Diaminopyrazole[1,5-a]pyrimidine-6-nitrile compounds as antagonists of adenosine 2A and adenosine 2B receptors

Abstract

This disclosure provides a compound of formula I, or a pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, stereoisomer, racemic compound, or a pharmaceutically active derivative thereof. The compound of formula I is used as an adenosine receptor antagonist. This disclosure also provides a method for preparing the compound of formula I and pharmaceutical compositions thereof.

Description

Technical Field

[0001] This disclosure relates to the field of medicinal chemistry, and more specifically to the development of heterocyclic compounds and methods for their preparation. More specifically, this disclosure relates to pyrazolopyrimidine compounds, particularly diaminopyrazolopyrimidine compounds as adenosine receptor antagonists. Background Technology

[0002] Adenosine is a purine nucleoside produced by cells and used in intracellular physiological processes and extracellular signal transduction. It is synthesized from inosine monophosphate (IMP), a nucleotide that forms adenosine monophosphate (AMP), or via the hydrolysis of adenosine triphosphate (ATP) from AMP. Besides being a structural unit of DNA, it is the primary energy source for cells as ATP and participates in all common signal transduction processes as cyclic adenosine monophosphate (cAMP). Extracellular adenosine regulates inflammation, strain homeostasis, and cognitive function in the brain, as well as vasodilation in the heart, lungs, and kidneys—all mediated by its binding to adenosine receptors.

[0003] Adenosine receptors are members of the guanine nucleotide protein-coupled receptor (GPCR) family on cell surfaces, and in humans they are represented by A1R, A... 2a R, A 2b R and A3R subtypes constitute the receptor (Jacobson et al., 2012, PMID: 22371149). A1 and A3 receptors interact with Ga... i / o Coupled, on the contrary, A 2a and A 2b Receptors and Ga s They are coupled to inhibit or stimulate adenylate cyclase (AC) respectively and are widely distributed throughout the body (Borea et al., 2018, DOI:10.1007 / 978-3-319-90808-3; Cheng et al., 2017, PMID:28712806). Their agonist or antagonist ligands are used as pharmacological interventions for various pro-inflammatory and anti-inflammatory mediators to manage asthma, chronic obstructive pulmonary disease, heart failure, arrhythmias, diabetic kidney disease, glaucoma, stroke, sleep disorders, anxiety disorders, neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and Huntington's disease, epilepsy, pain, cognition and memory disorders, and cancer (Sek et al., 2018, PMID:30513816).

[0004] During infection, injury, hypoxia, ischemia, or seizures, extracellular adenosine is upregulated in tissues as an adaptive mechanism to protect tissue damage from inflammatory responses. Similar immunosuppressive mechanisms of elevated adenosine levels have been identified in tumor immune evasion (in the tumor microenvironment (TME)). In the TME, adenosine interacts with Adenosine on various immune cells.2a R and A 2b R binds and inhibits them by activating cAMP-dependent protein kinase A (PKA) and blocking nuclear factor kappa B (NF-κB) and Janus kinase (JAK) signaling and transcriptional activator protein (STAT) signaling pathways (Allard et al., 2020, PMID:32514148). Releasing the effect of selective antagonists on A... 2a R and A 2b This inhibition of R can enable immune cells to kill tumor cells (Vijayan et al., 2017; PMID:29162946; Allard et al., 2020, PMID:32514148). Therefore, in the current context of increasing proliferative lesions or diseases, there is a huge demand for adenosine receptor antagonists. This will help treat conditions related to cancer or immune-related diseases mediated by these receptors. Summary of the Invention

[0005] In one aspect of this disclosure, a compound of formula I is provided.

[0006]

[0007] Formula I

[0008] Or its pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, stereoisomers, racemic compounds, or their pharmaceutically active derivatives.

[0009] Where A is selected from C. 5-10 Aryl, C 2-10 heteroaryl, C 3-6 cycloalkyl or C 1-10 Heterocyclic group; wherein C 5-10 Aryl, C 2-10 heteroaryl, C 3-6 cycloalkyl or C 1-10 The heterocyclic group is optionally selected from R6, R7, R8, R9, R 9a Or oxidized by one or more substituents;

[0010] R2 is selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Halogenated alkyl groups;

[0011] R3 is selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Halogenated alkyl; wherein C1-6 Alkyl groups are optionally C 1-6 Alkyl substitution;

[0012] R4 and R5 are independently selected from hydrogen, halogen, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -CO-N(R) 10 R 11 C 4-10 carbonyl group or C 1-10 Heterocyclic groups, where C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is optionally selected from C 3-6 cycloalkyl, C 1-6 Alkoxy or C 1-10 One or more groups of the heterocyclic group are substituted; or R4 and R5 are linked together to form C. 4-10 carbonyl group or C 1-10 Heterocyclic groups, where C 4-10 carbonyl group or C 1-10 The heterocyclic group is optionally and independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 The alkyl group is substituted with 1-3 groups of the alkyl halide;

[0013] R 10 and R 11 Independently selected from hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-6 Halogenated cycloalkyl, C 4-10 carbonyl group or C 1-10 Heterocyclic groups;

[0014] R6 is selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Aminoalkyl, C 3-6 cycloalkyl, C 3-6Halogenated cycloalkyl, -YOC 1-6 Alkyl, -YOC 3-6 cycloalkyl, Y-CO-NH-R 13 -YZ,C 4-10 carbonyl group or C 1-10 Heterocyclic groups, where C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Aminoalkyl, hydroxy C 1-6 Alkyl or C 1-10 The heterocyclic group is optionally selected from halogen, hydroxyl, amino, C 1-6 Alkoxy, C 3-6 Cycloalkyl, hydroxy C 1-6 Alkyl, C 1-6 Aminoalkyl, C 1-6 Halogenated alkoxy groups, C 4-10 carbonyl group or C 1-10 One or more groups of the heterocyclic group are substituted, wherein C 3-6 cycloalkyl or C 1-6 The aminoalkyl group may optionally be further selected independently from halogen, hydroxyl, hydroxyl C. 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)NH2, -C(O)-hydroxyC 1-6 Alkyl or C 1-10 One or more groups of the heterocyclic group are substituted, and C 1-10 The heterocyclic group has 1 to 4 heteroatoms independently selected from O, N, or S, and optionally independently selected from halogens, hydroxyl groups, C. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 The alkyl group is substituted with 1-3 groups of the alkyl halide;

[0015] Y is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl or C 3-6 Cycloalkenyl; and C 1-6 Alkyl groups are optionally C 3-6 Cycloalkyl substitution;

[0016] Z is selected from -OH, -NH2, -COOH, -SO2NH2, -SO2CH3, -S(O)CH3, -SCH3, CH2-NH-(C 1-6 Alkyl)-S(O)CH3, -OP(=O)(OH)2, -CONH2, -CONH(C 1-6 alkyl), -SO2NH(C1-6 Alkyl), CON(C) 1-6 Alkyl)2、-NHCO(C 1-6 Alkyl), C 4-10 carbonyl group or C 1-10 Heterocyclic groups, where C 1-10 The heterocyclic group has 1 to 4 heteroatoms independently selected from O, N, or S, and optionally independently selected from halogens, C, and S. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 The alkyl group is substituted with 1-3 groups of the alkyl halide;

[0017] R 13 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or C 3-6 Halogenated cycloalkyl groups;

[0018] R7, R8, R9 and R 9a Independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or C 3-6 Halogenated cycloalkyl groups;

[0019] as well as

[0020] n is 0, 1, or 2.

[0021] In another aspect of this disclosure, a method is provided for preparing a compound of formula I or a pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, stereoisomer, racemic compound, or pharmaceutically active derivative thereof, said method comprising: reacting formulas (A) and (B) in the presence of a base to obtain a compound of formula I.

[0022]

[0023] Formula (A) Formula (B) Formula (I)

[0024] Where R is selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 5-10 Aryl, C 2-10 heteroaryl or C 1-10 Heterocyclic groups; and substituents as defined above.

[0025] In another aspect of this disclosure, a pharmaceutical composition is provided comprising a compound of formula I disclosed herein and one or more additional therapeutic agents.

[0026] In another aspect of this disclosure, a method for treating and / or preventing adenosine receptor-mediated conditions or proliferative disorders or cancer is provided, the method comprising administering to a subject suffering from an adenosine receptor-mediated condition or disease or proliferative disorder or cancer a therapeutically effective amount of a compound of formula I disclosed herein or a pharmaceutical composition comprising a compound of formula I disclosed herein and one or more additional therapeutic agents.

[0027] In another aspect of this disclosure, compounds or pharmaceutical compositions disclosed herein are provided for use in the treatment of adenosine receptor A with other clinically relevant cytotoxic or non-cytotoxic agents. 2a R or A 2b R-mediated conditions; treatment and / or prevention of proliferative lesions or diseases or cancer or immune-related lesions or diseases or cancer; or use in the treatment of cancer.

[0028] In another aspect of this disclosure, compounds or pharmaceutical compositions disclosed herein are provided for use in the treatment of adenosine receptor A with other clinically relevant cytotoxic or non-cytotoxic agents. 2a R and A 2b R-mediated conditions; treatment and / or prevention of proliferative lesions or diseases or cancer or immune-related lesions or diseases or cancer; or use in the treatment of cancer.

[0029] These and other features, aspects, and advantages of this subject matter will be better understood with reference to the description below. This overview is provided to present the selection of concepts in a simplified form. This overview is not intended to identify key or essential features of this disclosure, nor is it intended to limit the scope of the subject matter. Attached Figure Description

[0030] Figure 1 Example 13, which describes an embodiment of the present disclosure, demonstrates the in vivo therapeutic effect on tumor volume.

[0031] Figure 2 The expression of tumor granzyme B according to one embodiment of the present disclosure is described in comparison with vector therapy. Detailed Implementation

[0032] Those skilled in the art will recognize that variations and modifications may be made to this disclosure beyond the specific description. It should be understood that this disclosure includes all such variations and modifications. This disclosure also includes all such steps, features, compositions, and compounds individually or collectively mentioned or indicated in this specification, as well as any combination of any one or more such steps or features.

[0033] definition

[0034] For convenience, certain terms used in the specification and embodiments are compiled herein before further description of this disclosure. These definitions should be read in accordance with the remainder of this disclosure and understood by those skilled in the art. The terms used herein have meanings that are generally recognized and known to those skilled in the art; however, for convenience and completeness, specific terms and their meanings are described below.

[0035] The articles “a” and “the” are used to refer to one or more (i.e., at least one) grammatical object in the text.

[0036] The term “comprising” is used in an inclusive, open-ended sense, meaning that it may include other elements. Throughout this specification, unless the context requires otherwise, the word “comprising” and its variations shall be understood to imply that the stated element or step or group of elements or steps is included, but does not exclude any other element or step or other group of elements or steps.

[0037] The term "including" is used to mean "including but not limited to". "Including" and "including but not limited to" are used interchangeably.

[0038] In the structural formulas given herein and throughout this disclosure, the following terms have been indicated with meaning unless otherwise expressly stated.

[0039] In this specification, C x-y The prefix C used in terms such as alkyl x-y (where x and y are integers) represents the numerical range of carbon atoms present in the group; for example, C 1-6 Alkyl groups include C1 alkyl groups (methyl (-CH3), (-CH2-)), C2 alkyl groups (ethyl (-C2H5), -CH2CH2-)), C3 alkyl groups (propyl and isopropyl), and C4 alkyl groups (butyl, 1-methylpropyl, 2-methylpropyl, and tert-butyl). Unless otherwise specified, the bonding atoms of the group can be any suitable atom of the group; for example, propyl includes 1-propyl and 2-propyl.

[0040] The term "alkyl" refers to a single-radical branched or unbranched saturated hydrocarbon chain having 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and n-hexyl. These groups may be optionally substituted.

[0041] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by the same number of the same or different halogen atoms. Examples of alkyl groups include chloromethyl, trifluoromethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, 2-fluoropropyl, and 2,2-difluoropropyl. Examples of alkyl groups include CF3, CHF2, and CH2F.

[0042] The term "aminoalkyl" refers to a group having both an amine and an alkyl group, where the amine can be a primary, secondary, or tertiary amine. The bonding point can be N or C, i.e., an amine or an alkyl group. The terms "aminoalkyl" and "alkylamino" are used interchangeably. Examples of groups used in the term "aminoalkyl" include -CH(CH3)2NH2, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH(NH2)CH3, -CH2CH2N(CH3)2, -NHCH3, -N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2NHCH2-, and -CH2NHCH2CH2-.

[0043] The term "alkylhydroxyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl (-OH) group. Examples of alkylhydroxyl groups include -CH2CH(CH3)2OH, -CH(CH3)2OH, -CH2OH, and CH2CH2OH.

[0044] The term "alkenyl" refers to a single radical of a straight-chain or branched unsaturated hydrocarbon group, preferably having 2, 3, 4, 5, or 6 carbon atoms and 1, 2, or 3 double bonds. The group may optionally be substituted.

[0045] The term "alkynyl" refers to a single radical of a straight-chain or branched unsaturated hydrocarbon group, preferably having 2, 3, 4, 5, or 6 carbon atoms and 1, 2, or 3 triple bonds. The group may optionally be substituted.

[0046] The term "cycloalkyl" refers to a carbocyclic group having 3 to 6 carbon atoms and a single cyclic ring or multiple fused rings. Such cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, etc. The group may optionally be substituted.

[0047] The term "cycloalkenyl" refers to a carbocyclic group of 3 to 6 carbon atoms that may be partially unsaturated and has a single cyclic ring or multiple fused rings.

[0048] As used in this article, "halocycloalkyl" refers to a cycloalkyl group that has been substituted with one or more halogen atoms. Halocycloalkyl refers to a cycloalkyl group containing 3 to 6 carbon atoms that has been substituted with one or more halogen atoms.

[0049] The term "alkoxy group" refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, etc. An "ether" is two hydrocarbons covalently linked by oxygen. Therefore, the substituent of the alkyl group forming an ether is or similar to an alkoxy group, for example, it can be represented by one of -O-alkyl, -O-alkenyl, or -O-ynyl. The alkoxy group may optionally be substituted.

[0050] "Halogen" or "halogen" alone or in combination with any other term means halogens, such as chlorine (Cl), fluorine (F), bromine (Br), and iodine (I).

[0051] The term "carbocyclic group" or "carbocyclic ring" refers to a saturated or unsaturated ring having 4 to 10 carbon atoms forming a cyclic system. The carbocyclic group can be helical or bridged, and can be saturated, unsaturated, or partially saturated. The carbocyclic group can optionally be substituted by one or more heteroatoms. The carbocyclic group can also refer to a heteroaryl group having one or more heteroatoms. Representative carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, etc.

[0052] The term "heterocyclic group" refers to a "carbocyclic group" as defined herein, in which one or more carbon atoms have been substituted by heteroatoms selected from O, N, or S. Heterocyclic groups may contain 1 to 10 carbons in a ring structure, which are substituted by one to four heteroatoms selected from O, N, or S. Heterocyclic groups may be saturated, unsaturated, or partially saturated. Representative examples of heterocyclic groups include ethylene oxide, oxetane, oxopentane, ethylene oxide, furanyl, dioxane, pyranyl, acridineyl, piperidinyl, tetrahydropyranyl, acridineyl, oxonitrile, and oxonitrile-heptane, etc.

[0053] The term "heteroaryl" refers to an aromatic ring containing 1 to 4 heteroatoms selected from N, O, and S. If defined herein, a "heteroaryl" group may be substituted with one or more substituents. "C" 2-6 A "heteroaryl" ring refers to a group having two or six carbon atoms as ring members and one to four heteroatoms.

[0054] The term "aryl" refers to an aromatic ring having a specific number of carbon atoms. For example, C 5-10 An aryl group refers to an aryl group having 5 to 10 or 6 member atoms. Preferred aryl groups include, but are not limited to, phenyl groups.

[0055] The term "haloalkoxy" refers to an alkoxy group further linked by a halogen bond as defined above. For example, C 1-6A haloalkoxy group is an alkoxy group having 1-6 carbon atoms further bonded to one or more halogens. Preferred haloalkoxy groups include, but are not limited to, -CH2OCF3, -CH2CH2OCF3, -CH2CH2OCHF2, -OCH2Cl, -OCHCl2, -CH2OCF3, etc.

[0056] As used herein, the term "substitution" is intended to include all permissible substituents in an organic compound. In a broad sense, permissible substituents include acyclic and cyclic, straight-chain or branched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents in organic compounds. Exemplary substituents include, for example, those described above. For a suitable organic compound, permissible substituents may be one or more and may be the same or different. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents in organic compounds that satisfy the heteroatom valence as described herein.

[0057] The term "effective amount" refers to the amount of a compound or composition sufficient to significantly and positively alleviate the symptoms and / or condition to be treated (e.g., provide a positive clinical response). The effective amount of the active ingredient used in a pharmaceutical composition will vary depending on the specific symptoms being treated, the severity of the condition, the duration of treatment, the nature of concurrent therapies, the specific active ingredient being used, the specific pharmaceutically acceptable excipient / carrier used, the route of administration, and similar factors within the knowledge and expertise of the attending physician.

[0058] The compounds described herein may contain one or more chiral centers and / or double bonds, and therefore may exist as stereoisomers, such as double-bonded isomers (i.e., geometric isomers), regioisomers, enantiomers, or diastereomers. Therefore, the chemical structures described herein include all possible enantiomers and stereoisomers of the listed or identified compounds, including pure stereoisomeric forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure forms) and mixtures of enantiomers and stereoisomers. Mixtures of enantiomers and stereoisomers can be decomposed into their constituent enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to those skilled in the art. These compounds may also exist in several tautomeric forms, including enol forms, ketone forms, and mixtures thereof. Therefore, the chemical structures described herein include all possible tautomeric forms of the listed or identified compounds.

[0059] The term "racemic compound" refers to a mixture containing a pair of optical isomers. A racemic compound is an equimolar mixture of a pair of enantiomers. Racemic compounds are not optically active.

[0060] The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within reasonable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that meet a reasonable benefit / risk ratio.

[0061] "Pharmaceutically acceptable salts" include salts that have a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, hydroiodic acid, and nitric acid, and organic acids, such as citric acid, fumaric acid, maleic acid, malic acid, mandelic acid, ascorbic acid, oxalic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal (e.g., sodium or potassium) and alkaline earth metal (e.g., calcium or magnesium) hydroxides and organic bases, such as alkylamines, aralkylamines, and heterocyclic amines.

[0062] The term "polymorph" refers to the crystalline form of the same molecule. Different polymorphs may have different physical properties, such as melting temperature, heat of fusion, solubility, dissolution rate, and / or vibrational spectrum due to the arrangement or conformation of the molecules in the crystal lattice.

[0063] Salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are used as intermediates, for example, in the preparation of other compounds of Formula I and their pharmaceutically acceptable salts. Therefore, one embodiment of this disclosure includes compounds of Formula I and their salts. Compounds of Formula I contain basic functional groups and are thus capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids. Representative pharmaceutically acceptable acid addition salts include hydrochlorides, hydrobromates, nitrates, methyl nitrates, sulfates, hydrogen sulfates, aminosulfonates, phosphates, acetates, hydroxyacetic acids, phenylacetic acids, propionates, butyrates, isobutyrates, valerates, maleates, hydroxymaleates, acrylates, fumarates, malates, tartrates, citrates, salicylates, glycolates, lactates, heptanoates, phthalates, oxalates, succinates, benzoates, o-acetylated benzoates, and chlorobenzoic acid. Salts, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, naphthate, hydroxynaphthate, mandelate, tannic acid salt, formate, stearate, ascorbate, palmitate, oleate, pyruvate, dihydroxynaphthate, malonate, laurate, glutamate, glutamate, etolate, mesylate, esylate, 2-hydroxyesylate, benzenesulfonate, aminobenzenesulfonate, p-toluenesulfonate, and naphthalene-2-sulfonate.

[0064] As used in this article, the term "solvent" refers to the crystalline form of a substance containing a solvent.

[0065] The term "complex" as used herein may be used interchangeably as "coordination complex" or "metal coordination complex," etc. It refers to a complex of an organic compound and a metal, empirically distinguishable from a simple metal salt of the organic compound based on physicochemical and / or spectroscopic properties. Coordination complexes typically exhibit enhanced covalentity compared to salts. However, it is not limited to this; the term "complex" as used herein also includes combinations of coordinate covalent bonds and / or ionic bonds. As used herein, the term "complex" also includes molecules lacking ionic components (e.g., neutral coordination complexes prior to deprotonation, where the pKa of the coordination complex falls within a physiologically acceptable range).

[0066] The term "hydrate" refers to a solvate in which water is the solvent.

[0067] Throughout this disclosure, once a term is described, it shall have the same meaning.

[0068] As discussed in the background section, significant efforts have been made to identify and develop new compounds as adenosine receptor antagonists for the treatment of proliferative lesions or diseases or conditions or diseases or cancers associated with immunosuppression. Heterocyclic compounds have been found to function as such antagonists, and compounds of Formula I, their synthetic preparation methods, and their bioactivity against adenosine receptors are disclosed in this disclosure. Compounds of Formula I have been found to be adenosine receptor antagonists, particularly adenosine A. 2a R and A 2b R receptor antagonists. Compounds of Formula I are suitably formulated with therapeutic agents to form pharmaceutical compositions. The pharmaceutical compositions and compounds of Formula I are used to treat adenosine receptor-mediated diseases, lesions, or conditions.

[0069] In one embodiment of this disclosure, a compound of formula I or a pharmaceutically acceptable salt thereof, a complex thereof, a hydrate thereof, a solvate thereof, a tautomer thereof, a polymorph thereof, a stereoisomer thereof, a racemic compound thereof, or a pharmaceutically active derivative thereof are provided.

[0070]

[0071] Formula I

[0072] Where A is selected from C. 5-10 Aryl, C 2-10 heteroaryl, C 3-6 cycloalkyl or C 1-10 Heterocyclic group; wherein C 5-10 Aryl, C 2-10 heteroaryl, C 3-6 cycloalkyl or C 1-10The heterocyclic group is optionally selected from R6, R7, R8, R9, R 9a Or oxidized by one or more substituents;

[0073] R2 is selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Halogenated alkyl groups;

[0074] R3 is selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Halogenated alkyl; wherein C 1-6 Alkyl groups are optionally C 1-6 Alkyl substitution;

[0075] R4 and R5 are independently selected from hydrogen, halogen, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -CO-N(R) 10 R 11 C 4-10 carbonyl group or C 1-10 Heterocyclic groups, where C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is optionally selected from C 3-6 cycloalkyl, C 1-6 Alkoxy or C 1-10 One or more groups of the heterocyclic group are substituted; or R4 and R5 are linked together to form C. 4-10 carbonyl group or C 1-10 Heterocyclic groups, where C 4-10 carbonyl group or C 1-10 The heterocyclic group is optionally and independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 The alkyl group is substituted with 1-3 groups of the alkyl halide;

[0076] R 10 and R 11 Independently selected from hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C3-6 Halogenated cycloalkyl, C 4-10 carbonyl group or C 1-10 Heterocyclic groups;

[0077] R6 is selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Aminoalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, -YOC 1-6 Alkyl, -YOC 3-6 cycloalkyl, Y-CO-NH-R 13 -YZ,C 4-10 carbonyl group or C 1-10 Heterocyclic groups, where C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Aminoalkyl, hydroxy C 1-6 Alkyl or C 1-10 The heterocyclic group is optionally selected from halogen, hydroxyl, amino, C 1-6 Alkoxy, C 3-6 Cycloalkyl, hydroxy C 1-6 Alkyl, C 1-6 Aminoalkyl, C 1-6 Halogenated alkoxy groups, C 4-10 carbonyl group or C 1-10 One or more groups of the heterocyclic group are substituted, wherein C 3-6 cycloalkyl or C 1-6 The aminoalkyl group may optionally be further selected independently from halogen, hydroxyl, hydroxyl C. 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)NH2, -C(O)-hydroxyC 1-6 Alkyl or C 1-10 One or more groups of the heterocyclic group are substituted, and C 1-10 The heterocyclic group is optionally and independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 The alkyl group is substituted with 1-3 groups of the alkyl halide;

[0078] Y is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 3-6 cycloalkyl or C 3-6 Cycloalkenyl; and C 1-6 Alkyl groups are optionally C 3-6 Cycloalkyl substitution;

[0079] Z is selected from -OH, -NH2, -COOH, -SO2NH2, -SO2CH3, -S(O)CH3, -SCH3, CH2-NH-(C 1-6 Alkyl)-S(O)CH3, -OP(=O)(OH)2, -CONH2, -CONH(C 1-6 alkyl), -SO2NH(C 1-6 Alkyl), CON(C) 1-6 Alkyl)2、-NHCO(C 1-6 Alkyl), C 4-10 carbonyl group or C 1-10 Heterocyclic groups, where C 1-10 The heterocyclic group has 1 to 4 heteroatoms independently selected from O, N, or S, and optionally independently selected from halogens, C, and S. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 The alkyl group is substituted with 1-3 groups of the alkyl halide;

[0080] R 13 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or C 3-6 Halogenated cycloalkyl groups;

[0081] R7, R8, R9 and R 9a Independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or C 3-6 Halogenated cycloalkyl groups;

[0082] as well as

[0083] n is 0, 1, or 2.

[0084] In one embodiment of this disclosure, a compound of formula I or a pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, stereoisomer, racemic compound, or pharmaceutically active derivative thereof is provided, wherein A is selected from C. 5-10 Aryl, C 2-10 heteroaryl or C1-10 Heterocyclic group; C 5-10 Aryl, C 2-10 heteroaryl or C 1-10 The heterocyclic group is optionally selected from R6, R7, R8, R9, R 9a Or oxidized by one or more substituents; R2 is selected from hydrogen, C 1-6 Alkyl or C 1-6 Haloalkyl; R3 is selected from hydrogen, C 1-6 Alkyl or C 1-6 Haloalkyl and wherein C 1-6 Alkyl groups are optionally C 1-6 Alkyl substitution; R4 and R5 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 4-10 carbonyl group or C 1-10 Heterocyclic groups, where C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is optionally selected from C 3-6 cycloalkyl, C 1-6 Alkoxy or C 1-10 One or more groups of the heterocyclic group are substituted; wherein C 1-10 The heterocyclic group has 1 to 3 heteroatoms independently selected from O, N, or S, and optionally independently selected from halogens, C, and S. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 The alkyl group of the haloalkoxy group is substituted with 1-3 groups; R6 is selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Aminoalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, -YOC 1-6 Alkyl, -YOC 3-6 cycloalkyl, Y-CO-NH-R 13 -YZ or C 1-10 Heterocyclic groups, where C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, hydroxyl C1-6 Alkyl, C 1-6 Aminoalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl or C 1-10 The heterocyclic group is optionally selected from halogen, hydroxyl, amino, C 1-6 Alkoxy, C 3-6 Cycloalkyl, hydroxy C 1-6 Alkyl, C 1-6 Aminoalkyl, C 1-6 Halogenated alkoxy or C 1-10 One or more groups of the heterocyclic group are substituted, wherein C 3-6 cycloalkyl or C 1-6 The aminoalkyl group may optionally be further selected from halogen, hydroxyl, hydroxyl C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)NH2, -C(O)-hydroxyC 1-6 Alkyl or C 1-10 One or more groups of the heterocyclic group are substituted; Y is selected from C 1-6 Alkyl or C 3-6 cycloalkyl; and C 1-6 Alkyl groups are optionally C 3-6 Cycloalkyl substitution; Z is selected from -OH, -NH2, -COOH, -SO2NH2, -SO2CH3, -S(O)CH3, -SCH3, CH2-NH-(C 1-6 Alkyl)-S(O)CH3, -OP(=O)(OH)2, -CONH2, -CONH(C 1-6 alkyl), -SO2NH(C 1-6 Alkyl), CON(C) 1-6 Alkyl)2, NHCO(C 1-6 alkyl) or C 1-10 Heterocyclic groups, where C 1-10 The heterocyclic group has 1-3 heteroatoms independently selected from O, N, or S, and optionally independently selected from halogens, C, and S. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Substitution of 1-3 groups of haloalkoxy groups; R 13 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or C 3-6 Halogenated cycloalkyl groups; R7, R8, R9 and R 9a Independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or C 3-6 Halogenated cycloalkyl; and n is 0, 1 or 2.

[0085] In one embodiment of this disclosure, a compound of formula I or a pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, stereoisomer, racemic compound, or pharmaceutically active derivative thereof is provided, wherein A is selected from...

[0086]

[0087]

[0088]

[0089]

[0090]

[0091] * indicates a connection point.

[0092] Where Q is N or CR1; and R1 is selected from cyano, hydrogen, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; and C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is optionally C 1-6 Alkyl-substituted.

[0093] In one embodiment of this disclosure, a compound of formula I or a pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, stereoisomer, racemic compound, or pharmaceutically active derivative thereof is provided, wherein A is selected from...

[0094]

[0095]

[0096]

[0097]

[0098] * indicates a connection point.

[0099] Q is either N or CR1;

[0100] R1 is selected from cyano, hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy group; R2 is hydrogen or C 1-6 Alkyl; R3 is hydrogen or C 1-6 Alkyl; wherein C 1-6 Alkyl groups are optionally C 1-6 Alkyl substitution; R4 and R5 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-10 Heterocyclic group; wherein C 1-6 Alkyl groups are optionally selected from C 3-6 cycloalkyl, C 1-6 Alkoxy or C 1-10 One or more groups of the heterocyclic group are substituted, wherein C 1-10 The heterocyclic group has 1-3 heteroatoms independently selected from O, N, or S, and optionally independently selected from halogens, C, and S. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 The alkyl halogen is substituted with 1-3 groups; R6 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Aminoalkyl, -Y-CO-NH-R 13 -YZ or C 1-10 Heterocyclic groups, where C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Aminoalkyl, hydroxy C 1-6 Alkyl, or C 1-10 The heterocyclic group is optionally selected from halogen, hydroxyl, amino, C 3-6 cycloalkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Aminoalkyl, C 1-6 Halogenated alkoxy or C 1-10 One or more groups of the heterocyclic group are substituted, C 1-10 The heterocyclic group has 1 to 4 heteroatoms independently selected from O, N, or S, wherein C3-6 cycloalkyl or C 1-6 The aminoalkyl group is optionally and independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl group, -C(O)C 1-6 Alkyl group, -C(O)NH2, -C(O)-hydroxy group 1-6 Alkyl or C 1-10 One to three groups of the heterocyclic group are substituted; Y is C 1-6 Alkyl or C 3-6 cycloalkyl, wherein C 1-6 Alkyl groups are optionally C 3-6 Cycloalkyl substitution; Z is selected from -OH, -NH2, -COOH, -SO2NH2, -SO2CH3, -S(=O)CH3, -SCH3, CH2-NH-(C 1-6 Alkyl)-S(O)CH3, -OP(=O)(OH)2, CONH2, CON(C 1-6 alkyl)2-CONH(C 1-6 alkyl), -SO2NH(C 1-6 alkyl) or -NHCO(C 1-6 Alkyl); R 13 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or C 3-6 Halogenated cycloalkyl groups; R7, R8, R9 and R 9a Independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or C 3-6 Halogenated cycloalkyl; and n is 0, 1 or 2.

[0101] In one embodiment of this disclosure, a compound of formula I or a pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, stereoisomer, racemic compound, or pharmaceutically active derivative thereof is provided, wherein A is selected from...

[0102]

[0103]

[0104]

[0105]

[0106] * indicates a connection point, where Q is N or CR1; R1 is selected from cyano, hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy group; R2 is hydrogen or C 1-6 Alkyl; R3 is hydrogen or C 1-6 Alkyl, and wherein C 1-6 Alkyl groups are optionally C 1-6 Alkyl substitution; R4 and R5 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy group, -CO-N(R 10 R 11 C 1-10 Heterocyclic groups, where C 1-6 Alkyl groups are optionally selected from C 3-6 cycloalkyl, C 1-6 Alkoxy or C 1-10 One or more groups of the heterocyclic group are substituted, wherein C 1-10 The heterocyclic group has 1 to 4 heteroatoms independently selected from O, N, or S, and optionally independently selected from halogens, C, and S. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Substitution of 1 to 3 groups of haloalkoxy groups; R 10 Is it hydrogen or C? 1-6 Alkyl; R 11 Selected from hydrogen, C 1-6 Alkyl or C 1-10 Heterocyclic groups, where C 1-6 Alkyl groups are optionally selected from halogens, C 3-6 cycloalkyl or C 1-10 One or more groups of the heterocyclic group are substituted; C 1-10 The heterocyclic group has 1 to 4 heteroatoms independently selected from O, N, or S, and optionally independently selected from halogens, C, and S. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Substitution of 1 to 3 groups of haloalkoxy groups,

[0107]

[0108]

[0109]

[0110] R6 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Aminoalkyl, -Y-CO-NH-R 13 -YZ or C 1-10 Heterocyclic groups, where C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Aminoalkyl, hydroxy C 1-6 Alkyl or C 1-10 The heterocyclic group is optionally selected from halogen, hydroxyl, amino, C 3-6 cycloalkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Aminoalkyl, C 1-6 Halogenated alkoxy or C 1-10 One or more groups of the heterocyclic group are substituted, C 1-10 The heterocyclic group has 1 to 4 heteroatoms independently selected from O, N, or S; wherein C 3-6 cycloalkyl or C 1-6 The aminoalkyl group may optionally be further selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)NH2, -C(O)-hydroxyC 1-6 Alkyl, C 1-10Heterocyclic, cyclopropyl, cyclobutyl, CH2CF3, CH2CHFCH3, CH2CF2CH3, CH2C(CH3)2OH, C(CH3)2OH, C(CD3)2OH, CH2OH, CH2OCH3, CH2OCF3, C(CH3CF3)OH, CH2CH2OH, CH2CH2OCH3, CH2CH(OCH3)CH3, C(CH3)2NH2, CH2NH2, CH2CH2NH2, CH2CH2NHCH3, CH2CH(NH2)CH3, CH2CH2N(CH3)2, CH2CHFCH2NH2, O One or more groups of CH3, OCF3, OCH2CF3, OCH2CH2OCH3, OCH2CH2OCHCF2, OCH2CH2OH, OCH2CH2OCF3, CH2CF2CH2OH, CH2C(CH3)2CH2OH, CHCF3OH, CHOHCH2OH, CHOHCH2OCH3, CH2CH2CH2OH, CH2CH2NHCH2CH2OH, CH2NHCH2CH2OH, CH2CH2NHCOCH3, CH2CH2S(=O)CH3, CH2CH2CH2S(=O)CH3 are substituted.

[0111]

[0112] ;

[0113] Y is C 1-6 Alkyl or C 3-6 cycloalkyl, wherein C 1-6 Alkyl groups are optionally C 3-6 Cycloalkyl substitution; Z is selected from -OH, -NH2, -COOH, -SO2NH2, -SO2CH3, -S(=O)CH3, -SCH3, CH2-NH-(C 1-6 Alkyl)-S(O)CH3, -OP(=O)(OH)2, CONH2, CON(C 1-6 alkyl)2-CONH(C 1-6 alkyl), -SO2NH(C 1-6 alkyl) or -NHCO(C 1-6 Alkyl); and R 13 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or C 3-6 Halogenated cycloalkyl groups; R7, R8, R9 and R 9a Independently selected from hydrogen, halogen, cyano, C1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or C 3-6 Halogenated cycloalkyl; and n is 0, 1 or 2.

[0114] In one embodiment of this disclosure, a compound of formula I or a pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, stereoisomer, racemic compound, or pharmaceutically active derivative thereof is provided, wherein A is selected from...

[0115]

[0116]

[0117]

[0118]

[0119] Q is N or CR1; R1 is selected from cyano, hydrogen, halogen, C 1-6 Alkyl or C 1-6 alkoxy group; R2 is hydrogen or C 1-6 Alkyl; R3 is hydrogen or C 1-6 Alkyl group; R4 and R5 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; wherein C 1-6 Alkyl groups are optionally selected from C 3-6 cycloalkyl or C 1-6 One or more alkoxy groups are substituted; R6 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Aminoalkyl, -Y-CO-NH-R 13 -YZ or C 1-10 Heterocyclic groups, where C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Aminoalkyl, hydroxy C 1-6 Alkyl or C 1-10 The heterocyclic group is optionally and independently selected from halogen, hydroxyl, C3-6 cycloalkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Aminoalkyl, C 1-6 Halogenated alkoxy groups, C 1-10 One or more groups of the heterocyclic group are substituted, wherein C 3-6 cycloalkyl or C 1-6 The aminoalkyl group may optionally be further selected independently from halogen, hydroxyl, hydroxyl C. 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)NH2 or -C(O)-hydroxyC 1-6 One or more groups of an alkyl group are substituted; Y is C 1-6 Alkyl or C 3-6 Cycloalkyl; Z is selected from -OH, -NH2, -COOH, -SO2NH2, -SO2CH3, -S(O)CH3, -SCH3, CH2-NH-(C 1-6 Alkyl)-S(O)CH3, -CONH2, -CONH(C 1-6 alkyl), -SO2NH(C 1-6 Alkyl), CON(C) 1-6 alkyl)2 or -NHCO(C 1-6 Alkyl); R 13 Selected from hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl groups; R7, R8, R9 and R 9a Independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Alkoxy group; and n is 0, 1 or 2.

[0120] In one embodiment of this disclosure, a compound of formula I or a pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, stereoisomer, racemic compound, or pharmaceutically active derivative thereof is provided, wherein A is selected from...

[0121]

[0122] Q is N;

[0123] R2 is hydrogen or C. 1-6 Alkyl; R3 is hydrogen or C 1-6 Alkyl group; R4 and R5 are independently selected from halogens, C 1-6 Alkyl, C 3-6cycloalkyl or C 1-6 Halogenated alkyl; wherein C 1-6 Alkyl groups are optionally C 3-6 Cycloalkyl substitution; R6 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Aminoalkyl, -Y-CO-NH-R 13 -YZ or C 1-10 Heterocyclic groups, where C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Aminoalkyl, hydroxy C 1-6 Alkyl or C 1-10 The heterocyclic group is optionally selected from halogen, hydroxyl, amino, C 1-6 Alkoxy, C 3-6 Cycloalkyl, hydroxy C 1-6 Alkyl, C 1-6 Aminoalkyl or C 1-10 One or more groups of the heterocyclic group are substituted; wherein C 3-6 cycloalkyl or C 1-6 The aminoalkyl group may optionally be further selected independently from halogen, hydroxyl, hydroxyl C. 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)NH2 or -C(O)-hydroxyC 1-6 One or more alkyl groups are substituted; Y is C 1-6 Alkyl or C 3-6 cycloalkyl;

[0124] Z is selected from -S(O)CH3, -SCH3, CH2-NH-(C 1-6 Alkyl)-SOCH4 or -NHCO(C 1-6 Alkyl); R 13 Selected from hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl groups; R7, R8, R9 and R 9a Independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy group; and n is 0 or 1.

[0125] In one embodiment of this disclosure, a compound of formula I or a pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, stereoisomer, racemic compound, or pharmaceutically active derivative thereof is provided, comprising groups selected from the following:

[0126] 1,7-Amino-2,3-dimethyl-5-{[1-(6-methylpyridin-2-yl)ethyl]amino}pyrazol[1,5-a]pyrimidine-6-onitrile;

[0127]

[0128] 2,7-Amino-2,3-dimethyl-5-{[(1S)-1-(6-methylpyridin-2-yl)ethyl]amino}pyrazol[1,5-a]pyrimidine-6-onitrile;

[0129]

[0130] 3. (R)-7-amino-3-ethyl-2-methyl-5-((1-(pyridin-2-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-onitrile;

[0131]

[0132] 4. (S)-7-amino-3-ethyl-2-methyl-5-((1-(pyridin-2-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-onitrile;

[0133]

[0134] 5. (S)-7-amino-3-ethyl-2-methyl-5-((1-(6-methylpyridin-2-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-onitrile;

[0135]

[0136] 6,7-Amino-2,3-dimethyl-5-{[(6-methylpyridin-2-yl)methyl]amino}pyrazol[1,5-a]pyrimidine-6-onitrile;

[0137]

[0138] 7,7-Amino-5-{[(6-ethylpyridin-2-yl)methyl]amino}-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-onitrile;

[0139]

[0140] 8,7-Amino-2,3-dimethyl-5-{methyl[(6-methylpyridin-2-yl)methyl]amino}pyrazol[1,5-a]pyrimidine-6-onitrile;

[0141]

[0142] 9,7-Amino-5-({[6-(2-hydroxypropane-2-yl)pyridin-2-yl]methyl}amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0143]

[0144] 10,7-Amino-2,3-dimethyl-5-((2-(5-methylpyridin-2-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-onitrile;

[0145]

[0146] 11,7-Amino-5-((2-(5-fluoropyridin-2-yl)ethyl)amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0147]

[0148] 12,7-Amino-5-((2-(6-methoxypyridin-2-yl)ethyl)amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0149]

[0150] 13,7-Amino-5-((2-(6-methylpyridin-2-yl)ethyl)amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0151]

[0152] 14. Chiral 7-amino-2,3-dimethyl-5-{[1-(6-methylpyridin-2-yl)propane-2-yl]amino}pyrazol[1,5-a]pyrimidine-6-nitrile (isomer 1);

[0153]

[0154] 15. Chiral 7-amino-2,3-dimethyl-5-{[1-(6-methylpyridin-2-yl)propane-2-yl]amino}pyrazol[1,5-a]pyrimidine-6-nitrile (isomer 2);

[0155]

[0156] 16,7-Amino-5-({2-[6-(2-hydroxypropane-2-yl)pyridin-2-yl]ethyl}amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0157]

[0158] 17.7-Amino-3-ethyl-2-methyl-5-((2-(6-methylpyridin-2-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-onitrile;

[0159]

[0160] 18.7-Amino-3-ethyl-2-methyl-5-((2-(5-methylpyridin-2-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-onitrile;

[0161]

[0162] 19.7-Amino-3-ethyl-5-((2-(5-methoxypyridin-2-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0163]

[0164] 20.7-Amino-3-ethyl-5-((2-(6-methoxypyridin-2-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-onitrile;

[0165]

[0166] 21.7-Amino-3-ethyl-5-((2-(5-fluoropyridin-2-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0167]

[0168] 22. Chiral 7-amino-3-ethyl-2-methyl-5-((1-(pyridin-2-yl)propane-2-yl)amino)pyrazol[1,5-a]pyrimidine-6-nitrile (isomer 1);

[0169]

[0170] 23. Chiral 7-amino-3-ethyl-2-methyl-5-((1-(pyridin-2-yl)propane-2-yl)amino)pyrazol[1,5-a]pyrimidine-6-nitrile (isomer 2);

[0171]

[0172] 24,7-Amino-3-ethyl-2-methyl-5-((1-(6-methylpyridin-2-yl)propane-2-yl)amino)pyrazol[1,5-a]pyrimidine-6-onitrile;

[0173]

[0174] 25.7-Amino-3-ethyl-5-({2-[6-(2-hydroxypropane-2-yl)pyridin-2-yl]ethyl}amino)-2-methylpyrazol[1,5-a]pyrimidine-6-onitrile;

[0175]

[0176] 26,7-Amino-3-(cyclopropylmethyl)-2-methyl-5-((2-(6-methylpyridin-2-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-onitrile;

[0177]

[0178] 27.7-Amino-3-(isopropylmethyl)-2-methyl-5-((2-(6-methylpyridin-2-yl)ethyl)amino)pyrazol[1, 5-a]pyrimidine-6-onitrile;

[0179]

[0180] 28.7-Amino-3-(isopropyl)-2-methyl-5-((2-(6-methylpyridin-2-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-onitrile;

[0181]

[0182] 29.7-Amino-5-{[2-(1-ethyl-1H-pyrazol-3-yl)ethyl]amino}-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0183]

[0184] 30.7-Amino-3-ethyl-5-{[2-(1-ethyl-1H-pyrazol-3-yl)ethyl]amino}-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0185]

[0186] 31.7-Amino-5-({2-[1-(1-hydroxy-2-methylpropane-2-yl)-1H-pyrazol-3-yl]ethyl}amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0187]

[0188] 32.7-Amino-3-ethyl-5-((2-(1-(1-hydroxy-2-methylpropane-2-yl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0189]

[0190] 33.7-Amino-3-chloro-5-((2-(6-(hydroxymethyl)pyridin-2-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0191]

[0192] 34.7-Amino-3-chloro-5-((2-(6-(1-(hydroxymethyl)cyclopropyl)pyridin-2-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-onitrile;

[0193]

[0194] 35.7-Amino-3-chloro-5-((2-(1-(2-hydroxyethyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0195]

[0196] 36.7-Amino-3-chloro-5-((2-(1-(1-hydroxy-2-methylpropane-2-yl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0197]

[0198] 37.7-Amino-3-chloro-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0199]

[0200] 38.7-Amino-3-chloro-5-((2-(6-(2-(hydroxymethyl)cyclopropyl)pyridin-2-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-onitrile;

[0201]

[0202] 39.7-Amino-3-ethyl-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-onitrile.

[0203]

[0204] 40. Amino-5-((2-(6-ethylpyridin-2-yl)ethyl)amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0205]

[0206] 41.7-Amino-5-((2-(3-fluoro-6-methylpyridin-2-yl)ethyl)amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0207]

[0208] 42.7-Amino-2-ethyl-3-methyl-5-((2-(6-methylpyridin-2-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-nitrile;

[0209]

[0210] 43.7-Amino-2-ethyl-5-((2-(6-(2-hydroxypropane-2-yl)pyridin-2-yl)ethyl)amino)-3-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0211]

[0212] 44.7-Amino-5-((2-(6-(hydroxymethyl)pyridin-2-yl)ethyl)amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0213]

[0214] 45.7-Amino-3-ethyl-5-((2-(6-(hydroxymethyl)pyridin-2-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0215]

[0216] 46.7-Amino-3-(cyclopropylmethyl)-5-((2-(6-(hydroxymethyl)pyridin-2-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-onitrile;

[0217]

[0218] 47.7-Amino-2-cyclopropyl-5-((2-(6-(2-hydroxypropane-2-yl)pyridin-2-yl)ethyl)amino)-3-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0219]

[0220] 48.7-Amino-2-(difluoromethyl)-3-ethyl-5-((2-(1-(1-hydroxy-2-methylpropane-2-yl)-1H-pyrazol-3-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-nitrile;

[0221]

[0222] 49.7-Amino-5-((2-(6-(1-(hydroxymethyl)cyclopropyl)pyridin-2-yl)ethyl)amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0223]

[0224] 50.7-Amino-3-ethyl-5-((2-(6-(1-(hydroxymethyl)cyclopropyl)pyridin-2-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-onitrile;

[0225]

[0226] 51.7-Amino-5-((2-(6-(2-(hydroxymethyl)cyclopropyl)pyridin-2-yl)ethyl)amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0227]

[0228] 52.7-Amino-3-ethyl-5-((2-(6-(1-hydroxy-2-methylpropane-2-yl)pyridin-2-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0229]

[0230] 53.7-Amino-5-((2-(6-(1-hydroxy-2-methylpropane-2-yl)pyridin-2-yl)ethyl)amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0231]

[0232] 54.7-Amino-3-ethyl-5-((2-(1-(2-hydroxyethyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0233]

[0234] 55.7-Amino-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0235]

[0236] 56.7-Amino-2-(difluoromethyl)-3-ethyl-5-((2-(6-(hydroxymethyl)pyridin-2-yl)ethyl)amino)pyrazol[1, 5-a]pyrimidine-6-onitrile;

[0237]

[0238] 57.7-Amino-5-(((1-(1-hydroxy-2-methylpropane-2-yl)-1H-pyrazol-3-yl)methyl)amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0239]

[0240] 58.7-Amino-2-(difluoromethyl)-3-ethyl-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-nitrile;

[0241]

[0242] 59.7-Amino-2-(difluoromethyl)-3-ethyl-5-((2-(6-(2-(hydroxymethyl)cyclopropyl)pyridin-2-yl)ethyl)amino)pyrazol[1, 5-a]pyrimidine-6-onitrile;

[0243]

[0244] 60.7-Amino-3-ethyl-5-((2-(6-(2-(hydroxymethyl)cyclopropyl)pyridin-2-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-onitrile;

[0245]

[0246] 61.7-Amino-3-chloro-5-((2-(4-(1-(hydroxymethyl)cyclopropyl)thiazolyl-2-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-onitrile;

[0247]

[0248] 62.7-Amino-3-ethyl-5-((2-(4-fluoro-1-(1-hydroxy-2-methylpropane-2-yl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0249]

[0250] 63.7-Amino-3-ethyl-5-((2-(1-((1-(hydroxymethyl)cyclopropyl)methyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0251]

[0252] 64.7-Amino-3-chloro-5-((2-(6-(1,1-difluoro-2-hydroxyethyl)pyridin-2-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-onitrile;

[0253]

[0254] 65.7-Amino-3-chloro-5-((2-(6-(1-hydroxy-2-methylpropane-2-yl)pyridin-2-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0255]

[0256] 66.7-Amino-3-ethyl-5-((2-(4-(1-(hydroxymethyl)cyclopropyl)thiazolyl-2-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0257]

[0258] 67.7-Amino-3-chloro-5-((2-(1-(2-(hydroxymethyl)cyclobutyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0259]

[0260] 68.7-Amino-5-((2-(1-(1-(aminomethyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)-3-chloro-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0261]

[0262] 69.7-Amino-3-bromo-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-onitrile;

[0263]

[0264] 70.7-Amino-3-chloro-5-((2-(1-ethyl-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0265]

[0266] 71.7-Amino-3-ethyl-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-nitrile;

[0267]

[0268] 72.7-Amino-3-bromo-5-((2-(6-(hydroxymethyl)pyridin-2-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-onitrile;

[0269]

[0270] 73.7-Amino-3-chloro-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-1H-pyrazol-4-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0271]

[0272] 74.7-Amino-3-(cyclopropylmethyl)-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0273]

[0274] 75.7-Amino-3-chloro-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-5-methyl-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0275]

[0276] 76.7-Amino-3-ethyl-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-5-methyl-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0277]

[0278] 77.N-((1-(3-(2-((7-amino-3-chloro-6-cyano-2-methylpyrazol[1, 5-a]pyrimidin-5-yl)amino)ethyl)-1H-pyrazol-1-yl)cyclopropyl)methyl)acetamide;

[0279]

[0280] 78. (+)-7-amino-3-ethyl-5-((2-(1-(2-(hydroxymethyl)cyclobutyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0281]

[0282] Example 78; Right-handed (+) rotation

[0283] 79. (-)-7-amino-3-ethyl-5-((2-(1-(2-(hydroxymethyl)cyclobutyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0284]

[0285] Example 79; Left-handed (-) rotation

[0286] 80.7-Amino-3-ethyl-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-5-methyl-1H-pyrazol-3-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-nitrile;

[0287]

[0288] 81.7-Amino-3-ethyl-5-((2-(1-(1-hydroxypropane-2-yl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0289]

[0290] 82. (+-)-7-amino-3-chloro-5-((2-(1-((3-hydroxycyclobutyl)methyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0291]

[0292] 83. (+)-7-amino-3-chloro-5-((2-(1-((3-hydroxycyclobutyl)methyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0293]

[0294] 84. (-)-7-amino-3-chloro-5-((2-(1-((3-hydroxycyclobutyl)methyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile (83b);

[0295]

[0296] 85.7-Amino-3-ethyl-5-((2-(1-((3-hydroxycyclobutyl)methyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0297]

[0298] 86.7-Amino-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-5-methyl-1H-pyrazol-3-yl)ethyl)amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0299]

[0300] 87.7-Amino-3-chloro-2-methyl-5-((2-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-nitrile;

[0301]

[0302] 88.7-Amino-3-ethyl-2-methyl-5-((2-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-nitrile;

[0303]

[0304] 89.7-Amino-3-bromo-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-5-methyl-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-onitrile;

[0305]

[0306] 90.7-Amino-3-chloro-5-((2-(6-((((2-hydroxyethyl)amino)methyl)pyridin-2-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0307]

[0308] 91.7-Amino-3-ethyl-5-((2-(5-fluoro-6-(hydroxymethyl)pyridin-2-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0309]

[0310] 92.7-Amino-3-chloro-5-((2-(1-(2-methoxyethyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0311]

[0312] 93.7-Amino-3-chloro-5-((2-(1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0313]

[0314] 94.7-Amino-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methyl-3-(trifluoromethyl)pyrazol[1, 5-a]pyrimidine-6-nitrile;

[0315]

[0316] 95.7-Amino-5-((2-(1-(2-(aminomethyl)cyclobutyl)-1H-pyrazol-3-yl)ethyl)amino)-3-chloro-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0317]

[0318] 96.7-Amino-3-ethyl-5-((2-(6-((((2-methoxyethyl)amino)methyl)pyridin-2-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0319]

[0320] 97.7-Amino-3-ethyl-5-((2-(6-((((2-hydroxyethyl)amino)methyl)pyridin-2-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0321]

[0322] 98.7-Amino-3-chloro-5-((2-(1-(1-((((2-hydroxyethyl)amino)methyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0323]

[0324] 99.N-((1-(3-(2-((7-amino-3-chloro-6-cyano-2-methylpyrazol[1, 5-a]pyrimidin-5-yl)amino)ethyl)-1H-pyrazol-1-yl)cyclopropyl)methyl)-3-hydroxypropionamide;

[0325]

[0326] 100.7-Amino-3-ethyl-5-((2-(6-(1-hydroxyethyl)pyridin-2-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0327]

[0328] 101.7-Amino-3-cyclopropyl-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0329]

[0330] 102.7-Amino-2-(difluoromethyl)-3-ethyl-5-((2-(1-(2-(hydroxymethyl)cyclobutyl)-1H-pyrazol-3-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-nitrile;

[0331]

[0332] 103, 104a and 104b. (+-)-7-amino-5-((2-(1-(2-(hydroxymethyl)cyclobutyl)-1H-pyrazol-3-yl)ethyl)amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-onitrile (103), (+)-7-amino-5-((2-(1-(2-(hydroxymethyl)cyclobutyl)-1H-pyrazol-3-yl)ethyl)amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-onitrile (104a), (-)-7-amino-5-((2-(1-(2-(2-(hydroxymethyl)cyclobutyl)-1H-pyrazol-3-yl)ethyl)amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-onitrile (104b);

[0333]

[0334] Example 103; Racemic (±)

[0335] Example 104a; Peak 1; Right-handed (+) rotation

[0336] Example 104b; Peak 2; Left-handed (-) rotation

[0337] 105.7-Amino-5-((2-(6-((((2-hydroxyethyl)amino)methyl)pyridin-2-yl)ethyl)amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0338]

[0339] 106.7-Amino-3-ethyl-5-((2-(1-(1-((((2-hydroxyethyl)amino)methyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0340]

[0341] 107.7-Amino-3-ethyl-5-((2-(1-(2-methoxyethyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0342]

[0343] 108.7-Amino-3-ethyl-5-((2-(1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0344]

[0345] 109.7-Amino-5-((2-(1-(2-(aminomethyl)cyclobutyl)-1H-pyrazol-3-yl)ethyl)amino)-3-ethyl-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0346]

[0347] 110.7-Amino-3-ethyl-5-((2-(1-(3-hydroxypropyl)-1H-pyrazol-5-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0348]

[0349] 111.7-Amino-3-ethyl-5-((2-(1-(3-hydroxypropyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0350]

[0351] 112.7-Amino-3-chloro-5-((2-(1-(1-(2-hydroxyethyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0352]

[0353] 113.7-Amino-3-ethyl-5-((2-(1-(3-hydroxypropyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0354]

[0355] 114.7-Amino-3-chloro-5-((2-(1-(2-(hydroxymethyl)cyclopentyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0356]

[0357] 115.7-Amino-3-ethyl-5-((2-(1-(2-(hydroxymethyl)cyclopentyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0358]

[0359] 116.7-Amino-3-(cyclopropylmethyl)-5-((2-(1-(2-(hydroxymethyl)cyclobutyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0360]

[0361] 117.7-Amino-3-chloro-5-((2-(1-(2-((((2-hydroxyethyl)amino)methyl)cyclobutyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0362]

[0363] 118.7-Amino-5-((2-(1-(2-(aminomethyl)cyclopentyl)-1H-pyrazol-3-yl)ethyl)amino)-3-chloro-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0364]

[0365] 119.7-Amino-3-chloro-2-methyl-5-((2-(6-methylpyridin-2-yl)ethyl)amino)pyrazol[1, 5-a]pyrimidine-6-onitrile;

[0366]

[0367] 120.7-Amino-3-chloro-5-((2-(6-ethylpyridin-2-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-onitrile;

[0368]

[0369] 121. (+-)-7-amino-3-ethyl-5-((2-(1-(4-(hydroxymethyl)tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0370] 122a. (+)-7-amino-3-ethyl-5-((2-(1-(4-(hydroxymethyl)tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0371] 122b. (-)-7-amino-3-ethyl-5-((2-(1-(4-(hydroxymethyl)tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0372]

[0373] Example 121; Racemic (±)

[0374] Example 122a; Peak 1; Right-handed (+) rotation

[0375] Example 122b; Peak 2; Left-handed (-) rotation

[0376] 123. 7-Amino-3-ethyl-5-((2-(1-(3-(hydroxymethyl)cyclobutyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-onitrile;

[0377]

[0378] 124.7-Amino-3-ethyl-5-((2-(1-(1-(2-hydroxyethyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0379]

[0380] 125.7-Amino-5-((2-(1-(2-aminoethyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)-3-chloro-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0381]

[0382] 126.7-Amino-5-((2-(1-(2-aminoethyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)-3-ethyl-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0383]

[0384] 127.7-Amino-3-chloro-5-((2-(1-(4-(hydroxymethyl)tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0385]

[0386] 128.7-Amino-3-ethyl-5-((2-(1-((3-hydroxycyclobutyl)methyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0387]

[0388] 129.7-Amino-5-((2-(1-(3-aminopropyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)-3-chloro-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0389]

[0390] 130.7-Amino-3-bromo-5-((2-(1-(2-(hydroxymethyl)cyclobutyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-onitrile;

[0391]

[0392] 131.7-Amino-2-(difluoromethyl)-3-ethyl-5-((2-(1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-nitrile;

[0393]

[0394] 132. (+-)-7-amino-5-((2-(1-(4-(hydroxymethyl)tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)ethyl)amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0395] 133a. (+)-7-amino-5-((2-(1-(4-(hydroxymethyl)tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)ethyl)amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0396] 133b. (-)-7-amino-5-((2-(1-(4-(hydroxymethyl)tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)ethyl)amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0397]

[0398] Example 132; Racemic (±)

[0399] Example 133a; Peak 1; Right-handed (+) rotation

[0400] Example 133b; Peak 2; Left-handed (-) rotation

[0401] 134. 2-(((2-(3-(2-((7-amino-6-cyano-3-ethyl-2-methylpyrazol[1, 5-a]pyrimidin-5-yl)amino)ethyl)-1H-pyrazol-1-yl)cyclobutyl)methyl)amino)acetamide;

[0402]

[0403] 135.7-Amino-3-ethyl-2-methyl-5-((2-(6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-nitrile;

[0404]

[0405] 136.7-Amino-5-((2-(1-(3-aminopropyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)-3-ethyl-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0406]

[0407] 137.7-Amino-3-(cyclobutylmethyl)-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0408]

[0409] 138.7-Amino-5-((2-(1-(3-hydroxypropyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0410]

[0411] 139.7-Amino-3-ethyl-5-((2-(6-(2-hydroxyethyl)pyridin-2-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0412]

[0413] 140.7-Amino-2,3-dimethyl-5-((2-(6-methylpyrazin-2-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-onitrile;

[0414]

[0415] 141.7-Amino-5-((2-(1-(3-aminopropyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0416]

[0417] 142.7-Amino-3-ethyl-2-methyl-5-((2-(1-(2-(methylthio)ethyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-nitrile;

[0418]

[0419] 143. Racemic (+-)7-amino-3-ethyl-2-methyl-5-((2-(1-(2-(methylsulfinyl)ethyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-nitrile;

[0420] 144a. (+)7-amino-3-ethyl-2-methyl-5-((2-(1-(2-(methylsulfinyl)ethyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-nitrile;

[0421] 144b. (-)7-amino-3-ethyl-2-methyl-5-((2-(1-(2-(methylsulfinyl)ethyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-nitrile;

[0422]

[0423] Example 143; Racemic (±)

[0424] Example 144a; Peak 1; Right-handed (+) rotation

[0425] Example 144b; Peak 2; Left-handed (-) rotation

[0426] 145. N-(3-(3-(2-((7-amino-6-cyano-3-ethyl-2-methylpyrazol[1, 5-a]pyrimidin-5-yl)amino)ethyl)-2-oxopyridin-1(2H)-yl)propyl)acetamide;

[0427]

[0428] 146.7-Amino-5-((2-(1-(1-(aminomethyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)-3-ethyl-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0429]

[0430] 147.N-((1-(3-(2-((7-amino-6-cyano-3-ethyl-2-methylpyrazol[1, 5-a]pyrimidin-5-yl)amino)ethyl)-1H-pyrazol-1-yl)cyclopropyl)methyl)acetamide;

[0431]

[0432] 148.7-Amino-5-((2-(1-(1-(2-aminoethyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)-3-ethyl-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0433]

[0434] 149. N-(2-(1-(3-(2-((7-amino-6-cyano-3-ethyl-2-methylpyrazol[1, 5-a]pyrimidin-5-yl)amino)ethyl)-1H-pyrazol-1-yl)cyclopropyl)ethyl)acetamide;

[0435]

[0436] 150. 7-Amino-3-ethyl-5-((2-(6-(2-hydroxyethoxy)pyridin-2-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0437]

[0438] 151. 7-Amino-5-((2-(1-(1-(2-aminoethyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)-3-chloro-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0439]

[0440] 152.7-Amino-5-((2-(6-(2-hydroxyethyl)pyridin-2-yl)ethyl)amino)-2,3-dimethylpyrazol[1,5-a]pyrimidine-6-nitrile;

[0441]

[0442] 153.7-Amino-3-ethyl-2-methyl-5-((2-(1-(3-(methylthio)propyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-nitrile;

[0443]

[0444] 154a. (-)-7-amino-3-ethyl-2-methyl-5-((2-(1-(3-(methylsulfinyl)propyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-onitrile;

[0445] 154b. (+)-7-amino-3-ethyl-2-methyl-5-((2-(1-(3-(methylsulfinyl)propyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-onitrile;

[0446]

[0447] Example 154a; Peak 1; Right-handed (+) rotation

[0448] Example 154b; Peak 2; Left-handed (-) rotation

[0449] 155. 7-Amino-3-ethyl-5-((2-(6-(3-hydroxypropyl)pyridin-2-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0450]

[0451] 156.7-Amino-5-((2-(1-(3-hydroxypropyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)-2-methyl-3-propylpyrazole[1,5-a]pyrimidine-6-nitrile;

[0452]

[0453] 157.7-Amino-5-((2-(6-(hydroxymethyl)pyridin-2-yl)ethyl)amino)-2-methyl-3-propylpyrazole[1,5-a]pyrimidine-6-nitrile;

[0454]

[0455] 158.7-Amino-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methyl-3-propylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0456]

[0457] 159a. (+)-7-amino-3-ethyl-5-((2-(6-(1-hydroxyethyl)pyridin-2-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0458] 159b. (-)-7-amino-3-ethyl-5-((2-(6-(1-hydroxyethyl)pyridin-2-yl)ethyl)amino)-2-methylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0459]

[0460] Example 159a; Peak 1; Right-handed (+) rotation

[0461] Example 159b; Peak 1; Left-handed (-) rotation

[0462] 160a. (+)7-amino-5-((2-(1-(4-(hydroxymethyl)tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)ethyl)amino)-2-methyl-3-propylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0463] 160b. (-)7-amino-5-((2-(1-(4-(hydroxymethyl)tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)ethyl)amino)-2-methyl-3-propylpyrazol[1, 5-a]pyrimidine-6-nitrile;

[0464]

[0465] Example 160a; Peak 1; Right-handed (+) rotation

[0466] Example 160b; Peak 2; Left-handed (-) rotation

[0467] 161.7-Amino-3-ethyl-2-methyl-5-((2-(1-(3-(methylthio)propyl)-1H-pyrazol-3-yl)ethyl)amino)pyrazol[1,5-a]pyrimidine-6-onitrile;

[0468]

[0469] 162a. (-)-7-amino-3-ethyl-2-methyl-5-((2-(1-(3-(methylsulfinyl)propyl)-1H-pyrazol-3-yl)ethyl)amino)pyrazol[1, 5-a]pyrimidine-6-onitrile;

[0470] 162b. (+)-7-amino-3-ethyl-2-methyl-5-((2-(1-(3-(methylsulfinyl)propyl)-1H-pyrazol-3-yl)ethyl)amino)pyrazol[1, 5-a]pyrimidine-6-nitrile;

[0471]

[0472] Peak 1; Example 162a; Left-handed (-) rotation

[0473] Peak 2; Example 162b; Right-handed (+) rotation

[0474] 163a. ​​(-)-7-amino-3-ethyl-2-methyl-5-((2-(1-(1-((((2-(methylsulfinyl)ethyl)amino)methyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)pyrazol[1, 5-a]pyrimidine-6-nitrile;

[0475] 163b. (+)-7-amino-3-ethyl-2-methyl-5-((2-(1-(1-((((2-(methylsulfinyl)ethyl)amino)methyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)pyrazol[1, 5-a]pyrimidine-6-nitrile;

[0476]

[0477] Peak 1; Example 163a; Left-handed (-) rotation

[0478] Peak 2; Example 163b; Right-handed (+) rotation

[0479] 164.7-Amino-2-methyl-5-((2-(6-methylpyridin-2-yl)ethyl)amino)-3-propylpyrazole[1, 5-a]pyrimidine-6-onitrile;

[0480]

[0481] 165a. (+)-7-amino-5-((2-(1-(2-(hydroxymethyl)cyclobutyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methyl-3-propylpyrazol[1, 5-a]pyrimidine-6-onitrile;

[0482] 165b. (-)-7-amino-5-((2-(1-(2-(hydroxymethyl)cyclobutyl)-1H-pyrazol-3-yl)ethyl)amino)-2-methyl-3-propylpyrazol[1, 5-a]pyrimidine-6-onitrile;

[0483]

[0484] Peak 1; Example 165a; Left-handed (-) rotation

[0485] Peak 2; Example 165b; Right-handed (+) rotation

[0486] 166. ( R )-7-amino-3-ethyl-2-methyl-5-((2-(6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)ethyl)amino)pyrazol[1, 5-a]pyrimidine-6-nitrile;

[0487]

[0488] 167. (-)-7-amino-3-ethyl-5-((2-(1-(4-(hydroxymethyl)tetrahydrofuran-3-yl)-5-methyl-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-nitrile; and

[0489]

[0490] Example 167; Peak 1; Left-handed (-) rotation

[0491] 168.(+)-7-amino-3-ethyl-5-((2-(1-(4-(hydroxymethyl)tetrahydrofuran-3-yl)-5-methyl-1H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazol[1,5-a]pyrimidine-6-onitrile.

[0492]

[0493] Example 168; Peak 2; Right-handed (-) rotation

[0494] In one embodiment of this disclosure, a compound of formula I disclosed herein, or a pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, stereoisomer, racemic compound, or pharmaceutically active derivative thereof, is provided for use as a medicament.

[0495] In one embodiment of this disclosure, an adenosine 2a receptor (A... 2a R) or adenosine 2b receptor (A) 2b R) or adenosine 2a receptor (A) 2a R) and adenosine 2b receptor (A 2b The combination of antagonists of formula I, or pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, stereoisomers, racemic compounds, and their pharmaceutically active derivatives thereof.

[0496] In one embodiment of this disclosure, a treatment for patients selected from at least partially derived from adenosine 2a receptors (A... 2a R) or adenosine 2b receptor (A) 2b R) or A 2a R and A 2b R refers to the combination of compounds of formula I disclosed herein, or their pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, stereoisomers, racemic compounds, or pharmaceutically active derivatives thereof, that mediate diseases, lesions, or conditions of cancer, Parkinson's disease, asthma, diabetes, and autoimmune diseases, lesions, or conditions.

[0497] In one embodiment of this disclosure, a method is provided for preparing compounds of formula I disclosed herein, or pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, stereoisomers, racemic compounds, and pharmaceutically active derivatives thereof, the method comprising: reacting formulas (A) and (B) in the presence of a base to obtain a compound of formula I.

[0498]

[0499] Formula (A) Formula (B) Formula (I)

[0500] Where R is selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 5-10 Aryl, C 2-10 heteroaryl or C 1-10 Heterocyclic groups; and substituents as disclosed herein.

[0501] In one embodiment of this disclosure, a method is provided for preparing compounds of formula I disclosed herein, or pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, stereoisomers, racemic compounds, or pharmaceutically active derivatives thereof, wherein the base is selected from triethylamine, diisopropylethylamine, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert-butoxide, sodium hydride, lithium bis(trimethylsilyl)amide (LiHMDS), N-diisopropylethylamine, or combinations thereof.

[0502] In one embodiment of this disclosure, a method is provided for preparing compounds of formula I disclosed herein, or pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, stereoisomers, racemic compounds, and pharmaceutically active derivatives thereof, wherein the method is carried out in the presence of a solvent selected from isopropanol, methanol, n-butanol, dichloromethane, tetrahydrofuran, dimethylformamide, n-methylpyrrolidone, dimethyl sulfoxide, water, dioxane, acetonitrile, or combinations thereof.

[0503] In one embodiment of this disclosure, a pharmaceutical composition is provided comprising a compound of formula I disclosed herein and one or more additional therapeutic agents.

[0504] In one embodiment of this disclosure, a pharmaceutical composition is provided comprising a compound of formula I and one or more adjunctive therapeutic agents selected from chemotherapeutic agents, immune checkpoint inhibitors, or combinations thereof. In another embodiment of this disclosure, a pharmaceutical composition is provided comprising a compound of formula I disclosed herein, wherein one or more adjunctive therapeutic agents are chemotherapeutic agents or immune checkpoint inhibitors.

[0505] In one embodiment of this disclosure, a pharmaceutical composition disclosed herein is provided, wherein one or more adjunctive therapeutic agents are selected from phosphatidylinositol-3 kinase (PI3K) inhibitors, tyrosine kinase inhibitors, signal transduction and transcription activator protein 3 (Stat-3) inhibitors, topoisomerase inhibitors, protein kinase B (AKT) inhibitors, c-Jun N-terminal kinase (JNK1 / K2) inhibitors, hypoxia-inducible factor 1α (HIF-1a) inhibitors, extracellular signal-regulated kinase (ERK) inhibitors, poly-ADP-ribose polymerase-1 (PARP-1) inhibitors, cisplatin, or oxaliplatin chemotherapeutic agents.

[0506] In one embodiment of this disclosure, a pharmaceutical composition disclosed herein is provided, wherein one or more adjunctive therapeutic agents are immune checkpoint inhibitors selected from programmed death 1 (PD-1) inhibitors, programmed death ligand 1 (PD-L1) inhibitors, anti-PD-1 antibodies, anti-PD-L1 antibodies, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, anti-CTLA-4 antibodies, T-cell immunoglobulin and ITIM domain (TIGIT) inhibitors, exonucleoside triphosphate diphosphate hydrolase 1 (E-NTPDase, CD39) inhibitors, or exonucleoside 5'-nucleotidase (Ecto5'NTase, CD79) inhibitors.

[0507] In one embodiment of this disclosure, a pharmaceutical composition is provided comprising a compound of formula I or a pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, stereoisomer, pharmaceutically active derivative thereof, and one or more adjunctive therapeutic agents selected from chemotherapeutic agents or immune checkpoint inhibitors, wherein the one or more adjunctive therapeutic agents are selected from phosphatidylinositol-3 kinase (PI3K) inhibitors, tyrosine kinase inhibitors, signal transduction and transcription activating protein 3 (Stat-3) inhibitors, topoisomerase inhibitors, protein kinase B (AKT) inhibitors, c-Jun N-terminal kinase (JNK1 / K2) inhibitors, hypoxia-inducible factor 1α (HIF-1α) inhibitors. Immune checkpoint inhibitors, including inhibitors of extracellular signal-regulated kinase (ERK), poly-ADP-ribose polymerase-1 (PARP-1), cisplatin, oxaliplatin, programmed death 1 (PD-1), programmed death ligand 1 (PD-L1), anti-PD-1 antibody, anti-PD-L1 antibody, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, anti-CTLA-4 antibody, T-cell immunoglobulin and ITIM domain (TIGIT) inhibitors, exonucleoside triphosphate diphosphate hydrolase 1 (E-NTPDase, CD39) inhibitor or exonucleoside 5'-nucleotidase (Ecto5'NTase, CD79) inhibitor.

[0508] In one embodiment of this disclosure, a method for treating and / or preventing adenosine receptor-mediated conditions or proliferative lesions or diseases or cancer is provided, the method comprising administering to a subject suffering from an adenosine receptor-mediated condition or disease or proliferative lesion or disease or cancer a therapeutically effective amount of a compound of formula I disclosed herein or a pharmaceutical composition comprising a compound of formula I and one or more additional therapeutic agents.

[0509] In one embodiment of this disclosure, a method for treating and / or preventing adenosine receptor-mediated conditions or proliferative lesions or diseases or cancer is provided, the method comprising administering to a subject suffering from an adenosine receptor-mediated condition or proliferative lesion or disease or cancer a therapeutically effective amount of a compound of formula I disclosed herein, or a pharmaceutical composition comprising a compound of formula I and one or more additional therapeutic agents, wherein the adenosine receptor-mediated condition or proliferative lesion or disease or cancer is at least partially caused by an adenosine 2a receptor (A... 2a R), adenosine 2b receptor (A) 2b R) or a combination thereof mediates.

[0510] In one embodiment of this disclosure, a method for treating and / or preventing adenosine receptor-mediated conditions, proliferative disorders, or cancer is provided, the method comprising administering to a subject suffering from an adenosine receptor-mediated condition, disease, proliferative disorder, or cancer a therapeutically effective amount of a compound of formula (I) disclosed herein or a pharmaceutical composition disclosed herein, wherein the compound of formula (I) administered in an effective amount reverses or stops adenosine 2a receptor (A... 2a R) or adenosine 2b receptor (A) 2b Progression of immunosuppression mediated by R or both.

[0511] In one embodiment of this disclosure, a method for treating and / or preventing adenosine receptor-mediated lesions or proliferative disorders or diseases or cancer is provided, the method comprising administering to a subject suffering from an adenosine receptor-mediated lesion or proliferative disorder or disease or cancer a therapeutically effective amount of a compound of formula I disclosed herein or a pharmaceutical composition disclosed herein, wherein the proliferative disorder or disease is cancer or an immune response-related lesion or disease or condition.

[0512] In one embodiment of this disclosure, a method for treating and / or preventing adenosine receptor-mediated conditions or proliferative disorders or diseases or cancer is provided, the method comprising administering to a subject suffering from an adenosine receptor-mediated condition or disease or proliferative disorder or cancer a therapeutically effective amount of a compound of formula I disclosed herein or a pharmaceutical composition disclosed herein, wherein the cancer is adrenal cancer, brain cancer, bladder cancer, breast cancer, bone cancer, colon cancer, endometrial cancer, esophageal cancer, head cancer, stomach cancer, kidney cancer, liver cancer, lung cancer, oral cancer, muscle cancer, neck cancer, pancreatic cancer, prostate cancer, retinal cancer, skin cancer, thyroid cancer, or leukemia, and the immune-related disease, lesion, or condition is selected from the group consisting of allergies, Alzheimer's disease, asthma, Crohn's disease, colitis, chronic obstructive pulmonary disease, diabetic nephropathy, glaucoma, lupus, rheumatoid arthritis, multiple sclerosis, pain, panic disorder, pancreatitis, Parkinson's disease, psoriasis, systemic sclerosis, and ulcerative colitis.

[0513] In one embodiment of this disclosure, compounds of Formula I disclosed herein or pharmaceutical compositions disclosed herein are provided together with other clinically relevant cytotoxic or non-cytotoxic agents for the treatment of adenosine receptor A. 2a R-mediated conditions; treatment and / or prevention of proliferative lesions or diseases or cancer or immune-related lesions or diseases or conditions; or use in the treatment of cancer.

[0514] In one embodiment of this disclosure, compounds of Formula I disclosed herein or pharmaceutical compositions disclosed herein are provided together with other clinically relevant cytotoxic or non-cytotoxic agents for the treatment of adenosine receptor A. 2bR-mediated conditions; treatment and / or prevention of proliferative lesions or diseases or cancer or immune-related lesions or diseases or conditions; or use in the treatment of cancer.

[0515] In one embodiment of this disclosure, compounds of Formula I disclosed herein or pharmaceutical compositions disclosed herein are provided together with other clinically relevant cytotoxic or non-cytotoxic agents for the treatment of adenosine receptor A. 2a R and A 2b R-mediated conditions; treatment and / or prevention of proliferative lesions or diseases or cancer or immune-related lesions or diseases or conditions; or use in the treatment of cancer.

[0516] Example

[0517] As used herein, the symbols and specifications used in these methods, procedures, and embodiments are consistent with those used in contemporary scientific literature. Unless otherwise stated, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the embodiments and throughout the specification:

[0518] abbreviation

[0519] The following abbreviations are used in the embodiments and elsewhere in this document:

[0520] TLC (Thin-Layer Chromatography)

[0521] HPLC (High-Performance Liquid Chromatography)

[0522] MPLC - Medium-pressure liquid chromatography;

[0523] NMR (Nuclear Magnetic Resonance Spectroscopy);

[0524] DMSO (dimethyl sulfoxide);

[0525] CDCl3-deuterated chloroform;

[0526] MeOD - deuterated methanol, i.e., D3COD;

[0527] MS (Mass Spectrometry); ESP (or ES) (Electrospray Electrodeionization); EI (Electron Collision Ionization); APCI (Atmospheric Pressure Chemical Ionization);

[0528] THF-tetrahydrofuran;

[0529] DCM - dichloromethane;

[0530] MeOH - methanol;

[0531] DMF - Dimethylformamide;

[0532] EtOAc - Ethyl acetate;

[0533] LC / MS - Liquid Chromatography / Mass Spectrometry;

[0534] h represents hours; min represents minutes.

[0535] d-day;

[0536] MTBD-N-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene;

[0537] TFA - trifluoroacetic acid; v / v - volume ratio;

[0538] Boc-tert-butyloxycarbonyl;

[0539] Cbz-benzyloxycarbonyl;

[0540] Bz-benzoyl group;

[0541] Atm - atmospheric pressure;

[0542] rt - room temperature;

[0543] mg stands for milligram; g represents gram.

[0544] µL;

[0545] mL - milliliters;

[0546] L-liter;

[0547] µM - micromolar;

[0548] nM-nanomolar

[0549] mM - millimoles; M represents moles;

[0550] DMAP-Dimethylaminopyridine;

[0551] TBDMS - tert-butyldimethylsilyl

[0552] N-normal; and

[0553] nm - nanometer.

[0554] The following examples provide detailed information regarding the synthesis, activity, and applications of the compounds disclosed herein. It should be understood that the following are merely representative examples, and the invention is not limited to the detailed information set forth in these examples.

[0555] Materials and methods:

[0556] Evaporation is carried out by vacuum rotary evaporation, followed by processing after removal of solid residues by filtration; temperatures are expressed in °C; operations are performed at room temperature, typically between 18 and 26 °C, without excluding air unless otherwise specified or if a technician works under an inert atmosphere; compounds are purified using column chromatography (by a rapid procedure) and column chromatography on Merck Kieselgel silica (section 9385) unless otherwise specified; typically, the reaction process is followed by TLC, HPLC, or LC / MS, and the given reaction times are for illustrative purposes only; the given yields are for illustrative purposes only and are not necessarily the maximum achievable yields; the structure of the final product of this invention is typically confirmed by NMR and mass spectrometry. Proton magnetic resonance spectroscopy is typically performed in DMSO d6, unless otherwise specified, using a Bruker DRX 300 or Bruker DRX-400 spectrometer at field strengths of 300 MHz or 400 MHz, respectively. In cases of complex NMR spectra, only diagnostic signals are reported. Chemical shifts in tetramethylsilane at low magnetic fields are reported as external standards (*scale), with the chemical shifts reported as parts per million (ppm) of tetramethylsilane at low magnetic fields (*scale). This demonstrates peak multiplicity: s, singlet; d, doublet; dd, double doublet; dt, double triplet; dm, double multiplet; t, triplet; m, multiplet; br, broad peak. Fast atom bombardment (FAB) mass spectrometry data are typically obtained using a platform spectrometer (provided by Micromass) operating in electrospray ionization, with positive or negative ion data collected where appropriate, or using an Agilent 1100 series LC / MS equipped with a Sedex 75ELSD, with both positive and negative ion data collected where appropriate. For molecules that exhibit multiple mass peaks due to isotopic splitting (e.g., in the presence of chlorine), the lowest mass main ion is reported. Reversed-phase HPLC was performed on an Agilent instrument using YMC Pack ODS AQ (100x20 mm Id, S 5 Å particle size, 12 nm pore size); each intermediate was purified to the standard required for subsequent stages and characterized in sufficient detail to confirm that the assigned structure was correct; purity was assessed by HPLC, TLC or NMR, and identity was determined by infrared (IR), mass spectrometry or NMR spectroscopy where appropriate.

[0557] Conventional methods for preparing compounds of formula (A)

[0558] The compound of formula (A) is prepared from formula (F) by using a suitable oxidizing agent (e.g., mCPBA), and the compound of formula (F) is synthesized by reacting the compound of formula (D) with the compound of formula (E) in the presence of a suitable base (e.g., pyridine). Formula (D) is obtained by treating formula (C) with carbon disulfide and methyl iodine in the presence of a suitable base (e.g., sodium hydride) (Scheme 1).

[0559]

[0560] Option 1

[0561] Conventional methods for preparing compounds of formula (B)

[0562] Compounds of formula (B) can be prepared in various ways, and many compounds of formula (B) are commercially available. A general route scheme 2 for formula (B) is given, in which formula (B) is obtained by treating a carbonyl compound of formula (B1) with an amine of formula (B2) using a suitable reducing agent.

[0563]

[0564] Option 2

[0565] Furthermore, the method for one of the representative compounds of formula (B) in which A is a six-membered ring is shown in formula (N) in scheme 3.

[0566]

[0567] Option 3

[0568] Compound of formula (B) is obtained by reducing a compound of formula (H) or (J) with a suitable reducing agent. Compound of formula (H) is obtained by treating a compound of formula (G) with nitromethane, wherein Q is an aldehyde. Compound of formula (J) is obtained by treating a compound of formula (G) with acetonitrile in the presence of a suitable alkali metal base (e.g., nBuLi), wherein Q is a halogen (e.g., Br or I).

[0569]

[0570] Option 4

[0571] Similar to the method for preparing compounds of formula (I), the method for preparing one of the representative compounds of formula (B) with a five-membered ring is shown in formula (M) in scheme 4.

[0572] The above embodiments illustrate some methods for synthesizing compounds of formula (A) and (B), which can also be used to synthesize compounds of formula (I). Where a particular solvent or reagent is shown or mentioned in the accompanying text, it should be understood that a person skilled in the art will be able to modify and / or replace that solvent or reagent as needed.

[0573] In another embodiment, the compound of formula I can be prepared by reacting the compound of formula (B) with the compound of formula (A) in the presence of a suitable base and solvent, as shown in Scheme 5.

[0574]

[0575] Option 5

[0576] This disclosure provides a method for preparing compounds of formula (I), which can be prepared in various ways. The methods and examples shown below illustrate some methods for synthesizing compounds and intermediates of formula (I), which can also be used to synthesize compounds of formula (I). Where a particular solvent or reagent is shown or mentioned in the appended text, it should be understood that those skilled in the art will be able to modify and / or replace the solvent or reagent as needed.

[0577] Synthesis of Intermediate :

[0578] Synthesis of 7-Amino-2, 3-dimethyl-5-(methylsulfonyl)pyrazolo[1, 5-a]pyrimidine-6-carbonitrile (I)

[0579]

[0580] Step 1: Synthesis of 2-(bis(methylthio)methylene)malononitrile (Ia)

[0581] A stirred solution of KOH (16.98 g, 302.75 mmol) in 100 mL of water was cooled to 0 °C, and 20 mL of dry THF containing malononitrile (10 g, 151.37 mmol) was added dropwise over 30 minutes under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour, and CS2 (17.2 g, 227.06 mmol) was added at 0 °C. After stirring the reaction mixture at room temperature for about 1 hour, dimethyl sulfate (24.8 g, 196.7 mmol) was added, and stirring was continued at room temperature for another 4 hours. After completion, the reaction mixture was quenched with ice-cold water, filtered, and the precipitated solid was dried under vacuum to give compound Ia (8 g, 31%) as a yellow solid, which did not require purification for further steps.

[0582] Step 2: Synthesis of 7-amino-2,3-dimethyl-5-(methylthio)pyrazole[1,5-a]pyrimidine-6-nitrile (Ic)

[0583] Ib (4.57 g, 41.17 mmol) was added to a stirred solution of Ia (10 g, 58.8 mmol) in ethanol (20 mL) at room temperature and under a nitrogen atmosphere. The resulting mixture was heated at 120 °C for 6 hours. The reaction mixture was then cooled to room temperature, filtered, and the precipitated solid was washed with ethanol to give an off-white solid, which was purified by silica gel column chromatography (230-400 mesh, ethyl acetate in 45% polyester ether) to give Ic (3.1 g, 32%); LC-MS calculations were performed. For C... 10 H 11 N5S: 233.29; after observation: 234.0; [M] + +H]. 1 H NMR (400MHz, DMSO-D6): δ 8.60(s, 2H), 2.68(s, 3H), 2.37(s, 3H), 2.13(s, 3H).

[0584] Step 3: Synthesis of 7-amino-2,3-dimethyl-5-(methanesulfonyl)pyrazole[1,5-a]pyrimidine-6-onitrile (I)

[0585] A stirred solution of Ic (5 g, 21.45 mmol) in dichloromethane (50 mL) was cooled to 0 °C, and m-CPBA (11.07 g, 64.37 mmol) was added under a N2 atmosphere. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was then quenched with 10% NaHCO3 solution and extracted with DCM (2 x 300 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to give compound I (3.1 g, 54%) as a creamy white solid, which required no purification for further steps. LC-MS calculations were performed. For C... 10 H 11 N5O2S: 265.29; after observation: 266.0; [M + +H]. 1 H NMR (400 MHz, DMSO-D6): δ 9.1(br s,2H), 3.42(s, 3H), 2.40(s, 3H), 2.17(s, 3H).

[0586] Synthesis of 7-Amino-3-ethyl-2-methyl-5-(methylsulfonyl)pyrazolo[1, 5-a]pyrimidine-6-carbonitrile (II)

[0587]

[0588] Step 1: 2-Ethyl-3-oxobutyronitrile (IIa)

[0589] To a three-necked RB flask, LDA (2 mL in THF, 36.17 mL, 0.0723 mol) was added, along with THF (82.5 mL), and the mixture was cooled to -78 °C. To this solution, butyronitrile (5 g, 0.0723 mol) in 10 mL of THF was added dropwise at -78 °C, and the reaction mixture was stirred at -78 °C for 1 hour. Then, ethyl acetate (6.42 mL, 0.0657 mol) was added dropwise at -78 °C, and the reaction mixture was stirred at -78 °C for 2 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C, quenched with a saturated NH4Cl solution (25 mL), and extracted with ethyl acetate (50 mL x 3). The mixture was dried over anhydrous Na2SO4, filtered, and the organic layer was evaporated under reduced pressure to give the title compound IIa as a yellow viscous oil; yield: (8 g, 100%). 1 H NMR (400 MHz, CDCl3): δ 3.237-3.205(q, 1H), 2.499(s, 3H), 1.153-1.137(d, J= 6.4Hz, 3H), 0.973-0.937(t, J= 7.2Hz, 3H).

[0590] Step 2: 4-Ethyl-5-methyl-1H-pyrazole-3-amine (IIb)

[0591] Hydrazine hydrate (23.80 mL) was added to a stirred solution of 2-ethyl-3-oxobutyronitrile 3 (8 g) in EtOH (80 mL), and the reaction mixture was heated at 120 °C for 1.5 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was dissolved in 6N HCl (25 mL) and washed with ethyl acetate (3 x 50 mL). The aqueous layer was alkalized to pH > 7 with ammonia solution and extracted with ethyl acetate (3 x 50 mL). The solution was dried over Na2SO4, filtered, and the organic layer was evaporated under reduced pressure to give the title compound IIa as a light brown viscous liquid, which did not require further purification for the next step; yield: (8.1 g, 90%). 1 H NMR (400 MHz, CD3OD): δ 2.354(q, J= 7.2Hz, 2H), 2.110(s, 3H), 1.087-1.049(t, J= 7.2Hz, 3H).

[0592] Step 3: 2-(bis(methylthio)methylene)malononitrile (Ia)

[0593] K₂CO₃ (11.4 g, 0.0833 mol) and CS₂ (5.03 g, 0.0833 mol) were added to a stirred solution of malononitrile (5.0 g, 0.075 mol) in DMSO (50 mL) cooled to 0 °C, and the mixture was stirred at room temperature for 3 h. The reaction mixture was then cooled to 0 °C and MeI (9.4 mL, 0.1514 mol) was added, and the mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water (50 mL), filtered / washed with cold water, and the precipitate was dried to give compound Ia as a brick-red solid, which required no further purification for the next step; yield: (6.2 g, 51%).

[0594] Step 4: 7-Amino-3-ethyl-2-methyl-5-(methylthio)pyrazole[1, 5-a]pyrimidine-6-onitrile (IIc)

[0595] 4-Ethyl-5-methyl-1H-pyrazole-3-amine (8.1 g, 0.0647 mol) was added to a stirred solution of 2-(bis(methylthio)methylene)malononitrile Ia (11.0 g, 0.0647 mol) in pyridine (80 mL), and the reaction mixture was heated at 120 °C for 2.5 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was evaporated, the residue was diluted with water (150 mL), and the resulting solid was stirred at 10–15 °C for 2 h. The solid was filtered and azeotropically reacted with toluene (2 x 50 mL) to give the dry title compound IIc. Yield: (12.3 g, 78%). 1 H NMR (400 MHz, CD3OD): δ 2.691-2.634(q, J= 7.6Hz, 2H), 2.583(s,3H), 2.371(s, 3H), 1.257-1.205(t, J= 8Hz, 3H).

[0596] Step 5: 7-Amino-3-ethyl-2-methyl-5-(methanesulfonyl)pyrazole[1,5-a]pyrimidine-6-onitrile(II)

[0597] m-CPBA (33.20 g, 0.19 mol) was slowly added to a stirred solution of 7-amino-3-ethyl-2-methyl-5-(methylthio)pyrazole[1,5-a]pyrimidine-6-onitrile IIc (11.2 g, 0.0481 mol) cooled to 0 °C in 120 mL of DCM, and the reaction mixture was stirred at room temperature for 30 min. The reaction progress was monitored by TLC (polar spot). After completion, the reaction mixture was quenched with NaHCO3 (150 mL) and extracted with DCM (150 mL x 3). The mixture was dried over Na2SO4, filtered, and the organic layer was evaporated under reduced pressure. The starting material was purified with ethyl acetate in 50% hexane to give the pure title compound. Yield: (9.5 g, 70%). LC-MS calculations were performed. For C 11 H 13 N5O2S: 279.10; after observation: 280.10; [M + +H]. 1 H NMR (400 MHz, CD3OD): δ 3.385(s, 3H), 2.777-2.721(q, J= 7.2Hz, 2H), 2.463(s, 3H), 1.260-1.230(t, J= 7.2Hz, 3H).

[0598] Synthesis of 7-amino-3-isopropyl-2-methyl-5-(methanesulfonyl)pyrazole[1,5-a]pyrimidine-6-onitrile(III)

[0599]

[0600] Step 1: 2-Acetyl-3-methylbutyronitrile (IIIa)

[0601] To a three-necked RB flask, LDA (2 mL in THF, 29.8 mL, 0.0595 mol) was added, along with 100 mL of THF, and the mixture was cooled to -78 °C. To this solution, 3-methylbutyronitrile (CAS: 625-28-5, 25 g, 0.0595 mol) in 40 mL of THF was added dropwise at -78 °C, and the reaction mixture was stirred at -78 °C for 1 hour. Then, ethyl acetate (CAS: 141-78-6, 5.2 mL, 0.0536 mol) was added dropwise at -78 °C, and the reaction mixture was stirred at -78 °C for 1 hour. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C, quenched with a saturated solution of NH4Cl (50 mL), and extracted with ethyl acetate (80 mL x 3). The mixture was dried over anhydrous Na2SO4, filtered, and the organic layer was evaporated under reduced pressure to give the title compound IIIa as a yellow viscous oil; yield: (6.5 g, 87%). Perform LC_MS calculation. For C7H 11 NO: 125.08; after observation: 124.10; [MH].

[0602] Step 2: 4-Isopropyl-5-methyl-1H-pyrazole-3-amine (IIIb)

[0603] Hydrazine hydrate (19.5 mL, 0.00438 mol) was added to a stirred solution of 2-acetyl-3-methylbutyronitrile IIIa (6.5 g, 0.0520 mol) in EtOH (65 mL), and the reaction mixture was heated at 120 °C for 1.5 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (80 mL x 3). The residue was dried over anhydrous Na₂SO₄, filtered, and the organic layer was evaporated under reduced pressure to give the title compound IIIb as a light brown viscous liquid. The crude product was used as is for the next step without further purification; yield: (4.5 g, 52%). 1 H NMR (400 MHz, CDCl3): δ 5.18(bs, 2H), 3.18(d, J =7.6Hz, 1H), 2.29-2.04(m,1H), 1.83(s, 3H), 1.22(d, J =10.0Hz, 1H), 1.11(d, J =6.8Hz, 3H), 1.01(d, J =6.8Hz, 3H).

[0604] Step 3: 2-(bis(methylthio)methylene)malononitrile (Ia)

[0605] K₂CO₃ (11.4 g, 0.0833 mol) and CS₂ (5.03 g, 0.0833 mol) were added to a stirred solution of malononitrile (5.0 g, 0.075 mol) in DMSO (50 mL) cooled to 0 °C, and the mixture was stirred at room temperature for 3 h. The reaction mixture was then cooled to 0 °C, and MeI (9.4 mL, 0.1514 mol) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water (50 mL), filtered, washed with cold water, and the precipitate was dried to give compound Ia as a brick-red solid, which required no further purification for the next step; yield: (6.2 g, 51%).

[0606] Step 4: 7-Amino-3-isopropyl-2-methyl-5-(methylthio)pyrazole[1, 5-a]pyrimidine-6-onitrile (IIIc)

[0607] Add 4-isopropyl-5-methyl-1H-pyrazole-3-amine IIIb (4.5 g, 0.0360 mol) to a stirred solution of 2-(bis(methylthio)methylene)malonitrile Ia (6.1 g, 0.0360 mol) in pyridine (50 mL), and heat the reaction mixture at 120 °C for 1.5 h. Monitor the reaction progress by TLC. After completion, add 200 mL of water to the reaction mixture, and collect the resulting pale yellow residue by filtration. Wash with 200 mL of fresh water and vacuum dry the solid to give the desired compound as a pale yellow solid. The starting material did not require further purification for the next step; yield: (6.0 g, 71%). Perform LC-MS calculations. For C 12 H 15 N5S: 261.10; After observation: 262.10; [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 6.20(bs, 2H), 3.09-3.06(m, 1H), 2.62(s, 3H), 2.40(s, 3H), 1.38(d, J =6.8Hz, 6H).

[0608] Step 5: 7-Amino-3-isopropyl-2-methyl-5-(methanesulfonyl)pyrazole[1,5-a]pyrimidine-6-onitrile(III)

[0609] To a stirred solution of 7-amino-3-isopropyl-2-methyl-5-(methylthio)pyrazole[1,5-a]pyrimidine-6-onitrile IIIc (6.0 g, 0.023 mol) cooled to 0 °C in 60 mL of DCM, m-CPBA (16.0 g, 0.092 mol) was added fractionally, and the reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC (polar spot). After completion, the reaction mixture was quenched with NaHCO3 (100 mL) and extracted with DCM (80 mL x 3). The mixture was dried over anhydrous Na2SO4, filtered, and the organic layer was evaporated under reduced pressure. The starting material was subjected to silica gel (100-200) column chromatography with ethyl acetate (0-30%) in n-hexane to give the desired compound III as a creamy white solid; yield: (1.5 g, 22%). LC-MS calculations were performed. For C 12 H 15 N5O2S: 293.09; after observation: 294.05; [M+H] + . 1 H NMR (400 MHz, DMSO-D6): δ 9.18(bs, 2H), 3.42(s, 3H), 3.15-3.12(m, 1H), 2.45(s, 3H), 1.34(d, J =6.8Hz, 6H).

[0610] Synthesis of 7-amino-3-isobutyl-2-methyl-5-(methanesulfonyl)pyrazole[1,5-a]pyrimidine-6-onitrile (1V)

[0611]

[0612] Step 1: 2-Acetyl-4-methylpentanilonitrile (IVa)

[0613] To a three-necked RB flask, LDA (2 mL, 2.5 mL, 0.00514 mol in THF) was added, followed by the addition of THF (10 mL), and the mixture was cooled to -78 °C. To this solution, 4-methylpentanilonitrile (CAS: 542-54-1, 0.5 g, 0.00514 mol) in THF (4 mL) was added dropwise at -78 °C, and the reaction mixture was stirred at -78 °C for 1 hour. Then, ethyl acetate (CAS: 141-78-6, 0.45 mL, 0.00468 mol) was added dropwise at -78 °C, and the reaction mixture was stirred at -78 °C for 2 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C, quenched with a saturated solution of NH4Cl (5 mL), and extracted with ethyl acetate (20 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give the title compound IVa as a yellow viscous oil; yield: (0.478 g, 66%). 1 H NMR (400 MHz, CDCl3): δ 3.46-3.42(m, 1H), 2.40(s, 3H), 1.89-1.76(m, 2H), 1.70-1.65(m, 1H), 1.0(d, J= 6.4Hz, 3H), 0.96(d, J= 6.4Hz, 3H).

[0614] Step 2: 4-Isobutyl-5-methyl-1H-pyrazole-3-amine (IVb)

[0615] Hydrazine hydrate (0.219 g, 0.00438 mol) was added to a stirred solution of 2-acetyl-4-methylpentanonitrile IVa (0.470 g, 0.00337 mol) in EtOH (20 mL), and the reaction mixture was heated at 90 °C for 15 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The residue was dried over Na₂SO₄, filtered, and the organic layer was evaporated under reduced pressure to give the raw material IVb as a light brown viscous liquid. The crude product obtained was used as is for the next step without further purification; yield: (0.478 g, 92%). 1 H NMR (400 MHz, DMSO-D6): δ 10.85(bs, 1H), 4.13(bs, 2H), 2.04(d, J= 7.2Hz, 2H), 1.98(s,3H), 1.69-1.62(m, 1H), 0.83(d, J= 6.8Hz, 6H).

[0616] Step 3: 2-(bis(methylthio)methylene)malononitrile (Ia)

[0617] K₂CO₃ (11.4 g, 0.0833 mol) and CS₂ (5.03 g, 0.0833 mol) were added to a stirred solution of malononitrile (CAS: 109-77-3, 5.0 g, 0.075 mol) in DMSO (50 mL) cooled to 0 °C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then cooled to 0 °C, and iodomethane (9.4 mL, 0.1514 mol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water (50 mL), filtered, washed with cold water, and the precipitate was dried to give compound Ia as a brick-red solid, which required no further purification for the next step; yield: (6.2 g, 51%).

[0618] Step 4: 7-Amino-3-isobutyl-2-methyl-5-(methylthio)pyrazole[1,5-a]pyrimidine-6-onitrile (IVc)

[0619] TEA (1.81 mL, 0.013 mol) and 4-isobutyl-5-methyl-1H-pyrazole-3-amine IVb (1.1 g, 0.0065 mol) were added to a stirred solution of 2-(bis(methylthio)methylene)malononitrile Ia (1.0 g, 0.0065 mol) in EtOH (10 mL), and the reaction mixture was microwave-heated at 100 °C for 1 hour. The reaction progress was monitored by TLC. After completion, the reaction mixture was evaporated, the residue was diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The residue was dried over Na₂SO₄, filtered, and the organic layer was evaporated under reduced pressure to give crude compound IVc. The crude product obtained did not require further purification for the next step; yield: (1.64 g, 92%). LC-MS calculations were performed. For C 13 H 17 N5S: 275.12; after observation: 276.20; [M + +H]. 1 H NMR (400 MHz, DMSO-D6): δ 8.51(bs, 2H), 2.53-2.50(m, 2H), 2.45(d, J= 7.2Hz, 2H), 2.37(t, J= 3.6Hz, 1H), 2.29(s, 3H), 1.95-1.88(m, 1H), 0.88-0.85(m, 6H).

[0620] Step 5: 7-Amino-3-isobutyl-2-methyl-5-(methanesulfonyl)pyrazole[1,5-a]pyrimidine-6-onitrile (IV)

[0621] m-CPBA (1.0 g, 0.0059 mol) was slowly added to a stirred solution of 7-amino-3-isobutyl-2-methyl-5-(methylthio)pyrazole[1,5-a]pyrimidine-6-nitrile IVc (0.65 g, 0.00236 mol) cooled to 0 °C in 10 mL of DCM, and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC (polar spot). After completion, the reaction mixture was quenched with NaHCO3 (50 mL) and extracted with DCM (50 mL x 3). The mixture was dried over Na2SO4, filtered, and the organic layer was evaporated under reduced pressure to give the title compound IV. The crude product was used as is for the next step without further purification; yield: (0.703 g, 97%). LC-MS calculations were performed. For C 13 H 17 N5O2S: 307.11; after observation: 308.15; [M + +H]. 1 H NMR (400 MHz, DMSO-D6): δ 9.19(bs, 2H), 3.40(s, 3H), 2.53-2.52(m, 2H), 2.41(s, 3H), 1.95-1.92(m, 1H), 0.96-0.87(m, 6H).

[0622] Synthesis of 7-amino-3-(cyclopropylmethyl)-2-methyl-5-(methanesulfonyl)pyrazole[1,5-a]pyrimidine-6-onitrile (V)

[0623]

[0624] Step 1: Methyl 2-cyclopropylethyl 4-benzenesulfonate (Va)

[0625] Add pyridine (12.6 mL) to a stirred solution of 2-cyclopropyl-1-ethanol 1 (CAS: 2566-44-1, 5.0 g, 0.0581 mol) in DCM (75 mL) cooled to 0 °C, then add... p-TsCl (8.9 g, 0.0470 mol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion, the mixture was diluted with diethyl ether (100 mL), washed successively with water (50 mL), 10% HCl (50 mL), and water (10 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated under reduced pressure to give compound Va as a colorless liquid. The crude product obtained did not require further purification for the next step; yield: (8.6 g, 66%). LC-MS calculations were performed. For C... 12 H 16 O3S: 140.32; After observation: 141.15; [M + +H]. 1 H NMR (400MHz, CDCl3): δ 7.81(d, J =8.4Hz, 2H), 7.35(d, J =8.4Hz, 2H), 4.9(t, J =6.4Hz, 2H), 2.46(s, 3H), 1.56-1.51(m, 2H), 0.67-0.65(m, 1H), 0.40-0.39(m, 2H), 0.04-0.01(m, 2H).

[0626] Step 2: 3-Cyclopropylpropionitrile (Vb)

[0627] TBAI (0.526 g) was added to a stirred solution of methyl 2-cyclopropylethyl 4-benzenesulfonate Va (8.6 g, 0.0357 mol) in DMF (32 mL), followed by sodium cyanide (5.2 g, 0.107 mol), and the reaction mixture was heated at 90 °C for 16 hours. The reaction progress was monitored by TLC. After completion, the mixture was diluted with diethyl ether (150 mL), washed with water (100 mL x 3) and brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated under reduced pressure to give the desired product Vb as a light brown viscous liquid. The crude product obtained required no further purification for the next step; yield: (3.3 g, 97%). 1 H NMR (400MHz, CDCl3): δ 3.74-3.72 (m, 1H), 2.42 (t, J =6.8Hz, 2H), 1.59-1.51(m, 2H), 0.86-0.81(m, 1H), 0.56-0.53(m, 2H), 0.16-0.13(m, 2H).

[0628] Step 3: 2-(cyclopropylmethyl)-3-oxobutyronitrile (Vc)

[0629] Under a nitrogen atmosphere, LDA (2 mL, 15.35 mL, 0.0315 mol) and THF (60 mL) were added to a three-necked RB flask. The resulting mixture was cooled to -78 °C, and a solution of 3-cyclopropylpropionitrile Vb (3.0 g, 0.0315 mol) in THF (24 mL) was added dropwise, maintaining the temperature at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour, and ethyl acetate (CAS: 141-78-6, 2.52 g, 0.0287 mol) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 2 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C, quenched with a saturated solution of NH4Cl (50 mL), and extracted with ethyl acetate (50 mL x 3). The organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give the title compound Vc as a pale yellow viscous oil; yield: (3.25 g, 76%). 1 H NMR (400 MHz, CDCl3): δ 3.50-3.47(m, 1H), 2.41(s, 3H), 1.92-1.82(m, 1H), 1.80-1.75(m, 1H), 0.9-0.86(m, 1H), 0.61-0.55(m, 2H), 0.25-0.23(m, 1H), 0.18-0.14(m, 1H).

[0630] Step 4: 4-(cyclopropylmethyl)-5-methyl-1H-pyrazole-3-amine (Vd)

[0631] Hydrazine hydrate (2.19 mL, 0.0349 g) was added to a stirred solution of 2-(cyclopropylmethyl)-3-oxobutyronitrile Vc (3.2 g, 0.0233 mol) in EtOH (50 mL), and the reaction mixture was heated at 90 °C for 16 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was diluted with NaHCO3 solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give the title compound Vd. The crude product was used for the next step without further purification; yield: (3.2 g, 91%). LC-MS calculations were performed. For C8H... 13 N3: 151.11; after observation: 152.20; [M] + +H]. 1 H NMR (400 MHz, CDCl3): δ3.80-3.60 (bs, 2H), 2.30 (d, J =5.6Hz 3H), 1.70-1.50(bs, 1H), 0.90-0.83(m, 1H), 0.48-0.44(m, 2H), 0.14-0.10(m, 2H).

[0632] Step 5: 2-(bis(methylthio)methylene)malononitrile (Ia)

[0633] K₂CO₃ (11.4 g, 0.0833 mol) and CS₂ (5.03 g, 0.0833 mol) were added to a stirred solution of malononitrile (CAS: 109-77-3, 5.0 g, 0.075 mol) in DMSO (50 mL) cooled to 0 °C, and the mixture was stirred at room temperature for 3 h. The reaction mixture was then cooled to 0 °C, and iodomethane (9.4 mL, 0.1514 mol) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water (50 mL), filtered, washed with cold water, and the precipitate was dried to give compound Ia as a brick-red solid, which required no further purification for the next step; yield: (6.2 g, 51%).

[0634] Step 6: 7-Amino-3-(cyclopropylmethyl)-2-methyl-5-(methylthio)pyrazole[1,5-a]pyrimidine-6-onitrile (Ve)

[0635] 4-(cyclopropylmethyl)-5-methyl-1H-pyrazole-3-amine Vd (3.0 g, 0.0198 mol) was added to a stirred solution of 2-(bis(methylthio)methylene)malononitrile Ia (3.3 g, 0.0198 mol) in pyridine (40 mL), and the reaction mixture was heated at 120 °C for 16 h under N2 atmosphere. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and poured into ice-cold water (50 mL). The mixture was filtered, dried, washed with a cold mixture of ethyl acetate (10%) and n-hexane (90%), and the precipitate was dried under vacuum to give the desired compound as a pale yellow solid; yield: (4.3 g, 80%). LC-MS calculations were performed. For C... 13 H 15 N5S: 273.10; after observation: 274.10; [M + +H]. 1 H NMR (400 MHz, CDCl3): δ6.26(bs,2H), 2.61-2.57(m, 5H), 2.41(s, 3H), 1.00-0.90(bs, 1H), 0.45-0.43(m, 2H), 0.24-0.22(m, 2H).

[0636] Step 7: 7-Amino-3-(cyclopropylmethyl)-2-methyl-5-(methanesulfonyl)pyrazole[1,5-a]pyrimidine-6-onitrile (V)

[0637] m-CPBA (5.8 g, 0.0337 mol) was slowly added to a stirred solution of 7-amino-3-(cyclopropylmethyl)-2-methyl-5-(methylthio)pyrazole[1,5-a]pyrimidine-6-nitrile Ve (2.3 g, 0.00842 mol) cooled to 0 °C in DCM (50 mL), and the reaction mixture was stirred at room temperature for 30 min. The reaction progress was monitored by TLC. After completion, the reaction was quenched with NaHCO3 (30 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with saturated NaHCO3 (30 mL x 2) and then with brine. The organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give compound V as a pale yellow solid; yield: (2.1 g, 81%). LC-MS calculations were performed. For C 13 H 15 N5O2S: 305.09; After observation: 306.10; [M + +H]. 1 H NMR (400 MHz, CDCl3): δ 7.00-6.60(bs, 2H), 3.39(s, 3H), 2.64(d, J =6.8Hz,2H), 2.50(s, 3H), 0.99-0.97(bs, 1H), 0.49-0.46(m, 2H), 0.24-0.22(m, 2H).

[0638] Synthesis of (6-methylpyridin-2-yl)hexamethylenetetramine (VI)

[0639]

[0640] Step 1: 6-Methylpyridinaldehyde (VIa)

[0641] At -78°C, n-BuLi (2.5 mL, 11.62 mL, 0.0290 mol in THF solution) was added dropwise to a solution of 2-bromo-6-methylpyridine (CAS: 5315-25-3, 5 g, 0.0290 mol) in toluene (50 mL). The reaction mixture was stirred at -78°C for 1 hour. DMF (2.69 mL, 0.0348 mol) was added dropwise to the solution at -78°C. The reaction mixture was stirred at -50°C for 1 hour, then at 5–10°C for 30 minutes, and finally at room temperature for 40 minutes. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0°C, quenched with a saturated solution of NH4Cl (50 mL), and extracted with ethyl acetate (2 x 75 mL). The mixture was washed with a brine solution (50 mL), dried over Na2SO4, filtered, and the organic layer was evaporated under reduced pressure to obtain the raw material, which was purified by column chromatography using a 60–120 silica gel column. The product was eluted with ethyl acetate in 5% hexane to give compound VIa as a pale yellow liquid. Yield: (1.4 g, 40%). LC-MS calculations were performed. For C7H7NO: 121.15; after observation: 122.15; [M + +1]. 1 HNMR (400 MHz, CDCl3): δ10.054(s, 1H), 7.745-7.799(m, 2H), 7.386-7.404(d, J= 6.8 Hz, 1H), 2.672 s, 3H.

[0642] Step 2: (6-Methylpyridin-2-yl)hexamethylenetetramine (VI)

[0643] Ammonium acetate (8.9 g, 0.115 mol) was added to a stirred solution of 6-methylpyridinaldehyde VIa (1.4 g, 0.0115 mol) in methanol (25 mL), and the reaction mixture was stirred at room temperature for 30 min. Sodium cyanoborohydride (0.58 g, 0.0092 mol) was then added fractionally, and stirring continued at room temperature for 10 h. The reaction progress was monitored by TLC. After completion, the solvent in the reactants was removed under reduced pressure. The residue was absorbed with water (50 mL) and alkalized with hydrated potassium hydroxide. The product was extracted with MeOH in 5% DCM (3 x 100 mL). The product was dried over Na₂SO₄, filtered, and the combined organic layers were concentrated under reduced pressure to give the title compound VI as a brown liquid. Yield: 1.2 g (85%). LC-MS calculations were performed. For C7H 10 N2: 122.08; After observation: 123.08; [M + +1]. 1 HNMR (400 MHz, CDCl3): δ7.516-7.554(t,J =7.6Hz, 1H), 7.091-7.072(d, J =7.6Hz, 1H), 7.025-7.006(d, J =7.6Hz, 1H), 3.935(s, 2H), 2.546(s, 3H).

[0644] Synthesis of (6-ethylpyridin-2-yl)hexamethylenetetramine (VII)

[0645]

[0646] Step 1: 6-((trimethylsilyl)ethynyl)pyridinecarboxylonite (VIIa)

[0647] A stirred solution of 6-bromopyridinecarboxynitrile (CAS: 122918-25-6, 1.5 g, 0.008 mol) was added to TEA (0.060 mol) and purified under nitrogen. Trimethylsilylacetylene (1.37 mL, 0.009 mol) was then added, followed by cuprous iodide (0.036 g, 0.0003 mol), and purification continued for at least 10 minutes. Subsequently, Pd(PPh3)2Cl2 (0.089 g, 0.0001 mol) was added. The reaction mixture was then stirred at room temperature for 30 minutes. The reaction progress was monitored by TLC. After completion, the reaction mixture was filtered through a diatomaceous earth bed and concentrated to give the desired crude product VIIa. Yield: (1.2 g, 75%). LC-MS calculations were performed. For C 11 H 12 N2Si: 200.08; after observation: 201.15; [M + +1]. 1 H NMR (400 MHz, CDCl3): δ 7.824-7.784(t, J= 8.4Hz, 1H), 7.652-7.617(t, J= 7.2 Hz (2H), 0.287 s (9H).

[0648] Step 2: 6-Ethynylpyridinecarboxynitrile (VIIb)

[0649] K₂CO₃ (0.829 g, 0.005 mol) was added to a stirred solution of 6-((trimethylsilyl)ethynyl)pyridinecarboxylonitrile VIIa (1.5 g, 0.005 mol) in MeOH (15 mL) cooled to 0 °C, and the reaction mixture was stirred at 0 °C for 30 min. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with water (20 mL) and extracted with DCM (3 x 50 mL). The mixture was dried over Na₂SO₄, filtered, and the organic layer was evaporated under reduced pressure. The starting material was eluted with ethyl acetate in 20% hexane and purified by column chromatography to give the title compound VIIb as a pale yellow solid; yield: (0.260 g, 34%). LC-MS calculations were performed. For C₈H₄N₂: 128.04; after observation: unionized. 1 H NMR (400 MHz, CDCl3): δ 7.857-7.818(d, J= 7.6Hz, 1H), 7.684-7.7.664 (d, J= 8Hz, 2H), 3.289s, H.

[0650] Step 3: (6-Ethylpyridin-2-yl)hexamethylenetetramine (VII)

[0651] Pd / C (0.100 g) was added to a stirred solution of 6-ethynylpyridinium carbide VIIb (0.260 g, 0.00203 mol) purified with N2 for 10 min in MeOH (3 mL), and the reaction mixture was stirred at room temperature under H2 atmosphere for 24 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated. The starting material was eluted with 20% ethyl acetate in hexane and purified by column chromatography to give the title compound VII as a pale yellow liquid; yield: (0.100 g, 36%). LC-MS calculations were performed. For C8H... 12 N2: 136.10; After observation: 137; [M + +1]. 1 H NMR (400MHz, CDCl3): δ 7.583-7.544(d, J= 7.6Hz, 1H), 7.094-7.075 (d, J= 7.6Hz, 1H), 7.040-7.021 (d, J= 7.6Hz, 1H), 3.959(s, 2H), 2.840-2.784(q, J= 7.6Hz, 2H), 1.322-1.255(t, J= 8Hz, 3H).

[0652] Synthesis of N-methyl-1-(6-methylpyridin-2-yl)hexamethylenetetramine (VIII)

[0653]

[0654] Step 1: (E)-N-methyl-1-(6-methylpyridin-2-yl)hexamethylenetetramine (VIIIa)

[0655] Methylamine (2 mL, 30% in methanol solution) was added to a stirred solution of 6-methylpyridinaldehyde VIa (0.1 g, 0.000825 mol) in methanol (5 mL) within a molecular sieve, and the resulting reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was filtered through a diatomaceous earth bed and evaporated under reduced pressure to give crude product VIIIa. The obtained crude compound was used directly in the next step. Yield: (0.12 g, 100%).

[0656] Step 2: N-Methyl-1-(6-methylpyridin-2-yl)hexamethylenetetramine (VIII)

[0657] Sodium borohydride (0.051 g, 0.00134 mol) was added to a stirred solution of (E)-N-methyl-1-(6-methylpyridin-2-yl)hexamethylenetetramine VIIIa (0.120 g, 0.00089 mol) in methanol (5 mL) at 0 °C. The temperature was then brought to room temperature, and the reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was evaporated under reduced pressure, diluted with 10 mL of water, and extracted with methanol in 10% DCM (20 mL x 3). The mixture was dried over Na2SO4, filtered, and the organic layer was evaporated under reduced pressure. Product VIII was obtained by eluting the crude product purified by manual column chromatography with methanol in 10% DCM. Yield: (0.123 g, 101%). LC-MS calculations were performed. For C8H 12 N2: 136.0; after observation: 137; [M + +H]. 1 H NMR (400 MHz, CDCl3): δ 7.647-7.608(t, J= 8Hz, 1H), 7.324-7.305 (d, J= 7.6Hz, 1H), 7.149-7.130 (d, J= 7.6Hz, 1H), 4.229(s, 2H), 2.730(s, 3H), 2.559(s, 3H).

[0658] Synthesis of 1-(6-methylpyridin-2-yl)propyl-2-amine (IX)

[0659]

[0660] Step 1: 1-(6-methylpyridin-2-yl)prop-2-one (IXa)

[0661] To a stirred solution of 2,6-dimethylpyridine (CAS: 108-48-5, 5.0 g, 0.046 mol) in THF (65 mL) at -78 °C, n-butyllithium (20.5 mL, 0.0512 mol) was added dropwise and stirred for 1 h. Then, N,N-dimethylacetamide (4.1 mL, 0.0443 mol) was slowly added at -78 °C and stirred at room temperature for 16 h. After completion (TLC), the reaction mixture was cooled to room temperature, quenched with 1.2 M HCl solution (25 mL), and stirred at room temperature for 30 min. The reaction mixture was then extracted with ethyl acetate (200 mL x 3). The mixture was dried over Na2SO4, filtered, and the organic layer was evaporated under reduced pressure. The starting material was eluted with ethyl acetate in 5% hexane and purified by rapid column chromatography to give the title compound IXa as a yellow liquid; yield: (0.713 g, 10.2%). 1 H NMR (400 MHz, CDCl3): δ 7.54(t, J= 7.6Hz, 1H), 7.05 (d, J= 7.6Hz, 1H), 7.00 (d, J= 8.0Hz, 1H), 3.89(s, 2H), 2.54(s, 3H), 2.22(s, 3H).

[0662] Step 2: 1-(6-methylpyridin-2-yl)propyl-2-amine (IX)

[0663] Ammonium acetate (3.7 g, 0.04753 mol) was added to a stirred solution of 1-(6-methylpyridin-2-yl)prop-2-one IXa (0.713 g, 0.00475 mol) in MeOH (20 mL), and the mixture was stirred at room temperature for 30 min. Then, NaCNBH3 (0.21 g, 0.003327 mol) was added sequentially, and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was then monitored by TLC. After completion, the reaction mixture was concentrated and diluted with a saturated solution of NaHCO3 (50 mL), and extracted with diethyl ether (50 mL x 3). The mixture was dried over Na2SO4, filtered, and the organic layer was evaporated under reduced pressure to give the desired product IX as a light green liquid. The crude product obtained did not require further purification for the next step; yield: (0.43 g, 60%).1 H NMR (400 MHz, DMSO-d6): δ 7.56(t, J= 7.6Hz, 1H), 7.04 (d, J= 7.6Hz, 1H), 7.00 (d, J= 7.6Hz, 1H), 3.21-3.18(m, 1H), 2.64(dd, J = 6.8Hz, 2.4Hz, 2H), 2.42(s, 3H), 0.98(dd, J= 6.4Hz, 2.4Hz, 3H).

[0664] Synthesis of 2-(6-(aminomethyl)pyridin-2-yl)prop-2-ol (X)

[0665]

[0666] Step 1: Pyridine-2,6-dicarboxylic acid (Xa)

[0667] 29.49 g of potassium permanganate (0.34 mol) was slowly added to a solution of 2,6-dimethylpyridine (CAS: 108-48-5, 10 g, 0.17 mol) in 250 mL of water, and the mixture was stirred. The mixture was refluxed until the purple color disappeared. The mixture was then cooled to room temperature, and another portion of potassium permanganate (29.49 g, 0.34 mol) and water (150 mL) were slowly added. The mixture was then refluxed at 100 °C for 16 hours until the purple color disappeared. The mixture was cooled to room temperature. The solvent was removed by filtration until the volume of the residue was reduced to 100 mL, and then sulfuric acid (70%, 17.5 mL) was slowly added. The precipitate was filtered to give pyridine-2,6-dicarboxylic acid Xa. Yield: (8.5 g, 55%). LC-MS calculations were performed. For C7H5NO4: 167.02; after observation: 168.02; [M + +1].

[0668] Step 2: Dimethylpyridine-2,6-dicarboxylic acid ester (Xb)

[0669] Concentrated sulfuric acid (4 mL) was added dropwise to a stirred solution of pyridine-2,6-dicarboxylic acid Xa (8.5 g, 0.00598 mol) in methanol (1 L). The reaction mixture was refluxed at 60 °C for 16 hours. After the reaction was complete, the solvent was removed by vacuum evaporation, water was added, the solid was filtered and dried to give the title compound Xb. Yield: (5 g, 51%). LC-MS calculations were performed. For C9H9NO4: 195.05; after observation: 196.15; [M ++1]. 1 H NMR (400 MHz, CDCl3): δ 8.338-8.314(m, 2H), 8.055-8.013(m, 1H), 4.036(s, 6H).

[0670] Step 3: Methyl 6-(hydroxymethyl)pyridinecarboxylate (Xc)

[0671] A solution of 2,6-dimethylpyridine-2,6-dicarboxylic acid ester Xb (5 g, 0.00487 mol) in a solvent mixture of methanol (174 mL) and dichloromethane (74 mL) was placed in a 500 mL round-bottom flask. NaBH4 (1.45 g, 0.00502 mol) was added fractionally to the reaction mixture at 0 °C. The resulting solution was stirred overnight at room temperature and then quenched by adding hydrated ammonium chloride (250 mL). The solution was extracted with dichloromethane (2 x 200 mL), dried over Na2SO4, filtered, and the combined organic layers were concentrated under vacuum. The residue was eluented with ethyl acetate / petroleum ether (1:1) onto a silica gel column to give methyl 6-(hydroxymethyl)pyridine-2-carboxylic acid ester Xc as a white solid. Yield: (3.9 g, 93%). LC-MS calculations were performed. For C8H9NO3: 167.16; after observation: 168.20; [M + +1]. 1 H NMR (400 MHz, CDCl3): δ 8.048-8.029(d, J=7.6Hz, 1H), 7.875-7.837(t, J=7.6Hz, 1H), 7.541-7.522(d, J=7.6Hz, 1H), 4.863(s,2H), 4.002(s, 3H).

[0672] Step 4: 2-(6-(hydroxymethyl)pyridin-2-yl)prop-2-ol (Xd)

[0673] Methylmagnesium bromide (3.4 mL, 0.0358 mol, 10.5 mL) was added dropwise to a stirred solution of methyl 6-(hydroxymethyl)pyridinecarboxylate Xc (3 g, 0.0179 mol) in diethyl ether (300 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 3 hours. After completion, the reaction mixture was quenched with NH4Cl and extracted with ethyl acetate (3 x 200 mL). The mixture was dried over Na2SO4, filtered, and the organic layer was evaporated under reduced pressure. The starting material was eluted with ethyl acetate in 30% hexane and purified by column chromatography to give the title compound as a pale yellow oil; yield: (2.2 g, 73%). LC-MS calculations were performed. For C8H9NO3: 167.16; after observation: 168.20; [M + +1].1 H NMR (400 MHz, CDCl3): δ 7.735-7.696(t, J= 8Hz, 1H), 7.333-7.313 (d, J= 8Hz, 1H), 7.201-7.182 (d, J= 7.6Hz, 1H), 4.783(s, 2H), 4.412(s, 1H), 3.190(s, 1H), 1.566(s, 6H).

[0674] Step 5: 2-(6-(azidomethyl)pyridin-2-yl)prop-2-ol (Xe)

[0675] DPPA (0.0832 mol) was added to a stirred solution of 2-(6-(hydroxymethyl)pyridin-2-yl)prop-2-ol Xd (0.4 g, 0.0832 mol) in THF (5 mL) at room temperature. The mixture was cooled to 0 °C, and DBU (0.0832 mol) was added at a rate not exceeding 20 °C internally. The reaction mixture was then heated to 40 °C and stirred for 16 hours. After completion, the reaction mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 x 20 mL). The mixture was dried over Na₂SO₄, filtered, and the organic layer was evaporated under reduced pressure. The starting material was eluted with ethyl acetate in 10% hexane and purified by column chromatography to give the title compound Xe as a brown liquid; yield: (0.26 g, 57%). LC-MS calculations were performed. For C9H 12 N4O: 192.10; after observation: 193.10; [M + +1]. 1 H NMR (400 MHz, CDCl3): δ 7.743-7.724(t, J= 7.6Hz, 1H), 7.337-7.317 (d, J= 8Hz, 1H), 7.245-7.226 (d, J= 7.6Hz, 1H), 4.905(s, 1H), 4.465(s, 2H), 1.550(s, 6H).

[0676] Step 6: 2-(6-(aminomethyl)pyridin-2-yl)prop-2-ol (X)

[0677] Pd / C (100 mg) was added to a stirred solution of 2-(6-(azidomethyl)pyridin-2-yl)prop-2-ol Xe (0.26 g) in methanol (10 mL) at room temperature. The reaction mixture was stirred under hydrogen atmosphere at the same temperature for 1 hour. After completion, the reaction mixture was filtered through a diatomaceous earth bed, and the bed was washed with methanol. The filtrate was concentrated under reduced pressure to give the title compound X as a brown liquid; yield: (0.3 g, crude product). The crude product obtained did not require further purification for the next step.

[0678] Synthesis of 2-(5-methylpyridin-2-yl)ethyl-1-amine (XI)

[0679]

[0680] Step 1: 2-(5-methylpyridin-2-yl)acetonitrile (XIa)

[0681] ACN (1.75 mL, 0.0388 mol) was added to a stirred solution of n-butyllithium (14 mL, 0.034 mol) in THF (75 mL) at -78 °C and stirred for 1 hour. Then, 2-bromo-5-methylpyridine (CAS: 3510-66-5, 1.67 g, 0.0097 mol) was slowly added and stirred at room temperature for 2 hours. After completion (TLC), the reaction mixture was diluted with ice-cold water (50 mL) and extracted with ethyl acetate (50 mL x 3). The mixture was dried over Na₂SO₄, filtered, and the organic layer was evaporated under reduced pressure to give the desired product XIA. Yield: (0.6 g, crude product). The crude product was used for the next step without further purification.

[0682] Step 2: 2-(5-methylpyridin-2-yl)ethyl-1-amine (XI)

[0683] BH3-Me2S (10 mL, 0.0020 mol) was added to a stirred solution of 2-(5-methylpyridin-2-yl)acetonitrile XIa (0.6 g, 0.0045 mol) in THF (100 mL) at room temperature and stirred at 70 °C for 2 h. After completion (TLC), the reaction mixture was cooled to room temperature, and then MeOH (5 mL) and 10 mL of 1N HCl were added. The aqueous layer was washed with ethyl acetate to separate the aqueous layer, alkalized with 1N NaOH, and extracted with DCM (100 mL x 3). The mixture was dried over Na2SO4, filtered, and the organic layer was evaporated under reduced pressure to give the title compound XI. The crude product did not require purification for the next step; yield: (0.2 g, 32%). LC-MS calculations were performed. For C8H 12 N2: 136.10; after observation: 137.2; [M + +H]. 1H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 7.42 (d, J= 7.6Hz, 1H), 7.06 (d, J= 8.0Hz, 1H), 3.12(t, J= 6.4Hz, 2H), 2.91(d, J= 6.4 Hz (2H), 2.3 s (3H).

[0684] Synthesis of 2-(5-fluoropyridin-2-yl)ethyl-1-amine (XII)

[0685]

[0686] Step 1: 5-Fluoropyridaldehyde (XIIa)

[0687] To a stirred solution of 2-bromo-5-fluoropyridine (CAS: 41404-58-4, 2.69 g, 0.0147 mol) in toluene (30 mL) at -78 °C, n-butyllithium (5.9 mL, 0.0147 mol) was added dropwise and stirred for 1 hour. Then, DMF (1.36 mL) was slowly added at -50 °C and stirred for 30 minutes. After completion (TLC), the reaction mixture was quenched with MeOH (30 mL) and stirred at 5–10 °C for 30 minutes. Then, NH4Cl solution (75 mL) was added and stirred at room temperature for 40 minutes, followed by extraction with ethyl acetate (100 mL x 3). The mixture was dried over Na2SO4, filtered, and the organic layer was evaporated under reduced pressure. The starting material was eluted with ethyl acetate in 5% hexane and purified by rapid column chromatography to give the title compound XIIa as a yellow liquid; yield: (1.01 g, 54.89%). LC-MS calculations were performed. For C6H4FNO: 125.03; after observation: 126.00; [M + +H]. 1 H NMR (400 MHz, CDCl3): δ 10.04 (s, 1H), 8.63 (d, J= 2.0Hz, 1H), 8.05-8.02(m, 1H), 7.58(dt, J= 8.4Hz, 2.8Hz, 1H).

[0688] Step-2: (E)-5-fluoro-2-(2-nitrovinyl)pyridine (XIIb)

[0689] TEA (2.24 mL, 0.0161 mol) and nitromethane (0.52 mL, 0.00968 mol) were added to a stirred solution of 5-fluoropyridinaldehyde XIIa (1.01 g, 0.00807 mol) in DCM (20 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was evaporated under reduced pressure. The starting material was dissolved in DCM (20 mL) and treated at 0 °C with TEA (1.77 mL, 0.0242 mol) and MsCl (2.75 mL, 0.0242 mol), and the reaction mixture was stirred at room temperature for 20 minutes. The reaction progress was monitored by TLC. After completion, the reaction mixture was evaporated under reduced pressure. The starting material was eluted with ethyl acetate in 10% hexane and purified by column chromatography to give the title compound XIIb as a green solid; yield: (1.2 g, 88.8%). LC-MS calculations were performed. For C7H5FN2O2: 168.03; after observation: 169.00; [M + +H]. 1 H NMR (400 MHz, CDCl3): δ 8.54 (s, 1H), 7.93 (q, J= 12.8Hz, 2H), 7.50-7.49(m, 2H).

[0690] Step 3: 2-(5-Fluoropyridin-2-yl)ethyl-1-amine (XII)

[0691] LAH (1 mL, 21.4 mL, 0.024 mol) was added dropwise to a stirred solution of (E)-5-fluoro-2-(2-nitrovinyl)pyridine XIIb (1.2 g, 0.0071 mol) in THF (50 mL) at -20 °C. The temperature was then brought to room temperature, and the reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C, quenched with a saturated solution of Na₂SO₄ (50 mL), and extracted with ethyl acetate (50 mL x 3). The mixture was dried over Na₂SO₄, filtered, and the organic layer was evaporated under reduced pressure. The starting material was eluted with methanol NH₃ in 10% DCM and purified by column chromatography to give the title compound as a light green liquid; yield: (0.35 g, 35%). LC-MS calculations were performed. For C₇H₉FN₂: 140.07; after observation: 141.2; [M + +H]. 1 H NMR (400 MHz, DMSO-d6): δ 8.45(d, J= 3.2Hz, 1H), 7.62 (dd, J=8.4Hz, 2.8Hz,1H), 7.34-7.31(m, 1H), 2.88(t, J= 6.4Hz, 2H), 2.81(d, J= 6.4 Hz (2H), 2.5 Hz (bs, 2H).

[0692] Synthesis of 2-(6-methoxypyridin-2-yl)ethyl-1-amine (XIII)

[0693]

[0694] Step-1: (E)-6-methoxy-2-(2-nitrovinyl)pyridine (XIIIa)

[0695] TEA (2.19 g, 0.0217 mol) and nitromethane (1.32 g, 0.0216 mol) were added to a stirred solution of 6-methoxypyridinaldehyde (CAS: 54221-96-4, 1.0 g, 0.00724 mol) in DCM (20 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was evaporated under reduced pressure. The starting material was dissolved in DCM (20 mL) and treated at 0 °C with TEA (2.19 g, 0.0217 mol) and methanesulfonyl chloride (2.47 g, 0.0217 mol), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction progress was monitored by TLC. After completion, the reaction mixture was evaporated under reduced pressure. The starting material was eluted with ethyl acetate in 7% hexane and purified by column chromatography to give the title compound XIIa as a yellow solid; yield: (0.8 g, 80%). 1 H NMR (400 MHz, CDCl3): δ 8.016-7.983(d, J= 13.2Hz, 1H), 7.845-7.812 (d, J= 13.2Hz, 1H), 7.652-7.614(t, J= 8Hz, 1H), 7.069-7.052 (d, J= 6.8Hz, 1H), 6.863-6.843 (d, J= 8Hz, 1H), 3.969s, 3H.

[0696] Step 2: 2-(6-methoxypyridin-2-yl)ethyl-1-amine (XIII)

[0697] LAH (1 mL, 13.3 mL, 0.0133 mol in THF solution) was added dropwise to a stirred solution of (E)-6-methoxy-2-(2-nitrovinyl)pyridine 2 (0.8 g, 0.0044 mol) in DEE (16 mL) at -10 °C. The temperature was then brought to room temperature, and the reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C and quenched with chilled water (10 mL), sodium hydroxide hydrated in 15 N (1 mL), and extracted with methanol in 10% DCM (20 mL x 3). The mixture was dried over Na2SO4, filtered, and the organic layer was evaporated under reduced pressure to give crude product XIII as a brown liquid. The crude product did not require purification for the next step; yield: (0.43 g, 63%). LC-MS calculations were performed. For C8H 12 N2O: 152; After observation: 153; [M] + +H]. 1 H NMR (400 MHz, CDCl3): δ 7.477(d, 1H), 6.733-6.726(d, J=2.8Hz, 1H), 6.570-6.560(m, 2H), 3.918(s, 3H), 3.108(t, 2H), 2.820(t, 2H).

[0698] Synthesis of 2-(6-methylpyridin-2-yl)ethyl-1-amine (XIV)

[0699]

[0700] Step-1: (E)-6-methoxy-2-(2-nitrovinyl)pyridine (XVa)

[0701] TEA (13.36 g, 0.132 mol) and nitromethane (5.15 g, 0.079 mol) were added to a stirred solution of 6-methylpyridinaldehyde VIa (8.0 g, 0.0660 mol) in DCM (80 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was evaporated under reduced pressure. The starting material was dissolved in DCM (80 mL), treated at 0 °C with TEA (20.03 g, 0.198 mol) and methanesulfonyl chloride (22.58 g, 0.198 mol), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction progress was monitored by TLC. After completion, the reaction mixture was evaporated under reduced pressure. The starting material was then eluted with ethyl acetate in 7-10% hexane and purified by column chromatography to give the title compound XVa as a brown liquid; yield: (9 g, 83.33%). 1H NMR (400 MHz, CDCl3): δ 8.076-8.042(d, J= 13.6Hz, 1H), 7.942-7.910 (d, J= 12.8Hz, 1H), 7.722-7.605(t, J= 7.2Hz, 1H), 7.331-7.314 (d, J= 6.8Hz, 1H), 7.278-7.266 (d, J= 4.8 Hz (1H), 2.263 s (3H).

[0702] Step 3: 2-(6-methylpyridin-2-yl)ethyl-1-amine (XIV)

[0703] LAH (1 mL, 224 mL, 0.22 mol in THF solution) was added dropwise to a stirred solution of (E)-6-methoxy-2-(2-nitrovinyl)pyridine 2 (9.18 g, 0.0559 mol) in DEE (700 mL) at 0 °C. The temperature was then raised to 40 °C and maintained for 2 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C and quenched with chilled water (50 mL), hydrated with sodium hydroxide in 15 N, and filtered through a diatomaceous earth bed. The diatomaceous earth bed was washed with DEE (250 mL). DEE in the filtrate was distilled off under reduced pressure to give the title compound XIV as a brown liquid, which did not require further purification for the next step. Yield: (5.09 g, 67%). LC-MS calculations were performed. For C8H 12 N2: 136; after observation: 137; [M] + +H]. 1 H NMR (400 MHz, CDCl3): δ 7.577-7.539(t, J= 8Hz, 1H), 7.050-7.012(m, 2H), 2.867-2.807(t, J= 6.8Hz, 2H), 2.771-2.750(t, J= 8.4 Hz (2H), 2.420 s (3H).

[0704] Synthesis of 2-(6-(2-aminoethyl)pyridin-2-yl)prop-2-ol (XV)

[0705]

[0706] Step 1: 6-(2-hydroxypropane-2-yl)pyridinaldehyde (XVa)

[0707] DMP (6.85 g, 0.0161 mol) was added fractionally to a stirred solution of 2-(6-(hydroxymethyl)pyridin-2-yl)prop-2-ol Xd (1.8 g, 0.0107 mol) in DCM (50 mL) at 0 °C. The reaction mixture was stirred at the same temperature for 30 min. The reaction was monitored by TLC. After completion, the reaction mixture was quenched with hydrated sodium bicarbonate (50 mL) and extracted with DCM (100 mL x 3). The mixture was dried over sodium sulfate, filtered, and the organic layer was concentrated under reduced pressure. The crude compound was purified by column chromatography, eluting the product with 10% ethyl acetate / hexane to give the title compound XVa as a pale yellow oil. Yield: (1.1 g, 62%). 1 H NMR (400MHz, CDCl3): δ 10.094(s, 1H), 7.929-7.870(m, 2H), 7.659-7.641(d, J=7.2Hz, 1H), 4.606(bs, 1H), 1.607(s, 6H).

[0708] Step-2: (E)-2-(6-(2-nitrovinyl)pyridin-2-yl)prop-2-ol (XVb)

[0709] TEA (0.613 g, 0.00606 mol) and nitromethane (0.1 g, 0.0016 mol) were added to a stirred solution of 6-(2-hydroxypropane-2-yl)pyridinaldehyde XVa (0.5 g, 0.00303 mol) in DCM (5 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was evaporated under reduced pressure. The starting material was dissolved in DCM (20 mL) and treated at 0 °C with TEA (0.67 g, 0.00663 mol) and methanesulfonyl chloride (0.756 g, 0.00663 mol), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction progress was monitored by TLC. After completion, the reaction mixture was evaporated under reduced pressure. The starting material was eluted with ethyl acetate in 7% hexane and purified by column chromatography to give the title compound XVb as a yellow solid; yield: (0.35 g, 76%). LC-MS calculations were performed. For C 10 H 12 N2O3: 208.08; after observation: 209.20; [M + +H]. 1 H NMR (400MHz, CDCl3): δ8.036-8.003(d, J=13.2Hz, 1H), 7.951-7.918(d, J=13.2Hz, 1H), 7.841-7.801(t, J=8Hz, 1H), 7.531-7.510(d, J=8.4Hz, 1H), 7.406-7.388(d, J=7.2Hz, 1H), 1.577(s, 6H).

[0710] Step 3: 2-(6-(2-aminoethyl)pyridin-2-yl)prop-2-ol (XV)

[0711] LAH (0.401 g, 0.0106 mol in THF solution, 1 mL) was added dropwise to a stirred solution of (E)-1-methyl-3-(2-nitrovinyl)-1H-pyrazole 3 (0.55 g, 0.00264 mol) in diethyl ether (26 mL) at 0 °C. The temperature was then lowered to room temperature, and the reaction mixture was stirred at 40 °C for 3 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C and quenched with chilled water (3 mL) and sodium hydroxide hydrated in 15 N (2 mL). The mixture was filtered and the inorganic salts were washed with DEE (25 mL). The solvent in the filtrate was concentrated under reduced pressure to give crude compound XV, which did not require further purification for the next step. Yield: (0.3 g, 63%). 1 H NMR (400 MHz, DMSO-d6): δ 7.666-7.628(t, J=7.2Hz, 1H), 7.450-7.432(d, J=7.2Hz, 1H), 7.069-7.050(d, J=7.6Hz, 1H), 2.886-2.870(t, J=6.4Hz, 2H), 2.784-2.766(t, J=7.2Hz, 2H), 1.414(s, 6H).

[0712] Synthesis of 2-(1-ethyl-1H-pyrazol-3-yl)ethyl-1-amine (XVI)

[0713]

[0714] Step 1: 1-Ethyl-1H-pyrazole-3-carboxaldehyde (XVIa)

[0715] Potassium carbonate (10 g, 0.0723 mol) and iodoethane (5.8 g, 0.0374 mol) were added to a stirred solution of 1H-pyrazole-3-carboxaldehyde (CAS: 3920-50-1, 3 g, 0.031 mol) in DMF (20 mL), and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion, water (30 mL) was added, and the mixture was extracted with ethyl acetate (3 x 30 mL). The combined ethyl acetate layer was washed with 10% saline solution (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give crude 1-ethyl-1H-pyrazole-3-carboxaldehyde, which was further purified by column chromatography with ethyl acetate in 30% hexane to give the title compound XVI as a yellow liquid. Yield: (2.4 g, 63%). 1 H NMR (400 MHz, CDCl3): δ 9.982(s,1H), 7.467-7.462, (d, J= 2Hz, 1H), 6.808-6.802(d, J= 2.4Hz, 1H), 4.307-4.252(q, J= 7.2Hz, 2H), 1.572-1.536(t, J= 7.2Hz, 3H).

[0716] Step 2: (E)-1-Ethyl-3-(2-nitrovinyl)-1H-pyrazole (XVIb)

[0717] Ammonium acetate (2.3 g, 0.029 mol) was added to a stirred solution of 1-ethyl-1H-pyrazole-3-carboxaldehyde 2 (2.4 g, 0.0193 mol) in nitromethane (22 mL), and the reaction mixture was stirred at 100 °C for 1 hour. The reaction progress was monitored by TLC. After completion, the solvent in the reactants was removed under reduced pressure. The residue was absorbed with water (50 mL) and extracted with ethyl acetate (3 x 35 mL). The combined ethyl acetate layer was washed with 10% brine solution (35 mL). The layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired product XVIb. The crude product was used for the next step without further purification. Yield: (1.6 g, 49%). 1 H NMR (400 MHz, CDCl3): δ 7.990-7.956 (d, J= 13.6Hz, 1H), 7.637-7.604 (d, J= 13.2Hz, 1H), 7.450-7.446 (d, J= 1.6Hz, 1H), 6.542-6.538 (d, J=1.6Hz, 1H), 4.253-4.190(q, J= 7.2Hz, 2H), 1.543-1.506(t, J= 7.2Hz, 3H).

[0718] Step 3: 2-(1-Ethyl-1H-pyrazole-3-yl)ethyl-1-amine (XVI)

[0719] LAH (1 mL, 36 mL, 0.036 mol in THF solution) was added dropwise to a stirred solution of (E)-1-ethyl-3-(2-nitrovinyl)-1H-pyrazole 3 (1.5 g, 0.0089 mol) in DEE (60 mL) at 0 °C. The temperature was then lowered to room temperature, and the reaction mixture was stirred at 40 °C for 3 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C and quenched with chilled water (2 mL) and 1 mL of hydrated sodium hydroxide in 15 N. The mixture was filtered and the inorganic salts were washed with DEE (25 mL). The solvent in the filtrate was concentrated under reduced pressure to give crude compound XVI, which did not require further purification for the next step. Yield: (1 g, 81%). 1 H NMR (400 MHz, CDCl3): δ 7.312(d, 1H), 6.054-6.050(d, 1H), 4.150-4.096(q, J = 7.2Hz, 2H), 3.008-2.974(t, 2H), 2.787-2.754(t, 2H), 1.483-1.432(t, J= 7.2Hz, 3H).

[0720] Synthesis of 2-(1-ethyl-1H-pyrazol-3-yl)ethyl-1-amine (XVII)

[0721]

[0722] Step 1: 1-Methyl-1H-pyrazole-3-carboxaldehyde (XVIIa)

[0723] Potassium carbonate (17.97 g, 0.13 mol) and methyl iodoform (8.86 g, 0.0624 mol) were added to a stirred solution of 1H-pyrazole-3-carboxaldehyde (CAS: 3920-50-1, 5 g, 0.052 mol) in DMF (25 mL), and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion, water (50 mL) was added and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined ethyl acetate layer was washed with 10% saline solution (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give the crude product 1-methyl-1H-pyrazole-3-carboxaldehyde, which was further purified by column chromatography with ethyl acetate in 30% hexane to give the title compound XVIIa as a yellow liquid. Yield: (2.6 g, 45%). 1 H NMR (400 MHz, CDCl3): δ 9.960(s,1H), 7.431-7.427(d, J= 1.6Hz, 1H), 6.812-6.805 (d, J= 2.8 Hz (1H), 4.020 s (1H).

[0724] Step 2: (E)-1-Methyl-3-(2-nitrovinyl)-1H-pyrazole (XVIIb)

[0725] Ammonium acetate (2.5 g, 0.031 mol) was added to a stirred solution of 1-methyl-1H-pyrazole-3-carboxaldehyde XVIIa (2.4 g, 0.020 mol) in nitromethane (43 mL), and the reaction mixture was stirred at 100 °C for 1 hour. The reaction progress was then monitored by TLC. After completion, the solvent in the reactants was removed under reduced pressure. The residue was absorbed with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined ethyl acetate layer was washed with 10% brine solution (50 mL). The layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate in 20% hexane to give the pure title compound XVIIb. Yield: (1.4 g, 49%). 1 H NMR (400 MHz, CDCl3): δ 7.970-7.936(d, J= 13.6Hz, 1H), 7.631-7.598 (d, J= 13.2Hz, 1H), 7.428-7.422 (d, J= 2.4Hz, 1H), 6.549-6.543 (d, J= 2.4 Hz (1H), 3.971 s (3H).

[0726] Step 3: 2-(1-Methyl-1H-pyrazole-3-yl)ethyl-1-amine (XVII)

[0727] LAH (1 mL, 29 mL, 0.029 mol in THF solution) was added dropwise to a stirred solution of (E)-1-methyl-3-(2-nitrovinyl)-1H-pyrazole 3 (1.4 g, 0.009 mol) in DEE (60 mL) at 0 °C. The temperature was then brought to room temperature, and the reaction mixture was stirred at 40 °C for 3 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C and quenched with chilled water (2 mL) and 1 mL of hydrated sodium hydroxide in 15 N. The mixture was filtered and the inorganic salts were washed with DEE (25 mL). The solvent in the filtrate was concentrated under reduced pressure to give crude compound XVII, which was used for the next step without further purification. Yield: (1 g, 87%). 1 H NMR (400 MHz, CDCl3): δ 7.278-7.268(d, J= 4Hz, 1H), 6.053-6.050 (d, J= 1.2Hz, H), 3.853(s, 3H), 3.008-2.969(t, J= 6.8Hz, 2H), 2.778-2.745(t, J= 6.8Hz, 2H).

[0728] Synthesis of 2-(3-(2-aminoethyl)-1H-pyrazol-1-yl)-2-methylprop-1-ol (XVIII)

[0729]

[0730] Step 1: Ethyl 2-(3-formyl-1H-pyrazole-1-yl)-2-methylpropionate (XVIIIa)

[0731] Potassium carbonate (3 g, 0.02 mol) and ethyl 2-bromo-2-methylpropionate (2 g, 0.01 mol) were added to a stirred solution of 1H-pyrazole-3-carboxaldehyde (CAS: 3920-50-1, 1 g, 0.01 mol) in DMF (5 mL), and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was then monitored by TLC. After completion, water (25 mL) was added and the mixture was extracted with ethyl acetate (3 x 25 mL). The combined ethyl acetate layer was washed with 10% saline solution (25 mL). The layer was dried over sodium sulfate, filtered, and concentrated to give the crude compound, which was further purified by column chromatography with ethyl acetate in 30% hexane to give the title compound XVIIIa. Yield: (1.8 g, 82%). LC-MS calculations were performed. For C 10 H14 N2O3: 210.06; after observation: 211.20; [M + +1]. 1 H NMR (400 MHz, CDCl3): δ 9.980(s, 1H), 7.623(s, 1H), 6.836(s, 1H), 4.217-4.164(q, J= 7.2Hz, 2H), 1.999(s, 6H), 1.235-1.200(t, J= 6.8Hz, 3H).

[0732] Step 2: Ethyl (E)-2-methyl-2-(3-(2-nitrovinyl)-1H-pyrazole-1-yl)propionate (XVIIIb)

[0733] Ammonium acetate (0.99 g, 0.0121 mol) was added to a stirred solution of ethyl 2-(3-formyl-1H-pyrazole-1-yl)-2-methylpropionate XVIIIa (1.8 g, 0.008 mol) in nitromethane (17 mL), and the reaction mixture was stirred at 100 °C for 1 h. The reaction progress was monitored by TLC. After completion, the solvent in the reactants was removed under reduced pressure. The crude product was purified by column chromatography with ethyl acetate in 20% hexane to give the pure title compound XVIIIb. Yield: (0.55 g, 25%). LC-MS calculations were performed. For C... 11 H 15 N3O4: 253.11; after observation: 254.20; [M + +1]. 1 H NMR (400 MHz, CDCl3): δ 8.007-7.973(d, J= 13.6Hz, 1H), 7.629-7.611(m, 2H), 7.509-7.504(d, J= 2Hz, 1H), 6.580-6.574 (d, J= 2.4Hz, 1H), 4.210-4.120(q, J= 7.6Hz, 2H), 1.187(s, 6H), 1.237-1.163(t, J= 7.6Hz, 3H).

[0734] Step 3: 2-(3-(2-aminoethyl)-1H-pyrazol-1-yl)-2-methylprop-1-ol (XVIII)

[0735] LAH (1 mL, 8.7 mL, 0.0086 mol in THF solution) was added dropwise to a stirred solution of ethyl (E)-2-methyl-2-(3-(2-nitrovinyl)-1H-pyrazole-1-yl)propionate 4 (0.55 g, 0.0021 mol) in DEE (15 mL) at 0 °C. The temperature was then brought to room temperature, and the reaction mixture was stirred at 40 °C for 3 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C and quenched with chilled water (2 mL) and 15 N hydrated sodium hydroxide (1 mL). The mixture was filtered and the inorganic salts were washed with DEE (25 mL). The solvent in the filtrate was concentrated under reduced pressure to give crude compound XVIII, which did not require further purification for the next step. Yield: (0.35 g, 88%). LC-MS calculations were performed. For C9H 17 N3O: 183.14; after observation: 184.30; [M + +1]. 1 H NMR (400 MHz, CDCl3): δ 7.449(s, 2H), 6.071(s, 1H), 3.76(s, 2H), 2.999-2.968(t, J= 7.6Hz, 2H), 2.811-2.740(t, J= 7.6 Hz (2H), 1.596 s (6H).

[0736] Synthesis of 2-(5-methoxypyridin-2-yl)ethyl-1-amine (XIX)

[0737]

[0738] Step 1: (E)-5-methoxy-2-(2-nitrovinyl)pyridine (XIXa)

[0739] TEA (4.04 mL, 0.029 mol) and nitromethane 2 (1.06 g, 0.0174 mol) were added to a stirred solution of 5-methoxypyridinaldehyde 1 (2.0 g, 0.0145 mol) in DCM (20 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was evaporated under reduced pressure. The starting material was dissolved in DCM (20 mL) and treated with TEA (6.06 mL, 0.0435 mol) and methanesulfonyl chloride (3.37 mL, 0.0435 mol) at 0 °C, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction progress was monitored by TLC. After completion, the reaction mixture was evaporated under reduced pressure. The crude product was eluted with ethyl acetate in 10% hexane and purified by column chromatography to give the title compound XIXa as a yellow solid; yield: (2.47 g, 94%). LC-MS calculations were performed. For C8H8N2O3: 180.05; after observation: 181.00; [M++H]. 1 H NMR (400 MHz, CDCl3): δ 8.38(d, J= 3.2Hz, 1H), 7.43 (d, J= 8.4Hz, 1H), 7.26(s, 1H), 7.22(dd, J= 8.4, 2.8Hz, 1H), 3.92 (s, 3H).

[0740] Step 2: 2-(5-methoxypyridin-2-yl)ethyl-1-amine (XIX)

[0741] LAH (1 mL, 45.6 mL, 0.0456 mol) was added dropwise to a stirred solution of (E)-5-methoxy-2-(2-nitrovinyl)pyridine 3 (2.74 g, 0.0152 mol) in THF (90 mL) at -10 °C. The temperature was then brought to room temperature, and the reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C, quenched with a saturated solution of Na₂SO₄ (50 mL), and extracted with ethyl acetate (50 mL x 3). The mixture was dried over Na₂SO₄, filtered, and the organic layer was evaporated under reduced pressure. The crude product was eluted with methanol NH₃ in 10% DCM and purified by column chromatography to give the title compound XIX as a brown liquid; yield: (0.8 g, 34.78%). 1 H NMR (400 MHz, DMSO): δ 8.19(d, J= 2.8Hz, 1H), 7.3 (dd, J= 8.4, 3.2 Hz, 1H), 7.19 (d, J=8.8Hz, 1H), 3.79(s, 3H), 2.88(t, J= 6.0Hz, 2H), 2.74(t, J= 6.8Hz, 2H).

[0742] 7-Amino-3-chloro-2-methyl-5-(methylsulfonyl)pyrazolo[1, 5-a]pyrimidine-6-carbonitrile (XX) and Synthesis of Mixture of Seven-Amino-3-chloro-2-methyl-5-(methylsulfinyl)pyrazolo[1, 5-a]pyrimidine-6-carbonitrile (XXa)

[0743]

[0744] Step 1: Synthesis of 4-chloro-3-methyl-1H-pyrazole-5-amine (XXb)

[0745] N-chlorosuccinimide (3.3 g, 0.025 mol) was added fractionally to a stirred solution of 3-methyl-1H-pyrazole-5-amine (CAS: 268724-49-8, 2.0 g, 0.021 mol) in DCM (50 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC. The reaction mixture was then diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give the crude product. The crude compound was purified by Biotage column chromatography using silica gel (230-400) and 1-5% methanol in DCM as eluent to give the desired product XXb as a creamy white solid. Yield: 2.0 g, 74%. LC-MS calculations were performed. For C₄H₆ClN₃: 131.56; after observation: 132.0; [M+H] + .

[0746] Step 2: Synthesis of 7-amino-3-chloro-2-methyl-5-(methylthio)pyrazole[1,5-a]pyrimidine-6-onitrile (XXc)

[0747] To a stirred solution of 4-chloro-5-methyl-1H-pyrazole-3-amine XXb (1.8 g, 0.0136 mol) in pyridine (5 mL), 2-(bis(methylthio)methylene)malonitrile Ia (2.8 g, 0.016 mol) was added. The resulting reaction mixture was heated at 120 °C for 2.5 h. The reaction progress was then monitored by TLC. The reaction mixture was cooled to room temperature and poured into ice-cold water (20 mL). The mixture was filtered and the precipitated compound was washed with cold water. The obtained solid was then dried under vacuum and purified by Biotage column chromatography using silica gel (230-400) and ethyl acetate in 5-20% hexane as eluent to give the desired product XXc as a light brown solid. Yield: 3.5 g, 99%. LC-MS calculations were performed. For C9H8ClN5S: 253.71; after observation: 254.0; [M+H] +. 1 HNMR (400 MHz, DMSO-D6): δ 8.90(bs, 2H), 2.57(s, 3H), 2.37(s, 3H).

[0748] Step 3: Synthesis of 7-amino-3-chloro-2-methyl-5-(methylsulfonyl)pyrazole[1,5-a]pyrimidine-6-onitrile (XX) and 7-amino-3-chloro-2-methyl-5-(methylsulfinyl)pyrazole[1,5-a]pyrimidine-6-onitrile (XXa)

[0749] In a stirred solution of XXc (3.5 g, 0.013 mol) of 7-amino-3-chloro-2-methyl-5-(methylthio)pyrazole[1, 5-a]pyrimidine-6-onitrile in DCM (50 mL), m-chloroperoxybenzoic acid (9.5 g, 0.055 mol) was added fractionally. The reaction mixture was stirred at room temperature for 3 hours. The reaction progress was then monitored by TLC. The reaction mixture was quenched with an aqueous solution of NaHCO3 (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, evaporated under reduced pressure, and dried under vacuum to give a mixture of XXc (3.5 g, 0.013 mol) and XXa (7-amino-3-chloro-2-methyl-5-(methylsulfinyl)pyrazole[1, 5-a]pyrimidine-6-onitrile as off-white solids. Yield (2.2 g, 56%). This raw material required no further purification and was used as is in the next step. LC-MS calculations were performed. For C9H8ClN5O2S: 285.71; after observation: 286.1; [M+H]. 1 H NMR (400 MHz, DMSO-D6): δ 9.48(bs, 2H), 3.42(s, 3H), 2.45(s, 3H).

[0750] ​

[0751]

[0752] Step 1: Synthesis of methyl 6-(methoxymethyl)pyridinecarboxylate (XXIa)

[0753] A solution of methyl 6-(hydroxymethyl)pyridinecarboxylate (CAS: 1197-10-0, 25 g, 0.15 mol) in DMF (250 mL) was cooled to 0 °C. NaH (7.2 g, 60% wt, 0.18 mol) was added fractionally, followed by dropwise addition of dimethyl sulfate (19 mL, 0.19 mol). The reaction mixture was stirred at room temperature for 3 hours. The reaction progress was then monitored by TLC. After completion, the reaction mixture was quenched with ice-cold water (200 mL), extracted with ethyl acetate (3 x 200 mL), and concentrated. The crude product was purified by gravity column chromatography through a 230-400 silica sieve. The desired product was eluted with ethyl acetate in 15-20% hexane to give XXIa as a yellow viscous oil. Yield: 21 g, 78%. LC-MS calculations were performed. For C9H... 11 NO3: 181.07; after observation: 182.20; [M+H]. 1 H NMR (400MHz, CDCl3): ​ 8.04(d, J= 7.6Hz, 1H), 7.86(t, J= 7.6Hz, 1H), 7.66 (d, J= 7.6Hz, 1H), 4.69(s, 2H), 4.00(s, 3H), 3.49(s, 3H).

[0754] Step 2: Synthesis of (6-(methoxymethyl)pyridin-2-yl)methanol (XXIb)

[0755] A solution of methyl 6-(methoxymethyl)pyridinecarboxylate XXIa (21 g, 0.12 mol) in THF (200 mL) was cooled to 0 °C, and NaBH4 (13 g, 0.35 mol) was added fractionally. The reaction mixture was then stirred at 25 °C for 3 hours. The reaction progress was monitored by TLC. The reaction mixture was concentrated under low vacuum, and NaHCO3 solution (100 mL) was added, followed by extraction with DCM (3 x 300 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude compound was purified by gravity column chromatography through a 230–400 silica sieve. The desired product was eluted with ethyl acetate in 25–30% hexane to give XXIb as a yellow viscous oil. Yield: 16.8 g, 93%. LC-MS calculations were performed. For C8H 11 NO2: 153.08; after observation: 154.25; [M+H] + . 1 H NMR (400MHz, CDCl3): ​ 7.69(t, J =7.6Hz, 1H), 7.33(d,J =7.6Hz, 1H), 7.14(d, J =7.6Hz, 1H), 4.74(d, J= 4.8Hz, 2H), 4.59(s, 2H), 3.77(t, J= 4.8, 5.2Hz, 1H), 3.48(s, 3H).

[0756] Step 3: Synthesis of methyl (6-(methoxymethyl)pyridin-2-yl)methanesulfonate (XXIc)

[0757] A solution of (6-(methoxymethyl)pyridin-2-yl)methanol XXIb (7 g, 0.05 mol) in DCM (140 mL) was cooled to 0 °C, and TEA (7 g, 0.01 L, 0.07 mol) and MsCl (4 mL, 0.05 mol) were added dropwise. The reaction mixture was stirred at 0 °C for 2 hours. The reaction progress was monitored by TLC. The reaction mixture was quenched with NaHCO3 solution (100 mL), extracted with DCM (3 x 200 mL), dried over anhydrous Na2SO4, filtered, and the combined organic layers were evaporated under reduced pressure to give a brown liquid XXIc. This brown liquid was used as is for the next step without further purification. Yield: 10 g, 92%. 1 H NMR (400 MHz, CDCl3): ​ 7.79-7.75(m,1H),7.42(d,1H, J= 8.0Hz), 7.38 (d, J= 7.6Hz, 1H), 5.32(s, 2H), 4.57(s, 2H), 3.48(s, 3H), 3.09(s, 3H).

[0758] Step 4: Synthesis of 2-(6-(methoxymethyl)pyridin-2-yl)acetonitrile (XXId)

[0759] To a stirred solution of methyl 6-(methoxymethyl)pyridin-2-yl)methanesulfonate XXIc (10 g, 0.043 mol) in DMF (100 mL), NaCN (2.3 g, 0.048 mol) was added fractionally, and the reaction mixture was stirred at 24 °C for 3 h. The reaction progress was monitored by TLC. The reaction mixture was quenched with ice-cold water (100 mL) and extracted with EtOAc (3 x 100 mL). The mixture was dried over anhydrous Na₂SO₄, filtered, and the combined organic layers were evaporated under reduced pressure. The obtained starting material was purified by rapid chromatography using silica gel (230-400 mesh), eluting the desired product with EtOAc in 20-25% hexane to give XXId as a yellow viscous oil. Yield: 5.1 g, 73%. LC-MS calculations were performed. For C9H 10 N₂O: 162.08; after observation: 163.25; [M+H] + . 1 H NMR (400 MHz, CDCl3): ​ 7.7-7.7(m, 1H), 7.40-7.26(m, 2H), 4.56(s, 2H), 3.92(s, 2H), 3.48(s, 3H).

[0760] Step 5: Synthesis of 2-(6-(methoxymethyl)pyridin-2-yl)ethyl-1-amine (XXI)

[0761] A solution of 2-(6-(methoxymethyl)pyridin-2-yl)acetonitrile XXId (5.1 g, 0.031 mol) in THF (80 mL) was cooled to 0 °C, and BH3·DMS (15 mL, 0.16 mol) was added dropwise. The reaction mixture was stirred at 70 °C for 3 hours. The reaction progress was monitored by TLC. After completion, the reaction was cooled to room temperature and quenched with MeOH (15 mL). The resulting mixture was stirred at room temperature for 30 minutes. The mixture was acidified with 1 M HCl solution (15 mL) and concentrated under reduced pressure. The obtained residue was dissolved in water (20 mL), and EtOAc (50 mL) and DCM (50 mL) were added to remove impurities. The aqueous layer was separated and alkalized with 2 N sodium hydroxide solution. The resulting mixture was extracted with DCM (3 x 300 mL). The mixture was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the desired compound XXI as a brown viscous liquid. The crude compound was used for the next step without further purification. Yield: 3.4 g, 65%. LC-MS calculations were performed. For C9H 11 NO3: 166.11; After observation: 167.30; [M+H] + . 1 H NMR (400 MHz, CDCL3): ​7.64-7.60 (m, 1H), 7.26 (d, J= 8Hz, 1H), 7.07 (d, J =7.6Hz, 1H), 4.56(s, 2H), 3.47(s,3H), 3.10-3.07(m, 2H), 2.93-2.90(m, 2H).

[0762] Synthesis of (1-(6-(2-aminoethyl)pyridin-2-yl)cyclopropyl)methanol (XXII)

[0763]

[0764] Step 1: Synthesis of ethyl 2-(6-bromopyridin-2-yl)acetate (XXIIa)

[0765] Under a nitrogen atmosphere, 2-bromo-6-methylpyridine (CAS: 5315-25-3, 5 g, 1 eq, 0.03 mol) was added dropwise to a solution of lithium diisopropylamine (8 g, 0.04 L, 2 m, 2.5 eq, 0.07 mol) in THF (150 mL) at -78 °C, and the mixture was stirred at -78 °C for 30 min. Diethyl carbonate (9 g, 2.5 eq, 0.07 mol) was then added. The mixture was stirred at -40 °C for 6 h. The reaction progress was monitored by TLC in the absence of starting material. The reaction was quenched with a saturated solution of NH4Cl (60 mL), and the mixture was extracted with ethyl acetate (70 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a light brown viscous liquid. The crude compound was purified by column chromatography using silica gel in hexane (100-200; 250 g) and EtOAc (0-10%) as eluents. The peak eluted with EtOAc in 7% hexane was concentrated to give the desired product XXIIa as a colorless, viscous liquid. Yield: 5.3 g, 70%. LC-MS calculations were performed. For C9H... 10 BrNO2: 242.99; after observation: 244.10; [M+H] + . 1 H NMR (400 MHz, CDCl3): ​ 7.53(t, J= 7.6Hz, 1H), 7.40 (d, J= 8.0Hz, 1H), 7.28(t, J= 7.2Hz, 1H), 4.19(q, J= 7.2Hz, 2H), 3.83(s, 2H), 1.27(t, J= 6.8Hz, 3H).

[0766] Step 2: Synthesis of ethyl 1-(6-bromopyridin-2-yl)cyclopropane-1-carboxylate (XXIIb)

[0767] A stirred solution of ethyl 2-(6-bromopyridin-2-yl)acetate XIIa (4.2 g, 1 eq, 17 mmol) in DMF (25 mL) was cooled to 0 °C, and sodium hydride (1.5 g, 60% wt, 2.2 eq, 38 mmol) was added. 1,2-dibromoethane (7.1 g, 2.2 eq, 38 mmol) was added dropwise to the resulting mixture, and the mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC in the absence of starting material. Ice-cold water (25 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (25 mL x 2). The mixture was washed with brine, dried over anhydrous sodium sulfate, filtered, and the combined organic layers were concentrated under reduced pressure to give a light brown viscous liquid. The crude compound was purified by silica gel (100-200; 24 g) column chromatography in hexane using EtOAc (0-20%). The peak eluted with EtOAc in 7% hexane was concentrated to give the desired product XXIIb as a light brown viscous liquid. Yield: 4.1 g, 88%. LC-MS calculations were performed. For C 11 H 12 BrNO2: 271.00; after observation: 272.05; [M+H] + . 1 H NMR (400 MHz, CDCl3): ​ 7.54(d, J= 7.6Hz, 1H), 7.50(t, J= 7.6Hz, 1H), 7.34 (d, J= 7.6Hz, 1H), 4.15(q, J= 7.2Hz, 2H), 1.67(t, J= 4.4Hz, 2H), 1.50(t, J= 4.4Hz, 2H), 1.23(t, J= 7.2Hz, 3H).

[0768] Step 3: Synthesis of ethyl 1-(6-vinylpyridin-2-yl)cyclopropane-1-carboxylate (XXIIc)

[0769] The solution of ethyl 1-(6-bromopyridin-2-yl)cyclopropane-1-carboxylic acid XXIIb (2.8 g, 1 eq, 10 mmol), potassium trifluoro(vinyl)borate (1.7 g, 1.2 eq, 12 mmol), and potassium tribasic phosphate (3.3 g, 1.3 mL, 1.5 eq, 16 mmol) in 20 mL of 1,4-dioxane was purified with N2 gas for 15 minutes with vigorous stirring. PdCl2 (dppf) (0.38 g, 0.05 eq, 0.52 mmol) was added to the reaction mixture, and the mixture was heated to 120 °C for 16 hours. The reaction progress was monitored by TLC analysis. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (70 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a light brown viscous liquid. The crude compound was purified by ethyl acetate in hexane via Combi-Flash (230-400, 120g packed) column chromatography, and the peak eluted with EtOAc in 5% hexane was concentrated to give XXIIc as a light brown viscous liquid; yield: 1g, 40%. LC-MS calculations were performed. For C... 13 H 15 NO2: 217.11; after observation: 218.25; [M+H] + . 1 H NMR (400 MHz, CDCl3): ​ 7.58(t, J= 7.6Hz, 1H), 7.41 (d, J= 7.6Hz, 1H), 7.19 (d, J= 7.6Hz, 1H), 6.78(q, J= 6.4Hz, 1H), 6.17 (dd, J= 17.4 & 1.6 Hz, 1H), 5.43 (dd, J= 11.0 & 1.2 Hz, 1H), 4.15 (q, J= 7.2Hz, 2H), 1.65-1.63(m,2H), 1.56-1.53(m, 2H), 1.21(t, J= 7.2Hz, 3H).

[0770] Step 4: Synthesis of ethyl 1-(6-formylpyridin-2-yl)cyclopropane-1-carboxylate (XXIId)

[0771] Osmium tetroxide (4.68 mL, 2.5% wt, 0.1 eq, 0.5 mmol in isobutanol) was added to a solution of ethyl 1-(3-vinylphenyl)cyclopropane-1-carboxylate XXIIc (1 g, 1 eq, 5 mmol) in THF (18 mL) and water (40 mL), and the reaction mixture was stirred at room temperature for 30 min. Sodium periodate (1 g, 0.4 mL, 1.5 eq, 7 mmol) was then added, and the reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC analysis. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The residue was dried over anhydrous Na₂SO₄, filtered, and the combined organic layers were evaporated under vacuum to give XXIId as a brown viscous liquid. This crude product required no further purification for the next step. Yield: 0.95 g, 90%. LC-MS calculations were performed. For C 13 H 14 O3: 219.09; after observation: 220.20; [M+H] + . 1 H NMR (400 MHz, CDCl3): ​ 10.02(s, 1H), 7.3(s, 3H), 4.18(q, J= 7.2Hz, 2H), 1.73-1.61(m, 4H), 1.22(t, J= 7.2Hz, 3H).

[0772] Step 5: Synthesis of (E)-1-(6-(2-nitrovinyl)pyridin-2-yl)cyclopropane-1-carboxylic acid ethyl ester (XXIIe)

[0773] A stirred solution of ethyl 1-(6-formylpyridin-2-yl)cyclopropane-1-carboxylate XXIId (950 mg, 1 eq, 4.33 mmol) in DCM (20 mL) was cooled to 0 °C. Nitromethane (317 mg, 280 µL, 1.2 eq, 5.20 mmol) and triethylamine (2.19 g, 3.02 mL, 5 eq, 21.7 mmol) were added to the resulting mixture under N2 atmosphere. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give a brown viscous liquid. The mixture was dissolved in fresh DCM (20 mL) and cooled to 0 °C. Triethylamine (2.19 g, 3.02 mL, 5 eq, 21.7 mmol) was then added to the reaction mixture, followed by dropwise addition of methanesulfonyl chloride (1.49 g, 1.01 mL, 3 eq, 13.0 mmol) under N2 atmosphere. The reaction mixture was stirred at room temperature for 30 minutes. The reaction progress was monitored by TLC analysis, indicating completion. The reaction mixture was concentrated under reduced pressure, water (15 mL) was added, and extraction was performed with ethyl acetate (15 mL x 2). The mixture was washed with brine, dried over anhydrous sodium sulfate, and the combined organic layers were concentrated under reduced pressure to give XIIe as a brown, viscous liquid. The crude product was used for the next step without further purification. Yield: 1.0 g, 86%. LC-MS calculations were performed. For C... 13 H 14 N₂O₄: 262.10; after observation: 263.20; [M + +H].

[0774] Step 6: Synthesis of (1-(6-(2-aminoethyl)pyridin-2-yl)cyclopropyl)methanol (XXII)

[0775] To an ice-cold solution of LiAlH4 (20 mL, 1 m, 4 eq) in dry diethyl ether (80 mL), a solution of (E)-1-(6-(2-nitrovinyl)pyridin-2-yl)cyclopropane-1-carboxylic acid ethyl ester XXIIe (1 g, 1 eq, 4 mmol) in dry diethyl ether (7 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC analysis, indicating completion. The reaction mixture was cooled to 0 °C and quenched first with water (2 mL) and then with 15% KOH solution (3 mL). Ethyl acetate (100 mL) was added to the mixture and stirred at room temperature for 20 minutes. The reaction mixture was filtered, and the residue was washed with 100 mL of ethyl acetate. The combined filtrates were concentrated under reduced pressure to give the desired compound XXII as a light brown viscous liquid. The crude product did not require further purification for the next step. Yield: 0.6 g, 80%. LC-MS calculations were performed. For C 11 H 16 N₂O: 192.13; after observation: 193.25; [M+H]+ . 1 H NMR (400 MHz, DMSO-D6): ​ 7.52-7.50 (m, 1H), 6.98 (d, J= 8.0Hz, 1H), 6.70 (d, J= 8.0Hz, 1H), 3.83(d, J= 3.6Hz, 4H), 3.13(t, J= 6.8Hz, 2H), 2.90(t, J= 6.4Hz, 2H), 1.05-1.01(m, 2H), 0.90-0.85(m, 2H).

[0776] Synthesis of 2-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)ethyl-1-amine (XXIII)

[0777]

[0778] Step 1: Synthesis of 1-(2-methoxyethyl)-1H-pyrazole-3-carboxaldehyde (XXIIIa)

[0779] 1-Bromo-2-methoxyethane (5.2 g, 0.037 mol) was added dropwise to a stirred solution of 1H-pyrazole-3-carboxaldehyde (CAS: 3920-50-1: 3.0 g, 0.031 mol) and CS₂CO₃ (20.0 g, 0.0624 mol) in DMF (50 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. The reaction mixture was then diluted with water (500 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (50 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give the crude product. The crude product was purified by Biotage column chromatography on silica gel (230-400 mesh) and eluted with ethyl acetate in 5-20% hexane to give XXIIIa as a colorless liquid. Yield: 3.2 g, 66%. LC-MS calculations were performed. For C7H 10 N₂O: 154.17; after observation: 155.2; [M+H] + . 1 H NMR (400 MHz, DMSO-D6): ​ 9.97 (s, 1H), 7.54 (d, J= 1.6Hz, 1H), 6.80 (d, J= 2.0Hz, 1H), 4.38(t, J=4.8Hz,2H),3.78(t, J =5.6Hz, 2H), 3.34s, 3H.

[0780] Step 2: Synthesis of (E)-1-(2-methoxyethyl)-3-(2-nitrovinyl)-1H-pyrazole (XXIIIb)

[0781] A mixture of 1-(2-methoxyethyl)-1H-pyrazole-3-carboxaldehyde XXIIIa (3.2 g, 0.019 mol), nitromethane (35 g, 31 mL, 0.57 mol), and ammonium acetate (2.2 g, 0.029 mol) was placed in a round-bottom flask and the reaction mixture was stirred at 100 °C for 2 hours. The reaction progress was then monitored by TLC in the absence of starting material. The reaction mixture was evaporated under vacuum to obtain a crude residue, which was purified by Biotage column chromatography using silica (230-400 mesh). The desired product was eluted with ethyl acetate in 5-20% hexane to give the desired product XXIIIb as a colorless liquid. Yield: 2.4 g, 60%. LC-MS calculations were performed. For C8H... 11 N3O3: 197.19; after observation: 198.2; [M+H] + .

[0782] Step 3: Synthesis of 2-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)ethyl-1-amine XXIII

[0783] Under an argon atmosphere at 0 °C, (E)-1-(2-methoxyethyl)-3-(2-nitrovinyl)-1H-pyrazole XXIIIb (2.4 g, 0.012 mol) in THF (5 mL) of stirred solution of LAH (1.0 mL in THF, 50 mL in THF) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction progress was then monitored by TLC. The reaction mixture was quenched with water (2.4 mL) at 0 °C, followed by the addition of 15% KOH solution (2.4 mL) and water (8 mL). The reaction mixture was then filtered and the solid was washed with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to give crude product XXIII as a pale yellow liquid. Yield: 1.5 g, 83%.

[0784] ​

[0785]

[0786] Step 1: Synthesis of methyl 1-(3-formyl-1H-pyrazole-1-yl)cyclopropane-1-carboxylic acid (XXIVa)

[0787] Methyl 2,4-dibromobutyrate (CAS: 29547-04-4, 35g, 0.14mol) was added to a stirred solution of 1H-pyrazole-3-carboxaldehyde (CAS: 3920-50-1, 10g, 0.1mol) and K2CO3 (58g, 0.42mol) in DMF (100mL) at 0°C. The reaction mixture was then stirred at room temperature for 16 hours. The reaction progress was monitored by TLC analysis. The reaction mixture was quenched with cold water and extracted with ethyl acetate (2 x 200mL). The combined organic layers were washed with water (3 x 100mL) followed by a saline solution, dried over anhydrous sodium sulfate, and concentrated. The starting material was purified by Combi-Flash column chromatography with 0-25% ethyl acetate:hexane to give XXIVa as a white solid. Yield: 13.5g, 67%. LC-MS calculations were performed. For C9H 10 N₂O₃: 194.07; after observation: 195.15; [M+H] + . 1 H NMR (400 MHz, CDCl3): ​ 9.97(s, 1H), 7.58(s, 1H), 6.82(s, 1H), 3.70(d, J= 6.8Hz, 3H), 1.93-1.90(m, 2H), 1.73-1.70(m, 2H).

[0788] Step 2: Synthesis of (E)-1(3-(2-nitrovinyl)-1H-pyrazole-1-yl)cyclopropane-1-carboxylic acid methyl ester (XXIVb)

[0789] Ammonium acetate (0.6 g, 0.0077 mol) and nitromethane (3.1 g, 0.051 mol) were added to a stirred solution of ethyl 1-(3-formyl-1H-pyrazole-1-yl)cyclopropane-1-carboxylic acid ester XXIVa (1 g, 0.0051 mol) in toluene (25 mL), and the mixture was stirred at 100 °C for 16 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with 1N HCl solution (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine solution (15 mL) and dried over anhydrous sodium sulfate. The solvent was removed under vacuum. The crude compound was purified by rapid column chromatography by elution with ethyl acetate in 10–20% hexane to give XXIVb as a white solid. Yield: 1.2 g, 35%. LC-MS calculations were performed. For C 10 H 11N3O4: 237.07; after observation: 238.15; [M+H] + . 1 H NMR (400 MHz, CDCl3): ​ 7.95(d, J= 13.6Hz, 1H), 7.61 (d, J= 13.6Hz, 1H), 7.57 (d, J= 2.4Hz, 1H), 6.56 (d, J= 2.4Hz, 1H), 3.7(s, 3H), 1.91-1.87(m, 2H), 1.7-1.66(m, 2H).

[0790] Step 3: Synthesis of (1-(3-(2-aminoethyl)-1H-pyrazole-1-yl)cyclopropyl)methanol (XXIV)

[0791] Methyl (E)-1-(3-(2-nitrovinyl)-1H-pyrazole-1-yl)cyclopropane-1-carboxylic acid ester XXIVb (0.430 g, 0.0018 mol) in THF (5 mL) was added dropwise to a stirred solution of LAH (1 m, 7.25 mL, 0.0072 mol) in Et₂O (10 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to 0 °C, quenched first with water (0.4 mL), then with 15% KOH solution (0.4 mL), followed by water (1.2 mL), and stirred for 15–20 minutes. The mixture was filtered and washed with EtOAc (3 x 20). It was dried over anhydrous sodium sulfate. The combined organic layers were concentrated under reduced pressure to give XXIV as a pale yellow oil. Yield: 0.329 g, 93.8%. LC-MS calculations were performed. For C9H 15 N3O: 181.24; after observation: 182.25; [M+H] + . 1 H NMR (400 MHz, DMSO-d6): ​ 7.40(d, J = 2.4Hz, 1H), 6.05 (d, J= 2.0Hz, 1H), 3.74(s, 3H), 2.98(t, J= 6.8Hz, 2H), 2.76(t, J= 7.2Hz, 2H), 1.26-1.23(m, 2H), 1.09-1.08(m, 2H).

[0792] Synthesis of (2-(6-(2-aminoethyl)pyridin-2-yl)cyclopropyl)methanol (XXV)

[0793]

[0794] Step 1: Synthesis of (E)-3-(6-bromopyridin-2-yl)ethyl acrylate (XXVa)

[0795] 2-(diethoxyphosphoryl)ethyl acetate (CAS: 867-13-0, 15 g, 1.25 eq, 67 mmol) was added dropwise to a suspension of sodium hydride (3.2 g, 55% wt, 1.35 eq, 73 mmol) in THF (300 mL) at 0 °C. After 30 min, a solution of 6-bromopyridaldehyde (10 g, 1 eq, 54 mmol) in THF was added, and the reaction mixture was stirred at room temperature for 4 h. The reaction progress was monitored by TLC analysis. After the reaction was complete, the reaction mixture was cooled to 0 °C, and water (75 mL) was added dropwise. The resulting mixture was extracted with ethyl acetate (75 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a light brown viscous liquid. The crude compound was purified by silica gel (100-200; 150 g) column chromatography with EtOAc (0-20%) in hexane. The peak eluted with EtOAc in 10% hexane was concentrated to give XXVa as a white solid. Yield: 10 g, 73%. LC-MS calculations were performed. For C 10 H 10 BrNO2: 254.99; after observation: 256.05; [M+H] + . 1 H NMR (400 MHz, CDCl3): ​ 7.60-7.54 (m, 2H), 7.45 (d, J= 8.0Hz, 1H), 7.35 (d, J= 7.6Hz, 1H), 6.96 (d, J= 15.2Hz, 1H), 4.27(q, J= 7.2Hz, 2H), 1.33(t, J= 7.2Hz, 3H).

[0796] Step 2: Synthesis of ethyl 2-(6-bromopyridin-2-yl)cyclopropane-1-carboxylate (XXVb)

[0797] Sodium hydride (2.2 g, 55% wt, 1.3 eq, 51 mmol) was added fractionally to a solution of trimethyl sulfoxide (CAS: 1774-47-6, 19 g, 2.2 eq, 86 mmol) in DMSO (140 mL), and the mixture was stirred at room temperature for 1 hour. A solution of ethyl (E)-3-(6-bromopyridin-2-yl)acrylate (10 g, 1 eq, 39 mmol) in a mixture of DMSO (60 mL) and THF (60 mL) was slowly added to the reaction mixture. The mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by TLC. After the reaction was complete, 1 N HCl (10 mL) was added, and the reaction mixture was extracted with diethyl ether (30 mL x 2). The mixture was dried over anhydrous sodium sulfate, and the combined organic layer was removed under vacuum. The crude compound was purified with ethyl acetate (7%) in hexane through a silica gel stopper (100-200; 120 g) to give the desired colorless viscous liquid compound XXVb. Yield: 6.0g, 60%. 1 H NMR (400MHz, CDCl3): ​ 7.57-7.39(m, 1H), 7.27-7.26(m, 1H), 7.18(d, J= 7.6Hz, 1H), 4.25-4.12(m, 2H), 2.58-2.51(m, 2H), 2.29-2.25(m, 2H), 1.34-1.23(m, 3H).

[0798] Step 3: Synthesis of ethyl 2-(6-vinylpyridin-2-yl)cyclopropane-1-carboxylate (XXVc)

[0799] The solution of ethyl 2-(6-bromopyridin-2-yl)cyclopropane-1-carboxylate (3.9 g, 1 eq, 14 mmol), potassium vinyltrifluoroborate (CAS: 13682-77-4, 2.1 g, 1.1 eq, 16 mmol), and potassium tribasic phosphate (4.6 g, 1.8 mL, 1.5 eq, 22 mmol) in 1,4-dioxane (60 mL) was purified with N2 gas for 15 minutes with vigorous stirring. PdCl2 (dppf) (0.53 g, 0.05 eq, 0.72 mmol) was added to the reaction mixture, the tube was sealed, and the mixture was heated to 120 °C for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. Water (80 mL) was added to the obtained residue, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a light brown viscous liquid. The crude compound was purified by Combi-Flash column chromatography (230-400, 120g packed column) using ethyl acetate in hexane. The peak eluted with EtOAc in 5% hexane was concentrated to give XXVc as a pale yellow viscous liquid. Yield: 1.8 g, 57%. LC-MS calculations were performed. For C... 13 H 15 NO2: 217.11; after observation; 218.20; [M+H] + . 1 H NMR (400 MHz, CDCl3): ​ 7.51(t, J= 7.2Hz, 1H), 7.10-7.07(m, 2H), 6.78-6.68(m, 1H), 6.78-6.68(m, 1H), 5.42-5.39(m, 1H), 4.19-4.14(m, 1H), 2.63-2.57(m, 2H), 2.31-2.29(m,1H), 1.66-1.56(m, 2H), 1.34-1.26(m, 3H).

[0800] Step 4: Synthesis of ethyl 2-(6-formylpyridin-2-yl)cyclopropane-1-carboxylate (XXVd)

[0801] To a solution of ethyl 2-(6-vinylpyridin-2-yl)cyclopropane-1-carboxylic acid ester XXVc (1.6 g, 1 eq, 7.4 mmol) in THF (4.4 mL) and water (10 mL), osmium tetroxide (7.4 mL, 2.5% wt in isobutanol, 0.1 eq, 0.74 mmol) was added, and the mixture was stirred at room temperature for 30 min. Then, sodium periodate (2.4 g, 0.59 mL, 1.5 eq, 11 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction progress was then monitored by TLC analysis, indicating completion. The mixture was diluted with water (35 mL) and extracted with EtOAc (30 mL x 2). The residue was dried over anhydrous Na₂SO₄, filtered, and the combined organic layers were evaporated under vacuum to give XXVd as a brown viscous liquid. The crude product was used as is for the next step without further purification. Yield: (1.56 g, 97%). LC-MS calculations were performed. For C 12 H 13 NO3: 219.09; After observation: 220.20; [M+H] + . 1 H NMR (400 MHz, CDCl3): ​ 9.95(s, 1H), 7.76-7.72(m, 2H), 7.47-7.45(m, 1H), 4.27-4.16(m, 2H), 2.70-2.65(m, 2H), 2.39-2.37(m, 2H), 1.30-1.27(m, 3H).

[0802] Step 5: Synthesis of (E)-2-(6-(2-nitrovinyl)pyridin-2-yl)cyclopropane-1-carboxylic acid ethyl ester (XXVe)

[0803] A stirred solution of ethyl 2-(6-formylpyridin-2-yl)cyclopropane-1-carboxylate XXVd (1.72 g, 1 eq, 7.85 mmol) in DCM (15 mL) was cooled to 0 °C. Nitromethane (575 mg, 1.2 eq, 9.41 mmol) and triethylamine (2.19 mL, 2.0 eq, 15.7 mmol) were added to the resulting mixture under N2 atmosphere. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give a brown, viscous liquid. The mixture was dissolved in fresh DCM (10 mL) and cooled to 0 °C. Triethylamine (3.02 mL, 5 eq, 21.7 mmol) was then added to the reaction mixture, followed by dropwise addition of methanesulfonyl chloride (1.49 g, 1.01 mL, 3 eq, 13.0 mmol) under N2 atmosphere. The reaction mixture was stirred at room temperature for 30 minutes. The reaction progress was monitored by TLC analysis, indicating completion. The reaction mixture was concentrated under reduced pressure, water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 2). The mixture was washed with brine, dried over anhydrous sodium sulfate, and the combined organic layers were concentrated under reduced pressure to give XXVe as a brown, viscous liquid. This crude product required no further purification for the next step. Yield: 1.87 g, 100%.

[0804] Step 6: Synthesis of (2-(6-(2-aminoethyl)pyridin-2-yl)cyclopropyl)methanol (XXV)

[0805] To LiAlH4 (30 mL, 1 m, 4 eq) in dry diethyl ether (160 mL) cooled in an ice bath, a solution of ethyl(E)-2-(6-(2-nitrovinyl)pyridin-2-yl)cyclopropane-1-carboxylic acid ester (2 g, 1 eq, 8 mmol) in dry diethyl ether (7 mL) was added dropwise. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC analysis to indicate completion. The reaction mixture was cooled to 0 °C and quenched first with water (3 mL) and then with 15% KOH solution (15 mL). Ethyl acetate (75 mL) was added to the mixture and stirred at room temperature for 20 minutes. The reaction mixture was filtered, and the residue was washed with 100 mL of ethyl acetate. The combined filtrates were concentrated under reduced pressure to give XXV as a light brown viscous liquid. The crude product was used as is for the next step without further purification. Yield: 1.03 g, 100%. LC-MS calculations were performed. For C 11 H 16 N₂O: 192.13; after observation: 193.25; [M+H] + .

[0806] Synthesis of 2-(6-ethylpyridin-2-yl)ethyl-1-amine (XXVI)

[0807]

[0808] Step 1: Ethyl 2-(6-bromopyridin-2-yl)ethyl acetate (XXVIa)

[0809] 2-Bromo-6-methylpyridine (CAS: 5315-25-3, 15 g, 87 mmol) was added dropwise to a stirred solution of lithium diisopropylamine (110 mL, 2 mol, 220 mmol) in dry THF (500 mL) at -78 °C under an inert atmosphere, and the mixture was stirred at -78 °C for 30 min. Then, diethyl carbonate (CAS: 105-58-8, 26 g, 220 mmol) was added, and the mixture was stirred at -40 °C for 4 h. The reaction progress was monitored by TLC. After completion, the reaction was quenched with saturated NH4Cl solution (150 mL), and the mixture was extracted with ethyl acetate (170 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a light brown viscous liquid. The crude compound was purified by silica gel (100-200) column chromatography with ethyl acetate (0-10%) in n-hexane. The peak eluted with ethyl acetate in 7% n-hexane was concentrated to give the desired product XXVIa as a colorless, viscous liquid. Yield: 12.2 g (57%). LC-MS calculations were performed. For C9H... 11 BrNO2: 246.00; after observation: 246.15; [M+H] + ; 1 H NMR (400 MHz, CDCl3): ​ 7.53(t, J = 7.6Hz, 1H), 7.40(d, J = 8.0Hz, 1H), 7.28(t, J = 7.6Hz, 1H), 4.19(q, J = 7.2Hz, 2H), 3.83(s, 2H), 1.27(t, J = 7.2Hz, 3H).

[0810] Step 2: Ethyl 2-(6-vinylpyridin-2-yl)ethyl acetate (XXVIb)

[0811] The solution of ethyl 2-(6-bromopyridin-2-yl)ethyl acetate XXVIa (3 g, 10.0 mmol), potassium trifluoro(vinyl)borate (2 g, 11.0 mol), and potassium tribasic phosphate (4 g, 20 mmol) in 1,4-dioxane (40 mL) was purified with N2 gas for 15 minutes with vigorous stirring. PdCl2 (dppf) (0.4 g, 0.6 mmol) was added to the reaction mixture, the tube was sealed, and the mixture was heated to 120 °C for 16 hours. The reaction progress was monitored by TLC. The reaction was cooled to room temperature and the reaction mixture was concentrated under reduced pressure. Water (70 mL) was added to the residue, and the mixture was extracted with ethyl acetate (75 mL x 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a light brown viscous liquid. The crude compound was purified by Combi-Flash (230-400) column chromatography with ethyl acetate in n-hexane, and the peak eluted with ethyl acetate in 3% hexane was concentrated to give the desired colorless viscous liquid, compound XXVIb. Yield: 2.0 g (90%). LC-MS calculations were performed. For C 11 H 14 NO2: 192.10; after observation: 192.25; [M+H] + ; 1 H NMR (400 MHz, CDCl3): ​ 7.62(t, J= 7.6Hz, 1H), 7.25 (d, J= 7.6Hz, 1H), 7.17 (d, J= 7.6Hz, 1H), 6.80(q, J= 6.4Hz, 1H), 6.19 (d, J= 17.6Hz, 1H), 5.47 (d, J= 10.8Hz, 1H), 4.19(q, J= 7.2Hz, 2H), 1.27(t, J= 7.2Hz, 3H).

[0812] Step 3: 2-(6-vinylpyridin-2-yl)-1-ethanol (XXVIc)

[0813] Sodium borohydride (2 g, 50 mmol) was added fractionally to a stirred solution of 2-(6-vinylpyridin-2-yl)ethyl acetate XXVIb (2 g, 10.0 mmol) in methanol (30 mL) at 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 30 min and then at room temperature for 6 h. The reaction progress was monitored by TLC analysis, indicating that the reaction was complete. A saturated solution of NaHCO3 (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (75 mL x 2). The mixture was washed with brine (35 mL), dried over anhydrous sodium sulfate, and the organic layer was concentrated under reduced pressure to give XXVIc as a colorless viscous liquid. The crude product was used for the next step without further purification. Yield: 1.2 g (80%). LC-MS calculations were performed. For C9H 12 NO: 150.09; After observation: 150.00; [M+H] + ; 1 H NMR (400 MHz, CDCl3): ​ 7.59(t, J= 7.6Hz, 1H), 7.19 (d, J= 7.6Hz, 1H), 7.02 (d, J= 8.0Hz, 1H), 6.81-6.74(m, 1H), 6.16(d, J= 17.6Hz, 1H), 5.47 (d, J= 10.8Hz, 1H), 4.03(t, J= 5.6Hz, 2H), 3.01(t, J= 5.6Hz, 2H).

[0814] Step 4: 2-(6-vinylpyridin-2-yl)ethyl methanesulfonic acid (XXVId)

[0815] Under a nitrogen atmosphere, triethylamine (4.5 mL, 32 mmol) was added to a stirred solution of 2-(6-vinylpyridin-2-yl)-1-ethanol XXVIc (1.2 g, 8.0 mmol) in DCM (30 mL). The resulting mixture was cooled to 0 °C, and methanesulfonyl chloride (0.81 mL, 10.0 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 30 min. The reaction progress was monitored by TLC analysis, indicating that the reaction was complete. Water (30 mL) was added to the reaction mixture, and it was extracted with DCM (30 mL x 3). The mixture was washed with brine (25 mL), dried over anhydrous sodium sulfate, and the organic layer was concentrated under reduced pressure to give XXVId as a brown viscous liquid. The crude product did not require further purification for the next step. Yield: 1.7 g (93%). LC-MS calculations were performed. For C 10 H 14NO3S: 228.08; after observation: 228.20; [M+H] + ; 1 H NMR (400 MHz, CDCl3): ​ 7.60(t, J= 7.6Hz, 1H), 7.22(d, J= 8.0Hz, 1H), 7.08 (d, J= 8.0Hz, 1H), 6.82-6.75(m, 1H), 6.22(d, J= 17.6Hz, 1H), 5.48 (d, J= 10.8Hz, 1H), 4.73-4.66(m, 2H), 3.21(t, J= 6.4 Hz (2H), 2.88 s (3H).

[0816] Step 5: 2-(2-Azideethyl)-6-vinylpyridine (XXVIe)

[0817] Sodium azide (1.5 g, 22 mmol) was added to a stirred solution of 2-(6-vinylpyridin-2-yl)ethyl methanesulfonic acid XXVId (1.7 g, 7.5 mmol) in DMF (20 mL) under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 4 hours. The reaction progress was monitored by TLC analysis. After the reaction was complete, water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was washed with brine (25 mL), dried over anhydrous sodium sulfate, and the organic layer was concentrated under reduced pressure to give a brown viscous liquid. The crude product was purified by Combi-Flash (silica gel 230-400) column chromatography with ethyl acetate (0-40%) in n-hexane. The peak eluted with 5% ethyl acetate was concentrated to give the desired compound XXVIe as a colorless viscous liquid. Yield: 0.87 g (67%). LC-MS calculations were performed. For C9H 11 N4: 175.10; after observation: 175.25; [M+H] + ; 1 H NMR (400 MHz, CDCl3): ​ 7.58(t, J= 7.6Hz, 1H), 7.21 (d, J= 7.6Hz, 1H), 7.06 (d, J= 7.6Hz, 1H), 6.84-6.77(m, 1H), 6.22(d, J= 17.6Hz, 1H), 5.47 (d, J= 10.8Hz, 1H), 3.74(t,J= 6.8Hz, 2H), 3.06(t, J= 6.8Hz, 2H).

[0818] Step 6: 2-(6-Ethylpyridin-2-yl)ethyl-1-amine (XXVI)

[0819] 2-(2-azidoethyl)-6-vinylpyridine XXVIe (0.87 g, 5.0 mmol) was dissolved in methanol (30 mL) in an RB flask and purified with nitrogen for 10 min. Carbon-supported palladium (450 mg, 10%) was added to this solution. The reaction mixture was evacuated and refilled with H2 gas, and this step was repeated 3–4 times with stirring at room temperature for 16 h under H2 atmosphere. The reaction progress was monitored by TLC. After completion, the mixture was filtered through a diatomaceous earth bed and washed with fresh methanol. The combined filtrates were concentrated under vacuum to give the desired compound XXVI as a pale yellow viscous liquid, which did not require further purification for the next step. Yield: 0.67 g (89%). LC-MS calculations were performed. For C9H... 15 N2: 151.13; after observation: 151.25; [M+H] + ; 1 H NMR (400MHz, CDCl3): ​ 7.54-7.46(m, 1H), 7.01-6.94(m, 2H), 3.09-2.73(m, 6H), 1.28(m, 3H).

[0820] Synthesis of 2-(3-fluoro-6-methylpyridin-2-yl)ethyl-1-amine (XXVII)

[0821]

[0822] Step 1: 3-Fluoro-6-methylpyridinaldehyde (XXVIIa)

[0823] 2-Bromo-3-fluoro-6-methylpyridine (CAS: 374633-36-0; 1.66 g, 8.74 mmol) and dried toluene (10 mL) were added to a double-necked RB flask equipped with a double stopcock, septum, and magnetic rod at room temperature and under a nitrogen atmosphere. The resulting mixture was cooled to -78 °C, and n-butyllithium (3.5 mL, 2 mL in THF, 8.74 mmol) was added dropwise while stirring the reaction mixture under a suitable nitrogen atmosphere, maintaining the temperature at -78 °C. Subsequently, dried DMF (1.92 g, 26.2 mmol) was slowly added at -78 °C under a nitrogen atmosphere. The reaction mixture was stirred for another 1 h at -78 °C under a nitrogen atmosphere, and then stirred for 2 h at -50 °C. The reaction progress was monitored by TLC analysis. The reaction was quenched at -78 °C by the slow addition of a saturated ammonium chloride solution. The resulting mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude brown semi-solid. The crude product was purified by silica gel (230-400 mesh) column chromatography with ethyl acetate in 0-10% n-hexane to give the desired compound XXVIIa as a grayish-white solid. Yield: 0.175 g (14.4%); calculated by LC-MS. For C7H7FNO: 140.05; after observation: 140.25; [M+H] + ; 1 H NMR (400 MHz, CDCl3): ​ 10.19(s, 1H), 7.49-7.38(m, 2H), 2.64(s, 3H).

[0824] Step 2: (E)-3-fluoro-6-methyl-2-(2-nitrovinyl)pyridine (XXVIIb)

[0825] Triethylamine (0.6 g, 6 mmol) and nitromethane (0.2 mL, 3 mmol) were added to a solution of 3-fluoro-6-methylpyridinaldehyde XXVIIa (0.4 g, 3 mmol) in DCM (4 mL) at room temperature under a N2 atmosphere. The reaction mixture was stirred at room temperature for 30 min, and the reaction progress was monitored by TLC. After completion, the mixture was concentrated under vacuum to a dry state, and the residue was dissolved in fresh, dry DCM (4 mL). The mixture was cooled to 0 °C under a N2 atmosphere, and TEA (1 mL, 9 mmol) was added. Subsequently, methanesulfonyl chloride (0.7 mL, 9 mmol) was slowly added at 0 °C under a N2 atmosphere. The mixture was stirred at room temperature under a N2 atmosphere for 1 h. The reaction progress was monitored by TLC. After completion, water (10 mL) was added, and the resulting mixture was extracted with DCM (5 mL × 3). The mixture was washed with brine, dried over anhydrous sodium sulfate, and the combined organic layers were concentrated under reduced pressure to give a brown semi-solid. The crude product was purified by silica gel (230-400) column chromatography with ethyl acetate in 0-10% n-hexane to obtain the desired compound XXVIIb as a colorless viscous liquid. Yield: 93 mg (20%); 1 H NMR (400 MHz, CDCl3): ​ 8.15(d, J= 13.2Hz, 1H), 8.04 (d, J= 13.6Hz, 1H), 7.39(t, J= 9.2Hz, 1H), 7.25(t, J= 3.6 Hz (1H), 2.57 s (3H).

[0826] Step 3: 2-(3-fluoro-6-methylpyridin-2-yl)ethyl-1-amine (XXVII)

[0827] Under a nitrogen atmosphere, dry diethyl ether was added to a 100 mL round-bottom flask with a double neck, and the solvent was cooled to 0 °C. LAH (1 mL, 2 mL in THF, 2.0 mmol) was added, followed by a solution of 1(E)-3-fluoro-6-methyl-2-(2-nitrovinyl)pyridine XXVIIb (93 mg, 0.51 mmol) in a dry diethyl ether:THF (1:1, 2 mL). The mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere. The reaction progress was monitored by TLC. After completion, the reaction was cooled to 0 °C and quenched with water (0.2 mL) and ethyl acetate (5 mL). The solution was filtered through a diatomaceous earth bed. The bed was washed first with ethyl acetate and then with MeOH in 10% DCM. The combined filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum to give raw material XXVII as a brown semi-solid. The crude product obtained required no further purification for the next step. Yield: 47 mg (60%).

[0828] Synthesis of 7-amino-2-ethyl-3-methyl-5-(methanesulfonyl)pyrazole[1,5-a]pyrimidine-6-onitrile (XXVIII)

[0829]

[0830] Step 1: 2-Methyl-3-oxopentanilonitrile (XXVIIIa)

[0831] At -78°C under an inert atmosphere, propionitrile (CAS: 107-12-0; 4 mL, 60 mmol) was added dropwise to a stirred solution of lithium diisopropylamine (110 mL, 2 mL, 60 mmol) in dry THF (56 mL), and the mixture was stirred at -78°C for 1 hour. Ethyl propionate (CAS: 105-37-3; 6 mL, 50 mmol) was then added, and the reaction was stirred again at -78°C for 1 hour. The reaction progress was monitored by TLC. After completion, the reaction was quenched with saturated NH4Cl solution (20 mL), and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a light brown viscous liquid. The crude compound was purified by silica gel (100-200) column chromatography with ethyl acetate (0-10%) in n-hexane. The peak eluted with ethyl acetate in 7% n-hexane was concentrated to give the desired product XXVIIIa as a colorless viscous liquid. The crude product requires no further purification and can be used in the next step. Yield: 4.3 g (71%).

[0832] Step 2: 5-Ethyl-4-methyl-1H-pyrazole-3-amine (XXVIIIb)

[0833] Hydrazine hydrate (1:1) (2.9 g, 58 mmol) was added to a stirred solution of 2-methyl-3-oxopentanonitrile XXVIIIa (4.3 g, 39 mmol) in ethanol (4 mL) at room temperature, and the reaction mixture was stirred at 120 °C for 2 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and concentrated to remove the solvent. The resulting residue was dissolved in water (50 mL) and extracted with methanol in 10% DCM (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the desired product XXVIIIb as a yellow viscous liquid. The crude product was used for the next step without further purification. Yield: 5.4 g (69%).

[0834] Step 3: 7-Amino-2-ethyl-3-methyl-5-(methylthio)pyrazole[1,5-a]pyrimidine-6-onitrile (XXVIIIc)

[0835] 2-(bis(methylthio)methylene)malonium Ia (4.0 g, 32 mmol) was added to a stirred solution of 5-ethyl-4-methyl-1H-pyrazole-3-amine XXVIIIb (5.4 g, 32 mmol) in pyridine (30 mL). The reaction mixture was then stirred at 120 °C for 3 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and then poured into ice-cold water (100 mL). The solid formed was filtered and washed with ice-cold water. The solid was dried under vacuum to give the desired product XXVIIIc as a creamy white solid. The crude product was used for the next step without further purification. Yield: 5.3 g (68%); calculated by LC-MS. For C 11 H 14 N5S: 248.32; Post-observation: 248.20; [M+H] + ; 1 H NMR (400 MHz, CDCl3): ​ 6.19 (bs, 2H), 2.75 (q, J= 7.6Hz, 2H), 2.62(s, 3H), 2.19(s, 3H), 1.3(t, J= 7.6Hz, 3H).

[0836] Step 4: 7-Amino-2-ethyl-3-methyl-5-(methanesulfonyl)-1,2-dihydropyrazole[1,5-a]pyrimidine-6-nitrile (XXVIII)

[0837] At 0 °C under an inert atmosphere, mCPBA (15 g, 87 mmol) was added fractionally to a stirred solution of 7-amino-2-ethyl-3-methyl-5-(methylthio)-1,2-dihydropyrazole[1,5-a]pyrimidine-6-nitrile XXVIIIc (5.4 g, 22 mmol) in DCM (60 mL). The mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by TLC analysis. After completion, the reaction mixture was quenched with NaHCO3 (50 mL) and extracted with DCM (50 mL x 3). The mixture was dried over anhydrous Na2SO4, filtered, and the organic layer was concentrated under reduced pressure to give the desired product XXVIII as a creamy white solid. The solid was washed with n-hexane (10 mL x 2). The crude solid was used for the next step without further purification. Yield: 1.0 g (18%); calculated by LC-MS. For C 11 H 16 N5O2S: 282.33; [M+H] + After observation: 280.25; [M+H] -2 .

[0838] Synthesis of 7-amino-2-cyclopropyl-3-methyl-5-(methanesulfonyl)pyrazole[1,5-a]pyrimidine-6-onitrile (XXIX)

[0839]

[0840] Step 1: 3-Cyclopropyl-2-methyl-3-oxopropionitrile (XXIXa)

[0841] At -78°C under an inert atmosphere, a solution of acrylonitrile (CAS: 107-12-0; 3 g, 50 mmol) in THF (20 mL) was added to a stirred solution of LDA (30 mL, 2 m, 50 mmol) in dry THF (70 mL), and the mixture was stirred at -78°C for 1 hour. Ethylcyclopropane carboxylate (6 g, 50 mmol) was then added, and the mixture was stirred at -70°C for 1 hour. The reaction progress was monitored by TLC. After completion, the reaction was quenched with saturated NH4Cl solution (50 mL), and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give XIXa as a light brown viscous liquid. The crude compound was used as is for the next step without further purification. Yield: 4.5 g (70%).

[0842] Step 2: 5-Cyclopropyl-4-methyl-1H-pyrazole-3-amine (XXIXb)

[0843] Hydrazine hydrate (3.3 mL, 50% wt, 34 mmol) was added to a stirred solution of 3-cyclopropyl-2-methyl-3-oxopropionitrile XIXa (4.2 g, 34 mmol) in ethanol (50 mL), and the reaction mixture was heated at 90 °C for 16 h. The reaction progress was monitored by TLC. After completion, the mixture was cooled to room temperature and evaporated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The residue was dried over anhydrous Na₂SO₄, filtered, and the combined organic layers were evaporated under reduced pressure. The resulting starting material XIXb was used as is for the next step without further purification. Yield: 4.2 g (90%); calculated by LC-MS. For C7H 12 N3: 138.20; after observation: 138.25; [M+H] + .

[0844] Step 3: 7-Amino-2-cyclopropyl-3-methyl-5-(methylthio)pyrazole[1,5-a]pyrimidine-6-onitrile (XXIXc)

[0845] To a stirred solution of 2-(bis(methylthio)methylene)malononitrile Ia (5.2 g, 31 mmol) in pyridine (35 mL), 5-cyclopropyl-4-methyl-1H-pyrazole-3-amine XXIXb (4.2 g, 31 mmol) was added, and the reaction mixture was heated at 120 °C for 1 hour under N2 atmosphere. The reaction progress was monitored by TLC analysis. After completion, the reaction mixture was cooled to room temperature and poured into ice-cold water (50 mL). The mixture was filtered, dried, and the precipitate was washed with a cold mixture of ethyl acetate (10%) and n-hexane (90%), and dried under vacuum to give the desired compound as a pale yellow solid. The crude compound XXIXc obtained did not require further purification for the next step. Yield: 4.1 g (52%); calculated by LC-MS. For C 12 H 14 N5S: 260.34; Post-observation: 260.20; [M+H] + .

[0846] Step 4: 7-Amino-2-cyclopropyl-3-methyl-5-(methanesulfonyl)pyrazole[1,5-a]pyrimidine-6-onitrile (XXIX)

[0847] At 0 °C and under a N2 atmosphere, mCPBA (4 g, 60% wt, 20 mmol) was added to a solution of 7-amino-2-cyclopropyl-3-methyl-5-(methylthio)pyrazole[1, 5-a]pyrimidine-6-nitrile XIXc (1 g, 4 mmol) in DCM (20 mL), and the mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by TLC analysis. After the reaction was complete, saturated NaHCO3 solution (50 mL) was added, and the mixture was stirred vigorously for 15 minutes. The organic layer was separated and washed with fresh saturated NaHCO3 solution (50 mL x 3). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum to give the desired compound as a pale yellow solid. Compound XIX did not require further purification for the next step. Yield: 0.35 g (30%); calculated by LC-MS. For C 12 H 14 N5O2S: 292.34; after observation: 292.20; [M+H] + .

[0848] Synthesis of 7-amino-2-(difluoromethyl)-3-ethyl-5-(methanesulfonyl)pyrazole[1,5-a]pyrimidine-6-onitrile (XXX)

[0849]

[0850] Step 1: 2-Ethyl-4,4-difluoro-3-oxobutyronitrile (XXXa)

[0851] At -78°C under an inert atmosphere, a solution of butyronitrile (1.0 g, 14 mmol) in THF (4 mL) was added dropwise to a solution of LiHMDS (2.4 g, 14 mmol) in THF (200 mL), and the reaction mixture was stirred at -78°C for 1 hour. Subsequently, ethyl 2,2-difluoroacetate (1.6 g, 13 mmol) was added dropwise at -78°C, and the reaction mixture was stirred for 2 hours. The reaction progress was monitored by TLC analysis. After the reaction was complete, the reaction mixture was cooled to 0°C, quenched with a saturated ammonium chloride solution (5 mL), and extracted with ethyl acetate (20 mL x 3). The mixture was dried over anhydrous Na₂SO₄, filtered, and the combined organic layers were evaporated under reduced pressure. The crude product was purified by silica gel (230-400 mesh) column chromatography with ethyl acetate in 0-10% n-hexane to give the desired compound XXXa as a light brown viscous liquid. Yield: 1.2 g (57%); calculated by LC-MS. For C6H6F2NO: 147.11; after observation: 146.12; [MH] - .

[0852] Step 2: 5-(difluoromethyl)-4-ethyl-1H-pyrazole-3-amine (XXXb)

[0853] Hydrazine hydrate (1:1) (0.49 g, 9.8 mmol) was added to a stirred solution of 2-ethyl-4,4-difluoro-3-oxobutyronitrile XXXa (1.2 g, 8.2 mmol) in ethanol (40 mL) at room temperature, and the reaction mixture was stirred at 120 °C for 2 h. The reaction progress was monitored by TLC analysis. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated to remove the solvent. The resulting residue was dissolved in water (30 mL) and extracted with methanol in 10% DCM (50 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the starting material XXXb. The crude product was used for the next step without further purification. LC-MS calculations were performed. For C6H9F2N3: 161.15; after observation: 160.10; [MH] - .

[0854] Step 3: 7-Amino-2-(difluoromethyl)-3-ethyl-5-(methylthio)pyrazole[1,5-a]pyrimidine-6-onitrile (XXXc)

[0855] To a stirred solution of 5-(difluoromethyl)-4-ethyl-1H-pyrazole-3-amine XXXb (0.6 g, 4 mmol) in pyridine (2 mL), 2-(bis(methylthio)methylene)malonitrile Ia (0.8 g, 4 mmol) was added, and the reaction mixture was heated at 120 °C for 2.5 h (using a protective tube). The reaction progress was monitored by TLC analysis. After completion, the reaction mixture was cooled to room temperature and poured into ice-cold water (100 mL). The mixture was filtered and the precipitate formed was washed with cold water. The solid obtained by azeotroping with toluene was dried to give the title compound as a pale yellow solid. The crude product was purified by silica gel (230-400) column chromatography with ethyl acetate in 0-30% n-hexane to give the desired compound XXXc as a pale yellow solid. Yield: 0.5 g (50%); calculated by LC-MS. For C 11 H 11 F2N5S: 283.29; after observation: 284.20; [M+H] + . 1 H NMR (400 MHz, CDCl3): ​ 6.77(s, 1H), 6.30(s, 2H), 2.87-2.81(m, 2H), 2.64(s, 3H), 1.29(t, J =8.0Hz, 3H).

[0856] Step 4: 7-Amino-2-(difluoromethyl)-3-ethyl-5-(methanesulfonyl)pyrazole[1,5-a]pyrimidine-6-onitrile (XXX)

[0857] At 0 °C, mCPBA (1 g, 7 mmol) was slowly added to a stirred solution of 7-amino-2-(difluoromethyl)-3-ethyl-5-(methylthio)pyrazole[1, 5-a]pyrimidine-6-onitrile XXXc (0.5 g, 2 mmol) in DCM (50 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After the reaction was complete, it was quenched with hydrated NaHCO3 (50 mL), and the reaction mixture was extracted with DCM (50 mL x 3). The mixture was dried over Na2SO4, filtered, and the organic layer was evaporated under reduced pressure. The crude product XXX was used for the next step without further purification. Yield: 0.3 g (50%); calculated by LC-MS. For C 11 H 11 F₂N₅O₂S: 315.28; after observation: 316.20; [M+H]⁺. ¹H NMR (400MHz, CDCl₃): ​ 9.53(s, 2H), 7.31(s, 1H), 3.33(s, 3H), 2.84-2.78(m, 2H), 1.23(t, J= 8Hz, 3H).

[0858] Synthesis of 2-(6-(1-(methoxymethyl)cyclopropyl)pyridin-2-yl)ethyl-1-amine (XXXI)

[0859]

[0860] Step-1: (1-(6-bromopyridin-2-yl)cyclopropyl)methanol (XXIIa)

[0861] Under a nitrogen atmosphere, at 0 °C, DIBAL-H (18 mL, 1 m, 18 mmol) was added to a solution of ethyl 1-(6-bromopyridin-2-yl)cyclopropane-1-carboxylic acid XXIIb (2.2 g, 8.1 mmol) in THF (88 mL), and the mixture was stirred at 0 °C for 30 min. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with saturated NH4Cl solution (25 mL), and ethyl acetate (50 mL) was added. The solid was filtered through a diatomaceous earth bed and washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure to give the desired compound XXXIa as a pale yellow viscous liquid. Yield: 1.68 g (90%); calculated by LC-MS. For C9H 10 BrNO: 228.08; after observation: 230.10; [M+H] + ; 1 H NMR (400 MHz, dmso-d6): ​ 7.64(t, J=8Hz, 1H), 7.53 (d, J= 8.0Hz, 1H), 7.38 (d, J= 8Hz, 1H), 4.82(t, J= 8Hz, 1H), 3.71(d, J= 8Hz, 2H), 1.07-1.04(m, 2H), 0.94-0.91(m, 2H).

[0862] Step 2: 2-Bromo-6-(1-(methoxymethyl)cyclopropyl)pyridine (XXXIb)

[0863] Sodium hydride (482 mg, 55% wt, 11.0 mmol) was added to a stirred solution of (1-(6-bromopyridin-2-yl)cyclopropyl)methanol XXXIa (1.68 g, 7.37 mmol) in DMF (10 mL) under an inert atmosphere, and the mixture was stirred at 0 °C for 5 min. Iodomethane (0.55 mL, 8.84 mmol) was then added, and the mixture was stirred at room temperature for 30 min. The reaction progress was monitored by TLC analysis. After completion, the reaction was quenched with ice-cold water (20 mL), and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give XXXIb as a light brown viscous liquid. The crude product was used for the next step without further purification. Yield: 1.79 g (99%); calculated by LC-MS. For C 10 H 12 BrNO: 242.12; after observation: 242.15; [M+H] + ; 1 H NMR (400 MHz, CDCl3): ​ 7.42(t, J= 8Hz, 1H), 7.35 (d, J= 4Hz, 1H), 7.23(t, J= 8.0Hz, 1H), 3.65(s, 2H), 3.4(s, 3H), 1.63-1.31(m, 2H), 1.26-0.96(m, 2H).

[0864] Step 3: 2-(1-(methoxymethyl)cyclopropyl)-6-vinylpyridine (XXXIc)

[0865] To a solution of 2-bromo-6-(1-(methoxymethyl)cyclopropyl)pyridine XXXIb (0.8 g, 3 mmol) in 1,4-dioxane (15 mL), 0.6 mL of vinylboronic acid pinacol ester (4 mmol) and tripotassium phosphate (1 g, 7 mmol) were added, and the mixture was purified with N2 gas for 15 min with vigorous stirring. PdCl2 (dppf) (0.1 g, 0.2 mmol) was then added and the mixture was heated to 120 °C for 16 h. The reaction progress was monitored by TLC. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (70 mL) was then added, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a light brown viscous liquid. The crude compound was purified by ethyl acetate in hexane via Combi-Flash (230-400, 120g packed) column chromatography, and the peak eluted with ethyl acetate in 5% hexane was concentrated to give the desired compound XXXIc as a creamy white solid. Yield: 0.42 g (70%); calculated by LC-MS. For C 12 H 15 NO: 189.26; Post-observation: 190.25; [M+H] + ; 1 H NMR (400 MHz, CDCl3): ​ 7.55-7.51 (m, 2H), 7.06 (d, J= 4Hz, 1H), 6.74(t, J= 8Hz, 1H), 6.18 (d, J= 16Hz, 1H), 5.38 (d, J= 8Hz, 1H), 3.72(s, 2H), 3.40(s, 3H), 1.35(d, J= 4Hz, 2H), 0.93(t, J= 4Hz, 2H).

[0866] Step 4: 6-(1-(methoxymethyl)cyclopropyl)pyridaldehyde (XXXId)

[0867] To a solution of 2-(1-(methoxymethyl)cyclopropyl)-6-vinylpyridine XXXIc (0.425 g, 2.25 mmol) in THF (9 mL) and water (20 mL), a solution of osmium tetroxide (0.06 mL, 1.12 mmol) was added, and the mixture was stirred at room temperature for 30 min. Sodium periodate (720 mg, 3.37 mmol) was then added, and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous Na₂SO₄, filtered, and the combined organic layers were evaporated under reduced pressure to give XXXId as a brown, viscous liquid. The crude product was used for the next step without further purification. Yield: 290 mg (67.5%); calculated by LC-MS. For C 11 H 14 NO2: 191.23; after observation: 192.25; [M+H] + ; 1 H NMR (400 MHz, CDCl3): ​ 9.97(s, 1H), 7.76-7.71(m, 2H), 7.63(d, J= 8.0Hz, 1H), 3.74(s, 2H), 3.43(s, 3H), 1.43(t, J= 4Hz, 2H), 1.02(t, J= 4Hz, 2H).

[0868] Step 5: (E)-2-(1-(methoxymethyl)cyclopropyl)-6-(2-nitrovinyl)pyridine (XXXIe)

[0869] At 0 °C and under an inert atmosphere, nitromethane (0.2 mL, 4 mmol) and triethylamine (2 mL, 20 mmol) were added to a solution of 6-(1-(methoxymethyl)cyclopropyl)pyridaldehyde XXXId (0.6 g, 3 mmol) in DCM (12 mL), and the mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion (CHO-OH), DCm was evaporated under reduced pressure to give a brown viscous liquid. Methanesulfonyl chloride (0.7 mL, 9 mmol) and triethylamine (2 mL, 20 mmol) in DCM (10 mL) were added dropwise to this solution at 0 °C under N2 gas. The reaction mixture was stirred at room temperature for 30 minutes. The reaction progress was monitored by TLC, indicating completion. The reaction mixture was concentrated under reduced pressure. Water (10 mL) was added and extracted with ethyl acetate (10 mL * 2). The combined organic layers were washed with brine and concentrated under reduced pressure to give XXXIe as a brown viscous liquid. The crude product was used for the next step without further purification. Yield: 0.7 g (99%); calculated by LC-MS. For C 12H 15 N₂O₃: 234.26; after observation: 235.25; [M+H] + .

[0870] Step 6: 2-(6-(1-(methoxymethyl)cyclopropyl)pyridin-2-yl)ethyl-1-amine (XXXI)

[0871] Under an inert atmosphere, at 0 °C, (E)-2-(1-(methoxymethyl)cyclopropyl)-6-(2-nitrovinyl)pyridine XXXIe (0.4 g, 2 mmol) in 7 mL of dry diethyl ether was added to a solution of LiAlH4 (0.06 g, 2 mmol) in 20 mL of dry diethyl ether, and the mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC analysis. After the reaction was complete, the reaction mixture was cooled to 0 °C and quenched with water (1 mL). 15% KOH solution was added to the resulting mixture and stirred for 10 minutes. Ethyl acetate (25 mL) was added and stirred at room temperature for 20 minutes. The resulting mixture was filtered through a diatomaceous earth bed, and the residue was washed with ethyl acetate (50 mL x 4). The combined filtrates were concentrated under reduced pressure to give the desired compound XXXI as a light brown viscous liquid. The crude product was used for the next step without further purification. Yield: 0.34 g (99%).

[0872] Synthesis of 2-(6-(2-aminoethyl)pyridin-2-yl)-2-methylprop-1-ol (XXXII)

[0873]

[0874] Step 1: Ethyl 2-(6-bromopyridin-2-yl)-2-methylpropionate (XXXIIa)

[0875] A solution of 2-(6-bromopyridin-2-yl)acetate (CAS: 955369-63-8; 1 g, 4 mmol) in THF (15 mL) was cooled to 0 °C, potassium tert-butoxide (1 g, 10 mmol) was added, and the mixture was stirred for 30 min under N2 atmosphere. Iodomethane (1 mL, 20 mmol) was then added dropwise, and the reaction mixture was stirred for 16 h at room temperature. The reaction progress was monitored by TLC analysis. After completion, the reaction mixture was concentrated under reduced pressure and water (25 mL) was added. The solution was extracted with ethyl acetate (25 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a light brown viscous liquid. The crude compound was purified by silica gel (200-300) column chromatography with ethyl acetate in 0-10% n-hexane to give the desired compound XXXIIa as a colorless viscous liquid. Yield: 1.18 g (100%); calculated by LC-MS. For C 11 H15 BrNO2: 274.03; after observation: 274.15; [M+H] + .

[0876] Step 2: Ethyl 2-methyl-2-(6-vinylpyridin-2-yl)propionate (XXXIIb)

[0877] Purify a solution of ethyl 2-(6-bromopyridin-2-yl)-2-methylpropionate XXXIIa (1 g, 4 mmol), potassium trifluoro(vinyl)borate (0.5 g, 4 mmol), and potassium tribasic phosphate (1 g, 6 mmol) in 20 mL of 1,4-dioxane with N2 gas for 15 minutes with vigorous stirring. Add PdCl2 (dppf) (0.1 g, 0.2 mmol) to the reaction mixture, seal the tube, and heat to 120 °C for 16 hours. Monitor the reaction progress by TLC. Cool the reaction mixture to room temperature and concentrate it under reduced pressure. Add water (70 mL) to the residue and extract the mixture with ethyl acetate (50 mL x 2). Dry the mixture with anhydrous sodium sulfate and concentrate the organic layer under reduced pressure to give a light brown viscous liquid. The crude compound was purified by Combi-Flash silica gel (230-400) column chromatography using ethyl acetate in n-hexane. The peak eluted with ethyl acetate in 5% n-hexane was concentrated to give the desired compound XXXIIb as a creamy white solid. Yield: 0.73 g (90%); calculated by LC-MS. For C 13 H 17 NO2: 220.17; after observation: 220.20; [M+H] + ; 1 H NMR (400 MHz, CDCl3): ​ 7.59(t, J= 7.6Hz, 1H), 7.15-7.13(m,2H), 6.25(d, J= 17.6Hz, 1H), 5.42 (d, J =10.8Hz, 1H), 4.16(q, J =7.2Hz, 2H), 1.57(s,6H), 1.18(t, J= 7.2Hz, 3H).

[0878] Step 3: Ethyl 2-(6-formylpyridin-2-yl)-2-methylpropionate (XXXIIc)

[0879] To a solution of ethyl 2-methyl-2-(6-vinylpyridin-2-yl)propionate XXXIIb (0.73 g, 3.3 mmol) in THF (14 mL) and water (25 mL), a solution of osmium tetroxide (680 µL, 0.33 mmol, 2.5% wt in isopropanol) was added, and the mixture was stirred at room temperature for 30 min. Then, sodium periodate (1.1 g, 5.0 mmol) was added, and the mixture was stirred for another 1 h. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 2). The residue was dried over anhydrous Na₂SO₄, filtered, and the combined organic layers were evaporated under vacuum to give XXXIIc as a brown, viscous liquid. The crude product was used for the next step without further purification. Yield: 0.503 g (68%); calculated by LC-MS. For C 12 H 16 NO3: 222.12; After observation: 222.20; [M+H] + ; 1 H NMR (400 MHz, CDCl3): ​ 10.03 (s, 1H), 7.83 (d, J= 3.6Hz, 2H), 7.53(t, J= 4.4Hz, 1H), 4.17(q, J= 7.2Hz, 2H), 1.57(s, 6H), 1.20(t, J= 7.2Hz, 3H).

[0880] Step 4: Ethyl (E)-2-methyl-2-(6-(2-nitrovinyl)pyridin-2-yl)propionate (XXXIId)

[0881] A stirred solution of ethyl 2-(6-formylpyridin-2-yl)-2-methylpropionate XXXIIc (506 mg, 2.29 mmol) in DCM (15 mL) was cooled to 0 °C, and nitromethane (168 mg, 2.74 mmol) and triethylamine (1.16 g, 1.59 mL, 11.4 mmol) were added under N2 atmosphere. The mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC analysis. After the reaction was complete, the solvent was evaporated under reduced pressure to give a brown viscous liquid. Fresh DCM (10 mL) was added to the reaction mixture and cooled to 0 °C. Then, methanesulfonyl chloride (786 mg, 6.86 mmol) was added dropwise under N2 atmosphere. The reaction mixture was stirred at room temperature for 30 minutes, and the reaction progress was monitored by TLC analysis. The reaction mixture was concentrated under reduced pressure and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine and concentrated under reduced pressure to give XXXIId as a brown viscous liquid. The crude product was used for the next step without further purification. Yield: 0.6 g (99.3%); calculated by LC-MS. For C 13 H 17 N₂O₄: 265.12; after observation: 265.20; [M+H] + ; 1 H NMR (400 MHz, CDCl3): ​ 8.03-7.89(m,2H), 7.75(t, J= 7.6Hz, 1H), 7.40-7.34(m, 2H), 4.17(q, J= 6.8Hz, 2H), 1.58(s, 6H), 1.20(t, J= 7.2Hz, 3H).

[0882] Step 5: 2-(6-(2-aminoethyl)pyridin-2-yl)-2-methylprop-1-ol (XXXII)

[0883] A solution of lithium aluminum hydride (9 mL, 1 mol, 9 mmol) in dry diethyl ether (50 mL) was cooled to 0 °C. A solution of ethyl (E)-2-methyl-2-(6-(2-nitrovinyl)pyridin-2-yl)propionate XXXIId (0.6 g, 2 mmol) in dry diethyl ether (10 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC analysis to indicate completion. The reaction mixture was cooled to 0 °C, and ice-cold water (1 mL) was added dropwise. A 15% KOH solution (5 mL) was added dropwise to the mixture, followed by ethyl acetate (50 mL). The mixture was stirred vigorously at room temperature for 15–20 minutes. The reaction mixture was filtered through a diatomaceous earth bed, and the residue was washed with fresh ethyl acetate (50 mL x 3). The combined filtrates were concentrated under reduced pressure to give the desired compound XXXII as a light brown viscous liquid. The crude product was used for the next step without further purification. Yield: 0.4 g (100%).

[0884] Synthesis of 2-(3-(aminomethyl)-1H-pyrazol-1-yl)-2-methylprop-1-ol (XXXIII)

[0885]

[0886] Step 1: Ethyl 2-(3-(hydroxymethyl)-1H-pyrazole-1-yl)-2-methylpropionate (XXXIIIa)

[0887] A stirred solution of ethyl 2-(3-formyl-1H-pyrazole-1-yl)-2-methylpropionate XVIIIa (1.0 g, 4.8 mmol) in ethanol (10 mL) was cooled to 0 °C, and sodium borohydride (90 mg, 2.4 mmol) was added fractionally. The reaction mixture was stirred at 0 °C for 30 min, and the reaction progress was monitored by TLC analysis (polar spots). The reaction mixture was diluted with water (1 mL), and the solvent was removed under vacuum. Water (10 mL) was added to the residue, and the mixture was extracted with DCM (10 mL x 3). The residue was dried over anhydrous Na₂SO₄, filtered, and the combined organic layers were concentrated under reduced pressure. The crude product XXXIIIa was used for the next step without further purification. Yield: 0.9 g (90%); calculated by LC-MS. For C 10 H 17 N₂O₃: 213.13; after observation: 213.25; [M+H] + ; 1 H NMR (400 MHz, CDCl3): ​ 7.52(d, J= 2.0Hz, 1H), 6.28 (d, J= 2.0Hz, 1H), 4.69 (d,J= 4.4Hz, 2H), 4.16(q, J= 6.8Hz, 2H), 2.09(s, 1H), 1.84(s, 6H), 1.21(t, J= 7.2Hz, 3H).

[0888] Step 2: Ethyl 2-(3-(bromomethyl)-1H-pyrazole-1-yl)-2-methylpropionate (XXXIIIb)

[0889] Under an inert atmosphere, a stirred solution of ethyl 2-(3-(hydroxymethyl)-1H-pyrazol-1-yl)-2-methylpropionate XXXIIIa (0.2 g, 0.9 mmol) in DCM (5 mL) was cooled to 0 °C, and PBr3 (0.1 mL, 1 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 12 hours. The reaction progress was monitored by TLC analysis (with few polar spots). The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The mixture was dried over anhydrous Na2SO4, filtered, and the organic layer was concentrated under reduced pressure. The crude compound was purified by silica gel (230-400 mesh) Combi-Flash column chromatography with ethyl acetate (0-10%) in n-hexane to give the desired compound XXXIIIb as a pale yellow viscous liquid. Yield: 0.16 g (53%); calculated by LC-MS. For C 10 H 16 BrN₂O₂: 275.04; after observation: 275.15; [M+H] + ; 1 H NMR (400 MHz, CDCl3): ​ 7.52(d, J= 2.0Hz, 1H), 6.28 (d, J= 2.0Hz, 1H), 4.69 (d, J= 4.4Hz, 2H), 4.16(q, J= 6.8Hz, 2H), 2.09(s, 1H), 1.84(s, 6H), 1.21(t, J= 7.2Hz, 3H).

[0890] Step 3: Ethyl 2-(3-(azidomethyl)-1H-pyrazole-1-yl)-2-methylpropionate (XXXIIIc)

[0891] Sodium azide (123 mg, 1.89 mmol) was added to a stirred solution of ethyl 2-(3-(bromomethyl)-1H-pyrazol-1-yl)-2-methylpropionate XXXIIIb (400 mg, 1.45 mmol) in DMF (4 mL), and the reaction mixture was heated at 50 °C for 2 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with ice-cold water (50 mL) and extracted with ethyl acetate (50 mL x 3). The mixture was dried over anhydrous Na₂SO₄, filtered, and the combined organic layers were concentrated under reduced pressure. The crude product was purified by Combi-Flash (230-400 mesh) column chromatography with ethyl acetate in 0-2% n-hexane to give the desired compound XXXIIIc as a pale yellow viscous liquid. Yield: 0.17 g (49.3%); 1 H NMR (400 MHz, CDCl3): ​ 7.55(d, J= 2.4Hz, 1H), 6.30 (d, J= 2.0Hz, 1H), 4.33(s, 2H), 4.16(q, J= 6.8Hz, 2H), 1.85(s, 6H), 1.20(t, J= 6.8Hz, 3H).

[0892] Step 4: Ethyl 2-(3-(aminomethyl)-1H-pyrazole-1-yl)-2-methylpropionate (XXXIIId)

[0893] Under a nitrogen atmosphere, Pd / C (76.3 mg, 10%, 0.717 mmol) was added to a stirred solution of ethyl 2-(3-(azidomethyl)-1H-pyrazol-1-yl)-2-methylpropionate XXXIIIc (170 mg, 0.717 mmol) in ethanol (5 mL). The mixture was evacuated and refilled with H2 gas. This process was repeated 3–4 times, with stirring for 16 hours at room temperature under H2 balloon pressure. The reaction progress was monitored by TLC analysis (polar spot). After completion, the reaction mixture was filtered through a diatomaceous earth bed, and the bed was washed with methanol. The combined filtrates were concentrated under reduced pressure. The crude product was purified by rapid silica gel (230–400 mesh) column chromatography with methanol in 0–5% DCM to give the desired compound XXXIIId as a pale yellow liquid. Yield: 0.15 g (99.3%); calculated by LC-MS. For C 10 H 18 N3O2: 212.14; after observation: 212.30; [M+H] + ; 1 H NMR (400 MHz, CDCl3): ​ 7.81(d,J= 2.4Hz, 1H), 6.27 (d, J= 2.4Hz, 1H), 4.07(q, J= 7.2Hz, 2H), 3.72(s, 2H), 1.72(s, 6H), 1.12(t, J= 6.8Hz, 3H).

[0894] Step 5: 2-(3-(aminomethyl)-1H-pyrazol-1-yl)-2-methylprop-1-ol (XXXIII)

[0895] At 0°C, a solution of ethyl 2-(3-(aminomethyl)-1H-pyrazol-1-yl)-2-methylpropionate XXXIIId (150 mg, 0.710 mmol) in diethyl ether (5 mL) was added dropwise to a stirred solution of LAH (2.84 mL, 1 m, 2.84 mmol) in diethyl ether (20 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C and quenched with water (0.15 mL), 15% NaOH (0.15 mL), and then with ethyl acetate (10 mL). The mixture was filtered through a diatomaceous earth bed and the residue was washed with ethyl acetate (50 mL x 3). The filtrate was concentrated under reduced pressure to give compound XXXIII as a pale yellow liquid. The crude product was used for the next step without further purification. Yield: 0.12 g (100%).

[0896] Synthesis of (1-(2-(2-aminoethyl)thiazolyl-4-yl)cyclopropyl)methanol (XXXIV)

[0897]

[0898] Step 1: 2-(2-bromothiazolyl-4-yl)ethyl acetate (XXXIVa)

[0899] To a stirred solution of ethyl 2-(2-aminothiazol-4-yl)acetate (CAS: 53266-94-7, 1.0 g, 5.4 mmol) in 10 mL of ACN, tert-butyl nitrite (0.84 g, 0.97 mL, 8.2 mmol) was added, and the reaction mixture was stirred at 60 °C for 30 min. Then, copper bromide (I) (0.77 g, 5.4 mmol) was added, and the reaction mixture was heated at 75 °C for 2 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was concentrated, and the residue was purified by silica gel (230-400) column chromatography with ethyl acetate in 0-10% n-hexane to give the desired compound as a pale yellow viscous liquid. Yield: 0.45 g (34.0%); calculated by LC-MS. For C7H9BrNO2S: 249.96; after observation: 250.00; [M+H]+ ; 1 H NMR (400 MHz, CDCl3): ​ 7.18(s, 1H), 4.20(q, J= 7.2Hz, 2H), 3.81(s, 2H), 1.28(t, J= 7.2Hz, 3H).

[0900] Step 2: Ethyl 1-(2-bromothiazol-4-yl)cyclopropane-1-carboxylate (XXXIVb)

[0901] A stirred solution of 2-(2-bromothiazol-4-yl)ethyl acetate XXXIVa (200 mg, 0.80 mmol) in DMF (2 mL) was cooled to 0 °C, and NaH (42.2 mg, 1.76 mmol) was added fractionally under an inert atmosphere. Then, 1,2-dibromoethane (330 mg, 1.76 mmol) was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. The reaction mixture was quenched with ice-cold water, and the reaction mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give the desired compound XXXIVb as a light brown viscous liquid. Yield: 160 mg (72%); calculated by LC-MS. For C9H 11 BrNO2S: 277.97; after observation: 278.10; [M+H] + ; 1 H NMR (400 MHz, CDCl3): ​ 7.47 (s, 1H), 4.17 (q, J= 7.2Hz, 2H), 1.70-1.68(m, 2H), 1.50-1.49(m, 2H), 1.26(t, J= 7.2Hz, 3H).

[0902] Step 3: Ethyl 1-(2-vinylthiazolyl-4-yl)cyclopropane-1-carboxylate (XXXIVc)

[0903] To a stirred solution of ethyl 1-(2-bromothiazol-4-yl)cyclopropane-1-carboxylate XXXIVb (2.2 g, 8.0 mmol) in 1,4-dioxane (40 mL), trifluoro(vinyl)-14-borane and its potassium salt (1.2 g, 8.8 mmol) were added, and the mixture was purified with argon for 10 min. Potassium phosphate (2.5 g, 12 mmol) was then added, and the mixture was further purified for 5 min before the addition of PdCl2 (dppf) (0.29 g, 0.40 mmol). The tube was sealed and heated at 120 °C for 3 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was concentrated under vacuum, and the residue was purified by silica gel (230-400 mesh) column chromatography with ethyl acetate in 0-10% n-hexane to give the desired compound XXXIVc as a light brown liquid. Yield: 1.1 g (61%); calculated by LC-MS. For C 11 H 14 NO2S: 224.08; after observation: 224.15; [M+H] + ; 1 H NMR (400 MHz, CDCl3): ​ 7.36 (s, 1H), 6.77 (q, J= 6.8Hz, 1H), 5.98 (d, J= 17.6Hz, 1H), 5.50 (d, J= 11.2Hz, 1H), 4.16(t, J= 7.2Hz, 2H), 1.69-1.66(m, 2H), 1.50-1.47(m, 2H), 1.28-1.22(m, 3H).

[0904] Step 4: Ethyl 1-(2-formylthiazolyl-4-yl)cyclopropane-1-carboxylate (XXXIVd)

[0905] A stirred solution of 1-(2-vinylthiazolyl-4-yl)cyclopropane-1-carboxylic acid ethyl ester XXXIVc (1.1 g, 4.9 mmol) in THF:water (2:1; 16.5 mL) was cooled to 0 °C, and osmium tetroxide (15.75 mL, 4% in water, 2.5 mmol) was added. The reaction mixture was stirred at 0 °C for 1 hour. Sodium periodate (1.6 g, 7.4 mmol) was then added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC analysis. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were concentrated under reduced pressure. The crude residue was purified by silica gel (230-400) column chromatography with 0-10% ethyl acetate / n-hexane to give the desired compound XXXIVd as a pale yellow viscous liquid. Yield: 1.0 g (90%); 1 H NMR (400 MHz, CDCl3): ​ 9.92(s, 1H), 8.04(s, 1H), 4.20(q, J= 7.2Hz, 2H), 1.79(t, J= 4.0Hz, 2H), 1.67-1.62(m, 2H), 1.28-1.22(m, 3H).

[0906] Step 5: (E)-1-(2-(2-nitrovinyl)thiazolyl-4-yl)cyclopropane-1-carboxylic acid ethyl ester (XXXIVe)

[0907] To a stirred solution of 1-(2-formylthiazolyl-4-yl)cyclopropane-1-carboxylic acid ethyl ester XXXIVd (1.1 g, 4.9 mmol) in DCM (14 mL), TEA (2.0 mL, 15 mmol) and nitromethane (0.53 mL, 9.8 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC analysis. After completion, the reaction mixture was concentrated under vacuum. The residue was immediately dissolved in fresh DCM (14 mL), and the resulting mixture was cooled to 0 °C. TEA (2.0 mL, 15 mmol) and methanesulfonyl chloride (0.76 mL, 9.8 mmol) were added, and the reaction mixture was stirred at 0 °C for 1 hour. The reaction was quenched with a saturated solution of NaHCO3 and extracted with DCM (10 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude compound XXXIVe was used for the next step without further purification. Yield: 1.2 g (92.3%); calculated by LC-MS. For C 11 H 13 N₂O₄S: 269.06; after observation: 269.15; [M+H] + ; 1H NMR (400 MHz, CDCl3): ​ 7.97 (m, 1H), 7.81 (s, J= 13.2Hz, 1H), 4.20(q, J= 7.2Hz, 2H), 1.72(q, J= 3.6Hz, 2H), 1.61-1.55(m, 4H), 1.29-1.24(m, 3H).

[0908] Step 6: (1-(2-(2-aminoethyl)thiazolyl-4-yl)cyclopropyl)methanol (XXXIV)

[0909] A stirred solution of (E)-1-(2-(2-nitrovinyl)thiazolyl-4-yl)cyclopropane-1-carboxylic acid ethyl ester XXXIVe (1.2 g, 4.5 mmol) in dried diethyl ether (25 mL) was cooled to 0 °C, and LiAlH4 solution (18 mL, 1 m, 18 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC analysis. The reaction was quenched with ice-cold water (1 mL) and 15% NaOH solution (1 mL). The resulting mixture was stirred at 0 °C for 10 minutes, and ethyl acetate (20 mL) was slowly added. The mixture was stirred for 10 minutes before filtration through a diatomaceous earth bed. The bed was thoroughly washed with ethyl acetate (100 mL x 3), dried with anhydrous sodium sulfate, and the combined filtrates were concentrated under reduced pressure to give the desired compound XXXIV as a pale yellow viscous liquid. Yield: 0.79 g (78.6%).

[0910] Synthesis of 2-(3-(2-aminoethyl)-4-fluoro-1H-pyrazol-1-yl)-2-methylprop-1-ol (XXXV)

[0911]

[0912] Step 1: Ethyl 4-fluoro-1H-pyrazole-3-carboxylate (XXXVa)

[0913] Selected fluorite (4 g, 11.3 mmol) was added to a stirred solution of ethyl 1H-pyrazole-3-carboxylate (CAS: 5932-27-4, 1 g, 7.0 mmol) in acetonitrile (15 mL), and the reaction mixture was stirred at 65 °C under a nitrogen atmosphere for 16 hours. The reaction progress was monitored by TLC. After completion, the reaction was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 3). The mixture was dried over anhydrous Na₂SO₄, filtered, and the combined organic layers were concentrated under reduced pressure. The crude product was purified by Combi-Flash silica gel column chromatography with ethyl acetate in 0–10% n-hexane to give the desired compound XXXVa as a creamy white solid. Yield: 0.5 g (50%); NMR (400 MHz, CDCl₃): ​ 10.95(bs, 1H), 7.59(s, 1H), 4.46-4.41(m, 2H), 1.41(t, J= 7.2Hz, 3H).

[0914] Step 2: (4-Fluoro-1H-pyrazole-3-yl)methanol (XXXVb)

[0915] A solution of LiAlH4 (15.2 mL, 1 mL in THF, 15.2 mmol) in diethyl ether (20 mL) was cooled to 0 °C, and a solution of ethyl 4-fluoro-1H-pyrazole-3-carboxylic acid ester XXXVa (600 mg, 3.79 mmol) in diethyl ether (5 mL) was added dropwise under an inert atmosphere. The reaction mixture was stirred at room temperature for 1 hour, and the reaction progress was monitored by TLC analysis. After completion, the reaction mixture was cooled in an ice bath and quenched dropwise with water (3.6 mL) and 15% NaOH (0.6 mL). Ethyl acetate (50 mL) was added to the resulting mixture and stirred at room temperature for 30 minutes. The mixture was filtered, and the residues were thoroughly washed with fresh ethyl acetate (50 mL x 2). The combined filtrates were concentrated under reduced pressure to give the desired compound XXXVb as a pale yellow liquid. The crude product was used for the next step without further purification. Yield: 0.40 g (90%). LC-MS calculations were performed. For C4H5FN2O: 116.10; after observation: 115.00; [MH] + .

[0916] Step 3: 4-Fluoro-1H-pyrazole-3-carboxaldehyde (XXXVc)

[0917] MnO2 (15.0 g, 172 mmol) was added to a stirred solution of (4-fluoro-1H-pyrazol-3-yl)methanol XXXVb (400 mg, 3.45 mmol) in THF (20 mL). The reaction mixture was stirred at 50 °C for 48 hours under a nitrogen atmosphere. The reaction was cooled to room temperature and filtered through a diatomaceous earth bed. The bed was washed with fresh ethyl acetate (10 mL x 3). The combined filtrates were concentrated under reduced pressure to give the desired product XXXVc as a pale yellow liquid. The crude product was used for the next step without further purification. Yield: 0.39 g (99%). LC-MS calculations were performed. For C4H3FN2O: 114.02; after observation: 113.10; [MH] + .

[0918] Step 4: Ethyl 2-(4-fluoro-3-formyl-1H-pyrazole-1-yl)-2-methylpropionate (XXXVd)

[0919] Cesium carbonate (2.28 g, 7.01 mmol) was added to a stirred solution of 4-fluoro-1H-pyrazole-3-carboxaldehyde XXXVc (400 mg, 3.51 mmol) in DMF (10 mL), followed by ethyl ethyl-2-bromo-2-methylpropionate (821 mg, 4.21 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. The reaction progress was monitored by TLC analysis. After completion, the reaction mixture was diluted with ice-cold water (200 mL) and extracted with ethyl acetate (100 mL x 3). The mixture was dried over anhydrous Na₂SO₄, filtered, and the organic layer was concentrated under reduced pressure. The starting material was purified by silica gel (230-400) column chromatography with ethyl acetate in 0-5% n-hexane to give the desired colorless liquid compound XXXVd. Yield: 0.9 g (100%); NMR (400 MHz, CDCl₃): ​ 9.93(s, 1H), 7.51-7.49(m, 1H), 4.22-4.17(m, 2H), 1.86(s, 6H), 1.23(t, J= 7.2Hz, 3H).

[0920] Step 5: Ethyl (E)-2-(4-fluoro-3-(2-nitrovinyl)-1H-pyrazole-1-yl)-2-methylpropionate (XXXVe)

[0921] Under a nitrogen atmosphere, nitromethane (2.84 mL, 52.6 mmol) and ammonium acetate (405 mg, 5.26 mmol) were added to a stirred solution of ethyl 2-(4-fluoro-3-formyl-1H-pyrazol-1-yl)-2-methylpropionate XXXVd (800 mg, 3.51 mmol) in toluene (20 mL). The mixture was stirred at 100 °C for 16 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to room temperature, diluted with 1N HCl (20 mL), and extracted with ethyl acetate (50 mL x 3). The mixture was dried over anhydrous Na₂SO₄, filtered, and the combined organic layers were concentrated under reduced pressure. The crude product was purified by Combi-Flash column chromatography with ethyl acetate in 0–2% n-hexane to give the desired compound XXXVe as a yellow solid. Yield: 0.5 g (52%); NMR (400 MHz, CDCl₃): ​ 7.94-7.93(m, 1H), 7.69-7.64(m, 1H), 7.51(d, J= 5.2Hz, 1H), 4.21-4.16(m, 2H), 1.83(s, 6H), 1.23(t, J= 7.2Hz, 3H).

[0922] Step 6: 2-(3-(2-aminoethyl)-4-fluoro-1H-pyrazol-1-yl)-2-methylprop-1-ol (XXXV)

[0923] A stirred solution of LiAlH4 (7.37 mL, 1 mL in THF, 7.37 mmol) in diethyl ether (80 mL) was cooled to 0 °C, and a solution of (E)-2-(4-fluoro-3-(2-nitrovinyl)-1H-pyrazole-1-yl)-2-methylpropionate ethyl ester XXXVe (500 mg, 1.84 mmol) in diethyl ether (10 mL) was added dropwise under a nitrogen atmosphere. The reaction was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC analysis. After completion, the reaction mixture was cooled to 0 °C, quenched with water (0.5 mL), 15% NaOH (0.5 mL), and then water (1.5 mL) was added. Ethyl acetate (30 mL) was added to the resulting mixture and stirred for 30 minutes. The mixture was filtered, and the residues were washed with fresh ethyl acetate (100 mL x 3). The combined filtrates were concentrated under reduced pressure to give the desired compound XXXV as a pale yellow liquid. The crude product was used for the next step without further purification. Yield: 0.35g (94%).

[0924] Synthesis of 7-amino-3-bromo-2-methyl-5-(methanesulfonyl)pyrazole[1,5-a]pyrimidine-6-onitrile (XXXVI)

[0925]

[0926] Step 1: 7-Amino-2-methyl-5-(methylthio)pyrazole[1,5-a]pyrimidine-6-onitrile (XXXVIa)

[0927] To a solution of 5-methyl-1H-pyrazole-3-amine (CAS: 31230-17-8, 2 g, 20 mmol) in pyridine (50 mL), 2-(bis(methylthio)methylene)malonitrile Ia (4 g, 20 mmol) was added, and the mixture was stirred at 120 °C for 3 h. The reaction progress was monitored by TLC. After the reaction was complete, water (500 mL) was added, and the solid was filtered to give the crude compound XXXVIa as a pink solid. The crude compound did not require further purification for the next step. Yield: 3.9 g (90.0%); LC-MS calculations: For C9H9N5S: 219.06; After observation: 220.25; [M+H] + . 1 H NMR (400 MHz, DMSO-D6): δ8.68(s, 2H), 6.25(s, 1H), 2.52(d, J =5.6Hz, 3H), 2.37s, 3H.

[0928] Step-2: 7-Amino-3-bromo-2-methyl-5-(methylthio)pyrazole[1,5-a]pyrimidine-6-onitrile (XXXVIb)

[0929] N-bromosuccinimide (1.89 g, 10.6 mmol) was added to a solution of 7-amino-2-methyl-5-(methylthio)pyrazole[1,5-a]pyrimidine-6-onitrile XXXVIa (1.89 g, 8.62 mmol) in acetonitrile (25 mL), and the mixture was stirred at 0 °C for 30 min. The reaction progress was monitored by TLC analysis. After the reaction was complete, water (50 mL) was added and the mixture was extracted with ethyl acetate (2 x 50 mL). The extract was dried over anhydrous sodium sulfate, filtered, and the combined organic layers were concentrated under reduced pressure to give the desired compound XXXVIb as a brown solid. The crude compound was used for the next step without any further purification. Yield: 1.9 g (74.0%); calculated by LC-MS. For C9H8BrN5S: 296.97; after observation: 298.15; [M+H] + . 1 HNMR (400 MHz, CDCl3): δ6.27(s,2H), 2.67(s, 3H), 2.43(s, 3H).

[0930] Step 3: 7-Amino-3-bromo-2-methyl-5-(methanesulfonyl)pyrazole[1,5-a]pyrimidine-6-onitrile (XXXVI)

[0931] At 0 °C, mCPBA (2.31 g, 13.4 mmol) was added to a solution of 7-amino-3-bromo-2-methyl-5-(methylthio)pyrazole[1,5-a]pyrimidine-6-onitrile XXXVIb (0.8 g, 2.68 mmol) in acetonitrile (15 mL), and the mixture was stirred at 0 °C for 30 min. The reaction progress was monitored by TLC analysis. After the reaction was complete, the reaction mixture was quenched with sodium bicarbonate (100 mL) and extracted with ethyl acetate (2 x 15 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the combined organic layers were concentrated under reduced pressure to give crude compound XXXVI as a brown solid. The crude compound was used for the next step without further purification. Yield: 600 mg (67.7%); calculated by LC-MS. For C9H8BrN5O2S: 328.96; after observation: 332; [M+H] + .

[0932] Synthesis of 2-(1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methyl)-1H-pyrazol-3-yl)ethyl-1-amine (XXXVII)

[0933]

[0934] Step-1: (1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methanol(XXXVIIa)

[0935] Imidazole (5 g, 0.07 mol) was added to a stirred solution of cyclopropane-1,1-diethanol (CAS: 39590-81-3, 5 g, 0.05 mol) in DCM (100 mL), and the mixture was stirred at room temperature for 10 min. The reaction mixture was then cooled to 0 °C, and TBDMS-Cl (7 g, 0.05 mol) was added dropwise under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 h, and the reaction was monitored by TLC analysis. After completion, the reaction was quenched with water (50 mL) and extracted with DCM (30 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate. The residue obtained after solvent removal was purified by silica gel (230-400 mesh) column chromatography with ethyl acetate in 0-30% n-hexane to give the desired colorless liquid compound XXXVIIa. Yield: 5.0 g (50%). 1 H NMR (400 MHz, CDCl3): ​ 3.61 (s, 2H), 3.57 (d, J= 5.6Hz, 2H), 2.74(t,J= 5.6Hz, 1H), 0.91(s,9H), 0.53-0.50(m,2H), 0.47-0.43(m,2H), 0.07(s, 6H).

[0936] Step 2: ((1-(bromomethyl)cyclopropyl)methoxy)(tert-butyl)dimethylsilane (XXXVIIb)

[0937] Triphenylphosphine (7 g, 30 mmol) was added to a stirred solution of (1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methanol XXXVIIa (4 g, 20 mmol) in DCM (100 mL), and the mixture was stirred at room temperature for 20 min. The reaction mixture was then cooled to 0 °C, and carbon tetrabromide (9 g, 30 mmol) was added dropwise under a nitrogen atmosphere. The reaction mixture was then stirred at room temperature for 1 h, and the reaction was monitored by TLC analysis. After completion, the reaction mixture was diluted with water (50 mL) and extracted with DCM (25 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate. The residue obtained after solvent removal was purified by silica gel (230-400 mesh) column chromatography with ethyl acetate in 0-20% n-hexane to give the desired colorless liquid compound XXXVIIb. Yield: 4.0 g (80%). 1 H NMR (400 MHz, CDCl3): ​ 3.56(s, 2H), 3.49(s, 2H), 0.93-0.89(m,9H), 0.74-0.71(m,2H), 0.61-0.57(m,2H), 0.07(s, 6H).

[0938] Step 3: 1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methyl)-1H-pyrazole-3-carboxaldehyde (XXXVIIc)

[0939] Cesium carbonate (7 g, 20 mmol) was added to a stirred solution of 1H-pyrazole-3-carboxaldehyde (1 g, 10 mmol) in DMF (10 mL), and the mixture was stirred at room temperature for 20 min. The reaction mixture was then cooled to 0 °C, and ((1-(bromomethyl)cyclopropyl)methoxy)(tert-butyl)dimethylsilane XXXVIIb (3 g, 10 mmol) was added dropwise under a nitrogen atmosphere. The reaction mixture was then stirred at room temperature for 16 h, and the reaction was monitored by TLC analysis. After completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate. The residues obtained after solvent removal were purified by silica gel (230-400 mesh) column chromatography with ethyl acetate in 0-20% n-hexane to give the desired compound XXXVIIc as a colorless liquid. Yield: 1.5 g (50%). LC-MS calculations were performed. For C 15 H 26 N₂O₂Si: 294.17; after observation: 295.25; [M+H] + ; 1 H NMR (400 MHz, CDCl3): ​ 9.97 (s, 1H), 7.52 (d, J= 1.6Hz, 1H), 6.80 (d, J =2.4Hz, 1H), 4.21(s, 2H), 3.32(s, 2H), 0.90(s, 9H), 0.70-0.68(m,2H), 0.58-0.56(m,2H), 0.02(s, 6H).

[0940] Step-4: (E)-1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methyl)-3-(2-nitrovinyl)-1H-pyrazole (XXXVIId)

[0941] To a stirred solution of 1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methyl)-1H-pyrazole-3-carboxaldehyde XXXVIIc (1.5 g, 5.1 mmol) in toluene (50 mL), nitromethane (4.7 g, 4.1 mL, 76 mmol) was added, and the mixture was stirred at room temperature for 10 min. Ammonium acetate (0.59 g, 7.6 mmol) was then added, and the reaction mixture was stirred at 100 °C for 16 h. The reaction progress was monitored by TLC analysis. After completion, the reaction mixture was cooled to room temperature, diluted with 1 N HCl (50 mL), and extracted with ethyl acetate (25 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate. The residue obtained after solvent removal was purified by silica gel (230-400 mesh) column chromatography with ethyl acetate in 0-30% n-hexane to give the desired compound XXXVIId as a pale yellow solid. Yield: 1.15 g (65%). LC-MS calculations were performed. For C 16 H 27 N3O3Si: 337.18; after observation: 338.20; [M+H] + ; 1 H NMR (400 MHz, CDCl3): ​ 7.96(d, J= 13.2Hz, 1H), 7.61 (d, J =13.2Hz, 1H), 7.26(s, 1H), 6.53(s, 1H), 4.16(s, 2H), 3.31(s,2H), 0.90(s, 9H), 0.67(m,2H), 0.55(m,2H), 0.02(s, 6H).

[0942] Step 5: 2-(1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methyl)-1H-pyrazole-3-yl)ethyl-1-amine (XXXVII)

[0943] To a stirred solution of lithium aluminum hydride (0.01 L, 1.0 mol in THF, 10 mmol) in diethyl ether (70 mL), (E)-1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methyl)-3-(2-nitrovinyl)-1H-pyrazole XXXVIId (1.15 g, 3.41 mmol) was added dropwise at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour, and the reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C, and 1.2 mL of ice-cold water and 1.2 mL of 15% KOH solution were added, followed by stirring at room temperature for another 30 minutes. The reaction mixture was diluted with 100 mL of ethyl acetate, filtered through a Buchner funnel, and the solid was thoroughly washed with 250 mL of ethyl acetate. The solid was dried over anhydrous sodium sulfate and the filtrate was concentrated under reduced pressure to give the desired compound XXXVII as a pale yellow liquid. The crude product was used for the next step without further purification. Yield: 0.81 g (100%). Perform LC_MS calculation. For C 16 H 31 N3OSi: 309.22; after observation: 310.30; [M+H] + .

[0944] Synthesis of 2-(6-(2-aminoethyl)pyridin-2-yl)-2,2-difluoro-1-ethanol (XXXVIII)

[0945]

[0946] Step 1: Ethyl 2,2-difluoro-2-(6-formylpyridin-2-yl)ethyl acetate (XXXVIIIa)

[0947] At room temperature and under a nitrogen atmosphere, copper (0.8 g, 0.01 mol) and ethyl 2-bromo-2,2-difluoroacetate (CAS: 667-27-6, 1 g, 7 mmol) were added to a solution of 6-bromopyridinaldehyde (CAS: 34160-40-2, 1 g, 5 mmol) in DMSO (5 mL) in a sealed tube with a PTFE screw stopper. The tube was sealed, and the reaction mixture was stirred at 100 °C for 2 hours. The reaction was monitored by TLC analysis. After completion, the reaction mixture was cooled to room temperature, and 50 mL of ethyl acetate and 50 mL of 1.3 mol potassium dihydrogen phosphate solution were added. The mixture was stirred at room temperature for 30 minutes. The solid was filtered off and thoroughly washed with ethyl acetate (30 mL x 2). The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained after solvent removal was removed by silica gel (230-400 mesh) column chromatography in 0-6% n-hexane to obtain the desired compound XXXVIIIa as a white solid. Yield: 0.93 g (80%). LC-MS calculations were performed. For C10 H9F2NO3: 229.05; after observation: 230.15; [M+H] + ; 1 H NMR (400 MHz, DMSO-D6): ​ 9.95(bs, 1H), 8.35-8.13(m,3H), 4.38(q, J= 7.2Hz, 2H), 1.25(t, J = 7.2Hz, 3H).

[0948] Step 2: Synthesis of (E)-2,2-difluoro-2-(6-(2-nitrovinyl)pyridin-2-yl)ethyl acetate (XXXVIIIb)

[0949] At room temperature and under a N2 atmosphere, triethylamine (1.13 mL, 8.12 mmol) and nitromethane (263 µL, 4.87 mmol) were added to a stirred solution of ethyl 2,2-difluoro-2-(6-(1-hydroxy-2-nitroethyl)pyridin-2-yl)acetate XXXVIIIa (930 mg, 4.06 mmol) in DCM (20 mL). The resulting reaction mixture was stirred at room temperature for 2 hours, and the reaction was monitored by TLC analysis. After completion, the DCM was concentrated to dryness, and the residue was immediately used as is in the next step. Triethylamine (1.70 mL, 12.17 mmol) was added to a solution of the starting material ethyl 2,2-difluoro-2-(6-(1-hydroxy-2-nitroethyl)pyridin-2-yl)acetate (1.177 g, 4.06 mmol) in DCM (25 mL) and cooled to 0 °C, followed by dropwise addition of methanesulfonyl chloride (1.394 g, 1.226 mL, 12.17 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC analysis. After completion, the reaction mixture was quenched with water (25 mL) and extracted with DCM (20 x 2). The combined organic layers were washed with 25 mL of brine, filtered through anhydrous sodium sulfate, and concentrated under reduced pressure. The residue after solvent removal was purified by silica gel (230-400 mesh) column chromatography with ethyl acetate in 0-6% n-hexane to give the desired compound XXXVIIIb as a brown viscous liquid. Yield: 0.77 g (70%). LC-MS calculations were performed. For C... 11 H 10 F₂N₂O₄: 272.06; after observation: 273.15; [M+H] + ; 1 H NMR (400 MHz, DMSO-D6): ​ 8.26-7.97 (m, 5H), 4.38 (q, J=7.2Hz, 2H), 1.25(t, J= 4.0Hz, 3H).

[0950] Step 3: Synthesis of 2-(6-(2-aminoethyl)pyridin-2-yl)-2,2-difluoro-1-ethanol (XXXVIII)

[0951] Under a nitrogen atmosphere, at 0 °C, a solution of (E)-2,2-difluoro-2-(6-(2-nitrovinyl)pyridin-2-yl)acetate XXXVIIIb (0.770 g, 2.83 mmol) in diethyl ether (5 mL) was added dropwise to a stirred solution of lithium aluminum hydride (11.3 mL, 1.0 mol in THF). The mixture was stirred at room temperature for 2 hours, and the reaction was monitored by TLC analysis. After completion, the reaction mixture was cooled to 0 °C, 0.7 mL of ice-cold water and 0.7 mL of 15% KOH solution were added, and the mixture was stirred again at room temperature for 30 minutes. The reaction mixture was diluted with 100 mL of ethyl acetate, filtered, and the solid was thoroughly washed with 100 mL of ethyl acetate. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the desired compound XXXVIII as a light brown viscous liquid. The crude product was used for the next step without further purification. Yield: 0.56 g (98%). Perform LC_MS calculation. For C9H 12 F2N2O: 202.09; after observation: 203.25; [M+H] + .

[0952] Synthesis of (2-(3-(2-aminoethyl)-1H-pyrazole-1-yl)cyclobutyl)methanol (XXXIX)

[0953]

[0954] Step 1: Ethyl cyclobut-1-ene-1-carboxylate (XXXIXa)

[0955] A stirred solution of DBU (54 mL, 312.3 mmol) in toluene (50 mL) was heated at 150 °C for 20 min, and ethyl 1-bromocyclobutane-1-carboxylate (CAS: 35120-18-4, 5.0 g, 52.050 mmol) was added dropwise through a septum under an inert atmosphere. The reaction mixture was stirred at 110 °C for 3.5 h. The reaction progress was monitored by TLC analysis. After completion, the reaction mixture was cooled to room temperature and diluted with ice-cold water (200 mL). The mixture was extracted with n-hexane (100 mL x 3). The combined organic layers were washed first with a saturated solution of hydrated NaHSO4 (100 mL) and then with water (100 mL). The layers were separated, dried over anhydrous Na2SO4, filtered, and concentrated at ambient temperature (20 °C, 100 mbar vacuum). (Note: The desired product appears to be volatile and may pass into the receiver during concentration in a rotary evaporator). By assuming a quantitative yield, crude compound XXXIXa (compound + a certain amount of toluene) is used for the next step.

[0956] Step 2: Ethyl 2-(3-formyl-1H-pyrazole-1-yl)cyclobutane-1-carboxylate (XXXIXb)

[0957] To a stirred solution of 1H-pyrazole-3-carboxaldehyde (CAS: 3920-50-1, 5.0 g, 52 mmol) in DMF (20 mL), K₂CO₃ (14 g, 100 mmol) was added, and the reaction mixture was cooled to 0 °C under an inert atmosphere. Subsequently, a mixture of ethylcyclobut-1-ene-1-carboxylic acid ester XXXIXa (16 g, 78 mmol) and toluene was added dropwise. The resulting mixture was stirred at room temperature for 48 hours, and the reaction progress was monitored by TLC analysis. After completion, the reaction mixture was diluted with ice-cold water (500 mL) and extracted with ethyl acetate (200 mL x 3). The mixture was dried over anhydrous Na₂SO₄, filtered, and the combined organic layers were concentrated under reduced pressure. The crude product was purified by Combi-Flash (230-400 silica) column chromatography with ethyl acetate in 0–5% n-hexane to give the desired compound XXXIXb as a colorless, viscous liquid. Yield: 1.4 g (10%); calculated by LC-MS. For C 11 H 14 N₂O₃: 222.10; after observation: 223.05; [M+1] + . 1 H NMR (400 MHz, CDCl3): ​ 9.99 (s, 1H), 7.50 (d, J= 1.6Hz, 1H), 6.79 (d, J= 2.0Hz, 1H), 5.00(t, J=8.8Hz, 1H), 4.16(q, J= 7.2Hz, 2H), 3.68-3.66(m,1H), 2.75-2.70(m,1H), 2.46-2.44(m,1H), 2.31-2.26(m,1H), 2.10-2.04(m,1H), 1.25(t, J= 7.2Hz, 3H).

[0958] Step 3: (E)-2-(3-(2-nitrovinyl)-1H-pyrazole-1-yl)cyclobutane-1-carboxylic acid ethyl ester (XXXIXc)

[0959] Under a nitrogen atmosphere, nitromethane (5.1 mL, 94 mmol) and ammonium acetate (0.73 g, 9.4 mmol) were added to a stirred solution of ethyl 2-(3-formyl-1H-pyrazole-1-yl)cyclobutane-1-carboxylic acid XXXIXb (1.4 g, 6.3 mmol) in toluene (20 mL). The resulting reaction mixture was stirred at 100 °C for 16 hours. The reaction was monitored by TLC analysis. After completion, the reaction mixture was cooled to room temperature and diluted with 1N HCl (100 mL). The mixture was extracted with ethyl acetate (300 mL x 3), and the combined organic layers were dried over Na2SO4. The solution was concentrated under reduced pressure. The crude product was purified by Combi-Flash (230-400) column chromatography with ethyl acetate in 0-5% n-hexane to give the desired compound XXXIXc as a pale yellow viscous liquid. Yield: 1.2 g (71%); calculated by LC-MS. For C 12 H 15 N3O4: 265.10; after observation: 267.30; [M+1] + . 1 H NMR (400 MHz, CDCl3): ​ 7.98(d, J= 13.6Hz, 1H), 7.63 (d, J= 13.6Hz, 1H), 7.48(s, 1H), 6.52(d, J= 2.0Hz, 1H), 4.95 (d, J= 8.4Hz, 1H), 4.19-4.13(m,2H), 3.67-3.60(m,1H), 2.45-2.38(m,1H), 2.33-2.25(m,1H), 2.10-2.00(m,1H), 2.09-1.99(m,1H), 1.27(t, J= 7.2Hz, 3H).

[0960] Step 4: (2-(3-(2-aminoethyl)-1H-pyrazole-1-yl)cyclobutyl)methanol (XXXIX)

[0961] Under an inert atmosphere, at 0 °C, a solution of (E)-2-(3-(2-nitrovinyl)-1H-pyrazole-1-yl)cyclobutane-1-carboxylic acid ethyl ester XXXIXc (1.2 g, 4.5 mmol) in diethyl ether (50 mL) was added dropwise to a stirred solution of LiAlH4 (18 mL, 1 mol, 18 mmol in THF). The resulting mixture was heated to room temperature and stirred for 1 hour. The reaction was monitored by TLC analysis. After completion, the reaction mixture was cooled to 0 °C and quenched with water (1.2 mL) and 15% KOH (1.2 mL). The mixture was stirred for 5 minutes and water (2.4 mL) was added again. The mixture was filtered and the residue was washed with ethyl acetate (200 mL x 3). The filtrate was concentrated under reduced pressure to give the desired compound XXXIX as a pale yellow liquid. The crude product was used for the next step without further purification. Yield: 1.1 g (88%).

[0962] Synthesis of 3-(2-aminoethyl)-1-methylpyridin-2(1H)-one (XL)

[0963]

[0964] Step 1: (E)-2-methoxy-3-(2-nitrovinyl)pyridine (XLa)

[0965] Ammonium acetate (4.64 g, 60.2 mmol) and nitromethane (32.4 mL, 602 mmol) were added to a stirred solution of 2-methoxynicotinaldehyde (CAS: 71255-09-9, 5.50 g, 40.1 mmol) in toluene (60 mL). The reaction mixture was stirred at 110 °C for 2 h, and the reaction progress was monitored by TLC analysis. After completion, the reaction mixture was cooled to room temperature and diluted with water (100 mL), and the resulting mixture was extracted with ethyl acetate (200 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography with ethyl acetate in 0–10% n-hexane to give the compound as a yellow solid. Yield: 4.5 g (62%). LC-MS calculations were performed. For C8H8N2O3: 180.05; after observation: 181.25; [M+H] + . 1 H NMR (400MHz, CDCl3): ​ 8.28-8.26(m,1H), 8.02-7.92(m,2H), 7.76-7.73(m,1H), 7.02-6.99(m,1H), 4.10(s, 3H).

[0966] Step 2: 2-(2-Methoxypyridin-3-yl)ethyl-1-amine (XLb)

[0967] At 0 °C and under an inert atmosphere, LiAlH4 (141 mL, 140 mmol in THF) was added dropwise over 20 minutes to a stirred solution of (E)-2-methoxy-3-(2-nitrovinyl)pyridine XLa (8.5 g, 47 mmol) in diethyl ether (170 mL). The reaction was stirred at room temperature for 2 hours, and the reaction progress was monitored by TLC. After completion, the reaction was quenched first with water (17 mL), then with 15% NaOH solution (8.5 mL) and ethyl acetate (200 mL). The mixture was diluted with ethyl acetate (300 mL) and stirred for 20 minutes. The resulting white precipitate was filtered and thoroughly washed with fresh ethyl acetate (300 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to give compound XLb as a brown liquid. Yield: 6.5 g (92%). 1 H NMR (400MHz, CDCl3): ​ 8.04-8.03(m,1H), 7.41-7.39(m,1H), 6.83-6.80(m,1H), 3.97-3.94(m,5H), 2.95-2.92(m,2H), 2.73-2.69(m,2H).

[0968] Step 3: 2-(2-(2-methoxypyridin-3-yl)ethyl)isoindoline-1,3-dione (XLc)

[0969] At room temperature, isobenzofuran-1,3-dione (5.1 g, 34 mmol) was added to a stirred solution of 2-(2-methoxypyridin-3-yl)ethyl-1-amine XLb (5.2 g, 34 mmol) in acetic acid (60 mL). The resulting reaction mixture was refluxed and stirred vigorously for 3 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was concentrated under vacuum. The residue was dissolved in acetic anhydride (19 mL, 20 mmol), refluxed, and stirred vigorously for 16 hours. The reaction progress was monitored by TLC. After completion, the reaction was cooled to room temperature and quenched with a saturated solution of NaHCO3 (200 mL). The mixture was extracted with DCM (300 mL x 3), and the combined organic layers were dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to give a crude compound, which was purified by Combi-Flash column chromatography with ethyl acetate in 0–20% n-hexane to give the desired product XLc as a yellow solid. Yield: 5.0 g (52%). Perform LC_MS calculation. For C 16 H 14N₂O₃: 282.10; after observation: 283.25; [M+H] + .

[0970] Step 4: 2-(2-(2-oxo-1,2-dihydropyridin-3-yl)ethyl)isoindoline-1,3-dione (XLd)

[0971] TMS-I (6.0 mL, 44 mmol) was added to a stirred solution of 2-(2-(2-methoxypyridin-3-yl)ethyl)isoindoline-1,3-dione XLc (2.5 g, 8.9 mmol) in chloroform (50 mL) at room temperature under an inert atmosphere. The reaction mixture was stirred at 85 °C for 16 h, and the reaction progress was monitored by TLC analysis. After completion, the reaction mixture was quenched by adding methanol (5 mL) and concentrated. The crude product was ground with ethanol / MTBE (1:3). The solid formed was collected by filtration and dried under vacuum to give the desired compound XLd as a yellow solid. Yield: 1.9 g (79%). LC-MS calculations were performed. For C 15 H 12 N₂O₃: 268.08; after observation: 269.05; [M+H] + . 1 HNMR (400 MHz, CDCl3): ​ 7.95(d, J= 6.4Hz, 1H), 7.80(t, J= 3.2Hz, 2H), 7.71-7.69(m,3H), 6.67(bs, 1H), 4.04(bs, 2H), 3.06(bs,2H).

[0972] Step 5: 2-(2-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)ethyl)isoindoline-1,3-dione (XLe)

[0973] To a stirred solution of 2-(2-(2-(2-oxo-1,2-dihydropyridin-3-yl)ethyl)isoindoline-1,3-dione XLd (700 mg, 5.69 mmol) in dimethoxymethane (14 mL), K₂CO₃ (1.57 g, 11.4 mmol) was added, followed by iodomethane (0.7 mL, 11.4 mmol). The reaction mixture was stirred at 90 °C under a nitrogen atmosphere for 24 hours. The reaction progress was monitored by TLC analysis. After completion, the reaction was cooled to room temperature, and the solid was filtered off. The filtrate was concentrated under vacuum, and the residue was purified by Combi-Flash silica gel (230-400) column chromatography with ethyl acetate in 0-20% n-hexane to give the desired product XLe as a yellow solid. Yield: 0.58 g (74%). LC-MS calculations were performed. For C 16 H 14 N₂O₃: 282.10; after observation: 283.25; [M] + +1]. 1 HNMR (400 MHz, CDCl3): ​ 7.82-7.80(m,2H), 7.71-7.68(m,2H), 7.19-7.17(m,1H), 7.11-7.10(m,1H), 5.99(t, J= 6.8Hz, 1H), 4.01(t, J= 6.8Hz, 2H), 3.55(s, 3H), 2.92(t, J= 6.4Hz, 2H).

[0974] Step 6: 3-(2-aminoethyl)-1-methylpyridin-2(1H)-one (XL)

[0975] Hydrazine hydrate (0.015 mL, 3.08 mmol) was added to a stirred solution of 2-(2-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)ethyl)isoindoline-1,3-dione XLe (580 mg, 2.05 mmol) in methanol (5 mL). The reaction mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction progress was monitored by TLC analysis. After completion, the reaction mixture was concentrated under vacuum. The mixture was then diluted with water (2 mL) and the crude product was acidified with concentrated HCl (pH=2). The solid formed was filtered and washed with water (2 mL). The mixture was alkalized with 1N NaOH solution and the aqueous layer was extracted with methanol in 10% DCM (100 mL x 3). The combined organic layers were dried with sodium sulfate and concentrated under vacuum to give the title compound XL as a pale yellow viscous liquid. The crude product was used for the next step without further purification. Yield: 0.3 g (95%). LC-MS calculations were performed. For C8H 12N₂O: 152.09; after observation: 153.00; [M+H] + .

[0976] Synthesis of 3-(2-aminoethyl)-1-ethylpyridin-2(1H)-one XLI

[0977]

[0978] Step 1: Synthesis of 2-(2-(1-ethyl-2-oxo-1,2-dihydropyridin-3-yl)ethyl)isoindoline-1,3-dione (XLIa)

[0979] K₂CO₃ (0.62 g, 4.47 mmol) and iodoethane (0.7 g, 4.47 mmol) were added to a solution of (2-(2-oxo-1,2-dihydropyridin-3-yl)ethyl)isoindoline-1,3-dione XLd (0.6 g, 2.24 mmol) in dimethoxyethane (3 mL). The reaction mixture was stirred at 90 °C for 24 h. The reaction progress was monitored by TLC analysis. After the reaction was complete, the mixture was filtered and concentrated under reduced pressure. The crude compound was purified by silica gel (230-400 mesh) column chromatography with ethyl acetate (0-50%) in hexane to give the desired compound XLIa as a yellow solid. Yield: 0.6 g (90.0%); calculated by LC-MS. For C 17 H 16 N₂O₃: 296.12; after observation: 297.20; [M+H] + .

[0980] Step 2: 3-(2-aminoethyl)-1-ethylpyridin-2(1H)-one (XLI)

[0981] To a solution of 2-(2-(1-ethyl-2-oxo-1,2-dihydropyridin-3-yl)ethyl)isoindoline-1,3-dione XLIa (0.6 g, 2.02 mmol) in methanol (6 mL), hydrazine hydrate (0.15 mL, 3.04 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC analysis. After the reaction was complete, the reaction mixture was concentrated and water (2 mL) was added, followed by acidification with concentrated HCl (pH=2). The solid was filtered, alkalized with sodium hydroxide (5 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound XLI. The crude compound was used for the next step without further purification. Yield: 0.3 g (89.02%); calculated by LC-MS. For C9H 14 N₂O: 166.11; after observation: 167.30; [M+H] + .

[0982] Synthesis of 7-amino-3-ethyl-5-(methanesulfonyl)pyrazole[1,5-a]pyrimidine-6-onitrile (XLII)

[0983]

[0984] Step 1: 2-Formylbutyronitrile (XLIIa)

[0985] At -78°C, butyronitrile (5 g, 70 mmol) was added to a solution of LiHMDS (20 g, 100 mmol) in THF (200 mL), and the mixture was stirred at the same temperature for 1 hour. Ethyl formate (6 mL, 70 mmol) was then added, and the mixture was stirred for 1 hour. The reaction progress was monitored by TLC analysis. After the reaction was complete, the reaction mixture was quenched with saturated ammonium chloride (50 mL) and extracted with diethyl ether (200 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and the combined organic layers were concentrated under reduced pressure to give the crude compound XLIIa as a pale yellow viscous liquid. The crude compound was used directly in the next step without any further purification. Yield: 7.1 g (89.0%); calculated by LC-MS. For C5H7NO: 97.05; after observation: 96.00; [M+H] + .

[0986] Step 2: 4-Ethyl-1H-pyrazole-5-amine (XLIIb)

[0987] Acetic acid (1.6 mL, 28 mmol) was added to a solution of 2-formylbutyronitrile XLIIa (7.9 g, 81 mmol) and hydrazine hydrate (1:1, 4.8 mL, 98 mmol) in ethanol (80 mL), and the mixture was stirred at 80 °C for 20 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated, water (100 mL) was added, and the mixture was extracted with methanol in 0.5% dichloromethane (300 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel (100-200 mesh) column chromatography with methanol (0-2%) in dichloromethane to give the desired compound XLIIb as a pale yellow viscous liquid. Yield: 5.0 g (60.0%).

[0988] Step 3: 7-Amino-3-ethyl-5-(methylthio)pyrazole[1,5-a]pyrimidine-6-onitrile (XLIIc)

[0989] To a solution of 4-ethyl-1H-pyrazole-3-amine XLIIb (1 g, 9 mmol) in pyridine (10 mL), 2-(bis(methylthio)methylene)malononitrile Ia (2 g, 10 mmol) was added, and the reaction mixture was stirred at 120 °C for 2 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was poured into ice-cold water and the solid was filtered off. The crude compound was purified by silica gel (100-200 mesh) column chromatography with ethyl acetate (0-10%) in n-hexane to give the desired compound XLIIc as a brown solid. Yield: 1.5 g (70.0%); calculated by LC-MS. For C 10 H 11 N5S: 233.07; After observation: 232.5; [M+H] + .

[0990] Step 4: 7-Amino-3-ethyl-5-(methanesulfonyl)pyrazole[1,5-a]pyrimidine-6-onitrile (XLII)

[0991] To a solution of 7-amino-3-ethyl-5-(methylthio)pyrazole[1,5-a]pyrimidine-6-onitrile (0.7 g, 3.00 mmol) in dichloromethane (20 mL), mCPBA (2.59 g, 15.0 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC analysis. After the reaction was complete, the reaction mixture was cooled to 0 °C, quenched with saturated sodium bicarbonate (5 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the starting material. The crude compound was washed with pentane and stirred with methanol (2 mL) for 10 min. The solid was filtered and the organic layer was concentrated to give the desired compound XLII as a creamy white solid. Yield: 125 mg (15.7%); calculated by LC-MS. For C 10 H 11 N₅O₂S: 265.06; after observation: 266.20; [M+H] + .

[0992] Synthesis of (6-(2-aminoethyl)pyridin-2-yl)methanol (XLIII)

[0993]

[0994] Step 1: Methyl 6-(((tert-butyldimethylsilyl)oxy)methyl)pyridinecarboxylate (XLIIIa)

[0995] Imidazole (20 g, 0.30 mol) was added to a stirred solution of methyl 6-(hydroxymethyl)pyridinecarboxylate (CAS: 39977-44-1, 25 g, 0.15 mol) in DCM (500 mL) at 0 °C under an inert atmosphere, and the mixture was stirred for 10 min. Subsequently, TBDMS-Cl (45 g, 0.30 mol) was added fractionally, and the mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC analysis. After completion, the reaction was quenched with water (500 mL), and the mixture was extracted with ethyl acetate (500 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel (100-200) column chromatography with ethyl acetate in 0-10% n-hexane to give the desired compound XLIIIa as a creamy white solid. Yield: 33 g (78.0%); calculated by LC-MS. For C 14 H 23 NO3Si: 281.14; after observation: 282.35; [M+H] + . 1 H NMR (400MHz, CDCl3): ​ 8.01(d, J= 7.6Hz, 1H), 7.86(t, J= 8.0Hz, 1H), 7.74 (d, J= 8.0Hz, 1H), 4.93(s, 2H), 3.99(s, 3H), 0.96(s, 9H), 0.12(s, 6H).

[0996] Step-2: (6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)methanol(XLIIIb)

[0997] A stirred solution of methyl 6-(((tert-butyldimethylsilyl)oxy)methyl)pyridinecarboxylate XLIIIa (33 g, 0.12 mol) in THF:MeOH (525 mL; 2:1) was cooled to 0 °C, and NaBH4 (13 g, 0.35 mol) was added fractionally over 20 minutes under an inert atmosphere, keeping the reaction temperature below 5 °C. The reaction mixture was stirred at room temperature for 16 hours, and the reaction progress was monitored by TLC analysis. After completion, the reaction mixture was concentrated under reduced pressure, and a saturated solution of NaHCO3 (300 mL) was added to the residue. The mixture was extracted with DCM (300 mL x 3), and the combined organic layers were dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The crude compound was purified by silica gel (100-200) column chromatography with ethyl acetate in 10-20% n-hexane to give the desired compound XLIIIb as a colorless viscous liquid. Yield: 29 g (99.0%); calculated by LC-MS. For C 13 H 23 NO2Si: 253.15; after observation: 254.30; [M+H] + . 1 H NMR (400 MHz, CDCl3): ​ 7.70(t, J= 7.6Hz, 1H), 7.40 (d, J= 8.0Hz, 1H), 7.08 (d, J= 8.0Hz, 1H), 4.33(s, 2H), 4.73(d, J= 4.8Hz, 2H), 3.78(t, J= 4.8Hz, 1H), 0.96(s, 9H), 0.13(s, 6H).

[0998] Step 3: Methyl (6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)methylsulfonate (XLIIIc)

[0999] A stirred solution of (6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)methanol XLIIIb (29 g, 0.11 mol) and TEA (24 mL, 0.17 mol) in DCM (300 mL) was cooled to 0 °C under an inert atmosphere. Methanesulfonyl chloride (11 mL, 1.2 eq, 0.14 mol) was added dropwise to the resulting mixture over 30 minutes, and the reaction mixture was stirred at 0 °C for 2 hours. The reaction progress was monitored by TLC analysis. After completion, the reaction mixture was quenched with a saturated solution of NaHCO3 (300 mL) and extracted with DCM (300 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the desired compound XLIIIc as a pale yellow solid. Yield: 40 g (100%); calculated by LC-MS. For C 14 H 25 NO4SSi: 331.13; after observation: 332.30; [M+H] + .

[1000] Step 4: 2-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)acetonitrile (XLIIId)

[1001] NaCN (6.49 g, 132 mmol) was added to a stirred solution of methyl 6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)methanesulfonate XLIIIc (40 g, 120 mmol) in DMF (300 mL), and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion, the reaction was quenched with water (500 mL), and the resulting mixture was extracted with ethyl acetate (500 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography with ethyl acetate in 0–15% n-hexane to give the desired compound XLIIId as a yellow viscous liquid. Yield: 21 g (66.7%); 1 H NMR (400 MHz, CDCl3): ​ 7.75(t, J= 8.0Hz, 1H), 7.48 (d, J= 7.6Hz, 1H), 7.29 (d, J= 7.6Hz, 1H), 4.80(s, 2H), 3.89(s, 2H), 0.96(s, 9H), 0.12(s, 6H).

[1002] Step 5: Synthesis of (6-(2-aminoethyl)pyridin-2-yl)methanol (XLIII)

[1003] At 0 °C, BH3·DMS (28.8 mL, 320 mmol) was added to a stirred solution of 2-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)acetonitrile (21 g, 80 mmol) in dried THF (250 mL), and the reaction mixture was stirred at 70 °C for 3 h. The reaction progress was monitored by TLC analysis. After completion, the reaction mixture was cooled to 0 °C, quenched with MeOH (15 mL), and stirred for 30 min. Water (20 mL) and 1 M HCl solution (15 mL) were then added, and the mixture was extracted first with ethyl acetate (50 mL) and then with DCM (50 mL) to remove impurities. The mixture was alkalized with 2 N NaOH solution and the aqueous layer was extracted with DCM (500 mL x 3). The combined organic layers were dried with anhydrous sodium sulfate and concentrated to give the desired compound XLIII as a brown viscous liquid. Yield: 9.8 g (81%); calculated by LC-MS. For C8H 12 N₂O: 152.09; after observation: 153.00; [M+H] + . 1 H NMR (400 MHz, CDCl3): ​ 7.61(t, J= 7.6Hz, 1H), 7.51 (d, J= 7.6Hz, 2H), 4.73(s, 2H), 3.11(q, J=6.4Hz, 2H), 2.92(q, J= 6.4Hz, 2H).

[1004] Synthesis of (1-(4-(2-aminoethyl)-1H-pyrazol-1-yl)cyclopropyl)methanol (XLIV)

[1005]

[1006] Step 1: Methyl 1-(4-formyl-1H-pyrazole-1-yl)cyclopropane-1-carboxylate (XLIVa)

[1007] K₂CO₃ (3.45 g, 25.0 mmol) was added to a stirred solution of 1H-pyrazole-4-carboxaldehyde (CAS: 35344-95-7; 600 mg, 6.24 mmol) in DMF (3 mL) at room temperature under an inert atmosphere. The reaction mixture was cooled to 0 °C and methyl 2,4-dibromobutyrate (CAS: 29547-04-4, 2.11 g, 8.12 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC analysis. After completion, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The mixture was dried over anhydrous Na₂SO₄, filtered, and the combined organic layers were concentrated under reduced pressure. The crude product was purified by Combi-Flash silica (230-400) column chromatography with ethyl acetate in 0-20% n-hexane to give the desired product XLIVA as a yellow liquid. Yield: 0.9 g (75%). LC-MS calculations were performed. For C9H 10 N₂O₃: 194.06; after observation: 195.20; [M+H] + . 1 HNMR (400 MHz, CDCl3): ​ 9.88(s, 1H), 8.06-8.01(m,1H), 7.98(s, 1H), 3.71(s, 3H), 1.92-1.89(m,2H), 1.70-1.67(m,2H).

[1008] Step 2: (E)-1-(4-(2-nitrovinyl)-1H-pyrazole-1-yl)cyclopropane-1-carboxylic acid methyl ester (XLIVb)

[1009] At room temperature, ammonium acetate (476 mg, 6.18 mmol) and nitromethane (3.77 g, 61.8 mmol) were added to a stirred solution of methyl 1-(4-formyl-1H-pyrazole-1-yl)cyclopropane-1-carboxylic acid ester XLIVa (800 mg, 4.12 mmol) in toluene (16 mL). The reaction mixture was stirred at 110 °C for 16 h. The reaction progress was monitored by TLC analysis. After completion, the reaction mixture was diluted with 1N HCl (20 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by rapid chromatography (silica gel 230-400 mesh) with ethyl acetate in 0-25% n-hexane to give compound XLIVb as a yellow solid. Yield: 0.6 g (62%). LC-MS calculations were performed. 10 H 11 N3O4: 237.07; after observation: 238.20; [M+H] + ;1 H NMR (400 MHz, CDCl3): ​ 7.92(d, J= 13.6Hz, 1H), 7.83(s,1H), 7.77(s, 1H), 7.44(d, J= 13.2Hz, 1H), 3.71(s, 3H), 1.92-1.88(m,2H), 1.68-1.58(m,2H).

[1010] Step 3: (1-(4-(2-aminoethyl)-1H-pyrazole-1-yl)cyclopropyl)methanol (XLIV)

[1011] A solution of LiAlH4 (15 mL, 1 mL, 0.02 mol in THF) in DEE (20 mL) was cooled to 0 °C, and a solution of (E)-1-(4-(2-nitrovinyl)-1H-pyrazole-1-yl)cyclopropane-1-carboxylic acid methyl ester XLIVb (0.9 g, 4 mmol) in THF (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC analysis. After completion, the reaction mixture was cooled to 0 °C and quenched with water (3 mL), 15% NaOH solution (1 mL), and ethyl acetate (30 mL). The mixture was stirred at room temperature for 30 minutes and filtered, and the residue was washed with fresh ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the desired compound XLIV as a brown liquid. The crude product was used for the next step without further purification. Yield: 0.6 g (75%).

[1012] Synthesis of (1-(3-(2-aminoethyl)-5-methyl-1H-pyrazol-1-yl)cyclopropyl)methanol XLV

[1013]

[1014] Step 1: Ethyl 5-methyl-1H-pyrazole-3-carboxylate (XLVa)

[1015] A solution of ethyl 2,4-dioxovalerate (CAS: 615-79-2, 5 g, 0.03 mol) in ethanol (4 mL) was cooled to 0 °C, and hydrazine hydrate (2 mL, 0.03 mol, 1:1) was added dropwise at 0 °C under an inert atmosphere. The reaction mixture was refluxed for 1 hour. The reaction progress was monitored by TLC analysis. After completion, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (50 mL). The mixture was extracted with ethyl acetate (50 mL x 3), washed with brine, and the combined organic layers were dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to obtain the desired product as a pale yellow solid. The crude product was used for the next step without further purification. Yield: 3.7 g (72%). LC-MS calculations were performed. For C7H 10 N₂O₂: 154.07; after observation: 155.05; [M+H] + ; 1 H NMR (400 MHz, CDCl3): δ6.60(s, 1H), 4.38(q, J= 6.8Hz, 2H), 2.36(s, 3H), 1.38(t, J= 6.8Hz, 3H).

[1016] Step 2: 5-Methyl-1H-pyrazole-3-carboxaldehyde (XLVb)

[1017] A solution of ethyl 5-methyl-1H-pyrazole-3-carboxylate XLVa (3.6 g, 23 mmol) in dried toluene (54 mL) was cooled to -78 °C under an inert atmosphere, and DIBAL-H (31 mL, 1.5 mol, 47 mmol) was added dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 1 h, and the reaction progress was monitored by TLC analysis. After completion, the reaction was quenched at -78 °C with water (10 mL) and methanol (2 mL). The mixture was stirred at room temperature for 10–15 min, and ethyl acetate (30 mL) was added. The mixture was filtered through a diatomaceous earth bed and washed thoroughly with ethyl acetate. The combined organic layers were separated, washed with brine, and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give the desired compound XLVb as a pale yellow solid. The crude product was used for the next step without further purification. Yield: 1.3 g (50%).

[1018] Step 3: Methyl 1-(3-formyl-5-methyl-1H-pyrazole-1-yl)cyclopropane-1-carboxylate (XLVc)

[1019] A solution of 5-methyl-1H-pyrazole-3-carboxaldehyde XLVb (1.3 g, 12 mmol) in DMF (11 mL) was cooled to 0 °C, and K₂CO₃ (6.5 g, 47 mmol) was added fractionally. Methyl 2,4-dibromobutyrate (2.2 mL, 15 mmol) was then added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC analysis. After completion, cold water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The extract was washed with brine, dried over anhydrous sodium sulfate, and the combined organic layers were concentrated to give the starting material. The starting material was purified by Combi-Flash (silica gel 230-400 mesh) column chromatography with ethyl acetate in 0-10% n-hexane to give the desired compound XLVc as a off-white solid. Yield: 0.47 g (18.7%). LC-MS calculations were performed. For C 10 H 12 N₂O₃: 208.08; after observation: 209.10; [M+H] + ; 1 H NMR (400 MHz, CDCl3): δ6.90(s, 1H), 6.56(s, 1H), 3.72(s, 3H), 2.32(s, 3H), 1.96(s, 2H), 1.72(s, 2H).

[1020] Step 4: (E)-1-(5-methyl-3-(2-nitrovinyl)-1H-pyrazole-1-yl)cyclopropane-1-carboxylic acid methyl ester (XLVd)

[1021] Under an inert atmosphere, ammonium acetate (267 mg, 3.46 mmol) and nitromethane (1.24 mL, 23.1 mmol) were added to a solution of methyl 1-(3-formyl-5-methyl-1H-pyrazol-1-yl)cyclopropane-1-carboxylic acid ester XLVc (480 mg, 2.31 mmol) in toluene (20 mL). The reaction mixture was stirred at 100 °C for 16 hours, and the reaction progress was monitored by TLC. After completion, the reaction was quenched by dropwise addition of 1N HCl solution (20 mL), and the resulting mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed first with 1N HCl solution (20 mL) and then with brine. The organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The raw material was purified by Combi-Flash silica gel (230-400 mesh) column chromatography with ethyl acetate in 0-10% n-hexane to give the desired product XLVd as a white solid. Yield: 0.383 g (66.14%); calculated by LC-MS. For C 11 H 13 N3O4: 251.09; after observation: 252.20; [M+H] +; 1 H NMR (400 MHz, CDCl3): δ7.90(d, J= 13.2Hz, 1H), 7.55 (d, J= 14.0Hz, 1H), 6.32(s, 1H), 3.71(s, 3H), 2.31(s, 3H), 1.94(s, 2H), 1.69(s, 2H).

[1022] Step 5: (1-(3-(2-aminoethyl)-5-methyl-1H-pyrazole-1-yl)cyclopropyl)methanol (XLV)

[1023] A solution of LiAlH4 (6.05 mL, 1 mL, 6.05 mmol in THF) in dried diethyl ether (20 mL) was cooled to 0 °C, and a solution of (E)-1-(5-methyl-3-(2-nitrovinyl)-1H-pyrazol-1-yl)cyclopropane-1-carboxylic acid methyl ester XLVd (380 mg, 1.51 mmol) in THF (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, and the reaction progress was monitored by TLC analysis. After completion, the reaction was cooled to 0 °C, and water (0.4 mL) was slowly added. Subsequently, 15% KOH solution (0.4 mL) and water (1.2 mL) were slowly added. The mixture was stirred at room temperature for 10 minutes, ethyl acetate (50 mL) was added, and stirring was continued at room temperature for another 15 minutes. The mixture was filtered through a diatomaceous earth bed and thoroughly washed with fresh ethyl acetate. The combined organic layers were dried with anhydrous sodium sulfate and concentrated to give the desired product XLV as a pale yellow oil. This compound was used as is for the next step without further purification. Yield: 0.370 g (crude product).

[1024] Synthesis of 3-((3-(2-aminoethyl)-1H-pyrazol-1-yl)methyl)cyclobut-1-one (XLVI)

[1025]

[1026] Step 1: Methyl (3,3-dimethoxycyclobutyl)methyl 4-benzenesulfonate (XLVIa)

[1027] Pyridine (8.3 mL, 1.00 mmol) was added to a stirred solution of (3,3-dimethoxycyclobutyl)methanol (CAS: 175021-11-1, 5.0 g, 34 mmol) in DCM (100 mL), and the reaction mixture was cooled to 0 °C. pTSCl (7.2 g, 38 mmol) was added fractionally under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC analysis. After completion, the reaction mixture was diluted with saturated NaHCO3 solution (100 mL) and extracted with DCM (100 mL x 3). The mixture was dried over anhydrous Na2SO4, filtered, and the combined organic layers were concentrated under reduced pressure. The crude compound was purified by Combi-Flash column chromatography (230-400 silica) with ethyl acetate in 0-15% n-hexane to give the desired colorless liquid compound XLVIa. Yield: 8.2 g (82%); 1 H NMR (400 MHz, CDCl3): ​ 7.79(d, J= 8.4Hz, 2H), 7.34 (d, J= 8.4Hz, 2H), 4.03 (d, J= 7.2Hz, 2H), 3.11(s, 3H), 3.06(s, 3H), 2.45(s, 3H), 2.39-2.36(m,1H), 2.27-2.23(m,2H), 1.83-1.78(m,2H).

[1028] Step 2: 1-((3,3-dimethoxycyclobutyl)methyl)-1H-pyrazole-3-carboxaldehyde (XLVIb)

[1029] Cesium carbonate (16 g, 50 mmol) was added to a stirred solution of 1H-pyrazole-3-carboxaldehyde (CAS: 3920-50-1, 2.4 g, 25 mmol) in DMF (20 mL), and the reaction mixture was cooled to 0 °C. Methyl 4-benzenesulfonate XLVIa (8.3 g, 27 mmol) was slowly added under a nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 12 hours. The reaction progress was monitored by TLC analysis. After completion, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 3). The mixture was dried over anhydrous Na₂SO₄, filtered, and the combined organic layers were concentrated under reduced pressure. The crude compound was purified by Combi-Flash column chromatography with ethyl acetate in 0–15% n-hexane to give the desired compound XLVIb as a pale yellow viscous liquid. Yield: 4.4 g (78%); Chemical formula: C 11 H 16 N2O3; 1H NMR (400 MHz, CDCl3): ​ 9.96 (s, 1H), 7.42 (d, J= 2.0Hz, 1H), 6.80 (d, J= 2.0Hz, 1H), 4.29 (d, J= 7.6Hz, 2H), 3.13(s, 6H), 2.70-2.45(m,1H), 2.34-2.32(m,2H), 1.96-1.91(m,2H).

[1030] Step 3: (E)-1-((3,3-dimethoxycyclobutyl)methyl)-3-(2-nitrovinyl)-1H-pyrazole (XLVIc)

[1031] To a stirred solution of 1-((3,3-dimethoxycyclobutyl)methyl)-1H-pyrazole-3-carboxaldehyde XLVIb (4.4 g, 20 mmol) in toluene (50 mL), nitromethane (16 mL, 290 mmol) was added, followed by ammonium acetate (2.3 g, 29 mmol). The mixture was stirred at 100 °C for 16 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to room temperature, diluted with 1N HCl (50 mL), and extracted with ethyl acetate (100 mL x 3). The mixture was dried over anhydrous Na₂SO₄, filtered, and the combined organic layers were concentrated under reduced pressure. The crude compound was purified by Combi-Flash column chromatography with ethyl acetate in 0–10% n-hexane to give the desired compound XLVIc as a pale yellow solid. Yield: 3.3 g (63%).

[1032] Step 4: 2-(1-((3,3-dimethoxycyclobutyl)methyl)-1H-pyrazol-3-yl)ethyl-1-amine (XLVId)

[1033] A stirred solution of LiAlH4 (49 mL, 1 mol, 49 mmol in THF) in diethyl ether (100 mL) was cooled to 0 °C, and a solution of (E)-1-((3,3-dimethoxycyclobutyl)methyl)-3-(2-nitrovinyl)-1H-pyrazole XLVIc (3.3 g, 12 mmol) was added dropwise under an inert atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC analysis. After completion, the reaction mixture was cooled to 0 °C, and quenched by slow addition of water (3.3 mL), 15% KOH solution (3.3 mL), and then 10 mL of water was added again. The resulting reaction mixture was stirred at room temperature for 20 minutes, and ethyl acetate (100 mL) was added. The mixture was filtered, and the residue was washed with fresh ethyl acetate (100 mL x 3). The mixture was dried over anhydrous Na2SO4, filtered, and the combined organic layers were concentrated under reduced pressure. The crude product XLVId was used directly in the next step without purification. Yield: 2.4 g (crude product); calculated by LC-MS. For C 12 H 21 N3O2: 239.32; after observation: 240.35; [M+H] + .

[1034] Step 5: 3-((3-(2-aminoethyl)-1H-pyrazol-1-yl)methyl)cyclobut-1-one (XLVI)

[1035] Under a nitrogen atmosphere, 2N HCl (3 mL) was slowly added to a stirred solution of 2-(1-((3,3-dimethoxycyclobutyl)methyl)-1H-pyrazol-3-yl)ethyl-1-amine XLVId (2.6 g, 11 mmol) in ethanol (50 mL). The reaction mixture was stirred at room temperature for 2 hours, and the reaction progress was monitored by TLC. After completion, the reaction mixture was concentrated under vacuum. The crude XLVI was used directly in the next step without further purification. Yield: 2.4 g (crude product).

[1036] Synthesis of 2-(3-(2-aminoethyl)-1H-pyrazol-1-yl)-1-propanol (XLVII)

[1037]

[1038] Step 1: Methyl 2-(3-formyl-1H-pyrazole-1-yl)propionate (XLVIIa)

[1039] To a solution of 1H-pyrazole-3-carboxaldehyde (CAS: 3920-50-1, 3.0 g, 31 mmol) in DMF (30 mL), K₂CO₃ (17 g, 0.12 mol) was added, and the solution was cooled to 0 °C under an inert atmosphere. Then, methyl 2-bromopropionate (CAS: 5445-17-0, 5.2 mL, 47 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC analysis. After completion, the reaction was quenched with cold water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the starting material was purified by Combi-Flash silica gel (230-400) column chromatography with ethyl acetate in 0-10% n-hexane to give the desired compound XLVIIa as a colorless oil. Yield: 0.70 g (13.0%); calculated by LC-MS. For C₈H 10 N₂O₃: 182.06; after observation: 183.25; [M+H] + . 1 H NMR (400MHz, CDCl3): ​ 9.98(s, 1H), 7.59(s, 1H), 6.86(s, 1H), 5.19(q, J= 7.2Hz, 1H), 3.78(s,3H), 1.86(d, J =6.8Hz, 3H).

[1040] Step-2: Methyl (E)-2-(3-(2-nitrovinyl)-1H-pyrazole-1-yl)propionate (XLVIIb)

[1041] Under an inert atmosphere, ammonium acetate (444 mg, 5.76 mmol) and nitromethane (2.07 mL, 38.4 mmol) were added to a solution of methyl 2-(3-formyl-1H-pyrazole-1-yl)propionate XLVIIa (700 mg, 3.84 mmol) dissolved in toluene (20 mL), and the mixture was stirred at 100 °C for 16 h. The reaction progress was monitored by TLC analysis. After completion, the reaction mixture was cooled to room temperature and quenched with 1N HCl solution (25 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (100 mL x 3). The aqueous layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The starting material was purified by Combi-Flash silica gel (230-400) column chromatography with ethyl acetate in 0-20% n-hexane to give the desired compound XLVIIb as a pale yellow oil. Yield: 560 mg (65.7%); calculated by LC-MS. For C9H 11N3O4: 225.07; after observation: 226.15; [M+H] + . 1 H NMR (400 MHz, CDCl3): ​ 7.97(d, J= 13.6Hz, 1H), 7.61 (d, J= 14.0Hz, 2H), 6.61(s, 1H), 5.14(q, J= 7.2Hz, 1H), 3.77(s, 3H), 1.83(d, J =7.2Hz, 3H).

[1042] Step 3: 2-(3-(2-aminoethyl)-1H-pyrazol-1-yl)prop-1-ol (XLVII)

[1043] A solution of LiAlH4 (9.95 mL, 1 mL, 9.95 mmol in THF) in diethyl ether (20 mL) was cooled to 0 °C under an inert atmosphere, and a solution of (E)-2-(3-(2-nitrovinyl)-1H-pyrazole-1-yl)propionate methyl ester XLVIIb (560 mg, 2.49 mmol) in diethyl ether (8 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, and the reaction progress was monitored by TLC analysis. After completion, the reaction mixture was cooled to 0 °C, and quenched by adding water (0.6 mL), 15% KOH solution (0.6 mL), and water (1.8 mL) in sequence. The reaction mixture was stirred at room temperature for 10 minutes, ethyl acetate (50 mL) was added, and stirring was continued for 15 minutes. The mixture was filtered and thoroughly washed with ethyl acetate (50 mL x 3). The combined organic layers were concentrated under reduced pressure to give the desired product XLVII as a pale yellow oil. Yield: 0.47 g (100%); calculated by LC-MS. For C8H 15 N3O: 169.12; after observation: 170.35; [M+H] + .

[1044] Synthesis of (6-(2-aminoethyl)-3-fluoropyridin-2-yl)methanol (XLVIII)

[1045]

[1046] Step 1: (6-bromo-3-fluoropyridin-2-yl)methanol (XLVIIIa)

[1047] NaBH4 (0.4 g, 10 mmol) was added to a solution of 6-bromo-3-fluoropyridinaldehyde (CAS: 885267-36-7, 2 g, 10 mmol) in methanol (20 mL) at 0 °C, and the mixture was stirred for 30 min at the same temperature. The reaction progress was monitored by TLC. After the reaction was complete, NaHCO3 (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 2). The extract was washed with brine (25 mL), dried over anhydrous sodium sulfate, and the combined organic layers were concentrated under reduced pressure to give the desired product XLVIIIa as a creamy white solid. The crude product was used for the next step without any further purification. Yield: 1.96 g (100.0%); calculated by LC-MS. For C6H5BrFNO: 204.95; after observation: 206.20; [M+H] + . 1 HNMR (400 MHz, CDCl3): δ7.74-7.63(m,2H), 5.47(t, J= 6.4Hz, 1H), 4.55-4.54(m,2H).

[1048] Step-2: 6-Bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridine (XLVIIIb)

[1049] To a solution of (6-bromo-3-fluoropyridin-2-yl)methanol XLVIIIa (1.96 g, 9.51 mmol) in DCM (50 mL), imidazole (0.972 g, 14.3 mmol) was added. The reaction mixture was stirred at room temperature for 30 min. Subsequently, TBDMS-Cl (1.72 g, 11.4 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC analysis. After the reaction was complete, water (50 mL) was added and the mixture was extracted with dichloromethane (50 mL x 2). The mixture was washed with brine (25 mL), dried over anhydrous sodium sulfate, and the combined organic layers were concentrated under reduced pressure. The crude compound was purified by silica gel (230-400 mesh) column chromatography with ethyl acetate (0-15%) in n-hexane to give the desired compound XLVIIIb as a colorless viscous liquid. Yield: 2.8 g (98.0%); calculated by LC-MS. For C 12 H 19 BrFNOSi: 319.04; after observation: 321.95; [M+H] + . 1 HNMR (400 MHz, CDCl3): δ7.41-7.38(m,1H), 7.28-7.24(m,1H), 4.82(d, J=6.0Hz, 2H), 0.91(s, 9H), 0.12(s, 6H).

[1050] Step 3: 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro-6-vinylpyridine (XLVIIIc)

[1051] To a solution of 6-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridine XLVIIIb (1.8 g, 5.6 mmol) and potassium trifluoro(vinyl)borate (1-) (0.90 g, 6.7 mmol) in 1,4-dioxane (20 mL), potassium tribasic phosphate (1.8 g, 8.4 mmol) was added, and the mixture was purified with N2 for 10 min. PdCl2 (dppf) (0.21 g, 0.28 mmol) was then added, and the mixture was stirred at 110 °C for 16 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and water (50 mL) was added, followed by extraction with ethyl acetate (50 mL x 2). The mixture was washed with brine...

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt, tautomer, stereoisomer, racemic compound thereof, Formula I wherein A is selected from ； Q is N; R2is selected from hydrogen or C 1-6 alkyl; R3is selected from hydrogen or C 1-6 alkyl; R4and R5are independently selected from halogen, C 1-6 alkyl, C 3-6 alkenyl, C 1-6 haloalkyl, wherein C 1-6 alkyl is optionally substituted with C 3-6 cycloalkyl; R6is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, hydroxyC 1-6 alkyl, C 1-6 aminoalkyl, -Y-Z or C 1-10 heterocyclyl, wherein C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 aminoalkyl, hydroxyC 1-6 alkyl or C 1-10 heterocyclyl is optionally substituted with one or more groups selected from halogen, hydroxy, amino, C 3-6 cycloalkyl, C 1-6 alkoxy, hydroxyC 1-6 alkyl, C 1-6 aminoalkyl, or C 1-10 heterocyclyl is optionally substituted with one or more groups selected from halogen, hydroxy, amino, C 3-6 cycloalkyl or C 1-6 aminoalkyl is optionally further substituted with one or more groups independently selected from halogen, hydroxy, hydroxyC 1-6 alkyl, -C(O)C 1-6 alkyl, -C(O)NH2or -C(O)-hydroxyC 1-6 alkyl is substituted with one or more groups independently selected from halogen, hydroxy, amino, C Y is selected from C 1-6 alkyl or C 3-6 cycloalkyl; Z is selected from -S(O)CH3, -SCH3, -CH2-NH-(C 1-6 alkyl)-S(O)CH3, or -NHCO(C 1-6 alkyl); R7, R8, and R9are independently selected from hydrogen, halogen, C 1-6 alkyl, or C 1-6 alkoxy; and n is 0 or 1.

2. The compound of claim 1 / or a pharmaceutically acceptable salt, tautomer, stereoisomer, racemic compound thereof, selected from the group consisting of:

1. 7-amino-2,3-dimethyl-5-{[l-(6-methylpyridin-2-yl)ethyl]amino}pyrazolo[l,5- a]pyrimidine-6-carbonitrile; 2. 7-amino-2,3-dimethyl-5-{[(lS)-l-(6-methylpyridin-2-yl)ethyl]amino}pyrazolo[l,5- a]pyrimidine-6-carbonitrile; 3. (R)-7-amino-3-ethyl-2-methyl-5-((l-(pyridin-2-yl)ethyl)amino)pyrazolo[l,5- a]pyrimidine-6-carbonitrile; 4. (S)-7-amino-3-ethyl-2-methyl-5-((l-(pyridin-2-yl)ethyl)amino)pyrazolo[l,5- a]pyrimidine-6-carbonitrile; 5. (S)-7-amino-3-ethyl-2-methyl-5-((l-(6-methylpyridin-2-yl)ethyl)amino)pyrazolo[l,5- a]pyrimidine-6-carbonitrile; 6. 7-amino-2,3-dimethyl-5-{[(6-methylpyridin-2-yl)methyl]amino}pyrazolo[l,5- a]pyrimidine-6-carbonitrile; 7. 7-amino-5-{[(6-ethylpyridin-2-yl)methyl]amino}-2,3-dimethylpyrazolo[l,5- a]pyrimidine-6-carbonitrile; 8. 7-amino-2,3-dimethyl-5-{methyl[(6-methylpyridin-2-yl)methyl]amino}pyrazolo[l,5- a]pyrimidine-6-carbonitrile; 9. 7-amino-5-({[6-(2-hydroxypropan-2-yl)pyridin-2-yl]methyl}amino)-2,3- dimethylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 10. 7-amino-2,3-dimethyl-5-((2-(5-methylpyridin-2-yl)ethyl)amino)pyrazolo[l,5- a]pyrimidine-6-carbonitrile; 11. 7-amino-5-((2-(5-fluoropyridin-2-yl)ethyl)amino)-2,3-dimethylpyrazolo[l,5- a]pyrimidine-6-carbonitrile; 12. 7-amino-5-((2-(6-methoxypyridin-2-yl)ethyl)amino)-2,3-dimethylpyrazolo[l,5- a]pyrimidine-6-carbonitrile; 13. 7-amino-5-((2-(6-methylpyridin-2-yl)ethyl)amino)-2,3-dimethylpyrazolo[l,5- a]pyrimidine-6-carbonitrile; 14. 7-amino-2,3-dimethyl-5-{[l-(6-methylpyridin-2-yl)propan-2-yl]amino}pyrazolo[l,5- a]pyrimidine-6-carbonitrile; 15. 7-amino-2,3-dimethyl-5-{[l-(6-methylpyridin-2-yl)propan-2-yl]amino}pyrazolo[l,5- a]pyrimidine-6-carbonitrile; 16. 7-Amino-5-({2-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]ethyl}amino)-2,3- dimethylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 17. 7-Amino-3-ethyl-2-methyl-5-((2-(6-methylpyridin-2-yl)ethyl)amino)pyrazolo[l,5- a]pyrimidine-6-carbonitrile; 18. 7-Amino-3-ethyl-2-methyl-5-((2-(5-methylpyridin-2-yl)ethyl)amino)pyrazolo[l,5- a]pyrimidine-6-carbonitrile; 19. 7-Amino-3-ethyl-5-((2-(5-methoxypyridin-2-yl)ethyl)amino)-2-methylpyrazolo[l,5- a]pyrimidine-6-carbonitrile; 20. 7-Amino-3-ethyl-5-((2-(6-methoxypyridin-2-yl)ethyl)amino)-2-methylpyrazolo[l,5- a]pyrimidine-6-carbonitrile; 21. 7-Amino-3-ethyl-5-((2-(5-fluoropyridin-2-yl)ethyl)amino)-2-methylpyrazolo[l,5- a]pyrimidine-6-carbonitrile; 22. 7-Amino-3-ethyl-2-methyl-5-((l-(pyridin-2-yl)propan-2-yl)amino)pyrazolo[l,5- a]pyrimidine-6-carbonitrile; 23. 7-Amino-3-ethyl-2-methyl-5-((l-(pyridin-2-yl)propan-2-yl)amino)pyrazolo[l,5- a]pyrimidine-6-carbonitrile; 24. 7-Amino-3-ethyl-2-methyl-5-((l-(6-methylpyridin-2-yl)propan-2-yl)amino)pyrazolo[l,5- a]pyrimidine-6-carbonitrile; 25. 7-Amino-3-ethyl-5-({2-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]ethyl}amino)-2- methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 26. 7-Amino-3-(cyclopropylmethyl)-2-methyl-5-((2-(6-methylpyridin-2-yl)ethyl)amino)pyrazolo[l,5-a]pyrimidine-6-carbonitrile; 27. 7-Amino-3-(isopropylmethyl)-2-methyl-5-((2-(6-methylpyridin-2-yl)ethyl)amino)pyrazolo[l,5-a]pyrimidine-6-carbonitrile; 28. 7-Amino-3-(isopropyl)-2-methyl-5-((2-(6-methylpyridin-2-yl)ethyl)amino)pyrazolo[l,5-a]pyrimidine-6-carbonitrile; 29. 7-Amino-5-{[2-(l-ethyl-lH-pyrazol-3-yl)ethyl]amino}-2,3-dimethylpyrazolo[l,5- a]pyrimidine-6-carbonitrile; 30. 7-Amino-3-ethyl-5-{[2-(l-ethyl-lH-pyrazol-3-yl)ethyl]amino}-2-methylpyrazolo[l,5- a]pyrimidine-6-carbonitrile; 31. 7-amino-5-({2-[l-(l-hydroxy-2-methylpropan-2-yl)-lH-pyrazol-3-yl]ethyl}amino)- 2,3-dimethylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 32. 7-amino-3-ethyl-5-((2-(l-(l-hydroxy-2-methylpropan-2-yl)-lH-pyrazol-3-yl)ethyl) amino)-2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 33. 7-amino-3-chloro-5-((2-(6-(hydroxymethyl)pyridin-2-yl)ethyl)amino)-2- methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 34. 7-amino-3-chloro-5-((2-(6-(l-(hydroxymethyl)cyclopropyl)pyridin-2-yl)ethyl) amino)-2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 35. 7-amino-3-chloro-5-((2-(l-(2-hydroxyethyl)-lH-pyrazol-3-yl)ethyl)amino)-2- methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 36. 7-amino-3-chloro-5-((2-(l-(l-hydroxy-2-methylpropan-2-yl)-lH-pyrazol-3- yl)ethyl)amino)-2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 37. 7-amino-3-chloro-5-((2-(l-(l-(hydroxymethyl)cyclopropyl)-lH-pyrazol-3- yl)ethyl)amino)-2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 38. 7-amino-3-chloro-5-((2-(6-(2-(hydroxymethyl)cyclopropyl)pyridin-2-yl)ethyl) amino)-2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 39. 7-amino-3-ethyl-5-((2-(l-(l-(hydroxymethyl)cyclopropyl)-lH-pyrazol-3- yl)ethyl)amino)-2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 40. Amino-5-((2-(6-ethylpyridin-2-yl)ethyl)amino)-2,3-dimethylpyrazolo[l,5- a]pyrimidine-6-carbonitrile; 41. 7-amino-5-((2-(3-fluoro-6-methylpyridin-2-yl)ethyl)amino)-2,3-dimethylpyrazolo [l,5-a]pyrimidine-6-carbonitrile; 42. 7-amino-2-ethyl-3-methyl-5-((2-(6-methylpyridin-2-yl)ethyl)amino)pyrazolo[l,5- a]pyrimidine-6-carbonitrile; 43. 7-amino-2-ethyl-5-((2-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)ethyl)amino)-3- methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 44. 7-amino-5-((2-(6-(hydroxymethyl)pyridin-2-yl)ethyl)amino)-2,3-dimethylpyrazolo [l,5-a]pyrimidine-6-carbonitrile; 45. 7-Amino-3-ethyl-5-((2-(6-(hydroxymethyl)pyridin-2-yl)ethyl)amino)-2- methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 46. 7-Amino-3-(cyclopropylmethyl)-5-((2-(6-(hydroxymethyl)pyridin-2- yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 47. 7-Amino-2-cyclopropyl-5-((2-(6-(2-hydroxypropan-2-yl)pyridin-2- yl)ethyl)amino)-3-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 48. 7-Amino-2-(difluoromethyl)-3-ethyl-5-((2-(1-(1-hydroxy-2- methylpropan-2-yl)-1H-pyrazol-3-yl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-6- carbonitrile; 49. 7-Amino-5-((2-(6-(1-(hydroxymethyl)cyclopropyl)pyridin-2- yl)ethyl)amino)-2,3-dimethylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 50. 7-Amino-3-ethyl-5-((2-(6-(1-(hydroxymethyl)cyclopropyl)pyridin-2- yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 51. 7-Amino-5-((2-(6-(2-(hydroxymethyl)cyclopropyl)pyridin-2- yl)ethyl)amino)-2,3-dimethylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 52. 7-Amino-3-ethyl-5-((2-(6-(1-hydroxy-2-methylpropan-2-yl)pyridin-2- yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 53. 7-Amino-5-((2-(6-(1-hydroxy-2-methylpropan-2-yl)pyridin-2- yl)ethyl)amino)-2,3-dimethylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 54. 7-Amino-3-ethyl-5-((2-(1-(2-hydroxyethyl)-1H-pyrazol-3- yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 55. 7-Amino-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-1H-pyrazol-3- yl)ethyl)amino)-2,3-dimethylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 56. 7-Amino-2-(difluoromethyl)-3-ethyl-5-((2-(6-(hydroxymethyl)pyridin-2- yl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-6-carbonitrile; 57. 7-Amino-5-(((1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-3- yl)methyl)amino)-2,3-dimethylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 58. 7-Amino-2-(difluoromethyl)-3-ethyl-5-((2-(1-(1- (hydroxymethyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)pyrazolo[1,5- a]pyrimidine-6-carbonitrile; 59. 7-amino-2-(difluoromethyl)-3-ethyl-5-((2-(6-(2- (hydroxymethyl)cyclopropyl)pyridin-2-yl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-6- carbonitrile; 60. 7-amino-3-ethyl-5-((2-(6-(2-(hydroxymethyl)cyclopropyl)pyridin-2- yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 61. 7-amino-3-chloro-5-((2-(4-(1-(hydroxymethyl)cyclopropyl)thiazol-2- yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 62. 7-amino-3-ethyl-5-((2-(4-fluoro-1-(1-hydroxy-2-methylpropan-2-yl)-1H- pyrazol-3-yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 63. 7-amino-3-ethyl-5-((2-(1-((1-(hydroxymethyl)cyclopropyl)methyl)-1H- pyrazol-3-yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 64. 7-amino-3-chloro-5-((2-(6-(1,1-difluoro-2-hydroxyethyl)pyridin-2- yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 65. 7-amino-3-chloro-5-((2-(6-(1-hydroxy-2-methylpropan-2-yl)pyridin-2- yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 66. 7-amino-3-ethyl-5-((2-(4-(1-(hydroxymethyl)cyclopropyl)thiazol-2- yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 67. 7-amino-3-chloro-5-((2-(1-(2-(hydroxymethyl)cyclobutyl)-1H-pyrazol-3- yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 68. 7-amino-5-((2-(1-(1-(aminomethyl)cyclopropyl)-1H-pyrazol-3- yl)ethyl)amino)-3-chloro-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 69. 7-amino-3-bromo-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-1H-pyrazol-3- yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 70. 7-amino-3-chloro-5-((2-(1-ethyl-2-oxo-1,2-dihydropyridin-3- yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 71. 7-amino-3-ethyl-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-1H-pyrazol-3- yl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-6-carbonitrile; 72. 7-amino-3-bromo-5-((2-(6-(hydroxymethyl)pyridin-2-yl)ethyl)amino)-2- methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 73. 7-amino-3-chloro-5-((2-(l-(l-(hydroxymethyl)cyclopropyl)-lH-pyrazol-4- yl)ethyl)amino)-2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 74. 7-amino-3-(cyclopropylmethyl)-5-((2-(l-(l-(hydroxymethyl)cyclopropyl)-lH- pyrazol-3-yl)ethyl)amino)-2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 75. 7-amino-3-chloro-5-((2-(l-(l-(hydroxymethyl)cyclopropyl)-5-methyl-lH-pyrazol- 3-yl)ethyl)amino)-2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 76. 7-amino-3-ethyl-5-((2-(l-(l-(hydroxymethyl)cyclopropyl)-5-methyl-lH-pyrazol- 3-yl)ethyl)amino)-2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 77. N-((l-(3-(2-((7-amino-3-chloro-6-cyano-2-methylpyrazolo[l,5-a]pyrimidin-5- yl)amino)ethyl)-lH-pyrazol-l-yl)cyclopropyl)methyl)acetamide; 78. (+)-7-amino-3-ethyl-5-((2-(l-(2-(hydroxymethyl)cyclobutyl)-lH-pyrazol-3- yl)ethyl)amino)-2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 79. (-)-7-amino-3-ethyl-5-((2-(l-(2-(hydroxymethyl)cyclobutyl)-lH-pyrazol-3- yl)ethyl)amino)-2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 80. 7-amino-3-ethyl-5-((2-(l-(l-(hydroxymethyl)cyclopropyl)-5-methyl-lH-pyrazol- 3-yl)ethyl)amino)pyrazolo[l,5-a]pyrimidine-6-carbonitrile; 81. 7-amino-3-ethyl-5-((2-(l-(l-hydroxypropan-2-yl)-lH-pyrazol-3-yl)ethyl)amino)- 2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 82. (+-)-7-amino-3-chloro-5-((2-(l-((3-hydroxycyclobutyl)methyl)-lH-pyrazol-3- yl)ethyl)amino)-2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 83. (+)-7-amino-3-chloro-5-((2-(l-((3-hydroxycyclobutyl)methyl)-lH-pyrazol-3- yl)ethyl)amino)-2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 84. (-)-7-amino-3-chloro-5-((2-(l-((3-hydroxycyclobutyl)methyl)-lH-pyrazol-3- yl)ethyl)amino)-2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile (83b); 85. 7-amino-3-ethyl-5-((2-(l-((3-hydroxycyclobutyl)methyl)-lH-pyrazol-3- yl)ethyl)amino)-2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 86. 7-amino-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-5-methyl-1H-pyrazol-3-yl)ethyl)amino)- 2,3-dimethylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 87. 7-amino-3-chloro-2-methyl-5-((2-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino) pyrazolo[1,5-a]pyrimidine-6-carbonitrile; 88. 7-amino-3-ethyl-2-methyl-5-((2-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino) pyrazolo[1,5-a]pyrimidine-6-carbonitrile; 89. 7-amino-3-bromo-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-5-methyl-1H-pyrazol-3-yl)ethyl) amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 90. 7-amino-3-chloro-5-((2-(6-(((2-hydroxyethyl)amino)methyl)pyridin-2-yl)ethyl)amino)-2- methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 91. 7-amino-3-ethyl-5-((2-(5-fluoro-6-(hydroxymethyl)pyridin-2-yl)ethyl)amino)-2- methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 92. 7-amino-3-chloro-5-((2-(1-(2-methoxyethyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)- 2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 93. 7-amino-3-chloro-5-((2-(1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)- 2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 94. 7-amino-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-1H-pyrazol-3-yl)ethyl)amino)-2- methyl-3-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile; 95. 7-amino-5-((2-(1-(2-(aminomethyl)cyclobutyl)-1H-pyrazol-3-yl)ethyl)amino)-3-chloro-2- methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 96. 7-amino-3-ethyl-5-((2-(6-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)ethyl)amino)-2- methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 97. 7-amino-3-ethyl-5-((2-(6-(((2-hydroxyethyl)amino)methyl)pyridin-2-yl)ethyl)amino)-2- methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 98. 7-amino-3-chloro-5-((2-(1-(1-(((2-hydroxyethyl)amino)methyl)cyclopropyl)-1H-pyrazol-3- yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 99. N-((1-(3-(2-((7-amino-3-chloro-6-cyano-2-methylpyrazolo[1,5-a]pyrimidin-5- yl)amino)ethyl)-1H-pyrazol-1-yl)cyclopropyl)methyl)-3-hydroxypropanamide; 100. 7-amino-3-ethyl-5-((2-(6-(1-hydroxyethyl)pyridin-2-yl)ethyl)amino)-2- methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 101. 7-amino-3-cyclopropyl-5-((2-(1-(1-(hydroxymethyl)cyclopropyl)-1H-pyrazol-3- yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 102. 7-amino-2-(difluoromethyl)-3-ethyl-5-((2-(1-(2-(hydroxymethyl)cyclobutyl)-1H- pyrazol-3-yl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-6-carbonitrile; 103. (+-)-7-amino-5-((2-(1-(2-(hydroxymethyl)cyclobutyl)-1H-pyrazol-3-yl)ethyl)amino)- 2,3-dimethylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 104. (+)-7-amino-5-((2-(1-(2-(hydroxymethyl)cyclobutyl)-1H-pyrazol-3-yl)ethyl)amino)- 2,3-dimethylpyrazolo[1,5-a]pyrimidine-6-carbonitrile (104a); 104b. (-)-7-amino-5-((2-(1-(2-(hydroxymethyl)cyclobutyl)-1H-pyrazol-3-yl)ethyl)amino)- 2,3-dimethylpyrazolo[1,5-a]pyrimidine-6-carbonitrile (104b); 105. 7-amino-5-((2-(6-(((2-hydroxyethyl)amino)methyl)pyridin-2-yl)ethyl)amino)-2,3- dimethylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 106. 7-amino-3-ethyl-5-((2-(1-(1-(((2-hydroxyethyl)amino)methyl)cyclopropyl)-1H- pyrazol-3-yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 107. 7-amino-3-ethyl-5-((2-(1-(2-methoxyethyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)- 2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 108. 7-amino-3-ethyl-5-((2-(1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl)amino)- 2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 109. 7-amino-5-((2-(1-(2-(aminomethyl)cyclobutyl)-1H-pyrazol-3-yl)ethyl)amino)-3- ethyl-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 110. 7-amino-3-ethyl-5-((2-(1-(3-hydroxypropyl)-1H-pyrazol-5-yl)ethyl)amino)-2- methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 111. 7-Amino-3-ethyl-5-((2-(1-(3-hydroxypropyl)-1H-pyrazol-3-yl)ethyl)amino)-2- methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 112. 7-Amino-3-chloro-5-((2-(1-(1-(2-hydroxyethyl)cyclopropyl)-1H-pyrazol-3- yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 113. 7-Amino-3-ethyl-5-((2-(1-(3-hydroxypropyl)-2-oxo-1,2-dihydropyridin-3-yl)ethyl) amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 114. 7-Amino-3-chloro-5-((2-(1-(2-(hydroxymethyl)cyclopentyl)-1H-pyrazol-3- yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 115. 7-Amino-3-ethyl-5-((2-(1-(2-(hydroxymethyl)cyclopentyl)-1H-pyrazol-3- yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 116. 7-Amino-3-(cyclopropylmethyl)-5-((2-(1-(2-(hydroxymethyl)cyclobutyl)-1H- pyrazol-3-yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 117. 7-Amino-3-chloro-5-((2-(1-(2-(((2-hydroxyethyl)amino)methyl)cyclobutyl)-1H- pyrazol-3-yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 118. 7-Amino-5-((2-(1-(2-(aminomethyl)cyclopentyl)-1H-pyrazol-3-yl)ethyl)amino)- 3-chloro-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 119. 7-Amino-3-chloro-2-methyl-5-((2-(6-methylpyridin-2-yl)ethyl)amino)pyrazolo[1,5- a]pyrimidine-6-carbonitrile; 120. 7-Amino-3-chloro-5-((2-(6-ethylpyridin-2-yl)ethyl)amino)-2-methylpyrazolo[1,5- a]pyrimidine-6-carbonitrile; 121. (+-)-7-Amino-3-ethyl-5-((2-(1-(4-(hydroxymethyl)tetrahydrofuran-3-yl)-1H- pyrazol-3-yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 122. (+)-7-Amino-3-ethyl-5-((2-(1-(4-(hydroxymethyl)tetrahydrofuran-3-yl)-1H- pyrazol-3-yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile (122a); 122b. (-)-7-Amino-3-ethyl-5-((2-(1-(4-(hydroxymethyl)tetrahydrofuran-3-yl)-1H- pyrazol-3-yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 123. 7-Amino-3-ethyl-5-((2-(l-(3-(hydroxymethyl)cyclobutyl)-lH-pyrazol-3-yl)ethyl)amino)- 2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 124. 7-Amino-3-ethyl-5-((2-(l-(l-(2-hydroxyethyl)cyclopropyl)-lH-pyrazol-3-yl)ethyl)amino)- 2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 125. 7-Amino-5-((2-(l-(2-aminoethyl)-2-oxo-l,2-dihydropyridin-3-yl)ethyl)amino)-3-chloro-2- methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 126. 7-Amino-5-((2-(l-(2-aminoethyl)-2-oxo-l,2-dihydropyridin-3-yl)ethyl)amino)-3-ethyl-2- methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 127. 7-Amino-3-chloro-5-((2-(l-(4-(hydroxymethyl)tetrahydrofuran-3-yl)-lH-pyrazol-3- yl)ethyl)amino)-2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 128. 7-Amino-3-ethyl-5-((2-(l-((3-hydroxycyclobutyl)methyl)-2-oxo-l,2-dihydropyridin-3- yl)ethyl)amino)-2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 129. 7-Amino-5-((2-(l-(3-aminopropyl)-2-oxo-l,2-dihydropyridin-3-yl)ethyl)amino)-3-chloro- 2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 130. 7-Amino-3-bromo-5-((2-(l-(2-(hydroxymethyl)cyclobutyl)-lH-pyrazol-3-yl)ethyl)amino)- 2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 131. 7-Amino-2-(difluoromethyl)-3-ethyl-5-((2-(l-(2-hydroxyethyl)-2-oxo-l,2-dihydropyridin- 3-yl)ethyl)amino)pyrazolo[l,5-a]pyrimidine-6-carbonitrile; 132. (+-)-7-Amino-5-((2-(l-(4-(hydroxymethyl)tetrahydrofuran-3-yl)-lH-pyrazol-3- yl)ethyl)amino)-2,3-dimethylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 133. (+)-7-Amino-5-((2-(l-(4-(hydroxymethyl)tetrahydrofuran-3-yl)-lH-pyrazol-3- yl)ethyl)amino)-2,3-dimethylpyrazolo[l,5-a]pyrimidine-6-carbonitrile (133a); 133b. (-)-7-Amino-5-((2-(l-(4-(hydroxymethyl)tetrahydrofuran-3-yl)-lH-pyrazol-3- yl)ethyl)amino)-2,3-dimethylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 134. 2-(((2-(3-(2-((7-amino-6-cyano-3-ethyl-2-methylpyrazolo[l,5-a]pyrimidin-5-yl)amino)ethyl)-lH-pyrazol-l- yl)cyclobutyl)methyl)amino)acetamide; 135. 7-Amino-3-ethyl-2-methyl-5-((2-(6-(2,2,2-trifluoro-l-hydroxyethyl)pyridin-2-yl)ethyl)amino)pyrazolo[l,5- a]pyrimidine-6-carbonitrile; 136. 7-Amino-5-((2-(l-(3-aminopropyl)-2-oxo-l,2-dihydropyridin-3-yl)ethyl)amino)-3-ethyl-2-methylpyrazolo[l,5- a]pyrimidine-6-carbonitrile; 137. 7-Amino-3-(cyclobutylmethyl)-5-((2-(l-(l-(hydroxymethyl)cyclopropyl)-lH-pyrazol-3-yl)ethyl)amino)-2- methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 138. 7-Amino-5-((2-(l-(3-hydroxypropyl)-2-oxo-l,2-dihydropyridin-3-yl)ethyl)amino)-2,3-dimethylpyrazolo[l,5- a]pyrimidine-6-carbonitrile; 139. 7-Amino-3-ethyl-5-((2-(6-(2-hydroxyethyl)pyridin-2-yl)ethyl)amino)-2-methylpyrazolo[l,5-a]pyrimidine-6- carbonitrile; 140. 7-Amino-2,3-dimethyl-5-((2-(6-methylpyrazin-2-yl)ethyl)amino)pyrazolo[l,5-a]pyrimidine-6-carbonitrile; 141. 7-Amino-5-((2-(l-(3-aminopropyl)-2-oxo-l,2-dihydropyridin-3-yl)ethyl)amino)-2,3-dimethylpyrazolo[l,5- a]pyrimidine-6-carbonitrile; 142. 7-Amino-3-ethyl-2-methyl-5-((2-(l-(2-(methylthio)ethyl)-2-oxo-l,2-dihydropyridin-3-yl)ethyl)amino)pyrazolo[l,5- a]pyrimidine-6-carbonitrile; 143. (+-) 7-Amino-3-ethyl-2-methyl-5-((2-(l-(2-(methylsulfinyl)ethyl)-2-oxo-l,2-dihydropyridin-3-yl)ethyl)amino)pyrazolo[l,5- a]pyrimidine-6-carbonitrile; 144a. (+) 7-Amino-3-ethyl-2-methyl-5-((2-(l-(2-(methylsulfinyl)ethyl)-2-oxo-l,2-dihydropyridin-3-yl)ethyl)amino)pyrazolo[l,5- a]pyrimidine-6-carbonitrile; 144b. (-) 7-Amino-3-ethyl-2-methyl-5-((2-(l-(2-(methylsulfinyl)ethyl)-2-oxo-l,2-dihydropyridin-3-yl)ethyl)amino)pyrazolo[l,5- a]pyrimidine-6-carbonitrile; 145. N-(3-(3-(2-((7-amino-6-cyano-3-ethyl-2-methylpyrazolo[l,5-a]pyrimidin-5- yl)amino)ethyl)-2-oxopyridin-l(2H)-yl)propyl)acetamide; 146. 7-amino-5-((2-(l-(l-(aminomethyl)cyclopropyl)-lH-pyrazol-3-yl)ethyl)amino)- 3-ethyl-2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 147. N-((l-(3-(2-((7-amino-6-cyano-3-ethyl-2-methylpyrazolo[l,5-a]pyrimidin-5- yl)amino)ethyl)-lH-pyrazol-l-yl)cyclopropyl)methyl)acetamide; 148. 7-amino-5-((2-(l-(l-(2-aminoethyl)cyclopropyl)-lH-pyrazol-3-yl)ethyl)amino)- 3-ethyl-2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 149. N-(2-(l-(3-(2-((7-amino-6-cyano-3-ethyl-2-methylpyrazolo[l,5-a]pyrimidin-5- yl)amino)ethyl)-lH-pyrazol-l-yl)cyclopropyl)ethyl)acetamide; 150: 7-amino-3-ethyl-5-((2-(6-(2-hydroxyethoxy)pyridin-2-yl)ethyl)amino)-2- methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 151. 7-amino-5-((2-(l-(l-(2-aminoethyl)cyclopropyl)-lH-pyrazol-3-yl)ethyl)amino)- 3-chloro-2-methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 152. 7-amino-5-((2-(6-(2-hydroxyethyl)pyridin-2-yl)ethyl)amino)-2,3-dimethyl pyrazolo[l,5-a]pyrimidine-6-carbonitrile; 153. 7-amino-3-ethyl-2-methyl-5-((2-(l-(3-(methylthio)propyl)-2-oxo-l,2- dihydropyridin-3-yl)ethyl)amino)pyrazolo[l,5-a]pyrimidine-6-carbonitrile; 154. (-)-7-amino-3-ethyl-2-methyl-5-((2-(l-(3-(methylsulfinyl)propyl)-2-oxo-l,2- dihydropyridin-3-yl)ethyl)amino)pyrazolo[l,5-a]pyrimidine-6-carbonitrile (154a); 154b. (+)-7-amino-3-ethyl-2-methyl-5-((2-(l-(3-(methylsulfinyl)propyl)-2-oxo-l,2- dihydropyridin-3-yl)ethyl)amino)pyrazolo[l,5-a]pyrimidine-6-carbonitrile; 155. 7-amino-3-ethyl-5-((2-(6-(3-hydroxypropyl)pyridin-2-yl)ethyl)amino)-2- methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 156. 7-amino-5-((2-(l-(3-hydroxypropyl)-2-oxo-l,2-dihydropyridin-3-yl)ethyl)amino)- 2-methyl-3-propylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 157. 7-amino-5-((2-(6-(hydroxymethyl)pyridin-2-yl)ethyl)amino)-2-methyl-3- propylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 158. 7-amino-5-((2-(l-(l-(hydroxymethyl)cyclopropyl)-lH-pyrazol-3-yl)ethyl)amino)- 2-methyl-3-propylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 159. (+)-7-amino-3-ethyl-5-((2-(6-(l-hydroxyethyl)pyridin-2-yl)ethyl)amino)-2- methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile (159a); 159b. (-)-7-amino-3-ethyl-5-((2-(6-(l-hydroxyethyl)pyridin-2-yl)ethyl)amino)-2- methylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 160. (+) 7-amino-5-((2-(l-(4-(hydroxymethyl)tetrahydrofuran-3-yl)-lH-pyrazol-3- yl)ethyl)amino)-2-methyl-3-propylpyrazolo[l,5-a]pyrimidine-6-carbonitrile (160a); 160b. (-) 7-amino-5-((2-(l-(4-(hydroxymethyl)tetrahydrofuran-3-yl)-lH-pyrazol-3- yl)ethyl)amino)-2-methyl-3-propylpyrazolo[l,5-a]pyrimidine-6-carbonitrile; 161. 7-amino-3-ethyl-2-methyl-5-((2-(l-(3-(methylthio)propyl)-lH-pyrazol-3- yl)ethyl)amino)pyrazolo[l,5-a]pyrimidine-6-carbonitrile; 162. (-)-7-amino-3-ethyl-2-methyl-5-((2-(l-(3-(methylsulfinyl)propyl)-lH-pyrazol- 3-yl)ethyl)amino)pyrazolo[l,5-a]pyrimidine-6-carbonitrile (162a); 162b. (+)-7-amino-3-ethyl-2-methyl-5-((2-(l-(3-(methylsulfinyl)propyl)-lH-pyrazol- 3-yl)ethyl)amino)pyrazolo[l,5-a]pyrimidine-6-carbonitrile; 163. (-)-7-amino-3-ethyl-2-methyl-5-((2-(l-(l-(((2-(methylsulfinyl)ethyl)amino) methyl)cyclopropyl)-lH-pyrazol-3-yl)ethyl)amino)pyrazolo[l,5-a]pyrimidine-6- carbonitrile (163a); 163b. (+)-7-amino-3-ethyl-2-methyl-5-((2-(l-(l-(((2-(methylsulfinyl)ethyl)amino) methyl)cyclopropyl)-lH-pyrazol-3-yl)ethyl)amino)pyrazolo[l,5-a]pyrimidine-6- carbonitrile; 164. 7-amino-2-methyl-5-((2-(6-methylpyridin-2-yl)ethyl)amino)-3- propylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 165. (+)-7-amino-5-((2-(1 -(2-(hydroxymethyl)cyclobutyl)-1 H-pyrazol-3- yl)ethyl)amino)-2-methyl-3-propylpyrazolo[1,5-a]pyrimidine-6-carbonitrile (165a); 165b. (-)-7-amino-5-((2-(1 -(2-(hydroxymethyl)cyclobutyl)-1 H-pyrazol-3- yl)ethyl)amino)-2-methyl-3-propylpyrazolo[1,5-a]pyrimidine-6-carbonitrile; 166.( R )- 7-amino-3-ethyl-2-methyl-5-((2-(6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2- yl)ethyl)amino)pyrazolo[l,5-a]pyrimidine-6-carbonitrile; 167. (-)-7-amino-3-ethyl-5-((2-(1 -(4-(hydroxymethyl)tetrahydrofuran-3-yl)-5- methyl-1 H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6- carbonitrile; and 168. (+)-7-amino-3-ethyl-5-((2-(1 -(4-(hydroxymethyl)tetrahydrofuran-3-yl)-5- methyl-1 H-pyrazol-3-yl)ethyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-6- carbonitrile.

3. Use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt, tautomer, stereoisomer, racemic compound thereof, in the manufacture of an antagonist of the adenosine 2a receptor (A2aR), the adenosine 2b receptor (A2bR), or a combination of the adenosine 2a receptor (A2aR) and the adenosine 2b receptor (A2bR). 2a R), the adenosine 2b receptor (A 2b R), or a combination of the adenosine 2a receptor (A2aR) and the adenosine 2b receptor (A2bR). 2a R), the adenosine 2b receptor (A 2b R), or a combination of the adenosine 2a receptor (A2aR) and the adenosine 2b receptor (A2bR).

4. Use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt, tautomer, stereoisomer, racemic compound thereof, in the manufacture of a medicament for the treatment of a disease, disorder, or condition selected from cancer, Parkinson’s disease, asthma, diabetes, and autoimmune diseases mediated at least in part by adenosine 2a receptor (A2AR), adenosine 2b receptor (A2BR), or a combination of A2AR and A2BR. 2a R), adenosine 2b receptor (A2BR), or a combination of A2AR and A2BR. 2b R), adenosine 2b receptor (A2BR), or a combination of A2AR and A2BR. 2a R), adenosine 2b receptor (A2BR), or a combination of A2AR and A2BR. 2b R), adenosine 2b receptor (A2BR), or a combination of A2AR and A2BR.

5. A method of preparing a compound of Formula I, a pharmaceutically acceptable salt, tautomer, stereoisomer, and racemic compound thereof according to claim 1 or 2, the method comprising: reacting a compound of formula (A) and formula (B) in the presence of a base to obtain a compound of formula I, wherein R is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 5-10 aryl, C 2-10 heteroaryl or C 1-10 heterocyclyl; and the substituents are as defined in claim 1.

6. The process of claim 5, wherein the base is selected from triethylamine, diisopropylethylamine, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert-butoxide, sodium hydride, lithium bis(trimethylsilyl)amide (LiHMDS), N- diisopropylethylamine, or a combination thereof.

7. The process of claim 5, wherein the process is carried out in the presence of a solvent selected from isopropanol, methanol, n-butanol, dichloromethane, tetrahydrofuran, dimethylformamide, n-methylpyrrolidinone, dimethylsulfoxide, water, dioxane, acetonitrile, or a combination thereof.

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