: m/z 478.0 [M+H] ⁺ , t _R = 1.40 min.

Step 12. ((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 (C-XIX)

To a stirred solution of ((2S,3S)-2-(6-(benzyloxy)pyridin-2-yl)-4-bromo-5-chloro-6-fluoro-3-methyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XIX-l) (2.00 g, 4.2 mmol), bis(pinacolato)dibrone (1.59 g, 6.3 mmol) and KOH (0.47 g, 8.4 mmol) in toluene (40 mL) was added PdCl ₂ (dppf).CH ₂ Cl ₂ adduct (0.34 g, 0.42 mmol) at 60 °C and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered through celite and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient: 0% to 30% EtOAc) to give the title compound (1.65 g) as a colorless foam. ¹ H NMR (600 MHz, DMSO -d ₆ ) δ 7.65 (t, J=7.8 Hz, 1H), 7.46-7.43 (m, 2H), 7.38 (t, J=7.4 Hz, 2H), 7.34-7.31 (m, 1H), 7.11 (d, J=9.7 Hz, 1H), 7.05 (d, J=7.4 Hz, 1H), 6.74 (d, J=8.3 Hz, 1H), 5.35 (dd, J=21.5, 12.3 Hz, 2H), 4.93 (t, J=5.5 Hz, 1H), 3.99-3.92 (m, 2H), 1.31-1.27 (m, 15H). UPLC-MS 1: mass/charge 526.1 [M+H] ⁺ , t _R =1.42 min.

Synthesis of (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-methylcyclohexan-1-ol (C-XX):

The title compound was synthesized by analogy with ((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 (C-XIX) from 1-(2-bromo-3-chloro-4-fluoro-6-hydroxyphenyl)ethanone (C-XIX-c) and ethyl 2-bromo-2-(pyridin-2-yl)acetate. The intermediate ((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methanol (see below) was oxidized to the corresponding aldehyde ((COCl) ₂ /TEA/DMSO, DCM) followed by reductive amination with trans-4-amino-1-methylcyclohexanol (compare with the alternative synthesis from example 114a) and formation of the boronate. UPLC-MS 1: m/z 531.3 [M+H] ⁺ , t _R = 0.95 min.

The racemic intermediate ((2S*,3S*)-4-bromo-5-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methanol was subjected to chiral SFC (ChiralPak IG, 250 × 30 mm, 5 μm, CO ₂ /(MeOH+1%IPAm) 85:15, flow rate: 80 ml/min) to afford the individual enantiomers with enantiomeric excess >98%, respectively:

((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methanol: chiral SFC (ChiralPak IG, 250 × 4.6 mm, 5 μm, CO ₂ /(MeOH+1%IPAm) 85:15, flow rate: 3 ml/min), t _R = 4.20 min.

((2R,3R)-4-bromo-5-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methanol: chiral SFC (ChiralPak IG, 250 × 4.6 mm, 5 μm, CO ₂ /(MeOH+1%IPAm) 85:15, flow rate: 3 ml/min), t _R = 5.20 min.

Synthesis of (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-methylcyclohexan-1-ol (C-XXI):

The title compound was synthesized by analogy with ((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 (C-XIX) from 1-(2-bromo-3-chloro-4-fluoro-6-hydroxyphenyl)ethanone (C-XIX-c) and ethyl 2-bromo-2-(pyridin-3-yl)acetate. The intermediate ((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-(pyridin-3-yl)-2,3-dihydrobenzofuran-2-yl)methanol (see below) was oxidized to the corresponding aldehyde ((COCl) ₂ /TEA/DMSO, DCM) followed by reductive amination with trans-4-amino-1-methylcyclohexanol (compare with the alternative synthesis from example 114a) and formation of the boronate. UPLC-MS 1: m/z 531.4 [M+H] ⁺ , t _R = 0.96 min.

The racemic intermediate ((2S*,3S*)-4-bromo-5-chloro-6-fluoro-3-methyl-2-(pyridin-3-yl)-2,3-dihydrobenzofuran-2-yl)methanol was subjected to chiral HPLC (ChiralPak IG, 250 × 30 mm, 5 μm, heptane/(EtOH+0.1% DEA) 1:1, flow rate: 20 mL/min) to afford the individual enantiomers with enantiomeric excess >98%, respectively:

((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-(pyridin-3-yl)-2,3-dihydrobenzofuran-2-yl)methanol: chiral SFC (ChiralPak IG, 250 × 4.6 mm, CO ₂ /(MeOH+0.1% NH ₃ ) 6:4, flow rate: 3 ml/min.), t _R = 3.71 min.

((2R,3R)-4-bromo-5-chloro-6-fluoro-3-methyl-2-(pyridin-3-yl)-2,3-dihydrobenzofuran-2-yl)methanol: chiral SFC (ChiralPak IG, 250 × 4.6 mm, CO ₂ /(MeOH+0.1% NH ₃ ) 6:4, flow rate: 3 ml/min.), t _R = 2.81 min.

Synthesis of 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 (C-XXII)

Reaction scheme C-XXII:

Step 1. 2-Bromo-6-fluoro-3-(trifluoromethyl)benzaldehyde (C-XXII-a)

LDA (53.5 mL, 107 mmol, 2 M in THF/heptane/ethylbenzene) was added to a stirred solution of 2-bromo-4-fluoro-1-(trifluoromethyl)benzene (20 g, 82 mmol) in THF (400 mL) over 1 min and the reaction mixture was stirred at -78 °C for 5 min. A solution of N-methylformanilide (10.67 mL, 86 mmol) in THF (20 mL) was added and the reaction mixture was quenched at -78 °C with saturated ammonium chloride solution. EtOAc was added followed by saturated NH ₄ Cl solution. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was triturated with _Et2O to give a white solid (discarded) and the filtrate was absorbed onto silica gel, dried at 40°C under vacuum and purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 10% EtOAc) to give the desired product (14.3 g). ¹ H NMR (400 MHz, DMSO _-d6 ) δ 10.21 (s, 1H), 8.13 (dd, J=8.9, 5.3 Hz, 1H), 7.61 (t, J=9.4 Hz, 1H).

Step 2. 2-Bromo-6-hydroxy-3-(trifluoromethyl)benzaldehyde (C-XXII-b)

At 0 °C, NaH (2.00 g, 50.1 mmol, 60% in mineral oil) was added to a stirred solution of 2-(trimethylsilyl)ethanol (6.67 mL, 46.5 mmol) in DMF (60 mL), and the reaction mixture was stirred at 0 °C for 15 min. A solution of 2-bromo-6-fluoro-3-(trifluoromethyl)benzaldehyde (C-XXII-a) (10 g, 35.8 mmol) in DMF (10 mL) was added and stirring at 0 °C was continued for 30 min. The reaction mixture was quenched with water and extracted with Et ₂ O. The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was treated with TBAF (4.68 g, 17.9 mmol) in THF (100 mL) for 4.5 h at rt. Water was added and the pH was adjusted to 5 with 2 N HCl. The aqueous layer was extracted with _Et2O , the combined organic extracts were washed with brine, dried over _{anhydrous Na2SO4} and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 10% EtOAc) to give the title compound (7.00 g) as a yellow powder. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.97 (s, 1H), 10.29 (s, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H). UPLC-MS 1: m/z 266.9/268.9 [MH] ^- . t _R =1.16 min.

Step 3. 6-(Benzyloxy)-2-bromo-3-(trifluoromethyl)benzaldehyde (C-XXII-c)

A mixture of 2-bromo-6-hydroxy-3-(trifluoromethyl)benzaldehyde (C-XXII-b) (7.00 g, 25.0 mmol), benzyl bromide (3.27 mL, 27.5 mmol), and _K2CO3 (5.18 g, 37.5 mmol) in DMF (70 mL) was stirred at rt for 20 _h . EtOAc and water were added. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over anhydrous _{Na2SO4 ,} and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 20% EtOAc) to give the title compound (8.49 g) as a colorless powder. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.26 (s, 1H), 7.96 (d, J=9.0 Hz, 1H), 7.51-7.28 (m, 6H), 5.32 (s, 2H). UPLC-MS 1: m/z 358.9/361.0 [M+H] ⁺ . t _R = 1.32 min.

Step 4. (6-(Benzyloxy)-2-bromo-3-(trifluoromethyl)phenyl)methanol (C-XXII-d)

_NaBH4 (0.850 g, 22.5 mmol) was added to a stirred suspension of 6-(benzyloxy)-2-bromo-3-(trifluoromethyl)benzaldehyde (C-XXII-c) (8.49 g, 22.5 mmol) in MeOH (100 mL) at 0 °C and stirring at 0 °C was continued for 15 min. The reaction mixture was quenched with acetone and concentrated. DCM and water were added. The organic phase was separated and the aqueous layer was extracted with DCM. _The combined organic extracts were washed with water and brine, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 10% to 30% EtOAc) to give the title compound (7.5 g) as a colorless powder. UPLC-MS 1: m/z 378.0/380.0 [M+NH ₄ ] ⁺ . t _R = 1.22 min. ^1H NMR (400 MHz, DMSO -d6 ) δ 7.72 (d, J=8.8 Hz, 1H), 7.52-7.28 (m, 5H) _, 7.22 (d, J=8.9 Hz, 1H), 5.24 (s, 2H), 4.96 (t, J=5.3 Hz, 1H), 4.71 (d, J=5.3 Hz, 2H).

Step 5. 1-(Benzyloxy)-3-bromo-2-(bromomethyl)-4-(trifluoromethyl)benzene (C-XXII-e)

CBr ₄ (9.52 g, 28.7 mmol) was added to a stirred solution of (6-(benzyloxy)-2-bromo-3-(trifluoromethyl)phenyl)methanol (C-XXII-d) (7.515 g, 19.1 mmol) and PPh ₃ (7.53 g, 28.7 mmol) in DCM (150 mL) at 0 °C and stirring was continued for 4 h. DCM and 0.5 N NaOH solution were added. The organic phase was separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 15% EtOAc) to give the title compound (7.51 g). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.79 (d, J = 8.9 Hz, 1H), 7.56-7.47 (m, 2H), 7.45-7.25 (m, 4H), 5.34 (s, 2H), 4.79 (s, 2H).

Step 6. Methyl 3-(6-(benzyloxy)-2-bromo-3-(trifluoromethyl)phenyl)-2-hydroxy-2-phenylpropanoate (C-XXII-f)

To a stirred solution of methyl 2-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)acetate (CIe) (6.58 g, 25.5 mmol) in THF (150 mL) was added LDA (15.30 mL, 30.6 mmol, 2 M in THF/heptane/ethylbenzene) over 5 min at -78 °C. After 30 min, a solution of 1-(benzyloxy)-3-bromo-2-(bromomethyl)-4-(trifluoromethyl)benzene (C-XXII-e) (7.51 g, 17.00 mmol) in THF (50 mL) was added over 10 min. After 30 min at -78 °C, the cooling bath was removed. The white suspension became a clear solution when the temperature reached 0 °C. Stirring at 0 °C was continued for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried over _{anhydrous Na2SO4} and concentrated. The crude product was dissolved in ACN (50 mL) and treated with 2 N HCl (30 mL) at rt for 15 min. The reaction mixture was poured into saturated _NaHCO3 solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried over _{anhydrous Na2SO4} and concentrated. The crude product was triturated with _Et2O to give the first crop of the title compound as a colorless powder. The filtrate was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 30% EtOAc) to give a second crop of the title compound. Both crops were combined (6.94 g). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.62 (d, J = 8.9 Hz, 1H), 7.46-7.40 (m, 2H), 7.36-7.20 (m, 8H), 7.05 (d, J = 8.8 Hz, 1H), 5.67 (s, 1H), 5.02 (q, J = 12.7 Hz, 2H), 3.97 (d, J = 13.6 Hz, 1H), 3.70 (d, J = 13.7 Hz, 1H), 3.47 (s, 3H). UPLC-MS 1: m/z 509.0/511.0 [M+H] ⁺ , t _R = 1.45 min.

Step 7. Methyl 3-(2-bromo-6-hydroxy-3-(trifluoromethyl)phenyl)-2-hydroxy-2-phenylpropanoate (C-XXII-g)

A mixture of methyl 3-(6-(benzyloxy)-2-bromo-3-(trifluoromethyl)phenyl)-2-hydroxy-2-phenylpropanoate (C-XXII-f) (6.94 g, 13.6 mmol) and Ra-Ni (1.5 g, 17.51 mmol) in MeOH (140 mL) was stirred under atmospheric pressure of _H2 at rt for 1 h. The reaction mixture was filtered through a pad of celite and concentrated. The crude product was flash chromatographed (silica, hexane/EtOAc, gradient: 0% to 30% EtOAc) to give the title compound (5.7 g). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.56-7.43 (m, 3H), 7.36-7.19 (m, 3H), 6.86 (d, J=8.6 Hz, 1H), 3.87 (d, J=13.8 Hz, 1H), 3.65-3.54 (m, 4H). UPLC-MS 1: m/z 417.0/419.0 [MH] ^- , t _R =1.22 min.

Step 8. Methyl 4-bromo-2-phenyl-5-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxylate (C-XXII-h)

DIAD (2.88 mL, 14.8 mmol) was added to a stirred solution of methyl 3-(2-bromo-6-hydroxy-3-(trifluoromethyl)phenyl)-2-hydroxy-2-phenylpropanoate (C-XXII-g) (5.7 g, 13.5 mmol) and _PPh3 (3.88 g, 14.8 mmol) in THF (80 mL) at 0 °C. The reaction mixture was stirred at rt for 20 h. For work-up, the reaction mixture was concentrated and EtOAc and water were added. The organic layer was separated and the aqueous layer was extracted with EtOAc. _The combined organic extracts were washed with brine, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 15% EtOAc) to give the title compound (5.13 g) as a colorless oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.67 (d, J = 8.6 Hz, 1H), 7.57-7.51 (m, 2H), 7.46-7.35 (m, 3H), 7.17 (d, J = 8.5 Hz, 1H), 4.14 (d, J = 16.8 Hz, 1H), 3.68 (s, 4H). UPLC-MS 1: m/z 399.0/401.1 [MH] ^- , t _R = 1.39 min.

Step 9. (S)-Methyl 4-bromo-2-phenyl-5-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxylate (C-XXII-i) and (R)-methyl 4-bromo-2-phenyl-5-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxylate (C-XXII-j)

Racemic methyl 4-bromo-2-phenyl-5-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxylate (C-XXII-h) (4.8 g, 11.96 mmol) was separated by chiral preparative HPLC (Chiralcel OJ, 500 × 100 mm, 20 μm, heptane/IPA 80:20, flow rate: 120 mL/min) to afford the title compounds as pure enantiomers with an enantiomeric excess of >99%, respectively:

(S)-methyl 4-bromo-2-phenyl-5-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxylate (C-XXII-i) (2.30 g): chiral HPLC (Chiralcel OJ-H, 250 × 4.6 mm, 5 μm, heptane/IPA 80:20, flow rate: 1 ml/min), t _R = 8.20 min. ¹ H NMR (400 MHz, DMSO -d6 ) δ 7.67 (d, J=8.5 Hz, 1H), 7.59-7.49 (m, 2H), 7.48-7.32 (m, 3H), _7.17 (d, J=8.5 Hz, 1H), 4.14 (d, J=16.8 Hz, 1H), 3.73-3.59 (m, 4H). UPLC-MS 1: mass/charge 418.0/419.9 [M+NH ₄ ] ⁺ . t _R =1.39 min.

(R)-methyl-4-bromo-2-phenyl-5-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxylate (C-XXII-j) (1.90 g): chiral HPLC (Chiralcel OJ-H , 250 × 4.6 mm, 5 µm heptane/IPA 80:20, flow rate: 1 ml/min.) t _R =17.39 min. ^1H NMR (400 MHz, DMSO -d6 ) δ 7.67 (d, J=8.5 Hz, 1H) _, 7.59-7.50 (m, 2H), 7.48-7.33 ( m, 3H), 7.17 (d, J=8.5 Hz, 1H), 4.14 (d, J=16.8 Hz, 1H), 3.73-3.58 (m, 4H). UPLC-MS 1: mass/charge 418.0/420.0 [M+NH ₄ ] ⁺ . t _R =1.39 min.

Step 10. (S)-4-Bromo-2-phenyl-5-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxylic acid (C-XXII-k)

At rt, to a stirred solution of (S)-methyl 4-bromo-2-phenyl-5-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxylate (C-XXII-i) (2.3 g, 5.7 mmol) in MeOH (30 mL) and THF (30 mL) was added 2 N NaOH (28.7 mL, 57.3 mmol) and the reaction mixture was stirred at rt for 30 min. The organic solvents were removed under reduced pressure, the remaining aqueous layer was acidified to pH 3 with 2 _N HCl and extracted with DCM. The combined organic extracts were dried over anhydrous _Na2SO4 and concentrated to give the title product (2.2 g) as a colorless powder. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.66 (d, J = 8.4 Hz, 1H), 7.61-7.51 (m, 2H), 7.48-7.32 (m, 3H), 7.15 (d, J = 8.4 Hz, 1H), 4.09 (d, J = 16.7 Hz, 1H), 3.62 (d, J = 16.7 Hz, 1H). UPLC-MS 1: m/z 385.1/387.1 [MH] ^- . t _R = 1.08 min.

Step 11. (S)-4-Bromo-2-phenyl-5-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxamide (C-XXII-l)

To a stirred solution of (S)-4-bromo-2-phenyl-5-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxylic acid (C-XXII-k) (2.2 g, 5.7 mmol) in DCM (40 mL) was added oxalyl chloride (0.647 mL, 7.39 mmol) followed by 3 drops of DMF at 0 °C. The ice bath was removed and stirring at rt was continued for 30 min. The acid chloride solution was slowly added via a dropping funnel to ice-cold ammonium hydroxide (40 mL, 308 mmol, 30% in water). The reaction mixture was stirred at 0 °C for 1 h. DCM and water were added and the mixture was filtered through celite. The filtrate was extracted with DCM and the combined organic extracts were washed with water and brine, dried over _{anhydrous Na2SO4} and concentrated to give the title product (1.9 g) as a colorless powder. ¹ H NMR (400 MHz, DMSO _-d6 ) δ 7.88 (s, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.63-7.51 (m, 3H), 7.49-7.31 (m, 3H), 7.11 (d, J=8.5 Hz, 1H), 4.09 (d, J=16.6 Hz, 1H), 3.48 (d, J=16.6 Hz, 1H). UPLC-MS 1: m/z 384.0/386.0 [MH] ^- . t _R =1.15 min.

Step 12. (S)-(4-Bromo-2-phenyl-5-(trifluoromethyl)-2,3-dihydrobenzofuran-2-yl)methanamine (C-XXII-m)

To a stirred solution of (S)-4-bromo-2-phenyl-5-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxamide (C-XXII-l) (1.94 g, 5.0 mmol) in THF (40 mL) was added borane-methyl sulfide complex (10.02 mL, 20.04 mmol) at rt and the reaction mixture was stirred at reflux for 18 h. After cooling to rt, MeOH (10 mL) was added. After 30 min at rt, 1 N HCl (30 mL) was added and the reaction mixture was stirred at rt for 72 h. DCM and saturated NaHCO ₃ solution were added, 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 flash chromatography (silica, DCM/MeOH, gradient: 0% to 5% MeOH) to give the title compound (1.58 g) as a colorless oil. ¹ H NMR (400 MHz, DMSO- d6 ) δ 7.60 (d, J=8.4 Hz, 1H), 7.52-7.23 (m, 5H) _, 7.04 (d, J=8.4 Hz, 1H), 3.85 (d, J=16.6 Hz, 1H), 3.22 (d, J=16.5 Hz, 1H), 3.01 (s, 2H), 1.90 (s, 2H). UPLC-MS 1: mass/charge 372.0/374.0 [M+H] ⁺ . t _R =0.85 min.

Step 13. tert-Butyl (S)-((4-bromo-2-phenyl-5-(trifluoromethyl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XXII-n)

Boc protection of (S)-(4-bromo-2-phenyl-5-(trifluoromethyl)-2,3-dihydrobenzofuran-2-yl)methanamine (C-XXII-m) was performed as described for intermediate CIp (step 14 of the synthesis of intermediate CI). UPLC-MS 1: m/z 372.0/374.0 [M+H-Boc] ⁺ . t _R = 1.43 min.

Step 14. 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 (C-XXII)

tert-Butyl (S)-((4-bromo-2-phenyl-5-(trifluoromethyl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XXII-n) was converted to the title compound by analogy with step 15 of the synthesis of intermediate CI. UPLC-MS 1: m/z 420.2 [M+H] ⁺ . t _R = 1.49 min.

Synthesis of (S)-2-(hydroxymethyl)-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-5-carbonitrile (C-XXIII):

Reaction scheme C-XXIII:

Step 1. 2-Bromo-4-fluoro-3-formylbenzonitrile (C-XXIII-a)

At -78 °C, to a stirred solution of 2-bromo-4-fluorobenzonitrile (10.5 g, 52.5 mmol) in THF (250 mL) was added a solution of LDA (31.5 mL, 63.0 mmol, 2 N in heptane) under Ar. The reaction mixture was stirred for 30 min at -78 °C before 4-formylmorpholine (6.33 mL, 63.0 mmol) was added. The reaction mixture was quenched with 0.1 M HCl (100 mL) and extracted with EtOAc. The combined organic extracts were washed with saturated NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient: 0% to 30% EtOAc) to give the title compound (9.2 g). UPLC-MS 1: m/z 224.0/226.0 [MH] ^- . t _R = 0.80 min.

Step 2. 2-Bromo-4-fluoro-3-(hydroxymethyl)benzonitrile (C-XXIII-b)

At 0 °C, to a stirred solution of 2-bromo-4-fluoro-3-formylbenzonitrile (C-XXIII-a) (9.3 g, 40.8 mmol) in MeOH (80 mL) was added NaBH ₄ (0.772 g, 20.4 mmol) under Ar atmosphere and stirring was continued at this temperature for 60 min. The reaction mixture was concentrated and quenched with sat. NH ₄ Cl solution. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with sat. NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient: 0% to 70% EtOAc) to give the desired product (8.18 g). ¹ H NMR (400 MHz, DMSO - _d6 ) δ 8.01 (dd, J=8.6, 5.6 Hz, 1H), 7.52 (t, J=8.8 Hz, 1H), 5.42 (t, J=5.6 Hz), 4.63 (dd, J=5.6, 2.5 Hz, 2H).

Step 3. 2-Bromo-3-(bromomethyl)-4-fluorobenzonitrile (C-XXIII-c)

At 0 °C under Ar atmosphere, to a stirred solution of 2-bromo-4-fluoro-3-(hydroxymethyl)benzonitrile (C-XXIII-b) (7.06 g, 30.7 mmol) in DCM (100 mL) were added CBr ₄ (15.27 g, 46.0 mmol) and triphenylphosphine (12.07 g, 46.0 mmol). Stirring at 0 °C was continued for 30 min before the reaction mixture was quenched with sat. NaHCO ₃ solution and extracted with EtOAc. The combined organic layers were washed with sat. NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc; gradient 0% to 20% EtOAc) to give the title product (7.43 g) as a colorless foam. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.03 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 3.76-3.72 (m, 4H), 3.23-3.19 (m, 4H).

Step 4. 2-Bromo-3-(((2S,4S)-2-(tert-butyl)-5-oxo-4-phenyl-1,3-dioxolan-4-yl)methyl)-4-fluorobenzonitrile ( C-XXIII-d)

At -78 °C under Ar, to a stirred suspension of (2S,5S)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one (CAS 81036-97-7) (8.21 g, 37.3 mmol) in THF (200 mL) was added LDA (18.64 mL, 37.3 mmol, 2 M in THF). The reaction mixture was stirred at this temperature for 30 min before a solution of 2-bromo-3-(bromomethyl)-4-fluorobenzonitrile (C-XXIII-c) (8.4 g, 28.7 mmol) in THF (20 mL) was added. The reaction mixture was allowed to warm to 0 °C, quenched with saturated NaHCO ₃ solution and extracted with EtOAc. The combined organic layers were washed with saturated _NaHCO3 solution, dried over _{anhydrous Na2SO4} and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc; gradient 0% to 15% EtOAc) to give the title product (12.21 g) as a colorless foam. UPLC-MS 1: m/z 449.2/451.2 [M+ _NH4 ] ⁺ , t _R = 1.37 min.

Step 5. (S)-Ethyl-4-bromo-5-cyano-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (C-XXIII-e)

At 0 °C, to a stirred solution of 2-bromo-3-(((2S,4S)-2-(tert-butyl)-5-oxo-4-phenyl-1,3-dioxolan-4-yl)methyl)-4-fluorobenzonitrile (C-XXIII-d) (12.21 g, 28.2 mmol) in EtOH (100 mL) was added sodium ethoxide solution (10.54 mL, 28.2 mmol, 21 wt % in EtOH) and stirring was continued at 0 °C for 30 min. The reaction mixture was quenched by addition of saturated NaHCO ₃ solution and extracted with DCM. The combined organic layers were washed with saturated NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc; gradient 0% to 10% EtOAc) to give the title product (7.81 g) as a colorless oil. UPLC-MS 1: m/z 389.2/391.2 [M+NH ₄ ] ⁺ , t _R = 1.24 min.

Step 6. (S)-4-Bromo-2-(hydroxymethyl)-2-phenyl-2,3-dihydrobenzofuran-5-carbonitrile (C-XXIII-f)

At rt, to a stirred solution of (S)-ethyl 4-bromo-5-cyano-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (C-XXIII-e) (6.26 g, 16.8 mmol) in THF (100 mL) were added MeOH (2.72 mL, 67.3 mmol) and LiBH4 (1.465 g, 67.3 mmol). After 16 h, the reaction mixture was quenched with sat. _NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with sat. _NaHCO3 solution, dried over anhydrous _{Na2SO4 ,} and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc; gradient 0% to 60% EtOAc) to give the title product (4.20 g) as a colorless oil. UPLC-MS 1: m/z 347.1/349.2 [M+NH ₄ ] ⁺ , t _R = 1.04 min.

Step 7. (S)-2-(Hydroxymethyl)-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-5-carbonitrile (C-XXIII)

(S)-4-Bromo-2-(hydroxymethyl)-2-phenyl-2,3-dihydrobenzofuran-5-carbonitrile (C-XXIII-f) was converted to the title compound by analogy with step 15 of the synthesis of intermediate CI. UPLC-MS 1: m/z 422.3 [M+formate] ^- , t _R = 1.18 min.

Synthesis of (S)-4-bromo-2-((((trans)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-5-carbonitrile (C-XXIV):

The title compound was prepared from (S)-4-bromo-2-(hydroxymethyl)-2-phenyl-2,3-dihydrobenzofuran-5-carbonitrile (C-XXIII-f) via oxidation ((COCl) ₂ /TEA/DMSO, DCM) to the corresponding aldehyde followed by reductive amination with trans-4-aminocyclohexanol using NaBH(OAc) _3, UPLC-MS 1: m/z 427.2/429.2 [M+H] ⁺ , t _R = 0.71 min.

Synthesis of tert-butyl (S)-((4-bromo-5-chloro-2-phenyl-2,3-dihydrofuro[2,3-b]pyridin-2-yl)methyl)carbamate (C-XXV):

Reaction scheme XXV:

Step 1 . (4-Bromo-2-fluoropyridin-3-yl)methanol (C-XXV-a)

4-Bromo-2-chloronicotinaldehyde (5.05 g, 24.8 mmol) was dissolved in THF (50 mL) under Ar. The reaction mixture was cooled to 0 °C and NaBH ₄ (0.936 g, 24.76 mmol) was added. The reaction mixture was warmed to rt and stirred for 5 h. The reaction mixture was quenched with ice-cold water and extracted with EtOAc. The aqueous phase was separated and extracted with EtOAc. The combined organic fractions were washed with brine, dried over anhydrous MgSO ₄ , filtered and the filtrate was concentrated under reduced pressure to give the title compound (5.19 g). UPLC-MS 1: t _R = 0.52 min, no mass ion observed.

Step 2. 4-Bromo-3-(bromomethyl)-2-fluoropyridine (C-XXV-b)

(4-Bromo-2-fluoropyridin-3-yl)methanol (C-XXV-a) (3.91 g, 15.0 mmol) was dissolved in DCM (40 mL) under Ar. The reaction mixture was cooled to 0 °C and PPh ₃ (6.69 g, 25.5 mmol) and CBr ₄ (8.45 g, 25.5 mmol) were added. The resulting solution was warmed to rt and stirred for 2.5 h. The reaction mixture was concentrated under reduced pressure; the crude residue was purified by flash chromatography (silica, hexane/EtOAc; gradient from 0% to 40% EtOAc) to give the title compound (3.17 g). UPLC-MS 1: t _R = 1.01 min, no mass ion observed.

Step 3. (2S,5S)-5-((4-Bromo-2-fluoropyridin-3-yl)methyl)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one (C-XXV-c)

4-Bromo-3-(bromomethyl)-2-fluoropyridine (C-XXV-b) (2.32 g, 8.63 mmol) and (2S,5S)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one (CAS 81036-97-7) (2.470 g, 11.22 mmol) were dissolved in DMF (50 mL) under Ar and the reaction mixture was cooled to 0 °C. Then NaH (0.518 g, 12.94 mmol, 60% in mineral oil) was added and the reaction mixture was stirred for 2 h at 0 °C. The reaction mixture was partitioned between saturated NaHCO ₃ solution and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic fractions were washed with brine, dried over anhydrous _MgSO4 , filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient 0% to 20% EtOAc) to give the title compound (2.71 g). UPLC-MS 1: 408.3 [M+H] ⁺ , t _R = 1.37 min.

Step 4. Ethyl (S)-4-bromo-2-phenyl-2,3-dihydrofuro[2,3-b]pyridine-2-carboxylate (C-XXV-d)

(2S,5S)-5-((4-Bromo-2-fluoropyridin-3-yl)methyl)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one (C-XXV-c) (2.7 g, 6.61 mmol) was dissolved in EtOH (27 mL) under Ar and cooled to 0 °C. Then a solution of sodium ethoxide (0.450 g, 6.61 mmol) in EtOH (27 mL) was added and the reaction mixture was stirred for 1.5 h at 0 °C. The reaction mixture was quenched by adding 0.1 N HCl and then EtOH was removed in vacuo. The aqueous layer was separated and extracted with EtOAc, then washed with brine. The organic layers were combined, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give the title compound (2.26 g), which was used for subsequent hydrolysis without further purification. UPLC-MS 1: 348.2 [M+H]⁺, t_R=1.18 min.

Step 5. (S)-4-Bromo-2-phenyl-2,3-dihydrofuro[2,3-b]pyridine-2-carboxylic acid (C-XXV-e)

Ethyl (S)-4-bromo-2-phenyl-2,3-dihydrofuro[2,3-b]pyridine-2-carboxylate (C-XXV-d) (2.26 g, 6.5 mmol) was dissolved in THF (13.5 mL) and diluted with water (9.0 mL). The solution was cooled to 0 °C then LiOH.H ₂ O (0.207 g, 8.64 mmol) was added. The reaction mixture was allowed to warm to rt and stirred for 2 h before it was quenched with citric acid (10% in water and ethyl acetate). The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were extracted with water and washed with brine. The organic layers were combined, dried over _{anhydrous Na2SO4} , filtered and the filtrate was concentrated under reduced pressure to give the title compound (2.20 g). UPLC-MS 1: 320.1 [M+H] ⁺ , t _R = 0.80 min.

Step 6. (S)-4-Bromo-2-phenyl-2,3-dihydrofuro[2,3-b]pyridine-2-carboxamide (C-XXV-f)

(S)-4-Bromo-2-phenyl-2,3-dihydrofuro[2,3-b]pyridine-2-carboxylic acid (C-XXV-e) (2.2 g, 5.6 mmol) was dissolved in DCM (22 mL) and cooled to 0 °C. DMF (7.3 µL, 0.095 mmol) and oxalyl chloride (677 µL, 7.89 mmol) were added. The reaction mixture was allowed to warm to rt and stirred at rt for 1.5 h. The reaction mixture was cooled to 0 °C and ammonia solution (16.5 mL, 133 mmol, 32% in water) was added. Stirring at 0 °C was continued for 1.25 h. The reaction mixture was quenched with saturated NaHCO ₃ solution and DCM was added. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with water, brine, dried over _{anhydrous Na2SO4} , filtered and the filtrate was concentrated under reduced pressure to give the title compound (1.59 g). UPLC-MS 1: 319.1 [M+H] ⁺ , t _R = 0.89 min.

Step 7. (S)-4-Bromo-5-chloro-2-phenyl-2,3-dihydrofuro[2,3-b]pyridine-2-carboxamide (C-XXV-g)

(S)-4-Bromo-2-phenyl-2,3-dihydrofuro[2,3-b]pyridine-2-carboxamide (C-XXV-f) (1.59 g, 4.98 mmol) was dissolved in ACN (33 mL). N-chlorosuccinimide (0.998 g, 7.47 mmol) was added and the reaction mixture was heated to 50 °C and stirred for 26 h at 50 °C. The reaction mixture was concentrated under reduced pressure. The crude residue was purified using flash chromatography (silica, n-heptane/EtOAc, gradient from 0% to 40% EtOAc) to give the title compound (989 mg). UPLC-MS 1: 353.1 [M+H] ⁺ , t _R = 1.02 min.

Step 8. (S)-(4-Bromo-5-chloro-2-phenyl-2,3-dihydrofuro[2,3-b]pyridin-2-yl)methanamine (C-XXV-h)

(S)-4-Bromo-5-chloro-2-phenyl-2,3-dihydrofuro[2,3-b]pyridine-2-carboxamide (C-XXV-g) (989 mg, 2.8 mmol) was dissolved in THF (4.7 mL). Borane-tetrahydrofuran complex solution (15.6 mL, 15.60 mmol, 1 M in THF) was added and the reaction mixture was stirred at rt for 2.5 h. The reaction mixture was quenched with MeOH (1 mL). The mixture was stirred at rt for 20 min, then 2 N HCl was added and the solution was stirred for 30 min at rt. To the mixture was added sat. NaHCO ₃ solution and EtOAc. The organic phase was separated and the aqueous layer was extracted with EtOAc. The combined organic fractions were washed with brine, dried over _{anhydrous Na2SO4} and concentrated to give the title compound (727 mg). UPLC-MS 1: 339.0 [M+H] ⁺ , t _R = 0.72 min.

Step 9. tert-Butyl (S)-((4-bromo-5-chloro-2-phenyl-2,3-dihydrofuro[2,3-b]pyridin-2-yl)methyl)carbamate (C-XXV)

To a solution of (S)-(4-bromo-5-chloro-2-phenyl-2,3-dihydrofuro[2,3-b]pyridin-2-yl)methanamine (C-XXV-h) (727 mg, 1.4 mmol) in DCM (17 mL) at 0 °C was added Boc-anhydride (467 mg, 2.14 mmol). The reaction mixture was stirred at 0 °C for 2.5 h before it was concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc; gradient 0% to 50% EtOAc) to give the title compound (367 mg). UPLC-MS: 383.1 [M+H-tBu] ⁺ , t _R = 1.31 min.

Synthesis of 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 (C-XXVI):

Reaction scheme C-XXVI:

Step 1. 7-Bromo-6-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XXVI-a)

At rt, to a stirred solution of 3-bromo-4-chloro-2-hydroxybenzaldehyde (3.00 g, 12.74 mmol) and 2-bromo-2-phenylacetonitrile (3.00 g, 15.3 mmol) in DCM (42 mL) was added DIPEA (3.34 mL, 19.1 mmol) and the reaction mixture was stirred at rt for 5 days to give a brown solution. The reaction mixture was filtered over Hyflo and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 10% to 30% EtOAc) to give the desired product (2.57 g) as a diastereomeric mixture. UPLC-MS 1: mass/charge 348.1/350.1 [MH] ^- . t _R =1.14 min.

Step 2. 2-(Aminomethyl)-7-bromo-6-chloro-2-phenyl-2,3-dihydrobenzofuran-3-ol (C-XXVI-b)

To a stirred solution of 7-bromo-6-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XXVI-a) (2.72 g, 7.76 mmol) in THF (30 mL) at rt was added borane methyl sulfide complex (19.40 mL, 38.8 mmol, 2 M in THF) and the reaction mixture was stirred at 65 °C for 2 h. After cooling to 0 °C, the reaction mixture was quenched by careful addition of 1 N NaOH (30 mL). The reaction mixture was concentrated and redissolved in EtOAc. The organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give the title compound as a diastereomeric mixture (2.9 g). UPLC-MS 1: m/z 354.1/356.1 [M+H] ⁺ . t _R =0.63 and 0.74 min.

Step 3. (7-Bromo-6-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine (C-XXVI-c)

At rt, to a solution of 2-(aminomethyl)-7-bromo-6-chloro-2-phenyl-2,3-dihydrobenzofuran-3-ol (C-XXVI-b) (2.9 g, 6.13 mmol) in DCM (50 mL) was added tripropylsilane (19.25 mL, 92 mmol), followed by boron trifluoride diethyl etherate (2.33 mL, 18.40 mmol) and TFA (1.14 mL, 18.40 mmol). The reaction solution was stirred at 50 °C for 4 h before it was quenched by adding saturated NaHCO ₃ solution at rt. The aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated to give the title compound (2.08 g). UPLC-MS 1: m/z 338.1/340.0 [M+H] ⁺ , t _R = 0.78 min.

Step 4. tert-Butyl ((7-bromo-6-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XXVI-d)

At rt, to a stirred solution of (7-bromo-6-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine (C-XXVI-c) (2.08 g, 6.13 mmol) in DCM (30 mL) were added Boc-anhydride (2.00 g, 9.20 mmol) and TEA (1.71 mL, 12.26 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was treated with saturated NaHCO ₃ solution. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 10% to 60% EtOAc) to give the title compound (1.30 g). UPLC-MS 1: m/z 438.2/440.0 [M+H] ⁺ . t _R = 1.43 min.

Step 5. 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 (C-XXVI)

At 80 °C, the adduct PdCl ₂ (dppf).CH ₂ Cl ₂ (146 g, 0.18 mmol) was added under Ar to a stirred suspension of tert-butyl ((7-bromo-6-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (C-XXVI-d) (1.29 g, 1.79 mmol), bis(pinacolato)diboron (683 mg, 2.7 mmol) and potassium acetate (528 mg, 5.4 mmol) in toluene (4 mL) and the reaction mixture was vigorously stirred at 110 °C for 16 h. The reaction mixture was cooled to rt, filtered through celite and concentrated to give the crude product, which was purified by flash chromatography (silica, eluent cyclohexane/EtOAc, gradient: 0% to 20% EtOAc) to give the title compound (480 mg). UPLC MS 1: m/z 486.3 [M+H] ⁺ . t _R = 1.49 min.

Synthesis of tert-butyl ((4-bromo-5-chloro-2-phenylbenzo[d][1,3]dioxol-2-yl)methyl)carbamate (C-XXVII):

Reaction scheme XXVII:

Step 1. Methyl 2-(4-bromo-2-phenylbenzo[d][1,3]dioxol-2-yl)acetate (C-XXVII-a)

To a stirred solution of 3-bromobenzene-1,2-diol (80.47 g, 425.7 mmol) and methyl 3-phenylpropiolate (75 g, 468.3 mmol) in toluene (600 mL) was added dodecacarbonyl triruthenium (13.61 g, 21.3 mmol) under N ₂ . The reaction mixture was heated to 130 °C and stirred for 5 h. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (silica, petroleum ether/EtOAc; gradient 0% to 30% EtOAc) to give the title compound (96.0 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65-7.63 (m, 2H), 7.42-7.40 (m, 3H), 6.95 (dd, J= 8.3, 1.0 Hz, 1H), 6.81-6.79 (m, 1H), 6.73-6.71 (m, 1H), 3.60 (s, 3H), 3.35 (s, 2H), 3.35 (s, 2H).

Step 2. Methyl 2-(4-bromo-5-chloro-2-phenylbenzo[d][1,3]dioxol-2-yl)acetate (C-XXVII-b)

To a stirred solution of methyl 2-(4-bromo-2-phenylbenzo[d][1,3]dioxol-2-yl)acetate (C-XXVII-a) (85 g, 0.24 mol) in ACN (1.3 L) were added N-chlorosuccinimide (38.99 g, 0.292 mol) and TFA (24.7 mL, 0.32 mol). The solution was heated to 60 °C and stirred for 18 h. The reaction mixture was diluted with TBME (500 mL). The organic fraction was washed twice with saturated NaHCO ₃ solution (300 mL). The residue was purified by flash chromatography (silica, PE/EtOAc; gradient 0% to 10% EtOAc) to give the title product (67.0 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.62-7.60 (m, 2H), 7.44-7.41 (m, 3H), 6.94 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 3.62 (s, 3H), 3.35 (s, 3H).

Step 3. 2-(4-Bromo-5-chloro-2-phenylbenzo[d][1,3]dioxol-2-yl)ethan-1-ol (C-XXVII-c)

To a stirred solution of methyl 2-(4-bromo-5-chloro-2-phenylbenzo[d][1,3]dioxol-2-yl)acetate (C-XXVII-b) (1.0 g, 2.61 mmol) added LiBH₄(1.30 mL, 2.61 mmol, 2 M in THF) was added via an addition funnel under Ar at 0 °C. The reaction mixture was warmed to rt and stirred for 4 days at rt. The reaction solution was cooled to 4 °C and then quenched by adding 10% aqueous citric acid solution (500 mL). The mixture was stirred for 5 min, then TBME (600 mL) was added. The aqueous phase was separated and extracted with TBME. The combined organic fractions were washed with brine, dried over anhydrous MgSO₄and then concentrated under reduced pressure to give a colorless oil. The residue was purified by flash chromatography (silica, heptane/EtOAc; gradient 0-10% EtOAc) to give the title compound (610 mg).¹H NMR (600 MHz, DMSO-d₆) δ ppm 7.57-7.51 (m, 2H), 7.49-7.37 (m, 3H), 7.08 (d, J=8.4 Hz, 1H), 6.98 (d, 8.4 Hz), 4.63 (s, 1H), 3.48 (dd, J=7.8, 6.9 Hz, 2H), 2.52 (dd, J=7.8, 6.8Hz, 2H).

Step 4. 2-(4-Bromo-5-chloro-2-phenylbenzo[d][1,3]dioxol-2-yl)acetic acid (C-XXVII-d)

2-(4-Bromo-5-chloro-2-phenylbenzo[d][1,3)]dioxol-2-yl)ethanol (C-XXVII-c) (5.0 g, 14.1 mmol) was dissolved in DCM (150 mL). Water (75 mL) was added and the reaction mixture was cooled to 0 °C. TEMPO (550 mg, 3.52 mmol) was added followed by (diacetoxyiodo)benzene (10.20 g, 31.7 mmol). The resulting pale brown emulsion was stirred for 1 h at 0 °C. The cooling bath was removed and the mixture was stirred at rt for 4 h. The reaction mixture was diluted with MeOH (3 mL) and stirred for 10 min. The reaction mixture was partitioned between water and DCM. The aqueous phase was extracted with DCM, dried over anhydrous _MgSO4 and evaporated to dryness. Petroleum benzene (50 mL) was added to the residue and the mixture was stirred at rt for 2 h, then stirred overnight at rt. The suspension was filtered and the resulting solid was dried at 50 °C, 0.1 mbar for 1 h to give 1.56 g of the title compound. A second crop was prepared from the original solution to give an additional 1.44 g of the title compound. UPLC-MS m/z 369.1 [M+H] ⁺ .

Step 5. 2-(4-Bromo-5-chloro-2-phenylbenzo[d][1,3]dioxol-2-yl)acetyl chloride (C-XXVII-e)

2-(4-Bromo-5-chloro-2-phenylbenzo[d][1,3]dioxol-2-yl)acetic acid (C-XXVII-d) (1.40 g, 3.8 mmol) was dissolved in DCM (30 mL) and DMF (3 mL). The resulting pale yellow solution was cooled to 0 °C. At this temperature, a solution of oxalyl dichloride (8.3 mL, 8.3 mmol, 1 M in DCM) was added over 15 min. The ice bath was removed and the solution was stirred at rt for 6 h. The reaction mixture was concentrated under reduced pressure to give the title product as a yellow gum (1.60 g). The acid chloride was used without further purification.

Step 6. 2-(4-Bromo-5-chloro-2-phenylbenzo[d][1,3]dioxol-2-yl)acetyl azide (C-XXVII-f)

Crude 2-(4-bromo-5-chloro-2-phenylbenzo[d][1,3]dioxol-2-yl)acetyl chloride (C-XXVII-e) (1.60 g, 4.1 mmol) was dissolved in acetone (40 mL). The resulting pale yellow solution was cooled to 0 °C and then added dropwise via an addition funnel to a stirred solution of sodium azide (20 mL, 20 mmol, 1 M in water). The cooling bath was removed and the reaction mixture was stirred at rt for 2 h. The reaction solution was concentrated under reduced pressure to give an orange residue. The residue (slurry) was diluted with EtOAc (100 mL) and water (50 mL). The aqueous phase was separated and extracted with EtOAc. The combined organic phases were washed with water and brine, then dried over anhydrous _MgSO4 and concentrated under reduced pressure to give the title compound (590 mg). Used without further purification. UPLC-MS m/z 394.1 [M+H] ⁺ .

Step 7. tert-Butyl ((4-bromo-5-chloro-2-phenylbenzo[d][1,3]dioxol-2-yl)methyl)carbamate (C-XXVII)

2-(4-Bromo-5-chloro-2-phenylbenzo[d][1,3]dioxol-2-yl)acetyl azide (C-XXVII-f) (590 mg, 1.5 mmol) was dissolved in t -BuOH (30 mL). The reaction mixture was heated to 100 °C and stirred at this temperature for 2 h. The solution was evaporated to dryness. The residue was purified by flash chromatography (silica, heptane/EtOAc; gradient from 0% to 30% EtOAc) to give the title product (474 mg). ^1H NMR (400 MHz, DMSO - _d6 ) δ ppm 7.55 (h, J =3.4, 2.9 Hz, 2H), 7.50-7.45 (m, 3H), 7.33 (t, J =6.4 Hz, 1H), 7.09 (d, J =8.4 Hz, 1H), 6.96 (d, J =8.3 Hz, 1H), 3.72 (q, J =8.7, 7.8 Hz, 2H), 1.31 (s, 9H).

Synthesis of (S)-2-(azidomethyl)-4-bromo-5-chloro-6-fluoro-2-phenylindoline (C-XXVIII):

Reaction scheme C-XXVIII:

Step 1. 2-Bromo-4,6-difluorobenzaldehyde (C-XXVIII-a)

To a stirred solution of 2-bromo-4,6-difluoroiodobenzene (638 g, 2.0 mol) in Me-THF (5 L) cooled at -10 °C under Ar was added dropwise isopropylmagnesium chloride complex LiCl (2000 mL, 2.6 mol, 1.3 M in THF). The reaction mixture was stirred for 30 min at -5 °C. Then 4-formylmorpholine (7.98 mL, 79 mmol) was added at -5 °C. Stirring at this temperature was continued for 1 h before the reaction mixture was quenched with 2 N HCl (1.5 L). The product was extracted with DCM (3 x 2 L). The organic layers were combined and washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 10% EtOAc) to give the title compound (265 g). UPLC-MS 1: t _R = 0.94 min.

Step 2. (2-Bromo-4,6-difluorophenyl)methanol (C-XXVIII-b)

At 0 °C, to a stirred solution of 2-bromo-4,6-difluorobenzaldehyde (C-XXVIII-a) (420 g, 1.90 mol) in MeOH (3.2 L) was added NaBH ₄ (36.1 g, 0.95 mol) portionwise. The reaction mixture was stirred at 0 °C for 1 h, then quenched with sat. NH ₄ Cl (1 L). The product was extracted with EtOAc (3 x 300 mL), dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 50% EtOAc) to give the title compound (311 g). UPLC-MS 1, t _R = 0.80 min.

Step 3. 1-Bromo-2-(bromomethyl)-3,5-difluorobenzene (C-XXVIII-c)

At 0 °C, to a stirred solution of (2-bromo-4,6-difluorophenyl)methanol (C-XXVIII-b) (105 g, 471 mmol) in DCM (800 mL) was added PPh ₃ (161 g, 612 mmol) followed by NBS (109 g, 612 mmol). The reaction mixture was stirred at 0 °C for 1 h. After concentration, the crude material was purified by flash chromatography (silica, hexane 100%) to give the title compound (95 g). UPLC-MS 1: t _R = 1.22 min. ^1H NMR (400 MHz, DMSO -d6 ) δ ppm 7.58 (td, J=8.2, 2.4 Hz, 1H) _, 7.47-7.41 (m, 1H), 4.65 (s, 2H).

Stage 4. Methyl 2-amino-3-(2-bromo-4,6-difluorophenyl)-2-phenylpropanoate (C-XXVIII-d)

To a stirred solution of methyl (E)-2-(benzylideneamino)-2-phenylacetate CAS [153924-62-0] (55 g, 217 mmol) in THF (500 mL) cooled at -5 °C was added KOtBu (261 mL, 261 mmol, 1 M in THF) dropwise over 30 min. The reaction mixture was stirred at rt for 1 h, then cooled to 0 °C and a solution of 1-bromo-2-(bromomethyl)-3,5-difluorobenzene (C-XXVIII-c) (68 g, 239 mmol) in THF (90 mL) was added. The reaction mixture was stirred for 30 min, then quenched with 1 N HCl. The mixture was stirred for 1 h and extracted with heptane (3 x 500 mL). The aqueous layer was adjusted to _pH ~8-9 and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine, dried over anhydrous _Na2SO4 and concentrated to give the racemic title compound (35 g), which was used in the next step without further purification. UPLC-MS 1: m/z 370.2/372.2 [M+H] ⁺ , t _R = 1.07 min.

Step 5. Methyl 4-bromo-6-fluoro-2-phenylindoline-2-carboxylate (C-XXVIII-e)

To a solution of methyl 2-amino-3-(2-bromo-4,6-difluorophenyl)-2-phenylpropanoate (C-XXVIII-d) (75 g, 203 mmol) in THF (1.5 L) cooled at 0 °C was added under Ar a solution of LDA (200 mL, 400 mmol, 2 M in THF). The reaction mixture was stirred for 30 min at 0 °C before it was quenched with 10% citric acid solution. The mixture was extracted with TBME (3 x 1 L). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give the racemic title compound (41 g), which was used in the next step without further purification. UPLC-MS 1: mass/charge 350.2/352.2 [M+H] ⁺ , t _R =1.31 min.

Step 6. Methyl 4-bromo-5-chloro-6-fluoro-2-phenylindoline-2-carboxylate (C-XXVIII-f)

To a solution of methyl 4-bromo-6-fluoro-2-phenylindoline-2-carboxylate (C-XXVIII-e) (35.0 g, 100 mmol) in THF (350 mL) cooled at 0 °C were added sequentially N-chlorosuccinimide (14.6 g, 110 mmol) and p-TsOH monohydrate (20.9 g, 110 mmol). The reaction mixture was stirred at 0 °C for 1 h before it was quenched with 10% Na ₂ S ₂ O ₃ solution (100 mL). The product was extracted with TBME (3 x 500 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient: 0% to 5% EtOAc) to give the title racemic product (23 g). UPLC-MS 1: m/z 384.1/386.1 [M+H] ⁺ , t _R = 1.37 min.

Step 7. (4-Bromo-5-chloro-6-fluoro-2-phenylindolin-2-yl)methanol (C-XXVIII-g)

To a solution of methyl 4-bromo-5-chloro-6-fluoro-2-phenylindoline-2-carboxylate (C-XXVIII-f) (10 g, 26 mmol) in THF (200 mL) cooled at 0 °C was added dropwise a solution of LiBH ₄ (13 mL, 26 mmol, 2 M in THF). The reaction mixture was stirred at 0 °C for 1 h, then at rt for 6 h. The mixture was cooled to 0 °C and quenched with 10% citric acid solution (500 mL), then extracted with TBME (2 x 1 L). The combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous Na ₂ SO ₄ and concentrated. The product was crystallized in a mixture of TBME (100 mL) and heptane (200 mL). The suspension was filtered, washed with heptane (50 mL), then dried in HV at 50°C to give the racemic title compound (8.3 g). UPLC-MS 1: m/z 356.1/358.1 [M+H] ⁺ , t _R = 1.21 min.

Step 8. 5-Bromo-6-chloro-7-fluoro-3a-phenyl-3a,4-dihydro-3H-[1,2,3]oxathiazolo[3,4-a]indole-1,1-dioxide (C-XXVIII-h)

To a solution of imidazole (19 g, 278 mmol) in THF (150 mL) cooled at -78 °C was added a solution of thionyl chloride (5.1 mL, 69.6 mmol) in THF (65 mL) over 20 min (a fairly exothermic reaction, the temperature was maintained between -60 °C and -40 °C). The suspension was stirred for 20 min at -78 °C. Then a solution of (4-bromo-5-chloro-6-fluoro-2-phenylindolin-2-yl)methanol (C-XXVIII-g) (8.3 g, 23.2 mmol) in THF (60 mL) was added over 5 min at -78 °C and the resulting suspension was stirred at 0 °C for 2 h. The mixture was diluted with EtOAc (500 mL), quenched with a solution of 2 N HCl (2 N HCl). citric acid (400 mL) and washed with brine (2×300 mL). The aqueous layers were back extracted with _EtOAc (500 mL). The combined organic layers were dried over anhydrous _Na2SO4 and concentrated to give the intermediate N-sulfoxide ketimine UPLC-MS 1: m/z 402.1/404.1 [M+H] ⁺ , t _R = 1.34 min.

The resulting crude material was quickly suspended in ACN (150 mL). To the mixture cooled at 0 °C were added sequentially ruthenium(III) chloride (0.270 g, 1.287 mmol) and sodium periodate (7.9 g, 36.8 mmol) followed by dropwise addition of water (105 mL) over 3 min. The reaction mixture was then stirred at 0 °C for 30 min and at rt for 1 h. Water (300 mL) was added and the mixture was extracted with EtOAc (2 x 600 mL). The organic layers were washed with water (300 mL) and brine (300 mL), then combined, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, 9:1) to give the title compound (3.7 g). UPLC-MS 1: m/z 462.2/464.2 [M+formate] ^- , t _R = 1.32 min.

Steps 9 and 10. (S)-2-(Azidomethyl)-4-bromo-5-chloro-6-fluoro-2-phenylindoline (C-XXVIII) and (R)-2-(azidomethyl)-4-bromo-5-chloro-6-fluoro-2-phenylindoline (C-XXVIII-j)

Sodium azide (0.6 g, 9.2 mmol) was added at rt to a solution of 5-bromo-6-chloro-7-fluoro-3a-phenyl-3a,4-dihydro-3H-[1,2,3]oxathiazolo[3,4-a]indole 1,1-dioxide (C-XXVIII-h) (3.7 g, 8.8 mmol) in DMF (100 mL). The reaction mixture was stirred at rt for 18 h, then quenched with sulfuric acid (49.5 mL, 4.95 mmol) at rt and stirred for an additional 1.5 h at rt. Water (500 mL) was added and the mixture was extracted with EtOAc (2×1 L). The organic layers were washed with brine (500 mL), combined, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, heptane/ _EtOAc 95:5) to afford the racemic product. Both enantiomers were separated by chiral SFC (Lux Amylose-1, 250 × 30 mm, 50 μm, CO ₂ / (MeOH + 0.1% NH ₃ ) 1:1, 40 °C, flow rate: 80 ml/min, 3 ml/injection, cycle time 11 min) to afford (S)-2-(azidomethyl)-4-bromo-5-chloro-6-fluoro-2-phenylindoline (C-XXVIII) (1.3 g) and (R)-2-(azidomethyl)-4-bromo-5-chloro-6-fluoro-2-phenylindoline (C-XXVIII-j) (1.3 g) with an enantiomeric excess of 99%, respectively.

(S)-2-(Azidomethyl)-4-bromo-5-chloro-6-fluoro-2-phenylindoline (C-XXVIII):

Chiral SFC: Chiralpak AD 100×4.6 mm, 5 μm, _CO2 /(MeOH+0.1% _NH3 ) 1:1, flow rate 3 mL/min.), t _R : 2.76 min, UPLC-MS 1: m/z 381.0/383.0 [M+H] ⁺ , t _R =1.42 min.

The other enantiomer, (R)-2-(azidomethyl)-4-bromo-5-chloro-6-fluoro-2-phenylindoline (C-XXVIII-j):

Chiral SFC: Chiralpak AD 100×4.6 mm, 5 μm, CO ₂ / (MeOH+0.1% NH ₃ ) 1:1, flow rate 3 mL/min), t _R : 1.12 min. UPLC-MS 1: m/z 381.0/383.0 [M+H] ⁺ , t _R =1.42 min.

Synthesis of tert-butyl-(((2S,3S)-5-chloro-6-fluoro-3-methyl-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (C-XXIX):

Reaction scheme C-XXIX:

Step 1. (2S,3S)-4-Bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carbaldehyde (C-XXIX-a)

To a stirred solution of oxalyl chloride (3.01 mL, 34.4 mmol) in DCM (60 mL) was added DMSO (4.9 mL, 68.9 mmol) in DCM (10 mL) at -78 °C and the reaction mixture was stirred at -78 °C for 15 min. A solution of ((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XVII-h) (8 g, 21.5 mmol) in DCM (30 mL) was then added and stirring at -78 °C was continued for 15 min. TEA (15.0 mL, 108 mmol) was added and the reaction mixture was allowed to warm to 0 °C over 30 min. The mixture was diluted in DCM and water, extracted twice with DCM and the combined organic extracts were washed with water and brine, dried over _{anhydrous Na2SO4} and concentrated to give the title compound (8.6 g) as a yellow foam, which was used without purification. UPLC-MS 1: m/z 367.0/368.8 [MH] ^- , t _R = 1.39 min.

Step 2. 1-((2S,3S)-4-Bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)-N-methylmethanamine (C-XXIX-b)

A solution of (2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carbaldehyde (C-XXIX-a) (8.6 g, 20.9 mmol) and methylamine hydrochloride (14.14 g, 209 mmol) (which was finely ground and dried for 1 h under HV) in DCM (100 mL) was stirred at rt for 14 h. Sodium triacetoxyborohydride (8.88 g, 41.9 mmol) was added and the reaction mixture was stirred at rt for 4 h before it was diluted with saturated _NaHCO3 and extracted with DCM. The combined organic extracts were washed with brine, dried over _{anhydrous Na2SO4} and concentrated. The crude product was purified by flash chromatography (silica, (7N ammonia in MeOH)/DCM, gradient 0% to 4% (7N ammonia in MeOH)) to give the title compound (5.27 g) as a yellow oil. UPLC-MS 1: m/z 383.7/385.7 [M+H] ⁺ , t _R = 0.87 min.

Step 3. tert-Butyl (((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (C-XXIX-c)

To a stirred solution of 1-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)-N-methylmethanamine (C-XXIX-b) (5.27 g, 13.29 mmol) and TEA (3.70 mL, 26.6 mmol) in DCM (50 mL) was added BOC anhydride (4.01 mL, 17.3 mmol) at rt and stirring was continued for 14 h. The reaction mixture was diluted in DCM and water, 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 flash chromatography (silica, EtOAc/Hep, gradient 0% to 30% EtOAc) to give the title compound (6.55 g) as a white foam. UPLC-MS 1: m/z 484.4/486.4 [M+H] ⁺ , t _R = 1.57 min.

Step 4. 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 (C-XXIX)

To a stirred solution of tert-butyl (((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (C-XXIX-c) (6.55 g, 13.1 mmol), bis(pinacolato)diboron (4.99 g, 19.7 mmol) and potassium hydroxide (1.838 g, 32.8 mmol) in toluene (60 mL) was added PdCl ₂ (dppf).CH ₂ Cl ₂ adduct (1.07 g, 1.31 mmol) at 60 °C and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered over Hyflo and concentrated. The crude product was purified by flash chromatography (silica, EtOAc/heptane, gradient 0% to 30% EtOAc) to give the title compound (6.1 g). ¹ H NMR (400 MHz, DMSO-d6) δ 7.53-7.02 (m, 6H), 4.61-3.43 (m, 3H), 2.69 (s, 3H), 1.38-1.10 (m, 24H). UPLC-MS 1: m/z 532.5 [M+H] ⁺ , t _R = 1.58 min.

Synthesis of 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 (C-XXX)

Reaction scheme C-XXX:

Step 1. 3-Bromo-4-chloro-5-fluoro-2-vinylphenol (C-XXX-a)

To a stirred suspension of methyltriphenylphosphonium bromide (67.7 g, 189 mmol) in THF (800 mL) was added potassium tert-butoxide (21.25 g, 189 mmol) at rt over 15 min and the reaction mixture was stirred at rt for 1 h. The mixture was cooled to -78 °C and a solution of 2-bromo-3-chloro-4-fluoro-6-hydroxybenzaldehyde (C-XII-e) (24 g, 95 mmol) in THF (200 mL) was added dropwise. The reaction mixture was allowed to warm slowly to 0 °C over 5 h and quenched with 400 mL of 1 N HCl. The crude mixture was diluted in water and extracted with EtOAc. The organic extract was washed with brine, dried over _{anhydrous Na2SO4} and concentrated. The crude product was purified by flash chromatography (silica, DCM/heptane, gradient 10% to 40% DCM) to give the title compound (15.85 g) as a colorless solid. UPLC-MS 1: m/z 249.0/251.0 [MH] ^- , t _R = 1.10 min.

Step 2. 2-(3-Bromo-4-chloro-5-fluoro-2-vinylphenoxy)-2-phenylacetic acid (X-XXX-b)

At 0 °C, to a stirred solution of 3-bromo-4-chloro-5-fluoro-2-vinylphenol (C-XXX-a) (15.83 g, 61.1 mmol) in THF (400 mL) was added sodium hydride (5.37 g, 134 mmol) portionwise, followed by the dropwise addition of a solution of 2-bromo-2-phenylacetic acid (14.44 g, 67.2 mmol) in THF (200 mL). The reaction mixture was stirred at 75 °C for 1 h before it was quenched with 1 N HCl. The crude mixture was diluted in water and extracted with EtOAc. _The organic extract was dried over anhydrous _Na2SO4 and concentrated to give the title compound (27 g) as a colorless solid. UPLC-MS 1: mass/charge 382.9/384.9 [MH] ^- , t _R =1.21 min.

Step 3. 7-Bromo-6-chloro-5-fluoro-2a-phenyl-2a,7b-dihydrocyclobuta[b]benzofuran-2(1H)-one (C-XXX-c)

To a stirred solution of tosyl chloride (22.69 g, 119 mmol) and TEA (41.5 mL, 298 mmol) in toluene (300 mL) was added a solution of 2-(3-bromo-4-chloro-5-fluoro-2-vinylphenoxy)-2-phenylacetic acid (C-XXX-b) (27 g, 59.5 mmol) in toluene (300 mL) at 100 °C and the reaction mixture was stirred at 100 °C for 1.5 h. The crude mixture was diluted in water and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, EtOAc/heptane, gradient 0% to 20% EtOAc) to afford, after trituration with heptane, the title compound (18.59 g) as a colorless solid. UPLC-MS 1: m/z 365.2/367.2 [MH] ^- , t _R = 1.36 min.

Step 4. ((7-Bromo-6-chloro-5-fluoro-2a-phenyl-2a,7b-dihydrocyclobuta[b]benzofuran-2-yl)oxy)triethylsilane (C-XXX-d)

To a stirred solution of 7-bromo-6-chloro-5-fluoro-2a-phenyl-2a,7b-dihydrocyclobuta[b]benzofuran-2(1H)-one (C-XXX-c) (18.59 g, 47.0 mmol) in DCM (300 mL) was added 2,6-lutidine (54.8 mL, 470 mmol) followed by _TfOSiEt3 (53.2 mL, 235 mmol) at rt and stirring of the reaction mixture was continued for 18 h at rt. Saturated _NaHCO3 solution was added and the mixture was extracted with DCM. The combined organic extracts were washed with water and brine, dried over _{anhydrous Na2SO4} and concentrated to give a brown oil. ¹ H NMR (400 MHz, CDCl3) δ 7.63-7.51 (m, 2H), 7.49-7.33 (m, 3H), 6.75 (d, J=9.2 Hz, 1H), 5.42 (s, 1H), 3.83 (s, 1H), 1.04-0.86 (m, 9H), 0.74-0.61 (m, 6H). UPLC-MS 1: non-ionizable product, t _R =1.79 min.

Step 5. 8-Bromo-7-chloro-6-fluoro-3a-phenyl-3a,8b-dihydrofuro[3,4-b]benzofuran-3(1H)-one (C-XXX-e)

At -78°CO ₃ was bubbled through a stirred solution of ((7-bromo-6-chloro-5-fluoro-2a-phenyl-2a,7b-dihydrocyclobuta[b]benzofuran-2-yl)oxy)triethylsilane (C-XXX-d) (38.9 g, 48.4 mmol) in DCM (450 mL) and MeOH (100 mL) until blue color appeared (45 min). After 10 min at -78°CO ₂ was bubbled through RM for 10 min, then through argon for 10 min (RM turned yellow again). Sodium borohydride (18.32 g, 484 mmol) was added portionwise and the reaction mixture was brought to rt. The crude mixture was diluted with brine and extracted with DCM. _The organic extract was dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, DCM/EtOAc, gradient 0% to 30% EtOAc) to give the title compound (17.09 g) as a colorless solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.65-7.58 (m, 2H), 7.56-7.46 (m, 3H), 7.42 (d, J=9.3 Hz, 1H), 5.07 (dd, J=9.8, 7.2 Hz, 1H), 4.84 (dd, J=9.8, 2.1 Hz, 1H), 4.76 (dt, J=7.2, 1.9 Hz, 1H). UPLC-MS 1: mass/charge 400.1/402.1 [M+H ₂ O] ⁺ , t _R =1.27 min.

Step 6. (3aS,8bR)-8-Bromo-7-chloro-6-fluoro-3a-phenyl-3a,8b-dihydrofuro[3,4-b]benzofuran-3(1H)-one (C-XXX- f) and (3aR,8bS)-8-bromo-7-chloro-6-fluoro-3a-phenyl-3a,8b-dihydrofuro[3,4-b]benzofuran-3(1H)-one (C-XXX-g)

The racemate of 8-bromo-7-chloro-6-fluoro-3a-phenyl-3a,8b-dihydrofuro[3,4-b]benzofuran-3(1H)-one (C-XXX-e) (22.65 g, 59.0 mmol) dissolved in DCM/MeOH (900 mL) was subjected to chiral SFC (ChiralPak IG, 250 × 30 mm i.d., 10 μm, CO2/(IPA+0.1% NH4OH) 6:4, 38 °C, flow rate: 200 mL/min, 5 mL per injection, cycle time 3.2 min) to afford (3aS,8bR)-8-bromo-7-chloro-6-fluoro-3a-phenyl-3a,8b-dihydrofuro[3,4-b]benzofuran-3(1H)-one (C-XXX-f) (9.77 g) and (3aR,8bS)-8-bromo-7-chloro-6-fluoro-3a-phenyl-3a,8b-dihydrofuro[3,4-b]benzofuran-3(1H)-one (C-XXX-g) (9.04 g) as pure enantiomers with an enantiomeric excess of >99%, respectively.

(3aS,8bR)-8-Bromo-7-chloro-6-fluoro-3a-phenyl-3a,8b-dihydrofuro[3,4-b]benzofuran-3(1H)-one (C-XXX-f): Chiral SFC: (Chiralpak IG 100×4.6 mm i.d., 3 μm, _CO2 /(IPA+0.05% DEA) 95/5 to 60/40, 35°C, flow rate: 2.5 ml/min), t _R = 4.03 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.65-7.58 (m, 2H), 7.56-7.45 (m, 3H), 7.42 (d, J=9.3 Hz, 1H), 5.07 (dd, J=9.8, 7.2 Hz, 1H), 4.84 (dd, J=9.9, 2.1 Hz, 1H), 4.80-4.71 (m, 1H). UPLC-MS 1: non-ionizable product, t _R =1.29 min.

(3aR,8bS)-8-Bromo-7-chloro-6-fluoro-3a-phenyl-3a,8b-dihydrofuro[3,4-b]benzofuran-3(1H)-one (C-XXX-g): Chiral SFC: (Chiralpak IG 100×4.6 mm i.d., 3 μm, _CO2 /(IPA+0.05% DEA) 95/5 to 60/40, 35°C, flow rate: 2.5 ml/min), t _R = 4.59 min. ¹ H NMR (400 MHz, DMSO-d6) δ 7.64-7.58 (m, 2H), 7.55-7.45 (m, 3H), 7.42 (d, J=9.3 Hz, 1H), 5.07 (dd, J=9.8, 7.2 Hz, 1H), 4.84 (dd, J=9.8, 2.1 Hz, 1H), 4.81-4.71 (m, 1H). UPLC-MS 1: product non ionisable, t _R =1.29 min.

Step 7. ((2S,3R)-4-Bromo-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-3-yl)methanol (C-XXX-h)

A solution of (3aS,8bR)-8-bromo-7-chloro-6-fluoro-3a-phenyl-3a,8b-dihydrofuro[3,4-b]benzofuran-3(1H)-one (C-XXX-f) (5 g, 12.4 mmol) in methylamine (100 mL, 200 mmol, 2 N in THF) was stirred at rt for 10 min, then at reflux for 10 min. After cooling, _BH3.DMS (31.0 mL, 61.9 mmol, 2 N in THF) was added and the reaction mixture was stirred at reflux for 2 h. More _BH3.DMS (5 mL, 10.00 mmol, 2 N in THF) was added and stirring at reflux was continued for 15 min. The reaction mixture was quenched by addition of MeOH. The crude mixture was concentrated. The crude residue was diluted in DCM and water and extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, DCM/(7N _ammonia in MeOH), gradient 0% to 13% (7N ammonia in MeOH)) to give the title compound (5.2 g) as a colorless foam. UPLC-MS 1: m/z 400.4/402.4 [M+H] ⁺ , t _R = 0.81 min.

Step 8. tert-Butyl (((2S,3R)-4-bromo-5-chloro-6-fluoro-3-(hydroxymethyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (C-XXX-i)

To a stirred solution of ((2S,3R)-4-bromo-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-3-yl)methanol (C-XXX-h) (1.8 g, 4.49 mmol) in DCM (20 mL) was added TEA (1.88 mL, 13.5 mmol) followed by Boc-anhydride (1.25 mL, 5.4 mmol) at rt and the reaction mixture was stirred at rt for 16 h. The crude mixture was diluted in water and extracted with DCM. _The combined organic extracts were washed with water and brine, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, EtOAc/heptane, gradient 0% to 50% EtOAc) to give the title compound (1.86 g) as a colourless foam. UPLC-MS 1: m/z 500.4/502.4 [M+1] ⁺ , t _R = 1.36 min.

Step 9. tert-Butyl (((2S,3R)-4-bromo-5-chloro-6-fluoro-3-(methoxymethyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (C-XXX-j)

To a stirred solution of tert-butyl (((2S,3R)-4-bromo-5-chloro-6-fluoro-3-(hydroxymethyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (C-XXX-i) (1.85 g, 3.69 mmol) in DMF (20 mL) was added sodium hydride (0.222 g, 5.54 mmol) at 0 °C and the reaction mixture was stirred at 0 °C for 15 min. Iodomethane (0.254 mL, 4.06 mmol) was added and the reaction mixture was stirred at rt for 30 min. The crude mixture was quenched with water, then diluted in EtOAc and water and extracted with EtOAc. The organic extract was washed with water and brine, dried over _{anhydrous Na2SO4} and concentrated. The crude product was purified by flash chromatography (silica, EtOAc/heptane, gradient 0% to 20% EtOAc) to give the title compound (1.57 g) as a colorless foam. UPLC-MS 1: m/z 514.5/516.4 [M+1] ⁺ , t _R = 1.56 min.

Step 10. 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 (C-XXX)

To a stirred solution of tert-butyl (((2S,3R)-4-bromo-5-chloro-6-fluoro-3-(methoxymethyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (C-XXX-j) (1.44 g, 2.18 mmol), bis(pinacolato)diboron (0.831 g, 3.27 mmol) and potassium hydroxide (0.306 g, 5.45 mmol) in toluene (15 mL) was added the adduct PdCl ₂ (dppf).CH ₂ Cl ₂ (0.178 g, 0.218 mmol) at 60 °C and the reaction mixture was stirred at 100 °C for 1.5 h. More bis(pinacolato)diboron (0.388 g, 1.527 mmol) and potassium hydroxide (0.184 g, 3.27 mmol) and the reaction mixture was stirred at 100 °C for an additional 30 min. The reaction mixture was filtered over Hyflo and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient 0% to 25% EtOAc) to give the title compound (1.07 g) as a colorless foam. UPLC-MS 1: m/z 562.4 [M+H] ⁺ , t _R = 1.53 min.

Synthesis of 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 (C-XXXI):

Reaction scheme C-XXXI:

Step 1. tert-Butyl (((2S,3R)-3-((benzyloxy)methyl)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (C-XXXI-a)

To a stirred solution of tert-butyl (((2S,3R)-4-bromo-5-chloro-6-fluoro-3-(hydroxymethyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (C-XXX-i) (2.00 g, 3.39 mmol) in DMF (25 mL) was added sodium hydride (0.204 g, 5.09 mmol, 60% dispersion in mineral oil) at 0 °C and the reaction mixture was stirred at 0 °C for 15 min. Benzyl bromide (0.444 mL, 3.73 mmol) was added and stirring at 0 °C was continued for 1 h. The reaction mixture was quenched by addition of water and extracted with EtOAc. _The combined organic extracts were washed with brine, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient 0% to 15% EtOAc) to give the title compound (1.76 g) as a colorless foam. UPLC-MS 1: m/z 490.4/492.5 [M+H-BOC] ⁺ , t _R = 1.65 min.

Step 2. 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 (C-XXXI)

To a stirred solution of tert-butyl (((2S,3R)-3-((benzyloxy)methyl)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (C-XXXI-a) (1.95 g, 3.30 mmol), bis(pinacolato)diboron (1.257 g, 4.95 mmol) and potassium hydroxide (0.555 g, 9.90 mmol) in toluene (20 mL) was added PdCl ₂ (dppf).CH ₂ Cl ₂ adduct (0.269 g, 0.33 mmol) at 60 °C and the reaction mixture was stirred at 100 °C for 1 h. The reaction mixture was filtered over Hyflo and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient 0% to 20% EtOAc) to give the title compound (1.85 g) as a colourless foam. UPLC-MS 1: m/z 638.7 [M+H] ⁺ , t _R = 1.68 min.

Synthesis of 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 (C-XXXII)

Reaction scheme C-XXXII:

Step 1. (S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-carbaldehyde (C-XXXII-a)

At -78 °C, DMSO (12.7 mL, 179 mmol) was added to a solution of oxalyl chloride (7.8 mL, 89 mmol) in DCM (150 mL). After 30 min, a solution of (S)-(4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XIII-d) (20 g, 55.9 mmol) in DCM (150 mL) was added, followed by TEA (39 mL, 280 mmol) at -78 °C. The reaction mixture was stirred for 1 h at -78 °C, then quenched with brine (250 mL). The mixture was extracted twice with DCM (2 x 150 mL). The combined organic layers were washed with brine (250 mL), dried over _{anhydrous Na2SO4} and concentrated to give the title product (21 g) as a colorless solid, which was used in the next step without further purification. UPLC-MS 1: m/z 399.1/401.2 [M+formate] ^- , t _R = 1.27 min.

Step 2. ((S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methylene)-2-methylpropane-2-sulfinamide (C-XXXII-b)

At rt, (S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-carbaldehyde (C-XXXII-a) (5 g, 8.44 mmol, 60%) and 2-methylpropane-2-sulfinamide (1.13 g, 9.28 mmol) were dissolved in DCE (211 mL). Tetraisopropoxytitanium (4.5 mL, 15.2 mmol) was added dropwise and the solution was heated to 60 °C under Ar. After 1 h, more 2-methylpropane-2-sulfinamide (0.41 g, 3.4 mmol) and tetraisopropoxytitanium (1.44 g, 5.6 mmol) were added. The reaction mixture was stirred for an additional 30 min until complete conversion. At rt, Hyflo and H₂O (15 ml) and the reaction mixture was stirred for 10 min. The reaction mixture was filtered over Hyflo and concentrated to give the title compound (6.1 g), which was used in the next step without further purification. UPLC-MS 1: mass/charge 458.0/460.0 [M+H]⁺.t_R=1.47/1.48 min.

Step 3. 2-((S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1-(tert-butylsulfinyl)aziridine (C-XXXII-c)

At rt, sodium hydride (1.1 g, 26.2 mmol, 60%) was added to a solution of trimethylsulfoxonium iodide (5.76 g, 26.2 mmol) in DMSO (81 mL). The mixture was stirred at rt for 1 h. The thus obtained solution was then added dropwise over 5 min to a solution of ((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methylene)-2-methylpropane-2-sulfinamide (C-XXXII-b) (5.0 g, 6.54 mmol, 60%) in toluene (40 mL). The reaction mixture was then stirred for 1 h at rt. Saturated NH ₄ Cl solution was added. The mixture was extracted twice with EtOAc. _The combined organic layers were washed with water and brine, dried over anhydrous _Na2SO4 and concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient 0% to 20% EtOAc) to afford the title compound (2.6 g) as a colorless foam as a mixture of diastereoisomers. UPLC-MS 1: m/z 472.0/474.0 [M+H] ⁺ , t _R = 1.43/1.44/1.45 min.

Step 4. 2-((S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1-(tert-butylsulfonyl)aziridine (C-XXXII-d)

A solution of 2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1-(tert-butylsulfinyl)aziridine (C-XXXII-c) (2.6 g, 5.5 mmol, 50%) in DCM (110 mL) was treated with mCPBA (2.1 g, 8.25 mmol, 70%) and the reaction mixture was stirred at rt for 10 min. Saturated _NaHCO3 solution was added. The mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over _{anhydrous Na2SO4} and concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient 0% to 20% EtOAc) to give the title compound (1.7 g) as a colourless foam as a mixture of diastereoisomers. UPLC-MS 1, no ionization, t _R = 1.42/1.45 min.

Step 5. 2-((S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1-(tert-butylsulfonyl)azetidine (C-XXXII-e)

At rt, sodium hydride (0.6 g, 14.2 mmol, 60%) was added to a solution of trimethylsulfoxonium iodide (3.12 g, 14.2 mmol) in DMSO (10 mL). The mixture was stirred at rt for 1 h. The thus obtained solution was then added dropwise over 5 min to a solution of 2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1-(tert-butylsulfonyl)azetidine (C-XXXII-d) (1.73 g, 3.54 mmol) in DMSO (25 mL). The mixture was extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried over _{anhydrous Na2SO4} and concentrated to give the title compound (1.8 g) as a mixture of diastereoisomers, which was used in the next step without further purification. UPLC-MS 1: m/z 501.9/503.9 [MH] ^- , t _R = 1.44/1.50 min.

Step 6. 2-((S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)azetidine (C-XXXII-f)

At 0 °C, to a solution of 2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1-(tert-butylsulfonyl)azetidine (C-XXXII-e) (1.8 g, 3.58 mmol) in DCM (72 mL) was added trifluoromethanesulfonic acid (1 mL, 10.7 mmol). The reaction mixture was stirred at 0 °C for 20 min, then at rt for 20 min. 1 M NaOH solution was added. The mixture was extracted twice with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give the title compound (1.4 g) as a mixture of diastereoisomers, which was used in the next step without further purification. UPLC-MS 1: mass/charge 381.9/383.9 [M+H] ⁺ , t _R =0.87/0.94 min.

Step 7. tert-Butyl 2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)azetidine-1-carboxylate (C-XXXII-g and C-XXXII-h)

At rt, to a solution of 2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)azetidine (C-XXXII-f) (1.4 g, 3.66 mmol) in dioxane (20 mL) were added TEA (1.5 mL, 11 mmol) and Boc-anhydride (0.88 g, 4.02 mmol) and the reaction mixture was stirred at rt for 4 h. Water was added. The mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over _{anhydrous Na2SO4} and concentrated. The resulting residue was purified by flash chromatography (silica, cyclohexane/EtOAc; gradient 0% to 20% EtOAc) to afford the title compounds as separated diastereoisomers.

Diastereomer 1 (C-XXXII-g): tert-butyl 2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)azetidine-1-carboxylate (340 mg, yellow resin). UPLC-MS 1: m/z 482.0/484.0 [M+H] ⁺ , t _R = 1.57 min.

Diastereomer 2 (C-XXXII-h): tert-butyl 2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)azetidine-1-carboxylate (350 mg, yellow resin). UPLC-MS 1: m/z 480.0/481.9 [MH] ^- , t _R = 1.50 min.

Step 8. 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 (C-XXXII)

A suspension of tert-butyl 2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)azetidine-1-carboxylate (C-XXXII-g) (340 mg, 0.74 mmol), bis(pinacolato)diboron (268 mg, 1.05 mmol), potassium acetate (207 mg, 2.11 mmol) and PdCl adduct₂(dppf).CH₂Cl₂(58 mg, 0.07 mmol) in toluene (1.8 mL) was purged with Ar, then stirred at 100°C for 16 h under Ar. The reaction mixture was diluted with DCM, filtered over Hyflo and concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient 5% to 40% EtOAc) to give the title compound (220 mg) as a solid foam. UPLC-MS 1: m/z 530.1/532.1 [M+H]⁺, t_R=1.60 min; the absolute configuration at the C-2 position of azetidine is not determined.

Synthesis of 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 (C-XXXIII)

Reaction scheme C-XXXIII:

Step 1. (2S,3S)-4-Bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carbaldehyde (C-XXXIII-a)

The title compound (13.2 g, yellow foam) was prepared from ((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XVII-h) (12 g, 32.3 mmol) using reaction conditions similar to those described for compound (CXXXII-a). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ (ppm) 9.93 (s, 1H), 7.62 (d, J= 7.7 Hz, 2H), 7.52-7.36 (m, 4H), 3.89 (q, J= 7.2 Hz, 1H), 1.36 (d, J= 6.9 Hz, 3H). UPLC-MS 1: mass/charge 367.0/366.8 [M+H] ⁺ , t _R =1.36 min.

Stage 2. N-((E)-((2S,3S)-4-Bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methylene)- 2-methylpropane-2-sulfinamide (C-XXXIII-b)

At rt under Ar atmosphere, Ti(OiPr) was added dropwise to a mixture of (2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carbaldehyde (C-XXXIII-a) (15.5 g, 25.2 mmol, 60%) and 2-methylpropane-2-sulfinamide (3.35 g, 27.7 mmol) dissolved in DCE (500 mL).₄(12.8 g, 45.3 mmol). The reaction mixture was stirred at 60°C. After 1 h, 2-methylpropane-2-sulfinamide (1.34 g, 11.10 mmol) and Ti(OiPr) were added.₄(5.15 g, 18.10 mmol). The reaction mixture was then stirred for 90 min. Hyflo and H were added at rt.₂O (50 mL) and the mixture was stirred for 10 min. The reaction mixture was filtered over Hyflo and concentrated to give the title compound (17.3 g, yellow gum) as a diastereomeric mixture, which was used in the next step without further purification. UPLC-MS 1: mass/charge 472.1/473.9 [M+H]⁺.t_R=1.46/1.49 min.

Step 3. 2-((2S,3S)-4-Bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1-(tert-butylsulfinyl)aziridine (C-XXXIII-c)

To a solution of trimethylsulfoxonium iodide (21.9 g, 100 mmol, 68%) in DMSO (310 mL) was added sodium hydride (3.98 g, 100 mmol, 60%). The mixture was stirred at rt for 1 h. The thus obtained solution was then added dropwise over 5 min to a solution of N-((E)-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methylene)-2-methylpropane-2-sulfinamide (C-XXXIII-b) (17.3 g, 24.90 mmol, 68%) in toluene (155 mL). The reaction mixture was then stirred for 30 min at rt. A saturated solution of NH ₄ Cl was added. The mixture was extracted twice with EtOAc. _The combined organic layers were washed with water and brine, dried over anhydrous _Na2SO4 and concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient 0% to 20% EtOAc) to give the title compound (10.9 g, colorless foam) as a diastereomeric mixture. UPLC-MS 1: m/z 486.0/488.0 [M+H] ⁺ , t _R = 1.46/1.49 min.

Step 4. 2-((2S,3S)-4-Bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1-(tert-butylsulfonyl)aziridine (C-XXXIII-d)

A solution of 2-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1-(tert-butylsulfinyl)aziridine (C-XXXIII-c) (10.9 g, 17.91 mmol, 80%) in DCM (360 mL) was treated with mCPBA (6.62 g, 26.9 mmol, 70%) and the reaction mixture was stirred at rt for 10 min. Saturated _NaHCO3 solution was added. The mixture was extracted twice with EtOAc. _The combined organic layers were washed with water and brine, dried over anhydrous _Na2SO4 and concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient 0% to 20% EtOAc) to give the title compound (8.7 g) as a colourless foam. UPLC-MS 1, no ionisation, t _R = 1.46 min.

Step 5. 2-((2S,3S)-4-Bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1-(tert-butylsulfonyl)azetidine (C-XXXIII-e)

To a solution of trimethylsulfoxonium iodide (14.32 g, 65.1 mmol) in DMSO (190 mL) was added sodium hydride (2.60 g, 65.1 mmol, 60%). The mixture was stirred at rt for 1 h. The thus obtained solution was then added dropwise over 5 min to a solution of 2-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1-(tert-butylsulfonyl)aziridine (C-XXXIII-d) (8.7 g, 16.3 mmol) in DMSO (115 mL). The reaction mixture was then stirred at 50 °C for 16 h. A saturated solution of NH ₄ Cl was added. The mixture was extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried over _{anhydrous Na2SO4} and concentrated to give the title compound (11.7 g) as a yellow gum, which was used in the next step without further purification. UPLC-MS 1: no ionization, t _R = 1.51 min.

Step 6. 2-((2S,3S)-4-Bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)azetidine (C-XXXIII-f)

To a solution of 2-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1-(tert-butylsulfonyl)azetidine ( ^C -XXXIII-e) (11.7 g, 14.9 mmol, 66%) in DCM (300 mL) was added trifluoromethanesulfonic acid (3.96 mL, 44.8 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then at rt for 24 h. Trifluoromethanesulfonic acid (3.96 mL, 44.8 mmol) was added and the mixture was stirred for 60 min until the conversion was complete. A solution of 1 M NaOH was added. The mixture was extracted twice with DCM. The combined organic layers were washed with water and brine, dried over _{anhydrous Na2SO4} and concentrated to give the title compound (7.1 g) as a yellow foam, which was used in the next step without further purification. UPLC-MS 1: m/z 396.0/398.0 [M+H] ⁺ , t _R = 0.90 min.

Step 7. tert-Butyl 2-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)azetidine-1-carboxylate (C-XXXIII-g)

At rt, to a solution of 2-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1-(tert-butylsulfonyl)azetidine (C-XXXIII-f) (7.1 g, 12.0 mmol, 67%) in dioxane (65 mL) were added TEA (5 mL, 36.0 mmol) and Boc-anhydride (2.90 g, 13.2 mmol). The reaction mixture was stirred at rt for 3 h. The mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over _{anhydrous Na2SO4} and concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient 0% to 20% EtOAc) to give the title compound (4.36 g) as a yellow foam. UPLC-MS 1: m/z 496.0/497.9 [M+H] ⁺ , t _R = 1.60 min.

Step 8. 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 (C-XXXIII)

A suspension of tert-butyl 2-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)azetidine-1-carboxylate (C-XXXIII-g) (4.36 g, 8.25 mmol), bis(pinacolato)diboron (3.14 g, 12.37 mmol), potassium acetate (2.4 g, 24.7 mmol) and PdCl adduct₂(dppf).CH₂Cl₂(675 mg, 0.825 mmol) in toluene (21 mL) was purged with Ar and then stirred at 100°C for 16 h under Ar. The reaction mixture was diluted with DCM, filtered over Hyflo and concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient 0% to 20% EtOAc) to give the title compound (1.3 g) as a colourless foam. UPLC-MS 1: m/z 544.3/546.2 [M+H]⁺, t_R=1.59 min; the absolute configuration at position C-2 of azetidine is not determined.

Synthesis of 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 (C-XXXIV)

The title product can be synthesized via the following routes:

Reaction scheme C-XXXIV-1:

Synthesis of 1-(3-bromopropyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine (C-XXXIV-a)

At 0 °C, TEA (172 mL, 1233 mmol) was added to a stirred solution of 3-bromopropan-1-amine in DCM (623 mL). After 5 min, a solution of 1,2-bis(chlorodimethylsilyl)ethane (97 g, 452 mmol) in DCM (200 mL) was added dropwise and the reaction mixture was stirred for 2.5 h at rt. The reaction mixture was then filtered and the filtrate was concentrated. The crude material was resuspended in pentane (500 mL), then stirred for 1 h. The mixture was filtered through celite and concentrated. The crude material was resuspended in pentane (200 mL) and worked up as before. The product was isolated as a colorless liquid, which was filtered and dried under HV for 2 min. The title compound (107 g) was used as is without further purification and stored for a limited period only. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ (ppm) 3.53-3.49 (m, 1H), 2.90 (t, J=6.9 Hz, 2H), 1.90-1.85 (m, 2H), 0.66 (s, 4H), 0.05 (s, 12H).

Step 1. (S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylic acid (C-XXXIV-b)

_LiOH.H2O (3.40 g, 42.0 mmol) was added to a solution of (S)-methyl 4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (C-XIII-a) (15.00 g, 38.9 mmol) in dioxane (70 mL) and water (70 mL). The reaction mixture was stirred at rt for 17 h. 2N HCl (100 mL) was added and the resulting white suspension was extracted with DCM. The organic layers were washed with brine, dried over _{anhydrous Na2SO4} and concentrated to give the title compound (17.2 g). ¹ H-NMR (600 MHz, DMSO - _d6 ) δ (ppm) 13.73 (s, 1H), 7.59-7.53 (m, 2H), 7.48-7.36 (m, 3H), 7.29 (d, J=9.4 Hz, 1H), 4.05 (dd, J=16.4, 1.3 Hz, 1H), 358 (dd, J=16.0, 2.0 Hz, 1H). UPLC-MS 1: mass/charge 369.1/371.9 [MH] ^- , t _R =1.12 min.

Step 2. (S)-4-Bromo-5-chloro-6-fluoro-N-methoxy-N-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carboxamide (C-XXXIV-c)

At rt, DIPEA (21.3 mL, 122 mmol) was added successively to a solution of (S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylic acid (C-XXXIV-b) (12.6 g, 30.5 mmol) in dioxane (500 mL),N, O-dimethylhydroxylamine hydrochloride (3.57 g, 36.6 mmol), DMAP (0.19 g, 1.53 mmol), and HATU (13.92 g, 36.6 mmol). The resulting solution was stirred at rt for 1.5 h. After concentration and exposure to reduced pressure, the residue was dissolved in EtOAc (500 mL) and washed successively with water (200 mL), 1 N HCl (150 mL), 1 N NaOH (150 mL), and brine (200 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated to give a crude product which was purified by flash chromatography (silica, hexane/EtOAc 9:1) to give the title compound (10.83 g). UPLC-MS 1: m/z 414.1/416.1 [M+H]⁺, t_R=1.36 min.

Step 3. (S)-5-(4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-3,4-dihydro-2H-pyrrole (C-XXXIV-d)

At rt, 60 mL of a solution of 1-(3-bromopropyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine (C-XXXIV-a) (89 g, 316 mmol) in Et ₂ O (300 mL) was added to a suspension of magnesium (8.3 g, 343 mmol) in Et ₂ O (150 mL), followed by iodine (4.58 g, 18.04 mmol). The reaction mixture was then heated under reflux. The rest of the solution of 1-(3-bromopropyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine in Et ₂ O (240 mL) was added over 27 min under reflux. The reaction mixture was then stirred at reflux for 1.5 h. The resulting mixture was added at rt over 15 min to a solution of (S)-4-bromo-5-chloro-6-fluoro-N-methoxy-N-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carboxamide (C-XXXIV-c) (37.4 g, 90 mmol) in THF (300 mL). The resulting suspension was stirred at rt for 2 h. The reaction mixture was quenched with 2 N citric acid (600 mL), neutralized with saturated NaHCO ₃ (1200 mL) and extracted twice with EtOAc (2 x 1000 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The yellow residue was then treated with MeOH (50 mL) and the resulting white suspension was stirred at rt for 16 h. The suspension was filtered, washed with MeOH (20 mL) to give the desired product. After concentration of the crude solution, the crude product was similarly worked up. The resulting crude solution was concentrated and purified by flash chromatography (silica, heptane/EtOAc 95:5). Overall, the title product (26.43 g) was obtained as a colorless solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.46-7.40 (m, 4H), 7.39-7.33 (m, 1H), 7.27 (d, J=9.5 Hz, 1H), 4.45 (dd, J=16.1, 1.4 Hz, 1H), 3.30 (dd, under d ₆ -DMSO peak), 3.90-3.75 (m, 2H), 2.69-2.56 (m, 1H), 2.38-2.12 (m, 2H), 1.90-1.71 (m, 2H). UPLC-MS 1: m/z 394.2/396.2 [M+H] ⁺ , t _R =1.49 min.

Step 4. (S)-2-((S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine (C-XXXIV-e) and (R)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine (C-XXXIV-f)

At 0 ^o C, sodium borohydride (8.1 g, 212 mmol) was added portionwise over 5 min to a solution of (S)-5-(4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-3,4-dihydro-2H-pyrrole (C-XXXIV-d) (27.9 g, 70.7 mmol) in THF/MeOH (220 mL, 1:1). The reaction mixture was stirred at rt for 1.5 h, then quenched with sat. NaHCO ₃ (400 mL) and extracted twice with EtOAc (2×1000 mL). The combined organic layers were washed with sat. _NaHCO3 solution (400 mL) and brine, dried over _{anhydrous Na2SO4} and concentrated. The residue was purified by flash chromatography (silica, hexane/EtOAc, gradient: 10% to 100% EtOAc) to give the title compound as a diastereomeric mixture (18.7 g) as a colorless oil. UPLC-MS 1: m/z 396.2/398.2 [M+H] ⁺ , t _R = 0.88 min and 0.91 min.

The diastereomeric mixture (18.7 g) was subjected to chiral SFC (ChiralPak IG, 250 x 30 mm i.d., 10 μm, _CO2 /IPA (0.1% ammonia) 1:1, 38°C, flow rate: 60 mL/min) to afford the title compounds as individual diastereoisomers with diastereomeric excess >99%, respectively:

(S)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine (C-XXXIV-e) (11.69 g): Chiral SFC: (Chiralpak IG 250×4.6 mm i.d., 5 μm, _CO2 /IPA (0.05% DEA) 6:4, flow rate: 2.5 ml/min), t _R = 6.92 min. ^1H NMR (400 MHz, DMSO - _d6 ) δ (ppm) 7.60-7.47 (m, 2H), 7.41-7.34 (m, 2H), 7.33-7.27 (m, 1H), 7.09 (d, J =9.6 Hz, 1H), 3.69 (dd, J =16.1, 1.9 Hz, 1H), 3.62-3.50 (m, 1H), 3.41-3.28 (m, 2H), 2.86-2.74 (m, 1H), 2.72-2.58 (m, 1H), 1.63-1.28 (m, 4H). UPLC-MS 1: m/z 396.2/398.2 [M+H] ⁺ , t _R = 0.85 min. The absolute configuration was confirmed by X-ray crystallography of the HCl salt of the title compound.

Another diastereoisomer, (R)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine (C-XXXIV-f) (5.70 g): Chiral SFC: (Chiralpak IG 250×4.6 mm i.d., 5 μm, _CO2 /IPA (0.05% DEA) 6:4, flow rate: 2.5 mL/min), t _R = 2.87 min. ^1H NMR (400 MHz, DMSO -d6 ) δ (ppm) 7.48-7.34 (m, 4H), 7.32-7.23 (m, 1H), 7.10 (d, J =9.6 Hz, 1H) _, 3.84 (dd, J =16.0, 1.9 Hz, 1H), 3.71-3.56 (m, 1H), 3.15 (dd, J =16.1, 1.6 Hz, 1H), 2.84-2.73 (m, 1H), 2.64-2.52 (m, 2H), 1.76-1.59 (m, 1H), 1.54-1.31 (m, 3H). UPLC-MS 1: mass/charge 396.2/398.2 [M+H] ⁺ , t _R =0.86 min.

Step 5. tert-Butyl (S)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (C-XXXIV-g)

At rt and under Ar atmosphere, to a solution of (S)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine (C-XXXIV-e) (11.1 g, 27.9 mmol) in THF (100 mL) were added Boc-anhydride (6.71 g, 30.7 mmol) and TEA (7.8 mL, 55.9 mmol). The reaction mixture was stirred at rt for 15 min, then quenched with sat. NaHCO ₃ solution (75 mL). The mixture was extracted twice with EtOAc (2×100 mL). The combined organic layers were washed with sat. _NaHCO3 solution (400 mL) and brine, dried over _{anhydrous Na2SO4} and concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 15% EtOAc) to give the title compound (14.2 g) as a colorless solid. ^1H NMR (400 MHz, DMSO -d6 ) δ (ppm) 7.52-7.27 (m, 5H), 7.18 (d, J =9.5 Hz, 1H) _, 4.42 (dd, J =7.0, 3.3 Hz, 1H), 4.22-3.85 (m, 1H), 3.48-3.31 (m, 1H), 2.92-2.70 (m, 1H), 1.94-1.77 (m, 2H), 1.56-1.21 (m, 10H), 1.10-0.65 (m, 1H). UPLC-MS 1: mass/charge 440.3/442.3 [M-tBu+H] ⁺ , t _R =1.63 min.

Step 6. 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 (C-XXXIV)

A suspension of tert-butyl (S)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (C-XXXIV-g) (14.2 g, 28.6 mmol), bis(pinacolato)diboron (10.9 g, 42.9 mmol), potassium acetate (8.4 g, 86 mmol) and PdCl adduct₂(dppf).CH₂Cl₂(2.3 g, 2.86 mmol) in toluene (100 mL) was purged with Ar, then stirred at 100°C for 16 h under Ar. The reaction mixture was diluted with DCM at rt, filtered through celite and concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient 0% to 15% EtOAc) to give the title compound (13.4 g) as a colourless solid. UPLC-MS 1: m/z 588.5 [M+formate]^-, t_R=1.65 min.

Alternative synthesis of intermediate C-XXXIV-b:

Step 1. (2S,5S)-5-(2-Bromo-4,6-difluorobenzyl)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one

At rt, (2S,5S)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one (CAS 81036-97-7) (28.2 g, 128.2 mmol) was added to a solution of 1-bromo-2-(bromomethyl)-3,5-difluorobenzene (CAS 1807193-40-3) (70.9 mmol) in THF (250 mL). The mixture was cooled to -10.0 °C and a solution of LiHMDS (108.1 g, 116 mmol, 1 M in THF) was slowly added over 1.5 h. The reaction mixture was allowed to warm to rt and stirred for an additional 18 h. 20% NH ₄ Cl solution (220 mL) was added. The mixture was extracted with MTBE (200 mL) and stirred for 1 h. The organic phase was separated and partially concentrated to give a solution of the title product in MTBE. UPLC-MS 1: t _R = 1.52 min.

Step 2. Potassium (S)-4-bromo-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate

A solution of (2S,5S)-5-(2-bromo-4,6-difluorobenzyl)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one in MTBE (103.11 mmol) was diluted with THF (400 mL) and cooled at 0±5 °C. tBuOK (34.7 g, 309.3 mmol) was added over 30 min, the mixture was warmed to rt and stirred for 18 h. 10% NH ₄ Cl solution (220 mL) was added. The mixture was extracted with isopropyl acetate and then stirred for 1 h. The organic phase was separated and partially concentrated. THF was gradually replaced by isopropyl acetate by iterative addition of IPAC and partial concentration. The mixture was then cooled to 10°C and stirred for 1 h. The solid was filtered and recrystallized with isopropyl acetate to give the title product (34 g) as a colorless solid.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.56 (d, J = 7.1 Hz, 2H), 7.49-7.35 (m, 3H), 7.05 (ddd, J = 15.8, 9.3, 2.2 Hz, 2H), 3.99 (d, J = 18.0 Hz, 1H), 3.51 (d, J = 18.0 Hz, 1H). UPLC-MS 1: m/z 335.0/337.0 [MH] ^- , t _R = 1.07 min.

Step 3. (S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylic acid (C-XXXIV-b)

To a solution of potassium (S)-4-bromo-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (30 g, 80.0 mmol) in ACN (255 mL) were added p-TsOH (21.3 g, 112 mmol) and N-chlorosuccinimide (11.68 g, 87.5 mmol) at 0±5°C. The reaction mixture was stirred for 1 h at 0°C. Upon completion, water (150 mL) was added. 10% aqueous _{Na2SO3 solution} was slowly added at 0-10°C. TBME (150 mL) was added and the mixture was stirred for 0.5 h. The two phases were separated. Toluene (150 mL) was added to the aqueous phase and the mixture was stirred for 0.5 h. The combined organic phases were washed with 2 N HCl solution (60 mL) and the resulting mixture was stirred for 1 h. The organic phase was separated and concentrated to give the title compound with an enantiomeric excess of 91%.

The resulting residue was dissolved in THF (200 mL). The mixture was heated to 60-65 °C and a solution of (R)-(+)-phenylethylamine (6.95 g) in THF (40 mL) was added over 30 min. The mixture was maintained stirring for 30 min and then slowly cooled to rt over 1 h and stirred for another 2 h. The mixture was filtered. The solid was washed with THF (24 mL) and then dried at 50 °C for 5 h under reduced pressure to give the title product (21.1 g), the (R)-(+)-phenylethylamine salt, which was suspended in toluene (105 mL) and water (30 mL). Concentrated HCl solution (6.4 g) was slowly added at rt to the mixture. The mixture was then stirred at rt. for 0.5 h. The aqueous phase was separated. The organic phase was washed with water (20 mL) and then concentrated under reduced pressure to give a solution of the title product as the (R)-(+)-phenylethylamine salt with an enantiomeric excess of 99%. This salt (60.0 g, 121.8 mmol) was slowly added to a solution of NaOH (7.5 g) in water (375 mL). The suspension was stirred at rt for 30 min, then extracted twice with DCM (2 x 250 mL). DCM (200 mL) was added to the aqueous layer and the pH was adjusted to pH = 1 with 2 N aq. HCl at 0-5 °C. The mixture was stirred for 10 min. The organic layer was separated and the aqueous layer was extracted with DCM (200 mL). The combined organic layers were dried over anhydrous _{Na2SO4 ,} filtered and concentrated to give the title product as the free acid.

Reaction scheme C-XXXIV-2:

Step 1. tert-Butyl (S)-2-vinylpyrrolidine-1-carboxylate (C-XXXIV-j)

At rt under nitrogen atmosphere, a suspension _{of Ph3PCH3Br} (161.4 g, 451.7 mmol) and ^KOtBu (50.7 g, 451.7 mmol) in THF (500 mL) was stirred for 4 h, then cooled to -70 °C. A solution of ( S )-tert-butyl 2-formylpyrrolidine-1-carboxylate (C-XXXIV-i) (75.0 g, 376 mmol) in THF (150 mL) was added dropwise over 30 min, while maintaining the internal temperature below -20 °C. The reaction mixture was then stirred for 16 h at rt. Upon completion of the reaction, 20 wt% _NH4Cl (200 mL) was added and the organic layer was separated. The aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated to give a pale yellow oil. Heptane (400 mL) was added and the resulting suspension was stirred vigorously at 0~5 °C for 1 h and filtered. The filtrate was dried in HV to give the title product (76 g) as a yellow oil, which was used directly in the next step without further purification.

Step 2. tert-Butyl (2S)-2-(oxiran-2-yl)pyrrolidine-1-carboxylate (C-XXXIV-k)

At 0°C under nitrogen atmosphere, mCPBA (155.4 g, 693.5 mmol, 77% w/w) was added portionwise to tert-butyl (S)-2-vinylpyrrolidine-1-carboxylate (C-XXXIV-j) (76 g, 424 mmol) dissolved in DCM (700 mL) while maintaining the internal temperature below 10 °C. The reaction mixture was then stirred for 2 h at rt. Upon completion of the reaction, a solution of Na₂S₂O₃(48.6 g, 385.3 mmol) in water (300 mL) to quench excess mCPBA. Saturated aq. Na₂CO₃(200 mL) was added to adjust the pH to 7-8. The organic layer was separated and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were washed with 5% NaHCO₃(100 ml), then with brine (100 ml), dried over Na₂SO₄, filtered and concentrated to a volume of approximately 100 ml. Heptane (600 ml) was added and the resulting suspension was filtered. The filtrate was concentrated and the resulting residue was purified by flash chromatography on silica gel withn-heptane/EtOAc to give the title product (62 g) as a yellow oil.

Step 3. tert-Butyl (2S)-2-(2-(2-bromo-4,6-difluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate (C-XXXIV-l)

At -70 °C under nitrogen atmosphere, to a solution of 1-bromo-3,5-difluoro-2-iodobenzene (120.5 g, 377.9 mmol) in THF (800 mL) was added dropwise over 30 min i PrMgCl (190 mL, 2.0 M in THF, 102.8 mmol) while maintaining the internal temperature in the range of -40 °C to -35 °C. The reaction mixture was stirred at this temperature for 1 h. Upon completion of the reaction, CuI (11.1 g, 58.1 mmol) was quickly added in one portion. A solution of tert-butyl (2S)-2-(oxiran-2-yl)pyrrolidine-1-carboxylate (C-XXXIV-k) (62 g, 290.7 mmol) in THF (100 mL) was added dropwise over 10 min while maintaining the internal temperature between -40 °C and -30 °C. The reaction mixture was then gradually warmed to rt and stirred overnight. 20 wt % aq NH ₄ Cl (700 mL) was carefully added to quench the reaction mixture, followed by the addition of MTBE (400 mL). The organic layer was separated and the aqueous layer was extracted with MTBE (200 mL). The combined organic layers were washed with 20 wt% brine (300 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated to give the title product (118 g) as a pale yellow oil, which was used directly in the next step. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.13 (dt, J = 8.1, 2.2 Hz, 1H), 6.80 (td, J = 9.1, 2.6 Hz, 1H), 4.63 (s, 1H), 4.04-3.94 (m, 1H), 3.86-3.72 (m, 1H), 3.58-3.44 (m, 1H), 3.41-3.28 (m, 1H), 3.01-2.78 (m, 2H), 2.14-1.81 (m, 4H), 1.47 (s, 9H). UPLC-MS 5: HRMS m/z calcd. for C ₁₂ H ₁₅ BrF ₂ NO [M-Boc] ⁺ 306.0300, the found value is 306.0292.

Step 4. tert-Butyl (S)-2-(2-(2-bromo-4,6-difluorophenyl)acetyl)pyrrolidine-1-carboxylate (C-XXXIV-m)

At rt under nitrogen atmosphere, to a solution of Dess-Martin periodinane (135.5 g, 319.5 mmol) in DCM (700 mL) was added dropwise over 30 min. At rt, a solution of tert-butyl (2S)-2-(2-(2-bromo-4,6-difluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate (C-XXXIV-l) (118 g, 290 mmol) in DCM (700 mL) was added dropwise over 30 min. The reaction mixture was stirred at rt for 45 min. Upon completion of the reaction, a solution of Na₂SO₃(58.6 g) in water (300 ml) to quench the reaction, while maintaining the internal temperature from 0 to 5°C. 15 wt.% Na was added₂CO₃(350 mL) to adjust the pH to 7-8 while maintaining the internal temperature below 10°C. The organic layer was separated and the aqueous layer was extracted with DCM (500 mL). The combined organic layers were washed with 5 wt% NaHCO₃(300 ml), then 20 wt.% saline solution (300 ml), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (silica, heptane/MTBE, gradient: 3% to 20% MTBE) to give the title product (75 g).¹H NMR (400 MHz, CDCl₃) δ 7.21-7.12 (m, 1H), 6.88-6.78 (m, 1H), 4.49 (dd, J=8.5, 4.5 Hz, 0.3H), 4.37 (dd, J=8.8, 5.2 Hz, 0.7H), 4.08-3.86 (m, 2H), 3.67-3.39 (m, 2H), 2.35-2.05 (m, 2H), 2.02-1.86 (m, 2H), 1.48 (s, 2.7H), 1.47 (s, 6.3H). UPLC-MS 5: HRMS m/z calc. for C₁₂H₁₃BrF₂NO [M-Boc]⁺304.0143, found value 303.9271.

Step 5. tert-Butyl (S)-2-((S)-2-(2-bromo-4,6-difluorophenyl)-1-hydroxy-1-phenylethyl)pyrrolidine-1-carboxylate (C-XXXIV-n)

At 0°C under nitrogen atmosphere to tert-butyl (S)-2-(2-(2-bromo-4,6-difluorophenyl)acetyl)pyrrolidine-1-carboxylate (C-XXXIV-m) (26 g, 64.3 mmol) in a mixture of DCM (260 mL) and heptane (260 mL) was added dropwise over 30 min. PhMgBr (40 mL, 128.6 mmol, 2.5 M in Et₂O), while maintaining the internal temperature at -5-0°C. The reaction mixture was stirred at 0°C for 10 min before it was quenched by slow addition of sat. aq. NH₄Cl (150 mL). MTBE (200 mL) was added and the organic layer was separated. The aqueous layer was extracted with MTBE (200 mL). The combined organic layers were washed with 20 wt% brine (300 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (silica, heptane/MTBE, gradient: 2% to 3% MTBE) to give the title product (14 g) as a light yellow solid.¹H NMR (400 MHz, DMSO-d ₆) δ 7.48 (s, 2H), 7.31 (dt,J=8.4, 2.1 Hz, 1H), 7.26-7.16 (m, 3H), 7.08-7.00 (m, 1H), 4.42-4.19 (m, 1H), 3.62-3.45 (m, 2H), 3.45-3.34 (m, 2H), 1.93-1.82 (m, 1H), 1.75-1.60 (m, 1H), 1.43 (s, 9H), 1.41-1.21 (m, 2H). UPLC-MS 5: HRMS m/z calc. for C₂₃H₂₇BrF₂NO₃[M+H]⁺482.1137, found value 481.9654.

Step 6. tert-Butyl (S)-2-((S)-4-bromo-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (C-XXXIV-o)

At 0°C under a nitrogen atmosphere, a solution of tert-butyl (S)-2-((S)-2-(2-bromo-4,6-difluorophenyl)-1-hydroxy-1-phenylethyl)pyrrolidine-1-carboxylate (C-XXXIV-n) (15 g, 31.1 mmol) in THF (150 mL) was added dropwise over 15 min. KOtBu (37.3 mL, 37.3 mmol, 1 M in THF) while maintaining the internal temperature at -5-0°C. The reaction mixture was stirred at -5-0°C for 30 min. Upon completion, the mixture was diluted with MTBE (200 mL) and quenched by adding 5 wt% aq. NaHCO₃(150 mL) while maintaining the internal temperature at -5-0°C. The mixture was stirred for 15 min at -5-0°C. The organic layer was separated and the aqueous layer was extracted with MTBE (200 mL). The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated to give the title product (14.3 g), which was used directly in the next step.¹H NMR (400 MHz, DMSO-d ₆) δ 7.45-7.28 (m, 5H), 6.98 (dd, J=9.1, 2.2 Hz, 1H), 6.90 (dd, J=9.5, 2.2 Hz, 1H), 4.41 (dd, J=6.9, 3.5 Hz, 1H), 4.19-3.78 (m, 1H), 3.44-3.19 (m, 2H), 2.91-2.72 (m, 1H), 1.90-1.83 (m, 2H), 1.57-1.47 (m, 1H), 1.35 (s, 2H), 1.34 (s, 7H), 1.28-1.21 (m, 1H). UPLC-MS 5: HRMS m/z calc. for C₁₈H₁₈BrFNO [M-Boc]⁺362.0550, found value 361.9654.

Step 7. tert-Butyl (S)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (C-XXXIV-g)

At 0 °C under nitrogen atmosphere, to a solution of tert-butyl (S)-2-((S)-4-bromo-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (C-XXXIV-o) (14 g, 30.3 mmol) in ACN (280 mL) and THF (140 mL) were added p-TsOH (6.9 g, 36.3 mmol) and N-chlorosuccinimide (4.85 g, 36.3 mmol) while maintaining the internal temperature at -8-0 °C. The reaction mixture was stirred at -8-0 °C for 3 h. The mixture was diluted with MTBE (200 mL) and quenched by adding 6 wt % aq. Na ₂ CO ₃ (150 mL). The organic layer was separated and the aqueous layer was extracted with MTBE (200 mL). The combined organic phases were washed with 6 wt% aq. _Na2CO3 , brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was purified by flash chromatography ( _silica , heptane/MTBE, 5% MTBE) to give the title product (14 g) as a light yellow foam.

Step 8. 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 (C-XXXIV)

A 250 mL three-neck round-bottomed flask was charged with tert-butyl (S)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (C-XXXIV-g) (20.0 g, 40.26 mmol), bis(pinacolato)diboron (13.3 g, 52.34 mmol), KOAc (11.9 g, 120.77 mmol), and toluene (140 mL). The mixture was degassed with nitrogen for 20 min. PdCl ₂ (dppf) (2.4 g, 3.22 mmol) was added in one portion under nitrogen. The mixture was heated to 100 °C and stirred for 16 h. The mixture was then cooled to rt, filtered through celite and concentrated to dryness. The residue was purified by flash chromatography (silica, heptane/MTBE 5:1) to afford the title compound (14.5) as a foam. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.46-7.41 (m, 2H), 7.34-7.27 (m, 3H), 6.70 (d, J =9.3 Hz, 1H), 4.54-4.38 (m, 1H), 4.34-3.98 (m, 1H), 3.45 (d, J =16.7 Hz, 2H), 3.06-2.83 (m, 1H), 2.09-1.78 (m, 2H), 1.58-1.46 (m, 2H), 1.42 (s, 9H), 1.36 (s, 12H). UPLC-MS 5: HRMS mass/charge calc. for C ₂₉ H ₃₇ BClFNO ₅ [M+H] ⁺ 544.2432, the found value is 544.2897.

Synthesis of 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 (C-XXXV)

Reaction scheme C-XXXV:

Step 1. (R)-N-(1-((S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (C-XXXV-a)

At 0 °C, to a solution of (R)-N-((E)-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methylene)-2-methylpropane-2-sulfinamide (C-XXXIV-h, prepared from aldehyde C-XXXII-a and ( R )-2-methylpropane-2-sulfinamide using Ti(OEt) ₄ as Lewis acid) (3.0 g, 3.27 mmol) in DCM (17 mL) was added dropwise allylmagnesium bromide (15 mL, 15 mmol, 1 M in Et ₂ O). RM was stirred at 0 °C for 1.5 h. Saturated NH ₄ Cl solution was added. The mixture was stirred for 10 min. at rt, then neutralized with 2N HCl solution. The mixture was extracted twice with DCM. The combined organic layers were washed with water and brine, dried over _{anhydrous Na2SO4} and concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient from 5% to 30% EtOAc) to give the title compound (1.0 g) as a colorless foam. UPLC-MS 1: m/z 500.2/502.2 [M+H] ⁺ , t _R = 1.43 min.

Step 2. N-(1-((S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-2-(oxiran-2-yl)ethyl)-2-methylpropane-2-sulfonamide (C-XXXV-b)

At rt, a solution of (R)-N-(1-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (C-XXXVa) (1.00 g, 1.92 mmol) in DCM (38 mL) was treated with mCPBA (1.42 g, 5.75 mmol, 70%). The reaction mixture was stirred at rt for 16 h. _Saturated NaHCO3 solution was added. The mixture was extracted twice with DCM. _The combined organic layers were washed with water and brine, dried over anhydrous _Na2SO4 and concentrated. The residue was purified by flash chromatography (silica, DCM/MeOH, gradient 0% to 10% MeOH) to give the title compound (930 mg) as a colourless solid. UPLC-MS 1, m/z 532.1/534.2 [M+H] ⁺ , t _R = 1.37 min.

Step 3. 5-((S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1-(tert-butylsulfonyl)pyrrolidin-3-ol (C-XXXV-c)

At rt, to a solution of N-(1-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-2-(oxiran-2-yl)ethyl)-2-methylpropane-2-sulfonamide (C-XXXV-b) (930 mg, 1.54 mmol, 88%) in DMF (15 mL) was added _K2CO3 (637 mg, 4.6 mmol). The mixture was stirred at 100 °C for 24 h. The reaction mixture was cooled to rt, then filtered and concentrated to give the title compound as _a diastereomeric mixture (1.1 g), which was used in the next step without further purification. UPLC-MS 2: mass/charge 576.1 /578.1 [M+formate] ^- , t _R =6.52/6.68/6.76/6.82 min.

Step 4. 5-((S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidin-3-ol (C-XXXV-d)

At 0 °C, to a solution of 5-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1-(tert-butylsulfonyl)pyrrolidin-3-ol (C-XXXV-c) (1.10 g, 1.54 mmol, 90%) in DCM (30 mL) was added trifluoromethanesulfonic acid (0.40 mL, 4.61 mmol). The reaction mixture was stirred at 0 °C for 90 min. 1 M NaOH solution was added. The mixture was extracted with DCM. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated to give the title compound as a diastereomeric mixture (800 mg), which was used in the next step without further purification. UPLC-MS 1: mass/charge 412.2/414.1 [M+H] ⁺ , t _R =0.84/0.86 min.

Step 5. tert-Butyl 2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxypyrrolidine-1-carboxylate (C-XXXV-e)

At rt, to a solution of 5-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidin-3-ol (C-XXXV-d) (800 mg, 1.54 mmol, 80%) in dioxane (8 mL) were added TEA (0.65 mL, 4.6 mmol) and Boc-anhydride (370 mg, 1.7 mmol). The reaction mixture was stirred at rt for 2 d. Water was added. The mixture was extracted with EtOAc. The organic layer was dried over _{anhydrous Na2SO4} and concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient 0% to 15% EtOAc) to give the title compound as a diastereomeric mixture (620 mg) as a yellowish foam. UPLC-MS 1: m/z 512.3/514.3 [M+H] ⁺ , t _R = 1.41/1.42/1.46/1.47 min.

Step 6. 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 (C-XXXV)

A suspension of tert-butyl 2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxypyrrolidine-1-carboxylate (C-XXXV-e) (610 mg, 1.15 mmol), bis(pinacolato)diboron (440 mg, 1.73 mmol), potassium acetate (340 mg, 4.46 mmol) and PdCl adduct₂(dppf).CH₂Cl₂(94 mg, 0.115 mmol) in toluene (2 mL) was purged with Ar, then stirred at 110°C for 16 h under Ar. The reaction mixture was diluted with EtOAc, filtered over Hyflo and concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 10% to 30% EtOAc) to give the title compound as a diastereomeric mixture (600 mg) as a solid foam. UPLC-MS 1: m/z 560.4/562.4 [M+H]⁺, t_R=1.46/1.47/1.49/1.51 min.

Synthesis of 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 (C-XXXVI)

Reaction scheme C-XXXVI:

Stage 1.(R)-N-(1-((S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-3-methylbut-3-en-1-yl)-2-methylpropane-2-sulfinamide (C-XXXVI-a)

At rt, a solution of 3-bromo-2-methylprop-1-ene (0.45 g, 3.37 mmol) in Et ₂ O (5 mL) and 2 drops of methyl iodide were added to a suspension of magnesium powder (1.23 g, 50 mmol) in Et ₂ O (5 mL). The remaining solution of 3-bromo-2-methylprop-1-ene (4.10 g, 30.3 mmol) in Et ₂ O (20 mL) was then added dropwise while maintaining the internal temperature below 35 °C. The reaction mixture was stirred at rt for 16 h. The thus obtained solution was added dropwise at rt. to a solution of (R)-N-((E)-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methylene)-2-methylpropane-2-sulfinamide (C-XXXIV-h) (1.7 g, 3.37 mmol) in Et ₂ O (24 mL). The reaction mixture was stirred at rt for 2 h. Saturated NH ₄ Cl solution was added and the reaction mixture was stirred for 10 min. Then the mixture was neutralized with 2 M HCl solution and extracted with EtOAc. The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the title compound as a diastereomeric mixture (1.9 g). UPLC-MS 1: mass/charge 514.2/516.3 [M+H] ⁺ , t _R =1.46/1.48 min.

Step 2. N -(1-((S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-2-(2-methyloxiran-2-yl )ethyl)-2-methylpropane-2-sulfonamide (C-XXXVI-b)

At rt, a solution of (R)-N-(1-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-3-methylbut-3-en-1-yl)-2-methylpropane-2-sulfinamide (C-XXXVI-a) (4.1 g, 6.29 mmol, 79%) in DCM (125 mL) was treated with mCPBA (4.65 g, 18.9 mmol, 70%). The reaction mixture was stirred at rt for 16 h, then quenched with sat. NaHCO₃The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (silica, DCM/MeOH, gradient 0% to 10% MeOH) to give the title compound as a diastereomeric mixture (3.06 g) as a colorless foam. UPLC-MS 2: m/z 544.1/546.1 [M-H]^-, t_R=7.28/7.33 min.

Step 3. 5-((S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1-(tert-butylsulfonyl)-3-methylpyrrolidin-3-ol (C-XXXVI-c and C-XXXVI-d)

To a solution of N-(1-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-2-(2-methyloxiran-2-yl)ethyl)-2-methylpropane-2-sulfonamide (C-XXXVI-b) (3.05 g, 4.80 mmol, 86%) in DMF (45 mL) was added K ₂ CO ₃ (1.99 g, 14.4 mmol). The mixture was stirred at 100 °C for 24 h, then at rt. The solids were filtered. After concentration, the residue was purified by flash chromatography (silica, cyclohexane/EtOAc; gradient 0% to 30% EtOAc) to afford two separate diastereoisomers.

Diastereomer C-XXXVI-c (420 mg): UPLC-MS 1: m/z 590.2/592.2 [M+formate] ^- , t _R =1.33 min.

Diastereomer C-XXXVI-d (1.0 g): UPLC-MS 1: m/z 590.2/592.2 [M+formate] ^- , t _R =1.40 min.

Step 4. ((5-((S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1-(tert-butylsulfonyl)-3-methylpyrrolidin-3-yl)oxy)methyl pivalate (C-XXXVI-e)

At 0°C, NaH (35.3 mg, 0.88 mmol, 60% in mineral oil) was added to a solution of 5-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1-(tert-butylsulfonyl)-3-methylpyrrolidin-3-ol (C-XXXVI-c) (420 mg, 0.77 mmol) in THF (10 mL) and the reaction mixture was stirred at 0°C for 45 min. Then chloromethyl pivalate (0.13 mL, 0.85 mmol) was added and the mixture was stirred at rt. for 16 h. More NaH (35.3 mg, 0.88 mmol, 60% in mineral oil) was added, followed by chloromethyl pivalate (130 mg, 0.85 mmol). The mixture was stirred for another 24 h before it was quenched with water. The mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over _{anhydrous Na2SO4} and concentrated to give the title compound (600 mg) as a colourless foam, which was used in the next step without further purification. UPLC-MS 1: m/z 677.3/679.3 [M+OH] ⁺ , t _R = 1.57 min.

Step 5. tert-Butyl 2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxy-4-methylpyrrolidine-1-carboxylate (C-XXXVI-f)

At rt, trifluoromethanesulfonic acid (0.20 mL, 2.30 mmol) was added to a solution of ((5-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1-(tert-butylsulfonyl)-3-methylpyrrolidin-3-yl)oxy)methyl pivalate (C-XXXVI-e) (508 mg, 0.77 mmol) in DCM (15 mL). The reaction mixture was stirred for 20 min at rt before it was quenched with 1 M NaOH. The mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over _{anhydrous Na2SO4} and concentrated to give the intermediate 5-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-3-methylpyrrolidin-3-ol (800 mg, UPLC-MS 1: m/z 426.1/428.1 [M+H] ⁺ , t _R = 1.00 min), which was redissolved in DCM (15 mL). TEA (0.32 mL, 2.3 mmol) and Boc-anhydride (250 mg, 1.2 mmol) were added and the reaction mixture was stirred at rt. for 16 h. After removal of the solvent, the residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient 0% to 20% EtOAc) to give the title compound (200 mg) as a colourless foam. UPLC-MS 1: m/z 526.2/528.2 [M+H] ⁺ , t _R = 1.42 min.

Step 6. 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 (C-XXXVI)

A suspension of tert-butyl 2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxy-4-methylpyrrolidine-1-carboxylate (C-XXXVI-f) (200 mg, 0.35 mmol), bis(pinacolato)diboron (134 mg, 0.53 mmol), potassium acetate (105 mg, 1.06 mmol) and PdCl adduct₂(dppf).CH₂Cl₂(29 mg, 0.035 mmol) in toluene (0.9 mL) was purged with Ar, then stirred at 100°C for 16 h under Ar. The reaction mixture was diluted with toluene, filtered over Hyflo and concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient 0% to 20% EtOAc) to give the title compound (150 mg) as a foam. UPLC-MS 1: m/z 574.4 [M+H]⁺, t_R=1.47 min; the absolute configuration at position C-2 and position C-4 of pyrrolidine is not determined.

Synthesis of tert-butyl (2S,4R)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-fluoropyrrolidine-1-carboxylate (C-XXXVII)

Reaction scheme C-XXXVII:

Step 1. (S)-N-Allyl-1-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)but-3-ene-1-amine (C-XXXVII-a) and (R)-N-allyl-1-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)but-3-ene-1-amine (C-XXXVII-b)

Under Ar atmosphere, to a stirred solution of (S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-carbaldehyde (C-XXXII-a) (12.3 g, 34.5 mmol) in DCM (75 mL) were added allylamine (13 mL, 173 mmol) and AcOH (2 mL, 34.5 mmol). The reaction mixture was stirred for 3 h at rt and concentrated. The crude intermediate was dissolved in THF (75 mL) and a solution of allylmagnesium bromide in Et ₂ O (52 mL, 52 mmol) was added at 0 °C. The reaction mixture was stirred for 1 h at rt, then quenched by adding a saturated solution of NH ₄ Cl (200 mL) and extracted twice with with EtOAc (2×200 mL). The combined organic layers were washed with saturated NaHCO ₃ solution (150 mL), dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was flash chromatographed (silica, cyclohexane/EtOAc; gradient from 0% to 6% EtOAc) to afford two separate diastereoisomers:

(S)-N-allyl-1-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)but-3-en-1-amine (C-XXXVII-a) (6.1 g): UPLC-MS 1: m/z 436.4/438.4 [M+H] ⁺ , t _R = 1.51 min.

(R)-N-allyl-1-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)but-3-en-1-amine (C-XXXVII-b) (5.7 g): UPLC-MS 1: m/z 436.1/438.1 [M+H] ⁺ , t _R = 1.54 min.

Step 2. (S)-1-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)but-3-en-1-amine (C-XXXVII-c)

Under Ar atmosphere, to a stirred solution of (S)-N-allyl-1-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)but-3-en-1-amine (C-XXXVII-a) (6.1 g, 14.0 mmol) in DCM (75 mL) were added N,N'-dimethylbarbituric acid (6.54 g, 41.9 mmol) and Pd(PPh ₃ ) ₄ (0.161 g, 0.140 mmol). The reaction mixture was stirred at 40 °C for 2 h. Saturated NaHCO ₃ solution was added and the mixture was extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 35% EtOAc) to give the title product (5.7 g). UPLC-MS 1: m/z 396.3/398.3 [M+H] ⁺ , t _R = 0.93 min.

Step 3. N-((S)-1-((S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (C-XXXVII-d)

Under Ar atmosphere, to a stirred solution of (S)-1-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)but-3-en-1-amine (C-XXXVII-c) (5.72 g, 14.42 mmol) in DCM (100 mL) were added TEA (4.02 mL, 28.8 mmol) and tert-butylsulfinyl chloride (2.0 mL, 15.9 mmol). The reaction mixture was stirred at 0 °C for 1 h. Saturated NaHCO ₃ (125 mL) was added and the mixture was extracted twice with DCM (2 x 100 mL). The combined organic extracts were washed with water and brine, dried (phase separation cartridge), and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 60% EtOAc) to give the title product (5.5 g) as a diastereomeric mixture. UPLC-MS 1: m/z 500.1/502.1 [M+H] ⁺ , t _R = 1.45 min.

Step 4. N-((1S)-1-((S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-2-(oxiran-2 -yl)ethyl)-2-methylpropane-2-sulfonamide (C-XXXVII-e)

At rt under Ar, to a stirred solution of N-((S)-1-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (C-XXXVII-d) (5.46 g, 10.9 mmol) in DCM (100 mL) was added mCPBA (8.1 g, 32.7 mmol). The reaction mixture was stirred at rt for 20 h. Saturated _NaHCO3 (50 mL) was added and the mixture was extracted twice with DCM (2×100 mL). The combined organic extracts were washed with water and brine, dried (phase separation cartridge), and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 50% EtOAc) to give the title product (5.1 g) as a diastereomeric mixture. UPLC-MS 1: m/z 530.0/532.0 [MH] ^- , t _R = 1.33 min.

Step 5. (5S)-5-((S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1-(tert-butylsulfonyl)pyrrolidin-3-ol (C-XXXVII-f)

Under Ar atmosphere, to a stirred solution of N-((1S)-1-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-2-(oxiran-2-yl)ethyl)-2-methylpropane-2-sulfonamide (C-XXXVII-e) (5.05 g, 9.48 mmol) in DMF (40 mL) were added KI (1.57 g, 9.48 mmol) and K ₂ CO ₃ (3.93 g, 28.4 mmol). The reaction mixture was stirred at 100 °C for 1 h. Saturated NaHCO ₃ solution (50 mL) was added and the mixture was extracted twice with EtOAC (2 x 75 mL). The combined organic extracts were washed with sat. _NaHCO3 solution (75 mL) and brine, dried over _{anhydrous Na2SO4} and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 55% EtOAc) to give the title product (4.9 g) as a diastereomeric mixture. UPLC-MS 1: m/z 551.1.1 [M+NH3] ⁺ , t _R = 1.34 min.

Step 6. (3S,5S)-5-((S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidin-3-ol (C-XXXVII-g) and (3R,5S)-5-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidin-3-ol (C-XXXVII-h)

At 0 ^o C under Ar atmosphere, to a stirred solution of (5S)-5-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1-(tert-butylsulfonyl)pyrrolidin-3-ol (C-XXXVII-f) (5.0 g, 9.35 mmol) in DCM (50 mL) was added dropwise triflic acid (2.5 mL, 28.0 mmol). The reaction mixture was stirred at 0 °C for 1 h. Saturated NaHCO ₃ solution (125 mL) was added and the mixture was extracted twice with DCM (2 x 100 mL). The combined organic extracts were washed with saturated NaHCO ₃ solution (125 mL) and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was subjected to flash chromatography (silica, DCM/MeOH, gradient: 0% to 7% MeOH) to separate the diastereoisomers:

(3S,5S)-5-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidin-3-ol (C-XXXVII-g) (1.2 g). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 7.52 (d, J = 7.5 Hz, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H), 7.07 (d, J = 9.5 Hz, 1H), 4.71 (t, J = 3.6 Hz, 1H), 4.05

(q, J=5.9 Hz, 1H), 3.80 (d, J=16.1 Hz, 1H), 3.55 (t, J=8.4 Hz, 1H), 3.36 (s , 1H), 2.90 (dd, J=10.2, 6.3 Hz, 1H), 2.45 (dd, J=10.5, 5.9 Hz, 1H), 1.74 (dt, J=13.6, 7.1 Hz, 1H), 1.31 (ddd, J=12.4, 9.5, 6.9 Hz, 1H). UPLC-MS 1: mass/charge 412.1/414.1 [M+H] ⁺ , t _R =0.83 min.

(3R,5S)-5-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidin-3-ol (C-XXXVII-h) (1.6 g) ¹ H NMR (600 MHz, DMSO- d ₆ ) δ (ppm) 7.53 (d, J=7.6 Hz, 2H), 7.37 (t, J=7.5 Hz, 2H), 7.30 (t, J=7.3 Hz, 1H), 7.09 (d, J=9.5 Hz, 1H), 4.53 (d, J=3.7 Hz, 1H), 3.99 (s, 1H), 3.79 (t, J=8.0 Hz, 1H), 3.66 (d, J=16.1 Hz, 1H), 2.69 (s, 3H), 1.50 (td, J=11.4, 9.2, 5.2 Hz, 1H), 1.41 (dd, J=13.4, 6.9 Hz, 1H). UPLC-MS 1: mass/charge 412.1/414.1 [M+H] ⁺ , t _R =0.84 min.

Step 7. tert-Butyl (2S,4S)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxypyrrolidine-1-carboxylate (C-XXXVII-i)

At rt, to a stirred solution of (3S,5S)-5-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidin-3-ol (C-XXXVII-g) (1.2 g, 2.81 mmol) in THF (20 mL) were added Boc-anhydride (0.75 mL, 3.10 mmol) and TEA (0.8 mL, 5.62 mmol). The reaction mixture was stirred at rt for 1 h. Saturated _NaHCO3 (75 mL) was added and the mixture was extracted twice with DCM (2×100 mL). The combined organic extracts were washed with water and brine, dried over _{anhydrous Na2SO4} and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 60% EtOAc) to give the title product (1.42 g). UPLC-MS 1: m/z 556.0/557.9 [M+formate] ^- , t _R = 1.38 min.

Step 8. tert-Butyl (2S,4S)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (C-XXXVII-j)

At 0 °C under Ar, to a stirred solution of tert-butyl (2S,4S)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxypyrrolidine-1-carboxylate (C-XXXVII-i) (100 mg, 0.195 mmol) in DCM (3 mL) were added methanesulfonic anhydride (68 mg, 0.390 mmol) and TEA (0.14 mL, 0.98 mmol). The reaction mixture was stirred at rt for 2 h. A sat. solution of NH ₄ Cl (100 mL) was added and the mixture was extracted twice with DCM (2 x 75 mL). The combined organic extracts were washed with sat. NaHCO ₃ solution (50 mL) and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give the title product. UPLC-MS 1: m/z 534.0/536.0 [M- tert- butyl] ⁺ , t _R = 1.42 min.

Step 9. tert-Butyl (2S,4R)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-fluoropyrrolidine-1-carboxylate (C-XXXVII)

At rt under Ar, to a stirred solution of tert-butyl (2S,4S)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (C-XXXVII-j) (890 mg, 1.51 mmol) in THF (10 mL) was added TBAF (15.1 mL, 15.1 mmol, 1 M in THF). The reaction mixture was then stirred at 40 °C for 1 h. Saturated NaHCO ₃ (50 mL) was added and the mixture was extracted twice with EtOAc (2 x 75 mL). The combined organic extracts were washed with sat. _NaHCO3 solution and brine, dried over _{anhydrous Na2SO4} and concentrated. The residue was purified by preparative HPLC (Waters Sunfire prep C18, OBD 5 μm. 30 X 100 mm, A: H2O+0.1% TFA, B: ACN, gradient: 25 to 100% B over 20 min, hold 1 min, flow 40 mL/min) to give the title product (109 mg). UPLC-MS 1: m/z 458.0/460.0 [M- tert- butyl] ⁺ , t _R = 1.43 min. ¹ H NMR (400 MHz, DMSO -d6 ) δ (ppm) 7.48-7.43 (m, 2H), 7.42-7.30 (m, 3H), 7.16 (d, J=9.5 Hz, 1H) _, 5.04 (d, J=54 Hz, 1H), 4.72 (dd, J=8.5, 5.6 Hz, 11H), 3.84 (sbr, 2H), 3.44 (d, J=16.7 Hz, 1H), 2.37-2.02 (m, 3H), 1.29 (s, 9H).

Synthesis 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 (C-XXXVIII)

Reaction scheme C-XXXVIII:

Step 1. (2S,3S)-4-Bromo-5-chloro-6-fluoro-3-(methoxymethoxy)-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XXXVIII-a)

At 0 °C under Ar atmosphere, to a stirred solution of (2S,3S)-4-bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XIV-c) (20 g, 54.3 mmol) in DMF (200 mL) was added NaH (1.65 g, 65.1 mmol, 95%). After 30 min, chloromethyl methyl ether (5.36 mL, 70.5 mmol) was added and the mixture was stirred at rt for another 2 h. A saturated solution of NaHCO ₃ (100 mL) was added, followed by extraction with EtOAc (2×100 mL). The combined organic extracts were washed with a saturated solution of NaHCO ₃ (50 mL) and dried over Na ₂ SO ₄ . Concentration afforded the crude product, which was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 15% EtOAc) to afford the title compound (10.6 g) as a white solid. UPLC-MS 1: no ionization, t _R = 1.33 min.

Step 2. (2R,3S)-4-Bromo-5-chloro-6-fluoro-3-(methoxymethoxy)-2-phenyl-2,3-dihydrobenzofuran-2-carboxamide (C-XXXVIII-b)

At rt, to a stirred solution of (2S,3S)-4-bromo-5-chloro-6-fluoro-3-(methoxymethoxy)-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XXXVIII-a) (10.6 g, 25.7 mmol) in dioxane (75 mL) and water (75 mL) was added LiOH (3.1 g, 128 mmol). After 2 h at 100 °C, the reaction mixture was quenched with 1 N HCl and extracted twice with DCM (2×100 mL). The combined organic layers were washed with 1 N HCl (100 mL), dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc; gradient 0% to 85% EtOAc) to give the title product (6.9 g) as a colorless solid. UPLC-MS 1: m/z 428.1/430.1 [MH] ^- , t _R = 1.11 min.

Step 3. (2R,3S)-4-Bromo-5-chloro-6-fluoro-3-(methoxymethoxy)-2-phenyl-2,3-dihydrobenzofuran-2-carboxylic acid (C-XXXVIII-c)

At rt, to a stirred solution of (2R,3S)-4-bromo-5-chloro-6-fluoro-3-(methoxymethoxy)-2-phenyl-2,3-dihydrobenzofuran-2-carboxamide (C-XXXVIII-b) (6.9 g, 16.02 mmol) in dioxane (20 mL) and water (20 mL) was added LiOH.H ₂ O (1.92 g, 80.0 mmol). After 20 h at 100 °C, the reaction mixture was quenched with 1 N HCl and extracted twice with DCM (2×100 mL). The combined organic layers were washed with 1 N HCl, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc; gradient 0% to 100% EtOAc) to give the title product (5.61 g) as a colorless solid. UPLC-MS 1: m/z 448.1/450.1 [M+NH3] ⁺ , t _R = 1.05 min.

Step 4. (2R,3S)-Methyl 4-bromo-5-chloro-6-fluoro-3-(methoxymethoxy)-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (C-XXXVIII-d)

At 0 °C, to a solution of (2R,3S)-4-bromo-5-chloro-6-fluoro-3-(methoxymethoxy)-2-phenyl-2,3-dihydrobenzofuran-2-carboxylic acid (C-XXXVIII-c) (5.61 g, 13.00 mmol) and oxalyl chloride (1.48 mL, 16.90 mmol) in DCM (50 mL) was added DMF (0.101 mL, 1.300 mmol). After 1 h at 0 °C, MeOH (26.3 mL, 650 mmol) was added and the reaction mixture was stirred at rt for an additional 1 h. The mixture was quenched by adding sat. NaHCO ₃ solution (100 mL), then extracted twice with DCM (2×125 mL). The organic layers were combined and washed with sat. NaHCO _{3 solution (} 125 mL), dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 25% EtOAc) to give the title product (3.39 g). UPLC-MS 1: m/z 462.1/464.1 [M+NH3] ⁺ , t _R = 1.31 min.

Step 5. ((2S,3S)-4-Bromo-5-chloro-6-fluoro-3-(methoxymethoxy)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XXXVIII-e)

At 0 ^o C under Ar, to a stirred solution of (2R,3S)-methyl 4-bromo-5-chloro-6-fluoro-3-(methoxymethoxy)-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (C-XXXVIII-d) (3.39 g, 7.61 mmol) in a mixture of THF (50 mL) and MeOH (1.23 mL, 30.4 mmol) was added LiBH ₄ (0.331 g, 15.21 mmol) portionwise. The reaction mixture was stirred for 1 h. The reaction mixture was then quenched by the addition of sat. NaHCO ₃ solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with sat. _NaHCO3 solution (75 mL), dried over anhydrous _Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica, _hexane /EtOAc; gradient 0% to 75% EtOAc) to give the title product (2.81 g). UPLC-MS 1: m/z 461.1/463.1 [M+formate] ^- , t _R = 1.24 min.

Step 6. (2R,3S)-4-Bromo-5-chloro-6-fluoro-3-(methoxymethoxy)-2-phenyl-2,3-dihydrobenzofuran-2-carbaldehyde (C-XXXVIII-f)

At -78 °C, DMSO (0.95 mL, 10.76 mmol) was added to a solution of oxalyl chloride (0.95 mL, 10.76 mmol) in DCM (15 mL). After 30 min at -78 °C, a solution of ((2S,3S)-4-bromo-5-chloro-6-fluoro-3-(methoxymethoxy)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XXXVIII-e) (2.81 g, 6.73 mmol) in DCM (10 mL) was added, followed by TEA (4.7 mL, 33.6 mmol). The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched by addition of brine (75 mL), then extracted twice with DCM (2×75 mL). The combined organic layers were washed with brine (75 mL), dried over _{anhydrous Na2SO4} and concentrated to give the title compound (2.85 g), which was used directly in the next step without further purification. UPLC-MS 1: t _R = 1.25 min.

Step 7. 4-Amino-1-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-(methoxymethoxy)-2-phenyl-2,3-dihydrobenzofuran-2-yl)butan-1-ol (C-XXXVIII-g)

Under Ar atmosphere, to a stirred suspension of magnesium (0.333 g, 13.71 mmol) in Et ₂ O (3 mL) were added a solution of 1-(3-bromopropyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine (C-XXXIV-a) (0.29 g, 1.03 mmol) in Et ₂ O (2 mL) and a crystal of I ₂ . The suspension was heated at reflux until the color disappeared, and another solution of 1-(3-bromopropyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine (C-XXXIV-a) (2.592 g, 9.26 mmol) in Et ₂ O (15 mL) was added. After 1 h at 40 °C, (2R,3S)-4-bromo-5-chloro-6-fluoro-3-(methoxymethoxy)-2-phenyl-2,3-dihydrobenzofuran-2-carbaldehyde (C-XXXVIII-f) (2.85 g, 6.86 mmol) in THF (15 mL) was added at 0 °C and stirring was continued for 1 h. The reaction mixture was quenched with saturated NH ₄ Cl (100 mL) and extracted twice with EtOAc (2 * 100 mL). The organic layers were combined and washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting crude product was purified by flash chromatography (silica, DCM/MeOH, gradient: 0% to 15% MeOH) to give the desired product (1.1 g) as a colorless solid. UPLC-MS 1: m/z 476.2/478.2 [M+H] ⁺ , t _R = 0.92 min.

Step 8. tert-Butyl (4-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-(methoxymethoxy)-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxybutyl)carbamate (C-XXXVIII-h)

At rt, to a stirred solution of 4-amino-1-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-(methoxymethoxy)-2-phenyl-2,3-dihydrobenzofuran-2-yl)butan-1-ol (C-XXXVIII-g) (1.03 g, 2.170 mmol) in THF (15 mL) were added Boc-anhydride (0.554 mL, 2.39 mmol) and TEA (0.61 mL, 4.34 mmol). The reaction mixture was stirred at rt for 1 h. Saturated _NaHCO3 solution (75 mL) was added and the mixture was extracted twice with EtOAc (2 * 100 mL). _The combined organic extracts were washed with water and brine, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 75% EtOAc) to afford the desired product (1.2 g). UPLC-MS 1: m/z 574.2/576.2 [M+H] ⁺ , t _R = 1.43 min.

Step 9. tert-Butyl ((2R,3S)-4-bromo-5-chloro-6-fluoro-3-(methoxymethoxy)-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-oxobutyl)carbamate (C-XXXVIII-i)

At -78°C, DMSO (0.47 mL, 6.68 mmol) was added to a solution of oxalyl chloride (0.292 mL, 3.34 mmol) in DCM (15 mL). After 30 min. At -78 °C, a solution of tert-butyl (4-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-(methoxymethoxy)-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxybutyl)carbamate (C-XXXVIII-h) (1.20 g, 2.09 mmol) in DCM (15 mL) was added, and TEA (1.46 mL, 10.5 mmol) was added, and the reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched by adding brine (100 mL), then extracted twice with DCM (2 * 100 mL). The organic layers were combined and washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 60% EtOAc) to give the title product (870 mg) as a colorless solid. UPLC-MS 1: m/z 572.2/574.2 [M+H] ⁺ , t _R = 1.45 min.

Step 10. (2S,3S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2-(pyrrolidin-2-yl)-2,3-dihydrobenzofuran-3-ol (C-XXXVIII-j and C-XXXVIII-k)

At rt, HCl (3.80 mL, 15.2 mmol, 4 M in dioxane) was added to tert-butyl (4-((2R,3S)-4-bromo-5-chloro-6-fluoro-3-(methoxymethoxy)-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-oxobutyl)carbamate (C-XXXVIII-i) (870 mg, 1.519 mmol) and the reaction mixture was stirred for 1 h. After removing the solvent, the residue was dissolved in DCM (3 mL), then NaBH(OAc) ₃ (966 mg, 4.56 mmol) was added and the mixture was stirred at rt for 16 h. _Saturated NaHCO3 solution (75 mL) was added and the mixture was extracted twice with EtOAc (2×75 mL). _The combined organic extracts were washed with water and brine, dried over anhydrous _Na2SO4 and concentrated. The resulting crude product was purified by flash chromatography (silica, DCM/MeOH, gradient: 0% to 10% MeOH) to afford the individual diastereoisomers:

Diastereomer C-XXXVIII-j (380 mg): ^1H NMR (400 MHz, DMSO - _d6 ) δ (ppm) ^1H NMR (400 MHz, DMSO - _d6 ) δ 7.66-7.58 (m, 2H), 7.36-7.23 (m, 5H), 5.15 (s, 1H), 3.93 (dd, J =8.2, 6.6 Hz, 1H), 3.79-3.63 (m, 1H), 2.82-2.72 (m, 1H), 2 .58-2.52 (m, 1H), 1.86-1.71 (m, 1H), 1.58-1.38 (m, 2H), 1.18-1.03 (m, 1H). UPLC-MS 1: mass/charge 414.1/416.1 [M+H] ⁺ , t _R =0.81 min.

Diastereomer C-XXXVIII-k (213 mg): UPLC-MS 1: mass/charge 414.1/416.2 [M+H] ⁺ , t _R =0.79 min.

Step 11. tert-Butyl 2-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (C-XXXVIII-l)

At rt, to a stirred solution of (2S,3S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2-(pyrrolidin-2-yl)-2,3-dihydrobenzofuran-3-ol (C-XXXVIII-j) (380 mg, 0.921 mmol) in THF (8 mL) were added Boc-anhydride (0.25 mL, 1.02 mmol) and TEA (0.26 mL, 1.84 mmol). The reaction mixture was stirred at rt for 1 h. _Saturated NaHCO3 (75 mL) was added and the mixture was extracted twice with EtOAc (2 * 100 mL). The combined organic extracts were washed with water and brine, dried over _{anhydrous Na2SO4} and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 20% EtOAc) to give the title product (328 mg). UPLC-MS 1: m/z 514.2 [M+H] ⁺ , t _R = 1.59 min.

Step 12. 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 (C-XXXVIII)

A deoxygenated suspension of tert-butyl 2-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (C-XXXVIII-l) (328 mg, 0.64 mmol), bis(pinacolato)diboron (244 mg, 0.959 mmol), KOAc (188 mg, 1.92 mmol) and PdCl adduct₂(dppf).CH₂Cl₂(52.2 mg, 0.064 mmol) in dioxane (6 ml) was stirred at 100°C for 16 h under Ar atmosphere. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, hexane/EtOAc; gradient: 0 to 100% EtOAc) to give the title product (399 mg) as a colorless solid. UPLC-MS 1: m/z 604.4 [M+formate]^-, t_R=1.61 min; the absolute configuration at position C-2 of pyrrolidine is not determined.

Synthesis tert-butyl-2-((2S,3S)-5-chloro-6-fluoro-3-methoxy-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-2,3-dihydrobenzofuran-2-yl)pyrrolidin-1-carboxylate (C-XXXIX)

Reaction scheme C-XXXIX:

Step 1. (2R,3S)-4-Bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carboxylic acid (C-XXXIX-a)

At rt, to a stirred solution of (2S,3S)-4-bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carbonitrile (C-XIV-c) (20 g, 54.3 mmol) in dioxane (100 mL) and water (100 mL) was added LiOH.H ₂ O (6.50 g, 271 mmol). After 2 h at 100 °C, the reaction mixture was quenched with 1 N HCl and extracted with DCM. The combined organic layers were washed with 1 N HCl, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, DCM/MeOH; gradient 0% to 8% MeOH) to give the title compound (21.5 g) as a colourless solid. LC-MS 1: m/z 386.9 [M+H] ⁺ , t _R = 0.92 min.

Step 2. (2R,3S)-Methyl 4-bromo-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (C-XXXIX-b)

Under Ar atmosphere, to a stirred solution of (2R,3S)-4-bromo-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-carboxylic acid (C-XXXIX-a) (21.5 g, 55.5 mmol) in DMF (200 mL) was added NaH (5.99 g, 150 mmol, 60% suspended in mineral oil) at 0 °C. After 30 min, MeI (7.98 mL, 128 mmol) was added and stirring at rt was continued for additional 2 h. For work-up, a saturated NaHCO ₃ solution was added, followed by extraction with EtOAc. The combined organic extracts were washed with a saturated NaHCO ₃ solution and dried over anhydrous Na ₂ SO ₄ . Concentration afforded a crude product which was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 10% EtOAc) to afford the title compound (10.7 g) as a colourless solid. UPLC-MS 1: m/z 432.0 [M+H] ⁺ , t _R = 1.33 min.

Step 3. ((2S,3S)-4-Bromo-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XXXIX-c)

Under Ar atmosphere, to a stirred solution of (2R,3S)-methyl 4-bromo-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (C-XXXIX-b) (10.7 g, 25.7 mmol) in a mixture of THF (200 mL) and MeOH (5 mL) was added LiBH ₄ (1.122 g, 51.5 mmol) portionwise at 0 °C and stirring was continued for 2 h. The reaction mixture was quenched by addition of saturated NaHCO ₃ solution and extracted with EtOAc. The combined organic layers were washed with saturated NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica, hexane/EtOAc; gradient 0% to 60% EtOAc) to give the title product (7.8 g) as a colorless solid. UPLC-MS 1: no ionization, t _R = 1.22 min.

Step 4. (2R,3S)-4-Bromo-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-carbaldehyde (C-XXXIX.d)

At -78 °C, DMSO (4.57 mL, 64.4 mmol) was added to a solution of oxalyl chloride (2.82 mL, 32.2 mmol) in DCM (50 mL). After 30 min at -78 °C, a solution of ((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanol (C-XXXIX-c) (7.8 g, 20.12 mmol) in DCM (50 mL) was added, as well as TEA (14.02 mL, 101 mmol), and the reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched by addition of brine and extracted with DCM. The organic layers were combined and washed with brine, dried over _{anhydrous Na2SO4} and concentrated to give the title compound (7.9 g) as a brownish powder. UPLC-MS 1: t _R = 1.26 min.

Step 5. 4-Amino-1-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)butan-1-ol (C-XXXIX-e)

Under Ar atmosphere, to a stirred suspension of magnesium (0.996 g, 41.0 mmol) in Et ₂ O (10 mL) were added a solution of 1-(3-bromopropyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine (C-XXXIV-a) (0.862 g, 3.07 mmol) in Et ₂ O (6.25 mL) and a crystal of I ₂ . The suspension was heated at reflux until the color disappeared, and another solution of 1-(3-bromopropyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine (C-XXXIV-a) (7.758 g, 27.63 mmol) in Et ₂ O (56.25 mL) was added. After 1 h at 40 °C, (2R,3S)-4-bromo-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-carbaldehyde (C-XXXIX-d) (7.9 g, 20.49 mmol) in THF (50 mL) was added at rt and stirring was continued for 1 h. The reaction mixture was quenched with saturated NH ₄ Cl solution and extracted with EtOAc. The organic layers were combined and washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting crude product was purified by flash chromatography (silica, DCM/MeOH, gradient: 0% to 10% MeOH) to give the desired product (6.65 g) as a colorless solid. UPLC-MS 1: mass/charge 446.1 [M+H] ⁺ , t _R =0.96 min.

Step 6. tert-Butyl (4-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxybutyl)carbamate (C-XXXIX-f)

At rt, to a stirred solution of 4-amino-1-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)butan-1-ol (C-XXXIX-e) (6.64 g, 14.93 mmol) in THF (100 mL) were added Boc-anhydride (3.81 mL, 16.42 mmol) and TEA (4.16 mL, 29.9 mmol). The reaction mixture was stirred at rt for 1 h. For work-up, saturated _NaHCO3 solution was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over _{anhydrous Na2SO4} and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 60% EtOAc) to give the desired product (6.3 g). UPLC-MS 1: m/z 546.1 [M+H] ⁺ , t _R = 1.40 min.

Step 7. tert-Butyl (4-((2R,3S)-4-bromo-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-oxobutyl)carbamate (C-XXXIX-g)

At -78 °C, DMSO (2.63 mL, 37.0 mmol) was added to a solution of oxalyl chloride (1.619 mL, 18.50 mmol) in DCM (50 mL). After 30 min at -78 °C, a solution of tert-butyl 4-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxybutyl)carbamate (C-XXXIX-f) (6.3 g, 11.56 mmol) in DCM (50 mL) and TEA (8.06 mL, 57.8 mmol) were added and the reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched by addition of brine, then extracted with DCM. The organic layers were combined and washed with brine, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 40% _EtOAc ) to give the title product (5.38 g) as a colorless solid. UPLC-MS 1: m/z 544.1 [M+H] ⁺ , t _R = 1.45 min.

Step 8. 2-((2S,3S)-4-Bromo-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine (C-XXXIX-h and C-XXXIX-i)

At rt, HCl (24.78 mL, 99 mmol, 4 M in dioxane) was added to tert-butyl (4-((2R,3S)-4-bromo-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-oxobutyl)carbamate (C-XXXIX-g) (5.38 g, 9.91 mmol) and the reaction mixture was stirred for 16 h. The reaction mixture was concentrated, the residue was dissolved in DCM (25 mL) and NaBH(OAc) ₃ (6.30 g, 29.7 mmol) was added before stirring for 1 h. A saturated solution of _NaHCO3 was added for work-up and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over anhydrous _Na2SO4 and concentrated. The resulting crude product was flash chromatographed (silica, DCM/MeOH, gradient: 0% to 10% _MeOH ) to afford the individual diastereoisomers, C-XXXIX-h and C-XXXIX-i:

Diastereoisomer C-XXXIX-h (1.48 g). ^1H NMR (400 MHz, DMSO -d6 ) δ (ppm) 7.69-7.56 (m, 2H), 7.38-7.23 (m, 4H) _, 4.84 (s, 1H) , 4.10-3.94 (m, 1H), 3.76 (s, 3H), 2.80-2.66 (m, 1H), 2.57-2.54 (m, 1H), 2.31-2.20 (m, 1H), 1.91-1.77 (m, 1H), 1.53-1 .32 (m, 2H), 1.11-0.97 (m, 1H). UPLC-MS 1: mass/charge 426.1 [M+H] ⁺ , t _R =0.96 min.

Diastereoisomer C-XXXIX-i (928 mg): UPLC-MS 1: m/z 426.4 [M+H] ⁺ , t _R =1.04 min.

Step 9. tert-Butyl 2-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (C-XXXIX-j)

At rt, to a stirred solution of 2-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine (C-XXXIX-h) (1.40 g, 3.28 mmol) in THF (15 mL) were added Boc-anhydride (0.838 mL, 3.61 mmol) and TEA (0.915 mL, 6.56 mmol). The reaction mixture was stirred at rt for 1 h. For work-up, saturated _NaHCO3 solution was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over _{anhydrous Na2SO4} and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 10% EtOAc) to give the desired product (1.69 g) as a colorless solid. UPLC-MS 1: m/z 528.1 [M+H] ⁺ , t _R = 1.64 min.

Step 10. 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 (C-XXXIX)

A deoxygenated suspension of tert-butyl 2-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (C-XXXIX-j) (1.28 g, 2.430 mmol), bis(pinacolato)diboron (0.925 g, 3.64 mmol), KOAc (0.715 g, 7.29 mmol) and PdCl adduct₂(dppf).CH₂Cl₂(0.198 g, 0.243 mmol) in dioxane (15 ml) was stirred at 100°C for 16 h under Ar atmosphere. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, hexane/EtOAc; gradient: 0 to 50%) to give the title product (403 mg) as a colorless solid. UPLC-MS 1: m/z 574.3 [M+H]⁺, t_R=1.61 min; the absolute configuration at position C-2 of pyrrolidine is not determined.

Synthesis of 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 (C-XL)

Reaction scheme of C-XL:

Step 1. 4-Amino-1-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)butan-1-ol (C-XL-a)

To magnesium (1.12 g, 46.0 mmol) in Et ₂ O (20 mL) at rt was added 3 mL of a solution of 1-(3-bromopropyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine (C-XXXIV-a) (9.28 g, 33.1 mmol) in Et ₂ O (40 mL). Iodine (0.233 g, 0.920 mmol) was added and the reaction mixture was stirred at 45 °C. The rest of the 1-(3-bromopropyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine solution was added dropwise at reflux temperature. After 1.5 h at reflux temperature, the Grignard solution was cooled to rt. and it was added dropwise at 0°C to a stirred solution of (2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carbaldehyde (C-XXXIII-a) (8 g, 18.40 mmol) in THF (40 mL). The reaction mixture was quenched with saturated NH ₄ Cl solution. The mixture was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude material was purified by flash chromatography (silica, DCM/(7N ammonia in MeOH), gradient 0% to 15% (7N ammonia in MeOH)) to give the title compound as a diastereomeric mixture (3.2 g) as a colourless foam. UPLC-MS 1: m/z 428.1/430.1 [M+H] ⁺ , t _R = 0.91 min and 0.93 min.

Step 2. tert-Butyl (4-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxybutyl)carbamate (C-XL-b)

To a stirred solution of 4-amino-1-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)butan-1-ol (C-XL-a) (3.23 g, 7.35 mmol) in DCM (30 mL) was added TEA (3.07 mL, 22.1 mmol) and Boc-anhydride (2.56 mL, 11.03 mmol) sequentially at rt. The reaction mixture was stirred at rt for 15 min. The crude mixture was diluted in DCM and water and extracted with DCM. _The combined organic extracts were washed with water and brine, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, EtOAc/Heptane, gradient 0% to 60% EtOAc) to give the title compound as a diastereomeric mixture (3.9 g) as a colorless foam. UPLC-MS 1: m/z 528.0/530.0 [M+H] ⁺ , t _R = 1.30 min and 1.34 min.

Step 3. tert-Butyl (4-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-oxobutyl)carbamate (C-XL-c)

At -78 °C, DMSO (1.675 mL, 23.60 mmol) in DCM (10 mL) was added to a stirred solution of oxalyl chloride (1.05 mL, 11.8 mmol) in DCM (20 mL). The reaction mixture was stirred for 15 min at -78 °C. Then a solution of tert-butyl (4-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxybutyl)carbamate (C-XL-b) (3.9 g, 7.37 mmol) in DCM (20 mL) was added and the mixture was stirred at -78 °C for 15 min. TEA (5.14 mL, 36.9 mmol) was added and the reaction mixture was warmed to rt. for 1 h. The crude material was purified by flash chromatography (silica, EtOAc/Heptane, gradient 0% to 40% EtOAc) to give the title compound (1.88 g) as a colourless foam. UPLC-MS 1: m/z 524.2/526.1 [MH] ^- , t _R = 1.46 min.

Step 4. 2-((2S,3S)-4-Bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine (C-XL-d)

At 0 °C, tert-butyl (4-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-oxobutyl)carbamate (C-XL-c) (1.87 g, 2.63 mmol) was treated with HCl (12 mL, 48.0 mmol, 4 M in dioxane). The reaction mixture was stirred at rt for 1 h. After removal of the solvent, the residue was taken up in MeOH (8 mL), then sodium triacetoxyborohydride (1.67 g, 7.88 mmol) was added at rt and the mixture was stirred for 1 h. A white suspension was obtained. THF (8 mL) was added, followed by sodium borohydride (1.49 g, 39.4 mmol). The reaction was quenched with acetone and water. The crude mixture was extracted twice with DCM. The combined organic extracts were washed with water and brine, dried over _{anhydrous Na2SO4} and concentrated. The crude product was purified by flash chromatography (silica, DCM/(7N ammonia in MeOH), gradient 0% to 5% (7N ammonia in MeOH)) to give the title compound (873 mg) as a colorless foam. UPLC-MS 1: m/z 410.0/412.0 [M+H] ⁺ , t _R = 0.93 min.

Step 5. tert-Butyl 2-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (C-XL-e)

At rt, to a stirred solution of 2-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine (C-XL-d) (875 mg, 1.96 mmol) in DCM (15 mL) was added TEA (0.82 mL, 5.87 mmol) followed by Boc-anhydride (0.681 mL, 2.93 mmol). The reaction mixture was stirred at rt for 16 h. Water was added and the mixture was extracted with DCM. _The combined organic extracts were washed with water and brine, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, EtOAc/Hep, gradient 0% to 20% EtOAc) to give the title compound (1.05 g) as a colorless foam. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ (ppm) 7.39 (d, J = 7.5 Hz, 2H), 7.34-7.14 (m, 4H), 4.63 (t, J = 5.9 Hz, 1H), 3.77 (s, 1H), 3.43-3.18 (m, 2H), 2.34-1.92 (m, 3H), 1.69-1.51 (m, 4H), 1.41-1.14 (m, 9H). UPLC-MS 1: mass/charge 510.2/512.2 [M+H] ⁺ , t _R =1.65 min.

Step 6. 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 (C-XL)

At 60 °C, to a stirred mixture of tert-butyl 2-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (C-XL-e) (1 g, 1.76 mmol), bis(pinacolato)diboron (0.671 g, 2.64 mmol) and potassium hydroxide (0.247 g, 4.40 mmol) in toluene (12 mL) was added the adduct PdCl ₂ (dppf).CH ₂ Cl ₂ (0.144 g, 0.176 mmol). The mixture was stirred at 100 °C for 15 min. The reaction mixture was filtered over Hyflo and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient 0% to 20% EtOAc) to give the title compound (1.2 g) as a colorless foam. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ (ppm) 7.43-7.11 (m, 6H), 4.59 (t, J=5.7 Hz, 1H), 3.90-3.77 (m, 1H), 2.11-1.95 (m, 2H), 1.69-1.57 (m, 4H), 1.50 (d, J=6.9 Hz, 3H), 1.35-1.24 (m, 21H). UPLC-MS 2: m/z 558.2 [M+H] ⁺ , t _R =8.99 min; the absolute configuration at the C-2 position of pyrrolidine is not determined.

Synthesis tert-butyl-(S)-2-((S)-5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)-2,3-dihydrobenzofuran-2-yl)piperidine-1-carboxylate (C-XLI)

Reaction scheme C-XLI:

Step 1. N-Allyl-1-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)but-3-en-1-amine (C-XLI-a)

Under Ar, to a stirred solution of ((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-carbaldehyde (C-XXXII-a) (8.7 g, 24.5 mmol) in DCM (75 mL) were added allylamine (9.2 mL, 122 mmol) and AcOH (1.401 mL, 24.47 mmol). The reaction mixture was stirred for 3 h, then concentrated and diluted in THF (75 mL). Allylmagnesium bromide in _Et2O (36.7 mL, 36.7 mmol) was then added at 0 °C and RM was stirred for 1 h. The mixture was then quenched by adding sat. _NaHCO3 solution and extracted with DCM. The combined organic layers were washed with sat. NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc; gradient 0% to 20% EtOAc) to give the title compound (9.1 g) as a diastereomeric mixture. UPLC-MS 1: m/z 436.4/438.4 [M+H] ⁺ , t _R = 1.53/1.56 min.

Step 2. (S)-2-((S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1,2,3,6-tetrahydropyridine (C-XLI-b) and (R)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1,2,3,6-tetrahydropyridine (C-XLI-c)

At rt under Ar, to a stirred solution of N-allyl-1-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)but-3-en-1-amine (C-XLI-a) (5 g, 11.45 mmol) in toluene (40 mL) was added Grubb's ^2nd generation catalyst, benzylidene(1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(tricyclohexylphosphine)ruthenium (0.194 g, 0.229 mmol). The reaction mixture was stirred at 80 °C for 1 h, then quenched with saturated NaHCO ₃ solution (100 mL) and extracted twice with EtOAc (2×100 mL). The combined organic layers were washed with _{saturated NaHCO3} solution (100 mL), dried over _{anhydrous Na2SO4} and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc; gradient from 0% to 25% EtOAc) to afford the title compounds as separate diastereoisomers:

(S)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1,2,3,6-tetrahydropyridine (C-XLI-b) (2.45 g) ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 7.56-7.48 (m, 2H), 7.45-7.27 (m, 3H), 7.12 (d, J=9.5 Hz, 1H), 5.72-5.58 (m, 2H), 3.85 (dd, J=16.4, 1.9 Hz, 1H), 3.42 (dd, J=16.4, 1.5 Hz, 1H), 3.28-3.22 (m, 2H), 3.10 (dd, J=10.5, 3.8 Hz, 1H), 2.03-1.91 (m, 1H), 1.91-1.77 (m, 1H), 1.75-1.61 (m, 1H). UPLC-MS 1: m/z 410.2/412.3 [M+H] ⁺ , t _R =0.91 min.

(R)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1,2,3,6-tetrahydropyridine (C-XLI-c) (1.15 g) ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 7.49-7.44 (m, 2H), 7.43-7.36 (m, 2H), 7.34-7.27 (m, 1H), 7.17 (d, J=9.6 Hz, 1H), 5.75-5.59 (m, 2H), 4.15 (dd, J=15.9, 2.0 Hz, 1H), 3.31-3.25 (m, 2H), 3.17-3.10 (m, 2H), 1.98-1.83 (m, 1H), 1.63-1.52 (m, 1H), 1.39-1.28 (m, 1H). UPLC-MS 1: m/z 410.3/412.3 [M+H] ⁺ , t _R =0.95 min.

Step 3. (S)-2-((S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)piperidine (C-XLI-d)

At rt, a solution of (S)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-1,2,3,6-tetrahydropyridine (C-XLI-b) (2.45 g, 5.99 mmol) in THF (50 mL) and MeOH (50 mL) was treated with Raney-Ni (500 mg) and hydrogenated at 0.1 bar overpressure in a shake flask for 20 h. The reaction mixture was filtered and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 50% EtOAc) to give the title compound (2.14 g). UPLC-MS 1: mass/charge 412.3 [M+H] ⁺ , t _R =0.95 min.

Step 4. tert-Butyl (S)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)piperidine-1-carboxylate (C-XLI-e)

At rt, to a stirred solution of (S)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)piperidine (C-XLI-d) (2.14 g, 5.21 mmol) in THF (20 mL) were added Boc-anhydride (1.331 mL, 5.73 mmol) and TEA (1.5 mL, 10.4 mmol). The reaction mixture was stirred at rt for 5 days. Then saturated NaHCO ₃ solution (75 mL) was added and the mixture was extracted twice with EtOAc (2×100 mL). The combined organic extracts were washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 10% EtOAc) to give the title product (2.14 g). UPLC-MS 1: m/z 454.3/456.3 [M- tert- butyl+H] ⁺ , t _R = 1.64 min.

Step 5. tert-Butyl-(S)-2-((S)-5-chloro-6-fluoro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-2,3-dihydrobenzofuran-2-yl)piperidin-1-carboxylate (C-XLI)

A deoxygenated suspension of tert-butyl (S)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)piperidine-1-carboxylate (C-XLI-e) (2.14 g, 4.19 mmol), bis(pinacolato)diboron (1.6 g, 6.3 mmol), KOAc (1.3 g, 12.6 mmol) and PdCl adduct₂(dppf).CH₂Cl₂(0.345 g, 0.420 mmol) in toluene (25 mL) was stirred at 100°C for 16 h under Ar atmosphere. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, hexane/EtOAc; gradient: 0 to 10%) to give the title product (1.94 g) as a colorless solid. UPLC-MS 1: m/z 558.6 [M+H]⁺, t_R=1.65 min.

Synthesis of 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 (C-XLII)

Reaction scheme C-XLII:

Step 1. 3-((S)-4-Bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)morpholine (C-XLII-a)

Under Ar atmosphere, (S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-carbaldehyde (C-XXXII-a) (2.5 g, 6.97 mmol) and 4A molecular sieve powder (approximately 100 mg/mmol) were added to a stirred solution of SnAP M reagent (2.5 g, 6.97 mmol) in DCM (20 mL). The reaction mixture was stirred at rt for 16 h and filtered through celite to remove molecular sieves. The filtrate was concentrated under reduced pressure to afford the pure imine. In a separate flask, anhydrous Cu(OTf) ₂ (2.5 g, 6.97 mmol) was suspended in HFIP (10 mL). 2,6-Lutidine (0.81 mL, 6.97 mmol) was added and the resulting suspension was stirred at rt for 1 h. A solution of the imine dissolved in DCM/HFIP (20 mL, 1:1) was added in one portion and the resulting mixture was stirred at rt for 16 h. Saturated _NaHCO3 (100 mL) was added and the mixture was extracted twice with DCM (2 x 75 mL). The combined organic extracts were washed with sat. _NaHCO3 (50 mL) and brine, dried over _{anhydrous Na2SO4} and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 100% EtOAc) to give the title product (1.34 g) as a diastereomeric mixture. UPLC-MS 1: m/z 412.1/414.1 [M+H] ⁺ , t _R = 0.92 and 0.95 min.

Step 2. tert-Butyl 3-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)morpholine-4-carboxylate (C-XLII-b)

At rt, to a stirred solution of 3-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)morpholine (C-XLII-a) (1.4 g, 3.30 mmol) in DCM (15 mL) were added Boc-anhydride (0.95 mL, 3.96 mmol) and TEA (0.7 mL, 4.95 mmol). The reaction mixture was stirred at rt for 1 h. Saturated _NaHCO3 (75 mL) was added and the mixture was extracted twice with EtOAc (2 * 75 mL). The combined organic extracts were washed with sat. _NaHCO3 (75 mL) and brine, dried over _{anhydrous Na2SO4} and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 50% EtOAc) to afford the desired product (1.7 g) as a diastereomeric mixture. UPLC-MS 1: m/z 556.1/558.1 [M+formate] ^- , t _R = 1.51 and 1.52 min.

Step 3. 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 (C-XLII)

A deoxygenated suspension of tert-butyl 3-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)morpholine-4-carboxylate (C-XLII-b) (995 mg, 1.94 mmol), bis(pinacolato)diboron (739 mg, 2.91 mmol), KOtBu (305 mg, 2.72 mmol) and PdCl adduct₂(dppf).CH₂Cl₂(158 mg, 0.194 mmol) in toluene (10 ml) was stirred at 100°C for 16 h under Ar atmosphere. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, hexane/EtOAc; gradient: 0 to 40%) to afford the title product (890 mg) as a diastereomeric mixture. UPLC-MS 1: m/z 560.4/562.4 [M+H]⁺, t_R=1.54 and 1.55 min.

Synthesis of 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 (C-XLIII)

Reaction scheme C-XLIII:

Step 1. (S)-4-Bromo-5-chloro-N-methoxy-N-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carboxamide (C-XLIII-a)

At rt, to a solution of (S)-4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylic acid (CIm) (2.0 g, 5.66 mmol) in dioxane (100 mL) were added sequentially DIPEA (4 mL, 22.7 mmol), HATU (2.58 g, 6.79 mmol), and DMAP (0.035 g, 0.283 mmol). N,O-Dimethylhydroxylamine (0.662 g, 6.79 mmol) was then added and RM was stirred at rt for 1.5 h. 1 N HCl and water were added. The layers were separated. The organic layer was washed with 1 N NaOH, then brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The crude material was purified by flash chromatography (silica, cyclohexane/EtOAc) to give the title compound (1.7 g) as a light beige solid. UPLC-MS 1: m/z 396.1/398.1 [M+H] ⁺ , t _R = 1.34 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.50-7.25 (m, 6H), 7.02 (d, J = 8.5 Hz, 1H), 4.24 (d, J = 17.0 Hz, 1H), 3.38 (d, J = 16.9 Hz, 1H), 3.27 (d, J = 13.6 Hz, 3H), 3.08 (s, 3H), 1.38 (s, 1H

Step 2 . (S)-4-Bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carbaldehyde (C-XLIII-b)

At -78 °C, to a solution of (S)-4-bromo-5-chloro-N-methoxy-N-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carboxamide (C-XLIII-a) (2.5 g, 6.30 mmol) in DCM (300 mL) was added dropwise DIBAL-H (20 mL, 19 mmol, 1 M in THF). The reaction mixture was stirred at -78 °C for 5 h before it was quenched with MeOH. The mixture was acidified with 1 N HCl and extracted twice with DCM. The combined organic extracts were washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient 0% to 10% EtOAc) to give the title compound (1.4 g). UPLC-MS 1: no ionization, t _R = 1.22 min.

Step 3. N-((E)-((S)-4-Bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methylene)-2-methylpropane-2-sulfinamide (C- XLIII-c)

The title compound (2.16 g) was prepared from (S)-4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carbaldehyde (C-XLIII-b) (1.4 g, 4.15 mmol) as a crude product, which was used directly in the next step without further purification, using reaction conditions similar to those described for intermediate C-XXXII, step 2. UPLC-MS 1: m/z 440.1/442.1 [M+H] ⁺ , t _R = 1.44/1.45 min.

Step 4. N-(1-((S)-4-Bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)ethyl)-2-methylpropane-2-sulfinamide (C-XLIII-d)

At 0 °C, to a solution of N-((E)-((S)-4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methylene)-2-methylpropane-2-sulfinamide (C-XLIII-c) (1.08 g, 2.45 mmol) in DCM (12 mL) was added dropwise MeMgBr (3.3 mL, 9.80 mmol, 3 M in Et ₂ O). The reaction mixture was stirred for 1 h at rt, then quenched with saturated NH ₄ Cl solution. 1 N HCl was added to adjust the pH to approximately 7. The mixture was extracted twice with DCM. The combined organic extracts were washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient 0% to 20% EtOAc) to afford the title compound as a diastereomeric mixture (375 mg) as a colourless foam. UPLC-MS 1: m/z 456.1/458.1 [M+H] ⁺ , t _R = 1.36/138 min.

Step 5. 1-((S)-4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)ethan-1-amine hydrochloride salt (C-XLIII-e)

At rt, a suspension of N-(1-((S)-4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)ethyl)-2-methylpropane-2-sulfinamide (C-XLIII-d) (370 mg, 0.761 mmol) in dioxane (7.7 mL) was treated with HCl (0.4 mL, 1.60 mmol, 4 M in dioxane). The reaction mixture was stirred at rt for 15 min, then filtered. The solid was washed with dioxane, then dried under HV to give the title compound as a diastereomeric mixture (240 mg) as a colorless solid. UPLC-MS 1: mass/charge 352.0/354.0 [M+H] ⁺ , t _R =0.87 min.

Step 6. tert-Butyl (1-((S)-4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)ethyl)carbamate (C-XLIII-f)

The title compound (290 mg, colourless oil) was prepared as a diastereomeric mixture from 1-((S)-4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)ethan-1-amine hydrochloride salt (C-XLIII-e) (240 mg, 0.617 mmol) using reaction conditions similar to those described for intermediate C-XXXIII, step 7. UPLC-MS 1: m/z 352.1/354.1 [M-BOC] ⁺ , t _R = 1.49/1.50 min.

Step 7. 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 (C-XLIII)

The title compound (190 mg, colourless foam) was obtained as a diastereomeric mixture from tert-butyl (1-((S)-4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)ethyl)carbamate (C-XLIII-f)

(240 mg, 0.617 mmol) using reaction conditions similar to those described for intermediate C-XXXIII, step 8. UPLC-MS 1: m/z 500.4 [M+H] ⁺ , t _R = 1.54 min.

Synthesis of 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 (C-XLIV)

Reaction scheme C-XLIV:

Step 1. (R)-N-((E)-((2S,3S)-4-Bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methylene)-2-methylpropane-2-sulfinamide (C-XLIV-a)

The title compound (1.51 g, white solid) was prepared from (2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carbaldehyde (C-XXXIII-a) (2.49 g, 6.74 mmol) and (R)-2-methyl-2-propanesulfinamide (0.98 g, 8.1 mmol) using reaction conditions similar to those described for intermediate C-XXXII, step 2. UPLC-MS 1: m/z 472.1/474.1 [M+H] ⁺ , t _R = 1.47/1.49 min.

Step 2. (R)-N-(1-((2S,3S)-4-Bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)ethyl)-2-methylpropane-2-sulfinamide (C-XLIV-b)

At 0 °C under Ar, to a stirred solution of (R)-N-((E)-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methylene)-2-methylpropane-2-sulfinamide (C-XLIV-a) (1.51 g, 3.19 mmol) in DCM (20 mL) was added MeMgBr (4.26 mL, 12.77 mmol, 3 M in Et ₂ O). The reaction mixture was stirred at rt for 1 h. For work-up, a sat. NH ₄ Cl solution was added and the mixture was extracted twice with EtOAc. The combined organic extracts were washed with a sat. NH ₄ Cl solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 75% EtOAc) to afford the desired product as a single diastereomer (1.05 g). UPLC-MS 1: m/z 488.1 [M+H] ⁺ , t _R = 1.44 min.

Step 3. 1-((2S,3S)-4-Bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)ethan-1-amine (C-XLIV-c)

At rt, to a solution of (R)-N-(1-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)ethyl)-2-methylpropane-2-sulfinamide (C-XLIV-b) (1.05 g, 2.15 mmol) in dioxane (10 mL) was added HCl ((2.15 mL, 8.6 mmol), 4 M in dioxane) and the reaction mixture was stirred for 1 h. For work-up, a saturated NaHCO ₃ solution was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 90% EtOAc) to afford the desired product (550 mg). UPLC-MS 1: m/z 384.1/386.1 [M+H] ⁺ , t _R = 0.87 min.

Step 4. tert-Butyl (1-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)ethyl)carbamate (C-XLIV-d)

Under Ar atmosphere, to a solution of 1-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)ethan-1-amine (C-XLIV-c) (550 mg, 1.43 mmol) in THF (10 mL) were added Boc-anhydride (343 mg, 1.57 mmol) and TEA (0.40 mL, 2.86 mmol). After 3 h, the reaction mixture was quenched by adding sat. NaHCO ₃ solution (75 mL) and extracted twice with EtOAc. The combined organic layers were washed with sat. NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated. Purification of the crude product by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 10% EtOAc) afforded the title product (638 mg) as a colourless solid. UPLC-MS 1: m/z 528.1/530.1 [M+formate] ^- , t _R = 1.57 min.

Step 4. 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 (C-XLIV)

The title compound (550 mg, colourless powder) was prepared from tert-butyl (1-((2S,3S)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)ethyl)carbamate (C-XLIV-d) (638 mg, 1.32 mmol) using reaction conditions similar to those described for intermediate C-XXXIII, step 8. UPLC-MS 1: m/z 576.3 [M+formate] ^- , t _R = 1.57 min; absolute configuration at position C-1 of ethyl carbamate not determined.

Synthesis of 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)indolin-1-carboxylate (C-XLV)

Reaction scheme XLV:

Step 1. Methyl (S)-4-bromo-5-chloro-6-fluoro-2-phenylindoline-2-carboxylate (C-XLV-a) and methyl (R)-4-bromo-5-chloro-6-fluoro-2-phenylindoline-2-carboxylate (C-XLV-b)

The racemate methyl 4-bromo-5-chloro-6-fluoro-2-phenylindoline-2-carboxylate (C-XXVIII-f) (37.0 g, 96.2 mmol) was subjected to chiral SFC (Chiralpak AY 300×50 mm i.d., 10 μm, _CO2 /EtOH (0.1% _{NH3.H2O )} 80:20, flow rate: 200 mL/min, column temperature 38°C) to afford two separate enantiomers with >99% ee, respectively.

Methyl (S)-4-bromo-5-chloro-6-fluoro-2-phenylindoline-2-carboxylate (C-XLV-a) (18.46 g):

Chiral HPLC: (Chiralpak AY 150×4.6 mm i.d., 3 µm, heptane/EtOH (0.1% DEA) 90:10, flow rate: 1 ml/min, column temperature 25°C) t _R =3.87 min; UPLC-MS 1: mass/charge 384.2/386.2 [M+H] ⁺ , t _R =1.36 min;

Methyl (R)-4-bromo-5-chloro-6-fluoro-2-phenylindoline-2-carboxylate (C-XLV-b) (18.44 g):

Chiral HPLC: (Chiralpak AY 150x4.6 mm i.d., 3 µm, heptane/EtOH (0.1% DEA) 90:10, flow rate: 1 ml/min, column temperature 25°C) t _R =2.73 min; UPLC-MS 1: mass/charge 384.2/386.2 [M+H] ⁺ , t _R =1.35 min;

Step 2. 1-(tert-Butyl)-2-methyl-(S)-4-bromo-5-chloro-6-fluoro-2-phenylindoline-1,2-dicarboxylate (C-XLV-c)

Under Ar atmosphere, to a stirred solution of methyl (S)-4-bromo-5-chloro-6-fluoro-2-phenylindoline-2-carboxylate (C-XLV-a) (2 g, 5.20 mmol) in DMF (52.0 mL) at 0 °C was added NaH (0.187 g, 7.80 mmol). After 15 min, Boc-anhydride (2.415 mL, 10.40 mmol) was added at 0 °C and stirring at rt was continued for another 18 h. More NaH (0.0935 g, 3.90 mmol) and Boc-anhydride (1.207 mL, 5.20 mmol) were added and stirring was continued at rt for 2 days. Water was added for work-up, followed by extraction with EtOAc. The combined organic extracts were washed with saturated _NaHCO3 solution and dried over anhydrous _Na2SO4 . Concentration afforded the crude product which was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 8% _EtOAc ) to give the title compound (2.0 g) as a yellow oil. ^1H NMR (400 MHz, DMSO -d6 ) δ (ppm) 7.81 (s, 1H), 7.45-7.28 (m, 5H), 3.92 (d, 1H) _, 3.78 (s, 3H), 3.33 (d, 1H), 1.37-1.13 (m, 9H). UPLC-MS 3: m/z 384.1 [M-Boc] ⁺ , t _R =1.45 min.

Step 3. tert-Butyl (S)-4-bromo-5-chloro-6-fluoro-2-(hydroxymethyl)-2-phenylindoline-1-carboxylate (C-XLV-d)

Under Ar atmosphere, to a stirred solution of 1-(tert-butyl)-2-methyl-(S)-4-bromo-5-chloro-6-fluoro-2-phenylindoline-1,2-dicarboxylate (C-XLV-c) (2 g, 2.89 mmol) in THF (28.9 mL) was added LiBH ₄ (0.189 g, 8.66 mmol) portionwise at 0 ^o C and stirring was continued for 18 h. More LiBH ₄ (0.189 g, 8.66 mmol) was added portionwise at 0 o C and stirring was continued for 18 h. The reaction mixture was quenched by addition of MeOH at 0 o C. The milky white reaction mixture was concentrated. Water was added for work-up, followed by extraction with EtOAc. _The combined organic extracts were washed with brine, dried over anhydrous _Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica, hexane/EtOAc; gradient 0% to 16% EtOAc) to give the title product (1.2 g) as a white foam. UPLC-MS 3: no ionization, t _R = 1.38 min.

Step 4. tert-Butyl (S)-4-bromo-5-chloro-6-fluoro-2-formyl-2-phenylindoline-1-carboxylate (C-XLV-e)

At -78 °C, DMSO (0.597 mL, 8.41 mmol) was added to a solution of oxalyl chloride (0.368 mL, 4.20 mmol) in DCM (30.7 mL). After 10 min at -78 °C, a solution of tert-butyl (S)-4-bromo-5-chloro-6-fluoro-2-(hydroxymethyl)-2-phenylindoline-1-carboxylate (C-XLV-d) (1.2 g, 2.63 mmol) in DCM (15.36 mL) was added, as well as TEA (1.831 mL, 13.14 mmol) and the reaction mixture was stirred at -78 °C for 20 min and at rt for 30 min. The reaction mixture was quenched by addition of brine, then extracted with DCM. The organic layers were combined and washed with brine, dried over _{anhydrous Na2SO4} and concentrated to give the title compound (1.1 g) as a yellow foam. ¹ H NMR (400 MHz, DMSO -d6 ) δ (ppm) 10.02 (s, 1H), 7.86 ₍ s, 1H), 7.50-7.31 (m, 5H), 3.82 (d, J=17.2 Hz, 1H), 3.08 (d, J=17.0 Hz, 1H), 1.21 (s, 9H). UPLC-MS 3: no ionization, t _R = 1.46 min.

Step 5. tert-Butyl (S)-4-bromo-2-((E)-(((R)-tert-butylsulfinyl)imino)methyl)-5-chloro-6-fluoro-2-phenylindoline-1-carboxylate (C-XLV-f)

At rt, to a stirred yellow solution of tert-butyl (S)-4-bromo-5-chloro-6-fluoro-2-formyl-2-phenylindoline-1-carboxylate (C-XLV-e) (1.1 g, 2.419 mmol) in THF (24.19 mL) were added Ti(OiEt)4 (1.014 mL, 4.84 mmol) and R(+)-2-methyl-2-propanesulfinamide (0.323 g, 2.66 mmol). The reaction mixture was stirred at 70 °C for 2 h before it was quenched with saturated NH ₄ Cl and extracted with EtOAc. The reaction mixture was cooled, brine was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over _Na2SO4 and concentrated to give the title compound (1.26 g) as a white foam. ¹ H NMR (400 MHz, DMSO _-d6 ) δ (ppm) 8.59 ( _s , 1H), 7.52-7.30 (m, 5H), 3.84 (d, J=17.3 Hz, 1H), 1.20-1.06 (br.s, 9H), 1.01 (s, 9H). UPLC-MS 3: t _R = 1.47 min.

Step 6. tert-Butyl (S)-4-bromo-2-((S)-1-(((R)-tert-butylsulfinyl)amino)but-3-en-1-yl)-5-chloro-6-fluoro-2-phenylindoline-1-carboxylate (C-XLV-g) and tert-butyl (S)-4-bromo-2-((R)-1-(((R)-tert-butylsulfinyl)amino)but-3-en-1-yl)-5-chloro-6-fluoro-2-phenylindoline-1-carboxylate (C-XLV-h)

At 0 °C, to a stirred solution of tert-butyl (S)-4-bromo-2-((E)-(((R)-tert-butylsulfinyl)imino)methyl)-5-chloro-6-fluoro-2-phenylindoline-1-carboxylate (C-XLV-f) (1.26 g, 2.26 mmol) in DCM (11.3 mL) was added allyl magnesium bromide (4.52 mL, 4.52 mmol). The reaction mixture was stirred at 0 °C for 1 h. For work-up, a saturated solution of NH4Cl was added and the mixture was extracted with DCM. _The combined organic extracts were washed with brine, dried over _Na2SO4 and concentrated. The crude product was purified twice by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 30% EtOAc) to afford tert-butyl (S)-4-bromo-2-((S)-1-(((R)-tert-butylsulfinyl)amino)but-3-en-1-yl)-5-chloro-6-fluoro-2-phenylindoline-1-carboxylate (C-XLV-g) (940 mg) and tert-butyl (S)-4-bromo-2-((R)-1-(((R)-tert-butylsulfinyl)amino)but-3-en-1-yl)-5-chloro-6-fluoro-2-phenylindoline-1-carboxylate (C-XLV-h) (300 mg).

tert-Butyl (S)-4-bromo-2-((S)-1-(((R)-tert-butylsulfinyl)amino)but-3-en-1-yl)-5-chloro-6-fluoro-2-phenylindoline-1-carboxylate (C-XLV-g): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.68 (s, 1H), 7.45-7.28 (m, 3H), 7.21 (d, J=7.7 Hz, 2H), 6.27 (s, 1H), 5.28-5.08 (m, 3H), 4.56 (s, 1H), 3.86 (d, J=17.7 Hz, 1H), 3.26-3.12 (m, 1H), 2.51 (s, 2H), 1.20 (s, 9H), 0.93 (s, 9H). UPLC-MS 3: m/z 599.2/601.2 [M+H] ⁺ , t _R =1.43 min.

tert-Butyl (S)-4-bromo-2-((R)-1-(((R)-tert-butylsulfinyl)amino)but-3-en-1-yl)-5-chloro-6-fluoro-2-phenylindoline-1-carboxylate (C-XLV-g): UPLC-MS 3: m/z 599.2/601.2 [M+H] ⁺ , t _R = 1.47 min.

Step 7. tert-Butyl (S)-4-bromo-2-((S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-5-chloro-6-fluoro-2-phenylindoline-1-carboxylate (C-XLV-h)

At 0 °C, to a solution of tert-butyl (S)-4-bromo-2-((S)-1-(((R)-tert-butylsulfinyl)amino)but-3-en-1-yl)-5-chloro-6-fluoro-2-phenylindoline-1-carboxylate (C-XLV-g) (940 mg, 1.567 mmol) in MeOH (5.2 mL) was added HCl (1.96 mL, 7.83 mmol, 4 M in dioxane). After 1 h at 0 °C, the reaction mixture was concentrated and taken up in THF (10 mL), treated with sat. aq. NaHCO3 (4.48 mL, 31.3 mmol) and Boc-anhydride (437 µL, 1.88 mmol). Stirring at rt. The reaction mixture was stirred for 18 h and worked up by adding water followed by extraction with EtOAc. The combined organic extracts were washed with brine, dried over _{anhydrous Na2SO4} and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica, hexane/EtOAc; gradient 0% to 5% EtOAc) to give the title product (0.81 g) as a white foam. ^1H NMR (400 MHz, DMSO - _d6 ) δ (ppm) 7.73 (s, 1H), 7.41-7.17 (m, 5H), 6.93 (s, 1H), 5.93 (s, 1H), 5.12 (m, 3H), 3.78 (d, J=17.8 Hz, 1H), 3.15 (d, J=17.9 Hz, 1H), 2.39 (m, 2H), 1.30 (s, 9H), 1.21 (br.s, 9H). UPLC-MS 3: mass/charge 597.2 [M+H] ⁺ , t _R =1.58 min.

Step 8. tert-Butyl (S)-4-bromo-2-((S)-1-((tert-butoxycarbonyl)amino)-4-hydroxybutyl)-5-chloro-6-fluoro-2-phenylindoline-1-carboxylate (C-XLV-i)

At 0 °C, 9-BBN (6.8 mL, 3.40 mmol) was added to a solution of tert-butyl (S)-4-bromo-2-((S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-5-chloro-6-fluoro-2-phenylindoline-1-carboxylate (C-XLV-h) (810 mg, 1.36 mmol) in THF (6.8 mL), and the reaction mixture was stirred at rt for 1 h. After cooling to 0 °C, 3 N NaOH (4531 μL, 13.59 mmol) was added, followed by H ₂ O ₂ (5553 μL, 54.4 mmol). Stirring at 0 °C was continued for 15 min. For work-up, brine was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous _Na2SO4 and concentrated. The resulting crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 30 _% EtOAc) to give the desired product (0.81 g) as a colorless oil. ^1H NMR (400 MHz, DMSO - _d6 ) δ (ppm) 7.73 (s, 1H), 7.40-7.18 (m, 5H), 6.86 (s, 1H), 4.94 (s, 1H), 4.47 (s, 1H), 3.77 (s, 1H), 3.55-3.39 (m, 2H), 3.11 (d, J=17.6 Hz, 1H), 1.81-1.66 (m, 1H), 1.62 (m, 2H), 1.50 (s, 1H), 1.31 (s, 9H), 1.27-1.07 (br.s, 9H). UPLC-MS 3: mass/charge 613.1 [M+H] ⁺ , t _R =1.43 min.

Step 9. tert-Butyl (S)-4-bromo-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenylindoline-1-carboxylate (C-XLV-j)

At 0 °C, to a stirred solution of tert-butyl (S)-4-bromo-2-((S)-1-((tert-butoxycarbonyl)amino)-4-hydroxybutyl)-5-chloro-6-fluoro-2-phenylindoline-1-carboxylate (C-XLV-i) (0.81 g, 1.319 mmol) and DIPEA (346 μL, 1.979 mmol) in DCM (6.6 mL) was added MsCl (123 μL, 1.583 mmol). The reaction mixture was stirred at rt for 30 min and concentrated. Brine was added for work-up and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over _{anhydrous Na2SO4} and concentrated to give the mesylate intermediate. To a stirred solution of the mesylate intermediate in THF (7 mL) was added NaO tBu (190 mg, 1.979 mmol) and stirring was continued at rt for 3 days, then at 60 °C for 18 h. More NaO tBu (190 mg, 1.98 mmol) was added and the reaction mixture was stirred at 60 °C for another 18 h. For work-up, water was added and the mixture was extracted with EtOAc. _The combined organic extracts were washed with brine, dried over anhydrous _Na2SO4 and concentrated. The resulting crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 20% EtOAc) to give the desired product (0.65 g) as a colorless solid. ^1H NMR (400 MHz, DMSO - _d6 ) δ (ppm) 7.58 (s, 1H), 7.44 (d, J=7.7 Hz, 2H), 7.40-7.21 (m, 3H), 5.32 (m, 1H), 3.57 (m, 1H), 3.36 (d, J=3.4 Hz, 2H), 2.78 (m, 1H), 2.60 (m, 1H), 1.95 (m, 3H), 1.23 (s, 9H), 1.12 (br.s, 9H). UPLC-MS 3: mass/charge 595.1 [M+H] ⁺ , t _R =1.58 min. An X-Ray structure confirmed the absolute configuration of the title compound.

Step 10. 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)indolin-1-carboxylate (C-XLV)

A deoxygenated suspension of tert-butyl (S)-4-bromo-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenylindoline-1-carboxylate (C-XLV-j) (440 mg, 0.738 mmol), bis(pinacolato)diboron (0.28 g, 1.108 mmol), PdCl₂(PPh₃)₂(51.8 mg, 0.074 mmol) and KOAc (0.217 g, 2.215 mmol) in toluene (7.5 mL) were stirred at 105°C for 16 h under Ar atmosphere. The reaction mixture was filtered through a PL-thiol cartridge and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, hexane/EtOAc; gradient: 0 to 10%) to afford the title product (220 mg) as a colorless oil. UPLC-MS 3: no ionization, t_R=1.49 min.

Examples and their synthesis

Example 1, example 1a and example 1b: (5-chloro-2,4-diphenyl-2,3-dihydrobenzofuran-2-yl)methanamine (Example 1),(S)-(5-chloro-2,4-diphenyl-2,3-dihydrobenzofuran-2-yl)methanamine (Example 1a) and (R)-(5-chloro-2,4-diphenyl-2,3-dihydrobenzofuran-2-yl)methanamine (Example 1b)

Reaction scheme of example 1

Step 1. 4-Bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxamide

4-Bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxylic acid (200 g, 566 mmol) (Clj) was dissolved in DCM (2400 mL) and cooled to 0 °C. Oxalyl chloride (94 g, 743 mmol) was added, then 3 drops of DMF were added and the reaction mixture was stirred at rt for 1 h. The resulting solution was added over 15 min to 30% ammonium hydroxide solution (2400 mL, 18.5 mol) at 0 °C. The resulting suspension was stirred at 0 °C for 30 min. The solids were filtered and washed with DCM. The organic phase of the filtrate was separated. The aqueous phase was extracted with DCM and the combined organic extracts were washed with brine, dried over _{anhydrous Na2SO4} and concentrated to give the title compound (198 g). UPLC-MS 1: m/z 353.0 [M+H] ⁺ . t _R = 1.14 min.

Step 2. (4-Bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine

4-Bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-carboxamide was dissolved in THF (3000 mL). Borane-methyl sulfide complex (1106 mL, 2.212 mol, 2 M in THF) was added over 30 min at rt. The solution was stirred at reflux for 7 h. The reaction mixture was cooled to rt and quenched by adding MeOH (1000 mL) over 30 min. The mixture was stirred at rt for 45 min. The reaction mixture was treated with 1 N HCL (2000 mL) and stirred at rt for 3 h. DCM was added for workup, followed by saturated _NaHCO3 solution. The aqueous phase was extracted with DCM and the combined organic extracts were washed with brine, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, DCM/(7N _NH3 in MeOH) 95:5) to give the title compound (110 g). UPLC- _MS 1: m/z 339.0 [M+H] ⁺ . t _R = 0.85 min.

Step 3. (5-Chloro-2,4-diphenyl-2,3-dihydrobenzofuran-2-yl)methanamine (Example 1)

_A mixture of (4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine (5.1 g, 15.1 mmol), phenylboronic acid (2.20 g, 18.1 mmol), _K2CO3 (6.25 g, 45.2 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.529 g, 0.75 mmol) in DMF (50 mL) was stirred at 100 °C for 1 h. The reaction mixture was diluted with EtOAc and water. The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with brine, dried over _{anhydrous Na2SO4} and concentrated. The crude product was purified by flash chromatography (silica, DCM/(DCM+10%MeOH), gradient: 0% to 30% (DCM+10%MeOH)) to give the racemic title compound (5.08 g). UPLC-MS 1: m/z 335.0 [M+H] ⁺ . t _R = 0.95 min.

Step 4. (S)-(5-Chloro-2,4-diphenyl-2,3-dihydrobenzofuran-2-yl)methanamine (Example 1a) and (R)-(5-chloro-2,4-diphenyl-2,3-dihydrobenzofuran-2-yl)methanamine (Example 1b)

The racemate (5-chloro-2,4-diphenyl-2,3-dihydrobenzofuran-2-yl)methanamine (1.9 g) was subjected to chiral SFC (ChiralPak IC, 250 x 30 mm, 5 μm, _CO2 /(IPA+1% isopropylamine) 7:3, 40 ^o C, flow rate: 100 ml/min, 3 ml/injection, 7 injections, cycle time 20 min) to afford the title compounds as single enantiomers with enantiomeric excess >99%, respectively:

(S)-(5-chloro-2,4-diphenyl-2,3-dihydrobenzofuran-2-yl)methanamine (example 1a) (785 mg): Chiral SFC: (Chiralpak IC 250×4.6 mm i.d., 5 μm, CO ₂ /(IPA+1% isopropylamine) 7:3, flow rate: 3 mL/min), t _R = 2.91 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.49-7.15 (m, 11H), 6.91 (d, J= 8.5 Hz, 1H), 3.60 (d, J= 16.3 Hz, 1H), 2.98-2.80 (m, 3H), 1.63 (s, 2H). UPLC-MS 1: m/z 336.1 [M+H] ⁺ . t _R =0.91 min.

(R)-(5-chloro-2,4-diphenyl-2,3-dihydrobenzofuran-2-yl)methanamine (example 1b) (894 mg): Chiral SFC: (Chiralpak IC 250×4.6 mm i.d., 5 μm, CO ₂ /(IPA+1% isopropylamine) 7:3, flow rate: 3 mL/min.) t _R = 8.52 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.49-7.15 (m, 11H), 6.91 (d, J= 8.5 Hz, 1H), 3.60 (d, J= 16.3 Hz, 1H), 2.98-2.80 (m, 3H), 1.63 (s, 2H). UPLC-MS 1: m/z 336.1 [M+H] ⁺ . t _R =0.91 min.

Example 2a, Example 2b, Example 2a-1 and Example 2a-2: N1-(2-((2S*,4S*)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenyl)ethane-1,2-diamine (Example 2a), N1-(2-((2S*,4R*)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenyl)ethane-1,2-diamine (Example 2b), N1-(2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenyl)ethane-1,2-diamine (Example 2a-1) and N1-(2-((2R,4R)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenyl)ethane-1,2-diamine (Example 2a-2)

Reaction scheme of example 2:

Step 1. tert-Butyl (((2S*,4S*)-4-(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-6-fluorophenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S*,4R*)-4-(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-6-fluorophenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate

To a mixture of 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 (C-II) (500 mg, 0.834 mmol), tert-butyl (2-((2-bromo-3-fluorophenyl)amino)ethyl)carbamate (NI) (315 mg, 0.92 mmol) and K ₃ PO ₄ (531 mg, 2.501 mmol) in dioxane (6 mL) and water (2 mL) was added Pd(dbpf)Cl ₂ (CAS 95408-45-0) (109 mg, 0.17 mmol) and the reaction mixture was stirred at 100 °C for 15 min. EtOAc and water were added. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous _Na2SO4 and concentrated. The remaining residue was dissolved in MeOH and passed through a PL-thiol resin MP cartridge (Agilent, _{StratoSpheres} SPE) to remove trace metals. After concentration, the crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 30% EtOAc) to afford a mixture of the racemic title compounds (490 mg). UPLC-MS 1: m/z 612.3 [M+H] ⁺ , t _R = 1.45 min and 1.48 min.

Step 2. N1-(2-((2S*,4S*)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenyl)ethane-1,2-diamine (Example 2a) and N1-(2-((2S*,4R*)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenyl)ethane-1,2-diamine (Example 2b)

To a stirred solution of a mixture of racemic tert-butyl (((2S*,4S*)-4-(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-6-fluorophenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and racemic tert-butyl (((2S*,4R*)-4-(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-6-fluorophenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (490 mg, 0.41 mmol) in DCM (3 mL) was added TFA (1 mL, 13.0 mmol) at rt and the reaction mixture was stirred at rt for 45 min. The reaction mixture was diluted with DCM and saturated _NaHCO3 solution, the organic phase was separated and _the aqueous phase was extracted with DCM. The combined organic extracts were dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by preparative HPLC (2 injections, Gilson gx-281, Column: Sunfire C18, 30×100 mm, 5 μm. Flow rate: 30 mL/min. Gradient: 5% to 40% B over 20 min; A=0.1% TFA in _H2O , B= _CH3CN . Detection: UV). The collected fractions were basified with saturated _NaHCO3 solution, ACN was evaporated under reduced pressure and the resulting aqueous phase was extracted with DCM. The organic extract was washed with brine, dried over _{anhydrous Na2SO4} and concentrated to give the title racemic compounds as separate diastereoisomers.

N1-(2-((2S*,4S*)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenyl)ethane-1,2-diamine (Example 2a) (98 mg): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.40-7.36 (m, 2H), 7.35-7.29 (m, 3H), 7.28-7.14 (m, 2H), 6.95 (d, J=8.6 Hz, 1H), 6.54 (d, J=8.2 Hz, 1H), 6.39 (t, J=8.8 Hz, 1H), 4.70 (t, J=5.5 Hz, 1H), 3.49 (d, J=16.0 Hz, 1H), 3.11-3.00 (m, 2H), 2.92 (s, 2H), 2.81 (d, J=16.4 Hz, 1H), 2.67 (t, J=6.1 Hz, 2H). UPLC-MS 1: m/z 412.2 [M+H] ⁺ . t _R =0.68 min.

N1-(2-((2S*,4R*)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenyl)ethane-1,2-diamine (Example 2b) (72 mg): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.42-7.36 (m, 2H), 7.36-7.29 (m, 3H), 7.28-7.22 (m, 1H), 7.22-7.15 (m, 1H), 6.94 (d, J=8.6 Hz, 1H), 6.50-6.43 (m, 2H), 4.37 (t, J=5.5 Hz, 1H), 3.38 (d, J=16.1 Hz, 1H), 2.95 (d, J=16.1 Hz, 1H), 2.95-2.79 (m, 4H), 2.46-2.38 (m, 1H), 2.29-2.21 (m, 1H). UPLC-MS 1: m/z 412.2 [M+H] ⁺ . t _R =0.50 min.

Step 3. N1-(2-((2S,4S)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenyl)ethane-1,2-diamine (Example 2a-1) and N1-(2-((2R,4R)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenyl)ethane-1,2-diamine (Example 2a-2)

Racemic N1-(2-((2S*,4S*)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenyl)ethane-1,2-diamine (Example 2a) (98 mg) was subjected to chiral preparative HPLC (ChiralPak OZI, 420 x 50 mm, 20 μm, heptane/DCM/IPA 60:25:15+0.1% TFA:, flow rate: 80 mL/min) to afford the title compounds as single enantiomers with enantiomeric excess >99%, respectively.

N1-(2-((2S,4S)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenyl)ethane-1,2-diamine (39 mg) (example 2a-1): Chiral HPLC (ChiralPak OZI, 250 × 4.6 mm, 20 µm. heptane/DCM/IPA 60:25:15+0.1% TFA:, flow rate: 0.7 ml/min.) t _R =23.09 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.43-7.13 (m, 7H), 6.95 (d, J=8.5 Hz, 1H), 6.54 (d, J= 8.3 Hz, 1H), 6.39 (t, J=8.8 Hz, 1H), 4.70 (t, J=5.6 Hz, 1H), 3.49 (d, J=16, 3 Hz, 1H), 3.11-3.00 (m, 2H), 2.93 (s, 2H), 2.81 (d, J=16.2 Hz, 1H), 2.67 (t, J=6.2 Hz, 2H). UPLC-MS 1 mass/charge 412.1 [M+H] ⁺ . t _R =0.68 min.

N1-(2-((2R,4R)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenyl)ethane-1,2-diamine (38 mg) (example 2a-2): Chiral HPLC (ChiralPak OZI, 250 × 4.6 mm, 20 µm. heptane/DCM/IPA 60:25:15+0.1% TFA:, flow rate: 0.7 ml/min.), t _R =16.29 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.43-7.13 (m, 7H), 6.95 (d, J=8.5 Hz, 1H), 6.54 (d, J= 8.3 Hz, 1H), 6.39 (t, J=8.8 Hz, 1H), 4.70 (t, J=5.6 Hz, 1H), 3.49 (d, J=16, 3 Hz, 1H), 3.11-3.00 (m, 2H), 2.93 (s, 2H), 2.81 (d, J=16.2 Hz, 1H), 2.67 (t, J=6.2 Hz, 2H). UPLC-MS 1: m/z 412.1 [M+H] ⁺ . t _R =0.68 min.

Example 3a and example 3b: 2-(2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenoxy)ethanamine (Example 3a) and 2-(2-((2R,4R)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenoxy)ethanamine (Example 3b)

Reaction scheme of example 3:

Step 1. tert-Butyl (2-(2-((2S*,4S*)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenoxy)ethyl)carbamate and tert-butyl (2-(2-((2S*,4R*)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenoxy)ethyl)carbamate

A mixture of (4-bromo-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanamine (racemic, prepared in analogy with intermediate CIo in Scheme CI) (250 mg, 0.74 mmol), tert-butyl (2-(3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)carbamate (N-III) (748 mg, 1.55 mmol), Pd(dbpf)Cl ₂ (48.1 mg, 0.07 mmol) and K ₃ PO ₄ (470 mg, 2.22 mmol) in dioxane (3 mL) and H ₂ O (1 mL) was stirred at 100 °C for 15 min. EtOAc and water were added and the organic phase was separated. The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried over anhydrous _Na2SO4 and concentrated. The crude mixture was diluted in MeOH and passed through a PL-thiol _resin MP cartridge (Agilent, StratoSpheres SPE) to remove traces of metals. Concentration afforded a yellow oil which was purified by flash chromatography (silica, DCM/MeOH, gradient: 0% to 5% MeOH) to afford a mixture of the racemic title compounds (410 mg). UPLC MS 1: m/z 513.2 [M+H] ⁺ , t _R = 0.98 min and 1.05 min.

Step 2. 2-(2-((2S*,4S*)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenoxy)ethan-1-amine and 2-(2-((2S*,4R*)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenoxy)ethan-1-amine

To a stirred solution of a mixture of racemic tert-butyl (((2S*,4S*)-4-(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-6-fluorophenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and racemic tert-butyl (((2S*,4R*)-4-(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-6-fluorophenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (410 mg, 0.57 mmol) in DCM (3 mL) was added TFA (1 mL, 13.0 mmol) at rt. After 10 min, DCM was added, then sat. NaHCO ₃ solution. The organic phase was separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by preparative HPLC (Gilson gx-281, Column: Sunfire C18, 30×100 mm, 5 μm. Flow rate: 30 mL/min. Gradient: 5% to 50% B over 18 min; A=0.1% TFA in H ₂ O, B=CH ₃ CN. Detection: UV). The collected fractions were basified with saturated NaHCO ₃ solution, acetonitrile was evaporated under reduced pressure and the resulting aqueous phase was extracted with DCM. The organic extract was dried over anhydrous _Na2SO4 and concentrated to give the title racemic compounds as separate _{diastereoisomers} .

2-(2-((2S*,4S*)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenoxy)ethan-1-amine (86 mg): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.49-7.16 (m, 7H), 6.99-6.82 (m, 3H), 3.84-3.65 (m, 2H), 3.43 (d, J=16.1 Hz, 1H), 3.01-2.81 (m, 3H), 2.37-2.21 (m, 2H), 1.49-1.15 (m, 4H). UPLC MS 1: m/z 413.1 [M+H] ⁺ ; t _R =0.66 min.

2-(2-((2S*,4R*)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenoxy)ethan-1-amine (16 mg): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.49-7.16 (m, 7H), 6.99-6.82 (m, 3H), 3.84-3.65 (m, 2H), 3.43 (d, J=16.1 Hz, 1H), 3.01-2.81 (m, 3H), 2.37-2.21 (m, 2H), 1.49-1.15 (m, 4H). UPLC MS 1: m/z 413.1 [M+H] ⁺ ; t _R =0.48 min.

Step 3. 2-(2-((2S,4S)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenoxy)ethanamine (Example 3a) and 2-(2-((2R,4R)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenoxy)ethanamine (Example 3b)

Racemic 2-(2-((2S*,4S*)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenoxy)ethan-1-amine (82 mg) was subjected to chiral preparative HPLC (ChiralPak OZI, 420 × 50 mm, 20 μm, heptane/DCM/IPA/EtOH 70:10:10:10+0.1% TFA:, flow rate: 80 mL/min) to afford the title compounds as single enantiomers with enantiomeric excess >99%, respectively. After chiral HPLC, both individual enantiomers were purified again by flash chromatography (silica, DCM/(7 N ammonia in MeOH), gradient: 0% to 12% (7 N ammonia in MeOH)):

2-(2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenoxy)ethanamine (40 mg, colourless foam) (Example 3a): Chiral HPLC (ChiralPak OZI, 250 × 4.6 mm, 20 μm, heptane/DCM/IPA/EtOH 70:10:10:10+0.1% TFA:, flow rate: 0.7 mL/min.), t _R = 22.34 min. ^1H NMR (400 MHz, DMSO - _d6 ) δ 7.44-7.35 (m, 3H), 7.35-7.29 (m, 2H), 7.29-7.20 (m, 2H), 6.98 (d, J=8.5 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 6.84 (t, J=8.7 Hz, 1H), 4.07-3.84 (m, 2H), 3.53 (d, J=16.2 Hz, 1H), 2.97-2.69 (m, 5H). UPLC-MS 1 mass/charge 413.1 [M+H] ⁺ . t _R =0.68 min.

2-(2-((2R,4R)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenoxy)ethanamine (36 mg, colourless foam) (Example 3b): Chiral HPLC (ChiralPak OZI, 250 × 4.6 mm, 20 μm, heptane/DCM/IPA/EtOH 70:10:10:10+0.1% TFA:, flow rate: 0.7 mL/min.), t _R = 15.92 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.45-7.20 (m, 7H), 6.98 (d, J=8.5 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 6.84 (t, J=8.7 Hz, 1H), 4.10-3.84 (m, 2H), 3.53 (d, J=16.2 Hz, 1H), 2.99-2.66 (m, 5H). UPLC-MS 1 m/z 413.1 [M+H] ⁺ . t _R =0.66 min.

Example 4a and example 4b: 2-((2S*,4S*)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide (Example 4a) and 2-((2S*,4R*)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide (Example 4b)

Reaction scheme of example 4:

Stage 1 . tert-Butyl-(((2S*,4S*)-5-chloro-4-(2-cyano-6-fluorophenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl-(((2S*,4R*)-5-chloro-4-(2-cyano-6-fluorophenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate

2-Bromo-3-fluorobenzonitrile (124 mg, 0.62 mmol), RuPhos Pd G1 (CAS 1028206-60-1) (45 mg, 0.06 mmol) and Na ₂ CO ₃ (327 mg, 3.1 mmol) were suspended in DMF (2 mL) and H ₂ O (0.6 mL) and the mixture was heated to 100°C slowly for 30 min. A solution of 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 (C-II) (300 mg, 0.62 mmol) in dioxane (2 mL) was added and the reaction mixture was stirred at 100 °C for 15 min. The reaction mixture was diluted in EtOAc/water, extracted with EtOAc and the combined organic extracts were washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 40% EtOAc) to give the title compound mixture (74 mg) as a colourless powder. UPLC-MS 1: non-ionizable products, t _R = 1.33 and 1.36 min.

Stage 2 . tert-Butyl-(((2S*,4S*)-4-(2-carbamoyl-6-fluorophenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl-(((2S*,4R*)-4-(2-carbamoyl-6-fluorophenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate

A solution of a mixture of tert-butyl (((2S*,4S*)-5-chloro-4-(2-cyano-6-fluorophenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S*,4R*)-5-chloro-4-(2-cyano-6-fluorophenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (72 mg, 0.15 mmol) in THF (2 mL), MeOH (2 mL) and NaOH (2 mL, 4.0 mmol, 2 N in water) was stirred at 80 °C for 40 h. The reaction mixture was diluted in DCM/water, extracted with DCM and the combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0% to 75%EtOAc) to give a mixture of the title compounds (55 mg). UPLC-MS 1: m/z 541.2 [M+formate] ^- , t _R = 1.16 and 1.22 min.

Step 3. 2-((2S*,4S*)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide (Example 4a) and 2-((2S*,4R*)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide (Example 4b)

At rt, to a stirred solution of a mixture of tert-butyl (((2S*,4S*)-4-(2-carbamoyl-6-fluorophenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S*,4R*)-4-(2-carbamoyl-6-fluorophenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (55 mg, 0.11 mmol) in DCM (1 mL) was added TFA (1 mL, 13.0 mmol) and the reaction mixture was stirred at rt for 10 min. The reaction mixture was diluted with DCM/sat. _NaHCO3 solution, extracted with DCM and the combined organic extracts were dried over anhydrous _Na2SO4 and concentrated. The residue was purified by flash chromatography (silica, DCM/(7N _ammonia in MeOH); gradient: 0% to 7% (7N ammonia in MeOH)) to afford the racemic title compounds as separate diastereoisomers.

2-((2S*,4S*)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide (18 mg) (Example 4a): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.68 (s br, 1H), 7.56-7.50 (m, 1H), 7.46-7.43 (m, 1H), 7.40-7.31 (m, 6H), 7.28-7.21 (m, 2H), 6.90 (d, J=8.6 Hz, 1H), 3.50 (d, J=16.4 Hz, 1H), 2.94-2.84 (m, 2H), 2.85 (d, J=16.4 Hz, 1H). UPLC-MS 1: m/z 397.2 [M+H] ⁺ , t _R =0.76 min.

2-((2S*,4R*)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide (19 mg) (Example 4b): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.61 (s br, 1H), 7.56-7.49 (m, 1H), 7.45-7.24 (m, 7H), 7.21 (d, J=8.2 Hz, 1H), 7.10 (s br, 1H), 6.86 (d, J=8.6 Hz, 1H), 3.30-3.25 (m, 1H), 3.14 (d, J=16.0 Hz, 1H), 2.95-2.83 (m, 2H). UPLC-MS 1: m/z 397.1 [M+H] ⁺ , t _R =0.58 min.

Example 5a and example 5b: 2-((2S,4S)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 5a) and 2-((2S,4R)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 5b)

Reaction scheme of example 5:

Step 1. tert-Butyl-(((2S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl )carbamate and tert-butyl-(((2S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate

A suspension of (S)-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 (CI) (4.5 g, 9.26 mmol), 2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV) (2.56 g, 11.12 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.424 g, 0.463 mmol), 4,6-bis(diphenylphosphino)-10H-phenoxazine (0.511 g, 0.926 mmol) and K ₃ PO ₄ (5.90 g, 27.8 mmol) in toluene (50 ml) and water (10 ml) were stirred at 100 °C for 16 h under Ar. The reaction mixture was quenched by adding sat. NaHCO ₃ solution then extracted with EtOAc. The organic layers were combined and washed with sat. NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, hexane/EtOAc, gradient 0% to 70% EtOAc) to give a mixture of the title compounds (4.08 g). UPLC-MS 1: m/z 509.3 [M+H] ⁺ , t _R = 1.31 min and 1.34 min.

Step 2. tert-Butyl-(((2S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl )carbamate and tert-butyl-(((2S,4R)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate

At k.t. To a solution of a mixture of tert-butyl (((2S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (4.08 g, 8.02 mmol) in EtOH (50 mL) and water (10 mL) was added hydrido(dimethylphosphinic acid-kP)[hydrogen bis(dimethylphosphinito-kP)]platinum(II) (CAS 173416-05-2) (0.688 g, 1.603 mmol). The reaction mixture was then stirred at 80 °C for 1 h. The reaction mixture was quenched by addition of saturated NaHCO ₃ solution and extracted with EtOAc. The organic layers were combined and washed with saturated NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, hexane/EtOAc, gradient from 0% to 100% EtOAc) to give a mixture of the title compounds (4.02 g). UPLC-MS 1: m/z 527.3 [M+H] ⁺ , t _R = 1.15 min and 1.20 min.

Step 3. 2-((2S,4S)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 5a) and 2-((2S,4R)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 5b)

At rt, to a solution of a mixture of tert-butyl (((2S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S,4R)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (4.02 g, 7.63 mmol) in DCM (80 mL) was added TFA (5.88 mL, 76 mmol) and stirring at rt was continued for 1 h. The reaction mixture was quenched by addition of saturated NaHCO ₃ solution and extracted with DCM. The organic layers were combined and washed with saturated _NaHCO3 solution, dried over _{anhydrous Na2SO4} and concentrated. The residue was purified by flash chromatography (silica, DCM/(MeOH/ _NH4OH (80:20)), gradient from 0% to 10% (MeOH/ _NH4OH (80:20))) to afford the desired compounds as individual diastereoisomers.

2-((2S,4S)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (example 5a) (1.36 g): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.53 (s br, 1H), 7.48 (d, J=8.6 Hz, 1H), 7.40-7.31 (m, 4H), 7.28-7.20 (m, 3H), 7.18 (s br, 1H), 6.88 (d, J=8.6 Hz, 1H), 3.88 (s, 3H), 3.45 (d, J=16.4 Hz, 1H), 2.90-2.81 (m, 3H), 1.40 (s br, 2H). UPLC-MS 1: m/z 427.2 [M+H] ⁺ , t _R =0.76 min.

2-((2S,4R)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 5b) (1.41 g): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.48-7.42 (m, 2H), 7.40-7.30 (m, 4H), 7.29-7.23 (m, 2H), 7.19 (d, J=8.6 Hz, 1H), 6.94 (s br, 1H), 6.85 (d, J=8.6 Hz, 1H), 3.92 (s, 3H), 3.30 (d, J=16.0 Hz, 1H), 3.07 (d, J=16.0 Hz, 1H), 2.86 (dd, J=19.9, 13.3 Hz, 2H), 1.46 (s br, 2H). UPLC-MS 1: m/z 427.3 [M+H] ⁺ , t _R =0.59 min.

The following compounds were prepared analogously to Example 5a.

Note: Structure/Chemical Name UPLC MS
mass/charge [M+H] ⁺
t _R [min.] (method) ¹ H NMR 4a-1
2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide;
2-bromo-3-fluorobenzonitrile used in the Suzuki coupling reaction
The absolute configuration was confirmed by X-ray diffraction analysis of a cocrystal of example 4a-1 bound to the YAP binding site of TEAD4 397.2
0.76 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.68 (s br, 1H), 7.56-7.50 (m, 1H), 7.47-7.43 (m, 1H), 7 .40-7.31 (m, 6H), 7.28-7.22 (m, 2H), 6.90 (d, J=8.6 Hz, 1H), 3.50 (d, J=16.0 Hz, 1H), 2.93-2.82 (m, 3H), 1.66 (s br, 2H) 6
2-((2S,4R)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-methylbenzamide;
2-bromo-3-methylbenzonitrile used in the Suzuki coupling reaction 393.2
0.85 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.51 (s br, 1H), 7.43-7.20 (m, 7H), 7.29-7.20 (m, 2H), 7 .18 (s br, 1H), 6.87 (d, J=8.6 Hz, 1H), 3.43 (d, J=16.4 Hz, 1H), 2.90 (dd, J=24.6, 14.1 Hz, 2H), 2.72 (d, J=16.0 Hz, 1H), 1.75 ( s, 3H) 7
trifluoroacetate salt of 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-chlorobenzamide;
2-bromo-3-chlorobenzonitrile used in the Suzuki coupling reaction 413.1
0.83 (1) (600 MHz, DMSO-d ₆ ) δ (ppm) 7.98 (s, 1H), 7.91 (s, 2H), 7.65 (d, J=7.9 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.50 (d, J=7.9 Hz, 2H), 7.45-7.40 (m, 3H), 7.38-7.31 (m, 2H), 7.00 (d, J=8.6 Hz, 1H ), 3.48 (d, J=16.4 Hz, 1H), 3.40 (s, 2H), 2.89 (d, J=16.3 Hz, 1H) 8
2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-chloro-3-fluorobenzamide;
2-bromo-4-chloro-3-fluorobenzonitrile used in the Suzuki coupling reaction 431.1
0.88 (1) (600 MHz, DMSO-d ₆ ) δ (ppm) 7.82 (s, 1H), 7.75 (t, J=7.7 Hz, 1H), 7.47 (d, J=8.4 Hz , 2H), 7.38 (d, J=7.6 Hz, 2H), 7.34 (t, J=7.5 Hz, 2H), 7.26 (t, J=7.7 Hz, 2H), 6.93 (d, J=8.7 Hz, 1H), 3.50 (d, J=16.2 Hz, 1H), 2, 93-2.80 (m, 3H), 1.35 (s, 2H) 9
2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3,4-difluorobenzamide;
2-bromo-3,4-difluorobenzonitrile used in the Suzuki coupling reaction 415.1
0.84 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.75 (s br, 1H), 7.64-7.55 (m, 1H), 7.54-7.47 (m, 1H), 7 .42-7.31 (m, 5H), 7.30-7.23 (m, 2H), 6.93 (d, J=8.2 Hz, 1H), 3.50 (d, J=16.4 Hz, 1H), 2.97-2.82 (m, 3H), 1.43 (s br, 2H) 10
2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;
2-bromo-3-fluoro-4-(2-hydroxyethoxy)benzonitrile (N-VII), used in the Suzuki coupling reaction
The absolute configuration was confirmed by X-ray diffraction analysis of a cocrystal of example 10 bound to the YAP binding site of TEAD4. 457.2
0.64 (1) (600 MHz, DMSO-d ₆ ) δ (ppm) 7.57 (s br, 1H), 7.44 (d, J=8.6 Hz, 1H), 7.38 (d, J=7.3 Hz, 2H), 7.33 (t, J=7.7 Hz, 2H), 7.26 (dt, J=8.3, 4.9 Hz, 2H), 7.23-7.16 (m, 2H), 6.89 (d, J=8.5 Hz, 1H), 4.93 (t, J=5.4 Hz, 1H), 4.11 (t, J=4.8 Hz, 2H), 3.72 (q, J=5.0 Hz, 2H), 3.45 (d, J=16.1 Hz, 1H), 2.92-2.81 (m, 3H), 1.60 (s br, 2H) 11
2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;
2-bromo-4-(difluoromethoxy)-3-fluorobenzonitrile (NV), used in the Suzuki coupling reaction 463.1
0.80 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.74 (s br, 1H), 7.53-7.46 (m, 2H), 7.42-7.31 (m, 6H), 7 .29-7.23 (m, 2H), 6.92 (d, J=8.6 Hz, 1H), 3.49 (d, J=16.4 Hz, 1H), 2.93-2.82 (m, 3H), 1.55 (s br, 2H) 12
2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-methoxyethoxy)benzamide;
2-bromo-3-fluoro-4-(2-methoxyethoxy)benzonitrile (N-IX), used in the Suzuki coupling reaction 471.2
0.78 (1) (600 MHz, DMSO-d ₆ ) δ (ppm) 7.59 (s br, 1H), 7.45 (d, J=8.6 Hz, 1H), 7.39 (d, J=7.7 Hz, 2H), 7.34 (t, J=7.6 Hz, 2H), 7.27 (t, J=7.5 Hz, 2H), 7.24-7.19 (m, 2H), 6.90 (d, J=8.5 Hz, 1H), 4.22 (s br, 2H), 3.70-3.63 ( m, 2H), 3.45 (d, J=16.2 Hz, 1H), 3.27 (s, 3H), 2.96-2.82 (m, 3H) 13
2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide;
(S)-2-bromo-3-fluoro-4-(2-hydroxypropoxy)benzonitrile (N-XIV) used in the Suzuki coupling reaction 471.3
0.70 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.50 (s br, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.40-7.29 (m, 4H ), 7.28-7.18 (m, 3H), 7.15 (s br, 1H), 6.88 (d, J=8.6 Hz, 1H), 4.90 (d, J=4.3 Hz, 1H), 3.99-3.86 (m, 3H), 3.44 (d, J=16.0 Hz, 1H), 2.90-2.81 (m, 3H), 1.34 (s br, 2H), 1.11 (d, J=5.9 Hz, 3H) 14
2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((R)-2-hydroxypropoxy)benzamide;
(R)-2-bromo-3-fluoro-4-(2-hydroxypropoxy)benzonitrile (N-XV) used in the Suzuki coupling reaction 471.3
0.69 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.51 (s br, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.38-7.28 (m, 4H ), 7.27-7.17 (m, 3H), 7.15 (s br, 1H), 6.88 (d, J=8.6 Hz, 1H), 4.90 (d, J=4.7 Hz, 1H), 3.97-3.87 (m, 3H), 3.44 (d, J=16.0 Hz, 1H), 2.90-2.80 (m, 3H), 1.33 (s br, 2H), 1.11 (d, J=5.5 Hz, 3H) 15
2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((R)-2-fluoropropoxy)benzamide;
(R)-2-bromo-3-fluoro-4-(2-fluoropropoxy)benzonitrile (N-VIII) used in the Suzuki coupling reaction 473.3
0.83 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.61 (s br, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.32-7.23 (m, 8H ), 6.93 (d, J=8.6 Hz, 1H), 5.06 (m, 1H), 4.36-4.18 (m, 2H), 3.49 (d, J=15.1 Hz, 1H), 2.95-2.86 (m, 3H), 1.38 (dd, J=23.6, 6.4 Hz, 3H). 16
trifluoroacetate salt of 2-(3-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-carbamoyl-2-fluorophenoxy)acetic acid;
ethyl 2-(3-bromo-4-cyano-2-fluorophenoxy)acetate (N-XVI) was used in a Suzuki coupling reaction. The ethyl ester was saponified before removal of the Boc protecting group 471.3
0.62 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.90 (s br, 3H), 7.75 (s, 1H), 7.50-7.29 (m, 7H), 7.22 (s br, 1H), 7.16 (t, J=8.6 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H), 4.81 (s, 2H), 3.48 (d, J=16.8 Hz, 1H), 3.44-3.31 (m, 2H), 2.94 (d, J=16 ,4 Hz, 1H). 17
4-(((R)-4-acetylmorpholin-2-yl)methoxy)-2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4- yl)-3-fluorobenzamide;
(R)-4-((4-acetylmorpholin-2-yl)methoxy)-2-bromo-3-fluorobenzonitrile (N-XVII) was used in a Suzuki coupling reaction 554.3
0.67 (1) (400 MHz, CD ₃ OD) δ (ppm) 7.52-7.48 (m, 1H), 7.42-7.33 (m, 7H), 6.90 (dd, J=8.6, 2.0 Hz, 1H), 4.49-4.45 (m, 1H), 4.30-4.25 (m, 1H), 4.21-4.16 (m, 3H), 3.96-3.71 (m, 4H), 3.61-3.37 (m, 3H), 3.27-3.20 (m, 1H ), 3.07-2.93 (m, 3H), 2.88-2.73 (m, 1H), 2.09 (d, J=5.9 Hz, 3H).

Example 18: 4-((2S,4S)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-methoxynicotinamide

Step 1. Methyl 4-((2S,4S)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro -6-methoxynicotinate and methyl-4-((2S,4R)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6- methoxynicotinate

A 20 mL MW vial was charged with (S)-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 (CI) (200 mg, 0.412 mmol), methyl 4-chloro-5-fluoro-6-methoxynicotinate (N-XXIX) (136 mg, 0.618 mmol), and K ₃ PO ₄ (262 mg, 1.235 mmol). Toluene (6 mL) and water (1.5 mL) were added and the mixture was degassed with nitrogen. Then N-Xantphos (22.71 mg, 0.041 mmol) and _Pd2 (dba) ₃ (18.85 mg, 0.021 mmol) were added, the vial was sealed and the reaction mixture was heated at 100 °C for 12 h. After cooling to rt, the reaction mixture was partitioned between water and EtOAc. The organic phase was separated and the aqueous phase was extracted with _EtOAc . The combined organic layers were washed with brine, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 10% to 20% EtOAc) to give a mixture of the title compounds (122 mg). UPLC-MS 2: mass/charge 543.1 [M+H] ⁺ , t _R =7.25 and 7.34 min.

Step 2. 4-((2S,4S)-2-(((tert-Butoxycarbonyl)amino)methyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-methoxynicotinic acid and 4-((2S,4R)-2-(((tert-Butoxycarbonyl)amino)methyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-methoxynicotinic acid

A mixture of methyl 4-((2S,4S)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-methoxynicotinate and 4-((2S,4R)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-methoxynicotinic acid (122 mg, 0.225 mmol) was dissolved in THF (5 mL) and water (1 mL). LiOH.H ₂ O (94 mg, 2.25 mmol) was added and the reaction mixture was stirred at 55 °C for 4 h. After cooling to rt, the reaction mixture was partitioned between EtOAc and sat. NaHSO ₄ solution. The organic phase was separated, dried over anhydrous Na ₂ SO ₄ and concentrated to give a mixture of the title compounds (124 mg). UPLC-MS 1: m/z 529.2 [M+H] ⁺ , t _R = 1.27 and 1.32 min.

Step 3. tert-Butyl-(((2S,4S)-4-(5-carbamoyl-3-fluoro-2-methoxypyridin-4-yl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2 -yl)methyl)carbamate and tert-butyl-(((2S,4R)-4-(5-carbamoyl-3-fluoro-2-methoxypyridin-4-yl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl) methyl)carbamate

A solution of a mixture of 4-((2S,4S)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-methoxynicotinic acid and 4-((2S,4R)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-methoxynicotinic acid (120 mg, 0.227 mmol), DIPEA (0.12 mL, 0.68 mmol) and HATU (129 mg, 0.34 mmol) in DMF (2 mL) was stirred for 5 min at rt. _NH3 (1.361 mL, 0.681 mmol, 0.5 M in dioxane) was added dropwise and stirring at rt was continued for 2 h. For work-up, EtOAc and 10% citric acid solution were added and the mixture was stirred vigorously for 5 min. The organic layer was separated and washed with _{saturated NaHCO3} solution and brine, dried over _{anhydrous Na2SO4} and concentrated to give a mixture of the title compounds. UPLC-MS 1: m/z 528.2 [M+H] ⁺ , t _R = 1.15 and 1.20 min.

Step 4. 4-((2S,4S)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-methoxynicotinamide (Example 18)

To a solution of a mixture of tert-butyl (((2S,4S)-4-(5-carbamoyl-3-fluoro-2-methoxypyridin-4-yl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S,4R)-4-(5-carbamoyl-3-fluoro-2-methoxypyridin-4-yl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (250 mg, 0.237 mmol) in DCM (4 mL) was added dropwise TFA (912 μL, 11.8 mmol) and stirring was continued at rt for 3 h. The reaction mixture was concentrated and azeotroped with DCM. The residue was purified by preparative HPLC and the diastereoisomers were separated:

4-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-methoxynicotinamide (25 mg) as a colorless powder (Example 18): ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm) 8.32 (s, 1H), 7.43-7.34 (m, 4H), 7.30-7.24 (m, 2H), 6.94 (d, J=8.6 Hz, 1H), 4.06 (s, 3H), 3.42 (d, J=16.0 Hz, 1H), 3.05 (d, J=16.4 Hz, 1H), 3.04 (d, J=14.1 Hz, 1H), 2.96 (d, J=14.1 Hz, 1H). UPLC-MS 1: m/z 428.2 [M+H] ⁺ , t _R =0.77 min. The absolute configuration was confirmed by X-ray diffraction analysis of a cocrystal of example 18 bound to the YAP binding site of TEAD3.

Another diastereoisomer, 4-((2S,4R)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-methoxynicotinamide (16 mg) as a colorless powder: UPLC-MS 1: m/z 428.2 [M+H] ⁺ , t _R = 0.64 min.

Example 19: 4-((2S,4S)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-6-(difluoromethoxy)-5-fluoronicotinamide

The title compound was prepared analogously to Example 18 from the intermediates 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 (C-I) and methyl 4-chloro-6-(difluoromethoxy)-5-fluoronicotinate (N-XXX).

4-((2S,4S)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-6-(difluoromethoxy)-5-fluoronicotinamide (Example 19): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.36 (s, 1H), 8.01 (s br, 1H), 7.80 (t, J=71.5 Hz, 1H), 7.58 (s br, 1H), 7.40-7.23 (m, 6H), 6.97 (d, J=8.6 Hz, 1H), 3.47 (d, J=16.4 Hz, 1H), 2.99 (d, J=16.0 Hz, 1H), 2.90 (s, 2H). UPLC-MS 1: m/z 464.2 [M+H] ⁺ , t _R =0.84 min.

Another diastereoisomer, 4-((2S,4R)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-6-(difluoromethoxy)-5-fluoronicotinamide: UPLC-MS 1: m/z 464.2 [M+H] ⁺ , t _R = 0.68 min.

Example 20: 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(methylamino)benzamide

Step 1. tert-Butyl-(((2S,4S)-5-chloro-4-(6-cyano-2,3-difluorophenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate And tert-butyl-(((2S,4R)-5-chloro-4-(6-cyano-2,3-difluorophenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate

A mixture of the title compounds (0.89 g, colourless powder) was prepared from (S)-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 (CI) (1.5 g, 3.1 mmol), 2-bromo-3,4-difluorobenzonitrile (0.81 g, 3.7 mmol) using reaction conditions similar to those described for Example 5a, step 1. UPLC-MS 1: m/z 397.1 [M+H-Boc] ⁺ , t _R = 1.35 min and 1.38 min.

Step 2. tert-Butyl-(((2S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-(methylamino)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2- yl)methyl)carbamate and tert-butyl-(((2S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-(methylamino)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl )carbamate

A 5 mL MW vial was charged with a mixture of tert-butyl (((2S,4S)-5-chloro-4-(6-cyano-2,3-difluorophenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S,4R)-5-chloro-4-(6-cyano-2,3-difluorophenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (85 mg, 0.171 mmol) and a solution of methylamine in THF (428 µL, 0.86 mmol, 2 M in THF), and the reaction mixture was heated at 100 °C for 1 h under MW irradiation. The reaction mixture was quenched with 75 mL of sat. _NaHCO3 solution, then extracted with EtOAc. The organic layers were combined and washed with saturated _NaHCO3 solution, dried over anhydrous _Na2SO4 and concentrated. The residue was purified by flash chromatography (silica, _hexane /EtOAc; gradient: 0% to 70% EtOAc) to give a mixture of the title compounds (86 mg) as a colorless powder. UPLC-MS 1: m/z 552.2 [M+formate] ^- , t _R = 1.28 min and 1.30 min.

Step 3. tert-Butyl-(((2S,4S)-4-(6-carbamoyl-2-fluoro-3-(methylamino)phenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2- yl)methyl)carbamate and tert-butyl-(((2S,4R)-4-(6-carbamoyl-2-fluoro-3-(methylamino)phenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl )carbamate

A mixture of the title compounds (80 mg) was prepared from a mixture of tert-butyl (((2S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-(methylamino)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-(methylamino)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate according to the procedure described for Example 5a, Step 2. UPLC-MS 1: mass/charge 526.2 [M+H]⁺, t_R=1.13 min. and 1.18 min.

Step 4. 2-((2S,4S)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(methylamino)benzamide (Example 20)

To a stirred solution of a mixture of tert-butyl (((2S,4S)-4-(6-carbamoyl-2-fluoro-3-(methylamino)phenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S,4R)-4-(6-carbamoyl-2-fluoro-3-(methylamino)phenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (80 mg, 0.15 mmol) in DCM (3 mL) was added TFA (0.117 mL, 1.52 mmol) and stirring at rt was continued for 2 h. The reaction mixture was quenched with saturated NaHCO ₃ solution, then extracted with DCM. The organic layers were combined and washed with saturated _NaHCO3 solution, dried over anhydrous _Na2SO4 and concentrated. The residue was purified by flash chromatography (silica:DCM/(MeOH/ _NH4OH :80/20), gradient: 0% to 10% (MeOH/ _NH4OH : _80/20 )) and the diastereoisomers were separated.

2-((2S,4S)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(methylamino)benzamide (Example 20): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.45-7.30 (m, 5H), 7.28-7.21 (m, 2H), 7.19 (d, J=8.6 Hz, 1H), 6.90 (s br, 1H), 6.86 (d, J=8.6 Hz, 1H), 6.66 (t, J=8.6 Hz, 1H), 5.99-5.93 (m, 1H), 3.43-3.24 (m, 2H), 2.88-2.85 (m, 2H), 2.73 (d, J=5.1 Hz, 3H). UPLC-MS 1: m/z 426.2 [M+H] ⁺ , t _R =0.75 min.

Another diastereoisomer, 2-((2S,4R)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(methylamino)benzamide: UPLC-MS 1: m/z 426.2 [M+H] ⁺ , t _R = 0.62 min.

Example 21: 2-((2S,4S)-5-chloro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide

Step 1. (S)-tert-Butyl ((5-chloro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate

At 0 °C, sodium hydride (78 mg, 3.09 mmol, 95%) was added to a solution of (S)-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 (CI) (500 mg, 1.03 mmol) in DMF (7 mL). After 5 min, methyl iodide (644 μL, 10.3 mmol) was added and the reaction mixture was stirred at rt for 3.5 h. Water was added and the reaction mixture was extracted with EtOAc. Drying of the combined organic layers using a phase separation cartridge and concentration afforded the crude product, which was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 20% EtOAc) to afford the title compound (283 mg) as a colourless foam. UPLC-MS 1: m/z 500.4 [M+H] ⁺ , t _R = 1.59 min.

Step 2. tert-Butyl-(((2S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl )(methyl)carbamate and tert-butyl-(((2S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl )carbamate

A mixture of the title compounds (67 mg, yellow oil) was prepared from (S)-tert-butyl ((5-chloro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (150 mg, 0.300 mmol) and 2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV) (83 mg, 0.36 mmol) using reaction conditions similar to those described for Example 5a, step 1. UPLC-MS 1: m/z 523.4 [M+H] ⁺ , t _R = 1.41 min (both diastereoisomers co-elute).

Step 3. tert-Butyl-(((2S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl )(methyl)carbamate and tert-butyl-(((2S,4R)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl )carbamate

The title compound mixture was prepared from a mixture of tert-butyl (((2S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl (((2S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate according to the procedure described for Example 5a, step 2. UPLC-MS 1: m/z 541.3 [M+H] ⁺ , t _R = 1.24 and 1.25 min.

Step 4. 2-((2S,4S)-5-Chloro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 21)

The title compound (9 mg, colourless powder) was prepared from a mixture of tert-butyl (((2S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl (((2S,4R)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (72 mg, 0.12 mmol) using reaction conditions similar to those described for Example 5a, step 3, followed by chromatographic separation of the diastereoisomers.

2-((2S,4S)-5-Chloro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 21): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.50 (d, 8.6 Hz, 1H), 7.47 (s br, 1H), 7.43-7.38 (m, 2H), 7.37-7.32 (m, 2H), 7.30-7.21 (m, 3H), 7.18 (s br, 1H), 6.91 (d, J=8.6 Hz, 1H), 3.88 (s, 3H), 3.48 (d, J=16.1 Hz, 1H), 3.00 (s, 2H), 2.86 (d, J=16.1 Hz, 1H), 2.26 (s, 3H). UPLC-MS 1: m/z 441.3 [M+H] ⁺ , t _R =0.79 min.

Another diastereoisomer, 2-((2S,4R)-5-chloro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide: UPLC-MS 1: m/z 441.3 [M+H] ⁺ , t _R = 0.63 min.

Example 22: 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxy-N-methylbenzamide

Step 1. Methyl-2-((2S,4S)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3,4 -difluorobenzoate and Methyl 2-((2S,4R)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3,4-difluorobenzoate

A mixture of the title compounds (365 mg) was prepared from (S)-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 (CI) (600 mg, 1.24 mmol) and methyl 2-bromo-3,4-difluorobenzoate (372 mg, 1.482 mmol) using reaction conditions similar to those described for Example 5a, step 1. UPLC-MS 1: m/z 530.3 [M+H] ⁺ , t _R = 1.42 min and 1.44 min.

Step 2. 2-((2S,4S)-2-(((tert-Butoxycarbonyl)amino)methyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3,4-difluorobenzoic acid and 2-((2S,4R)-2-(((tert-Butoxycarbonyl)amino)methyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3,4-difluorobenzoic acid

A mixture of the title compounds (300 mg, colourless powder) was prepared from a mixture of methyl 2-((2S,4S)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3,4-difluorobenzoate and methyl 2-((2S,4R)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3,4-difluorobenzoate (365 mg, 0.69 mmol) using reaction conditions similar to those described for Example 18, Step 2. UPLC-MS 1: m/z 514.4 [MH] ^- , t _R = 1.25 min and 1.31 min.

Step 3. tert-Butyl-(((2S,4S)-5-chloro-4-(2,3-difluoro-6-(methylcarbamoyl)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl) methyl)carbamate and tert-butyl-(((2S,4R)-5-chloro-4-(2,3-difluoro-6-(methylcarbamoyl)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate

To a solution of a mixture of 2-((2S,4S)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3,4-difluorobenzoic acid and 2-((2S,4R)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3,4-difluorobenzoic acid (157 mg, 0.23 mmol), methylamine hydrochloride (23.11 mg, 0.342 mmol) and DIPEA (239 μL, 1.37 mmol) in DMF (2.3 mL) was added HBTU (130 mg, 0.342 mmol). The reaction mixture was stirred at rt. for 15 h. EtOAc was added and the organic phase was washed with 1 N HCl, saturated NaHCO ₃ solution and brine. Drying (phase separation cartridge) and evaporation of the solvent provided the crude product. The title compounds were obtained by preparative HPLC (WatersSunfire C18 OBD, 5 μm, 30 * 100 mm, eluent A: H ₂ O + 0.1% TFA, B: ACN + 0.1% TFA, Gradient: 20 to 95% B over 20 min, hold 3 min, flow 40 mL/min) as separate diastereoisomers.

tert-Butyl (((2S,4S)-5-chloro-4-(2,3-difluoro-6-(methylcarbamoyl)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (39 mg, colorless powder): UPLC-MS 1: m/z 529.3 [M+H] ⁺ , t _R =1.31 min.

tert-Butyl (((2S,4R)-5-chloro-4-(2,3-difluoro-6-(methylcarbamoyl)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (50 mg, colorless powder): UPLC-MS 1: m/z 529.4 [M+H] ⁺ , t _R =1.24 min.

Step 4. tert-Butyl-(((2S,4S)-5-chloro-4-(2-fluoro-3-methoxy-6-(methylcarbamoyl)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2- yl)methyl)carbamate

To a solution of tert-butyl (((2S,4S)-5-chloro-4-(2,3-difluoro-6-(methylcarbamoyl)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (39 mg, 0.074 mmol) in MeOH (1.8 mL) was added sodium methoxide in methanol (169 μL, 0.737 mmol, 25%) and the reaction mixture was heated under microwave irradiation at 100 °C for 1 h. More sodium methoxide in methanol (169 μL, 0.737 mmol, 25%) was added and microwave heating was continued for another 1 h 15 min. Saturated NaHCO ₃ solution was added and the mixture was extracted with EtOAc. Drying (phase separation cartridge) of the combined organic layers and concentration afforded the title compound (36 mg, 0.057 mmol) as a colourless powder. UPLC-MS 1: m/z 541.3 [M+H] ⁺ , t _R = 1.25 min.

Step 5. 2-((2S,4S)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxy-N-methylbenzamide (example 22)

A solution of tert-butyl (((2S,4S)-5-chloro-4-(2-fluoro-3-methoxy-6-(methylcarbamoyl)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (36 mg, 0.057 mmol) in HCl (0.28 mL, 1.13 mmol, 4 M in dioxane) was stirred at rt. for 2 h. The solvent was evaporated and the crude product was purified by preparative HPLC (Waters X-Bridge C18 OBD, 5 μm, 30 * 100 mm, eluent A: H ₂ O + 7.3 mM NH ₄ OH, B: ACN, gradient: 20% over 4 min, then 20 to 80% B over 20 min, hold 3 min, flow 40 ml/min) to give the title compound (13 mg) as a colorless powder. ¹ H NMR (400 MHz, DMSO - _d6 ) δ (ppm) 8.11-8.07 (m, 1H), 7.47-7.34 (m, 5H), 7.33-7.27 (m, 2H), 7.25 (d, J=8.6 Hz, 1H), 6.92 (d, J=8.6 Hz, 1H), 3.91 (s, 3H), 3.45 (d, J=16.1 Hz, 1H), 2.91-2.84 (m, 3H), 2.63 (d, J=4.5 Hz, 3H). UPLC-MS 1: mass/charge 441.4 [M+H] ⁺ , t _R =0.79 min.

The following compounds were prepared similarly to Example 22.

Note: Structure/Chemical Name UPLC MS
mass/charge [M+H] ⁺
t _R [min.] (method) ¹ H NMR 23
2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-N-cyclopropyl-3-fluoro-4-methoxybenzamide 467.3
0.87 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 8.11 (d, J=3.8 Hz, 1H), 7.45-7.35 (m, 5H), 7.33-7.24 ( m, 3H), 6.95 (d, J=8.6 Hz, 1H), 3.90 (s, 3H), 3.46 (d, J=16.1 Hz, 1H), 2.98 (s, 2H), 2.88 (d, J=16.3 Hz, 1H), 2.66-2.59 (m, 1H) , 0.65-0.55 (m, 2H), 0.48-0.39 (m, 1H), 0.39-0.30 (m, 1H) 24
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 495.3
0.83 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.78-7.71 (m, 2H), 7.44-7.28 (m, 7H), 6.98 (d, J=8.6 Hz, 1H), 6.12 (d, J=1.8 Hz, 1H), 3.56 (s, 3H), 3.52 (d, J=16.3 Hz, 1H), 3.00 (d, J=16.4 Hz, 1H), 2.90 (s, 2H) 25
2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxy-N-(pyridin-3-yl)benzamide 504.3
0.80 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 10.5 (s, 1H), 8.75 (d, J=2.5 Hz, 1H), 8.27 (dd, J=4.7, 1.2 Hz, 1H), 8-04-7.99 (m, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.43-7.28, m, 6H), 7.25 (d, J=8.6 Hz, 1H), 6.92 (d, J=8.6 Hz, 1H), 3, 96 (s, 3H), 3.50 (d, J=16.3 Hz, 1H), 2.94 (d, J=16.3 Hz, 1H), 2.88 (d, J=2.5 Hz, 2H)

Example 26: 2-((2S,4S)-5-chloro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxy-N-methylbenzamide

The title compound was prepared analogously to Example 22 starting from (S)-tert-butyl ((5-chloro-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (Example 21, step 1) and methyl 2-bromo-3,4-difluorobenzoate. NMR (400 MHz, DMSO - _d6 ) δ (ppm) 8.06-8.01 (m, 1H), 7.47-7.33 (m, 5H), 7.32-7.26 (m, 2H), 7.24 (d, J=8.6 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 3.90 (s, 3H), 3.50 (d, J=16.0 Hz, 1H), 2.88 (s, 2H), 2.83 (d, J=16.0 Hz, 1H), 2.65 (d, J=4.5 Hz, 3H), 2.25 (s, 3H). UPLC-MS 1: mass/charge 455.3 [M+H] ⁺ , t _R =0.81 min.

Diastereoisomers were separated after formation of methylamide: tert-butyl (((2S,4S)-5-chloro-4-(2,3-difluoro-6-(methylcarbamoyl)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate: UPLC-MS 1: m/z 543.4 [M+H] ⁺ , t _R =1.36 min; tert-butyl (((2S,4R)-5-chloro-4-(2,3-difluoro-6-(methylcarbamoyl)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate: UPLC-MS 1: m/z 543.4 [M+H] ⁺ , t _R =1.34 min.

Example 27a and Example 27b: 2-((2S,4S)-5-chloro-2-(((trans-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 27a) and 2-((2S,4S)-5-chloro-2-(((cis-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 27b)

Reaction scheme of example 27:

At rt, to a solution of 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 5a) (600 mg, 1.406 mmol), 4-hydroxycyclohexanone (193 mg, 1.687 mmol) and acetic acid (0.080 mL, 1.406 mmol) in DCM (15 mL) was added sodium triacetoxyborohydride (894 mg, 4.22 mmol). The reaction mixture was then stirred at rt for 1 h. The reaction mixture was quenched by addition of sat. NaHCO ₃ solution, then extracted with DCM. The organic layers were combined and washed with sat. NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, DCM/MeOH, gradient from 0% to 10% MeOH) and the diastereoisomers were separated.

2-((2S,4S)-5-Chloro-2-((((trans)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (278 mg) (Example 27a): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.48 (d, J=8.7 Hz, 1H), 7.40-7.34 (m, 3H), 7.30 (t, J=7.4 Hz, 2H), 7.26-7.17 (m, 3H), 7.12 (s, 1H), 6.86 (d, J=8.6 Hz, 1H), 4.35 (d, J=4.4 Hz, 1H), 3.86 (s, 3H), 3.45 (d, J=15.9 Hz, 1H), 3.26-3.20 (m, 1H), 2.99-2.85 (m, 2H), 2.78 (d, J=15.9 Hz, 1H), 2.23-2.11 (m, 1H), 1.75-1.56 (m, 4H), 1.20-1.10 (m, 1H), 1.10-0.94 (m, 2H), 0.93-0.77 (m, 2H). UPLC-MS 2: m/z 525.3 [M+H] ⁺ , t _R =3.67 min. The absolute configuration was confirmed by X-ray diffraction analysis of a co-crystal of example 27a bound to the YAP binding site of TEAD4.

2-((2S,4S)-5-Chloro-2-((((cis)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (350 mg) (Example 27b): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.49 (d, J=8.6 Hz, 1H), 7.44 (s, 1H), 7.40-7.35 (m, 2H), 7.31 (t, J=7.6 Hz, 2H), 7.27-7.17 (m, 3H), 7.10 (s, 1H), 6.87 (d, J=8.5 Hz, 1H), 4.23 (d, J=3.6 Hz, 1H), 3.86 (s, 3H), 3.50 (d, J=16.0 Hz, 1H), 2.93 (s, 2H), 2.79 (d, J=15.9 Hz, 1H), 2.38-2.29 (m, 1H), 1.56-1.20 (m, 9H). UPLC-MS 2: mass/charge 525.3 [M+H] ⁺ , t _R =3.73 min.

Example 28a and example 28b: (trans)-4-((((2S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexanecarboxylic acid(example 28a)and (cis)-4-((((2S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexanecarboxylic acid (example 28b)

Step 1. (trans)-Methyl-4-((((2S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran- 2-yl)methyl)amino)cyclohexanecarboxylate and (cis)-methyl-4-((((2S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl )methyl)amino)cyclohexanecarboxylate

To a stirred solution of 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (example 5a) (100 mg, 0.23 mmol) in DCM (4 mL) were added methyl 4-oxocyclohexanecarboxylate (47.6 mg, 0.305 mmol), NaBH(OAc) ₃ (149 mg, 0.70 mmol) and AcOH (13 μL, 0.23 mmol) under Ar atmosphere. The reaction mixture was then stirred for 2.5 h at rt. The reaction mixture was quenched with saturated _NaHCO3 solution and extracted with DCM. The organic layers were combined and washed with brine, dried (phase separation cartridge) and concentrated. The residue was purified by preparative HPLC (Waters X-Bridge C18 OBD, 5 μm, 30 * 100 mm, eluent A: H ₂ O + 7.3 mM NH ₄ OH, B: ACN, gradient: 10% over 4 min, then 10 to 80% B over 20 min, hold 3 min, flow 40 mL/min). Both diastereoisomers were separated. Fractions from each diastereoisomer were extracted twice with EtOAc/sat. NaHCO ₃ solution. The combined organic layers were washed with brine and dried (phase separation cartridge) to give:

(trans)-methyl 4-((((2S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexanecarboxylate (21 mg): UPLC-MS 1: m/z 567.4 [M+H] ⁺ , t _R = 0.88 min.

(cis)-methyl 4-((((2S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexanecarboxylate (47 mg) as colorless powders. UPLC-MS 1: m/z 567.4 [M+H] ⁺ , t _R =0.89 min.

Step 2a. (trans)-4-((((2S,4S)-4-(6-Carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexanecarboxylic acid (Example 28a)

To a stirred solution of (trans)-methyl 4-((((2S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexanecarboxylate (21 mg, 0.037 mmol) in dioxane (1 mL) and water (0.35 mL) was added LiOH.H ₂ O (2.3 mg, 0.056 mmol). The reaction mixture was then stirred at rt. for 16 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (Waters X-Bridge C18 OBD, 5 μm, 30 * 100 mm, eluent A: H ₂ O + 7.3 mM NH ₄ OH, B: ACN, gradient: 10% over 4 min, then 10 to 95% B over 20 min, hold 3 min, flow 40 ml/min). Lyophilization of the product fractions provided the title compound (10 mg) as a colorless powder. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 11.99 (s br, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.43-7.19 (m, 9H), 6.91 (d, J=8.6Hz, 1H), 3.90 (s, 3H), 3.51 (d, J=16 Hz, 1H), 3.03-2.94 (m, 2H), 2.83 (d, J=16 Hz, 1H), 2.25-2.21 (m, 1H), 2.11-2.04 (m, 1H) 1.83-1.74 (m, 4H), 1.28-1.18 (m, 2H), 0.96-0.87 (m, 2H). UPLC-MS 1: m/z 553.3 [M+H] ⁺ , t _R =0.82 min. UPLC-MS 2: m/z 553.3 [M+H] ⁺ , t _R =3.79 min.

Stage 2b.(cis)-4-((((2S,4S)-4-(6-Carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexanecarboxylic acid (example 28b)

The title compound (18 mg, colourless powder) was prepared from (cis)-methyl 4-((((2S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexanecarboxylate (47 mg) using reaction conditions similar to those described for Example 28a. ^1H NMR (400 MHz, DMSO -d6 ) δ (ppm): 11.93 (sbr, 1H), 7.53-7.51 (m, 2H), 7.43-7.23 (m, 7H), 7.11 (sbr, 1H) _, 6.92 (d, J=8.6 Hz, 1H), 3.90 (s, 3H), 3.50 (d, J=16Hz, 1H), 2.96 (s br, 2H), 2.84 (d, J=16 Hz, 1H), 2.48-2.44 (m, 1H), 2.32-2.25 (m, 1H), 1.78-1.66 (m, 2H), 1.52-1.20 (m, 7H). UPLC-MS 1: mass/charge 553.3 [M+H] ⁺ , t _R =0.84 min. UPLC-MS 2: mass/charge 553.3 [M+H] ⁺ , t _R =3.90 min.

Example 29: 2-((2R,4S)-2-(aminomethyl)-5-chloro-2-(thiazol-4-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide

The title compound was prepared analogously to Example 5a from the intermediates 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 (C-III) and 2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV).

After final removal of the Boc protecting group, the racemic diastereoisomers were first separated by flash chromatography (silica, DCM/MeOH, gradient: MeOH from 0 to 10%): racemic (2R*,4S*) diastereoisomer: UPLC-MS 1: t _R = 0.68 min, racemic (2R*,4R*) diastereoisomer: UPLC-MS 1: t _R = 0.56 min. The (2R*,4S*) racemate was subjected to chiral HPLC (Chiralpak AD-H 250×30 mm, 5 μm, EtOH/MeOH 1:1+0.1% DEA, flow rate: 10 mL/min) to afford both enantiomers with an enantiomeric excess of >98%.

2-((2R,4S)-2-(Aminomethyl)-5-chloro-2-(thiazol-4-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 29): Chiral HPLC (Chiralpak AD-H 250×4.6 mm, 5 μm, EtOH/MeOH 1:1+0.1% DEA, flow rate: 1 ml/min.) t _R =3.55 min. ^1H NMR (400 MHz, DMSO -d6 ) δ 9.03 (d, J =1.9 Hz, 1H) _, 7.60 (d, J =1.9 Hz, 1H), 7.50 (s, 1H), 7.44 (d, J =8.6 Hz, 1H), 7.22 (t, J =8.5 Hz, 1H), 7.18 (d, J =8.5 Hz, 1H), 7.12 (s, 1H), 6.80 (d, J =8.5 Hz, 1H), 3.85 (s, 3H), 3.30 (d, J =16.3 Hz, 1H), 3.04 (d, J =16.2 Hz, 1H), 2.98 (s, 2H), 1.60 (br s, 2H). UPLC-MS 1: mass/charge 434.2 [M+H] ⁺ , t _R =0.68 min.

The other enantiomer, 2-((2S,4R)-2-(aminomethyl)-5-chloro-2-(thiazol-4-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide: Chiral HPLC (Chiralpak AD-H 250×4.6 mm, 5 μm, EtOH/MeOH 1:1+0.1% DEA, flow rate: 1 mL/min.) t _R = 10.56 min.

Example 30: 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide

The title compound was prepared analogously to Example 5a from the intermediates 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 (C-IV) and 2-bromo-3-fluorobenzonitrile.

After final removal of the Boc protecting group, the racemic diastereoisomers were first separated by flash chromatography (silica, DCM/(MeOH+2% 7 M _NH3 in MeOH), gradient: (MeOH+2% 7 M _NH3 in MeOH) from 20 to 100%): racemic (2S*,4S*) diastereoisomer: UPLC-MS 1: t _R = 0.83 min, racemic (2S*,4R*) diastereoisomer: UPLC-MS 1: t _R = 0.68 min. The racemate (2S*,4S*) was subjected to chiral HPLC (LuxCellulose 250×21 mm, 2.5 μm, heptane/IPA 7:3+0.05% DEA, flow rate: 10 mL/min) to afford both enantiomers with enantiomeric excess >98%, respectively.

2-((2S,4S)-2-(Aminomethyl)-5-chloro-2-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide (Example 30): Chiral HPLC (Chiralpak OZ-H 250×4.6 mm, 5 µm, heptane/IPA 6:4+0.05% DEA, flow rate: 1 ml/min.) t_R=8.73 min.¹H NMR (400 MHz, DMSO-d ₆) δ 7.76 (s, 1H), 7.58-7.51 (m, 1H), 7.45 (dd, J=7.7, 1.2 Hz, 1H), 7.43-7, 29 (m, 3H), 7.31-7.13 (m, 3H), 6.93 (d, J=8.5 Hz, 1H), 3.47 (d, J=16.3 Hz, 1H), 3.06-2.90 (m, 3H). UPLC-MS 1: mass/charge 477.0 [M+H]⁺, t_R=0.86 min.

The other enantiomer, 2-((2R,4R)-2-(aminomethyl)-5-chloro-2-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide: Chiral HPLC (Chiralpak OZ-H 250×4.6 mm, 5 μm, heptane/IPA 6:4+0.05% DEA, flow rate: 1 mL/min.) t _R = 12.22 min.

Example 31: 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-(2-fluorophenyl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide

The title compound was prepared analogously to Example 5a from 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 (C-V) (170 mg, 9.36 mmol) and 2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV).

2-((2S,4S)-2-(Aminomethyl)-5-chloro-2-(2-fluorophenyl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 31): ¹ H NMR (600 MHz, DMSO- d ₆ ) δ (ppm) 7.63 (s, 1H), 7.57 (t, J =7.7 Hz, 1H), 7.47 (d, J =8.6 Hz, 1H), 7.38-7.30 (m, 1H), 7.29-7.13 (m, 5H), 6.92 (d, J =8.6 Hz, 1H), 3.87 (s, 3H), 3.44 (d, J =16.0 Hz, 1H), 2.98 (d, J =14.2 Hz, 1H), 2.90 (br. d, J =17.5 Hz, 1H), 2.85 (br. d, J =14.9 Hz, 1H), 1.68 (br. s, 2H). UPLC-MS 1: m/z 445.1/447.2 [M+H] ⁺ , t _R =0.76 min.

Another diastereoisomer, 2-((2S,4R)-2-(aminomethyl)-5-chloro-2-(2-fluorophenyl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide: UPLC-MS 1: m/z 445.2/447.1 [M+H] ⁺ , t _R = 0.61 min.

Example 32a and example 32b: 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide (Example 32a) and 2-((2S,4R)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide (Example 32b)

Reaction scheme of example 32:

Stage 1 . tert-Butyl-(((2S,4S)-5-chloro-4-(2-cyano-6-fluorophenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl-(((2S,4R)-5-chloro-4-(2-cyano-6-fluorophenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate

A mixture of (S)-tert-butyl ((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 (C-XII) (220 mg, 0.44 mmol), 2-bromo-3-fluorobenzonitrile (114 mg, 0.57 mmol), tris(dibenzyldenacetone)dipalladium(0) (20 mg, 0.02 mmol), 4,6-bis(diphenylphosphimo)phenoxazine (24 mg, 0.04 mmol) and K ₃ PO ₄ (278 mg, 1.31 mmol) was suspended in toluene (2.5 mL) and water (0.5 mL) and purged with Ar. The reaction mixture was stirred at 100 °C for 12 h. Then EtOAc and sat. NaHCO ₃ solution were added. The aqueous layer was back extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc 4:1) to give a mixture of the title compounds (123 mg). UPLC-MS 1: m/z 497.2 [M+H] ⁺ , t _R = 1.36 and 1.39 min.

Stage 2 . tert-Butyl-(((2S,4S)-4-(2-carbamoyl-6-fluorophenyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl-(((2S,4R)-4-(2-carbamoyl-6-fluorophenyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate

To a suspension of a mixture of tert-butyl (((2S,4S)-5-chloro-4-(2-cyano-6-fluorophenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S,4R)-5-chloro-4-(2-cyano-6-fluorophenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (122 mg, 0.246 mmol) in EtOH (3 mL) and water (0.6 mL) was added hydrido(dimethylphosphinic acid-kP)[hydrogen bis(dimethylphosphinito-kP)]platinum(II) (21 mg, 0.05 mmol) at rt. The reaction mixture was stirred at 80 °C for 45 min. Saturated _NaHCO3 solution (30 mL) 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 a mixture of the title compounds (123 mg). UPLC-MS 1: m/z 515.2 [M+H] ⁺ , t _R = 1.18 and 1.26 min.

Step 3. 2-((2S,4S)-2-(Aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide (Example 32a) and 2-((2S,4R)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide (Example 32b)

A solution of a mixture of tert-butyl (((2S,4S)-4-(2-carbamoyl-6-fluorophenyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S,4R)-4-(2-carbamoyl-6-fluorophenyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (121 mg, 0.235 mmol) in DCM (1.5 mL) was treated with TFA (0.54 mL, 7.1 mmol). The reaction mixture was stirred at rt for 1 h, then diluted with DCM and concentrated. The crude product was purified by preparative HPLC (reverse phase, gradient: 5% to 100% ACN over 20 min) to afford the title compounds as individual diastereoisomers.

2-((2S,4S)-2-(Aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide (example 32a) (28 mg):¹H NMR (600 MHz, DMSO-d ₆) δ (ppm) 7.82 (br. s, 1H), 7.57 (dd, J=7.8 Hz, 1H), 7.48 (d, J=7.7 Hz, 1H), 7, 42 (d, J=8.3 Hz, 2H), 7.35 (dt, J=15.0, 7.6 Hz, 4H), 7.27 (t, J=6.9 Hz, 1H), 7.05 (d, J=9.6 Hz, 1H), 3.46 (d, J=15.9 Hz, 1H), 2.94-2 .80 (m, 3H), 1.65 (s, 2H). UPLC-MS 1: m/z 415.1 [M+H]⁺, t_R=0.77 min. The absolute configuration was confirmed by an X-ray cocrystal structure of Example 32a bound to the YAP binding site of TEAD3.

2-((2S,4R)-2-(Aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide (Example 32b) (20 mg): ¹ H NMR (600 MHz, DMSO- d ₆ ) δ (ppm) 7.76 (br. s, 1H), 7.57 (dd, J=7.7 Hz, 1H), 7.49-7.42 (m, 2H), 7.35 (dt, J=15.0, 7.7 Hz, 4H), 7.27 (t, J=7.1 Hz, 1H), 7.18 (s, 1H), 7.00 (d, J=9.7 Hz, 1H), 3.29 (d, J=15.8 Hz, 1H), 3.09 (d, J=15.9 Hz, 1H), 2.91-2.80 (m, 2H), 1.43 (br. s, 2H). UPLC-MS 1: m/z 415.1 [M+H] ⁺ , t _R =0.61 min.

The following compounds were prepared analogously to Example 32a.

Note: Structure/Chemical Name UPLC MS
mass/charge [M+H] ⁺
t _R [min.] (method) ¹ H NMR 33
2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;
2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV), used in the Suzuki coupling reaction 445.3
0.81 (1) (600 MHz, DMSO-d ₆ ) δ (ppm) 7.70 (br. s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.40-7.32 (m, 4H), 7.31-7.22 (m, 3H), 7.04 (d, J=9.7 Hz, 1H), 3.89 (s, 3H), 3.41 (d, J=15.9 Hz, 1H), 2.95-2.81 (m, 3H), 1.90 (br. s, 2H). 34
2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(cyclopropylmethoxy)-3-fluorobenzamide;
2-bromo-4-(cyclopropylmethoxy)-3-fluorobenzonitrile (NX), used in the Suzuki coupling reaction 485.1
0.95 (1) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm) 7.69 (s, 1H), 7.48 (dd, J=8.7, 1.2 Hz, 1H), 7.40-7 .32 (m, 4H), 7.30-7.21 (m, 3H), 7.04 (d, J=9.6 Hz, 1H), 3.95 (d, J=7.2 Hz, 2H), 3.41 (dd, J=15.9, 1.4 Hz, 2H), 2.96-2.79 (m, 3H ), 1.29-1.17 (m, 1H), 0.62-0.53 (m, 2H), 0.37-0.26 (m, 2H). 35
2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;
2-bromo-4-(difluoromethoxy)-3-fluorobenzonitrile (NV), used in the Suzuki coupling reaction 481.2
0.87 (1) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm) 7.89 (s, 1H), 7.57-7.51 (m, 2H), 7.47 (d, J=3.9 Hz , 1H), 7.39-7.33 (m, 5H), 7.30-7.25 (m, 1H), 7.08 (d, J=9.6 Hz, 1H), 3.45 (d, J=16.0 Hz, 1H), 2.96-2.79 (m, 3H), 1.45 (br s, 2H). 36
2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(1,1-difluoro-2-hydroxyethoxy)-3-fluorobenzamide;
2-bromo-4-(1,1-difluoro-2-hydroxyethoxy)-3-fluorobenzonitrile (N-XXII), used in the Suzuki coupling reaction 511.1
0.72 (1) ¹ H NMR (600 MHz, Chloroform-d ₃ ) δ (ppm) 7.56-7.43 (m, 2H), 7.39-7.18 (m, 8H), 6.80 (d, J=9.0 Hz, 1H), 4.04-3.93 (m, 2H), 3.46-3.29 (m, 2H), 3.14-2.99 (m, 2H). 37
2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-methoxyethoxy)benzamide;
2-bromo-3-fluoro-4-(2-methoxyethoxy)benzonitrile (N-IX), used in the Suzuki coupling reaction 489.3
0.66 (1) (600 MHz, DMSO-d ₆ ) δ (ppm) 7.67 (s, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.40-7.20 (m, 8H) , 7.03 (d, J=9.7 Hz, 1H), 4.27-4.18 (m, 2H), 3.71-3.62 (m, 2H), 3.41 (d, J=16.0 Hz, 1H), 2.94-2.81 (m, 3H), 1.46 (br s, 2H ) 38
2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;
2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzonitrile (N-VI), used in the Suzuki coupling reaction. The THP and Boc groups were cleaved in the last step. 475.2
0.72 (1) (600 MHz, DMSO-d ₆ ) δ (ppm) 7.66 (s, 1H), 7.51 (dd, J=8.7, 1.4 Hz, 1H), 7.42-7.35 ( m, 4H), 7.35-7.26 (m, 3H), 7.04 (d, J=9.6 Hz, 1H), 4.92 (t, J=5.4 Hz, 1H), 4.14 (t, J=4.8 Hz, 2H), 3.75 (q, J=5.1 Hz, 2H), 3, 43 (dd, J=15.9, 1.5 Hz, 1H), 2.94-2.82 (m, 3H), 1.42 (br s, 2H) 39
2-((2S,4R)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-((1,1-difluoro-2-hydroxyethyl)thio)benzamide;
2-bromo-4-((1,1-difluoro-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)thio)benzonitrile (N-XXIII), used in the Suzuki coupling reaction 509,0
0.78 (1) (600 MHz, DMSO- _d6 ) δ (ppm) 7.85 (s, 1H), 7.77-7.67 (m, 2H), 7.44 (s, 1H), 7.41-7, 31 (m, 5H), 7.32-7.24 (m, 1H), 7.03 (t, J=9.7 Hz, 1H), 6.04 (s, 1H), 3.77 (t, J=12.6 Hz, 2H), 3.39 (d, J=15.9 Hz, 1H), 2.99-2, 81 (m, 3H), 1.35 (br s, 2H). 40
2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((methylsulfonyl)methoxy)benzamide;
2-bromo-3-fluoro-4-((methylsulfonyl)methoxy)benzonitrile (N-XXIV), used in the Suzuki coupling reaction 523.2
0.68 (1) (400 MHz, DMSO- d ₆ ) δ (ppm) 7.76 (br s, 1H), 7.39 (s, 8 H), 7.06 (d, J=9.54 Hz,
1H), 5.37-5.58 (m, 2H), 3.44 (d, J=15.89 Hz, 1H), 3.06 (s, 3H), 2.84-2.95 (m, 3H), 1.88 (br s, 2H). 41
2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(3,3-difluoropropoxy)-3-fluorobenzamide;
2-bromo-4-(3,3-difluoropropoxy)-3-fluorobenzonitrile (N-XXV), used in the Suzuki coupling reaction 509.1
0.89 (1) (600 MHz, DMSO-d ₆ ) δ (ppm) 7.87 (s, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.50-7.45 (m, 2H) , 7.45-7.40 (m, 2H), 7.39-7.34 (m, 2H), 7.31 (s, 1H), 7.12 (d, J=9.3 Hz, 1H), 4.34-4.19 (m, 2H), 3.57-3.40 (m, 2H), 1.30-1 .17 (m, 5H). 42
4-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-methoxynicotinamide;
methyl 4-chloro-5-fluoro-6-methoxynicotinate (N-XXIX), used in the Suzuki coupling reaction, synthesis by analogy with example 18 446.2
0.79 (1) (400 MHz, DMSO-d ₆ ) δ 8.40 (br s, 1H), 8.00 (br s, 1H), 7.49 (br s, 1H), 7.47-7.25 (m, 5H), 7.13 (d, J=9.5 Hz, 1H), 4.04 (s, 3H), 3.45 (d, J=16.1 Hz, 1H), 3.02-2.88 (m, 3H).

Example 43: 4-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinamide

Step 1. Methyl 4-((2S,4S)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate and methyl 4-((2S,4R)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate

Mixture of (S)-tert-butyl-((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 (C-XII) (400 mg, 0.79 mmol), Methyl 4-chloro-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate (N-XXXI) (265 mg, 0.79 mmol), N-XantPhos Pd G3 (Aldrich cat. No. 794228) (37 mg, 0.04 mmol) and K ₃ PO ₄ (506 mg, 2.4 mmol) in toluene (5 ml) and H ₂ O (1 ml) The reaction mixture was stirred under Ar for 3 h at 105°C. The reaction mixture was diluted with sat. NaHCO ₃ solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried (phase separation cartridge), and concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient 0% to 70% EtOAc) to give the title compound mixture (182 mg). UPLC-MS 1: m/z 675.5 [M+H] ⁺ , t _R =1.47 min. and 1.48 min.

Step 2. 4-((2S,4S)-2-(((tert-Butoxycarbonyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinic acid and 4-((2S,4R)-2-(((tert-Butoxycarbonyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinic acid

A solution of a mixture of methyl 4-((2S,4S)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate and methyl 4-((2S,4R)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate (182 mg, 0.27 mmol) in THF (2.3 ml), 2 N NaOH (volume: 2.3 mL) and MeOH (2.3 mL) were stirred at 50 °C for 45 min. Water was added, followed by acidification to pH 1 with 1 N HCl. The mixture was extracted with EtOAc, the combined organic layers were washed with brine, dried (phase separation cartridge) and concentrated to give a mixture of the title compounds (184 mg). UPLC-MS 1: m/z 661.4 [M+H] ⁺ , t _R = 1.31 min and 1.35 min.

Step 3. tert-Butyl (((2S,4S)-4-(5-carbamoyl-3-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S,4R)-4-(5-carbamoyl-3-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate

A mixture of the title compounds (201 mg) was prepared from a mixture of 4-((2S,4S)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinic acid and 4-((2S,4R)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinic acid (184 mg) using reaction conditions similar to those described for Example 18, Step 3. UPLC-MS 1: mass/charge 660.4 [M+formate] ^- , t _R =1.26 min. and 1.32 min.

Step 4. 4-((2S,4S)-2-(Aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinamide (Example 43)

The title compound (56 mg, colourless powder) was prepared from a mixture of tert-butyl (((2S,4S)-4-(5-carbamoyl-3-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S,4R)-4-(5-carbamoyl-3-fluoro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (201 mg, 0.30 mmol) using reaction conditions similar to those which are described for example 22, step 5, followed by chromatographic separation of the diastereoisomers.

4-((2S,4S)-2-(Aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinamide (Example 43): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.37 (s, 1H), 8.00 (s br, 1H), 7.48 (s br, 1H), 7.44-7.35 (m, 4H), 7.34-7.28 (m, 1H), 7.13 (d, J=9.7 Hz, 1H), 4.94 (t, J=5.3 Hz, 1H), 4.50-4.41 (m, 2H), 3.80-3.75 (m, 2H), 3.46 (d, J=15.5 Hz, 1H), 2.99-2.93 (m, 3H). UPLC-MS 1: m/z 476.3 [M+H] ⁺ , t _R =0.68 min.

Another diastereoisomer, 4-((2S,4R)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinamide: UPLC-MS 1: m/z 476.3 [M+H] ⁺ , t _R = 0.55 min.

Example 44: 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide

Step 1. Methyl 2-((2S,4S)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate and methyl 2-((2S,4R)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate

A mixture of the title compounds (1.04 g) was prepared from (S)-tert-butyl ((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 (C-XII) (1.2 g, 2.14 mmol) and methyl 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate (N-XXVII) (0.89 g, 2.4 mmol) using reaction conditions similar to those described for Example 5a, step 1. UPLC-MS 1: m/z 718.4 [M+formate] ^- , t _R = 1.45 min. and 1.47 min.

Step 2. 2-((2S,4S)-2-(((tert-Butoxycarbonyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoic acid and 2-((2S,4R)-2-(((tert-Butoxycarbonyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoic acid

Added 4 N. NaOH (5.8 mL, 23.1 mmol) to a solution of a mixture of methyl (2S)-2-((S)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate and methyl (2R)-2-((S)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate (1.04 g, 1.54 mmol) in MeOH (15 mL) and THF (5 mL) and stirring at rt was continued overnight: The reaction mixture was diluted with water, cooled to 0 °C, acidified to pH 2 with 2 N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO ₄ and concentrated to give a mixture of the title compounds (1.10 g, colourless foam). UPLC-MS 1: m/z 658.3 [MH] ^- , t _R = 1.30 min and 1.35 min.

Step 3. tert-Butyl (((2S,4S)-5-chloro-6-fluoro-4-(2-fluoro-6-(methylcarbamoyl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S,4R)-5-chloro-6-fluoro-4-(2-fluoro-6-(methylcarbamoyl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate

A mixture of the title compounds (1.02 g) was prepared from a mixture of 2-((2S,4S)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoic acid and 2-((2S,4R)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoic acid (1.10 g, 1.5 mmol) using reaction conditions similar to those described for Example 22, stages 3. UPLC-MS 1: mass/charge 717.5 [M+formate] ^- , t _R =1.28 min and 1.34 min.

Step 4. 2-((2S,4S)-2-(Aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide (Example 44)

The title compound (274 mg, colourless powder) was prepared from a mixture of tert-butyl (((2S,4S)-5-chloro-6-fluoro-4-(2-fluoro-6-(methylcarbamoyl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S,4R)-5-chloro-6-fluoro-4-(2-fluoro-6-(methylcarbamoyl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (1.03 g, 1.48 mmol) using reaction conditions similar to those described for Example 22, step 5, followed by chromatographic separation of the diastereoisomers.

2-((2S,4S)-2-(Aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide (Example 44): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.18-8.12 (m, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.40-7.25 (m, 6H), 7.03 (d, J=9.7 Hz, 1H), 4.93 (t, J=5.5 Hz, 1H), 4.15-4.11 (m, 2H), 3.76-3.71 (m, 2H), 3.39 (d, J=15.7 Hz, 1H), 2.89 (s, 2H), 2.84 (d, J=15.5 Hz, 1H), 2.62 (d, J=4.5 Hz, 3H), 1.45 (s br, 2H). UPLC-MS 1: mass/charge 489.3 [M+H] ⁺ , t _R =0.72 min.

Another diastereoisomer, 2-((2S,4R)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide: UPLC-MS 1: m/z 489.3 [M+H] ⁺ , t _R = 0.65 min.

Example 45: 4-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide

The title compound was prepared analogously to Example 44 from the intermediates (S)-tert-butyl ((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 (C-XII) and methyl 4-chloro-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate N-XXXI, followed by chromatographic separation of the diastereoisomers.

4-((2S,4S)-2-(Aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)- N-Methylnicotinamide (Example 45): ^1H NMR (400 MHz, DMSO _-d6 ) δ (ppm) 8.48-8.43 (m, 1H), 8.28 (s, 1H), 7.40-7.33 (m, 4H), 7.31-7.26 (m, 1H), 7. 10 (d, J=9.7 Hz, 1H), 4.91 (t, J=5.4 Hz, 1H), 4.49-4.39 (m, 2H), 3.78-3.73 (m, 2H), 3.42 (d, J=16.0 Hz, 1H), 2.92 (d, J=16.8 Hz, 1H), 2.89 (s, 2H), 2.66 (d, J=4 .5 Hz, 3H), 1.41 (s br, 2H). UPLC-MS 1: mass/charge 490.1 [M+H] ⁺ , t _R =0.63 min.

Another diastereoisomer, 4-((2S,4R)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide: UPLC-MS 1: m/z 490.1 [M+H] ⁺ , t _R = 0.57 min.

Example 46: 2-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide

Stage 1. tert-Butyl-(((2S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2 -yl)methyl)carbamate and tert-butyl-(((2S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl) methyl)carbamate

A mixture of the title compounds (200 mg, yellow oil) was prepared from 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 (C-XII) (229 mg, 0.455 mmol) and 2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV) (136 mg, 0.59 mmol) using reaction conditions similar to those described for Example 5a, step 1. UPLC-MS 1: m/z 571.3 [M+formate] ^- , t _R = 1.34 min and 1.37 min.

Step 2. tert-Butyl-(((2S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2 -yl)methyl)(methyl)carbamate and tert-butyl-(((2S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl) methyl)(methyl)carbamate

At 0°C, NaH (31 mg, 0.78 mmol, 60% in mineral oil) was added to a solution of a mixture of tert-butyl (((2S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (200 mg, 0.38 mmol) in THF (2 mL). After 10 min, methyl iodide (0.05 mL, 2.11 mmol) was added and the reaction mixture was allowed to warm to rt. for 1.5 h. The reaction mixture was partitioned between EtOAc and saturated NaHCO ₃ solution. The organic layer was separated and the organic layer was extracted with EtOAc. The combined organic phases were dried over anhydrous Na ₂ SO ₄ and concentrated to give a mixture of the title compounds as a yellow oil. UPLC-MS 1: m/z 541.3 [M+H] ^- , t _R = 1.43 min and 1.44 min.

Step 3. tert-Butyl-(((2S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2 -yl)methyl)(methyl)carbamate and tert-butyl-(((2S,4R)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl) methyl)(methyl)carbamate

A mixture of the title compounds (142 mg, yellow oil) was prepared from a mixture of tert-butyl (((2S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl (((2S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate according to the procedure described for Example 5a, Step 2. UPLC-MS 1: m/z 559.3 [M+H]⁺, t_R=1.27 min. and 1.29 min.

Step 4. 2-((2S,4S)-5-Chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 46).

The title compound (31 mg, light beige powder) was prepared from a mixture of tert-butyl (((2S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl (((2S,4R)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (140 mg, 0.25 mmol) using reaction conditions similar to those described for Example 5a, step 3, followed by chromatographic separation of the diastereoisomers.

2-((2S,4S)-5-Chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (example 46): ^1H NMR (600 MHz, DMSO _-d6 ) δ (ppm) 7.61 (sbr, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.42-7.28 (m, 2H), 7.38-7.33 (m, 2H), 7.33-7 .27 (m, 2H), 7.25 (s br, 1H), 7.06 (d, J=9.7 Hz, 1H), 3.90 (s, 3H), 3.45 (d, J=15.8 Hz, 1H), 2.91 (s br, 2H), 2.85 (d, J=15.6 Hz, 1H), 2.23 (s, 3H). UPLC-MS 1: m/z 459.3 [ M+H] ⁺ , t _R =0.81 min.

Another diastereoisomer, 2-((2S,4R)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide: UPLC-MS 1: m/z 459.3 [M+H] ⁺ , t _R = 0.66 min.

Example 47: 4-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-methoxyethoxy)nicotinamide

The title compound was prepared analogously to Example 46 from the intermediates 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 (C-XII) and 4-chloro-5-fluoro-6-(2-methoxyethoxy)nicotinonitrile (N-XI) followed by chromatographic separation of diastereoisomers.

4-((2S,4S)-5-Chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-methoxyethoxy)nicotinamide (Example 47): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.36 (s, 1H), 7.88 (s br, 1H), 7.45-7.31 (m, 5H), 7.31-7.25 (m, 1H), 7.11 (d, J=9.8 Hz, 1H), 4.60-4.48 (m, 2H), 3.74-3.68 (m, 2H), 3.47 (d, J=15.9 Hz, 1H), 2.93 (d, J=15.7 Hz, 1H), 2.91 (s, 2H), 2.23 (s, 3H). UPLC-MS 1: m/z 504.2 [M+H] ⁺ , t _R =0.79 min.

Another diastereoisomer, 4-((2S,4R)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-methoxyethoxy)nicotinamide: UPLC-MS 1: m/z 504.2 [M+H] ⁺ , t _R = 0.66 min.

Example 48: 2-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide

Step 1. tert-Butyl (((2S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate

A mixture of (S)-tert-butyl ((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 (C-XII) (550 mg, 0.82 mmol), 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzonitrile (N-VI) (282 mg, 0.82 mmol), N-XantPhos Pd G3 (Aldrich cat. No. 794228) (75 mg, 0.082 mmol) and K ₃ PO ₄ (521 mg, 2.46 mmol) in toluene (3 mL) and H ₂ O (1 mL) stirred under Ar for 1 h at 105 °C. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried (phase separation cartridge) and concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient 0 to 50% EtOAc) to give the title compound mixture (382 mg) as a yellow sticky solid. UPLC-MS 1: w/z 658.6 [M+NH ₄ ] ⁺ , t _R = 1.41 min and w/z 641.6 [M+H] ⁺ , t _R = 1.44 min.

Step 2. tert-Butyl (((2S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl (((2S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate

At 0°C, NaH (23 mg, 0.91 mmol, 95%) was added to a solution of a mixture of tert-butyl (((2S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (195 mg, 0.30 mmol) in DMF (3 mL). After 5 min. Methyl iodide (190 µL, 3.0 mmol) was added and the reaction mixture was stirred at rt for 30 min. Water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried (phase separation cartridge) and concentrated to give a mixture of the title compounds (196 mg) as a yellow oil. UPLC-MS 1: m/z 699.6 [M+formate] ^- , t _R = 1.50 min and 1.51 min.

Step 3. tert-Butyl (((2S,4S)-4-(6-carbamoyl-2-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl (((2S,4R)-4-(6-carbamoyl-2-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate

A mixture of the title compounds (150 mg, colourless powder) was prepared from a mixture of tert-butyl (((2S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl (((2S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (196 mg) according to the procedure described for Example 5a, Step 2. UPLC-MS 1: mass/charge 673.5 [M+H] ⁺ , t _R =1.35 min. and 1.36 min.

Step 4. 2-((2S,4S)-5-Chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide (Example 48)

The title compound (21 mg, colourless powder) was prepared from a mixture of tert-butyl (((2S,4S)-4-(6-carbamoyl-2-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl (((2S,4R)-4-(6-carbamoyl-2-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (150 mg, 0.22 mmol) using reaction conditions similar to those described for Example 22, stage 5, followed by chromatographic separation of diastereoisomers.

2-((2S,4S)-5-Chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide (Example 48): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.55 (s br, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.41-7.24 (m, 6H), 7.19 (s br, 1H), 7.03 (d, J=9.7 Hz, 1H), 4.92 (t, J=5.4 Hz, 1H), 4.12 (t, J=4.7 Hz, 2H), 3.72 (dd, J=9.7, 5.0 Hz, 2H), 3.43 (d, J=15.9 Hz, 1H), 2.89 (s, 2H), 2.83 (d, J=15.7 Hz, 1H), 2.21 (s, 3H). UPLC-MS 1: m/z 489.4 [M+H] ⁺ , t _R =0.69 min.

Another diastereoisomer, 2-((2S,4R)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide: UPLC-MS 1: m/z 489.3 [M+H] ⁺ , t _R = 0.58 min.

Example 49: 4-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinamide

The title compound was prepared analogously to Example 48 from 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 (C-XII) and 5-fluoro-4-iodo-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinonitrile (N-XII).

4-((2S,4S)-5-Chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinamide (Example 49): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.36 (s, 1H), 7.90 (s br, 1H), 7.45-7.33 (m, 5H), 7.33-7.27 (m, 1H), 7.12 (d, J=9.5 Hz, 1H), 4.91 (t, J=5.1 Hz, 1H), 4.49-4.40 (m, 2H), 3.79-3.73 (m, 2H), 3.48 (d, J=15.9 Hz, 1H), 3.01 (s, 2H), 2.94 (d, J=15.9 Hz, 1H), 2.27 (s, 3H). UPLC-MS 1: m/z 490.1 [M+H] ⁺ , t _R =0.66 min.

Another diastereoisomer, 4-((2S,4R)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinamide: UPLC-MS 1: m/z 490.2 [M+H] ⁺ , t _R = 0.56 min.

Example 50: 2-((2S,4S)-5-chloro-2-(((cyclopropylmethyl)amino)methyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)- 3-fluorobenzamide

At rt, to a stirred solution of 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide (Example 35) (50 mg, 0.10 mmol) and cyclopropanecarbaldehyde (8.0 mg, 0.11 mmol) in THF (1 mL) was added sodium triacetoxyborohydride (110 mg, 0.52 mmol). After 1 h, saturated _NaHCO3 solution was added and the mixture was extracted with DCM. The combined organic layers were dried (phase separation cartridge) and concentrated. The residue was purified by preparative HPLC (Waters Sunfire OBD, 100×30 mm, 5 μm, eluent A: _H2O +0.1% TFA, eluent B: ACN, gradient: 5 to 100% B over 20 min, hold 1 min, flow 40 mL/min) to give the title compound (27 mg) as a colorless powder. ^1H NMR (600 MHz, DMSO - _d6 ) δ (ppm) 7.82 (sbr, 1H), 7.58-7.53 (m, 2H), 7.43-7.35 (m, 5H), 7.36 (t, J=72.8 Hz, 1H), 7.32-7.28 (m, 1H), 7.12 (d, J=9.5 Hz, 1H), 3.51 (d, J=15.8 Hz, 1H), 3.00 (s br, 2H), 2.90 (d, J=15.2 Hz, 1H), 2.36-2.29 (m, 2H), 0.82-0.74 (m, 1H), 0.36-0.29 (m, 2H), 0.03 - -0.05 (m, 2H). UPLC-MS 1: m/z 535.1 [M+H] ⁺ , t _R =1.01 min.

Example 51: 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 (2 P )-2-{(2 S )-5-chloro-6-fluoro-2-[(methylamino)methyl]-2-phenyl-

2,3-dihydro-1-benzofuran-4-yl}-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide

Reaction scheme of example 51:

Step 1. Methyl 2-((2S,4S)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate and methyl 2-((2S,4R)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate

In an Ar atmosphere, a suspension of (S)-tert-butyl ((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 (C-XII) (12 g, 21.44 mmol), methyl 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate (N-XXVII) (8.89 g, 23.58 mmol), K ₃ PO ₄ (13.65 g, 64.3 mmol), N-Xantphos (1.182 g, 2.144 mmol) and Pd ₂ (dba) ₃ (0.982 g, 1.072 mmol) in toluene/water (5:1, 240 mL) was heated at 100 °C for 19 h. The reaction mixture was cooled to rt, poured into 10% NaHCO ₃ solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO ₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 20% to 100% EtOAc) to give a mixture of the title compounds (11.65 g). UPLC-MS 1: m/z 718.2/719.2 [M+HCOO ^- ] ^- , t _R = 1.44/1.45 min.

Step 2. Methyl 2-((2S,4S)-2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate and methyl 2-((2S,4R)-2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate

At rt, to a stirred solution of a mixture of methyl 2-((2S,4S)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate and methyl 2-((2S,4R)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate (11.4 g, 16.91 mmol) in dry DMF (100 mL) was added portionwise NaH (1.353 g, 33.8 mmol) was added slowly to methyl iodide (2.64 mL, 42.3 mmol) and stirring at rt was continued for 15 min. After cooling to 0 °C, methyl iodide (2.64 mL, 42.3 mmol) was added slowly and the reaction mixture was stirred at 0 °C for 1.5 h and then at rt for an additional 30 min. For work-up, the reaction mixture was poured into 10% NH ₄ Cl solution and extracted with EtOAc. The organic layers were combined, dried over anhydrous MgSO ₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 15% to 60% EtOAc) to give a mixture of the title compounds (10.0 g). UPLC-MS 1: mass/charge 705.5/707.4 [M+NH4 ⁺ ] ⁺ , t _R =1.53 min.

Step 3. 2-((2S,4S)-2-(((tert-Butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoic acid and 2-((2S,4R)-2-(((tert-Butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoic acid

To a stirred solution of a mixture of methyl 2-((2S,4S)-2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate and methyl 2-((2S,4R)-2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate (10.0 g, 14.53 mmol) in MeOH (100 mL) in THF (50 mL) An aqueous solution of 4 M NaOH (36.3 mL, 145 mmol) was added. After stirring at 40 °C for 7.5 h, the reaction mixture was partially concentrated, diluted with water, cooled to 5 °C and acidified with aqueous 2 M HCl. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated to give a mixture of the title compounds (10.8 g). UPLC-MS 1: m/z 672.4 [MH] ^- , t _R = 1.39/1.40 min.

Step 4. tert-Butyl (((2S,4S)-5-chloro-6-fluoro-4-(2-fluoro-6-(methylcarbamoyl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl (((2S,4R)-5-chloro-6-fluoro-4-(2-fluoro-6-(methylcarbamoyl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate

To a stirred solution of a mixture of 2-((2S,4S)-2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoic acid and 2-((2S,4R)-2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoic acid (10.8 g, 14.42 mmol), DIPEA (15.11 mL, 87 mmol) and HATU (8.77 g, 23.07 mmol) was added to methylamine hydrochloride (1.947 g, 28.8 mmol) in DMF (100 mL). The reaction mixture was stirred at rt for 2 days, then more DIPEA (2.50 mL, 14.5 mmol), methylamine hydrochloride (1.0 g, 14.00 mmol) and HATU (4.35 g, 11.5 mmol) were added and stirring at rt was continued for another 24 h. The reaction mixture was then partially concentrated, poured into saturated NaHCO ₃ solution and extracted with TBME. The combined organic layers were washed with 10% NaHCO ₃ solution and brine, dried over anhydrous MgSO ₄ , filtered and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 15% to 100% EtOAc) to afford the title compounds as individual diastereoisomers.

tert-Butyl (((2S,4S)-5-chloro-6-fluoro-4-(2-fluoro-6-(methylcarbamoyl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (4.53 g): UPLC-MS 1: m/z 687.5 [M+H] ⁺ , t _R =1.41 min.

tert-Butyl (((2S,4R)-5-chloro-6-fluoro-4-(2-fluoro-6-(methylcarbamoyl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (3.92 g): UPLC-MS 1: m/z 687.5 [M+H] ⁺ , t _R =1.39 min.

Step 5. 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

(2 P )-2-{(2 S )-5-chloro-6-fluoro-2-[(methylamino)methyl]-2-phenyl-

2,3-dihydro-1-benzofuran-4-yl}-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide (Example 51)

To a solution of tert-butyl (((2S,4S)-5-chloro-6-fluoro-4-(2-fluoro-6-(methylcarbamoyl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (4.50 g, 6.55 mmol) in 1,4-dioxane (20 mL) was slowly added HCl (33 mL, 131 mmol, 4 M in dioxane) and stirring at rt was continued for 5 h. The reaction mixture was poured into saturated NaHCO ₃ solution, saturated with solid NaCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous _MgSO4 , filtered and concentrated. The crude product was purified by flash chromatography (silica, DCM/(DCM/MeOH 4:1+2% 7 M _NH3 in MeOH): gradient: 15% to 60% (DCM/MeOH 4:1+2% 7 M _NH3 in MeOH)) to give the title compound (2.85 g). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.13 (q, J=4.6 Hz, 1H), 7.47-7.41 (m, 1H), 7.41-7.21 (m, 6H), 7.03 (d, J=9.7 Hz, 1H), 4.93 (t, J=5.4 Hz, 1H), 4.12 (t, J=4.9 Hz, 2H), 3.73 (q, J=5.1 Hz, 2H), 3.44 (d, J=15.7 Hz, 1H), 2.88 (s, 2H), 2.79 (d, J=15.7 Hz, 1H), 2.64 (d, J=4.5 Hz, 3H), 2.23(s,3H). UPLC-MS 1: mass/charge 503.6 [M+H] ⁺ , t _R =0.70 min. The absolute configuration was confirmed by an X-ray cocrystal structure of Example 51 bound to the YAP binding site of TEAD4.

The following compounds were prepared similarly to Example 51.

Note: Structure/Chemical Name UPLC MS
mass/charge [M+H] ⁺
t _R [min.] (method) ¹ H NMR 52
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;
Methyl 2-bromo-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzoate (N-XXVIII) was used in the Suzuki coupling reaction 517.1 0.75 (1) (600 MHz, DMSO-d ₆ ) δ (ppm) 8.16 (q, J=4.7 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.41-7 .24 (m, 6H), 7.04 (d, J=9.5 Hz, 1H), 4.95 (d, J=4.2 Hz, 1H), 4.01-3.89 (m, 3H), 3.44 (d, J=15.8 Hz, 1H), 2.89 (s, 2H), 2.80 (d, J=15 .8 Hz, 1H), 2.63 (d, J=4.5 Hz, 3H), 2.24 (s, 3H), 1.13 (d, J=5.7 Hz, 3H) 53
4-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide;
methyl 4-chloro-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate (N-XXXI), used in the Suzuki coupling reaction 504.1 0.67 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 8.44 (q, J=4.5 Hz, 1H), 8.27 (s, 1H), 7.44-7.21 (m, 5H) , 7.10 (d, J=9.6 Hz, 1H), 5.75 (s, 1H), 4.91 (t, J=5.5 Hz, 1H), 4.49-4.37 (m, 2H), 3.79-3.71 (m, 2H), 3.47 (d, J=15.8 Hz, 1H ), 2.90-2.85 (m, 3H), 2.67 (d, J=4.5 Hz, 3H), 2.23 (s, 3H).

Example 54a and example 54b: 2-((2S,4S)-5-chloro-6-fluoro-2-((((cis)-4-(methylsulfonyl)cyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide (Example 54a) and 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 (Example 54b)

Reaction scheme of example 54:

At rt, to a solution of 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide (Example 35) (100 mg, 0.21 mmol), 4-(methylsulfonyl)cyclohexan-1-one (44 mg, 0.25 mmol) and acetic acid (0.012 mL, 0.21 mmol) in DCM (2 mL) was added NaBH(OAc) ₃ (132 mg, 0.62 mmol). The reaction mixture was then stirred at rt for 90 min. The reaction mixture was quenched by adding sat. _NaHCO3 solution and extracted with DCM. The organic layers were combined and washed with sat. NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, DCM/MeOH, gradient from 0% to 10% MeOH) and the diastereoisomers were separated.

2-((2S,4S)-5-Chloro-6-fluoro-2-((((cis)-4-(methylsulfonyl)cyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide (72 mg) (Example 54a): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.70 (s, 1H), 7.71-7.50 (m, 2H), 7.44-7.16 (m, 7H), 7.09 (d, J=9.6 Hz, 1H), 3.51 (d, J=15.9 Hz, 1H), 2.99-2.78 (m, 4H), 2.76 (s, 3H), 2.69 (s, 1H), 1.86-1.45 (m, 4H), 1.37-1.35 (m, 2H). UPLC-MS 2: m/z 641.3 [M+H] ⁺ , t _R =4.32 min.

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 (26 mg) (Example 54b): ¹ H NMR (400 MHz, CD ₃ OD) δ (ppm) 7.83-7.37 (m, 8H), 7.39-6.91 (m, 2H), 3.76-3.53 (m, 2H), 3.48 (s, 1H), 3.17 (d, J=15.8 Hz, 1H), 3.10 (t, J=12.2 Hz, 1H), 3.03 (s, 3H), 2.68-2.48 (m, 1H), 2.41-2.22 (m, 2H), 2.21 (d, J=13.4 Hz, 1H), 2.22-2.03 (m, 1H), 1.68-1.64 (m, 2H), 1.63-1.33 (m, 1H), 1.49-1.16 (m, 3H). UPLC-MS 2: mass/charge 641.3 [M+H] ⁺ , t _R =4.19 min.

The following compounds were prepared analogously to Example 54a and Example 54b.

Note: Structure/Chemical Name UPLC MS
mass/charge [M+H] ⁺
t _R [min.] (method) ¹ H NMR 55a
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;
4-(fluoromethyl)-4-hydroxycyclohexan-1-one (SI), used in reductive amination, absolute stereochemistry at the cyclohexyl ring unknown 611.3
0.91 (1) (600 MHz, DMSO-d ₆ ) δ (ppm) 7.86 (s, 1H), 7.66-7.02 (m, 10H), 4.41 (s, 1H), 4.05 (d, J=48.1 Hz, 2H), 3.50 (d, J=15.7 Hz, 1H), 3.00 (s, 2H), 2.87 (d, J=15.7 Hz, 1H), 2.22 (s, 1H), 1.58-1.47 (m, 2H), 1.45 (s, 2H), 1.24 (sbr, 4H). 55b
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;
Absolute stereochemistry at the cyclohexyl ring is unknown, stereoisomer of example 55a 611.3 0.89 (1) (600 MHz, DMSO-d ₆ ) δ (ppm) 7.84 (s, 1H), 7.66-7.01 (m, 10H), 4.45 (s, 1H), 4.12 (d, J=48.1 Hz, 2H), 3.49 (d, J=16.0 Hz, 1H), 2.94 (s, 2H), 2.88 (d, J=15.4 Hz, 1H), 1.70-1.45 (m, 5H), 1.28-1.04 (m, 4H). 56a
2-((2S,4S)-2-(((4-acetamidocyclohexyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy )-3-fluorobenzamide;
N-(4-oxocyclohexyl)acetamide, used in reductive amination, absolute stereochemistry at the cyclohexyl ring unknown 620.2 0.94 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.76 (s, 1H), 7.72-7.37 (m, 3H), 7.51-6.93 (m, 7H), 3, 48 (d, J=15.8 Hz, 1H), 3.42-3.32 (m, 1H), 3.00-2.90 (m, 2H), 2.84 (d, J=15.7 Hz, 1H), 2.17 (s, 1H), 1.78 -1.62 (m, 7H) , 1.22-0.78 (m, 4H). 56b
2-((2S,4S)-2-(((4-acetamidocyclohexyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy )-3-fluorobenzamide;
The absolute stereochemistry at the cyclohexyl ring is unknown, stereoisomer of example 56a. 620.2 0.93 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.84 (s, 1H), 7.69-7.20 (m, 8H), 7.18-6.95 (m, 1H), 3, 59 (sbr, 1H), 3.49 (d, J=15.8 Hz, 1H), 2.96 (sbr, 2H), 2.86 (d, J=15.8 Hz, 1H), 2.43 (s, 1H), 1.75 (s, 3H), 1.53-0.71 (m, 8H). 57a
2-((2S,4S)-5-chloro-6-fluoro-2-(((4-(methylsulfonamido)cyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;
N-(4-oxocyclohexyl)methanesulfonamide, used in reductive amination, absolute stereochemistry at the cyclohexyl ring unknown 656.3 0.89 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.76 (s, 1H), 7.68-7.37 (m, 2H), 7.51-6.93 (m, 7H), 6, 87 (d, J=7.2 Hz, 1H), 3.47 (d, J=16.0 Hz, 1H), 3.05-2.65 (m, 6H), 2.16 (s, 1H), 1.92-1.54 (m, 4H), 1.30-0.94 (m, 4H). 57b
2-((2S,4S)-5-chloro-6-fluoro-2-(((4-(methylsulfonamido)cyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;
Absolute stereochemistry at the cyclohexyl ring is unknown, stereoisomer of example 57a 656.3 0.90 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.83 (s, 1H), 7.69-7.13 (m, 7H), 7.27-6.95 (m, 1H), 6, 77 (d, J=6.7 Hz, 1H), 3.49 (d, J=15.9 Hz, 1H), 3.17 (sbr, 2H), 3.00-2.85 (m, 5H), 2.41 (s, 1H), 1.63-0.83 (m, 8H). 58a
2-((2S,4S)-5-chloro-2-(((4-(dimethylcarbamoyl)cyclohexyl)amino)methyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4 -(difluoromethoxy)-3-fluorobenzamide;
N,N-dimethyl-4-oxocyclohexanecarboxamide used in reductive amination, absolute stereochemistry at the cyclohexyl ring unknown 634.2 0.97 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.77 (s, 1H), 7.68-7.52 (m, 2H), 7.51-6.94 (m, 7H), 3, 47 (d, J=15.9 Hz, 1H), 3.04-2.89 (m, 5H), 2.84 (d, J=15.9 Hz, 1H), 2.75 (s, 3H), 2.42 (t, J=11.9 Hz, 1H), 2.26-2.15 (m, 1H), 1, 92-1.59 (m, 2H), 1.56 (d, J=13.2 Hz, 2H), 1.44-1.06 (m, 3H), 1.09-0.68 (m, 2H). 58b
2-((2S,4S)-5-chloro-2-(((4-(dimethylcarbamoyl)cyclohexyl)amino)methyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4 -(difluoromethoxy)-3-fluorobenzamide;
Absolute stereochemistry at the cyclohexyl ring is unknown, stereoisomer of example 58a 634.2 1.02 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.84 (s, 1H), 7.69-6.95 (m, 8H), 3.63 (d, J=15.8 Hz, 1H) , 3.18-2.65 (m, 9H), 2.63 (s, 1H), 2.53 (s, 1H), 1.66 -1.50 (m, 4H), 1.46-1.10 (m, 5H). 59a
2-((2S,4S)-5-chloro-6-fluoro-2-(((2-oxo-1-azaspiro[4.5]decan-8-yl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;
1-azaspiro[4.5]decane-2,8-dione, used in reductive amination, absolute stereochemistry at the spiro[4,5]decanyl ring unknown 632.3 0.87 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.77 (s, 1H), 7.61-7.48 (m, 4H), 7.42-7.14 (m, 7H), 7, 06 (d, J=9.5 Hz, 1H), 3.47 (d, J=15.8 Hz, 1H), 2.95 (s, 2H), 2.71 (d, J=15.8 Hz, 1H), 2.22 (s, 1H), 2.09 (t, J=8.0 Hz, 2H), 1.77 -1.55 (m, 4H), 1.46 (d, J=13.1 Hz, 2H), 1.44-1.10 (m, 4H), 1.05 (sbr, 2H). 59b
2-((2S,4S)-5-chloro-6-fluoro-2-(((2-oxo-1-azaspiro[4.5]decan-8-yl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;
The absolute stereochemistry at the spiro[4,5]decanyl ring is unknown, stereoisomer of example 59a 632.3 0.89 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.91 (s, 1H), 7.79 (s, 1H), 7.60-7.49 (m, 2H), 7.46-7, 12 (m, 5H), 7.07 (d, J=9.5 Hz, 1H), 3.50 (d, J=15.7 Hz, 1H), 2.97 (s br, 2H), 2.60 (d, J=15.7 Hz, 1H), 2.30 (s, 1H), 2.12 (t, J=7, 9 Hz, 2H), 1.74-1.65 (m, 2H), 1.52 (s, 4H), 1.34-1.16 (m, 6H). 60
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;
N,N-dimethyl-2-(4-oxopiperidin-1-yl)acetamide used in reductive amination 649.4 0.84 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.78 (s, 1H), 7.57-7.47 (m, 2H), 7.40-7.22 (m, 7H), 7, 07 (d, J=9.4 Hz, 1H), 3.48 (d, J=15.6 Hz, 1H), 3.14-2.59 (m, 11H), 2.25-2.14 (m, 1H), 2.05-1.81 (m, 2H), 1.68-1.55 (m, 2H ), 1.22 (s, 1H), 1.12 (s br, 2H). 61a
2-((2S,4S)-5-chloro-6-fluoro-2-(((4-(hydroxymethyl)cyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;
4-(hydroxymethyl)cyclohexanone, used in reductive amination, absolute stereochemistry at the cyclohexyl ring unknown 593.3 0.90 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.81 (s, 1H), 7.57-7.48 (m, 2H), 7.40-7.25 (m, 8H), 7, 07 (d, J=9.7 Hz, 1H), 4.24 (s, 1H), 3.47 (d, J=15.8 Hz, 1H), 3.18-3.06 (m, 3H), 3.00-2.81 (m, 3H), 2.48 (s, 2H), 1.50-0.90 (m, 8H). 61b
2-((2S,4S)-5-chloro-6-fluoro-2-(((4-(hydroxymethyl)cyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;
Absolute stereochemistry at the cyclohexyl ring is unknown, stereoisomer of example 61a 593.3 0.89 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.76 (s, 1H), 7.55-7.48 (m, 3H), 7.40-7.14 (m, 7H), 7, 07 (d, J=9.6 Hz, 1H), 4.28 (s, 1H), 3.47 (d, J=16.0 Hz, 1H), 3.13 (t, J=6.0 Hz, 2H), 2.97 (s br, 2H), 2.84 (d, J=16.0 Hz, 1H), 2.16 (sbr, 1H), 1.91 -1.57 (m, 4H), 1.34-1.02 (m, 2H), 0.93-0.72 (m, 2H). 62a
2-((2S,4S)-5-chloro-6-fluoro-2-(((3-(2-hydroxypropan-2-yl)cyclobutyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran- 4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;
3-(2-hydroxypropan-2-yl)cyclobutanone, used in reductive amination, absolute stereochemistry on the cyclobutyl ring unknown 593.2 1.02 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.80 (s, 1H), 7.68-7.40 (m, 2H), 7.37-7.15 (m, 5H), 7, 08 (d, J=9.7 Hz, 1H), 4.72 (d, J=5.7 Hz, 1H), 4.07-3.96 (m, 3H), 3.45 (d, J=15.9 Hz, 1H), 2.90-2.77 (m, 3H), 2.11 (dd, J= 7.1, 5.7 Hz, 1H), 1.88 (dd, J=17.3, 8.8 Hz, 2H), 1.91-1.53 (m, 2H), 1.60-1.28 (m, 1H), 1.23 (s, 1H), 0.98 (s, 3H), 0.91 (s, 3H). 62b
2-((2S,4S)-5-chloro-6-fluoro-2-(((3-(2-hydroxypropan-2-yl)cyclobutyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran- 4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;
Absolute stereochemistry on the cyclobutyl ring is unknown, stereoisomer of example 62a 593.2 0.98 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.80 (s, 1H), 7.58-7.48 (m, 2H), 7.42-7.14 (m, 5H), 7, 08 (d, J=9.6 Hz, 1H), 3.97 (s, 1H), 3.45 (d, J=15.1 Hz, 1H), 3.00 (s, 1H), 2.90-2.80 (m, 2H), 2.07 (s, 1H), 1.94 (s br, 2H), 1.51 ( sbr, 2H), 1.44-1.10 (m, 1H), 0.93 (s, 6H). 63
2-((2S,4S)-5-chloro-6-fluoro-2-(((1-(methylsulfonyl)piperidin-4-yl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;
1-(methylsulfonyl)piperidin-4-one used in reductive amination 642.3 0.92 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.80 (s, 1H), 7.60-7.50 (m, 2H), 7.45-7.15 (m, 6H), 7, 09 (d, J=9.6 Hz, 1H), 3.52 (d, J=15.7 Hz, 1H), 2.96 (s br, 2H), 2.80 (d, J=15.7 Hz, 1H), 2.77 (s, 3H), 2.73-2.63 (m, 4H), 1.72-1 .55 (m, 2H), 1.38-1.04 (m, 2H). 64a
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;
Example 38 and 3-(hydroxymethyl)cyclobutanone used in reductive amination 559.2 0.71 (1) (600 MHz, DMSO-d ₆ ) δ (ppm) 7.63 (s, 1H), 7.50 (dd, J=8.6, 1.3 Hz, 1H), 7.38-7.33 ( m, 6H), 7.18 (s, 1H), 7.04 (d, J=9.6 Hz, 1H), 4.94 (t, J=5.4 Hz, 1H), 4.42 (s, 1H), 4.11 (t, J=4.9 Hz, 2H), 3.72 (q, J=5.2 Hz , 2H), 3.45-3.37 (m, 1H), 3.30 (t, J=3.6 Hz, 2H), 3.11 (s, 1H), 2.90-2.75 (m, 3H), 2.07 (s, 1H), 1.78 (m, 2H), 1.61 (m, 3H). 64b
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;
Formed by reductive amination together with example 64a 559.2 0.73 (1) (600 MHz, DMSO-d ₆ ) δ (ppm) 7.64 (s, 1H), 7.55-7.49 (m, 1H), 7.41-7.24 (m, 6H), 7, 18 (s, 1H), 7.05 (d, J=9.6 Hz, 1H), 4.94 (t, J=5.4 Hz, 1H), 4.11 (t, J=4.8 Hz, 2H), 3.77-3.71 (m, 2H), 3.41 (d, J=15.7 Hz, 1H), 3.24 (d, J=5.8 Hz, 2H), 2.98-2.73 (m, 4H), 2.12-1.94 (m, 2H), 1.88 (s, 1H), 1.25 (s br, 3H). 65a
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;
Example 38 and (2R,6S)-2,6-dimethyldihydro-2H-pyran-4(3H)-one used in reductive amination 587.4 0.77 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.58 (s, 1H), 7.51 (dd, J=8.6, 1.4 Hz, 1H), 7.39 (d, J= 7.3 Hz, 2H), 7.34 (dd, J=8.6, 6.6 Hz, 2H), 7.31-7.23 (m, 2H), 7.16 (s, 1H), 7.03 (d, J=9.6 Hz, 1H), 4.93 (t, J=5.4 Hz, 1H), 4.13 (t, J=4.8 Hz, 2H), 3.77-3.72 (m, 3H), 3.46 (d, J=15.7 Hz, 1H), 3.30-3.22 (m, 2H), 2.96 (t, J=8.0 Hz, 2H), 2.80 (d, J=15.7 Hz, 1H), 1.73-1.60 (m, 2H), 1.03 (dd , J=6.2, 2.5 Hz, 6H), 0.68 (q, J=11.6 Hz, 2H). 65b
2-((2S,4S)-5-chloro-2-((((2R,4s,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;
Formed by reductive amination together with example 65a 587.4 0.81 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.67 (s, 1H), 7.57-7.47 (m, 1H), 7.41 (d, J=7.3 Hz, 2H) , 7.34 (t, J=7.6 Hz, 2H), 7.31-7.22 (m, 2H), 7.10 (s, 1H), 7.03 (d, J=9.6 Hz, 1H), 4.93 (t, J=5.4 Hz, 1H), 4.13 (t, J=4.8 Hz , 2H), 3.74 (q, J=5.1 Hz, 2H), 3.61-3.47 (m, 1H), 3.48-3.36 (m, 2H), 3.02-2.90 (m, 2H), 2.89-2.76 (m, 2H), 1.50-1.36 (m, 2H), 1.14-0.96 (m, 2H), 0.89 (dd, J= 11.6, 6.2 Hz, 6H). 66a
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;
Example 42 and 4-hydroxy-4-methylcyclohexanone used in reductive amination 558.3 0.82 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 8.40 (s, 1H), 7.94 (s br, 1H), 7.46-7.31 (m, 4H), 7.30 (d , J=7.1 Hz, 1H), 7.13 (d, J=9.6 Hz, 1H), 4.07 (s, 1H), 4.03 (s, 3H), 3.48 (d, J=15.8 Hz, 1H), 3.01-2.89 (m, 3H), 2.35 (s br, 1H) , 1.71-1.57 (m, 2H), 1.46-1.36 (m, 2H), 1.28-1.17 (m, 2H), 1.14-1.03 (m, 2H), 1.03 (s, 3H) 66b
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;
Formed by reductive amination together with example 66a 558.3 0.87 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 8.40 (s, 1H), 7.95 (s, 1H), 7.55-7.23 (m, 6H), 7.13 (d, J=9.7 Hz, 1H), 4.03 (s, 3H), 3.92 (s, 1H), 3.56-3.44 (m, 1H), 3.01-2.84 (m, 3H), 2.27-2.18 (m, 1H), 1.50-1.41 (m, 4H ), 1.29-1.14 (m, 4H), 1.05 (s, 3H). 67a
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;
2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(((R)-tetrahydrofuran-2-yl)methoxy)benzamide was used for reductive amination. This compound was prepared analogously to Example 32a using aryl bromide, (R)-2-bromo-3-fluoro-4-((tetrahydrofuran-2-yl)methoxy)benzonitrile (N-XVIII). 627.4 0.91 (1) (600 MHz, DMSO-d ₆ ) δ (ppm) 7.65 (s, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.43-7.38 (m, 2H) , 7.35 (t, J=7.7 Hz, 2H), 7.33-7.25 (m, 2H), 7.19 (s, 1H), 7.06 (d, J=9.6 Hz, 1H), 4.18 (qd, J=6.8, 3.5 Hz, 1H), 4.13 (dd, J= 10.4, 3.4 Hz, 1H), 4.06 (dd, J=10.3, 6.5 Hz, 1H), 3.91 (s, 1H), 3.79-3.72 (m, 1H), 3.70-3.63 (m, 1H), 3.46 (d, J=15.6 Hz, 1H), 2.98 (m, 2H), 2.80 (d, J=15.6 Hz , 1H), 2.23-2.17 (m, 1H), 2.03-1.95 (m, 1H), 1.92-1.77 (m, 2H), 1.70-1.62 (m, 1H), 1.49-1.40 (m, 4H), 1.29-1.21 (m, 2H), 1.19 -1 .13 (m, 3H), 1.04 (s, 3H). 67b
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;
Formed by reductive amination together with example 67a 627.4 0.89 (1) (600 MHz, DMSO-d ₆ ) δ (ppm) 7.64 (s, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.43-7.38 (m, 2H) , 7.37-7.32 (m, 2H), 7.32-7.25 (m, 2H), 7.18 (s, 1H), 7.05 (d, J=9.6 Hz, 1H), 4.20-4.15 (m, 1H), 4.13 (dd, J=10.4, 3.5 Hz, 1H ), 4.08-4.02 (m, 2H), 3.79-3.73 (m, 1H), 3.70-3.63 (m, 1H), 3.44 (d, J=15.7 Hz, 1H), 3.01-2.90 (m, 2H), 2.81 (d, J=15.7 Hz, 1H), 2.36-2.29 (m, 1H), 2.04 -1.96 (m, 1H), 1.91-1.77 (m, 2H), 1.71-1.62 (m, 2H), 1.61-1.57 (m, 1H), 1.43-1.34 (m, 2H), 1.26-1.15 (m, 3H), 1.09-1.03 (m, 2H ), 1.01 (s, 3H) 68a
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;
2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-ethyl-3-fluorobenzamide was used for reductive amination. This compound was prepared analogously to Example 32a using the aryl bromide, -2-bromo-4-ethyl-3-fluorobenzonitrile (N-XIX). 555.2 1.02 (1) (600 MHz, DMSO-d ₆ ) δ (ppm) 7.69 (s, 1H), 7.48-7.44 (m, 2H), 7.42-7.38 (m, 2H), 7, 38-7.32 (m, 2H), 7.31-7.25 (m, 2H), 7.05 (d, J=9.7 Hz, 1H), 4.06 (s, 1H), 3.46 (d, J=15.6 Hz, 1H), 3.00-2.89 (m, 2H), 2.81 (d, J =15.6 Hz, 1H), 2.69-2.60 (m, 2H), 2.37-2.27 (m, 1H), 1.67-1.55 (m, 2H), 1.42-1.35 (m, 2H), 1.27-1.17 (m, 2H), 1.17 (t, J=7.5Hz, 3H), 1.09-1.02 (m , 2H), 1.01 (s, 3H) 68b
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;
Formed by reductive amination together with example 68a 555.2 1.07 (1) (600 MHz, DMSO-d ₆ ) δ (ppm) 7.71 (s, 1H), 7.49-7.44 (m, 2H), 7.42-7.38 (m, 2H), 7, 38-7.33 (m, 2H), 7.32-7.25 (m, 2H), 7.06 (d, J=9.6 Hz, 1H), 3.91 (s, 1H), 3.47 (d, J=15.9 Hz, 1H), 3.02-2.93 (m, 2H), 2.80 (d, J =15.7 Hz, 1H), 2.67-2.59 (m, 2H), 2.25-2.15 (m, 1H), 1.48-1.40 (m, 4H), 1.30-1.20 (m, 2H), 1.20-1.11 (m, 5H), 1.04 (s, 3H). 69a
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;
2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(1H-imidazol-1-yl)benzamide was used for reductive amination. This compound was prepared analogously to Example 32a using aryl bromide, 2-bromo-3-fluoro-4-(1H-imidazol-1-yl)benzonitrile (N-XX) 593.3 0.68 (1) (600 MHz, DMSO-d ₆ ) δ (ppm) 8.29-8.23 (m, 1H), 8.17-8.10 (m, 2H), 7.90 (t, J=8.1 Hz, 11H), 7.69 (d, J=8.1 Hz, 1H), 7.64 (s, 1H), 7.59-7.54 (m, 2H), 7.49-7.45 (m, 2H), 7.43-7.39 (m, 1H), 7.24 (d, J=9.2 Hz, 1H), 7.15 (s, 1H), 4.47 (s, 1 H), 3.50 (d, J=15.2 Hz, 1 H), 3.19 (d, J=15.6 Hz, 1H), 3.00-2.93 (m, 2H), 1.91-1.86 (m, 1H), 1.58-1.52 (m, 2H), 1.48-1.35 (m, 2H), 1.35-1.20 (m, 4 H), 1.10 (s, 3H) 69b
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;
Formed by reductive amination together with example 69a 593.3 0.71 (1) (600 MHz, DMSO-d ₆ ) δ (ppm) 8.11 (s, 1H), 7.93 (s, 1H), 7.86 (t, J=7.9 Hz, 1H), 7.68 -7.62 (m, 2H), 7.48 (s, 1H), 7.44-7.41 (m, 2H), 7.35 (t, J=7.9 Hz, 2H), 7.30-7.26 (m, 1H), 77.15-7.10 (m, 2H), 3.91 (s, 1H) , 3.51 (d, J=16.0 Hz, 1H), 3.05-2.98 (m, 3H), 2.22-2.19 (m, 1H), 1.49-1.40 (m, 4H), 1.30-1.21 (m, 2H),1.19-1.12 (m, 2H), 1.05 (s, 3H) 70
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;
1-acetylpiperidin-4-one used in reductive amination 606.3 0.88 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.78 (s, 1H), 7.58-7.48 (m, 2H), 7.42-7.24 (m, 7H), 7, 15-7.04 (m, 2H), 3.99 (s br, 1H), 3.59 (d, J=13.5 Hz, 1H), 3.49 (d, J=15.7 Hz, 1H), 2.97 (s br, 2H), 2.85 (d, J=15.8 Hz, 1H), 2.60 (d, J=11.6 Hz, 1H), 1.92 (s, 3H), 1.75-0.80 (m, 9H). 71a
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;
2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(pyrimidin-2-ylmethoxy)benzamide was used for reductive amination. This compound was prepared analogously to Example 32a using aryl bromide, 2-bromo-3-fluoro-4-(pyrimidin-2-ylmethoxy)benzonitrile (N-XXI) 635.4 3.62 (2) (400 MHz, DMSO-d ₆ ) δ (ppm) 8.82 (d, J=4.9 Hz, 2H), 7.59 (s br, 1H), 7.52-7.20 (m, 9H ), 7.14 (s br, 1H), 7.03 (d, J=9.6 Hz, 1H), 5.42 (s, 2H), 4.02 (s, 1H), 3.44 (d, J=15.8 Hz, 1H), 2.94 (s br, 2H), 2.81 (d, J=15.7 Hz , 1H), 1.70-1.50 (m, 2H), 1.45-1.30 (m, 2H), 1.25-1.12 (m, 2H), 1.10-0.98 (m, 2H), 0.99 (s, 3H) 71b
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;
Formed by reductive amination together with example 71a 635.4 3.78 (2) (400 MHz, DMSO-d ₆ ) δ (ppm) 8.82 (d, J=5.0 Hz, 2H), 7.60 (s br, 1H), 7.52-7.35 (m, 4H ), 7.33 (t, J=7.5 Hz, 2H), 7.26 (t, J=8.3 Hz, 2H), 7.15 (s br, 1H), 7.03 (d, J=9.6 Hz, 1H), 5.42 (s, 2H), 3.87 (s, 1H), 3.45 (d, J=15.6 Hz, 1H), 2.97 (s br, 2H), 2.80 (d, J=15.9 Hz, 1H), 2.19 (sbr, 1H), 1.50-1.34 (m, 4H), 1.32-1.07 (m, 4H), 1.02 (s, 3H).

Example 72. 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

(2 P )-2-[(2 S )-5-chloro-6-fluoro-2-({[(1 r ,4 S )-4-hydroxycyclohexyl]amino}methyl)-2-phenyl-

2,3-dihydro-1-benzofuran-4-yl]-4-(difluoromethoxy)-3-fluorobenzamide

Reaction scheme for example 72

Step 1. 2-((2S,4R)-5-Chloro-6-fluoro-2-(hydroxymethyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzonitrile and 2-((2S,4S)-5-chloro-6-fluoro-2-(hydroxymethyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzonitrile

A suspension of (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 (C-XIII) (10 g, 17.30 mmol), 2-bromo-4-(difluoromethoxy)-3-fluorobenzonitrile (NV) (5.52 g, 20.76 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.792 g, 0.865 mmol), 4,6-bis(diphenylphosphino)-10H-phenoxazine (0.954 g, 1.730 mmol) and K ₃ PO ₄ (11.02 g, 51.9 mmol) in toluene (80 The reaction mixture was stirred at 100°C for 16 h under Ar. The reaction mixture was quenched by adding sat. _NaHCO3 solution, then extracted with EtOAc. The organic layers were combined and washed with sat. _NaHCO3 solution, dried over anhydrous _Na2SO4 and concentrated. The residue was purified by flash chromatography (silica, hexane/EtOAc, gradient 0% to 70 _% EtOAc) to afford the desired compounds as individual diastereoisomers.

2-((2S,4R)-5-Chloro-6-fluoro-2-(hydroxymethyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzonitrile (3.21 g): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.99 (dd, J=8.7, 1.4 Hz, 1H), 7.80-7.68 (m, 1H), 7.57-7.25 (m, 7H), 5.36 (t, J=5.9 Hz, 1H), 3.74-3.56 (m, 2H), 3.56-3.47 (m, 1H), 3.16-3.04 (m, 1H). UPLC-MS 1: m/z 481.3 [M+NH ₄ ] ⁺ , t _R =1.19 min.

2-((2S,4S)-5-Chloro-6-fluoro-2-(hydroxymethyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzonitrile (3.14 g): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.04 (dd, J=8.7, 1.4 Hz, 1H), 7.72 (t, J=8.2 Hz, 1H), 7.68-7.27 (m, 7H), 5.33 (t, J=5.9 Hz, 1H), 3.74-3.60 (m, 2H), 3.54 (d, J=16.2 Hz, 1H), 3.01 (d, J=16.2 Hz, 1H). UPLC-MS 1: mass/charge 508.2 [M+formate] ^- , t _R =1.20 min.

Step 2. 2-((2S,4S)-5-Chloro-6-fluoro-2-formyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzonitrile

At -78 °C, DMSO (0.99 mL, 13.90 mmol) was added to a solution of oxalyl chloride (0.61 mL, 6.95 mmol) in DCM (20 mL). After 30 min at -78 °C, a solution of 2-((2S,4S)-5-chloro-6-fluoro-2-(hydroxymethyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzonitrile (2.93 g, 6.32 mmol) in DCM (20 mL) and TEA (4.40 mL, 31.6 mmol) were added and the reaction mixture was stirred at -78 °C for 2 h. The reaction mixture was quenched by addition of brine, then extracted with DCM. The organic layers were combined and washed with brine, dried over _{anhydrous Na2SO4} and concentrated to give the title compound (2.92 g) as a brownish powder. UPLC-MS 1: t _R = 1.24 min.

Step 3. 2-((2S,4S)-5-Chloro-6-fluoro-2-(((trans-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl) -4-(difluoromethoxy)-3-fluorobenzonitrile

Under Ar atmosphere, to a solution of 2-((2S,4S)-5-chloro-6-fluoro-2-formyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzonitrile (2.92 g, 6.32 mmol) in 1,2-dichloroethane (25 mL) were added trans-4-aminocyclohexanol (1.457 g, 12.65 mmol) and AcOH (0.362 mL, 6.32 mmol). The reaction mixture was then stirred at 85 °C for 30 min. Sodium triacetoxyborohydride (4.02 g, 18.97 mmol) was added and the reaction mixture was stirred at 85 °C for 30 min. The reaction mixture was quenched by adding sat. NaHCO ₃ solution, then extracted with DCM. The organic layers were combined and washed with saturated NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, hexane/EtOAc, gradient from 0% to 100% EtOAc) to give the desired product (2.90 g) as a colorless powder. UPLC-MS 1: m/z 561.2 [M+H] ⁺ , t _R = 0.93 min.

Step 4. 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

(2 P )-2-[(2 S )-5-chloro-6-fluoro-2-({[(1 r ,4 S )-4-hydroxycyclohexyl]amino}methyl)-2-phenyl-

2,3-dihydro-1-benzofuran-4-yl]-4-(difluoromethoxy)-3-fluorobenzamide (Example 72)

At rt, hydrido(dimethylphosphinic acid-kP)[hydrogen-bis(dimethylphosphinito-kP)]platinum(II) (0.688 g, 1.603 mmol) was added to a solution of tert-butyl 2-((2S,4S)-5-chloro-6-fluoro-2-(((trans-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzonitrile (2.90 g, 5.17 mmol) in EtOH (20 mL) and water (20 mL). The reaction mixture was then stirred at 80 °C for 2 h. The reaction mixture was quenched with saturated NaHCO ₃ solution and then extracted with EtOAc. The organic layers were combined and washed with _saturated NaHCO3 solution, dried over anhydrous _Na2SO4 and concentrated. The residue was purified by flash chromatography (silica, DCM/MeOH, gradient from 0% to 10% _MeOH ) to give the title compound (2.33 g) as a colorless powder. ^1H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.79 (s, 1H), 7.60-7.50 (m, 2H), 7.44-7.15 (m, 7H), 7.09 (d, J=9.7 Hz, 1H), 4.40 (d, J=4.4 Hz, 1H), 3.48 (d, J=15.8 Hz, 1H), 3.31-3.22 (m, 1H), 3.03-2.90 (m, 2H), 2.85 (d, J=15.8 Hz, 1H), 2.26-2.15 (m, 1H), 1.83-1.57 (m, 4H), 1.25 (s, 1H), 1.13-0.98 (m, 2H), 0.96-0.79 (m, 2H). UPLC-MS 1: m/z 579.3 [M+H] ⁺ , t _R = 0.94 min. The absolute configuration was confirmed by X-ray diffraction analysis of a co-crystal of example 72 bound to the YAP binding site of TEAD4.

The following compounds were prepared similarly to Example 72.

Note: Structure/Chemical Name UPLC MS
mass/charge [M+H] ⁺
t _R [min.] (method) ¹ H NMR 73
2-((2S,4S)-2-((tert-butylamino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;
2-methylpropan-2-amine used in reductive amination 537.2
0.92 (1) (600 MHz, DMSO-d ₆ ) δ (ppm) 7.83 (s, 1H), 7.59-7.52 (m, 2H), 7.50-7.23 (m, 7H), 7, 10 (d, J=9.7 Hz, 1H), 3.52 (d, J=15.7 Hz, 1H), 2.98-2.88 (m, 2H), 2.85 (d, J=15.7 Hz, 1H), 1.12 (t, J=7.8 Hz, 1H), 0.92 (s , 9H) 74
2-((2S,4S)-5-chloro-6-fluoro-2-((((R)-2-hydroxypropyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;
(R)-1-aminopropan-2-ol used in reductive amination 539.3
0.93 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.81 (s, 1H), 7.59-7.14 (m, 9H), 7.10 (d, J=9.7 Hz, 1H) , 4.32 (d, J=4.5 Hz, 1H), 3.60-3.48 (m, 2H), 3.01-2.91 (m, 2H), 2.86 (d, J=15.7 Hz, 1H), 2.41-2.31 (m, 2H), 1.56 (br s, 1H ), 0.92 (d, J=6.2 Hz, 3H) 75
2-((2S,4S)-5-chloro-6-fluoro-2-((((S)-1-hydroxypropan-2-yl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4 -yl)-4-(difluoromethoxy)-3-fluorobenzamide;
(S)-2-amino-1-propanol used in reductive amination 539.3
0.91 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.81 (s, 1H), 7.59-7.15 (m, 9H), 7.09 (d, J=9.7 Hz, 1H) , 4.40 (t, J=5.3 Hz, 1H), 3.47 (d, J=15.9 Hz, 1H), 3.23-3.15 (m, 1H), 3.13-2.99 (m, 2H), 2.97-2.91 (m, 1H), 2.87 (d, J=15.8 Hz, 1H), 1.49 (br s, 1H), 1.24 (s, 1H), 0.79 (d, J=6.3 Hz, 3H) 76
2-((2S,4S)-5-chloro-6-fluoro-2-(((1-methylcyclopropyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy )-3-fluorobenzamide;
1-methylcyclopropanamine used in reductive amination 535.3
0.95 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.79 (s, 1H), 7.59-7.14 (m, 9H), 7.06 (d, J=9.7 Hz, 1H) , 3.44 (d, J=16.0 Hz, 1H), 3.09-2.90 (m, 2H), 2.82 (d, J=15.3 Hz, 1H), 1.69 (s, 1H), 1.09 (s, 3H), 0.37 (d, J=9.5 Hz, 1H), 0.28 (d, J=10.8 Hz, 1H), 0.18 (s, 2H) 77
2-((2S,4S)-5-chloro-6-fluoro-2-(((2-methoxyethyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;
2-methoxyethanamine used in reductive amination 540.2/541.1
1.03 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.83 (s, 1H), 7.59-7.52 (m, 2H), 7.49-7.23 (m, 7H), 7, 13 (d, J=9.6 Hz, 1H), 3.49 (d, J=14.9 Hz, 1H), 3.28 (t, J=5.5 Hz, 2H), 3.17 (s, 3H), 3.00 (br s, 2H), 2.88 (d, J=16.0 Hz, 1H), 2, 64-2.59 (m, 2H), 1.52 (br s, 1H) 78
2-((2S,4S)-5-chloro-6-fluoro-2-(((2-(2-oxopyrrolidin-1-yl)ethyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;
1-(2-aminoethyl)pyrrolidin-2-one used in reductive amination 592.2
0.90 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.79 (s, 1H), 7.63-7.12 (m, 9H), 7.07 (d, J=9.7 Hz, 1H) , 3.45 (d, J=15.8 Hz, 1H), 3.21-3.07 (m, 4H), 3.02-2.82 (m, 3H), 2.57 (br s, 2H), 2.12-2.03 (m, 2H), 1.83-1.71 (m, 2H), 1 .61 (br s, 1H) 79
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;
trans-4-(1H-tetrazol-1-yl)cyclohexanamine (S-II), used in reductive amination 631.3
0.90 (1) (400 MHz, CDCl3) δ (ppm) 8.54 (s, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.47-7.23 (m, 6H), 6, 82 (d, J=9.0 Hz, 1H), 6.60 (t, J=72.5 Hz, 1H), 5.52 (d, J=48.4 Hz, 2H), 4.43 (t, J=11.9 Hz, 1H), 3.46 (d, J=15.6 Hz, 1H), 3.20-2.97 ( m, 3H), 2.51 (t, J=11.1 Hz, 1H), 2.24 (d, J=11.0 Hz, 2H), 2.02 (dd, J=28.7, 14.6 Hz, 2H), 1.82 (q, J=12.4, 11.2 Hz, 2H), 1.23 (q, J=13.1, 12.3 Hz, 3H) 80
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;
trans-3-((difluoromethoxy)methyl)cyclobutanamine (S-III), used in reductive amination 615.3
0.97 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.80 (s, 1H), 7.61-7.14 (m, 9H), 7.08 (d, J=9.7 Hz, 1H) , 6.62 (t, J=76.4 Hz, 1H), 3.76 (d, J=7.3 Hz, 2H), 3.46 (d, J=15.7 Hz, 1H), 3.22-3.15 (m, 1H), 2.93-2.81 (m, 3H), 2.35-2.23 ( m, 1H), 1.88-1.65 (m, 4H) 81a
2-((2S,4S)-5-chloro-6-fluoro-2-((((1S,3R,4R)-3-fluoro-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;
(1R,2R,4S)-4-amino-2-fluorocyclohexanol (S-IV), used in reductive amination 597.2
0.99 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.94 (s, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.56-7.51 (m, 1H) , 7.50-7.22 (m, 7H), 7.09 (d, J=9.6 Hz, 1H), 5.08 (d, J=4.2 Hz, 1H), 4.48-4.33 (m, 1H), 3.54 (d, J=15.1 Hz, 1H), 3.49-3.43 ( m, 1H), 2.98-2.88 (m, 2H), 2.86 (d, J=15.7 Hz, 1H), 2.72 (br s, 1H), 1.81-1.69 (m, 1H), 1.58-1.32 (m, 6H) 81b
2-((2S,4S)-5-chloro-6-fluoro-2-((((1R,3S,4S)-3-fluoro-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;
(1S,2S,4R)-4-amino-2-fluorocyclohexanol (SV), used in reductive amination 597.2
0.97 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.91 (s, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.54 (t, J=7.9 Hz , 1H), 7.49-7.23 (m, 7H), 7.09 (d, J=9.6 Hz, 1H), 4.98 (d, J=4.3 Hz, 1H), 4.51-4.35 (m, 1H), 3.54-3.44 (m, 2H), 2.95 (d, J= 4.9 Hz, 2H), 2.87 (d, J=15.7 Hz, 1H), 2.70 (br s, 1H), 1.84-1.72 (m, 1H), 1.59-1.50 (m, 1H), 1.50-1.44 (m, 2H), 1.43-1.32 (m, 3H) 82
2-((2S,4S)-5-chloro-6-fluoro-2-(((trans-3-fluorocyclobutyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4- (difluoromethoxy)-3-fluorobenzamide;
trans-3-fluorocyclobutylamine, used in reductive amination 553.2
1.01 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.85 (s, 1H), 7.58-7.52 (m, 2H), 7.49-7.23 (m, 7H), 7, 10 (d, J=9.6 Hz, 1H), 5.13-4.98 (m, 1H), 3.50 (d, J=15.2 Hz, 1H), 3.32 (br s, 1H), 2.91-2.83 (m, 3H), 2.20-2.08 (m, 2H), 2.07- 1.97 (m, 2H), 1.92 (br s, 1H) 83
2-((2S,4S)-5-chloro-6-fluoro-2-((((1R,3S)-3-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl )-4-(difluoromethoxy)-3-fluorobenzamide;
(1S,3R)-3-aminocyclohexanol used in reductive amination 579.3
0.92 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.80 (br s, 1H), 7.59-7.13 (m, 9H), 7.12-7.03 (m, 1H), 3 .46 (d, J=15.5 Hz, 1H), 3.04-2.79 (m, 2H), 2.33-2.19 (m, 1H), 2.00-1.82 (m, 1H), 1.75-1.48 (m, 6H), 1.39-1.18 (m, 2H ), 0.98-0.67 (m, 3H) 84
2-((2S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-1-methylcyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;
trans-4-amino-4-methylcyclohexanol, used in reductive amination 593.2
0.97 (1) (400 MHz, MeOH-d ₄ ) δ (ppm) 7.85 (s, 1H), 7.60-7.13 (m, 9H), 7.07 (d, J=9.6 Hz, 1H) , 4.45 (d, J=3.5 Hz, 1H), 3.62 (d, J=15.8 Hz, 1H), 2.93-2.75 (m, 3H), 1.61-1.02 (m, 9H), 0.94 (s, 1H), 0.86 (s, 3H).

Example 85a and Example 85b. 2-((2S,4S)-5-Chloro-6-fluoro-2-(((6-hydroxyspiro[3.3]heptan-2-yl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide (Example 85a) and 2-((2S,4S)-5-chloro-6-fluoro-2-(((6-hydroxyspiro[3.3]heptan-2-yl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide (Example 85b)

The title compounds were prepared analogously to Example 72. Racemic 6-aminospiro[3.3]heptan-2-ol was used in the reductive amination. Both title compounds were isolated by chiral separation of the diastereomeric mixture after reductive amination using preparative chiral HPLC (Chiralpak IC 250×25 mm i.d., 5 μm, heptane/DCM/EtOH 8:1:1+0.05% DEA, flow rate: 15 mL/min). The absolute configuration of the spiro moiety in the respective title compounds was not determined.

2-((2S,4S)-5-Chloro-6-fluoro-2-(((6-hydroxyspiro[3.3]heptan-2-yl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide (Example 85a): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.85 (s, 1H), 7.58 (dd, J=8.5, 1.2 Hz, 1H), 7.51-7.36 (m, 6H), 7.31 (t, J=7.0 Hz, 1H), 7.15-6.73 (m, 2H), 4.05 (p, J=7.3 Hz, 1H), 3.62 (q, J=7.1 Hz, 1H), 3.41 (d, J=15.8 Hz, 1H), 3.13-2.93 (m, 4H), 2.39-2.28 (m, 1H), 2.26-2.01 (m, 3H), 1.91-1.78 (m, 2H), 1.73-1.62 (m, 2H), 1.31 (s, 1H), 1.19 (t, J=7.0 Hz, 1H). UPLC-MS 1: mass/charge 591.2 [M+H] ⁺ , t _R =0.88 min. Chiral HPLC (Chiralpak IC 250×4.6 mm ID, 5μm, heptane/DCM/EtOH 8:1:1+0.05% DEA, flow rate: 1 ml/min): t _R =10.63 min

2-((2S,4S)-5-Chloro-6-fluoro-2-(((6-hydroxyspiro[3.3]heptan-2-yl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide (Example 85b): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.58 (d, J=8.6 Hz, 1H), 7.51-7.27 (m, 8H), 7.14-6.75 (m, 2H), 4.04 (p, J=7.4 Hz, 1H), 3.41 (d, J=15.8 Hz, 1H), 3.13-2.94 (m, 4H), 2.37-2.27 (m, 1H), 2.21-2.07 (m, 3H), 1.84 (q, J=10.3 Hz, 2H), 1.68 (q, J=8.7 Hz, 2H), 1.30 (br s, 1H), 0.91 (br s, 1H). UPLC-MS 1: mass/charge 591.2 [M+H] ⁺ , t _R =0.89 min. Chiral HPLC (Chiralpak IC 250×4.6 mm ID, 5μm, heptane/DCM/EtOH 8:1:1+0.05% DEA, flow rate: 1 ml/min): t _R =11.85 min

Example 86. 2-((2S,3S,4S)-2-(Aminomethyl)-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide

The title compound was prepared analogously to Example 5a from 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 (C-VI) and 2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV).

2-((2S,3S,4S)-2-(Aminomethyl)-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 86): ¹ H NMR (400 MHz, DMSO -d ₆ ) δ (ppm) 7.53 (s br, 1H), 7.50-7.36 (m, 7H), 7.34-7.28 (m, 2H), 7.13 (d, J=8.6 Hz, 1H), 4.96 (s, 1H), 3.90 (s, 3H), 3.28 (d, J=13.9 Hz, 1H), 3.16 (d, J=13.8 Hz, 1H). UPLC-MS 1: mass/charge 443.3 [M+H] ⁺ , t _R =0.74 min.

Another diastereoisomer, 2-((2S,3S,4R)-2-(aminomethyl)-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide: UPLC-MS 1: m/z 443.3 [M+H] ⁺ , t _R = 0.58 min.

The following compounds were prepared similarly to Example 86.

Note: Structure/Chemical Name UPLC MS
mass/charge [M+H] ⁺
t _R [min.] (method) ¹ H NMR 87
2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;
2-bromo-4-(difluoromethoxy)-3-fluorobenzonitrile (NV), used in the Suzuki coupling reaction 479.2
0.78 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.61-7.53 (m, 4.3H), 7.50-7.43 (m, 3H), 7.41-7.36 (m , 3.4H), 7.34-7.29 (m, 1H), 7.19-7.14 (m, 1.3H), 5.01 (s, 1H), 3.25 (d, J=13.9 Hz, 1H), 3.14 (d, J=13.9 Hz, 1H) 88
2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-methoxyethoxy)benzamide;
2-bromo-3-fluoro-4-(2-methoxyethoxy)benzonitrile (N-IX), used in the Suzuki coupling reaction 487.4
0.73 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.52 (s br, 1H), 7.47-7.43 (m, 4H), 7.42-7.36 (m, 3H), 7 ,34-7.28 (m, 2H), 7.13 (d, J=8.6 Hz, 1H), 4.98 (s, 1H), 4.26-4.23 (m, 2H), 3.70-3.67 (m, 2H), 3.30 (s, 3H), 3.24 (d, J=13.9 Hz , 1H), 3.13 (d, J=13.9 Hz, 1H)

Example 89. 2-((2R,3S,4S)-2-(Aminomethyl)-5-chloro-3-hydroxy-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide

Reaction scheme for example 89

Step 1. tert-Butyl (((2R*,3S*,4S*)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-3-hydroxy-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2R*,3S*,4R*)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-3-hydroxy-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate

A mixture of the racemic title compounds (450 mg) was prepared from racemic 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 (C-VII) (847 mg, 1.35 mmol)And2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV) (403 mg, 1.75 mmol) using reaction conditions similar to those described for Example 5a, Step 1. UPLC-MS 1: m/z 526.2 [M+H]⁺, t_R=1.12 min. and 1.14 min.

Step 2. tert-Butyl (((2R*,3S*,4S*)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-3-hydroxy-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2R*,3S*,4R*)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-3-hydroxy-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate

The racemic title compounds were prepared as separate racemic diastereoisomers from a mixture of racemic tert-butyl (((2R*,3S*,4S*)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-3-hydroxy-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and racemic tert-butyl (((2R*,3S*,4R*)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-3-hydroxy-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (450 mg) using reaction conditions similar to those described for Example 5a, Step 2, followed by flash chromatography (dioxide silicon, EtOAc/MeOH, gradient: 0% to 5% MeOH).

tert-Butyl (((2R*,3S*,4S*)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-3-hydroxy-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (296 mg): UPLC-MS 1: m/z 544.1 [M+H] ⁺ , t _R =1.01 min.

tert-Butyl (((2R*,3S*,4R*)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-3-hydroxy-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (130 mg): UPLC-MS 1: m/z 544.1 [M+H] ⁺ , t _R = 0.93 min.

Step 3. tert-Butyl (((2R,3S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-3-hydroxy-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S,3R,4R)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-3-hydroxy-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate

The racemate of tert-butyl (((2R*,3S*,4S*)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-3-hydroxy-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (288 mg) was subjected to chiral HPLC (ChiralPak OZ-H, 250 x 20 mm, 5 μm, heptane/(EtOH+1% DEA) 7:3, flow rate: 10 mL/min, 1.5 mL/injection, 7 injections) to afford the title compounds as single enantiomers with an enantiomeric excess of >98%, respectively.

tert-Butyl (((2R,3S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-3-hydroxy-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (133 mg): chiral HPLC (ChiralPak OZ-H, 250 × 4.6 mm, 5 μm, heptane/(EtOH+1% DEA) 6:4, flow rate: 1 mL/min): t _R = 7.96 min. UPLC-MS 1: m/z 544.1 [M+H] ⁺ , t _R = 1.01 min.

tert-Butyl (((2S,3R,4R)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-3-hydroxy-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (121 mg): chiral HPLC (ChiralPak OZ-H, 250 × 4.6 mm, 5 μm, heptane/(EtOH+1% DEA) 6:4, flow rate: 1 mL/min): t _R = 11.70 min. UPLC-MS 1: m/z 544.1 [M+H] ⁺ , t _R = 1.01 min.

Step 4. 2-((2R,3S,4S)-2-(Aminomethyl)-5-chloro-3-hydroxy-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 89)

The title compound (100 mg) was prepared from tert-butyl (((2R,3S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-3-hydroxy-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (125 mg) using reaction conditions similar to those described for Example 5a, step 3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.59-8.56 (m, 1H), 7.76 (td, J=7.8, 2.0 Hz, 1H), 7.49-7.43 (m, 2H), 7.41 (d, J=8.6 Hz, 1H), 7.36 (s br, 1H), 7.33-7.24 (m, 3H), 7.11 (d, J=8.6 Hz, 1H), 6.85 (s br, 1H), 5.20 (s, 1H), 3.86 (s, 3H), 3.28 (d, J=13.7 Hz, 1H), 3.20 (d, J=13.7 Hz, 1H), 1.39 (sbr, 2H). UPLC-MS 1: mass/charge 444.1 [M+H] ⁺ , t _R =0.66 min.

The absolute configuration of example 89 was confirmed by X-ray diffraction analysis.

Example 90. 2-((2R,3S,4S)-2-(Aminomethyl)-5-chloro-3-hydroxy-2-(6-methoxypyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide

The title compound was prepared analogously to Example 89 from the racemic intermediate 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 (C-IX) And2-bromo-4-(difluoromethoxy)-3-fluorobenzonitrile (N-V).

Racemic diastereoisomers were separated after removal of the Boc protecting group by flash chromatography (silica, DCM/(7 N ammonia in MeOH), gradient: 0 to 10% (7 N ammonia in MeOH)): racemic

(2R*,3S*,4S*)-diastereoisomer: UPLC-MS 1: t _R = 0.77 min, racemic (2R*,3S*,4R*)-diastereoisomer: UPLC-MS 1: t _R = 0.63 min. The racemate of 2-((2R*,3S*,4S*)-2-(aminomethyl)-5-chloro-3-hydroxy-2-(6-methoxypyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide was subjected to chiral preparative SFC (ChiralPak OZ-H, 250 × 20 mm, 5 μm, column temperature 40°C, _CO2 /(EtOH+1% isopropylamine) 7:3, flow rate: 80 mL/min) to afford two enantiomers with enantiomeric excess >99%, respectively.

2-((2R,3S,4S)-2-(Aminomethyl)-5-chloro-3-hydroxy-2-(6-methoxypyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide (Example 90): chiral SFC (ChiralPak OZ-H, 250 × 4.6 mm, 5 μm, CO ₂ /(EtOH+1% isopropylamine) 7:3, flow rate: 3 mL/min): 2.41 min. ¹ H NMR (400 MHz, DMSO - _d6 ) δ (ppm) 7.65 (t, J=7.7 Hz, 1H), 7.54-7.45 (m, 4H), 7.44 (d, J=8.7 Hz, 1H), 7.33 (t, J=72.5 Hz, 1H), 7.11 (d, J=8.7 Hz, 1H), 7.06 (d, J=7.3 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 5.29 (s, 1H), 3.80 (s, 3H), 3.28-3.20 (m, 2H), 1.46 (s br, 1H). UPLC-MS 1: mass/charge 510.2 [M+H] ⁺ , t _R =0.77 min.

The other enantiomer, 2-((2S,3R,4R)-2-(aminomethyl)-5-chloro-3-hydroxy-2-(6-methoxypyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide: chiral SFC (ChiralPak OZ-H, 250 × 4.6 mm, 5 μm, CO ₂ /(EtOH+1% isopropylamine) 7:3, flow rate: 3 mL/min): 5.62 min.

Example 91. 2-((2S,3S,4S)-2-(Aminomethyl)-5-chloro-3-hydroxy-2-(2-methoxypyridin-3-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide

The title compound was prepared analogously to Example 89 from the racemic intermediate ((2S*,3S*)-2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-3-hydroxy-2-(2-methoxypyridin-3-yl)-2,3-dihydrobenzofuran-4-yl)boronic acid (C-X) and 2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV).

After final removal of the Boc protecting group, the racemic diastereoisomers were first separated by flash chromatography (silica, DCM/MeOH, gradient: MeOH from 0 to 10%): racemic (2S*,3S*,4R*)-diastereoisomer: UPLC-MS 1: t _R = 0.59 min, racemic (2S*,3S*,4S*)-diastereoisomer: UPLC-MS 1: t _R = 0.71 min. The racemic (2S*,3S*,4S*)-diastereoisomer was subjected to chiral HPLC (Chiralpak AD-H 250×30 mm i.d., 5 μm, EtOH/MeOH 1:1+1% DEA, flow rate: 10 mL/min) to afford both enantiomers with an enantiomeric excess of >98%.

2-((2S,3S,4S)-2-(Aminomethyl)-5-chloro-3-hydroxy-2-(2-methoxypyridin-3-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 91). Chiral HPLC (Chiralpak AD-H 250×4.6 mm i.d., 5 µm, n-heptane:EtOH 80:20+0.1% DEA, flow rate: 1 ml/min.) t_R=10.85 min.¹H NMR (400 MHz, DMSO-d ₆) δ 8.08 (dd, J=5.0, 1.9 Hz, 1H), 7.64 (dd, J=7.4, 1.9 Hz, 1H), 7.44 (dd, J= 8.6, 1.4 Hz, 1H), 7.42-7.36 (m, 2H), 7.30 (br s, 1H), 7.26 (t, J=8.5 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.94 (dd, J=7.5, 4.8 Hz, 1H), 4 .92 (s, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.31-3.24 (m, 3H), 1.22 (br s, 2H). UPLC-MS 1: mass/charge 474.1[M+H]⁺, t_R=0.71 min.

Other enantiomer: 2-((2R,3R,4R)-2-(aminomethyl)-5-chloro-3-hydroxy-2-(2-methoxypyridin-3-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide: chiral HPLC (Chiralpak AD-H 250×4.6 mm i.d., 5 μm, n-heptane:EtOH 80:20+0.1% DEA, flow rate: 1 mL/min.) t _R =6.31 min

Example 92. 2-((2S,3S,4S)-2-(Aminomethyl)-5-chloro-3-hydroxy-2-(2-oxo-1,2-dihydropyridin-3-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide

At rt, HCl (84 µl, 0.34 mmol, 4 N in dioxane) was added to 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-(2-methoxypyridin-3-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 91) (8 mg, 0.017 mmol). After stirring at 50°C for 3 h, the reaction mixture was concentrated. The residue was purified by preparative HPLC (Waters X-Bridge C18 OBD, 5 μm, 30 * 100 mm, eluent A: H ₂ O + 7.3 mM NH ₄ OH, eluent B: ACN, gradient: 5 to 100% B over 20 min, hold for 1 min, flow rate 40 mL/min) to give the title compound. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 7.49-7.39 (m, 3H), 7.39-7.34 (m, 2H), 7.33-7.26 (m, 2H), 7.10 (d, J=8.7 Hz, 1H), 6.20 (t, J=6.7 Hz, 1H), 5.07 (s, 1H), 3.89 (s, 3H), 3.43 (d, J=14.0 Hz, 1H), 3.38 (d, J=14.0 Hz, 1H), 1.24 (br s, 2H). UPLC-MS 1: m/z 460.1[M+H] ⁺ , t _R =0.63 min.

Example 93. 2-((2S,3S,4S)-2-(Aminomethyl)-5-chloro-3-hydroxy-2-(2-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide

The title compound was prepared analogously to Example 89 from the racemic intermediate, 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 (C-VIII) and 2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV).

After final removal of the Boc protecting group, the racemic diastereoisomers were first separated by flash chromatography (silica, DCM/MeOH, gradient: MeOH from 0% to 10%): racemic (2S*,3S*,4R*)-diastereoisomer: UPLC-MS 1: t _R = 0.67 min, racemic (2S*,3S*,4S*)-diastereoisomer: UPLC-MS 1: t _R = 0.81 min. The racemic (2S*,3S*,4S*)-diastereoisomer was subjected to chiral SFC (ChiralPak OZ-H, 250 × 25 mm, 5 μm, _CO2 /(EtOH+1% isopropylamine) 65:35, flow rate: 80 ml/min) to obtain both enantiomers with an enantiomeric excess of >99%.

2-((2S,3S,4S)-2-(Aminomethyl)-5-chloro-3-hydroxy-2-(2-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 93): chiral SFC (ChiralPak OZ-H, 250 × 4.6 mm, 5 μm, CO ₂ /(EtOH+1% isopropylamine) 65:35, flow rate: 3 ml/min.), t _R = 2.57 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.59-7.49 (m, 2H), 7.48-7.22 (m, 7H), 7.10 (d, J=8.6 Hz, 1H), 6.93 (s br, 1H), 4.90 (s, 1H), 3.85 (s, 3H), 3.41 (d, J=14.2 Hz, 1H), 3.19 (d, J=14.2 Hz, 1H), 1.42 (s br, 2H). UPLC-MS 1: m/z 527.1 [M+H] ⁺ , t _R =0.83 min.

2-((2R,3R,4R)-2-(Aminomethyl)-5-chloro-3-hydroxy-2-(2-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide: chiral SFC (ChiralPak OZ-H, 250 × 6 mm, 5 μm, CO ₂ /(EtOH+1% isopropylamine) 65:35, flow rate: 3 ml/min.), t _R = 7.15 min.

Example 94a and Example 94b. 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 (Example 94a) and 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 (Example 94b)

The title compounds were prepared analogously to Examples 27a and 27b from Example 87 and 4-hydroxycyclohexanone.

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 (example 94a): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.55-7.42 (m, 8.3H), 7.38-7.33 (m, 2.4H), 7.32-7.27 (m, 1H), 7.18-7.15 (m, 1.3H), 4.95 (s, 1H), 4.45 (d, J=4.4 Hz, 1H), 3.33-3.26 (m, 1H), 3.24 (s, 2H), 2.29-2.21 (m, 1H), 1.76-1.68 (m, 4H), 1.60-1.50 (s br, 1H), 1.13-1.02 (m, 2H), 0.99-0.85 (m, 2H). UPLC-MS 1: mass/charge 577.3 [M+H] ⁺ , t _R =0.78 min.

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 (Example 94b): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.55-7.44 (m, 8.2H), 7.39-7.34 (m, 2.6H), 7.32-7.27 (m, 1H), 7.19-7.16 (m, 1.2H), 4.97 (s, 1H), 4.27 (d, J=3.4 Hz, 1H), 3.60-3.56 (m, 1H), 3.23 (s, 2H), 2.37-2.33 (m, 1H), 1.50-1.30 (m, 8H). UPLC-MS 1: m/z 577.3 [M+H] ⁺ , t _R =0.80 min.

Example 95a and Example 95b. 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 (Example 95a) and 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 (Example 95b)

The title compounds were prepared analogously to Example 27a from Example 89 and 4-hydroxycyclohexanone.

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 (Example 95a): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.56 (d, J=4.9 Hz, 1H), 7.73 (td, J=7.7, 1.3 Hz, 1H), 7.47-7.40 (m, 3H), 7.30-7.24 (m, 4H), 7.12 (d, J=8.7 Hz, 2H), 5.15 (s, 1H), 4.39 (d, J=4.3 Hz, 1H), 3.86 (s, 3H), 3.30-3.20 (m, 2H), 2.21-2.13 (m, 1H), 1.73-1.59 (m, 4H), 1.11-0.95 (m, 2H), 0.95-0.74 (m, 2H). UPLC-MS 1: m/z 542.2 [M+H] ⁺ , t _R =0.70 min.

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 (Example 95b): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.56 (d, J=4.7 Hz, 1H), 7.75 (td, J=7.7, 1.6 Hz, 1H), 7.48-7.40 (m, 3H), 7.30-7.23 (m, 4H), 7.12 (d, J=8.7 Hz, 2H), 5.18 (s, 1H), 4.20 (d, J=3.4 Hz, 1H), 3.55-3.50 (m, 1H), 3.34-3.23 (m, 2H), 2.33-2.27 (m, 1H), 1.46-1.21 (m, 8H). UPLC-MS 1: m/z 542.2 [M+H] ⁺ , t _R =0.71 min.

Example 96. 2-((2S,3S,4S)-5-Chloro-2-((cyclobutylamino)methyl)-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide

The title compound was prepared analogously to Example 27a from Example 87 and cyclobutanone. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.56-7.52 (m, 3.3H), 7.48 (d, J=8.6 Hz, 1H), 7.45-7.42 (m, 2H), 7.39-7.34 (m, 2.4H), 7.32-7.27 (m, 1H), 7.19-7.10 (m, 2.3H), 4.94 (s, 1H), 3.18-3.08 (m, 3H), 2.07-1.96 (m, 2H), 1.65-1.46 (m, 4H). UPLC-MS 1: m/z 533.2 [M+H] ⁺ , t _R = 0.85 min. The absolute configuration was confirmed by X-ray diffraction analysis of a cocrystal of example 96 bound to the YAP binding site of TEAD4.

Example 97. 2-((2S,3S,4S)-2-(Aminomethyl)-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide

The title compound was prepared analogously to Example 5a from 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 (C-XIV) and 2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV) The final removal of the Boc protecting group was carried out as described in Example 22, step 5.

2-((2S,3S,4S)-2-(Aminomethyl)-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 97): ¹ H NMR (400 MHz, DMSO -d ₆ ) δ (ppm) 7.55 (s br, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.46-7.36 (m, 5H), 7.36-7.26 (m, 3H), 4.95 (s, 1H), 3.90 (s, 3H), 3.25 (d, J=13.9 Hz, 1H), 3.15 (d, J=13.9 Hz, 1H). UPLC-MS 1: mass/charge 461.2 [M+H] ⁺ , t _R =0.78 min.

Another diastereoisomer, 2-((2S,3S,4R)-2-(aminomethyl)-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide: UPLC-MS 1: m/z 461.2 [M+H] ⁺ , t _R = 0.61 min.

Example 98. 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

Step 1. tert-Butyl (((2S,3S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S,3S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate

The title compounds were prepared from 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 (C-XIV) (0.50 g, 0.96 mmol) and 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzonitrile (N-VI) (0.33 g, 0.96 mmol) using reaction conditions similar to those described for Example 5a, step 1, and isolated as separated diastereoisomers after chromatography.

tert-Butyl-(((2S,3S,4S)-5-chloro-6-fluoro-3-hydroxy-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (116 mg, colorless foam): UPLC-MS 1: mass/charge 657.3 [M+H] ⁺ , t _R =1.36 min.

tert-Butyl (((2S,3S,4R)-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 (61 mg, colorless oil): UPLC-MS 1: m/z 657.3 [M+H] ⁺ , t _R =1.34 min.

Step 2. tert-Butyl (((2S,3S,4S)-4-(6-carbamoyl-2-fluoro-3-(2-hydroxyethoxy)phenyl)-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate

The title compound (105 mg, slightly yellow foam) was prepared from tert-butyl (((2S,3S,4S)-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 (116 mg) using reaction conditions similar to those described for Example 5a, step 2. The THP group was removed during this reaction. UPLC-MS 1: m/z 591.3 [M+H] ⁺ , t _R = 1.03 min.

Step 3. 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 (Example 98)

The title compound (95 mg) was prepared from tert-butyl (((2S,3S,4S)-4-(6-carbamoyl-2-fluoro-3-(2-hydroxyethoxy)phenyl)-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (105 mg) using reaction conditions similar to those described for Example 22, Step 5. ¹ H NMR (600 MHz, DMSO-d6) δ: 7.57 (s br, 1H), 7.47 (d, J=8.6 Hz, 1H), 7.45-7.42 (m, 3H), 7.41-7.36 (m, 2H), 7.35-7.27 (m, 3H), 6.89 (s br, 1H), 4.97 (t, J=5.5 Hz, 1H), 4.94 (s, 1H), 4.16-4.10 (m, 2H), 3.73 (q, J=5.0 Hz, 2H), 3.24 (d, J=13.8 Hz, 1H), 3.13 (d, J=14.1 Hz, 1H). UPLC-MS 1: m/z 491.3 [M+H]+, t _R= 0.64.

Example 99. 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

The title compound was prepared analogously to Example 96 from Example 98 and cyclobutanone. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ (ppm) 7.50 (s br, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.42-7.39 (m, 3H), 7.38-7.27 (m, 5H), 6.92-6.90 (m, 1H), 4.96 (t, J = 5.5 Hz, 1H), 4.85 (s br, 1H), 4.15-4.09 (m, 2H), 3.73 (t, J = 5.0 Hz, 2H), 3.15-3.05 (m, 3H). 2.05-1.95 (m, 2H), 1.59-1.45 (m, 4H). UPLC-MS 1: m/z 545.3 [M+H] ⁺ , t _R =0.72 min.

Example 100a and Example 100b. 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

(2 P )-2-[(2 S ,3 S )-5-chloro-6-fluoro-3-hydroxy-2-({[(1 r ,4 S )-4-hydroxycyclohexyl]amino}methyl)-

2-phenyl-2,3-dihydro-1-benzofuran-4-yl]-4-(difluoromethoxy)-3-fluorobenzamide (Example 100a) and 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, or ( 2P )-2-[( 2S ,3S ) -5-chloro-6-fluoro-3-hydroxy-2-({[( 1S , 4R )-4-hydroxycyclohexyl]amino}methyl)-2-phenyl-2,3-dihydro-1-benzofuran-4-yl]-4-(difluoromethoxy)-3-fluorobenzamide (example 100b).

The title compounds were prepared analogously to Examples 94a and 94b.

2-((2 S ,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 (2 P )-2-[(2 S ,3 S )-5-chloro-6-fluoro-3-hydroxy-2-({[(1 r ,4 S )-4-hydroxycyclohexyl]amino}methyl)-2-phenyl-2,3-dihydro-1-benzofuran-4-yl]-4-(difluoromethoxy)-3-fluorobenzamide (example 100a): ¹ H NMR (600 MHz, DMSO- d ₆ ) δ (ppm) 7.56-7.50 (m, 4H), 7.43-7.40 (m, 2H), 7.36-7.26 (m, 4H), 7.33 (t, J=73 Hz, 1H), 4.90 (s, 1H), 4.45-4.42 (m, 1H), 3.29-3.18 (m, 3H), 2.27-2.20 (m, 1H), 1.72-1.66 (m, 4H), 1.09-1.00 (m, 2H), 0.96-0.86 (m, 2H). UPLC-MS 1: mass/charge 595.3 [M+H] ⁺ , t _R =0.87 min.

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 or ( 2P )-2-[( 2S , 3S )-5-chloro-6-fluoro-3-hydroxy-2-({[( 1s , 4R )-4-hydroxycyclohexyl]amino}methyl)-2-phenyl-2,3-dihydro-1-benzofuran-4-yl]-4-(difluoromethoxy)-3-fluorobenzamide (Example 100b):

¹ H NMR (600 MHz, DMSO- d ₆ ) δ (ppm) 7.56-7.52 (m, 4H), 7.44-7.41 (m, 2H), 7.36-7.26 (m, 4H), 7.34 (t, J=72.6 Hz, 1H), 4.92 (s, 1H), 4.25 (d, J=3.3 Hz, 1H), 3.57-3.52 (m, 1H), 3.20 (s, 2H), 2.36-2.31 (m, 1H), 1.45-1.27 (m, 8H). UPLC-MS 1: m/z 594.9 [M+H] ⁺ , t _R =0.89 min.

Example 101. 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

The title compound was prepared analogously to Example 5a and Example 48 from the intermediates 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 (C-XV) and 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzonitrile (N-VI).¹H NMR (400 MHz, DMSO-d6) δ: .7.61 (d, J=8.7 Hz, 1H), 7.53-7.48 (m, 2H), 7.48-7.42 ( m, 2H), 7.42-7.30 (m, 4H), 7.13 (sbr, 1H), 4.95 (t, J=5.1 Hz, 1H), 4.50 (s, 1H), 4.18. 4.09 (m, 2H), 3.76-3.70 (m, 2H), 3.58 (d, J=14.1 Hz, 1H), 3.46 (d, J=14.2 Hz , 1H), 3.05 (s, 3H). UPLC-MS 1: mass/charge 505.2 [M+H]+, t_R=0.64.

Diastereoisomers were separated after Suzuki coupling: tert-butyl (((2S,3S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate: UPLC-MS 1: m/z 671.3 [M+H]+, t _R= 1.43; tert-Butyl (((2S,3S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-6-fluoro-3-methoxy-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate: UPLC-MS 1: m/z 671.3 [M+H]+, t _R= 1.42.

Example 102a and Example 102b. 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 (Example 102a) and 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 (example 102b)

The title compounds were prepared analogously to Examples 94a and 94b.

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 (Example 102a): ¹ H NMR (600 MHz, DMSO- d ₆ ) δ (ppm) 7.64 (d, J=8.6 Hz, 1H), 7.56 (t, J=8.1 Hz, 1H), 7.48-7.29 (m, 8H), 7.23 (s, 1H), 4.49 (s, 1H), 4.46-4.42 (m, 1H), 3.31-3.19 (m, 3H), 3.03 (s, 3H), 2.23-2.16 (m, 1H), 1.75-1.64 (m, 4H), 1.10-1.01 (m, 2H), 0.94-0.79 (m, 2H). UPLC-MS 1: m/z 609.2 [M+H] ⁺ , t _R =0.87 min.

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 (Example 102b): ¹ H NMR (600 MHz, DMSO- d ₆ ) δ (ppm) 7.65 (d, J=9.0 Hz, 1H), 7.56 (t, J=8.1 Hz, 1H), 7.48-7.30 (m, 8H), 7.28-7.23 (m, 1H), 4.51 (s, 1H), .4.28-4.24 (m, 1H), 3.57-3.53 (m, 1H), 3.25-3.18 (m, 2H), 3.05 (s, 3H), 2.36-2.30 (m, 1H), 1.45-1.25 (m, 8H). UPLC-MS 1: mass/charge 609.2 [M+H] ⁺ , t _R =0.89 min.

Example 103. 2-((2S,3S,4S)-2-(Aminomethyl)-5-chloro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide

The title compound was prepared analogously to Example 5a from the intermediates 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 (C-XI) and 2-bromo-4-(difluoromethoxy)-3-fluorobenzonitrile (N-V).

2-((2S,3S,4S)-2-(Aminomethyl)-5-chloro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide (Example 103): ¹ H NMR (400 MHz, DMSO-d6) δ: 7.80-7.18 (m, 11H), 6.93 (d, J=8.5 Hz, 1H), 3.36-3.33 (m, 1H), 3.10-3.02 (m, 2H), 2.54-2.51(m, 1H), 1.07 (s br, 1H), 0.92 (d, J=7.2 Hz, 3H). UPLC-MS 1: mass/charge 477.2 [M+H]+, t _R= 0.78.

Another diastereoisomer, 2-((2S,3S,4R)-2-(aminomethyl)-5-chloro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide: UPLC-MS 1: m/z 477.2 [M+H]+, t _R= 0.69.

Example 104a and example 104b. 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 (Example 104a) and 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 (Example 104b)

The title compounds were prepared analogously to Examples 27a and 27b from Example 103 and 4-hydroxy-4-methylcyclohexanone.

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 (example 104a): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 7.84-7.13 (m, 12H), 6.97 (d, J = 8.6 Hz, 1H), 3.89 (s, 1H), 3.23-3.05 (m, 2H), 2.17 (br s, 1H), 1.48-1.39 (m, 4H), 1.33-1.10 (m, 4H), 1.04 (s, 3H), 0.96 (d, J =7.1 Hz, 3H), 0.88-0.70 (m, 1 H). UPLC-MS 1: m/z 589.3 [M+H]+, t _R= 0.84,

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 (example 104b): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 7.79-7.11 (m, 12H), 6.96 (d, J = 8.4 Hz, 1H), 4.06 (s, 1H), 3.09 (s br, 2H), 2.43-2.27 (m, 1H), 1.68-1.55 (m, 2 H), 1.44-1.13 (m, 4H), 1.13-0.93 (m, 8H), 0.91-0.82 (m, 1H). UPLC-MS 1: m/z 589.3 [M+H]+, t _R= 0.82.

Example 105. 2-((2S,3S,4S)-2-(Aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide

The title compound was prepared analogously to Example 5a from the intermediates 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 (C-XVI) and 2-bromo-4-(difluoromethoxy)-3-fluorobenzonitrile (N-V).

2-((2S,3S,4S)-2-(Aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide (Example 105): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.88 (s, 1H), 7.60 (dd, J=8.6, 1.1 Hz, 1H), 7.52 (t, J=8.1 Hz, 1H), 7.48-7.18 (m, 7H), 7.09 (d, J=9.5 Hz, 1H), 3.32-3.27 (m, 1H), 3.14-3.00 (m, 2H), 1.09 (s br, 2H), 0.91 (d, J=7.2 Hz, 3H). UPLC-MS 1: m/z 495.1 [M+H] ⁺ , t _R =0.88 min.

Another diastereoisomer, 2-((2S,3S,4R)-2-(aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide: UPLC-MS 1: m/z 495.1 [M+H] ⁺ , t _R = 0.79 min.

The following compounds were prepared similarly to Example 105.

Note: Structure/Chemical Name UPLC MS
mass/charge [M+H] ⁺
t _R [min.] (method) ¹ H NMR 106
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;
2-bromo-3-fluoro-4-(2-methoxyethoxy)benzonitrile (N-IX), used in the Suzuki coupling reaction 503.2
0.74 (1) (400 MHz, DMSO-d ₆ ) δ (ppm): 7.66 (s br, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.43-7.25 (m, 6H), 7.08 (s br, 1H), 7.04 (d, J=9.5 Hz, 1H), 4.30-4.14 (m, 2H), 3.65 (t, J=4.5 Hz, 2H), 3.30 (s, 3H), 1 proton under water peak, 3.16-2, 96 (m, 2H), 1.10 (s br, 2H), 0.90 (d, J=7.1 Hz, 3H) 107
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;
Aryl bromide, 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzonitrile (N-VI), used in the Suzuki coupling reaction. The Boc and THP groups were cleaved together in the last step. 489.3
0.64 (1) (400 MHz, DMSO-d ₆ ) δ (ppm): 7.69 (s br, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.44-7.28 (m, 6H), 7.11 (s br, 1H), 7.07 (d, J=9.5 Hz, 1H), 4.96-4.93 (m, 1H), 4.17-4.10 (m, 2H), 3.76-3.72 (m, 2H), 3.31-3.27 (m, 1H ), 3.14-3.06 (m, 2H), 1.11 (s br, 2H), 0.94 (d, J=7.0 Hz, 3H) 108
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;
Aryl bromide, methyl 4-chloro-5-fluoro-6-(2-methoxyethoxy)nicotinate (N-XXXII), used in the Suzuki coupling reaction, the synthesis is similar to example 18 504.3
0.78 (1) (400 MHz, DMSO-d ₆ ) δ (ppm): 8.43 (s, 1H), 8.05 (s, 1H), 7.98-7.89 (m, 3H), 7.55-7 .42 (m, 6H), 7.22 (d, J=9.3 Hz, 1H), 4.58-4.49 (m, 2H), 3.77-3.69 (m, 2H), 3.55 -3.40 (m, 1H), 3.30 (s, 3H), 2.70 (s, 2H), 0.98 (d, J=6.7 Hz, 3H) 109
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;
Boronate, 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 (C-XVIII), and aryl bromide, 2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV), used in the Suzuki coupling reaction 460.4
0.70 (1) (400 MHz, DMSO-d ₆ ) δ (ppm): 8.60-8.56 (m, 1H), 7.80 (td, J=7.8, 1.7 Hz, 1H), 7.68 (s br, 1H), 7.60 (dd, J=8.6, 1.2 Hz, 1H), 7.52 (d, J=8.1 Hz, 1H), 7.32 (qd, J=4.9, 1.0 Hz, 1H), 7.29 (t, J=8.3 Hz, 1H), 7.11- 7.05 (m, 2H), 3.89 (s, 3H), 3.50 (q, J=7.0 Hz, 1H), 3.22 (d, J=1.7 Hz, 2H), 0.92 (d, J=7.3 Hz, 3H)

Example 110. 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

The title compound was prepared analogously to Example 48 from the intermediate compounds 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 (C-XVI) and 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzonitrile (N-VI). During the conversion of the nitrile group to the amide group under standard conditions (example 5a, step 2), the THP group had already been cleaved before the removal of the Boc protecting group.

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 (Example 110): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.62 (s br, 1H), 7.58 (d, J=8.6 Hz, 1H), 7.45-7.27 (m, 6H), 7.12 (s br, 1H), 7.08 (d=9.4 Hz, 1H), 4.95-4.93 (m, 1H), 4.17-4.10 (m, 2H), 3.75-3.71 (m, 2H), 3.30-3.25 (m, 1H), 3.14-3.06 (m, 2H), 2.23 (s, 3H), 0.94 (d, J=7 Hz, 3H). UPLC-MS 1: m/z 503.4 [M+H] ⁺ , t _R =0.65 min.

Another diastereoisomer, 2-((2S,3S,4R)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide: UPLC-MS 1: m/z 503.4 [M+H] ⁺ , t _R = 0.59 min.

The following compounds were prepared similarly to Example 110.

Note: Structure/Chemical Name UPLC MS
mass/charge [M+H] ⁺
t _R [min.] (method) ¹ H NMR 111
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;
Boronate, 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 (C-XVIII), and aryl bromide, 2-bromo-3-fluoro-4-(2-methoxyethoxy)benzonitrile (N-IX), used in the Suzuki coupling reaction 518.4
0.73 (1) (400 MHz, DMSO-d ₆ ) δ (ppm): 8.59-8.53 (m, 1H), 7.77 (td, J=7.8, 1.7 Hz, 1H), 7.65 (s br, 1H), 7.59 (d, J=8.6, Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.34-7.27 (m, 2H), 7.12 (s br, 1H), 7.10 (d, J=9.5 Hz, 1H), 4.30-4, 20 (m, 2H), 3.69 (t, J=4.4 Hz, 2H), 3.53 (q, J=7.1 Hz, 1H), 3.31(s, 3H), 3.09(s, 2H), 2.17 (s, 3H), 0.95 (d, J=7.2 Hz, 3H) 112
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;
Boronate, 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 (C-XVIII), and aryl bromide, 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzonitrile (N-VI), used in the Suzuki coupling reaction 504.3
0.59 (1) (400 MHz, DMSO-d ₆ ) δ (ppm): 8.59-8.55 (m, 1H), 7.77 (t, J=7.7 Hz, 1H), 7.64 (s br, 1H), 7.59 (d, J=8.7, Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.34-7.28 (m, 2H), 7.14-7.07 (m, 2H), 4.95 (t, J=5.1 Hz, 1H), 4.20-4.09 ( m, 2H), 3.78-3.71 (m, 2H), 3.53 (q, J=7.5 Hz, 1H), 3.13-3.04 (m, 2H), 2.17 (s, 3H), 0.95 (d, J=7.1 Hz, 3H)

Example 113. 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

The title compound was prepared analogously to Example 51 from the intermediate compounds 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 (C-XVI) and methyl 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate (N-XXVII). The diastereoisomers were separated after final removal of the Boc and THP protecting groups.

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 ₍ example 113): ^1H NMR (400 MHz, DMSO- d6 ) δ (ppm): 8.20-8.12 (m, 1H), 7.50-7.28 (m, 7H), 7.06 (d, J=9.5 Hz, 1H), 4.92 -4.90 (m, 1H), 4.17-4.05 (m, 2H), 3.74-3.69 (m, 2H), 3.16-2.94 (m, 2H), 2.63-2.61 (m, 1H), 2.45 (s, 3H), 1.24 (s, 3H), 0.94 (d, J=6.9 Hz, 3H), 0.89 -0.81 (m, 1H). UPLC-MS 1: m/z 517.2 [M+H] ⁺ , t _R =0.66 min.

Another diastereoisomer, 2-((2S,3S,4R)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide: UPLC-MS 1: m/z 517.2 [M+H] ⁺ , t _R = 0.63 min.

Example 114a and Example 114b. 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 (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 (Example 114a) and 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 or (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 (example 114b)

Reaction scheme for example 114.

Step 1. tert-Butyl (((2S,3S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)phenyl)-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S,3S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)phenyl)-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate

A mixture of 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 (C-XVI) (550 mg, 1.06 mmol), 2-bromo-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile (N-XIII) (399 mg, 1.115 mmol), N-XantPhos Pd G3 CAS [1602922-03-1] (98 mg, 0.106 mmol) and K ₃ PO ₄ (376 mg, 3.19 mmol) The reaction mixture was suspended in toluene (6 mL) and water (2 mL) and purged with Ar. The reaction mixture was stirred at 100 °C for 21 h. EtOAc and saturated NaHCO ₃ solution were added. The aqueous layer was back extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 5% to 50% EtOAc) to give a mixture of the title compounds (453 mg). UPLC-MS 1: m/z 669.4 [M+H] ⁺ , t _R = 1.49 and 1.50 min.

Stage 2 . tert-Butyl-(((2S,3S,4S)-4-(6-carbamoyl-2-fluoro-3-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy) phenyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl-(((2S,3S,4R)-4-(6-carbamoyl-2-fluoro-3-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy) phenyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate

To a suspension of a mixture of tert-butyl (((2S,3S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)phenyl)-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S,3S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)phenyl)-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (450 mg, 0.672 mmol) in EtOH (8 mL) and water (2 ml) was added at rt hydrido(dimethylphosphinic acid-kP)[hydrogen-bis(dimethylphosphinito-kP)]platinum(II) (58 mg, 0.134 mmol). The reaction mixture was stirred at 80 °C for 1.5 h. Saturated NaHCO ₃ solution was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give a mixture of the title compounds (437 mg). UPLC-MS 1: m/z 687.4 [M+H] ⁺ , t _R = 1.34, 1.35, 1.36 and 1.38 min. (Due to the racemic THP protecting group used, 2 peaks are visible in UPLC for this mixture of title compounds).

Step 3. 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 and 2-((2S,3S,4R)-2-(aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide

A mixture of tert-butyl (((2S,3S,4S)-4-(6-carbamoyl-2-fluoro-3-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)phenyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S,3S,4R)-4-(6-carbamoyl-2-fluoro-3-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)phenyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (434 mg, 0.63 mmol) was dissolved in HCl (4 mL, 4 M in dioxane). The solution was stirred at rt for 1.5 h, then diluted with EtOAc and quenched with _saturated NaHCO3. The aqueous layer was back extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 5% to 50% _EtOAc ) to afford the desired compounds as individual diastereoisomers.

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 (117 mg):¹H NMR (600 MHz, DMSO-d ₆) δ (ppm) 7.68 (s, 1H), 7.56 (d, J=8.7 Hz, 1H), 7.44 (d, J=7.3 Hz, 2H), 7.36 ( t, J=7.5 Hz, 2H), 7.29 (t, J=7.4 Hz, 2H), 7.13-7.03 (m, 2H), 4.93 (d, J=3.8 Hz, 1H), 3.94 (dd, J=24.3, 5.7 Hz, 3H), 3.30-3.15 (m, 2H ), 3.11 (s, 1H), 1.91 (s, 2H), 1.12 (d, J=5.5 Hz, 3H), 0.92 (d, J=7.2 Hz, 3H). UPLC-MS 1: mass/charge 503.3 [M+H]⁺, t_R=0.69 min.

2-((2S,3S,4R)-2-(Aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide (169 mg): UPLC-MS 1: m/z 503.3 [M+H] ⁺ , t _R = 0.61 min.

Step 4. 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 ( 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 (Example 114a) and

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 or ( 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 (Example 114b)

To a solution of 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 (115 mg, 0.23 mmol) in DCM (2.8 mL) was added 4-hydroxy-4-methylcyclohexanone (35 mg, 0.27 mmol) at rt, followed by sodium triacetoxyborohydride (145 mg, 0.69 mmol) and acetic acid (0.015 mL). The suspension was stirred at rt for 45 min, then quenched with sat. _NaHCO3 (20 mL) and extracted with DCM. The combined organic layers were washed with sat. _NaHCO3 solution and brine, dried over anhydrous _Na2SO4 and concentrated. The crude material was purified by chiral SFC (Chiralpak AD-H 5 μm 250×30 mm, mobile phase: _CO2 /[IPA+1% _{NH3 ]} 70/30, flow rate 100 ml/min) to afford the title compounds as individual stereoisomers.

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 ( 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 (Example 114a) (44 mg): ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 7.61 (s br, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.43-7.41 (m, 2H), 7.33 (t, J=7.7 Hz, 2H), 7.30-7.24 (m, 2H), 7.08 (s br, 1H), 7.06 (d, J=9.5 Hz, 1H), 4.93 (sbr, 1H), 4.05 (sbr, 1H), 3.99-3.94 (m, 2H), 3.93-3.89 (m, 1H), 3.27 (q, J=7.1 Hz, 1H), 3.12-3.06 (m, 2H), 2.33-2.28 (m, 1H), 1.66-1.60 (m, 1H), 1.60-1.55 (m, 1H), 1.39-1.30 (m, 2H), 1.24-1.15 (m, 2H), 1.13 (d, J=6.2 Hz, 3H), 1.07-0.99 (m, 2H), 0.98 (s, 3H), 0.94 (d, J=7.3 Hz, 3H). UPLC-MS 1: mass/charge 615.3 [M+H] ⁺ , t _R =0.77 min. Chiral SFC (Chiralpak AD-H 250×4.6 mm, 5 μm, mobile phase: _CO2 /[IPA+1% isopropylamine] 75:25, flow rate: 3 ml/min): t _R = 4.49 min. The absolute configuration was confirmed by X-ray diffraction analysis of the cocrystal of example 114a bound to the YAP binding site of TEAD4.

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 or ( 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 (Example 114b) (23 mg): ¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm) 7.61 (s, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.42 (d, J=7.7 Hz, 2H), 7.33 (t, J=7.6 Hz, 2H), 7.30-7.27 (m, 1H), 7.25 (d, J=7.4 Hz, 1H), 7.07 (d, J=9.5 Hz, 2H), 4.93 (s, 1H), 4.00-3.89 (m, 3H), 3.87 (s, 1H), 3.25 (q, J=7.2 Hz, 1H), 3.15 (d, J=12.5 Hz, 1H), 3.10 (d, J=12.6 Hz, 1H), 2.17 (ddd, J=13.6, 8.2, 3.1 Hz, 1H), 1.45-1.38 (m, 4H), 1.24 (td, J=13.3, 6.6 Hz, 2H), 1.20-1.14 (m, 2H), 1.12 (d, J=5.8 Hz, 3H), 1.03 (s, 3H), 0.93 (d, J=7.1 Hz, 3H). UPLC-MS 1: m/z 615.4 [M+H] ⁺ , t _R = 0.75 min. Chiral SFC (Chiralpak AD-H 250×4.6 mm, 5 μm, mobile phase: CO ₂ /[IPA+1% isopropylamine] 75:25, flow rate: 3 mL/min): t _R = 7.46 min.

The following compounds were prepared analogously to Example 114a and Example 114b.

Note: Structure/Chemical Name UPLC MS
mass/charge [M+H] ⁺
t _R [min.] (method) ¹ H NMR 115a
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;
Example 105, used in reductive amination 593.3
0.82 (1) (400 MHz, DMSO-d6) δ (ppm): 7.80 (s br, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.53-7.49 (m, 1H ), 7.42-7.23 (m, 7H), 7.14-7.08 (m, 1H), 4.38 (d, J=4.3 Hz, 1H), 3.30-3.21 (m, 1H), 3.13-3.05 (m, 2H), 2.17-2.12 (m, 1H), 1 .69-1.63 (m, 4H), 1.11-0.97 (m, 2H), 0.91 (d, J=7.0 Hz, 3H), 0.87-0.77 (m, 4H) 115b
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;
formed in the reductive amination step together with example 115a 593.3
0.84 (1) (400 MHz, DMSO-d ₆ ) δ (ppm): 7.84 (s, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.57 -7.24 (m, 7H ), 7.12 (d, J=9.5 Hz, 1H), 4.20 (d, J=3.5 Hz, 1H), 3.55-3.49 (m, 1H), 3.30-3.24 (m, 1H), 3.13-3.04 (m, 2H), 2.32-2.24 (m, 1H ), 1.40-1.27 (m, 9H), 0.94 (d, J=7.1 Hz, 3H), 0.86-0.74 (m, 1H) 116a
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;
Example 106, used in reductive amination 615.5
0.81 (1) (400 MHz, DMSO-d ₆ ) δ (ppm): 7.62 (s br, 1H), 7.58 (d, J=8.6Hz, 1H), 7.44-7.41 (m, 2H ), 7.36-7.24 (4H), 7.09-7.06 (m, 2H), 4.29-4.18 (m, 2H), 4.03 (s, 1H), 3.68-3.66 (m, 2H), 3.29 (s, 3H), 3.27-3.24 (m, 1H), 3.09 (sbr, 2H), 2.35-2.27 (m, 1H), 1.70-1.46 (m, 2H), 1.40-1.15 (m, 4H), 1.10-1.00 (m, 2H), 0.98 (s, 3H), 0.94 (d, J=7.3 Hz, 3H) 116b
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;
formed in the reductive amination step together with example 116a 615.5
0.84 (1) (400 MHz, DMSO-d ₆ ) δ (ppm): 7.62 (s br, 1H), 7.58 (d, J=8.6 Hz, 1H), 7.43-7.28 (m, 6H), 7.08 (s, 1H), 7.07 (d, J=9.5 Hz, 1H), 4.28-4.20 (m, 2H), 3.86 (s, 1H), 3.68-3.66 (m, 2H), 3.29 (s, 3H), 3.26-3.22 (m, 1H), 3.17-3.09 (m, 2H), 2.19-2.13 (m, 1H), 1.47-1.39 (m, 4H), 1.25-1.15(m, 5H), 1.03 (s, 3H), 0.93 (d, J=7.3Hz, 3H) 117a
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 (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-(2-hydroxyethoxy)benzamide;
Example 107, used in reductive amination
The absolute configuration was confirmed by X-ray diffraction analysis of a cocrystal of example 117a bound to the YAP binding site of TEAD4. 601.2
0.69 (1)
601.2
2.95 (2) (600 MHz, DMSO-d ₆ ) δ (ppm): 7.64 (s br, 1H), 7.56 (dd, J=8.6, 1.3 Hz, 1H), 7.43-7, 40 (m, 2H), 7.35-7.31 (m, 2H), 7.30-7.24 (m, 2H), 7.09 (s br, 1H), 7.07 (d, J=9.5 Hz, 1H), 4.93 (t, J=5.5 Hz, 1H), 4.16-4.08 ( m, 2H), 4.05 (s, 1H), 3.72 (q, J=5.0 Hz, 2H), 3.25 (q, J=7.2 Hz, 1H), 3.12-3.06 (m, 2H), 2.33-2.26 (m, 1H), 1.65-1.54 (m, 2H), 1.38-1.27 (m, 2H), 1.26-1.15 ( m, 2H), 1.07-0.97 (m, 2H), 0.97 (s, 3H), 0.93 (d, J=7.3 Hz, 3H), 0.87 (sbr, 1H). 117b
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 or (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-(2-hydroxyethoxy)benzamide;
formed in the reductive amination step together with example 117a 601,5
0.71 (1)
601.3
3.13 (2) (600 MHz, DMSO-d ₆ ) δ (ppm) 7.64 (s br, 1H), 7.57 (dd, J=8.6 Hz, 0.9 Hz, 1H), 7.43-7, 40 (m, 2H), 7.35-7.32 (m, 2H), 7.30-7.24 (m, 2H), 7.08 (s br, 1H), 7.07 (d, J=9.5 Hz, 1H), 4.93 (t, J=5.5 Hz, 1H), 4.15-4.08 ( m, 2H), 3.87 (s, 1H), 3.72 (q, J=5.0 Hz, 2H), 3.24 (q, J=7.2 Hz, 1H), 3.18-3.13 (m, 1H), 3.12-3.08 (m, 1H), 2.19-2.13 (m, 1H), 1.45-1.39 (m, 4H), 1.27-1.11 ( m, 4H), 1.02 (s, 3H), 0.93 (d, J=7.3 Hz, 3H), 0.85 (s br, 1H) 118
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;
obtained by analogy with example 96 and example 107 543.4
0.71 (1) (400 MHz, MeOD) δ (ppm): 7.61 (d, J=8.6 Hz, 1H), 7.49-7.22 (m, 6H), 6.92 (d, J=9, 2 Hz, 1H), 4.21-4.14 (m, 2H), 3.91-3.89 (m, 2H), 3.42-3.36 (m, 1H), 3.21-3.15 (m, 1H), 3.13 (s, 2H), 2.19-2.07 (m, 2H), 1, 66-1.56 (m, 4H), 1.01 (d, J=7.2 Hz, 3H)

Examples such as those shown in the table above can also be prepared by an alternative synthetic route, as explained for Example 114a below.

Alternative synthesis for 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 or (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

Reaction scheme of the alternative synthesis of example 114a

Step 1. 2-((2S,3S,4S)-5-Chloro-6-fluoro-2-(hydroxymethyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile and 2-((2S,3S,4R)-5-chloro-6-fluoro-2-(hydroxymethyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile

A solution of ((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 (C-XVII) (15.53 g, 35.2 mmol) in toluene (60 mL) was added dropwise to a stirred solution of 2-bromo-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile (N-XIII) (13.88 g, 38.8 mmol), K ₃ PO ₄ (22.44 g, 106 mmol) and N-XantPhos Pd G3 (Aldrich Cat. No. 794228) (1.623 g, 1.762 mmol) in toluene (80 mL) and water (40 mL) at reflux and stirring at 105 °C was continued for 3 h. EtOAc and water were added and the organic phase was separated. The aqueous phase was extracted with EtOAc, the combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, EtOAc/heptane, gradient: 0% to 80% EtOAc) to give a mixture of the title compounds (10.41 g). UPLC-MS 1: product not ionizable; t _R = 1.27 min, 1.28 min and 1.30 min.

Step 2. 2-((2S,3S,4S)-5-Chloro-6-fluoro-2-formyl-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile and 2-((2S,3S,4R)-5-chloro-6-fluoro-2-formyl-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile

At -78°C, a solution of DMSO (5.80 ml, 82 mmol) in DCM (40 ml) was added to a stirred solution of oxalyl chloride (3.57 ml, 40.8 mmol) in DCM (100 ml) and stirring was continued at -78°C for 15 min. Then a solution of a mixture of 2-((2S,3S,4S)-5-chloro-6-fluoro-2-(hydroxymethyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile and 2-((2S,3S,4R)-5-chloro-6-fluoro-2-(hydroxymethyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile (14.55 g, 25.5 mmol) in DCM (20 mL) was added. After 15 min. TEA (17.79 mL, 128 mmol) was added and the reaction mixture was allowed to warm to 0 °C over a period of 30 min. DCM and water were added and the organic phase was separated. The organic phase was extracted with DCM and the combined organic extracts were washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give a mixture of the title compounds (14.50 g), which was used without further purification in the next step. UPLC-MS 1: m/z 567.3 [M+H] ⁺ . t _R = 1.38 min and 1.39 min.

Step 3. 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-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile and 2-((2S,3S,4R)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile

At k.t. to a stirred solution of a mixture of 2-((2S,3S,4S)-5-chloro-6-fluoro-2-formyl-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile and 2-((2S,3S,4R)-5-chloro-6-fluoro-2-formyl-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile (14.50 g, 25.5 mmol) and trans-4-amino-1-methylcyclohexanol (3.30 g, To a mixture of acetic acid (2.192 mL, 38.3 mmol) in DCE (100 mL) was added and stirring at 80 °C was continued for 1 h. Sodium triacetoxyborohydride (10.82 g, 51.1 mmol) was added at 60 °C and the reaction mixture was stirred at this temperature for an additional 15 min. DCM was added for work-up, followed by saturated NaHCO ₃ solution. The organic phase was separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, DCM/MeOH, gradient: 0% to 6% MeOH) to give a mixture of the title compounds (10.34 g). UPLC MS 1: m/z 681.3 [M+H] ⁺ ; t _R = 1.13 min, 1.15 min and 1.18 min (more than 2 peaks in UPLC due to racemic THP protecting group).

Step 4. 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-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzamide and 2-((2S,3S,4R)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzamide

To a stirred solution of a mixture of 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-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile and 2-((2S,3S,4R)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile (10.34 g, 15.17 mmol) in EtOH (70 mL) and water (30 mL) was added hydrido(dimethylphosphinic acid-kP)[hydrogen-bis(dimethylphosphinito-kP)]platinum(II) (0.5 g, 1.165 mmol) and the reaction mixture was stirred at 85 °C for 2 h. EtOAc and water were added and the organic phase was separated. The aqueous phase was extracted with EtOAc, the combined organic extracts were washed with brine, dried over _{anhydrous Na2SO4} and concentrated. The remaining residue was dissolved in MeOH and passed through a PL-thiol resin MP cartridge (Agilent, StratoSpheres SPE) to remove trace metals. Concentration afforded the crude product, which was purified by flash chromatography (silica, DCM/(7N ammonia in MeOH), gradient: 0% to 12% (7N ammonia in MeOH)) to afford the title compounds as separate diastereoisomers.

For each resolved diastereoisomer, 2 peaks are visible in UPLC due to the racemic THP protecting group.

2-((2S,3S,4R)-5-Chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzamide (5.53 g): UPLC-MS 1: m/z 699.3 [M+H] ⁺ , t _R = 0.92 min and 0.95 min.

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-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzamide (4.26 g): UPLC-MS 1: m/z 699.3 [M+H] ⁺ , t _R = 1.02 min and 1.04 min.

Step 5. 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 ( 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 (Example 114a)

To 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-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzamide (4.26 g, 6.09 mmol) was added HCl (50 mL, 4 M in dioxane) at rt and stirring at rt was continued for 2 h. The reaction mixture was quenched by addition of saturated _NaHCO3 solution and extracted with DCM. _The combined organic extracts were dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, DCM/(7N ammonia in MeOH), gradient: 0% to 13% (7N ammonia in MeOH)) to give the title compound (3.26 g). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 7.61 (s br, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.43-7.41 (m, 2H), 7.33 (t, J=7.7 Hz, 2H), 7.30-7.24 (m, 2H), 7.08 (s br, 1H), 7.06 (d, J=9.5 Hz, 1H), 4.93 (s br, 1H), 4.05 (s br, 1H), 3.99-3.94 (m, 2H), 3.93-3.89 (m, 1H), 3.27 (q, J=7.1 Hz, 1H), 3.12-3.06 (m, 2H), 2.33-2.28 (m, 1H), 1.66-1.60 (m, 1H), 1.60-1.55 (m, 1H), 1.39-1.30 (m, 2H), 1.24-1.15 (m, 2H), 1.13 (d, J=6.2 Hz, 3H), 1.07-0.99 (m, 2H), 0.98 (s, 3H), 0.94 (d, J=7.3 Hz, 3H). UPLC MS 1: m/charge 615.3 [M+H] ⁺ ; t _R =0.77 min. UPLC-MS 2: m/charge 615.3 [M+H] ⁺ ; t _R= 3.33 min.

Example 119. 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

The title compound was prepared analogously to Example 114a (alternative synthesis) from the intermediates ((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 (C-XVII) and 5-fluoro-4-iodo-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinonitrile (N-XII).¹H NMR (400 MHz, DMSO-d ₆) δ (ppm) 8.38 (s, 1H), 7.90 (s, 1H), 7.49-7.40 (m, 2H), 7.38-7.22 (m, 4H), 7 .17-7.09 (m, 1H), 4.93-4.85 (m, 1H), 4.51-4.34 (m, 2H), 4.05-3.93 (m, 1H), 3.78-3.68 (m, 2H), 3.09 (s, 2H), 1.60 (s, 3H), 1.29 (d, J=34.8 Hz, 9H), 1.08-0.74 (m, 5H). UPLC-MS 1: mass/charge 602.2 [M+H]⁺, t_R=0.71 min.

Diastereoisomers were separated before final removal of the Boc and THP protecting group. 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-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinamide: UPLC-MS 1: m/z 686.5 [M+H] ⁺ , t _R = 0.90 min; 4-((2S,3S,4R)-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-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinamide: UPLC-MS 1: m/z 686.8 [M+H] ⁺ , t _R =0.84 min.

Example 120. 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)benzonitrile or (2 P )-2-[(2 S ,3 S )-5-chloro-6-fluoro-2-({[(1 R ,4 S )-4-hydroxy-4-methylcyclohexyl]amino}methyl)-3-methyl-2-phenyl-2,3-dihydro-1-benzofuran-4-yl]-3-fluoro-4-[(2S)-2-hydroxypropoxy]benzonitrile

To a solution of a mixture of 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-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile and 2-((2S,3S,4R)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile (product To a mixture of pyridine p-toluenesulfonate (77 mg, 0.31 mmol) in EtOH (3 mL) (step 3 of the alternative synthesis of example 114a) (105 mg, 0.15 mmol) and EtOH (3 mL) was added and the reaction mixture was stirred at rt for 16 h and at 60 °C for 2 h. A saturated NaHCO ₃ solution was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with a saturated NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by preparative HPLC and the diastereoisomers were separated.

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)benzonitrile or ( 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]benzonitrile (Example 120, 26 mg): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.87 (dd, J=8.8, 1.2 Hz, 1H), 7.51-7.42 (m, 3H), 7.38-7.25 (m, 4H), 5.00 (d, J=4.7 Hz, 1H), 4.06-4.02 (m, 3H), .4.02-3.95 (m, 1H), 3.39-3.30 (m, 1H), 3.12 (s br, 2H), 2.33-2.26 (m, 1H), 1.67-1.55 (m, 2H), 1.40-1.27 (m, 2H), 1.26-1.25 (m, 2H), 1.13 (d, J=6.1 Hz, 3H), 1.07-1.00 (m, 2H), 1.01-0.97 (m, 6H). UPLC-MS 1: m/z 597.5 [M+H] ⁺ , t _R =0.83 min.

Another diastereoisomer, 2-((2S,3S,4R)-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)benzonitrile: UPLC-MS 1: m/z 597.6 [M+H] ⁺ , t _R = 0.80 min.

Example 121. 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 (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-(2-hydroxyethoxy)-N-methylbenzamide

Reaction scheme for example 121

Step 1. Methyl 2-((2S,3S,4S)-5-chloro-6-fluoro-2-(hydroxymethyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate and methyl 2-((2S,3S,4R)-5-chloro-6-fluoro-2-(hydroxymethyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate

A suspension of ((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 (C-XVII) (1 g, 2.388 mmol), methyl 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate (N-XXVII) (1.081 g, 2.87 mmol), Pd ₂ (dba) ₃ (0.109 g, 0.119 mmol), 4,6-bis(diphenylphosphino)-10H-phenoxazine (0.132 g, 0.239 mmol) and K ₃ PO ₄ (1.521 g, 7.17 mmol) in toluene (15 mL) and water (3 mL) was stirred at 100 °C for 16 h under Ar. The reaction mixture was quenched by adding sat. NaHCO ₃ solution, then extracted with EtOAc. The organic layers were combined and washed with sat. NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, hexane/EtOAc, gradient from 0% to 100% EtOAc) to give a mixture of the title compounds (206 mg). UPLC-MS 1: m/z 606.3 [M+17] ⁺ , t _R = 1.26 min.

Step 2. Methyl 2-((2S,3S,4S)-5-chloro-6-fluoro-2-formyl-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate and methyl 2-((2S,3S,4R)-5-chloro-6-fluoro-2-formyl-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate

At -78°C, DMSO (0.054 mL, 0.77 mmol) was added to a solution of oxalyl chloride (0.034 mL, 0.383 mmol) in DCM (4 mL). After 30 min. At -78°C, a solution of a mixture of methyl 2-((2S,3S,4S)-5-chloro-6-fluoro-2-(hydroxymethyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate and methyl 2-((2S,3S,4R)-5-chloro-6-fluoro-2-(hydroxymethyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate (205 g, 0.35 mmol) in DCM (2 ml) and TEA (0.24 ml, 1.740 mmol) was added and the reaction mixture was stirred at -78°C for 1 h. The reaction mixture was quenched by addition of brine then extracted with DCM. The organic layers were combined and washed with brine, dried over _{anhydrous Na2SO4} and concentrated to give a mixture of the title compounds (200 mg) as a brownish powder. UPLC-MS 1: t _R = 1.28 min.

Step 3. Methyl 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-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate and methyl 2-((2S,3S,4R)-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-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate

At k.t. to a stirred solution of a mixture of methyl 2-((2S,3S,4S)-5-chloro-6-fluoro-2-formyl-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate and methyl 2-((2S,3S,4R)-5-chloro-6-fluoro-2-formyl-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate (202 mg, 0.34 mmol) and trans-4-amino-1-methylcyclohexanol (0.89 g, 0.69 mmol) in DCE (3 mL) was added acetic acid (0.020 mL, 0.344 mmol) was added and the reaction mixture was stirred at 80 °C for 30 min. Sodium triacetoxyborohydride (219 mg, 1.032 mmol) was added and stirring at 80 °C was continued for 30 min. DCM and saturated NaHCO ₃ solution were added and the organic phase was separated. The aqueous phase was extracted with DCM and the combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient 0% to 100% EtOAc) to give a mixture of the title compounds (135 mg). UPLC-MS 1: mass/charge 700.4 [M+H] ⁺ , t _R =1.03 min.

Step 4. 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-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoic acid and 2-((2S,3S,4R)-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-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoic acid

At k.t. to a solution of a mixture of methyl 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-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate and methyl 2-((2S,3S,4R)-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-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate (130 mg, 0.186 mmol) in LiOH.H ₂ O (13.34 mg, 0.557 mmol) was added to dioxane/water (1:1, 4 mL). The neat solution was stirred at rt for 48 h. The reaction mixture was quenched by addition of 1 N HCl, then extracted with EtOAc. The organic layers were combined, dried over anhydrous Na ₂ SO ₄ and concentrated to give a 12:1 mixture of the title compounds (87 mg) (the THP group was partially released during workup). UPLC-MS 1: m/z 686.5 [M+H] ⁺ , t _R = 0.90 and 0.94 min.

Step 5. 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 ( 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-(2-hydroxyethoxy)-N - methylbenzamide (Example 121)

To a stirred solution of a mixture of 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-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoic acid and 2-((2S,3S,4R)-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-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoic acid (87 mg, 0.127 mmol), DIPEA (0.221 mL, 1.27 mmol) and methylamine hydrochloride (42.8 mg, 0.63 mmol) in DMF (4 mL) was added HATU (72 mg, 0.190 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched by adding sat. _NaHCO3 solution, then extracted with EtOAc. The organic layers were combined and washed with sat. _NaHCO3 solution, dried over _{anhydrous Na2SO4} and concentrated. The residue was then dissolved in dioxane (2 mL), HCl (0.158 mL, 0.634 mmol, 4 M in dioxane) was added and the clear solution was stirred at rt for 1 h. The reaction mixture was quenched by adding sat. _NaHCO3 solution, then extracted with EtOAc. The organic layers were combined and washed with saturated _NaHCO3 solution, dried over anhydrous _Na2SO4 and concentrated. The residue was purified by flash chromatography (silica, DCM, MeOH, gradient 0% to 10% _MeOH ) and then by preparative HPLC (Waters Sunfire C18 OBD, 5 μm, 30 * 100 mm, eluent A: _H2O +0.1% TFA, B:ACN, gradient: 5% to 100% B over 20 min, hold for 1 min, flow 40 mL/min) to give the title compound (17 mg) as a colorless powder (another diastereoisomer, 2-((2S,3S,4R)-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 was not isolated). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.21 (d, J=4.2 Hz, 1H), 7.48 (d, J=7.5 Hz, 1H), 7.45-7.37 (m, 2H), 7.36-7.23 (m, 4H), 7.07 (d, J=9.6 Hz, 1H), 4.93 (t, J=5.4 Hz, 1H), 4.17-4.06 (m, 2H), 4.04 (s, 1H), 3.72 (q, J=4.9 Hz, 2H), 3.28-3.22 (m, 1H), 3.10-3.06 (m, 2H), 2.62 (d, J=4.6 Hz, 3H), 2.32-2.26 (m, 1H), 1.70-1.50 (m, 2H), 1.42-1.27 (m, 2H), 1.27-1.12 (m, 2H), 1.10-1.00 (m, 2H), 0.98 (s, 3H), 0.94 (d, J=7.1 Hz, 3H). UPLC-MS 1: mass/charge 615.4 [M+H] ⁺ , t _R =0.71 min.

Example 122. 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 (2P)-2-{(2S,3S)-5-chloro-6-fluoro-3-methyl-2-[(methylamino)methyl]-2-phenyl-2,3-dihydro-1-benzofuran-4-yl}-3-fluoro-4-[( 2S)-2-hydroxypropoxy]-N-methylbenzamide

Reaction scheme for example 122

Step 1. Methyl 2-((2S,3S,4S)-2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzoate and methyl 2-((2S,3S,4R)-2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzoate

To a stirred solution of methyl 2-bromo-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzoate (N-XXVIII) (4.90 g, 12.5 mmol), N-XantPhos (0.576 g, 1.04 mmol), Pd ₂ dba ₃ (0.478 g, 0.52 mmol), and K ₃ PO ₄ (6.65 g, 31.3 mmol) in toluene (30 mL) and water (10 mL) was added a solution of 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 (C-XXIX) (5.55 g, 10.4 mmol) in toluene (20 mL) at 100 °C and stirring at 100 °C was continued for 16 h. The reaction mixture was diluted with EtOAc and water, the organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, EtOAc/heptane, gradient 0% to 100% EtOAc) to give a mixture of the title compounds (1.7 g) as a yellow foam. UPLC-MS 1: m/z 616.6 [M+H-BOC] ⁺ , t _R = 1.59 min.

Step 2. 2-((2S,3S,4S)-2-(((tert-Butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzoic acid and 2-((2S,3S,4R)-2-(((tert-Butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzoic acid

At k.t. to a stirred solution of a mixture of methyl 2-((2S,3S,4S)-2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzoate and methyl 2-((2S,3S,4R)-2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzoate (1.7 g, 2.11 mmol) in THF (12 mL) and MeOH (12 mL) was treated with sodium hydroxide (10.6 mL, 21.2 mmol, 2 N in water). The reaction mixture was stirred at rt for 1 h, then at 45 °C for 16 h. THF and MeOH were evaporated. The resulting aqueous phase was acidified with 2 N HCl to pH 3 and extracted with DCM. The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated to give a mixture of the title products (1.67 g). UPLC-MS 1: m/z 602.6 [M+H-BOC] ⁺ , t _R = 1.44 min, 1.45 min, 1.46 min and 1.47 min.

Stage 3. tert-Butyl-(((2S,3S,4S)-5-chloro-6-fluoro-4-(2-fluoro-6-(methylcarbamoyl)-3-((2S)-2-((tetrahydro-2H- pyran-2-yl)oxy)propoxy)phenyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl-(((2S,3S,4R)-5-chloro-6-fluoro-4-(2-fluoro-6-(methylcarbamoyl)-3-((2S)-2-((tetrahydro-2H -pyran-2-yl)oxy)propoxy)phenyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate

At k.t. to a stirred suspension of a mixture of 2-((2S,3S,4S)-2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzoic acid and 2-((2S,3S,4R)-2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzoic acid (1.6 g, To a mixture of methylamine hydrochloride (0.769 g, 11.4 mmol) and TBTU (1.097 g, 3.42 mmol) in DMF (25 mL) was added DIPEA (1.592 mL, 9.11 mmol) and the reaction mixture was stirred at rt for 1.5 h. The reaction mixture was diluted in EtOAc and water, the organic phase was separated and the aqueous phase was extracted with _EtOAc . The combined organic extracts were washed with brine, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, EtOAc/heptane, gradient 0% to 100% EtOAc) to give a mixture of the title compounds (1.62 g) as a colorless foam. UPLC-MS 1: m/z 715.7 [M+H] ⁺ , t _R = 1.45 min, 1.46 min and 1.48 min.

Step 4. 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 ( 2P )-2-{( 2S , 3S )-5-chloro-6-fluoro-3-methyl-2-[(methylamino)methyl]-2-phenyl-2,3-dihydro-1-benzofuran-4-yl}-3-fluoro-4-[( 2 S )-2-hydroxypropoxy]-N - methylbenzamide (Example 122)

To the mixture tert-butyl-(((2S,3S,4S)-5-chloro-6-fluoro-4-(2-fluoro-6-(methylcarbamoyl)-3-((2S)-2-((tetrahydro-2H- pyran-2-yl)oxy)propoxy)phenyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate And tert-butyl-(((2S,3S,4R)-5-chloro-6-fluoro-4-(2-fluoro-6-(methylcarbamoyl)-3-((2S)-2-((tetrahydro-2H- pyran-2-yl)oxy)propoxy)phenyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (1.62 g, 1.42 mmol) was added HCl (30 mL, 120 mmol, 4 N in dioxane) at 0°C and the reaction mixture was stirred at rt for 30 min. The reaction mixture was diluted in DCM and added to a saturated NaHCO solution₃. The mixture was extracted with DCM and the combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄and concentrated. The crude product was purified by flash chromatography (silica, (7N ammonia in MeOH)/DCM, gradient 0% to 12% (7N ammonia in MeOH)) to give a colorless foam, which was further purified by preparative HPLC (Waters X-Bridge C18 OBD, 5 μm, 30 * 100 mm, eluent A: H₂O+7.3 mM NH₄OH, eluent B: ACN, gradient: 15% B over 4 min, then 15 to 45% B over 40 min, hold for 3 min, flow rate 40 ml/min). Lyophilization of the product fractions provided separated diastereoisomers as colorless powders.

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

(2 P )-2-{(2 S ,3 S )-5-chloro-6-fluoro-3-methyl-2-[(methylamino)methyl]-2-phenyl-2,3-dihydro-1-benzofuran-4-yl}-3-fluoro-4-[(2 S )-2-hydroxypropoxy]- N -methylbenzamide (Example 122) (604 mg): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.16 (d, J=4.9 Hz, 1H), 7.48 (d, J=8.6 Hz, 1H), 7.45-7.38 (m, 2H), 7.38-7.23 (m, 4H), 7.06 (d, J=9.5 Hz, 1H), 4.93 (d, J=4.1 Hz, 1H), 4.00-3.88 (m, 3H), 3.29-3.21 (m, 1H), 3.14-2.95 (m, 2H), 2.63 (d, J=4.5 Hz, 3H), 2.20 (s, 3H), 1.12 (d, J=5.4 Hz, 3H), 0.93 (d, J=7.2 Hz, 3H). UPLC-MS 1: mass/charge 531.4 [M+H] ⁺ , t _R =0.72 min.

Another diastereoisomer, 2-((2S,3S,4R)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide (60 mg): UPLC-MS 1: m/z 531.5 [M+H] ⁺ , t _R = 0.67 min.

Example 123. 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

Reaction scheme for example 123

Step 1. 2-((2S,3S,4S)-2-((Benzylamino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile and 2-((2S,3S,4R)-2-((benzylamino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile

To a stirred solution of a mixture of 2-((2S,3S,4S)-5-chloro-6-fluoro-2-formyl-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile and 2-((2S,3S,4R)-5-chloro-6-fluoro-2-formyl-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile (the product from step 1 in the alternative synthesis of Example 114a) (200 mg, 0.35 mmol) and benzylamine (113 To a solution of acetic acid (0.030 mL, 0.53 mmol) in DCE (5 mL) was added and the reaction mixture was stirred at 80 °C for 30 min. After cooling to rt, sodium triacetoxyborohydride (149 mg, 0.70 mmol) was added and stirring at 80 °C was continued for 2 h. DCM was added followed by saturated NaHCO ₃ solution. The organic phase was separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient: 0% to 50% EtOAc) to give a mixture of the title compounds (178 mg). UPLC MS 1: mass/charge 659.3 [M+H] ⁺ , t _R =1.21 min. and 1.23 min.

Step 2. 2-((2S,3S,4S)-2-((Benzylamino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzamide and 2-((2S,3S,4R)-2-((benzylamino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzamide

To a stirred solution of a mixture of 2-((2S,3S,4S)-2-((benzylamino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile and 2-((2S,3S,4R)-2-((benzylamino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile (178 mg, 0.21 mmol) in EtOH (3 mL) and water (1 mL) Hydrido(dimethylphosphinic acid-kP)[hydrogen-bis(dimethylphosphinito-kP)]platinum(II) (17.62 mg, 0.041 mmol) was added and the reactants were stirred at 80 _° C for 1 h. EtOAc and water were added. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, EtOAc/heptane, gradient: 0% to 100% EtOAc) to give a mixture of the title compounds (130 mg). UPLC MS 1: m/z 677.3 [M+H] ⁺ , t _R = 1.00 min, 1.02 min, 1.03 min and 1.05 min (each diastereoisomer resolves into 2 peaks in UPLC due to the racemic THP group).

Step 3. 2-((2S,3S,4S)-2-((Benzylamino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide and 2-((2S,3S,4R)-2-((benzylamino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide

At 0°C, HCl (4 mL, 16.0 mmol, 4) was added to a mixture of 2-((2S,3S,4S)-2-((benzylamino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzamide and 2-((2S,3S,4R)-2-((benzylamino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzamide (130 mg, 0.15 mmol). M in dioxane) and stirring at 0 °C was continued for 15 min. DCM was added, then saturated NaHCO ₃ solution. The organic phase was separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, DCM/(7 N ammonia in MeOH), gradient: 0% to 8% (7 N ammonia in MeOH)) to give a mixture of the title compounds (90 mg). UPLC MS 1: m/z 593.2 [M+H] ⁺ , t _R = 0.76 min and 0.80 min.

Step 4. 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 (Example 123)

At k.t. To a stirred solution of a mixture of 2-((2S,3S,4S)-2-((benzylamino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide and 2-((2S,3S,4R)-2-((benzylamino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide (90 mg, 0.14 mmol) in MeOH (5 mL) was added Pd/C (10 mg, 0.094 mmol, 10 wt %) and the reaction mixture was stirred under H ₂ for 2.5 h at rt. The reaction mixture was filtered through celite and concentrated. The crude product was purified by flash chromatography (silica, DCM/(7N ammonia in MeOH), gradient: 0% to 12% (7N ammonia in MeOH)) followed by preparative HPLC (Waters X-Bridge C18 OBD, 5 μm, 30 * 100 mm, eluent A: H ₂ O + 7.3 mM NH ₄ OH, B:ACN, gradient: 10% to 50% B over 20 min, hold for 1 min, flow rate 40 ml/min). Acetonitrile from the fractions containing the product was evaporated and the resulting aqueous phase was extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous _Na2SO4 and concentrated to afford separated _{diastereoisomers} .

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 (Example 123) (10 mg): ¹ H NMR (600 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.46-7.40 (m, 2H), 7.39-7.32 (m, 2H), 7.32-7.22 (m, 2H), 7.10 (s, 1H), 7.05 (d, J=9.6 Hz, 1H), 4.95 (d, J=4.2 Hz, 1H), 4.04-3.82 (m, 3H), 3.28 (q, J=7.3 Hz, 1H), 3.15-3.02 (m, 2H), 1.38-1 .01 (m, 5H), 0.91 (d, J=7.2 Hz, 3H). UPLC MS 1: mass/charge 503.1 [M+H] ⁺ ; t _R =0.68 min.

Another diastereoisomer, 2-((2S,3S,4R)-2-(aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide: UPLC MS 1: m/z 503.1 [M+H] ⁺ , t _R = 0.59 min.

Example 124. 2-(2-((2S,3S,4S)-2-(Aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3,4-difluorophenoxy)ethan-1-ol

Step 1. tert-Butyl (((2S,3S,4S)-5-chloro-4-(2,3-difluoro-6-(2-hydroxyethoxy)phenyl)-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate and tert-butyl (((2S,3S,4R)-5-chloro-4-(2,3-difluoro-6-(2-hydroxyethoxy)phenyl)-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)carbamate

A mixture of tert-butyl (((2 S ,3 S )-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 (C-XVI) (300 mg, 0.58 mmol), 2-(2-bromo-3,4-difluorophenoxy)ethanol (N-II) (161 mg, 0.64 mmol), Pd(dbpf)Cl ₂ (76 mg, 0.12 mmol) and K ₃ PO ₄ (369 mg, 1.74 mmol) in dioxane (4.3 mL) and H ₂ O (1.4 mL) was stirred under Ar at 100°C for 30 min. After cooling to rt, the reaction mixture was diluted with EtOAc and water, the organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with sat. _NaHCO3 solution, dried (phase separation cartridge) and concentrated. The residue was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 70% EtOAc) to give a mixture of the title compounds (112 mg).

Step 2. 2-(2-((2S,3S,4S)-2-(Aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3,4-difluorophenoxy)ethan-1-ol

The title compound (6.5 mg) was obtained using reaction conditions similar to those described for Example 22, step 5, and the diastereoisomers were separated by preparative HPLC (Waters X-Bridge C18 OBD, 5 μm, 30 * 100 mm, eluent A: H ₂ O + 7.3 mM NH ₄ OH, B: ACN, gradient: 10% over 4 min, then 10 to 60% B over 20 min, hold for 3 min, flow rate 40 mL/min).

2-(2-((2S,3S,4S)-2-(Aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3,4-difluorophenoxy)ethan-1-ol (Example 124) (112 mg): ¹ H NMR (400 MHz, DMSO-d6) δ 7.50-7.30 (m, 6H), 7.21 (d, J=9.4 Hz, 1H), 7.03 (td, J=8.6, 3.6 Hz, 1H), 4.69-4.63 (m, 1H), 4.10-4.00 (m, 2H), 3.53-3.45 (m, 3H), 2 protons hidden under H ₂ O peak, 0.98 (d, J=7.2 Hz, 3H). UPLC MS 1: mass/charge 464.3 [M+H] ⁺ ; t _R =0.89 min.

Another diastereoisomer, 2-(2-((2S,3S,4R)-2-(aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3,4-difluorophenoxy)ethan-1-ol: UPLC MS 1: m/z 464.3 [M+H] ⁺ ; t _R =0.80 min.

Example 125. 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

The title compound was prepared analogously to the alternative synthesis of Example 114a from the intermediates ((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 (C-XIX) and 2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV). Reductive amination of the intermediate aldehyde with methylamine hydrochloride was carried out as described for Example 122 and the methylamine was kept unprotected. The benzyl protecting group was cleaved in the last step. ^1H NMR (600 MHz, DMSO - _d6 ) δ (ppm) 7.72 (sbr, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.36 (sbr, 1H), 7.29 (t, J=8.5 Hz, 1H), 7.11 (s, 1H), 7.08 (d, J=9.4 Hz, 1H), 6.35-6.00 (br, 2H), 3.90 (s, 3H), 3.30-3.15 (m, 2H), 2.99 (d, J=12.8 Hz, 1H), 2.22 (s, 3H), 0.87 (d, J=6.7 Hz, 3H). UPLC-MS 1: mass/charge 490.1 [M+H] ⁺ , t _R =0.63 min.

Diastereoisomers were separated before removal of the benzyl protecting group. 2-((2R,3S,4S)-2-(6-(Benzyloxy)pyridin-2-yl)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide: UPLC-MS 1: m/z 580.4 [M+H] ⁺ , t _R = 0.94 min; 2-((2R,3S,4R)-2-(6-(benzyloxy)pyridin-2-yl)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide: UPLC-MS 1: m/z 580.2 [M+H] ⁺ , t _R = 0.83 min.

Example 126. 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

The title compound was prepared analogously to Example 5a from (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-methylcyclohexan-1-ol (C-XX) and 2-bromo-3-fluoro-4-(2-methoxyethoxy)benzonitrile (N-IX) by a Suzuki coupling reaction followed by hydrolysis of the nitrile to the corresponding amide and separation of the diastereoisomers.

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 (Example 126): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.55-8.53 (m, 1H), 7.75 (td, J=7.7, 1.8 Hz, 1H), 7.67 (s, 1H), 7.58-7.56 (m, 1H), 7.50-7.48 (m, 1H), 7.37-7.23 (m, 2H), 7.19-6.99 (m, 2H), 4.31-4.16 (m, 2H), 4.00 (s, 1H), 3.68-3.66 (m, 2H), 3.53 (q, J=7.0 Hz, 1H), 3.29 (s, 3H), 3.13-3.11 (m, 2H), 2.30-2.23 (m, 1H), 1.69-0.82 (m, 15H). UPLC-MS 1: mass/charge 616.3 [M+H] ⁺ , t _R =0.72 min.

Another diastereoisomer, 2-((2R,3S,4R)-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: UPLC-MS 1: m/z 616.3 [M+H] ⁺ , t _R = 0.68 min.

Example 127. 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

The title compound was prepared analogously to example 5a from (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-methylcyclohexan-1-ol (C-XXI) and 2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV) via a Suzuki coupling reaction followed by hydrolysis of the nitrile to the corresponding amide and separation of the diastereoisomers.

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 (Example 127) : ^1H NMR (600 MHz, DMSO- d ₆ ) δ (ppm) 8.62 (d, J=1.8 Hz, 1H), 8.45 (dd, J=4.7, 1.3 Hz, 1H), 7 ,82-7.79 (m, 1H), 7.72 (s br, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.34 (dd, J=7.8, 4.9 Hz, 1H), 7.28 (t, J=8.5 Hz, 1H), 7.11 (d, J=9.5 Hz, 1H), 7.10 (s br, 1H), 4.04 (s, 1H), 3.88 (s, 3H), 3.23 (q, J=7.0 Hz, 1H), 3.15-3.08 (m, 2H), 2.31-2.25 (m, 1H), 1.64-1.59 (m, 1H), 1.59-1.54 (m, 1H ), 1.36-1.31 (m, 1H), 1.28-1.22 (m, 1H), 1.20-1.11 (m, 2H), 1.09-0.97 (m, 2H), 0.96 (s, 3H), 0.94 (d, J=7.1 Hz, 3H). UPLC-MS 1: m/z 572.2 [M+H] ⁺ , t _R =0.68 min.

Another diastereoisomer, 2-((2S,3S,4R)-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: UPLC-MS 1: m/z 572.2 [M+H] ⁺ , t _R = 0.67 min.

Example 128. 2-((2S,4R)-2-(Aminomethyl)-2-phenyl-5-(trifluoromethyl)-2,3-dihydrobenzofuran-4-yl)-4-methoxybenzamide

The title compound was prepared analogously to Example 5a, starting from 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 (C-XXII) and 2-bromo-4-methoxybenzonitrile.

2-((2S,4R)-2-(Aminomethyl)-2-phenyl-5-(trifluoromethyl)-2,3-dihydrobenzofuran-4-yl)-4-methoxybenzamide (Example 128): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.64 (d, J=8.6 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.43 (s br, 1H), 7.39-7.29 (m, 4H), 7.27-7.22 (m, 1H), 7.02-6.95 (m, 3H), 6.58 (d, J=2.7 Hz, 1H), 3.71 (s, 3H), 3.31 (d, J=16.4 Hz, 1H), 2.91-2.79 (m, 3H), 1.36 (s br, 2H). UPLC-MS 1: m/z 443.2 [M+H] ⁺ , t _R =0.89 min.

Another diastereoisomer, 2-((2S,4S)-2-(aminomethyl)-2-phenyl-5-(trifluoromethyl)-2,3-dihydrobenzofuran-4-yl)-4-methoxybenzamide: UPLC-MS 1: m/z 443.2 [M+H]+, t _R= 0.69.

Example 129. 2-((2S,4R)-5-Cyano-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxy-N-methylbenzamide

The title compound was prepared analogously to Example 121 from (S)-2-(hydroxymethyl)-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-5-carbonitrile (C-XXIII) and methyl 2-bromo-3-fluoro-4-methoxybenzoate (N-XXVI). UPLC-MS 1: m/z 544.4 [M+H] ⁺ , t _R = 0.77 min. According to UPLC-MS, no other diastereoisomer was formed.

Example 130. (S)-2-((((trans)-4-Hydroxycyclohexyl)amino)methyl)-2,4-diphenyl-2,3-dihydrobenzofuran-5-carbonitrile

To a stirred solution of (S)-4-bromo-2-((((trans)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-5-carbonitrile (C-XXIV) (120 mg, 0.281 mmol), phenylboronic acid (51.4 mg, 0.421 mmol) and K ₃ PO ₄ (238 mg, 1.123 mmol) in dioxane (4 mL) and H ₂ O (1.3 mL) was added the adduct PdCl ₂ (dppf).CH ₂ Cl ₂ (22.9 mg, 0.028 mmol). The reaction mixture was stirred at 100 °C for 1 h. The reaction mixture was quenched by addition of saturated NaHCO ₃ solution and extracted with EtOAc. The combined organic layers were washed with saturated _NaHCO3 solution, dried over _{anhydrous Na2SO4} and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc; gradient from 0% to 100% EtOAc) to give the title compound (103 mg) as a colorless foam. ¹ H NMR (400 MHz, DMSO -d6 ) δ 7.75 (d, J=8.3 Hz, 1H), 7.57-7.39 (m, 7H), 7.38-7.23 (m, 3H), _7.09 (d, J=8.3 Hz, 1H), 4.40 (d, J=4.4 Hz, 1H), 3.73 (d, J=16.1 Hz, 1H), 3.17-2.87 (m, 3H), 2.65-2.43 (m, 1H), 2.29-2.14 (m, 1H), 1.83-1.58 (m, 4H), 1.12-0.84 (m, 4H). UPLC-MS 1: mass/charge 425.3 [M+H] ⁺ , t _R =0.79 min.

Example 131. 2-((2S,4S)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-3-fluorobenzamide

The title compound was prepared analogously to Example 5a from the intermediates tert-butyl (S)-((4-bromo-5-chloro-2-phenyl-2,3-dihydrofuro[2,3-b]pyridin-2-yl)methyl)carbamate (C-XXV) and 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile. SPhos-Pd-G2 was used in the Suzuki coupling reaction. Racemic diastereoisomers were separated after hydrolysis of the nitrile to the amide by SFC (Reprospher PEI 250×30 mm, 5 μm, CO ₂ /MeOH from 15% to 25% over 10 min, flow rate: 30 mL/min): tert-butyl (((2S,4S)-4-(2-carbamoyl-6-fluorophenyl)-5-chloro-2-phenyl-2,3-dihydrofuro[2,3-b]pyridin-2-yl)methyl)carbamate: UPLC-MS 1 m/z 498.4 [M+H] ⁺ , t _R = 1.09 min, and tert-Butyl (((2S,4R)-4-(2-carbamoyl-6-fluorophenyl)-5-chloro-2-phenyl-2,3-dihydrofuro[2,3-b]pyridin-2-yl)methyl)carbamate: UPLC-MS 1 m/z 498.4 [M+H] ⁺ , t _R =1.03 min.

tert-Butyl (((2S,4S)-4-(2-carbamoyl-6-fluorophenyl)-5-chloro-2-phenyl-2,3-dihydrofuro[2,3-b]pyridin-2-yl)methyl)carbamate was deprotected with Boc to give the title compound.

2-((2S,4S)-2-(Aminomethyl)-5-chloro-2-phenyl-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-3-fluorobenzamide (Example 131): ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm 8.07 (s, 1H), 7.97 (s, 1H), 7.67-7.26 (m, 9H), 3.58 (d, J =16.8 Hz, 1H), 2.98 (d, J =16.8 Hz, 1H), 2.93 (s, 2H). UPLC-MS 1 m/z 398.3 [M+H] ⁺ , t _R =0.68 min.

Example 132. 2-(2-(Aminomethyl)-6-chloro-2-phenyl-2,3-dihydrobenzofuran-7-yl)-3-fluoro-4-methoxybenzamide

The title compound was prepared analogously to Example 5a from the intermediates 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 (C-XXVI) and 2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV).

After final removal of the Boc protecting group, the racemic diastereoisomers were first separated by preparative HPLC (SunFire RP18 30×100 mm, eluent: ACN/water): racemic diastereoisomer 1: UPLC-MS 1: t _R = 0.81 min, racemic diastereoisomer 2: UPLC-MS 1: t _R = 0.63 min. Racemic diastereoisomer 1 was subjected to chiral HPLC (Chiralpak AS-H 250×20 mm, 5 μm, heptane/EtOH 6:4+0.1% DEA, flow rate: 10 mL/min) to afford both enantiomers with an enantiomeric excess of >97%.

2-(2-(Aminomethyl)-6-chloro-2-phenyl-2,3-dihydrobenzofuran-7-yl)-3-fluoro-4-methoxybenzamide of unknown absolute configuration (Example 132): chiral HPLC (Chiralpak AS-H 250×4.6 mm, 5 μm, heptane/EtOH 6:4+0.1% DEA, flow rate: 1 mL/min), t _R = 8.11 min. ^1H NMR (400 MHz, DMSO - _d6 ) δ 7.63 (sbr, 1H), 7.47 (dd, J=8.6, 1.5 Hz, 1H), 7.36-7.17 (m, 7H), 7.17-7.07 (m, 2H), 6.92 (d, J=7.8 Hz, 1H), 3.93 (s, 3H), 3.79 (d, J=16.0 Hz, 1H), 3.19 (d, J=16.0 Hz, 1H), 2.96-2.78 (m, 2H). UPLC-MS 1: mass/charge 434.2 [M+H] ⁺ , t _R =0.68 min.

The other enantiomer, 2-(2-(aminomethyl)-6-chloro-2-phenyl-2,3-dihydrobenzofuran-7-yl)-3-fluoro-4-methoxybenzamide with unknown absolute configuration: chiral HPLC (Chiralpak AS-H 250×4.6 mm, 5 μm, heptane/EtOH 6:4+0.1% DEA, flow rate: 1 mL/min), t _R = 14.17 min.

Example 133. 2-(2-(Aminomethyl)-5-chloro-2-phenylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzamide

The title compound was prepared analogously to Example 5a from the intermediates tert-butyl ((4-bromo-5-chloro-2-phenylbenzo[d][1,3]dioxol2-yl)methyl)carbamate (C-XXVII) and 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile. SPhos-Pd-G2 was used in the Suzuki coupling reaction. Racemic diastereoisomers of tert-butyl ((5-chloro-4-(2-cyano-6-fluorophenyl)-2-phenylbenzo[d][1,3]dioxol-2-yl)methyl)carbamate were separated after Suzuki coupling by flash chromatography (silica, heptane/EtOAc; gradient 0% to 30% EtOAc). Racemic diastereoisomer 1: ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm 7.97-7.72 (m, 3H), 7.59-7.34 (m, 4H), 7.23-7.03 (m, 3H), 3.65 (s, 2H), 1.25 (s, 9H). UPLC-MS 1: mass/charge 481.3 [M+H] ⁺ , t _R =1.29 min. Racemic diastereoisomer 2: ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm 7.96-7.71 (m, 3H), 7.57-7.37 (m, 4H), 7.13 (td, J =17.4, 7.4 Hz, 3H), 3.65 (qd, J =15.1, 6.5 Hz, 2H), 1.27 (s, 9H). UPLC-MS 1: mass/charge 481.3 [M+H] ⁺ , t _R =1.34 min. The racemic diastereoisomer 2 was converted to the corresponding amide and the enantiomers of tert-butyl ((4-(2-carbamoyl-6-fluorophenyl)-5-chloro-2-phenylbenzo[d][1,3]dioxol-2-yl)methyl)carbamate were separated by chiral HPLC (Chiralcel OD-H 250×20 mm, 5 μm, heptane/EtOH/MeOH 90:5:5, flow rate: 10 mL/min).

Enantiomer 1: chiral HPLC (Chiralcel OD-3 100×2 mm, 3 µm, heptane/EtOH/MeOH 85:7.5:7.5, flow rate: 0.42 mL/min), t _R = 2.37 min.

Enantiomer 2: chiral HPLC (Chiralcel OD-3 100×2 mm, 3 µm, heptane/EtOH/MeOH 85:7.5:7.5, flow rate: 0.42 mL/min), t _R = 4.67 min.

Enantiomer 1 was deprotected with Boc to give the title compound of unknown absolute configuration. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm 7.87 (s, 1H), 7.65-7.36 (m, 9H), 6.94 (qd, J = 8.4, 1.8 Hz, 2H), 3.17-3.00 (m, 2H). UPLC-MS m /z 399.3 [M+H] ⁺ , t _R = 0.76 min. Chiral HPLC: (CHIRALPAK IA; heptane/DCM/EtOH 65:30:5, flow: 1 mL/min) t _R = 11.2 min, >99% ee.

Example 134. 2-((2S,4S)-2-(Aminomethyl)-5-chloro-6-fluoro-2-phenylindolin-4-yl)-3-fluorobenzamide

Reaction scheme for example 134

Step 1. 2-((2S,4S)-2-(Azidomethyl)-5-chloro-6-fluoro-2-phenylindolin-4-yl)-3-fluorobenzonitrile and 2-((2S,4R)-2- (azidomethyl)-5-chloro-6-fluoro-2-phenylindolin-4-yl)-3-fluorobenzonitrile

A mixture of (S)-2-(azidomethyl)-4-bromo-5-chloro-6-fluoro-2-phenylindoline (C-XXVIII) (645 mg, 1.69 mmol), 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (CAS 62741-47-5) (590 mg, 2.388 mmol), K ₃ PO ₄ (3.4 mL, 5.10 mmol, 1.5 M in water) and SPhos Pd G2 catalyst (140 mg, 0.194 mmol) suspended in THF (10 mL) was purged with Ar then stirred for 6 h at 90 °C. Water was added and the mixture was extracted with EtOAc. The aqueous layer was back extracted with EtOAc. The organic layers were washed with water and brine, combined, dried over _{anhydrous Na2SO4} and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAC from 5% to 22% EtOAc) to afford separated diastereoisomers.

2-((2S,4S)-2-(Azidomethyl)-5-chloro-6-fluoro-2-phenylindolin-4-yl)-3-fluorobenzonitrile (156 mg): UPLC-MS 1: wt/charge 422, 1/424.2 [M+H] ⁺ , t _R =1.27 min.

2-((2S,4R)-2-(Azidomethyl)-5-chloro-6-fluoro-2-phenylindolin-4-yl)-3-fluorobenzonitrile (217 mg): UPLC-MS 1: wt/charge 422, 2/424.1 [M+H] ⁺ , t _R =1.25 min.

Step 2 . 2-((2S,4S)-2-(Azidomethyl)-5-chloro-6-fluoro-2-phenylindolin-4-yl)-3-fluorobenzamide

The title compound (105 mg) was prepared from 2-((2S,4S)-2-(azidomethyl)-5-chloro-6-fluoro-2-phenylindolin-4-yl)-3-fluorobenzonitrile (150 mg, 0.36 mmol) using reaction conditions similar to those described for Example 5a, step 2. UPLC-MS 1: m/z 440.1/442.1 [M+H] ⁺ , t _R = 1.11 min.

Step 3. 2-((2S,4S)-2-(Aminomethyl)-5-chloro-6-fluoro-2-phenylindolin-4-yl)-3-fluorobenzamide (Example 134)

To a stirred solution of 2-((2S,4S)-2-(azidomethyl)-5-chloro-6-fluoro-2-phenylindolin-4-yl)-3-fluorobenzamide (100 mg, 0.227 mmol) in THF (5 mL) cooled to 0 °C was added trimethylphosphine (0.4 mL, 0.364 mmol, 1 M in THF) followed by water (0.1 mL). The reaction mixture was stirred at rt for 1.5 h. 5% NaHCO ₃ solution was added and the mixture was extracted with EtOAc. The organic phase was washed twice with brine. The aqueous layers were back extracted with EtOAc. The combined organic phases were dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, DCM/MeOH, gradient: 0% to 20% MeOH) to give the title compound (80 mg). UPLC-MS 1: m/z 414.2/416.2 [M+H] ⁺ , t _R = 0.77 min. ¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm) 7.51-7.45 (m, 2H), 7.35-7.30 (m, 4H), 7.25-7.20 (m, 2H), 6.59 (d, J=9.4 Hz, 1H), 6.25 (br s, 1H), 5.84 (br s, 1H), 5.61 (br s, 1H), 3.12 (d, J=12.9 Hz, 1H), 3.10-3.00 (m, 2H), 2.90 (dd, J=16.2, 1.9 Hz, 1H). The absolute configuration was confirmed by X-ray diffraction analysis of a cocrystal of example 134 bound to the YAP binding site of TEAD4.

The following examples were obtained in a similar manner to the previous examples.

Example 135. 2-((2S,4S)-5-Chloro-2-((cyclohexylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide

UPLC-MS 1: mass/charge 545.2 [M+H] ⁺ , t _R =1.03 min.

Example 136a and Example 136b. 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 and 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

Examples 136a and 136b have cis and trans configurations at the cyclohexyl ring, respectively. The absolute stereochemistry at the cyclohexyl ring has not been determined for the corresponding examples.

Example 136a: UPLC-MS 1: mass/charge 609.2 [M+H] ⁺ , t _R =0.94 min.

Example 136b: UPLC-MS 1: mass/charge 609.2 [M+H] ⁺ , t _R =0.96 min.

Example 137a and Example 137b. 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 (Example 137a) and 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 (Example 137b)

Example 137a: UPLC-MS 1: mass/charge 555.2 [M+H] ⁺ , t _R =0.99 min.

Example 137b: UPLC-MS 1: mass/charge 555.2 [M+H] ⁺ , t _R =0.96 min.

Example 138a and Example 138b. 2-((2S,4S)-2-((((Trans)-4-carbamoylcyclohexyl)amino)methyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide ( example 138a) and 2-((2S,4S)-2-((((cis)-4-carbamoylcyclohexyl)amino)methyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide ( example 138b)

Example 138a: UPLC-MS 1: mass/charge 522.3 [M+H] ⁺ , t _R =0.82 min.

Example 138b: UPLC-MS 1: mass/charge 522.3 [M+H] ⁺ , t _R =0.80 min.

Example 139a and Example 139b. 2-((2S,4S)-5-Chloro-2-((((trans)-4-(methylcarbamoyl)cyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3 -fluorobenzamide (example 139a) and 2-((2S,4S)-5-chloro-2-((((cis)-4-(methylcarbamoyl)cyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3 -fluorobenzamide (example 139b)

Example 139a: UPLC-MS 1: m/z 536.3 [M+H] ⁺ , t _R =0.81 min.

Example 139b: UPLC-MS 1: m/z 536.3 [M+H] ⁺ , t _R =0.85 min.

Example 140a and Example 140b. 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 and 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

Examples 140a and 140b have cis and trans configurations on the cyclobutyl ring, respectively. The absolute stereochemistry on the cyclobutyl ring for the corresponding examples has not been determined.

Example 140a: UPLC-MS 1: mass/charge 579.2 [M+H] ⁺ , t _R =0.76 min.

Example 140b: UPLC-MS 1: mass/charge 579.2 [M+H] ⁺ , t _R =0.79 min.

Example 141. 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

UPLC-MS 1: mass/charge 493.3 [M+H] ⁺ , t _R =0.72 min.

Example 142. 2-((2S,4S)-5-Chloro-6-fluoro-2-(((methyl-d3)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide

UPLC-MS 1: mass/charge 498.3 [M+H] ⁺ , t _R =0.84 min.

Example 143. 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

UPLC-MS 1: mass/charge 496.4 [M+H] ⁺ , t _R =0.67 min.

Example 144. 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 (2P)-2-{(2S,3S)-5-chloro-6-fluoro-3-methyl-2-[(methylamino)methyl]-2-phenyl-2,3-dihydro-1-benzofuran-4-yl}-3-fluoro-4-methoxybenzamide

Reaction scheme for example 144

Step 1. tert-Butyl-(((2S,3S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-6-fluoro-3-methyl-2-phenyl-2 ,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl-(((2S,3S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-6-fluoro-3-methyl-2-phenyl-2,3- dihydrobenzofuran-2-yl)methyl)(methyl)carbamate

To a stirred solution of 2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV) (12.77 g, 55.5 mmol), N-XantPhos (2.55 g, 4.63 mmol), Pd ₂ dba ₃ (2.12 g, 2.31 mmol) and K ₃ PO ₄ (29.5 g, 139 mmol) in toluene (100 mL) and water (40 mL) was added a solution of 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 (C-XXIX) (30 g, 46.3 mmol) in toluene (40 mL) at 100 °C. After stirring at 100 °C for 3 days, the crude mixture was diluted in water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, EtOAc/heptane, gradient 0% to 60% EtOAc) to give a mixture of the title compounds (12.86 g) as a yellow foam. UPLC-MS 1: m/z 499.2 [M+2H-tBu] ⁺ , t _R = 1.42 min and 1.44 min.

Step 2. tert-Butyl-(((2S,3S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2 ,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl(((2S,3S,4R)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran -2-yl)methyl)(methyl)carbamate

To a stirred solution of a mixture of tert-butyl (((2S,3S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl (((2S,3S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (12.86 g, 22.94 mmol) in EtOH (150 mL) and water (50 mL) was added hydrido(dimethylphosphinic acid-kP)[hydrogen-bis(dimethylphosphinito-kP)]platinum(II) (CAS 173416-05-2) (0.985 g, 2.29 mmol) and the reaction mixture was stirred at 80 °C for 2 h. The crude mixture was concentrated, then diluted in EtOAc and water and extracted with EtOAc. The organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude products were purified by flash chromatography (silica, EtOAc/heptane, gradient 0% to 100% EtOAc) to give a mixture of the title compounds (12.5 g) as a colorless foam. UPLC-MS 1: m/z 473.2 [M+H-BOC] ⁺ , t _R = 1.25 min and 1.27 min.

Step 3. 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 (2 P )-2-{(2 S ,3 S )-5-chloro-6-fluoro-3-methyl-2-[(methylamino)methyl]-2-phenyl-2,3-dihydro-1-benzofuran-4-yl}-3-fluoro-4-methoxybenzamide ( example 144)

To a stirred solution of a mixture of tert-butyl (((2S,3S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl (((2S,3S,4R)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (12.5 g, 21.81 mmol) in DCM (120 mL) was added TFA (60 mL, 779 mmol) at rt. After 30 min, the reaction was complete and the reaction mixture was slowly added to sat. NaHCO ₃ solution. The mixture was extracted with DCM and the combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, (7 N ammonia in MeOH)/DCM, gradient from 0% to 8% (7 N ammonia in MeOH)) to afford separated diastereoisomers as colorless foams.

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 (2 P )-2-{(2 S ,3 S )-5-chloro-6-fluoro-3-methyl-2-[(methylamino)methyl]-2-phenyl-2,3-dihydro-1-benzofuran-4-yl}-3-fluoro-4-methoxybenzamide (Example 144) (4.82 g) ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 7.68-7.55 (m, 2H), 7.48-7.39 (m, 2H), 7.39-7.22 (m, 4H), 7.13 (s, 1H), 7.06 (d, J=9.5 Hz, 1H), 3.89 (s, 3H), 3.25 (q, J=7.1 Hz, 1H), 3.12-2.96 (m, 2H), 2.18 (s, 3H), 1.10 (s br, 1H), 0.92 (d, J=7.1 Hz, 3H). UPLC-MS 1: m/z 473.2 [M+H] ⁺ , t _R =0.77 min. The absolute configuration was confirmed by X-ray diffraction analysis of a cocrystal of example 144 bound to the YAP binding site of TEAD4.

Another diastereoisomer, 2-((2S,3S,4R)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (4.37 g): UPLC-MS 1: m/z 473.2 [M+H] ⁺ , t _R = 0.69 min.

Example 145. 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 (4P)-4-{(2S,3S)-5-chloro-6-fluoro-3-methyl-2-[(methylamino)methyl]-2-phenyl-2,3-dihydro-1-benzofuran-4-yl}-5-fluoro-6-(2-hydroxyethoxy)-N-methylpyridine-3-carboxamide

Reaction scheme for example 145

Step 1. Methyl 4-((2S,3S,4S)-2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate and methyl 4-((2S,3S,4R)-2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate

To a stirred solution of methyl 4-chloro-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate (N-XXXI) (2.347 g, 7.03 mmol), N-XantPhos (0.323 g, 0.586 mmol), Pd ₂ dba ₃ (0.268 g, 0.29 mmol), and K ₃ PO ₄ (3.73 g, 17.58 mmol) in toluene (15 mL) and water (5 mL) was added a solution of 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 (C-XXIX) (3.667 g, 5.86 mmol) in toluene (10 mL) at 100 °C and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, EtOAc/heptane, gradient 0% to 50% EtOAc) to give a mixture of the title compounds (1.7 g) as a yellow foam. UPLC-MS 1: m/z 703.3 [M+H] ⁺ , t _R = 1.52 min.

Step 2. 4-((2S,3S,4S)-2-(((tert-Butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinic acid and 4-((2S,3S,4R)-2-(((tert-Butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinic acid

To a stirred solution of a mixture of methyl 4-((2S,3S,4S)-2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate and methyl 4-((2S,3S,4R)-2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate (1.7 g, 2.03 mmol) in THF (10 mL) and MeOH (10 mL) were added sodium hydroxide (10 mL, 20.0 mmol, 2 N in water) at rt and the reaction mixture was stirred at rt for 15 min, then at 50 °C for 1 h. THF and MeOH were evaporated and the resulting aqueous phase was acidified to pH 3-4 with 2 N HCl. The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with brine, dried over _{anhydrous Na2SO4} and concentrated. The crude product was purified by flash chromatography (silica, EtOAc/heptane, gradient from 0% to 100% EtOAc) to give a mixture of the title compounds (1.49 g) as a yellow foam. UPLC-MS 1: m/z 689.3 [M+H] ⁺ , t _R =1.37 min. and 1.39 min.

Step 3. tert-Butyl (((2S,3S,4S)-5-chloro-6-fluoro-4-(3-fluoro-5-(methylcarbamoyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl (((2S,3S,4R)-5-chloro-6-fluoro-4-(3-fluoro-5-(methylcarbamoyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate

To a stirred suspension of a mixture of 4-((2S,3S,4S)-2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinic acid and 4-((2S,3S,4R)-2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinic acid (1.489 g, 1.75 mmol), methylamine To a mixture of 1.0 g of ethyl acetate (0.591 g, 8.75 mmol) and TBTU (0.843 g, 2.63 mmol) in _DMF (12 mL) was added DIPEA (1.22 mL, 7.0 mmol) at rt and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted in water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, EtOAc/heptane, gradient 0% to 100% EtOAc) to give a mixture of the title compounds (1.5 g) as a colorless foam. UPLC-MS 1: m/z 702.8 [M+H] ⁺ , t _R =1.43 min. and 1.44 min.

Step 4. 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 (4 P )-4-{(2 S ,3 S )-5-chloro-6-fluoro-3-methyl-2-[(methylamino)methyl]-2-phenyl-2,3-dihydro-1-benzofuran-4-yl}-5-fluoro-6-(2-hydroxyethoxy) -N- methylpyridine-3-carboxamide (Example 145)

To a stirred solution of a mixture of tert-butyl (((2S,3S,4S)-5-chloro-6-fluoro-4-(3-fluoro-5-(methylcarbamoyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl (((2S,3S,4R)-5-chloro-6-fluoro-4-(3-fluoro-5-(methylcarbamoyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (1.5 g, To a solution of 1.47 mmol) in DCM (15 mL), TFA (10 mL, 130 mmol) was added at 0 °C and the reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was added to a saturated NaHCO ₃ solution and extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude products were purified by flash chromatography (silica, (7N ammonia in MeOH)/DCM, gradient 0% to 10% (7N ammonia in MeOH)) to give a colorless foam which was further purified by preparative HPLC (XBridge-C18 5 μm, 50×250 mm), eluent A: _H2O +0.1% TFA, eluent B: _CH3CN , gradient: 11% to 31% B over 21 min, flow rate: 100 mL/min). The collected fractions were debasified with sat. _NaHCO3 solution, acetonitrile was evaporated and the resulting _aqueous phases were extracted with DCM, the combined organic extracts were washed with brine, dried over anhydrous _Na2SO4 and concentrated to give the separated diastereoisomers as colorless solids.

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, (4 P )-4-{(2 S ,3 S )-5-chloro-6-fluoro-3-methyl-2-[(methylamino)methyl]-2-phenyl-2,3-dihydro-1-benzofuran-4-yl}-5-fluoro-6-(2-hydroxyethoxy)- N -methylpyridine-3-carboxamide (Example 145) (394 mg): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.44 (d, J=4.6 Hz, 1H), 8.31 (s, 1H), 7.47-7.39 (m, 2H), 7.38-7.32 (m, 2H), 7.30-7.24 (m, 1H), 7.13 (d, J=9.6 Hz, 1H), 4.90 (t, J=5.4 Hz, 1H), 4.55-4.29 (m, 2H), 3.74 (q, J=5.1 Hz, 2H), 3.39-3.26 (m, 1H), 3.14-2.97 (m, 2H), 2.66 (d, J=4.4 Hz, 3H), 2.20 (s, 3H), 0.98 (d, J=7.1 Hz, 3H). UPLC-MS 1: mass/charge 518.5 [M+H] ⁺ , t _R =0.66 min.

Another diastereoisomer, 4-((2S,3S,4R)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide (30 mg): UPLC-MS 1: m/z 518.5 [M+H] ⁺ , t _R = 0.63 min.

Example 146. 2-((2S,3R,4S)-5-Chloro-6-fluoro-3-(methoxymethyl)-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide

Reaction scheme for example 146

Step 1. tert-Butyl-(((2S,3R,4S)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-6-fluoro-3-(methoxymethyl)-2-phenyl -2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl-(((2S,3R,4R)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-6-fluoro-3-(methoxymethyl)-2-phenyl-2, 3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate

To a stirred solution of 2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV) (0.422 g, 1.84 mmol), N-XantPhos (0.084 g, 0.153 mmol), Pd ₂ dba ₃ (0.070 g, 0.076 mmol) and K ₃ PO ₄ (0.974 g, 4.59 mmol) in toluene (9 mL) and water (3 mL) was added a solution of 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 (C-XXX) (1.074 g, 1.53 mmol) in toluene (6 mL) at 105 °C and the reaction mixture was stirred at 105 °C for 6.5 h. The crude mixture was diluted in EtOAc and water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient 0% to 50% EtOAc) to give a mixture of the title compounds (620 mg) as a colorless foam. UPLC-MS 1: m/z 585.5 [M+H] ⁺ , t _R = 1.41 min.

Step 2. tert-Butyl-(((2S,3R,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro-3-(methoxymethyl)-2-phenyl -2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl-(((2S,3R,4R)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro-3-(methoxymethyl)-2-phenyl-2, 3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate

To a stirred solution of a mixture of tert-butyl (((2S,3R,4S)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-6-fluoro-3-(methoxymethyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl (((2S,3R,4R)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-6-fluoro-3-(methoxymethyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (620 mg, 1.04 mmol) in EtOH (6 mL) and water (2 mL) was added hydrido(dimethylphosphinic acid) acid-kP)[hydrogen-bis(dimethylphosphinito-kP)]platinum(II) (CAS 173416-05-2) (89 mg, 0.21 mmol) was added and the reaction mixture was stirred at 85 °C for 1.5 h. The crude mixture was diluted in EtOAc and water and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous _Na2SO4 and concentrated. The residue was diluted in MeOH and passed through a PL-thiol _MP resin cartridge (Agilent, StratoSpheres SPE) to remove trace metals. Concentration afforded a yellow oil. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient 0% to 100% EtOAc) to give a mixture of the title compounds (600 mg) as a colourless foam. UPLC-MS 1: m/z 603.5 [M+H] ⁺ , t _R = 1.25 min.

Step 3. 2-((2S,3R,4S)-5-Chloro-6-fluoro-3-(methoxymethyl)-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 146)

To a stirred solution of a mixture of tert-butyl (((2S,3R,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro-3-(methoxymethyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl (((2S,3R,4R)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro-3-(methoxymethyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (600 mg, 0.995 mmol) in DCM (3 mL) was added TFA (3 mL, 38.9 mmol) at rt and the reaction mixture was stirred at rt for 15 min. The reaction mixture was added to sat. _NaHCO3 solution and extracted with DCM, the combined organic extracts were washed with brine, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica, (7N DCM/ _ammonia in MeOH), gradient 0% to 10% (7N ammonia in MeOH)) to give a colorless foam, which was further purified by preparative HPLC (Waters X-Bridge C18 OBD, 5 μm, 30 * 100 mm, eluent A: _H2O + 7.3 mM _NH4OH , B:ACN, gradient: 15% to 60% B over 25 min, hold for 1 min, flow rate 40 mL/min). The collected fractions were basified with sat. NaHCO ₃ solution, acetonitrile was evaporated and the resulting aqueous phases were extracted with DCM. The organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give the separated diastereoisomers as colorless powders.

2-((2S,3R,4S)-5-Chloro-6-fluoro-3-(methoxymethyl)-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 146) (211 mg): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.61 (dd, J=8.6, 1.4 Hz, 1H), 7.41 (s, 1H), 7.38-7.22 (m, 6H), 7.16 (s, 1H), 7.12 (d, J=9.6 Hz, 1H), 3.88 (s, 3H), 3.53 (dd, J=10.6, 8.3 Hz, 1H), 3.39 (dd, J=8.2, 2.9 Hz, 1H), 3.23 (dd, J=10.6, 3.0 Hz, 1H), 3.18 (s, 2H), 2.98 (s, 3H), 2.19 (s, 3H), 1.43-0.89 (m, 1H). UPLC-MS 1: m/z 503.5 [M+H] ⁺ , t _R =0.77 min.

Another diastereoisomer, 2-((2S,3R,4R)-5-chloro-6-fluoro-3-(methoxymethyl)-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (140 mg): UPLC-MS 1: m/z 503.5 [M+H] ⁺ , t _R = 0.70 min.

Example 147. 2-((2S,3R,4S)-5-Chloro-6-fluoro-3-(hydroxymethyl)-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide

Reaction scheme for example 147

Step 1. tert-Butyl-(((2S,3R,4S)-3-((benzyloxy)methyl)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-6-fluoro- 2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl-(((2S,3R,4R)-3-((benzyloxy)methyl)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-6-fluoro-2-phenyl -2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate

To a stirred solution of 2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV) (387 mg, 1.682 mmol), N-XantPhos (CAS 261733-18-0) (46.4 mg, 0.084 mmol), Pd ₂ dba ₃ (38.5 mg, 0.042 mmol), and K ₃ PO ₄ (714 mg, 3.36 mmol) in toluene (9 mL) and water (3 mL) was added a solution of 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 (C-XXXI) (745 mg, 0.841 mmol) in toluene (6 mL) at 105 °C and the reaction mixture was stirred at 105 °C for 6 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient 0% to 50% EtOAc) to give a mixture of the title compounds (380 mg) as a colourless foam. UPLC-MS 1: m/z 661.7 [M+H] ⁺ , t _R = 1.51 min and 1.52 min.

Step 2. tert-Butyl-(((2S,3R,4S)-3-((benzyloxy)methyl)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro- 2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl-(((2S,3R,4R)-3-((benzyloxy)methyl)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro-2-phenyl -2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate

To a stirred solution of a mixture of tert-butyl (((2S,3R,4S)-3-((benzyloxy)methyl)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl (((2S,3R,4R)-3-((benzyloxy)methyl)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (380 mg, 0.55 mmol) in EtOH (6 mL) and water (2 mL) was added hydrido(dimethylphosphinic acid) acid-kP)[hydrogen-bis(dimethylphosphinito-kP)]platinum(II) (CAS 173416-05-2) (47.4 mg, 0.11 mmol) was added and the reaction mixture was stirred at 85 °C for 1.5 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was diluted in MeOH and passed through a PL-thiol MP resin cartridge (Agilent, StratoSpheres SPE) to remove trace metals. Concentration afforded a yellow oil. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient 50% to 100% EtOAc) to give a mixture of the title compounds (370 mg) as a colourless foam. UPLC-MS 1: m/z 679.6 [M+H] ⁺ , t _R = 1.33 min and 1.36 min.

Step 3. tert-Butyl-(((2S,3R,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro-3-(hydroxymethyl)-2-phenyl -2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl-(((2S,3R,4R)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro-3-(hydroxymethyl)-2-phenyl-2, 3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate

To a stirred solution of a mixture of tert-butyl (((2S,3R,4S)-3-((benzyloxy)methyl)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl (((2S,3R,4R)-3-((benzyloxy)methyl)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (370 mg, 0.54 mmol) in MeOH (10 mL) was added Pd-C (50 mg, 0.470 mmol, 10 wt%) at rt. and the reaction mixture was stirred under atmospheric pressure _H2 for 2 h at rt. More Pd-C (50 mg, 0.470 mmol, 10 wt%) was added and stirring under atmospheric pressure _H2 at rt was continued for 2 h. The reaction mixture was filtered over Hyflo and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient from 50% to 100% EtOAc) to give a mixture of the title compounds (298 mg) as a colorless foam. UPLC-MS 1: m/z 589.5 [M+H] ⁺ , t _R = 1.14 min and 1.22 min.

Step 4. 2-((2S,3R,4S)-5-Chloro-6-fluoro-3-(hydroxymethyl)-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 147)

To a stirred solution of a mixture of tert-butyl (((2S,3R,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro-3-(hydroxymethyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate and tert-butyl (((2S,3R,4R)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro-3-(hydroxymethyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)(methyl)carbamate (298 mg, 0.506 mmol) in DCM (3 mL) was added TFA (2 mL, 26.0 mmol) at rt and the reaction mixture was stirred at rt for 15 min. The reaction mixture was added to saturated _NaHCO3 solution and the resulting product was extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by preparative HPLC (Waters X-Bridge C18 OBD, 5 μm, 30 * 100 mm, eluent _A : _H2O + 7.3 mM _NH4OH , B:ACN, gradient: 15% to 60% B over 25 min, hold for 1 min, flow rate 40 mL/min). Acetonitrile from the collected fractions was evaporated and the resulting aqueous phases were extracted with DCM. The organic extracts were washed with brine, dried over anhydrous _Na2SO4 and concentrated to afford separated _{diastereoisomers} .

2-((2S,3R,4S)-5-Chloro-6-fluoro-3-(hydroxymethyl)-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 147) (131 mg): ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 7.64 (s, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.41 (d, J=7.7 Hz, 2H), 7.38-7.24 (m, 5H), 7.16 (d, J=9.4 Hz, 1H), 6.38 (br s, 1H), 3.88 (s, 3H), 3.74 (d, J=12.7 Hz, 1H), 3.35-3.30 (m, 2H), 3.12 (d, J=13.0 Hz, 1H), 3.07 (dd, J=12.7, 5.0 Hz, 1H), 2.23 (s, 3H). UPLC-MS 1: m/z 489.5 [M+H] ⁺ , t _R =0.77 min

Another diastereoisomer, 2-((2S,3R,4R)-5-chloro-6-fluoro-3-(hydroxymethyl)-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (63 mg): UPLC-MS 1: m/z 489.5 [M+H] ⁺ , t _R = 0.64 min.

Example 148. 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

Reaction scheme for example 148

Stage 1 . tert-Butyl-(((2S,3S,4S)-4-(6-carbamoyl-2-fluoro-3-((S)-2-hydroxypropoxy)phenyl)-5-chloro-6-fluoro-3-methyl -2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)((1r,4S)-4-hydroxy-4-methylcyclohexyl)carbamate

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 ( 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 (Example 114a) (2000 mg, 3.25 mmol) was dissolved in THF (50 mL) and water (10 mL). Boc ₂ O (1.06 g, 4.99 mmol) and 4 M NaOH (2.5 mL) were added and the reaction mixture was stirred at rt for 5 days. The reaction mixture was diluted with TBME and washed with water and brine. The aqueous phases were washed with TBME. The organic layers were combined, dried over MgSO ₄ and concentrated. The crude product was dissolved in MeOH (30 mL) and stirred with K ₂ CO ₃ (2 g) at rt overnight. The reaction mixture was filtered, concentrated and redissolved in EtOAc. The organic layer was washed with water and brine, dried over MgSO ₄ and concentrated. The crude product was purified by flash chromatography (silica, DCM/MeOH, gradient 2% to 10% MeOH) to afford the title compound (2000 mg) as a colourless powder. UPLC-MS 3: m/z 715.2 [M+H] ⁺ ; t _{R =} 1.10 min.

Step 2. tert-Butyl (((2S,3S,4S)-4-(6-carbamoyl-2-fluoro-3-(2-oxopropoxy)phenyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)((trans)-4-hydroxy-4-methylcyclohexyl)carbamate

To a solution of tert-butyl (((2S,3S,4S)-4-(6-carbamoyl-2-fluoro-3-((S)-2-hydroxypropoxy)phenyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)((trans)-4-hydroxy-4-methylcyclohexyl)carbamate (1750 mg, 2.447 mmol) in DCM (50 mL) was added Dess-Martin periodinane (1090 mg, 2.57 mmol) portionwise at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. The reaction mixture was diluted with DCM and washed with 10% Na ₂ S ₂ O ₃ solution, then with a saturated NaHCO ₃ solution. The organic layer was dried over anhydrous _MgSO4 and concentrated. The crude product was purified by flash chromatography (silica, DCM/MeOH, gradient 2% to 10% MeOH) to afford the title compound (1350 mg) as a beige powder. UPLC-MS 3: m/z 713.3 [M+H] ⁺ ; t _R= 1.10 min.

Stage 3 . tert-Butyl-(((2S,3S,4S)-4-(6-carbamoyl-2-fluoro-3-(2-hydroxy-2-methylpropoxy)phenyl)-5-chloro-6-fluoro-3-methyl -2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)((trans)-4-hydroxy-4-methylcyclohexyl)carbamate

tert-Butyl (((2S,3S,4S)-4-(6-carbamoyl-2-fluoro-3-(2-oxopropoxy)phenyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)((trans)-4-hydroxy-4-methylcyclohexyl)carbamate (100 mg, 0.140 mmol) was dissolved in THF (3 mL) and cooled to -20 °C under N ₂ . MeMgBr (0.280 mL, 0.840 mmol, 3 M in Et ₂ O) was added dropwise. The solution was stirred at -20 °C for 60 min, then quenched with 10% NH ₄ Cl solution. The aqueous layer was extracted with EtOAc. The combined organic layers were combined, dried over anhydrous _MgSO4 and concentrated. The crude product was purified by flash chromatography (silica, DCM/MeOH, gradient: 1% to 6% MeOH) to afford the title compound (25 mg) as a colourless solid. UPLC-MS 3: m/z 729.2 [M+H] ⁺ ; t _R= 1.13 min.

Step 4. 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 (Example 148)

tert-Butyl (((2S,3S,4S)-4-(6-carbamoyl-2-fluoro-3-(2-hydroxy-2-methylpropoxy)phenyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)((trans)-4-hydroxy-4-methylcyclohexyl)carbamate (25 mg, 0.034 mmol) was dissolved in HCl (0.4 mL, 4 M in dioxane). The solution was stirred at rt for 2.5 h and then quenched with saturated _NaHCO3 . The aqueous layer was extracted with DCM. The combined organic layers were concentrated. The crude product was recrystallized from diisopropyl ether to give the title compound (19.5 mg) as a colorless solid. ^1H NMR (600 MHz, DMSO -d6 ) δ 7.62 (sbr, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.46-7.38 (m, 2H) _, 7.37-7.21 (m, 4H), 7.06 (d, J=9.6 Hz, 1H), 4.66 (s, 1H), 4.03 (s, 1H), 3.90-3.79 (m, 2H), 3.26 (q, J=7.2 Hz, 1H), 3.08 (s br, 2H), 2.33-2.25 (m, 1H), 1.66-1.60 (m, 2H), 1.37-1.27 (m, 2H), 1.26-1.11 (m, 8H), 1.07-0.99 (m, 2H), 0.98 (s, 3H), 0.93 (d, J=7.2 Hz, 3H). UPLC-MS 3: m/z 630.4 [M+H] ⁺ , t _R =0.79 min.

Example 149. 2-((2S,4S)-2-(Azetidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide

Reaction scheme for example 149

Step 1. tert-Butyl 2-((2S,4S)-5-chloro-6-fluoro-4-(2-fluoro-6-(methoxycarbonyl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)azetidine-1-carboxylate and tert-butyl 2-((2S,4R)-5-chloro-6-fluoro-4-(2-fluoro-6-(methoxycarbonyl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)azetidine-1-carboxylate

At rt, a mixture of 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 (XXXII) (220 mg, 0.415 mmol), methyl 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate (N-XXVII) (235 mg, 0.623 mmol), and potassium triphosphate (264 mg, 1.25 mmol) suspended in toluene (4 mL) and water (0.8 mL) was degassed with Ar. N-Xantphos (22.9 mg, 0.042 mmol) and _Pd2 (dba) ₃ (19 mg, 0.021 mmol) were added. The reaction mixture was heated at 100 °C for 12 h. After cooling to rt, the reaction mixture was partitioned between water and EtOAc. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous _{Na2SO4 ,} filtered and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 30% EtOAc) to give a mixture of the title compounds (165 mg). UPLC-MS 1: mass/charge 700.3 [M+H] ⁺ , t _R =1.50 min.

Step 2. 2-((2S,4S)-2-(1-(tert-Butoxycarbonyl)azetidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoic acid and 2-((2S,4R)-2-(1-(tert-Butoxycarbonyl)azetidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoic acid

At k.t. to a stirred solution of a mixture of tert-butyl 2-((2S,4S)-5-chloro-6-fluoro-4-(2-fluoro-6-(methoxycarbonyl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)azetidine-1-carboxylate and tert-butyl 2-((2S,4R)-5-chloro-6-fluoro-4-(2-fluoro-6-(methoxycarbonyl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)azetidine-1-carboxylate (160 mg, 0.229 mmol) in MeOH (1.9 mL) and THF (0.95 mL) was added 4 M aq. NaOH (0.57 mL, 2.29 mmol). The reaction mixture was stirred at 40 °C for 5 h. After cooling to rt, water was added and the pH was adjusted to ~2 with 2 N HCl. The mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous _{Na2SO4 ,} filtered and concentrated to give a mixture of the title compounds, which were used in the next step without further purification. UPLC-MS 1: m/z 684.1/686.0 [MH] ^- , t _R = 1.37 and 1.39 min.

Step 3. tert-Butyl 2-((2S,4S)-5-chloro-6-fluoro-4-(2-fluoro-6-(methylcarbamoyl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)azetidine-1-carboxylate and tert-butyl 2-((2S,4R)-5-chloro-6-fluoro-4-(2-fluoro-6-(methylcarbamoyl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)azetidine-1-carboxylate

At k.t. to a stirred solution of a mixture of 2-((2S,4S)-2-(1-(tert-butoxycarbonyl)azetidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoic acid and 2-((2S,4R)-2-(1-(tert-butoxycarbonyl)azetidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoic acid (120 mg, 0.175 mmol) in DMF (1.4 mL) were added successively DIPEA (0.183 mL, 1.05 mmol), methylamine hydrochloride (24 mg, 0.35 mmol) and HATU (106 mg, 0.28 mmol). The reaction mixture was stirred at rt for 3 h. Saturated _NaHCO3 solution was added. The mixture was extracted twice with TBME. The combined organic layers were washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated to give a mixture of the title compounds (125 mg), which were used in the next step without further purification. UPLC-MS 1: m/z 743.1/745.1 [M+formate] ^- , t _R = 1.38 and 1.41 min.

Step 4. 2-((2S,4S)-2-(Azetidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide (Example 149) and 2-((2S,4R)-2-(azetidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide

To a stirred solution of a mixture of tert-butyl 2-((2S,4S)-5-chloro-6-fluoro-4-(2-fluoro-6-(methylcarbamoyl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)azetidine-1-carboxylate and tert-butyl 2-((2S,4R)-5-chloro-6-fluoro-4-(2-fluoro-6-(methylcarbamoyl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)azetidine-1-carboxylate in DCM (5 mL) was slowly added TFA (0.18 mL, 2.37 mmol). The reaction mixture was stirred at rt for 45 min, then quenched with saturated _NaHCO3 solution. The mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous _{Na2SO4 ,} filtered and concentrated. The crude material was purified by preparative HPLC and the diastereoisomers were separated.

2-((2S,4S)-2-(Azetidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide (Example 149) (6.8 mg): UPLC-MS 1: m/z 515.1/517.0 [M+H] ⁺ , t _R = 0.68 min.

Another diastereomer, 2-((2S,4R)-2-(azetidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide (example) (7 mg): UPLC-MS 1: m/z 515.1/517.0 [M+H] ⁺ , t _R = 0.64 min.

Example 150. 2-((2S,3S,4S)-2-(Azetidin-2-yl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3- fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide

The title compound was prepared analogously to Example 149 from 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 (C-XXXIII) and methyl (S)-2-bromo-3-fluoro-4-(2-hydroxypropoxy)benzoate (N-XXXIII). The diastereoisomers were separated after final removal of the Boc and THP protecting groups. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ (ppm) 8.22 (d, J=4.8 Hz, 1H), 7.46 (t, J=7.5 Hz, 3H), 7.35-7.19 (m, 5H), 7.17 (d, J=9.5 Hz, 1H), 4.95 (d, J=4.0 Hz, 1H), 4.46 (t, J=7.6 Hz, 1H), 3.95 (q, J=6.5 Hz, 2H), 3.89 (t, J=6.5 Hz, 1H), 3.23 (q, J=7.3 Hz, 1H), 2.94 (td, J=7.9, 4.1 Hz, 1H), 2.60 (d, J=4.6 Hz, 3H), 2.26-2.10 (m, 2H), 1.11 (d, J=5.3 Hz, 3H), 0.85 (d, J=7.2 Hz, 3H). UPLC-MS 1: mass/charge 543.2 /545.3 [M+H] ⁺ , t _R =0.72 min.

Example 151. (2-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide

Reaction scheme for example 151

Step 1. tert-Butyl (S)-2-((2S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-(2-hydroxyethoxy)phenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate and tert-butyl (S)-2-((2S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-(2-hydroxyethoxy)phenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate

A mixture of the title compounds (961 mg) was prepared from 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 (C-XXXIV) (1.4 g, 2.57 mmol) and 2-bromo-3-fluoro-4-(2-hydroxyethoxy)benzonitrile (N-VII) (0.736 g, 2.83 mmol) using reaction conditions similar to those described for Example 149, Step 1. UPLC-MS 1: m/z 597.4/599.4 [M+H] ⁺ , t _R = 1.34 min.

Step 2. 2-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzonitrile and 2-((2S,4R)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzonitrile

At rt, a mixture of tert-butyl (S)-2-((2S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-(2-hydroxyethoxy)phenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate and tert-butyl (S)-2-((2S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-(2-hydroxyethoxy)phenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (961 mg, 1.60 mmol) was treated with HCl (4 mL, 16.1 mmol, 4 M in dioxane) for 16 h. The reaction mixture was quenched with sat. NaHCO ₃ solution. The combined organic layers were washed with saturated NaHCO ₃ solution and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (silica, DCM/MeOH, gradient: 0% to 10% MeOH) to give a mixture of the title compounds (288 g) as a colorless solid. UPLC-MS 1: m/z 497.3/499.3 [M+H] ⁺ , t _R = 0.76 and 0.77 min.

Step 3. 2-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide (Example 151) and 2-((2S,4R)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide

A mixture of the title compounds was prepared from a mixture of 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzonitrile and 2-((2S,4R)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzonitrile (245 mg, 0.493 mmol) using reaction conditions similar to those described for Example 5a, step 2, followed by flash chromatography (silica, DCM/MeOH, gradient 4 to 14% MeOH) to separate diastereomers.

2-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide (Example 151) (107 mg): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.61 (s br, 1H), 7.51 (dd, J=8.7, 1.3 Hz, 1H), 7.48-7.41 (m, 2H), 7.37-7.18 (m, 5H), 7.02 (d, J=9.6 Hz, 1H), 4.96 (t, J=5.4 Hz, 1H), 4.14 (t, J=4.8 Hz, 2H), 3.75 (q, J=5.2 Hz, 2H), 3.52 (t, J=7.8 Hz, 1H), 3.47 (d, J=16.0 Hz, 1H), 2.87 (d, J=16.0 Hz, 1H), 2.74-2.66 (m, 1H), 2.62-2.55 (m, 1H), 1.62-1.52 (m, 1H), 1.51-1.37 (m, 2H), 1.38-1.27 (m, 1H). UPLC-MS 1: mass/charge 515.4/517.4 [M+H] ⁺ , t _R =0.66 min.

Another diastereomer, 2-((2S,4R)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide (112 mg) UPLC-MS 1: m/z 515.4/517.4 [M+H] ⁺ , t _R = 0.59 min.

Example 152. 2-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide

The title compound (92 mg, white powder) was prepared analogously to Example 151, starting from 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 (C-XXXIV) (600 mg, 1.103 mmol) and (S)-2-bromo-3-fluoro-4-(2-hydroxypropoxy)benzonitrile (N-XIV) (648 mg, 1.655 mmol). The diastereomers were separated at the last step.

2-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide (Example 152): ¹ H NMR (600 MHz, DMSO- d ₆ ) δ (ppm) 7.62 (s, 1H), 7.50 (d, J= 8.8 Hz, 1H), 7.47-7.40 (m, 2H), 7.36-7.18 (m, 5H), 7.02 (d, J= 9.6 Hz, 1H), 4.96 (d, J= 4.1 Hz, 1H), 4.08-3.87 (m, 3H), 3.61-3.50 (m, 1H), 3.46 (d, J= 15.9 Hz, 1H), 2.87 (d, J = 15.9 Hz, 1H), 2.77-2.66 (m, 1H), 2.66-2.56 (m, 1H), 1.69-1.52 (m, 1H), 1.52-1.38 (m, 2H), 1.38-1.26 (m, 1H), 1.14 (d, J= 5.5 Hz, 3H). UPLC-MS 1: mass/charge 529.3/531.3 [M+H] ⁺ , t _R =0.70 min.

Another diastereomer, 2-((2S,4R)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide UPLC-MS 1: m/z 529.4/531.4 [M+H] ⁺ , t _R = 0.65 min.

Example 153. 2-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide

Reaction scheme for example 153

Step 1. tert-Butyl (S)-2-((2S,4S)-5-chloro-6-fluoro-4-(2-fluoro-3-(2-hydroxyethoxy)-6-(methoxycarbonyl)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate and tert-butyl (S)-2-((2S,4R)-5-chloro-6-fluoro-4-(2-fluoro-3-(2-hydroxyethoxy)-6-(methoxycarbonyl)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate

A suspension of 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 (C-XXXIV) (3.73 g, 6.86 mmol), methyl 2-bromo-3-fluoro-4-(2-hydroxyethoxy)benzoate (N-XXXIV) (3.02 g, 10.29 mmol), K ₃ PO ₄ (4.37 g, 20.6 mmol), N-Xantphos (0.378 g, 0.686 mmol) and Pd ₂ (dba) ₃ (0.314 g, 0.343 mmol) in toluene/water (5:1, 240 mL) was degassed with Ar and heated at 100 °C for 19 h at rt, sat. NaHCO ₃ solution was added and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude products were purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 80% EtOAc) to give a mixture of the title compounds (3.95 g) as a yellow oil. UPLC-MS 1: m/z 630.6/632.6 [M+H] ⁺ , t _R = 1.37 and 1.38 min.

Step 2. 2-((2S,4S)-2-((S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzoic acid and 2-((2S,4R)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzoic acid

At rt, LiOH.H 2 O (0.721 g, 30.1 mmol) was added to a stirred solution of a mixture of tert-butyl (S)-2-((2S,4S)-5-chloro-6-fluoro-4-(2-fluoro-3-(2-hydroxyethoxy)-6-(methoxycarbonyl)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate and tert-butyl (S)-2-((2S,4R)-5-chloro-6-fluoro-4-( ₂ -fluoro-3-(2-hydroxyethoxy)-6-(methoxycarbonyl)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate in dioxane (15 mL) and water (15 mL). The reaction mixture was stirred for 6 h at 60 °C before it was quenched with water and acidified with 1 N HCl. The mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give a mixture of the title compounds (3.34 g) as a brown oil, which was used directly in the next step. UPLC-MS 1: m/z 614.5/616.5 [M+H] ⁺ , t _R = 1.19 and 1.20 min.

Step 3. tert-Butyl (S)-2-((2S,4S)-5-chloro-6-fluoro-4-(2-fluoro-3-(2-hydroxyethoxy)-6-(methylcarbamoyl)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate and tert-butyl (S)-2-((2S,4R)-5-chloro-6-fluoro-4-(2-fluoro-3-(2-hydroxyethoxy)-6-(methylcarbamoyl)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate

A mixture of the title compounds (2.64 g, brown oil) was prepared from a mixture of 2-((2S,4S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzoic acid and 2-((2S,4R)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzoic acid (3.34 g, 5.42 mmol) using reaction conditions similar to those described for Example 149, Step 3. UPLC-MS 1: m/z 629.5/631.5 [M+H] ⁺ , t _R =1.23 and 1.26 min.

Step 4. 2-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide (Example 153) and 2-((2S,4R)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide

A mixture of the title compounds was prepared from a mixture of tert-butyl (S)-2-((2S,4S)-5-chloro-6-fluoro-4-(2-fluoro-3-(2-hydroxyethoxy)-6-(methylcarbamoyl)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate and tert-butyl (S)-2-((2S,4R)-5-chloro-6-fluoro-4-(2-fluoro-3-(2-hydroxyethoxy)-6-(methylcarbamoyl)phenyl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (3.34 g, 5.42 mmol) using reaction conditions similar to those described for Example 22, Step 5. The diastereoisomers were separated by flash chromatography (silica, DCM/MeOH, gradient from 1 to 14% MeOH).

2-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide (Example 153) (303 mg): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.10 (q, J=4.5 Hz, 1H), 7.46-7.41 (m, 3H), 7.38-7.22 (m, 4H), 7.01 (d, J=9.7 Hz, 1H), 4.96 (, t, J=5.4 Hz, 1H), 4.14 (t, J=4.9 Hz, 2H), 3.75 (q, J=5.1 Hz, 2H), 3.58-3.52 (m, 1H), 3.42 (dd, J=16.0, 1.8 Hz, 1H), 2.87 (dd, J=15.8, 1.6 Hz, 1H), 2.79-2.71 (m, 1H), 2.70-2.65 (m, 1H), 2.63 (d, J=4.6 Hz, 3H), 1.60-1.36 (m, 4H). UPLC-MS 1: mass/charge 529.4/531.4 [M+H] ⁺ , t _R =0.67 min.

Another diastereomer, 2-((2S,4R)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide (Example) (375 mg):

UPLC-MS 1: mass/charge 529.5/531.5 [M+H] ⁺ , t _R =0.58 min.

Example 154. 2-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide

The title compound was prepared analogously to Example 153, starting from 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 (C-XXXIV) and methyl (S)-2-bromo-3-fluoro-4-(2-hydroxypropoxy)benzoate (N-XXXIII).

2-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide (Example 154): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.10 (q, J=4.5 Hz, 1H), 7.46-7.41 (m, 3H), 7.38-7.20 (m, 4H), 7.01 (d, J=9.6 Hz, 1H), 4.96 (d, J=4.3 Hz, 1H), 4.06-3.86 (m, 3H), 3.55 (t, J=6.7 Hz, 1H), 3.42 (dd, J=15.9 Hz, 1.7 Hz, 1H), 2.87 (dd, J=15.9 1.5 Hz, 1H), 2.78-2.71 (m, 1H), 2.69-2.65 (m, 1H), 2.63 (d, J=4.8 Hz, 3H), 1.67-1.34 (m, 4H), 1.15 (d, J=5.8 Hz, 3H). UPLC-MS 1: mass/charge 543.4 [M+H] ⁺ , t _R =0.74 min.

Another diastereomer, 2-((2S,4R)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide: UPLC-MS 1: m/z 543.4 [M+H] ⁺ , t _R = 0.67 min.

Example 155. 4-((2S,4S)-5-{lor-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide or (4P)-4-{(2S)-5-chloro-6-fluoro-2-phenyl-2-[(2S)-pyrrolidin-2-yl]-2,3-dihydro-1-benzofuran-4-yl}-5-fluoro-6-(2-hydroxyethoxy)-N-methylpyridine-3-carboxamide

The title compound can be synthesized via the following routes.

Reaction scheme 1 for example 155

Step 1. Methyl 4-((2S,4S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinate and methyl 4-((2S,4R)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinate

A suspension of 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 (C-XXXIV) (4.16 g, 7.65 mmol), methyl 4-chloro-5-fluoro-6-(2-hydroxyethoxy)nicotinate (N-XXXV) (2.86 g, 11.47 mmol), K ₃ PO ₄ (4.87 g, 22.95 mmol), N-Xantphos (0.421 g, 0.765 mmol) and Pd ₂ (dba) ₃ (0.350 g, 0.382 mmol) in toluene/water (5:1 ratio, 48 mL) was degassed with Ar and heated at 100 °C for 20 h. At rt, saturated NaHCO ₃ solution was added and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude products were purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 80% EtOAc) to give a mixture of the title compounds (1.1 g) as a yellow oil. UPLC-MS 1: m/z 631.3/633.3 [M+H] ⁺ , t _R = 1.39 min.

Step 2. 4-((2S,4S)-2-((S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinic acid and 4-((2S,4R)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinic acid

To a solution of a mixture of methyl 4-((2S,4S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinate and methyl 4-((2S,4R)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinate (1.45 g, 2.30 mmol) in dioxane (5 mL) and water (5 mL) was added LiOH.H ₂ O (0.55 g, 22.98 mmol) and The reaction mixture was stirred at 70 °C for 8 h. The reaction mixture was diluted with water (100 mL), acidified with 1 N HCl and extracted twice with DCM. The organic layers were combined, dried over anhydrous Na ₂ SO ₄ and concentrated to give a mixture of the title compounds (1.52 g) as a colorless powder, which was used without further purification in the next step. UPLC-MS 1: m/z 617.3/619.3 [M+H] ⁺ , t _R = 1.19 and 1.20 min.

Step 3. tert-Butyl (S)-2-((2S,4S)-5-chloro-6-fluoro-4-(3-fluoro-2-(2-hydroxyethoxy)-5-(methylcarbamoyl)pyridin-4-yl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate and tert-butyl (S)-2-((2S,4R)-5-chloro-6-fluoro-4-(3-fluoro-2-(2-hydroxyethoxy)-5-(methylcarbamoyl)pyridin-4-yl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of a mixture of 4-((2S,4S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinic acid and 4-((2S,4R)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinic acid (1.52 g, 2.46 mmol), DIPEA (2.6 mL, 14.8 mmol) and methylamine hydrochloride (0.35 g, 4.95 mmol) in DMF (15 mL) was added HATU (1.5 g, 3.94 mmol). The reaction mixture was stirred at rt for 1 h. Saturated _NaHCO3 solution was added and the mixture was extracted twice with EtOAc. The combined organic layers were washed with saturated _NaHCO3 solution and water, dried over _{anhydrous Na2SO4} , filtered and concentrated. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0% to 80% EtOAc) to afford the title compounds as separate diastereoisomers.

tert-Butyl (S)-2-((2S,4S)-5-chloro-6-fluoro-4-(3-fluoro-2-(2-hydroxyethoxy)-5-(methylcarbamoyl)pyridin-4-yl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (483 mg): UPLC-MS 1: m/z 630.3/632.3 [M+H] ⁺ , t _R = 1.26 min.

Another diastereomer, tert-butyl (S)-2-((2S,4R)-5-chloro-6-fluoro-4-(3-fluoro-2-(2-hydroxyethoxy)-5-(methylcarbamoyl)pyridin-4-yl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate

(634 mg): UPLC-MS 1: m/z 630.3/632.3 [M+H] ⁺ , t _R =1.23 min.

Step 4. 4-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide or (4 P )-4-{(2 S )-5-chloro-6-fluoro-2-phenyl-2-[(2 S )-pyrrolidin-2-yl]-2,3-dihydro-1-benzofuran-4-yl}-5-fluoro-6-(2-hydroxyethoxy) -N- methylpyridine-3-carboxamide (Example 155)

At rt, to a stirred solution of tert-butyl (S)-2-((2S,4S)-5-chloro-6-fluoro-4-(3-fluoro-2-(2-hydroxyethoxy)-5-(methylcarbamoyl)pyridin-4-yl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (483 mg, 0.767 mmol) in dioxane (10 mL) was added HCl (1.9 mL, 7.67 mmol, 4 M in dioxane). The reaction mixture was stirred at rt for 40 h, then quenched with sat. NaHCO ₃ solution and extracted twice with EtOAc. The combined organic layers were washed with sat. _NaHCO3 solution, dried over anhydrous _Na2SO4 , filtered and concentrated. The crude product was purified by flash chromatography (silica, DCM/ _MeOH , gradient: 0% to 15% EtOAc) to give the title compound (303 mg) as a colorless powder. ¹ H NMR (600 MHz, DMSO -d ₆ ) δ (ppm) 8.42 (q, J=4.6 Hz, 1H), 8.27 (s, 1H), 7.46 -7.42 (m, 2H), 7.33 (t, J=7.6 Hz, 2H), 7.26 (dd, J=8.3, 6.2 Hz, 1H), 7.07 (d, J=9.6 Hz, 1H), 4.95 (t, J=5.5 Hz, 1H), 4.44 (ddt, J=21.1, 10.9, 5.5 Hz, 2H), 3.76 (q, J=5.1 Hz, 2H), 3.51 (t, J=6.8 Hz, 1H), 3.43 (d, J=16.0 Hz, 1H), 2.96 (d, J=16.0 Hz, 1H), 2.74 (dt, J=12.6, 6.4 Hz, 1H), 2.66 (d, J=4.6 Hz, 3H), 2.65-2.60 (m, 1H), 2.29 (s br, 1H), 1.55-1.43 (m, 2H), 1.42-1.33 (m, 2H). UPLC-MS 1: m/charge 530.5/532.5 [M+H] ⁺ , t _R =0.69 min. UPLC-MS 2: m/charge 530.5/532.5 [M+H] ⁺ , t _R =3.02 min. The absolute configuration was confirmed by X-ray diffraction analysis of a cocrystal of example 155 bound to the YAP binding site of TEAD3.

Reaction scheme 2 for example 155

Step 1. Methyl 4-((2S,4S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate and methyl 4-((2S,4R)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate

A suspension of 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 (C-XXXIV) (8.83 g, 16.2 mmol), methyl 4-chloro-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate (N-XXXI) (6.50 g, 19.5 mmol), K ₃ PO ₄ (10.34 g, 48.7 mmol), N-Xantphos (0.896 g, 1.62 mmol) and Pd ₂ (dba) ₃ (0.743 g, 0.81 mmol) in toluene (175 mL) and water (35 mL) was stirred at 100 °C for 20 h at rt, sat. NaHCO ₃ solution was added and the mixture was extracted twice with EtOAc. The combined organic layers were washed with sat. NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography (silica, heptane/EtOAc, gradient: 10% to 33% EtOAc) to give a mixture of the title compounds (6.25 g). UPLC-MS 1: m/z 715.7 [M+H] ⁺ , t _R = 1.61 min.

Step 2. 4-((2S,4S)-2-((S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinic acid and 4-((2S,4R)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinic acid

NaOH (21.9 mL, 87 mmol, 4 M in water) was added to a solution of a mixture of methyl 4-((2S,4S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate and methyl 4-((2S,4R)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate (6.25 g, 8.7 mmol) in MeOH (50 mL) and THF (25 mL). The reaction mixture was stirred at rt for 2.5 h before it was cooled to 5 °C and quenched by addition of 10% aqueous NaH ₂ PO ₄ (500 mL). The resulting suspension was extracted twice with TBME, the combined organic layers were washed with water, dried over anhydrous Na ₂ SO ₄ and concentrated to give a mixture of the title products (5.84 g), which was used in the next step without further purification. UPLC-MS 1: m/z 701.7 [M+H] ⁺ , t _R = 1.45 and 1.46 min.

Step 3. tert-Butyl (2S)-2-((2S,4S)-5-chloro-6-fluoro-4-(3-fluoro-5-(methylcarbamoyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate and tert-butyl (2S)-2-((2S,4R)-5-chloro-6-fluoro-4-(3-fluoro-5-(methylcarbamoyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of a mixture of 4-((2S,4S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinic acid and 4-((2S,4R)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinic acid (5.84 g, 7.83 mmol) in DMF (40 mL) HATU (4.76 g, 12.5 mmol), DIPEA (8.20 mL, 47.0 mmol) and methylamine hydrochloride (1.32 g, 19.6 mmol) were added. The reaction mixture was stirred at rt for 3 h. Saturated NaHCO ₃ solution was added and the mixture was extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by flash chromatography (silica, TBME/EtOAc, gradient: 5% to 100% EtOAc) to give

tert-Butyl (2S)-2-((2S,4S)-5-chloro-6-fluoro-4-(3-fluoro-5-(methylcarbamoyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (535 mg): UPLC-MS 1: m/z 714.7 [M+H] ⁺ , t _R =1.50 min,

tert-Butyl (2S)-2-((2S,4R)-5-chloro-6-fluoro-4-(3-fluoro-5-(methylcarbamoyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (700 mg): UPLC-MS 1: m/z 714.7 [M+H] ⁺ , t _R =1.47 min.

A mixture of tert-butyl (2S)-2-((2S,4S)-5-chloro-6-fluoro-4-(3-fluoro-5-(methylcarbamoyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate and tert-butyl (2S)-2-((2S,4R)-5-chloro-6-fluoro-4-(3-fluoro-5-(methylcarbamoyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (2.548 g): UPLC-MS 1: mass/charge 714.7 [M+H] ⁺ , t _R =1.47 and 1.50 min.

Step 4. tert-Butyl (S)-2-((2S,4S)-5-chloro-6-fluoro-4-(3-fluoro-2-(2-hydroxyethoxy)-5-(methylcarbamoyl)pyridin-4-yl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate and tert-butyl (S)-2-((2S,4R)-5-chloro-6-fluoro-4-(3-fluoro-2-(2-hydroxyethoxy)-5-(methylcarbamoyl)pyridin-4-yl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate

To a solution of a mixture of tert-butyl (2S)-2-((2S,4S)-5-chloro-6-fluoro-4-(3-fluoro-5-(methylcarbamoyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate and tert-butyl (2S)-2-((2S,4R)-5-chloro-6-fluoro-4-(3-fluoro-5-(methylcarbamoyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (2.01 g, Pyridinium p-toluenesulfonate (1.414 g, 5.63 mmol) was added to EtOH (10 mL) and the reaction mixture was stirred at rt for 23 h. Saturated NaHCO ₃ was added and the mixture was extracted with EtOAc. The combined organic layers were washed with saturated NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was flash chromatographed (silica, EtOAc) to afford the title compounds as separate diastereoisomers:

tert-Butyl (S)-2-((2S,4S)-5-chloro-6-fluoro-4-(3-fluoro-2-(2-hydroxyethoxy)-5-(methylcarbamoyl)pyridin-4-yl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (917 mg): UPLC-MS 1: m/z 630.6 [M+H] ⁺ , t _R = 1.27 min.

tert-Butyl (S)-2-((2S,4R)-5-chloro-6-fluoro-4-(3-fluoro-2-(2-hydroxyethoxy)-5-(methylcarbamoyl)pyridin-4-yl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (557 mg): UPLC-MS 1: m/z 630.6 [M+H] ⁺ , t _R =1.24 min.

Step 5. 4-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide or (4P)-4-{(2S)-5-chloro-6-fluoro-2-phenyl-2-[(2S)-pyrrolidin-2-yl]-2,3-dihydro-1-benzofuran-4-yl}-5-fluoro-6-(2-hydroxyethoxy)-N-methylpyridine-3-carboxamide (Example 155)

To a solution of tert-butyl (S)-2-((2S,4S)-5-chloro-6-fluoro-4-(3-fluoro-2-(2-hydroxyethoxy)-5-(methylcarbamoyl)pyridin-4-yl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (1.254 g, 1.99 mmol) in dioxane (15 mL) was added HCl (6.05 mL, 199 mmol, 4 M in dioxane) over 5 min at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, 4 h at rt and an additional 12 h at 4 °C. Saturated NaHCO ₃ solution was added and the mixture was extracted twice with EtOAc. The combined organic layers were washed with sat. _NaHCO3 solution, dried over anhydrous _Na2SO4 and concentrated. The crude product was purified by flash chromatography (DCM/MeOH/(7N _ammonia in MeOH), gradient from 95:5:05 to 90:10:0.5) to give the title compound (743 mg) as a colourless foam. ¹ H NMR (600 MHz, DMSO -d ₆ ) δ (ppm) 8.42 (q, J=4.6 Hz, 1H), 8.27 (s, 1H), 7.46 -7.42 (m, 2H), 7.33 (t, J=7.6 Hz, 2H), 7.26 (dd, J=8.3, 6.2 Hz, 1H), 7.07 (d, J=9.6 Hz, 1H), 4.95 (t, J=5.5 Hz, 1H), 4.44 (ddt, J=21.1, 10.9, 5.5 Hz, 2H), 3.76 (q, J=5.1 Hz, 2H), 3.51 (t, J=6.8 Hz, 1H), 3.43 (d, J=16.0 Hz, 1H), 2.96 (d, J=16.0 Hz, 1H), 2.74 (dt, J=12.6, 6.4 Hz, 1H), 2.66 (d, J=4.6 Hz, 3H), 2.65-2.60 (m, 1H), 2.29 (s br, 1H), 1.55-1.43 (m, 2H), 1.42-1.33 (m, 2H). UPLC-MS 1: m/charge 530.5/532.5 [M+H] ⁺ , t _R =0.69 min. UPLC-MS 2: m/charge 530.5/532.5 [M+H] ⁺ , t _R =3.02 min.

Reaction scheme 3 for example 155

Step 1. Methyl 4-((2S,4S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate and methyl 4-((2S,4R)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate

A 1 L three-neck round bottom flask was charged with (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 (C-XXXIV) (22.1 g, 40.65 mmol), methyl 4-chloro-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate (N-XXXI) (14.9 g, 44.72 mmol), K ₃ PO ₄ (25.9 g, 121.96 mmol), water (100 mL), and toluene (300 mL). The mixture was degassed with nitrogen for 20 min. _Pd2 (dba) ₃ (1.86 g, 2.03 mmol) and N-Xantphos (2.24 g, 4.06 mmol) were added in one portion under nitrogen atmosphere. The mixture was heated at 100 °C for 20 h. The mixture was cooled to rt and the organic phase was separated. The aqueous phase was extracted with toluene (100 mL). The combined organic phases were filtered through celite and concentrated to dryness. The residue was purified by suspension in a mixture of toluene, MTBE and n -heptane. The resulting suspension was filtered. The filter cake was recrystallized from toluene and n -heptane to give methyl 4-((2S,4S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate (7.5 g) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 (s, 1H), 7.39-7.34 (m, 2H), 7.34-7.27 (m, 3H), 6.75 (d, J =9.1 Hz, 1H), 4.76-4.61 (m, 3H), 4.41-4.28 (m, 1H), 4.19-4.08 (m, 1H), 3.92-3.81 (m, 2H), 3.76 (s, 3H), 3.72-2.84 (m, 5H), 2.01-1.44 (m, 10H), 1.27 (s, 9H). UPLC-MS 5: HRMS mass/charge calc. for C ₃₇ H ₄₂ ClF ₂ N ₂ O ₈ [M+H] ⁺ 715.2592, the found value is 715.2544.

Step 2. 4-((2S,4S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate sodium

Methyl 4-((2S,4S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate (50.0 g, 69.91 mmol) and 1,4-dioxane (300 mL) were charged into a 1 L three-neck round-bottom flask. A solution of NaOH (5.6 g, 139.83 mmol) in water (150 mL) was added dropwise at rt. The mixture was heated to 40°C and stirred for 16 h. The mixture was concentrated to remove most of the 1,4-dioxane and extracted with MTBE (500 mL). The organic layer was washed with brine (500 mL), separated and concentrated to dryness to give the title compound (53.0 g) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.18 (s, 1H), 7.47 (d, J =7.5 Hz, 2H), 7.32 (dt, J =12.8, 7.1 Hz, 3H), 6.70 (d, J =8.9 Hz, 1H), 4.67 (s, 1H), 4.63-4.43 (m, 2H), 4.37-4.22 (m, 2H), 4.11-3.94 (m, 1H), 3.91-3.75 (m, 2H), 3.56-3.34 (m, 2H), 3.33-3.23 (m, 1H), 2.72-2.54 (m, 1H), 1.98-1.35 (m, 10H), 1.24 (s, 9H). UPLC-MS 5: HRMS mass/charge calcd. for C ₃₆ H ₃₈ ClF ₂ N ₂ O ₈ [M-Na] ^- 699.2290, found value 699.2238.

Step 3. tert-Butyl (2S)-2-((2S,4S)-5-chloro-6-fluoro-4-(3-fluoro-5-(methylcarbamoyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate

A 1 L three-neck round bottom flask was charged with sodium 4-((2S,4S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)nicotinate (20.0 g, 27.66 mmol) and DMA (100 mL). The solution was cooled to 5-10 °C. Then DIPEA (16.1 g, 124.46 mmol) and MeNH ₂ HCl (3.7 g, 55.32 mmol) were added in one portion. The mixture was stirred for 20 min. HATU (15.8 g, 41.49 mmol) was added portionwise at 5-10 °C. The reaction mixture was then stirred at rt for 2 h before it was diluted with MTBE (300 mL). A solution of NaOH (4.4 g, 110.6 mmol) in water (300 mL) was added dropwise at rt. The mixture was stirred for 10 min and the phases were separated. The aqueous phase was extracted with MTBE (200 mL). The combined organic phases were washed with water (200 mL), 15 wt% aq. citric acid (200 mL), brine (200 mL) and then concentrated to dryness to give the title compound (18.2 g) as a foam. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 7.45-7.32 (m, 5H), 7.07 (s, 1H), 6.81 (d, J =9.0 Hz, 1H), 4.77-4.53 (m, 3H), 4.20 (d, J =8.3 Hz, 1H), 4.15-4.05 (m, 1H), 3.94-3.78 (m, 2H), 3.74-3.61 (m, 1H), 3.55-3.45 (m, 1H), 3.30-3.09 (m, 2H), 2.90 (s, 1H), 2.72 (s, 3H), 2.05-1.45 (m, 10H), 1.28 (s, 9H). UPLC-MS 5: HRMS m/z calcd for C ₃₇ H ₄₃ ClF ₂ N ₃ O ₇ [M+H] ⁺ 714.2752, found 714.2723.

Step 4. 4-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide or (4 P )-4-{(2 S )-5-chloro-6-fluoro-2-phenyl-2-[(2 S )-pyrrolidin-2-yl]-2,3-dihydro-1-benzofuran-4-yl}-5-fluoro-6-(2-hydroxyethoxy) -N- methylpyridine-3-carboxamide (Example 155)

A 250 mL three-neck round bottom flask was charged with tert-butyl (2S)-2-((2S,4S)-5-chloro-6-fluoro-4-(3-fluoro-5-(methylcarbamoyl)-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)-2-phenyl-2,3-dihydrobenzofuran-2-yl)pyrrolidine-1-carboxylate (20.0 g, 28.00 mmol), IPA (100 mL), and ethane-1,2-diol (20 mL). HCl (28 mL, 5-6 N in IPA) was then added in one portion. The reaction mixture was stirred at rt for 16 h. The reaction mixture was cooled to 10 °C. IPAc (200 mL) and a solution of NaOH (7.8 g, 195.0 mmol) in water (200 mL) were added. The mixture was stirred at rt for 10 min and the phases were separated. The aqueous phase was extracted with IPAc (200 mL). The combined organic phases were washed with brine (200 mL) and concentrated to dryness. The residue was dissolved in THF (100 mL) to give a clear yellow solution. A solution of succinic acid (3.64 g, 30.8 mmol) in THF (75 mL) was added dropwise. The resulting white suspension was stirred for 13 h and filtered. The filter cake was dissolved in water (340 mL) and cooled to 10 °C. A solution of NaOH (2.3 g, 57.5 mmol) in water (85 mL) was added dropwise. The resulting suspension was stirred for 1 h and filtered. The filter cake was washed with water (85 ml x 2) and dried under vacuum to give the title compound (10.3 g) as an off-white solid. ¹ H NMR (600 MHz, DMSO -d ₆ ) δ (ppm) 8.42 (q, J=4.6 Hz, 1H), 8.27 (s, 1H), 7.46 -7.42 (m, 2H), 7.33 (t, J=7.6 Hz, 2H), 7.26 (dd, J=8.3, 6.2 Hz, 1H), 7.07 (d, J=9.6 Hz, 1H), 4.95 (t, J=5.5 Hz, 1H), 4.44 (ddt, J=21.1, 10.9, 5.5 Hz, 2H), 3.76 (q, J=5.1 Hz, 2H), 3.51 (t, J=6.8 Hz, 1H), 3.43 (d, J=16.0 Hz, 1H), 2.96 (d, J=16.0 Hz, 1H), 2.74 (dt, J=12.6, 6.4 Hz, 1H), 2.66 (d, J=4.6 Hz, 3H), 2.65-2.60 (m, 1H), 2.29 (s br, 1H), 1.55-1.43 (m, 2H), 1.42-1.33 (m, 2H). UPLC-MS 1: m/charge 530.5/532.5 [M+H] ⁺ , t _R =0.69 min. UPLC-MS 2: m/charge 530.5/532.5 [M+H] ⁺ , t _R =3.02 min.

Example 156 and example 157. 2-((4-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-5-(methylcarbamoyl)pyridin-2-yl)oxy)acetic acid (Example 156) and 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-hydroxy-N-methylnicotinamide (Example 157)

Reaction scheme for example 156 and example 157

At 0°C, to a stirred solution of (4 P )-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide or (4 P )-4-{(2 S )-5-chloro-6-fluoro-2-phenyl-2-[(2 S )-pyrrolidin-2-yl]-2,3-dihydro-1-benzofuran-4-yl}-5-fluoro-6-(2-hydroxyethoxy) -N- methylpyridine-3-carboxamide (Example 155) (200 mg, 0.377 mmol) in acetone (5 mL) was added Jones reagent (0.57 mL, 1.132 mmol). The reaction mixture was stirred at 0 °C for 2 h, then at rt for 2 h. The mixture was then poured into 10% aq. NaHCO3 and extracted twice with EtOAc. The aqueous phase was acidified to pH ~3 with 2 N HCl and extracted with EtOAc (3 times), then with DCM (3 times). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The crude material was purified by preparative SFC to afford the title products (17.5 mg) as beige solids. UPLC-MS 1: m/z 544.1/546.1 [M+H] ⁺ , t _R = 0.74 min .

2-((4-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-5-(methylcarbamoyl)pyridin-2-yl)oxy)acetic acid (17.5 mg) (Example 156): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.48 (q, J=4.5 Hz, 1H), 8.26 (s, 1H), 7.50-7.44 (m, 2H), 7.40-7.34 (m, 2H), 7.33-7.25 (m, 1H), 7.11 (d, J=9.6 Hz, 1H), 4.90 (d, J=3.3 Hz, 2H), 3.72-3.65 (m, 1H), 3.48 (d, J=J=16.0 Hz, 1H), 2.97 (d, J=16.1 Hz, 1H), 2.88-2.71 (m, 2H), 2.67 (d, J=4.5 Hz, 2H), 1.72-1.40 (m, 4H). UPLC-MS 3: mass/charge 544.1 [M+H] ⁺ , t _R =0.74 min.

4-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-hydroxy-N-methylnicotinamide (19 mg) (Example 157): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.22 (q, J=4.4 Hz, 1H), 7.70 (s, 1H), 7.52-7.46 (m, 2H), 7.45-7.24 (m, 4H), 7.06 (d, J=9.6 Hz, 1H), 3.78-3.68 (m, 1H), 3.47 (d, J=16.2 Hz, 1H), 3.08 (d, J=16.1 Hz, 1H), 2.86-2.74 (m, 2H), 2.61 (d, J=4.5 Hz, 3H), 1.73-1.43 (m, 4H). UPLC-MS 3: m/z 486.1 [M+H] ⁺ , t _R =0.70 min.

Example 158. 2-((2S,4S)-5-Chloro-6-fluoro-2-(4-hydroxypyrrolidin-2-yl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide

The title compound was prepared analogously to Example 5a, starting from 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 (C-XXXV) and 2-bromo-4-(difluoromethoxy)-3-fluorobenzonitrile (NV). The product with diastereomeric excess >98% was isolated by flash chromatography (silica, cyclohexane/EtOAc, gradient: 0-20% EtOAc) after Suzuki cross-coupling reaction followed by preparative chiral SFC separation (Chiralpak IC 250×25 mm i.d., 5 μm, _CO2 /MeOH (0.1% _NH3 ) 85:15, flow rate: 80 mL/min) in the last step. Chiral SFC: (Chiralpak IC 250×4.6 mm i.d., 5 μm, _CO2 /MeOH (0.1% _NH3 ) 85:15) t _R = 10.11 min; ¹ H NMR (600 MHz, DMSO- d ₆ ) δ (ppm) 7.85-7.36 (m, 7H), 7.34-6.92 (m, 2H), 4.41 (s, 1H), 4.07 (t, J=8.4 Hz, 1H), 3.65 (d, J=15.4 Hz, 1H), 3.21 (d, J=15.3 Hz, 1H), 3.16-3.10 (m, 1H), 2.88 (d, J=11.3 Hz, 1H), 2.04-1.85 (m, 2H), 1.47 (s br, 2H). UPLC-MS 1: m/z 537.2 [M+H] ⁺ , t _R =0.88 min.

Example 159. 2-((2S,4S)-5-Chloro-6-fluoro-2-(4-hydroxy-4-methylpyrrolidin-2-yl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide

Reaction scheme for example 159

Step 1. tert-Butyl 2-((2S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)phenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxy-4-methylpyrrolidine-1-carboxylate and tert-butyl 2-((2S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)phenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxy-4-methylpyrrolidine-1-carboxylate

A mixture of the title compounds (70 mg) was prepared from 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 (C-XXXVI) (145 mg, 0.169 mmol) and 2-bromo-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile (N-XIII) (80 mg, 0.22 mmol) using reaction conditions similar to those described for Example 149, Step 1. UPLC-MS 1: m/z 725.5 [M+H] ⁺ , t _R =1.41/1.42/1.43/1.47 min.

Step 2. tert-Butyl 2-((2S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-((S)-2-hydroxypropoxy)phenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxy-4-methylpyrrolidine-1-carboxylate and tert-butyl 2-((2S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-((S)-2-hydroxypropoxy)phenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxy-4-methylpyrrolidine-1-carboxylate

To a solution of a mixture of tert-butyl 2-((2S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)phenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxy-4-methylpyrrolidine-1-carboxylate and tert-butyl 2-((2S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)phenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxy-4-methylpyrrolidine-1-carboxylate (70 mg, 0.097 mmol) Pyridinium p -toluenesulfonate (49 mg, 0.19 mmol) was added to EtOH (0.5 mL) and the reaction mixture was stirred at rt for 16 h. Saturated NaHCO ₃ solution was added. The mixture was extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated to give a mixture of the title compounds (60 mg). UPLC-MS 1, m/z 641.4 [M+H] ⁺ , t _R = 1.19/1.21 min.

Step 3. tert-Butyl 2-((2S,4S)-4-(6-carbamoyl-2-fluoro-3-((S)-2-hydroxypropoxy)phenyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxy-4-methylpyrrolidine-1-carboxylate and tert-butyl 2-((2S,4R)-4-(6-carbamoyl-2-fluoro-3-((S)-2-hydroxypropoxy)phenyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxy-4-methylpyrrolidine-1-carboxylate

A mixture of the title compounds was prepared from a mixture of tert-butyl 2-((2S,4S)-5-chloro-4-(6-cyano-2-fluoro-3-((S)-2-hydroxypropoxy)phenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxy-4-methylpyrrolidine-1-carboxylate and tert-butyl 2-((2S,4R)-5-chloro-4-(6-cyano-2-fluoro-3-((S)-2-hydroxypropoxy)phenyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxy-4-methylpyrrolidine-1-carboxylate (60 mg, 0.085 mmol) using reaction conditions similar to those described for Example 5a, step 2. The resulting crude The material was used directly in the next step without further purification. UPLC-MS 1: m/z 659.4/661.4 [M+H] ⁺ , t _R =1.04 and 1.09 min.

Step 4. 2-((2S,4S)-5-Chloro-6-fluoro-2-(4-hydroxy-4-methylpyrrolidin-2-yl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide (Example 159) and 2-((2S,4R)-5-chloro-6-fluoro-2-(4-hydroxy-4-methylpyrrolidin-2-yl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide

The title compounds were prepared from a diastereomeric mixture of tert-butyl 2-((2S,4S)-4-(6-carbamoyl-2-fluoro-3-((S)-2-hydroxypropoxy)phenyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxy-4-methylpyrrolidine-1-carboxylate and tert-butyl 2-((2S,4R)-4-(6-carbamoyl-2-fluoro-3-((S)-2-hydroxypropoxy)phenyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-hydroxy-4-methylpyrrolidine-1-carboxylate using reaction conditions similar to those described for Example 149, step 4, followed by preparative HPLC to separate diastereomers.

2-((2S,4S)-5-Chloro-6-fluoro-2-(4-hydroxy-4-methylpyrrolidin-2-yl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide (Example 159) (11 mg): ¹ H NMR (600 MHz, DMSO- d ₆ ) δ (ppm) 7.51 (d, J=8.6 Hz, 1H), 7.48 (s, 1H), 7.43 (d, J=7.6 Hz, 2H), 7.36-7.25 (m, 4H), 7.22 (s, 1H), 7.00 (d, J=9.7 Hz, 1H), 4.98 (d, J=4.2 Hz, 1H), 4.41 (d, J=2.3 Hz, 1H), 4.02-3.90 (m, 3H), 3.57-3.47 (m, 2H), 2.90 (d, J=15.9 Hz, 1H), 1.52-1.38 (m, 2H), 1.17-1.11 (m, 6H). UPLC-MS 1: mass/charge 559.3 [M+H] ⁺ , t _R =0.74 min.

Another diastereomer, 2-((2S,4R)-5-chloro-6-fluoro-2-(4-hydroxy-4-methylpyrrolidin-2-yl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide (6 mg): UPLC-MS 1: m/z 559.3/561.3 [M+H] ⁺ , t _R = 0.63 min.

Example 160. (2S,4R)-2-((S)-5-Chloro-6-fluoro-2,4-diphenyl-2,3-dihydrobenzofuran-2-yl)-4-fluoropyrrolidine

Reaction scheme for example 160

Step 1. tert-Butyl (2S,4R)-2-((S)-5-chloro-6-fluoro-2,4-diphenyl-2,3-dihydrobenzofuran-2-yl)-4-fluoropyrrolidine-1-carboxylate)

A mixture of tert-butyl (2S,4R)-2-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)-4-fluoropyrrolidine-1-carboxylate (C-XXXVII) (109 mg, 0.212 mmol), phenylboronic acid (38.7 mg, 0.318 mmol), K ₃ PO ₄ (180 mg, 0.847 mmol) and the adduct PdCl ₂ (dppf).CH ₂ Cl ₂ (18 mg, 0.022 mmol) in dioxane (5 mL) and water (1 mL) was stirred at 100 °C for 1 h. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with brine, dried over anhydrous _Na2SO4 and concentrated. The residue was purified by flash chromatography (silica, hexane/EtOAc; gradient: 0 to 100%) to give the title _compound . UPLC-MS 1: m/z 512.1 [M+H] ⁺ , t _R = 1.44 min.

Step 2. (2S,4R)-2-((S)-5-Chloro-6-fluoro-2,4-diphenyl-2,3-dihydrobenzofuran-2-yl)-4-fluoropyrrolidine (Example 160)

The title compound was prepared from tert-butyl (2S,4R)-2-((S)-5-chloro-6-fluoro-2,4-diphenyl-2,3-dihydrobenzofuran-2-yl)-4-fluoropyrrolidine-1-carboxylate (105 mg, 0.205 mmol) using reaction conditions similar to those described for Example 149, step 4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.57-7.40 (m, 5H), 7.38-7.20 (m, 5H), 7.06 (d, J=9.6 Hz, 1H), 5.04 (dt, J=54.9, 3.5 Hz, 1H), 3.81 (dd, J=9.7, 6.8 Hz, 1H), 3.53 (dd, J=16.0, 1.8 Hz, 1H), 3.09 (dd, J=15.9, 1.5 Hz, 1H), 3.05-2.76 (m, 2H), 2.77-2.54 (m, 1H), 1.90-1.72 (m, 1H), 1.70-1.47 (m, 1H). UPLC-MS 1: mass/charge 412.1 [M+Hl] ⁺ , t _R =0.99 min.

Example 161. 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

The title compound was prepared analogously to Example 155 from 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 (C-XLI) and methyl 2-bromo-3-fluoro-4-(2-hydroxyethoxy)benzoate (N-XXXIV), followed by chromatographic separation of the diastereoisomers at the last stage of removing the N-Boc protecting group.

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 (Example 161): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.25 (q, J=4.5 Hz, 1H), 7.47-7.26 (m, 7H), 7.00 (d, J=9.6 Hz, 1H), 4.96 (t, J=5.4 Hz, 1H), 4.15 (t, J=4.8 Hz, 2H), 3.76 (q, J=5.1 Hz, 2H), 3.59 (dd, J=16.1, 1.9 Hz, 1H), 3.00-2.73 (m, 3H), 2.65 (d, J=4.5 Hz, 3H), 1.76-1.59 (m, 1H), 1.53-1.37 (m, 2H), 1.30-1.08 (m, 4H), 1.03-0.89 (m, 1H). UPLC-MS 1: m/z 543.5/545.5 [M+H]+, t _R =0.71 min.

Another diastereoisomer, 2-((2S,4R)-5-chloro-6-fluoro-2-phenyl-2-((S)-piperidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide (161 mg): UPLC-MS 1: m/z 543.5 [M+H]+, t _R = 0.66 min.

Example 162. (3-((S)-5-Chloro-6-fluoro-2,4-diphenyl-2,3-dihydrobenzofuran-2-yl)morpholine

A diastereomeric mixture of 3-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)morpholine (C-XLII-b) (36 mg, 0.087 mmol) was subjected to chiral resolution (ChiralPak IB-N, 530 × 250 mm i.d., 5 μm, CO2/MeOH+0.1% NH3, 90:10), 25°C, flow rate: 80 mL/min) to afford two diastereoisomers with diastereomeric excess >99%, respectively.

Diastereoisomer 1 (15 mg): chiral SFC: (Chiralpak AY-H 100×3 mm i.d., 3 μm, hexane/EtOH 96:4, flow rate: 0.420 mL/min), t _R = 2.25 min.

Diastereoisomer 2 (15 mg): chiral SFC: (Chiralpak AY-H 100×3 mm i.d., 3 μm, hexane/EtOH 96:4, flow rate: 0.420 mL/min), t _R = 3.22 min.

The title compound (15 mg, white solid) was prepared from 3-((S)-4-bromo-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-2-yl)morpholine (diastereomer 2) (15 mg, 0.036 mmol) and phenylboronic acid (6.65 mg, 0.055 mmol) using reaction conditions similar to those described for Example 160, step 1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.53-7.23 (m, 10H), 7.14 (d, J = 9.7 Hz, 1H), 3.57 (d, J = 10.5 Hz, 1H), 3.25-3.03 (m, 3H), 2.95-2.61 (m, 6H). UPLC-MS 1: m/z 410.1 [M+H] ⁺ , t _R =1.04 min.

Example 163. 2-((2S,4S)-5-Chloro-6-fluoro-2-(morpholin-3-yl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide

The title compound (39 mg) was prepared analogously to Example 5a from the intermediates 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 (C-XLII) (890 mg, 1.59 mmol) and 2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV) (439 mg, 1.91 mmol). After Suzuki coupling, two mixtures of 2 diastereoisomers were respectively isolated by flash chromatography (silica, hexane/EtOAc, gradient: 0 to 100% EtOAc). After final removal of the Boc protecting group, the two mixtures of the two diastereoisomers were respectively subjected to chiral SFC (method 1: ChiralCel OD, 250 x 30 mm i.d., 5 μm, (CO ₂ /IPA+0.1% NH ₃ .H ₂ O) 60:40, flow rate: 50 mL/min; method 2: Chiralpak AD, 250 x 30 mm i.d., 5 μm CO ₂ /(EtOH+0.1% NH ₃ .H ₂ O) 86:14, flow rate: 80 mL/min) to afford all four diastereoisomers with diastereomeric excess >99%, respectively.

2-((2S,4S)-5-Chloro-6-fluoro-2-(morpholin-3-yl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 163) - diastereoisomer 1: chiral SFC (ChiralCel OD, 150 × 4.6 mm i.d., 3 μm, CO2/IPA (+0.05% DEA) from 95:5 to 60:40; flow rate: 2.5 mL/min.), t _R = 6.35 min. ^1H NMR (400 MHz, DMSO - _d6 ) δ (ppm) 7.69 (s, 1H), 7.55 (d, J =8.6 Hz, 1H), 7.46-7.26 (m, 6H), 7.20 (s, 1H), 7.03 (d, J =9.5 Hz, 1H), 3.91 (s, 3H), 3.71-3.48 (m, 3H), 3.23-3.13 (m, 1H), 3.12-3.05 (m, 1H), 3.00 (t, J =10.3 Hz, 1H), 2.91 (d, J =16.0 Hz, 1H), 2.71 (t, J =15.8 Hz, 2H), 1.94 (s, 1H). UPLC-MS 1: mass/charge 501.1/503.1 [M+H] ⁺ , t _R =0.80 min.

Diastereoisomer 2 (61 mg): chiral SFC (ChiralCel OD, 150 x 4.6 mm i.d., 3 μm, CO2/IPA (+0.05% DEA), 5-40%), flow rate: 2.5 mL/min) t _R = 5.81 min, UPLC-MS 1: m/z 501.1/503.1 [M+H] ⁺ , t _R = 0.87 min.

Diastereoisomer 3 (24 mg): chiral SFC (ChiralPak AD, 100 x 4.6 mm i.d., 5 μm, CO2/MeOH (+20 mM NH ₄ OAc), 13%), t _R = 2.17 min. UPLC-MS 1: m/z 501.3/503.3 [M+H] ⁺ , t _R = 0.68 min.

Diastereoisomer 4 (59 mg): chiral SFC (ChiralPak AD, 100 x 4.6 mm i.d., 5 μm, CO2/MeOH (+20 mM NH ₄ OAc), 13%), t _R = 3.53 min. UPLC-MS 1: m/z 501.3/503.3 [M+H] ⁺ , t _R = 0.69 min.

The following compounds were prepared similarly to Example 5a.

Note: Structure/Chemical Name UPLC MS
mass/charge [M+H] ⁺
t _R [min.] (method) ¹ H NMR 164
2-((2S,3S,4S)-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2-(pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;
compound (C-XXXVIII) and the aryl bromide, 2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV), were used in a Suzuki coupling reaction 501.3 0.80 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) δ 7.67-7.53 (m, 3H), 7.53-7.40 (m, 2H), 7.40-7.19 (m, 5H), 7.08-6.86 (m, 1H), 4.97 (s, 1H), 3.99-3.69 (m, 4H), 2.80-2.64 (m, 1H), 1.84-1.63 (m, 1H), 1.58-1.30 (m, 2H), 1.22-1 .01 (m, 1H). 165
2-((2S,3S,4S)-5-chloro-6-fluoro-3-methoxy-2-phenyl-2-(pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide;
compound (C-XXXIX) and the aryl bromide, 2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV), were used in a Suzuki coupling reaction 515.3 0.75 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) δ 7.63-7.56 (m, 3H), 7.37-7.22 (m, 5H), 7.14 (s, 1H), 7 .00 (s, 1H), 4.53 (s, 1H), 4.00-3.88 (m, 4H), 3.04 (s, 3H), 2.77-2.62 (m, 1H), 2.39-2.21 (m, 2H), 1.88-1.74 (m, 1H), 1. 54-1.29 (m, 2H), 1.14-1.06 (m, 1H). 166
2-((2S,3S,4S)-5-chloro-6-fluoro-3-methoxy-2-phenyl-2-(pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;
compound (C-XXXIX) and aryl bromide, 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzonitrile (N-VI), were used in a Suzuki coupling reaction. 545.5 0.72 (1) (400 MHz, DMSO-d ₆ ) δ (ppm) 7.63-7.52 (m, 3H), 7.40-7.19 (m, 5H), 7.13 (s, 1H), 6, 99 (s, 1H), 4.92 (t, J=5.4 Hz, 1H), 4.53 (s, 1H), 4.23-4.05 (m, 2H), 4.01-3.85 (m, 1H), 3.85-3.64 (m, 2H), 3.06 (s, 3H), 2, 78-2.61 (m, 1H), 2.38-2.23 (m, 2H), 1.89-1.76 (m, 1H), 1.56-1.29 (m, 2H), 1.19-1.01 (m, 1H). 167
2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-phenyl-2-(pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide;
compound (C-XL) and aryl 2-bromo-3-fluoro-4-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)benzonitrile (N-XIII) were used in the Suzuki coupling reaction. 543.2 0.70 (1) (600 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.55 (d, J=8.7 Hz, 1H), 7.51 (d, J=7.7 Hz, 2H), 7.28 (q, J=7.5, 7.1 Hz, 3H), 7.23 (d, J=7.2 Hz, 1H), 7.07 (s, 1H), 7.05 (s, 1H), 4.95 (d, J=4.3 Hz, 1H), 4.02-3.93 (m, 2H), 3.91 (dd, J=8.9, 3.5 Hz, 1H), 3.80 (t, J=7.1 Hz, 1H), 3.28 (q, J=7.8 Hz, 1H), 2.66-2.61 (m, 1H), 2.26 (q, J=7.5 Hz, 1H), 1.83-1.76 (m, 1H), 1.43 (dq, J=13.7, 7.2 Hz, 1H), 1.33 (q, J=7.0 Hz, 1H), 1.13 (d, J=5.7 Hz, 3H), 1.02 (d, J=7.0 Hz, 3H), 0.95 (d, J=9.8 Hz, 1H)

Example 168. 2-((2S,4S)-2-(1-Aminoethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide

The title compound (39 mg) was prepared analogously to Example 5a from the intermediates 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 (C-XLIII) and 2-bromo-3-fluoro-4-methoxybenzonitrile (N-IV).

2-((2S,4S)-2-(1-Aminoethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Example 168): ¹ H NMR (600 MHz, DMSO- d ₆ ) δ (ppm) 7.61 (br s, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.43 (d, J=7.6 Hz, 2H), 7.35 (t, J=7.6 Hz, 2H), 7.28 (t, J=8.0 Hz, 2H), 7.20 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 1H), 3.90 (s, 3H), 3.52 (d, J=1 6.3 Hz, 1H), 3.16 (q, J=6.2 Hz, 1H), 2.93 (d, J=16.5 Hz, 1H), 0.85 (d, J=6.6 Hz, 3 H). UPLC-MS 1: m/z 441.3 [M+H] ⁺ , t _R =0.77 min.

Another diastereoisomer, 2-((2S,4R)-2-(1-aminoethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide: UPLC-MS 1: m/z 441.3 [M+H] ⁺ , t _R = 0.64 min.

Example 169. 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

The title compound (39 mg) was prepared analogously to Example 151 from the intermediates 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 (C-XLIV) and 2-bromo-3-fluoro-4-(2-methoxyethoxy)benzonitrile (N-IX).

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 (Example 169): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.69 (s br, 1H), 7.56 (dd, J=8.8, 1.4 Hz, 1H), 7.53-7.46 (m, 2H), 7.36-7.19 (m, 4H), 7.07 (s br, 1H), 7.04 (d, J=9.6 Hz, 1H), 4.33-4.18 (m, 2H), 3.70 (t, J=4.5 Hz, 2H), 3.45-3.37 (m, 2H), 3.30 (s, 3H), 1.24 (s br, 2H), 1.03 (d, J=6.9 Hz, 3H), 0.83 (d, J=6.4 Hz, 3H). UPLC-MS 1: mass/charge 517.3 [M+H] ⁺ , t _R =0.79 min.

Another diastereoisomer, 2-((2S,3S,4R)-2-(1-aminoethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-methoxyethoxy)benzamide: UPLC-MS 1: m/z 517.3 [M+H] ⁺ , t _R = 0.73 min.

Example 170. 2-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)indolin-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide or (2P)-2-{(2S)-5-chloro-6-fluoro-2-phenyl-2-[(2S)-pyrrolidin-2-yl]-2,3-dihydro-1H-indol-4-yl}-3-fluoro-4-(2-hydroxyethoxy)benzamide

The title compound was prepared analogously to Example 5a from the intermediates 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)indolin-1-carboxylate (C-XLV) and 2-bromo-3-fluoro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzonitrile (N-VI). After a Suzuki coupling reaction and conversion of the nitrile to the amide, the THP group was first cleaved using pyridinium p-toluenesulfonate before the two Boc groups were cleaved using 4 M HCl in dioxane. Diastereoisomers were separated after removal of the THP and BOC protecting groups.

2-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)indolin-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide (Example 170): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.45 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 7.5 Hz, 2H), 7.34-7.14 (m, 5H), 6.70 (s, 1H), 6.51 (d, J = 10.4 Hz, 1H), 4.92 (t, J = 5.4 Hz, 1H), 4.11 (t, J = 4.9 Hz, 2H), 3.73 (q, J = 5.1 Hz, 2H), 3.19 (d, J = 16.4 Hz, 1H), 2.52 (dd, 1H), 2.50-2.44 (m, 3H), 2.07-1.93 (m, 1H), 1.67 (s, 1H), 1.43 (d, J = 23.0 Hz, 3H). UPLC-MS 3: m/z 514.2 [M+H] ⁺ , t _R = 0.71 min.

Another diastereoisomer, 2-((2S,4R)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)indolin-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide: UPLC-MS 3: m/z 514.2 [M+H] ⁺ , t _R = 0.65 min.

The following examples were obtained in a similar manner to the previous examples.

Example 171. 2-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)indolin-4-yl)-3-fluoro-4-methoxybenzamide

UPLC-MS 3: mass/charge 484.2 [M+H] ⁺ , t _R =0.79 min.

Example 172. 2-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)indolin-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide

UPLC-MS 4: mass/charge 542.3 [M+H] ⁺ , t _R =0.65 min.

Example 173. 4-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)indolin-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide

UPLC-MS 4: mass/charge 529.1 [M+H] ⁺ , t _R =0.61 min.

Example 174. 2-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide

^1H NMR (400 MHz, DMSO -d6 ) δ (ppm) 7.59 (s,1H) _, 7.54 (dd, J=8.6, 1.4 Hz, 1H), 7.46-7 .40 (m, 2H), 7.37-7.20 (m, 5H), 7.01 (d, J=9.7 Hz, 1H), 3.90 (s, 3H), 3.54-3.42 (m, 2H), 2.87 (d, J=15.7 Hz, 1H), 2.70 (dt, J=9 ,8, 6.5 Hz, 1H), 2.58 (dt, J=9.7, 6.2 Hz, 1H), 2.30 (s br, 1H), 1.62-1.51 (m, 1H), 1.50-1.37 (m, 2H), 1.35-1.22 (m, 1H). UPLC-MS 4: m/z 485.3 [M+H] ⁺ , t _R = 0.71 min.

Example 175. 2-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro- 4-methoxy-N-methylbenzamide

^1H NMR (400 MHz, DMSO -d6 ) δ (ppm) 8.08 (d, J=4.8 Hz, 1H) _, 7.47 (dd, J=8.6, 1.4 Hz, 1H ), 7.45-7.40 (m, 2H), 7.35-7.22 (m, 4H), 7.00 (d, J=9.7 Hz, 1H), 3.90 (s, 3H), 3.50 (t, J=6.8 Hz, 1H), 3.40 (dd, J=15.9, 1.7 Hz, 1H), 2.86 (d, J=15.6 Hz, 1H), 2.76-2.68 (m, 1H), 2.65-2.58 (m, 1H), 2.62 (d, J=4.5 Hz, 3H), 2.32 (s br, 1H), 1.58-1.42 (m, 2H), 1.41-1.31 (m, 2H). UPLC-MS 4 : mass/charge 499.3 [M+H] ⁺ , t _R =0.70 min.

Example 176. 2-((2S,3S,4S)-2-(Aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4- methoxybenzamide

^1H NMR (600 MHz, DMSO - _d6 ) δ (ppm) 7.71 (s, 1H), 7.60 (dd, J=8.7, 1.2 Hz, 1H), 7.46-7 .40 (m, 2H), 7.40-7.33 (m, 2H), 7.33 -7.25 (m, 2H), 7.12 (s, 1H), 7.06 (d, J=9.5 Hz, 1H), 3.89 (s, 3H), 3.28 (q, J=7.1 Hz, 1H), 3.16-3-01 (m, 2H), 1.14 (s br, 2H), 0.92 (d, J=7.2 Hz, 3H). UPLC-MS 3: mass/charge 459.2 [M+H] ⁺ , t _R =0.76 min.

In vitro biochemical analyses

Avi-labeled human TEAD4 ^217-434 (1 nM, prepared as described in Hau et al. ChemBioChem 14, 1218, 2013) and LANCE streptavidin Eu-W1024 (0.5 nM, PerkinElmer) were first pre-incubated for 1 h at room temperature in HEPES (pH 7.4, 50 mM), KCl (100 mM), Tween-20 (0.05%), TCEP (0.25 mM), EDTA (1 mM), and BSA (0.05%). N-terminal Cy5-labeled human YAP ^60-100 (20 nM) was then added to this preparation. Compounds were dissolved at 10 mM in 100% DMSO and serially diluted in 100% DMSO. Diluted compound solutions were incubated in white 384-well plates (Greiner Bio-One) for 1 h at room temperature with the above mixture. The final concentration of DMSO present in the assay was 1%. Fluorescence was measured (50 μs delay between excitation and fluorescence, 75 μs integration time) with a Genios Pro reader (Tecan) using an excitation wavelength of 340 nm and emission wavelengths of 620 nm and 665 nm. These assays were performed using a TR-FRET emission ratio of 655 nm/620 nm. _IC50 values were estimated by fitting the data using nonlinear regression for fit (GraphPad Prism). In an "alternate" format, the assay was performed in the presence of 5 nM human His-TEAD4 ^217-434 , 10 nM N-biotinylated YAP ^60-100 , 0.2 nM europium-labeled anti-His antibody, and 10 nM SA-XL665. Results obtained in this alternative format are marked with an asterisk ^*) in the table below.

Example IC ₅₀ [µM] 1 6.8 ^*) 1a 1.22 1b >100 2a 0.036 ^*) 2b 247.8 ^*) 2a-1 0.026 2a-2 1.31 3a 0,016 3b 18 4a 0.034 4b >100 5a 0.005 5b 23.3 4a-1 0.02 6 0.376 7 0.065 8 0.004 9 0.004 10 0.003 11 0,021 12 0.0015 13 0.006 14 0,015 15 0.01 16 0.006 17 0,013 18 0.004 19 0.003 20 0.124 21 0.004 22 0,009 23 0,009 24 0.006 25 0.005 26 0,021 27a 0,001 27b 0,001 28a 0.003 28b 0.003 29 0.01 30 0.143 31 0.003 32a 0.033 ^*) 32b >100 33 0.003 34 0,009 35 0,009 36 0.01 37 0.002 38 0.002 39 0.102 40 0.042 41 0.089 42 0.006 43 0,005 44 0.006 45 0.01 46 0.003 47 0.004 48 0.002 49 0,005 50 0.03 51 0.003 52 0,011 53 0.006 54a 0.075 54b 0.022 55a <0.001 55b 0.002 56a 0.002 56b 0,011 57a 0.003 57b 0.006 58a 0.004 58b 0.006 59a 0.006 59b 0,005 60 0.02 61a 0,008 61b 0.01 62a 0,016 62b 0.006 63 0.069 64a 0.002 64b 0.003 65a 0.004 65b 0.455 66a 0.002 66b 0.002 67a 0.002 67b 0.003 68a 0.01 68b 0,012 69a 0,005 69b 0.004 70 0.02 71a 0.002 71b 0,001 72 0.002 73 0,014 74 0.033 75 0.038 76 0.05 77 0,071 78 0.16 79 0,011 80 0,014 81a 0.033 81b 0.032 82 0.119 83 0.024 84 0.041 85a 0.004 85b 0,007 86 0.003 87 0.03 88 0,007 89 0,019 90 0.022 91 0.022 92 0.022 93 0,009 94a 0.002 94b 0.003 95a 0,008 95b 0,007 96 0,005 97 0.004 98 0,005 99 0.002 100a 0.002 100b 0,005 101 0.003 102a 0.003 102b 0.004 103 0,005 104a 0.003 104b 0.002 105 0.002 106 <0.001 107 0.002 108 0.002 109 0.003 110 0,001 111 0.004 112 0,001 113 0.002 114a 0.002 114b 0.002 115a 0.002 115b 0.002 116a <0.001 116b 0,001 117a <0.001 117b 0,001 118 0,001 119 0.002 120 0.003 121 0.002 122 0.006 123 0.002 124 0,011 125 0,011 126 0.002 127 0.006 128 0.176 129 0.025 130 0.797 131 1.29 132 2.08 133 0.695 134 0.074 135 0,007 136a 0,007 136b 0,007 137a 0,005 137b 0.006 138a 0.018 ^*) 138b 0.018 ^*) 139a 0,021 139b 0,011 140a 0.004 140b 0.006 141 0,005 142 0,007 143 0.003 144 0.002 145 0,005 146 0.003 147 0,001 148 0.004 149 0,005 150 0.004 151 0.002 152 0.002 153 <0.001 154 0,008 155 0,009 156 0,011 157 0.075 158 0,005 159 0.122 160 4.4 161 0.029 162 1.52 163 0.13 164 0.004 165 0,005 166 0,008 167 0.01 168 0,012 169 0,007 170 0,001 171 0.002 172 0,015 173 0,014 174 0.003 175 0.004

In vitro cell assays

NCI-H2052 mesothelioma cells (RRID:CVCL_1518) harboring mutations activating the pathway upstream of YAP (homozygous LATS2 deletion and NF2 mutation) were obtained from ATCC, whereas MKN-45 gastric adenocarcinoma cells (RRID:CVCL_0434) with a genomic deletion of YAP were obtained from JCRB.

To control the activity of the YAP-dependent pathway, NCI-H2052 cells were stably transduced with a lentivirus expressing firefly luciferase under the control of a promoter consisting of 10× ATTCCTC sequence (based on the (5′-CATTCCT-3′) element of the muscle-specific cytidine-adenosine-thymidine (MCAT) promoter), which was cloned into the pGL4.27 vector (Promega, WI, USA) and subsequently subcloned into pLENTI6TR (Invitrogen, CA, USA). This cell line was also transduced with a Tet-pLKO-puro-based construct mediating tetracycline-inducible expression of a short hairpin directed against the 3′UTR of YAP1 mRNA (5′-CATGAGACAATTTCCATATA-3′). The resulting NCI-H2052 Tet-On shYAP_2371 pLenti6 MCAT_Luc cell line was selected and maintained in growth medium (RPMI 1640 (Amimed, Cat#1-41F01-I), 2 mM L-glutamine (Amimed, Cat#5-10K50-H), 1% MEM with nonessential amino acids (Amimed, Cat#5-13K00-H), 10% fetal bovine serum (Gibco, Cat#A31608-01, Lot#42F0863K), 1 mM sodium pyruvate (Amimed, Cat#5-60F00-H), 1x penicillin/streptomycin (Amimed, cat.№4-01F00-H)), containing 0.5 μg/ml puromycin (Gibco, cat.№A11138-03) and 1 μg/ml blasticidin (Gibco, cat.№A11139-03) at 37°C in a humidified incubator with 5% CO ₂ .

As a specificity control, MKN-45 cells were stably transduced with the Ubc-Luc reporter construct, in which constitutive expression of firefly luciferase is driven by the ubiquitin C housekeeping gene promoter. The resulting MKN-45/Ubc-luc cell line was selected and maintained in growth medium (RPMI 1640 (Amimed, #1-41F01-I), 2 mM L-glutamine (Amimed, Cat#5-10K50-H), 10% fetal bovine serum (Amimed, #2-01F30-I, lot K08815P), 1% MEM with nonessential amino acids (Amimed, Cat#5-13K00-H), 1x penicillin/streptomycin (Amimed, Cat#5-13K00-H), 1x α-amino acids (Amimed, Cat#5-13K00-H), 1x β ... No. 4-01F00-H)), containing 1 μg/ml blasticidin (Gibco, cat. No. A11139-03) at 37°C in a 5% _CO2 humidified incubator.

Solutions of compounds

Compound stock solutions were prepared at 10 mM in DMSO and stored at 4°C. Where a full dose-response curve was required, stock solutions were pre-diluted in DMSO to a 1000-fold reduction in the required starting concentration. The day after cell plating, eleven 2-fold serial dilutions of each compound were dispensed directly into cell assay plates using a contactless digital HP 300D dispenser (TECAN, Männedorf, Switzerland). The final DMSO concentration was normalized to 0.1% in all wells.

Analysis of YAP reporter gene activity

The ability of compounds to inhibit YAP-dependent transcription was assessed in NCI-H2052 Tet-On shYAP_2371 pLenti6 MCAT_Luc cells, while specificity (lack of non-specific inhibition of luciferase expression for activity) was assessed in MKN-45/Ubc-luc cells. Individual cell lines were seeded at 2500 cells/20 µl/well in 384-well white-walled, clear-bottomed plates (Greiner, Cat# 781098) and incubated overnight at 37°C before addition of serial dilutions of compounds as described above. Following 24 h incubation at 37°C, compound-mediated modulation of reporter gene activity was quantified at 5 min. after addition of 20 µl BrightGlo (Promega, Cat.# E2620) by measuring the luminescence intensity on a multi-mode plate reader (TECAN, Männedorf, Switzerland, 100 ms integration time). For data analysis, the assay background determined in wells containing medium but no cells was subtracted from all data points. Compound dose-response effects were expressed as % of vehicle control (luminescence signal produced by cells taking up DMSO alone) and IC ₅₀ values were calculated using a four-parameter fitting model.

Proliferation analysis

The functional effect of compounds on cell proliferation was assessed using NCI-H2052 Tet-On shYAP_2371 pLenti6 MCAT_Luc and MKN-45/Ubc-luc cells by quantifying the reducing capacity of live cells using the redox indicator dye resazurin. Briefly, individual cell lines were seeded at 750 cells/20 μl/well (NCI-H2052) or 500 cells/20 μl/well (MKN-45) in 384-well black-walled, clear-bottomed plates (Corning, Cat.#3712) and incubated overnight at 37°C before addition of serial dilutions of compounds as described above. Following incubation for 72 h at 37°C, compound-mediated modulation of cell viability was quantified 4 h after addition of 5 μl resazurin sodium salt (SIGMA, Cat# R7017, 0.85 μg/ml in phosphate buffered saline) by measuring the fluorescence intensity of resorufin (the reduced form of resazurin) on a multi-mode plate reader (TECAN, Männedorf, Switzerland, Exc/Emis 544/590 nm). For data analysis, the assay background determined in wells containing medium but no cells was subtracted from all data points. To allow differentiation of cytotoxic from cytostatic compounds, the number of viable cells was estimated relative to the number observed at the time of compound addition using a separate cell plate (day 0). The effect of a particular concentration of test compound on cell proliferation/viability was expressed as a percentage of the day 0-corrected fluorescence readings obtained for cells treated with vehicle medium alone (DMSO, final concentration 0.1%), which was set to 100%, with fluorescence readings for wells containing medium but no cells set to -100%. Compound concentrations producing half-maximal growth inhibition (GI ₅₀ ) were determined using standard four-parameter curve fitting.

Reporter gene assay Proliferation assay Example NCI-H2052
IC ₅₀ [µm] MKN-45
IC ₅₀ [µm] NCI-H2052
GI ₅₀ [µm] MKN-45
GI ₅₀ [µm] 5a 0.13 >20 0.28 >10 5b >10 >10 >10 >10 4a-1 0.6 >10 0.59 >10 10 0.064 >10 0.099 >10 11 0.173 >20 0.284 >10 12 0.037 >20 0.086 >10 13 0.102 >10 0.166 >10 14 0.176 >10 0.19 >10 15 0.27 >10 0.276 >10 18 0.379 19.5 0.553 >12.5 20 2.92 >10 6.88 >10 21 0.154 >10 0.247 >10 22 0.157 >20 0.256 >10 25 0.106 >10 0.145 >10 26 0.144 >20 0.31 >10 27a 0.026 >10 0.081 >10 27b 0.078 >10 0.182 >10 28a 0.086 >10 0.224 >10 28b 0.055 >10 0.148 >10 29 2,005 >10 1.85 >10 30 4.77 >10 6.84 >10 31 0.343 >10 0.346 >10 32a 0.498 >10 0.833 6.12 33 0.161 >10 0.161 >10 35 0.276 >10 0.31 >10 37 0.033 >10 0.052 >10 38 0.024 >10 0.029 >10 39 2.15 >10 2.83 >10 42 0.391 >10 0.493 9.4 43 0.047 >10 0.094 >10 44 0.069 >10 0.109 >10 47 0.05 >10 0.035 >10 51 0.062 >10 0,071 >10 52 0.109 >10 0.174 >10 54a 0.147 >10 0.67 >10 54b 0.118 >10 0.258 >10 56a 0.07 >10 0.195 >10 56b 0.194 7.6 0.372 >10 58a 0.067 >10 0.125 >10 58b 0.104 >10 0.167 >10 62a 0.203 >10 0.24 >10 62b 0.054 >10 0.089 >10 64a 0,015 >10 0.036 >10 64b 0.022 >10 0.041 >10 69a 0.08 >10 0,111 >10 69b 0.114 7.8 0.171 6.7 72 0.039 9.8 0.072 >10 74 0.419 >10 0.674 >10 81a 0.231 >10 0.467 >10 81b 0.316 >10 0.571 >10 83 0.394 >10 0.503 >10 86 0.119 >10 0.129 >10 88 0.091 >10 0.242 >10 89 0.596 >10 1.6 >10 90 1.43 >10 1.7 >10 91 0.96 >10 1.93 >10 94a 0.045 >10 0.068 >10 94b 0.083 >10 0.101 >10 96 0.084 >10 0.188 >10 97 0.065 >10 0.117 >10 99 0.023 >10 0.026 >10 101 0.067 >10 0.106 >10 103 0.108 >10 0.172 >10 104a 0.035 >10 0.144 6.2 104b 0.022 >10 0.055 >10 106 0,014 >10 0,013 >10 109 0.075 >10 0.086 >10 110 0,014 >4 0.027 >4 113 0,021 >10 0.029 >10 114a 0,018 >10 0.023 >10 114b 0.023 >10 0.034 >10 117a 0,015 >10 0,014 >10 117b 0,016 >10 0.03 >10 118 0.01 >5.5 0,015 >5.5 119 0.022 >10 0.028 >10 120 0.02 >10 0.022 >10 121 0.02 >10 0.036 >10 122 0.085 >10 0.059 >10 123 0.025 >10 0.044 >10 124 1.23 >10 1.07 >10 125 0.671 >10 1.18 >7.5 126 0.045 >10 0.076 >10 127 0.065 >10 0.141 >10 128 5.72 >10 7.05 >10 129 0.615 >10 0.892 >10 134 2.31 >10 1.57 >10 135 0.247 >10 0.627 8.64 138a 0.239 >20 0.366 >13.3 138b 0.221 7.63 0.435 >10 140a 0.023 >10 0.028 >10 140b 0.028 >10 0.029 >10 144 0.01 >8 0.01 >8 145 0.046 >20 0.058 >20 146 0.025 >10 0.023 >10 147 0,011 >3.3 0,005 >3.3 148 0.054 >20 0.053 >20 149 0.096 >10 0,1 >10 150 0.074 >10 0.085 >10 151 0,015 >10 0.022 >10 152 0.036 >10 0.025 >10 153 0.024 >10 0.104 >10 154 0,077 >10 0.059 >10 155 0.048 >20 0.041 >20 158 0.093 >10 0.181 >10 159 1.06 >15 0.856 >15 161 0.174 >10 0.167 >10 162 1.00 >10 1.76 >10 164 0.107 >10 0.107 >10 165 0.082 >10 0.131 >10 166 0.136 >10 0.256 >10 167 0.058 >10 0.082 >10 168 0.253 >10 0.267 >10 169 0.153 >10 0.246 7.83 170 0,012 >8 0.023 >8 171 0.116 15.5 0.073 13 172 0.144 >20 0.104 >20 173 0.187 >20 0.158 >20 174 0.037 12 0,021 11 175 0.062 13 0.05 7 176 0,018 11 0,021 16

As demonstrated by the data presented above, the compounds of the present invention are effective inhibitors of YAP/TAZ-TEAD PPI. The results indicate that the compounds may therefore be useful in the treatment of diseases or conditions mediated by YAP overexpression and/or YAP amplification and/or YAP/TAZ-TEAD interaction, such as cancers.

Thus, after describing several aspects of several embodiments, various changes, modifications and improvements should be understood by those skilled in the art. It is understood that such changes, modifications and improvements are part of the present invention and are within the spirit and scope of the present invention. Accordingly, the above description and drawings are given by way of example only.

Numerous equivalents to the specific embodiments specifically described herein will be apparent to those skilled in the art or may be able to ascertain such equivalents by no more than routine experimentation. Such equivalents are intended to be within the scope of the following claims.

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SEQUENCE LIST

<110>Novartis AG

<120>Biaryl derivatives as inhibitors of protein-protein

interactions

<130>N22608/236129

<140>110109036

<141>2021-03-12

<160>3

<170>PatentIn version 3.5

<210>1

<211>7

<212>DNA

<213>Artificial sequence

<220>

<223>Synthetic oligonucleotide

<400>1

attcctc 7

<210>2

<211>7

<212>DNA

<213>Artificial sequence

<220>

<223>Synthetic oligonucleotide

<400>2

cattcct 7

<210>3

<211>20

<212>DNA

<213>Artificial sequence

<220>

<223>Synthetic oligonucleotide

<400>3

catgagacaa tttccatata 20

<---

Claims (249)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, Where X is selected from CH; and N; A is phenyl; R _w is selected from (i) hydrogen; and (ii) C ₁ -C ₃ alkyl; Q is selected from (i) -C(R ⁷ ) ₂ -NH-R ₁ ; 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 is in the α-position with respect to the carbon atom linking Q to the remainder of the molecule, wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from hydroxy, C ₁ -C ₃ alkyl and halogen; R ₁ is selected from (i) C ₁ -C ₆ alkyl and (ii) R _1a ; where R _1a is C ₃ -C ₆ cycloalkyl optionally independently substituted once or more than once with hydroxy, C ₁ -C ₆ alkyl or halogen; R ₂ is a halogen; R ₃ is halogen; R ₄ is a halogen; R ₅ is selected from C ₁ -C ₆ alkoxy and hydroxyC ₁ -C ₆ alkoxy; R ₆ is C(O)NHR ^6a ; R ^6a is selected from (i) hydrogen and (ii) C ₁ -C ₃ alkyl; And each R ⁷ is a hydrogen. 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof of formula (Id), (Id). 3. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of (S)-(5-chloro-2,4-diphenyl-2,3-dihydrobenzofuran-2-yl)methanamine; N1-(2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenyl)ethane-1,2-diamine; 2-(2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorophenoxy)ethanamine; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,4R)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-methylbenzamide; trifluoroacetate salt of 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-chlorobenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-chloro-3-fluorobenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3,4-difluorobenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-methoxyethoxy)benzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((R)-2-hydroxypropoxy)benzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((R)-2-fluoropropoxy)benzamide; trifluoroacetate salt of 2-(3-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-carbamoyl-2-fluorophenoxy)acetic acid; 4-(((R)-4-acetylmorpholin-2-yl)methoxy)-2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4- yl)-3-fluorobenzamide; 4-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-methoxynicotinamide; 4-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-6-(difluoromethoxy)-5-fluoronicotinamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(methylamino)benzamide; 2-((2S,4S)-5-chloro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxy-N-methylbenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-N-cyclopropyl-3-fluoro-4-methoxybenzamide; 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; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxy-N-(pyridin-3-yl)benzamide; 2-((2S,4S)-5-chloro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxy-N-methylbenzamide; 2-((2S,4S)-5-chloro-2-(((trans-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4- methoxybenzamide; 2-((2S,4S)-5-chloro-2-(((cis-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4- methoxybenzamide; (trans)-4-((((2S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexanecarboxylic acid; (cis)-4-((((2S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexanecarboxylic acid; 2-((2R,4S)-2-(aminomethyl)-5-chloro-2-(thiazol-4-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-(2-fluorophenyl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(cyclopropylmethoxy)-3-fluorobenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(1,1-difluoro-2-hydroxyethoxy)-3-fluorobenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-methoxyethoxy)benzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide; 2-((2S,4R)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-((1,1-difluoro-2-hydroxyethyl)thio)benzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((methylsulfonyl)methoxy)benzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(3,3-difluoropropoxy)-3-fluorobenzamide; 4-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-methoxynicotinamide; 4-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide; 4-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 4-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-methoxyethoxy)nicotinamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide; 4-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinamide; 2-((2S,4S)-5-chloro-2-(((cyclopropylmethyl)amino)methyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)- 3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide; 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; 4-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((cis)-4-(methylsulfonyl)cyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 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; 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; 2-((2S,4S)-2-(((4-acetamidocyclohexyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy )-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(((4-(methylsulfonamido)cyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-2-(((4-(dimethylcarbamoyl)cyclohexyl)amino)methyl)-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4 -(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(((2-oxo-1-azaspiro[4.5]decan-8-yl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 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; 2-((2S,4S)-5-chloro-6-fluoro-2-(((4-(hydroxymethyl)cyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(((3-(2-hydroxypropan-2-yl)cyclobutyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran- 4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(((1-(methylsulfonyl)piperidin-4-yl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 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; 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; 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; 2-((2S,4S)-5-chloro-2-((((2R,4s,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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 2-((2S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)- 4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-2-((tert-butylamino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3 -fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((R)-2-hydroxypropyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((S)-1-hydroxypropan-2-yl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4 -yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(((1-methylcyclopropyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy )-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(((2-methoxyethyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(((2-(2-oxopyrrolidin-1-yl)ethyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 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; 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; 2-((2S,4S)-5-chloro-6-fluoro-2-((((1S,3R,4R)-3-fluoro-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((1R,3S,4S)-3-fluoro-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(((trans-3-fluorocyclobutyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4- (difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((1R,3S)-3-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl )-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-1-methylcyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(((6-hydroxyspiro[3.3]heptan-2-yl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-methoxyethoxy)benzamide; 2-((2R,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2R,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-(6-methoxypyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-(2-methoxypyridin-3-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-(2-oxo-1,2-dihydropyridin-3-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-(2-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 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; 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; 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; 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; 2-((2S,3S,4S)-5-chloro-2-((cyclobutylamino)methyl)-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 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; 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; 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; 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; 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; 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; 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; 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 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; 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; 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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)benzonitrile; 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; 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; 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; 2-(2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3,4-difluorophenoxy)ethan-1-ol; 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; 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; 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; 2-((2S,4R)-2-(aminomethyl)-2-phenyl-5-(trifluoromethyl)-2,3-dihydrobenzofuran-4-yl)-4-methoxybenzamide; 2-((2S,4R)-5-cyano-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxy-N-methylbenzamide; (S)-2-((((trans)-4-hydroxycyclohexyl)amino)methyl)-2,4-diphenyl-2,3-dihydrobenzofuran-5-carbonitrile; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-3-fluorobenzamide; 2-(2-(aminomethyl)-6-chloro-2-phenyl-2,3-dihydrobenzofuran-7-yl)-3-fluoro-4-methoxybenzamide; 2-(2-(aminomethyl)-5-chloro-2-phenylbenzo[d][1,3]dioxol-4-yl)-3-fluorobenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenylindolin-4-yl)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-2-((cyclohexylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 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; 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; 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; 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; 2-((2S,4S)-2-((((trans)-4-carbamoylcyclohexyl)amino)methyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide; 2-((2S,4S)-2-((((cis)-4-carbamoylcyclohexyl)amino)methyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-2-((((trans)-4-(methylcarbamoyl)cyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3 -fluorobenzamide; 2-((2S,4S)-5-chloro-2-((((cis)-4-(methylcarbamoyl)cyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3 -fluorobenzamide; 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; 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; 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; 2-((2S,4S)-5-chloro-6-fluoro-2-(((methyl-d3)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 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; 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro -4-methoxybenzamide; 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; 2-((2S,3R,4S)-5-chloro-6-fluoro-3-(hydroxymethyl)-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 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; 2-((2S,4S)-2-(azetidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide; 2-((2S,3S,4S)-2-(azetidin-2-yl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3- fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide; 2-((2S,3S,4S)-2-(azetidin-2-yl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3- fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide; (2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide; 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide; 2-((4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-5-(methylcarbamoyl)pyridin-2-yl)oxy)acetic acid; 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-hydroxy-N-methylnicotinamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(4-hydroxypyrrolidin-2-yl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(4-hydroxy-4-methylpyrrolidin-2-yl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide; (2S,4R)-2-((S)-5-chloro-6-fluoro-2,4-diphenyl-2,3-dihydrobenzofuran-2-yl)-4-fluoropyrrolidine; 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; (3-((S)-5-chloro-6-fluoro-2,4-diphenyl-2,3-dihydrobenzofuran-2-yl)morpholine; 2-((2S,4S)-5-chloro-6-fluoro-2-(morpholin-3-yl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2-(pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methoxy-2-phenyl-2-(pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methoxy-2-phenyl-2-(pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-phenyl-2-(pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide; 2-((2S,4S)-2-(1-aminoethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 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; 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)indolin-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)indolin-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)indolin-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide; 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)indolin-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide; 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro- 4-methoxy-N-methylbenzamide; And 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide. 4. A compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is 5. A compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is 6. A compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is 7. A compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is 8. A compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is 9. A compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is 10. A compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is 11. A compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is 12. A compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is 13. A compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is 14. A compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is 15. A compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is 16. A pharmaceutical composition having a YAP/TAZ-TEAD protein-protein interaction (PPI) inhibitory activity, comprising a therapeutically effective amount of a compound according to any one of claims 1-15 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. 17. A compound according to any one of claims 1-15 or a pharmaceutically acceptable salt thereof for use as a medicinal product. 18. A compound according to any one of claims 1-15 for use in the treatment of a cancer or tumor, optionally wherein the cancer or tumor carries (i) one or more YAP/TAZ fusions, (ii) one or more NF2/LATS1/LATS2 truncating or deletion mutations, or (iii) one or more functional YAP/TAZ fusions.