EA046212B1 - AZEPANE INHIBITORS OF MENIN–MLL INTERACTION - Google Patents

Description

Field of technology to which the invention relates

The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal and, in particular, to azepane compounds, a pharmaceutical composition containing such compounds, and their use as inhibitors of menin-MLL protein-protein interactions useful for the treatment diseases such as cancer, myelodysplastic syndrome (MDS) and diabetes.

BACKGROUND OF THE INVENTION

Chromosomal rearrangements affecting the mixed lineage leukemia associated gene (MLL; MLL1; KMT2A) result in aggressive acute leukemias across all age groups and are still virtually incurable diseases, highlighting the urgent need for new therapeutic approaches . Types of acute leukemia involving such MLL chromosomal translocations are lymphoid, myeloid or biphenotypic disease and account for 5 to 10% of acute leukemias in adults and approximately 70% in children (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 at lysine 4 (H3K4) and functions in multiprotein complexes. The use of inducible loss-of-function alleles of Mll1 has demonstrated that Mll1 plays an important role in hematopoietic stem cell (HSC) maintenance and B cell development, although its histone methyltransferase activity is not essential for hematopoiesis (Mishra et al., Cell Rep 2011. 7 (4), 1239-47).

To date, MLL fusions with over 60 different partners have been reported and have been associated with leukemia formation/progression (Meyer et al., Leukemia 2013. 27, 2165-2176). Interestingly, the SET domain (Su(var)3-9, zeste and trithorax enhancer) of MLL is not retained in the chimeric proteins but is replaced by a fusion partner (Thiel et al., Bioessays 2012. 34, 771-80). Recruitment of chromatin-modifying enzymes such as Dot1L and/or the pTEFb complex by a fusion partner results in enhanced transcription and transcriptional elongation of MLL target genes, including the HOXA genes (e.g., HOXA9) and the HOX cofactor MEIS1, as the most significant. Aberrant expression of these genes, in turn, blocks the differentiation of hematopoietic cells and enhances proliferation.

Menin, which is encoded by the multiple endocrine neoplasia type 1 associated gene (MEN1), is expressed ubiquitously and is predominantly localized to the nucleus. It has been shown to interact with numerous proteins and is therefore involved in a variety of cellular processes. The most studied function of menin is its role as an oncogenic cofactor of MLL-based fusion proteins. Menin interacts with two motifs in the N-terminal fragment of MLL, which is conserved in all fusion proteins, MBM1 (menin binding motif 1) and MBM2 (Thiel et al., Bioessays 2012. 34, 771-80). The menin-MLL interaction results in the formation of a new interaction surface for lens epithelial growth factor (LEDGF). Although MLL binds directly to LEDGF, the presence of menin is required for stable interaction between MLL and LEDGF and gene-specific recruitment of the MLL complex to chromatin via the PWWP domain of LEDGF (Cermakova et al., Cancer Res 2014. 15, 5139-51; Yokoyama & Cleary , Cancer Cell 2008. 8, 36-46). In addition, numerous genetic studies have shown that menin is clearly required for oncogenic transformation by MLL-based fusion proteins, implicating the menin-MLL interaction as an attractive therapeutic target. For example, conditional deletion of Men1 prevents leucomogenesis in bone marrow progenitor cells ectopically expressing MLL fusion products (Chen et al., Proc Natl Acad Sci 2006. 103, 1018-23). Likewise, genetic disruption of the menin-MLL fusion product interaction through loss-of-function mutations suppresses the oncogenic properties of MLL fusion proteins, blocks leukemia development in vivo, and reverses the differentiation block of MLL-transformed leukemic blast cells. These studies also showed that menin is required to maintain HOX gene expression by MLL-based fusion proteins (Yokoyama et al., Cell 2005. 123, 207-18). In addition, small molecule inhibitors of the menin-MLL interaction have been developed, demonstrating that this protein-protein interaction is useful as a drug target, and have also been demonstrated to be effective 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 an essential cofactor of MLL1 during normal hematopoiesis (Li et al., Blood 2013. 122, 2039-2046), such data establish disruption of the menin-MLL interaction as a promising new therapeutic approach for the treatment of leukemia with MLL rearrangement and other cancers with an active HOX/MEIS1 gene expression profile. For example, internal partial tandem duplication (PTD) in the 5′ region of the MLL gene is another major aberration that is found predominantly de novo and in secondary AML and myelodysplastic syndromes. Although the molecular mechanism and biological function of MLL-PTD are not well understood, new therapeutic strategies targeting menin- 1 046212

MLL may also be effective in treating MLL-PTD-associated leukemias. In addition, castration-resistant prostate cancer has been shown to be dependent on the menin-MLL interaction (Malik et al., Nat Med 2015. 21, 344-52).

Several literature sources describe inhibitors that specifically target the menin-MLL interaction: WO 2011029054, J Med Chem 2016, 59, 892-913 describes the preparation of thienopyrimidine and benzodiazepine derivatives; WO 2014164543 describes thienopyrimidine and thienopyridine derivatives; in Nature Chemical Biology March 2012, 8, 277-284 and Ren, J.; et al. Bioorg Med Chem Lett (2016), 26(18), 4472-4476 thienopyrimidine derivatives are described; J Med Chem 2014, 57, 1543-1556 describes hydroxy- and aminomethylpiperidine derivatives; Future Med Chem 2014, 6, 447462 discusses small molecule and peptidomimetic compounds; WO 2016/195776 describes derivatives of furo[2,3^]pyrimidine, 9H-purine, [1,3]oxazolo[5,4^]pyrimidine, [1,3]oxazolo[4,5d]pyrimidine, [1, 3]thiazolo[5,4^]pyrimidine, thieno[2,3-b]pyridine and thieno[2,3^]pyrimidine; and WO 2016/197027 describes derivatives of 5,6,7,8-tetrahydropyrido[3,4^]pyrimidine, 5,6,7,8tetrahydropyrido[4,3^]pyrimidine, pyrido[2,3^]pyrimidine and quinoline . WO 2017112768 describes inhibitors of the menin-MLL interaction. WO 2017161002 describes menin-MLL inhibitors. WO 2017161028 describes menin-MLL inhibitors.

Description of the invention

The present invention relates to new compounds of formula (I),

and to their tautomers and stereoisomeric forms, where

R ¹ is selected from the group consisting of CH ₃ , CH2F, CHF2 and CF3;

R ² is selected from the group consisting of hydrogen and CH ₃ ;

Y ¹ is selected from the group consisting of hydrogen; C _1-6 αlkyl; a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom, optionally substituted with a C _1-4 αlkyl or cyclopropyl substituent; and C _1-4 alkyl substituted with a substituent selected from the group consisting of fluorine, -CN, phenyl, -OR ^1Y and -NR ^2Y R ^2YY ;

where R ^1Y is selected from the group consisting of hydrogen; C _1-4 αlkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN and -C(=O)NR ^1y R ^2y ; ^^alkyl substituted with a substituent selected from the group consisting of -OR ^3y and -NR ^1y R ^2y ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;

each of R ^2Y and R ^2YY is independently selected from the group consisting of hydrogen; C _1-4 αlkyl, optionally substituted with a substituent representing -C(=O)NR ^1y R ^2y ;

With _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^3y and -NR ^1y R ^2y ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;

each of Y ² and Y ³ is independently selected from the group consisting of hydrogen; HE; NH2; -C(=O)NR ^1y R ^2y ; C1-6alkyl and C1-4αalkyl substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ^3Y and -NR ^4Y R ^4YY ; provided that if both Y ² and Y ³ are substituents on the same carbon atom and one of Y ² or Y ³ is OH or NH2, then the other Y ³ or Y ² is H, C1-6alkyl , C _1-4 alkyl substituted with a substituent selected from the group consisting of fluorine and CN, or C _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^3Y and -NR ^4Y R ^4YY ; Where

R ^3Y is selected from the group consisting of hydrogen; C1-4alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN and -C(=O)NR ^4y R ^5y ; C2-4alkyl substituted with a substituent selected from the group consisting of -OR ^6y and -NR ^4y R ^5y ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;

each of R ^4Y and R ^4YY is independently selected from the group consisting of hydrogen; C _1-4 αlkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN and -C(=O)NR ^1y R ^2y ; (A.d.lk.la, substituted with a substituent selected from the group consisting of -OR ^6y and -NR ^4y R ^5y ; and C-linked 4-7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur; wherein each of R ^1y , R ^2y , R ^3y , R ^4y , R ^5y and R ^6y is independently selected from the group consisting of hydrogen; C _1-4 αlkyl and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; and

- 2 046212

--LR ³ selected from (a), (b), (c), (d), (e) or (f):

(a) --LR ³ is -NHR ^1A , where R ^1A is selected from the group consisting of hydrogen; C1-6alkyl, optionally substituted with one, two or three substituents representing a fluorine atom; and C2-6 alkyl substituted with a substituent selected from the group consisting of -OR ^1a and -NR ^2a R ^2aa , wherein each of R ^1a , R ^2a and R ^2aa is independently selected from the group consisting of hydrogen, C1-4 alkyl and cyclopropyl; with the proviso that if R ^1A is hydrogen, then Y ¹ is not hydrogen; or (b) L is selected from the group consisting of -O-, -O-CR ^1b R ^1bb -, -N(R ^B )-, -N( ^RB )-CR ^1B R ^1BB - and -(NR ^b ) -CHR ^1b CHR2B-; And

R ³ is selected from the group consisting of Ar; Het ¹ ; Het ² and 7-10-membered saturated spirocarbobicyclic system; Where

R ^B is selected from the group consisting of hydrogen; C _1-4 alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, phenyl and -CN; and C _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^1b and -NR ^2b R ^2bb ; wherein each of R ^1b , R ^2b and R ^2bb is independently selected from the group consisting of hydrogen, C _1-4 alkyl and cyclopropyl;

R ^1B is selected from the group consisting of hydrogen; -C(=O)NR ^3B R ^3BB ;

C _1-4 alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, phenyl, Het ¹ and -CN; With _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^4B and -NR ^5B R ^5BB ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; and R ^1BB is selected from the group consisting of hydrogen and methyl; or R ^1B and R ^1BB together with the carbon atom to which they are attached form a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;

R ^2B is selected from the group consisting of hydrogen; -OR ^6B ; -NR ^7B R ^7BB ; -C(=O)NR ^8B R ^8BB ; C _1-4 alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ^4B and -NR ^5B R ^5BB ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; wherein each of R ^3B , R ^3BB , R ^4B , R ^5B , R ^5BB , R ^6B , R ^7B , R ^7BB , R ^8B and R ^8BB is independently selected from the group consisting of hydrogen; C1-4alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN and -C(=O)NR ^9B R ^9BB ; and C2-4alkyl substituted with a substituent selected from the group consisting of -OR ^10B and -NR ^11B R ^11BB ; wherein each of R ^9B , R ^9BB , R ^10B , R ^11b and R ^11BB is independently selected from the group consisting of hydrogen; C1-4alkyl and C-linked 4-7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; or (c) --LR ³ selected from the group consisting of -N(R ^c )-CHR ^1c -CO2R ^2C ; -N( ^RC )-CHR ^3C -CONR ^4C R ^4CC ; -N(R ^C )-COR ^5C ; -N( ^RC )-SO2-NR ^6C R ^6CC ; Where

R ^c is selected from the group consisting of hydrogen; C _1-4 alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, phenyl and -CN; and C _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^1c and -NR ^2c R ^2cc ;

R ^1c and R ^3C are each selected from the group consisting of hydrogen;

-C(=O)NR ^3c R ^3cc ; C1-4alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, phenyl, Het ¹ and -CN; C2-4alkyl substituted with a substituent selected from the group consisting of -OR ^4c and -NR ^5c R ^5cc ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;

R ^4C and R ^6C are each selected from the group consisting of hydrogen and C _1-4 alkyl, optionally substituted by a substituent selected from the group consisting of NR ^6c R ^6cc , Ar and Het ¹ ;

R2C is selected from the group consisting of hydrogen; C _1-4 alkyl, optionally substituted with Ar or Het ¹ ; Ar; Het ¹ ; Het ² and 7-10-membered saturated spirocarbobicyclic system;

R ^5C is selected from the group consisting of hydrogen; C _1-4 alkyl, optionally substituted with -NR ^2c R ^2cc , Ar or Het ¹ ; Ar; Het ¹ ; Het ² and 7-10-membered saturated spirocarbobicyclic system; wherein each of R ^1c , R ^2c , R ^2cc , R ^3c , R ^3cc , R ^4c , R ^5c and R ^5cc is independently selected from the group consisting of hydrogen and C _1-4 alkyl; and each of R ^6c and R ^6cc is independently selected from the group consisting of hydrogen and C _1-4 alkyl, optionally substituted with a substituent selected from the group consisting of -NHC _1-4 alkyl and cyclopropyl;

and each of R ^4CC and R ^6CC is independently selected from the group consisting of hydrogen; C _1-4 alkyl, optionally substituted with Ar or Het ¹ ; Ar; Het ¹ ; Het ² and 7-10-membered saturated spirocarbobicyclic system; or R ^4C and R ^4CC or R ^6C and r ^6CC together with the nitrogen atom to which they are attached form an N-linked Het ² ; or (d) L is selected from -N(R ^D ) -CR ^1d R ^1dd - and -N(R ^D )-CR ^1D R ^1DD -CR ^2D R ^2DD -; Where

R ^d is selected from the group consisting of hydrogen; Substitute with _1-4 alkyl, optionally substituted

- 3 046212 lem selected from the group consisting of fluorine and -CN; and C _2-4 alkyl substituted with a substituent selected from -OR ^1d and

-NR ^2d R ^2dd ; wherein R ^1d , R ^2d and R ^2dd are each independently selected from the group consisting of hydrogen and C ₁ . ₄ alkyl;

R ^1d , R ^1dd , R ^2D1 and r ^2DD are each independently selected from the group consisting of hydrogen and C ₁ . ₄ alkyl;

And

R ³ is selected from the group consisting of where each of R ^3D , R ^4D and R ^5D is independently selected from the group consisting of C ₁ . ₆ alkyl, optionally substituted with a -OH, -OC ₁ substituent. ₆ alkyl or -NH2; or (e) --LR ³ represents

RE is selected from the group consisting of hydrogen and C ₁ . ₄ alkyl;

R ^1e is selected from the group consisting of hydrogen, fluorine and ^^alkyl; And

R ^2E is selected from the group consisting of fluorine, -OC ₁ . ₄ alkyl and C ₁ . ₄ alkyl, optionally substituted with 1, 2 or 3 substituents representing a fluorine atom; or R ^1e and R ^2E are connected to the same carbon atom and together form an alkyl alkyl or a C-linked 4-6-membered heterocyclyl containing an oxygen atom; And

R ^3E is selected from the group consisting of hydrogen; C ₁ . ₄ alkyl, optionally substituted with a substituent representing a fluorine atom or -CN; and C _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^4E and -NR ^5E R ^5EE ; wherein each of R ^4E , R ^5E and R ^5EE is independently selected from the group consisting of hydrogen; C1.4alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN and -C(=O)NR ^6E R ^6EE ; C2. ₄ alkyl substituted with a substituent selected from the group consisting of -OR ^7E and -NR ^8E R ^8EE ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; wherein each of R ^6E , R ^6EE , R ^7E , R ^8E and r ^8EE is independently selected from the group consisting of hydrogen and C ₁ . ₄ alkyl; or (f) --LR ³ is a radical selected from the group consisting of

where R ^1f is selected from the group consisting of hydrogen, C _1-4 alkyl and -C ₂ . ₄ anKun-NR ^f R ^ff ; and each of R ^2F and R ^3F is independently selected from hydrogen and C _1-4 alkyl;

wherein each of R ^f and R ^ff is independently selected from the group consisting of hydrogen and C _1-4 alkyl;

and where

Ar is phenyl, optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -CN, -OR ⁴ , -NR5R ⁵ , C(=O)NR ⁵ R ⁵ and C ₁ . ₄ alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ⁶ , -NR7R ⁷ ' and -C(O)NR ⁸ R ⁸ ';

Het ¹ is a monocyclic heteroaryl selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 4- or 5-thiazolyl, isothiazolyl and isoxazolyl; each of which may be optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -CN, -OR ⁴ , -NR5R ⁵ and C ₁ . ₄ alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ⁶ , -NR ⁷ R ⁷ and -C(=O)NR ⁸ R ⁸ ; And

Het ² is a non-aromatic heterocyclyl, optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, CN, -OR ⁴ , -NR ⁵ R ^5' and C ₁ . ₄ alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ⁶ , -NR ⁷ R ⁷ and -C(=O)NR ⁸ R ⁸ ; wherein each of ^R4 , ^R5 , ^R5 ', ^R6 , ^R7 , ^R7 ', ^R8 and ^R8 ' is independently selected from the group consisting of hydrogen; C1 ₄ alkyl, optionally substituted with a substituent selected from the group consisting of fluorine and C(=O)NR ⁹ R ⁹ ; and ^^alkyl substituted with a substituent selected from the group consisting of -OR ¹⁰ and - 4 046212

NR ¹¹ R ¹¹ '; wherein each of R ⁹ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹¹ is independently selected from the group consisting of hydrogen; C _1-4 alkyl and C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;

and their pharmaceutically acceptable salts and solvates.

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

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

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

In a specific embodiment, said cancer is selected from leukemia, myeloma, or solid tumor cancer (e.g., prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma and glioblastoma, etc.). d.). In some embodiments, the leukemia types include acute leukemia types, chronic leukemia types, myeloid leukemia types, myelogenous leukemia types, lymphoblastic leukemia types, lymphocytic leukemia types, acute myelogenous leukemia (AML) types, chronic myelogenous leukemia (CML) types, acute lymphoblastic leukemia types leukemia (ALL), types of chronic lymphocytic leukemia (CLL), types of T-cell prolymphocytic leukemia (T-PLL), leukemia of large granular lymphocytes, hairy cell leukemia (HCL), types of leukemia with MLL rearrangement, types of leukemia associated with MLL- PTD, types of leukemia with MLL amplification, types of MLL-positive leukemia, types of leukemia characterized by HOX/MEIS1 gene expression profiles, etc.

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

Additionally, the present invention relates to a method for preparing a pharmaceutical composition in accordance with the present invention, which is characterized in that a pharmaceutically acceptable carrier is thoroughly mixed with a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof.

The present invention also provides a product containing a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof and an additional pharmaceutical agent, in the form of a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of cancer, myelodysplastic syndrome (MDS) and diabetes.

In addition, the present invention provides a method of treating or preventing a cell proliferation disease in a warm-blooded animal, which comprises administering to said animal an effective amount of a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof as defined herein, or a pharmaceutical composition or combinations defined herein.

Detailed Description of the Invention

The terms halogen or halogen as used herein mean fluorine, chlorine, bromine and iodine.

The prefix Cx _-y (where x and y are integers) as used herein refers to the number of carbon atoms in a given group. Thus, a C _1-6 alkyl group contains from 1 to 6 carbon atoms, etc.

The term C _1-4 alkyl, as used herein as a group or part of a group, means a straight or branched chain saturated hydrocarbon radical containing from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, tert-butyl, etc.

The term _C2-4 alkyl, as used herein as a group or part of a group, means a straight or branched chain saturated hydrocarbon radical containing from 2 to 4 carbon atoms, such as ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc.

The term C _1-6 alkyl, as used herein as a group or part of a group, means a straight or branched chain saturated hydrocarbon radical containing from 1 to 6 carbon atoms, such as the groups defined for C _1-4 alkyl, and n -pentyl, n-hexyl, 2-methylbutyl, etc.

The term _C2-6 alkyl, as used herein as a group or part of a group, means a straight or branched chain saturated hydrocarbon radical containing from 2 to 6 carbon atoms, such as those defined for _C2-4 alkyl, and n -pentyl, n-hexyl, 2-methylbutyl and

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etc.

It will be apparent to one skilled in the art that S(=O) ₂ , (SO2) or SO2 is a sulfonyl moiety.

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

As used herein, the expression spirobicyclic systems means cyclic systems where two rings are connected at one atom. Examples of 7-10 membered saturated spiro-

In general, in all applications in the present invention, the term substituted is intended to mean, unless otherwise stated or clearly evident from the context, one or more hydrogen atoms, particularly 1 to 4 hydrogen atoms, more particularly 1 to 3 hydrogen atoms, preferably 1 or 2 hydrogen atoms, more preferably 1 hydrogen atom, on the atom or radical designated by the expression using substituted, are replaced by one selected from the group indicated, provided that the normal valence is not exceeded and that the substitution results in a chemically stable connection, i.e. a compound that is stable enough to withstand isolation to a suitable degree of purity from the reaction mixture.

Combinations of substituents and/or variables are permissible only if such combinations result in chemically stable compounds. A stable compound is meant to mean a compound that is sufficiently stable to withstand isolation to a suitable degree of purity from the reaction mixture.

One skilled in the art will understand that when an atom or radical is substituted with a substituent, it is understood that said atom or radical is substituted with one substituent selected from said group.

One skilled in the art will appreciate that the term optionally substituted means that the atom or radical designated using the expression optionally substituted may or may not be substituted (meaning substituted or unsubstituted, respectively).

It will be apparent to one skilled in the art that if, for example, L is N(R ^B ) -CR ^1B R ^1BB - in option (b) -LR ³ , then this means that the nitrogen atom substituted by ^RB is attached to the azepane ring. This is similar for other definitions of L, such as, for example, -O-CR ^1B R ^1BB - (oxygen attached to the azepane ring), -(NR ^B )-CHR ^1B -CHR ^2B - (nitrogen atom substituted by ^RB attached to azepane ring), -N(R ^D )-CR ^1D R ^1DD - (nitrogen atom substituted with R ^D attached to the azepane ring), -N(R ^D )-CRR -CRR - (nitrogen atom substituted with R ^D attached to the azepane ring) or other similar definitions of L within the scope of the present invention.

If two or more substituents are present on a fragment, they may, if possible and unless otherwise indicated or clearly evident from the context, replace hydrogen atoms at the same atom, or they may replace hydrogen atoms at different atoms in the fragment.

It will be apparent to one skilled in the art that, unless otherwise stated or clearly apparent from the context, a substituent on a heterocyclyl group can replace any hydrogen atom on a ring carbon atom or a ring heteroatom (e.g., a hydrogen on a nitrogen atom can be replaced by a substituent).

In the context of the present invention, saturated means fully saturated unless otherwise indicated.

The non-aromatic group includes unsaturated ring systems of non-aromatic nature, partially saturated and fully saturated carbocyclic and heterocyclic ring systems. The term partially saturated refers to rings where the ring structure(s) contains at least one multiple bond, for example a C=C, N=C bond. The term fully saturated refers to rings where there are no multiple bonds between the ring atoms. Thus, a non-aromatic heterocyclyl is a non-aromatic monocyclic or bicyclic system, unless otherwise specified, containing, for example, 3-12 members

- 6 046212 rings, in a more typical case 5-10 ring members. Examples of monocyclic groups are those containing 4-7 ring members, more typically 5 or 6 ring members. Examples of bicyclic groups are those containing 8-12, more typically 9 or 10 ring members.

Non-limiting examples of monocyclic heterocyclyl systems containing at least one heteroatom selected from nitrogen, oxygen or sulfur (N, O, S) include, but are not limited to, 4-7 membered heterocyclyl systems such as azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl , piperazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and tetrahydro-2H-thiopyranyl-1,1-dioxide, in particular azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, morpho linyl and thiomorpholinyl. Non-limiting examples of bicyclic heterocyclyl systems containing at least one heteroatom selected from nitrogen, oxygen or sulfur (N, O, S) include, but are not limited to, octahydro-N-indolyl, indolinyl, '.

Unless otherwise indicated, each may be linked to the rest of the molecule of formula (I) by any available ring carbon atom (bonded to C) or nitrogen atom (bonded to N), and optionally they may be substituted, if possible, atom-wise carbon and/or nitrogen according to embodiments.

The term C-linked 4-7 membered heterocyclyl containing at least one nitrogen, oxygen or sulfur atom, used herein alone or as part of another group, means a saturated cyclic hydrocarbon radical containing at least one nitrogen, oxygen atom or sulfur, which contains from 4 to 7 ring members, as defined above, linked through an accessible carbon atom. It will be appreciated that the analogous term C-linked 4 to 6 membered heterocyclyl containing an oxygen atom, as used herein alone or as part of another group, means a saturated cyclic hydrocarbon radical containing one oxygen atom that contains from 4 to 6 members rings as defined above, linked through an accessible carbon atom (such as, for example, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl).

In all cases where substituents are represented by a chemical structure, - means a bond for attachment to the remainder of the molecule of formula (I).

Lines (such as -) drawn to ring systems indicate that the bond can be attached to any of the suitable ring atoms.

Het ¹ and Het ² may be attached to the remainder of the molecule of formula (I) via any available carbon or nitrogen atom in the ring, as appropriate, unless otherwise indicated.

It will be appreciated that a saturated cyclic moiety may, if possible, contain substituents on both carbon and nitrogen atoms, unless otherwise indicated or clearly implied by the context.

If any variable occurs more than once in any component, then each is defined independently.

If any variable appears more than once in any formula (for example, formula (I)), then each is defined independently.

The term subject as used herein refers to an animal, preferably a mammal (eg, a cat, dog, primate or human), more preferably a human, that is or has been the subject of treatment, observation or experiment.

The term therapeutically effective amount as used herein means that amount of an active compound or pharmaceutical agent that produces a biological or medical response in a tissue system in an animal or human being sought by a researcher, veterinarian, physician, or other clinician that includes relief or relief symptoms of the disease or disorder being treated.

The term composition is intended to cover a product containing certain ingredients in certain amounts, as well as any product that is obtained, directly or indirectly, from combinations of certain ingredients in certain quantities.

The term treatment as used herein is intended to include all modalities that may involve slowing, disrupting, suppressing or stopping the progression of a disease, but does not necessarily mean complete elimination of all symptoms.

The terms compound(s) of the present invention or compound(s) of the invention as used herein are intended to include the compounds of formula (I) and their pharmaceutically acceptable salts and solvates.

Any chemical formula used herein in which the bonds are shown only as solid lines and not as solid wedges or dotted wedges, or

- 7046212 otherwise shown as having a particular configuration (eg, R, S) around one or more atoms, provides each possible stereoisomer or mixture of two or more stereoisomers.

As used herein and below, the term compound(s) of formula (I) is meant to include tautomers thereof and stereoisomeric forms thereof.

The terms stereoisomers, stereoisomeric forms, or stereochemically isomeric forms above or below are used interchangeably herein.

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

Enantiomers are stereoisomers that are non-matching mirror images of each other when superimposed. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture.

Atropisomers (or atropisomers) are stereoisomers that have a specific spatial configuration formed as a result of limited rotation around a single bond due to significant steric hindrance. All atropisomeric forms of the compounds of formula (I) are intended to be 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 the compound contains a double bond, the substituents may be in the E- or Z-configuration.

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

Thus, the present invention includes enantiomers, atropisomers, diastereomers, racemates, E-isomers, Z-isomers, cis-isomers, trans-isomers and mixtures thereof, where chemically possible.

The meanings of all these terms, i.e. enantiomers, atropisomers, diastereomers, racemates, Eisomers, Z-isomers, cis-isomers, trans-isomers and mixtures thereof are known to one skilled in the art.

The absolute configuration is determined in accordance with the Cahn-Ingold-Prelog system. The configuration at an asymmetric atom is defined as either R or S. Isolated stereoisomers, the absolute configuration of which is unknown, can be designated as (+) or (-) depending on the direction in which they rotate the plane of polarization of light. For example, isolated enantiomers whose absolute configuration is unknown may be designated as (+) or (-) depending on the direction in which they rotate the plane of polarization of light.

If a particular stereoisomer is identified, this means that the specified stereoisomer contains essentially no other stereoisomers, i.e. is 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 other stereoisomers. Thus, if a compound of formula (I), for example, is indicated as (R), this means that the compound contains substantially no (b) isomer; if a compound of formula (I), for example, is indicated as E, this means that the compound contains substantially no Z-isomer; if a compound of formula (I), for example, is indicated as cis, this means that the compound contains substantially no trans isomer.

Some compounds according to formula (I) may also exist in their tautomeric form. It is intended that such forms, since they may exist although not explicitly shown in formula (I) above, are included within the scope of the present invention. It follows that one compound can exist in both stereoisomeric and tautomeric forms.

Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts can be prepared by conventional methods, for example, by reacting the free acid form or free base with one or more equivalents of the corresponding base or acid, optionally in a solvent or medium in which the salt is insoluble, followed by removal of said solvent or medium using standard techniques (for example, in vacuo, freeze-drying or filtration). Salts can also be prepared by exchanging the counterion of a compound of the present invention in salt form with another counterion, for example using a suitable ion exchange resin.

The pharmaceutically acceptable salts mentioned above or below herein are intended to include the therapeutically active, non-toxic acid and base salt forms that the compounds of formula (I) and solvates thereof may form.

Suitable acids include, for example, inorganic acids such as hydrohalic acids, for example 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, ethane

- 8 046212 sulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and similar acids. Conversely, these salt forms can be converted by treatment with an appropriate base to the free base form.

The compounds of formula (I) and their solvates containing an acidic proton can also be converted into their non-toxic metal or amine salt forms by treatment with appropriate organic and inorganic bases.

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

The term solvate includes solvent addition forms, as well as their salts, which can form compounds of formula (I). Examples of such solvent addition forms are, for example, hydrates, alcoholates, and the like.

The compounds of the present invention obtained in the methods described below can be synthesized as mixtures of enantiomers, in particular racemic mixtures of enantiomers, which can be separated from each other following separation procedures known in the art. A method for separating the enantiomeric forms of compounds of formula (I) and their pharmaceutically acceptable salts and solvates involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms can also be prepared from the corresponding pure stereochemically isomeric forms of the corresponding starting materials, provided that the reaction proceeds stereospecifically. If a specific stereoisomer is desired, it is preferred that said compound be synthesized using stereospecific preparation methods. These methods will advantageously employ enantiomerically pure starting materials.

The present invention also covers isotopically labeled compounds of the present invention that are identical to those provided herein, except that one or more atoms are replaced by an atom with an atomic mass or mass number different from the atomic mass or mass number typically found in nature (or the most common found in nature).

All isotopes and isotopic mixtures of any particular atom or element, as defined herein, are considered within the scope of the compounds of the present invention, both naturally occurring and synthetically produced, both in naturally occurring isotopic composition and in isotopically enriched form. Exemplary isotopes that may be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as ^2H , ^3H , ^PS , ^13C , ^14C , ¹³ N, ¹⁵ O, ¹⁷ O ^{, 18} O, ³² P, ^{33 P, 35 S} , ¹⁸ F, ³⁶ Cl, 122 I, ¹²³ I, ¹²⁵ I, ¹³¹ I, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br and ⁸² Br . Preferably, the radioactive isotope is selected from the group consisting of ² H, ³ H, ¹¹ C and ¹⁸ F. More preferably, the radioactive isotope is ² H. In particular, deuterated compounds are intended to be included within the scope of the present invention.

Certain isotopically labeled compounds of the present invention (eg, ³ H and ¹⁴ C labeled) may be useful, for example, in substrate tissue distribution assays. The isotopes tritium ( ^3H ) and carbon-14 ( ^14C ) are useful because they are easy to obtain and can be detected. Additionally, substitution with heavier isotopes such as deuterium (i.e., ^2H ) may provide certain therapeutic benefits due to greater metabolic stability (e.g., increased in vivo half-life or decreased dose requirement) and may therefore be preferred in some cases. Thus, in a particular embodiment of the present invention, R ² is selected from hydrogen or deuterium, in particular deuterium. Positron-active isotopes such as ¹⁵ O, ¹³ N, ¹¹ C and ¹⁸ F are suitable for positron emission tomography (PET) studies. PET imaging in cancer finds utility in helping to localize and identify tumors, stage the disease, and determine appropriate treatment. Human cancer cells overexpress a variety of receptors or proteins that are potential molecular targets for a particular disease. Radiolabeled tags that bind with high affinity and specificity to such receptors or proteins on tumor cells have great potential for diagnostic imaging and targeted radionuclide therapy (Charron, Carlie L. et al. Tetrahedron Lett. 2016, 57(37), 4119-4127). Additionally, target-specific PET radiolabels can be used as biomarkers to study and evaluate pathology, for example by measuring target expression and response to treatment (Austin R. et al. Cancer Letters (2016), doi:10.1016/j.canlet .2016.05.008).

- 9 046212

In particular, the present invention relates to the compounds of formula (I) as defined herein, and to their tautomers and stereoisomeric forms, wherein

R ¹ is selected from the group consisting of CH3, CH2F, CHF2 and CF3;

R ² is selected from the group consisting of hydrogen and CH3;

Y ¹ is selected from the group consisting of hydrogen; C _1-6 alkyl; a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom, optionally substituted with a C-alkyl or cyclopropyl substituent; and C1. ₄ alkyl substituted with a substituent selected from the group consisting of fluorine, -CN, phenyl, -OR ^1Y and -NR ^2Y R ^2YY ;

wherein each of R ^1Y , R ^2Y and R ^2YY is independently selected from the group consisting of hydrogen and C^alkyl;

each of Y ² and Y3 is independently selected from the group consisting of hydrogen and C1. ₆ alkyl; And

--LR ³ selected from (a), (b), (c), (e) or (f):

(a) --LR ³ is -NHR ^1A , where R ^1A is selected from the group consisting of hydrogen; C _1-6 alkyl, optionally substituted with one, two or three substituents representing a fluorine atom; and C _2-6 alkyl substituted with a substituent selected from the group consisting of -OR ^1a and -NR ^2a R ^2aa , where each of R ^1a , R ^2a and R ^2aa is independently selected from the group consisting of hydrogen, C ^ alkyl and cyclopropyl; or (b) L is selected from the group consisting of -N(R ^B )-, -N(R ^b )-CR ^1b R ^1bb -u -(NR ^B )-CHR ^1B -CHR ^2B -; and R ³ is selected from the group consisting of Ar; Het ¹ and Het ² ; Where

R ^B is selected from the group consisting of hydrogen; C^alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, phenyl and -CN; and C _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^1b and -NR ^2b R ^2bb ; wherein each of R ^1b , R ^2b and R ^2bb is independently selected from the group consisting of hydrogen, C^alkyl and cyclopropyl;

R ^1B is selected from the group consisting of hydrogen; C^alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, phenyl, Het ¹ and -CN; and C ₂ . ₄ alkyl substituted with a substituent selected from the group consisting of -OR ^4B and -NR ^5B R ^5BB ; and R ^1BB is selected from the group consisting of hydrogen and methyl; or R ^1B and R ^1BB together with the carbon atom to which they are attached form a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen atom or oxygen atom;

R ^2B is selected from the group consisting of hydrogen and C^alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ^4B and -NR ^5B R ^5BB ; where each of R ^4B , R ^5B and r ^5bb is independently selected from the group consisting of hydrogen and C^alkyl; or (c) --LR ³ selected from the group consisting of -N(R ^c )-CHR ^1c -CO2R ^2C ; -N( ^RC )-CHR ^3C -CONR ^4C R ^4CC ; -N(R ^C )-COR ^5C ; -N(R ^c )-SO2-NR ^6C R ^6CC ; Where

RC is selected from the group consisting of hydrogen; C1. ₄ alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, phenyl and -CN; and C ₂ . ₄ alkyl substituted with a substituent selected from the group consisting of -OR ^1c and -NR ^2c R ^2cc ;

R ^1C and R ^3C are each selected from the group consisting of hydrogen; C1.4alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, phenyl, Het ¹ and -CN; and C2. ₄ alkyl substituted with a substituent selected from the group consisting of -OR ^4c and -NR ^5c R ^5cc ;

R4C and R6C are each selected from the group consisting of hydrogen and C1. ₄ alkyl, optionally substituted with a substituent selected from the group consisting of NR ^6c R ^6cc , Ar and Het ¹ ;

R2C is selected from the group consisting of hydrogen; C1. ₄ alkyl, optionally substituted with Ar or Het ¹ ; Ar; Het ¹ and Het ² ;

R ^5C is selected from the group consisting of hydrogen; C1. ₄ alkyl, optionally substituted -NR ^2c R ^2cc , Ar or Het ¹ ; Ar; Het ¹ and Het ² ; wherein each of R ^1c , R ^2c , R ^2cc , R ^4c , R ^5c and R ^5cc is independently selected from the group consisting of hydrogen and C1. ₄ alkyl; and each of R ^6c and R ^6cc is independently selected from the group consisting of hydrogen and C1. ₄ alkyl, optionally substituted with a substituent selected from the group consisting of -KI _Cl . ₄ alkyl and cyclopropyl;

R ^4CC and R ^6CC are each independently selected from the group consisting of hydrogen; C1. ₄ alkyl, optionally substituted with Ar or Het ¹ ; Ar; Het ¹ and Het ² ; or R4C and ^R4CC or ^R6C and ^R6CC together with the nitrogen atom to which they are attached form an N-linked Het ² ; or (e) --LR ³ represents

Where

RE is selected from the group consisting of hydrogen and C1. ₄ alkyl;

R ^1E is selected from the group consisting of hydrogen, fluorine and C1. ₄ alkyl; And

R ^2E is selected from the group consisting of fluorine, ^C^alkyl and Cl. ₄ alkyls, optionally substituted

- 10 046212

1, 2 or 3 substituents representing a fluorine atom; or R ^1E and R ^2E are linked to the same carbon atom and together form a C _3-5 cycloalkyl or a C 4-6 membered heterocyclyl containing an oxygen atom; And

R ^3E is selected from the group consisting of hydrogen; C _1-4 alkyl, optionally substituted with a substituent representing a fluorine atom or -CN; and C _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^4E and -NR ^5E R ^5EE ; wherein each of R ^4E , R ^5E and R ^5EE is independently selected from the group consisting of hydrogen; C1-4alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN and -C(=O)NR ^6E R ^6EE ; C2-4alkyl substituted with a substituent selected from the group consisting of -OR ^7E and -NR ^8E R ^8EE ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; wherein each of R ^6E , R ^6EE , R ^7E , R ^8E and R ^8EE is independently selected from the group consisting of hydrogen and C _1-4 alkyl; or (f) --LR ³ is a radical selected from the group consisting of

where R ^1f is selected from the group consisting of hydrogen, C _1-4 alkyl and -Omalkyl-MK^; and each of R ^2F and R ^3F is independently selected from hydrogen and C1-4alkyl, in particular hydrogen; wherein each of ^Rf and ^Rff is independently selected from the group consisting of hydrogen and C1-4alkyl;

and where

Ar is phenyl, optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -CN, -OR ⁴ , -NR5R ⁵ , -C(=O)NR ⁵ R ⁵ and C _{1 -4} alkyl;

Het ¹ is a monocyclic heteroaryl selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl and 4- or 5-thiazolyl; each of which may be optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen and C _1-4 alkyl, optionally substituted by a substituent selected from the group consisting of fluorine, -CN, -OR ⁶ , -NR ⁷ R ⁷ and C(=O)NR ⁸ R ⁸ '; And

Het ² is a non-aromatic heterocyclyl selected from azetidinyl, pyrrolidinyl and piperidinyl, each of which may be optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -CN, -OR ⁴ , -NR5R ⁵ and C _1-4 alkyl; wherein each of R ⁴ , R ⁵ , R ⁵ , R ⁶ , R ⁷ , R ⁷ , R ⁸ and R ⁸ is independently selected from the group consisting of hydrogen and C _1-4 alkyl;

and their pharmaceutically acceptable salts and solvates.

In particular, the present invention relates to the compounds of formula (I) as defined herein, and to their tautomers and stereoisomeric forms, wherein

R ¹ is selected from the group consisting of CH ₃ , CH2F, CHF2 and CF ₃ ;

R ² is selected from the group consisting of hydrogen and CH3;

Y ¹ is selected from the group consisting of hydrogen; C _1-6 alkyl; a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom, optionally substituted with a C _1-4 alkyl or cyclopropyl substituent; and C _1-4 alkyl substituted with a substituent selected from the group consisting of fluorine, -CN, phenyl, -OR ^1Y and -NR ^2Y R ^2YY ;

where R ^1Y is selected from the group consisting of hydrogen; C _1-4 alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN and

-C(=O)NR ^1y R ^2y ; With _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^3y and -NR ^1y R ^2y ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;

each of R ^2Y and R ^2YY is independently selected from the group consisting of hydrogen; C _1-4 alkyl, optionally substituted with a substituent representing -C(=O)NR ^1y R ^2y ;

With _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^3y and -NR ^1y R ^2y ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;

each of Y ² and Y ³ is independently selected from the group consisting of hydrogen; HE; NH2; -C(=O)NR ^1y R ^2y ; C1-6alkyl and C1-4alkyl substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ^3Y and -NR ^4Y R ^4YY ; provided that if both Y ² and Y ³ are substituents on the same carbon atom and one of Y ² or Y ³ is OH or NH2, then the other Y ³ or Y ² is H, C1-6alkyl , C _1-4 alkyl substituted with a substituent selected from the group consisting of fluorine and

- 11 046212

-CN, or C _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^3Y and -NR ^4Y R ^4YY ;

where R ^3Y is selected from the group consisting of hydrogen; C1-4alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN and -C(=O)NR ^ly R.5 ^y ; C2-4alkyl substituted with a substituent selected from the group consisting of -OR ^6y and -NR ^4y R ^5y ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;

each of R ^4Y and R ^4YY is independently selected from the group consisting of hydrogen; C1-4alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN and -C(=O)NR ^1y R ^2y ; C24alkyl substituted with a substituent selected from the group consisting of -OR ^6y and -NR ^4y R ^5y ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; wherein each of R ^1y , R ^2y , R ^3y , R ^4y , R ^5y and R ^6y is independently selected from the group consisting of hydrogen; C14alkyl and C-linked 4-7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; And

--LR ³ selected from (a), (b), (c), (d) or (e):

(a) --LR ³ is -NHR ^1A , where R ^1A is selected from the group consisting of hydrogen; C1-6alkyl, optionally substituted with one, two or three substituents representing a fluorine atom; and C2-6alkyl substituted with a substituent selected from the group consisting of -OR ^1a and -NR ^2a R ^2aa , wherein each of R ^1a , R ^2a and R ^2aa is independently selected from the group consisting of hydrogen, C1-4alkyl and cyclopropyl; with the proviso that if R ^1A is hydrogen, then Y ¹ is not hydrogen; or (b) L is selected from the group consisting of -N(R ^B )-, -N(R ^B )-CR ^1B R ^1BB - and -(NR ^B )-CHR ^1B -CHR ^2B -; And

R ³ is selected from the group consisting of Ar; Het ¹ ; Het ² and 7-10-membered saturated spirocarbobicyclic system; Where

R ^B is selected from the group consisting of hydrogen; C _1-4 alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, phenyl and -CN; and C _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^1b and -NR ^2b R ^2bb ; wherein each of R ^1b , R ^2b and R ^2bb is independently selected from the group consisting of hydrogen, C _1-4 alkyl and cyclopropyl;

R ^1B is selected from the group consisting of hydrogen; -C(=O)NR ^3B R ^3BB ;

C _1-4 alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, phenyl, Het ¹ and -CN; With _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^4B and -NR ^5B R ^5BB ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; And

R ^1BB is selected from the group consisting of hydrogen and methyl; or

R ^1B and R ^1BB together with the carbon atom to which they are attached form a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;

R ^2B is selected from the group consisting of hydrogen; -OR ^6B ; -NR ^7B R ^7BB ; -C(=O)NR ^8B R ^8BB ; C _1-4 alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ^4B and -NR ^5B R ^5BB ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; wherein each of R ^3B , R ^3BB , R ^4B , R ^5B , R ^5BB , R6B, R ^7B , R ^7BB , R ^8B and R ^8BB is independently selected from the group consisting of hydrogen; C1-4alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN and -C(=O)NR ^9B R ^9BB ; and C2-4alkyl substituted with a substituent selected from the group consisting of -OR ^10B and -NR ^11B R ^11BB ; wherein each of R ^9B , R ^9BB , R ^10B , R ^11b and R ^11BB is independently selected from the group consisting of hydrogen; C _1-4 alkyl and C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; or (c) --LR ³ selected from the group consisting of -N(R ^c )-CHR ^1c -CO2R ^2C ; -N( ^RC )-CHR ^3C -CONR ^4C R ^4CC ; -N(R ^C )-COR ^5C ; - ( ^RC )-SO2-NR ^6C R ^6CC ; Where

R ^c is selected from the group consisting of hydrogen; C _1-4 alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, phenyl and -CN; and C _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^1c and -NR ^2c R ^2cc ;

R ^1c and R ^3C are each selected from the group consisting of hydrogen;

-C(=O)NR ^3c R ^3cc ; C1-4alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, phenyl, Het ¹ and -CN; C2-4alkyl substituted with a substituent selected from the group consisting of -OR ^4c and -NR ^5c R ^5cc ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;

R ^4C and R ^6C are each selected from the group consisting of hydrogen and C _1-4 alkyl, optionally substituted by a substituent selected from the group consisting of NR ^6c R ^6cc , Ar and Het ¹ ;

R2C is selected from the group consisting of hydrogen; C _1-4 alkyl, optionally substituted with Ar or Het ¹ ;

- 12 046212

Ar; Het ¹ ; Het ² and 7-10-membered saturated spirocarbobicyclic system;

R ^5C is selected from the group consisting of hydrogen; O^alkyl, optionally substituted -NR ^2c R ^2cc , Ar or Het ¹ ; Ar; Het ¹ ; Het ² and 7-10-membered saturated spirocarbobicyclic system; wherein each of R ^1c , R ^2c , R ^2cc , R ^3c , R ^3cc , R ^4c , R ^5c and R ^5cc is independently selected from the group consisting of hydrogen and C1. ₄ alkyl; and each of R ^6c and R ^6cc is independently selected from the group consisting of hydrogen and C1. ₄ alkyl, optionally substituted with a substituent selected from the group consisting of -CIS-alkyl and cyclopropyl;

and each of R ^4CC and R ^6CC is independently selected from the group consisting of hydrogen; C1. ₄ alkyl, optionally substituted with Ar or Het ¹ ; Ar; Het ¹ ; Het ² and 7-10-membered saturated spirocarbobicyclic system; or R ^4C and R ^4CC or R ^6C and R ^6CC together with the nitrogen atom to which they are attached form an N-linked Het ² ; or (d) L is selected from -N(R ^d ) -CR ^1D R ^1DD - and -N(R ^D )-CR ^1D R ^1DD -CR ^2D R ^2DD -; Where

R ^d is selected from the group consisting of hydrogen; ^^alkyl, optionally substituted with a substituent selected from the group consisting of fluorine and -CN; and C ₂ . ₄ alkyl substituted with a substituent selected from -OR ^1d and -NR ^2d R ^2dd ; wherein each of R ^1d , R ^2d and R ^2dd is independently selected from the group consisting of hydrogen and ^^alkyl;

each of R ^1D , R ^1DD , R ^2D and R ^2DD is independently selected from the group consisting of hydrogen and ^^alkyl;

R' ¹⁰ r'° and R ³ is selected from the group consisting of and H, wherein each of R ^3D , R ^4D and R ^5D is independently selected from the group consisting of C _1-6 alkyl, optionally substituted by a substituent representing -OH , -O^^alkyl or -NH2; or

(e) --LR ³ represents ' ^where

R ^e is selected from the group consisting of hydrogen and ^^alkyl;

R ^1E is selected from the group consisting of hydrogen, fluorine and ^^alkyl; And

R ^2E is selected from the group consisting of fluorine, -O^^alkyl and ^^alkyl, optionally substituted with 1, 2 or 3 substituents representing a fluorine atom; or

R ^1E and R ^2E are bonded to the same carbon atom and together form an O^cycloalkyl or a C-linked 4-6-membered heterocyclyl containing an oxygen atom; And

R ^3E is selected from the group consisting of hydrogen; ^^alkyl, optionally substituted with a substituent representing a fluorine atom or -CN; and C ₂ . ₄ alkyl substituted with a substituent selected from the group consisting of -OR ^4E and -NR ^5E R ^5EE ; wherein each of R ^4E , R ^5E and R ^5EE is independently selected from the group consisting of hydrogen; ^^alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN and -C(=O)NR ^6E R ^6EE ; C ₂ . ₄ alkyl substituted with a substituent selected from the group consisting of -OR ^7E and -NR ^8E R ^8EE ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; wherein each of R ^6E , R ^6EE , R ^7E , R ^8E and R ^8EE is independently selected from the group consisting of hydrogen and ^^alkyl;

and where Ar is phenyl, optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -CN, -OR ⁴ , -NR5R ⁵ , -C(=O)NR ⁵ R ⁵ and ^^alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ⁶ , -NR7R ⁷ ' and -C (=O)NR ⁸ R ⁸ ';

Het ¹ is a monocyclic heteroaryl selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 4- or 5-thiazolyl, isothiazolyl and isoxazolyl; each of which may be optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -CN, -OR ⁴ , -NR5R ⁵ and ^^alkyl, optionally substituted with a substituent selected from the group consisting of from fluorine, -CN, -OR ⁶ , -NR ⁷ R ^7' and -C (=O)NR ⁸ R ^8' ; And

Het ² is a non-aromatic heterocyclyl, optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, CN, -OR ⁴ , -NR5R ⁵ and ^^alkyl, optionally substituted with a substituent selected from the group, consisting of fluorine, -CN, -OR ⁶ , -NR7R ⁷ and -C(=O)NR ⁸ R ⁸ ;

wherein each of R ⁴ , R ⁵ , R ^5' , R ⁶ , R ⁷ , R ^7' , R ⁸ and R ⁸ is independently selected from the group consisting of hydrogen;

^^alkyl, optionally substituted with a substituent selected from the group consisting of fluorine and

- 13 046212

-C(=O)NR ⁹ R ⁹ ; and C ₂ . ₄ alkyl substituted with a substituent selected from the group consisting of -OR ¹⁰ and -NR ¹¹ R ¹¹ '; wherein each of R ⁹ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹¹ is independently selected from the group consisting of hydrogen; C1. ₄ alkyl and C-linked 4-7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;

and their pharmaceutically acceptable salts and solvates.

In particular, the present invention relates to the compounds of formula (I) as defined herein, and to their tautomers and stereoisomeric forms, wherein

R ¹ represents CF ₃ ;

R ² represents hydrogen;

Y ¹ represents hydrogen;

each of Y ² and Y ³ is independently selected from the group consisting of hydrogen and C1. ₆ alkyl;

--LR ³ selected from (a), (b), (c), (e) or (f):

(a) --LR ³ is -NHR ^1A , wherein R ^1A is selected from the group consisting of C1-6 alkyl optionally substituted with one, two or three fluorine substituents; and C2.6 alkyl substituted with a substituent selected from the group consisting of -OR ^1a and -NR ^2a R ^2aa , wherein each of R ^1a , R ^2a and R ^2aa is independently selected from the group consisting of hydrogen and C1.4 alkyl; or (b) L is selected from the group consisting of -O-, -O-CR ^1B R ^1BB -, -N(R ^B )- and -N( ^RB )-CR ^1B R ^1BB -; and R ³ is selected from the group consisting of Ar; Het ¹ and Het ² ; Where

R ^B is selected from the group consisting of hydrogen; C _1-4 alkyl, optionally substituted with phenyl; and C ₂ . ₄ alkyl substituted with a substituent selected from the group consisting of -OR ^1b and -NR ^2b R ^2bb ; wherein R ^1b , R ^2b and R ^2bb are each independently selected from the group consisting of hydrogen and C1. ₄ alkyl;

R ^1B is selected from the group consisting of hydrogen and C _1-4 alkyl; And

R ^1BB represents hydrogen; or (c) --LR ³ selected from the group consisting of -N(RC)-CHR ^3C -CONR ^4C R ^4CC and -N(R ^c )-COR ^5C ; Where

RC represents hydrogen;

R ^3C represents C _1-4 alkyl;

R ^4C represents hydrogen;

R5C is Het ² ; And

R ^4CC represents C _1-4 alkyl; or

(e) --LR ³ represents

R ^e represents hydrogen;

R ^1E and R ^2E are bonded to the same carbon atom and together form C _{3.5cycloalkyl} ; And

R ^3E represents hydrogen; or

(f) --LR ³ is a radical selected from the group consisting of and wherein Ar is phenyl, optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OR ⁴ , - C(=O)NR5R ⁵ and C^alkyl, optionally substituted with a substituent selected from the group consisting of -OR ⁶ and -NR7R ⁷ ';

Het ¹ is a monocyclic heteroaryl selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, pyridazinyl and pyrazolyl; each of which may be optionally substituted with one, two or three substituents, each independently selected from C1. ₄ alkyl, optionally substituted with a substituent of -OR ⁶ ; And

Het ² is a non-aromatic heterocyclyl, optionally substituted with one, two or three C^alkyl substituents; wherein each of R ⁴ , R ⁵ , R ⁵ , R ⁶ , R ⁷ and R ^7' is independently selected from the group consisting of hydrogen and C _1-4 alkyl;

and their pharmaceutically acceptable salts and solvates.

In particular, the present invention relates to the compounds of formula (I) as defined herein, and to their tautomers and stereoisomeric forms, wherein

R ¹ represents CF ₃ ;

R ² represents hydrogen;

Y ¹ represents hydrogen;

each of Y ² and Y ³ is independently selected from the group consisting of hydrogen and C1. ₆ alkyl;

--LR ³ selected from (a), (b), (c), (e) or (f):

- 14 046212 (a) --LR ³ represents -NHR ^1A , where R ^1A is selected from the group consisting of C1.6alkyl, optionally substituted with one, two or three substituents representing a fluorine atom; and C26alkyl substituted with a substituent selected from the group consisting of -OR ^1a and -NR ^2a R ^2aa , wherein each of R ^1a , R ^2a and R ^2aa is independently selected from the group consisting of hydrogen and C1. ₄ alkyl; or (b) L is selected from the group consisting of -N(R ^B )- and -N(R ^B )-CR ^1B R ^1BB -;

and R ³ is selected from the group consisting of Ar; Het ¹ and Het ² ; Where

R ^B is selected from the group consisting of hydrogen; C ₁ . ₄ alkyl, optionally substituted with phenyl; and C ₂ . ₄ alkyl substituted with a substituent selected from the group consisting of -OR ^1b and -NR ^2b R ^2bb ; wherein each of R ^1b , R ^2b and R ^2bb is independently selected from the group consisting of hydrogen and C ₁ . ₄ alkyl;

R ^1B is selected from the group consisting of hydrogen and C ₁ . ₄ alkyl; And

R ^1BB represents hydrogen; or (c) --LR ³ selected from the group consisting of -N( ^RC )-CHR ^3C -CONR ^4C R ^4C c and -N(RC)-COR ^5C ; Where

RC represents hydrogen;

R ^3C represents C _1-4 alkyl;

R ^4C represents hydrogen;

R5C is Het ² ; And

R ^4CC represents C _1-4 alkyl; or

(e) --LR ³ represents

R ^e represents hydrogen;

R ^1E and R ^2E are bonded to the same carbon atom and together form C _{3.5cycloalkyl} ; And

R ^3E represents hydrogen; and where

Ar is phenyl, optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OR ⁴ , -C(=O)NR5R ⁵ and C ₁ . ₄ alkyl, optionally substituted with a substituent selected from the group consisting of -OR ⁶ and -NR7R ⁷ ';

Het ¹ is a monocyclic heteroaryl selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, pyridazinyl and pyrazolyl; each of which may be optionally substituted with one, two or three substituents, each independently selected from C ₁ . ₄ alkyl, optionally substituted with a substituent of -OR ⁶ ; And

Het ² is a non-aromatic heterocyclyl, optionally substituted with one, two or three C ₁ substituents. ₄ alkyl; wherein each of R ⁴ , R ⁵ , R ^5' , R ⁶ , R ⁷ and R ^7' is independently selected from the group consisting of hydrogen and C ₁ . ₄ alkyl;

and their pharmaceutically acceptable salts and solvates.

In particular, the present invention relates to the compounds of formula (I) as defined herein, and to their tautomers and stereoisomeric forms, wherein

R ¹ represents CF ₃ ;

R ² represents hydrogen;

Y ¹ represents hydrogen;

Y ² and Y ³ represent hydrogen;

--LR ³ selected from (a) or (b):

(a) --LR ³ is -NHR ^1A where R ^1A is C ₁ . ₆ alkyl; or (b) L is -N( ^RB )-CR ^1B R ^1BB -;

and R ³ is selected from the group consisting of Ar; Het ¹ and Het ² ; Where

R ^B represents hydrogen;

R ^1B is selected from the group consisting of hydrogen and C ₁ . ₄ alkyl; And

R ^1BB represents hydrogen; and where

Ar represents phenyl, optionally substituted with one C ₁ . ₄ alkyl;

Het ¹ is pyrazolyl; And

Het ² is a non-aromatic heterocyclyl; in particular 3-azetidinyl;

and their pharmaceutically acceptable salts and solvates.

In particular, the present invention relates to the compounds of formula (I) as defined herein, and to their tautomers and stereoisomeric forms, wherein

R ¹ is selected from the group consisting of CH ₃ , CH ₂ F , CHF 2 and CF ₃ ;

R ² is selected from the group consisting of hydrogen and CH ₃ ;

Y ¹ is selected from the group consisting of hydrogen; C ₁ . ₆ alkyl; C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen atom, optionally substituted by

- 15 046212 a substituent representing C _1-4 alkyl or cyclopropyl; and C _1-4 alkyl substituted with a substituent selected from the group consisting of phenyl, -OR1Y and -NR ^2Y R ^2YY ; wherein each of R ^1Y , R ^2Y and R ^2YY is independently selected from the group consisting of hydrogen and C _1-4 alkyl;

Y ² and Y ³ represent hydrogen; And

--LR ³ selected from (a), (b), (c), (e) or (f):

(a) --LR ³ is -NHR ^1A , where R ^1A is selected from the group consisting of hydrogen; C1.6alkyl, optionally substituted with one, two or three substituents representing a fluorine atom; and C2.6alkyl substituted with a substituent selected from the group consisting of -OR ^1a and -NR ^2a R ^2aa , wherein each of R ^1a , R ^2a and R ^2aa is independently selected from the group consisting of hydrogen, C1. ₄ alkyl and cyclopropyl; or (b) L is selected from the group consisting of -N(R ^B )-, -N(R ^B ) -CR ^1B R ^1BB - and -(NR ^B )-CHR ^1B -CHR ^2B -; and R ³ is selected from the group consisting of Ar; Het ¹ and Het ² ; Where

R ^B is selected from the group consisting of hydrogen; C ₁ . ₄ alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, phenyl and -CN; and C _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^1b and -NR ^2b R ^2bb ; wherein each of R ^1b , R ^2b and R ^2bb is independently selected from the group consisting of hydrogen, C ₁ . ₄ alkyl and cyclopropyl;

R ^1B is selected from the group consisting of hydrogen; C1.4alkyl, optionally substituted with a phenyl or Het ¹ substituent; and C2. ₄ alkyl substituted with a substituent selected from the group consisting of -OH and -NH ₂ ; And

R ^1BB represents hydrogen; or R ^1B and R ^1BB together with the carbon atom to which they are attached form an oxetanyl ring; And

R ^2B represents hydrogen; or (c) --LR ³ selected from the group consisting of -N(R ^C ) -CHR ^3C -CONR ^4C R ^4C c; -N(R ^c )-COR ^5C ; -N(R ^c )-SO ₂ NR ^6C R ^6CC ; Where

R ^C is selected from the group consisting of hydrogen and C1. ₄ alkyl, optionally substituted with a phenyl substituent;

R ^3C represents hydrogen or C _1-4 alkyl;

R4C and R6C are each selected from the group consisting of hydrogen and C ₁ . ₄ alkyl;

R ^5C represents C ₁ . ₄ alkyl, optionally substituted -NR ^2c R ^2cc ; wherein each of R ^2c and R ^2cc is independently selected from the group consisting of hydrogen and C ₁ . ₄ alkyl; and each of R4CC and ^R6CC is independently selected from the group consisting of hydrogen and _C1 . ₄ alkyl; or R4C and R4CC or R6C and ^R6CC together with the nitrogen atom to which they are attached form an N-linked Het ² ; or |^' ^e ____

1G ^E LL\ θ

[N eL- (e) --LR ³ represents , where

R ^e is selected from the group consisting of hydrogen and C1. ₄ alkyl;

R ^1E is selected from the group consisting of hydrogen, fluorine and C1. ₄ alkyl; And

R ^2E is selected from the group consisting of fluorine, -OC1. ₄ alkyl and C1. ₄ alkyls, optionally substituted

1, 2 or 3 substituents representing a fluorine atom; or

R ^1E and R ^2E are bonded to the same carbon atom and together form a C _3-5 cycloalkyl; And

R ^3E is selected from the group consisting of hydrogen and C1. ₄ alkyl; or (f) --LR ³ is a radical selected from the group consisting of

where R ^1F represents hydrogen or C1. ₄ alkyl; and where

Ar is phenyl, optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -C(=O)NR ⁵ R ⁵ and C1.4alkyl; wherein each of R ⁵ and R ⁵ is independently selected from the group consisting of hydrogen and C1. ₄ alkyl;

Het ¹ is a monocyclic heteroaryl selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl and imidazolyl; each of which may be optionally substituted with one, two or three substituents, each of which is independently selected from the group consisting of halogen and C1.4alkyl; And

Het ² is a non-aromatic heterocyclyl selected from azetidinyl, pyrrolidinyl and piperidinyl, each of which may be optionally substituted with one, two or three

- 16 046212 substituents, each of which is independently selected from the group consisting of halogen and C1. ₄ alkyl;

and their pharmaceutically acceptable salts and solvates.

In particular, the present invention relates to the compounds of formula (I) as defined herein, and to their tautomers and stereoisomeric forms, wherein

R ¹ represents CF3;

R ² represents hydrogen;

Y ¹ is selected from the group consisting of hydrogen; C _1-6 alkyl; a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen atom, optionally substituted with a C1 substituent. ₄ alkyl; and C1. ₄ alkyl substituted with a substituent selected from the group consisting of phenyl, -OH and -OC1. ₄ alkyl;

Y ² and Y ³ represent hydrogen; And

- -L-R3 selected from (a), (b), (c), (e) or (f):

(a) --L-R3 is -NHR1A, wherein R ^1A is selected from the group consisting of hydrogen; C1-6alkyl, optionally substituted with one, two or three substituents representing a fluorine atom; and C2.6alkyl substituted with a substituent selected from the group consisting of -OR ^1a and -NR ^2a R ^2aa , wherein each of R ^1a , R ^2a and R ^2aa is independently selected from the group consisting of hydrogen, C1.4alkyl and cyclopropyl; or (b) L is selected from the group consisting of -N(R ^B )- and -N(R ^B )-CR ^1B R ^1BB -; And

R3 is selected from the group consisting of Ar; Het ¹ and Het ² ; Where

R ^B is selected from the group consisting of hydrogen; C1. ₄ alkyl, optionally substituted with a substituent of phenyl or -CN; and C _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^1b and -NR ^2b R ^2bb ; wherein R ^1b , R ^2b and R ^2bb are each independently selected from the group consisting of hydrogen and C1. ₄ alkyl;

R ^1B is selected from the group consisting of hydrogen; C1.4alkyl, optionally substituted with a phenyl or Het ¹ substituent; and C2. ₄ alkyl substituted with -OH; And

R ^1BB represents hydrogen; or

R ^1B and R ^1BB , together with the carbon atom to which they are attached, form an oxetanyl ring; or (c) --L-R3 is selected from the group consisting of -N(R ^C ) -CHR ^3C -CONR ^4C R ^4C c; -N(R ^c )-COR ^5C and -N(R ^C )-SO ₂ NR ^6C R ^6CC ; Where

R ^C is selected from the group consisting of hydrogen and C1. ₄ alkyl, optionally substituted with a phenyl substituent;

^R3C , R4C and R6C are each selected from the group consisting of hydrogen and C1. ₄ alkyl;

R5C is C1. ₄ alkyl, optionally substituted -NR ^2c R ^2cc ; wherein each of R ^2c and R ^2cc is independently selected from the group consisting of hydrogen and C1. ₄ alkyl; and each of R4CC and ^R6CC is independently selected from the group consisting of hydrogen and C1. ₄ alkyl; or

Ν' ₃ (AND E ^Ν (e) --LR ³ represents ' ^where

RE is selected from the group consisting of hydrogen and methyl;

each of R ^1e and R ^2E represents an independently selected substituent representing C1. ₄ alkyl; or

R ^1E and R ^2E are bonded to the same carbon atom and together form C ₃ . ₅ cycloalkyl; And

R ^3E represents hydrogen; or

Ν' [ί (f) --LR ³ represents ' and where

Ar is phenyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, -C(=O)NR ⁵ R ⁵ and C1.4alkyl; wherein each of R ⁵ and R ⁵ is independently selected from the group consisting of hydrogen and C1.4alkyl;

Het ¹ is a monocyclic heteroaryl selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl and imidazolyl; each of which may be optionally substituted with one or two substituents, each of which is independently selected from the group consisting of halogen and C1. ₄ alkyl; And

Het ² is a non-aromatic heterocyclyl selected from azetidinyl, pyrrolidinyl and piperidinyl, each of which may be optionally substituted with a C1 substituent. ₄ alkyl;

and their pharmaceutically acceptable salts and solvates.

- 17 046212

In particular, the present invention relates to the compounds of formula (I) as defined herein, and to their tautomers and stereoisomeric forms, wherein

R ¹ represents CF3;

R ² represents hydrogen;

Y ¹ , Y ² and Y3 represent hydrogen; And

--LR ³ selected from (a), (b), (c), (e) or (f):

(a) --LR ³ is -NHR ^1A , wherein R ^1A is selected from the group consisting of C _1-6 alkyl optionally substituted with one, two or three fluorine substituents; and C _2-6 alkyl substituted with a substituent selected from the group consisting of -OR ^1a and -NR ^2a R ^2aa ; wherein each of R ^1a , R ^2a and R ^2aa is independently selected from the group consisting of hydrogen, C^alkyl and cyclopropyl; or (b) L is -N(R ^B )-CR ^1B R ^1BB -, and R ³ is selected from the group consisting of Ar and Het ¹ ; Where

R ^B is selected from the group consisting of hydrogen; C^alkyl, optionally substituted with a substituent representing phenyl or -CN; and C ₂ . ₄ alkyl substituted with a substituent selected from the group consisting of -OR ^1b and -NR ^2b R ^2bb ; wherein each of R ^1b , R ^2b and R ^2bb is independently selected from the group consisting of hydrogen and C ₁ . ₄ αlkyl;

R ^1B is selected from the group consisting of hydrogen; C^alkyl, optionally substituted with a substituent representing Het ¹ ; and C ₂ . ₄ alkyl substituted with -OH; and R ^1BB is hydrogen; or R ^1B and R ^1BB together with the carbon atom to which they are attached form an oxetanyl ring; or (c) --LR ³ selected from the group consisting of -N(R ^C ) -CHR ^3C -CONR ^4C R ^4CC ; -N(R ^c )-COR ^5C and -N(R ^C )-SO2-NR ^6C R ^6CC ; Where

R ^C is selected from the group consisting of hydrogen and C _1-4 alkyl, optionally substituted with a phenyl substituent;

each of R ^3C , R ^4C and R ^6C is selected from the group consisting of hydrogen and C _1-4 alkyl;

R ^5C is C _1-4 alkyl, optionally substituted with -NR ^2c R ^2cc ; wherein each of R ^2c and R ^2cc is independently selected from the group consisting of hydrogen and C _1-4 alkyl; and each of R ^4CC and R ^6CC is independently selected from the group consisting of hydrogen and C _1-4 alkyl; or ι E and

ABOUT

D-E-E ^N (e) --LR ³ represents , where

RE is selected from the group consisting of hydrogen and methyl;

R ^1E and R ^2E each represent an independently selected C _1-4 alkyl substituent; or R ^1E and R ^2E are bonded to the same carbon atom and together form

C _3-5 cycloalkyl; And

R ^3E represents hydrogen; or

OS (f) --LR ³ represents ^; and where

Ar is phenyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, -C(=O)NR ⁵ R ⁵ and C _1-4 alkyl; wherein each of R ⁵ and R ⁵ is independently selected from the group consisting of hydrogen and C _1-4 alkyl; And

Het ¹ is a monocyclic heteroaryl selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl and imidazolyl; each of which may be optionally substituted with one or two substituents, each of which is independently selected from the group consisting of halogen and C _1-4 alkyl;

and their pharmaceutically acceptable salts and solvates.

Another embodiment of the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable salts and solvates or any subgroup thereof specified in any of the other embodiments, wherein

R ¹ represents CF ₃ ;

R ² represents hydrogen;

Y ¹ represents hydrogen;

each of Y ² and Y ³ is independently selected from the group consisting of hydrogen and C _1-6 alkyl.

In one embodiment, the present invention relates to such compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof specified in any of the other embodiments, wherein

--LR ³ selected from (a), (b), (c), (d) or (e).

In one embodiment, the present invention provides such compounds of formula

- 18 046212 (I) and their pharmaceutically acceptable salts and solvates or any subgroup thereof specified in any of the other embodiments, where --LR ³ represents (a).

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable salts and solvates or any subgroup thereof specified in any of the other embodiments, wherein --LR ³ represents (b).

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable salts and solvates or any subgroup thereof specified in any of the other embodiments, wherein --LR ³ represents (c).

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable salts and solvates or any subgroup thereof specified in any of the other embodiments, wherein --LR ³ represents (d).

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable salts and solvates or any subgroup thereof specified in any of the other embodiments, wherein --LR ³ represents (e).

In one embodiment, the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable salts and solvates or any subgroup thereof specified in any of the other embodiments, wherein --LR ³ represents (f).

In one embodiment, the present invention relates to such compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof specified in any of the other embodiments, wherein

--LR ³ selected from (a), (b), (c), (d) or (e); where (a), (c), (d) and (e) are defined in accordance with any of the other embodiments; and where (b) is defined as (b) L is selected from the group consisting of -N(R ^B )-, -N(R ^B )-CR ^1B R ^1BB - and -(NR ^B )-CHR ^1B -CHR ^2B - ; and R ³ is selected from the group consisting of Ar; Het ¹ ; Het ² and 7-10-membered saturated spirocarbobicyclic system; Where

R ^B is selected from the group consisting of hydrogen; and _-4 alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, phenyl and -CN; and C _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^1b and -NR ^2b R ^2bb ; wherein each of R ^1b , R ^2b and R ^2bb is independently selected from the group consisting of hydrogen, ^^alkyl and cyclopropyl;

R ^1B is selected from the group consisting of hydrogen; -C(=O)NR ^3B R ^3BB ;

u^alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, phenyl, Het ¹ and -CN; C2-4alkyl substituted with a substituent selected from the group consisting of -OR ^4B and -NR ^5B R ^5BB ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; and R ^1BB is selected from the group consisting of hydrogen and methyl; or R ^1B and R ^1BB together with the carbon atom to which they are attached form a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;

R ^2B is selected from the group consisting of hydrogen; -OR ^6B ; -NR ^7B R ^7BB ; -C(=O)NR ^8B R ^8BB ; C _1-4 alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ^4B and -NR ^5B R ^5BB ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; wherein each of R ^3B , R ^3BB , R ^4B , R ^5B , R ^5BB , R6B, R ^7B , R ^7BB , R ^8B and R ^8BB is independently selected from the group consisting of hydrogen; and ^alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN and -C(=O)NR ^9B R ^9BB ; and C _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^10B and -NR ^11B R ^11BB ; wherein each of R ^9B , R ^9BB , R ^10B , R ^11b and R ^11BB is independently selected from the group consisting of hydrogen; C1-4alkyl and C-linked 4-7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom.

In one embodiment, the present invention relates to such compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof specified in any of the other embodiments, wherein

--LR ³ selected from (a), (b), (c), (d) or (e); and provided that L in option (b) is not -O- or -O-CR ^1B R ^1BB -.

In one embodiment, the present invention relates to such compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof specified in any of the other embodiments, wherein

--LR ³ selected from (a), (b), (c), (d), (e) or (f); where (a), (c), (d) and (e) are defined in accordance with any of the other embodiments;

where (b) is defined as (b) L is selected from the group consisting of -N(R ^B )-, -N(R ^B )-CR ^1B R ^1BB - and -(NR ^B )-CHR ^1B -CHR ^2B -; and R ³ is selected from the group consisting of Ar; Het ¹ ; Het ² and 7-10-membered saturated spirocarbobicyclic system

- 19 046212 topics; Where

R ^B is selected from the group consisting of hydrogen; C _1-4 alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, phenyl and -CN; and C _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^1b and -NR ^2b R ^2bb ; wherein each of ^R1b , ^R2b and ^R2bb is independently selected from the group consisting of hydrogen, C^alkyl and cyclopropyl;

R ^1B is selected from the group consisting of hydrogen; -C(=O)NR ^3B R ^3BB ;

C^alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, phenyl, Het ¹ and -CN; ^^alkyl substituted with a substituent selected from the group consisting of -OR ^4B and -NR ^5B R ^5BB ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; and R ^1BB is selected from the group consisting of hydrogen and methyl; or R ^1B and R ^1BB together with the carbon atom to which they are attached form a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;

R ^2B is selected from the group consisting of hydrogen; -OR®; -NR ^7B R ^7BB ;

-C(=O)NR ^8B R ^8BB ; C^alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ^4B and -NR ^5B R ^5BB ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; wherein each of R ^3B , R ^3BB , R ^4B , R ^5B , R ^5BB , R ^6B , R ^7B , R ^7BB , R ^8B and R ^8BB is independently selected from the group consisting of hydrogen; C^alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN and -C(=O)NR ^9B R ^9BB ; and C _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^10B and -NR ^11B R ^11BB ; wherein each of R ^9B , R ^9BB , R ^10B , R ^11b and R ^11BB is independently selected from the group consisting of hydrogen; C14alkyl and C-linked 4-7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; and where (f) is defined as (f) --LR ³ is a radical selected from the group consisting of

In one embodiment, the present invention relates to such compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof specified in any of the other embodiments, wherein

--LR ³ selected from (a), (b), (c), (d), (e) or (f); where (a), (b), (c), (d) and (e) are defined in accordance with any of the other embodiments;

where (f) is defined as (f) --LR ³ is a radical selected from the group consisting of

Another embodiment of the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable salts and solvates or any subgroup thereof specified in any of the other embodiments, where one or more of the following limitations apply:

(i) R ¹ is CF3;

(ii) R ² represents hydrogen;

(iii) Y ¹ represents hydrogen;

(iv) Y ² and Y ³ represent hydrogen;

(v) --LR ³ selected from (a) or (b):

(a) --LR ³ represents -NHR ^1A where R ^1A represents C _1-6 alkyl; or (b) L is -N( ^RB )-CR ^1B R ^1BB -; and R ³ is selected from the group consisting of Ar; Het ¹ and Het ² ;

(vi) R ^B represents hydrogen;

(vii) R ^1B is selected from the group consisting of hydrogen and C^alkyl; and (viii) R ^1BB is hydrogen;

(ix) Ar is phenyl, optionally substituted with one C _1-4 alkyl;

(x) Het ¹ is pyrazolyl;

(xi) Het ² is a non-aromatic heterocyclyl; in particular 3-azetidinyl.

Another embodiment of the present invention relates to such compounds of formula (I) and their pharmaceutically acceptable salts and solvates or any subgroup thereof specified in any of the other embodiments, where one or more of the following restrictions apply:

(i) R ¹ is CF3;

(ii) R ² represents hydrogen;

- 20 046212 (iii) Y ¹ , Y ² and Y ³ represent hydrogen;

(iv) --LR ³ selected from (a), (b), (c) or (e):

(a) --LR ³ is -NHR ^1a wherein R ^1a is selected from the group consisting of C _1-6 alkyl optionally substituted with one, two or three fluorine substituents; And

C _2-6 alkyl substituted with a substituent selected from the group consisting of -OR ^1a and -NR ^2a R ^2aa , wherein each of R ^1a , R ^2a and R ^2aa is independently selected from the group consisting of hydrogen, C _1-4 alkyl and cyclopropyl; or (b) L is -N(R ^b )-CR ^1b R ^1bb -, and R ³ is selected from the group consisting of Ar and Het ¹ ; Where

R ^B is selected from the group consisting of hydrogen; C1-4alkyl, optionally substituted with a phenyl or -CN substituent; and C2-4alkyl substituted with a substituent selected from the group consisting of -OR ^1b and -NR ^2b R ^2bb ; wherein each of R ^1b , R ^2b and R ^2bb is independently selected from the group consisting of hydrogen and C1-4alkyl;

R ^1b is selected from the group consisting of hydrogen; C1-4alkyl, optionally substituted with a Het ¹ substituent; and C2-4alkyl substituted with -OH; and R ^1bb is hydrogen; or R ^1b and R ^1bb together with the carbon atom to which they are attached form an oxetanyl ring; or (c) --LR ³ selected from the group consisting of -N( ^RC )-CHR ^3C -CONR ^4C R ^4CC ; -N(R ^C )-COR ^5C and -N(R ^c )-SO ₂ Nr ^6C r ^6CC ; Where

R ^c is selected from the group consisting of hydrogen and C _1-4 alkyl, optionally substituted with a phenyl substituent;

each of R ^3C , R ^4C and R ^6C is selected from the group consisting of hydrogen and C _1-4 alkyl;

R ^5C is C _1-4 alkyl, optionally substituted with -NR ^2c R ^2cc ; wherein each of R ^2c and R ^2cc is independently selected from the group consisting of hydrogen and C _1-4 alkyl; and each of R ^4CC and R ^6CC is independently selected from the group consisting of hydrogen and C _1-4 alkyl; or

(e) --LR ³ represents

R ^e is selected from the group consisting of hydrogen and methyl;

R ^1e and R ^2E each represent an independently selected C1-4 alkyl substituent; or R ^1e and R ^2E are bonded to the same carbon atom and together form a C3-5 cycloalkyl; And

R ^3E represents hydrogen;

(v) --LR ³ selected from (a), (b), (c) or (e):

(a) --LR ³ is -NHR ^1a wherein R ^1a is selected from the group consisting of C _1-6 alkyl optionally substituted with one, two or three fluorine substituents; And

C _2-6 alkyl substituted with a substituent selected from the group consisting of -OR ^1a and -NR ^2a R ^2aa , wherein each of R ^1a , R ^2a and R ^2aa is independently selected from the group consisting of hydrogen, C _1-4 alkyl and cyclopropyl; or (b) L is -NH-CR ^1b R ^1bb -, and R ³ is selected from the group consisting of Ar and Het ¹ ; Where

R ^1b is selected from the group consisting of hydrogen; C1-4alkyl, optionally substituted with a Het ¹ substituent; and C2-4alkyl substituted with -OH; and R ^1bb is hydrogen; or R ^1b and R ^1bb together with the carbon atom to which they are attached form an oxetanyl ring; or (c) --LR ³ selected from the group consisting of -N(R ^c ) -CHR ^3C -CONR ^4C R ^4CC ; -N(R ^c )-COR ^5C and -N(R ^c )-SO ₂ Nr ^6C r ^6Cc ; Where

R ^c is selected from the group consisting of hydrogen and C _1-4 alkyl, optionally substituted with a phenyl substituent;

each of R ^3C , R ^4C and R ^6C is selected from the group consisting of hydrogen and C _1-4 alkyl;

R ^5C is C1-4alkyl, optionally substituted with -NR ^2c R ^2cc ; wherein each of R ^2c and R ^2cc is independently selected from the group consisting of hydrogen and C1-4alkyl; and each of R ^4CC and R ^6CC is independently selected from the group consisting of hydrogen and C _1-4 alkyl; or

(f) --LR ³ represents

R ^e is selected from the group consisting of hydrogen and methyl;

R ^1e and R ^2E each represent an independently selected C1-4 alkyl substituent; or R ^1e and R ^2E are bonded to the same carbon atom and together form a C3-5 cycloalkyl; And

- 21 046212

R ^3E represents hydrogen;

(vi) --LR ³ selected from (a), (b), (c) or (e):

(a) --LR ³ is -NHR ^1a where R ^1a is selected from the group consisting of C ₁ . ₆ alkyl, optionally substituted with one, two or three substituents representing a fluorine atom; And

C ₂ . ₆ alkyl substituted with a substituent selected from the group consisting of -OR ^1a and -NR ^2a R ^2aa , wherein each of R ^1a , R ^2a and R ^2aa is independently selected from the group consisting of hydrogen, C ₁ . ₄ alkyl and cyclopropyl; or (b) L is -NH-CR ^1b R ^1bb -, and R ³ is selected from the group consisting of Ar and Het ¹ ; Where

R ^1b is selected from the group consisting of hydrogen; C1.4alkyl, optionally substituted with a Het ¹ substituent; and C2. ₄ alkyl substituted with -OH; and R ^1bb is hydrogen; or (c) --LR ³ selected from the group consisting of -N ( ^RC ) -CHR ^3C -CONR ^4C R ^4C c; -N(R ^c )-COR ^5C and -N(R ^c )SO2-NR ^6C R ^6C c; Where

R ^c is selected from the group consisting of hydrogen and C ₁ . ₄ alkyl, optionally substituted with a phenyl substituent;

^R3C , R4C and ^R6C are each selected from the group consisting of hydrogen and C1. ₄ alkyl;

R5C represents _C1 . ₄ alkyl, optionally substituted -NR ^2c R ^2cc ; wherein each of R ^2c and R ^2cc is independently selected from the group consisting of hydrogen and C ₁ . ₄ alkyl; and each of R4CC and ^R6CC is independently selected from the group consisting of hydrogen and C1. ₄ alkyl; or

(f) --LR ³ represents

R ^e is selected from the group consisting of hydrogen and methyl;

R ^1e and R ^2E each represent an independently selected C1.4alkyl substituent; or R ^1e and R ^2E are bonded to the same carbon atom and together form C3. ₅ cycloalkyl; And

R ^3E represents hydrogen;

(vii) --LR ³ selected from (a), (b) or (e):

(a) --LR ³ is -NHR ^1a , wherein R ^1a is selected from the group consisting of C1.6 alkyl optionally substituted with one, two or three fluorine substituents; and C2.6alkyl substituted with a substituent selected from the group consisting of -OR ^1a and -NR ^2a R ^2aa , wherein each of R ^1a , R ^2a and R ^2aa is independently selected from the group consisting of hydrogen, C1.4alkyl and cyclopropyl; or (b) L is -NH-CR ^1b R ^1bb -, and R ³ is selected from the group consisting of Ar and Het ¹ ; where R ^1b is selected from the group consisting of hydrogen; C1.4alkyl, optionally substituted with a Het ¹ substituent; and C2. ₄ alkyl substituted with -OH; and R ^1bb is hydrogen; or

(e) --LR ³ represents

R ^e is selected from the group consisting of hydrogen and methyl;

R ^1e and R ^2E each represent an independently selected C1.4alkyl substituent; or R ^1e and R ^2E are bonded to the same carbon atom and together form C3. ₅ cycloalkyl; And

R ^3E represents hydrogen;

(vii) --LR ³ selected from (a), (b) or (e):

(a) --LR ³ is -NHR ^1a wherein R ^1a is selected from the group consisting of C _1-6 alkyl optionally substituted with one, two or three fluorine substituents; And

C ₂ . ₆ alkyl substituted with a substituent selected from the group consisting of -OR ^1a and -NR ^2a R ^2aa , wherein each of R ^1a , R ^2a and R ^2aa is independently selected from the group consisting of hydrogen, C ₁ . ₄ alkyl and cyclopropyl; or (b) L is -NH-CH2- and R ³ is selected from the group consisting of Ar and Het ¹ ; or

(e) --LR ³ represents

R ^e is selected from the group consisting of hydrogen and methyl;

- 22 046212 each of R ^1e and R ^2E represents an independently selected substituent representing C1-4alkyl; or R ^1e and R ^2E are bonded to the same carbon atom and together form a C3-5 cycloalkyl; And

R ^3E represents hydrogen;

(viii) Ar is phenyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, -C(=O)NR ⁵ R ⁵ and C _1-4 alkyl; where each of R ⁵ and R ⁵ is independently selected from the group consisting of hydrogen and ^^alkyl;

(ix) Ar is phenyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen and alkyl;

(x) Het ¹ is a monocyclic heteroaryl selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl and imidazolyl; each of which may be optionally substituted with one or two substituents, each of which is independently selected from the group consisting of halogen and ^alkyl;

(xi) Het ¹ is pyrazolyl, optionally substituted with a ^alkyl substituent;

(xii) Het ² is a non-aromatic heterocyclyl selected from azetidinyl, pyrrolidinyl and piperidinyl, each of which may be optionally substituted with an alkyl substituent.

It is intended that all possible combinations of the above embodiments fall within the scope of the present invention.

Specific compounds of formula (I) are:

including their stereoisomeric forms, pharmaceutically acceptable salts, in particular their hydrochloride salts, and solvates thereof.

Specific compounds of formula (I) are:

including their stereoisomeric forms, pharmaceutically acceptable salts, in particular their hydrochloride salts, and solvates thereof.

Methods for preparing compounds of formula (I).

In this section, as in all other sections, unless the context indicates otherwise, references to claim (I) also include all other subclauses and examples thereof, as defined herein.

General methods for preparing some representative examples of compounds of formula (I) are described in this document.

- 23 046212 this document and in specific examples, and, as a rule, they are prepared from starting materials that are either commercially available or obtained using standard synthetic methods commonly used by specialists in the art. It is intended that the following diagrams only represent examples of the present invention and are not intended to limit the present invention in any way.

Alternatively, the compounds of the present invention can also be prepared using reaction protocols similar to those described in the general schemes below, in combination with standard synthetic methods commonly used by those skilled in the art of organic chemistry.

One skilled in the art will appreciate that in the reactions described in the schemes, although not always explicitly shown, protection of reactive functional groups (eg hydroxy, amino or carboxy groups) may be necessary if they are needed in the final product in order to to avoid their unwanted participation in reactions. For example, in Scheme 5, the NH moiety on the azepanyl ring can be protected with a tert-butoxycarbonyl protecting group. In general, traditional protecting groups can be used in accordance with standard practice. The protecting groups can be removed at a suitable subsequent stage using methods known in the art. This is illustrated with specific examples.

One skilled in the art will appreciate that in the reactions described in the schemes, it may be advisable or necessary to conduct the reaction under an inert atmosphere, such as, for example, an atmosphere of N2 gas.

It will be apparent to one skilled in the art that it may be necessary to cool the reaction mixture before processing the reaction product (referring to a number of procedures necessary to isolate and purify the chemical reaction product(s), such as, for example, quenching, column chromatography, extraction) .

One skilled in the art will appreciate that heating the reaction mixture while stirring can increase the yield of the reaction. In some reactions, microwave heating can be used instead of traditional heating to reduce the overall reaction time.

One skilled in the art will appreciate that another sequence of chemical reactions shown in the diagrams below may also result in the desired compound of formula (I).

One skilled in the art will appreciate that the intermediates and final compounds shown in the diagrams below can be further functionalized in accordance with methods well known to one skilled in the art. The intermediates and compounds described herein can be isolated in free form or as a salt.

Scheme 1

In general, a compound of formula (I), wherein all variables are defined within the scope of the present invention, can be prepared according to the following Reaction Scheme 1. In Scheme 1, LG represents a leaving group such as, for example, halogen. All other variables in Scheme 1 are defined within the scope of the present invention.

In Scheme 1, the following reaction conditions are applied:

1: at a suitable temperature, such as, for example, room temperature, in the presence of a suitable base, such as, for example, diisopropylethylamine, in a suitable solvent, such as, for example, acetonitrile.

Scheme 2.

Alternatively, compounds of formula (I), wherein all variables are defined within the scope of the present invention, can be prepared in accordance with the following reaction scheme 2. In scheme 2, Y ¹ represents the hydrogen in compounds of formula (IV), (IV) and (Ib), and Y ^1a has the same meaning as Y ¹ as defined within the scope of the present invention, except for hydrogen in compounds of formula (VI), (VI') and (Ia), and all other variables are defined in accordance with scope of the present invention.

- 24 046212

In Scheme 2, the following reaction conditions are applied:

1: by adding a Grignard reagent to the ketone at a suitable temperature, such as, for example, -78°C, in a suitable solvent, such as, for example, tetrahydrofuran (THF);

2: by converting the hydroxyl moiety to a leaving group, such as, for example, a mesylate, or using the Mitsunobu reaction, by methods known to one skilled in the art;

3: under suitable reaction conditions, such as, for example, conditions for nucleophilic substitution, by interconversion of suitable functional groups using reagents that are either commercially available or can be prepared by methods known to one skilled in the art, to obtain a compound of formula (I), where Y ^1a has the same meaning as Y ^{1 2} except for hydrogen;

4: under suitable conditions for reduction, such as using NaBH ₄ for example, in a suitable solvent such as alcohol, at a suitable temperature.

Scheme 3.

Alternatively, compounds of formula (I), where all variables are defined in accordance with the scope of the present invention, can be prepared in accordance with the following reaction scheme 3. In scheme 3, Y ¹ represents the hydrogen in the compound of formula (Id), and Y ^1a has the same value as Y ¹ as defined within the scope of the present invention, except for the hydrogen in the compound of formula (Ic), -LR ^{3 * *} represents -N ( ^RB ) -R ³ , -N ( ^RB ) -CR ^1B R ^1BB -R ³ or -N(R ^B )-CHR ^1B -CHR ^2B -R ³ as defined in (b), or -LR ³ as defined in (c) or (d), herein referred to as -NQ -L ^a -R ³ , and all other variables are defined within the scope of the present invention. It will be apparent that Q represents R ^B , R ^C or RD respectively, and L ^a represents the rest of the definition of L except -NQ-.

In Scheme 3 the following reaction conditions are applied:

1: at a suitable temperature, for example 80°C, in a suitable solvent such as ethanol;

2: under suitable reaction conditions, by interconversion of suitable functional groups with a suitable organolithium reagent (Y ^1a -Li) or Grignard reagent (Y ^1a -Mg-halogen), which are either commercially available or can be prepared by methods known to one skilled in the art the field of technology to obtain a compound of formula (I), wherein Y ^1a has the same meaning as Y ¹ except for hydrogen;

3: at a suitable temperature, for example room temperature, in the presence of a suitable reducing agent, such as, for example, NaBH(OAc) ₃ in a suitable solvent such as ethanol; to obtain a compound of formula (I) wherein Y ¹ represents hydrogen.

- 25 046212

Scheme 3B.

Alternatively, compounds of formula (I), wherein

L ^b represents C _1-2 alkyl, optionally substituted with R ^2B ;

L ^b1 represents C _0-1 alkyl, optionally substituted with R ^2B ;

R ^3a is selected from Het ^{1 2 * *} or the 7-10 membered saturated spirocyclic system;

R ^Ba is selected from the group consisting of hydrogen; C _0-3 alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, phenyl and -CN; and C _1-3 αlkyl substituted with a substituent selected from the group consisting of -OR and -NRR; can be obtained in accordance with scheme 3B.

All other variables are defined within the scope of the present invention. One skilled in the art will appreciate that when R ^B is hydrogen, certain reactions of Scheme 3B can be eliminated.

: at a suitable temperature, such as room temperature, in a suitable solvent such as ethanol, THF, dichloroethane (DCE), with or without acetic acid (AcOH).

and 3: at a suitable temperature, for example room temperature, in the presence of a suitable reducing agent such as, for example, NaBH(OAc) ₃ , in a suitable solvent such as ethanol, THF, DCE, with or without acetic acid (AcOH), to obtain a compound of formula (I) wherein Y ¹ represents hydrogen.

One skilled in the art will appreciate that when preparing compounds, the order of steps 1 and 2 can be reversed with step 3 and that, for example, to prepare compounds (If), reagent ((XXIV) can be used before reagent (XXII).

Scheme 4.

Intermediates of formula (IV) can be prepared according to the following scheme about ^Λ

...W of reaction 4, wherein represents a suitable protecting group, such as, for example, an acetal protecting group, and all other variables are defined within the scope of the present invention.

In Scheme 4 the following reaction conditions are applied:

1: at a suitable temperature, such as, for example, 80°C, in the presence of a suitable base, such as, for example, diisopropylethylamine, in a suitable solvent, such as, for example, isopropanol.

2: under suitable reaction conditions for deprotection, such as, for example, in the presence of an acid such as hydrochloric acid, under reflux.

- 26 046212

Alternatively, intermediates of formula (IX), which are protected or unprotected, may be commercially available.

Scheme 4B.

Alternatively, additional intermediates of formula (IV) can be prepared according to the following reaction scheme 4B.

Scheme 4B uses the following reaction conditions:

1: at a suitable temperature, such as, for example, 80°C, in the presence of a suitable base, such as, for example, diisopropylethylamine, in a suitable solvent, such as, for example, isopropanol.

Scheme 4C.

Intermediates of formula (XXI) can be prepared according to the following reaction scheme 4b.

1: at a suitable temperature, such as, for example, 80°C, in the presence of a suitable base, such as, for example, diisopropylethylamine, in a suitable solvent, such as, for example, isopropanol. A suitable PG (protecting group) for compound (XXV) is, for example, tert-butyloxycarbonyl.

2: under suitable reaction conditions for deprotection, such as for example in the presence of an acid such as hydrochloric acid or trifluoroacetic acid at room temperature.

Scheme 5.

Intermediates of formula (III) can be prepared in accordance with the following reaction scheme 5, where Y ^{1 2} represents the hydrogen in the compound of formula (IIIb), and Y ^1a has the same meaning as Y ¹ as defined within the scope of the present invention, for excluding the hydrogen in the compound of formula (IIIa), -LR ^{3 4 *} is -N(R ^B )-R ³ , -N(R ^B )-CR ^1B R ^1BB -R ³ or -N(R ^B )-CHR ^1B -CHR ^2B -R ³ as defined in (b), or -LR ³ as defined in (c) or (d), herein referred to as -NQ-L ^a -R ³ or -NH-L ^a -R ³ . and all other variables are defined within the scope of the present invention.

In Scheme 5 the following reaction conditions are applied:

1: at a suitable temperature, for example 80°C, in a suitable solvent such as ethanol;

2: under suitable reaction conditions, by interconversion of suitable functional groups with a suitable organolithium reagent (Y ^1a -Li) or Grignard reagent (Y ^1a -Mg-halogen), which are either commercially available or can be prepared by methods known to one skilled in the art field of technology, obtaining a compound of formula (XIII), where Y ^1a has the same meaning as Y ¹ except for hydrogen;

3: at a suitable temperature, for example room temperature, in the presence of a suitable reducing agent, such as, for example, NaBH(OAc) ₃ in a suitable solvent such as ethanol, to obtain a compound of formula (XIV), where Y ¹ represents hydrogen;

4: at a suitable temperature, such as, for example, from 0°C to room temperature, in the presence of suitable conditions for decomposition, such as, for example, an acid such as hydrochloric

- 27 046212 acid in a suitable solvent such as acetonitrile if PG is tert-butyloxycarbonyl.

Alternatively, intermediates of formula (III) may be commercially available.

Circuit 5V.

Alternatively, additional intermediates of formula (III), referred to herein as (IIIc) and (IIId), can be prepared according to the following Reaction Scheme 5B. In Scheme 5B, Y ¹ represents hydrogen in compounds of formula (IIId), (XIX) and (XX), and Y ^1a has the same meaning as Y ¹ as defined within the scope of the present invention, except for hydrogen in compounds of formula (IIIc ), (XV), (XVI) and (XVII), and all other variables are defined within the scope of the present invention.

Scheme 5B uses the following reaction conditions:

1: by adding a Grignard reagent to the ketone at a suitable temperature, such as, for example, -78°C, in a suitable solvent, such as, for example, THF;

2: by converting the hydroxyl moiety to a leaving group, such as, for example, mesylate, or using the Mitsunobu reaction, by methods known to one skilled in the art;

3: under suitable reaction conditions, such as, for example, conditions for nucleophilic substitution, by interconversion of suitable functional groups using reagents that are either commercially available or can be prepared by methods known to one skilled in the art, to obtain a compound of formula (XVII) wherein Y ^1a has the same meaning as Y ¹ except for hydrogen, or the compound of formula (XX);

4: under suitable conditions for reduction, such as, for example, using NaBH ₄ in a suitable solvent such as alcohol, at a suitable temperature;

5: at a suitable temperature, such as, for example, from 0°C to room temperature, in the presence of suitable conditions for cleavage, such as, for example, an acid such as hydrochloric acid in a suitable solvent such as acetonitrile, if PG is tert-butyloxycarbonyl .

Alternatively, intermediates of formula (IIIc) and (IIId) may be commercially available.

Scheme 6.

Intermediates of formula (II) wherein R ^{2 3} is methyl can be prepared according to the following reaction scheme 6, where LG represents a suitable leaving group such as, for example, halogen or methanesulfonyl. All other variables in Scheme 6 are defined within the scope of the present invention.

In Scheme 6, the following reaction conditions are applied:

1: at a suitable temperature, such as, for example, reflux temperature, in the presence of acetic anhydride and a suitable base, such as, for example, trimethylamine, in a suitable solvent, such as, for example, toluene;

2: at a suitable temperature, such as, for example, reflux temperature, in the presence of a suitable base, such as potassium hydroxide, in a suitable solvent, such as, for example, ethanol;

3: under suitable reaction conditions to form a leaving group such as chlorine, for example by reacting with phosphorus trichloride at a suitable temperature such as 110°C.

Alternatively, intermediates of formula (II) may be commercially available.

It should be understood that if appropriate functional groups are present, the compounds of various formulas or any intermediates used to prepare them can be further derivatized by one or more standard synthetic methods using condensation, substitution, oxidation, reduction or cleavage reactions. Specific substitution approaches include traditional alkylation, arylation, heteroarylation, acylation, sulfonylation, halogenation, nitration, formylation and coupling procedures.

The compounds of formula (I) can be synthesized as racemic mixtures of enantiomers, which can be separated from each other following separation procedures known in the art. Racemic compounds of formula (I) containing a basic nitrogen atom can be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. These diastereomeric salt forms are then separated, for example by selective or fractional crystallization, and the enantiomers are isolated from there using alkali. An alternative method for separating the enantiomeric forms of compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms can also be prepared from the corresponding pure stereochemically isomeric forms of the corresponding starting materials, provided that the reaction proceeds stereospecifically.

When preparing the compounds of the present invention, it may be necessary to protect the remote functionality (eg, primary or secondary amine) of the intermediates. The need to provide such protection will vary depending on the nature of the individual functional group and the conditions of the preparation methods. Suitable amino protecting groups (NH-PG) include acetyl, trifluoroacetyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection will be readily determined by one skilled in the art. For a general description of protecting groups and their uses, see T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken, New Jersey, 2007.

Pharmacology.

The compounds of the present invention have been found to block the interaction of menin with MLL proteins and oncogenic MLL-based fusion proteins. Therefore, the compounds of the present invention and pharmaceutical compositions containing these compounds may be useful for the treatment or prevention, in particular the treatment, of diseases such as cancer, myelodysplastic syndrome (MDS) and diabetes.

In particular, the compounds of the present invention and pharmaceutical compositions based thereon may be useful in the treatment or prevention of cancer. In one embodiment, the types of cancer for which treatment with the menin-MLL inhibitors of the present invention may be appropriate include types of leukemia, myeloma, or cancer that is a solid tumor (eg, prostate cancer, lung cancer, breast cancer , pancreatic cancer, colon cancer, liver cancer, melanoma and glioblastoma, etc.). In some embodiments, the leukemia types include acute leukemia types, chronic leukemia types, myeloid leukemia types, myelogenous leukemia types, lymphoblastic leukemia types, lymphocytic leukemia types, acute myelogenous leukemia (AML) types, chronic myelogenous leukemia (CML) types, acute lymphoblastic leukemia types leukemia (ALL), types of chronic lymphocytic leukemia (CLL), types of T-cell prolymphocytic leukemia (T-PLL), leukemia of large granular lymphocytes, hairy cell leukemia (HCL), types of leukemia with MLL rearrangement, types of leukemia associated with MLL- PTD, types of leukemia with MLL amplification, types of MLL-positive leukemia, types of leukemia characterized by HOX/MEIS1 gene expression profiles, etc.

Therefore, the present invention relates to the compounds of formula (I), their tautomers and stereoisomeric forms, as well as their pharmaceutically acceptable salts and solvates for use as a drug.

The present invention also relates to the use of a compound of formula (I), a tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to the present invention for the manufacture of a medicinal product.

The present invention also relates to a compound of formula (I), a tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition in accordance with the present invention for use in the treatment, prevention, mitigation, control or reduction of the risk of developing disorders associated with the interaction of menin with MLL proteins and oncogenic MLL-based fusion proteins in a mammal, including humans, the treatment or prevention of which is dependent on or facilitated by blocking the interaction of menin with MLL proteins and oncogenic MLL-based fusion proteins.

Also, the present invention relates to the use of a compound of formula (I), a tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition in accordance with the present invention for the manufacture of a medicinal product

- 29 046212 for the treatment, prevention, amelioration, control or reduction of the risk of developing disorders associated with the interaction of menin with MLL proteins and oncogenic MLL-based fusion proteins in a mammal, including humans, the treatment or prevention of which depends on blocking the interaction of menin with or facilitated by MLL proteins and MLL-based oncogenic proteins.

The present invention also provides a compound of formula (I), a tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof for use in the treatment or prevention of any of the diseases mentioned herein above.

The present invention also provides a compound of formula (I), a tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof for use in the treatment or prevention of any of the diseases mentioned herein above.

The present invention also relates to the use of a compound of formula (I), a tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment or prevention of any of the disease states mentioned herein above.

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

In view of the usefulness of the compounds of formula (I), their tautomers and stereoisomeric forms, and their pharmaceutically acceptable salts and solvates, a method is provided for the treatment of warm-blooded animals, including humans, suffering from any of the diseases mentioned above herein.

Said method includes introducing, i.e. systemic or local administration, preferably oral administration, of a therapeutically effective amount of a compound of formula (I), a tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, to warm-blooded animals, including humans.

Therefore, the present invention also provides a method for treating or preventing any of the diseases mentioned herein above, comprising administering a therapeutically effective amount of a compound of the present invention to a patient in need thereof.

One skilled in the art will appreciate that a therapeutically effective amount of the compounds of the present invention is an amount sufficient to exhibit therapeutic activity, and that this amount varies inter alias depending on the type of disease, the concentration of the compound in the therapeutic composition, and the condition of the patient. In general, the amount of a compound of the present invention to be administered as a therapeutic agent for the treatment of the disorders described herein will be determined on a case-by-case basis by the attending physician.

Those skilled in the treatment of such diseases will be able to determine the effective therapeutic daily amount from the test results presented below in this document. An effective daily therapeutic amount will be from about 0.005 to 100 mg/kg, in particular from 0.005 to 50 mg/kg, in particular from 0.01 to 50 mg/kg body weight, more particularly from 0.01 to 25 mg /kg body weight, preferably from about 0.01 mg/kg to about 15 mg/kg, more preferably from about 0.01 to about 10 mg/kg, even more preferably from about 0.01 to about 1 mg/kg, most preferably from about 0.05 to about 1 mg/kg body weight. The specific effective daily therapeutic amount may be 1 mg/kg body weight, 2 mg/kg body weight, 4 mg/kg body weight, or 8 mg/kg body weight. The amount of a compound of the present invention, also referred to herein as the active ingredient, that is necessary to achieve a therapeutic effect may vary on a case-by-case basis, for example, for a particular compound, route of administration, age and condition of the recipient, and a particular disorder or condition. disease to be treated. The method of treatment may also include administering the active ingredient according to a schedule of one to four administrations per day. In these treatments, the compounds of the present invention are preferably formulated prior to administration. As described herein below, suitable pharmaceutical compositions are prepared by known procedures using well known and publicly available ingredients.

The present invention also provides compositions for the prevention or treatment of the disorders described herein. Said compositions contain a therapeutically effective amount of a compound of formula (I), a tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.

Although the active ingredient can be administered separately, it is preferable if it is presented in the form of a pharmaceutical composition. Therefore, the present invention further provides a pharmaceutical composition containing a compound of the present invention together with a pharmaceutically acceptable carrier or diluent. The carrier or diluent must

- 30 046212 be acceptable in terms of compatibility with the other ingredients of the composition and should not be harmful to patients receiving them.

The pharmaceutical compositions of the present invention can be prepared by any methods well known in the art of pharmacy, for example by 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).

A therapeutically effective amount of a particular compound, in base or salt form, as the active ingredient is combined in a uniform mixture with a pharmaceutically acceptable carrier, which may take a number of forms depending on the form of preparation required for administration. It is desirable that these pharmaceutical compositions be in unit dosage form, preferably suitable for systemic administration, such as oral, transdermal or parenteral administration; or for topical administration, such as by inhalation, nasal spray, eye drops, or by cream, gel, shampoo, or the like. For example, when preparing the compositions in the form of a dosage form for oral administration, any conventional pharmaceutical vehicles can be used, such as, for example, water, glycols, oils, alcohols, etc., in the case of liquid preparations for oral administration, such as suspensions, syrups , tinctures and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrants and the like, in the case of powders, pills, capsules and tablets. Due to their ease of administration, tablets and capsules are the most advantageous unit dosage forms for oral administration, in which case solid pharmaceutical carriers are of course used. For compositions for parenteral administration, the carrier will generally comprise sterile water, at least in large part, although other ingredients may be included, for example, to aid solubility. For example, injectable solutions can be prepared in which the carrier contains saline solution, glucose solution or a mixture of saline solution and glucose solution. Injectable suspensions can also be prepared, in which case suitable liquid carriers, suspending agents and the like can be used. In compositions suitable for transdermal administration, the carrier optionally contains a penetration enhancing agent and/or a suitable wetting agent, optionally in combination with suitable additives of any nature in minimal proportions, the additives not having any significant deleterious effects on the skin. These additives may facilitate administration into the skin and/or may be useful in preparing the desired compositions. These compositions can be administered in various ways, for example, through a transdermal patch, by spot application, or as an ointment.

It is particularly advantageous to formulate the above-mentioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage forms, as used herein and in the claims, refer to physically discrete units suitable as dosage units, each unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect, together with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including divisible or film-coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, heaped teaspoons, heaped tablespoons, and the like. ., as well as their individual multiples.

The compounds of the present invention can be used for systemic administration, such as oral, transdermal or parenteral administration; or for topical administration, such as by inhalation, nasal spray, eye drops, or by cream, gel, shampoo or the like. The compounds are preferably administered orally. The exact dosage and frequency of administration will depend on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, severity of the disorder and the general physical condition of the particular patient, as well as other drug treatment, which an individual may receive, as is well known to those skilled in the art. Moreover, it will be appreciated that said effective daily amount may be reduced or increased depending on the response of the subject being treated and/or depending on the judgment of the physician prescribing the compounds of the present invention.

The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. Combination therapy includes administration of a single dosage pharmaceutical formulation that contains a compound of the present invention and one or more additional therapeutic agents, as well as administration of a compound of the present invention and each additional therapeutic agent in its own separate dosage pharmaceutical composition. For example, a compound of the present invention and a therapeutic agent may be administered to a patient together in a single oral dosage composition, such as a tablet or capsule, or each agent may be administered separately in oral dosage formulations.

- 31 046212 nia.

Therefore, an embodiment of the present invention relates to a product containing, as a first active ingredient, a compound according to the present invention, and as a further active ingredient, one or more anticancer agents, in the form of a combination preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.

One or more other medicinal agents and a compound of the present invention may be administered simultaneously (eg, in separate or single compositions) or sequentially in a random order. In the latter case, two or more compounds will be administered over a period and in an amount and manner that are sufficient to ensure that an advantageous or synergistic effect is achieved. It should be understood that the preferred route and order of administration and the corresponding dosage levels and schedules for each component of the combination will depend on the particular other medicinal agent and compound of the present invention to be administered, their route of administration, the particular condition, in particular the tumor, to be treated, and specific host to be treated. The optimal route and order of administration, as well as dosage levels and schedules, can be readily determined by those skilled in the art using standard techniques and taking into account the information set forth herein.

The weight ratio of the compound of the present invention and one anticancer agent or several other anticancer agents administered in combination can be determined by one skilled in the art. The ratio, precise dosage, and frequency of administration depend on the particular compound of the present invention and other anticancer agent(s) used, the specific condition being treated, the severity of the condition being treated, age, body weight, sex, diet, the time of administration and the general physical condition of the particular patient, the route of administration, as well as other drug treatments that the individual may be receiving, as is well known to those skilled in the art. Moreover, it will be appreciated that the effective daily amount may be decreased or increased depending on the response of the subject being treated and/or depending on the judgment of the attending physician prescribing the compounds of the present invention. The specific weight ratio for a given compound of formula (I) and the other anticancer agent may be in the range of 1/10 to 10/1, more particularly 1/5 to 5/1, even more particularly 1/3 to 3/ 1.

The following examples further illustrate the present invention.

Examples

Some methods for preparing the compounds of the present invention are illustrated in the following examples. Unless otherwise stated, all starting materials were obtained from commercial suppliers and used without further purification.

Hereinafter the terms: ACN or CAN means acetonitrile, DCM means dichloromethane, DCE means dichloroethane, DIEA means NN-diisopropylethylamine. DIAD means diisopropyldiazodicarboxylate, h means hour(s), min. means minute(s), DMF means dimethylformamide, DSC means differential scanning calorimetry, EtOAc or AcOEt means ethyl acetate, Et2O means diethyl ether, EtOH means ethanol, THF means tetrahydrofuran, HPLC means high performance liquid chromatography, HBTU means 1-bis(dimethylamino) methylene benzotriazolium hexafluorophosphate (1-)3-oxide, iPrOH means isopropyl alcohol, TFA means trifluoroacetic acid, NaBH ₄ means sodium borohydride, TBAF means tetrabutylammonium fluoride, K ₂ CO ₃ means potassium carbonate, MgSO ₄ means magnesium sulfate, Na ₂ SO ₄ means sodium sulfate, Et ₃ N means triethylamine, PPh ₃ means triphenylphosphine, NaHCO ₃ means sodium bicarbonate, LC/MS means liquid chromatography/mass spectrometry, MeOH means methanol, NMR means nuclear magnetic resonance, r.t. means room temperature, SFC means supercritical fluid chromatography, M.R. or etc. means melting point, OR means optical rotation.

One skilled in the art will appreciate that compounds synthesized using these protocols may exist as a solvate, such as a hydrate, and/or may contain residual solvent or minor impurities. Compounds isolated in salt form may have integer stoichiometry, i.e. mono- or disols, or intermediate stoichiometry.

If a stereocenter is designated RS, it means that a racemic mixture with the indicated center was prepared, unless otherwise indicated.

The stereochemical configuration for centers in some compounds may be designated R or S if the mixture(s) are separated; For some compounds, the stereochemical configuration at the specified centers was designated as *R (eluted first from the column in the case of the column conditions described in the synthesis protocol and if only one stereocenter is present) or *S (eluted second from the column in the case of the conditions described in the synthesis protocol for the column). columns and if only one stereocenter is present) if the absolute stereochemistry is not determined (even if the bonds are

- 32 046212 are stereospecific), although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure.

For example, it will be understood that compound 11A is

Compounds characterized by two stereocenters, in which only one stereochemical configuration of one stereocenter is indicated by * (e.g., *R or *S) (see, e.g., compound 14A or 14B), follow a similar rule as stated above. This means that the absolute stereochemical configuration of the stereocenter indicated by * is not determined (even if the bonds are drawn stereospecifically), although the compound is enantiomerically pure at the center indicated.

For compounds such as, for example, 31, 32, 35, 36, 54A, 54B, 54C, 54D, 66A, 66B, 66C, 66D, 68A and 68B, where the stereochemical configuration of the two stereocenters is indicated by * (for example, *R or *S), the absolute stereochemistry of the stereocenters is not determined (even if the bonds are drawn stereospecifically), although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure. In this case, the configuration of the first stereocenter is independent of the configuration of the second stereocenter in the same compound.

For example, for connection 31,

this means that the connection is

- 33 046212

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.

If an intermediate or compound in the experimental section below is listed as an HCl salt or a TFA salt without specifying the number of HCl or TFA equivalents, it means that the number of HCl or TFA equivalents was not determined.

One skilled in the art will appreciate that, even if not explicitly stated in the experimental protocols below, typically, after purification by column chromatography, the required fractions are collected and the solvent is evaporated.

A. Preparation of intermediate compounds

Getting intermediate 1:

1,4-Dioxane-8-azaspiro[4.6]undecane mixture (1 g, 6.36 mmol) (CAS [16803-07-9]); 4-chloro-6-(2,2,2trifluoroethyl)thieno[2,3^]pyrimidine (CAS [1628317-85-0]) (1.46 g, 5.78 mmol), prepared as described in the Journal of Medicinal Chemistry (2016), 59(3), 892-913; and DIEA (3 ml, 17.35 mmol) in iPrOH (60 ml) were heated at 80°C for 3 hours. The mixture was cooled to room temperature, poured into ice water, extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: irregular particle SiOH, 15-40 µm, 40 g, mobile phase: 97% DCM, 3% MeOH (+ 10% NH4OH)). Fractions containing the product were collected and evaporated to dryness to obtain 2.28 g (yield 106%) 8-(6-(2,2,2-trifluoroethyl)thieno[2,3^]pyrimidin4-yl)-1, 4-dioxa-8-azaspiro[4.6]undecane (I-1), which was used without further purification in the next step.

The compound shown in the table below was prepared by using a method similar to that described for the preparation of the compound above, starting from the appropriate starting materials.

Intermediate connection number Structure Exit Intermediate 2 But WITH L 98%

- 34 046212

Getting intermediate 3:

Intermediate 1 (90 mg, 0.24 mmol) in HCl (1 mL, 6N) was stirred at reflux for 5 hours. The reaction mixture was cooled to room temperature, poured into ice water, and increased in basicity with NaOH solution (3N) and the product was extracted with DCM. The organic layer was separated, dried over MgSO ₄ , filtered and evaporated to dryness to obtain 58 mg (yield 73%) 1-(6-(2,2,2-trifluoroethyl)thieno[2,3^]pyrimidin-4-yl )azepan-4-one.

Getting intermediate 4:

A mixture of ^)-tert-butyl-4-(benzylamino)azepane-1-carboxylate (160 mg, 0.53 mmol) (CAS [139173007-6]) and a solution of HCl in dioxane (1.5 ml/4N, 6 mmol) in MeOH (3 ml) was stirred at room temperature. for 6 hours. The mixture was evaporated to dryness to obtain 129 mg of intermediate 4, which was used without further purification in the next step.

Intermediate 5 was prepared in a similar manner from N-tert-butyl-4-(benzylamino)azepan-1-carboxylate (CAS[1391730-08-7]).

Preparation of intermediate 6:

Under a stream of N _{2 ,} 2,2-difluoroethylamine (0.39 mL, 5.51 mmol) was added to a solution of tert-butyl-4oxoazepane-1-carboxylate (350 mg, 1.38 mmol), (CAS [188975-88-4 ]) and acetic acid (0.17 ml, 3.03 mmol) in THF (5 ml). The mixture was stirred at room temperature. for 30 min, then NaBH(OAc) ₃ (643 mg, 3.03 mmol) was added and the mixture was stirred at room temperature. during the night. The mixture was poured into ice water and decanted, the aqueous layer was extracted with DCM (x2). The organic layers were combined, washed with brine, then dried over MgSO ₄ and evaporated to give 380 mg of intermediate 6, which is tert-butyl 4-((2,2-difluoroethyl)amino)azepane-1-carboxylate. The crude product was used directly in the next step without any purification.

- 35 046212

Getting intermediate 7:

as salt HC1

At 5°C, a solution of HCl in dioxane (3.4 ml/4N, 13.65 mmol) was added dropwise to a solution of intermediate 5 (380 mg, 1.37 mmol) in DCM (10 ml) and the mixture was stirred at .T. for 5 hours. The reaction mixture was evaporated to dryness, the residue was taken up with Et ₂ O and the white precipitate was filtered and dried under vacuum to obtain 350 mg of intermediate 7 as the HCl salt.

Preparation of intermediate 8:

Mixture of 4-chloro-6-(2,2,2-trifluoroethyl)thieno[2,3L]pyrimidine (CAS [1628317-85-0]) (3 g, 11.87 mmol), tert-butyl-U-( azepan-4-yl)carbamate (CAS [454451-28-6]) (3.05 g, 14.25 mmol) and DIEA (8.2 mL, 47.5 mmol) in iPrOH (75 mL) were heated at 90 °C for 2 hours. The mixture was cooled to room temperature, then poured into water and the product was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: irregular particle SiOH, 15-40 µm, 40 g, GRACE, mobile phase: gradient 100% DCM to 0.1% NH4OH, 98% DCM, 2% MeOH). Fractions containing product were collected and evaporated to dryness to yield 4.8 g (94%) of intermediate 8.

Preparation of intermediate 8a and intermediate 8b:

The enantiomers of the racemic mixture of intermediate 8 were separated using chiral SFC (stationary phase: Chiralpak AD-H, 5 μm, 250x30 mm, mobile phase: 82% CO ₂ , 18% EtOH). Fractions containing product were collected and evaporated to dryness to yield 1.35 g (26% yield) of the first eluted enantiomer 8A (intermediate 8A; I-8A) ([α] = +4.78° (589 nm, s 0.293 w/v%, DMF, 20°C)) and 1.47 g (29% yield) of the second eluted enantiomer 8B (intermediate 8B; I-8B) ([α] = -4.95° (589 nm , with 0.364 w/v%, DMF, 20°C)).

- 36 046212

Getting intermediate 9:

At 5°C, HCl (11.6 mL, 46.46 mmol, 4 M solution in dioxane) was added dropwise to a solution of intermediate 8 (2 g, 4.65 mmol) in DCM (50 mL) and the mixture was stirred at .T. for 15 hours. The reaction mixture was evaporated to dryness. The residue was taken up in Et ₂ O and evaporated twice to dryness to give 1.8 g of intermediate 9 as the HCl salt, which was used without any further purification in the next step.

The compounds shown in the table below were prepared by using a method similar to that described for the preparation of intermediate 9 above, starting from the corresponding starting materials.

Preparation of intermediate 12a:

Under N2 flow at 10°C, HBTU (188 mg, 0.5 mmol) was added to a solution of (R)-5-Bocasaspiro[2.4]heptane-6-carboxylic acid (CAS [1129634-44-1]) (120 mg, 0.66 mmol) and DIEA (0.43 ml, 2.49 mmol) in DMF (5 ml). The solution was stirred at 10°C for 30 minutes. Intermediate 9 (200 mg, 0.55 mmol) was then added and the solution was stirred at RT. for 15 hours. The reaction mixture was then poured into cooled water and 10% K ₂ CO ₃ . The product was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (stationary phase:

- 37 046212

SiOH with irregular particles, 15-40 µm, 24 g, mobile phase: gradient from 0.1% NH ₄ OH, 98% DCM, 2% MeOH to 0.1% NH ₄ OH, 95% DCM, 5% MeOH ). Fractions containing product were collected and evaporated to dryness to yield 100 mg (36% yield) of intermediate 12A.

The compound shown in the table below was prepared by using a method similar to that described for the preparation of intermediate 12A above, starting from the corresponding starting materials

Preparation of intermediate 13:

In stream No. ₂ , a solution of intermediate 3 (223 mg, 0.68 mmol), L-valine ethyl ester hydrochloride (CAS: [17609-47-1]), (308 mg, 1.70 mmol) and acetic acid ( 78 µl, 1.35 mmol) in THF (6 ml) was stirred at room temperature. for 3 hours. NaBH(OAc) ₃ (308 mg; 1.7 mmol) was added and the mixture was stirred at room temperature. during the night. The mixture was poured into ice water, separated and the aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO ₄ and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: SiOH irregular particle, 15-40 µm, 24 g, MERCK, mobile phase: 97% DCM, 3% MeOH (+ 10% NH4OH)). Fractions containing product were collected and evaporated to dryness to yield 176 mg of intermediate 13 (26% yield). The product was further purified by silica gel chromatography (stationary phase: irregular particle SiOH, 15-40 µm, 24 g, mobile phase: 60% heptane, 35% AcOEt, 5% MeOH (+ 10% NH ₄ OH)). Fractions containing product were collected and evaporated to dryness to yield 82 mg of intermediate 13.

Preparation of intermediate 14:

F as TFA salt

TFA (1.6 mL, 20.9 mmol) was added at RT. to a solution of intermediate 8 (0.9 g, 2.1 mmol) in DCM (9 ml) and the mixture was stirred at RT. during the night. The reaction mixture was evaporated to dryness to obtain 1.5 g of intermediate 14 as the TFA salt, which

- 38 046212 was taken without any additional cleaning at the next stage.

The compounds shown in the table below were prepared by using a method similar to that described for the preparation of intermediate 14 above, starting from the corresponding starting materials.

Preparation of intermediate 17:

Tert-butyl-4-formyl-1H-pyrazole-1-carboxylate (CAS [821767-61-7]), (122 mg, 0.62 mmol) was added at 10°C under N ₂ to a solution of intermediate 15 ( 183 mg, 0.55 mmol) in MeOH (7 ml). The mixture was stirred at room temperature. for 5 hours. NaBH ₄ (31 mg, 0.83 mmol) was then added in portions and the mixture was stirred at room temperature. for 15 hours. The mixture was poured into ice water and extracted with DCM. The organic layer was dried over MgSO ₄ , filtered and evaporated to dryness to obtain 0.35 g of crude compound. The residue was purified by silica gel chromatography (stationary phase: irregular particle SiOH, 15-40 µm, 40 g, mobile phase: gradient 0.1% NH4OH, 97% DCM, 3% MeOH to 0.1% NH4OH, 95 % DCM, 5% MeOH). Fractions containing product were collected and evaporated to dryness to yield 150 mg (39% yield) of intermediate 17.

Preparation of intermediate 18:

Solution of 2-bromoethoxy-tert-butyldimethylsilane (CAS [86864-60-0]), (2.44 ml; 11.37 mmol), 1Hpyrazole-4-carbaldehyde (CAS [35344-95-7]), (0. 91 g; 9.5 mmol) and K ₂ CO ₃ (1.57 g; 11.37 mmol) in ACN (18 ml) were refluxed for 2 hours. The mixture was cooled, poured into ice water and saturated NaHCO solution ₃ , the aqueous layer was extracted with EtOAc. The organic layer was separated, dried over MgSO ₄ , filtered and evaporated to dryness to obtain the crude compound, which was purified by chromatography on silica gel (stationary phase: irregular particle SiOH, 15-40 µm, 120 g, mobile phase: gradient from 100 % DCM, 0% MeOH to 95% DCM, 5% MeOH). Fractions containing product were collected and evaporated to dryness to yield 1.56 g (65% yield) of intermediate 18.

- 39 046212

Preparation of intermediate 19:

The compound was prepared by using a method similar to that described for the preparation of intermediate 17, starting from the respective starting materials of intermediate 15 and intermediate 18.

Getting the intermediate connection 20A and 20B:

Intermediate connection 20A Intermediate connection 20V

Enantiomers of the racemic mixture of tert-butyl-3-(1-amino-2-methylpropyl)azetidine-1-carboxylate (CAS [1782590-67-3]), (900 mg, 3.94 mmol) were separated using chiral SFC (fixed phase: Lux Cellulose-2, 5 µm, 250x30 mm, mobile phase: 85% CO ₂ , 15% MeOH (0.3% iPrNH2)). Fractions containing the product were collected and evaporated to dryness to obtain 390 mg (43% yield) of the first eluted enantiomer 20A and 331 mg (37% yield) of the second eluted enantiomer 20B.

Preparation of intermediate 21

Under a stream of N2, a solution of intermediate 3 (473 mg, 1.44 mmol), intermediate 20B (331 mg, 1.45 mmol) and acetic acid (85 µl, 1.49 mmol) in THF (19 ml) was stirred at .T. during the night. NaBH(OAc) ₃ (918 mg, 4.33 mmol) was then added portionwise and the mixture was stirred at room temperature. for 24 hours. The mixture was carefully poured into ice water, increased in basicity with NaOH and extracted with EtOAc. The organic layers were combined, dried over MgSO ₄ , filtered and evaporated to dryness to obtain 1.1 g of crude compound. The residue was purified by silica gel chromatography (stationary phase: irregular particle SiOH, 15-40 µm, 40 g, mobile phase: 65% heptane, 5% MeOH, 35% EtOAc). Fractions containing product were collected and evaporated to dryness to yield 565 mg of intermediate 21 (72% yield).

Preparation of intermediate 21A and 21B:

- 40 046212

The diastereomer mixture of intermediate 21 (240 mg, 0.44 mmol) was separated using chiral SFC (stationary phase: CHIRACEL OJ-H, 5 µm, 250x30 mm, mobile phase: 85% CO2, 15% MeOH (0. 3% iPrNH2)). Fractions containing product were collected and evaporated to dryness to provide 84 mg (11% yield) of the first eluted isomer 21A and 97 mg (13% yield) of the second eluted isomer 21B.

Getting intermediate 22:

The compound was prepared by using a method similar to that described for the preparation of intermediate 21, starting from the respective starting materials of intermediate 3 and intermediate 20A.

Getting intermediate connection 22A and 22B:

Intermediate connection 22A Intermediate connection 22V

The mixture of diastereomers in intermediate 22 (240 mg, 0.44 mmol) was separated using chiral SFC (stationary phase: CHIRALPAK-AD-H, 5 µm, 250x30 mm, mobile phase: 70% CO ₂ , 30% iPrOH (0. 3% iPrNH2)). Fractions containing the product were collected and evaporated to dryness to obtain 96 mg (11% yield) of the first eluted isomer 22A and 110 mg (12% yield) of the second eluted isomer 22B.

Preparation of intermediate 27:

Under nitrogen atmosphere, acetic acid (139 μL; 2.43 mmol) was added at room temperature. to a solution of intermediate 3 (400 mg; 1.21 mmol) in THF (15 ml) followed by N-Boc-Nmethylethylenediamine (CAS [121492-06-6]) (423 mg; 2.43 mmol). The mixture was stirred at room temperature for 5 hours, then NaBH(OAc) ₃ (772 mg, 3.64 mmol) was added and the mixture was stirred at room temperature. for 24 hours. The mixture was poured into a mixture of ice water and 10% K ₂ CO ₃ solution, then extracted with EtOAc, washed with brine and the organic layer was dried over MgSO ₄ , filtered and evaporated to dryness to obtain 0.6 g or remainder. The residue was purified by silica gel chromatography (stationary phase: SiOH irregular particle, 15-40 µm, 300 g, MERCK, mobile phase: 0.1% NH4OH, 95% DCM, 5% MeOH). Fractions containing product were collected and evaporated to dryness to yield 460 mg (72%) of intermediate 27.

- 41 046212

Preparation of intermediate 28:

y ^: V

N—VO ..........

/—( o o

bg

Acetic acid (101 μL; 1.76 mmol) was added under nitrogen at room temperature. to a solution of intermediate 27 (430 mg; 0.88 mmol) and 1-methyl-1H-pyrazole-4-carbaldehyde (CAS [25016-11-9]) (194 mg; 1.76 mmol) in THF (15 ml ). The mixture was stirred at room temperature. for 3 hours. NaBH(GAe) ₃ (561 mg, 2.65 mmol) was then added in portions and the mixture was stirred at room temperature. for 15 hours. The mixture was poured into a mixture of water and 10% K ₂ CO ₃ solution. EtOAc was added and stirred at room temperature. for 15 min, and extracted with EtOAc (x2). The organic layers were combined, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: SiOH irregular particle, 15-40 µm, 24 g, GRACE, mobile phase: gradient 0.1% NH4OH, 97% DCM, 3% MeOH to 0.1% NH4OH , 95% DCM, 5% MeOH). Fractions containing product were collected and evaporated to dryness to yield 420 mg (82%) of intermediate 28.

Preparation of intermediate 33:

Under N2 atmosphere, a solution of intermediate 3 (255 mg; 0.78 mmol), ethyl 4(aminomethyl) benzoate (277 mg; 1.55 mmol) in a mixture of THF (7 ml) and acetic acid (67 μl; 1.16 mmol) was stirred at room temperature. for 3 hours. Then NaBH(OAc) ₃ (361 mg, 1.7 mmol) was added and the mixture was stirred at room temperature. during the night. The mixture was poured into ice water and separated. The aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with brine, then dried over MgSO ₄ and evaporated.

The crude material (350 mg) was purified by silica gel chromatography (stationary phase: irregular particle SiOH, 15-40 µm, 24 g, MERCK, mobile phase: gradient from 97% DCM, 3% MeOH (+ 10% NH ₄ OH) up to 95% DCM, 5% MeOH (+10% NH ₄ OH)). Fractions containing the product were mixed to obtain 81 mg (21%) of intermediate 33.

The compounds shown in the table below were prepared by using a method similar to that described for the preparation of intermediate 33, starting from the corresponding starting materials.

- 42 046212

Intermediate connection number Structure Exit Intermediate 32 from Intermediate 3 and Nbenzyl-2-{[tert-butyl(dimethyl)silyl]oxy}ethanamine (CAS: [227805-74-5] 1 S. g '/V 47% Intermediate 34 from intermediate 3 and dimethylaminobutylamine (CAS: [352910-0]) —N N.H. 78%

Preparation of intermediate 35:

LiOH hydrate solution (33 mg; 0.79 mmol) was added at RT. to a solution of intermediate 33 (65 mg; mmol) in a mixture of THF (4.6 ml) and water (0.5 ml). The reaction mixture was heated at 60°C for 24 hours. The reaction mixture was evaporated to dryness. The residue was diluted with water, acidified with 1N. HCl and evaporated to dryness to obtain 107 mg of intermediate 35 as the HCl salt.

Preparation of intermediate 42:

A mixture of 4-chloro-6-(2,2,2-trifluoroethyl)thieno[2,3^]pyrimidine (prepared as described in Journal of Medicinal Chemistry (2016), 59(3), 892-913) (CAS [1628317 -85-0]) (466 mg, 1.82 mmol), 3-methylazepanone (CAS [748712-34-7]) (255 mg, 2 mmol) and DIEA (0.94 ml, 5.47 mmol) in iPrOH (10 ml) was heated at 90°C for 5 hours. The mixture was cooled to RT, then poured into water and the product was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: irregular particle SiOH, 15-40 µm, 24 g, mobile phase: gradient from 99% DCM, 1% MeOH (+ 10% NH4OH)). Fractions containing the product were collected and evaporated to dryness to obtain 65 mg (10% yield) of pure compound. This fraction was lyophilized from ACN/water to obtain 44 mg of intermediate 42 as a white powder.

The intermediate shown in the table below was prepared by using a method similar to that described for the preparation of the intermediate above, starting from the appropriate starting materials.

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Intermediate connection number

Intermediate 43 (from 4-chloro-6-(2,2,2trifluoroethyl)thieno[2,3-d]pyrimidine and 5-methylazepan-4one)

Preparation of intermediate 44: tert-butyl 4-(benzyloxy)azepane-1-carboxylate NaH (60% dispersion in mineral oil) (89 mg; 2.23 mmol) was added at room temperature to a solution of 1H-azepine-1-carboxylic acid acid, hexahydro-4-hydroxy-1,1-dimethylethyl ester (CAS [478832-21-2]) (0.4 g; 1.86 mmol) in DMF (7.6 ml). After 30 minutes, benzyl bromide (0.221 mL; 1.86 mmol) was added in one portion and the reaction mixture was kept stirring at room temperature overnight. The mixture was poured into ice and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO ₄ , filtered and the solvent was evaporated. The residue was purified by chromatography on silica gel (15-40 µm, 40 g, eluent: heptane/EtOAc: 100/0 to 0/100). Fractions containing the product were collected and evaporated to dryness to yield 0.394 g (69%) of intermediate 44. Preparation of intermediate 45, 4(benzyloxy)azepane as HCl salt HCl (4N, in dioxane) (1.88 ml ; 7.5 mmol) was added dropwise at 0°C to a solution of intermediate 44 (0.382 g; 1.25 mmol) in DCM (8 ml) and the mixture was stirred at RT. for 15 hours. The reaction mixture was evaporated to dryness, the residue was taken up with Et2O and the white precipitate was filtered and dried under vacuum to give 0.285 g (94%) of intermediate 45 as the HCl salt.

B. Obtaining compounds.

Example B1.

Preparation of enantiomers B1A and B1B:

In a stream of N2, a solution of intermediate 3 (158 mg, 0.48 mmol), isobutylamine ([CAS: 7881-9]) (191 µL, 1.9 mmol) and acetic acid (60 µL, 1.1 mmol) in THF (3 ml) was stirred at room temperature. over 3 hours. NaBH(OAc) ₃ (224 mg, 1.06 mmol) was added in portions and the mixture was stirred at room temperature. during the night. The mixture was poured into ice water and the mixture was separated, the aqueous layer was extracted with EtOAc (x2). The organic layers were combined, washed with brine, then dried over MgSO ₄ and evaporated. The residue was purified by silica gel chromatography (stationary phase: irregular particle SiOH, 15-40 µm, 24 g, MERCK, mobile phase: gradient from 96% DCM, 4% MeOH (+ 10% NH4OH) to 90% DCM, 10 % MeOH (+ 10% NH4OH)). Fractions containing the product were collected and evaporated to dryness to obtain 123 mg (66% yield) of racemic Nisobutyl-1-(6-(2,2,2-trifluoroethyl)thieno[2,3^]pyrimidin-4-yl) azepan-4-amine.

The two enantiomers were separated by chiral SFC (stationary phase: CHIRALCEL OJ-H, 5 µm, 250x20 mm, mobile phase: 90% CO ₂ , 10% iPrOH (0.3% iPrNH2)). Fractions containing the product were collected and evaporated to dryness to obtain 47 mg (10% yield) of the first enantiomer A eluted and 48 mg (10% yield) of the second enantiomer B eluted.

Both enantiomers were individually lyophilized using ACN/water 20/80 to give compound B1A (enantiomer A) (0.041 g) and compound B1B (enantiomer B) (0.051 g).

NMR data for compound B1A: 1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.33 (s, 1H) 7.60 (s, 1H) 4.08 (q, J=11.0 Hz, 2H) 3.86-3.98 (m, 2H) 3.69-3.85 (m, 2H) 2.61 (br s, 1H) 2.46 (br s, 1H) 2.29 (br d, J =6.6 Hz, 2H) 2.00 (br d, J=6.6 Hz, 2H) 1.51-1.78 (m, 4H) 1.34-1.45 (m, 1H) 0, 83 (dd, J=6.5, 3.6 Hz, 6H).

Example B2.

- 44 046212

Receiving connection 3:

as salt HC1

A mixture of (C)-X-benzylazepan-4-amine intermediate 4 (129 mg, 0.465 mmol), 4-chloro-6-(2,2,2-trifluoroethyl)thieno[2,3L]pyrimidine (CAS [1628317-85-0]), (118 mg, 0.465 mmol), prepared as described in Journal of Medicinal Chemistry (2016), 59(3), 892-913, and DIEA (0.32 ml, 1.86 mmol ) in ACN (5 ml) was stirred at RT. during the night. The solution was cooled and the residue was poured into cooled water. K2CO3 (solid) was added and the mixture was extracted with DCM, the organic layer was dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: unmodified irregular silica, 40 g, mobile phase: gradient 100% DCM, 0% MeOH to 97% DCM, 3% MeOH, 0.1% NH4OH). Fractions containing the product were collected and evaporated to dryness to give 117 mg (60% yield) N)-N-benzyl-1-(6-(2,2,2-trifluoroethyl)thieno[2,3d]pyrimidine-4 -yl)azepan-4-amine. This residue was dissolved in acetone and converted to the hydrochloric acid salt by treatment with HCl (4N, in dioxane), the precipitate was filtered and the solid was dried to give 115 mg (yield 48.5%) of compound 3, which is C ₂₁ H ₂₃ F ₃ N4S. 1.7HCl. 1.4H ₂ O, mp: 134°C (Kofler), optical rotation: +59.1° (365 nm, DMF, 20°C, c = 3.03 mg/ml).

1H NMR (500 MHz, DMSO- _d6 ) δ ppm 9.22 (br s, 2H) 8.44 (s, 1H) 7.67 (s, 1H) 7.52-7.58 (m, 2H) 7.377.44 (m, 3H) 4.07-4.19 (m, 5H) 3.99-4.06 (m, 1H) 3.75-3.86 (m, 2H) 3.20 (br s , 1H) 2.47 (br s, 1H) 2.24 (br d, J=12.3 Hz, 1H) 2.03-2.13 (m, 1H) 1.97 (q, J=9, 9 Hz, 1H) 1.80 (br d, J=11.0 Hz, 1H) 1.59-1.71 (m, 1H).

Example B3.

Receiving connection 4:

Similar to compound 3, starting from (A)-X-benzylazepan-4-amine and intermediate 5, ^)-N-benzyl-1-(6-(2,2,2-trifluoroethyl)thieno[2,3L] was obtained pyrimidin-4-yl)azepan-4-amine (97 mg, 50% yield). This compound was dissolved in acetone and converted to the hydrochloric acid salt by treatment with HCl (4N, in dioxane), the precipitate was filtered and the solid was dried to give 80 mg (yield 34%) of compound 4, which is C ₂₁ H ₂₃ F ₃ N ₄ S. 1.6HCl. 1H ₂ O, mp: 230°C (Kofler), optical rotation: -60.6° (365 nm, DMF, 20°C, c = 2.84 mg/ml).

Example B4.

- 45 046212

Preparation of compound 3a:

and alternative preparation of compounds 3 and 4.

Mixture of N-benzylazepan-4-amine (166 mg, 0.81 mmol), (CAS [1565450-95-4]), 4-chloro-6-(2,2,2trifluoroethyl)thieno[2,3L]pyrimidine (CAS [1628317-85-0]), (186 mg, 0.74 mmol), prepared as described in Journal of Medicinal Chemistry (2016), 59(3), 892-913, and DIPEA (0.26 ml, 1, 48 mmol) in iPrOH (5 ml) was heated at 90°C overnight. The solution was cooled to RT, then concentrated and the residue was taken up with DCM, the organic layer was washed with water, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: SiOH irregular particle, 15-40 µm, 24 g, MERCK, mobile phase: gradient 95% DCM, 5% MeOH (+ 10% NH4OH)). Fractions containing the product were collected and evaporated to dryness to obtain 223 mg (yield 72%) of racemic N-benzyl-1-(6-(2,2,2trifluoroethyl)thieno[2,3L]pyrimidin-4-yl)azepan- 4-amine, which is compound 3A. The two enantiomers were separated by chiral SFC (stationary phase: CHIRALCEL OJ-H, 5 µm, 250x20 mm, mobile phase: 80% CO ₂ , 20% EtOH (0.3% iPrNH ₂ )). Fractions containing the product were collected and evaporated to dryness to obtain, respectively, 103 mg (33% yield) of the first eluted enantiomer A, which corresponds to compound 3 of the absolute configuration (R), and 102 mg (33% yield) of the second eluted enantiomer B, which corresponds to connection 4 of the absolute configuration (S).

Each enantiomer was individually dissolved in acetone and converted to the hydrochloric acid salt by treatment with HCl (4N, in dioxane), the precipitate was filtered and the solid was dried to give 100 mg of compound 3, which is C ₂₁ H ₂₃ F ₃ N ₄ S . 3.4HCl. 2.7H2O, mp: 130°C (Kofler; resin) and 98 mg of compound 4 C ₂₁ H ₂₃ F ₃ N ₄ S. 2.4HCl. 1H2O, mp.: 224°C (Kofler).

Alternative preparation of compound 3A.

In flow N2 at r.t. a solution of intermediate 3 (1.5 g, 4.55 mmol), benzylamine (1.49 mL, 13.66 mmol) and acetic acid (0.52 mL, 9.11 mmol) in MeOH (15 mL) and DCE (15 ml) was stirred at RT. for 2 hours. NaBN(OAc) ₃ (2.12 g, 10.02 mmol) was then added and the mixture was stirred at room temperature. for 48 hours. The solution was poured into cooled water, the basicity was increased with 3N. NaOH. The product was extracted with DCM. The organic layer was washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: irregular particle SiOH, 15-40 µm, 24 g, mobile phase: 96% DCM, 4% MeOH (+ 10% NH ₄ OH)). Fractions containing product were collected and evaporated to dryness to obtain 1.9 g of compound 3A (99% yield).

The compounds shown in the table below were prepared by using a method similar to that described for the preparation of the compound above, starting from the corresponding starting materials.

- 46 046212

Example B5.

Getting connection 6:

In a stream of N2, a solution of intermediate 3 (250 mg, 0.76 mmol), isoindoline (CAS[496-128]) (361 mg, 3.04 mmol) and acetic acid (96 μL, 1.67 mmol) in THF ( 10 ml) was stirred at room temperature. for 2 hours. NaBH(OAc) ₃ (354 mg, 1.67 mmol) was then added and the mixture was stirred at room temperature. during the night. The mixture was carefully poured into ice water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (stationary phase: SiOH irregular particle, 15-40 µm, 24 g, MERCK, mobile phase: gradient from 0.1% NH4OH, 98% DCM, 2% MeOH to 0.1% NH4OH , 95% DCM, 5% MeOH). Fractions containing product were collected and evaporated to dryness to obtain 130 mg of compound 6 (40% yield). This fraction was crystallized from Et ₂ O, the precipitate was filtered off and dried under vacuum to obtain 40 mg of compound 6, M.R. = 111°C (DSC).

The compounds shown in the table below were prepared by using a method similar to that described for the preparation of the compound above, starting from the corresponding starting materials.

- 47 046212

Connection number Structure Exit Compound 7 (from intermediate 3) F ''-MH 0 x _F Λ L j f N in the form of HCl salt Compound 8 (from intermediate 3) / У -F V—NH 0 , О ¹ ' /Т ^F . As HCl salt Compound 9 (from intermediate 3) \ ABOUT /\—NH 0' - i GM F as HCl salt Compound 12 (from intermediate 3) M.R. = 94°C (according to Kofler) NH 1 / ' N ''''(I ~ ^N F - J 1 • _F ,. 53% Compound 52 (from intermediate 3 and 23-2-amino-N,3dimethylbutanamide a CAS [87105-268]) 0, / _h 'Cgchn /—C ^z NH \ / Τ' Ϊ ' C- ¹ 1 - ¹ . b N F ⁴ 47% Compound 53 (from intermediate 3 and benzyl[3- (dimethylamino)opyl]amine, CAS: [32857-22-0]) ^s ' ]L / \ N— 1 / / X··''1'ΐ 7%

- 48 046212

Compound 54 (from intermediate 3 and 1-(1-methyl-1Hpyrazol-4yl)ethylamine, CAS: [91178833-5]) f Ν' Ml 1 / N 1 —' ί Ν /F 85% Compound 55 (from intermediate 3 and 1-tetrahydro-2Hpyran-4ylmethanamine, CAS: [13029079-8]) ΗΝ~~\ Ν' χ-ιϋ F in the form of salt HC1 Compound 56 (from intermediate 3 and Ν'-benzyl-N,Νdimethylethylenediamine, CAS: [109-55-7]) \ N— NH 0 A _f ^F in the form of salt HC1 Compound 57 (from intermediate 3 and Ν'-benzyl-N,Νdimethylethylenediamine, CAS: [103-55-9]) A Ν—χ / _ζ ---( Ν ί J Ν' _ Α' ^Ν 'U, s-'No. ^J 54%

- 49 046212

Compound 58 (from compound 11 and isobutyraldehyde a, CAS: [78-842]) X and . n _{g g} 1 I 62% Compound 59 (from the compound 3A and oxetan-3one, CAS: [6704-31-0]) .J.L. Chu __ kk-ch [ ^g ΓΊ Ό 34% Connection 60 (from connection BEHIND and 1-methyl-1Hpyrazole-4carbaldehyde, CAS [25016-11- 9] ) N --- i ' ¹ ' N '.--3' ? _ 1 ⁵ N > in the form of salt HC1 Compound 61 (from intermediate 34 and 1-methyl-1Hpyrazole-4carbaldehyde, CAS: [25016-119]) / k J w 1 Λ|' F ' ^J as salt HC1 Compound 62 (from intermediate 3 and 3dimethylaminopropylamine, CAS [109-55-7]) \n— \\NII Z A\''Ν' h vV 1 as HC1 salt Compound 63 (from compound 62 and 1-methyl-1Hpyrazole-4carbaldehyde, CAS [25016-119]) . And y h N— ^z ___/ / ^h 1 f in the form of salt HC1

- 50 046212

Example B6.

Preparation of compound 10a:

as salt HC1

HCl (0.45 mL, 1.81 mmol, 4 M solution in dioxane) was added dropwise at 5°C to a solution of intermediate 12A (100 mg, 0.18 mmol) in DCM (3 mL) and the mixture was stirred at k.t. for 15 hours. The reaction mixture was evaporated to dryness, the residue was taken up with Et ₂ O and the solvent was again evaporated to dryness (x2) to obtain a solid residue (60 mg) of compound 10A as the HCl salt (M.P = 22O °C according to Kofler).

The compound shown in the table below was prepared by using a method similar to that described for the preparation of the compound above, starting from the appropriate starting materials.

Connection number

Structure

12V)

M.R.

Kofler)

10V connection (from intermediate connection

205 °C (according to

Example B7.

Receiving connection 11:

1-Methyl-1H-pyrazole-4-carbaldehyde (CAS: [25016-11-9]) (100 mg, 0.9 mmol) was added dropwise at 20°C to a solution of intermediate 9 (300 mg, 0.9 mmol) and Et ₃ N (0.23 ml, 1.64 mmol) in MeOH (5 ml). The mixture was stirred at room temperature. for 4 hours. The mixture was cooled to 0°C, then NaBH ₄ (47 mg, 1.23 mmol) was added in portions and the mixture was stirred at room temperature. for 15 hours. The mixture was poured into ice water containing 10% NH4Cl and extracted three times with DCM. The organic layers were collected, washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: SiOH irregular particle, 15-40 µm, 24 g, GRACE, mobile phase: gradient 0.1% NH4OH, 97% DCM, 3% MeOH to 0.1% NH4OH , 95% DCM, 5% MeOH). Fractions containing product were collected and evaporated to dryness to obtain 140 mg (40% yield) of compound 11.

The compound shown in the table below was prepared by using a method similar to that described for the preparation of compound 11, starting from the corresponding starting material.

- 51 046212

Connection number Structure Compound 69 (from intermediate 14 and 4- pyrimidinecarboxaldehyde CAS[2435-50-9]) N Nl 1 N ^Y k/DA > ^J .%. ^s 'Ν' F ¹

Example B8.

Preparation of compounds 11a and 11b:

The enantiomers of the racemic mixture of compound 11 (135 mg) were separated using chiral SFC (stationary phase: Chiralpak AD-H, 5 μm, 250x30 mm, mobile phase: 60% CO ₂ , 40% iPrOH (0.3% iPrNH ₂ )). Fractions containing the product were collected and evaporated to dryness to provide 62 mg (46% yield) of the first enantiomer eluted, compound 11A, and 65 mg (48% yield) of the second enantiomer eluted (compound 11B free base).

Compound 11A was lyophilized with acetonitrile/water (20/80) to obtain 46 mg of compound 11A. Compound 11B in the form of a free base was dissolved in 2 ml of ACN, 6N was added dropwise. HCl in iPrOH (2 eq.) at 10°C, then Et ₂ O. The mixture was triturated, filtered and dried to obtain 25 mg of compound 11B (as HCl salt).

The compounds shown in the table below were prepared by using a method similar to that described for the preparation of the compound above, starting from the corresponding starting materials.

- 52 046212

- 53 046212

Connection 57A and connection 57B from separation

IL via

SFC •k connections (stationary phase:

CHIRALPAK AD-H, 5 µm, 250*30 mm, mobile phase:

Connection 57A Connection 57B

CO ₂ , 20% iPrOH (0.3% (as HC1 salt) (as HC1 salt) iPrNH ₂ ))

Connection connection separation by connection (fixed

Lux

Cellulose-2 microns,

250*21.2

58A

58V

58A Connection 58B

Compound mobile phase:

CO ₂ , 40% MeOH (as HC1 salt) (as HC1 salt) iPrNH ₂ ) ) separation by connection (stationary

CHIRALPAK AD-H mobile phase:

iPrNH ₂ ) )

Connection 59A connection 59B micron, 250*30 mm

CO ₂ , 40% MeOH (0

- 54 046212

Compound 60A and Compound 60B from SFC separation of Compound 60 (stationary phase: Lux Cellulose-2, 5 µm, 250*30 mm, mobile phase: 50% CO ₂ , 50% MeOH (0.3% iPrNH ₂ )) l % 1 J F /--\ J J 60A connection 60V connection (as HC1 salt) (as HC1 salt) Compound 67A and Compound 67B from SFC separation of Compound 67 (stationary phase: CHIRALPAK AD-H, 5 µm, 150*30 mm, mobile phase: 87% CO ₂ , 13% MeOH (0.3% !PrNH ₂ )) ΐί^η mixture mixture cis- || 'l trans- Ф°Р ^М forms Ό Ό Compound 67A Compound 67B (as HC1 salt) (as HC1 salt)

- 55 046212

Example B10.

Getting connection 15:

Under a stream of N2 at 0°C, DIAD (0.219 mL, 1.11 mmol) was added to a solution of intermediate 2 (0.3 g, 0.905 mmol), phenol (CAS: [108-95-2]), (102 mg, 1.09 mmol) and PPh ₃ (371 mg; 1.42 mmol) in THF (8 ml). We ensured that the mixture achieved and stirred overnight. The reaction mixture was evaporated to dryness.

The crude product was purified by silica gel column chromatography (eluent: heptane/EtOAc 1/0 to 3/1). The required fraction was collected and concentrated to give 0.211 g of crude compound, which was purified by reverse phase chromatography (stationary phase: YMC-actus Triart-C18, 10 µm, 30x150 mm, mobile phase: gradient from 40% NH4HCO3, 0.2% , 60% ACN to 0% NH4HCO3, 0.2%, 100% ACN). Fractions containing product were collected and evaporated to dryness to obtain 0.145 g (39% yield) of product, which crystallized from DIPE by sonication, the precipitate was filtered and dried to obtain: 0.095 g (26%) of compound 15.

Example B11.

Getting connection 16:

Nh\/

N

F. _x r4..1! J

Ar ^N

F as HC1 salt

In stream N ₂ a solution of intermediate 3 (200 mg, 0.544 mmol), 4-methylbenzylamine (CAS[104-84-7]) (66 mg, 0.544 mmol), and NaBH(OAc) ₃ (224 mg, 1.06 mmol) in DCE (10 ml) was stirred at room temperature. during the night. A saturated solution of NaHCO ₃ (10 ml) and DCM (10 ml) was added, the mixture was separated, the aqueous layer was extracted with DCM (10 ml x 2). The organic layers were combined, washed with water, then dried over Na ₂ SO ₄ and evaporated to obtain 300 mg of the crude compound. The residue was purified by silica gel chromatography (stationary phase: Kromasil, 150x25 mmx10 µm, mobile phase: gradient of 47% water (0.05% ammonium hydroxide, v/v), 53% ACN to 37% water (0.05 % ammonium hydroxide, v/v), 63% ACN). Fractions containing the product were collected and evaporated to dryness, the residue was dissolved in ACN (3 ml), water (20 ml) and HCl (12 M, 0.15 ml) were slowly added successively. The pure solvent was lyophilized to obtain 250 mg (97% yield) of compound 16 as HCl salt (mp: 262-264°C).

^1H NMR (400 MHz, DMSO-d6) δ ppm 9.55 (br s, 2H), 8.57 (s, 1H), 7.74 (s, 1H), 7.46 (br d, J= 7.5 Hz, 2H), 7.17 (br d, J=7.5 Hz, 2H), 4.15 (br d, J=11.0 Hz, 6H), 3.83 (br d, J =9.7 Hz, 2H), 3.14 (br d, J=13.2 Hz, 1H), 2.482.38 (m, 1H), 2.28 (s, 4H), 2.14-1, 96 (m, 2H), 1.84-1.71 (m, 2H).

The compounds shown in the table below were prepared by using a method similar to that described for the preparation of the compound above, starting from the appropriate starting materials.

- 56 046212

Connection number Structure Compound 17 (from intermediate 3 and 3(methylaminomethyl)benzylamin, CAS [1035316-05-2]) V. _ J 1 ^F in the form of salt HC1 Compound 18 (from intermediate 3 and 2methoxy-5methylphenyl)methanamine hydrochloride, CAS: [102439-19-0]) ' ----O 1 , , - j _h 1 ' F ^F in the form of salt HC1 Compound 19 (from intermediate 3 and 2-methylbenzylamine, CAS: [100-81-2]) Ό / _NH / ''1 'Ν' 1 J-./CN J Fy S- -N ^F as salt HC1 Compound 21 (from intermediate 3 and 2-hydroxybenzylamine, CAS: [932-30-9]) / \ y ^F as salt HC1 Compound 22 (from intermediate 3 and 2-methoxybenzylamine, CAS [6850-57-3]) .3, with .у/ / ''F ^F in the form of salt HC1

- 57 046212 z

and 3-methyl

CAS: [1

Example B12.

Getting connection 26:

HCl (0.74 ml, 2.94 mmol, 4 M solution in dioxane) was added dropwise at 5°C to a solution of intermediate 17 (150 mg, 0.29 mmol) in DCM (5 ml) and the mixture was stirred at .T. for 4 hours. The reaction mixture was evaporated to dryness, the residue was taken up with Et ₂ O, filtered and dried under vacuum overnight to obtain a precipitate (69 mg) of compound 26 as the HCl salt (mp = 156°C (Kofler), optical rotation: +40.24° (365 nm, DMF, 20°C, c = 2.79 mg/ml)).

1H NMR (400 MHz, DMSO-d6) δ ppm 9.18 (br s, 2H) 8.52 (s, 1H) 7.79 (s, 2H) 7.71 (s, 1H) 3.95-4 .25 (m, 6H) 3.62-3.91 (m, 2H) 3.15 (br s, 1H) 2.43 (br s, 1H) 2.15-2.26 (m, 1H) 2 .03-2.13 (m, 1H) 1.74-1.99 (m, 2H) 1.55-1.72 (m, 1H).

Example B13.

Getting connection 27:

At k.t. TBAF (0.35 ml; 0.35 mmol, 1 M in THF) was added dropwise to a solution of intermediate 19 (200 mg; 0.35 mmol) in THF (10 ml) and the reaction mixture was stirred at room temperature for 5 h.

The reaction mixture was poured into 10% aqueous K ₂ CO ₃ solution and extracted with EtOAc. The organic layer was washed with 10% aqueous K ₂ CO ₃ (2x30 ml), water (30 ml) and brine (30 ml), dried over MgSO ₄ , filtered and evaporated to dryness to obtain 150 mg of crude compound. The residue was purified by silica gel chromatography (stationary phase: irregular particle SiOH, 24 g, mobile phase: gradient from 0.1% _NH4OH , 95% DCM, 5% MeOH to 0.1% NH4OH, 90% DCM, 10% MeOH). Fractions containing the product

- 58 046212 was collected and evaporated to dryness to obtain 34 mg (yield 21%) of product, which was purified using reverse phase (stationary phase: YMC-actus Triart-C18, 10 µm, 30x150 mm, mobile phase: gradient from 75% NH4HCO3 (0.2%), 25% ACN to 35% NH4HCO3 (0.2%), 65% ACN). Fractions containing product were collected and evaporated to dryness to yield 25 mg (16% yield) of compound, which was lyophilized with ACN/water to yield 17 mg (11% yield) of compound 27.

The compound shown in the table below was prepared by applying a method similar to that described for the preparation of the compound above, starting from the corresponding starting material.

Example B14.

Getting connection 28:

1-Methyl-1H-imidazole-5-carboxaldehyde (CAS [39021-62-0]), (100 mg, 0.91 mmol) was added at 10°C under N ₂ to a solution of intermediate 15 (150 mg, 0 .45 mmol) in MeOH (6 ml).

The mixture was stirred at room temperature. for 5 hours. NaBH ₄ (26 mg, 0.68 mmol) was then added and the mixture was stirred at room temperature. for 15 hours. The mixture was poured into ice water and extracted with DCM.

The organic layer was dried over MgSO ₄ , filtered and evaporated to dryness to obtain 350 mg of crude compound.

The residue was purified by silica gel chromatography (stationary phase: irregular particle SiOH, 15-40 µm, 40 g, mobile phase: gradient 0.5% NH4OH, 93% DCM, 7% MeOH). Fractions containing product were collected and evaporated to dryness to yield 113 mg (59% yield) of compound, which was lyophilized with a mixture of ACN and water to yield 66 mg of compound 28.

The compounds shown in the table below were prepared by using a method similar to that described for the preparation of the compound above, starting from the corresponding starting materials.

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Example B15.

Getting connection 31:

HCl (0.4 ml, 1.6 mmol, 4 M solution in dioxane) was added dropwise at 5°C to a solution of intermediate 21A (84 mg, 0.16 mmol) in MeOH (4 ml) and the mixture was stirred at .T. for 24 hours. The reaction mixture was evaporated to dryness, cooled with an ice water bath, the residue was taken up with Et ₂ O, the precipitate was filtered and dried under vacuum overnight to give the compound as a solid (67 mg, ), compound 31 in the form of HCl salt, m.p. = 184°C (Kofler), (optical rotation: +13.97° (589 nm, DMF, 20°C, s=3.15 mg/ml)).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.44 (s, 1H) 8.23-8.36 (m, 1H) 7.68 (s, 1H) 4.12-4.27 (m , 5H) 3.91 (br d, J=7.3 Hz, 4H) 3.58-3.70 (m, 2H) 3.39-3.46 (m, 1H) 3.22 (br s, 1H) 2.43 (br s, 1H) 2.20 (br d, J=12.3 Hz, 1H) 1.83-2.13 (m, 4H) 1.60 (q, J=11.2 Hz, 1H) 0.93 (d, J=6.6 Hz, 3H) 0.88 (d, J=7.3 Hz, 3H).

The compounds shown in the table below were prepared by using a method similar to that described for the preparation of the compound above, starting from the corresponding starting materials.

Connection number Structure Connection 32 (from intermediate connection 21B) V _g<i NH ί / IJ Ν ' 1 L' ^N Λ - « in the form of salt HC1 Compound 33 (from intermediate 21) / V- |Ψ ^! ΗΝ O R. Ύ'7 X S-- '· _Ν ·' F in the form of salt HC1

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Example B18.

Getting connection 39:

TFA (1.05 ml; 13.75 mmol) was added dropwise at 5°C to a solution of intermediate 28 (200 mg; 0.34 mmol) in DCM (12 ml) and the mixture was stirred at room temperature. for 48 hours. The mixture was then evaporated to dryness, then the residue was taken up with DCM and H ₂ O, and its basicity was increased with 3N. NaOH. The organic layer was extracted (3 times), dried over MgSO ₄ and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: unmodified irregular silica, 40 g, mobile phase: 1% NH4OH, 90% DCM, 10% MeOH). Fractions containing product were collected and evaporated to dryness to give 110 mg (66%). This fraction was dissolved in ACN (2 ml) and converted with HCl (4 M, in dioxane) to the HCl salt (75 mg).

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Example B20.

Getting connection 44:

A mixture of 4-chloro-6-(2,2,2-trifluoroethyl)thieno[2,3^]pyrimidine prepared as described in Journal of Medicinal Chemistry (2016), 59(3), 892-913 (CAS[1628317- 85-0]) (0.248 g; 0.98 mmol), intermediate 45 (4-benzyloxyazepane HCl salt) (0.285 g), TEA (0.51 ml; 2.95 mmol) in iPrOH (8 ml) was heated at 90°C for 1 hour 30 minutes. The solution was cooled to RT, concentrated and the residue was taken up with DCM, the organic layer was washed with water, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (40 g, 15-40 µm, eluent: DCM/MeOH: 100/0 to 90/10). Fractions containing the product were collected and evaporated to dryness. The residue was lyophilized with acetonitrile/water 20/80 to give: 0.308 g of compound 44 (74%).

Example B23.

Getting connection 49.

Compound 49 in the table below was prepared by using a method similar to that described for the preparation of intermediates 12A and 12B, starting from the corresponding starting materials.

Connection number Structure Compound 49 (from intermediate 35 and methylamine hydrochloride, CAS [593-51-1]) y--(RS ^f y^ _s X _N JF

Example B24.

Obtaining connection 65.

In flow No. ₂ at r.t. added titanium ethoxide (CAS[3087-36-3]), (0.52 ml, 2.52 mmol) to a solution of intermediate-3 (410 mg, 1.25 mmol) and 1-methyl-4, 5,6,7-tetrahydroindazol-4-amine (CAS [927803-64-3]), (205 mg, 1.36 mmol) in MeOH (8 ml). The solution was stirred at room temperature. for 1 hour. NaBH(OAc) ₃ (804 mg, 3.79 mmol) was then added and the mixture was stirred at room temperature. within 2 days. The solution was poured into chilled water, increased in basicity with K ₂ CO ₃ powder, DCM was added and the mixture was filtered through a Celite® pad. The product was extracted with DCM. The organic layer was combined, washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: irregular particle SiOH, 15-40 µm, 40 g, mobile phase: gradient 100% DCM, 0% MeOH to 0.2% NH ₄ OH, 95% DCM, 5 % MeOH). Fractions containing product were collected and evaporated to dryness to give 417 mg (72% yield) of compound 65.

The compounds shown in the table below were prepared by using a method similar to that described above, starting from the appropriate starting materials.

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Connection number Structure Exit Compound 66 (from intermediate 3 and 2R-indazol-4amine, 4,5,6,7tetrahydro-2methyl-, hydrochloride (CAS[1803561-525])) 1 N O IIN—<; s/N Ar ^b 'E' F ^g 78% Compound 67 (from intermediate 42 and benzylamine (CAS[100-46-9]) O ·..·.· \ V IMH \ 1 F~% SS-'f' _F 69% as crude product Connection 68 (from intermediate 43 and benzylamine (CAS[100-46-9]) Ci ⁴ NH / .> % \ 1 'lA . A F-S'-NF F 110% as crude product

Example B25.

Preparation of compounds 65A, 65B, 65C and 65D:

Connection 65C Connection 65D

Compound 65 (417 mg; 0.9 mmol) was resolved using chiral SFC (stationary phase: Chiralpak AD-H, 5 µm, 250x30 mm, mobile phase: 65% CO ₂ , 35% EtOH (0.3% iPrNH ₂ ) ). Factions, with

- 63 046212 containing products were collected and evaporated to dryness to obtain 81 mg (yield 14%) of the first eluted diastereomer A. This fraction was lyophilized from ACN/water to obtain 79 mg of compound 65A as a white powder (optical rotation = -20 ° (589 nm, c = 2.60 mg/ml, DMF, 20°C)) to obtain 67 mg (12% yield) of the second eluted diastereomer B. This fraction was lyophilized from ACN/water to obtain 60 mg of compound 65B as a white powder (optical rotation = -21.72° (589 nm, c = 2.44 mg/ml, DMF, 20°C)) and yielded 84 mg (15% yield) of the third eluted diastereomer C. This fraction lyophilized from ACN/water to obtain 83 mg of compound 65C as a white powder (optical rotation = +10.74° (589 nm, c = 2.42 mg/ml, DMF, 20°C)) and to obtain 50 mg (9% yield) of the fourth eluted diastereomer D. This fraction was lyophilized from ACN/water to obtain 44 mg of compound 65D as a white powder (optical rotation = +11.34° (589 nm, c = 2.38 mg/ml, DMF, 20°C)).

The compounds shown in the table below were prepared by using a method similar to that described for the preparation of the compound above, starting from the corresponding starting materials.

Connection number Structure Compound 66A, Compound 66B, Compound 66C and Compound 66D from SFC separation of Compound 66 (stationary phase: CHIRALPAK AD-H, 5 µm, 250*30 mm, mobile phase: 65% CO ₂ , 35% EtOH (0.3% iPrNH ₂ ) ) i 1 O k - , ⁱ ·. and ' - —| b 1 L Connection 66A Connection 66B ! 1 N %__у % 1/ N / \ N , N /-5 \ , .;$ \____/ - s ) ¹ J 'M 'I- 1 - - 1 Ϊ ku-SGZ Connection 66C Connection 66D

- 64 046212 li in 2 ml of ACN, 3 equiv was added dropwise. 4n. HCl in dioxane (71 µl; 0.28 mmol) at 10°C, Et ₂ O was added and after 30 min the solution was evaporated to dryness, Et ₂ O was added and the precipitate was filtered and dried to obtain 20 mg of compound 68A (MR = 136 °C/Kofler). Fractions containing the second eluted diastereoisomer B were collected and evaporated to dryness to obtain 42 mg (yield 22%), which were dissolved in 2 ml ACN, 3 equiv was added dropwise. 4n. HCl in dioxane (210 µl; 0.84 mmol) at 10°C, Et ₂ O was added and after 30 min the solution was evaporated to dryness, Et ₂ O was added and the precipitate was filtered and dried to give 18 mg of compound 68B (MP= 150°C/Kofler).

The second mixture of diastereoisomers C, which was obtained during the first purification on silica gel, was purified using SFC (stationary phase: NH2 5 μm, 150x30 mm, mobile phase: 90% CO ₂ , 10% MeOH (0.3% iPrNH ₂ )). Fractions containing diastereoisomers C were collected and evaporated to dryness to obtain 14 mg (yield 7%) of compound 68C (mixture of cis isomers or mixture of trans isomers).

Example B27.

Preparation of compounds 54A, 54B, 54C and 54D:

Connection 54A connection 54B

N

Connection 54C connection 54D

Compound 54 (570 mg) was purified using chiral SFC (stationary phase: CHIRALPAK AD-H, 5 µm, 250x30 mm, mobile phase: 80% CO ₂ , 20% EtOH (0.3% iPrNH2)) to obtain 237 mg of the first eluted mixture of diastereoisomers A and B, 112 mg of the second eluted diastereoisomer C and 93 mg of the third eluted diastereoisomer D. The second separation was carried out with a mixture of diastereoisomers A and B using CHIRALPAK IC, 5 µm, 250x21.2 mm, mobile phase: 60% CO ₂ , 40% EtOH (0.3% iPrNH ₂ )) to obtain 116 mg of the first eluted diastereoisomer A and 100 mg of the second eluted diastereoisomer B. Diastereoisomer A was dissolved in 5 ml of MeOH, 2 eq. 4n. HCl in dioxane (133 µl; 0.53 mmol) at 10°C, Et ₂ O was added and after 30 min the solution was evaporated to dryness, Et 2 O was added and the precipitate was filtered and dried to obtain 116 mg of compound 54A as the HCl salt (MP =160°C/Kofler).

Diastereoisomer B was dissolved in 5 ml of MeOH, 2 equiv was added dropwise. 4n. HCl in dioxane (114 µl; 0.46 mmol) at 10°C, add Et ₂ O and after 30 min the solution is evaporated to dryness, add Et ₂ O and the precipitate is filtered and dried to obtain 104 mg of compound 54B as the HCl salt (MP=160°C/Kofler).

Diastereoisomer C was dissolved in 5 ml of MeOH, 2 equiv was added dropwise. 4n. HCl in dioxane (128 µl; 0.51 mmol) at 10°C, Et ₂ O was added and after 30 min the solution was evaporated to dryness, Et ₂ O was added and the precipitate was filtered and dried to obtain 123 mg (yield 17%) of the compound 54C in the form of HCl salt (MP=160°C/Kofler).

Diastereoisomer D was dissolved in 5 ml of MeOH, 2 equiv was added dropwise. 4n. HCl in dioxane (106 µl; 0.42 mmol) at 10°C, Et ₂ O was added and after 30 min the solution was evaporated to dryness, Et ₂ O was added and the precipitate was filtered and dried to obtain 95 mg (yield 13%) of the compound 54D in the form of HCl salt (MP=160°C/Kofler).

Analytical part

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NMR.

NMR experiments were performed using a Bruker Avance 500 spectrometer equipped with a 5 mm Bruker BBFO probe head with z-gradients and operating at 500 MHz for protons and 125 MHz for carbon atoms, or using a Bruker Avance DRX 400 spectrometer using an internal deuterium lock and equipped with a reverse double resonance probe head (1H, ^13C , SEI) with z-gradients and operating at 400 MHz for protons and 100 MHz for carbon atoms. Chemical shifts (δ) were recorded in parts per million (ppm). J values are expressed in Hz.

LCMS (liquid chromatography/mass spectrometry).

General procedure.

High performance liquid chromatography (HPLC) measurements were performed using an LC pump, diode array detector (DAD) or UV detector and column as described in the respective methods. If necessary, additional detectors were included (see table of methods below).

The column flow was directed to a mass spectrometer (MS), which was equipped with an atmospheric pressure ionization source. It is within the purview of one skilled in the art to set custom parameters (eg, scan range, dwell time, etc.) to obtain ions that allow the nominal monoisotopic molecular weight (MW) of a compound to be determined. Data collection was carried out using appropriate software.

Compounds were described by their experimental retention time (Rt) and ion values. Unless otherwise indicated in the data table, the molecular ion indicated corresponds to [M+H]+ (protonated molecule) and/or [M-H] ^- (deprotonated molecule). If the compound was not directly capable of ionization, the type of adduct was indicated (ie [M+NH ₄ ]+, [M+HCOO] ^- , etc.). For molecules with complex isotopic distributions (Br, Cl, etc.), the indicated value is the value obtained for the smallest isotope mass. All results are subject to experimental errors, which are usually associated with the method used.

As used herein, SQD means Single Quadrupole Detector, RT means Room Temperature, VEN means Bridged Ethyl Siloxane/Silica, HSS means High Strength Silicon Dioxide, DAD means Diode Array Detector.

Table 1a

LCMS method codes (flow rate in mL/min; column temperature (T) in °C; analysis time in minutes)

Method code Device Column Mobile phase Gradient Flow rate T columns Time I anal Iza 1 Waters: Acquity UPLC® - DAD and Quattro Micro™ Waters: VEN C18 (1.7 µm, 2.1x100 mm) A: 95% CH3COONH4 7 mM/5% CH ₃ CN, B: CH ₃ CN From 84.2% A for 0.49 min. up to 10.5% A in 2.18 minutes, holding at 0.343 40 6.2

- 66 046212

for 1.94 minutes, back to 84.2% A in 0.73 minutes. , hold for 0.73 min. 2 Waters: Acquity® H- Class - DAD and SQD2™ Waters: VEN C18 (1.7 µm, 2.1x100 mm) A: 95% CH3COONH4 7 mM/5% CH ₃ CN, B: CH ₃ CN From 84.2% A to 10.5% A in 2.18 minutes. , hold for 1.96 min., back to 84.2% A in 0.73 min. , hold for 0.73 min. 0.343 40 6.1 3 Waters: Acquity UPLC® H- Class- DAD and QDa BEH®-C18 (1.7 MKM, 2.1x100 mm) A: 95% CH3COONH4 7 mM/5% CH ₃ CN, B: CH ₃ CN From 95% A to 5% A in 1 minute, hold for 1.6 minutes, back to 95% A in 0.2 minutes, hold for 0.5 minutes. 0.5 40 h, 3 4 Waters: Acquity UPLC® H- Class- DAD and SQD 2 Waters BEH®C18 (1.7 MKM, 2.1x50 mm) A: 95% CH3COONH4 7 mM/5% CH ₃ CN, B: CH ₃ CN From 95% A to 5% A in 1 minute, hold for 1.6 minutes, back to 95% A in 0.2 minutes, hold for 0.5 minutes. 0.5 40 h, 3

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5 Agilent: 1200 - DAD and MSD6110 Phenomenex : Luna-C18 (5 µm, 2x50 mm) A: 0.1% CF ₃ COOH in water, B: 0.05% CF3COOH in CH ₃ CN From 100% A for 1 min. up to 40% A in 4 minutes, up to 15% A in 2.5 minutes, back to 100% A in 2 minutes. 0.8 50 10 6 Agilent: 1200 - DAD and MSD6110 Phenomenex : Luna-C18 (5 µm, 2x50 mm) A: 0.1% CF3COOH in water, B: 0.05% CF3COOH in CH ₃ CN From 90% A for 0.8 min. up to 20% A in 3.7 minutes. , holding for 3 minutes, back to 90% A in 2 minutes. 0.8 50 10

Melting points.

For a number of compounds, melting points (MPs) were determined using DSC1 (Mettler-Toledo). Melting points were measured at a temperature gradient of 100%/minute. The maximum temperature was 300°C. Values represent peak values.

For a number of compounds, melting points were obtained using a Kofler hot table (indicated as (K)), consisting of a heated plate with a linear temperature gradient, a sliding pointer, and a temperature scale in degrees Celsius.

Table 1b

LCMS and melting point data. Connection no. means connection number;

Rt means retention time in min.

No. conn. T . pl. (°C) Rt (min.) % area UV [M+N]+ Adduct Way LCMS 1-13 1.46 88% 459.5 3 BEHIND 1.2 421.3 3 3* 134°C (TO) 2.75 100 421, 1 479.3 [M+CH3COO]- 1 4* 230°C (TO) 2.74 100 421, 1 479.3 [M+CH3COO]- 1 1-1 1.24 93.84 374.4 3 1-2 2.4 97.56 332 330 1

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1-3 1.12 100 330, 1 328.1 3 5* 244°C (K) 2.67 100 395.4 453.3 [M+CH3COO]- 2 5a 2.67 97.56 395.4 453.3 [M+CH3COO]- 2 BIA 2.35 100 387.1 445.3 [M+CH3COO]- 1 BIB 2.35 100 387.1 445.4 [M+CH3COO]- 1 I 10* 18 100 331, 4 389.3 [M+CH3COO]- 2 I 11* 1.86 100 331, 4 389.4 [M+CH3COO]- 2 10B* 2.32 100 454.4 512.3 [M+CH3COO]- 2 6 111.41 °C / 27.83 J/g ^<a) 3.3 96.53 433.2 491.4 [M+CH3COO]- 1 7A* 176°C (K) 3.11 98.39 457.1 515.3 [M+CH3COO-]; 455.2 [M+H-] 1 7B* 180°C (K) 3, 1 100 457.1 515.3 [M+CH3COO-]; 455.1 [M+H-] 1 9A* 156°C (K) 3.15 97.46 449, 1 507.3 [M+CH3COO-]; 447.1 [M+H-] 1 9B* 160°C (K) 3.15 100 449, 1 507.4 [M+CH3COO-]; 447.6 [M+H-] 1 14 3.48 100 408.1 406.1 1 1-8 1.39 98.28 431, 4 489.3 [M+CH3COO]- 4 I-12A 1.31 100 554.6 612.4 [M+CH3COO]- 3 10A* 220°C (K) 2.43 100 454.2 512.5 [M+CH3COO]- 1

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10V* 205°C (K) 2.32 100 454.4 512.3 [M+CH ₃ COO]~ 4 eleven 2.13 97.17 425.1 483.4 [M+CH3COO]- 1 11V* 2.1 96, 63 425.1 483.4 [M+CH3COO]- 1 11A 2.1 98.27 425.1 483.4 [M+CH3COO]- 1 14A 2.37 98.19 417.1 475.4 [M+CH3COO]- 1 14B 2.38 98.13% 417.1 475.3 [M+CH3COO]- 1 12 94°C (K) 2.04 99.36 373, 4 431.2 [M+CH3COO]- 2 15 110°C (K) 3.48 100 408.1 1 16* 3.04 99.85 435 6 17* 3.18 99.05 464 5 18* 3.01 99, 96 465 6 19* 2.83 99.84 435 6 21* 3.72 99.01 451 5 22* 2.93 99.19 451 6 23* 3.00 99.85 435 6 24* 3.56 99, 93 385 5 26* 156°C (K) 2.07 100 411 469.3 [M+CH3COO-] 1 27 2.02 97.57 455.2 513.4 [ M+CH3COO-] 1 28 2.28 98.25 425.1 483.3 [M+CH3COO-] 1 29* 2.39 95.58 422.1 480.2 [M+CH3COO-] 1 thirty 2.32 96.07 423, 1 481.3[ M+CH3COO-] 1 31* 184°C (K) 2.53 100 442.2 500.4 [M+CH3COO]- 1 32* 190°C (K) 2.51 100 442.2 500.4 [M+CH3COO]- 1

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33* 200°C (TO) 2.52 95.36 442.1 500.2 [M+SNZSOO]- 1 34* 188°C (TO) 2.53 100 442.1 500.2 [M+SNZSOO]- 1 35* 193°С (TO) 2.53 100 442.2 500.4 [M+SNZSOO]- 1 36* 208°C (TO) 2.51 100 442.1 500.4 [M+SNZSOO]- 1 39* 2.26 100 482.2 540.5 [M+SNZSOO-] 1 Int. 42 92°C (K) 2.8 96, 61 344 402.1 [M+SNZSOO]- 1 44 3.54 100 100 1 49 2.33 72.15 478.2 536.6 [M+SNZSOO]- 1 50 3.13 95.25 465.2 523.4 [M+SNZSOO]- 1 52 2.67, 2.69 42.17, 56.50 444.2 502.4 [M+SNZSOO]- 1 53 2.86 95.8 506, 2 564.5 [M+SNZSOO-] 1 5 4A 160C (K) 2.17 98.28 439, 1 497.3 [M+SNZSOO]- 1 54V 160°С (TO) 2.18 99.45 439, 1 497.3 [M+SNZSOO]- 1 54C 178°С (TO) 2.17 100 439, 1 497.3 [M+SNZSOO]- 1 54D 160°С (TO) 2.17 100 439, 1 497.3 [M+SNZSOO]- 1 55* 110°С (TO) 100 429, 1 487.3 1 5 7 A* 150°С (TO) 2.73 1.05 492.3 550.4 [M+SNZSOO]- 1 57V* 2.8 95.73 495.3 550.4 [M+SNZSOO]- 1 5 8A* 3.24 100 481.2 539.4 [M+SNZSOO-] 1 58V* 3.24 98.24 481.2 539.4 1

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[M+SNZSOO-] 5 8A* 3.24 100 481.2 539.4 [M+SNZSOO-] 1 58V* 3.24 98.24 481.2 539.4 [M+SNZSOO-] 1 5 9A 3.32 97.49 477.2 535.3 [M+SNZSOO]- 1 5 9V 3.32 98.01 477.2 535.2 [M+SNZSOO]- 1 60A* 3.33 99.34 515.3 573.5 [M+SNZSOO-] 1 60V* 3.33 98.73 515.3 573.5 [M+SNZSOO-] 1 61* 110°C (TO) 2.21 99.37 524.3 582.5 [M+SNZSOO-] 1 62* 130°C (TO) 2.11 99.27 416, 1 474.3 [M+ SNZSOO-] 1 63* 2.29 100 510.3 568.5 [ M+SNZSOO-] 1 65A 2.33 98.72 465.1 523.2 [M+SNZSOO]- 1 65V 2.33 99.22 465.1 523.3 [M+SNZSOO]- 1 65С 2.32 99.27 465.2 523.4 [M+SNZSOO]- 1 65D 2.33 98.61 465.1 523.3 [M+SNZSOO]- 1 6 6A 2.31 97.71 465.2 523.3 [M+SNZSOO]- 1 66V 2.31 97.51 465.2 523.4 [M+SNZSOO]- 1 6 6C 2.31 97.4 254, 9 523.4 [M+SNZSOO]- 1 66D 2.31 97.49 465.2 523.3 [M+SNZSOO]- 1 67A 164°С (TO) 3.11 100 435.1 493.3 [M+SNZSOO]- 1 67V 180°С 3.37 100 435.1 493.3 1

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(TO) [M+SNZSOO]- 68A* 134°C (TO) 3.26 99.21 435.2 493.3 [M+SNZSOO]- 1 68V* 150°С (TO) 3.26 99.36 435.2 493.4 [M+SNZSOO]- 1 68C 3.34 95.32 435.2 493.4 [M+SNZSOO]- 1 69 2.24 97.62 423, 1 481.3 [M+SNZSOO]- 2 I 17 1.22 99.06 511, 1 569.3[ M+SNZSOO-] I 28 1.32 98.42 582.3 640.3 [M+ SNZSOO-] 1 I 34 0.87 87.31 430, 4 488.2 [M+SNZSOO-] 1 I 35* 0.92 85.27 465.5 3

(a) (25°C to 300°C/10°C min/40 µl Al).

* means hydrochloride salt.

SFCMS methods.

General procedure for SFC-MS methods.

SFC measurements were performed using a supercritical liquid chromatography analytical system equipped with a binary carbon dioxide (CO2) and modifier delivery pump, an automatic dispenser, a column oven, a diode array detector equipped with a high pressure flow cell, withstands values up to 400 bar. If equipped with a mass spectrometer (MS), the flow from the column was directed to (MS). It is within the purview of one skilled in the art to set custom parameters (eg, scan range, dwell time, etc.) to obtain ions that allow the nominal monoisotopic molecular weight (MW) of a compound to be determined. Data collection was carried out using appropriate software.

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Table 2a

SFC-MS analytical methods (flow rate expressed in ml/min; column temperature (T) in °C; analysis time in minutes, back pressure (BPR) in bar

Method code Column Mobile phase Gradient Flow rate T count. Analysis time BPR 1 Column Phenomenon Luxeellulose-2 (3 µm, 10 0 χ 4.6 mm) A:CO ₂ B: MeOH (+0.3% iPrNH ₂ ) 40% B, hold for 3 min. 3.5 35 3 103 2 Daicel Chiralpak® AD3 column (3 µm, 10 0 × 4.6 mm) A:CO ₂ B: EtOH 15% B, hold for 3 min. 3.5 35 3 103 3 Column Daicel Chiralcel® OJ3 (3 µm, 10 0 χ 4.6 mm) A:CO ₂ B: EtOH (+0.3% iPrNH ₂ ) 20% B, hold for 3 min. 3.5 35 3 103 4 Column Daicel Chiralcel® OJ3 (3 µm, 10 0 χ 4.6 mm) A:CO ₂ B: iPrOH (+0.3% iPrNH ₂ ) 10% B, hold for 3 min. 3.5 35 3 103 5 Daicel Chiralpak® AD3 column (3 µm, 10 0 × 4.6 mm) A: CO ₂ B: IPrOH 30% B, hold for 3 min. 3.5 35 3 103 6 Phenomenex Lux Cellulose 2 (3 µm, 10 0 χ 4.6 mm) A:CO ₂ B: EtOH (0.3% iPrNH2) 40% B, hold for 3 min. _f 3.5 35 3 105 7 Phenomenex Lux Cellulose 2 (3 µm, 10 0 χ 4.6 mm) A:CO ₂ B: MeOH (0.3% iPrNH2) 30% B, hold for 3 min. _f 3.5 35 3 105 8 Phenomenex Lux Cellulose 2 (3 µm, 10 0 χ 4.6 mm) A:CO ₂ B: MeOH (0.3% iPrNH2) 15% B, hold for 3 min. _f 3.5 35 3 105

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9 Daicel Chiralpak® AD3 (3 mkm, 10 0 x 4.6 mm) A:CO ₂ B: MeOH/iPrOH 50/50 (0.3% iPrNH ₂ ) 30% B, hold for 3 min. _f 3.5 35 3 105 10 Daicel Chiralpak® AD3 (3 mkm, 10 0 x 4.6 mm) B: MeOH(+0.3% iPrNH ₂ ) 20% B, hold for 3 min. _f 3.5 35 3 105 eleven Daicel Chiralpak® AD3 (3 mkm, 10 0 x 4.6 mm) B: MeOH(+0.3% iPrNH ₂ ) 30% B, hold for 3 min. _f 3.5 35 4 105 12 Column Daicel Chiralpak® AD3 (3 mkm, 10 0 x 4.6 mm) A: CO ₂ B: EtOH 30% in, hold for 3 min. 3.5 35 6 103 13 Daicel Chiralcel® OJ3 (3 mkm, 10 0 x 4.6 mm) A:CO ₂ B: EtOH (0.3% iPrNH2) 10%, hold for 3 min. _f 3.5 35 6 105 14 Column Daicel Chiralpak® AD3 (3 mkm, 10 0 x 4.6 mm) A: CO ₂ B: IPOH 30% in, hold for 3 min. 3.5 35 3 103 15 Daicel Chiralcel® OD3 (3 mkm, 10 0 x 4.6 mm) A:CO ₂ B: EtOH(+0.3% iPrNH2) 25% B, hold for 3 min. 3.5 35 3 105 16 Daicel Chiralpak® AD3 (3 mkm, 10 0 x 4.6 mm) A:CO ₂ B: MeOH/iPrOH 50/50(0.3% iPrNH ₂ ) 20% B, hold for 3 min. _f 3.5 35 10 105

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17 Daicel Chiralpak® AD3 column (3 µm, 10 0 χ 4.6 mm) A: CO ₂ B: EtOH 30% B, hold for 3 min. 3.5 35 3 103 19 Daicel Chiralpak® IC3 (3 µm, 10 0 x 4.6 mm) A: CO ₂ B: EtOH (+0.3% iPrNH ₂ ) 40% B, hold for 3 min. , 3.5 35 3 105 20 Column Daicel Chiralpak® ΑΏ- Ο (3 µm, 100 x 4.6 mm) A: CO ₂ B: EtOH 20% B, hold for 3 min. 3.5 35 6 103

Table 2b

SFC-MS data (elution of isomers in order A occurs before B,

B occurs before C, C occurs before D)

No. conn. % area UV Elution order of isomers Way SFCMS 110* 100 A 1 Ill* 100 IN 1 I-8A 100 A 2 I-8B 99, 56 IN 2 3* 99, 72 A 3 4 * 99.68 IN 3 ΒΙΑ 99, 63 A 4 BIB 96, 23 IN 4 13A 100 A 5 13V 100 IN 5 6 8 A* 100 A 6 68V* 100 IN 6 I20A 100 A 8 I20B 98.8 IN 8

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34* 100 A and D 9 33* 100 B and C 9 57* 100 A 10 57V* 100 IN 10 59A 100 A eleven 59V 100 IN eleven 65A 100 A 12 65V 100 IN 12 65C 100 WITH 12 65D 100 D 12 I21A 100 A 13 I21B 100 IN 13 5 8 A* 100 A 1 58V* 99, 73 IN 1 I 22A 100 A 14 I 22V 99, 04 IN 14 60A* 99, 84 A 15 60V* 98.01 IN 15 6 6A 100 A 16 6 6V 100 IN 16 6 6C 99, 05 WITH 16 6 6D 100 D 16 31* 100 A 17 32* 99.60 IN 17 35* 98, 64 A 17 36* 100 IN 17 54A 100 A 19 54V 99, 18 IN 19 54С 100 WITH 20 54D 100 D 20

* means hydrochloride salt.

Optical Rotation (OR).

The amount of optical rotation was measured using a Perkin Elmer 341 polarimeter. Polarized light was passed through the sample at a path length of 1 decimeter and a sample concentration of 0.2-0.4 grams per 100 milliliters. Weigh 2-4 mg of product into a vessel, then dissolve in 1-1.2 ml of spectroscopy solvent (eg DMF). The cuvette was filled with a solution and placed in a polarimeter at a temperature of 20°C. The OR value was read to the nearest 0.004°.

Concentration calculation: weight in grams x 100/volume in ml.

[α] d: (read rotation value x 100)/(1,000 dm x concentration).

^d indicates the sodium D line (589 nanometers) unless a different wavelength is specified.

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Table 3

OR data: solvent: DMF; temperature: 20°C; conc. Means concentration (g/100 ml); OR means optical rotation

Connection no. OR(°) Wavelength(nm) Conc. 5* + 3.85 546 0.286 110* +42.01 365 0.288 Ill* -45.2 365 0.25 I-8A + 4.78 589 0.293 I-8B -4.95 589 0.364 ΒΙΑ -3.73 589 0.295 BIB -4, 81 589 0.27 3* +59.08 365 0.303 4 * -60.56 365 0.284 11V -5.76 589 0.243 ON + 4.94 589 0.324 13A + 3, 19 589 0.313 13V -4.66 589 0.279 6 8 A* +72.79 365 0.294 68V* -68.05 365 0.266 5 7 A* +13.67 589 0.300 57V* -18.21 589 0.280 59A + 8.33 589 0.264 59V -14, 17 589 0.247

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34* -25 589 0.260 33* +18.04 589 0.388 65A -20 589 0.260 65V -21.72 589 0.244 65C +10.74 589 0.242 65D +11.34 589 0.238 5 8 A* + 5, 81 589 0.241 58V* -6, 67 589 0.285 60A* +22.87 589 0.328 60V* -23.36 589 0.274 52 -8.98 589 0.245 6 6A -10.81 589 0.259 6 6V -14.16 589 0.219 6 6C + 8.27 589 0.266 6 6D + 4, 03 589 0.248 31* +13.97 589 0.315 32* + 26, 85 589 0.365 35* -15.16 589 0.31 36* -26.87 589 0.335 54A -46, 38 589 0.345 54V +16.99 589 0.312 54С +49.15 589 0.352 54D -24.35 589 0.382 26* + 46, 24 365 0.279

* means hydrochloride salt.

Pharmacological part.

1. Fluorescent polarization analysis of menin-MLL interaction.

To a black 384-well microtiter plate with a non-binding surface, 50 nL of 160X test compound in DMSO and 4 μL of 2X menin in assay buffer (40 mM TrisHCl, pH 7.5, 50 mM NaCl, 1 mM DTT, and 0.001% Tween 20) were added. After incubating the test compound and menin for 10 min at ambient temperature, 4 μl of 2X FITC-labeled MBM1 peptide (FITC-β-αlanine-SARWRFPARPGT-NH ₂ ) in assay buffer was added, and the microtiter plate was centrifuged at 1000 rpm in for 1 min, and the analyzed mixtures were incubated for 15 min at ambient temperature. The relative amount of menin-FITCMBM1 complex present in the assay mixture was determined by measuring the fluorescence polarization (FP) of the FITC tag using a BMG PHERAstar plate reader (excitation at 485 nm/emission at 520 nm) at ambient temperature. The final reagent concentrations in the binding assay were 100 nM menin, 5 nM FITC-labeled MBM1 peptide, and 0.625% DMSO in assay buffer. Titration procedures for test compounds to investigate their dose-dependent effect were performed using an 11-point, three-fold serial dilution scheme starting at 31 μM.

The potency of compounds was determined by initially calculating the % inhibition for each compound concentration according to Equation 1:

% inhibition = ((HC - LC) - (pp compound _ LC) )/ (HC - LC) ) * 100 (Eq. 1) where LC and HC represent the FP values in the assay in the presence or absence of a saturating concentration of compound, which competes with FITC-MBM1 for binding to menin, and the ppc ^compound is the measured FP value in the presence of the test compound. FP NS and LC values are the average of at least 16 replicates per plate. For each test compound, the % inhibition values were plotted against the logarithm of the test compound concentration and the IC ₅₀ value was obtained by fitting these data according to Equation 2:

- 79 046212 % inhibition = lower + (upper-lower)/(1 + 10 ^l ((1odTC5olog[cmpd])*h)) (eq. 2}, where lower and upper represent the lower and upper asymptotes of the dose response curve, respectively -effect, IC50 is the concentration of compound that produces 50% signal inhibition, and h is the Hill coefficient.

2. Analysis of menin-MLL interaction by time-resolved homogeneous fluorescence (HTRF).

To an untreated white 384-well microtiter plate, add 40 nL of 200X test compound in DMSO and 4 µL of 2X terbium chelate-labeled menin (see preparation below) in assay buffer (40 mM Tris-HCl, pH 7.5, 50 mM NaCl , 1 mM DTT and 0.05% Pluronic F-127). After incubating the test compound and terbium chelate-labeled menin for 5 min at ambient temperature, 4 μl of 2X FITC-labeled MBM1 peptide (FITC-in-alanine SARWRFPARPGT-NH2) in assay buffer was added and the microtiter plate was centrifuged at 1000 vol/vol. min for 1 min, and the test mixtures were incubated for 15 min at ambient temperature. The relative amount of menin · FITC-MBM1 complex present in the assay mixture was determined by measuring homogeneous time-resolved fluorescence (HTRF) for the donor-acceptor pair of terbium/FITC fluorophores using a BMG PHERAstar plate reader (excitation at 337 nm/terbium emission at 490 nm/FITC emission at 520 nm) at ambient temperature. The degree of fluorescence resonance energy transfer (HTRF value) is expressed as the ratio of the fluorescence emission intensity values for FITC and terbium fluorophores ( ^Fem 520 nm/Fem 490 nm). The final reagent concentrations in the binding assay were 100 pM terbium chelate-labeled menin, 75 nM FITC-labeled MBM1 peptide, and 0.5% DMSO in assay buffer. Titration procedures for test compounds to examine their dose-dependent effects were performed using a 11-point, 3-fold serial dilution scheme, typically starting at 25 μM.

The potency of compounds was determined by initially calculating the % inhibition for each compound concentration according to Equation 1:

% inhibition = ( (HC - LC) - (NTIN ^compound - LC) ) / (HC LC)) * 100 (Eq. 1);

where LC and HC are the HTRF values in the assay in the presence or absence of a saturating concentration of the compound that competes with FITC-MBM1 for binding to menin, and HTRF™^™ ⁴² ™ ⁴² is the measured HTRF value in the presence of the test compound. HTRF HC and LC values are the average of at least 16 replicates per plate. For each test compound, the % inhibition values were plotted against the logarithm of the test compound concentration and the IC ₅₀ value was obtained by fitting these data according to Equation 2:

% inhibition = lower + (upper-lower) / (1 + 10 ^L ( (logTCso ^- log[cmpd])*h)) (eq. 2);

where lower and upper represent, respectively, the lower and upper asymptotes of the dose-response curve, IC ₅₀ is the concentration of the compound that produces 50% signal inhibition, and h is the Hill coefficient.

Preparation of menin labeled with terbium cryptate. Menin (amino acids 1-610-6xHis tag) was labeled with terbium cryptate as follows. The buffer for 2 mg menin was replaced with 1x phosphate-buffered saline. Incubate 16 μM menin with terbium NHS-cryptate (Cisbio Bioassays, Bedford, MA) in a 4-fold molar excess for 2 h at room temperature. The labeled protein was purified from free label by running the reaction mixture through a Superdex 200 Increase 10/300 GL column at 0.75 ml/min. Peak fractions were collected, aliquoted and frozen at -80°C.

Menin protein sequence (SEQ ID NO: 1).

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MGLKAAQKTLFPLRSIDDVVRLFAAELGREEPDLVLLSLVLGFVEHFLAVNRVIPTNVP ELTFQPSPAPDPPGGLTYFPVADLSIIALYARFTAQIRGAVDLSLYPREGGVSSRELVKKVSD VIWNSLSRSYFKDRAHIQSLFSFITGTKLDSSGVAFAVVGACQALGLRDVHLALSEDHAWWFG PNGEQTAEVTWHGKGNE DRRGQTVNAGVAERSWLYLKGSYMRCDRKMEVAFMVCAINPSIDLHT DSLELLQLQQKLLWLLYDLGHLERYPMALGNLADLEELEPTPGRPDPLTLYHKGIASAKTYYRD EHIYPYMYLAGYHCRNRNVREALQAWADTATVIQDYNYCREDEEIYKEFFEVANDVIPNLLKEA ASLLEAGEERPGEQSQGTQSQGSALQD PECFAHLLRFYDGICKWEEGSPTPVLHVGWATFLVQS LGRFEGQVRQKVRIVSREAEAEAEEPWGEEAREGRRRGPRRESKPEEPPPPKKPALDKGLGTG QGAVSGPPRKPPGTVAGTARGPEGGSTAQVPAPAASPPPEGPVLTFQSEKMKGMKELLVATKIN SSAIKLQLTAQSQVQMKKQKVSTPSDYTLS FLKRQRKGLHHHHHH

3. Proliferation analysis.

The antiproliferative effect of test compounds inhibiting the menin-MLL protein-protein interaction was assessed in human leukemia cell lines. Cell lines MV-4-11 and

MOLM14 contain MLL translocations and express MLL-based fusion proteins MLL-AF4 and MLLAF9, respectively, as well as the wild-type protein from the second allele. Consequently, the MLL rearranged cell lines MV-411 and MOLM14 are characterized by HOXA/MEIS1 gene expression profiles similar to those of stem cells. K562 was used as a control cell line containing two wild-type MLL alleles to exclude compounds showing common cytotoxic effects.

MV-4-11 and MOLM14 were cultured in RPMI-1640 (Sigma Aldrich) supplemented with 10% fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma Aldrich), and 50 μg/ml gentamicin (Gibco). K562 was propagated in RPMI-1640 (Sigma Aldrich) supplemented with 20% fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma Aldrich), and 50 μg/ml gentamicin (Gibco). Cells were maintained at 0.3–2.5 million cells per ml during culture, and the number of passages did not exceed 25.

To evaluate antiproliferative effects, 1500 MV-4-11 cells, 300 MOLM14 cells, or 750 K562 cells were seeded in 200 μl of medium per well in 96-well round-bottom ultra-low adhesion plates (Costar, catalog number 7007). The number of cells to be seeded was chosen based on growth curves to ensure linear growth throughout the experiment. Test compounds were added at various concentrations and the DMSO content was normalized to 0.3%. Cells were incubated for 8 days at 37°C and 5% CO ₂ . The growth of spheroid-like structures was monitored in real time by live cell imaging (IncuCyteZOOM, Essenbio, 4x objective) with one image taken every four hours for 8 days. Confluence (%) as an indicator of spheroid size was determined using a comprehensive analysis tool.

To determine the cumulative effect of test compounds over time, the area under the curve (AUC) was calculated from a confluency versus time plot.

Confluence at baseline (t=0) was used as the baseline for calculating AUC.

Absolute _IC50 values were calculated according to the following procedure:

% of control = (AUC of sample/AUC of control) * 100

Control AUC=average AUC of control samples (cells without compound/with DMSO as solvent control)

Nonlinear curve fitting was applied to the plot of % of control versus compound concentration using (ordinary) least squares fitting. Based on this, the absolute IC ₅₀ value (the half-maximal inhibitory concentration of the test compound causing 50% antiproliferative effect relative to the solvent control) was calculated.

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Table 4

Biological data from menin fluorescence polarization (FP) assay (1), menin-MLL interaction assay by homogeneous time-resolved fluorescence (HTRF) assay (2), and proliferation assay (3)

No. conn. (1) Menin FP assay (1C ₅₀ (µM)) (2) Menin HTRF Assay ( _IC5o (nM)) (3) Analysis of MV-4-11 spheroids (IC ₅₀ (mkM)) (3) Analysis of MOLM14 spheroids (1C ₅₀ (µM)) (3) Analysis of K5 62 spheroids B1A 0.054 50 2.5 11.3 NT В1В 0.44 788 8, 9 >15 NT 3 0.038 14 0.44 3.1 9, 7 4 0.23 330 2, 9 7.6 8, 8 5 6.36 9532 NT NT NT 5a 6, 15 8285 NT NT NT 6 NT 60 2.2 NT NT 7 NT 55 16 NT NT 8 NT 64 16 NT NT 9 NT 36 14 NT NT 10V NT 1315 5.0 14.2 NT eleven NT 69 2.0 NT NT 10A NT 1532 NT NT NT

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9A NT 548 NT NT NT 9V NT 22 0.9 NT NT 11V NT 1469 NT NT NT ON NT 55 16 NT NT 12 NT 5790 NT NT NT 13A NT 5269 NT NT NT 13V NT 2456 NT NT NT 14A NT 4468 NT NT NT 14V NT 767 NT NT NT 15 NT 606 NT NT NT 16 NT 21 0.8 4.9 NT 17 NT 33 1.3 NT NT 18 NT 563 4.7 NT NT 19 NT 41 2.0 NT NT 21 NT 97 10 6.1 NT 22 NT 78 2.5 9, 9 NT 23 NT 150 3, 1 9.4 NT 24 NT 53 1.2 NT NT 26 NT 27 NT NT NT 27 NT NT NT NT NT 28 NT 149 3, 4 NT NT 29 NT 40 2.1 NT NT thirty NT 186 4.45 NT NT 31 NT 34 14 NT NT 32 NT 758 NT NT NT 33 NT 27 2 NT NT 34 NT 216 3.2 NT NT 35 NT 1012 NT NT NT 36 NT 170 2.5 NT NT 39 NT 852 NT NT NT 44 NT 137 4.3 NT NT 49 NT 45 eleven NT NT 50 NT 185 2.3 NT NT 52 NT 20820 NT NT NT 53 NT 204 2.1 NT NT 54A NT 11888 NT NT NT 54V NT 13225 NT NT NT

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54С NT 1488 NT NT NT 54D NT 6764 NT NT NT 55 NT 227 NT NT NT 56 NT 724 NT NT NT 57A NT 194 2.8 NT NT 57V NT 222 4.4 NT NT 58A NT 1552 NT NT NT 58V NT 888 NT NT NT 5 9A NT 709 NT NT NT 59V NT 1150 NT NT NT 60A NT 493 5.5 NT NT 60V NT 295 2.4 NT NT 61 NT 181 NT NT NT 62 NT 724 NT NT NT 63 NT 369 NT NT NT 65A NT 3496 NT NT NT 65V NT 284 4.3 NT NT 65C NT 686 NT NT NT 65D NT 8694 NT NT NT 66A NT 7437 NT NT NT 66V NT 164 3, 8 NT NT 66С NT 5378 NT NT NT 66D NT 880 NT NT NT 67A NT 396 3, 6 NT NT 67V NT 348 3.7 NT NT 68A NT 103 19 NT NT 68V NT 522 NT NT NT 68C NT 282 4.4 7.7 NT 69 NT 598 NT NT NT

NT: not tested.

Claims (14)

1. Compound of formula (I), or a tautomer or stereoisomeric form thereof, where R ¹ is selected from the group consisting of CH3, CH2F, CHF2 and CF3; R ² is selected from the group consisting of hydrogen and CH3; Y ¹ is selected from the group consisting of hydrogen; ^-balkyl; a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom, optionally substituted with a C _1-4 alkyl or cyclopropyl substituent; and C _1-4 alkyl substituted with a substituent selected from the group consisting of fluorine, -CN, phenyl, -OR ^1Y and -NR ^2Y R ^2YY ; where R ^1Y is selected from the group consisting of hydrogen; C _1-4 alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN and -C(=O)NR ^1y R ^2y ; ^tsalkyl substituted with a substituent selected from the group consisting of -OR ^3y and -NR ^1y R ^2y ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; each of R ^2Y and R ^2YY is independently selected from the group consisting of hydrogen; C _1-4 alkyl, optional - 84 046212 heavily substituted with a substituent representing -C(=O)NR ^1y R ^2y ; With _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^3y and -NR ^1y R ^2y ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; each of Y ² and Y ³ is independently selected from the group consisting of hydrogen; HE; NH2; -G(=O)NR ^ly R ^2y ; C1-6 alkyl and C _1-4 alkyl substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ^3Y and -NR ^4Y R ^4YY ; provided that if both Y and Y ³ are substituents on the same carbon atom and one of Y ² or Y ³ is OH or NH2, then the other Y ³ or Y ² is H, C1-6alkyl, C _1-4 alkyl substituted with a substituent selected from the group consisting of fluorine and -CN, or O^alkyl substituted with a substituent selected from the group consisting of -OR ^3Y and -NR ^4Y R ^4YY ; where R ^3Y is selected from the group consisting of hydrogen; C1-4alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN and -C(=O)NR ^4y R ^5y ; C2-4alkyl substituted with a substituent selected from the group consisting of -OR ^6y and -NR ^4y R ^5y ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; each of R ^4Y and R ^4YY is independently selected from the group consisting of hydrogen; C1-4alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN and -C(=O)NR ^1y R ^2y ; C2-4alkyl substituted with a substituent selected from the group consisting of -OR ^6y and -NR ^4y R ^5y ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; wherein each of R ^1y , R ^2y , R ^3y , R ^4y , R ^5y and R ^6y is independently selected from the group consisting of hydrogen; C _1-4 alkyl and C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; And --LR ³ selected from (a), (b), (c), (d) or (e): (a) --LR ³ is -NHR ^1A , where R ^1A is selected from the group consisting of hydrogen; C1-6alkyl, optionally substituted with one, two or three substituents representing a fluorine atom; and C2-6alkyl substituted with a substituent selected from the group consisting of -OR ^1a and -NR ^2a R ^2aa , wherein each of R ^1a , R ^2a and R ^2aa is independently selected from the group consisting of hydrogen, C1-4alkyl and cyclopropyl; with the proviso that if R ^1A is hydrogen, then Y ¹ is not hydrogen; or (b) L is selected from the group consisting of -N(R ^B )-, -N(R ^B ) -CR ^1B R ^1BB - and -(NR ^B )-CHR ^1B -CHR ^2B -; and R ³ is selected from the group consisting of Ar; Het ¹ ; Het ² and 7-10-membered saturated spirocarbobicyclic system; Where R ^B is selected from the group consisting of hydrogen; C _1-4 alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, phenyl and -CN; and C _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^1b and -NR ^2b R ^2bb ; wherein each of R ^1b , R ^2b and R ^2bb is independently selected from the group consisting of hydrogen, C _1-4 alkyl and cyclopropyl; R ^1B is selected from the group consisting of hydrogen; -C(=O)NR ^3B R ^3BB ; C1-4alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, phenyl, Het ¹ and -CN; C2-4alkyl substituted with a substituent selected from the group consisting of -OR ^4B and -NR ^5B R ^5BB ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; and R ^1BB is selected from the group consisting of hydrogen and methyl; or R ^1B and R ^1BB together with the carbon atom to which they are attached form a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; R ^2B is selected from the group consisting of hydrogen; -OR ^6B ; -NR ^7B R ^7BB ; -C(=O)NR ^8B R ^8BB ; C _1-4 alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ^4B and -NR ^5B R ^5BB ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; wherein each of R ^3B , R ^3BB , R ^4B , R ^5B , R ^5BB , R ^6B , R ^7B , R ^7BB , R ^8B and R ^8BB is independently selected from the group consisting of hydrogen; C1-4alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN and -C(=O)NR ^9B R ^9BB ; and C2-4alkyl substituted with a substituent selected from the group consisting of -OR ^10B and -NR ^11B R ^11BB ; wherein each of R ^9B , R ^9BB , R ^10B , R ^11B and R ^11BB is independently selected from the group consisting of hydrogen; C _1-4 alkyl and C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; or (c) --LR ³ selected from the group consisting of -N( ^RC )-CHR ^1C -CO2R ^2C ; -N( ^RC )-CHR ^3C -CONR ^4C R ^4CC ; -N(R ^C )-COR ^5C ; -N( ^RC )-SO2-NR ^6C R ^6CC ; Where R ^C is selected from the group consisting of hydrogen; C _1-4 alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, phenyl and -CN; and C _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^1c and -NR ^2c R ^2cc ; R ^1C and R ^3C are each selected from the group consisting of hydrogen; -C(=O)NR ^3c R ^3cc ; C1-4alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, phenyl, Het ¹ and -CN; C2-4alkyl substituted with a substituent selected from the group consisting of -OR ^4c and -NR ^5c R ^5cc ; and tied - 85 046212 C-based 4-7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; R ^4C and R ^6C are each selected from the group consisting of hydrogen and C ₁ . ₄ alkyl, optionally substituted with a substituent selected from the group consisting of NR ^6c R ^6cc , Ar and Het ¹ ; R ^2C is selected from the group consisting of hydrogen; C ₁ . ₄ alkyl, optionally substituted with Ar or Het ¹ ; Ar; Het ¹ ; Het ² and 7-10-membered saturated spirocarbobicyclic system; R ^5C is selected from the group consisting of hydrogen; C ₁ . ₄ alkyl, optionally substituted -NR ^2c R ^2cc , Ar or Het ¹ ; Ar; Het ¹ ; Het ² and 7-10-membered saturated spirocarbobicyclic system; wherein R ^1c , R ^2c , R ^2cc , R ^3c , R ^3cc , R ^4c , R ^5c and R ^5cc are each independently selected from the group consisting of hydrogen and C ₁ . ₄ alkyl; and each of R ^6c and R ^6cc is independently selected from the group consisting of hydrogen and C ₁ . ₄ alkyl, optionally substituted with a substituent selected from the group consisting of -NHC ₁ . ₄ alkyl and cyclopropyl; and each of R ^4CC and R ^6CC is independently selected from the group consisting of hydrogen; C ₁ . ₄ alkyl, optionally substituted with Ar or Het ¹ ; Ar; Het ¹ ; Het ² and 7-10-membered saturated spirocarbobicyclic system; or R ^4C and R ^4CC or R ^6C and R ^6CC together with the nitrogen atom to which they are attached form an N-linked Het ² ; or (d) L is selected from -N(R ^D )-CR ^1D R ^1DD - and -N(R ^D )-CR ^1D R ^1DD -CR ^2D R ^2DD -; Where R ^d is selected from the group consisting of hydrogen; Ov^lkyl, optionally substituted with a substituent selected from the group consisting of fluorine and -CN; and ^^alkyl substituted with a substituent selected from -OR ^1d and -NR ^2d R ^2dd ; wherein each of R ^1d , R ^2d and R ^2dd is independently selected from the group consisting of hydrogen and C ₁ . ₄ alkyl; each of R ^1D , R ^1DD , R ^2D , and r ^2DD is independently selected from the group consisting of hydrogen and C ₁ . ₄ alkyl; 1 η R Si_. and R ³ is selected from the group consisting of each of R ^3D , R ^4D and R ^5D independently selected from the group consisting of C ₁ . ₆ alkyl, optionally substituted with a -OH, -OC ₁ substituent. ₆ alkyl or -NH ₂ ; or It'- _t . η Ν D-зь N E(e)--LR ³ represents ^l ' ^where R ^e is selected from the group consisting of hydrogen and C ₁ . ₄ alkyl; R ^1E is selected from the group consisting of hydrogen, fluorine and C^alkyl; And R ^2E is selected from the group consisting of fluorine, -OC ₁ . ₄ alkyl and C ₁ . ₄ alkyl, optionally substituted with 1, 2 or 3 substituents representing a fluorine atom; or R ^1E and R ^2E are connected to the same carbon atom and together form a C-cycloalkyl or a C-linked 4-6-membered heterocyclyl containing an oxygen atom; And R ^3E is selected from the group consisting of hydrogen; C ₁ . ₄ alkyl, optionally substituted with a substituent representing a fluorine atom or -CN; and C^alkyl substituted with a substituent selected from the group consisting of -OR ^4E and -NR ^5E R ^5EE ; wherein each of R ^4E , R ^5E and R ^5EE is independently selected from the group consisting of hydrogen; C ₁ . ₄ alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN and -C(=O)NR ^6E R ^6EE ; C^alkyl substituted with a substituent selected from the group consisting of -OR ^7E and -NR ^8E R ^8EE ; and a C-linked 4-7 membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; wherein each of R ^6E , R ^6EE , R ^7E , R ^8E and R ^8EE is independently selected from the group consisting of hydrogen and C ₁ . ₄ alkyl; and where Ar is phenyl, optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -CN, -OR ⁴ , -NR5R ⁵ , -C(=O)NR ⁵ R ⁵ and C ₁ . ₄ alkyl, optionally substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ⁶ , -NR7R ⁷ ' and -C(O)NR ⁸ R ⁸ '; Het ¹ is a monocyclic heteroaryl selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 4- or 5-thiazolyl, isothiazolyl and isoxazolyl; each of which may be optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -CN, -OR ⁴ , -NR5R ⁵ and C^alkyl, optionally substituted with a substituent selected from the group consisting of from fluorine, -CN, -OR ⁶ , -NR7R ⁷ and -C(=O)NR ⁸ R ⁸ ; And Het ² is a non-aromatic heterocyclyl, optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -CN, -OR ⁴ , -NR ⁵ R ⁵ and C ₁ . ₄ alkyl, optionally substituted with a substituent selected from the group with - 86 046212 consisting of fluorine, -CN, -OR ⁶ , -NR7R ⁷ and -C(=O)NR ⁸ R ⁸ ; wherein each of ^R4 , ^R5 , ^R5 ', ^R6 , ^R7 , ^R7 ', ^R8 and ^R8 is independently selected from the group consisting of hydrogen; C1.4alkyl, optionally substituted with a substituent selected from the group consisting of fluorine and -C(=O)NR ⁹ R ⁹ ; and C2. ₄ alkyl substituted with a substituent selected from the group consisting of -OR ¹⁰ and -NR ¹¹ R ^11' ; wherein each of R ⁹ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹¹ is independently selected from the group consisting of hydrogen; C1. ₄ alkyl and C-linked 4-7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; or a pharmaceutically acceptable salt or solvate thereof. 2. The connection according to claim 1, where R ¹ represents CF3; R ² represents hydrogen; Y ¹ represents hydrogen; each of Y ² and Y3 is independently selected from the group consisting of hydrogen and C1. ₆ alkyl; -- LR ³ selected from (a), (b), (c) or (e): (a) --LR ³ is -NHR ^1A , wherein R ^1A is selected from the group consisting of C1.6 alkyl optionally substituted with one, two or three fluorine substituents; and C2.6 alkyl substituted with a substituent selected from the group consisting of -OR ^1a and -NR ^2a R ^2aa , wherein each of R ^1a , R ^2a and R ^2aa is independently selected from the group consisting of hydrogen and C1.4 alkyl; or (b) L is selected from the group consisting of -N(R ^B )- and -N(R ^B ) -CR ^1B R ^1BB -; And R ³ is selected from the group consisting of Ar; Het ¹ and Het ² ; Where R ^B is selected from the group consisting of hydrogen; C1. ₄ alkyl, optionally substituted with phenyl; and C _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ^1b and -NR ^2b R ^2bb ; wherein each of R ^1b , R ^2b and R ^2bb is independently selected from the group consisting of hydrogen and C1. ₄ alkyl; R ^1B is selected from the group consisting of hydrogen and C1. ₄ alkyl; And R ^1BB represents hydrogen; or (c) --LR ³ selected from the group consisting of -N(R ^C ) -CHR ^3C -CONR ^4C R ^4CC and -N(R ^C ) -COR ^5C ; Where R ^C represents hydrogen; R ^3C represents C1. ₄ alkyl; R ^4C represents hydrogen; R ^5C is Het ² ; And R ^4CC represents C _1-4 alkyl; or N '%, (e) --LR ³ represents > where R ^e represents hydrogen; R ^1E and R ^2E are bonded to the same carbon atom and together form a C _3-5 cycloalkyl; And R ^3E represents hydrogen; and where Ar is phenyl, optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, -OR ⁴ , -C(=O)NR ⁵ R ⁵ and C _1-4 alkyl, optionally substituted with a substituent , selected from the group consisting of -OR ⁶ and -NR ⁷ R ^7' ; Het ¹ is a monocyclic heteroaryl selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, pyridazinyl and pyrazolyl; each of which may be optionally substituted with one, two or three substituents, each independently selected from C1. ₄ alkyl, optionally substituted with a substituent of -OR ⁶ ; And Het ² is a non-aromatic heterocyclyl, optionally substituted with one, two or three substituents representing C1. ₄ alkyl; wherein each of ^R4 , ^R5 , R5 ^' , ^R6 , ^R7 and R7 ^' is independently selected from the group consisting of hydrogen and C1. ₄ alkyl. 3. The connection according to claim 1, where R ¹ represents CF ₃ ; R ² represents hydrogen; Y ¹ represents hydrogen; Y ² and Y ³ represent hydrogen; --LR ³ selected from (a) or (b): (a) --LR ³ is -NHR ^1A where R ^1A is C1. ₆ alkyl; or (b) L is -N( ^RB )-CR ^1B R ^1BB -; and R ³ is selected from the group consisting of Ar; Het ¹ and Het ² ; Where R ^B represents hydrogen; - 87 046212 R ^1B is selected from the group consisting of hydrogen and C _1-4 alkyl; And R ^1BB represents hydrogen; and where Ar represents phenyl, optionally substituted with one substituent representing C1. ₄ alkyl; Het ¹ is pyrazolyl; And Het ² is a non-aromatic heterocyclyl; in particular 3-azetidinyl. 4. Connection according to claim 1, where --LR ³ represents (a). 5. The connection according to claim 1, where --LR ³ represents (b). 6. Connection according to claim 1, where --LR ³ represents (c) . 7. Connection according to claim 1, where --LR ³ represents (d) . 8. The connection according to claim 1, where --LR ³ represents (e). 9. A pharmaceutical composition containing a compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier or diluent. 10. A method for preparing a pharmaceutical composition according to claim 9, comprising mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound according to any one of claims 1 to 8. 11. Use of a compound according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9 as a medicinal product. 12. Use of a compound according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9 for the prevention or treatment of cancer, myelodysplastic syndrome (MDS) and diabetes. 13. Use according to claim 12, wherein the cancer is selected from leukemia, myeloma or solid tumor cancer such as prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma and glioblastoma. 14. Use according to claim 13, where the leukemia is selected from acute leukemia types, chronic leukemia types, myeloid leukemia types, myelogenous leukemia types, lymphoblastic leukemia types, lymphocytic leukemia types, acute myelogenous leukemia (AML) types, chronic myelogenous leukemia (CML) types ), types of acute lymphoblastic leukemia (ALL), types of chronic lymphocytic leukemia (CLL), types of T-cell prolymphocytic leukemia (T-PLL), types of large granular lymphocyte leukemia, hairy cell leukemia (HCL), types of leukemia with MLL rearrangement, types of leukemia , MLL-PTD-associated leukemias, MLL-amplified leukemias, MLL-positive leukemias, and leukemias characterized by HOX/MEIS1 gene expression profiles.