EA040339B1 - IMIDAZO[1,5-а]PYRAZINE DERIVATIVES AS PI3Kδ INHIBITORS - Google Patents

Description

Cross-reference to related applications

This application claims priority under international applications

PCT/CN2017/101058 filed on September 8, 2020, PCT/CN2017/119373 filed on December 28, 2017, and PCT/CN2018/086555 filed on May 11, 2018, the contents of which are hereby incorporated by reference in their entirety.

Technical field

The invention discloses an imidazo[1,5-a]pyrazine derivative or a stereoisomer or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing it. The present invention also discloses a method for the treatment of diseases associated with PI3K (in particular, diseases associated with PI3Kδ) using an imidazo[1,5-a]pyrazine derivative or a stereoisomer or a pharmaceutically acceptable salt thereof of the present invention. The present invention also discloses an imidazo[1,5-a]pyrazine derivative or stereoisomer or pharmaceutically acceptable salt thereof for use in the treatment of diseases associated with PI3K (in particular, diseases associated with PI3Kδ).

Prior Art

Phosphatidylinositol-4,5-bisphosphate-3-kinases (PI3K) are a family of enzymes involved in various primary cellular functions, including cell growth, proliferation, differentiation, motility, survival, metabolism, and intracellular transport [Vanhaesebroeck B., L. Stephens and P. Hawkins, PI3K signaling: the path to discovery and understanding. Nat. Rev. Mol. Cell Biol., 2012. 13(3): p. 195-203]. They are kinases capable of phosphorylation of phosphatidylinositol [Whitman M., et al., Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature, 1988. 332(6165): p. 644-6., Auger K.R. et al., PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells. Cell, 1989. 57(1): p. 167-75]. Phosphorylated phosphatidylinositols, which are called phosphoinositides, play an important role in signal transduction and membrane transport [Martin T.F., Phosphoinositide lipids as signaling molecules: common themes for signal transduction, cytoskeletal regulation, and membrane trafficking. Annu. Rev. celldev. Biol., 1998. 14: p. 231-64].

The PI3K family is divided into three classes (I, II and III) based on structure, regulation and substrate specificity [Vanhaesebroeck B. et al. The emerging mechanisms of isoform-specific PI3K signaling. Nat. Rev. Mol. Cell Biol., 2010. 11(5): p.329-41.]. Class I PI3K is further divided based on sequence similarity into class IA and class IB. Class IA PI3Ks include three closely related kinases, PI3Ka, PI3Ke and PI3Kδ, which exist as heterodimers consisting of a catalytic subunit (p110a, p110e or p110δ) and a regulatory subunit (p85) [Yu J. et al., Regulation of the p85/ p110 phosphatidylinositol 3'-kinase: stabilization and inhibition of the p110a catalytic subunit by the p85 regulatory subunit. Mol. Cell Biol., 1998. 18(3): p. 1379-87 Carpenter C.L. et al., Phosphoinositide 3-kinase is activated by phosphopeptides that bind to the SH2 domains of the 85-kDa subunit. J Biol. Chem., 1993. 268(13): p. 947883., Zhang X. et al., Structure of lipid kinase p110e/p85e elucidates an unusual SH2-domain-mediated inhibitory mechanism. Mol. Cell, 2011. 41(5): p. 567-78., Burke J.E. et al., Dynamics of the phosphoinositide 3-kinase p110δ interaction with p85a and membranes reveals aspects of regulation distinct from p110a. Structure, 2011. 19(8): p. 1127-37]. Class IB PI3K includes only PI3Ky, which consists of p110y [Stoyanov B. et al., Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase. Science, 1995. 269(5224): p. 690-3.] a catalytic subunit that can bind to p101 [Stephens L.R. et al., The Gey sensitivity of a PI3K is dependent upon a tightly associated adaptor, p101. Cell, 1997. 89(1): p. 10514., Brock C. et al., Roles of Gey in membrane recruitment and activation of p110y/p101 phosphoinositide 3kinase y. J Cell Biol, 2003. 160(1): p. 89-99.] or p84 [Suire S. et al., p84, a new Gey-activated regulatory subunit of the type IB phosphoinositide 3-kinase p110y. Curr. Biol., 2005. 15(6): p. 566-70.] regulatory subunit. PI3Ka and PI3Kδ respond to signaling, typically through receptor tyrosine kinases (RTKs) [Inukai K. et al., Five isoforms of the phosphatidylinositol 3-kinase regulatory subunit exhibit different associations with receptor tyrosine kinases and their tyrosine phosphorylations. FEBS Lett, 2001. 490(1-2): p. 32-8.], while PI3Ky signals through G protein-coupled receptors (GPCR) [Stoyanov B. et al., Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase. Science, 1995. 269(5224): p. 690-3., Maier U., A. Babich, and B. Nurnberg, Roles of non-catalytic subunits in gay-induced activation of class I phosphoinositide 3-kinase isoforms β and y. J Biol. Chem., 1999. 274(41): p. 29311-7.], and PI3Ke signals both ways [Kurosu H. et al., Heterodimeric phosphoinositide 3-kinase consisting of p85 and p110y is synergistically activated by the betagamma subunits of G proteins and phosphotyrosyl peptide. J Biol. Chem., 1997. 272(39): p. 24252-6.]. The PI3Ka and PI3Ke isoforms are ubiquitously expressed, while the expression pattern of PI3Kδ and PI3Ky appears to be more limited, with both isoforms found primarily in leukocytes [Kok K., B. Geering and B. Vanhaesebroeck, Regulation of phosphoinositide 3- kinase expression in health and disease. Trends Biochem Sci, 2009. 34(3): p. 115-27].

The relatively limited expression pattern of PI3Kδ, in addition to data collected from studies in mice where ΡΙ3Κδ was either genetically inactivated, hyperactivated, or pharmacologically inactivated, suggests that this isoform plays a major role in adaptive immune systems [Lucas C.L. et al., PI3Kδ and primary immunodeficiencies. Nat. Rev. Immunol., 2016]. In mice, loss of PI3Kδ function in B cells impairs T cell independent antibody response but does not affect class switch recombination (CSR) and somatic hypermutation (SHM) [Rolf J. et al., Phosphoinositide 3-kinase activity in T cells regulates the magnitude of the germinal center reaction. J. Immunol., 2010. 185(7): p. 4042-52.], and both of these mechanisms are important for the maturation and diversity of antibodies [Stavnezer J., J.E. Guikema and C.E. Schrader, Mechanism and regulation of class switch recombination. Annu Rev. Immunol., 2008. 26: p. 261-92., Li Z. et al., The generation of antibody diversity through somatic hypermutation and class switch recombination. Genes. Dev., 2004. 18(1): p. 1-11], while hyperactivation of ΡΙ3Κδ in mature B cells interferes with CSR and SHM and inhibits the proliferation of antigen-specific B cell populations [Janas M.L. et al., The effect of deleting p110δ on the phenotype and function of PTEN-deficient B cells. J. Immunol., 2008. 180(2): p. 739-46., Omori S.A. et al., Regulation of class-switch recombination and plasma cell differentiation by phosphatidylinositol 3-kinase signaling. Immunity, 2006. 25(4): p. 545-57., Sander S. et al., PI3 Kinase and f0xO1 Transcription Factor Activity Differentially Control In Cells in the Germinal Center Light and Dark Zones. Immunity, 2015. 43(6): p. 1075-86]. In addition, PI3Kδ is also a key signal transduction component for malignant B cells, making it an attractive drug target for B-cell malignancies [Wei M. et al., Targeting PI3Kδ: emerging therapy for chronic lymphocytic leukemia and beyond. Med. Res. Rev., 2015. 35(4): p. 720-52].

Meanwhile, PI3Kδ is required for differentiation of naive T cells towards T helper cells, including T _FH (follicular helper) [Rolf J. et al., Phosphoinositide 3-kinase activity in T cells regulates the magnitude of the germinal center reaction. J. Immunol., 2010. 185(7): p. 4042-52.], T _h 1, T _h 2 and T _h 17 [Okkenhaug K. et al., The p110δ isoform of phosphoinositide 3-kinase controls clonal expansion and differentiation of Th cells. J. Immunol., 2006. 177(8): p. 5122-8., Soond DR et al., PI3K p110δ regulates T-cell cytokine production during primary and secondary immune responses in mice and humans. Blood, 2010. 115(11): p. 2203-13., Kurebayashi Y. et al., PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating Gfil expression and nuclear translocation of RORy. Cell Rep, 2012. 1(4): p. 360-73]. Interference with T _fh development leads to a strong attenuation of the T-cell dependent mechanism of CSR (immunoglobulin class switching) and SHM (somatic hypermutation) in B cells [Rolf J. et al., Phosphoinositide 3kinase activity in T cells regulates the magnitude of the germinal center reaction. J. Immunol., 2010. 185(7): p. 4042-52], while reduction in T _h 2 and T _h 17 cells caused by PI3Kδ deficiency may confer protection in asthmatic mice [Nashed BF et al., Role of the phosphoinositide 3-kinase p110δ in generation of type 2 cytokine responses and allergic airway inflammation. Eur. J. Immunol., 2007. 37(2): p. 416-24.] or multiple sclerosis [Haylock-Jacobs S. et al., PI3Kδ drives the pathogenesis of experimental autoimmune encephalomyelitis by inhibiting effector T cell apoptosis and promoting Th17 differentiation. J. Autoimmun., 2011. 36(3-4): p. 278-87.] respectively. PI3Kδ is also important for homeostasis and function of Foxp ³⁺ T regulatory cells (Treg) [Patton DT et al., Cutting edge: the phosphoinositide 3-kinase p110 δ is critical for the function of CD4+CD25+Foxp3+ regulatory T cells. J. Immunol., 2006. 177(10): p. 6598-602]. Mice deficient in PI3Kδ develop colitis [Patton DT et al., Cutting edge: the phosphoinositide 3-kinase p110 δ is critical for the function of CD4+CD25+Foxp3+ regulatory T cells. J. Immunol., 2006. 177(10): p. 6598-602] due to decreased T _reg functions but have an increased immune response to tumors [Ali K. et al., Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer. Nature, 2014. 510(7505): p. 407-11.]. PI3Kδ also contributes, but is not necessary, to reprogram CD8+ T cells into fully activated effector cells [Pearce VQ et al., PI3Kδ Regulates the Magnitude of CD8+ T Cell Responses after Challenge with Listeria monocytogenes. J. Immunol., 2015. 195(7): p. 3206-17., Gracias DT et al., Phosphatidylinositol 3-Kinase p110δ Isoform Regulates CD8+ T Cell Responses during Acute Viral and Intracellular Bacterial Infections. J. Immunol., 2016. 196(3): p. 1186-98]. In contrast, generation of CD8+ memory T cells requires suppression of PI3Kδ signaling [Pearce VQ et al., PI3Kδ Regulates the Magnitude of CD8+ T Cell Responses after Challenge with Listeria monocytogenes. J. Immunol., 2015. 195(7): p. 3206-17].

PI3Kδ mutations leading to both gain of function (GOF) and loss of function (LOF) can cause primary immunodeficiency in humans [Lucas C.L. et al., PI3Kδ and primary immunodeficiencies. Nat. Rev. Immunol., 2016]. Patients lacking PI3Kδ function have recurrent infections and severe B-cell lymphopenia [Conley M.E. et al., Agammaglobulinemia and absent B lineage cells in a patient lacking the p85a subunit of PI3K. J. Exp. Med., 2012. 209(3): p. 463-70., Conley M.E. et al., Agammaglobulinemia and absent B lineage cells in a patient lacking the p85a subunit of PI3K. J. Exp. Med., 2012. 209(3): p. 463-70], while GOF mutations in PI3Kδ genes can cause combined immunodeficiency syndrome, which is called activated PI3Kδ syndrome (APDS) [Angulo, I. et al., Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. sci

- 2040339 ence, 2013. 342(6160): p. 866-71., Lucas C.L. et al. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat. Immunol., 2014. 15(1): p. 88-97., Deau M.C. et al., A human immunodeficiency caused by mutations in the PIK3R1 gene. J.Clin. Invest., 2015. 125(4): p. 1764-5., Lucas C.L. et al., Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K. J. Exp. Med., 2014. 211(13): p. 2537-47]. Patients with APDS were characterized by aging T cells, lymphadenopathy, and frequent infections [Elgizouli M. et al., Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency. Clin. Exp. Immunol., 2016. 183(2): p. 221-9., Elkaim E. et al., Clinical and immunological phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: A cohort study. J. Allergy Clin. Immunol., 2016. 138(1): p. 210-218 e9., Coulter T.I. et al., Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study. J. Allergy Clin. Immunol., 2016].

Because of the specific and critical functions of PI3Kδ in adaptive immune responses, PI3Kδ inhibitors are being developed for the treatment of autoimmune diseases (such as multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, and psoriasis) and inflammatory diseases (such as asthma and chronic obstructive pulmonary disease), hematological and solid tumors, as well as APDS [Lucas C.L. et al., PI3Kδ and primary immunodeficiencies. Nat. Rev. Immunol., 2016., Stark A.K. et al., PI3K inhibitors in inflammation, autoimmunity and cancer. Curr. Opin. Pharmacol., 2015. 23: p. 82-91]. Idelalisib is the first PI3Kδ inhibitor approved in 2014 for the treatment of B-cell leukemia [Yang Q. et al., Idelalisib: First-in-Class PI3K Delta Inhibitor for the Treatment of Chronic Lymphocytic Leukemia, Small Lymphocytic Leukemia, and Follicular Lymphoma. Clin. Cancer Res., 2015. 21(7): p. 1537-42]. In addition to idelalisib, at least 9 δ-specific and 5 δγ, δβ, or δα-dual inhibitors are in clinical development [Wei M. et al., Targeting PI3Kδ: emerging therapy for chronic lymphocytic leukemia and beyond. Med. Res. Rev., 2015. 35(4): p. 720-52]. Among them, the δγ-dual inhibitor duvelisib (NCT02004522) and the δ-specific inhibitor TGR-1202 (NCT02612311) are in Phase III clinical trials.

Recently, both idelalisib and duvelisib have been associated with a risk of increased lung infections [Okkenhaug K., M. Graupera, and B. Vanhaesebroeck, Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy. Cancer Discov, 2016. 6(10): p. 10901105.], which was found to be due to their relatively low selectivity for PI3Ky [Ruckle T., M.K. Schwarz, and C. Rommel, PI3Ky inhibition: towards an 'aspirin of the 21st century'? Nat. Rev. Drug Discov., 2006. 5(11): p. 903-18]. PI3Ky is important for immune cell chemotaxis [Hawkins R.T. and L.R. Stephens, PI3K signaling in inflammation. biochim. Biophys. Acta, 2015. 1851(6): p. 882-97] and plays a major role in the innate immune system [Ruckle T., M.K. Schwarz, and C. Rommel, PI3Ky inhibition: towards an 'aspirin of the 21st century'? Nat. Rev. drug. Discov., 2006. 5(11): p. 903-18.]. PI3Ky knockout mice have shown an increased susceptibility to pneumococcal infection [Maus U.A. et al., Importance of phosphoinositide 3-kinase γ in the host defense against pneumococcal infection. Am. J. Respir. Crit. Care Med., 2007. 175(9): p. 958-66]. It also works in conjunction with PI3Kδ in many immunosurveillance processes, including neutrophil recruitment [Liu L. et al., Leukocyte PI3Ky and PI3Kδ have temporally distinct roles for leukocyte recruitment in vivo. Blood, 2007. 110(4): p. 1191-8] and T cell development [Webb L.M. et al., Cutting edge: T cell development requires the combined activities of the p110Y and p110δ catalytic isoforms of phosphatidylinositol 3-kinase. J. Immunol., 2005. 175(5): p. 2783-7.]. Simultaneous genetic inactivation of PI3Kδ and PI3Ky in mice leads to more severe disorders of thymocyte development and inflammation of multiple organs [Ji H. et al., Inactivation of PI3Ky and PI3Kδ distorts Tcell development and causes multiple organ inflammation. Blood, 2007. 110(8): p. 2940-7] than in mice deficient in each isoform separately [Swat W. et al., Essential role of PI3Kδ and PI3Ky in thymocyte survival. Blood, 2006. 107(6): p. 2415-22].

Therefore, there is a need for PI3Kδ inhibitors with higher selectivity for PI3Ka, β, and γ, as selective PI3Kδ inhibitors are expected to have an improved safety profile and provide new therapeutic options for APDS, autoimmune and inflammatory diseases, and cancers such as glioblastoma. .

Brief description of the invention

The above need is met by the compounds, compositions and methods disclosed in the present invention.

The invention discloses a compound of formula (I)

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or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is -NR _a R _b , where Ra and R _b are each independently hydrogen,

R2 is hydrogen or -C _1-6 αkyl,

R ₃ and R ₄ , which may be the same or different, are each independently hydrogen or —C _1-6 alkyl,

R5 and R6 are each independently hydrogen,

R7 and _R8 are each independently hydrogen or halogen,

R ₁₀ is -OR12, where R12 is -C _1-6 alkyl;

R9 is -CONR ₁₂ R ₁₃ where

R12 and R ₁₃ , which may be the same or different, are each independently hydrogen, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each is -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 αlkynul, cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted with at least one R15 substituent.

Alternatively, R12 and _R13 together with the atom(s) to which they are attached form a 3-12 membered saturated ring containing 0 or 1 additional heteroatom independently selected from -NH, -O- or -S-, and said ring is optionally substituted with at least one R15 substituent,

R15 is independently hydrogen, halogen, -C _1-6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -OR ₁₆ , -COR ₁₆ , -CO ₂ R ₁₆ , -NR ₁₆ R ₁₇ , -C _1-6 αalkyl-NR ₁₆ R ₁₇ , wherein each said -C _1-6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with R19, -OR19, -COR19, or -CO2R19, where each R ₁₆ or R ₁₇ is independently is hydrogen or -C _1-6 alkyl, or

R ₁₆ and R ₁₇ together with the atom(s) to which they are attached form a 3-12 membered saturated, partially or fully unsaturated ring containing 0 or 1 additional heteroatom independently selected from -NH and -O-, and the specified the ring is optionally substituted with at least one R ₁₉ substituent, and wherein R19 is independently hydrogen, -C _1-6 alkyl, halo-C _1-6 alkyl, cycloalkyl, or heterocyclyl, wherein each said heterocyclyl is optionally substituted with -C _1-6 alkyl , and where the specified -C _1-6 alkyl is optionally substituted with cycloalkyl, where cycloalkyl contains 3-12 carbon atoms, aryl refers to phenyl, heteroaryl refers to a group selected from

5- or 6-membered aromatic monocyclic rings containing 1 heteroatom selected from N and O as ring atoms, where the remaining ring atoms are carbon;

heterocyclyl refers to a ring selected from 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered monocyclic and bicyclic, saturated rings containing 1-2 heteroatoms, selected from N, S or O as ring atoms.

The present invention also discloses a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed in the present invention, and a pharmaceutically acceptable excipient.

The compound of formula (I) disclosed in the present invention is useful as a PI3K inhibitor, in particular a PI3Kδ inhibitor. The compound of formula (I) disclosed in the present invention is thus useful for the treatment or prevention of idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia, vasculitis, systemic lupus erythematosus, lupus nephritis, pemphigus, membranous nephropathy, chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), hairy cell leukemia, mantle cell lymphoma, small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone cell lymphoma, diffuse large B-cell lymphoma of activated B-like cells (ABC), or diffuse large B-cell germinal center (GCB) B cell lymphomas in a subject. Thus, the present invention discloses compositions and methods for the treatment of various disorders or diseases mentioned above using a compound of formula (I), and also discloses the use of a compound of formula (I) for the preparation of medicaments for the treatment of various disorders or diseases mentioned above.

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Detailed description of the invention

In a first aspect, the invention discloses a compound of formula (I)

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is -NR _a R _b , where Ra and R _b are each independently hydrogen,

R2 is hydrogen or -C _1-6 alkyl,

R ₃ and R ₄ , which may be the same or different, are each independently hydrogen or —C _1-6 alkyl,

R5 and R6 are each hydrogen,

R ₇ and R ₈ are each independently hydrogen or halogen,

R ₁₀ is -OR12, where R12 is -C _1-6 alkyl;

R9 is -CONR ₁₂ R ₁₃ ,

R ₁₂ and R ₁₃ , which may be the same or different, each independently represents hydrogen, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 αlkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each said -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted with at least one R15 substituent,

Alternatively, R12 and _R13 together with the atom(s) to which they are attached form a 3-12 membered saturated ring containing 0 or 1 additional heteroatom independently selected from -NH, -O- or -S-, and said ring is optionally substituted with at least one R15 substituent,

R15 is independently at each occurrence hydrogen, halogen, -C _1-6 alkyl, -cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -OR ₁₆ , -COR ₁₆ , -CO ₂ R ₁₆ , -NR ₁₆ R ₁₇ , - C _1-6 αalkyl-NR ₁₆ R ₁₇ , wherein each said -C _1-6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with R19, -OR19, -COR19, or -CO2R19, where each R ₁₆ or R ₁₇ is independently is hydrogen or -C _1-6 alkyl, or

R ₁₆ and R ₁₇ together with the atom(s) to which they are attached form a 3-12 membered saturated, partially or fully unsaturated ring containing 0 or 1 additional heteroatom independently selected from -NH and -O-, and the specified the ring is optionally substituted with at least one R ₁₉ substituent, and where R19 is independently hydrogen, -C _1-6 alkyl, halo-C _1-6 alkyl, cycloalkyl, or heterocyclyl, wherein each said heterocyclyl is optionally substituted with -C _1-6 αlkul , and where the specified -C _1-6 alkyl is optionally substituted with cycloalkyl, heterocyclyl, aryl or heteroaryl, where cycloalkyl contains 3-12 carbon atoms, aryl refers to phenyl, heteroaryl refers to a group selected from

5- or 6-membered aromatic monocyclic rings containing 1 heteroatom selected from N and O as ring atoms, where the remaining ring atoms are carbon;

heterocyclyl refers to a ring selected from 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered monocyclic and bicyclic, saturated rings containing 1-2 heteroatoms, selected from N, S or O as ring atoms.

In an embodiment of the first aspect, R1 is -NH2.

In an embodiment of the first aspect, R2 is independently hydrogen or -C _1-6 alkyl.

In an embodiment of the first aspect, each R ₃ and R ₄ is independently hydrogen or —C _1-6 alkyl. In another embodiment of the first aspect, R ₃ is hydrogen and R ₄ is -C _1-6 alkyl, preferably R ₃ is hydrogen and R 4 is -C _1-3 alkyl, more preferably R ₃ is hydrogen and R ₄ is methyl.

In an embodiment of the first aspect, each R ₅ and R ₆ is hydrogen.

In an embodiment of the first aspect, each R ₇ and R ₈ is hydrogen or halogen. R ₁₀ is -OR ₁₂ where R ₁₂ is -C _1-6 alkyl. In a more preferred embodiment, each R ₇ and R ₈ is independently halogen and R ₁₀ is C _1-6 alkoxy. In an even more preferred embodiment, R ₇ is Cl, R ₈ is F, and R ₁₀ is isopropoxy.

In an embodiment of the first aspect, R9 is -CONR ₁₂ R ₁₃ , where R ₁₂ and R ₁₃ are as defined in formula (I).

In a preferred embodiment, R9 is -CONR ₁₂ R ₁₃ where each R ₁₂ and

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R ₁₃ is hydrogen or -C ₁ . ₆ alkyl optionally substituted with at least one R ₁₅ substituent. More preferably, each R12 and R ₁₃ is hydrogen or methyl, ethyl, npropyl or isopropyl, each of which is optionally substituted with at least one R ₁₅ substituent. In this embodiment, R ₁₅ is preferably hydrogen, cycloalkyl, aryl, heterocyclyl, -OR ₁₆ or -NR16R17, where R ₁₆ and R17 are as defined in formula (I), and where each specified cycloalkyl, aryl or heterocyclyl is independently optionally substituted with R ₁₉ , -OR ₁₉ , -COR ₁₉ or -CO 2 R 19 , where R ₁₉ is as defined in formula (I).

In a preferred embodiment, R ₉ is -CONR12R13, where R12 and R ₁₃ are each hydrogen or -C ₁ . ₆ alkyl optionally substituted with one R ₁₅ substituent which is heterocyclyl optionally substituted with R ₁₉ , -OR ₁₉ , -COR ₁₉ or -CO2 R19, wherein R19 is as defined in formula (I). More preferably R12 is hydrogen and R ₁₃ is C ₁ . ₆ alkyl optionally substituted with one substituent R ₁₅ which is a heterocyclyl optionally substituted with halogen, R ₁₉ , -OR ₁₉ , -COR ₁₉ or -CO 2 R ₁₉ , where R ₁₉ is as defined in formula (I). Even more preferably, the heterocyclyl group is a 4-, 5-, 6-, 7- or 8-membered saturated monocyclic ring containing one nitrogen heteroatom, or a 5-, 6-, 7- or 8-membered saturated monocyclic ring containing one nitrogen atom and 1 additional heteroatom selected from -NH, -O- or -S-, optionally substituted with halogen, R ₁₉ , -OR ₁₉ , -COR ₁₉ or -CO2 R19, where R ₁₉ is as defined in the formula ( I). Further, even more preferably, the heterocyclyl group is a piperidinyl (eg piperidin-1-yl or piperidin-4-yl) or piperazinyl (eg piperazin-1-yl) group optionally substituted with halo, R ₁₉ , -OR ₁₉ , -COR ₁₉ or -CO2R19, where R ₁₉ is as defined in formula (I). Further, even more preferably, the heterocyclyl group is a piperidinyl or piperazinyl group optionally substituted with halo or C ₁ . ₆ alkyl (eg methyl). Further, even more preferably, R12 is hydrogen, _R13 is ethyl, and _R15 is 4-methylpiperazin-1-yl. In particular, R ₉ is

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In a preferred embodiment, R ₉ is -CONR12R13 where R12 is hydrogen and R ₁₃ is cycloalkyl optionally substituted with at least one R15 substituent. More preferably R ₁₃ is C ₃ -C ₈ cycloalkyl optionally substituted with at least one R15 substituent. Even more preferably, R ₁₃ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with at least one R15 substituent. In this embodiment, R15 is preferably -OR16 or -CO2R16 or -C _1-6 alkyl optionally substituted with -OR ₁₉ where R16 and R ₁₉ are as defined in formula (I). In particular, R ₉ is selected from

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In a preferred embodiment, R ₉ is -CONR12R13 where R12 is hydrogen and R13 is a 5-8 membered heterocyclyl containing 1-2 heteroatoms selected from O, NH, S, optionally substituted with at least one R15 substituent . More preferably R13 is a 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from O or NH optionally substituted with at least one R15 substituent. Even more preferably R13 is tetrahydrofuranyl or tetrahydropyranyl, each of which is optionally substituted with at least one R15 substituent. In this embodiment, R15 is preferably halo or -C _1-6 alkyl. In particular, R ₉ is

In a preferred embodiment, R ₉ is -CONR12R13 where R12 is hydrogen and R13 is an aryl group selected from phenyl and naphthyl, optionally substituted with at least one R15 substituent. In this embodiment, R15 is preferably halo, -C _1-6 alkyl, -OR16 or heterocyclyl optionally substituted with R ₁₉ or -OR ₁₉ , where R16 and R ₁₉ are as defined in formula (I). In particular, R ₉ is selected from

In a preferred embodiment, R ₉ is -CONR12R13 where R12 and R13 together with the nitrogen atom to which they are attached form a 3-12 membered saturated ring containing 0 or 1 additional heteroatom independently selected from -NH, -O- or -S-, and said ring is optionally substituted with at least one R ₁₅ substituent.

More preferably R ₉ is -CONR12R13, where R12 and R ₁₃ together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, or 8-membered saturated monocyclic ring containing 0 additional heteroatoms, and said ring is optionally substituted with at least one R15 substituent. In particular, R12 and _R13 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, azepanyl or azocanyl ring, preferably an azetidinyl, pyrrolidinyl or piperidinyl ring. In this embodiment, R15 is preferably halo, -OR ₁₆ , -CO2R16 or -C _1-6 alkyl optionally substituted with -OR ₁₉ , where R ₁₆ and R ₁₉ are as defined in formula (I).

More preferably R ₉ is -CONR12R13 where R12 and R ₁₃ are taken together with the nitrogen atom, to

- 8 040339 to which they are attached form a 5-, 6-, 7-, or 8-membered saturated monocyclic ring containing 1 additional heteroatom selected from -NH, -O-, -S-, and said ring is optionally substituted with at least with one R ₁₅ substituent. Even more preferably, R12 and R13, together with the nitrogen atom to which they are attached, form a morpholinyl or piperazinyl ring, each of which is optionally substituted with at least one R15 substituent. In this embodiment, R15 is preferably hydrogen, halo, -C _1-6 alkyl or cycloalkyl, wherein each said C _1-6 alkyl or cycloalkyl is independently optionally substituted with R ₁₉ , -OR ₁₉ , -COR ₁₉ , or -CO2R19 where R ₁₉ is as defined in formula (I).

More preferably, R ₉ is -CONR12R13, where R12 and R13, together with the nitrogen atom to which they are attached, form a 7-12-membered (e.g., 7-membered, 8-membered, 9-membered, 10-membered) saturated bicyclic ring, containing 0 or 1 additional heteroatom selected from -N, -O- or -S-, and said ring is optionally substituted with at least one R ₁₅ substituent. Even more preferably R ₁₂ and R ₁₃ together with the nitrogen atom to which they are attached form a bicyclic bridged or spiro ring containing 0 or 1 additional heteroatom selected from -N, -O- or -S- and optionally substituted at at least one R ₁₅ substituent. Examples of bicyclic bridged or spiro rings include but are not limited to

methoxy, ethoxy, propoxy or

In an embodiment of the first aspect, R10 is isopropoxy. Preferably R10 is isopropoxy.

For example, R ₉ is selected from

In an embodiment of the first aspect, where the carbon atom to which R3 and R4 are attached is in the ^-configuration when R3 and R4 are different.

In an embodiment of the first aspect, the present invention discloses a compound selected from

- 9 040339

- 10 040339

- 11 040339

- 12 040339

- 13 040339

- 14 040339

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

In an embodiment of the first aspect, the present invention discloses a compound selected from

- 15 040339

- 16 040339

- 17 040339

- 18 040339

- 19 040339

Compound 73 or a pharmaceutically acceptable salt thereof.

The compounds disclosed in the present invention are effective ΡΙ3Κδ inhibitors. In particular, the compounds of the present invention have been found to be selective inhibitors of PI3Kδ over PI3Ka, β and/or γ. More specifically, the compounds of the present invention show better selectivity for PI3Kδ over each of PI3Ka, β and γ. In addition to the above selectivity, the compounds of the present invention have a good pharmacokinetic profile. For example, compound 73 of the present invention has an unexpectedly long half-life.

In a second aspect, the present invention discloses a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed in the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In a third aspect, the present invention discloses a method for treating or preventing the following disorders or diseases susceptible to inhibition of PI3Kδ activity using a compound of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable combination thereof.

- 20 040339 whether, the use of a compound disclosed in the present invention for the preparation of a medicament for the treatment or prevention of a disorder or disease susceptible to inhibition of PI3Kδ activity; and a compound disclosed in the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disorder or disease susceptible to inhibition of PI3Kδ activity, wherein the disorder or disease is an inflammatory disease, an autoimmune disease, or cancer. In some embodiments, the disorder or disease is selected from the group consisting of idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia, vasculitis, systemic lupus erythematosus, lupus nephritis, pemphigus, membranous nephropathy, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML). ), chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), chronic myeloid leukemia (CML), multiple myeloma (MM), hairy cell leukemia, mantle cell lymphoma (MCL), small cell lymphocytic lymphoma (SLL), follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone cell lymphoma, diffuse large B-cell lymphoma (DLBCL) from activated B-like cells (ABC) or diffuse large B-cell lymphoma (DLBCL) from germinal center B-cells (GCB), T-cell lymphoma, B -cell lymphoma, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD) Waldenström macroglobulinemia (WM), pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatic cell carcinoma, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS (central nervous system) cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, small cell lung cancer, colon cancer, myasthenia gravis, rheumatoid arthritis (RA), acute disseminated encephalomyelitis, multiple sclerosis (MS), Sjögren's syndrome, asthma, psoriasis, chronic obstructive pulmonary disease or lupus.

Definitions.

The following terms have the meanings indicated throughout the description:

In the context of this document, including the appended claims, the singular forms of words include their respective plural forms, unless the context clearly indicates otherwise.

The term or is used in the sense of and is used interchangeably with the term and/or unless the context clearly dictates otherwise.

The term alkyl as used herein refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups containing 1 to 18, such as 1 to 12, further, such as 1 to 10, still, such as 1 to 8, or 1 to 6, or 1 to 4 carbon atoms. Examples of alkyl groups containing from 1 to 6 carbon atoms (i.e. C ₁ . ₆ αkyl) include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl (n-Pr), 2-propyl or isopropyl (i-Pr), 1-butyl or n-butyl (n-Bu), 2-methyl-1-propyl or isobutyl (i-Bu), 1-methylpropyl or s-butyl (sBu), 1,1-dimethylethyl or tert-butyl (t-Bu), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1- butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3- pentyl, 2,3-dimethyl-2-butyl and 3,3-dimethyl-2-butyl groups.

The term halogen as used herein refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

The term haloalkyl as used herein refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms such as fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). Examples of haloalkyl include halo-C ₁ . ₈ alkyl, halo-C ₁ . ₆ alkyl or halo-C ₁ . ₄ alkyl, but not limited to -CF ₃ , -CH ₂ Cl, -CH ₂ CF ₃ , -CCl ₂ , CF ₃ and the like.

The term alkenyl as used herein refers to a hydrocarbon group selected from straight and branched hydrocarbon groups containing at least one C=C double bond and 2 to 18, such as 2 to 8, additionally, such as 2 to 6 carbon atoms. . Examples of an alkenyl group, such as C ₂ . ₆ alkenyl, include but are not limited to ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3- enyl, buta-1,3-dienyl, 2-methylbuta-1,3dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl groups .

The term alkynyl as used herein refers to a hydrocarbon group selected from a straight and branched hydrocarbon group containing at least one C=C triple bond and 2 to 18, such as 2 to 8, additionally, such as 2 to 6 carbon atoms. . Examples of an alkynyl group, such as C2. ₆ alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

The term alkyloxy as used herein refers to an alkyl group, as defined above, bonded to oxygen, represented by —Oalkyl. Examples of alkyloxy, eg C ₁ . ₆ αkyloxy or C1. ₄ alkyloxy include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy, and hexoxy, and the like.

- 21 040339

The term cycloalkyl as used herein refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, including monocyclic and polycyclic (eg, bicyclic and tricyclic) groups. For example, a cycloalkyl group may contain 3 to 12, eg 3 to 10, optionally, eg 3 to 8, optionally, eg 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Further, for example, the cycloalkyl group may be selected from a monocyclic group containing 3 to 12, eg 3 to 10, further, eg 3 to 8, 3 to 6 carbon atoms. Examples of the monocyclic cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl , 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl groups. In particular, examples of a saturated monocyclic cycloalkyl group, such as C ₃₈ cycloalkyl, include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In a preferred embodiment, cycloalkyl is a monocyclic ring containing 3 to 6 carbon atoms (abbreviated C _3-6 cycloαkyl), including but not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of bicyclic cycloalkyl groups include groups having 7 to 12 ring atoms arranged in a bicyclic ring selected from [4.4], [4.5], [5.5], [5.6] and [6, 6] ring systems or as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. Additional examples of bicyclic cycloalkyl groups include those arranged in a bicyclic ring selected from [5,6] and [6,6] ring systems, for example where wavy lines indicate points of attachment. The ring may be saturated or have at least one double bond (ie, partially unsaturated), but is not fully conjugated and is not aromatic, as is aromatic in the context of this document.

The term aryl, alone or in combination with other terms, refers to a group selected from:

a) 5- and 6-membered carbocyclic aromatic rings, for example phenyl;

b) bicyclic ring systems, such as 7-12 membered bicyclic ring systems, where at least one ring is carbocyclic and aromatic, such as naphthyl and indanyl, and,

c) tricyclic ring systems, such as 10-15 membered tricyclic ring systems, wherein at least one ring is carbocyclic and aromatic, eg fluorenyl.

The terms aromatic hydrocarbon ring and aryl are used interchangeably in the context of this document. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbons (ie, C5 _-1 oaryl). Examples of a monocyclic or bicyclic aromatic hydrocarbon ring include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthalene-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

The term heteroaryl as used herein refers to a group selected from:

a) 5-, 6-, or 7-membered aromatic monocyclic rings containing at least one heteroatom, such as 1 to 4 or in some embodiments 1 to 3, in some embodiments 1 to 2, heteroatoms selected from nitrogen (N), sulfur (S) and oxygen (O) as the ring atom(s), and the remaining ring atoms are carbon,

b) 8-12-membered bicyclic rings containing at least one heteroatom, for example 1 to 4 or in some embodiments 1 to 3, or in other embodiments 1 or 2, heteroatoms selected from N, O and S as ring atom(s), wherein the remaining ring atoms are carbon, and where at least one ring is aromatic and at least one heteroatom is present in the aromatic ring, and

c) 11-14 membered tricyclic rings containing at least one heteroatom, for example 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2, heteroatoms selected from N, O, and S as ring atom(s), wherein the remaining ring atoms are carbon, and where at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

In a preferred embodiment, heteroaryl is a 5-6 membered heteroaryl containing one nitrogen atom and 0 or 1 additional heteroatom selected from N, O and S, including

- 22 040339 tea, but not limited to, pyridinyl, isoxazolyl and oxazolyl.

When the total number of S and O atoms in a heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is no more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is no more than 1. When the heteroaryl group contains more than one heteroatomic ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides.

The terms aromatic heterocyclic ring and heteroaryl are used interchangeably throughout this specification. In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring has 5-, 6-, 7-, 8-, 9-, or 10 ring-forming members with 1, 2, 3, or 4 heteroatomic ring members independently selected from nitrogen (N) , sulfur (S) and oxygen (O), and the remaining members of the ring are carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is a monocyclic or bicyclic ring containing 1 or 2 heteroatomic ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is a 5-6 membered heteroaryl ring that is monocyclic and that has 1 or 2 heteroatomic ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O) . In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is an 8-10 membered heteroaryl ring that is bicyclic and has 1 or 2 heteroatomic ring members independently selected from nitrogen, sulfur, and oxygen.

Examples of a heteroaryl group or a monocyclic or bicyclic aromatic heterocyclic ring include, but are not limited to (as numbered from the bond position assigned priority 1) pyridyl (such as 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (such as 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl or 1,2,4-thiadiazolyl, or 1,2,4-thiadiazolyl, 3,4thiadiazolyl), tetrazolyl, thienyl (such as thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl or furanyl, benzofuryl, benzoimidazolyl, indolyl, isoindolyl, indolinyl, oxadiazolyl (such as 1,2, 3-oxadiazolyl, 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (such as 1,2,3-triazolyl, 1,2,4-triazolyl or 1 ,3,4-triazolyl), quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (such as 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (such as 1H-pyrazolo[3,4-b] pyridin-5-yl), benzoxazolyl (such as benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa- 2,5-diazolyl, 1-oxa-3,4-diazolyl, 1thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3, 4-diazolyl, furazanil (such as furazan-2-yl, furazan-3-yl), benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (such as benzo[d]thiazol-6-yl ), indazolyl (such as 1H-indazol-5-yl) and 5,6,7,8-tetrahydroisoquinoline.

The term heterocyclic or heterocycle or heterocyclyl as used herein refers to a ring selected from 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered monocyclic, bicyclic and tricyclic , saturated and partially unsaturated rings containing at least one carbon atom, in addition to at least one heteroatom, for example from 1 to 4 heteroatoms, additionally, for example from 1 to 3, or additionally, for example 1 or 2 heteroatoms selected from nitrogen (N), sulfur (S), oxygen (O), -SO- or -SO ₂ - as ring atom(s).

In some embodiments, the heterocyclyl group is a 4-, 5-, 6-, 7-, or 8-membered monocyclic ring with at least one heteroatom selected from N, O, and S. In some preferred embodiments, the heterocyclyl group is 4-, 5-, 6-, 7- or 8-membered saturated monocyclic ring containing one nitrogen heteroatom. A typical heterocyclyl group is azetidinyl, pyrrolidinyl, piperidinyl, azepanil and azocanyl. In another embodiment, the heterocyclyl group is a 5-, 6-, 7- or 8-membered saturated monocyclic ring containing one nitrogen atom and 1 additional heteroatom selected from -NH, -O-, -S-, -SO- or -SO2 -. A typical heterocyclyl group is a morpholino, morpholinyl or piperazinyl ring. In some embodiments, the heterocyclyl group is a 7-12 membered saturated bicyclic ring containing one nitrogen atom and 0, 1, or 2 additional heteroatoms selected from -NH, -O-, -S-, -SO, or -SO2-. In some preferred embodiments, the heterocyclyl group is a bicyclic bridged or spiro ring.

The term heterocycle herein also refers to a 5-7 membered heterocyclic ring containing at least one heteroatom selected from N, O and S fused to a 5-, 6- and/or 7-membered cycloalkyl, carbocyclic aromatic or heteroaromatic ring, provided that the point of attachment is on a heterocyclic ring when the heterocyclic ring is fused to a carbocyclic aromatic or heteroaromatic ring, and that the point of attachment may be on a cycloalkyl or heterocyclic ring when the hetero

- 23 040339 a cyclic ring is fused to a cycloalkyl. A heterocycle, as used herein, also refers to an aliphatic spiro ring containing at least one heteroatom selected from N, O, and S, provided that the point of attachment is on the heterocyclic ring. Rings may be saturated or have at least one double bond (ie, partially unsaturated). The heterocycle may be substituted by oxo. The point of attachment may be carbon or a heteroatom in the heterocyclic ring. The heterocycle is not heteroaryl, in the context of this document. In a preferred embodiment, heterocyclyl is a 5-6 membered heterocyclyl containing one nitrogen atom and 0 or 1 additional heteroatom selected from N, O, and S, including, but not limited to, pyrrolyl, dihydropyridine, morpholino, morpholinyl, and tetrahydropyranyl.

Examples of the heterocycle include, but are not limited to (as numbered from the bond position assigned priority 1) 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, 2-morpholinyl, 3-morpholinyl, oxiranil, aziridinyl, thiiranil, azetidinyl, oxetanil, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanil, oxepanil, thiepanil, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl, 1,4-dithiepanil, 1, 4thiazepanyl and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3- pyrrolinyl, indolinyl, 2H-pyranyl, 4Hpyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl , pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, 1,1-dioxothiomorpholinyl, 3-azabicyclo[3.1.0]hexanyl, 3azabicyclo[4.1.0]heptanyl, and azabicyclo[2.2.2]hexanyl. A substituted heterocycle also includes a ring system substituted with one or more oxo groups such as piperidinyl-N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.

The compounds disclosed in the present invention may contain an asymmetric center and thus may exist as enantiomers. Enantiomers refer to two stereoisomers of a compound that are mismatched mirror images when superimposed. When the compounds disclosed in the present invention have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. It is intended to include within the scope of the invention all such possible stereoisomers, both substantially pure separated enantiomers and their racemic mixtures, and mixtures of diastereomers. It is assumed that all stereoisomers of the compounds disclosed in the present invention and/or their pharmaceutically acceptable salts are included in the scope of the invention. Unless specifically stated otherwise, reference to one isomer refers to any of the possible isomers. When an isomeric composition is not indicated, all possible isomers are included.

The term substantially pure, in the context of this document, means that the target stereoisomer contains no more than 35%, for example no more than 30%, additionally, for example, no more than 25%, still, for example, no more than 20 wt.% of any other stereoisomer ( ov). In some embodiments, the implementation of the term essentially pure means that the target stereoisomer contains no more than 10%, for example, no more than 5%, for example, no more than 1 wt.% any other stereoisomer(s).

When the compounds of the present invention contain olefinic double bonds, unless otherwise indicated, such double bonds are meant to include both E and Z geometric isomers.

Some of the compounds of the present invention that may exist with different hydrogen attachment points are tautomers. For example, compounds containing carbonyl -CH ₂ C(O)- groups (keto forms) may undergo tautomerism to form hydroxyl -CH=C(OH)- groups (enol forms). Both the keto and enol forms, either singly or mixtures thereof, are also included within the scope of the invention where applicable.

It may be advantageous to separate the reaction products from each other and/or from the starting materials. The desired products of each step or series of steps are separated and/or purified (further separated) to the desired degree of homogeneity by methods known in the art. Typically, such separations include multiphase extraction, crystallization from a solvent or mixture of solvents, distillation, sublimation, or chromatography. Chromatography can include any number of methods including, for example: reversed phase and normal phase, size exclusion, ion exchange, high, medium and low pressure liquid chromatography methods and apparatus, analytical small scale, pseudo moving bed (SMB), and preparative thin or thick layer chromatography. , as well as small scale thin layer and flash chromatography methods. One skilled in the art can use the methods most likely to achieve the desired separation.

The term diastereomers refers to stereoisomers of a compound with two or more chiral centers, but which are not mirror images of each other. Diastereomeric mixtures may be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as chromatography and/or

- 24 040339 fractional crystallization. Enantiomers can be separated by converting an enantiomeric mixture to a diastereomeric mixture by reacting with an appropriate optically active compound (e.g., a chiral excipient such as a chiral alcohol or Mosher acid chloride), separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers . Enantiomers can also be separated using a chiral HPLC (High Performance Liquid Chromatography) column.

One stereoisomer, for example, a substantially pure enantiomer, can be obtained by separating a racemic mixture using a method, such as the formation of diastereomers, using optically active resolving agents [Eliel E. and Wilen S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller S.N. et al. Chromatographic resolution of enantiomers: Selective review. J. Chromatogr., 113(3) (1975): pp. 283-302]. Racemic mixtures of chiral compounds of the present invention may be resolved and isolated by any suitable method, including: (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatives of reagents, separation of diastereomers, and conversion to pure stereoisomers; and (3) separation of substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

Pharmaceutically acceptable salts refer to those salts that are medically suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and a reasonable benefit/risk ratio. A pharmaceutically acceptable salt can be obtained in situ during the final isolation and purification of the compounds of the present invention or separately by reacting the functional free base with a suitable organic acid or by reacting an acidic group with a suitable base.

In addition, when the compound of the present invention is obtained as an acid addition salt, the free base can be obtained by alkalizing the acid salt solution. Conversely, if the product is a free base, addition salt, such as a pharmaceutically acceptable addition salt, it can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid in accordance with conventional methods for preparing an acid addition salt from basic compounds. Those skilled in the art are aware of various synthetic methods that can be used without undue experimentation to produce non-toxic, pharmaceutically acceptable addition salts.

As defined herein, a pharmaceutically acceptable salt thereof includes salts of at least one compound of formula (I) and salts of stereoisomers of a compound of formula (I), such as salts of enantiomers and/or salts of diastereomers.

The terms administration, treatment, and processing, as used herein, in relation to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, means the contact of an exogenous pharmaceutical agent, therapeutic, diagnostic agent, or composition and an animal, human, subject, cell, tissue, organ or biological fluid. Treatment of a cell includes contact of a reagent with a cell, as well as contact of a reagent with a liquid, where the liquid is in contact with the cell. The terms administration and treatment also refer to in vitro and ex vivo treatment of, for example, a cell with a reagent, diagnostic compound, binder, or other cell. The term subject herein includes any organism, preferably an animal, more preferably a mammal (eg, rat, mouse, dog, cat, rabbit), and most preferably a human.

The term effective amount or therapeutically effective amount refers to the amount of an active ingredient, such as a compound, which, when administered to a subject for the treatment of a disease, or at least one of the clinical symptoms of the disease or disorder, is sufficient to affect such treatment of the disease, disorder, or symptom. . The therapeutically effective amount may vary depending on the compound, the disease, disorder and/or symptoms of the disease or disorder, the severity of the disease, disorder and/or symptoms of the disease or disorder, the age of the subject and/or the body weight of the subject being treated. The appropriate amount in any given case may be apparent to those skilled in the art, or may be determined by routine experimentation. In some embodiments, a therapeutically effective amount is an amount of at least one compound and/or at least one stereoisomer thereof and/or at least one pharmaceutically acceptable salt thereof disclosed in the present invention, effective for treating, as defined above, a disease or disorder in the subject. In the case of combination therapy, a therapeutically effective amount refers to the total number of combined entities for effective treatment of a disease, disorder or condition.

- 25 040339

The term at least one substituent as disclosed herein includes, for example, 1 to 5, such as 1 to 4, additionally 1, 2, or 3 substituents, provided valency permits. For example, at least one substituent R ₁₅ according to the present invention includes from 1 to 4, for example from 1 to 3, additionally 1 or 2 substituents selected from the list of R ₁₅ as defined in this document.

A pharmaceutical composition containing a compound of the present invention may be administered by oral, inhalation, rectal, parenteral, or topical administration to a subject in need thereof. For oral administration, the pharmaceutical composition may be in a conventional solid form such as tablets, powder, granules, capsules and the like, a liquid form such as an aqueous or oily suspension, or another liquid form such as a syrup, solution, suspension or the like, for parenteral administration, the pharmaceutical composition may be a solution, an aqueous solution, an oil suspension concentrate, a lyophilized powder, or the like. Preferably the form of the pharmaceutical composition is selected from a tablet, coated tablet, capsule, suppository, nasal spray or injection, more preferably a tablet or capsule. The pharmaceutical composition may be in a single dose dosage form. In addition, the pharmaceutical composition may further contain additional active ingredients.

All formulations of the pharmaceutical composition of the present invention can be obtained by conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients to then obtain the desired composition. Pharmaceutically acceptable excipient refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical composition, for example: a diluent, a carrier such as water, various organic solvents, etc., an excipient such as starch, sucrose, etc., a binder, such a cellulose derivative, alginates, gelatin and polyvinylpyrrolidone (PVP), a wetting agent such as glycerol, a leavening agent such as agar, calcium carbonate and sodium bicarbonate, an absorption enhancer such as a quaternary ammonium compound, a surfactant such as hexadecanol, an absorbent carrier such as kaolin and soap clay, a lubricant such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition further contains other pharmaceutically acceptable excipients such as a decentralized agent, a stabilizer, a thickener, a complexing agent, a buffering agent, a penetration enhancer, a polymer, flavoring agents, a sweetener, and a coloring agent.

The term disease refers to any disease, discomfort, illness, symptom, or indication, and may be used interchangeably with the term disorder or condition.

Throughout this specification and the following claims, unless the context otherwise requires, the term contain and variations such as contains and comprising are intended to indicate the presence of subsequent features, but do not exclude the presence or addition of one or more other features. The term containing, in the context of this document, may be replaced by the term consisting, including, or sometimes having.

Throughout the present description and the following claims, the term C _n _m denotes a range that includes endpoints, where n and m are integers and indicate the number of carbon atoms. Examples include C1. ₈ , _C1-6 and the like.

Unless specifically defined elsewhere in this document, all other technical and scientific terms used in this document have the meaning generally accepted by a person skilled in the art to which the present invention pertains.

General synthesis.

The compounds of the present invention, including their salts, can be obtained using known methods of organic synthesis and can be synthesized in accordance with any of the many possible synthetic routes.

The reaction to obtain the compounds described herein can be carried out in suitable solvents, which can be easily selected by a person skilled in the field of organic synthesis. Suitable solvents may not substantially react with the starting materials, intermediates, or products at the temperatures at which the reactions are carried out, for example, at temperatures that may differ from the boiling point of the solvent. This reaction can be carried out in a single solvent or a mixture of solvents.

The choice of an appropriate protecting group can be readily determined by one of ordinary skill in the art.

Reactions can be monitored according to any suitable method known in the art such as NMR (Nuclear Magnetic Resonance), UV (Ultra Violet Spectroscopy), HPLC, LC-MS, Liquid Chromatography with Mass Spectrometry and TLC (Thin Layer Chromatography). Compounds can be purified by a variety of methods, including HPLC and normal phase silica gel chromatography.

Chiral analytical HPLC is used to analyze the retention times of various chiral examples, the conditions are divided into methods as shown below, according to the column, the mobile phase, the amount of solvent used.

Method A

Column CHIRAL CEL OD-H Column size 4.6 cm χ 150 cm χ 5 µm Injection 0.3 ml mobile phase Hexane: EUN (ethyl acetate) (0.1% DEA) = 90:10 Flow rate 1 ml/min Wavelength UV 214 nm Temperature 35°C

Method B

Column CHIRAL CEL OD-H Column size 4.6 cm χ 150 cm χ 5 µm Injection 0.3 ml mobile phase Hexane:E1OH (0.1% DEA) = 85:15 Flow rate 1 ml/min Wavelength UV 214 nm Temperature 35°C

Method C

Column CHIRAL RKA IA Column size 4.6 cm χ 150 cm χ 5 µm Injection 0.3 ml mobile phase Hexane: EUN (0.1% DEA) = 85:15 Flow rate 1 ml/min Wavelength UV 214 nm Temperature 35°C

Method D

Column CHIRAL RKA IA Column size 4.6 cm χ 150 cm χ 5 µm Injection 0.3 ml mobile phase Hexane: EUN (0.1% DEA) = 90:10 Flow rate 1 ml/min Wavelength UV 214 nm Temperature 35°C

Method E

Column CHIRAL RKA AS-H Column size 4.6 cm x 150 cm x 5 µm Injection 0.3 ml mobile phase Hexane: EUN (0.1% DEA) = 85:15 Flow rate 1 ml/min Wavelength UV 214 nm Temperature 35°C

- 27 040339

Method F Column CHIRAL RKA AS-H Column size 4.6 cm x 150 cm x 5 µm Injection 0.3 ml mobile phase Hexane.EUUN (0.1% DEA) = 90:10 Flow rate 1 ml/min Wavelength UV 214 nm Temperature 35°C

Method G

Column CHIRAL RKA AS-H Column size 4.6 cm x 150 cm x 5 µm Injection 0.3 ml mobile phase Hexane: EUN (0.1% DEA) = 95:05 Flow rate 1 ml/min Wavelength UV 214 nm Temperature 35°C Method H

Column CHIRAL CEL OD-H Column size 4.6 cm x 150 cm χ 5 µm Injection 0.3 ml mobile phase Hexane:E1OH (0.1% DEA) = 95:05 Flow rate 1 ml/min Wavelength UV 214 nm Temperature 35°C

Method I

Column CHIRAL RKA AD-H Column size 4.6 cm x 150 cm x 5 µm Injection 0.3 ml mobile phase Hexane: EUN (0.1% DEA) = 90:10 Flow rate 1 ml/min Wavelength UV 214 nm Temperature 35°C

Way J

Column CHIRAL RKA IA Column size 4.6 cm x 150 cm x 5 µm Injection 0.3 ml mobile phase Hexane:E1OH (0.1% DEA) = 80:20 Flow rate 1 ml/min Wavelength UV 214 nm Temperature 35°C

- 28 040339

Way K

Column CHIRAL CEL OD-H Column size 4.6 cm χ 150 cm χ 5 µm Injection 0.3 ml mobile phase Hexane: EUN (0.1% DEA) = 80:20 Flow rate 1 ml/min Wavelength UV 214 nm Temperature 35°C

Method L

Column CHIRAL RKA AS-H Column size 4.6 cm χ 150 cm χ 5 µm Injection 0.3 ml mobile phase Hexane: EUN (0.1% DEA) = 92:08 Flow rate 1 ml/min Wavelength UV 214 nm Temperature 35°C

Scheme I

EDC1 - 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

For example, compounds of formula (I) where R9 is -CONR12R ₁₃ can be prepared as shown in Scheme I. Compound (i) can be halogenated with N-chlorosuccinamide, N-bromosuccinamide, or N-iodosuccinamide to give compound (ii ) where X1=Cl, Br or I, respectively. A Wittig reaction is then carried out from compound (ii) under standard conditions (eg Ph ₃ PCH ₃ Br/nBuLi or other bases such as NaH) to give compound (iii) which is carried out under standard Brown reaction conditions using BH3/ H2O2 to give compound (iv) which is oxidized directly with NaClO/NaClO2 or Jones reagent to give acidic compound (v), compound (v) is used for condensation under HOBt (Hydroxybenzotriazole) or EDCI conditions with a suitable amine according to Scheme I to give compound (vi), which was cyclized directly with Tf2O (Trifluoromethanesulfonic anhydride) or POCl ₃ to give compound (vii). Amination of compound (vii) to give compound (viii), which was used to introduce CO2 or CO under nBuLi or palladium catalyst conditions, to give compound (ix). Compound (ix) is then reacted with various amines in the presence of HOBt/EDCI to give compound (x) (ie formula (I) where R9 is -CONR12R13).

- 29 040339

Scheme II

Formula (I). where R ₉ is -CONR12R13

Compounds of formula (I) wherein R9 is -CONR12R ₁₃ can also be prepared by the route shown in Scheme II. Compound (i) can be converted to compound (ii) using a Tosmic reagent, followed by hydrolysis under acidic or basic conditions to give compound (iii), which is used for condensation under HOBt or EDCI conditions to give compound (iv). Compound (iv) is then subjected to cyclization under Tf ₂ O or POCl ₃ to give compound (v). Amination of compound (v) gives compound (vi) which is carried out using CO ₂ and a lithium reagent or CO and palladium catalysts to give compound (vii) which is used to condense with various amines to give compound (viii) (i.e. formula (I) where R9 is -CONR12R13).

Scheme III

Compounds of formula (I) wherein R9 is -CONR12R13 can also be prepared by the route shown in Scheme III. The acid (i.e., compound (i)) is subjected to a decarboxylated condensation reaction under metal catalysts or other radical reagent conditions with compound (ii) to obtain compound (iii), which is carried out using CO ₂ and a lithium reagent or CO and palladium catalysts to to obtain compound (iv) which is used for condensation with various amines to obtain compound (v) (ie formula (I) where R9 is -CONR12R13).

- 30 040339

Scheme IV

a -CONR12R13

Compounds of formula (I) wherein R9 is -CONR12R13 can also be prepared by the route shown in Scheme IV. Compound (i) can be chirally separated to give a chiral acid ii with an R or S configuration. The chiral compound (ii) is used for condensation under HOBt or EDCI conditions to give the chiral compound (iii), which is then subjected to cyclization under Tf ₂ O or POCl ₃ conditions to give the chiral compound (iv). Amination of a chiral compound iv gives a chiral compound v which is carried out using CO2 and a lithium reagent or CO and palladium catalysts to give a chiral compound (vi) which is used to condense with various amines to give a chiral compound (vii) (i.e. formula (I ) where R ₉ is -CONR ₁₂ R ₁₃ ). Scheme V

Formula (I)

For example, compounds of formula (I) where R9 is -NR ₁₂ CONR ₁₃ R ₁₄ can also be prepared by the route shown in Scheme V. Compound (i) can be subjected to a Curtius rearrangement to give compound (ii) which is then contacted with triphosgene and universal amines to obtain compound (iii) (ie formula (I), where R9 represents -NR ₁₂ CONR ₁₃ R ₁₄ ).

Scheme VI

Formula (I) where R ₉ is -CONR12R13

LDA - Lithium diisopropylamide

LiTMP - Lithium Tetramethylpiperidine

For example, compounds of formula (I) wherein R9 is -CONR12R13 can also be prepared by the route shown in Scheme VI. The halogen of compound (i) (i.e. X1) can be removed with iPrMgBr or iPrMgCl to give compound (ii) which is then contacted with LDA or LiTMP in the presence of CO ₂ to give compound (iii) which is used to couple various amines V

- 31 040339 in the presence of HATU (N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide), HOBt, EDCI, PyBOP ( benzotriazol-1-yl-hydroxytripyrrolidinophosphonium hexafluorophosphate), etc. to give compound (iv) (ie formula (I) where R ₉ is —CONR ₁₂ R ₁₃ ).

Abbreviations.

HOBt - Hydroxybenzotriazole;

EDCI - 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride;

Tf ₂ O - trifluoromethanesulfonic anhydride;

HATU - N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide;

RuBOP - benzotriazol-1-yl-hydroxytripyrrolidinophosphonium hexafluorophosphate;

LDA - lithium diisopropylamide;

LiTMP - lithium tetramethylpiperidine;

NBS - N-bromosuccinimide;

DMF - N,N-dimethylformamide;

THF - tetrahydrofuran;

PE - petroleum ether;

EA - ethyl acetate;

aq. - water;

TLC - thin layer chromatography;

DCM - dichloromethane;

i-PrOH - isopropanol;

EtOAc - ethyl acetate;

Examples

Example 1 1-(3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxybenzoyl)azetidine-3 -carboxylic acid (compound 1)

Step 1: 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one (1-1)

ABOUT

X T

To a 2 L three-necked flask equipped with a magnetic stirrer were added 4-chloro-3fluorophenol (160 g, 1.1 mol) and acetyl chloride (129 g, 0.69 mol). The mixture was stirred for 1 hour. Aluminum chloride (219 g, 1.6 mol) was then added portionwise to the mixture. The mixture is heated to 160°C and kept at 150°C for 2 hours the Mixture is cooled and diluted with HCl (2M, 500 ml). The resulting hot liquid is cooled and extracted with ethyl acetate (3x500 ml). The combined organic phase was washed with water (500 ml) and brine (500 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give 200 g (crude) 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethan- 1 it is in the form of a yellow solid. 1H NMR (400 MHz, CDCl ₃ ) δ 12.48-12.41 (m, 1H), 7.78 (d, J=8.1 Hz, 1H), 6.77 (d, J=10.3 Hz, 1H), 2.61(s, 3H).

Step 2: 1-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one (1-2)

About χ t nstut Br

To a solution of 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one (110 g, 412 mmol) in DMF (1 L) was added NBS (114 g, 640 mmol) in portions. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (3 L), extracted with ethyl acetate (3x1 L). The combined organic phase was washed with brine (3x1 L), dried over anhydrous sodium sulfate, filtered and concentrated to give 150 g (crude) 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one as yellow solid. 1H NMR (400 MHz, CDCl ₃ ) δ 13.21 (d, J=1.8 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 2.66 (s, 3H) .

Step 3: 1-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)ethan-1-one (1-3)

- 32 040339

To a solution of 1-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one (150 g, 560 mmol) and 2-iodopropane (143 g, 841 mmol) in DMF (1 L) add NaHCO ₃ (71 g, 845 mmol). The mixture is stirred at 60°C overnight. The mixture is cooled and diluted with water (3 l), extracted with ethyl acetate (3x1 l). The combined organic phase was washed with brine (3x1 L), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with hexane/ethyl acetate = 50/1) to obtain 140 g (80%) of 1-(3-bromo-5-chloro-4-fluoro-2isopropoxyphenyl)ethan-1-one as yellow oils. 1H NMR (400 MHz, CDCl ₃ ) δ 7.57 (d, J=8.2 Hz, 1H), 4.45-4.39 (m, 1H), 2.61 (s, 3H), 1, 31 (t, J=6.7 Hz, 6H).

Step 4: 3-bromo-1-chloro-2-fluoro-4-isopropoxy-5-(prop-1-en-2-yl)benzene (1-4)

To a mixture of bromo(methyl)triphenylphosphane (41 g, 115 mmol) in THF (400 ml) was added nBuLi (1.6 M, 72 ml, 115 mmol) dropwise at 0°C. The mixture is stirred at 0° C. for 30 minutes. A solution of 1-(3bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)ethan-1-one (30 g, 97 mmol) in THF (100 ml) was added dropwise to the mixture at 0°C. The mixture was stirred at 0° C. for 4 hours. The mixture was quenched with water (500 ml), extracted with ethyl acetate (3x200 ml). The combined organic phase is washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (elution with hexane/ethyl acetate=100/1) to give 5.0 g (17%) of 3bromo-1-chloro-2-fluoro-4-isopropoxy-5-(prop-1-ene- 2-yl)benzene as a yellow oil. 1H NMR (400 MHz, CDCl ₃ ) δ 7.21-7.17 (m, 1H), 5.20-5.16 (m, 1H), 5.13-5.10 (m, 1H), 4 .54-4.44 (m, 1H), 2.10-2.08 (m, 3H), 1.291.25 (m, 6H).

Step 5: 2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)propan-1-ol (1-5)

To a 3 L flask equipped with a magnetic stirrer, add 3-bromo-1-chloro-2-fluoro-4isopropoxy-5-(prop-1-en-2-yl)benzene (170 g, 553 mmol) and BH3-THF (1M, 1660 ml). The mixture is stirred overnight at room temperature. The mixture was carefully quenched with water (100 ml). A solution of NaOH (22 g, 550 mmol) in water (400 ml) was added dropwise to the mixture at 0°C, then H ₂ O ₂ (30%, 188 ml) was added dropwise to the mixture at 0°C. The mixture was stirred at room temperature for 4 hours. The mixture was carefully quenched with NaHSO ₃ solution (1 L) in an ice bath. The mixture is then extracted with ethyl acetate (3 x 1000 ml). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 200 g (crude) 2-(3-bromo-5-chloro-4fluoro-2-isopropoxyphenyl)propan-1-ol as a yellow oil .

Step 6: 2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)propanoic acid (1-6)

To a solution of 2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)propan-1-ol (200 g, 614 mmol) and TEMPO (0.8 g, 5.1 mmol) in acetonitrile (1 k) add phosphate buffer (pH 6.7, 1 l). The mixture is cooled in a water bath. A mixture of NaClO (10%, 500 ml) and NaClO ₂ (180 g in water, 500 ml) was added dropwise to the mixture over 30 minutes. The mixture is stirred for 2 h, then the mixture is extracted with ethyl acetate (2x1000 ml). The combined organic phase is treated with HCl (2M, 500 ml), the organic phase is separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with acetonitrile (150 ml) and the precipitate was collected by filtration to give 90 g (43%) of 2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)propanoic acid as a white solid. ¹ H NMR (400 MHz, DMSO^) δ 12.55 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 4.60-4.50 (m, 1H), 4 .03 (q, J=7.2 Hz, 1H), 2.08 (s, 3H), 1.37 (d, J=7.3 Hz, 3H), 1.31-1.27 (m, 6H). MS (Mass Spectrometry)) (ESI) (Electrospray Ionization) m/e [M-H] - 336.9, 338.9.

Step 7: 2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)-N-(1-(3-chloropyrazin-2-yl)ethyl)propanamide

- 33 040339 (1-7)

To a solution of 2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)propanoic acid (13.0 g, 38.3 mmol) and 1-(3-chloropyrazin-2-yl)ethan-1- amine (6.0 g, 38.1 mmol) in dichloromethane (150 ml) Et ₃ N (11.6 g, 114.6 mmol), HOBT (6.2 g, 45.9 mmol) and EDCI (8 .8 g, 45.9 mmol). The mixture was stirred for 3 hours. The mixture was diluted with water (300 ml), extracted with dichloromethane (3x100 ml). The combined organic phase is dried and concentrated. The residue was purified by silica gel column chromatography (elution with dichloromethane/ethyl acetate 20/1 to 5/1) to give 11.4 g (62%) of 2-(3-bromo-5chloro-4-fluoro-2-isopropoxyphenyl)-N -(1-(3-chloropyrazin-2-yl)ethyl)propanamide as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.30 (d, J=2.4 Hz, 1H), 8.26 (d, J=2.4 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 6.96 (d, J=7.6 Hz, 1H), 5.47-5.39 (m, 1H), 4.73-4.63 (m, 1H) , 4.15-4.07 (m, 1H), 1.51-1.42 (m, 9H), 1.32 (d, J=6.2 Hz, 3H). MS (ESI) m/e [M+1]+ 478.0, 480.0.

Step 8: 3-(1-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)ethyl)-8-chloro-1-methylimidazo[1,5-a]pyrazine (1-8)

To a solution of 2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)-N-(1-(3-chloropyrazin-2-yl)ethyl)propanamide (11.4 g, 23.8 mmol) in dichloromethane (130 ml) and a solution of Tf ₂ O in dichloromethane (30 ml) was added dropwise. Then a solution of pyridine (9.4 g, 119 mmol) in dichloromethane (40 ml) was added dropwise to the mixture. The mixture was stirred at room temperature for 1 hour. The mixture was quenched with water (200 ml), extracted with dichloromethane (3x100 ml). The combined organic phase is dried and concentrated. The residue was purified by silica gel column chromatography (elution with dichloromethane/ethyl acetate 20/1 to 5/1) to give 8.0 g (73%) of 3-(1-(3-bromo-5-chloro-4-)fluoro- 2-isopropoxyphenyl)ethyl)-8-chloro-1-methylimidazo[1,5-a]pyrazine as a yellow solid. 1H NMR (400 MHz, CDCl ₃ ) δ 7.57 (d, J=4.8 Hz, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.15 (d, J= 4.6 Hz, 1H), 4.84-4.69 (m, 2H), 2.82 (s, 3H), 1.86 (d, J=7.0 Hz, 3H), 1.53 ( d, J=6.1 Hz, 3H), 1.38 (d, J=6.1 Hz, 3H). MS (ESI) m/e [M+1]+ 459.9, 462.0.

Step 9: 3-(1-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)ethyl)-1-methylimidazo[1,5-a]pyrazine-8amine (1-9)

3-(1-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)ethyl)-8-chloro-1-methylimidazo[1,5-a]pyrazine mixture (1.01 g, 2.2 mmol) and NH3 in iPrOH (20 ml) in a steel tube, stirred at 90°C for 48 h. After completion, the mixture was evaporated in vacuo. To the residue was added 50 ml of ethyl acetate, washed with water (30 ml x 2), dried over Na ₂ SO ₄ , filtered and evaporated in vacuo to give the crude product, then the crude product was stirred in petroleum ether (250 ml) and filtered to obtain the product ( 0.96 g, 98.3%) as a white solid.

Step 10: 3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxybenzoic acid (1-10)

To a solution of compound 1-9 (1.15 g, 2.6 mmol) in THF (50 ml) was added dropwise n-BuLi (2.4M, 3.5 ml) at -78°C. The mixture is stirred for 10 minutes and CO2 gas is bubbled into the mixture. Mixture

- 34 040339 stirred for 30 minutes. The mixture is warmed to room temperature and quenched with water (50 ml), washed with ethyl acetate (30 ml). The aqueous layer was separated, acidified with concentrated HCl to pH 1 and concentrated to give 1.1 g (crude) 3-(1-(8-amino-1-methylimidazo[1,5a]pyrazin-3-yl)ethyl)- 5-chloro-6-fluoro-2-isopropoxybenzoic acid as a yellow solid. MS (ESI) m/e [M+H]+ 407.1.

Step 11: methyl 1-(3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2isopropoxybenzoyl)azetidine-3- carboxylate (1-11)

Et ₃ N (1.0 g, 10 mmol) and PyBOP ( 260 mg, 0.5 mmol). The mixture was stirred for 2 hours. The mixture was diluted with water (50 ml), extracted with ethyl acetate (3x30 ml). The combined organic phase was washed with water (50 ml), brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give 100 mg (crude) methyl 1-(3-(1-(8-amino-1- methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxybenzoyl)azetidine-3-carboxylate as a yellow oil. MS (ESI) m/e [M+H]+ 504.2.

Step 12: 1-(3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro2-isopropoxybenzoyl)azetidine-3- trifluoroacetate carboxylic acid (1-12)

To a solution of compound 1-11 (100 mg, crude) in MeOH (Methanol) (10 ml) was added an aqueous solution of NaOH (1M, 10 ml). The mixture is stirred for 6 hours and concentrated in vacuo. The residue was purified by preparative HPLC to give 30 mg (25%) of 1-(3-(1-(8-amino-1methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoroacetate -2-isopropoxybenzoyl)azetidine-3-carboxylic acid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.51 (brs, 2H), 7.53-7.43 (m, 2H), 6.93 (d, J=5.9 Hz, 0.5H ), 6.86 (d, J=5.9 Hz, 0.5H), 4.88-4.80 (m, 1H), 4.44-4.36 (m, 1H), 4.23 ( t, J=9.5 Hz, 1H), 4.11-4.01 (m, 2H), 3.96-3.85 (m, 1H), 3.50-3.37 (m, 1H) , 2.64 (s, 3H), 1.64 (t, J=6.6 Hz, 3H), 1.26-1.11 (m, 6H). MS (ESI) m/e [M+H]+ 490.1.

Example 2 1-(3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxybenzamido)cyclopropan-1 -carboxylic acid (compound 2)

The desired compound was prepared from compound 1-10 and ethyl 1-aminocyclopropane-1-carboxylate analogously to compound 1 in Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (s, 1H), 8, 60 (s, 2H), 7.54-7.47 (m, 2H), 6.95 (d, J=5.8 Hz, 1H), 4.85 (q, J=7.0 Hz, 1H ), 4.78-4.67 (m, 1H), 2.64 (s, 3h), 1.61 (d, J=7.0 Hz, 3H), 1.46-1.38 (m, 1H), 1.15 (d, J=5.9 Hz, 3H), 1.10-1.01 (m, 5H). MS (ESI) m/e [M+H]+ 490.1.

Example 3 (3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)(3-hydroxyazetidine- 1-yl) methanone (compound 3)

- 35 040339

The desired compound was obtained from compound 1-10 and azetidin-3-ol in a manner analogous to the preparation of compound 1-11 in Example 1. 1 NMR (400 MHz, DMSO-d ₆ ) δ 7.39-7.33 (m, 1H), 7 .24-7.19 (m, 1H), 6.876.78 (m, 1H), 6.46 (s, 2H), 5.90-5.80 (m, 1H), 4.81-4.73 (m, 1H), 4.57-4.45 (m, 1H), 4.42-4.30 (m, 1H), 4.284.19 (m, 1H), 4.07-3.99 (m , 1H), 3.81-3.67 (m, 2H), 2.57 (s, 3H), 1.70-1.55 (m, 3H), 1.40-1.15 (m, 6H ). MS (ESI) m/e [M+1]+ 462.1.

Example 4 (3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)(morpholino)methanone ( Connection 4)

4A 4B

The desired compound is obtained from compound 1-10 and morpholine in a similar manner to compound 1-11 in Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.46 (d, J=8.7 Hz, 0.3H ), 7.36 (d, J=8.5 Hz, 0.7H), 7.26 (d, J=5.0 Hz, 0.3H), 7.17 (d, J=5.0 Hz , 0.7H), 6.86 (d, J=5.0 Hz, 0.3H), 6.82 (d, J=5.0 Hz, 0.7H), 6.53-6.42 ( m, 2H), 4.81-4.70 (m, 1H), 4.45-4.35 (m, 0.7H), 4.31-4.21 (m, 0.3H), 3, 79-3.55 (m, 4H), 3.55-3.46 (m, 2H), 3.15-2.99 (m, 2H), 2.59-2.55 (m, 3H), 1.67 (d, J=7.1 Hz, 2H), 1.56 (d, J=7.1 Hz, 1H), 1.25 (t, J=6.5 Hz, 4H), 1, 17 (d, J=6.1 Hz, 1H), 0.99 (d, J=6.0 Hz, 1H). MS (ESI) m/e [M+1]+ 476.1.

Compound 4 was separated using a chiral column to give compound 4A (peak 1, S or R, retention time (RT) at 8.78 min in chiral analysis, method A) and compound 4B (peak 2, R or S, retention time ( RT) at 8.19 min in chiral analysis, method A).

Compound 4A: 1H NMR (400 MHz, DMSOCH) δ 7.46 (d, J=8.7 Hz, 0.3H), 7.36 (d, J=8.5 Hz, 0.7H), 7. 26 (d, J=5.0 Hz, 0.3H), 7.17 (d, J=5.0 Hz, 0.7H), 6.86 (d, J=5.0 Hz, 0.3H ), 6.82 (d, J=5.0 Hz, 0.7H), 6.53-6.42 (m, 2H), 4.81-4.70 (m, 1H), 4.45- 4.35 (m, 0.7H), 4.31-4.21 (m, 0.3H), 3.79-3.55 (m, 4H), 3.55-3.46 (m, 2H ), 3.152.99 (m, 2H), 2.59-2.55 (m, 3H), 1.67 (d, J=7.1 Hz, 2H), 1.56 (d, J=7, 1 Hz, 1H), 1.25 (t, J=6.5 Hz, 4H), 1.17 (d, J=6.1 Hz, 1H), 0.99 (d, J=6.0 Hz , 1H). MS (ESI) m/e [M+1]+ 476.1.

Compound 4B: 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.46 (d, J=8.7 Hz, 0.3H), 7.35 (d, J=8.5 Hz, 0.7H) , 7.25 (d, J=5.1 Hz, 0.3H), 7.16 (d, J=5.0 Hz, 0.7H), 6.85 (d, J=5.0 Hz, 0.3H), 6.82 (d, J=5.0 Hz, 0.7H), 6.53-6.42 (m, 2H), 4.81-4.70 (m, 1H), 4 .45-4.35(m, 0.7H), 4.31-4.21(m, 0.3H), 3.79-3.55(m, 4H), 3.55-3.45( m, 2H), 3.143.00 (m, 2H), 2.59-2.55 (m, 3H), 1.67 (d, J=7.1 Hz, 2H), 1.56 (d, J =7.1 Hz, 1H), 1.25 (t, J=6.5 Hz, 4H), 1.17 (d, J=6.1 Hz, 1H), 0.99 (d, J=6 .0 Hz, 1H). MS (ESI) m/e [M+1]+ 476.1.

Chiral separation conditions are shown below

Column CHIRALPAK IG Column size 2 cm χ 25 cm χ 5 µm Injection 1 ml mobile phase Hexane (0.2% isopropylamine):isopropylamine = 70:30 Flow rate 20 ml/min Wavelength UV 220 nm Temperature 25°C Sample solution 15.3 mg/mL in DXM: EUN = 1:2 Equipment for preparative HPLC Prep-Gilson-HPLC

Example 5 3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-X-(1-(hydroxymethyl)cyclopropyl) -2-isopropoxybenzamide (compound 5)

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The desired compound was prepared from compound 1-10 and (1-aminocyclopropyl)methanol in a similar manner to compound 1-11 in Example 1. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (s, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.23 (d, J=5.1 Hz, 1H), 6.85 (d, J=5.0 Hz, 1H), 6.44 (s , 2H), 4.75 (q, J=6.9 Hz, 1H), 4.67 (t, J=5.6 Hz, 1H), 4.49 (dt, J=12.1, 6, 0 Hz, 1H), 3.55 (d, J=5.7 Hz, 2H), 2.56 (s, 3H), 1.56 (d, J=7.1 Hz, 3H), 1.18 (d, J=6.0 Hz, 3H), 1.08 (d, J=6.0 Hz, 3H), 0.78 (t, J=5.7 Hz, 2H), 0.61 (t , J=5.7 Hz, 2H). MS (ESI) m/e [M+1]+ 476.4.

Compound 5 was separated using a chiral column to give compound 5A (peak 1, S, retention time (RT) at 4.80 min in chiral analysis, method A) and compound 5B (peak 2, R, retention time (RT) at 6.11 min in chiral analysis, method A).

Compound 5A: 1H NMR (400 MHz, DMSO-d^ δ 8.92 (s, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.23 (d, J=5.1 Hz, 1H), 6.85 (d, J=5.0 Hz, 1H), 6.44 (s, 2H), 4.75 (q, J=6.9 Hz, 1H), 4.67 ( t, J=5.6 Hz, 1H), 4.49 (dt, J=12.1, 6.0 Hz, 1H), 3.55 (d, J=5.7 Hz, 2H), 2, 56 (s, 3H), 1.56 (d, J=7.1 Hz, 3H), 1.18 (d, J=6.0 Hz, 3H), 1.08 (d, J=6.0 Hz, 3H), 0.78 (t, J=5.7 Hz, 2H), 0.61 (t, J=5.7 Hz, 2H).MS (ESI) m/e [M+1]+ 476.4 The absolute (S) configuration of the chiral center in compound 5A was confirmed by X-ray analysis of the single crystal.

Compound 5B: 1H NMR (400 MHz, DMSO^) δ 8.92 (s, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.23 (d, J=5.1 Hz , 1H), 6.85 (d, J=5.0 Hz, 1H), 6.44 (s, 2H), 4.75 (q, J=6.9 Hz, 1H), 4.67 (t , J=5.6Hz, 1H), 4.49 (dt, J=12.1, 6.0Hz, 1H), 3.55 (d, J=5.7Hz, 2H), 2.56 (s, 3H), 1.56 (d, J=7.1Hz, 3H), 1.18 (d, J=6.0Hz, 3H), 1.08 (d, J=6.0Hz , 3H), 0.78 (t, J=5.7 Hz, 2H), 0.61 (t, J=5.7 Hz, 2H). MS (ESI) m/e [M+1]+ 476.4.

Chiral separation conditions are shown below

Example 6 3-hydroxypyrrolidin-1-yl) methanone (compound 6)

The desired compound was obtained from compound 1-10 and (S)-pyrrolidin-3-ol in a similar manner to compound 1-11 in Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.42-7.27 ( m, 1H), 7.26-7.13 (m, 1H), 6.87-6.75 (m, 1H), 6.49-6.42 (m, 2H), 5.08-4, 99 (m, 1H), 4.82-4.71 (m, 1H), 4.48-4.30 (m, 1.5 H), 4.304.19 (m, 0.5H), 3.68 -3.38 (m, 2H), 3.23-3.04 (m, 1H), 3.03-2.92 (m, 1H), 2.60-2.55 (m, 3H), 2 .04-1.72 (m, 2H), 1.66 (d, J=6.8 Hz, 2H), 1.54 (d, J=6.5 Hz, 1H), 1.29 -1, 13 (m, 5H), 0.92 (dd, J=12.8, 6.0 Hz, 1H). MS (ESI) m/e [M+1]+ 476.1.

Example 7 (3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)(4-hydroxypiperidine- 1-yl)methanone (compound 7)

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The desired compound was obtained from compound 1-10 and piperidin-4-ol in a similar manner to compound 1-11 in Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.36-7.27 (m, 1H) , 7.17-7.12 (m, 1H), 6.84 (dd, J=5.0, 1.9 Hz, 0.3H), 6.79-6.75 (m, 0.7H) , 6.17 (s, 2H), 4.80-4.68 (m, 1H), 4.64-4.28 (m, 2H), 4.174.09 (m, 0.4H), 4.07 -3.96(m, 0.4H), 3.95-3.87(m, 0.3H), 3.84-3.66(m, 1H), 3.48-3.39(m, 0.3H), 3.39-3.24(m, 0.7H), 3.24-3.12(m, 1H), 2.98-2.87(m, 1H), 2.58( s, 3H), 1.88-1.73 (m, 1H), 1.71-1.65 (m, 3H), 1.58 (d, J=7.0 Hz, 1H), 1.48 -1.35 (m, 2H), 1.28 (d, J=6.1 Hz, 1H), 1.27-1.19 (m, 3.5H), 1.17 (d, J=6 .1 Hz, 0.5N), 1.04 (dd,

J=9.6, 6.1 Hz, 1H). MS (ESI) m/e [M+1]+ 490.1.

Example 8 3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyN-(2-methoxyethyl)benzamide (connection 8)

The desired compound was obtained from compound 1-10 and 2-methoxyethane-1-amine analogously to the preparation of compound 1-11 in Example 1. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.78 (t, J=5.4 Hz, 1H), 7.38 (d, J=8.6 Hz, 1H), 7.25 (d, J=5.0 Hz, 1H), 6.85 (d, J=5.0 Hz, 1H), 6.48 (s, 2H), 4.77 (q, J=7.1 Hz, 1H), 4n52-4.45(m, 1H), 3.45-3.37 (m , 4H), 3.25 (s, 3H), 2.57 (s, 3H), 1.58 (d, J=7.1 Hz, 3H), 1.18 (d, J=6.0 Hz , 3H), 1.08 (d, J=6.0 Hz, 3H). MS (ESI) m/e [M+1]+ 464.1.

Example 9 )-2-isopropoxybenzamide (compound 9)

The desired compound was prepared from compound 1-10 and (R)-1-aminopropan-2-ol analogously to the preparation of compound 1-11 in Example 1. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.65 (t, J =5.6Hz, 1H), 7.38(d, J=8.5Hz, 1H), 7.24(d, J=5.0Hz, 1H), 6.85(d, J=4 .4 Hz, 1H), 6.42 (s, 2H), 4.81-4.73 (m, 1H), 4.69 (d, J=2.8 Hz, 1H), 4.53-4 .42 (m, 1H), 3.78-3.68 (m, 1H), 3.27-3.18 (m, 1H), 3.15-3.05 (m, 1H), 2.56 (s, 3H), 1.58 (d, J=6.9Hz, 3H), 1.18 (d, J=6.0Hz, 3H), 1.11-1.05 (m, 6H) . MS (ESI) m/e [M+1]+ 464.1.

Example 10 3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-I-((1-hydroxycyclopropyl)methyl) -2-isopropoxybenzamide (compound 10)

The desired compound was obtained from compound 1-10 and 1-(aminomethyl)cyclopropan-1-ol analogously to the preparation of compound 1-11 in Example 1. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.71 (t, J= 5.7 Hz, 1H), 7.37 (d, J=8.6 Hz, 1H), 7.24 (d, J=5.0 Hz, 1H), 6.85 (d, J=5, 1 Hz, 1H), 6.42 (s, 2H), 5.26 (s, 1H), 4.77 (q, J=6.9 Hz, 1H), 4.59-4.52 (m, 1H), 3.40 (d, J=5.8 Hz, 2H), 2.57 (s, 3H), 1.58 (d, J=7.1 Hz, 3H), 1.19 (d, J=6.0 Hz, 3H), 1.09 (d, J=6.0 Hz, 3H), 0.54 (s, 4H). MS (ESI) m/e [M+1]+ 476.1.

Example 11 3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-N-cyclopropyl-6fluoro-2-isopropoxybenzamide (compound 11)

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The desired compound was obtained from compound 1-10 and cyclopropylamine in a similar manner to compound 1-11 in Example 1. 1H NMR (400 MHz, DMSO-dg) δ 8.73 (d, J=4.1 Hz, 1H), 7, 40 (d, J=8.6 Hz, 1H), 7.25 (d, J=5.0 Hz, 1H), 6.86 (d, J=4.9 Hz, 1H), 6.43 ( s, 2H), 4.76 (q, J=7.0 Hz, 1H), 4.46-4.37 (m, 1H), 2.85-2.76 (m, 1H), 2.56 (s, 3H), 1.57 (d, J=7.0Hz, 3H), 1.19 (d, J=6.0Hz, 3H), 1.07 (d, J=6.0Hz , 3H), 0.70 (q, J=6.5 Hz, 2H), 0.49-0.43 (m, 2H). MS (ESI) m/e [M+1]+ 446.1.

Example 12 3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyN-phenylbenzamide (compound 12)

The desired compound was obtained from compound 1-10 and aniline in a similar manner to compound 1-11 in Example 1. ¹ H NMR (400 MHz, DMSO) δ 10.72 (s, 1H), 7.65 (d, J=8, 0 Hz, 2H), 7.52 (d, J=8.6 Hz, 1H), 7.36 (t, J=7.8 Hz, 2H), 7.30 (d, J=5.0 Hz , 1H), 7.13 (t, J=7.3 Hz, 1H), 6.87 (d, J=4.9 Hz, 1H), 6.43 (s, 2H), 4.81 (q , J=6.8 Hz, 1H), 4.49-4.39 (m, 1H), 2.57 (s, 3H), 1.61 (d, J=7.0 Hz, 3H), 1 .19 (d, J=6.0 Hz, 3H), 1.05 (d, J=6.0 Hz, 3H). MS (ESI) m/e [M+1]+ 482.1.

Example 13 (3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)(4,4- difluoropiperidin-1-yl)methanone (compound 13)

The desired compound was prepared from compound 1-10 and 4,4-difluoropiperidine in a manner analogous to the preparation of compound 1-11 in Example 1. 1H NMR (400 MHz, DMSO-dg) δ 7.51-7.46 (m, 0.3H) , 7.42-7.35(m, 0.7H), 7.28-7.23(m, 0.3H), 7.20-7.14(m, 0.7H), 6.88- 6.81 (m, 1H), 6.45 (s, 2H), 4.81-4.70 (m, 1H), 4.34-4.34 (m, 1H), 4.04-3, 94 (m, 1H), 3.84-3.72 (m, 1H), 3.65-3.55 (m, 1H), 3.22-3.15 (m, 1H), 2.57 ( s, 3H), 2.18-1.87 (m, 4H), 1.71-1.65 (m, 2H), 1.60-1.54 (m, 1H), 1.27-1, 20 (m, 4H), 1.17-1.12 (m, 1H), 1.00-0.95 (m, 1H). MS (ESI) m/e [M+1]+ 510.1.

Compound 13 was separated using a chiral column to give compound 13A (peak 1, S or R, retention time (RT) at 8.65 min in chiral analysis, method H) and compound 13B (peak 2, R or S, retention time ( RT) at 11.06 min in chiral analysis, method H).

Compound 13A: 1H NMR (400 MHz, DMSO^) δ 7.51-7.46 (m, 0.3H), 7.42-7.35 (m, 0.7H), 7.28-7.23 (m, 0.3H), 7.20-7.14 (m, 0.7H), 6.88-6.81 (m, 1H), 6.45 (s, 2H), 4.81-4 .70 (m, 1H), 4.34-4.34 (m, 1H), 4.04-3.94 (m, 1H), 3.84-3.72 (m, 1H), 3.65 -3.55(m, 1H), 3.22-3.15(m, 1H), 2.57(s, 3H), 2.18-1.87(m, 4H), 1.71-1 .65 (m, 2H), 1.60-1.54 (m, 1h), 1.27-1.20 (m, 4n), 1.17-1.12 (m, 1h), 1.00 -0.95 (m, 1H). MS (ESI) m/e [M+1]+ 510.1.

Compound 13B: 1H NMR (400 MHz, DMSOCH) δ 7.48 (d, J=8.6 Hz, 0.3H), 7.38 (d, J=8.5 Hz, 0.7H), 7, 25 (d, J=4.7 Hz, 0.3H), 7.16 (d, J=4.9 Hz, 0.7H), 6.87-6.81 (m, 1H), 6.44 (s, 2H), 4.80-4.70 (m, 1H), 4.44-4.34 (m, 1H), 4.03-3.93 (m, 1H), 3.84-3 .72 (m, 1H), 3.65-3.55 (m, 1H), 3.22-3.15 (m, 1H), 2.57 (s, 3H), 2.18-1.86 (m, 4H), 1.67 (d, J=7.0 Hz, 2H), 1.56 (d, J=7.1 Hz, 1H), 1.23 (t, J=5.7 Hz , 4H), 1.14 (d, J=6.0 Hz, 1H), 0.97 (d, J=5.9 Hz, 1H). MS (ESI) m/e [M+1]+ 510.1.

Chiral separation conditions are shown below

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Column CHIRAL ART Cellulose-SB Column size 2 cm χ 25 cm χ 5 µm Injection 0.4 ml mobile phase Hexane: EUN = 80:20 Flow rate 20 ml/min Wavelength UV 220 nm Temperature 25°C Sample solution 21 mg/ml in NUN:DXM = 3:1 Equipment for preparative HPLC Prep-Gilson-HPLC

Example 14 3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1S,3R)-3hydroxycyclopentyl )-2-isopropoxybenzamide (compound 14)

The desired compound was obtained from the compound according to the method for preparing compound 1-11 in Example 1.

1-10 and (1R,3S)-3-aminocyclopentan-1-ol analogous to 1H NMR (400 MHz, DMSO-d6) 8.70 (d, J=7.3 Hz, 1H),

7.41 (d, J=8.5 Hz, 1H), 7.31 (d, J=5.1 Hz, 1H), 6.91-6.74 (m, 3H), 4.79 (q , J=6.8 Hz, 1H), 4.61 (d, J=3.8 Hz, 1H), 4.51-4.41 (m, 1H), 4.17-4.03 (m, 2H), 2.58 (s, 3H), 2.23-2.14 (m, 1H), 1.90-1.80 (m, 1H), 1.76-1.64 (m, 1H) , 1.64-1.49 (m, 5H), 1.42-1.32 (m, 1H), 1.19 (d, J=6.0 Hz, 3H), 1.07 (d, J =6.0 Hz, 3H). MS (ESI) m/e [M+1]+ 490.1.

Compound 14 was separated using a chiral column to give compound 14A (peak 1, S or R, retention time (RT) at 5.17 min in chiral analysis, method I) and compound 14B (peak 2, R or S, retention time (RT) at 8.01 min in chiral analysis, method I).

Compound 14A: 1H NMR (400 MHz, DMSO^) δ 8.70 (d, J=7.3 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.31 (d , J=5.1 Hz, 1H), 6.91-6.74 (m, 3H), 4.79 (q, J=6.8 Hz, 1H), 4.61 (d, J=3, 8 Hz, 1H), 4.51-4.41 (m, 1H), 4.174.03 (m, 2H), 2.58 (s, 3H), 2.23-2.14 (m, 1H), 1.90-1.80 (m, 1H), 1.76-1.64 (m, 1H), 1.64-1.49 (m, 5H), 1.421.32 (m, 1H), 1, 19 (d, J=6.0 Hz, 3H), 1.07 (d, J=6.0 Hz, 3H). MS (ESI) m/e [M+1]+ 490.1.

Compound 14B: ¹ H NMR (400 MHz, DMSO-dg) δ 8.69 (d, J=7.3 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.28 (d, J=5.1Hz, 1H), 6.87 (d, J=5.0Hz, 1H), 6.68 (s, 2H), 4.78 (q, J=6.8Hz , 1H), 4.61 (d, J=3.8 Hz, 1H), 4.51-4.41 (m, 1H), 4.17-4.03 (m, 2H), 2.57 ( s, 3H), 2.23-2.14 (m, 1H), 1.90-1.80 (m, 1H), 1.76-1.64 (m, 1H), 1.64-1, 49 (m, 5H), 1.42-1.32 (m, 1H), 1.19 (d, J=6.0 Hz, 3H), 1.08 (d, J=6.0 Hz, 3H ). MS (ESI) m/e [M+1]+ 490.1.

Chiral separation conditions are shown below

Column CHIRAL ART Cellulose-SB Column size 2 cm χ 25 cm χ 5 µm Injection 0.4 ml mobile phase Hexane: EtOH = 80:20 Flow rate 20 ml/min Wavelength UV 220 nm Temperature 25°C Sample solution 21 mg/ml in NUN:DXM = 3:1 Equipment for preparative HPLC Prep-Gilson-HPLC

Example 15 (S)-3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-N-(1-(ethoxymethyl)cyclopropyl) -6-fluoro-2-isopropoxybenzamide (compound 15)

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Step 1: 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one (15-1)

To a 2 L three-necked flask equipped with a magnetic stirrer, add 4-chloro-3fluorophenol (160 g, 1.1 mol) and acetyl chloride (129 g, 1.6 mmol). The mixture was stirred for 1 hour. Aluminum chloride (219 g, 1.6 mmol) was then added portionwise to the mixture. The mixture is heated to 160°C and maintained at 160°C for 2 hours the Mixture is cooled and diluted with HCl (2M, 500 ml). The resulting hot liquid was cooled and extracted with EtOAc (500 mlx3). The combined organic phase was washed with water (500 ml) and brine (500 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give the product (200 g, crude) as a yellow solid. 1H NMR (400 MHz, CDCl ₃ ) δ 12.48-12.41 (m, 1H), 7.78 (d, J=8.1 Hz, 1H), 6.77 (d, J=10.3 Hz, 1H), 2.61(s, 3H).

Step 2: 1-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one (15-2)

To a solution of 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one (110 g, 583 mmol) in DMF (1 L) was added NBS (114 g, 640 mmol) in portions. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (3 L), extracted with EtOAc (1 L x 3). The combined organic phase was washed with brine (1 L x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give the product (150 g, crude) as a yellow solid. 1H NMR (400 MHz, CDCl ₃ ) δ 13.21 (d, J=1.8 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 2.66 (s, 3H) .

Step 3: 1-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)ethan-1-one (15-3)

To a solution of 1-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one (150 g, 560 mmol) and 2-iodopropane (143 g, 841 mmol) in DMF (1 L) add NaHCO ₃ (71 g, 845 mmol). The mixture is stirred at 60°C overnight. The mixture was cooled and diluted with water (3 L), extracted with EtOAc (1 Lx3). The combined organic phase is washed with brine (1 Lx3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with hexane/ethyl acetate = 50/1) to give the product (140 g, 80%) as a yellow oil. 1H NMR (400 MHz, CDCl ₃ ) δ 7.57 (d, J=8.2 Hz, 1H), 4.45-4.39 (m, 1H), 2.61 (s, 3H), 1, 31 (t, J=6.7 Hz, 6H).

Step 4: 2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)propanenitrile (15-4)

To 1-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)ethan-1-one (165 g, 533 mmol) in DME (420 ml) was added TOSMIC (156 g, 799 mmol), the solution was stirred at 0°C, a solution of t-BuOK (119.6 g, 1066 mmol) in t-BuOH (840 ml) was added dropwise to the above solution under N2 atmosphere and the temperature was kept below 10°C, the resulting solution was stirred at room temperature for during the night. Upon completion, the reaction mixture was washed with water (1 L) and extracted with ethyl acetate (500 mlx3), dried over MgSO ₄ , filtered and evaporated in vacuo. The residue was purified by column chromatography (PE/EA = 20:1 approx. 10:1) to give the product (118 g, 69.2%) as a yellow solid. 1H NMR (400 MHz, CDCl ₃ ) δ 7.51 (d, J=7.8 Hz, 1H), 4.69 (dt, J=12.3, 6.2 Hz, 1H), 4.31 ( q, J=7.2 Hz, 1H), 1.56 (d, J=7.2 Hz, 3H), 1.44 (d, J=6.2 Hz, 3H), 1.30 (d, J=6.2 Hz, 3H).

Step 5: 2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)propanoic acid (15-5)

- 41 040339

To 2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)propanenitrile (118 g, 369 mmol) in EtOH (307 mL) was added aq. NaOH (6N, 307 ml), the resulting solution was stirred at 100°C overnight. After completion, the reaction mixture is cooled to room temperature, bring the pH to a value of from 3 to 4 by adding 1N. HCl, extracted with ethyl acetate (500 ml x 3), the combined ethyl acetate dried over MgSO ₄ , filtered and evaporated to give the crude product (122 g, 97.4%) as a yellow oil which was used in the next step without further purification. LC-MS (M-H) + = 336.9.

Step 6: (S)-2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)propanoic acid (15-6)

2-(3-Bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)propanoic acid (122 g, 359 mmol) and (1R,2S)-1amino-2,3-dihydro-1H-inden-2-ol (54 g, 359 mmol) in i-PrOH (500 ml) stirred at 100°C for 1 h, cooled to room temperature, concentrated to give the crude salt, which was suspended in PE/EA=10:1 (500 ml ) for 1 to about 2 hours, the undissolved solid is collected and refluxed in PE/EA/i-PrOH = 20:2:1 (230 ml) for another 1 hour, the solid is collected by filtration and dried in vacuum, to obtain a chiral salt, which is neutralized by adding aq. HCl (1N) to pH approximately 2-3, extracted with ethyl acetate (200 mlx3), dried over MgSO ₄ , concentrated to give the product as a yellow oil (44.2 g, 36.2%). 1H NMR (400 MHz, DMSOL), δ 12.59 (s, 1H), 7.52 (d, J=8.4 Hz, 1H), 4.55 (dt, J=12.3, 6.1 Hz, 1H), 4.04 (q, J=7.0, 1H), 1.38 (d, J=7.3 Hz, 3H), 1.34-1.26 (m, 6H). LC-MS (M-H) + = 336.9. Retention time in chiral HPLC: 2.61 min. The absolute (S) configuration of the chiral center in compound 15-6 was confirmed by X-ray diffraction analysis of the single crystal.

Step 7: (2S)-2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)-N-(1-(3-chloropyrazin-2-yl)ethyl)propanamide (15-7)

(S)-2-(3-Bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)nponanoic acid (52 g, 153 mmol), 1-(3-chloropyrazin-2-yl)ethan-1-amine hydrochloride (29 .7 g, 153 mmol), EDCI (43.9 g, 229.7 mmol), HOBT (31 g, 229.7 mmol) and Et ₃ N (49.5 g, 489.6 mmol) in DCM (500 ml) was stirred at room temperature overnight under N2. After completion, the reaction solution was washed with water (500 ml), extracted with DCM (500 ml x3), the combined DCM phase was dried over MgSO ₄ , concentrated and purified by column chromatography (PE/EA = approximately 10:1 to 5:1) with obtaining the product (69 g, 94%) as a yellow oil. LC-MS (M+H) + = 479.6.

Step 8: (S)-3-(1-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)ethyl)-8-chloro-1-methylimidazo[1,5a]pyrazine (15-8)

To (2S)-2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)-N-(1-(3-chloropyrazin-2-yl)ethyl)propanamide (69 g, 144 mmol) in DCM (1 L) was added dropwise with Tf ₂ O (89.4 g, 317 mmol) at 0°C, then pyridine (28.5 g, 360 mmol) was added dropwise at 0°C, TLC showed that the reaction is over

- 42 040339 add H ₂ O (500 ml), extract with DCM (500 ml x 3), dry the combined DCM phase over MgSO ₄ , concentrate to give the crude product, which is suspended in i-PrOH (60 ml) for 1 to 2 hours , filtered to give the crude product as a white solid (55 g,

83.4%. LC-MS (M+H) + = 461.9.

Step 9: (S)-3-(1-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)ethyl)-1-methylimidazo[1,5-a]pyrazine8-amine (15-9)

To a pressure vessel equipped with a magnetic stirrer, add (S)-3-(1-(3-bromo-5-chloro4-fluoro-2-isopropoxyphenyl)ethyl)-8-chloro-1-methylimidazo[1,5-a ]pyrazine (45 g, 97.6 mmol) and NH ₃ in iPrOH (30 w/w%, 300 ml, excess). The mixture is then stirred at 90° C. for two days. The mixture was cooled and diluted with DCM (500 ml), washed with water (100 ml x 3), brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the product (41 g, 95%) as a yellow solid , which is used in the next step without further purification. 1H NMR (400 MHz, CDCl ₃ ) δ 7.27 (d, J=7.6 Hz, 1H), 7.15 (d, J=5.1 Hz, 1H), 6.88 (d, J= 5.0 Hz, 1H), 4.78-4.69 (m, 2H), 2.72 (s, 3H), 1.80 (d, J=7.2 Hz, 3H), 1.49 ( d, J=6.2 Hz, 3H), 1.39 (d, J=6.2 Hz, 3H). LC-MS (M+H)+ = 441.0, 443.0.

Step 10: (S)-6-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-2-bromo-4-chloro-3-fluorophenol (15- 10)

To a mixture of (S)-3-(1-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)ethyl)-1-methylimidazo[1,5-a]pyrazine8-amine (41 g, 92, 8 mmol) in DCM (500 ml) was added dropwise BBr ₃ (70 g, 279 mmol) at 0°C. The mixture is then stirred at room temperature overnight. The mixture is cooled to 0° C. and then carefully quenched with MeOH (400 ml). The mixture is concentrated, the residue is diluted with a mixture of DCM (500 ml) and i-PrOH (100 ml). The mixture is then washed with saturated NaHCO ₃ solution (100 mlx2). The organic layers are separated, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the product (38 g, 100%) as a yellow solid, which is used in the next step without further purification. 1H NMR (400 MHz, CDCl ₃ ) δ 7.18 (d, J=5.2 Hz, 1H), 7.12 (d, J=7.9 Hz, 1H), 7.02 (d, J= 5.1 Hz, 1H), 4.28 (q, J=7.3 Hz, 1H), 4.08-398 (m, 1H), 2.72 (s, 3H), 1.70 (d, J=7.3 Hz, 3H), 1.21 (d, J=6.1 Hz, 6H). LC-MS (M+H)+ = 399.0, 401.0.

Step 11: Ethyl (S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2hydroxybenzoate (15-11 )

To a mixture of (S)-6-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-2-bromo-4-chloro-3-fluorophenol (38 g, 32.5 mmol) in EtOH (1000 ml) add Pd(dppf)Cl ₂ (3.5 g, 4.8 mmol) and NaOAc (11.7 g, 143 mmol). The mixture is degassed and refilled with CO (1 atm). The mixture is stirred at 70°C overnight. The mixture is cooled and concentrated in vacuo. The residue was diluted with water (200 ml), extracted with EtOAc (200 mlx3).

The combined organic phase is washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (DCM/MeOH from DCM 100% to 20/1) to give the product (32 g, 82%) as a yellow solid. 1H NMR (400 MHz, CDCl ₃ ) δ 7.28-43 040339

7.24 (m, 1H), 7.07 (d, J=5.1 Hz, 1H), 6.85 (d, J=5.1 Hz, 1H), 5.30 (s, 1H), 4.81 (q, J=7.1 Hz, 1H), 4.48 (q, J=7.1

Hz, 2H), 2.75 (s, 3H), 1.74 (d, J=7.1 Hz, 3H), 1.43 (t, J=7.1 Hz, 3H). LC-MS (M+H)+ = 393.1.

Step 12: ethyl (S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2isopropoxybenzoate (15-12 )

Ethyl (S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-hydroxybenzoate (32 g, 81.5 mmol), i-PrOH (24.4 g, 406.7 mmol), PPh ₃ (49.1 g, 187.5 mmol) in toluene (400 ml) add di-tert-butyl (E)- diazene-1,2-dicarboxylate (43.2 g, 187.5 mmol) at room temperature. The resulting solution was stirred at 60° C. for 3 hours under nitrogen. After completion, the reaction mixture was concentrated in vacuo, washed with H ₂ O (500 ml), extracted with EtOAc (500 ml x 3), the combined EtOAc phase was dried over MgSO ₄ , purified using column chromatography (PE/EA = 20:1) to obtain the product ( 25.4 g, 71.8%) as a yellow solid. LC-MS (M+H) + = 435.1.

Step 13: (S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxybenzoic acid (15 -13)

Ethyl (S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxybenzoate (25.4 g (58.5 mmol) in MeOH (100 ml) and H ₂ O (100 ml) NaOH (18.7 g, 468 mmol) was added and the resulting solution was stirred at room temperature overnight After completion, the reaction solution was concentrated in vacuo to remove most of the MeOH, the remaining solution was extracted with EtOAc (100 ml x 2), the aqueous phase was adjusted to pH 2 to 3, the purged solid was precipitated, collected by filtration, dried in vacuo to give the product (15.8 g), aqueous phase extracted with DCM (100 mlx5), the combined DCM phase was dried over MgSO ₄ and concentrated in vacuo to give another portion of the product (2.2 g), overall yield (18 g, 75.6%) 1H NMR (400 MHz, DMSO -d ₆ ) δ 7.78 (brs, 2H), 7.40-7.32 (m, 2H), 6.93 (d, J=5.3 Hz, 1H), 4.80 (q, J =7.0Hz, 1H), 4.55(dt, J=12.1, 6.0Hz, 1H), 2.60(s, 3H), 1.60(d, J=7.0Hz , 3H), 1.20 (d, J=6.0 Hz, 3H), 1.13 (d, J=6.0 Hz, 3H) LC-MS (M+H) + = 407.1.

Step 14: (S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-N-(1-(ethoxymethyl)cyclopropyl) -6-fluoro-2-isopropoxybenzamide (15-14)

To a solution of (S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isononoxybenzoic acid (100 mg , 0.25 mmol) and 1-(ethoxymethyl)cyclopropan-1-amine hydrochloride (60 mg, 0.4 mmol) in DMF (10 ml) Et ₃ N (125 mg, 1.25 mmol) and PyBop (210 mg, 0.4 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (30 ml), extracted with EtOAc (30 mlx3). The combined organic layers are washed with water (50 mlx2) and brine (50 ml), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by thin layer chromatography (DCM/MeOH=15/1) to give the product (90 mg, 71%). 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (brs, 1H), 7.36 (d, J=8.9 Hz, 1H), 7.24 (brs, 1H), 6.86 ( brs, 1H), 6.44 (brs, 2H), 4.77 (brs, 1H), 4.51 (brs, 1H), 3.56-3.41 (m, 4H), 2.57 (s , 3H), 1.58 (brs, 3H), 1.19 (brs, 3H), 1.09 (brs, 6H), 0.77 (brs, 2H), 0.70 (brs, 2H). LC-MS

- 44 040339 (M+H)+ = 504.2. Chiral HPLC retention time: 2.75 min, method J.

Example 16 (S)-3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-N-(2-(dimethylamino)ethyl) -6-fluoro-2-isopropoxybenzamide (compound 16)

This compound (50.3 mg, 21.4%) was prepared from compound 15-13 and N ¹ ,N ¹ -dimethylethane-1,2diamine analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO- d ₆ ) δ 8.66 (t, J=5.5 Hz, 1H), 7.38 (d, J=8.6 Hz, 1H), 7.25 (d, J=5.0 Hz, 1H ), 6.85 (d, J=5.0 Hz, 1H), 6.43 (s, 2H), 4.77 (q, J=7.0 Hz, 1H), 4.52 (dt, J =12.2, 6.1 Hz, 1H), 3.35-3.25(m, 2H), 2.56(s, 3H), 2.37(s, 2H), 2.17(s, 6H), 1.58 (d, J=7.1Hz, 3H), 1.18 (d, J=6.0Hz, 3H), 1.08 (d, J=6.0Hz, 3H) . LC-MS (M+H) + = 477.2. Chiral HPLC retention time: 4.34 min, method A.

Example 17 (3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)( (S)-2-(methoxymethyl)pyrrolidin-1-yl)methanone (compound 17)

This compound (26.4 mg, 10.6%) was prepared from compound 15-13 and (S)-2-(methoxymethyl)pyrrolidine analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.43-7.29(m, 1H), 7.27-7.16(m, 1H), 6.90-6.75(m, 1H), 6.56-6.34( m, 2H), 4.76 (dd, J=13.8, 7.0 Hz, 1H), 4.39 (ddd, J=24.1, 12.2, 6.0 Hz, 1H), 3 .73-3.41 (m, 3H), 3.33-3.27 (m, 3H), 3.22-3.10 (m, 1H), 3.00-2.80 (m, 1H) , 2.62-2.54 (m, 3H), 2.02-1.72 (m, 4H), 1.70-1.63 (m, 3H), 1.30-1.15 (m, 6H). LC-MS (M+H)+ = 504.2. Retention times in chiral HPLC: 4.36 min and 4.82 min, method C.

Example 18 (S)-3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-(4fluorophenyl)- 2-isopropoxybenzamide (compound 18)

This compound (8 mg, 6.5%) was prepared from compound 15-13 and 4-fluoroaniline analogously to the preparation of compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 10.79 (s, 1H), 7.75-7.62 (m, 2H), 7.57-7.30 (m, 2H), 7.28-7.05 (m, 3H), 6.92-6.68 ( m, 2H), 4.89-4.75 (m, 1H), 4.48-4.36 (m, 1H), 2.60-2.54 (m, 3H), 1.69-1, 51 (m, 3H), 1.20-1.11 (m, 3H), 1.07-0.98 (m, 3H). LC-MS (M+H)+ = 500.1. Retention time in chiral HPLC: 4.10 min, method C.

Example 19 4-methoxypiperidin-1-yl) methanone (compound 19)

- 45 040339

This compound (36.4 mg, 14.6%) was prepared from compound 15-13 and 4-methoxypiperidine in a similar manner to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.47- 7.13 (m, 2H), 6.89-6.75 (m, 1H), 6.74-6.47 (m, 2H), 4.86-4.67 (m, 1H), 4. 48-4.23(m, 1H), 4.19-3.71(m, 1H), 3.60-3.36(m, 2H), 3.29-3.23(m, 3H), 3.21-2.89 (m, 2H), 2.62-2.55 (m, 3H), 2.01-1.29 (m, 7H), 1.29-0.94 (m, 6H ). LCMS (M+H)+ = 504.2. Retention time on chiral HPLC: 4.35 min, method C.

Example 20 (3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)( (S)-3-hydroxypiperidin-1-yl)methanone (compound 20)

This compound (31 mg, 12.8%) was prepared from compound 15-13 and ^)-piperidin-3-ol analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7 .46-7.10 (m, 2H), 6.90-6.76 (m, 1H), 6.72-6.42 (m, 2H), 5.15-4.65 (m, 2H) , 4.51-4.26(m, 1H), 3.24-2.90(m, 2H), 2.89-2.64(m, 2H), 2.61-2.55(m, 3H), 2.01-1.71(m, 1H), 1.71-1.61(m, 3H), 1.59-1.53(m, 1H), 1.42-1.31( m, 2H), 1.30-1.12 (m, 6H). LC-MS (M+H) + = 490.2. Chiral HPLC retention time: 5.68 min, method C.

Example 21 3-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N- ((S)-1-phenylethyl)benzamide (compound 21)

This compound (46 mg, 36.5%) was prepared from compound 15-13 and (S)-1-phenylethane-1-amine analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.21 (d, J=8.1 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 7.42-7.30 (m, 5H), 7.28 -7.17 (m, 2H), 6.91 (d, J=5.2 Hz, 1H), 5.10 (p, J=7.0 Hz, 1H), 4.79 (q, J= 6.8Hz, 1H), 4.27(dt, J=12.0, 6.0Hz, 1H), 2.58(s, 3H), 1.57(d, J=7.0Hz, 3H), 1.40 (d, J=7.0Hz, 3H), 1.03 (d, J=6.0Hz, 3H), 0.86 (d, J=5.9Hz, 3H) . LC-MS (M+H)+ = 509.8. Chiral HPLC retention time: 2.67 min, method F.

Example 22 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N- ((R)-1-phenylethyl)benzamide (compound 22)

- 46 040339

This compound (26 mg, 20.7%) was prepared from compound 15-13 and (R)-1-phenylethane-1-amine analogously to compound 15-14 in Example 15. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.21 (d, J=8.1 Hz, 1H), 7.47 (d, J=8.6 Hz, 1H), 7.41-7.31 (m, 5H), 7, 30-7.09 (m, 2H), 6.90 (d, J=5.3 Hz, 1H), 5.09 (p, J=7.0 Hz, 1H), 4.79 (q, J =6.9 Hz, 1H), 4.28-4.16 (m, 1H), 2.58 (s, 3H), 1.56 (d, J=7.0 Hz, 3H), 1.40 (d, J=7.0 Hz, 3H), 1.01 (d, J=6.0 Hz, 3H), 0.87 (d, J=6.0 Hz, 3H). LC-MS (M+H)+ = 509.8. Chiral HPLC retention time: 5.35 min, method A.

Example 23 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1R, 2S)2-hydroxycyclopentyl)-2-isopropoxybenzamide (compound 23)

This compound (14.1 mg, 11.7%) was prepared from compound 15-13 and (1S,2R)-2-aminocyclopentan1-ol analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO- d ₆ ) δ 8.29 (d, J=7.4 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.24 (d, J=5.1 Hz, 1H ), 6.85 (d, J=5.0 Hz, 1H), 6.53 (s, 2H), 4.77 (q, J=7.4 Hz, 1H), 4.61-4.47 (m, 2H), 4.08-3.94 (m, 2H), 2.57 (s, 3H), 1.92-1.67 (m, 3H), 1.65-1.44 (m , 6H), 1.19 (d, J=6.0 Hz, 3H), 1.11 (d, J=6.0 Hz, 3H). LC-MS (M+H) + = 489.8. Retention time on chiral HPLC: 4.63 min, method A.

Example 24 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N- (((S)-tetrahydrofuran-2-ul)methyl)benzamide (compound 24)

This compound (20.63 mg, 17.1%) was prepared from compound 15-13 and (S)-(tetrahydrofuran-2yl)methanamine analogously to compound 15-14 in Example 15. 1H NMR (400 MHz), DMSO- d ₆ ) δ 8.78 (t, J=5.8 Hz, 1H), 7.41 (d, J=8.6 Hz, 1H), 7.32 (d, J=5.3 Hz, 1H ), 6.90 (s, 2H), 6.88 (d, J=5.2 Hz, 1H), 4.79 (q, J=7.0 Hz, 1H), 4.49 (dt, J =12.1, 6.0 Hz, 1H), 3.92 (p, J=6.3 Hz, 1H), 3.75 (dd, J=14.0, 7.2 Hz, 1H), 3 .61 (dd, J=14.5, 7.3 Hz, 1H), 3.31-3.26 (m, 2H), 2.58 (s, 3H), 1.96-1.74 (m , 3H), 1.64-1.50 (m, 4H), 1.18 (d, J=6.0 Hz, 3H), 1.08 (d, J=6.1 Hz, 3H). LC-MS (M+H) + = 489.8. Chiral HPLC retention time: 5.52 min, method A.

Example 25 2R)2-hydroxycyclopentyl)-2-isopropoxybenzamide (compound 25)

- 47 040339

This compound (23.32 mg, 19.3%) was prepared from compound 15-13 and (1R,2S)-2-aminocyclonentan1-ol analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO- dg) δ 8.34 (d, J=7.1 Hz, 1H), 7.57 (s, 2H), 7.46-7.38 (m, 2H), 6.93 (d, J=5 .4 Hz, 1H), 4.82 (q, J=6.8 Hz, 1H), 4.60 (d, J=2.7 Hz, 1H), 4.52 (dt, J=11.9 , 5.9 Hz, 1H), 4.01 (brs, 2H), 2.60 (s, 3H), 1.90-1.65 (m, 3H), 1.64-1.43 (m, 6H), 1.18 (d, J=6.1 Hz, 3H), 1.04 (d, J=5.9 Hz, 3H). LC-MS (M+H) + = 489.8. Chiral HPLC retention time: 4.68 min, method A.

Example 26 (S)-3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxu-N- (2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide (compound 26)

This compound (15 mg, 11.8%) was prepared from compound 15-13 and 2-(tetrahydro-2H-pyran-4yl)ethan-1-amine analogously to compound 15-14 in Example 15. ¹ H NMR (400 MHz, DMSO-dQ δ 8.66 (t, J=5.5 Hz, 1H), 7.41 (d, J=8.6 Hz, 1H), 7.29 (d, J=5.1 Hz , 1H), 6.87 (d, J=4.9 Hz, 1H), 6.65 (s, 2H), 4.78 (q, J=7.0 Hz, 1H), 4.45 (dt , J=12.1, 5.9 Hz, 1H), 3.93-3.74 (m, 2H), 3.34-3.15 (m, 3H), 2.57 (s, 3H), 1.65-1.50 (m, 6H), 1.47-1.37 (m, 2H), 1.27-1.12 (m, 5H), 1.08 (d, J=6.0 Hz, 3H) LC-MS (M+H)+ = 517.8 Retention time in chiral HPLC: 6.39 min, method A.

Example 27 (S)-3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxu-N- methylbenzamide (compound 27)

This compound (11 mg, 10.6%) was prepared from compound 15-13 and methanamine analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-dQ δ 8.60 (t, J=4, 7 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.26 (d, J=5.1 Hz, 1H), 6.87 (d, J=5.0 Hz , 1H), 6.58 (s, 2H), 4.77 (q, J=7.0 Hz, 1H), 4.39 (dt, J=12.1, 6.0 Hz, 1H), 2 .75 (d, J=4.6 Hz, 3H), 2.57 (s, 3H), 1.58 (d, J=7.1 Hz, 3H), 1.19 (d, J=6, 1 Hz, 3H), 1.09 (d, J=6.1 Hz, 3H) LC-MS (M+H)+ = 419.8 Chiral HPLC retention time: 4.44 min, method A.

Example 28 (S)-3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N- ethyl benzamide (compound 28)

This compound (36.1 mg, 33.8%) was obtained from compound 15-13 and ethanamine in a similar manner to

- 48 040339 preparation of compound 15-14 in example 15. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.68 (t, J=5.3 Hz, 1H), 7.41 (d,

J=8.6Hz, 1H), 7.28(d, J=5.1Hz, 1H), 6.87(d, J=5.1Hz, 1H), 6.60(s, 2H) , 4.78 (q, J=7.1 Hz, 1H), 4.45 (dt,

J=12.1, 6.0Hz, 1H), 3.28-3.18(m, 2H), 2.57(s, 3H), 1.58(d, J=7.1Hz, 3H ), 1.19 (d, J=6.0 Hz, 3H), 1.13-1.04 (m, 6H). LC-MS (M+H)+ = 433.8. Retention time in chiral HPLC: 5.12 min, method A.

Example 29 (S)-3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N- (4-methoxyphenyl)benzamide (compound 29)

This compound (35 mg, 18.2%) was prepared from both 15-13 and 4-methoxyaniline analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 10.60 (s, 1H), 7.60-7.50 (m, J=8.7, 4.2 Hz, 3H), 7.43 (d, J=5.4 Hz, 1H), 7.39 (s, 2H ), 6.98-6.87 (m, 3H), 4.85 (q, J=6.9Hz, 1H), 4.45 (dt, J=12.1, 6.2Hz, 1H) , 3.74 (s, 3H), 2.60 (s, 3H), 1.61 (d, J=7.1 Hz, 3H), 1.18 (d, J=6.1 Hz, 3H) , 1.04 (d, J=6.1 Hz, 3H). LCMS (M+H)+ = 511.8. Retention time on chiral HPLC: 3.97 min, method B.

Example 30 (S)-3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N- ((1-methylpiperidin-4-yl)methyl)benzamide (compound 30)

This compound (13 mg, 10.2%) was prepared from compound 15-13 and (1-methylpiperidin-4yl)methanamine analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 10 .50 (brs, 1H), 8.84 (t, J=5.8 Hz, 1H), 7.63 (brs, 1H), 7.50 (d, J=8.5 Hz, 1H), 7 .44 (d, J=5.5Hz, 1H), 6.96 (d, J=5.4Hz, 1H), 4.82 (q, J=6.9Hz, 1H), 4.43 (dt, J=11.8, 6.0 Hz, 1H), 3.43-3.34 (m, 2H), 3.18-3.05 (m, 2H), 2.96-2.82 (m, 2H), 2.68 (s, 3H), 2.59 (s, 3H), 1.84 (d, J=13.3 Hz, 2H), 1.78-1.65 (m, 1H), 1.59 (d, J=7.0 Hz, 3H), 1.54-1.39 (m, 2H), 1.18 (d, J=6.0 Hz, 3H), 1, 07 (d, J=6.0Hz, 3H). LC-MS (M+H) + = 516.8. Retention time on chiral HPLC: 2.78 min, method B.

Example 31 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N- (((R)-tetrahydrofuran-2-yl)methyl)benzamide (compound 31)

This compound (8 mg, 6.6%) was prepared from compound 15-13 and (R)-(tetrahydrofuran-2 yl)methanamine analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.78 (t, J=5.7 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.28 (d, J=5.1 Hz, 1H), 6.87 (d, J=5.1 Hz, 1H), 6.65 (s, 2H), 4.78 (q, J=6.9 Hz, 1H), 4.48 (dt, J=12 .2, 6.1Hz, 1H), 3.92 (dt, J=12.0, 6.4Hz, 1H), 3.75 (dd, J=14.2, 7.0Hz, 1H) , 3.61 (dd, J=14.4, 7.3 Hz, 1H), 3.35-3.22 (m, 2H), 2.57 (s, 3H), 1.97-1.73 (m, 3H), 1.63-1.51 (m, 4H),

- 49 040339

1.18 (d, J=6.1 Hz, 3H), 1.08 (d, J=6.0 Hz, 3H). LC-MS (M+H) + = 489.8. retention time in chiral

HPLC: 3.49 min, method B.

Example 32 (S)-3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N, N-dimethylbenzamide (compound 32)

This compound (26 mg, 24.4%) was prepared from compound 15-13 and dimethylamine analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.53-6.97 ( m, 4H), 6.946.79 (m, 1H), 4.86-4.73 (m, 1H), 4.42-4.15 (m, 1H), 3.08-2.97 (m, 3H), 2.91-2.71(m, 3H), 2.59(s, 3H), 1.751.51(m, 3H), 1.30-0.92(m, 6H). LC-MS (M+H) + = 433.8. Chiral HPLC retention times: 4.05 min and 4.01 min, method B.

Example 33 (S)-3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N- (pyridin-2-ylmethyl)benzamide (compound 33)

This compound (103 mg, 83.1%) was prepared from compound 15-13 and pyridin-2-ylmethanamine analogously to compound 15-14 in Example 15. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.33 (brs, 1H), 8.51 (brs, 1H), 7.83-7.79 (m, 1H), 7.48-7.45 (m, 1H), 7.40-7.34 (m , 2H), 7.30-7.28 (m, 1H), 7.18 (brs, 2H), 6.91-6.90 (m, 1H), 4.81-4.79 (m, 1H ), 4.52 (brs, 2H), 4.42-4.40 (m, 1H), 2.59-2.58 (m, 3H), 1.60-1.58 (m, 3H), 1.12-1.10 (m, 3H), 0.99-0.98 (m, 3H). LC-MS (M+H) + = 497.2. Retention time on chiral HPLC: 2.83 min, method E.

Example 34 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N- (((R)-tetrahydrofuran-3-yl)methyl)benzamide (compound 34)

This compound (93.8 mg, 81.7%) was prepared from compound 15-13 and (H)-(tetrahydrofuran-3yl)methanamine analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.83 (brs, 1H), 7.47-7.45 (m, 1H), 7.38-7.37 (m, 1H), 7.18-7.07 (brs, 2H) , 6.91-6.90(m, 1H), 4.814.77(m, 1H), 4.44-4.41(m, 1H), 3.75-3.59(m, 3H), 3 .43-3.40 (m, 1H), 3.21-3.17 (m, 2H), 2.58 (brs, 3H), 2.442.40 (m, 2H), 1.95-1.91 (m, 1H), 1.59-1.58 (m, 3H), 1.07-1.06 (m, 3H). LC-MS (M+H) + = 490.2. Retention time on chiral HPLC: 2.59 min, method E.

Example 35 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N- (((S)-tetrahydrofuran-3-yl)methyl)benzamide (compound 35)

- 50 040339

This compound (93.0 mg, 78.2%) was prepared from compound 15-13 and (S)-(tetrahydrofuran-3yl)methanamine analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSOd6) δ 8.83-8.80 (t, 1H), 7.45-7.43 (d, J=8.4 Hz, 1H), 7.33-7.32 (d, J=5.2 Hz, 1H), 6.89-6.87 (d, J=5.2 Hz, 1H), 6.83(brs, 2H), 4.82-4.76 (m, 1H), 4.47-4 .41 (m, 1H), 3.75-3.59 (m, 3H), 3.45-3.40 (m, 1H), 3.27-3.14 (m, 2H), 2.57 (s, 3H), 2.47-2.37 (m, 2H), 1.98-1.89 (m, 1H), 1.62-1.53 (m, 4H), 1.19-1 .17 (d, J=6.4 Hz, 3H), 1.08-1.07 (d, J=6.0 Hz, 3H). LC-MS (M+H) + = 490.1. Retention time on chiral HPLC: 3.56 min, method F.

Example 36 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N- ((R)-1-(4-methoxyphenyl)ethyl)benzamide (compound 36)

This compound (98.3 mg, 82.1%) was prepared from compound 15-13 and (K)-1-(4-methoxyphenyl)ethan-1amine in a similar manner to compound 15-14 in Example 15.

1H NMR (400 MHz, DMSO-d6) δ 9.14-9.12 (d, J=8.0 Hz, 1H), 7.45-7.43 (d, J=8.4 Hz, 1H) , 7.35-7.34 (d, J=5.2 Hz, 1H), 7.39-7.26 (d, J=8.4 Hz, 2H), 7.05 (brs, 2H), 6.91-6.89(m, 3H), 5.07-5.03(m, 1H), 4.80-4.75(m, 1H), 4.25-4.21(m, 1H ), 3.73 (s, 3H), 2.57 (s, 3H), 1.57-1.55 (d, J=7.2 Hz, 3H), 1.39-1.37 (d, J=6.8 Hz, 3H), 1.01-1.03 (d, J=6.0 Hz, 3H), 0.89-0.90 (d, J=6.0 Hz, 3H). LC-MS (M+H) + = 539.8. Chiral HPLC retention time: 8.996 min, method G.

Example 37 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-ul)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N- ((1S,2S)-2-hydroxycyclopentyl)benzamide (compound 37)

This compound (78.0 mg, 74.7%) was prepared from compound 15-13 and (1S,2S)-2-aminocyclopentan1-ol analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO- d ₆ ) δ 8.60-8.58 (d, J=8.0 Hz, 1H), 7.43-7.41 (d, J=8.8 Hz, 1H), 7.33-7, 32 (d, J=5.2 Hz, 1H), 6.89-6.88 (m, 3H), 4.804.75 (m, 2H), 4.52-4.48 (m, 1H), 3 .95-3.90 (m, 2H), 2.57 (s, 3H), 1.99-1.96 (m, 1H), 1.78-1.74 (m, 1H), 1.661.61 (m, 2H), 1.58-1.56 (d, J=7.2 Hz, 3H), 1.48-1.36 (m, 3H), 1.18-1.16 (d, J =6.4Hz, 3H), 1.06-1.05 (d, J=5.6Hz, 3H). LC-MS (M+H) + = 489.8. Chiral HPLC retention time: 3.012 min, method F.

Example 38 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N- ((1S,3R)-3-hydroxy-1-methylcyclobutyl)benzamide (compound 38)

This compound (58.3 mg, 52.9%) was prepared from compound 15-13 and (18,3B)-3-amino-3-methylcyclobutan-1-ol in a similar manner to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO d ₆ ) δ 8.84 (s, 1H), 7.43-7.41 (d, J=8.8 Hz, 1H), 7.36-7.34 (d, J= 5.6 Hz, 1H), 7.06 (brs, 1H), 6.91-6.90 (d, J=5.2 Hz, 1H), 5.08-5.06 (d, J=6 .4 Hz, 1H), 4.82-4.77 (m, 1H), 4.58-4.52 (m, 1H), 4.03-3.97 (m, 1H), 2.58 ( s, 3H), 2.39-2.34 (m, 2H), 2.05-2.00 (m, 2H), 1.59-1.57 (d, J=6.8 Hz, 3H) , 1.36 (s, 3H), 1.21-1.19 (d, J=6.0 Hz, 3H), 1.10-1.09 (d, J=6.0 Hz, 3H). LC-MS (M+H) + = 489.8. Chiral HPLC retention time: 5.309 min, method A.

Example 39 3S)3-hydroxy-1-methylcyclobutyl)-2-isopropoxybenzamide (compound 39)

- 51 040339

This compound (61.2 mg, 56.3%) was prepared from compound 15-13 and (1R,3R)-3-amino-3-methylcyclobutan-1-ol in a similar manner to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSOCH) δ 8.70 (s, 1H), 7.43-7.41 (d, J=8.8 Hz, 1H), 7.36-7.34 (d, J=5, 2 Hz, 1H), 7.02 (brs, 1H), 6.91-6.90 (d, J=5.2 Hz, 1H), 5.06-5.05 (d, J=5.6 Hz, 1H), 4.82-4.77 (m, 1H), 4.56-4.49 (m, 1H), 4.12-4.07 (m, 1H), 2.63-2, 60 (m, 2H), 2.58 (s, 3H), 1.82-1.77 (m, 2H), 1.58-1.57 (d, J=6.8 Hz, 3H), 1 .43 (s, 3H), 1.20-1.18 (d, J=6.4 Hz, 3H), 1.08-1.07 (d, J=6.0 Hz, 3H). LC-MS (M+H) + = 489.8. Retention time in chiral HPLC: 5.500 min, method A.

Example 40 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1R, 4S)4-hydroxy-1-methylcyclohexyl)-2-isopropoxybenzamide (compound 40)

This compound (61.2 mg, 54.1%) was prepared from compound 15-13 and (1R,4R)-4-amino-4-methylcyclohexan-1-ol in a similar manner to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.11 (s, 1H), 7.42-7.37 (m, 2H), 7.13 (brs, 1H), 6.92-6.91 (d , J=5.2 Hz, 1H), 4.83-4.78 (m, 1H), 4.63-4.56 (m, 1H), 4.53-4.52 (m, 1H), 3.45-3.42 (m, 2H), 2.58 (s, 3H), 2.24-2.16 (m, 2H), 1.59-1.54 (m, 5H), 1, 42-1.38 (m, 2H), 1.30 (s, 3H), 1.27-1.23 (m, 2H), 1.20-1.18 (d, J=5.6 Hz, 3H), 1.09-1.07 (d, J=6.0 Hz, 3H). LC-MS (M+H)+ = 417.8. Chiral HPLC retention time: 5.609 min, method A.

Example 41 (S)-3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N- propylbenzamide (compound 41)

This compound (63 mg, 57.3%) was prepared from compound 15-13 and propane-1-amine analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-dg) δ 8.66 (s , 1H), 7.41 (d, J=4.8 Hz, 1H), 7.31 (brs, 1H), 6.86 (brs, 3H), 4.77 (brs, 1H), 4.44 (brs, 1H), 3.21-3.10 (m, 2H), 2.56 (s, 3H), 1.57 (brs, 3H), 1.48 (brs, 2H), 1.17 ( brs, 3H), 1.06 (brs, 3H), 0.87 (brs, 3H). LC-MS (M+H) + = 448.2. Retention time on chiral HPLC: 3.43 min, method C.

Example 42 (S)-3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-N-(cyclopropylmethyl)-6-fluoro- 2-isopropoxybenzamide (compound 42)

This compound (73 mg, 64.3%) was prepared from compound 15-13 and cyclopropylmethanamine analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-dg) δ 8.81 (s, 1H),

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7.41(brs, 1H), 7.28(brs, 1H), 6.88(brs, 1H), 6.52(s, 2H), 4.79(brs, 1H), 4.53(brs , 1H), 3.11 (brs, 2H), 2.57 (s,

3H), 1.59 (brs, 3H), 1.20 (brs, 3H), 1.10 (brs, 3H), 0.99-0.91 (m, 1H), 0.45 (brs, 2H ), 0.22 (brs, 2H). LC-MS (M+H) + = 460.2. Retention time on chiral HPLC: 3.7 min, method C.

Example 43 2 S, 6S)-2,6-dimethylmorpholino) methanone (compound 43)

This compound (59 mg, 47.6%) was prepared from compound 15-13 and (2S,6S)-2,6-dimethylmorpholine analogously to compound 15-14 in Example 15. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.47 (d, J=8.8 Hz, 0.3H), 7.37-7.30 (m, 1H), 7.22 (d, J=4.4 Hz, 0.7H ), 7.03-6.69 (m, 3H), 4.86-4.66 (m, 1H), 4.43-4.15 (m, 1H), 4.10-3.89 (m , 1H), 3.87-3.58 (m, 2H), 3.40-3.33 (m, 1H), 3.09-2.94 (m, 1H), 2.92-2.72 (m, 1H), 2.602.51 (m, 3H), 1.65 (d, J=6.9 Hz, 2H), 1.52 (d, J=6.7 Hz, 1H), 1.33 -1.17 (m, 4H), 1.15-1.05 (m, 4H), 0.99 (d, J=6.3 Hz, 1H), 0.90 (d, J=6.2 Hz, 1H), 0.86 (d, J=5.6 Hz, 2H). LC-MS (M+H)+ = 504.2. Chiral HPLC retention times: 2.77 min and 3.98 min, method F.

Example 44 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopronoxy-N- ((R)-tetrahydro-2H-pyran-3-yl)benzamide (compound 44)

This compound (82 mg, 68%) was prepared from compound 15-13 and (R)-tetrahydro-2H-pyran-3-amine analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 (d, J=7.7 Hz, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.22 (d, J=5.0 Hz, 1H), 6.82 (d, J=5.0 Hz, 1H), 6.40 (s, 2H), 4.76-4.71 (m, 1H), 4.48-4.37 (m, 1H) , 3.85-3.77(m, 1H), 3.76-3.70(m, 1H), 3.69-3.62(m, 1H), 3.29-3.25(m, 1H), 3.15-3.09 (m, 1H), 2.53 (s, 3H), 1.89-1.81 (m, 1H), 1.69-1.62 (m, 1H) , 1.54 (d, J=7.1 Hz, 3H), 1.50-1.40 (m, 2H), 1.15 (d, J=6.1 Hz, 3H), 1.03 ( d, J=6.5, 3H). LC-MS (M+H) + = 490.1. Retention time on chiral HPLC: 3.47 min, method F.

Example 45 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N- ((S)-tetrahydro-2H-pyran-3-yl)benzamide (compound 45)

This compound (31 mg, 25.7%) was prepared from compound 15-13 and (8)-tetrahydro-2H-pyran-3 amine analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.71 (d, J=7.5Hz, 1H), 7.42 (d, J=8.6Hz, 1H), 7.30 (d, J=5.2Hz, 1H) , 6.88 (d, J=5.1 Hz, 1H), 6.73 (s, 2H), 4.764.71 (m, 1H), 4.51-4.41 (m, 1H), 3, 85-3.76(m, 1H), 3.76-3.71(m, 1H), 3.69-3.63(m, 1H), 3.31-3.27(m, 1H), 3.20 3.11 (m, 1H), 2.57 (s, 3H), 1.90-1.87 (m, 1H), 1.69-1.65 (m, 1H), 1.57 (d, J=7.0 Hz, 3H), 1.54-1.41 (m, 2H), 1.18 (d, J=6.0 Hz, 3H), 1.06 (d, J= 6.0 Hz, 3H). LC-MS (M+H) + = 489.8. Chiral HPLC retention time: 9.75 min, method D.

Example 46 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1S, 2S)2-hydroxycyclohexyl)-2-isopropoxybenzamide (compound 46)

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This compound (32 mg, 26%) was prepared from compound 15-13 and (1S,2S)-2-aminocyclohexan-1-ol analogously to compound 15-14 in Example 15. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.53 (d, J=7.9Hz, 1H), 7.36 (d, J=8.5Hz, 1H), 7.27 (d, J=5.1Hz, 1H) , 6.87 (d, J=5.1 Hz, 1H), 6.64 (s, 2H), 4.81-4.74 (m, 1H), 4.69-4.58 (m, 1H ), 4.48 (d, J=5.6 Hz, 1H), 3.65-3.55 (m, 1H), 3.29-3.22 (m, 1H), 2.57 (s, 3H), 1.96-1.78 (m, 2H), 1.65-1.59 (m, 2H), 1.56 (d, J=7.1 Hz, 3H), 1.37-1 .17 (m, 4H), 1.15 (d, J=6.0 Hz, 3H), 1.02 (d, J=6.0 Hz, 3H). LC-MS (M+H)+ = 503.8. Retention time in chiral HPLC: 3.12 min, method F.

Example 47 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-Na(( 1 S, 2R)2-hydroxycyclohexyl)-2-isopropoxybenzamide (compound 47)

This compound (26 mg, 21%) was prepared from compound 15-13 and (1R,2S)-2-aminocyclohexan-1ol analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.36 (d, J=8.1 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 7.31 (d, J=5.2 Hz, 1H), 6, 88 (d, J=5.1 Hz, 1H), 6.79 (s, 2H), 4.80-4.75 (m, 1H), 4.55-4.50 (m, 1H), 4 .48 (d, J=3.6 Hz, 1H), 3.90-3.82 (m, 1H), 3.80-3.75 (m, 1H), 2.57 (s, 3H), 1.721.63 (m, 2H), 1.61-1.51 (m, 5H), 1.50-1.42 (m, 2H), 1.35-1.22 (m, 2H), 1, 17 (d, J=5.9 Hz, 3H), 1.04 (d, J=6.0 Hz, 3H). LC-MS (M+H)+ = 503.8. Chiral HPLC retention time: 6.17 min, method D.

Example 48 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1R, 2S)2-hydroxycyclohexyl)-2-isopropoxybenzamide (compound 48)

This compound (43 mg, 34.7%) was prepared from compound 15-13 and (1S,2R)-2-α-minocyclohexan-1ol analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.33 (d, J=8.1Hz, 1H), 7.36 (d, J=8.5Hz, 1H), 7.27 (d, J=5.2Hz, 1H), 6.86 (d, J=5.1 Hz, 1H), 6.69 (s, 2H), 4.81-4.73 (m, 1H), 4.58-4.49 (m, 1H) , 4.46 (d, J=3.6 Hz, 1H), 3.90-3.83 (m, 1H), 3.81-3.75 (m, 1H), 2.57 (s, 3H ), 1.731.64 (m, 2H), 1.62-1.51 (m, 5H), 1.50-1.43 (m, 2H), 1.34-1.25 (m, 2H), 1.18 (d, J=6.0 Hz, 3H), 1.10 (d, J=6.0 Hz, 3H). LC-MS (M+H)+ = 503.8. Chiral HPLC retention time: 6.14 min, method D.

Example 49 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1R, 2R)2-hydroxycyclohexyl)-2-isopropoxybenzamide (compound 49)

This compound (53 mg, 42.7%) was prepared from compound 15-13 and (1R,2R)-2-α-minocyclohexan-1ol analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.50

- 54 040339 (d, J=7.9Hz, 1H), 7.37 (d, J=8.5Hz, 1H), 7.26 (d, J=5.1Hz, 1H), 6, 86 (d, J=5.1 Hz, 1H), 6.60 (s, 2H), 4.81-4.73 (m, 1H), 4.69-4.59 (m, 1H), 4 .48 (d, J=5.6 Hz, 1H), 3.64-3.54 (m, 1H), 3.30-3.24 (m, 1H), 2.57 (s, 3H), 1.961.79 (m, 2H), 1.65-1.60 (s, 2H), 1.57 (d, J=7.1 Hz, 3H), 1.33-1.17 (m, 4H) , 1.16 (d, J=6.0 Hz, 3H), 1.08 (d, J=5.9

Hz, 3H). LC-MS (M+H)+ = 503.8. Chiral HPLC retention time: 6.63 min, method D.

Example 50 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N- ((tetrahydro-2H-pyran-3-yl)methyl)benzamide (compound 50).

This compound (66 mg, 53%) was prepared from compound 15-13 and (tetrahydro-2H-pyran-3yl)methanamine analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d6) δ 8, 66 (t, J=5.8 Hz, 1H), 7.39 (d, J=8.6 Hz, 1H), 7.28 (d, J=5.2 Hz, 1H), 6.83 ( d, J=5.1 Hz, 1H), 6.73 (s, 2H), 4.78-4.70 (m, 1H), 4.45-4.35 (m, 1H), 3.76 -3.70(m, 1H), 3.69-3.63(m, 1H), 3.26-3.22(m, 1H), 3.093.02(m, 3H), 2.53(s , 3H), 1.78-1.65 (m, 2H), 1.54 (d, J=7.1 Hz, 3H), 1.51-1.48 (m, 1H), 1.45- 1.33 (m, 1H), 1.22-1.17 (m, 1H), 1.14 (d, J=6.1 Hz, 3H), 1.04 (d, J=6.0 Hz , 3H). LC-MS (M+H)+ = 504.2. Chiral HPLC retention time: 3.31 min, method F.

Example 51 (S)-3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N- ((tetrahydro-2H-pyran-4-yl)methyl)benzamide (compound 51)

This compound (61 mg, 49%) was prepared from compound 15-13 and (tetrahydro-2H-pyran-4-yl)methanamine analogously to compound 15-14 in Example 15. ¹ H NMR (400 MHz, DMSO-46) δ 8.69 (t, J=5.7 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.29 (d, J=5.2 Hz, 1H), 6 .84 (d, J=5.2 Hz, 1H), 6.79 (s, 2H), 4.804.71 (m, 1H), 4.47-4.36 (m, 1H), 3.84- 3.78 (m, 2H), 3.24-3.17 (m, 2H), 3.08 (t, J=6.3 Hz, 2H), 2.54 (s, 3H), 1.74 -1.64(m, 1H), 1.59-1.50(m, 5H), 1.21-1.11(m, 5H), 1.04(d, J=6.1Hz, 3H ). LC-MS (M+H)+ = 504.2. Chiral HPLC retention time: 4.68 min, method L.

Example 52 (3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-uzopropoxyphenyl)( 8-oxa-3-azabicyclo[3.2.1]octan-3-yl)methanone (compound 52)

This compound (32 mg, 26%) was prepared from compound 15-13 and 8-oxa-3-azabicyclo[3.2.1]octane, analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.50-7.33 (m, 1H), 7.31-7.11 (m, 1H), 6.91-6.81 (m, 0.6H), 6.80-6.70 (m, 0.4H), 6.55-6.31 (m, 2H), 4.85-4.66 (m, 1H), 4.64-4.51 (m, 0.4H), 4 .42 (brs, 1H), 4.33-3.99 (m, 2.6H), 3.29-3.23 (m, 1H), 3.16-3.03 (m, 1H), 3 .03-2.78(m, 2H), 2.57(s, 3H), 1.87(brs, 2H), 1.77-1.63(m, 3H), 1.58-1.49 (m, 1H), 1.37-1.10 (m, 6H), 0.96-0.77 (m, 1H). LC-MS (M+H)+ = 501.8. Retention time on chiral HPLC: 5.17 min, method B.

Example 53 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1R, 3R)3-hydroxycyclopentyl)-2-isopropoxybenzamide (compound 53)

- 55 040339

This compound (45 mg, 37.5%) was prepared from compound 15-13 and (1R,3R)-3-aminocyclopentan-1ol analogously to compound 15-14 in Example 15. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 (d, J=7.5Hz, 1H), 7.45 (d, J=8.6Hz, 1H), 7.40 (d, J=5.4Hz, 1H) , 7.38-7.25(m, 2H), 6.92(d, J=5.3Hz, 1H), 4.84-4.76(m, 1H), 4.54(d, J =3.6 Hz, 1H), 4.50-4.41 (m, 1H), 4.39-4.30 (m, 1H), 4.19-4.13 (m, 1H), 2, 58 (s, 3H), 2.07-1.97 (m, 1H), 1.84 (d, J=3.9 Hz, 2H), 1.61-1.54 (m, 4H), 1 .50-1.35 (m, 2H), 1.17 (d, J=6.1 Hz, 3H), 1.05 (d, J=6.1 Hz, 3H). LC-MS (M+H) + = 489.8. Retention time on chiral HPLC: 3.45 min, method B.

Example 54 (S)-3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-N-(1-((dimethylamino)methyl )cyclopropyl)-6-fluoro-2-isopropoxybenzamide (compound 54)

This compound (33 mg, 26.6%) was prepared from compound 15-13 and 1-((dimethylamino)methyl)cyclopropan-1-amine analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO- d6) δ 9.21 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.38 (d, J=5.2 Hz, 1H), 7.03 (s, 2H), 6.91 (d, J=5.2 Hz, 1H), 4.83-4.74 (m, 1H), 4.38-4.24 (s, 1H), 3.30-3 .17 (m, 2H), 2.77 (s, 6H), 2.57 (s, 3H), 1.58 (d, J=7.0 Hz, 3H), 1.20-1.11 ( m, 5H), 1.05 (d, J=6.0 Hz, 3H), 0.93-0.78 (m, 2H). LC-MS (M+H)+ = 502.8. Chiral HPLC retention time: 3.57 min, method A.

Example 55 (S)-3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((3- hydroxyoxetan-3-yl)methyl)-2-isopropoxybenzamide (compound 55)

This compound (51 mg, 42%) was prepared from compound 15-13 and 3-(aminomethyl)xetan-3-ol analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8 .87 (t, J=5.7Hz, 1H), 7.41 (d, J=8.5Hz, 1H), 7.30 (d, J=5.2Hz, 1H), 6.88 (d, J=5.1 Hz, 1H), 6.80 (s, 2H), 5.87 (s, 1H), 4.834.73 (m, 1H), 4.54-4.74 (m, 1H), 4.47-4.42 (m, 2H), 4.41-4.36 (m, 2H), 3.64-3.48 (m, 2H), 2.58 (s, 3H) , 1.58 (d, J=7.0 Hz, 3H), 1.18 (d, J=6.0 Hz, 3H), 1.08 (d, J=6.0 Hz, 3H). LC-MS (M+H)+ = 491.8. Retention time on chiral HPLC: 5.8 min, method B.

Example 56 (S)-3-(1-(8-Amino-1-methylimidazo[1,5-α]πyrazin-3-yl)ethyl)-5-chloro-N-(1-((4-( cyclopropylmethyl)piperazin-1-yl)methyl)cyclopropyl)-6-fluoro-2-isopropoxybenzamide (compound 56)

This compound (55 mg, 37.4%) was obtained from compound 15-13 and 1-((4-(cyclopropylmethyl)pipe

- 56 040339 razin-1-yl)methyl)cyclopropan-1-amine analogously to the preparation of compound 15-14 in example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.83 (s, 1H), 7, 34 (d, J=8.5 Hz, 1H), 7.24 (d, J=5.0 Hz, 1H), 6.85 (d, J=5.0 Hz, 1H), 6.43 ( s, 2H), 4.81-4.72 (m, 1H), 4.71-4.61 (m, 1H), 3.33-3.24 (m, 2H), 2.56 (s, 3H), 2.47-2.23 (m, 7H), 2.13 (d, J=6.4 Hz, 2H), 1.56 (d, J=7.0 Hz, 3H), 1, 18 (d, J=5.9 Hz, 3H), 1.07 (d, J=5.9 Hz, 3H), 0.82-0.74 (m, 1H), 0.73-0.69 (m, 2H), 0.68-0.60 (m, 2H), 0.47-0.37 (m, 2H), 0.08-0.01 (m, 2H). LC-MS (M+H) + = 597.8. Retention time on chiral HPLC: 2.6 min, method B.

Example 57 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((S) -2hydroxypropyl)-2-isopropoxybenzamide (compound 57)

This compound (19 mg, 16.7%) was prepared from compound 15-13 and (S)-1-aminopropan-2-ol in a manner similar to compound 15-14 in Example 15. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 (t, J=5.6Hz, 1H), 7.41 (d, J=8.5Hz, 1H), 7.32 (d, J=5.0Hz, 1H) , 7.00-6.70 (m, 3H), 4.88-4.74 (m, 1H), 4.70 (d, J=4.6 Hz, 1H), 4.54-4.42 (m, 1H), 3.78-3.66 (m, 1H), 3.24-3.16 (m, 1H), 3.15-3.07 (m, 1H), 2.58 (s , 3H), 1.58 (d, J=7.0 Hz, 3H), 1.18 (d, J=6.0 Hz, 3H), 1.07 (t, J=5.6 Hz, 6H ). LC-MS (M+H)+ = 463.8. Retention time on chiral HPLC: 3.02 min, method B.

Example 58 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1R, 2R)2-hydroxycyclopentyl)-2-isopropoxybenzamide (compound 58)

This compound (81 mg, 67%) was prepared from compound 15-13 and (1R,2R)-2-aminocyclopentan-1ol analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.57 (d, J=7.2Hz, 1H), 7.39 (d, J=8.6Hz, 1H), 7.28 (d, J=5.2Hz, 1H), 6, 85 (d, J=5.1 Hz, 1H), 6.69 (s, 2H), 4.81-4.71 (m, 2H), 4.53-4.43 (m, 1H), 3 .98-3.85 (m, 2H), 2.55 (s, 3H), 2.01-1.91 (m, 1H), 1.80-1.70 (m, 1H), 1.68 -1.59 (m, 2H), 1.55 (d, J=7.1 Hz, 3H), 1.48-1.33 (m, 2H), 1.16 (d, J=6.1 Hz, 3H), 1.04 (d, J=6.0 Hz, 3H). LC-MS (M+H) + = 489.8. Retention time on chiral HPLC: 2.99 min, method B.

Example 59 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N- ((S)-1-(2-(trifluoromethyl)pyridin-4-yl)ethyl)benzamide (compound 59A) and 3-((S)-1-(8-amino-1methylimidazo[1,5-a]pyrazine -3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-X-((K)-1-(2-(trifluoromethyl)pyridin-4-yl)ethyl)benzamide (compound 59B)

These compounds were prepared from compound 15-13 and 1-(2-(trifluoromethyl)pyridin-4-yl)ethan1-amine analogously to compound 15-14 in Example 15. The isomers were prepared by chiral resolution.

Compound 59A: 136 mg, 31.9%. 1H NMR (400 MHz, DMSO-b ₆ ) δ 9.42 (d, J=7.6 Hz, 1H), 8.77 (d, J=5.0 Hz, 1H), 7.89 (s, 1H), 7.71 (d, J=4.9Hz, 1H), 7.49 (d, J=8.7Hz, 1H), 7.29 (d, J=5.1Hz, 1H) , 6.86 (d, J=5.0 Hz, 1H), 6.46 (s, 2H), 5.26-5.16 (m, 1H), 4.81-4.73 (m, 1H ), 4.27-4.16 (m, 1H), 2.56 (s, 3H), 1.57 (d, J=7.1 Hz, 3H),

- 57 040339

1.43 (d, J=7.1 Hz, 3H), 1.07 (d, J=6.1 Hz, 3H), 0.93 (d, J=6.1 Hz, 3H). LC-MS (M+H)+ = 578.7. Retention time on chiral HPLC: 3.68 min, method C.

Compound 59B: 103 mg, 24%. 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.42 (d, J=7.5 Hz, 1H), 8.77 (d, J=4.6 Hz, 1H), 7.89 (s, 1H), 7.72 (d, J=4.1Hz, 1H), 7.46 (d, J=8.5Hz, 1H), 7.28 (d, J=4.7Hz, 1H) , 6.85 (d, J=4.7 Hz, 1H), 6.47 (s, 2H), 5.29-5.17 (m, 1H), 4.82-4.69 (m, 1H ), 4.32-4.18 (m, 1H), 2.56 (s, 3H), 1.59 (d, J=6.8 Hz, 3H), 1.43 (d, J=6, 8 Hz, 3H), 1.06 (d, J=5.7 Hz, 3H), 0.89 (d, J=5.7 Hz, 3H). LC-MS (M+H)+ = 578.7. Retention time on chiral HPLC: 4.18 min, method C.

Column CHIRALPAK GO Column size 2 cm x 25 cm x 5 µm Injection 0.3 ml mobile phase Hexane (10 mM NH ₃ -MeOH): EtOH = 80:20 Flow rate 20 ml/min Wavelength UV 220 nm Temperature 25°C Sample solution 58 mg/ml in EtOH:DCM = 3:1 Equipment For Prep-HPLC-Gilson preparative HPLC

Example 60 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((trans) 4-hydroxycyclohexyl)-2-isopropoxybenzamide (compound 60)

This compound (50 mg, 39%) was prepared from compound 15-13 and trans-4-aminocyclohexan-1-ol analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8, 57 (d, J=7.8 Hz, 1H), 7.38 (d, J=8.6 Hz, 1H), 7.25 (d, J=5.1 Hz, 1H), 6.85 ( d, J=5.0 Hz, 1H), 6.42 (brs, 2H), 4.76 (q, J=7.2 Hz, 1H), 4.55 (d, J=4.3 Hz, 1H), 4.51-4.43(m, 1H), 3.65(brs, 1H), 3.34(brs, 1H), 2.56(s, 3H), 1.87-1.76 (m, 4H), 1.56 (d, J=7.1 Hz, 3H), 1.28-1.20 (m, 4H), 1.17 (d, J=6.0 Hz, 3H) , 1.06 (d, J=6.0 Hz, 3H). LC-MS (M+H)+ = 504.2. Retention time on chiral HPLC: 4.372 min, method C.

Example 61 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((trans) 3-hydroxycyclobutyl)-2-isopropoxybenzamide (compound 61)

This compound (80 mg, 75%) was prepared from compound 15-13 and trans-3-aminocyclobutan-1-ol analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8, 96 (brs, 1H), 7.45 (d, J=8.7 Hz, 1H), 7.32 (brs, 1H), 6.89 (brs, 1H), 6.72 (brs, 2H), 5.09 (brs, 1H), 4.79 (brs, 1H), 4.44 (brs, 1H), 4.28 (brs, 2H), 2.58 (s, 3H), 2.16 (brs , 4H), 1.58 (brs, 3H), 1.19 (brs, 3H), 1.07 (brs, 3H). LC-MS (M+H)+ = 476.2. Chiral HPLC retention time: 2.669 min, method K.

Example 62 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((cis) -4hydroxycyclohexyl)-2-isopropoxybenzamide (compound 62)

- 58 040339

This compound (70 mg, 55%) was prepared from compound 15-13 and cis-4-aminocyclohexan-1-ol analogously to compound 15-14 in Example 15. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8 .61 (brs,

1H), 7.35 (d, J=8.4 Hz, 1H), 7.25 (brs, 1H), 6.85 (brs, 1H), 6.50 (brs, 2H), 4.76 ( brs, 1H), 4.48 (brs, 1H), 4.38 (brs, 1H), 3.75 (brs, 1H), 3.66 (brs, 1H), 2.55 (brs, 3H), 1.69-1.41 (m, 8H), 1.17 (brs, 3H), 1.05 (brs, 3H). LCMS (M+H)+ = 504.2. Chiral HPLC retention time: 2.045 min, method L.

Example 63 3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]n-yrazin-3-ul)ethyl)-5-chloro-6-fluoro-N-((cis) -3hydroxycyclobutyl)-2-isopropoxybenzamide (compound 63)

This compound (70 mg, 59%) was prepared from compound 15-13 and cis-3-aminocyclobutan-1-ol analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8, 89 (brs, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.32 (brs, 1H), 6.89 (brs, 1H), 6.81 (brs, 2H), 5.13 (brs, 1H), 4.79 (brs, 1H), 4.42 (brs, 1H), 3.82 (brs, 2H), 2.59-2.51 (m, 5H), 1 .77 (brs, 2H), 1.58 (brs, 3H), 1.19 (brs, 3H), 1.07 (brs, 3H). LCMS (M+H)+ = 476.2. HPLC: 214 nm, 98%, 254 nm, 98%. Retention time in chiral HPLC: 3.358 min. Chiral HPLC retention time: 3.36 min, method F.

Example 64 2-oxa-7-azaspiro[3,5]nonan-7-yl)methanone (compound 64)

This compound (70 mg, 54%) was prepared from compound 15-13 and 2-oxa-7-azaspiro[3,5]nonane oxalate analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO d ₆ ) δ 7.41 (d, J=6.5 Hz, 0.3H), 7.31 (d, J=6.5 Hz, 0.7H), 7.25 (brs, 0.3H), 7 .16 (brs, 0.7H), 6.85 (brs, 1H), 6.56 (brs, 2H), 4.74 (brs, 1H), 4.43-4.17 (m, 4.7H ), 3.76 (brs, 0.6H), 3.57 (brs, 0.6H), 3.34 (brs, 0.8H), 3.14 (brs, 0.8H), 2.95 ( brs, 1.5H), 2.59-2.53(m, 3H), 1.87(brs, 1H), 1.82-1.60(m, 5H), 1.57-1.52( brs, 1H), 1.20 (brs, 4H), 1.13 (brs, 1H), 0.95 (brs, 1H). LC-MS (M+H)+ = 516.2. Chiral HPLC retention time: 6.206 min, method F.

Example 65 (3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)( (8)-3-methoxypiperidin-1-yl)methanone (compound 65)

This compound (70 mg, 55%) was prepared from compound 15-13 and (8)-3-methoxypiperidine in a similar manner to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) 7.51- 7.22 (m, 2H), 7.00 (brs, 2H), 6.92-6.79 (m, 1H), 4.87-4.72 (m, 1H), 4.57-4, 46 (m, 0.3H), 4.46-4.34 (m, 0.6H), 4.30-4.21 (m, 0.2H), 4.14 (d, J=13.2 Hz, 0.3H), 4.06-3.94(m, 0.5H), 3.60(brs, 0.3H), 3.52-3.40(m, 0.7H), 3 .31(s, 1.5H), 3.27(s, 1H), 3.24-3.10(m, 1H), 3.08-2.88(m, 2.5H), 2, 58 (brs, 3H), 2.02-1.78 (m, 1H), 1.77-1.60 (m, 3H), 1.601.52 (m, 1.5H), 1.51-1, 29 (m, 1.5H), 1.29-1.12 (m, 4.8H), 0.97 (d, J=5.9 Hz, 0.8H), 0.88 (d, J= 5.8 Hz, 0.4H). LC-MS (M+H)+ = 516.2. Retention time in chiral HPLC: 6.817 min, method G.

Example 66 (S)-3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1- hydroxycyclopropyl)methyl)-2-isopropoxybenzamide (compound 66)

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This compound (50 mg, 42%) was prepared from compound 15-13 and 1-(aminomethyl)cyclopropan-1ol analogously to compound 15-14 in Example 15. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8, 74 (t, J=5.7 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.35 (d, J=5.3 Hz, 1H), 7.08 ( brs, 2H), 6.89 (d, J=5.2 Hz, 1H), 5.28 (s, 1H), 4.80 (q, J=7.0 Hz, 1H), 4.60- 4.51 (m, 1H), 3.39 (d, J=5.9 Hz, 2H), 2.58 (s, 3H), 1.58 (d, J=7.0 Hz, 3H), 1.18 (d, J=6.0 Hz, 3H), 1.08 (d, J=6.0 Hz, 3H), 0.54 (brs, 4H). LC-MS (M+H)+ = 476.1. Chiral HPLC retention time: 3.187 min, method F.

Example 67 (3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)( (2R,6S)-2,6-dimethylmorpholino)methanone (compound 67)

This compound (40 mg, 31%) was prepared from compound 15-13 and (2R,6S)-2,6-dimethylmorpholine analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.51-7.41 (m, 0.6H), 7.36-7.28 (m, 0.6H), 7.26 (d, J=5.2 Hz, 0.4H), 7. 22 (d, J=5.1 Hz, 0.4H), 6.87 (d, J=5.1 Hz, 0.3H), 6.84-6.80 (m, 0.7H), 6 .64 (brs, 2H), 4.82-4.72 (m, 1H), 4.53-4.33 (m, 1.5H), 4.32-4.22 (m, 0.4H) , 4.15-4.07 (m, 0.2H), 3.52 (brs, 1.9H), 3.02 (d, J=12.0 Hz, 0.5H), 2.90-2 .72 (m, 1H), 2.70-2.64 (m, 0.5H), 2.60-2.56 (m, 3H), 2.49-2.43 (m, 1H), 1 .68 (t, J=6.9 Hz, 2.2H), 1.59-1.54 (m, 0.8H), 1.29 (d, J=6.0 Hz, 1H), 1, 27-1.21 (m, 4H), 1.18-1.12 (m, 3H), 1.08-1.00 (m, 1H), 0.97-0.85 (m, 3H). LC-MS (M+H)+ = 503.8. Chiral HPLC retention time: 2.602 min, method F.

Example 68 (S)-(3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)( 6-oxa-2-azaspiro[3.4]octan-2-yl)methanone (compound 68)

This compound (40 mg, 31%) was prepared from compound 15-13 and 6-oxa-2-azaspiro[3.4]octane oxalate analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.41 (d, J=8.4 Hz, 1H), 7.30-7.26 (m, 1H), 6.83 (brs, 1H), 6.69 (brs, 2H), 4, 82-4.74 (m, 1H), 4.35 (brs, 1H), 4.04 (brs, 2H), 3.87-3.61 (m, 6H), 2.57 (s, 3H) , 2.22-2.00 (m, 2H), 1.65 (brs, 3H), 1.23 (d, J=10.2 Hz, 6H). LC-MS (M+H)+ = 501.8. Chiral HPLC retention time: 11.092 min, method A.

Example 69 (R)-3-methoxypiperidin-1-yl)methanone (compound 69)

This compound (70 mg, 55%) was prepared from compound 15-13 and (R)-3-methoxypiperidine analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) 7.48-7 .27 (m,

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2H), 7.07 (brs, 2H), 6.92-6.80 (m, 1H), 4.86-4.72 (m, 1H), 4.58-4.48 (m, 0, 5H), 4.45-4.30 (m, 0.5H), 4.30-4.12 (m, 0.5H), 3.82-3.37 (m, 2H), 3.29 ( brs, 2H), 3.23-3.10 (m, 1.5H), 3.10-2.88 (m, 1.5H), 2.83 (brs, 0.5H), 2.60- 2.56 (m, 3H), 1.89 (brs, 1H), 1.79-1.62 (m, 4H), 1.63-1.53 (m, 1H), 1.32-1, 14 (m, 6H), 1.06-1.02 (m, 0.4H), 0.99-0.92 (m, 0.6H). LC-MS (M+H)+ = 501.8. Chiral HPLC retention time: 5.630 min, method A.

Example 70 (3-((S)-1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-uzopropoxyphenyl)( (S)-3-methoxypyrrolidin-1-yl)methanone (compound 70)

This compound (70 mg, 57%) was prepared from compound 15-13 and (S)-3-methoxypyrrolidine in a similar manner to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) 7.50-7 .24 (m, 2H), 7.19-6.74 (m, 3H), 4.85-4.75 (m, 1H), 4.47-4.33 (m, 0.6H), 4 .33-4.20(m, 0.4H), 4.09-3.92(m, 0.6H), 3.88(brs, 0.4H), 3.68-3.37(m, 2H), 3.27-2.91 (m, 5H), 2.65-2.54 (m, 3H), 1.97 (brs, 2H), 1.65 (brs, 2H), 1.54 (brs, 1H), 1.26-1.14 (m, 5H), 0.94-0.84 (m, 1H). LC-MS (M+H)+ = 501.8. Chiral HPLC retention time: 3.679 min, method F.

Example 71 3S)3-hydroxycyclopentyl)-2-isopropoxybenzamide (compound 71)

This compound (49 mg, 40%) was prepared from compound 15-13 and (1S,3S)-3-aminocyclopentan-1ol analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 (d, J=7.6 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 7.41-7.24 (m, 3H), 6.92 (d , J=5.3 Hz, 1H), 4.81 (q, J=7.0 Hz, 1H), 4.57-4.51 (m, 1H), 4.50-4.40 (m, 1H), 4.40-4.30 (m, 1H), 4.17 (brs, 1H), 2.58 (s, 3H), 2.09-1.97 (m, 1H), 1.911.78 (m, 2H), 1.63-1.54 (m, 4H), 1.50-1.34 (m, 2H), 1.18 (d, J=6.0 Hz, 3H), 1, 06 (d, J=6.0Hz, 3H). LC-MS (M+H) + = 489.8. Retention time on chiral HPLC: 6.423 min, method A.

Example 72 3R)3-hydroxybutan-2-yl)-2-isopropoxybenzamide (compound 72)

This compound (80 mg, 66%) was prepared from compound 15-13 and (2R,3R)-3-aminobutan-2-ol analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (d, J=8.2Hz, 1H), 7.40 (d, J=8.6Hz, 1H), 7.31 (d, J=5.1Hz, 1H) , 6.88 (d, J=5.1 Hz, 1H), 6.79 (brs, 2H), 4.79 (q, J=6.7 Hz, 1H), 4.61 (d, J= 5.0 Hz, 1H), 4.56-4.46(m, 1H), 3.97-3.88(m, 1H), 3.73-3.64(m, 1H), 2.57 (s, 3H), 1.57 (d, J=7.1 Hz, 3H), 1.17 (d, J=6.0 Hz, 3H), 1.08-1.03 (m, 6H) , 1.02 (d, J=6.3 Hz, 3H). LC-MS (M+H) + = 477.8. Retention time on chiral HPLC: 3.655 min, method C.

Example 73 (S)-3-(1-(8-Amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-X- (2-(4-methylpiperazin-1-yl)ethyl)benzamide (compound 73)

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This compound (93 mg, 72.1%) was prepared from compound 15-13 and 2-(4-methylpiperazin-1-yl)ethan1-amine analogously to compound 15-14 in Example 15. 1H NMR (400 MHz, DMSO -d ₆ ) δ 8.64-8.61 (t, 1H), 7.39-7.37 (d, J=8.8 Hz, 1H), 7.25-7.24 (d, J= 5.2 Hz, 1H), 6.86-6.85 (d, J=4.8 Hz, 1H), 6.43 (brs, 2H), 4.80-4.74 (m, 1H), 4.52-4.46(m, 1H), 3.41-3.28(m, 4H), 2.56(s, 3H), 2.43-2.18(m, 8H), 2, 14 (s, 3H), 1.59-1.57 (d, J=6.8 Hz, 3H), 1.19-1.18 (d, J=5.6 Hz, 3H), 1.10 -1.08 (d, J=5.6 Hz, 3H). LC-MS (M+H) + = 532.1. HPLC: 214 nm, 96.79%, 254 nm, 100%. Retention time on chiral HPLC: 3.67 min, method B.

The following compounds are prepared in a similar way

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biological analyses.

I. Analysis of ΡΙ3Κδ.

Compounds of the invention are tested for inhibition of ΡΙ3Κδ kinase activity using a commercial ADP-Glo™ Kinase Assay (Promega Corporation) and following the manufacturer's instructions. Briefly, recombinant PI3K enzyme (p110δ/p85α), lipid kinase substrate and compounds of the present invention in serial dilution were incubated for 0.5 h at room temperature. ATP is added to initiate the kinase reaction. After incubation for 1 hour at room temperature, the ADP-Glo™ reagent is added to terminate the kinase reaction and deplete the remaining ATP. After incubation for 1 h at room temperature, a kinase detection reagent is added to simultaneously convert ADP to ATP and measure the newly synthesized

- 64 040339 bath ATP using the reaction luciferase/luciferin. After incubation for 0.5 h at room temperature, the resulting luminescence was measured on a PHERAstar FS reader (BMG LABTECH). Residual enzyme activity in the presence of increasing concentrations of compounds is calculated from luminescence. The IC ₅₀ for each compound was obtained by fitting the data to a four parameter logistic equation using the Graphpad Prism software. Values IC ₅₀ examples are presented in table. 1 as determined by PI3K delta analysis.

II. PI3Ka, β and γ assays.

The compounds disclosed in the present invention are tested for inhibition of recombinant PI3K (p110a/p85a), PI3K (p110b/p85a) and PI3K φ110γ) using the same method as PI3K (p110δ/p85α), except that incubation in for 2 h was applied to the PI3K (p110b/p85a) kinase reaction. The selectivity of the examples is presented in table. 1 as determined by PI3K α, β and γ assays.

Table 1. Enzymatic activity IC ₅₀ or maximum inhibition (%) at 0.5 μM for the compounds of the invention

Compound Enzymatic activity IC50 (nM) or maximum inhibition (%) at 0.5 µM ΡΙ3Κα ΡΙ3Κβ ΡΙ3Κ5 ΡΙ3Κγ 1 more than 50000 more 50000 9.7 9800 2 more than 50000 more 14 5500

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50000 3 49000 34000 6.3 19000 4 25000 24000 1.9 3100 4A 13000 11000 1.0 2000 4V — — over 1000 — 5 56000 16000 3.3 10000 5A 21000 20000 1.5 6300 5V — — 93 — 6 more than 50000 more 50000 2.9 17000 7 more 50000 more 50000 6.0 17000 8 49000 16000 2.3 6800 9 43000 18000 2.9 9200 10 34000 22000 h, o 9000 AND 31000 6200 2.0 7300 12 more than 50000 more 50000 3.7 14000 13A 20000 more 50000 h, o 9300 13V — — over 1000 — 14A 18000 13000 1.4 7900 14V — — 320 — 15 36000 more 50000 1.8 6700 16 20000 17000 4.0 11000 17 77000 72000 3.8 14000 18 19000 12000 2.4 6500 19 33000 60000 2.0 10000 20 — — 2.1 — 21 33000 28000 1.4 3900 22 — — 3.7 — 23 — — 9.9 — 24 36000 16000 1.6 5800

- 66 040339

25 24000 8700 1.9 6000 26 24000 17000 0.86 6500 27 32000 3000 0.93 3900 28 24000 6800 1.2 4800 29 11000 9900 1.1 2100 thirty 17000 14000 0.97 7700 31 25000 16000 3.1 6200 32 — — 3.2 — 33 9300 13000 1.3 2200 34 36000 11000 1.4 3200 35 46000 19000 1.3 6000 36 9500 13000 2.0 460 37 11000 11000 0.56 2500 38 6100 25000 1.4 3200 39 10000 2300 0.90 28000 40 — — 6.5 — 41 20000 4900 0.99 5500 42 36000 21000 1.2 4800 43 21000 more 50000 2.2 3400 44 20000 30000 0.74 5000 45 16000 32000 1.1 2800 46 9700 39000 0.94 2100 47 27000 26000 2.5 5800 48 — — 9.1 — 49 — — 3.9 — 50 15000 20000 1.2 6100 51 27000 6400 0.97 4500 52 10000 40000 1.4 2500 53 14000 11000 0.68 2400 54 — — AND — 55 13000 11000 1.8 2200 56 28000 44000 1.9 4500 57 18000 12000 1.1 4900

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58 14000 16000 2.2 2800 59A 8300 14000 2.1 1200 59B 14000 26000 1.5 2800 60 11000 35000 0.95 6300 61 21000 12000 1.4 4500 62 17000 29000 1.4 9000 63 38000 7400 1.1 4200 64 more 50000 more 50000 1.6 14000 65 50000 more 50000 2.9 6900 66 14000 12000 2.2 3400 67 - - 8.0 - 68 40000 23000 1.7 4600 69 more than 50000 more 50000 2.0 5200 70 41000 more 50000 1.9 6700 71 14000 13000 1.4 3400 72 - - 6.8 - 73 14000 14000 2.8 9500

The following assays were also used to determine pharmacokinetic (PK) and blood-brain barrier (BBB) data for some examples of the compounds of the invention.

III. Pharmacokinetic properties of compounds in Sprague-Dawley rats after intravenous (IV) and oral (OR) administration.

Receiving a dose of the composition.

A dose solution for injection was prepared as follows: 1.0 mg of test compound was weighed and dissolved in 0.32 ml of dimethylacetamide (DMA). The solution is then further diluted with 0.36 ml of ethanol and 0.32 ml of propylene glycol. The final concentration of the test compound was 1.0 mg-ml' ¹ .

Dose solution for oral administration is prepared as follows: 5.0 mg of the test compound is weighed and dispersed in 10 ml of 0.5% methylcellulose (MC). The final concentration of the test compound was 1 mg-ml' ¹ .

Animals.

Male Sprague-Dawley rats (data also summarized in Table 2) are housed in hard-bottomed polypropylene cages with sterilized bedding and receive a sterilized diet and sterilized water. The room is monitored for humidity (target average range 40 to 70%) and temperature (target average range 18 to 26° C.) with 10 to 20 air changes/hour. The light cycle is maintained at 12 hours of light and 12 hours of darkness. Only animals that appeared healthy were selected for the present study based on general health, body weight, or other relevant information. Animals are treated in accordance with a specific treatment regimen, as shown in table. 3.

Table 2. Animal Information

Genus Floor View Source Age Weight (g) Ordered Selected Rat Male Sprague-Dawley (SD) vital River 8 weeks 220-250 7 6

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Table 3. Animal treatment schedule

Groups Quantity Dose values (mg-kg-1) Concentration walkie-talkie (mg-ml-1) Carrier Dosing route Mode Hunger/Nutrition Time to take a measurement 1-3 3 1D 1.0 32% DMA, 36% ethanol, 32% propylene- glycol tail vein BB One time Hunger Pre-dose, 5, 15, 30 min, 1, 2, 4, 8, 24 hours 4-6 3 5.0 or 10.0 1.0 0.5% MC Peroral but One time Hunger Pre-dose, 15, 30 min, 1, 2, 4, 8, 24 hours

Study design.

All procedures performed on animals are carried out in accordance with established guidelines, reviewed and approved by an independent institutional review board.

Male Sprague Dawley rats were fasted overnight with free access to drinking water prior to treatment. On the first day, the animals are weighed and the actual dose volume for each animal is calculated using the following formula:

Dose volume (ml) = [Nominal dose (mg kg / Dose concentration (mgml' ¹ )] x

Animal body weight (kg) (1)

Three rats were given a single intravenous dose of 1 mg-ml' ¹ by injection into the tail vein, and the other three rats were given a single oral dose of 5 or 10 mg-ml' ¹ . Dose solutions were freshly prepared prior to dosing. Actual body weight and actual volume administered are recorded, respectively. Four hours after dosing, the rats are allowed to eat.

Blood samples (approximately 150 µl) are taken at various times from the jugular vein catheter into EDTA-K2 tubes. Whole blood is processed by centrifugation at 3000 g for 10 min. Plasma samples are collected and stored at -80°C in a freezer prior to analysis. The time of blood sampling is recorded accordingly.

Sample testing.

Dose samples for IV and SR administration are diluted with MeOH:H2O (4:1, v/v) to reach a concentration of 2 μg-ml' ¹ , respectively. 47.5 µl pure plasma is then added to 2.5 µl of the diluted samples and then treated as a plasma sample. A 10 μl aliquot of the mixture is injected into the LCMS/MS system. Pharmacokinetic (PK) data of the test compounds are obtained as shown in table. 4.

Table 4. PK data in rats for compounds 60 and 73

Compound BB (1 mg/kg) PR (5 mg/kg for compound 60 and 10 mg/kg for compound 73) tl/2 (h) C1 (ml kg' Gmin' AUCo-inf (chngml ‘) Vass (l kg' ¹ ) tl/2 (h) Saks (h) Smake (ngml ‘) AUCO-inf (chngml' ¹ ) F% ‘) 60 0.6 76.6 218.4 3.3 2.0 0.3 132.8 159.1 14.6 73 8.2 86.6 193.7 59.4 5.6 1.5 220.3 918.1 34.9

IV. Brain penetration of compounds in male C57BL/6 mice following oral administration.

Receiving a dose of the composition.

Approximately 4 mg of test compound is weighed and dispersed in 0.5% methylcellulose (MC). After that, the whole mixture is shaken until a solution or suspension is formed. The final concentration of the test compound was 1 mg-ml' ¹ . The concentration of the test compound in the dosed compositions is determined in the range from 85 to 115% of the nominal values.

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Animals.

Male C57BL/6 mice are housed in polypropylene hard bottom cages with sterilized bedding. The room is monitored for humidity (target average range 40 to 70%) and temperature (target average range 20 to 25°C) with 10 to 20 air changes/hour. The room is maintained on a 12-hour light/dark cycle, except for breaks for learning activities. The mice are given a sterilized diet and water. All animals were examined upon receipt and acclimatized for at least 3 days. Only animals that appeared to be healthy were selected for study based on general health, body weight, or other relevant data as appropriate.

Study design.

All procedures performed on animals are carried out in accordance with established guidelines, reviewed and approved by an independent institutional review board. Animals are treated according to a specific schedule.

Male mice are fasted overnight with free access to drinking water until treatment. On the first day, the animals are weighed and the actual dose volume for each animal is calculated using the following formula:

Dose volume (ml) = [Nominal dose (mg-kg'b/Dose concentration (mg ml' ¹ )] ^x

Animal body weight (kg) (I)

Mice are administered the test compound at a dose of 10 mg-ml' ¹ via oral gavage, respectively. The dose formulations were freshly prepared. Actual body weight and actual volume administered are recorded, respectively.

Three mice are sacrificed under carbon dioxide for sampling at 1, 2, and 4 hours post-dose, respectively. Blood samples (approximately 0.2 ml) are collected by cardiac puncture into anticoagulant (EDTA-Ka) tubes. The tubes are gently inverted several times to ensure mixing. Whole blood is centrifuged to collect plasma at 5500 rpm for 10 minutes. The brain is harvested immediately after euthanasia. Sample collection times are recorded accordingly. After removal of excess water, the brain is weighed and homogenized with water 5x (w/v) in an ice bath. Samples are stored at temperatures below minus 20°C in a freezer until analysis.

Sample testing.

For plasma samples: To a 10 µl aliquot of sample, add 500 µl of acetonitrile containing IS (verapamil, 5 ng-ml' ¹ and glibenclamide, 50 ng-ml' ¹ ) to precipitate the protein, the mixture was vortexed for 1 min, then centrifuge at 13,000 rpm for 8 min, then add 70 µl of water to 70 µl of the supernatant, then shake on a vortex for 10 min. A 10 μl aliquot of the mixture is injected into the LC-MS/MS system.

For brain samples: To a 50 µl aliquot of the sample, add 250 µl of acetonitrile containing IS (verapamil, 5 ng-ml' ¹ and glibenclamide, 50 ng-ml' ¹ ) to precipitate the protein, the mixture is vortexed for 1 min, then centrifuge at 13,000 rpm for 8 min, then add 70 µl of water to 70 µl of the supernatant, then shake on a vortex for 10 min. A 10 μl aliquot of the mixture is injected into the LC-MS/MS system. Get data on the blood-brain barrier (BBB) for the tested compounds.

Although the foregoing written description of the invention allows a person skilled in the art to obtain and apply what is currently considered his best option, those skilled in the art will understand and appreciate the existence of variations, combinations and equivalents of specific embodiments, methods and examples, given in this document. Therefore, the invention should not be limited to the above described embodiments, methods and examples, but should be limited to all embodiments and methods within the scope and spirit of the invention as claimed.

Claims (37)

CLAIM 1. Compound of formula (I) ^R, ° R, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, where R1 is -NR _a R _b , where R _a and R _b are each independently hydrogen, R2 is hydrogen or _-C1-6 alkyl, R ₃ and R ₄ , which may be the same or different, each independently represents co - 70 040339 fight hydrogen or -C ₁ . ₆ alkyl, R5 and _R6 are each hydrogen, R7 and R8 are each independently hydrogen or halogen, R ₁₀ is -OR12, where R12 is -C _1-6 alkyl; R ₉ is -CONR ₁₂ R ₁₃ where R12 and R ₁₃ , which may be the same or different, are each independently hydrogen, -C ₁ . ₆ alkul, -C ₂ . ₆ alkenyl, -C ₂ . ₆ αlkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each is -C ₁ . ₆ alkul, -C ₂ . ₆ alkenyl, -C ₂ . ₆ alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted with at least one R ₁₅ substituent, alternatively, R 12 and R ₁₃ together with the atom(s) to which they are attached form a 3-12 membered saturated ring, containing 0 or 1 additional heteroatom independently selected from -NH, -O- or -S-, and said ring is optionally substituted with at least one R ₁₅ substituent, R ₁₅ is independently at each occurrence hydrogen, halogen, -C ₁ . ₆ alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -OR ₁₆ , -COR ₁₆ , -CO ₂ R ₁₆ , -NR ₁₆ R ₁₇ , -C ₁ . ₆ alkyl-NR ₁₆ R ₁₇ where each is -C ₁ . ₆ αalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with R ₁₉ , -OR ₁₉ , -COR ₁₉ , or -CO ₂ R ₁₉ , where R ₁₆ or R 17 are each independently hydrogen or -C ₁ . ₆ alkyl, or R ₁₆ and R 17 together with the atom(s) to which they are attached form a 3-12 membered saturated, partially or fully unsaturated ring containing 0 or 1 additional heteroatom independently selected from -NH and -O-, and said ring optionally substituted with at least one R ₁₉ substituent, and where R ₁₉ is independently hydrogen, -C ₁ . ₆ alkyl, halo-C ₁ . ₆ alkyl, cycloalkyl or heterocyclyl, wherein each said heterocyclyl is optionally substituted with -C ₁ . ₆ alkyl and where the specified -C ₁ . ₆ αkyl is optionally substituted with cycloalkyl; where cycloalkyl contains 3-12 carbon atoms, aryl refers to phenyl, heteroaryl refers to a group selected from 5- or 6-membered aromatic monocyclic rings containing 1 heteroatom selected from N and O as ring atoms, where the remaining ring atoms are carbon; heterocyclyl refers to a ring selected from 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered monocyclic and bicyclic, saturated rings containing 1-2 heteroatoms, selected from N, S or O as ring atoms. 2. A compound according to claim 1, wherein R ₃ is hydrogen and R 4 is -C ₁ . ₆ alkyl. 3. The compound according to claim 1, where each R ₁₂ and R ₁₃ represents hydrogen or -C ₁ . ₆ alkyl optionally substituted with at least one R15 substituent. 4. The compound according to claim 3, where each R ₁₂ and R ₁₃ represents hydrogen or methyl, ethyl, n-propyl or isopropyl, each of which is optionally substituted with at least one substituent R ₁₅ . 5. The compound according to claim 1 or claim 3, where R ₁₅ represents hydrogen, cycloalkyl, aryl, heterocyclyl, -OR ₁₆ or -NR ₁₆ R ₁₇ where R ₁₆ and R ₁₇ are as defined in claim 1 , and where each specified cycloalkyl, aryl or heterocyclyl is independently optionally substituted with R ₁₉ , -OR ₁₉ or -COR ₁₉ , where R ₁₉ is as defined in claim 1. 6. A compound according to claim 1 or 3, wherein R ₁₂ is hydrogen and R ₁₃ is -C ₁ . ₆ alkyl optionally substituted with one R ₁₅ substituent which is a heterocyclyl optionally substituted with R ₁₉ , -OR ₁₉ or -COR ₁₉ , where R ₁₉ is as defined in claim 1. 7. The compound according to claim 6, where the heterocyclyl group is a 4-, 5-, 6-, 7-, or 8-membered saturated monocyclic ring containing one nitrogen heteroatom, or a 5-, 6-, 7-, or 8-membered a saturated monocyclic ring containing one nitrogen atom and 1 additional heteroatom selected from -NH or -O-, optionally substituted with R ₁₉ , -OR ₁₉ or -COR ₁₉ , where R ₁₉ is as defined in claim 1. 8. A compound according to claim 7 wherein the heterocyclyl group is a piperidinyl or piperazinyl group optionally substituted with -C ₁ . ₆ alkyl. 9. A compound according to claim 1 wherein R ₁₂ is hydrogen and R ₁₃ is cycloalkyl optionally substituted with at least one R ₁₅ substituent. 10. A compound according to claim 9 wherein R ₁₃ is C ₃ -C ₈ cycloalkyl optionally substituted with at least one R15 substituent. 11. A compound according to claim 10 wherein R ₁₃ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with at least one R15 substituent. 12. A compound according to any one of claims 9-11, wherein R ₁₅ is -OR ₁₆ , -CO ₂ R ₁₆ , or -C ₁ . ₆ alkylNR ₁₆ R ₁₇ , or -C ₁ . ₆ alkyl optionally substituted with -OR ₁₉ where R ₁₆ and R ₁₇ together with the atom(s) to which they are attached optionally form a 5-8 membered saturated ring containing 0 or 1 additional heteroatom independently selected from -NH, and said ring is optionally substituted - 71 040339 but at least one substituent R _i9 , and where R _i6 , R _i7 and R _i9 are as defined in paragraph 1. 13. The compound of claim 1 wherein R _i2 is hydrogen and R _i3 is a 5-8 membered heterocyclyl containing 1 or 2 heteroatoms selected from O, NH or S, optionally substituted with at least one Ri ₅ substituent. 14. The compound of claim 13 wherein R _i3 is a 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from O or NH, optionally substituted with at least one Ri ₅ substituent. 15. A compound according to claim 14 wherein R _i3 is tetrahydrofurfuryl or tetrahydropyranyl, each of which is optionally substituted with at least one R ₁₅ substituent. 16. A compound according to any one of claims 13-15, wherein R _i5 is halo or _{-C1_6} alkyl. 17. The compound of claim 1 wherein R _i2 is hydrogen and R _i3 is an aryl group selected from phenyl and naphthyl optionally substituted with at least one R ₁₅ substituent. 18. The compound according to claim 17, where R _i5 is halogen, -C1_ ₆ alkyl, -OR _i6 or heterocyclyl, optionally substituted with R ₁₉ or -OR _i9 , where R ₁₆ and R ₁₉ are as defined in claim 1 . 19. The compound according to claim 1, where R _i2 and R _i3 together with the nitrogen atom to which they are attached, form a 3-12-membered saturated, partially or fully unsaturated ring containing 0 or 1 additional heteroatom, independently selected from NH or -0-, and said ring is optionally substituted with at least one R ₁₅ substituent. 20. The compound according to claim 19, wherein R _i2 and R ₁₃ together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, or 8-membered saturated monocyclic ring containing 0 additional heteroatoms, and said ring is optionally substituted with at least one R ₁₅ substituent. 21. The compound according to claim 20, where R _i5 is halogen, -OR _i6 , -CO ₂ R _i6 or -C1_ ₆ alkyl, optionally substituted with -OR _i9 , where R ₁₆ and R ₁₉ are as defined in paragraph 1. 22. The compound according to claim 19, where R _i2 and R ₁₃ together with the nitrogen atom to which they are attached, form a 5-, 6-, 7- or 8-membered saturated monocyclic ring containing 1 additional heteroatom selected from -NH or -0-, and said ring is optionally substituted with at least one R ₁₅ substituent. 23. The compound of claim 22 wherein R _i2 and R ₁₃ together with the nitrogen atom to which they are attached form a morpholinyl or piperazinyl ring, each of which is optionally substituted with at least one R ₁₅ substituent. 24. The compound according to claim 22 or 23, where Ri ₅ represents hydrogen, halogen, -C ^ alkyl or cycloalkyl, where each specified -C1_ ₆ alkyl or cycloalkyl is independently optionally substituted with R ₁₉ , -ORi ₉ or -COR _i9 , where R ₁₉ is as defined in claim 1. 25. The compound according to claim 19, where R _i2 and R ₁₃ together with the nitrogen atom to which they are attached, form a 7-12-membered saturated bicyclic ring containing 0 or 1 additional heteroatom selected from -N or -0-, and said ring is optionally substituted with at least one R15 substituent. 26. The compound of claim 25, wherein the ring is a bicyclic bridged or spiro ring optionally substituted with at least one R ₁₅ substituent. 27. The compound according to claim 26, where the ring is - | / \ p 28. The compound according to claim 1, where R ₉ represents Rnh O ⁴ — \ o — -72040339 - 73 040339 or 29. A compound according to any one of claims 1 to 28, wherein R _w is methoxy, ethoxy, propoxy, or isopropoxy. 30. A compound according to claim 29 wherein R ₁₀ is isopropoxy. 31. A compound according to any one of claims 1 to 30, wherein the carbon atom to which R ₃ and R 4 are attached is in the ^-configuration when R 3 and R 4 are different. - 74 040339 32. The compound according to claim 1, which is - 75 040339 - 76 040339 - 77 040339 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 33. The compound according to claim 1, which is - 78 040339 - 79 040339 - 80 040339 - 81 040339 - 82 040339 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 34. A pharmaceutical composition containing a therapeutically effective amount of a compound according to any one of claims 1 to 33, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 35. A method of treating or preventing a disorder or disease susceptible to inhibition of PI3Kδ activity in a subject, comprising administering to the subject a compound according to any one of claims 1 to 33, or a stereoisomer or a pharmaceutically acceptable salt thereof. - 83 040339 36. The method of claim 35, wherein the disorder or disease is an inflammatory disease, an autoimmune disease, or cancer. 37. The method of claim 35, wherein the disorder or disease is selected from the group consisting of idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia, vasculitis, systemic lupus erythematosus, lupus nephritis, pemphigus, membranous nephropathy, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), chronic myeloid leukemia (CML), multiple myeloma (MM), hairy cell leukemia, mantle cell lymphoma (MCL), small cell lymphocytic lymphoma (SLL), follicular lymphoma , lymphoplasmacytic lymphoma, extranodal marginal zone cell lymphoma, diffuse large B-cell lymphoma (DLBCL) from activated B-like cells (ABC), or diffuse large B-cell lymphoma (DLBCL) from germinal center B-cells (GCB), T -cell lymphoma, B-cell lymphoma, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), m acroglobulinemia Waldenström (WM), pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatic cell cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer , melanoma, neuroendocrine cancer, CNS (central nervous system) cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, small cell lung cancer, colon cancer, myasthenia gravis, rheumatoid arthritis (RA), acute disseminated encephalomyelitis, multiple sclerosis (MS), Sjögren's syndrome, asthma, psoriasis, chronic obstructive pulmonary disease, or lupus. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2