PYRAZOLOPYRAZINE CARBOXAMIDES AND THEIR USES AS PDGFR INHIBITORS CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit of United States Provisional Application No.63/354,276, filed June 22, 2022, the entirety of which is incorporated by reference herein. TECHNICAL FIELD [0002] The disclosure is directed to PDGFR inhibitors and methods of their use. BACKGROUND [0003] Protein kinases are a family of enzymes that catalyze the phosphorylation of specific residues in proteins. Protein kinases play a critical role in the control cell growth, proliferation, differentiation, metabolism, apoptosis, cell mobility, transcription, translation and other signaling processes. The overexpression or inappropriate expression of protein kinases plays a significant role in the development of many diseases and disorders including central nervous system disorders, inflammatory disorders, metabolic disorders, autoimmune diseases, cardiovascular diseases, fibrotic diseases, transplantation rejection, cancer and infectious diseases. [0004] Growth factors (GF) are important regulators of human homeostasis involved in maintaining a delicate balance between cell growth, differentiation, and proliferation. Consequently, dysregulation of GF signaling are implicated in many diseases including oncology, immunology, fibroproliferative, cardiovascular, vascular disorders and pulmonary hypertension. GF bind to several different receptors that amplify the signal through activation of the specific receptor through phosphorylation, leading to confirmation changes increasing the affinity for ATP and the phosphorylation of downstream proteins leading to activation of several signaling cascades. Therefore, small changes in GF or the cognate receptors can significantly alter the local signaling and have dramatic effects on initiation and progression of many diseases. [0005] Platelet-derived growth factor (PDGF) is one of many GFs that regulate cell growth and division. PDGF exerts its biological responses via activation of two highly specific, transmembrane receptor tyrosine kinases, termed PDGFR α and PDGFR β, which can form three different dimeric receptors – αα, ββ and αβ. These receptors can interact with the different dimeric PDGF ligands (PDGF-AA, PDGF-BB, PDGF-CC, PDGF-DD and PDGF-AB) with different specificities and efficacies. The receptors are activated by ligand- induced dimerization, leading to autophosphorylation on specific tyrosine residues. PDGFR phosphorylation recruits signaling proteins containing Tyr(P)-binding domains. Several of these signaling proteins include Src kinase family members, phospholipase C-y1, the p38a subunit of PI3K, GTPase-activating protein. The formation of receptor-signaling complexes then initiates the activation of various signaling pathways, including the Ras-mitogen activated protein (MAP) kinase pathway, the PI3kinase-Akt pathway, the PLC-y1 and the Src pathway. Activation of PDGFRα or PDGFRβ by PDGFs, leads to protein synthesis, proliferation, migration, protection against apoptosis and cellular transformation, key mechanisms associated with several vascular diseases including pulmonary hypertension. Platelet-derived growth factor (PDGF) and its receptors (PDGFR), including PDGFRα and PDGFRβ, play important roles in tumorigenesis, tumor progression, and the regulation of stromal cell function. Constitutive activation of PDGFR signaling, gene rearrangement, and activating mutations of PDGFR have been identified in various types of human tumors and malignancies. [0006] PDGFR signaling is implicated in the development and progression of pulmonary hypertension. PDGFs are expressed in ECs, SMCs and macrophages and are strong mitogens and chemokines. Increased signaling through PDGFRβ leads to smooth muscle cell proliferation which contributes to the development of vascular remodeling. PDGF and PDGF receptors (α and β) are upregulated in human and animals with pulmonary hypertension. Preclinically, efficacy in preventing and reversing vascular remodeling in experimentally induced pulmonary hypertension was demonstrated through non-selective inhibition of PDGF receptors. Clinically, imatinib (also known as Gleevec), a non-selective tyrosine kinase inhibitor including PDGF receptors improved exercise capacity and hemodynamics in patients with advanced pulmonary hypertension. Conversely, dasatinib, a receptor tyrosine kinases inhibitor, was linked to cardiotoxicity and the development of pulmonary hypertension, emphasizing the importance of the appropriate kinase selectivity, and associated differentiated profile. [0007] A need exists for additional PDGFR inhibitors for the treatment of pulmonary hypertension and other conditions in which PDGFR signaling is implicated. SUMMARY [0008] The present disclosure provides PDGFR inhibitors. [0009] In some aspects, the disclosure is directed to compounds of formula (I): or a pharmaceutically acceptable salt thereof, wherein X is N or CH; R ¹ is H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, -CN, or C ₁ -C ₄ fluoroalkyl; R ⁷ is H, C ₁ -C ₆ alkyl, or -OC ₁ -C ₆ alkyl; R ² is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted spiroheterocycloalkyl; R ³ and R ⁴ are each independently optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted spirocycloalkyl, or optionally substituted heterocycloalkyl; or one of R ³ or R ⁴ may be H; or R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form an optionally substituted 3-12-membered heterocycloalkyl ring, an optionally substituted 5-12-membered bridged heterocycloalkyl ring, an optionally substituted 4- 12-membered fused heterocycloalkyl ring system, or an optionally substituted 5-12- membered spiroheterocycloalkyl ring system, wherein said 3-12-membered heterocycloalkyl ring, 5-12-membered bridged heterocycloalkyl ring, 4-12-membered fused heterocycloalkyl ring system, or 5-12-membered spiroheterocycloalkyl ring system may include, in addition to the nitrogen atom to which both R ³ and R ⁴ are attached, 1-3 other heteroatoms that are each independently O, S, or N; each R ⁵ and each R ⁶ is independently H, C ₁ -C ₆ alkyl, or C ₃ -C ₅ cycloalkyl; or an R ⁵ and R ⁶ attached to the same carbon atom, together with that carbon atom, may form a C ₃ -C ₆ cycloalkyl ring; or an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3- 12-membered heterocycloalkyl ring, an optionally substituted 5-12-membered bridged heterocycloalkyl ring, an optionally substituted 4-12-membered fused heterocycloalkyl ring system, or an optionally substituted 5-12-membered spiroheterocycloalkyl ring system; n is 1, 2, or 3; L is -C(O)NH-, -NHC(O)O-, -NHC(O)-, -NHC(O)NH-, or -NHC(O)NR ⁸ -; wherein when L is -NHC(O)NR ⁸ -, an R ⁵ or an R ⁶ attached to a carbon atom, together with R ⁸ , form a heterocycloalkyl ring; and wherein when L is -C(O)NH-, -NHC(O)O-, -NHC(O)NR ⁸ -, or -NHC(O)NH-, n is 2 or 3, and when L is -NHC(O)-, n is 1, 2, or 3. [0010] Pharmaceutical compositions comprising such compounds, and methods of using such compounds in treating conditions in which PDGFR signaling is implicated are also provided. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS [0011] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The terminology used in the description is for describing particular embodiments only and is not intended to be limiting of the disclosure. [0012] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise (such as in the case of a group containing a number of carbon atoms in which case each carbon atom number falling within the range is provided), between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the disclosure. [0013] The following terms are used to describe the present disclosure. In instances where a term is not specifically defined herein, that term is given an art-recognized meaning by those of ordinary skill applying that term in context to its use in describing the present disclosure. [0014] The articles “a” and “an” as used herein and in the appended claims are used herein to refer to one or to more than one (e.g., to at least one) of the grammatical object of the article unless the context clearly indicates otherwise. By way of example, “an element” means one element or more than one element. [0015] The term “compound”, as used herein, unless otherwise indicated, refers to any specific chemical compound disclosed herein and includes tautomers, optical isomers (enantiomers) and other stereoisomers (diastereomers) thereof, as well as pharmaceutically acceptable salts and derivatives, including prodrug and/or deuterated forms thereof where applicable. Deuterated small molecules contemplated are those in which one or more of the hydrogen atoms contained in the drug molecule have been replaced by deuterium. It is understood by those of ordinary skill that molecules which are described herein are stable compounds as generally described hereunder. [0016] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, e.g., in humans. [0017] “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N- methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. [0018] A “pharmaceutically acceptable excipient” refers to a substance that is non- toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith. [0019] A “solvate” refers to a physical association of a compound of formula (I) with one or more solvent molecules. [0020] The term “alkyl,” when used alone or as part of a substituent group, refers to a straight- or branched-chain hydrocarbon group having from 1 to 12 carbon atoms (“C ₁ - C ₁₂ ”), preferably 1 to 6 carbons atoms (“C ₁ -C ₆ ”), in the group. Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n- hexyl, n-heptyl, n-octyl, and the like. In some embodiments, the alkyl group is a C ₁ -C ₆ alkyl; in some embodiments, it is a C ₁ -C ₄ alkyl. [0021] When a range of carbon atoms is used herein, for example, C ₁ -C ₆ , all ranges, as well as individual numbers of carbon atoms are encompassed. For example, “C ₁ -C ₃ ” includes C ₁ -C ₃ , C ₁ -C ₂ , C ₂ -C ₃ , C ₁ , C ₂ , and C ₃ . [0022] The term “cycloalkyl” when used alone or as part of a substituent group refers to cyclic-containing, non-aromatic hydrocarbon groups having from 3 to 10 carbon atoms (“C _3- C ₁₀ ”), preferably from 3 to 6 carbon atoms (“C _3- C ₆ ”). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, indenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.1.0]heptanyl, spiro[3.3]heptanyl, and spiro[3.4]octanyl. [0023] The term “fluoroalkyl” when used alone or as part of a substituent group refers to an alkyl group wherein one or more of the hydrogen atoms has been replaced with one or more fluorine atoms. Examples of fluoroalkyl groups include -CF ₃ , CHF ₂ , -CH ₂ F and the like. [0024] The term “heterocycloalkyl” when used alone or as part of a substituent group refers to any three to twelve-membered monocyclic, saturated or partially unsaturated ring containing at least one heteroatom that is O, N or S. The heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure. Examples of heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and the like. [0025] The term “bridged heterocycloalkyl ring” refers to any 5 to 12 membered heterocycloalkyl ring system that contains at least one bridged ring. Examples of bridged heterocycloalkyl rings include azabicyclo[3.1.1]heptane, azabicyclo[3.1.1]heptane, azabicyclo[2.2.2]octane, azabicyclo[2.2.1]heptane, azabicyclo[2.1.1]hexane, azabicyclo[1.1.1]pentane, azabicyclo[1.1.1]pentane, 6-oxa-azabicyclo[3.1.1]heptane, 6- diazabicyclo[3.1.1]heptane, 3-thia-azabicyclo[3.1.1]heptane, and the like. [0026] The term “fused heterocycloalkyl ring system” refers to a heterocycloalkyl ring to which another ring is fused. The other ring that is fused to the heterocycle ring may be another heterocycloalkyl ring, a cycloalkyl ring, an aryl ring, or a heteroaryl ring. In some embodiments, the fused heterocycloalkyl ring system is a 4 to 12 membered fused heterocycloalkyl ring system. [0027] The term “spiroheterocycloalkyl ring system” refers to a heterocycloalkyl ring that is substituted with a spirocyclic ring. The spirocyclic ring can be a cycloalkyl ring of a heterocycloalkyl ring. In some embodiments, the spiroheterocycloalkyl ring system is a 5-12-membered spiroheterocycloalkyl ring system. [0028] The terms “halo” or “halogen”, by itself or as part of another substituent, means a fluorine, chlorine, bromine, or iodine atom. [0029] The term “aryl” when used alone or as part of a substituent group also refers to a mono- or bicyclic- aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein one or more of the carbon atoms in the ring is optionally substituted. The term “aryl” also includes a mono- or bicyclic- aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein two adjacent carbon atoms in the ring are optionally substituted such that said two adjacent carbon atoms and their respective substituents form a cycloalkyl or heterocycloalkyl ring. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1, 2, 3,4-tetrahydronaphthyl, and the like. [0030] The term “heteroaryl” when used alone or as part of a substituent group refers to a mono- or bicyclic- aromatic ring structure including carbon atoms as well as up to four heteroatoms that are each independently nitrogen, oxygen, or sulfur. Heteroaryl rings can include a total of 5, 6, 9, or 10 ring atoms. The heteroaryl moiety can be unsubstituted, or one or more of the carbon atoms in the ring can be substituted. Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3- b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole. [0031] The term “optionally substituted,” as used herein to describe a substituent defined herein, means that the substituent may, but is not required to be, substituted with one or more suitable functional groups or other substituents as provided herein. For example, a substituent may be optionally substituted with one or more of: halo (i.e., -F, -Cl, -Br, -I), cyano, -OH, -C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C _1- C ₆ haloalkyl, -C ₁ - C ₆ alkoxy, -C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylamino, -NH ₂ , -NH(C ₁ -C ₆ alkyl), - N(C ₁ -C _-6 alkyl) ₂ , -NH(C ₁ -C ₆ alkoxy), -C(O)NHC ₁ -C ₆ alkyl, -C(O)N(C ₁ -C ₆ alkyl) ₂ , -COOH, - C _1- C ₆ alkylCOOH _{, -} C _3- C ₆ cycloalkylCOOH, -C(O)NH ₂ , C _1- C ₆ alkylCONH _{2, -} C _3- C ₆ cycloalkylCONH ₂ , C _1- C ₆ alkylCONHC _1- C ₆ alkyl _, C _1- C ₆ alkylCON(C _1- C ₆ alkyl) _2, C _1- C ₆ alkylCN, -C(O)C _1- C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, -NHCO(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)C(O)(C ₁ -C ₆ alkyl), -S(O)C ₁ -C ₆ alkyl, -S(O) ₂ C ₁ -C ₆ alkyl, oxo, 6-12 membered aryl, or 5 to 12 membered heteroaryl groups. [0032] In particular, a substituent may be optionally substituted with one or more of: halo (i.e., -F, -Cl, -Br, -I), cyano, -C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, -C ₁ -C ₆ alkoxy, -C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylamino, -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C- ₆ alkyl) ₂ , -NH(C ₁ -C ₆ alkoxy), -C(O)NHC ₁ -C6 alkyl, -C(O)N(C ₁ -C ₆ alkyl) ₂ , -COOH, -C ₁ -C ₆ alkylCOOH, -C ₃ -C ₆ cycloalkylCOOH, - C(O)NH ₂ , C ₁ -C ₆ alkylCONH ₂ , -C ₃ -C6cycloalkylCONH ₂ , C ₁ -C ₆ alkylCONHC ₁ -C ₆ alkyl, C ₁ - C ₆ alkylCON(C ₁ -C ₆ alkyl) ₂ , -C(O)C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, -NHCO(C ₁ -C ₆ alkyl), - N(C ₁ -C ₆ alkyl)C(O)(C ₁ -C ₆ alkyl), -S(O)C ₁ -C ₆ alkyl, -S(O) ₂ C ₁ -C ₆ alkyl, oxo, 6-12 membered aryl, or 5 to 12 membered heteroaryl groups. In some embodiments, each of the above optional substituents are themselves optionally substituted by one or two groups. [0033] In other embodiments, a substituent may be optionally substituted with one or more of: halo (i.e., -F, -Cl, -Br, -I), cyano, -OH, -C ₁ -C ₆ alkyl, -CH ₂ CH ₂ OH, - CH ₂ CH ₂ CH(OH)CH ₂ (OH), -CH ₂ CH(OH)CH ₂ (OH), -CH ₂ CH(OH)CH ₃ , -CH ₂ OH, -C (CH ₃ ) ₂ CH ₂ (OH), -CH ₂ OCH ₃ , -CH ₂ CH ₂ OCH ₃ , -CH ₂ -(C ₃ -C ₆ cycloalkyl), -C ₃ -C ₆ cycloalkyl, C ₂ - C ₆ alkenyl, C ₂ -C ₆ alkynyl, -C _1- C ₆ haloalkyl, -C ₁ -C ₆ alkoxy, -OCH ₃ , -C ₁ -C ₆ haloalkoxy, - OCH ₂ CH ₂ F, -C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylamino, -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C _-6 alkyl) ₂ , - NH(C ₁ -C ₆ alkoxy), -C(O)NHC ₁ -C ₆ alkyl, -CH ₂ C(O)NHC ₁ -C ₆ alkyl, -C(O)N(C ₁ -C ₆ alkyl) ₂ , - COOH, -C _1- C ₆ alkylCOOH _{, -} C _3- C ₆ cycloalkylCOOH, -C(O)NH ₂ , -C _1- C ₆ alkylCONH ₂ , -C _1- C ₆ alkyl-CN, -C _3- C ₆ cycloalkylCONH ₂ , -C _1- C ₆ alkylCONHC _1- C ₆ alkyl _, C _1- C ₆ alkylCON(C _1- C ₆ alkyl) _2, -C(O)C _1- C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, -NHCO(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)C(O)(C ₁ -C ₆ alkyl), -S(O)C ₁ -C ₆ alkyl, -S(O) ₂ C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl-S(O) ₂ C ₁ -C ₆ alkyl, oxo, a 4-7 membered heterocycloalkyl group, -CH ₂ -(4-7 membered heterocycloalkyl), 6-12 membered aryl, 5 to 12 membered heteroaryl groups, -CH ₂ -(5 to 12 membered heteroaryl)-O- CH ₂ -(6-12 membered aryl), -CH ₂ -(5 to 12 membered heteroaryl)-OH. In some embodiments, each of the above optional substituents are themselves optionally substituted by one or two groups. [0034] As used herein, the term “alkenyl” refers to a straight- or branched-chain group having from 2 to 12 carbon atoms (“C _2- C ₁₂ ”), preferably 2 to 4 carbons atoms (“C ₂ - C ₄ ”), in the group, wherein the group includes at least one carbon-carbon double bond. Examples of alkenyl groups include vinyl (-CH=CH ₂ ; C ₂ alkenyl) allyl (-CH ₂ - CH=CH ₂ ; C ₃ alkenyl), propenyl (-CH=CHCH ₃ ; C ₃ alkenyl); isopropenyl (-C(CH ₃ )=CH ₂ ; C ₃ alkenyl), butenyl (-CH=CHCH ₂ CH ₃ ; C ₄ alkenyl), sec-butenyl (-C(CH ₃ )=CHCH ₃ ; C ₄ alkenyl), iso- butenyl (-CH=C(CH ₃ ) ₂ ; C ₄ alkenyl), 2-butenyl (-CH ₂ CH=CHCH ₃ ; C ₄ alkyl), pentenyl (-CH=CHCH ₂ CH ₂ CH ₃ ; C ₅ alkenyl), and the like. [0035] As used herein, the term “alkynyl” refers to a straight- or branched-chain group having from 1 to 12 carbon atoms (“C _1- C ₁₂ ”), preferably 1 to 4 carbons atoms (“C ₂ - C ₄ ”), in the group, and wherein the group includes at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl (-C≡CH; C ₂ alkynyl); propargyl (-CH ₂ -C≡CH; C ₃ alkynyl), propynyl (-C≡CCH ₃ ; C ₃ alkynyl); butynyl (-C≡CCH ₂ CH ₃ ; C ₄ alkynyl), pentynyl (-C≡CCH ₂ CH ₂ CH ₃ ; C ₅ alkynyl), and the like. [0036] As used herein, the term “alkoxy” refers to an oxygen radical attached to an alkyl group by a single bond. Examples of alkoxy groups include methoxy (-OCH ₃ ), ethoxy (-OCH ₂ CH ₃ ), isopropoxy (-OCH(CH ₃ ) ₂ ) and the like. [0037] As used herein, the term “haloalkoxy” refers to an oxygen radical attached to a haloalkyl group by a single bond. Examples of haloalkoxy groups include -OCF ₃ , - OCH ₂ CF ₃ , -OCH(CF ₃ ) ₂ , and the like. [0038] The term “haloalkyl” refers to an alkyl group wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms. [0039] The term “haloalkoxy” refers to an alkoxy group wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms. [0040] As used herein, the term “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space, e.g., enantiomers, diastereomers or tautomers. [0041] The term “patient” or “subject” is used throughout the specification to describe an animal, preferably a human or a domesticated animal, to whom treatment, including prophylactic treatment, with the compositions according to the present disclosure is provided. For treatment of those conditions or disease states which are specific for a specific animal such as a human patient, the term patient refers to that specific animal, including a domesticated animal such as a dog or cat or a farm animal such as a horse, cow, sheep, etc. In general, in the present disclosure, the term patient refers to a human patient unless otherwise stated or implied from the context of the use of the term. [0042] The term “effective” is used to describe an amount of a compound, composition or component which, when used within the context of its intended use, effects an intended result. The term effective subsumes all other effective amount or effective concentration terms, which are otherwise described or used in the present application. [0043] “Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (e.g., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder. [0044] In some aspects, the disclosure is directed to a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein X is N or CH; R ¹ is H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, -CN, or C ₁ -C ₄ fluoroalkyl; R ⁷ is H, C ₁ -C ₆ alkyl, or -OC ₁ -C ₆ alkyl; R ² is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted spiroheterocycloalkyl; R ³ and R ⁴ are each independently optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted spirocycloalkyl, or optionally substituted heterocycloalkyl; or one of R ³ or R ⁴ may be H; or R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form an optionally substituted 3-12-membered heterocycloalkyl ring, an optionally substituted 5-12- membered bridged heterocycloalkyl ring, an optionally substituted 4-12-membered fused heterocycloalkyl ring system, or an optionally substituted 5-12-membered spiroheterocycloalkyl ring system, wherein said 3-12-membered heterocycloalkyl ring, 5-12- membered bridged heterocycloalkyl ring, 4-12-membered fused heterocycloalkyl ring system, or 5-12-membered spiroheterocycloalkyl ring system may include, in addition to the nitrogen atom to which both R ³ and R ⁴ are attached, 1-3 other heteroatoms that are each independently O, S, or N; each R ⁵ and each R ⁶ is independently H, C ₁ -C ₆ alkyl, or C ₃ -C ₅ cycloalkyl; or an R ⁵ and R ⁶ attached to the same carbon atom, together with that carbon atom, may form a C ₃ -C ₆ cycloalkyl ring; or an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12- membered heterocycloalkyl ring, an optionally substituted 5-12-membered bridged heterocycloalkyl ring, an optionally substituted 4-12-membered fused heterocycloalkyl ring system, or an optionally substituted 5-12-membered spiroheterocycloalkyl ring system; n is 1, 2, or 3; L is -C(O)NH-, -NHC(O)O-, -NHC(O)-, -NHC(O)NH-, or -NHC(O)NR ⁸ -; wherein when L is -NHC(O)NR ⁸ -, an R ⁵ or an R ⁶ attached to a carbon atom, together with R ⁸ , form a heterocycloalkyl ring; and wherein when L is -C(O)NH-, -NHC(O)O-, -NHC(O)NR ⁸ -, or -NHC(O)NH-, n is 2 or 3, and when L is -NHC(O)-, n is 1, 2, or 3. [0045] In some aspects, X in the compounds of formula (I) is N or CH. [0046] In some embodiments, X is N. [0047] In other embodiments, X is CH. [0048] In some aspects, R ¹ in the compounds of formula (I) is H, C ₁ -C ₆ alkyl, C ₃ - C ₆ cycloalkyl, halogen, -CN, or C ₁ -C ₄ fluoroalkyl. [0049] In some embodiments, R ¹ is H. [0050] In other embodiments, R ¹ is C ₁ -C ₆ alkyl, such as, for example, C ₁ -C ₆ alkyl, C ₁ -C ₅ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₂ alkyl, C ₆ alkyl, C ₅ alkyl, C ₄ alkyl, C ₃ alkyl, C ₂ alkyl, C ₁ alkyl, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n- hexyl, and the like. [0051] In some embodiments, R ¹ is methyl. [0052] In some embodiments, R ¹ is C ₃ -C ₆ cycloalkyl, such as, for example, C ₃ - C ₅ cycloalkyl, C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. [0053] In some embodiments, R ¹ is halogen, such as, for example, -F, -Cl, -Br, or -I. [0054] In some embodiments, R ¹ is -F. [0055] In some embodiments, R ¹ is -Cl. [0056] In some embodiments, R ¹ is cyano, i.e., -CN. [0057] In some embodiments, R ¹ is C ₁ -C ₄ fluoroalkyl, such as, for example, C ₄ fluoroalkyl, C ₃ fluoroalkyl, C ₂ fluoroalkyl, C ₁ fluoroalkyl, -CF ₃ , -CHF ₂ , or -CH ₂ F. [0058] In some aspects, R ⁷ in the compounds of formula (I) is H, C ₁ -C ₆ alkyl, or - OC ₁ -C ₆ alkyl. [0059] In some embodiments, R ⁷ is H. [0060] In other embodiments, R ⁷ is C ₁ -C ₆ alkyl, such as, for example, C ₁ -C ₆ alkyl, C ₁ -C ₅ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₂ alkyl, C ₆ alkyl, C ₅ alkyl, C ₄ alkyl, C ₃ alkyl, C ₂ alkyl, C ₁ alkyl, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n- hexyl, and the like. [0061] In some embodiments, R ⁷ is methyl. [0062] In other embodiments, R ⁷ is -OC ₁ -C ₆ alkyl, such as, for example, -OC ₁ - C ₆ alkyl, -OC ₁ -C ₅ alkyl, -OC ₁ -C ₄ alkyl, -OC ₁ -C ₃ alkyl, -OC ₁ -C ₂ alkyl, -OC ₆ alkyl, -OC ₅ alkyl, - OC ₄ alkyl, -OC ₃ alkyl, -OC ₂ alkyl, -OC ₁ alkyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n- butoxy, t-butoxy, iso-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and the like. [0063] In some embodiments, R ⁷ is methoxy. [0064] In some aspects, R ² in the compounds of formula (I) is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted spiroheterocycloalkyl. [0065] In some embodiments, R ² in the compounds of formula (I) is optionally substituted aryl, such as, for example, phenyl, indenyl, naphthyl, 1, 2, 3,4-tetrahydronaphthyl, and the like. [0066] In some embodiments wherein R ² is optionally substituted aryl, the optionally substituted aryl is an optionally substituted phenyl. [0067] In some embodiments, the optionally substituted phenyl is substituted with one or more -C(O)NH ₂ , halogen, or -CN. [0068] In some embodiments, the optionally substituted phenyl is substituted with one or more of -C(O)NH ₂ , F, or -CN. [0069] In some embodiments, the optionally substituted phenyl is substituted with one or more of -C(O)NH ₂ , -C(O)NH(CH ₂ CH ₂ OCH ₃ ), F, or -CN. [0070] In some embodiments, the optionally substituted phenyl is 2-fluoro- benzamid-4-yl. [0071] In some embodiments, the optionally substituted phenyl is 2-fluoro- benzamid-5yl. [0072] In some embodiments, the optionally substituted phenyl is 2-fluoro-N- methyl-benzamid-4-yl. [0073] In some embodiments, the optionally substituted phenyl is 2-fluoro- benzonitril-4-yl. [0074] In some embodiments, the optionally substituted phenyl is 2-fluoro-N-(2- methoxyethyl)-benzamid-4-yl, i.e., : . [0075] In some embodiments, R ² in the compounds of formula (I) is optionally substituted heteroaryl, such as, for example, an optionally substituted pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)- one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole, or 6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine, and in particular an optionally substituted pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)- one, triazolyl, or 4,5,6,7-tetrahydro-1H-indazole. [0076] In some embodiments, R ² in the compounds of formula (I) is optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted isothiazolyl, optionally substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, or optionally substituted 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl. [0077] In some embodiments, R ² in the compounds of formula (I) is pyridin-2(1H)- one-6-yl. [0078] In some embodiments wherein R ² is optionally substituted heteroaryl, the optionally substituted heteroaryl is substituted with optionally substituted C ₁ -C ₆ alkyl, optionally substituted 3-6 membered cycloalkyl, OC ₁ -C ₆ alkyl; optionally substituted 4-6 membered heterocycloalkyl, preferably oxetanyl, tetrahydropyranyl, or morpholinyl. [0079] In some embodiments wherein R ² is optionally substituted heteroaryl, the optionally substituted heteroaryl is substituted with optionally substituted C ₁ -C ₆ alkyl, such as, for example, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₅ alkyl, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₁ -C ₃ alkyl, optionally substituted C ₁ -C ₂ alkyl, optionally substituted C ₆ alkyl, optionally substituted C ₅ alkyl, optionally substituted C ₄ alkyl, optionally substituted C ₃ alkyl, optionally substituted C ₂ alkyl, optionally substituted C ₁ alkyl, optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted iso-propyl, optionally substituted n-butyl, optionally substituted t-butyl, optionally substituted iso-butyl, optionally substituted sec-butyl, optionally substituted n- pentyl, optionally substituted n-hexyl, and the like. [0080] In some embodiments, the optionally substituted C ₁ -C ₆ alkyl is -CH ₃ , - CH(CH ₃ )C(O)NH ₂ , -CH ₂ CH ₂ C(O)NH ₂ , -CH ₂ CH ₂ CN, or -CH ₂ CH ₂ OCH ₃ . [0081] In some embodiments wherein R ² is optionally substituted heteroaryl, the optionally substituted heteroaryl is substituted with optionally substituted 3-6 membered cycloalkyl, such as, for example, 3- membered cycloalkyl, 4-membered cycloalkyl, 5- membered cycloalkyl, or 6-membered cycloalkyl. [0082] In some embodiments, the optionally substituted heteroaryl is substituted with -cyclopropyl. [0083] In other embodiments wherein R ² is optionally substituted heteroaryl, the optionally substituted heteroaryl is substituted with optionally substituted OC ₁ -C ₆ alkyl, such as, for example, optionally substituted OC ₁ -C ₆ alkyl, optionally substituted OC ₁ -C ₅ alkyl, optionally substituted OC ₁ -C ₄ alkyl, optionally substituted OC ₁ -C ₃ alkyl, optionally substituted OC ₁ -C ₂ alkyl, optionally substituted OC ₆ alkyl, optionally substituted OC ₅ alkyl, optionally substituted OC ₄ alkyl, optionally substituted OC ₃ alkyl, optionally substituted OC ₂ alkyl, optionally substituted OC ₁ alkyl, optionally substituted methoxy, optionally substituted ethoxy, optionally substituted n-propoxy, optionally substituted iso-propoxy, optionally substituted n-butoxy, optionally substituted t-butoxy, optionally substituted iso-butoxy, optionally substituted sec-butoxy, optionally substituted n-pentoxy, optionally substituted n- hexoxy, and the like and the like. [0084] In some embodiments the optionally substituted heteroaryl is substituted with OCH ₃ . [0085] In some embodiments wherein R ² is optionally substituted heteroaryl, the optionally substituted heteroaryl is substituted with optionally substituted 4-6 membered heterocycloalkyl, such as, for example, optionally substituted 4- membered heterocycloalkyl, optionally substituted 5- membered heterocycloalkyl, or optionally substituted 6- membered heterocycloalkyl. [0086] In some embodiments, the optionally substituted 4-6 membered heterocycloalkyl is oxetanyl, tetrahydropyranyl, or morpholinyl. [0087] In some embodiments of R ² , the optionally substituted heteroaryl is benzo[d]oxazol-2(3H)-one-5-yl. [0088] In other embodiments, R ² is 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl. [0089] In other embodiments, R ² is 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3- yl. [0090] In other embodiments, R ² is 4,5,6,7-tetrahydro-3-pyrazolo[1,5-a]pyridine. [0091] In other embodiments, R ² is 7-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5- a]pyrazin-3-yl. [0092] In other embodiments, R ² is 5-benzyl-7-methyl-4,5-dihydro-pyrazolo[1,5- a]pyrazin-6(7H)-one-3-yl. [0093] In other embodiments, R ² is 4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-5-ol- 3-yl. [0094] In other embodiments, R ² is 2-methyl-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazin-6-ol-3-yl. [0095] In other embodiments, R ² is 7-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5- a]pyrazin-3-yl. [0096] In other embodiments, R ² is 7-methyl-6,7-dihydro-pyrazolo[1,5-a]pyrazin- 4(5H)-one-3-yl. [0097] In some embodiments wherein R ² is optionally substituted heteroaryl, the optionally substituted heteroaryl is an optionally substituted 5-membered heteroaryl. [0098] In some embodiments, R ² is an optionally substituted pyrazolyl, an optionally substituted triazolyl, an optionally substituted isoxazolyl, an optionally substituted oxadiazolyl, an optionally substituted thiophenyl, or an optionally substituted thiazolyl. [0099] In some embodiments wherein R ² is optionally substituted heteroaryl, the optionally substituted heteroaryl is an optionally substituted 6-membered heteroaryl. [00100] In some embodiments, R ² is an optionally substituted pyridinyl, or an optionally substituted pyrimidinyl. [00101] In some embodiments, the optionally substituted heteroaryl is substituted with C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxyl, C ₁ -C ₆ alkoxyl, -C ₁ -C ₆ alk-O-C ₁ -C ₆ alkyl, hydroxyl, hydroxyalkyl, halo, cyano, cyclopropyl, 6-membered heterocycloalkyl, 5- membered heterocycloalkyl, 4-membered heterocycloalkyl, -C ₁ -C ₆ alk-SO ₂ -C ₁ -C ₆ alkyl, 6- membered heteroaryl, 5-membered heteroaryl, -C(O)NH ₂ , hydroxy-substituted-4-membered heterocycloalkyl, -C ₁ -C ₆ alk-CO ₂ H, or -NH ₂ . [00102] Thus, in some embodiments, the optionally substituted heteroaryl is substituted with one or more of

, wherein represents the point(s) of attachment to the heteroaryl ring. [00103] In some embodiments of R ² , the optionally substituted heteroaryl is substituted with an optionally substituted C ₁ -C ₆ alkyl, such as, for example, C ₁ -C ₆ alkyl, C ₁ - C ₅ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₂ alkyl, C ₆ alkyl, C ₅ alkyl, C ₄ alkyl, C ₃ alkyl, C ₂ alkyl, C ₁ alkyl, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n- hexyl, and the like; or an optionally substituted C ₃ -C ₅ cycloalkyl, such as, for example, C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, and the like. [00104] In some embodiments of R ² , the optionally substituted heteroaryl is an optionally substituted 5-membered heteroaryl. [00105] In some embodiments of R ² , the optionally substituted 5-membered heteroaryl is substituted with an optionally substituted C ₁ -C ₆ alkyl, such as, for example, C ₁ - C ₆ alkyl, C ₁ -C ₅ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₂ alkyl, C ₆ alkyl, C ₅ alkyl, C ₄ alkyl, C ₃ alkyl, C ₂ alkyl, C ₁ alkyl, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n- pentyl, n-hexyl, and the like; or an optionally substituted C ₃ -C ₅ cycloalkyl, such as, for example, C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, and the like. [00106] In some embodiments of R ² , the optionally substituted 5-membered heteroaryl is an is an optionally substituted pyrrolyl. [00107] In some embodiments of R ² , the optionally substituted pyrrolyl is an unsubstituted pyrrolyl. [00108] In some embodiments of R ² , unsubstituted pyrrolyl is pyrrol-3-yl. [00109] In some embodiments of R ² , the optionally substituted pyrrolyl is 1- (methylsulfonyl)-1H-pyrrol-3-yl. [00110] In some embodiments of R ² , the optionally substituted 5-membered heteroaryl is an is an optionally substituted pyrazolyl. [00111] In some embodiments of R ² , the optionally substituted pyrazolyl is an unsubstituted pyrazolyl. [00112] In some embodiments of R ² , the unsubstituted pyrazolyl is pyrazol-1-yl. [00113] In some embodiments of R ² , the unsubstituted pyrazolyl is pyrazol-3-yl. [00114] In some embodiments of R ² , the unsubstituted pyrazolyl is pyrazol-4-yl. [00115] In some embodiments of R ² , the optionally substituted pyrazolyl is substituted with an optionally substituted C ₁ -C ₆ alkyl, such as, for example, C ₁ -C ₆ alkyl, C ₁ - C ₅ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₂ alkyl, C ₆ alkyl, C ₅ alkyl, C ₄ alkyl, C ₃ alkyl, C ₂ alkyl, C ₁ alkyl, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n- hexyl, and the like; or an optionally substituted C ₃ -C ₅ cycloalkyl, such as, for example, C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, and the like. [00116] In some embodiments of R ² , the optionally substituted pyrazolyl is substituted with a methyl group, i.e., -CH ₃ . [00117] In some embodiments of R ² , the optionally substituted pyrazolyl is substituted with a 2-hydroxyethyl group, i.e., -CH ₂ CH ₂ OH. [00118] In some embodiments of R ² , the optionally substituted pyrazolyl is substituted with a 2-(C ₁ -C ₆ alkoxy)ethyl group, i.e., -CH ₂ CH ₂ O(C ₁ -C ₆ alkyl). [00119] In some embodiments of R ² , the optionally substituted pyrazolyl is substituted with a 2-methoxyethyl group, i.e., -CH ₂ CH ₂ OCH ₃ . [00120] In other embodiments of R ² , the optionally substituted pyrazolyl is substituted with a cyclopropyl group. [00121] In some embodiments of R ² , the optionally substituted pyrazolyl is 1- methyl-pyrazol-3-yl, 1-methyl-pyrazol-4-yl, 1-methyl-pyrazol-5-yl, 1-cyclopropyl-pyrazol-3- yl, 1-cyclopropyl-pyrazol-4-yl, 1-cyclopropyl-pyrazol-5-yl, 1-(2-hydroxyethyl)-pyrazol-3-yl, 1-(2-hydroxyethyl)-pyrazol-4-yl, 1-(2-hydroxyethyl)-pyrazol-5-yl, or 1-(2-methoxyethyl)- 1H-pyrazol-4-yl, and in particular optionally substituted pyrazolyl is 1-methyl-pyrazol-3-yl, 1-methyl-pyrazol-4-yl, 1-methyl-pyrazol-5-yl, 1-cyclopropyl-pyrazol-3-yl, 1-cyclopropyl- pyrazol-4-yl, 1-cyclopropyl-pyrazol-5-yl, 1-(2-hydroxyethyl)-pyrazol-3-yl, 1-(2- hydroxyethyl)-pyrazol-4-yl, 1-(2-hydroxyethyl)-pyrazol-5-yl. [00122] In some embodiments of R ² , the optionally substituted pyrazolyl is 3- methylpyrazol-4-yl. [00123] In some embodiments of R ² , the optionally substituted pyrazolyl is 1- ethylpyrazol-5-yl. [00124] In some embodiments of R ² , the optionally substituted pyrazolyl is 1- (cyclopropylmethyl)pyrazol-4-yl. [00125] In some embodiments of R ² , the optionally substituted pyrazolyl is 1- cyclobutanyl-pyrazol-4-yl. [00126] In some embodiments of R ² , the optionally substituted pyrazolyl is 1-(2- methoxyethyl)-pyrazol-4-yl. [00127] In some embodiments of R ² , the optionally substituted pyrazolyl is 1-(2- methoxyethyl)-3,5-dimethyl-pyrazol-4-yl. [00128] In some embodiments of R ² , the optionally substituted pyrazolyl is 1- methyl-pyrazol-4-yl. [00129] In some embodiments of R ² , the optionally substituted pyrazolyl is 1- cyclopropyl-pyrazol-4-yl. [00130] In some embodiments of R ² , the optionally substituted pyrazolyl is 1- methyl-pyrazol-5-yl. [00131] In other embodiments of R ² , the optionally substituted pyrazolyl is substituted with two or three methyl groups. [00132] In other embodiments of R ² , the optionally substituted pyrazolyl is 1,5- dimethyl-pyrazol-4-yl, 1,3-dimethyl-pyrazol-4-yl, 1-(2-methoxyethyl)-3,5-dimethyl-pyrazol- 4-yl, 3,5-dimethyl-pyrazol-4-yl, 1,4-dimethyl-pyrazol-5-yl, or 1,3,5-trimethyl-pyrazol-4-yl. [00133] In some embodiments of R ² , the optionally substituted pyrazolyl is 1,3- dimethyl-pyrazol-4-yl. [00134] In some embodiments of R ² , the optionally substituted pyrazolyl is 1,3- dimethyl-pyrazol-5-yl. [00135] In some embodiments of R ² , the optionally substituted pyrazolyl is 1,5- dimethyl-pyrazol-4-yl. [00136] In some embodiments of R ² , the optionally substituted pyrazolyl is 1- methyl-3-methoxy-pyrazol-4-yl. [00137] In some embodiments of R ² , the optionally substituted pyrazolyl is 1,3,5- trimethyl-pyrazol-4-yl. [00138] In some embodiments of R ² , the optionally substituted pyrazolyl is 3,5- dimethyl-pyrazol-4-yl. [00139] In other embodiments of R ² , the optionally substituted pyrazolyl is 1- methyl-3-trifluoromethyl-pyrazol-4-yl. [00140] In other embodiments of R ² , the optionally substituted pyrazolyl is 1- trifluoromethyl-pyrazol-4-yl. [00141] In other embodiments of R ² , the optionally substituted pyrazolyl is 1-(2,2,2- trifluoroeth-1-yl)-pyrazol-4-yl. [00142] In some embodiments of R ² , the optionally substituted pyrazolyl is 1- difluoromethylpyrazol-4-yl. [00143] In other embodiments of R ² , the optionally substituted pyrazolyl is 3,5- dimethyl-1-(2-methoxyethyl)-pyrazol-4-yl. [00144] In other embodiments of R ² , the optionally substituted pyrazolyl is 3,5- dimethyl-1-(oxetan-3-yl)-1H-pyrazol-4-yl. [00145] In other embodiments of R ² , the optionally substituted pyrazolyl is 1- (thietan-3-yl 1,1-dioxide)-pyrazol-4-yl, i.e., . [00146] In other embodiments of R ² , the optionally substituted pyrazolyl is 1- (oxetan-3-yl)-1H-pyrazol-4-yl. [00147] In other embodiments of R ² , the optionally substituted pyrazolyl is 1- (oxetan-3-yl-methyl)-pyrazol-4yl. [00148] In other embodiments of R ² , the optionally substituted pyrazolyl is 1- ((methylsulfonyl)methyl)-pyrazol-4-yl. [00149] In other embodiments of R ² , the optionally substituted pyrazolyl is 5- (methoxymethyl)-1-methyl-pyrazol-4-yl. [00150] In other embodiments of R ² , the optionally substituted pyrazolyl is 1- (tetrahydrofuran-3-yl)-pyrazol-4-yl. [00151] In other embodiments of R ² , the optionally substituted pyrazolyl is (R)-1- (tetrahydrofuran-3-yl)-pyrazol-4-yl. [00152] In other embodiments of R ² , the optionally substituted pyrazolyl is (S)-1- (tetrahydrofuran-3-yl)-pyrazol-4-yl. [00153] In other embodiments of R ² , the optionally substituted pyrazolyl is 1- (tetrahydro-2H-pyran-4-yl)-pyrazol-4-yl. [00154] In other embodiments of R ² , the optionally substituted pyrazolyl is 1- ((cyano)methyl)-pyrazol-4-yl. [00155] In other embodiments of R ² , the optionally substituted pyrazolyl is 1-(1- (cyano)eth-1-yl)-pyrazol-4-yl. [00156] In other embodiments of R ² , the optionally substituted pyrazolyl is 1-(2- (cyano)eth-1-yl)-pyrazol-4-yl. [00157] In other embodiments of R ² , the optionally substituted pyrazolyl is (1- hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl [00158] In other embodiments of R ² , the optionally substituted pyrazolyl is 1- (acetamid-2-yl)-pyrazol-4-yl. [00159] In other embodiments of R ² , the optionally substituted pyrazolyl is 1-(N- methylacetamid-2-yl)pyrazol-4-yl. [00160] In other embodiments of R ² , the optionally substituted pyrazolyl is 1- (propanamid-3-yl)-pyrazol-4-yl. [00161] In other embodiments of R ² , the optionally substituted pyrazolyl is 1-(N- methylacetamid-2-yl)-pyrazol-4-yl. [00162] In other embodiments of R ² , the optionally substituted pyrazolyl is 1- (propanamide-2-yl)-pyrazol-4-yl. [00163] In other embodiments of R ² , the optionally substituted pyrazolyl is 1-(4- piperidinyl)-pyrazol-4-yl. [00164] In other embodiments of R ² , the optionally substituted pyrazolyl is 1-(2- (methylsulfonyl)ethyl)-1H-pyrazol-4-yl. [00165] In other embodiments of R ² , the optionally substituted pyrazolyl is 1-(2,3- dihydroxy-propan-1-yl)-pyrazol-3-yl. [00166] In other embodiments of R ² , the optionally substituted pyrazolyl is 1-(2,3- dihydroxy-propan-1-yl)-pyrazol-4-yl. [00167] In other embodiments of R ² , the optionally substituted pyrazolyl is 1-(2- hydroxy-propan-1-yl)-pyrazol-4-yl. [00168] In other embodiments of R ² , the optionally substituted pyrazolyl is 1-(3,4- dihydroxy-butan-1yl)-pyrazol-4-yl. [00169] In other embodiments of R ² , the optionally substituted pyrazolyl is 1-((3- hydroxy-isoxazol-5-yl)methyl)-pyrazol-4-yl. [00170] In other embodiments of R ² , the optionally substituted pyrazolyl is 1-((3- benzyloxy-isoxazol-5-yl)methyl)-pyrazol-4-yl. [00171] In other embodiments of R ² , the optionally substituted pyrazolyl is 1- (pyridin-3-yl)-pyrazol-4-yl. [00172] In other embodiments of R ² , the optionally substituted pyrazolyl is 3- (hydroxymethyl)-1-methyl-pyrazol-4-yl. [00173] In other embodiments of R ² , the optionally substituted pyrazolyl is 1-(1- hydroxy-2-methylpropan-2-yl)-pyrazol-4-yl. [00174] In other embodiments of R ² , the optionally substituted pyrazolyl is 1-(3- N,N-dimethylaminopropan-1-yl)pyrazol-4-yl. [00175] In other embodiments of R ² , the optionally substituted pyrazolyl is 1-(4- tetrahydro-2H-thiopyran 1,1-dioxide)-pyrazol-4-yl, i.e., . [00176] In some embodiments of R ² , the optionally substituted 5-membered heteroaryl is an is an optionally substituted triazolyl. [00177] In some embodiments of R ² , the optionally substituted triazolyl is substituted with an optionally substituted C ₁ -C ₆ alkyl, such as, for example, C ₁ -C ₆ alkyl, C ₁ - C ₅ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₂ alkyl, C ₆ alkyl, C ₅ alkyl, C ₄ alkyl, C ₃ alkyl, C ₂ alkyl, C ₁ alkyl, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n- hexyl, and the like; or an optionally substituted C ₃ -C ₅ cycloalkyl, such as, for example, C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, and the like. [00178] In some embodiments of R ² , the optionally substituted 5-membered heteroaryl is 2,4-dimethyl-1,2,3-triazol-5-yl. [00179] In some embodiments of R ² , the optionally substituted 5-membered heteroaryl is 2-methyl-1,2,3-triazol-4-yl. [00180] In some embodiments of R ² , the optionally substituted 5-membered heteroaryl is an optionally substituted imidazolyl. [00181] In some embodiments of R ² , the optionally substituted imidazolyl is 1- methyl-imidazol-4-yl. [00182] In some embodiments of R ² , the optionally substituted imidazolyl is 1- methyl-imidazol-5-yl. [00183] In some embodiments of R ² , the optionally substituted 5-membered heteroaryl is an optionally substituted isoxazolyl. [00184] In some embodiments of R ² , the optionally substituted isoxazolyl is 3,5- dimethyl-isoxazol-4-yl. [00185] In some embodiments of R ² , the optionally substituted 5-membered heteroaryl is an optionally substituted isothiazolyl. [00186] In some embodiments of R ² , the optionally substituted 5-membered heteroaryl is isothiazol-4-yl. [00187] In some embodiments of R ² , the optionally substituted 5-membered heteroaryl is an optionally substituted furanyl. [00188] In some embodiments of R ² , the optionally substituted furanyl is 2- (hydroxymethyl)-furan-5-yl. [00189] In some embodiments of R ² , the optionally substituted 5-membered heteroaryl is furan-3-yl. [00190] In some embodiments of R ² , the optionally substituted 5-membered heteroaryl is an optionally substituted thiophenyl. [00191] In some embodiments of R ² , the optionally substituted thiophenyl is thiopheny-3-yl. [00192] In some embodiments of R ² , the optionally substituted thiophenyl is 2- hydroxymethyl-thiophen-5-yl. [00193] In some embodiments, R ² in the compounds of formula (I) is an optionally substituted 6-membered heteroaryl. [00194] In some embodiments of R ² , the optionally substituted 6-membered heteroaryl is an optionally substituted pyridinyl, an optionally substituted pyridazinyl, or an optionally substituted pyrimidinyl. [00195] In some embodiments of R ² , the optionally substituted 6-membered heteroaryl is substituted with an optionally substituted C ₁ -C ₆ alkyl, such as, for example, C ₁ - C ₆ alkyl, C ₁ -C ₅ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₂ alkyl, C ₆ alkyl, C ₅ alkyl, C ₄ alkyl, C ₃ alkyl, C ₂ alkyl, C ₁ alkyl, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n- pentyl, n-hexyl, and the like; or an optionally substituted C ₃ -C ₅ cycloalkyl, such as, for example, C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, and the like. [00196] In some embodiments of R ² , the optionally substituted 6-membered heteroaryl is an is an optionally substituted pyridinyl. [00197] In some embodiments of R ² , the optionally substituted pyridinyl is substituted with an optionally substituted C ₁ -C ₆ alkyl, such as, for example, C ₁ -C ₆ alkyl, C ₁ - C ₅ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₂ alkyl, C ₆ alkyl, C ₅ alkyl, C ₄ alkyl, C ₃ alkyl, C ₂ alkyl, C ₁ alkyl, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n- hexyl, and the like; or an optionally substituted C ₃ -C ₅ cycloalkyl, such as, for example, C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, and the like. [00198] In some embodiments of R ² , the optionally substituted pyridinyl is unsubstituted pyridinyl. [00199] In some embodiments of R ² , the unsubstituted pyridinyl is pyridine-2-yl. [00200] In some embodiments of R ² , the unsubstituted pyridinyl is pyridine-3-yl. [00201] In some embodiments of R ² , the unsubstituted pyridinyl is pyridine-4-yl. [00202] In some embodiments of R ² , the optionally substituted pyridinyl is C ₁ - C ₆ alkoxyl substituted pyridinyl. [00203] In some embodiments of R ² , the optionally substituted pyridinyl is methoxy substituted pyridinyl, such as, for example, 4-methoxypyridin-3-yl. [00204] In some embodiments of R ² , the optionally substituted pyridinyl is 2- methoxypyridin-3-yl. [00205] In some embodiments of R ² , the optionally substituted pyridinyl is 2- methoxypyridin-5-yl. [00206] In some embodiments of R ² , the optionally substituted pyridinyl is 2- methoxypyridin-6-yl. [00207] In some embodiments of R ² , the optionally substituted pyridinyl is 4- methoxypyridin-3-yl. [00208] In some embodiments of R ² , the optionally substituted pyridinyl is 3- methoxypyridin-4-yl. [00209] In some embodiments of R ² , the optionally substituted pyridinyl is 2- ethoxypyridin-3-yl. [00210] In some embodiments of R ² , the optionally substituted pyridinyl is 2- trifluoromethoxypyridin-3-yl. [00211] In some embodiments of R ² , the optionally substituted pyridinyl is 2- hydroxypyridin-3-yl. [00212] In some embodiments of R ² , the optionally substituted pyridinyl is 2- hydroxypyridin-5-yl. [00213] In some embodiments of R ² , the optionally substituted pyridinyl is 2- methylpyridin-3-yl. [00214] In some embodiments of R ² , the optionally substituted pyridinyl is 2- methylpyridin-4-yl. [00215] In some embodiments of R ² , the optionally substituted pyridinyl is 2- methylpyridin-5-yl. [00216] In some embodiments of R ² , the optionally substituted pyridinyl is 2- ethylpyridin-3-yl. [00217] In some embodiments of R ² , the optionally substituted pyridinyl is 2-(2- fluoroethoxy)pyridin-3-yl. [00218] In some embodiments of R ² , the optionally substituted pyridinyl is 2- amino-3-fluoro-pyridin-5-yl. [00219] In some embodiments of R ² , the optionally substituted pyridinyl is 2- amino-pyridin-5-yl or 6-aminopyridin-3-yl. [00220] In some embodiments of R ² , the optionally substituted pyridinyl is 2-(4- morpholinyl)-pyridin-4-yl. [00221] In some embodiments of R ² , the optionally substituted pyridinyl is 2- (dimethylamino)pyridin-4-yl. [00222] In some embodiments of R ² , the optionally substituted pyridinyl is 3- (methylsulfonyl)pyridin-5-yl. [00223] In some embodiments of R ² , the optionally substituted pyridinyl is: In some embodiments of R ² , the optionally substituted pyridinyl is: [00225] [00226] In some embodiments of R ² , the optionally substituted pyridinyl is 4- (acetylamino)-pyridin-2-yl. [00227] In some embodiments of R ² , the optionally substituted pyridinyl is 3- (acetylamino)-pyridin-5-yl. [00228] In some embodiments of R ² , the optionally substituted pyridinyl is 2- (acetylamino)-pyridin-4-yl. [00229] In some embodiments of R ² , the optionally substituted pyridinyl is 2-(N- methylacetamid)-pyridin-4-yl, i.e., . [00230] In some embodiments of R ² , the optionally substituted 6-membered heteroaryl is an is an optionally substituted pyridazinyl. [00231] In some embodiments of R ² , the optionally substituted pyridaziny is 3- methyl-pyridazin-5-yl. [00232] In some embodiments of R ² , the optionally substituted pyridaziny is 3,6- dimethoxy-pyridazin-4-yl. [00233] In some embodiments of R ² , the optionally substituted pyridaziny is 3- hydroxy-pyridazin-6-yl. [00234] In some embodiments of R ² , the optionally substituted 6-membered heteroaryl is an is an optionally substituted pyrimidinyl. [00235] In some embodiments of R ² , the optionally substituted pyrimidinyl is pyrimidin-5-yl. [00236] In some embodiments of R ² , the optionally substituted pyrimidinyl is 2- methoxy-4-hydroxy-pyrimidin-5-yl. [00237] In some embodiments of R ² , the optionally substituted pyrimidinyl is 2,4- dimethoxy-pyrimidin-5-yl. [00238] In some embodiments of R ² , the optionally substituted pyrimidinyl is 4- methyl-pyrimidin-5-yl. [00239] In some embodiments of R ² , the optionally substituted heteroaryl is an optionally substituted 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine. [00240] In some embodiments of R ² , the optionally substituted 6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine is 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl. [00241] In some embodiments of R ² , the optionally substituted heteroaryl is 6,7- dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl. [00242] In some embodiments of R ² , the optionally substituted heteroaryl is 5,6- dihydro-8H-imidazo[2,3-c][1,4]oxazin-3-yl. [00243] In some embodiments of R ² , the optionally substituted heteroaryl is 7,8- dihydro-5H-imidazo[3,2-c][1,3]oxazin-3-yl. [00244] In some embodiments of R ² , the optionally substituted heteroaryl is an optionally substituted 1-methylindazol-4-yl. [00245] In some embodiments of R ² , the optionally substituted heteroaryl is an optionally substituted 1H-pyrazolo[3,4-b]pyridin-1-yl. [00246] In some embodiments of R ² , the optionally substituted 1H-pyrazolo[3,4- b]pyridin-1-yl is unsubstituted 1H-pyrazolo[3,4-b]pyridin-1-yl. [00247] In some embodiments of R ² , the optionally substituted heteroaryl is an optionally substituted 1H-pyrazolo[3,4-b]pyridine-5-yl [00248] In some embodiments of R ² , the optionally substituted heteroaryl is an optionally substituted indolyl. [00249] In some embodiments of R ² , the optionally substituted indolyl is an unsubstituted indolyl. [00250] In some embodiments of R ² , the unsubstituted indolyl is indol-3-yl. [00251] In some embodiments of R ² , the optionally substituted heteroaryl is 2-oxo- 2,3-dihydrobenzo[d]oxazol-5-yl. [00252] In some embodiments, R ² in the compounds of formula (I) is optionally substituted heterocycloalkyl. [00253] In some embodiments, the optionally substituted heterocycloalkyl is an optionally substituted dihydropyran, an optionally substituted tetrahydropyran, or an optionally substituted morpholine. [00254] In some embodiments the optionally substituted heterocycloalkyl is substituted with hydroxy, hydroxyalkyl, C ₁ -C ₆ alkoxyl, or -C ₁ -C ₆ alk-O-C ₁ -C ₆ alkyl. [00255] In some embodiments, the optionally substituted heterocycloalkyl is

_, . [00256] In some embodiments of R ² , the optionally substituted heterocycloalkyl is 1-(2-fluoroethyl)-2-oxo-1,2-dihydropyridin-3-yl. [00257] In some embodiments of R ² , the optionally substituted heterocycloalkyl is 1-methyl-6-oxo-1,6-dihydropyridin-3-yl. [00258] In some embodiments of R ² , the optionally substituted heterocycloalkyl is morpholin-4-yl. [00259] In some aspects, n in the compounds of formula (I) is 1, 2, or 3. [00260] In some embodiments, n in the compounds of formula (I) is 1. [00261] In some embodiments, n in the compounds of formula (I) is 2. [00262] In some embodiments, n in the compounds of formula (I) is 3. [00263] In some aspects of the compounds of formula (I), L is -C(O)NH-, - NHC(O)O-, -NHC(O)-, -NHC(O)NH-, or -NHC(O)NR ⁸ -, wherein when L is -NHC(O)NR ⁸ -, an R ⁵ or an R ⁶ attached to a carbon atom, together with R ⁸ , form a heterocycloalkyl ring; and wherein when L is -C(O)NH-, -NHC(O)O-, -NHC(O)NR ⁸ -, or -NHC(O)NH-, n is 2 or 3, and when L is -NHC(O)-, n is 1, 2, or 3. [00264] The diradicals “-L-,” as used herein, are written from left-to-right such that the left hand side of L is attached to the pyridinyl moiety in the compounds of the disclosure. [00265] In some embodiments of the compounds of formula (I), n is 1 and L is - NHC(O)-. [00266] In some embodiments of the compounds of formula (I), n is 2, or 3 L is - NHC(O)-. [00267] In some embodiments of the compounds of formula (I), n is 2 and L is - NHC(O)-. [00268] In some embodiments of the compounds of formula (I), n is 3 and L is - NHC(O)-. [00269] In some embodiments of the compounds of formula (I), n is 2, or 3 and L is -C(O)NH-. [00270] In some embodiments of the compounds of formula (I), n is 2 and L is - C(O)NH-. [00271] In some embodiments of the compounds of formula (I), n is 3 and L is - C(O)NH-. [00272] In some embodiments of the compounds of formula (I), n is 2, or 3 and L is -NHC(O)O-. [00273] In some embodiments of the compounds of formula (I), n is 2 and L is - NHC(O)O-. [00274] In some embodiments of the compounds of formula (I), n is 3 and L is - NHC(O)O-. [00275] In some embodiments of the compounds of formula (I), n is 2 or 3 and L is -NHC(O)NH. [00276] In some embodiments of the compounds of formula (I), n is 2 and L is - NHC(O)NH. [00277] In some embodiments of the compounds of formula (I), n is 3 and L is - NHC(O)NH. [00278] In some embodiments of the compounds of formula (I), n is 2 or 3 and L is -NHC(O)NR ⁸ - wherein an R ⁵ or an R ⁶ attached to a carbon atom, together with R ⁸ , form a heterocycloalkyl ring. [00279] In some embodiments of the compounds of formula (I), n is 2 or 3 and L is -NHC(O)NR ⁸ - wherein an R ⁵ or an R ⁶ attached to a carbon atom, together with R ⁸ , form a heterocycloalkyl ring, the structure o u a s . [00280] In some embodiments, the structure formula (I) is . [00281] In some embodiments, the heterocycloalkyl ring is a 4-membered heterocycloalkyl ring. [00282] In some embodiments of the compounds of formula (I), n is 2 and L is - NHC(O)NR ⁸ - wherein an R ⁵ or an R ⁶ attached to a carbon atom, together with R ⁸ , form a heterocycloalkyl ring. [00283] In some embodiments of the compounds of formula (I), n is 3 and L is - NHC(O)NR ⁸ - wherein an R ⁵ or an R ⁶ attached to a carbon atom, together with R ⁸ , form a heterocycloalkyl ring. [00284] In some aspects, R ³ and R ⁴ in the compounds of formula (I) are each independently optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted spirocycloalkyl, or optionally substituted heterocycloalkyl; or one of R ³ or R ⁴ in the compounds of formula (I) may be H. [00285] In some embodiments, one of R ³ or R ⁴ in compounds of formula (I) is H. [00286] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) is optionally substituted aryl, such as, for example, optionally substituted phenyl, indenyl, naphthyl, or 1,2,3,4-tetrahydronaphthyl. [00287] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) is optionally substituted heteroaryl, such as, for example, optionally substituted pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8- tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3- b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, or 4,5,6,7-tetrahydro-1H-indazole. [00288] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) is pyridinyl. In some embodiments, R ³ or R ⁴ in the compounds of formula (I) is 2-pyridinyl. [00289] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) or the compounds of formula (I) is optionally substituted alkyl, such as, for example, optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₅ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₂ alkyl, C ₆ alkyl, C ₅ alkyl, C ₄ alkyl, C ₃ alkyl, C ₂ alkyl, C ₁ alkyl, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso- butyl, sec-butyl, n-pentyl, n-hexyl, and the like. [00290] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) or the compounds of formula (I) is -CH ₃ . [00291] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) or the compounds of formula (I) is -CH ₂ CH(CH ₃ ) ₂ . [00292] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) or the compounds of formula (I) is -CH ₂ CH ₂ CH ₃ . [00293] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) or the compounds of formula (I) is -CH(CH ₃ ) ₂ . [00294] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) or the compounds of formula (I) is -C(CH ₃ ) ₃ . [00295] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) or the compounds of formula (I) is -CH ₂ CH ₂ OCH ₃ . [00296] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) or the compounds of formula (I) is -CH ₂ CH ₂ OH. [00297] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) or the compounds of formula (I) is -CH ₂ -cyclohexyl. [00298] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) or the compounds of formula (I) is -CH ₂ -cyclopentyl. [00299] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) or the compounds of formula (I) is -CH ₂ -cyclopropyl. [00300] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) is optionally substituted cycloalkyl, such as, for example, optionally substituted C ₃ - C ₇ cycloalkyl, C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, C ₇ cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. [00301] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) is optionally substituted cyclopentyl. [00302] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) is unsubstituted cyclopentyl. [00303] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) is optionally substituted cyclobutyl. [00304] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) is 1- methyl-cyclobut-1-yl. [00305] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) is unsubstituted cyclobutyl. [00306] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) is optionally substituted cyclohexyl. [00307] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) is unsubstituted cyclohexyl. [00308] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) is optionally substituted cycloheptyl. [00309] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) is unsubstituted cycloheptyl. [00310] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) is optionally substituted heterocycloalkyl, such as, for example, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, isoxazolidinyl, oxazolidinyl, pyrazolidinyl, imidazolidinyl, or thiazolidinyl. [00311] In some embodiments, R ³ or R ⁴ in the compounds of formula (I) is tetrahydropyran-4-yl. [00312] In some embodiments, R ³ is optionally substituted alkyl or optionally substituted C ₄ -C ₅ cycloalkyl; and R ⁴ is optionally substituted C ₄ -C ₅ cycloalkyl or optionally substituted heteroaryl. [00313] In some aspects, R ³ and R ⁴ in the compounds of formula (I), together with the nitrogen atom to which they are both attached, form an optionally substituted 3-12- membered heterocycloalkyl ring, an optionally substituted 5-12-membered bridged heterocycloalkyl ring, an optionally substituted 4-12-membered fused heterocycloalkyl ring system, or an optionally substituted 5-12-membered spiroheterocycloalkyl ring system, wherein said 3-12-membered heterocycloalkyl ring, 5-12-membered bridged heterocycloalkyl ring, 4-12-membered fused heterocycloalkyl ring system, or 5-12-membered spiroheterocycloalkyl ring system may include, in addition to the nitrogen atom to which both R ³ and R ⁴ are attached, 1-3 other heteroatoms that are each independently O, S, or N. [00314] In some aspects, R ³ and R ⁴ in the compounds of formula (I), together with the nitrogen atom to which they are both attached, form an optionally substituted 3-12- membered heterocycloalkyl ring. Non-limiting examples of such heterocycloalkyl rings include the following: [00315] In some embodiments, the optionally substituted 3-12-membered heterocycloalkyl ring is an optionally substituted azetidinyl, an optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted azepanyl, optionally substituted piperazinyl, optionally substituted oxazepanyl, optionally substituted thiomorpholinyl 1,1-dioxide, or optionally substituted morpholinyl. [00316] In some embodiments, the optionally substituted 3-12-membered heterocycloalkyl ring is . [00317] In some embodiments, the optionally substituted 3-12-membered heterocycloalkyl ring is . [00318] In some embodiments, the optionally substituted 3-12-membered heterocycloalkyl ring is . [00319] In some embodiments, the optionally substituted 3-12-membered heterocycloalkyl ring is . [00320] In some embodiments, the optionally substituted 3-12-membered heterocycloalkyl ring is . [00321] In some embodiments, the optionally substituted 3-12-membered heterocycloalkyl ring is . [00322] In some embodiments, the optionally substituted 3-12-membered heterocycloalkyl ring is . [00323] In some embodiments, the optionally substituted 3-12-membered heterocycloalkyl ring is . [00324] In some embodiments, the optionally substituted 3-12-membered heterocycloalkyl ring is . [00325] In some embodiments, the optionally substituted 3-12-membered heterocycloalkyl ring is . [00326] In some embodiments, the optionally substituted 3-12-membered heterocycloalkyl ring is . [00327] In some embodiments, the optionally substituted 3-12-membered heterocycloalkyl ring is substituted with C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyl, -C ₁ -C ₆ alk-O-C ₁ -C ₆ alkyl, hydroxyl, hydroxyalkyl, halo, carbonyl (i.e., (=O)), cyano, cyclopropyl, or 5-membered heteroaryl. [00328] In some embodiments, the optionally substituted 3-12-membered heterocycloalkyl ring is substituted with at least one C ₁ -C ₆ alkyl group, such as, for example, C ₁ -C ₆ alkyl, C ₁ -C ₅ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₂ alkyl, C ₆ alkyl, C ₅ alkyl, C ₄ alkyl, C ₃ alkyl, C ₂ alkyl, C ₁ alkyl, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec- butyl, n-pentyl, n-hexyl, and the like. [00329] In some embodiments, the optionally substituted 3-12-membered heterocycloalkyl ring is substituted with at least one -CH ₃ group. [00330] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2,2-dimethylpyrrolidin-1-yl group, . [00331] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form, . [00332] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3,3-dimethylpyrrolidin-1-yl group, . [00333] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3,3-dimethylazetidin-1-yl group, . [00334] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2,2-dimethylazetidin-1-yl group, . [00335] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form . [00336] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2-isopropylazetidin-1-yl group, . [00337] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2-methyl-pyrrolidin-1-yl group, . [00338] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a (R)-2-methyl-pyrrolidin-1-yl group. [00339] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a (S)-2-methyl-pyrrolidin-1-yl group. [00340] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a piperidin-1-yl group, . [00341] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2-methyl-piperidin-1-yl group, . [00342] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a (R)-2-methyl-piperidin-1-yl group. [00343] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a (S)-2-methyl-piperidin-1-yl group. [00344] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3-methyl-piperidin-1-yl group, . [00345] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a (R)-3-methyl-piperidin-1-yl group. [00346] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a (S)-3-methyl-piperidin-1-yl group. [00347] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 4-methyl-piperidin-1-yl group, . [00348] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a (R)-4-methyl-piperidin-1-yl group. [00349] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a (S)-4-methyl-piperidin-1-yl group. [00350] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 4-hydroxymethyl-piperidin-1-yl group, . [00351] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 4-methoxy-piperidin-1-yl group, . [00352] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a (R)-4- methoxy -piperidin-1-yl group. [00353] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a (S)-4- methoxy -piperidin-1-yl group. [00354] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form . [00355] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form . [00356] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form: . [00357] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 1,2,5-trimethyl-4-piperazinyl: . [00358] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a (2S, 5R)-1,2,5-trimethyl-4-piperazinyl. [00359] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a (2S, 5S)-1,2,5-trimethyl-4-piperazinyl. [00360] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a (2R, 5R)-1,2,5-trimethyl-4-piperazinyl. [00361] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a (2R, 5S)-1,2,5-trimethyl-4-piperazinyl. [00362] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form: . [00363] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form _. [00364] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form . [00365] In some embodiments, the optionally substituted 3-12-membered heterocycloalkyl ring is substituted with a cyclopropyl group. [00366] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a . [00367] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a . [00368] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a . [00369] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form: . [00370] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form: . [00371] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form: . [00372] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2-methoxymethyl-pyrrolidin-1-yl group: . [00373] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a (R)-2- methoxymethyl-pyrrolidin-1-yl group. [00374] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a (S)-2- methoxymethyl-pyrrolidin-1-yl group. [00375] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3-methoxy-pyrrolidin-1-yl group: . [00376] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a (R)-3-methoxy-pyrrolidin-1-yl group. [00377] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a (S)-3-methoxy-pyrrolidin-1-yl group. [00378] In some embodiments, the optionally substituted 3-12-membered heterocycloalkyl ring is substituted with at least one halogen atom. In some embodiments, the halogen atom is -F. [00379] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 4,4-difluoropiperidin-1-yl group, _. [00380] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 4-fluoropiperidin-1-yl group, _. [00381] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 4-hydroxypiperidin-1-yl group, _. [00382] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 4,4-dimethylpiperidin-1-yl group, . [00383] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 4-(methoxymethyl)piperidin-1-yl group, . [00384] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 4-(cyanomethyl)piperidin-1-yl group, _. [00385] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 4-(acetamid-2-yl)piperidin-1-yl group, . [00386] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2,2-dimethylpiperidin-1-yl group, . [00387] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2,2-dimethylpiperidin-1-yl group, . [00388] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3,3-difluoropiperidin-1-yl group, . [00389] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 4-morpholinyl group, . [00390] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3-methylmorpholino group, . [00391] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3(R)-methylmorpholino group. [00392] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3(S)-methylmorpholino group. [00393] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3-ethylmorpholino group, . [00394] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3(R)-ethylmorpholino group. [00395] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3(S)-ethylmorpholino group. [00396] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3,5-dimethylmorpholino group, . [00397] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3(R),5(R)-dimethylmorpholino group. [00398] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3(S),5(S)-dimethylmorpholino group. [00399] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3(R),5(S)-dimethylmorpholino group. [00400] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3(S),5(R)-dimethylmorpholino group. [00401] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3,5-dimethylpiperidinyl group, . [00402] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3(R),5(R)- dimethylpiperidinyl group. [00403] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3(S),5(S)- dimethylpiperidinyl group. [00404] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3(R),5(S)- dimethylpiperidinyl group. [00405] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3(S),5(R)- dimethylpiperidinyl group. [00406] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form: . [00407] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form: . [00408] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3,3-dimethylmorpholino group, . [00409] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form, . [00410] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2,2-dimethylmorpholino group, . [00411] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2,6-dimethylmorpholino group, . [00412] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2(R),6(R)-dimethylmorpholino group. [00413] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2(S),6(S)-dimethylmorpholino group. [00414] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2(R),6(S)-dimethylmorpholino group. [00415] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2(S),6(R)-dimethylmorpholino group. [00416] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3-methylmorpholino group, . [00417] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3(R)-methylmorpholino group. [00418] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3(S)-methylmorpholino group. [00419] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2-methylmorpholino group, . [00420] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2(R)-methylmorpholino group. [00421] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2(S)-methylmorpholino group. [00422] In some embodiments, the optionally substituted 3-12-membered heterocycloalkyl ring is substituted with a 5-membered heteroaryl group. [00423] In some embodiments, the 3-12-membered heterocycloalkyl ring substituted with a 5-membered heteroaryl group is a pyrrolidinyl ring substituted with a 5- membered heteroaryl group or a piperidinyl ring substituted with a 5-membered heteroaryl group. [00424] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form: . [00425] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form: . [00426] In some aspects, R ³ and R ⁴ in the compounds of formula (I), together with the nitrogen atom to which they are both attached, form an optionally substituted 5-12- membered bridged heterocycloalkyl ring. Non-limiting examples of such bridged heterocycloalkyl ring systems include:

. [00427] In some embodiments, the optionally substituted 5- to 12-membered bridged heterocycloalkyl ring is an optionally substituted 7-azabicyclo[2.2.2]octan-7-yl, an optionally substituted 7-azabicyclo[2.2.1]heptan-7-yl, an optionally substituted 2- azabicyclo[2.2.1]heptan-2-yl, an optionally substituted azabicyclo[3.1.1]heptane, an optionally substituted 8-azabicyclo[3.2.1]octan-8-yl, an optionally substituted 2,5- diazabicyclo[2.2.1]heptan-5-yl, an optionally substituted 6-azabicyclo[3.2.1]octan-6-yl, an optionally substituted 3-azabicyclo[3.2.1]octan-3-yl, an optionally substituted 2- azabicyclo[2.2.2]octan-2yl, an optionally substituted diazabicyclo[2.2.1]heptanyl, an optionally substituted 2-oxa-5-azabicyclo[2.2.2]octan-5-yl, an optionally substituted 2-oxa-5- azabicyclo[2.2.1]heptan-5-yl, an optionally substituted 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, an optionally substituted 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl, an optionally substituted 8- oxa-3-azabicyclo[3.2.1]octan-3-yl, an optionally substituted 3,9-diazabicyclo[4.2.1]nonan-3- yl, an optionally substituted 2-oxa-6-azaadamantan-6-yl, (an optionally substituted 3-oxa- azabicyclo[3.2.1]octanyl, or an optionally substituted 2-oxa-azabicyclo[2.2.1]heptanyl. [00428] In some embodiments, the optionally substituted 5-12-membered bridged heterocycloalkyl ring is substituted with C ₁ -C ₆ alkyl, hydroxy, or hydroxyalkyl. [00429] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2-azabicyclo[2.2.2]octan-2-yl group: . [00430] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form an 9-azabicyclo[3.3.1]nonan-9-yl group: . [00431] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form an 3-azabicyclo[3.1.1]heptan-3-yl group, . [00432] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form an 3-azabicyclo[3.2.1]octan-3-yl group, . [00433] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form: . [00434] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form an 3-oxa-8-azabicyclo[3.2.1]octan-8-yl group, . [00435] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form an 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl group, . [00436] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form (1S,4R)-2-azabicyclo[2.2.1]heptan-2-yl group, . [00437] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a (1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl group, . [00438] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl group, . [00439] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl group, . [00440] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 8-oxa-3-azabicyclo[3.2.1]octan-3-yl group, . [00441] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2-oxa-5-azabicyclo[2.2.2]octan-5-yl group, . [00442] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 7-azabicyclo[2.2.1]heptan-7-yl group, . [00443] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2-azabicyclo[2.2.1]heptan-2-yl group, . [00444] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form: _. [00445] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form: . [00446] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form . [00447] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form: . [00448] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form: . [00449] In other embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form: . [00450] In some aspects, R ³ and R ⁴ in the compounds of formula (I), together with the nitrogen atom to which they are both attached, form an optionally substituted 5-12- membered spiroheterocycloalkyl ring. Non-limiting examples of such ring systems include:

[00451] In some embodiments, the optionally substituted 5-12-membered spiroheterocycloalkyl ring is an optionally substituted 7-azaspiro[3.5]nonan-7-yl, an optionally substituted 4-azaspiro[2.4]heptan-4-yl, an optionally substituted 1- azaspiro[3.3]heptan-1-yl, an optionally substituted 2-azaspiro[3.3]heptan-2-yl, an optionally substituted 6-azaspiro[2.5]octan-6-yl, an optionally substituted 2-oxa-7-azaspiro[4.4]nonan- 7-yl, an optionally substituted 1-oxa-7-azaspiro[4.4]nonan-7-yl, an optionally substituted 2- oxa-6-azaspiro[3.4]octan-6-yl, an optionally substituted 5-azaspiro[2.4]heptan-5-yl, an optionally substituted 4-azaspiro[2.4]heptan-4-yl, an optionally substituted 2- azaspiro[4.5]decan-2-yl, an optionally substituted 8-azaspiro[4.5]decan-8-yl, an optionally substituted 2-azaspiro[4.4]nonan-2-yl, an optionally substituted 5-azaspiro[3.5]nonan-5-yl, an optionally substituted 7-oxa-4-azaspiro[2.5]octan-4-yl, an optionally substituted 5- azaspiro[3.4]octan-5-yl, an optionally substituted 1-oxa-7-azaspiro[3.5]nonan-7-yl, an optionally substituted 2-oxa-6-azaspiro[3.4]octan-6-yl, an optionally substituted 2-oxa-7- azaspiro[3.5]nonan-7-yl, an optionally substituted 2-oxa-5-azaspiro[3.4]octan-5-yl, an optionally substituted 8-oxa-5-azaspiro[3.5]nonan-5-yl, an optionally substituted 1- azaspiro[4.4]nonan-1-yl, an optionally substituted 7-oxa-4-azaspiro[2.5]octan-4-yl, an optionally substituted 2,5-dioxa-8-azaspiro[3.5]nonan-8-yl, an optionally substituted 8-oxa-2- azaspiro[4.5]decan-2-yl, an optionally substituted 2-oxa-5-azaspiro[3.5]nonan-5-yl, an optionally substituted 4-oxa-7-azaspiro[2.5]octan-7-yl, an optionally substituted 1- azaspiro[4.5]decan-1-yl, an optionally substituted 6-azaspiro[4.5]decan-6-yl, an optionally substituted 7-azaspiro[3.5]nonan-7-yl, an optionally substituted 3-oxa-9- azaspiro[5.5]undecane-9-yl, an optionally substituted 8-oxa-1-azaspiro[4.5]decan-1-yl, an optionally substituted 1,8-diazaspiro[4.5]decan-1-yl, or an optionally substituted 5-oxa-8- azaspiro[3.5]nonan-8-yl. [00452] In some embodiments, the optionally substituted 5-12-membered spiroheterocycloalkyl ring is substituted with C ₁ -C ₆ alkyl, halo, or hydroxyalkyl. [00453] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 4-azaspiro[2.4]heptan-4-yl group, . [00454] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 5-azaspiro[3.4]octan-5-yl group, . [00455] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 6-azaspiro[3.4]octan-6-yl group, . [00456] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 6-azaspiro[2.5]octan-6-yl group, . [00457] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 7-azaspiro[3.5]nonan-7-yl group, . [00458] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 4-azaspiro[2.5]octan-4-yl group, . [00459] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 5-azaspiro[2.5]octan-5-yl group, . [00460] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 1-azaspiro[3.3]heptan-1-yl group, . [00461] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2-azaspiro[3.3]heptan-2-yl group, . [00462] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 6-fluoro-2-azaspiro[3.3]heptan-2-yl group, . [00463] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 7-oxa-2-azaspiro[3.5]nonan-2-yl group, . [00464] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2-oxa-6-azaspiro[3.3]heptan-6-yl group, . [00465] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 5-oxa-2-azaspiro[3.5]nonan-2-yl group, . [00466] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 5-azaspiro[2.4]heptan-5-yl group, . [00467] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2-oxa-5-azaspiro[3.5]nonan-5-yl group, . [00468] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2-oxa-6-azaspiro[3.5]nonan-6-yl group, . [00469] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 7-azaspiro[4.4]nonan-7-yl group, . [00470] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 1-azaspiro[4.4]nonan-1-yl group, . [00471] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2-oxa-7-azaspiro[4.4]nonan-7-yl group, . [00472] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 1-oxa-7-azaspiro[4.4]nonan-7-yl group, . [00473] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2-oxa-5-azaspiro[3.4]octan-5-yl group, . [00474] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2-oxa-6-azaspiro[3.4]octan-6-yl group, . [00475] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 8-oxa-1-azaspiro[4.5]decan-1-yl group, . [00476] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 8-oxa-2-azaspiro[4.5]decan-2-yl group, . [00477] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 8-methyl-1,8-diazaspiro[4.5]decan-1-yl group, . [00478] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2-oxa-7-azaspiro[3.5]nonan-7-yl group, . [00479] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 7-oxa-4-azaspiro[2.5]octan-4-yl group, . [00480] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 4-oxa-7-azaspiro[2.5]octan-7-yl group, . [00481] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 8-oxa-5-azaspiro[3.5]nonan-5-yl group, . [00482] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 5-oxa-8-azaspiro[3.5]nonan-8-yl group, . [00483] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2,5-dioxa-8-azaspiro[3.5]nonan-8-yl group, . [00484] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 1-oxa-7-azaspiro[3.5]nonan-7-yl group, . [00485] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form: . [00486] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2-azaspiro[4.5]decan-2-yl group: . [00487] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 1-azaspiro[4.5]decan-1-yl group: . [00488] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 5-azaspiro[3.5]nonan-5-yl group, N . [00489] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 6-azaspiro[4.5]decan-6-yl group, N . [00490] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3-oxa-9-azaspiro[5.5]undecan-9-yl group, . [00491] In some aspects, R ³ and R ⁴ in the compounds of formula (I), together with the nitrogen atom to which they are both attached, form an optionally substituted 4-12- membered fused heterocycloalkyl ring system. Non-limiting examples of such ring systems include:

_, , [00492] In some embodiments, the optionally substituted 4-12-membered fused heterocycloalkyl ring system is an optionally substituted 3-azabicyclo[3.2.0]heptan-3-yl, an optionally substituted 3-azabicyclo[3.1.0]hexan-3-yl, an optionally substituted 2- azabicyclo[3.1.0]hexan-2-yl, an optionally substituted hexahydro-1H-2-pyrrolo[2,1- c]pyrazinyl, an optionally substituted 5,8-dihydro-6H-7-1,7-naphthyridinyl, an optionally substituted hexahydro-2H-6-furo[2,3-c]pyridinyl, an optionally substituted tetrahydro-1H,3H- 5-furo[3,4-c]pyrrolyl, an optionally substituted 2-oxa-5-azabicyclo[4.1.0]heptanyl, an optionally substituted 4,7-dihydro-5H-6-thieno[2,3-c]pyridinyl, an optionally substituted 2- isoindolinyl, an optionally substituted 3,4-dihydro-1H-2-2,7-naphthyridinyl, an optionally substituted 3,4-dihydro-1H-2-2,6-naphthyridinyl, an optionally substituted 1,4,5,7-tetrahydro- 6-pyrazolo[3,4-c]pyridinyl, 3,4,6,7-tetrahydro-5-imidazo[4,5-c]pyridinyl, an optionally substituted 5,6-dihydro-8H-7-imidazo[2,1-c]pyrazinyl, an optionally substituted 3,4-dihydro- 1H-2-2,6-naphthyridinyl, an optionally substituted 6,7-dihydro-4H-5-thiazolo[4,5- c]pyridinyl, an optionally substituted 7,8-dihydro-5H-6-pyrido[3,4-b]pyrazinyl, an optionally substituted 5,8-dihydro-6H-7-pyrido[3,4-d]pyrimidinyl, an optionally substituted 1,4,6,7- tetrahydro-5-pyrazolo[4,3-c]pyridinyl, an optionally substituted 3,4-dihydro-1H-2- isoquinolinyl, an optionally substituted 1,4,6,7-tetrahydro-5-pyrrolo[3,2-c]pyridinyl, an optionally substituted 6,7-dihydro-4H-5-thiazolo[5,4-c]pyridinyl, an optionally substituted 5,7-dihydro-6-pyrrolo[3,4-b]pyridinyl, an optionally substituted 5,6-dihydro-8H-7- [1,2,4]triazolo[5,1-c]pyrazinyl, an optionally substituted 7,8-dihydro-5H-6-pyrido[4,3- d]pyrimidinyl, an optionally substituted 4,6-dihydro-5-pyrrolo[3,4-d]thiazolyl, an optionally substituted 6,7-dihydro-4H-5-[1,2,3]triazolo[5,1-c]pyrazinyl, an optionally substituted 5,7- dihydro-6-pyrrolo[3,4-d]pyrimidinyl, an optionally substituted 5,6-dihydro-8H-7- imidazo[5,1-c]pyrazinyl, an optionally substituted 6,7-dihydro-4H-5-pyrazolo[5,1- c]pyrazinyl, an optionally substituted 5,6-dihydro-8H-7-[1,2,4]triazolo[3,4-c]pyrazinyl, an optionally substituted 6,7-dihydro-4H-5-oxazolo[4,5-c]pyridinyl, an optionally substituted 1,3-dihydro-2-pyrrolo[3,4-c]pyridinyl, an optionally substituted 6,7-dihydro-4H-5- oxazolo[5,4-c]pyridinyl, or an optionally substituted 4-azatricyclo[3.3.0.01,3]octanyl. [00493] In some embodiments, the optionally substituted 4-12-membered fused heterocycloalkyl ring system is substituted with a C ₁ -C ₆ alkyl, halo, carbonyl (i.e., (=O)), or spirocyclopropyl [00494] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3,4-dihydro-2,7-naphthyridin-2(1H)-yl group: . [00495] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 1-methyl-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl group: . [00496] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 5H-pyrrolo[3,4-b]pyridin-6(7H)-yl group: . [00497] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-yl group: . [00498] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 5,7-dihydro-pyrrolo[3,4-b]pyrazin-6-yl group: . [00499] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2-isoindoline group: . [00500] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl group: . [00501] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3-methyl-3,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-yl group: . [00502] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 1-methyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-yl group: . [00503] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 1-methyl-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-yl group: . [00504] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 5,6-dihydro-8H-[1,2,4]triazolo[5,1-c]pyrazin-7-yl group: . [00505] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 7,8-dihydro-5H-[1,2,4]triazolo[1,5-c]pyrimidin-6-yl group: . [00506] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl group: . [00507] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 4,7-dihydro-5H-6-thieno[2,3-c]pyridine-6-yl group: . [00508] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 5,6-dihydro-1,7-naphthyridin-7(8H)-yl group: . [00509] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl group: . [00510] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl group: S N N . [00511] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2-methyl-6,7-dihydro-4H-oxazolo[4,5-c]pyridin-5-yl group: . [00512] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2-methyl-6,7-dihydro-4H-oxazolo[5,4-c]pyridine-5-yl group: . [00513] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3,4-dihydro-2,6-naphthyridin-2(1H)-yl group: . [00514] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 7,8-dihydro-1,6-naphthyridin-6(5H)-yl group: . [00515] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl group: . [00516] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 5,6-dihydro-8H-imidazo[5,1-c]pyrazin-7-yl group: . [00517] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 6,7-dihydro-4H-pyrazolo[5,1-c]pyrazin-5-yl group: . [00518] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 6,7-dihydro-4H-[1,2,3]triazolo[5,1-c]pyrazin-5-yl group: they are both attached, form a 4H-pyrrolo[3,4-d]thiazol-5(6H)-yl group: . [00520] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 1H-pyrrolo[3,4-c]pyridin-2(3H)-yl group: . [00521] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl group: . [00522] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a hexahydro-2H-6-furo[2,3-c]pyridine-6-yl group: . [00523] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a tetrahydro-1H-2-pyrrolo[2,1-c]pyrazin-4(3H)-one group: . [00524] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a (S)-tetrahydro-1H-2-pyrrolo[2,1-c]pyrazin-4(3H)-one group: . [00525] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3-azabicyclo[3.2.0]heptan-3-yl group: . [00526] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a (1R,5S)-3-azabicyclo[3.2.0]heptan-3-yl group: . [00527] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2-azabicyclo[3.1.0]hexan-2-yl group: N . [00528] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 4-azatricyclo[3.3.0.0 ^1,3 ]octanyl group: . [00529] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl group: . [00530] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl group: . [00531] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3,4-dihydroisoquinolin-2(1H)-yl group: . [00532] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl group: . [00533] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl group: . [00534] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 3',4'-dihydro-spirocyclopropane-1,1'-isoquinolin-2-yl group: . [00535] In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are both attached, form a 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl group: . [00536] In some aspects, each R ⁵ and each R ⁶ in the compounds of formula (I) independently H, C ₁ -C ₆ alkyl, or C ₃ -C ₅ cycloalkyl; or an R ⁵ and R ⁶ attached to the same carbon atom, together with that carbon atom, may form a C ₃ -C ₆ cycloalkyl ring, or an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, an optionally substituted 5-12-membered bridged heterocycloalkyl ring, an optionally substituted 4-12-membered fused heterocycloalkyl ring system, or an optionally substituted 5-12-membered spiroheterocycloalkyl ring system. [00537] In some embodiments, R ⁵ or R ⁶ in the compounds of formula (I) is H. [00538] In some embodiments, R ⁵ or R ⁶ in the compounds of formula (I) is C ₁ - C ₆ alkyl, such as, for example, C ₁ -C ₆ alkyl, C ₁ -C ₅ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₂ alkyl, C ₆ alkyl, C ₅ alkyl, C ₄ alkyl, C ₃ alkyl, C ₂ alkyl, C ₁ alkyl, methyl, ethyl, n-propyl, iso-propyl, n- butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl, and the like. [00539] In some embodiments, R ⁵ or R ⁶ is methyl (i.e., -CH ₃ ). [00540] In some embodiments, an R ⁵ and an R ⁶ are methyl (i.e., -CH ₃ ). [00541] In some embodiments, R ⁵ or R ⁶ in the compounds of formula (I) is C ₃ - C ₅ cycloalkyl, such as, for example, C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, and the like. [00542] In some embodiments, an R ⁵ and R ⁶ in the compounds of formula (I) attached to the same carbon atom, together with that carbon atom, form a C ₃ -C ₆ cycloalkyl ring, such as, for example, C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. [00543] In some embodiments, an R ⁵ and R ⁶ in the compounds of formula (I) attached to the same carbon atom, together with that carbon atom, form a cyclopropyl group. [00544] In some embodiments of the compounds of formula (I), an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, an optionally substituted 5-12-membered bridged heterocycloalkyl ring, an optionally substituted 4-12-membered fused heterocycloalkyl ring system, or an optionally substituted 5-12-membered spiroheterocycloalkyl ring system. [00545] In some embodiments of the compounds of formula (I), an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, such as, for example, an optionally substituted azetidnyl ring, an optionally substituted pyrrolidinyl ring, or an optionally substituted piperidinyl ring. [00546] In some embodiments, the optionally substituted 3-12-membered heterocycloalkyl ring is a 4-8 membered heterocycloalkyl ring. [00547] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is . [00548] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is . [00549] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is [00550] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is [00551] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is . [00552] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is . [00553] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is . [00554] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is . [00555] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is . [00556] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure . [00557] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is [00558] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is [00559] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is [00560] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is [00561] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is [00562] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is [00563] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is [00564] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is [00565] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is [00566] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is [00567] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is [00568] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is [00569] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is [00570] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is [00571] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is [00572] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is , , . [00573] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is , , . [00574] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is [00575] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is , , . [00576] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is , , . [00577] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is [00578] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is , , . [00579] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is [00580] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is . [00581] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered heterocycloalkyl ring, the structure formula (I) is . [00582] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered . [00583] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered . [00584] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered . [00585] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered . [00586] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered . [00587] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered . [00588] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 3-12-membered . [00589] In some embodiments of the compounds of formula (I), an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 4-12-membered fused heterocycloalkyl ring system. [00590] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 4-12-membered fused heterocycloalkyl ring system, the structure formula (I) is . [00591] In some embodiments of the compounds of formula (I) wherein an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 4-12-membered fused heterocycloalkyl ring system, the structure formula (I) is . [00592] In some embodiments of the compounds of formula (I), an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 5-12-membered bridged heterocycloalkyl ring. [00593] In some embodiments of the compounds of formula (I), an R ⁵ or R ⁶ , together with an R ³ or R ⁴ may form an optionally substituted 5-12-membered spiroheterocycloalkyl ring system. [00594] In some aspects, the compounds according to formula (I) are those that have an IC ₅₀ <20 nM in a PDGFR cellular assay such as, for example, that described in the Examples section below. [00595] In some embodiments, the compounds according to formula (I) are those that have an IC ₅₀ <5 nM in a PDGFR cellular assay such as, for example, that described in the Examples section below. [00596] In some aspects, the compound of the disclosure is one of Examples 1-90, or a pharmaceutically acceptable salt thereof, as described in the Examples section below. [00597] In other aspects, the compound of the disclosure is one of Examples 91- 190, or a pharmaceutically acceptable salt thereof, as described in the Examples section below. [00598] Stereoisomers of compounds of formula (I) are also contemplated by the present disclosure. Thus, the disclosure encompasses all stereoisomers and constitutional isomers of any compound disclosed or claimed herein, including all enantiomers and diastereomers. [00599] Pharmaceutically acceptable salts and solvates of the compounds of formula (I) are also within the scope of the disclosure. [00600] Isotopic variants of the compounds of formula (I) are also contemplated by the present disclosure. Pharmaceutical compositions and methods of administration [00601] The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the present disclosure as the active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. In some embodiments, the pharmaceutical compositions contain a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. [00602] The subject pharmaceutical compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. Where desired, the one or more compounds of the invention and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time. [00603] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number in the range defined by and including any two numbers above) w/w, w/v or v/v. [00604] In some embodiments, the concentration of one or more compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25% , 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number in the range defined by and including any two numbers above) w/w, w/v, or v/v. [00605] In some embodiments, the concentration of one or more compounds of the invention is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w/w, w/v or v/v. [00606] In some embodiments, the concentration of one or more compounds of the invention is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v or v/v. [00607] In some embodiments, the amount of one or more compounds of the invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g (or a number in the range defined by and including any two numbers above). [00608] In some embodiments, the amount of one or more compounds of the invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, , 0.15 g, 0.2 g, , 0.25 g, 0.3 g, , 0.35 g, 0.4 g, , 0.45 g, 0.5 g, 0.55 g, 0.6 g, , 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5g, 7 g, 7.5g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g (or a number in the range defined by and including any two numbers above). [00609] In some embodiments, the amount of one or more compounds of the invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g. [00610] In some embodiments, the compounds according to the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician. [00611] Unless otherwise noted, the amounts of the compounds described herein are set forth on a free base basis. That is, the amounts indicate that amount of the compound administered, exclusive of, for example, solvent (such as in solvates) or counterions (such as in pharmaceutically acceptable salts). [00612] Described below are non- limiting exemplary pharmaceutical compositions and methods for preparing the same. Pharmaceutical compositions for oral administration. [00613] In some embodiments, the invention provides a pharmaceutical composition for oral administration containing a compound of the invention, and a pharmaceutical excipient suitable for oral administration. [00614] In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of a compound of the invention; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains: (iv) an effective amount of a third agent. [00615] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in- water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. [00616] This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds. For example, water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf- life or the stability of formulations over time. Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms of the invention which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs. [00617] An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. [00618] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof. [00619] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. [00620] Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof. [00621] Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition. [00622] When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof. [00623] The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. [00624] Surfactant which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed. [00625] A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (" HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. [00626] Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions. [00627] Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di- glycerides; and mixtures thereof. [00628] Within the aforementioned group, ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof. [00629] Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP -phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof. [00630] Hydrophilic non-ionic surfactants may include, but are not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide. [00631] Other hydrophilic-non-ionic surfactants include, without limitation, PEG- 10 laurate, PEG- 12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG- 12 oleate, PEG- 15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG- 100 succinate, PEG-24 cholesterol, polyglyceryl-lOoleate, Tween 40, Tween 60, sucrose monostearate, sucrose mono laurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers. [00632] Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides. [00633] In one embodiment, the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use, e.g., compositions for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion. [00634] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG ; amides and other nitrogen-containing compounds such as 2- pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water. [00635] Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N- methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol. [00636] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a subject using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%o, 50%), 100%o, or up to about 200%> by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as 5%>, 2%>, 1%) or even less. Typically, the solubilizer may be present in an amount of about 1%> to about 100%, more typically about 5%> to about 25%> by weight. [00637] The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof. [00638] In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para- bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium. [00639] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like. Pharmaceutical compositions for injection. [00640] In some embodiments, the invention provides a pharmaceutical composition for injection containing a compound of the present invention and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the compositions are as described herein. [00641] The forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. [00642] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. [00643] Sterile injectable solutions are prepared by incorporating the compound of the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. [00644] Pharmaceutical compositions for topical (e.g. transdermal) delivery. [00645] In some embodiments, the invention provides a pharmaceutical composition for transdermal delivery containing a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery. [00646] Compositions of the present invention can be formulated into preparations in solid, semisolid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions. In general, carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients. In contrast, a solution formulation may provide more immediate exposure of the active ingredient to the chosen area. [00647] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration- enhancing molecules known to those trained in the art of topical formulation. [00648] Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. [00649] Another exemplary formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the present invention in controlled amounts, either with or without another agent. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos.5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Pharmaceutical compositions for inhalation. [00650] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. [00651] Compositions for inhalation may be delivered as a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant. Such devices are referred to in, for example, WO2013030802. [00652] Where the inhalable form of the active ingredient is an aerosol composition, the inhalation device may be an aerosol vial provided with a valve adapted to deliver a metered dose, i.e. a metered dose inhaler. Where the inhalable form of the active ingredient is a nebulizable aqueous, organic or aqueous/organic dispersion, the inhalation device may be a nebulizer, such as an airjet nebulizer, or an ultrasonic nebulizer, or a hand- held nebulizer, sometimes referred to as a soft mist or soft spray inhaler, or a mechanical device which allows much smaller nebulized volumes than conventional nebulizers. Such devices are referred to in, for example, WO2013030802. [00653] Where the inhalable form of the active ingredient is the finely divided particulate form, the inhalation device may be, for example, a dry powder inhalation device adapted to deliver dry powder from a capsule or blister containing a dry powder comprising a dosage unit or a multidose dry powder inhalation (MDPI) device adapted to deliver dry powder comprising a dosage unit upon actuation. The dry powder composition preferably contains a diluent or carrier, such as lactose, and a compound that helps to protect against product performance deterioration due to moisture e.g. magnesium stearate. Dry powder inhalation devices are referred to in, for example, WO2013030802 [00654] Thus, in some embodiments, the invention also includes (A) a compound of the invention, or a pharmaceutically acceptable salt thereof, in inhalable form; (B) an inhalable medicament comprising the compound in inhalable form together with a pharmaceutically acceptable carrier in inhalable form; (C) a pharmaceutical product comprising such a compound in inhalable form in association with an inhalation device; and (D) an inhalation device containing such a compound in inhalable form. Other pharmaceutical compositions. [00655] Pharmaceutical compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001 ; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety. [00656] Administration of the compounds or pharmaceutical composition of the present invention can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g. transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. Compounds can also be administered intraadiposally or intrathecally. [00657] The amount of the compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g. by dividing such larger doses into several small doses for administration throughout the day. [00658] In some embodiments, a compound of the invention is administered in a single dose. [00659] Typically, such administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly. However, other routes may be used as appropriate. A single dose of a compound of the invention may also be used for treatment of an acute condition. [00660] In some embodiments, a compound of the invention is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment a compound of the invention and another agent are administered together about once per day to about 6 times per day. In another embodiment the administration of a compound of the invention and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary. [00661] Administration of the compounds of the invention may continue as long as necessary. In some embodiments, a compound of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound of the invention is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects. [00662] An effective amount of a compound of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra- arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant. [00663] The compositions of the invention may also be delivered via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer. Such a method of administration may, for example, aid in the prevention or amelioration of restenosis following procedures such as balloon angioplasty. Without being bound by theory, compounds of the invention may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall which contribute to restenosis. A compound of the invention may be administered, for example, by local delivery from the struts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent. In some embodiments, a compound of the invention is admixed with a matrix. Such a matrix may be a polymeric matrix, and may serve to bond the compound to the stent. Polymeric matrices suitable for such use, include, for example, lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g. PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g. polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters. Suitable matrices may be nondegrading or may degrade with time, releasing the compound or compounds. Compounds of the invention may be applied to the surface of the stent by various methods such as dip/spin coating, spray coating, dip-coating, and/or brush-coating. The compounds may be applied in a solvent and the solvent may be allowed to evaporate, thus forming a layer of compound onto the stent. Alternatively, the compound may be located in the body of the stent or graft, for example in microchannels or micropores. When implanted, the compound diffuses out of the body of the stent to contact the arterial wall. Such stents may be prepared by dipping a stent manufactured to contain such micropores or microchannels into a solution of the compound of the invention in a suitable solvent, followed by evaporation of the solvent. Excess drug on the surface of the stent may be removed via an additional brief solvent wash. In yet other embodiments, compounds of the invention may be covalently linked to a stent or graft. A covalent linker may be used which degrades in vivo, leading to the release of the compound of the invention. Any bio-labile linkage may be used for such a purpose, such as ester, amide or anhydride linkages. Compounds of the invention may additionally be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds via the pericard or via advential application of formulations of the invention may also be performed to decrease restenosis. [00664] A variety of stent devices which may be used as described are disclosed, for example, in the following references, all of which are hereby incorporated by reference: U.S. Pat. No.5451233; U.S. Pat. No.5040548; U.S. Pat. No.5061273; U.S. Pat. No. 5496346; U.S. Pat. No.5292331; U.S. Pat. No.5674278; U.S. Pat. No.3657744; U.S. Pat. No.4739762; U.S. Pat. No.5195984; U.S. Pat. No.5292331 ; U.S. Pat. No.5674278; U.S. Pat. No.5879382; U.S. Pat. No.6344053. [00665] The compounds of the invention may be administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound of the invention may be found by routine experimentation in light of the instant disclosure. [00666] When a compound of the invention is administered in a composition that comprises one or more agents, and the agent has a shorter half- life than the compound of the invention unit dose forms of the agent and the compound of the invention may be adjusted accordingly. [00667] The subject pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc. [00668] Exemplary parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired. Methods of Use [00669] The method typically comprises administering to a subject a therapeutically effective amount of a compound of the invention. The therapeutically effective amount of the subject combination of compounds may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of proliferation or downregulation of activity of a target protein. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried. [00670] It should be understood that references herein to methods of treatment using one or more compounds or formulations thereof, or methods of using the compounds described herein to treat a disease or disorder, should also be interpreted as references to: (i) one or more compounds or formulations thereof for use in methods of treatment; and/or (ii) the use of one or more compounds or formulations thereof in the manufacture of a medicament for treating a pathological condition set forth herein. [00671] The disclosure also relates to methods of using the compounds described herein to treat in a subject in need thereof, a disease or disorder in which PDGFR signaling is implicated. These methods are accomplished by administering to the subject a compound of the disclosure in an amount effective to treat the disease or disorder. [00672] In some aspects, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is pulmonary hypertension (PH). [00673] In some embodiments, the pulmonary hypertension is pulmonary arterial hypertension (PAH) (WHO PH Group 1); PH secondary to heart failure (WHO PH Group 2); PH secondary to lung diseases and/or hypoxia (WHO PH Group 3); PH due to pulmonary artery obstruction (WHO Group 4); or PH due to unknown or rare diseases (WHO PH Group 5). [00674] In some embodiments, the PAH (WHO PH Group 1) is idiopathic PAH, PAH with vasoreactivity, heritable PAH, drugs and toxins-induced PAH, PAH associated with connective tissue disease, PAH associated with HIV infection, PAH associated with portal hypertension, PAH associated with congenital heart disease, PAH associated with schistosomiasis, PAH in long-term responders to calcium channel blockers, PAH with overt signs of venous/capillaries involvement; persistent PH of the Newborn syndrome; or systemic sclerosis-associated PAH (SSc-PAH). [00675] In some embodiments, the PAH secondary to heart failure (WHO PH Group 2) is PH due to heart failure with preserved ejection fraction, PH due to heart failure with reduced ejection fraction, valvular heart disease, or congenital post-capillary obstructive lesions. [00676] In some embodiments, the PH secondary to lung diseases and/or hypoxia (WHO PH Group 3) is PH due to obstructive lung disease, PH due to restrictive lung disease, PH due to other lung diseases with mixed restrictive/obstructive pattern, PH due to hypoxia without lung disease, PH due to developmental lung disorders. [00677] In some embodiments, the PH due to obstructive lung disease is PH due to chronic obstructive pulmonary disease (COPD). [00678] In some embodiments, the PH due to restrictive lung disease is PH due to interstitial lung diseases (ILDs). [00679] In some embodiments, the PH due to interstitial lung diseases (ILDs) is PH due to idiopathic pulmonary fibrosis (IPF). [00680] In some embodiments, the PH due to pulmonary artery obstruction (WHO Group 4) is chronic thromboembolic PH (CTEPH) or PH due to other pulmonaty artery obstructions. [00681] In some embodiments, the PH due to unknown or rare diseases (WHO PH Group 5) is PH due to hematologic disorders, PH due to systemic disorders, PH due to other disorders, or PH due to complex congenital heart disease. [00682] In some aspects, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is a respiratory disease. [00683] In some embodiments, the respiratory disease is asthma. [00684] In some aspects, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is a fibrotic disease. [00685] In some embodiments, the fibrotic disease is pulmonary fibrosis, cardiac fibrosis or liver fibrosis. [00686] In some embodiments, the fibrotic disease is pulmonary fibrosis. [00687] In some embodiments, the pulmonary fibrosis is an interstitial lung disease. [00688] In some embodiments, the interstitial lung disease is idiopathic pulmonary fibrosis. [00689] In some embodiments, the interstitial lung disease is rheumatoid arthritis- associated interstitial lung disease. [00690] In some embodiments, the interstitial lung disease is systemic sclerosis- associated interstitial lung disease. [00691] In some embodiments, the interstitial lung disease is connective tissue disease-associated interstitial lung disease. [00692] In some embodiments, the interstitial lung disease is nonspecific interstitial pneumonia. [00693] In some embodiments, the interstitial lung disease is unclassifiable interstitial lung disease. [00694] In some embodiments, the interstitial lung disease is hypersensitivity pneumonitis. [00695] In some embodiments, the interstitial lung disease is sarcoidosis. [00696] In some embodiments, the interstitial lung disease is non-idiopathic pulmonary fibrosis interstitial lung disease. [00697] In some aspects, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is a dermatological disease. [00698] In some embodiments, the dermatological disease or disorder is atopic dermatitis, scleroderma, or urticaria. [00699] In some aspects, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is an inflammatory disease or disorder. [00700] In some embodiments, the inflammatory disease or disorder is allergic rhinitis, irritable bowel syndrome (IBS); or inflammatory bowel disease (IBD). [00701] In some aspects, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is an autoimmune disorder. [00702] In some aspects, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is a metabolic disease. [00703] In some aspects, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is vascular restenosis; age-related macular degeneration (AMD); irritable bowel syndrome (IBS); inflammatory bowel disease (IBD); obesity-cell related diseases; type I diabetes or type II diabetes. [00704] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is pulmonary arterial hypertension (PAH). [00705] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH secondary to heart failure (WHO PH Group 2). [00706] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH due to heart failure with preserved ejection fraction. [00707] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH due to heart failure with reduced ejection fraction. [00708] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is valvular heart disease. [00709] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is congenital post-capillary obstructive lesions. [00710] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH secondary to lung diseases and/or hypoxia (WHO PH Group 3). [00711] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH due to pulmonary artery obstruction (WHO Group 4). [00712] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is chronic thromboembolic PH (CTEPH). [00713] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH due to unknown or rare diseases (WHO PH Group 5). [00714] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is idiopathic PAH. [00715] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PAH associated with connective tissue disease. [00716] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is systemic sclerosis-associated PAH (SSc-PAH). [00717] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH secondary to interstitial lung diseases (ILDs). [00718] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH secondary to chronic obstructive pulmonary disease (COPD). [00719] In other embodiments, the disclosure is directed to methods of using the compounds described herein to treat a disease or disorder in a subject in need thereof, wherein the disease or disorder is PH secondary to idiopathic pulmonary fibrosis (IPF). [00720] In treatment methods according to the disclosure, an effective amount of a pharmaceutical agent according to the disclosure is administered to a subject suffering from or diagnosed as having such a disease or disorder. An "effective amount" means an amount or dose sufficient to generally bring about the desired therapeutic benefit in patients in need of such treatment for the designated disease or disorder. Effective amounts or doses of the compounds of the present disclosure may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease or disorder, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. An example of a dose is in the range of from about 0.001 to about 200 mg of compound per kg of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g., BID, TID, QID). For a 70-kg human, an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day. [00721] In addition, the compounds of the disclosure may be used in combination with additional active ingredients in the treatment of the above diseases or disorders. The additional active ingredients may be coadministered separately with a compound of the disclosure or included with such an agent in a pharmaceutical composition according to the disclosure. The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of an active agent according to the disclosure), decrease one or more side effects, or decrease the required dose of the active agent according to the disclosure. Examples [00722] Compounds of Formula (I) in the present invention can be synthesized in accordance with general synthetic methods to those who are skilled in the art. The following reaction schemes are only meant to represent examples of the invention and are in no way meant to be a limit of the invention. [00723] A compound of formula (I): [00724] Compounds of Formula I in the present invention can be synthesized in accordance with general synthetic methods to those who are skilled in the art. The following reaction schemes are only meant to represent examples of the invention and are in no way meant to be a limit of the invention. Scheme 1 [00725] Scheme 1 illustrates the synthesis of intermediate 1. Ethyl 2-(5- chloropyrazin-2-yl)acetate (1-1) is reacted with N,N-dimethylformamide dimethyl acetal, optionally in a solvent such as ethanol, to give ethyl 2-(5-chloropyrazin-2-yl)-3- (dimethylamino)acrylate (1-2). Ethyl 2-(5-chloropyrazin-2-yl)-3-(dimethylamino)acrylate (1- 2) is treated with ammonium acetate in the presence of acetic acid, optionally in a solvent such as 1,4-dioxane, to give ethyl 3-amino-2-(5-chloropyrazin-2-yl)acrylate (1-3), which is treated with (diacetoxyiodo)benzene in a solvent such as dichloromethane to give intermediate 1. Scheme 2 [00726] Scheme 2 illustrates the synthesis of intermediates 2, wherein R ⁷ is OCH ₃ or CH ₃ . Chloropyrazine (2-1) is reacted with O-(mesitylsulfonyl)hydroxylamine in a solvent such as dichloromethane to give compound (2-2). Compound (2-2) is reacted with ethyl propiolate, in the presence of a base such as triethylamine, in a solvent such as DMF, to give intermediate 2. [00727] Scheme 3 illustrates the synthesis of intermediates 3. The intermediates 1 or 2 is coupled with boronic ester or boronic acid (3-1), in the presence of a catalyst such as PdCl ₂ (dppf), Pd(Ph ₃ ) ₄ , a base such as Cs ₂ CO ₃ , K ₂ CO ₃ , Na ₂ CO ₃ , K ₃ PO ₄ , and in a solvent such as dioxane-water, DME-water; to give compound (3-2). The ester of compound (3-2) is hydrolyzed in the presence of a base such as LiOH, NaOH, in a solvent such as THF-water, THF-MeOH-water, to give intermediate acid 3. Scheme [00728] Scheme 4 illustrates an alternate synthesis of intermediates 3, wherein R ⁷ = H. 2-Chloropyrazine is coupled with boronic ester or boronic acid (3-1), in the presence of a catalyst such as PdCl ₂ (dppf), Pd(Ph ₃ ) ₄ , a base such as Cs ₂ CO ₃ , K ₂ CO ₃ , Na ₂ CO ₃ , K ₃ PO ₄ , and in a solvent such as dioxane-water, DME-water; to give pyrazine compound (4-1). The pyrazine (4-1) is reacted with O-(mesitylsulfonyl)hydroxylamine in a solvent such as dichloromethane to give compound (4-2). Compound (4-2) is reacted with ethyl propiolate, in the presence of a base such as triethylamine, in a solvent such as DMF, to give pyrazolo- pyrazine compound (4-3). The ester of compound (4-3) is hydrolyzed in the presence of a base such as LiOH, NaOH, in a solvent such as THF-water, THF-MeOH-water, to give intermediate acid 3. [00729] Scheme 5 illustrates the synthesis of Formula I wherein L = CONH. Pyridinyl acid (I-1) is coupled with amine (I-2), in the presence of a coupling reagent such as HATU, EDCI, a base such as DIEA, Et ₃ N, in a solvent such as DMF, pyridine; to give an amide compound (I-3). The acetal group of I-3 is hydrolyzed in the presence of an acid such as acetic acid, in a solvent such as water, to give an aldehyde (I-4). The aldehyde (I-4) is reacted with amine (I-5), in the presence of a reducing reagent such as Na(OAc) ₃ BH, NaCNBH ₃ , in a solvent such as 1,2-dichloroethan, MeOH, optionally in the presence of an acid such as acetic acid, to give an amine compound (I-6). The nitro group of compound I-6 is reduced by hydrogen, in the presence of a catalyst such as Pd/C, in a solvent such as THF, to give aminopyridine compound I-7. Compound I-7 is coupled with intermediate 3, in the presence of a coupling agent such as TCFH, in the presence of NMI, in a solvent such as CH ₂ Cl ₂ , CH ₃ CN, to yield Formula I. S h 6 [00730] Scheme 6 illustrates the alternate synthesis of Formula I wherein L = CONH. Pyridinyl acid (I-8) is coupled with diamine compound (I-9), in the presence of a coupling reagent such as TCFH, EDCI, HATU, optionally in the presence of NMI, in a solvent such as CH ₃ CN, CH ₂ Cl ₂ , pyridine, to give amide compound (I-10). This amide compound (I-10) is coupled with intermediate 3, in the presence of a coupling reagent such as TCFH, in the presence of NMI, in a solvent such as CH ₃ CN, CH ₂ Cl ₂ , to yield Formula I. Scheme 7

[00731] Scheme 7 illustrates the synthesis of Formula I, wherein L = NHCO. The nitropyridinylamine (I-11) is reacted with an acid chloride (I-12), in the presence of a base such as TEA, in a solvent such as DCM, to give chloro compound (I-13) which is then treated with an amine (I-5), in the presence of a base such as K ₂ CO ₃ , in a solvent such as CH ₃ CN, DMF, to give amine compound (I-14). Alternatively, the nitropyridinylamine (I-11) is reacted with acid (I-15), in the presence of a coupling reagent such as TCFH, in the presence of NMI, in a solvent such as CH3CN, CH2Cl2, to give compound (I-14). The nitro group of the amine compound (I-14) is reduced to an amino group by H ₂ , in the presence of a catalyst such as Pd/C, in a solvent such as THF, to give aminopyridine compound (I-16). The aminopyridine compound (I-16) is reacted with intermediate 3, in the presence of a coupling reagent such as TCFH, in the presence of NMI, in a solvent such as CH ₃ CN, CH ₂ Cl ₂ , to yield Formula I. Alternatively, the aminopyridine compound is reacted with acid I-17, in the presence of a coupling reagent such as TCFH, in the presence of NMI, in a solvent such as CH ₃ CN, CH ₂ Cl ₂ , to give the chloro compound (I-18), which is coupled with boronated reagent (3-1), in the presence of a catalyst such as PdCl ₂ (dppf), in the presence of a base such as Cs ₂ CO ₃ , and in a solvent such as dioxane-water to give Formula I. Scheme 8

[00732] Scheme 8 illustrates an alternate synthesis of Formula I, wherein L = NHCO. The intermediate 3 is coupled with aminopyridine (I-19), in the presence of a coupling reagent such as HATU, EDCI, in the presence of a base such as DIEA, in a solvent such as DMF, pyridine, to give amide compound (I-20). The Boc protecting group of compound (I-20) is deprotected with an acid such HCl, TFA, in a solvent such as 1,4- dioxane, CH ₂ Cl ₂ , to give the amine (I-21). The amine (I-21) is coupled with acid (I-15), in the presence of a coupling reagent such as HATU, in the presence of a base such as DIEA, in a solvent such as DMF, to give Formula I. Scheme 9 [00733] Scheme 9 illustrates the synthesis of Formula I, wherein L = NHCO; R ⁵ , R ⁶ = H; n = 2. The pyridinylamine (I-21) is reacted with acryloyl chloride, in the presence of a base such as Et ₃ N, in a solvent such as CH ₂ Cl ₂ , to give acrylamide (I-22), which is reacted with amine (I-5), in the presence of a base such as K ₂ CO ₃ , Cs ₂ CO ₃ , in a solvent such as MeOH, to give Formula I. Scheme 10

[00734] Scheme 10 illustrates the synthesis of Formula I, wherein L = NHCO, m = 0, 1, p = 0, 1, 2, q = 1, 2, 3, 4. The nitropyridinylamine (I-11) is reacted with protected cyclic amine (I-23), in the presence of a coupling reagent such as HATU, TCFH, in the presence of NMI when the coupling reagent is TCFH, optionally in the presence of a base such as DIEA, in a solvent such as DMF, CH ₂ Cl ₂ , CH ₃ CN, to give the amide compound (I-24). The amine protecting group (such as Boc group) of compound (I-24) is deprotected with an acid such as HCl, TFA, in a solvent such as EtOAc, 1,4-dioxane, CH ₂ Cl ₂ , to give cyclic amine (I-25). The cyclic amine (I-25) is reacted with an alkylating reagent (I-26), wherein X is a leaving group such as I, Br, Cl, OTs, in the presence of a base such as K ₂ CO ₃ , Cs ₂ CO ₃ , in a solvent such as CH ₃ CN, DMF, to give amine compound (I-28). Alternative, the cyclic amine (I-25) is subjected to a reductive amination with a carbonyl compound (I-27), in the presence of a reduction reagent such as NaCNBH3, Na(OAc)3BH, optionally in the presence of an acid such as HOAc, in a solvent such as MeOH, 1,2-dichloroethan, to give the amine compound (I-28). The nitro group of compound (I-28) is reduced to an amino group by H ₂ , in the presence of a catalyst such as Pd/C, in a solvent such as THF. The resulting pyridinylamine (I-29) is coupled with intermediate 3, in the presence of a coupling reagent TCFH, in the presence of NMI, in a solvent such as CH ₃ CN, CH ₂ Cl ₂ , to give Formula I. Scheme 11

[00735] Scheme 11 illustrates an alternate synthesis of Formula I, wherein L = NHCO, m = 0, 1, p = 0, 1, 2, q = 1, 2, 3, 4. The pyridinylamine (I-21) is reacted with protected cyclic amine (I-23), in the presence of a coupling reagent such as EDCI, in a solvent such as pyridine, to give amide compound (I-30). The amine protecting group (such as Boc group) of compound (I-30) is deprotected with an acid such as HCl, TFA, in a solvent such as EtOAc, 1,4-dioxane, CH ₂ Cl ₂ , to give cyclic amine (I-31). The cyclic amine (I-31) is reacted with an alkylating reagent (I-26), wherein X is a leaving group such as I, Br, Cl, OTs, in the presence of a base such as K ₂ CO ₃ , Cs ₂ CO ₃ , in a solvent such as CH ₃ CN, DMF, to give Formula I. Alternative, the cyclic amine (I-31) is subjected to a reductive amination with a carbonyl compound (I-27), in the presence of a reduction reagent such as NaCNBH ₃ , Na(OAc) ₃ BH, optionally in the presence of an acid such as HOAc, in a solvent such as MeOH, 1,2-dichloroethan, to give Formula I. pyridinylamine (I-21) is first treated with CDI, in the presence of a base such as Et ₃ N, in a solvent such as DMF, and is then reacted with azetidine compound (I-32), to give Formula I. Intermediate Example 1. Ethyl 6-chloropyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate A) Step 1. Synthesis of ethyl 2-(5-chloropyrazin-2-yl)-3-(dimethylamino)acrylate solution of ethyl 2-(5-chloropyrazin-2-yl)acetate (10.0 g, 49.94 mmol) in EtOH (40 mL) was added N,N-dimethylformamide dimethyl acetal (11.6 mL, 87.40 mmol). The reaction was heated under nitrogen at 70 °C overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc/heptane (0% - 60%) to afford ethyl 2-(5-chloropyrazin-2-yl)-3-(dimethylamino)acrylate as a brown oil (11.8 g, yield 92.8 %). LCMS (ESI) calcd. for C ₁₁ H ₁₄ ClN ₃ O ₂ : 255.1 m/z, found: 256.0 [M+H] ⁺ . Step 2. Synthesis of ethyl 3-amino-2-(5-chloropyrazin-2-yl)acrylate [00738] A mixture of ethyl 2-(5-chloropyrazin-2-yl)-3-(dimethylamino)acrylate (10 g, 39.11 mmol) and ammonium acetate (30 g, 389.2 mmol) in HOAc (22 mL) and 1,4- dioxane (22 mL) was heated at 80°C for 45 min. The reaction mixture was cooled to room temperature and concentrated. The residue was basified with aq. NaHCO ₃ and extracted with EtOAc (100 mL x 3). The organic layers were combined, washed with brine, and concentrated. The residue was diluted with Et ₂ O and the resulting mixture was filtered. The solid was collected, rinsed with Et ₂ O, and dried to yield ethyl 3-amino-2-(5-chloropyrazin-2- yl)acrylate as a tan solid. The solution was concentrated and the residue was recrystallized from CH3CN to yield additional ethyl 3-amino-2-(5-chloropyrazin-2-yl)acrylate (6.39 g total, yield 71.8%). LCMS (ESI) calcd. for C ₉ H ₁₀ ClN ₃ O ₂ : 227.0 m/z, found: 228.1 [M+H] ⁺ . Step 3. Synthesis of ethyl 6-chloropyrazolo[1,5-a]pyrazine-3-carboxylate [00739] A mixture of ethyl 3-amino-2-(5-chloropyrazin-2-yl)acrylate (8.23 g, 36.15 mmol) and (diacetoxyiodo)benzene (15 g, 46.57 mmol) in DCM (100 mL) was stirred at room temperature for 4 h. The reaction was quenched carefully with a mixed solution of 1/1/1 aq. NaHCO ₃ /aq. Na ₂ S ₂ O ₃ /water (150 mL total) under vigorous stirring. Additional aq. NaHCO ₃ (100 mL) was added and the resulting mixture was stirred for 0.5 h. The organic layer was separated, and the aqueous layer was extracted with DCM (2x). The organic layers were combined and washed aq. NaHCO ₃ and aq. NaCl, and concentrated. The resulting crude product was stirred with Et ₂ O and filtered. The solid was collected, rinsed with Et ₂ O, and dried under vacuum to yield ethyl 6-chloropyrazolo[1,5-a]pyrazine-3-carboxylate as a tan solid (5.7 g, yield 69.9%). LCMS (ESI) calcd. for C ₉ H ₈ ClN ₃ O ₂ : 225.0 m/z, found: 226.0 [M+H] ⁺ . 1H NMR (CHLOROFORM-d) δ: 9.41 (d, J=1.0 Hz, 1H), 8.54 (d, J=1.5 Hz, 1H), 8.47 (s, 1H), 4.44 (q, J=7.3 Hz, 2H), 1.44 (t, J=7.1 Hz, 3H). Intermediate Example 2 Ethyl 6-chloro-4-methoxypyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate B) Step 1. Synthesis of 1-amino-3-chloro-5-methoxypyrazin-1-ium 2,4,6- trimethylbenzenesulfonate of TFA (59 g, 517.4 mmol) and water (7 mL) at 0 °C was added (Z)-(ethyl n-[(2,4,6-trimethylbenzenesulfonyl)oxy]ethanimidate) (49 g, 171.7 mmol). The reaction was stirred for 1 h before ice water (500 mL) was added. The resulting mixture was filtered and the solid was collected. The solid was dissolved in DCM and dried with anhydrous Na ₂ SO ₄ . The resulting solution was added dropwise to a solution of 2-chloro-6- methoxypyrazinee (5 g, 4.588 mmol) in DCM (120 mL) at 0 °C. The reaction was stirred at room temperature overnight. MTBE (500 mL) was added and the resulting mixture was filtered. The solid was collected and dried under vacuum to give 1-amino-3-chloro-5- methoxypyrazin-1-ium 2,4,6-trimethylbenzenesulfonate as a yellow solid (12 g, crude). LCMS(ESI) calcd. for C ₅ H ₇ ClN ₃ O ₃ : 160.0, found: 160.1 [M] ⁺ . Step 2. Synthesis of ethyl 6-chloro-4-methoxypyrazolo[1,5-a]pyrazine-3-carboxylate [00741] To a mixture of 1-amino-3-chloro-5-methoxypyrazin-1-ium 2,4,6- trimethylbenzenesulfonate (5.0 g, 13.90 mmol) and Et ₃ N (2.8 g, 27.67 mmol) in DMF (20 mL) at 0 °C was added dropwise ethyl propiolate (2.7 g, 27.52 mmol). The reaction was stirred at room temperature overnight. The residue was purified by silica gel column chromatography (0-40% EtOAc/petroleum ether) to give ethyl 6-chloro-4- methoxypyrazolo[1,5-a]pyrazine-3-carboxylate as a white solid (740 mg 18.8% yield). LCMS (ESI) calcd. for C ₁₀ H ₁₀ ClN ₃ O ₃ : 255.0 m/z, found 256.0 [M+H] ⁺ . [00742] The following intermediate was similarly prepared according to the procedure described in Intermediate Example 2 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art. ethyl 6-chloro-4-methylpyrazolo[1,5-a]pyrazine-3-carboxylate (Intermediate C) Intermediate Example 3 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carbox ylic acid (Intermediate D) Step 1. Synthesis of ethyl 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3- carboxylate [00743] A mixture of ethyl 6-chloropyrazolo[1,5-a]pyrazine-3-carboxylate (2 g, 8.86 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole (2.2 g, 10.57 mmol), Cs ₂ CO ₃ (5 g, 15.35 mmol), and PdCl ₂ (dppf) (650 mg, 0.888 mmol) in 1,4- dioxane (60 mL) and water (15 mL) was heated at 95-100 ^o C for 8 h. The reaction mixture was cooled to rt and concentrated. The residue was diluted with H ₂ O and filtered. The solid was collected, washed with CH ₂ Cl ₂ (20 mL x 2), and dried under vacuum to give ethyl 6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxylate . The CH ₂ Cl ₂ solution was concentrated and the resulting residue was purified with silica gel column (2% MeOH/CH ₂ Cl ₂ ) to give additional ethyl 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazine-3-carboxylate (2.02 g total, yield 84.0%). LCMS (ESI) calcd. for C ₁₃ H ₁₃ N ₅ O ₂ : 271.1 m/z, found: 272.1 [M+H] ⁺ . ¹ H NMR (DMSO-d6) δ: 9.44 (s, 1H), 9.32 (d, J=1.5 Hz, 1H), 8.57 (s, 1H), 8.34 (s, 1H), 8.11 (s, 1H), 4.36 (d, J=7.3 Hz, 2H), 3.91 (s, 3H), 1.38 (t, J=7.1 Hz, 3H). Step 2. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carbox ylic acid [00744] A mixture of ethyl 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3- carboxylate (960 mg, 3.539 mmol) and LiOH (340 mg, 14.197 mmol) in THF (20 mL) and H ₂ O (10 mL) was stirred at room temperature overnight. To the reaction mixture was added 2N HCl aq. solution (~7 mL) to adjust pH to 2~3. The resulting mixture was filtered. The solid was collected, rinsed with H ₂ O, and dried under vacuum to give 6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxylic acid (710 mg, yield 82.5%). LCMS (ESI) calcd. for C ₁₁ H ₉ N ₅ O ₂ : 243.1 m/z, found: 244.1 [M+H] ⁺ . [00745] The following intermediates were similarly prepared according to the procedure described in Intermediate Example 3 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art. 6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-c arboxylic acid (Intermediate E) 6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin e-3-carboxylic acid (Intermediate F) 6-(pyridin-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate H) -4-yl)pyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate I) 6-(pyridin-3-yl)pyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate J) 6-(pyridin-2-yl)pyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate K) 6-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrazolo[1,5-a] pyrazine-3-carboxylic acid (Intermediate L) O 6-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)pyrazolo[1 ,5-a]pyrazine-3-carboxylic acid (Intermediate M) 6-(4-cyano-3-fluorophenyl)pyrazolo[1,5-a]pyrazine-3-carboxyl ic acid (Intermediate n) O 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin e-3-carboxylic acid (Intermediate O) 4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine -3-carboxylic acid (Intermediate P) Intermediate Example 4 6-morpholinopyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate Q) Step 1. Synthesis of ethyl 6-morpholinopyrazolo[1,5-a]pyrazine-3-carboxylate [00746] A mixture of ethyl 6-chloropyrazolo[1,5-a]pyrazine-3-carboxylate (300 mg, 1.33 mmol), morpholine (180 mg, 2.07 mmol), RuPhos (60 mg, 0.13 mmol), RuPhos Pd G3 (105 mg, 0.13 mmol), and Cs ₂ CO ₃ (870 mg, 2.67 mmol) in 1,4-dioxane (10 mL) was stirred at 90 °C under nitrogen overnight. The reaction mixture was concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc/petroleum ether) to afford ethyl 6- morpholinopyrazolo[1,5-a]pyrazine-3-carboxylate as a yellow solid (300 mg, 75.3% yield). LCMS (ESI) calcd. for C13H16N4O3: 276.1 m/z, found 277.0 [M+H] ⁺ . Step 2. Synthesis of 6-morpholinopyrazolo[1,5-a]pyrazine-3-carboxylic acid [00747] A mixture of ethyl 6-morpholinopyrazolo[1,5-a]pyrazine-3-carboxylate (380 mg, 1.38 mmol) and lithium hydroxide aqueous solution (3 M, 1.4 mL, 4.2 mmol) in THF (4 mL) and ethanol (1 mL) was stirred at room temperature overnight. The pH value of the reaction mixture was adjusted to 5~7 with HCl solution (1 M). The resulting mixture was filtered and the solid was dried to afford 6-morpholinopyrazolo[1,5-a]pyrazine-3-carboxylic acid as a yellow solid (250 mg, 65.3% yield). LCMS (ESI) calcd. for C ₁₁ H ₁₂ N ₄ O ₃ : 248.1 m/z, found 249.2 [M+H] ⁺ . Intermediate Example 5 6-Chloropyrazolo[1,5-a]pyrazine-3-carboxylic acid (Intermediate R) [00748] To a clear light orange solution of methyl 6-chloropyrazolo[1,5-a]pyrazine- 3-carboxylate (2.66 g, 11.78 mmol) in1,4-dioxane (40 mL) was added a hazy solution of LiOH (0.85 g, 35.52 mmol) in water (15 mL), resulting in an immediate darker yellow color and precipitate. The reaction was stirred at rt for 2.5 h. The reaction was concentrated and acidified with 1N HCl with vigorous stirring to yield a thick suspension. The solid was collected, washed with water, dried under vacuum in the filter funnel, stripped down 3x with MeCN to remove residual water, and dried under high vacuum overnight to yield 6- chloropyrazolo[1,5-a]pyrazine-3-carboxylic acid (2.0 g, 86%) as a yellow solid. LCMS (ESI): mass calcd. for C ₇ H ₄ ClN ₃ O ₂ , 197.58; m/z found, 198.0 [M+H] ⁺ . Example 1 6-(1-cyclopropyl-1H-pyrazol-4-yl)-N-(5-((2-(2,2-dimethylpyrr olidin-1- yl)ethyl)carbamoyl)-2-methylpyridin-3-yl)pyrazolo[1,5-a]pyra zine-3-carboxamide Step 1. Synthesis of 5-amino-N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6- methylnicotinamide [00749] A mixture of 5-amino-6-methylnicotinic acid (13 g, 85.44 mmol), 2-(2,2- dimethylpyrrolidin-1-yl)ethan-1-amine (30.4 g, 213.7 mmol), TCFH (72.0 g, 256.6 mmol), and NMI (42.1 g, 512.8 mmol) in ACN (500 mL) was stirred at room temperature under nitrogen overnight. The solvent was removed under vacuum and the residue was purified by silica gel column with MeOH/DCM (0%-40%) to afford 5-amino-N-(2-(2,2- dimethylpyrrolidin-1-yl)ethyl)-6-methylnicotinamide as a off-white solid (15.8 g, 62.1% yield). LCMS (ESI) calcd. for C ₁₅ H ₂₄ N ₄ O: 276.2 m/z, found 277.10 [M+H] ⁺ . Step 2. Synthesis of 6-(1-cyclopropyl-1H-pyrazol-4-yl)-N-(5-((2-(2,2- dimethylpyrrolidin-1-yl)ethyl)carbamoyl)-2-methylpyridin-3-y l)pyrazolo[1,5- a]pyrazine-3-carboxamide [00750] A mixture of 6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3- carboxylic acid (70 mg, 0.26 mmol), 5-amino-N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-6- methylnicotinamide (70 mg, 0.25 mmol), T ₃ P (50% in EA, 830 mg, 1.30 mmol), and DIEA (168 mg, 1.30 mmol) in DMF (5 mL) was stirred at 60°C for 2 days. The residue was purified by C18 column with CH ₃ CN/water with 0.05% TFA (5%-50%). The resulting product was purified again by Prep-Chiral-HPLC [Column: XBridge Prep OBD C18 Column, 30*150 mm, 5µm; Mobile Phase A: Water (10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17% B to 35% B in 9 min; Wave Length: 254/220 nm] to afford 6-(1-cyclopropyl-1H-pyrazol-4-yl)-N-(5-((2-(2,2-dimethylpyrr olidin-1-yl)ethyl)carbamoyl)- 2-methylpyridin-3-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide as a white solid (8.3 mg, 6.0% yield). LCMS (ESI): mass calcd. for C ₂₈ H ₃₃ N ₉ O ₂ , 527.3; m/z found, 528.3 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6) δ 10.12 (s, 1H), 9.54 (d, J = 1.4 Hz, 1H), 9.30 (d, J = 1.5 Hz, 1H), 8.83 (s, 1H), 8.78 (d, J = 2.0 Hz, 1H), 8.58 (t, J = 5.7 Hz, 1H), 8.43 (s, 1H), 8.24 (d, J = 2.1 Hz, 1H), 8.09 (s, 1H), 3.73 – 3.86 (m, 1H), 3.22 – 3.30 (m, 2H), 2.70 – 2.84 (m, 3H), 2.52 – 2.60 (m, 4H), 1.61 – 1.74 (m, 2H), 1.48 – 1.59 (m, 2H), 1.06 – 1.15 (m, 2H), 0.96 – 1.05 (m, 2H), 0.91 (s, 6H). [00751] The following examples were similarly prepared according to the procedure described in Example 1 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art.

Example 5 N-(5-((2-(5-azaspiro[3.4]octan-5-yl)ethyl)carbamoyl)-2-methy lpyridin-3-yl)-4-methoxy- 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carbox amide Step 1. Synthesis of N-(2,2-dimethoxyethyl)-6-methyl-5-nitronicotinamide [00752] To a 250 ml flask equipped with a stir bar was added 6-methyl-5- nitronicotinic acid (2.0 g, 10.98 mmol), 2,2-dimethoxyethylamine (1.2 g, 11.41 mmol), HATU (6.2 g, 16.31 mmol), DIEA (4.2 g, 32.48 mmol), and DMF (15 mL). The reaction was stirred at room temperature for 2 h. The resulting mixture was diluted with H ₂ O and extracted with EtOAc (2 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel chromatography with ethyl acetate/petroleum ether (0-70%) to afford N-(2,2- dimethoxyethyl)-6-methyl-5-nitronicotinamide as a yellow oil (2.6 g, 85.3% yield). LCMS (ESI) calcd. for C ₁₁ H ₁₅ N ₃ O ₅ : 269.1 m/z, found 270.1 [M+H] ⁺ . Step 2. Synthesis of 6-methyl-5-nitro-N-(2-oxoethyl)nicotinamide [00753] To a 40 ml vial equipped with a stir bar was added N-(2,2-dimethoxyethyl)- 6-methyl-5-nitronicotinamide (1.0 g, 3.71 mmol), CH ₃ CO ₂ H (5 mL), and 5 mL water. The mixture was stirred at 50°C overnight. The residue was purified by C18 column with CH ₃ CN/ water with 0.05% NH ₄ HCO ₃ (5%-20%) to afford 6-methyl-5-nitro-N-(2- oxoethyl)nicotinamide as a yellow oil (680 mg, 78.9% yield). LCMS (ESI) calcd. for C ₉ H ₉ N ₃ O ₄ : 223.1 m/z, found 224.0 [M+H] ⁺ . Step 3. Synthesis of N-(2-(5-azaspiro[3.4]octan-5-yl)ethyl)-6-methyl-5- nitronicotinamide [00754] A mixture of 6-methyl-5-nitro-N-(2-oxoethyl)nicotinamide (250 mg, 1.12 mmol) and 5-azaspiro[3.4]octane (210 mg, 1.89 mmol) in MeOH (10 mL) was stirred at room temperature for 0.5 h. The reaction was cooled to 0°C and NaBH ₃ CN (75 mg, 1.19 mmol) was added. The resulting mixture was warmed up to room temperature and stirred for 1 h. The reaction mixture was concentrated and the residue was purified by C18 column with ACN/ water with 0.05% TFA (5%-30%) to afford N-(2-(5-azaspiro[3.4]octan-5-yl)ethyl)-6- methyl-5-nitronicotinamide as a yellow oil (180 mg, 40.0% yield). LCMS (ESI) calcd. for C ₁₆ H ₂₂ N ₄ O ₃ : 318.2 m/z, found 319.1 [M+H] ⁺ . Step 4. Synthesis of N-(2-(5-azaspiro[3.4]octan-5-yl)ethyl)-5-amino-6- methylnicotinamide [00755] A mixture of N-(2-(5-azaspiro[3.4]octan-5-yl)ethyl)-6-methyl-5- nitronicotinamide (180 mg, 0.57 mmol) and Pd/C (180 mg) in THF (10 mL) was maintained under hydrogen and stirred at room temperature for 1 h. The reaction mixture was filtered and the solution was concentrated under reduced pressure. The crude product was purified by C18 column with ACN/H2O with 0.05% TFA (5%-30%) to afford N-(2-(5- azaspiro[3.4]octan-5-yl)ethyl)-5-amino-6-methylnicotinamide as a yellow oil (100 mg, 60.3% yield). LCMS (ESI) calcd. for C ₁₆ H ₂₄ N ₄ O: 288.2 m/z, found 289.2 [M+H] ⁺ . Step 5. Synthesis of N-(5-((2-(5-azaspiro[3.4]octan-5-yl)ethyl)carbamoyl)-2- methylpyridin-3-yl)-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)py razolo[1,5-a]pyrazine-3- carboxamide [00756] A mixture of 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazine-3-carboxylic acid (70 mg, 0.26 mmol), N-(2-(5-azaspiro[3.4]octan-5-yl)ethyl)-5- amino-6-methylnicotinamide (73 mg, 0.25 mmol), TCFH (700 mg, 2.50 mmol), and NMI (700 mg, 8.53 mmol) in ACN (4 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by C18 column with ACN/H ₂ O with 0.05% TFA (5%-40%). The purified product was purified again by Prep-Chiral-HPLC [Column: YMC-Actus Triart C18 ExRS, 20*250 mm, 5µm; Mobile Phase A: H ₂ O (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 30% B to 46% B in 11 min; Wave Length: 254/220 nm] to afford N-(5-((2-(5-azaspiro[3.4]octan-5- yl)ethyl)carbamoyl)-2-methylpyridin-3-yl)-4-methoxy-6-(1-met hyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamide as a white solid (14.6 mg, 10.3% yield). LCMS (ESI): mass calcd. for C ₂₈ H ₃₃ N ₉ O ₃ , 543.3; m/z found, 544.3 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.94 (s, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.63 (t, J = 5.7 Hz, 1H), 8.55 (d, J = 2.1 Hz, 1H), 8.49 (s, 1H), 8.32 (s, 1H), 8.11 (d, J = 0.8 Hz, 1H), 4.24 (s, 3H), 3.92 (s, 3H), 3.34 – 3.41 (m, 2H), 2.70 (t, J = 7.1 Hz, 4H), 2.62 (s, 3H), 2.04 – 2.18 (m, 2H), 1.80 – 1.89 (m, 2H), 1.48 – 1.75 (m, 6H). [00757] The following examples were similarly prepared according to the procedure described in Example 5 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art. Example 9 N-(5-(2-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)acetamido)-2 -methylpyridin-3-yl)-6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide Step 1. Synthesis of 2-chloro-N-(6-methyl-5-nitropyridin-3-yl)acetamide [00758] To a solution of 6-methyl-5-nitropyridin-3-amine (10.0 g, 65.30 mmol) and Et ₃ N (19.8 g, 196.67 mmol) in DCM (100 mL) at 0 °C was added 2-chloroacetyl chloride (11.1 g, 98.28 mmol) dropwise. The reaction was stirred at room temperature overnight. The resulting mixture was concentrated and the residue was purified by silica gel chromatography (0-70% EtOAc/petroleum ether) to afford 2-chloro-N-(6-methyl-5-nitropyridin-3- yl)acetamide as a yellow solid (10.0 g 65.0% yield). LCMS (ESI) calcd. for C8H8ClN3O3, 229.0 m/z, found 230.1 [M+H] ⁺ . Step 2. Synthesis of 2-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-N-(6-methyl-5- nitropyridin-3-yl)acetamide [00759] A mixture of 2-azabicyclo[2.2.1]heptane (406 mg, 2.178 mmol) and K ₂ CO ₃ (602 mg, 4.356 mmol) in CH ₃ CN (10 mL) was stirred for 5 min. 2-Chloro-N-(6-methyl-5- nitropyridin-3-yl)acetamide (500 mg, 4.179 mmol) was then added. The reaction was stirred at room temperature overnight. The resulting mixture was concentrated and the residue was purified by normal phase chromatography (mobile phase: PE/EA, 0~80%) and the product obtained was purified by Prep-SFC with the following conditions: [Column: CHIRALPAK IG-3, 3.0*50mm, 3µm; Mobile Phase B: MEOH (0.1%DEA); Flow rate: 2 mL/min; Gradient: isocratic 25% B; Wave Length: 220 nm] to afford 2-((1R,4S)-2- azabicyclo[2.2.1]heptan-2-yl)-N-(6-methyl-5-nitropyridin-3-y l)acetamide (280 mg, 44.2% yield) as a brown solid and 2-((1S,4R)-2-azabicyclo[2.2.1]heptan-2-yl)-N-(6-methyl-5- nitropyridin-3-yl)acetamide (300 mg, 47.4% yield). LCMS(ESI) calcd. for C ₁₄ H ₁₈ N ₄ O ₃ : 290.1 m/z, found 291.1 [M+H] ⁺ . Step 3. Synthesis of N-(5-amino-6-methylpyridin-3-yl)-2-((1R,4S)-2- azabicyclo[2.2.1]heptan-2-yl)acetamide [00760] To a solution of 2-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-N-(6-methyl- 5-nitropyridin-3-yl)acetamide (280 mg, 0.964 mmol) in MeOH (20 mL) was added Pd/C (10%, 28 mg). The reaction was maintained under H ₂ and stirred at 25 °C for 4 hrs. The resulting mixture was filtered and the solution was concentrated to give N-(5-amino-6- methylpyridin-3-yl)-2-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-y l)acetamide as a white solid (140 mg, 91.3 yield) which will be used for next step without further purification. LCMS (ESI) calcd. for C ₁₄ H ₂₀ N ₄ O: 260.2 m/z, found 261.0 [M+H] ⁺ . Step 4. Synthesis of N-(5-(2-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)acetamido)-2 - methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5 -a]pyrazine-3- [00761] A mixture of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3- carboxylic acid (150 mg, 0.62 mmol), N-(5-amino-6-methylpyridin-3-yl)-2-((1R,4S)-2- azabicyclo[2.2.1]heptan-2-yl)acetamide (128 mg, 0.49 mmol), TCFH (525 mg, 1.87 mmol), and NMI (300 mg, 3.65 mmol) in ACN (10 mL) was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was first purified by C18 column with CH ₃ CN/ water with 0.05% TFA (5%-50%). The resulting product was purified again by Prep-HPLC [Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5µm; Mobile Phase A: Water(10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 35% B in 8 min; Wave Length: 254/220 nm] to afford N-(5-(2-((1R,4S)-2- azabicyclo[2.2.1]heptan-2-yl)acetamido)-2-methylpyridin-3-yl )-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamide as a light yellow solid (109.9 mg, 35.0% yield). LCMS (ESI): mass calcd. for C ₂₅ H ₂₇ N ₉ O ₂ , 485.2; m/z found, 486.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.86 (s, 1H), 9.52 (d, J = 1.4 Hz, 1H), 9.30 (d, J = 1.5 Hz, 1H), 8.82 (s, 1H), 8.60 (d, J = 2.3 Hz, 1H), 8.33 (s, 1H), 8.11 (d, J = 2.3 Hz, 1H), 8.09 (s, 1H), 3.90 (s, 3H), 3.20 – 3.30 (m, 3H), 2.80 – 2.91 (m, 1H), 2.32 (s, 3H), 2.21 – 2.38 (m, 2H), 1.63 – 1.82 (m, 2H), 1.35 – 1.59 (m, 1H), 1.19 – 1.32 (m, 2H). [00762] The following examples were similarly prepared according to the procedure described in Example 9 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art.

Example 48 6-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(2-(pyrrolidin-1- yl)propanamido)pyridin- 3-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide Step 1. Synthesis of tert-butyl (6-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazine-3-carboxamido)pyridin-3-yl)carbamate [00763] A mixture of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3- carboxylic acid (300 mg, 1.233mmol), tert-butyl (5-amino-6-methylpyridin-3-yl)carbamate (700 mg, 3.135 mmol), HATU (700 mg.1.841 mmol), and DIEA (500 mg, 3.869 mmol) in DMF (6 mL) was stirred at 60 °C for 6 hours. The reaction was diluted with EtOAc (150 mL) and washed with H ₂ O (20 mL × 2) and NaCl aq. (20mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel chromatography with MeOH/DCM (0-10%) to afford tert-butyl (6-methyl-5-(6- (1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxam ido)pyridin-3-yl)carbamate as a yellow solid (300 mg, 54.2% yield). LCMS (ESI) calcd. for C ₂₂ H ₂₄ N ₈ O ₃ : 448.2 m/z, found: 449.2 [M+H] ⁺ . Step 2. Synthesis of N-(5-amino-2-methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamide [00764] A mixture of tert-butyl (6-methyl-5-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamido)pyridin-3-yl)carbam ate (200 mg, 0.446 mmol) in TFA (1 mL) and DCM (5 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated. The residue was dissolved in MeOH (5 mL) and K ₂ CO ₃ (1 g) was added. The resulting mixture was stirred for 10 min. The mixture was concentrated and purified by silica gel column with MeOH/DCM (0~18%) to afford N-(5-amino-2-methylpyridin-3-yl)-6- (1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxam ide (150 mg, 86.6% yield) as a yellow solid. LCMS (ESI) calcd. for C ₁₇ H ₁₆ N ₈ O: 348.1 m/z, found: 349.3 [M+H] ⁺ . Step 3. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(2-(pyrrolidin-1- yl)propanamido)pyridin-3-yl)pyrazolo[1,5-a]pyrazine-3-carbox amide [00765] A mixture of 2-(pyrrolidin-1-yl)propanoic acid (60 mg, 0.42 mmol), N-(5- amino-2-methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyra zolo[1,5-a]pyrazine-3- carboxamide (144 mg, 0.41 mmol), HATU (240 mg, 0.63 mmol), and DIEA (168 mg, 1.30 mmol) in DMF (5 mL) was stirred at room temperature for 2 h to yield a yellow mixture. The resulting mixture was diluted with H ₂ O and extracted with EtOAc (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by Prep-HPLC [Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5µm; Mobile Phase A: Water (10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 14% B to 35% B in 8 min; Wave Length: 254/220 nm] to afford 6-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(2-(pyrrolidin-1- yl)propanamido)pyridin-3-yl)pyrazolo[1,5-a]pyrazine-3-carbox amide as an off-white solid (38.7 mg, 19.0 % yield). LCMS (ESI): mass calcd. for C ₂₄ H ₂₇ N ₉ O ₂ , 473.2; m/z found, 474.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.98 (s, 1H), 9.54 (d, J = 1.5 Hz, 1H), 9.31 (d, J = 1.5 Hz, 1H), 8.83 (s, 1H), 8.60 (d, J = 2.4 Hz, 1H), 8.35 (s, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.11 (s, 1H), 3.91 (s, 3H), 3.03 – 3.12 (m, 1H), 2.52 – 2.69 (m, 4H), 2.43 (s, 3H), 1.68 – 1.79 (m, 4H), 1.28 (d, J = 6.8 Hz, 3H). [00766] The following examples were similarly prepared according to the procedure described in Example 48 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art. Example 50 N-(5-(2-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)acetamido)-2 -methylpyridin-3-yl)-6- (1,3-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carb oxamide Step 1. Synthesis of N-(5-(2-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)acetamido)-2 - methylpyridin-3-yl)-6-chloropyrazolo[1,5-a]pyrazine-3-carbox amide [00767] A suspension of 6-chloropyrazolo[1,5-a]pyrazine-3-carboxylic acid (245 mg, 1.24 mmol), N-(5-amino-6-methylpyridin-3-yl)-2-((1R,4S)-2-azabicyclo[2.2 .1]heptan-2- yl)acetamide (325 mg, 1.25 mmol), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (1.04 g, 3.72 mmol) in DCM (20 mL) under nitrogen was treated with 1-methylimidazole (0.59 mL, 7.44 mmol). The resulting gummy mixture was stirred vigorously overnight at rt to yield a less thick uniform dark orange suspension. The reaction was concentrated, the residue was taken up in DMF, filtered, and purified directly in four portions by prep-HPLC (23% - 43% MeCN/10 mM NH ₄ OH) to yield N-(5-(2-((1R,4S)-2- azabicyclo[2.2.1]heptan-2-yl)acetamido)-2-methylpyridin-3-yl )-6-chloropyrazolo[1,5- a]pyrazine-3-carboxamide (395 mg, 72%) as a pale yellow solid. LCMS (ESI): mass calcd. for C ₂₁ H ₂₂ ClN ₇ O ₂ , 439.90; m/z found, 440.2 [M+H] ⁺ . Step 2. Synthesis of N-(5-(2-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)acetamido)-2 - methylpyridin-3-yl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrazolo [1,5-a]pyrazine-3- carboxamide [00768] A mixture of N-(5-(2-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)acetamido)- 2-methylpyridin-3-yl)-6-chloropyrazolo[1,5-a]pyrazine-3-carb oxamide (46 mg, 0.1 mmol), 1,3-dimethyl-1H-pyrazole-4-boronic acid pinacol ester (45 mg, 0.2 mmol), cesium carbonate (114 mg, 0.35 mmol), and 1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II) (9 mg, 0.012 mmol) in 1,4-dioxane (1.6 mL) and water (0.5 mL) under nitrogen in a capped 5 mL microwave vial was sparged with nitrogen for 10 min and heated at 130°C in the microwave for 1 h then stirred with Si-trisamine overnight. Drops of DMF were added to the mixture to solubilize precipitated product, and the mixture was filtered and purified by prep-HPLC (5% - 25% MeCN/water/0.1% TFA). The product fractions were concentrated to a yellow gum, dissolved in DMSO, basified with 10% NH ₄ OH, and further purified by prep-HPLC (20% - 40% MeCN/10 mM NH ₄ OH) to yield N-(5-(2-((1R,4S)-2-azabicyclo[2.2.1]heptan-2- yl)acetamido)-2-methylpyridin-3-yl)-6-(1,3-dimethyl-1H-pyraz ol-4-yl)pyrazolo[1,5- a]pyrazine-3-carboxamide (22 mg, 42%) as a white solid. LCMS (ESI): mass calcd. for C ₂₆ H ₂₉ N ₉ O ₂ , 499.58; m/z found, 500.2 [M+H] ⁺ . ¹ H NMR (METHANOL-d4) δ 9.62 (d, J=1.0 Hz, 1H), 8.82 (d, J=1.5 Hz, 1H), 8.68 (s, 1H), 8.61 (d, J=2.0 Hz, 1H), 8.29 (d, J=2.4 Hz, 1H), 8.08 (s, 1H), 3.89 (s, 3H), 3.32-3.39 (m, 3H), 2.94 (dt, J=9.2, 3.2 Hz, 1H), 2.52 (s, 6H), 2.38-2.45 (m, 2H), 1.74-1.89 (m, 3H), 1.49-1.70 (m, 3H), 1.34-1.44 (m, 2H). [00769] The following examples were similarly prepared according to the procedure described in Example 50 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art. 64 65 66 Example 67 N-(5-(2-(cyclopentylamino)acetamido)-2-methylpyridin-3-yl)-6 -(1-cyclopropyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide Step 1. Synthesis of 2-(cyclopentylamino)-N-(6-methyl-5-nitropyridin-3-yl)acetami de [00770] A mixture of cyclopentanamine (595 mg, 6.988 mmol) and K ₂ CO ₃ (1.45 g, 10.492 mmol) in CH ₃ CN (10 mL) was stirred for 5 min before 2-chloro-N-(6-methyl-5- nitropyridin-3-yl)acetamide (800 mg, 3.484 mmol) was added. The reaction was stirred at room temperature overnight. The mixture was concentrated and purified by silica gel column with MeOH/DCM (0% to 10%) to afford 2-(cyclopentylamino)-N-(6-methyl-5-nitropyridin- 3-yl)acetamide as a brown oil (880 mg, yield 83.8%). LCMS (ESI) calcd. for C ₁₃ H ₁₈ N ₄ O ₃ : 278.1 m/z, found: 279.1 [M+H] ⁺ . Step 2. Synthesis of tert-butyl cyclopentyl(2-((6-methyl-5-nitropyridin-3-yl)amino)-2- oxoethyl)carbamate [00771] A solution of 2-(cyclopentylamino)-N-(6-methyl-5-nitropyridin-3- yl)acetamidee (880 mg, 3.162 mmol), di-tert-butyl dicarbonate (760 mg, 3.482 mmol), and Et ₃ N (959 mg, 9.477 mmol) in DCM (10 mL) was stirred at room temperature overnight. The reaction was diluted with DCM (500 mL), washed with H ₂ O (100 mL×3) and NaCl aq. (100 mL×1). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by silica gel chromatography with ethyl acetate/petroleum ether (0-80%) to afford tert-butyl cyclopentyl(2-((6-methyl-5- nitropyridin-3-yl)amino)-2-oxoethyl)carbamate as a white solid (980 mg, 81.9% yield). LCMS (ESI) calcd. for C ₁₈ H ₂₆ N ₄ O ₅ : 378.2 m/z, found: 379.2 [M+H] ⁺ . Step 3. Synthesis of tert-butyl (2-((5-amino-6-methylpyridin-3-yl)amino)-2- oxoethyl)(cyclopentyl)carbamate [00772] To a solution of tert-butyl cyclopentyl(2-((6-methyl-5-nitropyridin-3- yl)amino)-2-oxoethyl)carbamate (980 mg, 2.590 mmol) in THF (20 mL) was added Pd/C (10%, 98 mg). The resulting mixture was maintained under H ₂ and stirred at 25 °C for 4 hrs. The resulting mixture was filtered and the solution was concentrated to give tert-butyl (2-((5- amino-6-methylpyridin-3-yl)amino)-2-oxoethyl)(cyclopentyl)ca rbamate as a white solid (770 mg, 85.3 yield) which was used for next step without further purification. LCMS (ESI) calcd. for C ₁₈ H ₂₈ N ₄ O ₃ : 348.2 m/z, found 349.2 [M+H] ⁺ . Step 4. Synthesis of tert-butyl cyclopentyl(2-((5-(6-(1-cyclopropyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamido)-6-methylpyridin-3- yl)amino)-2- oxoethyl)carbamate [00773] A mixture of 6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3- carboxylic acid (120 mg, 0.446 mmol), tert-butyl (2-((5-amino-6-methylpyridin-3-yl)amino)- 2-oxoethyl)(cyclopentyl)carbamate (155 mg, 0.445 mmol), TCFH (375 mg, 0.110 mmol), and NMI (220 mg, 2.679 mmol) in CH ₃ CN (6.0 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by C18 column with ACN/H ₂ O (0.05% TFA) (0~50%) to afford tert-butyl cyclopentyl(2-((5-(6-(1- cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carbox amido)-6-methylpyridin-3- yl)amino)-2-oxoethyl)carbamate (250 mg, 93.5% yield) as a brown oil. LCMS (ESI) calcd. for C ₃₁ H ₃₇ N ₉ O ₄ : 599.3 m/z, found: 600.3 [M+H] ⁺ . Step 5. Synthesis of N-(5-(2-(cyclopentylamino)acetamido)-2-methylpyridin-3-yl)-6 -(1- cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carbox amide [00774] A mixture of tert-butyl cyclopentyl(2-((5-(6-(1-cyclopropyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamido)-6-methylpyridin-3- yl)amino)-2- oxoethyl)carbamate (200 mg, 0.334 mmol) and HCl (2M/L in EA, 0.6 mL, 1.2 mmol) in EA (6 mL) was stirred at room temperature for 5 h. The solvent was removed under vacuum and the residue obtained was purified by Prep-HPLC with the following conditions: [Column: XSelect CSH Fluoro Phenyl, 30*150 mm, 5µm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 53% B in 9 min; Wave Length: 254/220 nm] to afford N-(5-(2-(cyclopentylamino)acetamido)-2- methylpyridin-3-yl)-6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazol o[1,5-a]pyrazine-3- carboxamide (27.0 mg, 15.9% yield) as a white solid. LCMS (ESI): mass calcd. for C ₂₆ H ₂₉ N ₉ O ₂ , 499.2; m/z found, 500.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.54 (d, J = 1.5 Hz, 1H), 9.30 (d, J = 1.5 Hz, 1H), 8.83 (s, 1H), 8.57 (d, J = 2.3 Hz, 1H), 8.44 (s, 1H), 8.22 (d, J = 2.4 Hz, 1H), 8.10 (d, J = 0.8 Hz, 1H), 3.79 - 3.85 (m, 1H), 3.29 - 3.32 (m, 2H), 3.00 – 3.09 (m, 1H), 2.43 (s, 4H), 1.60 – 1.77 (m, 4H), 1.40 - 1.56 (m,2H), 1.29 - 1.38 (m, 2H), 1.05 – 1.15 (m, 2H), 0.96 – 1.08 (m, 2H). [00775] The following examples were similarly prepared according to the procedure described in Example 67 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art.

Example 70 N-(5-(3-(2-azabicyclo[2.2.2]octan-2-yl)propanamido)-2-methyl pyridin-3-yl)-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide Step 1. Synthesis of N-(5-acrylamido-2-methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol -4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamide [00776] To a mixture of N-(5-amino-2-methylpyridin-3-yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (140 mg, 0.402 mmol) and Et ₃ N (44 mg, 0.486 mmol) in DCM (5 mL) under N ₂ at 0 °C was added acryloyl chloride (125 mg, 1.235 mmol) dropwise. The reaction was stirred at room temperature overnight. The resulting mixture was concentrated and the residue was purified by silica gel chromatography with MeOH/DCM (0-12%) to afford N-(5-acrylamido-2-methylpyridin-3-yl)-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide as a yellow solid (140 mg 86.5% yield). LCMS (ESI) calcd. for C ₂₀ H ₁₈ N ₈ O ₂ : 402.2 m/z, found: 403.3 [M+H] ⁺ . Step 2. Synthesis of N-(5-(3-(2-azabicyclo[2.2.2]octan-2-yl)propanamido)-2- methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5 -a]pyrazine-3- carboxamide [00777] To a 100 ml flask equipped with a stir bar was added N-(5-acrylamido-2- methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5 -a]pyrazine-3-carboxamide (100 mg, 0.25 mmol), 2-azabicyclo[2.2.2]octane hydrochloride (55 mg, 0.37 mmol), K2CO3 (69 mg, 0.50 mmol) and MeOH (2 mL). The reaction was stirred at 80 °C for 1 h. The mixture was purified by Prep-HPLC [Column: XBridge Prep OBD C18 Column, 19*250 mm, 5µm; Mobile Phase A: Water(10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: MeOH; Flow rate: 25 mL/min; Gradient: 43% B to 57% B in 10 min; Wave Length: 254 nm] to afford the N-(5-(3-(2-azabicyclo[2.2.2]octan-2-yl)propanamido)-2-methyl pyridin-3-yl)-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide as a off-white solid (22.0 mg, 16.4% yield). LCMS (ESI): mass calcd. for C ₂₇ H ₃₁ N ₉ O ₂ , 513.3; m/z found, 514.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 10.01 (s, 1H), 9.54 (d, J = 1.5 Hz, 1H), 9.30 (d, J = 1.5 Hz, 1H), 8.80 – 8.86 (m, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.35 (s, 1H), 8.19 (d, J = 2.3 Hz, 1H), 8.11 (s, 1H), 3.91 (s, 3H), 2.77 (t, J = 7.0 Hz, 2H), 2.69 (d, J = 2.6 Hz, 2H), 2.58 (s, 2H), 2.40 – 2.48 (m, 4H), 1.81 – 1.93 (m, 2H), 1.39 – 1.65 (m, 7H). [00778] The following examples were similarly prepared according to the procedure described in Example 70 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art.

Example 76 (R)-N-(5-(1-isopropylpyrrolidine-2-carboxamido)-2-methylpyri din-3-yl)-6-(1-(2- methoxyethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carb oxamide Step 1. Synthesis of (R)-1-isopropyl-N-(6-methyl-5-nitropyridin-3-yl)pyrrolidine- 2- carboxamide [00779] To a 100 ml flask equipped with a stir bar was added isopropyl-L-proline (250 mg, 0.59 mmol), 6-methyl-5-nitropyridin-3-amine (288 mg, 0.88 mmol), TCFH (1.3 g, 4.63 mmol), NMI (763 mg, 9.29 mmol) and ACN (10 mL). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by C18 column with CH ₃ CN/ water with 0.05% TFA (5%-25%) to afford (R)-1-isopropyl-N- (6-methyl-5-nitropyridin-3-yl)pyrrolidine-2-carboxamide as a yellow oil (400 mg, 76.4% yield). LCMS (ESI) calcd. for C ₁₄ H ₂₀ N ₄ O ₃ , 292.2 m/z, found 293.1 [M+H] ⁺ . Step 2. Synthesis of (R)-N-(5-amino-6-methylpyridin-3-yl)-1-isopropylpyrrolidine- 2- carboxamide [00780] To a 100 ml flask equipped with a stir bar was added (R)-1-isopropyl-N-(6- methyl-5-nitropyridin-3-yl)pyrrolidine-2-carboxamide (380 mg, 1.30 mmol), palladium hydroxide (380 mg) and MeOH (10 mL). The resulting mixture was maintained under hydrogen and stirred at room temperature for 1 h. The reaction mixture was filtered and the solution was concentrated under reduced pressure to afford (R)-N-(5-amino-6-methylpyridin- 3-yl)-1-isopropylpyrrolidine-2-carboxamide as a yellow solid (300 mg, 81.0% yield). LCMS (ESI) calcd. for C ₁₄ H ₂₂ N ₄ O, 262.2 m/z, found 263.1 [M+H] ⁺ . Step 3. Synthesis of (R)-N-(5-(1-isopropylpyrrolidine-2-carboxamido)-2-methylpyri din- 3-yl)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]p yrazine-3-carboxamide [00781] To a 40 mL vial equipped with a stir bar was added 6-(1-(2-methoxyethyl)- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxylic acid (60 mg, 0.21 mmol), (R)-N-(5- amino-6-methylpyridin-3-yl)-1-isopropylpyrrolidine-2-carboxa mide (102 mg, 0.39 mmol), TCFH (234 mg, 0.83 mmol), NMI (102 mg, 1.24 mmol), and ACN (5 mL). The mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated and the residue was purified by C18 column with CH ₃ CN/ water with 0.05% TFA (5%-30%). The resulting product was purified again by Prep-HPLC [Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5µm; Mobile Phase A: Water(10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 21% B to 44% B in 9 min; Wave Length: 220/254 nm] to afford (R)-N-(5-(1-isopropylpyrrolidine-2-carboxamido)-2-methylpyri din-3-yl)-6-(1-(2- methoxyethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carb oxamide as a off-white solid (29.2 mg, 26.0% yield). LCMS (ESI): mass calcd. for C ₂₇ H ₃₃ N ₉ O ₃ , 531.3; m/z found, 532.3 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.96 (s, 1H), 9.55 (d, J = 1.4 Hz, 1H), 9.34 (d, J = 1.5 Hz, 1H), 8.84 (s, 1H), 8.64 (d, J = 2.4 Hz, 1H), 8.37 (s, 1H), 8.26 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 0.7 Hz, 1H), 4.33 (t, J = 5.2 Hz, 2H), 3.74 (t, J = 5.2 Hz, 2H), 3.29 – 3.33 (m, 1H), 3.26 (s, 3H), 3.10 – 3.19 (m, 1H), 2.70 – 2.88 (m, 1H), 2.53 – 2.61 (m, 1H), 2.44 (s, 3H), 2.00 – 2.15 (m, 1H), 1.70 – 1.87 (m, 2H), 1.00 – 1.12 (m, 6H). [00782] The following examples were similarly prepared according to the procedure described in Example 76 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art. Example 78 N-(5-((2S,4R)-1,4-dimethylpyrrolidine-2-carboxamido)-2-methy lpyridin-3-yl)-6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide Step 1. Synthesis of tert-butyl (2S,4R)-4-methyl-2-((6-methyl-5-(6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamido)pyridin-3 - yl)carbamoyl)pyrrolidine-1-carboxylate

[00783] A mixture of (2S,4R)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2- carboxylic acid (200 mg, 0.87 mmol), N-(5-amino-2-methylpyridin-3-yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (455 mg, 1.31 mmol), TCFH (734 mg, 2.62 mmol), and NMI (430 mg, 5.24 mmol) in ACN (10 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue was purified by silica gel column with MeOH/DCM (0%-10%) to give tert-butyl (2S,4R)-4-methyl-2-((6- methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin e-3-carboxamido)pyridin-3- yl)carbamoyl)pyrrolidine-1-carboxylate as a yellow solid (180 mg, 20.2% yield). LCMS (ESI) calcd. for C ₂₈ H ₃₃ N ₉ O ₄ : 559.3 m/z, found 560.2 [M+H] ⁺ . Step 2. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-((2S,4R)-4- methylpyrrolidine-2-carboxamido)pyridin-3-yl)pyrazolo[1,5-a] pyrazine-3-carboxamide [00784] A mixture of tert-butyl (2S,4R)-4-methyl-2-((6-methyl-5-(6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamido)pyridin-3 -yl)carbamoyl)pyrrolidine-1- carboxylate (170 mg, 0.30 mmol) in hydrochloric acid solution (4 M in EA, 10 mL, 40.00 mmol) was stirred at room temperature overnight. The reaction mixture was filtered to give 6-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-((2S,4R)-4-methyl pyrrolidine-2- carboxamido)pyridin-3-yl)pyrazolo[1,5-a]pyrazine-3-carboxami de as a yellow solid (100 mg, 70.0% yield). LCMS (ESI) calcd. for C ₂₃ H ₂₅ N ₉ O ₂ , 459.2 m/z, found 460.2 [M+H] ⁺ . Step 3. Synthesis of N-(5-((2S,4R)-1,4-dimethylpyrrolidine-2-carboxamido)-2- methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5 -a]pyrazine-3- carboxamide

[00785] To a mixture of 6-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-((2S,4R)-4- methylpyrrolidine-2-carboxamido)pyridin-3-yl)pyrazolo[1,5-a] pyrazine-3-carboxamide (90 mg, 0.20 mmol) and DIEA (54 mg, 0.42 mmol) in DMF (5 mL) under nitrogen at 0 °C was added CH ₃ I (34 mg, 0.24 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The residue was first purified by C18 column with CH ₃ CN/ water with 5mM NH ₄ HCO ₃ (5%-50%). The purified product was then purified by Prep-HPLC [Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5µm; Mobile Phase A: Water (10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 16% B to 41% B in 9 min; Wave Length: 254/220 nm] to afford N-(5-((2S,4R)-1,4-dimethylpyrrolidine-2- carboxamido)-2-methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine- 3-carboxamide as a off-white solid (25.7 mg, 27.6% yield). LCMS (ESI): mass calcd. for C24H27N9O2, 473.2; m/z found, 474.3 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6) δ 10.04 (s, 1H), 9.96 (s, 1H), 9.55 (d, J = 1.4 Hz, 1H), 9.31 (d, J = 1.5 Hz, 1H), 8.83 (s, 1H), 8.64 (d, J = 2.4 Hz, 1H), 8.36 (s, 1H), 8.28 (d, J = 2.3 Hz, 1H), 8.12 (d, J = 0.8 Hz, 1H), 3.91 (s, 3H), 3.15 – 3.26 (m, 1H), 2.98 – 3.09 (m, 1H), 2.44 (s, 3H), 2.36 (s, 3H), 2.17 – 2.33 (m, 1H), 1.92 – 2.07 (m, 2H), 1.69 – 1.86 (m, 1H), 0.99 (d, J = 6.6 Hz, 3H). Example 79 (S)-N-(5-(2-(1-(cyclopentylmethyl)pyrrolidin-2-yl)acetamido) -2-methylpyridin-3-yl)-6- (1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxam ide Step 1. Synthesis of tert-butyl (S)-2-(2-((6-methyl-5-nitropyridin-3-yl)amino)-2- oxoethyl)pyrrolidine-1-carboxylate [00786] A mixture of (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (500 mg, 2.18 mmol), 6-methyl-5-nitropyridin-3-amine (400 mg, 2.61 mmol), TCFH (1.8 g, 6.42 mmol), and NMI (1.0 g, 12.18 mmol) in ACN (10 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (0-5% MeOH/DCM) to afford tert-butyl (S)-2-(2-((6-methyl-5-nitropyridin- 3-yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate as a yellow oil (800 mg, 98.3% yield). LCMS (ESI) calcd. for C ₁₇ H ₂₄ N ₄ O ₅ : 364.2 m/z, found 365.1 [M+H] ⁺ . Step 2. Synthesis of (S)-N-(6-methyl-5-nitropyridin-3-yl)-2-(pyrrolidin-2-yl)acet amide [00787] A mixture of tert-butyl (S)-2-(2-((6-methyl-5-nitropyridin-3-yl)amino)-2- oxoethyl)pyrrolidine-1-carboxylate (800 mg, 2.20 mmol) in a solution of HCl in EtOAc (4 M, 20 mL, 80 mmol) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and azeotroped repeatedly with THF to give (S)-N-(6-methyl-5- nitropyridin-3-yl)-2-(pyrrolidin-2-yl)acetamide as a yellow solid (590 mg, 91.4 yield). LCMS (ESI) calcd. for C ₁₂ H ₁₆ N ₄ O ₃ : 264.1 m/z, found 265.0 [M+H] ⁺ . Step 3. Synthesis of (S)-2-(1-(cyclopentylmethyl)pyrrolidin-2-yl)-N-(6-methyl-5- nitropyridin-3-yl)acetamide [00788] A mixture of (S)-N-(6-methyl-5-nitropyridin-3-yl)-2-(pyrrolidin-2- yl)acetamide (300 mg, 1.14 mmol), (bromomethyl)cyclopentane (550 mg, 3.37 mmol), and K ₂ CO ₃ (312 mg, 2.26 mmol) in ACN (10 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (0-8% MeOH/DCM) to afford (S)-2-(1-(cyclopentylmethyl)pyrrolidin-2-yl)- N-(6-methyl-5-nitropyridin-3-yl)acetamide as a yellow solid (160 mg, 35.4% yield). LCMS (ESI) calcd. for C ₁₈ H ₂₆ N ₄ O ₃ : 346.2 m/z, found 347.1 [M+H] ⁺ . Step 4. Synthesis of (S)-N-(5-amino-6-methylpyridin-3-yl)-2-(1- (cyclopentylmethyl)pyrrolidin-2-yl)acetamide [00789] A mixture of (S)-2-(1-(cyclopentylmethyl)pyrrolidin-2-yl)-N-(6-methyl-5- nitropyridin-3-yl)acetamide (160 mg, 0.46 mmol) and Pd/C (160 mg) in THF (10 mL) was stirred at room temperature under hydrogen for 1 h. The reaction mixture was filtered and the solution was concentrated under reduced pressure to afford (S)-N-(5-amino-6- methylpyridin-3-yl)-2-(1-(cyclopentylmethyl)pyrrolidin-2-yl) acetamide as a yellow solid (140 mg, 90.8% yield). LCMS (ESI) calcd. for C ₁₈ H ₂₈ N ₄ O: 316.2 m/z, found 317.2 [M+H] ⁺ . Step 5. Synthesis of N-(5-(2-(1-(cyclopentylmethyl)pyrrolidin-2-yl)acetamido)-2- methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5 -a]pyrazine-3- carboxamide [00790] A mixture of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3- carboxylic acid (70 mg, 0.29 mmol), (S)-N-(5-amino-6-methylpyridin-3-yl)-2-(1- (cyclopentylmethyl)pyrrolidin-2-yl)acetamide (100 mg, 0.32 mmol), TCFH (700 mg, 2.50 mmol), and NMI (700 mg, 8.53 mmol) in ACN (5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was first purified by C18 column with CH ₃ CN/water with 0.05% TFA (5%-30%). The purified product was purified again by Prep-HPLC [Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5µm; Mobile Phase A: water (10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 24% B to 46% B in 8 min; Wave Length: 254/220 nm] to give N-(5-(2-(1- (cyclopentylmethyl)pyrrolidin-2-yl)acetamido)-2-methylpyridi n-3-yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide as a white solid (45.0 mg, 20.1% yield). LCMS (ESI): mass calcd. for C ₂₉ H ₃₅ N ₉ O ₂ , 541.3; m/z found, 542.3 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6) δ 10.43 (s, 1H), 10.03 (s, 1H), 9.54 (d, J = 1.4 Hz, 1H), 9.32 (d, J = 1.5 Hz, 1H), 8.83 (s, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.36 (s, 1H), 8.20 (d, J = 2.3 Hz, 1H), 8.12 (d, J = 0.8 Hz, 1H), 3.91 (s, 3H), 3.07 – 3.20 (m, 1H), 2.54 – 2.82 (m, 3H), 2.43 (s, 3H), 2.26 – 2.40 (m, 1H), 1.80 – 2.20 (m, 4H), 1.62 – 1.77 (m, 4H), 1.38 – 1.60 (m, 5H), 0.99 – 1.35 (m, 2H). [00791] The following examples were similarly prepared according to the procedure described in Example 79 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art. Example 85 N-(5-(1-cycloheptylazetidine-3-carboxamido)-2-methylpyridin- 3-yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide Step 1. Synthesis of tert-butyl 3-((6-methyl-5-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamido)pyridin-3-yl)carbam oyl)azetidine-1- carboxylate [00792] A mixture of N-(5-amino-2-methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamide hydrochloride (129 mg, 0.335 mmol), 1-(tert- butoxycarbonyl)azetidine-3-carboxylic acid (100 mg, 0.497 mmol), and EDCI (110 mg, 0.574 mmol) in pyridine (3 mL) was stirred at room temperature overnight. Additional 1- (tert-butoxycarbonyl)azetidine-3-carboxylic acid (50 mg, 0.249 mmol) and EDCI (55 mg, 0.287 mmol) was added and the reaction was heated at 55 ^o C for 4 h. The reaction mixture was concentrated and diluted with H ₂ O. The resulting mixture was filtered and the solid was washed with CH ₂ Cl ₂ and dried to give tert-butyl 3-((6-methyl-5-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamido)pyridin-3-yl)carbam oyl)azetidine-1-carboxylate. The CH ₂ Cl ₂ washing solution was concentrated and purified with silica gel column (8% MeOH/CH ₂ Cl ₂ with 0.4 NH4OH) to give additional tert-butyl 3-((6-methyl-5-(6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamido)pyridi n-3-yl)carbamoyl)azetidine- 1-carboxylate (140 mg total, yield 78.6%). LCMS (ESI): mass calcd. for C ₂₆ H ₂₉ N ₉ O ₄ , 531.2; m/z found, 532.2 [M+H] ⁺ . Step 2. Synthesis of N-(5-(azetidine-3-carboxamido)-2-methylpyridin-3-yl)-6-(1-me thyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide [00793] A mixture of tert-butyl 3-((6-methyl-5-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamido)pyridin-3-yl)carbam oyl)azetidine-1-carboxylate (140 mg, 0.263 mmol) in TFA (0.6 mL) and CH ₂ Cl ₂ (3 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated. The resulting residue was washed with ether and dried to give N-(5-(azetidine-3-carboxamido)-2-methylpyridin-3-yl)-6-(1-me thyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide trifluoroacetate which was used in next step without further purification. Step 3. Synthesis of N-(5-(1-cycloheptylazetidine-3-carboxamido)-2-methylpyridin- 3- yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-ca rboxamide [00794] A mixture of N-(5-(azetidine-3-carboxamido)-2-methylpyridin-3-yl)-6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide trifluoroacetate (48 mg, 0.088 mmol), cycloheptanone (30 mg, 0.267 mmol), and NaBH(OAc) ₃ (50 mg, 0.236 mmol) in HOAc (0.2 mL) and DCE (2 mL) was stirred at room temperature overnight. Additional NaBH(OAc) ₃ (50 mg, 0.236 mmol) was added and the reaction was heated at 55 ^o C for 30 min. The reaction was cooled to room temperature and quenched with aq. NaHCO ₃ . The resulting mixture was extracted with 10% MeOH/CH ₂ Cl ₂ (5 x). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was purified with silica gel column (12% MeOH/CH ₂ Cl ₂ with 0.6% NH ₄ OH) to give N-(5-(1-cycloheptylazetidine-3-carboxamido)-2- methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5 -a]pyrazine-3-carboxamide (25.1 mg, yield 54.1%). LCMS (ESI): mass calcd. for C ₂₈ H ₃₃ N ₉ O ₂ , 527.3; m/z found, 528.3 [M+H] ⁺ . ¹ H NMR (METHANOL-d4) δ 9.52 (d, J=1.5 Hz, 1H), 8.93 (d, J=1.5 Hz, 1H), 8.64 (s, 1H), 8.52 (d, J=2.4 Hz, 1H), 8.33 (d, J=2.4 Hz, 1H), 8.15 (s, 1H), 8.03 (s, 1H), 3.96 (s, 3H), 3.54-3.63 (m, 2H), 3.36-3.45 (m, 1H), 3.31-3.36 (m, 2H), 2.51 (s, 3H), 2.28-2.37 (m, 1H), 1.66-1.81 (m, 4H), 1.39-1.65 (m, 6H), 1.13-1.31 (m, 2H). [00795] The following examples were similarly prepared according to the procedure described in Example 85 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art.

Example 88 N-(5-(1-cyclohexylazetidine-3-carboxamido)-2-methylpyridin-3 -yl)-6-(pyridin-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamide Step 1. Synthesis of tert-butyl 3-((6-methyl-5-nitropyridin-3-yl)carbamoyl)azetidine-1- carboxylate [00796] To a mixture of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (1.3 g, 6.461 mmol), 6-methyl-5-nitropyridin-3-amine (1.0 g, 6.53 mmol), and HATU (3.8 g, 9.994 mmol) in DMF (10 mL) was added DIEA (3.4 mL, 19.52 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0% to 100% EtOAc/petroleum ether) to afford tert-butyl 3-((6-methyl-5-nitropyridin-3- yl)carbamoyl)azetidine-1-carboxylate as a brown solid (2.1 g, yield 95.6%). LCMS (ESI) calcd. for C ₁₅ H ₂₀ N ₄ O ₅ : 336.1 m/z, found: 337.2 [M+H] ⁺ . Step 2. Synthesis of N-(6-methyl-5-nitropyridin-3-yl)azetidine-3-carboxamide [00797] A mixture of tert-butyl 3-((6-methyl-5-nitropyridin-3- yl)carbamoyl)azetidine-1-carboxylate (2.1 g, 6.244 mmol) and a solution of HCl in EtOAc (2 M, 20 mL, 40 mmol) in EtOAc (6 mL) was stirred at room temperature for 4 h. The reaction mixture was filtered and the solid was collected to give N-(6-methyl-5-nitropyridin-3- yl)azetidine-3-carboxamide as a brown solid (1.4 g, yield 94.9 %). LCMS (ESI) calcd. for C ₁₀ H ₁₂ N ₄ O ₃ : 236.1 m/z, found: 237.1 [M+H] ⁺ . Step 3. Synthesis of 1-cyclohexyl-N-(6-methyl-5-nitropyridin-3-yl)azetidine-3- carboxamide [00798] A mixture of N-(6-methyl-5-nitropyridin-3-yl)azetidine-3-carboxamide (500 mg, 2.216 mmol), cyclohexanone (554 mg, 2.663 mmol), and HOAc (1 drop) in MeOH (1mL) was heated at 60 °C for 1 h. The reaction was then cooled to 0 ℃, and NaCNBH ₃ (554 mg, 2.663 mmol) was added. The reaction was warmed up to room temperature and stirred at for 1 h. After that, the reaction was heated at 50 ℃ for another 1 h. The residue was purified by C18 column with ACN/H ₂ O (0.05% NH ₄ HCO ₃ ) (0~40%) to afford 1- cyclohexyl-N-(6-methyl-5-nitropyridin-3-yl)azetidine-3-carbo xamide (300 mg, 55.6% yield) as a yellow oil. LCMS(ESI) calcd. for C ₁₆ H ₂₂ N ₄ O ₃ : 318.2 m/z, found 319.1 [M+H] ⁺ . Step 4. Synthesis of N-(5-amino-6-methylpyridin-3-yl)-1-cyclohexylazetidine-3- carboxamide [00799] A mixture of 1-cyclohexyl-N-(6-methyl-5-nitropyridin-3-yl)azetidine-3- carboxamide (300 mg, 0.942 mmol) and Pd/C (10%, 30 mg) in THF (20 mL) was maintained under H ₂ and stirred at room temperature for 4 h. The resulting mixture was filtered and the solution was concentrated to give N-(5-amino-6-methylpyridin-3-yl)-1- cyclohexylazetidine-3-carboxamide as a white solid (240 mg, 88.3% yield). LCMS (ESI) calcd. for C ₁₆ H ₂₄ N ₄ O: 288.2 m/z, found 289.1 [M+H] ⁺ . Step 5. Synthesis of N-(5-(1-cyclohexylazetidine-3-carboxamido)-2-methylpyridin-3 -yl)- 6-(pyridin-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide [00800] A mixture of 6-(pyridin-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxylic acid (42 mg, 0.175 mmol), N-(5-amino-6-methylpyridin-3-yl)-1-cyclohexylazetidine-3-car boxamide (50 mg, 0.173 mmol), TCFH (420 mg, 1.497 mmol), NMI (250 mg, 3.045 mmol) in ACN (1.0 mL) was stirred at room temperature overnight. The residue was first purified by C18 column chromatography with ACN/H ₂ O (0.05% NH ₄ HCO ₃ ) (0~60%). The purified product was purified again by Prep-HPLC with the following conditions: [Column: Xselect CSH C18 OBD Column 30*150mm 5µm; Mobile Phase A: H ₂ O (0.05%HCl ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 18% B in 5 min; Wave Length: 254/220 nm] to afford N-(5-(1-cyclohexylazetidine-3-carboxamido)-2-methylpyridin-3 -yl)-6-(pyridin-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (14.6 mg, 16.2% yield) as a yellow solid. LCMS (ESI): mass calcd. for C ₂₈ H ₃₀ N ₈ O ₂ , 510.3; m/z found, 511.3 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6) δ 10.00 (d, J = 1.4 Hz, 1H), 9.70 (d, J = 1.3 Hz, 1H), 9.03 (s, 1H), 8.92 (d, J = 6.1 Hz, 2H), 8.66 – 8.81 (m, 3H), 8.49 (s, 1H), 4.15 - 4.30 (m, 4H), 3.60 – 3.86 (m, 1H), 3.01 - 3.10 (m, 1H), 2.51 - 2.59 (m, 3H), 1.90 (s, 2H), 1.73 (s, 2H), 1.58 (s, 1H), 1.01 - 1.25 (m, 5H). Example 89 6-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(3-(piperidin-1-y l)azetidine-1- carboxamido)pyridin-3-yl)pyrazolo[1,5-a]pyrazine-3-carboxami de [00801] To a mixture of N-(5-amino-2-methylpyridin-3-yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide hydrochloride (50 mg, 0.13 mmol) in DMF (1.5 mL) was added Et ₃ N (0.07 mL, 0.504 mmol) followed by CDI (55 mg, 0.339 mmol). The reaction was stirred at room temperature for 1 h. To the reaction mixture was added 1-(azetidin-3-yl)piperidine dihydrochloride (70 mg, 0.328 mmol) followed by Et ₃ N (0.12 mL, 0.863 mmol). The reaction was stirred at room temperature for 30 min. The reaction was quenched with aq. NaHCO ₃ and extracted with 20% MeOH/CH ₂ Cl ₂ (5 x). The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was washed with 5% MeOH/CH ₂ Cl ₂ (5 mL x 2), and the solid was collected to give 6-(1-methyl-1H-pyrazol-4-yl)- N-(2-methyl-5-(3-(piperidin-1-yl)azetidine-1-carboxamido)pyr idin-3-yl)pyrazolo[1,5- a]pyrazine-3-carboxamide . The washing solution was concentrated and purified with silica gel column (12% MeOH/CH ₂ Cl ₂ with 0.6% NH ₄ OH) to give additional 6-(1-methyl-1H- pyrazol-4-yl)-N-(2-methyl-5-(3-(piperidin-1-yl)azetidine-1-c arboxamido)pyridin-3- yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (30 mg total, yield 44.9%). LCMS (ESI): mass calcd. for C ₂₆ H ₃₀ N ₁₀ O ₂ , 514.3; m/z found, 515.3 [M+H] ⁺ . ¹ H NMR (METHANOL-d4) δ 9.68 (d, J=1.5 Hz, 1H), 8.71 (d, J=1.5 Hz, 1H), 8.59-8.67 (m, 1H), 8.33 (d, J=2.4 Hz, 1H), 8.06-8.10 (m, 1H), 8.03-8.06 (m, 1H), 7.94-8.03 (m, 1H), 4.08-4.13 (m, 2H), 4.00 (s, 3H), 3.93-3.99 (m, 2H), 3.17 (dt, J=12.6, 6.2 Hz, 1H), 2.50 (s, 3H), 2.29-2.41 (m, 4H), 1.58-1.71 (m, 4H), 1.51 (br s, 2H). Example 90 N-(5-(2-(2-azabicyclo[2.2.1]heptan-2-yl)acetamido)-2-methylp yridin-3-yl)-6-(4- carbamoyl-3-fluorophenyl)pyrazolo[1,5-a]pyrazine-3-carboxami de [00802] A mixture of N-(5-(2-(2-azabicyclo[2.2.1]heptan-2-yl)acetamido)-2- methylpyridin-3-yl)-6-(4-cyano-3-fluorophenyl)pyrazolo[1,5-a ]pyrazine-3-carboxamide (Example 46, 100 mg, 0.19 mmol) in H ₂ SO ₄ (2 mL) and TFA (2 mL) was stirred at 60°C for 1 h. The residue was first purified by C18 column with ACN/H ₂ O with 0.05% NH ₄ HCO ₃ (5% - 40%). The purified product was purified again by Prep-HPLC [Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5µm; Mobile Phase A: H ₂ O (10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 16% B to 40% B in 10 min; Wave Length: 254/220 nm] to afford N-(5-(2-(2-azabicyclo[2.2.1]heptan-2- yl)acetamido)-2-methylpyridin-3-yl)-6-(4-carbamoyl-3-fluorop henyl)pyrazolo[1,5- a]pyrazine-3-carboxamide as a light yellow solid (26.4 mg, 24.7% yield). LCMS (ESI): mass calcd. for C ₂₈ H ₂₇ FN ₈ O ₃ , 542.2; m/z found, 543.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6) δ 10.11 (s, 1H), 9.82 (s, 1H), 9.73 (d, J = 1.5 Hz, 1H), 9.65 (d, J = 1.4 Hz, 1H), 8.92 (s, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 2.3 Hz, 1H), 8.05 – 8.16 (m, 2H), 7.73 – 7.86 (m, 2H), 7.70 (s, 1H), 3.17 – 3.28 (m, 3H), 2.78 – 2.89 (m, 1H), 2.43 (s, 3H), 2.32 (s, 1H), 2.24 (d, J = 8.9 Hz, 1H), 1.63 – 1.82 (m, 2H), 1.39 – 1.60 (m, 2H), 1.19 – 1.38 (m, 2H). [00803] The following examples were similarly prepared according to the procedure described in Example 90 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art.

[00804] The following examples were similarly prepared according to the procedure described in Example 49 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art.

Example 104, (S)-N-(5-(2-(1-cyclohexylpyrrolidin-2-yl)acetamido)-2-methyl pyridin-3- yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-ca rboxamide Step 1. Synthesis of tert-butyl (S)-2-(2-((6-methyl-5-nitropyridin-3-yl)amino)-2- oxoethyl)pyrrolidine-1-carboxylate [00805] A mixture of (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (1.1 g, 4.80 mmol), 6-methyl-5-nitropyridin-3-amine (900 mg, 5.88 mmol), TCFH (4.0 g, 14.26 mmol), and NMI (2.3 g, 28.01 mmol) in ACN (10 mL) was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was purified by silica gel chromatography (0-70% EA/PE) to afford tert-butyl (S)-2-(2-((6-methyl-5-nitropyridin-3- yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate as a yellow oil (1.7 g, 84.9% yield). LCMS (ESI): mass calcd. for C ₁₇ H ₂₄ N ₄ O5, 364.2; m/z found 365.0 [M+H] ⁺ . Step 2. Synthesis of (S)-N-(6-methyl-5-nitropyridin-3-yl)-2-(pyrrolidin-2-yl)acet amide [00806] A mixture of tert-butyl (S)-2-(2-((6-methyl-5-nitropyridin-3-yl)amino)-2- oxoethyl)pyrrolidine-1-carboxylate (1.7 g, 4.67 mmol) and HCl (4 M in EA, 20 mL, 80 mmol) was stirred at room temperature overnight to yield a yellow mixture. The mixture was concentrated in vacuo and the resulting residue was suspended in THF and concentrated repeatedly to give (S)-N-(6-methyl-5-nitropyridin-3-yl)-2-(pyrrolidin-2-yl)acet amide as a yellow solid (1.0 g). LCMS (ESI) calcd. for C ₁₂ H ₁₆ N ₄ O ₃ , 264.1; m/z, found 265.1 [M+H] ⁺ . Step 3. Synthesis of (S)-2-(1-cyclohexylpyrrolidin-2-yl)-N-(6-methyl-5-nitropyrid in-3- yl)acetamide [00807] A mixture of (S)-N-(6-methyl-5-nitropyridin-3-yl)-2-(pyrrolidin-2- yl)acetamide (200 mg, 0.76 mmol) and cyclohexanone (223 mg, 2.27 mmol) in MeOH (10 mL) was stirred at room temperature for 0.5 h before the reaction mixture was cooled to 0°C and NaBH ₃ CN (70 mg, 0.11 mmol) was added. The resulting mixture was warmed up to room temperature and stirred for 1 h. The reaction mixture was concentrated and the residue was purified with C18 column with CH ₃ CN/0.05% NH ₄ HCO ₃ water (5%-30%) to afford (S)- 2-(1-cyclohexylpyrrolidin-2-yl)-N-(6-methyl-5-nitropyridin-3 -yl)acetamide as a yellow oil (200 mg). LCMS (ESI): mass calcd. for C ₁₈ H ₂₆ N ₄ O ₃ , 346.22; m/z, found 347.2 [M+H] ⁺ . Step 4. Synthesis of (S)-N-(5-amino-6-methylpyridin-3-yl)-2-(1-cyclohexylpyrrolid in-2- yl)acetamide [00808] A mixture of (S)-2-(1-cyclohexylpyrrolidin-2-yl)-N-(6-methyl-5- nitropyridin-3-yl)acetamide (200 mg, 0.56 mmol) and Pd/C (200 mg) in THF (10 mL) was maintained under hydrogen and stirred at room temperature for 1 h. The reaction mixture was filtered and the solution was concentrated under reduced pressure to afford the crude product which was purified by C18 column with CH ₃ CN/0.05% NH ₄ HCO ₃ water (5%-50%) to afford (S)-N-(5-amino-6-methylpyridin-3-yl)-2-(1-cyclohexylpyrrolid in-2-yl)acetamide as a yellow oil (150 mg). LCMS (ESI): mass calcd. for C ₁₈ H ₂₈ N ₄ O, 316.2; m/z, found 317.2 [M+H] ⁺ . Step 5. Synthesis of (S)-N-(5-(2-(1-cyclohexylpyrrolidin-2-yl)acetamido)-2- methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5 -a]pyrazine-3- carboxamide [00809] A mixture of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3- carboxylic acid (100 mg, 0.41 mmol), (S)-N-(5-amino-6-methylpyridin-3-yl)-2-(1- cyclohexylpyrrolidin-2-yl)acetamide (140 mg, 0.44 mmol), TCFH (1.0 g, 3.56 mmol), and NMI (1.0 g, 12.18 mmol) in ACN (5 mL) was stirred at room temperature overnight to yield a yellow mixture. The reaction mixture was concentrated. The residue was first purified by C18 column with CH ₃ CN/0.05% NH ₄ HCO ₃ water (5%-50%). The purified product was then purified by Prep-HPLC [Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5µm; Mobile Phase A: Water(10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 19% B to 33% B in 10.5 min; Wave Length: 254 nm] to give (S)-N-(5-(2-(1- cyclohexylpyrrolidin-2-yl)acetamido)-2-methylpyridin-3-yl)-6 -(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamide as a light yellow solid (38.3 mg, 17.0% yield). LCMS (ESI): mass calcd. for C ₂₉ H ₃₅ N ₉ O ₂ , 541.3; m/z found, 542.3 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 10.01 (s, 1H), 9.54 (d, J = 1.4 Hz, 1H), 9.31 (d, J = 1.5 Hz, 1H), 8.82 (s, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.35 (s, 1H), 8.18 (d, J = 2.3 Hz, 1H), 8.11 (s, 1H), 3.91 (s, 3H), 3.20 – 3.31 (m, 1H), 2.71 – 2.84 (m, 1H), 2.55 – 2.65 (m, 2H), 2.48 – 2.50 (m, 1H), 2.40 – 2.47 (m, 3H), 2.15 – 2.35 (m, 1H), 1.62 – 1.92 (m, 7H), 1.46 – 1.61 (m, 2H), 0.99 – 1.32 (m, 5H). Example 105, N-(5-(2-(3,3-dimethylazetidin-1-yl)acetamido)-2-methylphenyl )-6-(1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide Step 1. Synthesis of ethyl 6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxylate [00810] To a solution of ethyl 6-chloropyrazolo[1,5-a]pyrazine-3-carboxylate (1.6 g, 7.09 mmol) in DME (30 mL) and H ₂ O (8 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (2.6 g, 8.86 mmol), Na ₂ CO ₃ (2.3 g, 21.27 mmol), and Pd(dppf)Cl ₂ (290 mg, 0.36 mmol). The resulting mixture was maintained under nitrogen and stirred at 90 °C overnight. The reaction was cooled to room temperature and diluted with water. The resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-10% MeOH/DCM) to afford ethyl 6-(1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxylate as a yellow solid (1.3 g, 71.3% yield). LCMS (ESI): mass calcd. for C ₁₂ H ₁₁ N ₅ O ₂ , 257.1; found, 258.3 [M+H] ⁺ . Step2. Synthesis of 6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxylic acid [00811] A mixture of ethyl 6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3- carboxylate (1.15 g, 4.470 mmol) and LiOH (3 M in H2O, 1 mL, 3 mmol) in THF (18 mL) and EtOH (6 mL) was stirred at room temperature overnight. The organic solvent was removed under vacuum and the residue was dissolved in H ₂ O. The pH value was adjusted to 6 with HCl (2M) and a yellow participate formed. The participate was collected by filtration to give 6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxylic acid as a yellow solid (730 mg ,yield 71.2 %). LCMS (ESI): calcd. for C ₁₀ H ₇ N ₅ O ₂ , 229.1; m/z, found: 230.1 [M+H] ⁺ . Step 3. Synthesis of N-(5-(2-(3,3-dimethylazetidin-1-yl)acetamido)-2-methylphenyl )-6- (1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide [00812] A mixture of 6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxylic acid (200 mg, 0.873 mmol), N-(3-amino-4-methylphenyl)-2-(3,3-dimethylazetidin-1-yl)acet amide (220 mg, 0.889 mmol), TCFH (1.2 g, 4.277 mmol), and NMI (570 mg, 6.942 mmol) in ACN (10 mL) was stirred at room temperature overnight to yield a yellow mixture. The reaction mixture was concentrated and the resulting residue was stirred in H ₂ O (~30ml). The resulting mixture was filtered and the solid was washed again with H ₂ O. The resulting solid was collected and washed with 20%MeOH/CH ₂ Cl ₂ and filtered (2x). The solution was concentrated and the crude product was purified by Prep-HPLC [Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5µm; Mobile Phase A: Water(10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 21% B to 43% B in 10 min; Wave Length: 254/220 nm] to afford N-(5-(2-(3,3-dimethylazetidin-1-yl)acetamido)-2- methylphenyl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-c arboxamide as a light yellow solid (57.5 mg, 14% yield). LCMS (ESI): mass calcd. for C ₂₉ H ₃₅ N ₉ O ₂ , 541.3; m/z found, 542.3 [M+H]+. ¹ H NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 10.01 (s, 1H), 9.54 (d, J = 1.4 Hz, 1H), 9.31 (d, J = 1.5 Hz, 1H), 8.82 (s, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.35 (s, 1H), 8.18 (d, J = 2.3 Hz, 1H), 8.11 (s, 1H), 3.91 (s, 3H), 3.20 – 3.31 (m, 1H), 2.71 – 2.84 (m, 1H), 2.55 – 2.65 (m, 2H), 2.48 – 2.50 (m, 1H), 2.40 – 2.47 (m, 3H), 2.15 – 2.35 (m, 1H), 1.62 – 1.92 (m, 7H), 1.46 – 1.61 (m, 2H), 0.99 – 1.32 (m, 5H). Example 106, N-(5-(3-((2,2-dimethylpyrrolidin-1-yl)methyl)azetidine-1-car boxamido)-2- methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5 -a]pyrazine-3- carboxamide Step 1. Synthesis of N-(5-(3-(hydroxymethyl)azetidine-1-carboxamido)-2- methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5 -a]pyrazine-3- carboxamide [00813] To a mixture of N-(5-amino-2-methylpyridin-3-yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (100 mg, 0.26 mmol) in DMF (3 mL) was added Et ₃ N (0.14 mL, 1.007 mmol) followed by CDI (110 mg, 0.678 mmol). The reaction was stirred at room temperature for 1 hour before additional Et ₃ N (0.15 mL, 1.079 mmol) was added followed by azetidin-3-ylmethanol (85 mg, 0.688 mmol). The reaction was stirred at room temperature for another 1 hour. The reaction mixture was diluted with H ₂ O and filtered. The solid was washed with CH ₂ Cl ₂ (5 mL x 2) and dried to give N-(5-(3- (hydroxymethyl)azetidine-1-carboxamido)-2-methylpyridin-3-yl )-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (95 mg, yield 79%). LCMS (ESI): mass calcd. for C ₂₂ H ₂₃ N ₉ O ₃ , 461.2; m/z found, 462.1 [M+H] ⁺ . Step 2. (1-((6-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] pyrazine-3- carboxamido)pyridin-3-yl)carbamoyl)azetidin-3-yl)methyl 4-methylbenzenesulfonate [00814] To N-(5-(3-(hydroxymethyl)azetidine-1-carboxamido)-2-methylpyri din-3- yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-ca rboxamide (67 mg, 0.145 mmol) in pyridine (3 mL) was added 4-methylbenzenesulfonyl chloride (80 mg, 0.42 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated and the resulting residue was suspended in aq. NaHCO ₃ and filtered. The solid was collected and purified with silica gel column (8-9%MeOH/CH ₂ Cl ₂ ) to give (1-((6- methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin e-3-carboxamido)pyridin-3- yl)carbamoyl)azetidin-3-yl)methyl 4-methylbenzenesulfonate (46 mg, yield 51%). LCMS (ESI): mass calcd. for C ₂₉ H ₂₉ N ₉ O ₅ S, 615.2; m/z found, 616.2 [M+H] ⁺ . Step 3. Synthesis of N-(5-(3-((2,2-dimethylpyrrolidin-1-yl)methyl)azetidine-1- carboxamido)-2-methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrazine-3-carboxamide [00815] A mixture of (1-((6-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazine-3-carboxamido)pyridin-3-yl)carbamoyl)azetidin-3-y l)methyl 4- methylbenzenesulfonate (46 mg, 0.0747 mmol), 2,2-dimethylpyrrolidine (25 mg, 0.252 mmol), Cs ₂ CO ₃ (50 mg, 0.153 mmol), and KI (15 mg, 0.0904 mmol) in ACN (2 mL) was heated at 75 ^o C for 7 hours. The reaction was diluted with 10%MeOH/CH ₂ Cl ₂ and filtered. The solution was concentrated and the residue was suspended in 1N HCl (5 mL) and washed with EtOAc (2x). The remaining aqueous layer was basified with aq. NaHCO ₃ and filtered. The solid was collected and purified with silica gel column (14%MeOH/CH ₂ Cl ₂ with 0.7%NH ₄ OH) to give N-(5-(3-((2,2-dimethylpyrrolidin-1-yl)methyl)azetidine-1- carboxamido)-2-methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine- 3-carboxamide (5 mg, yield 12%). LCMS (ESI): mass calcd. for C ₂₈ H ₃₄ N ₁₀ O ₂ , 542.3; m/z found, 543.3 [M+H] ⁺ . ¹ H NMR (METHANOL-d4) δ: 9.58 (d, J=1.5 Hz, 1H), 9.00 (d, J=1.5 Hz, 1H), 8.67 (s, 1H), 8.47 (d, J=2.4 Hz, 1H), 8.21 (s, 1H), 8.16 (d, J=2.4 Hz, 1H), 8.01-8.14 (m, 1H), 4.17-4.24 (m, 2H), 3.98 (s, 3H), 3.74-3.81 (m, 2H), 2.74-3.01 (m, 5H), 2.48-2.52 (m, 3H), 1.81-1.92 (m, 2H), 1.71-1.80 (m, 2H), 1.12 (s, 6H). Example 107, (S)-6-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(2-(1-propylp yrrolidin-2- yl)acetamido)pyridin-3-yl)pyrazolo[1,5-a]pyrazine-3-carboxam ide Step 1. Synthesis of tert-butyl (S)-2-(2-((5-amino-6-methylpyridin-3-yl)amino)-2- oxoethyl)pyrrolidine-1-carboxylate [00816] A mixture of tert-butyl (S)-2-(2-((6-methyl-5-nitropyridin-3-yl)amino)-2- oxoethyl)pyrrolidine-1-carboxylate (1.6 g, 4.39 mmol) and palladium hydroxide (20%, 1.6 g, 2.28 mmol) in THF (20 mL) was maintained under hydrogen and stirred at room temperature for 1 hour. The reaction mixture was filtered and the solution was concentrated under reduced pressure to give tert-butyl (S)-2-(2-((5-amino-6-methylpyridin-3-yl)amino)-2- oxoethyl)pyrrolidine-1-carboxylate as a white solid (1.45 g). LCMS (ESI): mass calcd. for C ₁₇ H ₂₆ N ₄ O ₃ , 334.2 m/z, found 335.1 [M+H] ⁺ . Step 2. Synthesis of tert-butyl (S)-2-(2-((6-methyl-5-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamido)pyridin-3-yl)amino) -2-oxoethyl)pyrrolidine- [00817] A mixture of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3- carboxylic acid (1.0 g, 4.11 mmol), tert-butyl (S)-2-(2-((5-amino-6-methylpyridin-3- yl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate (1.4 g, 4.19 mmol), TCFH (5.7 g, 20.32 mmol), and NMI (2.7 g, 32.89 mmol) in DCM (15 mL) was stirred at room temperature overnight to yield a yellow mixture. The reaction was quenched with H ₂ O (50 mL) and the resulting mixture was extracted with DCM (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-10% MeOH/DCM) to give tert-butyl (S)-2-(2-((6-methyl-5-(6- (1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxam ido)pyridin-3-yl)amino)-2- oxoethyl)pyrrolidine-1-carboxylate as a yellow solid (1.5 g). LCMS (ESI): mass calcd. for C ₂₈ H ₃₃ N ₉ O ₄ , 559.3; m/z, found 560.3 [M+H] ⁺ . Step 3. Synthesis of (S)-6-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(2-(pyrrolidi n-2- yl)acetamido)pyridin-3-yl)pyrazolo[1,5-a]pyrazine-3-carboxam ide [00818] A mixture of tert-butyl (S)-2-(2-((6-methyl-5-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamido)pyridin-3-yl)amino) -2-oxoethyl)pyrrolidine-1- carboxylate (1.5 g, 2.680 mmol) and hydrochloric acid (4 M in EA, 30 mL, 120 mmol) was stirred at room temperature overnight to yield a yellow mixture. The reaction mixture was concentrated in vacuo and the residue was diluted with THF and concentrated repeatedly to give (S)-6-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(2-(pyrrolidi n-2-yl)acetamido)pyridin- 3-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide as a yellow solid (1.2 g). LCMS (ESI): mass calcd. for C ₂₃ H ₂₅ N ₉ O ₂ , 459.2; m/z, found 460.2 [M+H] ⁺ . Step 4. Synthesis of (S)-6-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(2-(1- propylpyrrolidin-2-yl)acetamido)pyridin-3-yl)pyrazolo[1,5-a] pyrazine-3-carboxamide [00819] A mixture of (S)-6-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(2- (pyrrolidin-2-yl)acetamido)pyridin-3-yl)pyrazolo[1,5-a]pyraz ine-3-carboxamide (150 mg, 0.326 mmol), propionaldehyde (60 mg, 1.033 mmol), and AcOH (1 drop) in MeOH (5 mL) was maintained at room temperature for 0.5 h. The reaction mixture was cooled to 0°C and NaBH ₃ CN (45 mg, 0.716 mmol) was added. The resulting mixture was warmed up to room temperature and stirred for 1 hour. The reaction was quenched with H ₂ O (10 mL). The mixture was concentrated under reduced pressure to afford the crude product which was purified by Prep-HPLC [Column: YMC-Actus Triart C18, 30*150 mm, 5µm; Mobile Phase A: Water(10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17% B to 43% B in 12 min; Wave Length: 254/220 nm] to afford (S)-6-(1-methyl-1H- pyrazol-4-yl)-N-(2-methyl-5-(2-(1-propylpyrrolidin-2-yl)acet amido)pyridin-3- yl)pyrazolo[1,5-a]pyrazine-3-carboxamide as a white solid (32.2 mg). LCMS (ESI): mass calcd. For C ₂₆ H ₃₁ N ₉ O ₂ , 501.3; m/z found, 502.3 [M+H]+. ¹ H NMR (300 MHz, DMSO-d6) δ 10.36 (s, 1H), 10.03 (s, 1H), 9.54 (d, J = 1.5 Hz, 1H), 9.31 (d, J = 1.5 Hz, 1H), 8.83 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.35 (s, 1H), 8.19 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 0.8 Hz, 1H), 3.91 (s, 3H), 3.00 – 3.12 (m, 1H), 2.65 – 2.80 (m, 2H), 2.58 (dd, J = 14.1, 4.5 Hz, 1H), 2.43 (s, 3H), 2.22 – 2.39 (m, 1H), 2.05 – 2.19 (m, 2H), 1.84 – 2.00 (m, 1H), 1.62 – 1.78 (m, 2H), 1.34 – 1.59 (m, 3H), 0.86 (t, J = 7.3 Hz, 3H). [00820] The following examples were similarly prepared according to the procedure described in Example 107 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art.

Example 136, N-(5-(1-(3,3-dimethylbutan-2-yl)azetidine-3-carboxamido)-2- methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5 -a]pyrazine-3- carboxamide Step 1. Synthesis of tert-butyl 3-((6-methyl-5-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamido)pyridin-3-yl)carbam oyl)azetidine-1- carboxylate [00821] A mixture of N-(5-amino-2-methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamide hydrochloride (128.917 mg, 0.335 mmol), 1-(tert- butoxycarbonyl)azetidine-3-carboxylic acid (100 mg, 0.497 mmol), and EDCI (110 mg, 0.574 mmol) in pyridine (4 mL) was heated at 60 ^o C for 4 hours. Additional 1-(tert- butoxycarbonyl)azetidine-3-carboxylic acid (50 mg, 0.249 mmol) and EDCI (55 mg, 0.287 mmol) was added. The reaction was heated at 60 ^o C for another 2.5 hours. The reaction mixture was concentrated. The residue was stirred in H ₂ O (~50 mL) for 5 min and the resulting mixture was filtered. The solid was collected and washed with CH ₂ Cl ₂ (~5 mL). The remaining solid was purified with silica gel column (8%MeOH/CH ₂ Cl ₂ with 0.4% NH ₄ OH) to give tert-butyl 3-((6-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazine-3-carboxamido)pyridin-3-yl)carbamoyl)azetidine-1- carboxylate (153 mg). LCMS (ESI): mass calcd. for C ₂₆ H ₂₉ N ₉ O ₄ , 531.2; m/z found, 532.2 [M+H] ⁺ . Step 2. Synthesis of N-(5-(azetidine-3-carboxamido)-2-methylpyridin-3-yl)-6-(1-me thyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide [00822] A mixture of tert-butyl 3-((6-methyl-5-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamido)pyridin-3-yl)carbam oyl)azetidine-1-carboxylate (153 mg, 0.288 mmol) in TFA (0.6 mL, 7.84 mmol) and DCM (3 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was washed with diethyl ether. The remaining solid was dried to give N-(5-(azetidine-3-carboxamido)-2- methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5 -a]pyrazine-3-carboxamide trifluoroacetate which will be used in next step without further purification. LCMS (ESI): mass calcd. for C ₂₁ H ₂₁ N ₉ O ₂ , 431.2; m/z found, 432.2 [M+H] ⁺ . Step 3. Synthesis of N-(5-(1-(3,3-dimethylbutan-2-yl)azetidine-3-carboxamido)-2- methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5 -a]pyrazine-3- carboxamide [00823] A solution of N-(5-(azetidine-3-carboxamido)-2-methylpyridin-3-yl)-6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide trifluoroacetate (0.096 mmol), 3,3-dimethylbutan-2-one (0.1 mL, 0.8 mmol), and Et ₃ N (0.04 mL, 0.288 mmol) in MeOH (2 mL) was stirred at room temperature for 30 min before NaCNBH ₃ (25 mg, 0.398 mmol) was added. The reaction was stirred at 60 ^o C for 6 hours. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was suspended in H ₂ O and filtered. The solid was collected and purified by silica gel column chromatography (10%MeOH/CH ₂ Cl ₂ with 0.5% NH ₄ OH) to give N-(5-(1-(3,3-dimethylbutan-2-yl)azetidine- 3-carboxamido)-2-methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5- a]pyrazine-3-carboxamide (30 mg). LCMS (ESI): mass calcd. for C ₂₇ H ₃₃ N ₉ O ₂ , 515.3; m/z found, 516.1 [M+H]+. ¹ H NMR (METHANOL-d4) δ: 9.58 (d, J=1.5 Hz, 1H), 9.00 (d, J=1.0 Hz, 1H), 8.68 (s, 1H), 8.57 (d, J=2.4 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 8.21 (s, 1H), 8.07 (s, 1H), 3.98 (s, 3H), 3.68-3.75 (m, 1H), 3.55-3.60 (m, 1H), 3.47-3.53 (m, 2H), 3.38-3.46 (m, 1H), 2.53 (s, 3H), 2.18-2.26 (m, 1H), 0.90-0.97 (m, 12H). Example 137, (R*)-N-(5-(1-(3,3-dimethylbutan-2-yl)azetidine-3-carboxamido )-2- methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5 -a]pyrazine-3- carboxamide Example 138, (S*)-N-(5-(1-(3,3-dimethylbutan-2-yl)azetidine-3-carboxamido )-2- methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5 -a]pyrazine-3- carboxamide [00824] N-(5-(1-(3,3-dimethylbutan-2-yl)azetidine-3-carboxamido)-2- methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5 -a]pyrazine-3-carboxamide was separated by Prep-Chiral-HPLC [Column: CHIRALPAK IA, 5*25 cm, 5 µm; Mobile Phase A: Hex: DCM=3: 1 (0.5% 2M NH ₃ -MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 31 min; Wave Length: 220/254 nm; Sample Solvent: EtOH; Injection Volume: 1 mL] to give (R*)-N-(5-(1-(3,3-dimethylbutan-2-yl)azetidine-3- carboxamido)-2-methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine- 3-carboxamide as light yellow solid (23.5 mg), [LCMS (ESI): mass calcd. for C27H33N9O2, 515.3; m/z found, 516.3 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6) d 10.31 – 10.35 (m, 1H), 9.85 (s, 1H), 9.45 – 9.50 (m, 1H), 9.22 (d, J = 1.5 Hz, 1H), 8.81 (s, 1H), 8.55 – 8.59 (m, 1H), 8.30 (s, 1H), 8.20 – 8.25 (m, 1H), 8.07 (d, J = 0.7 Hz, 1H), 4.19 – 4.59 (m, 4H), 3.91 (s, 3H), 3.73 – 3.82 (m, 1H), 3.18 – 3.26 (m, 1H), 2.45 – 2.50 (m, 3H), 1.22 – 1.26 (m, 3H), 0.95 – 0.99 (m, 9H)], followed by (S*)-N-(5-(1-(3,3-dimethylbutan-2-yl)azetidine-3-carboxamido )- 2-methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazine-3-carboxamide as white solid (21.9 mg), [LCMS (ESI): mass calcd. for C ₂₇ H ₃₃ N ₉ O ₂ , 515.3; m/z found, 516.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.98 – 10.28 (m, 1H), 9.81 – 9.88 (m, 1H), 9.51 – 9.56 (m, 1H), 9.18 – 9.24 (m, 1H), 8.76 – 8.83 (m, 1H), 8.49 – 8.60 (m, 1H), 8.30 (s, 1H), 8.12 – 8.24 (m, 1H), 8.07 (s, 1H), 4.23 – 4.51 (m, 1H), 3.92 – 3.96 (m, 3H), 3.16 – 3.82 (m, 3H), 2.91 – 3.09 (m, 2H), 2.46 (d, J = 2.0 Hz, 3H), 1.17 – 1.22 (m, 1H), 1.02 – 1.09 (m, 2H), 0.84 – 0.99 (m, 9H)]. Example 139, N-(5-((2-(2,2-dimethylpyrrolidin-1-yl)ethyl)carbamoyl)-2-met hylpyridin- 3-yl)-6-(pyridin-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide Step 1. Synthesis of ethyl 6-methyl-5-(6-(pyridin-4-yl)pyrazolo[1,5-a]pyrazine-3- carboxamido)nicotinate [00825] A mixture of 6-(pyridin-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxylic acid (200 mg, 0.833 mmol), ethyl 5-amino-6-methylnicotinate (165 mg, 0.916 mmol), TCFH (2 g, 7.128 mmol), and NMI (1.2 mL, 15.054 mmol) in CH ₃ CN (4.0 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by C18 column with CH ₃ CN/H ₂ O (0.05% NH ₄ HCO ₃ ) from 0~60% to afford ethyl 6-methyl- 5-(6-(pyridin-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamido)nic otinate as a yellow solid (200 mg). LCMS (ESI): mass calcd. for C ₂₁ H ₁₈ N ₆ O ₃ , 402.4, m/z, found, 403.2 [M+H] ⁺ . Step 2. Synthesis of 6-methyl-5-(6-(pyridin-4-yl)pyrazolo[1,5-a]pyrazine-3- carboxamido)nicotinic acid [00826] A mixture of ethyl 6-methyl-5-(6-(pyridin-4-yl)pyrazolo[1,5-a]pyrazine-3- carboxamido)nicotinate (200 mg, 0.497 mmol) and LiOH (3 M in H ₂ O, 0.5 mL, 1.5 mmol) in THF (4 mL) and EtOH (1 mL) was stirred at room temperature overnight. The organic solvent was removed under vacuum and the residue was dissolved in H ₂ O. The pH value was adjusted to 6 with HCl (2M) and a yellow participate formed. The participate was collected by filtration to give 6-methyl-5-(6-(pyridin-4-yl)pyrazolo[1,5-a]pyrazine-3- carboxamido)nicotinic acid as a yellow solid (120 mg). LCMS (ESI): mass calcd. for C ₁₉ H ₁₄ N ₆ O ₃ , 374.1, m/z, found: 375.1 [M+H] ⁺ . Step 3. Synthesis of N-(5-((2-(2,2-dimethylpyrrolidin-1-yl)ethyl)carbamoyl)-2- methylpyridin-3-yl)-6-(pyridin-4-yl)pyrazolo[1,5-a]pyrazine- 3-carboxamide [00827] A mixture of 6-methyl-5-(6-(pyridin-4-yl)pyrazolo[1,5-a]pyrazine-3- carboxamido)nicotinic acid (120 mg, 0.321 mmol), 2-(2,2-dimethylpyrrolidin-1-yl)ethan-1- amine (90 mg, 0.633 mmol), TCFH (360 mg, 1.283 mmol), and NMI (0.2 mL, 2.509 mmol) in CH ₃ CN (1.0 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by Prep-TLC (PE/EA=5:1). The product obtained was purified again by Prep-HPLC: [Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5µm; Mobile Phase A: Water(10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 11% B to 35% B in 8 min; Wave Length: 254/220 nm] to afford N-(5- ((2-(2,2-dimethylpyrrolidin-1-yl)ethyl)carbamoyl)-2-methylpy ridin-3-yl)-6-(pyridin-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (6.0 mg) as a white solid. LCMS (ESI): mass calcd. For C ₂₇ H ₃₀ N ₈ O ₂ , 498.2; m/z found, 499.3 [M+H]+. ¹ H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.85 (d, J = 1.6 Hz, 1H), 9.70 (d, J = 1.5 Hz, 1H), 8.97 (d, J = 1.8 Hz, 1H), 8.81 (d, J = 2.1 Hz, 1H), 8.70 – 8.77 (m, 2H), 8.62 (s, 1H), 8.27 (d, J = 2.1 Hz, 1H), 8.16 – 8.22 (m, 2H), 3.29 - 3.31 (m, 2H), 2.77 (t, J = 7.2 Hz, 2H), 2.57 (d, J = 1.7 Hz, 3H), 2.47 - 2.48 (m, 2H), 1.63 - 1.78 (m, 2H), 1.51 – 1.59 (m, 2H), 0.93 (d, J = 1.7 Hz, 6H). The following example was similarly prepared according to the procedure described in Example 139 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art.

Example 141, N-(5-((2-(2,2-dimethylpyrrolidin-1-yl)ethyl)carbamoyl)-2-flu orophenyl)-6- (1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxam ide Step 1. Synthesis of N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-4-fluoro-3-nitroben zamide [00828] A mixture of 4-fluoro-3-nitrobenzoic acid (150 mg, 0.810 mmol), 2-(2,2- dimethylpyrrolidin-1-yl)ethan-1-amine (120 mg, 0.844 mmol), HATU (464 mg, 1.220 mmol), and DIEA (315 mg, 2.437 mmol) in DMF (4 mL) was stirred at room temperature overnight to yield a yellow mixture. The reaction was quenched with H ₂ O (10 mL). The resulting mixture was extracted with EA (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (MeOH/DCM = 0%-10%) to afford N-(2-(2,2- dimethylpyrrolidin-1-yl)ethyl)-4-fluoro-3-nitrobenzamide as a yellow oil (160 mg). LCMS (ESI): mass calcd. for C ₁₅ H ₂₀ FN ₃ O ₃ , 309.2, m/z, found 310.2 [M+H] ⁺ . Step 2. Synthesis of 3-amino-N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-4- fluorobenzamide [00829] A mixture of N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-4-fluoro-3- nitrobenzamide (160 mg, 0.517 mmol), palladium hydroxide (20%, 160 mg, 0.228 mmol) in THF (10 mL) was maintained under hydrogen and stirred at room temperature for 1 hour. The reaction mixture was filtered and the solution was concentrated under reduced pressure to afford 3-amino-N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-4-fluoroben zamide as a yellow oil (160 mg). LCMS (ESI): mass calcd. for C ₁₅ H ₂₂ FN ₃ O, 279.2, m/z, found 280.2 [M+H] ⁺ . Step 3. Synthesis of N-(5-((2-(2,2-dimethylpyrrolidin-1-yl)ethyl)carbamoyl)-2- fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyr azine-3-carboxamide [00830] A mixture of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3- carboxylic acid (100 mg, 0.411 mmol), 3-amino-N-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-4- fluorobenzamide (125 mg, 0.447 mmol), TCFH (578 mg, 2.060 mmol), and NMI (270 mg, 3.289 mmol) in ACN (5 mL) was stirred at room temperature overnight to yield a yellow mixture. The reaction was concentrated and the residue was first purified by C18 column chromatography (CH ₃ CN/0.05% NH ₄ HCO ₃ water = 5%-50%). The product obtained was then purified by Prep-HPLC [Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5µm; Mobile Phase A: Water(10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 16% B to 39% B in 10 min; Wave Length: 254/220 nm] to afford N-(5- ((2-(2,2-dimethylpyrrolidin-1-yl)ethyl)carbamoyl)-2-fluoroph enyl)-6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide as a light yellow solid (16.9 mg). LCMS (ESI): mass calcd. for C ₂₆ H ₂₉ FN ₈ O ₂ , 504.2; m/z found 505.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d6) δ 10.26 (s, 1H), 9.56 (d, J = 1.5 Hz, 1H), 9.32 (d, J = 1.5 Hz, 1H), 8.87 (s, 1H), 8.47 (t, J = 5.7 Hz, 1H), 8.36 (s, 1H), 8.20 (dd, J = 7.5, 2.2 Hz, 1H), 8.13 (d, J = 0.8 Hz, 1H), 7.72 – 7.82 (m, 1H), 7.38 – 7.49 (m, 1H), 3.92 (s, 3H), 3.23 – 3.33 (m, 2H), 2.77 (t, J = 7.1 Hz, 2H), 2.52 – 2.61 (m, 2H), 1.63 – 1.78 (m, 2H), 1.51 – 1.61 (m, 2H), 0.94 (s, 6H). [00831] The following examples were similarly prepared according to the procedure described in Example 141 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art.

Example 146, 6-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)-N-(2-methyl -5-(2- (piperidin-1-yl)acetamido)pyridin-3-yl)pyrazolo[1,5-a]pyrazi ne-3-carboxamide Step 1. Synthesis of 2-fluoro-4-(3-((2-methyl-5-(2-(piperidin-1-yl)acetamido)pyri din-3- yl)carbamoyl)pyrazolo[1,5-a]pyrazin-6-yl)benzoic acid [00832] A mixture of 6-(4-cyano-3-fluorophenyl)-N-(2-methyl-5-(2-(piperidin-1- yl)acetamido)pyridin-3-yl)pyrazolo[1,5-a]pyrazine-3-carboxam ide (200 mg, 0.390 mmol) and KOH (10% in H ₂ O, 5 mL) in ethanol (5 mL) was stirred at 90 °C for 1 hour. The pH value of the reaction mixture was adjusted to 5~7 by the addition of HCl solution (1 M in H ₂ O). The organic layer was concentrated to afford 2-fluoro-4-(3-((2-methyl-5-(2-(piperidin- 1-yl)acetamido)pyridin-3-yl)carbamoyl)pyrazolo[1,5-a]pyrazin -6-yl)benzoic acid (100 mg). LCMS (ESI): mass calcd. for C ₂₇ H ₂₆ FN ₇ O ₄ , 531.2, m/z, found 532.2 [M+H] ⁺ . Step 2. Synthesis of 6-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)-N-(2-methyl -5- (2-(piperidin-1-yl)acetamido)pyridin-3-yl)pyrazolo[1,5-a]pyr azine-3-carboxamide [00833] A mixture of 2-fluoro-4-(3-((2-methyl-5-(2-(piperidin-1- yl)acetamido)pyridin-3-yl)carbamoyl)pyrazolo[1,5-a]pyrazin-6 -yl)benzoic acid (90 mg, 0.169 mmol), 2-methoxyethan-1-amine (27 mg, 0.359 mmol), TCFH (243 mg, 0.866 mmol), and NMI (117 mg, 1.425 mmol) in ACN (4 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was first purified by C18 column with CH ₃ CN/0.05% TFA water (5%-50%). The product obtained was then purified by Prep- HPLC [Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5µm; Mobile Phase A: Water(10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 28% B to 42% B in 10 min; Wave Length: 254/220 nm] to afford 6-(3-fluoro-4-((2- methoxyethyl)carbamoyl)phenyl)-N-(2-methyl-5-(2-(piperidin-1 -yl)acetamido)pyridin-3- yl)pyrazolo[1,5-a]pyrazine-3-carboxamide as a white solid (30.7 mg). LCMS (ESI): mass calcd. for C ₃₀ H ₃₃ FN ₈ O ₄ , 588.3; m/z found, 589.3 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6) δ 10.13 (s, 1H), 9.93 (s, 1H), 9.76 (d, J = 1.5 Hz, 1H), 9.67 (d, J = 1.4 Hz, 1H), 8.94 (s, 1H), 8.61 (d, J = 2.3 Hz, 1H), 8.37 – 8.44 (m, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.07 – 8.19 (m, 2H), 7.77 (t, J = 8.0 Hz, 1H), 3.42 – 3.54 (m, 4H), 3.30 (s, 3H), 3.11 (s, 2H), 2.42 – 2.50 (m, 7H), 1.53 – 1.65 (m, 4H), 1.35 – 1.47 (m, 2H). ¹⁹ F NMR (282 MHz, DMSO-d6) d -113.36. [00834] The following examples were similarly prepared according to the procedure described in Example 146 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art.

[00835] The following examples were similarly prepared according to the procedure described in Example 50 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art.

Example 158. N-(5-(2-((1S,4R)-2-azabicyclo[2.2.1]heptan-2-yl)acetamido)-2 - methylpyridin-3-yl)-7-methyl-4-oxo-4,5,6,7-tetrahydro-[3,6'- bipyrazolo[1,5-a]pyrazine]- 3'-carboxamide Step a: ethyl 1-(1-((tert-butoxycarbonyl)amino)propan-2-yl)-4-iodo-1H-pyra zole-5- carboxylate [00836] Di-tert-butyl azodicarboxylate (4.67 g, 20.3 mmol) was added to a stirred solution of ethyl 4-iodo-1H-pyrazole-5-carboxylate (3 g, 11.28 mmol), tert-butyl (2- hydroxypropyl)carbamate (4.44 g, 22.55 mmol) and triphenylphosphine (5.32 g, 20.3 mmol) in THF (56 mL) under nitrogen. The mixture was stirred at rt for 5 h. The solvent was evaporated in vacuo and the crude product was triturated with DIPE. The solid was filtered and the filtrate was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 0 – 30% EtOAc/heptane). The desired fractions were collected, and the solvents evaporated in vacuo to give ethyl 1-(1-((tert-butoxycarbonyl)amino)propan-2- yl)-4-iodo-1H-pyrazole-5-carboxylate as a colorless oil (4.9 g, 91% purity, 93%). Step b: ethyl 1-(1-aminopropan-2-yl)-4-iodo-1H-pyrazole-5-carboxylate [00837] A 4M solution of HCl in 1,4-dioxane (10 mL, 40 mmol) was added to a solution of ethyl 1-(1-((tert-butoxycarbonyl)amino)propan-2-yl)-4-iodo-1H-pyra zole-5- carboxylate (4.2 g, 9.63 mmol) in acetonitrile (20 mL). The mixture was stirred at 80 °C for 2 h. The solvent was evaporated in vacuo to yield ethyl 1-(1-aminopropan-2-yl)-4-iodo-1H- pyrazole-5-carboxylate (3.5 g, 97%). Step c: 3-iodo-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one [00838] Ethyl 1-(1-aminopropan-2-yl)-4-iodo-1H-pyrazole-5-carboxylate as HCl salt (180 g, 350.4 mmol) was dissolved in a sat. sol. of NaHCO ₃ (2 L). The mixture was stirred at rt for 12 h. The mixture was diluted with water and extracted with DCM. The organic layers were separated, dried (Na ₂ SO ₄ ), filtered and the solvents evaporated in vacuo. Then the residue was washed with tertbutyl methyl ether to yield 3-iodo-7-methyl-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (92 g, 90%). Step d: 7-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7 - dihydropyrazolo[1,5-a]pyrazin-4(5H)-one [00839] To a suspension of 3-iodo-7-methyl-6,7-dihydro-5H-pyrazolo[1,5- A]pyrazin-4-one (261 mg, 0.94 mmol) in 2-MeTHF (6.5 mL) at 0°C under nitrogen was added isopropylmagnesium chloride (1.88 mL, 2 M, 3.77 mmol) rapidly dropwise (clear solution which becomes turbid) and the ice bath was removed. The reaction was stirred at rt for 4 h to yield a pale yellow suspension, then returned to 0°C. 2-Isopropoxy-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (0.77 mL, 3.77 mmol) was added dropwise to yield a hazy pale yellow solution and the ice bath was removed and the reaction was stirred at rt for 1 h. The reaction was diluted with DCM and water was added. The layers were separated (milky organics) and the aqueous extracted with DCM. The combined organics were washed with brine and concentrated to a pale yellow solid which was dried under high vacuum overnight to yield a crude solid contaminated with Mg salts. The solid was taken up in DCM, sonicated, and stripped down with silica gel for dry load. Purified by flash column, 0 - 50% (10% MeOH/EtOAc)/EtOAc. The major peak was concentrated to 7-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydropyrazolo[1,5 -a]pyrazin-4(5H)-one (103 mg, 39%) as a pale yellow gummy solid. LCMS (ESI): mass calcd. for C ₁₃ H ₂₀ BN ₃ O ₃ 277.30; m/z found, 278.2 [M+H]+. ¹ H NMR (METHANOL-d4) δ: 7.60 (d, J=2.0 Hz, 1H), 6.86 (d, J=2.0 Hz, 1H), 4.57 (quind, J=6.7, 4.6 Hz, 1H), 3.81 (dd, J=13.2, 4.9 Hz, 1H), 3.47 (dd, J=13.2, 7.3 Hz, 1H), 1.55-1.59 (m, 3H), 1.21-1.28 (m, 12H). Step e: N-(5-(2-((1S,4R)-2-azabicyclo[2.2.1]heptan-2-yl)acetamido)-2 -methylpyridin-3- yl)-7-methyl-4-oxo-4,5,6,7-tetrahydro-[3,6'-bipyrazolo[1,5-a ]pyrazine]-3'-carboxamide [00840] A mixture of N-(5-(2-((1S,4R)-2-azabicyclo[2.2.1]heptan-2-yl)acetamido)- 2-methylpyridin-3-yl)-6-chloropyrazolo[1,5-a]pyrazine-3-carb oxamide (64 mg, 0.1 mmol), 7- methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-d ihydropyrazolo[1,5-a]pyrazin- 4(5H)-one (48 mg, 0.17 mmol), cesium carbonate (85 mg, 0.26 mmol), and 1,1'- bis(diphenylphosphino)ferrocenedichloro palladium(II) (10 mg, 0.014 mmol) in 1,4-dioxane (1.6 mL) and water (0.5 mL) under nitrogen in a capped 5 mL microwave vial was sparged with nitrogen for 10 min and heated at 130°C in the microwave for 1 h. Added more 1,1'- bis(diphenylphosphino)ferrocenedichloro palladium(II) (10 mg, 0.014 mmol), placed under vacuum, back-filled with nitrogen, and returned to the microwave at 130°C for 1 h. The reaction was stirred with Si-trisamine for 3 h, filtered, and purified by prep-HPLC (8% - 30% MeCN/water/0.1% TFA) to yield mhawkins_1170_3 (6 mg, 11%) as a pale yellow solid. LCMS (ESI): mass calcd. for C ₂₈ H ₃₀ N ₁₀ O ₃ 554.62; m/z found, 555.3 [M+H]+. ¹ H NMR (METHANOL-d4) δ: 10.14-10.17 (m, 1H), 9.64 (d, J=1.5 Hz, 1H), 8.78 (d, J=2.4 Hz, 1H), 8.74 (s, 1H), 8.53 (d, J=2.0 Hz, 1H), 8.33 (s, 1H), 4.63-4.73 (m, 1H), 4.13-4.33 (m, 3H), 3.88 (dd, J=13.2, 4.4 Hz, 1H), 3.70-3.81 (m, 1H), 3.49-3.62 (m, 2H), 3.14-3.22 (m, 1H), 2.88-2.97 (m, 1H), 2.72-2.83 (m, 1H), 2.65 (s, 3H), 1.77-2.14 (m, 5H), 1.56-1.70 (m, 4H). Example 159. N-(5-(2-(2,2-dimethylpyrrolidin-1-yl)acetamido)-2-methylpyri din-3-yl)-7- methyl-4,5,6,7-tetrahydro-[3,6'-bipyrazolo[1,5-a]pyrazine]-3 '-carboxamide Step a: 6-chloro-N-(5-(2-(2,2-dimethylpyrrolidin-1-yl)acetamido)-2-m ethylpyridin-3- yl)pyrazolo[1,5-a]pyrazine-3-carboxamide [00841] A suspension of N-(5-amino-6-methylpyridin-3-yl)-2-(2,2- dimethylpyrrolidin-1-yl)acetamide (0.53 g, 1.56 mmol), 6-chloropyrazolo[1,5-a]pyrazine-3- carboxylic acid (319 mg, 1.61 mmol), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (1.39 g, 4.95 mmol) in DCM (25 mL) under nitrogen in a 100 mL round bottle flask was treated with 1-methylimidazole (0.74 mL, 9.34 mmol) dropwise to yield a heterogeneous mixture which was stirred vigorously overnight, resulting in freely stirring milky suspension. The reaction was concentrated. The resulting solid was sonicated with water/DCM and a solid was collected and washed well with water and DCM in the filter funnel to yield a tan solid which was transferred to a round bottle flask and stripped down with MeCN to remove residual water, yielding 6-chloro-N-(5-(2-(2,2-dimethylpyrrolidin-1- yl)acetamido)-2-methylpyridin-3-yl)pyrazolo[1,5-a]pyrazine-3 -carboxamide (766 mg, 66%) as a tan solid which was used without purification. Step b: tert-butyl 7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylat e [00842] To a solution of 7-methyl-4H,5H,6H,7H-pyrazolo[1,5-A]pyrazine (250 mg, 1.82 mmol) in DCM (25 mL) was added BOC-anhydride (437.5 mg, 2 mmol) and the reaction was stirred at rt under nitrogen overnight. The reaction was concentrated and purified by flash column, 0 - 60% EtOAc/heptane to yield tert-butyl 7-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (347 mg, 80%) as a a colorless viscous oil. LCMS (ESI): mass calcd. for C ₁₂ H ₁₉ N ₃ O ₂ , 237.30; m/z found, 238.1 [M+H]+. Step c: tert-butyl 7-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7 - dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate [00843] To a mixture of bis(pinacolato)diboron (161 mg, 0.63 mmol), bis(1,5- cyclooctadiene)dimethoxydiiridium (15 mg, 0.023 mmol), and 3,4,7,8-tetramethyl-1,10- phenanthroline (13 mg, 0.055 mmol) under nitrogen in a capped 5 mL microwave vial was added 2-MeTHF (2.5 mL) and the mixture was sparged for 10 min then heated at 75°C for 1 hr. A nitrogen sparged solution of tert-butyl 7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (100 mg, 0.42 mmol) in 2-MeTHF (2 mL) was added and the reaction was heated overnight. The reaction was cooled to room temperature, concentrated, dissolved in DCM, loaded onto a silica precolumn, dried, and purified by flash column, 0 - 50% EtOAc/heptane to yield tert-butyl 7-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (216 mg, 56%) as an impure white gum. The product was used without further purification in next reaction. Step d: N-(5-(2-(2,2-dimethylpyrrolidin-1-yl)acetamido)-2-methylpyri din-3-yl)-7- methyl-4,5,6,7-tetrahydro-[3,6'-bipyrazolo[1,5-a]pyrazine]-3 '-carboxamide

[00844] A mixture of 6-chloro-N-(5-(2-(2,2-dimethylpyrrolidin-1-yl)acetamido)-2- methylpyridin-3-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (66 mg, 0.15 mmol), tert-butyl 7- methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-d ihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (216 mg, 0.24 mmol), cesium carbonate (150 mg, 0.46 mmol), and 1,1'- bis(diphenylphosphino)ferrocenedichloro palladium(II) (11 mg, 0.015 mmol) in 1,4-dioxane (1.8 mL) and water (0.6 mL) under nitrogen in a capped 5 mL microwave vial was sparged with nitrogen for 10 min and heated at 130°C in the microwave for 1 h. The reaction was stirred with Si-trisamine for 2.5 h, filtered, and purified by prep-HPLC, 10% - 32% MeCN/water/0.1% TFA. to yield a pale yellow solid which was dissolved in DCM and treated with an equal volume of TFA to yield a bright yellow solution which was allowed to stand at rt for 20 min. The reaction was concentrated, dissolved in DMSO, basified with a drop of 10% NH ₄ OH, and purified by prep-HPLC (20% - 40% MeCN/10 mM NH ₄ OH) to yield N-(5-(2-(2,2-dimethylpyrrolidin-1-yl)acetamido)-2-methylpyri din-3-yl)-7-methyl- 4,5,6,7-tetrahydro-[3,6'-bipyrazolo[1,5-a]pyrazine]-3'-carbo xamide (15 mg, 22%) as a white solid. LCMS (ESI): mass calcd. for C28H34N10O2, 542.65; m/z found, 543.3 [M+H]+. ¹ H NMR (METHANOL-d4) δ: 9.64 (d, J=1.5 Hz, 1H), 8.96 (d, J=1.5 Hz, 1H), 8.70 (s, 1H), 8.64 (d, J=2.4 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 8.10 (s, 1H), 4.31-4.55 (m, 4H), 3.39-3.49 (m, 3H), 2.96-3.10 (m, 3H), 2.55 (s, 3H), 1.89-1.99 (m, 2H), 1.81-1.89 (m, 2H), 1.59 (d, J=6.8 Hz, 3H), 1.18 (s, 6H). Example 160. N-(5-(2-((1S,4R)-2-azabicyclo[2.2.1]heptan-2-yl)acetamido)-2 - methylpyridin-3-yl)-7-methyl-4,5,6,7-tetrahydro-[3,6'-bipyra zolo[1,5-a]pyrazine]-3'- carboxamide

[00845] A mixture of N-(5-(2-((1S,4R)-2-azabicyclo[2.2.1]heptan-2-yl)acetamido)- 2-methylpyridin-3-yl)-6-chloropyrazolo[1,5-a]pyrazine-3-carb oxamide (55 mg, 0.13 mmol), tert-butyl 7-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7 -dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (87 mg, 0.24 mmol), cesium carbonate (128 mg, 0.39 mmol), and 1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II) (9 mg, 0.013 mmol) in 1,4- dioxane (1.6 mL) and water (0.5 mL) under nitrogen in a capped 5 mL microwave vial was sparged with nitrogen for 10 min and heated at 130°C in the microwave for 1 h. The reaction mixture was filtered through a Si-thiol cartridge to remove metals and purified by flash column, 12% - 32% MeCN/water/0.1% TFA to yield a tan solid which was dissolved in DCM and treated with an equal volume of TFA and the resulting orange solution was allowed to stand at rt. After 25 min the reaction was concentrated, the residue dissolved in DMSO, basified with drops 10% NH ₄ OH, and purified by prep-HPLC, 25% - 35% MeCN/10 mM NH ₄ OH to yield N-(5-(2-((1S,4R)-2-azabicyclo[2.2.1]heptan-2-yl)acetamido)-2 - methylpyridin-3-yl)-7-methyl-4,5,6,7-tetrahydro-[3,6'-bipyra zolo[1,5-a]pyrazine]-3'- carboxamide (25 mg, 37%) as a white solid. LCMS (ESI): mass calcd. for C28H32N10O2, 540.63; m/z found, 541.2 [M+H]+. ¹ H NMR (METHANOL-d4) δ: 9.61 (d, J=1.5 Hz, 1H), 8.93 (d, J=1.5 Hz, 1H), 8.67 (s, 1H), 8.61 (d, J=2.4 Hz, 1H), 8.29 (d, J=2.4 Hz, 1H), 8.07 (s, 1H), 4.28-4.52 (m, 4H), 3.34-3.46 (m, 4H), 2.92-3.01 (m, 2H), 2.52 (s, 3H), 2.39-2.48 (m, 2H), 1.76-1.89 (m, 2H), 1.50-1.70 (m, 5H), 1.35-1.44 (m, 2H). Example 161. N-(5-(2-(2,2-dimethylpyrrolidin-1-yl)acetamido)-2-methylpyri din-3-yl)-6- (6-oxo-1,6-dihydropyridin-2-yl)pyrazolo[1,5-a]pyrazine-3-car boxamide

[00846] To a mixture of 6-chloro-N-(5-(2-(2,2-dimethylpyrrolidin-1-yl)acetamido)- 2-methylpyridin-3-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (64 mg, 0.086 mmol), 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-o ne (58 mg, 0.26 mmol), cesium carbonate (98 mg, 0.3 mmol), and 1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II) (9.5 mg, 0.013 mmol) in 1,4-dioxane (1.6 mL) and water (0.5 mL) under nitrogen in a capped 5 mL microwave vial was sparged with nitrogen for 10 min and heated at 130°C in the microwave for 1 h, cooled to rt, and stirred with Si-trisamine overnight. The reaction was filtered and purified by prep-HPLC (2% - 25% MeCN/water/0.1% TFA) to yield a semi-pure product which was further purified by prep-HPLC (10% - 45% MeCN/10mM NH ₄ OH) to yield N-(5-(2-(2,2-dimethylpyrrolidin-1-yl)acetamido)-2-methylpyri din-3-yl)-6- (6-oxo-1,6-dihydropyridin-2-yl)pyrazolo[1,5-a]pyrazine-3-car boxamide (1.4 mg, 4%) as a white solid. LCMS (ESI): mass calcd. for C ₂₆ H ₂₈ N ₈ O ₃ , 500.56; m/z found, 501.1 [M+H]+. ¹ H NMR (METHANOL-d4) δ: 9.73 (d, J=1.5 Hz, 1H), 9.43 (d, J=1.5 Hz, 1H), 8.76 (s, 1H), 8.58 (d, J=2.4 Hz, 1H), 8.39 (d, J=2.4 Hz, 1H), 7.73 (dd, J=9.0, 7.1 Hz, 1H), 7.24 (br d, J=6.8 Hz, 1H), 6.61-6.67 (m, 1H), 3.25 (s, 2H), 2.91 (t, J=7.3 Hz, 2H), 2.55 (s, 3H), 1.76-1.94 (m, 5H), 1.11 (s, 6H). [00847] The following example was similarly prepared according to the procedure described in Example 161 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art. Example 163. N-(5-(2-(2,2-dimethylpyrrolidin-1-yl)acetamido)-2-methylpyri din-3-yl)-6- (5-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyr azolo[1,5-a]pyrazine-3- carboxamide Step a: 5-((tetrahydro-2H-pyran-2-yl)oxy)-4,5,6,7-tetrahydropyrazolo [1,5-a]pyridine [00848] To mixture of 4H,5H,6H,7H-pyrazolo[1,5-A]pyridin-5-ol (289 mg, 2.09 mmol) and pyridinium p-toluenesulfonate (53 mg, 0.21 mmol) under nitrogen was added THF (5 mL) followed by 3,4-dihydro-2H-pyran (0.36 mL, 0.99 g/mL, 4.18 mmol) and the reaction was stirred overnight. The reaction was transferred to a microwave vial and heated to 60°C in the microwave for 1 h, filtered, concentrated, and purified by flash column, 0% - 75% EtOAc/heptane to yield 5-((tetrahydro-2H-pyran-2-yl)oxy)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridine (274 mg, 59%) as a clear viscous oil. LCMS (ESI): mass calcd. for C ₁₅ H ₁₈ N ₂ O ₂ 222.29; m/z found, 223.1 [M+H]+. ¹ H NMR (METHANOL-d4) δ: 7.41 (t, J=1.7 Hz, 1H), 6.05 (d, J=1.0 Hz, 1H), 4.81-4.87 (m, 1H), 4.10-4.32 (m, 3H), 3.82- 3.98 (m, 1H), 3.49-3.61 (m, 1H), 2.90-3.14 (m, 2H), 2.14-2.31 (m, 2H), 1.66-1.89 (m, 2H), 1.46-1.64 (m, 4H). Step b: 5-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2- yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine [00849] To a mixture of bis(pinacolato)diboron (237 mg, 0.93 mmol), bis(1,5- cyclooctadiene)dimethoxydiiridium (23 mg, 0.035 mmol), and 3,4,7,8-tetramethyl-1,10- phenanthroline (22 mg, 0.094 mmol) under nitrogen in a capped 5 mL microwave vial was added 2-MeTHF (3 mL) and the mixture was sparged with nitrogen for 10 min then heated at 80°C for 1 h. A nitrogen-sparged solution of 5-((tetrahydro-2H-pyran-2-yl)oxy)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridine (137 mg, 0.62 mmol) in 2-MeTHF (2 mL) was added and the reaction was heated at 80°C overnight. The reaction was concentrated, the residue dissolved in a small volume of DCM, loaded onto a pre-column, and purified by flash column, 0 - 100% EtOAc/heptane to yield 5-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyraz olo[1,5-a]pyridine (309 mg, 50% purity, 70%) as a clear viscous oil which solidifies under vacuum to an opaque gum which was used as is in the next step. Step c: N-(5-(2-(2,2-dimethylpyrrolidin-1-yl)acetamido)-2-methylpyri din-3-yl)-6-(5- hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrazo lo[1,5-a]pyrazine-3- carboxamide [00850] A mixture of 6-chloro-N-(5-(2-(2,2-dimethylpyrrolidin-1-yl)acetamido)-2- methylpyridin-3-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (65 mg, 0.087 mmol), 5- ((tetrahydro-2H-pyran-2-yl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridine (122 mg, 0.18 mmol), cesium carbonate (88 mg, 0.27 mmol), and 1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II) (8 mg, 0.011 mmol) in 1,4-dioxane (1.6 mL) and water (0.5 mL) under nitrogen in a capped 5 mL microwave vial was sparged with nitrogen for 10 min and heated at 130°C in the microwave for 1 h. The reaction was stirred reaction with Si-trisamine overnight, filtered, and purified by prep- HPLC, 8% - 30% MeCN/water/0.1% TFA to yield a yellow solid, which was dissolved in DMSO and basified with drops 10% NH ₄ OH and purified by prep-HPLC, 20% - 40% MeCN/10 mM NH ₄ OH to yield N-(5-(2-(2,2-dimethylpyrrolidin-1-yl)acetamido)-2- methylpyridin-3-yl)-6-(5-hydroxy-4,5,6,7-tetrahydropyrazolo[ 1,5-a]pyridin-3- yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (12 mg, 25%) as a white solid. LCMS (ESI): mass calcd. for C ₂₈ H ₃₃ N ₉ O ₃ , 543.63; m/z found, 544.3 [M+H]+. ¹ H NMR (METHANOL-d4) δ: 9.64 (d, J=1.5 Hz, 1H), 8.90 (d, J=1.5 Hz, 1H), 8.70 (s, 1H), 8.64 (d, J=2.4 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 8.04 (s, 1H), 4.33-4.42 (m, 2H), 4.21-4.29 (m, 1H), 3.45 (dd, J=17.1, 4.4 Hz, 1H), 3.21-3.31 (m, 3H), 2.93 (br t, J=7.1 Hz, 2H), 2.55 (s, 3H), 2.16-2.33 (m, 3H), 1.84- 1.95 (m, 2H), 1.77-1.84 (m, 2H), 1.12 (s, 6H). Example 164. N-(5-(2-(2,2-dimethylpyrrolidin-1-yl)acetamido)-2-methylpyri din-3-yl)-6- (6-hydroxy-2-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazi n-3-yl)pyrazolo[1,5- a]pyrazine-3-carboxamide Step a: 2-((1,3-dibromopropan-2-yl)oxy)tetrahydro-2H-pyran [00851] To a mixture of 1,3-dibromo-2-propanol (1 g, 4.59 mmol) and pyridinium p-toluenesulfonate (116.5 mg, 0.46 mmol) in THF (10 mL) under nitrogen in a 20 mL vial was added 3,4-dihydro-2H-pyran (0.78 mL, 9.18 mmol) and the reaction was stirred at rt overnight. The reaction was diluted with 50 mL EtOAc, washed 3x water then 1x brine, filtered through cotton, and concentrated to a clear colorless oil. The crude oil was purified by flash column, 0 - 10% EtOAc/heptane to yield 2-((1,3-dibromopropan-2- yl)oxy)tetrahydro-2H-pyran (1.23 g, 88%) as a clear colorless oil. ¹ H NMR (CHLOROFORM-d) δ: 4.79 (dd, J=4.2, 3.2 Hz, 1H), 3.99-4.06 (m, 1H), 3.90-3.98 (m, 1H), 3.62-3.72 (m, 2H), 3.51-3.60 (m, 3H), 1.71-1.91 (m, 2H), 1.55-1.70 (m, 3H), 1.50-1.54 (m, 1H). Step b: 2-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-6,7-dihydro-5H-py razolo[5,1- b][1,3]oxazine [00852] A mixture of 3-methyl-1H-pyrazol-5-ol (275 mg, 2.8 mmol), 2-((1,3- dibromopropan-2-yl)oxy)tetrahydro-2H-pyran (1 g, 3.31 mmol), and K ₂ CO ₃ (1.33 g, 9.65 mmol) in DMF (15 mL) under nitrogen in a 50 mL rbf was heated at 100° for 15 h. The reaction was poured into 10% LiCl and extracted 4x EtOAc. The combined organics were washed 3x brine, filtered through cotton, and concentrated to an orange oil which was purified by flash column, 0 - 100% EtOAc/heptane. Trace DMF in the purified material. Dissolved in EtOAc and washed 3x 10% LiCl, 3x brine, filtered through cotton, and concentrated, dried under high vacuum overnight to yield 2-methyl-6-((tetrahydro-2H-pyran- 2-yl)oxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (163 mg, 24%) as an oil which crystallizes on standing. LCMS (ESI): mass calcd. for C ₁₂ H ₁₈ N ₂ O ₃ , 238.29; m/z found, 239.2 [M+H]+. 1H NMR (CHLOROFORM-d) d: 5.30-5.34 (m, 1H), 4.79-4.89 (m, 1H), 4.08-4.35 (m, 5H), 3.76-3.97 (m, 1H), 3.51-3.60 (m, 1H), 2.19 (s, 3H), 1.67-1.88 (m, 2H), 1.48-1.67 (m, 6H). Step c: 2-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4,4,5,5-tetram ethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin e [00853] A mixture of bis(pinacolato)diboron (263 mg, 1.03 mmol), bis(1,5- cyclooctadiene)dimethoxydiiridium (26.5 mg, 0.04 mmol), and 3,4,7,8-tetramethyl-1,10- phenanthroline (18.5 mg, 0.078 mmol) in 2-MeTHF (3 mL) under nitrogen in a capped 5 mL microwave vial was sparged with nitrogen for 10 min and heated for 1 h at 80°C in a heating block. A nitrogen-sparged solution of 2-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (163 mg, 0.68 mmol) in 2-MeTHF (2 mL) was added and heating was continued overnight. The reaction was stripped down and purified by flash column, (0 - 100% EtOAc/heptane) to yield 2-methyl-6-((tetrahydro-2H-pyran-2- yl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7- dihydro-5H-pyrazolo[5,1- b][1,3]oxazine (228 mg, 92%) as an amber gum. LCMS (ESI): mass calcd. for C ₁₈ H ₂₉ BN ₂ O ₅ , 364.25; m/z found, 365.2 [M+H]+. Step d: N-(5-(2-(2,2-dimethylpyrrolidin-1-yl)acetamido)-2-methylpyri din-3-yl)-6-(6- hydroxy-2-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3 -yl)pyrazolo[1,5- a]pyrazine-3-carboxamide [00854] A mixture of 6-chloro-N-(5-(2-(2,2-dimethylpyrrolidin-1-yl)acetamido)-2- methylpyridin-3-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (60 mg, 0.081 mmol), 2-methyl- 6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (36 mg, 0.099 mmol), cesium carbonate (79 mg, 0.24 mmol), and 1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II) (6 mg, 0.0081 mmol) in 1,4-dioxane (1.6 mL) and water (0.5 mL) under nitrogen in a capped 5 mL microwave vial was sparged with nitrogen for 10 min and heated at 130°C in the microwave for 1 h. The reaction was stirred with Si-trisamine overnight. The reaction was filtered and purified by prep-HPLC, 15% - 25% MeCN/water/0.1% TFA to yield a yellow solid, which was dissolved in DMSO, basified with drops 10% NH ₄ OH and purified by prep-HPLC, 18% - 38% MeCN/10 mM NH ₄ OH to yield N-(5-(2-(2,2-dimethylpyrrolidin-1-yl)acetamido)-2- methylpyridin-3-yl)-6-(6-hydroxy-2-methyl-6,7-dihydro-5H-pyr azolo[5,1-b][1,3]oxazin-3- yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (3 mg, 7%) as a white solid. LCMS (ESI): mass calcd. for C ₂₈ H ₃₃ N ₉ O ₄ , 559.63; m/z found, 560.2 [M+H]+. ¹ H NMR (METHANOL-d4) δ: 9.48 (br s, 1H), 8.69 (br s, 1H), 8.53 (br d, J=9.8 Hz, 2H), 8.19 (br s, 1H), 4.30-4.43 (m, 3H), 4.20 (br d, J=12.7 Hz, 1H), 3.96 (br d, J=12.7 Hz, 1H), 3.16 (br s, 2H), 2.75-2.85 (m, 2H), 2.41 (br d, J=12.2 Hz, 6H), 1.77 (br s, 2H), 1.68 (br d, J=5.4 Hz, 2H), 1.00 (br s, 6H). Example 165.5-benzyl-N-(5-(2-(2,2-dimethylpyrrolidin-1-yl)acetamido) -2- methylpyridin-3-yl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-[3,6'- bipyrazolo[1,5-a]pyrazine]- 3'-carboxamide Step a: tert-butyl ((1H-pyrazol-5-yl)methyl)(benzyl)carbamate [00855] To a suspension of 1H-pyrazole-3-carbaldehyde (3 g, 31.22 mmol) under nitrogen in MeOH (30 mL, 0.79 g/mL, 739.65 mmol) was added benzylamine (3.44 mL, 31.22 mmol) at rt and stirred for 1.5 h to yield a mustard-colored thick suspension. Sodium borohydride (1.19 g, 31.22 mmol) was added slowly in portions (gas evolution) and the reaction was stirred cold for 30 min until all chunks of NaBH ₄ are gone, resulting in a hazy orange solution. Water (6 mL) was added slowly to the reaction, and di-tert-butyl dicarbonate (6.88 g, 31.22 mmol) was added. After 2.5 h the reaction was concentrated to a viscous orange oil/white solid, which was partitioned between brine and EtOAc. The layers were separated, the aqueous was extracted 3x EtOAc, and the combined organics were backwashed with brine, filtered through cotton, and concentrated. The crude material was loaded onto a pre-column and purified by flash column (0 - 60% EtOAc/heptane) to yield tert-butyl ((1H-pyrazol-5-yl)methyl)(benzyl)carbamate (6 g, 67%) as a yellow-tinted viscous oil. LCMS (ESI): mass calcd. for C ₁₆ H ₂₁ N ₃ O ₂ , 287.36; m/z found, 310.1 [M+Na]. Step b: N-((1H-pyrazol-5-yl)methyl)-1-phenylmethanamine [00856] A solution of tert-butyl ((1H-pyrazol-5-yl)methyl)(benzyl)carbamate (6 g, 20.88 mmol) in EtOAc (20 mL) in a 500 mL round bottle of equipped with an addition funnel was chilled in an ice bath under nitrogen. HCl (1M in EtOAc, 50 mL, 50 mmol) was transferred via cannula to the addition funnel, then added rapidly dropwise. After the addition was complete, the ice bath was removed, and the reaction was stirred at rt. Slow gas evolution and formation of precipitate. Left stirring over the weekend. Collected solid, washed well with EtOAc, and dried in the filter and then under high vacuum to yield N-((1H- pyrazol-5-yl)methyl)-1-phenylmethanamine (3.93 g, 84%) as a white solid. LCMS (ESI): mass calcd. for C ₁₁ H ₁₃ N ₃ , 187.25; m/z found, 188.2 [M+H]+. Step c: 5-benzyl-7-methyl-4,5-dihydropyrazolo[1,5-a]pyrazin-6(7H)-on e [00857] A suspension of N-((1H-pyrazol-5-yl)methyl)-1-phenylmethanamine (0.58 g, 2.59 mmol) under nitrogen in DCM (7.5 mL) in a 50 mL round bottle flask was treated with DIPEA (2.68 mL, 15.56 mmol) and the mixture was stirred until a clear solution resulted. The solution was chilled on an ice bath, 2-chloropropionyl chloride (0.38 mL, 3.89 mmol) was added dropwise, and the ice bath was removed. After 1 h the reaction was poured into 2N KHSO ₄ and the layers were separated. \The aqueous was extracted 2x with DCM and the combined organics were backwashed once with 2N KHSO ₄ , washed with brine, filtered through cotton, concentrated, and dried under high vacuum overnight to yield a viscous hazy yellow oil (0.87 g, 61%). To a solution of this crude product in DMF (10 mL) under nitrogen was added Cs ₂ CO ₃ (1.28 g, 3.92 mmol) and the mixture was heated at 100°C. After 40 min, the reaction was cooled to rt, diluted with EtOAc, and poured into 10% LiCl. The layers were separated, and the organics washed with 10% LiCl. The combined aqueous was back-extracted with EtOAc, and the combined extracts were washed 2x 10% LiCl, 1x brine, filtered through cotton, and concentrated. The crude product was purified by flash column, 0 - 100% EtOAc/heptane to yield 5-benzyl-7-methyl-4,5-dihydropyrazolo[1,5- a]pyrazin-6(7H)-one (309 mg, 82%) as a clear viscous amber gum. LCMS (ESI): mass calcd. for C ₁₄ H ₁₅ N ₃ O, 241.29; m/z found, 242.1 [M+H]+. Step d: 5-benzyl-7-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-4,5- dihydropyrazolo[1,5-a]pyrazin-6(7H)-one [00858] To a mixture of bis(pinacolato)diboron (511 mg, 2.01 mmol), bis(1,5- cyclooctadiene)dimethoxydiiridium (47 mg, 0.071 mmol), and 3,4,7,8-tetramethyl-1,10- phenanthroline (47.5 mg, 0.2 mmol) under nitrogen in a capped 20 mL microwave vial was added 2-MeTHF (5 mL) and the mixture was sparged with nitrogen for 10 min, then transferred to a heating block at 80°C for 1 h. A nitrogen-sparged solution of 5-benzyl-7- methyl-4,5-dihydropyrazolo[1,5-a]pyrazin-6(7H)-one (309 mg, 1.28 mmol) in 2-MeTHF (5 mL) was added and the reaction was heated overnight. The reaction was concentrated, a small volume DCM added, loaded onto a pre-column, dried under suction, and purified by flash column, 0 - 100% EtOAc/heptane to yield 5-benzyl-7-methyl-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-4,5-dihydropyrazolo[1,5-a]pyrazin-6 (7H)-one (531 mg, 113%) as a viscous hazy oil. LCMS (ESI): mass calcd. for C ₂₀ H ₂₆ BN ₃ O ₃ , 367.26; m/z found, 368.2 [M+H]+. Step e: 5-benzyl-N-(5-(2-(2,2-dimethylpyrrolidin-1-yl)acetamido)-2-m ethylpyridin-3-yl)- 7-methyl-6-oxo-4,5,6,7-tetrahydro-[3,6'-bipyrazolo[1,5-a]pyr azine]-3'-carboxamide [00859] A mixture of 6-chloro-N-(5-(2-(2,2-dimethylpyrrolidin-1-yl)acetamido)-2- methylpyridin-3-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (65 mg, 0.087 mmol), 5-benzyl- 7-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5 -dihydropyrazolo[1,5-a]pyrazin- 6(7H)-one (83 mg, 0.23 mmol), cesium carbonate (94 mg, 0.29 mmol), and 1,1'- bis(diphenylphosphino)ferrocenedichloro palladium(II) (7 mg, 0.0094 mmol) in 1,4-dioxane (1.6 mL) and water (0.5 mL) under nitrogen in a capped 5 mL microwave vial was sparged with nitrogen for 10 min and heated at 130°C in the microwave for 1 h. The reaction mixture was filtered through a Si-thiol cartridge to remove metals and purified by flash column, 9% - 29% MeCN/water/0.1% TFA to yield 5-benzyl-N-(5-(2-(2,2-dimethylpyrrolidin-1- yl)acetamido)-2-methylpyridin-3-yl)-7-methyl-6-oxo-4,5,6,7-t etrahydro-[3,6'-bipyrazolo[1,5- a]pyrazine]-3'-carboxamide (17 mg, 30%) as a pale yellow solid. LCMS (ESI): mass calcd. for C ₃₅ H ₃₈ N ₁₀ O ₃ , 646.76; m/z found, 647.3 [M+H]+. ¹ H NMR (METHANOL-d4) δ: 9.45 (d, J=1.5 Hz, 1H), 8.95 (d, J=1.5 Hz, 1H), 8.61 (d, J=2.4 Hz, 1H), 8.59 (s, 1H), 8.33 (d, J=2.4 Hz, 1H), 8.08 (s, 1H), 7.17-7.30 (m, 5H), 4.76-5.00 (m, 4H), 4.16-4.29 (m, 1H), 3.83-4.03 (m, 2H), 3.23-3.32 (m, 1H), 2.50 (s, 3H), 1.95-2.17 (m, 4H), 1.70 (d, J=6.8 Hz, 3H), 1.23- 1.51 (m, 6H). Example 166. N-(5-(2-(2-azabicyclo[2.2.1]heptan-2-yl)acetamido)-2-fluorop henyl)-6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide Step a: tert-butyl (3-(6-chloropyrazolo[1,5-a]pyrazine-3-carboxamido)-4- fluorophenyl)carbamate [00860] To a mixture of 6-chloropyrazolo[1,5-a]pyrazine-3-carboxylic acid (227 mg, 1.15 mmol), tert-butyl 3-amino-4-fluorophenylcarbamate (295 mg, 1.3 mmol), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (977 mg, 3.48 mmol) under nitrogen in a 50 mL rbf was added 1-methylimidazole (0.55 mL, 1.03 g/mL, 6.89 mmol) dropwise to yield a clumpy mixture which was stirred vigorously overnight at rt. Water was added and the resulting solid was filtered, washing well with water, DCM and dried in the filter funnel. The layers in the filtrate were separated and the organics washed with sat'd NaHCO ₃ , brine, filtered through cotton, and concentrated to yield tert-butyl (3-(6- chloropyrazolo[1,5-a]pyrazine-3-carboxamido)-4-fluorophenyl) carbamate (759 mg, 100%) as a tan solid which was used without purification in the next step. LCMS (ESI): mass calcd. for C ₁₈ H ₁₇ ClFN ₅ O ₃ , 405.81; m/z found, 350.0 [M-tBu]. Step b: N-(5-amino-2-fluorophenyl)-6-chloropyrazolo[1,5-a]pyrazine-3 -carboxamide hydrochloride [00861] To a suspension of tert-butyl (3-(6-chloropyrazolo[1,5-a]pyrazine-3- carboxamido)-4-fluorophenyl)carbamate (759 mg, 1.15 mmol) in MeOH (10 mL) under nitrogen was added HCl (4M in dioxane, 6 mL, 24 mmol) to yield a clear yellow solution, which was heated to 50°C. After 30 min the reaction was cooled and concentrated to a yellow solid. The product was stripped down twice from EtOAc and dried under high vacuum overnight to yield N-(5-amino-2-fluorophenyl)-6-chloropyrazolo[1,5-a]pyrazine-3 - carboxamide hydrochloride (770 mg, 98%) as a yellow solid which was used without purification in the next reaction. LCMS (ESI): mass calcd. for C ₁₃ H ₉ ClFN ₅ O, 305.70; m/z found, 306.1 [M+H]+. Step c: 6-chloro-N-(5-(2-chloroacetamido)-2-fluorophenyl)pyrazolo[1, 5-a]pyrazine-3- carboxamide [00862] To a clear pale orange solution of N-(5-amino-2-fluorophenyl)-6- chloropyrazolo[1,5-a]pyrazine-3-carboxamide hydrochloride (770 mg, 1.13 mmol) in DCM (15 mL) and DIPEA (0.87 mL, 5.06 mmol) under nitrogen was added 2-chloroacetyl chloride (0.11 mL, 1.35 mmol) dropwise. After 1.25 h added drops more DIPEA and 2-chloroacetyl chloride. After an additional 2 h, added an equal volume of water to the reaction and stirred vigorously to yield a thick purple mixture which was filtered, yielding a dark solid which was stripped down from MeCN 3x to remove residual water and dried under high vacuum overnight to yield a crude solid which was sonicated with DCM and collected to yield 6- chloro-N-(5-(2-chloroacetamido)-2-fluorophenyl)pyrazolo[1,5- a]pyrazine-3-carboxamide (297 mg, 69%) as a tan solid which was used without further purification. LCMS (ESI): mass calcd. for C ₁₅ H ₁₀ Cl ₂ FN ₅ O ₂ , 382.18; m/z found, 382.0 [M+H]+. Step d: N-(5-(2-(2-azabicyclo[2.2.1]heptan-2-yl)acetamido)-2-fluorop henyl)-6- chloropyrazolo[1,5-a]pyrazine-3-carboxamide [00863] To a mixture of 6-chloro-N-(5-(2-chloroacetamido)-2- fluorophenyl)pyrazolo[1,5-a]pyrazine-3-carboxamide (297 mg, 0.78 mmol), 2- azabicyclo[2.2.1]heptane (96 mg, 0.99 mmol), and Cs ₂ CO ₃ (760 mg, 2.33 mmol) under nitrogen was treated with DMF (6 mL) and the dark mixture was heated to 50°C. After 2 h the reaction was cooled to rt, filtered, and purified by prep-HPLC in three portions, 40% - 60% MeCN/10 mM NH ₄ OH to yield N-(5-(2-(2-azabicyclo[2.2.1]heptan-2-yl)acetamido)-2- fluorophenyl)-6-chloropyrazolo[1,5-a]pyrazine-3-carboxamide (172 mg, 50%) as a grey solid. LCMS (ESI): mass calcd. for C ₂₁ H ₂₀ ClFN ₆ O ₂ , 442.88; m/z found, 443.0 [M+H]+. Step e: N-(5-(2-(2-azabicyclo[2.2.1]heptan-2-yl)acetamido)-2-fluorop henyl)-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide [00864] A mixture of N-(5-(2-(2-azabicyclo[2.2.1]heptan-2-yl)acetamido)-2- fluorophenyl)-6-chloropyrazolo[1,5-a]pyrazine-3-carboxamide (43 mg, 0.097 mmol), 1- methylpyrazole-4-boronic acid, pinacol ester (46 mg, 0.21 mmol), cesium carbonate (98 mg, 0.3 mmol), and 1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II) (10.5 mg, 0.014 mmol) in 1,4-dioxane (1.6 mL) and water (0.5 mL) under nitrogen in a capped 5 mL microwave vial was sparged with nitrogen for 10 min and heated at 130°C in the microwave for 1 h. The reaction was stirred with Si-trisamine for 2 h, filtered, and purified by prep- HPLC, 10% - 30% MeCN/water/0.1% TFA. Thre product fractions were concentrated to a yellow solid, dissolved in DMSO, basified with drops 10% NH ₄ OH, and purified by flash column, 28% - 48% MeCN/10 mM NH ₄ OH to yield N-(5-(2-(2-azabicyclo[2.2.1]heptan-2- yl)acetamido)-2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)py razolo[1,5-a]pyrazine-3- carboxamide (18 mg, 38%) as a white solid. LCMS (ESI): mass calcd. for C ₂₅ H ₂₅ FN ₈ O ₂ , 488.53; m/z found, 489.3 [M+H]+. ¹ H NMR (METHANOL-d4) δ: 9.60 (d, J=1.5 Hz, 1H), 9.00 (d, J=1.5 Hz, 1H), 8.68 (s, 1H), 8.21 (s, 1H), 8.10 (dd, J=6.8, 2.4 Hz, 1H), 8.07 (s, 1H), 7.49 (ddd, J=8.9, 4.3, 2.9 Hz, 1H), 7.19 (dd, J=10.0, 9.0 Hz, 1H), 3.97 (s, 3H), 3.34 (s, 2H), 2.93 (dt, J=9.0, 3.3 Hz, 1H), 2.40-2.47 (m, 2H), 1.74-1.88 (m, 2H), 1.50-1.70 (m, 3H), 1.35- 1.44 (m, 2H). [00865] The following examples were similarly prepared according to the procedure described in Example 166 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art. Example 169. N-(5-(2-(2-azabicyclo[2.2.1]heptan-2-yl)acetamido)-2-fluorop henyl)-7- methyl-4,5,6,7-tetrahydro-[3,6'-bipyrazolo[1,5-a]pyrazine]-3 '-carboxamide [00866] A mixture of N-(5-(2-(2-azabicyclo[2.2.1]heptan-2-yl)acetamido)-2- fluorophenyl)-6-chloropyrazolo[1,5-a]pyrazine-3-carboxamide (44 mg, 0.099 mmol), tert- butyl 7-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7 -dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (75 mg, 0.21 mmol), cesium carbonate (95 mg, 0.29 mmol), and 1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II) (7 mg, 0.0097 mmol) in 1,4- dioxane (1.6 mL) and water (0.5 mL) under nitrogen in a capped 5 mL microwave vial was sparged with nitrogen for 10 min and heated at 130°C in the microwave for 1 h. The reaction was gravity filtered through a Si-thiol column and purified by prep-HPLC, 23% - 43% MeCN/water/0.1% TFA to yield a yellow solid which was dissolved in ~1 mL DCM and an equal volume of TFA. After 30 min the reaction was concentrated, taken up in DMSO, basified with drops 10% NH ₄ OH, and purified by prep-HPLC, 23% - 47% MeCN/10 mM NH ₄ OH to yield N-(5-(2-(2-azabicyclo[2.2.1]heptan-2-yl)acetamido)-2-fluorop henyl)-7- methyl-4,5,6,7-tetrahydro-[3,6'-bipyrazolo[1,5-a]pyrazine]-3 '-carboxamide (19 mg, 35%) as a white solid. LCMS (ESI): mass calcd. for C ₂₈ H ₃₀ FN ₉ O ₂ , 543.61; m/z found, 544.2 [M+H]+. ¹ H NMR (METHANOL-d4) δ: 9.61 (d, J=1.5 Hz, 1H), 8.91 (d, J=1.5 Hz, 1H), 8.67 (s, 1H), 8.09 (dd, J=6.8, 2.9 Hz, 1H), 8.06 (s, 1H), 7.49 (ddd, J=8.9, 4.3, 2.9 Hz, 1H), 7.19 (dd, J=10.0, 9.0 Hz, 1H), 4.28-4.51 (m, 3H), 3.40 (dd, J=13.5, 4.6 Hz, 1H), 3.34 (s, 3H), 2.91-3.01 (m, 2H), 2.40-2.46 (m, 2H), 1.75-1.87 (m, 2H), 1.51-1.70 (m, 5H), 1.36-1.44 (m, 2H). [00867] The following examples were similarly prepared according to the procedure described in Example 169 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art. Example 172, N-(5-(2-((1S,4R)-2-azabicyclo[2.2.1]heptan-2-yl)acetamido)-2 - methylpyridin-3-yl)-6-(1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrazi ne-3-carboxamide Step a: ethyl 6-(1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrazine-3-carboxylate [00868] To a mixture of methyl 6-chloropyrazolo[1,5-a]pyrazine-3-carboxylate (138 mg, 0.61 mmol), pyrazole (81 mg, 1.19 mmol), cuprous iodide (12.8 mg, 0.067 mmol), Cs ₂ CO ₃ (598 mg, 1.84 mmol), and neocuproine (26 mg, 0.13 mmol) under nitrogen in a capped 5 mL microwave vial was added 1,4-dioxane (4.5 mL) and the mixture was sparged for 10 min with nitrogen then heated at 125°C in the microwave for 48 h. The reaction was filtered through a Si-thiol column and purified by prep-HPC, 30% - 50% MeCN/10 mM NH ₄ OH to yield ethyl 6-(1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrazine-3-carboxylate (18 mg, 11%) as an pale pink solid. LCMS (ESI): mass calcd. for C ₁₂ H ₁₁ N ₅ O ₂ 257.25; m/z found, 258.1 [M+H]+. Step b: 6-(1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrazine-3-carboxylic acid [00869] To a pale orange solution of ethyl 6-(1H-pyrazol-1-yl)pyrazolo[1,5- a]pyrazine-3-carboxylate (38 mg, 0.15 mmol) in 1,4-dioxane (1.5 mL) was added a clear colorless solution of LiOH (11 mg, 0.46 mmol) in water (0.3 mL) to yield a milky mixture which was stirred at rt overnight. The reaction was concentrated and acidified with 1N HCl. A solid was collected, washing well with water then stripped down from MeCN to remove residual water and dried under vacuum to 6-(1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrazine-3- carboxylic acid (32 mg, 95%) as a white solid. LCMS (ESI): mass calcd. for C ₁₀ H ₇ N ₅ O ₂ 229.20; m/z found, 230.0 [M+H]+. Step c: N-(5-(2-((1S,4R)-2-azabicyclo[2.2.1]heptan-2-yl)acetamido)-2 -methylpyridin-3- yl)-6-(1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide [00870] A suspension of 6-(1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrazine-3-carboxylic acid (32 mg, 0.14 mmol), N-(5-amino-6-methylpyridin-3-yl)-2-((1S,4R)-2- azabicyclo[2.2.1]heptan-2-yl)acetamide (40 mg, 0.15 mmol), and chloro-N,N,N',N'- tetramethylformamidinium hexafluorophosphate (118 mg, 0.42 mmol) in DCM (3 mL) under nitrogen was sonicated to yield a uniform milky suspension which was treated with 1- methylimidazole (67 µL, 0.84 mmol) and the reaction was stirred at rt overnight. Poor conversion. Added 3 mL MeCN. Little change in appearance of mixture. Added 2 mL DMF - appears to increase the fraction of material in solution. Stripped down the reaction to remove DCM, some MeCN, added an additional 1 mL DMF, and added an additional 3 equivalents chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate and 6 equivalents 1-methylimidazole and continued stirring the milky solution at rt. The reaction was stirred over the weekend, filtered, and purified by prep-HPLC, 20% - 60% MeCN/10 mM NH ₄ OH to yield N-(5-(2-((1S,4R)-2-azabicyclo[2.2.1]heptan-2-yl)acetamido)-2 - methylpyridin-3-yl)-6-(1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrazi ne-3-carboxamide (23 mg, 35%) as an off-white solid. LCMS (ESI): mass calcd. for C ₂₄ H ₂₅ N ₉ O ₂ 471.53; m/z found, 472.1 [M+H]+. ¹ H NMR (METHANOL-d4) δ: 9.57 (d, J=1.5 Hz, 1H), 9.19 (d, J=1.0 Hz, 1H), 8.74 (s, 1H), 8.61 (d, J=2.0 Hz, 2H), 8.30 (d, J=2.4 Hz, 1H), 7.81 (d, J=1.5 Hz, 1H), 6.56-6.63 (m, 1H), 3.32-3.39 (m, 3H), 2.94 (dt, J=9.3, 3.4 Hz, 1H), 2.53 (s, 3H), 2.38-2.44 (m, 2H), 1.75-1.88 (m, 2H), 1.49-1.69 (m, 2H), 1.34-1.44 (m, 2H). Example 173. (R)-N-(2-fluoro-5-(2-(2-methylmorpholino)acetamido)phenyl)-6 -(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide Step a: tert-butyl (4-fluoro-3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyra zine-3- carboxamido)phenyl)carbamate [00871] A mixture of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3- carboxylic acid (100 mg, 0.41 mmol), tert-butyl 3-amino-4-fluorophenylcarbamate (106 mg, 0.47 mmol), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (367 mg, 1.31 mmol) in DMF (4 mL) under nitrogen in a 50 mL rbf was sonicated to give a milky mixture. 1-methylimidazole (0.2 mL, 2.47 mmol) was added, resulting in a clear amber solution which quickly formed a precipitate. The reaction was stirred overnight. Water was added (~0.5 mL) until the reaction becomes clear. The solution was filtered and purified by prep-HPLC, 30% - 50% MeCN/10 mM NH ₄ OH to yield tert-butyl (4-fluoro-3-(6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamido)phenyl )carbamate (124 mg, 67%) as an off-white solid. LCMS (ESI): mass calcd. for C ₂₂ H ₂₂ FN ₇ O ₃ , 451.46; m/z found, 452.2 [M+H]+. Step b: N-(5-amino-2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyraz olo[1,5- a]pyrazine-3-carboxamide hydrochloride [00872] To a suspension of tert-butyl (4-fluoro-3-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamido)phenyl)carbamate (124 mg, 0.27 mmol) in MeOH (2 mL) was added HCl (4M in dioxane, 1 mL, 4 mmol) to yield a clear yellow solution with exotherm. After 3 h added another 0.8 mL 4N HCl and heated at 55°C overnight. Concentrated reaction. Added DMSO and drops water to the residue, yielding a milky greeenish yellow suspension which was filtered of a pale yellow solid which was washed with MeCN and dried under high vacuum overnight. A second crop collected, rinsed with MeCN, combined with the first crop, and dried under high vac overnight to yield N-(5-amino- 2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]p yrazine-3-carboxamide hydrochloride (75 mg, 71%) as an off-white solid. LCMS (ESI): mass calcd. for C ₁₇ H ₁₄ FN ₇ O, 351.35; m/z found, 352.1 [M+H]+. Step c: N-(5-(2-chloroacetamido)-2-fluorophenyl)-6-(1-methyl-1H-pyra zol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamide [00873] To a milky suspension of N-(5-amino-2-fluorophenyl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide hydrochloride (55 mg, 0.14 mmol) in DCM (2 mL) and DIPEA (61 µL, 0.35 mmol) was added 2-chloroacetyl chloride (17 µL, 0.21 mmol) and the reaction was stirred overnight. An additional 30 uL DIPEA and 15 uL 2- chloroacetyl chloride were added. After 3 h the reaction was concentrated and the residue stirred with water. The dark solid was collected, rinsed well with water, and dried under vacuum in the filter funnel. The solid was stripped down from MeCN to remove residual water and dried under vacuum to yield N-(5-(2-chloroacetamido)-2-fluorophenyl)-6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (64 mg, 105%) as a brown solid. LCMS (ESI): mass calcd. for C ₁₉ H ₁₅ ClFN ₇ O ₂ , 427.82; m/z found, 428.1 [M+H]+. Step d: (R)-N-(2-fluoro-5-(2-(2-methylmorpholino)acetamido)phenyl)-6 -(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide [00874] A mixture of N-(5-(2-chloroacetamido)-2-fluorophenyl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (32 mg, 0.075 mmol), (R)-2- methylmorpholine (23 mg, 0.23 mmol), and Cs ₂ CO ₃ (122 mg, 0.37 mmol) in DMF (2 mL) was heated at 50°C for 2 h, then cooled to rt overnight. The reaction was filtered and purified by prep-HPLC, 12% - 35% MeCN/10 mM NH ₄ OH to yield (R)-N-(2-fluoro-5-(2-(2- methylmorpholino)acetamido)phenyl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine- 3-carboxamide (23 mg, 62%) as a pale tan solid. LCMS (ESI): mass calcd. for C ₂₄ H ₂₅ FN ₈ O ₃ , 492.52; m/z found, 493.1 [M+H]+. ¹ H NMR (METHANOL-d4) δ: 9.60 (d, J=1.5 Hz, 1H), 9.00 (d, J=1.5 Hz, 1H), 8.68 (s, 1H), 8.21 (s, 1H), 8.11 (dd, J=7.1, 2.7 Hz, 1H), 8.07 (s, 1H), 7.47-7.54 (m, 1H), 7.19 (dd, J=10.3, 9.3 Hz, 1H), 3.97 (s, 3H), 3.71-3.89 (m, 3H), 3.18 (s, 2H), 2.82-2.88 (m, 1H), 2.79 (br dd, J=11.5, 1.7 Hz, 1H), 2.28-2.39 (m, 1H), 1.99-2.06 (m, 1H), 1.14 (d, J=6.4 Hz, 3H). [00875] The following example was similarly prepared according to the procedure described in Example 173 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art. Example 175. N-(2-fluoro-5-(2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)- yl)acetamido)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1, 5-a]pyrazine-3- Step a: tert-butyl (3-(6-chloropyrazolo[1,5-a]pyrazine-3-carboxamido)-4- fluorophenyl)carbamate [00876] A mixture of 6-chloropyrazolo[1,5-a]pyrazine-3-carboxylic acid (212 mg, 1.07 mmol), tert-butyl 3-amino-4-fluorophenylcarbamate [361548-95-0] (263 mg, 1.16 mmol), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (950 mg, 3.39 mmol) in DCM (15 mL) was sonicated until a uniform fine suspension resulted. 1- methylimidazole (0.51 mL, 6.44 mmol) was added with vigorous stirring to yield a mixture that briefly cleared, then formed a precipitate. The reaction was stirred at rt overnight. The reaction was concentrated, sonicated with water, and a solid was collected. The solid was stirred with 10% MeOH/DCM and filtered (rinsing 4x with small volumes of 10% MeOH/DCM) to yield a dark filtrate which was concentrated and dried under high vacuum overnight to give crude tert-butyl (3-(6-chloropyrazolo[1,5-a]pyrazine-3-carboxamido)-4- fluorophenyl)carbamate which was carried forward without purification. Step b: N-(5-amino-2-fluorophenyl)-6-chloropyrazolo[1,5-a]pyrazine-3 -carboxamide hydrochloride [00877] To a suspension of tert-butyl (3-(6-chloropyrazolo[1,5-a]pyrazine-3- carboxamido)-4-fluorophenyl)carbamate (506 mg, 1.07 mmol) in MeOH (10 mL) under nitrogen was added HCl (4M in dioxane, 6 mL, 24 mmol) and the mixture was heated to 50°C to yield a light brown solution. After 1.75 h the reaction was concentrated. MeCN was added and reconcentrated to remove residual MeOH/HCl to yield N-(5-amino-2- fluorophenyl)-6-chloropyrazolo[1,5-a]pyrazine-3-carboxamide hydrochloride (507 mg, 111%) as a tan solid. LCMS (ESI): mass calcd. for C ₁₃ H ₉ ClFN ₅ O, 305.7; m/z found, 306.0 [M+H]+. Step c: 6-chloro-N-(5-(2-chloroacetamido)-2-fluorophenyl)pyrazolo[1, 5-a]pyrazine-3- carboxamide [00878] To a clear reddish solution of N-(5-amino-2-fluorophenyl)-6- chloropyrazolo[1,5-a]pyrazine-3-carboxamide hydrochloride (507 mg, 1.19 mmol) in DCM (15 mL) and DIPEA (0.9 mL, 5.22 mmol) under nitrogen was added 2-chloroacetyl chloride (0.14 mL, 1.78 mmol) to yield a clear purplish solution (exotherm) which was stirred at rt overnight. An additional 0.65 mL 2-chloroacetyl chloride and 0.30 mL DIPEA were added. After 4 h the reaction was stirred with water and a dark solid was collected and rinsed well with water and DCM and left to dry in the filter funnel over the weekend to yield 6-chloro-N- (5-(2-chloroacetamido)-2-fluorophenyl)pyrazolo[1,5-a]pyrazin e-3-carboxamide (129 mg, 29%) as a tan solid. LCMS (ESI): mass calcd. for C ₁₅ H ₁₀ Cl ₂ FN ₅ O ₂ , 382.18; m/z found, 382.0/384.0 [M+H]+. Step d: 6-chloro-N-(2-fluoro-5-(2-(tetrahydro-1H-furo[3,4-c]pyrrol-5 (3H)- yl)acetamido)phenyl)pyrazolo[1,5-a]pyrazine-3-carboxamide [00879] A mixture of 6-chloro-N-(5-(2-chloroacetamido)-2- fluorophenyl)pyrazolo[1,5-a]pyrazine-3-carboxamide (68 mg, 0.18 mmol), hexahydro-1H- furo[3,4-C]pyrrole (40 mg, 0.35 mmol), and Cs ₂ CO ₃ (116 mg, 0.36 mmol) in DMF (2 mL) was heated at 50°C for 2 h, then allowed to cool to rt overnight. The reaction was filtered and purified by prep-HPLC, 20% - 40% MeCN/10 mM NH ₄ OH to yield 6-chloro-N-(2- fluoro-5-(2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)acetam ido)phenyl)pyrazolo[1,5- a]pyrazine-3-carboxamide (20 mg, 24.5%) as a tan solid. LCMS (ESI): mass calcd. for C ₂₁ H ₂₀ ClFN ₆ O ₃ , 458.88; m/z found, 459.0 [M+H]+. Step e: N-(2-fluoro-5-(2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)a cetamido)phenyl)- 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carbox amide [00880] A mixture of 6-chloro-N-(2-fluoro-5-(2-(tetrahydro-1H-furo[3,4-c]pyrrol- 5(3H)-yl)acetamido)phenyl)pyrazolo[1,5-a]pyrazine-3-carboxam ide (20 mg, 0.044 mmol), 1- methylpyrazole-4-boronic acid, pinacol ester (22 mg, 0.1 mmol), 1,1'- bis(diphenylphosphino)ferrocenedichloro palladium(II) (5 mg, 0.0072 mmol), and cesium carbonate (49 mg, 0.15 mmol) in 1,4-dioxane (1 mL) and water (0.3 mL) under nitrogen in a capped 5 mL microwave vial was sparged with nitrogen for 10 min and heated at 130°C in the microwave for 1 h. The reaction was stirred with Si-trisamine over the weekend. The mixture was filtered, rinsed with dioxane and a small volume DMF then purified by prep- HPLC, 5% - 25% MeCN/water/0.1% TFA to yield N-(2-fluoro-5-(2-(tetrahydro-1H-furo[3,4- c]pyrrol-5(3H)-yl)acetamido)phenyl)-6-(1-methyl-1H-pyrazol-4 -yl)pyrazolo[1,5-a]pyrazine- 3-carboxamide (18 mg, 67%) as an off-white solid. LCMS (ESI): mass calcd. for C ₂₅ H ₂₅ FN ₈ O ₃ , 504.53; m/z found, 505.1 [M+H]+. ¹ H NMR (METHANOL-d4) δ: 9.60 (d, J=1.5 Hz, 1H), 9.02 (d, J=1.5 Hz, 1H), 8.69 (s, 1H), 8.20-8.25 (m, 2H), 8.07 (s, 1H), 7.44- 7.52 (m, 1H), 7.22 (dd, J=10.3, 9.3 Hz, 1H), 4.02-4.27 (m, 4H), 3.97 (s, 3H), 3.90 (br d, J=9.3 Hz, 2H), 3.53-3.78 (m, 4H), 3.15-3.24 (m, 2H). [00881] The following examples were similarly prepared according to the procedure described in Example 175 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art. Example 181, (S)-N-(2-fluoro-5-(2-(3-methoxypyrrolidin-1-yl)acetamido)pyr idin-3-yl)-6- (1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxam ide Step a: ethyl 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carbox ylate [00882] To a mixture of ethyl 6-chloropyrazolo[1,5-a]pyrazine-3-carboxylate (3.0 g, 13.3 mmol) in dioxane (60 mL) and H ₂ O (15 mL).Then 1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.3 g, 25.2 mmol), K ₂ CO ₃ (5.1 g, 37.1 mmol) and Pd- 118 (606 mg, 0.93 mmol) was added. The reaction mixture was purged with N ₂ for 2 minutes. The mixture reaction was warmed to 90°C for 16 hrs. The mixture was concentrated under vacuum and purified by silica gel chromatography (eluent: DCM/MeOH from 100/0 to 90/10). The product fractions were collected and the solvent was evaporated to give ethyl 6- (1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxyl ate (4.0 g, crude) as a brown solid. LCMS (ESI): mass calcd. for C ₁₃ H ₁₃ N ₅ O ₂ , 271.3 m/z found, 272.1 [M+H] ⁺ . Step b: 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carbox ylic acid [00883] To a solution of ethyl 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazine-3-carboxylate (2.0 g, 7.4 mmol) in THF/MeOH=1/1 (30 mL)was added lithium hydroxide hydrate (393 mg, 9.4 mmol) in H ₂ O (10 mL) and the reaction was stirred at 20°C for 16 hours. The mixture was concentrated under vacuum and poured into 100 mL of ice- water carefully and acidified with 1N HCl to pH=5. The mixture was filtered, rinsed with H ₂ O (50 mL× 3). The filter cake was dried in vacuo to afford 6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxylic acid (2.4 g, crude) as a yellow solid. LCMS (ESI): mass calcd. for C ₁₁ H ₉ N ₅ O ₂ , 243.2 m/z found, 244.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.39 - 9.44 (m, 1H), 9.28 - 9.35 (m, 1H), 8.43 - 8.57 (m, 1H), 8.31 - 8.38 (m, 1H), 8.06 - 8.14 (m, 1H), 3.88 - 3.94 (m, 3H) Step c: tert-butyl (6-fluoro-5-nitropyridin-3-yl)carbamate [00884] To a mixture of 5-bromo-2-fluoro-3-nitropyridine (2.0 g, 9.1 mmol), tert- butyl carbamate (1.3 g, 10.9 mmol) in dioxane (60 mL) was added Cs ₂ CO ₃ (4.8 g, 14.7 mmol) and XPhos (0.88 g, 1.8 mmol), then Pd ₂ (dba) ₃ (1.3 g, 1.4 mmol) was added at 25°C under N ₂ . The mixture reaction was warmed to 90°C overnight. The mixture was concentrated under vacuum and purified by silica gel chromatography (eluent: petroleum ether/DCM from 100/0 to 0/100). The product fractions were collected and the solvent was evaporated to give tert- butyl (6-fluoro-5-nitropyridin-3-yl)carbamate (2.1 g, crude) as a brown solid. LCMS (ESI): mass calcd. for C ₁₀ H ₁₂ FN ₃ O ₄ , 257.2 m/z found, 258.1 [M+H] ⁺ . Step d: tert-butyl (5-amino-6-fluoropyridin-3-yl)carbamate [00885] To a mixture of tert-butyl (6-fluoro-5-nitropyridin-3-yl)carbamate (1.3 g, 4.0 mmol) in THF/Ethanol/H ₂ O (THF/Ethanol/H ₂ O=5:5:2, 36 mL) was added NH ₄ Cl (0.88 g, 16.4 mmol) and Fe (0.91 g, 16.3 mmol).The resulting mixture was stirred at 80 °C for 2 hrs. The reaction mixture was filtered, and the filtrate was concentrated under vacuum and purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate from 100/0 to 50/50). The product fractions were collected and the solvent was evaporated to give tert-butyl (5-amino-6- fluoropyridin-3-yl)carbamate (3.2 g, crude) as a yellow solid. LCMS (ESI): mass calcd. for C ₁₀ H ₁₄ FN ₃ O ₂ , 227.2 m/z found, 228.1 [M+H] ⁺ . Step e: tert-butyl (6-fluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyra zine-3- carboxamido)pyridin-3-yl)carbamate [00886] The mixture of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3- carboxylic acid (4.0 g, 15.8 mmol) and SOCl ₂ (55 mL) was added. Then the reaction mixture was stirred at 70°C for 1 hour. The reaction mixture was concentrated under vacuum to give tert-butyl (5-amino-6-fluoropyridin-3-yl)carbamate as a yellow solid. To the mixture of tert- butyl (5-amino-6-fluoropyridin-3-yl)carbamate (2.7 g, 12.0 mmol) in THF (45 mL) was added TEA (7 mL, 50.2 mmol). Then a solution of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazine-3-carbonyl chloride (4.1 g, 12.0 mmol) in THF (45 mL) was added slowly. The reaction mixture was stirred at 90°C for 1 hour. The mixture was filtered, rinsed with ethyl acetate (50 mL× 3). The filter cake was dried in vacuo to afford tert-butyl (6-fluoro-5-(6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamido )pyridin-3-yl)carbamate (4.7 g, 80% ) as a yellow solid. LCMS (ESI): mass calcd. for C ₂₁ H ₂₁ FN ₈ O ₃ , 452.4 m/z found, 453.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.24 - 10.31 (m, 1H), 9.71 - 9.81 (m, 1H), 9.50 - 9.59 (m, 1H), 9.27 - 9.35 (m, 1H), 8.82 - 8.90 (m, 1H), 8.44 - 8.52 (m, 1H), 8.33 - 8.38 (m, 1H), 8.10 - 8.15 (m, 1H), 8.01 - 8.09 (m, 1H), 3.89 - 3.94 (m, 3H), 1.44 - 1.54 (m, 9H) Step f: N-(5-amino-2-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl )pyrazolo[1,5- a]pyrazine-3-carboxamide [00887] To a solution of tert-butyl (6-fluoro-5-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamido)pyridin-3-yl)carbam ate (500 mg, 1.0 mmol) in DCM (8 mL) was added 4M HCl in dioxane (8 mL, 32 mmol) at room temperature for 4 hrs. The mixture was collected, dried in vacuo to give N-(5-amino-2-fluoropyridin-3-yl)-6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (400 mg, 88%) as a yellow solid. LCMS (ESI): mass calcd. for C ₁₆ H ₁₃ FN ₈ O, 352.3 m/z found, 353.1 [M+H] ⁺ . Step g: N-(5-(2-chloroacetamido)-2-fluoropyridin-3-yl)-6-(1-methyl-1 H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamide [00888] To the mixture of N-(5-amino-2-fluoropyridin-3-yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (400 mg, 0.89 mmol) in DMF (15 mL) was added NaHCO ₃ (237 mg, 2.8 mmol), then 2-chloroacetyl chloride (153 mg, 1.4 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was filtered and the filtrate was concentrated under vacuum to afford N-(5-(2-chloroacetamido)-2- fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5 -a]pyrazine-3-carboxamide (390 mg, 76%) as a brown solid. LCMS (ESI): mass calcd. for C ₁₈ H ₁₄ ClFN ₈ O ₂ , 428.8 m/z found, 429.1 [M+H] ⁺ . Step h: (S)-N-(2-fluoro-5-(2-(3-methoxypyrrolidin-1-yl)acetamido)pyr idin-3-yl)-6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide [00889] To the mixture of N-(5-(2-chloroacetamido)-2-fluoropyridin-3-yl)-6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (200 mg, 0.35 mmol) in DMF (10 mL) was added (S)-3-methoxypyrrolidine (77 mg, 0.76 mmol), K ₂ CO ₃ (204 mg, 1.5 mmol) and NaI (68 mg, 0.45 mmol). The reaction mixture was stirred at 50°C for 1 hour. Then the mixture was concentrated under vacuum to give the crude product, which was purified by preparative high-performance liquid chromatography over column: Phenomenex C18 80*40mm*3um to give the title compound (S)-N-(2-fluoro-5-(2-(3-methoxypyrrolidin-1- yl)acetamido)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyraz olo[1,5-a]pyrazine-3- carboxamide (36.1 mg, 21%) as a white solid. LCMS (ESI): mass calcd. for C ₂₃ H ₂₄ FN ₉ O ₃ , 493.5 m/z found, 494.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.66 - 10.88 (m, 2H), 9.52 - 9.61 (m, 1H), 9.23 - 9.37 (m, 1H), 8.79 - 8.93 (m, 1H), 8.62 - 8.71 (m, 1H), 8.33 - 8.39 (m, 1H), 8.26 - 8.31 (m, 1H), 8.07 - 8.16 (m, 1H), 3.92 - 3.97 (m, 1H), 3.88 - 3.92 (m, 3H), 3.27 - 3.31 (m, 2H), 3.16 - 3.23 (m, 3H), 2.86 - 2.94 (m, 1H), 2.66 - 2.74 (m, 1H), 2.56 - 2.65 (m, 2H), 1.95 - 2.10 (m, 1H), 1.67 - 1.79 (m, 1H) Example 182, (R)-N-(2-fluoro-5-(2-(2-(methoxymethyl)pyrrolidin-1- yl)acetamido)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyraz olo[1,5-a]pyrazine-3- carboxamide [00890] To the mixture of N-(5-(2-chloroacetamido)-2-fluoropyridin-3-yl)-6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (200 mg, 0.35 mmol) in DMF (10 mL) was added (R)-2-(methoxymethyl)pyrrolidine (115 mg, 0.76 mmol), K ₂ CO ₃ (204 mg, 1.5 mmol) and NaI (67 mg, 0.45 mmol). The reaction mixture was stirred at 50°C for 1 hour. Then the mixture was concentrated under vacuum to give the crude product, which was purified by preparative high-performance liquid chromatography over column: Phenomenex C18 80*40mm*3um to give the title compound (R)-N-(2-fluoro-5-(2-(2- (methoxymethyl)pyrrolidin-1-yl)acetamido)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (36.1 mg, 20%) as a white solid. LCMS (ESI): mass calcd. for C ₂₄ H ₂₆ FN ₉ O ₃ , 507.5 m/z found, 508.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.26 - 10.36 (m, 1H), 9.96 - 10.11 (m, 1H), 9.48 - 9.63 (m, 1H), 9.25 - 9.40 (m, 1H), 8.82 - 8.95 (m, 1H), 8.64 - 8.72 (m, 1H), 8.34 - 8.38 (m, 1H), 8.30 - 8.34 (m, 1H), 8.09 - 8.15 (m, 1H), 3.86 - 3.97 (m, 3H), 3.52 - 3.63 (m, 1H), 3.38 - 3.42 (m, 1H), 3.25 - 3.31 (m, 2H), 3.20 - 3.25 (m, 3H), 3.04 - 3.16 (m, 1H), 2.78 - 2.90 (m, 1H), 2.44 - 2.49 (m, 1H), 1.82 - 1.97 (m, 1H), 1.62 - 1.79 (m, 2H), 1.46 - 1.57 (m, 1H). [00891] The following examples were similarly prepared according to the procedure described in Example 181 above, selecting and substituting suitable starting materials and reagents, as would be readily recognized by those skilled in the art.

Biological Assays [00892] PDGFRβ HTRF assay [00893] I. Materials [00894] Reagents

[00895] Instrumentation: a. Compound liquid handling: LabCyte Echo; b. Reagent liquid handling: Thermo Scientific Multidrop Combi; c. BMG PHERAStar multilabel plate reader. [00896] Protein Reagent: His6-TEV-PDGFRβ Protein Prep prepared at Accelagen. [00897] II. Methods and Procedures [00898] Stock solutions: [00899] Assay buffer stock solution, contains 50 mM Hepes, 10 mM MgCl ₂ , 1 mM EGTA, and 0.01% Brij-35, 0.01% ovalbumin, 2 mM DTT at pH 7.5, in molecular biology grade water. Store at room temperature. [00900] DTT, 2 M in molecular biology grade water, store at -20°C in aliquots. [00901] Ovalbumin, 10% or 100 mg/mL, prepare fresh on experimental day. [00902] PDGFRβ, 116 µM (PDGFRb_08 Prep 02), produced at Accelagen. Store at -80°C in aliquots. [00903] TK-biotin peptide, 0.5 µM in molecular biology grade water, store at - 20°C in aliquots. [00904] ATP, 100 mM in molecular biology grade water, store at -20°C in aliquots. [00905] HTRF KinEASE-TK kit: Allow the contents of the Cisbio kit to warm up to room temperature before use. This kit contains HTRF detection buffer, TK-Antibody labeled with Eu ^3+- cryptate, TK-substrate biotin and Streptavidin-XL665. [00906] TK Substrate-Biotin, reconstitute 500 µg lyopholized with 574 µL molecular biology grade water to prepare a 500 µM stock; After use, aliquot the rest and store at -20°C. [00907] TK Antibody-Cryptate, reconstitute lyophilized with 1 mL of molecular biology grade water (100x solution) then add 99 mL detection buffer to prepare a ready to use TK-antibody-cryptate solution; the concentration of the TK-antibody-cryptate reagent is not known. After use, aliquot the rest and store at -20°C. [00908] Streptavidin-XL665, reconstitute 3 mg lyophilized with 3 mL molecular biology grade water to prepare a 1 mg/mL or 16.67 µM stock; MW = 60 kDa; After use, aliquot the rest and store at -20°C. [00909] Freshly prepared solutions: [00910] Assay buffer. Dilute 5x Kinase buffer 5-fold with molecular biology grade water and add DTT to 2 mM and ovalbumin to 0.1 mg/mL (or 0.01%). [00911] 2X protein solution. Make a working solution of 100 pM PDGFRβ in assay buffer. Keep on ice until use to maintain enzyme stability. [00912] 2X substrate solution. Make a working solution of 1.6 mM ATP and 1 µM TK-substrate biotin peptide in assay buffer. [00913] 3X quench/detection solution. Make a working solution of 0.1875 µM SA-XL665 and the TK-antibody cryptate diluted by ½ of total quench/detection volume in assay buffer. [00914] Keep final streptavidin/biotin ratio at 1 to 8. [00915] Example of 3x quench/detection solution preparation: 8 mL total volume. [00916] 1x assay buffer – 3910 µL [00917] TK antibody-cryptate in detection buffer – 4000 µL [00918] 0.1875 µM SA-XL665 – 90 uL [00919] The kinase reaction is stopped by the addition of the detection reagents which contain EDTA (detection step). [00920] Assay Procedure: [00921] Assay in white ProxiPlate 384-well [00922] Step 1. Dispensing inhibitors/DMSO and low control: Using the ECHO 555 acoustic dispenser, spot desired compound serial dilutions in DMSO, NEAT DMSO to represent the uninhibited enzyme control, and 10 µM final [imatinib] to the represent the 100% inhibited enzyme control [00923] Step 2. PDGFRβ E + I pre-incubation: Add 2 µL 2x protein solution to columns 1-24 using the Multidrop Combi. Centrifuge at 1000 rpm for 1 min. Incubate 30 min at RT [00924] Step 2. Enzymatic reaction: Add 2 µL substrate solution to columns 1-24 to initiate the reaction using the Multidrop Combi; cover/seal the assay plate to reduce evaporation. Centrifuge at 1000 rpm for 1 min. Incubate at room temperature for 3 hours. [00925] Final concentrations of components in PDGFRβ cascade assay: [00926] 50 mM Hepes, pH 7.5 [00927] 10 mM MgCl2 [00928] 0.01% Brij-35 [00929] 1 mM EGTA [00930] 2 mM DTT [00931] 0.01% Ovalbumin [00932] 50 pM inactive PDGFRβ [00933] 0.5 µM TK-substrate biotin peptide [00934] 62.5 nM SA-XL-665 [00935] TK antibody-Eu3+-cryptate (diluted by 1/3 final from stock) [00936] 800 µM ATP [00937] ≤ 1% DMSO [00938] Step 3. Quench/Detection: Add 2 µl 3x quench/detection solution to columns 1-24 using the Multidrop Combi; cover/seal the plate. Centrifuge 1 min 1000 rpm. Incubate at RT for 60 min. Read the plate in PHERAstar (or similar instrument) on HTRF setting at excitation 337nm - dual emission - 665/620 nm ratio. [00939] III. Calculations and Formulas [00940] HTRF ratio values calculated by the instrument (Ratio is acceptor counts/donor counts * 10,000) is exported from the plate reader and used in data analysis. The exported data will be used to calculate 1) compound activity and 2) assay statistics. Compound activity is represented by % Inhibition when testing a single dose of a compound or IC50 when testing a dose response of a compound. Assay statistics can include Robust Z’ and Signal to Background. [00941] % Inhibition Calculation: Percent inhibition will be calculated for sample ^{wells based on the equation:} ( _{^^^^ − ^^^^ ^^^^) % ^^^^ ^^^^ℎ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ =� ( ^^^^ ^^^^ − ^^^^ ^^^^)� ∗ 100)} [00942] Where, x: sample activity; cr: central reference is calculated based on wells containing all assay components and no compound (DMSO only); sr: scale reference is calculated based on wells inhibited with 10 µM Imatinib (these wells will contain the enzyme and substrate solutions) [00943] IC ₅₀ Calculation: For IC ₅₀ determination, full 11- point dose response data will be processed using the following equation: [00944] Where S0=Activity level at zero concentration of test compound; SInf=Activity level at infinite concentration; IC50: Concentration at which activity reaches 50% of maximum level; c= Concentration in logarithmic units corresponding to the values on the x-axis of the dose-response curve plot; Hill coefficient n= Measure of the slope at IC50. See Table 1, below. [00945] Registered Parameters (when applicable): % Activity, IC ₅₀ , nHill Slope, S _inf , S ₀ , and Comments [00946] Robust Z’ Calculation: Robust Z prime (RZ’) value will be calculated as defined by the following equation: mediancr − median sr [00947] Where, RSD: Robust standard deviation; cr: central reference is calculated based on wells containing all assay components and no compound (DMSO only); sr: scale reference is calculated based on wells inhibited with 10 µM Imatinib compound (these wells will contain the enzyme and substrate solutions) [00948] Signal to Background, S/B, Calculation [00949] Where, CR, Central Reference (no compound wells); SR, Scale Reference (inhibitor control wells). [00950] PDGFRβ LanthaScreen assay [00951] I. Materials [00952] II. Methods and Procedures [00953] Stock solutions: [00954] Assay buffer stock contains 50 mM HEPES pH7.5, 10 mM MgCl ₂ , 0.01% Brij- 35, 1 mM EGTA. [00955] Tb-labeled inactive PDGFRβ.3.6 µM in 50 mM HEPES, pH 7.4, 150 mM NaCl, 0.005% Tween-20 and 10% glycerol. Store at -80 ^o C in aliquots. [00956] Tracer 222, 50 µM in DMSO, store at -20 ^o C. [00957] Freshly prepared solutions: [00958] Assay buffer. Add DTT to 2 mM and ovalbumin to 0.1 mg/mL to Assay buffer stock. [00959] Kinase-Tracer solution. Make a working solution of 0.2 nM Tb-labeled inactive PDGFRβ and 40 nM Tracer 222 in Assay buffer. Keep on ice until use. [00960] Assay Procedure: [00961] Step 1. Dispensing inhibitors: Using Echo, dispense 40nL/well (or less) compound serial dilutions in DMSO onto the assay plate. [00962] Step 2. Dispensing Kinase-Tracer solution: Add 4 µL/well Kinase-Tracer solution. Seal the plate with optically transparent plate seal. Centrifuge at 1000 rpm for 1 min. [00963] Final concentrations of components in the assay: [00964] [Tb-PDGFRβ] = 0.2 nM; [00965] [Tracer 222] = 40 nM; [00966] [DMSO] ^ 1%. [00967] Step 3. Detection: Read TR-FRET signals after 18 hours incubation at room temperature. [00968] III. Calculations and Formulas [00969] % Inhibition: % Inhibition = (NC – sample) / (NC – PC) * 100 where NC is the mean of negative control (reactions without inhibitor), and PC is the mean of positive control (1µM sunitinib). [00970] IC50 determination: Compounds are serially diluted 3-fold and tested in an 11- point dose response. IC ₅₀ values are determined from a 4-parameter fit, using the following equation: Y = Bottom + (Top – Bottom) / (1+10((Log IC ₅₀ -X)*Hill slope)), where X = log ₁₀ of the compound concentration; top can be defined by PC; bottom defined by NC. See Table 1, below. [00971] PDGFRβ cellular assay [00972] I. Materials [00973] II. Methods and Procedures [00974] Cell Culture and Preparation: Cells are cultured according to ATCC procedure (5) with the addition of the antibiotic penicillin-streptomycin. If working from frozen, cells should be thawed according to ATCC procedure. Depending on the cell density of frozen vial, cells will need time to recover from thaw. An 80% confluent T75 flask should be enough for one 384 well plate. [00975] Stock Solutions: Rat PDGFBB. A 100ug/mL stock is prepared by reconstituting 50ug in 500uL of 4mM HCl and 0.1% BSA. It can be stored for a month at 4°C, or aliquoted out and frozen in the -20/-80°C to avoid multiple free-thaw cycles. [00976] Freshly Prepared Solutions: [00977] 1x Cisbio cell lysis buffer. The cell lysis buffer is diluted 4-fold with molecular grade water. The blocking agent is then diluted 25-fold in the diluted lysis buffer. [00978] Antibody solutions. Equal amounts d2 and cryptate antibody are diluted 20-fold in detection buffer. [00979] Rat PDGFBB. A working stock of 100ng/mL is created from the stock solution in 10%FBS culture media. [00980] Assay Steps [00981] Step 1: Plating Cells: Media from the A10 cell flask is aspirated. The cells are rinsed with PBS and then trypsinized to disperse the cell layer. The cells are then pelleted are resuspended to 1.25e5 cells/mL. 40uL of cells are then plated in 384 Greiner TC treated plates at a density of 5000 cells/well using the Combi. Plates are covered and placed in the incubator (37°C 5% CO2) overnight to allow cells to adhere. [00982] Step 2: Compound Dispense: Approximately 18 hours after plating, dispense 40nL compound onto cells using Echo. Column 12 is the neutral control DMSO, column 24 is the inhibitor control 10 mM Imatinib (10uM final assay concentration). The plate is returned to the incubator for 3 hours. [00983] Step 3: Activation by PDGFbb: 6uL of the working stock of 100ng/mL PDGFbb is dispensed using the Tempest to give a final assay concentration of 15ng/mL (EC80). After 10 minutes the media is removed by flicking the plate. [00984] Step 4: Cell lysis and antibody addition: 20uL lysis buffer per well is added to the plate via Tempest. 5uL antibody solution is added per well via the Tempest. The plate is placed on the shaker at 230 rpm for 1 hour at room temperature. [00985] Step 5: Detection: The plate is read using the HTRF module on the BMG Pherastar. Data is analyzed using Genedata Screener. [00986] III. Calculations and Formulas: [00987] % Inhibition: % Inhibition = (NC – sample) / (NC – PC) * 100 where NC is the mean of negative control (reactions without inhibitor), and PC is the mean of positive control (10µM imatinib). [00988] IC50 determination: Compounds are serially diluted 3-fold and tested in an 11- point dose response. IC ₅₀ values are determined from a 4-parameter fit, using the following equation: Y = Bottom + (Top – Bottom) / (1+10((Log IC ₅₀ -X)*Hill slope)), where X = log ₁₀ of the compound concentration; top can be defined by PC; bottom defined by NC. See Table 1, below. [00989] VEGFR ADP GLO assay [00990] I. Materials

[00991] II. Methods and Procedures [00992] Stock solutions: [00993] Assay buffer stock contains 50mM HEPES pH7.5, 10mM MgCl2, 0.01% Brij-35, and 1mM EGTA. [00994] Unphosphorylated VEGFR2.52.6 µM in 50 mM Tris-HCl, pH 8.0, 50 mM NaCl, 5% Glycerol, 0.5 mM TCEP. Store at -80 ^o C in aliquots. [00995] 10mg/mL srctide solution, prepared in Assay buffer (Assay buffer stock with 2mM DTT, 0.1% Pluronic F-127, and 0.1mg/mL ovalbumin). Sonicate 10 mg/ml Srctide solution for 10 minutes and then vacuum filter. [00996] Freshly prepared solutions [00997] Assay buffer. Add DTT to 2mM, Pluronic F-127 to 0.1% and ovalbumin to 0.1mg/mL to Assay buffer stock. [00998] 2X kinase solution. Make a working solution of 10 nM unphosphorylated VEGFR2 in Assay buffer. Vacuum filter 2x kinase solution prior to running assay. Keep on ice until use. [00999] 2X substrate/ATP solution. Make a working solution of 2mg/mL srctide and 2.4mM ATP in Assay buffer. Keep on ice until use. [001000] Assay Procedure: [001001] Step 1. Dispensing inhibitors/controls: Using Echo, dispense 10nL/well compound serial dilutions in DMSO to columns 1-22 (in 384-well plates) or columns 1-44 (in 1536-well plates). Dilution series = 11 pt, 3-fold dilutions. The top compound concentration in the source plate is 4 mM. The top compound concentration in the assay plate is 10 uM. Using Echo, dispense 10 nl/well DMSO to column 23 (in 384-well plates) or columns 45-47 (in 1536-well plates). These wells will serve as negative control wells Using Echo, dispense 10 nl/well 400 uM TAK-593 in DMSO to column 24 (in 384-well plates) or column 48 (in 1536-well plates). The final concentration of TAK-593 in the assay should be 1 uM. These wells will serve as positive control wells. [001002] Step 2. Pre-incubation of inhibitors with kinase: Add 2 µL/well 2X kinase solution. Centrifuge at 1000 rpm for 1 min. Incubate at room temperature for 30 min. [001003] Step 3. Kinase cascade reaction: Add 2 µL/well 2X substrate/ATP solution to initiate kinase reactions. Centrifuge at 1000 rpm for 1 min. Incubate at room temperature for 180 min. [001004] Final concentrations of components in the assay: [001005] [VEGFR2] = 5 nM; [001006] [ATP] = 1.2 mM; [001007] [Srctide] = 1 mg/mL; [001008] [DMSO] ^ 1%. [001009] Step 4. Quench: Add 2 uL/well ADP Glo Reagent + 0.05% CHAPS. Centrifuge at 1000 rpm for 1 min; Incubate at room temperature for one hour. [001010] Step 5. Detection: Add 2uL/well Kinase Detection Reagent + 0.05% CHAPS. Centrifuge at 1000 rpm for 1 min; Incubate at room temperature for 1 hour; Read Luminescence on a plate reader. [001011] III. Calculations and Formulas [001012] % Inhibition: % Inhibition = (NC – sample) / (NC – PC) * 100 where NC is the mean of negative control (reactions without inhibitor), and PC is the mean of positive control (1µM TAK-593). [001013] IC50 determination: Compounds are serially diluted 3-fold and tested in an 11- point dose response. IC ₅₀ values are determined from a 4-parameter fit, using the following equation: Y = Bottom + (Top – Bottom) / (1+10 ^{(Log IC50-X)*Hill slope} ), where X = log ₁₀ of the compound concentration; top can be defined by PC; bottom defined by NC. See Table 1, below. [001014] Table 1: