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 syndrome (MDS) and diabetes. [Background technology]

[0002] Chromosomal rearrangements affecting the mixed lineage leukemia genes (MLL; MLL1; KMT2A) result in aggressive acute leukemia across all age groups, which remains largely incurable, highlighting the urgent need for novel therapeutic approaches. Acute leukemias with these MLL chromosomal rearrangements represent lymphoid, myeloid, or biphenotypic disorders and comprise 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 proteins 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 the pTEFb complex, by the fusion partner results in enhanced transcription and transcription elongation of MLL target genes, 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 primarily localized in the nucleus. It has been shown to interact with numerous proteins and is therefore involved in various cellular processes. The best-understood function of menin is its role as an oncogenic cofactor for MLL fusion proteins. Menin interacts with two motifs within the N-terminal fragment of MLL, MBM1 (menin-binding motif 1) and MBM2, which are conserved in all fusion proteins (Thiel et al., Bioessays 2012.34,771-80). The 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 the stable interaction between MLL and LEDGF and for 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, numerous 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 myeloid 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 in vivo, and releases a differentiation block in MLL-transformed leukemic blasts. These studies also demonstrated 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 demonstrating 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 for MLL1 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 and myelodysplastic syndromes. Although the molecular mechanisms and biological functions of MLL-PTD are not fully understood, novel therapeutic targeting strategies that affect the 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 the 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 describe 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 describe 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. International Publication No. 2016197027 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 International Publication No. 2016040330 describes thienopyrimidine and thienopyridine compounds. International Publication No. 2017192543 describes piperidines as menin inhibitors. International Publication Nos. 2017112768, 2017207387, 2017214367, 2018053267, and 2018024602 describe inhibitors of menin-MLL interaction. WO2017161002 and WO2017161028 describe inhibitors of menin-MLL.International Publication Nos. 2018050686, 2018050684, and 2018109088 describe inhibitors of menin-MLL interaction. International Publication No. 2018226976 describes methods and compositions for inhibiting the interaction between menin and MLL proteins. International Publication No. 2019060365 describes menin-MLL substitution inhibitors. Krivtsov et al., Cancer Cell 2019. No. 6 Vol. 36, 660-673, describes menin-MLL inhibitors.

[0008] International Publication No. 2020069027 discloses inhibitors of menin. International Publication No. 2018175746 discloses methods for treating hematological malignancies and Ewing's sarcoma. International Publication No. 2020045334 discloses azabicyclo derivatives for use in pharmaceutical compositions. International Publication No. 2019120209 discloses substituted heterocyclic compounds as menin / MLL protein / protein interaction inhibitors. Chinese Patent No. 111297863 discloses the use of menin mixed lineage leukemia (MLL) inhibitors. International Publication No. 2021121327 describes substituted linear spiro derivatives and their use as menin / MLL protein / protein interaction inhibitors. Summary of the Invention

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

[0010] [ka] and tautomers and stereoisomers thereof, wherein R 1a represents Het, Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2 or 3 nitrogen atoms and optionally a carbonyl moiety; 3~6 cycloalkyl, and the monocyclic 5- or 6-membered aromatic ring is optionally substituted with C 3~6Cycloalkyl, cyano, and C 1~4 optionally substituted with one or two additional substituents selected from the group consisting of alkyl; R 1b represents F or Cl; Y 1 -CR 5a R 5b -, -O-, -S-, or -NR 5c - represents; 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 represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 represents CH, and X 2 represents N; R 4 is C 1~5 alkyl;

[0011] [ka] represents; R 5a , R 5b , R 5c , R 7a , and R 7b is hydrogen, C 1~4 Alkyl and C 3~6 are each independently selected from the group consisting of 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- to 7-membered monocyclic fully saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; the heterocyclyl may optionally 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 independently selected from O, S, and N, wherein the S atom is 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 independently selected from O, S, and N, wherein the S atom is optionally substituted to form S(=O) or S(=O)2; The heterocyclyl optionally has on one nitrogen atom R 6 , -C(=O)-Cy 1 , 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 , Het6a , Het 6b , C 1~4 Alkyl, oxo, -NR 9a R 9b and -OH; Het 2 represents a C-linked pyrazolyl or triazolyl; optionally, R on one nitrogen atom 6a may be substituted with; R 6 and R 6a teeth, Het 3 ;Het 4 ;-C(=O)-NH-Cy 1 ;-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 3~6 cycloalkyl; -C(=O)-OH, -NR 11a R 11b , and -NH-S(=O)2-C 1~4 alkyl; -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 and -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, and -NH-S(=O)2-C1~4 C optionally substituted with one substituent selected from the group consisting of alkyl 1~4 are each independently selected from the group consisting of alkyl; R 8 -OC 1~6 Alkyl, C 1~6 Alkyl; or -OH, halo, cyano, -NR 11a R 11b , Het 3a and Het 6a C substituted with 1, 2 or 3 substituents each independently selected from 1~6 represents alkyl; Het 3 , Het 3a , Het 5 and Het 5a each independently represent a monocyclic C-bonded 4-7-membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from O, S and N, wherein the S atoms are 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 independently selected from O, S and N, wherein the S atoms are optionally substituted to form S(=O) or S(=O)2; The heterocyclyl may optionally be C 1~4 Alkyl, halo, -OH, -NR 11a R 11b or oxo; the heterocyclyl may optionally be substituted on one nitrogen atom by C 1~4 optionally substituted with alkyl; Het 4 and Het 7each independently represent a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, 3, or 4 heteroatoms each independently selected from O, S, and N; the aromatic ring optionally contains, on one nitrogen atom, a C 1~4 Alkyl or -(C=O)-OC 1~4 The aromatic ring may be optionally substituted with -OH, halo, C 1~4 Alkyl, -OC 1~4 Alkyl, -NR 11a R 11b , C 1~4 Alkyl-NR 11a R 11b , -NH-C(=O)-C 1~4 Alkyl, cyano, -COOH, -NH-C(=O)-OC 1~4 Alkyl, -NH-C(=O)-Cy 3 , -NH-C(=O)-NR 10a R 10b , -(C=O)-OC 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, Het 8a , -C 1~4 Alkyl-Het 8a , Het 8b , Het 9 and -C(=O)-NR 10a R 10b and optionally substituted on one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of: Het 6a , Het 8 and Het 8a 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, which S atom may be substituted to form S(=O) or S(=O)2; the heterocyclyl may optionally be substituted on one or two carbon atoms with halo, -OH, oxo, -NH-C(=O)-C 1~4 Alkyl, -NH-C(=O)-Cy 3 , -(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 alkyl, and the heterocyclyl is optionally substituted on one nitrogen by a —C(═O)—C 1~4 Alkyl and -(C=O)-NR 10a R 10b optionally substituted with a substituent selected from the group consisting of: Het 6b and Het 8b each independently represent 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, which S atom may be substituted to form S(=O) or S(=O)2; the heterocyclyl may optionally be 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 The heterocyclyl may optionally be 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-OC1~4 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; Het 9 each independently represent a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N; the aromatic ring optionally has a C bond on one nitrogen atom 1~4 The aromatic ring may be optionally substituted on one or two carbon atoms with -OH, halo, and C 1~4 optionally substituted with a total of 1 or 2 substituents each independently 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 is C 3~7 represents cycloalkyl; 3~7 Cycloalkyl may optionally be substituted with halo, R 6 , Het 6a , Het 6b , -NR 9a R 9b , -OH, C 1~4 Alkyl and Het 3a , Het 6a , Het 6b C substituted with 1 or 2 substituents each independently selected from the group consisting of 1~4 Alkyl, and -NR 9a R 9b and optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of: Cy 3 is C 3~7 represents cycloalkyl; 3~7 The 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; -C(=O)-C 1~4 Alkyl; -C(=O)-C 3~6 Cycloalkyl; -S(=O)2-C 1~4 Alkyl;Het 5 ;Het 7 ;-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 11b and cyano; 3~6 cycloalkyl; and Halo, -OH, -OC 1~4 Alkyl, -NR 11a R 11b and C substituted with 1, 2 or 3 substituents selected from the group consisting of cyano 1~4 selected from the group consisting of alkyl; R 11a , R 11b , R 13a , R 13b , R 15a , R 15b , R 17a , and R 17b is hydrogen and C 1~4 are each independently selected from the group consisting of alkyl; R 10a and R10b is hydrogen, C 1~4 Alkyl and C 3~6 are each independently selected from the group consisting of cycloalkyl; R 14 Het 5a ;Het 7 ;Het 8a ;-OC 1~4 Alkyl; -C(=O)NR 15a R 15b ;-OC 1~4 C substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and halo 3~6 cycloalkyl; or -OC 1~4 Alkyl, -NR 13a R 13b , Halo, Cyano, -OH, Het 8a , and Cy 1 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 pharmaceutically acceptable salts and solvates thereof.

[0012] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

[0013] Furthermore, the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, for use as a medicament, and to a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of cancer, myelodysplastic syndrome (MDS) and diabetes.

[0014] In a particular embodiment, the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer or in the prevention of cancer.

[0015] In certain embodiments, the cancer is selected from leukemia, myeloma, or solid tumor cancer (e.g., prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma, and glioblastoma, etc.). In some embodiments, the leukemia includes acute leukemia, chronic leukemia, myeloid leukemia, myeloid leukemia, lymphoblastic leukemia, lymphocytic leukemia, 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, leukemia exhibiting a HOX / MEIS1 gene expression signature, etc.

[0016] The present invention also relates to the use of a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, in combination with an additional pharmaceutical agent for use in the treatment or prevention of cancer, myelodysplastic syndrome (MDS) and diabetes.

[0017] Furthermore, the present invention relates to a process for preparing a pharmaceutical composition according to the present invention, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof.

[0018] The present invention also relates to a product comprising a compound of formula (I), a pharmaceutically 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 syndrome (MDS), and diabetes.

[0019] Furthermore, the present invention relates to a method for treating or preventing a cell proliferative disorder in a warm-blooded animal, which method comprises administering to said animal an effective amount of a compound of formula (I) as defined herein, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition or combination. DETAILED DESCRIPTION OF THE INVENTION

[0020] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0021] 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 on.

[0022] As used herein, "C" refers to a group or part of a group. 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.

[0023] As used herein, "C" refers to a group or part of a group. 3~6 The term "cycloalkyl" defines a saturated cyclic hydrocarbon radical having from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0024] As used herein, "C" refers to a group or part of a group. 3~7 The term "cycloalkyl" defines a saturated cyclic hydrocarbon radical having from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0025] It will be apparent to those skilled in the art that S(=O)2 or SO2 represents a sulfonyl moiety.

[0026] It will be apparent to one skilled in the art that CO or C(=O) represent a carbonyl moiety.

[0027] It will be apparent to one skilled in the art that groups such as -CRR- represent:

[0028] [ka] An example of such a group is -CR 5a R 5b -It is.

[0029] Groups such as -NR-

[0030] [ka] It will be clear to one skilled in the art that an example of such a group is -NR 5c -It is.

[0031] The term "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 defines a fully saturated cyclic hydrocarbon radical having 4 to 7 ring members and containing at least 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- 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 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- to 7-membered monocyclic fully saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N.

[0032] The term "monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms 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 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, C-linked tetrahydrothiopyranyl, and C-linked piperidinyl. The term "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" defines a fully saturated cyclic hydrocarbon radical having 4 to 7 ring members and containing two nitrogen atoms and optionally one additional heteroatom selected from O, S, and N, such as N-linked piperazinyl and N-linked 1,4-diazepanyl.

[0033] For clarity, a 4- to 7-membered fully or partially saturated heterocyclyl has 4 to 7 ring members, including the heteroatom.

[0034] Non-limiting examples of "monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 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-triazolyl, 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.

[0035] Those skilled in the art will recognize that 5- or 6-membered monocyclic aromatic rings containing 1, 2, or 3 nitrogen atoms and a carbonyl moiety include, but are not limited to:

[0036] [ka] You will understand that:

[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, C-linked thiazolyl, C-linked thiadiazolyl, C-linked oxadiazolyl, 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 that share two atoms and a bond between those atoms.

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

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

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

[0044] [ka] Examples include:

[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] Examples include:

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

[0048] [ka] Examples include:

[0049] Examples of fused bicyclic C-linked 9 or 10 membered aromatic rings containing 1, 2, 3 or 4 heteroatoms each independently selected from O, S and N include, but are not limited to:

[0050] [ka] Examples include:

[0051] The substituents are chemical structures, e.g.

[0052] [ka] If represented by "----" represents the bond to the remainder of the molecule of formula (I).

[0053] When any variable occurs more than one time in any constituent, each definition is independent.

[0054] When any variable occurs more than one time in any formula (eg, formula (I)), each definition is independent.

[0055] In this context, it will also be clear 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."

[0056] Generally, whenever the term "substituted" is used herein, unless otherwise indicated or apparent from the context, "substituted" is used to indicate that one or more hydrogens, particularly 1 to 4 hydrogens, more particularly 1 to 3 hydrogens, preferably 1 or 2 hydrogens, and 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 valence is not exceeded, and that the substitution results in a chemically stable compound, i.e., a compound sufficiently robust to withstand isolation to a useful degree of purity from a reaction mixture. In certain embodiments, when the number of substituents is not explicitly specified, the number of substituents is 1.

[0057] 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.

[0058] Those skilled 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).

[0059] 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.

[0060] Within the context of the present invention, "saturated" means "fully saturated" unless otherwise specified.

[0061] 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) through any available ring carbon atom (C-bonded) or nitrogen atom (N-bonded).

[0062] 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.

[0063] 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.

[0064] 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.

[0065] The term "composition" is intended to encompass a product containing specified ingredients in specified amounts, and any product that results directly or indirectly from a combination of specified ingredients in specified amounts.

[0066] 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 complete elimination of all symptoms.

[0067] As used herein, the term "compounds of the invention" or "compounds according to the invention" is meant to include compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof.

[0068] 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.

[0069] Above and below, the term "compounds of formula (I)" is meant to include its tautomers and its stereoisomers.

[0070] Above and below the terms "stereoisomer", "stereoisomeric form" or "stereochemically isomeric form" are used interchangeably.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e., they are not related as mirror images. If the compound contains double bonds, the substituents may be in either the E or Z configuration.

[0075] 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.

[0076] Thus, the present invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, whenever chemically possible.

[0077] 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 those skilled in the art.

[0078] 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 as (+) or (-) depending on the direction they rotate plane-polarized light. For example, resolved enantiomers whose absolute configuration is not known can be designated as (+) or (-) depending on the direction they rotate plane-polarized light.

[0079] 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.

[0080] Some of the compounds according to formula (I) may exist in their tautomeric forms. Such forms, to the extent they may exist, are intended to be included within the scope of the present invention, even though they are not explicitly shown in formula (I) above. It follows that a single compound may exist in both stereoisomeric and tautomeric forms.

[0081] for example,

[0082] [ka] also includes other tautomeric forms.

[0083] [ka] for example,

[0084] [ka] also includes other tautomeric forms.

[0085] [ka]

[0086] 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, followed by removing the solvent or medium using standard techniques (for example, in vacuo, by lyophilization, or by filtration). Salts can also be prepared by exchanging the counterion of a compound of the present disclosure in the form of a salt with another counterion, for example, using a suitable ion exchange resin.

[0087] The pharmaceutically 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 are able to form.

[0088] Suitable acids include, for example, inorganic acids such as hydrohalic acids, e.g., hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, 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.

[0089] 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.

[0090] 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, for example, 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, base forms can be converted to the free base forms by treatment with acid.

[0091] 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 and the like.

[0092] The compounds of the present invention prepared by the processes described below may be synthesized in the form of mixtures of enantiomers, particularly racemic mixtures of enantiomers, which can be separated from one another according to art-known resolution procedures. Methods for separating the enantiomeric forms of the compound of formula (I) and its pharmaceutically acceptable salts and solvates include liquid chromatography using chiral stationary phases. Such 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, if a specific stereoisomer is desired, the compound will be synthesized by stereospecific preparative methods. These methods will advantageously employ enantiomerically pure starting materials.

[0093] As used herein, the term "enantiomerically pure" means that a 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.

[0094] The present invention also includes isotopically labeled compounds of the present invention that are identical to those enumerated herein, but due to 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).

[0095] All isotopes and isotopic mixtures of any particular atom or element identified herein, whether naturally occurring or synthetically produced, 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 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, etc. Preferably, the isotope is 2 H, 3 H, 11 C, and 18 F. More preferably, the isotope is selected from the group 2 H. In particular, deuterated compounds are intended to be included within the scope of the present invention.

[0096] Certain isotopically labeled compounds of the present 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 in vivo half-life or reduced dosage requirements) and therefore may be preferred in some circumstances. 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 is useful for helping to localize and identify tumors, stage disease, and determine appropriate 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).

[0097] The present invention relates in particular to compounds of formula (I) as defined herein, and tautomers and stereoisomers thereof, wherein: R 1a represents Het; Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2 or 3 nitrogen atoms and optionally a carbonyl moiety; 3~6 cycloalkyl, and the monocyclic 5- or 6-membered aromatic ring is optionally substituted with C 3~6 Cycloalkyl, cyano, and C 1~4 optionally substituted with one or two additional substituents selected from the group consisting of alkyl; R 1brepresents F or Cl; Y 1 -CR 5a R 5b -, -O-, -S-, or -NR 5c - represents; 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 represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 represents CH, and X 2 represents N; R 4 is C 1~5 alkyl;

[0098] [ka] represents; R 5a , R 5b , R 5c , R 7a , and R 7b is hydrogen, C 1~4 Alkyl and C 3~6 are each independently selected from the group consisting of 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 1~6represents 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- to 7-membered monocyclic fully saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; the heterocyclyl may optionally 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 independently selected from O, S, and N, wherein the S atom is optionally substituted to form S(=O) or S(=O)2; or a bicyclic C-bonded 6-11 membered fully saturated heterocyclyl containing an N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom is optionally substituted to form S(=O) or S(=O)2; The heterocyclyl optionally has on one nitrogen atom 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 9band -OH; Het 2 is R on one nitrogen atom 6a represents a C-linked pyrazolyl or triazolyl substituted with 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 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 and -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 is -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, 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 each independently represent a monocyclic C-bonded 4-7-membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from O, S and N, wherein the S atoms are 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 independently selected from O, S and N, wherein the S atoms are optionally substituted to form S(=O) or S(=O)2; The heterocyclyl may optionally be C 1~4 Alkyl, halo, -OH, -NR 11a R 11b or oxo; the heterocyclyl may optionally be substituted on one nitrogen atom by C 1~4 optionally substituted with alkyl; Het 3a and Het 5aeach independently represent a monocyclic C-bonded 4-7 membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom is 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 independently selected from O, S, and N, wherein the S atom is optionally substituted to form S(=O) or S(=O)2; The heterocyclyl may optionally be C 1~4 Alkyl, halo, -OH, -NR 11a R 11b or oxo; the heterocyclyl may optionally be 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, or 3 heteroatoms each independently selected from O, S, and N; the 5-membered aromatic ring optionally has a C bond on one nitrogen atom 1~4 the 5- or 6-membered aromatic ring may optionally be 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, which S atom may be substituted to form S(=O) or S(=O)2; the heterocyclyl may optionally be 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, C1~4 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 may be optionally substituted with a total of 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl; 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 represent 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, wherein the S atom may be substituted to form S(=O) or S(=O)2; the heterocyclyl may optionally be 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, 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 may be optionally substituted with a total of 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl; 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, wherein the S atom may be substituted to form S(=O) or S(=O)2; the heterocyclyl may optionally be substituted on one or two carbon atoms by 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 alkyl, and the heterocyclyl is optionally substituted with a total of 1 or 2 substituents each independently selected from the group consisting of -C(=O)-C 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 on one nitrogen 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 is -NR 9a R 9b ;Het 6a ;Het 6b ; and Het 3a , Het 6a , Het 6b and NR 9a R9b C substituted with one or two substituents each independently selected from the group consisting of 1~6 C substituted with 1 or 2 additional substituents each independently selected from the group consisting of alkyl 3~7 represents cycloalkyl; 3~7 Cycloalkyl may optionally be substituted with halo, R 6 , C 1~4 optionally substituted with one or two additional substituents each independently selected from the group consisting of alkyl and —OH; Cy 3 is C 3~7 represents cycloalkyl; 3~7 The 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 11b and C substituted with 1, 2 or 3 substituents selected from the group consisting of cyano 3~6 cycloalkyl; and Halo, -OH, -OC 1~4 Alkyl, -NR 11a R 11b and C substituted with 1, 2 or 3 substituents selected from the group consisting of cyano 1~4 are each independently selected from the group consisting of alkyl; R 11a , R 11b , R 13a , R 13b , R 15a , R 15b , R 17a , and R 17bis hydrogen and C 1~4 are each independently selected from the group consisting of alkyl; R 10a and R 10b is hydrogen, C 1~4 Alkyl and C 3~6 are each independently selected from the group consisting of cycloalkyl; 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] and pharmaceutically acceptable salts and solvates thereof.

[0099] The present invention relates in particular to compounds of formula (I) as defined herein, and tautomers and stereoisomers thereof, wherein: R 1a represents Het; Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2 or 3 nitrogen atoms and optionally a carbonyl moiety; 3~6 cycloalkyl, and the monocyclic 5- or 6-membered aromatic ring is optionally substituted with cyano, and C 1~4 optionally substituted with one or two additional substituents selected from the group consisting of alkyl; R 1b represents F; Y 1 represents -O-; R 2 is hydrogen, U stands for N; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 represents CH, and X 2 represents N; R 4 is C 1~5 alkyl; or

[0100] [ka] R 3 Het 1 and Cy 2 selected from the group consisting of: Het 1 represents a monocyclic C-bonded 4-7 membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the 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 independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; The heterocyclyl optionally has on one nitrogen atom R 6 and -C(=O)-R 8 wherein 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 oxo and —OH; R 6 and R 6a teeth, Het 4 ;Het 3 , Het 6a and Cy 1 C optionally substituted with 1 or 2 substituents each independently selected from the group consisting of 1~6 alkyl; and C3~6 are each independently selected from the group consisting of cycloalkyl; R 8 But, -OC 1~6 represents alkyl; Het 3 , Het 3a , Het 5 and Het 5a 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, wherein the S atom may be substituted to form S(=O) or S(=O)2; The heterocyclyl may optionally have a C on one carbon atom. 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, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, 3, or 4 heteroatoms each independently selected from O, S, and N; the aromatic ring optionally contains, on one nitrogen atom, a C 1~4 Alkyl or -(C=O)-OC 1~4 The aromatic ring may be optionally substituted with -OH, halo, C 1~4 Alkyl, -OC 1~4 Alkyl, -NR 11a R 11b , C 1~4 Alkyl-NR 11a R 11b , -NH-C(=O)-C 1~4 Alkyl, cyano, -COOH, -NH-C(=O)-OC 1~4 Alkyl, -NH-C(=O)-NR 10a R 10b , -(C=O)-OC 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, Het 8a , -C 1~4 Alkyl-Het 8a, Het 8b , Het 9 and -C(=O)-NR 10a R 10b and optionally substituted on one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of: Het 6a , Het 8 and Het 8a 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, which S atom may be substituted to form S(=O) or S(=O)2; the heterocyclyl may optionally be substituted on one or two carbon atoms with halo, -OH, oxo, -NH-C(=O)-C 1~4 Alkyl, -NH-C(=O)-Cy 3 , -(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 and -OC 1~4 alkyl; the heterocyclyl is optionally substituted with a total of 1, 2, 3, or 4 substituents 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 6b and Het 8b each independently represent 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, which S atom may be substituted to form S(=O) or S(=O)2; the heterocyclyl may optionally be C 1~4Alkyl, -OH, oxo, -(C=O)-NR 10a R 10b , -NH-C(=O)-C 1~4 Alkyl, -NH-C(=O)-Cy 3 , and -OC 1~4 alkyl, and the heterocyclyl is optionally substituted with a total of 1 or 2 substituents each independently selected from the group consisting of -C(=O)-C 1~4 Alkyl, -C(=O)-Cy 3 , and C 1~4 optionally substituted on one nitrogen with a substituent selected from the group consisting of alkyl; Het 9 represent a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N; the aromatic ring optionally has a C bond on 1 or 2 carbon atoms; 1~4 optionally substituted with alkyl; Cy 1 -OH and 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 C 3~7 represents cycloalkyl; 3~7 Cycloalkyl is optionally R 6 , Het 6a , Het 6b , -NR 9a R 9b , -OH, and C 1~4 optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl; Cy 3 is C 3~7 represents cycloalkyl; 3~7 The cycloalkyl may be optionally substituted with 1, 2, or 3 halo substituents; R 9a and R 9b is hydrogen; C 1~4 Alkyl; C3~6 Cycloalkyl; -C(=O)-C 1~4 Alkyl; -C(=O)-C 3~6 Cycloalkyl;Het 5 ;Het 7 ;-C 1~4 Alkyl-R 16 ;-C(=O)-C 1~4 Alkyl-Het 3a ;-C(=O)-R 14 ;and Halo, -OH and -OC 1~4 C substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl 1~4 are each independently selected from the group consisting of alkyl; R 11a , R 11b , R 13a , R 13b , R 17a , and R 17b is hydrogen and C 1~4 are each independently selected from the group consisting of alkyl; R 10a and R 10b is hydrogen, C 1~4 Alkyl and C 3~6 are each independently selected from the group consisting of cycloalkyl; R 14 OC 1~4 Alkyl;-OC 1~4 C substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and halo 3~6 cycloalkyl; or -OC 1~4 Alkyl, -NR 13a R 13b and C substituted with 1, 2 or 3 substituents selected from the group consisting of cyano 1~4 represents alkyl; R 16 is -C(=O)-NR 17a R 17b or -S(=O)2-C 1~4 represents alkyl] and pharmaceutically acceptable salts and solvates thereof.

[0101] The present invention relates in particular to compounds of formula (I) as defined herein, and tautomers and stereoisomers thereof, wherein: R 1a represents Het; Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2 or 3 nitrogen atoms and optionally a carbonyl moiety; 3~6 cycloalkyl, and the monocyclic 5- or 6-membered aromatic ring is optionally substituted with cyano, and C 1~4 optionally substituted with one or two additional substituents selected from the group consisting of alkyl; R 1b represents F; Y 1 represents -O-; R 2 represents hydrogen, U represents N; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 represents CH, and X 2 represents N; R 4 is C 1~5 alkyl; or

[0102] [ka] represents; R 3 Het 1 and Cy 2 selected from the group consisting of: Het 1represents a monocyclic C-bonded 4-7 membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the 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 independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; The heterocyclyl optionally has on one nitrogen atom R 6 wherein 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 oxo and —OH; R 6 teeth, Het 3 , Het 6a and Cy 1 C optionally substituted with 1 or 2 substituents each independently selected from the group consisting of 1~6 alkyl; and C 3~6 cycloalkyl; R 6a 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- 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 optionally substituted to form S(=O) or S(=O)2; the heterocyclyl optionally has a C 1~4 optionally substituted with alkyl; Het3a is 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, wherein the S atom is optionally substituted to form S(=O) or S(=O)2; The heterocyclyl may optionally have a C on one carbon atom. 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, or 3 heteroatoms each independently selected from O, S, and N; the 5-membered aromatic ring optionally has a C bond on one nitrogen atom 1~4 the 5- or 6-membered aromatic ring may optionally be 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, which S atom may be substituted to form S(=O) or S(=O)2; the heterocyclyl may optionally be 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, -C 1~4 Alkyl-OH and -OC 1~4 The heterocyclyl may optionally be 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 Alkyl and -(C=O)-NR 10a R 10b optionally substituted 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, wherein the S atom may be substituted to form S(=O) or S(=O)2; the heterocyclyl may optionally be substituted on one or two carbon atoms by 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 alkyl, and the heterocyclyl is optionally substituted with a total of 1 or 2 substituents each independently selected from the group consisting of -C(=O)-C 1~4 Alkyl, -C(=O)-Cy 3 , and C 1~4 optionally substituted on one nitrogen with a substituent selected from the group consisting of alkyl; Cy 1 -OH and 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 one or two substituents each independently selected from the group consisting of 3~7 represents cycloalkyl; and 3~7 Cycloalkyl is optionally R 6 , C 1~4 optionally substituted with one or two additional substituents each independently selected from the group consisting of alkyl, and —OH; Cy 3 is C 3~7 represents cycloalkyl; 3~7 The cycloalkyl may be optionally substituted with 1, 2, or 3 halo substituents; R9a 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 11b and C substituted with 1, 2 or 3 substituents selected from the group consisting of cyano 3~6 cycloalkyl; and -OH and -OC 1~4 C substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl 1~4 are each independently selected from the group consisting of alkyl; R 11a , R 11b , R 13a , R 13b , R 17a , and R 17b is hydrogen and C 1~4 are each independently selected from the group consisting of alkyl; R 10a and R 10b is hydrogen, C 1~4 Alkyl and C 3~6 are each independently selected from the group consisting of cycloalkyl; R 14 is one, two or three -NR 13a R 13b C substituted with a substituent 1~4 represents alkyl; R 16 is -C(=O)-NR 17a R 17b or -S(=O)2-C 1~4 represents alkyl] and pharmaceutically acceptable salts and solvates thereof.

[0103] The present invention relates in particular to compounds of formula (I) as defined herein, and tautomers and stereoisomers thereof, wherein: R 1a represents Het; Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2 or 3 nitrogen atoms; the monocyclic 5- or 6-membered aromatic ring is 3~6 cycloalkyl, and the monocyclic 5- or 6-membered aromatic ring is optionally substituted with one C 1~4 optionally substituted with alkyl; R 1b represents F; Y 1 represents -O-; R 2 represents hydrogen, U represents N; n1 is 1, n2 is 2, n3 is 1, and n4 is 1; X 1 represents CH, and X 2 represents N; R 4 represents isopropyl; R 3 Cy 2 represents; Het 6a represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom; Het 6b represents a fused bicyclic N-linked 6-11 membered fully saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O and N; the heterocyclyl optionally has a —C(═O)—C bond on one nitrogen atom; 1~4 optionally substituted with alkyl; Cy 2 Het 6a , Het 6b , and -NR 9a R 9b C substituted with one substituent selected from the group consisting of 3~7 represents cycloalkyl; R 9a and R 9b However, independently, C 1~4 alkyl, and pharmaceutically acceptable salts and solvates thereof.

[0104] The present invention relates in particular to compounds of formula (I) as defined herein, and tautomers and stereoisomers thereof, wherein: R 1a represents Het; Het

[0105] [ka] represents; R 1b represents F; Y 1 represents -O-; R 2 represents hydrogen, U represents N; n1 is 1, n2 is 2, n3 is 1, and n4 is 1; X 1 represents CH, and X 2 represents N; R 4 represents isopropyl; R 3 Cy 2 represents; Het 6a represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom; Het 6b represents a fused bicyclic N-linked 6-11 membered fully saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O and N; the heterocyclyl optionally has a —C(═O)—C bond on one nitrogen atom; 1~4 optionally substituted with alkyl; Cy 2 Het 6a , Het 6b , and -NR 9a R 9b represents cyclobutyl substituted by one substituent selected from the group consisting of: R 9a and R 9b However, independently, C 1~4 alkyl, and pharmaceutically acceptable salts and solvates thereof.

[0106] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 1b represents F.

[0107] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 2 represents hydrogen.

[0108] In one embodiment, the invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein n1 is 1, n2 is 2, n3 is 1 and n4 is 1.

[0109] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Y 1 represents -O-.

[0110] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Y 1 represents -O-; U represents N.

[0111] In one embodiment, the invention relates to those compounds of formula (I) and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, as described in any of the other embodiments, wherein U represents N.

[0112] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Y 1 represents -O-; U represents N; R 1b represents F; R 2 represents hydrogen.

[0113] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Y 1 represents -O-; U represents N; R 1b represents F; R 2 represents hydrogen; R 4 represents isopropyl.

[0114] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 4 represents isopropyl.

[0115] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 4 represents the following equation:

[0116] [ka]

[0117] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R4 isopropyl; or represents the formula

[0118] [ka]

[0119] In an embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 6 and R 6a teeth, Het 4 ;Het 3 and Cy 1 C optionally substituted with 1 or 2 substituents each independently selected from the group consisting of 1~6 Alkyl; and C 3~6 are each independently selected from the group consisting of cycloalkyl; Het 3 , Het 3a , Het 5 and Het 5a each independently represent 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, and the S atom may be substituted to form S(=O) or S(=O)2.

[0120] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het represents

[0121] [ka]

[0122] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het represents

[0123] [ka]

[0124] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any of the other embodiments and pharmaceutically 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, wherein the S atom may be substituted to form S(=O) or S(=O)2; The heterocyclyl optionally has on one nitrogen atom R 6 , -C(=O)-Cy 1 , 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.

[0125] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any of the other embodiments and pharmaceutically acceptable salts and solvates thereof or any subgroup thereof, wherein 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, wherein the S atom may be substituted to form S(=O) or S(=O)2; The heterocyclyl optionally has on one nitrogen atom R 6 , -C(=O)-Cy 1 and -C(=O)-R 8 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 oxo and —OH.

[0126] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any of the other embodiments and pharmaceutically acceptable salts and solvates thereof or any subgroup thereof, wherein Het 1 represents a bicyclic C-bonded 6-11 membered fully saturated heterocyclyl containing at least one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; The heterocyclyl optionally has on one nitrogen atom R 6 , -C(=O)-Cy 1 , 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.

[0127] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any of the other embodiments and pharmaceutically acceptable salts and solvates thereof or any subgroup thereof, wherein Het 1 represents a bicyclic C-bonded 6-11 membered fully saturated heterocyclyl containing at least one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; The heterocyclyl optionally has on one nitrogen atom R 6 , -C(=O)-Cy 1 and -C(=O)-R 8 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 oxo and —OH.

[0128] In one embodiment, the present invention relates to the compounds of formula (I) as mentioned in any of the other embodiments, and pharmaceutically acceptable salts, solvates thereof or any subgroup thereof, wherein R 6 Het 4 ;C 3~6 Cycloalkyl; and Het 3 and Cy 1 C optionally further substituted with one or two substituents each independently selected from the group consisting of 1~6 alkyl.

[0129] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 6 and R 6a teeth, Het 3 ;Het 4 ;-C(=O)-NH-Cy 1 ;-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 and -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.

[0130] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically 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 and -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; 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.

[0131] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 6 and R 6a teeth, Het 4 ;Het 3 , Het 6a , and Cy 1C optionally substituted with 1 or 2 substituents each independently selected from the group consisting of 1~6 alkyl.

[0132] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 6 Het 4 ;Het 3 , 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; R 6a Het 3a and Het 6a C substituted with one substituent selected from the group consisting of 1~6 Represents alkyl.

[0133] In one embodiment, the present invention relates to the compounds of formula (I) as mentioned in any of the other embodiments, and pharmaceutically acceptable salts, solvates thereof or any subgroup thereof, wherein R 6 Het 4 ; and Het 3 and Cy 1 C optionally further substituted with 1 or 2 substituents each independently selected from the group consisting of 1~6 alkyl.

[0134] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het 1 teeth,

[0135] [ka] represents an optionally substituted nitrogen as defined 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 pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het 3 represents the following equation:

[0137] [ka]

[0138] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof as mentioned in any of the other embodiments or any subgroup thereof, wherein Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2 or 3 nitrogen atoms; 3~6 cycloalkyl, and the monocyclic 5- or 6-membered aromatic ring is optionally substituted with C 3~6 Cycloalkyl, cyano, and C 1~4 It may be substituted with one or two additional substituents selected from the group consisting of alkyl.

[0139] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof as mentioned in any of the other embodiments or any subgroup thereof, wherein Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2 or 3 nitrogen atoms; 3~6 cycloalkyl, and the monocyclic 5- or 6-membered aromatic ring is optionally substituted with C 3~6 Cycloalkyl, cyano, and C 1~4 optionally substituted with one or two additional substituents selected from the group consisting of alkyl; R 1b represents F.

[0140] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof as mentioned in any of the other embodiments or any subgroup thereof, wherein Het represents a monocyclic 5- or 6-membered aromatic ring containing 1 or 2 nitrogen atoms; 3~6 The monocyclic 5- or 6-membered aromatic ring is optionally substituted with one cyano.

[0141] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof as mentioned in any of the other embodiments or any subgroup thereof, wherein Het represents a monocyclic 5- or 6-membered aromatic ring containing 1 or 2 nitrogen atoms; 3~6 cycloalkyl, wherein the monocyclic 5- or 6-membered aromatic ring is optionally substituted with one cyano; R 1b represents F.

[0142] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof as mentioned in any of the other embodiments or any subgroup thereof, wherein Het represents a monocyclic 6-membered aromatic ring containing 1, 2 or 3 nitrogen atoms; 3~6 cycloalkyl, and the monocyclic 6-membered aromatic ring is optionally substituted with C 3~6 Cycloalkyl, cyano, and C 1~4 It may be substituted with one or two additional substituents selected from the group consisting of alkyl.

[0143] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof as mentioned in any of the other embodiments or any subgroup thereof, wherein Het represents a monocyclic 6-membered aromatic ring containing 1, 2 or 3 nitrogen atoms; 3~6 cycloalkyl, and the monocyclic 6-membered aromatic ring is optionally substituted with C 3~6 Cycloalkyl, cyano, and C1~4 optionally substituted with one or two additional substituents selected from the group consisting of alkyl; R 1b represents F.

[0144] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof as mentioned in any of the other embodiments or any subgroup thereof, wherein Het represents a monocyclic 6-membered aromatic ring containing 1, 2 or 3 nitrogen atoms; 3~6 It is substituted with cycloalkyl.

[0145] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof as mentioned in any of the other embodiments or any subgroup thereof, wherein Het represents a monocyclic 6-membered aromatic ring containing 1, 2 or 3 nitrogen atoms; 3~6 substituted with cycloalkyl; R 1b represents F.

[0146] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het is of the formula

[0147] [ka] each optionally containing one cyano or C 1~4 It may be substituted with alkyl.

[0148] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 Cy 2 Represents.

[0149] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Cy 2 is C 3~7 represents cycloalkyl; 3~7 Cycloalkyl is Het 6a , Het 6b , and -NR 9a R 9b and is substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of:

[0150] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Cy 2 is C 3~7 represents cycloalkyl; 3~7 Cycloalkyl is Het 6a and Het 6b and is substituted with one or two substituents each independently selected from the group consisting of:

[0151] In one embodiment, the present invention relates to the compounds of formula (I) as mentioned in any of the other embodiments and pharmaceutically acceptable salts, and solvates thereof or any subgroup thereof, wherein R 3 Cy 2 and Cy 2 is C 3~7 represents cycloalkyl; 3~7 Cycloalkyl is Het 6a and Het 6b and is substituted with one or two substituents each independently selected from the group consisting of:

[0152] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3represents cyclobutyl as defined in any of the other embodiments.

[0153] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein the compounds of formula (I) are limited to compounds of formula (Iy):

[0154] [ka] In the formula, R 3 is as defined for the compounds of formula (I) or any subgroup thereof according to any of the other embodiments.

[0155] In one embodiment, the present invention relates to those compounds of formula (I) as described in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein the compounds of formula (I) are limited to compounds of formula (Iz):

[0156] [ka] In the formula, Cy 2 is as defined for the compounds of formula (I) or any subgroup thereof according to any of the other embodiments.

[0157] In one embodiment, the present invention provides a compound of formula (Iz)

[0158] [ka] and tautomers and stereoisomers thereof, wherein Cy 2 is C 3~7 represents cycloalkyl; 3~7 Cycloalkyl is a group having one or two carbon atoms, such as Het 6a , Het 6b , and -NR 9aR 9b and is substituted with one substituent selected from the group consisting of: R 9a and R 9b is hydrogen; C 1~4 Alkyl; C 3~6 Cycloalkyl; -C(=O)-C 1~4 Alkyl; -C(=O)-C 3~6 cycloalkyl; -S(=O)2-C 1~4 are each independently selected from the group consisting of alkyl; Het 6a represents a monocyclic, N-linked, 4- to 7-membered, fully saturated heterocyclyl containing one N atom; the heterocyclyl optionally has an —OC group on one or two carbon atoms. 1~4 Alkyl;-OC 3~6 cycloalkyl; -S(=O)2-C 1~4 Alkyl; and C 1~4 optionally substituted with a total of 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl; Het 6b represents a bicyclic N-linked 6-11 membered fully saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O and N; the heterocyclyl optionally contains one —O—C group on one carbon atom. 1~4 If a second nitrogen atom is present in the heterocyclyl, the second nitrogen atom is optionally substituted with -C(=O)-C 1~4 Alkyl and C 1~4 and substituted with a substituent selected from the group consisting of alkyl. and pharmaceutically acceptable salts and solvates thereof.

[0159] In one embodiment, the present invention relates to a subgroup of formula (I) as defined in the general reaction scheme:

[0160] In one embodiment, the compound of formula (I) is an exemplified compound: its tautomers and its stereoisomers, and any of the free bases, any pharmaceutically acceptable salts and solvates thereof.

[0161] All possible combinations of the above embodiments are considered to fall within the scope of the present invention.

[0162] Process for preparing compounds of formula (I) In this section, and in all other sections, unless the context indicates otherwise, reference to formula (I) also includes all other subgroups and embodiments thereof defined herein.

[0163] 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.

[0164] Alternatively, compounds of the present invention may also be prepared by analogous reaction protocols as described in the following general schemes, in combination with standard synthetic processes commonly used by those skilled in the art.

[0165] Those skilled in the art will understand 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 prevent their undesired participation in the reaction. Generally, 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.

[0166] 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 under an atmosphere of N2 gas.

[0167] It will be apparent to one skilled in the art that it may be necessary to cool the reaction mixture before working on 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.).

[0168] 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.

[0169] Those skilled in the art will appreciate that the alternative series of chemical reactions shown in the following schemes may also lead to the desired compounds of formula (I).

[0170] Those skilled in the art will understand 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 mixtures of tautomers and stereoisomers, which can be separated from one another according to art-known resolution procedures.

[0171] 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 present invention.

[0172] [ka]

[0173] 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 dimethyl sulfoxide, 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, for example room temperature, in the presence of a suitable catalyst, for example palladium on charcoal (Pd / C), in a suitable solvent, for example methanol, under H2 pressure, for example 1-3 bar, optionally in the presence of a base, for example triethylamine; Alternatively, at a suitable temperature, for example, room temperature, in the presence of a suitable catalyst, for example, 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, a suitable reducing agent, for example, sodium borohydride, a suitable base, for example, N,N,N′,N′-tetramethylethylenediamine, in a suitable solvent, for example, tetrahydrofuran; Step 4: 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; 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;

[0174] Scheme 2 In general, Y 1 is limited to -CH2-, and 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.

[0175] [ka]

[0176] 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 in the range of 60°C to 100°C.

[0177] 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.

[0178] Scheme 3 In general, Y1 Ga-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 present invention.

[0179] [ka]

[0180] In Scheme 3, the following reaction conditions apply: Step 1: At a suitable temperature in the range of 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.

[0181] 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.

[0182] 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 before or according to the scope of the invention.

[0183] [ka]

[0184] 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 dimethyl sulfoxide, 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, for example room temperature, in the presence of a suitable catalyst, for example palladium on charcoal (Pd / C), in a suitable solvent, for example methanol, under H2 pressure, for example 1-3 bar; Alternatively, at a suitable temperature, for example, room temperature, in the presence of a suitable catalyst, for example, 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, a suitable reducing agent, for example, sodium borohydride, a suitable base, for example, N,N,N′,N′-tetramethylethylenediamine, in a suitable solvent, for example, tetrahydrofuran; Process 4:PG 1 is tert-butyloxycarbonyl, 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), at a suitable temperature range, for example, 0° C. to room temperature; Step 5: represents any type of reaction, such as reductive amination, nucleophilic substitution, etc., leading to the final example (Ib).

[0185] 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.

[0186] Scheme 5 In general, U is limited to N and Y 1 But Y is O 1b Compounds of formula (I) limited to: 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 in accordance with the scope of the present invention.

[0187] [ka]

[0188] 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 in a suitable solvent such as a mixture of tetrahydrofuran, ethanol and water at a suitable temperature such as room temperature; 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 of molecular sieves at a suitable temperature such as 65°C, in the presence or absence of 2,2,2-trifluoroethanol as a solvent, 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, 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), at a suitable temperature range, for example, 0° C. to room temperature; Step 8: Represents any type of reaction, such as reductive amination, nucleophilic substitution, etc., leading to the final example (Iba).

[0189] 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, for example benzyloxycarbonyl, etc. All other variables are defined according to the scope of the present invention or as defined in the previous schemes.

[0190] [ka]

[0191] 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, 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), at a suitable temperature range, for example, 0° C. to room temperature; Step 3: represents any type of reaction, such as reductive amination, nucleophilic substitution leading to intermediate IIIa.

[0192] 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.

[0193] The compounds of formula (I) may be synthesized in the form of racemic mixtures of enantiomers, which can be separated from one another according to art-known resolution procedures. Racemic compounds of formula (I) containing a basic nitrogen atom can be converted to 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 compounds of formula (I) involves 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.

[0194] In preparing 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 of ordinary skill in the art. For a general description of protecting groups and their use, see T.W. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken, New Jersey, 2007.

[0195] 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 the treatment, of diseases such as cancer, myelodysplastic syndrome (MDS) and diabetes.

[0196] In particular, the compounds according to the present 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 present 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 leukemia, chronic leukemia, myeloid leukemia, myeloid leukemia, lymphoblastic leukemia, lymphocytic leukemia, 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.

[0197] Thus, the present invention relates to compounds of formula (I), their tautomers and stereoisomers, and their pharmaceutically acceptable salts and solvates, for use as medicaments.

[0198] The present invention also relates to the use of a compound of formula (I), a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to the invention, for the manufacture of a medicament.

[0199] The present invention also relates to a compound of formula (I), a tautomer or stereoisomer thereof, or a pharmaceutically 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 facilitated by blocking the interaction of menin with MLL proteins and oncogenic MLL fusion proteins.

[0200] The present invention also relates to the use of a compound of formula (I), a tautomer or stereoisomer thereof, or a pharmaceutically 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.

[0201] The present invention also relates to a compound of formula (I), a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of any one of the above diseases.

[0202] The present invention also relates to a compound of formula (I), a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in treating or preventing any one of the diseases mentioned herein above.

[0203] The present invention also relates to the use of a compound of formula (I), a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for treating or preventing any one of the disease conditions described herein above.

[0204] The compounds of the present invention can be administered to mammals, preferably humans, for the treatment or prevention of any one of the diseases mentioned herein above.

[0205] In view of the availability of compounds of formula (I), their tautomers and stereoisomers, and pharmaceutically acceptable salts and solvates thereof, methods are provided for treating warm-blooded animals (including humans) suffering from any one of the diseases described above herein.

[0206] The method comprises the administration, i.e., systemic or local administration, of a therapeutically effective amount of a compound of formula (I), a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof to a warm-blooded animal, including a human.

[0207] Therefore, the present invention also relates to a method for the treatment or prevention of any one of the diseases mentioned herein above, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to the invention.

[0208] 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, and that this amount will vary depending, among other things, on the type of disease, the concentration of the compound in the therapeutic formulation, and the condition of the patient. An effective daily therapeutic dose 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, depending, for example, on the specific compound, the route of administration, the age and condition of the recipient, and the specific disorder or disease being treated. Treatment methods may also include administering the active ingredient in a regimen of one to four intakes per day. In these treatment methods, the compound according to the present invention is preferably formulated prior to administration.

[0209] The present invention also provides compositions for preventing or treating the disorders mentioned herein, which comprise a therapeutically effective amount of a compound of formula (I), a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.

[0210] 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. Accordingly, the present invention further provides pharmaceutical compositions comprising a compound of the present invention together with a pharmaceutically 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.

[0211] Pharmaceutical compositions can be prepared, for example, as described by Gennaro et al. in Remington's Pharmaceutical Sciences (18 th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical preparations and their Manufacture), or by any method well known in the art of pharmacy.

[0212] The compounds of the present 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 present invention and one or more additional therapeutic agents, as well as administering a compound according to the present invention and each additional therapeutic agent in its own separate pharmaceutical dosage formulation.

[0213] 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.

[0214] The one or more other pharmaceutical agents and the compound according to the present invention can 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, 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 route of administration, the particular condition, particularly tumor, being treated, and the particular host being treated.

[0215] The following examples further illustrate the present invention. [Example]

[0216] 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.

[0217] [Table 1-1]

[0218] [Table 1-2]

[0219] [Table 1-3]

[0220] 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 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 an intermediate or compound in the experimental section below is referred to as an "HCl salt" without indicating the number of equivalents of HCl, this means that the number of equivalents of HCl was not determined.

[0221] The stereochemical configuration of the centers in some compounds can 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 if the absolute stereochemistry has not been determined (even if the bonds are drawn stereospecifically), the stereochemical configuration of the indicated centers can be designated "R" or "S." * R" or " * It is named "S."

[0222] For example, compound 5

[0223] [ka] It will be clear that is the following equation:

[0224] [ka]

[0225] For example, compound 14

[0226] [ka] It will be clear that is the following equation:

[0227] [ka]

[0228] For example, if the stereochemical configuration of the two stereocenters is * (for example, * R or * In the case of compounds such as 214 and 215, designated S), the compounds themselves have been isolated as single stereoisomers and are enantiomerically pure, but the absolute stereochemistry of the stereocenters has not been determined (even though the bonds are drawn stereospecifically). In this case, the configuration of the first stereocenter is independent of the configuration of the second stereocenter in the same compound.

[0229] For example, for compound 214:

[0230] [ka] This means that the compound

[0231] [ka] This means that

[0232] The above paragraph regarding stereochemical configuration also applies to intermediates.

[0233] As used herein, the term "enantiomerically pure" means that a 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.

[0234] 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.

[0235] When stereochemistry is not indicated, this means a mixture of stereoisomers unless otherwise indicated or clear from the context.

[0236] When a stereocenter is designated "RS," this means that a racemic mixture was obtained at the designated center, unless otherwise stated.

[0237] 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.

[0238] When two enantiomers, diastereomers or isomers are present in one and the same cell of the table below (e.g., compound 1a and compound 1b), one skilled in the art will understand that these intermediates or compounds have been separated from each other by using suitable chromatographic methods, such as SFC or reverse phase separation.

[0239] Preparation of intermediates For intermediates that were used in the next reaction step as crude or partially purified intermediates, in some cases either no molar amount is stated for such intermediate in the next reaction step or an estimated molar amount or theoretical molar amount for such intermediate in the next reaction step is given in the reaction protocols set out below.

[0240] Example A1 Preparation of intermediate 2:

[0241] [ka]

[0242] Benzyl chloroformate (6.03 g, 35.3 mmol) was added to a 0 °C (ice / water) mixture of tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (5.00 g, 23.6 mmol), TEA (16.5 mL, 117 mmol), and CHCl (50 mL). DMAP (57.5 mg, 0.471 mmol) was then added to the mixture. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated to dryness under reduced pressure to give the crude product, which was purified by FCC (eluent: petroleum ether:ethyl acetate = 100:1 to 2:1) to give intermediate 2 (7.00 g, 83.7% yield) as a yellow oil.

[0243] Preparation of intermediate 3:

[0244] [ka]

[0245] To a solution of intermediate 2 (25.0 g, 72.2 mmol) in dry dichloromethane (15 mL) was added trifluoroacetic acid (30 mL). The reaction mixture was stirred at 25° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure to give a residue, which was suspended in aqueous NaOH (4 g in HO (40 mL)) and extracted with dichloromethane (20 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give intermediate 3 (16.0 g) as a yellow oil.

[0246] Example A2 Preparation of Intermediate 5

[0247] [ka]

[0248] 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 hours. The mixture was diluted with ethyl acetate (500 mL). The mixture was washed with 1M HCl (150 mL), saturated NaHCO (100 mL × 2) and brine (300 mL × 3), dried over NaSO, filtered and concentrated under reduced pressure to give intermediate 5 (11.0 g, crude) as a white solid, which was used in the next step without further purification.

[0249] Preparation of Intermediate 6

[0250] [ka]

[0251] To a solution of intermediate 5 (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 a N atmosphere. The mixture was stirred at room temperature under a N atmosphere for 12 hours. The mixture was quenched with saturated NH Cl (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 Na SO , 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, TLC: petroleum ether:ethyl acetate = 5:1, Rf = 0.4) to give intermediate 6 (6.30 g) as a white solid.

[0252] Preparation of intermediate 7:

[0253] [ka]

[0254] To a solution of intermediate 3 (2.80 g, 11.4 mmol) and intermediate 6 (3.00 g, 12.4 mmol) in MeOH (50 mL) was added acetic acid (1.50 g, 24.6 mmol). The mixture was stirred at 45° C. for 0.5 h. Then, sodium cyanotrihydroborate (1.54 g, 24.5 mmol) was added. The mixture was stirred at 45° C. for 12 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with DCM (100 mL). The mixture was washed with saturated NaHCO (50 mL×2) and brine (50 mL×2), dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluent: dichloromethane:methanol 1:0 to 10:1, TLC: dichloromethane:methanol = 10:1, Rf = 0.5) to give Intermediate 7 (3.40 g, purity 53.6% as determined by LCMS) as a colorless oil.

[0255] Preparation of intermediate 293:

[0256] [ka]

[0257] Intermediate 7 (10.0 g, 21.2 mmol) was subjected to SFC (column: DAICEL CHIRALCEL OD (250 mm * 50 mm, 10 um), eluent: 0.1% NH3H2O ​​25% (v / v) supercritical CO2 in EtOH, flow rate: 200 mL / min) to give Intermediate 293 (3.80 g, 38% yield) as a yellow oil.

[0258] Preparation of intermediate 8:

[0259] [ka]

[0260] To a solution of intermediate 7 (1.00 g, 2.12 mmol, 53.6% purity) in MeOH (50 mL) were added 1,1,2-trichloroethane (424 mg, 3.18 mmol) and Pd / C (500 mg, w / w% = 10% Pd loading). The mixture was stirred at 40 °C under H atmosphere (50 psi) for 4 h. The reaction mixture was filtered through a pad of Celite®, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluent: dichloromethane:methanol (0.5% NH3.HO) 1:0 to 3:1, TLC: dichloromethane:methanol (0.5% NH3.HO) = 3:1, Rf = 0.4) to give intermediate 8 (380 mg, 99.1% yield) as a white solid.

[0261] Example A3 Preparation of Intermediate 10:

[0262] [ka]

[0263] To a solution of 5-bromopyrimidine (30 g, 189 mmol) in 1000 mL of THF was added cyclopropylmagnesium bromide (396 mL, 198 mmol, 0.5 M) under a N atmosphere at 0° C. After the addition, the reaction mixture was stirred at room temperature for 4 hours, and 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (42.8 g, 189 mmol) in 500 mL of THF was added dropwise to the reaction mixture at 0° C. After the addition, the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, and the residue was diluted with 200 mL of EtOAc and 200 mL of water, then separated, and the aqueous layer was extracted with EtOAc (200 mL × 3), and the combined extracts were washed with 1 N NaOH (200 mL × 2), brine (200 mL), dried over Na2SO4, filtered, concentrated in vacuo, and the residue was purified by column chromatography (PE / EtOAc 100 / 0 to 85 / 15) to give Intermediate 10 (21.4 g, 55% yield) as a white solid.

[0264] The intermediates reported below were prepared following methods analogous to those described for intermediate 10, starting from the corresponding starting materials:

[0265] [Table 2]

[0266] Preparation of intermediate 11:

[0267] [ka]

[0268] A mixture of Intermediate 10 (16.4 g, 82.4 mmol), (5-fluoro-2-hydroxyphenyl)boronic acid (16.1 g, 103 mmol), Pd(dppf)Cl (3.56 g, 4.86 mmol), and NaCO (2 M in water, 82.6 mL, 165 mmol) in dioxane (600 mL) was heated at 90 °C for 3 h. The reaction mixture was combined with another batch (prepared starting from 15 g of Intermediate 10) for workup and purification. The combined solution was filtered through a pad of Celite®, and the filtrate was concentrated in vacuo. The residue was diluted with 200 mL of EtOAc and 200 mL of water, then separated, and the aqueous layer was extracted with EtOAc (200 mL × 3). The combined extracts were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated in vacuo until 100 mL remained, and filtered to give Intermediate 11 (20.0 g) as a brown solid. The filtrate was concentrated, and the residue was purified by column chromatography (PE / EtOAc 100 / 0 to 50 / 50) to give Intermediate 11 (10 g) as a brown solid. Total: 30.0 g of Intermediate 11 (84% yield).

[0269] The intermediates reported below were prepared following a similar method as described for intermediate 11, starting from the corresponding intermediate:

[0270] [Table 3]

[0271] Preparation of intermediate 12:

[0272] [ka]

[0273] K2CO3 (9.27 g, 67.1 mmol) was added to a solution of intermediate 11 (5.15 g, 22.4 mmol) and ethyl 6-chloro-1,2,4-triazine-5-carboxylate (5.60 g, 29.9 mmol) in DMF (50 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate (80 mL) and washed with HO (40 mL × 2) and brine (40 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by FCC (eluting with petroleum ether:ethyl acetate = 100:0 to 1:1) to give intermediate 12 (7.00 g, 59.1% yield) as a white solid.

[0274] The intermediates reported below were prepared following a similar method as described for intermediate 12, starting from the corresponding intermediate:

[0275] [Table 4]

[0276] Preparation of intermediate 13:

[0277] [ka]

[0278] LiOH.HO (3.85 g, 91.7 mmol) was added to a solution of Intermediate 12 (7.00 g, 18.3 mmol) in THF (50 mL), HO (10 mL), and EtOH (5 mL). The mixture was stirred at 25 °C for 2 h. The resulting solution was acidified to pH = 5-6 with 0.5 M HCl and extracted with ethyl acetate (10 mL). The aqueous phase was purified by Phenomenex Gemini-NX 150 * 30mm * The mixture was purified by preparative high-performance liquid chromatography on a 5 μm column (eluent: (water (0.225% FA):ACN) 95:5 to 65:35 v / v). Pure fractions were collected and volatiles were removed under reduced pressure. The residue was lyophilized to remove solvent residues, affording Intermediate 13 (3.85 g, 59.4% yield) completely as a white solid.

[0279] Alternative preparation of intermediate 13: A solution of Intermediate 12 (1.80 g, crude) in THF (30 mL) was added to LiOH . A solution of HO (300 mg, 7.15 mmol) in HO (10 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 3-4 with 1 N HCl and then concentrated under reduced pressure to give a residue, which was purified by reverse-phase chromatography on a high-performance silica column (column: 80 g Agela C18, mobile phase A: water, mobile phase B: acetonitrile, flow rate: 80 mL / min, gradient conditions: 5% B to 40% B) to give Intermediate 13 (1.40 g) as a white solid.

[0280] The intermediates reported below were prepared following a similar method as described for intermediate 13, starting from the corresponding intermediate:

[0281] [Table 5]

[0282] Preparation of intermediate 298:

[0283] [ka]

[0284] To a mixture of 3,6-dichloropyridazine (20.0 g, 134 mmol) in DCM (660 mL) and HO (600 mL) was added cyclopropanecarboxylic acid (23.0 g, 267 mmol), 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-dium tetrafluoroborate (95.0 g, 268 mmol), and TFA (10.0 mL, 135 mmol) under a N atmosphere at 25° C. The resulting mixture was stirred at 25° C. for 5 min, and then AgNO (68.0 mL, 27.2 mmol, 0.4 M in HO) was added, and the resulting mixture was stirred at 55° C. for 10 h under a N atmosphere. After cooling to room temperature, the reaction mixture was quenched with 2N NaOH (90 mL), extracted with EtOAc (500 mL × 3), and the combined organic layers were dried over NaSO. After filtration and concentration, the crude residue was purified by preparative HPLC (YMC-Triart Prep C18 250 * 50mm * The mixture was purified by HPLC using a 10 μm column chromatography (mobile phase A: water (0.225% formic acid), mobile phase B: ACN, flow rate: 100 mL / min, gradient conditions: 15% B to 55% B). The desired fractions were collected and lyophilized to give intermediate 298 (6.00 g, 24% yield) as a colorless oil.

[0285] Preparation of Intermediate 299 and Intermediate 300:

[0286] [ka]

[0287] To a solution of intermediate 298 (6.00 g, 28.6 mmol) in MeOH (50 mL) was added sodium methanolate (7.72 g, 143 mmol) portionwise under N2 atmosphere at 25 °C, and the reaction was stirred at this temperature for 0.5 h. The resulting mixture was quenched with 1 N HCl (100 mL) to adjust the pH to 7 and extracted with EtOAc (135 mL × 3). The combined organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo to give a mixture of intermediate 299 and intermediate 300 (5.6 g, crude) as a colorless oil, which was used directly in the next step without further purification.

[0288] Preparation of intermediate 301:

[0289] [ka]

[0290] To a solution of a mixture of intermediate 299 and intermediate 300 (5.60 g, crude) in dioxane (120 mL) and HO (24 mL) was added (5-fluoro-2-hydroxyphenyl)boronic acid (9.63 g, 61.7 mmol), NaCO (9.82 g, 92.6 mmol), and Pd(PPh) (1.78 g, 1.54 mmol). The resulting reaction mixture was stirred at 90 °C under a N atmosphere for 8 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the crude residue was purified by FCC (PE to PE / EtOAc = 3 / 1) to give intermediate 301 (1.20 g) as a white solid.

[0291] Preparation of intermediate 302:

[0292] [ka]

[0293] To a solution of intermediate 301 (1.80 g, 6.92 mmol) in ACN (40 mL) was added cerium(III) chloride (2.56 g, 10.4 mmol) and NaI (1.56 g, 10.4 mmol). The resulting mixture was stirred at 70 °C for 8 h. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with EtOAc (30 mL × 2). The filtrate was concentrated under reduced pressure, and the crude residue was purified by FCC (PE to pure EtOAc) to give intermediate 302 (1.4 g, 74% yield) as a white solid.

[0294] Preparation of intermediate 14:

[0295] [ka]

[0296] 1,3-Dibromo-1,3,5-triazinane-2,4,6-trione (1.22 g, 4.25 mmol) was added to a solution of intermediate 13 (1.00 g, 2.83 mmol) in DCE (20 mL). The resulting mixture was stirred at room temperature for 0.5 h. The mixture was quenched with HO (1 mL), filtered, and the filter cake was washed with CHCl (10 mL × 2). The filtrate was concentrated under reduced pressure to give the crude product, which was purified by FCC (eluting with ethyl acetate:methanol = 100:0 to 10:1) to give intermediate 14 (600 mg, 60.8% yield) as a yellow solid.

[0297] Alternative preparation of intermediate 14: To a solution of intermediate 13 (700 mg, 1.98 mmol) in DCE (30 mL) was added 1,3-dibromo-1,3,5-triazinane-2,4,6-trione (900 mg, 3.14 mmol). The resulting mixture was stirred at room temperature for 0.5 h. The suspension was isolated by filtration. The filter cake was purified by FCC (EtOAc:MeOH=10:1) to give intermediate 14 (500 mg, 73% yield) as a light brown solid.

[0298] Preparation of intermediate 15:

[0299] [ka]

[0300] To a solution of intermediate 14 (200 mg, 0.615 mmol) in CHCl (10 mL) was added oxalyl chloride (134 μL, 1.23 mmol) followed by two drops of DMF at room temperature. The mixture was stirred at this temperature for 1.5 hours. The mixture was concentrated under reduced pressure to give intermediate 15 (200 mg, crude) as a brown solid, which was used directly in the next reaction step.

[0301] Example A4 Preparation of intermediate 17:

[0302] [ka]

[0303] HATU (99.5 g, 262 mmol) was added portionwise to a mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (50.0 g, 218 mmol), N,O-dimethylhydroxylamine hydrochloride (23.4 g, 240 mmol), and EtN (90.9 mL, 654 mmol) in dichloromethane (500 mL) at 0 °C (ice / water). The reaction mixture was stirred at room temperature for 12 h and then concentrated to dryness under reduced pressure. The residue was diluted with water (1500 mL) and extracted with dichloromethane (500 mL × 3). The combined organic extracts were dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure to give the crude product, which was purified by FCC (eluent: petroleum ether:ethyl acetate = 1:0 to 1:1) to give Intermediate 17 (54 g) as a yellow oil.

[0304] The intermediates reported below were prepared following analogous methods as described for intermediate 17, starting from the corresponding intermediates or starting materials:

[0305] [Table 6]

[0306] Preparation of intermediate 18:

[0307] [ka]

[0308] Intermediate 17 (54.0 g, 198 mmol) and THF (500 mL) were added to a 1 L three-necked round-bottom flask. Then, i-PrMgCl (198 mL, 397 mmol, 2 M in THF) was added dropwise to the mixture at 0 °C (ice / water) under N. The mixture was stirred for 10 h while warming to room temperature, then poured into water (2000 mL) and extracted with EtOAc (1000 mL × 3). The organic layer was washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel FCC (eluent: petroleum ether:ethyl acetate 1:0 to 2:1, TLC: petroleum ether:ethyl acetate = 2:1, R f =0.6) to give Intermediate 18 (19.2 g) as a yellow oil.

[0309] The intermediates reported below were prepared following a similar method as described for intermediate 18, starting from the corresponding intermediate:

[0310] [Table 7]

[0311] Example A5 Preparation of intermediate 22:

[0312] [ka]

[0313] To a solution of Intermediate 3 (6.00 g, 24.4 mmol) and Intermediate 18 (6.22 g, 24.4 mmol) in dry methanol (180 mL) was added ZnCl (6.64 g, 48.7 mmol). The reaction mixture was heated and stirred at 65 °C for 3 hours, and then NaBHCN (4.59 g, 73.1 mmol) was added. The reaction mixture was stirred at 65 °C for 12 hours. Then, an additional amount of Intermediate 18 was added (6.22 g, 24.4 mmol), and the reaction mixture was stirred at 65 °C for an additional 20 hours. The reaction mixture was cooled to room temperature, suspended in saturated NaHCO (180 mL), and stirred for 30 minutes. The mixture was filtered, and the filter cake was washed with EtOAc (50 mL). The filtrate was extracted with EtOAc (200 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel FCC (eluent: petroleum ether: ethyl acetate 1:0 to 0:1, TLC: petroleum ether: ethyl acetate = 0:1, R f =0.3) to give Intermediate 22 (9.80 g) as a colorless oil.

[0314] Preparation of intermediates 23 and 24: Intermediate 23:

[0315] [ka] Intermediate 24:

[0316] [ka]

[0317] Intermediate 22 (50.0 g, 103 mmol) was further purified by SFC on a DAICEL CHIRALPAK AD (isocratic elution: i-PrOH (containing 0.1% of 25% aqueous NH):supercritical CO, 25%:75% to 25%:75% (v / v)). Pure fractions were collected and volatiles were removed under reduced pressure to give Intermediate 23 (22 g, 44% yield) as a yellow oil and Intermediate 24 (23 g, 46% yield) as a yellow oil.

[0318] Preparation of intermediate 26:

[0319] [ka]

[0320] HCl / 1,4-dioxane (10 mL, 40 mmol) was added to a solution of intermediate 23 (1.0 g, 2.1 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated to dryness under reduced pressure, and then NH3HO (5 mL; concentrated, typically 25-28%) was added to the mixture. The residue was suspended in water (10 mL), and the mixture was frozen using dry ice / acetone and then lyophilized to dryness to give intermediate 26 (900 mg, crude) as a yellow solid, which was used in the next step without further purification.

[0321] Preparation of intermediate 27:

[0322] [ka]

[0323] TEA (1.3 mL, 9.3 mmol) was added to a solution of intermediate 26 (900 mg, crude) in dichloromethane (10 mL). To the above solution, oxetane-3-carbaldehyde (310 mg, 14 mmol) was added and stirred at room temperature for 0.5 h. NaBH(OAc) (1.5 g, 7.1 mmol) was then added to the above solution, and the resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with dichloromethane (30 mL) and washed with saturated NaHCO (10 mL × 3). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product, which was purified by HPLC using a Waters Xbridge Prep OBD C18 150 * 40mm *The pure product was purified by preparative HPLC using 10 μm and water (0.05% ammonia hydroxide v / v) / ACN 100 / 0 to 20 / 80 (v / v). The product was suspended in water (10 mL) and the mixture was frozen using dry ice / acetone, then lyophilized to dryness to give Intermediate 27 (500 mg) as a colorless oil.

[0324] Preparation of intermediate 28:

[0325] [ka]

[0326] Intermediate 27 (500 mg, 1.10 mmol) and dry Pd / C (150 mg, w / w%=10% Pd loading) were suspended in THF (30 mL). The reaction mixture was stirred under H (50 Psi) at 45 °C for 4 h. The suspension was filtered through a pad of Celite®, which was washed with THF (50 mL). The filtrate was concentrated to dryness under reduced pressure to give Intermediate 28 (350 mg) as a colorless oil, which was used in the next step without further purification.

[0327] Example A6 Preparation of Intermediate 25:

[0328] [ka]

[0329] Dry Pd / C (1 g) was added to a mixture of intermediate 23 (7.5 g, 15 mmol), 1,1,2-trichloroethane (2.3 mL, 25 mmol), and MeOH (200 mL) under Ar. The mixture was stirred under H (50 psi) at 40 °C for 4 h. The mixture was filtered, and the phytate was concentrated to dryness to give intermediate 25 as a white solid (5.8 g, HCl salt, 97% yield).

[0330] The intermediates reported below were prepared following a similar method as described for intermediate 25, starting from the corresponding intermediate:

[0331] [Table 8]

[0332] Example A7 Preparation of Intermediate 1:

[0333] [ka]

[0334] Pyridinium-p-toluene-sulfonate (2.16 g, 8.61 mmol) was added to a solution of methyl 1-hydroxycyclopropanecarboxylate (10.0 g, 86.1 mmol) and 3,4-dihydropyran (7.68 g, 91.3 mmol) in DCM (100 mL). After the addition, the reaction mixture was stirred at 20 °C overnight. The reaction mixture was washed with HO (70 mL), saturated aqueous brine solution (50 mL), dried over sodium sulfate, and concentrated in vacuo to give an oil. The oil was purified by FCC (PE:EA = 10:1) to give Intermediate 1 (13.5 g, 78% yield) as a colorless oil.

[0335] Preparation of intermediate 4:

[0336] [ka]

[0337] To a solution of LiAlH (2.00 g, 52.7 mmol) in 80 mL of THF was added a solution of intermediate 1 (8.00 g, 40.0 mmol) in 20 mL of THF at 0 °C under a N atmosphere. After the addition, the reaction mixture was stirred at 0 °C for 2 h. After the reaction mixture was cooled to 0 °C, water (2 mL), 10% aqueous NaOH (2 mL), water (6 mL), and 20 g of NaSO were added sequentially to the reaction mixture. The resulting mixture was filtered. The filter cake was washed with THF (80 mL), and the combined filtrate was concentrated under reduced pressure to give the title intermediate 3A (6.23 g, 81% yield) as a colorless oil.

[0338] Preparation of Intermediate 9:

[0339] [ka]

[0340] To a solution of intermediate 4 (4.00 g, 23.2 mmol) in 100 mL of DCM was added Dess-Martin periodinane (16.0 g, 37.7 mmol). After the addition, the reaction mixture was stirred at 15 °C for 1.5 h. The reaction mixture was diluted with 50 mL of DCM and stirred with 60 mL of saturated NaHCO3 and 60 mL of saturated Na2S2O3 for 10 min. The mixture was then extracted three times with DCM (50 mL). Brine (100 mL) was then added, and the organic and brine layers were separated. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give intermediate 9 (2.98 g, 70% yield) as a pale yellow oil.

[0341] Example A8 Preparation of intermediate 29:

[0342] [ka]

[0343] To a solution of compound 3 (240 mg, crude) and intermediate 9 (500 mg, 2.94 mmol) in DCM (20 mL) was added TEA (363 mg, 3.59 mmol). The mixture was stirred at room temperature for 10 minutes, and then NaBHCN (300 mg, 4.77 mmol) was added portionwise. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM (50 mL) and washed with HO (20 mL) and brine (20 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give intermediate 29 (250 mg, crude) as a light brown oil (used directly in the next reaction step without further purification).

[0344] Example A9 Preparation of intermediate 30:

[0345] [ka]

[0346] At room temperature, tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (1.27 g; 5.96 mmol) and triethylamine (1.7 mL; 11.93 mmol) were added to a solution of trichlorotriazine (1.1 g; 5.96 mmol) in DCM (40 mL). The reaction mixture was stirred at room temperature overnight, then diluted with water and extracted with DCM. The organic layer was washed with water and brine, dried (MgSO), filtered, and concentrated. The residue was taken up with EtO. The precipitate was filtered and dried, yielding 1.76 g of intermediate 30 (81%).

[0347] Preparation of intermediate 31:

[0348] [ka]

[0349] A mixture of intermediate 30 (3.25 g; 9.017 mmol), intermediate 11 (2.18 g; 9.468 mmol), and cesium carbonate (3.23 g; 9.919 mmol) in DMF (100 mL) was stirred at room temperature overnight. The solution was cooled to room temperature, poured into cold water, and extracted with EtOAc. The organic layer was decanted, washed with water and then brine, dried over MgSO4, filtered, and evaporated to dryness. The residue (5.8 g) was purified by chromatography on silica gel (irregular SiOH, 40 g + 80 g; mobile phase: 40% EtOAc, 60% heptane, gradient from 100% EtOAc, 0% heptane). The pure fractions were collected and evaporated to dryness to give 3.41 g (68%) of intermediate 31 and 600 mg of an impure fraction, which was collected together with another impure fraction (700 mg) coming from the reaction carried out on 1 g of intermediate 30. The residue obtained was purified by chromatography on silica gel (irregular SiOH, 24 g + 24 g; mobile phase: 40% EtOAc, 60% heptane gradient to 100% EtOAc, 0% heptane). The pure fractions were collected and evaporated to dryness to give a further 1.04 g of intermediate 31.

[0350] Preparation of intermediate 32:

[0351] [ka]

[0352] A mixture of intermediate 31 (500 mg; 0.902 mmol), Pd / C (144 mg; 0.135 mmol) in MeOH (25 mL) and triethylamine (125 μL; 0.902 mmol) was hydrogenated under a pressure of H (1 bar) for 40 min. The catalyst was removed by filtration through a pad of Celite® and washed with DCM. The filtrate was washed with water, decanted, filtered through Chromabond®, and evaporated to dryness. The residue (520 mg) was purified by chromatography on silica gel (irregular SiOH, 24 g; mobile phase: 0% NH4OH, 0% MeOH, 100% DCM gradient to 0.5% NH4OH, 5% MeOH, 95% DCM). Pure fractions were collected and evaporated to dryness to give 300 mg (64%) of intermediate 32.

[0353] Alternative preparation: A mixture of Intermediate 31 (13.60 g, 24.58 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1.00 g, 1.23 mmol), sodium borohydride (1.58 g, 41.73 mmol), and N,N,N′,N′-tetramethylethylenediamine (6.3 mL, 41.73 mmol) in THF (280 mL) was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was quenched with water (250 mL) and extracted with EtOAc (4 × 250 mL). The combined organic layers were washed with water (600 mL), brine (600 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (mobile phase: 10:1 EtOAc / petroleum ether). The pure fractions were collected and evaporated to dryness, yielding 10.4g (79%) of intermediate 32 as a pale yellow oil.

[0354] Preparation of intermediate 33:

[0355] [ka]

[0356] TFA (1 mL; 13.067 mmol) was added to a solution of intermediate 32 (300 mg; 0.577 mmol) in DCM (10 mL) and the reaction mixture was stirred at room temperature for 4 hours. The reaction was diluted with ACN and evaporated to dryness several times. The residue was then dissolved in DCM and basified with diluted 15% aqueous NH4OH. The organic layer was decanted, washed again with water, filtered through Chromabond® and evaporated to dryness to give 245 mg of intermediate 33.

[0357] Preparation of intermediate 34:

[0358] [ka]

[0359] To a solution of 2-methyl-1-(4-piperidinyl)-1-propanone (450 mg; 0.23 mmol) and oxetane-3-carbaldehyde (1 g; 5.22 mmol) in DCM (50 mL) under N2, a solution of triethylamine (4.65 mL; 26.13 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes, then NaBH(OAc)3 (3.32 g; 15.7 mmol) was added portionwise, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, extracted with DCM (twice), and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated to dryness. The residue (1.4 g) was purified by silica gel chromatography (stationary phase: irregular SiOH 15-40 μm 40 g, mobile phase: 100% heptane, 0% EtOAc gradient to 80% heptane, 20% EtOAc) to give 0.88 g (75%) of intermediate 34.

[0360] Example A10 Preparation of intermediate 35:

[0361] [ka]

[0362] 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 35 (16.0 g, crude), which was used in the next step without further purification.

[0363] Preparation of intermediate 36:

[0364] [ka]

[0365] The reaction was carried out twice on 15.7 g of intermediate 35 and the reaction media from each were combined for workup and purification. To a solution of Intermediate 35 (15.7 g, 77.7 mmol) in THF (420 mL) was added isopropylmagnesium chloride (178.5 mL, 232 mmol, 2 M in THF) dropwise at 0° C. under N atmosphere. The reaction mixture was stirred at room temperature under N atmosphere for 12 hours and then poured into ice water and a 10% aqueous solution of NH Cl. The resulting mixture was cooled to 20° C. nd The mixture obtained from the reaction was combined and the combined mixture was extracted with EtOAc. The combined organic layer was 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). The pure fractions were collected and evaporated to dryness to give 22 g (76%) of intermediate 36 as a colorless oil.

[0366] Example A11 Intermediate 37, 37a( * S) and 37b( * Preparation of R):

[0367] [ka]

[0368] The reaction was carried out twice, once on 5.09 g of Intermediate 33 and once on 10.9 g of Intermediate 33. The resulting crude mixtures were combined for workup and purification. A mixture of intermediate 33 (5.09 g; 12.14 mmol), intermediate 36 (2.26 g; 12.14 mmol), AcOH (764 μL; 13.35 mmol), and NaBHCN (763 mg; 12.14 mmol) in MeOH (50 mL) was stirred at 50 °C overnight. The two reaction mixtures were combined and poured into a 10% aqueous solution of KCO. DCM was added. The layers were separated, and the aqueous layer was extracted with DCM (3x). The organic layer was dried over MgSO, filtered, and the solvent was evaporated. The crude product was purified by chromatography on silica gel (mobile phase: 100% DCM to 95% DCM, 5% MeOH, 0.5% NHOH). The pure fractions were collected and the solvent was evaporated, yielding 7.84 g of intermediate 37. This residue was combined with another batch obtained from the same reaction carried out on 10.9 g of intermediate 33. The resulting intermediate 37 (18 g) was then purified by chiral SFC (CHIRALPAK AD-H 5 μm 250 * 30 mm, mobile phase: 78% CO, 22% EtOH (0.3% iPrNH)). The pure fractions were collected and the solvent was evaporated to give 9.04 g of intermediate 37a ( * S) (ee 100%) and 8.88 g of intermediate 37b ( * R) was obtained as an off-white foam (ee 98.9%).

[0369] Preparation of intermediates 38, 38a and 38b:

[0370] [ka]

[0371] At 5°C, TFA (4 mL; 52.7 mmol) was added dropwise to a solution of intermediate 37 (1.55 g; 2.63 mmol) in DCM (40 mL), and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with ACN and evaporated to dryness. The residue was dissolved in DCM and basified with 30% aqueous NH4OH at 0-5°C. The mixture was stirred at room temperature for 1 h. The organic layer was decanted, washed with water, dried over MgSO4, filtered, and the solvent was evaporated to give 1.4 g (100%) of intermediate 38 as an off-white foam.

[0372] [ka]

[0373] The reaction was repeated to give 4.44 g of intermediate 37b ( * R) were performed twice and the resulting mixtures were combined for workup. At 5 °C, TFA (11.5 mL; 150.6 mmol) was added to intermediate 37b ( * R) (4.44 g; 7.53 mmol) in DCM (110 mL) was added dropwise and the reaction mixture was stirred at room temperature for 18 hours. The resulting mixture was combined with the mixture from the second reaction, and the combined mixture was diluted with ACN and evaporated to dryness. The residue was dissolved in DCM and basified with 30% aqueous NH4OH at 0-5 °C. The mixture was stirred at room temperature for 1 hour. The organic layer was decanted, washed with water, dried over MgSO4, filtered and the solvent was evaporated to give 7.87 g (96%) of intermediate 38b ( * R) was obtained as an off-white foam.

[0374] [ka]

[0375] At 5 °C, TFA (13 mL; 170 mmol) was added to intermediate 37a ( *S) (5 g; 8; 48 mmol) in DCM (130 mL) was added dropwise and the reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with ACN and evaporated to dryness. The residue was dissolved in DCM and basified with 30% aqueous NH4OH at 0-5 °C. The mixture was stirred at room temperature for 1 h. The organic layer was decanted, washed with water, dried over MgSO4, filtered and the solvent was evaporated to give 4.6 g (100%) of intermediate 38a ( * S) was obtained as an off-white foam.

[0376] Example A12 Preparation of intermediate 39:

[0377] [ka]

[0378] NaBH3CN (278 mg; 4.42 mmol) was added to a mixture of intermediate 38b (1.2 g; 2.21 mmol), tert-butyl-diphenyl-(4-piperidyloxy)silane (2.4 g; 7.1 mmol), and AcOH (126 μL; 2.21 mmol) in MeOH (65 mL). The reaction mixture was then heated at 60 °C for 48 h. The reaction mixture was cooled to room temperature, diluted with DCM, and poured into a 10% aqueous solution of K2CO3. The organic layer was extracted with DCM (3x), dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by chromatography on silica gel (mobile phase: gradient from 0% NH4OH, 0% MeOH, 100% DCM to 0.7% NH4OH, 7% MeOH, 93% DCM). Pure fractions were collected and evaporated to dryness to give 1.09 g (57%) of intermediate 39 ( * R) was obtained.

[0379] Example A13 Preparation of intermediate 40:

[0380] [ka]

[0381] To a solution of 2,3-dichloropyridine (6.0 g, 40.54 mmol) in THF (210 mL) and N-methyl-2-pyrrolidinone (54 mL) was added ferric acetylacetonate (530 mg, 1.50 mmol). Cyclopropylmagnesium bromide (47 mL, 46.63 mmol) was then added at 0° C. After stirring at room temperature for 1 h, additional cyclopropylmagnesium bromide (23 mL, 23.313 mmol) was added. After stirring at room temperature for 2 h, the reaction mixture was quenched with a saturated aqueous solution of NH4Cl. The solid was filtered off, and the filtrate was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (mobile phase: ethyl acetate / hexane, 1:20) to give 3.0 g (48% yield) of intermediate 40 as a pale yellow oil.

[0382] Preparation of intermediate 41:

[0383] [ka]

[0384] To a solution of intermediate 40 (4.5 g, 29.30 mmol) in 1,4-dioxane (90 mL) was added 4-fluoro-2-hydroxyphenylboronic acid (4.6 g, 29.30 mmol), Pd(amphos)Cl (1.0 g, 1.46 mmol), and NaCO (30 mL, 2 M in water). After stirring at 90 °C for 2 h, the reaction mixture was cooled to room temperature, quenched with water, and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (mobile phase: ethyl acetate / hexane, 1:2) to give 5.5 g (81.1% yield) of intermediate 41 as a yellow solid.

[0385] Preparation of intermediate 42:

[0386] [ka]

[0387] To a solution of intermediate 41 (5.5 g, 24.0 mmol) in THF (137 mL) were added intermediate 30 (8.6 g, 24.0 mmol) and DBU (3.6 g, 24.0 mmol). After stirring at room temperature overnight, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography column (mobile phase: ethyl acetate / hexane, 1:1) to give 8.8 g (63.5% yield) of intermediate 42 as a yellow solid.

[0388] Preparation of intermediate 43:

[0389] [ka]

[0390] To intermediate 42 (6.7 g, 12.12 mmol) in THF (167 mL) was added 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (989 mg, 1.21 mmol), sodium borohydride (779 mg, 20.60 mmol), and N,N,N′,N′-tetramethylethylenediamine (2.4 g, 20.60 mmol). After stirring overnight at room temperature, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (mobile phase: ethyl acetate / hexane, 2:3) to give 6.1 g (95.5% yield) of intermediate 43 as a tan solid.

[0391] Preparation of intermediate 44:

[0392] [ka]

[0393] At 0°C, TFA (16 mL; 212 mmol) was added to a solution of intermediate 43 (7.33 g; 14.1 mmol) in DCM (150 mL) and the reaction mixture was stirred at room temperature for 5 hours. The reaction was concentrated in vacuo. The residue was dissolved in 40 mL of water and the solution was basified with 15% aqueous NH4OH. The aqueous layer was diluted with DCM ( * The organic layer was decanted, washed again with brine, dried over MgSO, filtered and evaporated to dryness to give 6.3 g of intermediate 44, which was used in the next step without further purification.

[0394] Intermediate 45, 45a( * R) and 45b( * Preparation of S):

[0395] [ka]

[0396] A mixture of intermediate 44 (5 g; 11.2 mmol), intermediate 36 (2.51 g; 13.5 mmol), AcOH (707 μL; 12.4 mmol), and NaBHCN (2.1 g; 34 mmol) in MeOH (47 mL) was stirred at 50° C. overnight. The reaction mixture was poured into a 10% aqueous solution of KCO and DCM was added. This mixture was extracted with DCM (3×). The organic layer was dried over MgSO, filtered, and the solvent was evaporated. The crude product was purified by chromatography on silica gel (mobile phase: 99% DCM, 1% i-PrOH to 88% DCM, 12% i-PrOH). Pure fractions were collected and the solvent was evaporated. The residue (4.6 g) was purified by chiral SFC (CHIRALPAK AD-H 5 μm 250 * 30 mm, mobile phase: 85% CO, 15% EtOH (0.3% iPrNH)). The pure fractions were collected and the solvent was evaporated to give 1.98 g (30%) of intermediate 45a ( * R) (ee 100%) and 2.09 g (31%) of intermediate 45b ( * S) was obtained as an off-white foam (ee 99.4%).

[0397] Intermediate 46a( * R) and 46b( * Preparation of S):

[0398] [ka]

[0399] At 5 °C, TFA (5.1 mL; 67 mmol) was added to intermediate 45a ( * R) (1.98 g; 3.36 mmol) in DCM (76 mL) was added dropwise and the reaction mixture was stirred at room temperature for 2 hours. The reaction was evaporated to dryness. The residue was dissolved in DCM and basified with 30% aqueous NH4OH at 0-5 °C. The mixture was stirred at room temperature for 1 hour. The organic layer was decanted, washed with water, dried over MgSO4, filtered and the solvent was evaporated to give intermediate 46a ( * R) 1.90 g (100%) was obtained.

[0400] At 5 °C, TFA (5.4 mL; 71 mmol) was added to intermediate 45b ( * S) (2.09 g; 3.55 mmol) in DCM (81 mL) was added dropwise and the reaction mixture was stirred at room temperature for 2 hours. The reaction was evaporated to dryness. The residue was dissolved in DCM and basified with 30% aqueous NH4OH at 0-5 °C. The mixture was stirred at room temperature for 1 hour. The organic layer was decanted, washed with water, dried over MgSO4, filtered and the solvent was evaporated to give intermediate 46b ( * S) 1.95 g (97%) was obtained.

[0401] Example A14 Preparation of intermediate 47:

[0402] [ka]

[0403] A mixture of 2-chloro-3-cyclopropylpyridine (5 g; 32.55 mmol), 5-fluoro-2-hydroxyphenylboronic acid pinacol ester (10.1 mL; 48.82 mmol), and potassium fluoride (9.46 g; 162.75 mmol) in dioxane (125 mL) and water (30 mL) was prepared. The reaction mixture was degassed, and Sphos Pd G2 (469 mg; 0.65 mmol) was added. The reaction was then heated at 100 °C for 2 h. The mixture was cooled to RT and then poured into water. EtOAc was added, and the reaction mixture was filtered through a pad of Celite®. The organic layer was decanted, washed with brine and then water, dried over MgSO4, filtered, and evaporated to dryness. The residue was crystallized from Et2O. The precipitate was filtered and dried to give 6.8 g (91%) of intermediate 47.

[0404] Preparation of intermediate 48:

[0405] [ka]

[0406] To a solution of intermediate 47 (5.6 g, 15.7 mmol) in THF (180 mL) was added intermediate 30 (3.6 g, 15.7 mmol) and DBU (4.9 mL, 33 mmol). After stirring at room temperature for 72 h, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography column (mobile phase: gradient from 0.1% NH4OH, 1% MeOH, 99% DCM to 0.3% NH4OH, 3% MeOH, 97% DCM) to give 6.4 g (74%) of intermediate 48.

[0407] Preparation of intermediate 49:

[0408] [ka]

[0409] To intermediate 48 (6.4 g, 11.58 mmol) in THF (300 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (956 mg, 1.16 mmol), sodium borohydride (875 mg, 24 mmol), and N,N,N',N'-tetramethylethylenediamine (3.5 mL, 23.14 mmol). After stirring overnight at room temperature, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (mobile phase from 0.1% NH4OH, 1% MeOH, 99% DCM) to give 3 g (50% yield) of intermediate 49.

[0410] Preparation of intermediate 50:

[0411] [ka]

[0412] At 0°C, TFA (8.9 mL; 73.28 mmol) was added to a solution of intermediate 49 (3 g; 5.78 mmol) in DCM (90 mL) and the reaction mixture was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo. The residue was dissolved in 40 mL of water and the solution was basified with 15% aqueous NH4OH. The aqueous layer was diluted with DCM ( * The organic layer was decanted, washed again with brine, dried over MgSO, filtered and evaporated to dryness to give 2.4 g of intermediate 50, which was used in the next step without further purification.

[0413] The intermediates reported below were prepared following a similar method as described for intermediate 50, starting from the corresponding intermediate:

[0414] [Table 9]

[0415] Intermediate 51, 51a ( * R), 51b(* Preparation of S):

[0416] [ka]

[0417] A solution of intermediate 50 (1.3 g; 3.1 mmol), intermediate 36 (0.752 g; 4.08 mmol), AcOH (178 μL; 3.11 mmol), and NaBHCN (0.29 g; 4.66 mmol) in MeOH (50 mL) was stirred at 50° C. overnight. The reaction mixture was poured into a 10% aqueous solution of KCO and DCM was added. This mixture was extracted with DCM (3×). The organic layer was dried over MgSO, filtered, and the solvent was evaporated. The crude product was purified by chromatography on silica gel (mobile phase: gradient from 0% NHOH, 5% MeOH, 99% DCM to 0.1% NHOH, 5% MeOH, 95% DCM). Pure fractions were collected and the solvent was evaporated. The residue (1.2 g) was purified by chiral SFC (CHIRALPAK AD-H 5 μm 250 * The pure fractions were collected and the solvent was evaporated to give 464 mg (25%) of intermediate 51a ( * R) (ee 100%) and 476 mg (26%) of intermediate 51b ( * S) was obtained as an off-white (ee 100%) solid.

[0418] Intermediate 52a( * R), 52b( * Preparation of S):

[0419] [ka]

[0420] At 5 °C, TFA (1.2 mL; 15.76 mmol) was added to intermediate 51a ( *R) (464 mg; 0.79 mmol) in DCM (16 mL) was added dropwise and the reaction mixture was stirred at room temperature for 15 hours. The reaction was evaporated to dryness. The residue was dissolved in DCM and basified with a 10% aqueous solution of K2CO3. The organic layer was decanted, washed with water, dried over MgSO4, filtered and the solvent was evaporated to give intermediate 52a ( * R) 400 mg (94%) was obtained.

[0421] At 5 °C, TFA (1.2 mL; 15.76 mmol) was added to intermediate 51b ( * S) (476 mg; 0.81 mmol) in DCM (15 mL) was added dropwise and the reaction mixture was stirred at room temperature for 15 hours. The reaction was evaporated to dryness. The residue was dissolved in DCM and basified with 10% aqueous K2CO3. The organic layer was decanted, washed with water, dried over MgSO4, filtered and the solvent was evaporated to give intermediate 52b ( * S) 430 mg (98%) was obtained.

[0422] The intermediates reported below were prepared following similar methods as described for intermediate 52a and intermediate 52b, starting from the corresponding intermediate:

[0423] [Table 10] Example A15 Preparation of intermediate 53:

[0424] [ka]

[0425] Under a nitrogen atmosphere, tert-butylchlorodimethylsilane (2.9 g, 19.3 mmol) and 1H-imidazole (1.66 g, 24.3 mmol) were added to a solution of 3-hydroxycyclobutane-1-carboxylic acid (1.13 g, 9.7 mmol) in THF (15 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered to remove insoluble material, washed with DCM, and then concentrated in vacuo to give 2.9 g of intermediate 53. The intermediate was used in the next step without further purification.

[0426] Preparation of intermediate 54:

[0427] [ka]

[0428] A solution of K2CO3 (141 mg; 1 mmol) in water (2.2 mL) was added to a solution of intermediate 53 (913 mg; 2.54 mmol) in MeOH (6.5 mL) and THF (2.2 mL). The reaction mixture was stirred at room temperature for 4 h. The solvent was evaporated. The reaction was cooled to 0 °C in an ice bath. Aqueous HCl (1.5 N) was then added dropwise until the pH was < 2. The mixture was extracted twice with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated to give 493 mg (79%) of intermediate 54, which was used directly in the next step without further purification.

[0429] Preparation of intermediate 55:

[0430] [ka]

[0431] A mixture of intermediate 54 (261 mg; 1 mmol), EDCI (307 mg; 1.6 mmol), N,O-dimethylhydroxylamine hydrochloride (156 mg; 1.6 mmol), DMAP (6.5 mg; 0.054 mmol), and DIPEA (0.75 mL; 4.3 mmol) in DCM (6 mL) was stirred overnight at room temperature. The reaction mixture was diluted with DCM (10 mL) and washed with aqueous HCl (1 N) (2 × 5 mL), water (10 mL), and then with a saturated solution of NaHCO (2 × 10 mL). The organic layer was separated, dried over MgSO, filtered, and evaporated to dryness to give 144 mg of intermediate 55 (45%), which was used directly in the next step without further purification.

[0432] Preparation of intermediate 56:

[0433] [ka]

[0434] Under a nitrogen atmosphere, isopropylmagnesium chloride (2.3 mL; 3 mmol, 1.3 M in THF) was added to a solution of Intermediate 55 (144 mg; 0.5 mmol) in THF (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The solution was then allowed to warm slowly to room temperature and stirred for 2 h. The reaction mixture was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated to dryness to give 117 mg (86%) of Intermediate 56.

[0435] Preparation of intermediate 57:

[0436] [ka]

[0437] A mixture of intermediate 33 (140 mg; 0.33 mmol), intermediate 56 (117 mg; 0.43 mmol), AcOH (19 μL, 0.33 mmol), and NaBHCN (47 mg; 0.75 mmol) in MeOH (5 mL) was stirred at 50 °C overnight. The reaction mixture was poured into a saturated solution of NaHCO and DCM was added. This mixture was extracted with DCM (3x). The organic layer was dried over MgSO, filtered, and the solvent was evaporated. The crude product (258 mg) was purified by chromatography on silica gel (mobile phase: gradient from 99% DCM, 1% MeOH (+10% NHOH) to 95% DCM, 5% MeOH (+10% NHOH)). Pure fractions were collected and the solvent was evaporated, yielding 104 mg (46%) of intermediate 57.

[0438] Example A16 Preparation of intermediate 59:

[0439] [ka]

[0440] To a mixture of 2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (900 mg; 3.7 mmol) and N,O-dimethylhydroxylamine hydrochloride (400 mg; 4.1 mmol) in DCM (15 mL) was added HATU (2.1 g; 5.6 mmol) and DIPEA (0.96 mL; 5.6 mmol) at room temperature. The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into water. Saturated aqueous NaHCO3 and DCM were added. The organic layer was separated, dried over MgSO4, filtered, and the solvent was removed in vacuo. The residue (2.26 g) was purified by chromatography on silica gel (mobile phase: gradient from 80% heptane, 20% EtOAc to 40% heptane, 60% EtOAc). Pure fractions were collected and the solvent was evaporated, yielding 1 g (100%) of intermediate 59.

[0441] Intermediate 60 reported below was prepared following an analogous method starting from 1-boc-1-azaspiro[3.3]heptane-6-carboxylic acid.

[0442] [Table 11]

[0443] Preparation of intermediate 61:

[0444] [ka]

[0445] Under nitrogen atmosphere at 0° C., isopropylmagnesium chloride (29 mL; 37.3 mmol, 1.3 M in THF) was added to a solution of intermediate 59 (2.12 g; 7.46 mmol) in THF solution and dried (36 mL). The reaction mixture was stirred at 0° C. for 1 h. The solution was then slowly warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with a 10% aqueous solution of NH4Cl and EtOAc was added. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated to dryness. The residue (1.9 g) was purified by chromatography on silica gel (mobile phase: gradient from 80% heptane, 20% EtOAc to 40% heptane, 60% EtOAc). Collection of pure fractions and evaporation of the solvent gave 1.47 g (74%) of intermediate 61.

[0446] Intermediate 62 reported below was prepared following an analogous method starting from intermediate 60.

[0447] [Table 12]

[0448] Example A17 Intermediate 58, reported below, was prepared following a similar method to the preparation of compound 7, starting from intermediate 38b and methyl-3-methylpyrrolidine-3-carboxylate.

[0449] [Table 13]

[0450] Preparation of intermediate 67:

[0451] [ka]

[0452] Lithium hydroxide (101 mg; 2.41 mmol) was added to a solution of intermediate 58 (270 mg; 0.4 mmol) in THF (25 mL) and water (3 mL). The mixture was stirred at room temperature overnight and then concentrated to dryness. The crude product was then taken up in EtO and filtered to give 280 mg of intermediate 67, which was used directly in the next step without further purification.

[0453] Example A18 Preparation of intermediate 68:

[0454] [ka]

[0455] (NH)SO (15 g; 65.73 mmol) and AgNO (8.5 g; 50 mmol) were added to water (150 mL), cyclopropanecarboxylic acid (2.1 mL; 26.47 mmol), followed by 5-bromo-2-chloropyrimidine (5 g; 25.85 mmol) and CHCN (150 mL). The reaction mixture was stirred at room temperature for 72 hours and quenched by slow addition of ice water. EtOAc was added, followed by saturated NaCl solution. The solution was filtered through a Celite® layer, then extracted with EtOAc (2 × 500 mL), dried over MgSO, filtered, and concentrated. The residue (5.83 g) was purified by silica gel chromatography (mobile phase: 40% DCM, 60% heptane). Pure fractions were collected and the solvent was evaporated to dryness, yielding 3.05 g (51%) of intermediate 68.

[0456] Preparation of intermediate 69:

[0457] [ka]

[0458] At room temperature, TBACN (1.75 g; 6.52 mmol) and DABCO (0.72 g; 6.42 mmol) were added to a solution of intermediate 68 (1 g; 4.28 mmol) in MeCN (20 mL), and the solution was stirred at room temperature for 2 hours. The solution was poured into cold water, and the product was extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered, and evaporated to dryness. The residue (1.6 g) was purified by chromatography on silica gel (mobile phase gradient 0% DCM, 100% heptane to 30% DCM, 70% heptane). Pure fractions were collected, and the solvent was evaporated to dryness, yielding 860 mg (90%) of intermediate 69.

[0459] Preparation of intermediate 70:

[0460] [ka]

[0461] To a pre-degassed mixture of intermediate 69 (860 mg; 3.84 mmol), 5-fluoro-2-hydroxyphenylboron pinacol ester (1.3 g; 5.46 mmol), and potassium fluoride (1.1 g; 18.93 mmol) in 1,4-dioxane (20 mL) was added water (3.9 mL) and SPhos Pd G2 (56 mg; 0.08 mmol). The mixture was heated in a Schlenk apparatus at 100 °C for 2.30 h. The mixture was cooled at room temperature and poured into water. EtOAc was added, and the mixture was filtered through a pad of Celite®. The organic layer was decanted, washed with brine and then with water, dried over MgSO4, filtered, and evaporated to dryness. The residue (2.12 g) was purified by silica gel chromatography (mobile phase: 100% DCM, 0% MeOH gradient to 98% DCM, 2% MeOH). The pure fractions were collected and the solvent was evaporated to dryness, yielding 630 mg (64%) of intermediate 70.

[0462] Preparation of intermediate 71:

[0463] [ka]

[0464] A solution of intermediate 70 (2 g; 7.835 mmol), intermediate 30 (2.8 g; 7.77 mmol) and DBU (5.7 mL; 38.94 mmol) in THF (100 mL) was stirred at room temperature for 24 hours. The solution was poured into cold water and the product was extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered and evaporated to dryness. The residue (5 g) was purified by chromatography on silica gel (mobile phase: 0.1% NH4OH, 99% DCM, 1% MeOH). Pure fractions were collected and the solvent was evaporated to dryness. Chiral SFC (stationary phase: CHIRALPAK IC 5 μm 250 * A second purification (3.5 g) was performed via 30 mm, mobile phase: 50% CO2, 50% MeOH). The pure fractions were collected and the solvent was evaporated to dryness, yielding 2.6 g (57%) of intermediate 71.

[0465] Preparation of intermediate 72:

[0466] [ka]

[0467] A mixture of Intermediate 71 (2.6 g; 4.49 mmol) and TMEDA (1 mL; 6.71 mmol) in dry THF (100 mL) was degassed by bubbling N2. Next, Pd(dppf)Cl2.DCM (415 mg; 0.50 mmol) and NaBH4 (260 mg; 6.87 mmol) were added. The reaction mixture was stirred overnight at 50 °C in a sealed glassware. The solution was cooled, poured into cold water, and EtOAc was added. The mixture was filtered through a pad of Celite®. The product was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (mobile phase: gradient from 100% DCM, 0% MeOH (+10% NH4OH) to 95% DCM, 5% MeOH (+10% NH4OH)). The pure fractions were collected and the solvent was evaporated to dryness, yielding 1.84g (75%) of intermediate 72.

[0468] Preparation of intermediate 73:

[0469] [ka]

[0470] A solution of intermediate 72 (3 g; 5.51 mmol) and TFA (9 mL; 117.5 mmol) in DCM (90 mL) was stirred at room temperature overnight. The solution was evaporated to dryness, the mixture was poured into cold water, basified with NHOH, and the product was extracted with EtOAc. The organic layer was dried over MgSO, filtered, and evaporated to dryness to give 2.49 g of intermediate 73, which was used directly for the next step.

[0471] Preparation of intermediate 74:

[0472] [ka]

[0473] To a mixture of intermediate 73 (2 g; 4.5 mmol), intermediate 36 (1.1 g; 5.91 mmol), and AcOH (260 μL; 4.55 mmol) in MeOH (60 mL) at room temperature under N was added NaBHCN (424 mg; 6.75 mmol), and the reaction was heated at 60 °C overnight. The reaction mixture was cooled and poured into a mixture of 10% aqueous KCO and EtOAc. The mixture was extracted with EtOAc (3x). The organic layer was dried over MgSO, filtered, and the solvent was evaporated. The residue was purified by chromatography on silica gel (2.6 g) (mobile phase: gradient from 100% DCM, 0% MeOH (+10% NHOH) to 95% DCM, 5% MeOH (+10% NHOH)). Pure fractions were collected and the solvent was evaporated to dryness, yielding 450 mg (16% over two steps) of intermediate 74.

[0474] Preparation of intermediate 75:

[0475] [ka]

[0476] At 5°C, TFA (1.2 mL; 15.7 mmol) was added dropwise to a solution of intermediate 74 (450 mg; 0.73 mmol) in DCM (12 mL) and the reaction mixture was stirred at room temperature for 3 h. MeCN was added and the solution was evaporated to dryness. The residue was dissolved in EtOAc and basified with 30% aqueous NH4OH at 0-5°C. The organic layer was decanted, washed with water, dried over MgSO4, filtered and the solvent was evaporated to give 414 mg (99%) of intermediate 75, which was used directly in the next step.

[0477] Example A19 Preparation of intermediate 76:

[0478] [ka]

[0479] In a 1 L Schlenk round-bottom flask, 0.5 M cyclopropylzinc bromide in THF (100 mL; 50 mmol) was added dropwise to a pre-degassed solution of 4-bromo-3-chloropyridine (6.41 g; 33.33 mmol) and Pd(PPh3)4 (1.93 g; 1.67 mmol) in THF (200 mL). The reaction was heated at 65 °C for 18 h. The reaction mixture was cooled to room temperature, neutralized with 10% aqueous K2CO3, and extracted with Et2O (twice). The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by chromatography on silica gel (irregular SiOH, 80 g; mobile phase: 10% EtOAc, 90% heptane, gradient from 20% EtOAc, 80% heptane). The pure fractions were collected and evaporated to dryness, yielding 3.93g (77%) of intermediate 76.

[0480] Preparation of intermediate 77:

[0481] [ka]

[0482] In a Schlenk round-bottom flask, a pre-degassed mixture of intermediate 76 (3.91 g; 25.4 mmol), 5-fluoro-2-hydroxyphenylboron pinacol ester (7.88 g; 33.09 mmol), potassium fluoride (7.39 g; 127 mmol), and SPhos Pd G2 (366 mg; 0.509 mmol) in dioxane (80 mL) and water (27 mL) was refluxed for 3 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, and poured into water. The organic layer was decanted, washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The residue was allowed to stand over the weekend. The residue was dissolved in DCM, and the precipitate was then filtered, washed with Et2O, and dried to give 4.86 g (83%) of intermediate 77.

[0483] Example A21 Preparation of intermediate 81:

[0484] [ka]

[0485] In a sealed tube, di-μ-iodobis(tri-t-butylphosphino)dipalladium(I) (180 mg; 207 μmol) was added to a mixture of 5-bromo-6-chloronicotinonitrile (1.8 g; 8.3 mmol) and cyclopropylzinc bromide 0.5 M in THF (17 mL; 8.7 mmol) in dry THF (34 mL). The reaction mixture was stirred at room temperature for 1 h and quenched with a few drops of water. MgSO and celite were added, and the solvent was removed in vacuo to give a dry product, which was purified by chromatography on silica gel (irregular SiOH, 80 g; mobile phase: heptane / EtOAc 95:5 to 80:20 gradient). The product-containing fractions were combined and evaporated in vacuo to give 1.06 g (72%) of intermediate 81 as a brown oil, which crystallized upon storage at room temperature.

[0486] Preparation of Intermediate 82:

[0487] [ka]

[0488] Under a stream of N2, Cs2CO3 (7.92 g; 24.3 mmol) followed by Pd(PPh3)4 (1.40 g; 1.22 mmol) were added to a stirred solution of intermediate 81 (2.17 g; 12.1 mmol) and 5-fluoro-2-hydroxyphenyl)boronic acid (4.17 g; 26.7 mmol) in a mixture of water (9.5 mL) and dioxane (28.6 mL). The reaction was degassed with N2 and then stirred at 90 °C for 18 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, and water was added. The organic layer was decanted, washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by chromatography on silica gel (irregular SiOH, 80 g, dry load; mobile phase: heptane / EtOAc 95 / 5 to 70 / 30 gradient). The product containing fractions were combined and evaporated to give 2.41 g (78%) of intermediate 82 as a yellow solid.

[0489] Example A22 Preparation of intermediate 83:

[0490] [ka]

[0491] In a Schlenk, a solution of 5-bromo-4-hydroxy-nicotinonitrile (2.00 g; 10.1 mmol), 2-benzyloxy-5-fluorophenylboronic acid (3.09 g; 12.6 mmol), and KPO (3.20 g; 15.1 mmol) in a mixture of dioxane (40 mL) and HO (13.3 mL) was purged with nitrogen. CatacXium A Pd G (439 mg; 603 μmol) was added. The reaction mixture was again purged with nitrogen and stirred at 80 °C for 17 h. The reaction mixture was poured into water and extracted twice with a mixture of DCM / MeOH (98:2). The organic layers were combined, dried over MgSO, filtered, and evaporated to dryness. The residue was warmed in i-PrOH (8 mL) and cooled to room temperature. The precipitate was filtered, washed with diethyl ether and dried in vacuo to give 854 mg of intermediate 83 (27%) as a yellow solid.

[0492] Preparation of intermediate 84:

[0493] [ka]

[0494] A mixture of intermediate 83 (854 mg; 2.67 mmol) in MeCN (10 mL) was treated with POCl (2.03 mL; 21.9 mmol). The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was then cooled to room temperature, quenched with a 10% aqueous solution of KCO and extracted with DCM. The organic layer was dried over MgSO, filtered and evaporated in vacuo to give 914 mg (quantitative) of intermediate 84 as a yellow solid.

[0495] Preparation of intermediate 85:

[0496] [ka]

[0497] A solution of intermediate 84 (914 mg; 2.70 mmol), cyclopropylboronic acid (464 mg; 5.40 mmol), and KPO (859 mg; 4.05 mmol) in a mixture of dioxane (11 mL) and HO (3.6 mL) was purged with nitrogen. CatacXium A Pd G3 (117 mg; 0.162 mmol) was added. The reaction mixture was again purged with nitrogen and stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic mixture was washed with water and then brine, dried over MgSO, filtered, and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (irregular SiOH, 40 g, dry load; mobile phase: gradient heptane / EtOAc from 85 / 15 to 70 / 30). The product-containing fractions were combined and evaporated to give 471 mg (51%) of intermediate 85 as a yellow gummy solid.

[0498] Preparation of intermediate 86:

[0499] [ka]

[0500] A solution of intermediate 85 (450 mg; 1.31 mmol) and ammonium formate (412 mg; 6.53 mmol) in EtOH (7.6 mL) was treated with palladium on charcoal (278 mg; 0.131 mmol) and stirred at 75 °C for 45 min. The reaction mixture was cooled to room temperature, diluted with DCM, and filtered through a pad of Celite®. The filtrate was evaporated in vacuo to give a residue that was purified by silica gel chromatography (irregular SiOH, 12 g; mobile phase: gradient DCM / MeOH 100 / 0 to 98 / 2). The product-containing fractions were combined and evaporated to give 190 mg of intermediate 86 (57%) as a yellow foam.

[0501] Example A23 Preparation of intermediate 87:

[0502] [ka]

[0503] To a mixture of 2,3-dichloropyrazine (5.0 g; 33.562 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.64 g; 33.562 mmol), and Pd(amphos)Cl (2.38 g; 3.356 mmol) in 1,4-dioxane (100 mL) was added a solution of sodium carbonate (2 M in water; 50.3 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 5 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with water and then brine, dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EA 100 / 0 to 80 / 20). The product containing fractions were combined and evaporated to give 3.0 g of intermediate 87 (57%) as a colorless oil.

[0504] Preparation of intermediate 88:

[0505] [ka]

[0506] To a mixture of intermediate 87 (1.21 g, 7.762 mmol) and tetrakis(triphenylphosphine)palladium (370 mg; 0.323 mmol) in 1,4-dioxane (50 mL) was added a solution of sodium carbonate (10 mL; 1 M in water), and the reaction was stirred at 90 °C under a nitrogen atmosphere for 3.5 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by chromatography on silica gel (mobile phase: ethyl acetate / petroleum ether 2:1). The product-containing fractions were combined and evaporated to give 1.25 g of intermediate 88 (84%) as a pale yellow solid.

[0507] Example A24 Preparation of intermediate 89:

[0508] [ka]

[0509] To a stirred solution of 5-bromo-2,4-dimethoxypyrimidine (10.0 g; 45.66 mmol) in 1,4-dioxane was added cyclopropylboronic acid (4.71 g; 65.74 mmol), sodium carbonate (2 M in water, 50 mL), and dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (3.23 g; 219.04 mmol). The reaction mixture was stirred overnight at room temperature, quenched with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: PE:EtOAc:93:7). The product-containing fractions were combined and evaporated to give 4.3 g of intermediate 89 (50%) as a colorless oil.

[0510] Preparation of Intermediate 90:

[0511] [ka]

[0512] To a stirred solution of intermediate 89 (4.8 g; 26.64 mmol) in MeCN (96 mL) was added sodium iodide (12.0 g; 79.91 mmol). The reaction mixture was cooled to 0° C., and chlorotrimethylsilane (8.7 g; 79.91 mmol) was added. After stirring at room temperature overnight, the reaction mixture was quenched with water and stirred for 15 minutes. The solid was filtered and dried under vacuum to give 3.0 g of intermediate 90 (73% yield) as a yellow solid.

[0513] Preparation of intermediate 91:

[0514] [ka]

[0515] To a solution of intermediate 90 (3.5 g; 23.00 mmol) in phosphorus oxychloride (300 mL) was added N,N-dimethylformamide (0.70 mL). After stirring at 100° C. for 2 hours, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in a small amount of DMF and poured into ice water, followed by extraction with EtOAc. The combined organic layers were washed with water and then brine, dried over NaSO, filtered, and concentrated under reduced pressure to give 4.2 g of intermediate 91 (96%) as a yellow oil.

[0516] Preparation of Intermediate 92:

[0517] [ka]

[0518] To a stirred solution of intermediate 91 (5.4 g; 28.56 mmol) in 1,4-dioxane (162 mL) was added (5-fluoro-2-hydroxyphenyl)boronic acid (4.45 g; 28.56 mmol), tetrakis(triphenylphosphine)palladium (1.65 g; 1.43 mmol), and sodium bicarbonate (2 M in water, 54 mL). After stirring at 80 °C under nitrogen for 2 h, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: PE:EtOAc 3:1). The product-containing fractions were combined and evaporated to give 2.7 g of intermediate 92 (29% purity, 81% as assessed by LCMS) as a pale yellow solid.

[0519] Preparation of intermediate 93:

[0520] [ka]

[0521] To a stirred solution of intermediate 92 (1.0 g; 2.08 mmol) in MeOH (55 mL) was added EtN (382 mg; 3.78 mmol) and 10% Pd / C (683 mg). After stirring under a stream of hydrogen (1 atm) at room temperature for 30 minutes, the catalyst was filtered off. The filtrate cake was washed with methanol. The combined filtrates were concentrated under reduced pressure to give 550 mg of intermediate 93 (62%).

[0522] Example A25 Preparation of intermediate 94:

[0523] [ka]

[0524] To a stirred solution of 4,5-dibromopyridazin-3(2H)-one (50 g; 196.95 mmol) in THF (300 mL) was added p-toluenesulfonic acid (3.4 g; 19.694 mmol) and 3,4-dihydro-2H-pyran (82.8 g; 988.72 mmol). After stirring at 60 °C overnight, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with water and then brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: PE / EtOAc 81 / 19). The product-containing fractions were combined and evaporated to give 65 g of intermediate 94 (83%) as a pale yellow solid.

[0525] Preparation of intermediate 95:

[0526] [ka]

[0527] To a stirred solution of intermediate 94 (25 g; 73.97 mmol) in 1,2-dimethoxyethane (200 mL) was added sodium borohydride (5.6 g; 147.93 mmol) at 0° C. After stirring at room temperature for 18 hours, the reaction mixture was cooled to 0° C., quenched with water, and extracted with ethyl acetate. The combined organic layers were washed with water, then brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: PE / EA 70 / 30). The product-containing fractions were combined and evaporated to give 2.3 g of intermediate 95 (12%) as a white solid.

[0528] Preparation of Intermediate 96:

[0529] [ka]

[0530] To a mixture of intermediate 95 (2.7 g, 10.42 mmol), (5-fluoro-2-hydroxyphenyl)boronic acid (1.6 g; 10.42 mmol), and Pd(PPh3)4 (1.2 g; 1.042 mmol) in dioxane (50 mL) was added sodium carbonate solution (20 mL; 2 M in water). After stirring at 90 °C for 5 h, the reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with water and then brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: PE / EA: 100 / 0 to 80 / 20). The product-containing fractions were combined and evaporated to give 2.46 g of intermediate 96 (78%) as a yellow solid.

[0531] Preparation of intermediate 97:

[0532] [ka]

[0533] A mixture of intermediate 96 (2.46 g; 8.47 mmol), benzyl chloride (2 mL; 16.95 mmol), and K2CO3 (5.9 g; 42.37 mmol) in acetone (50 mL) was stirred at 60 °C overnight. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The filtrate was purified by silica gel chromatography (mobile phase: PE / EA: 100 / 0 to 80 / 20). The product-containing fractions were combined and evaporated to give 2.0 g of intermediate 97 (60%) as a yellow oil.

[0534] Preparation of intermediate 98:

[0535] [ka]

[0536] A solution of intermediate 97 (2.0 g; 5.26 mmol) in hydrochloric acid (37% in water, 5 mL) and methanol (15 mL) was stirred at 50° C. for 1 hour. The solution was concentrated under reduced pressure. The residue was dissolved in EtO. The precipitate was filtered and dried under vacuum to give 1.0 g of intermediate 98 (64%) as a yellow solid.

[0537] Preparation of intermediate 99:

[0538] [ka]

[0539] A solution of intermediate 98 (1 g; 3.38 mmol) in phosphorus oxychloride (15 mL) was stirred at 100° C. for 2 hours. The solution was concentrated under reduced pressure. The residue was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water, then brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: PE / EA 100 / 0 to 30 / 70). The product-containing fractions were combined and evaporated to give 600 mg of intermediate 99 (52%) as a yellow oil.

[0540] Preparation of Intermediate 100:

[0541] [ka]

[0542] To a solution of intermediate 99 (200 mg; 0.64 mmol) in THF (7.0 mL) were added palladium(II) acetate (14 mg; 0.06 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (52 mg; 0.13 mmol). The resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was cooled to 0 °C, and cyclopropylzinc bromide (0.5 M in THF; 1.9 mL; 0.95 mmol) was added dropwise. After stirring overnight at room temperature, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (irregular SiOH, 40 g; mobile phase: petroleum ether:ethyl acetate 70%:30%). The product-containing fractions were combined and evaporated to give 150 mg of intermediate 100 (67%) as a light brown oil.

[0543] Preparation of Intermediate 101:

[0544] [ka]

[0545] To a solution of Intermediate 100 (150 mg; 0.47 mmol) in MeOH (10 mL) was added 10% Pd / C (150 mg; 0.14 mmol). After stirring under a hydrogen atmosphere (2-3 atm) at room temperature for 1 h, the reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure to give 100 mg of Intermediate 101 (88%) as a light brown solid.

[0546] Example A26 Preparation of Intermediate 102:

[0547] [ka]

[0548] 3,4-Dihydro-2H-pyran (28 mL; 306.5 mmol) was added to a mixture of 4-chloropyridazin-3(2H)-one (10 g; 76.61 mmol) and p-toluenesulfonic acid (1.4 g; 7.67 mmol in THF (200 mL)) at room temperature. The mixture was stirred at 70 °C overnight. After cooling to room temperature, the reaction solution was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and then brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (mobile phase: PE / EA: 100 / 0 to 30 / 70). The product-containing fractions were combined and evaporated to give 16 g (84%) of intermediate 102 as a yellow solid.

[0549] Preparation of intermediate 103:

[0550] [ka]

[0551] A mixture of intermediate 102 (5 g; 23.29 mmol), cyclopropylboronic acid (2.1 g; 24.46 mmol), and Pd(amphos)Cl (1.65 g; 2.33 mmol) in 1,4-dioxane (75 mL) and a solution of 2 M aqueous sodium carbonate (25 mL) was stirred at 90 °C for 5 h. After cooling to room temperature, the reaction solution was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and then brine, dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: PE / EA: 100 / 0 to 30 / 70). The product-containing fractions were combined and evaporated to give 3.5 g of intermediate 103 (67%) as a yellow solid.

[0552] Preparation of intermediate 104:

[0553] [ka]

[0554] A solution of intermediate 103 (10.0 g; 45.40 mmol) in hydrochloric acid (37% in water, 50 mL) and methanol (150 mL) was stirred at 50° C. for 1 hour. The solution was evaporated under reduced pressure. The residue was dissolved in water. The resulting solution was adjusted to pH=7 with NaOH (2 M in water) and extracted with (MeOH / DCM=1 / 10). The combined organic layers were dried over Na2SO4. The solid was filtered off. The filtrate was concentrated under reduced pressure to give 5.2 g of intermediate 104 (76%) as a yellow solid.

[0555] Preparation of Intermediate 105:

[0556] [ka]

[0557] To a solution of intermediate 104 (12.1 g; 88.14 mmol) in acetonitrile (200 mL) was added a solution of POCl3 (41.1 mL; 440.69 mmol). After stirring at 50 °C for 1.5 h, the solution was slowly poured into ice-water (200 mL). The resulting solution was adjusted to pH = 7 with a saturated aqueous solution of Na2CO3 and extracted with ethyl acetate. The combined organic layers were washed with water and then brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (PE / EA: 100 / 0 to 30 / 70). The product-containing fractions were combined and evaporated to give 9.0 g of intermediate 105 (61%) as a yellow oil.

[0558] Preparation of Intermediate 106:

[0559] [ka]

[0560] A mixture of intermediate 105 (9 g; 58.22 mmol), 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (13.86 g; 58.22 mmol), Pd(PPh3)4 (3.36 g; 2.91 mmol), and sodium carbonate solution (43.9 mL; 2 M) in 1,4-dioxane (130 mL) was stirred at 90 °C for 3 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and then brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: PE / EA: 100 / 0 to 30 / 70). The product-containing fractions were combined and evaporated to give 13 g of intermediate 106 (86%) as a pale yellow solid.

[0561] Example A27 Preparation of intermediate 107:

[0562] [ka]

[0563] To a solution of 5-bromopyridazin-4-amine (7.7 g; 44.25 mmol) in 1,4-dioxane (130 mL) was added cyclopropylboronic acid (5.7 g; 66.38 mmol), bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (4.7 g; 6.64 mmol), and sodium carbonate solution (2 M in water; 66.4 mL; 132.8 mmol). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 36 hours. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (120 g; mobile phase: dichloromethane / methanol 95% / 5%). The product containing fractions were combined and evaporated to give 2.5 g of intermediate 107 (39%) as a red oil.

[0564] Preparation of intermediate 108:

[0565] [ka]

[0566] To a solution of intermediate 107 (2.5 g; 18.50 mmol) in acetonitrile (50 mL) were added cupric bromide (3.31 g; 14.80 mmol) and isoamyl nitrite (2.73 mL; 20.35 mmol). The resulting mixture was stirred at 70° C. under a nitrogen atmosphere for 2.5 hours. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (60 g; mobile phase: petroleum ether / ethyl acetate 50 / 50). The product-containing fractions were combined and evaporated to give 1.6 g of intermediate 108 (42%) as a yellow oil.

[0567] Preparation of intermediate 109:

[0568] [ka]

[0569] To a solution of intermediate 108 (1.6 g; 8.04 mmol) in 1,4-dioxane (24 mL) was added (5-fluoro-2-hydroxyphenyl)-boronic acid (1.38 g; 8.84 mmol), bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (570 mg; 0.80 mmol), and sodium carbonate solution (2 M in water; 12.1 mL, 24.11 mmol). The resulting mixture was stirred at 90 °C for 16 h. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (irregular SiOH, 60 g; mobile phase: PE / EA: 100 / 0 to 0 / 100). The product containing fractions were combined and evaporated to give 1.3 g of intermediate 109 (62%) as a red solid.

[0570] Example A28 Preparation of Intermediate 110:

[0571] [ka]

[0572] A stirred solution of 2-bromo-6-methoxypyridine (16.8 g; 89.35 mmol) in 1,4-dioxane (450 mL) was added to (2-(benzyloxy)-5-fluorophenyl)boronic acid (22 g; 89.35 mmol), Pd(PPh3)4 (5.1 g; 34.69 mmol), and sodium carbonate (168 mL; 2 M). The reaction mixture was stirred at 90 °C under nitrogen for 2 h, quenched with water, and extracted with ethyl acetate. The combined organic layers were washed with water and then brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: PE:EA 98:2). The product-containing fractions were combined and evaporated to give 26 g of intermediate 110 (94%) as a colorless oil.

[0573] Preparation of intermediate 111:

[0574] [ka]

[0575] To a stirred solution of intermediate 110 (23.0 g; 74.353 mmol) in acetonitrile (400 mL) was added p-toluenesulfonic acid monohydrate (17.0 g; 89.24 mmol) and lithium iodide (20.0 g; 148.71 mmol). After stirring at 80 °C for 1 h, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: PE:EA 50:50). The product-containing fractions were combined and evaporated to give 23.0 g of intermediate 111 (90%) as a gray solid.

[0576] Preparation of Intermediate 112:

[0577] [ka]

[0578] To a stirred solution of Intermediate 111 (6.0 g; 20.32 mmol) in acetonitrile (60 mL) was added potassium cyclopropyltrifluoroborate (9.0 g; 60.9 mmol), cupric acetate (923 mg; 5.08 mmol), o-phenanthroline (458 mg; 2.540 mmol), potassium carbonate (5.6 g; 40.64 mmol), and water (18 mL). After stirring overnight at 70 °C under an oxygen atmosphere, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA: 35:65). The product-containing fractions were combined and evaporated to give 2.9 g of Intermediate 112 (39%) as an off-white solid.

[0579] Preparation of intermediate 113:

[0580] [ka]

[0581] To a stirred solution of intermediate 112 (1.0 g, 2.98 mmol) in acetonitrile (15 mL) was added iodotrimethylsilane (17.9 g, 89.45 mmol). After stirring at room temperature overnight, the reaction mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with water, then brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (DCM:MeOH 96:4). The product-containing fractions were combined and evaporated to give 630 mg of intermediate 113 (83%) as a dark brown solid.

[0582] Example A29 (all remaining intermediates) Preparation of intermediate 114:

[0583] [ka]

[0584] To a solution of 5-bromo-2-methoxypyrimidine (23.8 g, 0.13 mol) in diethyl ether (950 mL) and THF (170 mL) was added cyclopropylmagnesium bromide (133 mL, 0.13 mol, 1 M in THF) at 0° C. After stirring at room temperature for 1 hour, the resulting mixture was quenched with water (2.3 mL, 0.13 mol), followed by the addition of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (28.6 g, 0.13 mol, dissolved in 70 mL of tetrahydrofuran). The resulting mixture was stirred overnight at room temperature, quenched with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: EtOAc / hexane (1 / 10)). The pure fractions were collected and evaporated to dryness, yielding 12.0 g (40%) of the desired intermediate 114 as a yellow solid.

[0585] Preparation of Intermediate 115:

[0586] [ka]

[0587] To a solution of intermediate 114 (2.0 g, 8.73 mmol) in 1,4-dioxane (100 mL) were added (5-fluoro-2-hydroxyphenyl)boronic acid (1.6 g, 10.48 mmol), tetrakis(triphenylphosphine)palladium (500 mg, 0.44 mmol), and sodium carbonate solution (17.5 mL, 1 M in water, 17.5 mmol). After stirring at 90 °C for 2 h, the reaction mixture was cooled to room temperature, quenched with water, and extracted with EtOAc. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (mobile phase: EtOAc / hexane, 2 / 3). Pure fractions were collected and evaporated to dryness to give 1.4 g of the desired intermediate 115 (63%) as a pale yellow solid.

[0588] Preparation of Intermediate 116:

[0589] [ka]

[0590] To a solution of intermediate 115 (1.5 g, 5.76 mmol) in THF (45 mL) was added intermediate 30 (2.1 g, 5.76 mmol) and DBU (877 mg, 5.76 mmol). The resulting solution was stirred at room temperature for 48 h, then quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (mobile phase: ethyl acetate / hexane: 1 / 1). Pure fractions were collected and evaporated to dryness to give 3.0 g of the desired intermediate 116 (78% pure by LC / MS, 87%) as a yellow solid.

[0591] Preparation of intermediate 117:

[0592] [ka]

[0593] To a solution of intermediate 116 (2.9 g, 5.0 mmol) in MeOH (175 mL) was added palladium on activated carbon (10% palladium on activated carbon, 67% water) (1.6 g, 1.49 mmol). After stirring under a hydrogen atmosphere (1 atm) at room temperature for 1 hour, the resulting mixture was filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure to give 2.7 g (96%) of the desired intermediate 117 as a yellow solid.

[0594] Preparation of Intermediate 118:

[0595] [ka]

[0596] To a solution of intermediate 117 (2.2 g, 4.0 mmol) in DCM (70 mL) was added TFA (24 mL) at 0° C. The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water, and the pH was adjusted to 9 with NaOH solution (1 M in water). The resulting solution was extracted eight times with DCM. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 1.6 g (81%) of the desired intermediate 118 as a white solid.

[0597] Preparation of Intermediate 232:

[0598] [ka]

[0599] To a solution of tert-butyl 3-nitrocyclobutanecarboxylate (1.00 g, 4.72 mmol) (synthesis see U.S. Patent Application Publication No. 20170283406(A1)) and methyl acrylate (0.840 g, 9.76 mmol) in ACN (10 mL) was added DBU (1.45 g, 9.53 mmol) at 0 °C, and the mixture was stirred at the same temperature for 20 min. The reaction was quenched with saturated aqueous NH4Cl (20 mL), and the mixture was extracted with EtOAc (30 mL × 2). The combined organic layers were washed with water (50 mL) and brine (50 mL) and dried over anhydrous Na2SO4. After filtration and concentration, the crude residue was purified by FCC (PE:EA = 100:0 to 80:20) to give intermediate 232 (0.8 g, 59% yield) as a colorless oil.

[0600] Preparation of intermediate 233:

[0601] [ka]

[0602] To a mixture of intermediate 232 (1.58 g, 5.50 mmol) and nickel(II) chloride hexahydrate (1.2 g, 5.05 mmol) in MeOH (40 mL) was added NaBH (0.95 g, 25.1 mmol) slowly in three portions at −10° C. The mixture was stirred at the same temperature for 3 h. The reaction was quenched with aqueous KCO (0.416 g / mL) at 0° C. The resulting mixture was stirred at 0° C. for 3 h and further stirred at room temperature for another 2 h. The mixture was passed through a Celite® pad, and the filtrate was concentrated in vacuo to give intermediate 233 (0.87 g, crude), which was used directly in the next step without further purification.

[0603] Preparation of intermediate 234:

[0604] [ka]

[0605] A solution of intermediate 233 (0.5 g, 2.22 mmol) in HCl / dioxane (7 mL, 4 M) was stirred at room temperature for 12 hours. The mixture was concentrated in vacuo to give intermediate 234 (350 mg, crude) as a white solid, which was used directly in the next step without further purification.

[0606] Preparation of Intermediate 250:

[0607] [ka]

[0608] To a mixture of bicyclo[1.1.1]pentane-1-carboxylic acid (1.00 g, 8.92 mmol), tert-butyl 4-iodopiperidine-1-carboxylate (4.71 g, 17.8 mmol), 2,2′-bipyridine (696 mg, 4.46 mmol), nickel(II) acetylacetonate (916 mg, 3.57 mmol), MgCl (2.55 g, 26.8 mmol), zinc powder (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 BocO (7.79 g, 35.7 mmol) under an Ar atmosphere at 25° C. After the addition, the reaction mixture was stirred at 25° C. for 60 h. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (150 mL × 2). The combined layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by column chromatography (EtOAc / PE = 0-15%) to give intermediate 250 (560 mg, 16% yield) as a colorless oil.

[0609] The intermediates reported below were prepared following methods analogous to those described for intermediate 250, starting from the corresponding intermediates:

[0610] [Table 14]

[0611] Preparation of intermediate 237:

[0612] [ka]

[0613] NaH (71 mg, 1.8 mmol, 60% in mineral oil) was added to a solution of tert-butyl 5-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (200 mg, 0.884 mmol) in THF (8 mL) cooled at 0 °C under a N atmosphere. The reaction mixture was stirred at this temperature for 1 h. Then, MeI (1.48 g, 10.4 mmol) was added dropwise to the reaction mixture at 0 °C, and the mixture was slowly warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo to give intermediate 237 (210 mg, crude) as a brown oil, which was used directly in the next step without further purification.

[0614] The intermediates reported below were prepared following methods analogous to those described for intermediate 237, starting from the corresponding commercially available starting materials:

[0615] [Table 15]

[0616] Preparation of intermediate 238:

[0617] [ka]

[0618] Intermediate 237 (210 mg, 0.874 mmol) was added to a solution of TFA (0.5 mL) in DCM (5 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to give Intermediate 238 (300 mg, crude) as a brown oil, which was used directly in the next step without further purification.

[0619] The intermediates reported below were prepared following methods analogous to those described for intermediate 238, starting from the corresponding intermediates or commercially available starting materials:

[0620] [Table 16]

[0621] Preparation of Intermediate 242:

[0622] [ka]

[0623] To a mixture of tert-butyl 3-amino-3-(hydroxymethyl)azetidine-1-carboxylate (500 mg, 2.47 mmol) and TEA (1.0 mL, 7.42 mmol) in THF (15 mL) cooled to 0 °C, a solution of bis(trichloromethyl)carbonate (800 mg, 2.70 mmol) in THF (5 mL) was added under a N atmosphere. The reaction mixture was stirred at 0 °C for 0.5 h and then at room temperature for an additional 3 h. The reaction mixture was poured into saturated aqueous NaHCO (30 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL) and dried over anhydrous NaSO. After filtration, the solvent was removed in vacuo to give intermediate 242 (600 mg, crude) as a red solid, which was used directly in the next step without further purification.

[0624] Preparation of Intermediate 252:

[0625] [ka]

[0626] DIC (5.0 g, 39.6 mmol) was added to a solution of bicyclo[1.1.1]pentane-1-carboxylic acid (4.0 g, 35.7 mmol), 2-hydroxyisoindoline-1,3-dione (6.50 g, 39.8 mmol), and DMAP (450 mg, 3.68 mmol) in DCM (100 mL). The resulting mixture was stirred at 25 °C overnight. The reaction mixture was filtered through a pad of Celite®, and the filtrate was concentrated in vacuo to give the crude product, which was purified by FCC (PE: EtOAc = 10:1) to give intermediate 252 (7.7 g, 84% yield) as a white solid.

[0627] Preparation of intermediate 253:

[0628] [ka]

[0629] Anhydrous ACN (20 mL) and THF (30 mL) were added via syringe to a mixture of Intermediate 252 (3.0 g, 11.7 mmol), 3,3-dimethoxycyclobutane-1-carboxylic acid (3.75 g, 23.4 mmol), Ni(BPhen)Cl·2DMF (710 mg, 1.16 mmol), zinc powder (2.40 g, 36.7 mmol), benzoic anhydride (5.30 g, 23.4 mmol), MgCl (1.67 g, 17.7 mmol), and LiBr (1.02 g, 11.7 mmol) under a N atmosphere. The resulting mixture was stirred at 25 °C overnight. The mixture was diluted with EtOAc (200 mL), washed with 1 N NaOH (100 mL × 2) and brine (50 mL × 2), and dried over anhydrous NaSO. After filtration and concentration, the crude product was purified by FCC (PE:EA=10:1) to give intermediate 253 (1.40 g, 57% yield) as a colorless oil.

[0630] Preparation of intermediate 254:

[0631] [ka]

[0632] To a solution of tert-butyl (3-hydroxycyclobutyl)carbamate (900 mg, 4.81 mmol), 1H-imidazole (982 mg, 14.4 mmol), and Ph3P (2.52 g, 9.61 mmol) in toluene (15 mL) was added I2 (1.83 g, 7.21 mmol). The mixture was stirred at 110 °C for 1 h. After cooling to room temperature, the mixture was diluted with EtOAc (50 mL), washed with brine (20 mL × 2), and further dried over anhydrous Na2SO4. After filtration and concentration, the crude residue was purified by FCC (PE:EA = 5:1) to give intermediate 254 (620 mg, 43% yield) as a white solid.

[0633] Preparation of intermediate 267:

[0634] [ka]

[0635] To a suspension of LiAlH4 (1.17 g, 30.8 mmol) in THF (10 mL) cooled to -10 °C, a solution of cis-3-hydroxy-3-methylcyclobutanecarboxylic acid (1.00 g, 7.68 mmol) in THF (5 mL) was added dropwise. The resulting mixture was slowly warmed to 25 °C and stirred for 2 h. The reaction was quenched with water (10 mL). The mixture was filtered through a pad of Celite®, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel FCC (PE:EA 1:0 to 0:1) to give intermediate 267 (550 mg, 62% yield) as a colorless oil.

[0636] Preparation of Intermediate 268:

[0637] [ka]

[0638] To a solution of intermediate 267 (200 mg, 1.72 mmol) in DCM (10 mL) was added TEA (0.74 mL, 5.3 mmol, 0.73 g / mL) at 0 °C. Then, MsCl (750 mg, 6.54 mmol) was added dropwise at 0 °C. The mixture was slowly warmed to 20 °C and stirred for 1 h. The mixture was washed with water (1 mL), and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel FCC (PE:EA 1:0 to 1:2) to give intermediate 268 (150 mg, 45% yield) as a colorless oil.

[0639] Preparation of intermediate 269:

[0640] [ka]

[0641] To a solution of cis-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)methanol (500 mg, 2.31 mmol), TEA (1 mL, 7 mmol), and DMAP (57 mg, 0.47 mmol) in DCM (10 mL) cooled at 0 °C was added TsCl (500 mg, 2.62 mmol) portionwise. The resulting mixture was slowly warmed to room temperature and stirred for 12 h. The mixture was poured into HO (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were dried over anhydrous NaSO. After filtration and concentration, the crude product was purified by FCC (PE:EtOAc = 1:0 to 10:1) to give intermediate 269 (700 mg, 82% yield) as a white solid.

[0642] The intermediates reported below were prepared following methods analogous to those described for intermediate 269, starting from the corresponding commercially available starting materials:

[0643] [Table 17]

[0644] Preparation of Intermediate 270:

[0645] [ka]

[0646] A mixture of compound 3 (600 mg, 1.07 mmol), intermediate 269 (500 mg, 1.35 mmol), K2CO3 (230 mg, 1.66 mmol), and KI (36 mg, 0.22 mmol) in ACN (10 mL) was stirred at 90 °C for 16 h. After cooling to room temperature, the reaction mixture was poured into HO (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by FCC (DCM:MeOH = 1:0 to 15:1) to give intermediate 270 (700 mg, 80% yield) as a white solid.

[0647] The intermediates reported below were prepared following a similar method as described for intermediate 270, starting from the corresponding intermediate:

[0648] [Table 18]

[0649] Preparation of intermediate 273:

[0650] [ka]

[0651] To a solution of cyclopropanecarboxamide (3.00 g, 35.3 mmol) in toluene (30 mL) was added N,N-dimethylformamide dimethyl acetal (8.40 g, 70.5 mmol). The mixture was stirred at 120° C. for 2 hours. After cooling to room temperature, the mixture was concentrated in vacuo to give intermediate 273 (5.0 g, crude) as a yellow solid, which was used directly in the next step without further purification.

[0652] Preparation of intermediate 274:

[0653] [ka]

[0654] A solution of 5-fluoro-2-methoxyaniline (10.0 g, 70.9 mmol) in 12 M HCl (30 mL) and HO (15 mL) was stirred at 0 °C for 20 min, and then a solution of NaNO (6.36 g, 92.2 mmol) in HO (15 mL) was added slowly at 0 °C. The resulting mixture was slowly warmed to 25 °C and stirred for 1 h. Then, SnCl (26.9 g, 142 mmol) in HCl (30 mL) was added at −20 °C, and the mixture was stirred at −20 °C for 2 h. The mixture was basified with NaOH (2 M) at −20 °C to adjust the pH to 12. After slowly warming to room temperature, the mixture was extracted with DCM (500 mL), washed with brine (200 mL × 3), and further dried over anhydrous NaSO. After filtration, the filtrate was concentrated in vacuo to give intermediate 274 (7.5 g, crude) as a brown oil, which was used directly in the next step without further purification.

[0655] Preparation of intermediate 275:

[0656] [ka]

[0657] To a solution of intermediate 274 (5.50 g, crude) in AcOH (50 mL) was added intermediate 273 (5.00 g, crude) at 0 °C. The resulting mixture was warmed to room temperature and stirred for 12 h. The mixture was basified with NaOH (2 M) to adjust the pH value to 12 and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL × 3) and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by silica gel FCC (PE:EA, 1:0 to 2:1) to give intermediate 275 (3.0 g) as a brown solid.

[0658] Preparation of Intermediate 276:

[0659] [ka]

[0660] To a solution of intermediate 275 (3.00 g, 12.9 mmol) in DCM (30 mL) was slowly added BBr3 (3.60 mL, 38.1 mmol) under a N2 atmosphere at -78 °C. The mixture was stirred at -78 °C for 1 h and then at room temperature for 12 h. The mixture was basified with NaOH (2 M) to adjust the pH to 12 and extracted with DCM (200 mL). The organic layer was washed with brine (100 mL × 3). The combined aqueous phase was extracted again with DCM (100 mL × 3), and the combined organic layer was dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by silica gel FCC (1:0 to 1:1 PE:EtOAc) to give intermediate 276 (1.90 g, 66% yield) as a brown solid.

[0661] The intermediates reported below were prepared following a similar method as described for intermediate 276, starting from the corresponding intermediate:

[0662] [Table 19]

[0663] Preparation of Intermediate 280:

[0664] [ka]

[0665] Intermediate 279 (450 mg, 1.13 mmol) was dissolved in THF (15 mL) and then isoamyl nitrite (0.55 mL, 4.1 mmol) was added. The reaction was heated at 65° C. for 3 h and then cooled to room temperature. The reaction mixture was concentrated in vacuo and the crude product was purified by FCC (EA:PE, 1:10 to 1:3) to give Intermediate 280 (200 mg, 46% yield) as a yellow oil.

[0666] Preparation of intermediate 294:

[0667] [ka]

[0668] A mixture of intermediate 13 (3.5 g, 9.91 mmol), molecular sieves (6.0 g, 4 Å), and 2,2,2-trifluoroethanol (30 mL) was first purged with Ar gas three times and stirred at 65° C. for 3 h. Then, 1,3-dibromo-1,3,5-triazinane-2,4,6-trione (5.69 g, 19.8 mmol) was added to the mixture at 25° C., and the mixture was further stirred at 65° C. for 8 h. After cooling to room temperature, the mixture was filtered through a pad of Celite® and concentrated under reduced pressure to give the crude product, which was purified by FCC (eluent: PE:EA, 1:0 to 3:1) to give intermediate 294 (1.8 g, 45% yield) as a yellow oil.

[0669] The intermediates reported below were prepared following a similar method as described for intermediate 294, starting from the corresponding intermediate:

[0670] [Table 20]

[0671] Preparation of intermediate 285:

[0672] [ka]

[0673] To a solution of 5-fluoro-2-methoxybenzoic acid (10.0 g, 58.8 mmol) in DCM (150 mL) and MeOH (150 mL) cooled to 0 °C, TMSCHN (88.0 mL, 176 mmol, 2 M in hexanes) was slowly added. The reaction mixture was slowly warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by FCC (PE:EtOAc = 10:1 to 3:1) to give intermediate 285 (12 g, 89% purity, 99% yield) as a yellow oil.

[0674] Preparation of Intermediate 286:

[0675] [ka]

[0676] A mixture of intermediate 285 (4.00 g, 21.7 mmol) and hydrazine hydrate (2.02 mL, 65.0 mmol) in EtOH (10 mL) was stirred for 16 hours at 90° C. After cooling to room temperature, the reaction mixture was concentrated in vacuo to give intermediate 286 (2.9 g, crude) as a white solid, which was used directly in the next step without further purification.

[0677] Preparation of intermediate 287:

[0678] [ka]

[0679] To a solution of intermediate 286 (2.80 g, 15.2 mmol) in ACN (60 mL) was added N,N-dimethylformamide dimethyl acetal (1.85 mL, 19.8 mmol), and the reaction mixture was stirred at 50° C. for 1 h. Then, cyclopropanamine (5.27 mL, 76.0 mmol) in ACN (10 mL) was added to the above mixture, followed by AcOH (1.74 mL, 30.4 mmol). The reaction mixture was further stirred at 120° C. for 16 h. After cooling to room temperature, the reaction mixture was concentrated, and the residue was purified by preparative HPLC (Welch Xtimate C18 150* 40mm * Purification was carried out on a 10 μm column, eluent: water (0.2% formic acid)-ACN, 15% ACN to 45% ACN (v / v). The desired fractions were collected and lyophilized to give intermediate 287 (465 mg, 10% yield) as a white solid.

[0680] Preparation of Intermediate 303

[0681] [ka]

[0682] To a stirred solution of Intermediate 3 (15 g, 60.900 mmol) in methanol (300 mL) was added Intermediate 36 (13.61 g, 73.080 mmol) and acetic acid (4.02 g, 66.990 mmol). After stirring at room temperature for 0.5 h, sodium cyanoborohydride (7.65 g, 121.800 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 solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (EA / PE, 0% EA to 50%) to give 17.8 g (69% yield) of the desired compound as a pale yellow oil.

[0683] Preparation of Intermediates 304 and 305

[0684] [ka]

[0685] 170 g of benzyl 2-(1-(3,3-dimethoxycyclobutyl)-2-methylpropyl)-2,6-diazaspiro[3.4]octane-6-carboxylate 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 to give two fractions.

[0686] Fraction A: 67.0 g (39% yield, retention time 1:5.88 min) of intermediate 304 was obtained as a pale yellow oil.

[0687] Fraction B: 65 g (38% yield, retention time 2:4.45 min) of intermediate 305 as a pale yellow oil.

[0688] Preparation of Intermediate 306

[0689] [ka]

[0690] To a solution of intermediate 304 (15 g, 36.010 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 atmospheres) at room temperature for 5 hours. The mixture was diluted with methanol and filtered through Celite®. The filtrate was evaporated under reduced pressure to give 9.5 g of intermediate 306 as a yellow oil.

[0691] Preparation of Intermediate 307

[0692] [ka]

[0693] 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 306 (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 under nitrogen for 3 hours, 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) of Intermediate 307 as a yellow solid.

[0694] Preparation of Intermediate 308

[0695] [ka]

[0696] To a solution of 4-bromo-5-chloro-2-methylpyridine (8.8 g, 42.62 mmol) in tetrahydrofuran (90 mL) was added tetrakis(triphenylphosphine)palladium (2.5 g, 2.13 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour, and then cyclopropylzinc(II) bromide (340 mL, 0.5 M in THF) was added. After stirring at 65° C. for 2 hours under a nitrogen atmosphere, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified on 100 g of silica gel (eluent: petroleum ether-ethyl acetate 75%:25%) to give 7.2 g (97% yield) of intermediate 308 as a yellow solid.

[0697] Preparation of Intermediate 309

[0698] [ka]

[0699] To a stirred solution of intermediate 308 (7.2 g, 42.95 mmol) in 1,4-dioxane (216 mL) was added (5-fluoro-2-hydroxyphenyl)boronic acid (8.0 g, 51.54 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (1.5 g, 2.15 mmol), and aqueous sodium carbonate (2 M in water, 72 mL). After stirring at 100 °C under a nitrogen atmosphere for 3 hours, the reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified on 100 g of silica gel (eluent: petroleum ether-ethyl acetate 70%:30%) to give 5.8 g (54% yield) of intermediate 309 as a yellow solid.

[0700] Preparation of Intermediate 310

[0701] [ka]

[0702] To a solution of intermediate 307 (4.3 g, 9.87 mmol) in tetrahydrofuran (80 mL) was added intermediate 309 (3.0 g, 12.33 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.9 g, 25.90 mmol). After stirring at room temperature for 3 days, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified on 100 g of silica gel (eluent: petroleum ether-ethyl acetate 34%:66%) to give 5.0 g (64% yield) of intermediate 310 as a green solid.

[0703] Preparation of intermediate 311

[0704] [ka]

[0705] To a solution of intermediate 310 (5.3 g, 8.32 mmol) in tetrahydrofuran (100 mL) under a nitrogen atmosphere, sodium borohydride (535 mg, 14.14 mmol), N,N,N',N'-tetramethylethylenediamine (1.6 g, 14.14 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (680 mg, 0.83 mmol) were added. After stirring overnight at room temperature under a nitrogen atmosphere, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified on 100 g of silica gel (eluent: dichloromethane-methanol 93%:7%) to give 4.9 g (88% yield) of intermediate 311 as a brown solid.

[0706] Preparation of Intermediate 312

[0707] [ka]

[0708] To a solution of intermediate 311 (4.9 g, 8.13 mmol) in acetone (80 mL) was added p-toluenesulfonic acid (7.0 g, 40.65 mmol) and water (40 mL). The resulting mixture was stirred at 65 °C overnight. After cooling to room temperature, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (100 g, eluent: dichloromethane-methanol 98%:2%) to give 4.2 g (88% purity as assessed by LCMS, 81% yield) of intermediate 312 as a yellow solid.

[0709] Preparation of intermediate 313

[0710] [ka]

[0711] To a solution of 3-bromo-2-chloro-5-methylpyridine (16.0 g, 79.55 mmol) in tetrahydrofuran (160 mL) was added cyclopropylzinc(II) bromide (350.0 mL, 175.000 mmol, 0.5 M in THF) and tetrakis(triphenylphosphine)palladium (4.6 g, 3.98 mmol). After stirring at 65 °C under a nitrogen atmosphere for 10 hours, the reaction mixture was quenched with 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 flash chromatography on 320 g of silica gel (eluent: petroleum ether-ethyl acetate / 0% to 10%) to afford 12 g of intermediate 313 as a colorless oil (82.8% purity, 75% yield, as assessed by LC / MS).

[0712] Preparation of Intermediate 314

[0713] [ka]

[0714] To a solution of intermediate 313 (15.0 g, 89.48 mmol) in 1,4-dioxane (420 mL) and water (140 mL) was added 5-fluoro-2-hydroxyphenylboronic acid (16.74 g, 107.4 mmol), sodium carbonate (28.45 g, 268.44 mmol), and tetrakis(triphenylphosphine)palladium(0) (10.34 g, 8.95 mmol). The resulting mixture was stirred under nitrogen at 100 °C for 18 hours. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. The solids were filtered off. The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography on 320 g of silica gel (eluent: petroleum ether-ethyl acetate / 0% to 100%) to give the crude product. The crude product was triturated in ethyl acetate / petroleum ether in a ratio of 1:10 to give 18.0 g (82% yield) of intermediate 314 as an off-white solid.

[0715] Preparation of Intermediate 315

[0716] [ka]

[0717] To a solution of intermediate 307 (13.0 g, 30.21 mmol) in tetrahydrofuran (400 mL) was added intermediate 314 (8.8 g, 36.25 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (11.0 mL, 75.52 mmol). After stirring at room temperature for 3 days, the reaction mixture was quenched with water and then extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over sodium sulfate. The solids were filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on 100 g of silica gel (eluent: petroleum ether-ethyl acetate / 0% to 100%) to give two fractions of intermediate 315.

[0718] Fraction A: 8.89 g (97.5% purity as assessed by LCMS; 45% yield) as a white solid.

[0719] Fraction B: 2.5 g (88.7% purity, 11% yield) as a yellow solid.

[0720] Preparation of Intermediate 316

[0721] [ka]

[0722] To a solution of intermediate 315 (7.89 g, 12.38 mmol) in tetrahydrofuran (160.0 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (506 mg, 0.62 mmol), sodium borohydride (796 mg, 21.05 mmol), and N,N,N',N'-tetramethylethylenediamine (3.2 mL, 21.05 mmol). After stirring overnight at room temperature under a nitrogen atmosphere, the reaction mixture was quenched with water and then extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on 120 g of silica gel (eluent: petroleum ether-ethyl acetate: 0% to 100%) to give 6.0 g (81% yield) of intermediate 316 as a yellow solid.

[0723] Preparation of Intermediate 317

[0724] [ka]

[0725] To a solution of intermediate 316 (5.4 g, 8.96 mmol) in dichloromethane (26.0 mL) was added trifluoroacetic acid (78.0 mL) at 0° C. The resulting mixture was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure. The residue was quenched with saturated sodium bicarbonate solution and then extracted three times with dichloromethane. The organic layers were combined, washed with brine, and dried over sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure to give 4.0 g (80% yield) of intermediate 317 as a yellow solid.

[0726] Preparation of Intermediate 318

[0727] [ka]

[0728] Acetic anhydride (375 mg, 3.67 mmol) was added to a solution of (trans)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (750 mg, 2.48 mmol), EtN (1.0 g, 9.9 mmol), and DCM (20 mL). The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was partitioned between HO (30 mL) and DCM (30 mL). The aqueous phase was extracted with DCM (20 mL × 3), and the combined extracts were dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure to give 600 mg (95% yield) of intermediate 318 (mixture of trans isomers) as a yellow solid.

[0729] Preparation of Intermediate 319

[0730] [ka]

[0731] TFA (1.3 mL, 18 mmol) was added to a solution of intermediate 318 (600 mg, 2.36 mmol) in DCM (15 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure to give the crude product as a yellow oil, which was dissolved in water (20 mL). The pH of the mixture was adjusted to 10 with NH3·H2O and then lyophilized to give 500 mg (crude) of intermediate 319 (trans mixture) as a yellow solid, which was used in the next step without further purification.

[0732] Preparation of Intermediate 320

[0733] [ka]

[0734] A stir bar, 5-bromo-2-methylpyrimidine (36.0 g, 208 mmol), and dry tetrahydrofuran (250 mL) were added to a 2 L three-necked round-bottom flask. The mixture was then cooled to 0 °C in an ice-water bath and purged with nitrogen three times. Cyclopropylmagnesium bromide (500 mL, 250 mmol, 0.5 M in THF) was then added dropwise over 2 h. The reaction mixture was gradually warmed to room temperature and stirred at room temperature for 1.5 h. The mixture was again cooled to 0 °C in an ice-water bath. A solution of DDQ (47.2 g, 208 mmol) in dry tetrahydrofuran (250 mL) was added dropwise to the mixture over 1.5 h. The reaction mixture was gradually warmed to room temperature and stirred at room temperature for an additional 16 h. 400 mL of EtOAc and 50 mL of saturated NH4Cl were added to the reaction mixture and stirred for 0.5 h. The reaction mixture was filtered through Celite® and washed with EtOAc (100 mL × 3). The organic phase was concentrated under reduced pressure. The residue was purified by FCC (eluent: petroleum ether: ethyl acetate = 1:0 to 20:1) to give 24.31 g (yield 55%) of intermediate 320 as a yellow oil.

[0735] Preparation of Intermediate 321

[0736] [ka]

[0737] Pd(dppf)Cl (4.17 g, 5.70 mmol) was added to a mixture of intermediate 320 (24.3 g, 114 mmol), 5-fluoro-2-hydroxyphenyl)boronic acid (21.3 g, 137 mmol), and NaCO (24.18 g, 228 mmol) in dioxane (300 mL) and HO (60 mL). The mixture was stirred at 90 °C for 16 hours under an inert atmosphere. The reaction mixture was cooled to room temperature, filtered through a pad of Celite®, and washed with EtOAc (50 mL × 2). The filtrate was concentrated in vacuo, and the residue was dissolved in EtOAc (300 mL). The mixture was washed with brine (50 mL × 3), dried over NaSO, filtered, and concentrated in vacuo. The residue was dissolved in EtOAc (30 mL), stirred for 30 minutes, filtered, and washed with EtOAc (10 mL × 2). The filter cake was collected and dried to give 22.3 g (78% yield) of intermediate 321 as a pale solid.

[0738] Preparation of Intermediate 322

[0739] [ka]

[0740] DBU (2.94 g, 19.3 mmol) was added to a solution of Intermediate 307 (7.0 g, 16.3 mmol) and Intermediate 321 (3.98 g, 16.3 mmol) in THF (200 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between HO (200 mL) and ethyl acetate (200 mL). The aqueous phase was extracted with ethyl acetate (200 mL x 3). The combined extracts were dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure to give the crude product. This was mixed with another portion of the crude product (2 g) and purified by FCC (petroleum ether:ethyl acetate = 1:0 to 0:1) to give 7.0 g of Intermediate 322 (53% overall yield based on 8 g of Intermediate 307) as a yellow solid.

[0741] Preparation of Intermediate 323

[0742] [ka]

[0743] Pd(dppf)Cl·DCM (540 mg, 0.661 mmol) was added to a solution of intermediate 322 (6.0 g, 9.4 mmol), NaBH (620 mg, 16.4 mmol), TMEDA (2.1 g, 18 mmol), and THF (150 mL) under N. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was partitioned between HO (300 mL) and ethyl acetate (200 mL). The aqueous phase was extracted with ethyl acetate (150 mL × 3). The combined extracts were dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure to give the crude product, which was mixed with another crude product (1.2 g) and purified by FCC (petroleum ether:ethyl acetate = 1:0 to 0:1) to give 4.5 g (66% overall yield from 7 g of intermediate 322) of intermediate 323 as a yellow solid.

[0744] Preparation of Intermediate 324

[0745] [ka]

[0746] TFA (9.6 mL, 129 mmol) was added to a solution of intermediate 323 (4.0 g, 6.6 mmol) in DCM (100 mL). The reaction mixture was stirred at room temperature for 4 hours. The mixture was poured into 10% aqueous KCO solution (300 mL) and extracted with dichloromethane (200 mL × 3). The combined organic extracts were washed with brine (300 mL), aqueous NaHCO (300 mL), HO (300 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure to give 3.3 g (84% yield) of intermediate 324 as a yellow solid, which was used in the next step without further purification.

[0747] Preparation of Intermediate 325

[0748] [ka]

[0749] To a solution of 4-bromo-6-methylpyridazin-3(2H)-one (5.00 g, 26.45 mmol) in tetrahydrofuran (100 mL) were added 3,4-dihydro-2H-pyran (9.65 mL, 105.82 mmol) and p-toluenesulfonic acid (455 mg, 2.65 mmol). The resulting mixture was stirred at 70 °C overnight. The reaction was quenched with water and then extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel column chromatography (EA / PE, 0% EA to 20% EA) to give 4.2 g of intermediate 325 (52% yield, 89.2% purity based on LCMS) as a yellow solid.

[0750] Preparation of Intermediate 326

[0751] [ka]

[0752] To a solution of intermediate 325 (8.30 g, 24.62 mmol; 81% purity based on LCMS) in 1,4-dioxane (120 mL) was added cyclopropylboronic acid (2.33 g, 27.08 mmol), Pd(amphos)Cl (871 mg, 1.23 mmol), and sodium carbonate (40 mL, 2 M in water, 80.00 mmol). The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel column chromatography (EA / PE, 0% EA to 13% EA) to give 3.4 g of intermediate 326 (50% yield, 84.7% purity based on LCMS) as a yellow oil.

[0753] Preparation of Intermediate 327

[0754] [ka]

[0755] To a solution of intermediate 326 (2.40 g, 8.61 mmol, 84.7% purity based on LCMS) in dichloromethane (30 mL) was added trifluoroacetic acid (10 mL). The resulting mixture was stirred at 50° C. for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water and adjusted to pH=7 with ammonium hydroxide (33% in water). The mixture was extracted five times with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 870 mg (58% yield) of intermediate 327 as a yellow solid.

[0756] Preparation of Intermediate 328

[0757] [ka]

[0758] To a solution of intermediate 327 (2.46 g, 16.38 mmol) in acetonitrile (50 mL) was added POCl (7.6 mL, 81.90 mmol). After stirring at 50 °C overnight, the reaction solution was slowly poured into ice water. The resulting solution was adjusted to pH = 7 with NaOH solution (2 M in water) and extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried over Na SO . The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (EA / PE, 0% EA to 30% EA) to give 2.1 g of intermediate 328 as a yellow oil.

[0759] Preparation of Intermediate 329

[0760] [ka]

[0761] A mixture of intermediate 328 (5.0 g, 29.65 mmol), 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (7.06 g, 29.65 mmol), and Pd(PPh) (1.71 g, 1.48 mmol) in 1,4-dioxane (75 mL) was stirred with sodium carbonate solution (25 mL, 2 M in water, 50.00 mmol) at 90 °C for 3 h. After cooling to room temperature, the reaction solution was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried over NaSO. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (EA / PE, 0% EA to 60% EA) to give 6.0 g of intermediate 329 as a yellow solid.

[0762] Preparation of Intermediate 330

[0763] [ka]

[0764] To a solution of intermediate 307 (8 g, 18.6 mmol) in tetrahydrofuran (200 mL) was added intermediate 329 (5.45 g, 22.31 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (6.94 mL, 46.47 mmol). The resulting mixture was stirred at room temperature over the weekend. The reaction was quenched with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel column chromatography (EA / PE, 0% EA to 90% EA) to give 7.56 g of intermediate 330 (62% yield) as a yellow solid.

[0765] Preparation of Intermediate 331

[0766] [ka]

[0767] To a solution of intermediate 330 (7.26 g, 10.92 mmol) in THF (140 mL) was added Pd(dppf)Cl (446 mg, 0.55 mmol), NaBH (702 mg, 18.57 mmol), and TMEDA (2.78 mL, 18.57 mmol). After stirring overnight at room temperature under a nitrogen atmosphere, the reaction was quenched with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (EA / PE, 0% EA to 91% EA) to give 416 mg of intermediate 331 (65% yield) as a yellow solid.

[0768] Preparation of Intermediate 332

[0769] [ka]

[0770] To a solution of intermediate 331 (500 mg, 0.75 mmol) in acetone (7.5 mL) and water (2.5 mL) was added TsOH (649 mg, 3.77 mmol). After stirring at 65° C. overnight, the reaction was quenched with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 480 mg of intermediate 332 (98% yield) as a brown solid.

[0771] Preparation of intermediate 333

[0772] [ka]

[0773] Intermediate 283 (2.7 g, 6.58 mmol), 3,5,6-trichloro-1,2,4-triazine (1.21 g, 6.56 mmol) in DCM (100 mL) was stirred at 25 °C for 10 min, and TEA (2.74 mL, 19.7 mmol) was added. The mixture was stirred at 25 °C for 10 h. The mixture was poured into water (100 mL × 2) and extracted with dichloromethane (50 mL × 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by FCC (eluent: dichloromethane:methanol = 1:0 to 10:1) to give Intermediate 333 as a yellow solid (3.32 g, 81.7% yield).

[0774] Preparation of Intermediate 336

[0775] [ka]

[0776] A solution of intermediate 5 (9.91 g, 38.364 mmol) in anhydrous THF (191.8 mL) was cooled to 0 °C. 3.4 M MeMgBr in THF (25.952 mL, 3.4 M, 88.236 mmol) was slowly added. Upon complete addition, the reaction was allowed to warm to room temperature and stirred over the weekend. The reaction was quenched by adding saturated ammonium chloride solution. The aqueous phase was extracted several times with diethyl ether. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated to give the crude material (8 g, 97.775% yield). The material was purified by FCC (silica gel, 10% to 30% EA in n-heptane) to give compound 336 (1.16 g, 14.2% yield) as a white powder.

[0777] Preparation of Intermediate 338

[0778] [ka]

[0779] 2-Chloro-1,3-thiazole-5-carboxylic acid (0.5 g, 3.057 mmol) was dissolved in EtOAc (5.2 mL) and treated with T3P 50% and acetohydrazide (226 mg, 3.057 mmol) in EtOAc (4.41 mL). The resulting solution was stirred at 70 °C over the weekend. The reaction mixture was hydrolyzed and extracted with ethyl acetate (3x). The combined organic phases were washed with brine. Volatile components were removed on a rotary evaporator. The material was analyzed by HPLC and NMR, showing intermediate 338 (240 mg, 39% yield) containing T3P impurity. This material was used without further purification.

[0780] Preparation of Intermediate 339

[0781] [ka]

[0782] tBuXPhos Pd G3 (36.5 mg, 0.046 mmol) was added to a solution of compound 1a (250 mg, 0.459 mmol), 5-chloro-1-(4-methoxybenzyl)-1,8-naphthyridin-2(1H)-one (262 mg, 0.871 mmol), and NaOtBu (132 mg, 1.37 mmol) in 1,4-dioxane (8 mL) under an argon atmosphere. The mixture was stirred at 100 °C for 1 h under microwave irradiation. The mixture was cooled to room temperature, diluted with dichloromethane (20 mL), and washed with HO (10 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluent: dichloromethane:methanol = 1:0 to 10:1) to give intermediate 339 (180 mg, yield 37.06%) as a yellow oil.

[0783] Preparation of Intermediate 340 (1-(benzyloxy)-4-fluoro-2-nitrobenzene):

[0784] [ka]

[0785] To a solution of 4-fluoro-2-nitro (5 g, 31.827 mmol) and Cs2CO3 (20.74 g, 63.653 mmol) in DMF (50 mL) was added benzyl bromide (4 mL, 33.418 mmol) at room temperature for 6 h.

[0786] Upon completion (TLC), the reaction mixture was diluted with EtOAc (100 mL) and washed with water (200 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (0 to 10% EtOAc in heptane) to afford intermediate 340 (1-(benzyloxy)-4-fluoro-2-nitrobenzene) (7.85 g, 99% yield) as a thick yellow oil.

[0787] Preparation of intermediate 341 (2-benzyloxy-5-fluoro-aniline):

[0788] [ka]

[0789] To a mixture of intermediate 340 (1 g, 4.045 mmol) and NH4Cl (2.15 g, 40.196 mmol) in EtOH (30 mL) was added zinc powder (2.63 g, 40.208 mmol) at ambient temperature, and the mixture was then heated to 50°C overnight. The mixture was diluted with EtOAc, filtered through a pad of Celite®, and the solvent was removed under reduced pressure. The residue was partitioned between EtOAc (50 mL) and water. The aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with water, brine, dried over anhydrous MgSO4, and rotary evaporated to give intermediate 340 (2-benzyloxy-5-fluoro-aniline) (875 mg, 99% yield) as a brown oil.

[0790] Preparation of Intermediate 342 (N-(2-benzyloxy-5-fluoro-phenyl)cyclopropanecarboxamide):

[0791] [ka]

[0792] To a solution of intermediate 341 (2-benzyloxy-5-fluoro-aniline) (1.37 g, 6.306 mmol) and EtN (2.64 mL, 19.92 mmol) in anhydrous dichloromethane (20 mL) was added 0° cyclopropanecarbonyl chloride (0.7 mL, 7.57 mmol) and the reaction mixture was stirred at room temperature for 1 hour.

[0793] Upon completion (TLC), the reaction mixture was diluted with dichloromethane (100 mL) and washed with water (100 mL). The aqueous layer was extracted with dichloromethane (30 mL × 2), and the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (0 to 60% EtOAc in heptane) to afford intermediate 342 (N-(2-benzyloxy-5-fluoro-phenyl)cyclopropanecarboxamide) (1.55 g, 86% yield) as a colorless solid.

[0794] Preparation of Intermediate 343 (N-(2-benzyloxy-5-fluoro-phenyl)cyclopropanecarbothioamide):

[0795] [ka]

[0796] To a solution of intermediate 342 (N-(2-benzyloxy-5-fluoro-phenyl)cyclopropanecarboxamide) (1 g, 3.505 mmol) in 1,4-dioxane (30 mL) was added Lawesson's reagent (0.8 g, 1.963 mmol), and the resulting mixture was heated to 100° C. for 6 h. The reaction mixture was then concentrated in vacuo, and the residue was purified by flash column chromatography (0 to 15% EtOAc in heptane) to afford intermediate 343 (N-(2-benzyloxy-5-fluoro-phenyl)cyclopropanecarbothioamide) (0.815 g, 77%) as a pale yellow solid.

[0797] Preparation of intermediate 344 (4-(2-benzyloxy-5-fluoro-phenyl)-3-cyclopropyl-5-methyl-1,2,4 triazole):

[0798] [ka]

[0799] Hydrazine hydrate (0.28 mL, 2.883 mmol) was added dropwise to a stirred solution of intermediate 343 (N-(2-benzyloxy-5-fluoro-phenyl)cyclopropanecarbothioamide) (790 mg, 2.622 mmol) in THF (20 mL) at ambient temperature. After 60 min, the solution was concentrated under reduced pressure and the residue was treated with triethyl orthoacetate (5 mL). The mixture was heated at 80° C. for 30 min, cooled to ambient temperature, and concentrated under reduced pressure. The residue was treated with ice-cold dilute aqueous ammonia (15 mL), water (25 mL), and extracted with EtOAc (70 mL×3). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and rotary evaporated. The residue was purified by flash column chromatography (0 to 100% EtOAc in heptane) to give intermediate 344 (4-(2-benzyloxy-5-fluoro-phenyl)-3-cyclopropyl-5-methyl-1,2,4-triazole) (530 mg, 62% yield) as a cream-colored fluffy solid.

[0800] Preparation of Intermediate 345 (2-(3-cyclopropyl-5-methyl-1,2,4-triazol-4-yl)-4-fluorophenol):

[0801] [ka]

[0802] Pd / C (10%) (27 mg) was added to a solution of intermediate 344 (4-(2-benzyloxy-5-fluoro-phenyl)-3-cyclopropyl-5-methyl-1,2,4-triazole) (200 mg, 0.62 mmol) in methanol (50 mL) and maintained for hydrogenation at ambient temperature overnight. Upon completion (TLC), the catalyst was filtered off through a Celite® bed, washed several times with MeOH, and the combined organic layers were concentrated in vacuo to give intermediate 345 (2-(3-cyclopropyl-5-methyl-1,2,4-triazol-4-yl)-4-fluorophenol) (135 mg, 93% yield) as a colorless solid.

[0803] Preparation of intermediate 346 (7-[3-chloro-6-[2-(3-cyclopropyl-5-methyl-1,2,4-triazol-4-yl)-4-fluoro-phenoxy]-1,2,4-triazin-5-yl]-2-[(1R)-1-(3,3-dimethoxycyclobutyl)-2-methyl-propyl]-2,7-diazaspiro[3.4]octane):

[0804] [ka]

[0805] A mixture of intermediate 307 (130 mg, 0.3 mmol), intermediate 345 (2-(3-cyclopropyl-5-methyl-1,2,4-triazol-4-yl)-4-fluorophenol) (70 mg, 0.3 mmol), and DBU (0.225 mL, 1.5 mmol) in THF (4 mL) was stirred at room temperature for 48 h. Upon completion, the reaction mixture was diluted with EtOAc (30 mL) and washed with water. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with water, brine, dried over anhydrous MgSO4, and rotary evaporated. The crude compound was purified by flash column chromatography (0 to 70% n-heptane in EtOAc) to give intermediate 346 (60 mg, 31% yield) as a colorless oil.

[0806] Preparation of intermediate 347 (7-[6-[2-(3-cyclopropyl-5-methyl-1,2,4-triazol-4-yl)-4-fluoro-phenoxy]-1,2,4-triazin-5-yl]-2-[(1R)-1-(3,3-dimethoxycyclobutyl)-2-methyl-propyl]-2,7-diazaspiro[3.4]octane):

[0807] [ka]

[0808] A solution of intermediate 346 (60 mg, 0.0957 mmol) and N,N,N',N'-tetramethylethylenediamine (50 μL, 0.335 mmol) in THF (10 mL) was degassed for 5 min, then Pd(dppf)Cl.DCM (12 mg, 0.0144 mmol) and NaBH (26 mg, 0.67 mmol) were added. The mixture was purged with nitrogen (three times) and stirred at room temperature for 18 h. The reaction mixture was quenched with a 10% aqueous solution of KCO and then extracted with dichloromethane (3 × 25 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO, filtered, evaporated in vacuo, and purified by flash column chromatography (0 to 3% MeOH in dichloromethane as eluent) to give intermediate 347 (30 mg, 52% yield) as a colorless fluffy solid as a mixture of atropisomers.

[0809] Preparation of intermediate 348 (3-[(1R)-1-[7-[6-[2-(3-cyclopropyl-5-methyl-1,2,4-triazol-4-yl)-4-fluoro-phenoxy]-1,2,4-triazin-5-yl]-2,7-diazaspiro[3.4]octan-2-yl]-2-methyl-propyl]cyclobutanone):

[0810] [ka]

[0811] To a solution of intermediate 347 (252 mg, 0.425 mmol) in anhydrous dichloromethane (3 mL) was added TFA (0.65 mL, 8.5 mmol), and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was then diluted with dichloromethane. The organic layer was saturated with NaHCO3, then dried over MgSO4, filtered, and evaporated in vacuo to give intermediate 348 (233 mg) as a cream-colored fluffy solid as a mixture of atropisomers.

[0812] Preparation of intermediate 349 (5-cyclopropyl-3-methyl-isoxazole):

[0813] [ka]

[0814] A mixture of 1-cyclopropylbutane-1,3-dione (5 g, 39.634 mmol), NHOH.HCl (3.31 g, 47.56 mmol) in EtOH was heated at 130 °C for 5 min under microwave irradiation. Water (25 mL) was added to the mixture, which was then extracted with EtOAc (3 times). The organic layer was separated, dried over anhydrous MgSO and concentrated in vacuo. The residue was subjected to flash column purification (0 to 90% EtOAc in heptane as eluent) to give 5-cyclopropyl-3-methyl-isoxazole (2.4 g, 44%) as the major regioisomer. The mixture of regioisomers was used in the next step without separation.

[0815] Preparation of intermediate 350 (4-bromo-5-cyclopropyl-3-methyl-isoxazole):

[0816] [ka]

[0817] N-Bromosuccinimide (1.532 g, 8.607 mmol) was added to a solution of Intermediate 349 (0.5 g, 4.06 mmol) in DMF (8 mL) and stirred at room temperature for 4 hours.

[0818] Upon completion (LCMS), water was added to the reaction mixture and extracted with diethyl ether (3 x 25 mL). The combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated in vacuo. The residue was subjected to flash column purification (0 to 90% EtOAc in heptane as eluent) to afford intermediate 350 as the major regioisomer 600 mg, 73%).

[0819] Preparation of intermediate 351 (5-cyclopropyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole):

[0820] [ka]

[0821] Intermediate 350 (6 g, 29.696 mmol) was dissolved in THF (250 mL) and cooled to −78° C. under N. n-BuLi (2.5 M in hexanes) (17.8 mL, 2.5 M, 44.5 mmol) was slowly added to the solution, which was then stirred at −78° C. for 30 minutes. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxoborolane (7.27 mL, 35.635 mmol) was added to the reaction mixture, which was stirred at −78° C. for an additional 2 hours, then warmed to room temperature and stirred overnight. The reaction was quenched by adding saturated NH4Cl solution. The mixture was then extracted with EtOAc, washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (0 to 5% EtOAc in heptane as eluent) to afford intermediate 51 (5 g, 67%) as a mixture of regioisomers.

[0822] Preparation of intermediate 352 (5-cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-3-methyl-isoxazole):

[0823] [ka]

[0824] To a solution of intermediate 351 (1.823 g, 7.316 mmol) and 2-bromo-4-fluoro-1-methoxy-benzene (1 g, 4.877 mmol) in dioxane (250 mL), saturated NaHCO (50 mL) was added, and the mixture was degassed for 10 minutes. To this was added [PhP]Pd (1.127 g, 0.975 mmol), and the reaction mixture was stirred at 60 °C for 2 hours. Dichloromethane and water were added to the mixture, and the layers were separated. The aqueous layer was washed with dichloromethane (2x). The combined organic layers were washed with brine, dried over MgSO, filtered, and evaporated in vacuo. The residue was purified by flash column chromatography (0 to 70% EtOAc in heptane as eluent) to give 5-cyclopropyl-4-(5-fluoro-2-methoxy-phenyl)-3-methyl-isoxazole (0.65 g, 53%).

[0825] Preparation of intermediate 353 (2-(5-cyclopropyl-3-methyl-isoxazol-4-yl)-4-fluoro-phenol):

[0826] [ka]

[0827] A solution of intermediate 352 (150 mg, 0.607 mmol) in dichloromethane (10 mL) was cooled to a temperature of 5-10 °C. Boron tribromide (169 μL, 1.82 mmol) was added dropwise thereto. The resulting reaction mixture was then stirred at 0 °C for 2.5 h. Water (10 mL) was added to the mixture, and the layers were separated. The aqueous layer was extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and evaporated in vacuo. The residue was purified by flash column chromatography (0 to 70% EtOAc in heptane as eluent) to give intermediate 353 (70 mg, 49%).

[0828] Preparation of intermediate 354 (4-[2-[[3-chloro-5-[2-[(1R)-1-(3,3-dimethoxycyclobutyl)-2-methyl-propyl]-2,7-diazaspiro[3.4]octan-7-yl]-1,2,4 triazin-6-yl]oxy]-5-fluorophenyl]-5-cyclopropyl-3-methyl-isoxazole)

[0829] [ka]

[0830] A mixture of intermediate 307 (700 mg, 1.626 mmol), intermediate 353 (392 mg, 1.678 mmol), and DBU (1.2 mL, 8.13 mmol) in THF (90 mL) was stirred at room temperature for 72 hours. Upon completion, the reaction mixture was diluted with dichloromethane (100 mL) and washed with water. The layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 50 mL). The combined organic layers were washed with water, brine, dried over anhydrous MgSO4, and rotary evaporated. The residue was purified by flash column chromatography (0 to 2% MeOH in dichloromethane) to give intermediate 354 (380 mg, 37% yield).

[0831] Preparation of intermediate 355 (5-cyclopropyl-4-[5-fluoro-2-[[5-[2-[(1 R)-1-(3,3-dimethoxycyclobutyl)-2-methyl-propyl]-2,7-diazaspiro[3.4]octan-7-yl]-1,2,4 triazin-6-yl]oxy]phenyl]-3-methyl-isoxazole)

[0832] [ka]

[0833] Pd / C (10%) (45 mg) was added to a solution of intermediate 354 (260 mg, 0.415 mmol) and thiophene (0.10 mL, 0.4 M, 0.041 mmol) in MeOH (50 mL) at ambient temperature, and the mixture was stirred under H (1 atm) for 1 h. Upon completion (LCMS), the mixture was filtered through dicalite and the solvent was evaporated in vacuo to give intermediate 355 (100 mg, 41%).

[0834] Preparation of intermediate 356 (3-[(1R)-1-[7-[6-[2-(5-cyclopropyl-3-methyl-isoxazol-4-yl)-4-fluoro-phenoxy]-1,2,4 triazin-5-yl]-2,7-diazaspiro[3.4]octan-2-yl]-2-methyl-propyl]cyclobutanone):

[0835] [ka]

[0836] To a solution of intermediate 355 (300 mg, 0.51 mmol) in anhydrous dichloromethane (30 mL) was added trifluoroacetic acid (0.775 mL, 10.123 mmol), and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was then diluted with dichloromethane. The organic layer was washed with a 10% aqueous solution of Na2CO3, then dried over anhydrous MgSO4, filtered, and evaporated in vacuo to give intermediate 356 in quantitative yield.

[0837] Preparation of compounds Compound 1:

[0838] [ka]

[0839] To a solution of compound 490 (250 mg, 0.388 mmol) in CHCl (3 mL) was added TFA (2.0 mL, 26 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h. The mixture was adjusted to pH = 13 with aqueous NaOH (2 M). The resulting mixture was then extracted with CHCl (10 mL × 2). The combined organic extracts were washed with brine (20 mL), dried over NaSO, filtered, and concentrated to dryness under reduced pressure to give compound 1 (185 mg, crude) as a yellow oil, which was used in the next step without further purification.

[0840] The compounds reported below were prepared following a method similar to that described for compound 1, starting from the corresponding intermediates:

[0841] [Table 21-1]

[0842] [Table 21-2]

[0843] [Table 21-3]

[0844] Alternative Preparation of Compound 1a and Compound 1b

[0845] [ka]

[0846] The reaction was carried out twice with 6 g of compound 490. The resulting crude mixtures were combined for workup and purification. To a solution of compound 490 (6 g, 9.4 mmol) in CHCl (150 mL) was added TFA (14 mL, 186 mmol) at 0° C. The mixture was stirred at room temperature for 18 hours. The mixture was adjusted to pH=13 with aqueous NaOH (2 M). The resulting mixture of both reactions was then extracted with CHCl (10 mL×2). The combined organic extracts were washed with brine (20 mL), dried over NaSO, filtered, and concentrated to dryness under reduced pressure. The residue (10.1 g) was purified by chiral SFC (stationary phase: Chiralpak IG 5 μm 250 * 30 mm, mobile phase: 60% CO, 40% mixture of EtOH / iPrOH / DCM 40 / 40 / 20 v / v / v (+3.0% iPrNH)). Pure fractions were collected and the solvent was evaporated under vacuum to give 3.8 g of compound 1a and 3.8 g of compound 1b.

[0847] Preparation of Compound 2:

[0848] [ka]

[0849] To a solution of compound 1 (150 mg, crude) and acetic acid (36 μL, 0.63 mmol) in CHCl (5 mL) was added TP (403 mg, 0.633 mmol, 50% purity) and DIEA (147 μL, 0.828 mmol). The mixture was stirred at 20 °C for 12 h. The mixture was diluted with CHCl (20 mL). The mixture was washed with saturated NaHCO (10 mL), brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: ACE 5 C18-AR 150 * 30mm * The eluate was purified using a 5 μm column, mobile phase A: water (10 mM NH4HCO3)-ACN, mobile phase B: acetonitrile, flow rate: 30 mL / min, gradient conditions: 25% B to 55% B. Pure fractions were collected, and the solvent was evaporated under vacuum to give a residue, which was partitioned between acetonitrile (2 mL) and water (8 mL). The solution was lyophilized to dryness to give compound 2 (60.0 mg) as a white powder.

[0850] 1 H NMRCDCl3(Varian_400MHz):δ8.93(br.s.,1H),8.46(s,1H),8.40(br.s.,1H),7.49- 7.31(m,1H),7.26-7.18(m,1H),7.16-7.08(m,1H),6.02(br.s.,0.2H),5.60(br.s.,0 .6H),4.26-4.12(m,1H),3.80-3.42(m,4H),3.19-2.99(m,3H),2.52-2.35(m,2H),2. 08-1.98(m,3H),1.94(s,3H),1.89-1.55(m,6H),1.19-0.94(m,3H),0.92-0.62(m,7H) 19 F NMR(376MHz,CDCl3):-115.85(s,1F)

[0851] The compounds reported below were prepared following a method similar to that described for compound 2 starting from compound 1:

[0852] [Table 22]

[0853] Preparation of compound 2a:

[0854] [ka]

[0855] The reaction was carried out twice on 1.7 g of compound 1a, and the resulting crude mixtures were combined for workup and purification. To a solution of compound 1a (1.7 g, 3.12 mmol) and acetic acid (0.4 mL, 7.1 mmol) in DCM (25 mL) was added T3P (4.3 mL, 7.2 mmol, 50% purity) and DIEA (1.7 mL, 9.4 mmol). The mixture was stirred at 20 °C for 12 h. The mixture was diluted with DCM. The combined mixture of both reactions was washed with saturated NaHCO3, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: gradient from 0.1% NH4OH, 5% MeOH, 95% DCM to 0.1% NH4OH, 8% MeOH, 92% DCM). Pure fractions were collected, and the solvent was evaporated under vacuum to give a residue that was partitioned between acetonitrile (2 mL) and water (8 mL). The solution was lyophilized to give compound 2a (1.69; 46%) as a white powder.

[0856] 1 H NMR(500MHz,DMSO-d6)δppm8.80-9.02(m,1H),8.41(brs,2H),7.98(brd,J=7.2H z,1H),7.52-7.63(m,1H),7.39-7.50(m,2H),3.95(dq,J=16.2,8.2Hz,1H),3.37- 3.83(m,4H),3.05(brs,3H),2.84-2.99(m,1H),2.13-2.31(m,2H),1.89-2.03(m, 3H),1.78-1.88(m,1H),1.65-1.77(m,5H),1.50-1.64(m,2H),0.61-1.18(m,10H)

[0857] Alternative preparation of compound 2a and compound 2b:

[0858] [ka]

[0859] Compound 2 (30 mg, 0.051 mmol) was purified by SFC (column: DAICEL CHIRALCEL OD-H (250 mm *The mixture was separated using a column chromatography column (30 mm, 5 μm), eluent: 0.1% NH3H2O, 30% (v / v) supercritical CO2 in EtOH, flow rate: 50 mL / min. The desired fractions were collected and the solvent was evaporated in vacuo. The residue was redissolved in ACN and water and lyophilized to give compound 2a (13 mg, 43% yield) and compound 2b (11 mg, 37% yield), both as white powders.

[0860] Preparation of Compound 303:

[0861] [ka]

[0862] To a solution of compound 1a (100 mg, 0.184 mmol) and cyclopropanecarboxylic acid (36.2 mg, 0.420 mmol) in DCM (5 mL) was added T3P (268 mg, 0.421 mmol, 50% in EtOAc) and DIEA (118 mg, 0.913 mmol). The resulting mixture was stirred at 25 °C for 12 h. The mixture was extracted with DCM (10 mL), HO (10 mL), and brine (10 mL). After drying over Na2SO4, the mixture was filtered, and the filtrate was 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 a 5 μm column, mobile phase A: water (0.04% NH3H2O ​​+ 10 mM NH4HCO3), mobile phase B: ACN, flow rate: 30 mL / min, gradient from 40% B to 70% B. The desired fractions were collected and lyophilized to give compound 303 (50 mg, 44% yield) as a white powder.

[0863] 1H NMRCDCl3(Bruker_400MHz):δ8.94(s,1H),8.46(s,1H),8.44-8.34(m,1H),7.39(s,1H), 7.26-7.18(m,1H),7.17-7.08(m,1H),6.31-5.68(m,1H),4.29-4.13(m,1H),3.82-3.30(m ,4H),3.26-2.91(m,4H),2.56-2.35(m,2H),2.20-1.93(m,4H),1.80-1.55(m,4H),1.36- 1.22(m,1H),1.20-1.03(m,2H),1.02-0.91(m,3H),0.91-0.79(m,7H),0.76-0.64(m,2H).

[0864] The compounds reported below were prepared starting from the appropriate starting material (e.g., compound 1a or other appropriate starting material) following methods analogous to those described for compound 2a or compound 303:

[0865] [Table 23-1]

[0866] [Table 23-2]

[0867] [Table 23-3]

[0868] [Table 23-4]

[0869] [Table 23-5]

[0870] Preparation of Compound 508

[0871] [ka]

[0872] To a solution of intermediate 14 (500 mg, 1.54 mmol) in DMF (0.1 mL) in DCM (30 mL) was added oxalyl dichloride (1.05 g, 8.27 mmol) at 0° C. under a N atmosphere. The mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure (below 35° C.) to give a residue. The residue was dissolved in DCM (30 mL), and TEA (5.0 mL, 35.9 mmol) was added at 0° C. under a N atmosphere. The mixture was stirred at 0° C. for 3 minutes. Intermediate 25 (600 mg, 1.55 mmol) in DCM (2 mL) was added dropwise at 0° C. under a N atmosphere. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (50 mL) and washed with HO (20 mL) and brine (20 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by FCC (PE: EtOAc = 1:3 to 0:1) to give compound 508 (260 mg, 18% yield) as a white solid.

[0873] Preparation of Compound 3

[0874] [ka]

[0875] To a solution of compound 508 (260 mg, 0.395 mmol) in dioxane (5 mL) was added 4 M HCl / dioxane (3.00 mL, 12 mmol). The mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated to give compound 3 (240 mg, crude HCl salt) as a light brown solid (without further purification).

[0876] Preparation of Compound 4:

[0877] [ka]

[0878] To a solution of intermediate 29 (370 mg, crude) in DCM (3 mL) was added 4 M HCl / dioxane (0.2 mL, 0.8 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated. The resulting residue was first purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 * 40mm * 10 μm, mobile phase A: water (10 mM NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions: 30% B to 80% B), followed by preparative HPLC (column: Boston Prime C18 150 * 30mm * The mixture was purified using a 5 μm column, mobile phase A: water (0.04% NH3H2O ​​+ 10 mM NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient from 55% B to 85% B. Pure fractions were collected and lyophilized to give compound 4 (8.00 mg, 2% yield) as a white powder.

[0879] 1 H NMRCDCl3(Bruker-400MHz):δ8.93(s,1H),8.46(s,1H),8.38(s,1H),7.38(s,1H),7.22(d,J=8.0Hz,1H),7.12(d,J=6.4Hz,1H),3.38-3.8 7(m,5H),2.93-3.27(m,6H),2.44(s,2H),2.01(d,J=7.2Hz,3H),1.33-1.91(m,11H),1.11(brs,2H),0.67-0.99(m,8H),0.30-0.40(m,2H)

[0880] Preparation of Compound 5:

[0881] [ka]

[0882] PyBrOP (108 mg, 0.232 mmol) was added to a solution of intermediate 14 (50 mg; 0.15 mmol), intermediate 28 (61 mg, 0.16 mmol), TEA (0.12 mL, 0.88 mmol), and DMF (0.5 mL). The reaction mixture was stirred at room temperature for 0.5 h. The mixture was purified by preparative high-performance liquid chromatography on a Phenomenex Gemini-NX 150 × 30 mm × 5 μm column (eluent: water (0.04% NH3H2O ​​+ 10 mM NH4HCO3) / ACN 65 / 35 to 41 / 59 v / v). Pure fractions were collected and lyophilized to dryness to completely remove solvent residues, yielding compound 5 (7.64 mg) as a white solid.

[0883] 1 H NMRCDCl3(Varian_400MHz):δ8.93(s,1H),8.46(s,1H),8.38(s,1H),7.37(br.s,1H),7.25-7.18( m,1H),7.15-7.09(m,1H),4.83-4.73(m,2H),4.40(t,J=6.4Hz,2H),3.75-3.42(m,4H),3.41-3.16( m,2H),3.16-3.03(m,3H),3.03-2.93(m,1H),2.81-2.73(m,2H),2.69-2.62(m,2H),2.05-1.99(m,2 H),1.88-1.76(m,4H),1.56-1.39(m,4H),1.37-1.28(m,1H),1.16-1.03(m,2H),0.98-0.63(m,8H).

[0884] Preparation of Compound 6:

[0885] [ka]

[0886] Sodium cyanoborohydride (30 mg; 0.477 mmol) was added to a mixture of intermediate 33 (100 mg; 0.238 mmol), intermediate 34 (107 mg; 0.477 mmol), and acetic acid (14 μL; 0.238 mmol) in MeOH (5 mL), and the reaction mixture was heated at 70° C. for 60 h. The reaction mixture was cooled to room temperature, diluted with DCM, and poured into a 10% aqueous solution of KCO. The organic layer was decanted, filtered through Chromabond®, and evaporated to dryness. The residue (190 mg) was purified by chromatography on silica gel (irregular SiOH, 4 g + 4 g; mobile phase: gradient from 0% NHOH, 0% MeOH, 100% DCM to 1% NHOH, 10% MeOH, 90% DCM). Pure fractions were collected and evaporated to dryness to give 54 mg of material which was lyophilized (10 mL; 20% ACN, 80% water) to give 52 mg (35% yield) of compound 6.

[0887] The compounds in the following table were prepared by SFC separation of compound 6.

[0888] [Table 24]

[0889] Preparation of Compound 7 and Compound 8:

[0890] [ka]

[0891] NaBHCN (139 mg; 2.21 mmol) was added to intermediate 38b ( *To a mixture of MeOH (30 mL) containing R) (600 mg; 1.1 mmol), dimethylamine solution (2.76 mL; 5.52 mmol; 2 M in THF), and AcOH (63 μL; 1.1 mmol) was added. The reaction mixture was then heated at 60° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with DCM, and poured into a 10% aqueous solution of K2CO3. The organic layer was extracted with DCM (3×), dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by chromatography on silica gel (mobile phase: gradient from 0% NH4OH, 0% MeOH, 100% DCM to 0.7% NH4OH, 7% MeOH, 93% DCM). Pure fractions were collected and evaporated to dryness. The residue (650 mg) was purified by achiral SFC (CHIRALPAK AD-H 5 μm 250 * Purification was carried out by HPLC at 30 mm, mobile phase: 82% CO, 18% EtOH (0.3% iPrNH). Pure fractions were collected and the solvent was evaporated to give 425 mg of compound 7 as a white foam and 62 mg of compound 8 as a colorless oil. Compound 7 was lyophilized with water-ACN to give 420 mg (66%) of the final compound as a white solid.

[0892] compound 7 1 H NMR(500MHz,DMSO-d6)δppm8.92(br,1H)8.41(brs,2H)7.57(brs,1H)7.46(brd,J=7.6Hz,2H)3.40-3.79(m,4H)2.89-3.14(m,4H) 2.27-2.38(m,1H)2.05(m,2H)1.97(s,9H)1.72-1.87(m,2H)1.61(m,2H)1.45(q,J=9.6Hz,1H)1.01(m,3H)0.82(brt,J=6.0Hz,7H)

[0893] The compounds reported below can be prepared from appropriate starting materials (e.g., intermediate 38( * R) or other appropriate starting material) following a method similar to that reported for the preparation of compound 7:

[0894] [Table 25-1]

[0895]

Table 25-2

[0896]

Table 26-1

[0897]

Table 26-2

[0898]

Table 26-3

[0899]

Table 26-4

[0900]

Table 26-5

[0901]

Table 26-6

[0902]

Table 26-7

[0903]

Table 26-8

[0904]

Table 26-9

[0905]

Table 26-10

[0906]

Table 26-11

[0907]

Table 26-12

[0908]

Table 26-13

[0909]

Table 26-14

[0910]

Table 26-15

[0911]

Table 26-16

[0912]

Table 26-17

[0913]

Table 26-18

[0914]

Table 26-19

[0915] The compounds reported below can be prepared from appropriate starting materials, e.g., intermediate 38a ( * S) or other appropriate starting material) according to a method similar to that reported for the preparation of compound 7:

[0916] [Table 27-1]

[0917] [Table 27-2]

[0918] [Table 27-3]

[0919] [Table 27-4]

[0920] [Table 27-5]

[0921] [Table 27-6]

[0922] [Table 27-7]

[0923] [Table 27-8]

[0924] [Table 27-9]

[0925] [Table 27-10]

[0926] [Table 27-11]

[0927] [Table 27-12]

[0928] The compounds reported below were prepared following methods similar to those reported for the preparation of compound 7, starting from the appropriate starting material (e.g., intermediate 38b or other appropriate starting material). Standard cleavage of protecting groups was applied, if necessary:

[0929] [Table 28-1]

[0930] [Table 28-2]

[0931] [Table 28-3]

[0932] [Table 28-4]

[0933] [Table 28-5]

[0934] [Table 28-6]

[0935] Preparation of Compound 331 and Compound 332:

[0936] [ka]

[0937] NaBHCN (433 mg, 6.89 mmol) was added to a solution of intermediate 249a (800 mg, 1.38 mmol), (S)-3-methoxypyrrolidine hydrochloride (418 mg, 4.13 mmol), MeOH (10 mL), and AcOH (0.237 mL). The mixture was stirred at 60 °C for 12 h. After cooling to room temperature, the mixture was adjusted to pH 8 with NH3HO and purified by preparative HPLC using a Phenomenex Gemini 150 mm × 25 mm × 10 μm column (eluent: 30%–60% (v / v) ACN and HO containing 0.05% NH3HO). The desired fractions were collected and lyophilized to give compound 331 (321 mg, 36% yield) and compound 332 (49 mg, 5% yield) as white solids.

[0938] Compound 331: 1 H NMRMethanol-d4(Varian_400MHz):δ9.01-8.85(m,1H),8.29(s,1H),7.63-7.47(m,1H),7.45-7.2 8(m,2H),7.21-7.07(m,1H),4.02-3.90(m,1H),3.88-3.68(m,2H),3.64-3.43(m,2H),3.29-3.16(m ,7H),2.81-2.70(m,1H),2.70-2.60(m,2H),2.60-2.53(m,1H),2.49-2.39(m,1H),2.26-2.13(m,3 H),2.11-1.96(m,4H),1.86-1.66(m,5H),1.08-0.98(m,2H),0.97-0.86(m,6H),0.83-0.75(m,2H).

[0939] Compound 332: 1 H NMRMethanol-d4(Varian_400MHz):δ9.00-8.87(m,1H),8.30(s,1H),7.60-7.48(m,1H),7.45 -7.32(m,2H),7.19-7.10(m,1H),4.03-3.92(m,1H),3.85-3.69(m,2H),3.67-3.57(m,1H),3.5 6-3.45(m,1H),3.30-3.14(m,7H),2.95-2.86(m,1H),2.81-2.53(m,4H),2.32-2.16(m,2H),2 .15-1.97(m,6H),1.89-1.66(m,4H),1.08-0.98(m,2H),0.96-0.85(m,6H),0.84-0.74(m,2H).

[0940] The compound reported below was prepared as intermediate 249a ( * S) were prepared following methods similar to those described for compounds 331 and 332:

[0941] [Table 29-1]

[0942] [Table 29-2]

[0943] [Table 29-3]

[0944] [Table 29-4]

[0945] [Table 29-5]

[0946] [Table 29-6]

[0947] The compound reported below was prepared as intermediate 249b ( * Prepared starting from (R) following a similar method as described for compound 331:

[0948] [Table 30-1]

[0949] [Table 30-2]

[0950] Preparation of Compound 9:

[0951] [ka]

[0952] NaBHCN (162 mg; 2.58 mmol) was added to intermediate 38b ( * To a mixture of (R) (700 mg; 1.288 mmol), 4-(methylsulfonyl)piperidine (1.05 g; 6.438 mmol), AcOH (74 μL; 1.3 mmol) in MeOH (41 mL) was added. The reaction mixture was then heated at 60° C. for 24 h. The reaction mixture was cooled to room temperature, diluted with DCM, and poured into a 10% aqueous solution of KCO. The organic layer was extracted with DCM (3×), dried over MgSO, filtered, and evaporated to dryness. The residue was purified by chromatography on silica gel (mobile phase: gradient from 0% NHOH, 0% MeOH, 100% DCM to 0.7% NHOH, 7% MeOH, 93% DCM). Pure fractions were collected and evaporated to dryness. The residue (684 mg) was lyophilized with water-ACN to give 655 mg (73%) of the final compound 9.

[0953] 1 H NMR(500MHz,DMSO-d6)δppm8.95(br,1H)8.41(brs,2H)7.57(brd,J=3.4Hz,1H)7.41-7.49(m,2H)3.39-3.79(m,4H)2.85-3.15(m,10 H)2.38-2.47(m,1H)2.02-2.16(m,2H)1.96(brd,J=9.8Hz,5H)1.80-1.89(m,1H)1.41-1.78(m,8H)1.00(m,3H)0.82(t,J=6.2Hz,7H)

[0954] Preparation of Compound 10 and Compound 33:

[0955] [ka] The piperidine moiety is one cis isomer (which cis is undetermined).

[0956] [ka] The piperidine moiety is one cis isomer (which cis is undetermined).

[0957] NaBHCN (40.7 mg; 0.65 mmol) was added to intermediate 38b ( * A mixture of cis-3-fluoropiperidin-4-ol (176.1 mg; 0.33 mmol), cis-3-fluoropiperidin-4-ol (201.6 mg; 1.30 mmol), and AcOH (19 μL; 0.32 mmol) in MeOH (15 mL) was added. The reaction mixture was then heated at 60° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with DCM, and poured into a 10% aqueous solution of K2CO3. The organic layer was extracted with DCM (3×), dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by chromatography on silica gel (mobile phase: gradient from 0% NH4OH, 0% MeOH, 100% DCM to 0.1% NH4OH, 12% MeOH, 88% DCM). Pure fractions were collected and evaporated to dryness. The residue (650 mg) was purified by achiral SFC (CHIRALPAK AD-H 5 μm 250 *The mixture was purified by HPLC at 30 mm, mobile phase: 80% CO, 20% EtOH (0.3% iPrNH). Pure fractions were collected and the solvent was evaporated. After lyophilization with a mixture of water-ACN, 29 mg (14%) of compound 10 and 25 mg (12%) of compound 33 were obtained.

[0958] Compound 10: 1 H NMR(500MHz,DMSO-d6)δppm8.88-8.97(m,1H),8.41(brs,2H),7.57(brs,1H),7.47(brd,J=7.5Hz,2H),4.89(d,J=4.7Hz,1H), 4.43-4.60(m,1H),3.38-3.79(m,6H),2.87-3.14(m,5H),1.39-2.32(m,15H),1.00(brd,J=6.9Hz,3H),0.83(brt,J=5.8Hz,7H)

[0959] Preparation of Compound 12 and Compound 13

[0960] [ka]

[0961] NaBHCN (35 mg; 0.55 mmol) was added to intermediate 38b ( *To a mixture of (R) (150 mg; 0.28 mmol), (3S)-3-methylpyrrolidin-3-ol (140 mg; 1.38 mmol), and AcOH (16 μL; 0.28 mmol) in MeOH (9 mL) was added. The reaction mixture was then heated at 60° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with DCM, and poured into a 10% aqueous solution of KCO. The organic layer was extracted with DCM (3×), dried over MgSO, filtered, and evaporated to dryness. The residue was purified by chromatography on silica gel (mobile phase: gradient from 0.3% NHOH, 3% MeOH, 97% DCM to 1% NHOH, 10% MeOH, 90% DCM). Pure fractions were collected and evaporated to give 130 mg of a mixture of compound 12 and compound 13. The residue (130 mg) was purified by reverse phase (mobile phase: gradient from 65% NH4CO3 (0.2%), 35% ACN to 25% NH4CO3 (0.2%), 75% ACN). Pure fractions were collected, evaporated to dryness, and lyophilized from water-ACN to give 80 mg (46%) of the final compound 12 as a white solid.

[0962] compound 12 1 H NMR(400MHz,DMSO-d6)δppm8.88-8.96(m,1H),8.41(brs,2H),7.57(brd,J=2 .0Hz,1H),7.41-7.51(m,2H),4.45(s,1H),3.38-3.77(m,4H),2.88-3.20(m, 4H),2.58-2.64(m,1H),2.36-2.44(m,1H),2.32(s,3H),1.90-2.08(m,4H),1 .46-1.90(m,8H),1.21(s,3H),0.90-1.07(m,3H),0.82(dd,J=6.8,3.1Hz,7H)

[0963] Preparation of Compound 14 and Compound 15

[0964] [ka]

[0965] NaBHCN (35 mg; 0.55 mmol) was added to intermediate 38b ( * To a mixture of 1H-furo[3,4-C]pyrrole (156 mg; 1.38 mmol), hexahydro-1H-furo[3,4-C]pyrrole (156 mg; 1.38 mmol), and AcOH (16 μL; 0.28 mmol) in MeOH (9 mL) was added. The reaction mixture was then heated at 60° C. for 48 h. The reaction mixture was cooled to room temperature, diluted with DCM, and poured into a 10% aqueous solution of KCO. The organic layer was extracted with DCM (3×), dried over MgSO, filtered, and evaporated to dryness. The residue was purified by chromatography on silica gel (mobile phase: gradient from 0.3% NHOH, 3% MeOH, 97% DCM to 0.7% NHOH, 7% MeOH, 93% DCM). The pure fractions were collected and evaporated to give 79 mg, which was lyophilized with water-ACN to give 79 mg (44%) of compound 14 as a white solid and 95 mg of a mixture of compounds 14 and 15, which was not further purified.

[0966] compound 14 1 H NMR(500MHz,DMSO-d6)δppm8.88-8.98(m,1H),8.36-8.46(m,2H),7.56(brd,J=4.1Hz ,1H),7.41-7.50(m,2H),3.66-3.76(m,3H),3.39-3.63(m,4H),3.35(brdd,J=8.5,3.7 Hz,3H),2.88-3.16(m,4H),2.62-2.68(m,2H),2.53-2.61(m,2H),2.34-2.48(m,4H), 2.14-2.22(m,2H),1.48-2.11(m,12H),0.91-1.05(m,3H),0.82(dd,J=6.9,4.9Hz,7H)

[0967] Preparation of Compound 16 and Compound 17

[0968] [ka]

[0969] NaBHCN (139 mg; 2.21 mmol) was added to intermediate 38b ( * To a mixture of R) (600 mg; 1.1 mmol), 4-methoxypiperidine (636 mg; 5.52 mmol), AcOH (64 μL; 1.1 mmol) in MeOH (15 mL) was added. The reaction mixture was then heated at 60° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with DCM, and poured into a 10% aqueous solution of KCO. The organic layer was extracted with DCM (3×), dried over MgSO, filtered, and evaporated to dryness. The residue was purified by chromatography on silica gel (mobile phase: gradient from 0% NHOH, 0% MeOH, 100% DCM to 0.1% NHOH, 6% MeOH, 94% DCM). Pure fractions were collected and evaporated to dryness to give 355 mg of compound 16 and 155 mg of a mixture of compound 16 and compound 17. Compound 16 (355 mg) was further purified by reverse-phase chromatography (mobile phase: gradient from 40% NH4CO3 (0.2%), 60% ACN to 10% NH4CO3 (0.2%), 90% ACN). Pure fractions were collected and evaporated to dryness to give 264 mg of compound 16, which was lyophilized from water-ACN to give 250 mg (35%) of the final compound as a white solid.

[0970] compound 16 1 H NMR(400MHz,DMSO-d6)δppm8.88-8.98(m,1H),8.41(brs,2H),7.57(brs,1H), 7.40-7.50(m,2H),3.39-3.79(m,4H),3.20(s,3H),2.88-3.16(m,6H),2.36-2. 43(m,1H),2.00-2.18(m,2H),1.70-2.00(m,10H),1.55-1.67(m,2H),1.46(q, J=9.7Hz,1H),1.29-1.40(m,2H),1.00(brs,3H),0.82(brdd,J=6.9,3.9Hz,7H)

[0971] Preparation of Compound 18:

[0972] [ka]

[0973] Compound 18 was converted to intermediate 38b ( * R) and pyrrolidine by a procedure similar to that used for the synthesis of compounds 12 and 13. 40 mg (36%) of compound 18 was obtained.

[0974] Preparation of Compound 20 and Compound 21:

[0975] [ka]

[0976] Compound 20 and compound 21 were reacted with intermediate 38b ( * R) and 2-oxa-6-azaspiro[3.3]heptane, by a procedure similar to that used for the synthesis of compounds 7 and 8. 45 mg (26%) of compound 20 and 45 mg (26%) of compound 21 were obtained.

[0977] compound 20 1 H NMR(500MHz,DMSO-d6)δppm8.93(brs,1H),8.41(brs,2H),7.57(brs,1H),7.37-7.49(m,2H),4.56(s,4H),3.39-3.82(m,4H),3.13-3.23(m,4) H),2.85-3.12(m,4H),2.71-2.83(m,1H),1.84-2.07(m,5H),1.68-1.8 3(m,2H),1.51-1.67(m,2H),1.42(q,J=9.8Hz,1H),0.62-1.09(m,10H)

[0978] Preparation of Compound 22:

[0979] [ka]

[0980] TBAF (11.5 mL; 11.3 mmol; 1 M in THF) was added to a solution of intermediate 39 (1.09 g; 1.26 mmol) in MeTHF (25 mL), and the reaction was stirred at room temperature for 24 hours. The mixture was poured into a 10% aqueous solution of K2CO3. The organic layer was extracted with EtOAc (3x), dried over MgSO4, filtered, and evaporated to dryness. The residue (1.36 g) was purified by chromatography on silica gel (mobile phase: 0% NH4OH, 0% MeOH, 100% DCM gradient to 0.7% NH4OH, 7% MeOH, 93% DCM). Pure fractions were collected and evaporated to dryness. The residue (604 mg) was purified by reverse phase (mobile phase: 75% NH4CO3 (0.2%), 25% ACN gradient to 35% NH4CO3 (0.2%), 65% ACN gradient). The pure fractions were collected, evaporated to dryness, and lyophilized from water-ACN to give 313 mg (40%) of compound 22 as a white solid.

[0981] Preparation of Compound 313 and Compound 314:

[0982] [ka]

[0983] ZnCl2 (450 mg, 3.30 mmol) was added to a solution of intermediate 236 (200 mg, 1.02 mmol) and intermediate 33 (450 mg, 1.07 mmol) in MeOH (10 mL). The mixture was stirred at 70 °C for 2 h. NaBH3CN (200 mg, 3.18 mmol) was then added. The resulting mixture was stirred at 70 °C for another 2 h. After cooling to room temperature, the mixture was quenched with water and filtered. The filtrate was evaporated to give the crude product, which was first purified by preparative HPLC (column: Phenomenex Gemini NX-C 18 75 * 30mm *The mixture was purified by SFC (DAICEL CHIRALPAK AD-H (250 mm), mobile phase A: HO (0.05% NH3HO + 10 mM NH4HCO3), mobile phase B: ACN, gradient conditions: 35% B to 65% B). Pure fractions were collected and lyophilized to give 100 mg of residue. * The residue was further purified by HPLC (30 mm, 10 μm); mobile phase: A: supercritical CO, B: 0.1% NHH O / EtOH, A:B = 50:50, 80 mL / min). The desired fractions were collected and the volatiles were removed in vacuo. The residue was resuspended in water (10 mL) and lyophilized to give compound 313 (23 mg, 4% yield) and compound 314 (30 mg, 5% yield) as white powders.

[0984] The compounds reported below were prepared following methods analogous to those described for compound 313 and compound 314, starting from the appropriate intermediates:

[0985] [Table 31-1]

[0986] [Table 31-2]

[0987] Preparation of Compound 347:

[0988] [ka]

[0989] Compound 1a (150 mg, 0.275 mmol), N,N-dimethylacrylamide (55 mg, 0.56 mmol), and TEA (110 mg, 1.09 mmol) were added to a 10 mL sealed tube, followed by EtOH (5 mL). The mixture was stirred at 70 °C for 12 hours and then cooled to room temperature. The reaction mixture was concentrated in vacuo to give compound 347 (200 mg, crude) as a yellow oil, which was used directly in the next step without further purification.

[0990] The compounds reported below were prepared starting from compound 1a following a method similar to that described for compound 347:

[0991] [Table 32]

[0992] Preparation of Compound 357:

[0993] [ka]

[0994] Formic acid (0.2 mL, 5.3 mmol) was added dropwise to a solution of intermediate 270 (350 mg, 0.462 mmol) in ACN (3 mL) and HO (1 mL). The resulting mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by preparative HPLC (Welch Xtimate C18 150 * 30mm * The mixture was purified using a 5 μm column (mobile phase A: water containing 0.225% formic acid, mobile phase B: ACN, gradient conditions: 8% B to 30% B v / v). The desired fractions were collected and lyophilized to give compound 357 (305 mg, 87% yield) as a white solid.

[0995] The compounds reported below were prepared following a similar method as described for compound 357, starting from the corresponding intermediates:

[0996] [Table 33]

[0997] Preparation of Compound 23:

[0998] [ka]

[0999] NaBHCN (46 mg; 0.74 mmol) was added to intermediate 46b ( * To a mixture of 2-(methylsulfonyl)piperidine (200 mg; 0.37 mmol), 4-(methylsulfonyl)piperidine (301 mg; 1.84 mmol), and AcOH (21 μL; 0.36 mmol) in MeOH (12 mL) was added. The reaction mixture was then heated at 60° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with DCM, and poured into a 10% aqueous solution of KCO. The organic layer was extracted with DCM (3×), dried over MgSO, filtered, and evaporated to dryness. The residue was purified by chromatography on silica gel (mobile phase: gradient from 0.3% NHOH, 3% MeOH, 97% DCM to 0.7% NHOH, 10% MeOH, 90% DCM). Pure fractions were collected and evaporated to dryness. The resulting residue was lyophilized with water-ACN to give 145 mg (57%) of compound 23 as a white solid.

[1000] The compound reported below was prepared as intermediate 46b ( * S) following a similar method as described for compound 23:

[1001] [Table 34]

[1002] Preparation of Compound 351:

[1003] [ka]

[1004] To a solution of compound 352 (40 mg, 0.072 mmol) in ACN (3 mL) was added intermediate 268 (35 mg, 0.180 mmol), K2CO3 (50 mg, 0.359 mmol), and KI (24 mg, 0.145 mmol). The resulting mixture was stirred at 70 °C for 24 h. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The resulting residue was partitioned between DCM (8 mL) and H2O (5 mL). The aqueous layer was extracted with DCM (8 mL × 2). The combined organic layers were washed with brine (5 mL) and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by preparative HPLC (Phenomenex Gemini-NX 80 mm × 40 mm 3 μm column, mobile phase A: HO (0.05% NH HO + 10 mM NH HC0 ), mobile phase B: ACN, flow rate: 30 mL / min, gradient conditions: 40% B to 70% B). The desired fractions were collected and lyophilized to give compound 351 (14 mg, 28% yield) as a white powder.

[1005] Preparation of Compound 25:

[1006] [ka]

[1007] NaBHCN (25 mg; 0.41 mmol) was added to intermediate 52a ( * To a mixture of R) (110 mg; 0.2 mmol), 4-(methylsulfonyl)piperidine (165 mg; 1.01 mmol), and AcOH (12 μL; 0.2 mmol) in MeOH (8 mL) was added. The reaction mixture was then heated at 60° C. for 24 h. The reaction mixture was cooled to room temperature, diluted with DCM, and poured into a 10% aqueous solution of KCO. The organic layer was extracted with DCM (3×), dried over MgSO, filtered, and evaporated to dryness. The residue was purified by chromatography on silica gel (mobile phase: gradient from 0% NHOH, 0% MeOH, 100% DCM to 0.1% NHOH, 5% MeOH, 95% DCM). Pure fractions were collected and evaporated to dryness. The residue (72 mg) was lyophilized with water-ACN to give 65 mg (47%) of compound 25 as a white solid.

[1008] The compounds reported below can be prepared from appropriate starting materials, e.g., intermediate 52a ( * R) or any other related intermediate) following a method similar to that reported for the preparation of compound 25:

[1009] [Table 35-1]

[1010] [Table 35-2]

[1011] Preparation of Compound 26:

[1012] [ka]

[1013] NaBHCN (23 mg; 0.37 mmol) was added to intermediate 52b ( * To a mixture of 26 (S) (100 mg; 0.2 mmol), 4-(methylsulfonyl)piperidine (165 mg; 1.01 mmol), and AcOH (11 μL; 0.18 mmol) in MeOH (8 mL) was added. The reaction mixture was then heated at 60° C. for 24 h. The reaction mixture was cooled to room temperature, diluted with DCM, and poured into a 10% aqueous solution of KCO. The organic layer was extracted with DCM (3×), dried over MgSO, filtered, and evaporated to dryness. The residue was purified by chromatography on silica gel (mobile phase: gradient from 0% NHOH, 0% MeOH, 100% DCM to 0.1% NHOH, 5% MeOH, 95% DCM). Pure fractions were collected and evaporated to dryness. The residue (90 mg) was lyophilized with water-ACN to give 77 mg (61%) of compound 26 as a white solid.

[1014] The compounds reported below can be prepared from appropriate starting materials, e.g., intermediate 52b ( *S) or any other related intermediate) following a method similar to that reported for the preparation of compound 26:

[1015] [Table 36]

[1016] Preparation of Compound 159 and Compound 160:

[1017] [ka]

[1018] A solution of tetrabutylammonium fluoride (0.7 mL, 0.7 mmol, 1 M) was added dropwise to a solution of intermediate 5 (94 mg, 0.14 mmol) in THF (3 mL) at room temperature. The reaction mixture was stirred overnight at room temperature. The mixture was poured into ice water and EtOAc was added. The mixture was basified with a solution of K2CO3 10%, the organic layer was separated, washed with brine, dried over MgSO4, filtered and the solvent was evaporated to give 106 mg of residue. The residue was purified by chromatography on silica gel (mobile phase: gradient from 98% DCM, 2% MeOH (+10% NH4OH) to 90% DCM, 10% MeOH (+10% NH4OH)). The product-containing fractions were collected and evaporated to dryness. The compound obtained (59 mg) was purified by chiral SFC (stationary phase: CHIRALPAK AD-H 5 μm 250 * Separation was performed on a 21.2 mm column using a mobile phase of 75% CO, 25% iPOH (0.3% iPrNH). The product-containing fractions were collected and evaporated to dryness to give 26 mg, which was lyophilized with water-ACN to give 22 mg (28%) of compound 159 and 24 mg, which was lyophilized with water-ACN to give 21 mg (27%) of compound 160 as a white solid.

[1019] Preparation of Compound 161 and Compound 162:

[1020] [ka]

[1021] To a solution of intermediate 67 (250 mg, 0.38 mmol) in DMF (15 mL) were added T3P (0.5 mL, 0.75 mmol, 50% purity) and Et3N (0.16 mL, 1.13 mmol). The mixture was stirred at room temperature for 12 hours. The mixture was diluted with EtOAc. The mixture was washed with saturated NaHCO3, brine, dried over Mg2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: gradient from 0.1% NH4OH, 0% MeOH, 100% DCM to 0.1% NH4OH, 10% MeOH, 90% DCM). Pure fractions were collected, and the solvent was evaporated under vacuum. The residue (300 mg) was purified by reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30 * Purification was performed by 150 mm, mobile phase: 40% NH4HCO3 0.2% pH=9.5, 35% ACN, 70% MeOH (gradient to 20% NH4HCO3 0.2% pH=10, 40% ACN, 40% MeOH). Pure fractions were collected and the solvent was evaporated in vacuo.

[1022] Compound 161 was partitioned between acetonitrile (2 mL) and water (8 mL). The solution was lyophilized to dryness to give 58 mg of compound 161 as a white solid.

[1023] Compound 162 was partitioned between acetonitrile (2 mL) and water (8 mL). The solution was lyophilized to dryness to give 14 mg of compound 162 as a white solid.

[1024] Preparation of Compound 166, Compound 167 and Compound 168:

[1025] [ka]

[1026] NaBHCN (92 mg; 1.46 mmol) was added to a mixture of intermediate 75 (414 mg; 0.73 mmol), hexahydro-1H-furo[3,4-C]pyrrole (240 μL; 2.19 mmol), and AcOH (41 μL; 0.72 mmol) in MeOH (19 mL). The reaction mixture was stirred at 60 °C for 6 h. The reaction mixture was poured into a 10% aqueous solution of KCO and EtOAc. The mixture was extracted with EtOAc (3x). The organic layer was dried over MgSO, filtered, and the solvent was evaporated. The resid...

Claims

1. Formula (I) 【Chemistry 1】 or a tautomer or stereoisomer thereof, R １ａ represents Het, Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2 or 3 nitrogen atoms and optionally a carbonyl moiety; said monocyclic 5- or 6-membered aromatic ring is ３～６ cycloalkyl, and the monocyclic 5- or 6-membered aromatic ring is optionally substituted with C ３～６ Cycloalkyl, cyano, and C １～４ may be substituted with one or two additional substituents selected from the group consisting of 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 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 2】 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 substituted to S(=O) or S(=O) ２ wherein said heterocyclyl is optionally selected from 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 substituted to 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 substituted to S(=O) or S(=O) ２ represents a bicyclic C-linked 6-11 membered fully saturated heterocyclyl which may form, on one nitrogen, ６ , -C(=O)-Cy １ 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; optionally, R ６ａ may be substituted with; R ６ and R ６ａ Het ３ Het ４ ;-C(=O)-NH-Cy １ ;-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, 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 ８ is -O-C １～６ Alkyl, C １～６ Alkyl; or -OH, halo, cyano, -NR １１ａ R １１ｂ , Het ３ａ and Het ６ａ C substituted with 1, 2 or 3 substituents each independently selected from １～６ represents alkyl; Het ３ , Het ３ａ , Het ５ and Het ５ａ are each independently a monocyclic C-linked 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 substituted to 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 substituted to form S(=O) or S(=O). ２ wherein the heterocyclyl optionally has at least one carbon atom selected from the group consisting of C １～４ Alkyl, halo, -OH, -NR １１ａ R １１ｂ or oxo; said heterocyclyl is optionally substituted on one nitrogen atom by C １～４ may be substituted with alkyl; Het ４ and Het ７ each independently represent a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms each independently selected from O, S and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, 3 or 4 heteroatoms each independently selected from O, S and N; said aromatic rings may optionally be bonded to one nitrogen atom by C １～４ Alkyl or -(C=O)-O-C １～４ The aromatic ring may be optionally substituted on the 11 or 2 carbon atoms with -OH, halo, C １～４ Alkyl, —O—C １～４ Alkyl, -NR １１ａ R １１ｂ , C １～４ Alkyl-NR １１ａ R １１ｂ , -NH-C(=O)-C １～４ Alkyl, cyano, -COOH, -NH-C(=O)-O-C １～４ Alkyl, -NH-C(=O)-Cy ３ , -NH-C(=O)-NR １０ａ R １０ｂ , -(C=O)-OC １～４ Alkyl, -NH-S(=O) ２ -C １～４ Alkyl, Het ８ａ , -C １～４ Alkyl-Het ８ａ , Het ８ｂ , Het ９ and -C(=O)-NR １０ａ R １０ｂ and optionally substituted with a total of 1 or 2 substituents each independently selected from the group consisting of: Het ６ａ , Het ８ and Het ８ａ each independently represent a 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, said S atom being substituted to S(=O) or S(=O) ２ wherein the heterocyclyl may optionally be joined at one or two carbon atoms with halo, -OH, oxo, -NH-C(=O)-C １～４ Alkyl, -NH-C(=O)-Cy ３ , -(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, wherein the heterocyclyl is optionally substituted on one nitrogen by 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 may be substituted with a substituent selected from the group consisting of: Het ６ｂ and Het ８ｂ each independently represent 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 said heterocyclyl may optionally be joined at one or two carbon atoms to form 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 -O-C １～４ alkyl; said heterocyclyl is optionally substituted on one nitrogen with a total of 1 or 2 substituents each independently selected from the group consisting of -C(=O)-C 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 may be substituted with a substituent selected from the group consisting of alkyl; Het ９ 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, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2 or 3 heteroatoms each independently selected from O, S and N; said aromatic ring optionally has, on one nitrogen atom, １～４ The aromatic ring may be optionally substituted on one or two carbon atoms with -OH, halo, and C １～４ optionally substituted with a total of 1 or 2 substituents each independently selected from the group consisting of alkyl; Cy １ is optionally -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 C ３～７ represents cycloalkyl; ３～７ Cycloalkyl is optionally selected from halo, R ６ , Het ６ａ , Het ６ｂ , -NR ９ａ R ９ｂ , -OH, C １～４ Alkyl and Het ３ａ , Het ６ａ , Het ６ｂ , and -NR ９ａ R ９ｂ C substituted with 1 or 2 substituents each independently selected from the group consisting of １～４ optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl; 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; -C(=O)-C １～４ Alkyl; -C(=O)-C ３～６ Cycloalkyl; -S(=O) ２ -C １～４ Alkyl; Het ５ Het ７ ;-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 １０ａ and R １０ｂ is hydrogen, C １～４ Alkyl and C ３～６ cycloalkyl; R １４ Het ５ａ Het ７ Het ８ａ ;-O-C １～４ Alkyl; -C(=O)NR １５ａ R １５ｂ ;-O-C １～４ C substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and halo ３～６ cycloalkyl; or -O-C １～４ Alkyl, -NR １３ａ R １３ｂ , halo, cyano, -OH, Het ８ａ , and Cy １ 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. Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2 or 3 nitrogen atoms and optionally a carbonyl moiety; said monocyclic 5- or 6-membered aromatic ring is ３～６ cycloalkyl, and the monocyclic 5- or 6-membered aromatic ring is optionally substituted with C ３～６ Cycloalkyl, cyano, and C １～４ may be substituted with one or two additional substituents selected from the group consisting of alkyl; 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: 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, wherein the S atom is substituted to S(=O) or S(=O) ２ wherein said heterocyclyl is optionally selected from 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 substituted to S(=O) or S(=O) ２ or a bicyclic C-bonded 6-11 membered fully saturated heterocyclyl containing an N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom is substituted to form S(=O) or S(=O). ２ represents a bicyclic C-linked 6-11 membered fully saturated heterocyclyl which may form The heterocyclyl optionally has on one nitrogen atom 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 is R on one nitrogen atom ６ａ represents a C-linked pyrazolyl or triazolyl 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, 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 optionally -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-linked 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 substituted to 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 substituted to form S(=O) or S(=O). ２ wherein the heterocyclyl optionally has at least one carbon atom selected from the group consisting of C １～４ Alkyl, halo, -OH, -NR １１ａ R １１ｂ or oxo; said heterocyclyl is optionally substituted on one nitrogen atom by C １～４ may be 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 substituted to 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 substituted to form S(=O) or S(=O). ２ wherein the heterocyclyl optionally has at least one carbon atom selected from the group consisting of C １～４ Alkyl, halo, -OH, -NR １１ａ R １１ｂ or oxo; said heterocyclyl is optionally substituted on one nitrogen atom by C １～４ may be substituted with alkyl; Het ４ and Het ７ each independently represent 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-membered aromatic ring optionally has a C bond on one nitrogen atom １～４ said 5- or 6-membered aromatic ring may be optionally substituted on one carbon atom with -OH; Het ６ａ and Het ８ each independently represent a 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, said S atom being substituted to S(=O) or S(=O) ２ wherein the heterocyclyl may be selected from the group consisting of halo, -OH, oxo, -(C=O)-NR, on one or two carbon atoms; 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; said heterocyclyl is optionally substituted 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 4-7 membered fully saturated heterocyclyl containing two N atoms and optionally one additional heteroatom selected from O, S and N, said S atom being substituted to S(=O) or S(=O) ２ wherein the heterocyclyl may optionally be joined on one or two carbon atoms with 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; said heterocyclyl is optionally substituted 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 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 The heterocyclyl may be formed on one or two carbon atoms by 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 alkyl, wherein the heterocyclyl is -C(=O)-C 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 on one nitrogen 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 optionally 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 additional 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 １０ａ and R １０ｂ is hydrogen, C １～４ Alkyl and C ３～６ cycloalkyl; 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 2. The compound according to claim 1 , wherein

3. Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2 or 3 nitrogen atoms and optionally a carbonyl moiety; said monocyclic 5- or 6-membered aromatic ring is ３～６ cycloalkyl, and the monocyclic 5- or 6-membered aromatic ring is optionally substituted with cyano, and １～４ may be substituted with one or two additional substituents selected from the group consisting of alkyl; R １ｂ represents F; Y １ represents -O-; R ２ is hydrogen, U represents N; n1, n2, n3, and n4 are each independently selected from 1 and 2; R ４ But, C １～５ Alkyl; or 【Chemistry 3】 represents; R ３ Het １ and Cy ２ selected from the group consisting of: 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 substituted to 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 substituted to form S(=O) or S(=O). ２ represents a bicyclic C-linked 6-11 membered fully saturated heterocyclyl which may form, on one nitrogen, ６ and -C(=O)-R ８ wherein said 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 oxo and -OH; R ６ and R ６ａ Het ４ Het ３ , Het ６ａ and Cy １ C optionally substituted with 1 or 2 substituents each independently selected from the group consisting of １～６ Alkyl; and C ３～６ cycloalkyl; R ８ But -O-C １～６ represents alkyl; Het ３ , Het ３ａ , Het ５ and Het ５ａ each independently represent a monocyclic C-linked 4-7 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N, said S atoms being substituted to S(=O) or S(=O) ２ said heterocyclyl may optionally have at one carbon atom a C １～４ may be substituted with alkyl; Het ４ and Het ７ each independently represent a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms each independently selected from O, S and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, 3 or 4 heteroatoms each independently selected from O, S and N; said aromatic rings may optionally be bonded to one nitrogen atom by C １～４ Alkyl or -(C=O)-O-C １～４ The aromatic ring may be optionally substituted on one or two carbon atoms with -OH, halo, C １～４ Alkyl, —O—C １～４ Alkyl, -NR １１ａ R １１ｂ , C １～４ Alkyl-NR １１ａ R １１ｂ , -NH-C(=O)-C １～４ Alkyl, cyano, -COOH, -NH-C(=O)-O-C １～４ Alkyl, -NH-C(=O)-NR １０ａ R １０ｂ , -(C=O)-OC １～４ Alkyl, -NH-S(=O) ２ -C １～４ Alkyl, Het ８ａ , -C １～４ Alkyl-Het ８ａ , Het ８ｂ , Het ９ and -C(=O)-NR １０ａ R １０ｂ and optionally substituted with a total of 1 or 2 substituents each independently selected from the group consisting of: Het ６ａ , Het ８ and Het ８ａ each independently represent a 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, said S atom being substituted to S(=O) or S(=O) ２ wherein the heterocyclyl may optionally be joined at one or two carbon atoms with halo, -OH, oxo, -NH-C(=O)-C １～４ Alkyl, -NH-C(=O)-Cy ３ , -(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 and -O-C １～４ alkyl, 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 ６ｂ and Het ８ｂ each independently represent 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 said heterocyclyl may optionally be joined at one or two carbon atoms to form 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 -O-C １～４ alkyl, wherein the heterocyclyl is optionally substituted with a total of 1 or 2 substituents each independently selected from the group consisting of -C(=O)-C １～４ Alkyl, -C(=O)-Cy ３ , and C １～４ optionally substituted on one nitrogen with a substituent selected from the group consisting of alkyl; Het ９ each independently represents a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms selected from O, S, and N; said aromatic ring optionally has a C bond on 1 or 2 carbon atoms; １～４ may be substituted with alkyl; Cy １ is -OH and 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 C ３～７ represents cycloalkyl; ３～７ Cycloalkyl is optionally R ６ , Het ６ａ , Het ６ｂ , -NR ９ａ R ９ｂ , —OH, and C １～４ optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl; 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; -C(=O)-C １～４ Alkyl; -C(=O)-C ３～６ Cycloalkyl; Het ５ Het ７ ;-C １～４ Alkyl-R １６ -C(=O)-C １～４ Alkyl-Het ３ａ -C(=O)-R １４ ;and; Halo, —OH and —O—C １～４ C substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl １～４ alkyl; R １１ａ , R １１ｂ , R １３ａ , R １３ｂ , R １７ａ , and R １７ｂ is hydrogen and C １～４ alkyl; R １０ａ and R １０ｂ is hydrogen, C １～４ Alkyl and C ３～６ cycloalkyl; R １４ is O-C １～４ Alkyl; -O-C １～４ C substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and halo ３～６ Cycloalkyl; or; —O—C １～４ Alkyl, -NR １３ａ R １３ｂ and cyano; １～４ alkyl; R １６ is -C(=O)-NR １７ａ R １７ｂ Or -S(=O) ２ -C １～４ The compound of claim 1 , which represents alkyl.

4. Het is 【Chemistry 4】 2. The compound of claim 1 ,

5. 2. The compound of claim 1, wherein U represents N.

6. Y １ The compound of claim 1 , wherein represents —O—.

7. R １ｂ The compound according to claim 1 , wherein

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 leukemia, myelogenous leukemia, 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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