CA3215379A1 - Substituted spiro derivatives - Google Patents

Abstract

The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, pharmaceutical composition comprising such compounds, and their use as menin/MLL protein/protein interaction inhibitors, useful for treating diseases such as cancer, myelodysplastic syndrome (MDS) and diabetes.

Description

SUBSTITUTED SPIRO DERIVATIVES
FIELD OF THE INVENTION
The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, pharmaceutical composition comprising such compounds, and their use as menin/MLL protein/protein interaction inhibitors, useful for treating diseases such as cancer, myelodysplastic syndrome (MD S) and diabetes.
BACKGROUND OF THE INVENTION
Chromosomal rearrangements affecting the mixed lineage leukemia gene (MLL;
MLL1;
KAJT2A) result in aggressive acute leukemias across all age groups and still represent mostly incurable diseases emphasizing the urgent need for novel therapeutic approaches. Acute leukemias harboring these chromosomal translocations of MLL represent as lymphoid, myeloid or biphenotypic disease and constitute 5 to 10% of acute leukemias in adults and approximately 70% in infants (Marschalek, Br J Haematol 2011 152(2), 141-54; Tomizawa et al., Pediatr Blood Cancer 2007 49(2), 127-32).
MLL is a histone methyltransferase that methylates histone H3 on lysine 4 (H3K4) and functions in multiprotein complexes. Use of inducible loss-of-function alleles of Mill demonstrated that M111 plays an essential role in sustaining hematopoietic stem cells (HSCs) and developing B cells although its histone methyltransferase activity is dispensable for hematopoiesis (Mishra et al., Cell Rep 2014. 7(4), 1239-47).
Fusion of MLL with more than 60 different partners has been reported to date and has been 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 MILL is not retained in chimeric proteins but is replaced by the fusion partner (Thiel et al., Bioessays 2012.
34, 771-80). Recruitment of chromatin modifying enzymes like Dot1L and/or the pTEFb complex by the fusion partner leads to enhanced transcription and transcriptional elongation of MLL target genes including HOXA genes (e.g. HOXA 9) and the HOX cofactor AIEISl as the most prominent ones. Aberrant expression of these genes in turn blocks hematopoietic differentiation and enhances proliferation.
Menin which is encoded by the Multiple Endocrine Neoplasia type 1 (MENI) gene is expressed ubiquitously and is predominantly localized in the nucleus. It has been shown to interact with numerous proteins and is, therefore, involved in a variety of cellular processes. The best understood function of menin is its role as an oncogenic cofactor of MILL
fusion proteins. Menin interacts with two motifs within the N-terminal fragment of MILL that is retained in all fusion proteins, MBM1 (menin-binding motif 1) and 1V1BM2 (Thiel et al., Bioessays 2012. 34, 771-80). Menin/MLL interaction leads to the formation of a new interaction surface for lens epithelium-derived growth factor (LEDGF). Although MLL directly binds to LEDGF, menin is obligatory for the stable interaction between MILL and LEDGF and the 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 MILL fusion proteins suggesting the menin/MLL interaction as an attractive therapeutic target. For example, conditional deletion of Men] prevents leukomogenesis in bone marrow progenitor cells ectopically expressing MILL fusions (Chen et al., Proc Natl Acad Sci 2006. 103, 1018-23). Similarly, genetic disruption of menin/MLL fusion interaction by loss-of-function mutations abrogates the oncogenic properties of the MILL fusion proteins, blocks the development of leukemia in vivo and releases the differentiation block of MLL-transformed leukemic blasts. These studies also showed that menin is required for the maintenance of HOX
gene expression by MILL fusion proteins (Yokoyama et al., Cell 2005. 123, 207-18). In addition, small molecule inhibitors of menin/MLL interaction have been developed suggesting druggability of this protein/protein interaction and have also demonstrated efficacy in preclinical models of AML (Borkin et al., Cancer Cell 2015. 27, 589-602;
Cierpicki and Grembecka, Future Med Chem 2014. 6, 447-462). Together with the observation that menin is not a requisite cofactor of MLL1 during normal hem atopoiesi s (Li et al., Blood 2013. 122, 2039-2046), these data validate the disruption of menin/MLL interaction as a promising new therapeutic approach for the treatment of MLL rearranged leukemia and other cancers with an active HOXIMEISI gene signature. For example, an internal partial tandem duplication (PTD) within the 5'region of the MLL gene represents another major aberration that is found predominantly in de novo and secondary AML as well as myeloid dysplasia syndromes.
Although the molecular mechanism and the biological function of MLL-PTD is not well understood, new therapeutic targeting strategies affecting the menin/MLL
interaction might also prove effective in the treatment of MILL-PTD-related leukemias.
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).
MILL protein is also known as Hi stone-lysine N-methyltransferase 2A (KMT2A) protein in the scientific field (UniProt Accession # Q03164).
Several references describe inhibitors targeting the menin-MILL interaction:
W02011029054, J Med Chem 2016, 59, 892-913 describe the preparation of thienopyrimidine and benzodiazepine derivatives; W02014164543 describes thienopyrimidine and thienopyridine derivatives; Nature Chemical Biology March 2012, 8, 277-284 and Ren, J.; et al. Bioorg Med Cheri Lett (2016), 26(18), 4472-4476 describe thienopyrimidine derivatives; J
Med Chem 2014, 57, 1543-1556 describes hydroxy- and aminomethylpiperidine derivatives, Future Med Chem 2014, 6, 447-462 reviews small molecule and peptidomimetic compounds;

- 2 -describes furo[2,3-d]pyrimidine, 9H-purine, [1,3]oxazolo[5,4-d]pyrimidine, [1,3]oxazolo[4,5-d]pyrimidine, [1,3 ]thi azolo[5,4 -d]pyrimi dine, thieno[2,3 -b]pyri dine and thi eno[2,3-d]pyrimi dine derivatives; W02016197027 describes 5,6,7, 8-tetrahydropyri do[3,4-d]pyrimi dine, 5,6,7,8-tetrahydropyrido]4,3-d]pyrimidine, pyrido[2,3-d]pyrimidine and quinoline derivatives; and W02016040330 describes thienopyrimidine and thienopyridine compounds. W02017192543 describes piperidines as Menin inhibitors.
W02017112768, W02017207387, W02017214367, W02018053267 and W02018024602 describe inhibitors of the menin-MLL interaction. W02017161002 and W02017161028 describe inhibitors of menin-MLL. W02018050686, W02018050684 and W02018109088 describe inhibitors of the menin-MLL interaction. W02018226976 describes methods and compositions for inhibiting the interaction of menin with MILL proteins. W02019060365 describes substituted inhibitors of menin-MLL. Krivtsov et al., Cancer Cell 2019. No.6 Vol.36, 660-673 describes a menin-MLL inhibitor.
W02020069027 discloses inhibitors of Menin. W02018175746 discloses methods for treating hematological malignancies and ewing's sarcoma. W02020045334 discloses azabicyclic derivative used in pharmaceutical compositions. W02019120209 discloses substituted heterocyclic compounds as menin/lVILL protein/protein interaction inhibitors CN111297863 discloses use of menin-mixed lineage leukemia (MLL) inhibitors.
W02021121327 describes substituted straight chain Spiro derivatives and their use as menin/MLL protein/protein interaction inhibitors.
DESCRIPTION OF THE INVENTION
The present invention concerns novel compounds of Formula (I), R---,X1/R3 n3(X)n4 n1( )n2 R1 a (I) L.rLj ---Rib PSI U
and the tautomers and the stereoisomeric forms thereof, wherein <N> xa xb R1 a represents -C(=0)- xNR aRxb; or N R R

- 3 -R" and 10 are each independently selected from the group consisting of hydrogen;
C3_6cycloalky1; C3_4alkyl, C3_4alkyl substituted with 1, 2 or 3 halo atoms;
and C3_4alkyl substituted with one -OH, -0C3_4alkyl, or NR11eR11d;
lb x represents F or Cl;
Y1 represents -CleaR513 - , -0-, - S - , or R2 is selected from the group consisting of hydrogen, halo, Ci_4alkyl, -0-Ci_4alky1, and -NR7aleb;
U1 and U2 each independently represent N or CH;
nl, n2, n3 and n4 are each independently selected from 1 and 2;
X1 represents CH, and X2 represents N;
R4 represents Ci_salkyl, ss.,.
,.; or ''= ;
R'a, RTh, R', R7a, and RTh, are each independently selected from the group consisting of hydrogen, CiAalkyl and C3_6cycloalkyl;
R3 is selected from the group consisting of Het', Het2, Cy2, and -Ci_6alkyl-NR"Rxd;
R' represents Cy'; Het5; -C1_6a1ky1-Cy1; -C1_6alkyl-Het3; -Ci_6a1ky1-Het4;
or -Ci_6a1ky1-phenyl;
It'd represents hydrogen, C1_4a1ky1, or Ci_4alkyl substituted with one, two or three sub stituents selected from the group consisting of halo, -OH, -0-C3_4a1ky1, and cyano, or We and It'd are taken together to form together with the N-atom to which they are attached a 4- to 7-membered monocyclic fully saturated heterocyclyl containing one N-atom and optionally one additional heteroatom selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2; wherein said heterocyclyl is optionally substituted with one, two or three substituents selected from the group consisting of halo, -OH, -O-Ci and cyano, Heti represents 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 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2; or a bicyclic C-linked 6- to 11-membered fully saturated heterocyclyl containing one N-atom and optionally one or two additional heteroatoms each independently selected from

- 4 -0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2;
wherein said heterocyclyl is optionally substituted on one nitrogen with a substituent selected from the group consisting of R6 and -C(=0)-R8; and wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four substituents each independently selected from the group consisting of halo, R6, Het' Het6b, , Ci_4alkyl, oxo, -NR9aR9b and -OH, Het2 represents C-linked pyrazolyl or triazolyl; which is substituted on one nitrogen atom with R6a;
R6 is selected from the group consisting of Het3; -C(=0)-NH-R8;
C1_6alkyl optionally substituted with one or two substituents each independently selected from the group consisting of Het3, Het4, Het", Het6b, Cy', -CN, -OH, -0-C1_4alkyl, -C(=0)-NH-C1_4a1kyl, -C(=0)-NH-Ci_4alkyl-C3_6cycloalkyl, -C(=0)-0H, -NRI laR1 lb and --I\TH_=-, (_ 0)2-Ci_4alkyl; and C3_6cycloalky1 optionally substituted by one or two substituents each independently selected from the group consisting of -CN, -OH, -0-C1_4alkyl, -C(=0)-NH-Ci_4a1kyl, -NH-S(=0)2-Ci_4alkyl, and C1_4alkyl optionally substituted with one substituent selected from the group consisting of OH, -0-C14alkyl, -C(=0)-NH-C1_4alkyl and -NH-S(=0)2-Ci_4alkyl;
R6a represents C16alkyl substituted with one substituent selected from the group consisting of _NR1 laR1 lb, Het3', and Het", Rs represents Ci_6a1ky1 optionally substituted with one, two or three substituents each independently selected from -OH, halo, cyano, -NRilaR1 lb, He.t3a, and Het";
Het3 and Het' each independently represent a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2; or a bicyclic C-linked 6- to 11-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2;
wherein said heterocyclyl is optionally substituted on one carbon atom with Ci_4alkyl, halo, -OH, -NRilaR1 lb, or oxo; and wherein said heterocyclyl is optionally substituted on one nitrogen atom with C1_4alkyl;
Het3a and Hee' each independently represent a monocyclic C-linked 4- to 7-membered fully

- 5 -

6 saturated heterocyclyl containing one N-atom, and optionally one or two additional heteroatoms each independently selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2; or a bicyclic C-linked 6- to 11-membered fully saturated heterocyclyl containing one N-atom, and optionally one or two additional heteroatoms each independently selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2;
wherein said heterocyclyl is optionally substituted on one carbon atom with C1_4alkyl, halo, -OH, -NR1 laR1 lb, or oxo; and wherein said heterocyclyl is optionally substituted on one nitrogen atom with Ci_4alkyl;
Hee and Het7 each independently represent a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two, three or four heteroatoms each independently selected from 0, S, and N; wherein said 5-membered aromatic ring is optionally substituted on one nitrogen atom with C1_4alkyl; and wherein said 5- or 6-membered aromatic ring is optionally substituted on one carbon atom with -OH;
Het' and Het' 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 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2; wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four substituents each independently selected from the group consisting of halo, -OH, oxo, -(C=0)-ONR1 aRl0b,0-C3_6cycloalkyl, -S(=0)2-Ci_4alkyl, cyano, Ch4alkyl, -Ci_4alkyl-OH, -0-C1_4alkyl, _o_(C=0)_NR10aR101), and -0-(C=0)-C1_4alkyl; and wherein said heterocyclyl is optionally substituted on one nitrogen with a sub stituent selected from the group consisting of -C(=0)-Ci_4alkyl and -(C=0)-NR'0aRlOb;
Het 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 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2;
wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four substituents each independently selected from the group consisting of halo, -OH, oxo, -(C=0)-NR'OaRl0b, -0-C3_6cycloalkyl, -S(=0)2-C1_4a1ky1, cyano, Ci_4alkyl, Ci_4alkyl-OH, -0-Ci_4alkyl, -0-(C=0)-NR 01 aR1013, and -0-(C=0)-Ci_4alkyl; and wherein said heterocyclyl is optionally substituted on one nitrogen with a substituent selected from the group consisting of -C(=0)-C1_4alkyl and -(C=0)-NRimaRiob;
Het' represents a bicyclic N-linked 6- to 11-membered fully saturated heterocyclyl containing one N-atom and optionally one or two additional heteroatoms each independently selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2; wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one or two sub stituents each independently selected from the group consisting of Ci_ 4a1ky1, -OH, oxo, -(C=0)-N1R10aR1013, _ NH-C(=0)-C1_4alkyl, -NH-C(=0)-Cy3, and -0-C1_4alkyl; and wherein said heterocyclyl is optionally substituted on one nitrogen with a substituent selected from the group consisting of -C(=0)-C1_4alkyl, -C(=0)-Cy3, -(C=0)-C1_4alkyl-OH, -C(=0)-Ci_4alkyl-O-Ci_4alkyl, -C(=0)-Ci_4alkyl-NR'laR11b, and Ci_4alkyl;
Cy' represents C3_6cycloalkyl optionally substituted with one, two or three substituents selected from the group consisting of -OH, -NH-C(=0)-C1_4alkyl, -NH-S(=0)2-Ci_4alkyl, -S(=0)2-C1_4alkyl, and -0-Ci_4alkyl, Cy 2 represents C3_7cycloalkyl substituted with one or two substituents each independently selected from the group consisting of -NleaRTh, Het", Het', and Ci_6alkyl substituted with one or two substituents each independently selected from the group consisting of Het', Het', Het', and -NR9aR9b; and said C3_7cycloalky1 is optionally substituted with one or two additional substituents each independently selected from the group consisting of halo, R6, C1_4alkyl, and -OH;
Cy3 represents C3_7cycloalkyl; wherein said C3_7cycloalkyl is optionally substituted with one, two or three halo substituents;
R9a and R9b are each independently selected from the group consisting of hydrogen, Ci_4alkyl, C3_6cycloalkyl, Hee, -C1_4alkyl-R16, -C(=0)-Ci_4alkyl-Het3a; -C(=O)-R'4;
C3_6cycloalkyl substituted with one, two or three substituents selected from the group consisting of halo, -OH, -0-C1_4alkyl, -NR1laRllb, and cyano, and Ci_4alkyl substituted with one, two or three substituents selected from the group consisting of halo, -OH, -0-Ci_4alkyl, -NRilaRllb, and cyano;
Rua., R13a, R13b, R15a, R15b, R17a, and Itl7b are each independently selected from the group consisting of hydrogen and Ci_4alkyl, Rile and R' are each independently selected from the group consisting of hydrogen, C1_6alkyl, and -C(=0)-Ci_4alkyl, -tc represents Het'; Hee', or Ci_4alkyl substituted with one, two or three substituents selected from the group consisting of 4R13aRl3b and Het';

I( represents -C(=0)-NR17aRl7b, _S(=0)2-C1_4alkyl, Het5, Het7, or Het8;

- 7 -and the pharmaceutically acceptable salts and the solvates thereof.
The present invention al so relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, and a pharmaceutically acceptable carrier or ex ci pi ent.
Additionally, the invention relates to a compound of Formula (T), a pharmaceutically acceptable salt, or a solvate thereof, for use as a medicament, and to a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, for use in the treatment or in the prevention of cancer, myelodysplastic syndrome (MDS) and diabetes.
In a particular embodiment, the invention relates to a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, for use in the treatment or in the prevention of cancer.
In a specific embodiment said cancer is selected from leukemias, myeloma or a 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 leukemias include acute leukemias, chronic leukemias, myeloid leukemias, myelogeneous leukemias, lymphoblastic leukemias, lymphocytic leukemias, Acute myelogeneous leukemias (AML), Chronic myelogenous leukemias (CML), Acute lymphoblastic leukemias (ALL), Chronic lymphocytic leukemias (CLL), T cell prolymphocytic leukemias (T-PLL), Large granular lymphocytic leukemia, Hairy cell leukemia (HCL), MLL-rearranged leukemias, MLL-PTD
leukemias, MILL
amplified leukemias, MILL-positive leukemias, leukemias exhibiting HOXIMEIS1 gene expression signatures etc.
The invention also relates to the use of a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, in combination with an additional pharmaceutical agent for use in the treatment or prevention of cancer, myelodysplastic syndrome (MD S) and diabetes.
Furthermore, the invention relates to a process for preparing a pharmaceutical composition according to the 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 a solvate thereof.
The invention also relates to a product comprising a compound of Formula (I), a pharmaceutically acceptable salt, or a 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.
Additionally, the invention relates to a method of treating or preventing a cell proliferative disease in a warm-blooded animal which comprises administering to the said animal an effective amount of a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate

- 8 -thereof, as defined herein, or a pharmaceutical composition or combination as defined herein.
DETAILED DESCRIPTION OF THE INVENTION
The term 'halo' or 'halogen' as used herein represents fluor , chloro, bromo and iodo.
The prefix 'C,' (where x and y are integers) as used herein refers to the number of carbon atoms in a given group. Thus, a C1_6alky1 group contains from 1 to 6 carbon atoms, and so on.
The term `Ci_4a1kyr as used herein as a group or part of a group represents 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.
Similar, the term `Ci_6alkyr as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl and the like.
The term C3_6cycloalkyl' as used herein as a group or part of a group defines a saturated, cyclic hydrocarbon radical having from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term C3_7cycloalkyl' as used herein as a group or part of a group defines a saturated, cyclic hydrocarbon radical having from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
It will be clear for the skilled person that S(=0)2 or SO2 represents a sulfonyl moiety.
It will be clear for the skilled person that CO or C(=0) represents a carbonyl moiety.
It will be clear for the skilled person that a group such as -CRR- represents R R
-C-. An example of such a group is -CR-SaR-5b-.
It will be clear for the skilled person that a group such as -NR- represents -N-. An example of such a group is -NR-.
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 0, S, and N', defines a fully saturated, cyclic hydrocarbon radical having from 4 to 7 ring members and containing 1 nitrogen atom and optionally one or two additional heteroatoms each independently selected from 0, S, and N, such as for example 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 0, S, and N', is defined similar but is

- 9 -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 to form together with the N-atom to which they are attached a 4- to 7-membered monocyclic fully saturated heterocyclyl containing one N-atom and optionally one additional heteroatom selected from 0, S, and N, are defined similar.
The term `monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from 0, S, and N', defines a fully saturated, cyclic hydrocarbon radical having from 4 to 7 ring members and containing one, two or three heteroatoms each independently selected from 0, S, and N, such as for example C-linked azetidinyl, C-linked pyrrolidinyl, C-linked morpholinyl, C-linked tetrahydrofuranyl, C-linked thiolanyl, C-linked oxetanyl, C-linked thietanyl, C-linked tetrahydropyranyl, and C-linked piperidinyl. The term cmonocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing two N-atoms and optionally one additional heteroatom selected from 0, S, and N', defines a fully saturated, cyclic hydrocarbon radical having from 4 to 7 ring members and containing 2 nitrogen atoms and optionally one additional heteroatom selected from 0, S, and N, such as for example N-linked piperazinyl, and N-linked 1,4-diazepanyl.
For clarity, the 4- to 7-membered fully or partially saturated heterocyclyls have from 4 to 7 ring members including the heteroatoms.
Non-limiting examples of `monocyclic 5- or 6-membered aromatic rings containing one or two 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.
Non-limiting examples of `monocyclic C-linked 5-or 6-membered aromatic rings containing one, two or three heteroatoms each independently selected from 0, S. and N', include, but are not limited to C-linked pyrazolyl, C-linked imidazolyl, C-linked pyridinyl, C-linked triazolyl, C-linked pyridazinyl, C-linked pyrimidinyl, C-linked oxazolyl, C-linked furanyl, C-linked isothiazolyl, or C-linked pyrazinyl.
Within the context of this invention, bicyclic C-linked 6- to 11-membered fully saturated heterocyclyl groups, include fused, spiro and bridged bicycles Within the context of this invention, bicyclic N-linked 6-to 11-membered fully saturated heterocyclyl groups, include fused, Spiro and bridged bicycles.
Fused bicyclic groups are two cycles that share two atoms and the bond between these atoms.

- 10 -Spiro bicyclic groups are two cycles that are joined at a single atom Bridged bicyclic groups are two cycles that share more than two atoms.
Examples of bicyclic C-linked 6- to 11-membered fully saturated heterocyclyl containing one N-atom and optionally one or two additional heteroatoms each independently selected from 0, S, and N, include, but are not limited to NH
, N C H H

Of) and the like.
Examples of bicyclic C-linked 6- to 11-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from 0, S, and N, include, but are not limited to N H H H
N O H H
N H N
OK>

J
and the like.

- 11 -Examples of bicyclic N-linked 6- to 11-membered fully saturated heterocyclyl containing one N-atom and optionally one or two additional heteroatoms each independently selected from 0, S, and N, include, but are not limited to N/ ________________________________________________________________ X:D>
N(r>
NH N )00 ----N
H ,7N1 - - -N
H

- -N

- -and the like

- 12 -Whenever substituents are represented by chemical structure, such as for example H
represents the bond of attachment to the remainder of the molecule of Formula (T) When any variable occurs more than one time in any constituent, each definition is independent.
When any variable occurs more than one time in any formula (e.g. Formula (I)), each definition is independent.
In this context, it will also be clear that a term like "optionally substituted with one, two or three sub stituents selected from the group consisting of' is equivalent to "optionally substituted with one, two or three substituents each independently selected from the group consisting of'.
In general, whenever the term 'substituted' is used in the present invention, it is meant, unless otherwise indicated or clear from the context, to indicate that one or more hydrogens, in particular from 1 to 4 hydrogens, more in particular from 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using 'substituted' are replaced with a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture. In a particular embodiment, when the number of substituents is not explicitly specified, the number of sub stituents is one.
Combinations of sub stituents 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.
The skilled person will understand that the term 'optionally substituted' means that the atom or radical indicated in the expression using 'optionally substituted' may or may not be substituted (this means substituted or unsubstituted respectively).
When two or more substituents are present on a moiety they may, where possible and unless otherwise indicated or clear from the context, replace hydrogens on the same atom or they may replace hydrogen atoms on different atoms in the moiety.
Within the context of this invention 'saturated' means 'fully saturated', if not otherwise specified.
Unless otherwise specified or clear from the context, aromatic rings and heterocyclyl goups, can be attached to the remainder of the molecule of Formula (I) through any available ring carbon atom (C-linked) or nitrogen atom (N-linked).

- 13 -Unless otherwise specified or clear from the context, aromatic rings and heterocyclyl goups, may optionally be substituted, where possible, on carbon and/or nitrogen atoms according to the embodiments.
The term "subject" as used herein, refers to an animal, preferably a mammal (e.g. cat, dog, primate or human), more preferably a human, who is or has been the object of treatment, observation or experiment.
The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medicinal doctor or other clinician, which includes alleviation or reversal of the symptoms of the disease or disorder being treated.
The term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
The term "treatment", as used herein, is intended to refer to all processes wherein there may be a slowing, interrupting, arresting or stopping of the progression of a disease, but does not necessarily indicate a total elimination of all symptoms.
The term "compound(s) of the (present) invention" or "compound(s) according to the (present) invention" as used herein, is meant to include the compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof.
As used herein, any chemical formula with bonds shown only as solid lines and not as solid wedged or hashed wedged bonds, or otherwise indicated as having a particular configuration (e.g. R, S) around one or more atoms, contemplates each possible stereoisomer, or mixture of two or more stereoisomers.
Hereinbefore and hereinafter, the term "compound(s) of Formula (I)" is meant to include the tautomers thereof and the stereoisomeric forms thereof.
The terms "stereoisomers", "stereoisomeric forms" or "stereochemically isomeric forms"
hereinbefore or hereinafter are used interchangeably.
The invention includes all stereoisomers of the compounds of the invention either as a pure stereoisomer or as a mixture of two or more stereoisomers.
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.
Atropisomers (or atropoisomers) are stereoisomers which have a particular spatial configuration, resulting from a restricted rotation about a single bond, due to large steric hindrance. All atropisomeric forms of the compounds of Formula (I) are intended to be

- 14 -included within the scope of the present invention.
Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration.
Sub stituents on bivalent cyclic saturated or partially saturated radicals may have either the cis- or trans-configuration; for example if a compound contains a di substituted cycloalkyl group, the substituents may be in the cis or trans configuration.
Therefore, the invention includes enantiomers, atropisomers, diastereomers, racemates, E
isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.
The meaning of all those terms, i.e. enantiomers, atropisomers, di astereomers, racemates, E
isomers, Z isomers, cis isomers, trans isomers and mixtures thereof are known to the skilled person.
The absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration at an asymmetric atom is specified by either R or S. Resolved stereoisomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light. For instance, resolved enantiomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other stereoisomers. Thus, when a compound of Formula (1) is for instance specified as (R), this means that the compound is substantially free of the (S) isomer; when a compound of Formula (I) is for instance specified as E, this means that the compound is substantially free of the Z isomer; when a compound of Formula (I) is for instance specified as cis, this means that the compound is substantially free of the trans isomer.
Some of the compounds according to Formula (I) may also exist in their tautomeric form.
Such forms in so far as they may exist, although not explicitly indicated in the above Formula (I) are intended to be included within the scope of the present invention.
For example N-NH N-N ______ OH
___________________________ 0 is equivalent to It follows that a single compound may exist in both stereoisomeric and tautomeric form.

- 15 -Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form with one or more equivalents of an appropriate base or acid, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
The pharmaceutically acceptable salts as mentioned hereinabove or hereinafter are meant to comprise the therapeutically active non-toxic acid and base salt forms which the compounds of Formula (I) and solvates thereof, are able to form.
Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g.
hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e.
ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.
The compounds of Formula (I) and solvates thereof containing an acidic proton may also be converted into their non-toxic metal or amine salt forms by treatment with appropriate organic and inorganic bases.
Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, cesium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrroli dine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form.
The term solvate comprises the solvent addition forms as well as the salts thereof, which the compounds of Formula (I) are able to form. Examples of such solvent addition forms are e.g.
hydrates, alcoholates and the like.
The compounds of the invention as prepared in the processes described below may be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers, that can be separated from one another following art-known resolution

- 16 -procedures. A manner of separating the enantiomeric forms of the compounds of Formula (I), and pharmaceutically acceptable salts, and solvates thereof, involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
Preferably if a specific stereoisomer is desired, said compound would be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
The term "enantiomerically pure" as used herein means that the product contains at least 80%
by weight of one enantiomer and 20% by weight or less of the other enantiomer.
Preferably the product contains at least 90% by weight of one enantiomer and 10% by weight or less 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 1%
or less of the other enantiomer.
The present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for 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 usually found in nature (or the most abundant one found in nature).
All isotopes and isotopic mixtures of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form.
Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2H, 3H, 11c, 13c, 14c , 13N, 150, 170, 180, 32Fb, 3313, 35s, 18F, 36c1, 1221, 1231, 1251, 131=, 1 75Br, 76Br, .77Br and 'Br. Preferably, the isotope is selected from the group of 2H, 3H, "C and "F.
More preferably, the isotope is 2H. In particular, deuterated compounds are intended to be included within the scope of the present invention.
Certain isotopically-labeled compounds of the present invention (e.g., those labeled with 3H
and "C) may be useful for example in substrate tissue distribution assays.
Tritiated (3H) and carbon-14 ("C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
Positron emitting isotopes such as 150, 13N, "C and 18F are useful for positron emission tomography (PET) studies. PET imaging in cancer finds utility in helping locate and identify tumours, stage the disease and determine suitable treatment. Human cancer cells overexpress many receptors or proteins that are potential disease-specific molecular targets.
Radiolabelled tracers that bind with high affinity and specificity to such receptors or proteins on tumour

- 17 -cells have great potential for diagnostic imaging and targeted radionuclide therapy (Charron, Carlie L. et al. Tetrahedron Lett. 2016, 57(37), 4119-4127). Additionally, target-specific PET
radiotracers may be used as biomarkers to examine and evaluate pathology, by for example, measuring target expression and treatment response (Austin R. et al. Cancer Letters (2016), doi: 10.1016/j.canlet.2016.05.008).
The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein RxaRxb R1 represents -C(=0)-NRxa Rxb; or R" and Wb are each independently selected from the group consisting of hydrogen;
C3_6cycloalkyl; Ci_4alkyl; and Ci-ialkyl substituted with 1, 2 or 3 halo atoms;
Rib represents F or Cl;
Y1 represents -CR5aR5b-, -0-, -S-, or -NR5'-;
R2 is selected from the group consisting of hydrogen, halo, Ci-ialkyl, -0-Ci_4alkyl, and -NR7aRM ;
and U2 each independently represent N or CH;
nl, n2, n3 and n4 are each independently selected from 1 and 2;
X1 represents CH, and X2 represents N;
R4 represents Ci_salkyl;
(1:).
s.,.
or R5a, R5b, R5e, R7a, and km, are each independently selected from the group consisting of hydrogen, Ci_4alkyl and C3_6cycloalkyl;
R3 is selected from the group consisting of Het', Het2, Cy2, and -C1_6alkyl_NRxeRxd;
R' represents Cy'; Het5; -Ci_ 6alkyl-Cyl; -CI -6alkyl-Het3; -Ci_6a1ky1-Het4;
or -C1_6alkyl-phenyl;
It'd represents hydrogen; Ci_4a1ky1; or Ci_4alkyl substituted with one, two or three sub stituents selected from the group consisting of halo, -OH, -0-Ci_4a1ky1, and cyano;

- 18 -or R" and IV' are taken together to form together with the N-atom to which they are attached a 4- to 7-membered monocyclic fully saturated heterocyclyl containing one N-atom and optionally one additional heteroatom selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2; wherein said heterocyclyl is optionally substituted with one, two or three substituents selected from the group consisting of halo, -OH, -0-Ci_4alkyl, and cyano, Heti represents 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 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2, or a bicyclic C-linked 6- to 11-membered fully saturated heterocyclyl containing one N-atom and optionally one or two additional heteroatoms each independently selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2;
wherein said heterocyclyl is optionally substituted on one nitrogen with a substituent selected from the group consisting of R6 and -C(=0)-1e; and wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four substituents each independently selected from the group consisting of halo, R6, Het6a, Het6b, C1_4alkyl, oxo, -NR9aR" and -OH, Het2 represents C-linked pyrazolyl or triazolyl; which is substituted on one nitrogen atom with lea;
R6 is selected from the group consisting of Het3; -C(=0)-NH-R8;
C1_6alkyl optionally substituted with one or two substituents each independently selected from the group consisting of Het3, Hee, Het6a, Het6b, Cy', -CN, -OH, -0-C1_4alkyl, -C(=0)-NH-C1-4a1ky1, -C(=0)-NH-Ci_4alkyl-C3_6cycloalkyl, -C(=0)-0H, -NR 11 aR1 lb and 4,414_,-, 4alkyl, and C3_6cycloalkyl optionally substituted by one or two substituents each independently selected from the group consisting of -CN, -OH, -0-C1_4alkyl, -C(=0)-NH-Ci_4a1kyl, -NH-S(=0)2-Ci_4alkyl, and Ci_4alkyl optionally substituted with one substituent selected from the group consisting of OH, -0-C1_4alkyl, -C(=0)-NH-C1_4alkyl and -NH-S(=0)2-Ci_4alkyl, -rs 6a K represents C1-6alkyl substituted with one substituent selected from the group consisting of _NR1 laR1 lb, He, 3a, t and Het6a, R8 represents C1_6a1kyl substituted with one substituent selected from the group consisting of -OH, -NR1 laR1 lb, Het3', and Het6a;

- 19 -Het3 and Het5 each independently represent a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2; or a bicyclic C-linked 6- to 11-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2;
wherein said heterocyclyl is optionally substituted on one carbon atom with C1_4alkyl, halo, -OH, -NR1 laR1 lb, or oxo; and wherein said heterocyclyl is optionally substituted on one nitrogen atom with Ci_4alkyl;
Hee' and Hee' each independently represent 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 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2; or a bicyclic C-linked 6- to 11-membered fully saturated heterocyclyl containing one N-atom, and optionally one or two additional heteroatoms each independently selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2;
wherein said heterocyclyl is optionally substituted on one carbon atom with CI-4alkyl, halo, -OH, _NRI aR1 lb, or oxo; and wherein said heterocyclyl is optionally substituted on one nitrogen atom with C1_4alkyl;
Het4 and Het7 each independently represent a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from 0, S, and N; wherein said 5-membered aromatic ring is optionally substituted on one nitrogen atom with C1_4alkyl; and wherein said 5- or 6-membered aromatic ring is optionally substituted on one carbon atom with -OH;
Het6a and Het' 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 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2; wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four substituents each independently selected from the group consisting of halo, -OH, oxo, -(C=0)-ONR1 aRl0b,0-C3_6cycloalkyl, -S(=0)2-C1_4a1ky1, cyano, Ci_4alkyl, -Ci_4alkyl-OH, -0-C1_4alkyl, -0-(C=0)-NR10aRlOb, and -0-(C=0)-Ci_4alkyl; and wherein said heterocyclyl is optionally substituted on one nitrogen with a substituent selected from the group consisting of -C(=0)-Ci_4alkyl and -(C=0)-NR10aRlOb;
Het each independently represent a monocyclic N-linked 4- to 7-membered fully saturated

- 20 -heterocyclyl containing two N-atoms and optionally one additional heteroatom selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2;
wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four substituents each independently selected from the group consisting of halo, -OH, oxo, -(C=0)-NR1 OaR101), -0-C3_6cycloalkyl, -S(=0)2-C1_4a1ky1, cyano, Ci_4alkyl, Ci_4alkyl-OH, -0-C
14a1ky1, -0-(C=0)-NR10aR1 013, and -0-(C=0)-C1_4alkyl; and wherein said heterocyclyl is optionally substituted on one nitrogen with a substituent selected from the group consisting of -C(=0)-C1_4alkyl and -(C=0)-NR10aRiob;
Het" represents a bicyclic N-linked 6- to 11-membered fully saturated heterocyclyl containing one N-atom and optionally one or two additional heteroatoms each independently selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2; wherein said heterocyclyl is optionally substituted on one carbon atom with a substituent selected from the group consisting of -OH, oxo, -(C=0)-NR'OaRlOb, -NH-C(=0)-Ci_4a1ky1, -NH-C(=0)-Cy3, and -0-C1_4a1ky1, and wherein said heterocyclyl is optionally substituted on one nitrogen with a substituent selected from the group consisting of -C(=0)-Ci_4alkyl, -C(=0)-Cy3, and C1_4a1ky1;
Cy' represents C3_6cycloalkyl optionally substituted with one, two or three substituents selected from the group consisting of -OH, -NH-C(=0)-C1_4alkyl, C1_4alkyl, -NH-S(=0)2-C1_4alkyl, -S(=0)2-C1_4alkyl, and -0-C1_4alkyl, Cy2 represents C3_7cycloalkyl substituted with one or two substituents each independently selected from the group consisting of -NleaR", Het", Het', and Ci_6alkyl substituted with one or two substituents each independently selected from the group consisting of Het3', Het6', Het', and -NleaR", and said C3_7cycloalkyl is optionally substituted with one or two additional substituents each independently selected from the group consisting of halo, R6, C1_4alkyl, and -OH;
Cy3 represents C3_7cycloalkyl; wherein said C3_7cycloa1kyl is optionally substituted with one, two or three halo substituents, R9a and R" are each independently selected from the group consisting of hydrogen;
C1_4alkyl; C3_6cycloa1kyl, Het5; -C1_4alkyl-R16; -C(=0)-Ci_4alkyl-Het3a; -C(=0)-R1-4;
C3_6cycloa1kyl substituted with one, two or three substituents selected from the group consisting of halo, -OH, -0-C1_4alkyl, and cyano, and C1_4alkyl substituted with one, two or three substituents selected from the group consisting of halo, -OH, -0-Ci_4alkyl, and cyano;

- 21 -Rioa, Riob, Riia, let), R13a, Ri3b, Risa, Ri5b, R17a, and Rim are each independently selected from the group consisting of hydrogen and Ci-lalkyl;

tc represents Het''; Het; or Ct-talkyl substituted with one, two or three substituents selected from the group consisting of _NR13aR1313 and Het8a;
1-c - 16 represents -C(=0)-NR17aRl7b, _S(=0)2-C1_4a11cy1, Het', Het', or Het';
and the pharmaceutically acceptable salts and the solvates thereof.
The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein Rla represents -C(=0)-NRxaRxb;
R' and Wb are each independently selected from the group consisting of C3_6cycloalkyl; C1_4a1ky1; and CI-talky] substituted with 1, 2 or 3 halo atoms;
R"
represents F;
Y1 represents -0-;
R2 represents hydrogen;
U1 and U2 each independently represent N or CH;
nl, n2, n3 and n4 are each independently selected from 1 and 2;
X1 represents CH, and X2 represents N;
R4 represents Ci_salkyl;
Nor ''=
R3 is selected from the group consisting of Het' and Cy2;
Heti represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom;
wherein said heterocyclyl is optionally substituted on one nitrogen with a substituent selected from the group consisting of R6 and -C(=0)-W; and wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four halo substituents;
R6 is selected from the group consisting of Het3;
C1_6alkyl optionally substituted with one or two substituents each independently selected from the group consisting of Het3, Heft, Het6a, Cy', -OH, -0-Ct-4a1ky1, -C(=0)-NH-C1_4alky1, -C(=0)-NH-C1_4alkyl-C3_6cyc1oalkyl, and -NH-S(=0)2-C1_4alkyl;
R8 represents C1_6a1kyl substituted with one substituent selected from the group consisting of -

- 22 -OH and -NR11111 lb, Het3 and Het5 each independently represent a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2;
wherein said heterocyclyl is optionally substituted on one carbon atom with -OH or oxo;
Het4 represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from 0, S, and N; wherein said 5-or 6-membered aromatic ring is optionally substituted on one carbon atom with -OH;
Het' represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom and optionally one or two additional heteroatoms each independently selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2; wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four substituents each independently selected from the group consisting of oxo, -S(=0)2-C1_4alkyl, and -0-Ci_4alkyl; and wherein said heterocyclyl is optionally substituted on one nitrogen with -C(=0)-Ci_4a1ky1;
Heel' represents a bicyclic N-linked 6- to 11-membered fully saturated heterocyclyl containing one N-atom and optionally one or two additional heteroatoms each independently selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2, wherein said heterocyclyl is optionally substituted on one carbon atom with -(C=0)-NRioartiob, and wherein said heterocyclyl is optionally substituted on one nitrogen with -C(=0)-C1_4a1ky1, Cy' represents C3_6cycloalkyl optionally substituted with one, two or three substituents selected from the group consisting of -OH, -NH-C(=0)-Ci_4alkyl, C1_4alkyl, -NH-S(=0)2-C1_4a1ky1, and -0-C 1_4a1ky1;
Cy2 represents C3_7cycloalkyl substituted with one or two substituents each independently selected from the group consisting of -NleaR9b, Het"; and Heeb;
R9a and R91' are each independently selected from the group consisting of hydrogen;
Ci_4alkyl; C3_6cycloalkyl, Het5; -Ci_4alkyl-R16; and C1_4alkyl substituted with one, two or three -0-C1_4alkyl substituents;
R10', R1011, R1 1 a, and R1 lb represent Ci_4alkyl;

- 23 --=-= 16 tc represents Hee;
and the pharmaceutically acceptable salts and the solvates thereof.
The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein Ria represents -C(=0)- aNRx Rxb;
It' and Rxb represent C1_4alkyl;
tc represents F;
Y1 represents -0-;
R2 represents hydrogen;
U1 and U2 each independently represent N or CH;
nl, n2, n3 and n4 are each independently selected from 1 and 2;
X' represents CH, and X2 represents N;
R4 represents isopropyl;
K3 is selected from the group consisting of Het' and Cy2;
Het' represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom;
wherein said heterocyclyl is optionally substituted on one nitrogen with a substituent selected from the group consisting of R6;
R6 represents C1_6a1kyl substituted with one Het3;
Het3 represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2;
Het6a represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom; wherein said heterocyclyl is optionally substituted on one carbon atom with one -0-Ci_4alkyl;
Heeb represents a bicyclic N-linked 6- to 11-membered fully saturated heterocyclyl containing one N-atom and optionally one or two additional heteroatoms each independently selected from 0 and N; wherein said heterocyclyl is optionally substituted on one carbon

- 24 -atom with -(C=0)-ONR1 aRlOb; and wherein said heterocyclyl is optionally substituted on one nitrogen with -C(=0)-Ci4alkyl;
Cy2 represents C3_7cycloalkyl substituted with one substituents selected from the group consisting of Het' and Het6b;
Rma and Ri" represent C1_4alkyl;
and the pharmaceutically acceptable salts and the solvates thereof.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Rla represents -C(=0)- aNRx Rxb.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein T's tc represents F.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R2 represents hydrogen.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein n1 is 1, n2 is 2, n3 is 1, and n4 is 1.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ul represents N
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ul represents N, and U2 represents N.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein U' represents CH, and U2 represents N
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as

- 25 -

26 mentioned in any of the other embodiments, wherein Y1 represents -0-.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Y1 represents -0-; and U2 represents N
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Y1 represents -0-; and U1 represents N.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Y1 represents -0-;
U2 represents N;
tc represents F; and R2 represents hydrogen.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Y1 represents -0-, U1 represents N, Rib represents F, and R2 represents hydrogen.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Y1 represents -0-, U1 represents N;
lb Rrepresents F;
R2 represents hydrogen; and R4 represents isopropyl.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R`i represents isopropyl.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3 represents Het' or Cy2.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3 represents Cy2 In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3 represents Het'.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Heti represents 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 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2; or a bicyclic C-linked 6- to 11-membered fully saturated heterocyclyl containing one N-atom and optionally one or two additional heteroatoms each independently selected from 0, S, and N, wherein said S-atom might be substituted to form S(-0) or S(=0)2;
wherein said heterocyclyl is optionally substituted on one nitrogen with R6, and wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four substituents each independently selected from the group consisting of halo, R6, Hee', Ci_4alkyl, oxo, -NR9aR9b and -OH.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3 represents He-0;
Heti represents 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 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2, or a bicyclic C-linked 6- to 11-membered fully saturated heterocyclyl containing one N-atom and optionally one or two additional heteroatoms each independently selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2;

- 27 -wherein said heterocyclyl is optionally substituted on one nitrogen with R6;
and wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four substituents each independently selected from the group consisting of halo, R6, Het6a, Het6b, Ci_4alkyl, oxo, -NR9aR9b and -OH.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R6 is selected from the group consisting of Hct3; -C(=0)-NH-R8;
C1_6alkyl optionally substituted with one or two sub stituents each independently selected from the group consisting of Het3, Hee, Het6a, Het6b, Cy', -CN, -OH, -0-C1_4alkyl, -C(=0)-NH-Ci-4alkyl, -C(=0)-NII-Ch4a1ky1-C3_6cyc1oalkyl, -C(=0)-0H, -NR.11aR1 lb and -NH-S(=0)2-C1-4alkyl; and C3_6cycloalkyl substituted by one or two substituents each independently selected from the group consisting of -CN, -OH, -0-C1_4alky1, -C(-0)-NH-Ci_4alkyl, -NH-S(=0)2-Ci_4alkyl, and C1_4a1kyl optionally substituted with one substituent selected from the group consisting of OH, -0-C1_4a1kyl, -C(=0)-NH-Ci_4a1kyl and -NH-S(=0)2-Ci_4alkyl.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R6 is selected from the group consisting of Het3; -C(=0)-NH-R8;
C1_6alkyl substituted with one or two substituents each independently selected from the group consisting of Het3, Heft, Het6a, Het6b, Cy', _CN, -OH, -0-Ci_4a1ky1, -C(=0)-NH-Ci_4a1ky1, -C(=0)-NH-C1_4alkyl-C3_6cycloalkyl, -C(=0)-0H, -NR'laR1 lb and -NH-S(=0)2-Ci_4a1ky1, and C3_6cycloalkyl substituted by one or two substituents each independently selected from the group consisting of -CN, -OH, -0-Ci_4a1ky1, -C(=0)-NH-C1_4alkyl, -NH-S(=0)2-Ci_4a1ky1, and Ci_4a1ky1 optionally substituted with one substituent selected from the group consisting of OH, -0-C1_4a1ky1, -C(=0)-NH-C1_4alkyl and -NH-S(=0)2-Ci_4a1ky1.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R4 represents

- 28 -s'.s..
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3 represents Het';
Heti represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom;
wherein said heterocyclyl is substituted on one nitrogen with R6; and wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four halo sub stituents;
R6 is selected from the group consisting of C1_6alkyl optionally substituted with one or two sub stituents each independently selected from the group consisting of Het3, Het4, Hee', and Cy'.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein 151 represents N;
R3 represents Het';
Heti represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom;
wherein said heterocyclyl is substituted on one nitrogen with R6; and wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four halo sub stituents;
R6 is selected from the group consisting of Ci_6alkyl optionally substituted with one or two sub stituents each independently selected from the group consisting of Het3, Het4, Hee', and Cy'.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein represents N;

- 29 -Y1 represents -0-;
R" represents F;
R2 represents hydrogen;
Rzi represents isopropyl;
R3 represents Hal;
Heti represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom;
wherein said heterocyclyl is substituted on one nitrogen with R6; and wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four halo sub stituents;
R6 is selected from the group consisting of Ci_6alkyl optionally substituted with one or two sub stituents each independently selected from the group consisting of Het3, Het4, Het6a, and Cy'.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3 represents Het';
Het' represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom;
wherein said heterocyclyl is substituted on one nitrogen with R6;
R6 represents C1_6alky1 substituted with one Het3.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein IJ1 represents N;
R3 represents Het';
Het' represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom;
wherein said heterocyclyl is substituted on one nitrogen with R6;
R6 represents C1_6alkyl substituted with one Het3.
In an embodiment, the present invention relates to those compounds of Formula (I) and the

- 30 -pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein 151 represents N;
Y1 represents -0-, Rib represents F;
R2 represents hydrogen;
R4 represents isopropyl;
R3 represents Het';
Heti represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom;
wherein said heterocyclyl is substituted on one nitrogen with R6;
R6 represents C1_6a1kyl substituted with one Het3 In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (I) are restricted to compounds of Formula (I-y):
X
X
n3(g)n4 n1( )n2 Ri a (I-y) U, -1\1 wherein R3 is as defined for the compounds of Formula (I) or any subgroup thereof as mentioned in any of the other embodiments.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (I) are restricted to compounds of Formula (I-y):

- 31 -X
n3( )n4 n1(8 )n2 R1 a (I-y) wherein R3 represents Het'.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (I) are restricted to compounds of Formula (I-y):
po3 X
n3(g)n4 n1( )n2 R1a (I-y) U
wherein R3 represents Cy2.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (I) are restricted to compounds of Formula (I-z):

r(j2 U

- 32 -wherein R3 is as defined for the compounds of Fon-nula (I) or any subgroup thereof as mentioned in any of the other embodiments.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (I) are restricted to compounds of Formula (I-z):

Rla CY-3 0 ylc, (I-Z) U
wherein R3 represents Het'.
In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (I) are restricted to compounds of Formula (I-z):

Rla 0 yl,õ 2 411 (1-4 U
wherein R3 represents Cy2.
In an embodiment, the present invention relates to a subgroup of Formula (I) as defined in the general reaction schemes.
In an embodiment the compound of Formula (I) is selected from the group consisting of any of the exemplified compounds, tautomers and stereoisomeric forms thereof, and the free bases, any pharmaceutically acceptable salts, and the solvates thereof.

- 33 -All possible combinations of the above indicated embodiments are considered to be embraced within the scope of the invention.
METHODS FOR THE PREPARATION OF COMPOUNDS OF FORMULA (I) In this section, as in all other sections unless the context indicates otherwise, references to Formula (I) also include all other sub-groups and examples thereof as defined herein.
The general preparation of some typical examples of the compounds of Formula (I) is described hereunder and in the specific examples, and are generally prepared from starting materials which 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 only meant to represent examples of the invention and are in no way meant to be a limit of the invention.
Alternatively, compounds of the present invention may also be prepared by analogous reaction protocols as described in the general schemes below, combined with standard synthetic processes commonly used by those skilled in the art.
The skilled person will realize that in the reactions described in the Schemes, although this is not always explicitly shown, it may be necessary to protect reactive functional groups (for example hydroxy, amino, or carboxy groups) where these are desired in the final product, to avoid their unwanted participation in the reactions. In general, conventional protecting groups can be used in accordance with standard practice. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The skilled person will realize that in the reactions described in the Schemes, it may be advisable or necessary to perform the reaction under an inert atmosphere, such as for example under N2-gas atmosphere.
It will be apparent for the skilled person that it may be necessary to cool the reaction mixture before reaction work-up (refers to the series of manipulations required to isolate and purify the product(s) of a chemical reaction such as for example quenching, column chromatography, extraction).
The skilled person will realize 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 shorten the overall reaction time.
The skilled person will realize that another sequence of the chemical reactions shown in the Schemes below, may also result in the desired compound of Formula (I).

- 34 -The skilled person will realize that intermediates and final compounds shown in the Schemes below may be further functionalized according to methods well-known by the person skilled in the art. The intermediates and compounds described herein can be isolated in free form or as a salt, or a solvate thereof. The intermediates and compounds described herein may be synthesized in the form of mixtures of tautomers and stereoisomeric forms that can be separated from one another following art-known resolution procedures.

In general, compounds of Formula (I) wherein Yl- is limited to Yla being -0-or -NR5c-, hereby named compounds of Formula (Ia), (Ib), (Ic), (Id), (Ie), can be prepared according to the following reaction Scheme 1. In Scheme 1, W1 represents fluoro, chloro, bromo or iodo; all other variables are defined according to the scope of the present invention.

R
i_ 4 R3 L.R3 R ---,xi.

X m1(S )m2 Rla ml (5 )m2 m1(8 )m2 yl aH
WIn1( )n2 n1( )n2 Illa N
W1 1 N Rik) Ri a n1( N
)n2 v\& 1, u IV
--N -W step 1 N ...-,....õ
W1 step 2 Rib N
-"'N W
II III (la) R1,1=z3 12 step 3 HNR7aFeb vv2mgcl_oikyi x H 0-Ci_olkyl VI
VII
m1(8 )m2 V step 4 at 5 step R1 a n1( N )n2 R4-õ..xi,R3 R4 yl_a _.., u R,_R3 N ,...,--2 X'I 2 X
Ft b I. '1\1 ml( X )m2 m1(8 )m2 ml( X )m2 (lb) )n2 RI,.
n1( )n2 Rth n1( N
1,1a n1( N )n2 N

410 NI_ ,...i.... Rib 0 N ....õ-1, m 7b Rib C1-4alkyl (Id) (le) (lc) In Scheme 1, the following reaction conditions apply:
Step 1: at a suitable temperature such as ranged from room temperature to 90 C, in the presence of a suitable base such as for example diisopropylethylamine or triethylamine or sodium carbonate, in a suitable solvent such as for example acetonitrile or di m ethyl formami de or dichloromethane;
Step 2: at a suitable temperature range from room temperature to 130 C, in presence of a suitable base such as for example cesium carbonate, in a suitable solvent such as for example

- 35 -dimethylformamide or 1-methy1-2-pyrrolidinone;
Alternatively, at a suitable temperature such as for example room temperature, in the presence of a suitable deprotonating agent such as for example sodium hydride, in a suitable solvent such as for example dimethylsulfoxidc;
Alternatively, at a suitable temperature such as room temperature, in the presence a suitable base such as 1,8-Di azabi cyclo[5.4.0]undec-7-ene (DRU), in a suitable solvent such as for example tetrahydrofuran;
Step 3: at a suitable temperature such as room temperature, in the presence of a suitable catalyst such as palladium on charcoal (Pd/C), in a suitable solvent such as methanol, under H2 pressure such as for example from 1 to 3 bar, optionally in the presence of a base such as triethylamine;
Alternatively, at a suitable temperature such as room temperature, in the presence of a suitable catalyst such as for example 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex, a suitable reducing agent such sodium borohydride, a suitable base such as for example /V,N,N',AP-tetramethylethylenediamine, in a suitable solvent such as for example tetrahydrofuran;
Step 4: at a suitable temperature range from 100 to 130 C, in presence of a suitable base such as for example cesium carbonate, in a suitable solvent such as for example dimethylformamide or 1-methy1-2-pyrrolidinone;
Step 5: at a suitable temperature range from 100 to 130 C, in presence of a suitable base such as for example cesium carbonate, in a suitable solvent such as for example dimethylformamide or 1-methy1-2-pyrrolidinone;
alternatively, at a suitable temperature ranged from 80 to 100 C, in presence of a suitable catalyst such as palladium acetate (Pd(OAc)2), in presence of a suitable ligand such as for example 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, in presence of a suitable base such as cesium carbonate, in a suitable solvent such as for example dioxane;
Step 6: at a suitable temperature from room temperature to 60 C, in presence of a suitable catalyst such as palladium acetate (Pd(OAc)2) or Tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3), in presence or not of a suitable ligand such as for example triphenylphosphine, in a suitable solvent such as for example dioxane;

In general, compounds of Formula (I) wherein Y1 is limited to -CH2-, and R2 is limited to W1, hereby named compounds of Formula (If), can be prepared according to the following reaction

- 36 -Scheme 2. In Scheme 2, all other variables are defined according to the scope of the present invention.

t_rcx1,R3 r, -"X

X X
Ri a n3( )n4 n3( S )n4 CH2Zn Br Rib VIII
NI lb NI
VV .."1\1 W
step 1 In Scheme 2, the following reaction conditions apply:
Step 1: at a suitable temperature ranged from 60 C to 100 C, in 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), in a suitable solvent such as for example tetrahydrofuran or dioxane.
The skilled person will realize that starting from compound (If), analogous chemistry as reported in steps 3, 4, 5 and 6 in scheme 1 could be performed.

In general, compounds of Formula (I) wherein Yl is limited to -CR5aR5b- and R2 is limited to Wl, hereby named compounds of Formula (Ig), can be prepared according to the following reaction Scheme 3. In Scheme 3 at least one of R5a and R5b is other than hydrogen. All other variables are defined according to the scope of the present invention.
R4,1-R3 R4 R3 -X

Ri a R5a n3( )n4 R5b n3( g )n4 n1( )n2 n1( )n2 Ri a R5a R5b N
Rib Villa , I
wi step 1 Rib III (Ig) In Scheme 3, the following reaction condition apply:

- 37 -Step 1: at a suitable temperature ranged from 80 C to 200 C, in presence of a suitable catalyst such as palladium acetate (Pd(OAc)2), in the presence of a suitable ligand such as for example triphenylphosphine or tricyclohexylphosphine, in a suitable solvent such as for example dioxane, preferably in sealed conditions, optionally under microwave irradiation.
The skilled person will realize that starting from compound (Ig), analogous chemistry as reported in steps 3, 4, 5 and 6 in scheme 1 could be performed.

In general, compounds of Formula (I) hereby named compounds of Formula (Ib) can be alternatively prepared according to the following reaction Scheme 4. In Scheme 4, PG1 represents a suitable protecting group, such as for example tert-butyloxycarbonyl and LG1 is a leaving group such as for example chloro, bromo, iodo or tosylate or mesylate;
all other variables are defined as listed before or according to the scope of the present invention.

)1/4'2 X X
n3( g )n4 n3( S )n4 R1' n3( X
)n4 Y1 alH
WI n1( )n2 n1( )n2 1:21a n1( )n2 N IX N N
w H W I Rno IV
--==<"-L"----;(1-Y-LU
N j...,. , N ..,J, 1 I I
VV step 1 -'N¨ W step 2 R1'' II x XI

R--õõ.% iR

)1( L
n3( )n4 R4)..R3 X1113 n3( X )n4 n3( )n4 R1 n1( R

iRi, n1( N )n2 1 n1( S )n2 N)n2 1 2 ' YiY U R R XIllb Y1Y1 u Yi.YLI Rib N, ,j- Ri IV b ' N step 5 :lb 101 NC NC) step 3 step 4 xii XIII (lb) In Scheme 4, the following reaction conditions apply:
Step 1: at a suitable temperature such as ranged from room temperature to 90 C, in the presence of a suitable base such as for example diisopropylethylamine or triethylamine or sodium carbonate, in a suitable solvent such as for example acetonitrile or dimethylformamide or dichloromethane;
Step 2: at a suitable temperature range from room temperature to 130 C, in presence of a suitable base such as for example cesium carbonate, in a suitable solvent such as for example dimethylformamide or 1-methyl-2-pyrrolidinone;
Alternatively, at a suitable temperature such as for example room temperature, in the presence

- 38 -of a suitable deprotonating agent such as for example sodium hydride, in a suitable solvent such as for example dimethylsulfoxide;
Alternatively, at a suitable temperature such as room temperature, in the presence a suitable base such as 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), in a suitable solvent such as for example tetrahydrofuran;
Step 3: at a suitable temperature such as room temperature, in the presence of a suitable catalyst such as palladium on charcoal (Pd/C), in a suitable solvent such as methanol, under H2 pressure such as for example from 1 to 3 bar;
Alternatively, at a suitable temperature such as room temperature, in the presence of a suitable catalyst such as for example 1, r-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex, a suitable reducing agent such sodium borohydride , a suitable base such as for example /V,N,N;N'-tetramethylethylenediamine, in a suitable solvent such as for example tetrahydrofuran;
Step 4: when PG' is tert-butyloxycarbonyl, at a suitable temperature range such as for example from 0 C to room temperature, in the presence of suitable cleavage conditions, such as for example an acid such as HCl or trifluoroacetic acid in a suitable solvent such as acetonitrile or DCM or methanol (Me0H);
Step 5: represents all type of reactions, such as for examples reductive amination, nucleophilic substitution, leading to final examples (lb);
The skilled person will realize that starting from intermediate XI, analogous chemistry as reported in steps 3, 4, 5 and 6 in scheme 1 could be performed.

In general, compounds of Formula (I) wherein U is limited to N and Y1 is limited to Ylb being 0, hereby named compounds of Formula (Iba) can be prepared according to the following reaction Scheme 5. In Scheme 5, PG' represents a suitable protecting group, such as for example tert-butyloxycarbonyl and 1A/2 a leaving group such as for example chloro, tosylate or mesylate; all other variables are defined according to the scope of the present invention.

- 39 -Ria lb 0 O-C1-4alkY1 Y.--- 0 0-C1_4alkyl Ri a 0 0 H
CI Rib IV yziX
yz j.....
YNji _________________________ a I N ___________ s I
NI
N'N-., "NI,--I
"NI
step 1 Rib 41 N step 2 Rib 0 N
II )(IV X\/

R

tõR3 X
i a n3( )n4 12 X
R OH Ria n3( )n4 ylb ,....1,_ VV2 n1( )n2 ¨a- N'N. ¨3.- .`=N H Illa 1 n1(2 )n2 -Nri _) , R a N
R l b 401 step 3 step 4 R1 b 4111 'N step 5 Yi IYN
XVI X\/II Rib 1 N I
"N,J

P Gi 1 (lba) n3( X )n4 R4)c3 Alia step 6 ni( )n2 LGI
N IX step 8 H
R4,X.."'R3 )(Mb 1_2 n3( )n4 n3( 2 )n2 )n4 N
Ria n1( )n2 Ri, n1( yz Ri b Si rei.....,,N
__________________________________________________________ r N"N-) -N1-1"N-) step 7 Rib 140 XVIII >ix In Scheme 5, the following reaction conditions apply:
Step 1: at a suitable temperature such as room temperature, in the presence of a suitable base such as for example potassium carbonate, in a suitable solvent such as for example dimethylformamide;
Step 2: at a suitable temperature such as room temperature, in presence of a suitable base such as lithium hydroxyde, in a suitable solvent such as for example a mixture of tetrahydrofuran, ethanol and water;
Step 3: at a suitable temperature such as room temperature, in the presence of a dibromoisocyanurate, in a suitable solvent such as dichloroethane;
Step 4: when W2 is chloro, at a suitable temperature range such as room temperature, in the presence of a chlorinating reagent such as oxalyl chlorine, in the presence of a catalytic amount of dimethylformamide, in the presence of a suitable base such as triethylamine, in a suitable

- 40 -solvent such as dichloromethane;
When W2 is a trifluoroethoxy, at a suitable temperature such as 65 C, in the presence of 2,2,2-trifluoroethanol as solvent or not, suitable activating agents such as 1,3-dibromo-1,3,5-triazinane-2,4,6-trione, in the presence of molecular sieve;
Step 5: At a suitable temperature such as room temperature, 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;
Step 6: At a suitable temperature such as room temperature, 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;
Step 7: when PG' is tert-butyloxycarbonyl, at a suitable temperature range such as for example from 0 C to room temperature, in the presence of suitable cleavage conditions, such as for example an acid such as HC1 or trifluoroacetic acid in a suitable solvent such as acetonitrile or DCM or methanol (Me0H);
Step 8: represents all type of reactions, such as for examples reductive amination, nucleophilic substitution leading to final examples (Ib a).

In general, intermediates of formula Ma can be prepared according to the following reaction Scheme 5. In Scheme 5, PG2 represents a suitable protecting group, such as for example benzyloxycarbonyl; all other variables are defined according to the scope of the present invention or as defined in the previous schemes.
GPI GPI
R4---)LR3 XIlla R1R3 X

X
n3( )n4 n3( )n4 n3( )n4 XIllb n3( )n4 n1( )n2 n1( )n2 3, n1( )n2 n1 (X )n2 step 1 GP step 2 GP
step 3 XX XXI XXII
Illa Step 1: at a suitable temperature such as room temperature, in the presence of benzyl chloroformate, in the presence of a suitable base such as as for example triethymaine, in a suitable solvent such as for example dichloromethane;
Step 2: when PG' is tert-butyloxycarbonyl, at a suitable temperature range such as for example from 0 C to room temperature, in the presence of suitable cleavage conditions, such as for example an acid such as HC1 or trifluoroacetic acid in a suitable solvent such as acetonitrile or DCM or methanol (Me0H);

- 41 -Step 3: represents all type of reactions, such as for examples reductive amination, nucleophilic substitution leading to intermediate Ma.

In general, intermediates of formula XXVI can be prepared according to the following reaction Scheme 7. Variables are defined according to the scope of the present invention or as defined in the previous schemes.
Ria Rla Ye RIRS
1,1"- step 1 step 2 step 3 R, XXIII XXIV XXV
XXVI
Step 1: at a suitable temperature such as 120 C, in the presence of a suitable base such as for example cesium carbonate, in a suitable solvent such as for example dimethylacetamide;
Step 2: at a suitable temperature such as 0 C to room temperature, in the presence of a suitable oxidative agent such as for example urea hydrogen peroxide, in the presence of a suitable reagent such as trifluoroacetic anhydride, in a suitable solvent such as for example tett-ally drefuran, Step 3: at a suitable temperature such as 0 C to room temperature, in the presence of a suitable chlorinated agent such as for example phosphoryl chloride, in the presence of a suitable base such as diisopropylethylamine, in a suitable solvent such as for example ethyl acetate;
It will be clear for someone skilled in the art that starting from intermediate XXVI, similar chemistry as reported in Scheme 4 starting from intermediate II could be performed.

In general, intermediates of formula XXVIII can be prepared according to the following reaction Scheme 8. Variables are defined according to the scope of the present invention or as defined in the previous schemes.

X2 n3( g)n4 n3( g)n4 n1( )n2 n1( )n2 wi IX
N
1 5 _, 2 1 5 W1 step 1 N W1 XXVII
XXVIII
Step 1: at a suitable temperature such as ranged from room temperature to 90 C, in the presence of a suitable base such as for example diisopropylethylamine or triethylamine or sodium

- 42 -carbonate, in a suitable solvent such as for example acetonitrile or dimethylformamide or dichloromethane;
It will be clear for someone skilled in the art that starting from intermediate XXVIII, similar chemistry as reported in Scheme 1 (ie steps 3, 4, 5 and 6) could be applied to functionalize first position 2. Then, from the obtained intermediate, similar chemistry as reported in scheme 2 and 3 could be applied to functionalize position 5 with intermediates IV, VIII and VIIa.
It will be appreciated that where appropriate functional groups exist, compounds of various formulae 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 approaches include conventional alkylation, aryl ation, heteroarylation, acylation, sulfonylation, halogenation, nitration, formylation and coupling procedures.
The compounds of Formula (I) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of Formula (I) containing a basic nitrogen atom may be converted into the corresponding di astereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of Formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
In the preparation of compounds of the present invention, protection of remote functionality (e.g., primary or secondary amine) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, t-butoxycarbonyl (B oc), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W.
Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken, New Jersey, 2007.
PHARMACOLOGY
It has been found that the compounds of the present invention block the interaction of menin with MILL proteins and oncogenic MILL fusion proteins. Therefore the compounds according to the present invention and the pharmaceutical compositions comprising such compounds may be useful for the treatment or prevention, in particular treatment, of diseases such as

- 43 -cancer, myelodysplastic syndrome (MDS) and diabetes.
In particular, the compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment or prevention of cancer.
According to one embodiment, cancers that may benefit from a treatment with menin/MLL
inhibitors of the invention comprise leukemias, myeloma or a 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 leukemias include acute leukemias, chronic leukemias, myeloid leukemias, myelogeneous leukemias, lymphoblastic leukemias, lymphocytic leukemias, Acute myelogeneous leukemias (AML), Chronic myelogenous leukemias (CML), Acute lymphoblastic leukemias (ALL), Chronic lymphocytic leukemias (CLL), T cell prolymphocytic leukemias (T-PLL), Large granular lymphocytic leukemia, Hairy cell leukemia (HCL), MILL-rearranged leukemias, MLL-PTD leukemias, MLL
amplified leukemias, MILL-positive leukemias, leukemias exphibiting 1-10XIMEISI gene expression signatures etc.
Hence, the invention relates to compounds of Formula (I), the tautomers and the stereoisomeric forms thereof, and the pharmaceutically acceptable salts, and the solvates thereof, for use as a medicament.
The invention also relates to the use of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, or a pharmaceutical composition according to the invention, for the manufacture of a medicament.
The present invention also relates to a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, or a pharmaceutical composition according to the invention, for use in the treatment, prevention, amelioration, control or reduction of the risk of disorders associated with the interaction of menin with MILL proteins and oncogenic MLL fusion proteins in a mammal, including a human, the treatment or prevention of which is affected or facilitated by blocking the interaction of menin with MLL proteins and oncogenic MILL fusion proteins.
Also, the present invention relates to the use of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a 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 disorders associated with the interaction of menin with MLL proteins and oncogenic MILL fusion proteins in a mammal, including a human, the treatment or prevention of which is affected or facilitated by blocking the interaction of menin with MILL proteins and oncogenic MILL fusion proteins.
The invention also relates to a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, for use in the treatment or prevention of any one of the diseases mentioned hereinbefore.

- 44 -The invention also relates to a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, for use in treating or preventing any one of the diseases mentioned hereinbefore.
The invention also relates to the use of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, for the manufacture of a medicament for the treatment or prevention of any one of the disease conditions mentioned hereinbefore 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 hereinbefore In view of the utility of the compounds of Formula (I), the tautomers and the stereoisomeric forms thereof, and the pharmaceutically acceptable salts, and the solvates thereof, there is provided a method of treating warm-blooded animals, including humans, suffering from any one of the diseases mentioned hereinbefore.
Said method comprises the administration, i.e. the systemic or topical administration, of a therapeutically effective amount of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, to warm-blooded animals, including humans.
Therefore, the invention also relates to a method for the treatment or prevention of any one of the diseases mentioned hereinbefore comprising administering a therapeutically effective amount of compound according to the invention to a patient in need thereof One skilled in the art will recognize that a therapeutically effective amount of the compounds of the present invention is the amount sufficient to have therapeutic activity and that this amount varies inter alias, depending on the type of disease, the concentration of the compound in the therapeutic formulation, and the condition of the patient. An effective therapeutic daily amount would be from 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, which is required to achieve a therapeutically effect may vary on case-by-case basis, for example with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated. A method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per day. In these methods of treatment the compounds according to the invention are preferably formulated prior to administration.
The present invention also provides compositions for preventing or treating the disorders referred to herein. Said compositions comprising a therapeutically effective amount of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, and a pharmaceutically acceptable carrier or diluent.

- 45 -While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. Accordingly, the present invention further provides a pharmaceutical composition comprising a compound according to 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 recipients thereof.
The pharmaceutical compositions may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al.
Remington's Pharmaceutical Sciences (18th ed., Mack Publishing Company, 1990, see especially Part 8 :
Pharmaceutical preparations and their Manufacture).
The compounds of the present invention may be administered alone or in combination with one or more additional therapeutic agents. Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound according to the present invention and one or more additional therapeutic agents, as well as administration of the compound according to the present invention and each additional therapeutic agent in its own separate pharmaceutical dosage formulation.
Therefore, an embodiment of the present invention relates to a product containing as first active ingredient a compound according to the invention and as further active ingredient one or more anticancer agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.
The one or more other medicinal agents and the compound according to the present invention may be administered simultaneously (e.g. in separate or unitary compositions) or sequentially in either order. In the latter case, the two or more compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. It will be appreciated that the preferred method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular other medicinal agent and compound of the present invention being administered, their route of administration, the particular condition, in particular tumour, being treated and the particular host being treated.
The following examples further illustrate the present invention.
EXAMP1,kS
Several methods for preparing the compounds of this invention are illustrated in the following examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification, or alternatively can be synthesized by a skilled person by using well-known methods.

- 46 -As understood by a person skilled in the art, compounds synthesized using the protocols as indicated may exist as a solvate e.g. hydrate, and/or contain residual solvent or minor impurities.
Compounds isolated as a salt form, may be integer stoichiometric i.e. mono- or di-salts, or of intermediate stoichiometry. When an intermediate or compound in the experimental part below is indicated as 'HCl salt' without indication of the number of equivalents of HC1, this means that the number of equivalents of HC1 was not determined.
The stereochemical configuration for centers in some compounds may be designated "R" or "S"
when the mixture(s) was separated; for some compounds, the stereochemical configuration at indicated centers has been designated as "*R" or "*S" when the absolute stcreochemistry is undetermined (even if the bonds are drawn stereo specifically) although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure.
For example, it will be clear that Compound 3 N *R
NO
ON
is d_112---cR
N s N N
or ,11\1 N
I
N
F
The paragraphs above about stereochemical configurations, also apply to intermediates.
The term "enantiomerically pure" as used herein means that the product contains at least 80%
by weight of one enantiomer and 20% by weight or less of the other enantiomer.
Preferably the product contains at least 90% by weight of one enantiomer and 10% by weight or less 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 1%
or less of the other enantiomer.
A skilled person will realize that, even where not mentioned explicitly in the experimental protocols below, typically after a column chromatography purification, the desired fractions

- 47 -were collected and the solvent was evaporated.
In case no stereochemistry is indicated, this means it is a mixture of stereoisomers, unless otherwise is indicated or is clear from the context.
When a stereocenter is indicated with `RS' this means that a racemic mixture was obtained at the indicated centre, unless otherwise indicated.
A skilled person will understand that when Intermediates or Compounds are reported in Tables, the synthetic methodology from the indicated starting material to desired Intermediate/Compound might go over one or more reaction steps.
When two enantiomers, diastereomers or isomers are present in the same cell of one of the tables below, a skilled person will understand that these Intermediates or Compounds were separated from each other by using a suitable chromatographic method e.g. SFC
or reversed phase separation.
Preparation of intermediates For intermediates that were used in a next reaction step as a crude or as a partially purified intermediate, in some cases no mol amounts are mentioned for such intermediate in the next reaction step or alternatively estimated mol amounts or theoretical mol amounts for such intermediate in the next reaction step are indicated in the reaction protocols described below.
Hereinafter, the terms : `ACNI or `MeCN' means acetonitrile, `DCM' means dichloromethane, `DIPEA or DMA' means N,N-diisopropylethylamine, 'h' means hours(s), 'min' means minute(s), `DMF' means 107,N-dimethylformamide, 'TEA' or 'Et3N' means triethyl amine, 'Et0Ac' or 'EA' means ethyl acetate, 'THE' means tetrahydrofuran; `HPLC' means High-performance Liquid Chromatography, Prep-I-IPLC ' means preparative I-TPLC;
MeOIT means methanol, `NMIR' means Nuclear Magnetic Resonance, or `RT' means room temperature, SFC' means supercritical fluid chromatography, `q.s.' means quantum satis, 'DMS0' means dimethylsulfoxide, `Pd/C'or "Pd/C (10%)" means palladium on carbon, 'atm' means atmosphere, 'cc' means enantiomeric excess, 'PE' means petroleum ether, `NaBH(OAc)3' means sodium triacetoxyborohydride, `TFA' means trifluoroacetic acid, `DCE' means dichloroethane, and 'DMA' means N,N-dimethylacetamide; "IPA" means isopropyl alcohol;
"iPrNH2" means isopropylamine; NH4OH means ammonium hydroxide; "Pd(OH)2 means palladium hydroxide; DBU means 1,8-diazabicyclo[5.4.01undec-7-ene; Cbz" means benzoylcarbonyl; NaBH3CN means sodium cyanoborohydride; NaBH4 means sodium borohydride; tic means thin-layer chromatography; FCC means Flash Column Chromatography; HATU means 1-[Bi s(dimethyl amino)methyl ene]-1H-1,2,3 -tri azol o [4, 5-

- 48 -b]pyridinium 3 -oxid hexafluorophosphate, N-RDimethyl amino)-1H-1,2,3 -triazol o-[4, 5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide;
EDCI
means N-(3 -Dimethylaminopropy1)-N'-ethyl carbodiimide hydrochloride, `HOBT' or `HOBt' means 1-Hy droxyb enzotri azol e hydrate; TMEDA
means N,N,N' ,AP -Tetram ethyl ethyl enedi amine; Pd(dppf)C12.DCM means [1,1'-Bis(diphenylphosphino)ferroceneldichloropalladium(II), complex with dichloromethane;
"Ni(acac)2" means Nickel(II) acetylacetonate; "Zn" means Zinc; "MS" means molecular sieve;
"Boc20" means di-tert-butyl decarbonate; "Ar" means argon; "FA" means formic acid; "CC"
means column chromatography; "T3P" means propyl phosphonic anhydride.
A. Preparation of the intermediates Example Al Preparation of intermediate 1 N,Boc RS

A mixture of 2,6-diazaspiro[3.3]heptane-2-carboxylic acid, phenylmethyl ester (1.084g. 4.667 mmol), tert-butyl 3 -i sobutyryl azeti di ne-1 - carb oxyl ate (1.3 g, 5.6 mmol), sodium cyanoborohydride (1.5 g, 23.33 mmol) and acetic acid (267 pL, 4.67 mmol) in methanol (50 mL) was stirred at 50 C overnight. The mixture was gathered with another reaction performed on 100 mg of 2,6-diazaspiro[3.3]heptane-2-carboxylic acid, phenylmethyl ester and poured onto 10% aqueous solution of K2CO3. The resulting mixture was extracted with DCM. The organic layer was decanted, washed with water, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by chromatography over silica gel (irregular SiOH, 40g;
mobile phase: gradient from 0% NH4OH, 0% Me0H, 100% DCM to 03% NH4OH, 3% Me0H, 97% DCM). The pure fractions were collected and evaporated to dryness. The resulting residue was purified a second time by chromatography over silica gel (irregular SIOH, 40g; mobile phase: gradient from 40% Et0Ac, 60% heptane to 60% Et0Ac, 40% heptane). The pure fractions were collected and evaporated to dryness yielding 1.58 g of intermediate 1 (70% yield).

- 49 -Preparation of intermediate 2 N H
RS
0'.0' A mixture of intermediate 1 (500 mg; 1.127 mmol) and TF A (1.5 mL) in DCM (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ACN and evaporated to dryness (twice). The residue was dissolved in DCM and basified with 15%
aqueous solution of NH4OH. The organic layer was washed again with 15% aqueous solution of NH4OH, then, with water, filtered over Chromabond and evaporated to dryness yielding 330 mg of intermediate 2 (85%) which was directly engaged in the next step without any further purification.
Preparation of intermediate 3 N

RS
X

Acetic acid (55 [iL; 0,96 mmol) was added at room temperature to a solution of intermediate 2 (330 mg; 0.96 mmol) and oxetane-3-carbaldehyde (132 jut; 1.92 mmol) in THF (12 mL). The mixture was stirred at rt for overnight then NaBH(OAc)3 (611 mg; 2.88 mmol) was added portionwise. The mixture was stirred at rt for 3 hours. The reaction mixture was partitioned between aqueous 10% K2CO3 and Et0Ac. The layers were separated and the aqueous layer was extracted once with DCM. The organic layers were mixed, dried over MgSO4 and evaporated to dryness. The residue was purified by chromatography over silica gel (irregular SiOH, 10g-F24g; mobile phase: gradient from 0.5% NH4OH, 5% Me0H, 95% DCM to 1%
NH4OH, 10% Me0H, 90% DCM). The pure fractions were collected and evaporated to dryness yielding 264 mg of intermediate 3 (66% yield).

- 50 -Preparation of intermediate 4 NO
RS
A mixture of intermediate 3 (264 mg; 0.638 mmol) and Pd/C (10%) (68 mg; 0.0638 mmol) in ethanol (10 mL) was hydrogenated under 3 bars of H2 for 2 hours. Pd/C (10%) was removed by filtration over celite and the solvent was evaporated to dryness yielding 173 mg of intermediate 4 (97% yield).
Example A2 Preparation of intermediate 5 Boc RS

In a round bottom flask, 2,6-diazaspiro[3.4]octane-6-carboxylic acid, phenylmethyl ester (500 mg; 2.03 mmol), tert-butyl 3-isobutyrylazetidine-1-carboxylate (553.7 mg; 2.43 mmol), sodium cyanoborohydride (382.7 mg; 6.09 mmol) and acetic acid (0.116 mL; 2.03 mmol) were diluted in Me0H. Then, the reaction mixture was heated overnight at 50 C and cooled down to room temperature. Carefully, a saturated solution of Na,HCO3 was added until pH >
9. The resulting mixture was extracted with DCM. The organic layer was decanted, washed with water, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by chromatography over silica gel (irregular SiOH, 40g; mobile phase: gradient from 0% NH4OH, 0%
Me0H, 100%
DCM to 0.3% NI-140H, 3% Me0H, 97% DCM). The pure fractions were collected and evaporated to dryness to afford 700 mg of intermediate 5 (75% yield) Preparation of intermediate 6

-51 -NH
RS

In a round bottom flask, at 0 C, TFA (2.34 mL, 30.59 mmol) was added to intermediate 5 (700 mg, 1.53 mmol) in DCM (33.7 mL). Then, the reaction was warmed to room temperature and the reaction mixture was stirred overnight at room temperature The residue was dissolved in 4 mL of water. Then, the solution was basified with a solution of NaOH 1M (12 mL) until pH=8-9. After stirring for 10 min at room temperature, the resulting mixture was extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over MgSO4, filtered and evaporated till dryness to give 482 mg of intermediate 6 which was directly engaged in the next step without any further treatment.
Preparation of intermediate 7 N
RS

Acetic acid (119 ttL; 207 mmol) was added at room temperature to a solution of intermediate 6 (482 mg; 1.34 mmol) and oxetane-3-carbaldehyde (188 pL; 2.72 mmol) in THF
(20 mL). The mixture was stirred at rt for 4h then NaBH(OAc)3 (870 mg; 4.1 mmol) was added portionwise.
The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, basified with an aqueous solution of K2CO3 10% and Et0Ac was added.
The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated till dryness to give 438 mg of an intermediate residue. The residue (438 mg) was purified by silica gel chromatography (Stationary phase: irregular SiOH 15-401.tm 24g Mobile phase:
Gradient from 97% DCM, 3% Me0H (+10% NH4OH) to 90% DCM, 10% Me0H (+10% N1140H)). The fractions containing the product were mixed and concentrated to give 127 mg of intermediate 7 (22% yield).

- 52 -Preparation of intermediate 8 RS
NH
A mixture of intermediate 7 (63 mg; 0.147 mmol), Pd(OH)2 (21 mg; 0.174 mmol) in Me0H (3 mL) and THF (0.5 mL) was hydrogenated under atmospheric pressure overnight.
The catalyst was removed by filtration through a pad of celite', washed with Me0H and the filtrate was evaporated to give 35 mg of intermediate 8 (81% yield).
Example A3 Preparation of intermediate 9 To the mixture of 5-fluoro-2-methoxybenzoic acid (8.00 g, 47.0 mmol) and N-ethylpropan-2-amine (8.19 g, 94.0 mmol) in dry DCM (150 mL) cooled at 0 C, were slowly added HATU
(21.5 g, 56.5 mmol) and DIEA (9.10 g, 70.4 mmol) in portions. The resulting mixture was slowly warmed to RT and stirred for 8 h. The organic layer was washed with water (20 mL x 3) and dried over anhydrous Na2SO4. After filtration, the solvent was removed under reduced pressure and the crude product was purified by FCC (Et0Ac/PE = 0% to 20% of Et0Ac) to afford intermediate 9 (12.0 g, 96% yield) as a white solid.
The following intermediate was synthesized by an analogous method as described above for the preparation of intermediate 9 Int. No. Structure Starting Materials 0 5 -fluoro-2-m ethoxyb enzoi c acid, 0 dii sopropyl amine

- 53 -Preparation of intermediate 11 (Method A) F
To the solution of intermediate 9(12.0 g, 50.1 mmol) in dry DCM (100 mL) cooled at -78 C
was slowly added BBr3 (14.4 mL, 152 mmol) and the resulting mixture was slowly warmed to RT and stirred for 8 h. The mixture was cooled to -78 C again and Me0H (5 mL) was added dropwise to quench the reaction. The resulting mixture was slowly warmed to RT
and the pH
value was adjusted to about 8 by adding a saturated solution of NaHCO3. The aqueous layer was extracted by DCM (50 mL x 3) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product which was purified by FCC (Et0Ac/PE = 0% to 20% of Et0Ac) to afford intermediate 11(9.0 g, 78%
yield) as a white solid.
Alternative preparation of intermediate 11 (Method B) OH
A solution of 5-fluorosalicylic acid (30.0 g, 192.2 mmol) in thionyl chloride (200 mL) was stirred for 5 hours at 80 C. Then, the resulting mixture was concentrated under reduced pressure to give the acyl chloride. To a stirred solution of N-ethylpropan-2-amine (33.5 g, 384.3 mmol) and triethyl amine (58.3 g, 576.5 mmol) in dichloromethane (200 mL) was added a solution of acyl chloride in dichloromethane (100 mL) dropwise at 0 'C.
After stirring overnight at room temperature, the resulting mixture was concentrated under reduced pressure.
The crude product was dissolved in methanol (300 mL). Then, a solution of sodium hydroxide (20 g) in water (100 mL) was added. After stirring for 1 hour at room temperature, the resulting mixture was diluted with water (100 mL) and concentrated under reduced pressure to remove the excess methanol, adjusted to pH value 4 and extracted with ethyl acetate (2 x 150 mL).
The combined organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA/PE, 16.3:83.7) to afford 29.4 g (66% yield) of intermediate 11 as an off-white solid.

- 54 -The following intermediate was synthesized by an analogous method as described above for intermediate 11 (Method A) Int. No. Structure Starting Materials 12 intermediate 10 F
The following intermediate was synthesized by an analogous method as described above for intermediate 11 (Method B) Int. No. Structure Starting Materials 81 OH 5-fluorosalicylic acid Example A4 Preparation of intermediate 13 ,Boc CI
*LI N
N ,NCI
To the solution of 3,5,6-trichloro-1,2,4-triazine (10.0 g, 54.2 mmol) and TEA
(15.2 mL, 109 mmol) in DCM (100 mL) cooled at 0 C was added tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (9.21 g, 43.4 mmol) and the mixture was warmed to RT and stirred for 1 h. The mixture was diluted with water (20 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product which was purified by FCC on silica gel (Mobile phase A: PE; Mobile phase B: Et0Ac, eluent from 0-25% Mobile phase B) to afford intermediate 13 (12.0 g, 58% yield) as a yellow solid.

- 55 -Preparation of intermediate 14 Boc Oy-LN
N,N-õ-1,CI
The mixture of intermediate 13 (12.0 g, 33.3 mmol), intermediate 11(7.5 g, 33.3 mmol) and DB U (6.1 g, 40.1 mmol) in TI-IF (120 mL) was stirred at 25 C for 8 h. The mixture was diluted with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product which was purified by FCC on silica gel (Mobile phase A: PE;
Mobile phase B: Et0Ac, eluent from 0-25% Mobile phase B) to afford intermediate 14 (14.0 g, 73% yield) as a green solid.
The following intermediates was synthesized by an analogous method as described above for intermediate 14 Int. No. Structure Starting Materials Boc 0 intermediate 12, intermediate 13 N,NCI
Preparation of intermediate 16 ,Boc 0 yk\ N
I
Method A:
To the mixture intermediate 14 (20 g, 36.4 mmol), NaBH4 (2.48 g, 65.7 mmol) and TMEDA

- 56 -(8.54 g, 73.5 mmol) in THF (500 mL) was added Pd(dppf)C12=DCM (1.70 g, 2.08 mmol) under N2 atmosphere. After addition, the reaction mixture was stirred at 25 C for 14 h. The reaction mixture was filtered, and the filtrate was concentrated, the residue was purified by FCC on silica gel (eluent with Et0Ac) to afford intermediate 16 (15 g, 74% yield) as brown solid.
Method B:
To the solution of intermediate 14 (22.0 g, 40.1 mmol), TEA (15 mL) in Me0H
(100 mL) was added Pd/C (wet, 5.0 g, 10%) The resulting mixture was stirred under H2 atmosphere (30 psi) at 25 C for 8hr. The reaction mixture was filtered through a celite pad and the filtrate was concentrated in vacuo to afford intermediate 16 (25.0 g, crude), which was used directly in next step without further purification.
The following intermediate was synthesized by an analogous method described above for intermediate 16 Int. No. Structure Starting Material Conditions ,Boc Pd/C, H2, 17 intermediate 15 TEA, Me0H
I I
F N
Preparation of intermediate 18 NH
NO
ON

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

- 57 -The following intermediate was synthesized by an analogous method described above for intermediate 18 Int. No. Structure Starting Material NH

intermediate 17 N
I
NN
Example A5 Preparation of intermediate 20:
\ /
NH
O¨N H
0 Boc To a solution of cis-3- [[(1,1-dimethylethoxy)carbonyl]amino]-cyclobutanecarboxylic acid (10.0 g, 46.5 mmol) in DIN,IF (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,0-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 1 M HC1 (150 mL), saturated NaHCO3 (100 mL x 2) and brine (300 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give intermediate 20 (11.0 g, crude) as a white solid, which was used in the next step without further purification.
Preparation of intermediate 21:
NH
0 Boc To a solution of intermediate 20 (11.0 g, 6.97 mmol) in TEM (100 mL) was added isopropylmagnesium chloride (64.0 mL, 128 mmol, 2M in THF) dropwise at 0 C
under N2 atmosphere. The mixture was stirred at room temperature for 12 hours under N2 atmosphere.
The mixture was quenched with saturated NH4CI (100 mL). The mixture was filtered through

- 58 -a pad of Celite and the filtrate was concentrated under reduced pressure. The mixture was extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography over silica gel (eluent:
petroleum ether:
ethyl acetate from 1:0 to 5:1, to yield intermediate 21(6.30 g) as a white solid.
Example A6 Preparation of intermediate 22:
N HBoc RS

0 ,L.N
I
N,N-;) Under N2, at rt, to a mixture of intermediatel8 (1 g, 2.41 mmol), intermediate 21(873 mg, 3.62 mmol), acetic acid (276 uL, 4.83 mmol) in Me0H (50 mL) was added NaBH3CN (455 mg, 7.24 mmol). Then, the reaction was heated at 50 C overnight. The reaction mixture was cooled to rt, poured into ice water, basified with a saturated solution of NaHCO3 and DCM was added.
The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated till dryness. The crude was purified by silica gel chromatography (Stationary phase: irregular SiOH 15-40 m 40g, Mobile phase: Gradient from 0% NH4OH, 100% DCM, 0% Me0H to 0.1%
NH4OH, 95% DCM, 5% Me0H). The fraction containing the product were mixed and concentrated to afford 1.37g (89% yield) of intermediate 22.
Example A7 Preparation of intermediate 23:
\ /
0¨N
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 Et0Ac) 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 hours. The mixture was poured onto a saturated solution NaHCO3 and Et0Ac was added. The organic layer was separated, washed with brine,

- 59 -dried over MgSO4, filtered and concentrated under reduced pressure to give intermediate 23 (16.0 g, crude) which was used in the next step without further purification.
Preparation of intermediate 24:

0 0' The reaction was performed twice on 15.7 g of intermediate 23 and respective reaction media were mixed for the work-up and purification. To a solution of intermediate 23 (15.7 g, 77.7 mmol) in THE (420 mL) was added isopropylmagnesium chloride (178.5 mL, 232 mmol, 2M
in THF) dropwise at 0 C under N2 atmosphere. The reaction mixtures were stirred at room temperature for 12 hours under N2 atmosphere and then, poured onto ice-water and a 10%
aqueous solution of NH4C1. The mixture obtained was combined with the mixture obtained from the second reaction, and the combined mixture was extracted with Et0Ac.
The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography over silica gel (mobile phase: Heptane: Et0Ac 9:1). The pure fractions were collected and evaporated to dryness yielding 22 g (76% yield) of intermediate 24 as a colourless oil.
Example A8 Preparation of intermediate 25 o ON
I
A mixture of intermediate 18 (10 g, 24.13 mmol), intermediate 24 (4.94 g, 26.54 mmol) and acetic acid (1.5 mL, 26.54 mmol) in Me0H (80 mL) was stirred at room temperature for 20 min. Then, NaBH3CN (1.82 g, 28.95 mmol) was added and the mixture was stirred at 50 C
overnight. The reaction solution was poured into ice water and extracted with DCM. The organic layer was washed with water and brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Mobile phase A: PE; Mobile phase B: Et0Ac, eluent from 0-100%
Et0Ac) to give 9.21 g (64% yield) of intermediate 25 as a light yellow solid.

- 60 -Preparation of intermediate 26 ¨/
N R
N
I
N., -,;) and intermediate S

N,N
Intermediate 25 (9.2g) was purified via chiral SFC (Stationary phase:
C+HIRALPAK AD-H
5pm 250*21.2mm, Mobile phase: 83% CO2, 17% mixture of Et0H/ACN 80/20 v/v(+0.3%iPrNH2)). The fractions containing the products were mixed and concentrated to afford 4.07g (44% yield) of intermediate 26 and 4.06 g (44% yield) of intermediate 27 and 273 mg of a residual fraction of intermediate 25.
Method A for intermediate 27:
To a solution of intermediate 35 (2.24 g, 3.618 mmol) in methanol (45 mL) was added palladium on activated carbon (10% palladium) (635 mg, 0.597 mmol). Then, the mixture was stirred at room temperature for 5 hours under the hydrogen. The mixture was diluted with methanol, filtered through a pad of Celite and the filtrate was evaporated under reduced pressure. The residue was dissolved with ethyl acetate, washed with sodium hydroxide solution (1M in water) and brine. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure to give 1.4 g (62% yield) of intermediate 27 as a yellow solid.
Method B for intermediate 27:
A mixture of intermediate 35 (1.44 g; 2.33 mmol) and TMEDA (0.54 mL; 3.63 mmol) in dry THE (55 mL) was degassed by N2 bubbling. Then, Pd(dppf)C12.DCM (216 mg; 0.26 mmol) and sodium borohydride (144 mg; 3.81 mmol) were added. The reaction mixture was stirred at 50 C overnight in a sealed glassware. The solution was cooled, poured out into cooled water.

- 61 -Et0Ac was added and the mixture was filtered through a celite . The product was extracted with Et0Ac and the organic layer was dried over MgSO4, filtered and evaporated to dryness.
The crude residue (1.7g) was purified by silica gel chromatography (Stationary phase: irregular SiOH 40 p.m 40 g, Mobile phase: Gradient from 100% DCM, 0% Me0H (+10% NH4OH) to 95% DCM, 5% Me0H (+10% NH4OH)). The fractions containing the product were mixed and concentrated to afford 2 fractions of intermediate 27 (680 mg, 50% yield, 96%
purity by LCMS
and 360 mg; 26% yield, 91% purity by LCMS) Preparation of intermediate 28:

NO N
I , , N
A solution of intermediate 26 (2 g, 3.42 mmol) and TFA (2.9 mL, 37.9 mmol) in DCM (29 mL) was stirred at rt overnight. ACN was then added and the solution was evaporated to dryness.
The residue was then dissolved in Et0Ac and iced water, basified with NH4OH.
The layers were separated, and the aqueous layer was extracted with Et0Ac. The combined organic layers were dried over MgSO4, filtered and evaporated to give 1.80 g (98% yield) of intermediate 28.
Preparation of intermediate 29:
NO N
N õN
Intermediate 27 (1.87 g, 3.20 mmol) in TFA (2.7 mL) and DCM (27 mL) was stirred at rt overnight. The solution was evaporated to dryness. The residue was then dissolved in DCM and iced water, basified with a 30% aqueous NH4OH solution. The aqueous layer was extracted with DCM The combined organic layers were dried over MgSO4, filtered and evaporated to give 1.35 g (78% yield) of intermediate 29 as a pale yellow solid.

- 62 -Alternative preparation of intermediate 29:
To a solution of intermediate 27 (1.40 g, 2.25 mmol) in acetone (30 mL) and water (14 mL) was added p-Toluenesulfonic acid (1.94 g, 11.276 mmol). The reaction solution was stirred at 65 degrees for 5 hours. The resulting mixture was quenched with water and ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate. The solid was filtered off. The residue was concentrated under reduce pressure to give 1.01 g (78%) of intermediate 29 as a yellow solid.
Preparation of intermediate 29a:
N RS
I
N,N) Intermediate 29a was prepared accordingly to intermediate 28 starting from intermediate 25 Example A9 Preparation of intermediate 30:
0¨

d_1_\AI RS
L)z To a stirring solution of 2,6-diazaspiro[3.4]octane-6-carboxylic acid, phenylmethyl ester (15 g, 60.9 mmol) in methanol (300 mL) was added intermediate 24 (13.61 g, 73.08 mmol) and acetic acid (4.02 g, 66.99 mmol). After stirring for 0.5 hour at room temperature, sodium cyanoborohydride was added (7.65 g, 121.8 mmol). After stirring overnight at 50 C, the reaction mixture was quenched with a 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 (Mobile phase A: PE; Mobile phase B: Et0Ac, eluent from 0-50% Et0Ac) to give 17.8 g (69%
yield) of intermediate 30 as a light yellow oil.

- 63 -Preparation of intermediate 31:
s 0¨ N R
Cbz and intermediate 32: Cbz 170 g of intermediate 30 was purified by SFC with the following conditions:
Column:
CH1RALPAK_ 1G, 5 *25 cm,1 Oum; Mobile Phase A: CO2, Mobile Phase B:Et0H: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 Volumn:3.8 ml; Number of Runs:237 to give two fractions. Fraction A: 67.0 g (>99% purity by LCMS, 39% yield, retention time 2:5.88 min) of intermediate 31 as a light-yellow oil. Fraction B: 65 g (99% purity, 38%
yield, retention time 1: 4.45 min) of intermediate 32 as a light-yellow oil.
Preparation of intermediate 33 so-To a solution of intermediate 31(15 g, 36.01 mmol) in methanol (300 mL) was added palladium on activated carbon (10% palladium) (8g, 7.517 mmol). Then the mixture was stirred at room temperature for 5 hours under the hydrogen (2-3 atm.). The mixture was diluted with methanol and filtered through a pad of Celite . The filtrate was evaporated under reduced pressure to give 9.5 g of desired product as a yellow oil which was directly used in the next step without any further modifications.
Preparation of intermediate 34 CI N
N,NCI

- 64 -To a solution of 3,5,6-trichloro-1,2,4-triazine (9.4 g, 50.99 mmol) in dichloromethane (100 mL) were added the mixture of intermediate 33 (12.0 g, 42.49 mmol) and triethylamine (12 mL, 84.98 mmol) in dichloromethane (150 mL) under nitrogen at 0 C. After stirring for 3 hours at room temperature under nitrogen, the mixture was quenched with water and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate. The solid was filtered off The filtrate was concentrated under reduced pressure to give 17.3 g (83%
yield, 88% purity by LCMS) of intermediate 34 as a yellow solid.
Preparation of intermediate 35.

N

F Ni -1\1CI
A solution of intermediate 34 (1.6g; 3.72 mmol), intermediate 11 (1g; 4.44 mmol) and DBU
(2.7 mL; 18.45 mmol) in THE (150 mL) was stirred at rt for 72 hours. The solution was poured into cooled water and the product was extracted with Et0Ac. The organic layer was dried over MgSO4, filtered and evaporated to dryness. The crude (3g) was purified by silica gel chromatography (Stationary phase: irregular bare silica 80g, Mobile phase: 63%
Heptane, 2%
Me0H (+10% NH4OH), 35% Et0Ac). The fraction containing the product were mixed and concentrated to afford 1.48g (64% yield) of intermediate 35.
Alternative preparation of intermediate 35:
To a solution of intermediate 34(3.00 g, 6.971 mmol) and intermediate 11(1.88 g, 8.365 mmol) in tetrahydrofuran (60 mL) was added tetramethylguanidine (1.37 g, 11.85 mmol). The reaction solution was stirred for 2 days at room temperature. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with sodium hydroxide (0.5 MIL), water and brine, dried over anhydrous sodium sulfate. The solid was filtered off The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography column (ethyl acetate/hexane 2:1) to give 2.60 g (59%
yield) of intermediate 35 as a yellow solid.

- 65 -Preparation of intermediate 82:
N S

N,NCI
To a mixture of intermediate 34(10.0 g, 23.27 mmol) and intermediate 81 (5.89 g, 27.887 mmol) in THE (250 mL) was added tetramethylguanidine (7.3 mL, 58.09 mmol). After stirring at room temperature for 48 hours, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (Mobile phase A: PE; Mobile phase B: Et0Ac, eluent from 0-93% Et0Ac) to give 7.5 g (49% yield) of intermediate 82 as a yellow solid.
Preparation of intermediate 83 doN
NJ
To a mixture of intermediate 82 (7.0 g, 11.57 mmol) in tetrahydrofuran (140 mL) were added 1, l'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (472 mg, 0.58 mmol), sodium borohydride (744 mg, 19.67 mmol) and N,N,N',N'-tetramethylethylenediamine (2.9 mL, 19.67 mmol). After stirring at room temperature overnight under the N2 atmosphere, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (Me0H/DCM, 0%Me0H to 9%Me0H) to give 4.8 g (54% yield, 85.1% purity based on LC/MS) of intermediate 83 as a brown solid.

- 66 -Preparation of intermediate 84:
N S
NO
N
I
To a mixture of intermediate 83 (4.8 g, 8.32 mmol) in acetone (100 mL) and water (50 mL) was added p-toluenesulfonic acid (7.17 g, 41.62 mmol). After stirring at 65 C
overnight, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 3.1 g (45%
yield, 62.8%
purity based on LC/MS) of intermediate 84 as a brown solid.
Example Al 0 Preparation of intermediate 36:
\ /
0¨N
)/. _____________ CN¨Boc To a stirring solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (30.0 g, 149.09 mmol), 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (42.9 g, 223.64 mmol) and N,0-dimethylhydroxylamine (21.8 g, 223.64 mmol) in DCM (500 mL) were added NN-diisopropylethylamine (61.7 mL,372.73 mmol) and 4-dimethylaminopyridine (3.6 g, 29.82 mmol). After stirring overnight at room temperature, the reaction solution was diluted with DCM (500 mL) and washed with water, 10% of citric acid aqueous solution, water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 24.0 g of intermediate 36 as a light-yellow oil.
Preparation of intermediate 37:
______________________ N¨Boc To a stirred solution of intermediate 36 (26.5 g,108.5 mmol) in tetrahydrofuran (250 mL) was

- 67 -added isopropylmagnesium chloride (271 mL, 542.0 mmol, 2M in TFIF) at 0 C.
After stirring overnight at room temperature, the reaction mixture was quenched with brine (300 mL) at 0 C
and extracted with ethyl acetate (3 x 500 mL). The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 8:2) to give 19.5 g of intermediate 37 (87% purity, 68% yield) as a light yellow oil.
Preparation of intermediate 39:
,Boc Cbz To a stirred mixture of tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (25.5 g, 120.12 mmol) in tetrahydrofuran (250 mL) and potassium carbonate (36.52 g, 264.262 mmol) in water (250 mL) was added benzyl chloroformate (20.3 mL, 144.143 mmol) at 0 C. After stirring overnight at room temperature, the reaction mixture was extracted with ethyl acetate (3 x 300 mL). The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue purified by silica gel column chromatography (PE/EA, 6:4) to give 39.10 g of intermediate 39 (99%
purity, 93%
yield) as a light-yellow oil.
Preparation of intermediate 40:
NH
TFA salt Cbz To a solution of intermediate 39 (55.5 g, 160.2 mmol) in DCM (550 mL) was added TFA (110 mL). After stirring for 2 hours at room temperature, the reaction solution was concentrated. The residue was dissolved in water (300 mL). The resulting aqueous solution was basified to pH=8 with a saturated solution of NaHCO3 and extracted with DCM/Me0H (10:1, 4 x 500 mL). The combined organic layer was washed with brine (2 x 300 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give 45.3 g (74% yield) of intermediate 40 as TFA salt and as a light brown solid.

- 68 -Preparation of intermediate 41:
N¨Boc jN RS
Cbz To a stirred solution of intermediate 40 (5.00 g, 13.88 mmol) in methanol (50 mL) was intermediate 37 (3.79 g, 16.65 mmol). After stirring for 0.5 hour at room temperature, sodium cyanoborohydride (4.36 g, 69.38 mmol) was added. The resulting mixture was stirring overnight at 50 C. Additional intermediate 37 (1.58 g, 6.94 mmol) and sodium cyanoborohydride (2.62 g, 41.63 mmol) were added. After stirring for 6 hours at 50 C, additional sodium cyanoborohydride (1.31 g, 20.814 mmol) was added. After stirring overnight at 50 C, the reaction mixture was quenched with saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic layer was washed with water, brine and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE/EA, 7:3) to give 4.5 g (67% yield) of intermediate 41 as a light yellow oil Preparation of intermediate 42:
S N¨Boc N R
To a stirred solution of intermediate 41(3.60 g, 7.87 mmol) in ethanol (40 mL) was added palladium on activated carbon 10% Pd (800 mg). After stirring under a hydrogen stream (2-3 atm) at room temperature for 2 hours, the reaction mixture was filtered through a pad of Celite which was washed with ethanol and DCM. The filtrate was concentrated under reduced pressure to give 2.5 g of intermediate 42 as a grey oil.

- 69 -Preparation of intermediate 43:
N¨Boc N RS
CI, )=,,, N
N CI
To a stirred solution of 3,4,6 -tri chl oropyri dazine (700 m g,2.
164 mmol) in N, N-dim ethylformami de (15 ml) was added intermediate 42 (397 mg, 2.164 mmol) and triethylamine (0.9 mL, 6.492 mmol). After stirring 3h at temperature, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with water, brine and dried over anhydrous sodium sulfate and filtered off The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE: EA = 55:45) to give 900 mg (84% yield) of intermediate 43 as a white solid.
Preparation of intermediate 44:
N¨Boc N RS

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

- 70 -Preparation of intermediate 45:
N¨Boc N RS
NO
o To a stirred solution of intermediate 44 (750 mg, 1.138 mmol) in ethyl acetate (15 mL) was added palladium on activated carbon 10% Pd (800 mg). After stirring under a hydrogen stream (2-3 atm) at room temperature overnight, the reaction mixture was filtered through a pad of Celite which was washed with ethyl acetate and ethanol. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (DCM: Me0H = 6:4) to give 303 mg of intermediate 45 (42% yield) as an off-white solid.
Preparation of intermediate 50:
N¨Boc N RS

N
N
A mixture of intermediate 18 (740 mg, 1.78 mmol), intermediate 37 (487 mg, 2.1 mmol), NaBH3CN (337 mg, 5.4 mmol) and acetic acid (102 [iL, 1.78 mmol) in Me0H (15 mL) was stirred at 50 C overnight. The reaction mixture was mixed with another reaction performed on 220 mg of intermediate 18. The resulting reaction mixture was poured into ice water, basified with a saturated solution of NaHCO3 and DCM was added. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated till dryness. The residue was purified by silica gel chromatography (Stationary phase: irregular SiOH 15-40m 24g MERCK, Mobile phase: Gradient from 99% DCM, 1% MeON (+10% NH4OH) to 95% DCM, 5% MeON
(+10% NH4OH)). The fractions containing the product were mixed and concentrated to afford 1.04g (93% yield) of intermediate 50.

- 71 -Preparation of intermediate 51:
N *R
NO

N
N
and intermediate 52:
N¨Boc N *S

N
Intermediate 50 (1.04g) was purified by chiral SFC (Stationary phase:
CHIRALPAK IC 5i.tm 250*30mm, Mobile phase: 50% CO2, 50% Et0H (0.3% iPrNH2)). The fractions containing the products were mixed and concentrated to afford 411 mg (37% yield) of intermediate 51 and 427 mg (38% yield) of intermediate 52.
Alternative preparation of intermediate 50:
Under N2 flow, intermediate 18(854 mg; 1.13 mmol) and intermediate 37 (385 mg;
1.7 mmol) in TI-IF (15 mL) were stirred at rt for 24h. Then, sodium triacetoxyb orohydri de (718 mg; 3.39 mmol) was added portionwise The mixture was stirred at room temperature for 24h. The solution was poured out into cooled water, basified with a solution of NaOH 3N
and Et0Ac was added. The organic layer was separated, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (Stationary phase: irregular SiOH 15-40[Im 12g, Mobile phase: Gradient from 99% DCM, 1% Me0H (+10% NH4OH) to 95% DCM, 5% Me0H (+10% NH4OH)). The fractions containing the product were mixed and concentrated to afford 200mg (28% yield) of intermediate 50.
Example Al2 Preparation of intermediate 53

- 72 -CI
CI
N ,N<7--Phosphorus oxychl ori de (9.42 g, 61.4 mmol) was added dropwi se to a 0 C
(ice/water) solution consisting of 4-chloropyridazin-3-ol (2.00 g, 38.3 mmol) and ACN (20 mL).
Then, the reaction mixture was heated and stirred at 80 C for 3 hours before cooling to RT. The reaction mixture was slowly poured into water (50 mL) and adjusted to pH=8 by the saturated solution of sodium bicarbonate. The mixture was extracted with DCM (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product which was purified by FCC (silica gel, Mobile Phase A: PE;
Mobile Phase B: Et0Ac, eluent with 0-25% Et0Ac) to give the intermediate 53 (2.00 g, 88%
yield) as a yellow solid.
Preparation of intermediate 54:
Boc CIy A stir bar, intermediate 53 (500 mg, 3.36 mmol), tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (712 mg, 3.35 mmol), triethylamine (1.02 g, 10.1 mmol) and dry DCM
(10 mL) were added to a 40 mL glass bottle before the resultant mixture was stirred at 25 C for 8 h.
The mixture was diluted into DCM (20 mL) and washed with water (10 mL x 3).
The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude which was purified by FCC (silica gel, Mobile Phase A: PE;
Mobile Phase B:
Et0Ac, eluent with 0-100% Et0Ac) to give the intermediate 54 (500 mg, 42%
yield) as a yellow solid.
Preparation of intermediate 55 ,Boc N,

- 73 -A stir bar, intermediate 11(346 mg, 1.54 mmol), intermediate 54 (500 mg, 1.54 mmol), cesium carbonate (1.51 g, 4.63 mmol) and dry N,N-dimethylformamide (10 mL) were added to a 50 mL round-bottomed flask before the resultant mixture was heated and stirred at 130 C for 8 h.
The mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was suspended into dichloromethane (20 mL) and washed with water (10 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude which was purified by FCC (silica gel, Mobile Phase A:
Et0Ac; Mobile Phase B: Me0H, cluent with 0-10% Me0H) to give the intermediate 55 (700 mg, 80% yield) as a yellow solid.
Preparation of intermediate 56:
NH

N, F
A stir bar, intermediate 55 (700 mg, 1.36 mmol), trifluoroacetic acid (4 mL) and dry dichloromethane (2 mL) were added to a 25 mL round-bottomed flask before the mixture was stirred at 25 'V for 40 min. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted into dichloromethane (20 mL) and pH
wasadjusted to pH =12 by a solution of sodium hydroxide (3 M, 8 mL). The aqueous layer was extracted with dichloromethane (10 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give intermediate 56 (600 mg, crude) as a yellow oil.
Preparation of intermediate 57:
\ /
O¨N
N¨Boc 0 _________________ HATU (99.5 g, 262 mmol) was added in portions to a 0 C (ice/water) mixture consisting of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (50.0 g, 218 mmol), N,0-dimethylhydroxylamine hydrochloride (23.4 g, 240 mmol), Et3N (90.9 mL, 654 mmol), and dichloromethane (500 mL). The reaction mixture was stirred at room -temperature for 12 hours.
The reaction mixture was concentrated to dryness under reduced pressure. The residue was

- 74 -diluted with water (1500 mL) and extracted with dichloromethane (500 mL x 3).
The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to afford the crude product, which was purified by FCC
(silica gel, Mobile Phase A: PE; Mobile Phase B: Et0Ac, eluent with 0-50% Et0Ac) to afford the intermediate 57 (54 g, yield: 82%) as a yellow oil.
Preparation of intermediate 58:
cN-Boo Intermediate 57 (54.0 g, 198 mmol) and THF (500 mL) were added into a 1 L
three-necked round-bottomed flask. i-PrMgC1 (198 mL, 397 mmol, 2 M in THF) was added dropwise into the mixture at 0 C (ice/water) under N2. The mixture was stirred with warming to room temperature for 10 hours before pouring into water (2000 mL) and extracted with Et0Ac (1000 mL x 3). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude which was purified by flash column chromatography on silica gel (silica gel, Mobile Phase A: PE; Mobile Phase B:
Et0Ac, eluent with 0-35% Et0Ac) to give the intermediate 58 (19.2 g, 34% yield) as a yellow oil.
Preparation of intermediate 59:
N-Boc N RS

A stir bar, intermediate 58 (278 mg, 1.09 mmol), intermediate 56 (300 lug, 0.726 mmol), zinc chloride (200 mg, 1.47 mmol) and dry methanol (6 mL) were added to a 40 mL
glass bottle before the mixture was heated and stirred at 45 C for 4 h. Then, sodium cyanotrihydroborate (91.2 mg, 1.45 mmol) was added to the mixture. The resultant mixture was stirred at 45 C for another 40 h. The mixture was diluted into dichloromethane (40 mL) and washed with water (10 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude which was purified by FCC (silica gel, Mobile Phase A: Et0Ac; Mobile Phase B: Me0H, eluent with 0-10% Me0H) to give intermediate 59 (150

- 75 -mg, 29% yield) as a yellow solid.
Example Al2 Preparation of intermediate 60:
N¨Boc oy,N
I
Intermediate 18 (120 mg, 0.29 mmol), intermediate 58 (150 mg, 0.585 mmol) and ZnC12 (80 mg, 0.59 mmol) were added to a 25 mL round bottomed flask and the resulting mixture was dissolved in Me0H (5 mL). The mixture was heated and stirred at 80 C for 4 hours. Sodium cyanoborohydride (37 mg, 0.59 mmol) was added to the mixture. Then, the mixture was stirred at 80 C for 16 hours. Then, additional intermediate 58 (150 mg, 0.585 mmol), ZnC12 (80 mg, 0.59 mmol), and NaBH3CN (37 mg, 0.59 mmol) were added into the above solution.
Then, the mixture was stirred at 80 C for 6 hours. The reaction mixture was concentrated to dryness under reduced pressure to give the crude product which was purified by preparative HPLC
using a Boston Green ODS 150 mm x 30 mm x 5 ttm column (eluent: 25% to 55%
(v/v) CH3CN
and H20 with 0.04%NH3H20+10mM NH4HCO3) to afford pure intermediate 60 which was suspended in water (10 mL). The mixture was frozen using dry ice/acetone, and then lyophilized to dryness to afford the intermediate 60 (60 mg) as a white solid.
Preparation of intermediate 60a ¨/
N'KIIII
N¨Boc *R

I
N N
and intermediate 60b:

- 76 -N *S N¨Boc 01-"LN
I
Intermediate 60 (375 mg, 0.57 mmol) was purified by supercritical fluid chromatography (Separation condition: DAICEL CHIRALPAK IG (250 mm x 30 mm x 10 urn), Mobile phase:
A: Supercritical CO2, B: 0.1%NH3H20 IPA, A:B =45:55 at 80 mL/min; Column Temp:
38 ;
Nozzle Pressure: 100Bar; Nozzle Temp: 60; Evaporator Temp: 20; Trimmer Temp:
25 ;
Wavelength: 220nm). The pure fractions were collected, and the volatiles were removed under vacuum. The resulting product was lyophilized to dryness to remove the solvent residue completely. Desired product intermediate 60a (15 mg, 4% yield) and intermediate 60b (19 mg, 5% yield) were obtained as white solid.
Preparation of intermediate 61:
\ /
O¨N ifBoo C

EDCI (34.0 g, 177 mmol) was added to a solution consisting of (R) - 1 -(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (25.0 g, 116 mmol), HOBT (24.0 g, 178 mmol), DIPEA (102.5 mL, 586.9 mmol) and DMf (250 mL) at 0 C. The reaction mixture was stirred at for 5 min. /V, 0-dimethylhydroxylamine (12.5 g, 128 mmol) was added the reaction mixture.
The reaction mixture was stirred at room-temperature for 10 h before cooling to room temperature. The mixture was poured into water (1000 mL) and extracted with ethyl acetate (400 mL x 3). The organic phase was washed with 5% aqueous citric acid solution (400 mL x 3), sat. NaHCO3 (400 mL x 2), brine (400 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give cnide intermediate 61 (26 g, 82% yield) as a colourless oil.
Preparation of intermediate 62:

- 77 -i-PrMgC1 (101 mL, 202 mmol, 2 M, in THE) was added dropwi se to a 0 C
(ice/water) solution of intermediate 61(26.0 g, 101 mmol) and THF (250 mL). The reaction mixture was stirred at room-temperature for 10 hours. The mixture was quenched with a saturated solution of NH4C1 (500 mL) and extracted with ethyl acetate (500 mL x 3) .The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuum to give the product which was purified by FCC (silica gel, Mobile Phase A: PE; Mobile Phase B: Et0Ac, eluent with 0-50% Et0Ac) to afford the intermediate 62 (15.0 g, 56% yield) as a yellow oil.
Preparation of intermediate 63:
,Boc N
N
N
and intermediate 64:
Boc N *S
0 4..N
I
To a solution of intermediate 18 (300 mg, 0.724 mmol) and intermediate 62 (524 mg, 2.17 mmol) in 15 mL of Me0H was added ZnC12 (395 mg, 2.90 mmol). After addition, the reaction mixture was stirred at 75 C for 3 hours, then NaBH3CN (182 mg, 2.90 mmol) was added into the reaction and the mixture was stirred at the same temperature for 4 hours.
Additional intermediate 62 (300 mg) was added and the mixture was stirred at 75 C for 16 hours. The reaction mixture was concentrated in vacuum and the residue was purified by preparative HPLC
(Column Welch Xtimate C18 150 x 25mm x 5um, Mobile Phase A: water (0.04%NH3H20+10mM NH4HCO3), Mobile Phase B: acetonitrile, Flow rate: 30 mL/min, gradient condition from 61% B to 81% B). The pure fractions were collected, and the solvent was evaporated under vacuum. The aqueous layers were lyophilized to afford intermediate 63 (75.0 mg, 16% yield) as a white solid and intermediate 64 (88 mg, 18% yield) as a white solid.

- 78 -Preparation of intermediate 65:
\O-N/ -Boc (3)/
(S)-1-(tert-Butoxycarbonyl)pyrrolidine-3-carboxylic acid (15.0 g, 69.7 mmol), EDCI (20.039 g, 104.53 mmol), HOBT (14.125 g, 104.53 mmol) and DlEA (45.034 g, 348.44 mmol) were added to DIVif (100 mL) at 10 C. After 5 min N,0-dimethylhydroxylamine hydrochloride (7.477 g, 76.66 mmol) was added to the mixture. The mixture was stirred at 40 C for 10 h before poured into water (400 mL) and extracted with ethyl acetate (300 mL x 3). The organic phase was washed with 5% aqueous citric acid solution (3 x 300 mL), sat.
NaHCO3 (2 x 300 mL), brine (2 x 300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the intermediate 65 (12.41 g, 74%) as a yellow oil.
Preparation of intermediate 66:
o/
The intermediate 65 (12.4 g, 48.0 mmol) and THF (20 mL) were added into a 250 mL round-bottomed flask. Isopropylmagnesium chloride (49 mL, 98 mmol, 2 M in THE) was added dropwise into the mixture at 0 C (ice/water) under N2. The mixture was stirred with warming to room temperature for 10 h. The mixture was quenched with a saturated aqueous solution of NH4C1 (100 mL) and extracted with Et0Ac (200 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give the crude product which was purified by FCC (silica gel, Mobile Phase A:
PE; Mobile Phase B: Et0Ac, eluent with 0-35% Et0Ac) to afford the intermediate 66 (7.6 g, 65%) as a light yellow oil.
Preparation of intermediate 67:
Boc /,., Nõ

I

- 79 -and intermediate 68:
*S

N
To a solution of intermediate 18 (300 mg, 0.724 mmol) and intermediate 66 (524 mg, 2.17 mmol) in 15 mL of Me0H was added ZnC12 (395 mg, 2.90 mmol). After addition, the reaction mixture was stirred at 75 C for 3 hours. Then, NaBH3CN (182 mg, 2.90 mmol) was added into the reaction mixture and the mixture was stirred at the same temperature for 4 hours. Additional intermediate 67 (300 mg) was added and the mixture was stirred at 75 C for 16 hours. The reaction mixture was cooled to 25 C and concentrated in vacuum. The residue was purified by preparative UPLC (Column Welch Xtimate C18 150 x 25mm x 5um, Mobile Phase A:
water (0.04%NH3H20+10mM NH4HCO3), Mobile Phase B: acetonitrile, Flow rate: 30 mL/min, gradient condition from 61% B to 81% B). The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layers were lyophilized to afford the intermediate 67 (100 mg, 21% yield) as a white solid and the intermediate 68 (105 mg, 22%
yield) as a white solid.
Preparation of intermediate 70:
N-13cic N RS

ON

A mixture of 2-[(4-chl oro-5-pyrimi di nyl)oxy] -N-ethyl -5 -fluoro-N-(1 -m ethyl ethyl)-b enzami de (4.5 g, 13.322 mmol) and intermediate 42 (4.31 g, 13.322 mmol) in acetonitrile (100 mL) was added sodium carbonate (5.65 g, 53.29 mmol) at room temperature. After stirring for 2 hours at 90 C, the resulting mixture was cooled to room temperature and filtered through a pad of celite . The filtrate was concentrated under reduced pressure. The residue was purified by silica

- 80 -gel column chromatography, eluted with (DCM/1V1e0H, 96.7:3.3) to afford 6.7g (78% yield) of intermediate 70.
Preparation of intermediate 71:
¨Boc N *S

NO
N
) and intermediate 72 ________________________________ N¨Boc *R
4,N) ) Intermediate 70 (6.7g) was purified by via chiral SFC (Stationary phase:
CHIRACEL OJ-H
51.tm 250*30mm, Mobile phase: 94% CO2, 6% Me0H (0.3% iPrNH2)). The ft-action containing the product were mixed and concentrated to afford 3.18g (47% yield) of intermediate 71 and 3.16g (47%yield) of intermediate 72.
Preparation of intermediate 73:
F
N¨Boc EDCI (3.12 g, 13.7 mmol) was added to a solution of 1-(tert-butoxycarbony1)-3-fluoroazetidine-3-carboxylic acid (2.00 g, 9.12 mmol), DIEA (6.5 mL, 36.7 mmol), N,0-dimethylhydroxylamine hydrochloride (1.78 g, 18.2 mmol), and HOBT (1.85 g, 13.7 mmol) in acetonitrile (20 mL) and the reaction mixture was allowed to stirred at 25 C
under N2 for 2 h.
The mixture was quenched with water (50 mL) and extracted with Et0Ac (100 mL x 3). The Et0Ac layer was dried over Na2SO4, filtered and evaporated to give a residue, which was purified by FCC (silica gel, from PE:EA=100:0 to 60:40) to give intermediate 73 (1.5 g, 63%
yield) as a light yellow oil.

- 81 -Preparation of intermediate 74:
F \N¨Boc Under N2 at 5 C, i-PrMgC1 2M in THF (10 mL, 20 mmol) was added to a solution of intermediate 73 (3.00 g, 11.4 mmol) in THF (30 mL) dropwise. The solution was stirred at 5 C
for 30 min, allowed to slowly rise to 20 C and stirred for 12h. The reaction mixture was poured out into a mixture of ice water and a saturated aqueous NH4C1 solution and extracted with Et0Ac (200 mL x 2). The organic layer was decanted, dried over Na2SO4, filtered and evaporated to dryness. The resulting crude was purified by FCC (silica gel, from PE: EA=100:0 to 70:30) to yield intermediate 74 (1.6 g, 51 % yield) as a colourless oil.
Preparation of intermediate 75:
N Boc To a solution of bicyclo[1.1.1]pentane- 1 -carboxylic acid (1.00 g, 8.92 mmol), tert-butyl 4-bromopiperidine- 1 -carboxylate (4.71 g, 17.8 mmol), 2,2'-bipyridine (696 mg, 4.46 mmol), Ni(acac)2 (916 mg, 3.57 mmol), MgCl2 (2.55 g, 26.8 mmol), Zn (4.00 g, 61.2 mmol), 4A MS
(10.0 g) and DlEA (4.5 mL, 27.2 mmol) in THF/DMF (100 mL/30 mL) was added B
oc20 (7.79 g, 35.7 mmol) under an Ar atmosphere at 30 C. After addition, the reaction mixture was stirred at 30 C for 60 hours. The reaction mixture was poured into 150 mL of water and extracted with Et0Ac (150 mL x 2). The combined extracts were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuum. The resulting residue was purified by column chromatography (silica gel, eluent from PE/Et0Ac = 100:0 to 85:15) to afford intermediate 75 (580 mg, purity 60% based on LCMS, 14% yield) as a colourless oil.
Preparation of intermediate 76:
NBoc N RS

I
N

- 82 -To a solution of intermediate 75 (580 mg, 60% purity, 1.25 mmol), intermediate 18 (568 mg, 1.37 mmol) and AcOH (449 mg, 7.47 mmol) in 50 mL of Me0H was added NaBH3CN
(470 mg, 7.47 mmol). After addition, the reaction mixture was stirred at 60 C for 16 hours. The reaction mixture was concentrated under vacuum and the residue was diluted with 100 mL of water and extracted with Et0Ac (100 mL x 2). The combined extracts were concentrated in vacuum and the resulting residue was purified by preparative HPLC (Column Phenomenex Gemini NX-C18 (75*30mm*3um), Mobile Phase A: water (0.2% FA), Mobile Phase B:
acetonitrile, Flow rate: 30 mL/min, gradient condition from 25%B to 55%B). The pure fractions were collected and lyophilized to afford intermediate 76 (310 mg, 37% yield) as a white solid.
Preparation of intermediate 76:
Li¨CI
Mg-<>
Br LiC1 (565.2 mg, 13.333 mmol) was dried under high vacuum by heating with a heat gun and allowed afterwards to cool to room temperature. Then, Mg turnings (324 mg, 13.333 mmol) and THF (11.1 mL, 1 M, 11.1 mmol) were added. The reaction mixture was cooled to 0 C and bromocyclobutane (1.5 g, 11.1 mmol) was then added. The reaction mixture was stirred at room temperature for 2 hrs. In this time a grey solution was formed. The THF
solution of cyclobutylmagnesium bromide. LiC1 or intermediate 76 (approx. 1 M) was used directly in the following reaction.
Preparation of intermediate 77:
NBoc In flask, intermediate 57 (1.01 g, 3.704 mmol) was dissolved in dry THF (10 mL). The solution was cooled in an ice bath and treated with a solution of freshly prepared intermediate 76 (11.1mL, approx. 1 M, 11.1 mmol) dropwise at this temperature. The reaction mixture was stirred over night and was allowed to come to room temperature. Then saturated ammonium chloride solution was added, and the water phase was extracted with ethyl acetate for three times. After the organic phase was dried with magnesium sulfate and filtered, the organic phase was evaporated. The crude product (953 mg) was purified with flash CC (silica gel, 15% EA in n-heptane) to give 833 mg (28% yield) of intermediate 77 as a colorless oil.

- 83 -Preparation of intermediate 78:
NBoc N RS

Oyk-,N
I
N, intermediate 79:
[2:2 N'h-CNBoc R' 0, -1\1 N,N ) and intermediate 80:
NBoc N s*

N
I
To a solution of intermediate 18 (90.0 mg, 0.217 mmol), 2 drops of acetic acid and intermediate 77 (145.1 mg, 0.543 mmol) in methanol (4 mL) was added sodium cyanob orohydri de (54.6 mg, 0.869 mmol). After stirring at 60 C overnight, the solvent was removed under vacuum. Then, the reaction was quenched with a saturated solution of sodium carbonate and extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over anhydrous magnesium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure. The crude product (200 mg) was obtained as a colorless oil and purified by preparative CC (12 g silica gel, eluent from 2.5 to 5% Me0H in DCM) to give intermediate 78 (106 mg, 73% yield) as a white solid. A enantiomeri c separation was performed via Preparative SFC (Stationary phase: Chiralpak Daicel IG 20 x 250 mm, Mobile phase: CO, Et0H
+ 0.4

- 84 -iPrNH2) yielding 224 mg of intermediate 79 and 261 mg intermediate 80 containing 5% of intermediate 79.
Preparation of intermediate 85:
Boc I X
To a mixture of 4-chloro-3-iodopyridine (2.00 g, 8.35 mmol) in DMF (30 mL) was added tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (1.95 g, 9.19 mmol) and Cs2CO3 (8.2 g, 25.2 mmol). The resultant mixture was stirred at 110 C overnight. The reaction was cooled to room temperature and diluted by water (100 mL), extracted with ethyl acetate (40 mL
x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduce pressure to give the crude which was purified by FCC
(100% petroleum ether to petroleum ether: ethyl acetate = 1:1) to give intermediate 85 (1.7 g, purity 100%, yield 49%) as a white solid.
Preparation of intermediate 86:
,Boc To a mixture of intermediate 11(2.72 g, 12.1 mmol) in N-methyl-2-pyrrolidone (20 mL) was added intermediate 85 (1.70 g, 4.09 mmol) and Cs2CO3 (4.00 g, 12.3 mmol). The mixture was replaced with argon. Then CuCl (255 mg, 2.58 mmol) and 2,2,6,6-tetramethy1-3,5-heptanedione (0.4 mL, 1.91 mmol) was added under the protection of argon. The resultant mixture was stirred at 140 C overnight under argon atmosphere. The mixture was cooled to room temperature and diluted by water (100 mL), extracted with ethyl acetate (40 mL x 3). The combined organic layers was washed by brine (20 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduce pressure to give the crude, which was purified by FCC
(100% DCM to DCM: Me0H = 10:1) to afford intermediate 86 (780 mg, purity 89.93%, yield

- 85 -33%) as a brown solid.
Preparation of intermediate 87:

To a mixture of intermediate 86 (200 mg, 0.390 mmol) in DCM (2 mL) was added TFA (0.5 mL) at room temperature. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was evaporated under reduce pressure. The residue was diluted by 2 M
NaOH (5 mL), extracted with DCM (10 mL x3). The combined organic layers was dried over by anhydrous Na2SO4, filtered and concentrated under reduce pressure to give intermediate 87 (160 mg, 99%
yield) as a yellow solid, which was used in next step without further purification.
Preparation of intermediate 88:
Boc N RS NH

To a mixture of intermediate 87 (160 mg, 0.388 mmol) in Me0H (4 mL) was added intermediate 21(187 mg, 0.775 mmol) and AcOH (47 mg, 0.783 mmol). The mixture was stirred at 70 C for 1 h. Then the mixture was cooled to room temperature and NaBH3CN (48 mg, 0.764 mmol) was added to the mixture. The resultant mixture was stirred at 70 C for another 1 h. The reaction mixture was cooled to room temperature and evaporated to remove solvent. The residue was diluted by saturated NaHCO3 aqueous solution (10 mL), extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude, which was purified by FCC (100% petroleum ether to 100% ethyl acetate; TLC: ethyl acetate, Rf = 0.1) to give intermediate 88 (100 mg, purity 99%, yield 40%) as a yellow solid.

- 86 -Preparation of intermediate 89:
N¨Boc N RS
0 J., N
F NN
To a solution of intermediate 19 (800 mg, 1.475 mmol) in Me0H (10 mL) was added intermediate 37 (838 mg, 3.686 mmol). The mixture was stirring at room temperature for 1 h.
The mixture was added NaBHCN (556 mg, 8.848 mmol) at 0 C. The mixture was stirring at room temperature for overnight. The mixture was quenched with Sodium bicarbonate solution, extracted with EA, washed with water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (silica gel, eluent from 100% DCM to 10% Me0H in DCM) to give 300 mg of intermediate 89 as a yellow oil.
B. Preparation of compounds Preparation of compound 1:
RS

I
A mixture of 2-[(4-chl oro-5-pyrimi di nyl)oxy] -N-ethyl -5 -fluoro-N-(1 -m ethyl ethyl)-b enzami de (174 mg; 0.516 mmol), intermediate 4 (173 mg; 0.62 mmol) and sodium carbonate (218 mg;
2.064 mmol) in ACN (20 mL) was refluxed (90 C) for 2 hours. The reaction mixture was cooled to RT, poured onto iced water and extracted with DCM. The organic layer was decanted, washed with water, filtered over Chromabond and evaporated to dryness. The residue was purified by chromatography over silica gel (irregular SiOH, 24g; mobile phase:
gradient from 0% NH4OH, 0% Me0H, 100% DCM to 1% NH4OH, 10% Me0H, 90% DCM). The pure fractions were collected and evaporated to dryness yielding 150 mg of compound 1 (50% yield).

- 87 -Preparation of compound 2 N
LOLN
I
A mixture of 2-1(4-chl oro-5-pyri rni di nyl)oxy] -N-ethyl -5 -fluoro-N-(1 -m ethyl ethyl)-b enzami de (33.5 mg; 0.099 mmol), intermediate 8 (35 mg; 0.119 mmol) and sodium carbonate (42 mg;
0.398 mmol) in ACN (3.7 mL) was refluxed (90 C) for 2h. A similar work up and purification than the one used to isolate compound 1 was applied and led to compound 2.
Preparation of compound 3:

*R
jr 21 '1\1 and compound 4:
ON

N *S

Compound 2 (361 mg) was purified via chiral SFC (Stationary phase: CHIRALPAK
AD-H
5pm 250*30mm, Mobile phase: 88% CO2, 12% Et0H (0.3% iPrNH2)). The fractions containing the product were mixed and concentrated to afford 156 mg of a fraction A which was taken up with Et20 and evaporated till dryness to give 150 mg of compound 3 and 156 mg of fraction B which was taken up with Et20 and evaporated till dryness to give compound 4.

- 88 -Alternative preparation of compound 4:
The reaction was performed twice on (1.3g; 2.48 mmol) of compound 76.
Under N2 flow, NaBH(OAc)3 (1.56 g, 7.43 mmol) was added dropwise to a solution of compound 76 (2.6 g; 5 mmol), oxetane-3-carbaldehyde (0.37 mL; 5.35 mmol) in THF (100 mL). Then, the reaction mixture was stirred at RT for 2h. Both reactions (performed on 1.3g of compound 76) were mixed with another reaction performed on 700 mg of compound 76 and the resulting mixture was poured into ice water, basified with an aqueous solution of K2CO3 10% and Et0Ac was added. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated till dryness to give 3.93 g of crude compound 4 which was mixed with additional 392 mg of crude compound 4. The resulting crude was purified by silica gel chromatography (Stationary phase: irregular SiOH 15-40 m 80g MERCK, Mobile phase:
Gradient from 97% DCM, 3% Me0H (+10% NH4OH) to 90% DCM, 10% Me0H (+10%
NH4OH)). The fractions containing the product were mixed and concentrated to afford 2.5 g of compound 4 (white product) and 1.2 g of impure (71.6% purity evaluated by LC/MC) compound 4 Analogous reaction protocols as reported for compounds 1 and 2 could be used for the preparation of compounds listed in the table below starting from the appropriate starting materials.
C\.0 RS
N RSN

N
I
Compound 5 Compound 6

- 89 -\---0__\
7--- _/
'-,z_ \..--0_, r s CN N
si\N * --1 *R

N 0 4,N -õ,__N 0 N
0õA 0.,)-.
F I
Th\J F -` N
I
-1\1 Compound 7 Compound 8 -----/ H 1-1_ _ -S S
N *R N *S
N N
N 0 --N,,,,-0 N N
I
FN Fõ---,,,õ--,.-- ----.N-;---Compound 9 Compound 10 ------H H
N------)R
*R N *S R
N N
--_,,N
N N
C:1) 0,AN N

F F 'N
Compound 11 Compound 12 N I-1' R N I-1 R
N
N N
0.-1., F

F N
Compound 13 Compound 14

- 90 -N
. -Rh_ic2 *s N H s N H s N 0 -...,..N 0 N N

F
Compound 15 Compound 16 o N RS D N RS
D D
--,õ---,,,N 0 -,,,N 0 N N

F -" N
I
Compound 17 Compound 18 NS
--1 -'1 N
I N
I ) F N F N
Compound 19 Compound 20 CN
N *S
N
0,.),,,, F I
Th\1 Compound 21

- 91 -Preparation of compound 22:

N RS

I
NN
At 0 C, TFA (3.2mL; 42.2mmo1) was added to intermediate 22 (1.35g; 2.11mmol) in DCM (32 mL). Then, the reaction was warmed to room temperature and stirred for 15h at room temperature.
The reaction mixture was concentrated, and the residue was dissolved in 40 mL
of water. The solution was basified with a solution of NaOH 1M until pH=8-9. After stirring for 10 min at room temperature, the resulting mixture was extracted with DCM. The combined organic layers were washed with brine and dried over MgSO4, filtered and evaporated till dryness to give 0.84g (74%) of compound 22.
Preparation of corn pound 32 NH
N RS

N,N
A solution of intermediate 45 (100 mg; 0.16 mmol) and TFA (0.25 mL; 3.27 mmol) in DCM
(2.5 mL) was stirred at rt overnight. TFA was eliminated by evaporation. The residue was taken up with water, basified with an aqueous solution of NH4OH. The organic layer was extracted with DCM, dried over MgSO4 and evaporated to dryness to give 84 mg of compound (quantitative).

- 92 -Preparation of compound 33:
NH
N RS

N
N N
At 0 C, TFA (0.49 mL; 6.4 mmol) was added to a solution of intermediate 50 (200 mg; 0.32 mmol) in DCM (7 mL). The reaction mixture was stirred overnight at RT. The residue was evaporated till dryness. The residue (420 mg) was purified by silica gel chromatography (Stationary phase: irregular SiOH 15-40m 12g, Mobile phase: Gradient from 90%
DCM, 10%
Me0H (+10% NH4OH) to 85% DCM, 15% Me0H (+10% NH4OH)). The fraction containing the product were mixed and concentrated to afford 144 mg (85% yield) of compound 33.
Preparation of compound 34:
H

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

- 93 -Preparation of compound 35:
r\T7c;NH

N
N
NJ
Compound 35 was prepared accordingly to compound 34 starting from intermediate 52.
Preparation of compound 36:
NH
N RS
TEA salt N
A stir bar, intermediate 59 (130 mg, 0.199 mmol), trifluoroacetic acid (2 mL) and dry di chl oromethane (1 mL) were added to a 25 mL round-bottomed flask before the resultant mixture was stirred at 25 C for 1 h. The mixture was concentrated under reduced pressure to give e compound 36 (130.0 mg, crude) as colourless oil which was used to the next step directly without further purification.
Preparation of compound 37:
NH
_Li¨N RS

N
Ni Intermediate 60 (40 mg, 0.061 mmol), 1,4-dioxane (0.5 mL) and HC1/1,4-dioxane (0.2 mL, 4 M) were added to a 10 mL round-bottomed flask. The reaction mixture was stirred at room-temperature for 12 hours. The reaction mixture was concentrated to dryness under reduced

- 94 -pressure to afford the title compound which was dissolved in H20 (10 mL). The resultant solution was basified with solid NaHCO3 to pH = 8 and extracted with ethyl acetate (10 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was suspended in water (10 mL).
The mixture was frozen using dry ice/acetone and then lyophilized to afford compound 37 (30 mg, crude), as a white solid which was used in the next step without further purification.
Preparation of compound 78:
N17:FTCNH
HCI salt NO
F NN
HC1/dioxane (200 uL, 0.400 mmol, 2M) was added to a solution consisting of intermediate 60a (15 mg, 0.023 mmol) in dioxane (1 mL). The reaction mixture was stirred at r.t. for 2 hr. White solid was precipitated. The solvent was removed by syringe and the white solid was concentrated to dryness under reduced pressure to afford the title compound which was suspended in water (10 mL) and frozen using dry ice/ethanol, and then lyophilized to dryness to afford the compound 78 (6.47 mg, 47% yield) as a white solid.
Preparation of compound 79:
NH
N *s HCI salt NO N
N, HC1/dioxane (200 uL, 0.400 mmol) was added to a solution consisting of intermediate 60b (19 mg, 0.029 mmol) and dioxane (1 mL). The reaction mixture was stirred at r.t.
for 2 h. White solid was precipitated. The solvent was removed by syringe and the white solid was concentrated to dryness under reduced pressure to afford the title compound which was suspended in water (10 mL) and frozen using dry ice/ethanol, and then lyophilized to dryness

- 95 -to afford compound 79 (7.32 mg, 42% yield) as a white solid.
Preparation of compound 45:
¨/
CNN
*R

4.N HCl salt NO
N,N!) HC1/dioxane (150 uL, 0.300 mmol, 2 M) was added to a solution consisting of intermediate 63 (20 mg, 0.031 mmol) and dioxane (1 mL). The reaction mixture was stirred at room-temperature for 4 hours. The white solid was precipitated. The solvent (dioxane) was removed by syringe and the white solid was concentrated to dryness under reduced pressure to afford the title compound which was suspended in water (10 mL). The mixture was frozen using dry ice/ethanol and then lyophilized to dryness to afford the compound 45 (3.17 mg, 17% yield) as a white solid.
Preparation of compound 46 _______________________________ FC_IJVH
N *S
HCI salt F NN

HC1/dioxane (150 uL, 0.300 mmol, 2 M) was added to a solution consisting of intermediate 64 (19 mg, 0.030 mmol) and dioxane (1 mL). The reaction mixture was stirred at room-temperature for 4 hours. The white solid was precipitated. The solvent (dioxane) was removed by syringe and the white solid was concentrated to dryness under reduced pressure to afford the title compound which was suspended in water (10 mL). The mixture frozen using dry ice/ethanol and then lyophilized to dryness to afford the compound 46 (8.01 mg, 46% yield) as a white solid.

- 96 -Preparation of compound 49:
/
N *R
ii HCl/1,4-dioxane (0.3 mL) was added to the mixture consisting of intermediate 67 (25 mg, 0.039 mmol) and 1,4-dioxane (1 mL) at 0 C. The resultant mixture was stirred at room-temperature for 1 h. The reaction mixture was concentrated to dryness under reduced pressure to afford the crude product which was purified by preparative HPLC using a YMC-Triart Prep C18 250 x 50 mm x 10 .ina column (eluent: 45% to 75% (v/v) CH3CN with 0.04% NH3H20-E 1 OmM
NH4HCO3) to afford pure product. The product was suspended in water (10 mL).
The mixture was frozen using dry ice/ethanol, and then lyophilized to dryness to afford the compound 49 (3.88 mg, 89%. purity based on LC/MS, 16% yield) as a white solid.
Alternative procedure for the preparation of compound 49.
A stir bar, intermediate 67 (70.0 mg, 0.109 mmol) and hydrochloric acid/dioxane (2 mL, 8.0 mmol, 4 M in dioxane) were added to a 10 mL round-bottomed flask before the mixture was stirred at 25 C for 1 h. The mixture was concentrated under reduced pressure to give 70 mg of crude compound 49 (HC1 salt) as a white solid which was used in the next step without further purification.
Preparation of compound 50:
NH
N *S
F

N, To a solution of intermediate 68 (40.0 mg, 0.063 mmol) in 1 mL of dioxane was added HC1/dioxane (3 mL). After addition, the reaction mixture was stirred at 10 C
for 45 minutes.
The reaction mixture was concentrated in vacuum and the residue was purified by preparative

- 97 -HPLC (Column Boston Prime C18 150 x 30mm x 5um, Mobile Phase A: water (0.04%N1-13H20+10mM NH4HCO3), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 45% B to 75%). The pure fractions were collected, and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to afford compound 50 (12 mg, 34% yield) as white solid.
Preparation of compound 76:
N H

In a round bottom flask, at 0 C, TFA (12.7mL; 166 mmol) was added to intermediate 71(5.18 g; 8.29 mmol) in DCM (175 mL). Then, the reaction was warmed to room temperature and the reaction mixture was stirred overnight at room temperature. The residue was dissolved in 20 mL of water. Then, the solution was basified with a solution of NaOH 1M (70 mL) until pH=8-9. After stirring for 10 min at room temperature the resulting mixture was extracted with dichloromethane (5 x 100 mL).The combined organic layers were washed with brine (1 x 150 mL) and dried over MgSO4, filtered and evaporated till dryness to give 4 g (92% yield) of compound 76.
The compounds listed in the table below were prepared following analogous reaction protocols as reported for the preparation of compounds 76 starting from the corresponding starting materials.
Compound number Compound structure ¨/
NI/

N
From intermediate 72

- 98 -¨/
F
/ \L \
¨NR NH

01),N
I
NN
From intermediate 18 and intermediate 74 F\L
N S NH

0,T)N
I
NN
From intermediate 18 and intermediate 74 Preparation of compound 80:
NH
N RS
TFA salt F NN
O'rLN
To a solution of intermediate 76 (380 mg, 0.561 mmol) in 3 mL of DCM was added TFA (6 mL). After addition, the reaction mixture was stirred at 27 C for 1 hour.
The reaction mixture was concentrated in vacuum to afford compound 80 (350 mg, crude, TFA salt) which was used in next step without any purification.

- 99 -Preparation of compound 112:
NH
N *S

N
NJ
In a vial intermediate 80 (208 mg, 0.312 mmol) was dissolved in DCM (3.00 mL, 46.9 mmol) and cooled to 0 C. The mixture was treated with TFA (0.478 mL, 6.25 mmol), then the cooling bath was removed. After stirring overnight sat. sodium carbonate solution was added as well as DCM. The water phase was further basified with 1 N aqueous NaOH solution to pH
13. The water phase was extracted multiple times with DCM and then with ethyl acetate.
The collected organic solvents were dried with MgSO4, filtered, then the solvents were removed to yield compound 112 (150 mg, 85% yield) as a white solid.
Preparation of compound 113:
N *R

In a vial intermediate 79 (224 mg, 0.336 mmol) was dissolved in DCM (3.23 mL, 50.5 mmol) and cooled to 0 C. The mixture was treated with TFA (0.515 mL, 6.73 mmol).
The cooling bath was removed. After stirring overnight saturated sodium carbonate solution was added as well as DCM. The water phase was further basified with 1 N aqueous NaOH
solution to pH 13.
The water phase was extracted multiple times with DCM and ethyl acetate. The collected organic solvents were dried with MgSO4, filtered, then the solvents were removed to yield crude compound 113 (239 mg). 35 mg of crude compound 113 were used and purified via preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10nm,30x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) yielding 16 mg of compound 113 as white solid.

- 100 -Preparation of compound 54:

N.N
compound 55:
)1rii oI
N S NO-d's oIN
NNJ
and compound 56 HH
oI
N S

(DN
I
N
Ni In a sealed tube, NaBH3CN (45.8 mg, 0.729 mmol) was added to a mixture of intermediate 29 (157 mg, 0.291 mmol), (S)-3-methoxypyrrolidine (88.4 mg, 0.874 mmol) and acetic acid (16.7 p,L, 0.291 mmol) in methanol (4 mL). The reaction mixture was stirred at 60 C
for 18 h. A
saturated aqueous solution of NaHCO3 and Et0Ac were added. The layers were separated. The aqueous layer was extracted with Et0Ac. The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated and purified by silica gel chromatography (irregular SiOH 40 Jim, 12 g, liquid loading (DCM), mobile phase gradient: from DCM/(Me0H/ aq. NH3:
9/1): 99/1 to 90/10). The fractions containing product were evaporated to give 164 mg of compound 54 which was purified by reverse phase (Stationary phase: YMC-actus Triart C18 10 i_tm 30*150 mm, Mobile phase: Gradient: (aq. NH4HCO3 0.2%, pH=9.5)/(MeCN/MeOH:
1/1): from 40/60 to 10/90). The fractions containing products were evaporated, solubilized in MeCN, extended with water and freeze-dried to give 81 mg (45% yield) of compound 55 as a white fluffy solid and 22 mg (12% yield) of compound 56 as a white fluffy solid.

- 101 -Preparation of compound 57:
H cis N S No N
I
N
NJ
and compound 58:
¨001 H cis I
NN
NaBH3CN (47 mg; 0.75 mmol) was added to a mixture of intermediate 29 (200 mg;
0.37 mmol), (cis)-hexahydro-1H-furo[3,4-c]pyrrole (0.13 mL; 1.12 mmol) and AcOH (21 pL;
0.37 mmol) in THU (10 mL) and the reaction mixture was stirred at 60 C for 18 h. The reaction mixture was cooled to RT, poured onto a 10% aqueous solution of K2CO3 and Et0Ac. The organic layer was decanted, separated, dried over MgSO4, filtered and evaporated to dryness g. The crude (340 mg) was purified by silica gel chromatography (Stationary phase:
irregular bare silica 12g, Mobile phase: Gradient from 99% DCM, 1% Me0H (+10% NH4OH) to 90% DCM, 10%
Me0H (+10% NH4OH)). The fractions containing the product were mixed and concentrated to afford an intermediate fraction (220mg) which was purified via reverse phase (Stationary phase:
YMC-actus Trion C18 15 p.m 35*220 mm, Mobile phase: Gradient from 40% (aq.

0.2% pH=9.5)/MeCN/Me0H to 40/30/30 to 20/40/40). yielding 135 mg of compound 57 which were freeze dried with acetonitrile/water 20/80 to give 120 mg (55 % yield) of compound 57 as a white powder and 40 mg of compound 58 which were freeze-dried with acetonitrile/water 20/80 to give 38 mg (16% yield) of compound 58 as a white powder.
The compounds listed in the table below were prepared following the same procedures as reported for the preparation of compounds 54, 55 and 56 starting from the corresponding starting materials.

- 102 -Compound number Compound structure N S

I
NN
From intermediate 29 and 4-(isopropylsulfonyl)piperidine H H
N

NN
From intermediate 28 and 4-(isopropylsulfonyl)piperidine -00Fri N S

N
I
NN
From intermediate 29 and 2-methoxy-N-methylethan-1-amine N S N N

Cj'srj'N
I
N
F- N-From intermediate 29 and 1-(piperazin-1-yl)ethan-1-one

- 103 -Compound number Compound structure H H H =
cis N
I
N,N
H H H =
cis I
N,N=-;) From intermediate 28 and (c, i s)-h exahy dro-1H-furo [3 ,4-c]pyrrol e FjoitiN

HH

N,N

I
N
From intermediate 29 and 2-oxa-6-azaspiro[3.31heptane

- 104 -Compound number Compound structure H H

0)A N
I
NN
H H
NNKO

68 o N
I
From intermediate 28 and 2-oxa-6-azaspiro[3.3]heptane N S

(:)))N
F NN
N
N S H

0=.y.k., I
N,N-;) From intermediate 29 and cyclopropanamine

- 105 -Compound number Compound structure HH
S.

I
N,N
HH

N RS

I
N,N_4) From intermediate 29a and morpholine N S

I

N S
\T/

F NN
From intermediate 12, intermediate 34 and 1-(2,6-diazaspiro[3.31hept-2-yeethenone, TFA salt

- 106 -Compound number Compound structure N S

129 0)AN
I
N,N
/

0)AN
I
From intermediate 29 and 4-methoxypiperidine Preparation of compound 131:
Ncis ,0 N S
/1\1--,N 0 N
I
and compound 132:
,0 HN
N S N

Oyt. N
I
To a solution of intermediate 29 (120 mg, 0.22 mmol) in methanol (2 ml) was added the cis-

- 107 -N,N-dimethy1-3-azabicyclo[3.1.0]hexane-6-carboxamide (41 mg, 0.27 mmol). After stirring for 20 minutes at room temperature, sodium cyanoborohydride (28 mg, 0.47 mmol) was added to the mixture. After stirring at 50 C overnight, the resulting mixture was quenched with a saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were washed with water and brine and dried over anhydrous sodium sulfate. The solid was filtered off The filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 5um,19*150mm ; Mobile Phase A: Water(lOmmon NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 30%B to 60%B in 7 min;
220 nnr, retention time 1: 6.35 min; retention time 2: 6.90 min. Mixed of the pure fractions and lyophilization afforded 46.5 mg (30.6% yield, retention time 1: 6.35 min) of compound 131 as white solid and 3 mg (1.9% yield, retention time 2: 6.90 min) of compound 132 as white solid.
Preparation of compound 120:
H cis N, and compound 121:
H cis To a solution of intermediate 84 (2.5 g, 2.99 mmol, 62.8% purity) in Me0H (50 mL) was added cis-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride (1.07 g, 7.15 mmol). After stirring at room temperature for 30 minutes, NaBH3CN (599 mg, 9.53 mmol) was added to the reaction mixture.
The resulting reaction mixture was stirred at 50 'V overnight and quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced

- 108 -pressure to give 800 mg of crude product as a yellow solid. The crude product was purified by preparative-HPLC ( YMC-Actus Triart C18, 30 mm X 150 mm, 5um; Mobile Phase A:Water(10 mmol/L NH4HCO3+0.1%NH3.H20), Mobile Phase B:ACN; Flow rate:60 mL/min;
Gradient:40%B to 60%B in 7 min; 254 nm; RT1: 6.95 min; RT2: 8.27 min). The fractions containing the products were mixed. The solvents were concentrated and both compounds were freeze dried to afford to give 102.6 mg of compound 120 as a white solid and 23.1 mg of compound 121 as a white solid.
CONVERSION
Preparation of compound 23:
F-joFt_i N H
N RS

I
F" N"
compound 24:

H H c_) N H

NI
N,N
and compound 25:
¨00;1 0 N *S
N H

N,N

-109-At room temperature, NaBH(OAc)3 (144 mg; 0.68 mmol) was added to a solution of compound 22 (240 mg; 0.445 mmol) and tetrahydro-4H-pyran-4-one (48 !IL; 0.53 mmol) in dichloroethane (6 mL). The mixture was stirred at rt overnight. The solution was cooled and poured into cooled water, basified with K2CO3 powder and the product was extracted with DCM. The organic layer was dried over MgSO4, filtered and evaporated to dryness giving 380 mg of compound 23 Separation of the enantiomers (380 mg of compound 23) was performed via chiral SFC
(Stationary phase: Chiralpak IG 5 m 250*20mm, Mobile phase: 50% CO2, 50% Et0H
(0.3%
iPrNH2)). The fractions containing the products were mixed, concentrated and freeze-dried with a mixture of acetonitrile/water (20/80) to afford 90 mf (32% yield) of compound 24 as a white powder and 98 mg (35% yield) of compound 25 as a white powder.
The compounds listed below were prepared by using analogous reaction protocols as reported for compound 23 starting from the respective starting materials Compound Structure number /
NH RS
N RS
Compound Oyk,, I IN
N
From compound 22 and dihydro-3(2H)-furanone

- 110 -N1-1 *s N RS
Compound 0-1-1)k-N

N

/
NH *R
N RS
0 ,N) Compound From chiral SFC separation of compound 26: Stationary phase:
Chiralpak IG 5pm 250*30mm, Mobile phase: 55% CO2, 45%
mixture of Et0H/DCM 80/20 v/v +0.3%iPrNH2 H H
NH * R
NM? Or¨
Compound N
I
NH *R
*S
Compound 0 I
N
NJ
From chiral SFC separation of compound 28: Stationary phase:
CH1RALPAK AD-H 5nm 250*21.2mm, Mobile phase: 85% CO2, 15% Et0H 0.3% iPrNH2

- 111 -NH
N RS
Compound N 0 31 oI N
N N
From compound 22 and oxetane-3 -carbaldehyde using NaBH3CN
as reductive agent Preparation of compound 38:

N RS
M
NO

N N
Acetic acid (16 L; 0.28 mmol) was added at room temperature to a solution of compound 32 (88 mg; 0.17 mmol) and oxetane-3-carbaldehyde (24 L; 0.35 mmol) in THF (3 mL). The mixture was stirred at rt for 4h. Then, NaBH(OAc)3 (107 mg; 0.51 mmol) was added portionwise. The mixture was stirred at room temperature for 2 hours and then, poured into ice water, basified with a 10% aqueous solution of K2CO3. Et0Ac was added. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated till dryness. The resulting residue (98 mg) was purified by silica gel chromatography (Stationary phase: irregular SiOH 40 um 4 g, Mobile phase: Gradient from 100% DCM to 80% DCM, 20% Me0H
(+10%
NH4OH)). The fractions containing the product were mixed and concentrated to give 60 mg of compound 38 which was further purified via reverse phase (Stationary phase:
YMC-actus Triart C18 lOnm 30*150mm, Mobile phase: Gradient from 40% NH4HCO3 0.2%, 60% Me0H to 20% NH4HCO3 0.2%, 80% Me0H). The fractions containing the product were mixed and concentrated to give 26 mg of compound 38 which was freeze-dried with acetonitrile/water (20/80) to give 24 mg (25% yield) of compound 38 as a white powder.

- 112 -Preparation of compound 39:

N RS

N
N
NJ
Acetic acid (24 ttL; 0.42 mmol) was added at room temperature to a solution of compound 33 (144 mg; 0.27 mmol) and oxetane-3-carbaldehyde (38 L; 0.55 mmol) in THE (4 mL). The mixture was stirred at rt overnight then NaBH(OAc)3 (177 mg; 0.83 mmol) was added portionwise. The mixture was stirred at room temperature for 24 hours. The mixture was poured into iced water. The aqueous layer was basified with K2CO3 powder and the mixture was extracted with Et0Ac (x2). The organic layers were combined, dried over MgSO4 and evaporated till dryness. The residue (137 mg) was purified by silica gel chromatography (Stationary phase: irregular SiOH 15-40[tm 12g, Mobile phase: Gradient from 97% DCM, 3%
Me0H (+10% NH4OH) to 90% DCM, 10% Me0H (+10% NH4OH)). The fractions containing the product were mixed and concentrated to give 90 mg of an intermediate impure fraction which was further purified by reverse phase (Stationary phase: YMC-actus Triart C18 10um 30*150mm, Mobile phase: Gradient from 65% NH4HC030.2% , 35% ACN to 25% NH4HCO3 0.2%, 75% ACN). The fraction containing the product were mixed and concentrated and the resulting residue (44 mg) was freeze-dried with Acetonitrile/water (20/80) to give 42 mg (26%
yield) of compound 39.
Preparation of compound 40:
N *R

F
N
I
N
NaBH(OAc)3 (91 mg; 0.43 mmol) was added dropwise to a solution of compound 34 (150 mg;
0.28 mmol) and oxetane-3-carbaldehyde (214; 0.3 mmol) in THF (6 mL). The reaction mixture was stirred at RT for 1.5 It The reaction mixture was poured into ice water, basified

- 113 -with a solution of K2CO3 10% and Et0Ac was added. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated till dryness.The residue (143 mg) was purified by silica gel chromatography (Stationary phase: irregular SiOH 15-40 m 12g, Mobile phase: Gradient from 97% DCM, 3% Me0H (+10% NH4OH) to 85% DCM, 15% Me0H (+10%
NH4OH)). The fractions containing the product were mixed, concentrated and the resulting residue (54 mg) was freeze-dried with acetonitrile/water (20/80) to give 50 mg (29% yield) of compound 40.
Preparation of compound 41:

N *s I
NaBH(OAc)3 (82 mg; 0.39 mmol) was added dropwi se to a solution of compound 35 (135 mg;
0.25 minol) and oxetane-3-carbal dehyde (190,, 0.27 rnmol) in TT-1F (5 mT,).
The reaction mixture was stirred at RT for 1.5 h. The reaction mixture was poured into ice water, basified with a solution of K2CO3 10% and Et0Ac was added. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated till dryness. The residue (130 mg) was purified by silica gel chromatography (Stationary phase: irregular SiOH 15-40pm 12g, Mobile phase: Gradient from 95% DCM, 5% Me0H (+10% NH4OH) to 92% DCM, 8% Me0H (+10%
NH4OH)). The fractions containing the product were mixed and concentrated to afford a fraction of 84 mg which was taken up with Et20 and evaporated till dryness to give 70 mg (45%
yield) of compound 41.
Preparation of compound 42:

d_r1 RS
áON
I
NO N
NJ

- 114 -A stir bar, compound 37 (130 mg, 0.195 mmol), oxetane-3-carbaldehyde (16.8 mg, 0.195 mmol), triethylamine (98.7 mg, 0.975 mmol) and dry dichloromethane (4 mL) were added to a 8 mL glass bottle before the mixture was stirred at 25 'V for 1 h. Then, sodium cyanotrihydroborate (36.7 mg, 0.584 mmol) was added to the mixture. The resultant mixture was stirred at 25 C for another 1 h. The mixture was diluted into dichloromethane (40 mL) and washed with water (20 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude which was purified by preparative HPLC (Column: Phenomenex Gemini-NX 150*30mm*5um, Mobile Phase A:
water(0.04%NH3H20+10mM w NH4HCO3), Mobile Phase B: acetonitrile, Flow rate: 30 mL/min, gradient condition from 43% B to 71% B). The pure fractions were collected, and the solvent was evaporated under vacuum to give a residue. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give compound 42 (24.34 mg, 19% yield) as a white powder.
Preparation of compound 43:

cif_\31 *R

N
N
and compound 44:

N-fr N *S

N
F NN
NaBH(OAc)3 (120 mg, 0.566 mmol) was added in portions to a 0 C (ice/water) solution consisting of compound 37 (100 mg, crude), oxetane-3-carbaldehyde (30.0 mg, 0.348 mmol), Et3N (100 uL, 0.719 mmol) and dichloromethane (5 mL). The resultant mixture was stirred at room-temperature of 1.5 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC using a Welch Xtimate C18

- 115 -150*25mm*5um (eluent: 38% to 68% (v/v) CH3CN and H20 with 0.04%NH3H20+10mM
NH4HCO3) to afford pure product which was suspended in water (10 mL). The mixture frozen using dry ice/acetone, and then lyophilized to dryness to afford a white solid (80 mg) which was further purified by SFC (DAICEL CHIRALPAK AD-H(250mm*30mm,5um), isocratic elution: i-PrOH (containing 0.1% of 25% aq. NH3): supercritical CO2, 30%: 70%
to 30%: 70%
(v/v)). The pure fractions were collected, and the volatiles were removed under reduced pressure. The product was suspended in water (10 mL). The mixture was frozen using dry ice/acetone and then, lyophilized to dryness to afford compound 43 (37.00 mg, 41% yield) as a white solid and compound 44 (33.96 mg, 38% yield) as alight yellow solid.
The compounds listed in the table below were prepared following analogous reaction protocols as reported for the preparation of compounds 39 or 42 starting from the corresponding starting materials.
Compound number Compound structure D/ID
NO N
di RS

122 lfjL
From N-(ethyl-d5)-5-fluoro-2-hydroxy-N-isopropylbenzamide, intermediate 13 and 1-azeti di necarb oxyli c acid, 3 -(2-m ethyl -1-oxopropyl )-, 1,1-dimethylethyl ester

- 116 -Compound number Compound structure N RS

N
From N-cyclopropy1-5-fluoro-2-hydroxy-7V-isopropylbenzamide, intermediate 13 and 1-Azetidinecarboxylic acid, 3-(2-methyl-1-oxopropy1)-, 1,1-dimethylethyl ester N RS

ON
I
NN
From intermediate 18 and 1-aetidinecarboxylic acid, 3-(2-methyl-l-oxopropy1)-, 1,1-dimethylethyl ester using sodium cyanoborodeuteride as reducing agent N-fr N RS

N
I
N
Ni From intermediate 18 and intermediate 58 using sodium cyanoborodeuteride as reducing agent

- 117 -Compound number Compound structure DD RS
D

I
N
From N-(ethyl -d5)-5 -flu oro-2-hy droxy -N-isopropylbenzamide, intermediate 13 and intermediate 58 Preparation of compound 47:
N
N

0 yk'= N
I
NN) To a solution of compound 45 (70.0 mg, 0.130 mmol) and oxetane-3-carbaldehyde (50 mg, 0.581 mmol) in DCM (5 mL) was added TEA (80.0 mg, 0.791 mmol). The mixture was stirred at rt for 10 mins, then NaBH3CN (100 mg, 1.59 mmol) was added. The reaction mixture was stirred at rt for 1 hour and then concentrated to give a residue. The residue was purified by preparative HPLC (Column: YMC-Triart Prep C18 250 x 50mm x 10um, Mobile Phase A:
water (0.04%NH3H20+10mM NH4HCO3), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition: from 45% B to 75% B) to afford compound 47 (20.0 mg, 24%
yield) as white solid.
Preparation of compound 48:
______________________________ 17Ã(7) N *S
NO
I
N

- 118 -To a solution of compound 46 (75.0 mg, crude), oxetane-3-carbaldehyde (35.9 mg, 0.417 mmol) and TEA (70.3 mg, 0.695 mmol) in 5 mL of DCM was added NaBH3CN. After addition, the reaction mixture was stirred at 10 C for 2 hours. The reaction mixture was concentrated in vacuum and the residue was purified by prep-HPLC (Column Boston Prime C18 150 x 30mm x 5um, Mobile Phase A: water (0.04%NH3H20+10mM NH4HCO3, Mobile Phase B:
acetonitrile, Flow rate: 25 mL/min, gradient condition from 45% B to 75%). The pure fractions were collected and lyophilized to afford the compound 48 (7.0 mg) as white powder.
Preparation of compound 51:
2 , No N

N
I
N
A stir bar, the compound 49 hydrochloride (70.0 mg, 0.121 mmol), oxetane-3-carbaldehyde (15.7 mg, 0.182 mmol), sodium cyanoborohydride (15.3 mg, 0.243 mmol), triethylamine (61.5 mg, 0.608 mmol) and dry dichloromethane (2 mL) were added to a 10 mL round-bottomed flask before the resultant mixture was stirred at 25 C for 1 h. The mixture was concentrated under reduced pressure to give the crude which was purified by preparative HPLC (Column:
Boston Prime C18 150*30mm*5um, Mobile Phase A: water(0.04%NH3H20 10mM
NH4HCO3), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 40%
B to 70%). The pure fractions were collected, and the solvent was evaporated under vacuum to give a residue. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give the compound 51(14.3 mg, 19%
yield) as a white powder.
Preparation of compound 52:
N *S
0 d---3 (Y-N
I
N
NJ

- 119 -To a solution of the compound 50 (50.0 mg, 0.093 mmol), oxetane-2-carbaldehyde (23.9 mg, 0.278 mmol) and TEA (18.8 mg, 0.185 mmol) in 5 mL of DCM was added NaBH3CN
(29.1 mg, 0.463 mmol). After addition, the reaction mixture was stirred at 10 "V for 1 hour. The reaction mixture was concentrated in vacuum and the residue was purified by preparative HPLC
(Column Boston Prime C18 150 x 30mm x Sum, Mobile Phase A: water (0.04%NH3H20+10mM NH4HCO3), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 45% B to 75% B). The pure fractions were collected and lyophilized to afford the compound 52 (8.38 mg, 1 15% yield) as white solid.
Preparation of compound 53:

N-fr .cirl RS
NO
A stir bar, compound 36 (130 mg, 0.195 rnmol), oxetane-3-carbaldehyde (16.8 mg, 0.195 mmol), triethylamine (98.7 mg, 0.975 mmol) and dry dichloromethane (4 mL) were added to a 8 mL glass bottle and the mixture was stirred at 25 'V for 1 h. Then, sodium cyanoborohydride (36.7 mg, 0.584 mmol) was added to the mixture which was stirred at 25 C for another 1 h.
The mixture was diluted into dichloromethane (40 mL) and washed with water (20 mL x 3).
The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude which was purified by preparative HPLC (Column:
Phenomenex Gemini-NX 150*30mm*5um, Mobile Phase A: water(0.04%NH3H2O-F10mM NH4HCO3), Mobile Phase B: acetonitrile, Flow rate: 30 mL/min, gradient condition from 43% B to 71%).
The pure fractions were collected, and the solvent was evaporated under vacuum to give a residue which was partitioned between acetonitrile (2 mL) and water (10 mL).
The solution was lyophilized to dryness to give compound 53 (24.3 mg, 19. yield) as a white powder.

- 120 -Preparation of compound 71:
N *S
N
1\1, Sodium triacetoxyborohydrate (50 mg; 0.24 mmol) was added at room temperature to a solution of compound 35 (60 mg; 0.11 mmol) and dihydro-3(211)-furanone (18 [IL; 0.23 mmol) in dichloroethane (8 mL). The mixture was stirred at rt for 2.5 h. The solution was poured into cooled water, basified with K2CO3 powder and the product was extracted with DCM. The organic layer was dried over MgSO4, filtered and evaporated to dryness. The crude (79 mg) was purified via Reverse phase (Stationary phase: YMC-actus Triart C18 10 m 30*150mm, Mobile phase: Gradient from 65% NH4HCO3 0.2%, 35% ACN to 35% NH4HCO3 0.2%, 65%
ACN). The fractions containing the product were mixed and concentrated to afford 48 mg of an intermediate fraction which was freeze-dried with acetonitrile/water (20/80) to give 40 mg (59 % yield) of compound 71 as a white powder and a mixture of two diastereoisomers.
The compounds listed in the table below were prepared accordingly to compound 71 started from the corresponding intermediates.
Compound number Structure N *S

Compound 72 0 N, From compound 35 and dihydro-2H-pyran-3(4H)-one

- 121 -Compound number Structure RS
Compound 73 0 ) 0 I
N,N
From compound 35 and 1-(tetrahydro-2H-pyran-4-yl)ethanone Preparation of compound 81:
NRS

N,FN
To a solution of compound 80 (350 mg, TFA salt, 0.506 mmol), oxetane-2-carbaldehyde (200 mg, 2.32 mmol) and TEA (500 mg, 4.94 mmol) in 50 mL of DCM was added NaBH3CN
(200 mg, 3.18 mmol). After addition, the reaction mixture was stirred at 28 C for 3 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuum and the residue was purified by preparative-HPLC (Column Boston Prime C18 150*30mm*5um, Mobile Phase A:
water (0.04%Nn31420+10mM Nn4HCO3), Mobile Phase B: acetonitrile, Flow rate: 25 mLimin, gradient condition from 50%B to 80%B). The pure fractions were collected and lyophilized to afford compound 81(170 mg, 45% yield) as white solid.
Preparation of compound 82:
N *R

I

- 122 -and compound 83:
N *S

N
I
N
170 mg of compound 81 were separated by Supercritical Fluid Chromatography (separation condition: DA10EL CH1RALPAK AS-H (250mm*30mm, Sum; Mobile phase: A:
Supercritical CO2, B: 0.1%NH3H20-ETOH, A:B =55:45 at 80 mL/min) to afford impure compound 82 (60 mg, 91.5% purity based on LCMS) and impure compound 83 (60 mg, 94.5% purity based on LCMS) both as white solid. The compound 82 (60 mg, 91.5% purity based on LCMS) was further purified by preparative HPLC (Column Boston Prime C18 150*30mm*5um, Mobile Phase A: water (0.04%N1-13H20+10mM NH4HCO3, Mobile Phase B: acetonitrile, Flow rate: 30 mL/min, gradient condition from 50%B to 80%B) to afford compound 82 (40.0 mg, 27% yield) as white solid_ The compound 83 (60 mg, 94.5% purity based on LCMS) was further purified by preparative }PLC (Column Boston Prime C18 150*30mm*5um, Mobile Phase A:
water (0.04%Nfl3f120+10mM NFLIFIC03, Mobile Phase B: acetonitrile, Flow rate: 30 mL/min, gradient condition from 50%B to 80%B) to afford compound 83 as white solid.
The compounds listed in the table below were prepared following analogous reaction protocols as reported for the preparation of compounds 81, 82 and 83 starting from the corresponding starting materials. Someone skilled in the art, will realize that in some cases, additional deprotection steps might be required to get the final compounds.
Compound number Compound structure YoH
*R

I
NN
From compound 78

- 123 -Compound number Compound structure N¨YOH
N *S

N
N,N
From compound 79 S, N*R

N
From compound 78 SIp N *S

N
N_N
From compound 79 N RS

N
N
NJ
From compound 37

- 124 -Compound number Compound structure <-(3>

- OH
N RS

N
I
N
From compound 37 F
Ni*R

N
I
N
From compound 88 N RS
¨N
H

r\I
I
N
NJ
From compound 37 N R
N Rs I
F N
From compound 37

- 125 -Compound number Compound structure N RS N
N/ ) N

N, N-;,-=, From compound 37 N
N RS

-- N

N
o'IAN

F NN
From compound 37 F
____/----OH
N
N *S
.'1 N

F NN
From compound 89 NyNH
cill RS
-') 98 -õ ,N, 0 T N

F N,N-;) From compound 37

- 126 -Compound number Compound structure ¨/
*R

O N
I
N,N
From compound 78 N *S

ON
N,N
From compound 79 Cr0 N H
N RS

O N
N,N
From compound 37 )NH
N
N RS

.0, ", IT N
F N
From compound 37

- 127 -Compound number Compound structure ¨/ HO OH
N *R

)-A-'N
I
From compound 78 HO OH
N *S

I
From compound 79 OH
N RS

ON
FU NN) From compound 37 N RS

I
N,N
From compound 37

- 128 -Compound number Compound structure ciNj1 RS N
HN-s--C) N
N.N
From compound 37 N RS
N}-11 108 N 0,N
I N
I _1 F N
From compound 37 109 -õ_,N 0 N
From compound 37 d_11 RS

N
From compound 37

- 129 -Compound number Compound structure N *R
F

--y-"t"-N
I
N, From intermediate 13, intermediate 58 and 5-fluoro-2-hydroxy-N-isopropyl-N-(2,2,2-trifluoroethyl)b enzami de Preparation of compound 114:
N *R
N
NI _Nr,--) In a flask compound 113 (59 mg, 0.104 mmol) was dissolved in methanol (1.27 mL, 31.3 mmol) and treated with oxetane-3-carbaldehyde (35.9 mg, 0.417 rnmol), sodium cyanoborohydride (32.8 mg, 0.521 mmol) and 2 drops of AcOH. The mixture was stirred over night at 60 C. The solvent was evaporated and then, a saturated sodium carbonate solution was added along with DCM. Then, the water phase was further basified with 1 N aqueous NaOH solution until pH
13. The water phase was extracted multiple times with DCM and ethyl acetate.
Drying with magnesium sulfate, filtration and evaporation of solvents afforded the crude material that was purified. The purification was performed via preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 m,30x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) yielding 42 mg (63% yield) of compound 114 as a white solid.

- 130 -Preparation of compound 115:
NON
¨

N *S

I
In a flask, compound 112 (50 mg, 0.0884 mmol) was dissolved in Me0H (1.07 mL, 26.5 mmol) and treated with formaldehyde, 37% aqueous. solution (0.132 mL, 1.77 mmol), 2 drops of HOAc, and, then with sodium cyanoborohydride (27.8 mg, 0.442 mmol). The mixture was heated over 2 h at 60 C. The solvent was evaporated. Then, a saturated.
sodium carbonate solution was added along with DCM. The water phase was basified with 1 N
aqueous NaOH
solution to pH 13. The water phase was extracted multiple times with DCM and ethyl acetate.
Drying with magnesium sulfate, filtration and evaporation of solvents afforded crude product (60 mg). A purification was performed via preparative HPLC (Stationary phase:
RP XBridge Prep C18 OBD-10 m,30x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) affording of compound 115 as a white solid.
The compounds listed below were prepared following an analogous reaction protocol as reported for the preparation of compounds 114 and 115 Compound Number Compound Structure *S
1,N) 0-1/L.14 I
NN
From compound 112 and oxetane-3-carbaldehyde

- 131 -N N-"R

N
I
N
NJ
From compound 113 and formaldehyde, 37% aqueous. solution Preparation of compound 116:
/ _______________________________________ 0 NO N

II
F N
In a flask, compound 112 (45 mg, 0.0795 mmol) was dissolved in dry DMF (1.23 mL, 15.9 mmol) and treated with DIPEA (0.0411 mL, 0.239 mmol) and bromomethoxyethane (12.2 mg, 0.0875 mmol). The reaction was stirred for 3 h at 80 C. A saturated sodium carbonate solution was added along with DCM. Then, the water phase was basified with 1 N aqueous NaOH
solution to p14 13 The water phase was extracted multiple times with DCM and ethyl acetate.
Drying with magnesium sulfate, filtration and evaporation of solvents afforded the crude product. A purification was performed via preparative HPLC (Stationary phase:
RP XBridge Prep C18 OBD-10 m,30x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) affording 19 mg (yield 38%) of compound 116 as a white solid.
Preparation of compound 119:

NH
N RS

I
N,N

- 132 -To a solution of compound 37 (200 mg, 0.36 mmol) in ACN (5 mL) were added 2-bromo-N,2-dimethylpropanamide (98 mg, 0.54 mmol) and K2CO3 (250 mg, 1.81 mmol). After stirring at 70 C overnight, the reaction mixture was quenched with a saturated solution sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by preparative-TLC (Me0H/DCM, 1:10). The obtained crude product (200 mg; white solid) was purified by preparative -HPLC (Column: XBridge Shield Column, 19*250mm,10um; Mobile Phase A:Water (10 mmol/L NH4HCO3), Mobile Phase B:ACN; Flow rate:25 mL/min; Gradient:55%B to 65%B in 7 min; 254/220 nm;
RT:5.93 min).
The fractions containing the product were mixed and concentrated to afford 40.4 mg (16% yield) of compound 119 as a white solid.
Preparation of compound 133:
N RS

To a mixture of intermediate 88(100 mg, 0.157 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The mixture was stirred at room temperature for 0.5 h.
The reaction mixture was evaporated under reduce pressure. The residue was diluted by 2M
NaOH (5 mL), extracted with DCM (5 mL x 5). The combined organic layers was dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduce pressure to afford compound 133 (84 mg, 99.6% yield) as a yellow solid.
Preparation of compound 134:
HH
N RS

- 133 -To a mixture of compound 133 (84 mg, 0.156 mmol) in Me0H (2 mL) was added formaldehyde (257 mg, 3.17 mmol, 37% in water) and acetic acid (20 mg, 0.333 mmol). The mixture was stirred at room temperature for 30 minutes. Then NaBH3CN (20 mg, 0.318 mmol) was added to the mixture and the resultant mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated to remove solvent. The residue was diluted by 2M NaOH
(5 mL), extracted with DCM (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude, which was purified by preparative HPLC (Column: Welch Xtimate C18 150*30mm*5 m, Mobile Phase A:
water (0.05%NH3H20+10mM NH4HCO3), Mobile Phase B: acetonitrile, Flow rate: 30 mL/min, gradient condition from 55% B to 85%) to afford two fractions. The pure desired fraction were collected and the volatile solvent was removed by evaporation. The aqueous residue was lyophilized to afford compound 134 (40 mg, 99.52% purity, yield 45%) as white powder. The impure desired fraction were collected and the volatile solvent was removed by evaporation.
The aqueous residue was lyophilized to afford compound 134 (12 mg, yield 14%, ¨95% purity by NAIR) as white powder.
Preparation of compound 135:
¨/

N *R

and compound 136 HH
N *S
NO N
foiL
F
Compound 134 (40 mg, 0.071 mmol) was purified by SFC (column: DAICEL CHIRALCEL

OD-H (250mm*30mm,5um), Mobile phase: A: Supercritical CO2, B: 0.1%NH3H20 IPA;
Isocratic: A:B = 75:25; Flow rate: 80 mL/min) to afford two fractions. The pure fractions of

- 134 -first peak were collected and the volatile solvent was evaporated under vacuum. The residue was treated with H20 (3 mL) and CH3CN (1 mL). The mixture was lyophilized to give compound 135 (11 mg, 98.17% purity, yield 27%) as white powder. The pure fractions of second peak were collected and the volatile solvent was evaporated under vacuum. The residue was treated with H20 (3 mL) and CH3CN (1 mL). The mixture was lyophilized to give compound 136 (10 mg, 96.28 purity, yield 24%) as a white powder.
Preparation of compound 137:
N--N *3 N

I
ON
To a solution of compound 76 (200 mg, crude) and 3-(dimethylamino)propanoic acid hydrochloride (49.0 mg, 0.32 mmol) in DCM (10 mL) was added HATU (121 mg, 0.32 mmol) and DIEA (0.21 mL, 1.26 mmol). The mixture was stirred for 16 hours at rt. 20 mL DCM and mL H20 was added to the mixture solution. The mixture was extracted with DCM
(30 mL
x 2), the combined extracts were washed with brine (30 mL) and dried over Na2SO4, the mixture 15 was filtered and the filtrate was concentrated in vacuum. The residue was purified by pre-HPLC
(Column: YlVIC-Triart Prep C18 250*50mm*10um, Mobile Phase A: water (0.04%NH3H20+10mM NH4HCO3), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 45% B to 75%). The pure fractions were collected and the solvent was lyophilized to give the title compound compound 137 (20 mg, 96.7% purity, 12%
yield) as a 20 light yellow solid.
Preparation of compound 138:
NH
N RS
F NN

I

- 135 -To a solution of intermediate 89 (150 mg, 0.23 mmol) in dichloromethane (5.0 mL) were added Trifluoroacetic acid (1.7 mL) at 0 C. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure to give 150 mg of compound 138 (97.5% purity, as trifluoroacetate) as a colorless oil.
Preparation of compound 139:

N RS
OH

N,N
To a mixture of compound 138 (150 mg, 0.241 mmol, purity 86.63%), glycolic acid (22 mg, 0.289 mmol) and N,N-dii sopropylethylamine (0.12 mL, 0.722 mmol) in NN-dimethylformamide (2 mL) was added HATU (110 mg, 0.289 mmol) in portions at 0 C and stirred for 2 hours at room temperature. The reaction mixture was quenched by the addition of water (5 mL) and extracted with ethyl acetate (4 x 5 mL). The combined organic layers were washed with water (3 x 20 mL), brine (20 mL) and dried over anhydrous sodium sulfate.
Filtration, concentration and the residue was pirified by reverse flash chromatography with the following conditions: Column: SunFire C18 OBD Prep Column, 19 mm X 250 mm;
Mobile Phase A :Water(0.1%NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min;
Gradient: 15%
B to 40% B in 11 min; 254/220 nm; Rt: 9.12 min to afford 46.9 mg of compound 139 as a white solid.
LCMS (Liquid chromatography/Mass spectrometry) General procedure The High-Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below).
Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the

- 136 -tune parameters (e.g. scanning range, dwell time...) in order to obtain ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW).
Data acquisition was performed with appropriate software.
Compounds are described by their experimental retention times (Rt) and ions.
If not specified differently in the table of data, the reported molecular ion corresponds to the [MH-H1+
(protonated molecule) and/or [M-H]- (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M-FNH4]', [M-FLIC00]-, etc...). For molecules with multiple isotopic patterns (Br, Cl..), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used.
Hereinafter, -SQD" means Single Quadrupole Detector, "RT" room temperature, -BEH"
bridged ethyl siloxane/silica hybrid, "FISS" High Strength Silica, "DAD" Diode Array Detector.
Table la: LCMS Method codes (Flow expressed in mL/min; column temperature (T) in 'V;
Run time in minutes). "TFA" means trifluoroacetic acid Flow Method Run Instrument Column Mobile phase Gradient code time Column T
1 Waters: Waters: BEH A: 95% 84.2% A for 0.343 6.2 Acquity C18 (1.7[1m, CH3COONH4 0.49min, to 10.5%
UPLC - 2.1x100mm) 7mM / 5% A in 2.18min, held DAD and CH3CN, B: for 1.94m i n, back Quattro CH3CN to 84.2% A in MicroTM 0.73min, held for 0.73min.

- 137 -Flow Method Run Instrument Column Mobile phase Gradient code time Column T
Agilent Waters A: water with First, 100 % A
was 0.8 10 XBridge Shield 0.05% hold for 1 minute.
RP18 NH3 .H2 0; Then a gradient 2.1*50 mm, 5 B: acetonitrile was applied to UM 40 % A and 60 % 40 B in 4 minutes and then to 5% A and 95 % B in 2.5 minutes. Finally return to 100% A
in 2 minutes and hold for 0.5 minute. Post Time is 0.5minute.
3 Agilent Waters A:
water with 100%A was hold 0.8 10 Xbridge-C18 0.04 % TFA; for 1 minute, A
2.1*50 mm, 5 mobile phase, gradient from urn B: acetonitrile 100% A to 40% A
with 0.02% is applied in 4 TFA minutes, and 40%A down to 15%A in 2.5 minutes. And then return to 100%A in 2 minutes and hold for 0.5 minutes.
The post time is 0.5min.

- 138 -Flow Method Run Instrument Column Mobile phase Gradient code time Column T
4 Agilent Waters mobilephaseA:
First, 90 % A was 0.8 10 Xbridge-C18 waterwith hold for 0.8 2.1*50 mm, 5 0.04%TFA; minute. Then a UM mobilephaseB: gradient was acetonitrilewith applied to 20 % A
0.02%TFA and 80% B in 3.7 minutes and hold for 3 minutes. And then return to 90%
A in 2 minutes and hold for 0.5 minutes. The post time is 0.5min.
5 Waters: 0.5 3.3 A: 95% From 85%A/15%Bto Acquity Waters BEH CH3COONH4 10% A in 2.1min, held UPLC H-C18 (1.7um, 7mM / 5%
for2min,backto85% 40 Class -2.1x100mm) CH3CN, B: A/15%B in 0.8min, DAD and CH3CN held for 0.7min.
QDa 6 Shimadzu Poroshell ACN-Water- 0.0 min 10 % B -> L2 3.00 LCMS- HPH-C18 6.5 mM 2.0 min 95 % B
2020 NH4HCO3 + ->2.6 min 95% B
NH3H20 -> 2.75 min 10%
B->3.00 min Controller

- 139 -Flow Method Run Instrument Column Mobile phase Gradient code time Column T
7 Shimadzu Ascentis ACN -Water-0.0 min 5 % B -> 1.5 3.00 LCMS- Express C18 0.05% TFA 2.0 min 95% B ->
2020 2.7 min 95% B->
2.8 min 5%
B->3.00 min Controller 8 Shimadzu Kinetex EVO ACN-Water- 0.0 min 5 % B -> 1.2 3.00 LCMS- C18 0.03% 2.0 min 95 % B
2020 NH3H20 ->2.7 min 95% B
-> 2.75 min 5% B
-> 3.00 min Controller 9 Shimadzu Poroshell ACN-Water-0.0 min 5 % B -> 1.2 3.00 LCMS- HPH-C18 5mM 2.0 min 95% B
->
2020 NH4HCO3 2.7 min 95%
B->2.75 min 5% B
->3.00 min Controller 10 Shimadzu Poroshell ACN-Water-0.0 min 10 % B -> 1.2 2.85 LCMS- HPH-C18 5mM 2.0 min 95% B
->
2020 NH4HCO3 2.7 min 95% B->
2.75 min 10% B
->2.85 min Controller 11 Shimadzu Ascentis ACN-Water-0.0 min 5 % B -> 1.5 3.00 LCMS- Express C18 0.05% TFA 2.0 min 100% B ->
2020 2.7 min 100%
B->2.75 min 5%
->3.00 min Controller

- 140 -Flow Method Run Instrument Column Mobile phase Gradient code time Column T
12 Shimadzu Kinetex EVO ACN-Water- 0.0 min 10 % B -> 1.2 2.85 LCMS- C18 100A 5mM 2.0 min 95 % B
2020 NH4HCO3 ->2.7 min 95% B
-> 2.75 min 10% B
->2.85 min Controller 13 Shimadzu Gemini NX- ACN-Water- 0.0 min 5 % B -> 1.5 3.00 LCMS- C18 5mM 1.0 min 95% B ->
2020 NH4HCO3 2.7 min 95% B->
2.75 min 5% B
->3.00 min Controller 14 Shimadzu Poroshell ACN-Water- 0.0 min 10 % B -> 1.2 3.00 LCMS- HPH-C18 6.5 mM 2.0 min 95 % B
2020 NH4HCO3 + ->2.7 min 95% B
NH3H20 -> 2.75 min 10% B
-> Controller 15 Waters: Waters : BEH A: 10mM 0.8 2.00 Acquity C18 CH3COONH4 From 95% A to upLce - (1.7um, in 95% H20 + 5% A in 1.3min, held for 0.7 min DAD and 2.1*50mm) 5% CH3CN
SQD B: CH3CN
16 Waters: Waters :BEH A: 10mM From 100% A to 0.6 3.50 Acquity (1.8um, NH4HCO3 5% A in 2.10min, UPLC - 2.1*100mm) in 95% H2 0 + t o 0% Amn 1.4 min 55 DAD and 5% CH3CN
SQD2 B: Me0H

- 141 -Flow Method Run Instrument Column Mobile phase Gradient code time Column T
17 Waters: Waters :BEH A: 0.1%
From 100% A to 0.6 3.50 Acquity (1.8 um, NH4HCO3 5% A in 2.10min, UPLC - 2.1*100mm) in 95% H20 + to 0% A in 1.4min 55 DAD and 5% CH3CN
SQD2 B: CH3CN
18 ACQUITY Aquity UPLC A: CH3OH From 5% A to 95% 0.7 2.0 BEH C18 A in 1.20 min, held UPLC B: 10mM
1.7um for 0.2 mm, to 5%
System 2.1x5Omm NH4Ac in A in 0.20 min. 70 with SQD- Column90% H20 and detector 10% CH3CN
Waters BEH A: From 95% A/5% B 0.5 19 Waters:
3.5 Acquity C18 (1.7Pm, CH3COONH4 to 5% A in lmin, H-Class - 2.1x50mm) 7mM 95%/ held for 1.6min, back DAD CH3CN5%, to 95% A/5%B in 40 and B: CH3CN 0.2min, held for 0.5min.
Table lb: LCMS and melting point data. Co. No. means compound number; Rt means retention time in min.
Co. No. Rt (min) [M-I-H]' [M+CH3C00]- LCMS Method 1 2.32 581.5 639.7 1 2 2.47 595.7 653.7 1 3 2.38 595.7 653.8 1 4 2.38 595.7 653.9 1 2.46 609.6 667.8 1 6 2.46 607.6 665.6 1

- 142 -Co. No. Rt (min) [M+F-1] [M+CH3COO] LCMS Method 7 2.61 607.6 665.8 1 8 2.52 607.6 665.8 1 9 2.59 623.6 681.7 1 2.61 623.6 681.7 1 11 2.62 623.6 681.7 1 12 2.59 623.6 681.8 1 13 2.46 609.6 667.6 1 14 2.50 609.6 667.8 1 2.50 609.6 667.8 1 16 2.46 609.6 667.6 1 17 5.109 623.4 2 18 4.952 612.5 2 19 2.055 609.5 4 5.195 609.4 2 21 2.956 595.4 3 22 2.10 540.5 598.6 1 24 2.18 624.6 682.8 1 2.18 624.6 682.7 1 27 2.21 610.6 668.5 1 29 2.23 610.6 668.7 1 2.22 610.6 668.7 1 31 2.19 610.6 668.7 1 34 2.91 526.2 3 2.93 526.4 3

- 143 -Co. No. Rt (min) [M+F-I] [M+CH3COO] LCMS Method 38 2.31 595.5 653.7 1 39 2.31 596.6 654.7 1 40 2.32 596.6 654.7 1 41 2.33 596.6 654.7 1 42 2.999 624.3 3 43 3.040 624.3 3 44 3.032 624.3 3 45 2.935 540.4 3 46 2.953 540.4 3 47 4.635 610.4 2 48 4.688 610.4 2 49 2.950 540.4 3 50 3.008 540.4 3 51 3.031 610.4 3 52 3.081 610.4 3 53 2.99 623.5 3 55 2.40 624.7 682.5 1 56 2.58 624.6 682.5 1 57 2.37 636.7 694.8 1 58 2.53 636.7 694.7 1 59 2.50 714.8 772.8 1 60 1.27 714.5 19 61 2.40 612.6 670.5 1 62 2.29 651.7 709.8 1

- 144 -Co. No. Rt (min) [M+F-1] [M+CH3COO] LCMS Method 63 2.33 636.7 694.7 1 64 2.53 636.7 694.7 1 65 2.26 622.7 680.7 1 66 2.38 622.7 680.8 1 67 2.14 622.5 5 68 2.28 622.4 5 69 2.46 580.6 638.6 1 70 2.52 580.6 638.6 1 71 2.43 596.6 654.7 1 2.44; 668.7 72 610.6 1 2.50 73 2.47 638.6 696.8 1 74 2.41 610.6 668.6 1 75 2.50 610.6 669.4 1 76 1.09 525.4 583.4 19 77 1.15 525.5 583.6 19 78 2.979 554.4 3 79 2.989 554.4 3 82 4.710 648.3 2 83 4.711 648.3 2 84 3.053 624.5 3 85 3.079 624.5 3 86 3.096 675.4 3 87 4.852 675.4 2

- 145 -Co. No. Rt (min) [M+F-1] [M+CH3COO] LCMS Method 88 2.976 544.4 3 89 2.959 544.4 3 90 3.028 598.5 3 91 3.006 640.5 3 92 3.053 588.4 3 93 3.000 662.4 3 94 3.035 651.5 3 95 3.197 635.4 3 96 3.093 635.4 3 97 3.058 588.4 3 98 2.208 665.5 4 99 3.101 665.5 3 100 3.094 665.5 3 101 4.632 651.5 2 102 4.736 666.5 2 103 4.756 628.4 2 104 4.699 628.5 2 105 3.119 652.5 3 106 3.094 665.5 3 107 3.136 701.5 3 108 4.871 635.4 2 109 3.153 686.4 3 110 3.092 672.3 3 111 3.241 678.3 3

- 146 -Co. No. Rt (min) [M+F-1] [M+CH3COO] LCMS Method 112 0.82 566.4 15 113 2.10 566.7 16 114 2.39 636.8 16 115 0.86 580.5 15 116 0.89 624.5 15 117 0.86 636.5 15 118 1.84 580.5 17 119 2.026 653.25 9 120 1.406 622.45 12 121 1.497 622.45 12 122 1.413 601.50 6 123 4.484 608.45 6 124 0.794 597.65 7 125 1.851 625.10 8 126 1.688 629.55 8 127 1.397 677.45 10 128 0.825 677.40 11 129 1.185 638.35 13 130 1.809 638.35 14 131 1.596 677.35 14 132 1.654 677.40 9 134 2.884 566.3 3 135 2.872 566.6 3 136 2.868 566.4 3

- 147 -Co. No. Rt (min) [M+F-I] [M+CH3COO] LCMS Method 137 3.042 624.5 3 139 1.090 598.4 18 SFC-Methods General procedure for SFC methods The SFC measurement was performed using an Analytical Supercritical fluid chromatography (SFC) system composed by a binary pump for delivering carbon dioxide (CO2) and modifier, an autosampler, a column oven, a diode array detector equipped with a high-pressure flow cell standing up to 400 bars. If configured with a Mass Spectrometer (MS) the flow from the column was brought to the (MS). It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time...) in order to obtain ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW).
Data acquisition was performed with appropriate software.
Table 2a. Analytical SFC Methods (Flow expressed in mL/min; column temperature (T) in C;
Run time in minutes, Backpressure (BPR), "DEA" means diethylamine.
Run Method Flow column mobile phase gradient time code Col T BPR
AD, 3 [1..m, 3.5 CO2/Et0H/iPrNH2 1 4.6*100 90/10/0.3 (CHIRALPAK)) 35 103 bar from 5% to 40% of B in 2 Chiralpak AD-3 min and hold A: CO2 B:iso-propanol 2 50x4.6mm ID., 40% for 1.2 (0 05% DEA) 3um min, then 5% 35 (PSI) of B for 0.8 min

- 148 -from 5% to ChiralPak AD-3 40%
of B in 2.5 7 bar A: CO2 B:Ethanol (0.05%
3 150x4.6mm I.D. 5.5min , then DEA) 3um 5% of B 40 100 bar for 1.5 min from 5% to 4 4 40% of B in 4 Chiralcel OJ-3 min and hold 35 A: CO2 B:ethanol (0.05%
(PSI) 4 100x4.6mm ID., 40% for 2.5 DEA) 3um min, then 5%
35 100 bar of B for 1.5 min ChiralPAK IC-3 3.5 CO2/Et0H/iPrNH2 100x4.6mm I.D.
45/55/0.3 35 103 bar 3um.
ChiralPAK IG-3 3.5 CO2/Et0H/iPrNH2 6 100x4.6mm ID., 60/40/0.3 35 103 bar 3um.
ChiralPAK AD-3 3.5 CO2/Et0H/iPrNH2 7 100x4.6mm I.D.
85/15/0.3 35 103 bar 3um AD, 3 !lin, 3.5 CO2/Et0H/iPrNH2 8 4.6*100 45/55/0.3 (CHIRALPAK)) 35 103 bar Instrument:
from 5% to 2.5 10 Waters UPCC
40% of B in 5 with PDA
A:Supercritical CO2, min and hold Detector 9 Mobile phase B: iso- 40% for 2.5 Column:

propanol (0.05% DEA) min, then 5% 35 Chiralpak AD-3 (PSI) of B for 150x4.6mm ID., 2.5 min 3um

- 149 -Instrument:
1.5 Shimadzu LC-20AB with PDA A: Hexane(0.1%DEA) 90% B hold 10 detector column: B:Et0H(0.1%DEA) min 25 7.40 Chiralcel OD
MPa

150*4.6mm 3um Instrument:
2.8 Waters UPCC
with PDA
A: CO2 B:ethanol (0.05% hold 15% for 11 Detector column :
DEA) 10 min Chiralcel OD-3 35 (PSI) 100 x4.6mm ID., 3um Table 2b. SFC data.
Isomer elution SFC
Co. No. RI (min) UV% Area order Method 3 5.28 100 1 1 4 7.46 97.26 2 1 7 2.14 100 1 7 8 2.59 100 2 7 9 3.49 100 3 5 10 4.36 100 4 5 11 3.03 100 2 5 12 2.75 100 1 5 13 3.50 100 3 6 14 3.04 100 2 6 2.69 100 1 6 Isomer elution SFC
Co. No. Rt (min) UV% Area order Method 16 4.02 100 4 6 17 1.37/1.43 46.25/53.75 racemate 2 19 1.53/2.02 99.66/0.34 1 4 20 3.82/4.09 49.225/50.775 racemate 3 21 1.42/1.53 87.43/12.57 1 2 40 3.35 100 2 8 41 2.96 100 1 8 43 4.806 100 1 9 44 5.253 100 2 9 45 6.86 100 2 10 46 6.14 99.19 1 10 47 4.953 93.671 2 3 48 4.682 90.26 1 3 49 7.048 99.11 2 11 50 5.929 97.40 1 11 OPTICAL ROTATION (OR) Optical Rotation is measured with a polarimeter 341 Perkin Elmer. The polarized light is passed through a sample with a path length of 1 decimeter and a sample concentration of 0.2 to 0.4 gram per 100 milliliters. 2 to 4 mg of the product in vial are weight, then dissolved with 1 to 1.2 ml of spectroscopy solvent (DMF for example). The cell is filled with the solution and put into the polarimeter at a temperature of 20 C. The OR is read with 0.004 of precision.
Calculation of the concentration: weight in gram x 100/ volume in ml [a] d20 : (read rotation x 100) / (1.000 dm x concentration).
d is sodium D line (589 nanometer).

- 151 -Table 3. OR data: wavelength: 589 nm (specicied if different); solvent: DMF
(specicied if different); temperature: 20 C; 'conc' means concentration (g/100 mL); 'OR' means optical rotation.
Co. No. OR ( ) Conc.
3 -15.14 0.284 4 +8.3 0.265 7 -10.38 0.26 8 +12.6 0.262 24 +15.72 0.318 25 -16.59 0.416 27 + 14.22 0.228 29 - 18.04 0.316 30 - 16.67 0.728 40 -12.5 0.26 41 +13.67 0.256 55 +12.75 0.251 56 -4.43 0.271 62 + 10.4 0.25 NMR
Some NMR experiments were carried out using a Bruker Avance 500 spectrometer equipped with a Bruker 5mm BYWO probe head with z gradients and operating at 500 MT-Tz for the proton and 125 MI-Iz for carbon. Chemical shifts (d) are reported in parts per million (ppm). J values are expressed in Hz.
NMR experiments were carried out using a Bruker Avance III 400 spectrometer, using internal deuterium lock and equipped with reverse double-resonance (H, 13C, SET) probe head with z

- 152 -gradients and operating at 400 MHz for the proton and 100MHz for carbon.
Chemical shifts (d) are reported in parts per million (ppm). J values are expressed in Hz.
Some NMR experiments were carried out using a Bruker Avance III 400 spectrometer at ambient temperature (298.6 K), using internal deuterium lock and equipped with BBO 400MHz Si 5 mm probe head with z gradients and operating at 400 MHz for the proton and 1001VIHz for carbon. Chemical shifts (d) are reported in parts per million (ppm). J
values are expressed in Hz.
Some NIVER experiments were carried out using a Varian 400-MR spectrometer at ambient temperature (298.6 K), using internal deuterium lock and equipped with Varian probe head with z gradients and operating at 400 MHz for the proton and 100MHz for carbon.
Chemical shifts (d) are reported in parts per million (ppm). J values are expressed in Hz.
Some NIVIR experiments were carried out using a Varian 400-VNIVIRS
spectrometer at ambient temperature (298.6 K), using internal deuterium lock and equipped with Varian probe head with z gradients and operating at 400 MHz for the proton and 100MHz for carbon.
Chemical shifts (d) are reported in parts per million (ppm). J values are expressed in Hz.
Compound 4 Major rotamer (75%) 1H NMR (400 MHz, DMSO-d6) 6 ppm 8.30 (s, 1H), 7.69 - 7.81 (m, 1H), 7.15 - 7.38 (m, 2H), 6.88 - 7.02 (m, 1H), 4.55 (dd, J=7 .7 , 5.9 Hz, 2H), 4.20 (t, J=5.5 Hz, 2H), 3.73 - 3.84 (m, 1H), 3.37 - 3.70 (m, 5H), 3.12 - 3.27 (m, 3H), 3.05 (br d, J=6.2 Hz, 1H), 2.92 -3.02 (m, 3H), 2.86 (dt, J=14.1, 7.1 Hz, 1H), 2.73 (br t, J=7.2 Hz, 1H), 2.60 (br dd, J=8.7, 6.4 Hz, 1H), 2.54 (br d, J=7.6 Hz, 2H), 2.23 -2.36 (m, IH), 2.12 (br d, J=9.4 Hz, 1H), 1.95 (br t, J=7.0 Hz, 2H), 1.45 -1.59 (m, 1H), 1.21 (br dõ/=3.4 Hz, 2H), 0.98- 1.15 (m, 7H), 0.72 - 0.80 (m, 6H) Minor rotamer (25%) 1H NMR (400 MHz, DMSO-d6) 6 ppm 8.28 (s, 1H), 7.69 - 7.81 (m, 1H), 7.15 - 7.38 (m, 2H), 6.88 - 7.02 (m, 1H), 4.55 (dd, J=7 .7 , 5.9 Hz, 2H), 4.41 (dt, .1=13.8, 6.8 Hz, 1H), 4.20 (t, .1=5.5 Hz, 21-1), 3.37 -3.70 (m, 51-1), 3.12 - 3.27 (m, 31-I), 3.05 (br d, J=6.2 Hz, 1H), 2.92 - 3.02 (m, 3H), 2.86 (dt, J=14.1, 7.1 Hz, 1H), 2.73 (br t, J=7.2 Hz, 1H), 2.60 (br dd, J=8.7, 6.4 Hz, 1H), 2.54 (br d, J=7.6 Hz, 2H), 2.23 -2.36 (m, 1H), 2.12 (br d, J=9.4 Hz, 1H), 1.95 (br t, J=7.0 Hz, 2H), 1.45- 1.59 (m, 1H), 1.21 (br d, J=3.4 Hz, 2H), 0.98 - 1.15 (m, 7H), 0.72 -0.80 (m, 6H)

- 153 -Compound 38 1-1-1N1VIR (500 MHz, DMSO-d6) 6 ppm 8.4 (d, J=5.7 Hz, 1H), 7.2 - 7.4 (m, 3H), 6.5 (br d, J=5.7 Hz, 1H), 4.6 (dd, J=7 .7 , 5.8 Hz, 2H), 4.2 (td, J=6.0, 2.2 Hz, 2H), 3.3 - 3.8 (m, 7H), 3.0 - 3.1 (m, 5H), 2.9 (dt, J=14.3, 6.9 Hz, 1H), 2.7 -2.8 (m, 1H), 2.5 - 2.6 (m, 3H), 2.3 -2.4 (m, 1H), 2.2 (dd, J=9.5, 1.9 Hz, 1H), 2.0 (br t, J=6.8 Hz, 2H), 1.5 - 1.6 (m, 1H), 1.0 (br d, J=6.3 Hz, 4H), 0.9 -1.0 (m, 4H), 0.8 (dd, J=12.9, 6.9 Hz, 6H), 0.6 (br s, 2H) Compound 41 I-HM/1R (500 MHz, DMSO-d6) 6 ppm 8.48 (s, 1H), 7.22 - 7.52 (m, 3H), 4.56 (br t, J=6.8 Hz, 2H), 4.17 - 4.30 (m, 2H), 3.87 - 4.13 (m, 2H), 3.49 - 3.72 (m, 3H), 3.30 -3.41 (m, 1H), 2.97 -3.20 (m, 6H), 2.88 (dt, J=14.3, 6.9 Hz, 1H), 2.77 (br d, J=1.3 Hz, 114), 2.55 -2.69 (m, 2H), 2.30 -2.37 (m, 1H), 2.17 (br d, J=7.6 Hz, 1H), 1.96 - 2.10 (m, 2H), 1.51 - 1.66 (m, 1H), 0.92- 1.15 (m, 8H), 0.65 -0.84 (m, 9 H) Compound 42 1H NMft (400 MHz, CDC13) 6 ppm 8.43 - 8.36 (m, 1H), 7.23 - 7.16 (m, 1H), 7.13 -7.06 (m, 1H), 7.05 - 6.98 (m, 1H), 6.33 - 6.28 (m, 1H), 4.83 - 4.76 (m, 2H), 4.44 -4.34 (m, 2H), 4.01 -3.89 (m, 1H), 3.75 -3.56 (m, 4H), 3.55 - 3.47 (m, 1H), 3.27 - 3.05 (m, 6H), 2.82 - 2.72 (m, 2H), 2.66 (d, J = 7.2 Hz, 2H), 2.14 - 2.06 (m, 2H), 1.93 - 1.72 (m, 4H), 1.50 -0.98 (m, 12H), 0.93 -0.84 (m, 6H), 0.71 (d, J= 6.4 Hz, 2H).
Compound 43 1-1-1NMIR (400 MHz, CDC13) 6 ppm 8.50 (s, 1H), 7.26 - 7.19 (m, 1H), 7.18 -7.09 (m, 1H), 7.08 - 6.97 (m, 1H), 4.89 - 4.73 (m, 2H), 4.49 - 4.34 (m, 2H), 4.33 - 4.01 (m, 2H), 4.00 - 3.83 (m, 1H), 3.81 -3.60 (m, 2H), 3.59 - 3.38 (m, 1H), 3.31 - 3.03 (m, 6H), 2.86 -2.61 (m, 4H), 2.21 -2.07 (m, 2H), 1.96 - 1.71 (m, 5H), 1.56 - 1.33 (m, 5H), 1.15 - 1.05 (m, 6H), 0.93 - 0.84 (m, 6H), 0.82 - 0.72 (m, 2H) Compound 44 1-H N1VIR (400 MHz, CDC13) 6 ppm 8.53 -8.44 (m, 1H), 7.27 - 7.18 (m, 1H), 7.18 -7.09 (m, 1H), 7.08 -6.97 (in, 111), 4.81 (t, J= 6.8 Hz, 2H), 4.51 -4.35 (in, 2H), 4.30 -3.84 (m, 3H), 3.79 -3.55 (m, 2H), 3.54 - 3.41 (m, 1H), 3.38 - 3.06 (m, 6H), 3.01 -2.62 (m, 4H), 2.21 -2.11 (m, 2H), 2.11 - 1.64 (m, 5H), 1.64 - 1.29 (m, 5H), 1.14 - 1.03 (m, 6H), 0.95 -0.85 (m, 6H), 0.82 -0.70 (m, 2H).

- 154 -Compound 45 IH NMR (400 MHz, CD30D) 6 ppm 8.87 - 8.69 (m, 1H), 7.67 - 7.42 (m, 1H), 7.39-7.18(m, 2H), 4.66 -4.15 (m, 6H), 4.12 - 3.76 (m, 2H), 3.74 - 3.53 (m, 4H), 3.52 - 3.31 (m, 3H), 3.26 -3.15 (m, 1H), 3.08 -2.94 (m, 1H), 2.79 -2.23 (m, 3H), 2.21 - 2.09 (m, 1H), 2.00 - 1.85 (m, 1H), 1.31 - 0.86 (m, 15H) Compound 46 NMR (400 MHz, CD30D) 6 ppm 8.95 - 8.76 (m, 1H), 7.74 - 7.41 (m, 1H), 7.39 -7.22 (m, 2H), 4.69 - 4.09 (m, 6H), 4.06 - 3.78 (m, 2H), 3.76- 3.50(m, 4H), 3.50 - 3.32 (m, 3H), 3.26 -3.10 (m, 2H), 2.80 - 2.27 (m, 3H), 2.25 - 2.09 (m, 1H), 1.93 - 1.73 (m, 1H), 1.33 - 0.96 (m, 15H).
Compound 47 41 NMR_ (400 MHz, CD30D) 6 ppm 8.50 (s, 1H), 7.19-7.25 (m, 1H), 7.13 (s, 1H), 6.98-7.07 (m, 1H), 4.78 (t, J= 6.8 Hz, 2H), 4.37-4.45 (m, 2H), 3.95-4.25 (m, 2H), 3.82-3.93 (m, 1H), 3.73 (s, 1H), 3.44 - 3.68 (m, 2H), 3.20 (d, J = 9.2 Hz, 6H), 2.62-2.82 (m, 4H), 2.27 (d, J= 6.4 Hz, 211), 2.06-2.19 (m, 3H), 2.03 (s, 1H), 1.89 (s, 1H), 1.67-1.81 (m, 2H), 1.01-1.22 (m, 7H), 0.72-0.91 (m, 8H).
Compound 48 NMR (400 1VIHz, CDC13) 6 ppm 8.50 (br. s, 1H), 7.18-7.25 (m, 1H), 7.08-7.17 (m, 1H), 6.94-7.07 (m, 1H), 4.69-4.87 (m, 2H), 4.37-4.49 (m, 2H), 3.97-4.34 (m, 2H), 3.40-3.92 (m, 4H), 3.03-3.32(m, 6H), 2.52-2.85 (m, 4H), 2.19-2.45 (m, 3H), 2.03-2.17 (m, 3H), 1.83-1.95 (m, 1H), 1.70-1.79 (m, 111), 1.48-1.58 (m, 1H), 1.00-1.33 (m, 7H), 0.68-0.96 (m, 811).
Compound 49 111 NMR (400 MHz, CDCb) 6 ppm 8.48 (s, 1H), 7.52 - 7.40 (m, 1H), 7.39 - 7.31 (m, 211), 4.30 - 3.86 (m, 2H), 3.67 - 3.59 (m, 2H), 3.27 -2.97 (m, 9H), 2.94 -2.75 (m, 2H), 2.24 - 1.82 (m, 5H), 1.77 - 1.62 (m, 2H), 1.11 - 0.57 (m, 16H) Compound 50 N1VIR (400 MHz, DMSO-d6) 6 ppm 8.48 (s, 1H), 7.40-7.48 (m, 1H), 7.29-7.39 (m, 2H), 3.47-4.31 (m, 9H), 3.24-3.45 (m, 3H), 2.92-3.12 (m, 3H), 1.93-2.22 (m, 4H), 1.50-1.92 (m, 3H),

- 155 -0.91-1.14 (m, 7H), 0.88 (d, J= 6.80 Hz, 3H), 0.83 (d, J= 6.40 Hz, 3H), 0.61-0.79 (m, 2H).
Compound 51 1-1-1NMR_ (400 MHz, CDC13) 6 ppm 8.50 (s, 1H), 7.26 - 7.23 (m, 114), 7.17 -7.10 (m, 1H), 7.07 - 6.99 (m, 1H), 4.84 - 4.75 (m, 2H), 4.46 -4.38 (m, 2H), 4.34 - 4.26 (m, 0.2H), 4.22 - 3.99 (m, 2H), 3.92 -3.82 (m, 0.8H), 3.80 -3.71 (m, 1H), 3.68 - 3.60 (m, 1H), 3.56 -3.45 (m, 1H), 3.30 - 3.14 (m, 5H), 3.13 - 3.04 (m, 114), 2.82 -2.63 (m, 4H), 2.34 -2.23 (m, 214), 2.16 - 2.10 (m, 2H), 2.06 -2.02 (m, 1H), 1.97 - 1.85 (m, 1H), 1.80 - 1.67 (m, 3H), 1.12 - 1.02 (m, 614), 0.91 -0.72 (m, 9H).
Compound 52 11-1 NMR (400 MHz, CDC13) 6 ppm 8.50 (s, 1H), 7.19-7.25 (m, 1H), 7.08-7.18 (m, 1H), 6.96-7.08 (m, 1H), 4.71-4.89 (m, 2H), 4.38-4.48 (m, 2H), 3.44-4.34 (m, 6H), 3.01-3.32 (m, 6H), 2.50-2.89 (m, 3H), 2.19-2.47 (m, 314), 2.04-2.18 (m, 3H), 1.83-1.95 (m, 1H), 1.70-1.77 (m, 1H), 1.62-1.70 (m, 1H), 1.50-1.60 (m, 1H), 1.01-1.27 (m, 7H), 0.72-0.92 (m, 8H).
Compound 78 IHNMIR CD3OD (Varian-400 MHz): 9.00 - 8.78 (m, 1H), 7.69 - 7.44 (m, 1H), 7.41 -7.19 (m, 2H), 4.56 -4.13 (m, 6H), 4.05 - 3.78 (m, 2H), 3.58 (s, 1H), 3.49 - 3.32 (m, 5H), 3.13 - 2.97 (m, 2H), 2.72 -2.51 (m, 1H), 2.49 -2.31 (m, 1H), 2.23 - 1.91 (m, 4H), 1.89 - 1.65 (m, 214), 1.29 -0.93 (m, 15H).
Compound 79 1H NMR CD3OD (Varian-400 MHz): 8.97 - 8.81 (m, 114), 7.72 -7.43 (m, 1H), 7.40 -7.15 (m, 2H),4.61 - 4.15 (m, 6H), 4.08 - 3.70 (m, 2H), 3.58 (s, 1H),3.50 - 3.34 (m, 5H), 3.14 - 2.94 (m, 2H), 2.73 - 2.52 (m, 1H), 2.50 - 2.30 (m, 1H), 2.22- 1.89(m, 4H), 1.89-1.64(m, 2H), 1.29 -1.02 (m, 15H) Compound 82:
1H -NIMR (400 MHz, CDC13): 8.55 - 8.41 (m, 114), 7.25 -7.18 (m, 11-1), 7.17 -7.07 (m, 1H), 7.06 -6.95 (in, 1H), 4.78 ( t, J= 6.8 Hz, 2H), 4.39 ( t, J = 6.0 Hz, 2H), 4.31 - 3.95 (m, 2H), 3.93 - 3.81 (m, 1H), 3.78 - 3.42 (m, 3H), 3.39 - 2.99 (m, 514), 2.85 - 2.57 (m, 4H), 2.49 - 2.34 (m, 1H), 2.21 -2.00 (m, 3H), 1.91 - 1.70 (m, 1314), 1.49- 1.38 (m, 1H), 1.35- 1.22 (m, 1H), 1.18 -0.69 (m, 8H).

-156 -Compound 83:
1H NAIR (400 MHz, CDC13): 8.54- 8.39(m, 1H), 7.25 - 7.19(m, 1H), 7.13 (s, 1H), 7.06 - 6.97 (m, 1H), 4.78 ( t, J= 6.8 Hz, 2H), 4.39 ( t, 1= 6.2 Hz, 2H), 4.32 - 3.95 (m, 2H), 3.93 - 3.00 (m, 8H), 2.87 - 2.57 (m, 4H), 2.40 (s, 1H), 2.24 - 1.98 (m, 3H), 1.91 - 1.68 (m, 14H), 1.50 - 1.38 (m, 1H), 1.36- 1.22 (m, 111), 1.18 -0.67 (m, 8H).
Pi IARMACOLOGICAL PART
1) Menin/MLL homogenous time-resolved fluorescence (HTRF) assay To an untreated, white 384-well microtiter plate was added 40 nL 200X test compound in DMSO and 4 [11_, 2X terbium chelate-labeled menin (vide infra for preparation) in assay buffer (40 mM Tris=HC1, pH 7.5, 50 mM NaCl, 1 mM DTT (dithiothreitol) and 0.05%
Pluronic F-127). After incubation of test compound and terbium chelate-labeled menin for 30 min at ambient temperature, 4 uL 2X FITC-MBM1 peptide (FTTC-13-alanine-SARWRFPARPGT-NH2) ("FITC" means fluorescein isothiocyanate) in assay buffer was added, the microtiter plate centrifuged at 1000 rpm for 1 min and the assay mixtures incubated for 15 min at ambient temperature. The relative amount of menin=FITC-MBM1 complex present in an assay mixture is determined by measuring the homogenous time-resolved fluorescence (HTRF) of the terbium/FITC donor /acceptor fluorphore pair using an EnVision microplate reader (ex. 337 nm/terbium em. 490 nm/FITC em. 520 nm) at ambient temperature. The degree of fluorescence resonance energy transfer (the HTRF value) is expressed as the ratio of the fluorescence emission intensities of the FITC and terbium fluorophores (Fern 520 nm/Fm 490 nm). The final concentrations of reagents in the binding assay are 200 pM terbium chelate-labeled menin, 75 nM FITC-MBM1 peptide and 0.5% DMSO in assay buffer. Dose-response titrations of test compounds are conducted using an 11 point, four-fold serial dilution scheme, starting typically at 10 M.
Compound potencies were determined by first calculating % inhibition at each compound concentration according to equation 1:
% inhibition = ((HC - LC) - (HTRFcompound LC)) / (HC - LC)) *100 (Eqn 1) Where LC and HC are the HTRF values of the assay in the presence or absence of a saturating concentration of a compound that competes with FITC-MBM1 for binding to menin, and HTRF compound is the measured HTRF value in the presence of the test compound.
HC and LC
HTRF values represent an average of at least 10 replicates per plate. For each test compound, %
inhibition values were plotted vs. the logarithm of the test compound concentration, and the

- 157 -/C50 value derived from fitting these data to equation 2:
% inhibition = Bottom + (Top -Bottom)/(1+10^((log/C50-log[cmpd])*h)) (Eqn 2) Where Bottom and Top are the lower and upper asymptotes of the dose-response curve, respectively, /C50 is the concentration of compound that yields 50% inhibition of signal and h is the Hill coefficient.
Preparation of Terbium cryptate labeling of Menin: Menin (a.a 1-610-6xhis tag, 2.3 mg/mL in 20mM Hepes (2-[4-(2-Hydroxyethyl)-1-piperazinyl]ethane sulfonic acid), 80 mM
NaCl, 5mM
DTT (Dithiothreitol), pH 7.5) was labeled with terbium cryptate as follows.
200 jig of Menin was buffer exchanged into lx Hepes buffer. 6.67 tiM Menin was incubated with 8-fold molar excess NHS (N-hydroxysuccinimide)-terbium cryptate for 40 minutes at room temperature.
Half of the labeled protein was purified away from free label by running the reaction over a NAPS column with elution buffer (0.1M Hepes, pH 7 + 0.1% BSA (bovine serum albumin)).
The other half was eluted with 0.1M phosphate buffered saline (PBS), pH7. 400 j.tl of eluent was collected for each, aliquoted and frozen at -80 C. The final concentration of terbium-labeled Menin protein was 115 ittg/mL in Hepes buffer and 85 ittg/mL in PBS
buffer, respectively.
MENIN Protein Sequence (SEQ ID NO: 1):
MGLKAAQKTLFPLRSIDDVVRLFAAELGREEPDLVLLSLVLGFVEHFLAVNRVIPTNV
PELTF QP SPAPDPPGGLTYFPVADLSIIAALYARFTAQIRGAVDLSLYPREGGVS SREL
VKKVSDVIWNSLSRSYFKDRAHIQ SLF SF ITGTKLD SSGVAFAVVGACQALGLRDVH
LALSEDHAWVVFGPNGEQTAEVTWHGKGNEDRRGQTVNAGVAERSWLYLKGSYM
RCDRKIVIEVAFMVCAINP SIDLHTD SLELLQLQQKLLWLLYDLGHLERYPMALGNLA
DLEELEPTPGRPDPLTLYHKGIASAKTYYRDEHIYPYMYLAGYHCRNRNVREALQA
WADT A TVIQDYNYCREDEEIYKEF FEV ANDVIPNLLKE A A SLLEAGEERPGEQ S Q GT
Q S Q GS ALQDPECF AHLLRF YD GICKWEEGSP TPVLHVGWATFLVQ SLGRFEGQVRQK
VRIVSREAEAAEAEEPWGEEAREGRRRGPRRESKPEEPPPPKKPALDKGLGTGQGAV
SGPPRKPPGTVAGTARGPEGGSTAQVPAPAASPPPEGPVLTFQ SEKMKGMKELLVAT
KINSS A IKLQLTAQ S QVQMKK QK VS TP SDYTLSFLKRQRK GLEFITITHIH
2a) Proliferation assay The anti-proliferative effect of menin/MLL protein/protein interaction inhibitor test compounds

- 158 -was assessed in human leukemia cell lines. The cell line MOLM14 harbors a MLL
translocation and expresses the MILL fusion protein MILL-AF9, respectively, as well as the wildtype protein from the second allele. OCI-AMIL3 cells that carry the NPM1c gene mutation were also tested. MILL rearranged cell lines (e.g. M0LM14) and NPM1c mutated cell lines exhibit stem cell-like HOXA/MEIS1 gene expression signatures. KO-52 was used as a control cell line containing two MLL (KIVIT2A) wildtype alleles in order to exclude compounds that display general cytotoxic effects.
MOLM14 cells were cultured in RPMI-1640 (Sigma Aldrich) supplemented with 10%
heat-inactivated fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma Aldrich) and 50 g/m1 gentamycin (Gibco). KO-52 and OCI-AML3 cell lines were propagated in alpha-MEM
(Sigma Aldrich) supplemented with 20% heat-inactivated fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma Aldrich) and 50pg/m1 gentamycin (Gibco). Cells were kept at 0.3 ¨ 2.5 million cells per ml during culturing and passage numbers did not exceed 20.
In order to assess the anti-proliferative effects, 200 MOLM14 cells, 200 OCI-A1V1L3 cells or 300 KO-52 cells were seeded in 200u] media per well in 96-well round bottom, ultra-low attachment plates (Costar, catalogue number 7007). Cell seeding numbers were chosen based on growth curves to ensure linear growth throughout the experiment. Test compounds were added at different concentrations and the DMSO content was normalized to 0.3%.
Cells were incubated for 8 days at 37 C and 5% CO2. Spheroid like growth was measured in real-time by live-cell imaging (IncuCyteZOOM, Essenbio, 4x objective) acquiring images at day 8.
Confluence (%) as a measure of spheroid size was determined using an integrated analysis tool.
In order to determine the effect of the test compounds over time, the confluence in each well as a measure of spheroid size, was calculated. Confluence of the highest dose of a reference compound was used as baseline for the LC (Low control) and the confluence of DMSO treated cells was used as 0% cytotoxicity (High Control, HC).
Absolute IC50 values were calculated as percent change in confluence as follows:
LC = Low Control: cells treated with e.g. I ?AM of the cytotoxic agent staurosporin, or e.g. cells treated with a high concentration of an alternative reference compound HC = High Control: Mean confluence (%) (DMSO treated cells)

- 159 -% Effect = 100 - (100*(Sample-LC)/(HC-LC)) GraphPad Prism (version 7.00) was used to calculate the IC5o. Dose-response equation was used for the plot of % Effect vs Log10 compound concentration with a variable slope and fixing the maximum to 100% and the minimum to 0%.
2b) MEIS1 mRNA expression assay 1V1EIS1 mRNA expression upon treatment of compound was examined by Quantigene Singleplex assay (Thermo Fisher Scientific). This technology allows for direct quantification of mRNA targets using probes hybridizing to defined target sequences of interest and the signal is detected using a Multimode plate reader Envision (PerkinElmer). The MOLM14 cell line was used for this experiment. Cells were plated in 96-well plates at 3,750 cells/well in the presence of increasing concentrations of compounds. After incubation of 48 hours with compounds, cells were lysed in lysis buffer and incubated for 45 minutes at 55 C Cell lysates were mixed with human MEIS1 specific capture probe or human RPL28 (Ribosomal Protein L28) specific probe as a normalization control, as well as blocking probes.
Cell lysates were then transferred to the custom assay hybridization plate (Theimo Fisher Scientific) and incubated for 18 to 22 hours at 55 C. Subsequently, plates were washed to remove unbound materials followed by sequential addition of preamplifiers, amplifiers, and label probe. Signals (= gene counts) were measured with a Multimode plate reader Envision. IC5os were calculated by dose-response modelling using appropriate software. For all non-housekeeper genes response equal counts corrected for background and relative expression. For each sample, each test gene signal (background subtracted) was divided by the normalization gene signal (RPL28:
background subtracted). Fold changes were calculated by dividing the normalized values for the treated samples by the normalized values for the DMSO treated sample. Fold changes of each target gene were used for the calculation of IC5os.

- 160 -Table 3. Biological data - HTRF assay, proliferation assay, and MEIS1 mRNA
expression assay HTRF- MEIS1 spheroid OCI- spheroid Compound 30min ICso assay_OneTime AML3 assay_OneTime Number incubation ( M) M0LM14 IC50 ICso KO-52 1050 (nM) (11,M) (111,M) (IM) 1 1.03 >2.5 2 0.3 0.084 0.047 0.23 >15 3 8.3 1.89 1.81 >15 4 0.25 0.042 0.044 0.31 5.89 0.81 1.23 0.81 12.18 6 0.4 0.26 0.23 >15 7 8.11 >2.5 >3.75 >15 8 0.24 0.13 0.11 6.4 9 0.28 0.29 0.18 9.58 5.27 2.15 2.09 >15 11 0.28 0.19 0.26 11.67 12 3.61 >2.5 2.41 >15 13 2.1 1.64 14 0.16 0.18 0.14 13.57 2.44 1.51 0.8 >15 16 0.06 0.15 0.065 >15 17 0.25 0.14 0.11 4.02 18 0.65 0.66 0.6 11.75 19 0.39 0.14 0.071 11.89 0.14 >2.5 21 0.077 0.09 0.068 10.67 22 0.18 0.049 0.043 0.57 14.69 24 0.095 0.01 0.009 12.18 2.28 0.69 0.63 >15 27 0.074 0.025 0.009 7.93 29 1.94 0.65 0.21 >15 2.6 0.33 0.22 13.33

-161 -HTRF- MEIS1 spheroid OCI- spheroid Compound 30min IC50 assay_OneTime AML3 assay_OneTime Number incubation ( 1V1) MOLM14 IC5o ICso KO-52 IC50 (nM) (111M) (PM) (1[11V1) 31 0.18 0.032 0.02 13 34 0.056 0.48 35 1.24 >2.5 38 0.62 0.7 1.05 >15 39 0.61 0.12 0.11 6.09 40 6.23 >2.5 1.85 >15 41 0.097 0.052 0.04 9.06 42 0.2 0.15 0.1 9.76 43 0.049 0.13 0.089 0.48 8.32 44 2.72 1.88 45 0.64 >2.5 46 0.29 1.31 47 2.26 1.25 48 0.16 0.19 49 0.58 1.48 50 0.39 >2.5 51 0.2 0.19 0.23 11.04 52 0.73 1.21 0.96 >15 53 0.13 0.38 0.43 >15 55 0.17 0.0014 0.0018 0.012 13.59 56 0.056 57 0.064 0.002 0.0018 0.0085 3.82 58 0.21 0.051 0.038 0.16 7.17 59 0.29 0.014 0.012 0.081 4.88 60 36.38 61 0.15 <0.0034 0.006 0.022 7.87 62 1.21 0.038 63 3.03 0.38 64 1.97 >1

- 162 -HTRF- MEIS1 spheroid OCI- spheroid Compound 30min IC50 assay_OneTime AML3 assay_OneTime Number incubation ( 1V1) MOLM14 IC5o ICso KO-52 IC50 (nM) (111M) (PM) (1[11V1) 65 0.074 0.0066 0.012 0.057 1.7 66 0.21 0.027 0.16 67 1.65 68 3.69 69 0.073 0.0052 0.012 0.067 1.6 70 0.23 0.064 0.043 0.73 >15 71 0.13 0.13 0.08 2 72 0.22 0.18 0.08 2.2 73 0.21 0.11 0.08 6.34 74 0.4 0.093 0.048 0.26 9.06 75 1.12 0.71 1.13 10.83 78 2.73 >2.5 >3.75 >15 79 0.067 0.64 0.73 >15 82 0.3 0.11 0.068 0.34 8.53 83 0.35 0.29 0.21 9.24 84 0.16 0.12 0.056 >15 85 2.84 2.47 0.89 >15 86 0.19 0.28 0.11 >15 87 2.12 >2.5 1.59 >15 88 7.51 >2.5 1.78 >15 89 0.42 0.25 0.1 >15 90 0.38 0.2 0.17 >15 91 0.24 0.15 7.61 92 101.23 >2.5 >3.75 >15 93 1.09 0.51 1.1 >15 94 0.44 0.32 0.49 >15 95 0.92 0.41 0.5 6.12 96 2.35 0.51 0.55 10.58 97 2.45 0.73 1.41 >15

- 163 -HTRF- MEIS1 spheroid OCI- spheroid Compound 30min IC50 assay_OneTime AML3 assay_OneTime Number incubation ( 1V1) MOLM14 IC5o ICso KO-IC50 (nM) (111M) (PM) (1[11V1) 98 0.71 0.26 0.19 8.46 99 1.46 0.11 6.08 100 1.49 1.33 >15 101 0.68 0.33 0.31 >15 102 0.49 0.47 >15 103 0.25 0.25 0.17 >15 104 8.91 2.08 3.28 >15 105 0.49 0.096 0.087 12.52 106 0.57 1.45 1.1 >15 107 0.38 0.25 0.14 12.56 108 0.55 0.38 0.18 9.32 109 1.65 0.63 0.27 5.91 110 1.5 0.68 0.22 14.56 111 0.25 0.2 0.03 >15 112 0.56 >1 >0.94 9.64 >15 113 0.25 0.48 0.34 1.41 >15 114 0.12 0.048 0.029 0.14 12.61 115 0.97 0.58 0.77 2.48 15.67 116 0.34 >0.94 1.32 13.29 117 0.89 0.4 0.57 1.89 6.67 118 0.048 0.13 0.32 9.55 119 0.9 0.41 0.47 13.1 120 0.093 0.0046 0.0053 0.035 121 0.44 0.17 0.091 1.16 122 0.36 0.13 0.13 6.4 123 0.35 0.17 0.22 5.89 124 0.38 0.14 0.12 14.6 125 0.22 0.16 0.13 11.35 126 0.4 0.19 0.095 11.54

- 164 -HTRF- MEIS1 spheroid OCI- spheroid Compound 30min IC5o assay_OneTime AML3 assay_OneTime Number incubation ( 1V1) MOLM14 IC5o IC5o KO-52 IC5o IC50 (nM) (111M) (PM) (11M) 127 0.26 0.032 0.0058 0.17 128 0.1 0.027 0.029 0.075 129 0.066 0.0044 0.006 0.049 131 0.22 0.0052 0.007 0.026 132 0.68 134 0.18 0.037 135 0.15 0.026 136 2.2 0.27 137 0.45 0.39 0.37 >15 139 3.07 0.91

- 165 -

Claims (15)

PCT/CN2022/091065

1. A compound of Formula (1) or a tautomer or a stereoisomeric form thereof, wherein R1a represents -C(=0)-NR"Rth; or Rxa and Rxb are each independently selected from the group consisting of hydrogen;
C3_6cyc1oa1ky1; Ci_4a1ky1, Ci_4a1ky1 substituted with 1, 2 or 3 halo atoms;
and Ci_4a1ky1 substituted with one -OH, -0C1_4a1ky1, or NR11 R11d;
-=-= lb tc represents F or Cl;
Y' represents -Clealeb-, -0-, -S-, or R2 is selected frorn the group consisting of hydrogen, halo, C1_4a1ky1, -0-C1_4a1ky1, and -NR7aR7b;
U1 and U2 each independently represent N or CH;
ill, n2, n3 and 114 ate each independently selected fioni 1 and 2, X1 represents CH, and X2 represents N;
R4 represents Cl_5alkyl;
R5a, R5b, R5', R7a, and R7b, are each independently selected from the group consisting of hydrogen, C1_4alkyl and C3_6cycloalkyl;
R3 is selected from the group consisting of Het', Het2, Cy2, and -C1-6 alkyl_NRxcRxd;
It' represents Cy 1; Het5; -Ci_6a1ky1-Cyl; -Ci_6alkyl-Het3; -Ch6alkyl-Het4;
or -C1_6alkyl-phenyl;
Rxd represents hydrogen; C 1-4 alkyl; or Cl_4alkyl substituted with one, two or three sub stituents selected from the group consi sting of halo, -OH, -0-Ch4alkyl, and cyano;
or R"C and Rxd are taken together to form together with the N-atom to which they are attached a 4- to 7-membered monocyclic fully saturated heterocyclyl containing one N-atom and optionally one additional heteroatom selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2; wherein said heterocyclyl is optionally substituted with one, two or three substituents selected from the group consisting of halo, -OH, -0-Ci_4a1ky1, and cyano;
Het' represents 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 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2; or a bicyclic C-linked 6- to 11-membered fully saturated heterocyclyl containing one N-atom and optionally one or two additional heteroatoms each independently selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2;
wherein said heterocyclyl is optionally substituted on one nitrogen with a substituent selected from the group consisting of le and -C(=0)-1e; and wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four substituents each independently selected from the group consisting of halo, R6, Het6", Het6b, Ch4alkyl, oxo, -NR9aR9b and -OH;
Hee represents C-linked pyrazolyl or triazolyl; which is substituted on one nitrogen atom with R6';
R6 is selected from the group consisting of Het3; -C(=0)-NH-R8;
Ci_6a1ky1 optionally substituted with one or two substituents each independently selected from the group consisting of Hee, Het4,Hetúa, Het6b, Cy% _CN, -OH, -0-Cl_4alkyl, -C(=0)-NH-C1_4alkyl, -C(=0)--NH-C1_4alkyl-C3_6cyc1oa1ky1, -C(=0)-0H, -NRi laR1 lb and -NH-S(=0)2-Ci_4a1ky1; and C3_6cycloalkyl optionally substituted by one or two substituents each independently selected from the group consisting of -CN, -OH, -0-C1_4alkyl, -C(=0)-NH-Ci_4alkyl, -NH-S(=0)2-Ci_4a1ky1, and C1-4alkyl optionally substituted with one substituent selected from the group consisting of OH, -0-C1_4alkyl, -C(=0)-NH-C1_4alkyl and -NH-S(=0)2-C1_4alkyl;

R' represents Ci_6a1ky1 substituted with one substituent selected from the group consisting of _NR1 laR1 ib, Het', and Het', R8 represents Ci_6a1ky1 optionally substituted with one, two or three substituents each independently selected from -OH, halo, cyano, -NRi 1 aRl lb, Het 3a7 and Het', Het3 and Het5 each independently represent a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2; or a bicyclic C-linked 6- to 11-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2;
wherein said heterocyclyl is optionally substituted on one carbon atom with Ci_4a1ky1, halo, -OH, -NR1laRl lb, or oxo; and wherein said heterocyclyl is optionally substituted on one nitrogen atom with Cl_ztalkyl;
Het3a and Het5a each independently represent 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 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2; or a bicyclic C-linked 6- to 11-membered fully saturated heterocyclyl containing one N-atom, and optionally one or two additional heteroatoms each independently selected from 0, S, and N, wherein said S-atorn might be substituted to form S(=0) or S(=0)2;
wherein said heterocyclyl is optionally substituted on one carbon atom with Cl_4a1ky1, halo, -OH, -NR1 1 aR1 lb, or oxo; and wherein said heterocyclyl is optionally substituted on one nitrogen atom with Cl_aalkyl;
Het4 and Het' each independently represent a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two, three or four heteroatoms each independently selected from 0, S, and N; wherein said 5-membered aromatic ring is optionally substituted on one nitrogen atom with Ci_aalkyl; and wherein said 5- or 6-membered aromatic ring is optionally substituted on one carbon atom with -OH;
Het" and Het' 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 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2; wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four substituents each independently selected from the group consisting of halo, -OH, oxo, -(C=0)-NR10aR1013, -0-C3_ócycloalkyl, -S(=0)2-Ch4alkyl, cyano, Ci_4alkyl, -Ci_4alkyl-OH, -0-C1_4alkyl, -0-(C=0)-NR1 oaR1 ob, and -0-(C=0)-Ci_4a1ky1; and wherein said heterocyclyl is optionally substituted on one nitrogen with a substituent selected from the group consisting of -C(=0)-Ci_4a1ky1 and -(C=0)-NRloaRlob Het'a each independently represent a monocyclic N-linked 4- to 7-membered fully saturated heterocycly1 containing two N-atoms and optionally one additional heteroatom selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2;
wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four substituents each independently selected from the group consisting of halo, -OH, oxo, -(C=0)-NR10aRlOb, -0-C3_6cyc1oa1ky1, -S(=0)2-Cl_4alkyl, cyano, C1-4alkyl, Cl_4alkyl-OH, -0-Ci_4alkyl, -0-(C=0)-NRIOaRlob, and -0-(C=0)-Ci_4alkyl, and wherein said heterocyclyl is optionally substituted on one nitrogen with a substituent selected from the group consisting of -C(=0)-_(c=0)_N-Ri oaRlob;
Cl_4alkyl and Het6b represents a bicyclic N-linked 6- to 11-membered fully saturated heterocyclyl containing one N-atom and optionally one or two additional heteroatoms each independently selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2; wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one or two sub stituents each independently selected from the group consisting of Ci_ 4alkyl, -OH, oxo, -(C=0)-NR10aR1 Ob, -NH-C(=0)-Ci_4a1ky1, -NH-C(=0)-Cy3, and -0-Ci_4alkyl; and wherein said heterocyclyl is optionally substituted on one nitrogen with a substituent selected from the group consisting of -C(=0)-Ci_4alkyl, -C(=0)-Cy3, -(C=0)-Ci_4alkyl-OH, -C(=0)-Ci_4a1ky1-0-Ci_4a1ky1, -C(=0)-1 aR1 lb, and Ci_4alkyl;
Cyi represents C3_6cyc1oa1ky1 optionally substituted with one, two or three substituents selected from the group consisting of -OH, -NH-C(=0)-Ci_4a1ky1, Ci_4alkyl, -NH-S(=0)2-C1-4alkyl, -S(=0)2-Ci_4alkyl, and -0-Ci_4alkyl, Cy2 represents C3_7cyc1oa1ky1 substituted with one or two substituents each independently selected from the group consisting of _NR9aR9b, Het6a; Het6b; and Cl_6a1ky1 substituted with one or two substituents each independently selected from the group consisting of Het3a, Het6a, Het6b, and -NR9aR9b; and said C3_7cyc1oa1ky1 is optionally substituted with one or two additional substituents each independently selected from the group consisting of halo, R6, Ch4alkyl, and -OH;
Cy3 represents C3_7cyc1oa1ky1; wherein said C3_7cyc1oa1ky1 is optionally substituted with one, two or three halo substituents;
lea and R" are each independently selected from the group consisting of hydrogen;
Ci_4a1ky1; C3_6cyc1oa1ky1; Het5; -C1_4a1ky1-R16; -C(=0)-Ci_4a1ky1-Het3a; -C(=0)-Rm;
C3_6cyc1oa1ky1 substituted with one, two or three substituents selected from the group consisting of halo, -OH, -0-Ci_4a1ky1, -NRllaRllb, and cyano; and Cl_4alkyl substituted with onc, two or three substitucnts selccted from thc group consisting of halo, -OH, -NRllaRllb, and cyano;
Rua, Rub, R13a, R13b, R15a, R15b, R17a, and Rim are each independently selected frorn the group consisting of hydrogen and Ci¨ialkyl;
Riic and Rild are each independently selected from the group consisting of hydrogen, Ci_6a1ky1, and -C(=0)-Ci_4a1ky1;

represents Het5a; Heea; or Ci4alkyl substituted with one, two or three substituents selected from the group consisting of -NW 3aRnh and Heea;

K represents _g=0)_NR17aR17b, _S(=0)2-C1_4alkyl, Hee, Het7, or Hee;
or a pharmaceutically acceptable salt or a solvate thereof.

2. The compound according to claim 1, wherein Ria represents _C(=c1)_NRxaRxb;
R' and Rxb are each independently selected from the group consisting of C3_6cycloalkyl; Ci_4a1ky1; and Ci_aalkyl substituted with 1, 2 or 3 halo atoms;
lb tc represents F;
)(1 represents -0-;
R2 represents hydrogen;
R4 represents Ci_5a1ky1;
R3 is selected from the group consisting of Het' and Cy2;
Het' represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom;
wherein said heterocyclyl is optionally substituted on one nitrogen with a substituent selected from the group consisting of R6 and -C(=0)-R8; and wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four halo substituents;
R6 is selected from the group consisting of Het3;
Cl_6alkyl optionally substituted with one or two substituents each independently selected from the group consisting of Het3, Hee, Het6a, Cyl, -OH, -0-Ci_4a1ky1, -C(=0)-NH-Cr_4alkyl, -C(=0)-NH-Cr_4a1ky1-C3_6cyc1oa1ky1, and -NH-S(=0)2-C1_4a1ky1;
R8 represents Cr_6a1ky1 substituted with one substituent selected from the group consisting of -OH and -NR1laR1 lb, Het3 and Het' each independently represent a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from 0, S, and N, wherein said S-atom might be substituted to form S(=0) or S(=0)2;
wherein said heterocyclyl is optionally substituted on one carbon atom with -OH or oxo;
Het4 represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from 0, S, and N; wherein said 5-or 6-membered aromatic ring is optionally substituted on one carbon atom with -OH;
Het6a represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom and optionally one or two additional heteroatoms each independently selected from 0, S, and N, wherein said S-atorn might be substituted to form S(=0) or S(=0)2, wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four substituents each independently selected from the group consisting of oxo, -S(=0)2-C1-4alkyl, and -0-Ci_4a1ky1, and wherein said heterocyclyl is optionally substituted on one nitrogen with -C(=0)-C1_4alkyl;
Het6b represents a bicyclic N-linked 6- to 11-membered fully saturated heterocyclyl containing one N-atom and optionally one or two additional heteroatoms each independently selected from 0, S, and N, wherein said S-atorn might be substituted to form S(=0) or S(=0)2; wherein said heterocyclyl is optionally substituted on one carbon atom with -(C=0)-NRiOaRlob; and wherein said heterocyclyl is optionally substituted on one nitrogen with -C(=0)-C1-4alkyl;
Cyi represents C3_6cyc1oa1ky1 optionally substituted with one, two or three substituents selected from the group consisting of -OH, -NH-C(=0)-C1-4alkyl, -NH-S(=0)2-C1_4a1ky1, and -0-C1-4alkyl;

Cy2 represents C3_7cyc1oa1ky1 substituted with one or two substituents each independently selected from the group consisting of -Wale); Het6a; and Het6b;
R' and leb are each independently selected from the group consisting of hydrogen;
C1_4alkyl; C3_6cycloalkyl; Hee; -C1_4a1ky1-R16; and Ci_4a1ky1 substituted with one, two or three -0-Cl_4alkyl sub stituents;
R10a, Rlob, Rlla, and Rilb represent Ci_4a1ky1;
-=-= 16 tc represents Hee.

3. The compound according to claim 1, wherein Rla represents -C(=0)-NmaRxb;
R" and le' represent Ci_Lialkyl;
-=-= lb tc represents F;
Y1 represents -0-;
R2 represents hydrogen;
R4 represents isopropyl;
R3 is selected from the group consisting of Het' and Cy2;
Het' represents a rnonocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atorn;
wherein said heterocyclyl is optionally substituted on one nitrogen with a substituent selected from the group consisting of R6;
R6 represents C1-6alkyl substituted with one Het3, Het3 represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from 0, S, and N, wherein said S-atom rnight be substituted to form S(=0) or S(=0)2;
Het6a represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atorn; wherein said heterocyclyl is optionally substituted on one carbon atom with one -0-C1_4alkyl;
Het6b represents a bicyclic N-linked 6- to 11-membered fully saturated heterocyclyl containing one N-atorn and optionally one or two additional heteroatorns each independently selected frorn 0 and N; wherein said heterocyclyl is optionally substituted on one carbon atom with -(C=0)-NR10aRlob and wherein said heterocyclyl is optionally substituted on one nitrogen with -C(=0)-Ci_4a1ky1;
Cy2 represents C3_7cyc1oa1ky1 substituted with one substituents selected frorn the group consisting of Het6a and Hee";
Rma and R1013 represent Ci_Lialkyl.

4. The compound according to claim 1, wherein R3 represents Het'.

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

6. The cornpound according to claim 1, wherein U1- represents N.

7. The compound according to claim I, wherein R3 represents Het' ;
Het' represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom;
wherein said heterocyclyl is substituted on one nitrogen with R6; and wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four halo sub stituents;
R6 is selected from the group consisting of Cl_6alkyl optionally substituted with one or two substituents each independently selected from the group consisting of Het3, Het4, Het6a, and Cy' .

8. A pharmaceutical composition comprising a compound as clairned in any one of claims 1 to 7 and a pharmaceutically acceptable carrier or diluent.

9. A process for preparing a pharmaceutical composition as defined in claim 8 comprising mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound according to any one of clairns 1 to 7.

10. A compound as claimed in any one of claims 1 to 7 or a pharmaceutical composition as claimed in claim 8 for use as a medicament

11. A compound as claimed in any one of claims 1 to 7 or a pharmaceutical composition as claimed in claim 8 for use in the prevention or treatment of cancer, myelodysplastic syndrome (MDS) and diabetes.

12. The compound or a pharmaceutical composition for use according to claim 11, wherein cancer is selected from leukemias, myeloma or a solid tumor cancer such as prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma and glioblastoma.

13. The compound or a pharmaceutical composition for use according to claim 12, wherein the leukemia is selected from acute leukemias, chronic leukemias, myeloid leukemias, myelogeneous leukemias, lymphoblastic leukemias, lymphocytic leukemias, Acute myelogeneous leukemias (AML), Chronic myelogenous leukemias (CML), Acute lymphoblastic leukemias (ALL), Chronic lymphocytic leukemias (CLL), T cell prolymphocytic leukemias (T-PLL), Large granular lymphocytic leukemia, Hairy cell leukemia (HCL), MLL-rearranged leukemias, MLL-PTD leukemias, MLL amplified leukemias, MLL-positive leukemias, and leukemias exhibiting TIOXIMEIS 1 gene expression signatures.

14. A method of treating or preventing a disorder selected from cancer, myelodysplastic syndrome (MDS) and diabetes comprising administering to a subject in need thereof, a therapeutically effective amount of a compound as claimed in any one of claims 1 to 7 or a pharmaceutical composition as claimed in claim 8.

15. The method according to claim 13 wherein the disorder is cancer.