Carboxamides as ubiquitin-specific protease inhibitors

Abstract

The present disclosure relates to modulators, such as inhibitors, of at least one pathway chosen from USP28 and USP25, pharmaceutical compositions comprising the inhibitors, and methods of using the inhibitors. The modulators, such as inhibitors, of at least one pathway chosen from USP28 and USP25 can be useful in the treatment of cancers, among other ailments.

Description

DEMANDE OU BREVET VOLUMINEUX LA PRÉSENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND PLUS D'UN TOME. CECI EST LE TOME 1 DE 3 CONTENANT LES PAGES 1 À 229 NOTE: Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS / PATENTS THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE THAN ONE VOLUME THIS IS VOLUME 1 OF 3 CONTAINING PAGES 1 TO 229 NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME : NOTE POUR LE TOME / VOLUME NOTE: CARBOXAMIDES AS UBIQUITIN-SPECIFIC PROTEASE INHIBITORS TECHNICAL FIELD

[0001] The present disclosure is directed to modulators of at least one pathway chosen from ubiquitin-specific protease 28 (USP28) and / or ubiquitin-specific protease 25 (USP25) useful in the treatment of diseases or disorders associated with at least one pathway chosen from USP28 and USP25 enzymes. Specifically, the disclosure is concerned with chemical entities and compositions inhibiting at least one pathway chosen from USP28 and USP25, methods of treating diseases or disorders associated with at least one pathway chosen from USP28 and USP25, and methods of synthesis of these compounds. BACKGROUND

[0002] USP28 and USP25 are cysteine isopeptidases of the USP sub-family of DUBs containing three distinct domains: an N-terminal UBA-like domain; a pair of ubiquitin-interacting motifs (UIM) and a USP domain that is predicted to have the conserved fold of the USP sub-family (Nijman et al., Cell 2005, 123, 773-786; Komander et al., Mol. Cell Bio. 2009, 10, 550-563). USP28 and USP25 exert their function through regulating the stability of a plethora of cellular proteins. USP28 has been characterized as a tumor-promoting factor and has been found to stabilize many oncoproteins. USP25 has been characterized as a tumor-promoting factor and as a regulator of cellular responses related to autoimmune disease, inflammation, and infectious diseases (such as viruses and bacteria).

[0003] Amplification, deletions and mutations of USP28 have been identified in multiple cancer types, including breast cancer, AML, ovarian cancer, and colorectal cancer. (cbioportal; http: / / www.cbioportal.org; Diefenbacher et al., J. of Clin. Investi. 2014, 124, 3407-3418; Popov et al., Nat. Cell. Biol. 2007, 9, 729-731). Furthermore, USP28 overexpression has been correlated with poor prognosis in patients with glioblastoma, non-small cell lung carcinoma and bladder cancers suggesting that USP28 plays an important role in tumorigenesis of these tumor types. (Wang et al. Exp. Biol. Med. 2016, 255-264; Zhang et al. J. Cell. Mol. Med. 2015, 19, 799-805; Guo et al., Tumor Bio. 2014, 35, 4017-4022).

[0004] A large-scale shRNA screen has also identified a role of USP28 in the control of the stability of MYC protein. (Popov, Nat. Cell. Biol., 765-774). MYC is a master regulator of the transcription of genes involved in cell growth, proliferation and apoptosis and is essential for tumor initiation and maintenance in many tumor types. (Meyer et al., Nat. Rev. Cancer 2008, 8, 976-990; Conacci-Sorrell et al., Cold Spring Harb. Perspect. Med. 2014, 4, 1-24; Huang et al., Cold Spring Harb. Perspect. Med. 2013; Roussel et al., Cold Spring Harb. Perspect. Med. 2013; Gabay et al., Cold Spring Harb. Perspect. Med. 2014; Schmitz et al., Cold Spring Harb. Perspect. Med. 2014). In addition, MYC is the most frequently amplified oncogene in human cancer, with alterations in many tumor types including breast, lung and prostate. (Beroukhim et al., Nature 2010, 463, 899- 905). Knockdown of the USP28 gene has been shown to lead to a decrease of MYC protein and an associated inhibition of growth in a panel of human cancer cell lines in vitro. (Popov, Nat. Cell Biol., 765-774).

[0005] USP28 has also been reported to be required to impart stability on the LSD1 (lysine- specific demethylase 1) protein. (Wu et al., Cell Rep. 2013, 5, 224-236). LSD1 is a histone demethylase that complexes with many partner proteins to control cellular pluripotency and differentiation. (Metzger et al. Nature 2005, 437, 436-439; Toffolo et al, J. Neurochem. 2014 128, 603-616, 2014; Periz et al., PloS Biology 2015). Knockdown of USP28 in tumor cells has been shown to lead to the destabilization of LSD1 protein, the suppression of cancer stem cell (CSC)- like characteristics in vitro, and the inhibition of tumor growth in vivo. (Wu, Cell Rep., 224-236). Small molecule inhibitors of LSD1 have shown antitumor activity in models of AML and Ewing sarcoma. (Sankar et al., "Reversible LSD1 inhibition interferes with global EWS / ETS transcriptional activity and impedes Ewing sarcoma tumor growth" Clin Cancer Res. 2014 4584- 4597; Schenk et al., Nat. Med. 2012, 18, 605-611). Thus, USP28 inhibition represents an alternate approach to targeting LSD1 in these tumor types.

[0006] USP28 inhibition has also been shown to reduce NICD1-Levels and to lead to inhibition of the NOTCH pathway activity. (Diefenbacher et al.). NOTCH signaling controls diverse cellular differentiation decisions and drives tumorigenesis in certain tumor types. NOTCH1 is a potent T-cell oncogene, with >50% of T-cell acute lymphoblastic leukemia (T-ALL) cases carrying activating mutations in NOTCH1. (Weng et al. Science 2004, 306, 269-271). Increased NOTCH1 protein levels have also been associated with disease progression in colon cancer. (Meng et al., Cancer Res. 2009, 69, 573-582). NOTCH1 rearrangements lead to constitutive pathway activation and drive tumorigenesis in many cancer types, including triple- negative breast cancer. (Stoeck et al., Cancer Discov. 2014, 4, 1154-1167).

[0007] Other reported substrates of USP28 include c-Jun, Cyclin E, HIF-1\alpha, Claspin, 53BP1, and Mdc1, many of which play important roles in tumorigenesis in humans. (Diefenbacher et al.; Flügel et al. Blood 2012, 119, 1292-1301; Zhang et al., "A role for the deubiquitinating enzyme USP28 in control of the DNA-damage response" Cell 2006, 126, 529-542). Interestingly, many USP28 substrates are recognized by FBW7, the substrate recognition subunit of SCF (FBW7) E3 ubiquitin ligase. (Diefenbacher et al.). FBW7 recognizes USP28 substrates in a phosphorylation- dependent manner and targets them for ubiquitination ultimately leading to their proteasomal degradation. The antagonizing roles of USP28 and FBW7 on their shared oncoprotein substrates indicate the intricate nature of protein stability control and may provide additional therapeutic opportunities for cancer treatment.

[0008] Mice with a germline knockout of USP28 have been shown to be viable and fertile, confirming that USP28 activity is not required for normal development and reproductive function. (Knobel et al., Molecular and Cellular Biology 2014, 34, 2062-2074). Conditional knockout of USP28 in mouse intestine led to the reduction of oncoproteins including c-Myc, active NOTCH (NICD1) and c-JUN which was associated with decreased intestinal cell proliferation and enhanced differentiation. More importantly, intestinal tumorigenesis induced by APC mutation was effectively blocked with acute USP28 depletion suggesting that USP28 could be an appealing target to reduce tumor burden and improve survival for intestinal cancers. (Diefenbacher et al.).

[0009] In summary, USP28 and USP25 play important roles in promoting tumorigenesis in cells and modulating immune responses. Its major role being in the deubiquitination and stabilization of diverse oncoproteins and epigenetic drivers and immunomodulatory proteins among other cellular factors, which are necessary for immune responses and tumor initiation and growth in humans. Inhibition of USP28 and / or USP25 with small molecule inhibitors therefore can be developed for medical use, such as for the treatment for cancer such as lung cancer. For this reason, there remains a considerable need for novel and potent small molecule inhibitors of USP28 and / or USP25. SUMMARY

[0010] The present disclosure relates to chemical entities chosen from compounds of Formula (I) [Image disponible dans le document PDF, Image available in the PDF document] (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, wherein: X is chosen from <semantics>C(R)2<annotation encoding="application / x-tex">C(R)_2< / annotation>< / semantics> and <semantics>O<annotation encoding="application / x-tex">O< / annotation>< / semantics>; Y is chosen from C and N; R is chosen from H, halogens, C1-C6 alkyl, -OH, and -CN, wherein any R group containing hydrogen can have one or more hydrogen replaced with deuterium; R1 is chosen from 6-12 membered heteroaryls optionally substituted with one or more substituent chosen from R5 and R6, wherein a 6-membered nonfused heteroaryl is substituted with one or more R6, and further wherein any R1 group containing hydrogen can have one or more hydrogen replaced with deuterium; R2 is chosen from N-linked and C-linked 4-12 membered heterocyclyls, and an O linked to a heterocyclyl, wherein the heterocyclyls are optionally substituted with one or more R5, a sulfur member of the heterocyclyls can be <semantics>S(O)<annotation encoding="application / x-tex">S(O)< / annotation>< / semantics> or <semantics>S(O)2<annotation encoding="application / x-tex">S(O)2< / annotation>< / semantics>, and further wherein any <semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics> group containing hydrogen can have one or more hydrogen replaced with deuterium; <semantics>R3<annotation encoding="application / x-tex">R_3< / annotation>< / semantics> is independently chosen from H, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> C6) haloalkoxy, halogen, -OH, -CN, (C3-C8) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups, wherein alkyls are optionally substituted with one or more substituent independently chosen from (C1-C6) alkoxy and -OH, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or more R7; R4 is chosen from H, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkoxy, halogen, -OH, -CN, (C3-C8) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups, wherein alkyls are optionally substituted with one or more substituent independently chosen from (C1-C6) alkoxy and –OH, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or more R5, and further wherein any R4 group containing hydrogen can have one or more hydrogen replaced with deuterium; R5 is independently chosen from <semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>, <semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl groups, wherein alkyls are optionally substituted with one or more substituent independently chosen from (C1-C6) alkoxy and –OH, and wherein any R5 group containing hydrogen can have one or more hydrogen replaced with deuterium; R6 is chosen from <semantics>−N(C1−C6)<annotation encoding="application / x-tex">-N(C_1-C_6)< / annotation>< / semantics> alkyl-aryls, <semantics>−N(C1−C6)<annotation encoding="application / x-tex">-N(C_1-C_6)< / annotation>< / semantics> alkyl-heteroaryls, and <semantics>−N(C1−C6)<annotation encoding="application / x-tex">-N(C_1-C_6)< / annotation>< / semantics> alkyl- heterocyclyl groups, wherein the groups are optionally substituted with one or more substituent chosen from -OH, -NH, halogens, (C1-C6) alkyl, (C1-C6) alkoxy, and (C1-C6) haloalkyl groups, and further wherein any R6 group containing hydrogen can have one or more hydrogen replaced with deuterium; R7 is independently chosen from <semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>, <semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl groups, wherein alkyls are optionally substituted with one or more substituent independently chosen from <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy and <semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>; and n is 0, 1, 2, or 3.

[0011] The compound of Formula (I) can be a compound, or pharmaceutically acceptable salt thereof, wherein: X is chosen from <semantics>C(R)2<annotation encoding="application / x-tex">C(R)_2< / annotation>< / semantics> (e.g., <semantics>C(R)(R)<annotation encoding="application / x-tex">C(R)(R)< / annotation>< / semantics> where each R is the same or different) and O; Y is chosen from C (e.g., CH or C(R) where R is the same or different from R in moiety X) and N; R is independently chosen from H, halogens, C1-C6 alkyl, -OH, and -CN; R1 is chosen from 6-12 membered heteroaryls optionally substituted with one or more substituent chosen from R5 and R6, wherein a 6-membered nonfused heteroaryl is substituted with one or more <semantics>R6<annotation encoding="application / x-tex">R_6< / annotation>< / semantics>; R2 is chosen from N-linked 4-12 membered heterocyclyls, C-linked 4-12 membered heterocyclyls, and O-linker to a heterocyclyl, wherein the N-linked, C-linked or O-linker heterocyclyls are optionally substituted with one or more R5; <semantics>R3<annotation encoding="application / x-tex">R_3< / annotation>< / semantics> is independently chosen from H, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> C6) haloalkoxy, halogen, -OH, -CN, (C3-C8) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups, wherein alkyls are optionally substituted with one or more substituent independently chosen from (C1-C6) alkoxy and –OH, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or more R7; R4 is chosen from H, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkoxy, halogen, -OH, -CN, (C3-C8) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups, wherein alkyls are optionally substituted with one or more substituent independently chosen from (C1-C6) alkoxy and -OH, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or more R5; R5 is independently chosen from <semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>, <semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl groups, wherein alkyls are optionally substituted with one or more substituent independently chosen from <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy and <semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>; R6 is chosen from -N-(C1-C6)alkyl-aryls, -N-(C1-C6)alkyl-heteroaryls, and -N-(C1- C6)alkyl-heterocyclyl groups, wherein the groups are optionally substituted with one or more substituent chosen from -OH, -NH, halogens, (C1-C6) alkyl, (C1-C6) alkoxy, and (C1-C6) haloalkyl groups; R7 is independently chosen from -OH, -NH2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl groups, wherein alkyls are optionally substituted with one or more substituent independently chosen from (C1-C6) alkoxy and –OH; and n is 0, 1, 2, or 3.

[0012] In other examples, the compound of Formula (I) can be a compound, or pharmaceutically acceptable salt thereof, wherein: X is chosen from <semantics>C(R)2<annotation encoding="application / x-tex">C(R)_2< / annotation>< / semantics> (e.g., <semantics>C(R)(R)<annotation encoding="application / x-tex">C(R)(R)< / annotation>< / semantics> where each R is the same or different) and O; Y is chosen from C (e.g., CH or C(R) where R is the same or different from R in moiety X) and N; each R in X and Y is independently chosen from H, halogens, C1-C6 alkyl, -OH, and - CN; R1 is chosen from heteroaryls optionally substituted with one or more substituent chosen from R5 and R6, wherein the heteroaryl is optionally substituted with one or more R6; R2 is chosen from N-linked-heterocyclyls, C-linked-heterocyclyls, and O-linker- heterocyclyls, wherein the N-linked, C-linked or O-linker heterocyclyls are optionally substituted with one or more R5; each <semantics>R3<annotation encoding="application / x-tex">R_3< / annotation>< / semantics> is independently chosen from H, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, (C1-C6) haloalkoxy, halogen, -OH, -CN, (C3-C8) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups, wherein the alkyls are each optionally substituted with one or more substituent independently chosen from <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy and <semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or more R7; each R4 is independently chosen from H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, -OH, -CN, (C3-C8) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups, wherein alkyls are each optionally substituted with one or more substituent independently chosen from <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy and <semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or more R5; each R5 is independently chosen from –OH, –NH2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl groups, wherein the alkyls are each optionally substituted with one or more substituent independently chosen from (C1-C6) alkoxy and –OH; each R6 is independently chosen from amino-alkyl-aryls (e.g., -N-(C1-C6)alkyl-aryls), amino-alkyl-heteroaryls (e.g., -N-(C1-C6)alkyl-heteroaryls), amino-alkyl-cyclyl and amino-alkyl- heterocyclyl (e.g., -N-(C1-C6)alkyl-heterocyclyls) groups, wherein these groups are optionally substituted with one or more substituent chosen from -OH, -NH, halogens, (C1-C6) alkyl, (C1-C6) alkoxy, and (C1-C6) haloalkyl groups; each R7 is independently chosen from -OH, -NH2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl groups, wherein the alkyls are each optionally substituted with one or more substituent independently chosen from (C1-C6) alkoxy and –OH; and n is 0, 1, 2, or 3.

[0013] Another aspect of the present disclosure relates to a method of treating a disease or disorder associated with inhibition of USP28. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with inhibition of USP28 an effective amount of at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0014] Another aspect of the disclosure relates to a method of treating a disease or disorder associated with inhibition of USP25. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with inhibition of USP25 an effective amount of a at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0015] Another aspect of the disclosure relates to a method of treating a disease or disorder associated with inhibition of at least one pathway chosen from USP28 and USP25. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with inhibition of at least one pathway chosen from USP28 and USP25 effective amount of at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0016] Another aspect of the disclosure is directed to a method of inhibiting USP28. The method involves administering to a patient in need thereof an effective amount of at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0017] Another aspect of the disclosure is directed to a method of inhibiting USP25. The method involves administering to a patient in need thereof an effective amount of at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0018] Another aspect of the disclosure is directed to a method of inhibiting at least one pathway chosen from USP28 and USP25. The method involves administering to a patient in need thereof an effective amount of at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0019] Another aspect of the disclosure relates to a method of treating cancer. The method comprises administering to a patient in need thereof an effective amount of at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0020] Another aspect of the disclosure is directed to pharmaceutical compositions comprising at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0021] Another aspect of the present disclosure relates to at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, for use in the manufacture of a medicament for treating a disease associated with inhibiting USP28.

[0022] Another aspect of the present disclosure relates to the use of at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, in the treatment of a disease associated with inhibiting USP28.

[0023] Another aspect of the present disclosure relates to the use of at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, in the treatment of a disease associated with inhibiting USP25.

[0024] Another aspect of the present disclosure relates to the use of at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, in the treatment of a disease associated with inhibiting at least one pathway chosen from USP28 and USP25. DESCRIPTION OF THE EMBODIMENTS

[0025] Compounds useful for inhibiting USP 28 and / or USP25 are disclosed herein, including USP25 Inhibitor compounds, USP28 Inhibitor compounds and USP28 / 25 Inhibitor compounds as defined herein. The USP28 / 25 Inhibitor, USP28 Inhibitor and / or USP25 Inhibitor compounds can be a compound disclosed herein, including a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of Formula (IV), a compound of Formula (V), a compound of Formula (VI), and / or a compound of Formula (VII).

[0026] The term "USP28 Inhibitor" compound as used herein refers to a compound disclosed herein (e.g., a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of Formula (IV), a compound of Formula (VI), a compound of Formula (VI), and / or a compound of Formula (VII)) having an IC50 of 2 micromolar or less in the Ubiquitin- Rhodamine 110 Assay for USP28 as described in Example A-1(a) and / or the Ubiquitin- Rhodamine 110 Assay for USP28 as described in Example A-1(b) herein. For example, the USP28 Inhibitor can be a compound of a formula disclosed herein having an IC50 value of up to 2 micromolar using the Ubiquitin-Rhodamine 110 Assay for USP28 as described in Example A- <semantics>1(a)<annotation encoding="application / x-tex">1(a)< / annotation>< / semantics>, including IC50 values ranging from <semantics>0.001−2<annotation encoding="application / x-tex">0.001 - 2< / annotation>< / semantics> micromolar, preferably <semantics>0.001−0.2<annotation encoding="application / x-tex">0.001 - 0.2< / annotation>< / semantics> micromolar, and more preferably 0.001-0.05 micromolar. The USP28 Inhibitor can be a compound of a formula disclosed herein having an IC50 value of up to 2 micromolar using the Ubiquitin-Rhodamine 110 Assay for USP28 as described in Example A-1(b), including IC50 values ranging from <semantics>0.001−2<annotation encoding="application / x-tex">0.001 - 2< / annotation>< / semantics> micromolar, preferably 0.001-0.2 micromolar, more preferably from 0.001-0.05 micromolar. The USP28 Inhibitor can be a compound of a formula disclosed herein having an IC50 values of up to 2 micromolar using both the Ubiquitin-Rhodamine 110 Assay for USP28 as described in Example A-1(a) and the Ubiquitin-Rhodamine 110 Assay for USP28 as described in Example A-1(b), including IC50 values of <semantics>0.001−2<annotation encoding="application / x-tex">0.001 - 2< / annotation>< / semantics> micromolar, preferably <semantics>0.001−0.2<annotation encoding="application / x-tex">0.001-0.2< / annotation>< / semantics> micromolar, more preferably 0.001-0.05 micromolar for both assays.

[0027] The term "USP25 Inhibitor" as used herein refers to a compound disclosed herein (e.g., a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of Formula (IV), a compound of Formula (V), a compound of Formula (VI), and / or a compound of Formula (VII)) having an IC50 of 2 micromolar or less in the Ubiquitin-Rhodamine 110 Assay for USP25 as described in Example A-2 herein. For example, the USP25 Inhibitor can be a compound of a formula disclosed herein having an IC50 value of up to 2 micromolar using the Ubiquitin-Rhodamine 110 Assay for USP25 as described in Example A-2, including IC50 values ranging from 0.001 – 2 micromolar, preferably 0.001-0.2 micromolar, more preferably 0.001-0.05 micromolar. The USP25 Inhibitor can be a compound of a formula disclosed herein having an IC50 value of up to 2 micromolar using the Ubiquitin-Rhodamine 110 Assay for USP25 as described in Example A-2, including IC50 values ranging from <semantics>0.001−2<annotation encoding="application / x-tex">0.001 - 2< / annotation>< / semantics> micromolar, preferably 0.001-0.2 micromolar, more preferably 0.001-0.05 micromolar. The USP25 Inhibitor can be a compound of a formula disclosed herein having an IC50 values of up to 2 micromolar using both the Ubiquitin-Rhodamine 110 Assay for USP25 as described in Example A-2 and the Ubiquitin- Rhodamine 110 Assay for USP25 as described in Example A-2, including IC50 values ranging from 0.001 – 2 micromolar, preferably 0.001-0.2 micromolar, more preferably 0.001-0.05 micromolar for both assays.

[0028] The term "USP28 / 25 Inhibitor" as used herein refers to a compound disclosed herein (e.g., a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of Formula (IV), a compound of Formula (V), a compound of Formula (VI), and / or a compound of Formula (VII)) that is a USP28 Inhibitor or a USP25 Inhibitor or both a USP28 Inhibitor and USP25 Inhibitor, as defined herein.

[0029] Optionally, any one or more hydrogen atoms in a compound of Formula (I), Formula (II), a compound of Formula (III), a compound of Formula (IV), a compound of Formula (V), a compound of Formula (VI), and / or a compound of Formula (VII) can independently be replaced with deuterium or other hydrogen isotope.

[0030] In a first aspect of the disclosure, the chemical entities are chosen from compounds of Formula (I): [Image disponible dans le document PDF, Image available in the PDF document] (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, are described wherein X, Y, R1, R2, R3, R4, and n are as described herein above.

[0031] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0032] The articles "a" and "an" are used in this disclosure to refer to one or more than one (e.g., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0033] The term "and / or" is used in this disclosure to mean either "and" or "or" unless indicated otherwise.

[0034] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, -OH, -CN, -COOH, -CH2CN, -O-(C1-C6) alkyl, (C1-C6) alkyl, (C1-C6) alkoxy, (C1- C6) haloalkyl, (C1-C6) haloalkoxy, -O-(C2-C6) alkenyl, -O-(C2-C6) alkynyl, (C2-C6) alkenyl, (C2- C6) alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6) alkyl, -C(O)(C1-C6) alkyl, -OC(O)O(C1-C6) alkyl, -NH2, -NH((<semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>-<semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>) alkyl), -N((<semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>-<semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>) alkyl)2, -NHC(O)(<semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>-<semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>) alkyl, -C(O)NH(<semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>-<semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>) alkyl, <semantics>−S(O)2(C1−C6)<annotation encoding="application / x-tex">-S(O)_2(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>−S(O)NH(C1−C6)<annotation encoding="application / x-tex">-S(O)NH(C_1-C_6)< / annotation>< / semantics> alkyl, and <semantics>S(O)N((C1−C6)<annotation encoding="application / x-tex">S(O)N((C_1-C_6)< / annotation>< / semantics> alkyl)2. The substituents can themselves be optionally substituted. "Optionally substituted" as used herein also refers to substituted or unsubstituted whose meaning is described below.

[0035] As used herein, the term "substituted" means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.

[0036] As used herein, the term "unsubstituted" means that the specified group bears no substituents.

[0037] Unless otherwise specifically defined, the term "aryl" refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, -H, -halogen, -O-<semantics>(C1<annotation encoding="application / x-tex">(C_1< / annotation>< / semantics>-C6) alkyl, (C1-C6) alkyl, -O-<semantics>(C2<annotation encoding="application / x-tex">(C_2< / annotation>< / semantics>-C6) alkenyl, -O-<semantics>(C2<annotation encoding="application / x-tex">(C_2< / annotation>< / semantics>-C6) alkynyl, <semantics>(C2−C6)<annotation encoding="application / x-tex">(C_2-C_6)< / annotation>< / semantics> alkenyl, <semantics>(C2−C6)<annotation encoding="application / x-tex">(C_2-C_6)< / annotation>< / semantics> alkynyl, <semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>, <semantics>−OP(O)(OH)2<annotation encoding="application / x-tex">-OP(O)(OH)_2< / annotation>< / semantics>, <semantics>−OC(O)(C1−C6)<annotation encoding="application / x-tex">-OC(O)(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>−C(O)(C1−C6)<annotation encoding="application / x-tex">-C(O)(C_1-C_6)< / annotation>< / semantics> alkyl, -OC(O)O(C1-C6) alkyl, -NH2, NH((C1-C6) alkyl), N((C1-C6) alkyl)2, -S(O)2-(C1-C6) alkyl, <semantics>−S(O)NH(C1−C6)<annotation encoding="application / x-tex">-S(O)NH(C_1-C_6)< / annotation>< / semantics> alkyl, and <semantics>−S(O)N((C1−C6)<annotation encoding="application / x-tex">-S(O)N((C_1-C_6)< / annotation>< / semantics> alkyl)2. The substituents can themselves be optionally substituted. Furthermore when containing two fused rings the aryl groups herein defined may have an unsaturated or partially saturated ring fused with a fully saturated ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

[0038] Unless otherwise specifically defined, "heteroaryl" means a monovalent monocyclic aromatic radical of 5 to 24 ring atoms or a polycyclic aromatic radical, containing one or more ring heteroatoms selected from N, O, and S, the remaining ring atoms being C. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, and S. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3- c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl, dibenzo[b,d] thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3- c]pyridinyl, 1H-pyrido[3,4-b][1,4] thiazinyl, benzooxazolyl, benzoisoxazolyl, furo[2,3- b|pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5- a]pyridinyl, benzo [1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, <semantics>3,4<annotation encoding="application / x-tex">3,4< / annotation>< / semantics>-dihydro-<semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>-pyrazolo <semantics>[1,5−b][1,2]<annotation encoding="application / x-tex">[1,5-b][1,2]< / annotation>< / semantics>oxazinyl, <semantics>4,5,6,7<annotation encoding="application / x-tex">4,5,6,7< / annotation>< / semantics>-tetrahydropyrazolo<semantics>[1,5−a]<annotation encoding="application / x-tex">[1,5-a]< / annotation>< / semantics>pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, thieno[2,3- d]thiazole, 1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine, 3H-indolyl, and derivatives thereof. Furthermore the terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3- dihydrobenzofuran, indolinyl, indolyl, isoindolyl and dihydrobenzoxanyl.

[0039] Halogen or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0040] Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of a (C1-C6) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0041] "Alkoxy" refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal "O" in the chain, e.g., -O(alkyl). Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0042] The term "alkylene" or "alkylenyl" refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. As herein defined, alkylene may also be a C0-C6 alkylene. An alkylene may further be a C0-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, - C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2-, and the like.

[0043] "Cycloalkyl" or "carbocyclyl" means monocyclic or polycyclic saturated carbon rings containing 3-18 carbon atoms. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl and derivatives thereof. A C3-C8 cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms. A cycloalkyl group can be fused (e.g., decalin) or bridged (e.g., norbornane).

[0044] "Heterocyclyl" or "heterocycloalkyl" monocyclic or polycyclic rings containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur and wherein there is not delocalized <semantics>π<annotation encoding="application / x-tex">\pi< / annotation>< / semantics> electrons (aromaticity) shared among the entire ring carbon or heteroatoms. The heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents can themselves be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl. As used herein, "heterocyclyl" and "heterocycloalkyl" also includes bridged and spirocyclic ring systems where at least one atom is a heteroatom. A heterocyclic ring as a substituent may attach via a ring heteroatom (e.g. "N-linked") or via a ring carbon (e.g. "C-linked").

[0045] The term "hydroxyalkyl" means an alkyl group as defined above, where the alkyl group is substituted with one or more OH groups. Examples of hydroxyalkyl groups include HO-CH2-, HO-CH2-CH2- and CH3-CH(OH)-.

[0046] The term "haloalkyl" as used herein refers to an alkyl group, as defined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0047] The term "haloalkoxy" as used herein refers to an alkoxy group, as defined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

[0048] The term "cyano" as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, e.g., <semantics>C=N<annotation encoding="application / x-tex">C=N< / annotation>< / semantics>.

[0049] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the disclosure may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.

[0050] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.

[0051] The disclosure also includes pharmaceutical compositions comprising an effective amount of a disclosed compound and a pharmaceutically acceptable carrier.

[0052] The term "treating" with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.

[0053] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0054] The term "administer", "administering", or "administration" as used in this disclosure refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.

[0055] The term "prodrug," as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.

[0056] The term "cancer" includes, but is not limited to, the following cancers: bladder cancer, breast cancer (e.g., ductal carcinoma), cervical cancer (e.g.: squamous cell carcinoma), colorectal cancer (e.g., adenocarcinoma), esophageal cancer (e.g., squamous cell carcinoma), gastric cancer (e.g.: adenocarcinoma, medulloblastoma, colon cancer, choriocarcinoma, squamous cell carcinoma), head and neck cancer, hematologic cancer (e.g., acute lymphocytic anemia, acute myeloid leukemia, acute lymphoblastic B cell leukemia, anaplastic large cell lymphoma, B-cell lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia, chronic eosinophillic leukemia / hypereosinophillic syndrome, chronic myeloid leukemia, Hodgkin's lymphoma, mantle cell lymphoma, multiple myeloma, T-cell acute lymphoblastic leukemia), lung cancer (e.g., bronchioloalveolar adenocarcinoma, mesothelioma, mucoepidermoid carcinoma, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma), liver cancer (e.g., hepatocellular carcinoma), lymphoma, neurological cancer (e.g., glioblastoma, neuroblastoma, neuroglioma), ovarian (e.g., adenocarcinoma), pancreatic cancer (e.g., ductal carcinoma), prostate cancer (e.g., adenocarcinoma), renal cancer (e.g., renal cell carcinoma, clear cell renal carcinoma), sarcoma (e.g., chondrosarcoma, Ewings sarcoma, fibrosarcoma, multipotential sarcoma, osteosarcoma, rhabdomyosarcoma, synovial sarcoma), skin cancer (e.g., melanoma, epidermoid carcinoma, squamous cell carcinoma), thyroid cancer (e.g., medullary carcinoma), and uterine cancer.

[0057] The present disclosure relates to chemical entities chosen from compounds and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, capable of inhibiting at least one pathway chosen from USP28 and USP25, which are useful for the treatment of diseases and disorders associated with modulation of at least one pathway chosen from USP28 and USP25. The disclosure further relates to chemical entities chosen from compounds and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, which are useful for inhibiting at least one pathway chosen from USP28 and USP25.

[0058] In any of the embodiments as disclosed herein, the cancer can be any cancer in any organ, for example, a cancer is selected from the group consisting of glioma, thyroid carcinoma, breast carcinoma, small-cell lung carcinoma, non-small-cell carcinoma, gastric carcinoma, colon carcinoma, gastrointestinal stromal carcinoma, pancreatic carcinoma, bile duct carcinoma, CNS carcinoma, ovarian carcinoma, endometrial carcinoma, prostate carcinoma, renal carcinoma, anaplastic large-cell lymphoma, leukemia, multiple myeloma, mesothelioma, and melanoma, and combinations thereof.

[0059] The present disclosure relates to chemical entities chosen from compounds and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, capable of inhibiting at least one pathway chosen from USP28 and USP25, which are useful for the treatment of diseases and disorders associated with modulation of at least one pathway chosen from USP28 and / or USP25 enzyme. The present disclosure further relates to chemical entities chosen from compounds and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, which are useful for inhibiting at least one pathway chosen from USP28 and USP25.

[0060] In one embodiment, the chemical entities are chosen from compounds of Formula (II): [Image disponible dans le document PDF, Image available in the PDF document] (II), wherein X, Y, R1, R2, R3, R4, and n are as described herein above, and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0061] In another embodiment, the chemical entities are chosen from compounds of Formula (III): [Image disponible dans le document PDF, Image available in the PDF document] (III), wherein X, Y, R1, R2, R3, R4, and n are as described herein above, and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0062] In another embodiment, the chemical entities are chosen from compounds of Formula (IV): [Image disponible dans le document PDF, Image available in the PDF document] (IV) wherein X, Y, R1, R2, R3, R4, and n are as described herein above and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0063] In another embodiment, the chemical entities are chosen from compounds of Formula (V): [Image disponible dans le document PDF, Image available in the PDF document] (V), wherein X, Y, R1, R2, R3, R4, and n are as described herein above and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0064] In some embodiments, the chemical entities are chosen from compounds of Formula (VI): [Image disponible dans le document PDF, Image available in the PDF document] (VI), or a pharmaceutically acceptable salt thereof, wherein: X is chosen from <semantics>C(R)(R″)<annotation encoding="application / x-tex">C(R)(R'')< / annotation>< / semantics> and O; each of <semantics>Y1<annotation encoding="application / x-tex">Y_1< / annotation>< / semantics>, <semantics>Y2<annotation encoding="application / x-tex">Y_2< / annotation>< / semantics>, and <semantics>Y3<annotation encoding="application / x-tex">Y_3< / annotation>< / semantics> is independently chosen from <semantics>C(R3)<annotation encoding="application / x-tex">C(R_3)< / annotation>< / semantics> and <semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>; R' is chosen from H, deuterium, and CH3; each of R and R'' is independently chosen from H, halogens, -OH, -CN, C1-C6 alkyl optionally substituted with one or more Ri, or R and R'' together with the carbon they are attached form a spirocyclic cyclopropyl optionally substituted with one or more Ri, wherein any R, R'', or Ri group being or containing hydrogen can independently have one or more hydrogen replaced with deuterium; each Ri is independently chosen from halogen, -OH, and CH3; R1 is chosen from 6-12 membered fused and nonfused heteroaryls optionally substituted with one or more substituent chosen from R5 and / or R6, and further wherein any R1 group containing hydrogen can have one or more hydrogen replaced with deuterium; R2 is chosen from N-linked 4-12 membered heterocyclyls, C-linked 4-12 membered heterocyclyls, and an O linker attached to a 4-12 membered heterocyclyl, wherein the 4-12 membered heterocyclyls are optionally substituted with one or more R5 (which can be the same or different from the one or more R5 of R1), and further wherein any hydrogen in a R2 group can have one or more hydrogen replaced with deuterium; each R3 is independently chosen from H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, -OH, -CN, (C3-C8) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups, wherein each of (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or more R7; R4 is chosen from H, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkoxy, halogen, -OH, -CN, (C3-C8) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups, wherein each of (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C3-C8) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R5, and further wherein any R4 group containing hydrogen can have one or more hydrogen replaced with deuterium; each R5 is independently chosen from -OH, -NH2, amido-(C1-C6) alkyl, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl groups, wherein each of -NH2, amido-(C1-C6) alkyl, (C1-C6) alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkoxy, cycloalkyl, heterocycloalkyl, and <semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>- heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C1-C6) alkyl, (C1-C6) alkoxy, -NH2, and -OH, and wherein any R5 group containing hydrogen can have one or more hydrogen replaced with deuterium; each R6 is independently chosen from -amino alkyl-aryls, -amino alkyl-heteroaryls, - amino alkyl-cyclyl, and -amino alkyl-heterocyclyl groups, wherein each of the R6 groups are optionally substituted with one or more substituent chosen from -OH, -NH, halogens, (C1-C6) alkyl, (C1-C6) alkoxy, and (C1-C6) haloalkyl groups, and further wherein any R6 group containing hydrogen can have one or more hydrogen replaced with deuterium; each R7 is independently chosen from -OH, -NH2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, -C(O)-cycloalkyl, heterocycloalkyl, and - C(O)-heterocycloalkyl groups, wherein each of –NH2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, -C(O)-cycloalkyl, heterocycloalkyl, and - C(O)-heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C1-C6) alkyl, (C1-C6) alkoxy, and –OH; and n is 0, 1, 2, or 3.

[0065] The compound of Formula (VI) or a pharmaceutically acceptable salt thereof, wherein: X is chosen from <semantics>C(R)(R″)<annotation encoding="application / x-tex">C(R)(R'')< / annotation>< / semantics> and O; each of <semantics>Y1<annotation encoding="application / x-tex">Y_1< / annotation>< / semantics>, <semantics>Y2<annotation encoding="application / x-tex">Y_2< / annotation>< / semantics>, and <semantics>Y3<annotation encoding="application / x-tex">Y_3< / annotation>< / semantics> is independently chosen from <semantics>C(R3)<annotation encoding="application / x-tex">C(R_3)< / annotation>< / semantics> and <semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>; R' is chosen from H, and CH3; each of R and R'' is independently chosen from H, halogens, -OH, -CN, C1-C6 alkyl optionally substituted with one or more Ri, or R and R'' together with the carbon they are attached form a spirocyclic cycloalkyl (e.g., spirocyclic cyclopropyl) optionally substituted with one or more Ri, wherein any R, R''; each Ri is independently chosen from halogen, -OH, and CH3; R1 is chosen from a fused or nonfused heteroaryls (e.g., 6-12 membered fused or nonfused heteroaryls) optionally substituted with one or more substituent chosen from R5 and / or <semantics>R6<annotation encoding="application / x-tex">R_6< / annotation>< / semantics> (e.g., a 6-membered nonfused heteroaryl optionally substituted with one or more <semantics>R6<annotation encoding="application / x-tex">R_6< / annotation>< / semantics>); R2 is chosen from N-linked-heterocyclyls (e.g., 4-12 membered heterocyclyls), C-linked- heterocyclyls (e.g., 4-12 membered heterocyclyls), and O-linker-heterocyclyls (e.g., 4-12 [Image disponible dans le document PDF, Image available in the PDF document] membered heterocyclyls such as , wherein any of the -N-linked-, -C-linked or - O-linked (e.g., 4-12 membered) heterocyclyls is optionally substituted with one or more R5 (which can be the same or different from the one or more <semantics>R5<annotation encoding="application / x-tex">R_5< / annotation>< / semantics> of <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>); each <semantics>R3<annotation encoding="application / x-tex">R_3< / annotation>< / semantics> is independently chosen from H, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, (C1-C6) haloalkoxy, halogen, -OH, -CN, (C3-C8) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups, wherein each of <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or more R7; R4 is chosen from H, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkoxy, halogen, -OH, -CN, (C3-C8) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups, wherein each of (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C3-C8) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R5; each R5 is independently chosen from -OH, -NH2, amido-(C1-C6) alkyl, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl groups, wherein each of -NH2, amido-(C1-C6) alkyl, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, cycloalkyl, heterocycloalkyl, and -C(O)- heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C1-C6) alkyl, (C1-C6) alkoxy, -NH2, and -OH; each R6 is independently chosen from -amino alkyl-aryls, -amino alkyl-heteroaryls, - amino alkyl-cyclyl, and -amino alkyl-heterocyclyl groups, wherein each of the R6 groups are optionally substituted with one or more substituent chosen from -OH, -NH, halogens, (C1-C6) alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, and <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl groups; each R7 is independently chosen from -OH, -NH2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, -C(O)-cycloalkyl, heterocycloalkyl, and - <semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>-heterocycloalkyl groups, wherein each of <semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, -C(O)-cycloalkyl, heterocycloalkyl, and - C(O)-heterocycloalkyl are optionally substituted with one or more substituent independently chosen from <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, and <semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>; and n is 0, 1, 2, or 3.

[0066] In some embodiments, a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V) and / or Formula (VI) above includes X (if present) as CH2 (e.g., R and R'' are both hydrogen in Formula (VI)). In other embodiments, a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V) and / or Formula (VI) above includes X (if present) as O.

[0067] In another embodiment, the chemical entities are chosen from compounds of Formula (VI) and pharmaceutically acceptable salts thereof, wherein: X is chosen from <semantics>C(R)(R″)<annotation encoding="application / x-tex">C(R)(R'')< / annotation>< / semantics> and O; each of <semantics>Y1<annotation encoding="application / x-tex">Y_1< / annotation>< / semantics>, <semantics>Y2<annotation encoding="application / x-tex">Y_2< / annotation>< / semantics>, and <semantics>Y3<annotation encoding="application / x-tex">Y_3< / annotation>< / semantics> is independently chosen from <semantics>C(R3)<annotation encoding="application / x-tex">C(R_3)< / annotation>< / semantics> and <semantics>N3<annotation encoding="application / x-tex">N_3< / annotation>< / semantics>; R' is chosen from H and CH3; each of R and R'' is independently chosen from H, halogens, -OH, -CN, C1-C6 alkyl optionally substituted with one or more Ri; each Ri is independently chosen from halogen, -OH, and CH3; R1 is chosen from 6-12 membered fused and nonfused heteroaryls optionally substituted with one or more R5, wherein a 6-membered nonfused heteroaryl is substituted with one or more R6; R2 is chosen from N-linked and C-linked 4-12 membered heterocyclyls, wherein the 4-12 membered heterocyclyls are optionally substituted with one or more R5 (which can be the same or different from the one or more <semantics>R5<annotation encoding="application / x-tex">R_5< / annotation>< / semantics> of <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>); each R3 is independently chosen from H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, -OH, and -CN, wherein each of (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, and (C1-C6) haloalkoxy groups are optionally substituted with one or more R7; R4 is chosen from H, (C1-C6) alkyl, halogen, -OH, and -CN, wherein the (C1-C6) alkyls are optionally substituted with one or more substituent independently chosen from <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy and –OH; each R5 is independently chosen from –OH, –NH2, -NHC(O)CH3, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and -C(O)- heterocycloalkyl groups, wherein alkyls are optionally substituted with one or more substituent independently chosen from (C1-C6) alkoxy, -NH2, and -OH; each R6 is independently chosen from -NH(C1-C6)alkyl-aryls, -NH(C1-C6)alkyl- heteroaryls, -NH(C1-C6)alkyl-cyclyl and -NH(C1-C6)alkyl-heterocyclyl groups, wherein each of the R6 groups are optionally substituted with one or more substituent chosen from -OH, -NH, halogens, (C1-C6) alkyl, (C1-C6) alkoxy, and (C1-C6) haloalkyl groups; each R7 is independently chosen from -OH, -NH2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, -C(O)-cycloalkyl, heterocycloalkyl, and - C(O)-heterocycloalkyl groups, wherein the (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1- C6) haloalkoxy, halogen, cycloalkyl, -C(O)-cycloalkyl, heterocycloalkyl, and -C(O)- heterocycloalkyl groups are optionally substituted with one or more substituent independently chosen from <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy and <semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>; and n is 0, 1, 2, or 3.

[0068] In another embodiment, the chemical entities are chosen from compounds of Formula (VII): [Image disponible dans le document PDF, Image available in the PDF document] (VII), or a pharmaceutically acceptable salt thereof, wherein Y is chosen from <semantics>C(R3)<annotation encoding="application / x-tex">C(R_3)< / annotation>< / semantics> and N; R' is chosen from H, deuterium, and CH3; R1 is chosen from 6-11 membered heteroaryls optionally substituted with one or more substituent chosen from R5 and / or R6; R2 is chosen from N-linked 4-12 membered heterocyclyls and C-linked 4-12 membered heterocyclyls, wherein the heterocyclyls are optionally substituted with one or more R5, and further wherein any R2 group containing hydrogen can have one or more hydrogen replaced with deuterium; each R3 (if present) is independently chosen from H, deuterium, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, -OH, -CN, wherein each of (C1- C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or more R7; each R4 is chosen from H, deuterium, (C1-C6) alkyl, halogen, -OH, -CN, and further wherein any R4 group containing hydrogen can have one or more hydrogen replaced with deuterium; each R5 (if present) is independently chosen from -OH, -NH2, NHC(O)CH3, - C(O)NHCH3, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl groups, wherein each of -NH2, -NHC(O)CH3, -C(O)NHCH3, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C1-C6) alkoxy, -NH2, and -OH, and wherein any R5 group containing hydrogen can have one or more hydrogen replaced with deuterium; each R6 (if present) is chosen from -NH(C1-C6)alkyl-aryls, -NH(C1-C6)alkyl-heteroaryls, -NH(C1-C6)alkyl-heterocyclyl groups, and -NH(C1-C6)alkyl-heterocyclyl groups, wherein each of the R6 groups are optionally substituted with one or more substituent chosen from -OH, -NH, halogens, (C1-C6) alkyl, (C1-C6) alkoxy, and (C1-C6) haloalkyl groups, and further wherein any R6 group containing hydrogen can have one or more hydrogen replaced with deuterium; each R7 (if present) is independently chosen from -OH, -NH2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, -C(O)-cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl groups, wherein each of -NH2, (C1-C6) alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkoxy, halogen, cycloalkyl, <semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>- cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C1-C6) alkyl, (C1-C6) alkoxy, and – OH; and n is 0, 1, 2, or 3.

[0069] In some embodiments of the Formulae above, X is CH2. In another embodiments, X is O.

[0070] In some embodiments of the Formulae above, R1 is chosen from 6-12 membered heteroaryls optionally substituted with one or more R5. In some embodiments of the Formulae above, R1 is chosen from 6 membered heteroaryls substituted with one or more R6. In some embodiments of the Formulae above, any R1 group or optional substituent containing hydrogen can have one or more hydrogen replaced with deuterium.

[0071] In some embodiments of the Formulae above, R2 is chosen from N-linked 4-10 membered heterocyclyls optionally substituted with one or more R5, and wherein a sulfur member of the heterocyclyls can be <semantics>S(O)<annotation encoding="application / x-tex">S(O)< / annotation>< / semantics> or <semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>. In some embodiments of the Formulae above <semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics> is chosen from C-linked 4-10 membered heterocyclyls optionally substituted with one or more R5, and wherein a sulfur member of the heterocyclyls can be <semantics>S(O)<annotation encoding="application / x-tex">S(O)< / annotation>< / semantics> or <semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>. In some embodiments of the Formulae above R2 is chosen from O linked to a heterocyclic entity that is optionally substituted with one or more R5, and wherein a sulfur member of the heterocyclyls can be S(O) or S(O)2. In some embodiments of the Formulae above, any R2 group or optional substituent containing hydrogen can have one or more hydrogen replaced with deuterium.

[0072] In some embodiments of the Formulae above, R3 is independently chosen from H, (C1- C6) alkyl, (C1-C6) haloalkoxy, halogen, and –CN.

[0073] In some embodiments of the Formulae above, R4 is chosen from H and (C1-C6) alkyls. In some embodiments of the Formulae above, one or more hydrogen of R4 can be replaced with deuterium.

[0074] In some embodiments of the Formulae above, n is 0, 1, or 2. In another embodiment, n is 0 or 1. In yet another embodiment, n is 1, 2, or 3. In another embodiment, n is 1 or 2. In another embodiment, n is 2 or 3. In another embodiment, n is 0. In another embodiment, n is 1. In another embodiment, n is 2. In another embodiment, n is 3.

[0075] In some embodiments of the Formulae above, R1, optionally substituted with R5 and / or R6, is chosen from the groups of Table A. Preferably, a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI) and / or Formula (VII) comprises R1 (alone or as substituted with one of more R5 and / or R6) that is selected from the groups in Table A below. Table A [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0076] In some embodiments of the Formulae above, R2, optionally substituted with R5, is chosen from the groups of Table B below. Preferably, a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI) and / or Formula (VII) can comprises R2 (alone or as substituted with one of more R5 and / or R6, which can be the same or different) that is selected from the groups in Table B below. Table R [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0077] Preferably, a compound of Formula (I), Formula (II), Formula (IV), Formula (V), Formula (VI) and / or Formula (VII) can comprises both R1 (alone or as substituted with one of more R5 and / or R6, which can be the same or different) that is selected from the groups in Table A above, and R2 (alone or as substituted with one of more R5 and / or R6, which can be the same or different) that is selected from the groups in Table B above.

[0078] In some embodiments, the chemical entities are chosen from compounds of Formula (IIa): [Image disponible dans le document PDF, Image available in the PDF document] (IIa), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7 and n are as defined in Formula (I), and / or from compounds of Formula (IIaa): [Image disponible dans le document PDF, Image available in the PDF document] (IIaa), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R5, R6, R7 and n are as defined in Formula (I). In some embodiments, the chemical entities are chosen from compounds of Formula (IIb): [Image disponible dans le document PDF, Image available in the PDF document] (IIb'), or a pharmaceutically acceptable salt thereof, wherein R', R1, R2, R3, R4, R5, R6, R7 and n are each independently as defined Formula (VI).

[0079] In some embodiments, the chemical entities are chosen from compounds of Formula (IIaa): [Image disponible dans le document PDF, Image available in the PDF document] . . . or a pharmaceutically acceptable salt thereof, wherein R1 is chosen from 8-9-membered heteroaryls substituted with one or more substituent chosen from R5 and R6; R2 is chosen from N-linked 6-12 membered heterocyclyls or C-linked 6-12 membered heterocyclyls, wherein the 6-12 membered heterocyclyls are optionally substituted with one or more R5; R3 is independently chosen from H, (C1-C6) alkyl, halogen, and –CN; and wherein R5, R6, R7 and n are each independently as defined in Formula (I).

[0800] In preferred embodiments of Formula (IIaa), R1, optionally substituted with R5 and / or R6, is chosen from [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] • [Image disponible dans le document PDF, Image available in the PDF document]

[0081] In some embodiments, the chemical entities are chosen from compounds of Formula (IIb'): [Image disponible dans le document PDF, Image available in the PDF document] (IIb'), or a pharmaceutically acceptable salt thereof, wherein R' is chosen from H and CH3; R1 is chosen from 8-9 membered heteroaryls substituted with one or more substituent chosen from R5 and R6; R2 is chosen from N-linked 6-12 membered heterocyclyls or C-linked 6-12 membered heterocyclyls, wherein the 6-12 membered heterocyclyls are optionally substituted with one or more R5; R3 is independently chosen from H and halogen; and R5, R6, R7 and n are each independently as defined in Formula (VI).

[0082] In preferred embodiments of Formula (IIb'), R1, optionally substituted with R5 and / or R6, is chosen from [Image disponible dans le document PDF, Image available in the PDF document] HŅ HŅ R2, optionally substituted with R5, is chosen from [Image disponible dans le document PDF, Image available in the PDF document]

[0083] In some embodiments, the chemical entities are chosen from compounds of Formula (IIIa): [Image disponible dans le document PDF, Image available in the PDF document] (IIIa), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7 and n are each independently as defined Formula (I); and / or from compounds Formula (IIIb): [Image disponible dans le document PDF, Image available in the PDF document] (IIIb), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7 and n are each independently as defined Formula (I).

[0084] In some embodiments, the chemical entities are chosen from compounds of Formula (IIIaa): [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt thereof, wherein R1 is chosen from 8-11 membered heteroaryls optionally substituted with one or more R5; R2 is chosen from N-linked 4-12 membered heterocyclyls and C-linked 4-12 membered heterocyclyls, optionally substituted with one or more R5; each R5 (if present) is independently chosen from -OH, -NH2, NHC(O)CH3, (C1-C6) alkyl, (C1- C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and - C(O)-heterocycloalkyl groups, wherein each of –NH2, -NHC(O)CH3, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, cycloalkyl, heterocycloalkyl, and -C(O)- heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C1-C6) alkoxy, -NH2, and -OH; and n is 0, 1, 2, or 3.

[0085] In preferred embodiments of Formula (IIIaa), R1 is chosen from [Image disponible dans le document PDF, Image available in the PDF document] wherein B is chosen from a bond or C; Z is chosen from N, S, C(Rii); Rii is chosen from H, CH3 and R5; R2 is chosen from N-linked 5-8 membered heterocyclyls substituted with one to three R5; each R5 (if present) is independently chosen from -OH, -NH2, NHC(O)CH3, (C1-C6) alkyl, (C1- C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and - C(O)-heterocycloalkyl groups, wherein each of -NH2, -NHC(O)CH3, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, cycloalkyl, heterocycloalkyl, and -C(O)- heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C1-C6) alkoxy, -NH2, and -OH; and n is 0, 1, 2, or 3.

[0086] In further preferred embodiments of Formula (IIIaa), R1, optionally substituted with R5, is chosen from [Image disponible dans le document PDF, Image available in the PDF document] and R2, optionally substituted with R5, is chosen from [Image disponible dans le document PDF, Image available in the PDF document]

[0087] In some embodiments, the chemical entities are chosen from compounds of Formula (IVa): [Image disponible dans le document PDF, Image available in the PDF document] (IVa), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, R5, R6, R7 and n are each independently as defined Formula (I).

[8800] In some embodiments, the chemical entities are chosen from compounds of Formula (Va): [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7 and n are each independently as defined Formula (I).

[0089] In some embodiments, the chemical entity is chosen from compounds of Formula (Vaa): [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt thereof, wherein R1 is chosen from 8-membered heteroaryls substituted with one or more substituent chosen from R5 and R6; R2 is chosen from N-linked 5-membered heterocyclyls; and R5, R6, R7 and n are each independently as defined Formula (I). In further preferred embodiments of Formula (Vaa), R1 substituted with R5 is chosen from [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , and R2 is chosen from

[0090] In some embodiments, the chemical entities are chosen from compounds of Formula (VIIa'): [Image disponible dans le document PDF, Image available in the PDF document] (VIIa'), or a pharmaceutically acceptable salt thereof, wherein R', R1, R2, R3, R4, R5, R6, R7 and n are each independently as defined Formula (VI).

[0091] In at least one embodiment, the chemical entities are chosen from compounds of Formula (VIIaa): [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt thereof, wherein . <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> is chosen from 8-9 membered heteroaryls optionally substituted with one or more <semantics>R5<annotation encoding="application / x-tex">R_5< / annotation>< / semantics>; R2 is chosen from N-linked 4-12 membered heterocyclyls optionally substituted with one or more R5; each R5 (if present) is independently chosen from -OH, -NH2, NHC(O)CH3, (C1-C6) alkyl, (C1- C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and - C(O)-heterocycloalkyl groups, wherein each of -NH2, -NHC(O)CH3, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, cycloalkyl, heterocycloalkyl, and -C(O)- heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C1-C6) alkoxy, -NH2, and -OH; and n is 0, 1, 2, or 3.

[0092] In preferred embodiments of Formula (VIIaa), R1 is chosen from [Image disponible dans le document PDF, Image available in the PDF document] wherein B is chosen from a bond or C; Z is chosen from N, S, C(Rii); Rii is chosen from H, CH3 and R5; R2 is chosen from N-linked 5-8 membered heterocyclyls substituted with one to three R5; each R5 (if present) is independently chosen from -OH, -NH2, NHC(O)CH3, (C1-C6) alkyl, (C1- C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and - C(O)-heterocycloalkyl groups, wherein each of -NH2, -NHC(O)CH3, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, cycloalkyl, heterocycloalkyl, and -C(O)- heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C1-C6) alkoxy, -NH2, and -OH; and n is 0, 1, 2, or 3.

[0093] In further preferred embodiments of Formula (VIIaa), R1, optionally substituted with R5, is chosen from [Image disponible dans le document PDF, Image available in the PDF document] and R2, optionally substituted with R5, is chosen from [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0094] Preferably, the compound is a compound of Formula (I), (II), (III), (IV), (VI), (VII), (IIa), (IIa), (IIb'), (IIIa), (IIIb), (IIIaa), (IVa), (Va), (Vaa), (VIIa') or Formula (VIIaa) that is USP28 Inhibitor, a USP25 Inhibitor and / or a USP 28 / 25 Inhibitor as defined herein.

[0095]

[0096]

[0097] In another embodiment of the disclosure, the compounds of Formula (I) are enantiomers. In some embodiments the compounds are the <semantics>(S)<annotation encoding="application / x-tex">(S)< / annotation>< / semantics>-enantiomer. In other embodiments the compounds are the <semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>-enantiomer. In yet other embodiments, the compounds of Formula (I) may be (+) or (-) enantiomers.

[0098] It should be understood that all isomeric forms are included within the present disclosure, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans configuration. All tautomeric forms are also intended to be included.

[0099] Compounds of the disclosure, and pharmaceutically acceptable salts, hydrates, solvates, stereoisomers and prodrugs thereof may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present disclosure.

[00100] The compounds of the disclosure may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the disclosure as well as mixtures thereof, including racemic mixtures, form part of the present disclosure. In addition, the present disclosure embraces all geometric and positional isomers. For example, if a compound of the disclosure incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the disclosure. Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound. The compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry. The assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.

[00101] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of the disclosure may be atropisomers (e.g., substituted biaryls) and are considered as part of this disclosure. Enantiomers can also be separated by use of a chiral HPLC column.

[00102] It is also possible that the compounds of the disclosure may exist in different tautomeric forms, and all such forms are embraced within the scope of the disclosure. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the disclosure.

[00103] All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this disclosure, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the disclosure. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the disclosure.) Individual stereoisomers of the compounds of the disclosure may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present disclosure can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", "ester," "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the compounds disclosed herein.

[00104] The compounds disclosed herein may form salts which are also within the scope of this disclosure.

[00105] The present disclosure relates to compounds which are modulators of at least one pathway chosen from USP28 and USP25. In one embodiment, the compounds of the present disclosure are inhibitors of at least one pathway chosen from USP28 and USP25.

[00106] The present disclosure is directed to chemical entities chosen from compounds as described herein and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, and pharmaceutical compositions comprising at least one chemical entity chosen from compounds as described herein, and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

[00107] Another aspect of the disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with modulation of USP28. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP28 an effective amount the compositions and chemical entities of Formula (I). In one embodiment, the disease or disorder is cancer.

[00108] In another aspect, the present disclosure is directed to a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with inhibition of USP28. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP28 an effective amount the compositions and chemical entities of Formula (I). In one embodiment, the disease or disorder is cancer.

[00109] In another aspect, the present disclosure is directed to a method of inhibiting USP28. The method involves administering to a patient in need thereof an effective amount of a chemical entity of Formula (I).

[00110] Another aspect of the disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with modulation of USP25. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP25 an effective amount the compositions and chemical entities of Formula (I). In one embodiment, the disease or disorder is cancer.

[00111] In another aspect, the present disclosure is directed to a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with inhibition of USP25. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP25 an effective amount the compositions and chemical entities of Formula (I). In one embodiment, the disease or disorder is cancer.

[00112] In another aspect, the present disclosure is directed to a method of inhibiting USP25. The method involves administering to a patient in need thereof an effective amount of a chemical entity of Formula (I).

[00113] Another aspect of the disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with modulation of USP28. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP28 an effective amount the compositions and chemical entities of Formula (I). In one embodiment, the disease or disorder is cancer. In another aspect, the present disclosure is directed to a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with inhibition of USP28. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP28 an effective amount the compositions and chemical entities of Formula (I). In one embodiment, the disease or disorder is cancer. The method can comprise administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP28 and / or USP25 an effective amount of a pharmaceutical composition comprising a USP28 Inhibitor, USP25 Inhibitor, and / or USP28 / 25 Inhibitor as disclosed herein. In another aspect, the present disclosure is directed to a method of inhibiting at least one pathway chosen from USP28 and USP25. The method involves administering to a patient in need thereof an effective amount of a chemical entity of Formula (I). The method can comprise administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP28 and / or USP25 an effective amount of a pharmaceutical composition comprising a USP28 Inhibitor, USP25 Inhibitor, and / or USP28 / 25 Inhibitor as disclosed herein.

[00114] Another aspect of the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in a patient associated with the inhibition of USP28, the method comprising administering to a patient in need thereof an effective amount of a chemical entity of Formula (I). In one embodiment, the disease or disorder is cancer. The method can comprise administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP28 and / or USP25 an effective amount of a pharmaceutical composition comprising a USP28 Inhibitor, USP25 Inhibitor, and / or USP28 / 25 Inhibitor as disclosed herein.

[00115] Another aspect of the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in a patient associated with the inhibition of USP25, the method comprising administering to a patient in need thereof an effective amount of a chemical entity of Formula (I). In one embodiment, the disease or disorder is cancer. The method can comprise administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP28 and / or USP25 an effective amount of a pharmaceutical composition comprising a USP28 Inhibitor, USP25 Inhibitor, and / or USP28 / 25 Inhibitor as disclosed herein.

[00116] Another aspect of the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in a patient associated with the inhibition of at least one pathway chosen from USP28 and USP25, the method comprising administering to a patient in need thereof an effective amount of a chemical entity of Formula (I). In one embodiment, the disease or disorder is cancer. The method can comprise administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP28 and / or USP25 an effective amount of a pharmaceutical composition comprising a USP28 Inhibitor, USP25 Inhibitor, and / or USP28 / 25 Inhibitor as disclosed herein.

[00117] In another aspect, the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating cancer. The method comprises administering to a patient in need of a treatment for cancer an effective amount of a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof. The method can comprise administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP28 and / or USP25 an effective amount of a pharmaceutical composition comprising a USP28 Inhibitor, USP25 Inhibitor, and / or USP28 / 25 Inhibitor as disclosed herein.

[00118] Another aspect of the present disclosure relates to a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, for use in a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with inhibiting USP28. In one embodiment, the disease or disorder is cancer. The method can comprise administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP28 and / or USP25 an effective amount of a pharmaceutical composition comprising a USP28 Inhibitor, USP25 Inhibitor, and / or USP28 / 25 Inhibitor as disclosed herein.

[00119] In another aspect, the present disclosure relates to a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, for use in a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with inhibiting USP25. In one embodiment, the disease or disorder is cancer.

[00120] Another aspect of the present disclosure relates to a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, for use in a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with inhibiting at least one pathway chosen from USP28 and USP25. In one embodiment, the disease or disorder is cancer.

[00121] In another aspect, the present disclosure relates to a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, for use in a method for treating, preventing, inhibiting, or eliminating cancer.

[00122] Another aspect of the present disclosure relates to the use of a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or disorder associated with inhibiting USP28. In one embodiment, the disease or disorder is cancer.

[00123]

[00124] Another aspect of the present disclosure relates to the use of a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or disorder associated with inhibiting at least one pathway chosen from USP28 and USP25. In one embodiment, the disease or disorder is cancer.

[00125] In another aspect, the present disclosure relates to the use of a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating cancer.

[00126] In other embodiments, the present disclosure relates to the use of an inhibitor of USP28 for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a disease or disorder associated with cancer.

[00127] The present disclosure also relates to the use of an inhibitor of USP28 for the preparation of a medicament used in the treatment, prevention, inhibition, or elimination of a disease or condition mediated by USP28, wherein the medicament comprises a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof. The present disclosure also relates to the use of an inhibitor of USP28 for the preparation of a medicament used in the treatment, prevention, inhibition, or elimination of a disease or condition mediated by USP28, wherein the medicament comprises a chemical entity chosen from compounds of Formulae (II), (III), (IV), (V), (VI), (VII), (IIa), (IIaa), (IIb'), (IIIa), (IIIb), (IIIaa), (IVa), (Va), (Va), (VIIa') or Formula (VIIaa) that is USP28 Inhibitor, a USP25 Inhibitor and / or a USP 28 / 25 Inhibitor as defined herein.

[00128] The present disclosure also relates to the use of an inhibitor of USP25 for the preparation of a medicament used in the treatment, prevention, inhibition, or elimination of a disease or condition mediated by USP25, wherein the medicament comprises a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof. The present disclosure also relates to the use of an inhibitor of USP25 for the preparation of a medicament used in the treatment, prevention, inhibition, or elimination of a disease or condition mediated by USP25, wherein the medicament comprises a chemical entity chosen from compounds of Formulae (II), (III), (IV), (V), (VI), (VII), (IIa), (IIaa), (IIb'), (IIIa), (IIIb), (IIIaa), (IVa), (Va), (Va), (VIIa') or Formula (VIIaa) that is USP28 Inhibitor, a USP25 Inhibitor and / or a USP 28 / 25 Inhibitor as defined herein.

[00129] In another aspect, the present disclosure relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or condition mediated by at least one pathway chosen from USP28 and USP25, wherein the medicament comprises a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof. These mechanisims have been shown to be useful in treating cancer such as lung cancer and brain cancer.

[00130] In some embodiments, the patient is selected for treatment based on gene amplification and / or elevated tumor expression of USP28, MYC, LSD1, NICD1, and / or reduced expression of FBXW7 relative to tissue-matched expression.

[00131] In some embodiments, the patient is selected for treatment based on gene amplification and / or elevated tumor expression of USP28, USP25, MYC, LSD1, NICD1, and / or reduced expression of FBXW7 relative to tissue-matched expression.

[00132] In some embodiments, administration of a compound of Formula (I) or a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier induces a change in the cell cycle, cell viability, cell apoptosis, or differentiation.

[00133] For example, the change in the cell cycle or cell viability or differentiation may be indicated by decreased tumor levels of MYC, LSD1, NICD1, PIM1, CDK1, POLA2, HEY1, and / or CCND1, and / or increased levels of CD86, p21, LGALS4, and / or DLL1.

[00134] Another aspect of the disclosure is directed to pharmaceutical compositions comprising a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. Another aspect of the disclosure is directed to pharmaceutical compositions comprising a chemical entity chosen from compounds of Formulae (II), (III), (IV), (V), (VI), (VII), (IIa), (IIaa), (IIb'), (IIIa), (IIIb), (IIIaa), (IVa), (Va), (Vaa), (VIIa') or Formula (VIIaa) that is USP28 Inhibitor, a USP25 Inhibitor and / or a USP 28 / 25 Inhibitor as defined herein.

[00135] In one embodiment, are provided methods of treating a disease or disorder associated with modulation of USP28 including cancer comprising administering to a patient suffering from at least one of said diseases or disorder a chemical entity of Formula (I). The methods of treating a disease or disorder associated with modulation of USP28 including cancer can comprise administering to a patient suffering from at least one of said diseases or disorder a chemical entity of Formulae (II), (III), (IV), (V), (VI), (VII), (IIa), (IIa), (IIb'), (IIIa), (IIIb), (IIIaa), (IVa), (Va), (Vaa), (VIIa') or Formula (VIIaa) that is USP28 Inhibitor, a USP25 Inhibitor and / or a USP 28 / 25 Inhibitor as defined herein.

[00136] In another embodiment, are provided methods of treating a disease or disorder associated with modulation of USP25 including cancer, comprising administering to a patient suffering from at least one of said diseases or disorder a chemical entity of Formula (I). The methods of treating a disease or disorder associated with modulation of USP25 including cancer, can comprise administering to a patient suffering from at least one of said diseases or disorder a chemical entity of Formulae (II), (III), (IV), (V), (VI), (VII), (IIa), (IIa), (IIb), (IIIb), (IIIaa), (IVa), (Va), (Vaa), (VIIa') or Formula (VIIaa) that is USP28 Inhibitor, a USP25 Inhibitor and / or a USP 28 / 25 Inhibitor as defined herein.

[00137] In another embodiment, are provided methods of treating a disease or disorder associated with modulation of at least one pathway chosen from USP28 and USP25 including cancer, comprising administering to a patient suffering from at least one of said diseases or disorder a chemical entity of Formula (I). The methods of treating a disease or disorder associated with modulation of at least one pathway chosen from USP28 and USP25 including cancer, can also comprise administering to a patient suffering from at least one of said diseases or disorder a chemical entity of Formulae (II), (III), (IV), (V), (VI), (VII), (IIa), (IIaa), (IIb'), (IIIa), (IIIb), (IIIaa), (IVa), (Va), (Vaa), (VIIa') or Formula (VIIaa) that is USP28 Inhibitor, a USP25 Inhibitor and / or a USP 28 / 25 Inhibitor as defined herein.

[00138] One therapeutic use of the compounds or compositions of the present disclosure which inhibit USP28 is to provide treatment to patients or subjects suffering from cancer.

[00139] Another therapeutic use of the compounds or compositions of the present disclosure which inhibit USP25 is to provide treatment to patients or subjects suffering from cancer.

[00140] Another therapeutic use of the compounds or compositions of the present disclosure which inhibit at least one pathway chosen from USP28 and USP25 is to provide treatment to patients or subjects suffering from cancer.

[00141] The compounds of the disclosure can be administered in effective amounts to treat or prevent a disorder and / or prevent the development thereof in subjects.

[00142] Administration of the disclosed compounds can be accomplished via any mode of administration for therapeutic agents.

[00143] Another aspect of the disclosure is directed to pharmaceutical compositions comprising a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[00144] The dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

[00145] Non-limiting examples of compounds according to Formulae (I)-(VII) of the disclosure include those of Tables 9-25 below. Method of Synthesizing the Compounds

[00146] The compounds of the present disclosure can be prepared in a number of ways known to those skilled in the art of organic synthesis. The compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes provided herein. The compounds disclosed herein may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described herein, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds disclosed herein (including, e.g., compounds of Formula (I)).

[00147] The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes. Those skilled in the art will recognize if a stereocenter exists in the compounds disclosed herein. Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and / or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

[00148] By way of example, compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. General procedures to prepare compounds of the instant invention are described in General Scheme 1. An appropriately substituted and protected bicyclic intermediate 1 can be reacted with an appropriately substituted protected amine intermediate 2 under palladium-catalyzed carbon-nitrogen coupling protocols using an appropriate palladium complex, ligand, and base (such as but not limited to: RuPhos 3rd generation palladium precatalyst and cesium carbonate) in a suitable solvent such as toluene at an appropriate temperature (such as 100 °C) to afford intermediate 3. The protecting group 1 (PG1; typically a Cbz group) can be removed under suitable deprotection conditions (such as but not limited to: hydrogen (gas), with palladium on carbon in an appropriate solvent such as methanol, ethanol, or ethyl acetate) to afford amine intermediate 4. The suitably substituted amine intermediate 4 can be reacted with a suitably substituted carboxylic acid under amide coupling conditions (such as but not limited to: the coupling reagents EDC and HOBt with an appropriate base such as Et3N or DIEA in a solvent such as DMF or DMA) to afford the penultimate amide intermediate 5. The protecting group 2 (PG2; typically a boc group) can be removed under appropriate conditions such as TFA in a solvent such as DCM or HCl in a solvent such as MeOH or dioxane to afford the final compounds 6. The final compounds can be typically purified by preparative HPLC and isolated as the free base. In the case where mixtures of enantiomers and / or diastereomers are formed, the individual stereoisomers can be purifed at an appropriate stage, in many cases by chiral HPLC. General Scheme 1 [Image disponible dans le document PDF, Image available in the PDF document] General Methods for the Preparation of Selected Intermediates

[00149] General procedures to prepare intermediates of the instant invention are described in Intermediate General Scheme 1. An appropriately substituted leaving group containing starting material 1 (LG1; typically a bromide) can be reacted with the lithiated chiral auxiliary 2 (formed by reacting 2 with a strong base such as nBuLi) in an appropriate solvent such as THF at low temperature (typically -78 °C) to afford intermediate 3. Hydrolysis to remove the auxiliary under conditions such as aqueous HCl in a solvent such as acetonitrile, followed by reduction (typically using NaBH4 in a solvent such as MeOH) can afford amino alcohol 4. Amino alcohol 4 can be cyclized using a strong base such as NaH in a solvent such as DMSO at low temperature (typically -70 °C) to afford Intermediate 4. Addition of an appropriate protecting group (PG1; typically a CBz group) to the corresponding intermediate can result in an appropriately substituted bicyclic intermediate 5. Intermediate General Scheme 1. [Image disponible dans le document PDF, Image available in the PDF document]

[00150] General procedures to prepare intermediates of the instant invention are described in Intermediate General Scheme 2. An appropriately substituted ketone 1 can be reacted under reductive amination conditions (typically with ammonium acetate as the amine source, NaBH3CN as the reductant, and a solvent such as MeOH) to afford the amine intermediate 2. Amine 2 is then protected (PG1; typically a CBz group) to afford the appropriately substituted intermediate 3. Intermediate General Scheme 2. [Image disponible dans le document PDF, Image available in the PDF document]

[00151] General procedures to prepare intermediates of the instant invention are described in Intermediate General Scheme 3. Acid chloride 1 can be reacted under a lewis acid promoted ethylene addition (typically using AlCl3 and ethylene gas in a solvent such as DCM) to afford ketone 2. Ketone 2 can then either be converted to an oxime then reduced (using O- Methylhydroxylamine hydrochloride, pyridine and EtOH to form the oxime; reduction using hydrogen gas, Raney Ni in EtOH solvent) or reacted under reductive amination conditions (typically with ammonium acetate as the amine source, NaBH3CN as the reductant, and a solvent such as MeOH) to afford amine 3. Amine 3 can be then protected (PG1; typically a CBz group) to afford the appropriately substituted intermediate 4. Intermediate General Scheme 3. [Image disponible dans le document PDF, Image available in the PDF document]

[00152] General procedures to prepare intermediates of the instant invention are described in Intermediate General Scheme 4. 2-Pyridone 2 can be obtained by the Michael addition of enamino ketone (typically generated in situ by treatment of a mono-protected cyclohexane-1,4-dione such as 1 with ammonia in methanol) with propynoic ester. Pyridone 2 can be converted to incorporate a leaving group (LG; typically a triflate group which can be obtained by treatment with triflic anhydride in the presence of a base, such as triethylamine). Following removal of the ketone protecting group, ketone 4 can then be reacted under reductive amination conditions (typically with ammonium acetate as the amine source, NaBH3CN as the reductant, and a solvent such as MeOH) to afford amine 5. Amine 5 can be then protected (PG1; typically a Cbz group) to afford the appropriately substituted intermediate 6. Intermediate General Scheme 4. [Image disponible dans le document PDF, Image available in the PDF document]

[00153] General procedures to prepare intermediates of the instant invention are described in Intermediate General Scheme 5. Ketone 1 can be condensed with dimethyl-formamide dimethyl acetal in a solvent (such as toluene) to provide enamino ketone 2. Ketone 2 can be treated with quinidine and a base (such as sodium ethoxide) to provide pyrimidin-2-amine 3. Pyrimidin-2- amine 3 can be converted to incorporate a leaving group (LG; typically a chloride group which can be obtained by treatment with CuCl2 and tert-butyl nitrite) to afford the appropriately substituted intermediate 4. Intermediate General Scheme 5. [Image disponible dans le document PDF, Image available in the PDF document]

[00154] General procedures to prepare intermediates of the instant invention are described in Intermediate General Scheme 6. An appropriately substituted intermediate 1 can be reacted with an appropriately substituted boronic ester 2 (or boronic acid) under palladium catalyzed carbon- carbon bond forming conditions (using an appropriate palladium catalyst such as Pd(dppf)Cl2 dichloromethane complex) in a solvent such as 1,4-dioxane / water mixture, and a base such as potassium carbonate at a temperature such as 100 °C) to afford the coupled intermediate 3. The olefin double bond present in intermediate 3 can then be functionalized using standard methods such as but not limited to: olefin reduction and epoxidation followed by reduction of the resultant epoxide to afford an appropriately substitued intermediate 4. Intermediate General Scheme 6. [Image disponible dans le document PDF, Image available in the PDF document]

[00155] General procedures to prepare intermediates of the instant invention are described in Intermediate General Scheme 7. An appropriately substituted intermediate 1 can be reacted under palladium-catalyzed boronic ester forming conditions (using a palladium catalyst such as Pd(dppf)Cl2-CH2Cl2 complex and a boronic ester source such as Bis(pinacolato)diboron in a solvent such as dioxane at a temperature such as 80 °C) to afford the boronic ester 2. Boronic ester 2 can be reacted in the presence of a suitable oxidant (such as urea-hydrogen peroxide complex in a solvent such as MeOH) to afford the phenol intermediate 3. The phenol intermediate can then be alkylated with a suitable electrophile (for example by using Mitsonobu-type conditions: such as DIAD with PPh3) to afford the appropriately substituted intermediate 4. Intermediate General Scheme 7. [Image disponible dans le document PDF, Image available in the PDF document] EXAMPLES

[00156] The disclosure is further illustrated by the following examples and synthesis schemes, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and / or scope of the appended claims. Analytical Methods, Materials, and Instrumentation

[00157] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Unless otherwise noted, reactions were conducted under an inert atmosphere of nitrogen. Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker or Varian spectrometers at 300 or 400 MHz. Spectra are given in ppm (<semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Purity and mass spectral data were measured using one of the two following methods. Method 1: Waters Acquity i-class ultra-performance liquid chromatography (UPLC) system with Acquity Photo Diode Array Detector, Acquity Evaporative Light Scattering Detector (ELSD) and Waters ZQ Mass Spectrometer. Data was acquired using Waters MassLynx 4.1 software and purity characterized by UV wavelength 220 nm, evaporative light scattering detection (ELSD) and electrospray positive ion (ESI). (Column: Acquity UPLC BEH C18 1.7 µm 2.1 x 50 mm; Flow Rate 0.6 mL / min; Solvent A (95 / 5 / 0.1%: 10 mM Ammonium Formate / Acetonitrile / Formic Acid), Solvent B (95 / 5 / 0.09%: Acetonitrile / Water / Formic Acid); gradient: 5-100% B from 0 to 2 mins, hold 100% B to 2.2 min and 5%B at 2.21 min). Method 2: SHIMADZU LCMS consisting of an UFLC 20-AD and LCMS 2020 MS detector. (Column: Shim-pack XR-ODS, 2.2 µm, 3.0 x 50 mm; Solvent: (acetonitrile / water, containing 0.05% NH4HCO3)). Preparatory HPLC purifications were conducted as designated below with a Flow Rate of 20 mL / min and detection by UV wavelength 220 nm and 254 nm, unless otherwise noted. The absolute configuration of the separated enantiomers of the compounds in the examples described herein was occasionally determined. In all other cases the absolute configuration of the separated enantiomers was not determined and in those instances the configuration of the resolved materials were arbitrarily assigned as R or S in each case. Abbreviations used in the following examples and elsewhere herein are: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] PREPARATION OF INTERMEDIATES Intermediates 1, 2, and 3. Benzyl (7-bromochroman-3-yl)carbamate, Benzyl (R)-(7- bromochroman-3-yl)carbamate, and Benzyl (S)-(7-bromochroman-3-yl)carbamate [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 7-Bromo-3-nitro-2H-chromene

[00158] A mixture of 4-bromo-2-hydroxybenzaldehyde (21.6 g, 108 mmol), 1,3-dihydro-2- benzofuran-1,3-dione (32 g, 216 mmol) and dibutylamine (7.0 g, 54 mmol) in toluene (800 mL) was heated to reflux under an atmosphere of N2. 2-Nitroethan-1-amine (50 g, 550 mmol) was added in portions over 2 h. The mixture was stirred at reflux overnight using a Dean-Stark apparatus. After cooling to room temperature, the solids were filtered out. Eight batches were thus run in parallel and the filtrate from the eight batches were combined and concentrated under vacuum. The residue was diluted with EtOAc (2 L) and washed with 1N NaOH (2 L). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:6 EtOAc / pet. ether) afforded 7-bromo-3-nitro-2H- chromene as a yellow solid. MS: (ESI, m / z): 256, 258 [M+H]+. Step 2. 7-Bromochroman-3-amine

[00159] To a solution of 7-bromo-3-nitro-2H-chromene (27 g, 106 mmol) in THF (300 mL) were added BH3 (1M in THF, 600 mL, 600 mmol) and NaBH4 (201 mg, 5.3 mmol). The mixture was stirred overnight at 65 °C. After cooling to room temperature, the reaction was then quenched by the addition of 600 mL of MeOH and stirred for 8 h at 80 °C. After cooling to room temperature, the mixture was concentrated under vacuum. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase A: water (10 mM NH4HCO3), B: ACN; Gradient: 0% to 50% B over 40 min) to afford 7-bromochroman-3-amine as a white solid. MS: <semantics>(ESI,m / z)<annotation encoding="application / x-tex">(ESI, m / z)< / annotation>< / semantics>: 228, 230 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step 3. Benzyl (7-bromochroman-3-yl)carbamate (Intermediate 1)

[00160] A solution of K2CO3 (19.3 g, 140 mmol) in water (150 mL) was added to a solution of 7-bromochroman-3-amine (16.0 g, 70.1 mmol) in EtOAc (300 mL). Benzyl chloroformate (17.8 g, 104 mmol) was added at -10 °C and the reaction mixture was stirred for 30 min at room temperature. The mixture was diluted with EtOAc (200 mL). The organic layer was collected, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was washed with 1:1 EtOAc / pet. ether (200 mL) to give benzyl-(7-bromochroman-3-yl)carbamate as a white solid. MS: (ESI, m / z): 362, 364 [M+H]+. Step 4. Benzyl (R)-(7-bromochroman-3-yl)carbamate (Intermediate 2) and Benzyl (S)-(7- bromochroman-3-yl)carbamate (Intermediate 3)

[00161] The racemate benzyl (7-bromochroman-3-yl)carbamate (12.5 g, 34.6 mmol) was separated by SFC (Column: ChiralArt Amylose-SA, 2x25 cm, 5 µm; Mobile phase A: CO2, 80%, B: EtOH, 20%; Flow rate: 40 mL / min) to afford the title compounds as follows: benzyl (R)-(7- bromochroman-3-yl)carbamate (first eluting isomer, <semantics>RT=7.98 min<annotation encoding="application / x-tex">RT = 7.98 \text{ min}< / annotation>< / semantics>) as a white solid and benzyl (S)-<semantics>(7<annotation encoding="application / x-tex">(7< / annotation>< / semantics>-bromochroman-3-yl)carbamate (second eluting isomer, RT = 9.21 min) as a white solid. First eluting isomer: <semantics>1H<annotation encoding="application / x-tex">{}^{1}H< / annotation>< / semantics> NMR (CDCl3, 400 MHz) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>(ppm): 7.35-7.32 (m, 5H), 7.03-7.01 (m, 2H), 6.90 (d, <semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics> Hz, 1H), 5.22-5.10 (m, 3H), 4.25 (s, 1 H), 4.17-4.09 (m, 2H), 3.04 (dd, <semantics>J=16.8<annotation encoding="application / x-tex">J = 16.8< / annotation>< / semantics> Hz, 4.8 Hz, 1H), 2.73 (d, <semantics>J=16.8<annotation encoding="application / x-tex">J = 16.8< / annotation>< / semantics> Hz, 1H). MS: (ESI, m / z): 362, 364 [M+H]+. Second eluting isomer: <semantics>1H<annotation encoding="application / x-tex">{}^{1}H< / annotation>< / semantics> NMR (CDCl3, 400 MHz) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>(ppm): 7.35-7.32 (m, 5H), 7.03-7.01 (m, 2H), 6.90 (d, <semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics> Hz, 1H), 5.22-5.07 (m, 3H), 4.25 (s, 1 H), 4.18-4.09 (m, 2H), 3.04 (dd, <semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics> 16.8 Hz, 4.8 Hz, 1H), 2.73 (d, <semantics>J=16.80<annotation encoding="application / x-tex">J = 16.80< / annotation>< / semantics> Hz, 1H). MS: (ESI, m / z): 362, 364 [M+H]+. Intermediate 4-1. tert-Butyl 4-(3-amino-8-fluorochroman-7-yl)piperazine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 3,4-Difluoro-2-hydroxybenzaldehyde

[00162] Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added a 2,3-difluorophenol (10.0 g, 75.33 mmol), ACN (200 mL), HCHO (23.06 g, 738 mmol), Et3N (21.0 mL, 146 mmol), and MgCl2 (14.6 g, 150.28 mmol). The resulting solution was stirred for 16 h at 60 °C. The reaction mixture was cooled to 26 °C, then was diluted with 200 mL of water. The resulting solution was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford a residue that was purified by silica gel chromatography with ethyl acetate / pet. ether (1:4) to afford 3,4-difluoro-2-hydroxybenzaldehyde as light yellow oil. Step 2. tert-Butyl 4-(2-fluoro-4-formyl-3-hydroxyphenyl)piperazine-1-carboxylate

[00163] Into a 250-mL round-bottom flask was added 3,4-difluoro-2-hydroxybenzaldehyde (5 g, 31.63 mmol), tert-butyl piperazine-1-carboxylate (5.9 g, 31.68 mmol), DMSO (100 mL), and DIEA (6.1 g, 47.20 mmol). The resulting solution was stirred for 6 h at 120 °C. After cooling to room temperature, the reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with ethyl acetate (3x100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford a residue that was purified by silica gel chormatography with ethyl acetate / pet. ether (0-30%) to afford tert- butyl 4-(2-fluoro-4-formyl-3-hydroxyphenyl)piperazine-1-carboxylate as yellow oil. Step 3. tert-Butyl 4-(8-fluoro-3-nitro-2H-chromen-7-yl)piperazine-1-carboxylate

[00164] Into a 100-mL round-bottom flask was added tert-butyl 4-(2-fluoro-4-formyl-3- hydroxyphenyl)piperazine-1-carboxylate (185 mg, 0.48 mmol), 1,3-dihydro-2-benzofuran-1,3- dione (166 mg, 1.06 mmol, 95%), 2-nitroethan-1-ol (104 mg, 1.08 mmol), dibutylamine (37 mg, 0.27 mmol), and toluene (10 mL). The resulting solution was stirred for 8 h at 100 °C in an oil bath. The reaction mixture was cooled to room temperature, then was quenched by addition of 5 mL water, and extracted with DCM (3x10 mL). The organic layers were combined, washed with brine (3x10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford a residue that was purified by a silica gel chromatography with ethyl acetate / pet. ether (1:3) to afford tert-butyl 4-(8-fluoro-3-nitro-2H-chromen-7-yl)piperazine-1-carboxylate as a red solid. Step 4. tert-Butyl 4-(3-amino-8-fluorochroman-7-yl)piperazine-1-carboxylate

[00165] Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was added tert-butyl 4-(8-fluoro-3-nitro-2H-chromen-7-yl)piperazine-1- carboxylate (150 mg, 0.39 mmol), and THF (20 mL). Borane-THF complex (4 mL, 4 mmol) was added dropwise with stirring at 0 °C. To this reaction mixture was added NaBH4 (73 mg, 1.93 mmol). The resulting solution was stirred for 12 h at 65°C, then was quenched by the addition of methanol (20 mL), and concentrated under vacuum to afford a residue that was purified by silica gel chromatography with ethyl acetate / pet. ether (0-100%) to afford tert-butyl 4-(3-amino-8- fluoro-3,4-dihydro-2H-1-benzopyran-7-yl)piperazine-1-carboxylate as yellow oil.

[00166] The following intermediate in Table 1 was prepared using standard chemical manipulations and procedures similar to those used for the preparation of Intermediate 4-1. Table 1: [Image disponible dans le document PDF, Image available in the PDF document] 1Notes on procedures: Step 1 was not necessary. Intermediate 5-1. Benzyl (R)-(7-bromo-5-fluorochroman-3-yl)carbamate Method 1. [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 5-Bromo-2-(bromomethyl)-1,3-difluorobenzene

[00167] A mixture of 48% HBr (130 mL, 1149 mmol) and (4-bromo-2,6- difluorophenyl)methanol (40 g, 179 mmol) was heated to reflux overnight. After cooling to room temperature, the reaction mixture was poured into 80 mL of water and was extracted with hexanes (2 x 300 mL). The combined organic layers were washed with sodium bicarbonate solution, dried over MgSO4, filtered, and concentrated to afford 5-bromo-2-(bromomethyl)-1,3-difluorobenzene. 1H NMR (CDCl3, 300 MHz) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>(ppm): 6.94-7.22 (m, 2H), 4.46 (s, 2H). Step 2. (2R,5S)-2-(4-bromo-2,6-difluorobenzyl)-5-isopropyl-3,6-dimethoxy-2,5- dihydropyrazine

[00168] A solution of nBuLi (6.78 mL, 10.86 mmol, 1.6 M) in hexanes was added dropwise to a solution of (S)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (2.0 g, 10.86 mmol) in 20 mL of THF at -78 °C. After stirring for 30 min at -78 °C, a solution of 5-bromo-2-(bromomethyl)-1,3- difluorobenzene (3.10 g, 10.86 mmol) in 10 mL of THF was added and the reaction mixture was stirred at -78 °C for 3 h. Then 20 mL of saturated NH4Cl solution was added. After the reaction mixture was warmed to room temperature, 150 mL of water was added and the mixture was extracted with EtOAc three times. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (eluting with 0 to 15%) EtOAc / Hexanes) afforded (2R,5S)-2-(4-bromo-2,6-difluorobenzyl)-5-isopropyl-3,6-dimethoxy- 2,5-dihydropyrazine. 1H NMR (CDCl3, 300 MHz) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>(ppm): 7.03 (d, <semantics>J=7.04<annotation encoding="application / x-tex">J = 7.04< / annotation>< / semantics> Hz, 2H), 4.14-4.32 (m, 1H), 3.71 (s, 3H), 3.58 (s, 3H), 3.13-3.33 (m, 1H), 2.79-2.93 (m, 1H), 2.13-2.33 (m, 1H), 1.00 <semantics>(d,J=7.04 Hz,3H),0.64(d,J=7.04 Hz,3H). MS:(ESI,m / z):389,391[M+H]+.<annotation encoding="application / x-tex">(d, J = 7.04 \text{ Hz}, 3H), 0.64 (d, J = 7.04 \text{ Hz}, 3H). \text{ MS}: (ESI, m / z): 389, 391 [M+H]^+.< / annotation>< / semantics> Step 3. Methyl (R)-2-amino-3-(4-bromo-2,6-difluorophenyl)propanoate

[00169] A solution of (2R,5S)-2-(4-bromo-2,6-difluorobenzyl)-5-isopropyl-3,6-dimethoxy- 2,5-dihydropyrazine (3.1 g, 8.02 mmol) in acetonitrile (60 mL) was treated with HCl (53.5 ml, 16.04 mmol, 0.3 N). The reaction mixture was stirred at room temperature for 60 min. The reaction was made basic with sat. aq. NaHCO3 solution and the mixture was extracted with CH2Cl2 three times. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (eluting with 0 to 100% EtOAc / Hexanes) afforded methyl (R)-2-amino-3-(4-bromo-2,6-difluorophenyl)propanoate. 1H NMR (CDCl3, 300 MHz) <semantics>δ(ppm)<annotation encoding="application / x-tex">\delta(ppm)< / annotation>< / semantics>: 7.07 (d, <semantics>J=6.74<annotation encoding="application / x-tex">J = 6.74< / annotation>< / semantics> Hz, 2H), 3.54-3.80 (m, 4H), 3.01-3.24 (m, 1H), 2.93 (s, 1H), 1.62 (br s, 2H). MS: (ESI, m / z): 294, 296 [M+H]+. Step 4. (R)-2-amino-3-(4-bromo-2,6-difluorophenyl)propan-1-ol

[00170] To a solution of methyl (R)-2-amino-3-(4-bromo-2,6-difluorophenyl)propanoate (2.3) g, 7.85 mmol) in MeOH (70 mL) at room temperature was added NaBH4 (1.043 g, 27.57 mmol) in portions. The mixture was stirred at room temperature overnight. Water was added and the MeOH was removed under reduced pressure. The aqueous mixture was extracted with choroform three times. The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford (R)-2-amino-3-(4-bromo-2,6-difluorophenyl)propan-1-ol. 1H NMR (CDCl3, 300 MHz) <semantics>δ(ppm)<annotation encoding="application / x-tex">\delta(ppm)< / annotation>< / semantics>: 7.08 (d, <semantics>J=6.74<annotation encoding="application / x-tex">J = 6.74< / annotation>< / semantics> Hz, 2H), 3.54-3.72 (m, 1H), 3.36 (dd, <semantics>J=10.55<annotation encoding="application / x-tex">J = 10.55< / annotation>< / semantics>, 7.62 Hz, 1H), 3.09 (br s, 1H), 2.51-2.86 (m, 2H), 1.74 (br s, 3H). MS: (ESI, m / z): 266, 268 [M+H]+. Step 5. (R)-7-bromo-5-fluorochroman-3-amine

[00171] To a sloution of (R)-2-amino-3-(4-bromo-2,6-difluorophenyl)propan-1-ol (500 mg, 1.88 mmol) in DMSO (3 mL) at room temperature was added NaH (113 mg, 2.82 mmol). The mixture was stirred at room temperature for 30 min, then at 70 °C for 30 min, and kept stirring at 50 °C overnight. After cooling to room temperature, 30 mL of water, and the mixture was extracted with EtOAc three times. The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated to afford crude (R)-7-bromo-5-fluorochroman-3-amine. H NMR <semantics>(CDCl3,300 MHz)δ(ppm):6.61−6.92 (m, 2H),4.01−4.32 (m, 1H),3.67−3.88 (m, 1H),3.35 (ddt, J<annotation encoding="application / x-tex">(CDCl_3, 300 \text{ MHz}) \delta(ppm): 6.61-6.92 \text{ (m, 2H)}, 4.01-4.32 \text{ (m, 1H)}, 3.67-3.88 \text{ (m, 1H)}, 3.35 \text{ (ddt, } J< / annotation>< / semantics> <semantics>=7.00,3.19,1.80,1.80 Hz,1H,2.79−3.03 (m, 1H),2.46 (br d, J=6.74 Hz,1H),1.40−1.89 (m, 2H).<annotation encoding="application / x-tex">= 7.00, 3.19, 1.80, 1.80 \text{ Hz}, 1\text{H}, 2.79-3.03 \text{ (m, 1H)}, 2.46 \text{ (br d, } J = 6.74 \text{ Hz}, 1\text{H)}, 1.40-1.89 \text{ (m, 2H)}.< / annotation>< / semantics> MS: (ESI, m / z): 246, 248 [M+H]+. Step 6. Benzyl (R)-(7-bromo-5-fluorochroman-3-yl)carbamate

[00172] To a solution of (R)-7-bromo-5-fluorochroman-3-amine (467 mg, 1.90 mmol) and saturated solution of sodium hydrogen carbonate (10 mL) in MeOH (20 mL) at 0 °C was added benzyl chloroformate (0.405 mL, 2.85 mmol) dropwise. The mixture was stirred overnight, allowing the temperature to warm to room temperature. 20 mL of water was added and the mixture was extracted with EtOAc three times. The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (eluting with 7% to 60% EtOAc / Hexanes) afforded benzyl (R)-(7-bromo-5-fluorochroman-3- yl)carbamate. 1H NMR (CDCl3, 300 MHz) δ(ppm): 7.34 (s, 5 H), 6.65-6.97 (m, 2H), 5.10 (s, 2H), 4.90-5.08 (m, 1H), 4.26 (br s, 1H), 3.97-4.21 (m, 3H), 2.89 (m, 1H), 2.78 (m, 1H). MS: (ESI, m / z): 380, 382 [M+H]+. Intermediate 5-1. Benzyl (R)-(7-bromo-5-fluorochroman-3-yl)carbamate Method 2. [Image disponible dans le document PDF, Image available in the PDF document] Step 1. Diethyl 2-acetamido-2-(4-bromo-2,6-difluorobenzyl)malonate

[00173] To a stirred solution of diethyl 2-acetamidomalonate (59.2 g, 0.273 mol) in DMF (500 mL) was added t-BuOK (33.1 g, 0.295 mol) in portions at room temperature. The mixture was stirred at room temperature for 1 h and 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (65.0 g, 0.227 mol) was added. The reaction mixture was stirred at room temperature for 3 h. Water (2000 mL) was added slowly and the mixture was stirred for 1 h. The resulting precipitate was collected by filtration, washed with water (3 x 250 mL) and dried under vacuum to give diethyl 2-acetamido- 2-(4-bromo-2,6-difluorobenzyl)malonate as an off-white solid. Step 2. 2-Acetamido-3-(4-bromo-2,6-difluorophenyl)propanoic acid

[00174] To a stirred solution of of diethyl 2-acetamido-2-(4-bromo-2,6- difluorobenzyl)malonate (80 g, 0.189 mol) in ethanol (500 mL) was added a solution of NaOH (30 g, 0.758 mol) in water (500 mL). The reaction mixture was heated at reflux for 5 h and then cooled to room temperature. The mixture was adjusted to pH=5-6 with 2N aqueous HCl and heated at reflux overnight. The mixture was cooled to room temperature and adjusted to pH=8-9 with 10% aqueous NaOH. The resulting mixture was washed with MTBE (300 mL) and the aqueous phase was adjusted to pH 2-3 with 2N aqueous HCl and then extracted with EtOAc (500 mL×2). The combined extracts were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was treated with a mixture of EtOAc (100 mL) and pet. ether (150 mL) under stirring for 1 h. The resulting precipitate was collected by filtration, washed with pet. ether and dried under vacuum to give 2-acetamido-3-(4-bromo-2,6-difluorophenyl)propanoic acid as a white solid. 1H NMR (DMSO-<semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>, 400 MHz) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>(ppm): 12.86 (br s, 1H), 8.31 (br s, 1H), 7.43 (d, <semantics>J=6.8<annotation encoding="application / x-tex">J = 6.8< / annotation>< / semantics> Hz, 2H), 4.43 (m, 1H), 3.08-2.87 (m, 2H), 1.77 (s, 3H). MS: (ESI, m / z): 322, 324 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step 3. (R)-2-Acetamido-3-(4-bromo-2,6-difluorophenyl)propanoic acid

[00175] To a suspension of 2-acetamido-3-(4-bromo-2,6-difluorophenyl)propanoic acid (55 g, 0.171 mol) in distilled water (1.1 L) was added 10% aqueous NaOH dropwise to adjust pH to 8.5. The mixture was heated to 35-38 °C and L-acylase (11.0 g) was added. The reaction mixture was stirred at this temperature for 48 h while keeping the pH at 8.5 with 10% aqueous NaOH. The mixture was adjusted to pH 4-5 with 2N aqueous HCl and activated carbon (2 g) was added. The mixture was heated at 60 °C for 2 h and then cooled to room temperature. The mixture was adjusted to pH 9.5-10 with 10% aqueous NaOH and filtered. The filtrate was adjusted to pH 2-3 with 2N aqueous HCl and then extracted with EtOAc (400 mL x 2). The combined extracts were washed with 0.5N aqueous HCl (200 mL x 2) and brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was treated with a mixture of EtOAc (60 mL) and pet. ether (80 mL) under stirring for 1 h. The resulting precipitate was collected by filtration, washed with pet. ether and dried under vacuum to give (R)-2-acetamido-3-(4-bromo-2,6- difluorophenyl)propanoic acid as a white solid. Step 4. (R)-2-Amino-3-(4-bromo-2,6-difluorophenyl)propanoic acid hydrochloride

[00176] A mixture of (R)-2-acetamido-3-(4-bromo-2,6-difluorophenyl)propanoic acid (26 g, 80.7 mmol) in 6N aqueous HCl (260 mL) was heated under reflux for 5 h. The mixture was concentrated and the residue was dried under vacuum at 50 °C to provide crude (R)-2-amino-3-(4- bromo-2,6-difluorophenyl)propanoic acid hydrochloride as a white solid. Step 5. (R)-Methyl 2-amino-3-(4-bromo-2,6-difluorophenyl)propanoate

[00177] To a solution of (R)-2-amino-3-(4-bromo-2,6-difluorophenyl)propanoic acid hydrochloride (25.4 g, 80.7 mmol) in MeOH (125 mL) was added MeOH / HCl (8M, 125 mL). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was suspended in 5% aqueous Na2CO3 (250 mL) and then extracted with EtOAc (250 mL) x 2). The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give (R)-methyl 2-amino-3-(4-bromo-2,6-difluorophenyl)propanoate as an oil. 1H NMR (CDCl3, 400 MHz) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>(ppm): 7.08 (m, 2H), 3.73 (s, 3H), 3.70 (m, 1H), 3.09-2.87 (m, 2H), 1.55 (br s, 2H). MS: (ESI, m / z): 294, 296 [M+H]+. Step 6. (R)-2-Amino-3-(4-bromo-2,6-difluorophenyl)propan-1-ol

[00178] To a stirred solution of (R)-methyl 2-amino-3-(4-bromo-2,6- difluorophenyl)propanoate (23.5 g, 79.9 mmol) in MeOH (500 mL) was added NaBH4 (6.08 g, 159.9 mmol) portionwise. The reaction mixture was stirred at room temperature for 3 h and NaBH4 (1.52 g, 39.9 mmol) was added. The reaction mixture was stirred at room temperature overnight. Water (500 mL) was added and MeOH was removed by evaporation under vacuum. The resulting mixture was extracted with CH2Cl2 (250 mL x 3) and the combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated to afford crude (R)-2-amino-3-(4-bromo-2,6- difluorophenyl)propan-1-ol as a white solid. MS: (ESI, m / z): 266, 268 [M+H]+. Step 7. (R)-7-Bromo-5-fluorochroman-3-amine

[00179] To a stirred solution of (R)-2-amino-3-(4-bromo-2,6-difluorophenyl)propan-1-ol (18.5) g, 69.5 mmol) in DMSO (100 mL) was added NaH (60% in mineral oil, 4.17 g) at room temperature. The reaction mixture was stirred at 35 °C for 3 h and ice-water (500 mL) was added carefully to quench the reaction. The resulting mixture was extracted with EtOAc (300 mL x 3) and the combined extracts were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give crude (R)-7-bromo-5-fluorochroman-3-amine. MS: (ESI, m / z): 246, 248 [M+H]+. Step 8. Benzyl (R)-(7-bromo-5-fluorochroman-3-yl)carbamate

[00180] To a stirred mixture of crude (R)-7-bromo-5-fluorochroman-3-amine (17 g, 69.5 mmol) and saturated aqueous NaHCO3 (200 mL) in MeOH (400 mL) was added benzyl chloroformate (17.7 g, 104.2 mmol) drowise. The reaction mixture was stirred at room temperature overnight and then diluted with water (500 mL). The resulting mixture was extracted with EtOAc (300 mL x 2) and the combined extracts were washed with water (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography to give benzyl (R)-(7-bromo-5-fluorochroman-3-yl)carbamate. MS: (ESI, m / z): 380, 382 [M+H]+.

[00181] The following intermediate in Table 2 may be prepared using standard chemical manipulations and procedures similar to Method 2 of Intermediate 5-1. Table 2: [Image disponible dans le document PDF, Image available in the PDF document] 1Notes on procedures: Step 3 and Step 8 were not performed. In Step 1, 5-bromo-2-(bromomethyl-d2)- 1,3-difluorobenzene was prepared from methyl 4-bromo-2,6-difluorobenzoate in two steps: Methanol (0.806 ml, 19.92 mmol) was carefully added dropwise to a stirring solution of methyl 4-bromo-2,6- difluorobenzoate (5 g, 19.92 mmol), sodium tetrahydroborate-d4 (0.834 g, 19.92 mmol) in THF (15 mL). The reaction was then allowed to stir at 70 °C for 2 h. The reaction was cooled to room temperature and 10 mL sat. aq. NH4Cl was added. The reaction was allowed to stir at room temperature for 2 h. The organic layer was separated. The aqueous layer was extracted with 2 x 15 mL DCM. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under vacuum to afford (4-bromo-2,6- difluorophenyl)methan-d2-ol. A solution of (4-bromo-2,6-difluorophenyl)methan-d2- ol (3.00 g, 13.33 mmol) and PBr3 (14.21 mL, 14.21 mmol) in DCM (30 mL) was stirred at 40 °C for 30 min. After cooling to room temperature, the reaction was quenched by the addition of water (7.5 mL). The resulting mixture was extracted with DCM (3 x 10 mL) and the organic layers were combined, dried over Na2SO4, filtered, and concentrated to afford a crude pale yellow oil. The oil was purified by normal phase chromatography using Biotage (KP-SIL 50g, 2% EtOAc / hexanes up to 25% EtOAc / hexanes. Desired fractions were combined and concentrated to afford 5-bromo-2-(bromomethyl-d2)-1,3-difluorobenzene. 1H NMR (CDCl3, 300 MHz) δ(ppm): 1.54 (s, 1H) 4.46 (br d, <semantics>J=3.8<annotation encoding="application / x-tex">J = 3.8< / annotation>< / semantics> Hz, 1H) 7.05-7.21 (m, 2H). Intermediate 6. tert-Butyl (R)-4-(3-amino-8-bromo-5-fluorochroman-7-yl)piperazine-1- carboxylate and Intermediate 7-1. tert-Butyl (R)-4-(3-amino-6-cyano-5-fluorochroman-7-yl)piperazine-1- carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Step 1: tert-Butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)-8-bromo-5-fluorochroman-7- yl)piperazine-1-carboxylate and tert-butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)-6- bromo-5-fluorochroman-7-yl)piperazine-1-carboxylate

[00182] Into a 20-mL vial, was added tert-butyl 4-[(3R)-3-[[(benzyloxy)carbonyl]amino]-5- fluoro-3,4-dihydro-2H-1-benzopyran-7-yl]piperazine-1-carboxylate (570 mg, 1.17 mmol), THF (10 mL), and NBS (314 mg, 1.76 mmol). The resulting solution was stirred for 2 h at 25 °C, then was quenched by the addition of water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by prep-HPLC (Column: XSelect CSH Prep C18 OBD, 5 µm, 19x150 mm; Mobile phase A: water (0.05% TFA), B: ACN; Gradient: 45% B increasing to 70% B within 15 min). The collected fraction was concentrated under vacuum to afford tert-butyl 4-[(3R)-3-[[(benzyloxy)carbonyl]amino]-8-bromo-5-fluoro-3,4- dihydro-2H-1-benzopyran-7-yl]piperazine-1-carboxylate (peak 1) (Intermediate 6) as an off- white solid and tert-butyl 4-[(3R)-3-[[(benzyloxy)carbonyl]amino]-6-bromo-5-fluoro-3,4- dihydro-2H-1-benzopyran-7-yl]piperazine-1-carboxylate (peak 2) as off-white solid. MS (ESI, m / z): 564, 566 [M+H]+. These two compounds were carried on indepedently into subsequent synthetic steps. Step 2: tert-Butyl 4-[(3R)-3-[[(benzyloxy)carbonyl]amino]-6-cyano-5-fluoro-3,4-dihydro- 2H-1-benzopyran-7-yl]piperazine-1-carboxylate

[00183] Into a 10-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was added tert-butyl 4-[(3R)-3-[[(benzyloxy)carbonyl]amino]-6-bromo-5-fluoro-3,4-dihydro-2H- 1-benzopyran-7-yl]piperazine-1-carboxylate (80 mg, 0.14 mmol), Zn(CN)2 (13 mg, 0.11 mmol), Pd(PPh3)4 (8 mg, 0.01 mmol), PPh3 (7 mg, 0.03 mmol), and NMP (5 mL). The resulting solution was stirred for 1 h at 120 °C. After cooling to 25 °C, the reaction was quenched by the addition of 10 mL of water. The resulting mixture was extracted with 3 x 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford a residue that was purified via reverse phase chromatography (Column: C18 silica gel; Mobile phase A: 0.1% TFA in H2O, B: ACN; Flow rate: 50 mL / min; Gradient: 0% B increasing to 80% B within 30 min). The collected fractions were concentrated under vacuum to afford tert-butyl 4-[(3R)-3-[[(benzyloxy)carbonyl]amino]-6-cyano-5-fluoro-3,4-dihydro-2H-1- benzopyran-7-yl]piperazine-1-carboxylate as an off-white solid. MS (ESI, m / z): 511 [M+H]+. Step 3: tert-Butyl 4-[(3R)-3-amino-6-cyano-5-fluoro-3,4-dihydro-2H-1-benzopyran-7- yl|piperazine-1-carboxylate

[00184] Into a 25-mL round-bottom flask purged and maintained with nitrogen, was placed tert- butyl 4-[(3R)-3-[[(benzyloxy)carbonyl]amino]-6-cyano-5-fluoro-3,4-dihydro-2H-1-benzopyran- 7-yl]piperazine-1-carboxylate (40 mg, 0.08 mmol), ethyl acetate (4 mL), and 10% Palladium on carbon (40 mgs). The resulting mixture was stirred for 2 h at 25 °C under hydrogen atmosphere. The solids were removed by filtration through Celite and the filtrate was concentrated under vacuum to afford tert-butyl 4-[(3R)-3-amino-6-cyano-5-fluoro-3,4-dihydro-2H-1-benzopyran-7- yl]piperazine-1-carboxylate (Intermediate 7-1) as yellow oil. MS (ESI, m / z): 377 [M+H]+. The following intermediate in Table 3 may be prepared using standard chemical manipulations and procedures similar to those used for the preparation of Intermediate 7-1. Table 3: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Intermediate 8. Benzyl (6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate; Intermediate 9. Benzyl (S)-(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate and Intermediate 10. Benzyl (R)-(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 6-Bromo-1,2,3,4-tetrahydronaphthalen-2-amine

[00185] A solution of 6-bromo-3,4-dihydronaphthalen-2(1H)-one (5 g, 22.21 mmol), NH4OAc (13.8 g, 179 mmol), and NaBH3CN (1.68 g, 26.67 mmol) in MeOH (250 mL) was stirred for 1 h at room temperature. The reaction mixture was acidified with 2N HCl solution to pH 4-5 and was concentrated under vacuum. The residual solution was washed with CH2Cl2 (200 mL x 2). The aqueous layer was basified with 1N NaOH solution to pH 10, then extracted with CH2Cl2 (200 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to afford 6-bromo-1,2,3,4-tetrahydronaphthalen-2-amine as a yellow oil. MS: (ESI, m / z): 226, 228 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step 2. Benzyl (6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate (Intermediate 8)

[00186] A solution of 6-bromo-1,2,3,4-tetrahydronaphthalen-2-amine (1.8 g, 7.96 mmol), benzyl chloroformate (1.6 g, 9.55 mmol), and Cs2CO3 (3 g, 21.71 mmol) in THF (20 mL) and water (20 mL) was stirred at 60 °C overnight. After cooling to room temperature, the reaction mixture was extracted with EtOAc (30 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with gradient 1:100 to 1:3 EtOAc / pet. ether) afforded benzyl (6-bromo-1,2,3,4- tetrahydronaphthalen-2-yl)carbamate (Intermediate 8) as a solid. MS: (ESI, m / z): 360, 362 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step 3. Benzyl (S)-(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate (Intermediate 9) and Benzyl (R)-(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate (Intermediate 10)

[00187] The racemate benzyl (6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate was separated by SFC (Column: Chiralpak IA-SFC-03, 5x25 cm, 5 µm; Mobile phase A: CO2, B: MeOH; Flow rate: 170 mL / min) to afford the title compounds as follows: benzyl (S)-(6-bromo- <semantics>1,2,3,4<annotation encoding="application / x-tex">1,2,3,4< / annotation>< / semantics>-tetrahydronaphthalen-<semantics>2<annotation encoding="application / x-tex">2< / annotation>< / semantics>-yl)carbamate (first eluting isomer, RT = <semantics>6.54<annotation encoding="application / x-tex">6.54< / annotation>< / semantics> min) as a white solid and benzyl (R)-(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate (second eluting isomer, <semantics>RT=9.06 min<annotation encoding="application / x-tex">RT = 9.06 \text{ min}< / annotation>< / semantics>) as a white solid. First eluting isomer: <semantics>1H<annotation encoding="application / x-tex">{}^{1}H< / annotation>< / semantics> NMR (CDCl3, 400 MHz) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>(ppm): 7.30-7.21 (m, 5H), 7.17-7.13 (m, 2H), <semantics>6.85−6.83<annotation encoding="application / x-tex">6.85-6.83< / annotation>< / semantics> (d, <semantics>J=8.00<annotation encoding="application / x-tex">J = 8.00< / annotation>< / semantics> Hz, 1H), <semantics>5.02<annotation encoding="application / x-tex">5.02< / annotation>< / semantics> (s, 2H), <semantics>4.70<annotation encoding="application / x-tex">4.70< / annotation>< / semantics> (br, 1H), <semantics>3.95<annotation encoding="application / x-tex">3.95< / annotation>< / semantics> (m, 1H), <semantics>3.01−2.96<annotation encoding="application / x-tex">3.01-2.96< / annotation>< / semantics> (dd, <semantics>J=4.00<annotation encoding="application / x-tex">J = 4.00< / annotation>< / semantics> Hz, 16.00 Hz, 2H), 2.79-2.75 (m, 2H), 2.53-2.47 (m, 1H), 2.00-1.97 (m, 1H), 1.68-1.66 (m, 1H). MS: (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 360, 362 [M+H]+. Second eluting isomer: <semantics>1H<annotation encoding="application / x-tex">{}^{1}H< / annotation>< / semantics> NMR (CDCl3, 400 MHz) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>(ppm): 7.30-7.23 (m, 5H), 7.17-7.13 (m, 2H), <semantics>6.84−6.82<annotation encoding="application / x-tex">6.84-6.82< / annotation>< / semantics> (d, <semantics>J=8.00<annotation encoding="application / x-tex">J = 8.00< / annotation>< / semantics> Hz, 1H), <semantics>5.02<annotation encoding="application / x-tex">5.02< / annotation>< / semantics> (s, 2H), <semantics>4.70<annotation encoding="application / x-tex">4.70< / annotation>< / semantics> (br, 1H), <semantics>4.06−3.95<annotation encoding="application / x-tex">4.06-3.95< / annotation>< / semantics> (m, 1H), <semantics>3.01−2.96<annotation encoding="application / x-tex">3.01-2.96< / annotation>< / semantics> (dd, <semantics>J=4.00 Hz<annotation encoding="application / x-tex">J = 4.00 \text{ Hz}< / annotation>< / semantics>, 16.0 Hz, 2H), 2.79-2.75 (m, 2H), 2.51-2.47 (m, 1H), 2.00-1.96 (m, 1H), 1.68-1.66 (m, 1H). MS: (ESI, m / z): 360, 362 [M+H]+. Intermediate 11-1. Benzyl (6-bromo-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 2-(4-Bromo-2-fluorophenyl) acetyl chloride A 250-mL round-bottom flask was charged with 2-(4-bromo-2-fluorophenyl)acetic acid (10 g, 42.05 mmol), DCM (50 mL), and thionyl chloride (6.3 mL, 85.11 mmol). The resulting solution was stirred for 16 h at 40 °C. After cooling to 25 °C, the reaction mixture was concentrated under vacuum to afford 2-(4-bromo-2-fluorophenyl)acetyl chloride as brown oil. Step 2. 6-Bromo-8-fluoro-3,4-dihydronaphthalen-2(1H)-one A 500-mL round-bottom flask was charged with 2-(4-bromo-2-fluorophenyl)acetyl chloride (5.0 g, 18.49 mmol) and DCM (100 mL). AlCl3 (7.15 g, 53.09 mmol) was then added in portions at 0 °C. The resulting mixture was stirred for 10 min at 0 °C, then a gentle stream of ethylene gas was bubble into the reaction mixture for 5 h at 0 °C. The reaction mixture was poured into ice and concentrated hydrochloric acid (5 mL) was added. The resulting solution was extracted with DCM (3 x 50 mL), the organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford a crude residue that was purified by column chromatography eluting with ethyl acetate / pet. ether (1:2) to afford 6-bromo-8-fluoro-3,4-dihydronaphthalen-2(1H)-one as a brown solid. 1H NMR (400 MHz, DMSO-<semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>(ppm): 2.49 (t, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>=8.0Hz, 2H), 3.08 (t, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>=8.0Hz, 2H), 3.49 (s, 2H), 7.40-7.42 (m, 2H). Step 3. (2E)-6-Bromo-8-fluoro-N-methoxy-1,2,3,4-tetrahydronaphthalen-2-imine A 250-mL round-bottom flask was charged with 6-bromo-8-fluoro-3,4-dihydronaphthalen-2(1H)- one (4.2 g, 16.07 mmol), the HCl salt of O-methylhydroxylamine (2.16 g, 25.60 mmol), ethanol (50 mL) and pyridine (5 mL, 61.50 mmol). The resulting mixture was stirred for 16 h at 80 °C in an oil bath, then was cooled to 25 °C. After cooling, the resulting mixture was concentrated under vacuum to afford a residue that was purified by column chromatography eluting with ethyl acetate / pet. ether (1:2) to afford (2E)-6-bromo-8-fluoro-N-methoxy-1,2,3,4-tetrahydronaphthalen- 2-imine as a brown solid. MS: (ESI, m / z) 272, 274 [M+H]+. Step 4. 6-Bromo-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-amine A 250-mL round-bottom flask that was purged with nitrogen was charged with (2E)-6-bromo-8- fluoro-N-methoxy-1,2,3,4-tetrahydronaphthalen-2-imine (3.5 g, 11.58 mmol, 90%), ethanol (50 mL) and Raney Ni (2.0 g, 23.11 mmol). To this hydrogen (g) was introduced in. The resulting mixture was stirred for 48 h at 25 °C. The solids were removed by filtration over Celite. The filtrate was concentrated under vacuum to afforad a residue that was purified by column chromatography eluting with DCM / methanol (10:1) to afford 6-bromo-8-fluoro-1,2,3,4-tetrahydronaphthalen-2- amine as a brown solid. MS: (ESI, m / z): 244, 246 [M+H]+. Step 5. Benzyl (6-bromo-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate A 100-mL round-bottom flask was charged with 6-bromo-8-fluoro-1,2,3,4-tetrahydronaphthalen- 2-amine (930 mg, 3.43 mmol), ethyl acetate (15 mL), water (15 mL), potassium carbonate (1.58 g, 11.32 mmol), and benzyl chloroformate (780 mg, 4.53 mmol). The resulting mixture was stirred for 16 h at 60 °C in an oil bath. After cooling to 25 °C, the reaction was diluted with water (30 mL). The resulting solution was extracted with ethyl acetate (3 x 40 mL), the organic layers combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford a residue that was purified by column chromatography eluting with ethyl acetate / pet. ether (1:5) to afford benzyl (6-bromo-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate as an off-white solid. MS: (ESI, m / z): 378, 380 [M+H]+.

[00188] The following intermediates in Table 4 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Intermediate 11-1. Table 4: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 1Notes on procedures: In Step 2, a mixture of regioisomers 6-bromo-7-methyl-3,4-dihydronaphthalen- 2(1H)-one and 6-bromo-5-methyl-3,4-dihydronaphthalen-2(1H)-one (3:1, respectively) were generated. The mixture was carried through Step 5. The regioisomers and enantiomers were separated by SFC using the chiral column Phenomenex Lux 5µm Cellulose-3 and mobile phase 50% CO2 / IPA (2 mM NH3-MeOH) to provide Intermediate 11-4 as the first eluting isomer, Intermediate 11-2 as the second eluting isomer, Intermediate 11-5 as the third eluting isomer, and Intermediate 11-3 as the fourth eluting isomer. Stereochemistry of the separated enantiomers were arbitrarily assigned. Intermediate 12. tert-Butyl 4-(3-aminochroman-7-yl)piperazine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 7-Bromo-2H-chromene-3-carbonitrile

[00189] A solution of 4-bromo-2-hydroxybenzaldehyde (10 g, 47.26 mmol) and triethylenediamine (1.12 g, 9.49 mmol) in acrylonitrile (16 mL) was stirred for 24 h at 80 °C. After cooling to room temperature, the reaction was quenched with 1N NaOH (400 mL). The resulting solution was extracted with EtOAc (300 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 20:1-9:1 pet. ether / EtOAc) to give 7-bromo-2H-chromene-3- carbonitrile as a yellow solid. MS: (ESI, m / z): 236, 238 [M+H]+. Step 2. tert-Butyl 4-(3-cyano-2H-chromen-7-yl)piperazine-1-carboxylate

[00190] A mixture of 7-bromo-2H-chromene-3-carbonitrile (1 g, 3.81 mmol), tert-butyl piperazine-1-carboxylate (950 mg, 4.85 mmol), Pd(dppf)Cl2 (327 mg, 0.42 mmol), XPhos (191 mg, 0.38 mmol) and Cs2CO3 (3.9 g, 11.37 mmol) in toluene (20 mL) was stirred for 18 h at 100 °C. After cooling to room temperature, the reaction was quenched by the addition of 30 mL of water. The resulting mixture was extracted with EtOAc (30 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 9:1-4:1 pet. ether / EtOAc) to give 0.7 g of tert-butyl 4-(3-cyano-2H-chromen-7-yl)piperazine-1-carboxylate as a yellow solid. MS: (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 342 [M+H]+. Step 3. tert-Butyl 4-(3-carbamoyl-2H-chromen-7-yl)piperazine-1-carboxylate

[00191] A solution of tert-butyl 4-(3-cyano-2H-chromen-7-yl)piperazine-1-carboxylate (500 mg, 1.32 mmol), 30% hydrogen peroxide (0.2 mL, 2.58 mmol), and potassium carbonate (304 mg, 2.09 mmol) in a mixture of DMSO (2 mL) and ethanol (10 mL) was stirred for 3 h at room temperature. The reaction was quenched by the addition of 50 mL of water. The resulting mixture was extracted with EtOAc (50 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 10:1-3:1 pet. ether / EtOAc) to give tert-butyl 4-(3-carbamoyl-2H- chromen-7-yl)piperazine-1-carboxylate as a yellow solid. MS: (ESI, m / z): 360 [M+H]+. Step 4. tert-Butyl 4-(3-carbamoylchroman-7-yl)piperazine-1-carboxylate

[00192] A mixture of tert-butyl 4-(3-carbamoyl-2H-chromen-7-yl)piperazine-1-carboxylate (700 mg, 1.95 mmol) and Pd / C (100 mg, 10%) in THF (50 mL) was stirred for 18 h at room temperature under an atmosphere of hydrogen. The solids were filtered away and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with EtOAc) to give tert-butyl 4-(3-carbamoylchroman-7-yl)piperazine-1-carboxylate as a light yellow solid. MS: (ESI, m / z): 362 [M+H]+. Step 5. tert-Butyl 4-(3-aminochroman-7-yl)piperazine-1-carboxylate

[00193] To a stirring solution of (diacetoxyiodo)benzene (468 mg, 1.45 mmol) in a mixture of DMF (3.88 mL) and water (3.88 mL) was added tert-butyl 4-(3-carbamoylchroman-7- yl)piperazine-1-carboxylate (350 mg, 0.97 mmol). The resulting solution was stirred for 18 h at room temperature. Additional (diacetoxyiodo)benzene (936 mg, 2.90 mmol) was added in two portions over 24 h. The resulting solution was diluted with 20 mL of water and was extracted with EtOAc (50 mL). The aqueous layer was concentrated under vacuum. The residue was purified by prep-HPLC (Column: SunFire Prep C18, 19x150 mm; Mobile phase A: water (0.05% NH4HCO3), B: ACN; Gradient: 15% B to 70% B in 15 min) to afford tert-butyl 4-(3-aminochroman-7- yl)piperazine-1-carboxylate as a light yellow solid. MS: (ESI, m / z): 334 [M+H]+. Intermediate 13. tert-Butyl 3-(3-aminochroman-7-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 7-Chlorochroman-3-amine

[00194] A solution of 7-chlorochroman-3-one (700 mg, 3.83 mmol) and NH4OAc (2.37 g, 30.75 mmol) in MeOH (35 mL) was stirred for 4 h at room temperature. To this was added NaBH3CN (364 mg, 5.79 mmol). The resulting mixture was stirred for 14 h at room temperature and then concentrated under vacuum. The residue was diluted with 50 mL of water. The pH value of the mixture was adjusted to 5 with 1N HCl. The resulting mixture was extracted with CH2Cl2 (20 mL x 2). The pH value of the aqueous layer was adjusted to 10 with 1M NaOH solution. The resulting solution was extracted with CH2Cl2 (30 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford 7-chlorochroman-3-amine as a light yellow oil. MS: (ESI, m / z): 184 [M+H]+. Step 2. Benzyl (7-chlorochroman-3-yl)carbamate

[00195] A mixture of 7-chlorochroman-3-amine (350 mg, 1.91 mmol), potassium carbonate (786.6 mg, 5.69 mmol), and benzyl chloroformate (390 mg, 2.29 mmol) in a mixture of EtOAc (15 mL) and water (15 mL) was stirred for 3 h at 60 °C. After cooling to room temperature, the reaction mixture was poured into 10 mL of water and was extracted with EtOAc (10 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 7:1 pet. ether / EtOAc) to afford benzyl (7-chlorochroman-3-yl)carbamate as a white solid. MS: (ESI, m / z): 318 [M+H]+. Step 3. tert-Butyl 3-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[00196] Into a 20-mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed benzyl (7-chlorochroman-3-yl)carbamate (95 mg, 0.26 mmol), tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 0.33 mmol), Cs2CO3 (294 mg, 0.90 mmol), toluene (5 mL) and RuPhos Pd G3 (25.1 mg, 0.03 mmol). The reaction mixture was treated with microwave radiation for 5 h at 120 °C. After cooling to room temperature, the reaction mixture was then poured into 10 mL of water. The resulting mixture was extracted with CH2Cl2 (10 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 2:1 pet. ether / EtOAc) to afford tert-butyl 3-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate as light yellow oil. MS: (ESI, m / z): 494 [M+H]+. Step 4. tert-Butyl 3-(3-aminochroman-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[00197] A mixture of tert-butyl 3-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.60 mmol) and Pd / C (60 mg, 10%) in MeOH (25 mL) was stirred for 2 h at room temperature under an atmosphere of hydrogen. The solids were filtered away and the filtrate was concentrated to give tert-butyl 3-(3-aminochroman-7-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate as a yellow oil. MS: (ESI, m / z): 360 [M+H]+. Intermediate 14-1. tert-Butyl 3-(3-aminochroman-7-yl)-3,9-diazabicyclo[3.3.1]nonane-9- carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Step 1. tert-Butyl 3-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-3,9- diazabicyclo[3.3.1]nonane-9-carboxylate

[00198] A mixture of benzyl-(7-bromochroman-3-yl)carbamate, Intermediate 1, (400 mg, 1.07 mmol), tert-butyl 3,9-diazabicyclo[3.3.1]nonane-9-carboxylate (300 mg, 1.31 mmol), Pd(dppf)Cl2-CH2Cl2 (90 mg, 0.11 mmol), Xphos (52 mg, 0.11 mmol), and Cs2CO3 (722 mg, 2.22 mmol) in toluene (6 mL) was stirred at 100 °C for 14 h. After cooling to room temperature, water was added and the reaction mixture was extracted with EtOAc (70 mL x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification by prep-TLC (eluting with 1:3 EtOAc / pet. ether) afforded tert-butyl 3-(3- (((benzyloxy)carbonyl)amino)chroman-7-yl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate as a pale yellow solid. MS: (ESI, m / z): 508 [M+H]+. Step 2. tert-Butyl 3-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-3,9- diazabicyclo[3.3.1]nonane-9-carboxylate

[00199] <semantics>𝑨<annotation encoding="application / x-tex">\mathbf{A}< / annotation>< / semantics> mixture of tert-butyl 3-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-3,9- diazabicyclo[3.3.1]nonane-9-carboxylate (120 mg, 0.22 mmol) and Pd / C (60 mg, 10%) in MeOH (5 mL) was stirred for 1 h at room temperature under an atmosphere of hydrogen. The solids were filtered away and the filtrate was concentrated under vacuum to afford tert-butyl 3-(3- (((benzyloxy)carbonyl)amino)chroman-7-yl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate as colorless oil. MS: (ESI, m / z): 374 [M+H]+.

[00200] The following intermediate in Table 5 was prepared using standard chemical manipulations and procedures similar to those used for the preparation of Intermediate 14-1. Table 5: [Image disponible dans le document PDF, Image available in the PDF document] 1Notes on Procedures: In Step 1, RuPhos Pd G3 / RuPhos was used as the catalyst / ligand system. Intermediate 15-1. tert-Butyl 3-(3-amino-5-fluorochroman-7-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 2,4-Difluoro-6-hydroxybenzaldehyde

[00201] A solution of 3,5-difluorophenol (10 g, 73 mmol), paraformaldehyde (23 g, 728 mmol), Et3N (21 mL), and MgCl2 (14.6 g, 153.34 mmol) in ACN (200 mL) was stirred for 14 h at 60 °C. After cooling to room temperature, the reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with DCM (2 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with gradient 1:10 to 1:1 EtOAc / pet. ether) afforded 2,4- difluoro-6-hydroxybenzaldehyde as a pale yellow solid. MS: (ESI, m / z): 159 [M+H]+. Step 2. tert-Butyl 3-(3-fluoro-4-formyl-5-hydroxyphenyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[00202] A solution of 2,4-difluoro-6-hydroxybenzaldehyde (600 mg, 3.80 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 3.75 mmol), and DIEA (700 mg, 5.42 mmol) in DMSO (10 mL) was stirred for 2 h at 100 °C. After cooling to room temperature the reaction was quenched by the addition of water (10 mL). The resulting mixture was extracted with DCM (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:4 EtOAc / pet. ether) afforded tert-butyl 3-(3-fluoro-4-formyl-5-hydroxyphenyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. MS: (ESI, m / z): 351 [M+H]+. Step 3. tert-Butyl 3-(3-(allyloxy)-5-fluoro-4-formylphenyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[00203] A solution of tert-butyl 3-(3-fluoro-4-formyl-5-hydroxyphenyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.4 g, 3.60 mmol), potassium carbonate (3 g, 21.71 mmol), and allylbromide (500 mg, 4.13 mmol) in DMF (20 mL) was stirred for 2 h at 100 °C. After cooling to room temperature the reaction was quenched by the addition of water (20 mL). The resulting mixture was extracted with DCM (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:5 EtOAc / pet. ether) afforded tert-butyl 3-(3-(allyloxy)- 5-fluoro-4-formylphenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. MS: <semantics>(ESI,m / z)<annotation encoding="application / x-tex">(ESI, m / z)< / annotation>< / semantics>: 392 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step 4. tert-Butyl 3-(3-(allyloxy)-5-fluoro-4-vinylphenyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[00204] To a solution of methyltriphenylphosphonium bromide (3.3 g, 8.86 mmol) in THF (25 mL) was added sodium hydride (178 mg, 4.45 mmol, 60% dispersion in oil) in portions at 0°C. The reaction mixture was stirred for 4 h at room temperature. This was followed by the dropwise addition of a solution of tert-Butyl 3-(3-(allyloxy)-5-fluoro-4-formylphenyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.2 g, 2.77 mmol) in THF (20 mL) and stirring continued for 3 h at 30°C. The reaction was quenched by the addition of water (60 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with gradient 1:6 to 1:1 EtOAc / pet. ether) afforded tert-butyl 3-(3-(allyloxy)-5-fluoro-4-vinylphenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a colorless oil. MS: (ESI, m / z): 389 [M+H]+. Step 5. tert-Butyl 3-(5-fluoro-2H-chromen-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[00205] <semantics>𝑨<annotation encoding="application / x-tex">\mathbf{A}< / annotation>< / semantics> solution of tert-butyl 3-(3-(allyloxy)-5-fluoro-4-vinylphenyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 2.06 mmol) and Grubbs CatalystTM 2nd Gen (48 mg, 0.05 mmol) in DCM (10 mL) was stirred for 1 h at room temperature. The mixture was concentrated under vaccum. Purification by silica gel chromatography (eluting with 1:3) EtOAc / pet. ether) afforded tert-butyl 3-(5-fluoro-2H-chromen-7-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate as a colorless oil. MS: (ESI, m / z): 361 [M+H]+. Step 6. tert-Butyl 3-(5-fluoro-3-nitro-2H-chromen-7-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[00206] A solution of KNO2 (945 mg, 11.10 mmol) and 18-crown-6 (2.2 g, 8.32 mmol) in THF (20 mL) was stirred for 1 h at room temperature. Then I2 (2.3 g, 9.06 mmol) was added and stirring was continued for 1 h. Finally, a solution of tert-butyl 3-(5-fluoro-2H-chromen-7-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1 g, 2.77 mmol) and pyridine (110 mg, 1.39 mmol) in THF (10 mL) was added to the solution and stirring was continued for 14 h. The reaction was quenched by the addition of water (20 mL). The resulting mixture was extracted with DCM (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:6 EtOAc / pet. ether) afforded tert-butyl 3-(5-fluoro-3-nitro-2H-chromen-7-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. MS: (ESI, m / z): 406 [M+H]+. Step 7. tert-Butyl 3-(3-amino-5-fluorochroman-7-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[00207] Α solution of tert-butyl 3-(5-fluoro-3-nitro-2H-chromen-7-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.30 mmol), BH3-THF (1 M, 20 mL, 20.0 mmol), and NaBH4 (116 mg, 3.07 mmol) in THF (20 mL) was stirred for 14 h at 65 °C. Then methanol (20 mL) was added and stirring was continued for 4 h at 85 °C. The mixture was concentrated under vaccum. Purification by reverse phase chromatography (Column: C18 silica gel; Mobile phase A: water with 10 mM NH4HCO3, B: ACN; Flow rate: 50 mL / min; Gradient: 0% to 50% B over 40 min) gave tert-butyl 3-(3-amino-5-fluorochroman-7-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate as a colorless oil. MS: (ESI, m / z): 378 [M+H]+.

[00208] The following intermediates in Table 6 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Intermediate 15-1. Table 6: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 1 Notes on procedures: Step 6: nitration was conducted by sonicating a solution of tert-butyl 4-[6- (trifluoromethoxy)-2H-chromen-7-yl] piperazine-1-carboxylate (800 mg, 2.00 mmol), ACN (2.2 g, 4.00 mmol), NaNO2 (1.4 g, 20.29 mmol) and acetic acid (1.44 g, 23.98 mmol) in chloroform (40 mL) for 6 h at 50 °C. The reaction was quenched with sat. aq. NaHCO3 solution (40 mL) and an extractive work up was performed with EtOAc. Intermediate 16. 3-Amino-5-fluoro-6-methylthieno[2,3-b]pyridine-2-carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 2-Chloro-5-fluoro-6-methylnicotinonitrile

[00209] A mixture of 2,6-dichloro-5-fluoropyridine-3-carbonitrile (5 g, 26.18 mmol), methylboronic acid (1.58 g, 26.36 mmol), Na2CO3 (8.33 g, 78.54 mmol), and Pd(dppf)Cl2-CH2Cl2 (958mg, 1.31 mmol) in DMF (40 mL) and water (20 mL) was stirred for 3 h at 80 °C. After cooling to room temperature, the reaction mixture was diluted with 50 mL of water. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:5 EtOAc / pet. ether) afforded 2-chloro-5-fluoro-6-methylnicotinonitrile as a pink solid. MS: (ESI, m / z): 171 [M+H]+. Step 2. Methyl 3-amino-5-fluoro-6-methylthieno[2,3-b]pyridine-2- carboxylate

[00210] A solution of 2-chloro-5-fluoro-6-methylnicotinonitrile (1.40 g, 8.21 mmol), KOH (1.38 g, 24.63 mmol), and methyl 2-mercaptoacetate (1.74 g, 16.42 mmol) in DMF (20 mL) and water (20 mL) was stirred for 3 h at room temperature. The pH value of the solution was adjusted to 5 with 1N HCl solution. The solids were collected by filtration to afford methyl 3-amino-5- fluoro-6-methylthieno[2,3-b]pyridine-2-carboxylate as a yellow solid. MS: (ESI, m / z): 241 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step 3. 3-Amino-5-fluoro-6-methylthieno[2,3-b]pyridine-2-carboxylic acid

[00211] A solution of methyl 3-amino-5- fluoro-6-methylthieno[2,3-b]pyridine-2-carboxylate (200 mg, 0.83 mmol) and NaOH (66 mg, 1.66 mmol) in MeOH (2 mL) and water (1 mL) was stirred for 1 h at 60 °C. After cooling to room temperature, the resulting mixture was concentrated under vacuum. The residue was diluted with 20 mL of water. The pH value of the mixture was adjusted to 5 with 1N HCl solution. The solids were collected by filtration to give 3-amino-5- fluoro-6-methylthieno[2,3-b]pyridine-2-carboxylic acid as a yellow solid. MS: (ESI, m / z): 227 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Intermediate 17. 3-amino-5-fluorothieno[2,3-b]pyridine-2-carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document] Step 1. Methyl 3-amino-5-fluorothieno[2,3-b]pyridine-2-carboxylate

[00212] Sodium (230 mg, 10.00 mmol) was added to MeOH (20 mL) at 0 °C and the resulting mixture was stirred for 30 min at 0 °C until the sodium was consumed. To the reaction mixture was added 2-chloro-5-fluoronicotinonitrile (900 mg, 5.75 mmol) and methyl 2-mercaptoacetate (1.8 mL, 14.98 mmol). The resulting solution was stirred for 16 h at room temperature. The reaction was quenched by the addition of 50 mL of water and was extracted with DCM (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:1 EtOAc / pet. ether) afforded methyl 3-amino-5-fluorothieno[2,3-b]pyridine-2-carboxylate as a yellow solid. MS: (ESI, m / z): 227 [M+H]+. Step 2. 3-Amino-5-fluorothieno[2,3-b]pyridine-2-carboxylic acid

[00213] A solution of methyl 3-amino-5-fluorothieno[2,3-b]pyridine-2-carboxylate (1 g, 3.76 mmol) and LiOH (100 mg, 3.97 mmol) in water (10 mL) and dioxane (10 mL) was stirred for 1 h at room temperature. The reaction was diluted with 20 mL of water and was extracted with EtOAc (3 x 30 mL). The pH value of the aqueous layer was adjusted to 6 with 6N HCl solution. The solids were collected by filtration to afford 3-amino-5-fluorothieno[2,3-b]pyridine-2-carboxylic acid as a yellow solid. MS: (ESI, m / z): 213 [M+H]+. Intermediate 18. 3-Amino-6-fluorothieno[2,3-b]pyridine-2-carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 2,6-Difluoronicotinonitrile

[00214] A mixture of 2,6-dichloronicotinonitrile (6.92 g, 40.00 mmol) and KF (6.98 g, 120.14 mmol) in DMF (30 mL) was stirred overnight at 90 °C. After cooling to room temperature, the reaction was quenched by the addition of 100 mL of water. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatograpy (eluting with 1:3 EtOAc / pet. ether) afforded 2,6-difluoronicotinonitrile as a white solid. MS: (ESI, m / z): 141 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step 2. Benzyl 2-((3-cyano-6-fluoropyridin-2-yl)thio)acetate

[00215] To a mixture of 2,6-difluoronicotinonitrile (1 g, 6.42 mmol) and NaOAc (878 mg, 10.70 mmol) in THF (20 mL) was added benzyl 2-mercaptoacetate (1.17 g, 6.42 mmol) at -70°C. The resulting solution was warmed to room temperature slowly and then stirred for 30 min. The reaction was quenched by the addition of 20 mL of water. The resulting mixture was extracted with DCM (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 2:25 EtOAc / pet. ether) afforded benzyl 2-((3-cyano-6-fluoropyridin-2-yl)thio)acetate as a white solid. MS: (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 303[M+H]+. Step 3. Benzyl 3-amino-6-fluorothieno[2,3-b]pyridine-2-carboxylate

[00216] A solution of benzyl 2-((3-cyano-6-fluoropyridin-2-yl)thio)acetate (120 mg, 0.40 mmol) in THF (2 mL) was added dropwise at -50°C to a solution of DBU (120 mg, 0.79 mmol) in THF (3 mL). The mixture was then warmed to room temperature and stirred overnight. The resulting solution was concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:1 EtOAc / pet. ether) afforded benzyl 3-amino-6-fluorothieno[2,3-b]pyridine-2- carboxylate as an off-white solid. MS: (ESI, m / z): 303 [M+H]+. Step 4. 3-Amino-6-fluorothieno[2,3-b]pyridine-2-carboxylic acid

[00217] A mixture of benzyl 3-amino-6-fluorothieno[2,3-b]pyridine-2-carboxylate (89 mg, 0.29 mmol) and Pd / C (20 mg, 10%) in EtOAc (15 mL) was was stirred for 1 h at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum to give 3-amino-6- fluorothieno[2,3-b]pyridine-2-carboxylic acid as a light yellow solid. MS: (ESI, m / z): 213 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Intermediate 19. 3-Amino-6-methoxythieno[2,3-b]pyridine-2-carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 2-Chloro-6-methoxynicotinonitrile

[00218] Sodium (1.5 g, 65.22 mmol) was added to MeOH (25 mL) at 0 °C and the resulting mixture was stirred for 30 min at room temperature until the sodium was consumed. To the reaction mixture was added 2,6-dichloronicotinonitrile (5 g, 28.90 mmol) over 5 min, maintaining reaction temperature below 10 °C. The resulting solution was stirred overnight at room temperature. The solids were filtered away and the filtrate was concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 EtOAc / hexanes) afforded 2-chloro-6-methoxynicotinonitrile as a white solid. MS: (ESI, m / z): 169 [M+H]+. Step 2. Methyl 3-amino-6-methoxythieno[2,3-b]pyridine-2-carboxylate

[00219] To a solution of 2-chloro-6-methoxynicotinonitrile (3.9 g, 23.13 mmol) in DMF (10 mL) was added KOH (5.2 g) at 0 °C over 5 min, followed by the addition of methyl 2- mercaptoacetate (2.46 g, 23.18 mmol). The resulting solution was stirred for 1 h at 0 °C. The reaction was quenched by the addition of 20 mL of water. The resulting mixture was extracted with EtOAc (3x30 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:10 to 1:1 EtOAc / hexanes) afforded methyl 3-amino-6-methoxythieno[2,3-b]pyridine-2-carboxylate as a light yellow solid. 1H NMR (DMSO-<semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>, 300 MHz) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>(ppm): 8.40 (d, <semantics>J=8.7<annotation encoding="application / x-tex">J = 8.7< / annotation>< / semantics> Hz, 1H), 7.24 (br, 2H), 6.89 (d, <semantics>J=9.0<annotation encoding="application / x-tex">J = 9.0< / annotation>< / semantics> Hz, 1H), 3.93 (s, 3H), 3.77 (s, 3H). MS: (ESI, m / z): 239 [M+H]+. Step 3. 3-Amino-6-methoxythieno[2,3-b]pyridine-2-carboxylic acid

[00220] A solution of methyl 3-amino-6-methoxythieno[2,3-b]pyridine-2-carboxylate (110 mg, 0.46 mmol) and LiOH (100 mg, 4.18 mmol) in THF (4 mL) and water (1.5 mL) was stirred for 2 h at 60 °C. After cooling to room temperature, the resulting mixture was concentrated under vacuum. The residue was diluted with 2 mL of water. The pH value of the solution was adjusted to 7 with 1N HCl. The solids were collected by filtration to afford 3-amino-6-methoxythieno[2,3- b]pyridine-2-carboxylic acid as a yellow solid. MS: (ESI, m / z): 225 [M+H]+. Intermediate 20. 3-Amino-5-fluoro-6-methoxythieno[2,3-b]pyridine-2-carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 2-Chloro-5-fluoro-6-methoxynicotinonitrile

[00221] A mixture of 2,6-dichloro-5-fluoropyridine-3-carbonitrile (3.0 g, 15.71 mmol) and MeONa (1.28 g, 23.70 mmol) in MeOH (30 mL) was stirred for 5 h at room temperature. The resulting mixture was concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 EtOAc / pet. ether) afforded 2-chloro-5-fluoro-6-methoxynicotinonitrile as a yellow solid. MS: (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 187, 189 [M+H]+. Step 2. Methyl 3-amino-5-fluoro-6-methoxythieno[2,3-b]pyridine-2-carboxylate

[00222] A solution of 2-chloro-5-fluoro-6-methoxynicotinonitrile (1.90 g, 10.22 mmol) methyl 2-mercaptoacetate (1.3 g, 12.26 mmol), and DBU (7.2 g, 47.29 mmol) in THF (30 mL) was stirred overnight at room temperature. The reaction was quenched by the addition of 50 mL of water and was extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 EtOAc / pet. ether) afforded methyl 3-amino-5-fluoro-6-methoxythieno[2,3- b]pyridine-2-carboxylate as a yellow solid. MS: (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 257 [M+H]+. Step 3. 3-Amino-5-fluoro-6-methoxythieno[2,3-b]pyridine-2-carboxylic acid

[00223] A mixture of methyl 3-amino-5-fluoro-6-methoxythieno[2,3-b]pyridine-2-carboxylate (500 mg, 1.95 mmol) and LiOH (236 mg, 9.85 mmol) in THF (8 mL) and water (8 mL) was stirred overnight at 60 °C. After cooling to room temperature, the solvent was removed under vacuum. The pH value of the residue was adjusted to 7 with 3N HCl. The solids were collected by filtration to afford 3-amino-5-fluoro-6-methoxythieno[2,3-b]pyridine-2-carboxylic acid as a yellow solid. MS: (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 243 [M+H]+. Intermediate 21. 3-Amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxylic [Image disponible dans le document PDF, Image available in the PDF document] Step 1. Methyl 3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxylate

[00224] To a solution of 2-chloro-4,6-dimethylnicotinonitrile (2.000 g, 12.00 mmol) and DBU (5.00 g, 32.84 mmol) in DMF (20 mL) was added methyl 2-sulfanylacetate (1.019 g, 9.60 mmol) dropwise with stirring at -50°C. The resulting solution was stirred overnight at room temperature. The mixture was poured into water (50 mL) and the solids were collected by filtration to give methyl 3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxylate as a light yellow solid. MS: <semantics>(ESI,m / z)<annotation encoding="application / x-tex">(ESI, m / z)< / annotation>< / semantics>: 237 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step 2. 3-Amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxylic acid

[00225] To a solution of methyl 3-amino-4,6- dimethylthieno[2,3-b]pyridine-2-carboxylate (300 mg, 1.27 mmol) in MeOH (5 mL) was added a solution of NaOH (254 mg, 6.35 mmol) in water (5 mL). The resulting solution was stirred for 3 h at 70°C. After cooling to room temperature, the solvent was removed under vacuum. The pH value of the residue was adjusted to 6 with 3N HCl. The solids were collected by filtration to afford 3-amino-4,6-dimethylthieno[2,3-b]pyridine- 2-carboxylic acid as a yellow solid. MS: (ESI, m / z): 223 [M+H]+. Intermediate 22. 3-Amino-6-methyl-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 6-Methyl-2-thioxo-4-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile

[00226] A solution of 2-cyanoethanethioamide (2 g, 19.97 mmo) 1,1,1-trifluoropentane-2,4- dione (3 g, 19.47 mmol), and triethylamine (0.1 mL) in in ethanol (20 mL) was stirred for 1 h at 90 °C. After cooling to room temperature, the solids were collected by filtration and dried in an oven under reduced pressure to afford 6-methyl-2-thioxo-4-(trifluoromethyl)-1,2- dihydropyridine-3-carbonitrile as a yellow solid. MS: (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 219 [M+H]+. Step 2. Ethyl 3-amino-6-methyl-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylate

[00227] A solution of 6-methyl-2-thioxo-4-(trifluoromethyl)-1,2-dihydropyridine-3- carbonitrile (800 mg, 3.67 mmol), ethyl 2-bromoacetate (609 mg, 3.65 mmol), and NaOEt (297 mg, 4.37 mmol) in ethanol (20 mL) was stirred overnight at 80 °C. The solvent was removed under vacuum. The residue was diluted with 30 mL of water and was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:10 to 1:1 EtOAc / pet. ether) afforded ethyl 3-amino-6-methyl-4-(trifluoromethyl)thieno[2,3-b]pyridine-2- carboxylate as a yellow solid. MS: (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 305 [M+H]+. Step 3. 3-Amino-6-methyl-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylic acid

[00228] A solution of ethyl 3-amino-6-methyl-4-(trifluoromethyl)thieno[2,3-b]pyridine-2- carboxylate (1.0 g, 3.29 mmol) and sodium hydroxide (470 mg, 11.75 mmol) in water (2 mL) and methanol (10 mL) was stirred for 2 h at 60 °C. The resulting mixture was concentrated under vacuum. The residue was diluted with 10 mL of water. The pH value of the solution was adjusted to 3 with 3N HCl. The solids were collected by filtration to give 3-amino-6-methyl-4- (trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylic acid as a yellow solid. MS: (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 277 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Intermediate 23. Methyl 6-amino-2-methylthieno[2,3-d]thiazole-5-carboxylate and Intermediate 24. 6-Amino-2-methylthieno[2,3-d]thiazole-5-carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 4-Chloro-2-methylthiazole-5-carbonitrile

[00229] A mixture of 2,4-dichlorothiazole-5-carbonitrile (1.00 g, 5.59 mmol), dimethylzing (1M in Et2O) (8.8 mL, 8.80 mmol), and Pd(dppf)Cl2 CH2Cl2 (911 mg, 1.12 mmol) in toluene (30 mL) was stirred for 4 h at 40 °C. The reaction was quenched by the addition of 20 mL of water. The resulting mixture was extracted with EtOAc (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:5 EtOAc / pet. ether) afforded 4-chloro-2-methylthiazole- 5-carbonitrile as a light yellow solid. MS: (ESI, m / z): 159 [M+H]+. Step 2. Methyl 6-amino-2-methylthieno[2,3-d]thiazole-5-carboxylate

[00230] To a solution of 4-chloro-2-methylthiazole-5-carbonitrile (550 mg, 3.47 mmol) and DBU (1.06 g, 6.94 mmol) in THF (20 mL) was added a solution of methyl 2-mercaptoacetate (443 mg, 4.17 mmol) in THF (2 mL) dropwise with stirring at -40 °C. The resulting solution allowed to warm to to room temperature while stirring overnight. The reaction was quenched with 20 mL of water. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:7 EtOAc / pet. ether) afforded methyl 6-amino-2- methylthieno[2,3-d]thiazole-5-carboxylate as a light yellow solid. MS: (ESI, m / z): 229 [M+H]+. Step 3. 6-Amino-2-methylthieno[2,3-d]thiazole-5-carboxylic acid

[00231] To a solution of methyl 6-amino-2-methylthieno[2,3-d]thiazole-5-carboxylate (174) mg, 0.76 mmol) in ACN (11 mL) was added a solution of LiOH (100 mg, 4.18 mmol) in water (5 mL). The resulting solution was stirred overnight at 30 °C, then was concentrated under vacuum. The residue was diluted with 1 mL of water. The pH value of the residue was adjusted to 7 with 1N HCl solution. The solids were collected by filtration to give 6-amino-2-methylthieno[2,3- d]thiazole-5-carboxylic acid as an off-white solid. MS: (ESI, m / z): 214 [M+H]+. Intermediate 25. 1-Ethyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document]

[00232] To a solution of methyl 1H-pyrrolo[2,3-b]pyridine-5-carboxylate (3 g, 17.03 mmol) in DMF (80 mL) was added sodium hydride (2.04 g, 51.09 mmol, 60% dispersion in oil) in portions at 0 °C. The reaction mixture was stirred for 1 h at 0 °C. Then iodoethane (5.32 g, 34.06 mmol) was added at 0 °C. The resulting solution was stirred for 10 h at room temperature. The reaction was quenched with 10 mL of water. After stirred for 30 min, the pH value of the solution was adjusted to 7~8 with 3N HCl. The resulting mixture was extracted with EtOAc (6 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give of 1-ethyl-1H-pyrrolo[2,3-b]pyridine-5- carboxylic acid as a yellow solid (crude, 90% purity). MS: (ESI, m / z): 191 [M+H]+. Intermediate 26. 7-Ethyl-7H-pyrrolo[2,3-c]pyridazine-3-carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 3-Chloro-7-ethyl-7H-pyrrolo[2,3-c]pyridazine

[00233] To a solution of 3-chloro-7H-pyrrolo[2,3-c]pyridazine (700 mg, 4.56 mmol) in DMF (17 mL) was added NaH (365 mg, 9.12 mmol, 60% dispersion in oil) in portions at 0 °C. The reaction mixture was stirred for 30 min at 0 °C. Then iodoethane (856 mg, 5.49 mmol) was added at 0 °C and the reaction mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of 40 mL of water. The resulting mixture was extracted with EtOAc (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by prep-TLC (eluting with 1:1 EtOAc / pet. ether) afforded 3-chloro-7- ethyl-7H-pyrrolo[2,3-c]pyridazine as yellow oil. MS: (ESI, m / z): 182, 183 [M+H]+. Step 2. Methyl 7-ethyl-7H-pyrrolo[2,3-c]pyridazine-3-carboxylate

[00234] In a 30-mL pressure tank reactor, a solution of 3-chloro-7-ethyl-7H-pyrrolo[2,3- c]pyridazine (300 mg, 1.65 mmol), Pd(dppf)Cl2.CH2Cl2 (121 mg, 0.15 mmol), and Et3N (0.69 mL, 4.96 mmol) in MeOH (15 mL) was stirred for 48 h at 120 °C under 50 atm of CO (g). After cooling to room temperature, the resulting mixture was concentrated under vacuum. The residue was diluted with 20 mL of water. The resulting mixture was extracted with EtOAc (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by prep-TLC (eluting with 1:1 EtOAc / pet. ether) afforded methyl 7- ethyl-7H-pyrrolo[2,3-c]pyridazine-3-carboxylate as a yellow solid. MS: (ESI, m / z): 206 [M+H]+. Step 3. 7-Ethyl-7H-pyrrolo[2,3-c]pyridazine-3-carboxylic acid

[00235] A mixture of methyl 7-ethyl-7H-pyrrolo[2,3-c]pyridazine-3-carboxylate (238 mg, 1.04) mmol), and sodium hydroxide (206 mg, 5.20 mmol) in THF (10 mL) and water (10 mL was stirred for 18 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was diluted with 10 mL of water. The pH value of the mixture was adjusted to 5 with 2N HCl. The resulting mixture was extracted with EtOAc (3 x 30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 7-ethyl-7H- pyrrolo[2,3-c]pyridazine-3-carboxylic acid as a light yellow solid (crude). MS: (ESI, m / z): 192 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Intermediate 27. 3-Amino-6-methylfuro[2,3-b]pyridine-2-carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document] Step 1. Ethyl 3-amino-6-methylfuro[2,3-b]pyridine-2-carboxylate

[00236] A solution of 2-chloro-6-methylnicotinonitrile (5 g, 32.77 mmol), ethyl 2- hydroxyacetate (3.36 g, 32.28 mmol), and Cs2CO3 (32.2 g, 98.83 mmol) in NMP (80 mL) was stirred overnight at 75 °C. After cooling to room temperature, the mixture was poured into 100 mL of water. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 ethyl acetate / pet. ether) afforded ethyl 3-amino-6-methylfuro[2,3-b]pyridine-2-carboxylate as a pink solid. MS: (ESI, m / z): 221 [M+H]+. Step 2. 3-Amino-6-methylfuro[2,3-b]pyridine-2-carboxylic acid

[00237] To a solution of ethyl 3-amino-6-methylfuro[2,3-b]pyridine-2-carboxylate (110 mg, 0.53 mmol) in methanol (1 mL) and THF (1 mL) was added a solution of LiOH (24 mg, 1.00 mmol) in water (0.5 mL) dropwise with stirring. The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 8 with 1N HCl. The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by reverse phase chromatography (Column: C18 silica gel; Mobile phase A: water (0.1% formic acid), B: ACN; Flow rate: 50 mL / min; Gradient: 0% B to 100% B in 30 min) afforded 3-amino-6- methylfuro[2,3-b]pyridine-2-carboxylic acid as a light yellow solid. MS: (ESI, m / z): 193 [M+H]+. Intermediate 28. 8-(tert-Butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3- carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document] Step 1. Methyl 5,6,7,8-tetrahydro-1,8-naphthyridine-3-carboxylate

[00238] In a 30-mL pressure tank reactor, a mixture of tert-butyl 6-bromo-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate (300 mg, 0.86 mmol), Pd(dppf)Cl2-CH2Cl2 (90 mg, 0.11 mmol), and Et3N (1 mL) in MeOH (5 mL) was stirred for 48 h at 120°C under 5 atm of CO (g). After cooling to room temperature, the solvent was removed under vacuum. The residue was diluted with water (10 mL) and was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:5 EtOAc / pet. ether) to afford 0.15 g of methyl 5,6,7,8- tetrahydro-1,8-naphthyridine-3-carboxylate as a white solid. MS: (ESI, m / z): 193 [M+H]+. Step 2. 1-(tert-Butyl) 6-methyl 3,4-dihydro-1,8-naphthyridine-1,6(2H)-dicarboxylate

[00239] A solution of methyl 5,6,7,8-tetrahydro-1,8-naphthyridine-3-carboxylate (110 mg, 0.52 mmol), DMAP (126 mg, 1.03 mmol), and (Boc)2O (227 mg, 1.04 mmol) in DMF (5 mL) was stirred for 1 h at room temperature. The reaction was quenched by the addition of 5 mL of water. The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:8 EtOAc / pet. ether) to afford 1-(tert-butyl) 6-methyl 3,4- dihydro-1,8-naphthyridine-1,6(2H)-dicarboxylate as a white solid. MS: (ESI, m / z): 293 [M+H]+. Step 3. 8-(tert-Butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carboxylic acid

[00240] A solution of 1-(tert-butyl) 6-methyl 3,4-dihydro-1,8-naphthyridine-1,6(2H)- dicarboxylate (280 mg, 0.86 mmol) and LiOH (81 mg, 3.38 mmol) in THF (5 mL) and water (5 mL) was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase A: water (0.05% formic acid), B: ACN; Gradient: 0% B to 60% B in 40 min) to afford 8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carboxylic acid as a white solid. MS: (ESI, m / z): 279 [M+H]+. Intermediate 29. 2',3'-Dihydro-1'H-spiro[cyclopropane-1,4'-[1,8]naphthyridine]-6'- carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 6-Bromo-1,2,3,4-tetrahydro-1,8-naphthyridine

[00241] To a solution of 6-bromo-3,4-dihydro-1,8-naphthyridin-2(1H)-one (5.0 g, 21.80 mmol) and NaBH4 (4.18 g, 110.49 mmol) in THF (140 mL) was added BF3-Et2O (20 mL, 157.83 mmol) dropwise at 0 °C. The reaction mixture was stirred for 16 h at room temperature. 1N HCl solution (100 mL) was added and the reaction mixture was stirred for an additional 16 h at room temperature. The pH value of the mixture was then adjusted to 8 with aq. sat. NaHCO3 solution. The resulting mixture was extracted with ethyl acetate (3 x 150 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 6-bromo-1,2,3,4-tetrahydro-1,8-naphthyridine as a white solid. MS: (ESI, m / z): 213, 215 [M+H]+. Step 2. tert-Butyl 6-bromo-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate

[00242] To a mixture of sodium hydride (1.41 g, 58.76 mmol, 60% dispersion in oil) in THF (100 mL) was added a solution of 6-bromo-1,2,3,4-tetrahydro-1,8-naphthyridine (5.0 g, 22.53) mmol) in THF (100 mL) at 0 °C. The reaction mixture was stirred for 30 min at 0 °C. To the mixture was then added a solution of (Boc)2O (10.15 g, 46.51 mmol) in THF (50 mL). The resulting mixture was heated at reflux for 16 h. After cooling to room temperature, the reaction was quenched by the addition of water (150 mL). The resulting mixture was extracted with ethyl acetate (3 x 150 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 EtOAc / pet. ether) afforded tert-butyl 6-bromo-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate as a light yellow solid. MS: (ESI, m / z): 313, 315 [M+H]+. Step 3. tert-Butyl 6-bromo-4-oxo-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate

[00243] To a solution of tert-butyl 6-bromo-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (2.0 g, 6.13 mmol) and NaH2PO4 (1.92 g, 16.00 mmol) in tert-butanol (20 mL) and water (15 mL) was added a solution of NaMnO4-H2O (6.13 g, 38.31 mmol) in water (5mL) dropwise at 50 °C. The reaction mixture was stirred for 3 h at 50 °C. After cooling to room temperature, Na2SO3 was added and the mixture was stirred for 30 min at room temperature. The solids were filtered away and the filtrate was diluted with 50 mL of water. The resulting mixture was extracted with ethyl acetate (3 x 50 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 EtOAc / pet. ether) afforded tert-butyl 6-bromo-4-oxo-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate as a white solid. MS: (ESI, m / z): 327, 329 [M+H]+. Step 4. tert-Butyl 6-bromo-4-methylene-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate

[00244] A solution of methyltriphenylphosphonium bromide (3.29 g, 9.21 mmol) and t-BuOK (1M in THF) (9.2 mL, 9.02 mmol) in toluene (30 mL) was stirred for 1 h at 100 °C. To the reaction mixture was added a solution of tert-butyl 6-bromo-4-oxo-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate (1.5 g, 4.40 mmol) in toluene (5 mL). The resulting solution was for 1 h at 100 °C. After cooling to room temperature, the reaction was quenched by the addition of water (50 mL). The resulting mixture was extracted with ethyl acetate (3x50 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with gradient 1:100 to 1:3 EtOAc / pet. ether) afforded tert- butyl 6-bromo-4-methylene-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate as a white solid. MS: (ESI, m / z): 325, 327 [M+H]+. Step 5. tert-Butyl 6'-bromo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[1,8]naphthyridine]- 1'-carboxylate

[00245] To a solution of potassium hydroxide (4.8 g, 85.55 mmol) in water (7.2 mL) was added a solution of 2-nitrosopropanamide (3.76 g, 36.83 mmol) in Et2O (30 mL) was added. The resulting solution was stirred for 1 h at 0 °C. The organic phase was separated to obtain the solution of diazomethane in Et2O. To a solution of tert-butyl 6-bromo-4-methylene-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate (400 mg, 1.18 mmol) in THF (30 mL) was added the solution of diazomethane at 0 °C, followed by the addition of a mixture of Pd(OAc)2 (28 mg, 0.12 mmol) in THF (3 mL). The reaction mixture was stirred for an additional 3 h at room temperature. The solids were filtered away and the filtrate was concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 EtOAc / pet. ether) afforded tert-butyl 6'-bromo-2',3'-dihydro- 1'H-spiro[cyclopropane-1,4'-[1,8]naphthyridine]-1'-carboxylate as a light yellow solid. MS: (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 339, 341 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step 6. 2',3'-Dihydro-1'H-spiro[cyclopropane-1,4'-[1,8]naphthyridine]-6'-carboxylic acid

[00246] Into a 30-mL pressure tank reactor fitted with a magnetic stir bar, was placed a mixture of tert-butyl 6'-bromo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[1,8]naphthyridine]-1'- carboxylate (140 mg, 0.40 mmol), sodium acetate trihydrate (167 mg, 1.23 mmol), and Pd(dppf)Cl2-CH2Cl2 (65 mg, 0.08 mmol) in DMF (6 mL) and water (2 mL). The reaction mixture was stirred for 16 h at 120 °C under an atmosphere of carbon monoxide at 50 atm. After cooling to room temperature, the reaction was quenched by the addition of 20 mL of water. The resulting solution was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by reverse phase chromatography (Column: C18 silica gel; Mobile phase A: water, B: ACN; Gradient: 0% B to 10% B in 10 min) afforded 2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[1,8]naphthyridine]-6'- carboxylic acid as an off-white solid. MS: (ESI, m / z): 205 [M+H]+. Intermediate 30. 3-(tert-Butoxycarbonyl)-1a,2,3,7b-tetrahydro-1H- cyclopropa[c][1,8]naphthyridine-6-carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 2-(Allylamino)-5-bromonicotinaldehyde

[00247] Into two parallel 30 ml sealed tubes, each was placed 5-bromo-2-fluoronicotinaldehyde (1.83 g, 9.0 mmol), allylamine (1.03 g, 18.0 mmol) and ethanol (15 mL). The resulting solution was stirred for 3 h at 80 °C. After cooling room temperature, the resulting solution was poured into 30 mL of hydrochloric acid (1N) and the resulting mixture was stirred for 10 min and then extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:10 EtOAc / pet. ether) afforded 2-(allylamino)-5-bromonicotinaldehyde as a light yellow solid. MS: (ESI, m / z): 241, 243 [M+H]+. Step 2. N-Allyl-5-bromo-3-vinylpyridin-2-amine

[00248] A solution of methyltriphenylphosphonium bromide (6.22 g, 17.42 mmol) and potassium tert butoxide (1.96 g, 17.42 mmol) in THF (30 mL) was stirred for 1 h at room temperature. Then a solution of 2-(allylamino)-5-bromonicotinaldehyde (2.10 g, 87.1 mmol) in THF (5 mL) was added dropwise at room temperature and the reaction mixture was stirred overnight at room temperature. The reaction was quenched by the addition of 20 mL of water and was extracted with DCM (3 x 40). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:20 EtOAc / pet. ether) afforded N-allyl-5-bromo-3-vinylpyridin-2-amine as a light yellow liquid. MS: (ESI, m / z): 239, 241 [M+H]+. Step 3. tert-Butyl allyl(5-bromo-3-vinylpyridin-2-yl)carbamate

[00249] A solution of N-allyl-5-bromo-3-vinylpyridin-2-amine (590 mg, 2.47 mmol), di-tert- butyl dicarbonate (1.62 g, 7.40 mmol), triethylamine (749 mg, 7.40 mmol) and 4- dimethylaminopyridine (90 mg, 0.74 mmol) in THF (15 mL) was stirred overnight at 70 °C. After cooling to room temperature, the reaction was quenched by the addition of 50 mL of water. The resulting mixture was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:30 EtOAc / pet. ether) afforded tert-butyl allyl(5-bromo- 3-vinylpyridin-2-yl)carbamate as an off-white solid. MS: (ESI, m / z): 339, 341 [M+H]+. Step 4. tert-Butyl 6-bromo-1,8-naphthyridine-1(2H)-carboxylate

[00250] A solution of tert-butyl allyl(5-bromo-3-vinylpyridin-2-yl)carbamate (600 mg, 1.77 mmol) and dichloro[1,3-bis(2,4,6-trimethylphenyl)-2- imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II) (Grubbs CatalystTM 2nd Gen) (75 mg, 0.09 mmol) in DCM (10 mL) was stirred overnight at 50 °C. After cooling to room temperature, the resulting mixture was concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:20 EtOAc / pet. ether) afforded tert-butyl 6-bromo-1,8- naphthyridine-1(2H)-carboxylate as an off-white solid. MS: (ESI, m / z): 311, 313 [M+H]+. Step 5. tert-Butyl 6-bromo-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3- carboxylate

[00251] To a solution of potassium hydroxide (5.68 g, 101.24 mmol) in water (8 mL) was added a solution of 1-methyl-1-nitrosourea (2.98 g, 28.92 mmol) in Et2O (40 mL) dropwise at 0°C. The reaction mixture was stirred for 1 h at 0 °C. Then the organic phase was separated to obtain the solution of diazomethane in Et2O. To a solution of tert-butyl 6-bromo-1,8-naphthyridine-1(2H)- carboxylate (450 mg, 1.45 mmol) in THF (15 mL) was added the solution of diazomethane in Et2O (40 mL), followed by the addition of a solution of Pd(OAc)2 (32 mg, 0.14 mmol) in THF (7 mL). The resulting solution was stirred overnight at room temperature. The solids were filtered away and the filtrate was concentrated under vacuum. Purification by silica gel chromatography (eluting with gradient 1:50 to 1:20 EtOAc / pet. ether) afforded tert-butyl 6-bromo-1,1a,2,7b-tetrahydro-3H- cyclopropa[c][1,8]naphthyridine-3-carboxylate as an off-white solid. MS: (ESI, m / z): 325, 327 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step 6. 3-(tert-Butoxycarbonyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine- 6-carboxylic acid

[00252] Into a 30-mL pressure tank reactor, was placed tert-butyl 6-bromo-1,1a,2,7b- tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-carboxylate (200 mg, 0.62 mmol), Pd(dppf)Cl2 (90 mg, 0.12 mmol), NaOAc (151 mg, 1.85 mmol), DMF (4.5 mL) and water (1.5 mL). The reaction mixture was stirred for 18 h at 120 °C under 50 atm of CO (g). After cooling to room temperature, the reaction mixture was diluted with 10 mL of water. The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by reverse phase chromatography (Column: C18 silica gel; Mobile phase A: water (0.1% formic acid), B: ACN; Flow rate: 50 mL / min; Gradient: 0% B to 100% B in 30 min) afforded 3-(tert-butoxycarbonyl)- 1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-carboxylic acid as a light yellow solid. MS: (ESI, m / z): 291 [M+H]+. Intermediate 31. 6-(Benzylamino)nicotinic acid [Image disponible dans le document PDF, Image available in the PDF document] Step 1. Methyl 6-(benzylamino)nicotinate

[00253] A mixture of methyl 6-fluoropyridine-3-carboxylate (1 g, 6.12 mmol), phenylmethanamine (1.38 g, 12.88 mmol), and potassium carbonate (2.67 g, 19.32 mmol) in DMF (10 mL) was stirred for 2 h at 80 °C. After cooling to room temperature, the reaction was quenched by the addition of 20 mL of water. The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 3:10 EtOAc:pet. ether) afforded methyl 6-(benzylamino)nicotinate as a white solid. MS: (ESI, m / z): 243 [M+H]+. Step 2. 6-(Benzylamino)nicotinic acid

[00254] A mixture of methyl 6-(benzylamino)nicotinate (500 mg, 1.86 mmol), methanol (20 mL), water (2 mL), and NaOH (165 mg, 4.13 mmol) was stirred for 3 h at 80 °C. After cooling to room temperature, the resulting mixture was concentrated under vacuum. The residue was dissolved in 10 mL of water. The pH value of the solution was adjusted to 6 with hydrochloric acid (6 N). The solids were collected by filtration to afford 6-(benzylamino)nicotinic acid as a white solid. MS: (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 229 [M+H]+. Intermediate 32. tert-Butyl 9,9-difluoro-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Step1: tert-Butyl 7-benzyl-9,9-difluoro-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate

[00255] A solution of tert-butyl 7-benzyl-9-oxo-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (5 g, 14.94 mmol) and DAST (12.2 g, 75.69 mmol) in CH2Cl2 (80 mL) was stirred for 16 h at room temperature. The reaction was then quenched by the addition of 50 mL of saturated aqueous NaHCO3 solution. The resulting mixture was extracted with CH2Cl2 (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 5:1 pet. ether / EtOAc) afforded 700 mg of tert-butyl 7-benzyl-9,9-difluoro-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate as a yellow solid. MS: <semantics>(ESI,m / z)<annotation encoding="application / x-tex">(ESI, m / z)< / annotation>< / semantics>: 353 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step 2: tert-Butyl 9,9-difluoro-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate

[00256] A mixture of tert-butyl 7-benzyl-9,9-difluoro-3,7-diazabicyclo[3.3.1]nonane-3- carboxylate (460 mg, 1.24 mmol) and Pd / C (50 mg, 10%) in EtOAc (20 mL) was stirred at 50 °C for 2 h under an atmosphere of hydrogen. After cooling to room temperature, the solids were filtered away and the filtrate was concentrated under vacuum. The residue was purified by pre- HPLC (Column: XBridge Prep C18 OBD, 19x250 mm; Mobile phase A: water (10 mM) NH4HCO3), B: ACN; Gradient: 20% B to 45% B in 7 min) to afford tert-butyl 9,9-difluoro-3,7- diazabicyclo[3.3.1]nonane-3-carboxylate as a light yellow solid. MS: (ESI, m / z): 263 [M+H]+. Intermediate 33. 5-Benzyl-2-oxa-5,8-diazaspiro[3.5]nonane [Image disponible dans le document PDF, Image available in the PDF document] Step 1. Methyl 2-(3-(nitromethyl)oxetan-3-ylamino)acetate

[00257] To a solution of oxetan-3-one (5 g, 69.38 mmol), nitromethane (5.93 g, 97.15 mmol), and Et3N (2.1 g, 13.28 mmol) in DCM (70 mL) was added a solution of MsCl (10 g, 87.30 mmol) in DCM (70 mL) at -80 °C. Stirring continued at -80 °C for an additional 90 min. Separately, a solution of glycine ethyl ester hydrochloride (19.4 g, 139 mmol) and Et3N (21 g, 139 mmol) in DCM (300 mL) was allowed to react, with stirring, for 10 min at room temperature. The resulting solution was added into the first reaction mixture at -80 °C in portions. After addition, the reaction mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of 100 mL of water and was extracted with 2 x 300 mL of DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by prep-HPLC (Column: XBridge Prep C18 OBD, 19x150 mm, 5 µm; Mobile phase A: water (10 mM NH4HCO3), B: ACN; Gradient: 10% B to 50% B in 30 min) afforded methyl 2-(3- (nitromethyl)oxetan-3-ylamino)acetate as a yellow oil. MS: (ESI, m / z): 205 [M+H]+. Step 2. 2-Oxa-5,8-diazaspiro[3.5]nonan-7-one

[00258] A suspension of methyl 2-(3-(nitromethyl)oxetan-3-ylamino)acetate (8.5 g, 41.63) mmol) and Raney Ni (2 g) in MeOH (50 mL) was stirred for 16 h at room temperature under an atmosphere of hydrogen. The solids were filtered away and the filtrate was concentrated under vacuum. Purification by prep-HPLC (Column: XBridge Prep C18 OBD, 19x150 mm, 5 μm; Mobile phase A: water (10 mM NH4HCO3), B: ACN; Gradient: 10% B to 80% B in 30 min) afforded 2-oxa-5,8-diazaspiro[3.5]nonan-7-one as a red solid. MS: (ESI, m / z): 143 [M+H]+. Step 3. 5-Benzyl-2-oxa-5,8-diazaspiro[3.5]nonan-7-one

[00259] A mixture of 2-oxa-5,8-diazaspiro[3.5]nonan-7-one (4 g, 28.14 mmol), (bromomethyl)benzene (12 g, 70.16 mmol), Na2CO3 (20.9 g, 197.18 mmol), and NaI (10.5 g, 70.05 mmol) in acetonitrile (200 mL) was stirred for 3 h at 80 °C. After cooling to room temperature, the solvent was removed under vacuum. The residue was diluted with water (200 mL). The resulting mixture was extracted with DCM (2 x 300 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:10 MeOH / CH2Cl2) afforded 5-benzyl-2-oxa-5,8- diazaspiro[3.5]nonan-7-one as a yellow solid. MS: (ESI, m / z): 233 [M+H]+. Step 4. 5-Benzyl-2-oxa-5,8-diazaspiro[3.5]nonane-7-thione

[00260] A solution of 5-benzyl-2-oxa-5,8-diazaspiro [3.5]nonan-7-one (2.9 g, 11.86 mmol) and 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (Lawesson reagent) (2.44 g, 6.03 mmol) in THF (150 mL) was stirred for 16 h at room temperature and then stirred for an additional 3 h at 65 °C. The reaction mixture was then poured into water (100 mL) and was extracted with DCM (2 x 150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 EtOAc / pet. ether) afforded 5-benzyl-2-oxa-5,8-diazaspiro[3.5]nonane-7-thione as a white solid. MS: (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 249 [M+H]+. Step 5. 5-Benzyl-2-oxa-5,8-diazaspiro[3.5]nonane

[00261] A solution of 5-benzyl-2-oxa-5,8-diazaspiro [3.5]nonane-7-thione (300 mg, 1.15) mmol) and sodium borohydride (412 mg, 11.19 mmol) in THF (15 mL) and MeOH (30 mL) was stirred for 2 h at room temperature. The reaction was quenched with water (15 mL) and was stirred for an additional 14 h at room temperature. The resulting mixture was extracted with DCM (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by prep-HPLC (Column: XBridge Prep C18 OBD, 19x150 mm, 5 µm; Mobile phase A: water (10 mM NH4HCO3), B: ACN; Gradient: 10% B to 75% B in 30 min) afforded 5-benzyl-2-oxa-5,8-diazaspiro[3.5]nonane as a white solid. MS: (ESI, m / z): 219 [M+H]+. Intermediate 34. tert-Butyl 2-oxa-5,8-diazaspiro[3.5]nonane-8-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Step 1. tert-Butyl 5-benzyl-2-oxa-5,8-diazaspiro[3.5]nonane-8-carboxylate

[00262] A solution of 5-benzyl-2-oxa-5,8-diazaspiro[3.5]nonane, Intermediate 31, (200 mg, <semantics>0.82 mmol<annotation encoding="application / x-tex">0.82 \text{ mmol}< / annotation>< / semantics>), <semantics>(Boc)2O<annotation encoding="application / x-tex">(Boc)_2O< / annotation>< / semantics> (200 mg, <semantics>0.92 mmol<annotation encoding="application / x-tex">0.92 \text{ mmol}< / annotation>< / semantics>), <semantics>Et3N<annotation encoding="application / x-tex">Et_3N< / annotation>< / semantics> (185 mg, 1.83 mmol), and 4- dimethylaminopyridine (11 mg, 0.09 mmol) in DCM (4 mL) was stirred for 2.5 h at room temperature. The reaction was quenched by the addition of water (20 mL) and was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:4 EtOAc / pet. ether) afforded of tert-butyl 5-benzyl-2-oxa-5,8-diazaspiro[3.5]nonane-8- carboxylate as a yellow oil. MS: (ESI, m / z): 319 [M+H]+. Step 2. tert-Butyl 2-oxa-5,8-diazaspiro[3.5]nonane-8-carboxylate

[00263] A mixture of tert-butyl 5-benzyl-2-oxa-5,8-diazaspiro[3.5]nonane-8-carboxylate (190 mg, 0.60 mmol) and Pd / C (20 mg, 10%) in EtOAc (10 mL) was stirred for 1 h at room temperature. The solids were filtered away and the filtrate was concentrated under vacuum to afford tert-butyl 2-oxa-5,8-diazaspiro[3.5]nonane-8-carboxylate as a yellow oil. MS: (ESI, m / z): 229 [M+H]+. Intermediate 35. tert-Butyl N-(4-methoxypyrrolidin-3-yl)carbamate [Image disponible dans le document PDF, Image available in the PDF document] Step 1. Benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylate

[00264] A solution of benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (5 g, 22.81 mmol), NaN3 (3 g, 46.15 mmol), NH4Cl (1.23 g, 22.99 mmol) in MeOH (60 mL) and water (10 mL) was stirred for 16 h at 65 °C. After cooling to room temperature, the pH value was adjusted to 7-8 with aq. 0.5N NaOH. The resulting mixture was extracted with DCM (2 x 150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylate as light-yellow solid. MS: (ESI, m / z): 263 [M+H]+. Step 2. Benzyl 3-azido-4-methoxypyrrolidine-1-carboxylate

[00265] To a solution of benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylate (4 g, 15.25 mmol) in DMF (40 mL) was added NaH (1.2 g, 60% dispersion in oil) at < 10 °C. The resulting solution was stirred for 1 h at room temperature. Iodomethane (2.8 mL, 44.98 mmol) was added and stirring was continued for another 1 h. The reaction was quenched by the addition of water (50 mL). The resulting mixture was extracted with Et2O (2 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:1 EtOAc / pet. ether) afforded benzyl 3-azido-4- methoxypyrrolidine-1-carboxylate as a colorless oil. MS: (ESI, m / z): 277 [M+H]+. Step 3. Benzyl 3-amino-4-methoxypyrrolidine-1-carboxylate

[00266] A solution of benzyl 3-azido-4-methoxypyrrolidine-1-carboxylate (2 g, 7.24 mmol) and PPh3 (2.1 g, 8.01 mmol) in THF (50 mL) and water (5 mL) was stirred for 1 h at room temperature, then for an additional 5 h at 50°C. After cooling to room temperature, the reaction was concentrated under vacuum. Purification by prep-HPLC (Column: XBridge Prep C18 OBD, 19x50 mm, 5 μm; Mobile phase A: water (10 mM NH4HCO3), B: ACN; Gradient: 10% B to 80% B in 30 min) afforded benzyl 3-amino-4-methoxypyrrolidine-1-carboxylate as a colorless oil. MS: <semantics>(ESI,m / z)<annotation encoding="application / x-tex">(ESI, m / z)< / annotation>< / semantics>: 251 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step 4. Benzyl 3-((tert-butoxycarbonyl)amino)-4-methoxypyrrolidine-1-carboxylate

[00267] A solution of benzyl 3-amino-4-methoxypyrrolidine-1-carboxylate (600 mg, 2.40 mmol), Et3N (457 mg, 4.52 mmol), and (Boc)2O (786 mg, 3.60 mmol) in THF (12 mL) and water (12 mL) was stirred for 30 min at room temperature. The resulting mixture was extracted with DCM (2 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:1 EtOAc / pet. ether) to give benzyl 3-((tert-butoxycarbonyl)amino)-4- methoxypyrrolidine-1-carboxylate as a white solid. MS: (ESI, m / z): 351 [M+H]+. Step 5. tert-Butyl N-(4-methoxypyrrolidin-3-yl)carbamate

[00268] A mixture of benzyl 3-((tert-butoxycarbonyl)amino)-4-methoxypyrrolidine-1- carboxylate (200 mg, 0.57 mmol) and Pd / C (200 mg, 10%) in EtOAc (10 mL) was stirred for 3 h at room temperature under an atmosphere of hydrogen. The solids were filtered out and washed with EtOAc (3x10mL). The filtrate was concentrated under vacuum to give tert-butyl N-(4- methoxypyrrolidin-3-yl)carbamate as a white solid. MS: (ESI, m / z): 217 [M+H]+. Intermediate 36. tert-butyl ((3S,4S)-4-methoxypyrrolidin-3-yl)carbamate [Image disponible dans le document PDF, Image available in the PDF document] Step 1. Benzyl (3S,4S)-3-azido-4-hydroxypyrrolidine-1-carboxylate

[00269] To a mixture of benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (10 g, 44.70 mmol) and (1R,2R)-(-)-[1,2-cyclohexanediamino-N N'-bis(3,5-di-t-butylsalicylidene)]chromium (III) chloride (Jacobsen's Chromium catalyst) (682 mg, 1.08 mmol) was added azidotrimethylsilane (6.52 g, 56.59 mmol) at 30 °C. The reaction mixture was stirred for 16 h at 30 °C. Methanol (30 mL) and trifluoroacetic acid (0.5 mL) were added. The resulting solution was stirred at 30 °C for 3 h, then concentrated under vacuum. The residue was diluted with 100 mL of water and was extracted with ethyl acetate (3x100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:2 EtOAc / pet.ether) afforded benzyl (3S,4S)-3-azido-4- hydroxypyrrolidine-1-carboxylate as a light yellow oil. MS: (ESI, m / z): 263 [M+H]+. Step 2. Benzyl (3S,4S)-3-azido-4-methoxypyrrolidine-1-carboxylate

[00270] The title compound was prepared according to the procedures of Intermediate 35, Step 2, starting from benzyl (3S,4S)-3-azido-4-hydroxypyrrolidine-1-carboxylate. MS: (ESI, m / z): 277 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step 3. Benzyl (3S,4S)-3-amino-4-methoxypyrrolidine-1-carboxylate

[00271] The title compound was prepared according to the procedures of Intermediate 35, Step 3, starting from benzyl (3S,4S)-3-azido-4-methoxypyrrolidine-1-carboxylate. MS: (ESI, m / z): 251 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step 4. Benzyl (3S,4S)-3-((tert-butoxycarbonyl)amino)-4-methoxypyrrolidine-1-carboxylate

[00272] The title compound was prepared according to the procedures of Intermediate 35, Step 4, starting from benzyl (3S,4S)-3-amino-4-methoxypyrrolidine-1-carboxylate. MS: (ESI, m / z): 351 [M+H]+. Step 5. tert-butyl ((3S,4S)-4-methoxypyrrolidin-3-yl)carbamate

[00273] The title compound was prepared according to the procedures of Intermediate 35, Step 5, starting from benzyl (3S,4S)-3-((tert-butoxycarbonyl)amino)-4-methoxypyrrolidine-1- carboxylate. MS: (ESI, m / z): 217 [M+H]+. Intermediate 37. tert-Butyl 3-(trifluoromethyl)piperidin-3-ylcarbamate [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 1-Benzyl 3-methyl 3-(trifluoromethyl)piperidine-1,3-dicarboxylate

[00274] To a solution of 1-benzyl 3-methyl piperidine-1,3-dicarboxylate (2.0 g, 7.14 mmol) in THF (60 mL) was added LDA (2.0 M in THF) (10.8 mL, 21.66 mmol) dropwise at -78 °C. After the solution was stirred for 30 min at -78 °C, S-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate (4.35 g, 10.81 mmol) was added. After addition, the resulting solution was allowed to react, with stirring, for an additional 2 h at -40 °C. The reaction was then quenched by the addition of 30 mL of a saturated aqueous solution of NH4Cl. The resulting mixture was extracted with EtOAc (3 x 70 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:4 EtOAc / pet. ether) afforded 1-benzyl 3-methyl 3-(trifluoromethyl)piperidine-1,3- dicarboxylate as a yellow oil. MS: (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 346 [M+H]+. Step 2. 1-((Benzyloxy)carbonyl)-3-(trifluoromethyl)piperidine-3-carboxylic acid

[00275] A solution of 1-benzyl 3-methyl 3-(trifluoromethyl)piperidine-1,3-dicarboxylate (310) mg, 0.83 mmol) in MeOH (10 mL) and aq. 1N NaOH (2.7 mL, 2.70 mmol) was stirred for 2 h at 50 °C and then concentrated under vacuum. The residue was diluted with 5 mL of water. The pH value of the solution was adjusted to 3-4 with 6N HCl. The solids were collected by filtration to give of 1-((benzyloxy)carbonyl)-3-(trifluoromethyl)piperidine-3-carboxylic acid as a yellow solid. MS: (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 332 [M+H]+. Step 3. Benzyl 3-((tert-butoxycarbonyl)amino)-3-(trifluoromethyl)piperidine-1-carboxylate

[00276] A solution of 1-((benzyloxy)carbonyl)-3-(trifluoromethyl)piperidine-3-carboxylic acid (250 mg, 0.76 mmol), Et3N (229 mg, 2.26 mmol), and DPPA (415 mg, 1.51 mmol) in toluene (8 mL) was stirred for 2 h at 90 °C. tert-Butanol (279 mg, 3.76 mmol) was added and the reaction mixture was stirred for an additional 16 h at 90 °C. After cooling to room temperature, the reaction was quenched by the addition of water (20 mL) and was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:10 to 1:3 EtOAc / pet. ether) afforded benzyl 3-((tert-butoxycarbonyl)amino)-3-(trifluoromethyl)piperidine-1- carboxylate as a yellow solid. MS: (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 403 [M+H]+. Step 4. tert-Butyl (3-(trifluoromethyl)piperidin-3-yl)carbamate

[00277] A mixture of benzyl 3-((tert-butoxycarbonyl)amino)-3-(trifluoromethyl)piperidine-1- carboxylate (90 mg, 0.21 mmol) and Pd / C (10 mg, 10%) in EtOAc (5 mL) was stirred for 1 h at room temperature under an atmosphere of hydrogen. The solids were filtered away and the filtrate was concentrated under vacuum to give tert-butyl (3-(trifluoromethyl)piperidin-3-yl)carbamate as yellow oil. MS: (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 269 [M+H]+. Intermediate 38. tert-Butyl (4-(trifluoromethoxy)pyrrolidin-3-yl)carbamate [Image disponible dans le document PDF, Image available in the PDF document] Step 1. Benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylate

[00278] A solution of benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (5 g, 22.81 mmol), NaN3 (3 g, 46.15 mmol), NH4Cl (1.23 g, 22.99 mmol) in MeOH (60 mL) and water (10 mL) was stirred for 16 h at 65 °C. After cooling to room temperature, the pH value was adjusted to 7-8 with aq. 0.5N NaOH. The resulting mixture was extracted with DCM (2 x 150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylate as light-yellow solid. MS: (ESI, m / z): <semantics>263[M+H]+<annotation encoding="application / x-tex">263 [M+H]^+< / annotation>< / semantics>. Step 2. Benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypyrrolidine-1-carboxylate

[00279] A solution of benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylate (6 g, 22.88 mmol), aq. 1 N NaOH (46 mL, 46 mmol), PMe3 (1M in THF) (70 mL, 70 mmol), and (Boc)2O (15.0 g, 68.73 mmol) in THF (228 mL) was stirred for 3 h at room temperature. The reaction mixture was diluted with 50 mL of water and was extracted with CH2Cl2 (3 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Purification by reverse phase chromatography (Column: C18 silica gel; Mobile phase A: water (10 mM) NH4HCO3), B: ACN; Flow rate: 50 mL / min; Gradient: 0% B to 70% B in 40 min) afforded benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypyrrolidine-1-carboxylate as a white solid. MS: (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 337 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step 3. Benzyl 3-((tert-butoxycarbonyl)amino)-4-(trifluoromethoxy)pyrrolidine-1- carboxylate

[00280] Α solution of benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypyrrolidine-1- carboxylate (1 g, 2.97 mmol), Selectfluor® (5.26 g, 14.85 mmol), AgOTf (7.6 g, 29.7 mmol), KF (1.72 g, 29.61 mmol), 2-fluoropyridine (2.88 g, 29.66 mmol) and TMS-CF3 (4.22 g, 29.68 mmol) in EtOAc (14 mL) was stirred overnight at room temperature. The solids were filtered out and washed with CH2Cl2 (3 x 50 mL). The combined filtrate was concentrated under vacuum and purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase A: water (10 mM NH4HCO3), B: ACN; Flow rate: 50 mL / min; Gradient: 0% B to 80% B in 40 min) to give benzyl 3-((tert-butoxycarbonyl)amino)-4-(trifluoromethoxy)pyrrolidine-1-carboxylate as yellow oil. MS: (ESI, m / z): 405 [M+H]+. Step 4. tert-Butyl (4-(trifluoromethoxy)pyrrolidin-3-yl)carbamate

[00281] A mixture of benzyl 3-((tert-butoxycarbonyl)amino)-4-(trifluoromethoxy)pyrrolidine- 1-carboxylate (190 mg, 0.47 mmol) and Pd / C (20 mg, 10%) in EtOAc (10 mL) was stirred for 2 h at room temperature under an atmosphere of hydrogen. The solids were filtered away and the filtrate was concentrated under vacuum to give tert-butyl (4-(trifluoromethoxy)pyrrolidin-3- yl)carbamate as a yellow oil. MS: (ESI, m / z): 271 [M+H]+. Intermediate 39. 4-(tert-butyldimethylsilyloxy)piperidine [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 1-Benzyl-4-(tert-butyldimethylsilyloxy)piperidine

[00282] A soluition of 1-benzylpiperidin-4-ol (1 g, 5.23 mmol), imidazole (712 mg, 10.46 mmol), and tert-butyldimethylsilyl chloride (867 mg, 5.75 mmol) in DCM (20 mL) was stirred for 3 h at room temperature and then diluted with 20 mL of water. The resulting mixture was extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 EtOAc / pet. ether) afforded 1-benzyl-4-(tert-butyldimethylsilyloxy)piperidine as colorless oil. MS: (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 306 [M+H]+. Step 2. 4-(tert-Butyldimethylsilyloxy)piperidine

[00283] A mixture of 1-benzyl-4-(tert-butyldimethylsilyloxy)piperidine (500 mg, 1.64 mmol) and Pd / C (50 mg, 10%) in EtOAc (20 mL) was stirred for 2 h at room temperature under an atmosphere of hydrogen. The solids were filtered out and the filtrate was concentrated under vacuum to give 4-(tert-butyldimethylsilyloxy)piperidine as colorless oil. MS: (ESI, m / z): 216 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Intermediate 40. 3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidine [Image disponible dans le document PDF, Image available in the PDF document]

[00284] A solution of 3-methylpiperidin-3-ol (500 mg, 3.91 mmol), tert-butyldimethylsilyl chloride (497 mg, 3.30 mmol), and Et3N (837 mg, 8.27 mmol) in DCM (20 mL) was stirred for 24 h at room temperature. The reaction was quenched by the addition of 50 mL of water. The resulting mixture was extracted with DCM (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with gradient 1:20 to 1:5 EtOAc / pet.ether) afforded 3-((tert- butyldimethylsilyl)oxy)-3-methylpiperidine as colorless oil. MS: (ESI, m / z): 230 [M+H]+. Intermediate 41. tert-Butyl 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Step 1. tert-Butyl 3-(2-ethoxy-2-oxoethylidene)azetidine-1-carboxylate

[00285] To a solution of ethyl 2-(diethoxyphosphoryl)acetate (26.2 g, 116.86 mmol) in THF (60 mL) was added NaH (4.68 g, 117.01 mmol, 60% dispersion in oil) in portions at 0 °C. The resulting solution was stirred for 30 min at room temperature. To the reaction mixture was added tert-butyl 3-oxoazetidine-1-carboxylate (10 g, 58.41 mmol) with stirring at 0 °C. The resulting solution was stirred for an additional 30 min at room temperature. The reaction was then quenched by the addition of 30 mL of a water / ice mixture. The resulting solution was extracted with DCM (3 x 40 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:5 EtOAc / pet. ether) afforded tert-butyl 3-(2-ethoxy -2-oxoethylidene)azetidine-1-carboxylate as yellow oil. MS: (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 242 [M+H]+. Step 2: 2-(tert-Butyl) 8-ethyl 7-oxo-5-oxa-2-azaspiro[3.4]octane-2,8-dicarboxylate

[00286] To a solution of NaH (1.2 g, 30.00 mmol, 60% dispersion in oil) in Et2O (20 mL) was added methyl 2-hydroxyacetate (2.69 g, 29.86 mmol) at 0 °C. The resulting solution was stirred for 30 min at room temperature and then concentrated under vacuum. The residue was diluted with 20 mL of DMSO and tert-butyl 3-(2-ethoxy-2-oxoethylidene)azetidine-1-carboxylate (6 g, 24.87 mmol) was added. The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 4-5 with hydrochloric acid (1N). The resulting mixture was extracted with Et2O (4 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with gradient 1:10 to 1:5 EtOAc / pet. ether) afforded 2-(tert-butyl) 8-ethyl 7-oxo-5-oxa-2- azaspiro[3.4]octane-2,8-dicarboxylate as a light yellow solid. MS: (ESI, m / z): 300 [M+H]+. Step 3. tert-Butyl 7-oxo-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[00287] A solution of 2-(tert-butyl) 8-ethyl 7-oxo-5-oxa-2-azaspiro[3.4]octane-2,8- dicarboxylate (4 g, 13.4 mmol) and NaCl (1.33 g, 22.76 mmol) in DMSO / water (10:1, 20 mL) was stirred for 2 h at 120 °C. After cooling to room temperature, the reaction was quenched with 20 mL of water. The resulting mixture was extracted with Et2O (4 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 EtOAc / pet. ether) afforded tert-butyl 7-oxo-5-oxa- 2-azaspiro[3.4]octane-2-carboxylate as a white solid. MS: (ESI, m / z): 228 [M+H]+. Step 4. tert-Butyl 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[00288] To a solution of tert-butyl 7-oxo-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (1.1 g, 4.84 mmol) in THF (8 mL) was added NaH (276 mg, 7.49 mmol) in portions at 0 °C. The resulting mixture was stirred for 30 min at room temperature. The reaction was quenched with 50 mL of a water / ice mixture. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. Purification by reverse phase chromatography (Column: C18 silica gel; Mobile phase A: water (0.5% TFA), B: ACN; Gradient: 0% to 50% B over 35 min) afforded tert-butyl 7-hydroxy- 5-oxa-2-azaspiro[3.4]octane-2-carboxylate as yellow oil. MS: (ESI, m / z): 230 [M+H]+. Intermediate 42. Benzyl (R)-(7-chloro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-yl)carbamate [Image disponible dans le document PDF, Image available in the PDF document] Step 1. (4,6-Dichloropyridin-3-yl)methanol

[00289] Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4,6-dichloronicotinaldehyde (8 g, 43.18 mmol) and ethanol (200 mL). NaBH4 (5.2 g, 141.21 mmol) was added in portions at 0 °C. Then the resulting solution was stirred for 2 h at 25 °C. The reaction was then quenched by the addition of water (200 mL). The resulting mixture was extracted with DCM (3 x 300 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:10 ethyl acetate / pet. ether) to give of ((4,6-dichloropyridin-3-yl)methanol as a colorless oil. MS: (ESI, m / z): 178,180 [M+H]+. Step 2. 5-(Bromomethyl)-2,4-dichloropyridine

[00290] Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (4,6-dichloropyridin-3-yl)methanol (5 g, 26.68 mmol), DCM (100 mL) and PBr3 (7.7 g, 28.45 mmol). The resulting solution was stirred for 30 min at 40 °C in an oil bath. After cooling to 25 °C, the reaction was then quenched by the addition of water (120) mL). The resulting mixture was extracted with DCM (2 x 150 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:30 ethyl acetate / pet. ether) to give 5-(bromomethyl)-2,4-dichloropyridine as a colorless oil. MS: (ESI, m / z): 240, 242, 244 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step 3. (2R,5S)-2-((4,6-Dichloropyridin-3-yl)methyl)-5-isopropyl-3,6-dimethoxy-2,5- dihydropyrazine

[00291] Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (2S)-3,6-dimethoxy-2-(propan-2-yl)-2,5-dihydropyrazine (3 g, 15.47 mmol) and THF (200 mL). A solution of n-BuLi in n-hexane (2.5 M) (9.8 mL, 24.5 mmol) was added at -80 °C in a liquid nitrogen bath. The resulting solution was stirred for 30 min at -80 °C in a liquid nitrogen bath. Then a solution of 5-(bromomethyl)-2,4-dichloropyridine (4.7 g, 18.53 mmol) in THF (10mL) was added. The resulting solution was allowed to react, with stirring, for an additional 1 h while the temperature was maintained at -80°C in a liquid nitrogen bath. The reaction was then quenched by the addition of 120 mL of ammonium chloride (sat. aq.). The resulting mixture was extracted with DCM (2 x 150 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:10 ethyl acetate / pet. ether) to afford (2R,5S)- 2-[(4,6-dichloropyridin-3-yl)methyl]-3,6-dimethoxy-5-(propan-2-yl)-2,5-dihydropyrazine as a white solid. MS: (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 344, 346 [M+H]+. Step 4. Methyl (2R)-2-amino-3-(4,6-dichloropyridin-3-yl)propanoate

[00292] Into a 250-mL round-bottom flask, was placed (2R,5S)-2-[(4,6-dichloropyridin-3- yl)methyl]-3,6-dimethoxy-5-(propan-2-yl)-2,5-dihydropyrazine (3.5 g, 9.66 mmol), hydrochloride acid (0.3M) (70 mL) and ACN (80 mL). The resulting solution was stirred for 2 h at 25 °C. The reaction was then quenched by the addition of 100 mL of sodium bicarbonate (sat. aq.). The resulting mixture was extracted with 2 x 150 mL of DCM and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give methyl (2R)- 2-amino-3-(4,6-dichloropyridin-3-yl)propanoate as colorless oil. MS: (ESI, m / z): 249, 251 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step 5. (2R)-2-Amino-3-(4,6-dichloropyridin-3-yl)propan-1-ol

[00293] Into a 250-mL round-bottom flask, was placed methyl (2R)-2-amino-3-(4,6- dichloropyridin-3-yl)propanoate (1.5 g, 5.72 mmol) and methanol (50 mL). NaBH4 (690 mg, 18.24 mmol) was added in portion at 0 °C. The resulting solution was stirred for 3 h at 25 °C. The reaction was then quenched by the addition of water (20 mL). The resulting mixture was extracted with DCM (2 x 50 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:10 methanol / DCM) to afford (2R)-2-amino-3-(4,6-dichloropyridin-3-yl)propan-1- ol as a white solid. MS: (ESI, m / z): 221, 223 [M+H]+. Step 6. (R)-7-Chloro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-amine

[00294] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (2R)-2-amino-3-(4,6-dichloropyridin-3-yl)propan-1-ol (1 g, 4.30 mmo), sodium hydride (271 mg, 6.78 mmol, 60%) and DMSO (10 mL). The resulting solution was stirred for 16 h at 50 °C in an oil bath. After cooling to 25 °C, the reaction was then quenched by the addition of water (20 mL). The resulting mixture was extracted with DCM (2 x 30 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase A: water (0.1% formic acid), B: ACN; Flow rate: 50 mL / min; Gradient: 0% B to 30% B in 30 min). The collected fraction was concentrated under vacuum to give (R)-7-chloro- 3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-amine as a white solid. MS: (ESI, m / z): 185, 187 [M+H]+. Step 7. Benzyl (R)-(7-chloro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-yl)carbamate

[00295] Into a 50-mL round-bottom flask, was placed (R)-7-chloro-3,4-dihydro-2H- pyrano[3,2-c]pyridin-3-amine (500 mg, 2.57 mmol, ethyl acetate (15 mL, 153.23 mmol), water (15 mL), benzyl chloroformate (558 mg, 3.27 mmol) and potassium carbonate (751 mg, 5.43 mmol). The resulting mixture was stirred for 30 min at 25 °C. The resulting mixture was extracted with 3 x 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:1 ethyl acetate / pet. ether) to afford benzyl (R)-(7-chloro-3,4- dihydro-2H-pyrano[3,2-c]pyridin-3-yl)carbamate as a white solid. MS: (ESI, m / z): 319, 321 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Intermediate 43. Benzyl (R)-(7-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-3- yl)carbamate [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 3-(Bromomethyl)-2,6-dichloropyridine

[00296] Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (2,6-dichloropyridin-3-yl)methanol (10 g, 56.17 mmol), DCM (200 mL) and PBr3 (15.3 g, 56.52 mmol). The resulting solution was stirred for 30 min at 40 °C in an oil bath. The pH value of the solution was adjusted to 7 with NH4HCO3 (sat. aq.). The resulting mixture was extracted with 3 x 200 mL of DCM. The organic layers combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:10 to 1:5 ethyl acetate / pet. ether) to give 3- (bromomethyl)-2,6-dichloropyridine as an off-white solid. MS: (ESI, m / z): 240, 242, 244 [M+H]+. Step 2. (2R,5S)-2-((2,6-Dichloropyridin-3-yl)methyl)-5-isopropyl-3,6-dimethoxy-2,5- dihydropyrazine

[00297] Into two 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (2S)-3,6-dimethoxy-2-(propan-2-yl)-2,5-dihydropyrazine (2 g, 10.86 mmol) and THF (15 mL). This was followed by the addition of butyllithium (2.5 M) (6.5 mL, 16.25 mmol) at -78 °C. The resulting solution was stirred for 30 min. To this was added 3- (bromomethyl)-2,6-dichloropyridine (2.62 g, 10.88 mmol). The resulting solution was stirred for an additional 1 h at -78°C. The reaction was then quenched by the addition of 5 mL of NH4HCO3 (saturated) and the mixture was diluted with 10 mL of H2O. The resulting mixture of two batches was combined and extracted with 3 x 50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1 / 5 ethyl acetate / pet. ether) to afford (2R,5S)- 2-((2,6-dichloropyridin-3-yl)methyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine as a colorless oil. MS: (ESI, m / z): 344, 346 [M+H]+. Step 3. Methyl (R)-2-amino-3-(2,6-dichloropyridin-3-yl)propanoate

[00298] Into a 500-mL round-bottom flask, was placed (2R,5S)-2-((2,6-dichloropyridin-3- yl)methyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (5.4 g, 16.35 mmol), acetonitrile (100 mL) and hydrochloric acid (0.3 N) (157 mL). The resulting solution was stirred for 1 hour at 24 °C. The solvent was removed under vacuum and the residue was extracted with 3x100 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:5 to 1:1 ethyl acetate / pet. ether) to afford to give methyl (R)-2-amino-3-(2,6-dichloropyridin-3- yl)propanoate as an off-white solid. MS: (ESI, m / z): 249, 251 [M+H]+. Step 4. (R)-2-Amino-3-(2,6-dichloropyridin-3-yl)propan-1-ol

[00299] Into a 250-mL round-bottom flask, was placed methyl (R)-2-amino-3-(2,6- dichloropyridin-3-yl)propanoate (3.2 g, 12.85 mmol), methanol (15 mL), THF (60 mL) and NaBH4 (1.46 g, 39.65 mmol). The resulting solution was stirred for 2 h at 24 °C. The reaction was then quenched by the addition of 5 mL of water. The solvent was removed under vacuum. The residue was diluted with 50 mL of water. The resulting mixture was extracted with 3 x 50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:20 methanol / DCM) to afford (R)-2-amino-3-(2,6-dichloropyridin-3-yl)propan-1-ol as an off- white solid. MS: (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 221, 223 [M+H]+. Step 5. (R)-7-Chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-3-amine

[00300] Into a 250-mL round-bottom flask fitted with a hydrogen balloon, was placed (R)-2- amino-3-(2,6-dichloropyridin-3-yl)propan-1-ol (2.6 g, 11.76 mmol) and DMSO (30 mL). This was followed by the addition of sodium hydride (706 mg, 29.42 mmol, 60%) at 0 °C. The resulting solution was stirred at 24 °C for 30 min and then stirred overnight at 50 °C. After cooling to 25°C, the reaction was then quenched by the addition of 60 mL of water. The resulting mixture was extracted with 3 x 60 mL of ethyl acetate. The organic layers combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase A: water (10 mM NH4HCO3), B: ACN; Flow rate: 50 mL / min; Gradient: 0% B to 30% B in 30 min). The collected fraction was concentrated under vacuum to give (R)-7-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-3-amine as an off-white solid. MS: (ESI, m / z): 185, 187 [M+H]+. Step 6. Benzyl (R)-(7-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-3-yl)carbamate

[00301] Into a 100-mL round-bottom flask, was placed (R)-7-chloro-3,4-dihydro-2H- pyrano[2,3-b]pyridin-3-amine (1.3 g, 6.34 mmol), ethyl acetate (15 mL), water (10 mL), potassium carbonate (1.95 g, 14.11 mmol) and benzyl chloroformate (1.44 g, 8.44 mmol). The resulting solution was stirred for 2 h at 25 °C. The reaction was then quenched by the addition of 30 mL of water. The resulting mixture was extracted with 3x30 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by re-crystallization from pet. ether. The solids were collected by filtration to give benzyl (R)-(7-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-3-yl)carbamate as a white solid. MS: (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 319, 321 [M+H]+. Intermediate 44. tert-Butyl 4-[(3R)-3-[[(benzyloxy)carbonyl]amino]-3,4-dihydro-2H-1- benzopyran-7-yl]-4-fluoropiperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 7-Bromo-4-methyl-3-nitro-3,4-dihydro-2H-1-benzopyran To a solution of 7-bromo-3-nitro-2H-chromene (2.2 g, 8.59 mmol) in THF (30 mL) was added CH3MgBr (1 M in THF) (13 mL, 13.00 mmol) at -78 °C. The resulting solution was stirred for 20 min at -78 °C. The reaction was then quenched by the addition of 20 mL of saturated aqueous NH4Cl solution. The resulting mixture was extracted with 3 x 50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 3:1 pet. ether / ethyl acetate) to afford 7-bromo-4-methyl-3-nitro-3,4-dihydro-2H-1-benzopyran as yellow oil. GCMS: <semantics>(ESI,m / z)<annotation encoding="application / x-tex">(ESI, m / z)< / annotation>< / semantics>: 271, 273 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step 2. 7-Bromo-4-methyl-3,4-dihydro-2H-1-benzopyran-3-amine To a solution of BH3-THF (1M) (40 mL, 40.00 mmol) and NaBH4 (1.26 g, 33.30 mmol) in THF (40 mL) was added 7-bromo-4-methyl-3-nitro-3,4-dihydro-2H-1-benzopyran (900 mg, 3.31 mmol). The resulting mixture was stirred in a sealed tube for 16 h at 75 °C. Then methanol (40 mL) was added and the reaction mixture was stirred for 6 h at 80 °C. After cooling to 25 °C, the solvent was removed under vacuum. The residue was diluted with 50 mL of ice / water. The resulting mixture was extracted with 3 x 50 of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reverse phase chromatography (Column: C18 silica gel; Mobile phase A: water (0.05%) TFA), B: ACN; Gradient: 0% B to 40% over 45 min) to afford 7-bromo-4-methyl-3,4-dihydro- 2H-1-benzopyran-3-amine as a white solid. MS: (ESI, m / z): 242, 244 [M+H]+. Step 3. Benzyl N-(7-bromo-4-methyl-3,4-dihydro-2H-1-benzopyran-3-yl) carbamate A solution of 7-bromo-4-methyl-3,4-dihydro- 2H-1-benzopyran-3-amine (500 mg, 2.07 mmol) and CbzCl (423 mg, 2.48 mmol) in ethyl acetate (8 mL) and a solution of potassium carbonate (567 mg, 4.10 mmol) in water (8 mL) was stirred for 1 h at 25 °C. The resulting solution was diluted with 20 mL of water. The resulting mixture was extracted with 3 x 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 3:1 pet. ether / ethyl acetate) to afford benzyl N-(7-bromo-4-methyl-3,4-dihydro-2H-1-benzopyran-3- yl)carbamate as a white solid. MS: (ESI, m / z): 376, 378 [M+H]+. Intermediate 45. tert-Butyl 6-((tert-butyldimethylsilyl)oxy)-1,4-diazepane-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] . . Step 1. 1,4-Dibenzyl-1,4-diazepan-6-ol A solution of 1,3-dibromopropan-2-ol (12.37 g, 56.77 mmol), benzyl(2-(benzylamino)ethyl)amine (13.56 g, 56.42 mmol), and Et3N (17.17 g, 169.68 mmol) in toluene (50 mL) was stirred for 48 h at 120 °C. After cooling to 25 °C, the reaction was then quenched by the addition of 100 mL of water. The resulting mixture was extracted with 2 x 100 mL of ethyl acetate and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:2 ethyl acetate / pet. ether) to afford 1,4-dibenzyl-1,4-diazepan-6-ol as yellow oil. MS: (ESI, m / z): 297 [M+H]+. Step 2. 1,4-Dibenzyl-6-((tert-butyldimethylsilyl)oxy)-1,4-diazepane A solution of 1,4-dibenzyl-1,4-diazepan-6-ol (2.0 g, 6.61 mmol), imidazole (900 mg, 13.22 mmol) and TBS-Cl (1.2 g, 7.96 mmol) in DMF (10 mL) was stirred for 16 h at 25 °C. The reaction was then quenched by the addition of 50 mL of water. The resulting mixture was extracted with 2 x 50 mL of ethyl acetate and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:5 ethyl acetate / pet. ether) to afford 1,4-dibenzyl-6-((tert-butyldimethylsilyl)oxy)- 1,4-diazepane as yellow oil. MS: (ESI, m / z): 411 [M+H]+. Step 3. 6-((tert-Butyldimethylsilyl)oxy)-1,4-diazepane A mixture of 1,4-dibenzyl-6-((tert-butyldimethylsilyl)oxy)-1,4-diazepane (1.5 g, 3.47 mmol) and Pd(OH)2 on carbon (20 mg, 10%) in ethyl acetate (10 mL) was stirred under an atmosphere of hydrogen for 28 h at 20 °C. The solids were filtered out. The filtrate was concentrated under vacuum to afford 6-((tert-butyldimethylsilyl)oxy)-1,4-diazepane as colorless oil. MS: (ESI, m / z): <semantics>231[M+H]+<annotation encoding="application / x-tex">231 [M+H]^{+}< / annotation>< / semantics> Step 4. tert-Butyl 6-((tert-butyldimethylsilyl)oxy)-1,4-diazepane-1-carboxylate A solution of 6-((tert-butyldimethylsilyl)oxy)-1,4-diazepane (1.2 g, 4.95 mmol), Boc2O (700 mg, 3.21 mmol), and triethylamine (500 mg, 4.94 mmol) in DCM (20 mL) was stirred for 2 h at -40°C in a dry ice / ethanol bath and stirred for an additional 1 h at 20 °C. The reaction was then quenched by the addition of 40 mL of water. The resulting mixture was extracted with 2 x 40 mL of ethyl acetate and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:10 methanol / DCM) to afford tert-butyl 6-((tert-butyldimethylsilyl)oxy)-1,4-diazepane-1- carboxylate as colorless oil. MS: (ESI, m / z): 331 [M+H]+. Intermediate 46. tert-Butyl 6-((tert-butyldimethylsilyl)oxy)-1,4-diazepane-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a solution of tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate (1 g, 4.39 mmol) and triethylamine (1.53 mL, 10,98 mmol) in DCM (20 mL) was added tert-butyl(chloro)dimethylsilane (693 mg, 4.60 mmol). The resulting solution was stirred overnight at 20 °C. The reaction was then quenched by the addition of 20 mL of water. The resulting mixture was extracted with 3 x 20 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 20:1 ethyl DCM / methanol) to afford tert-butyl 6-((tert-butyldimethylsilyl)oxy)-1,4-diazepane-1- carboxylate as an off-colorless oil. MS: (ESI, m / z): 331 [M+H]+. Intermediate 47-1. Benzyl N-[2-[(trifluoromethane)sulfonyloxy]-5,6,7,8-tetrahydroquinolin- 6- yl]carbamate Intermediate 47-2. Benzyl N-[(6S)-2-(trifluoromethanesulfonyloxy)-5,6,7,8- tetrahydroquinolin-6-yl|carbamate Intermediate 47-3. Benzyl N-[(6R)-2-(trifluoromethanesulfonyloxy)-5,6,7,8- tetrahydroquinolin-6-yl]carbamate Method 1. Chiral separation [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 7',8'-Dihydro-5'H-spiro[1,3-dioxolane-2,6'-quinoline]-2'-ol A solution of 1,4-dioxaspiro[4.5]decan-8-one (50.0 g, 320 mmol), ethyl prop-2-ynoate (68 mL, 672 mmol) and a solution of NH3 in MeOH (230 mL, 7M) in isopropanol (1.3 L) was stirred for 14 h at 130 °C. The reaction mixture was cooled to 20 °C. The solvent was removed under vacuum. The solids were collected by filtration. The cake was washed with 2 x 30 mL of pet. ether and dried under vacuum to give 7',8'-dihydro-5'H-spiro[1,3-dioxolane-2,6'-quinoline]-2'-ol as an off- white solid. MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 208 [M+H]+. Step 2. 7',8'-Dihydro-5'H-spiro[1,3-dioxolane-2,6'-quinoline]-2'-yl trifluoromethanesulfonate To a solution of 7',8'-dihydro-5'H-spiro[1,3-dioxolane-2,6'-quinoline]-2'-ol (24.0 g, 116 mmol) and triethylamine (64.4 mL, 464 mmol) in DCM (500 mL) was added a solution of trifluoromethanesulfonic anhydride (58.4 mL, 347 mmol) in DCM (100 mL) at 10 °C. The resulting solution was stirred for 1 h at 20 °C. The mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 3:1 ethyl acetate / pet. ether) to afford 7',8'-dihydro-5'H-spiro[1,3-dioxolane-2,6'-quinoline]-2'-yl trifluoromethanesulfonate as a yellow oil. MS (ESI, m / z): 340 [M+H]+. Step 3. 6-Oxo-5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate A solution of 7',8'-dihydro-5'H-spiro[1,3-dioxolane-2,6'-quinoline]-2'-yl trifluoromethanesulfonate (35.0 g, 103 mmol) and hydrochloric acid (206 mL, 1N) in acetone (300 mL) was stirred for 1 h at 75 °C. The mixture was cooled to 20 °C. The acetone was concentrated under vacuum. The pH value of the residue was adjusted to 7-8 with NaHCO3 (sat., aq.). The resulting mixture was extracted with 3 x 100 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by recrystallization with 100 mL of the mixture solvent of ethyl acetate and pet. ether (10:1) to give 6-oxo-5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate as an off-white solid. MS (ESI, m / z): 296 [M+H]+. Step 4. 6-Amino-5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate A mixture of 6-oxo-5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate (16.0 g, 54.2 mmol) and NH4OAc (50.1 g, 650 mmol) in methanol (250 mL) was stirred for 1 h at 20 °C. NaBH3CN (4.10 g, 65.2 mmol) was added in portions at 10 °C. The resulting mixture was allowed to react for 13 h at 20 °C. The reaction was then quenched by the addition of 50 mL of water / ice. The solvent was concentrated under vacuum. The residue was diluted with 100 mL of hydrochloric acid (1N). The resulting mixture was extracted with 2 x 100 mL of DCM. The pH value of aqueous phase was adjusted to 10 with Na2CO3 (sat., aq.). The aqueous phase was extracted with 4 x 100 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 6-amino-5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate as a yellow oil. MS (ESI, m / z): 297 [M+H]+. Step 5. Benzyl N-[2-[(trifluoromethane)sulfonyloxy]-5,6,7,8-tetrahydroquinolin-6- yl]carbamate A mixture of 6-amino-5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate (12.0 g, 40.5mmol), potassium carbonate (14.0 g, 101 mmol) and CbzCl (7.4 mL, 52.8 mmol) in ethyl acetate (100 mL) was stirred for 2 h at 20 °C. The reaction was then quenched by the addition of 100 mL of water / ice. The mixture was extracted with 3 x 100 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by recrystallization with 80 mL of the mixture solvent of ethyl acetate and pet. ether (10:1) to give benzyl N-[2-[(trifluoromethane)sulfonyloxy]-5,6,7,8- tetrahydroquinolin-6-yl]carbamate as an off-white solid. MS (ESI, m / z): 431 [M+H]+. Step 6. Benzyl N-[(6S)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6- yl]carbamate and benzyl N-[(6R)-2-(trifluoromethanesulfonyloxy)-5,6,7,8- tetrahydroquinolin-6-yl]carbamate The racemate benzyl N-[2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl] carbamate (Intermediate 47-1) (7.00 g, 16.3 mmol,) was separated by SFC (Column: Chiralpak AD-H SFC, 5 x 25 cm, 5 µm; Mobile Phase, A: CO2: 55% and B: MeOH: 45%; Flow rate: 150 mL / min). The first eluting isomer (RT = 4.23 min) was collected and concentrated under vacuum to give benzyl N-[(6S)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6- yl]carbamate (Intermediate 47-2) as an off-white solid. And the second eluting isomer (<semantics>RT=5.16<annotation encoding="application / x-tex">RT = 5.16< / annotation>< / semantics> min) was collected and concentrated under vacuum to give benzyl N-[(6R)-2- (trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (Intermediate 47-3) as an off-white solid. MS (ESI, m / z) for both isomers: 431 [M+H]+. Intermediate 47-2. Benzyl N-[(6S)-2-(trifluoromethanesulfonyloxy)-5,6,7,8- tetrahydroquinolin-6-yl]carbamate Method 2. Chiral resolution [Image disponible dans le document PDF, Image available in the PDF document] Step 1. (S)-6-Amino-5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate A solution of 6-amino-5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate (183 g, 525.65 mmol) and L-(-)-mandelic acid (39.99 g, 262.83 mmol) in EtOH (1830 mL) was stirred at 70 °C for 2 h. The mixture was allowed to cool down to 25 °C slowly and stirred for overnight. The precipitate that was formed was collected by filtration and dried under vacuum to afford the chiral salt as a white solid. The salt was dissolved in H2O (350 mL) and the pH value of aqueous phase was adjusted to 12 - 14 with NaOH (1 N, aq). The aqueous phase was extracted with EtOAc (500 mL). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to afford the free base of the chiral amine (S)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate as a yellow oil. MS (ESI, m / z): 297 [M+H]+. 1H NMR (DMSO-d6, 400 mHz) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>(ppm): 7.79 (d, <semantics>J=8.0<annotation encoding="application / x-tex">J = 8.0< / annotation>< / semantics> Hz, 1H), 7.25 (d, <semantics>J=8.4<annotation encoding="application / x-tex">J = 8.4< / annotation>< / semantics> Hz, 1H), 3.14-3.11 (m, 1H), 2.97- 2.81 (m, 3H), 2.54-2.52 (m, 1H), 2.61-2.58 (m, 2H), 1.64-1.59 (m, 1H). Step 2. Benzyl N-[(6S)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6- yl]carbamate To a solution of (S)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate (48.0 g, 162.02 mmol) and K2CO3 (55.98 g, 405.04 mmol) in EtOAc (480 mL) was added drop-wise CbzCl (35.93 g, 210.62 mmol, 29.94 mL) at 0 °C. The mixture was stirred at 20 °C for 30 min. The reaction was then quenched by water / ice (150 mL). The mixture was extracted with ethyl acetate (350 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude was triturated with pet. ether (200 mL) at 20 °C. The resulting precipitate was collected by filtration and dried under vacuum to afford benzyl N-[(6S)-2- (trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate as a pale pink solid. MS (ESI, m / z): 431 [M+H]+. 1H NMR (DMSO-d6, 400 mHz) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>(ppm): 7.82 (d, <semantics>J=8.0<annotation encoding="application / x-tex">J = 8.0< / annotation>< / semantics> Hz, 1H), 7.49 (m, 1H), <semantics>7.37−7.28<annotation encoding="application / x-tex">7.37-7.28< / annotation>< / semantics> (m, 6H), <semantics>5.04<annotation encoding="application / x-tex">5.04< / annotation>< / semantics> (s, 2H), <semantics>3.82<annotation encoding="application / x-tex">3.82< / annotation>< / semantics> (m, 1H), <semantics>3.08<annotation encoding="application / x-tex">3.08< / annotation>< / semantics> (dd, <semantics>J=16.8<annotation encoding="application / x-tex">J = 16.8< / annotation>< / semantics> Hz, <semantics>4.8<annotation encoding="application / x-tex">4.8< / annotation>< / semantics> Hz, <semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>), <semantics>2.91−<annotation encoding="application / x-tex">2.91-< / annotation>< / semantics> 2.88 (m, 2H), 2.76-2.72 (m, 1H), 2.02-2.00 (m, 1H), 1.83-1.75 (m, 1H). The following intermediate in Table 7 was prepared using standard chemical manipulations and procedures similar to those used for the preparation of Intermediate 47-1. Table 7: [Image disponible dans le document PDF, Image available in the PDF document] 1 Notes on procedures: In Step 1, the ketone used was 6,9-dioxadispiro[2.1.45.33]dodecan-12-one, which was prepared by the following method: (2-chloroethyl)dimethylsulfonium iodide (88.0 g, 347 mmol) was slowly added to a solution of 1,4-dioxaspiro[4.5]decan-8-one (60.0 g, 384 mmol) and t-BuOK (88.0 g, 784 mmol) in t-BuOH (1.50 L) over 4 h. The resulting solution was stirred for 1 h at 25 °C. The solids were filtered. The filtrate was concentrated under vacuum. The residue was diluted with water (400 mL). The resulting mixture was extracted with DCM (3 x 400 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified via reverse phase chromatography to afford 6,9-dioxadispiro[2.1.45.33]dodecan-12-one as a pale yellow oil. MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 183 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Intermediate 48-1. cis-tert-Butyl N-[4-(methoxymethyl)pyrrolidin-3-yl]carbamate; Intermediate 48-2. tert-Butyl N-[(3R,4R)-4-(methoxymethyl)pyrrolidin-3-yl]carbamate and Intermediate 48-3. Benzyl (3R,4R)-3-[[(tert-butoxy)carbonyl]amino]-4- (methoxymethyl)pyrrolidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Step 1. cis-Benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(hydroxymethyl)pyrrolidine-1- carboxylate A solution of cis-benzyl 3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate (2.00 g, 7.99 mmol), Et3N (2.13 mL, 23.7 mmol) and (Boc)2O (2.20 g, 10.1 mmol) in THF (40 mL) and water (20 mL) was stirred for 2 h at 20 °C. The solvent was removed under vacuum. The residue was diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by a silica gel chromatography (eluting with 1:3 ethyl acetate / pet. ether) to give cis-benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(hydroxymethyl)pyrrolidine-1-carboxylate as an off-white solid. MS (ESI, m / z): 351 [M+H]+. Step 2. cis-Benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1- carboxylate A solution of trimethyloxoniumtetrafluoroborate (1.50 g, 10.4 mmol) in DCM (20 mL) was added to a stirring solution of 1,8-bis(dimethylamino)naphthalene (2.20 g, 10.3 mmol) and cis-benzyl 3- [[(tert-butoxy)carbonyl]amino]-4-(hydroxymethyl)pyrrolidine-1-carboxylate (2.20 g, 6.09 mmol) in DCM (100 mL). The resulting mixture was stirred for 3 h at 40 °C. The pH of the mixture was adjusted to 4-6 with HCl (3N, aq.). The resulting mixture was extracted with ethyl acetate (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:1 ethyl acetate / pet. ether) to afford cis- benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1-carboxylate as white solid. MS (ESI, m / z): 365 [M+H]+. Step 3. cis-tert-Butyl N-[4-(methoxymethyl)pyrrolidin-3-yl]carbamate A mixture of cis-benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1- carboxylate (1.00 g, 2.74 mmol) and palladium on carbon (1.00 g, 10%) in ethyl acetate (50 mL) was stirred for 1 h at 20 °C under a hydrogen atmosphere (balloon). The solids were filtered out. The filtrate was concentrated under vacuum to give cis-tert-butyl <semantics>N−[4−<annotation encoding="application / x-tex">N-[4-< / annotation>< / semantics> (methoxymethyl)pyrrolidin-3-yl]carbamate (Intermediate 48-1) as yellow oil (crude). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 231 [M+H]+. Step 4. tert-Butyl N-[(3R,4R)-4-(methoxymethyl)pyrrolidin-3-yl]carbamate The racemate cis-benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1- carboxylate was separated into its enantiomers by SFC (Column: Chiralpak IA-SFC, 5 x 25 cm, 5 μm; Mobile Phase, A: CO2: 70% and B: MeOH (containing 2 mM NH3 in MeOH): 30%; Flow rate: 150 mL / min). The first eluting isomer (RT = 3.91 min) was collected and concentrated under vacuum to give benzyl (3S,4S)-3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine- 1-carboxylate as a yellow solid. The second eluting isomer (<semantics>RT=5.04 min<annotation encoding="application / x-tex">RT = 5.04 \text{ min}< / annotation>< / semantics>) was collected and concentrated under vacuum to give benzyl (3R,4R)-3-[[(tert-butoxy)carbonyl]amino]-4- (methoxymethyl)pyrrolidine-1-carboxylate (Intermediate 48-3) as a yellow solid. MS (ESI, m / z): 365 [M+H]+. A mixture of benzyl (3R,4R)-3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1- carboxylate (Intermediate 48-3) (0.800 g, 2.20 mmol) and palladium on carbon (0.800 g, 10%) in ethyl acetate (30 mL) was stirred for 1 h at 25 °C under a hydrogen atmosphere (balloon). The solids were filtered out. The filtrate was concentrated under vacuum to give tert-butyl N-[(3R,4R)- 4-(methoxymethyl)pyrrolidin-3-yl]carbamate (Intermediate 48-2) as a yellow oil (crude). MS <semantics>(ESI,m / z)<annotation encoding="application / x-tex">(ESI, m / z)< / annotation>< / semantics>: 231 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Intermediate 48-3. Benzyl (3R,4R)-3-[[(tert-butoxy)carbonyl]amino]-4- (methoxymethyl)pyrrolidine-1-carboxylate Method 2. [Image disponible dans le document PDF, Image available in the PDF document] Step 1. Benzyl N-(2,2-dimethoxyethyl)carbamate A solution of 2,2-dimethoxyethan-1-amine (1600 g, 15.22 mol) in toluene (8 L), was added a solution of NaOH (858 g, 21.45 mol) in water (4.42 L). This was followed by the addition of CbzCl (2598 g, 15.23 mol) dropwise with stirring at <20 °C. The resulting solution was stirred for 4 h at room temperature. The organic layer was separated and washed with 3x5 L of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford benzyl N-(2,2-dimethoxyethyl)carbamate as a white solid. Step 2. Benzyl N-(2,2-dimethoxyethyl)-N-(prop-2-en-1-yl)carbamate To a solution of benzyl N-(2,2-dimethoxyethyl)carbamate (1700 g, 7.10 mol), KOH (1755 g, 31.28 mol) and benzyltriethylammonium chloride (32.37g, 142.1 mmol) in toluene (7.82 L) was added 3-bromoprop-1-ene (1117.4 g, 9.24 mol) dropwise with stirring at room temperature. The resulting solution was stirred for 24 h at room temperature. Two batches were thus run in parallel. The reaction was then quenched by the addition of 10 L of water. The resulting solution was extracted with 2x7 L of toluene and the organic layers combined. The organic phase was washed with 2x10 L of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to afford benzyl N-(2,2-dimethoxyethyl)-N-(prop-2-en-1-yl)carbamate as pale yellow oil. Step 3. Benzyl N-(2-oxoethyl)-N-(prop-2-en-1-yl)carbamate A solution of benzyl N-(2,2-dimethoxyethyl)-N-(prop-2-en-1-yl)carbamate (3900 g, 13.96 mol) in 88% formic acid (5460 mL) was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was diluted with 20 L of ethyl acetate, washed with 4x10 L of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to afford benzyl N-(2-oxoethyl)-N-(prop-2-en-1-yl)carbamate as brown oil. Step 4. Benzyl N-[2-(hydroxyimino)ethyl]-N-(prop-2-en-1-yl)carbamate To a solution of benzyl N-(2-oxoethyl)-N-(prop-2-en-1-yl)carbamate (1700 g, 7.29 mol) and NH2OH-HCl (638 g, 9.18 mol) in ACN (9.52 L) was added a solution of NaOAc (669 g, 8.16 mol) in H2O (4.96 L). The resulting solution was stirred for 20 h at room temperature. Two batches were thus run in parallel. The resulting mixture was concentrated under vacuum and extracted with 3x10 L of ethyl acetate and the organic layers combined. The organic phase was washed with 3x5 L of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel chromatography (eluting with 1:9 EtOAc / pet. ether) to afford benzyl N-[2-(hydroxyimino)ethyl]-N-(prop-2-en-1-yl)carbamate as colorless oil. Step 5. cis-Benzyl 3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate A solution of benzyl N-[2-(hydroxyimino)ethyl]-N-(prop-2-en-1-yl)carbamate (1200 g, 4.83 mol) and xylene (6 L) was stirred overnight at 130 °C. The mixture was cooled to room temperature. HOAc (6 L) was added to the mixture. Then Zn (1200 g, 18.35 mol) was added into the mixture at 15 °C. The resulting solution was stirred overnight at room temperature in a water bath. Two batches were thus run in parallel. The batches were combined and filtered. The filtered cake was washed with xylene. The combined filtrate was diluted with 20 L of water. The mixture was extracted with xylene (4x5 L). The aqueous phase was concentrated under vacuum. The pH value of the residue was adjusted to 9-10 with saturated sodium carbonate. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was extracted with 5 L of THF and concentrated under vacuum to afford cis-benzyl 3-amino-4-(hydroxymethyl)pyrrolidine-1- carboxylate as brown oil. Step 6. cis-Benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(hydroxymethyl)pyrrolidine-1- carboxylate To a solution of cis-benzyl 3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate (900 g, 3.60 mol) and triethylamine (728 g, 7.19 mol) in methanol (9 L) was added di-tert-butyl dicarbonate (863 g, 3.95 mol) dropwise with stirring at room temperature. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by silica gel chromatography (eluting with 2:3 EtOAc / pet. ether) to afford cis-benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(hydroxymethyl)pyrrolidine-1-carboxylate as a white solid. Step 7. cis-Benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1- carboxylate To a mixture of cis-benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(hydroxymethyl)pyrrolidine-1- carboxylate (600 g, 1.71 mol) and 2,6-di-tert-butyl-4-methylpyridine (1406 g, 6.85 mol) in DCM (12 L) was added trimethyloxonium tetrafluoroborate (506.5 g, 3.42 mol). The reaction was stirred overnight at room temperature. The resulting solution was concentrated under vacuum. The crude product was purified by silica gel chromatography (eluting with 3:7 EtOAc / pet. ether) to afford cis-benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1-carboxylate as a white solid. Step 8. Benzyl (3R,4R)-3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1- carboxylate The racemate cis-benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1- carboxylate was separated into its enantiomers by SFC (Column: Lux 5µm Amylose-1, 5x25 cm, 5 μm; Mobile Phase A: CO2: 50%, and B: MeOH: 50%; Flow rate: 160 mL / min). The first eluting isomer (RT = <semantics>4.2 min<annotation encoding="application / x-tex">4.2 \text{ min}< / annotation>< / semantics>) was collected and concentrated under vacuum to give benzyl (<semantics>3S,4S<annotation encoding="application / x-tex">3S,4S< / annotation>< / semantics>)-3- [[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1-carboxylate as a white solid. MS (ESI, m / z): 387 [M+Na]+. 1H NMR (CDCl3, 300 MHz) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>(ppm): 7.31-7.44 (m, 5H), 5.14-5.36 (m, 3H), 4.28 (s, 1H), 3.46-3.70 (m, 4H), 3.32-3.46 (m, 5H), 2.54 (s, 1H), 1.47 (s, 9H). The second eluting isomer (<semantics>RT=5.7 min<annotation encoding="application / x-tex">RT = 5.7 \text{ min}< / annotation>< / semantics>) was collected and concentrated under vacuum to give benzyl (3R,4R)-3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1-carboxylate (Intermediate 48-3) as a white solid. MS (ESI, m / z): 387 [M+Na]+. 1H NMR (CDCl3, 300 MHz) <semantics>δ(ppm)<annotation encoding="application / x-tex">\delta(ppm)< / annotation>< / semantics>: 7.33-7.40 (m, 5H), 5.09-5.40 (m, 3H), 4.28 (s, 1H), 3.46-3.73 (m, 4H), 3.32-3.46 (m, 5H), 2.53-5.55 (m, 1H), 1.46 (s, 9H). Intermediate 49. tert-Butyl ((3S,4S)-4-(methoxy-d3)pyrrolidin-3-yl)carbamate [Image disponible dans le document PDF, Image available in the PDF document] Step 1. Benzyl (3S,4S)-3-azido-4-(methoxy-d3)pyrrolidine-1-carboxylate To a solution of benzyl (3S,4S)-3-azido-4-hydroxypyrrolidine-1-carboxylate (202.7 mg, 0.773 mmol) in anhydrous DMF (5 mL) was added NaH (60% dispersion in mineral oil, 37.1 mg, 0.927 mmol). The reaction was allowed to stir at room temperature for 1 h. Then, iodomethane-d3 (0.058 ml, 0.927 mmol) was added and the reaction was stirred at 22 °C for 6 h. The reaction was diluted with 5 mL of EtOAc and washed with 2 x 3mL of H2O. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated to afford crude benzyl (3S,4S)-3-azido-4- (methoxy-d3)pyrrolidine-1-carboxylate as a yellow oil. MS: (ESI, m / z): 280 [M+H]+. Step 2. Benzyl (3S,4S)-3-amino-4-(methoxy-d3)pyrrolidine-1-carboxylate A solution of benzyl (3S,4S)-3-azido-4-(methoxy-d3)pyrrolidine-1-carboxylate (215.8 mg, 0.773 mmol) and triphenylphosphine (223 mg, 0.850 mmol) in THF (1.405 mL) and water (0.14 mL) was stirred for 1 h at room temperature. The reaction was then heated at 50 °C for 5 h. After cooling to room temperature, the reaction was concentrated under vacuum. The residue was purified by prep-HPLC (Column: Waters XBridge Prep C18 OBD 5µm, 19x50 mm; Mobile Phase gradient 0% to 35% ACN, 0.1% formic acid over 8 min; Flow rate: 23 mL / min) to afford benzyl (3S,4S)- 3-amino-4-(methoxy-d3)pyrrolidine-1-carboxylate as a colorless oil. MS: (ESI, m / z): 254 [M+H]+. Step 3. Benzyl (3S,4S)-3-((tert-butoxycarbonyl)amino)-4-(methoxy-d3)pyrrolidine-1- carboxylate A solution of benzyl (3S,4S)-3-amino-4-(methoxy-d3)pyrrolidine-1-carboxylate (217 mg, 0.858) mmol), Et3N (225 μl, 1.61 mmol), and Boc2O (0.299 mL, 1.29 mmol) in THF (1.43 mL) and water (1.43 mL) was stirred for 30 min at room temperature. The resulting mixture was extracted with 2 x 30 mL of DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford benzyl (3S,4S)-3-((tert-butoxycarbonyl)amino)-4-(methoxy- d3)pyrrolidine-1-carboxylate as a colorless oil. MS: (ESI, m / z): 354 [M+H]+. Step 4. tert-Butyl ((3S,4S)-4-(methoxy-d3)pyrrolidin-3-yl)carbamate A mixture of benzyl 3-((tert-butoxycarbonyl)amino)-4-methoxypyrrolidine-1-carboxylate (200 mg, 0.57 mmol) and Pd / C (200 mg, 10%) in EtOAc (10 mL) was stirred for 3 h at room temperature under an atmosphere of hydrogen. The solids were filtered out and washed with 3 x 10 mL of EtOAc. The filtrate was concentrated under vacuum to afford tert-butyl N-(4-methoxypyrrolidin- 3-yl)carbamate as a colorless oil. MS: (ESI, m / z): 220 [M+H]+. 1H NMR (CDCl3, 300 MHz) δ(ppm): 8.04-8.26 (m, 1H), 4.41-4.86 (m, 1H), 3.93-4.22 (m, 1H), 3.09-3.92 (m, 3H), 1.46 (s, 9H). Intermediate 50. Benzyl N-(7-chloro-6,8-difluoro-3,4-dihydro-2H-1-benzopyran-3- yl)carbamate [Image disponible dans le document PDF, Image available in the PDF document] Step 1. 4-Chloro-3,5-difluoro-2-hydroxybenzaldehyde A solution of 3-chloro-2,4-difluorophenol (4.00 g, 23.6 mmol) and HMTA (6.60 g, 47.2 mmol) in TFA (60 mL) was stirred for 3h at 100 °C. After cooling to 0 °C, conc. H2SO4 (10 mL) and H2O (50 mL) were added into the mixture at 0 °C. The mixture was stirred for 2h at 20 °C and then diluted with H2O (40 mL). The pH value of the mixture was adjusted to 7-8 with dibutylamine. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1: 5 ethyl acetate / pet. ether) to afford 4-chloro-3,5-difluoro-2-hydroxybenzaldehyde as an off-white solid. GCMS (ESI, m / z): 192,194 [M+H]+. Step 2. 7-Chloro-6,8-difluoro-3-nitro-2H-chromene 2-Nitroethan-1-ol (3.72 mL, 51.9 mmol) was added to a stirring solution of 4-chloro-3,5-difluoro- 2-hydroxybenzaldehyde (1.50 g, 7.77 mmol), dibutylamine (0.659 mL, 3.89 mmol) and phthalic anhydride (2.20 g, 14.8 mmol) in toluene (80 mL) via an injection pump with the flowrate of 0.5 mL / h at 125 °C. The resulting solution was refluxed for 16h at 125 °C. After cooling to 20 °C, the resulting mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:10 ethyl acetate / pet. ether) to give 7-chloro-6,8-difluoro-3-nitro- 2H-chromene as a yellow solid. MS (ESI, m / z): 248, 250 [M+H]+. Step 3. 7-Chloro-8-fluoro-3,4-dihydro-2H-1-benzopyran-3-amine A mixture of 7-chloro-6,8-difluoro-3-nitro-2H-chromene (1.30 g, 5.25 mmol), BH3 (40 mL, 1M in THF), and NaBH4 (399 mg, 10.5 mmol) was stirred for 16h at 65 °C. MeOH (80 mL) was added into the mixture slowly at <10 °C. The resulting solution was stirred for 8h at 80 °C. After cooling to 20 °C, the resulting mixture was concentrated under vacuum. The residue was purified via reverse phase chromatography (Column: C18 silica gel; Mobile phase, A: water (10 mM NH4HCO3) and B: ACN (5% to 75% in 20 min)) to afford 7-chloro-8-fluoro-3,4-dihydro-2H-1- benzopyran-3-amine as an off-white solid. MS (ESI, m / z): 220, 222 [M+H]+. Step 4. Benzyl N-(7-chloro-6,8-difluoro-3,4-dihydro-2H-1-benzopyran-3-yl)carbamate CbzCl (0.500 mL, 3.55 mmol) was added to a mixture of 7-chloro-6,8-difluoro-3,4-dihydro-2H- 1-benzopyran-3-amine (650 mg, 2.96 mmol) and potassium carbonate (822 mg, 5.92 mmol) in ethyl acetate (20 mL) and water (20 mL) at <10 °C. The resulting solution was then stirred for 1h at 25 °C and diluted with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:5 ethyl acetate / pet. ether) to afford benzyl N-(7-chloro-6,8-difluoro-3,4-dihydro-2H-1- benzopyran-3-yl)carbamate as an off-white solid. MS (ESI, m / z): 354, 356 [M+H]+. Intermediate 51-1. tert-Butyl N-[(3R,4S)-4-(difluoromethyl)pyrrolidin-3-yl]carbamate Intermediate 51-2. tert-Butyl N-[(3S,4R)-4-(difluoromethyl)pyrrolidin-3-yl]carbamate [Image disponible dans le document PDF, Image available in the PDF document] Step 1. Ethyl 4,4-difluoro-3-hydroxybutanoate NaBH4 (34.2 g, 902 mmol) was added into a stirring solution of ethyl 4,4-difluoro-3-oxobutanoate (100 g, 602 mmol) in toluene (1 L) at 0 °C. The resulting mixture was stirred for 2h at 0 °C, and then warmed up to 25 °C and stirred for 16h. The reaction was quenched with water (400 mL). The resulting mixture was extracted with ethyl acetate (2 x 1 L). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford ethyl 4,4-difluoro-3-hydroxybutanoate as a light yellow oil. GCMS (ESI, m / z): 168 [M+H]+. Step 2. Ethyl (2E)-4,4-difluorobut-2-enoate To a solution of ethyl 4,4-difluoro-3-hydroxybutanoate (40.0 g, 238 mmol) and Et3N (99.0 mL, 712 mmol) in DCM (300 mL) was added MsCl (28.0 mL, 244 mmol) dropwise at 0 °C. The resulting mixture was warmed to 25 °C and stirred for 16h. The reaction was quenched with water (500 mL). The resulting mixture was extracted with DCM (2 x 500 mL). The organic layers were combined, washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:10 ethyl acetate / pet. ether) to afford ethyl (2E)-4,4-difluorobut-2-enoate as a yellow green oil. GCMS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 150 [M+H]+. Step 3. trans-Ethyl 1-benzyl-4-(difluoromethyl)pyrrolidine-3-carboxylate To a stirring solution of ethyl (2E)-4,4-difluorobut-2-enoate (12.0 g, 79.9 mmol) and benzyl(methoxymethyl)[(trimethylsilyl)methyl]amine (30.7 mL, 120 mmol) in DCM (250 mL) was added a solution of TFA (0.59 mL, 5.21 mmol) in DCM(20 mL) dropwise over 2 min at 0 °C. The resulting mixture was warm to 25 °C and was stirred for 14h. The reaction was quenched by the addition of water (500 mL). The resulting mixture was extracted with DCM (2 x 300 mL). The organic layers were combined, washed with sodium bicarbonate solution (sat., 300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:10 to 1:5 ethyl acetate / pet. ether). The collected fraction was concentrated under vacuum to afford trans-ethyl 1-benzyl-4-(difluoromethyl)pyrrolidine-3- carboxylate as a yellow oil. MS (ESI, m / z): 284 [M+H]+. Step 4. trans-Ethyl 4-(difluoromethyl)pyrrolidine-3-carboxylate A mixture of trans-ethyl-1-benzyl-4-(difluoromethyl)pyrrolidine-3-carboxylate (5.50 g, 19.4) mmol) and Pd(OH)2 / C (2.00 g, 10%) in MeOH (30 mL) was stirred for 2h at 25 °C under hydrogen atmosphere (balloon). The solids were filtered out and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure to afford trans-ethyl 4- (difluoromethyl)pyrrolidine-3-carboxylate as a white solid. MS (ESI, m / z): 194 [M+H]+. Step 5. trans-Benzyl 3-(difluoromethyl)-4-[ethoxy(hydroxy)methyl]pyrrolidine-1- carboxylate CbzCl (4.05 g, 23.741 mmol) was added into a stirring solution of trans-ethyl 4- (difluoromethyl)pyrrolidine-3-carboxylate (3.90 g, 19.8 mmol) and K2CO3 (8.20 g, 59.3 mmol) in H2O (20 mL) and ethyl acetate (40 mL) at 0 °C. The resulting mixture was stirred for 1 h at 25 °C. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with DCM (2 x 200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reverse phase chromatography (column, C18 silica gel; Mobile phase, A: water (containing 0.1% TFA) and B: ACN (0% to 60% in 30 min)) to afford trans-benzyl 3-(difluoromethyl)-4- [ethoxy(hydroxy)methyl]pyrrolidine-1-carboxylate as a yellow oil. MS (ESI, m / z): 328 [M+H]+. Step 6. trans-1-[(Benzyloxy)carbonyl]-4-(difluoromethyl)pyrrolidine-3-carboxylic acid To a stirring solution of trans-benzyl 3-(difluoromethyl)-4-[ethoxy(hydroxy)methyl]pyrrolidine- 1-carboxylate (6.00 g, 18.0 mmol) in THF (80 mL) and MeOH (20 mL) was added a solution of LiOH (4.30 g, 180 mmol) in water (10 mL). The resulting mixture was stirred for 1 h at 25 °C. The solvent was removed under vacuum. pH value of the residue was adjusted to 5-6 with NH4Cl (sat. aq.). The resulting mixture was extracted with DCM (3 x 50 mL). The organic layers were combined, washed with sodium bicarbonate solution (sat., 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reverse phase chromatography (column: C18 silica gel; Mobile phase, A: water (containing 0.1% TFA) and B: ACN <semantics>(0%)<annotation encoding="application / x-tex">(0\%)< / annotation>< / semantics> to 60% in 30 min)) to afford trans-1-[(benzyloxy)carbonyl]-4- (difluoromethyl)pyrrolidine-3-carboxylic acid as a colorless oil. MS (ESI, m / z): 300 [M+H]+. Step 7. trans-Benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(difluoromethyl)pyrrolidine-1- carboxylate To a stirring solution of...

Claims

<pat:Claims com:id="claims"> <pat:Claim com:id="CLM-00001"> <pat:ClaimNumber>1< / pat:ClaimNumber> <pat:ClaimText>1. A compound of Formula (VI) [Image disponible dans le document PDF, Image available in the PDF document] (VI), or a pharmaceutically acceptable salt thereof, wherein: X is chosen from C(R)(R") and O; each of Y1, Y2, and Y3 is independently chosen from C(R3) and N; R' is chosen from H, deuterium, and CH3; each of R and R" is independently chosen from H, halogens, -OH, -CN, C1-C6 alkyl optionally substituted with one or more Ri, R and R'' together with the carbon they are attached form a spirocyclic cyclopropyl optionally substituted with one or more Ri, wherein any R, R", or Ri group being or containing hydrogen can independently have one or more hydrogen replaced with deuterium; each Ri is independently chosen from halogen, -OH, and CH3; R1 is chosen from 6-12 membered fused and nonfused heteroaryls optionally substituted with one or more substituent chosen from R5 and / or R6, and further wherein any R1 group containing hydrogen can have one or more hydrogen replaced with deuterium; R2 is chosen from N-linked 4-12 membered heterocyclyls, C-linked 4-12 membered heterocyclyls, and an -O- linked 4-12 membered heterocyclyl, wherein the 4-12 membered heterocyclyls are optionally substituted with one or more R5, which can be the same or different from the one or more R5 of R1, and further wherein any hydrogen in a R2 group can have one or more hydrogen replaced with deuterium; each R3 is independently chosen from H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, -OH, -CN, (C3-C8) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups, wherein each of (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or more R7; <semantics>R4<annotation encoding="application / x-tex">R_4< / annotation>< / semantics> is chosen from H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, -OH, -CN, (C3-C8) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups, wherein each of (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C3-C8) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R5, and further wherein any R4 group containing hydrogen can have one or more hydrogen replaced with deuterium; each R5 is independently chosen from -OH, -NH2, amido-(C1-C6) alkyl, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl groups, wherein each of <semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>, amido-<semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkoxy, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C1-C6) alkyl, (C₁-C6) alkoxy, -NH2, and -OH, and wherein any R5 group containing hydrogen can have one or more hydrogen replaced with deuterium; each R6 is independently chosen from -amino alkyl-aryls, -amino alkyl- heteroaryls, -amino alkyl-cyclyl, and -amino alkyl-heterocyclyl groups, wherein each of the R6 groups are optionally substituted with one or more substituent chosen from -OH, -NH2, halogens, (C1-C6) alkyl, (C1-C6) alkoxy, and (C1-C6) haloalkyl groups, and further wherein any R6 group containing hydrogen can have one or more hydrogen replaced with deuterium; each R7 is independently chosen from -OH, -NH2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, -C(O)-cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl groups, wherein each of –NH2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, -C(O)-cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C1-C6) alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, and <semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>; and n is 0, 1, 2, or 3. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00002"> <pat:ClaimNumber>2< / pat:ClaimNumber> <pat:ClaimText>2. The compound of claim 1, of Formula (II): [Image disponible dans le document PDF, Image available in the PDF document] (II), or a pharmaceutically acceptable salt thereof, wherein each of X, R1, R2, R3, R7 and n are as defined in Formula (VI); R4 is chosen from H, (C1-C6) alkyl, halogen, and -OH; each R5 is independently chosen from –OH, –NH2, -NHC(O)CH3, <semantics>−C(O)NHCH3<annotation encoding="application / x-tex">-C(O)NHCH_3< / annotation>< / semantics>, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl groups, wherein each of <semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>, <semantics>−NHC(O)CH3<annotation encoding="application / x-tex">-NHC(O)CH_3< / annotation>< / semantics>, <semantics>−C(O)NHCH3<annotation encoding="application / x-tex">-C(O)NHCH_3< / annotation>< / semantics>, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, (C1-C6) haloalkoxy, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl are optionally substituted with one or more substituent independently chosen from <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>, and <semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>; and each R6 is independently chosen from -NH(C1-C6)alkyl-aryls, -NH(C1-C6)alkyl- heteroaryls, -NH(C1-C6)alkyl-cyclyl, and -NH(C1-C6)alkyl-heterocyclyl groups, wherein each of the R6 groups are optionally substituted with one or more substituent chosen from -OH, -NH2, halogens, (C1-C6) alkyl, (C1-C6) alkoxy, and (C1-C6) haloalkyl groups. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00003"> <pat:ClaimNumber>3< / pat:ClaimNumber> <pat:ClaimText>3. The compound of claim 1, of Formula (Ilaa): [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt thereof, wherein R1 is chosen from 8-9-membered heteroaryls substituted with one or more substituent chosen from R5 and R6, wherein each R5 and R6 are independently as defined in Formula (II); R2 is chosen from N-linked 6-12 membered heterocyclyls or C-linked 6-12 membered heterocyclyls optionally substituted with one or more R5, wherein each R5 is independently chosen from -OH, -NH2, -NHC(O)CH3, -C(O)NHCH3, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl groups, wherein each of <semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>, <semantics>−NHC(O)CH3<annotation encoding="application / x-tex">-NHC(O)CH_3< / annotation>< / semantics>, <semantics>−C(O)NHCH3<annotation encoding="application / x-tex">-C(O)NHCH_3< / annotation>< / semantics>, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, (C1-C6) haloalkoxy, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl are optionally substituted with one or more substituent independently chosen from <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>, and <semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>; and R3 is independently chosen from H, (C1-C6) alkyl, halogen, and –CN, wherein the (C1-C6) alkyl groups are optionally substituted with R7 wherein each R7 is independently as defined in Formula (VI). < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00004"> <pat:ClaimNumber>4< / pat:ClaimNumber> <pat:ClaimText>4. The compound of claim 1, of Formula (IIb'): [Image disponible dans le document PDF, Image available in the PDF document] (IIb') or a pharmaceutically acceptable salt thereof, wherein R' is chosen from H and CH3; R1 is chosen from 8-9 membered heteroaryls substituted with one or more substituent chosen from R5 and R6, wherein each R5 and / or R6 (if present) are independently as defined in Formula (VI); R2 is chosen from N-linked 6-12 membered heterocyclyls or C-linked 6-12 membered heterocyclyls optionally substituted with one or more R5, wherein each R5 is independently as defined in Formula (VI); and R3 is independently chosen from H, (C1-C6) alkyl, halogen, and –CN, wherein the (C1-C6) alkyl groups are optionally substituted with R7 wherein each R7 is independently as defined in Formula (VI). < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00005"> <pat:ClaimNumber>5< / pat:ClaimNumber> <pat:ClaimText>5. The compound of any one of claims 1-4, wherein R1, optionally substituted with R₅ and / or R₆, is chosen from [Image disponible dans le document PDF, Image available in the PDF document] <semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics> ΗÓ N. > 2 0 HŅ H <semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics> * NS * ( ) N S , > NH2 F. `` _* 2 2 Oşy S. S <semantics>H2N<annotation encoding="application / x-tex">H_2N< / annotation>< / semantics> > , Ś `S <semantics>H2N<annotation encoding="application / x-tex">H_2N< / annotation>< / semantics> N * 2 7 ,H, N N> > HN N. <semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics> N. 7 7 ÇI H .N N- , * , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 3 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] _Br , and [Image disponible dans le document PDF, Image available in the PDF document] < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00006"> <pat:ClaimNumber>6< / pat:ClaimNumber> <pat:ClaimText>6. The compound of any one of claims 1-4, wherein R2, optionally substituted with R5, is chosen from [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] HN N-* , [Image disponible dans le document PDF, Image available in the PDF document] HN N.*, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics> [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] _N.* FFF > [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] HN * [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] HN N.*, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] • [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] . [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] t 7 > [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] and 2 < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00007"> <pat:ClaimNumber>7< / pat:ClaimNumber> <pat:ClaimText>7. The compound of any one of claims 1-4, wherein R1, optionally substituted with R5 and / or R6, is chosen from [Image disponible dans le document PDF, Image available in the PDF document] R2, optionally substituted with R5, is chosen from [Image disponible dans le document PDF, Image available in the PDF document] < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00008"> <pat:ClaimNumber>8< / pat:ClaimNumber> <pat:ClaimText>8. The compound of any one of claims 1-4, wherein R1, optionally substituted with R5 and / or R6, is chosen from [Image disponible dans le document PDF, Image available in the PDF document] R2, optionally substituted with R5, is chosen from [Image disponible dans le document PDF, Image available in the PDF document] HN- HN' NH < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00009"> <pat:ClaimNumber>9< / pat:ClaimNumber> <pat:ClaimText>9. The compound of claim 1, of Formula (VII): [Image disponible dans le document PDF, Image available in the PDF document] (VII), or a pharmaceutically acceptable salt thereof, wherein Y is chosen from C(R3) and N; R' is chosen from H, deuterium, and CH3; R1 is chosen from 6-11 membered heteroaryls optionally substituted with one or more substituent chosen from R5 and / or R6; R2 is chosen from N-linked 4-12 membered heterocyclyls and C-linked 4-12 membered heterocyclyls, wherein the heterocyclyls are optionally substituted with one or more R5, and further wherein any R2 group containing hydrogen can have one or more hydrogen replaced with deuterium; each R3 is independently chosen from H, deuterium, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, -OH, -CN, wherein each of (C1-C6) alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or more R7; R4 is chosen from H, (C1-C6) alkyl, halogen, -OH, -CN, and further wherein any R4 group containing hydrogen can have one or more hydrogen replaced with deuterium; each R5, if present, is independently chosen from -OH, -NH2, NHC(O)CH3, <semantics>−C(O)NHCH3<annotation encoding="application / x-tex">-C(O)NHCH_3< / annotation>< / semantics>, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl groups, wherein each of <semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>, <semantics>−NHC(O)CH3<annotation encoding="application / x-tex">-NHC(O)CH_3< / annotation>< / semantics>, <semantics>−C(O)NHCH3<annotation encoding="application / x-tex">-C(O)NHCH_3< / annotation>< / semantics>, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, (C1-C6) haloalkoxy, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C1-C6) alkoxy, -NH2, and -OH, and wherein any R5 group containing hydrogen can have one or more hydrogen replaced with deuterium; each R6, if present, is chosen from -NH(C1-C6)alkyl-aryls, -NH(C1-C6)alkyl-heteroaryls, -NH(C₁-C₆)alkyl-heterocyclyl groups, and -NH(C₁-C₆)alkyl-heterocyclyl groups, wherein each of the R6 groups are optionally substituted with one or more substituent chosen from -OH, -NH₂, halogens, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, and (C₁-C₆) haloalkyl groups, and further wherein any R6 group containing hydrogen can have one or more hydrogen replaced with deuterium; each R7 is independently chosen from -OH, -NH2, (C1-C6) alkyl, (C1-C6) alkoxy, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> haloalkoxy, halogen, cycloalkyl, <semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>-cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl groups, wherein each of –NH2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, -C(O)-cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C1-C6) alkyl, <semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics> alkoxy, and <semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>; and n is 0, 1, 2, or 3. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00010"> <pat:ClaimNumber>10< / pat:ClaimNumber> <pat:ClaimText>10. The compound of claim 9, of Formula (Illaa): [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt thereof, wherein R1 is chosen from 8-11 membered heteroaryls optionally substituted with one or more R5; R2 is chosen from N-linked 4-12 membered heterocyclyls and C-linked 4-12 membered heterocyclyls, optionally substituted with one or more R5; each R5, if present, is independently chosen from -OH, -NH2, NHC(O)CH3, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl groups, wherein each of –NH2, -NHC(O)CH3, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C1-C6) alkoxy, -NH2, and -OH; and n is 0, 1, 2, or 3. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00011"> <pat:ClaimNumber>11< / pat:ClaimNumber> <pat:ClaimText>11. The compound of claim 9, of Formula (VIIaa): [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt thereof, wherein R1 is chosen from 8-9 membered heteroaryls optionally substituted with one or more R5; R2 is chosen from N-linked 4-12 membered heterocyclyls optionally substituted with one or more R5; each R5, if present, is independently chosen from -OH, -NH2, NHC(O)CH3, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl groups, wherein each of -NH2, -NHC(O)CH3, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C1-C6) alkoxy, -NH2, and -OH; and n is 0, 1, 2, or 3. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00012"> <pat:ClaimNumber>12< / pat:ClaimNumber> <pat:ClaimText>12. The compound of any one of claims 10 or 11, wherein R₁ is chosen from [Image disponible dans le document PDF, Image available in the PDF document] wherein B is chosen from a bond or C; Z is chosen from N, S, C(Rii); Rii is chosen from H, CH3 and R5; R2 is chosen from N-linked 5-8 membered heterocyclyls substituted with one to three R5; each R5, if present, is independently chosen from -OH, -NH2, NHC(O)CH3, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl groups, wherein each of -NH2, -NHC(O)CH3, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, cycloalkyl, heterocycloalkyl, and -C(O)-heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C1-C6) alkoxy, -NH2, and -OH; and n is 0, 1, 2, or 3. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00013"> <pat:ClaimNumber>13< / pat:ClaimNumber> <pat:ClaimText>13. The compound of any one of claims 9-11, wherein R1, optionally substituted with R5, is chosen from [Image disponible dans le document PDF, Image available in the PDF document] and R2, optionally substituted with R5, is chosen from [Image disponible dans le document PDF, Image available in the PDF document] < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00014"> <pat:ClaimNumber>14< / pat:ClaimNumber> <pat:ClaimText>14. The compound claim 1, chosen from any of the following compounds [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] > > [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 1 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] ¹, *, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , > [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] > , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , 1 > [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] > ŀ [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] . · [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] > , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 2 > 7 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] ! , ı [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , • • 9 1 , , #W 9 , M Har , , [Image disponible dans le document PDF, Image available in the PDF document] The state of the state of the state of the state of the state of the state of the state of the state of the state of the state of the state of the state of the state of the state of the state of the state of the state of t The state of 9 , ''MH 9 , HW, , , 9 , 16 網剛 TOWN. , , MH H , , , 9 ř H , , H , , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 9 9 > , > 2 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] > > > > > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > ” # * > > AND DE > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > H ing. N.Hanis is ' > > Name of Street, 44 Man > 2 *** 7 7 [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > was in Aller * 制掘線 > > 10000 Many 1 * History (St.) H n 📮 m ne i > > H. NW I p xo M C a i 💭 7 7 [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > > , (Manager) (HASOGRAPH) > > No. > > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] ( , > > > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 7 [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] 2 > > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > MH > , N > 2 H > , [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 7 7 [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 H, N ○NH H2N O <semantics>∩<annotation encoding="application / x-tex">\cap< / annotation>< / semantics> H F > > HM 0 O H.M 2 > 圖 H 102 7 7 [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] 7 7 [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] > > [Image disponible dans le document PDF, Image available in the PDF document] > 7 7 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] > > > > 7 > [Image disponible dans le document PDF, Image available in the PDF document] > 2 7 > [Image disponible dans le document PDF, Image available in the PDF document] < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00015"> <pat:ClaimNumber>15< / pat:ClaimNumber> <pat:ClaimText>15. The compound of claim 1, which is: 10-1: (R)-3-amino-N-(5-fluoro-7-(piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide; 10-5: (S)-3-amino-N-(5-fluoro-7-(piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide; 10-15: 3-amino-N-[(3R)-5-fluoro-7-(piperazin-1-yl)-3,4-dihydro-2H-1- benzopyran-3-yl]-N,6-dimethylthieno[2,3-b]pyridine-2-carboxamide; 10-16: 3-amino-N-[(3S)-5-fluoro-7-(piperazin-1-yl)-3,4-dihydro-2H-1- benzopyran-3-yl]-N,6-dimethylthieno[2,3-b]pyridine-2-carboxamide; 11-1: N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide; 11-2: N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide; 23-1: 7-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide; 23-2: 7-amino-N-[(6R)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide; 23-3: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide; 23-4: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 23-5: 3-amino-N-[(6R)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 23-6: 7-amino-3-methyl-N-[(6S)-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin- 6-yl]thieno[2,3-b]pyrazine-6-carboxamide; 23-7: 3-amino-6-methyl-N-[(6S)-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin- 6-yl]thieno[2,3-b]pyridine-2-carboxamide; 23-8: 3-amino-6-methyl-N-[(6R)-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin- 6-yl]thieno[2,3-b]pyridine-2-carboxamide; 23-9: 6-amino-2-methyl-N-[(6S)-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin- 6-yl]thieno[2,3-d][1,3]thiazole-5-carboxamide; 23-12: 3-amino-N-[(6S)-2-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 23-13: 7-amino-N-[(6S)-2-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5,6,7,8- tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide; 23-14: 3-amino-4,6-dimethyl-N-[(6S)-2-(piperazin-1-yl)-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3-b]pyridine-2-carboxamide; 23-17: 3-amino-N-[(6S)-4-fluoro-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin- 6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 23-18: 3-amino-N-[(6S)-2-{3,8-diazabicyclo[3.2.1]octan-3-yl}-4-fluoro-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 24-1: 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 24-2: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 25: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 26-1: 3-amino-N-[(6S)-2-[(3S,4R)-3-(methoxymethyl)-4- (methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide; 26-2: 3-amino-N-[(6S)-2-[(3R,4S)-3-(methoxymethyl)-4- (methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide; 27-1: 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 27-2: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 28-1: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(2-methoxyethoxy)pyrrolidin-1- yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 28-2: 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(2-methoxyethoxy)pyrrolidin-1- yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 29-1: 3-amino-N-[(6S)-2-[(9S)-9-amino-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 29-2: 3-amino-N-[(6S)-2-[(9R)-9-amino-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 30-1: 3-amino-N-[(6S)-3-fluoro-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6- yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 30-2: 3-amino-N-[(6R)-3-fluoro-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6- yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 31-3: 3-amino-6-methyl-N-[(6'S)-2'-(piperazin-1-yl)-6',7'-dihydro-5'H- spiro[cyclopropane-1,8'-quinoline]-6'-yl]thieno[2,3-b]pyridine-2-carboxamide; 31-4: 3-amino-6-methyl-N-[(6'R)-2'-(piperazin-1-yl)-6',7'-dihydro-5'H- spiro[cyclopropane-1,8'-quinoline]-6'-yl]thieno[2,3-b]pyridine-2-carboxamide; 142: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-ethoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 203: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-5-fluoro-6-methylthieno[2,3-b]pyridine-2-carboxamide; 204: 3-amino-5-fluoro-6-methyl-N-[(6S)-2-(piperazin-1-yl)-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3-b]pyridine-2-carboxamide; 205: 3-amino-6-methyl-N-[(6S,8S)-8-methyl-2-(piperazin-1-yl)-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3-b]pyridine-2-carboxamide; 206: 3-amino-6-methyl-N-[(6R,8S)-8-methyl-2-(piperazin-1-yl)-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3-b]pyridine-2-carboxamide; 207: 3-amino-6-methyl-N-[(6S,8R)-8-methyl-2-(piperazin-1-yl)-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3-b]pyridine-2-carboxamide; 208: 3-amino-6-methyl-N-[(6R,8R)-8-methyl-2-(piperazin-1-yl)-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3-b]pyridine-2-carboxamide; 210: 3-amino-N-[(6S)-2-[(3S,4S)-4-amino-3-methoxy-3-methylpyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 211: 3-amino-N-[(6S)-2-[(3R,4R)-4-amino-3-methoxy-3-methylpyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 239: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxy-3-methylpyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 240: 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-methoxy-3-methylpyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 254: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-ethoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 255: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-ethoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 269: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 270: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 279: 7-amino-N-[(6S)-2-[(3S,4S)-4-amino-3-methoxy-3-methylpyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide; 280: 7-amino-N-[(6S)-2-[(3R,4R)-4-amino-3-methoxy-3-methylpyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide; 285: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-cyclobutoxypyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 296: 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 297: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 298: 7-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide; 299: 7-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide; 300: 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-3- fluoro-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 301: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-3- fluoro-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 302: 3-amino-N-[(6R)-2-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-3- fluoro-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 303: 3-amino-N-[(6R)-2-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-3- fluoro-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 311: 3-amino-N-[(6S)-2-[(3S,4S)-3-methoxy-4-(methylamino)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 312: 3-amino-N-[(6S)-2-[(3S,4S)-3-methoxy-4-(methylamino)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 320: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(propan-2-yloxy)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 321: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-(propan-2-yloxy)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 322: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-(propan-2-yloxy)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 327: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 328: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 331: 3-amino-N-[(6S)-2-[(3R,4S)-3-hydroxy-3-methyl-4- (methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide; 332: 3-amino-N-[(6S)-2-[(3S,4R)-3-hydroxy-3-methyl-4- (methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide; 341: 3-amino-N-[(6S)-2-[(3S,4R)-4-amino-3-(methoxymethyl)-3- methylpyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide; 342: 3-amino-N-[(6S)-2-[(3R,4R)-4-amino-3-(methoxymethyl)-3- methylpyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide; 343: 3-amino-N-[(6S)-2-[(3S,4S)-4-amino-3-(methoxymethyl)-3- methylpyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide; 344: 3-amino-N-[(6S)-2-[(3R,4S)-4-amino-3-(methoxymethyl)-3- methylpyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide; 345: 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 346: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 347: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 354: 3-amino-N-[(6S)-2-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5,6,7,8- tetrahydroquinolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide; 363: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-(trifluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 364: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-(trifluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 376: 3-amino-N-[(6S)-2-[(3S,4R)-3-(difluoromethyl)-4-(methylamino)pyrrolidin- 1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 377: 3-amino-N-[(6S)-2-[(3R,4S)-3-(difluoromethyl)-4-(methylamino)pyrrolidin- 1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 384: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 385: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 427: 3-amino-N-[(6S)-2-[(3R,4S)-4-amino-3-methoxy-3-methylpyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 428: 3-amino-N-[(6S)-2-[(3S,4R)-4-amino-3-methoxy-3-methylpyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 430: 3-amino-N-[(6S)-2-[(5S,9R)-9-amino-2-oxa-7-azaspiro[4.4]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 431: 3-amino-N-[(6S)-2-[(5R,9S)-9-amino-2-oxa-7-azaspiro[4.4]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 437: 3-amino-N-[(6S)-2-[(5R,9R)-9-amino-2-oxa-7-azaspiro[4.4]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 441: 3-amino-N-[(6S)-2-[(3R,4R)-3-(fluoromethyl)-4-(methylamino)pyrrolidin-1- yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; or 442: 3-amino-N-[(6S)-2-[(3S,4S)-3-(fluoromethyl)-4-(methylamino)pyrrolidin-1- yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide. < / pat:ClaimText> < / pat:Claim> < / pat:Claims>