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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
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  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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  • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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  • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Definitions

• NIK NF-kB-inducing kinase
• MAP3K14 NF-kB-inducing kinase
• NIK neuropeptides
• pharmaceutical compositions comprising such compounds.
• diseases such as cancer (such as B-cell malignancies including leukemias, lymphomas and myeloma), inflammatory disorders, autoimmune disorders, immunodermatologic disorders such as palmoplantar pustulosis and hidradenitis suppurativa, and metabolic disorders such as obesity and diabetes.
• diseases such as cancer (such as B-cell malignancies including leukemias, lymphomas and myeloma), inflammatory disorders, autoimmune disorders, immunodermatologic disorders such as palmoplantar pustulosis and hidradenitis suppurativa, and metabolic disorders such as obesity and diabetes.
• the present invention also relates to methods of preventing or treating such diseases.
• BACKGROUND OF THE INVENTION NIK is a serine/threonine kinase transcription factor propitiating the expression of various genes involved in immune response disorders, cell proliferation disorders, adhesion, apoptosis
• NIK-dependent transcriptional activation is a tightly controlled signaling pathway, through sequential events including phosphorylation and protein degradation.
• NIK activation pathway known as a non-canonical pathway
• activation is accomplished by phosphorylating the catalytic complex subunit IKKa, leading to the partial proteolysis of the gene product p100, liberating DNA-binding protein p52 which then heterodimerizes with another DNA-binding protein RelB, translocates to the nucleus and mediates gene expression.
• the non-canonical pathway is activated by ligands such as CD40 ligands, B-cell activating factor (BAFF), lymphotoxin b receptor ligands, TNF-related weak inducer of apoptosis (TWEAK) cytokine, and receptor activator of nuclear factor kappa-B ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11).
• ligands such as CD40 ligands, B-cell activating factor (BAFF), lymphotoxin b receptor ligands, TNF-related weak inducer of apoptosis (TWEAK) cytokine, and receptor activator of nuclear factor kappa-B ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11).
• NIK nuclear factor kappa-B ligand
• NIK baculoviral-IAP-repeat-containing-3
• CIAP2 baculoviral-IAP-repeat-containing-3
• TRAF2 and TRAF3 TNF receptor associated factors
• NIK level increase is undesirable, and one way to mitigate or eliminate the adverse effect associated with such increase is NIK inhibition.
• BAFF/BAFF-R is a clinically validated therapeutic target whose inhibition is deemed beneficial for systemic lupus erythematosus (SLE) treatment.
• Belimumab anti- BAFF antibody
• CD40L/CD40 pathway plays a key role in T-dependent B cell activation, dendritic cell maturation and tissue
• mice lacking functional NIK have no peripheral lymph nodes, defective B and T cells, and impaired receptor activator of NIK ligand–stimulated osteoclastogenesis.
• K. Aya, et al. investigated the role of NIK in murine models of inflammatory arthritis using NIK–/– mice. Reportedly, the serum transfer arthritis model was initiated by preformed antibodies and required only intact neutrophil and
• NIK–/– mice had inflammation equivalent to that of NIK+/+ controls
• Ada et al.
• NIK–/– mice were completely resistant to antigen-induced arthritis (AIA), which requires intact antigen presentation and lymphocyte function but not lymph nodes.
• AIA antigen-induced arthritis
• transfer of NIK+/+ splenocytes or T cells to Rag2–/– mice conferred susceptibility to AIA, while transfer of NIK–/– cells did not.
• NIK–/– mice were also resistant to a genetic, spontaneous form of arthritis, generated in mice expressing both the KRN T cell receptor and H-2g7.
• NIK activation pathway relies on inducible degradation of IkB kinases, particularly IkBa, leading to nuclear translocation of various NF-kB complexes, predominantly the p50/RelA dimer.
• IKK IkB kinase
• the degradation of IkBa is mediated through its phosphorylation by the IkB kinase (IKK), a trimeric complex composed of two catalytic subunits, IKKa and IKKb, and a regulatory subunit, IKKg (also named NF-kB essential modulator or NEMO).
• the RelB/p52 NF-kB complex is activated using a mechanism that relies on the inducible processing of p100 instead of degradation of IkBa. See, e.g., S.-C. Sun, Cell Res.2011 Jan; 21(1): 71-85).
• NIK is also a promising therapeutic target for other BAFF, CD40L or lymphotoxin b receptor ligands driven autoimmune disorders such as Sjogren's syndrome (J. Groom, et al., J. Clin. Invest.2002;109(1):59-68); proliferative lupus glomerulonephritis (D.T. Boumpas, et al., Arthritis & Rheumatism 2003;48(3):719-27): multiple sclerosis (J. Tan, et al., J. Neuroimmunol, 1999;97(1-2):77-85), J. Krumbholz, et al., J. Exp. Med.
• Sjogren's syndrome J. Groom, et al., J. Clin. Invest.2002;109(1):59-68
• proliferative lupus glomerulonephritis D.T. Boumpas, et al., Arthritis & Rhe
• Embodiments of this invention include compounds of Formula (I), and pharmaceutically acceptable salts thereof
• R 1 is H or -CH 3 ;
• R 2 is H or -CH3
• R 3 is H, -C 1 -C 5 alkyl, -OCH 3 , or -O-C 1 -C 3 haloalkyl;
• R 4 is H or -CH 3 ; moiety
• R aa is H or -CH3
• R bb is H, -CH3 or -CF3
• R cc is -CH 3 , -CD 3 or -CH 2 CF 3 ;
• E is N or CH
• F is O, S, NH or NCH3;
• R a is H or -CH 3 ;
• R b is H, D, -OH, F, -C 1 -C 5 alkyl, -CH 2 OCH 3 , -C 1 -C 5 haloalkyl, -NH 2 , cyclopropyl, or -CH2OH;
• R c is H, D or -CH 3 ;
• R d is H, -CN, -CF 3 , -C 1 -C 5 alkyl, -C 3 -C 6 cycloalkyl, -O-C 1 -C 3 alkyl, -N(R 6 )R 7 ,
• R 6 is H or -C1-C3alkyl
• R 7 is H, -C1-C3alkyl, -SO2CH3, -COCH3, -C1-C4haloalkyl or -CH2CN, or R 6 and R 7 are taken together with the nitrogen to which they are attached to form
• R 8 is H, F or -C 1 -C 3 alkyl
• R 9 is H, F or -C1-C3alkyl
• R e is H, -CD 3 , Br, -C 1 -C 5 alkyl , -C 3 -C 6 cycloalkyl,
• R g is -NH 2 , or F;
• R 10 is H or F
• R 11 is H or F;
• R f is H, -CH 3 or R h is -CH 3 , -NH 2 or ;
• R i is H, -CH3, -CN, Br, ;
• R j is -NH2 or
• R k is H, -CF3, I, Cl, Br, -CN, -C1-C6alkyl,
• R 12 is H or -CH3
• R 13 is H, -CH 3 , -CH 2 (C)(CH 3 ) 2 OH, -(CH 2 ) 3 CN, or -(CH 2 ) 2 NH 2 ;
• R 14 is H or -CH 3 ;
• R l is H, -C1-C4alkyl, -CF3,
• R m is H or -CH3
• R n is -NH 2 ;
• R o is H or -CH3
• R p is H or -CH3
• R q is H, -CN, F, Cl, -OCH 3 , -CF 3 , or -CH 3 ; and R s is -NH 2 or
• Illustrative embodiments of compounds of Formula (I) are compounds (R)-3-[2-[3-(8-Aminopyrido[3,4-d]pyrimidin-2-yl)phenyl]ethynyl]-3-hydroxy-1- methyl-pyrrolidin-2-one;
• Embodiments of the present invention relate to compounds, pharmaceutical compositions containing them, methods of making and purifying them, methods of using them as NIK inhibitors and methods for using them in the treatment of disease states, disorders, and conditions mediated by NIK.
• Additional embodiments of the invention are methods of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by NIK using compounds of the invention.
• alkyl refers to a straight- or branched-chain alkyl group having from 1 to 8 carbon atoms in the chain.
• alkyl groups include methyl (Me), ethyl (Et), n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl (tBu), pentyl, iso-pentyl, tert-pentyl, hexyl, iso-hexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
• “C 1 -C 4 alkyl” refers to straight- or branched-chain alkyl group having from 1 to 4 carbon atoms in the chain.
• halo represents chloro, fluoro, bromo, or iodo.
• haloalkyl refers to a straight- or branched-chain alkyl group having from 1 to 6 carbon atoms in the chain optionally substituting one or more H with halo.
• C 1 -C 4 haloalkyl refers to a straight- or branched-chain alkyl group having from 1 to 4 carbon atoms in the chain, optionally substituting one or more H with halo.
• haloalkyl include trifluoromethyl (CF3),
• cycloalkyl refers to a saturated, monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from 3 to 10 ring atoms per carbocycle.
• Illustrative examples of cycloalkyl groups include the following entities, in the form of properly bonded moieties, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
• substituted means that the specified group or moiety bears one or more substituents.
• unsubstituted means that the specified group bears no substituents.
• optionally substituted means that the specified group is unsubstituted or substituted by one or more substituents. Where the term“substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system.
• any formula given herein is intended to represent a racemate, one or more of its enantiomeric forms, one or more of its diastereomeric forms, and mixtures thereof, unless expressly indicated otherwise.
• Certain examples contain chemical structures that comprise (R*) or (S*) terminology.
• (R*) or (S*) is used in the name of a compound or in the chemical representation of the compound, it is intended to mean that the compound is a single isomer at that stereocenter, however absolute configuration of that stereocenter has not been established.
• a compound designated as (R*) refers to a compound that is a single isomer at that stereocenter with an absolute configuration of either (R) or (S).
• a compound designated as (S*) refers to a compound that is a single isomer at that stereocenter with an absolute configuration of either (R) or (S).
• the structures are named using (R) or (S).
• the use of the term (R, S) or“racemic” in the name of the compound indicates that the compound is a racemate.
• references to a compound herein stands for a reference to any one of: (a) the actually recited form of such compound, and (b) any of the forms of such compound in the medium in which the compound is being considered when named.
• reference herein to a compound such as R-COOH encompasses reference to any one of, for example, R-COOH (s) , R-COOH (sol) , and R-COO- ( sol) .
• R-COOH (s) refers to the solid compound, as it could be for example in a tablet or some other solid pharmaceutical composition or preparation
• R-COOH(sol) refers to the undissociated form of the compound in a solvent
• R-COO- ( sol) refers to the dissociated form of the compound in a solvent, such as the dissociated form of the compound in an aqueous environment, whether such dissociated form derives from R-COOH, from a salt thereof, or from any other entity that yields R-COO- upon dissociation in the medium being considered.
• an expression such as“exposing an entity to compound of formula R-COOH” refers to the exposure of such entity to the form, or forms, of the compound R-COOH that exists, or exist, in the medium in which such exposure takes place.
• an expression such as“reacting an entity with a compound of formula R-COOH” refers to the reacting of (a) such entity in the chemically relevant form, or forms, of such entity that exists, or exist, in the medium in which such reacting takes place, with (b) the chemically relevant form, or forms, of the compound R-COOH that exists, or exist, in the medium in which such reacting takes place.
• any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
• Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number in an enriched form.
• isotopes that can be incorporated into compounds of the invention in a form that exceeds natural abundances include isotopes of hydrogen, carbon, nitrogen, and oxygen such as 2 H (or D), 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, and 17 O, respectively.
• Such isotopically labeled compounds are useful in metabolic studies (for example with 14 C), reaction kinetic studies (with, for example deuterium (i.e., D or 2 H); or tritium (i.e., T or 3 H)), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
• PET positron emission tomography
• SPECT single-photon emission computed tomography
• an 18 F or 11 C labeled compound may be used for PET or SPECT studies.
• substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased local in vivo half-life or reduced dosage requirements.
• Isotopically labeled compounds of this invention can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
• Tautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen and electrons. Thus, two structures that have an H member in different positions may be in equilibrium while satisfying valency rules. For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. When referring to any formula given herein that comprises at least one tautomer, such given formula is meant to encompass all the related tautomers unless indicated expressly otherwise.
• e xample is one of S1 and S2, and substituent S 2
• e xample is S 3 ;
• S 1 example is S2 and S 2 example is S4; and equivalents of each one of such choices.
• example is one of S1 and S2, and S 2
• example is one of S3 and S4” or “S 1
• e xample is S 1 or S 2 , and S 2
• embodiments of this invention comprise the various groupings that can be made from the listed assignments, taken independently, and equivalents thereof.
• substituent Sexample is one of S1, S2, and S3
• this listing refers to embodiments of this invention for which Sexample is S1; Sexample is S2; Sexample is S3; Sexample is one of S1 and S2; Sexample is one of S1 and S3; Sexample is one of S2 and S3; Sexample is one of S1, S2 and S3; and S example is any equivalent of each one of these choices.
• substituents is meant to refer to embodiments of this invention for which each and every one of the number of carbon members, from i to j including i and j, is
• C1-C3 refers independently to embodiments that have one carbon member (C1), embodiments that have two carbon members (C 2 ), and embodiments that have three carbon members (C 3 ).
• Ci-Cjalkyl refers to an aliphatic chain, whether straight or branched, with a total number N of carbon members in the chain that satisfies i £ N £ j, with i > j.
• a “pharmaceutically acceptable salt” is a salt of a compound, such as
• Compounds of the invention may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
• pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlor
• methoxybenzoates phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, g-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.
• the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, and phosphoric acid, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a
• an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, and phosphoric acid
• an organic acid such as acetic acid, phenylacetic acid
• pyranosidyl acid such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p- toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.
• Embodiments of this invention include compounds of Formula (I), and
• R 1 is H or -CH 3 ;
• R 2 is H or -CH3;
• R 3 is H, -C1-C5alkyl, -OCH3, or -O-C1-C3haloalkyl;
• R 4 is H or -CH3; moiety is
• R aa is H or -CH3
• R bb is H, -CH 3 or -CF 3 ;
• R cc is -CH 3 , -CD 3 or -CH 2 CF 3 ;
• E is N or CH
• F is O, S, NH or NCH3;
• R a is H or -CH 3 ;
• R b is H, D, -OH, F, -C 1 -C 5 alkyl, -CH 2 OCH 3 , -C 1 -C 5 haloalkyl, -NH 2 , cyclopropyl, or -CH2OH;
• R c is H, D or -CH 3 ;
• R d is H, -CN, -CF 3 , -C 1 -C 5 alkyl, -C 3 -C 6 cycloalkyl, -O-C 1 -C 3 alkyl, -N(R 6 )R 7 ,
• R 6 is H or -C 1 -C 3 alkyl
• R 7 is H, -C1-C3alkyl, -SO2CH3, -COCH3, -C1-C4haloalkyl or CH2CN; or R 6 and R 7 are taken together with the nitrogen to which they are attached to form
• R 8 is H, F or -C 1 -C 3 alkyl
• R 9 is H, F or -C 1 -C 3 alkyl
• R e is H, -CD3, Br, -C1-C5alkyl, -C3-C6cycloalkyl,
• R g is -NH 2 , or F;
• R 10 is H or F
• R 11 is H or F;
• R f is H, -CH 3 or R h is -CH 3 , -NH 2 or R i is H, -CH3, -CN, Br, R j is -NH2 or
• R k is H, -CF3, I, Cl, Br, -CN, -C1-C6alkyl,
• R 12 is H or -CH3
• R 13 is H, -CH3, -CH2(C)(CH3)2OH, -(CH2)3CN, or -(CH2)2NH2;
• R 14 is H or -CH 3 ;
• R l is H, -C1-C4alkyl, -CF3,
• R m is H or -CH3
• R n is -NH 2 ;
• R o is H or -CH 3 ;
• R p is H or -CH3
• R q is H, -CN, F, Cl, -OCH3, -CF3, or -CH3; and R s is -NH2 or provided that when said moiety is and R 1 , R 2 , R 3 and R 4 are
• Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein moiety is
• Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein moiety is
• Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein moiety is
• Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein R 1 is H; R 2 is H; R 3 is H; R 4 is H;
• Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein R 1 is H; R 2 is H; R 3 is H or -C1- C 5 alkyll; R 4 is H;
• R 1 is H;
• R 2 is H;
• R 3 is H or -C 1 -C 5 alkyl;
• R 4 is H;
• Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein
• Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein R 1 is H; R 2 is H; R 3 is H; R 4 is H;
• R b is -CH3.
• Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein moiety is
• Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein moiety is
• Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein moiety is
• Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein moiety is .
• Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein moiety is Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein moiety is Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein moiety is
• Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein moiety is
• Additional illustrative embodiments of the invention are compounds of Formula (I)
• Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein moiety is . Additional illustrative embodiments of the invention are compounds of Formula (I)
• Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein
• Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein moiety .
• Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein
• Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein
• An additional illustrative embodiments of the invention is are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein moiety
• An additional illustrative embodiments of the invention is are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein moiety .
• An additional illustrative embodiments of the invention is are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein moiety
• Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein moiety
• Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein moiety and moiety Additional illustrative embodiments of the invention are compounds of Formula (I)
• R 3 is H.
• R 3 is H and R e is H.
• R 3 is H
• R e is H
• R d is N(R 6 )R 7
• R b is CH 3 .
• R 3 is H
• R a is H
• R e is H
• R d is N(R 6 )R 7
• R b is CH3
• R 6 is H or C 1 -C 3 alkyl
• R 7 is H or C 1 -C 3 alkyl.
• R 3 is H
• R a is H
• R e is H
• R d is N(R 6 )R 7
• R b is CH 3
• R 6 is C 1 -C 3 alkyl
• R 7 is C 1 -C 3 alkyl.
• R 3 is H
• R a is H
• R e is H
• R d is N(R 6 )R 7
• R b is CH 3
• R 6 and R 7 are taken together with the nitrogen to which they are attached to form the
• Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein moiety is
• R 3 is H
• R a is H
• R e is H
• R d is N(R 6 )R 7
• R b is CH3
• R 6 and R 7 are taken together with the nitrogen to which they are attached to
• R 3 is H
• R a is H
• R e is H
• R d is N(R 6 )R 7
• R b is CH3
• R 6 and R 7 are taken together with the nitrogen to which they are attached to
• Additional illustrative embodiments of the invention are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein moiety is
• R 3 is H
• R a is H
• R e is H
• R d is N(R 6 )R 7
• R b is CH3
• R 6 and R 7 are taken together with the nitrogen to which they are attached to
• Illustrative embodiments of compounds of Formula (I) are compounds (R)-3-[2-[3-(8-Aminopyrido[3,4-d]pyrimidin-2-yl)phenyl]ethynyl]-3-hydroxy-1- methyl-pyrrolidin-2-one;
• Illustrative embodiments of compounds of Formula (I) are compounds (R)-3-[2-[3-(8-Aminopyrido[3,4-d]pyrimidin-2-yl)phenyl]ethynyl]-3-hydroxy-1- methyl-pyrrolidin-2-one;

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