Substituted Spiro Derivatives

Abstract

The present invention relates to medicaments useful for the treatment and / or prevention in mammals, pharmaceutical compositions comprising such compounds, and their use as menin / MLL protein / protein interaction inhibitors useful in the treatment of diseases such as cancer, myelodysplastic syndromes (MDS) and diabetes.

Description

[Technical field]

[0001] The present invention relates to medicaments useful for the treatment and / or prevention in mammals, pharmaceutical compositions comprising such compounds, and their use as menin / MLL protein / protein interaction inhibitors useful in the treatment of diseases such as cancer, myelodysplastic syndromes (MDS) and diabetes. [Background technology]

[0002] Chromosomal rearrangements affecting the mixed lineage leukemia gene MLL; MLL1 KMT2A) result in aggressive acute leukemia across all age groups that remains largely incurable, highlighting the urgent need for novel therapeutic approaches. Acute leukemias with these chromosomal translocations of MLL represent lymphoid, myeloid or biphenotypic diseases and constitute 5-10% of acute leukemias in adults and approximately 70% of acute leukemias in infants (Marschalek, Br J Haematol 2011.152(2),141-54; Tomizawa et al., Pediatr Blood Cancer 2007.49(2),127-32).

[0003] MLL is a histone methyltransferase that methylates histone H3 on lysine 4 (H3K4) and functions in a multiprotein complex. The use of an inducible loss-of-function allele of Mll1 demonstrated that Mll1 plays an essential role in hematopoietic stem cell (HSC) maintenance and B cell development, but its histone methyltransferase activity is dispensable for hematopoiesis (Mishra et al., Cell Rep 2014.7(4),1239-47).

[0004] Fusions of MLL with over 60 different partners have been reported to date and are associated with leukemia formation / progression (Meyer et al., Leukemia 2013.27,2165-2176). Interestingly, the SET (Su(var)3-9, enhancer of zeste, and trithorax) domain of MLL is not retained in the chimeric protein but is replaced by the fusion partner (Thiel et al., Bioessays 2012.34,771-80). Recruitment of chromatin modifying enzymes such as Dot1L and / or pTEFb complex by the fusion partner results in enhanced transcription and transcriptional elongation of MLL target genes, including most notably HOXA genes (e.g., HOXA9) and the HOX cofactor MEIS1. Aberrant expression of these genes blocks hematopoietic differentiation and enhances proliferation.

[0005] Menin, encoded by the multiple endocrine neoplasia type 1 (MEN 1) gene, is ubiquitously expressed and mainly localized in the nucleus. It has been shown to interact with numerous proteins and is therefore involved in a variety of cellular processes. The best understood function of menin is its role as an oncogenic cofactor of MLL fusion proteins. Menin interacts with two motifs, MBM1 (menin binding motif 1) and MBM2, within the N-terminal fragment of MLL that is retained in all fusion proteins (Thiel et al., Bioessays 2012.34,771-80). Menin / MLL interaction results in the formation of a new interaction surface for lens epithelium-derived growth factor (LEDGF). While MLL directly binds to LEDGF, menin is essential for stable interaction between MLL and LEDGF and gene-specific chromatin recruitment of the MLL complex via the PWWP domain of LEDGF (Cermakova et al., Cancer Res 2014.15,5139-51; Yokoyama & Cleary, Cancer Cell 2008.8,36-46). Furthermore, many genetic studies have shown that menin is strictly required for oncogenic transformation by MLL fusion proteins, suggesting the menin / MLL interaction as an attractive therapeutic target. For example, conditional deletion of Men1 prevents leukocyte formation in bone marrow progenitor cells ectopically expressing MLL fusions (Chen et al., Proc Natl Acad Sci 2006.103,1018-23). Similarly, genetic disruption of the menin / MLL fusion interaction by loss-of-function mutations abrogates the oncogenic properties of MLL fusion proteins, prevents leukemia development in vivo, and releases a differentiation block in MLL-transformed leukemic blasts. These studies also showed that menin is required for the maintenance of HOX gene expression by MLL fusion proteins (Yokoyama et al., Cell 2005.123,207-18).Furthermore, small molecule inhibitors of the menin / MLL interaction have been developed, suggesting the druggability of this protein / protein interaction, and have also demonstrated efficacy in preclinical models of AML (Borkin et al., Cancer Cell 2015.27,589-602; Cierpicki and Grembecka, Future Med Chem 2014.6,447-462). Combined with the observation that menin is not an essential cofactor of MLL 1 during normal hematopoiesis (Li et al., Blood 2013.122,2039-2046), these data validate disruption of the menin / MLL interaction as a promising new therapeutic approach for the treatment of MLL-rearranged leukemias and other cancers with an active HOX / MEIS1 gene signature. For example, internal partial tandem duplications (PTDs) within the 5' region of the MLL gene represent another major abnormality found primarily in de novo and secondary AML as well as myelodysplastic syndromes. Although the molecular mechanism and biological function of MLL-PTD are not fully understood, new therapeutic targeting strategies that affect menin / MLL interaction may also prove effective in treating MLL-PTD-associated leukemia. Furthermore, castration-resistant prostate cancer has been shown to be dependent on menin / MLL interaction (Malik et al., Nat Med 2015.21,344-52).

[0006] The MLL protein is also known in the scientific community as the histone-lysine N-methyltransferase 2A (KMT2A) protein (UniProt accession number Q03164).

[0007] Several references describe inhibitors targeting the menin-MLL interaction: WO 2011029054, J Med Chem 2016, 59, 892-913 describes the preparation of thienopyrimidine and benzodiazepine derivatives, WO 2014164543 describes thienopyrimidine and thienopyridine derivatives, Nature Chemical Biology March 2012, 8, 277-284 and Ren, J.; et al. Bioorg Med Chem Lett (2016), 26(18), 4472-4476 describe thienopyrimidine derivatives, J Med Chem 2014, 57, 1543-1556 describes hydroxy and aminomethylpiperidine derivatives, Future Med Chem 2014,6,447-462 reviews small molecule and peptidomimetic compounds, and WO 2016195776 describes furo[2,3-d]pyrimidine, 9H-purine, [1,3]oxazolo[5,4-d]pyrimidine, [1,3]oxazolo[4,5-d]pyrimidine, [1,3]thiazolo[5,4-d]pyrimidine, thieno[2,3-b]pyridine and thieno[2,3-d]pyrimidine derivatives. WO2016197027 describes 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, 5,6,7,8-tetrahydropyrido]4,3-d]pyrimidine, pyrido[2,3-d]pyrimidine and quinoline derivatives, and WO2016040330 describes thienopyrimidine and thienopyridine compounds. WO2017192543 describes piperidines as menin inhibitors. WO2017112768, WO2017207387, WO2017214367, WO2018053267 and WO2018024602 describe inhibitors of menin-MLL interaction. WO2017161002 and WO2017161028 describe inhibitors of menin-MLL.WO2018050686, WO2018050684 and WO2018109088 describe inhibitors of menin-MLL interaction. WO2018226976 describes methods and compositions for inhibiting the interaction of menin with MLL proteins. WO2019060365 describes substitution inhibitors of menin-MLL. Krivtsov et al., Cancer Cell 2019.No.6 Vol.36,660-673 describes menin-MLL inhibitors.

[0008] WO2020069027 discloses inhibitors of menin. WO2018175746 discloses methods for treating hematological malignancies and Ewing's sarcoma. WO2020045334 discloses azabicyclo derivatives for use in pharmaceutical compositions. WO2019120209 discloses substituted heterocyclic compounds as menin / MLL protein / protein interaction inhibitors. CN111297863 discloses the use of menin mixed lineage leukemia (MLL) inhibitors. WO2021121327 describes substituted linear spiro derivatives and their use as menin / MLL protein / protein interaction inhibitors. Summary of the Invention [Means for solving the problem]

[0009] The present invention relates to a compound represented by formula (I)

[0010] [ka] The present invention relates to novel compounds of the formula: R 1a is -C(=O)-NR xa R xb represents; or

[0011] [ka] represents; R xa and R xb is hydrogen; C 3~6 Cycloalkyl;C 1~4 Alkyl; C substituted with 1, 2 or 3 halo atoms 1~4 Alkyl; and one -OH, -OC 1~4 Alkyl or NR 11c R 11d C replaced with 1~4 each independently selected from the group consisting of alkyl; R 1b represents F or Cl; Y 1 -CR 5a R 5b -, -O-, -S-, or -NR 5c - stands for; R 2 is hydrogen, halo, C 1~4 Alkyl, -OC 1~4 Alkyl, and -NR 7a R 7b selected from the group consisting of; U 1 and U 2 each independently represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 stands for CH, and X 2 represents N; R 4 is C 1~5 Alkyl;

[0012] [ka] represents; R 5a , R 5b , R 5c , R 7a , and R 7b is hydrogen, C 1~4 Alkyl and C 3~6 cycloalkyl; R 3 Het1 , Het 2 , Cy 2 and -C 1~6 Alkyl-NR xc R xd selected from the group consisting of; R xc Cy 1 ;Het 5 ;-C 1~6 Alkyl-Cy 1 ;-C 1~6 Alkyl-Het 3 ;-C 1~6 Alkyl-Het 4 ; or -C 1~6 represents alkyl-phenyl; R xd is hydrogen; C 1~4 Alkyl; or halo, -OH, -OC 1~4 C substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and cyano 1~4 represents alkyl; Or R xc and R xd taken together with the N atom to which they are attached form a 4-7 membered monocyclic fully saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S and N, where the S atom may be substituted to form S(=O) or S(=O)2; the heterocyclyl may be selected from halo, -OH, -OC 1~4 optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and cyano; Het 1represents a monocyclic C-bonded 4-7 membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, which S atom may be substituted to form S(=O) or S(=O)2; or a bicyclic C-bonded 6-11 membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, which S atom may be substituted to form S(=O) or S(=O)2; The heterocyclyl has R on one nitrogen. 6 and -C(=O)-R 8 and the heterocyclyl is optionally substituted on one or two carbon atoms with a substituent selected from the group consisting of halo, R 6 , Het 6a , Het 6b , C 1~4 Alkyl, oxo, -NR 9a R 9b and -OH; Het 2 represents a C-linked pyrazolyl or triazolyl; 6a is replaced by; R 6 Het 3 ;-C(=O)-NH-R 8 ; or Het 3 , Het 4 , Het 6a , Het 6b , Cy 1 C, optionally substituted with 1 or 2 substituents each independently selected from the group consisting of -CN, -OH, 1~6 Alkyl; -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl-C 3~6Cycloalkyl, -C(=O)-OH, -NR 11a R 11b and -NH-S(=O)2-C 1~4 Alkyl; and; -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 C optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 3~6 Cycloalkyl, -NH-S(=O)2-C 1~4 Alkyl, as well as OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, and -NH-S(=O)2-C 1~4 C, optionally substituted with one substituent selected from the group consisting of alkyl 1~4 selected from the group consisting of alkyl; R 6a -NR 11a R 11b , Het 3a , and Het 6a C substituted with one substituent selected from the group consisting of 1~6 represents alkyl; R 8 -OH, halo, cyano, -NR 11a R 11b , Het 3a , and Het 6a C optionally substituted with 1, 2 or 3 substituents each independently selected from 1~6 represents alkyl; Het 3 and Het 5each independently represent a monocyclic C-bonded 4-7 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N, the S atom being optionally substituted to form S(=O) or S(=O)2; or a bicyclic C-bonded 6-11 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N, the S atom being optionally substituted to form S(=O) or S(=O)2; the heterocyclyl is a C-bonded 6-11 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N, the S atom being optionally substituted to form S(=O) or S(=O)2; 1~4 Alkyl, halo, -OH, -NR 11a R 11b or oxo; the heterocyclyl is optionally substituted on one nitrogen atom by C 1~4 optionally substituted with alkyl; Het 3a and Het 5a each independently represent a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, the S atom being optionally substituted to form S(=O) or S(=O)2; or a bicyclic C-bonded 6- to 11-membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, the S atom being optionally substituted to form S(=O) or S(=O)2; 1~4 Alkyl, halo, -OH, -NR 11a R 11b or oxo; the heterocyclyl is optionally substituted on one nitrogen atom by C 1~4 optionally substituted with alkyl; Het 4 and Het 7each independently represent a monocyclic C-linked 5- or 6-membered aromatic ring containing 1, 2, 3, or 4 heteroatoms each independently selected from O, S, and N; the 5-membered aromatic ring is bonded to a C on one nitrogen atom; 1~4 the 5- or 6-membered aromatic ring is optionally substituted on one carbon atom with -OH; Het 6a and Het 8 each independently represent a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, the S atom being optionally substituted to form S(=O) or S(=O)2; the heterocyclyl is selected from halo, -OH, oxo, -(C=O)-NR 10a R 10b , -OC 3~6 Cycloalkyl, -S(=O)2-C 1~4 Alkyl, Cyano, C 1~4 Alkyl, -C 1~4 Alkyl-OH, -OC 1~4 Alkyl, -O-(C=O)-NR 10a R 10b , and -O-(C=O)-C 1~4 The heterocyclyl is optionally substituted on 1 or 2 carbon atoms with a total of 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl, -C(=O)-C 1~4 Alkyl and -(C=O)-NR 10a R 10b and optionally substituted on one nitrogen with a substituent selected from the group consisting of: Het 8a each independently represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing two N atoms and optionally one additional heteroatom selected from O, S and N, the S atom being optionally substituted to form S(=O) or S(=O)2; the heterocyclyl is selected from halo, -OH, oxo, -(C=O)-NR 10a R 10b , -OC 3~6Cycloalkyl, -S(=O)2-C 1~4 Alkyl, Cyano, C 1~4 Alkyl, C 1~4 Alkyl-OH, -OC 1~4 Alkyl, -O-(C=O)-NR 10a R 10b , and -O-(C=O)-C 1~4 The heterocyclyl is optionally substituted on 1 or 2 carbon atoms with a total of 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl, -C(=O)-C 1~4 Alkyl and -(C=O)-NR 10a R 10b and optionally substituted on one nitrogen with a substituent selected from the group consisting of: Het 6b represents a bicyclic N-linked 6-11 membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, the S atom being optionally substituted to form S(=O) or S(=O)2; the heterocyclyl is optionally substituted on one or two carbon atoms with C 1~4 Alkyl, -OH, oxo, -(C=O)-NR 10a R 10b , -NH-C(=O)-C 1~4 Alkyl, -NH-C(=O)-Cy 3 , and -OC 1~4 and the heterocyclyl is optionally substituted on one nitrogen with a total of 1 or 2 substituents each independently selected from the group consisting of: 1~4 Alkyl, -C(=O)-Cy 3 , -(C=O)-C 1~4 Alkyl-OH, -C(=O)-C 1~4 Alkyl-OC 1~4 Alkyl, -C(=O)-C 1~4 Alkyl-NR 11a R 11b , and C 1~4 optionally substituted with a substituent selected from the group consisting of alkyl; Cy 1-OH, -NH-C(=O)-C 1~4 Alkyl, C 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl and -OC 1~4 C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl 3~6 represents cycloalkyl; Cy 2 -NR 9a R 9b ;Het 6a ;Het 6b ; and Het 3a , Het 6a , Het 6b and N.R. 9a R 9b C substituted with 1 or 2 substituents each independently selected from the group consisting of 1~6 C substituted with 1 or 2 substituents each independently selected from the group consisting of cycloalkyl 3~7 Represents alkyl; 3~7 Cycloalkyl is halo, R 6 , C 1~4 optionally substituted with 1 or 2 further substituents each independently selected from the group consisting of alkyl and -OH; Cy 3 is C 3~7 represents cycloalkyl; 3~7 Cycloalkyl may be optionally substituted with 1, 2 or 3 halo substituents; R 9a and R 9b is hydrogen; C 1~4 Alkyl;C 3~6 Cycloalkyl;Het 5 ;-C 1~4 Alkyl-R 16 ;-C(=O)-C 1~4 Alkyl-Het 3a ;-C(=O)-R 14 ; Halo, -OH, -OC 1~4 Alkyl, -NR 11a R 11band cyano; 3~6 Cycloalkyl; and; halo, -OH, -OC 1~4 Alkyl, -NR 11a R 11b and cyano; 1~4 alkyl; R 11a , R 11b , R 13a , R 13b , R 15a , R 15b , R 17a , and R 17b is hydrogen and C 1~4 each independently selected from the group consisting of alkyl; R 11c and R 11d is hydrogen, C 1~6 Alkyl and -C(=O)-C 1~4 each independently selected from the group consisting of alkyl; R 14 Het 5a ;Het 8a ; or -NR 13a R 13b and Het 8a C substituted with 1, 2 or 3 substituents selected from the group consisting of 1~4 represents alkyl; R 16 is -C(=O)-NR 17a R 17b , -S(=O)2-C 1~4 Alkyl, Het 5 , Het 7 Or Het 8 [representing] and the pharma- ceutically acceptable salts and solvates thereof.

[0013] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier or excipient.

[0014] Furthermore, the present invention relates to a compound of formula (I), a pharma- ceutically acceptable salt or solvate thereof for use as a medicament, and to a compound of formula (I), a pharma- ceutically acceptable salt or solvate thereof for use in the treatment or prophylaxis of cancer, myelodysplastic syndrome (MDS) and diabetes.

[0015] In a particular embodiment, the present invention relates to a compound of formula (I), a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment or prevention of cancer.

[0016] In certain embodiments, the cancer is selected from leukemia, myeloma, or solid tumor cancer (such as prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma, and glioblastoma). In some embodiments, leukemias include acute leukemias, chronic leukemias, myeloid leukemias, myelogeneous leukemias, lymphoblastic leukemias, lymphocytic leukemias, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), MLL-rearranged leukemia, MLL-PTD leukemia, MLL-amplified leukemia, MLL-positive leukemia, leukemias exhibiting a HOX / MEIS1 gene expression signature, and the like.

[0017] The present invention also relates to the use of a compound of formula (I), a pharma- ceutically acceptable salt or solvate thereof, in combination with an additional pharmaceutical agent for use in the treatment or prevention of cancer, myelodysplastic syndromes (MDS) and diabetes.

[0018] Furthermore, the present invention relates to a process for preparing a pharmaceutical composition according to the present invention, characterized in that a pharma- ceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound of formula (I), a pharma- ceutically acceptable salt or solvate thereof.

[0019] The present invention also relates to a product comprising a compound of formula (I), a pharma- ceutically acceptable salt or solvate thereof, and an additional pharmaceutical agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of cancer, myelodysplastic syndromes (MDS) and diabetes.

[0020] Furthermore, the present invention relates to a method for treating or preventing a cell proliferative disorder in a warm-blooded animal, comprising administering to said animal an effective amount of a compound of formula (I) as defined herein, a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition or combination. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0022] As used herein, the prefix "C x~y " (where x and y are integers) refers to the number of carbon atoms in a given group. Thus, C 1~6 The alkyl group contains 1 to 6 carbon atoms, and so forth.

[0023] As used herein as a group or part of a group, "C 1~4 The term "alkyl" refers to a straight or branched chain saturated hydrocarbon radical having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, and the like.

[0024] Similarly, when used herein as a group or part of a group, "C 1~6 The term "alkyl" refers to a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0025] As used herein as a group or part of a group, "C 3~6The term "cycloalkyl" defines a saturated cyclic hydrocarbon radical having three to six carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0026] As used herein as a group or part of a group, "C 3~7 The term "cycloalkyl" defines a saturated cyclic hydrocarbon radical having three to seven carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0027] It will be apparent to those skilled in the art that S(=O)2 or SO2 represents a sulfonyl moiety.

[0028] It will be apparent to one skilled in the art that CO or C(=O) represent a carbonyl moiety.

[0029] It will be apparent to one of skill in the art that a group such as -CRR- represents

[0030] [ka] An example of such a group is -CR 5a R 5b -It is.

[0031] Groups such as -NR-

[0032] [ka] It will be apparent to one skilled in the art that the aryl group represents an alkyl group such as -NR 5c -It is.

[0033] The term "monocyclic C-linked 4-7 membered fully saturated heterocyclyl" containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N defines a fully saturated cyclic hydrocarbon radical having 4 to 7 ring members and containing one nitrogen atom and optionally one or two additional heteroatoms each independently selected from O, S and N, such as C-linked azetidinyl, C-linked pyrrolidinyl, C-linked morpholinyl and C-linked piperidinyl. The term "monocyclic N-linked 4-7 membered fully saturated heterocyclyl" containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N is similarly defined but is attached to the remainder of the molecule of formula (I) via a nitrogen atom. Examples are N-linked azetidinyl, N-linked pyrrolidinyl, N-linked morpholinyl, N-linked thiomorpholinyl, N-linked piperazinyl, N-linked 1,4-diazepanyl, and N-linked piperidinyl. Two R groups taken together with the N atom to which they are attached are similarly defined as forming a 4-7 membered monocyclic fully saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S and N.

[0034] The term "monocyclic C-linked 4-7 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N" defines a fully saturated cyclic hydrocarbon radical having 4 to 7 ring members and containing 1, 2 or 3 heteroatoms each independently selected from O, S and N, such as C-linked azetidinyl, C-linked pyrrolidinyl, C-linked morpholinyl, C-linked tetrahydrofuranyl, C-linked thiolanyl, C-linked oxetanyl, C-linked thietanyl, C-linked tetrahydropyranyl, and C-linked piperidinyl. The term "monocyclic N-linked 4-7 membered fully saturated heterocyclyl containing 2 N atoms and optionally one additional heteroatom selected from O, S and N" defines a fully saturated cyclic hydrocarbon radical having 4 to 7 ring members and containing 2 nitrogen atoms and optionally one additional heteroatom selected from O, S and N, such as N-linked piperazinyl and N-linked 1,4-diazepanyl.

[0035] For clarity, a 4- to 7-membered fully or partially saturated heterocyclyl has from 4 to 7 ring members, including the heteroatom.

[0036] Non-limiting examples of "monocyclic 5- or 6-membered aromatic ring containing 1 or 2 nitrogen atoms and optionally a carbonyl moiety" include, but are not limited to, pyrazolyl, imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazinyl, 1,2-dihydro-2-oxo-5-pyrimidinyl, 1,2-dihydro-2-oxo-6-pyridinyl, 1,2-dihydro-2-oxo-4-pyridinyl, and 1,6-dihydro-6-oxo-3-pyridazinyl.

[0037] Non-limiting examples of monocyclic C-linked 5- or 6-membered aromatic rings containing 1, 2, or 3 heteroatoms, each independently selected from O, S, and N, include, but are not limited to, C-linked pyrazolyl, C-linked imidazolyl, C-linked pyridinyl, C-linked triazolyl, C-linked pyridazinyl, C-linked pyrimidinyl, C-linked oxazolyl, C-linked furanyl, C-linked isothiazolyl, or C-linked pyrazinyl.

[0038] Within the context of this invention bicyclic C-linked 6-11 membered fully saturated heterocyclyl groups include fused, spiro and bridged rings.

[0039] Within the context of this invention bicyclic N-linked 6-11 membered fully saturated heterocyclyl groups include fused, spiro and bridged rings.

[0040] A fused bicyclic group is two rings which share two atoms and a bond between those atoms.

[0041] A spiro bicyclic group has two rings joined at a single atom.

[0042] A bridged bicyclic group has two rings which have three or more atoms in common.

[0043] Examples of bicyclic C-linked 6-11 membered fully saturated heterocyclyls containing one N atom, each independently selected from O, S and N, and optionally one or two additional heteroatoms, include, but are not limited to,

[0044] [ka] etc.

[0045] Examples of bicyclic C-linked 6-11 membered fully saturated heterocyclyls containing 1, 2 or 3 heteroatoms each independently selected from O, S and N include, but are not limited to,

[0046] [ka] etc.

[0047] Examples of bicyclic N-linked 6-11 membered fully saturated heterocyclyls containing one N atom each independently selected from O, S and N and optionally one or two additional heteroatoms include, but are not limited to,

[0048] [ka] etc.

[0049] For example, if the substituents are chemical structures, e.g.

[0050] [ka] When expressed by, etc. "----" represents the bond to the remainder of the molecule of formula (I).

[0051] When any variable occurs more than one time in any constituent, each definition is independent.

[0052] When any variable occurs more than one time in any formula (eg, formula (I)), each definition is independent.

[0053] In this context, it will also be apparent that a term such as "optionally substituted with 1, 2 or 3 substituents selected from the group consisting of" is equivalent to "optionally substituted with 1, 2 or 3 substituents, each independently selected from the group consisting of."

[0054] In general, whenever the term "substituted" is used in the present invention, unless otherwise indicated or apparent from the context, it is meant to indicate that one or more hydrogens, particularly 1 to 4 hydrogens, more particularly 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen, on the atom or radical shown in the expression are replaced with a selection from the group shown, provided that the normal valences are not exceeded, and that the replacement results in a chemically stable compound, i.e., a compound that is sufficiently robust to survive isolation to a useful purity from a reaction mixture. In certain embodiments, when the number of substituents is not explicitly specified, the number of substituents is 1.

[0055] Combinations of substituents and / or variables are permissible only if such combinations result in chemically stable compounds. "Stable compound" is meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture.

[0056] Those of skill in the art will understand that the term "optionally substituted" means that the atom or radical designated in the expression using "optionally substituted" may be substituted or unsubstituted (which means substituted or unsubstituted, respectively).

[0057] When two or more substituents are present on a moiety, they may replace hydrogen atoms on the same atom or they may replace hydrogen atoms on different atoms in the moiety, unless otherwise stated or apparent from the context.

[0058] Within the context of the present invention, "saturated" means "fully saturated" unless otherwise stated.

[0059] Unless otherwise specified or apparent from the context, aromatic rings and heterocyclyl groups may be attached to the remainder of the molecule of formula (I) via any available ring carbon atom (C-bonded) or nitrogen atom (N-bonded).

[0060] Unless otherwise specified or apparent from the context, aromatic rings and heterocyclyl groups may be optionally substituted on carbon and / or nitrogen atoms in accordance with embodiments where such is possible.

[0061] As used herein, the term "subject" refers to an animal, preferably a mammal (e.g., a cat, dog, primate, or human), more preferably a human, who is or has been the object of treatment, observation, or experiment.

[0062] As used herein, the term "therapeutically effective amount" means that amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human, that is sought by a researcher, veterinarian, physician or other clinician, including the alleviation or reversal of symptoms of the disease or disorder being treated.

[0063] The term "composition" is intended to encompass a product comprising specified ingredients in specified amounts, and any product that results directly or indirectly from a combination of the specified ingredients in the specified amounts.

[0064] As used herein, the term "treatment" is intended to refer to any process that can slow, hinder, inhibit, or halt the progression of a disease, although it does not necessarily indicate the complete disappearance of all symptoms.

[0065] As used herein, the term "compounds of the invention" or "compounds according to the invention" is meant to include compounds of formula (I) and their pharma- ceutically acceptable salts and solvates.

[0066] As used herein, any chemical formula with bonds shown only as solid lines and not as solid wedge bonds or hashed wedge bonds, or otherwise shown as having a particular configuration (e.g., R, S) around one or more atoms contemplates each possible stereoisomer, or a mixture of two or more stereoisomers.

[0067] In the above and below, the term "compounds of formula (I)" is meant to include its tautomers and its stereoisomers.

[0068] Above and below, the terms "stereoisomer", "stereoisomeric form" or "stereochemically isomeric form" are used interchangeably.

[0069] The present invention includes all stereoisomers of the compounds of the present invention, either as a pure stereoisomer or as a mixture of two or more stereoisomers.

[0070] Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture.

[0071] Atropisomers (or atropoisomers) are stereoisomers with specific spatial configurations resulting from restricted rotation about a single bond due to significant steric hindrance. All atropisomers of the compounds of formula (I) are intended to be included within the scope of the present invention.

[0072] Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e., they are not related as mirror images. When a compound contains double bonds, the substituents may be in the E or Z configuration.

[0073] Substituents on a divalent cyclic saturated or partially saturated radical can have either the cis or trans configuration; for example, if the compound contains a disubstituted cycloalkyl group, the substituents can be in either the cis or trans configuration.

[0074] Thus, the present invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, whenever chemically possible.

[0075] The meanings of all terms, i.e. enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, are known to the person skilled in the art.

[0076] Absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration at the asymmetric atom is specified by either R or S. Resolved stereoisomers for which the absolute configuration is not known are They can be designated (+) or (-) depending on the direction they rotate plane-polarized light. For example, resolved enantiomers whose absolute configuration is not known can be designated (+) or (-) depending on the direction they rotate plane-polarized light.

[0077] When a particular stereoisomer is specified, this means that the stereoisomer is substantially free of other stereoisomers, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, particularly less than 2%, and most preferably less than 1% of other stereoisomers. Thus, when a compound of formula (I) is specified, for example, as (R), this means that the compound is substantially free of the (S) isomer, when a compound of formula (I) is specified, for example, as E, this means that the compound is substantially free of the Z isomer, and when a compound of formula (I) is specified, for example, as cis, this means that the compound is substantially free of the trans isomer.

[0078] Some of the compounds according to formula (I) may exist in their tautomeric forms. Such forms, insofar as they may exist, are intended to be included within the scope of the present invention, although not explicitly shown in formula (I) above.

[0079] for example,

[0080] [ka] is equivalent to

[0081] It follows that a single compound may exist in both stereoisomeric and tautomeric forms.

[0082] Pharmaceutically acceptable salts include acid addition salts and base addition salts.Such salts can be formed by conventional means, for example, by reacting a free acid form or a free base form with one or more equivalents of a suitable base or acid, optionally in a solvent or in a medium in which the salt is insoluble, and then removing the solvent or medium using standard techniques (for example, in vacuum, by lyophilization, or by filtration).Salts can also be prepared by exchanging the counterion of the compound of the present disclosure in the form of a salt with another counterion, for example, by using a suitable ion exchange resin.

[0083] The pharma- ceutically acceptable salts referred to above or hereinafter are meant to include the therapeutically active non-toxic acid and base salt forms which the compounds of formula (I) and their solvates may form.

[0084] Suitable acids include, for example, inorganic acids such as hydrohalic acids, e.g., hydrochloric or hydrobromic acids, sulfuric, nitric, phosphoric acids, and the like; or organic acids such as, for example, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, oxalic acid (i.e., ethanedioic acid), malonic acid, succinic acid (i.e., butanedioic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, and the like. Conversely, the above salt forms can be converted to the free base form by treatment with an appropriate base.

[0085] The compounds of formula (I) or solvates thereof containing acidic protons may be converted into their non-toxic metal or amine salt forms by treatment with appropriate organic and inorganic bases.

[0086] Suitable base salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts such as lithium, sodium, potassium, cesium, magnesium, calcium salts, and the like, salts with organic bases such as primary, secondary and tertiary aliphatic amines and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline, and isoquinoline; benzathine, N-methyl-glucamine, hydrabamine salts, and salts with amino acids such as arginine, lysine, and the like. Conversely, the base forms can be converted to the free base forms by treatment with acid.

[0087] The term solvates comprises the solvent addition forms, which the compounds of formula (I) are able to form, as well as the salts thereof. Examples of such solvent addition forms are, for example, hydrates, alcoholates, etc.

[0088] The compounds of the present invention prepared by the process described below may be synthesized in the form of a mixture of enantiomers, in particular a racemic mixture of enantiomers, which can be separated from each other according to resolution procedures known in the art. Methods for separating the enantiomeric forms of the compounds of formula (I) and their pharma-ceutically acceptable salts and solvates include liquid chromatography using chiral stationary phases. Said pure stereochemically isomers may also be derived from the corresponding pure stereochemically isomers of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, when a specific stereoisomer is desired, said compound will be synthesized by stereospecific preparation methods. These methods will advantageously employ enantiomerically pure starting materials.

[0089] As used herein, the term "enantiomerically pure" means that the product contains at least 80% by weight of one enantiomer and no more than 20% by weight of the other enantiomer. Preferably, the product contains at least 90% by weight of one enantiomer and no more than 10% by weight of the other enantiomer. In the most preferred embodiment, the term "enantiomerically pure" means that the composition contains at least 99% by weight of one enantiomer and no more than 1% of the other enantiomer.

[0090] The present invention also includes isotopically labeled compounds of the present invention which are identical to those enumerated herein, but by virtue of the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature (or the most abundant atom found in nature).

[0091] All isotopes and isotopic mixtures of any particular atom or element identified herein, whether naturally occurring or synthetically produced, either at natural abundance or in isotopically enriched form, are contemplated within the scope of the compounds of the invention. Exemplary isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine; 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br, and 82 Br. Preferably, the isotope is 2 H, 3 H, 11 C, and 18 F. More preferably, the isotope is selected from the group 2 H. Deuterated compounds are specifically intended to be included within the scope of the present invention.

[0092] Certain isotopically labeled compounds of the invention (e.g., 3 H and 14 C) can be useful, for example, in substrate tissue distribution assays. 3 H) and carbon-14 ( 14 C) isotopes are useful for their ease of preparation and detectability. Additionally, heavier isotopes, such as deuterium (i.e., 2H), may result in greater metabolic stability (e.g., increased half-life in vivo or reduced dosage requirements), which may result in certain therapeutic advantages and therefore may be preferred in some circumstances. For example, 15 O. 13 N, 11 C, and 18 Positron-emitting isotopes such as F are useful in positron emission tomography (PET) studies. PET imaging in cancer finds utility in helping to localize and identify tumors, stage disease, and determine suitable treatments. Human cancer cells overexpress many receptors or proteins that are potential disease-specific molecular targets. Radiolabeled tracers that bind with high affinity and specificity to such receptors or proteins on tumor cells have great potential for diagnostic imaging and targeted radionuclide therapy (Charron, Carlie L. et al. Tetrahedron Lett. 2016, 57(37), 4119-4127). Furthermore, target-specific PET radiotracers can be used as biomarkers to investigate and evaluate pathology, for example, by measuring target expression and treatment response (Austin R. et al. Cancer Letters (2016), doi:10.1016 / j.canlet.2016.05.008).

[0093] The present invention relates in particular to compounds of formula (I) as defined herein, and to the tautomers and stereoisomers thereof, wherein R 1a is -C(=O)-NR xa R xb or

[0094] [ka] represents; R xa and R xb is hydrogen; C 3~6 Cycloalkyl;C 1~4 Alkyl; and C substituted with 1, 2 or 3 halo atoms1~4 each independently selected from the group consisting of alkyl; R 1b represents F or Cl; Y 1 -CR 5a R 5b -, -O-, -S-, or -NR 5c - stands for; R 2 is hydrogen, halo, C 1~4 Alkyl, -OC 1~4 Alkyl, and -NR 7a R 7b selected from the group consisting of; U 1 and U 2 each independently represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 stands for CH, and X 2 represents N; R 4 is C 1~5 Alkyl;

[0095] [ka] represents; R 5a , R 5b , R 5c , R 7a , and R 7b is hydrogen, C 1~4 Alkyl and C 3~6 cycloalkyl; R 3 Het 1 , Het 2 , Cy 2 and -C 1~6 Alkyl-NR xc R xd selected from the group consisting of; R xc Cy 1 ;Het 5 ;-C 1~6 Alkyl-Cy 1 ;-C 1~6Alkyl-Het 3 ;-C 1~6 Alkyl-Het 4 ; or -C 1~6 represents alkyl-phenyl; R xd is hydrogen; C 1~4 Alkyl; or halo, -OH, -OC 1~4 C substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and cyano 1~4 represents alkyl; Or R xc and R xd taken together with the N atom to which they are attached form a 4-7 membered monocyclic fully saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S and N, where the S atom may be substituted to form S(=O) or S(=O)2; the heterocyclyl may be selected from halo, -OH, -OC 1~4 optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and cyano; Het 1 represents a monocyclic C-bonded 4-7 membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, the S atom being optionally substituted to form S(=O) or S(=O)2; or a bicyclic C-bonded 6-11 membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, the S atom being optionally substituted to form S(=O) or S(=O)2; The heterocyclyl has R on one nitrogen. 6 and -C(=O)-R 8 and the heterocyclyl is optionally substituted on one or two carbon atoms with a substituent selected from the group consisting of halo, R 6 , Het 6a , Het 6b, C 1~4 Alkyl, oxo, -NR 9a R 9b and -OH; Het 2 represents a C-linked pyrazolyl or triazolyl; 6a is replaced by; R 6 Het 3 ;-C(=O)-NH-R 8 ;Het 3 , Het 4 , Het 6a , Het 6b , Cy 1 , -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl-C 3~6 Cycloalkyl, -C(=O)-OH, -NR 11a R 11b , and -NH-S(=O)2-C 1~4 C optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 1~6 Alkyl; and; -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 C optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 3~6 Cycloalkyl, -NH-S(=O)2-C 1~4 Alkyl, as well as OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, and -NH-S(=O)2-C 1~4 C, optionally substituted with one substituent selected from the group consisting of alkyl 1~4 selected from the group consisting of alkyl; R 6a -NR 11a R 11b , Het 3a , and Het6a C substituted with one substituent selected from the group consisting of 1~6 represents alkyl; R 8 -OH, -NR 11a R 11b , Het 3a , and Het 6a C substituted with one substituent selected from the group consisting of 1~6 represents alkyl; Het 3 and Het 5 each independently represent a monocyclic C-bonded 4-7 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N, the S atom being optionally substituted to form S(=O) or S(=O)2; or a bicyclic C-bonded 6-11 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N, the S atom being optionally substituted to form S(=O) or S(=O)2; 1~4 Alkyl, halo, -OH, -NR 11a R 11b or oxo; the heterocyclyl is optionally substituted on one nitrogen atom by C 1~4 optionally substituted with alkyl; Het 3a and Het 5aeach independently represent a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, the S atom being optionally substituted to form S(=O) or S(=O)2; or a bicyclic C-bonded 6- to 11-membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, the S atom being optionally substituted to form S(=O) or S(=O)2; 1~4 Alkyl, halo, -OH, -NR 11a R 11b or oxo; the heterocyclyl is optionally substituted on one nitrogen atom by C 1~4 optionally substituted with alkyl; Het 4 and Het 7 each independently represent a monocyclic C-linked 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms each independently selected from O, S and N; the 5-membered aromatic ring is bonded to a C on one nitrogen atom 1~4 the 5- or 6-membered aromatic ring is optionally substituted on one carbon atom with -OH; Het 6a and Het 8 each independently represent a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, the S atom being optionally substituted on one or two carbon atoms to form S(=O) or S(=O)2; the heterocyclyl may be optionally substituted on one or two carbon atoms with halo, -OH, oxo, -(C=O)-NR 10a R 10b , -OC 3~6 Cycloalkyl, -S(=O)2-C 1~4 Alkyl, Cyano, C 1~4 Alkyl, -C1~4 Alkyl-OH, -OC 1~4 Alkyl, -O-(C=O)-NR 10a R 10b , and -O-(C=O)-C 1~4 The heterocyclyl is optionally substituted with a total of 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl, -C(=O)-C 1~4 Alkyl and -(C=O)-NR 10a R 10b and optionally substituted on one nitrogen with a substituent selected from the group consisting of: Het 8a each independently represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing two N atoms and optionally one additional heteroatom selected from O, S and N, the S atom being optionally substituted to form S(=O) or S(=O)2; the heterocyclyl is selected from halo, -OH, oxo, -(C=O)-NR 10a R 10b , -OC 3~6 Cycloalkyl, -S(=O)2-C 1~4 Alkyl, Cyano, C 1~4 Alkyl, C 1~4 Alkyl-OH, -OC 1~4 Alkyl, -O-(C=O)-NR 10a R 10b , and -O-(C=O)-C 1~4 The heterocyclyl is optionally substituted on 1 or 2 carbon atoms with a total of 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl, -C(=O)-C 1~4 Alkyl and -(C=O)-NR 10a R 10b and optionally substituted on one nitrogen with a substituent selected from the group consisting of: Het 6brepresents a bicyclic N-linked 6-11 membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, the S atom being optionally substituted to form S(=O) or S(=O)2; the heterocyclyl may be substituted on one carbon atom with -OH, oxo, -(C=O)-NR 10a R 10b , -NH-C(=O)-C 1~4 Alkyl, -NH-C(=O)-Cy 3 , and -OC 1~4 and the heterocyclyl is optionally substituted on one nitrogen with a substituent selected from the group consisting of -C(=O)-C 1~4 Alkyl, -C(=O)-Cy 3 and C 1~4 optionally substituted with a substituent selected from the group consisting of alkyl; Cy 1 -OH, -NH-C(=O)-C 1~4 Alkyl, C 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl and -OC 1~4 C optionally substituted with 1, 2 or 3 optionally substituted substituents selected from the group consisting of alkyl 3~6 represents cycloalkyl; Cy 2 -NR 9a R 9b ;Het 6a ;Het 6b ; and Het 3a , Het 6a , Het 6b and N.R. 9a R 9b C substituted with 1 or 2 substituents each independently selected from the group consisting of 1~6 C substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 3~7 represents cycloalkyl; 3~7 Cycloalkyl is halo, R 6 , C 1~4optionally substituted with 1 or 2 further substituents each independently selected from the group consisting of alkyl and -OH; Cy 3 is C 3~7 represents cycloalkyl; 3~7 Cycloalkyl may be optionally substituted with 1, 2 or 3 halo substituents; R 9a and R 9b is hydrogen; C 1~4 Alkyl;C 3~6 Cycloalkyl;Het 5 ;-C 1~4 Alkyl-R 16 ;-C(=O)-C 1~4 Alkyl-Het 3a ;-C(=O)-R 14 ; Halo, -OH, -OC 1~4 C substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, and cyano 3~6 Cycloalkyl; and; halo, -OH, -OC 1~4 C substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and cyano 1~4 each independently selected from the group consisting of alkyl; R 10a , R 10b , R 11a , R 11b , R 13a , R 13b , R 15a , and R 15b , R 17a , and R 17b is hydrogen and C 1~4 each independently selected from the group consisting of alkyl; R 14 Het 5a ;Het 8a ; or -NR 13a R 13b and Het 8a C substituted with 1, 2 or 3 substituents selected from the group consisting of 1~4 represents alkyl; R 16 is -C(=O)-NR17a R 17b , -S(=O)2-C 1~4 Alkyl, Het 5 , Het 7 Or Het 8 represents] and the pharma- ceutically acceptable salts and solvates thereof.

[0096] The present invention relates in particular to compounds of formula (I) as defined herein, and to the tautomers and stereoisomers thereof, wherein R 1a is -C(=O)-NR xa R xb represents; R xa and R xb is C 3~6 Cycloalkyl;C 1~4 Alkyl; and C substituted with 1, 2 or 3 halo atoms 1~4 each independently selected from the group consisting of alkyl; R 1b represents F; Y 1 represents -O-; R 2 represents hydrogen; U 1 and U 2 each independently represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 stands for CH, and X 2 represents N; R 4 is C 1~5 Alkyl;

[0097] [ka] represents; R 3 Het 1 and Cy 2 selected from the group consisting of; Het 1represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing one N atom; the heterocyclyl is bonded to one nitrogen atom by R 6 and -C(=O)-R 8 said heterocyclyl optionally being substituted on one or two carbon atoms with a total of one, two, three or four halo substituents; R 6 Het 3 ;Het 3 , Het 4 , Het 6a , Cy 1 , -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl-C 3~6 Cycloalkyl and -NH-S(=O)2-C 1~4 C optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 1~6 alkyl; R 8 -OH and -NR 11a R 11b C substituted with one substituent selected from the group consisting of 1~6 represents alkyl; Het 3 and Het 5 each independently represent a monocyclic C-bonded 4-7 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N, the S atom being optionally substituted to form S(=O) or S(=O)2; the heterocyclyl is optionally substituted on one carbon atom by -OH or oxo; Het 4 represents a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N; said 5- or 6-membered aromatic ring is optionally substituted on one carbon atom with -OH; Het 6a represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, the S atom being optionally substituted to form S(=O) or S(=O)2; the heterocyclyl may be optionally substituted on one or two carbon atoms with oxo, -S(=O)2-C 1~4 Alkyl and -OC 1~4 The heterocyclyl is optionally substituted on one nitrogen with a total of 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl, -C(=O)-C 1~4 optionally substituted with alkyl; Het 6b represents a bicyclic N-linked 6-11 membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, the S atom being optionally substituted to form S(=O) or S(=O)2; the heterocyclyl is a -(C=O)-NR 10a R 10b the heterocyclyl is optionally substituted on one nitrogen with -C(=O)-C 1~4 optionally substituted with alkyl; Cy 1 -OH, -NH-C(=O)-C 1~4 Alkyl, C 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl and -OC 1~4 C is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, 3~6 represents cycloalkyl; Cy 2 -NR 9a R 9b , Het 6a , and Het 6b C substituted with 1 or 2 substituents each independently selected from the group consisting of 3~7 represents cycloalkyl; R 9a and R 9b is hydrogen; C 1~4 Alkyl;C 3~6 Cycloalkyl;Het 5 ;-C 1~4 Alkyl-R 16 and 1, 2 or 3 -OC 1~4 Alkyl-substituted C 1~4 each independently selected from the group consisting of alkyl; R 10a , R 10b , R 11a and R 11b is C 1~4 represents alkyl; R 16 Het 5 represents] and the pharma- ceutically acceptable salts and solvates thereof.

[0098] The present invention relates in particular to compounds of formula (I) as defined herein, and to the tautomers and stereoisomers thereof, wherein R 1a is -C(=O)-NR xa R xb represents; R xa and R xb is C 1~4 represents alkyl; R 1b represents F; Y 1 represents -O-; R 2 represents hydrogen; U 1 and U 2 each independently represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 stands for CH, and X 2 represents N; R 4 stands for isopropyl; R 3 Het 1 and Cy 2selected from the group consisting of; Het 1 represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing one N atom; the heterocyclyl is 6 and optionally substituted with a substituent selected from the group consisting of: R 6 is one Het 3 C replaced with 1~6 represents alkyl; Het 3 represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N, the S atom being optionally substituted to form S(=O) or S(=O)2; Het 6a represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom; the heterocyclyl is 1~4 optionally substituted with alkyl; Het 6b represents a bicyclic N-linked 6-11 membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O and N; the heterocyclyl is represented by the formula: -(C=O)-NR 10a R 10b the heterocyclyl is optionally substituted on one nitrogen with -C(=O)-C 1~4 optionally substituted with alkyl; Cy 2 Het 6a and Het 6b C substituted with one substituent selected from the group consisting of 3~7 represents cycloalkyl; R 10a and R 10b is C 1~4 represents alkyl] and the pharma- ceutically acceptable salts and solvates thereof.

[0099] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 1a is -C(=O)-NR xa R xb Represents.

[0100] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 1b represents F.

[0101] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 2 represents hydrogen.

[0102] In certain embodiments, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein n1 is 1, n2 is 2, n3 is 1, and n4 is 1.

[0103] In certain embodiments, the present invention relates to compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein U 1 represents N.

[0104] In certain embodiments, the present invention relates to compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein U 1 stands for N, and U 2 represents N.

[0105] In certain embodiments, the present invention relates to compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein U 1 stands for CH, and U 2 represents N.

[0106] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Y 1 represents -O-.

[0107] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Y 1 represents -O-; and U 2 represents N.

[0108] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Y 1 represents -O-; and U 1 represents N.

[0109] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Y 1 represents -O-; U 2 represents N; R 1b represents F; R 2 represents hydrogen.

[0110] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Y 1 represents -O-; U 1 represents N; R 1b represents F; R 2 represents hydrogen.

[0111] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Y 1 represents -O-; U 1 represents N; R 1b represents F; R 2 represents hydrogen; R 4 represents isopropyl.

[0112] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 4 represents isopropyl.

[0113] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 3 Het 1 Or Cy 2 Represents.

[0114] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 3 Cy 2 Represents.

[0115] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 3 Het 1 Represents.

[0116] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Het 1 represents a monocyclic C-bonded 4-7 membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, the S atom being optionally substituted to form S(=O) or S(=O)2; or a bicyclic C-bonded 6-11 membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, the S atom being optionally substituted to form S(=O) or S(=O)2; The heterocyclyl has R on one nitrogen. 6 wherein the heterocyclyl is optionally substituted with halo, R 6 , Het 6a , Het 6b , C 1~4 Alkyl, oxo, -NR 9a R 9band -OH, optionally substituted on 1 or 2 carbon atoms with a total of 1, 2, 3, or 4 substituents each independently selected from the group consisting of:

[0117] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 3 Het 1 represents; Het 1 represents a monocyclic C-bonded 4-7 membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, the S atom being optionally substituted to form S(=O) or S(=O)2; or a bicyclic C-bonded 6-11 membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, the S atom being optionally substituted to form S(=O) or S(=O)2; The heterocyclyl has R on one nitrogen. 6 wherein the heterocyclyl is optionally substituted with halo, R 6 , Het 6a , Het 6b , C 1~4 Alkyl, oxo, -NR 9a R 9b and -OH, optionally substituted on 1 or 2 carbon atoms with a total of 1, 2, 3, or 4 substituents each independently selected from the group consisting of:

[0118] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 6 teeth, Het 3;-C(=O)-NH-R 8 ; Het 3 , Het 4 , Het 6a , Het 6b , Cy 1 , -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl-C 3~6 Cycloalkyl, -C(=O)-OH, -NR 11a R 11b , and -NH-S(=O)2-C 1~4 C optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 1~6 Alkyl; and; -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, as well as OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -NH-S(=O)2-C 1~4 C, optionally substituted with one substituent selected from the group consisting of alkyl 1~4 C optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 3~6 cycloalkyl.

[0119] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 6 Het 3 ;-C(=O)-NH-R 8 ;Het 3 , Het 4 , Het 6a , Het 6b , Cy 1, -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl-C 3~6 Cycloalkyl, -C(=O)-OH, -NR 11a R 11b , and -NH-S(=O)2-C 1~4 C substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 1~6 Alkyl; and; -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, as well as OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -NH-S(=O)2-C 1~4 C, optionally substituted with one substituent selected from the group consisting of alkyl 1~4 C optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 3~6 cycloalkyl.

[0120] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 4 represents the following formula:

[0121] [ka]

[0122] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 3 Het 1 represents; Het1 represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing one N atom; the heterocyclyl is 6 said heterocyclyl is optionally substituted on 1 or 2 carbon atoms with a total of 1, 2, 3 or 4 halo substituents; R 6 But, Het 3 , Het 4 , Het 6a and Cy 1 C optionally substituted with 1 or 2 substituents each independently selected from the group consisting of 1~6 alkyl.

[0123] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: U 1 represents N; R 3 Het 1 represents; Het 1 represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing one N atom; the heterocyclyl is 6 said heterocyclyl is optionally substituted on 1 or 2 carbon atoms with a total of 1, 2, 3 or 4 halo substituents; R 6 But, Het 3 , Het 4 , Het 6a and Cy 1 C optionally substituted with 1 or 2 substituents each independently selected from the group consisting of 1~6 alkyl.

[0124] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: U 1 represents N; Y 1 represents -O-; R 1b represents F; R 2 represents hydrogen; R 4 stands for isopropyl; R 3 Het 1 represents; Het 1 represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing one N atom; the heterocyclyl is 6 said heterocyclyl is optionally substituted on 1 or 2 carbon atoms with a total of 1, 2, 3 or 4 halo substituents; R 6 But, Het 3 , Het 4 , Het 6a and Cy 1 C optionally substituted with 1 or 2 substituents each independently selected from the group consisting of 1~6 alkyl.

[0125] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 3 Het 1 represents; Het 1 represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing one N atom; the heterocyclyl is 6 is replaced by; R 6 is one Het 3 C replaced with1~6 Represents alkyl.

[0126] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: U 1 represents N; R 3 Het 1 represents; Het 1 represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing one N atom; the heterocyclyl is 6 is replaced by; R 6 is one Het 3 C replaced with 1~6 Represents alkyl.

[0127] In certain embodiments, the present invention relates to those compounds of formula (I), as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: U 1 represents N; Y 1 represents -O-; R 1b represents F; R 2 represents hydrogen; R 4 stands for isopropyl; R 3 Het 1 represents; Het 1 represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing one N atom; the heterocyclyl is 6 is replaced by; R 6 is one Het 3 C replaced with 1~6 Represents alkyl.

[0128] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein the compounds of formula (I) are limited to compounds of formula (Iy):

[0129] [ka] In the formula, R 3 is as defined for the compounds of formula (I) or any subgroup thereof as described in any of the other embodiments.

[0130] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein the compounds of formula (I) are limited to compounds of formula (Iy):

[0131] [ka] In the formula, R 3 Het 1 Represents.

[0132] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein the compounds of formula (I) are limited to compounds of formula (Iy):

[0133] [ka] R 3 Cy 2 Represents.

[0134] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein the compounds of formula (I) are limited to compounds of formula (Iz):

[0135] [ka] In the formula, R 3 is as defined for the compounds of formula (I) or any subgroup thereof as described in any of the other embodiments.

[0136] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein the compounds of formula (I) are limited to compounds of formula (Iz):

[0137] [ka] In the formula, R 3 Het 1 Represents.

[0138] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharma- ceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein the compounds of formula (I) are limited to compounds of formula (Iz):

[0139] [ka] R 3 Cy 2 Represents.

[0140] In one embodiment, the present invention relates to a subgroup of formula (I) defined in the general reaction scheme:

[0141] In one embodiment, the compound of formula (I) is an exemplified compound, its tautomers and its stereoisomers, and any of the free bases, any pharma- ceutically acceptable salts, and solvates thereof.

[0142] All possible combinations of the above embodiments are considered to be within the scope of the present invention.

[0143] Process for the preparation of compounds of formula (I) In this section, and in all other sections, unless the context indicates otherwise, references to formula (I) also include all other subgroups and embodiments thereof defined herein.

[0144] The general preparation of some representative examples of compounds of formula (I) is described below, and in certain examples, they are usually prepared from starting materials that are either commercially available or prepared by standard synthetic processes commonly used by those skilled in the art of organic chemistry. The following schemes are merely illustrative of examples of the present invention and are not intended to limit the present invention in any way.

[0145] Alternatively, the compounds of the present invention may also be prepared by analogous reaction protocols as depicted in the following general schemes in combination with standard synthetic processes commonly used by those skilled in the art.

[0146] Those skilled in the art will appreciate that in the reactions depicted in the schemes, although this is not always explicitly shown, it may be necessary to protect reactive functional groups (e.g., hydroxy, amino, or carboxy groups) if these are desired in the final product to avoid their undesired participation in the reaction. In general, conventional protecting groups can be used in accordance with standard practice. The protecting groups can be removed at a subsequent convenient stage using methods well known in the art.

[0147] Those skilled in the art will appreciate that in the reactions depicted in the schemes, it may be advisable or necessary to carry out the reactions under an inert atmosphere, such as an atmosphere of N2 gas.

[0148] It will be apparent to one skilled in the art that it may be necessary to cool the reaction mixture prior to working up the reaction (e.g., referring to a series of operations required to isolate and purify the products of a chemical reaction, such as quenching, column chromatography, extraction, etc.).

[0149] Those skilled in the art will appreciate that heating the reaction mixture under stirring may enhance the reaction outcome. In some reactions, microwave heating may be used instead of conventional heating to reduce the overall reaction time.

[0150] Those skilled in the art will appreciate that the alternative series of chemical reactions shown in the schemes below may also lead to the desired compounds of formula (I).

[0151] Those skilled in the art will appreciate that the intermediates and final compounds shown in the following schemes can be further functionalized according to methods well known to those skilled in the art. The intermediates and compounds described herein can be isolated in free form or as a salt or solvate thereof. The intermediates and compounds described herein can be synthesized in the form of a mixture of tautomers and stereoisomers, which can be separated from one another according to resolution procedures known in the art.

[0152] Scheme 1 In general, Y 1 is -O or -NR 5c -Y 1a Compounds of formula (I), designated herein as compounds of formula (Ia), (Ib), (Ic), (Id), and (Ie), can be prepared according to the following reaction scheme 1. In scheme 1, W 1 represents fluoro, chloro, bromo or iodo; all other variables are defined in accordance with the scope of the invention.

[0153] [ka]

[0154] In Scheme 1, the following reaction conditions apply: Step 1: in the presence of a suitable base such as diisopropylethylamine or triethylamine or sodium carbonate in a suitable solvent such as acetonitrile or dimethylformamide or dichloromethane at a suitable temperature such as in the range of room temperature to 90° C.; Step 2: in the presence of a suitable base such as cesium carbonate in a suitable solvent such as dimethylformamide or 1-methyl-2-pyrrolidinone at a suitable temperature range from room temperature to 130° C.; Alternatively, in the presence of a suitable deprotonating agent, for example sodium hydride, in a suitable solvent, for example dimethylsulfoxide, at a suitable temperature, for example room temperature; Alternatively, in the presence of a suitable base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in a suitable solvent, such as tetrahydrofuran, at a suitable temperature, such as room temperature; Step 3: at a suitable temperature, e.g. room temperature, in the presence of a suitable catalyst, e.g. palladium on charcoal (Pd / C), in a suitable solvent, e.g. methanol, under H2 pressure, e.g. 1-3 bar, optionally in the presence of a base, e.g. triethylamine; Alternatively, at a suitable temperature, e.g., room temperature, in the presence of a suitable catalyst, e.g., 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, a suitable reducing agent, e.g., sodium borohydride, a suitable base, e.g., N,N,N',N'-tetramethylethylenediamine, in a suitable solvent, e.g., tetrahydrofuran; Step 4: In the presence of a suitable base such as cesium carbonate at a suitable temperature range of 100-130° C. in a suitable solvent such as dimethylformamide or 1-methyl-2-pyrrolidinone; Step 5: In the presence of a suitable base such as cesium carbonate in a suitable solvent such as dimethylformamide or 1-methyl-2-pyrrolidinone at a suitable temperature range of 100-130°C; Alternatively, in the presence of a suitable catalyst, for example palladium acetate (Pd(OAc)2), in the presence of a suitable ligand, for example 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, in the presence of a suitable base, for example cesium carbonate, in a suitable solvent, for example dioxane, at a suitable temperature in the range of 80-100°C; Step 6: In a suitable solvent such as dioxane, in the presence of a suitable catalyst such as palladium acetate (Pd(OAc)2) or tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3), in the presence or absence of a suitable ligand such as triphenylphosphine, at a suitable temperature between room temperature and 60° C.;

[0155] Scheme 2 In general, Y 1 is limited to -CH2-, R 2 W 1 Compounds of formula (I) limited to, herein referred to as compounds of formula (If), can be prepared according to the following reaction scheme 2, in which all other variables are defined in accordance with the scope of the present invention.

[0156] [ka]

[0157] In Scheme 2, the following reaction conditions apply: Step 1: In a suitable solvent such as tetrahydrofuran or dioxane in the presence of a suitable catalyst such as palladium acetate (Pd(OAc)2) or tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) or tetrakis(triphenylphosphine)palladium(0) at a suitable temperature ranging from 60° C. to 100° C.

[0158] Those skilled in the art will appreciate that starting from compound (If), chemistry similar to that reported in steps 3, 4, 5 and 6 of scheme 1 can be performed.

[0159] Scheme 3 In general, Y1 -CR 5a R 5b - Limited to R 2 W 1 Compounds of formula (I) limited to (herein referred to as compounds of formula (Ig)) can be prepared according to the following Reaction Scheme 3. In Scheme 3, R 5a and R 5b is other than hydrogen. All other variables are defined in accordance with the scope of the invention.

[0160] [ka]

[0161] In Scheme 3, the following reaction conditions apply: Step 1: At a suitable temperature ranging from 80° C. to 200° C., optionally under microwave irradiation, in the presence of a suitable catalyst such as palladium acetate (Pd(OAc)2), in the presence of a suitable ligand such as triphenylphosphine or tricyclohexylphosphine, in a suitable solvent such as dioxane, preferably under sealed conditions.

[0162] Those skilled in the art will appreciate that starting from compound (Ig), chemistry similar to that reported in steps 3, 4, 5 and 6 of Scheme 1 can be performed.

[0163] Scheme 4 Compounds of formula (I), generally referred to herein as compounds of formula (Ib), can alternatively be prepared according to the following reaction scheme 4. In scheme 4, PG 1 represents a suitable protecting group, such as, for example, tert-butyloxycarbonyl, and LG 1 is a leaving group such as, for example, chloro, bromo, iodo, or tosylate or mesylate. All other variables are defined as recited prior to or in accordance with the scope of the invention.

[0164] [ka]

[0165] In Scheme 4, the following reaction conditions apply: Step 1: in the presence of a suitable base such as diisopropylethylamine or triethylamine or sodium carbonate in a suitable solvent such as acetonitrile or dimethylformamide or dichloromethane at a suitable temperature such as in the range of room temperature to 90° C.; Step 2: in the presence of a suitable base such as cesium carbonate in a suitable solvent such as dimethylformamide or 1-methyl-2-pyrrolidinone at a suitable temperature range from room temperature to 130° C.; Alternatively, in the presence of a suitable deprotonating agent, for example sodium hydride, in a suitable solvent, for example dimethylsulfoxide, at a suitable temperature, for example room temperature; Alternatively, in the presence of a suitable base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in a suitable solvent, such as tetrahydrofuran, at a suitable temperature, such as room temperature; Step 3: at a suitable temperature, e.g. room temperature, in the presence of a suitable catalyst, e.g. palladium on charcoal (Pd / C), in a suitable solvent, e.g. methanol, under H2 pressure, e.g. 1-3 bar; Alternatively, at a suitable temperature, e.g., room temperature, in the presence of a suitable catalyst, e.g., 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, a suitable reducing agent, e.g., sodium borohydride, a suitable base, e.g., N,N,N',N'-tetramethylethylenediamine, in a suitable solvent, e.g., tetrahydrofuran; Process 4:PG 1 is tert-butyloxycarbonyl, at a suitable temperature range, for example 0° C. to room temperature, under suitable cleavage conditions, for example in the presence of an acid such as HCl or trifluoroacetic acid, in a suitable solvent, for example acetonitrile or DCM or methanol (MeOH); Step 5: represents any type of reaction, such as reductive amination, nucleophilic substitution, etc., leading to the final example (Ib). Those skilled in the art will appreciate that starting from intermediate XI, chemical reactions similar to those reported in steps 3, 4, 5 and 6 of scheme 1 can be carried out.

[0166] Scheme 5 In general, U is limited to N and Y 1 Y is O 1b Compounds of formula (I) limited to the formula (Iba), herein referred to as compounds of formula (Iba), can be prepared according to the following reaction scheme 5. In scheme 5, PG 1 represents a suitable protecting group, such as, for example, tert-butyloxycarbonyl; W 2 represents a leaving group, such as, for example, chloro, tosylate or mesylate. All other variables are defined according to the scope of the present invention.

[0167] [ka]

[0168] In Scheme 5, the following reaction conditions apply: Step 1: in a suitable solvent, such as dimethylformamide, in the presence of a suitable base, such as potassium carbonate, at a suitable temperature, such as room temperature; Step 2: in the presence of a suitable base such as lithium hydroxide at a suitable temperature such as room temperature, in a suitable solvent such as, for example, a mixture of tetrahydrofuran, ethanol and water; Step 3: in a suitable solvent such as dichloroethane in the presence of dibromoisocyanurate at a suitable temperature such as room temperature; Process 4:W 2 when is chloro, in the presence of a chlorinating reagent such as oxalyl chloride, in the presence of a catalytic amount of dimethylformamide, in the presence of a suitable base such as triethylamine, in a suitable solvent such as dichloromethane, at a suitable temperature range such as room temperature; W 2is trifluoroethoxy, in the presence or absence of 2,2,2-trifluoroethanol as a solvent, at a suitable temperature such as 65° C., in the presence of molecular sieves, and a suitable activating agent such as 1,3-dibromo-1,3,5-triazinane-2,4,6-trione; Step 5: in the presence of a suitable base, such as, for example, triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in a suitable solvent, such as, for example, dichloromethane or acetonitrile, at a suitable temperature, such as room temperature; Step 6: in the presence of a suitable base, such as, for example, triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in a suitable solvent, such as, for example, dichloromethane or acetonitrile, at a suitable temperature, such as room temperature; Process 7:PG 1 is tert-butyloxycarbonyl, at a suitable temperature range, for example 0° C. to room temperature, under suitable cleavage conditions, for example in the presence of an acid such as HCl or trifluoroacetic acid, in a suitable solvent, for example acetonitrile or DCM or methanol (MeOH); Step 8: represents any type of reaction, such as reductive amination, nucleophilic substitution, etc., leading to the final example (Iba).

[0169] Scheme 6 In general, intermediates of formula IIIa can be prepared according to the following reaction scheme 5. In scheme 5, PG 2 represents a suitable protecting group, such as, for example, benzyloxycarbonyl. All other variables are defined according to the scope of the present invention or as defined in the previous schemes.

[0170] [ka]

[0171] Step 1: in the presence of benzyl chloroformate in the presence of a suitable base, such as triethylamine, in a suitable solvent, such as dichloromethane, at a suitable temperature, such as room temperature; Process 2:PG 1is tert-butyloxycarbonyl, at a suitable temperature range, for example 0° C. to room temperature, under suitable cleavage conditions, for example in the presence of an acid such as HCl or trifluoroacetic acid, in a suitable solvent, for example acetonitrile or DCM or methanol (MeOH); Step 3: represents any type of reaction, such as reductive amination, nucleophilic substitution leading to intermediate IIIa.

[0172] Scheme 7 In general, intermediates of formula XXVI can be prepared according to the following Reaction Scheme 7: The variables are defined according to the scope of the present invention or as defined in the previous schemes.

[0173] [ka]

[0174] Step 1: in a suitable solvent, such as dimethylacetamide, in the presence of a suitable base, such as cesium carbonate, at a suitable temperature, such as 120° C.; Step 2: In the presence of a suitable oxidizing agent, e.g., urea hydrogen peroxide, in the presence of a suitable reagent, e.g., trifluoroacetic anhydride, in a suitable solvent, e.g., tetrahydrofuran, at a suitable temperature, e.g., 0° C. to room temperature; Step 3: in a suitable solvent, such as ethyl acetate, in the presence of a suitable chlorinating agent, such as phosphoryl chloride, in the presence of a suitable base, such as diisopropylethylamine, at a suitable temperature, such as 0° C. to room temperature; It will be clear to those skilled in the art that starting from intermediate XXVI, similar chemical reactions can be carried out as reported in Scheme 4 starting from intermediate II.

[0175] Scheme 8 In general, intermediates of formula XXVIII can be prepared according to the following reaction scheme 8: The variables are defined according to the scope of the present invention or as defined in the previous schemes.

[0176] [ka]

[0177] Step 1: in the presence of a suitable base such as diisopropylethylamine or triethylamine or sodium carbonate in a suitable solvent such as acetonitrile or dimethylformamide or dichloromethane at a suitable temperature such as in the range of room temperature to 90° C.; It will be clear to those skilled in the art that starting from intermediate XXVIII, the first 2-position can be functionalized applying chemistry similar to that reported in scheme 1 (i.e. steps 3, 4, 5 and 6). From the intermediate obtained, the 5-position can then be functionalized in intermediates IV, VIII and VIIa applying chemistry similar to that reported in schemes 2 and 3.

[0178] It will be understood that, where appropriate functional groups are present, the compounds of the various formulas, or any intermediates used in their preparation, may be further derivatized by one or more standard synthetic methods employing condensation, substitution, oxidation, reduction, or cleavage reactions. Particular substitution techniques include conventional alkylation, arylation, heteroarylation, acylation, sulfonylation, halogenation, nitration, formylation, and coupling procedures.

[0179] The compounds of formula (I) may be synthesized in the form of racemic mixtures of enantiomers, which may be separated from each other according to resolution procedures known in the art. Racemic compounds of formula (I) containing a basic nitrogen atom may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric salt forms are then separated, for example, by selective or fractional crystallization, and the enantiomers are liberated therefrom by alkali. An alternative method for separating the enantiomeric forms of the compounds of formula (I) includes liquid chromatography using a chiral stationary phase. The pure stereochemically isomers may also be derived from the corresponding pure stereochemically isomers of the appropriate starting materials, provided that the reaction occurs stereospecifically.

[0180] In the preparation of the compounds of the present invention, protection of remote functional groups (e.g., primary or secondary amines) of intermediates may be necessary. The need for such protection will vary with the nature of the remote functional group and the conditions of the preparation method. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see TW Greene and PG M Huts, Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken, New Jersey, 2007.

[0181] Pharmacology The compounds of the present invention have been found to block the interaction of menin with MLL proteins and oncogenic MLL fusion proteins. Thus, the compounds according to the present invention and pharmaceutical compositions comprising such compounds may be useful in the treatment or prevention, particularly in the treatment, of diseases such as cancer, myelodysplastic syndrome (MDS) and diabetes.

[0182] In particular, the compounds according to the invention and pharmaceutical compositions thereof may be useful for the treatment or prevention of cancer. According to one embodiment, cancers that may benefit from treatment with the menin / MLL inhibitors of the invention include leukemia, myeloma or solid tumor cancers (such as prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma and glioblastoma). In some embodiments, leukemias include acute leukemias, chronic leukemias, myeloid leukemias, myelogeneous leukemias, lymphoblastic leukemias, lymphocytic leukemias, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), MLL-rearranged leukemia, MLL-PTD leukemia, MLL-amplified leukemia, MLL-positive leukemia, leukemias exhibiting a HOX / MEIS1 gene expression signature, and the like.

[0183] Thus, the present invention relates to compounds of formula (I), their tautomers and stereoisomers, and their pharma- ceutically acceptable salts and solvates, for use as medicaments.

[0184] The present invention also relates to the use of a compound of formula (I), a tautomer or stereoisomer thereof, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to the invention, for the manufacture of a medicament.

[0185] The present invention also relates to a compound of formula (I), a tautomer or stereoisomer thereof, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to the invention, for use in the treatment, prevention, amelioration, control or reduction of the risk of a disorder associated with the interaction of menin with MLL proteins and oncogenic MLL fusion proteins in a mammal, including a human, whose treatment or prevention is affected or promoted by blocking the interaction of menin with MLL proteins and oncogenic MLL fusion proteins.

[0186] The present invention also relates to the use of a compound of formula (I), a tautomer or stereoisomer thereof, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to the invention, for the manufacture of a medicament for treating, preventing, ameliorating, controlling or reducing the risk of a disorder associated with the interaction of menin with MLL proteins and oncogenic MLL fusion proteins in a mammal, including a human, whose treatment or prevention is affected or promoted by blocking the interaction of menin with MLL proteins and oncogenic MLL fusion proteins.

[0187] The present invention also relates to a compound of formula (I), a tautomer or stereoisomer thereof, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment or prevention of any one of the above mentioned diseases.

[0188] The present invention also relates to a compound of formula (I), a tautomer or stereoisomer thereof, or a pharma- ceutically acceptable salt or solvate thereof, for use in treating or preventing any one of the diseases mentioned herein above.

[0189] The present invention also relates to the use of a compound of formula (I), a tautomer or stereoisomer thereof, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment or prevention of any one of the disease conditions mentioned herein above.

[0190] The compounds of the invention can be administered to mammals, preferably humans, for the treatment or prevention of any one of the diseases mentioned herein above.

[0191] In view of the availability of the compounds of formula (I), their tautomers and stereoisomers, and their pharma- ceutically acceptable salts and solvates, there is provided a method for treating a warm-blooded animal, including humans, suffering from any one of the diseases mentioned herein above.

[0192] The method comprises the administration, i.e. systemic or local, of a therapeutically effective amount of a compound of formula (I), a tautomer or stereoisomer thereof, or a pharma- ceutically acceptable salt or solvate thereof to a warm-blooded animal, including man.

[0193] Therefore, the present invention also relates to a method for the treatment or prevention of any one of the diseases mentioned hereinbefore, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to the invention.

[0194] Those skilled in the art will recognize that a therapeutically effective amount of a compound of the present invention is an amount sufficient to have therapeutic activity, which amount will vary depending on, among other things, the type of disease, the concentration of the compound in the therapeutic formulation, and the condition of the patient. An effective daily therapeutic amount will be about 0.005 mg / kg to 100 mg / kg. The amount of a compound according to the present invention (also referred to herein as the active ingredient) required to achieve a therapeutic effect may vary in some cases, for example, depending on the specific compound, the route of administration, the age and condition of the recipient, and the specific disorder or disease being treated. The treatment method may also include administering the active ingredient in a regimen of 1 to 4 intakes per day. In these treatment methods, the compound according to the present invention is preferably formulated prior to administration.

[0195] The present invention also provides a composition for preventing or treating the disorders mentioned herein, comprising a therapeutically effective amount of a compound of formula (I), a tautomer or stereoisomer thereof, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier or diluent.

[0196] While it is possible for the active ingredient (e.g., a compound of the present invention) to be administered alone, it is preferable to administer it as a pharmaceutical composition. Thus, the present invention further provides a pharmaceutical composition comprising a compound according to the present invention together with a pharma- ceutically acceptable carrier or diluent. The carrier or diluent must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

[0197] Pharmaceutical compositions can be prepared, for example, as described in Gennaro et al., Remington's Pharmaceutical Sciences (18 th They may be prepared by any method well known in the art of pharmacy, using methods such as those described in "Pharmaceutical preparations and their Manufacture," ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical preparations and their Manufacture.

[0198] The compounds of the invention can be used alone or in combination with one or more additional therapeutic agents. Combination therapy includes administering a single pharmaceutical dosage formulation containing a compound according to the invention and one or more additional therapeutic agents, as well as administering a compound according to the invention and each additional therapeutic agent in its own separate pharmaceutical dosage formulation.

[0199] Thus, one embodiment of the present invention relates to a product comprising a compound according to the invention as a first active ingredient and one or more anti-cancer agents as further active ingredients as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.

[0200] One or more other pharmaceutical agents and the compound according to the present invention may be administered simultaneously (e.g., in separate or single compositions) or sequentially in any order. In the latter case, the two or more compounds are administered within a period and in an amount and manner sufficient to ensure that an advantageous or synergistic effect is achieved. It will be understood that the preferred method and order of administration of each component of the combination, as well as the respective dosages and dosing regimens, will depend on the particular other pharmaceutical agents and compounds of the present invention administered, their routes of administration, the particular condition, particularly the tumor, being treated, and the particular host being treated.

[0201] The following examples further illustrate the invention. EXAMPLES

[0202] Several methods for preparing the compounds of the present invention are illustrated in the following examples. Unless otherwise specified, all starting materials were obtained from commercial suppliers and used without further purification, or alternatively, could be synthesized by one skilled in the art by using well-known methods.

[0203] As will be understood by those skilled in the art, compounds synthesized using the protocols shown may exist as solvates, such as hydrates, and / or may contain residual solvents or trace impurities. Compounds isolated as salt forms may be of integer stoichiometry, i.e., mono- or di-salt, or of intermediate stoichiometry. When intermediates or compounds in the experimental section below are shown as "HCl salts" without indicating the number of equivalents of HCl, this means that the number of equivalents of HCl was not determined.

[0204] The stereochemical configuration of the centers in some compounds may be designated "R" or "S" when the mixture is isolated, and for some compounds, the compounds themselves have been isolated as single stereoisomers and are enantiomerically pure, but when the absolute stereochemistry has not been determined (even if the bonds are drawn stereospecifically), the stereochemical configuration of the indicated centers may be designated "R" or "S". * R" or " * It is named "S."

[0205] For example, compound 3,

[0206] [ka] It will be clear that

[0207] [ka]

[0208] The above paragraph regarding stereochemical configuration also applies to the intermediates.

[0209] As used herein, the term "enantiomerically pure" means that the product contains at least 80% by weight of one enantiomer and no more than 20% by weight of the other enantiomer. Preferably, the product contains at least 90% by weight of one enantiomer and no more than 10% by weight of the other enantiomer. In the most preferred embodiment, the term "enantiomerically pure" means that the composition contains at least 99% by weight of one enantiomer and no more than 1% of the other enantiomer.

[0210] Those skilled in the art will understand that, even if not explicitly mentioned in the experimental protocols below, typically after column chromatography purification, the desired fractions were collected and the solvent was evaporated.

[0211] When stereochemistry is not indicated, this is meant to be a mixture of stereoisomers unless otherwise indicated or clear from the context.

[0212] When a stereocenter is designated "RS," this means that a racemic mixture was obtained at the indicated center, unless otherwise indicated.

[0213] Those skilled in the art will appreciate that where intermediates or compounds are reported in tables, the synthetic methodology from the indicated starting material to the desired intermediate / compound may involve one or more reaction steps.

[0214] Where two enantiomers, diastereomers or isomers are present in one and the same cell of the tables below, the skilled artisan will understand that these intermediates or compounds have been separated from one another by using appropriate chromatographic methods, such as SFC or reverse phase separation.

[0215] Preparation of intermediates For intermediates that were used in the next reaction step either as crude intermediates or as partially purified intermediates, in some cases either no molar amount is mentioned for such intermediate in the next reaction step or an estimated or theoretical molar amount is indicated for such intermediate in the next reaction step in the reaction protocols described below.

[0216] Hereinafter, the term "ACN" or "MeCN" means acetonitrile, "DCM" means dichloromethane, "DIPEA or DIEA" means N,N-diisopropylethylamine, "h" means hours, "min" means minutes, "DMF" means N,N-dimethylformamide, "TEA" or "Et3N" means triethylamine, "EtOAc" or "EA" means ethyl acetate, "THF" means tetrahydrofuran, "HPLC" means high performance liquid chromatography, "Prep-HPLC" means preparative HPLC, "MeOH" means methanol, "NMR" means nuclear magnetic resonance, "rt or "RT" means room temperature, and "SFC" means supercritical fluid chromatography. "Qs" means quantity, "DMSO" means dimethylsulfoxide, "Pd / C" or "Pd / C(10%)" means palladium on carbon, "atm" means atmosphere, "ee" means enantiomeric excess, "PE" means petroleum ether, "NaBH(OAc)3" means sodium triacetoxyborohydride, "TFA" means trifluoroacetic acid, "DCE" means dichloroethane, "DMA" means N,N-dimethylacetamide, "IPA" means isopropyl alcohol, "iPrNH2" means isopropylamine, NH4OH means ammonium hydroxide, and "Pd(OH)2" means palladium hydroxide.DBU means 1,8-diazabicyclo[5.4.0]undec-7-ene, "Cbz" means benzoylcarbonyl, NaBH3CN means sodium cyanoborohydride, NaBH4 means sodium borohydride, tlc means thin layer chromatography, FCC means flash column chromatography, HATU means 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, N-[(dimethylamino)-1H-1,2,3-triazolo[ "4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; EDCI means N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; "HOBT" or "HOBt" means 1-hydroxybenzotriazole hydrate; TMEDA means N,N,N',N'-tetramethylethylenediamine; and Pd(dppf)Cl2.DCM means [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane. "Ni(acac)2" means nickel(II) acetylacetonate, "Zn" means zinc, "MS" means molecular sieves, "Boc2O" means di-tert-butyl decarboxylate, "Ar" means argon, "FA" means formic acid, "CC" means column chromatography, and "T3P" means propylphosphonic anhydride.

[0217] A. Preparation of intermediates Example A1 Preparation of intermediate 1

[0218] [ka]

[0219] A mixture of 2,6-diazaspiro[3.3]heptane-2-carboxylic acid, phenylmethyl ester (1.084 g, 4.667 mmol), tert-butyl 3-isobutyrylazetidine-1-carboxylate (1.3 g, 5.6 mmol), sodium cyanoborohydride (1.5 g, 23.33 mmol) and acetic acid (267 μL, 4.67 mmol) in methanol (50 mL) was stirred at 50 °C overnight. The mixture was collected and another reaction was carried out with 100 mg of 2,6-diazaspiro[3.3]heptane-2-carboxylic acid, phenylmethyl ester, poured into 10% aqueous K2CO3. The resulting mixture was extracted with DCM. The organic layer was decanted, washed with water, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (irregular SiOH, 40 g; mobile phase: gradient from 0% NH4OH, 0% MeOH, 100% DCM to 0.3% NH4OH, 3% MeOH, 97% DCM). Pure fractions were collected and evaporated to dryness. The obtained residue was purified again by chromatography on silica gel (irregular SiOH, 40 g; mobile phase: gradient from 40% EtOAc, 60% heptane to 60% EtOAc, 40% heptane). Pure fractions were collected and evaporated to dryness to give 1.58 g of intermediate 1 (70% yield).

[0220] Preparation of intermediate 2

[0221] [ka]

[0222] A mixture of intermediate 1 (500 mg; 1.127 mmol) and TFA (1.5 mL) in DCM (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ACN and evaporated to dryness (twice). The residue was dissolved in DCM and basified with 15% aqueous NH4OH. The organic layer was washed again with 15% aqueous NH4OH, then with water, filtered through Chromabond® and evaporated to dryness to give 330 mg of intermediate 2 (85%), which was directly taken on to the next step without further purification.

[0223] Preparation of intermediate 3

[0224] [ka]

[0225] Acetic acid (55 μL; 0.96 mmol) was added to a solution of intermediate 2 (330 mg; 0.96 mmol), oxetane-3-carbaldehyde (132 μL; 1.92 mmol) in THF (12 mL) at room temperature. The mixture was stirred overnight at room temperature, then NaBH(OAc)3 (611 mg; 2.88 mmol) was added dropwise. The mixture was stirred at room temperature for 3 hours. The reaction mixture was partitioned between 10% aqueous K2CO3 and EtOAc. The layers were separated and the aqueous layer was extracted once with DCM. The organic layers were combined, dried over MgSO4 and evaporated to dryness. The residue was purified by chromatography on silica gel (irregular SiOH, 10 g + 24 g; mobile phase: gradient from 0.5% NH4OH, 5% MeOH, 95% DCM to 1% NH4OH, 10% MeOH, 90% DCM). The pure fractions were collected and evaporated to dryness, yielding 264 mg of intermediate 3 (66% yield).

[0226] Preparation of intermediate 4

[0227] [ka]

[0228] A mixture of intermediate 3 (264 mg; 0.638 mmol) and Pd / C (10%) (68 mg; 0.0638 mmol) in ethanol (10 mL) was hydrogenated under 3 bar of H for 2 h. The Pd / C (10%) was removed by filtration over Celite® and the solvent was evaporated to dryness to give 173 mg of intermediate 4 (97% yield).

[0229] Example A2 Preparation of intermediate 5

[0230] [ka]

[0231] In a round bottom flask, 2,6-diazaspiro[3.4]octane-6-carboxylic acid, phenylmethyl ester (500 mg; 2.03 mmol), tert-butyl 3-isobutyrylazetidine-1-carboxylate (553.7 mg; 2.43 mmol), sodium cyanoborohydride (382.7 mg; 6.09 mmol) and acetic acid (0.116 mL; 2.03 mmol) were diluted in MeOH. The reaction mixture was then heated at 50° C. overnight and cooled to room temperature. Carefully, a saturated solution of NaHCO3 was added until pH>9. The resulting mixture was extracted with DCM. The organic layer was decanted, washed with water, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (irregular SiOH, 40 g; mobile phase: 0% NHOH, 0% MeOH, 100% DCM gradient to 0.3% NHOH, 3% MeOH, 97% DCM). Pure fractions were collected and evaporated to dryness to give 700 mg of intermediate 5 (75% yield).

[0232] Preparation of intermediate 6

[0233] [ka]

[0234] In a round bottom flask at 0° C., TFA (2.34 mL, 30.59 mmol) was added to intermediate 5 (700 mg, 1.53 mmol) in DCM (33.7 mL). The reaction was then warmed to room temperature and the reaction mixture was stirred at room temperature overnight. The residue was dissolved in 4 mL of water. The solution was then basified with 1 M NaOH solution (12 mL) until pH=8-9. After stirring at room temperature for 10 min, the resulting mixture was extracted with dichloromethane (3×30 mL). The combined organic layers were washed with brine (1×50 mL), dried over MgSO4, filtered and evaporated to dryness to give 482 mg of intermediate 6, which was directly taken on to the next step without further treatment.

[0235] Preparation of intermediate 7

[0236] [ka]

[0237] Acetic acid (119 μL; 2.07 mmol) was added to a solution of intermediate 6 (482 mg; 1.34 mmol) and oxetane-3-carbaldehyde (188 μL; 2.72 mmol) in THF (20 mL) at room temperature. The mixture was stirred at room temperature for 4 h, then NaBH(OAc)3 (870 mg; 4.1 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. The reaction mixture was poured into ice water, basified with 10% aqueous K2CO3 solution, and EtOAc was added. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated to dryness to give 438 mg of intermediate residue. The residue (438 mg) was purified by silica gel chromatography (stationary phase: irregular SiOH 15-40 μm 24 g mobile phase: gradient from 97% DCM, 3% MeOH (+10% NH4OH) to 90% DCM, 10% MeOH (+10% NH4OH)). The product-containing fractions were combined and concentrated to give 127 mg of intermediate 7 (yield 22%).

[0238] Preparation of intermediate 8

[0239] [ka]

[0240] A mixture of intermediate 7 (63 mg; 0.147 mmol), Pd(OH)2 (21 mg, 0.174 mmol) in MeOH (3 mL) and THF (0.5 mL) was hydrogenated overnight under atmospheric pressure. The catalyst was removed by filtration through a pad of Celite®, washed with MeOH, and the filtrate was evaporated to give 35 mg of intermediate 8 (81% yield).

[0241] Example A3 Preparation of intermediate 9

[0242] [ka]

[0243] To a mixture of 5-fluoro-2-methoxybenzoic acid (8.00 g, 47.0 mmol) and N-ethylpropan-2-amine (8.19 g, 94.0 mmol) in dry DCM (150 mL) cooled to 0 °C, HATU (21.5 g, 56.5 mmol) and DIEA (9.10 g, 70.4 mmol) were added slowly in small portions. The resulting mixture was slowly warmed to room temperature and stirred for 8 h. The organic layer was washed with water (20 mL x 3) and dried over anhydrous Na2SO4. After filtration, the solvent was removed under reduced pressure and the crude product was purified by FCC (EtOAc / PE = 0% to 20% EtOAc) to give intermediate 9 (12.0 g, 96% yield) as a white solid.

[0244] The following intermediates were synthesized by methods similar to those described above for the preparation of intermediate 9.

[0245] [Table 1]

[0246] Preparation of intermediate 11 (Method A).

[0247] [ka]

[0248] To a solution of intermediate 9 (12.0 g, 50.1 mmol) in dry DCM (100 mL) cooled to -78 °C, BBr3 (14.4 mL, 152 mmol) was added slowly, and the resulting mixture was slowly warmed to room temperature and stirred for 8 h. The mixture was cooled to -78 °C again, and MeOH (5 mL) was added dropwise to quench the reaction. The resulting mixture was slowly warmed to room temperature, and the pH value was adjusted to about 8 by adding a saturated solution of NaHCO3. The aqueous layer was extracted with DCM (50 mL × 3), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by FCC (EtOAc / PE = 0% to 20% EtOAc) to give intermediate 11 (9.0 g, 78% yield) as a white solid.

[0249] Alternative Preparation of Intermediate 11 (Method B)

[0250] [ka]

[0251] A solution of 5-fluorosalicylic acid (30.0 g, 192.2 mmol) in thionyl chloride (200 mL) was stirred at 80° C. for 5 hours. The resulting mixture was then concentrated under reduced pressure to obtain the acyl chloride. To a stirred solution of N-ethylpropan-2-amine (33.5 g, 384.3 mmol) and triethylamine (58.3 g, 576.5 mmol) in dichloromethane (200 mL) was added dropwise a solution of the acyl chloride in dichloromethane (100 mL) at 0° C. After stirring overnight at room temperature, the resulting mixture was concentrated under reduced pressure. The crude product was dissolved in methanol (300 mL). A solution of sodium hydroxide (20 g) in water (100 mL) was then added. After stirring for 1 hour at room temperature, the resulting mixture was diluted with water (100 mL), concentrated under reduced pressure to remove excess methanol, adjusted to a pH value of 4, and extracted with ethyl acetate (2×150 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (EA / PE, 16.3:83.7) to give 29.4 g of intermediate 11 (66% yield) as an off-white solid.

[0252] The following intermediates were synthesized by a similar method as described above for intermediate 11 (Method A).

[0253] [Table 2]

[0254] The following intermediates were synthesized by a similar method as described above for intermediate 11 (Method B).

[0255] [Table 3]

[0256] Example A4 Preparation of intermediate 13

[0257] [ka]

[0258] To a solution of 3,5,6-trichloro-1,2,4-triazine (10.0 g, 54.2 mmol) and TEA (15.2 mL, 109 mmol) in DCM (100 mL) cooled to 0 °C, tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (9.21 g, 43.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 1 h. The mixture was diluted with water (20 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel FCC (mobile phase A: PE; mobile phase B: EtOAc, eluent 0-25% mobile phase B) to give intermediate 13 (12.0 g, 58% yield) as a yellow solid.

[0259] Preparation of intermediate 14

[0260] [ka]

[0261] A mixture of intermediate 13 (12.0 g, 33.3 mmol), intermediate 11 (7.5 g, 33.3 mmol) and DBU (6.1 g, 40.1 mmol) in THF (120 mL) was stirred at 25 °C for 8 h. The mixture was diluted with water (30 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel FCC (mobile phase A: PE; mobile phase B: EtOAc, eluent 0-25% mobile phase B) to give intermediate 14 (14.0 g, 73% yield) as a green solid.

[0262] The following intermediates were synthesized by a similar method as described above for intermediate 14.

[0263] [Table 4]

[0264] Preparation of intermediate 16

[0265] [ka]

[0266] Method A: To a mixture of intermediate 14 (20 g, 36.4 mmol), NaBH4 (2.48 g, 65.7 mmol) and TMEDA (8.54 g, 73.5 mmol) in THF (500 mL) was added Pd(dppf)Cl2×DCM (1.70 g, 2.08 mmol) under N2 atmosphere. After addition, the reaction mixture was stirred at 25° C. for 14 h. The reaction mixture was filtered, the filtrate was concentrated and the residue was purified by silica gel FCC (eluent with EtOAc) to give intermediate 16 (15 g, 74% yield) as a brown solid.

[0267] Method B: To a solution of intermediate 14 (22.0 g, 40.1 mmol), TEA (15 mL) in MeOH (100 mL) was added Pd / C (wet, 5.0 g, 10%). The resulting mixture was stirred under H2 atmosphere (30 psi) at 25° C. for 8 h. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated in vacuo to give intermediate 16 (25.0 g, crude), which was used directly in the next step without further purification.

[0268] The following intermediates were synthesized by a similar method to that described above for intermediate 16.

[0269] [Table 5]

[0270] Preparation of intermediate 18

[0271] [ka]

[0272] To a solution of intermediate 16 (300 mg, 0.583 mmol) in DCM (5 mL), TFA (0.5 mL, 6.4 mmol) was added and the resulting mixture was stirred at room temperature for 3 h. Then, 10% NaOH (5 mL) solution was slowly added to the mixture to adjust the pH value to about 12, and the resulting mixture was extracted with DCM (10 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give intermediate 18 (220 mg, 90% yield) as a white solid.

[0273] The following intermediates were synthesized by a similar method to that described above for intermediate 18.

[0274] [Table 6]

[0275] Example A5 Preparation of intermediate 20:

[0276] [ka]

[0277] To a solution of cis-3-[[(1,1-dimethylethoxy)carbonyl]amino]-cyclobutanecarboxylic acid (10.0 g, 46.5 mmol) in DMF (100 mL) was added HOBt (8.15 g, 60.3 mmol), EDCI (11.6 g, 60.5 mmol) and DIEA (30.0 mL, 182 mmol, 0.782 g / mL) at 0° C. Then, N,O-dimethylhydroxylamine hydrochloride (5.90 g, 60.5 mmol) was added at 0° C. The mixture was stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate (500 mL). The mixture was washed with 1M HCl (150 mL), saturated NaHCO3 (100 mL x 2) and brine (300 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give intermediate 20 (11.0 g, crude) as a white solid, which was used in the next step without further purification.

[0278] Preparation of intermediate 21:

[0279] [ka]

[0280] To a solution of intermediate 20 (11.0 g, 6.97 mmol) in THF (100 mL) was added isopropylmagnesium chloride (64.0 mL, 128 mmol, 2 M in THF) dropwise at 0° C. under N2 atmosphere. The mixture was stirred at room temperature under N2 atmosphere for 12 h. The mixture was quenched with saturated NH4Cl (100 mL). The mixture was filtered through a pad of Celite® and the filtrate was concentrated under reduced pressure. The mixture was extracted with ethyl acetate (200 mL×2). The combined organic layers were washed with brine (200 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluent: petroleum ether:ethyl acetate, 1:0 to 5:1) to give intermediate 21 (6.30 g) as a white solid.

[0281] Example A6 Preparation of intermediate 22:

[0282] [ka]

[0283] To a mixture of intermediate 18 (1 g, 2.41 mmol), intermediate 21 (873 mg, 3.62 mmol), acetic acid (276 μL, 4.83 mmol) in MeOH (50 mL) at room temperature under N2, NaBH3CN (455 mg, 7.24 mmol) was added. The reaction was then heated at 50 °C overnight. The reaction mixture was cooled to room temperature, poured into ice water, basified with a saturated solution of NaHCO3, and DCM was added. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The crude product was purified by silica gel chromatography (stationary phase: irregular SiOH 15-40 μm 40 g, mobile phase: 0% NH4OH, 100% DCM, gradient from 0% MeOH to 0.1% NH4OH, 95% DCM, 5% MeOH). The product containing fractions were combined and concentrated to give 1.37 g (89% yield) of intermediate 22.

[0284] Example A7 Preparation of intermediate 23:

[0285] [ka]

[0286] To a solution of 3,3-dimethoxycyclobutanecarboxylic acid (12.0 g, 75 mmol) in DCM (145 mL) was added T3P (100 mL, 168 mmol, 50% in EtOAc) and DIEA (64 mL, 372 mmol) at 0° C. Then N,O-dimethylhydroxylamine hydrochloride (8.8 g, 89.5 mmol) was added at 0° C. The mixture was stirred at room temperature for 16 h. The mixture was poured into a saturated solution of NaHCO3 and EtOAc was added. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give intermediate 23 (16.0 g, crude), which was used in the next step without further purification.

[0287] Preparation of intermediate 24:

[0288] [ka]

[0289] The reaction was carried out twice with 15.7 g of intermediate 23 and the respective reaction media were combined for workup and purification. To a solution of intermediate 23 (15.7 g, 77.7 mmol) in THF (420 mL) was added isopropylmagnesium chloride (178.5 mL, 232 mmol, 2 M in THF) dropwise under N2 atmosphere at 0° C. The reaction mixture was stirred for 12 h at room temperature under N2 atmosphere and then poured into ice water and a 10% aqueous solution of NH4Cl. The mixture obtained was combined with the mixture obtained from the second reaction and the combined mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (mobile phase: heptane:EtOAc 9:1). Pure fractions were collected and evaporated to dryness to give 22 g (76% yield) of intermediate 24 as a colorless oil.

[0290] Example A8 Preparation of intermediate 25

[0291] [ka]

[0292] A mixture of intermediate 18 (10 g, 24.13 mmol), intermediate 24 (4.94 g, 26.54 mmol) and acetic acid (1.5 mL, 26.54 mmol) in MeOH (80 mL) was stirred at room temperature for 20 min. Then NaBH3CN (1.82 g, 28.95 mmol) was added and the mixture was stirred at 50 °C overnight. The reaction solution was poured into ice water and extracted with DCM. The organic layer was washed with water and brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (mobile phase A: PE; mobile phase B: EtOAc, eluent 0-100% EtOAc) to give 9.21 g (64% yield) of intermediate 25 as a pale yellow solid.

[0293] Preparation of intermediate 26

[0294] [ka] and intermediate 27

[0295] [ka]

[0296] Intermediate 25 (9.2 g) was purified by chiral SFC (stationary phase: C+HIRALPAK AD-H 5 μm 250 * 21.2 mm, mobile phase: 83% CO2, 17% mixture of EtOH / ACN 80 / 20 v / v (+0.3% iPrNH2)). The fractions containing the product were combined and concentrated to give 4.07 g (44% yield) of intermediate 26 and 4.06 g (44% yield) of intermediate 27 and a remaining fraction of 273 mg of intermediate 25.

[0297] Method A for intermediate 27: To a solution of intermediate 35 (2.24 g, 3.618 mmol) in methanol (45 mL) was added palladium on activated carbon (10% palladium) (635 mg, 0.597 mmol). The mixture was then stirred under hydrogen at room temperature for 5 h. The mixture was diluted with methanol, filtered through a pad of Celite®, and the filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with sodium hydroxide solution (1M in water) and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 1.4 g (62% yield) of intermediate 27 as a yellow solid.

[0298] Method B for Intermediate 27: A mixture of intermediate 35 (1.44 g; 2.33 mmol) and TMEDA (0.54 mL; 3.63 mmol) in dry THF (55 mL) was degassed by bubbling N2. Then Pd(dppf)Cl2.DCM (216 mg; 0.26 mmol) and sodium cyanoborohydride (144 mg, 3.81 mmol) were added. The reaction mixture was stirred overnight at 50 °C in a closed glassware. The solution was cooled and poured out into cold water. EtOAc was added and the mixture was filtered through Celite®. The product was extracted with EtOAc and the organic layer was dried over MgSO4, filtered and evaporated to dryness. The crude residue (1.7 g) was purified by silica gel chromatography (stationary phase: 40 g irregular SiOH 40 μm, mobile phase: 100% DCM, 0% MeOH (+10% NH4OH) gradient to 95% DCM, 5% MeOH (+10% NH4OH)). The product-containing fractions were combined and concentrated to give two fractions of intermediate 27 (680 mg, 50% yield, 96% purity by LCMS and 360 mg; 26% yield, 91% purity by LCMS).

[0299] Preparation of intermediate 28:

[0300] [ka]

[0301] A solution of intermediate 26 (2 g, 3.42 mmol) and TFA (2.9 mL; 37.9 mmol) in DCM (29 mL) was stirred at room temperature overnight. ACN was then added and the solution was evaporated to dryness. The residue was then dissolved in EtOAc and ice water and basified with NH4OH. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and evaporated to give 1.80 g of intermediate 28 (98% yield).

[0302] Preparation of intermediate 29:

[0303] [ka]

[0304] Intermediate 27 (1.87 g, 3.20 mmol) in TFA (2.7 mL) and DCM (27 mL) was stirred at room temperature overnight. The solution was evaporated to dryness. The residue was then dissolved in DCM and ice water and basified with 30% aqueous NH4OH. The aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4, filtered and evaporated to give 1.35 g of intermediate 29 (78% yield) as a pale yellow solid.

[0305] Alternative preparation of intermediate 29: To a solution of intermediate 27 (1.40 g, 2.25 mmol) in acetone (30 mL) and water (14 mL) was added p-toluenesulfonic acid (1.94 g, 11.276 mmol). The reaction solution was stirred at 65 degrees for 5 hours. The resulting mixture was quenched with water and ethyl acetate. The combined organic layers were washed with water and brine and dried over anhydrous sodium sulfate. The solid was filtered off. The residue was concentrated under reduced pressure to give 1.01 g (78%) of intermediate 29 as a yellow solid.

[0306] Preparation of intermediate 29a:

[0307] [ka]

[0308] Intermediate 29a was prepared according to intermediate 28 starting from intermediate 25.

[0309] Example A9 Preparation of intermediate 30:

[0310] [ka]

[0311] To a stirred solution of 2,6-diazaspiro[3.4]octane-6-carboxylic acid, phenylmethyl ester (15 g, 60.9 mmol) in methanol (300 mL) was added intermediate 24 (13.61 g, 73.08 mmol) and acetic acid (4.02 g, 66.99 mmol). After stirring at room temperature for 0.5 h, sodium cyanoborohydride (7.65 g, 121.8 mmol) was added. After stirring at 50 °C overnight, the reaction mixture was quenched with potassium carbonate solution (10% in water) and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solids were filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase A: PE; mobile phase B: EtOAc, eluent 0-50% EtOAc) to give 17.8 g (69% yield) of intermediate 30 as a pale yellow oil.

[0312] Preparation of intermediate 31:

[0313] [ka] and intermediate 32:

[0314] [ka]

[0315] 170 g of intermediate 30 was purified by SFC using the following conditions: Column: CHIRALPAK IG, 5 *25 cm, 10 um; mobile phase A: CO2, mobile phase B: EtOH:ACN:DCM = 1:1:1; flow rate: 150 mL / min; gradient: 40% B; 220 nm; retention time 1 = 4.45 min; retention time 2 = 5.88 min; injection volume: 3.8 mL; run number: 237 giving two fractions. Fraction A: 67.0 g (purity >99% by LCMS, yield 39%, retention time 2: 5.88 min) of intermediate 31 as a pale yellow oil. Fraction B: 65 g (purity 99%, yield 38%, retention time 1: 4.45 min) of intermediate 32 as a pale yellow oil.

[0316] Preparation of intermediate 33

[0317] [ka]

[0318] To a solution of intermediate 31 (15 g, 36.01 mmol) in methanol (300 mL) was added palladium on activated carbon (10% palladium) (8 g, 7.517 mmol). The mixture was then stirred under hydrogen (2-3 atm) at room temperature for 5 h. The mixture was diluted with methanol and filtered through a pad of Celite®. The filtrate was evaporated under reduced pressure to give 9.5 g of the desired product as a yellow oil, which was used directly in the next step without further modification.

[0319] Preparation of intermediate 34

[0320] [ka]

[0321] To a solution of 3,5,6-trichloro-1,2,4-triazine (9.4 g, 50.99 mmol) in dichloromethane (100 mL) was added a mixture of intermediate 33 (12.0 g, 42.49 mmol) and triethylamine (12 mL, 84.98 mmol) in dichloromethane (150 mL) at 0° C. under nitrogen. After stirring at room temperature for 3 h under nitrogen, the mixture was quenched with water and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure to give 17.3 g (83% yield, 88% purity by LCMS) of intermediate 34 as a yellow solid.

[0322] Preparation of intermediate 35:

[0323] [ka]

[0324] A solution of intermediate 34 (1.6 g; 3.72 mmol), intermediate 11 (1 g; 4.44 mmol) and DBU (2.7 mL; 18.45 mmol) in THF (150 mL) was stirred at room temperature for 72 h. The solution was poured into cold water and the product was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to dryness. The crude (3 g) was purified by silica gel chromatography (stationary phase: 80 g of irregular bare silica, mobile phase: 63% heptane, 2% MeOH (+10% NH4OH), 35% EtOAc). The fractions containing the product were combined and concentrated to give 1.48 g (64% yield) of intermediate 35.

[0325] Alternative preparation of intermediate 35: To a solution of intermediate 34 (3.00 g, 6.971 mmol) and intermediate 11 (1.88 g, 8.365 mmol) in tetrahydrofuran (60 mL) was added tetramethylguanidine (1.37 g, 11.85 mmol). The reaction solution was stirred at room temperature for 2 days. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with sodium hydroxide (0.5 M / L), water and brine, and dried over anhydrous sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography column (ethyl acetate / hexane 2:1) to give 2.60 g (59% yield) of intermediate 35 as a yellow solid.

[0326] Preparation of intermediate 82:

[0327] [ka]

[0328] To a mixture of intermediate 34 (10.0 g, 23.27 mmol) and intermediate 81 (5.89 g, 27.887 mmol) in THF (250 mL) was added tetramethylguanidine (7.3 mL, 58.09 mmol). After stirring at room temperature for 48 h, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (mobile phase A: PE; mobile phase B: EtOAc, eluent 0-93% EtOAc) to give 7.5 g (49% yield) of intermediate 82 as a yellow solid.

[0329] Preparation of intermediate 83

[0330] [ka]

[0331] To a mixture of intermediate 82 (7.0 g, 11.57 mmol) in tetrahydrofuran (140 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (472 mg, 0.58 mmol), sodium borohydride (744 mg, 19.67 mmol) and N,N,N',N'-tetramethylethylenediamine (2.9 mL, 19.67 mmol). After stirring overnight at room temperature under N2 atmosphere, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (MeOH / DCM, 0% MeOH to 9% MeOH) to give 4.8 g (54% yield, 85.1% purity based on LC / MS) of intermediate 83 as a brown solid.

[0332] Preparation of intermediate 84:

[0333] [ka]

[0334] To a mixture of intermediate 83 (4.8 g, 8.32 mmol) in acetone (100 mL) and water (50 mL) was added p-toluenesulfonic acid (7.17 g, 41.62 mmol). After stirring at 65° C. overnight, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 3.1 g (45% yield, 62.8% purity based on LC / MS) of intermediate 84 as a brown solid.

[0335] Example A10 Preparation of intermediate 36:

[0336] [ka]

[0337] To a stirred solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (30.0 g, 149.09 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (42.9 g, 223.64 mmol) and N,O-dimethylhydroxylamine (21.8 g, 223.64 mmol) in DCM (500 mL) was added N,N-diisopropylethylamine (61.7 mL, 372.73 mmol) and 4-dimethylaminopyridine (3.6 g, 29.82 mmol). After stirring at room temperature overnight, the reaction solution was diluted with DCM (500 mL), washed with water, 10% aqueous citric acid, water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 24.0 g of intermediate 36 as a pale yellow oil.

[0338] Preparation of intermediate 37:

[0339] [ka]

[0340] To a stirred solution of intermediate 36 (26.5 g, 108.5 mmol) in tetrahydrofuran (250 mL) was added isopropylmagnesium chloride (271 mL, 542.0 mmol, 2M in THF) at 0° C. After stirring at room temperature overnight, the reaction mixture was quenched with brine (300 mL) at 0° C. and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA, 8:2) to give 19.5 g of intermediate 37 (87% purity, 68% yield) as a pale yellow oil.

[0341] Preparation of intermediate 39:

[0342] [ka]

[0343] To a stirred mixture of tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (25.5 g, 120.12 mmol) and potassium carbonate (36.52 g, 264.262 mmol) in tetrahydrofuran (250 mL) in water (250 mL) was added benzyl chloroformate (20.3 mL, 144.143 mmol) at 0° C. After stirring overnight at room temperature, the reaction mixture was extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA, 6:4) to give 39.10 g of intermediate 39 (purity 99%, yield 93%) as a pale yellow oil.

[0344] Preparation of intermediate 40:

[0345] [ka]

[0346] To a solution of intermediate 39 (55.5 g, 160.2 mmol) in DCM (550 mL) was added TFA (110 mL). After stirring at room temperature for 2 h, the reaction solution was concentrated. The residue was dissolved in water (300 mL). The resulting aqueous solution was basified to pH=8 with a saturated solution of NaHCO3 and extracted with DCM / MeOH (10:1, 4×500 mL). The combined organic layers were washed with brine (2×300 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give 45.3 g (74% yield) of intermediate 40 as a TFA salt and as a light brown solid.

[0347] Preparation of intermediate 41:

[0348] [ka]

[0349] To a stirred solution of intermediate 40 (5.00 g, 13.88 mmol) in methanol (50 mL) was added intermediate 37 (3.79 g, 16.65 mmol). After stirring at room temperature for 0.5 h, sodium cyanoborohydride (4.36 g, 69.38 mmol) was added. The resulting mixture was stirred at 50° C. overnight. Additional intermediate 37 (1.58 g, 6.94 mmol) and sodium cyanoborohydride (2.62 g, 41.63 mmol) were added. After stirring at 50° C. for 6 h, additional sodium cyanoborohydride (1.31 g, 20.814 mmol) was added. After stirring at 50° C. overnight, the reaction mixture was quenched with saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with (PE / EA, 7:3) to give 4.5 g (67% yield) of intermediate 41 as a pale yellow oil.

[0350] Preparation of intermediate 42:

[0351] [ka]

[0352] To a stirred solution of intermediate 41 (3.60 g, 7.87 mmol) in ethanol (40 mL) was added palladium on activated carbon 10% Pd (800 mg). After stirring at room temperature under a stream of hydrogen (2-3 atm) for 2 h, the reaction mixture was filtered through a pad of Celite®, which was washed with ethanol and DCM. The filtrate was concentrated under reduced pressure to give 2.5 g of intermediate 42 as a grey oil.

[0353] Preparation of intermediate 43:

[0354] [ka]

[0355] To a stirred solution of 3,4,6-trichloropyridazine (700 mg, 2.164 mmol) in N,N-dimethylformamide (15 mL) was added intermediate 42 (397 mg, 2.164 mmol) and triethylamine (0.9 mL, 6.492 mmol). After stirring at room temperature for 3 h, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE:EA=55:45) to give 900 mg (84% yield) of intermediate 43 as a white solid.

[0356] Preparation of intermediate 44:

[0357] [ka]

[0358] To a stirred solution of intermediate 43 (800 mg, 1.701 mmol) in N,N-dimethylacetamide (15 mL) was added intermediate 11 (383 mg, 1.70 mmol) and cesium carbonate (1.66 g, 5.10 mmol). After stirring at 130° C. for 3 h, the reaction mixture was cooled to room temperature, quenched with water (100 mL), and extracted with EA (3×80 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE:EA=55:45) to give 800 mg (70% yield) of intermediate 44 as a white solid.

[0359] Preparation of intermediate 45:

[0360] [ka]

[0361] To a stirred solution of intermediate 44 (750 mg, 1.138 mmol) in ethyl acetate (15 mL) was added palladium 10% Pd on activated carbon (800 mg). After stirring overnight at room temperature under a flow of hydrogen (2-3 atm), the reaction mixture was filtered through a pad of Celite®, which was washed with ethyl acetate and ethanol. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (DCM:MeOH=6:4) to give 303 mg (42% yield) of intermediate 45 as an off-white solid.

[0362] Preparation of intermediate 50:

[0363] [ka]

[0364] A mixture of intermediate 18 (740 mg, 1.78 mmol), intermediate 37 (487 mg, 2.1 mmol), NaBH3CN (337 mg, 5.4 mmol) and acetic acid (102 μL, 1.78 mmol) in MeOH (15 mL) was stirred at 50 °C overnight. The reaction mixture was combined with another reaction carried out on 220 mg of intermediate 18. The resulting reaction mixture was poured into ice water, basified with a saturated solution of NaHCO3 and DCM was added. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: irregular SiOH 15-40 μm 24 g MERCK, mobile phase: gradient from 99% DCM, 1% MeOH (+10% NH4OH) to 95% DCM, 5% MeOH (+10% NH4OH)). The product containing fractions were combined and concentrated to give 1.04 g (93% yield) of intermediate 50.

[0365] Preparation of intermediate 51:

[0366] [ka] and intermediate 52:

[0367] [ka]

[0368] Intermediate 50 (1.04 g) was purified by chiral SFC (stationary phase: CHIRALPAK IC 5 μm 250 * 30 mm, mobile phase: 50% CO, 50% EtOH (0.3% iPrNH)). The product-containing fractions were combined and concentrated to give 411 mg (37% yield) of intermediate 51 and 427 mg (38% yield) of intermediate 52.

[0369] Alternative preparation of intermediate 50: Intermediate 18 (854 mg; 1.13 mmol) and intermediate 37 (385 mg; 1.7 mmol) in THF (15 mL) were stirred at room temperature for 24 h under a stream of N2. Sodium triacetoxyborohydride (718 mg; 3.39 mmol) was then added in portions. The mixture was stirred at room temperature for 24 h. The solution was poured into cold water, basified with a solution of NaOH 3N, and EtOAc was added. The organic layer was separated, dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: 12 g irregular SiOH 15-40 μm, mobile phase: gradient from 99% DCM, 1% MeOH (+10% NH4OH) to 95% DCM, 5% MeOH (+10% NH4OH)). The fractions containing the product were combined and concentrated to give 200 mg (28% yield) of intermediate 50.

[0370] Example A12 Preparation of intermediate 53

[0371] [ka]

[0372] Phosphorus oxychloride (9.42 g, 61.4 mmol) was added dropwise to a solution of 4-chloropyridazin-3-ol (2.00 g, 38.3 mmol) and ACN (20 mL) at 0 °C (ice / water). The reaction mixture was then heated and stirred at 80 °C for 3 h, and then cooled to room temperature. The reaction mixture was slowly poured into water (50 mL) and adjusted to pH = 8 with a saturated solution of sodium bicarbonate. The mixture was extracted with DCM (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified using FCC (silica gel, mobile phase A: PE; mobile phase B: EtOAc, eluent 0-25% EtOAc) to give intermediate 53 (2.00 g, 88% yield) as a yellow solid.

[0373] Preparation of intermediate 54:

[0374] [ka]

[0375] After adding a stir bar, intermediate 53 (500 mg, 3.36 mmol), tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (712 mg, 3.35 mmol), triethylamine (1.02 g, 10.1 mmol) and dry DCM (10 mL) to a 40 mL glass bottle, the resulting mixture was stirred at 25 °C for 8 h. The mixture was diluted in DCM (20 mL) and washed with water (10 mL × 3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified using FCC (silica gel, mobile phase A: PE; mobile phase B: EtOAc, eluent 0-100% EtOAc) to give intermediate 54 (500 mg, 42% yield) as a yellow solid.

[0376] Preparation of intermediate 55

[0377] [ka]

[0378] After adding a stir bar, intermediate 11 (346 mg, 1.54 mmol), intermediate 54 (500 mg, 1.54 mmol), cesium carbonate (1.51 g, 4.63 mmol) and dry N,N-dimethylformamide (10 mL) to a 50 mL round-bottom flask, the resulting mixture was heated and stirred at 130 °C for 8 h. The mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was suspended in dichloromethane (20 mL) and washed with water (10 mL × 3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by FCC (silica gel, mobile phase A: EtOAc; mobile phase B: MeOH, eluent 0-10% MeOH) to give intermediate 55 (700 mg, 80% yield) as a yellow solid.

[0379] Preparation of intermediate 56:

[0380] [ka]

[0381] After adding a stir bar, intermediate 55 (700 mg, 1.36 mmol), trifluoroacetic acid (4 mL) and dry dichloromethane (2 mL) to a 25 mL round bottom flask, the mixture was stirred at 25° C. for 40 min. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted in dichloromethane (20 mL) and the pH was adjusted to pH=12 with sodium hydroxide solution (3 M, 8 mL). The aqueous layer was extracted with dichloromethane (10 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give intermediate 56 (600 mg, crude) as a yellow oil.

[0382] Preparation of intermediate 57:

[0383] [ka]

[0384] HATU (99.5 g, 262 mmol) was added in portions to a 0 °C (ice / water) mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (50.0 g, 218 mmol), N,O-dimethylhydroxylamine hydrochloride (23.4 g, 240 mmol), Et3N (90.9 mL, 654 mmol) and dichloromethane (500 mL). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was diluted with water (1500 mL) and extracted with dichloromethane (500 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to give the crude product, which was purified by FCC (silica gel, mobile phase A: PE; mobile phase B: EtOAc, eluted with 0-50% EtOAc) to give intermediate 57 (54 g, yield: 82%) as a yellow oil.

[0385] Preparation of intermediate 58:

[0386] [ka]

[0387] Intermediate 57 (54.0 g, 198 mmol) and THF (500 mL) were added to a 1 L three-neck round-bottom flask. i-PrMgCl (198 mL, 397 mmol, 2 M in THF) was added dropwise to the mixture at 0 °C (ice / water) under N2. The mixture was stirred for 10 h while warming to room temperature, then poured into water (2000 mL) and extracted with EtOAc (1000 mL x 3). The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography on silica gel (silica gel, mobile phase A: PE; mobile phase B: EtOAc, eluent 0-35% EtOAc) to give intermediate 58 (19.2 g, 34% yield) as a yellow oil.

[0388] Preparation of intermediate 59:

[0389] [ka]

[0390] After adding a stir bar, intermediate 58 (278 mg, 1.09 mmol), intermediate 56 (300 mg, 0.726 mmol), zinc chloride (200 mg, 1.47 mmol) and dry methanol (6 mL) to a 40 mL glass bottle, the mixture was heated and stirred at 45 °C for 4 h. Then, sodium cyanotrihydroborate (91.2 mg, 1.45 mmol) was added to the mixture. The resulting mixture was stirred at 45 °C for another 40 h. The mixture was diluted in dichloromethane (40 mL) and washed with water (10 mL × 3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by FCC (silica gel, mobile phase A: EtOAc; mobile phase B: MeOH, eluent 0-10% MeOH) to give intermediate 59 (150 mg, 29% yield) as a yellow solid.

[0391] Example A12 Preparation of intermediate 60:

[0392] [ka]

[0393] Intermediate 18 (120 mg, 0.29 mmol), Intermediate 58 (150 mg, 0.585 mmol) and ZnCl2 (80 mg, 0.59 mmol) were added to a 25 mL round bottom flask and the resulting mixture was dissolved in MeOH (5 mL). The mixture was heated and stirred at 80° C. for 4 h. Sodium cyanoborohydride (37 mg, 0.59 mmol) was added to the mixture. The mixture was then stirred at 80° C. for 16 h. Then, further Intermediate 58 (150 mg, 0.585 mmol), ZnCl2 (80 mg, 0.59 mmol) and NaBH3CN (37 mg, 0.59 mmol) were added to the above solution. The mixture was then stirred at 80° C. for 6 h. The reaction mixture was concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative HPLC using a Boston Green ODS 150 mm×30 mm×5 μm column (eluent: 25%-55% (v / v) CH3CN and 0.04% NH3H2O+10 mM NH4HCO3 in H2O) to give the pure intermediate 60, which was suspended in water (10 mL). The mixture was frozen using dry ice / acetone and then lyophilized to dryness to give intermediate 60 (60 mg) as a white solid.

[0394] Intermediate 60a

[0395] [ka] and preparation of intermediate 60b:

[0396] [ka]

[0397] Intermediate 60 (375 mg, 0.57 mmol) was purified by supercritical fluid chromatography (separation conditions: DAICEL CHIRALPAK IG (250 mm x 30 mm x 10 um); mobile phase: A: supercritical CO2, B: 0.1% NH3H2O ​​IPA, A:B = 45:55 at 80 mL / min; column temperature: 38; nozzle pressure: 100 bar; nozzle temperature: 60; evaporator temperature: 20; trimmer temperature: 25; wavelength: 220 nm). Pure fractions were collected and volatiles were removed under reduced pressure. The resulting product was lyophilized to dryness to completely remove solvent residues. The desired product intermediate 60a (15 mg, 4% yield) and intermediate 60b (19 mg, 5% yield) were obtained as white solids.

[0398] Preparation of intermediate 61:

[0399] [ka]

[0400] EDCI (34.0 g, 177 mmol) was added to a solution of (R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (25.0 g, 116 mmol), HOBT (24.0 g, 178 mmol), DIPEA (102.5 mL, 586.9 mmol) and DMF (250 mL) at 0° C. The reaction mixture was stirred for 5 min. N,O-dimethylhydroxylamine (12.5 g, 128 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 10 h and then cooled to room temperature. The mixture was poured into water (1000 mL) and extracted with ethyl acetate (400 mL×3). The organic phase was washed with 5% aqueous citric acid (400 mL x 3), saturated NaHCO3 (400 mL x 2), brine (400 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate 61 (26 g, 82% yield) as a colorless oil.

[0401] Preparation of intermediate 62:

[0402] [ka]

[0403] i-PrMgCl (101 mL, 202 mmol, 2M in THF) was added dropwise to a solution of intermediate 61 (26.0 g, 101 mmol) and THF (250 mL) at 0 °C (ice / water). The reaction mixture was stirred at room temperature for 10 h. The mixture was quenched with a saturated solution of NH4Cl (500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the product, which was purified by FCC (silica gel, mobile phase A: PE; mobile phase B: EtOAc, elution with 0-50% EtOAc) to give intermediate 62 (15.0 g, 56% yield) as a yellow oil.

[0404] Intermediate 63:

[0405] [ka] and preparation of intermediate 64:

[0406] [ka]

[0407] To a solution of intermediate 18 (300 mg, 0.724 mmol) and intermediate 62 (524 mg, 2.17 mmol) in 15 mL of MeOH, ZnCl2 (395 mg, 2.90 mmol) was added. After the addition, the reaction mixture was stirred at 75° C. for 3 hours, then NaBH3CN (182 mg, 2.90 mmol) was added to the reaction, and the mixture was stirred at the same temperature for 4 hours. Further intermediate 62 (300 mg) was added, and the mixture was stirred at 75° C. for 16 hours. The reaction mixture was concentrated in vacuum, and the residue was purified by preparative HPLC (column Welch Xtimate C18 150×25 mm×5 um, mobile phase A: water (0.04% NH3H2O+10 mM NH4HCO3), mobile phase B: acetonitrile, flow rate: 30 mL / min, gradient conditions from 61% B to 81% B). The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to give intermediate 63 (75.0 mg, 16% yield) as a white solid and intermediate 64 (88 mg, 18% yield) as a white solid.

[0408] Preparation of intermediate 65:

[0409] [ka]

[0410] (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (15.0 g, 69.7 mmol), EDCI (20.039 g, 104.53 mmol), HOBT (14.125 g, 104.53 mmol) and DIEA (45.034 g, 348.44 mmol) were added to DMF (100 mL) at 10° C. After 5 min, N,O-dimethylhydroxylamine hydrochloride (7.477 g, 76.66 mmol) was added to the mixture. The mixture was stirred at 40° C. for 10 h, then poured into water (400 mL) and extracted with ethyl acetate (300 mL×3 times). The organic phase was washed with 5% aqueous citric acid (3×300 mL), saturated NaHCO (2×300 mL), brine (2×300 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure to give Intermediate 65 (12.41 g, 74%) as a yellow oil.

[0411] Preparation of intermediate 66:

[0412] [ka]

[0413] Intermediate 65 (12.4 g, 48.0 mmol) and THF (20 mL) were added to a 250 mL round bottom flask. Isopropylmagnesium chloride (49 mL, 98 mmol, 2 M in THF) was added dropwise to the mixture at 0 °C (ice / water) under N2. The mixture was stirred for 10 h while warming to room temperature. The mixture was quenched with a saturated aqueous solution of NH4Cl (100 mL) and extracted with EtOAc (200 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give the crude product, which was purified by FCC (silica gel, mobile phase A: PE; mobile phase B: EtOAc, eluent 0-35% EtOAc) to give intermediate 66 (7.6 g, 65%) as a pale yellow oil.

[0414] Intermediate 67

[0415] [ka] and preparation of intermediate 68:

[0416] [ka]

[0417] To a solution of intermediate 18 (300 mg, 0.724 mmol) and intermediate 66 (524 mg, 2.17 mmol) in 15 mL of MeOH, ZnCl2 (395 mg, 2.90 mmol) was added. After the addition, the reaction mixture was stirred at 75° C. for 3 hours. Then, NaBH3CN (182 mg, 2.90 mmol) was added to the reaction mixture, and the mixture was stirred at the same temperature for 4 hours. Further intermediate 67 (300 mg) was added, and the mixture was stirred at 75° C. for 16 hours. The reaction mixture was cooled to 25° C. and concentrated in vacuo. The residue was purified by preparative HPLC (column Welch Xtimate C18 150×25 mm×5 um, mobile phase A: water (0.04% NH3H2O+10 mM NH4HCO3), mobile phase B: acetonitrile, flow rate: 30 mL / min, gradient conditions from 61% B to 81% B). The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to give intermediate 67 (100 mg, 21% yield) as a white solid and intermediate 68 (105 mg, 22% yield) as a white solid.

[0418] Preparation of intermediate 70:

[0419] [ka]

[0420] To a mixture of 2-[(4-chloro-5-pyrimidinyl)oxy]-N-ethyl-5-fluoro-N-(1-methylethyl)-benzamide (4.5 g, 13.322 mmol) and intermediate 42 (4.31 g, 13.322 mmol) in acetonitrile (100 mL) was added sodium carbonate (5.65 g, 53.29 mmol) at room temperature. After stirring at 90° C. for 2 h, the resulting mixture was cooled to room temperature and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with (DCM / MeOH, 96.7:3.3) to give intermediate 70, 6.7 g (78% yield).

[0421] Preparation of intermediate 71:

[0422] [ka] and intermediate 72

[0423] [ka]

[0424] Intermediate 70 (6.7 g) was purified by chiral SFC (stationary phase: CHIRACEL OJ-H 5 μm 250 * 30 mm, mobile phase: 94% CO, 6% MeOH (0.3% iPrNH)). The product containing fractions were combined and concentrated to give 3.18 g (47% yield) of intermediate 71 and 3.16 g (47% yield) of intermediate 72.

[0425] Preparation of intermediate 73:

[0426] [ka]

[0427] EDCI (3.12 g, 13.7 mmol) was added to a solution of 1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-carboxylic acid (2.00 g, 9.12 mmol), DIEA (6.5 mL, 36.7 mmol), N,O-dimethylhydroxylamine hydrochloride (1.78 g, 18.2 mmol) and HOBT (1.85 g, 13.7 mmol) in acetonitrile (20 mL), and the reaction mixture was stirred under N2 at 25 °C for 2 h. The mixture was quenched with water (50 mL) and extracted with EtOAc (100 mL x 3). The EtOAc layer was dried over Na2SO4, filtered and evaporated to give a residue, which was purified by FCC (silica gel, PE:EA = 100:0 to 60:40) to give intermediate 73 (1.5 g, 63% yield) as a pale yellow oil.

[0428] Preparation of intermediate 74:

[0429] [ka]

[0430] i-PrMgCl 2M in THF (10 mL, 20 mmol) was added dropwise to a solution of intermediate 73 (3.00 g, 11.4 mmol) in THF (30 mL) under N2 at 5 °C. The solution was stirred at 5 °C for 30 min, slowly warmed to 20 °C and stirred for 12 h. The reaction mixture was poured into a mixture of ice water and saturated aqueous NH4Cl solution and extracted with EtOAc (200 mL x 2). The organic layer was decanted, dried over Na2SO4, filtered and evaporated to dryness. The obtained crude product was purified by FCC (silica gel, PE:EA = 100:0 to 70:30) to give intermediate 74 (1.6 g, 51% yield) as a colorless oil.

[0431] Preparation of intermediate 75:

[0432] [ka]

[0433] To a solution of bicyclo[1.1.1]pentane-1-carboxylic acid (1.00 g, 8.92 mmol), tert-butyl 4-bromopiperidine-1-carboxylate (4.71 g, 17.8 mmol), 2,2'-bipyridine (696 mg, 4.46 mmol), Ni(acac)2 (916 mg, 3.57 mmol), MgCl2 (2.55 g, 26.8 mmol), Zn (4.00 g, 61.2 mmol), 4Å MS (10.0 g) and DIEA (4.5 mL, 27.2 mmol) in THF / DMF (100 mL / 30 mL) was added Boc2O (7.79 g, 35.7 mmol) under Ar atmosphere at 30° C. After the addition, the reaction mixture was stirred at 30° C. for 60 h. The reaction mixture was poured into 150 mL of water and extracted with EtOAc (150 mL×2). The combined extracts were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, eluent PE / EtOAc=100:0 to 85:15) to give intermediate 75 (580 mg, 60% purity based on LCMS, 14% yield) as a colorless oil.

[0434] Preparation of intermediate 76:

[0435] [ka]

[0436] To a solution of intermediate 75 (580 mg, 60% purity, 1.25 mmol), intermediate 18 (568 mg, 1.37 mmol) and AcOH (449 mg, 7.47 mmol) in 50 mL of MeOH was added NaBH3CN (470 mg, 7.47 mmol). After addition, the reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was concentrated in vacuo and the residue was diluted with 100 mL of water and extracted with EtOAc (100 mL×2). The combined extracts were concentrated in vacuo and the resulting residue was purified by preparative HPLC (column Phenomenex Gemini NX-C18 (75 * 30mm *The mixture was purified by HPLC using a 300 rpm column (3 μm), mobile phase A: water (0.2% FA), mobile phase B: acetonitrile, flow rate: 30 mL / min, gradient conditions from 25% B to 55% B). Pure fractions were collected and lyophilized to give intermediate 76 (310 mg, 37% yield) as a white solid.

[0437] Preparation of intermediate 76:

[0438] [ka]

[0439] LiCl (565.2 mg, 13.333 mmol) was dried under high vacuum by heating with a heat gun and then cooled to room temperature. Mg turnings (324 mg, 13.333 mmol) and THF (11.1 mL, 1M, 11.1 mmol) were then added. The reaction mixture was cooled to 0° C. and then bromocyclobutane (1.5 g, 11.1 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. During this time a grey solution was formed. Cyclobutylmagnesium bromide in THF. LiCl or intermediate 76 (approximately 1M) was used directly in the following reaction.

[0440] Preparation of intermediate 77:

[0441] [ka]

[0442] In a flask, intermediate 57 (1.01 g, 3.704 mmol) was dissolved in dry THF (10 mL). The solution was cooled in an ice bath and treated dropwise at this temperature with a solution of freshly prepared intermediate 76 (11.1 mL, ca. 1 M, 11.1 mmol). The reaction mixture was stirred overnight and allowed to reach room temperature. Saturated ammonium chloride solution was then added and the aqueous phase was extracted three times with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and then the organic phase was evaporated. The crude product (953 mg) was purified by flash CC (silica gel, 15% EA in n-heptane) to give 833 mg (28% yield) of intermediate 77 as a colorless oil.

[0443] Preparation of intermediate 78:

[0444] [ka] Intermediate 79:

[0445] [ka] and intermediate 80:

[0446] [ka]

[0447] To a solution of intermediate 18 (90.0 mg, 0.217 mmol), 2 drops of acetic acid and intermediate 77 (145.1 mg, 0.543 mmol) in methanol (4 mL) was added sodium cyanoborohydride (54.6 mg, 0.869 mmol). After stirring at 60° C. overnight, the solvent was removed under vacuum. The reaction was then quenched with a saturated solution of sodium carbonate and extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over anhydrous magnesium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure. The crude product (200 mg) was obtained as a colorless oil and purified by preparative CC (12 g silica gel, eluent 2.5 to 5% MeOH in DCM) to give intermediate 78 (106 mg, 73% yield) as a white solid. Enantiomer separation was performed by preparative SFC (stationary phase: Chiralpak Daicel IG 20×250 mm, mobile phase: CO, EtOH+0.4 iPrNH 2 ) to give 224 mg of intermediate 79 and 261 mg of intermediate 80 containing 5% of intermediate 79.

[0448] Preparation of intermediate 85:

[0449] [ka]

[0450] To a mixture of 4-chloro-3-iodopyridine (2.00 g, 8.35 mmol) in DMF (30 mL) was added tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (1.95 g, 9.19 mmol) and Cs2CO3 (8.2 g, 25.2 mmol). The resulting mixture was stirred at 110 °C overnight. The reaction was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by FCC (100% petroleum ether to petroleum ether:ethyl acetate = 1:1) to give intermediate 85 (1.7 g, 100% purity, 49% yield) as a white solid.

[0451] Preparation of intermediate 86:

[0452] [ka]

[0453] To a mixture of intermediate 11 (2.72 g, 12.1 mmol) in N-methyl-2-pyrrolidone (20 mL), intermediate 85 (1.70 g, 4.09 mmol) and Cs2CO3 (4.00 g, 12.3 mmol) were added. The mixture was replaced with argon. Then CuCl (255 mg, 2.58 mmol) and 2,2,6,6-tetramethyl-3,5-heptanedione (0.4 mL, 1.91 mmol) were added under the protection of argon. The resulting mixture was stirred overnight at 140° C. under argon atmosphere. The mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (40 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by FCC (100% DCM to DCM:MeOH=10:1) to give intermediate 86 (780 mg, 89.93% purity, 33% yield) as a brown solid.

[0454] Preparation of intermediate 87:

[0455] [ka]

[0456] To a mixture of intermediate 86 (200 mg, 0.390 mmol) in DCM (2 mL) was added TFA (0.5 mL) at room temperature. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was evaporated under reduced pressure. The residue was diluted with 2M NaOH (5 mL) and extracted with DCM (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give intermediate 87 (160 mg, 99% yield) as a yellow solid, which was used in the next step without further purification.

[0457] Preparation of intermediate 88:

[0458] [ka]

[0459] To a mixture of intermediate 87 (160 mg, 0.388 mmol) in MeOH (4 mL) was added intermediate 21 (187 mg, 0.775 mmol) and AcOH (47 mg, 0.783 mmol). The mixture was stirred at 70 °C for 1 h. Then the mixture was cooled to room temperature and NaBH3CN (48 mg, 0.764 mmol) was added to the mixture. The resulting mixture was stirred at 70 °C for another 1 h. The reaction mixture was cooled to room temperature and evaporated to remove the solvent. The residue was diluted with saturated aqueous NaHCO3 (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by FCC (100% petroleum ether to 100% ethyl acetate; TLC: ethyl acetate, Rf=0.1) to give intermediate 88 (100 mg, 99% purity, 40% yield) as a yellow solid.

[0460] Preparation of intermediate 89:

[0461] [ka]

[0462] To a solution of intermediate 19 (800 mg, 1.475 mmol) in MeOH (10 mL) was added intermediate 37 (838 mg, 3.686 mmol). The mixture was stirred at room temperature for 1 h. To the mixture was added NaBHCN (556 mg, 8.848 mmol) at 0° C. The mixture was stirred at room temperature overnight. The mixture was quenched with sodium bicarbonate solution, extracted with EA, washed with water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (silica gel, eluent 100% DCM to 10% MeOH in DCM) to give 300 mg of intermediate 89 as a yellow oil.

[0463] B. Compound Preparation Preparation of Compound 1:

[0464] [ka]

[0465] A mixture of 2-[(4-chloro-5-pyrimidinyl)oxy]-N-ethyl-5-fluoro-N-(1-methylethyl)-benzamide (174 mg; 0.516 mmol), intermediate 4 (173 mg; 0.62 mmol) and sodium carbonate (218 mg; 2.064 mmol) in ACN (20 mL) was refluxed for 2 h (90° C.). The reaction mixture was cooled to room temperature, poured into ice water and extracted with DCM. The organic layer was decanted, washed with water, filtered through Chromabond® and evaporated to dryness. The residue was purified by chromatography on silica gel (irregular SiOH, 24 g; mobile phase: gradient from 0% NH4OH, 0% MeOH, 100% DCM to 1% NH4OH, 10% MeOH, 90% DCM). Pure fractions were collected and evaporated to dryness to give 150 mg of compound 1 (50% yield).

[0466] Preparation of compound 2

[0467] [ka]

[0468] A mixture of 2-[(4-chloro-5-pyrimidinyl)oxy]-N-ethyl-5-fluoro-N-(1-methylethyl)-benzamide (33.5 mg; 0.099 mmol), intermediate 8 (35 mg; 0.119 mmol) and sodium carbonate (42 mg; 0.398 mmol) in ACN (3.7 mL) was refluxed (90° C.) for 2 h. Similar work-up and purification as used to isolate compound 1 was applied to give compound 2.

[0469] Compound 3:

[0470] [ka] and compound 4: Preparation of

[0471] [ka]

[0472] Compound 2 (361 mg) was transferred to chiral SFC (stationary phase: CHIRALPAK AD-H 5 μm 250 * The product was purified by HPLC using a 30 mm column chromatography (mobile phase: 88% CO2, 12% EtOH (0.3% iPrNH2)). The product-containing fractions were combined and concentrated to give 156 mg of fraction A, which was dissolved with Et2O and evaporated to dryness to give 150 mg of compound 3 and 156 mg of fraction B, which was dissolved with Et2O and evaporated to dryness to give compound 4.

[0473] Alternative preparation of compound 4: The reaction was carried out twice on (1.3 g; 2.48 mmol) of compound 76.

[0474] Under a stream of N2, NaBH(OAc)3 (1.56 g; 7.43 mmol) was added dropwise to a solution of compound 76 (2.6 g; 5 mmol), oxetane-3-carbaldehyde (0.37 mL; 5.35 mmol) in THF (100 mL). The reaction mixture was then stirred at room temperature for 2 h. Both reactions (performed on 1.3 g of compound 76) were combined with another reaction performed on 700 mg of compound 76, the resulting mixture was poured into ice water, basified with a 10% aqueous solution of K2CO3, and EtOAc was added. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and evaporated to dryness to give 3.93 g of crude compound 4, which was further combined with 392 mg of crude compound 4. The resulting crude product was purified by silica gel chromatography (stationary phase: irregular SiOH 15-40 μm 80 g MERCK, mobile phase: gradient from 97% DCM, 3% MeOH (+10% NH4OH) to 90% DCM, 10% MeOH (+10% NH4OH)). The product-containing fractions were combined and concentrated to give 2.5 g of compound 4 (white product) and 1.2 g of impure (71.6% purity as assessed by LC / MC) compound 4.

[0475] Similar reaction protocols as reported for compounds 1 and 2 can be used to prepare the compounds listed in the table below, starting from the appropriate starting materials.

[0476] [Table 7-1]

[0477] [Table 7-2]

[0478] Preparation of compound 22:

[0479] [ka]

[0480] TFA (3.2 mL; 42.2 mmol) was added to intermediate 22 (1.35 g; 2.11 mmol) in DCM (32 mL) at 0° C. The reaction was then allowed to warm to room temperature and stirred at room temperature for 15 h.

[0481] The reaction mixture was concentrated and the residue was dissolved in 40 mL of water. The solution was basified with a 1M solution of NaOH until pH=8-9. After stirring at room temperature for 10 min, the resulting mixture was extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to dryness to give 0.84 g (74%) of compound 22.

[0482] Preparation of compound 32:

[0483] [ka]

[0484] A solution of intermediate 45 (100 mg; 0.16 mmol) and TFA (0.25 mL; 3.27 mmol) in DCM (2.5 mL) was stirred at room temperature overnight. TFA was removed by evaporation. The residue was dissolved in water and basified with aqueous NH4OH. The organic layer was extracted with DCM, dried over MgSO4 and evaporated to dryness to give 84 mg of compound 32 (quantitative).

[0485] Preparation of compound 33:

[0486] [ka]

[0487] At 0° C., TFA (0.49 mL; 6.4 mmol) was added to a solution of intermediate 50 (200 mg; 0.32 mmol) in DCM (7 mL). The reaction mixture was stirred at room temperature overnight. The residue was evaporated to dryness. The residue (420 mg) was purified by silica gel chromatography (stationary phase: 12 g irregular SiOH 15-40 μm, mobile phase: 90% DCM, 10% MeOH (+10% NH4OH) gradient to 85% DCM, 15% MeOH (+10% NH4OH)). The fractions containing the product were combined and concentrated to give 144 mg (85% yield) of compound 33.

[0488] Preparation of compound 34:

[0489] [ka]

[0490] At 0° C., TFA (0.42 mL; 5.5 mmol) was added to a solution of intermediate 51 (173 mg; 0.28 mmol) in DCM (6 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was dissolved in water. The solution was then basified with NaOH 1M solution until pH=9-10. After stirring at room temperature for 10 min, the resulting mixture was extracted with dichloromethane (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to dryness to give 150 mg (quantitative) of compound 34.

[0491] Preparation of compound 35:

[0492] [ka]

[0493] Compound 35 was prepared according to compound 34 starting from intermediate 52.

[0494] Preparation of compound 36:

[0495] [ka]

[0496] After adding a stir bar, intermediate 59 (130 mg, 0.199 mmol), trifluoroacetic acid (2 mL) and dry dichloromethane (1 mL) to a 25 mL round-bottom flask, the resulting mixture was stirred for 1 h at 25° C. The mixture was concentrated under reduced pressure to give compound 36 (130.0 mg, crude) as a colorless oil, which was used directly in the next step without further purification.

[0497] Preparation of compound 37:

[0498] [ka]

[0499] Intermediate 60 (40 mg, 0.061 mmol), 1,4-dioxane (0.5 mL) and HCl / 1,4-dioxane (0.2 mL, 4 M) were added to a 10 mL round bottom flask. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated to dryness under reduced pressure to give the title compound, which was dissolved in H2O (10 mL). The resulting solution was basified to pH=8 with solid NaHCO3 and extracted with ethyl acetate (10 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was suspended in water (10 mL). The mixture was frozen using dry ice / acetone and then lyophilized to give compound 37 (30 mg, crude) as a white solid, which was used in the next step without further purification.

[0500] Preparation of compound 78:

[0501] [ka]

[0502] HCl / dioxane (200 uL, 0.400 mmol, 2M) was added to a solution of intermediate 60a (15 mg, 0.023 mmol) in dioxane (1 mL). The reaction mixture was stirred at room temperature for 2 h. A white solid precipitated. The solvent was removed by syringe and the white solid was concentrated to dryness under reduced pressure to give the title compound, which was suspended in water (10 mL), frozen using dry ice / ethanol, and then lyophilized to dryness to give compound 78 (6.47 mg, 47% yield) as a white solid.

[0503] Preparation of compound 79:

[0504] [ka]

[0505] HCl / dioxane (200 uL, 0.400 mmol) was added to a solution of intermediate 60b (19 mg, 0.029 mmol) and dioxane (1 mL). The reaction mixture was stirred at room temperature for 2 hours. A white solid precipitated. The solvent was removed by syringe and the white solid was concentrated to dryness under reduced pressure to give the title compound, which was suspended in water (10 mL), frozen using dry ice / ethanol, and then lyophilized to dryness to give compound 79 (7.32 mg, 42% yield) as a white solid.

[0506] Preparation of compound 45:

[0507] [ka]

[0508] HCl / dioxane (150 uL, 0.300 mmol, 2M) was added to a solution of intermediate 63 (20 mg, 0.031 mmol) and dioxane (1 mL). The reaction mixture was stirred at room temperature for 4 hours. A white solid precipitated. The solvent (dioxane) was removed by syringe and the white solid was concentrated to dryness under reduced pressure to give the title compound, which was suspended in water (10 mL). The mixture was frozen using dry ice / ethanol and then lyophilized to dryness to give compound 45 (3.17 mg, 17% yield) as a white solid.

[0509] Preparation of compound 46

[0510] [ka]

[0511] HCl / dioxane (150 uL, 0.300 mmol, 2M) was added to a solution of intermediate 64 (19 mg, 0.030 mmol) and dioxane (1 mL). The reaction mixture was stirred at room temperature for 4 hours. A white solid precipitated. The solvent (dioxane) was removed by syringe and the white solid was concentrated to dryness under reduced pressure to give the title compound, which was suspended in water (10 mL). The mixture was frozen using dry ice / ethanol and then lyophilized to dryness to give compound 46 (8.01 mg, 46% yield) as a white solid.

[0512] Preparation of compound 49:

[0513] [ka]

[0514] HCl / 1,4-dioxane (0.3 mL) was added to a mixture of intermediate 67 (25 mg, 0.039 mmol) and 1,4-dioxane (1 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative HPLC using a YMC-Triart Prep C18 250×50 mm×10 μm column (eluent: 45%-75% (v / v) CH3CN with 0.04% NH3H2O+10 mM NH4HCO3) to give the pure product. The product was suspended in water (10 mL). The mixture was frozen using dry ice / ethanol and then lyophilized to dryness to give compound 49 (3.88 mg, 89%. Purity based on LC / MS, 16% yield) as a white solid.

[0515] Alternative procedure for the preparation of compound 49: After adding a stir bar, intermediate 67 (70.0 mg, 0.109 mmol) and hydrochloric acid / dioxane (2 mL, 8.0 mmol, 4 M in dioxane) to a 10 mL round-bottom flask, the mixture was stirred for 1 h at 25° C. The mixture was concentrated under reduced pressure to give 70 mg of crude compound 49 (HCl salt) as a white solid, which was used in the next step without further purification.

[0516] Preparation of compound 50:

[0517] [ka]

[0518] To a solution of intermediate 68 (40.0 mg, 0.063 mmol) in 1 mL of dioxane was added HCl / dioxane (3 mL). After addition, the reaction mixture was stirred at 10° C. for 45 min. The reaction mixture was concentrated in vacuum and the residue was purified by preparative HPLC (column Boston Prime C18 150×30 mm×5 um, mobile phase A: water (0.04% NH3H2O+10 mM NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 45% B to 75%). Pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to give compound 50 (12 mg, 34% yield) as a white solid.

[0519] Preparation of compound 76:

[0520] [ka]

[0521] In a round bottom flask at 0 °C, TFA (12.7 mL; 166 mmol) was added to intermediate 71 (5.18 g; 8.29 mmol) in DCM (175 mL). The reaction was then warmed to room temperature and the reaction mixture was stirred at room temperature overnight. The residue was dissolved in 20 mL of water. The solution was then basified with NaOH 1M solution (70 mL) until pH = 8-9. After stirring at room temperature for 10 min, the resulting mixture was extracted with dichloromethane (5 x 100 mL). The combined organic layers were washed with brine (1 x 150 mL), dried over MgSO4, filtered and evaporated to dryness to give 4 g (92% yield) of compound 76.

[0522] The compounds listed in the table below were prepared following similar reaction protocols as reported for the preparation of compound 76 starting from the corresponding starting materials.

[0523] [Table 8]

[0524] Preparation of compound 80:

[0525] [ka]

[0526] To a solution of intermediate 76 (380 mg, 0.561 mmol) in 3 mL of DCM was added TFA (6 mL). After the addition, the reaction mixture was stirred at 27° C. for 1 h. The reaction mixture was concentrated in vacuo to give compound 80 (350 mg, crude TFA salt), which was used in the next step without purification.

[0527] Preparation of compound 112:

[0528] [ka]

[0529] In a vial, intermediate 80 (208 mg, 0.312 mmol) was dissolved in DCM (3.00 mL, 46.9 mmol) and cooled to 0° C. The mixture was treated with TFA (0.478 mL, 6.25 mmol) and then the cooling bath was removed. After stirring overnight, saturated sodium carbonate solution was added as well as DCM. The aqueous phase was further basified to pH 13 with 1N aqueous NaOH. The aqueous phase was extracted multiple times with DCM and then ethyl acetate. The combined organic solvents were dried over MgSO4, filtered, and the solvent was removed to give compound 112 (150 mg, 85% yield) as a white solid.

[0530] Preparation of compound 113:

[0531] [ka]

[0532] In a vial, intermediate 79 (224 mg, 0.336 mmol) was dissolved in DCM (3.23 mL, 50.5 mmol) and cooled to 0° C. The mixture was treated with TFA (0.515 mL, 6.73 mmol). The cooling bath was removed. After stirring overnight, saturated sodium carbonate solution was added as well as DCM. The aqueous phase was further basified to pH 13 with 1N aqueous NaOH. The aqueous phase was extracted multiple times with DCM and ethyl acetate. The collected organic solvent was dried over MgSO4, filtered, and the solvent was then removed to give crude compound 113 (239 mg). 35 mg of crude compound 113 was used for purification via preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30×150 mm, mobile phase: 0.25% NH4HCO3 in water, CH3CN) to give 16 mg of compound 113 as a white solid.

[0533] Compound 54:

[0534] [ka] Compound 55:

[0535] [ka] and preparation of compound 56

[0536] [ka]

[0537] In a sealed tube, NaBH3CN (45.8 mg, 0.729 mmol) was added to a mixture of intermediate 29 (157 mg, 0.291 mmol), (S)-3-methoxypyrrolidine (88.4 mg, 0.874 mmol) and acetic acid (16.7 μL, 0.291 mmol) in methanol (4 mL). The reaction mixture was stirred at 60 °C for 18 h. Saturated aqueous NaHCO3 and EtOAc were added. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated and purified by silica gel chromatography (irregular SiOH 40 μm, 12 g, liquid loading (DCM), mobile phase gradient: DCM / (MeOH / NH3 aq: 9 / 1): 99 / 1 to 90 / 10). The fractions containing the product were evaporated to give 164 mg of compound 54, which was purified by reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30 * Purification was performed at 150 mm, mobile phase: gradient: (NH4HCO3 aqueous solution 0.2%, pH=9.5) / (MeCN / MeOH:1 / 1):40 / 60 to 10 / 90). The product-containing fractions were evaporated, solubilized in MeCN, diluted with water, and lyophilized to give 81 mg (45% yield) of compound 55 as a white fluffy solid and 22 mg (12% yield) of compound 56 as a white fluffy solid.

[0538] Compound 57:

[0539] [ka] and compound 58 Preparation of:

[0540] [ka]

[0541] NaBH3CN (47 mg; 0.75 mmol) was added to a mixture of intermediate 29 (200 mg; 0.37 mmol), (cis)-hexahydro-1H-furo[3,4-c]pyrrole (0.13 mL; 1.12 mmol) and AcOH (21 μL; 0.37 mmol) in THF (10 mL) and the reaction mixture was stirred at 60 °C for 18 h. The reaction mixture was cooled to room temperature and poured into a 10% aqueous solution of K2CO3 and EtOAc. The organic layer was decanted, separated, dried over MgSO4, filtered and evaporated to dryness (g). The crude product (340 mg) was purified by silica gel chromatography (stationary phase: 12 g of irregular bare silica, mobile phase: gradient from 99% DCM, 1% MeOH (+10% NH4OH) to 90% DCM, 10% MeOH (+10% NH4OH)). The fractions containing the product were combined and concentrated to give an intermediate fraction (220 mg), which was purified by reverse phase (stationary phase: YMC-actus Triart C18 15 μm 35 * Purification was performed by 220 mm, mobile phase: gradient from 40% (aqueous NH4HCO3 0.2% pH=9.5) / MeCN / MeOH from 40 / 30 / 30 to 20 / 40 / 40). 135 mg of compound 57 was lyophilized with acetonitrile / water 20 / 80 to give 120 mg (55% yield) of compound 57 as a white powder, and 40 mg of compound 58 was lyophilized with acetonitrile / water 20 / 80 to give 38 mg (16% yield) of compound 58 as a white powder.

[0542] The compounds listed in the table below were prepared following the same procedures reported for the preparation of compounds 54, 55 and 56 starting from the corresponding starting materials.

[0543] [Table 9-1]

[0544] [Table 9-2]

[0545] [Table 9-3]

[0546] [Table 9-4]

[0547] [Table 9-5]

[0548] Compound 131:

[0549] [ka] and compound 132 Preparation of:

[0550] [ka]

[0551] To a solution of intermediate 29 (120 mg, 0.22 mmol) in methanol (2 mL) was added cis-N,N-dimethyl-3-azabicyclo[3.1.0]hexane-6-carboxamide (41 mg, 0.27 mmol). After stirring at room temperature for 20 minutes, sodium cyanoborohydride (28 mg, 0.47 mmol) was added to the mixture. After stirring at 50° C. overnight, the resulting mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were washed with water and brine and dried over anhydrous sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC using the following conditions (Column: XSelect CSH Prep C18 OBD Column, 5 um, 19 *150 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 30% B to 60% B in 7 min; 220 nm; retention time 1: 6.35 min; retention time 2: 6.90 min. Pure fractions were combined and lyophilized to give 46.5 mg (30.6% yield, retention time 1: 6.35 min) of compound 131 as a white solid and 3 mg (1.9% yield, retention time 2: 6.90 min) of compound 132 as a white solid.

[0552] Compound 120:

[0553] [ka] and compound 121 Preparation of:

[0554] [ka]

[0555] To a solution of intermediate 84 (2.5 g, 2.99 mmol, 62.8% purity) in MeOH (50 mL) was added cis-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride (1.07 g, 7.15 mmol). After stirring at room temperature for 30 min, NaBH3CN (599 mg, 9.53 mmol) was added to the reaction mixture. The resulting reaction mixture was stirred at 50° C. overnight, quenched with saturated sodium bicarbonate solution, and extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 800 mg of crude product as a yellow solid. The crude product was purified by preparative HPLC (YMC-Actus Triart C18, 30 mm x 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40% B to 60% B in 7 min; 254 nm; RT1: 6.95 min; RT2: 8.27 min). The fractions containing the product were combined. The solvent was concentrated and both compounds were lyophilized to give 102.6 mg of compound 120 as a white solid and 23.1 mg of compound 121 as a white solid.

[0556] conversion Compound 23:

[0557] [ka] Compound 24:

[0558] [ka] and compound 25 Preparation of:

[0559] [ka]

[0560] At room temperature, NaBH(OAc)3 (144 mg; 0.68 mmol) was added to a solution of compound 22 (240 mg; 0.445 mmol), tetrahydro-4H-pyran-4-one (48 μL; 0.53 mmol) in dichloroethane (6 mL). The mixture was stirred at room temperature overnight. The solution was cooled, poured into cold water, basified with K2CO3 powder and the product was extracted with DCM. The organic layer was dried over MgSO4, filtered and evaporated to dryness to give 380 mg of compound 23.

[0561] The separation of the enantiomers (380 mg of compound 23) was carried out by chiral SFC (stationary phase: Chiralpak IG 5 μm 250 * 20 mm, mobile phase: 50% CO2, 50% EtOH (0.3% iPrNH2)). The product-containing fractions were combined, concentrated, and lyophilized with a mixture of acetonitrile / water (20 / 80) to give 90 mg (32% yield) of compound 24 as a white powder and 98 mg (35% yield) of compound 25 as a white powder.

[0562] The compounds listed below were prepared by starting from the respective starting materials and using a reaction protocol similar to that reported for compound 23.

[0563] [Table 10-1]

[0564] [Table 10-2]

[0565] Preparation of compound 38:

[0566] [ka]

[0567] Acetic acid (16 μL; 0.28 mmol) was added at room temperature to a solution of compound 32 (88 mg; 0.17 mmol) and oxetane-3-carbaldehyde (24 μL; 0.35 mmol) in THF (3 mL). The mixture was stirred at room temperature for 4 h. NaBH(OAc)3 (107 mg; 0.51 mmol) was then added dropwise. The mixture was stirred at room temperature for 2 h, then poured into ice water and basified with a 10% aqueous solution of K2CO3. EtOAc was added. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated to dryness. The obtained residue (98 mg) was purified by silica gel chromatography (stationary phase: 4 g irregular SiOH 40 μm, mobile phase: gradient from 100% DCM to 80% DCM, 20% MeOH (+10% NH4OH)). The product-containing fractions were combined and concentrated to give 60 mg of compound 38, which was purified by reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30 * Further purification was performed via elution with 150 mm mobile phase: 40% NH4HCO3 0.2%, 60% MeOH gradient to 20% NH4HCO3 0.2%, 80% MeOH. The product-containing fractions were combined and concentrated to give 26 mg of compound 38, which was lyophilized with acetonitrile / water (20 / 80) to give 24 mg (25% yield) of compound 38 as a white powder.

[0568] Preparation of compound 39:

[0569] [ka]

[0570] Acetic acid (24 μL; 0.42 mmol) was added to a solution of compound 33 (144 mg; 0.27 mmol) and oxetane-3-carbaldehyde (38 μL; 0.55 mmol) in THF (4 mL) at room temperature. The mixture was stirred at room temperature overnight, then NaBH(OAc)3 (177 mg; 0.83 mmol) was added dropwise. The mixture was stirred at room temperature for 24 h. The mixture was poured into ice water. The aqueous layer was basified with K2CO3 powder and the mixture was extracted with EtOAc (2 times). The organic layers were combined, dried over MgSO4 and evaporated to dryness. The residue (137 mg) was purified by silica gel chromatography (stationary phase: 12 g of irregular SiOH 15-40 μm, mobile phase: gradient from 97% DCM, 3% MeOH (+10% NH4OH) to 90% DCM, 10% MeOH (+10% NH4OH)). The product-containing fractions were combined and concentrated to give 90 mg of an intermediate impurity, which was purified by reverse phase (stationary phase: 30 g of YMC-actus Triart C18 10 μm). * Further purification was performed by elution with 150 mm mobile phase: 65% NH4HCO3 0.2%, 35% ACN to 25% NH4HCO3 0.2%, 75% ACN gradient. The product-containing fractions were combined and concentrated, and the resulting residue (44 mg) was lyophilized from acetonitrile / water (20 / 80) to give 42 mg (26% yield) of compound 39.

[0571] Preparation of compound 40:

[0572] [ka]

[0573] NaBH(OAc)3 (91 mg; 0.43 mmol) was added dropwise to a solution of compound 34 (150 mg; 0.28 mmol) and oxetane-3-carbaldehyde (21 μL; 0.3 mmol) in THF (6 mL). The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was poured into ice water, basified with a solution of K2CO3 10%, and EtOAc was added. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The residue (143 mg) was purified by silica gel chromatography (stationary phase: 12 g irregular SiOH 15-40 μm, mobile phase: gradient from 97% DCM, 3% MeOH (+10% NH4OH) to 85% DCM, 15% MeOH (+10% NH4OH)). The product-containing fractions were combined and concentrated, and the resulting residue (54 mg) was lyophilized from acetonitrile / water (20 / 80) to give 4050 mg of compound (29% yield).

[0574] Preparation of compound 41:

[0575] [ka]

[0576] NaBH(OAc)3 (82 mg; 0.39 mmol) was added dropwise to a solution of compound 35 (135 mg; 0.25 mmol) and oxetane-3-carbaldehyde (19 μL; 0.27 mmol) in THF (5 mL). The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was poured into ice water, basified with a solution of K2CO3 10%, and EtOAc was added. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The residue (130 mg) was purified by silica gel chromatography (stationary phase: 12 g irregular SiOH 15-40 μm, mobile phase: gradient from 95% DCM, 5% MeOH (+10% NH4OH) to 92% DCM, 8% MeOH (+10% NH4OH)). The product-containing fractions were combined and concentrated to give a 84 mg fraction which was dissolved with Et2O and evaporated to dryness to give 70 mg (45% yield) of compound 41.

[0577] Preparation of compound 42:

[0578] [ka]

[0579] A stir bar, compound 37 (130 mg, 0.195 mmol), oxetane-3-carbaldehyde (16.8 mg, 0.195 mmol), triethylamine (98.7 mg, 0.975 mmol) and dry dichloromethane (4 mL) were added to an 8 mL glass bottle, and the mixture was stirred at 25° C. for 1 h. Sodium cyanotrihydroborate (36.7 mg, 0.584 mmol) was then added to the mixture. The resulting mixture was stirred at 25° C. for another 1 h. The mixture was diluted in dichloromethane (40 mL) and washed with water (20 mL×3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: Phenomenex Gemini-NX 150 * 30mm * The mixture was purified using 5 um, mobile phase A: water (0.04% NH3H2O ​​+ 10 mM w NH4HCO3), mobile phase B: acetonitrile, flow rate: 30 mL / min, gradient conditions 43% B to 71% B). Pure fractions were collected and the solvent was evaporated under vacuum to give a residue. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give compound 42 (24.34 mg, 19% yield) as a white powder.

[0580] Compound 43:

[0581] [ka] and compound 44 Preparation of:

[0582] [ka]

[0583] NaBH(OAc)3 (120 mg, 0.566 mmol) was added in portions to a solution of 37 (100 mg, crude), oxetane-3-carbaldehyde (30.0 mg, 0.348 mmol), Et3N (100 uL, 0.719 mmol) and dichloromethane (5 mL) at 0 °C (ice / water). The resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by Welch Xtimate C18 150 * 25mm * Purification by preparative HPLC using 5 μm (eluent: H2O containing 38%-68% (v / v) CH3CN and 0.04% NH3H2O ​​+ 10 mM NH4HCO3) gave the pure product, which was suspended in water (10 mL). The mixture was frozen using dry ice / acetone and then lyophilized to dryness to give a white solid (80 mg), which was purified using SFC (DAICEL CHIRALPAK AD-H (250 mm * The product was further purified by isocratic elution: i-PrOH (containing 0.1% of 25% aqueous solution of NH3:supercritical CO2, 30%:70% to 30%:70% (v / v)). Pure fractions were collected and volatiles were removed under reduced pressure. The product was suspended in water (10 mL). The mixture was frozen using dry ice / acetone and then lyophilized to dryness to give compound 43 (37.00 mg, 41% yield) as a white solid and compound 44 (33.96 mg, 38% yield) as a pale yellow solid.

[0584] The compounds listed in the following table were prepared following similar reaction protocols as reported for the preparation of compounds 39 or 42 starting from the corresponding starting materials.

[0585] [Table 11-1]

[0586] [Table 11-2]

[0587] Preparation of compound 47:

[0588] [ka]

[0589] To a solution of compound 45 (70.0 mg, 0.130 mmol) and oxetane-3-carbaldehyde (50 mg, 0.581 mmol) in DCM (5 mL) was added TEA (80.0 mg, 0.791 mmol). The mixture was stirred at room temperature for 10 min, then NaBH3CN (100 mg, 1.59 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, then concentrated to give a residue. The residue was purified by preparative HPLC (column: YMC-Triart Prep C18 250×50 mm×10 um, mobile phase A: water (0.04% NH3H2O+10 mM NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient condition: 45% B to 75% B) to give compound 47 (20.0 mg, 24% yield) as a white solid.

[0590] Preparation of compound 48:

[0591] [ka]

[0592] To a solution of compound 46 (75.0 mg, crude), oxetane-3-carbaldehyde (35.9 mg, 0.417 mmol) and TEA (70.3 mg, 0.695 mmol) in 5 mL of DCM was added NaBH3CN. After addition, the reaction mixture was stirred at 10° C. for 2 h. The reaction mixture was concentrated in vacuum and the residue was purified by preparative HPLC (column Boston Prime C18 150×30 mm×5 um, mobile phase A: water (0.04% NH3H2O+10 mM NH4HCO3, mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient condition from 45% B to 75%). Pure fractions were collected and lyophilized to give compound 48 (7.0 mg) as a white powder.

[0593] Preparation of compound 51:

[0594] [ka]

[0595] A stir bar, compound 49 hydrochloride (70.0 mg, 0.121 mmol), oxetane-3-carbaldehyde (15.7 mg, 0.182 mmol), sodium cyanoborohydride (15.3 mg, 0.243 mmol), triethylamine (61.5 mg, 0.608 mmol) and dry dichloromethane (2 mL) were added to a 10 mL round-bottom flask, and the resulting mixture was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: Boston Prime C18 150 * 30mm * The mixture was purified by HPLC using a 500 sq. m column (5 μm, mobile phase A: water (0.04% NH3H2O ​​10 mM NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions: 40% B to 70%). Pure fractions were collected and the solvent was evaporated under vacuum to give a residue. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give compound 51 (14.3 mg, 19% yield) as a white powder.

[0596] Preparation of compound 52:

[0597] [ka]

[0598] To a solution of compound 50 (50.0 mg, 0.093 mmol), oxetane-2-carbaldehyde (23.9 mg, 0.278 mmol) and TEA (18.8 mg, 0.185 mmol) in 5 mL of DCM was added NaBH3CN (29.1 mg, 0.463 mmol). After the addition, the reaction mixture was stirred at 10° C. for 1 h. The reaction mixture was concentrated in vacuum and the residue was purified by preparative HPLC (column Boston Prime C18 150×30 mm×5 um, mobile phase A: water (0.04% NH3H2O+10 mM NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient condition from 45% B to 75% B). The pure fractions were collected and lyophilized to give compound 52 (8.38 mg, yield 1 15%) as a white solid.

[0599] Preparation of compound 53:

[0600] [ka]

[0601] A stir bar, compound 36 (130 mg, 0.195 mmol), oxetane-3-carbaldehyde (16.8 mg, 0.195 mmol), triethylamine (98.7 mg, 0.975 mmol) and dry dichloromethane (4 mL) were added to an 8 mL glass bottle and the mixture was stirred at 25 °C for 1 h. Sodium cyanoborohydride (36.7 mg, 0.584 mmol) was then added to the mixture, which was stirred at 25 °C for another 1 h. The mixture was diluted in dichloromethane (40 mL) and washed with water (20 mL × 3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: Phenomenex Gemini-NX 150 * 30mm *Purification was performed using 5 μm, mobile phase A: water (0.04% NH3H2O ​​+ 10 mM NH4HCO3), mobile phase B: acetonitrile, flow rate: 30 mL / min, gradient conditions 43%B to 71%). Pure fractions were collected and the solvent was evaporated under vacuum to give a residue which was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give compound 53 (24.3 mg, 19% yield) as a white powder.

[0602] Preparation of compound 71:

[0603] [ka]

[0604] Sodium triacetoxyborate hydrate (50 mg; 0.24 mmol) was added at room temperature to a solution of compound 35 (60 mg; 0.11 mmol) and dihydro-3(2H)-furanone (18 μL; 0.23 mmol) in dichloroethane (8 mL). The mixture was stirred at room temperature for 2.5 h. The solution was poured into cold water, basified with K2CO3 powder and the product was extracted with DCM. The organic layer was dried over MgSO4, filtered and concentrated to dryness. The crude product (79 mg) was purified by reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30 * The mixture was purified by elution with 150 mm mobile phase: 65% NH4HCO3 0.2%, 35% ACN to 35% NH4HCO3 0.2%, 65% ACN gradient. The product-containing fractions were combined and concentrated to give 48 mg of an intermediate fraction, which was lyophilized from acetonitrile / water (20 / 80) to give 40 mg (59% yield) of compound 71 as a white powder and a mixture of two diastereoisomers.

[0605] The compounds listed in the table below were prepared according to compound 71 starting from the corresponding intermediate.

[0606] [Table 12]

[0607] Preparation of compound 81:

[0608] [ka]

[0609] To a solution of compound 80 (350 mg, TFA salt, 0.506 mmol), oxetane-2-carbaldehyde (200 mg, 2.32 mmol) and TEA (500 mg, 4.94 mmol) in 50 mL of DCM was added NaBH3CN (200 mg, 3.18 mmol). After the addition, the reaction mixture was stirred at 28 °C for 3 h. The reaction mixture was filtered, the filtrate was concentrated in vacuo and the residue was purified by preparative HPLC (column Boston Prime C18 150 * 30mm * The mixture was purified by elution with 5 μm, mobile phase A: water (0.04% NH3H2O ​​+ 10 mM NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 50% B to 80% B. Pure fractions were collected and lyophilized to give compound 81 (170 mg, 45% yield) as a white solid.

[0610] Compound 82:

[0611] [ka] and compound 83 Preparation of:

[0612] [ka]

[0613] 170 mg of compound 81 was subjected to supercritical fluid chromatography (separation conditions: DAICEL CHIRALPAK AS-H (250 mm *30 mm, 5 um; mobile phase: A: supercritical CO2, B: 0.1% NH3H2O-ETOH, A:B = 55:45 at 80 mL / min) to give both impure compound 82 (60 mg, 91.5% purity based on LCMS) and impure compound 83 (60 mg, 94.5% purity based on LCMS) as white solids. Compound 82 (60 mg, 91.5% purity based on LCMS) was purified by preparative HPLC (column Boston Prime C18 150 * 30mm * Further purification by 5 um, mobile phase A: water (0.04% NH3H2O ​​+ 10 mM NH4HCO3, mobile phase B: acetonitrile, flow rate: 30 mL / min, gradient conditions from 50% B to 80% B) gave compound 82 (40.0 mg, 27% yield) as a white solid. Compound 83 (60 mg, 94.5% purity based on LCMS) was purified by preparative HPLC (column Boston Prime C18 150 * 30mm * Further purification with 5 um, mobile phase A: water (0.04% NH3H2O+10 mM NH4HCO3, mobile phase B: acetonitrile, flow rate: 30 mL / min, gradient conditions from 50% B to 80% B) gave compound 83 as a white solid.

[0614] The compounds listed in the following table were prepared following similar reaction protocols as reported for the preparation of compounds 81, 82 and 83 starting from the corresponding starting materials. Those skilled in the art will appreciate that in some cases, an additional deprotection step may be required to obtain the final compound.

[0615] [Table 13-1]

[0616] [Table 13-2]

[0617] [Table 13-3]

[0618] [Table 13-4]

[0619] [Table 13-5]

[0620] [Table 13-6]

[0621] Preparation of compound 114:

[0622] [ka]

[0623] In a flask, compound 113 (59 mg, 0.104 mmol) was dissolved in methanol (1.27 mL, 31.3 mmol) and treated with oxetane-3-carbaldehyde (35.9 mg, 0.417 mmol), sodium cyanoborohydride (32.8 mg, 0.521 mmol) and 2 drops of AcOH. The mixture was stirred at 60° C. overnight. The solvent was evaporated and then saturated sodium carbonate solution was added along with DCM. The aqueous phase was then further basified to pH 13 with 1N aqueous NaOH. The aqueous phase was extracted multiple times with DCM and ethyl acetate. Drying over magnesium sulfate, filtration and evaporation of the solvent gave the crude material, which was purified. Purification was carried out by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30×150 mm, mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to give 42 mg (63% yield) of compound 114 as a white solid.

[0624] Preparation of Compound 115:

[0625] [ka]

[0626] In a flask, compound 112 (50 mg, 0.0884 mmol) was dissolved in MeOH (1.07 mL, 26.5 mmol) and treated with 37% aqueous formaldehyde (0.132 mL, 1.77 mmol), 2 drops of HOAc, and then sodium cyanoborohydride (27.8 mg, 0.442 mmol). The mixture was heated at 60° C. for 2 h. The solvent was evaporated. Then, saturated sodium carbonate solution was added along with DCM. The aqueous phase was basified to pH 13 with 1N aqueous NaOH. The aqueous phase was extracted multiple times with DCM and ethyl acetate. After drying over magnesium sulfate, filtration, and evaporation of the solvent, the crude product (60 mg) was obtained. Purification was carried out by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30×150 mm, mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to give compound 115 as a white solid.

[0627] The compounds listed below were prepared following similar reaction protocols as reported for the preparation of compounds 114 and 115.

[0628] [Table 14]

[0629] Preparation of Compound 116:

[0630] [ka]

[0631] In a flask, compound 112 (45 mg, 0.0795 mmol) was dissolved in dry DMF (1.23 mL, 15.9 mmol) and treated with DIPEA (0.0411 mL, 0.239 mmol) and bromomethoxyethane (12.2 mg, 0.0875 mmol). The reaction was stirred at 80° C. for 3 h. Saturated sodium carbonate solution was added along with DCM. The aqueous phase was then basified to pH 13 with 1N aqueous NaOH. The aqueous phase was extracted multiple times with DCM and ethyl acetate. Drying over magnesium sulfate, filtration and evaporation of the solvent gave the crude product. Purification was carried out by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30×150 mm, mobile phase: 0.25% NH4HCO3 in water, CH3CN) to give 19 mg (38% yield) of compound 116 as a white solid.

[0632] Preparation of compound 119:

[0633] [ka]

[0634] To a solution of compound 37 (200 mg, 0.36 mmol) in ACN (5 mL) was added 2-bromo-N,2-dimethylpropanamide (98 mg, 0.54 mmol) and K2CO3 (250 mg, 1.81 mmol). After stirring at 70 °C overnight, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by preparative TLC (MeOH / DCM, 1:10). The obtained crude product (200 mg; white solid) was purified by preparative HPLC (Column: XBridge Shield RP18 OBD Column, 19 *250 mm, 10 um; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 55% B to 65% B in 7 min; 254 / 220 nm; RT: 5.93 min). The product-containing fractions were combined and concentrated to give 40.4 mg (16% yield) of compound 119 as a white solid.

[0635] Preparation of compound 133:

[0636] [ka]

[0637] To a mixture of intermediate 88 (100 mg, 0.157 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was evaporated under reduced pressure. The residue was diluted with 2M NaOH (5 mL) and extracted with DCM (5 mL x 5). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give compound 133 (84 mg, 99.6% yield) as a yellow solid.

[0638] Preparation of compound 134:

[0639] [ka]

[0640] To a mixture of compound 133 (84 mg, 0.156 mmol) in MeOH (2 mL), formaldehyde (257 mg, 3.17 mmol, 37% in water) and acetic acid (20 mg, 0.333 mmol) were added. The mixture was stirred at room temperature for 30 min. Then, NaBH3CN (20 mg, 0.318 mmol) was added to the mixture and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated to remove the solvent. The residue was diluted with 2M NaOH (5 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: Welch Xtimate C18 150 * 30mm * 5 μm, mobile phase A: water (0.05% NH3H2O ​​+ 10 mM NH4HCO3), mobile phase B: acetonitrile, flow rate: 30 mL / min, gradient conditions from 55% B to 85% yielded two fractions. The pure desired fraction was collected and the volatile solvents were removed by evaporation. The aqueous residue was lyophilized to give compound 134 (40 mg, 99.52% purity, 45% yield) as a white powder. The impure desired fraction was collected and the volatile solvents were removed by evaporation. The aqueous residue was lyophilized to give compound 134 (12 mg, 14% yield, approx. 95% purity by NMR) as a white powder.

[0641] Compound 135:

[0642] [ka] and preparation of compound 136

[0643] [ka]

[0644] Compound 134 (40 mg, 0.071 mmol) was subjected to SFC (column: DAICEL CHIRALCEL OD-H (250 mm *The mixture was purified by HPLC using a 300-mL column chromatography (30 mm, 5 um), mobile phase: A: supercritical CO2, B: 0.1% NH3H2O ​​IPA; isocratic: A:B=75:25; flow rate: 80 mL / min) to give two fractions. The pure fractions of the first peak were collected and the volatile solvents were evaporated under vacuum. The residue was treated with H2O (3 mL) and CH3CN (1 mL). The mixture was lyophilized to give compound 135 (11 mg, purity 98.17%, yield 27%) as a white powder. The pure fractions of the second peak were collected and the volatile solvents were evaporated under vacuum. The residue was treated with H2O (3 mL) and CH3CN (1 mL). The mixture was lyophilized to give compound 136 (10 mg, purity 96.28, yield 24%) as a white powder.

[0645] Preparation of compound 137:

[0646] [ka]

[0647] To a solution of compound 76 (200 mg, crude) and 3-(dimethylamino)propanoic acid hydrochloride (49.0 mg, 0.32 mmol) in DCM (10 mL) was added HATU (121 mg, 0.32 mmol) and DIEA (0.21 mL, 1.26 mmol). The mixture was stirred at room temperature for 16 h. 20 mL of DCM and 20 mL of H2O were added to the mixture solution. The mixture was extracted with DCM (30 mL x 2), the combined extracts were washed with brine (30 mL), dried over Na2SO4, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: YMC-Triart Prep C18 250 * 50mm * Purification was performed with 10 um, mobile phase A: water (0.04% NH3H2O ​​+ 10 mM NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions 45% B to 75%). Pure fractions were collected and the solvent was lyophilized to give the title compound Compound 137 (20 mg, purity 96.7%, yield 12%) as a pale yellow solid.

[0648] Preparation of compound 138:

[0649] [ka]

[0650] To a solution of intermediate 89 (150 mg, 0.23 mmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (1.7 mL) at 0° C. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure to give 150 mg of compound 138 (97.5% pure as trifluoroacetate) as a colorless oil.

[0651] Preparation of compound 139:

[0652] [ka]

[0653] To a mixture of compound 138 (150 mg, 0.241 mmol, purity 86.63%), glycolic acid (22 mg, 0.289 mmol) and N,N-diisopropylethylamine (0.12 mL, 0.722 mmol) in N,N-dimethylformamide (2 mL) was added HATU (110 mg, 0.289 mmol) in portions at 0° C. and stirred at room temperature for 2 h. The reaction mixture was quenched by addition of water (5 mL) and extracted with ethyl acetate (4×5 mL). The combined organic layers were washed with water (3×20 mL), brine (20 mL) and dried over anhydrous sodium sulfate. Filtration, concentration and the residue was purified by reverse phase flash chromatography using the following conditions: Column: SunFire C18 OBD Prep Column, 19 mm x 250 mm; Mobile phase A: water (0.1% NH4HCO3), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 15% B to 40% B in 11 min; 254 / 220 nm; Rt: 9.12 min to give 46.9 mg of compound 139 as a white solid.

[0654] LCMS (Liquid Chromatography / Mass Spectrometry) General Procedure High performance liquid chromatography (HPLC) measurements were performed using the LC pump, diode-array (DAD) or UV detector and column specified in each method. Additional detectors were included if necessary (see methods table below).

[0655] The flow from the column was brought to a mass spectrometer (Mass Spectrometer, MS) configured with an atmospheric pressure ion source. It is within the knowledge of one skilled in the art to set tuning parameters (e.g., scan range, dwell time, etc.) to obtain ions that allow identification of the nominal monoisotopic molecular weight (MW) of the compound. Data collection was performed with appropriate software.

[0656] Compounds were identified based on their experimental retention times (R t ) and ions. Unless otherwise specified in the tables of data, the molecular ions reported are [M+H] + (protonated molecule) and / or [MH] - (deprotonated molecule). If the compound is not directly ionizable, the type of adduct is specified (i.e., [M+NH4] + , [M+HCOO] - , etc.). For molecules with multiple isotopic patterns (Br, Cl), the values ​​reported are those obtained for the lowest isotopic mass. All results were obtained with experimental uncertainties typically associated with the methods used.

[0657] In the following, "SQD" means single quadrupole mass spectrometer, "RT" means room temperature, "BEH" means bridged ethylsiloxane / silica hybrid, "HSS" means high strength silica, and "DAD" means diode array detector.

[0658] [Table 15-1]

[0659] [Table 15-2]

[0660] [Table 16-1]

[0661] [Table 16-2]

[0662] [Table 16-3]

[0663] SFC method General procedure of the SFC method SFC measurements were performed using an analytical supercritical fluid chromatography (SFC) system configured with a binary pump and modifier to deliver carbon dioxide (CO2), an autosampler, a column oven, a diode array detector equipped with a high-pressure flow cell capable of withstanding up to 400 bar. If configured with a mass spectrometer (MS), the flow from the column was brought to the (MS). It is within the knowledge of a person skilled in the art to set tuning parameters (e.g., scan range, residence time, etc.) to obtain ions that allow identification of the nominal monoisotopic molecular weight (MW) of the compound. Data collection was performed with appropriate software.

[0664] [Table 17]

[0665] [Table 18]

[0666] Optical rotation (OR) Optical Rotation is measured on a polarimeter 341 Perkin Elmer. Polarized light is passed through a sample with a path length of 1 decimeter and a sample concentration of 0.2-0.4 grams per 100 milliliters. If the product weighs 2-4 mg in a vial, it is dissolved in 1-1.2 mL of spectroscopy solvent (e.g., DMF). The cell is filled with the solution and placed in the polarimeter at a temperature of 20°C. The OR is read with an accuracy of 0.004°.

[0667] Calculate concentration: weight in grams x volume in 100 / mL [α] d 20 :(Read rotation value x 100) / (1.000dm x concentration). d is the sodium D (589 nanometer) line.

[0668] [Table 19]

[0669] NMR Some NMR experiments were performed using a Bruker Avance 500 spectrometer equipped with a Bruker 5 mm BBFO probehead with z-gradients, operating at 500 MHz for proton and 125 MHz for carbon. Chemical shifts (d) are reported in parts per million (ppm). J values ​​are expressed in Hz.

[0670] NMR experiments were performed on a Bruker Avance III 400 spectrometer using an internal deuterium lock and inverse double resonance ( 1 H, 13 The measurements were performed using a 100 MHz (C,SEI) probehead operating at 400 MHz for proton and 100 MHz for carbon. Chemical shifts (d) are reported in parts per million (ppm). J values ​​are in Hz.

[0671] Some NMR experiments were performed at ambient temperature (298.6 K) using a Bruker Avance III 400 spectrometer equipped with a BBO 400 MHz S1 5 mm probehead with an internal deuterium lock and z-gradients operating at 400 MHz for protons and 100 MHz for carbon. Chemical shifts (d) are reported in parts per million (ppm). J values ​​are expressed in Hz.

[0672] Some NMR experiments were performed at ambient temperature (298.6 K) using a Varian 400-MR spectrometer equipped with a Varian 400 4NUC PFG probehead with an internal deuterium lock and z-gradients operating at 400 MHz for protons and 100 MHz for carbon. Chemical shifts (d) are reported in parts per million (ppm). J values ​​are expressed in Hz.

[0673] Some NMR experiments were performed at ambient temperature (298.6 K) using a Varian 400-VNMRS spectrometer equipped with an internal deuterium lock and a Varian 400 ASW PFG probehead with z-gradients, operating at 400 MHz for proton and 100 MHz for carbon. Chemical shifts (d) are reported in parts per million (ppm). J values ​​are expressed in Hz.

[0674] compound 4 Major isomer (75%) 11H NMR (400 MHz, DMSO-d6) δ ppm 8.30 (s, 1H), 7.69 - 7.81 (m, 1H), 7.15 - 7.38 (m, 2H), 6.88 - 7.02 (m, 1H), 4.55 (dd, J = 7.7, 5.9 Hz, 2H), 4.20 (t, J = 5.5 Hz, 2H), 3.73 - 3.84 (m, 1H), 3.37 - 3.70 (m, 5H), 3.12 - 3.27 (m, 3H), 3.05 (br d, J = 6.2 Hz, 1H), 2.92 - 3.02 (m, 3H), 2.86 (dt, J = 14.1, 7.1 Hz, 1H), 2.73 (br t, J = 7.2 Hz, 1H), 2.60 (br dd, J = 8.7, 6.4 Hz, 1H), 2.54 (br d, J = 7.6 Hz, 2H), 2.23 - 2.36 (m, 1H), 2.12 (br d, J = 9.4 Hz, 1H), 1.95 (br t, J = 7.0 Hz, 2H), 1.45 - 1.59 (m, 1H), 1.21 (br d, J = 3.4 Hz, 2H), 0.98 - 1.15 (m, 7H), 0.72 - 0.80 (m, 6H)

[0675] Minor isomer (25%) 1 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (s, 1H), 7.69 - 7.81 (m, 1H), 7.15 - 7.38 (m, 2H), 6.88 - 7.02 (m, 1H), 4.55 (dd, J = 7.7, 5.9 Hz, 2H), 4.41 (dt, J = 13.8, 6.8 Hz, 1H), 4.20 (t, J = 5.5 Hz, 2H), 3.37 - 3.70 (m, 5H), 3.12 - 3.27 (m, 3H), 3.05 (br d, J = 6.2 Hz, 1H), 2.92 - 3.02 (m, 3H), 2.86 (dt, J = 14.1, 7.1 Hz, 1H), 2.73 (br t, J = 7.2 Hz, 1H), 2.60 (br dd, J = 8.7, 6.4 Hz, 1H), 2.54 (br d, J = 7.6 Hz, 2H), 2.23 - 2.36 (m, 1H), 2.12 (br d, J = 9.4 Hz, 1H), 1.95 (br t, J = 7.0 Hz, 2H), 1.45 - 1.59 (m, 1H), 1.21 (br d, J = 3.4 Hz, 2H), 0.98 - 1.15 (m, 7H), 0.72 - 0.80 (m, 6H)

[0676] Compound 38 1 H NMR(500MHz,DMSO-d6)δ ppm 8.4(d,J=5.7Hz,1H),7.2-7.4(m,3H),6.5(br d,J=5.7Hz,1H),4.6(dd,J=7.7,5.8Hz,2H),4.2(td,J=6.0,2.2Hz,2H),3.3-3.8(m,7H),3.0-3.1(m,5H),2.9(dt,J=14.3,6.9Hz,1H),2.7-2.8(m,1H),2.5-2.6(m,3H),2.3-2.4(m,1H),2.2(dd,J=9.5,1.9Hz,1H),2.0(br t,J=6.8Hz,2H),1.5-1.6(m,1H),1.0(br d,J=6.3Hz,4H),0.9-1.0(m,4H),0.8(dd,J=12.9,6.9Hz,6H),0.6(br s,2H) H NMR (500 MHz, DMSO-d6) δ ppm: 8.4 (d, J = 5.7 Hz, 1H), 7.2 - 7.4 (m, 3H), 6.5 (br d, J = 5.7 Hz, 1H), 4.6 (dd, J = 7.7, 5.8 Hz, 2H), 4.2 (td, J = 6.0, 2.2 Hz, 2H), 3.3 - 3.8 (m, 7H), 3.0 - 3.1 (m, 5H), 2.9 (dt, J = 14.3, 6.9 Hz, 1H), 2.7 - 2.8 (m, 1H), 2.5 - 2.6 (m, 3H), 2.3 - 2.4 (m, 1H), 2.2 (dd, J = 9.5, 1.9 Hz, 1H), 2.0 (br t, J = 6.8 Hz, 2H), 1.5 - 1.6 (m, 1H), 1.0 (br d, J = 6.3 Hz, 4H), 0.9 - 1.0 (m, 4H), 0.8 (dd, J = 12.9, 6.9 Hz, 6H), 0.6 (br s, 2H)

[0677] Compound 41 1 H NMR(500MHz,DMSO-d6)δ ppm 8.48(s,1H),7.22-7.52(m,3H),4.56(br t,J=6.8Hz,2H),4.17-4.30(m,2H),3.87-4.13(m,2H),3.49-3.72(m,3H),3.30-3.41(m,1H),2.97-3.20(m,6H),2.88(dt,J=14.3,6.9Hz,1H),2.77(br d,J=1.3Hz,1H),2.55-2.69(m,2H),2.30-2.37(m,1H),2.17(br d,J=7.6Hz,1H),1.96-2.10(m,2H),1.51-1.66(m,1H),0.92-1.15(m,8H),0.65-0.84(m,9 H) H NMR (500 MHz, DMSO-d6) δ ppm: 8.48 (s, 1H), 7.22 - 7.52 (m, 3H), 4.56 (br t, J = 6.8 Hz, 2H), 4.17 - 4.30 (m, 2H), 3.87 - 4.13 (m, 2H), 3.49 - 3.72 (m, 3H), 3.30 - 3.41 (m, 1H), 2.97 - 3.20 (m, 6H), 2.88 (dt, J = 14.3, 6.9 Hz, 1H), 2.77 (br d, J = 1.3 Hz, 1H), 2.55 - 2.69 (m, 2H), 2.30 - 2.37 (m, 1H), 2.17 (br d, J = 7.6 Hz, 1H), 1.96 - 2.10 (m, 2H), 1.51 - 1.66 (m, 1H), 0.92 - 1.15 (m, 8H), 0.65 - 0.84 (m, 9H)

[0678] Compound 42 11H NMR (400 MHz, CDCl3) δ ppm 8.43 - 8.36 (m, 1H), 7.23 - 7.16 (m, 1H), 7.13 - 7.06 (m, 1H), 7.05 - 6.98 (m, 1H), 6.33 - 6.28 (m, 1H), 4.83 - 4.76 (m, 2H), 4.44 - 4.34 (m, 2H), 4.01 - 3.89 (m, 1H), 3.75 - 3.56 (m, 4H), 3.55 - 3.47 (m, 1H), 3.27 - 3.05 (m, 6H), 2.82 - 2.72 (m, 2H), 2.66 (d, J = 7.2 Hz, 2H), 2.14 - 2.06 (m, 2H), 1.93 - 1.72 (m, 4H), 1.50 - 0.98 (m, 12H), 0.93 - 0.84 (m, 6H), 0.71 (d, J = 6.4 Hz, 2H).

[0679] Compound 43 1 1H NMR (400 MHz, CDCl3) δ ppm 8.50 (s, 1H), 7.26 - 7.19 (m, 1H), 7.18 - 7.09 (m, 1H), 7.08 - 6.97 (m, 1H), 4.89 - 4.73 (m, 2H), 4.49 - 4.34 (m, 2H), 4.33 - 4.01 (m, 2H), 4.00 - 3.83 (m, 1H), 3.81 - 3.60 (m, 2H), 3.59 - 3.38 (m, 1H), 3.31 - 3.03 (m, 6H), 2.86 - 2.61 (m, 4H), 2.21 - 2.07 (m, 2H), 1.96 - 1.71 (m, 5H), 1.56 - 1.33 (m, 5H), 1.15 - 1.05 (m, 6H), 0.93 - 0.84 (m, 6H), 0.82 - 0.72 (m, 2H)

[0680] Compound 44 1H NMR(400MHz, CDCl3)δ ppm 8.53-8.44(m,1H),7.27-7.18(m,1H),7.18-7.09(m,1H),7.08-6.97(m,1H),4.81 (t,J=6.8Hz,2H),4.51-4.35(m,2H),4.30-3.84(m,3H),3.79-3.55(m,2H),3.54-3 .41(m,1H),3.38-3.06(m,6H),3.01-2.62(m,4H),2.21-2.11(m,2H),2.11-1.64(m ,5H),1.64-1.29(m,5H),1.14-1.03(m,6H),0.95-0.85(m,6H),0.82-0.70(m,2H).

[0681] Compound 45 1 H NMR(400MHz,CD3OD)δ ppm 8.87-8.69(m,1H),7.67-7.42(m,1H),7.39-7.18(m,2H),4.66-4.15(m,6H),4.12-3.76(m,2H),3.74-3.53(m,4H),3.52-3.3 1(m,3H),3.26-3.15(m,1H),3.08-2.94(m,1H),2.79-2.23(m,3H),2.21-2.09(m,1H),2.00-1.85(m,1H),1.31-0.86(m,15H)

[0682] Compound 46 1 H NMR(400MHz,CD3OD)δ ppm 8.95-8.76(m,1H),7.74-7.41(m,1H),7.39-7.22(m,2H),4.69-4.09(m,6H),4.06-3.78(m,2H),3.76-3.50(m,4H), 3.50-3.32(m,3H),3.26-3.10(m,2H),2.80-2.27(m,3H),2.25-2.09(m,1H),1.93-1.73(m,1H),1.33-0.96(m,15H).

[0683] Compound 47 1H NMR(400MHz,CD3OD)δ ppm 8.50(s,1H),7.19-7.25(m,1H),7.13(s,1H),6.98-7.07(m,1H),4.78(t,J=6.8Hz,2H) ,4.37-4.45(m,2H),3.95-4.25(m,2H),3.82-3.93(m,1H),3.73(s,1H),3.44-3.68(m, 2H),3.20(d,J=9.2Hz,6H),2.62-2.82(m,4H),2.27(d,J=6.4Hz,2H),2.06-2.19(m,3H ),2.03(s,1H),1.89(s,1H),1.67-1.81(m,2H),1.01-1.22(m,7H),0.72-0.91(m,8H).

[0684] Compound 48 1 H NMR(400MHz, CDCl3)δ ppm 8.50(br.s,1H),7.18-7.25(m,1H),7.08-7.17(m,1H),6.94-7.07(m,1H),4.69- 4.87(m,2H),4.37-4.49(m,2H),3.97-4.34(m,2H),3.40-3.92(m,4H),3.03-3.32 (m,6H),2.52-2.85(m,4H),2.19-2.45(m,3H),2.03-2.17(m,3H),1.83-1.95(m, 1H),1.70-1.79(m,1H),1.48-1.58(m,1H),1.00-1.33(m,7H),0.68-0.96(m,8H).

[0685] Compound 49 1 H NMR(400MHz, CDCl3)δ ppm 8.48(s,1H),7.52-7.40(m,1H),7.39-7.31(m,2H),4.30-3.86(m,2H),3.67-3.59(m,2H),3. 27-2.97(m,9H),2.94-2.75(m,2H),2.24-1.82(m,5H),1.77-1.62(m,2H),1.11-0.57(m,16H)

[0686] Compound 50 1H NMR(400MHz,DMSO-d6)δ ppm 8.48(s,1H),7.40-7.48(m,1H),7.29-7.39(m,2H),3.47-4.31(m,9H),3.24-3.45(m,3H),2.92-3.12(m,3H),1.93-2 .22(m,4H),1.50-1.92(m,3H),0.91-1.14(m,7H),0.88(d,J=6.80Hz,3H),0.83(d,J=6.40Hz,3H),0.61-0.79(m,2H).

[0687] Compound 51 1 H NMR(400MHz, CDCl3)δ ppm 8.50(s,1H),7.26-7.23(m,1H),7.17-7.10(m,1H),7.07-6.99(m,1H),4.84-4.75(m,2H),4.46-4.38(m, 2H),4.34-4.26(m,0.2H),4.22-3.99(m,2H),3.92-3.82(m,0.8H),3.80-3.71(m,1H),3.68-3.60(m,1H), 3.56-3.45(m,1H),3.30-3.14(m,5H),3.13-3.04(m,1H),2.82-2.63(m,4H),2.34-2.23(m,2H),2.16-2.1 0(m,2H),2.06-2.02(m,1H),1.97-1.85(m,1H),1.80-1.67(m,3H),1.12-1.02(m,6H),0.91-0.72(m,9H).

[0688] Compound 52 1H NMR(400MHz, CDCl3)δ ppm 8.50(s,1H),7.19-7.25(m,1H),7.08-7.18(m,1H),6.96-7.08(m,1H),4.71-4. 89(m,2H),4.38-4.48(m,2H),3.44-4.34(m,6H),3.01-3.32(m,6H),2.50-2.89( m,3H),2.19-2.47(m,3H),2.04-2.18(m,3H),1.83-1.95(m,1H),1.70-1.77(m,1 H),1.62-1.70(m,1H),1.50-1.60(m,1H),1.01-1.27(m,7H),0.72-0.92(m,8H).

[0689] Compound 78 1 H NMR CD3OD(Varian-400MHz):9.00-8.78(m,1H),7.69-7.44(m,1H),7.41-7.19(m,2H),4.56-4.13(m,6H),4.05-3.78(m,2H),3.58(s,1H), 3.49-3.32(m,5H),3.13-2.97(m,2H),2.72-2.51(m,1H),2.49-2.31(m,1H),2.23-1.91(m,4H),1.89-1.65(m,2H),1.29-0.93(m,15H).

[0690] Compound 79 1 H NMR CD3OD(Varian-400MHz):8.97-8.81(m,1H),7.72-7.43(m,1H),7.40-7.15(m,2H),4.61-4.15(m,6H),4.08-3.70(m,2H),3.58(s,1H), 3.50-3.34(m,5H),3.14-2.94(m,2H),2.73-2.52(m,1H),2.50-2.30(m,1H),2.22-1.89(m,4H),1.89-1.64(m,2H),1.29-1.02(m,15H)

[0691] Compound 82: 1H NMR(400MHz, CDCl3):8.55-8.41(m,1H),7.25-7.18(m,1H),7.17-7.07(m,1H),7.06-6.9 5(m,1H),4.78(t,J=6.8Hz,2H),4.39(t,J=6.0Hz,2H),4.31-3.95(m,2H),3.93-3.81(m, 1H),3.78-3.42(m,3H),3.39-2.99(m,5H),2.85-2.57(m,4H),2.49-2.34(m,1H),2.21-2 .00(m,3H),1.91-1.70(m,13H),1.49-1.38(m,1H),1.35-1.22(m,1H),1.18-0.69(m,8H).

[0692] Compound 83: 1 H NMR(400MHz, CDCl3):8.54-8.39(m,1H),7.25-7.19(m,1H),7.13(s,1H),7. 06-6.97(m,1H),4.78(t,J=6.8Hz,2H),4.39(t,J=6.2Hz,2H),4.32-3.95(m, 2H),3.93-3.00(m,8H),2.87-2.57(m,4H),2.40(s,1H),2.24-1.98(m,3H),1 .91-1.68(m,14H),1.50-1.38(m,1H),1.36-1.22(m,1H),1.18-0.67(m,8H).

[0693] part of the science of medicine 1) Minin / MLL uniform time decomposition light (HTRF) アッセイ To a non-treated white 384-well microtiter plate, 40 nL of 200X test compound in DMSO and 4 μL of 2X terbium chelate-labeled menin (preparation see below) in assay buffer (40 mM Tris·HCl, pH 7.5, 50 mM NaCl, 1 mM DTT (dithiothreitol) and 0.05% Pluronic F-127) were added. After incubating the test compound and terbium chelate-labeled menin for 30 minutes at ambient temperature, 4 μL of 2X FITC-MBM 1 peptide (FITC-β-alanine-SARWRFPARPGT-NH2) ("FITC" means fluorescein isothiocyanate) in assay buffer was added, the microtiter plate was centrifuged at 1000 rpm for 1 minute, and the assay mixture was incubated at ambient temperature for 15 minutes. The relative amount of menin·FITC-MBM1 complex present in the assay mixture is determined by measuring the homogeneous time-resolved fluorescence (HTRF) of the terbium / FITC donor / acceptor fluorophore pair at ambient temperature using an EnVision microplate reader (e.g. 337 nm / terbium em. 490 nm / FITC em. 520 nm). The extent of fluorescence resonance energy transfer (HTRF value) is calculated as the ratio of the fluorescence emission intensities of the FITC and terbium fluorophores (F em 520nm / F em The binding assay is expressed as a function of time (nm) at 490. The final concentrations of reagents in the binding assay are 200 pM terbium chelate-labeled menin, 75 nM FITC-MBM1 peptide and 0.5% DMSO in assay buffer. Dose-response titrations of test compounds are typically performed using an 11-point, four-fold serial dilution scheme starting at 10 μM.

[0694] Compound potency was determined by first calculating the % inhibition at each compound concentration according to Equation 1: % Inhibition = ((HC-LC)-(HTRF 化合物 -LC)) / (HC-LC)) * 100 (formula 1) where LC and HC are the HTRF values ​​of the assay in the presence or absence of a saturating concentration of a compound that competes with FITC-MBM1 for binding to menin, and HTRF化合物 is the HTRF value measured in the presence of test compound. HC and LC HTRF values ​​represent the average of at least 10 replicates per plate. For each test compound, the % inhibition values ​​were plotted against the logarithm of the test compound concentration and the IC was obtained from fitting these data to Equation 2. 50 The values ​​were plotted: Inhibition%=Bottom+(Top-Bottom) / (1+10^((logIC 50 -log[cmpd]) * h)) (Equation 2) If Bottom and Top are the lower and upper asymptote of the dose-response curve, respectively, then IC 50 is the concentration of compound that produces 50% inhibition of the signal and h is the Hill coefficient.

[0695] Preparation of terbium cryptate labeling of menin: Menin (aa 1-610-6xhis tag, 2.3 mg / mL in 20 mM Hepes (2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid), 80 mM NaCl, 5 mM DTT (dithiothreitol), pH 7.5) was labeled with terbium cryptate as follows: 200 μg of menin was buffer exchanged into 1X Hepes buffer. 6.67 μM of menin was incubated with an 8-fold molar excess of NHS (N-hydroxysuccinimide)-terbium cryptate for 40 min at room temperature. Half of the labeled protein was purified from the free label by running the reaction on a NAP5 column with elution buffer (0.1 M Hepes, pH 7 + 0.1% BSA (bovine serum albumin)). The remaining half was eluted with 0.1 M phosphate-buffered saline (PBS), pH 7. 400 μl of each eluate was collected, aliquoted, and frozen at −80° C. The final concentrations of terbium-labeled menin protein were 115 μg / mL in Hepes buffer and 85 μg / mL in PBS buffer, respectively.

[0696] Menin protein sequence (SEQ ID NO:1): MGLKAAQKTLFPLRSIDDVVRLFAAELGREEPDLVLLSLVLGFVEHFLAVNRVIPTNVPELTFQPSPAPDPPGGLTYFPVADLSIIAALYARFTAQIRGAVDLSLYPREGGVSSRELVKKVSDVIWNSLSRSYFKDRAHIQSLFSFITGTKLDS SGVAFAVVGACQALGLRDVHLALSEDHAWVVFGPNGEQTAEVTWHGKGNEDRRGQTVNAGVAERSWLYLKGSYMRCDRKMEVAFMVCAINPSIDLHTDSLELLQLQQKLLWLLYDLGHLERYPMALGNLADLEELEPTPGRPDPLTLYHKGIAS AKTYYRDEHIYPYMYLAGYHCRNRNVREALQAWADTATVIQDYNYCREDEEIYKEFFEVANDVIPNLLKEAASLLEAGEERPGEQSQGTQSQGSALQDPECFAHLLRFYDGICKWEEGSPTPVLHVGWATFLVQSLGRFEGQVRQKVRIVSREA EAAEAEEPWGEEAREGRRRGPRRESKPEEPPPPKKPALDKGLGTGQGAVSGPPRKPPGTVAGTARGPEGGSTAQVPAPAASPPPEGPVLTFQSEKMKGMKELLVATKINSSAIKLQLTAQSQVQMKKQKVSTPSDYTLSFLKRQRKGLHHHHHH

[0697] 2a) Proliferation assay The anti-proliferative effect of menin / MLL protein / protein interaction inhibitor test compounds was evaluated in human leukemia cell lines. The cell line MOLM14 carries an MLL translocation and expresses the MLL fusion protein MLL-AF9 and the wild-type protein from the second allele, respectively. OCI-AML3 cells with NPM1c gene mutation were also tested. MLL-rearranged cell lines (e.g., MOLM14) and NPM1c mutant cell lines show stem cell-like HOXA / MEIS1 gene expression signatures. KO-52 was used as a control cell line containing two MLL (KMT2A) wild-type alleles to exclude compounds that show general cytotoxic effects.

[0698] MOLM14 cells were cultured in RPMI-1640 (Sigma Aldrich) supplemented with 10% heat-inactivated fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma Aldrich) and 50 μg / ml gentamicin (Gibco). KO-52 and OCI-AML3 cell lines were grown in alpha-MEM (Sigma Aldrich) supplemented with 20% heat-inactivated fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma Aldrich) and 50 μg / ml gentamicin (Gibco). Cells were maintained at 0.3–2.5 million cells / mL in culture and did not exceed 20 passages.

[0699] To evaluate the anti-proliferative effect, 200 MOLM14 cells, 200 OCI-AML3 cells or 300 KO-52 cells were seeded in 200 μl medium / well in 96-well round-bottom ultra-low attachment plates (Costar, Cat. No. 7007). The cell seeding number was selected based on the growth curve to ensure linear growth throughout the experiment. Test compounds were added at different concentrations and DMSO content was normalized to 0.3%. Cells were incubated for 8 days at 37°C and 5% CO2. Spheroid growth was measured in real time by live cell imaging (IncuCyteZOOM, Essenbio, 4x objective) acquiring images on day 8. Confluence (%) as a measure of spheroid size was determined using the integrated analysis tool.

[0700] To determine the effect of test compounds over time, measures of confluence and spheroid size in each well were calculated. The confluence of the highest dose of reference compound was used as the baseline for LC (low control) and the confluence of DMSO-treated cells was used as 0% cytotoxicity (high control, HC).

[0701] Absolute IC 50 Values ​​were calculated as percentage change in confluence as follows: LC = low control: cells treated with, for example, 1 μM of the cytotoxic agent staurosporine, or cells treated with, for example, a high concentration of a surrogate reference compound HC = high control: mean confluence (%) (DMSO treated cells). %Effect=100-(100 * (Sample-LC) / (HC-LC)).

[0702] IC was calculated using GraphPad Prism (version 7.00). 50 The dose-response equation was used to plot % effect versus Log10 compound concentration with a variable slope, with the maximum fixed at 100% and the minimum fixed at 0%.

[0703] 2b) MEIS1 mRNA expression assay MEIS1 mRNA expression upon compound treatment was examined by Quantigene Singleplex assay (Thermo Fisher Scientific). This technology allows direct quantification of mRNA targets using probes hybridizing to defined target sequences of interest, and the signal is detected using the multimode plate reader Envision (PerkinElmer). The MOLM14 cell line was used for this experiment. Cells were seeded at 3,750 cells / well in 96-well plates in the presence of increasing concentrations of compounds. After 48 h of incubation with compounds, cells were lysed in lysis buffer and incubated at 55 °C for 45 min. Cell lysates were mixed with a human MEIS1-specific capture probe or a human RPL28 (ribosomal protein L28)-specific probe as a normalization control, as well as a blocking probe. Cell lysates were then transferred to a custom assay hybridization plate (Thermo Fisher Scientific) and incubated at 55 °C for 18–22 h. The plate was then washed to remove unbound material, after which the preamplifier, amplifier, and labeled probes were added sequentially. Signals (= gene counts) were measured using the multimode plate reader Envision. IC 50was calculated by dose-response modeling using appropriate software. All non-housekeeper genes respond to equal counts corrected for background and relative expression. For each sample, each test gene signal (background subtracted) was divided by the normalized gene signal (RPL28: background subtracted). Fold changes were calculated by dividing the normalized value of the treated sample by the normalized value of the DMSO-treated sample. The fold change of each target gene was calculated as IC 50 was used to calculate.

[0704] [Table 20-1]

[0705] [Table 20-2]

[0706] [Table 20-3]

Claims

1. Formula (I) 【Chemistry 1】 or a tautomer or stereoisomer thereof, R １ａ is -C(=O)-NR ｘａ R ｘｂ or 【Chemistry 2】 represents; R ｘａ and R ｘｂ is hydrogen; ３～６ Cycloalkyl; C １～４ Alkyl; C substituted with 1, 2 or 3 halo atoms １～４ Alkyl; and one -OH, -OC １～４ Alkyl or NR １１ｃ R １１ｄ C substituted with １～４ alkyl; R １ｂ represents F or Cl; Y １ is -CR ５ａ R ５ｂ -, -O-, -S-, or -NR ５ｃ - represents; R ２ is hydrogen, halo, C １～４ Alkyl, —O—C １～４ Alkyl, and -NR ７ａ R ７ｂ selected from the group consisting of: U １ and U ２ each independently represents N or CH; n1, n2, n3, and n4 are each independently selected from 1 and 2; X １ represents CH; X ２ represents N; R ４ is C １～５ Alkyl; 【Chemistry 3】 represents; R ５ａ , R ５ｂ , R ５ｃ , R ７ａ , and R ７ｂ is hydrogen, C １～４ Alkyl and C ３～６ cycloalkyl; R ３ Het １ , Het ２ , Cy ２ and -C １～６ Alkyl-NR ｘｃ R ｘｄ selected from the group consisting of: R ｘｃ Cy １ Het ５ ;-C １～６ Alkyl-Cy １ ;-C １～６ Alkyl-Het ３ ;-C １～６ Alkyl-Het ４ or -C １～６ represents alkyl-phenyl; R ｘｄ is hydrogen; C １～４ Alkyl; or halo, -OH, -O-C １～４ C substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and cyano １～４ represents alkyl; Or, R ｘｃ and R ｘｄ taken together with the N atom to which they are attached form a 4-7 membered monocyclic fully saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S and N, where the S atom is S(=O) or S(=O) ２ wherein the heterocyclyl is optionally substituted to form halo, —OH, —O—C １～４ optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and cyano; Het １ is a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom is S(=O) or S(=O) ２ or a bicyclic C-bonded 6-11 membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom is S(=O) or S(=O) ２ represents a bicyclic C-linked 6-11 membered fully saturated heterocyclyl, optionally substituted to form The heterocyclyl has R ６ and -C(=O)-R ８ and the heterocyclyl is optionally substituted on one or two carbon atoms with a substituent selected from the group consisting of halo, R ６ , Het ６ａ , Het ６ｂ , C １～４ Alkyl, oxo, -NR ９ａ R ９ｂ and -OH; Het ２ represents a C-linked pyrazolyl or triazolyl; ６ａ is substituted with; R ６ Het ３ ;-C(=O)-NH-R ８ Het ３ , Het ４ , Het ６ａ , Het ６ｂ , Cy １ , -CN, -OH, -OC １～４ Alkyl, -C(=O)-NH-C １～４ Alkyl, -C(=O)-NH-C １～４ Alkyl-C ３～６ Cycloalkyl, -C(=O)-OH, -NR １１ａ R １１ｂ And -NH-S(=O) ２ -C １～４ C optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl １～６ Alkyl; and; -CN, -OH, -O-C １～４ Alkyl, -C(=O)-NH-C １～４ Alkyl, -NH-S(=O) ２ -C １～４ Alkyl, as well as OH, —O—C １～４ Alkyl, -C(=O)-NH-C １～４ Alkyl, and -NH-S(=O) ２ -C １～４ C optionally substituted with one substituent selected from the group consisting of alkyl １～４ C, optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl, ３～６ cycloalkyl; R ６ａ is -NR １１ａ R １１ｂ , Het ３ａ , and Het ６ａ C substituted with one substituent selected from the group consisting of １～６ represents alkyl; R ８ is -OH, halo, cyano, -NR １１ａ R １１ｂ , Het ３ａ , and Het ６ａ C optionally substituted with 1, 2 or 3 substituents each independently selected from １～６ represents alkyl; Het ３ and Het ５ are each independently a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N, said S atoms being S(=O) or S(=O) ２ or a bicyclic C-bonded 6-11-membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N, wherein the S atom is S(=O) or S(=O) ２ represents a bicyclic C-linked 6-11 membered fully saturated heterocyclyl, optionally substituted on one carbon atom to form １～４ Alkyl, halo, -OH, -NR １１ａ R １１ｂ or oxo; said heterocyclyl is optionally substituted on one nitrogen atom by C １～４ optionally substituted with alkyl; Het ３ａ and Het ５ａ are each independently a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom is S(=O) or S(=O) ２ or a bicyclic C-bonded 6-11 membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom is S(=O) or S(=O) ２ represents a bicyclic C-linked 6-11 membered fully saturated heterocyclyl, optionally substituted on one carbon atom to form １～４ Alkyl, halo, -OH, -NR １１ａ R １１ｂ or oxo; said heterocyclyl is optionally substituted on one nitrogen atom by C １～４ optionally substituted with alkyl; Het ４ and Het ７ each independently represent a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, 3, or 4 heteroatoms each independently selected from O, S, and N; said 5-membered aromatic ring is bonded to a C on one nitrogen atom; １～４ said 5- or 6-membered aromatic ring optionally substituted on one carbon atom with -OH; Het ６ａ and Het ８ each independently represent a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, said S atom being S(=O) or S(=O) ２ wherein the heterocyclyl is optionally substituted to form halo, —OH, oxo, —(C═O)—NR １０ａ R １０ｂ , -O-C ３～６ Cycloalkyl, -S(=O) ２ -C １～４ Alkyl, Cyano, C １～４ Alkyl, -C １～４ Alkyl-OH, —O—C １～４ Alkyl, —O—(C═O)—NR １０ａ R １０ｂ and -O-(C=O)-C １～４ alkyl, optionally substituted on 1 or 2 carbon atoms with a total of 1, 2, 3, or 4 substituents each independently selected from the group consisting of: -C(=O)-C １～４ Alkyl and -(C=O)-NR １０ａ R １０ｂ and optionally substituted on one nitrogen with a substituent selected from the group consisting of: Het ８ａ each independently represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing two N atoms and optionally one additional heteroatom selected from O, S and N, said S atom being S(=O) or S(=O) ２ wherein the heterocyclyl is optionally substituted to form halo, —OH, oxo, —(C═O)—NR １０ａ R １０ｂ , -O-C ３～６ Cycloalkyl, -S(=O) ２ -C １～４ Alkyl, Cyano, C １～４ Alkyl, C １～４ Alkyl-OH, —O—C １～４ Alkyl, —O—(C═O)—NR １０ａ R １０ｂ and -O-(C=O)-C １～４ and the heterocyclyl is optionally substituted on 1 or 2 carbon atoms with a total of 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl, -C(=O)-C １～４ Alkyl and -(C=O)-NR １０ａ R １０ｂ and optionally substituted on one nitrogen with a substituent selected from the group consisting of: Het ６ｂ represents a bicyclic N-linked 6-11 membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, said S atom being substituted to S(=O) or S(=O) ２ wherein said heterocyclyl may be, at one or two carbon atoms, １～４ Alkyl, -OH, oxo, -(C=O)-NR １０ａ R １０ｂ , -NH-C(=O)-C １～４ Alkyl, -NH-C(=O)-Cy ３ , and -O-C １～４ The heterocyclyl is optionally substituted on one nitrogen with a total of 1 or 2 substituents each independently selected from the group consisting of alkyl; １～４ Alkyl, -C(=O)-Cy ３ , -(C=O)-C １～４ Alkyl-OH, -C(=O)-C １～４ Alkyl-O-C １～４ Alkyl, -C(=O)-C １～４ Alkyl-NR １１ａ R １１ｂ and C １～４ optionally substituted with a substituent selected from the group consisting of alkyl; Cy １ is -OH, -NH-C(=O)-C １～４ Alkyl, C １～４ Alkyl, -NH-S(=O) ２ -C １～４ Alkyl, -S(=O) ２ -C １～４ Alkyl, and —O—C １～４ C optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl ３～６ represents cycloalkyl; Cy ２ is -NR ９ａ R ９ｂ Het ６ａ Het ６ｂ and Het ３ａ , Het ６ａ , Het ６ｂ and N.R. ９ａ R ９ｂ C substituted with 1 or 2 substituents each independently selected from the group consisting of １～６ C substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl ３～７ represents cycloalkyl; ３～７ Cycloalkyl is halo, R ６ , C １～４ optionally substituted with 1 or 2 further substituents each independently selected from the group consisting of alkyl and -OH; Cy ３ is C ３～７ represents cycloalkyl; ３～７ Cycloalkyl may be optionally substituted with 1, 2 or 3 halo substituents; R ９ａ and R ９ｂ is hydrogen; １～４ Alkyl; C ３～６ Cycloalkyl; Het ５ ;-C １～４ Alkyl-R １６ -C(=O)-C １～４ Alkyl-Het ３ａ -C(=O)-R １４ ; Halo, -OH, -O-C １～４ Alkyl, -NR １１ａ R １１ｂ and cyano, ３～６ Cycloalkyl; and; halo, —OH, —O—C １～４ Alkyl, -NR １１ａ R １１ｂ and cyano; １～４ alkyl; R １１ａ , R １１ｂ , R １３ａ , R １３ｂ , R １５ａ , R １５ｂ , R １７ａ , and R １７ｂ is hydrogen and C １～４ alkyl; R １１ｃ and R １１ｄ is hydrogen, C １～６ Alkyl and -C(=O)-C １～４ alkyl; R １４ Het ５ａ Het ８ａ or -NR １３ａ R １３ｂ and Het ８ａ C substituted with 1, 2 or 3 substituents selected from the group consisting of １～４ represents alkyl; R １６ is -C(=O)-NR １７ａ R １７ｂ , -S(=O) ２ -C １～４ Alkyl, Het ５ , Het ７ Or Het ８ Represents Or a pharma- ceutically acceptable salt or solvate thereof.

2. R １ａ is -C(=O)-NR ｘａ R ｘｂ represents; R ｘａ and R ｘｂ is C ３～６ Cycloalkyl; C １～４ alkyl; and C substituted with 1, 2 or 3 halo atoms １～４ alkyl; R １ｂ represents F; Y １ represents -O-; R ２ represents hydrogen; R ４ is C １～５ Alkyl; 【Chemistry 4】 represents; R ３ Het １ and Cy ２ selected from the group consisting of: Het １ represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom; said heterocyclyl is represented by R ６ and -C(=O)-R ８ said heterocyclyl optionally being substituted at one or two carbon atoms with a total of one, two, three or four halo substituents; R ６ Het ３ Het ３ , Het ４ , Het ６ａ , Cy １ , —OH, —O—C １～４ Alkyl, -C(=O)-NH-C １～４ Alkyl, -C(=O)-NH-C １～４ Alkyl-C ３～６ Cycloalkyl and -NH-S(=O) ２ -C １～４ C optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl １～６ alkyl; R ８ is -OH and -NR １１ａ R １１ｂ C substituted with one substituent selected from the group consisting of １～６ represents alkyl; Het ３ and Het ５ are each independently a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N, said S atoms being S(=O) or S(=O) ２ represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl, optionally substituted to form The heterocyclyl may be optionally substituted on one carbon atom with -OH or oxo; Het ４ each independently represent a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms selected from O, S, and N; said 5- or 6-membered aromatic ring may be optionally substituted on one carbon atom with -OH; Het ６ａ is a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom is substituted to S(=O) or S(=O) ２ and represents a monocyclic N-linked 4-7 membered fully saturated heterocyclyl which may have, on one or two carbon atoms, an oxo, -S(=O) ２ -C １～４ Alkyl and -O-C １～４ The heterocyclyl may be optionally substituted on one nitrogen with a total of 1, 2, 3 or 4 substituents each independently selected from the group consisting of: alkyl; -C(=O)-C １～４ optionally substituted with alkyl; Het ６ｂ represents a bicyclic N-linked 6-11 membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, said S atom being substituted to S(=O) or S(=O) ２ wherein the heterocyclyl may be substituted on one carbon atom with -(C=O)-NR １０ａ R １０ｂ said heterocyclyl being optionally substituted on one nitrogen with -C(=O)-C １～４ optionally substituted with alkyl; Cy １ is -OH, -NH-C(=O)-C １～４ Alkyl, C １～４ Alkyl, -NH-S(=O) ２ -C １～４ Alkyl, and —O—C １～４ C optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl ３～６ represents cycloalkyl; Cy ２ is -NR ９ａ R ９ｂ , Het ６ａ , and Het ６ｂ C substituted with 1 or 2 substituents each independently selected from the group consisting of ３～７ represents cycloalkyl; R ９ａ and R ９ｂ is hydrogen; １～４ Alkyl; C ３～６ Cycloalkyl; Het ５ ;-C １～４ Alkyl-R １６ and; 1, 2 or 3 -O-C １～４ Alkyl-substituted C １～４ alkyl; R １０ａ , R １０ｂ , R １１ａ and R １１ｂ is C １～４ represents alkyl; R １６ Het ５ Represents, The compound of claim 1.

3. R １ａ is -C(=O)-NR ｘａ R ｘｂ represents; R ｘａ and R ｘｂ is C １～４ represents alkyl; R １ｂ represents F; Y １ represents -O-; R ２ represents hydrogen; R ４ represents isopropyl; R ３ Het １ and Cy ２ selected from the group consisting of: Het １ represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom; said heterocyclyl is ６ and optionally substituted with a substituent selected from the group consisting of: R ６ is one Het ３ C substituted with １～６ represents alkyl; Het ３ is a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N, wherein the S atom is S(=O) or S(=O) ２ represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl, optionally substituted to form Het ６ａ represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom; said heterocyclyl is １～４ optionally substituted with alkyl; Het ６ｂ represents a bicyclic N-linked 6-11 membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O and N; said heterocyclyl is joined on one carbon atom by -(C=O)-NR １０ａ R １０ｂ said heterocyclyl being optionally substituted on one nitrogen with -C(=O)-C １～４ optionally substituted with alkyl; Cy ２ Het ６ａ and Het ６ｂ C substituted with one substituent selected from the group consisting of ３～７ represents cycloalkyl; R １０ａ and R １０ｂ is C １～４ Represents alkyl, The compound of claim 1.

4. R ３ Het １ 2. The compound according to claim 1 , wherein

5. The compound of claim 1, wherein n1 is 1, n2 is 2, n3 is 1, and n4 is 1.

6. U １ The compound of claim 1 , wherein represents N.

7. R ３ Het １ represents; Het １ represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing one N atom; said heterocyclyl is bonded to R on one nitrogen atom; ６ said heterocyclyl is optionally substituted at 1 or 2 carbon atoms with a total of 1, 2, 3 or 4 halo substituents; R ６ But, ３ , Het ４ , Het ６ａ and Cy １ C optionally substituted with 1 or 2 substituents each independently selected from the group consisting of １～６ selected from the group consisting of alkyl, The compound of claim 1.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 and a pharma- ceutically acceptable carrier or diluent.

9. A process for preparing a pharmaceutical composition according to claim 8, comprising mixing a pharma- ceutically acceptable carrier with a therapeutically effective amount of a compound according to any one of claims 1 to 7.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 for use as a medicament.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 for use in the prevention or treatment of cancer, myelodysplastic syndrome (MDS) and diabetes.

12. 12. The pharmaceutical composition of claim 11, wherein the cancer is selected from leukemia, myeloma or solid tumor cancer, such as prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma and glioblastoma.

13. 13. The pharmaceutical composition of claim 12, wherein the leukemia is selected from acute leukemia, chronic leukemia, myeloid leukemias, myelogeneous leukemias, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), MLL-rearranged leukemia, MLL-PTD leukemia, MLL-amplified leukemia, MLL positive leukemia, and leukemia exhibiting a HOX / MEIS1 gene expression signature.

14. The pharmaceutical composition of claim 11 for use in the prevention or treatment of cancer.

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