TW201823250A - Spiro bicyclic inhibitors of menin-mll interaction - Google Patents

Abstract

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

Description

   Spirobicyclic inhibitors of MENIN-MLL interaction   

The present invention relates to pharmaceutical agents for treatment and / or prophylaxis in mammals, and in particular to spirobicyclic compounds, pharmaceutical compositions containing such compounds, and their inhibition as a menin / MLL protein / protein interaction The agent is used for treating diseases such as cancer, myelodysplastic syndrome (MDS), and diabetes.

Chromosomal rearrangements affecting mixed lineage leukemia genes ( MLL ; MLL1 ; KMT2A ) lead to invasive acute leukemia of all age groups, and are still primarily manifested as incurable diseases that emphasize the urgent need for new treatments. Acute leukemias carrying these MLL chromosomal translocations represent lymphatic, bone marrow, or biphenotypic diseases and account for 5% to 10% of adult acute leukemias and approximately 70% of infants (Marschalek, Br J Haematol 2011.152 (2 ), 141-54; Tomizawa et al., Pediatr Blood Cancer 2007.49 (2), 127-32).

MLL is a histone methyltransferase that methylates histone H3 on lysine 4 (H3K4) and functions in a multiprotein complex. Inducible loss of function alleles using Mll1 suggest that Mll1 plays an important role in maintaining hematopoietic stem cells (HSC) and developing B cells, although its histone methyltransferase activity is not necessary for hematopoietic lines (Mishra et al. Cell Rep. 2011.7 (4), 1239-47).

To date, MLL has been reported to fuse with more than 60 different partners and is associated with leukemia formation / progression (Meyer et al., Leukemia [Leukemia] 2013.27, 2165-2176). Interestingly, the SET (Su (var) 3-9, enhancer and trithorax) domain of MLL is not retained in the chimeric protein, but is replaced by the fusion partner (Thiel et al., Bioessays [Biological Analysis ] 2012, 34, 771-80). Recruitment of chromatin modifying enzymes such as Dot1L and / or pTEFb complexes by fusion partners results in enhanced transcription and transcriptional extension including MLL target genes as the most prominent HOXA gene (eg, HOXA9 ) and HOX cofactor MEIS1 . The abnormal performance of these genes in turn blocks hematopoietic differentiation and enhances proliferation.

Menin, encoded by the multiple endocrine tumor type 1 ( MEN1 ) gene, is commonly expressed and is mainly located in the nucleus. It has been shown to interact with many proteins and therefore involves a variety of cellular processes. The function that best understands menin is its role as an oncogenic cofactor for MLL fusion proteins. Menin interacts with two motifs retained in the N-terminal fragment of MLL in all fusion proteins, MBM1 (menin binding motif 1) and MBM2 (Thiel et al., Bioessays [Bioassay] 2012, 34, 771-80 ). Menin / MLL interactions have led to the formation of new interaction surfaces for lens epithelial-derived growth factor (LEDGF). Although MLL binds directly to LEDGF, the stable interaction between MLL and LEDGF and the gene-specific chromatin recruitment system of MLL complexes via the PWWP domain of LEDGF are necessary (Cermakova et al. Cancer Res [Cancer Research] 2014.15, 5139-51; Yokoyama & Cleary, Cancer Cell [Cancer Cell] 2008.8, 36-46). In addition, many genetic studies have shown that the menin line strictly requires carcinogenic transformation by MLL fusion proteins, suggesting that the menin / MLL interaction is an attractive therapeutic target. For example, the conditional deletion of Men1 prevents leukemia in ectopically expressed MLL fusion myeloid progenitor cells (Chen et al., Proc Natl Acad Sci [Journal of the National Academy of Sciences] 2006.103, 1018-23). Similarly, the genetic disruption of the menin / MLL fusion interaction by a loss-of-function mutation eliminated the oncogenic properties of the MLL fusion protein, blocked the development of leukemia in vivo, and released the differentiation block of MLL-transformed leukemia mother cells. These studies also indicate that menin is required to maintain HOX gene expression by MLL fusion proteins (Yokoyama et al., Cell [Cell] 2005, 123, 207-18). In addition, small molecule inhibitors of menin / MLL interactions have been developed that demonstrate the drug-induced protein / protein interactions, and have also demonstrated efficacy in preclinical models of AML (Borkin et al. Cancer Cell [Cancer Cell] 2015.27, 589-602; Cierpicki and Grembecka, Future Med Chem [Future Medical Chemistry] 2014.6, 447-462). Together with observations that menin is not an essential cofactor for MLL1 during normal hematopoietic periods (Li et al., Blood [blood] 2013.122, 2039-2046), these data confirm the disruption of the menin / MLL interaction for the treatment of MLL Rows of leukemia and other cancer lines with active HOX / MEIS1 gene markers promise promising new treatments. For example, an internal partial tandem repeat (PTD) within the 5 'region of the MLL gene represents another major aberration that occurs predominantly in de novo and secondary AML and bone marrow dysplasia syndrome. Although the molecular mechanism and biological functions of MLL-PTD have not been fully understood, new therapeutic targeting strategies that affect MLM-MLL interactions can also be effective in the treatment of MLL-PTD-related leukemias. In addition, castration-resistant prostate cancer has been shown to depend on the menin / MLL interaction (Malik et al., Nat Med [Natural Medical Journal] 2015.21, 344-52).

Several references describe inhibitors targeting menin-MLL interactions: WO 2011029054, J Med Chem [Journal of Medical Chemistry] 2016, 59, 892-913 describes the preparation of thienopyrimidines and benzodiazepine derivatives; WO 2014164543 describes thienopyrimidine and thienopyridine derivatives; Nature Chemical Biology [Natural Chemical Biology] March 2012, 8 , 277-284 and Ren, J. et al. Bioorg Med Chem Lett [Bioorganic and Medicinal Chemistry Newsletter ] (2016), http://dx.doi.org/10.1016/j.bmcl.2016.07.074 describes thienopyrimidine derivatives; J Med Chem [Journal of Medical Chemistry] 2014, 57 , 1543-1556 describes hydroxyl groups -And amine methylpiperidine derivatives; and Future Med Chem 2014, 6, 447-462 reviewed small molecules and peptidomimetic compounds. Inhibitors of menin-MLL interaction are described in WO 2017112768.

The invention relates to novel compounds of formula (I) And its tautomeric forms and stereoisomers thereof, in which R ¹ is chosen from the group consisting _{of: CH 3, CH 2 F,} CHF 2, and CF _3; R ² is selected from the group consisting of Group: hydrogen and CH ₃ ; L ¹ represents a 7- to 10-membered saturated spiro heterobicyclic system containing one or two N atoms, provided that it is N-connected to a thienopyrimidinyl heterocycle; and --L ² -R ^{3 is} selected from (a), (b), (c), (d), (e), (f), or (g), wherein (a) L ^{2 is} selected from the group consisting of: > SO ₂ ,> CR ^4a R ^4b , and -CHR ^4a CHR ^5- ; (i) when L ^{2 is} connected to the carbon atom of L ¹ , then R ^4a and R ⁵ are each independently selected from the group consisting of Group: hydrogen; -OR ⁶ ; -NR ^7a R ^7b ; -C (= O) NR ^7a R ^7b ; optionally a C _1-4 alkyl group substituted with a substituent selected from the group consisting of Item composition: fluorine, -CN, -OR ⁸ , and -NR ^9a R ^9b ; and a C-linked 4- to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen, or sulfur atom; (ii) when L ² when L is connected to the nitrogen ^atom, then R ^4a is selected from the group consisting of: ^{hydrogen; -C (= O) NR 7a} R 7b; optionally Substituents selected from the group C _1-4 alkyl group substituted by the group consisting of: fluorine, -CN, -OR ^8, and -NR ^9a R ^9b; and containing at least one nitrogen, oxygen or sulfur atom, C-attached 4- to 7-membered non-aromatic heterocyclic groups; R ^{5 is} selected from the group consisting of: hydrogen; -OR ⁶ ; -NR ^7a R ^7b ; -C (= O) NR ^7a R ^7B; optionally substituted group selected from the group C _1-4 alkyl substituted by the group consisting of: fluorine, -CN, -OR ^8, and -NR ^9a R ^9b; and containing at least one nitrogen C-attached 4- to 7-membered non-aromatic heterocyclic groups of a hydrogen, oxygen or sulfur atom; R ^{4b is} selected from the group consisting of: hydrogen and methyl; or R ^4a and R ^4b together with them attached Carbon atoms together form a C _3-5 cycloalkyl group or a C-linked 4- to 6-membered heterocyclic group containing an oxygen atom; wherein R ⁶ , R ^7a , R ^7b , R ⁸ , R ^9a and R ^9b are each independently Ground is selected from the group consisting of: hydrogen; optionally a C _1-4 alkyl group substituted with a substituent selected from the group consisting of fluorine, -CN, and -C (= O) NR ^10a R ^10b; and is selected from the group of substituents of C _2-4 alkyl The group consisting of: -OR ¹¹ and -NR ^10a R ^10b; wherein R ^10a, R ^10b and R are each independently selected from the group ¹¹ consisting of: hydrogen; C _1-4 alkyl; and A C-linked 4- to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen, or sulfur atom; and R ^{3 is} selected from the group consisting of: Ar, Het ¹ , Het ² , and 7-membered To 10-membered saturated spirocarbon bicyclic ring system; or (b) L ^{2 is} selected from the group consisting of:> CR ^4c R ^4d and -CHR ^4c CHR ^5a- , wherein R ^4c , R ^4d , and R ^5a 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: with Wherein R ^12a , R ^12b , and R ^12c are each independently selected from the group consisting of: a C _1-6 alkyl group optionally substituted with -OH or -NH ₂ substituent; and -OC _1-6 alkane Or (c)-L ² -R ³ is a C _1-6 alkyl optionally substituted with one, two, or three fluorine substituents; or (d) L ² is O, and R ^{3 is} selected from A group consisting of: C _3-6 alkyl optionally substituted with one, two or three fluorine substituents; Ar; Het ¹ ; Het ² ; 7 to 10 member saturated spirocarbobicyclic systems; -CH ₂ -Ar; -CH ₂ -Het ¹ ; -CH ₂ -Het ² ; and -CH _2- (7 to 10-membered saturated spiro-carbon bicyclic ring system); when L ^{2 is} connected to the carbon atom of L ¹ Or (e)-L ² -R ³ is -O-CHR ⁵ -R ³ , when L ^{2 is} connected to the carbon atom of L ¹ , wherein R ^{5 is} selected from the group consisting of: -C ( = O) NR ^13a R ^13b ; optionally a C _1-4 alkyl group substituted with a substituent selected from the group consisting of: fluorine, -OR ¹⁴ , and -NR ^15a R ^15b ; and containing at least one C- 4 nitrogen, oxygen or sulfur atom attached to the 7-membered non-aromatic heterocyclic group; wherein ^{R 13a, R 13b, R 14} , R 15a and R ^15b are each independently Is chosen from the group consisting of: hydrogen; optionally substituted group selected from C _1-4 alkyl group substituted by the group consisting of: fluorine and -C (= O) NR ^16a R ^16b ; and C _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ¹⁷ and -NR ^16a R ^16b ; wherein R ^16a , R ^16b and R ¹⁷ are each independently Selected from the group consisting of: hydrogen; C _1-4 alkyl; and a C-linked 4- to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen, or sulfur atom; and R ^{3 is} selected A group consisting of: hydrogen; C _1-4 alkyl optionally substituted with one, two, or three fluorine substituents; -CN; Ar; Het ¹ ; Het ² ; and 7 to 10 members Saturated spiro carbon bicyclic ring system; or (f)-L ² -R ³ series , Wherein R ^{18 is} selected from the group consisting of: hydrogen; C _1-4 alkyl optionally substituted with fluorine or -CN substituent; and C _2-4 alkyl substituted with substituent selected from This group consists of the following: -OR ¹⁹ and -NR ^20a R ^20b ; wherein R ¹⁹ , R ^20a and R ^20b are each independently selected from the group consisting of: hydrogen; and optionally, selected from the following: C _1-4 alkyl substituted with substituents of the group consisting of: fluorine, -CN and -C (= O) NR ^21a R ^21b ; C _2- substituted with substituents selected from the group _4- alkyl, the group consisting of: -OR ²² and NR ^21a R ^21b ; and a C-linked 4- to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen or sulfur atom; wherein R ^21a , R ^21b, and R ²² are each independently selected from the group consisting of: hydrogen and C _1-4 alkyl; and R ^{18a is} selected from the group consisting of: hydrogen, fluorine, and C _1-4 Alkyl; R ^{18b is} selected from the group consisting of: fluorine, -OC _1-4 alkyl, and optionally C _1-4 alkyl substituted with 1, 2, or 3 fluorine substituents; or R ^18a and R ^{18b is} bonded to the same carbon atom and forms a C _3-5 ring together An alkyl group or a C-linked 4- to 6-membered heterocyclic group containing an oxygen atom; or (g)-L ² -R ³ system or And wherein Ar is phenyl or naphthyl, 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, -CN,- OR ²⁴ , -NR ^25a R ^25b , and optionally a _C1-4 alkyl group substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C (= O) NR ^27a R ^27b ; Het ¹ is a monocyclic heteroaryl group selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, Pyridine Base , Furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 4- or 5-thiazolyl, isothiazolyl, thiadiazolyl, and isopropyl Oxazolyl; or a bicyclic heteroaryl group selected from the group consisting of imidazothiazolyl, imidazomidazolyl, benzofuranyl, benzophenylthio, benzimidazolyl, benzene and Oxazolyl, isobenzo Oxazolyl Oxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, innosyl, isoinnoyl, ind Group, dihydroindolyl, isoindolino, indazolyl, pyrazolopyridyl, pyrazolopyrimidyl, imidazopyridyl, imidazopyridine Imidazo Groups; 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, -CN, -OR ²⁴ , -NR ^25a R ^25b , And optionally C _1-4 alkyl substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C (= O) NR ^27a R ^27b ; and Het ² is a non-aromatic heterocyclic group optionally substituted with one, two or three substituents, each substituent is independently selected from the group consisting of: halogen, -CN , -OR ²⁴ , -NR ^25a R ^25b , and optionally a C _1-4 alkyl group substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C (= O) NR ^27a R ^27b ; wherein R ²⁴ , R ^25a , R ^25b , R ²⁶ , R ^27a , and R ^27b are each 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 ^28a R ^28b ; and substituted with a substituent selected from the group consisting of: C _2-4 alkyl, the group consists of the following groups Into: -OR ²⁹ and -NR ^28a R ^28b ; wherein R ^28a , R ^28b and R ²⁹ are each independently selected from the group consisting of: hydrogen; C _1-4 alkyl; and containing at least one nitrogen, oxygen Or C-linked 4-membered to 7-membered non-aromatic heterocyclic groups of sulfur atoms; and pharmaceutically acceptable salts and solvates thereof; the premises are the following compounds, and pharmaceutically acceptable addition salts and solvents thereof Compounds are excluded:

It should be understood that the above conditions apply to all embodiments of the invention described below.

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

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

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

In specific embodiments, the cancer is selected from the group consisting of leukemia, myeloma, or solid tumor cancer (e.g., prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma, and glioblastoma ( glioblastoma), etc.). In some embodiments, the leukemia includes acute leukemia, chronic leukemia, myeloid leukemia, myeloid leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and acute lymphoblast Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), Pre-T Lymphocytic Leukemia (T-PLL), Large Granular Lymphocytic Leukemia, Hair Cell Leukemia (HCL), MLL-Rearranged Leukemia, MLL-PTD Leukemia, MLL Increased leukemia, MLL-positive leukemia, leukemia displaying HOX / MEIS1 gene expression markers, etc.

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

Furthermore, the present invention relates to a method for preparing a pharmaceutical composition according to the present invention, characterized in that a pharmaceutically acceptable carrier is in close contact with a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof. To mix.

The present invention also relates to a product comprising a compound having the formula (I), a pharmaceutically acceptable salt or solvate thereof, and another pharmaceutical agent, as a combination for simultaneous, separate or continuous use in the treatment or prevention of cancer, myeloproliferative disorders Combination of myelodysplastic syndrome (MDS) and diabetes.

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

The term 'halo' or 'halogen' as used herein means fluorine, chlorine, bromine and iodine.

The first code 'C _xy ' as used herein (where x and y are integers) 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, a C _3-6 cycloalkyl group contains from 3 to 6 carbon atoms, and so on.

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 group having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl , Isopropyl, n-butyl, secondary butyl, tertiary butyl, etc.

The term 'C _2-4 alkyl' as used herein as a group or part of a group means a straight or branched chain saturated hydrocarbon group having from 2 to 4 carbon atoms, such as ethyl, n-propyl, isopropyl Propyl, n-butyl, secondary butyl, tertiary 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 group having from 1 to 6 carbon atoms, as defined for C _1-4 alkyl As well as n-pentyl, n-hexyl, 2-methylbutyl and the like.

The term 'C _3-6 alkyl' as used herein as a group or part of a group means a straight or branched chain saturated hydrocarbon group having from 3 to 6 carbon atoms, such as n-propyl, isopropyl, N-butyl, secondary butyl, tertiary butyl, n-pentyl, n-hexyl, 2-methylbutyl and the like.

The term 'C _3-5 cycloalkyl' as used herein as a group or part of a group defines a saturated cyclic hydrocarbon group having from 3 to 5 carbon atoms, such as cyclopropyl, cyclobutyl and Cyclopentyl.

The term 'spirobicyclic' as used herein as a group or part of a group refers to a ring system in which two rings are connected at a single atom. Examples of such systems are 7 to 10-membered saturated spiroheterobicyclic systems containing one or two N atoms, wherein one of the nitrogen atoms is usually attached to a compound of formula (I) as defined herein Thienopyrimidinyl heterocycle. Such spiro ring systems include, but are not limited to, systems from, for example, piperidine, pyrrolidine, azetidine, and a combination of cyclobutane rings. Examples of such systems include, but are not limited to the following (a), (b), (c), (d), (e), (f), (g), etc.

Where a represents the position attached to the thienopyrimidinyl heterocycle. The skilled person will understand that in these specific examples, when L ^{2 is} connected to the nitrogen atom of L ¹ , the option for --L ² -R ³ defined here applies to examples (a)-(f) ; However, when L ^{2 is} attached to the carbon atom of L ¹ , the option for --L ² -R ³ defined here applies to Example (g).

Examples of 7- to 10-membered saturated spirocarbon bicyclic ring systems include, but are not limited to Wait.

Generally, whenever the term 'substituted' is used in the present invention, unless otherwise specified or clear from the context, it means to indicate one or more of the atoms or groups indicated in the expression using 'substituted'. Hydrogen (in particular from 1 to 4 hydrogens, more particularly from 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen) is replaced by an option selected from the indicated group Provided that the normal valence is not exceeded, and that the substitution results in a chemically stable compound (ie, a compound that is robust enough to withstand separation from the reaction mixture to a useful purity).

Combinations of substituents and / or variables are permissible as long as such combinations result in chemically stable compounds. 'Stable compound' is intended to indicate a compound that is sufficiently robust to withstand isolation from the reaction mixture to a suitable degree of purity.

The skilled person will understand that when an atom or group is substituted with a 'substituent', it means that the atom or group in question is substituted with a substituent selected from the specified group.

The skilled person will understand that the term 'optionally substituted' means that the atom or group represented using 'optionally substituted' may or may not be substituted (this means substituted or unsubstituted, respectively).

When two or more substituents are present on a moiety, where possible and unless otherwise specified or clear from context, such substituents may replace hydrogen on the same atom, or such substituents may replace A hydrogen atom on a different atom in this part.

It will be clear to the skilled person that, unless otherwise specified or clear from the context, a substituent on a heterocyclyl can replace any hydrogen atom on a ring carbon atom or a ring heteroatom.

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

The 'non-aromatic group' includes unsaturated ring systems having no aromatic properties, partially saturated and fully saturated carbocyclic and heterocyclic systems. The term 'partially saturated' means a ring in which one or more ring structures contain at least one multiple bond (e.g., C = C, N = C bond). The term 'fully saturated' means a ring in which there are no multiple bonds between ring atoms. Thus, unless stated otherwise, a 'non-aromatic heterocyclyl' system is, for example, a non-aromatic monocyclic or bicyclic system having 3 to 12 ring members, more usually 5 to 10 ring members. Examples of monocyclic groups are groups containing 4 to 7 ring members, more typically 5 or 6 ring members. Examples of bicyclic groups are those containing 8 to 12, more usually 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- to 7-membered heterocyclyl systems, such as aza Cyclobutyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperidinyl Group, piperanyl, dihydropiperanyl, tetrahydropiperanyl, Phosphono, thio Phenyl, and tetrahydro-2H-thiopiperanyl 1,1-dioxide, especially azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperidine Group, piperanyl, dihydropiperanyl, tetrahydropiperanyl, Phenyl and thio Porphyrinyl. 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-1H-indole, dihydroindole base, or . Unless otherwise stated, each may be bonded to the remainder of the molecule of formula (I) by any available ring carbon (C-linked) or nitrogen (N-linked) atom, and where possible in The carbon and / or nitrogen atom according to the embodiment may be optionally substituted.

Examples of C-linked 4- to 7-membered non-aromatic heterocyclic groups containing at least one nitrogen atom include, but are not limited to, azetidinyl, pyrrolidinyl, and piperidinyl, with available carbon atoms Binding to the rest of the molecule.

The term 'C-linked 4-membered to 6-membered heterocyclic group containing an oxygen atom' as used herein alone or as part of another group defines a saturated cyclic hydrocarbon group containing an oxygen atom, the cyclic hydrocarbon group having from 4 From 6 to 6 ring members, such as oxetanyl, tetrahydrofuranyl, and tetrahydropiperanyl.

Whenever a substituent is represented by a chemical structure, '---' represents a bond to the remainder of the molecule of formula (I).

A line drawn in a ring system (e.g., '---') indicates that the bond can be attached to any suitable ring atom.

Unless otherwise stated, Het ¹ and Het ² may be suitably attached to the remainder of the molecule having formula (I) by any available ring carbon or nitrogen atom.

It will be clear that, where possible, saturated ring moieties may have substituents on both carbon and N-atoms, unless otherwise stated or clear from the context.

It will be clear that when L ² series> SO ₂ , this is equivalent to L ² series -SO _2- . It will be clear that when L ² series> CR ^4a R ^4b , this is equivalent to L series . For example, in Compound 1, L ² is> CR ^4a R ^4b , where both R ^4a and R ^4b are hydrogen.

Similarly, it will be clear that when L ² series> CR ^4c R ^4d , this is equivalent to L series

When any variable occurs more than once in any constituent, each definition is independent.

When any variable occurs more than once in any formula (eg, formula (I)), each definition is independent.

As used herein, the term 'subject' refers to an animal that is or has been the object of treatment, observation or experiment, preferably a mammal (such as a cat, dog, primate, or human), and more preferably It's human.

As used herein, the term 'therapeutically effective amount' means the amount of an active compound or pharmaceutical agent that elicits a biological or medical response in a tissue system (animal or human) that is being investigated by a researcher, veterinarian, medical doctor, or Other clinicians seek to reduce or reverse the symptoms of the disease or disorder being treated.

The term 'composition' is intended to encompass a product containing a specified amount of a specified ingredient, as well as any product that results directly or indirectly from a combination of specified amounts of a specified ingredient.

As used herein, the term 'treatment' is intended to mean all processes in which it is possible to slow, interrupt, contain or prevent the progression of the disease, but does not necessarily indicate that all symptoms are completely eliminated.

As used herein, the term 'one or more compounds of the present invention' or 'one or more compounds according to the present invention' is meant to include compounds having formula (I) and pharmaceutically acceptable salts and solvents thereof Compound.

As used herein, any formula that has a bond that is shown only as a solid line and not as a real wedge or virtual wedge bond, or is otherwise expressed as a chemical formula with a special configuration (eg, R , S ) around one or more atoms Consider each possible stereoisomer, or a mixture of two or more stereoisomers.

Above and below, the term 'one or more compounds having formula (I)' is meant to include its tautomers and its stereoisomeric forms.

Above or below, the terms 'stereoisomers', 'stereoisomeric forms' or 'stereochemically isomeric forms' are used interchangeably.

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

Mirror isomers are stereoisomers that are non-overlapping mirror images of each other. A 1: 1 mixture of mirror image isomers is a racemate or a racemic mixture.

Atropisomer (or atropoisomer) is a stereoisomer with a specific spatial configuration that is restricted by a large steric hindrance around a single bond. Resulting from rotation. All atropisomers of the compounds of formula (I) are intended to be included within the scope of the present invention.

Non-images (or non-image isomers) are stereoisomers that are not mirror images, that is, they are not related in a mirror image. If the compound contains a double bond, the substituents can be in the E or Z configuration.

Substituents on divalent ring-saturated or partially-saturated groups can have a cis- (cis-) or trans- (trans-) configuration, for example, if the compound contains a disubstituted cycloalkyl, then the substitution The base can be in cis or trans configuration.

Accordingly, the present invention includes enantiomers, atropisomers, non-enantiomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and the like As long as it is chemically possible.

All those terms (i.e., mirror isomers, atropisomers, non-image isomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and their The meaning of "mixture" is known to the skilled person.

The absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration at the asymmetric atom is specified by R or S. The resolved stereoisomers whose absolute configuration is unknown can be specified by (+) or (-) depending on the direction in which they rotate the plane polarized light. For example, split mirror isomers whose absolute configuration is unknown can be specified by (+) or (-) depending on the direction in which they rotate the plane polarized light.

When identifying a specific stereoisomer, this means that the stereoisomer is substantially free of other stereoisomers, that is, less than 50%, preferably less than 20%, more preferably less Other stereoisomers are related at 10%, even more preferably less than 5%, especially less than 2% and most preferably less than 1%. Therefore, when a compound of formula (I) is specified, for example, as (R), this means that the compound is substantially free of (S) isomers; when a compound of formula (I) is specified, for example, as E, it means that the compound is substantially Z isomers are not included on this; when a compound of formula (I) is specified, for example, as cis, this means that the compound is substantially free of trans isomers.

Some compounds according to formula (I) can also exist in their tautomeric forms. Although not explicitly indicated in the above formula (I), such forms are intended to be included within the scope of the present invention where they may exist. It follows that single compounds can exist in stereoisomeric and tautomeric forms.

Pharmaceutically acceptable salts include acid addition salts and base addition salts. This can be done by conventional means, for example by reacting the free acid or free base form with one or more equivalents of an appropriate base or acid, optionally in a solvent or in a medium in which the salt is insoluble, followed by the use of standards Techniques (e.g., in vacuum, by freeze drying or by filtration) remove the solvent or the medium to form such salts. A variety of salts can also be prepared by exchanging one counterion of the compound of the invention in salt form with another counterion, for example using a suitable ion exchange resin.

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

Suitable acids include, for example, inorganic acids such as hydrohalic acids (such as hydrochloric or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, and similar acids; or organic acids such as, for example, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvate , Oxalic acid (i.e. oxalic acid), malonic acid, succinic acid (i.e. succinic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, P-Toluenesulfonic acid, cyclohexylaminosulfonic acid, salicylic acid, p-aminosalicylic acid, acetic acid, and similar acids. Conversely, the salt form can be converted to the free base form by treatment with a suitable base.

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

Suitable alkali salt forms include, for example, ammonium, alkali and alkaline earth metal salts, such as lithium, sodium, potassium, cesium, magnesium, calcium salts and the like, and salts of the following organic bases: for example, primary, secondary and tertiary Aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, Pyrrolidine, piperidine, Phthaloline, trimethylamine, triethylamine, tripropylamine, Pyridine, pyridine, quinoline and isoquinoline; benzathine, N -methyl-D-glucosamine, hydrabamine salt, and salts of the following amino acids: for example, like spermidine Amino acid, lysine and so on. Conversely, the salt form can be converted to the free acid form by treatment with an acid.

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

The compounds of the present invention, as prepared in the methods described below, can be synthesized as a mixture of enantiomers, especially racemic mixtures of enantiomers, which can be made according to known in the art The splitting procedures are separated from each other. One way to isolate the mirror-isomeric forms of a compound having formula (I) and its pharmaceutically acceptable salts and solvates involves liquid chromatography using a chiral stationary phase. The pure stereochemically isomeric form may also be derived from the corresponding pure stereochemically isomeric form of an appropriate starting material, provided that the reaction occurs stereospecifically. Preferably, if a particular stereoisomer system is desired, the compound will be synthesized by a stereotactic method of preparation. These methods will advantageously use mirror-isomer-pure starting materials.

The present invention also includes the isotopically-labeled compounds of the present invention, which are the same as those listed herein, but in fact one or more of the atoms have an atomic mass or mass number different from that normally found in nature (or natural (The one found most often).

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

Certain isotopically-labeled compounds of the invention (eg, those labeled with ³ H and ¹⁴ C) can be useful, for example, in substrate tissue distribution assays. Tritiated ( ³ H) and carbon-14 ( ¹⁴ C) isotopes are useful because they make preparation and detectability easy. In addition, replacement with heavier isotopes such as deuterium (i.e., ² H) can provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore in some The environment can be better. Therefore, in a specific embodiment of the invention, R ^{2 is} selected from hydrogen or or deuterium, especially deuterium. In another embodiment, L ² may be> C ( ² H) ₂ . Positron emission isotopes (such as ¹⁵ O, ¹³ N, ¹¹ C, and ¹⁸ F) are useful for positron emission tomography (PET) research departments. PET imaging in cancer is effective in helping to locate and identify tumors, the stage of the disease, and determine the appropriate treatment. Human cancer cells overexpress receptors or proteins for many potential disease-specific molecular targets. Radiolabeled tracers that bind this receptor or protein on tumor cells with high affinity and specificity have great potential for diagnostic imaging and targeted radionuclide therapy (Charron, Carlie L. et al., Tetrahedron Lett. [ Tetrahedron Communications] 2016, 57 (37), 4119-4127). In addition, target-specific PET radiotracers can be used as biomarkers to examine and evaluate pathology, such as by measuring target performance and therapeutic response (Austin R. et al. Cancer Letters [Cancer Communication] (2016), doi : 10.1016 / j.canlet.2016.05.008).

The invention particularly relates to a compound having formula (I) and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, as mentioned in any one of the embodiments, wherein the following compounds and their pharmaceutically Acceptable addition salts and solvates:

The invention particularly relates to a compound having formula (I) and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, as mentioned in any one of the embodiments, which is excluded from WO 2017/112768 Described intermediates and compounds (to the extent they are covered by the present invention).

The invention particularly relates to compounds of formula (I), as defined herein, and tautomers and stereoisomeric forms thereof, wherein R ¹ is CF ₃ ; R ^{2 is} selected from the group consisting of: hydrogen and CH ₃ ; L ¹ represents a 7- to 10-membered saturated spiro-heterobicyclic system containing one or two N atoms, provided that it is N-linked to a thienopyrimidinyl heterocycle; and --L ² -R ^{3 is} selected From (a), (b), (c), (d), (f) or (g), where (a) L ^{2 is} selected from the group consisting of:> CR ^4a R ^4b and -CHR ^4a CHR ^5- ; wherein L ^{2 is} connected to the nitrogen atom of L ¹ ; R ^{4a is} selected from the group consisting of: hydrogen; -C (= O) NR ^7a R ^7b ; optionally selected from the group consisting of substituents A substituted C _1-4 alkyl group, the group consisting of: -OR ⁸ , and -NR ^9a R ^9b ; and a C-linked 4- to 7-membered non-aromatic heterocyclic group containing at least one nitrogen atom R ^{5 is} selected from the group consisting of: hydrogen; -OR ⁶ ; and C _1-4 alkyl; R ^{4b is} selected from the group consisting of: hydrogen and methyl; or R ^4a and R ^4b Together with the carbon atoms to which they are attached form a C _3-5 cycloalkyl or C-linked 4- to 6-membered heterocyclyl; wherein R ⁶ , R ^7a , R ^7b , R ⁸ , R ^9a, and R ^9b are each independently selected from the group consisting of: hydrogen; and a substituent selected from the group consisting of -Substituted C _2-4 alkyl, the group consisting of -OR ¹¹ and -NR ^10a R ^10b ; wherein R ^10a , R ^10b and R ¹¹ 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 Ar, Het ¹ , Het ² , and a 7- to 10-membered saturated spiro-carbon bicyclic ring system; or (b) L ² System> CR ^4c R ^4d , where R ^4c and R ^4d are hydrogen; and R ³ is ; Wherein R ^12a , R ^12b , and R ^12c are C _1-6 alkyl 1; or (c)-L ² -R ³ are C _1-, optionally substituted with one, two, or three fluorine substituents ₆ alkyl; or (d) L ² is O, and R ³ is -CH ₂ -Ar; or (f)-L ² -R ³ is Wherein R ^{18 is} selected from the group consisting of: hydrogen; and C _1-4 alkyl; R ^{18a is} selected from the group consisting of: hydrogen; and fluorine; R ^{18b is} selected from the group consisting of: Group: fluorine, -OC _1-4 alkyl and optionally C _1-4 alkyl substituted with 1, 2 or 3 fluorine substituents; or R ^18a and R ^18b combine with the same carbon atom and together form C _3-5 cycloalkyl; or (g)-L ² -R ³ series ; And wherein Ar is a phenyl group optionally substituted with one, two, or three substituents, each substituent is independently selected from the group consisting of: halogen, -OR ²⁴ , and optionally- OR ²⁶ substituted C _1-4 alkyl; Het ¹ is a monocyclic heteroaryl group selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, pyridine Base Base, pyrrolyl, pyrazolyl, imidazolyl, 4- or 5-thiazolyl, isothiazolyl, and iso Oxazolyl; or a bicyclic heteroaryl group selected from the group consisting of indnoyl, imidazopyridyl; each of which may be optionally substituted with one, two, or three substituents, each Substituents are independently selected from the group consisting of halogen, -CN, -OR ^24b , and optionally _C1-4 alkyl substituted with a substituent selected from the group consisting of Composition: -CN, -OR ²⁶ , and -NR ^27a R ^27b ; and Het ² is a non-aromatic heterocyclic group optionally substituted with one, two, or three substituents, each of which is independently selected from the following A group consisting of: halogen, -CN, and optionally C _1-4 alkyl substituted with -OR ²⁶ ; wherein R ²⁴ , R ²⁶ , R ^27a , and R ^27b are each independently selected from the group consisting of Groups: hydrogen; C _1-4 alkyl; and C _2-4 alkyl substituted with -NR ^28a R ^28b ; wherein R ^28a and R ^28b are hydrogen; and pharmaceutically acceptable salts and solvates thereof.

The invention particularly relates to compounds of formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein (a) L ^{2 is} selected from the group consisting of:> SO ₂ ,> CR ^4a R ^4b , and -CHR ^4a CHR ^5- ; wherein (i) when L ^{2 is} connected to the carbon atom of L ¹ , then R ^4a and R ⁵ are each independently selected from the group consisting of: hydrogen; -OR ⁶ ; -NR ^7a R ^7b ; -C (= O) NR ^7a R ^7b ; optionally a C _1-4 alkyl group substituted with a substituent selected from the group consisting of: fluorine, -CN, -OR ⁸ , and -NR ^9a R ^9b ; and a C-linked 4- to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen, or sulfur atom; (ii) when L ^{2 is} connected to L ¹ nitrogen atom, then R ^{4a is} selected from the group consisting of: hydrogen; -C (= O) NR ^7a R ^7b ; optionally a C _1-4 alkyl group substituted with a substituent selected from the group , This group consists of: fluorine, -CN, -OR ⁸ , and -NR ^9a R ^9b ; and a C-linked 4- to 7-membered non-aromatic heterocyclic ring containing at least one nitrogen, oxygen, or sulfur atom R ^{5 is} selected from the group consisting of: hydrogen; -OR ⁶ ; -NR ^7a R ^7b ; -C (= O) NR ^7a R ^7b ; optionally a C _1-4 alkyl group substituted with a substituent selected from the group consisting of: fluorine, -CN, -OR ⁸ , and -NR ^9a R ^9b ; and a C-linked 4- to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen or sulfur atom; R ^{4b is} selected from the group consisting of: hydrogen and methyl; Or> CR ^4a R ^4b forms> C _3-5 cycloalkanediyl or> C-linked 4- to 6-membered heterocyclic diyl containing an oxygen atom; wherein R ⁶ , R ^7a , R ^7b , R ⁸ , R ^9a and R ^9b are each 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 ^10a R ^10b ; and C _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ¹¹ and -NR ^10a R ^10b ; wherein R ^10a , R ^10b and R ¹¹ 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: Ar, Het ¹ , Het ^2, and a 7-10 carbon saturated bicyclic spiro system; consisting of or (b) L ² is selected from the group consisting of The group:> CR ^4c R ^4d and -CHR ^4c CHR ^5a -, wherein R ^4c, R ^4d, and R ^5a are each independently chosen from the group consisting of: hydrogen and C _1-4 alkyl; and R ^{3 is} selected from the group consisting of: with ; Wherein R ^12a , R ^12b , and R ^12c are each independently selected from the group consisting of: a C _1-6 alkyl group optionally substituted with -OH or -NH ₂ substituent; or (c)- L ² -R ³ is a C _1-6 alkyl optionally substituted with one, two or three fluorine substituents; or (d) L ² is O, and R ^{3 is} selected from the group consisting of: Ar, Het ¹ ; -CH ₂ -Ar, -CH ₂ -Het ¹ , and -CH _2- (7 to 10-membered saturated spiro-carbon bicyclic ring system); when L ^{2 is} connected to the carbon atom of L ¹ ; or (e)-L ² -R ^{3 is} selected from the group consisting of: Where R ¹⁸ is hydrogen; or (f)-L ² -R ³ or ; And wherein Ar is a phenyl group optionally substituted with one, two, or three substituents, each substituent is independently selected from the group consisting of: halogen, -CN, and optionally C _1-4 alkyl substituted with substituents of the group consisting of: fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C (= O) NR ^27a R ^27b ; Het ¹ Is a monocyclic heteroaryl group selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, pyridine Base , Furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 4- or 5-thiazolyl, isothiazolyl, thiadiazolyl, and isopropyl Oxazolyl; or bicyclic heteroaryl, the bicyclic heteroaryl is selected from imidazopyridyl, especially imidazo [1,2-a] pyridyl; each of which can be one, two, or three as appropriate Substituent substitution, each substituent is independently selected from the group consisting of halogen, -CN, and optionally C _1-4 alkyl substituted with a substituent selected from the group consisting of Composition: fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C (= O) NR ^27a R ^27b ; and Het ² is selected from the group consisting of azetidinyl, pyrrolidinyl, and piperidinyl Non-aromatic heterocyclic groups; wherein R ²⁶ , R ^27a , and R ^27b are each independently selected from the group consisting of: hydrogen and C _1-4 alkyl; and pharmaceutically acceptable salts and solvates thereof .

The invention particularly relates to compounds of formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, 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 ; L ¹ represents a 7- to 10-membered saturated spiro-bicyclic system containing one or two N atoms, provided that it is N- is attached to a thienopyrimidinyl heterocyclic ring; and --L ² -R ^{3 is} selected from (a), (b), (d), (e), or (f), wherein (a) L ^{2 is} selected from A group consisting of:> SO ₂ ,> CR ^4a R ^4b , and -CHR ^4a CHR ^5- ; where (i) when L ^{2 is} connected to the carbon atom of L ¹ , then R ^4a and R ⁵ are independent Ground is selected from the group consisting of: hydrogen; -OR ⁶ ; -NR ^7a R ^7b ; -C (= O) NR ^7a R ^7b ; C _1-4 optionally substituted by a substituent selected from the group Alkyl, the group consisting of: fluorine, -CN, -OR ⁸ , and -NR ^9a R ^9b ; and C-linked 4- to 7-membered non-aromatic containing at least one nitrogen, oxygen, or sulfur atom a heterocyclic group; (ii) when L ² is connected to the nitrogen atom of L is ^1, then R ^4a is selected from the group consisting of the following The ^{group: -C (= O) NR 7a} R 7b; optionally substituted group selected from the group C _1-4 alkyl substituted by the group consisting of: fluorine, -CN, -OR ⁸ , And -NR ^9a R ^9b ; and a C-linked 4- to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen or sulfur atom; R ^{5 is} selected from the group consisting of: hydrogen;- OR ⁶ ; -NR ^7a R ^7b ; -C (= O) NR ^7a R ^7b ; optionally a C _1-4 alkyl group substituted with a substituent selected from the group consisting of: fluorine,- CN, -OR ⁸ , and -NR ^9a R ^9b ; and a C-linked 4- to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen, or sulfur atom; R ^{4b is} selected from the group consisting of Group: hydrogen and methyl; or R ^4a and R ^4b together with the carbon atom to which they are attached form a C _3-5 cycloalkyl or C-linked 4- to 6-membered heterocyclic group containing an oxygen atom; where R ⁶ , R ^7a , R ^7b , R ⁸ , R ^9a, and R ^9b are each independently selected from the group consisting of: hydrogen; optionally a C _1-4 alkyl group substituted with a substituent selected from the group consisting of the group consisting of: fluorine, -CN, and ^{-C (= O) NR 10a R} 10b; and is selected from Substituted with C _2-4 alkyl group, the group consisting of: -OR ¹¹ and -NR ^10a R ^10b; wherein R ^10a, R ^10b and R ¹¹ are each independently selected from the group consisting of The group: hydrogen; a C _1-4 alkyl group; and a C-linked 4-membered to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen, or sulfur atom; and R ^{3 is} selected from the group consisting of Group: Ar, Het ¹ , Het ² , and 7- to 10-membered saturated spirocarbon bicyclic ring system; or (b) L ^{2 is} selected from the group consisting of:> CR ^4c R ^4d and -CHR ^4c CHR ^5a- , wherein R ^4c , R ^4d , and R ^5a 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: with ; Wherein R ^12a , R ^12b , and R ^12c are each independently selected from the group consisting of: a C _1-6 alkyl group optionally substituted with -OH or -NH ₂ substituent; and -OC _1-6 Alkyl; or (d) L ² is O, and R ^{3 is} selected from the group consisting of: C _3-6 alkyl optionally substituted with one, two, or three fluorine substituents; Ar; Het ¹ ; Het ² ; 7- to 10-membered saturated spiro-carbon bicyclic ring system; -CH ₂ -Ar; -CH ₂ -Het ¹ ; -CH ₂ -Het ² ; and -CH _2- (7 to 10-membered saturated spiro Carbon bicyclic ring system); when L ^{2 is} connected to the carbon atom of L ¹ ; or (e)-L ² -R ³ is -O-CHR ⁵ -R ³ when L ^{2 is} connected to the carbon atom of L ¹ Where R ^{5 is} selected from the group consisting of: -C (= O) NR ^13a R ^13b ; optionally a C _1-4 alkyl group substituted with a substituent selected from the group consisting of Composition: Fluorine, -OR ¹⁴ , and -NR ^15a R ^15b ; and C-linked 4-membered to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen or sulfur atom; wherein R ^13a , R ^13b , R ^14, R ^15a and R ^15b are each independently selected from the group consisting of: hydrogen; optionally substituted group selected from the group which C _1-4 alkyl, the group consisting of: fluorine and ^{-C (= O) NR 16a R} 16b; and the substituents are selected from the group of the substituted C _2-4 alkyl group, the group consisting of Consisting of: -OR ¹⁷ and -NR ^16a R ^16b ; wherein R ^16a , R ^16b and R ¹⁷ are each independently selected from the group consisting of: hydrogen; C _1-4 alkyl; and containing at least one A C-linked 4- to 7-membered non-aromatic heterocyclic group of a nitrogen, oxygen or sulfur atom; and R ^{3 is} selected from the group consisting of: hydrogen; optionally substituted with one, two or three fluorines -Substituted C _1-4 alkyl; -CN; Ar; Het ¹ ; Het ² ; and 7- to 10-membered saturated spirocarbon bicyclic ring system; or (f)-L ² -R ³ system , Wherein R ^{18 is} selected from the group consisting of: hydrogen; C _1-4 alkyl optionally substituted with fluorine or -CN substituent; and C _2-4 alkyl substituted with substituent selected from This group consists of the following: -OR ¹⁹ and -NR ^20a R ^20b ; wherein R ¹⁹ , R ^20a and R ^20b are each independently selected from the group consisting of: hydrogen; and optionally, selected from the following: C _1-4 alkyl substituted with substituents of the group consisting of: fluorine, -CN and -C (= O) NR ^21a R ^21b ; C _2- substituted with substituents selected from the group _4- alkyl, the group consisting of: -OR ²² and NR ^21a R ^21b ; and a C-linked 4- to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen or sulfur atom; wherein R ^21a , R ^21b, and R ²² are each independently selected from the group consisting of: hydrogen and C _1-4 alkyl; and R ^{18a is} selected from the group consisting of: hydrogen, fluorine, and C _1-4 Alkyl; R ^{18b is} selected from the group consisting of: fluorine, -OC _1-4 alkyl, and optionally C _1-4 alkyl substituted with 1, 2 or 3 fluorine substituents; or R ^18a and R ^18b bind to the same carbon atom and together form a C _3-5 An alkyl group or a C-linked 4-membered to 6-membered heterocyclic group containing an oxygen atom; and wherein Ar is phenyl or naphthyl, each of which may be optionally substituted with one, two, or three substituents, each substituted Is independently selected from the group consisting of halogen, -CN, -OR ²⁴ , -NR ^25a R ^25b , and optionally C _1-4 alkyl substituted with a substituent selected from the group consisting of: It consists of the following: fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C (= O) NR ^27a R ^27b ; Het ¹ is a monocyclic heteroaryl group selected from the group consisting of Compositions of: pyridyl, 4-, 5- or 6-pyrimidinyl, pyridine Base , Furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 4- or 5-thiazolyl, isothiazolyl, thiadiazolyl, and isopropyl Oxazolyl; or a bicyclic heteroaryl group selected from the group consisting of imidazothiazolyl, imidazomidazolyl, benzofuranyl, benzophenylthio, benzimidazolyl, benzene and Oxazolyl, isobenzo Oxazolyl Oxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, innosyl, isoinnoyl, ind Group, dihydroindolyl, isoindolino, indazolyl, pyrazolopyridyl, pyrazolopyrimidyl, imidazopyridyl, imidazopyridine Imidazo Groups; 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, -CN, -OR ²⁴ , -NR ^25a R ^25b , And optionally C _1-4 alkyl substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C (= O) NR ^27a R ^27b ; and Het ² is a non-aromatic heterocyclic group optionally substituted with one, two or three substituents, each substituent is independently selected from the group consisting of: halogen, -CN , -OR ²⁴ , -NR ^25a R ^25b , and optionally a C _1-4 alkyl group substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C (= O) NR ^27a R ^27b ; wherein R ²⁴ , R ^25a , R ^25b , R ²⁶ , R ^27a , and R ^27b are each 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 ^28a R ^28b ; and substituted with a substituent selected from the group consisting of: C _2-4 alkyl, the group consists of the following groups Into: -OR ²⁹ and -NR ^28a R ^28b ; wherein R ^28a , R ^28b and R ²⁹ are each independently selected from the group consisting of: hydrogen; C _1-4 alkyl; and containing at least one nitrogen, oxygen Or a C-linked 4- to 7-membered non-aromatic heterocyclic group of a sulfur atom; and pharmaceutically acceptable salts and solvates thereof.

The invention particularly relates to compounds of formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein R ¹ is CF ₃ ; (a) L ² is> CR ^4a R ^4b ; wherein R ^{4a is} selected from the group consisting of: hydrogen; -C (= O) NR ^7a R ^7b ; C _1-4 alkyl; and C-linked 4 to 7 members containing at least one nitrogen, oxygen, or sulfur atom A non-aromatic heterocyclic group; and R ^{4b is} selected from the group consisting of: hydrogen and methyl; wherein R ^7a and R ^7b are each independently selected from the group consisting of: hydrogen; C _{1- 4} alkyl; and C _2-4 alkyl substituted with a substituent selected from the group consisting of: -OR ¹¹ and -NR ^10a R ^10b ; wherein R ^10a , R ^10b and R ¹¹ 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: Ar, Het ¹ , Het ² , and 7 to 10 member saturated helical A carbobicyclic system; or (b) L ² > CR ^4c R ^4d , wherein R ^4c and R ^4d are each independently selected from the group consisting of hydrogen and C _1-4 alkyl; and R ^{3 is} Freedom of groups consisting of: with ; Wherein R ^12a , R ^12b , and R ^12c are each independently selected from the group consisting of a C _1-6 alkyl group optionally substituted with a -NH ₂ substituent; or (c)-L ^2- R ³ is a C _1-6 alkyl optionally substituted with one, two or three fluorine substituents; or (d) L ² is O, and R ^{3 is} selected from the group consisting of Ar, Het ¹ , -CH ₂ -Ar, -CH ₂ -Het ¹ , and -CH _2- (7 to 10-membered saturated spiro-carbon bicyclic ring system); when L ^{2 is} connected to the carbon atom of L ¹ ; or (e) --L ² -R ^{3 is} selected from the group consisting of: Where R ¹⁸ is hydrogen; or (f)-L ² -R ³ or ; And wherein Ar is a phenyl group optionally substituted with a halogen substituent; Het ¹ is a monocyclic heteroaryl group selected from the group consisting of pyridyl, 4-, 5-, or 6-pyrimidine Base Base , Pyrrolyl, pyrazolyl, imidazolyl, and 4- or 5-thiazolyl; or a bicyclic heteroaryl, the bicyclic heteroaryl is selected from imidazopyridyl, especially imidazo [1,2- a] pyridyl; each may optionally be substituted by one, two or three substituents, each substituent being independently selected from the group consisting of halogen and optionally a substituent selected from the group consisting of A substituted C _1-4 alkyl group, the group consisting of: fluoro, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C (= O) NR ^27a R ^27b ; and Het ² is selected from Non-aromatic heterocyclic groups of azetidinyl, pyrrolidinyl, and piperidinyl; wherein R ²⁶ , R ^27a , and R ^27b are each independently selected from the group consisting of: hydrogen and C _{1- 4} alkyl; and pharmaceutically acceptable salts and solvates thereof.

The invention particularly relates to compounds of formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein R ¹ is CF ₃ ; L ¹ represents an N-linkage containing one or two N atoms 7- to 10-membered saturated spirobicyclic ring system, the N atom is selected from the group consisting of (a), (b), (c), (d), (e), (f), and (g)

Where a represents a position attached to a thienopyrimidinyl heterocyclic ring; (a) L ² is> CH ₂ ; and R ^{3 is} selected from the group consisting of: Ar, Het ¹ , and 7 to 10 saturated spiro A carbobicyclic system; or (b)-L ² -R ³ is a C _1-6 alkyl optionally substituted with one, two, or three fluorine substituents; and wherein Ar is optionally substituted with a halogen substituent Het ¹ is a monocyclic heteroaryl group selected from the group consisting of 4-, 5- or 6-pyrimidinyl, pyridine Base , Pyrrolyl, pyrazolyl, imidazolyl, and 4- or 5-thiazolyl; or a bicyclic heteroaryl, the bicyclic heteroaryl is selected from imidazopyridyl, especially imidazo [1,2- a] pyridyl; each of which may be optionally substituted with one or two substituents, each substituent being independently selected from the group consisting of: halogen and C _1-4 alkyl; and pharmaceutically acceptable Salts and solvates.

The invention particularly relates to compounds of formula (I), as defined herein, and tautomers and stereoisomeric forms thereof, wherein R ¹ is CF ₃ ; R ² is hydrogen; L ¹ represents one or two N A 7- to 10-membered saturated spiro heterobicyclic system of an N-link of an atom selected from the group consisting of (a), (b), (c), (d), (e) , (F) and (g)

Where a represents a position attached to a thienopyrimidinyl heterocyclic ring; (a) L ² is> CH ₂ ; and R ^{3 is} selected from the group consisting of: Ar, Het ¹ , and 7 to 10 saturated spiro A carbobicyclic system; or (b)-L ² -R ³ is a C _1-6 alkyl optionally substituted with one, two, or three fluorine substituents; and wherein Ar is optionally substituted with a halogen substituent Het ¹ is a monocyclic heteroaryl group selected from the group consisting of 4-, 5- or 6-pyrimidinyl, pyridine Base Group, pyrrolyl, pyrazolyl, and imidazolyl; or a bicyclic heteroaryl, the bicyclic heteroaryl is selected from imidazopyridyl, especially imidazo [1,2-a] pyridyl; each may be Optionally substituted with one or two substituents, each substituent being independently selected from the group consisting of: halogen and C _1-4 alkyl; and pharmaceutically acceptable salts and solvates thereof.

Another embodiment of the present invention relates to those compounds of formula (I), and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, as mentioned in any other embodiment, wherein one of the following limitations (A) R ¹ is CF ₃ ; (b) R ² is hydrogen; (c) L ¹ is an N-linked 7- to 10-membered saturated spirobicyclic ring containing one or two N atoms System, the N atom is selected from the group consisting of (a), (b), (c), (d), (e), (f), and (g) as defined herein; (d) ) L ¹ is an N-linked 7- to 10-membered saturated spiroheterobicyclic system containing one or two N atoms, the N atom being selected from the group consisting of: (a), as defined herein, (b), (c), (d), (e), and (f); (e) L ¹ is an N-linked 7- to 10-membered saturated spiro-heterobicyclic system containing one or two N atoms , The N atom is selected from the group consisting of (c) and (e); (f) L ² > CH ₂ ; (g) L ² > CH ₂ ; and R ^{3 is} selected from Group consisting of: Ar, Het ¹ , and 7- to 10-membered saturated spirocarbon bicyclic ring system; (h)-L ² -R ^{3 is} selected from the group consisting of: ,with ; Wherein R ^{18 is} selected from the group consisting of: hydrogen; a C _1-4 alkyl group optionally substituted with a fluorine or -CN substituent; and a C _2-4 alkane substituted with a substituent selected from the group consisting of: This group consists of the following: -OR ¹⁹ and -NR ^20a R ^20b ; wherein R ¹⁹ , R ^20a and R ^20b are each independently selected from the group consisting of: hydrogen; optionally selected from the following: C _1-4 alkyl substituted with substituents of the group consisting of: fluorine, -CN and -C (= O) NR ^21a R ^21b ; C _2- substituted with substituents selected from the group _4- alkyl, the group consisting of: -OR ²² and NR ^21a R ^21b ; and a C-linked 4- to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen or sulfur atom; wherein R ^21a , R ^21b and R ²² are each independently selected from the group consisting of: hydrogen and C _1-4 alkyl; (i) Ar is benzene optionally substituted with one or two independently selected halogen substituents (J) Ar is a phenyl group optionally substituted with a halogen substituent; (k) Ar is a phenyl group; (l) Het ¹ is a monocyclic heteroaryl group selected from the group consisting of Composition: pyrazolyl, imidazolyl, pyrrolyl, 4- or 5-thiazolyl, pyridyl, da , 4-, 5- or 6-pyrimidinyl, and pyridine Or a bicyclic heteroaryl, the bicyclic heteroaryl is selected from imidazopyridyl, especially imidazo [1,2-a] pyridyl; each of which may be substituted with one or two substituents as appropriate Each substituent is 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 ²⁵ , -NR ^26a R ^26b , and -C (= O) NR ^26a R ^26b ; wherein R ²⁵ , R ^26a , and R ^26b are each independently selected from the group consisting of: hydrogen and C _{1 -4} alkyl; (m) Het ¹ is a monocyclic heteroaryl group selected from the group consisting of pyrazolyl, imidazolyl, pyrrolyl, 4- or 5-thiazolyl, pyridyl ,despair , 4-, 5- or 6-pyrimidinyl, and pyridine Or a bicyclic heteroaryl, the bicyclic heteroaryl is selected from imidazopyridyl, especially imidazo [1,2-a] pyridyl; each of which may be substituted with one or two substituents as appropriate Each substituent is independently selected from the group consisting of halogen and C _1-4 alkyl optionally substituted with a substituent selected from the group consisting of: -CN,- OR ²⁵ , -NR ^26a R ^26b , and -C (= O) NR ^26a R ^26b ; wherein R ²⁵ , R ^26a , and R ^26b are each independently selected from the group consisting of: hydrogen and C _1-4 Alkyl; (n) Het ¹ is a monocyclic heteroaryl group selected from the group consisting of pyrazolyl, imidazolyl, pyrrolyl, da , 4-, 5- or 6-pyrimidinyl, and pyridine Or a bicyclic heteroaryl, the bicyclic heteroaryl is selected from imidazopyridyl, especially imidazo [1,2-a] pyridyl; each of which may be substituted with one or two substituents as appropriate Each substituent is independently selected from the group consisting of: halogen and C _1-4 alkyl; (o) Het ¹ is a monocyclic heteroaryl group selected from the group consisting of :despair , 4-, 5- or 6-pyrimidinyl, and pyridine Groups, each of which may be optionally substituted with a halogen substituent; (p) Het ¹ is a bicyclic heteroaryl group selected from imidazopyridyl, especially imidazo [1,2-a] pyridine 6-yl or imidazo [1,2-a] pyridin-2-yl; (q) 7- to 10-membered saturated spirocarbobicyclic systems are in specific

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R ¹ is CF ₃ .

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R ¹ is CF ₃ And wherein R ² is hydrogen.

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Ar is according to other implementations Any one of the modes is optionally substituted phenyl.

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein L ^{2 is} connected to L ¹ carbon atom.

In one embodiment, the present invention relates to those compounds of formula (I), and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein --L ^2- R ³ is (a).

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein --L ^2- R ³ is (b).

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein --L ^2- R ³ series (c).

In one embodiment, the present invention relates to those compounds of formula (I), and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein --L ^2- R ³ series (d).

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein --L ^2- R ³ series (e).

In one embodiment, the present invention relates to those compounds of formula (I), and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein --L ^2- R ³ series (f).

In one embodiment, the present invention relates to those compounds of formula (I), and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein --L ^2- R ³ series (g).

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein --L ^2- R ³ is (a), (b), (d), (e) or (f); and R ^4a is not hydrogen. In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein --L ^2- R ³ is (a) or (f); and R ^4a is not hydrogen. In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein --L ^2- R ³ is (a); and R ^4a is not hydrogen.

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein --L ^2- R ³ is (a); and when L ^{2 is} connected to the nitrogen atom of L ¹ , then R ^4a is not hydrogen.

In one embodiment, the present invention relates to those compounds of formula (I), and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein --L ^2- R ³ is (a) or (f); and when L ^{2 is} connected to the nitrogen atom of L ¹ , then R ^4a is not hydrogen.

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein --L ^2- R ³ is (a), (b), (d), (e) or (f); and when L ^{2 is} connected to the nitrogen atom of L ¹ , then R ^4a is not hydrogen.

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein L ¹ represents

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein --L ^2- R ³ is (a); R ³ is Het ¹ or Het ² .

In one embodiment, the present invention relates to those compounds of formula (I), and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein --L ^2- R ³ is (a); R ³ is Het ¹ .

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein --L ^2- R ³ is (a); R ³ is Het ¹ ; and Het ¹ is an optionally substituted azetidinyl group as defined in any of the other embodiments.

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein --L ^2- R ³ is (a); R ³ is Het ¹ or Het ² ; Het ¹ is a monocyclic heteroaryl group selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidine Base Base , Pyrrolyl, pyrazolyl, and imidazolyl; each may be optionally substituted with one, two, or three substituents, each substituent being independently selected from the group consisting of: halogen, -CN , -OR ²⁴ , -NR ^25a R ^25b , and optionally a C _1-4 alkyl group substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b and -C (= O) NR ^27a R ^27b ; and Het ² is a non-aromatic heterocyclic group selected from the group consisting of azetidinyl, pyrrolidinyl, And piperidinyl; each may be optionally substituted with one, two, or three substituents, each of which is independently selected from the group consisting of: halogen, -CN, -OR ²⁴ , -NR ^25a R ^25b , and optionally C _1-4 alkyl substituted with a substituent selected from the group consisting of: fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C ( = O) NR ^27a R ^27b .

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Ar is phenyl, The phenyl group may be optionally substituted with one, two or three substituents, each substituent being independently selected from the group consisting of: halogen, -CN, -OR ²⁴ , -NR ^25a R ^25b , and _C1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C (= O) NR ^27a R ^27b ; Het ¹ is a monocyclic heteroaryl group selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, pyridine Base , Furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 4- or 5-thiazolyl, isothiazolyl, thiadiazolyl, and isopropyl Oxazolyl; each of which may be optionally substituted with one, two or three substituents, each substituent being independently selected from the group consisting of: halogen, -CN, -OR ²⁴ , -NR ^25a R ^25b , And optionally C _1-4 alkyl substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ²⁶ , -NR2 ^7a R ^27b , and -C (= O ) NR ^27a R ^27b ; and Het ² is a monocyclic non-aromatic heterocyclic group optionally substituted with one, two or three substituents, each substituent being independently selected from the group consisting of: halogen , -CN, -OR ²⁴ , -NR ^25a R ^25b , and optionally a C _1-4 alkyl group substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C (= O) NR ^27a R ^27b .

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein --L ^2- R ³ is (a), wherein L ^{2 is} selected from the group consisting of:> CR ^4a R ^4b , and -CHR ^4a CHR ^5- ; wherein L ^{2 is} connected to the nitrogen atom of L ¹ ; R ^{4a is} selected from A group consisting of: -C (= O) NR ^7a R ^7b ; and a C-linked 4-membered to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen or sulfur atom; R ^{5 is} selected from The groups of each component: hydrogen; -OR ⁶ ; -NR ^7a R ^7b ; -C (= O) NR ^7a R ^7b ; C _1-4 alkyl substituted with a substituent selected from the group, as appropriate, the The group consists of: fluorine, -CN, -OR ⁸ , and -NR ^9a R ^9b ; R ^{4b is} selected from the group consisting of: hydrogen and methyl; and R ^{3 is} selected from the group consisting of Group: Ar, Het ¹ , Het ² , and 7- to 10-membered saturated spiro-carbon bicyclic ring systems.

In one embodiment, the present invention relates to those compounds of formula (I), and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein --L ^2- R ³ is (a), wherein L ² is> CR ^4a R ^4b ; wherein L ^{2 is} connected to the nitrogen atom of L ¹ ; R ^{4a is} selected from the group consisting of: -C (= O) NR ^7a R ^7b ; And a C-linked 4- to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen, or sulfur atom; R ^4b is hydrogen; and R ^{3 is} selected from the group consisting of: Ar, Het ¹ , Het ² , and 7- to 10-membered saturated spirocarbon bicyclic ring systems.

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein --L ^2- R ³ is (a), wherein L ² is> CR ^4a R ^4b ; wherein L ^{2 is} connected to the nitrogen atom of L ¹ ; R ^{4a is} selected from the group consisting of: -C (= O) NR ^7a R ^7b And a C-linked 4- to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen, or sulfur atom; R ^4b is hydrogen; and R ^{3 is} selected from the group consisting of: Ar and Het ² .

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein --L ^2- R ³ is (a), wherein L ^{2 is} selected from the group consisting of:> CR ^4a R ^4b , and -CHR ^4a CHR ^5- ; wherein L ^{2 is} connected to the nitrogen atom of L ¹ ; R ^4a is -C (= O) NR ^7a R ^7b ; R ^{5 is} selected from the group consisting of: hydrogen; -OR ⁶ ; -NR ^7a R ^7b ; -C (= O) NR ^7a R ^7b ; optionally selected from the following: C _1-4 alkyl substituted with a substituent of the group consisting of: fluorine, -CN, -OR ⁸ , and -NR ^9a R ^9b ; R ^{4b is} selected from the group consisting of: hydrogen And methyl; and R ^{3 is} selected from the group consisting of Ar, Het ¹ , Het ² , and a 7- to 10-membered saturated spirocarbon bicyclic ring system.

In one embodiment, the present invention relates to those compounds of formula (I), and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein --L ^2- R ³ is (a), wherein L ² is> CR ^4a R ^4b ; wherein L ^{2 is} connected to the nitrogen atom of L ¹ ; R ^4a is -C (= O) NR ^7a R ^7b ; R ^4b is hydrogen; and R ³ From the group consisting of: Ar, Het ¹ , Het ² , and a 7- to 10-membered saturated spirocarbon bicyclic ring system.

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein --L ^2- R ³ is (a), wherein L ² is> CR ^4a R ^4b ; wherein L ^{2 is} connected to the nitrogen atom of L ¹ ; R ^4a is -C (= O) NR ^7a R ^7b ; R ^4b is hydrogen; and R ³ From the group consisting of: Ar and Het ² .

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein --L ^2- R ³ is (a), wherein L ^{2 is} selected from the group consisting of:> CR ^4a R ^4b , and -CHR ^4a CHR ^5- ; wherein L ^{2 is} connected to the nitrogen atom of L ¹ ; R ^4a contains at least C-linked 4- to 7-membered non-aromatic heterocyclic group of one nitrogen, oxygen or sulfur atom; R ^{5 is} selected from the group consisting of: hydrogen; -OR ⁶ ; -NR ^7a R ^7b ; -C (= O) NR ^7a R ^7b ; optionally a C _1-4 alkyl group substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ⁸ , and -NR ^9a R ^9b ; R ^{4b is} selected from the group consisting of: hydrogen and methyl; and R ^{3 is} selected from the group consisting of: Ar, Het ¹ , Het ² , and 7 to 10 members of saturated spirocarbon di Ring system.

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein --L ^2- R ³ is (a), where L ² is> CR ^4a R ^4b ; wherein L ^{2 is} connected to the nitrogen atom of L ¹ ; R ^4a is a C-linked 4 to 7 member containing at least one nitrogen, oxygen or sulfur atom A non-aromatic heterocyclic group; R ^4b is hydrogen; and R ^{3 is} selected from the group consisting of Ar, Het ¹ , Het ² , and a 7- to 10-membered saturated spirocarbon bicyclic ring system.

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein --L ^2- R ³ is (a), where L ² is> CR ^4a R ^4b ; wherein L ^{2 is} connected to the nitrogen atom of L ¹ ; R ^4a is a C-linked 4 to 7 member containing at least one nitrogen, oxygen or sulfur atom A non-aromatic heterocyclic group; R ^4b is hydrogen; and R ^{3 is} selected from the group consisting of Ar and Het ² .

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein L ^{2 is} connected to L ¹ nitrogen atom.

In one embodiment, the present invention relates to those compounds of formula (I), and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein --L ^2- R ^{3 is} selected from the group consisting of:

In one embodiment, the present invention relates to those compounds of formula (I), and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein --L ^2- R ^{3 is} selected from the group consisting of:

Among them, R ¹⁸ is hydrogen or methyl.

In one embodiment, the present invention relates to those compounds of formula (I) and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, mentioned in any other embodiment, wherein L ¹ Or N-linked 7 to 10 membered saturated spiroheterobicyclic system of two N atoms, the N atom is selected from the group consisting of (a), (b), (c), (d) , (E), (f), (g), (h), and (i)

Where a represents the position attached to the thienopyrimidinyl heterocycle.

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het ² is as in Monocyclic heterocyclyls described in other embodiments are optionally substituted with one, two or three substituents.

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het ² is non-aromatic Family heterocyclyl, the heterocyclyl is selected from the group consisting of azetidinyl, oxetanyl, tetrahydrofuranyl, piperidinyl, tetrahydropiperanyl, tetrahydro-2H-thiopiperyl Aryl 1,1-dioxide, with , Each of which is optionally substituted with one, two or three substituents as described in other embodiments.

In one embodiment, the invention relates to those compounds of formula (I) mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het ² is non-aromatic Group heterocyclyl, selected from the following:

Each of them is optionally substituted with one, two or three substituents as described in the other embodiments.

Specific compound compounds of formula (I) are compounds 82, 84, 273, and 274, including their stereoisomeric forms, pharmaceutically acceptable salts, especially their hydrochloride salts, and their solvates.

Specific compound compounds of formula (I) are compounds 82, 84, 273, and 274.

In one embodiment, the compound of formula (I) is selected from the group consisting of any one of the exemplified compounds, and its free base, a pharmaceutically acceptable addition salt, and a solvate.

All possible combinations of the embodiments indicated above are considered to be included within the scope of the present invention.

Method for preparing a compound having formula (I)

In this section, as in all other sections, unless the context indicates otherwise, references to formula (I) also include all other subgroups and their instances, as defined herein.

The general preparation of some typical examples of compounds of formula (I) is described below and in the specific examples, and is usually prepared starting from a commercially available or prepared by standard synthetic procedures commonly used by those skilled in the art material. The following schemes are only intended to represent examples of the invention and are in no way intended to be limiting of the invention.

Alternatively, the compounds of the invention can also be prepared by combining similar reaction test protocols as described in the general scheme below with standard synthetic procedures commonly used by those of ordinary skill in the art of organic chemistry.

Those skilled in the art will recognize that in the reactions described in the schemes, although not always explicitly shown, the protection of the reactive functional groups (such as hydroxyl, amine, or carboxyl groups) desired in the end product may be Necessary to avoid their involvement in unwanted reactions. For example, in Scheme 1, the NH moiety on a L ¹ N-linked 7- to 10-membered saturated spiroheterobicyclic system containing one or two N atoms can be protected with a tertiary butoxycarbonyl protecting group. Generally, conventional protecting groups can be used according to standard practice. Protecting groups can be removed at a convenient subsequent stage using methods known in the art. This is illustrated in a specific example.

The skilled person will recognize that in the reactions described in the schemes, it may be desirable or necessary to carry out the reaction under an inert atmosphere ( such as under a N2 atmosphere).

It will be clear to the skilled person that it may be necessary to cool the reaction mixture before reaction processing (referring to a series of operations necessary to separate and purify one or more products of a chemical reaction, such as quenching, column chromatography, extraction).

The skilled person will recognize that heating the reaction mixture with stirring can increase the reaction output. In some reactions, microwave heating can be used instead of conventional heating to shorten the overall reaction time.

The skilled person will recognize that chemical reactions of another sequence shown in the scheme below may also lead to the desired compound of formula (I).

The skilled person will recognize that the intermediates and final compounds shown in the schemes below can be further functionalized according to methods well known to those skilled in the art. Intermediates and compounds described herein can be isolated in free form or in salt form.

plan 1

In general, compounds having formula (I), in which all variables are defined according to the scope of the present invention, can be prepared according to the following reaction scheme 1. In scheme 1, L ¹ represents a 7- to 10-membered saturated spiro heterobicyclic system containing two N atoms, and the bicyclic ring system is a thienopyrimidinyl heterocyclic ring to which N is attached, and LG ¹ and LG ² each represent an appropriate leaving group Groups such as, for example, halogen or methanesulfonyl; PG ¹ represents a suitable protecting group, such as for example tertiary butoxycarbonyl; R ^3a -PG ² represents a group having a suitable protecting group as defined in formula (I) R ³ , for example like tertiary butoxycarbonyl (when the R ³ substituent carries an amine group). In formula (XI), X represents CH or N (in formula (XI), L ² may be attached to a carbon atom or an N atom). All other variables in scheme 1 are defined within the scope of the invention.

In Scheme 1, the following reaction conditions apply:

1: at a suitable temperature (such as in the range from room temperature to 90 ° C), in the presence of a suitable base (such as diisopropylethylamine), in a suitable solvent (such as acetonitrile or isopropyl) Alcohol or ethanol);

2: In a suitable temperature range (e.g. like from 0 ° C to room temperature), in the presence of appropriate cleavage conditions (e.g. like an acid, such as HCl or trifluoroacetic acid), in an appropriate solvent (such as acetonitrile or dichloride) Methane) (when PG ¹ is tertiary butoxycarbonyl); alternatively, at a suitable temperature (e.g. like room temperature) in a suitable solvent (e.g. acetic acid)

3: At a suitable temperature (such as room temperature or reflux), in the presence of a suitable base (such as potassium carbonate or 1,8-diazabicyclo [5.4.0] undec-7-ene), In a suitable solvent (e.g. like acetonitrile or DMSO);

4: At a suitable temperature (eg like room temperature or 90 ° C) in the presence of a suitable base (eg like potassium carbonate or 1,8-diazabicyclo [5.4.0] undec-7-ene) In a suitable solvent (such as acetonitrile or DMSO);

5: In an appropriate reaction temperature range (for example, from 0 ° C to room temperature), in the presence of appropriate cleavage conditions (for example, like an acid such as HCl or trifluorolactic acid), in an appropriate solvent (such as acetonitrile or dichloromethane) In methyl chloride), when PG ² is a tertiary butoxycarbonyl group.

6: At a suitable temperature (e.g. like room temperature), finally in the presence of a suitable base (e.g. like trimethylamine) or a suitable acid (e.g. like acetic acid) in a suitable solvent (e.g. like anhydrous dichloromethane) , Dichloroethane or tetrahydropiperan);

7: At a suitable temperature (such as room temperature), in the presence of a suitable reducing agent (such as NaBH (OAc) ₃ ), in a suitable solvent (such as dichloromethane, dichloroethane, or tetrahydropiperan) ); Yielding a compound having formula (I), wherein L ¹ is an N-linked 7- to 10-membered saturated spiro heterobicyclic system containing two N atoms, and L ² is CH ₂ .

Steps 6 and 7 can be conveniently performed as a one-pot method.

Alternatively, steps 6 and 7 can be in the presence of a suitable acid (e.g. like acetic acid), a suitable catalyst (e.g. platinum oxide), a suitable solvent (e.g. like ethanol), at a suitable temperature (e.g. like 60 ° C) ); 8: at a suitable temperature (e.g. like at 90 ° C), in the presence of a suitable base (e.g. like diisopropylethylamine), in a suitable solvent (e.g. like acetonitrile or isopropanol) )in. In step 8, in the reagent having the formula (XI), X represents CH or N, and L ² and R ³ are as defined according to the scope of the present invention. Reagents of formula (XI) are commercially available or can also be prepared from commercially available starting materials by methods known to the skilled person, for example by means of suitable protection / deprotection steps and functional group interchange, starting from Starting materials (such as 2-azaspiro [3.3] heptan-6-ol (CAS [1256352-97-2])).

Scenario 2

Intermediates having formula (II) (wherein R ² is methyl) can be prepared according to the following reaction scheme 2, where LG ¹ represents a suitable leaving group (such as, for example, a halogen or methylsulfonyl). All other variables in scheme 2 are defined within the scope of the invention.

In Scheme 2, the following reaction conditions apply:

1: at a suitable temperature (for example, like at reflux temperature), in the presence of acetic anhydride and a suitable base (for example, like trimethylamine), in a suitable solvent (for example, like toluene); 2: at a suitable temperature (E.g. like at reflux temperature), in the presence of a suitable base (e.g. potassium hydroxide), in a suitable solvent (e.g. like ethanol); 3: under appropriate reaction conditions to form leaving groups ( (E.g. like chlorine), for example by carrying out the reaction with trichlorophosphonium at a suitable temperature (e.g. 110 ° C).

Option 3

Generally, compounds having formula (Ia) (where variables are defined according to the scope of the present invention, but where L ^{2 is} limited to L ^2a (an option obtainable by this scheme)) can be prepared according to the following reaction scheme 3. All other variables in scheme 3 are defined according to the scope of the invention or as previously defined.

In Scheme 3, the following reaction conditions apply:

1: At a suitable temperature (such as room temperature or 45 ° C), in the presence of titanium (IV) ethoxide or titanium (IV) isopropoxide, in a suitable solvent (such as tetrahydropiperan, dichloroethyl) Alkane or a mixture of dichloroethane and methanol); alternatively, at the appropriate temperature (e.g. like room temperature), with or without the appropriate acid (e.g. like trifluoroacetic acid), Solvent (e.g., like tetrahydropiperan); 2: at a suitable temperature (e.g., like room temperature), in a suitable reducing agent (e.g., In the presence of sodium hydride), in a suitable solvent (such as, for example, tetrahydropiperan, dichloroethane, or a mixture of dichloroethane and methanol); steps 1 and 2 can be performed as a one-pot process.

Option 4

In general, compounds having formula (Ib) (wherein R ^{4a is} restricted to R ^4a1 being a C _1-4 alkyl group or a C-linked 4- to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen or sulfur atom ) Can be prepared according to the following reaction scheme 4. In scheme 4, halogen means chlorine, bromine or iodine. All other variables in scheme 4 are defined within the scope of the invention or as previously defined.

In Scheme 4, the following reaction conditions apply:

1: at a suitable temperature (such as room temperature or 45 ° C) in the presence of titanium (IV) ethoxide or titanium (IV) isopropoxide in a suitable solvent (such as tetrahydropiperan); 2 : In a suitable temperature range from 0 ° C to room temperature, in a suitable solvent (for example, like tetrahydrofuran).

Steps 1 and 2 can be performed as a one-pot method.

Option 5

In general, compounds of formula (Ic) (wherein R ^{3 is} restricted to R ^3c is ) Can be prepared according to the following reaction scheme 5. All other variables in scheme 5 are defined according to the scope of the invention or as previously defined. In scheme 5, L ^{2 is} connected to the N atom of L ¹ .

In Scheme 5, the following reaction conditions apply:

1: At a suitable temperature (eg like room temperature), in a suitable acid coupling agent, such as 1- [bis (dimethylamino) methylene] -1H-benzotriazolium hexafluorophosphate (1-) 3-oxide (HBTU) or 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3- In the presence of the oxide hexafluorophosphate (HATU), in the presence of a suitable base (e.g. like N -ethyl- N- (1-methylethyl) -2-propylamine (DIPEA)), Solvents (eg N , N -dimethylformamide (DMF); scheme 6

In general, a compound having the formula (Id) in which L ^{2 is} limited to SO ₂ can be prepared according to the following reaction scheme 6. All other variables in scheme 6 are defined according to the scope of the invention or as previously defined. In Scheme 6, L ² (> SO ₂ in Scheme 6) is connected to the N atom of L ¹ .

In Scheme 6, the following reaction conditions apply:

1: At a suitable temperature (e.g. room temperature), in the presence of a suitable base (e.g. like potassium carbonate), in a suitable solvent (e.g. like acetonitrile).

Option 7

In general, compounds having formulae (Ie) and (If) can be prepared according to the following reaction scheme 7. In both (Ie) and (If), the L ² portion of the molecule is connected to the nitrogen atom of L ¹ . All other variables are defined within the scope of the invention or as previously defined.

In Scheme 7, the following reaction conditions apply:

1: At a suitable temperature (e.g. like 60 ° C) in a suitable solvent (e.g. like ethanol).

It will be understood that in the presence of appropriate functional groups, compounds having different formulas or any intermediates used for their preparation may be further derivatized by one or more standard synthetic methods using condensation, substitution, oxidation, reduction or cleavage reactions. Specific substitution methods include conventional alkylation, arylation, heteroarylation, tritiation, sulfonation, halogenation, nitration, formazanization, and coupling procedures.

Compounds of formula (I) can be synthesized as racemic mixtures of mirror isomers that can be separated from each other following resolution procedures known in the art. A racemic compound having a formula (I) (containing a basic nitrogen atom) can be converted into the corresponding non-mirromeric salt form by reaction with a suitable chiral acid. The non-mirromeric salt form is then separated, for example, by selective or stepwise crystallization, and the mirror isomer is released therefrom by a base. An alternative way to isolate the mirror-isomeric form of a compound having formula (I) involves liquid chromatography using a chiral stationary phase. The pure stereochemically isomeric form may also be derived from the corresponding pure stereochemically isomeric form of an appropriate starting material, provided that the reaction occurs stereospecifically.

In the preparation of the compounds of the present invention, protection of remote functional groups (such as primary or secondary amines) of the intermediate may be necessary. The need for such protection will vary depending on the nature of the remote functional group and the conditions of the preparation method. Suitable amine protecting groups (NH-Pg) include ethenyl, trifluoroethenyl, tertiary butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxy Carbonyl (Fmoc). The need for such protection is easily determined by those skilled in the art. For a general description of protecting groups and their uses, see TWGreene and PGMWuts, Protective Groups in Organic Synthesis, 4th Edition, Wiley Publishing, Hoboken, New Jersey (New Jersey), 2007.

Pharmacology

It has been found that compounds of the invention block the interaction of menin with MLL proteins and oncogenic MLL fusion proteins. Therefore, the compound according to the present invention and a pharmaceutical composition containing such a compound can be used for the treatment or prevention, particularly for the treatment of diseases such as cancer, myelodysplastic syndrome (MDS), and diabetes.

In particular, the compounds according to the present invention and their pharmaceutical compositions are useful for treating or preventing cancer. According to one embodiment, cancers that can benefit from treatment with a menin / MLL inhibitor of the invention include leukemia, myeloma, or solid tumor cancers (e.g., prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma, and Glioblastoma, etc.). In some embodiments, the leukemia includes acute leukemia, chronic leukemia, myeloid leukemia, myeloid leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and acute lymphoblast Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), Pre-T Lymphocytic Leukemia (T-PLL), Large Granular Lymphocytic Leukemia, Hair Cell Leukemia (HCL), MLL-Rearranged Leukemia, MLL-PTD Leukemia, MLL Increased leukemia, MLL-positive leukemia, leukemia displaying HOX / MEIS1 gene expression markers, etc.

The present invention therefore relates to compounds having the formula (I), their tautomeric and stereoisomeric forms, and their pharmaceutically acceptable salts and solvates for use as pharmaceuticals.

The invention also relates to the use of a compound of formula (I), its tautomeric or stereoisomeric forms or its pharmaceutically acceptable salts or solvates or the pharmaceutical composition according to the invention for the manufacture of a medicament.

The present invention relates to a compound having 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 use in treatment, prevention, Ameliorate, control, or reduce the risk of mammalian (including human) disorders related to the interaction of menin and MLL proteins and oncogenic MLL fusion proteins, which are treated or prevented by blocking menin and MLL proteins and oncogenic MLL fusions Protein interactions to influence or promote.

Likewise, the present invention relates to a compound having 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 use in the production of Use of a medicament for the treatment, prevention, amelioration, control or reduction of the risk of mammalian (including human) disorders associated with the interaction of menin and MLL proteins and oncogenic MLL fusion proteins, which are treated or prevented by blocking Menin and MLL proteins and oncogenic MLL fusion proteins interact to influence or promote.

The present invention also relates to a compound having formula (I), a tautomeric 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 above .

The present invention also relates to a compound having formula (I), a tautomeric 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 above .

The present invention also relates to the use of a compound of formula (I), a tautomeric or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a compound for treating or preventing the aforementioned A medicament for any of the disease conditions.

The compounds of the invention may be administered to a mammal, preferably a human, in order to treat or prevent any of the diseases mentioned above.

In view of the utility of a compound of formula (I), its tautomeric or stereoisomeric forms, and its pharmaceutically acceptable salts and solvates, a treatment for any of the diseases mentioned above is provided. Method for warm-blooded animals (including humans).

The method includes administering a therapeutically effective amount of a compound of formula (I), a tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof (i.e., systemically or locally), It is preferably administered orally to warm-blooded animals (including humans).

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

Those skilled in the art will recognize that a therapeutically effective amount of a compound of the present invention is an amount sufficient to be therapeutically active, and that this amount is particularly different depending on the type of disease, the concentration of the compound in the therapeutic formulation, and the condition of the patient. Generally, the amount of a compound of the present invention administered as a therapeutic agent for the treatment of the conditions mentioned herein will be determined by the attending physician depending on the circumstances.

In the treatment of such diseases, those skilled in the art can determine the effective daily dose from the test results provided below. The effective daily dose should be from about 0.005 mg / kg to 100 mg / kg body weight, especially 0.005 mg / kg to 50 mg / kg body weight, especially 0.01 mg / kg to 50 mg / kg body weight, and more particularly from 0.01 mg / kg To 25 mg / kg body weight, preferably from about 0.01 mg / kg to about 15 mg / kg, more preferably from about 0.01 mg / kg to about 10 mg / kg, and even more preferably from about 0.01 mg / kg kg to about 1 mg / kg, and most preferably from about 0.05 mg / kg to about 1 mg / kg of body weight. A particularly effective daily dose should 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 the compound (also referred to herein as the active ingredient) required to achieve a therapeutic effect may, depending on the circumstances, depend, for example, on the particular compound, the route of administration, the age and condition of the recipient, and the particular condition or disease being treated. different. Treatment also includes administering the active ingredient on a regimen of between one and four intakes per day. In such methods of treatment, the compounds according to the invention are preferably formulated prior to administration. As described herein below, suitable pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients.

The invention also provides compositions for preventing or treating the conditions mentioned herein. The composition comprises a therapeutically effective amount of a compound having 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 may be administered alone, it is preferably present as a pharmaceutical composition. Accordingly, the invention further provides a pharmaceutical composition comprising a compound according to the invention together with a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be "acceptable" in a sense compatible with the other ingredients of the composition and harmless to its recipient.

The pharmaceutical composition of the present invention can be prepared by any method well known in the pharmaceutical field, for example, using methods such as those described in Gennaro et al. Remington's Pharmaceutical Sciences (18th edition, Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical preparations and their Manufacture [Part 8: Pharmaceutical Preparations and Their Manufacture]). A therapeutically effective amount of a specific compound as an active ingredient in a base form or a salt form is combined with a pharmaceutically acceptable carrier into an intimate mixture, and the carrier may take a variety of forms depending on the form of the preparation desired for administration. These pharmaceutical compositions are desirably in a unitary dosage form, and are preferably suitable for systemic administration, such as oral, transdermal, or parenteral administration; or topical administration, such as via inhalation, nasal spray, eye drops, or via milk Cream, gel, shampoo, etc. For example, when preparing a composition in an oral dosage form, any common pharmaceutical medium can be used, such as in the case of oral liquid preparations (such as suspensions, syrups, elixirs, and solutions), such as water, glycols, and oils. , Alcohol, etc .; or in the case of powders, pills, capsules, and tablets, it is a solid carrier, such as starch, sugar, kaolin, lubricants, binders, disintegrants, and the like. Tablets and capsules represent the most advantageous oral unit dosage forms due to their ease of administration, in which case solid pharmaceutical carriers are clearly used. For parenteral compositions, the carrier will typically include at least most of the sterile water, but may also include other ingredients such as to aid solubility. For example, injection solutions can be prepared in which the carrier comprises a saline solution, a glucose solution or a mixture of saline and glucose solutions. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. In compositions suitable for transdermal administration, the carrier optionally includes a penetration enhancer and / or a suitable humectant, and optionally a small proportion of suitable additives of any nature, which additives do not cause any damage to the skin Significantly harmful effects. The additives may facilitate administration to the skin and / or may assist in preparing the desired composition. These compositions can be administered in different ways, for example as a transdermal patch, as a drop or as an ointment.

It is particularly advantageous to formulate the aforementioned pharmaceutical composition into a unit dosage form to achieve ease of administration and uniformity of dosage. A unit dosage form as used in this specification and the scope of a patent application refers herein to a physically discrete unit suitable as a unit dose, each unit containing a predetermined amount calculated to combine with the required pharmaceutical carrier to produce the desired therapeutic effect Active ingredient. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packs, waxy rice capsules (wafer), injectable solutions or suspensions, teaspoonfuls, spoons (tablespoonfuls) and similar dosage forms, and their separate multiples.

The compounds of the present invention can be used for systemic administration, such as oral, transdermal or parenteral administration; or topical administration, such as via inhalation, nasal spray, eye drops or via creams, gels, shampoos, and the like. The compound is preferably administered orally. The exact dose 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, degree of illness, and generality of the particular patient. Physical conditions and other medications that individuals can take, as is well known to those skilled in the art. In addition, it will be apparent that the effective daily dose may be reduced or increased, depending on the response of the subject being treated and / or on the evaluation of the physician who prescribes the compound of the invention.

The compounds of the invention may be administered alone or in combination with one or more additional therapeutic agents. Combination therapies include administering a single pharmaceutical dosage formulation containing a compound according to the present invention and one or more additional therapeutic agents, as well as administering a compound according to the present invention and each additional therapeutic agent (in the form of its own separate pharmaceutical dosage formulation) . For example, a compound and a therapeutic agent according to the present invention may be administered to a patient together in the form of a single oral dosage composition, such as a tablet or capsule, or each agent may be administered in the form of a separate oral dosage formulation.

Accordingly, one embodiment of the present invention relates to a product comprising a compound according to the present invention as a first active ingredient and one or more anticancer agents as another active ingredient for simultaneous, separate or continuous use in therapy in the form of a combined preparation Patients with cancer.

One or more other pharmaceutical agents and the compound according to the invention may be administered simultaneously (for example in the form of a separate or monolithic composition) or sequentially in either order. In the latter case, two or more compounds will be administered over a period of time and in an amount and manner sufficient to ensure that an advantageous or synergistic effect is achieved. It should be understood that the preferred method and sequence of administration of each component of the combination, as well as the corresponding doses and schedules, will depend on the particular other pharmaceutical agent and compound of the invention administered, its route of administration, specific conditions, and in particular The tumor being treated and the specific host being treated. Optimal methods and sequences of administration and dosages and schedules can be easily determined by those skilled in the art using conventional methods and in light of the information presented herein.

When given in combination, the weight ratio of the compound according to the invention to one or more other anticancer agents can be determined by those skilled in the art. As is well known to those skilled in the art, the ratio, as well as the precise dosage and frequency of administration, will depend on the particular compound according to the invention used and one or more other anticancer agents, the particular condition being treated, the condition being treated, Severity, specific patient's age, weight, sex, diet, time of administration and general physical condition, mode of administration along with other drugs that the individual can take. In addition, it is clear that the effective daily dose can be reduced or increased, depending on the response of the subject being treated and / or on the evaluation of the physician giving the prescription of the compound of the invention. The specific weight ratio of the compound having the formula (I) of the present invention to another anticancer agent may be from 1/10 to 10/1, more particularly from 1/5 to 5/1, and even more particularly from 1/3 to Within 3/1.

The following examples further illustrate the invention.

    [Example]    

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

In the following, the term: 'ACN or' MeCN 'means acetonitrile;' DCM 'means dichloromethane;' DIPEA 'means N, N-diisopropylethylamine;' DIPE or 'DiPE' means diisopropyl ether; 'h 'Means one or more hours;' min 'means one minute or more;' DMF 'means dimethylformamide;' DSC 'means differential scanning calorimetry;' TEA or 'Et ₃ N' means Triethylamine; 'Et ₂ O' means diethyl ether; 'EtOAc' or 'EA' means ethyl acetate; 'EtOH' means ethanol; 'HPLC' means high performance liquid chromatography; 'iPrOH' means isopropanol; 'LC / MS' means liquid chromatography / mass spectrometry; 'MeOH' means methanol; 'NMR' means nuclear magnetic resonance; 'rt or' RT 'means room temperature;' SFC 'means supercritical fluid chromatography;' OR ' Means optical rotation; 'sat.aq.' means saturated aqueous solution; 'AcCl' means acetyl chloride; 'AcOH' or 'HOAc' means acetic acid; 'BOC' or 'Boc' means tertiary-butoxycarbonyl group; 'Celite ^® 'for diatomaceous earth;' CH ₃ COONH ₄ 'for ammonium acetate;' COMU® 'for (1-cyano-2-ethoxy-2- pendant ethyleneethyleneaminooxy) dimethyl Amine- Porphyrin-carbohexafluorophosphate; 'CO ₂ ' for carbon dioxide; 'DCE' for dichloroethane; 'DMAP' for dimethylaminopyridine; 'DMSO' for dimethylsulfinium; 'DBU' for 1,8-diazabicyclo [5.4.0] undecene-7; 'EDCI.HCl' means 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ; 'Ee' means mirror image excess; 'eq.' Or 'equiv.' Means equivalent weight; 'EtMgBr' means ethyl magnesium bromide; 'Et ₂ O' means diethyl ether; 'EtOAc' means ethyl acetate; 'Et ₃ N 'or' TEA 'means triethylamine;' EtOH 'means ethanol;' h 'means one or more hours;' HATU 'means O- (7-azabenzotriazol-1-yl) -N , N, N, N-tetramethylurea hexafluorophosphate; 'HCl' means hydrochloric acid; 'HOBT' means N-hydroxybenzotriazole monohydrate; 'H ₂ O' means water; 'iPrMgCl' means iso Propyl magnesium chloride; 'iPrNH ₂ ' means isopropylamine; 'K ₂ CO ₃ ' means potassium carbonate; 'Me-THF' means 2-methyl-tetrahydrofuran; 'MeMgBr' or 'CH ₃ MgBr' means methyl bromide Magnesium; 'MeOH' for methanol; 'MgSO ₄ ' for magnesium sulfate; 'min' for one or more minutes; 'NaBH (OAc) ₃ ' for sodium triethoxylate borohydride; 'NaBH ₃ C N 'stands for sodium cyanoborohydride;' Na ₂ CO ₃ 'stands for sodium carbonate;' NaH 'stands for sodium hydride;' NaHCO ₃ 'stands for sodium bicarbonate;' NaOH 'stands for sodium hydroxide;' Na ₂ SO ₄ 'stands for Sodium sulfate; 'NH ₄ Cl' means ammonium chloride; 'NH ₄ HCO ₃ ' means ammonium bicarbonate; 'NH ₄ OH' means 30% aqueous solution of ammonia solution; 'Quant. Or quant' means quantitative; 'R _t 'retention time;' SFC 'for supercritical fluid chromatography;' T 'table temperature;' TBAF 'for tetrabutylammonium fluoride;' TBDMS 'or' SMDBT 'for tertiary butyldimethylsilicon Group; 'TFA' or 'CF ₃ COOH' represents trifluoroacetic acid; 'THF' represents tetrahydrofuran; 'Ti (OEt) ₄ ' represents titanium ethoxide; 'Ti (OiPr) ₄ ' represents titanium isopropoxide; 'v. 'Means volume;' F ₃ C 'or' CF ₃ 'means trifluoromethyl;' HBTU 'means 1- [bis (dimethylamino) methylene] -1H-benzotriazolium hexafluorophosphate Salt (1-) 3-oxide.

As understood by those skilled in the art, compounds synthesized using the scheme shown may exist as solvates (eg, hydrates and / or contain residual solvents or trace impurities). Compounds isolated in salt form can be integer stoichiometric, ie mono- or di-salt, or intermediate stoichiometry.

When one or more mixtures are separated, the stereochemical configuration at the center of some compounds is designated as " R " or " S "; for some compounds, when the absolute stereochemistry is not determined (even if the bonds are Stereoselectively plotted), although the compound itself has been separated into a single stereoisomer and is pure as the isomer, the stereochemical configuration at the center shown is designated as "* R " (first In the case of column conditions described in the synthesis scheme and eluted from the column when only one stereo center is present) or "* S " (second time in the case of column conditions described in the synthesis scheme and when only one stereo Centered out from the column).

For example, it will be clear that compound 179 system

Compounds with two stereo centers follow a similar rule as above, and the stereochemical configuration of only one of the stereo centers is represented by * (for example, * R or * S) (see, for example, compound 186 or 281). This indicates that the absolute stereo configuration of the stereo center represented by * is not determined (even though the bonds are stereo-selectively drawn), although the compound is mirror-isomeric pure at the specified center.

For compounds (such as 188, 189, 190, 191, 235, 236, 237, and 238), the stereochemical configuration of the two stereocenters is represented by * (for example, * R or * S). The absolute stereochemistry is undetermined (even though the bonds are drawn stereoselectively), although the compounds themselves have been separated into single stereoisomers and are pure isomers. 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 compound 188

This shows that the compound is or or

The above paragraphs on stereochemical configuration 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 another enantiomer. It is preferred that the product contains at least 90% by weight of one enantiomer and 10% by weight or less of another enantiomer. In the most preferred embodiment, the term "mirromeric isomer" means that the composition contains at least 99% by weight of one mirror isomer and 1% or less of another mirror isomer.

When the intermediate or compound in the following experimental section is represented as 'HCl salt', 'HCOOH salt' or 'TFA salt', no equivalent number of HCl or TFA is indicated, which indicates that no equivalent number of HCl or TFA is determined.

The skilled person will be aware that, even if not explicitly mentioned in the following experimental protocol, typically after column chromatography purification, the desired fractions are collected and the solvent is evaporated.

Where stereochemistry is not indicated in the spiro ring represented by L1, this indicates that it is a mixture of stereoisomers, unless otherwise stated or clear from the context.

When the stereocenter is represented by 'RS', this indicates that a racemic mixture is obtained at the designated center, unless stated otherwise.

A. Preparation of intermediates

Preparation of intermediate 1:

4-Chloro-6- (2,2,2-trifluoroethyl) thieno [] will be prepared as described in Journal of Medicinal Chemistry [2016], 59 (3), 892-913 2,3-d] pyrimidine (525 mg, 2.08 mmol), tertiary butyl 2,7-diazaspiro [4.5] decane-2-formate (550 mg, 2.29 mmol), and DIPEA (1.43 mL, 8.3 A mixture of mmol) in ACN (12 mL) was heated at 80 ° C. overnight. The solution was cooled and the mixture was poured into cold water and the product was extracted with EtOAc, the organic layer was dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: irregular 15 μm to 40 μm 50 g, mobile phase: DCM / MeOH: gradient from 100/0 to 99/1). The product-containing fractions were collected and evaporated to dryness, yielding 770 mg (81% yield) of Intermediate 1.

By using a method similar to that described for the preparation of Intermediate 1, starting with the respective starting materials, the compounds in the table below were prepared.

Preparation of Intermediate 3:

4-Chloro-6- (2,2,2-trifluoroethyl) thieno [2,3-d] pyrimidine (11.4 g; 44.96 mmol), tertiary butyl 2,6 diazaspiro [3.4 ] A solution of octane-2-formate (10.5 g; 49.46 mmol) and DIPEA (15.5 mL; 89.93 mmol) in iPrOH (183 mL) was heated at 90 ° C overnight. The solution was cooled to room temperature, and the solution was poured into water and then extracted with EtOAc (3 ×). Dried the organic layer was washed with brine MgSO _4, and filtered off.

The precipitate (in the aqueous layer) was filtered off, washed with a small amount of DCM, and combined with the previous filtrate. The solvent was evaporated to give 19.9 g of a brown solid. The residue was taken up with ether and the precipitate was filtered and dried to give 18.5 g of intermediate 3 (96%) as a light brown solid.

Alternative preparation of intermediate 3: To 4-chloro-6- (2,2,2-trifluoroethyl) thieno [2,3-d] pyrimidine (3.00 g, 11.9 mmol) and tertiary butyl 2, To a mixture of 6-diazaspiro [3.4] octane-2-formate (2.5 g, 11.8 mmol) in EtOH (50 mL) was added DIPEA (2 g, 15.5 mmol) in one portion. The mixture was stirred at room temperature for 18 h. The mixture was evaporated and the residue was diluted in EA (200 mL). This solution was washed with water (100 mL * 2), dried over Na ₂ SO ₄ , filtered, and evaporated to give Intermediate 3 (5.10 g, 11.9 mmol, 100% yield) as a brown oil.

Preparation of intermediate 6:

Intermediate 1 (770 mg, 1.69 mmol) and 4N HCl in ACN (45 mL) A mixture of the solutions in (4.22 mL, 16.9 mmol) was stirred at room temperature overnight. The mixture was poured into ice water, basified with 3N NaOH, the product was extracted with DCM, and the organic layer was dried over MgSO ₄ and evaporated To dryness, 670 mg of intermediate 6 was provided, which was used in the next step without further purification.

By using a method similar to that described for the preparation of Intermediate 6, starting with the respective starting materials, the compounds in the table below were prepared.

Preparation of intermediate 9:

In a sealed tube, 4-chloro-6- (2,2, prepared at 90 ° C, as described in Journal of Medicinal Chemistry [2016], 59 (3), 892-913, 2-trifluoroethyl) thieno [2,3-d] pyrimidine (0.6 g, 2.37 mmol), tert-butyl 2,6-diazaspiro [3.3] heptane-2-formate (0.57 g, 2.85 mmol), DIPEA (0.82 mL, 4.75 mmol) was heated in iPrOH (15 mL) for 2 h. The solution was cooled to room temperature, and the reaction mixture was poured into water and then extracted with EtOAc. The organic layer was washed with water, dried over MgSO _4, filtered and evaporated to dryness. This crude product was crystallized from Et ₂ O to provide 0.6 g (61% yield) of Intermediate 9.

Preparation of Intermediate 10:

A mixture of intermediate 9 (4.43 g; 10.69 mmol) in formic acid (24 mL) was stirred at room temperature overnight. The reaction mixture was evaporated. The residue was taken up twice with Et ₂ O and evaporated to dryness. The residue was purified by silica gel chromatography (irregular SiOH; 80 g; mobile phase: 90% DCM, 10% MeOH, 1% NH ₄ OH). The pure fractions were collected and evaporated to dryness to yield 3.34 g (99%) of Intermediate 10.

Preparation of intermediate 10b:

A mixture of intermediate 9 (0.55 g, 1.33 mmol) in formic acid (3 mL) was stirred at room temperature for 20 h. The mixture was evaporated in vacuo to give a residue, which was taken up twice with Et ₂ O and evaporated to dryness to give 0.4 g (yield 96%) of intermediate 10b (formate). This crude product was used without any further purification in the next step.

The compounds in the table below were prepared by using similar methods as described for the preparation of intermediate 10b, starting with the respective starting materials.

Preparation of intermediate 11:

A mixture of intermediate 3 (8.57 g; 20 mmol) in formic acid (51 mL) was stirred at room temperature for 20 h. The reaction mixture was stirred at room temperature over the weekend. The mixture was evaporated, and the residue was cooled to 5 ° C, taken up with DCM, and neutralized with an aqueous solution of NaOH 3N. The organic layer was washed with water, dried over MgSO _4, filtered and the solvent was evaporated. The residue (7.63 g of orange oil) was purified by silica gel chromatography (120 g of irregular naked silica, mobile phase: 1% NH ₄ OH, 85% DCM, 15% MeOH). The pure fractions were collected and the solvent was evaporated to give 3.65 g of intermediate 11 (56%) as a yellow oil.

Alternative preparation of intermediate 11: TFA (17.9 mL; 233.38 mmol) was added to a solution of intermediate 3 (5 g; 11.67 mmol) in DCM (130 mL) at 5 ° C, and the reaction mixture was at room temperature Stir for 4h. The reaction mixture was diluted with heptane and evaporated to dryness (3X) to give 10.7 g of a brown oil. The residue was purified by silica gel chromatography (irregular SiOH 40 μm; 220 g, mobile phase: 1% NH ₄ OH, 90% DCM, 10% MeOH). The pure fractions were collected and the solvent was evaporated. The residue (4 g) was dissolved in DCM and the product was crystallized. The mixture was evaporated and taken up several times with ACN, and the solvent was evaporated to give 4 g of intermediate 11 as a pale yellow solid.

Preparation of intermediate 11b:

TFA (2.2 mL; 28 mmol) was added to a solution of intermediate 3 (600 mg; 1.4 mmol) in DCM (13 mL) at 0 ° C, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated until dryness to give 1.26 g of intermediate 11b as a TFA salt. This product was used without purification.

Preparation of intermediate 11c:

HCl 4M at room temperature (150 mL) was added to intermediate 3 (6.5 g; 15.17 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was evaporated in vacuo to give 5.7 g of intermediate 11c as a yellow solid as the HCl salt. This product was used in the next step without purification.

Preparation of intermediate 13:

Acetic anhydride (1 mL, 10.7 mmol) was added dropwise to 2-amino-5- (2,2,2-trifluoroethyl) thiophene-3-carboxamide (2 g, 8.92 mmol) at room temperature. In a solution of toluene (50 mL) and trimethylamine (6.2 mL, 44.6 mmol). The solution was heated at reflux for 5 h, poured into water, extracted with EtOAc, and washed with brine (x2). The organic layer was dried over MgSO ₄ , filtered, and evaporated to dryness, the crude product was taken up with Et ₂ O, and the precipitate was filtered to provide 1.5 g of intermediate 13 (yield 63% / brown solid).

Preparation of intermediate 14:

To a solution of intermediate 13 (1.5 g, 5.63 mmol) in EtOH (70 mL) was added dropwise a 1M solution of KOH at room temperature. The reaction mixture was stirred at room temperature for 30 min, and then the mixture was heated under reflux for 3 h. The reaction mixture was cooled to room temperature, then poured into ice water, acidified with 3N HCl, extracted with DCM and decanted. The combined organic layers were washed with brine, and dried over MgSO _4, filtered and evaporated to dryness. The residue was crystallized from Et ₂ O to give 0.7 g of intermediate 14 (yield 50%), which was used in the next step without further purification.

Preparation of Intermediate 15:

Intermediate 14 (0.7 g, 2.82 mmol) and trichlorophosphorane (5 mL) were heated at 110 ° C for 2 h. The reaction mixture was cooled to room temperature and then evaporated to dryness. The residue was carefully absorbed with ice and DCM, basified with an aqueous solution of K ₂ CO ₃ (10%), and the organic layer was washed with water, dried over MgSO ₄ , filtered and evaporated to dryness to give 0.75 g ( Yield 99%) of Intermediate 15 which was used in the next step without further purification.

Preparation of intermediate 16:

Spiro [3.3] heptan-2-ylmethyl mesylate

To a solution of spiro [3.3] heptan-2-ylmethanol (153 mg, 1.08 mmol) in 4 mL of DCM was added TEA (0.464 mL, 3.2 mmol), and the reaction mixture was cooled to 0 ° C. Methanesulfonyl chloride (0.184 g, 1.605 mmol) was then added dropwise, and the mixture was allowed to warm to room temperature and stirred for 2 h. Saturated NaHCO ₃ (30mL) and DCM (30mL) aqueous solution. The mixture was separated, the organic layer was collected, washed with brine (10 mL), dried over Na ₂ SO ₄ and evaporated to give 300 mg of intermediate 16 as a yellow oil, which was used in the next step without further purification. .

Preparation of intermediate 17:

Under a stream of N ₂ , to a solution of intermediate 11c (400 mg) and TEA (0.38 mL, 2.76 mmol) in DCM (20 mL) was added 1- [2- (acetamyloxy) ethyl] -1H-pyrrole-2 -Formaldehyde (200 mg, 1.11 mmol). The mixture was stirred at room temperature for 4 h. NaBH (OAc) ₃ (390 mg, 1.84 mmol) was added and the mixture was stirred at room temperature for 48 h. Then, it was poured into ice water, and the mixture was separated, and the aqueous layer was extracted with DCM. The organic layers were combined, etc., washed with brine, then dried over MgSO _4, and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: irregular SiOH 15 μm to 40 μm 24 g, mobile phase: DCM / MeOH: 97/3). The pure fractions were collected and the solvent was evaporated under vacuum to yield 180 mg of intermediate 17.

Intermediate 35 Preparation

1H-pyrazole-4-carbaldehyde (0.5 g; 5.2 mmol) and cesium carbonate (3.39 g; 10.4 mmol) were diluted in ACN (10 mL). Then, 2-bromoethyl methyl ether (0.636 mL; 6.77 mmol) was added, and the reaction mixture was refluxed for 2 hours. The reaction mixture was partitioned between saturated NaHCO ₃ solution and EtOAc. The organic layer was separated, dried over MgSO _4, filtered and concentrated.

The residue was purified by silica gel chromatography (Irregular _{SiO 2, 120g, DCM / MeOH} : 100/0 to 95/5) for purification. This fraction containing the product was mixed and concentrated to provide 439 mg (55%) of intermediate 35.

Preparation of intermediate 20:

At room temperature, intermediate 11 (150 mg, 0.46 mmol), (+/-)-methyl α-bromophenylacetate (0.08 mL, 0.50 mmol) and K ₂ CO ₃ (127 mg; 0.92 mmol) Stir in DMF (10 mL) for 5 h. The reaction mixture was poured into ice water and EtOAc was added. 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 SiOH 15 μm to 40 μm 24 g, mobile phase: DCM / MeOH (+ 10% NH ₄ OH): gradient from 97/3 to 95/5). The pure fractions were collected and evaporated to dryness, yielding 162 mg (74% yield) of Intermediate 20.

Intermediate 32 Preparation

To a solution of intermediate 20 (162 mg; 0.34 mmol) in THF (3 mL) and water (3 mL) was added lithium hydroxide monohydrate (71 mg; 1.7 mmol) at room temperature. The mixture was stirred at room temperature overnight, then concentrated and acidified with an aqueous solution of HCl 3N (pH = 2-4). The precipitate was filtered and dried to give 33 mg (21%) of Intermediate 32 (90% purity based on LC / MS). The mother layer was evaporated until dryness to give 243 mg of an impure fraction of intermediate 32.

Intermediate 54 Preparation

Intermediate 11c (333 mg), methyl 2-formamylbenzoate (148.5 mg; 0.905 mmol), NaBH (OAc) ₃ (872 mg; 4.11 mmol) and trimethylamine (250 mg; 2.47 mmol) were added in dichloro Ethane (16 mL) was mixed and the reaction was stirred at room temperature overnight. Then, NaHCO ₃ aqueous solution (1 mL), and the mixture was extracted with DCM (4 * 15mL). Etc. The organic layer was separated, combined, dried over MgSO _4, filtered and concentrated to provide 450mg of Intermediate 54 as a white solid.

The intermediates in the table below were prepared by using similar methods to those described for the preparation of intermediate 54 starting with the respective starting materials.

Intermediate 47 Preparation

Intermediate 10b (150 mg), 1- (tetrahydro-2H-piperan-2-yl) -1H-pyrazole-4-carbaldehyde (225 mg; 1.249 mmol), and AcOH (24 μL; 0.416 mmol) ) The mixture in dichloroethane (4.5 mL) was stirred for 2 hours. The reaction mixture was cooled to room temperature, and NaBH (OAc) ₃ (265 mg; 1.249 mmol) was added. The reaction mixture was stirred at room temperature overnight, poured into 10% K ₂ CO ₃ aqueous solution, and extracted with DCM. The organic layer was decanted, dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (irregular SiOH, 24 g; mobile phase: gradient from 0% MeOH, 100% DCM to 10% MeOH, 90% DCM). The pure fractions were collected and evaporated to dryness to give 150 mg of intermediate 47.

The intermediates in the table below were prepared by using similar methods to those described for the preparation of intermediate 47, starting with the respective starting materials.

Preparation of Intermediate 25:

(4S) -1-Boc-4-methyl-L-proline (174 mg, 0.761 mmol), HBTU (288 mg, 0.761 mmol) and DIPEA (0.65 mL, 3.804 mmol) in DMF (7.5 mL) The mixture was stirred for 1 h. Then, a solution of intermediate 10 (250 mg, 0.761 mmol) in DMF (5 mL) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water and basified with ₂ CO ₃ 10% aqueous solution of K, and extracted with EtOAc. The organic layer was washed with water, then brine, dried over MgSO _4, filtered and evaporated to dryness. The residue (490 mg of) by silica gel chromatography (Irregular SiOH, 40g; mobile _{phase: NH 4 OH / DCM / MeOH} : 0.5 / 95/5) was purified. The pure fractions were collected and evaporated to dryness, yielding 330 mg (82% yield) of Intermediate 25.

The intermediates in the table below were prepared by using similar methods to those described for the preparation of intermediate 25, starting with the respective starting materials.

Intermediate 104 Preparation

DIPEA (0.48 mL; 2.775 mmol) was added to a solution of intermediate 10b (200 mg), 3-carboxybenzaldehyde (100 mg; 0.666 mmol) and HATU (317 mg; 0.833 mmol) in DMF (10 mL) and the reaction The mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was decanted, washed with water then brine, dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (irregular SiOH, 24 g; mobile phase: gradient from 0% MeOH, 100% DCM to 10% MeOH, 90% DCM). The pure fractions were collected and evaporated to dryness to yield 62 mg of intermediate 104.

Preparation of intermediate 41:

₂ a stream of N, at room temperature, and Intermediate 11 (250mg, 0.76mmol) was added to the DCM (12mL) solution of Intermediate 42 (246mg, 0.91mmol). The mixture was stirred at room temperature for 3 h. The mixture was cooled to 5 ° C, NaBH (OAc) ₃ (323 mg, 1.52 mmol) was added, and the mixture was stirred at room temperature overnight. Then, it was poured into ice water, and the layers were separated. The aqueous layer was extracted with DCM. The organic layers were combined, etc., washed with brine, then dried over MgSO _4, and evaporated. The residue was crystallized from Et ₂ O and pentane. The white precipitate was filtered off and dried under vacuum to yield 55 mg (yield 100%) of intermediate 41.

Preparation of intermediate 43:

At room temperature, Intermediate 11 (500 mg, 1.52 mmol), 2- (chloromethyl) -1,1-dimethylethyl-1H-pyrrole-1-carboxylic acid) (493 mg, 2.28 mmol) and K ₂ CO ₃ (1.05g, _7.61mmol) was stirred 24h in ACN (12mL). The reaction mixture was poured into ice water and EtOAc was added. 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 SiOH 15 μm to 40 μm 24 g, mobile phase: NH ₄ OH / DCM / MeOH: gradient from 0.1 / 97/3 to 0.1 / 95/5). The pure fractions were mixed and evaporated to yield 100 mg (yield 14%) of intermediate 43.

The intermediates in the table below were prepared by using similar methods to those described for the preparation of intermediate 43 starting with the respective starting materials.

Preparation of intermediate 50:

To a solution of intermediate 11 (202 mg, 0.62 mmol) in DCM (10 mL) under a stream of N ₂ was added tert-butyl 4-methylfluorenyl-1H-pyrazole-1-formate (133 mg, 0.68 mmol ) And AcOH (35 μL, 0.62 mmol). The mixture was stirred at room temperature for 2 h. NaBH (OAc) ₃ (521 mg, 2.46 mmol) was added, and the mixture was stirred at room temperature overnight, poured into ice water, and the layers were separated. The aqueous layer was extracted with DCM. The organic layers were combined, etc., washed with brine, then dried over MgSO _4, and evaporated. The residue was purified by silica gel chromatography (stationary phase: irregular SiOH 15 μm to 40 μm 24 g, mobile phase: DCM / MeOH (+ 10% NH ₄ OH): 97/3). The pure fractions were mixed and evaporated to yield 145 mg (46% yield) of Intermediate 50.

Preparation of intermediate 55:

In a sealed tube, under a stream of N ₂ , intermediate 53 (349 mg, 1.37 mmol) and Ti (OiPr) ₄ (436 μL, 1.83 mmol) were added to a solution of intermediate 11 (300 mg, 0.914 mmol) in THF (6 mL) in. The solution was stirred at 50 ° C for 5 hours and then at room temperature overnight. The reaction mixture was cooled to 5 ° C, and 2N iPrMgCl in THF (2.28 mL, 4.57 mmol) was added dropwise. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc, and poured into 10% K ₂ CO ₃ aqueous solution. The insoluble material removed by filtration through celite ^®. The organic layer was decanted, washed with brine, dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (irregular SiOH, 40 g; mobile phase: MeOH / DCM: gradient from 0/100 to 10/90). Pure fractions were collected and evaporated to dryness yield: 0.3 g (54% yield) of Intermediate 55.

Intermediate 63 Preparation of intermediate 63a

And intermediate 63b

At 45 ° C, tertiary butyl 3-ethenylazetidin-1-carboxylic acid ester (364 mg; 1.83 mmol), intermediate 11 (400 mg; 1.22 mmol), and titanium (IV) isopropoxide A solution of (725 μL; 2.44 mmol) in ethanol (2 mL) was stirred for 30 min (the solution turned dark yellow). Ethanol (12 mL) and NaBH ₄ (138 mg; 3.66 mmol) were added, and the solution became pale yellow. The reaction mixture was stirred at room temperature overnight. Then, it was poured into 10% K ₂ CO ₃ DCM and aqueous solution. Filter insoluble material through Celite ^® pad. The organic layer was decanted, filtered through chromabond ^®, and the solvent was evaporated, the pale yellow oil by silica gel 624mg chromatography (SiO _2; 25g; mobile phase: gradient from 98% DCM, 2% MeOH to 96% DCM, 4% MeOH). This fraction containing the product was collected and the solvent was evaporated to give 223 mg (36%) of intermediate 63 as a white foam. Intermediate 63 was purified by chiral SFC (stationary phase: CHIRALCEL OJ-H 5 μm 250 x 20 mm, mobile phase: 92% CO2, 8% MeOH (0.3% iPrNH ₂ )). Pure fractions were collected and the solvent was evaporated to give 83 mg (13%) of intermediate 63a as a colorless oil and 90 mg (14%) of intermediate 63b.

The intermediates in the table below were prepared by using similar methods to those described for the preparation of intermediate 63, starting with the respective starting materials.

Intermediate 68

Intermediate 68a Preparation

Intermediate 68b And compound 61:

A solution of intermediate 113 (1.67 g; 6.54 mmol) in THF (15 mL) was added to a solution of intermediate 11 (1.4 g; 4.36 mmol) and TFA (2 mL; 26.16 mmol) in THF (30 mL). The reaction mixture was stirred at room temperature overnight. NaBH (OAc) ₃ (2.77 g; 13.08 mmol) was then added in portions. The reaction mixture was stirred at room temperature for 10 days. The solution was poured into 10% K ₂ CO ₃ aqueous solution, and adding EtOAc. The mixture was extracted with EtOAc (3x). The organic layers were combined and the like, washed with brine, dried over MgSO _4, filtered, and the solvent was evaporated. The residue (2.9 g; yellow oil) was subjected to silica gel chromatography (SiO ₂ ; 40 g; eluent: from 97% DCM, 3% MeOH, 0.3% NH ₄ OH to 90% DCM, 10% MeOH, 1 % NH ₄ OH). The desired fractions were collected and the solvent was evaporated to give 266 mg of intermediate 68 as a colorless oil and 215 mg of fraction 1 as a colorless oil.

Intermediate 68 was purified by chiral SFC (Lux-cellulose-2 5 μm 250 * 30 mm, mobile phase: 50% CO ₂ , 50% MeOH (0.3% iPrNH ₂ )). Pure fractions were collected and the solvent was evaporated to give 114 mg (5%) of intermediate 68a as a colorless oil and 109 mg (4%) of intermediate 68b as a colorless oil.

Fraction 1 was reversed (YMC-actus Triart C18 10μm 30 * 150mm, mobile phase: gradient from 65% NH ₄ HCO ₃ 0.2%, 35% ACN to 25% NH ₄ HCO ₃ 0.2%, 75% ACN) Perform purification. This fraction containing the product was collected and the solvent was evaporated. The residue (160 mg; colorless oil) was freeze-dried with water-ACN to give 90 mg (6%) of compound 61 as a white solid.

Intermediate 69 Preparation of intermediate 69a

And intermediate 69b

At 90 ° C, 4-chloro-6- (2,2,2-trifluoroethyl) thieno [2,3-d] pyrimidine (5.07 g; 20.08 mmol), 2-BOC-2,7- A solution of diaza-spiro [4.4] nonane (5 g; 22.09 mmol) and DIPEA (6.9 mL; 40.17 mmol) in iPrOH (80 mL) was heated overnight. The solution was cooled to room temperature, and the solution was poured into water and then extracted with EtOAc (3X). The organic layer was washed with brine and dried over MgSO _4, and the solvent was evaporated to dryness. The residue (9 g, light brown solid) was taken up with diethyl ether, the precipitate was filtered and dried to give 8.4 g of intermediate 69 (95%, off-white solid). Intermediate 69 was purified by chiral SFC (Chiralpak IG 5 μm 250 * 20 mm, mobile phase: 65% CO ₂ , 35% iPrOH (0.3% iPrNH ₂ )). The pure fractions were collected and the solvent was evaporated to give 4.07 g of intermediate 69a (46%, yellow foam) and 4.29 g of intermediate 69b (48%, yellow foam).

Preparation of intermediate 70a:

Intermediate 70a is prepared by using a similar method to that described for the alternative preparation of intermediate 11 starting with the respective starting material intermediate 69a.

The intermediates in the table below were prepared by using similar methods to those described for the alternative preparation of intermediate 11 starting with the respective starting materials.

Intermediate 71 Preparation, intermediate 71a

And intermediate 71b

Method A : A mixture of intermediate 11b (4.2 g) and intermediate 72 (1.6 g; 7 mmol) in THF (50 mL) was stirred at room temperature overnight. Then, NaBH (OAc) ₃ (3 g; 14 mmol) was added in portions. The reaction mixture was stirred at room temperature for 24 hours. The solution was poured into cold water, basified with an aqueous solution of NaOH 3N, and EtOAc was added. The organic layer was separated, dried over MgSO _4, filtered and evaporated to dryness. The residue was subjected to silica gel chromatography (irregular SiOH 80g, mobile phase: gradient from 98% DCM, 2% MeOH (+ 10% NH ₄ OH) to 95% DCM, 5% MeOH (+ 10% NH ₄ OH )) For purification. The pure fractions were collected and evaporated to dryness to give 852 mg of intermediate 71.

These mirror image isomers were separated by chiral SFC (CHIRALCEL OD-H 5 μm 250 * 30 mm; mobile phase: 70% CO ₂ , 30% EtOH). The pure fractions were collected and evaporated to dryness, yielding 294 mg of intermediate 71a and 303 mg of intermediate 71b.

Method B: The experiment was performed 6 times with the same amount (640 mg; 1.95 mmol). Ti (OEt) ₄ (0.8 mL; 3.9 mmol) was added to intermediate 11 (640 mg; 1.95 mmol) and intermediate 72 (665 mg; 2.92 mmol) in DCE (20 mL) and MeOH (8 mL) at room temperature. In solution. The reaction mixture was stirred at room temperature for 24 h, cooled at 10 ° C, and then NaBH ₃ CN (367 mg; 5.84 mmol) was added in portions. The reaction mixture was stirred at room temperature for 8 days. The solution was collected for work-up: poured into cold water, basified with K ₂ CO ₃ powder, and extracted with DCM. The suspension was filtered through a Celite® pad. The filtrate was decanted, dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (Irregular SiOH, 40g; mobile phase: gradient from 100% DCM, 0% MeOH to 97% DCM, 3% MeOH, 0.1% NH 4 OH) for purification. The pure fractions were collected and evaporated to dryness to give 1.7 g (28%) of intermediate 71.

Mirror isomers were separated by chiral SFC (Chiralcel OD-H 5 μm 250 * 30 mm; mobile phase: 70% CO ₂ , 30% EtOH (0.3% iPrNH ₂ )). Pure fractions were collected and evaporated to dryness to yield 697 mg (11%) of intermediate 71a and 727 mg (12%) of intermediate 71b.

Following the method A described for the preparation of intermediates 71, 71a and 71b, starting with the respective starting materials, the intermediates in the table below were prepared.

Intermediate 77 Preparation of intermediate 77a

And intermediate 77b

Reaction mixture 1: In a sealed tube, a solution of Intermediate 78 (2 equivalents), Intermediate 11 (100 mg; 0.305 mmol) and Ti (OiPr) ₄ (6 equivalents) in EtOH (0.2 mL) at 45 ° C Heat for 1 hour. The mixture was cooled to room temperature, diluted with EtOH (3 mL), and NaBH ₄ (2 equivalents) was added. Following LC / MS 60% formation of intermediate 77, the reaction mixture was stirred at room temperature for 4 hours.

Reaction mixtures 2 and 3: The reaction was performed twice in the same amount: in a sealed tube, intermediate 78 (2 equivalents), intermediate 11 (450 mg; 1.37 mmol) and Ti (OiPr) ₄ (6 equivalents) in EtOH The solution in (0.9 mL) was heated at 45 ° C for 1 hour. The mixture was cooled to room temperature, diluted with EtOH (13 mL), and NaBH ₄ (2 equivalents) was added. The reaction mixture was stirred at room temperature for 18 hours.

The three kinds of the reaction mixture was diluted with EtOAc, and the mixture was poured into 10% K ₂ CO ₃ and brine in. The suspension was sonicated 30min, and filtered through a pad of Celite ^®. The organic layer was decanted, washed with 10% aqueous K ₂ CO ₃ then brine, dried over MgSO _4, filtered, and evaporated to dryness. The residue (2.6 g) was subjected to silica gel chromatography (irregular SiOH, 50 g; mobile phase: gradient from 0% NH ₄ OH, 0% MeOH, 100% DCM to 0.7% NH ₄ OH, 7% MeOH, 93 % DCM). The pure fractions were collected and evaporated to dryness. The residue (1.5 g; 89%) was subjected to a second step by silica gel chromatography (irregular SiOH, 40 g; mobile phase: 60% heptane, 35% EtOAc, 5% MeOH (+ 10% NH ₄ OH)) Purification. This fraction containing the product was collected and evaporated to dryness to yield 980 mg (58%; based on LC / MS, 82% purity) of Intermediate 77.

The impure fraction of intermediate 77 was further purified by chiral SFC (diethylaminopropyl 5 μm 150 x 30 mm; mobile phase: 90% CO2, 10% MeOH). The pure fractions were collected and evaporated to dryness to yield 620 mg (37%) of Intermediate 77.

These mirror image isomers were separated by chiral SFC (Lux cellulose-2 5 μm 250 * 30 mm; mobile phase: 50% CO ₂ , 50% MeOH (0.3% iPrNH ₂ )). The fractions containing the product were collected and evaporated to dryness to yield 276 mg (16%) of intermediate 77a and 269 mg (16%) of intermediate 77b.

Using methods similar to those described for the preparation of intermediates 77, 77a and 77b, starting with the respective starting materials, the intermediates in the table below were prepared.

Preparation of intermediate 72:

IPrMgCl 2M in THF (19 mL; 38.33 mmol) was added to a solution of intermediate 73 (4.6 g; 18.83 mmol) in THF (70 mL) under N ₂ at 5 ° C. The solution was stirred at 5 ° C for 30min, allowed to slowly rise to room temperature, then stirred for 1h, and heated at 40 ° C for 5h. The reaction mixture was cooled to room temperature, the mixture was poured into ice-water and saturated aqueous NH ₄ Cl solution, and extracted with EtOAc. The organic layer was decanted, dried over MgSO _4, filtered and evaporated to dryness to yield 4.7g of intermediate 72 (quantitative).

Using a method similar to that described for the preparation of intermediate 72, starting with the respective starting materials, the intermediates in the table below were prepared.

Preparation of intermediate 73:

Under N ₂ , 1-Boc-azetidine-3-carboxylic acid (5 g; 24.9 mmol) and N, O-dimethylhydroxylamine hydrochloride (3.64 g; 37.3 mmol) were placed in a round bottom flask . DCM (75 mL) was added, followed by EDCI.HCl (7.15 g; 37.3 mmol), DMAP (155 mg; 1.27 mmol), and DIPEA (6.5 mL, 37.4 mmol). The reaction mixture was stirred at room temperature for 16 h and diluted with DCM (100 mL). The organic layer was washed with aqueous 1M HCl (2 x 50mL), saturated NaHCO ₃ solution (50mL), and brine (50mL). The organic phase was decanted, dried over MgSO _4, filtered, and evaporated to dryness to yield 6.04g (99%) of intermediate 73.

Using a method similar to that described for the preparation of intermediate 73, starting with the respective starting materials, the intermediates in the table below were prepared.

Preparation of intermediate 85:

Under N ₂ at room temperature, intermediate 11 (204 mg; 0.62 mmol), intermediate 86 (217 mg; 0.81 mmol) and Ti (OEt) ₄ (0.26 mL; 1.24 mmol) in DCE (7 mL) The solution was stirred overnight. NaBH ₃ CN (129 mg; 2 mmol) was added and the solution was stirred for 4 days. Water was added dropwise and the solution was filtered through a Celite ^® pad. This filtrate was separated. The organic layer was washed with water, dried over MgSO _4, filtered and evaporated till dryness. The residue was subjected to silica gel chromatography (irregular SiOH, 24 g; mobile phase: gradient from 97% DCM, 3% MeOH (+ 10% NH ₄ OH) to 95% DCM, 5% MeOH (+ 10% NH ₄ OH)). The pure fractions were collected and evaporated to dryness to give 209 mg (80%) of intermediate 85.

Using a method similar to that described for the preparation of intermediate 85, starting with the corresponding starting materials, the intermediates in the table below were prepared.

Preparation of intermediate 86:

2-Bromo-1- (1-methyl-1H-pyrazol-4-yl) -ethanone (0.5 g; 2.46 mmol) in DMF (10 mL) was added to potassium phthalimide ( 0.46 g; 2.46 mmol). The reaction mixture was stirred at room temperature for 5 h, poured into water-ice, and EtOAc was added. The organic layer was separated, washed with water, brine, dried over MgSO _4, filtered, and evaporated till dryness. The residue was purified by silica gel chromatography (irregular SiOH 15 μm to 40 μm, 24 g; mobile phase: 97% DCM, 3% MeOH (+ 10% NH ₄ OH)). The pure fractions were collected and evaporated to dryness to give 460 mg (69%) of intermediate 86.

Preparation of intermediate 89:

Under N ₂ , n-BuLi 1.6M in hexane (6.2 mL; 9.92 mmol) was added to 4-iodo-1-methyl-1H-pyrazole (1.7 g; 8.17 mmol) at -70 ° C. ) In THF (35 mL). The reaction mixture was stirred at -70 ° C for 1 hour, and then a solution of intermediate 73 (2 g; 8.19 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at -70 ° C for 2 hours, allowed to warm to room temperature and stirred overnight. The solution was poured into ice - water mixture and saturated NH ₄ Cl solution, and then add the EtOAc. The organic layer was decanted, dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (Irregular SiOH, 50g; mobile phase: gradient from 100% DCM, 0% MeOH to 98% DCM, 2% MeOH, 0.1% NH 4 OH) for purification. The pure fractions were collected and evaporated to dryness to give 320 mg (15%) of Intermediate 89.

Preparation of intermediate 92:

Under N _2, the HBTU (210mg; 0.555mmol) was added to BOC-L- proline (119mg; 0.555mmol) and DIPEA (0.48mL; 2.775mmol) solution in DMF (10mL)'s. The solution was stirred for 30 min. Then, intermediate 10b (200 mg) was added and the solution was stirred at room temperature over the weekend. Subsequently, the reaction mixture was poured into ice water, basified with a 10% aqueous K ₂ CO ₃ solution, and extracted with EtOAc. The organic layer was washed with water, dried over MgSO _4, filtered and evaporated to dryness. The residue was subjected to silica gel chromatography (irregular SiOH, 24 g; mobile phase: gradient from 0.5% NH ₄ OH, 5% MeOH, 95% DCM to 1% NH ₄ OH, 10% MeOH, 90% DCM). purification. The pure fractions were collected and evaporated to dryness to yield 168 mg of intermediate 92.

Using a similar method to that described for the preparation of intermediate 92, starting with the respective starting materials, the intermediates in the table below were prepared.

Intermediate 107 Preparation

Under nitrogen, a solution of intermediate 11 (250 mg; 0.761 mmol), N- Boc-4-methylpiperidine (195 mg; 0.914 mmol) in THF (7 mL) was stirred at room temperature for 3 h. NaBH (OAc) ₃ (323 mg; 1.52 mmol) was added, and the mixture was stirred at room temperature overnight. 10% of K ₂ CO ₃ aqueous solution and DCM. The organic layer was separated, dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (irregular SiOH, 24 g; mobile phase: gradient from 100% DCM 0% MeOH (0% NH ₄ OH) to 90% DCM 10% MeOH (10% NH ₄ OH)) . This fraction containing the product was mixed and evaporated to dryness to yield 383 mg (96%) of Intermediate 107.

Preparation of intermediate 110:

DIPEA (0.45 mL, 3.24 mmol) was added to an ice-cold solution of 2- (4-fluorophenyl) propanol (CAS [59667-20-8]) (0.25 g, 1.62 mmol) in DCM (1.4 mL) Then, methanesulfonium chloride (0.155 mL, 1.95 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was diluted with DCM (20 mL) and washed with a saturated sodium bicarbonate solution (15 mL). The solution was dried over MgS0 ₄ , filtered, and concentrated under reduced pressure to yield 0.377 g of intermediate 110. This product was used in the next step without further purification.

Preparation of intermediate 112:

A solution of intermediate 111 (607 mg, 2.1 mmol) and titanium isopropoxide (1.25 mL, 1.37 mmol) in EtOH (4.6 mL) was added dropwise to intermediate 11 at room temperature (within 5 min to 10 min). (459mg, 1.4mmol) and NaBH ₃ CN (264mg, 4.2mmol) in a mixture of EtOH (9.2mL)'s. The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM, and and poured into 10% K ₂ CO ₃ aqueous solution. The suspension was filtered through a pad of Celite®. The organic layer was decanted, washed with brine, dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (irregular SiOH, 24 g; mobile phase: DCM / MeOH: gradient from 100/0 to 90/10). The pure fractions were collected and evaporated to dryness to yield 0.521 g (62%) of Intermediate 112 (62%).

B. Preparation of compounds

Example B1

Preparation of Compound 1:

TEA (88.5 mg, 0.875 mmol) and benzaldehyde (46.4 mg, 0.44 mmol) were sequentially added to a solution of intermediate 11 (190 mg, 0.44 mmol) in anhydrous DCM (4 mL), and the mixture was at room temperature Stir for 30 min. NaBH (OAc) ₃ (185.4 mg, 0.875 mmol) was then added, and the mixture was stirred at room temperature overnight. Saturated aqueous NaHCO ₃ (10mL) and DCM (10mL) and the mixture was decanted. The aqueous layer was extracted twice with DCM (10 mL). The organic layers were combined and the like, washed with brine (10 mL), dried over Na ₂ SO _4, and evaporated to give a yellow oil. The crude residue was purified by silica gel chromatography (column Gemini 150 * 25 5um, mobile phase: water (0.05% ammonium hydroxide v / v) / ACN: gradient from 55/45 to 25/75). The residue was then freeze-dried to give 65 mg of Compound 1 as a yellow solid (35% yield).

Example B2

Preparation of compound 2: Intermediate 11 (100 mg, 0.3 mmol), 3,3,3-trifluoropropanal (51 mg, 0.46 mmol) were stirred in dry DCM (3 mL) at room temperature for 1 h, and then NaBH (OAc) ₃ (129 mg, 0.61 mmol), and the mixture was stirred at room temperature overnight. The mixture was poured into water, then 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: irregular SiOH 15 μm to 40 μm 24 g, mobile phase: NH ₄ OH / DCM / MeOH: 0.1 / 97/3). The fractions containing the product were collected and evaporated to dryness to yield 58 mg (45%) of compound 2 which was freeze-dried with ACN / water 20/80 to give 45 mg of compound 2.

Compound 13 Preparation

A mixture of intermediate 11c (600 mg), isobutyraldehyde (160 mg; 2.221 mmol), NaBH (OAc) ₃ (1.57 g; 7.405 mmol), and Et ₃ N (0.64 mL; 4.443 mmol) in DCE (12 mL) was placed in Stir overnight at room temperature. Saturated aqueous solution of NaHCO ₃ (20mL) and DCM (20mL). The organic layer was decanted, and the aqueous layer was extracted with DCM (20 mL * 2). The combined organic layers were washed with brine and the like (30mL), dried over Na ₂ SO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (mobile phase: gradient from petroleum ether / EtOAc from 100/0 to 0/100, then EtOAc / MeOH from 100/0 to 85/15). The pure fractions were collected, evaporated to dryness, and freeze-dried to yield 320 mg of compound 13.

By using a similar method to that described for the preparation of compound 2, starting with the respective starting materials, the compounds in the table below were prepared.

Example B3

Preparation of compound 14: Intermediate 10b (0.42 g), benzyl bromide (0.19 mL, 1.6 mmol), and K ₂ CO ₃ (0.55 g, 4.0 mmol) in ACN (20 mL) were stirred at room temperature. overnight. The mixture was poured into water, extracted with EtOAc, and the organic layer was washed with brine, then dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: irregular SiOH 15 μm to 40 μm 40 g, mobile phase: NH ₄ OH / DCM / MeOH: 0.1 / 97/3). The product-containing fractions were collected and evaporated to dryness to yield 170 mg (31%) of compound 14, which was crystallized from DIPE, filtered and dried to give 103 mg of compound 14.

By using methods similar to those described for the preparation of compound 14, starting with the respective starting materials, the compounds and intermediates in the table below were prepared.

Example B4

Preparation of compound 20:

4-Chloro-6- (2,2,2-trifluoroethyl) thieno [] will be prepared as described in Journal of Medicinal Chemistry [2016], 59 (3), 892-913 2,3-d] pyrimidine (150 mg, 0.59 mmol), 2-benzyl 2,7-diaza-spiro- [4.4] nonane (CAS [885275-27-4]) (129 mg, 0.59 mmol), and A mixture of DIPEA (0.31 mL, 1.78 mmol) in ACN (15 mL) was heated at 80 ° C overnight. The mixture was cooled and poured into cold water, and the product was extracted with EtOAc, the organic layer was dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: 24 g of irregular naked silica, mobile phase: DCM / MeOH / NH ₄ OH: 97/3 / 0.1). The product containing fractions were collected and evaporated to dryness to give 200 mg (78% yield) of Compound 20 (racemic mixture).

Mirror isomer 20a And 20b Preparation

Mirror isomers were separated by chiral SFC (stationary phase: Lux cellulose-4 5 μm 250 * 21.2 mm, mobile phase: CO _{2 /} MeOH (0.3% iPrNH ₂ ): 70/30). The product containing fractions were collected and evaporated to dryness to yield 80 mg (yield 31%) of the first eluted fraction F1 and 81 mg (yield 31%) of the second eluted fraction F2.

F1 (80 mg; 0.185 mmol) was dissolved in acetone at 10 ° C and added in two (2 equivalents, 0.37 mmol, 93 μL) in 4N HCl, followed by the addition of Et ₂ O. The mixture was evaporated to dryness and absorbed with Et ₂ O, the precipitate was filtered and dried to give 65 mg (yield 20%) of compound 20a (1.95 HCl.1.25 H ₂ O.0.19 .0.06 Et ₂ O).

F2 (81 mg, 0.187 mmol) was dissolved in acetone at 10 ° C, and (2 equivalents, 0.37 mmol, 93 μL) in 4N HCl, followed by the addition of Et ₂ O. The mixture was evaporated to dryness, absorbed with Et ₂ O, and the precipitate was filtered and dried to give 49 mg (yield 15%) of compound 20b (2.0 HCl. 1.8 H ₂ O) as the hydrochloride salt.

Example B5

Preparation of compound 18:

A mixture of intermediate 6 (222 mg, 0.63 mmol), benzyl bromide (82 μL, 0.685 mmol) and K ₂ CO ₃ (430 mg, 3.11 mmol) in ACN (20 mL) was stirred at room temperature overnight. The solution was poured into cold water, and the product was extracted with EtOAc, the organic layer was dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: irregular 15 μm to 40 μm, 30 g, mobile phase: DCM / MeOH / NH ₄ OH: gradient from 100/0/0 to 97/3 / 0.1). The product containing fractions were collected and evaporated to dryness to yield 170 mg (61% yield) of compound 18 (racemic mixture).

Mirror Isomer Compound 21a Preparation and Compound 21b

Compound 18 was separated into its mirror image isomer via chiral SFC (stationary phase: Lux cellulose-2 5 μm 250 * 30 mm, mobile phase: CO ₂ / MeOH: 75/25). The fractions containing the product were collected and evaporated to dryness yielding 72 mg (26% yield) of the first eluted fraction F1 and 76 mg (27% yield) of the second eluted fraction F2.

F1 was dissolved in acetone (3mL), and 4N HCl was added dropwise at 10 ° C. (2 equivalents, 80 μL, 0.32 mmol), added Et ₂ O, and after 30 min, the precipitate was filtered and dried to give 54 mg (yield 16%) of compound 21a (1.8HCl.1.9H as a hydrochloride salt) ₂ O).

F2 was dissolved in acetone (3mL), and 4N HCl was added dropwise at 10 ° C. (2 equivalents, 85 μL, 0.34 mmol), Et ₂ O was added, and after 30 min, the precipitate was filtered and dried to give 34 mg (yield 10%) of compound 21b (1.8HCl.2.1H as a hydrochloride salt) ₂ O).

Example B6

Preparation of compound 22:

To a solution of intermediate 11 (200 mg, 0.51 mmol) in ACN (5 mL) was added intermediate 16 (220 mg, 1.08 mmol) and K ₂ CO ₃ (221.4 mg, 1.53 mmol). The mixture was heated to 90 ° C and stirred overnight. Water (10 mL) and DCM (10 mL) were added to the reaction mixture. The organic phase was separated and the aqueous layer was extracted with DCM (10 mL). The organic layers were combined, washed with brine (10 mL), and evaporated to give a residue. The residue was subjected to silica gel chromatography (column: Gemini 150 * 25 5u; mobile phase: water (0.05% ammonium hydroxide) v / v) / CH ₃ CN: gradient from 42/58 to 12/88, gradient time (min): 10; 100% B retention time (min): 2; flow rate (ml / min): 25) for purification.

The desired fractions were collected and dried in vacuo to give a residue. The residue was lyophilized to give 65 mg (28% yield) of Compound 22 as a pale yellow solid.

Example B7

Preparation of compound 24:

Intermediate 17 (180 mg, 0.36 mmol) and 3N NaOH (0.61 mL, 1.82 mmol) in MeOH (10 mL) were stirred at room temperature for 1 h. The mixture was cooled to room temperature, poured into water and extracted with EtOAc. The organic layer was dried over MgSO _4, filtered and evaporated to dryness. The residue was freeze-dried with acetonitrile / water 20/80 to yield 130 mg of compound 24 (79% yield).

Example B8

Preparation of Compound 25:

To a solution of Intermediate 43 (100 mg, 0.2 mmol) in DCM (10 mL) at 5 ° C was added dropwise over two hours. (246 μL, 0.99 mmol) of 4N HCl, and the mixture was stirred at room temperature for 15 h. The reaction was evaporated to dryness. Then, the residue was taken up in DCM, washed with NaHCO _3. The organic layer was dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: irregular SiOH 15 μm to 40 μm 24 g, mobile phase: NH ₄ OH / DCM / MeOH gradient from 0.5 / 95/5 to 1/90/10). The pure fractions were collected and evaporated to dryness. The residue was freeze-dried with acetonitrile / water 20/80 to yield 25 mg of compound 25 (31% yield).

By using a method similar to that described for the preparation of compound 25, starting with the respective starting materials, the compounds in the table below were prepared.

Example B9

Preparation of compound 26:

In a sealed tube, 4-chloro-6- (2,2,2-trifluoroethyl) thieno [2,3-d] pyrimidine (0.15 g, 0.594 mmol), 6- ( Phenylmethoxy) -2-azaspiro [3.3] heptane (0.145 g, 0.713 mmol) and DIPEA (0.205 mL, 1.19 mmol) were heated in isopropanol (2 mL) overnight. The solution was cooled to room temperature and poured into water and then extracted with EtOAc. The organic layer was washed with water, dried over MgSO _4, filtered and evaporated to dryness. The crude product was crystallized from Et ₂ O and dried. The residue was purified by silica gel chromatography (15 μm to 40 μm, 24 g, eluent: heptane / EtOAc: 80/20 to 20/80). The pure fractions were mixed and the solvent was evaporated. The residue was taken up by Et ₂ O, filtered and dried to give 0.111 g of compound 26 (45% yield).

Example B10

Preparation of compound 28:

A mixture of intermediate 10b (200 mg), 1-methyl-1H-pyrazole-4-carbaldehyde (183 mg; 1.66 mmol), and AcOH (32 μL; 0.555 mmol) in DCE (6 mL) was stirred at 50 ° C. 2 hour. The reaction mixture was cooled to room temperature, and NaBH (OAc) ₃ (353 mg; 1.665 mmol) was added. The reaction mixture was stirred at room temperature overnight, poured into 10% K ₂ CO ₃ aqueous solution, and extracted with DCM. The organic layer was decanted, dried over MgSO _4, filtered and evaporated to dryness. The residue was subjected to silica gel chromatography (irregular SiOH, 24 g; mobile phase: gradient from 0% NH ₄ OH, 0% MeOH, 100% DCM to 1% NH ₄ OH, 10% MeOH, 90% DCM). purification. Pure fractions were collected and evaporated to dryness to give 165 mg of compound 28 (73%) as an oil. Compound 28 was dissolved in ACN and HCl (4N in Middle) (277 μL; 1.11 mmol). The HCl salt was filtered, but it appeared to be too hygroscopic. The residue was then dissolved in DCM / MeOH, and the organic layer was washed with an aqueous solution of ₂ CO ₃ 10% K, dried over MgSO _4, filtered and evaporated to dryness. The resulting residue was dissolved in ACN, and fumaric acid (47 mg; 0.404 mmol; 1 equivalent) was added, and the solution was allowed to stand until crystallized (overnight). The precipitate was filtered, washed with ACN, and then washed with ₂ O Et, and dried to yield compound as a fumarate 188mg 28 (based on 1H NMR, 1 eq).

By using methods similar to those described for the preparation of compound 28, starting with the respective starting materials, the compounds in the table below were prepared.

Example B11

Preparation of compound 29:

At 10 ° C 4N HCl (0.7 mL; 2.85 mmol) was added to a solution of intermediate 50 (145 mg; 0.28 mmol) in ACN (7 mL). The solution was stirred at room temperature overnight. The solution was evaporated to dryness. The residue was taken up in ice water, basified with NH ₄ OH, and added DCM. The organic layer was separated, dried over MgSO _4, filtered, and evaporated till dryness. The residue was purified by silica gel chromatography (stationary phase: irregular SiOH 15 μm to 40 μm 12 g, mobile phase: DCM / MeOH / NH ₄ OH 90/10/10). The pure fractions were collected and evaporated to dryness. The residue was freeze-dried with acetonitrile / water 20/80, yielding 0.050 g (43% yield) of compound 29.

By using a method similar to that described for the preparation of compound 29, starting with the respective starting materials, the compounds in the table below were prepared.

Example B12

Preparation of compound 36:

To a solution of intermediate 11 (287 mg, 0.87 mmol) in DCM (14 mL) under a stream of N ₂ was added 1-isopropyl-1H-pyrazole-4-carbaldehyde (133 mg, 0.68 mmol) and AcOH (51 μL, 0.87 mmol). The mixture was stirred at room temperature for 2 h. NaBH (OAc) ₃ (742 mg, 3.5 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was poured into ice water and separated. The aqueous layer was extracted with DCM. The organic layer was washed with brine, then dried over MgSO _4, filtered and evaporated. The residue was purified by silica gel chromatography (stationary phase: irregular SiOH 15 μm to 40 μm 24 g, mobile phase: DCM / MeOH (+ 10% NH ₄ OH): gradient from 97/3 to 90/10). The pure fractions were collected and evaporated to dryness. The residue was freeze-dried with acetonitrile / water: 20/80 to yield 0.057 g (15% yield) of compound 36.

By using a method similar to that described for the preparation of compound 36, starting with the respective starting materials, the compounds in the table below were prepared.

Example B13

Compound 45 Preparation

To a solution of intermediate 11c (200 mg) in dichloroethane (10 mL) was added 2-methylbenzaldehyde (59 mg; 0.494 mmol), NaBH (OAc) ₃ (523 mg; 2.47 mmol), and triethylamine (150 mg ; 1.48 mmol). The mixture was stirred at room temperature overnight, and then added NaHCO ₃ (10mL) and a saturated aqueous solution of DCM (10mL). The mixture was separated and the aqueous layer was extracted with DCM (10 mL * 2).

The organic layers were combined, washed with water (10 mL), dried over Na ₂ SO ₄ and evaporated to give 300 mg of a yellow oil. The yellow oil was subjected to preparative high performance liquid chromatography (column: Kromasil 150 * 25mm) * 10um; Conditions: A: water (0.05% ammonia hydroxide v / v), B: MeCN, at the beginning: A (52%) and B (48%), and at the end: A: (22%) and B (78%), gradient time (min) 8; flow rate (ml / min): 30).

This fraction containing the product was collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give 150 mg (70%) of Compound 45 as a white solid.

By using a method similar to that described for the preparation of compound 45, starting with the respective starting materials, the compounds in the table below were prepared.

Example B14

Compound 108 Preparation

S) -5-methyl-5-azaspiro [2.4] heptane-6-carboxylic acid (94 mg; 0.61 mmol), HBTU (231 mg; 0.61 mmol) and DIPEA (0.52 mL; 3.04 mmol) The mixture in) was stirred for 1 hour. Then, a solution of intermediate 10b (200 mg) in DMF (5 mL) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water and basified with ₂ CO ₃ 10% aqueous solution of K, and extracted with EtOAc. The organic layer was washed with H ₂ O then brine, dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (irregular SiOH, 10 g; mobile phase: gradient from 3% MeOH, 97% DCM to 10% MeOH, 90% DCM). The product containing fractions were collected and evaporated to dryness to yield 144 mg of impure fraction 1. A second purification (Irregular SiOH, 40g; mobile _{phase: 0.5% NH 4 OH, 95} % DCM, 5% MeOH). The product containing fractions were collected and evaporated to dryness to yield 43 mg of impure fraction 2.

Fraction 2 was purified again by silica gel chromatography (irregular SiOH, 10 g; mobile phase: gradient from 3% MeOH, 97% DCM to 10% MeOH, 90% DCM). The product containing fractions were collected and evaporated to dryness. The resulting residue was taken up with diisopropyl ether. The solid was filtered and dried to yield 17 mg of compound 108.

By using a method similar to that described for the preparation of compound 108, starting with the respective starting materials, the compounds in the table below were prepared.

Example B18

Preparation of compound 57:

LiAlH ₄ (66 mg, 1.73 mmol) was added to intermediate 54 (450 mg, 0.693 mmol) in THF (12 mL). The reaction was stirred at room temperature for 1.5 h. Cl aqueous solution, the reaction was quenched with saturated NH _4, and extracted with DCM, and and concentrated to provide a white solid. The solid was subjected to preparative high performance liquid chromatography (column: Xtimate C18 150 * 25mm * 10um, conditions: water (0.05% ammonium hydroxide, v / v) / ACN: gradient from 52/48 to 42/58 ) For purification. To the aqueous layer was added 0.1 mL of 1N HCl. The solution was freeze-dried to give 30 mg of compound 57 as a yellow solid (HCl salt).

Example B19

Preparation of compound 58:

To a solution of intermediate 8 (200 mg, 0.5 mmol) in THF (10 mL) was added isobutyraldehyde (70 μL, 0.77 mmol) and TEA (0.37 mL, 2.63 mmol). The mixture was stirred at room temperature for 3 h. NaBH (OAc) ₃ (317 mg, 1.5 mmol) was added and the solution was stirred at room temperature overnight. The solution was poured into cold water, and treated with K ₂ CO ₃ powder was basified. The product was extracted with EtOAc. The organic layer was dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: 40 g of irregular naked silica, mobile phase: NH ₄ OH / DCM / MeOH: 0.2 / 98/2). Dissolve the residue in 5 mL of ACN at 10 ° C and add dropwise (117 μL; 0.47 mmol) in 2 equivalents of 4N HCl. 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 yield 38 mg of compound 58 (HCl salt).

By using methods similar to those described for the preparation of compound 58, starting with the respective starting materials, the compounds in the table below were prepared.

Example B21

Preparation of compound 62:

1M TBAF in THF (0.815 mL, 0.815 mmol) was added dropwise to a solution of intermediate 55 (0.248 g, 0.407 mmol) in Me-THF (8 mL), and the reaction mixture was stirred at room temperature overnight . 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 (30mL), water (30mL) and brine (30mL), dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (80 g, 15 μm to 40 μm, eluent: DCM / MeOH: 97/3 to 88/12). The pure fractions were mixed and the solvent was evaporated to yield 0.043 g of compound 62 (21% yield).

Example B22

Preparation of compound 63:

At room temperature, 2,2-dimethyl-tetrahydropiperan-4-carbaldehyde (87 mg; 0.609 mmol) and NaBH (OAc) ₃ (645 mg; 3.045 mmol) were added to intermediate 11 (200 mg; 0.609 mmol) ) In a solution of DCE (4 mL), and the reaction mixture was stirred overnight. The reaction mixture was diluted with DCM, and and poured into 10% K ₂ CO ₃ aqueous solution. The organic layer was decanted, dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (Irregular SiOH, 24g; mobile _{phase: NH 4 OH / MeOH / DCM} : gradient from 0.7 to 0/0/100 / 7/93) was purified. The pure fractions were collected and evaporated to dryness. The residue was freeze-dried from water / ACN (80/20; 10 mL) to yield 155 mg of compound 63 (56% yield).

By using a method similar to that described for the preparation of compound 63, starting with the respective starting materials, the compounds in the table below were prepared.

Example B23

Preparation of compound 64:

At room temperature, intermediate 11 (150 mg, 0.457 mmol), 2,2,2-trifluoroethyltrifluoromethanesulfonate (69 μL, 0.502 mmol), and DBU (CAS [6674-22-2] ) (136 μL, 0.914 mmol) in DMSO (3 mL) was stirred for 18 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and then washed several times with brine, dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (Irregular SiOH, 24g; mobile _{phase: NH 4 OH / MeOH / DCM} : gradient from 0.7 to 0/0/100 / 7/93) was purified. The pure fractions were collected and evaporated to dryness. The residue was purified a second time by silica gel chromatography (irregular SiOH, 10 g; mobile phase: EtOAc / heptane: gradient from 60/40 to 80/20). The pure fractions were collected and evaporated to dryness. The residue was crystallized from DIPE and dried under vacuum at 50 ° C to give 100 mg of compound 64 (53% yield).

Example B24

Preparation of compound 67:

Under N ₂ , a solution of intermediate 11 (100 mg; 0.31 mmol), 2- (tetrahydro-2H-piperan-4-yl)) acetaldehyde (48 μL; 0.37 mmol) in THF (3 mL) was placed in a chamber. Stir at warm for 3h. NaBH (OAc) ₃ (129 mg; 0.61 mmol) was added, and the mixture was stirred at room temperature overnight. Was added 10% aqueous K ₂ CO ₃ solution and EtOAc. The mixture was extracted with EtOAc (x3). The organic layers were combined, washed with brine, then dried over MgSO _4, filtered, and the solvent was evaporated.

The residue (136 mg) was subjected to silica gel chromatography (SiO ₂ , 4 g; gradient: from 95% DCM, 5% MeOH, 0.5% NH ₄ OH to 90% DCM, 10% MeOH, 1% NH ₄ OH) purification. The product-containing fractions were collected, and the solvent was evaporated to give 90 mg of a colorless oil, which was recrystallized from diisopropyl ether. The precipitate was filtered and dried to give 45 mg (34%) of compound 67 as a white solid.

Example B25

Compound 71 Preparation

In a sealed tube, under N ₂ , intermediate 35 (211 mg; 1.37 mmol) and Ti (OiPr) ₄ (436 μL; 1.83 mmol) were added to intermediate 11 (300 mg; 0.914 mmol) in THF (6 mL) In solution. The solution was stirred at 50 ° C for 5 hours and then at room temperature overnight. The reaction mixture was cooled to 5 ° C, and isopropylmagnesium chloride 2M in THF (2.28 mL; 4.57 mmol) was added dropwise. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc, and poured into 10% K ₂ CO ₃ aqueous solution. The precipitate was removed by filtration through Celite ^®. The organic layer was decanted, washed with brine, dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (irregular SiOH, 40 g; mobile phase: gradient from 0% MeOH, 100% DCM to 10% MeOH, 90% DCM). This fraction containing the product was collected and evaporated to dryness to give 0.337 g of intermediate residue, which was analyzed by chromatography through reversed phase (stationary phase: YMC-actus Triart C18 10 μm 30 * 150 mm, flowing Phase: Gradient from 55% NH ₄ HCO ₃ 0.2%, 45% ACN to 0% NH ₄ HCO ₃ 0.2%, 100% ACN) was purified again. The pure fractions were collected and evaporated to dryness. The residue was freeze-dried with acetonitrile / water 20/80 to provide 120 mg (26%) of compound 71.

Example B26

Preparation of Compound 77:

Hydrazine (36 μL, 0.92 mmol) was added to a solution of intermediate 41 (110 mg, 0.18 mmol) in ethanol (5 mL). The solution was heated at 70 ° C. for 1 h 30 min. The reaction was cooled to room temperature, then poured into water and extracted with DCM. The organic layer was washed with brine, then dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: 40 g of irregular naked silica, mobile phase: NH ₄ OH / DCM / MeOH: 1/85/15). The pure fractions were collected and evaporated to dryness. The residue was dissolved in 2 mL of ACN, and 3 equivalents of 6N HCl in iPrOH were added dropwise at 10 ° C. After adding Et ₂ O and 30 min, the precipitate was filtered and dried to yield 83 mg of compound 77 (37% yield).

Example B28

Preparation of Compound 82:

TFA (1.5 mL) was added to a solution of intermediate 25 (300 mg, 0.571 mmol) in DCM (15 mL), and the reaction mixture was stirred for 18 h. The reaction mixture was poured into 10% K ₂ CO ₃ aqueous solution and extracted with DCM. The organic layer was decanted, filtered through chromabond ^® and evaporated to dryness. The residue was purified by silica gel chromatography (Irregular SiOH, 10g; mobile _{phase: NH 4 OH / MeOH / DCM} : gradient from 0.3 / 3/97 to 1.5 / 15/85) was purified. The pure fractions were collected and evaporated to dryness. The residue was crystallized from DIPE and dried to yield 118 mg of compound 82 (48% yield).

By using methods similar to those described for the preparation of compound 82, starting with the respective starting materials, the compounds in the table below were prepared.

Example B29

Preparation of Compound 84:

Intermediate 11b (198 mg) and 4-fluorophenylacetone (68 μL, 0.51 mmol) were stirred in THF (5 mL) at room temperature overnight. NaBH (OAc) ₃ (161 mg, 0.76 mmol) was then added in portions. The mixture was stirred at room temperature for 24 h. The solution was poured into cold water and basified with a 3N NaOH solution, and EtOAc was added. The organic layer was separated, dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: 40 g of irregular naked silica, mobile phase: NH ₄ OH / DCM / MeOH: 0.1 / 97/3). The pure fractions were collected and the solvent was evaporated under vacuum. The residue was freeze-dried with acetonitrile / water 20/80 to yield 30 mg of compound 84.

By using methods similar to those described for the preparation of compound 84, starting with the respective starting materials, the compounds in the table below were prepared.

Example B32

Compound 133 Preparation of compound 137

And compound 138

Ti (OEt) ₄ (251 μL; 1.2 mmol) was added to intermediate 11 (200 mg; 0.6 mmol) and 2,5,6,7-tetrahydro-2-methyl- 4H -indazole at room temperature. A solution of 4-one (120 mg; 0.8 mmol) in dichloroethane (5 mL) and MeOH (1.5 mL). The mixture was stirred at room temperature for 2 hours, and then NaBH ₃ CN (127 mg; 2 mmol) was added in portions. The mixture was stirred at room temperature for 2 days. The solution was poured into cold water and DCM was added. The mixture was filtered with K ₂ CO ₃ powder was basified by Celite ^® pad. The product was extracted with DCM. The organic layer was dried over MgSO _4, filtered and evaporated to dryness.

The residue (361 mg) was purified by silica gel chromatography (stationary phase: irregular naked silica 40 g, mobile phase: 0.5% NH ₄ OH, 95% DCM, 5% MeOH). The product containing fractions were mixed and concentrated to provide 120 mg (43%) of compound 133.

Chiral separation of compound 133 was performed via chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250 * 30 mm, mobile phase: 70% CO ₂ , 30% MeOH (0.3% iPrNH ₂ )). This fraction containing the product is mixed and concentrated to provide:

-45 mg of fraction 1 which was freeze-dried with acetonitrile / water 20/80 to give 40 mg (43%) of compound 137 as a white powder.

-46 mg of Fraction 2, which was freeze-dried with acetonitrile / water 20/80 to give 42 mg (46%) of Compound 138 as a white powder.

Example B33

Compound 145 Preparation of compound 154

And compound 155

At 45 ° C, 1-tetrahydro-2H-piperan-4-yl ethyl ketone (351 mg; 2.74 mmol), intermediate 11 (600 mg; 1.83 mmol), Ti (OiPr) ₄ (870 μL; 2.92 mmol) The solution in EtOH (3 mL) was stirred for 2 hours. Additional EtOH (18 mL) and NaBH ₄ (138 mg; 3.65 mmol) were added. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with DCM ,, and poured into 10% K ₂ CO ₃ aqueous solution. The insoluble material removed by filtration through celite ^®. The organic layer was separated, washed with water, dried over MgSO _4, filtered and evaporated to dryness. The residue was subjected to silica gel chromatography (irregular SiOH, 24 g; mobile phase: gradient from 0% NH ₄ OH, 0% MeOH, 100% DCM to 1% NH ₄ OH, 10% MeOH, 90% DCM). purification. This fraction containing the product was collected and evaporated to dryness to yield 487 mg (60%) of compound 145. The mirror image isomer of compound 145 was separated by chiral SFC (CHIRALPAK AD-H 5 μm 250 * 30 mm; mobile phase: 70% CO ₂ , 30% mixture of EtOH / iPrOH 50/50 v / v). This fraction containing the product was collected and evaporated to dryness. These residues were freeze-dried from water / ACN (80/20; 10 mL) to yield 171 mg (21%) of compound 154 and 178 mg (22%) of compound 155.

By using a similar method to that described for the preparation of compound 145, starting with the respective starting materials, the compounds in the table below were prepared. The most relevant small deviations are indicated in the 'compound number' column.

Compound 312 (non-mirromeric isomer A (mixture of 2 compounds (RR and SS) or (RS and SR)) and compound 313 (non-mirromeric isomer B (2 compounds (RS and SR) or Preparation of a mixture of SS)):

Reaction mixture 1: 3-methyl-1- (6-oxaspiro [4.5] dec-9-yl) -1-butanone (1.5 equivalents), intermediate 11 (100 mg; 0.285 mmol) at 45 ° C ), A solution of Ti (OiPr) ₄ (1.6 equivalents) in ethanol (0.25 mL) and stirred for 2 hours. Ethanol (3 mL) and NaBH ₄ (2 equivalents) were added. The reaction mixture was stirred at room temperature for 18 hours.

Reaction mixture 2: 3-methyl-1- (6-oxaspiro [4.5] dec-9-yl) -1-butanone (546 mg; 2.436 mmol; 2 equivalents), intermediate 11 at 45 ° C (400 mg; 1.22 mmol), a solution of Ti (OiPr) ₄ (580 μL; 1.95 mmol) in ethanol (1 mL) was stirred for 2 hours. Ethanol (12 mL) and NaBH ₄ (92 mg; 2.436 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours.

The reaction mixture was collects two, and diluted with EtOAc, poured into 10% K ₂ CO ₃ aqueous solution and filtered through a pad of Celite ^®. The organic layer was decanted, washed with brine, dried over MgSO _4, filtered and evaporated to dryness. The residue was subjected to silica gel chromatography (irregular SiOH, 24 g; mobile phase: gradient from 0% NH ₄ OH, 0% MeOH, 100% DCM to 0.9% NH ₄ OH, 9% MeOH, 91% DCM). Purification. The desired fractions were collected and evaporated to dryness.

The residue (280 mg of) by silica gel chromatography (Irregular SiOH, 24g; mobile phase: 67% heptane, 33% EtOAc (containing 10% NH ₄ OH to + 5% MeOH)) further separated. Collect the desired fractions and evaporate to dryness:

-100mg (12%) of compound 312 (first elution; not sufficiently pure), the compound was subjected to silica gel chromatography (irregular SiOH, 24g; mobile phase: gradient from 0% NH ₄ OH, 0% MeOH, 100% DCM to _{0.5% NH 4 OH, 5%} MeOH, 95% DCM) is further purification. The pure fractions were collected and evaporated to dryness. Pure fractions were freeze-dried from water / ACN (80/20; 10 mL) to yield 80 mg (10%) of compound 312.

-110mg (13%) of compound 313 (second elution; not sufficiently pure), the compound was subjected to silica gel chromatography (irregular SiOH, 24g; mobile phase: gradient from 0% NH ₄ OH, 0% MeOH, 100% DCM to _{0.5% NH 4 OH, 5%} MeOH, 95% DCM) is further purification. The pure fractions were collected and evaporated to dryness. Pure fractions were freeze-dried from water / ACN (80/20; 10 mL) to yield 70 mg (9%) of compound 313.

Example B34

Preparation of compound 147:

A mixture of intermediate 60a (216 mg; 0.4 mmol) and TFA (1 mL; 13.067 mmol) in DCM (10 mL) was stirred at room temperature for 4 h. The reaction mixture was diluted with DCM, and washed with 10% and of K ₂ CO ₃ aqueous solution was basified. The organic layer was decanted, washed with water, filtered through chromabond®, and evaporated to dryness. The residue (200 mg) was purified by silica gel chromatography (irregular SiOH, 10 g; mobile phase: 85% DCM, 14% MeOH, 1% NH ₄ OH). The pure fractions were collected and evaporated to dryness. The residue was freeze-dried from water / ACN (80/20; 10 mL) to yield 136 mg of compound 147 (77%).

By using a method similar to that described for the preparation of compound 147, starting with the respective starting materials, the compounds in the table below were prepared.

Example B35

Compound 156 Preparation

Compound 193 Compound 162

And compound 157:

A solution of 2-methyl-1- (tetrahydro- 2H -piperan-4-yl) -1-acetone (1.66 g; 10.63 mmol) in THF (30 mL) was added to intermediate 11 (2.33 g; 7.08 mmol) and TFA (3.3 mL; 42.5 mmol) in THF (45 mL). The reaction mixture was stirred at room temperature overnight. NaBH (OAc) ₃ (4.5 g; 21.25 mmol) was then added in portions. The reaction mixture was stirred at room temperature for 7 days. The reaction mixture was stirred at room temperature for 3 days. The solution was poured into 10% aqueous K ₂ CO ₃ was added EtOAc. The mixture was extracted with EtOAc (3x). The organic layers were combined and the like, washed with brine, dried over MgSO _4, filtered, and the solvent was evaporated. The residue (3.9 g; yellow oil) was subjected to silica gel chromatography (SiO ₂ ; 40 g; eluent: from 97% DCM, 3% MeOH, 0.3% NH ₄ OH to 90% DCM, 10% MeOH, 1 % NH ₄ OH). The pure fractions were collected and the solvent was evaporated to give 666 mg of compound 156 as a light brown solid.

Compound 156 was performed by reversed phase (YMC-actus Triart C18 10μm 30 * 150mm, mobile phase: gradient from 50% NH ₄ HCO ₃ 0.2%, 50% ACN to 0% NH ₄ HCO ₃ 0.2%, 100% ACN) purification. Pure fractions were collected and the solvent was evaporated to give 66 mg of compound 157 (colorless oil) and 264 mg of compound 156 (8%; colorless oil).

50 mg of compound 156 was freeze-dried with water-ACN to give 47 mg of compound 156 (white solid).

Compound 157 was freeze-dried with water-ACN to give 53 mg of compound 157 (2%, white solid).

Compound 156 (214 mg) was purified by chiral SFC (CHIRALPAK AD-H 5 μm 250 * 30 mm, mobile phase: 75% CO ₂ , 25% EtOH (0.3% iPrNH ₂ )). Pure fractions were collected and the solvent was evaporated to give 82 mg of compound 193 (colorless oil) and 82 mg of compound 162 (colorless oil).

Compound 193 was freeze-dried with water-ACN to give 72 mg of compound 193 (2%, white solid).

Compound 162 was freeze-dried with water-ACN to give 77 mg of compound 162 (2%, white solid).

By using a method similar to that described for the preparation of compound 193, starting with the respective starting materials, the compounds in the table below were prepared.

Example B36

Compound 161 Preparation

Compound 166:

And compound 167:

In a sealed tube, under N ₂ , 1,3-dimethyl-1H-pyrazole-4-carboxaldehyde (284 mg; 2.28 mmol) and Ti (iPrO) ₄ (727 μL; 3.05 mmol) were added to intermediate 11 (500 mg; 1.52 mmol) in THF (10 mL). The solution was stirred at 50 ° C for 2h. The reaction mixture was cooled to 5 ° C, and iPrMgCl (3.8 mL; 7.61 mmol) was added dropwise. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was poured into 10% K ₂ CO ₃ aqueous solution and EtOAc. The insoluble material was filtered through a pad of Celite®, and the organic layer was decanted, dried over MgSO _4, filtered, and the solvent was evaporated. The residue (866 mg, brown oil) was subjected to silica gel chromatography (SiO ₂ ; 40 g; eluent: from 96% DCM, 4% MeOH, 0.4% NH ₄ OH to 93% DCM, 7% MeOH, 0.7% NH ₄ OH) for purification. The pure fractions were collected and the solvent was evaporated to dryness. The residue (496 mg, yellow oil) was recrystallized from ether. The precipitate was filtered and dried to give 324 mg of compound 161 (45%, white solid).

270 mg of compound 161 was purified by chiral SFC (CHIRALPAK AD-H 5 μm 250 * 30 mm, mobile phase: 70% CO ₂ , 30% iPOH (0.3% iPrNH ₂ )). Pure fractions were collected and the solvent was evaporated to give 128 mg of compound 166 (18%, colorless oil) and 131 mg of compound 167 (18%, colorless oil).

Compound 166 was freeze-dried with water-ACN to give 110 mg of compound 166 (15%, white solid).

Compound 167 was freeze-dried with water-ACN to give 115 mg of compound 167 (16%, white solid).

By using methods similar to those described for the preparation of compound 161, starting with the respective starting materials, the compounds in the table below were prepared. The most relevant small deviations are indicated in the yield column.

Example B38

Preparation of Compound 170:

Intermediate 11b (198 mg) and 1- (3,5-difluorophenyl) propan-2-one) (86 mg; 0.51 mmol) in THF (5 mL). The mixture was stirred at room temperature overnight. NaBH (OAc) ₃ (161 mg; 0.76 mmol) was then added in portions. The mixture was stirred at room temperature for 24 h. The solution was poured into cold water, basified with a solution of NaOH 3N, and EtOAc was added. The organic layer was separated, dried over MgSO _4, filtered and evaporated to dryness. The residue (141 mg) was purified by silica gel chromatography (40 g of irregular naked silica, mobile phase: 0.1% NH ₄ OH, 97% DCM, 3% MeOH). The pure fractions were collected and the solvent was evaporated. The residue (50 mg) was freeze-dried with ACN / water 20/80 to give 16 mg of compound 170.

By using a similar method to that described for the preparation of compound 170, starting with the respective starting materials, the compounds in the table below were prepared.

Example B39

Preparation of compound 184:

A mixture of intermediate 70a (250 mg; 0.73 mmol), isobutyraldehyde (200 μL; 2.19 mmol) and AcOH (42 μL; 0.73 mmol) in DCE (8 mL) was stirred at 50 ° C for 3 h. The reaction mixture was cooled to room temperature, and NaBH (OAc) ₃ (464 mg; 2.19 mmol) was added. The reaction mixture was stirred at room temperature overnight, poured into 10% K ₂ CO ₃ aqueous solution, and extracted with DCM. The organic layer was decanted, dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (Irregular SiOH, 24g; mobile phase: gradient from 100% DCM to 10% MeOH (+ 10% NH 4 OH), 90% DCM) was purified. The pure fractions were collected and evaporated to dryness. The hydrochloride was prepared: the residue (110 mg, 38%) was dissolved in ACN and added at 1,4-di (2 eq.) HCl 4N. The solution was evaporated to dryness and absorbed several times with ACN. The residue was crystallized from Et ₂ O to yield compound 184 120mg (HCl salt).

By using methods similar to those described for the preparation of compound 184, starting with the respective starting materials, the compounds in the table below were prepared.

Example B40

Compound 289 Preparation

A solution of intermediate 70a (100 mg; 0.29 mmol), p-tolualdehyde (50 μL; 0.35 mmol) in dichloroethane (3 mL) was stirred at room temperature for 3 h. NaBH (OAc) ₃ (124 mg; 0.58 mmol) was added, and the mixture was stirred at room temperature overnight. 10% of K ₂ CO ₃ aqueous solution and DCM. The organic layer was decanted, filtered through chromabond ^® and evaporated to dryness. The residue was purified by silica gel chromatography (Irregular SiOH, 10g; mobile phase: gradient from 0% NH4OH, 0% MeOH, 100% DCM to _{0.5% NH 4 OH, 5%} MeOH, 95% DCM) was purified. The pure fractions were collected and evaporated to dryness. The residue was freeze-dried from water / ACN (80/20; 10 mL) to yield 73 mg (56%) of compound 289.

By using a method similar to that described for the preparation of compound 289, starting with the respective starting materials, the compounds in the table below were prepared. The most relevant small deviations are indicated in the yield column.

Example B41

Compound 273 Preparation

Compound 200

And compound 222

A mixture of intermediate 71 (546 mg; 1.01 mmol) and TFA (1.5 mL; 19.6 mmol) in DCM (15 mL) was stirred at room temperature for 4 hours. The mixture was evaporated to dryness. The residue was taken up with DCM and H ₂ O and then basified with aqueous NaOH 3N. The organic layer was decanted, dried over MgSO _4, filtered and evaporated to yield compound 222 was dried 400mg (90%) of.

These mirror image isomers were separated by chiral SFC (Chiralpak AD-H 5 μm 250 * 30 mm; mobile phase: 50% CO ₂ , 50% EtOH (0.3% iPrNH ₂ )). Pure fractions were collected and evaporated to dryness to yield 106 mg (24%) of compound 273 and 130 mg (29%) of compound 200.

Compound 273 can also be prepared from intermediate 71a using the same method. Compound 200 can also be prepared from intermediate 71b using the same method. Using a similar method to that described for the preparation of compound 273, starting with the respective starting materials, the compounds in the table below were prepared.

Example B42

Compound 274 Preparation

And compound 203

Under N ₂ , 1-methyl-1H-pyrazole-4-carbaldehyde (100 mg; 0.913 mmol) and Ti (OEt) ₄ (0.25 mL; 1.233 mmol) were added to intermediate 11 (200 mg) at room temperature. 0.609 mmol) in THF (3 mL). The solution was stirred at room temperature for 20 hours. The reaction mixture was cooled to 5 ° C, and iPrMgCl 2M in THF (1.5 mL; 3.045 mmol) was added dropwise. The reaction mixture was stirred at 5 ° C. for 30 min, allowed to slowly rise to room temperature within 6 hours, and poured into a cold aqueous solution of K ₂ CO ₃ . DCM was added and the reaction mixture was filtered through a pad of Celite®. The insoluble material was washed several times with DCM. The organic layer was decanted, filtered through chromabond ^® and evaporated to dryness. The residue was subjected to silica gel chromatography (irregular SiOH, 24 g; mobile phase: gradient from 0% NH ₄ OH, 0% MeOH, 100% DCM to 0.8% NH ₄ OH, 8% MeOH, 92% DCM). purification. The pure fractions were collected and evaporated to dryness to yield 195 mg (69%) of the racemic compound. These mirror isomers were separated by chiral SFC (Lux cellulose-25 μm 250 * 30 mm; mobile phase: 55% CO ₂ , 45% MeOH (0.3% iPrNH ₂ )). Two fractions were freeze-dried from water / ACN (80/20; 12 mL) to yield 80 mg (28%) of compound 274 and 82 mg (29%) of compound 203.

Example B43

Compound 197 Preparation of compound 198

And compound 199

Under N ₂ at room temperature, 1-methyl-1H-pyrazole-4-carbaldehyde (99 mg; 0.9 mmol) and Ti (OEt) ₄ (0.25 mL; 1.2 mmol) were added to intermediate 11 (197 mg 0.6 mmol) in a solution in THF (3 mL), and the solution was stirred at room temperature for 20 hours. The reaction mixture was cooled to 0 ℃, and was added dropwise CH ₃ MgBr (3M in Et ₂ O in; 1mL; 3mmol). The solution was stirred at 0 ° C for 30 min and allowed to slowly rise to room temperature for 6 hours. The solution was poured into cold water and saturated aqueous NH ₄ Cl mixture, and then add the EtOAc. The mixture was filtered through a pad of Celite ^®, and extracted with EtOAc. The organic layer was dried over MgSO _4, filtered and evaporated to dryness. The residue was subjected to silica gel chromatography (irregular SiOH, 24 g; mobile phase: gradient from 0% NH ₄ OH, 0% MeOH, 100% DCM to 0.5% NH ₄ OH, 5% MeOH, 95% DCM). purification. Pure fractions were collected and evaporated to dryness to yield 130 mg (50%) of compound 197. These mirror image isomers were separated by chiral SFC (Lux cellulose-45 μm 250 * 21.2 mm; mobile phase: 60% CO ₂ , 40% MeOH (+ 0.3% iPrNH ₂ )). Pure fractions were collected, evaporated and lyophilized from water / ACN (80/20) to yield 46 mg (17%) of compound 198 and 45 mg (17%) of compound 199.

Using a similar method to that described for the preparation of compound 274, starting with the respective starting materials, the compounds in the table below were prepared.

Example B44

Compound 195 Preparation

Hydrazine monohydrate (34 μL; 0.86 mmol) was added to a solution of intermediate 85 (100 mg; 0.17 mmol) in EtOH (4 mL). The solution was heated at 50 ° C for 2h 30min. The reaction mixture was poured into ice water and extracted with DCM. The organic layer was separated, dried over MgSO _4, filtered, and evaporated till dryness. The residue was purified by silica gel chromatography (irregular SiOH, 12 g; mobile phase: 90% DCM, 10% MeOH (+ 10% NH ₄ OH)). The pure fractions were collected and evaporated to dryness. The residue was taken up with Et ₂ O and evaporated to dryness to give 35 mg (45%) of compound 195.

Example B45

Compound 287 Preparation of compound 201

And compound 202

A mixture of intermediate 87 (145 mg; 0.24 mmol) and TFA (0.7 mL; 9.15 mmol) in DCM (7 mL) was stirred at room temperature overnight. The reaction mixture was evaporated to dryness. The residue was diluted with DCM and then with H ₂ O and basified with aqueous NaOH 3N. The organic layer was decanted, dried over MgSO _4, filtered and evaporated to yield compound 287 was dried 100mg (83%) of.

Mirror isomers were separated by chiral SFC (CHIRALPAK IC 5 μm 250 x 20 mm; mobile phase: 50% CO ₂ , 50% MeOH (+ 2% iPrNH ₂ )). The fractions containing each mirror image isomer were collected, evaporated to dryness and subjected to reversed phase chromatography (YMC-actus Triart-C18 10 μm 30 * 150 mm; mobile phase: gradient from 75% NH ₄ HCO ₃ 0.2%, 25 % ACN to 35% NH ₄ HCO ₃ 0.2%, 65% ACN). Pure fractions were collected, evaporated to dryness and freeze dried from ACN / water (20/80) to yield 21 mg (17%) of compound 201 and 23 mg (19%) of compound 202.

Example B46

Compound 224 Preparation of compound 251

And compound 252

A mixture of intermediate 11b (1 g) and 5-acetamidin-1-methylpyrazole (168 mg, 1.35 mmol) in THF (15 mL) was stirred at room temperature under N ₂ overnight. Then, NaBH (OAc) ₃ (718 mg; 3.4 mmol) was added in portions. The reaction mixture was stirred at room temperature for 72 h, poured into cold water, basified with K ₂ CO ₃ powder, and extracted with EtOAc. The organic layer was dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (irregular SiOH, 12 g; mobile phase: gradient from 100% DCM, 0% MeOH to 95% DCM, 5% MeOH, 0.3% NH ₄ OH). The fractions were collected and evaporated to dryness. The residue (300mg) was subjected to reversed phase chromatography (YMC-actus Triart C18 10μm 30 * 150mm; mobile phase: gradient from 65% NH ₄ HCO ₃ 0.2% aqueous solution, 35% ACN to 25% NH ₄ HCO ₃ 0.2% aqueous solution, 75% ACN) was purified a second time. The pure fractions were collected and evaporated to dryness to yield 104 mg of compound 224.

Compound 224 was subjected to chiral SFC separation ((stationary phase: ChiralcelOD-H 5 μm 250 x 21.2 mm, mobile phase: 70% CO2, 30% EtOH (0.3% iPrNH ₂ )).

This fraction containing the product was mixed, concentrated and freeze-dried (ACN / water: 80/20) to provide 48 mg of compound 251 and 46 mg of compound 252.

Using a similar method to that described for the preparation of compound 224, starting with the respective starting materials, the compounds in the table below were prepared.

Example B47

Compound 234 Preparation

At room temperature, intermediate 88 (130 mg; 0.225 mmol) and (0.7 mL; 2.8 mmol) of a mixture of HCl 4M in MeOH (7 mL) was stirred for 24 hours. The solution was cooled at 5 ° C and Et ₂ O was added. The precipitate was filtered and dried to give 111 mg of compound 234 (HCl salt).

Example B48

Compound 270 Preparation

And compound 271

A mixture of intermediate 11 (300 mg; 0.854 mmol) and (R) -styrene oxide (293 μL; 2.563 mmol) in EtOH (6 mL) was stirred at 60 ° C. for 4 hours. The reaction mixture was evaporated to dryness and the residue was subjected to silica gel chromatography (irregular SiOH, 12 g; mobile phase: gradient from 0% NH ₄ OH, 0% MeOH, 100% DCM to 1% NH ₄ OH, 10% MeOH, 90% DCM). The fractions containing the product were collected and evaporated to dryness to yield 157 mg of intermediate residue. The residue was subjected to reversed phase chromatography (YMC-actus Triart C18 10 μm 30 * 150 mm; mobile phase: gradient from 60% NH ₄ HCO ₃ 0.2% aqueous solution, 40% ACN to 40% NH ₄ HCO ₃ 0.2% aqueous solution, 60% ACN) for purification. This fraction containing the product was collected, evaporated to dryness and freeze dried from water / ACN (80/20; 10 mL) to yield 58 mg (15%) of compound 270 and 62 mg (16%) of compound 271.

Example B50

Compound 105 Preparation

TFA (2.5 mL) was added to a solution of intermediate 93 (500 mg; 0.95 mmol) in DCM (25 mL), and the reaction mixture was stirred for 18 hours. The reaction mixture was poured into 10% K ₂ CO ₃ aqueous solution and extracted with DCM. The organic layer was separated, dried over Chromabond ^® filtered, and evaporated to dryness. The residue was purified by silica gel chromatography (Irregular SiOH, 10g; mobile _{phase: 0.7% NH 4 OH, 7} % MeOH, 93% DCM) was purified. The pure fractions were collected and evaporated to dryness. The residue was crystallized from diisopropyl ether and dried to give 120 mg (29%) of compound 105.

Using a method similar to that described for the preparation of compound 105, starting with the respective starting materials, the compounds in the table below were prepared.

Example B51

Compound 89 Preparation

Will be at 1,4-two (0.708 mL; 2.833 mmol) was added to a solution of intermediate 101 (150 mg; 0.283 mmol) in ACN (7.5 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 10% K ₂ CO ₃ aqueous solution and extracted with DCM. The organic layer was decanted, filtered through chromabond ^® and evaporated to dryness. The residue was purified by silica gel chromatography (irregular SiOH, 12 g; mobile phase: gradient from 0% MeOH, 100% DCM to 15% MeOH, 85% DCM). The pure fractions were collected and evaporated to dryness. The residue was taken up several times with Et ₂ O to yield 30 mg (25%) of compound 89.

Using a similar method to that described for the preparation of compound 89, starting with the respective starting materials, the compounds in the table below were prepared.

Example B56

Preparation of compound 317:

Intermediate 11 (266 mg, 0.812 mmol), intermediate 110 (377 mg, 1.62 mmol) and K ₂ CO ₃ were stirred at 90 ° C. in ACN (8 mL) overnight. The mixture was poured into water and then extracted with EtOAc. The organic layer was dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (stationary phase: irregular SiOH 15 μm to 40 μm 40 g, mobile phase: DCM / MeOH: gradient from 100/0 to 92/8). The residue was reversed by silica gel chromatography (stationary phase: YMC-actus Triart-C18 10 μm 30 * 150 mm, mobile phase: 0.2% NH ₄ HCO ₃ / ACN: gradient from 60/40 to 0/100) Perform purification. The product containing fractions were collected and evaporated to dryness. The obtained residue was dissolved in ACN, and 2 equivalents of 4N HCl solution. The mixture was concentrated and then freeze-dried with acetonitrile / water 20/80 to yield 0.091 g of compound 317 (HCl salt).

Example B57

Compound 320 Preparation

To a solution of intermediate 11b (200 mg) in ethanol (5 mL) was added 1- (3-methoxyphenyl) propan-2-one (200 mg, 1.218 mmol), PtO ₂ (20 mg), and AcOH (2 drops) . After stirring under H ₂ at 60 ° C. overnight, the reaction mixture was concentrated to give a residue, which was subjected to preparative HPLC (column: SunFire 19 * 250mm 10um, mobile phase A: 0.1% TFA / H ₂ O, B: ACN) was purified to give 35mg (12%) as a yellow solid compound 320.

Using a similar method to that described for the preparation of compound 320, starting with the respective starting materials, the compounds in the table below were prepared.

Example B57

Compound 61 was synthesized with intermediates 68, 68a, and 68b. See synthetic schemes for intermediates 68, 68a and 68b.

Conversion

Transformation C1

Compound 196 Preparation

A solution of compound 273 (106 mg; 0.24 mmol), aqueous formaldehyde 37% w / w (110 μL; 1.48 mmol), and MgSO ₄ (580 mg; 4.83 mmol) in DCM (5 mL) was stirred at room temperature for 1 hour. NaBH (OAc) ₃ (614 mg; 2.9 mmol) was added, and the reaction mixture was stirred at room temperature for 15 hours. The solution was poured into ice water, basified with K ₂ CO _3, and extracted with DCM (x2). The organic layer was washed with brine, dried over MgSO _4, filtered and evaporated to dryness. The residue was subjected to silica gel chromatography (irregular SiOH, 10 g, mobile phase: gradient from 100% DCM, 0% MeOH, 0% NH ₄ OH to 90% DCM, 10% MeOH, 0.5% NH ₄ OH). purification. Pure fractions were collected, evaporated to dryness and the residue was freeze-dried from ACN / water (20/80) to yield 70 mg (64%) of compound 196.

Using a method similar to that described for the preparation of compound 196, starting with the respective starting materials, the compounds in the table below were prepared.

Transformation C2

Compound 216 Preparation

A solution of compound 200 (110 mg; 0.25 mmol) and aqueous formaldehyde 37% w / w (19 μL; 0.25 mmol) in MeOH (5 mL) was stirred at room temperature for 3 hours. Add NaBH ₄ (19mg; 0.5mmol), and the reaction mixture was stirred at room temperature for 15 hours, poured into ice water, basified with K ₂ CO _3, and extracted with DCM (x2). The organic layer was washed with brine, then dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (irregular SiOH 300 g; mobile phase: gradient from 0.1% NH ₄ OH, 5% MeOH, 95% DCM to 1% NH ₄ OH, 10% MeOH, 90% DCM) . Pure fractions were collected, evaporated to dryness, and freeze-dried from ACN / water 20/80 to yield 15 mg (13%) of compound 216.

Transformation C3

Compound 303 Preparation

Under N ₂ , bromoethyl (45 μL; 0.6 mmol) was added to a solution of compound 222 (150 mg; 0.34 mmol) and DIPEA (207 μL; 1.2 mmol) in THF (3 mL) at 10 ° C. The solution was stirred at room temperature overnight and then poured into cold water. The product was extracted with EtOAc. The organic layer was dried over MgSO _4, filtered and evaporated to dryness. The residue (164 mg) was subjected to silica gel chromatography (stationary phase: 12 g of irregular naked silica), mobile phase: gradient from 100% DCM, 0% MeOH (+ 10% NH ₄ OH) to 90% DCM, 10% _{MeOH (+ 10% NH 4 OH} )) for purification. This fraction containing the product was mixed and concentrated to provide 77 mg of the intermediate fraction. The intermediate fraction was reversed-phase (stationary phase: YMC-actus Triart C18 10 μm 30 * 150 mm, mobile phase: gradient from 65% NH ₄ HCO ₃ 0.2%, 35% ACN to 25% NH ₄ HCO ₃ 0.2%, 75% ACN) for further purification. This fraction containing the product was mixed and concentrated to provide a residue of 40 mg, whose residue was freeze-dried with acetonitrile / water 20/80 to give 34 mg (21%) of compound 303 as a white powder.

Transformation C4

Compound 316 Preparation

A solution of compound 315 (114 mg; 0.237 mmol), formaldehyde (37% in water) (106 μL; 1.42 mmol), and MgSO ₄ (568 mg) in DCM (5 mL) was stirred at room temperature for 1 hour. Then, _{NaBH (OAc) 3 (602mg;} 2.84mmol) and the mixture was stirred overnight at room temperature the reaction mixture was diluted with DCM, and with ₂ CO ₃ and the aqueous solution basified with 10% K.. The organic layer was decanted, dried over MgSO _4, filtered and evaporated to dryness. The residue was subjected to silica gel chromatography (irregular SiOH, 12 g; mobile phase: gradient from 0% NH ₄ OH, 0% MeOH, 100% DCM to 1% NH ₄ OH, 10% MeOH, 90% DCM). purification. This fraction containing the product was collected, evaporated to dryness and freeze-dried from water / ACN (80/20; 10 mL) to yield 110 mg (94%) of compound 316.

Analysis section

LCMS (liquid chromatography / mass spectrometry)

Universal program

High performance liquid chromatography (HPLC) measurements were performed using an LC pump, a diode array (DAD) or UV detector, and a column as specified in the corresponding method. Include additional detectors if necessary (see method table below).

Bring the flow from the column to a mass spectrometer (MS) equipped with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set tuning parameters (e.g. scan range, dwell time, etc.) in order to obtain ions that allow identification of compounds with a nominal single isotope molecular weight (MW). Use appropriate software for data acquisition.

Compounds are described by their experimental retention time (R _t ) and ions. If not specified differently in the data sheet, the reported molecular ions correspond to [M + H] ⁺ (protonated molecule) and / or [MH] ^- (deprotonated molecule). In the case where the compound is ionizable can not directly specify the type of the adduct (i.e., ^{_{[M + NH 4] +,}} [M + HCOO] - , etc.). For molecules with multiple isotopic patterns (Br, Cl, etc.), the reported values are those obtained for the lowest isotope mass. All results obtained have experimental uncertainties that are usually related to the method used.

In the following, "SQD" means single quadrupole detector, "RT" room temperature, "BEH" bridged ethylsiloxane / silica dioxide hybrid, "HSS" high-strength silicon dioxide, "DAD" Polar Body Array Detector. All other abbreviations used are as defined above.

SFCMS-Method

General procedure for SFC-MS method

SFC measurements were performed using an analytical supercritical fluid chromatography (SFC) system consisting of a binary pump for the delivery of carbon dioxide (CO ₂ ) and modifiers, an autosampler, a column oven, equipped with Diode array detector capable of withstanding a high pressure flow cell of 400 bar. If configured with a mass spectrometer (MS), the flow from the column is directed to the (MS). It is within the knowledge of the skilled person to set tuning parameters (such as scan range, dwell time, etc.) in order to obtain ions of a nominal single isotope molecular weight (MW) that allow identification of the compound. Use appropriate software for data acquisition.

SFC-MS was also measured for compounds 188, 189, 190, and 191 under the same SFCMS conditions. The results are shown in Table 2c. (Isomeric eluting sequence 'A' precedes 'B', 'B' precedes 'C', and 'C' precedes 'D')

Optical rotation (OR)

The optical rotation was measured with a polarimeter 341 Perkin Elmer. Polarized light was passed through the sample with a path length of 1 decimeter and a sample concentration of 0.2 to 0.4 g / 100 ml. The product in a 2 mg to 4 mg vial is weighed and then dissolved with 1 ml to 1.2 ml of a spectral solvent such as DMF. The battery was filled with the solution and put into a polarimeter at a temperature of 20 ° C. Read the OR with an accuracy of 0.004 °.

Calculation of concentration: weight in grams x 100 / volume (in ml)

Specific rotation (OR): [α] _d ²⁰ : (optical rotation reading x 100) / (1.000dm x concentration).

^d is the sodium D line (589 nm).

NMR

NMR tests were performed using a Bruker Avance 500 spectrometer (equipped with a Bruker 5mm BBFO probe with z gradient) and working at 500 MHz for protons and 125 MHz for carbon, or using a Bruker Avance DRX 400 spectrometer, using internal deuterium Locked and equipped with a reverse dual resonance ( ¹ H, ¹³ C, SEI) probe with a z-gradient, and works at 400 MHz for protons and 100 MHz for carbon. Chemical shifts (δ) are reported in parts per million (ppm). The J value is expressed in Hz. Alternatively, some NMR tests were performed using the following instrument: at ambient temperature (298.6K) using a Bruker Avance III 400 spectrometer, using internal deuterium lock, and equipped with a 5mm PABBO BB-probe with z gradient, and for protons at 400 MHz And work at 100 MHz for carbon. Chemical shifts (δ) are reported in parts per million (ppm). The J value is expressed in Hz.

Compound 13: 1H NMR (400MHz, chloroform-d) δ ppm 8.42 (s, 1H), 7.38 (s, 1H), 3.95 (br s, 2H), 3.83 (br t, J = 6.6 Hz, 2H), 3.63 (q, J = 10.1Hz, 2H), 3.27 (br s, 4H), 2.32 (d, J = 6.8Hz, 2H), 2.28-2.18 (m, 2H), 1.69-1.57 (m, 1H), 0.90 (d, J = 6.6Hz, 6H)

Compound 20b: ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 11.64 (br s, 1H) 8.49 (s, 1H) 7.77 (s, 1H) 7.67 (br d, J = 3.8 Hz, 2H) 7.35-7.51 (m, 3H) 4.32-4.48 (m, 2H) 4.03-4.18 (m, 2H) 3.91 (br s, 4H) 3.17-3.61 (m, 4H) 2.00-2.32 (m, 4H)

Compound 82: ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.35 (s, 1H) 7.39 (s, 1H) 4.28-4.77 (m, 6H) 4.01-4.19 (m, 4H) 3.62 (br t, J = 7.9Hz, 1H) 2.88 (dd, J = 9.9,6.8Hz, 1H) 2.45 (br dd, J = 9.9,7.7Hz, 1H) 2.00-2.21 (m, 2H) 1.17-1.28 (m, 1H) 0.95 (d, J = 6.3Hz, 3H)

Compound 84: ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.33 (s, 1H) 7.72 (s, 1H) 7.22 (dd, J = 8.4, 5.8 Hz, 2H) 7.09 (t, J = 9.0 Hz, 2H) 4.08 (q, J = 11.0Hz, 2H) 3.66-3.96 (m, 4H) 3.17 (s, 4H) 2.65-2.73 (m, 1H) 2.38-2.45 (m, 1H) 2.27 (dd, J = 12.9 , 8.5Hz, 1H) 2.14 (br s, 2H) 0.72 (d, J = 6.3Hz, 3H)

Compound 193: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.32 (s, 1H) 7.70 (s, 1H) 4.07 (q, J = 11.1 Hz, 2H) 3.65-3.91 (m, 6H) 3.07-3.30 (m, 6H) 2.14 (br s, 2H) 1.85 (br s, 1H) 1.70-1.82 (m, 1H) 1.63 (br s, 1H) 1.28-1.52 (m, 4H) 0.88 (dd, J = 9.6, 7.1Hz, 6H)

Compound 196: ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.32 (s, 1H) 7.70 (s, 1H) 4.07 (q, J = 10.9 Hz, 2H) 3.52-3.97 (m, 4H) 3.34-3.43 (m, 2H) 3.02-3.22 (m, 4H) 2.72 (dd, J = 8.5,6.3Hz, 1H) 2.58 (dd, J = 8.8,6.6Hz, 1H) 2.51-2.53 (m, 1H) 2.28-2.35 (m, 1H) 2.19 (dd, J = 9.5,2.2Hz, 1H) 2.12 (s, 4H) 1.58 (td, J = 7.1,2.2Hz, 1H) 0.79 (dd, J = 14.8,6.9Hz, 6H)

Compound 273: ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.32 (s, 1H) 7.67 (s, 1H) 4.03 (q, J = 11.0 Hz, 2H) 3.87 (s, 2H) 3.79 (t, J = 6.9Hz, 2H) 3.61 (br t, J = 7.6Hz, 1H) 3.46 (br t, J = 7.9Hz, 1H) 3.12-3.34 (m, 7H) 2.66-2.77 (m, 1H) 2.28 (dd, J = 9.1, 2.2 Hz, 1H) 2.15 (t, J = 6.9 Hz, 2H) 1.62 (td, J = 6.9, 2.2 Hz, 1H) 0.82 (dd, J = 14.2, 6.9 Hz, 6H)

Compound 274: ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.31 (s, 1H) 7.69 (s, 1H) 7.45 (s, 1H) 7.20 (s, 1H) 4.07 (q, J = 10.9 Hz, 2H ) 3.58-3.93 (m, 7H) 2.97-3.08 (m, 4H) 2.52-2.55 (m, 1H) 2.12 (br s, 2H) 1.7 (td, J = 6.6,4.4Hz, 1H) 0.70 (dd, J (= 12.6, 6.6Hz, 6H)

Compound 320: 1H NMR (400 MHz, CD ₃ OD) δ 8.37 (s, 1H), 7.63 (s, 1H), 7.28 (t, J = 8.8 Hz, 1H), 6.87-6.86 (m, 3H), 4.30-4.18 (m, 5H), 4.08-3.93 (m, 3H), 3.91-3.88 (m, 2H), 3.88-3.85 (s, 3H), 3.72-3.70 (m, 1H), 3.06 (dd, J = 5.2Hz , J = 13.6Hz, 1H), 2.64 (dd, J = 9.2Hz, J = 13.6Hz, 1H), 2.47-2.385 (m, 2H), 1.19-1.18 (d, J = 6.8Hz 3H)

Compound 321: ¹ H NMR (400 MHz, DMSO) δ 8.38 (d, J = 5.2 Hz 1 H), 7.65 (s, 1 H), 7.21 (d, J = 8.4 Hz, 2 H), 6.92 (d, J = 8.4 Hz , 2H), 3.75-4.33 (m, 11H), 3.74 (s, 3H), 3.61 (s, 1H), 2.93 (dd, J = 3.6Hz, 12.8Hz, 1H), 2.27-2.36 (m, 2H, ), 1.03 (d, J = 5.6Hz, 3H).

Compound 322: ¹ H NMR (400 MHz, CD ₃ OD) δ 8.40 (s, 1H), 7.66 (s, 1H), 7.38-7.34 (m, 2H), 7.22-1.13 (m, 2H), 4.37-4.26 ( m, 5H), 4.13 (s, 1H), 4.01 (s, 2H), 3.91 (q, J = 10.4Hz, 2H), 3.74-3.69 (m, 1H), 2.98 (dd, J = 3.6Hz, 13.2 Hz 1H), 2.68 (dd, J = 9.6Hz, 13.2Hz 1H), 2.47 (s, 2H), 1.20 (d, J = 6.4Hz 3H).

Compound 323: ¹ HNMR (400MHz, CD ₃ OD) δ 8.38 (s, 1H), 7.64 (s, 1H), 7.10 (d, J = 8.4Hz, 2H), 6.78 (d, J = 8.4Hz, 2H) , 3.86-7.27 (m, 10H), 3.60-6.62 (m, 1H), 2.96 (dd, J = 4.8Hz, 14.0Hz, 1H), 2.60 (dd, J = 4.8Hz, 14.0Hz1H), 2.37-2.46 (m, 2H), 1.18 (d, J = 6.8 Hz, 3H).

Compound 324: 1H NMR (400MHz, CD ₃ OD) δ 8.36 (s, 1H), 7.62 (s, 1H), 7.19-7.15 (m, 4H), 4.28-4.16 (m, 5H), 4.14-3.98 (m , 4H), 3.93-3.87 (m, 2H), 3.66-3.64 (m, 1H), 3.04 (dd, J = 4.8Hz, J = 13.6Hz, 1H), 2.63 (dd, J = 9.2Hz, J = 13.6Hz 1H), 2.46-2.32 (m, 5H), 1.18 (d, J = 6.4Hz, 3H).

Pharmacology

1) Menin / MLL fluorescence polarization measurement

To a non-surface bound, black 384-well microtiter plate was added 50 nL of 160X test compound in DMSO and 4 μL in assay buffer (40 mM Tris.HCl, pH 7.5, 50 mM NaCl, 1 mM DTT and 0.001% Tween 20). 2X menin. After incubating the test compound and menin for 10 min at ambient temperature, 4 μL of 2X FITC-MBM1 peptide (FITC-β-alanine-SARWRFPARPGT-NH ₂ ) in the assay buffer was added, and the microtiter plate was centrifuged at 1000 rpm for 1 min. And the assay mixture was incubated at ambient temperature for 15 min. At ambient temperature, the presence of menin in the assay mixture was determined by measuring FITC-labeled fluorescence polarization (FP) with a BMG Pherastar plate reader (ex. 485nm / em. 520nm). Relative amount of FITC-MBM1 complex. The final concentration of the reagents in the binding assay was 100 nM menin, 5 nM FITC-MBM1 peptide and 0.625% DMSO in the assay buffer. A dose-response titration of test compounds was started at 31 μM using an 11-point, three-fold serial dilution scheme.

Compound efficacy was determined by first calculating the% inhibition at each compound concentration according to the following formula 1:% inhibition = ((HC-LC)-(FP ^compound- LC)) / (HC-LC)) * 100 ( formula 1 )

The LC and HC based FP values were determined in the presence or absence of the saturated concentration of the compound, the compound competed with FITC-MBM1 for menin binding, and the FP value was measured with the FP ^compound in the presence of the test compound. HC and LC FP values represent the average of at least 16 replicates / plate. For each test compound, the% inhibition value is plotted against the logarithm of the test compound concentration, and the IC ₅₀ value is derived from fitting these data according to formula 2:% inhibition = bottom + (top-bottom) / (1 + 10 ^ ( (log IC ₅₀ -log [cmpd]) * h )) ( Equation 2 )

The bottom and top are the lower and higher asymptotes of the dose-response curve, the IC ₅₀ is the concentration of the compound that produces 50% signal suppression, and the h is the Hill coefficient.

2) proliferation assay

The antiproliferative effects of menin / MLL protein / protein interaction inhibitor test compounds were evaluated in human leukemia cell lines. The cell lines MV-4-11 and MOLM14 carry MLL translocations and express the MLL fusion proteins MLL-AF4 and MLL-AF9, respectively, and wild-type proteins from the second allele. Therefore, the MLL rearranged cell lines MV-4-11 and MOLM14 display stem cell-like HOXA / MEIS1 gene expression markers. K562 and KG1 were used as control cell lines containing two MLL wild-type alleles to facilitate the exclusion of compounds showing general cytotoxic effects.

MV-4-11 and MOLM14 were supplemented with 10% fetal bovine serum (HyClone), 2mM L-glutamine (Sigma Aldrich), and 50 μg / ml gentamicin (Gibco). RPMI-1640 (Sigma-Aldrich). K562 was added to RPMI supplemented with 20% fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma Aldrich), and 50 μg / ml gentamicin (Gibco) -1640 (Sigma-Aldrich). KG1 was added to Iscove's supplemented with 20% fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma Aldrich) and 50 μg / ml gentamicin (Gibco) Culture was performed in MDM (Gibco). Cells were maintained at 0.3 to 2.5 million cells / ml during culture, and the number of passages did not exceed 25.

To evaluate the anti-proliferative effect, 1,500MV-4-11, 300MOLM14, 750K562, or 1,300KG1 cells were seeded at 200 μl medium / well in a 96-well round bottom, ultra-low attachment plate (Costar, catalog number 7007). The number of cell seedings was selected based on the growth curve to ensure linear growth throughout the experiment. Test compounds were added at different concentrations and the DMSO content was normalized to 0.3%. The cells were incubated for 8 d at 37 ° C and 5% CO ₂ . Spheroid-like growth was monitored in real time by live-cell imaging (IncuCyteZOOM, Essenbio, 4x objective lens), and images were acquired every four hours for 8 days. The degree of fusion (%) as a measure of spherical size was determined using an integrated analysis tool.

To determine the cumulative effect of the test compound over time, the area under the curve (AUC) in the plot of fusion versus time was calculated. The degree of fusion was used as a baseline for AUC calculations at the beginning of the trial (t = 0).

Calculate the absolute IC ₅₀ value according to the following method:% control = (AUC sample / AUC control) * 100

AUC control = average AUC of control values (cells without compound / DMSO as vehicle control)

A non-linear curve fit was applied to the plot of% control versus compound concentration using the least squares (general) fitting method. Based on this, an absolute IC ₅₀ value (relative to the vehicle control, half the maximum inhibitory concentration of the test compound causing 50% of the anti-proliferative effect relative to the vehicle control) was calculated.

3) Menin / MLL homogeneous time-resolved fluorescence (HTRF) measurement

To an untreated, white 384-well microtiter plate was added 40nL 200X test compound in DMSO and in assay buffer (40mM Tris.HCl. PH 7.5, 50mM NaCl, 1mM DTT and 0.05% Pluronic F-127 4 μL of 2X 鋱 chelate-labeled menin (see below for preparation). After incubating the test compound and tritium chelate-labeled menin for 5 minutes at ambient temperature, 4 μL of 2X FITC-MBM1 peptide (FITC-β-alanine-SARWRFPARPGT-NH ₂ ) in measurement buffer was added, and the test compound was added at 1000 rpm. The microtiter plate was centrifuged for 1 min, and the assay mixture was incubated at ambient temperature for 15 min. At ambient temperature, a BMG Pherastar plate reader (ex. 337nm / 鋱 em. 490nm / FITC em. 520nm) was used to measure the homogeneous time-resolved fluorescence (HTRF) of the 鋱 / FITC donor / acceptor fluorescence pair. ) To determine the presence of menin in the assay mixture. Relative amount of FITC-MBM1 complex. The degree of fluorescence resonance energy transfer (HTRF value) is expressed as the ratio of the fluorescence emission intensity of FITC and the fluorene fluorescence ( F ^em 520 nm / F ^em 490 nm). The final concentration of the reagents in the binding assay was 100 pM tritium chelate-labeled menin, 75 nM FITC-MBM1 peptide, and 0.5% DMSO in the assay buffer. A dose-response titration of test compounds was started at 31 μM using an 11-point, three-fold serial dilution scheme.

Compound potency was determined by first calculating the% inhibition at each compound concentration according to the following formula 1:% inhibition = ((HC-LC)-(HTRF ^compound- LC)) / (HC-LC)) * 100 ( formula 1 )

The HTRF value of LC and HC based on the presence or absence of the saturated concentration of the compound, the compound competes with FITC-MBM1 for binding to menin, and the HTRF value is measured with the HTRF ^compound in the presence of the test compound. HC and LC HTRF values represent the average of at least 16 replicates / plate. For each test compound, the% inhibition value is plotted against the logarithm of the test compound concentration, and the IC ₅₀ value is derived from fitting these data according to formula 2:% inhibition = bottom + (top-bottom) / (1 + 10 ^ ( (log IC ₅₀ -log [cmpd]) * h )) ( Equation 2 )

The bottom and top are the lower and higher asymptotes of the dose-response curve, respectively, the IC ₅₀ is the concentration of the compound that produces 50% signal suppression, and h is the Hill coefficient.

Preparation of Menin's acupoint compound label: Menin (a.a.1-610-6xhis tag) was labeled with a acupoint compound as follows. 2mg Menin's buffer was exchanged for 1x phosphate buffered saline. 16 uM Menin was incubated with a 4-fold molar excess of NHS- 过量 acupoint compound (Cisbio Bioassays, Bedford, Massachusetts) at room temperature for 2 hours. The labeled protein was passed through a Superdex 200 Increase 10/300 GL column at 0.75 ml / min. The run was purified and clarified from the free label. Peak fractions were collected, aliquoted and frozen at -80 ° C.

MENIN protein sequence (SEQ ID NO: 1):

<110> Belgian Shangjiansheng Pharmaceutical Company

<120> Spirobicyclic inhibitor of MENIN-MLL interaction

<130> JAB6091

<150> EP16192431.1

<151> 2016-10-05

<150> US62 / 394295

<151> 2016-09-14

<160> 1

<170> BiSSAP 1.3.6

<210> 1

<211> 616

<212> PRT

<213> Artificial sequence

<220>

<223> His-tagged MENIN protein sequence

<400> 1

Claims (18)

A compound having formula (I) Or tautomers or stereoisomeric forms thereof, 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 ; L ¹ represents a 7- to 10-membered saturated spiro heterobicyclic system containing one or two N atoms, provided that it is N-connected to a thienopyrimidinyl heterocyclic ring; and --L ^2- R ^{3 is} selected from (a), (b), (c), (d), (e), (f), or (g), wherein (a) L ^{2 is} selected from the group consisting of:> SO ₂ ,> CR ^4a R ^4b , and -CHR ^4a CHR ^5- ; where (i) when L ^{2 is} connected to the carbon atom of L ¹ , then R ^4a and R ⁵ are each independently selected from the group consisting of Group: hydrogen; -OR ⁶ ; -NR ^7a R ^7b ; -C (= O) NR ^7a R ^7b ; optionally a C _1-4 alkyl group substituted with a substituent selected from the group consisting of Composition: fluorine, -CN, -OR ⁸ , and -NR ^9a R ^9b ; and a C-linked 4- to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen, or sulfur atom; (ii) when L L ² is connected to ^a nitrogen atom, then R ^4a is selected from the group consisting of: ^{hydrogen; -C (= O) NR 7a} R 7b; is selected from optionally Substituted with C _1-4 alkyl group, the group consisting of: fluorine, -CN, -OR ^8, and -NR ^9a R ^9b; C and containing at least one nitrogen, oxygen or sulfur atom -A connected 4- to 7-membered non-aromatic heterocyclic group; R ^{5 is} selected from the group consisting of: hydrogen; -OR ⁶ ; -NR ^7a R ^7b ; -C (= O) NR ^7a R ^7b ; optionally substituted is selected from the group C _1-4 alkyl group substituted with the group consisting of: fluorine, -CN, -OR ^8, and -NR ^9a R ^9b; and containing at least one nitrogen, oxygen Or a C-linked 4- to 7-membered non-aromatic heterocyclic group of a sulfur atom; R ^{4b is} selected from the group consisting of: hydrogen and methyl; or R ^4a and R ^4b together with the carbon to which they are attached The atoms together form a C _3-5 cycloalkyl or C-linked 4- to 6-membered heterocyclic group containing an oxygen atom; wherein R ⁶ , R ^7a , R ^7b , R ⁸ , R ^9a and R ^9b are each independently selected A group consisting of: hydrogen; a C _1-4 alkyl group optionally substituted with a substituent selected from the group consisting of fluorine, -CN, and -C (= O) NR ^10a R ^10b; and is selected from the group of substituents of C _2-4 alkyl, which Consisting of: -OR ¹¹ and -NR ^10a R ^10b; wherein R ^10a, R ^10b and R ¹¹ are each independently selected from the group consisting of: hydrogen; C _1-4 alkyl; and containing at least A C-linked 4- to 7-membered non-aromatic heterocyclic group of one nitrogen, oxygen or sulfur atom; and R ^{3 is} selected from the group consisting of: Ar, Het ¹ , Het ² , and 7 to 10 members A saturated spiro-carbon bicyclic ring system; or (b) L ^{2 is} selected from the group consisting of:> CR ^4c R ^4d and -CHR ^4c CHR ^5a- , wherein R ^4c , R ^4d , and R ^5a are each independently Is selected from the group consisting of: hydrogen and C _1-4 alkyl; and R ^{3 is} selected from the group consisting of: with ; Wherein R ^12a , R ^12b , and R ^12c are each independently selected from the group consisting of: a C _1-6 alkyl group optionally substituted with -OH or -NH ₂ substituent; and -OC _1-6 Alkyl; or (c)-L ² -R ³ is a C _1-6 alkyl optionally substituted with one, two, or three fluorine substituents; or (d) L ² is O, and R ^{3 is} selected A group consisting of: a C _3-6 alkyl group optionally substituted with one, two, or three fluoro substituents; Ar; Het ¹ ; Het ² ; 7- to 10-membered saturated spirocarbon bicyclic ring system -CH ₂ -Ar; -CH ₂ -Het ¹ ; -CH ₂ -Het ² ; and -CH _2- (7 to 10-membered saturated spiro-carbon bicyclic ring system); when L ^{2 is} connected to the carbon atom of L ¹ Or (e)-L ² -R ³ is -O-CHR ⁵ -R ³ , when L ^{2 is} connected to the carbon atom of L ¹ , wherein R ^{5 is} selected from the group consisting of: -C (= O) NR ^13a R ^13b ; a C _1-4 alkyl group optionally substituted by a substituent selected from the group consisting of: fluorine, -OR ¹⁴ , and -NR ^15a R ^15b ; and C- 4 containing at least one nitrogen, oxygen or sulfur atom attached to the 7-membered non-aromatic heterocyclic group; wherein ^{R 13a, R 13b, R 14} , R 15a and R ^15b are each Site selected from the group consisting of: hydrogen; optionally substituted group selected from C _1-4 alkyl group substituted by the group consisting of: fluorine and -C (= O) NR ^16a R ^16b ; and C _2-4 alkyl substituted with a substituent selected from the group consisting of -OR ¹⁷ and -NR ^16a R ^16b ; wherein R ^16a , R ^16b and R ¹⁷ are each independently Ground is selected from the group consisting of: hydrogen; C _1-4 alkyl; and a C-linked 4- to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen, or sulfur atom; and R ³ Selected from the group consisting of: hydrogen; C _1-4 alkyl optionally substituted with one, two, or three fluoro substituents; -CN; Ar; Het ¹ ; Het ² ; and 7 to 10 -Membered saturated spiro-carbon bicyclic ring system; or (f)-L ² -R ³ series , Wherein R ^{18 is} selected from the group consisting of: hydrogen; C _1-4 alkyl optionally substituted with fluorine or -CN substituent; and C _2-4 alkyl substituted with substituent selected from This group consists of the following: -OR ¹⁹ and -NR ^20a R ^20b ; wherein R ¹⁹ , R ^20a and R ^20b are each independently selected from the group consisting of: hydrogen; and optionally, selected from the following: C _1-4 alkyl substituted with substituents of the group consisting of: fluorine, -CN and -C (= O) NR ^21a R ^21b ; C _2- substituted with substituents selected from the group _4- alkyl, the group consisting of: -OR ²² and NR ^21a R ^21b ; and a C-linked 4- to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen or sulfur atom; wherein R ^21a , R ^21b, and R ²² are each independently selected from the group consisting of: hydrogen and C _1-4 alkyl; and R ^{18a is} selected from the group consisting of: hydrogen, fluorine, and C _1-4 Alkyl; R ^{18b is} selected from the group consisting of: fluorine, -OC _1-4 alkyl, and optionally C _1-4 alkyl substituted with 1, 2, or 3 fluorine substituents; or R ^18a and R ^{18b is} bonded to the same carbon atom and forms a C _3-5 ring together An alkyl group or a C-linked 4- to 6-membered heterocyclic group containing an oxygen atom; or (g)-L ² -R ³ system or And wherein Ar is phenyl or naphthyl, 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, -CN,- OR ²⁴ , -NR ^25a R ^25b , and optionally a _C1-4 alkyl group substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C (= O) NR ^27a R ^27b ; Het ¹ is a monocyclic heteroaryl group selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, Pyridine Base , Furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 4- or 5-thiazolyl, isothiazolyl, thiadiazolyl, and isopropyl Oxazolyl; or a bicyclic heteroaryl group selected from the group consisting of imidazothiazolyl, imidazomidazolyl, benzofuranyl, benzophenylthio, benzimidazolyl, benzene and Oxazolyl, isobenzo Oxazolyl Oxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indole Base, dihydroindolyl, isoindolyl, indazolyl, pyrazolopyridyl, pyrazolopyrimidyl, imidazopyridyl, imidazopyridine Imidazo Groups; 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, -CN, -OR ²⁴ , -NR ^25a R ^25b , And optionally C _1-4 alkyl substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C (= O) NR ^27a R ^27b ; and Het ² is a non-aromatic heterocyclic group optionally substituted with one, two or three substituents, each substituent is independently selected from the group consisting of: halogen, -CN , -OR ²⁴ , -NR ^25a R ^25b , and optionally a C _1-4 alkyl group substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C (= O) NR ^27a R ^27b ; wherein R ²⁴ , R ^25a , R ^25b , R ²⁶ , R ^27a , and R ^27b are each 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 ^28a R ^28b ; and substituted with a substituent selected from the group consisting of: C _2-4 alkyl, the group consists of the following groups Into: -OR ²⁹ and -NR ^28a R ^28b ; wherein R ^28a , R ^28b and R ²⁹ are each independently selected from the group consisting of: hydrogen; C _1-4 alkyl; and containing at least one nitrogen, oxygen Or a C-linked 4- to 7-membered non-aromatic heterocyclic group of a sulfur atom; or a pharmaceutically acceptable salt or solvate thereof; provided that the following compounds, and pharmaceutically acceptable addition salts and solvents thereof Compounds are excluded: The compound according to item 1 of the scope of patent application, wherein (a) L ^{2 is} selected from the group consisting of:> SO ₂ ,> CR ^4a R ^4b , and -CHR ^4a CHR ^5- ; wherein (i) When L ^{2 is} connected to the carbon atom of L ¹ , then R ^4a and R ⁵ are each independently selected from the group consisting of: hydrogen; -OR ⁶ ; -NR ^7a R ^7b ; -C (= O) NR ^7a R ^7b ; optionally a C _1-4 alkyl group substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ⁸ , and -NR ^9a R ^9b ; and containing at least A C-linked 4- to 7-membered non-aromatic heterocyclic group of one nitrogen, oxygen or sulfur atom; (ii) when L ^{2 is} connected to the nitrogen atom of L ¹ , then R ^{4a is} selected from the group consisting of Group: hydrogen; -C (= O) NR ^7a R ^7b ; C _1-4 alkyl optionally substituted with a substituent selected from the group consisting of: fluorine, -CN, -OR ⁸ , And -NR ^9a R ^9b ; and a C-linked 4- to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen, or sulfur atom; R ^{5 is} selected from the group consisting of: hydrogen;- OR ⁶ ; -NR ^7a R ^7b ; -C (= O) NR ^7a R ^7b ; as appropriate, taken by a substituent selected from the group Substituted C _1-4 alkyl groups, the group consisting of: fluorine, -CN, -OR ⁸ , and -NR ^9a R ^9b ; and a C-linked 4-member containing at least one nitrogen, oxygen or sulfur atom To 7-membered non-aromatic heterocyclic groups; R ^{4b is} selected from the group consisting of: hydrogen and methyl; or> CR ^4a R ^4b forms> C _3-5 cycloalkanediyl or> C containing an oxygen atom -A connected 4- to 6-membered heterocyclic diyl; wherein R ⁶ , R ^7a , R ^7b , R ⁸ , R ^9a and R ^9b are each independently selected from the group consisting of: hydrogen; optionally C _1-4 alkyl substituted with a substituent from the group consisting of: fluorine, -CN, and -C (= O) NR ^10a R ^10b ; and substituted with a substituent selected from the group C _2-4 alkyl, the group consisting of -OR ¹¹ and -NR ^10a R ^10b ; wherein R ^10a , R ^10b and R ¹¹ 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 Ar, Het ¹ , Het ² , and a 7- to 10-membered saturated spirocarbobicyclic system; or (b) L ^{2 is} selected from A group consisting of:> CR ^4c R ^4d and -CHR ^4c CHR ^5a- , where R ^4c and R ^4d And R ^5a 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: with ; Wherein R ^12a , R ^12b , and R ^12c are each independently selected from the group consisting of: a C _1-6 alkyl group optionally substituted with -OH or -NH ₂ substituent; or (c)- L ² -R ³ is a C _1-6 alkyl optionally substituted with one, two or three fluorine substituents; or (d) L ² is O, and R ^{3 is} selected from the group consisting of: Ar, Het ¹ ; -CH ₂ -Ar, -CH ₂ -Het ¹ , and -CH _2- (7 to 10-membered saturated spiro-carbon bicyclic ring system); when L ^{2 is} connected to the carbon atom of L ¹ ; or (e)-L ² -R ^{3 is} selected from the group consisting of: Where R ¹⁸ is hydrogen; or (f)-L ² -R ³ or ; And wherein Ar is a phenyl group optionally substituted with one, two, or three substituents, each substituent is independently selected from the group consisting of: halogen, -CN, and optionally C _1-4 alkyl substituted with substituents of the group consisting of: fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C (= O) NR ^27a R ^27b ; Het ¹ Is a monocyclic heteroaryl group selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, pyridine Base , Furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 4- or 5-thiazolyl, isothiazolyl, thiadiazolyl, and isopropyl Oxazolyl; or bicyclic heteroaryl, the bicyclic heteroaryl is selected from imidazopyridyl, especially imidazo [1,2-a] pyridyl; each of which can be one, two, or three as appropriate Substituent substitution, each substituent is independently selected from the group consisting of halogen, -CN, and optionally C _1-4 alkyl substituted with a substituent selected from the group consisting of Composition: fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C (= O) NR ^27a R ^27b ; and Het ² is selected from the group consisting of azetidinyl, pyrrolidinyl, and piperidinyl Non-aromatic heterocyclic groups; wherein R ²⁶ , R ^27a , and R ^27b are each independently selected from the group consisting of hydrogen and C _1-4 alkyl. The compound as described in claim 1 or 2, wherein R ¹ is CF ₃ ; (a) L ² is> CR ^4a R ^4b ; wherein R ^{4a is} selected from the group consisting of: hydrogen; -C (= O) NR ^7a R ^7b ; C _1-4 alkyl; and a C-linked 4- to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen or sulfur atom; and R ^{4b is} selected from the group consisting of A group consisting of: hydrogen and methyl; wherein R ^7a and R ^7b are each independently selected from the group consisting of: hydrogen; C _1-4 alkyl; and substituted with a substituent selected from the group consisting of C _2-4 alkyl, the group consisting of: -OR ¹¹ and -NR ^10a R ^10b ; wherein R ^10a , R ^10b and R ¹¹ 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: Ar, Het ¹ , Het ² , and a 7- to 10-membered saturated spirocarbon bicyclic ring system; or (b) the L ² series> CR ^4c R ^4d , wherein R ^4c and R ^4d 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: with ; Wherein R ^12a , R ^12b , and R ^12c are each independently selected from the group consisting of a C _1-6 alkyl group optionally substituted with a -NH ₂ substituent; or (c)-L ^2- R ³ is a C _1-6 alkyl optionally substituted with one, two or three fluorine substituents; or (d) L ² is O, and R ^{3 is} selected from the group consisting of Ar, Het ¹ , -CH ₂ -Ar, -CH ₂ -Het ¹ , and -CH _2- (7 to 10-membered saturated spiro-carbon bicyclic ring system); when L ^{2 is} connected to the carbon atom of L ¹ ; or (e) --L ² -R ^{3 is} selected from the group consisting of: Where R ¹⁸ is hydrogen; or (f)-L ² -R ³ or ; And wherein Ar is a phenyl group optionally substituted with a halogen substituent; Het ¹ is a monocyclic heteroaryl group selected from the group consisting of pyridyl, 4-, 5-, or 6-pyrimidine Base Base , Pyrrolyl, pyrazolyl, imidazolyl, and 4- or 5-thiazolyl; or a bicyclic heteroaryl, the bicyclic heteroaryl is selected from imidazopyridyl, especially imidazo [1,2- a] pyridyl; each may optionally be substituted by one, two or three substituents, each substituent being independently selected from the group consisting of halogen and optionally a substituent selected from the group consisting of Substituted C _1-4 alkyl, the group consisting of: fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C (= O) NR ^27a R ^27b ; and Het ² is selected from Non-aromatic heterocyclic groups of azetidinyl, pyrrolidinyl, and piperidinyl; wherein R ²⁶ , R ^27a , and R ^27b are each independently selected from the group consisting of: hydrogen and C _{1- 4} alkyl. The compound according to any one of claims 1 to 3, wherein R ¹ is CF ₃ ; L ¹ represents an N-linked 7-membered to 10-membered saturated spirobicyclic ring containing one or two N atoms System, the N atom is selected from the group consisting of (a), (b), (c), (d), (e), (f), and (g) Where a represents a position attached to a thienopyrimidinyl heterocyclic ring; (a) L ² is> CH ₂ ; and R ^{3 is} selected from the group consisting of: Ar, Het ¹ , and 7 to 10 saturated spiro A carbobicyclic system; or (b)-L ² -R ³ is a C _1-6 alkyl optionally substituted with one, two, or three fluorine substituents; and wherein Ar is optionally substituted with a halogen substituent Het ¹ is a monocyclic heteroaryl group selected from the group consisting of 4-, 5- or 6-pyrimidinyl, pyridine Base , Pyrrolyl, pyrazolyl, imidazolyl, and 4- or 5-thiazolyl; or a bicyclic heteroaryl, the bicyclic heteroaryl is selected from imidazopyridyl, especially imidazo [1,2- a] pyridyl; each may optionally be substituted by one or two substituents, each substituent being independently selected from the group consisting of halogen and C _1-4 alkyl. The compound according to any one of claims 1 to 4, wherein R ¹ is CF ₃ ; R ² is hydrogen; L ¹ represents 7 to 10 members of an N-linkage containing one or two N atoms Saturated spiro heterobicyclic system, the N atom is selected from the group consisting of (a), (b), (c), (d), (e), (f), and (g) Where a represents a position attached to a thienopyrimidinyl heterocyclic ring; (a) L ² is> CH ₂ ; and R ^{3 is} selected from the group consisting of: Ar, Het ¹ , and 7 to 10 saturated spiro A carbobicyclic system; or (b)-L ² -R ³ is a C _1-6 alkyl optionally substituted with one, two, or three fluorine substituents; and wherein Ar is optionally substituted with a halogen substituent Het ¹ is a monocyclic heteroaryl group selected from the group consisting of 4-, 5- or 6-pyrimidinyl, pyridine Base Group, pyrrolyl, pyrazolyl, and imidazolyl; or a bicyclic heteroaryl, the bicyclic heteroaryl is selected from imidazopyridyl, especially imidazo [1,2-a] pyridyl; each may be It is optionally substituted with one or two substituents, each of which is independently selected from the group consisting of halogen and C _1-4 alkyl. The compound as described in item 1 of the scope of patent application, wherein R ¹ is CF ₃ ; R ^{2 is} selected from the group consisting of hydrogen and CH ₃ ; L ¹ represents 7 members containing one or two N atoms to 10-membered saturated spiro heterobicyclic system, provided that it is N-linked to the thienopyrimidinyl heterocyclic ring; and --L ² -R ^{3 is} selected from (a), (b), (c), (d), (f) or (g), wherein (a) L ^{2 is} selected from the group consisting of:> CR ^4a R ^4b and -CHR ^4a CHR ^5- ; wherein L ^{2 is} connected to the nitrogen atom of L ¹ ; R ^4a Is selected from the group consisting of: hydrogen; -C (= O) NR ^7a R ^7b ; a C _1-4 alkyl group optionally substituted with a substituent selected from the group consisting of: -OR ⁸ , and -NR ^9a R ^9b ; and a C-linked 4- to 7-membered non-aromatic heterocyclic group containing at least one nitrogen atom; R ^{5 is} selected from the group consisting of: hydrogen; -OR ⁶ ; and C _1-4 alkyl; R ^{4b is} selected from the group consisting of: hydrogen and methyl; or R ^4a and R ^4b together with the carbon atom to which they are attached form C _3-5 cycloalkyl or 4 C- containing an oxygen atom attached to the 6-membered heterocyclyl; wherein ^{R 6, R 7a, R 7b} , R 8, R 9a R ^9b are each independently selected from the group consisting of: hydrogen; and is selected from the group of substituents of C _2-4 alkyl, the group consisting of: -OR ¹¹ and -NR ^10a R ^10b ; wherein R ^10a , R ^10b and R ¹¹ 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: Ar, Het ¹ , Het ² , and 7- to 10-membered saturated spiro-carbon bicyclic ring systems; or (b) L ² > CR ^4c R ^4d , where R ^4c and R ^4d are hydrogen; and R ³ ; Wherein R ^12a , R ^12b , and R ^12c are C _1-6 alkyl 1; or (c)-L ² -R ³ are C _1-, optionally substituted with one, two, or three fluorine substituents ₆ alkyl; or (d) L ² is O, and R ³ is -CH ₂ -Ar; or (f)-L ² -R ³ is Wherein R ^{18 is} selected from the group consisting of: hydrogen; and C _1-4 alkyl; R ^{18a is} selected from the group consisting of: hydrogen; and fluorine; R ^{18b is} selected from the group consisting of: Group: fluorine, -OC _1-4 alkyl and optionally C _1-4 alkyl substituted with 1, 2 or 3 fluorine substituents; or R ^18a and R ^18b combine with the same carbon atom and together form C _3-5 cycloalkyl; or (g)-L ² -R ³ series ; And wherein Ar is a phenyl group optionally substituted with one, two, or three substituents, each substituent is independently selected from the group consisting of: halogen, -OR ²⁴ , and optionally- OR ²⁶ substituted C _1-4 alkyl; Het ¹ is a monocyclic heteroaryl group selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, pyridine Base Group, pyrrolyl, pyrazolyl, imidazolyl, 4- or 5-thiazolyl, isothiazolyl, and isoxazolyl; or a bicyclic heteroaryl group selected from the group consisting of: ind Indyl, imidazopyridyl; 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, -CN, -OR ²⁴ , And optionally C _1-4 alkyl substituted with a substituent selected from the group consisting of -CN, -OR ²⁶ , and -NR ^27a R ^27b ; and Het ² is optionally , Two or three substituents substituted non-aromatic heterocyclic groups, each substituent independently selected from the group consisting of: halogen, -CN, and optionally C _1- substituted with -OR ²⁶ ₄ alkyl; wherein R ²⁴ , R ²⁶ , R ^27a , and R ^27b are each independently selected from the group consisting of: hydrogen; C _1-4 alkyl; and C ₂ substituted with -NR ^28a R ^28b _-4 alkyl; wherein R ^28a and R ^28b are hydrogen. The compound according to item 1 of the scope of patent application, 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 ; L ¹ represents a 7- to 10-membered saturated spiro heterobicyclic system containing one or two N atoms, provided that it is N-connected to a thienopyrimidinyl heterocyclic ring; and --L ^2- R ^{3 is} selected from (a), (b), (d), (e), or (f), wherein (a) L ^{2 is} selected from the group consisting of:> SO ₂ ,> CR ^4a R ^4b , And -CHR ^4a CHR ^5- ; wherein (i) when L ^{2 is} connected to the carbon atom of L ¹ , then R ^4a and R ⁵ are each independently selected from the group consisting of: hydrogen; -OR ⁶ ; -NR ^7a R ^7b ; -C (= O) NR ^7a R ^7b ; optionally a C _1-4 alkyl group substituted by a substituent selected from the group consisting of fluorine, -CN,- OR ⁸ and -NR ^9a R ^9b ; and a C-linked 4- to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen, or sulfur atom; (ii) when L ^{2 is} connected to the nitrogen atom of L ¹ , Then R ^{4a is} selected from the group consisting of: -C (= O) NR ^7a R ^7b ; as appropriate, it is selected from the following group: Substituted C _1-4 alkyl groups, the group consisting of: fluorine, -CN, -OR ⁸ , and -NR ^9a R ^9b ; and C-linked, containing at least one nitrogen, oxygen or sulfur atom 4- to 7-membered non-aromatic heterocyclic groups; R ^{5 is} selected from the group consisting of: hydrogen; -OR ⁶ ; -NR ^7a R ^7b ; -C (= O) NR ^7a R ^7b ; as appropriate C _1-4 alkyl substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ⁸ , and -NR ^9a R ^9b ; and containing at least one nitrogen, oxygen, or sulfur atom C-linked 4- to 7-membered non-aromatic heterocyclic groups; R ^{4b is} selected from the group consisting of: hydrogen and methyl; or R ^4a and R ^4b are formed together with the carbon atoms to which they are attached C _3-5 cycloalkyl or a C-linked 4- to 6-membered heterocyclic group containing an oxygen atom; wherein R ⁶ , R ^7a , R ^7b , R ⁸ , R ^9a and R ^9b are each independently selected from the group consisting of The group consisting of: hydrogen; optionally a C _1-4 alkyl group substituted with a substituent selected from the group consisting of fluorine, -CN, and -C (= O) NR ^10a R ^10B; and is selected from the group of substituents of C _2-4 alkyl, which group consisting To: -OR ¹¹ and -NR ^10a R ^10b; wherein R ^10a, R ^10b and R ¹¹ are each independently selected from the group consisting of: hydrogen; C _1-4 alkyl; and containing at least one nitrogen, oxygen Or a C-linked 4- to 7-membered non-aromatic heterocyclic group of a sulfur atom; and R ^{3 is} selected from the group consisting of Ar, Het ¹ , Het ² , and 7- to 10-membered saturated spirocarbons A bicyclic system; or (b) L ^{2 is} selected from the group consisting of:> CR ^4c R ^4d and -CHR ^4c CHR ^5a- , wherein R ^4c , R ^4d , and R ^5a are each independently selected from the group consisting of A group consisting of: hydrogen and C _1-4 alkyl; and R ^{3 is} selected from the group consisting of: with ; Wherein R ^12a , R ^12b , and R ^12c are each independently selected from the group consisting of: a C _1-6 alkyl group optionally substituted with -OH or -NH ₂ substituent; and -OC _1-6 Alkyl; or (d) L ² is O, and R ^{3 is} selected from the group consisting of: C _3-6 alkyl optionally substituted with one, two, or three fluorine substituents; Ar; Het ¹ ; Het ² ; 7- to 10-membered saturated spiro-carbon bicyclic ring system; -CH ₂ -Ar; -CH ₂ -Het ¹ ; -CH ₂ -Het ² ; and -CH _2- (7 to 10-membered saturated spiro Carbon bicyclic ring system); when L ^{2 is} connected to the carbon atom of L ¹ ; or (e)-L ² -R ³ is -O-CHR ⁵ -R ³ when L ^{2 is} connected to the carbon atom of L ¹ Where R ^{5 is} selected from the group consisting of: -C (= O) NR ^13a R ^13b ; optionally a C _1-4 alkyl group substituted with a substituent selected from the group consisting of Composition: Fluorine, -OR ¹⁴ , and -NR ^15a R ^15b ; and C-linked 4-membered to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen or sulfur atom; wherein R ^13a , R ^13b , R ^14, R ^15a and R ^15b are each independently selected from the group consisting of: hydrogen; optionally substituted group selected from the group which C _1-4 alkyl, the group consisting of: fluorine and ^{-C (= O) NR 16a R} 16b; and the substituents are selected from the group of the substituted C _2-4 alkyl group, the group consisting of Consisting of: -OR ¹⁷ and -NR ^16a R ^16b ; wherein R ^16a , R ^16b and R ¹⁷ are each independently selected from the group consisting of: hydrogen; C _1-4 alkyl; and containing at least one A C-linked 4- to 7-membered non-aromatic heterocyclic group of a nitrogen, oxygen or sulfur atom; and R ^{3 is} selected from the group consisting of: hydrogen; optionally substituted with one, two or three fluorines -Substituted C _1-4 alkyl; -CN; Ar; Het ¹ ; Het ² ; and 7- to 10-membered saturated spirocarbon bicyclic ring system; or (f)-L ² -R ³ system , Wherein R ^{18 is} selected from the group consisting of: hydrogen; C _1-4 alkyl optionally substituted with fluorine or -CN substituent; and C _2-4 alkyl substituted with substituent selected from This group consists of the following: -OR ¹⁹ and -NR ^20a R ^20b ; wherein R ¹⁹ , R ^20a and R ^20b are each independently selected from the group consisting of: hydrogen; and optionally, selected from the following: C _1-4 alkyl substituted with substituents of the group consisting of: fluorine, -CN and -C (= O) NR ^21a R ^21b ; C _2- substituted with substituents selected from the group _4- alkyl, the group consisting of: -OR ²² and NR ^21a R ^21b ; and a C-linked 4- to 7-membered non-aromatic heterocyclic group containing at least one nitrogen, oxygen or sulfur atom; wherein R ^21a , R ^21b, and R ²² are each independently selected from the group consisting of: hydrogen and C _1-4 alkyl; and R ^{18a is} selected from the group consisting of: hydrogen, fluorine, and C _1-4 Alkyl; R ^{18b is} selected from the group consisting of: fluorine, -OC _1-4 alkyl, and optionally C _1-4 alkyl substituted with 1, 2, or 3 fluorine substituents; or R ^18a and R ^{18b is} bonded to the same carbon atom and forms a C _3-5 ring together An alkyl group or a C-linked 4-membered to 6-membered heterocyclic group containing an oxygen atom; and wherein Ar is phenyl or naphthyl, each of which may be optionally substituted with one, two, or three substituents, each substituted Is independently selected from the group consisting of halogen, -CN, -OR ²⁴ , -NR ^25a R ^25b , and optionally C _1-4 alkyl substituted with a substituent selected from the group consisting of: It consists of the following: fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C (= O) NR ^27a R ^27b ; Het ¹ is a monocyclic heteroaryl group selected from the group consisting of Compositions of: pyridyl, 4-, 5- or 6-pyrimidinyl, pyridine Base , Furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 4- or 5-thiazolyl, isothiazolyl, thiadiazolyl, and isopropyl Oxazolyl; or a bicyclic heteroaryl group selected from the group consisting of imidazothiazolyl, imidazomidazolyl, benzofuranyl, benzophenylthio, benzimidazolyl, benzene and Oxazolyl, isobenzo Oxazolyl Oxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indole Base, dihydroindolyl, isoindolyl, indazolyl, pyrazolopyridyl, pyrazolopyrimidyl, imidazopyridyl, imidazopyridine Imidazo Groups; 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, -CN, -OR ²⁴ , -NR ^25a R ^25b , And optionally C _1-4 alkyl substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C (= O) NR ^27a R ^27b ; and Het ² is a non-aromatic heterocyclic group optionally substituted with one, two or three substituents, each substituent is independently selected from the group consisting of: halogen, -CN , -OR ²⁴ , -NR ^25a R ^25b , and optionally a C _1-4 alkyl group substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C (= O) NR ^27a R ^27b ; wherein R ²⁴ , R ^25a , R ^25b , R ²⁶ , R ^27a , and R ^27b are each 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 ^28a R ^28b ; and substituted with a substituent selected from the group consisting of: C _2-4 alkyl, the group consists of the following groups Into: -OR ²⁹ and -NR ^28a R ^28b ; wherein R ^28a , R ^28b and R ²⁹ are each independently selected from the group consisting of: hydrogen; C _1-4 alkyl; and containing at least one nitrogen, oxygen Or a C-linked 4- to 7-membered non-aromatic heterocyclic group of a sulfur atom. The compound according to item 1 of the scope of patent application, wherein --L ² -R ³ is (a); R ³ is Het ¹ or Het ² ; Het ¹ is a monocyclic heteroaryl group selected from the group consisting of Consists of: pyridyl, 4-, 5- or 6-pyrimidinyl, pyridine Base , Pyrrolyl, pyrazolyl, and imidazolyl; each may be optionally substituted with one, two, or three substituents, each of which is independently selected from the group consisting of: halogen, -CN, -OR ²⁴ , -NR ^25a R ^25b , and optionally a C _1-4 alkyl group substituted with a substituent selected from the group consisting of fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C (= O) NR ^27a R ^27b ; and Het ² is a non-aromatic heterocyclic group selected from the group consisting of azetidinyl, pyrrolidinyl, and Piperidinyl; each of which may be optionally substituted with one, two, or three substituents, each substituent being independently selected from the group consisting of: halogen, -CN, -OR ²⁴ , -NR ^25a R ^25b , and optionally _C1-4 alkyl substituted with a substituent selected from the group consisting of: fluorine, -CN, -OR ²⁶ , -NR ^27a R ^27b , and -C (= O) NR ^27a R ^27b .     A pharmaceutical composition comprising the compound as described in any one of claims 1 to 8 and a pharmaceutically acceptable carrier or diluent.         A method for preparing a pharmaceutical composition as described in item 9 of the scope of patent application, the method comprising: combining a pharmaceutically acceptable carrier with a therapeutically effective amount as described in any one of scopes of patent application 1 to 8 The compounds mentioned are mixed.         The compound according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 9 is used as a medicine.         The compound as described in any one of claims 1 to 8 or the pharmaceutical composition as described in any one of claims 9 to 8 for the prevention or treatment of cancer, myelodysplastic syndrome (MDS) and diabetes use.         The compound or pharmaceutical composition for use as described in claim 12 of the application, wherein the cancer is selected from the following: leukemia, myeloma, or solid tumor cancer, such as prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer , Liver cancer, melanoma and glioblastoma.     The compound or pharmaceutical composition for use according to item 13 of the scope of the patent application, wherein the leukemia is selected from the following: acute leukemia, chronic leukemia, myeloid leukemia, myeloid leukemia, lymphoblastic leukemia, and lymphocytic leukemia , Acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prelymphocytic leukemia (T-PLL), large granular lymphocytes Leukemia, hairy cell leukemia (HCL), MLL-rearranged leukemia, MLL-PTD leukemia, leukemia with increased MLL, MLL-positive leukemia, and leukemia displaying HOX / MEIS1 gene expression markers.     A use of a compound according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9 for the preparation or treatment of a compound selected from cancer, myelodysplastic syndrome ( MDS) and medicines for diabetic conditions.         Use according to item 15 of the scope of patent application, wherein the condition is cancer.         The use as described in claim 16, wherein the cancer is selected from the group consisting of leukemia, myeloma, or solid tumor cancer, such as prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma, and glioblastoma Cell tumor.     The use as described in claim 16 or claim 17, wherein the leukemia is selected from the group consisting of acute leukemia, chronic leukemia, myeloid leukemia, myeloid leukemia, lymphoblastic leukemia, lymphocytic leukemia, and acute myeloid leukemia ( AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prelymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia ( (HCL), MLL-rearranged leukemia, MLL-PTD leukemia, MLL-increased leukemia, MLL-positive leukemia, and leukemia displaying HOX / MEIS1 gene expression markers.