PYRROLOPYRID AZINE COMPOUNDS AS KINASE INHIBITORS

FIELD OF THE INVENTION

The present invention relates generally to inhibitors of JAK kinase, pharmaceutical compositions comprising them, processes for preparing them and uses of such inhibitors to treat or prevent diseases, disorders and conditions associated with kinase function.

BACKGROUND

Ulcerative colitis is a chronic inflammatory disease of the colon. The disease is characterized by inflammation and ulceration of the mucosal layer of the rectum and the large intestine. Common symptoms include diarrhea, bloody stools, and abdominal pain. The clinical course is intermittent, marked by alternating periods of exacerbation and remission. Incidence seems to be greater in developed than in developing countries. An estimated 1.2 million people in major industrialized countries suffer from ulcerative colitis and the numbers are expected to increase along with population growth. Patients with ulcerative colitis are at an increased risk of developing colorectal cancer.

Although there exists a variety of therapeutic options to promote and maintain remission of ulcerative colitis (UC) in patients, none is ideal. Sulfasalazine-related treatments are often effective in mild UC, but much less so in moderate to severe disease. Corticosteroids are often used to provide rapid induction of remission in patients with moderate to severe UC. However, chronic use of steroids to maintain remission is discouraged due to their association with longer term adverse effects (e.g., osteoporosis and fractures, infections, cataracts, slower wound healing and suppression of adrenal gland hormone production). Systemic immunosuppressants such as azathioprine, cyclosporine and methotrexate have a slow onset and modest efficacy in moderate to severe UC patients, but prolonged use can be problematic due to consequences of long term systemic immunosuppression (e.g., increased risk of infections and lymphoma). Anti-TNFa antibodies (e.g., infliximab and adalimumab), while expensive and requiring subcutaneous or intravenous administration, are efficacious in approximately 60-70 % of UC patients with moderate to severe disease. However, up to one third of patients fail to respond adequately, while another third of initial responders develop tolerance over a few weeks.

Vedolizumab (ENTYVIO), an anti-integrin a4p7 antibody, is an approved therapy for moderate to severe UC patients although its parenteral route is suboptimal, and the consequences of long-term immunosuppression via this mechanism remain to be determined. Despite existing therapeutic options, about 10 to 20 % of UC patients still require colectomy within 10 years of diagnosis. It is clear there remains an unmet medical need for an effective therapy to promote and maintain remission of moderate to severe UC without the safety concerns resulting from chronic, systemic immunosuppression.

While the mechanism underlying ulcerative colitis is not completely understood, it is believed that environmental factors in genetically susceptible individuals evoke an inappropriate (excessive) reaction by the immune system to gut microbiota, resulting in colonic inflammation, tissue damage, and the associated symptoms characteristic of the disease.

Although the precise pathogenesis of UC is unclear, it is apparent that proinflammatory cytokines play a pivotal role in the immunological response. Many of the proinflammatory cytokines most commonly elevated in UC, rely on the JAK family of tyrosine kinases (i.e., JAK1, JAK2, JAK3 and TYK2) for signal transduction. Binding of a cytokine to a JAK-dependent cytokine receptor induces receptor dimerization which results in phosphorylation of tyrosine residues on the JAK kinase, effecting JAK activation. Phosphorylated JAKs, in turn, bind and phosphorylate various STAT proteins which dimerize, internalize in the cell nucleus and directly modulate gene transcription, leading, among other effects, to the downstream effects associated with inflammatory disease. The JAKs usually associate with cytokine receptors in pairs as homodimers or heterodimers. Specific cytokines are associated with specific JAK pairings.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease affecting ~14 million people in the United States. Elevation of proinflammatory cytokines that rely on the JAK- STAT pathway, (in particular, IL-4, IL-5, IL-10, IL-12, IL-13, IFNy, and TSLP), has been associated with AD, and upregulation of IL-31, another cytokine that signals through a JAK pairing, plays a role in the pruritis associated with chronic of AD.

Inhibition of the family of JAK enzymes could inhibit signaling of many key pro- inflammatory cytokines. Thus JAK inhibitors are likely to be useful in the treatment of ulcerative colitis, and other gastrointestinal inflammatory diseases such as Crohn's disease and immune checkpoint inhibitor induced colitis, atopic dermatitis, and other inflammatory skin diseases, allergic rhinitis, asthma, and chronic obstructive pulmonary disease (COPD). However, due to the modulating effect of the JAK/STAT pathway on the immune system, systemic exposure to JAK inhibitors may have an adverse systemic immunosuppressive effect. It would be desirable, therefore, to provide new JAK inhibitors with effects at the site of action without significant systemic effects. In particular, for the treatment of gastrointestinal inflammatory diseases, such as ulcerative colitis, it would be desirable to provide new JAK inhibitors which can be administered orally and achieve therapeutically relevant exposure in the gastrointestinal tract with minimal systemic exposure. It would also be desirable to provide new JAK inhibitors for the treatment of atopic dermatitis, which can be administered topically with minimal systemic exposure.

BRIEF SUMMARY

In one aspect, compounds are provided having the structure of Formula (I): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein A, B, X, Z, R ¹ , R ² , R ³ and R ⁴ are as defined below.

In one embodiment, a pharmaceutical composition is provided comprising a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, and at least one pharmaceutically acceptable excipient.

In one embodiment, a method of inhibiting one or more JAK enzymes is provided, comprising contacting one or more JAK enzymes with an effective amount of a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof.

In one embodiment, a method for treating a JAK mediated condition is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof.

In one embodiment, the use of a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof is provided, in the manufacture of a medicament. In some embodiments the medicament is usefuly for treating inflammatory disease, in particular gastrointestinal inflammatory diseases.

DETAILED DESCRIPTION Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the detailed description is exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting.

Although various features of the invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the invention may be described herein in the context of separate embodiments for clarity, the invention may also be implemented in a single embodiment.

Reference in the specification to "some embodiments", "an embodiment", "one embodiment" or "other embodiments" means that a particular feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments, of the inventions.

As used herein, ranges and amounts can be expressed as "about" a particular value or range. About also includes the exact amount. Hence "about lOOpL" means "about lOOpL" and also " lOOpL." In some embodiments, about means within 5% of the value. Hence, "about lOOpL" means 95-105uL. Generally, the term "about" includes an amount that would be expected to be within experimental error.

As used herein, "alkyl" means a straight chain or branched saturated hydrocarbon group. "Lower alkyl" means a straight chain or branched alkyl group having from 1 to 8 carbon atoms, in some embodiments from 1 to 6 carbon atoms, in some embodiments from 1 to 4 carbon atoms, and in some embodiments from 1 to 2 carbon atoms. Examples of straight chain lower alkyl groups include, but are not limited to, methyl, ethyl, w-propyl, //-butyl, w-pentyl, w-hexyl, n- heptyl, and //-octyl groups. Examples of branched lower alkyl groups include, but are not limited to, isopropyl, Ao-butyl, sec-butyl, /-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.

"Alkenyl" groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to -CH=CH ₂ , -CH=CH(CH ₃ ), -CH=C(CH ₃ ) ₂ , -C(CH ₃ )=CH ₂ , -C(CH ₃ )=CH(CH ₃ ), -C(CH ₂ CH ₃ )=CH ₂ , -CH=CHCH ₂ CH ₃ , -CH=CH(CH ₂ ) ₂ CH ₃ , -CH=CH(CH ₂ ) ₃ CH ₃ , -CH=CH(CH ₂ ) ₄ CH ₃ , vinyl, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.

"Alkynyl" groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to -C^CH, -C=C(CH ₃ ), -C=C(CH ₂ CH ₃ ), -CH ₂ C =CH, -CH ₂ C =C(CH ₃ ), and -CH ₂ C =C(CH ₂ CH ₃ ), among others.

As used herein, "alkylene" means a divalent alkyl group. Examples of straight chain lower alkylene groups include, but are not limited to, methylene (i.e., -CH ₂ -), ethylene (i.e., — CH ₂ CH ₂ — ), propylene (i.e., -CH ₂ CH ₂ CH ₂ -), and butylene (i.e., -CH ₂ CH ₂ CH ₂ CH ₂ -). As used herein, "heteroalkylene" is an alkylene group of which one or more carbon atoms is replaced with a heteroatom such as, but not limited to, N, O, S, or P.

"Alkoxy" refers to an alkyl as defined above joined by way of an oxygen atom (i.e., ~Q~ alkyl). Examples of lower alkoxy groups include, but are not limited to, methoxy, ethoxy, n- propoxy, //-butoxy, isopropoxy, .scc-butoxy, Zc/7-butoxy, and the like.

The terms "carbocyclic" and "carbocycle" denote a ring structure wherein the atoms of the ring are carbon. Carbocycles may be monocyclic or polycyclic. Carbocycle encompasses both saturated and unsaturated rings. Carbocycle encompasses both cycloalkyl and aryl groups. In some embodiments, the carbocycle has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7. Unless specifically indicated to the contrary, the carbocyclic ring can be substituted with as many as N substituents wherein N is the size of the carbocyclic ring with for example, alkyl, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

"Cycloalkyl" groups are alkyl groups forming a ring structure, which can be substituted or unsubstituted. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups can be mono- substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6- disubstituted cyclohexyl groups or mono-, di- or tri -substituted norbomyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

"Aryl" groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain 6-14 carbons in the ring portions of the groups. The terms "aryl" and "aryl groups" include fused rings wherein at least one ring, but not necessarily all rings, are aromatic, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).

"Carbocyclealkyl" refers to an alkyl as defined above with one or more hydrogen atoms replaced with carbocycle. Examples of carbocyclealkyl groups include, but are not limited to, benzyl and the like.

As used herein, "heterocycle" or "heterocyclyl" groups include aromatic and non-aromatic ring compounds (heterocyclic rings) containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, S, or P. A heterocycle group as defined herein can be a heteroaryl group or a partially or completely saturated cyclic group including at least one ring heteroatom. In some embodiments, heterocycle groups include 3 to 20 ring members, whereas other such groups have 3 to 15 ring members. At least one ring contains a heteroatom, but every ring in a polycyclic system need not contain a heteroatom. For example, a dioxolanyl ring and a benzodioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocycle groups within the meaning herein. A heterocycle group designated as a C2-heterocycle can be a 5- membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms and so forth. Likewise, a C4-heterocycle can be a 5- membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. A saturated heterocyclic ring refers to a heterocyclic ring containing no unsaturated carbon atoms. "Heteroaryl" groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. A heteroaryl group designated as a C ₂ -heteroaryl can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms and so forth. Likewise, a C ₄ -heteroaryl can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthal enyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, and quinazolinyl groups. The terms "heteroaryl" and "heteroaryl groups" include fused ring compounds such as wherein at least one ring, but not necessarily all rings, are aromatic, including tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl and 2,3-dihydro indolyl.

"Heterocyclealkyl" refers to an alkyl as defined above with one or more hydrogen atoms replaced with heterocycle. Examples of heterocyclealkyl groups include, but are not limited to, morpholinoethyl and the like.

"Halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

"Haloalkyl" refers to an alkyl as defined above with one or more hydrogen atoms replaced with halogen. Examples of lower haloalkyl groups include, but are not limited to, ^— CF ₃ , ^— CH ₂ CF ₃ , and the like.

"Haloalkoxy" refers to an alkoxy as defined above with one or more hydrogen atoms replaced with halogen. Examples of lower haloalkoxy groups include, but are not limited to -OCF ₃ , -OCH ₂ CF ₃ , and the like.

"Hydroxy alkyl" refers to an alkyl as defined above with one or more hydrogen atoms replaced with -OH. Examples of lower hydroxyalkyl groups include, but are not limited to -CH ₂ OH, -CH ₂ CH ₂ OH, and the like.

As used herein, the term "optionally substituted" refers to a group (e.g., an alkyl, carbocycle, or heterocycle) having 0, 1, or more substituents, such as 0-25, 0-20, 0-10 or 0-5 substituents. Substituents include, but are not limited to -OR ^a , -NR ^a R ^b , -S(O) ₂ R ^a or -S(O) ₂ OR ^a , halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl, wherein each R ^a and R ^b is, independently, H, alkyl, haloalkyl, carbocycle, or heterocycle, or R ^a and R ^b , together with the atom to which they are attached, form a 3-8 membered carbocycle or heterocycle.

"Isomer" is used herein to encompass all chiral, diastereomeric or racemic forms of a structure (i.e., stereoisomers), unless a particular stereochemistry or isomeric form is specifically indicated. Such compounds can be enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be synthesized to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of certain embodiments of the disclosure. The isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called "enantiomers." Single enantiomers of a pure compound are optically active (i.e., they can rotate the plane of plane polarized light and designated R or S).

"Isolated optical isomer" means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula. For example, the isolated isomer may be at least about 80%, at least 80% or at least 85% pure. In other embodiments, the isolated isomer is at least 90% pure or at least 98% pure, or at least 99% pure by weight.

"Substantially enantiomerically or diastereomerically" pure means a level of enantiomeric or diastereomeric enrichment of one enantiomer with respect to the other enantiomer or diastereomer of at least about 80%, and more specifically in excess of 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%.

The terms "racemate" and "racemic mixture" refer to an equal mixture of two enantiomers. A racemate is labeled "(±)" because it is not optically active (i.e., will not rotate plane-polarized light in either direction since its constituent enantiomers cancel each other out).

A "hydrate" is a compound that exists in combination with water molecules. The combination can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts. As the term is used herein a "hydrate" refers to a solid form; that is, a compound in a water solution, while it may be hydrated, is not a hydrate as the term is used herein.

A "solvate" is similar to a hydrate except that a solvent other that water is present. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometric or non-stoichiometric. As the term is used herein a "solvate" refers to a solid form; that is, a compound in a solvent solution, while it may be solvated, is not a solvate as the term is used herein.

"Isotope" refers to atoms with the same number of protons but a different number of neutrons, and an isotope of a compound of Formulas (I) includes any such compound wherein one or more atoms are replaced by an isotope of that atom. For example, carbon 12, the most common form of carbon, has six protons and six neutrons, whereas carbon 13 has six protons and seven neutrons, and carbon 14 has six protons and eight neutrons. Hydrogen has two stable isotopes, deuterium (one proton and one neutron) and tritium (one proton and two neutrons). While fluorine has several isotopes, fluorine 19 is longest-lived. Thus, an isotope of a compound having the structure of Formulas (I) includes, but not limited to, compounds of Formulas (I) wherein one or more carbon 12 atoms are replaced by carbon-13 and/or carbon-14 atoms, wherein one or more hydrogen atoms are replaced with deuterium and/or tritium, and/or wherein one or more fluorine atoms are replaced by fluorine- 19.

“Tautomer” refers to compounds formed by an interconvertible reaction called tautomerization, whereby there is a formal migration of a hydrogen atom along with a switch of a single bond and an adjacent double bond. For example, in the context of compound having the structure of Formula (I), tautomerization may be associated with conversion of the depicted amine to the corresponding imine.

"Salt" generally refers to an organic compound, such as a carboxylic acid or an amine, in ionic form, in combination with a counter ion. For example, salts formed between acids in their anionic form and cations are referred to as "acid addition salts". Conversely, salts formed between bases in the cationic form and anions are referred to as "base addition salts."

The term "pharmaceutically acceptable" refers an agent that has been approved for human consumption and is generally non-toxic. For example, the term "pharmaceutically acceptable salt" refers to nontoxic inorganic or organic acid and/or base addition salts (see, e.g., Lit et al., Salt Selection for Basic Drugs, Int. J. Pharm., 33, 201-217, 1986) (incorporated by reference herein).

Pharmaceutically acceptable base addition salts of compounds of the disclosure include, for example, metallic salts including alkali metal, alkaline earth metal, and transition metal salts such as, for example, calcium, magnesium, potassium, sodium, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N’ dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, hippuric, malonic, oxalic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, panthothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, phydroxybutyric, salicylic, -galactaric, and galacturonic acid.

Although pharmaceutically unacceptable salts are not generally useful as medicaments, such salts may be useful, for example as intermediates in the synthesis of the compounds described herein, for example in their purification by recrystallization.

In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, together with at least one pharmaceutically acceptable carrier, diluent, or excipient. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it can be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid carrier, for example contained in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone. Similarly, the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl di stearate, alone or mixed with a wax. As used herein, the term "pharmaceutical composition" refers to a composition containing one or more of the compounds described herein, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, homolog or salt thereof, formulated with a pharmaceutically acceptable carrier, which can also include other additives, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal.

As used herein, the term "pharmaceutically acceptable carrier" refers to any ingredient other than the disclosed compounds, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, homolog or salt thereof (e.g., a carrier capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (com), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

The route of administration can be any route which effectively transports the active compound of the disclosure to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution, or an ointment, the oral route being preferred. In some embodiments, the active compounds acts locally.

Dosage forms can be administered once a day, or more than once a day, such as twice or thrice daily. Alternatively, dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician. Dosing regimens include, for example, dose titration to the extent necessary or useful for the indication to be treated, thus allowing the patient’s body to adapt to the treatment and/or to minimize or avoid unwanted side effects associated with the treatment. Other dosage forms include delayed or controlled-release forms. Suitable dosage regimens and/or forms include those set out, for example, in the latest edition of the Physicians’ Desk Reference, incorporated herein by reference.

As used herein, the term "administering" or "administration" refers to providing a compound, a pharmaceutical composition comprising the same, to a subject by any acceptable means or route, including (for example) by oral, parenteral (e.g., intravenous), or topical administration.

As used herein, the term "treatment" refers to an intervention that ameliorates a sign or symptom of a disease or pathological condition. As used herein, the terms "treatment", "treat" and "treating," with reference to a disease, pathological condition or symptom, also refers to any observable beneficial effect of the treatment. The beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, a reduction in the number of relapses of the disease, an improvement in the overall health or well- being of the subject, or by other parameters well known in the art that are specific to the particular disease. A prophylactic treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs, for the purpose of decreasing the risk of developing pathology. A therapeutic treatment is a treatment administered to a subject after signs and symptoms of the disease have developed.

As used herein, the term "subject" refers to an animal (e.g., a mammal, such as a human). A subject to be treated according to the methods described herein may be one who has been diagnosed with a neurodegenerative disease involving demyelination, insufficient myelination, or underdevelopment of a myelin sheath, e.g., a subject diagnosed with multiple sclerosis or cerebral palsy, or one at risk of developing the condition. Diagnosis may be performed by any method or technique known in the art. One skilled in the art will understand that a subject to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition. As used herein, the term "effective amount" refers to a quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that agent. Ideally, an effective amount of an agent is an amount sufficient to inhibit or treat the disease without causing substantial toxicity in the subject. The effective amount of an agent will be dependent on the subject being treated, the severity of the affliction, and the manner of administration of the pharmaceutical composition. Methods of determining an effective amount of the disclosed compound sufficient to achieve a desired effect in a subject will be understood by those of skill in the art in light of this disclosure.

As used herein, the terms "modulate" or "modulating" refer to the ability to increase or decrease the activity of one or more protein kinases. Accordingly, compounds of the invention can be used in methods of modulating a protein kinase by contacting the protein kinase with any one or more of the compounds or compositions described herein. In some embodiments, the compounds can act as inhibitors of one or more protein kinases. In some embodiments, the compounds can act to stimulate the activity of one or more protein kinases. In further embodiments, the compounds of the invention can be used to modulate activity of a protein kinase in an individual in need of modulation of the receptor by administering a modulating amount of a compound as described herein.

As used herein, the term "JAK-mediated" or JAK-modulated or " JAK-dependent" diseases or disorders means any disease or other deleterious condition in which JAK, or a mutant thereof, is known to play a role. Accordingly, another embodiment of the present application relates to treating or lessening the severity of one or more diseases in which JAK, or a mutant thereof, is known to play a role. In particular, the present application relates to a method of treating or lessening the severity of a lung disease or condition, wherein said method comprises administering to a patient in need thereof a compound of Formula (I) or a composition according to the present application.

Also described herein are methods of inhibiting one or more JAK enzymes, comprising contacting the JAK enzyme with an effective amount of a compound of formula (I), or any of any of the compounds specifically disclosed herein, including those listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.

Also described herein are methods of treating or preventing an inflammatory disease, comprising administering an effective amount of a compound of formula (I), or any of any of the compounds specifically disclosed herein, including those listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.

JAK Enzyme Inhibitors

Described herein are inhibitors of the JAK family of enzymes: JAK1, JAK2, JAK3, and TYK2. Inhibition of JAK enzymes inhibits signaling of many key pro-inflammatory cytokines. As such, JAK inhibitors are useful in the treatment of inflammatory diseases, including gastrointestinal inflammatory diseases, such as ulcerative colitis, Crohn's disease, immune checkpoint inhibitor induced colitis and the like; inflammatory and pruritic skin diseases, such as atopic dermatitis; and respiratory conditions such as allergic rhinitis, asthma, and chronic obstructive pulmonary disease (COPD).

Gastrointestinal Inflammatory Disease

JAK enzyme inhibitors are expected to be useful for the treatment of a variety of gastrointestinal inflammatory indications including, but are not limited to, ulcerative colitis (proctosigmoiditis, pancolitis, ulcerative proctitis and left-sided colitis), Crohn's disease, collagenous colitis, lymphocytic colitis, Behcet's disease, celiac disease, immune checkpoint inhibitor induced colitis, ileitis, eosinophilic esophagitis, graft versus host disease-related colitis, and infectious colitis. In particular, JAK inhibitors are useful for the induction and maintenance of remission of ulcerative colitis, and for the treatment of Crohn's disease, immune checkpoint inhibitor induced colitis, and the gastrointestinal adverse effects in graft versus host disease.

In some embodiments, the invention provides a method of treating a gastrointestinal inflammatory disease in a mammal (e.g., a human), the method comprising administering to the mammal a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof

In some embodiments, the invention provides a method of treating ulcerative colitis in a mammal, comprising administering to the mammal a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.

When used to treat ulcerative colitis, the compounds of the invention will typically be administered orally in a single daily dose or in multiple doses per day, although other forms of administration may be used. The amount of active agent administered per dose or the total amount administered per day will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

Suitable doses for treating ulcerative colitis and other gastrointestinal inflammatory disorders are expected to range from about 1 to about 400 mg/day of active agent, including from about 5 to about 300 mg/day and from about 20 to about 70 mg per day of active agent for an average 70 kg human.

Combination Therapy

The compounds described herein may be used in combination with one or more additional agents useful for the treatment of gastrointestinal inflammatory disorders. Useful classes of agents for combination therapy include, but are not limited to, aminosalicylates, steroids, systemic immunosuppressants, anti-TNFa antibodies, anti-VLA-4 antibodies, anti-integrin a4p7 antibodies, anti-bacterial agents, and anti-diarrheal medicines. Aminosalicylates include, but are not limited to, mesalamine, osalazine and sulfasalazine. Steroids include, but are not limited to, prednisone, prednisolone, hydrocortisone, budesonide, beclomethasone, and fluticasone.

Systemic immunosuppressants include, but are not limited to cyclosporine, azathioprine, methorexate, 6-mercaptopurine, and tacrolimus. Anti-TNFa antibodies include, but are not limited to, infliximab, adalimumab, golimumab, and certolizumab. Anti-VLA-4 antibodies include, but are not limited to, natalizumab, anti-integrin a4P? antibodies, such as vedolizumab, anti-bacterial agents, such as rifaximin, and anti -diarrheal medicines, such as loperamide

In another aspect, therefore, the invention provides a therapeutic combination for use in the treatment of gastrointestinal inflammatory disorders, the combination comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof and one or more other therapeutic agents useful for treating gastrointestinal inflammatory disorders. In some embodiments, the additional agent(s) are selected from aminosalicylates, steroids, systemic immunosuppressants, anti-TNFa antibodies, anti-VLA-4 antibodies, anti-integrin a4P? antibodies, anti-bacterial agents, and anti -diarrheal medicines.

Secondary agent(s), when included, are present in a therapeutically effective amount, i.e. in any amount that produces a therapeutically beneficial effect when co-administered with a compound as described herein. Also provided, are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof and one or more other therapeutic agents useful for treating gastrointestinal inflammatory disorders.

Also described herein are methods of treating gastrointestinal inflammatory disorders, the method comprising administering to the mammal a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof and one or more other therapeutic agents useful for treating gastrointestinal inflammatory disorders.

When used in combination therapy, the agents may be formulated in a single pharmaceutical composition, or the agents may be provided in separate compositions that are administered simultaneously or at separate times, by the same or by different routes of administration. When administered separately, the agents are administered sufficiently close in time so as to provide a desired therapeutic effect. Such compositions can be packaged separately or may be packaged together as a kit. The two or more therapeutic agents in the kit may be administered by the same route of administration or by different routes of administration.

Inflammatory Skin Disease

Atopic dermatitis has been associated with elevation of proinflammatory cytokines that rely on the JAK-STAT pathway, in particular, IL-4, IL-5, IL-10, IL-13, and TFNy. Therefore, JAK inhibitors are expected to inhibit the proinflammatory cytokines characteristic of atopic dermatitis and other inflammatory skin diseases.

Sustained dermal levels of JAK inhibitors in the absence of significant systemic levels should result in potent local anti-inflammatory and anti-pruritic activity in the skin without systemically-driven adverse effects. Such compounds are expected to be beneficial in a number of dermal inflammatory or pruritic conditions that include, but are not limited to atopic dermatitis, alopecia areata, vitiligo, cutaneous T cell lymphoma, prurigo nodularis, lichen planus, primary localized cutaneous amyloidosis, bullous pemphigoid, skin manifestations of graft versus host disease, pemphigoid, discoid lupus, granuloma annulare, lichen simplex chronicus, vulvar/scrotal/perianal pruritus, lichen sclerosus, post herpetic neuralgia itch, lichen planopilaris, and foliculitis decalvans. These diseases are characterized by elevation of certain cytokines that signal via JAK activation. Accordingly, JAK inhibitors may be able to alleviate associated dermal inflammation or pruritus driven by these cytokines. In particular, compounds of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof are expected to be useful for the treatment of atopic dermatitis and other inflammatory skin diseases.

In one aspect, therefore, the invention provides a method of treating an inflammatory skin disease in a mammal (e.g., a human), the method comprising applying a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof and a pharmaceutical carrier to the skin of the mammal. In one aspect, the inflammatory skin disease is atopic dermatitis.

Compounds of the invention may also be used in combination with gram positive antibiotics, such as mupirocin and fusidic acid, to treat inflammatory skin disease. In one aspect, therefore, the invention provides a method of treating an inflammatory skin disease in a mammal, the method comprising applying a compound of the invention and a gram positive antibiotic to the skin of the mammal. In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, a gram positive antibiotic, and a pharmaceutically- acceptable carrier.

Compounds

Disclosed herein are compounds having the structure of formula (I): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein:

A is H, halo or -CN, or a 5- or 6- membered aromatic ring comprising 0, 1 or 2 N atoms and substituted with 0, 1, 2 or 3 R ^A substituents, wherein each R ^A is independently Ci-4alkyl, halo, -CN, -CHF2, -CF ₃ , -OH,

OMe, -NH ₂ , -NHMe, -NMe ₂ , -CH ₂ OH, -CH ₂ OMe, -CH ₂ NH ₂ , -CH ₂ NMe ₂ , - CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ NMe2, -NH-C(=O)Me, -O-CH ₂ -COOH, -O-CH ₂ - COOMe, -O-CH ₂ -COOEt, -CH ₂ -CH ₂ -OH, -C(=O)-O-C _1-4 alkyl, -NH- C(=O)-NH- or -O-(CH ₂ CH ₂ O) _X -Me, wherein x is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

B is a C _5-10 non-aromatic cycloalkane, a C _5-10 non-aromatic bicycloalkane or a C _5-10 non- aromatic tri cycloalkane, or a 5-, 6- or 7-membered non-aromatic heterocycle containing 1 N atom or 1 O atom, wherein B is substituted with 0, 1, 2, 3 or 4 R ^B substituents, and each R ^B is independently oxo, Ci.4alkyl, -OH, -NH ₂ , -C(=O)-CH=CH ₂ , -C(=O)OC _1-4 alkyl, -NH-C(=O)-NH- C _1-4 alkyl, -NH-C(=O)-NH- C _1-4 alkylene-OH, - CH ₂ -COOH, -CH ₂ -COOMe, -CH ₂ -COOEt, -CH ₂ -CH ₂ -CN, -CH ₂ -CH ₂ -NH ₂ , -CH ₂ -CH ₂ -NHMe, -CH ₂ -CH ₂ -NMe2 or -NH-SO ₂ -C _1-4 alkyl;

X is O, S or NH;

Z is C or NH;

R ¹ is H, methyl, ethyl, halo, cyclopropyl or -CH ₂ CF ₃ ;

R ² is H, halo, OH, methoxy or NH ₂ ;

R ³ is H or F;

R ⁴ is H, F, Cl or methyl; and wherein at least one of R ¹ , R ² or R ³ is not H.

In some embodiments, A is H, halo or -CN.

In other embodiments, A is H.

In other embodiments, A is halo.

In other embodiments, A is -CN.

In some embodiments, A is a 5- or 6- membered aromatic ring comprising 0, 1 or 2 N atoms and substituted with 0, 1, 2 or 3 R ^A substituents.

In other embodiments, A is a 5- membered aromatic ring comprising 0, 1 or 2 N atoms and substituted with 0, 1, 2 or 3 R ^A substituents.

In other embodiments, A is a 6- membered aromatic ring comprising 0, 1 or 2 N atoms and substituted with 0, 1, 2 or 3 R ^A substituents.

In some embodiments, A is a 5-membered aromatic ring.

In other embodiments, A is a 5-membered aromatic ring comprising O atoms.

In other embodiments, A is a 5-membered aromatic ring comprising 1 N atom.

In other embodiments, A is a 5-membered aromatic ring comprising 2 N atoms. In other embodiments, A is a 5-membered aromatic ring comprising 0 or 1 N atoms.

In other embodiments, A is a 5-membered aromatic ring comprising 1 or 2 N atoms.

In other embodiments, A is a 6-membered aromatic ring.

In other embodiments, A is a 6-membered aromatic ring comprising O atoms.

In other embodiments, A is a 6-membered aromatic ring comprising 1 N atom.

In other embodiments, A is a 6-membered aromatic ring comprising 2 N atoms.

In other embodiments, A is a 6-membered aromatic ring comprising 0 or 1 N atoms.

In other embodiments, A is a 6-membered aromatic ring comprising 1 or 2 N atoms.

In some embodiments, A is a 5- or 6- membered aromatic ring substituted with 0, 1, 2 or 3 R ^A substituents.

In other embodiments, A is a 5-membered aromatic ring substituted with 0, 1, 2 or 3 R ^A substituents.

In other embodiments, A is a 6- membered aromatic ring substituted with 0, 1, 2 or 3 R ^A substituents.

In some embodiments, A is unsubstituted.

In other embodiments, A is substituted.

In other embodiments, A is substituted with 1 or 2 R ^A substituents.

In other embodiments, A is substituted with 1 R ^A substituent.

In other embodiments, A is substituted with 2 R ^A substituents.

In some embodiments, A is an unsubstituted 5-membered aromatic ring.

In other embodiments, A is a substituted 5-membered aromatic ring.

In other embodiments, A is a 5-membered aromatic ring substituted with 1 R ^A substituent.

In other embodiments, A is a 5-membered aromatic ring substituted with 2 R ^A substituents.

In other embodiments, A is a 5-membered aromatic ring substituted with 3 R ^A substituents.

In some embodiments, A is an unsubstituted 6-membered aromatic ring.

In other embodiments, A is a substituted 6-membered aromatic ring.

In other embodiments, A is a 6-membered aromatic ring substituted with 1 R ^A substituent.

In other embodiments, A is a 6-membered aromatic ring substituted with 2 R ^A substituents. In other embodiments, A is a 6-membered aromatic ring substituted with 3 R ^A substituents.

In some embodiments, A is a 5-membered aromatic ring comprising 0, 1 or 2 N atoms and substituted with 0, 1 or 2 R ^A substituents.

In other embodiments, A is a 5-membered aromatic ring substituted with 0, 1 or 2 R ^A substituents.

In other embodiments, A is a 5-membered aromatic ring comprising 1 or 2 N atoms and substituted with 0, 1 or 2 R ^A substituents.

In some embodiments, A is a 6-membered aromatic ring comprising 0, 1 or 2 N atoms and substituted with 0, 1 or 2 R ^A substituents.

In some embodiments, A is a 6-membered aromatic ring substituted with 0, 1 or 2 R ^A substituents.

In other embodiments, A is a 6-membered aromatic ring comprising 1 or 2 N atoms and substituted with 0, 1 or 2 R ^A substituents.

In some embodiments, A is:

In some embodiments, each R ^A is independently Ci.4alkyl, halo, -CN, -CHF2, -CF ₃ , -OH, -OMe, -NH ₂ , -NHMe or -NMe2.

In some embodiments, B is a C _5-10 non-aromatic cycloalkane, a C _5-10 non-aromatic bicycloalkane or a C _5-10 non-aromatic tricycloalkane.

In other embodiments, B is a C _5-10 non-aromatic cycloalkane.

In other embodiments, B is cyclopentyl, cyclohexyl or cycloheptyl.

In other embodiments, B is a C _5-10 non-aromatic bicycloalkane.

In other embodiments, B is a C _5-10 non-aromatic tricycloalkane.

In other embodiments, B is adamantyl.

In some embodiments, B is:

In some embodiments, B is an unsubstituted cyclopentyl, cyclohexyl or cycloheptyl.

In other embodiments, B is a substituted cyclopentyl, cyclohexyl or cycloheptyl.

In other embodiments, B is unsubstituted adamantly.

In other embodiments, B is substituted adamantly.

In some embodiments, B is a 5-, 6- or 7-membered non-aromatic heterocycle.

In other embodiments, B is a 5-, 6- or 7-membered non-aromatic heterocycle containing 1 N atom or 1 O atom.

In other embodiments, B is a 5-, 6- or 7-membered non-aromatic heterocycle containing 1 N atom.

In other embodiments, B is a 5-, 6- or 7-membered non-aromatic heterocycle containing 1 O atom.

In some embodiments, B is a 5-membered non-aromatic heterocycle.

In other embodiments, B is a 5-membered non-aromatic heterocycle containing 1 N atom or 1 O atom.

In other embodiments, B is a 5-membered non-aromatic heterocycle containing 1 N atom.

In other embodiments, B is a 5-membered non-aromatic heterocycle containing 1 O atom.

In some embodiments, B is a 6-membered non-aromatic heterocycle.

In other embodiments, B is a 6-membered non-aromatic heterocycle containing 1 N atom or 1 O atom.

In other embodiments, B is a 6-membered non-aromatic heterocycle containing 1 N atom.

In other embodiments, B is a 6-membered non-aromatic heterocycle containing 1 O atom.

In some embodiments, B is a 7-membered non-aromatic heterocycle.

In other embodiments, B is a 7-membered non-aromatic heterocycle containing 1 N atom or 1 O atom.

In other embodiments, B is a 7-membered non-aromatic heterocycle containing 1 N atom.

In other embodiments, B is a 7-membered non-aromatic heterocycle containing 1 O atom. In some embodiments, B is:

In some embodiments, B is unsubstituted piperidinyl.

In other embodiments, B is substituted piperidinyl.

In other embodiments, B is piperidinyl substituted with 1, 2, 3 or 4 R ^B substituents.

In some embodiments, B is unsubstituted.

In other embodiments, B is substituted with 1 R ^B substituent.

In other embodiments, B is substituted with 2 R ^B substituents.

In other embodiments, B is substituted with 4 R ^B substituents.

In other embodiments, each R ^B is independently methyl, ethyl, -OH or -NH ₂ .

In some embodiments X is S.

In other embodiments X is O.

In other embodiments X is NH.

In some embodiments Z is C.

In other embodiments Z is C and X is S.

In other embodiments Z is C and X is O.

In other embodiments Z is C and X is NH.

In some embodiments Z is NH.

In other embodiments Z is NH and X is S.

In other embodiments Z is NH and X is O.

In other embodiments Z is NH and X is NH.

In some embodiments R ¹ is H.

In other embodiments R ¹ is not H.

In other embodiments R ¹ is methyl or ethyl.

In other embodiments R ¹ is methyl.

In other embodiments R ¹ is ethyl.

In other embodiments R ¹ is halo.

In other embodiments R ¹ is cyclopropyl.

In other embodiments R ¹ is CH ₂ CF ₃ .

In some embodiments R ² is H. In other embodiments R ² is not H.

In other embodiments R ² is halo.

In other embodiments R ² is OH.

In other embodiments R ² is methoxy.

In other embodiments R ² is NH ₂ .

In some embodiments R ³ is H.

In other embodiments R ³ is not H.

In other embodiments R ³ is F.

In some embodiments R ⁴ is H.

In other embodiments R ⁴ is not H.

In other embodiments R ⁴ is F.

In other embodiments R ⁴ is Cl.

In other embodiments R ⁴ is methyl.

In some embodiments one of R ¹ , R ² or R ³ is not H.

In other embodiments two of R ¹ , R ² or R ³ are not H.

In other embodiments three of R ¹ , R ² or R ³ are not H.

In one embodiment, a compound of Formula (I) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of a compound of Table 1, below:

Table 1

Representative Compounds of Formula (I)

In further embodiments are pharmaceutically acceptable salts of compounds of formula (I). In other embodiments are solvates of compounds of formula (I). In other embodiments are hydrates of compounds of formula (I). In other embodiments are isomers of compounds of formula (I). In other embodiments are tautomers of compounds of formula (I). In other embodiments are racemates of compounds of formula (I). In other embodiments are isotopic forms of compounds of formula (I).

Also described herein are pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, adjuvant or vehicle. Also described herein are methods of inhibiting one or more JAK enzymes, comprising contacting the JAK enzyme with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.

Also described herein are methods of treating or preventing a disease, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof. In some embodiments, the disease is an inflammatory disease. In some embodiments, the inflammatory disease is atopic dermatitis. In some embodiments, the inflammatory disease is a gastrointestinal inflammatory disease. In some embodiments, the disease is Crohn's disease or ulcerative colitis. In some embodiments, the method further comprises administering one or more other therapeutic agents useful for treating an inflammatory disease. In some embodiments, the method further comprises administering one or more other therapeutic agents useful for treating a gastrointestinal inflammatory disease.

Also described herein are compounds of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, for use in the treatment of a disease in a mammal. In some embodiments, the disease is an inflammatory disease. In some embodiments, the disease is a gastrointestinal inflammatory disease. In some embodiments, the disease is Crohn's disease or ulcerative colitis.

Also described herein are use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, in the manufacture of a medicament. In some embodiments, the medicament is for the treatment of an inflammatory disease. In some embodiments, the medicament is for the treatment of a gastrointestinal inflammatory disease. In some embodiments, the medicament is for the treatment of Crohn's disease or ulcerative colitis.

Also described herein are compounds of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, for use in combination with one or more other therapeutic agents useful for treating a disease. In some embodiments, the disease is an inflammatory disease. In some embodiments, the disease is a gastrointestinal inflammatory disease. In some embodiments, the disease is Crohn's disease or ulcerative colitis.

Compound Synthesis Compounds having the structure of Formulas (I) may be synthesized using standard synthetic techniques known to those of skill in the art. For example, compounds of the present disclosure can be synthesized using the general synthetic procedures set forth in below.

Common intermediate, R ¹ , R ² , R ³ -substiuted (Z)-6-bromo-4-chloro-N'-phenylpyrrolo[l,2- b]pyridazine-3-carboximidamide, is prepared by coupling R ¹ , R ² , R ³ -substiuted aniline with 6- bromo-4-chloropyrrolo[l,2-b]pyridazine-3 -carboxamide in the presence of trimethyl aluminum.

Compounds of formula (I), wherein X is NH, are prepared according to the general synthetic scheme depicted below.

Compounds of formula (I), wherein X is O, may be prepared according to the general synthetic scheme depicted below.

Compounds of formula (I), wherein X is S, may be prepared according to the general synthetic scheme depicted below. To this end, the reactions, processes and synthetic methods described herein are not limited to the specific conditions described in the following experimental section, but rather are intended as a guide to one with suitable skill in this field. For example, reactions may be carried out in any suitable solvent, or other reagents to perform the transformationfs] necessary. Generally, suitable solvents are protic or aprotic solvents which are substantially non-reactive with the reactants, the intermediates or products at the temperatures at which the reactions are carried out (i.e., temperatures which may range from the freezing to boiling temperatures). A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction, suitable solvents for a particular work-up following the reaction may be employed.

Unless otherwise indicated, conventional methods of mass spectroscopy (MS), liquid chromatography-mass spectroscopy (LCMS), NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are employed. Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 7th Edition, John Wiley and Sons, Inc (2013). Alternate reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. As necessary, the use of appropriate protecting groups may be required. The incorporation and cleavage of such groups may be carried out using standard methods described in Peter G. M. Wuts and Theodora W. Green, Protecting Groups in Organic Synthesis, 4th Edition, Wiley -Interscience. (2006). All starting materials and reagents are commercially available or readily prepared.

EXAMPLE 1

COMPOUNDS OF FORMULA (I) WHEREIN

X IS NH, B IS UNSUBSTITUTED CYCLOPENTANE Synthesis of N'-(2-bromophenyl)-4-(cyclopentylamino)pyrrolor 1 ,2-b]pyridazine-3 - carboximidamide

Step 1 : N'-(2-bromophenyl)-4-chloropyrrolorL2-b]pyridazine-3 -carboximidamide

To a solution of 4-chloropyrrolo[l,2-b]pyridazine-3 -carboxamide (100 mg, 511.2 pmol) in toluene (5 mL) was added 2-bromoaniline (52.8 mg, 306.7 pmol). The mixture was cooled to 0 °C and trimethylaluminium (0.77 mL, 2.0 M in toluene) was added. After stirring for 30 minutes at room temperature and then heating to 110 °C for 3 hours, the reaction mixture was cooled to room temperature, quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 50 mg, 24%. LCMS (ESI) m/z = 349.2 (M+H).

Step 2: N'-(2-bromophenyl)-4-(cyclopentylamino)pyrrolorL2-b1pyridazi ne-3 -carboximidamide

To a solution of N'-(2-bromophenyl)-4-chloropyrrolo[l,2-b]pyridazine-3-carbox amidine (45 mg, 128.7 pmol) in N,N-dimethylacetamide (2 mL) were added cyclopentanamine (16.4 mg, 193.1 pmol) and N,N-diisopropylethylamine (49.9 mg, 386.1 pmol). After stirring for 2 hours at 100 °C, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with lOmmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-(2-bromophenyl)-4-(cyclopentylamino)pyrrolo[1,2-b]pyridaz ine-3- carboxamidine as a light yellow solid. Yield: 10 mg, 19%. LCMS (ESI) m/z = 398.3 (M+H). ¹ H NMR (400 MHz, DMSO-d6) δ 11.65 (d, 1H, J=6.8 Hz), 8.18 (s, 1H), 7.62-7.67 (m, 2H), 7.30- 7.34 (m, 1H), 6.93-7.03 (m, 3H), 6.65-6.67 (m, 1H), 6.25 (s, 2H), 4.55-4.65 (m, 1H), 1.99-2.03 (m, 2H), 1.60-1.70 (m, 6H). EXAMPLE 1B Synthesis of 4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxy-phenyl)-6-(1H-pyr azol-4- yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-(cyclopentylamino)- pyrrolo[1,2-b]pyridazine-3-carboxamidine 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro-pyrrolo[1,2- b]pyridazine-3-carboxamidine (180 mg, 354.4 umol) was suspended in DMA (2 mL). Cyclopentanamine (36 mg, 425.2 umol, 42 uL) and DIEA (137 mg, 1.06 mmol) were added to the suspension at room temperature. The resulting mixture was stirred at 90°C for 2 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column (petroleum ether/ethyl acetate, 3:1) afforded the title compound as a yellow solid. Yield: 123 mg, 62%. LCMS (ESI) m/z = 557.2 (M+H) Step 2: 4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxy-phenyl)-6-(1H-pyr azol-4-yl)pyrrolo[1,2-b]- pyridazine-3-carboxamidine To a stirred solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4- (cyclopentylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidine (80 mg, 143.7 umol) in DMF (2 mL) and water (0.43 mL) were added tripotassium phosphate (91.5 mg, 431.2 umol), tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carb oxylate (84.6 mg, 287.4 umol) and Pd(dtbpf)Cl2 (9.37 mg, 14.4 umol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 115°C for 2 h. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate) afforded 4- (cyclopentylamino)-N'-(2-ethyl-4-hydroxy-phenyl)-6-(1H-pyraz ol-4-yl)pyrrolo[1,2-b]pyridazine- 3-carboxamidine as a brown solid. Yield: 29.9 mg, 46 %. LCMS (ESI) m/z = 430.1 (M+H). ¹ H NMR (CD ₃ OD, 300 MHz) δ 8.04 (s, 1H), 7.89 (brs, 2H), 7.75 (s, 1H), 7.09 (s, 1H), 6.76 (s, 1H), 6.63-6.71 (m, 2H), 4.73-4.75 (m, 1H), 2.51 (q, 2H, J=7.5 Hz), 2.09-2.13 (m, 2H), 1.63-1.80 (m, 6H), 1.16 (t, 3H, J=7.5 Hz). EXAMPLE 1C Synthesis of N'-(2-chloro-5-fluoro-phenyl)-4-(cyclopentylamino)-6-(1H-pyr azol-4- yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: 6-bromo-N'-(2-chloro-5-fluoro-phenyl)-4-(cyclopentylamino)py rrolo[1,2-b]pyridazine-3- carboxamidine To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine (250 mg, 621.8 μmol) and cyclopentanamine (53 mg, 621.8 μmol) in N,N-dimethylacetamide (2 mL) was added N,N-diisopropylethylamine (241.1 mg, 1.87 mmol). After stirring for 2 hours at 80 °C, the reaction mixture was cooled to room temperature and purified by reverse phase column chromatography (acetonitrile/water 100%) to afford the title compound as a yellow solid. Yield: 260 mg, 93%. LCMS (ESI) m/z = 452.0 (M+H). Step 2: N'-(2-chloro-5-fluoro-phenyl)-4-(cyclopentylamino)-6-(1-tetr ahydropyran-2-ylpyrazol-4- yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a mixture of 6-bromo-N'-(2-chloro-5-fluoro-phenyl)-4-(cyclopentylamino)py rrolo[1,2- b]pyridazine-3-carboxamidine (100 mg, 221.9 μmol) and 1-tetrahydropyran-2-yl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (61.7 mg, 221.9 μmol) in 1,4-dioxane (2 mL) and water (0.2 mL) were added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (14.5 mg, 22.2 μmol) and potassium phosphate (141.3 mg, 665.6 μmol). The resulting mixture was purged with nitrogen gas and stirred for 2 hours at 90 °C under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water 90%) afforded the title compound as a yellow solid. Yield: 100 mg, 86%. LCMS (ESI) m/z = 522.0 (M+H). Step 3: N'-(2-chloro-5-fluoro-phenyl)-4-(cyclopentylamino)-6-(1H-pyr azol-4-yl)pyrrolo[1,2- b]pyridazine-3-carboxamidine To a solution of N'-(2-chloro-5-fluoro-phenyl)-4-(cyclopentylamino)-6-(1- tetrahydropyran-2-ylpyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3- carboxamidine (150 mg, 287.4 μmol) in dichloromethane (1 mL) was added 2,2,2-trifluoroacetic acid (1 mL). After stirring for 16 hours at 25 °C, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-(2-chloro-5-fluoro-phenyl)-4-(cyclopentylamino)-6-(1H-pyr azol-4- yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as a yellow solid. Yield: 16.0 mg, 12%. LCMS (ESI) m/z = 438.1 (M+H). ¹ H-NMR (DMSO-d6, 300 MHz) δ 12.81 (s, 1H), 11.34 (d, 1H, J=6.9 Hz), 8.05-8.22 (m, 2H), 7.84-7.98 (m, 2H), 7.45-7.55 (m, 1H), 7.12 (d, 1H, J=1.8 Hz), 6.80-6.99 (m, 2H), 6.49 (s, 2H), 4.70 (s, 1H), 2.00-2.15 (m, 2H), 1.60-1.70 (m, 6H). ¹⁹ F-NMR (DMSO-d6, 282 MHz) δ -114.45 (s, 1F). EXAMPLE 1D Synthesis of 4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxy-phenyl)-6-(1-meth ylpyrazol-4- yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a stirred solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4- (cyclopentylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidine (100 mg, 179.7 umol) in DMF (2 mL) and water (0.54 mL) were added tripotassium phosphate (114.4 mg, 539 umol), 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (74.8 mg, 359.3 umol) and Pd(dtbpf)Cl2 (11.7 mg, 18.0 umol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 115°C for 2 h. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate) afforded 4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxy-phenyl)-6-(1-meth ylpyrazol-4-yl)pyrrolo[1,2- b]pyridazine-3-carboxamidine as a light brown solid. Yield: 38.4 mg, 46 %. LCMS (ESI) m/z = 444.2 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.21 (d, 1H, J=6.8 Hz), 8.92 (s, 1H), 8.14 (s, 1H), 8.05 (s, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.06 (s, 1H), 6.68 (s, 1H), 6.57-6.62 (m, 2H), 5.88 (brs, 2H), 4.67-4.72 (m, 1H), 3.89 (s, 3H), 2.41 (q, 2H, J=7.6 Hz), 2.05-2.12 (m, 2H), 1.62-1.71 (m, 6H), 1.10 (t, 3H, J=7.6 Hz). EXAMPLE 1E Synthesis of N'-(2-chlorophenyl)-4-(cyclopentylamino)-6-(1-methylpyrazol- 4-yl)pyrrolo[1,2- b]pyridazine-3-carboxamidine Step 1: 6-bromo-N'-(2-chlorophenyl)-4-(cyclopentylamino)pyrrolo[1,2- b]pyridazine-3- carboxamidine To a solution of 6-bromo-4-chloro-N'-(2-chlorophenyl)pyrrolo[1,2-b]pyridazine -3-carboxamidine (200 mg, 520.8 μmol) and cyclopentanamine (44.3 mg, 520.8 μmol) in N,N-dimethylacetamide (2 mL) was added N,N-diisopropylethylamine (201.9 mg, 1.56 mmol). After stirring for 2 hours at 100 °C, the reaction mixture was cooled to room temperature and then purified by reverse phase column chromatography (acetonitrile/water) to afford the title compound as a yellow solid. Yield: 200 mg, 89%. LCMS (ESI) m/z = 434.0 (M+H). Step 2: N'-(2-chlorophenyl)-4-(cyclopentylamino)-6-(1-methylpyrazol- 4-yl)pyrrolo[1,2-b]- pyridazine-3-carboxamidine To a mixture of 6-bromo-N'-(2-chlorophenyl)-4-(cyclopentylamino)pyrrolo[1,2- b]pyridazine-3- carboxamidine (80 mg, 184.9 μmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazole (46.2 mg, 221.8 μmol) and potassium phosphate (117.7 mg, 554.6 μmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (12.1 mg, 18.5 μmol). The resulting mixture was purged with nitrogen gas and stirred for 2 hours at 100 °C. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide and filtered. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-(2-chlorophenyl)-4-(cyclopentylamino)-6-(1-methylpyrazol- 4- yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as a yellow solid. Yield: 18.0 mg, 22%. LCMS (ESI) m/z = 434.1 (M+H). ¹ H-NMR (DMSO-d6, 400 MHz) δ 8.14 (s, 1H), 8.05 (s, 1H), 7.88 (s, 1H), 7.80 (s, 1H), 7.47 (d, 1H, J= 8.0 Hz), 7.28 (t, 1H, J=7.6 Hz), 6.99-7.10 (m, 3H), 4.69 (d, 1H, J=5.2 Hz), 3.85 (s, 3H), 2.02-2.11 (m, 2H), 1.60-1.72 (m, 6H). EXAMPLE 1F Synthesis of (Z)-4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxyphenyl)-6-phen ylpyrrolo[1,2- b]pyridazine-3-carboximidamide Step 1: (Z)-6-bromo-N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylphen yl)-4-chloropyrrolo[1,2-b]- pyridazine-3-carboximidamide 4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-aniline (200.0 mg, 795.42 umol) and 6-bromo-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamide (0.20 g, 728.59 umol) were suspended in toluene (5 mL) in an oven-dried screw cap vial equipped with a stir bar. The mixture was stirred at 0 °C while trimethylaluminum (2 M, 1.09 mL) was added dropwise via syringe. After 5 min the mixture was warmed to room temperature and after an additional 15 min it was warmed to 110 °C in a heating block. After 20 h the reaction mixture was cooled to room temperature, diluted with ethyl acetate and cooled to 0 °C. Water was added slowly until bubbling ceased. The mixture was diluted with 1M aqueous Rochelle salt. The layers were separated, and the aqueous phase extracted with ethyl acetate three times. The combined organic material was washed once with brine. The organic phase was dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purification via silica gel chromatography (0 to 65 % ethyl acetate in heptanes) afforded the title compound as a yellow oil. Yield: 341 mg (at 66 % purity), 61 % yield. LCMS Mass: 509.4, 511.4 (M ⁺ +H). Step 2: ((Z)-6-bromo-N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylphe nyl)-4-(cyclopentylamino)- pyrrolo[1,2-b]pyridazine-3-carboximidamide Cyclopentanamine (26.8 mg, 220.8 umol, 31.1 uL) and 6-bromo-N'-[4-[tert- butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-chloro-pyrrolo[1, 2-b]pyridazine-3-carboxamidine (0.083 g, 107.8 umol) were dissolved in DMA (1.3 mL) in an oven-dried screw cap vial equipped with a stir bar. Diisopropylethylamine (41.8 mg, 323.5 umol, 56.3 uL) was added and the mixture stirred at room temperature for 5 min and then warmed to 90°C in a heating block for 2 h. The reaction mixture was cooled to room temperature and stirred overnight. The mixture was diluted with ethyl acetate washed twice with a 1:1 brine:water solution, and then once more with 100 % brine. The organic phase was dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purification via silica gel chromatography (0-65 % ethyl acetate in heptane) afforded the product as a yellow residue, contaminated with impurities from starting material. Yield 51 mg at 85 % purity, 70 %. LCMS Mass: 558.5 (M ⁺ +H). Step 3: (Z)-N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylphenyl)-4-(c yclopentylamino)-6-phenyl- pyrrolo[1,2-b]pyridazine-3-carboximidamide A bottle of anhydrous DMF was purged with nitrogen gas for 30 min. phenylboronic acid (9.3 mg, 76.3 umol) were dissolved in DMF (1 mL) in an oven-dried screw cap vial equipped with a stir bar. Aqueous tripotassium;phosphate (1 M, 114 uL) was added and the mixture was purged with argon for 5 min. Dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II ) (1.2 mg, 1.9 umol) was added, the vial sealed and the mixture stirred at 95 °C for 90 min. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed twice with a 1:1 brine:water solution, and then once more with 100 % brine. The organic phase was dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purification via silica gel chromatography (0 to 65 % ethyl acetate in heptanes) and subsequent re-purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded the title compound as a white solid. Yield: 16.7 mg, 51 %. LCMS (ESI) m/z = 441.94 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 12.34 (br d, 1H, J=7.5 Hz), 8.93 (s, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 7.80 (d, 2H, J=7.5 Hz), 7.40 (t, 2H, J=7.6 Hz), 7.0-7.3 (m, 2H), 6.5- 6.7 (m, 3H), 5.85 (br s, 2H), 4.5-4.9 (m, 2H), 2.3-2.5 (m, 2H), 2.09 (br dd, 2H, J=6.0, 12.2 Hz), 1.5-1.7 (m, 5H), 1.24 (s, 1H), 1.0-1.2 (m, 3H) EXAMPLE 1G Synthesis of 4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxy-phenyl)-6-(o-toly l)pyrrolo[1,2- b]pyridazine-3-carboxamidine Step 1: N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-(cycl opentylamino)-6-(o-tolyl)- pyrrolo[1,2-b]pyridazine-3-carboxamidine 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-(cyclopentylamino)pyrrolo[1,2- b]pyridazine-3-carboxamidine (100 mg, 179.7 umol) was suspended in 1,4- dioxane (6 mL) and water (2 mL). o-tolylboronic acid (48.9 mg, 359.3 umol), tripotassium phosphate (114.3 mg, 539.0 umol) and Pd(dtbpf)Cl2 (11.7 mg, 18.0 umol) were added to the suspension under nitrogen atmosphere. The resulting mixture was heated at 95°C for 2 h. After cooling to room temperature, the reaction mixture was concentrated and purified by silica gel column (petroleum ether/ethyl acetate, 2:1) to afford the titled as light yellow oil. Yield: 90 mg, 88%. LCMS (ESI) m/z = 568.3 (M+H) Step 2: 4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxy-phenyl)-6-(o-toly l)pyrrolo[1,2-b]pyridazine- 3-carboxamidine To a stirred solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-(cycl opentylamino)- 6-(o-tolyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (105 mg, 184.9 umol) in DMF (2 mL) was added cesium fluoride (112.4 mg, 739.7 umol, 27.3 uL) at room temperature under nitrogen atmosphere. After stirring for 2 h, the reaction mixture was purified via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) to afford 4-(cyclopentylamino)-N'-(2-ethyl-4- hydroxy-phenyl)-6-(o-tolyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine as a light yellow solid. Yield: 6.3 mg, 7.5 %. LCMS (ESI) m/z = 454.1 (M+H). ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.55 (brs, 1H), 8.00 (s, 1H), 7.77 (s, 1H), 7.43-7.45 (m, 1H), 7.20-7.31 (m, 4H), 7.04 (d, 1H, J=6.8 Hz), 6.86 (s, 1H), 6.76-6.80 (m, 1H), 4.51-4.60 (m, 1H), 2.62 (q, 2H, J=7.6 Hz), 2.49 (s, 3H), 2.15-2.19 (m, 2H), 1.70-1.89 (m, 6H), 1.28 (t, 3H, J=7.6 Hz). EXAMPLE 1H Synthesis of 4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxy-phenyl)-6-(m-toly l)pyrrolo[1,2- b]pyridazine-3-carboxamidine Step 1: N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-(cycl opentylamino)-6-(m-tolyl)- pyrrolo[1,2-b]pyridazine-3-carboxamidine 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-(cyclopentylamino)pyrrolo[1,2- b]pyridazine-3-carboxamidine (100 mg, 179.7 umol) was suspended in 1,4- dioxane (6 mL) and water (2 mL). m-tolylboronic acid (48.9 mg, 359.3 umol), tripotassium phosphate (114.3 mg, 539.0 umol) and Pd(dtbpf)Cl ₂ (11.7 mg, 18.0 umol) were added to the suspension under nitrogen atmosphere. The resulting mixture was heated at 95°C for 2 h, cooled to room temperature, and concentrated under reduced pressure. Purification via silica gel column (petroleum ether/ethyl acetate, 2:1) afforded the titled compound as light yellow oil. Yield: 80 mg, 78%. LCMS (ESI) m/z = 568.4 (M+H) Step 2: 4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxy-phenyl)-6-(m-toly l)pyrrolo[1,2- To a stirred solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-(cycl opentylamino)- 6-(m-tolyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (103 mg, 181.4 umol) in DMF (2 mL) was added cesium fluoride (110.2 mg, 725.6 umol) at room temperature under nitrogen atmosphere. After stirring for 2 h, the reaction mixture was purified via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) to afford 4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxy-phenyl)- 6-(m-tolyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as a yellow solid. Yield: 8.8 mg, 10.7 %. LCMS (ESI) m/z = 454.1 (M+H). ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.51 (s, 1H), 8.02 (s, 1H), 7.94 (s, 1H), 7.56 (s, 1H), 7.52 (d, 1H, J=8.0 Hz), 7.43 (s, 1H), 7.30 (t, 1H, J=7.6 Hz), 7.10-7.15 (m, 2H), 6.89 (s, 1H), 6.80-6.83 (m, 1H), 4.50-4.53 (m, 1H), 2.65 (q, 2H, J=7.6 Hz), 2.42 (s, 3H), 2.17- 2.22 (m, 2H), 1.73-1.89 (m, 6H), 1.29 (t, 3H, J=7.6 Hz). EXAMPLE 1I Synthesis of (Z)-4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxyphenyl)-6-(4- hydroxyphenyl)pyrrolo[1,2-b]pyridazine-3-carboximidamide Step 1: (Z)-6-bromo-N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylphen yl)-4-chloropyrrolo[1,2- b]pyridazine-3-carboximidamide 4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-aniline (200.0 mg, 795.42 umol) and 6-bromo-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamide (0.20 g, 728.59 umol) were suspended in toluene (5 mL) in an oven-dried screw cap vial equipped with a stir bar. The mixture was stirred at 0 °C while trimethylaluminum (2 M, 1.09 mL) was added dropwise via syringe. After 5 min the mixture was warmed to room temperature and after an additional 15 min it was warmed to 110 °C in a heating block. After 20 h the reaction mixture was cooled to room temperature, diluted with ethyl acetate and cooled to 0 °C. Water was added slowly until bubbling ceased. The mixture was diluted with 1M aqueous Rochelle salt. The layers were separated, and the aqueous phase extracted with ethyl acetate three times. The combined organic material was washed once with brine. The organic phase was dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purification via silica gel chromatography (0 to 65 % ethyl acetate in heptanes) afforded the titled compound as a yellow oil. Yield: 341 mg (at 66 % purity), 61 % yield. LCMS Mass: 509.4, 511.4 (M ⁺ +H). Step 2: ((Z)-6-bromo-N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylphe nyl)-4-(cyclopentylamino)- pyrrolo[1,2-b]pyridazine-3-carboximidamide Cyclopentanamine (26.8 mg, 220.8 umol, 31.1 uL) and 6-bromo-N'-[4-[tert- butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-chloro-pyrrolo[1, 2-b]pyridazine-3-carboxamidine (0.083 g, 107.8 umol) were dissolved in DMA (1.3 mL) in an oven-dried screw cap vial equipped with a stir bar. Diisopropylethylamine (41.8 mg, 323.5 umol, 56.3 uL) was added and the mixture stirred at room temperature for 5 min and then warmed to 90°C in a heating block for 2 h. The reaction mixture was cooled to room temperature and stirred overnight. The mixture was diluted with ethyl acetate washed twice with a 1:1 brine:water solution, and then once more with 100 % brine. The organic phase was dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purification via silica gel chromatography (0-65 % ethyl acetate in heptane) afforded the titled compound as a yellow residue, contaminated with impurities from starting material. Yield 51 mg at 85 % purity, 70 %. LCMS Mass: 558.5 (M ⁺ +H). Step 3: (Z)-4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxyphenyl)-6-(4-h ydroxyphenyl)pyrrolo[1,2- b]pyridazine-3-carboximidamide A bottle of anhydrous DMF was purged with nitrogen gas for 30 min. 6-bromo-N'-[4-[tert- butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-(cyclopentylamino )pyrrolo[1,2-b]pyridazine-3- carboxamidine (0.18 g, 194.03 umol) and (4-hydroxyphenyl)boronic acid (53.5 mg, 388.06 umol) were dissolved in DMF (4 mL) and aq. potassium phosphate (1 M, 582.0 uL) in an oven-dried screw cap vial equipped with a stir bar. The mixture was purged with argon for 5 min. Pd(dtbpf)Cl2 (6.3 mg, 9.70 umol) was added, the vial sealed and heated in a heating block at 90 °C. After 2 h additional (4-hydroxyphenyl)boronic acid (53.5 mg, 388.0 umol) and Pd(dtbpf)Cl2 (6.3 mg, 9.70 umol) were added. After an additional 15 min at 90 °C the reaction mixture was cooled to room temperature. The mixture was diluted with ethyl acetate washed twice with a 1:1 brine:water solution, and then once more with 100 % brine. The organic phase was dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded (Z)-4-(cyclopentylamino)-N'-(2- ethyl-4-hydroxyphenyl)-6-(4-hydroxyphenyl)pyrrolo[1,2-b]pyri dazine-3-carboximidamide as a tan solid. Yield: 54 mg, 61 %. LCMS (ESI) m/z = 457.2 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.16 (d, 2H, J=9.7 Hz), 8.0-8.0 (m, 1H), 7.59 (d, 2H, J=8.6 Hz), 7.16 (s, 1H), 6.80 (d, 2H, J=8.6 Hz), 6.6-6.7 (m, 3H), 5.7-6.1 (br s, 1H), 4.72 (br s, 1H), 2.4-2.5 (m, 2H), 2.0-2.1 (m, 2H), 1.6-1.7 (m, 6H), 1.08 (t, 3H, J=7.4 Hz). EXAMPLE 1J Synthesis of ethyl 2-(4-(3-(N'-(2-chloro-4-hydroxy-phenyl)carbamimidoyl)-4- (cyclopentylamino)pyrrolo[1,2-b]pyridazin-6-yl)phenoxy)aceta te Step 1: 6-Bromo-N'-(4-(tert-butyl(dimethyl)silyl)oxy-2-chloro-phenyl )-4-(cyclopentylamino) pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-(4-(tert-butyl(dimethyl)silyl)oxy-2-chloro-phenyl )-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (150 mg, 291.7 μmol) and cyclopentanamine (24.8 mg, 291.7 μmol) in N,N-dimethylacetamide (2 mL) was added N,N-diisopropylethylamine (113.1 mg, 875.0 μmol). After stirring for 2 hours at 80 °C, the reaction mixture was cooled to room temperature and purified by reverse phase column chromatography (acetonitrile/water, 90%) to afford the titled compound as a yellow solid. Yield: 140 mg, 85%. LCMS (ESI) m/z = 564.0 (M+H). Step 2: Ethyl 2-(4-(3-(N'-(4-(tert-butyl(dimethyl)silyl)oxy-2-chloro-pheny l)carbamimidoyl)-4- (cyclopentylamino)pyrrolo[1,2-b]pyridazin-6-yl)phenoxy)aceta te To a mixture of 6-bromo-N'-(4-(tert-butyl(dimethyl)silyl)oxy-2-chloro-phenyl )-4- (cyclopentylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidine (120 mg, 213.1 μmol), ethyl 2-(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate (65.3 mg, 213.1 μmol) and potassium phosphate (135.7 mg, 639.4 μmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was added [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladi um(II) (13.9 mg, 21.3 μmol). The resulting mixture stirred for 2 hours at 90 °C under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water 100%) afforded the titled compound as a white solid. Yield: 110 mg, 77%. LCMS (ESI) m/z = 662.0 (M+H). Step 3: Ethyl 2-(4-(3-(N'-(2-chloro-4-hydroxy-phenyl)carbamimidoyl)-4-(cyc lopentylamino)- pyrrolo[1,2-b]pyridazin-6-yl)phenoxy)acetate To a solution of ethyl 2-(4-(3-(N'-(4-(tert-butyl(dimethyl)silyl)oxy-2-chloro- phenyl)carbamimidoyl)-4-(cyclopentylamino)pyrrolo[1,2-b]pyri dazin-6-yl)phenoxy)acetate (100 mg, 151.0 μmol) in N,N-dimethylformamide (2 mL) was added cesium fluoride (68.8 mg, 453.0 μmol). After stirring for 16 hours at room temperature, the resulting mixture was filtered through a celite pad. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded ethyl 2-(4-(3-(N'-(2-chloro-4-hydroxy-phenyl)carbamimidoyl)-4-(cyc lopentyl- amino)pyrrolo[1,2-b]pyridazin-6-yl)phenoxy)acetate as a yellow solid. Yield: 22.6 mg, 26%. LCMS (ESI) m/z = 548.4 (M+H). ¹ H-NMR (DMSO-d6, 400 MHz) δ 11.86 (d, 1H, J=6.4 Hz), 9.44 (s, 1H), 8.14 (d, 1H, J=4.0 Hz), 8.07 (s, 1H), 7.68-7.76 (m, 2H), 7.22 (s, 1H), 6.93-6.99 (m, 2H), 6.81-6.90 (m, 2H), 6.69-6.75 (m, 1H), 6.17 (s, 2H), 4.81 (s, 2H), 4.75 (s, 1H), 4.18 (q, 2H, J=6.8 Hz), 1.95-2.10 (m, 2H), 1.60-1.69 (m, 6H), 1.23 (t, 3H, J=6.8 Hz). EXAMPLE 1K Synthesis of 4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxy-phenyl)-6-(3-pyri dyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine To a stirred solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4- (cyclopentylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidine (80 mg, 143.73 umol) in DMF (2 mL) and water (0.43 mL) were added tripotassium phosphate (91.5 mg, 431.2 umol), 3- pyridylboronic acid (35.3 mg, 287.5 umol) and Pd(dtbpf)Cl2 (9.37 mg, 14.37 umol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 115 °C for 2 h. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1% formic acid) afforded 4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxy-phenyl)-6-(3-pyri dyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine as a yellow solid. Yield: 25.0 mg, 39 %. LCMS (ESI) m/z = 441.1 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 12.28 (brs, 1H), 9.07 (s, 1H), 8.44 (d, 1H, J=3.9 Hz), 8.27 (s, 1H), 8.15-8.20 (m, 2H), 7.42-7.44 (m, 2H), 6.57-6.68 (m, 3H), 5.92 (brs, 1H), 4.72-4.80 (m, 1H), 2.42 (q, 2H, J=7.5 Hz), 2.08-2.13 (m, 2H), 1.59-1.70 (m, 6H), 1.10 (t, 3H, J=7.5 Hz). EXAMPLE 1L Synthesis of N'-(2-chloro-5-fluoro-phenyl)-4-(cyclopentylamino)-6-(6-meth yl-3- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a mixture of 6-bromo-N'-(2-chloro-5-fluoro-phenyl)-4-(cyclopentylamino)py rrolo[1,2-b]- pyridazine-3-carboxamidine (100 mg, 221.9 μmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (58.3 mg, 266.2 μmol) in 1,4-dioxane (2 mL) and water (0.2 mL) were added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (14.5 mg, 22.2 μmol) and potassium phosphate (141.3 mg, 665.6 μmol) at room temperature. The resulting mixture was purged with nitrogen gas and stirred for 2 hours at 90 °C under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (acetonitrile/water 90%) and then further purified via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) to afford N'-(2-chloro-5-fluoro-phenyl)-4-(cyclopentylamino)-6- (6-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as a yellow solid. Yield: 19.8 mg, 19%. LCMS (ESI) m/z = 463.1 (M+H). ¹ H-NMR (DMSO-d6, 300 MHz) δ 11.48 (d, 1H, J=7.5 Hz), 8.93 (s, 1H), 8.05-8.28 (m, 3H), 7.24-7.55 (m, 3H), 6.83-6.94 (m, 2H), 6.55 (s, 2H), 4.78 (s, 1H), 2.49 (s, 3H), 2.00-2.18 (m, 2H), 1.60-1.72 (m, 6H). ¹⁹ F-NMR (DMSO-d6, 282 MHz) δ -114.01 (s, 1F). EXAMPLE 1M Synthesis of 4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-meth yl-3- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-(cycl opentylamino)-6-(6-methyl-3- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-(cyclopentylamino)pyrrolo[1,2- b]pyridazine-3-carboxamidine (100 mg, 179.7 umol) was suspended in 1,4- dioxane (2 mL) and water (0.5 mL). (6-methyl-3-pyridyl)boronic acid (49.2 mg, 359.3 umol), tripotassium phosphate (114.4 mg, 539.0 umol) and Pd(dtbpf)Cl2 (11.7 mg, 18.0 umol) were added to the suspension under nitrogen atmosphere. The resulting mixture was stirred at 90°C for 3 h. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column (petroleum ether/ethyl acetate, 2:3) afforded the titled compound as a yellow solid. Yield: 70 mg, 68%. LCMS (ESI) m/z = 569.3 (M+H). Step 2: 4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-meth yl-3-pyridyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine To a stirred solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-(cycl opentylamino)- 6-(6-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidi ne (70 mg, 123.1 umol) in DMF (2 mL) was added cesium fluoride (37.4 mg, 246.1 umol, 9.1 uL) at room temperature under nitrogen atmosphere. After stirring for 2 h, the reaction mixture was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxy-phenyl)-6- (6-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as a yellow solid. Yield: 18.8 mg, 33 %. LCMS (ESI) m/z = 455.2 (M+H). ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.78 (s, 1H), 8.55 (s, 1H), 8.02-8.08 (m, 3H), 7.42 (s, 1H), 7.37 (d, 1H, J=8.4 Hz), 6.97-7.02 (m, 1H), 6.85 (s, 1H), 6.77 (d, 1H, J=8.4 Hz), 4.55-4.65 (m, 1H), 2.57-2.62 (m, 5H), 2.15-2.21 (m, 2H), 1.70-1.90 (m, 6H), 1.25 (t, 3H, J=7.6 Hz). EXAMPLE 1N Synthesis of 4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxy-phenyl)-6-(3-meth yl-4- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-(cycl opentylamino)-6-(3-methyl-4- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-(cyclopentylamino)pyrrolo[1,2- b]pyridazine-3-carboxamidine (100 mg, 179.7 umol) was suspended in 1,4- dioxane (2 mL) and water (0.5 mL). (3-methyl-4-pyridyl)boronic acid (49.2 mg, 359.3 umol), tripotassium phosphate (114.4 mg, 539.0 umol) and Pd(dtbpf)Cl ₂ (11.7 mg, 18.0 umol) were added to the suspension under nitrogen atmosphere. The resulting mixture was stirred at 90°C for 3 h. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column (petroleum ether/ethyl acetate, 2:3) afforded the titled compound as a yellow solid. Yield: 70 mg, 68%. LCMS (ESI) m/z = 569.3 (M+H). Step 2: 4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxy-phenyl)-6-(3-meth yl-4-pyridyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine To a solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-(cycl opentylamino)-6-(3- methyl-4-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (70 mg, 123.1 umol) in DMF (2 mL) was added cesium fluoride (37.4 mg, 246.1 umol, 9.1 uL) at room temperature under nitrogen atmosphere. After stirring for 2 h, the reaction mixture was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxy-phenyl)-6- (3-methyl-4-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as a yellow solid. Yield: 30.4 mg, 54 %. LCMS (ESI) m/z = 455.1 (M+H). ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.50 (s, 1H), 8.46 (s, 1H), 8.39 (d, 1H, J=5.2 Hz), 8.00-8.05 (m, 2H), 7.59 (d, 1H, J=5.2 Hz), 7.45 (s, 1H), 7.14 (d, 1H, J=8.4 Hz), 6.90 (s, 1H), 6.82 (d, 1H, J=8.4 Hz), 4.48-4.53 (m, 1H), 2.62-2.68 (m, 2H), 2.58 (s, 3H), 2.17-2.21 (m, 2H), 1.73-1.89 (m, 6H), 1.29 (t, 3H, J=7.6 Hz). EXAMPLE 1O Synthesis of (Z)-4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxyphenyl)-6-(6-m ethoxypyridin-3- yl)pyrrolo[1,2-b]pyridazine-3-carboximidamide Step 1: (Z)-6-bromo-N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylphen yl)-4-chloropyrrolo[1,2-b]- pyridazine-3-carboximidamide 4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-aniline (200.0 mg, 795.42 umol) and 6-bromo-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamide (0.2 g, 728.59 umol) were suspended in toluene (5 mL) in an oven-dried screw cap vial equipped with a stir bar. The mixture was stirred at 0 °C while trimethylaluminum (2 M, 1.09 mL) was added dropwise via syringe. After 5 min the mixture was warmed to room temperature and after an additional 15 min it was warmed to 110 °C in a heating block. After 16 h the reaction mixture was cooled to room temperature, diluted with ethyl acetate and cooled to 0 °C. Water was added slowly until bubbling ceased. The mixture was diluted with 1M aqueous Rochelle salt. The layers were separated, and the aqueous phase extracted with ethyl acetate three times. The combined organic phase was washed once with brine, dried over magnesium sulfate, filtered, and the solvent removed in vacuo. Purification via silica gel chromatography (0 to 65 % ethyl acetate in heptanes) afforded the titled compound as a yellow oil. Yield: 341 mg (at 66 % purity), 61 % yield. LCMS Mass: 509.4, 511.4 (M+H). Step 2: ((Z)-6-bromo-N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylphe nyl)-4-(cyclopentylamino)- pyrrolo[1,2-b]pyridazine-3-carboximidamide Cyclopentanamine (26.8 mg, 220.8 umol, 31.1 uL) and 6-bromo-N'-[4-[tert- butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-chloro-pyrrolo[1, 2-b]pyridazine-3-carboxamidine (0.083 g, 107.8 umol) were dissolved in DMA (1.3 mL) in an oven-dried screw cap vial equipped with a stir bar. Diisopropylethylamine (41.8 mg, 323.5 umol, 56.3 uL) was added and the mixture was stirred at room temperature for 5 min and then warmed to 90°C in a heating block for 2 h. The reaction mixture was cooled to room temperature and stirred overnight. The mixture was then diluted with ethyl acetate, washed twice with a 1:1 brine:water solution, and then once more with 100 % brine. The organic phase was dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purification via silica gel chromatography (0-65 % ethyl acetate in heptane) afforded the titled compound as a yellow residue, contaminated with impurities from starting material. Yield 51 mg at 85 % purity, 70 %. LCMS Mass: 558.5 (M ⁺ +H). Step 3: (Z)-4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxyphenyl)-6-(6-m ethoxypyridin-3-yl)- pyrrolo[1,2-b]pyridazine-3-carboximidamide ((Z)-6-bromo-N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylphe nyl)-4-(cyclopentylamino)pyrrolo- [1,2-b]pyridazine-3-carboximidamide (compound 4, 26.0 mg, 39.7 mmol) and (6-methoxy-3- pyridyl)boronic acid (12.1 mg, 79.4 umol) were dissolved in DMF (1 mL) in an oven-dried screw cap vial equipped with a stir bar. Aqueous potassium phosphate (1 M, 119.1 uL, 0.11 mmol) was added and the mixture was purged with argon for 5 min. Dichloro[1,1'-bis(di-t- butylphosphino)ferrocene]palladium(II) (39.70 umol) was added, the vial sealed and mixture stirred at 95 °C for 2 h. The reaction mixture was cooled to room temperature. The mixture was diluted with ethyl acetate, washed twice with a 1:1 brine:water solution, and then once more with 100 % brine. The organic phase was dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purification via silica gel chromatography (0 to 65 % ethyl acetate in heptanes) afforded the titled compound as a tan solid. Yield: 7.8 mg, 39 %. LCMS (ESI) m/z = 471.54 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 8.91 (s, 1H), 8.63 (d, 1H, J=2.4 Hz), 8.1-8.2 (m, 1H), 7.27 (s, 1H), 6.85 (d, 1H), 6.58 (s, 1H), 5.83 (br s, 1H), 4.75 (bs, 1H)3.87 (s, 1H), 2.40 (q, J=7.4 Hz, 2H), 2.0- 2.1 (m, 1H), 1.5-1.7 (m, 2H), 1.23 (s, 1H), 1.06 (t, 1H, J=7.4 Hz). EXAMPLE 1P Synthesis of 4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxy-phenyl)-6-pyrimid in-5-yl-pyrrolo[1,2- b]pyridazine-3-carboxamidine To a stirred solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4- (cyclopentylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidine (100 mg, 179.7 umol) in DMF (2 mL) and water (0.54 mL) were added tripotassium phosphate (114.4 mg, 539.0 umol), pyrimidin- 5-ylboronic acid (44.5 mg, 359.3 umol) and Pd(dtbpf)Cl2 (11.7 mg, 18.0 umol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 115°C for 2 h. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate) afforded 4-(cyclopentylamino)-N'-(2-ethyl-4-hydroxy-phenyl)-6-pyrimid in-5-yl- pyrrolo[1,2-b]pyridazine-3-carboxamidine as a pink solid. Yield: 37.8 mg, 46 %. LCMS (ESI) m/z = 440.2 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.45 (d, 1H, J=7.6 Hz), 9.29 (s, 2H), 9.06 (s, 1H), 8.93 (s, 1H), 8.37 (s, 1H), 8.23 (s, 1H), 7.50 (s, 1H), 6.68 (s, 1H), 6.57-6.63 (m, 2H), 5.88 (s, 2H), 4.77-4.80 (m, 1H), 2.42 (q, 2H, J=7.6 Hz), 2.08-2.14 (m, 2H), 1.57-1.69 (m, 6H), 1.10 (t, 3H, J=7.6 Hz). EXAMPLE 1Q Synthesis of N'-(2-chlorophenyl)-4-(cyclopentylamino)-6-pyrimidin-5-yl-py rrolo[1,2- b]pyridazine-3-carboxamidine To a mixture of 6-bromo-N'-(2-chlorophenyl)-4-(cyclopentylamino)pyrrolo[1,2- b]pyridazine-3- carboxamidine (90 mg, 208.0 μmol), pyrimidin-5-ylboronic acid (30.9 mg, 249.6 μmol) and potassium phosphate (132.4 mg, 623.9 μmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (13.8 mg, 20.8 μmol). The resulting mixture was stirred for 2 hours at 100 °C under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in N, N-dimethylformamide and filtered. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-(2-chlorophenyl)-4-(cyclopentylamino)-6-pyrimidin-5-yl-py rrolo[1,2-b]pyridazine-3- carboxamidine as a yellow solid. Yield: 17.6 mg, 20%. LCMS (ESI) m/z = 432.1 (M+H). ¹ H- NMR (DMSO-d6, 300 MHz) δ 11.76 (d, 1H, J=7.2 Hz), 9.30 (s, 2H), 9.06 (s, 1H), 8.40 (d, 1H, J=1.7 Hz), 8.23 (s, 1H), 7.44-7.57 (m, 2H), 7.24-7.35 (m, 1H), 7.00-7.10 (m, 2H), 6.34 (s, 2H), 4.80 (s, 1H), 2.05-2.16 (m, 2H), 1.60-1.71 (m, 6H). EXAMPLE 1R Synthesis of (Z)-N'-(2-chloro-4-hydroxyphenyl)-4-(cyclopentylamino)-6-(2- fluoro-4,5- dimethoxyphenyl)pyrrolo[1,2-b]pyridazine-3-carboximidamide Compound 1R was prepared according to the methods described in the previous example and synthetic schemes from the correspondingly appropriate starting materials. LCMS (ESI) m/z = 525.03 (M+H) ⁺ . ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ 11.92 (br d, 1H, J=6.8 Hz), 9.45 (br d, 1H, J=1.3 Hz), 8.19 (s, 1H), 8.15 (s, 1H), 8.06 (s, 1H), 7.34 (d, 1H, J=7.7 Hz), 7.26 (s, 1H), 6.98 (d, 1H, J=13.0 Hz), 6.8-6.9 (m, 2H), 6.72 (br d, 1H, J=9.0 Hz), 6.20 (br s, 2H), 4.7-4.8 (m, 1H), 3.85 (s, 3H), 3.80 (s, 4H), 2.0-2.1 (m, 2H), 1.6-1.7 (m, 7H). ¹⁹ F NMR (DMSO-d ₆ , 282 MHz) δ 122.7 (s, 1F). EXAMPLE 2 COMPOUNDS OF FORMULA (I) WHEREIN X IS O, B IS UNSUBSTITUTED CYCLOPENTANE Synthesis of 4-(cyclopentoxy)-N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy- 3- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-(cyclopentoxy)pyrrolo- [1,2-b]pyridazine-3-carboxamidine To a solution of cyclopentanol (102 mg, 1.2 mmol) in 1,4-dioxane (10.0 mL) was added lithium bis(trimethylsilyl)azanide (1.2 mL, 1.2 mmol, 1.0 M in tetrahydrofuran). The mixture was stirred for 30 minutes at room temperature and then 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl- phenyl]-4-chloro-pyrrolo[1,2-b]pyridazine-3-carboxamidine (300 mg, 590.6 umol) was added. After stirring for 2 hours at 100 °C, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a yellow solid. Yield: 300 mg, 91%. LCMS (ESI) m/z = 557.2 (M+H). Step 2: N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-(cycl opentoxy)-6-(6-methoxy-3- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a mixture of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-(cyclopentoxy)- pyrrolo[1,2-b]pyridazine-3-carboxamidine (300 mg, 538.0 umol) and (6-methoxy-3- pyridyl)boronic acid (165 mg, 1.10 mmol) in 1,4-dioxane (10.0 mL) and water (1.0 mL) were added diacetoxypalladium (12.1 mg, 53.8 umol), potassium phosphate (342.6 mg, 1.6 mmol) and dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (51.3 mg, 107.6 umol). The resulting mixture was stirred for 2 hours at 100 °C under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a yellow solid. Yield: 300 mg, 95%. LCMS (ESI) m/z = 586.3 (M+H). Step 3: 4-(cyclopentoxy)-N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy- 3-pyridyl) pyrrolo[1,2-b] pyridazine-3-carboxamidine To a solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-(cycl opentoxy)-6-(6- methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (300 mg, 512.1 umol) in N,N- dimethylformide (6.0 mL) was added cesium fluoride (155.6 mg, 1.0 mmol). After stirring for 2 hours at 25 °C, the reaction mixture was filtered. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-(cyclopentoxy)-N'-(2-ethyl-4- hydroxy-phenyl)-6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridaz ine-3-carboxamidine as a yellow solid. Yield: 37.8 mg, 15%. LCMS (ESI) m/z = 472.4 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz): 8.72 (s, 1H), 8.45-8.48 (m, 2H), 8.29 (s, 1H), 8.19-8.22 (m, 1H), 7.37 (s, 1H), 6.89 (d, 1H, J=8.8 Hz), 6.64-6.72 (m, 3H), 5.67 (t, 1H, J=3.2 Hz), 3.89 (s, 3H), 2.44-2.49 (m, 2H), 1.85-1.94 (m, 4H), 1.76-1.81 (m, 2H), 1.60-1.69 (m, 2H), 1.00-1.10 (m, 3H). EXAMPLE 3 COMPOUNDS OF FORMULA (I) WHEREIN X IS S, B IS UNSUBSTITUTED CYCLOPENTANE Synthesis of 4-cyclopentylsulfanyl-N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-met hoxy-3- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-cyclopentylsulfanyl- pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (300 mg, 590.6 umol) in 1-Methyl-2-pyrrolidinone (5.0 mL) was added cyclopentanethiol (120.7 mg, 1.18 mmol) and N-ethyl-N-isopropyl-propan-2- amine (305.3 mg, 2.36 mmol). After stirring for 4 hours at 100 C, the reaction mixture was cooled to room temperature, diluted with brine and extracted with ethyl acetate (x3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a yellow solid. Yield: 260 mg, 76%. LCMS (ESI) m/z = 573.1 (M+H). Step 2: 4-cyclopentylsulfanyl-N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-met hoxy-3- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a mixture of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-cyclopentyl- sulfanyl-pyrrolo[1,2-b]pyridazine-3-carboxamidine (50 mg, 87.2 umol) and (6-methoxy-3- pyridyl)boronic acid (20 mg, 130.7 umol) in N,N-dimethylformide (3.0 mL) and water (0.3 mL) were added diacetoxypalladium (2 mg, 8.7 umol), dicyclohexyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane (8.3 mg, 17.4 umol) and potassium phosphate (55.5 mg, 261.5 umol). The mixture was stirred for 2 hours at 100 °C under nitrogen atmosphere. After cooling down to room temperature, the reaction mixture was diluted with brine and extracted with ethyl acetate (x3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-cyclopentylsulfanyl-N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-met hoxy-3-pyridyl)pyrrolo-[1,2- b]pyridazine-3-carboxamidine as a yellow solid. Yield: 12.6 mg, 29%. LCMS (ESI) m/z = 488.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 8.85 (brs, 1H), 8.72 (d, 1H, J=2.0 Hz), 8.48 (s, 1H), 8.18-8.23 (m, 2H), 7.26 (s, 1H), 6.88 (d, 1H, J=8.4 Hz), 6.57-6.64 (m, 3H), 6.20 (br, 2H), 4.15- 4.25 (m, 1H), 3.89 (s, 3H), 2.55-2.65 (m, 2H), 1.87-1.96 (m, 2H), 1.68-1.80 (m, 2H), 1.42-1.60 (m, 4H), 1.12 (t, 3H, J=7.6 Hz). EXAMPLE 4 COMPOUNDS OF FORMULA (I) WHEREIN X IS NH, B IS MONOSUBSTITUTED CYCLOPENTANE EXAMPLE 4A Synthesis of (Z)-4-(((1R,3S)-3-aminocyclopentyl)amino)-N'-(2-chlorophenyl )-6-(4-methoxy-2- methylphenyl)pyrrolo[1,2-b]pyridazine-3-carboximidamide Step 1: tert-butyl ((1S,3R)-3-((6-bromo-3-((Z)-N'-(2-chlorophenyl)carbamimidoyl )pyrrolo[1,2-b]- pyridazin-4-yl)amino)cyclopentyl)carbamate N-ethyl-N-isopropyl-propan-2-amine (168.26 mg, 1.30 mmol, 226.76 μL) 6-bromo-4-chloro-N'- (2-chlorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (0.25 g, 650.94 μmol) and tert-butyl N-[(1S,3R)-3-aminocyclopentyl]carbamate (169.48 mg, 846.23 μmol) were dissolved in DMA (3 mL) in a vial equipped with a sit bar. The mixture was heated to 55 °C ia heating block.c After 5.5 h the mixture was cooled to room temperature and stirred overnight. The mixture was diluted with ethyl acetate washed twice with a 1:1 brine:water solution, and then once more with 100 % brine. The organic phase was dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purification via silica gel chromatography (0 to 65 % ethyl acetate in heptanes) afforded the titled product as a tan solid. Yield: 85 mg, 26 % LCMS (ESI) m/z = 685.7 (M+H). Step 2: tert-butyl ((1S,3R)-3-((3-((Z)-N'-(2-chlorophenyl)carbamimidoyl)-6-(4-m ethoxy-2- methyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl)amino)cyclopentyl )carbamate Tert-butyl N-[(1S,3R)-3-[[6-bromo-3-[(Z)-N'-(2-chlorophenyl)carbamimido yl]pyrrolo[1,2-b]- pyridazin-4-yl]amino]cyclopentyl]carbamate (0.35 g, 638.83 μmol) (4-methoxy-2-methyl- phenyl)boronic acid (116 mg, 702 μmol) and PdCl2(Dtbpf) (24.95 mg, 38.33 μmol) were suspended in a mixture of dioxane (6 mL) and aqueous potassium phosphate (91.83 mg, 432.60 μmol, 0.43 mL).in a screw capped vial equipped with a stir bar. The mixture was sparged with argon gas for 1 min, the vial then sealed and heated to 65°C. After 75 min the reaction mixture was cooled to room temperature. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and then aqueous phase was extracted with ethyl acetate two times. The combined organic material was washed with brine, dried over magnesium sulfate, filtered, and solvent removed in vacuo. The residue was diluted with acetonitrile and DMSO. Purification via reverse-phase HPLC (10 to 50 % acetonitrile in water) afforded the titled product as a tan solid. Yield: 29 mg, 51 %. Step 3: (Z)-4-(((1R,3S)-3-aminocyclopentyl)amino)-N'-(2-chlorophenyl )-6-(4-methoxy-2- methyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carboximidamide A solution of the compound from step 2 in 5 mL of DCM was added 1 mL of TFA was stirred for 16h then concentrated and chromatographed using reverse phase HPLC to afford the titled compound. ¹ H NMR (300 MHz, DMSO-d6) δ 11.64 (brs, 1H), 8.20 (s, 1H), 7.79 (s, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.25-7.33 (m, 1H), 7.01-7.08 (m, 2H), 6.97 (s, 1H), 6.88 (s, 1H), 6.83 (d, J = 8.7 Hz, 1H), 6.30 (brs, 2H), 4.54-4.69 (m, 1H), 3.78 (s, 3H), 3.22-3.30 (m, 1H), 2.44 (s, 3H), 2.33-2.42 (m, 1H), 2.02-2.14 (m, 1H), 1.71-1.90 (m, 2H), 1.63 (d, J = 0.9 Hz, 2H), 1.30-1.48 (m, 2H). LCMS m/z (ES+) (M + H) ⁺ = 489.38. EXAMPLES 4B-4E Compounds 4B - 4E were prepared according to the methods described in the previous examples and synthetic schemes from the correspondingly appropriate starting materials. Structure, name and analytical characterization of these compounds are presented below.

EXAMPLE 5 COMPOUNDS OF FORMULA (I) WHEREIN X IS NH, B IS TETRASUBSTITUTED CYCLOPENTANE Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -chloro-4-hydroxy- phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-phenyl]-4-chlo ro-pyrrolo[1,2-b]pyridazine- 3-carboxamidine To a suspension of 4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (400 mg, 2.04 mmol) and 4- [tert-butyl(dimethyl)silyl]oxy-2-chloro-aniline (791 mg, 3.07 mmol) in toluene (4.0 mL) was added trimethylaluminium (0.55 mL, 1.10 mmol, 2.0 M in toluene) dropwise via syringe at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 5 minutes at 0 °C and 15 minutes at room temperature, then heated to 110 °C for 15 hours. After cooling to room temperature, the reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate three times. The combined organic layers were washed with brine, then dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a light yellow solid. Yield: 110 mg, 12%. LCMS (ESI) m/z = 436.4 (M+H). Step 2: 3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2-chloro-4-hy droxy- phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-phenyl]-4-chlo ro-pyrrolo[1,2- b]pyridazine-3-carboxamidine (90 mg, 206.0 μmol) and (1S,3R)-1,2,2-trimethylcyclopentane-1,3- diamine (140 mg, 310.0 μmol) in N,N-dimethylacetamide (2 mL) was added N-ethyl-N-isopropyl- propan-2-amine (80 mg, 137.8 μmol). After stirring for 2 hours at 100 °C, the reaction mixture was cooled to room temperature, and then cesium fluoride (95.9 mg, 137.8 μmol) added. The resulting mixture was stirred for 2 hours at room temperature and filtered. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -chloro-4-hydroxy- phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as an off-white solid. Yield: 44.0 mg, 49%. LCMS (ESI) m/z = 427.3 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.92 (s, 1H), 9.39 (s, 1H), 8.17 (s, 1H), 7.61-7.63 (m, 1H), 6.77-6.89 (m, 3H), 6.63-6.74 (m, 2H), 6.07 (s, 2H), 4.43 (d, 1H, J=4.8 Hz), 2.18-2.30 (m, 1H), 1.50-1.70 (m, 3H), 1.04 (s, 3H), 0.83 (d, 6H, J=9.3 Hz). EXAMPLE 5B Synthesis of (Z)-4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-N' -(2- cyclopropylphenyl)pyrrolo[1,2-b]pyridazine-3-carboximidamide Step 1: 6-bromo-4-chloro-N'-(2-cyclopropylphenyl)pyrrolo[1,2-b]pyrid azine-3-carboxamidine 2-Cyclopropylaniline (80.0 mg, 601.0 umol) and 6-bromo-4-chloro-pyrrolo[1,2-b]pyridazine-3- carboxamide (0.11 g, 400.7 umol) were suspended in toluene (4 mL) in an oven-dried screw cap vial equipped with a stir bar. The mixture was stirred at 25 °C while trimethylaluminum (2 M, 601 uL) was added dropwise via syringe. After 5 min the mixture was warmed to 110 °C in a heating block. After 17 h the reaction mixture was cooled to room temperature and diluted with ethyl acetate. It was stirred vigorously while water was added until gas evolution ceased. The mixture was diluted with ethyl acetate and 1M aqueous Rochelle salt. The layers were separated, and aqueous phase extracted 3 times with ethyl acetate. The organic material was washed once with brine, dried over magnesium sulfate, filtered, and the solvent removed in vacuo. Purification via silica gel chromatography (0 to 65 % ethyl acetate in heptanes) afforded the titled compound as a yellow solid. Yield: 111 mg, at 80 % purity, 56 %. LCMS (ESI) m/z = 390.9, 392.8 (M+H). Step 2: (Z)-4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6- bromo-N'-(2-cyclopropyl- phenyl)pyrrolo[1,2-b]pyridazine-3-carboximidamide (1S,3R)-1,2,2-trimethylcyclopentane-1,3-diamine (70.7 mg, 336.2 umol) in DMF (0.5 mL) and 6- bromo-4-chloro-N'-(2-cyclopropylphenyl)pyrrolo[1,2-b]pyridaz ine-3-carboxamidine (106.1 mg, 258.6 umol) were dissolved in DMF (2 mL) in an oven-dried screw cap vial equipped with a stir bar. N-ethyl-N-isopropyl-propan-2-amine (66.8 mg, 517.3, umol, 90 uL) was added and the mixture was stirred at 85 °C. After 24 h the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed twice with a 1:1 brine:water solution, and then once more with 100 % brine. The organic phase was dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded the titled compound as a tan solid. Yield: 128 mg, 44 %. LCMS (ESI) m/z = 496.6 (M+H). Step 3: ((Z)-4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-N '-(2-cyclopropylphenyl)-6- (1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboximidamide A bottle of anhydrous DMF was purged with nitrogen gas for 10 min. 4-(4,4,5-trimethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (13.9 mg, 75.9 umol) and 4-[[(1R,3S)-3-amino-2,2,3-trimethyl- cyclopentyl]amino]-6-bromo-N'-(2-cyclopropylphenyl)pyrrolo[1 ,2-b]pyridazine-3-carboxamidine (0.033 g, 63.27 umol) were dissolved in DMF (1 mL) and aqueous potassium phosphate (1 M, 253.1 uL) in an oven-dried screw cap vial equipped with a stir bar. The mixture was purged with nitrogen for 5 min. Dichloro[1,1'-bis(di-t-butylphosphino)ferrocene] palladium(II) (63.2 umol) was added, and the mixture stirred at 85 °C in a heating block. After 6 h the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed twice with a 1:1 brine:water solution, and then once more with 100 % brine. The organic phase was dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded ((Z)-4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-N '- (2-cyclopropylphenyl)pyrrolo[1,2-b]pyridazine-3-carboximidam ide as a white powder. Yield 3.8 mg, 14 %. LCMS (ESI) m/z = 417.6 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.27-8.3 (m, 1H), 8.23 (s, 1H), 7.6-7.7 (m, 1H), 7.1-7.2 (m, 1H), 6.97 (t, 1H, J=7.4 Hz), 6.8-6.9 (m, 2H), 6.67 (dd, 1H, J=2.8, 4.2 Hz), 4.47 (br t, 1H, J=8.5 Hz), 2.2-2.3 (m, 1H), 1.7-2.0 (m, 3H), 1.57 (br d, 1H, J=7.2 Hz), 1.20 (s, 3H), 0.89 (s, 3H), 0.8-0.9 (m, 2H), 0.6-0.7 (m, 2H). EXAMPLE 5C Synthesis of (Z)-4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6- bromo-N'-(2-ethyl-4- hydroxyphenyl)pyrrolo[1,2-b]pyridazine-3-carboximidamide Step 1: (Z)-6-bromo-N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylphen yl)-4-chloropyrrolo[1,2- b]pyridazine-3-carboximidamide 4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-aniline (0.31 g, 1.25 mmol) and 6-bromo-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamide (311.6 mg, 1.14 mmol) were suspended in toluene (7 mL) in an oven-dried screw cap vial equipped with a stir bar. The mixture was stirred at 0 °C while trimethylaluminum (2 M, 1.70 mL) was added dropwise via syringe. After 5 min the mixture was warmed to room temperature and after another 5 min to 110 °C in a heating block. After 48 h the reaction mixture was cooled to room temperature and then diluted with ethyl acetate. It was washed once with 1M aqueous Rochelle salt, and the aqueous phase extracted with ethyl acetate three times. The organic material was washed with brine, dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purification via silica gel chromatography (0 to 65 % ethyl acetate in heptanes) afforded impure material that was further purified via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid). This afforded (Z)-6-bromo-N'-(4-((tert-butyldimethylsilyl)oxy)- 2-ethylphenyl)-4-chloropyrrolo[1,2-b]pyridazine-3-carboximid amide as a yellow residue. Yield 210 mg, 32 %. LCMS (ESI) m/z = 509.0 (M+H). Step 2: (Z)-4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6- bromo-N'-(2-ethyl-4- hydroxyphenyl)pyrrolo[1,2-b]pyridazine-3-carboximidamide (1R,3S)-1,2,2-trimethylcyclopentane-1,3-diamine (84.4 mg, 593.5 umol) in DMF (0.5 mL) and 6- bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4 -chloro-pyrrolo[1,2-b]pyridazine-3- carboxamidine (0.3 g, 395.7 umol) were dissolved in DMF (2 mL) in an oven-dried screw cap vial equipped with a stir bar. Diisopropylamine (127.8 mg, 989.3 umol, 172.3 uL) was added and the mixture was stirred at 95 °C in a heating block. After 7 h the reaction mixture was cooled to room temperature. The mixture was diluted with ethyl acetate, washed twice with a 1:1 brine:water solution, and then once more with 100 % brine. The organic phase was dried over magnesium sulfate, filtered, and the solvent removed in vacuo. Purification via reverse-phase HPLC (5 to 50 % acetonitrile in water) afforded (Z)-4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6- bromo-N'-(2-ethyl-4-hydroxyphenyl)pyrrolo[1,2-b]pyridazine-3 -carboximidamide as a tan solid. Yield: 116 mg, 47 %. LCMS (ESI) m/z = 615.2 (M+H) Step 3: (Z)-4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6- bromo-N'-(2-ethyl-4- hydroxyphenyl)pyrrolo[1,2-b]pyridazine-3-carboximidamide 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-[4-[tert-butyl(dimethyl)- silyl]oxy-2-ethyl-phenyl]pyrrolo[1,2-b]pyridazine-3-carboxam idine (0.049 g, 51.9 umol) and fluorocesium (39.4 mg, 259.4 umol) were dissolved in DMF (3 mL) in an oven-dried screw cap vial equipped with a stir bar. The mixture was stirred at room temperature for 2.5 h. The solution was filtered through a syringe filter. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded (Z)-4-(((1R,3S)-3-amino-2,2,3- trimethylcyclopentyl)amino)-6-bromo-N'-(2-ethyl-4-hydroxyphe nyl)pyrrolo[1,2-b]pyridazine-3- carboximidamide as a tan solid. Yield: 23 mg, 84 %. LCMS (ESI) m/z = 501.2 (M+H). ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.79 (s, 1H), 7.41 (s, 1H), 6.5-6.6 (m, 4H), 2.1-2.4 (m, 3H), 1.8-1.8 (m, 1H), 1.66 (br d, 1H, J=7.5 Hz), 1.17 (s, 3H), 0.99 (t, 3H), 0.87 (s, 7H), 0.66 (m, 2H). EXAMPLE 5D Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl] amino]-6-bromo-N'-(4-ethyl-6- methoxy-3-pyridyl) pyrrolo[1,2-b] pyridazine-3-carboxamidine Step 1: 4-ethyl-5-nitro-pyridin-2-amine To a stirred solution of 4-ethylpyridin-2-amine (2.00 g, 16.37 mmol) in sulfuric acid (1.5 mL) was added a solution of nitric acid (1.03 g, 16.37 mmol) in sulfuric acid (2.0 mL) dropwise at 0 °C. After stirring for 2 hours at 25 °C, the reaction mixture was poured into a mixture of crushed ice and water (50 g), adjusted to pH = 7 to 8 with solid sodium carbonate. The solid was collected by filtration, washed with cooled water three times and dried in vacuo. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a yellow solid. Yield: 1.1 g, 40%. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.72 (s, 1H), 7.26 (br, 2H), 6.33 (s, 1H), 2.83 (q, 2H, J=7.5 Hz), 1.14 (t, 3H, J=7.5 Hz). Step 2: 4-ethyl-5-nitro-pyridin-2-ol To a solution of 4-ethyl-5-nitro-pyridin-2-amine (1.10 g, 6.58 mmol) in sulfuric acid (1 mL) was added water (15 mL) dropwise, then cooled down to 0 °C, followed by the addition of sodium nitrite (681 mg, 9.87 mmol, 313.8 uL). After stirring for 2 hours at 25 °C, the reaction mixture was diluted with water, adjusted to pH = 9 with 10% aqueous solution of sodium hydroxide and then extracted with ethyl acetate three times. The combined organic layers were washed with brine three times, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound as a yellow solid. Yield: 0.80 g, 67%. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.56 (s, 1H), 6.30 (s, 1H), 3.50 (br, 1H), 2.82 (q, 2H, J=7.2 Hz), 1.14(t, 3H, J=7.2 Hz). Step 3: 2-chloro-4-ethyl-5-nitro-pyridine 4-ethyl-5-nitro-pyridin-2-ol (0.70 g, 4.16 mmol) was dissolved in phosphorus oxychloride (2 mL) and stirred for 2 hours at 100 °C. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as brown oil. Yield: 0.72 g, 92%. LCMS (ESI) m/z = 187.1 (M+H). Step 4: 4-ethyl-2-methoxy-5-nitro-pyridine To a solution of 2-chloro-4-ethyl-5-nitro-pyridine (0.70 g, 3.75 mmol) in methanol (20 mL) were added cuprous iodide (2.14 g, 11.25 mmol) and sodium methoxide (1.01 g, 18.76 mmol). The reaction mixture was stirred for 4 hours under reflux, then cooled to room temperature and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a light-yellow solid. Yield: 0.61 g, 80%. LCMS (ESI) m/z = 183.1 (M+H). Step 5: 4-ethyl-6-methoxy-pyridin-3-amine To a solution of 4-ethyl-2-methoxy-5-nitro-pyridine (0.61 g, 3.35 mmol) in methanol (30 mL) was added 5% Pd/C (0.20 g) under nitrogen atmosphere. The mixture was stirred for 16 hours at 25 °C under hydrogen atmosphere (1-2 atm). The reaction mixture was filtered through a celite pad and the filtrate concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as brown oil. Yield: 0.26 g, 51%. LCMS (ESI) m/z = 153.3 (M+H). Step 6: 6-bromo-4-chloro-N'-(4-ethyl-6-methoxy-3-pyridyl)pyrrolo[1,2 -b]pyridazine-3- carboxamidine To a mixture of 4-ethyl-6-methoxy-pyridin-3-amine (60 mg, 394.2 μmol) and 6-bromo-4-chloro- pyrrolo[1,2-b] pyridazine-3-carboxamide (108.2 mg, 394.2 μmol) in toluene (3 mL) was added trimethylaluminium (1.2 mL, 1.0 M in heptanes, 1.2 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 30 min at room temperature, heated to 80 °C for 16 hours, and then cooled to room temperature.10.0 g of sodium sulfate decahydrate was added. The resulting mixture was stirred for 2 hours and filtered and the filtrate concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the titled compound as a yellow solid. Yield: 50 mg, 24%. LCMS (ESI) m/z = 409.9 (M+H). Step 7: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-(4-ethyl-6- methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-4-chloro-N'-(4-ethyl-6-methoxy-3-pyridyl)pyrrolo[1,2 -b]pyridazine-3- carboxamidine (50 mg, 96.7 μmol) and (1S,3R)-1,2,2-trimethylcyclopentane-1,3-diamine (27.5 mg, 193.3 μmol) in chloroform (3 mL) was added N-ethyl-N-isopropyl-propan-2-amine (37.5 mg, 290.0 μmol, 50.5 μL). After stirring for 6 hours at 80 °C, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification via prep-TLC (petroleum ether/ethyl acetate 4:1) afforded 12 mg of the crude product, which was further purified by reverse phase HPLC (acetonitrile/water) to afford 4-[[(1R,3S)-3-amino-2,2,3-trimethyl- cyclopentyl]amino]-6-bromo-N'-(4-ethyl-6-methoxy-3-pyridyl)p yrrolo[1,2-b]pyridazine-3- carboxamidine as a yellow solid. Yield: 3.8 mg, 6 %. LCMS (ESI) m/z = 514.4 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.43 (s, 1H), 7.83 (d, 1H, J=1.5 Hz), 7.58 (s, 1H), 6.90 (d, 1H, J=1.5 Hz), 6.67 (d, 1H, J=5.4 Hz), 6.25 (br, 2H), 4.30 (t, 1H, J= 7.5 Hz), 3.81 (s, 3H), 2.40-2.50 (m, 2H), 2.17- 2.38 (m, 1H), 1.52-1.77 (m, 3H), 1.00-1.10 (m, 6H), 0.80 (s, 6H). EXAMPLE 5E Synthesis of 4-[(3-amino-2,2,3-trimethyl-cyclopentyl)amino]-N'-(4-hydroxy phenyl)-6-phenyl- pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-4-chloro -pyrrolo[1,2-b]pyridazine-3- carboxamidine 6-bromo-4-chloro-pyrrolo[1,2-b]pyridazine-3-carboxamide (300 mg, 1.09 mmol) and 4-(tert- butyldimethylsilyloxy)benzenamine (293 mg, 1.31 mmol) were suspended in toluene (30 mL) in an oven-dried screw cap vial equipped with a stir bar. The mixture was stirred at 0 °C while trimethylaluminum (2 M in toluene, 1.64 mL) was added dropwise via syringe. After 5 min, the mixture was warmed to 110 °C and stirred overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed once with saturated aqueous sodium bicarbonate solution, and the aqueous phase extracted with ethyl acetate (x3). The organic extracts were washed with brine (3x), dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purification via silica gel column (petroleum ether/ethyl acetate, 2:3) afforded the titled compound. Yield: 350 mg, 66%. LCMS (ESI) m/z = 481.0 (M+H) Step 2: 4-[(3-amino-2,2,3-trimethyl-cyclopentyl)amino]-6-bromo-N'-[4 -[tert-butyl(dimethyl)- silyl]oxyphenyl]pyrrolo[1,2-b]pyridazine-3-carboxamidine 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-4-chloro -pyrrolo[1,2-b]pyridazine-3- carboxamidine (270 mg, 562.6 umol) was suspended in DMA (8 mL). 1,2,2- trimethylcyclopentane-1,3-diamine (120 mg, 844.0 umol) and DIEA (218 mg, 1.69 mmol) were added to the suspension at room temperature. The reaction mixture was irradiated with microwave at 100 °C for 2 h. After cooling, the mixture was diluted with water, extracted with ethyl acetate (x3) and the combined organic layers washed with brine (x3), dried over anhydrous sodium sulfate, filtered, and solvent removed in vacuo. Purification via silica gel column (ethyl acetate, 100%) afforded the titled compound. Yield: 240 mg, 73%. LCMS (ESI) m/z = 585.1, 587.1 (M+H) Step 3: 4-[(3-amino-2,2,3-trimethyl-cyclopentyl)amino]-N'-[4-[tert-b utyl(dimethyl)silyl]- oxyphenyl]-6-phenyl-pyrrolo[1,2-b]pyridazine-3-carboxamidine 4-[(3-amino-2,2,3-trimethyl-cyclopentyl)amino]-6-bromo-N'-[4 -[tert-butyl(dimethyl)silyl] oxyphenyl]pyrrolo[1,2-b]pyridazine-3-carboxamidine (200 mg, 341.5 umol) was suspended in dioxane/water = 5/1 (42 mL). Phenylboronic acid (83 mg, 683.0 umol), tripotassium phosphate (217 mg, 1.02 mmol) and Pd(dtbpf)Cl2 (22.27 mg, 34.1 umol) were added to the suspension under nitrogen atmosphere. The resulting mixture was heated at 90°C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column (dichoromethane/methanol, 10:1- 4:1) afforded the titled compound. Yield: 170 mg, 85%. LCMS (ESI) m/z = 583.3 (M+H) Step 4: 4-[(3-amino-2,2,3-trimethyl-cyclopentyl)amino]-N'-(4-hydroxy phenyl)-6-phenyl-pyrrolo- [1,2-b]pyridazine-3-carboxamidine 4-[(3-amino-2,2,3-trimethyl-cyclopentyl)amino]-N'-[4-[tert-b utyl(dimethyl)silyl]oxyphenyl]-6- phenyl-pyrrolo[1,2-b]pyridazine-3-carboxamidine (170 mg, 291.7 umol) was suspended in DMF (2.5 mL). Cesium fluoride (177.2 mg, 1.17 mmol, 43 uL) was added at room temperature under nitrogen atmosphere. After stirring for 2 h, the reaction mixture was purified via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) to afford 4-[(3-amino-2,2,3-trimethyl- cyclopentyl)amino]-N'-(4-hydroxyphenyl)-6-phenyl-pyrrolo[1,2 -b]pyridazine-3-carboxamidine as a light yellow solid. Yield: 60 mg, 44 %. LCMS (ESI) m/z = 469.2 (M+H). ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.50 (brs, 2H), 8.09 (s, 1H), 8.00 (s, 1H), 7.74 (d, 2H, J=7.2 Hz), 7.41-7.46 (m, 3H), 7.27-7.31 (m, 1H), 7.22 (d, 2H, J=8.4 Hz), 6.97 (d, 2H, J=8.4 Hz), 4.22 (t, 1H, J=8.0 Hz), 2.31- 2.37 (m, 1H), 1.95-2.15 (m, 3H), 1.40 (s, 3H), 1.15 (s, 3H), 1.05 (s, 3H). EXAMPLE 5F Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -ethyl-4-hydroxy- phenyl)-6-[4-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]phenyl]pyr rolo[1,2-b]pyridazine-3- carboxamidine Step 1: 2-[2-(2-methoxyethoxy)ethoxy]ethyl 4-methylbenzenesulfonate 2-[2-(2-methoxyethoxy)ethoxy]ethanol (3.00 g, 18.27 mmol) was dissolved in THF (6 mL). A solution of sodium hydroxide (24%, 6 mL) was added slowly at 25°C and stirred for 5 min. 4- methylbenzenesulfonyl chloride (5.22 g, 27.41 mmol) in THF (10.5 mL) was added slowly. After stirring at 25 °C for 12 h, the mixture was quenched with ice water. The resulting mixture was extracted with chloroform and the organic layers washed with brine, dried with anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to afford the titled compound. Yield: 5.7 g crude. LCMS (ESI) m/z = 337.2 (M+H ₂ O+H). Step 2: 2-[4-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]phenyl]-4,4,5,5-te tramethyl-1,3,2- dioxaborolane To a stirred solution of 2-[2-(2-methoxyethoxy)ethoxy]ethyl 4-methylbenzenesulfonate (3 g, 9.42 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.07 g, 9.42 mmol, 1.97 mL) in acetonitrile (15 mL) was added potassium carbonate (1.30 g, 9.42 mmol). After stirring at 80 °C for 12 h, the reaction mixture was filtered and quenched with water. The aqueous layer was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded the titled compound. Yield: 3.1 g, 90 %. ¹ H NMR (CDCl3, 400 MHz) δ 7.75 (d, 2H, J=8.0 Hz), 6.92 (d, 2H, J=8.0 Hz), 4.16-4.19 (m, 2H), 3.87-3.89 (m, 2H), 3.74-3.77 (m, 2H), 3.66-3.71 (m, 4H), 3.55-3.58 (m, 2H), 3.41 (s, 3H), 1.35 (s, 12H). Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -ethyl-4-hydroxy- phenyl)-6-[4-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]phenyl]pyr rolo[1,2-b]pyridazine-3- carboxamidine 2-[4-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]phenyl]-4,4,5,5-te tramethyl-1,3,2-dioxaborolane (90 mg, 245.7 umol) and 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-[4- [tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]pyrrolo[1,2-b] pyridazine-3-carboxamidine (150.8 mg, 245.7 umol) in DMF (12 mL) and water (3 mL) were added tripotassium phosphate (104.3 mg, 491.5 umol) and Pd(dtbpf)Cl ₂ (16.0 mg, 25.6 umol) at room temperature under protection of nitrogen atmosphere. The resulting mixture was stirred at 100°C for 2 h. After cooling to room temperature, the reaction mixture was quenched with water. The aqueous layer was extracted with dichloromethane and the organic layer dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate) afforded 4-[[(1R,3S)-3-amino-2,2,3-trimethyl- cyclopentyl]amino]-N'-(2-ethyl-4-hydroxy-phenyl)-6-[4-[2-[2- (2-methoxy- ethoxy)ethoxy]ethoxy]phenyl]pyrrolo[1,2-b]pyridazine-3-carbo xamidine as a white solid. Yield: 28.3 mg, 17 %. LCMS (ESI) m/z = 659.2 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.20 (brs, 1H), 8.89 (s, 1H), 8.17 (s, 1H), 8.04 (s, 1H), 7.66 (d, 2H, J=8.4 Hz), 6.99-7.04 (m, 3H), 6.67 (s, 1H), 6.59-6.62 (m, 2H), 5.80 (brs, 2H), 4.52 (t, 1H, J=8.0 Hz), 4.11-4.14 (m, 2H), 3.75-3.78 (m, 2H), 3.52-3.62 (m, 6H), 3.43-3.46 (m, 2H), 3.25 (s, 3H), 2.40 (q, 2H, J=7.6 Hz), 2.32-2.35 (m, 1H), 1.60-1.68 (m, 2H), 1.52-1.58 (m, 1H), 1.05-1.09 (m, 6H), 0.85 (s, 6H). EXAMPLE 5G Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -chloro-4-hydroxy- phenyl)-6-[4-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]etho xy]ethoxy]phenyl]pyrrolo[1,2- b]pyridazine-3-carboxamidine Step 1: 4-((tert-butyldimethylsilyl)oxy)-2-chloroaniline To a solution of 4-amino-3-chloro-phenol (1.00 g, 6.97 mmol) in dichloromethane (20 mL) were added imidazole (948.3 mg, 13.93 mmol) and tert-butyldimethylsilyl chloride (1.26 g, 8.36 mmol). After stirring for 2 hours at 25 °C, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a brown oil. Yield: 1.5 g, 77 %. LCMS (ESI) m/z = 258.2 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 6.68-6.72 (m, 2H), 6.10-6.57 (m, 1H), 4.90 (s, 2H), 0.93 (s, 9H), 0.13 (s, 6H). Step 2: 6-bromo-N'-(4-((tert-butyldimethylsilyl)oxy)-2-chlorophenyl) -4-chloropyrrolo[1,2-b]- pyridazine-3-carboximidamide To a mixture of 6-bromo-4-chloro-pyrrolo[1,2-b]pyridazine-3-carboxamide (1.0 g, 3.64 mmol) and 4-((tert-butyldimethylsilyl)oxy)-2-chloroaniline (1.41 g, 5.46 mmol) in toluene (15 mL) was added trimethylalumane (5.5 mL, 2 M in toluene) at 0 °C. After stirring for 6 hours at 110 °C, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as yellow oil. Yield: 0.9 g, 48%. LCMS (ESI) m/z = 515.0 (M+H). Step 3: 4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6-brom o-N'-(2-chloro-4- hydroxy-phenyl)pyrrolo[1,2-b]pyridazine-3-carboximidamide To a solution of 6-bromo-N'-(4-((tert-butyldimethylsilyl)oxy)-2-chlorophenyl) -4-chloropyrrolo- [1,2-b]pyridazine-3-carboximidamide (1.40 g, 2.72 mmol) and (1S,3R)-1,2,2- trimethylcyclopentane-1,3-diamine (580.8 mg, 4.08 mmol) in N,N-dimethylacetamide (10 mL) was added N-ethyl-N-isopropyl-propan-2-amine (703.6 mg, 5.44 mmol). After stirring for 2 hours at 85 °C, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the titled compound as a yellow oil. Yield: 1.0 g, 59%. LCMS (ESI) m/z = 504.2. Step 4: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -chloro-4-hydroxy- phenyl)-6-[4-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]etho xy]ethoxy] phenyl]pyrrolo[1,2- b]-pyridazine-3-carboxamidine To a solution of 4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6-brom o-N'-(2-chloro-4- hydroxyphenyl)pyrrolo[1,2-b]pyridazine-3-carboximidamide (70 mg, 138.4 μmol) in 1,4-dioxane (2 mL) and water (0.5 mL) were added potassium phosphate (58.8 mg, 276.8 μmol), [1,1′-bis(di- tert-butylphosphino)ferrocene]dichloropalladium(II) (9.2 mg, 13.8 μmol) and 2-[4-[2-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]phenyl]-4,4,5,5-te tramethyl-1,3,2-dioxaborolane (75.5 mg, 166.1 μmol). The resulting mixture was purged with nitrogen gas and stirred for 1 hour at 80 °C. After cooling to room temperature, the resulting mixture was filtered through a celite pad and washed with ethyl acetate and methanol. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afford 4- [[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2-c hloro-4-hydroxy-phenyl)-6-[4-[2- [2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy] phenyl]pyrrolo[1,2-b]-pyridazine-3- carboxamidine as a pink solid. Yield: 8.1 mg, 7.6 %. LCMS (ESI) m/z = 755.6 (M+H). ¹ H NMR (DMSO-d6, 300 MHz,) δ 8.19 (s, 1H), 8.08 (s, 1H), 7.71 (d, 2H, J =8.7 Hz), 7.13 (s, 1H), 6.96-7.05 (m, 2H), 6.82-6.92 (m, 2H), 6.71-6.78 (m, 1H), 4.53-4.59 (m, 1H), 4.08-4.16 (m, 2H), 3.72-3.79 (m, 2H), 3.40-3.60 (m, 16H), 3.14 (s, 3H), 2.28-2.36 (m, 1H), 1.80-1.90 (m, 2H), 1.61-1.76 (m, 1H), 1.25 (s, 3H), 0.91 (s, 6H). EXAMPLE 5H Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -chloro-5-fluoro- phenyl)-6-[4-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]e thoxy]ethoxy]ethoxy] phenyl]pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-(2-chloro- 5-fluoro-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (0.16 g, 315.1 μmol) in N,N- dimethylformamide (10 mL) and water (2 mL) were added 2-[4-[2-[2-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]phenyl]-4,4 ,5,5-tetramethyl-1,3,2- dioxaborolane (314.1 mg, 630.1 μmol), sodium tert-butoxide (60.6 mg, 630.1 μmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (20.5 mg, 31.5 μmol). The resulting mixture was stirred for 1 hour at 70 °C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -chloro-5-fluoro-phenyl)- 6-[4-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]et hoxy]ethoxy]-phenyl]pyrrolo[1,2- b]pyridazine-3-carboxamidine as brown oil. Yield: 13.4 mg, 5 %. LCMS (ESI) m/z = 799.4 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.39 (br.1H), 8.17 (s, 1H), 8.06 (s, 1H), 7.65-7.69 (m, 2H), 7.44-7.50 (m, 1H), 6.83-7.07 (m, 5H), 6.41 (brs, 2H), 4.51-4.54 (m, 1H), 4.12 (d, 2H, J=5.1 Hz), 3.77 (d, 2H, J=4.8 Hz), 3.48-3.60 (m, 18H), 3.34-3.44 (m, 2H), 3.23 (s, 3H), 2.31-2.52 (m, 1H), 1.60-1.69 (m, 3H), 1.08 (s, 3H), 0.86 (s, 6H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -114.72 (s, 1F). EXAMPLE 5I Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -ethyl-4-hydroxy- phenyl)-6-[4-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethox y]ethoxy]ethoxy]ethoxy]ethoxy] phenyl]pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl] amino]-N'-[4-[tert-butyl(dimethyl)silyl] oxy-2-ethyl-phenyl]-6-[4-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy]ethoxy]phenyl]pyrrolo[1,2-b]pyridazine-3-carboxamidin e To a mixture of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-[4-[tert- butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]pyrrolo[1,2-b]pyrida zine-3-carboxamidine (0.20 g, 325.9 μmol), 2-[4-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy ]ethoxy]ethoxy] ethoxy]phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (265.2 mg, 488.8 μmol) and potassium phosphate (207.5 mg, 977.7 μmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (21.2 mg, 32.6 μmol). The mixture was stirred for 2 hours at 120 °C under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered through a celite pad and the filtrate concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the titled compound as a yellow solid. Yield: 0.15 g.29 %. LCMS (ESI) m/z = 971.7 (M+Na). Step 2: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl] amino]-N'-(2-ethyl-4-hydroxy-phenyl)- 6-[4-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy]ethoxy]- phenyl]pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl] amino]-N'-[4-[tert- butyl(dimethyl)silyl] oxy-2-ethyl-phenyl]-6-[4-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy]ethoxy]phenyl]pyrrolo[1,2-b]pyridazine-3-carboxamidin e (190 mg, 120.1 umol) in N,N-dimethylformamide (5 mL) was added cesium fluoride (54.7 mg, 360.3 umol). After stirring for 2 hours at 25°C, the reaction mixture was filtered. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-[[(1R,3S)-3-amino- 2,2,3-trimethyl-cyclopentyl] amino]-N'-(2-ethyl-4-hydroxy-phenyl)-6-[4-[2-[2-[2-[2-[2-[2- (2- methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy]ethoxy]phenyl]pyrrolo[1,2-b]pyridazine- 3-carboxamidine as a yellow solid. Yield: 39.9 mg. 39%. LCMS (ESI) m/z = 833.6 (M-H). ¹ H NMR (DMSO-d ₆ +D ₂ O, 300 MHz) δ 8.36-8.38 (m, 1H), 8.00-8.10 (m, 2H), 7.30 (d, 2H, J=8.4 Hz), 7.24-7.28 (m, 1H), 7.05 (d, 2H, J=8.4 Hz), 6.73-6.86 (m, 3H), 4.52-4.58 (m, 1H), 4.10-4.20 (m, 2H), 3.71-3.80 (m, 2H), 3.43-3.62 (m, 24H), 3.24 (s, 3H), 2.33-2.50 (m, 3H), 1.70-2.10 (m, 3H), 1.36 (s, 3H), 1.11-1.19 (m, 3H), 0.90-1.00 (m, 6H). EXAMPLE 5J Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl] amino]-N'-(2-ethyl-4-hydroxy- phenyl)-6-[4-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy) ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]phenyl]pyrrolo[1,2-b]pyridazine-3-carboxamidin e Step 1: 2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl 4-methylbenzenesulfonate To a solution of 2,5,8,11,14,17,20,23-octaoxapentacosan-25-ol (2.00 g, 5.20 mmol) in tetrahydrofuran (20.0 mL) was added sodium hydroxide (2.08 g, 52.02 mmol) and 4- methylbenzenesulfonyl chloride (1.49 g, 7.80 mmol). After stirring for 15 hours at 25 °C, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound as light-yellow oil. Yield: 2.50 g, 89%. LCMS (ESI) m/z = 539.7 (M+H). Step 2: 2-(4-((2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl)oxy)phen yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane To a solution of 2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl 4-methylbenzenesulfonate (1.50 g, 2.78 mmol) in acetonitrile (20.0 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (612.9 mg, 2.78 mmol) and cesium carbonate (2.72 g, 8.35 mmol). After stirring for 4 hours at 100 °C, the reaction mixture was cooled to room temperature, diluted with brine and extracted with ethyl acetate (x3). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the titled compound as a light-yellow oil. Yield: 1.50 g, 91%. LCMS (ESI) m/z = 587.7 (M+H). Step 3: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-[2 -ethyl-4-[tert- butyl(dimethyl)silyl]oxy-phenyl]-6-[4-[2-[2-[2-[2-[2-[2-[2-( 2-methoxyethoxy)ethoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]phenyl]pyrrolo[1,2-b]pyri dazine-3-carboxamidine To a mixture of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-[2-ethyl-4- [tert-butyl(dimethyl)silyl]oxy-phenyl]pyrrolo[1,2-b]pyridazi ne-3-carboxamidine (200 mg, 326.3 umol) and 2-(4-((2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl)oxy)phen yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (286.9 mg, 489.5 umol) in 1,4-dioxane (10 mL) and water (0.1 mL) were added potassium phosphate (207.5 mg, 978.9 umol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (21.2 mg, 32.6 umol). The mixture was stirred for 2 hours at 100 °C under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (methanol/dichloromethane) afforded the titled compound as a brown solid. Yield: 400 mg, 73%. LCMS (ESI) m/z = 993.3 (M+H). Step 4: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -ethyl-4-hydroxy-phenyl)- 6-[4-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]eth oxy]ethoxy] ethoxy]ethoxy]ethoxy]-phenyl]pyrrolo[1,2-b]pyridazine-3-carb oxamidine To a solution of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-[2 -ethyl-4-[tert- butyl(dimethyl)silyl]oxy-phenyl]-6-[4-[2-[2-[2-[2-[2-[2-[2-( 2-methoxyethoxy)ethoxy]ethoxy]- ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]phenyl]pyrrolo[1,2-b]pyri dazine-3-carboxamidine (300 mg, 302.3 umol) in N,N-dimethylformide (10.0 mL) was added cesium fluoride (91.8 mg, 604.6 umol). After stirring for 2 hours at room temperature, the reaction mixture was filtered and the filtrate purified via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) to afford 4-[[(1R,3S)-3-amino-2,2,3-trimethyl- cyclopentyl]amino]-N'-(2-ethyl-4-hydroxy-phenyl)-6-[4-[2-[2- [2-[2-[2-[2-[2-(2-methoxyethoxy)- ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]phenyl]pyrrolo[1,2-b]pyridazine-3- carboxamidine as a brown solid. Yield: 34.1 mg, 12%. LCMS (ESI) m/z = 879.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz): 8.91 (s, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 7.65 (d, 2H, J=8.8 Hz), 6.98-7.04 (m, 3H), 6.58-6.66 (m, 3H), 5.75 (br, 2H), 4.50-4.55 (m, 1H), 4.11-4.13 (m, 2H), 3.75-3.77 (m, 2H), 3.28-3.61 (m, 28H), 3.23 (s, 3H), 2.34-2.43 (m, 3H), 1.45-1.67 (m, 3H),1.04-1.08 (m, 6H), 0.84 (s, 6H). EXAMPLE 5K Synthesis of 6-(3-aminophenyl)-4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclop entyl]amino]-N'-(2- ethyl-4-hydroxy-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamid ine Step 1: 6-(3-aminophenyl)-4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclop entyl]amino]-N'-[4-[tert- butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]pyrrolo[1,2-b]pyrida zine-3-carboxamidine To a solution of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-[4-[tert- butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]pyrrolo[1,2-b]pyrida zine-3-carboxamidine (100 mg, 162.9 umol) and (3-aminophenyl)boronic acid (44.6 mg, 325.9 umol) in 1,4-dioxane (5 mL) and water (1 mL) were added tripotassium phosphate (103.6 mg, 488.8 umol) and Pd(dtbpf)Cl ₂ (10.6 mg, 16.3 umol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 95°C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification by silica gel column (dichloromethane/ methanol, 10:1) afforded the titled compound. Yield: 85 mg, 83 %. LCMS (ESI) m/z = 626.5 (M+H) Step 2: 6-(3-aminophenyl)-4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclop entyl]amino]-N'-(2-ethyl- 4-hydroxy-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine 6-(3-aminophenyl)-4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclop entyl]amino]-N'-[4-[tert-butyl- (dimethyl)silyl]oxy-2-ethyl-phenyl]pyrrolo[1,2-b]pyridazine- 3-carboxamidine (90 mg, 143.8 umol) was suspended in DMF (2.0 mL). Cesium fluoride (43.7 mg, 287.6 umol) was added at room temperature under nitrogen atmosphere. After the reaction was complete, it was extracted with ethyl acetate (x3) and the organic extracts dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 6-(3-aminophenyl)-4-[[(1R,3S)-3- amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2-ethyl-4-hydro xy-phenyl)pyrrolo[1,2-b]- pyridazine-3-carboxamidine as a yellow solid. Yield: 30.7 mg, 42 %. LCMS (ESI) m/z = 510.2 (M-H). ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.51 (brs, 2H), 7.98-8.01 (m, 2H), 7.29 (s, 1H), 7.17 (t, 1H, J=8.0 Hz), 7.06-7.12 (m, 2H), 7.02 (d, 1H, J=8.4 Hz), 6.88 (s, 1H), 6.79-6.81 (m, 1H), 6.67- 6.70 (m, 1H), 4.37-4.40 (m, 1H), 2.62 (q, 2H, J=7.6 Hz), 2.40-2.50 (m, 1H), 2.01-2.09 (m, 3H), 1.41 (s, 3H), 1.27 (t, 3H, J=7.6 Hz), 1.13 (s, 3H), 1.09 (s, 3H). EXAMPLE 5L Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -ethyl-4-hydroxy- phenyl)-6-(3-hydroxyphenyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine Step 1: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-[4 -[tert-butyl(dimethyl)silyl]- oxy-2-ethyl-phenyl]-6-(3-hydroxyphenyl)pyrrolo[1,2-b]pyridaz ine-3-carboxamidine To a solution of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-[4-[tert- butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]pyrrolo[1,2-b]pyrida zine-3-carboxamidine (100 mg, 162.9 umol) and (3-hydroxyphenyl)boronic acid (45.0 mg, 325.9 umol) in 1,4-dioxane (5 mL) and water (1 mL) were added tripotassium phosphate (103.6 mg, 488.8 umol) and Pd(dtbpf)Cl ₂ (10.6 mg, 16.3 umol) at room temperature under protection of nitrogen atmosphere. The resulting mixture was stirred at 95°C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification by silica gel column (dichloromethane/ methanol, 10:1) afforded the titled compound. Yield: 80 mg, 78 %. LCMS (ESI) m/z = 627.5 (M+H) Step 2: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -ethyl-4-hydroxy-phenyl)- 6-(3-hydroxyphenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-[4 -[tert-butyl(dimethyl)silyl]oxy-2- ethyl-phenyl]-6-(3-hydroxyphenyl)pyrrolo[1,2-b]pyridazine-3- carboxamidine (90 mg, 143.6 umol) was suspended in DMF (2.0 mL). Cesium fluoride (43.7 mg, 287.6 umol) was added at room temperature under nitrogen atmosphere. After the reaction was complete, the mixture was extracted with ethyl acetate (x3). The organic extracts were dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-[[(1R,3S)-3-amino-2,2,3-trimethyl- cyclopentyl]amino]-N'-(2-ethyl-4-hydroxy-phenyl)-6-(3-hydrox yphenyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine as a yellow solid. Yield: 32.5 mg, 44 %. LCMS (ESI) m/z = 511.1 (M-H). ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.51 (brs, 2H), 8.01 (s, 2H), 7.32 (s, 1H), 7.20-7.26 (m, 2H), 7.15 (s, 1H), 7.02 (d, 1H, J=8.4 Hz), 6.88 (s, 1H), 6.79-6.82 (m, 1H), 6.72-6.75 (m, 1H), 4.35- 4.41 (m, 1H), 2.63 (q, 2H, J=7.6 Hz), 2.40-2.50 (m, 1H), 1.99-2.11 (m, 3H), 1.42 (s, 3H), 1.27 (t, 3H, J=7.6 Hz), 1.13 (s, 3H), 1.09 (s, 3H). EXAMPLE 5M Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -ethyl-4-hydroxy- phenyl)-6-[3-(hydroxymethyl)phenyl]pyrrolo[1,2-b]pyridazine- 3-carboxamidine Step 1: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-[4 -[tert-butyl(dimethyl)- silyl]oxy-2-ethyl-phenyl]-6-[3-(hydroxymethyl)phenyl]pyrrolo [1,2-b]pyridazine-3- carboxamidine To a solution of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-[4-[tert- butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]pyrrolo[1,2-b]pyrida zine-3-carboxamidine (100 mg, 162.9 umol) and [3-(hydroxymethyl)phenyl]boronic acid (49.5 mg, 325.9 umol) in 1,4-dioxane (5 mL) and water (1 mL) were added tripotassium phosphate (103.6 mg, 488.8 umol) and Pd(dtbpf)Cl2 (10.6 mg, 16.3 umol) at room temperature under protection of nitrogen atmosphere. The resulting mixture was stirred at 95°C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification by silica gel column (dichloromethane/ methanol, 10:1) afforded the titled compound. Yield: 80 mg, 77 %. LCMS (ESI) m/z = 641.6 (M+H) Step 2: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -ethyl-4-hydroxy-phenyl)- 6-[3-(hydroxymethyl)phenyl]pyrrolo[1,2-b]pyridazine-3-carbox amidine 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-[4 -[tert-butyl(dimethyl)silyl]oxy-2- ethyl-phenyl]-6-[3-(hydroxymethyl)phenyl]pyrrolo[1,2-b]pyrid azine-3-carboxamidine (90 mg, 140.4 umol) was suspended in DMF (2.0 mL). Cesium fluoride (42.7 mg, 280.8 umol) was added at room temperature under nitrogen atmosphere. After stirring for 2 h, the reaction was diluted with ethyl acetate (x3). The organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-[[(1R,3S)-3-amino-2,2,3-trimethyl- cyclopentyl]amino]-N'-(2-ethyl-4-hydroxy-phenyl)-6-[3-(hydro xymethyl)phenyl]-pyrrolo[1,2- b]pyridazine-3-carboxamidine as a yellow solid. Yield: 35 mg, 47 %. LCMS (ESI) m/z = 525.2 (M-H). ¹ H NMR (CD3OD, 400 MHz) δ 8.49 (s, 2H), 8.09 (s, 1H), 8.01 (s, 1H), 7.76 (s, 1H), 7.66 (d, 1H, J=7.6 Hz), 7.40-7.43 (m, 2H), 7.29 (d, 1H, J=7.6 Hz), 7.04 (d, 1H, J=8.4 Hz), 6.89 (s, 1H), 6.81 (d, 1H, J=8.4 Hz), 4.79 (s, 2H), 4.33-4.38 (m, 1H), 2.63 (q, 2H, J=7.6 Hz), 2.42-2.49 (m, 1H), 1.96-2.12 (m, 3H), 1.42 (s, 3H), 1.28 (t, 3H, J=7.6 Hz), 1.13 (s, 3H), 1.08 (s, 3H). EXAMPLE 5N Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -ethyl-4-hydroxy- phenyl)-6-[3-(2-hydroxyethyl)phenyl]pyrrolo[1,2-b]pyridazine -3-carboxamidine Step 1: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-[4 -[tert- butyl(dimethyl)silyl]-oxy-2-ethyl-phenyl]-6-[3-(2-hydroxyeth yl)phenyl]pyrrolo[1,2-b]pyridazine- 3-carboxamidine To a solution of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-[4-[tert- butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]pyrrolo[1,2-b]pyrida zine-3-carboxamidine (100 mg, 162.9 umol) and [3-(2-hydroxyethyl)phenyl]boronic acid (54.1 mg, 325.9 umol) in 1,4-dioxane (5 mL) and water (1 mL) were added tripotassium phosphate (103.6 mg, 488.8 umol) and Pd(dtbpf)Cl ₂ (10.6 mg, 16.3 umol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 95°C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification by silica gel column (dichloromethane/ methanol, 10:1) afforded the titled compound. Yield: 90 mg, 84 %. LCMS (ESI) m/z = 655.5 (M+H) Step 2: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -ethyl-4-hydroxy-phenyl)- 6-[3-(2-hydroxyethyl)phenyl]pyrrolo[1,2-b]pyridazine-3-carbo xamidine 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-[4 -[tert-butyl(dimethyl)silyl]oxy-2- ethyl-phenyl]-6-[3-(2-hydroxyethyl)phenyl]pyrrolo[1,2-b]pyri dazine-3-carboxamidine (90 mg, 137.4 umol) was suspended in DMF (2.0 mL). Cesium fluoride (41.8 mg, 274.8 umol) was added at room temperature under nitrogen atmosphere. After the reaction was complete, it was extracted with ethyl acetate (x3). The organic layers were dried over anhydrous sodium sulfate filtered and the filtrate concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-[[(1R,3S)-3-amino-2,2,3-trimethyl- cyclopentyl]amino]-N'-(2-ethyl-4-hydroxy-phenyl)-6-[3-(2-hyd roxyethyl)phenyl]-pyrrolo[1,2- b]pyridazine-3-carboxamidine as a yellow solid. Yield: 35 mg, 47 %. LCMS (ESI) m/z = 539.1 (M-H). ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.51 (brs, 2H), 8.06 (s, 1H), 8.01 (s, 1H), 7.57-7.65 (m, 2H), 7.34-7.38 (m, 2H), 7.18 (d, 1H, J=8.0 Hz), 7.02 (d, 1H, J=8.4 Hz), 6.88 (s, 1H), 6.78-6.82 (m, 1H), 4.35-4.39 (m, 1H), 3.84 (t, 2H, J=7.2 Hz), 2.91 (t, 2H, J=7.2 Hz), 2.63 (q, 2H, J=7.2 Hz), 2.40-2.47 (m, 1H), 1.97-2.09 (m, 3H), 1.42 (s, 3H), 1.27 (t, 3H, J=7.2 Hz), 1.13 (s, 3H), 1.09 (s, 3H). EXAMPLE 5O Synthesis of 6-[3-amino-5-(hydroxymethyl)phenyl]-4-[[(1R,3S)-3-amino-2,2, 3-trimethyl- cyclopentyl]amino]-N'-(2-ethyl-4-hydroxy-phenyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine Step 1: [3-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen yl]methanol To a stirred solution of methyl 3-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo ate (300 mg, 1.08 mmol) and THF (5 mL) was added a solution of borane in THF (423.8 ul, 4.33 mmol,) at room temperature. The resulting mixture was stirred at 60°C for 2 h. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane/ methanol, 10:1) afforded the titled compound as a yellow solid. Yield: 210 mg, 78 %. LCMS (ESI) m/z = 250.1 (M+H). Step 2: 6-[3-amino-5-(hydroxymethyl)phenyl]-4-[[(1R,3S)-3-amino-2,2, 3-trimethyl-cyclopentyl]- amino]-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]p yrrolo[1,2-b]pyridazine-3- carboxamidine To a solution of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-[4-[tert- butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]pyrrolo[1,2-b]pyrida zine-3-carboxamidine (100 mg, 162.9 umol) and [3-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen yl]methanol (81.2 mg, 325.9 umol), in 1,4-dioxane (5 mL) and water (1 mL) were added tripotassium phosphate (103.6 mg, 488.8 umol) and Pd(dtbpf)Cl2 (10.6 mg, 16.3 umol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 95°C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane/ methanol, 6:1) afforded the titled compound as light yellow oil. Yield: 80 mg, 75 %. LCMS (ESI) m/z = 656.5 (M+H). Step 3: 6-[3-amino-5-(hydroxymethyl)phenyl]-4-[[(1R,3S)-3-amino-2,2, 3-trimethyl-cyclopentyl]- amino]-N'-(2-ethyl-4-hydroxy-phenyl)pyrrolo[1,2-b]pyridazine -3-carboxamidine 6-[3-amino-5-(hydroxymethyl)phenyl]-4-[[(1R,3S)-3-amino-2,2, 3-trimethyl-cyclopentyl]amino]- N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]pyrrolo[ 1,2-b]pyridazine-3-carboxamidine (80 mg, 122.0 umol) was suspended in DMF (2.0 mL). Cesium fluoride (55.6 mg, 365.9 umol) was added at room temperature under nitrogen atmosphere. After stirred for 1.5 h, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 6-[3-amino-5-(hydroxymethyl)phenyl]-4-[[(1R,3S)-3- amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2-ethyl-4-hydro xy-phenyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine as a light yellow solid. Yield: 19.8 mg, 30 %. LCMS (ESI) m/z = 542.2 (M+H). ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.50 (brs, 2H), 8.00 (s, 2H), 7.30 (s, 1H), 7.09 (s, 1H), 7.00-7.06 (m, 2H), 6.88 (s, 1H), 6.78-6.81 (m, 1H), 6.69 (s, 1H), 4.59 (s, 2H), 4.35-4.41 (m, 1H), 2.62 (q, 2H, J=7.6 Hz), 2.41-2.50 (m, 1H), 1.99-2.13 (m, 3H), 1.42 (s, 3H), 1.27 (t, 3H, J=7.6 Hz), 1.13 (s, 3H), 1.08 (s, 3H). EXAMPLE 5P Synthesis of 4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-N'-(2- chloro-4- hydroxyphenyl)-6-(5-((dimethylamino)methyl)-1-methyl-1H-pyrr ol-3-yl)pyrrolo[1,2- b]pyridazine-3-carboximidamide Step 1: Methyl 4-bromo-1-methyl-1H-pyrrole-2-carboxylate To a solution of methyl 4-bromo-1H-pyrrole-2-carboxylate (3.00 g, 14.70 mmol) in N,N- dimethylformamide (20 mL) was added sodium hydride (1.18 g, 29.41 mmol, 60%) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for an hour at 0 °C, followed by addition of iodomethane (2.50 g, 17.65 mmol) dropwise. After stirring for 2 hours at 25 °C, the resulting mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a yellow solid. Yield: 2.50 g, 77%. Step 2: 4-bromo-1-methyl-1H-pyrrole-2-carboxylic acid To a solution of methyl 4-bromo-1-methyl-1H-pyrrole-2-carboxylate (500 mg, 2.29 mmol) in methanol (7 mL) was added 2.0 M aqueous solution of sodium hydroxide (3.0 mL). After stirring for 2 hours at 70 °C, the reaction mixture was cooled to room temperature, adjusted to pH = 3 with 2N hydrochloric acid and then extracted with ethyl acetate twice. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a yellow oil. Yield: 400 mg, 85%. LCMS (ESI) m/z = 205.9 (M+H). Step 3: 4-bromo-N,N,1-trimethyl-1H-pyrrole-2-carboxamide To a solution of 4-bromo-1-methyl-1H-pyrrole-2-carboxylic acid (3.10 g, 15.19 mmol) in dichloromethane (30 mL) were added N,N-dimethylformamide (0.2 mL) and oxalyl chloride (19.29 g, 151.95 mmol) at 0 °C. The resulting mixture was stirred for an hour at 25 °C and then concentrated under reduced pressure. The residue was dissolved in dichloromethane (30 mL), and then triethylamine (7.69 g, 75.97 mmol) and dimethylamine (60 mL, 2.0 M in tetrahydrofuran) were added. After stirring for 12 hours at 25 °C, the resulting mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a yellow oil. Yield: 2.70 g, 76%. LCMS (ESI) m/z = 233.0 (M+H). Step 4: 1-(4-bromo-1-methyl-1H-pyrrol-2-yl)-N, N-dimethylmethanamine To a solution of 4-bromo-N,N,1-trimethyl-1H-pyrrole-2-carboxamide (1.50 g, 6.49 mmol) in tetrahydrofuran (30 mL) was added Lithium aluminum hydride (492.7 mg, 12.98 mmol) at 0 °C. After stirring for 2 hours at 25 °C under nitrogen atmosphere, the reaction mixture was treated with sodium sulfate decahydrate (5g), stirred for 10 minutes, then filtered and washed with ethanol. The filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethanol/ethyl acetate) afforded the titled compound as light-yellow oil. Yield: 0.68 g, 48%. LCMS (ESI) m/z = 217.2 (M+H). Step 5: (5-((dimethylamino)methyl)-1-methyl-1H-pyrrol-3-yl)boronic acid To a solution of 1-(4-bromo-1-methyl-1H-pyrrol-2-yl)-N, N-dimethylmethanamine (300 mg, 1.38 mmol) and trimethyl borate (430.8 mg, 4.15 mmol) in tetrahydrofuran (9 mL) was added n- butyllithium (1.1 mL, 2.5 M in hexanes) at -78 °C under nitrogen atmosphere. After stirring for 2 hours at -78 °C, the resulting mixture was quenched with water (2 mL) and concentrated under reduced pressure to afford the crude compound (365 mg), which was used for next step without further purification. Step 6: 4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-N'-(2- chloro-4-hydroxyphenyl)- 6-(5-((dimethylamino)methyl)-1-methyl-1H-pyrrol-3-yl)pyrrolo [1,2-b]pyridazine-3- carboximidamide To a solution of (5-((dimethylamino)methyl)-1-methyl-1H-pyrrol-3-yl)boronic acid (143.8 mg, 0.79 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) were added 4-[[(1R,3S)-3-amino-2,2,3- trimethyl-cyclopentyl]amino]-6-bromo-N'-(2-chloro-4-hydroxy- phenyl)pyrrolo[1,2-b]pyridazine- 3-carboxamidine (80 mg, 158.2 μmol), potassium phosphate (67.1 mg, 316.3 μmol) and 1,1-bis(di- t-butylphosphino)ferrocene palladium(II) dichloride (10.5 mg, 15.8 μmol). The resulting mixture was purged with nitrogen and stirred for 1 hour at 80 °C under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was filtered and washed with methanol. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded (Z)-4-(((1R,3S)-3- amino-2,2,3-trimethylcyclopentyl)amino)-N'-(2-chloro-4-hydro xy-phenyl)-6-(5- ((dimethylamino)methyl)-1-methyl-1H-pyrrol-3-yl)pyrrolo[1,2- b]pyridazine-3-carboximidamide as a yellow solid. Yield: 4.6 mg, 4.7%. LCMS (ESI) m/z = 563.2 (M+H). ¹ H NMR (DMSO-d6, 300 MHz,) δ 8.11 (s, 1H), 7.73 (s, 1H), 7.06 (d, 1H, J=1.8 Hz), 6.81-6.87 (m, 3H), 6.64-6.73 (m, 1H), 6.21 (d, 1H, J=1.8 Hz), 4.40-4.51 (m, 1H), 3.60 (s, 3H), 3.20-3.30 (m, 2H), 2.25-2.31 (m, 1H), 2.15 (s, 6H), 1.50-1.80 (m, 3H), 1.13 (s, 3H), 0.90 (s, 6H). EXAMPLE 5Q Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-(1H -pyrazol-5-yl)-N'-(2- ethyl-4-hydroxy-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamid ine Step 1: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-[4-[tert-butyl- (dimethyl)silyl]oxy-2-ethyl-phenyl]pyrrolo[1,2-b]pyridazine- 3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (600 mg, 1.18 mmol) and (1S,3R)-1,2,2- trimethylcyclopentane-1,3-diamine (252.0 mg, 1.77 mmol) in DMF (5 mL) was added DIEA (457.2 mg, 3.54 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 2 h. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate (x3) and the combined organic layers washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via silica gel column (dichloromethane/ methanol, 10:1) afforded the titled compound as light yellow oil. Yield: 0.55 g, 76%. LCMS (ESI) m/z = 655.5 (M+CH ₃ CN+H) Step 2: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-[4 -[tert-butyl(dimethyl)silyl]- oxy-2-ethyl-phenyl]-6-(2-tetrahydropyran-2-ylpyrazol-3-yl)py rrolo[1,2-b]pyridazine-3- carboxamidine To a solution of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-[4-[tert- butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]pyrrolo[1,2-b]pyrida zine-3-carboxamidine (100 mg, 162.9 umol) and 1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxabor olan-2-yl)pyrazole (90.7 mg, 325.9 umol) in 1,4-dioxane (5 mL) and water (1 mL) were added tripotassium phosphate (103.6 mg, 488.8 umol) and Pd(dtbpf)Cl2 (10.6 mg, 16.3 umol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 95°C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification by silica gel column (dichloromethane/ methanol, 8:1) afforded the titled compound. Yield: 90 mg, 80 %. LCMS (ESI) m/z = 685.5 (M+H). Step 3: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -ethyl-4-hydroxy-phenyl)- 6-(2-tetrahydropyran-2-ylpyrazol-3-yl)pyrrolo[1,2-b]pyridazi ne-3-carboxamidine 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-[4 -[tert-butyl(dimethyl)silyl]oxy-2- ethyl-phenyl]-6-(2-tetrahydropyran-2-ylpyrazol-3-yl)pyrrolo[ 1,2-b]pyridazine-3-carboxamidine (85 mg, 124.1 umol) was suspended in DMF (4.0 mL). Cesium fluoride (37.7 mg, 248.2 umol) was added at room temperature under nitrogen atmosphere. After stirring for 2 h, the reaction mixture was extracted with ethyl acetate (x3) and the combined organic layers washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the titled compound as light yellow oil, which was used in next step without further purification. Yield: 60 mg crude, 85 %. LCMS (ESI) m/z = 571.3 (M+H). Step 4: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -ethyl-4-hydroxy-phenyl)- 6-(1H-pyrazol-5-yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -ethyl-4-hydroxy-phenyl)-6-(2- tetrahydropyran-2-ylpyrazol-3-yl)pyrrolo[1,2-b]pyridazine-3- carboxamidine (60 mg, 104.8 umol) in DCM (10 mL) was added TFA (1 mL) at room temperature. After stirring overnight, the mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-[[(1R,3S)-3-amino-2,2,3-trimethyl- cyclopentyl]amino]-6-(1H-pyrazol-5-yl)-N'-(2-ethyl-4-hydroxy -phenyl)pyrrolo[1,2-b]- pyridazine-3-carboxamidine as a light yellow solid. Yield: 29.8 mg, 58 %. LCMS (ESI) m/z = 485.1 (M-H). ¹ H NMR (CD3OD, 400 MHz) δ 8.10 (s, 1H), 8.00 (s, 1H), 7.71 (s, 1H), 7.48 (s, 1H), 7.11 (d, 1H, J=8.8 Hz), 6.92 (s, 1H), 6.82-6.86 (m, 1H), 6.67 (s, 1H), 4.31 (t, 1H, J=8.0 Hz), 2.65 (q, 2H, J=7.6 Hz), 2.41-2.47 (m, 1H), 2.14-2.18 (m, 1H), 2.00-2.10 (m, 2H), 1.46 (s, 3H), 1.30 (t, 3H, J=7.6 Hz), 1.17 (s, 3H), 1.09 (s, 3H). EXAMPLE 5A Synthesis of (Z)-4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-N' -(2- cyclopropylphenyl)-6-(1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazi ne-3-carboximidamide Step 1: 6-bromo-4-chloro-N'-(2-cyclopropylphenyl)pyrrolo[1,2-b]pyrid azine-3-carboxamidine 2-Cyclopropylaniline (80.0 mg, 601.0 umol) and 6-bromo-4-chloro-pyrrolo[1,2-b]pyridazine-3- carboxamide (0.11 g, 400.7 umol) were suspended in toluene (4 mL) in an oven-dried screw cap vial equipped with a stir bar. The mixture was stirred at 25 °C while trimethylaluminum (2 M, 601 uL) was added dropwise via syringe. After 5 min the mixture was warmed to 110 °C in a heating block. After 17 h the reaction mixture was cooled to room temperature and diluted with ethyl acetate. It was stirred vigorously while water was added until gas evolution ceased. The mixture was diluted with ethyl acetate and 1M aqueous Rochelle salt. The layers were separated, and the aqueous phase extracted 3 times with ethyl acetate. Th organic phase was washed once with brine and then dried over magnesium sulfate, filtered, and the solvent removed in vacuo. Purification via silica gel chromatography (0 to 65 % ethyl acetate in heptanes) afforded the titled compound as a yellow solid. Yield: 111 mg, at 80 % purity, 56 %. LCMS (ESI) m/z = 390.9, 392.8 (M+H). Step 2: (Z)-4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6- bromo-N'-(2-cyclopropyl- phenyl)pyrrolo[1,2-b]pyridazine-3-carboximidamide (1S,3R)-1,2,2-trimethylcyclopentane-1,3-diamine (70.7 mg, 336.2 umol) in DMF (0.5 mL) and 6- bromo-4-chloro-N'-(2-cyclopropylphenyl)pyrrolo[1,2-b]pyridaz ine-3-carboxamidine (106.1 mg, 258.6 umol) were dissolved in DMF (2 mL) in an oven-dried screw cap vial equipped with a stir bar. N-ethyl-N-isopropyl-propan-2-amine (66.8 mg, 517.3, umol, 90 uL) was added and the mixture was stirred at 85 °C in a heating block overnight. After 24 h the reaction mixture was cooled to room temperature. The mixture was diluted with ethyl acetate washed twice with a 1:1 brine:water solution, and then once more with 100 % brine. The organic phase was dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded the titled compound as a tan solid. Yield: 128 mg, 44 %. LCMS (ESI) m/z = 496.6 (M+H) Step 3: ((Z)-4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-N '-(2-cyclopropylphenyl)-6- (1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboximidamide A bottle of anhydrous DMF was purged with nitrogen gas for 10 min. 4-(4,4,5-trimethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (13.9 mg, 75.9 umol) and 4-[[(1R,3S)-3-amino-2,2,3-trimethyl- cyclopentyl]amino]-6-bromo-N'-(2-cyclopropylphenyl)pyrrolo[1 ,2-b]pyridazine-3-carboxamidine (0.033 g, 63.27 umol) were dissolved in DMF (1 mL) and aqueous potassium phosphate (1 M, 253.1 uL) in an oven-dried screw cap vial equipped with a stir bar. The mixture was purged with nitrogen for 5 min. Dichloro[1,1'-bis(di-t-butylphosphino)ferrocene] palladium(II) (63.2 umol) was added, and the mixture stirred at 85 °C in a heating block. After 6 h the reaction mixture was cooled to room temperature. The mixture was diluted with ethyl acetate washed twice with a 1:1 brine:water solution, and then once more with 100 % brine. The organic phase was dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded ((Z)-4-(((1R,3S)-3-amino-2,2,3- trimethylcyclopentyl)amino)-N'-(2-cyclopropylphenyl)-6-(1H-p yrazol-4-yl)pyrrolo[1,2-b]- pyridazine-3-carboximidamide as a white powder. Yield 4.0 mg, 14 %. LCMS (ESI) m/z = 484.7 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 8.30 (d, 1H, J=4.2 Hz), 8.22 (d, 2H, J=6.1 Hz), 8.0-8.1 (m, 2H), 7.92 (s, 1H), 7.1-7.2 (m, 2H), 6.9-7.0 (m, 2H), 6.8-6.9 (m, 2H), 4.52 (br t, 1H, J=8.6 Hz), 2.3-2.5 (m, 1H), 1.8-2.0 (m, 3H), 1.61 (br s, 1H), 1.30 (s, 3H), 0.94 (s, 6H), 0.8-0.9 (m, 2H), 0.63 (br d, 2H, J=3.3 Hz) EXAMPLE 5S Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -chlorophenyl)-6-(1- methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-(2-chlorophenyl)- pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-4-chloro-N'-(2-chlorophenyl)pyrrolo[1,2-b]pyridazine -3-carboxamidine (120 mg, 312.5 μmol) and (1S,3R)-1,2,2-trimethylcyclopentane-1,3-diamine (44.4 mg, 312.5 μmol) in N,N-dimethylacetamide (2 mL) was added N,N-diisopropylethylamine (121.2 mg, 937.4 μmol). After stirring for 2 hours at 80 °C, the reaction mixture was cooled to room temperature and purified by reverse phase column chromatography (acetonitrile/water 100%) to afford the titled compound as a yellow solid. Yield: 110 mg, 71%. LCMS (ESI) m/z = 491.0 (M+H). Step 2: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -chlorophenyl)-6-(1- methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a mixture of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-(2- chlorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (100 mg, 204.2 μmol), 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (51 mg, 245.0 μmol) and potassium phosphate (130 mg, 612.5 μmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was added 1,1'-bis (di- t-butylphosphino)ferrocene palladium dichloride (13.5 mg, 20.4 μmol). The resulting mixture was stirred for 2 hours at 90 °C under nitrogen atmosphere, cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved in N, N-dimethylformamide and filtered. The filtrate was purified by reverse phase chromatography (acetonitrile/water) and then further purified via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) to afford 4-[[(1R,3S)-3-amino-2,2,3-trimethyl- cyclopentyl]amino]-N'-(2-chlorophenyl)-6-(1-methylpyrazol-4- yl)pyrrolo[1,2-b]pyridazine-3- carboxamidine as a yellow solid. Yield: 18.9 mg, 18%. LCMS (ESI) m/z = 491.2 (M+H). ¹ H- NMR (DMSO-d ₆ , 400 MHz) δ 11.48 (s, 1H), 8.09 (s, 1H), 7.98 (d, 1H, J=3.4 Hz), 7.80 (s, 1H), 7.71 (d, 1H, J=3.4 Hz), 7.38 (d, 1H, J=8.1 Hz), 7.21 (s, 1H), 6.95 (d, 2H, J=8.5 Hz), 6.84 (s, 1H), 6.10 (s, 2H), 4.39 (s, 1H), 3.80 (s, 3H), 2.20-2.22 (m, 1H), 1.50-1.63 (m, 3H), 1.00 (s, 3H), 0.78 (s, 6H). EXAMPLE 5T Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -chloro-5-fluoro- phenyl)-6-(1-methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-c arboxamidine Step 1: 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine To a solution of 6-bromo-4-chloro-pyrrolo[1,2-b]pyridazine-3-carboxamide (400 mg, 1.46 mmol) and 2-chloro-5-fluoro-aniline (212.1 mg, 1.46 mmol) in toluene (3 mL) was added trimethylaluminium (2.2 mL, 4.4 mmol, 2.0 M in toluene) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 mins at 0 °C and then heated to 100 °C for 16 hours. After cooling to room temperature, the resulting mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate (x3). The combined organic extracts were washed with brine (x2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water 30%) afforded the titled compound as a yellow solid. Yield: 380 mg, 65%. LCMS (ESI) m/z = 403.0 (M+H). Step 2: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-(2-chloro-5-fluoro- phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (160 mg, 398.0 μmol) and (1S,3R)-1,2,2-trimethylcyclopentane-1,3-diamine (56.6 mg, 398.0 μmol) in N,N-dimethylacetamide (2 mL) was added N,N-diisopropylethylamine (154.3 mg, 1.19 mmol). After stirring for 2 hours at 80 °C, the reaction mixture was purified by reverse phase chromatography (acetonitrile/water 100%) to afford the titled compound as a yellow solid. Yield: 140 mg, 69%. LCMS (ESI) m/z = 509.0 (M+H). Step 3: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -chloro-5-fluoro-phenyl)-6- (1-methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamidi ne To a mixture of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-(2-chloro- 5-fluoro-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (150 mg, 295.4 μmol), 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (73.8 mg, 354.5 μmol) and potassium phosphate (188.1 mg, 886.1 μmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (19.3 mg, 29.5 μmol). The resulting mixture was purged with nitrogen and stirred for 2 hours at 90 °C under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide and filtered. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -chloro-5-fluoro-phenyl)-6-(1- methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as a red solid. Yield: 29.6 mg, 19%. LCMS (ESI) m/z = 509.2 (M+H). ¹ H-NMR (DMSO-d6, 400 MHz) δ 11.37 (s, 1H), 8.14 (s, 1H), 8.05 (s, 1H), 7.88 (s, 1H), 7.78 (s, 1H), 7.42-7.49 (m, 1H), 6.82-6.96 (m, 3H), 6.40 (s, 2H), 4.45 (s, 1H), 3.86 (s, 3H), 2.20-2.25 (m, 1H), 1.50-1.70 (m, 3H), 1.09 (s, 3H), 0.85 (s, 6H). ¹⁹ F-NMR (DMSO-d6, 376 MHz) δ -114.71 (s, 1F). EXAMPLE 5U Synthesis of 4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6-(1-m ethyl-1H-pyrazol-4- yl)-N'-(4-((E)-phenyldiazenyl)phenyl)pyrrolo[1,2-b]pyridazin e-3-carboximidamide Step 1: 6-bromo-4-chloro-N'-(4-(phenyldiazenyl)phenyl)pyrrolo[1,2-b] pyridazine-3- carboximidamide To a solution of 6-bromo-4-chloro-pyrrolo[1,2-b]pyridazine-3-carboxamide (200 mg, 728.6 μmol) and 4-[(E)-phenylazo]aniline (215.6 mg, 1.09 mmol) in toluene (20 mL) was added trimethylalumane (1.1 mL, 2.0 M in toluene) at 0 °C. After stirring for 16 hours at 80 °C under nitrogen atmosphere, the reaction mixture was poured into water and extracted with ethyl acetate x3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a yellow oil. Yield: 70 mg, 21%. Step 2: 4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6-brom o-N'-(4-((E)-phenyl- diazenyl)phenyl)pyrrolo[1,2-b]pyridazine-3-carboximidamide To a solution of 6-bromo-4-chloro-N'-(4-(phenyldiazenyl)phenyl)pyrrolo[1,2-b] pyridazine-3- carboximidamide (70 mg, 154.3 μmol) and (1S,3R)-1,2,2-trimethylcyclopentane-1,3-diamine (32.9 mg, 231.4 μmol) in N,N-dimethylacetamide (2 mL) was added N,N-diisopropylethylamine (59.8 mg, 462.8 μmol). After stirring for 2 hours at 80 °C, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as yellow oil. Yield: 51 mg, 59%. LCMS (ESI) m/z = 559.1 (M+H). Step 3: 4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6-(1-m ethyl-1H-pyrazol-4-yl)- N'-(4-((E)-phenyldiazenyl)phenyl)pyrrolo[1,2-b]pyridazine-3- carboximidamide To a solution of 4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6-brom o-N'-(4-((E)- phenyldiazenyl)phenyl)pyrrolo[1,2-b]pyridazine-3-carboximida mide (51 mg, 91.2 μmol) in 1,4- dioxane (2 mL) and water (0.5 mL) were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazole (28.5 mg, 136.7 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (5.9 mg, 9.1 μmol) and potassium phosphate (58.1 mg, 273.5 μmol). The resulting mixture was purged with nitrogen gas and stirred for an hour at 80 °C. After cooling to room temperature, the reaction mixture was filtered through a celite pad and washed with ethyl acetate and methanol. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6-(1-m ethyl-1H- pyrazol-4-yl)-N'-(4-((E)-phenyldiazenyl)phenyl)pyrrolo[1,2-b ]pyridazine-3-carboximidamide as a yellow solid. Yield: 2.6 mg, 4.8%. LCMS (ESI) m/z = 561.3 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 8.33 (s, 1H), 8.18 (d, 1H, J=3.6 Hz), 8.06 (s, 1H), 7.80-7.92 (m, 6H), 7.53-7.62 (m, 3H), 7.11-7.14 (m, 2H), 6.91-6.95 (m, 1H), 4.45 (d, 1H, J=6.6 Hz), 3.87 (s, 3H), 2.30-2.40 (m, 1H), 1.50-1.85 (m, 3H), 1.10 (s, 3H), 0.94 (s, 3H), 0.90 (s, 3H). EXAMPLE 5V Synthesis of (Z)-4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-N' -(2-ethyl-4- hydroxyphenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyr idazine-3-carboximidamide Step 1: (Z)-6-bromo-N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylphen yl)-4-chloropyrrolo[1,2- b]pyridazine-3-carboximidamide 4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-aniline (200.0 mg, 795.4 umol) and 6-bromo-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamide (0.2 g, 728.5 umol) were suspended in toluene (5 mL) in an oven-dried screw cap vial equipped with a stir bar. The mixture was stirred at 0 °C while trimethylaluminum (2 M, 1.09 mL) was added dropwise via syringe. After 5 min the mixture was warmed to room temperature and after an additional 15 min heated to 110 °C. After 20 h the reaction mixture was cooled to room temperature and diluted with ethyl acetate and water. The mixture was extracted with ethyl acetate (x3) and washed with brine. The organic extracts were dried over magnesium sulfate, filtered, and the solvent removed in vacuo. Purification via silica gel chromatography (0 to 65 % ethyl acetate in heptanes) afforded the titled compound in 66 % purity. Yield: 341 mg, 61 % yield. LCMS (ESI) m/z = 509.7 (M+H). Step 2: (Z)-4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6- bromo-N'-(4-((tert-butyl- dimethylsilyl)oxy)-2-ethylphenyl)pyrrolo[1,2-b]pyridazine-3- carboximidamide (1S,3R)-1,2,2-trimethylcyclopentane-1,3-diamine (39.4 mg, 235.84 umol) and 6-bromo-N'-[4- [tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-chloro-pyrr olo[1,2-b]pyridazine-3- carboxamidine (0.121 g, 157.2 umol) were dissolved in DMF (4 mL) in an oven-dried screw cap vial equipped with a stir bar. Diisopropylethylamine (60.9 mg, 471.6 umol, 82.16 uL) was added and the mixture stirred at room temperature for 2 min and then warmed to 100 °C for 21 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed twice with a 1:1 brine:water solution, and then once more with 100 % brine. The organic phase was dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded a mixture of the title compound and its de-silylated analogue ((Z)-4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6 -bromo- N'-(2-ethyl-4-hydroxyphenyl)pyrrolo[1,2-b]pyridazine-3-carbo ximidamide) in a 2:1 ratio. These materials were combined for the next step without further purification. LCMS (ESI) m/z = 613.80 (product M+H), 508.97 (side product M+H) Step 3: (Z)-4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-N' -(2-ethyl-4- hydroxyphenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyr idazine-3-carboximidamide 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyra zole (35.6 mg, 171.0 umol) and 4- [[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bromo -N'-[4-[tert-butyl(dimethyl)silyl]- oxy-2-ethyl-phenyl]pyrrolo[1,2-b]pyridazine-3-carboxamidine (0.035 g, 57.0 umol) were dissolved in potassium phosphate (1 M, 171.0 uL) and DMF (1.2 mL) in an oven-dried screw cap vial equipped with a stir bar. The mixture was purged with argon gas for 10 min and then Pd(dtbpf)Cl2 (2.5 mg, 3.9 umol) was added. The vial was sealed and heated to 80 °C for 18 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with a 1:1 brine:water solution(x2), and 100 % brine (x1). The organic extract was dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded the titled compound as a tan solid. Yield: 7.3 mg, 24 %. LCMS (ESI) m/z = 501.5 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.30 (s, 1H), 8.16 (s, 1H), 8.06 (s, 1H), 7.88 (s, 1H), 7.81 (s, 1H), 6.91 (s, 1H), 6.6-6.7 (m, 2H), 6.6-6.6 (m, 1H), 4.47 (br t, 1H, J=8.5 Hz), 3.87 (s, 3H), 2.3-2.5 (m, 3H), 1.7-1.9 (m, 2H), 1.57 (m, 1H), 1.23 (s, 3H), 1.0-1.1 (t, 3H), 0.90 (s, 6H). EXAMPLE 5W Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -chloro-4-hydroxy- phenyl)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]pyrrolo[1,2-b]pyri dazine-3-carboxamidine To a solution of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-(2-chloro- 4-hydroxy-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (100 mg, 197.7 μmol) in 1,4- dioxane (2 mL) and water (0.5 mL) were added potassium phosphate (83.9 mg, 395.4 μmol), 1,1'- bis (di-t-butylphosphino)ferrocene palladium dichloride (13.1 mg, 20.1 μmol) and 2-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]ethanol (94.1 mg, 395.4 μmol). The resulting mixture was stirred for 2 hours at 90 °C under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure and the resulting residue dissolved in N,N-dimethylformamide and filtered. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-[[(1R,3S)-3-amino-2,2,3-trimethyl- cyclopentyl]amino]-N'-(2-chloro-4-hydroxy-phenyl)-6-[1-(2-hy droxyethyl)pyrazol-4- yl]pyrrolo[1,2-b]pyridazine-3-carboxamidine as a yellow solid. Yield: 16.1 mg, 15%. LCMS (ESI) m/z = 537.5 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.29 (s, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.90 (d, 1H, J=1.2 Hz), 7.84 (s, 1H), 6.95 (s, 1H), 6.82-6.88 (m, 2H), 6.70-6.74 (m, 1H), 4.48-4.54 (m, 1H), 4.10-4.17 (m, 2H), 3.71-3.78 (m, 2H), 2.21-2.37 (m, 1H), 1.55-1.94 (m, 3H), 1.30 (s, 3H), 0.84 (s, 6H). EXAMPLE 5X Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl] amino]-N'-(2-ethyl-4-hydroxy- phenyl)-6-(6-methoxy-3-pyridyl) pyrrolo[1,2-b] pyridazine-3-carboxamidine Step 1: 3-bromo-4-nitro-phenol To a solution of sodium hydroxide (15 g, 375.03 mmol) in water (100 mL) was added 2-bromo-4- fluoro-1-nitro-benzene (10 g, 45.46 mmol) in portions at 100 °C. The reaction mixture was stirred for 2 h at 100 °C. The resulting mixture was cooled to room temperature and acidified by addition of conc. hydrochloric acid. The solid was collected by filtration, washed with water and dried in air to afford the titled compound as a light yellow solid. Yield: 9.1 g, 92%. ¹ H NMR (DMSO-d6, 400 MHz) δ 11.21 (s, 1H), 7.99 (d, 1H, J=8.8 Hz), 7.17 (d, 1H, J=2.4 Hz), 6.91 (dd, 1H, J=2.4, 8.8 Hz). Step 2: 4-nitro-3-vinyl-phenol To a solution of 3-bromo-4-nitro-phenol (4.36 g, 20.00 mmol) in 1,4-dioxane (50 mL) and water (10 mL) were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (4.62 g, 30.00 mmol), 1,1'- Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.63 g, 2.00 mmol) and potassium phosphate (8.49 g, 40.00 mmol). The reaction mixture was purged with nitrogen atmosphere and stirred for 2 hours at 100 °C under nitrogen atmosphere. The resulting mixture was cooled to room temperature, acidified with 3N hydrochloric acid, diluted with ethyl acetate and filtered. The filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a yellow solid. Yield: 3.10 g, 94%. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 10.91 (s, 1H), 7.96 (d, 1H, J=8.8 Hz), 7.08-7.16 (m, 1H), 6.97 (d, 1H, J=2.4 Hz), 6.83-6.87 (m, 1H), 5.66-5.76 (m, 1H), 5.41- 5.44 (m, 1H). Step 3: tert-butyldimethyl(4-nitro-3-vinyl-phenoxy)silane To a solution of 4-nitro-3-vinyl-phenol (6.6 g, 39.96 mmol) in dichloromethane (66 mL) were added imidazole (2.72 g, 39.96 mmol) and tert-butyldimethylsilyl chloride (6.02 g, 39.96 mmol). The resulting mixture was stirred for 15 hours at 25 °C under nitrogen atmosphere. The reaction mixture was diluted with dichloromethane and washed with water (x2) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a light orange oil. Yield: 7.00 g, 63%. ¹ H NMR (Chloroform-d, 400 MHz) δ 7.98 (d, 1H, J=9.2 Hz), 7.22-7.30 (m, 1H), 6.97 (d, 1H, J=2.8 Hz), 6.79-6.82 (m, 1H), 5.62-5.67 (m, 1H), 5.44-5.47 (m, 1H), 1.00 (s, 9H), 0.26 (s, 6H). Step 4: 4-[tert-butyl(dimethyl)silyl] oxy-2-ethyl-aniline To a solution of tert-butyldimethyl(4-nitro-3-vinyl-phenoxy)silane (3.00 g, 10.74 mmol) in ethanol (20 mL) was added 5% Pd/C (1.50 g) under nitrogen atmosphere. The reaction mixture was stirred for 4 hours at 25 °C under hydrogen atmosphere (1-2 atm). The resulting mixture was filtered through a short silica gel column. The filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether 1:4) afforded the titled compound as a light yellow solid. Yield: 2.40 g, 89%. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 6.39-6.50 (m, 3H), 4.40 (brs, 2H), 2.38 (q, 2H, J=7.6 Hz), 1.10 (t, 3H, J=7.6 Hz), 0.93 (s, 9H), 0.12 (s, 6H). Step 5: 6-bromo-4-chloro-pyrrolo[1,2-b] pyridazine-3-carboxamide 6-bromo-4-chloro-pyrrolo[1,2-b] pyridazine-3-carbonitrile (3.00 g, 11.70 mmol) was dissolved in sulfuric acid (10 mL) and stirred for 30 minutes at 80 °C. After cooling to room temperature, the reaction mixture was poured into a mixture of crushed ice and water slowly. The yellow solid was collected by filtration, washed with cooled water three times and then dried in vacuo to afford the titled compound as a light yellow solid. Yield: 2.80 g, 84%. LCMS (ESI) m/z: 271.6 (M-H). ¹ H NMR (DMSO-d6, 300 MHz) δ 8.33 (s, 2H), 8.06 (s, 1H), 7.91 (s, 1H), 7.01 (s, 1H). Step 6: 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl] oxy-2-ethyl-phenyl]-4-chloro-pyrrolo[1,2-b] pyridazine-3-carboxamidine To a mixture of 6-bromo-4-chloro-pyrrolo[1,2-b] pyridazine-3-carboxamide (1.00 g, 3.64 mmol) and 4-[tert-butyl(dimethyl)silyl] oxy-2-ethyl-aniline (1.10 g, 4.37 mmol) in toluene (40 mL) was added trimethylaluminium (1.0 M in heptane, 10.9 mmol, 10.9 mL) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 minutes at room temperature and then heated to 110°C for 6 hours. After cooling to room temperature, sodium sulfate decahydrate (15.0 g) was added and the resulting mixture was stirred for 2 hours and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water 95:5) afforded the titled compound as a yellow solid. Yield: 0.92 g, 47%. LCMS (ESI) m/z: 509.0 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 8.36 (s, 1H), 8.31 (m, 1H), 6.97 (m, 1H), 6.72-7.62 (m, 3H), 2.48-2.50 (m, 2H), 1.11 (t, 3H, J=7.5 Hz), 0.97 (s, 9H), 0.20 (s, 6H). Step 7: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl] amino]-6-bromo-N'-[4-[tert-butyl- (dimethyl)silyl] oxy-2-ethyl-phenyl] pyrrolo[1,2-b] pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl] oxy-2-ethyl-phenyl]-4-chloro- pyrrolo[1,2-b] pyridazine-3-carboxamidine (0.92 g, 1.81 mmol) and (1S,3R)-1,2,2- trimethylcyclopentane-1,3-diamine (515.3 mg, 3.62 mmol) in N, N-dimethylacetamide (5 mL) was added N-Ethyl-N-isopropyl-propan-2-amine (468.2 mg, 3.62 mmol, 631.0 uL) dropwise. After stirring for 2 hours at 100 °C, the reaction mixture was cooled to room temperature and purified by reverse phase column chromatography (acetonitrile, 100%) to afford the titled compound as a yellow solid. Yield: 0.82 g, 73%. LCMS (ESI) m/z: 613.2 (M+H). Step 8: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl] amino]-N'-[4-[tert-butyl(dimethyl)silyl] oxy-2-ethyl-phenyl]-6-(6-methoxy-3-pyridyl) pyrrolo[1,2-b] pyridazine-3-carboxamidine To a solution of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl] amino]-6-bromo-N'-[4-[tert- butyl(dimethyl)silyl] oxy-2-ethyl-phenyl] pyrrolo[1,2-b]pyridazine-3-carboxamidine (0.50 g, 814.7 umol) in 1,4-dioxane (8 mL) and water (1 mL) were added 2-methoxy-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (287.3 mg, 1.22 mmol) , potassium phosphate (518.8 mg, 2.44 mmol) and 1,1'-Bis (di-t-butylphosphino)ferrocene palladium dichloride (53.1 mg, 81.47 umol) under nitrogen atmosphere. The reaction mixture was purged with nitrogen gas (x3) and stirred for 2 hours at 120 °C under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile, 100%) afforded the titled compound as a yellow solid. Yield: 0.30 g, 37%. LCMS (ESI) m/z: 642.3 (M+H). Step 9: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl] amino]-N'-(2-ethyl-4-hydroxy-phenyl)- 6-(6-methoxy-3-pyridyl) pyrrolo[1,2-b] pyridazine-3-carboxamidine To a solution of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl] amino]-N'-[4-[tert- butyl(dimethyl)silyl] oxy-2-ethyl-phenyl]-6-(6-methoxy-3-pyridyl) pyrrolo[1,2-b] pyridazine-3- carboxamidine (453 mg, 458.7 umol) in N, N-dimethylformamide (5 mL) was added cesium fluoride (139.4 mg, 917.4 umol) in portions. After stirring for 2 hours at 25 °C, the reaction mixture was filtered and the filtrate concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-[[(1R,3S)-3-amino-2,2,3- trimethyl-cyclopentyl] amino]-N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-3-pyridyl) pyrrolo[1,2-b] pyridazine-3-carboxamidine as a yellow solid. Yield: 126 mg, 51%. LCMS (ESI) m/z = 528.5 (M+H). ¹ H NMR (CD ₃ OD-d ₄ , 400 MHz) δ 8.47-8.50 (m, 3H), 7.99-8.06 (m, 2H), 7.37 (s, 1H), 7.01-7.04 (m, 1H), 6.86-6.89 (m, 2H), 6.77-6.81 (m, 1H), 4.30-4.32 (m, 1H), 3.94 (s, 3H), 2.61 (q, 2H, J=7.6 Hz), 2.38-2.43 (m, 1H), 1.95-2.10 (m, 3H), 1.40 (s, 3H), 1.25 (t, 3H, J=7.6 Hz), 1.12 (s, 3H), 1.06 (s, 3H). EXAMPLE 5Y Synthesis of 4-[[(1R)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2-et hyl-5-fluoro-4- hydroxy-phenyl)-6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridaz ine-3-carboxamidine Step 1: 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-5-fluor o-phenyl]-4-chloropyrrolo- [1,2-b]pyridazine-3-carboxamidine (compound 3) 4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-5-fluoro-aniline (250 mg, 927.9 umol) and 6-bromo-4- chloro-pyrrolo[1,2-b]pyridazine-3-carboxamide (212.3 mg, 773.2 umol) were suspended in toluene (25 mL) in an oven-dried screw cap vial equipped with a stir bar. The mixture was stirred at 0 °C while trimethylaluminum (1.6 M in toluene, 1.44 mL) was added dropwise via syringe. After 5 min the mixture was warmed to 110 °C in a heating block and stirred overnight. The reaction mixture was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic material was washed with brine, dried over sodium sulfate, filtered, and solvent removed in vacuo. Purification via silica gel column (petroleum ether/ethyl acetate, 3:1) afforded the titled compound. Yield: 290 mg, 71%. LCMS (ESI) m/z = 527.2 (M+H). Step 2: 4-[[(1R)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bromo- N'-[4-[tert-butyl- (dimethyl)silyl]oxy-2-ethyl-5-fluoro-phenyl]pyrrolo[1,2-b]py ridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-5-fluor o-phenyl]-4- chloropyrrolo[1,2-b]pyridazine-3-carboxamidine (140 mg, 266.2 umol) in DMA (2 mL) were added (1S,3R)-1,2,2-trimethylcyclopentane-1,3-diamine (151.5 mg, 1.06 mmol) and DIEA (103.2 mg, 798.6 μmol, 139.1 μL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90°C for 3 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via silica gel column (ethyl acetate, 100%) afforded the titled compound. Yield: 160 mg, 95%. LCMS (ESI) m/z = 633.2 (M+H). Step 3: 4-[[(1R)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2-et hyl-5-fluoro-4-hydroxy- phenyl)-6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-ca rboxamidine To a solution of 4-[[(1R)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bromo- N'-[4-[tert- butyl(dimethyl)silyl]oxy-2-ethyl-5-fluoro-phenyl]pyrrolo[1,2 -b]pyridazine-3-carboxamidine (160 mg, 253.3 umol) and 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyr idine (119.1 mg, 506.6 umol) in 1,4-dioxane (1.2 mL) and water (0.3 mL) were added tripotassium phosphate (228.2 mg, 759.9 umol) and Pd(dtbpf)Cl ₂ (16.5 mg, 25.3 umol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90°C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonia) afforded 4-[[(1R)-3-amino-2,2,3-trimethyl- cyclopentyl]amino]-N'-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-6- (6-methoxy-3-pyridyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine as an off-white solid. Yield: 22.5 mg, 16%. LCMS (ESI) m/z = 546.3 (M+H). ¹ H NMR (CD3OD, 400 MHz) δ 8.46 (s, 1H), 8.12 (s, 1H), 7.99-8.02 (m, 1H), 7.91 (s, 1H), 7.11 (s, 1H), 6.84-6.90 (m, 2H), 6.61 (d, 1H, J=12.0 Hz), 4.64 (t, 1H, J=8.0 Hz), 3.95 (s, 3H), 2.41-2.53 (m, 3H), 1.83-1.88 (m, 2H), 1.70-1.76 (m, 1H), 1.24 (s, 3H), 1.17 (t, 3H, J=7.6 Hz), 1.02 (s, 3H), 1.00 (s, 3H). EXAMPLE 5Z Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-[4 -hydroxy-2-(2,2,2- trifluoroethyl)phenyl]-6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b] pyridazine-3-carboxamidine Step 1: (1E)-5-hydroxy-2-nitro-benzaldehyde hydrazone To a solution of 5-hydroxy-2-nitro-benzaldehyde (3.0 g, 18.0 mmol) in ethanol (60 mL) was added hydrazine hydrate at 0°C. After stirring at 25°C for 3 h, the resulting mixture was concentrated under vacuum to afford the titled compound as an orange solid. Yield: 3 g crude, 92%. ¹ H NMR (DMSO-d6, 400 MHz) δ 8.20 (s, 1H), 7.89 (d, 1H, J=9.2 Hz), 7.35 (brs, 2H), 7.19 (s, 1H), 6.65 (d, 1H, J=9.2 Hz). Step 2: 4-nitro-3-(2,2,2-trifluoroethyl)phenol To a solution of (1E)-5-hydroxy-2-nitro-benzaldehyde hydrazone (2.0 g, 11.04 mmol) in DMSO (20 mL) was added 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one (5.23 g, 16.56 mmol) at 25°C under nitrogen atmosphere. After stirring at 80°C for 12 h, the reaction mixture was cooled to 25°C and quenched with water. The aqueous layer was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification via reverse phase HPLC (acetonitrile/water) afforded the titled compound as a yellow solid. Yield: 1.4 g, 57%. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.08 (brs, 1H), 8.03-8.06 (m, 1H), 6.91-6.97 (m, 2H), 4.11 (q, 2H, J=12.0 Hz). Step 3: tert-butyl-dimethyl-[4-nitro-3-(2,2,2-trifluoroethyl)phenoxy ]silane To a stirred solution of 4-nitro-3-(2,2,2-trifluoroethyl)phenol (1.4 g, 6.33 mmol) and imidazole (1.29 g, 19.0 mmol) in DMF (2.8 mL) was added tert-butyl-chloro-dimethyl-silane (1.91 g, 12.66 mmol, 2.36 mL) at 25°C under Argon atmosphere. After stirring at 85°C for 2 h, the reaction mixture was cooled to 25°C and quenched with aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification via reverse phase HPLC (acetonitrile/water) afforded the titled compound as yellow oil. Yield: 1.2 g, 57%. ¹ H NMR (DMSO-d6, 400 MHz) δ 8.07 (d, 1H, J=8.0 Hz), 7.15 (s, 1H), 7.08-7.11 (m, 1H), 4.14 (q, 2H, J=12.0 Hz), 0.96 (s, 9H), 0.27 (s, 6H). Step 4: 4-[tert-butyl(dimethyl)silyl]oxy-2-(2,2,2-trifluoroethyl)ani line To a solution of tert-butyl-dimethyl-[4-nitro-3-(2,2,2-trifluoroethyl)phenoxy ]silane (1.2 g, 3.58 mmol) in methanol (12 mL) was added Pd/C (0.24 g). The resulting mixture was stirred at 25°C for 2 h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with methanol and the filtrate was concentrated under reduced pressure to afford the titled compound as a yellow oil. Yield: 1.05 g, 96%. ¹ H NMR (DMSO-d6, 400 MHz) δ 6.57 (brs, 3H), 4.73 (brs, 2H), 3.48 (q, 2H, J=12.0 Hz), 0.93 (s, 9H), 0.12 (s, 6H). Step 5: 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-(2,2,2-triflu oroethyl)phenyl]-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine 4-[tert-butyl(dimethyl)silyl]oxy-2-(2,2,2-trifluoroethyl)ani line (252 mg, 825.12 umol) and 6- bromo-4-chloro-pyrrolo[1,2-b]pyridazine-3-carboxamide (271.8 mg, 990.1 umol) were suspended in toluene (3 mL) in an oven-dried screw cap vial equipped with a stir bar. The mixture was stirred at 0 °C while trimethylaluminum (1 M, 2.48 mL) was added dropwise via syringe. After 10 min the mixture was warmed to 110 °C in a heating block. After stirring for 12 h, the reaction mixture was cooled to room temperature. The mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic material was washed with brine, dried over sodium sulfate, filtered, and solvent removed in vacuo. Purification via reverse phase HPLC (acetonitrile/water) afforded the titled compound as a yellow solid. Yield: 230 mg, 50%. LCMS (ESI) m/z = 563.1 (M+H). Step 6: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-[4-[tert-butyl- (dimethyl)silyl]oxy-2-(2,2,2-trifluoroethyl)phenyl]pyrrolo[1 ,2-b]pyridazine-3-carboxamidine To a stirred solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-(2,2,2-triflu oroethyl)- phenyl]-4-chloro-pyrrolo[1,2-b]pyridazine-3-carboxamidine (200 mg, 355.9 umol) and (1S,3R)- 1,2,2-trimethylcyclopentane-1,3-diamine (75.8 mg, 532.9 umol) in DMA (2 mL) was added DIEA (137.8 mg, 1.07 mmol, 185.6 uL) at room temperature under argon atmosphere. The resulting mixture was stirred at 85°C for 2 h. After cooling to room temperature, the reaction mixture was purified via reverse phase HPLC (acetonitrile/water) to afford the titled compound as a yellow oil. Yield: 186 mg, 78%. LCMS (ESI) m/z = 666.0 (M-H). Step 7: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-[4 -hydroxy-2-(2,2,2- trifluoroethyl)phenyl]-6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b] pyridazine-3-carboxamidine To a stirred mixture of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-[4- [tert-butyl(dimethyl)silyl]oxy-2-(2,2,2-trifluoroethyl)pheny l]pyrrolo[1,2-b]pyridazine-3- carboxamidine (170 mg, 254.6 umol) and 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine in DMF (2 mL) and water (0.4 mL) were added tripotassium phosphate (108.1 mg, 509.2 umol) and Pd(dtbpf)Cl2 (17 mg, 25.5 umol) at room temperature under argon atmosphere. The resulting mixture was stirred at 90°C for 2 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonia) afforded 4-[[(1R,3S)- 3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-[4-hydroxy-2-( 2,2,2-trifluoroethyl)-phenyl]-6-(6- methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as a pink solid. Yield: 46.5 mg, 31%. LCMS (ESI) m/z = 582.3 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.97 (brs, 1H), 9.14 (s, 1H), 8.60 (s, 1H), 8.06-8.20 (m, 3H), 7.12 (s, 1H), 6.74-6.89 (m, 4H), 5.96 (brs, 2H), 4.45-4.55 (m, 1H), 3.88 (s, 3H), 2.36-2.50 (m, 2H), 2.30-2.40 (m, 1H), 1.50-1.65 (m, 3H), 1.06 (s, 3H), 0.75- 0.85 (m, 6H). EXAMPLE 5AA Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -chloro-4-hydroxy- phenyl)-6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-ca rboxamidine Step 1: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-(2-chloro-4- hydroxyphenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-phenyl ]-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (0.45 g, 875.0 μmol) and (1S,3R)-1,2,2- trimethylcyclopentane-1,3-diamine (187 mg, 1.31 mmol) in N,N-dimethylacetamide (2 mL) was added N-ethyl-N-isopropyl-propan-2-amine (339 mg, 2.62 mmol). The resulting mixture was stirred for an hour at 90°C, then cooled to room temperature and cesium fluoride (398.7 mg, 2.62 mmol) was added. After stirring for a further 2 hours at room temperature, the reaction mixture was filtered. The filtrate was purified by reverse phase column chromatography (acetonitrile/water 95:5) to afford the titled compound as a brown oil. Yield: 0.17 g, 38 %. LCMS (ESI) m/z = 507.1 (M+H). Step 2: 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -chloro-4-hydroxy- phenyl)-6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-ca rboxamidine To a solution of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-(2-chloro- 4-hydroxy-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (60 mg, 118.6 μmol) in 1,4-dioxane (5 mL) and water (0.5 mL) were added 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (27.9 mg, 118.6 μmol), potassium phosphate (75.5 mg, 355.9 μmol) and 1,1'-bis (di-t- butylphosphino)ferrocene palladium dichloride (7.7 mg, 11.9 μmol). The resulting mixture was purged with nitrogen gas and stirred for 2 hours at 100 °C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water (x2) and brine (x2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-[[(1R,3S)-3- amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2-chloro-4-hydr oxy-phenyl)-6-(6-methoxy-3- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as an off-white solid. Yield: 17.8 mg, 27 %. LCMS (ESI) m/z = 534.5 (M+H). ¹ H NMR (DMSO-d ₆ +D ₂ O, 300 MHz) δ 8.54 (d, 1H, J=3.9 Hz), 8.04-8.15 (m, 3H), 7.11 (s, 1H), 6.71-6.89 (m, 4H), 4.48-4.54 (m, 1H), 3.85 (s, 3H), 2.29-2.35 (m, 1H), 1.50-1.85 (m, 3H), 1.18 (s, 3H), 0.87 (s, 6H). EXAMPLE 5BB Synthesis of 4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-N'-(2- chloro-5-fluoro-4- hydroxyphenyl)-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyrida zine-3-carboximidamide Step 1: 1-chloro-4,5-difluoro-2-nitrobenzene Into a three-necked flask was placed 4-chloro-1,2-difluoro-benzene (10 g, 67.32 mmol), followed by the addition of sulfuric acid (18 mL) and con. nitric acid (4.67 g, 74.06 mmol) at 0 °C. After stirring for 5 hours at room temperature, the resulting mixture was poured into ice/water and extracted with ethyl acetate (x3). The combined organic extracts were washed with a saturated aqueous solution of sodium bicarbonate (x2) and brine (x2), and then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound as yellow oil. Yield: 12.07 g, 93%. ¹ H NMR (DMSO-d6, 400 MHz) δ 8.45 (dd, 1H, J=7.6, 10.0 Hz), 8.14 (dd, 1H, J=7.2, 10.3 Hz). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -127.41 (s, 1F), -134.81 (s, 1F). Step 2: 5-chloro-2-fluoro-4-nitrophenol To a stirred solution of potassium hydroxide (2.90 g, 51.67 mmol) in water (77 mL) was added 1- chloro-4,5-difluoro-2-nitrobenzene (5.00 g, 25.84 mmol) at room temperature. The reaction mixture was stirred for 3 hours at 100 °C. After cooling to 0 °C, the reaction mixture was acidified with 6 N hydrochloric acid and extracted with dichloromethane (x2). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the titled compound as a yellow solid. Yield: 4.35 g, 88%. ¹ H NMR (DMSO-d6, 400 MHz) δ 7.64-7.74 (m, 1H), 6.20-6.28 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO-d6) δ -139.45 (t, 1F). Step 3: 4-amino-5-chloro-2-fluorophenol To a solution of 5-chloro-2-fluoro-4-nitrophenol (4.35 g, 22.71 mmol) in ethanol (22 mL) and water (8 mL) were added ammonium chloride (9.72 g, 181.68 mmol) and iron (5.07 g, 90.84 mmol) at room temperature. After stirring for 15 hours at room temperature, the reaction mixture was diluted with a mixture of methanol and ethyl acetate and then filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (x2). The combined organic extracts were washed with brine (x3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a white solid. Yield: 2.45 g, 67%. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.11 (s, 1H), 6.80 (d, 1H, J=8.7 Hz), 6.61 (d, 1H, J=12.9 Hz), 4.91 (s, 2H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -136.38 (s, 1F). Step 4: 4-((tert-butyldimethylsilyl)oxy)-2-chloro-5-fluoroaniline To a stirred solution of 4-amino-5-chloro-2-fluorophenol (2.45 g, 15.16 mmol) in N,N- dimethylformamide (30 mL) were added imidazole (1.03 g, 15.16 mmol) and tert- butyldimethylsilyl chloride (2.29 g, 15.16 mmol) at room temperature. After stirring for 1 hour at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as yellow oil. Yield: 3.66 g, 88%. LCMS (ESI) m/z = 276.1 (M+H). Step 5: 6-bromo-N'-(4-((tert-butyldimethylsilyl)oxy)-2-chloro-5-fluo rophenyl)-4-chloropyrrolo- [1,2-b]pyridazine-3-carboximidamide To a suspension of 6-bromo-4-chloro-pyrrolo[1,2-b]pyridazine-3-carboxamide (273 mg, 994.5 μmol) in toluene (5 mL) were added 4-((tert-butyldimethylsilyl)oxy)-2-chloro-5-fluoroaniline (274.3 mg, 994.5 μmol) and trimethylaluminium (1.5 mL, 2.0M in toluene) at 0 °C. The resulting mixture was stirred for 30 minutes at room temperature and then heated to 110 °C for 15 hours. After cooling to room temperature, the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as yellow solid. Yield: 400 mg, 55%. LCMS (ESI) m/z = 533.3 (M+H). Step 6: 4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6-brom o-N'-(2-chloro-5-fluoro- 4-hydroxyphenyl)pyrrolo[1,2-b]pyridazine-3-carboximidamide To a solution of 6-bromo-N'-(4-((tert-butyldimethylsilyl)oxy)-2-chloro-5-fluo rophenyl)-4- chloropyrrolo[1,2-b]pyridazine-3-carboximidamide (200 mg, 375.7 μmol) in N,N- dimethylacetamide (5 mL) were added (1S,3R)-1,2,2-trimethylcyclopentane-1,3-diamine (80.2 mg, 563.6 μmol) and N,N-diisopropylethylamine (145.7 mg, 1.13 mmol). After stirring for 2 hours at 90 °C under nitrogen atmosphere, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, and then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound as a yellow solid. Yield: 170 mg, 66%. LCMS (ESI) m/z = 525.4 (M+H). Step 7: 4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-N'-(2- chloro-5-fluoro-4- hydroxyphenyl)-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyrida zine-3-carboximidamide To a solution of 4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6-brom o-N'-(2-chloro-5- fluoro-4-hydroxyphenyl)pyrrolo[1,2-b]pyridazine-3-carboximid amide (120 mg, 229.1 μmol) in 1,4-dioxane (5 mL) and water (1 mL) were added 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (80.8 mg, 343.6 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (14.9 mg, 22.9 μmol) and potassium phosphate (97.3 mg, 458.2 μmol). The resulting mixture was purged with nitrogen gas and stirred for 2 hours at 90 °C. After cooling to room temperature, the reaction mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-(((1R,3S)-3- amino-2,2,3-trimethylcyclopentyl)amino)-N'-(2-chloro-5-fluor o-4-hydroxyphenyl)-6-(6- methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboximidami de as a light brown solid. Yield: 35.2 mg, 27%. LCMS (ESI) m/z = 552.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz,) δ 11.75 (s, 1H), 8.61 (d, 1H, J=2.0 Hz), 8.15-8.18 (m, 2H), 8.08-8.12 (m, 1H), 7.13 (d, 1H, J=1.6 Hz), 7.02 (d, 1H, J=8.8 Hz), 6.88 (d, 1H, J=8.4 Hz), 6.81 (d, 1H, J=12.0 Hz), 6.31 (s, 2H), 4.45-4.55 (m, 1H), 3.88 (d, 3H, J =3.6 Hz), 2.32 - 2.37 (m, 1H), 1.48-1.70 (m, 3H), 1.09 (s, 3H), 0.83 (d, J = 6.0 Hz, 6H). ¹⁹ F NMR (DMSO-d6, 376 MHz,) δ -136.23 (s, 1F). EXAMPLE 5CC Synthesis of 4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-N'-(2- chloro-4- hydroxyphenyl)-6-(5-((dimethylamino)methyl)pyridin-3-yl)pyrr olo[1,2-b]pyridazine-3- carboximidamide Step 1: (5-bromopyridin-3-yl)methanol To a solution of 5-bromopyridine-3-carbaldehyde (3.00 g, 16.13 mmol) in methanol (30 mL) and tetrahydrofuran (30 mL) was added sodium borohydride (1.53 g, 40.32 mmol) in portions. After stirring for 2 hours at 0 °C, the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate (x2). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as yellow oil. Yield: 1.79 g, 59 %. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.58 (d, 1H, J=2.0 Hz), 8.51 (d, 1H, J=1.6 Hz), 7.96 (t, 1H, J=2.0 Hz), 5.46 (t, 1H, J=5.6 Hz), 4.54 (d, 2H, J=4.4 Hz). Step 2: 1-(5-bromopyridin-3-yl)-N,N-dimethylmethanamine To a solution of (5-bromopyridin-3-yl)methanol (1.77 g, 9.41 mmol) in dichloromethane (35 mL) were added methylsulfonyl chloride (1.62 g, 14.12 mmol) and triethylamine (1.43 g, 14.12 mmol). The resulting mixture was stirred for 2 hours at 0 °C under nitrogen atmosphere, followed by the addition of dimethylamine (2.7 mL, 2.0 M in tetrahydrofuran). After stirring for an hour at 25 °C, the resulting mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (methanol/dichloromethane) afforded the titled compound as a yellow oil. Yield: 1.55 g, 76%. LCMS (ESI) m/z = 217.1 (M+H). Step 3: (5-((dimethylamino)methyl)pyridin-3-yl)boronic acid To a solution of 1-(5-bromo-3-pyridyl)-N,N-dimethyl-methanamine (215 mg, 999.6 μmol) in 1,4- dioxane (8 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (304.60 mg, 1.20 mmol), potassium acetate (294.3 mg, 3.0 mmol) and 1,1'-Bis(diphenylphosphino)ferrocene- palladium(II) dichloride dichloromethane complex (37 mg, 50.0 μmol). The mixture was stirred for 4 hours at 110 °C under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure to afford the crude titled compound as a brown oil, which was used for next step without further purification. Yield: 0.62 g. LCMS (ESI) m/z = 181.2 (M+H). Step 4: 4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-N'-(2- chloro-4-hydroxyphenyl)- 6-(5-((dimethylamino)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyrid azine-3-carboximidamide To a solution of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-(2-chloro- 4-hydroxy-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (100 mg, 197.7 μmol) in 1,4- dioxane (2 mL) and water (0.5 mL) were added (5-((dimethylamino)methyl)pyridin-3-yl)boronic acid (35.3 mg, 197.7 μmol), potassium phosphate (83.9 mg, 395.4 μmol) and 1,1'-bis (di-t- butylphosphino)ferrocene palladium dichloride (13.1 mg, 19.8 μmol). The resulting mixture was stirred for 2 hours at 80 °C under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was dissolved in N,N- dimethylformamide and filtered. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-(((1R,3S)-3-amino-2,2,3- trimethylcyclopentyl)amino)-N'-(2-chloro-4-hydroxyphenyl)-6- (5-((dimethylamino)- methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboximidami de as a yellow solid. Yield: 4.7 mg, 4.1 %. LCMS (ESI) m/z = 561.5 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.44-9.48 (m, 1H), 8.92 (s, 1H), 8.42 (s, 1H), 8.18-8.26 (m, 2H), 8.00 (s, 1H), 7.23 (s, 1H), 6.82-6.90 (m, 2H), 6.71- 6.78 (m, 1H), 6.05-6.30 (m, 1H), 4.50-4.60 (m, 1H), 3.66-3.81 (m, 2H), 2.19-2.24 (m, 1H), 2.12 (s, 6H), 1.39-1.80 (m, 3H), 1.13 (s, 3H), 0.87 (s, 6H). EXAMPLES 5DD – 5JJJ Compounds 5DD – 5JJJ were prepared according to the methods described in the previous examples and synthetic schemes from the correspondingly appropriate starting materials. Structure, name and analytical characterization of these compounds are presented below.

EXAMPLE 6

COMPOUNDS OF FORMULA (I) WHEREIN

X IS NH, B IS MONOSUBSTITUTED CYCLOHEXANE

EXAMPLE 6 A

Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-4-((2-methylcyclohexyl)amino)p yrrolor 1 ,2- b]pyridazine-3-carboxamidine Step 1: N'-(4-(tert-butyl(dimethyl)silyl)oxy-2-ethyl-phenyl)-4-((2-m ethylcyclohexyl)amino)- pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-(4-(tert-butyl(dimethyl)silyl)oxy-2-ethyl-phenyl) -4-((2- methylcyclohexyl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamid ine (150 mg, 256.6 μmol) in methanol (3 mL) was added 5% palladium on carbon (30 mg) under nitrogen atmosphere. The reaction mixture was purged with hydrogen gas and stirred for 2 hours at 20°C under hydrogen atmosphere. The resulting mixture was filtered through a pad of celite and washed with methanol. The filtrate was concentrated under reduced pressure to afford the titled compound as a yellow solid. Yield: 120 mg, 92%. LCMS (ESI) m/z = 506.3 (M+H). Step 2: N'-(2-ethyl-4-hydroxy-phenyl)-4-((2-methylcyclohexyl)amino)p yrrolo[1,2-b]pyridazine- 3-carboxamidine To a solution of N'-(4-(tert-butyl(dimethyl)silyl)oxy-2-ethyl-phenyl)-4-((2-m ethylcyclohexyl)- amino)pyrrolo[1,2-b]pyridazine-3-carboxamidine (100 mg, 197.7 μmol) in N,N- dimethylformamide (3 mL) was added cesium fluoride (90.1 mg, 593.2 μmol). After stirring for 2 hours at room temperature, the resulting mixture was filtered through a celite pad. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate) afforded N'-(2-ethyl-4-hydroxy-phenyl)-4-((2-methylcyclohexyl)amino)p yrrolo[1,2-b]pyridazine-3- carboxamidine as a light yellow solid. Yield: 33.9 mg, 41%. LCMS (ESI) m/z = 392.2 (M+H). ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ 12.13-12.50 (m, 1H), 8.94 (d, 1H, J=3.9 Hz), 8.18 (d, 1H, J=2.3 Hz), 7.58-7.66 (m, 1H), 6.74-6.86 (m, 1H), 6.55-6.69 (m, 4H), 5.72-5.96 (m, 2H), 3.62-4.47 (m, 1H), 2.41 (q, 2H, J=7.5 Hz), 1.56-1.94 (m, 3H), 1.36-1.53 (m, 3H), 1.15-1.31 (m, 3H), 1.02-1.12 (m, 3H), 0.84-1.00 (m, 3H). EXAMPLE 6B Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-4-[(2-methylcyclohexyl) amino]-6-phenyl- pyrrolo[1,2-b] pyridazine-3-carboxamidine Step 1: 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl] oxy-2-ethyl-phenyl]-4-[(2-methylcyclohexyl) amino] pyrrolo[1,2-b] pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl] oxy-2-ethyl-phenyl]-4-chloro- pyrrolo[1,2-b] pyridazine-3-carboxamidine (0.30 g, 590.6 umol) and 2-methylcyclohexanamine (133.7 mg, 1.18 mmol, 155.9 uL) in N,N-dimethylacetamide (2 mL) was added N-ethyl-N- isopropyl-propan-2-amine (229.0 mg, 1.77 mmol, 308.6 uL). After stirring for 2 hours at 110 °C, the reaction mixture was cooled to room temperature and purified by reverse phase column chromatography (acetonitrile/water, 90%) to afford the titled compound as a yellow solid. Yield: 0.26 g, 65%. LCMS (ESI) m/z = 584.1 (M+H). Step 2: N'-[4-[tert-butyl(dimethyl)silyl] oxy-2-ethyl-phenyl]-4-[(2-methylcyclohexyl) amino]-6- phenyl-pyrrolo[1,2-b] pyridazine-3-carboxamidine To a mixture of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl] oxy-2-ethyl-phenyl]-4-[(2- methylcyclohexyl) amino] pyrrolo[1,2-b] pyridazine-3-carboxamidine (0.25 g, 427.6 umol), phenylboronic acid (78.2 mg, 641.4 umol) and potassium phosphate (272.3 mg, 1.28 mmol) in 1,4- dioxane (10 mL) and water (1 mL) was added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (27.9 mg, 42.8 μmol). The reaction mixture was stirred for 2 hours at 100 °C under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was filtered through a celite pad and the filtrate concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (acetonitrile/water, 90%) to afford the titled compound as a light yellow solid. Yield: 0.18 g, 67%. LCMS (ESI) m/z = 582.6 (M+H). Step 3: N'-(2-ethyl-4-hydroxy-phenyl)-4-[(2-methylcyclohexyl) amino]-6-phenyl-pyrrolo[1,2-b] pyridazine-3-carboxamidine To a solution of N'-[4-[tert-butyl(dimethyl)silyl] oxy-2-ethyl-phenyl]-4-[(2-methylcyclohexyl) amino]-6-phenyl-pyrrolo[1,2-b] pyridazine-3-carboxamidine (0.18 g, 309.4 umol) in acetonitrile (10 mL) was added cesium fluoride (141 mg, 928.1 umol). After stirring for 2 hours at 25 °C, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.05% ammonia) afforded N'-(2-ethyl- 4-hydroxy-phenyl)-4-[(2-methylcyclohexyl)amino]-6-phenyl-pyr rolo[1,2-b] pyridazine-3- carboxamidine as a light-yellow solid. Yield: 46.8 mg, 30%. LCMS (ESI) m/z = 468.2 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 12.21-12.50 (m, 1H), 8.91 (d, 1H, J=3.9 Hz), 8.13-8.20 (m, 2H), 7.77-7.80 (m, 2H), 7.39-7.44 (m, 2H), 7.20-7.37 (m, 2H), 6.59-6.67 (m, 3H), 5.82-5.93 (m, 2H), 3.73-4.52 (m, 1H), 2.50-2.38 (m, 2H), 2.21-2.34 (m, 1H), 1.80-1.90 (m, 1H), 1.60-1.80 (m, 2H), 1.45-1.60 (m, 3H), 1.25-1.38 (m, 2H), 0.72-1.10 (m, 6H). EXAMPLES 6C and 6D Synthesis of N'-(2-ethyl-4-hydroxyphenyl)-6-phenyl-4-((cis-2- (trifluoromethyl)cyclohexyl)amino)pyrrolo[1,2-b]pyridazine-3 -carboximidamide and N'-(2-ethyl-4-hydroxyphenyl)-6-phenyl-4-((trans-2- (trifluoromethyl)cyclohexyl)amino)pyrrolo[1,2-b]pyridazine-3 -carboximidamide Step 1: 2-(trifluoromethyl)cyclohexan-1-amine To a solution of 2-(trifluoromethyl)aniline (10 g, 62.06 mmol) in trifluoroacetic acid (10 mL) was added dioxoplatinum (750 mg, 3.30 mmol) under nitrogen atmosphere. The reaction mixture was purged with hydrogen gas and stirred for 16 hours at 25 °C under hydrogen atmosphere (1.5 atm), and then filtered through a celite pad. The filtrate was concentrated under reduced pressure and the resulting residue treated with 40% aqueous solution of sodium hydroxide (20 mL) for 5 minutes and then extracted with diethyl ether (x3). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound as colorless oil. Yield: 3.0 g, 28%. LCMS (ESI) m/z = 168.2 (M+H). Step 2: 6-bromo-N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylphenyl)- 4-((2-(trifluoromethyl)- cyclohexyl)amino)pyrrolo[1,2-b]pyridazine-3-carboximidamide To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (300 mg, 590.6 umol) in N,N-dimethylacetamide (2 mL) were added N-ethyl-N-isopropyl-propan-2-amine (229 mg, 1.77 mmol) and 2- (trifluoromethyl)cyclohexan-1-amine (197.5 mg, 1.18 mmol). After stirring for 2 hours at 100 °C, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as yellow oil. Yield: 300 mg, 79 %. LCMS (ESI) m/z = 640.3 (M+H). Step 3: N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylphenyl)-6-phenyl -4-((2-(trifluoromethyl)- cyclohexyl)amino)pyrrolo[1,2-b]pyridazine-3-carboximidamide To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[2- (trifluoromethyl)cyclohexyl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine (300 mg, 469.8 umol) in 1,4-dioxane (4 mL) and water (1 mL) were added phenylboronic acid (74.5 mg, 610.7 umol) and dichloro[1,1-bis(di-t-butylphosphino)ferrocene]palladium(II) (30.6 mg, 47.0 umol) and potassium phosphate (199.4 mg, 939.5 umol). The mixture was purged with stirred for 2 hours at 100 °C under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was filtered through a celite pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as yellow oil. Yield: 200 mg, 66 %. LCMS (ESI) m/z = 636.2 (M+H). Step 4: N'-(2-ethyl-4-hydroxyphenyl)-6-phenyl-4-((cis-2-(trifluorome thyl)cyclohexyl)- amino)pyrrolo[1,2-b]pyridazine-3-carboximidamide and N'-(2-ethyl-4-hydroxyphenyl)-6-phenyl-4-((trans-2-(trifluoro methyl)cyclohexyl)amino)pyrrolo- [1,2-b]pyridazine-3-carboximidamide To a solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-6-pheny l-4-[[2- (trifluoromethyl)cyclohexyl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine (300 mg, 469.8 umol) in N,N-dimethylformamide (2 mL) was added cesium fluoride (356.8 mg, 2.35 mmol). After stirring for 2 hours at 25 °C, the reaction mixture was filtered and the filtrate concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded two fractions: Fraction 1: N'-(2-ethyl-4-hydroxy-phenyl)-6-phenyl-4-[[(1R,2S)-2-(triflu oromethyl)cyclohexyl]- amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine as a brown solid. Yield: 47.2 mg, 18%. LCMS (ESI) m/z = 522.2 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.95 (d, 1H, J=9.2 Hz), 8.94 (s, 1H), 8.23 (s, 1H), 8.17 (d, 1H, J=1.6 Hz), 7.81 (d, 2H, J=7.2 Hz), 7.38-7.42 (m, 2H), 7.23-7.28 (m, 2H), 6.67 (d, 1H, J=2.4 Hz), 6.55-6.61 (m, 2H), 5.88 (s, 2H), 5.08 (d, 1H, J=6.8 Hz), 2.59- 2.72 (m, 1H), 2.37-2.43 (m, 2H), 1.94-2.02 (m, 1H), 1.31- 1.76 (m, 7H), 0.99-1.01(m, 3H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -68.31 (s, 1F). Fraction 2: N'-(2-ethyl-4-hydroxyphenyl)-6-phenyl-4-(((1R,2R)-2-(trifluo romethyl)cyclohexyl)- amino)pyrrolo[1,2-b]pyridazine-3-carboximidamide as a brown solid. Yield: 5.3 mg, 2.0%. LCMS (ESI) m/z = 522.2 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 12.61 (s, 1H), 8.95 (s, 1H), 8.18-8.22 (m, 2H), 7.82 (d, 2H, J= 7.2 Hz), 7.38-7.44 (m, 2H), 7.20-7.28 (m, 2H), 6.57-6.67 (m, 3H), 5.89 (s, 2H), 4.52 (d, 1H, J=6.9 Hz), 2.37-2.51 (m, 3H), 2.20-2.30 (m, 1H), 1.89-2.02 (m, 1H), 1.25-1.75 (m, 6H), 0.99-1.15 (m, 3H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -66.66 (s, 1F). EXAMPLE 6E Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-4-[(3-hydroxycyclohexyl) amino]-6-phenyl- pyrrolo[1,2-b] pyridazine-3-carboxamidine Step 1: 6-bromo-N'-(2-ethyl-4-hydroxy-phenyl)-4-[(3-hydroxycyclohexy l) amino] pyrrolo[1,2-b] pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl] oxy-2-ethyl-phenyl]-4-chloro- pyrrolo[1,2-b] pyridazine-3-carboxamidine (100 mg, 196.9 umol) and 3-aminocyclohexanol (45.4 mg, 394 umol) in N, N-dimethylacetamide (2 mL) was added N, N-diisopropylethylamine (25.5 mg, 197 μmol, 34.3 μL). After stirring for 2 hours at 80 °C, the reaction mixture was cooled to room temperature and purified by reverse phase column chromatography (acetonitrile/water) to afford the titled compound. Yield: 63 mg, 51%. LCMS (ESI) m/z = 472.1 (M+H). Step 2: N'-(2-ethyl-4-hydroxy-phenyl)-4-[(3-hydroxycyclohexyl) amino]-6-phenyl-pyrrolo[1,2-b] pyridazine-3-carboxamidine To a mixture of 6-bromo-N'-(2-ethyl-4-hydroxy-phenyl)-4-[(3-hydroxycyclohexy l) amino] pyrrolo[1,2-b] pyridazine-3-carboxamidine (99 mg, 209.6 μmol), phenylboronic acid (38.3 mg, 314.4 μmol) and potassium phosphate (133.5 mg, 628.7 μmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (13.7 mg, 21 μmol). The reaction mixture was stirred for 2 hours at 100 °C under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was filtered through a celite pad and the filtrate concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded N'-(2-ethyl-4-hydroxy-phenyl)-4-[(3- hydroxycyclohexyl) amino]-6-phenyl-pyrrolo[1,2-b] pyridazine-3-carboxamidine as a yellow solid. Yield: 38.5 mg, 38%. LCMS (ESI) m/z = 470.4 (M+H). ¹ H NMR (DMSO-d6+D2O, 300 MHz) δ 8.28 (s, 1H), 8.06-8.15 (m, 2H), 7.76-7.79 (m, 2H), 7.41-7.44 (m, 3H), 7.26-7.31 (m, 1H), 6.83-6.95 (m, 1H), 6.66-6.75 (m, 2H), 4.40-4.60 (m, 1H), 3.95-4.05 (m, 1H), 2.44-2.50 (m, 2H), 1.92-2.05 (m, 2H), 1.67-1.74 (m, 2H), 1.46-1.53 (m, 4H), 1.12 (t, 3H, J=7.2 Hz). EXAMPLE 6F Synthesis of (Z)-4-((trans-3-aminocyclohexyl)amino)-N'-(2-chloro-4-hydrox yphenyl)-6-(6- methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboximidami de Step 1: benzyl N-[trans-3-[[6-bromo-3-[(Z)-N'-[4-[tert-butyl(dimethyl)silyl ]oxy-2-chloro- phenyl]-carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cyc lohexyl]carbamate To a solution of (Z)-6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-ph enyl]-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (380 mg, 738.8 μmol) and benzyl N-[trans-3- aminocyclohexyl]carbamate (231.4 mg, 812.7 μmol) in 1,4-dioxane (10.0 mL) was added N-ethyl- N-isopropyl-propan-2-amine (286.5 mg, 2.22 mmol). After stirring for 24 hours at 100 °C, the reaction mixture was cooled down to room temperature and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a light-yellow solid. Yield: 420 mg, 78%. LCMS (ESI) m/z = 727.4 (M+H). Step 2: benzyl N-[trans-3-[[3-[(Z)-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-c hloro-phenyl]- carbamimidoyl]-6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazi n-4-yl]amino]cyclohexyl]- carbamate To a solution of benzyl N-[trans-3-[[6-bromo-3-[(Z)-N'-[4-[tert-butyl(dimethyl)silyl ]oxy-2- chloro-phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]ami no]cyclohexyl]carbamate (0.42 g, 576.5 μmol) in 1,4-dioxane (5.0 mL) and water (0.5 mL) were added (6-methoxy-3-pyridyl)boronic acid (105.8 mg, 691.8 μmol), potassium phosphate (367.1 mg, 1.73 mmol) and 1,1'-bis(di-tert- butylphosphino)ferrocene palladium dichloride (40.0 mg, 57.7 μmol). The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a yellow solid. Yield: 360 mg, 82%. LCMS (ESI) m/z = 754.6 (M+H). Step 3: (Z)-4-[[trans-3-aminocyclohexyl]amino]-N'-(2-chloro-4-hydrox y-phenyl)-6-(6-methoxy- 3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of benzyl N-[trans-3-[[3-[(Z)-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-c hloro- phenyl]carbamimidoyl]-6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b]p yridazin-4- yl]amino]cyclohexyl]-carbamate (230 mg, 304.9 μmol) in acetic acid (4.0 mL) was added hydrobromic acid (1.5 mL, 48% in water). After stirring for 2 hours at 50 °C, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded (Z)-4-[[trans-3-aminocyclohexyl]amino]-N'-(2-chloro- 4-hydroxy-phenyl)-6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyrid azine-3-carboxamidine as a yellow solid. Yield: 36.9 mg, 23%. LCMS (ESI) m/z = 506.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz): 12.18 (d, 1H, J=8.0 Hz), 8.66-8.67 (m, 1H), 8.41 (s, 1H), 8.14-8.23 (m, 3H), 7.34 (s, 1H), 6.83-6.90 (m, 3H), 6.72-6.75 (m, 1H), 6.21 (s, 2H), 4.71-4.84 (m, 1H), 3.88 (s, 3H), 3.74 (s, 1H), 3.15-3.25 (m, 1H), 2.09-2.12 (m, 1H), 1.50-1.87 (m, 6H), 1.35-1.47 (m, 1H). EXAMPLE 6G Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-4-hydroxy-ph enyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine Step 1: Methyl 1-aminopyrrole-2-carboxylate To a solution of methyl 1H-pyrrole-2-carboxylate (10 g, 79.92 mmol) in 1-methyl-2-pyrrolidinone (100 mL) was added potassium 2-methylpropan-2-olate (49.93 g, 119.88 mmol) at 0 °C under nitrogen atmosphere. The mixture was stirred for half an hour at room temperature, followed by the addition of a solution of amino 4-nitrobenzoate (18.20 g, 99.90 mmol) in 1-methyl-2- pyrrolidinone (100 mL). After stirring for 3 hours at room temperature, the resulting mixture was quenched with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (x3). The combined organic extracts were washed with water (x3) and brine (x3), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the titled compound as a brown oil. Yield: 20 g, 80%. LCMS (ESI) m/z = 141.3 (M+H). Step 2: methyl 1-((3-ethoxy-3-oxo-prop-1-enyl)amino)pyrrole-2-carboxylate To a mixture of methyl 1-aminopyrrole-2-carboxylate (3.40 g, 24.26 mmol) and ethyl 3,3- diethoxypropanoate (4.62 g, 24.26 mmol) in N,N-dimethylformamide (40 mL) was added 4- methylbenzenesulfonic acid hydrate (18.27 g, 24.26 mmol). After stirring for 15 hours at 90 °C, the reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (x3). The combined organic extracts were washed with water (x3) and brine (x3), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the titled compound as a brown oil. Yield: 1.30 g, 32%. LCMS (ESI) m/z = 239.3 (M+H). Step 3: ethyl 4-hydroxypyrrolo[1,2-b]pyridazine-3-carboxylate To a solution of methyl 1-((3-ethoxy-3-oxo-prop-1-enyl)amino)pyrrole-2-carboxylate (1.30 g, 5.46 mmol) in ethanol (18 mL) was added potassium 2-methylpropan-2-olate (2.27 g, 5.46 mmol) at 0 °C under nitrogen atmosphere. After stirring for 15 hours at 90 °C, the reaction mixture was cooled to room temperature, quenched with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (x3). The combined organic extracts were washed with water and brine, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the titled compound as a brown oil. Yield: 800 mg, 42%. LCMS (ESI) m/z = 207.2 (M+H). Step 4: ethyl 4-chloropyrrolo[1,2-b]pyridazine-3-carboxylate To a solution of ethyl 4-hydroxypyrrolo[1,2-b]pyridazine-3-carboxylate (800 mg, 3.88 mmol) in acetonitrile (8 mL) were added N-ethyl-N-isopropyl-propan-2-amine (501.4 mg, 3.88 mmol) and benzyl(triethyl)ammonium chloride (1.33 g, 5.82 mmol), followed by the addition of phosphorus oxychloride (1.78 g, 11.64 mmol) at 0 °C under nitrogen atmosphere. After stirring for 24 hours at 90 °C, the reaction mixture was cooled in an ice/water bath, then poured into ice/water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a yellow solid. Yield: 300 mg, 50%. LCMS (ESI) m/z = 225.6 (M+H). Step 5: 4-chloropyrrolo[1,2-b]pyridazine-3-carboxylic acid To a solution of ethyl 4-chloropyrrolo[1,2-b]pyridazine-3-carboxylate (300 mg, 1.34 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was added lithium hydroxide (96 mg, 4.01 mmol) at °C. After stirring for 15 hours at room temperature, the resulting mixture was adjusted to pH= 4 with 1N hydrochloric acid. The solids were collected, washed with water three times and then dried in vacuo to afford the titled compound as a yellow solid. Yield: 100 mg, 40%. LCMS (ESI) m/z = 197.0 (M+H). Step 6: 4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide 4-Chloropyrrolo[1,2-b]pyridazine-3-carboxylic acid (180 mg, 915.6 μmol) was dissolved in oxalyl chloride (2 mL), then two drops of N,N-dimethylformamide were added at 0 °C. The mixture was stirred for 2 hours at room temperature and then concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 mL) and added into a mixture of ammonia (4.6 mL, 1.83 mmol, 0.4 M in 1,4-dioxane) and N,N-diethylethanamine (463.3 mg, 4.58 mmol) in dichloromethane (2 mL) at 0 °C. After stirring for 2 hours at room temperature, the resulting mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a light yellow solid. Yield: 50 mg, 27%. LCMS (ESI) m/z = 196.1 (M+H). Step 7: N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-phenyl]-4-chlo ro-pyrrolo[1,2-b]pyridazine- 3-carboxamidine To a suspension of 4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (70 mg, 357.9 μmol) and 4- [tert-butyl(dimethyl)silyl]oxy-2-chloro-aniline (138.4 mg, 536.8 μmol) in toluene (4.0 mL) was added trimethylaluminium (0.7 mL, 1.4 mmol, 2.0 M in toluene) dropwise via syringe at 0 °C under nitrogen atmosphere. The mixture was stirred for 5 minutes at 0 °C and 15 minutes at room temperature, then heated to 110 °C for 15 hours. After cooling to room temperature, the resulting mixture was quenched with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a light yellow solid. Yield: 50 mg, 32%. LCMS (ESI) m/z = 436.4 (M+H). Step 8: tert-butyl trans-N-[4-[[3-[N'-(2-chloro-4-hydroxy-phenyl)carbamimidoyl] pyrrolo[1,2-b]- pyridazin-4-yl]amino]cyclohexyl]carbamate To a solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-phenyl]-4-chlo ro-pyrrolo[1,2- b]pyridazine-3-carboxamidine (50 mg, 114.8 μmol) and tert-butyl trans-N-(4- aminocyclohexyl)carbamate (36.9 mg, 172.2 μmol) in N,N-dimethylacetamide (1.5 mL) was added N-ethyl-N-isopropyl-propan-2-amine (44.5 mg, 344.5 μmol). After stirring for 2 hours at 100 °C, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (x2). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the titled compound as a brown oil. Yield: 90 mg, 55%. LCMS (ESI) m/z = 499.0 (M+H). Step 9: 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-4-hydroxy-ph enyl)pyrrolo[1,2-b]- pyridazine-3-carboxamidine To a solution of tert-butyl trans-N-[4-[[3-[N'-(2-chloro-4-hydroxy-phenyl)carbamimidoyl] - pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohexyl]carbamate (85 mg, 59.6 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.5 mL). The reaction mixture was stirred for 2 hours at room temperature and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-4-hydroxy-ph enyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine as a light yellow solid. Yield: 2.1 mg, 8%. LCMS (ESI) m/z = 399.1 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 8.24 (s, 1H), 8.16 (s, 1H), 7.65-7.67 (m, 1H), 6.67-6.90 (m, 4H), 4.00-4.10 (m, 1H), 3.00-3.10 (m, 1H), 2.12-2.20 (m, 2H), 1.92-2.01 (m, 2H), 1.35-1.59 (m, 4H). EXAMPLE 6H Synthesis of 4-(trans-(4-aminocyclohexyl)amino)-N'-(2-chloro-4-hydroxy-ph enyl)-6-(4-(2-(2-(2- (2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy )ethoxy)phenyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine Step 1: tert-butyl trans-N-(4-((3-((Z)-N'-(2-chloro-4-hydroxy-phenyl)carbamimid oyl)-6-(4-(2-(2- (2-(2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ethoxy)ethoxy)eth oxy)ethoxy)phenyl) pyrrolo[1,2- b]pyridazin-4-yl)amino)cyclohexyl)carbamate To a mixture of tert-butyl trans-N-(4-((6-bromo-3-((Z)-N'-(2-chloro-4-hydroxy- phenyl)carbamimidoyl)pyrrolo[1,2-b]pyridazin-4-yl)amino)cycl ohexyl)carbamate (200 mg, 346.1 μmol), 2-(4-(2-(2-(2-(2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ethoxy )ethoxy)ethoxy)ethoxy)- phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (225.3 mg, 415.3 μmol) and potassium phosphate (220.4 mg, 1.04 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) were added palladium (II) acetate (7.8 mg, 34.6 μmol) and XPhos (49.5 mg, 103.8 μmol). The mixture was purged stirred for 1.5 hours at 80 °C under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was concentrated under reduce pressure. Purification via reverse phase column chromatography (acetonitrile/water, 100%) afforded the titled compound as a yellow solid. Yield: 220 mg, 69%. LCMS (ESI) m/z = 911.0 (M-H). Step 2: Synthesis of 4-(trans-(4-aminocyclohexyl)amino)-N'-(2-chloro-4-hydroxy-ph enyl)-6-(4- (2-(2-(2-(2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ethoxy)etho xy)ethoxy)ethoxy)phenyl) pyrrolo-[1,2-b]pyridazine-3-carboxamidine To a solution of tert-butyl trans-N-(4-((3-((Z)-N'-(2-chloro-4-hydroxy-phenyl)carbamimid oyl)-6- (4-(2-(2-(2-(2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ethoxy)e thoxy)ethoxy)ethoxy)phenyl) pyrrolo[1,2-b]pyridazin-4-yl)amino)cyclohexyl)carbamate (200 mg, 218.94 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After stirring for an hour at 20 °C, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-(trans-(4-aminocyclohexyl)amino)-N'-(2-chloro-4-hydroxy-ph enyl)-6-(4-(2-(2-(2-(2-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)phen yl)pyrrolo[1,2-b]-pyridazine- 3-carboxamidine as a yellow solid. Yield: 38.6 mg, 21%. LCMS (ESI) m/z = 811.5 (M-1). ¹ H- NMR (400 MHz, DMSO-d ₆ , ppm) δ 11.80 (d, 1H, J=8.0 Hz), 8.37 (d, 1H, J=1.6 Hz), 8.17 (s, 1H), 8.09 (d, 1H, J=1.6 Hz), 7.65-7.72 (m, 2H), 6.95-7.10 (m, 3H), 6.82-6.92 (m, 2H), 6.68-6.75 (m, 1H), 6.24 (s, 2H), 4.15-4.23 (m, 1H), 4.09-4.13 (m, 2H), 3.73-3.80 (m, 2H), 3.38-3.60 (m, 24H), 3.23 (s, 3H), 3.00-3.06 (m, 1H), 2.16-2.24 (m, 2H), 1.92-2.03 (m, 2H), 1.53-1.67 (m, 2H), 1.35- 1.48 (m, 2H). EXAMPLE 6I Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(1H-pyrazol- 4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: trans-tert-butyl N-[4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6-(1-t etrahydro- pyran-2-ylpyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cy clohexyl]carbamate To a mixture of trans-tert-butyl (4-((6-bromo-3-(N'-(2-chloro-5-fluorophenyl)carbamimidoyl)- pyrrolo[1,2-b]pyridazin-4-yl)amino)cyclohexyl)carbamate (100 mg, 172.5 μmol) and 1- tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol an-2-yl)pyrazole (95.9 mg, 344.9 μmol) in 1,4-dioxane (1 mL) and water (0.2 mL) were added 1,1'-bis (di-t- butylphosphino)ferrocene palladium dichloride (11.2 mg, 17.2 μmol) and potassium phosphate (109.8 mg, 517.3 μmol). The resulting mixture was stirred for 2 hours at 90 °C under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a light yellow semi-solid. Yield: 100 mg, 76%. LCMS (ESI) m/z = 651.1 (M+H). Step 2: 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(1H-pyrazol-4-yl)- pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of trans-tert-butyl N-[4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6-(1- tetrahydropyran-2-ylpyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-y l]amino]cyclohexyl]carbamate (80 mg, 122.7 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). After stirring for 2 hours at room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-5- fluoro-phenyl)-6-(1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3 -carboxamidine as a light yellow solid. Yield: 35.5 mg, 60%. LCMS (ESI) m/z = 467.1 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.23 (d, 1H, J=7.8 Hz), 8.45 (s, 1H), 8.16 (s, 1H), 7.90-8.01 (m, 3H), 7.44-7.55 (m, 1H), 6.82- 7.00 (m, 3H), 6.54 (s, 2H), 4.14 (d, 1H, J=7.8 Hz), 2.77-2.86 (m, 1H), 2.05-2.20 (m, 2H), 1.83- 1.94 (m, 2H), 1.34-1.53 (m, 4H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -114.40 (s, 1F). EXAMPLE 6J Synthesis of 4-((trans-4-aminocyclohexyl)amino)-N'-(2-chloro-5-fluoro-phe nyl)-6-(1- methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: trans-tert-butyl (4-((6-bromo-3-(N'-(2-chloro-5-fluorophenyl)carbamimidoyl)py rrolo[1,2- b]pyridazin-4-yl)amino)cyclohexyl)carbamate To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (130 mg, 323.3 μmol) and trans-tert-butyl N-(4-aminocyclohexyl)carbamate (69.3 mg, 323.3 μmol) in N,N-dimethylacetamide (2 mL) was added N,N-diisopropylethylamine (125.4 mg, 970.0 μmol). After stirring for 2 hours at 80 °C, the reaction mixture was cooled to room temperature and purified by reverse phase column chromatography (acetonitrile/water 100%) to afford the titled compound as a yellow solid. Yield: 140 mg, 75%. LCMS (ESI) m/z = 581.0 (M+H). Step 2: trans-tert-butyl N-(4-((3-(N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl)-6-(1-m ethyl- pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)cyclohexyl)c arbamate To a mixture of trans-tert-butyl (4-((6-bromo-3-(N'-(2-chloro-5-fluorophenyl)carbamimidoyl)- pyrrolo[1,2-b]pyridazin-4-yl)amino)cyclohexyl)carbamate (120 mg, 206.9 μmol) and 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (43.1 mg, 206.9 μmol) in 1,4-dioxane (2 mL) and water (0.2 mL) were added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (13.5 mg, 20.7 μmol) and potassium phosphate (131.8 mg, 620.8 μmol) at room temperature. The resulting mixture was stirred for 2 hours at 90 °C under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water 100%) afforded the titled compound as a yellow solid. Yield: 100 mg, 83%. LCMS (ESI) m/z = 581.0 (M+H). Step 3: 4-((trans-4-aminocyclohexyl)amino)-N'-(2-chloro-5-fluoro-phe nyl)-6-(1-methylpyrazol- 4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of trans-tert-butyl N-(4-((3-(N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl)-6-(1- methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)cycloh exyl)carbamate (90 mg, 154.9 μmol) in dichloromethane (4 mL) was added 2,2,2-trifluoroacetic acid (1 mL). After stirring for 1 hour at 20 °C, the resulting mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-((trans-4- aminocyclohexyl)amino)-N'-(2-chloro-5-fluoro-phenyl)-6-(1-me thylpyrazol-4-yl)pyrrolo[1,2-b]- pyridazine-3-carboxamidine as an off-white solid. Yield: 16.7 mg, 22%. LCMS (ESI) m/z = 481.4 (M+H). ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 11.24 (d, 1H, J=6.0 Hz), 8.14 (s, 1H), 8.05 (s, 1H), 7.89 (d, 1H, J=1.2 Hz), 7.78 (d, 1H, J=6.0 Hz), 7.46-7.52 (m, 1H), 6.83-6.95 (m, 3H), 6.53 (s, 2H), 4.10 (s, 1H), 3.86 (s, 3H), 2.61-2.65 (m, 1H), 2.06-2.15 (m, 2H), 1.76-1.85 (m, 2H), 1.31-1.41 (m, 4H). ¹⁹ F-NMR (DMSO-d ₆ , 376 MHz) δ -114.18 (s, 1F). EXAMPLE 6K Synthesis of (Z)-4-[(trans-4-aminocyclohexyl)amino]-N'-(2-ethyl-4-hydroxy -phenyl)-6-(1- methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: trans-tert-butyl N-[4-[[6-bromo-3-[(Z)-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2 -ethyl- phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate To a solution of (Z)-6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phe nyl]-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (200 mg, 393.7 μmol) and tert-butyl trans-N-(4- aminocyclohexyl)carbamate (126.5 mg, 590.6 μmol) in N,N-dimethylacetamide (2 mL) was added N,N-diisopropylethylamine (101.7 mg, 787.5 μmol). After stirring for an hour at 100 °C, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water (x2) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the titled compound as a yellow solid. Yield: 0.17 g, 62%. LCMS (ESI) m/z = 687.1 (M+H). Step 2: trans-tert-butyl N-[4-[[3-[(Z)-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-p henyl]- carbamimidoyl]-6-(1-methylpyrazol-4-yl)pyrrolo[1,2-b]pyridaz in-4-yl]amino]cyclohexyl]- carbamate To a solution of trans-tert-butyl N-[4-[[6-bromo-3-[(Z)-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2 - ethyl-phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclohexyl]carbamate (0.16 g, 233.3 μmol) in 1,4-dioxane (5 mL) and water (1.0 mL) were added 1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (48.5 mg, 233.3 μmol), potassium phosphate (148.6 mg, 700 μmol) and 1,1'-bis(di-t-butylphosphino)ferrocenepalladium dichloride (15.2 mg, 23.3 μmol). The mixture was stirred for 1 hour at 100 °C under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the titled compound as a yellow solid. Yield: 0.12 g, 62%. LCMS (ESI) m/z = 687.3 (M+H). Step 3: trans-tert-butyl N-[4-[[3-[(Z)-N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-6- (1-methyl- pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohexyl]c arbamate To a solution of trans-tert-butyl N-[4-[[3-[(Z)-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl- phenyl]carbamimidoyl]-6-(1-methylpyrazol-4-yl)pyrrolo[1,2-b] pyridazin-4- yl]amino]cyclohexyl]-carbamate (0.11 g, 160.1 μmol) in acetonitrile (10 mL) was added cesium fluoride (73 mg, 480.4 μmol). After stirring for 3 hours at 25 °C, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound as a yellow solid. Yield: 0.12 g, 86%. LCMS (ESI) m/z = 573.3 (M+H). Step 4: (Z)-4-[(trans-4-aminocyclohexyl)amino]-N'-(2-ethyl-4-hydroxy -phenyl)-6-(1-methyl- pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of trans-tert-butyl N-[4-[[3-[(Z)-N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-6- (1-methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyc lohexyl]carbamate (0.12 g, 138.3 μmol) in dichloromethane (5 mL) was added 2,2,2-trifluoroacetic acid (5 mL). After stirring for 2 hours at 25 °C, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded (Z)-4-[(trans-4-aminocyclohexyl)amino]-N'-(2-ethyl-4-hydroxy -phenyl)-6-(1- methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as a light-yellow solid. Yield: 22 mg, 32%. LCMS (ESI) m/z = 473.4 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.09-12.12 (m, 1H), 8.95 (s, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 7.87 (s, 1H), 7.78 (s, 1H), 6.90 (s, 1H), 6.56-6.67 (m, 3H), 5.87 (s, 2H), 3.97-4.21 (m, 2H), 3.87 (s, 3H), 2.60-2.74 (m, 1H), 2.45 (q, 2H, J=7.5 Hz), 2.11- 2.17 (m, 2H), 1.76-1.87 (m, 2H), 1.20-1.44 (m, 4H), 1.08 (t, 3H, J=7.5 Hz). EXAMPLE 6L Synthesis of ((Z)-4-(trans)-4(4-aminocyclohexyl)amino)-N'-(2-chlorophenyl )-6-(1-methyl-1H- pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboximidamide Step 1: (Z)-6-bromo-4-chloro-N'-(2-chlorophenyl)pyrrolo[1,2-b]pyrida zine-3-carboximidamide 2-Chloroaniline (278.8 mg, 2.1 mmol) and 6-bromo-4-chloro-pyrrolo[1,2-b]pyridazine-3- carboxamide (0.40 g, 1.46 mmol) were suspended in toluene (12 mL) in an oven-dried screw cap vial equipped with a stir bar. The mixture was stirred at 25 °C while trimethylaluminum (2 M in toluene, 2.19 mL, 4.38 mmol) was added dropwise via syringe over 6 min. After 5 min the mixture was warmed to 110 °C in a heating block. After stirring for 18 h the reaction mixture was cooled to room temperature. The mixture was diluted with ethyl acetate and stirred vigorously while water (50 mL) was slowly added. 1M aqueous Rochelle salt was added, the layers separated, and the aqueous phase extracted with ethyl acetate (x2). The combined organic material was washed with brine (1x), dried over magnesium sulfate, filtered, and the solvent removed in vacuo. Purification via silica gel chromatography (0 to 65 % ethyl acetate in heptanes) afforded the titled compound as a tan solid. Yield: 55 mg, 10 % LCMS (ESI) m/z = 387.1, 389.1 (M+H). Step 2: tert-butyl (trans)-4-((6-bromo-3-((Z)-N'-(2-chlorophenyl)carbamimidoyl) pyrrolo[1,2-b]- pyridazin-4-yl)amino)cyclohexyl)carbamate Trans-tert-butyl N-(4-aminocyclohexyl)carbamate (40.4 mg, 188.7 umol), 6-bromo-4-chloro-N'- (2-chlorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (29.0 mg, 75.5 umol), and N,N diisopropylethylamine (52.68 uL, 302.46 umol) were dissolved in DMF (2 mL) in an oven-dried screw cap vial equipped with a stir bar. The mixture was stirred at 75 °C for 2.5 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with a 1:1 brine:water solution (x2), and 100 % brine (x1). The organic phase was dried over magnesium sulfate, filtered, and solvent removed in vacuo. This afforded the titled compound as a yellow oil, contaminated with DMF solvent. Yield: 101 mg, 95 %. LCMS (ESI) m/z = 563.3, 565.3 (M+H). Step 3: tert-butyl ((trans)-4-((3-((Z)-N'-(2-chlorophenyl)carbamimidoyl)-6-(1-m ethyl-1H-pyrazol- 4-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)cyclohexyl)carbamate A bottle of anhydrous dioxane was purged with nitrogen gas for 30 min. 1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (0.041 g, 197.0 umol), tert-butyl N-[4-[[6-bromo-3- [(Z)-N'-(2-chlorophenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazi n-4-yl]amino]cyclohexyl]- carbamate (42.2 mg, 75.1 umol) and Pd(dtbpf)Cl ₂ (3.3 mg, 5.1 umol) were dissolved in aqueous potassium phosphate (1 M, 225.3 uL) and 1,4 dioxane (2.5 mL) in an oven-dried screw cap vial equipped with a stir bar. The mixture was purged with argon gas for 5 min and then the vial was sealed and heated to 80 °C for 2.5 h. More catalyst was added (17 mg) and the mixture heated for an additional 18 h. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and the aqueous phase extracted with ethyl acetate (x2). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded the titled compound as a tan solid in 50 % purity. Yield: 42.2 mg, 34 %. LCMS (ESI) m/z = 563.3 (M+H) Step 4: (Z)-4-(trans)-4-aminocyclohexyl)amino)-N'-(2-chloro-4-hydrox yphenyl)-6-(6-methoxy- pyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboximidamide tert-Butyl N-[4-[[3-[(Z)-N'-(2-chlorophenyl)carbamimidoyl]-6-(1-methylp yrazol-4- yl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohexyl]carbamate (0.022 g, 39.0 μmol) was dissolved in DCM (3 mL) in a vial equipped with a stir bar. It was stirred at room temperature and trifluoroacetic acid (0.3 mL) was added slowly via syringe. After stirring overnight, solvent was removed in vacuo. Purification via reverse-phase HPLC (5 to 35% acetonitrile in water buffered with formic acid) afforded the titled product as a tan solid. Yield 3.6 mg, 19 %. LCMS (ESI) m/z = 463.6 (M+H). ¹ H NMR (CHLOROFORM-d, 300 MHz) δ 8.1-8.2 (m, 2H), 8.00 (s, 1H), 7.90 (s, 1H), 7.76 (s, 1H), 7.47 (d, 1H, J=8.3 Hz), 7.28 (t, 1H, J=7.3 Hz), 7.0-7.1 (m, 2H), 6.90 (s, 1H), 6.34 (br s, 2H), 4.0-4.2 (m, 1H), 3.86 (s, 3H), 3.08 (br t, 3H, J=11.1 Hz), 2.1-2.3 (m, 2H), 1.98 (br d, 2H, J=10.6 Hz), 1.6-1.7 (m, 1H), 1.4-1.6 (m, 2H). EXAMPLE 6M Synthesis of N'-(4-amino-2-chlorophenyl)-4-((trans-4-aminocyclohexyl)amin o)-6-(1-methyl-1H- pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboximidamide Step 1: 3-chloro-N,N-bis(4-methoxybenzyl)-4-nitroaniline To a solution of 2-chloro-4-fluoro-1-nitro-benzene (3.00 g, 17.09 mmol) in dimethyl sulfoxide (5 mL) was added 1-(4-methoxyphenyl)-N-[(4-methoxyphenyl)methyl]methanamine (5.28 g, 20.51 mmol). After stirring for 12 hours at 80 °C, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the titled compound as a yellow solid. Yield: 4.20 g, 59 %. LCMS (ESI) m/z = 413.2 (M+H). Step 2: 3-chloro-N ¹ , N ¹ -bis(4-methoxybenzyl)benzene-1,4-diamine To a solution of 3-chloro-N,N-bis(4-methoxybenzyl)-4-nitroaniline (4.20 g, 10.17 mmol) in methanol (2 mL) were added zinc (5.32 g, 81.38 mmol) and ammonium chloride (4.35 g, 81.38 mmol). After stirring for an hour at 25 °C, the reaction mixture was filtered and washed with methanol. The filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a yellow solid. Yield: 2.40 g, 61%. LCMS (ESI) m/z = 383.1 (M+H). Step 3: N'-(4-(bis(4-methoxybenzyl)amino)-2-chlorophenyl)-6-bromo-4- chloropyrrolo[1,2-b]- pyridazine-3-carboximidamide To a mixture of 6-bromo-4-chloro-pyrrolo[1,2-b]pyridazine-3-carboxamide (150 mg, 546.4 μmol) and 3-chloro-N ¹ , N ¹ -bis(4-methoxybenzyl)benzene-1,4-diamine (313.8 mg, 819.7 μmol) in toluene (20 mL) was added trimethylaluminium (118.2 mg, 1.64 mmol). After stirring for 2 hours at 100 °C, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a yellow oil. Yield: 70 mg, 20%. LCMS (ESI) m/z = 640.3 (M+H). Step 4: tert-butyl (trans-4-((3-((Z)-N'-(4-(bis(4-methoxybenzyl)amino)-2-chloro phenyl)- carbamimidoyl)-6-bromopyrrolo[1,2-b]pyridazin-4-yl)amino)cyc lohexyl) carbamate To a solution of N'-(4-(bis(4-methoxybenzyl)amino)-2-chlorophenyl)-6-bromo-4- chloropyrrolo[1,2-b]pyridazine-3-carboximidamide (140 mg, 218.97 μmol) and (trans)-tert-butyl N-(4-aminocyclohexyl)carbamate (56.3 mg, 262.8 μmol) in N,N-dimethylacetamide (2 mL) was added N,N-diisopropylethylamine (84.9 mg, 656.9 μmol). After stirring for 1 hour at 80 °C, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a yellow oil. Yield: 120 mg, 67%. LCMS (ESI) m/z = 818.1 (M+H). Step 5: tert-butyl (trans-4-((3-(N'-(4-(bis(4-methoxybenzyl)amino)-2-chlorophen yl)- carbamimidoyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyr idazin-4-yl)amino)cyclohexyl)- carbamate To a solution of tert-butyl (trans-4-((3-((Z)-N'-(4-(bis(4-methoxybenzyl)amino)-2- chlorophenyl)carbamimidoyl)-6-bromopyrrolo[1,2-b]pyridazin-4 -yl)amino)cyclohexyl)- carbamate (120 mg, 146.8 μmol) in 1,4-dioxane (2 mL) and water (0.5 mL) were added 1-methyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (30.6 mg, 146.8 μmol), potassium phosphate (93.5 mg, 440.5 μmol) and1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (9.7 mg, 14.7 μmol). The resulting mixture was purged with nitrogen gas and stirred for an hour at 80 °C. After cooled to room temperature, the reaction mixture was filtered through a celite pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as yellow oil. Yield: 70 mg, 58%. LCMS (ESI) m/z = 818.5 (M+H). Step 6: N'-(4-amino-2-chlorophenyl)-4-((trans-4-aminocyclohexyl)amin o)-6-(1-methyl-1H- pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboximidamide To a solution of tert-butyl (trans-4-((3-(N'-(4-(bis(4-methoxybenzyl)amino)-2- chlorophenyl)carbamimidoyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrr olo[1,2-b]pyridazin-4-yl)amino)- cyclohexyl)carbamate (70 mg, 85.5 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (3.5 mL). After stirring for an hour at 25 °C, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-(4-amino-2-chlorophenyl)-4-((trans-4- aminocyclohexyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1 ,2-b]pyridazine-3- carboximidamide as a yellow solid. Yield: 14.2 mg, 33%. LCMS (ESI) m/z = 478.4 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.82-11.92 (m, 1H), 8.38 (s, 2H), 8.14 (s, 1H), 8.04 (s, 1H), 7.77- 7.88 (m, 2H), 7.01(s, 1H), 6.71-6.78 (m, 2H), 6.51-6.55 (m, 1H), 6.13 (s, 2H), 4.08-4.20 (m, 1H), 3.87 (s, 3H), 2.90-3.10 (m, 1H), 2.07-2.19 (m, 2H), 1.92-2.02 (m, 2H), 1.58-1.76 (m, 2H), 1.34- 1.47 (m, 2H). EXAMPLE 6N Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-4-hydroxy-ph enyl)-6-(1- methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt Step 1: (Z)-6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-ph enyl]-4-chloro-pyrrolo[1,2- b]-pyridazine-3-carboxamidine To a mixture of 6-bromo-4-chloro-pyrrolo[1,2-b]pyridazine-3-carboxamide (0.70 g, 2.55 mmol) and 4-((tert-butyldimethylsilyl)oxy)-2-chloroaniline (854.7 mg, 3.32 mmol) in toluene (15 mL) was added trimethylaluminium (3.8 mL, 2.0 M in Toluene, 7.6 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 30 minutes at room temperature and then heated to 100 °C for 6 hours. After cooling to room temperature, the resulting mixture was quenched with saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (x3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water 95:5) afforded the titled compound as a yellow solid. Yield: 0.63 g, 48%. LCMS (ESI) m/z = 515.3 (M+H). Step 2: tert-butyl N-[trans-4-[[6-bromo-3-[(Z)-N'-(2-chloro-4-hydroxy-phenyl)ca rbamimidoyl]- pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohexyl]carbamate To a solu tion of (Z)-6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-ph enyl]-4-chloro- pyrrolo[1,2-b] pyridazine-3-carboxamidine (0.70 g, 1.36 mmol) and trans-tert-butyl N-(4- aminocyclohexyl) carbamate (437.5 mg, 2.04 mmol) in N, N-dimethylacetamide (5 mL) was added N-ethyl-N-isopropyl-propan-2-amine (527.7 mg, 4.08 mmol). After stirring for 2 hours at 80 °C, the reaction mixture was cooled to room temperature and purified by reverse phase column chromatography (acetonitrile/water) to afford the titled compound as a yellow solid. Yield: 0.60 g, 68%. LCMS (ESI) m/z = 579.1 (M+H). Step 3: tert-butyl N-[trans-4-[[3-[(Z)-N'-(2-chloro-4-hydroxy-phenyl)carbam imidoyl]-6-(1- methyl-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclo hexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[(Z)-N'-(2-chloro-4-hydroxy-phenyl) carbamimidoyl] pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohexyl]carbamate (0.18 g, 311.47 μmol) in 1,4-dioxane (10 mL) and water (1 mL) were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazole (77.8 mg, 374 μmol), potassium phosphate (198 mg, 934 μmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (20.3 mg, 31.2 μmol). The resulting mixture was stirred for an hour at 100 °C under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was diluted with ethyl acetate (100 mL) and filtered through a celite pad. The filtrate was washed with brine, dried over anhydrous sodium sulfate filtered, and then concentrated under reduced pressure to afford the titled compound as a yellow solid. Yield: 0.12 g, 55%. LCMS (ESI) m/z = 579.2 (M+H) Step 4: (Z)-4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-4-hydrox y-phenyl)-6-(1-methyl- pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt To a solution of tert-butyl N-[trans-4-[[3-[(Z)-N'-(2-chloro-4-hydroxy-phenyl)carbamimid oyl]-6- (1-methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyc lohexyl]carbamate (0.14 g, 200.7 μmol) in dichloromethane (3 mL) was added 2,2,2-trifluoroacetic acid (1 mL). After stirring for 2 hours at 25 °C, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-[(trans-4- aminocyclohexyl)amino]-N'-(2-chloro-4-hydroxy-phenyl)-6-(1-m ethylpyrazol-4-yl)pyrrolo[1,2- b]pyridazine-3-carboxamidine as a yellow solid. Yield: 48.9 mg, 46%. LCMS (ESI) m/z = 479.4 (M+H). ¹ H NMR (DMSO-d6+D2O, 300 MHz) δ 8.15 (s, 0.4H), 7.92-8.14 (m, 3H), 7.72-7.79 (m, 1H), 7.41-7.50 (m, 1H), 7.18-7.25 (m, 1H), 7.06 (s, 1H), 6.90-6.93 (m, 1H), 3.86 (s, 3H), 3.70- 3.80 (m, 1H), 2.96-3.09 (m, 1H), 1.95-2.13 (m, 4H), 1.31-1.59 (m, 4H). EXAMPLE 6O Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-6-[1-(2-aminoethyl)pyrazo l-4-yl]-N'-(2-chloro- 4-hydroxy-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: trans-tert-butyl N-[2-[4-[4-[[4-(tert-butoxycarbonylamino) cyclohexyl]amino]-3-[N'-(2- chloro-4-hydroxy-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazi n-6-yl]pyrazol-1-yl]ethyl]- carbamate To a mixture of trans-tert-butyl N-[4-[[6-bromo-3-[(Z)-N'-(2-chloro-4-hydroxy-phenyl)- carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohexyl] carbamate (450 mg, 778.4 μmol) and tert-butyl N-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol -1-yl]ethyl]-carbamate (175 mg, 519.0 μmol) in 1,4-dioxane (4 mL) and water (0.8 mL) were added 1,1'-bis (di-t- butylphosphino)ferrocene palladium dichloride (33.8 mg, 51.9 μmol) and potassium phosphate (330.5 mg, 1.56 mmol). The resulting mixture was stirred for 2 hours at 100 °C under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a light yellow solid. Yield: 160 mg. 72%. LCMS (ESI) m/z = 708.2 (M+H). Step 2: 4-[(trans-4-aminocyclohexyl)amino]-6-[1-(2-aminoethyl)pyrazo l-4-yl]-N'-(2-chloro-4- hydroxy-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of trans-tert-butyl N-[2-[4-[4-[[4-(tert-butoxycarbonylamino)cyclohexyl]amino]-3 - [N'-(2-chloro-4-hydroxy-phenyl)carbamimidoyl]pyrrolo[1,2-b]p yridazin-6-yl]pyrazol-1- yl]ethyl]-carbamate (160 mg, 225.9 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). After stirring for an hour at room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-[(trans-4-aminocyclohexyl)amino]-6-[1-(2-aminoethyl)pyrazo l-4- yl]-N'-(2-chloro-4-hydroxy-phenyl)pyrrolo[1,2-b]pyridazine-3 -carboxamidine as a light-yellow solid. Yield: 67.0 mg, 57%. LCMS (ESI) m/z = 508.2 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.34 (s, 1H), 10.55 (s, 1H), 9.72 (s, 1H), 8.89 (s, 1H), 7.85-8.20 (m, 7H), 7.42-7.48 (m, 1H), 7.31 (s, 1H), 6.85-7.11 (m, 3H), 4.38 (t, 2H, J=6.0 Hz), 3.58-3.68 (m, 1H), 3.24-3.29 (m, 2H), 2.97-3.08 (m, 1H), 1.90-2.10 (m, 4H), 1.30-1.62 (m, 4H). EXAMPLE 6P Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-4-hydroxy-ph enyl)-6-(6- methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt Step 1: tert-butyl N-[trans-4-[[3-[(Z)-N'-(2-chloro-4-hydroxy-phenyl)carbam imidoyl]-6-(6- methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohe xyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[(Z)-N'-(2-chloro-4-hydroxy-phenyl) carbamimidoyl] pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohexyl]carbamate (0.18 g, 311.5 μmol) in 1,4-dioxane (10 mL) and water (1 mL) were added 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (87.9 mg, 373.8 μmol), potassium phosphate (198.3 mg, 934.4 μmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (20.3 mg, 31.2 μmol). The mixture was stirred for an hour at 100 °C under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered through a celite pad. The filtrate was washed with brine, dried over anhydrous sodium sulfate and filtered, then concentrated under reduced pressure to afford the titled compound as a yellow solid. Yield: 0.15 g, 58%. LCMS (ESI) m/z = 606.1(M+H). Step 2: 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-4-hydroxy-ph enyl)-6-(6-methoxy-3- pyridyl)-pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt To a solution of tert-butyl N-[trans-4-[[3-[(Z)-N'-(2-chloro-4-hydroxy-phenyl)carbamimid oyl]-6- (6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (0.15 g, 183.1 μmol) in dichloromethane (10 mL) was added 2,2,2-trifluoroacetic acid (3 mL). After stirring for 2 hours at 25°C, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-[(trans-4- aminocyclohexyl)amino]-N'-(2-chloro-4-hydroxy-phenyl)-6-(6-m ethoxy-3-pyridyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine as a yellow solid. Yield: 37.5 mg, 36%. LCMS (ESI) m/z = 506.4 (M+H). ¹ H NMR (DMSO-d6+D2O, 300 MHz) δ 8.59 (m, 1H), 8.32 (m, 1H), 8.15 (s, 0.4H), 8.06- 8.09 (m, 1H), 7.97 (m, 1H), 7.45-7.49 (m, 2H), 7.09 (m, 1H), 6.90-6.97 (m, 2H), 3.89 (s, 3H), 3.70- 3.80 (m, 1H), 2.96-3.10 (m, 1H), 2.01-2.09 (m, 4H), 1.43-1.63 (m, 4H). EXAMPLES 6Q – 6FF Compounds 6Q – 6FF were prepared according to the methods described in the previous examples and synthetic schemes from the correspondingly appropriate starting materials. Structure, name and analytical characterization of these compounds are presented below.

EXAMPLE 7 COMPOUNDS OF FORMULA (I) WHEREIN X IS NH, B IS DISUBSTITUTED CYCLOHEXANE EXAMPLE 7A Synthesis of 4-[[(2R)-3-amino-2-methyl-cyclohexyl]amino]-N'-(2-ethyl-4-hy droxy-phenyl)-6-(6- methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt Step 1: 6-vinyltetrahydropyran-2-ol To a stirred solution of pentanedial (15 g, 149.83 mmol, 14.15 mL) in THF (150 mL) was added bromo(vinyl)magnesium (19.67 g, 149.83 mmol) dropwise at 0 °C for 2 h. The reaction was quenched with ammonium chloride aqueous at 0 °C. The resulting mixture was extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column (petroleum ether/ethyl acetate, 4:1) afforded the titled compound. Yield: 4 g, 21%. Step 2: Synthesis of 2-methyl-N-(6-vinyltetrahydropyran-2-yl)propane-2-sulfinamid e To a stirred mixture of 6-vinyltetrahydropyran-2-ol (4 g, 31.21 mmol) and 2-methylpropane-2- sulfinamide (3.78 g, 31.21 mmol) in DCM (40 mL) was added cesium carbonate (15.25 g, 46.81 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was heated at 40°C for 3 h. After cooled to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate (x2). The combined organic extracts were washed with brine (x2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column (petroleum ether/ethyl acetate, 4:1-1:1) afforded the titled compound. Yield: 3.8 g, 52%. Step 3: 2-methyl-N-[(2R)-2-methyl-3-oxo-cyclohexyl]propane-2-sulfina mide Lithium triethylborohydride (16 mL, 1.64 mmol) was added dropwise over 5 mins to a stirred solution of NiCl2(dppe) (867.5 mg, 1.64 mmol) in THF (40 mL) at room temperature, under nitrogen atmosphere. Magnesium bromide (302.3 mg, 1.64 mmol) was added at room temperature and the mixture then cooled to -50°C. 2-methyl-N-(6-vinyltetrahydropyran-2-yl)propane-2- sulfinamide (3.8 g, 16.43 mmol) was added at -50°C, and the reaction warmed to room temperature. After stirring for 16 h, the reaction was quenched with water at room temperature and extracted with ethyl acetate (x2). The combined organic extracts were washed with brine (x2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column (petroleum ether/ethyl acetate, 1:1-3:7) afforded the titled compound. Yield: 1.1 g, 29%. LCMS (ESI) m/z = 232.0 (M+H). Step 4: N-[(2S)-3-amino-2-methyl-cyclohexyl]-2-methyl-propane-2-sulf inamide To a stirred solution of 2-methyl-N-[(2R)-2-methyl-3-oxo-cyclohexyl]propane-2-sulfina mide (400 mg, 1.73 mmol) in methanol (6 mL) was added ammonium acetate (665.7 mg, 8.64 mmol) at room temperature under nitrogen atmosphere over 5 mins. The mixture was heated at 50 °C for 30 mins and then cooled to 0°C. Sodium cyanoborohydride (326.8 mg, 5.19 mmol) was added at 0°C. The mixture was warmed to room temperature and stirred for 3 h. After quenched with water at room temperature, the resulting mixture was extracted with ethyl acetate three times. The combined organic layers were washed with brine twice, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column (dichloromethane/methanol, 17:3) afforded the titled compound as a clear solid. Yield: 130 mg, 32%. LCMS (ESI) m/z = 233.0 (M+H). Step 5: 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[(2S)-3-(tert-butyl- sulfinylamino)-2-methyl-cyclohexyl]amino]pyrrolo[1,2-b]pyrid azine-3-carboxamidine 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro-pyrrolo[1,2-b]pyridazine- 3-carboxamidine (90 mg, 177.2 umol) was suspended in DMA (2 mL). N-[(2S)-3-amino-2-methyl- cyclohexyl]-2-methyl-propane-2-sulfinamide (164.7 mg, 708.8 umol) and DIEA (68.6 mg, 531.6 umol) were added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 85°C for 16 h. After cooling to room temperature, the reaction mixture was purified via reversed phase column (acetonitrile/water, 100%) to afford the titled compound as a yellow oil. Yield: 70 mg, 56%. LCMS (ESI) m/z = 705.0 (M+H). Step 6: N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylphenyl)-4-(((2S) -3-((tert-butylsulfinyl)amino)- 2-methylcyclohexyl)amino)-6-(6-methoxypyridin-3-yl)pyrrolo[1 ,2-b]pyridazine-3- carboximidamide To a stirred solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[(2S)-3- (tert-butylsulfinylamino)-2-methyl-cyclohexyl]amino]pyrrolo[ 1,2-b]pyridazine-3-carboxamidine (83.9 mg, 119.1 umol) in 1,4-dioxane (2 mL) and water (0.5 mL) were added tripotassium phosphate (75 mg, 353.8 umol), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (56 mg, 238.2 umol) and Pd(dtbpf)Cl2 (7.8 mg, 12.0 umol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 1 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by TLC (dichloromethane/ methanol, 10:1) afforded the titled compound as an off-white solid. Yield: 50 mg, 57 %. LCMS (ESI) m/z = 732.2 (M+H). Step 7: 4-[[(2R)-3-amino-2-methyl-cyclohexyl]amino]-N'-(2-ethyl-4-hy droxy-phenyl)-6-(6- methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt To a stirred solution of N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylphenyl)-4-(((2S) -3-((tert- butylsulfinyl)amino)-2-methylcyclohexyl)amino)-6-(6-methoxyp yridin-3-yl)pyrrolo[1,2-b]- pyridazine-3-carboximidamide (59.4 mg, 81.2 umol) in DMF (4 mL) and water (1 mL) was added cesium carbonate (7.9 mg, 24.4 umol) at room temperature under nitrogen atmosphere. After stirring for 16 h, the reaction was quenched with water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in DCM (4 mL) and hydrogen chloride in dioxane (2 mL) was added at room temperature and stirred for 1 h. The reaction was quenched with sat. sodium bicarbonate and extracted with ethyl acetate (x3). The combined organic extracts were washed with brine (x2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-[[(2R)-3-amino-2-methyl- cyclohexyl]amino]-N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy -3-pyridyl)-pyrrolo[1,2- b]pyridazine-3-carboxamidine formic acid salt as an off-white solid. Yield: 9.1 mg, 22 %. LCMS (ESI) m/z = 514.2 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.50 (brs, 1H), 8.65 (s, 1H), 8.12- 8.28 (m, 4H), 7.32 (s, 1H), 6.87-6.90 (m, 1H), 6.69 (s, 1H), 6.61 (s, 2H), 5.88 (brs, 2H), 4.68-4.73 (m, 1H), 3.89 (s, 3H), 2.72-2.81 (m, 1H), 2.41 (q, 2H, J=7.6 Hz), 2.08-2.22 (m, 1H), 1.23-1.91 (m, 8H), 1.06-1.10 (m, 3H), 1.01 (d, 3H, J=6.8 Hz). EXAMPLE 8 COMPOUNDS OF FORMULA (I) WHEREIN X IS NH, B IS CYCLOHEPTANE Synthesis of 4-(cycloheptylamino)-N'-(2-ethyl-4-hydroxy-phenyl)-6-phenyl- pyrrolo[1,2- b]pyridazine-3-carboxamidine Step 1: 6-bromo-N'-(4-(tert-butyl(dimethyl)silyl)oxy-2-ethyl-phenyl) -4-(cycloheptylamino)- pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-(4-(tert-butyl(dimethyl)silyl)oxy-2-ethyl-phenyl) -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (100 mg, 196.9 μmol) and cycloheptanamine (33.4 mg, 295.3 μmol) in N,N-dimethylacetamide (2 mL) was added N-ethyl-N-isopropyl-propan-2-amine (76.3 mg, 590.6 μmol). After stirring for 1 hour at 100 °C, the resulting mixture was cooled to room temperature and purified by reverse phase chromatography (acetonitrile/water) to afford the titled compound as a yellow solid. Yield: 100 mg, 86%. LCMS (ESI) m/z = 586.1 (M+H). Step 2: N'-(4-(tert-butyl(dimethyl)silyl)oxy-2-ethyl-phenyl)-4-(cycl oheptylamino)-6-phenyl- pyrrolo[1,2-b]pyridazine-3-carboxamidine To a mixture of 6-bromo-N'-(4-(tert-butyl(dimethyl)silyl)oxy-2-ethyl-phenyl) -4- (cycloheptylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidine (100 mg, 171.0 μmol), phenylboronic acid (20.9 mg, 171.0 μmol) and potassium phosphate (108.9 mg, 513.1 μmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was added [1,1'-bis(di-t-butylphosphino)ferrocene]- palladium(II) dichloride (11.3 mg, 17.1 μmol). The mixture was stirred for 0.8 hour at 120 °C under nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated under reduced pressure and the resulting residue diluted with water and extracted with ethyl (x2). The combined organic extracts were washed with brine (x2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the titled compound as a yellow solid. Yield: 80 mg, 80%. LCMS (ESI) m/z = 582.3 (M+H). Step 3: 4-(cycloheptylamino)-N'-(2-ethyl-4-hydroxy-phenyl)-6-phenyl- pyrrolo[1,2-b]pyridazine- 3-carboxamidine To a solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-(cycl oheptylamino)-6- phenyl-pyrrolo[1,2-b]pyridazine-3-carboxamidine (120 mg, 206.2 umol) in N,N- dimethylformamide (2 mL) was added cesium fluoride (94 mg, 618.7 umol). After stirring for 15 hours at 20 °C, the resulting mixture was filtered through a Celite pad. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-(cycloheptylamino)-N'-(2-ethyl-4-hydroxy-phenyl)-6-phenyl- pyrrolo[1,2- b]pyridazine-3-carboxamidine as a yellow solid. Yield: 34.7 mg, 35%. LCMS (ESI, pos. ion) m/z: 468.2 (M+1). ¹ H-NMR (300 MHz, DMSO-d6, ppm) δ 12.20 (s, 1H), 8.11-8.21 (m, 2H), 7.73-7.83 (m, 2H), 7.41 (t, 2H, J=7.6 Hz), 7.15-7.30 (m, 2H), 6.55-6.73 (m, 3H), 5.90 (s, 2H), 4.49 (s, 1H), 2.44 (q, 2H, J=7.5 Hz), 2.03-2.16 (m, 2H), 1.45-1.75 (m, 10H), 1.09 (t, 3H, J=7.5 Hz). EXAMPLE 9 COMPOUNDS OF FORMULA (I) WHEREIN X IS NH, B IS UNSUBSTITUTED ADAMANTANE Synthesis of 4-(2-adamantylamino)-N'-(4-hydroxy-2-methyl-phenyl)-6-(6-met hoxy-3- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: 4-[tert-butyl(dimethyl)silyl]oxy-2-methyl-aniline To a solution of 4-amino-3-methylphenol (3.00 g, 24.4 mmol) and imidazole (4.15 g, 60.9 mmol) in N,N-dimethylformide (30 mL) was added tert-butyldimethylsilyl chloride (4.41 g, 29.2 mmol). After stirring for 15 hours at room temperature, the reaction mixture was quenched with an aqueous solution of ammonium chloride and extracted with ethyl acetate (x3). The combined organic layers were washed with brine (x2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a brown oil. Yield: 4.20 g, 73%. LCMS (ESI) m/z = 238.4 (M+H). Step 2: 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-methyl-phenyl ]-4-chloro-pyrrolo[1,2-b]- pyridazine-3-carboxamidine 4-[tert-Butyl(dimethyl)silyl]oxy-2-methyl-aniline (285.4 mg, 1.2 mmol) and 6-bromo-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamide (300 mg, 1.09 mmol) were suspended in toluene (5 mL) in a screw cap vial equipped with a stir bar. Trimethylaluminum (1 M in toluene, 3.3 mL) was added dropwise via syringe at 0 °C and the mixture stirred for 5 minutes at 0 °C and then heated to 110 °C for 15 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with saturated Rochelle salt. The aqueous phase was extracted with ethyl acetate (x3) and the combined organic extracts washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as yellow oil. Yield: 490 mg, 91%. LCMS (ESI) m/z = 493.1 (M+H). Step 3: 4-(2-adamantylamino)-6-bromo-N'-[4-[tert-butyl(dimethyl)sily l]oxy-2-methyl-phenyl]- pyrrolo[1,2-b]pyridazine-3-carboxamidine 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-methyl-phenyl ]-4-chloro-pyrrolo[1,2-b]- pyridazine-3-carboxamidine (490 mg, 0.99 mmol), adamantan-2-amine hydrochloride salt (319 mg, 1.19 umol), N-ethyl-N, N-diisopropylamine (383 mg, 2.97 mmol, 526 uL) and N,N- dimethylacetamide (10.0 mL) were heated for 2 hours at 100 °C The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and washed with brine (x2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a yellow gum. Yield: 515 mg, 71%. LCMS (ESI) m/z = 608.2 (M+H). Step 4: 4-(2-adamantylamino)-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2- methyl-phenyl]-6-(6- methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 4-(2-adamantylamino)-6-bromo-N'-[4-[tert-butyl(dimethyl)sily l]oxy-2-methyl- phenyl]pyrrolo[1,2-b]pyridazine-3-carboxamidine (500 mg, 0.82 mmol) in 1,4-dioxane (6.0 mL) and water (0.6 mL) were added (6-methoxy-3-pyridyl)boronic acid (150 mg, 0.98 mmol), diacetoxypalladium (9.2 mg, 41.1 umol), dicyclohexyl-[2-(2,4,6-triisopropylphenyl)- phenyl]phosphane (39.2 mg, 82.1 umol) and potassium phosphate (523 mg, 2.46 mmol). The resulting mixture was stirred for 2 hours at 100 °C under argon. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with brine (x2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a yellow solid. Yield: 356 mg, 68%. LCMS (ESI) m/z = 637.7 (M+H). Step 5: 4-(2-adamantylamino)-N'-(4-hydroxy-2-methyl-phenyl)-6-(6-met hoxy-3-pyridyl)pyrrolo- [1,2-b]pyridazine-3-carboxamidine To a solution of 4-(2-adamantylamino)-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2- methyl-phenyl]-6- (6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidin e (300 mg, 471.0 umol) in N,N- dimethylformide (5.0 mL) was added cesium fluoride (143.1 mg, 942.1 umol). After stirring for 2 hours at room temperature, the reaction mixture was filtered and the filtrate concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-(2-adamantylamino)-N'-(4-hydroxy-2- methyl-phenyl)-6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazi ne-3-carboxamidine as a yellow solid. Yield: 36.2 mg, 14%. LCMS (ESI) m/z = 523.2 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 12.70 (d, 1H, J=8.4 Hz), 8.91 (s, 1H), 8.61 (s, 1H), 8.06-8.22 (m, 3H), 7.04 (s, 1H), 6.88 (d, 1H, J=8.4 Hz), 6.56-6.65 (m, 3H), 5.87 (s, 2H), 4.52 (d, 1H, J=7.8 Hz), 3.88 (s, 3H), 2.08-2.03 (m, 4H), 1.93-1.97 (m, 3H), 1.82-1.87 (m, 5H), 1.60-1.78 (m, 3H), 1.45-1.53 (m, 2H). EXAMPLE 10 COMPOUNDS OF FORMULA (I) WHEREIN X IS NH, B IS SUBSTITUTED ADAMANTANE Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-4-((5-hydroxy-2-adamantyl)amin o)pyrrolo[1,2- b]pyridazine-3-carboxamidine Step 1: 6-bromo-N'-(4-(tert-butyl(dimethyl)silyl)oxy-2-ethyl-phenyl) -4-((5-hydroxy-2- adamantyl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-(4-(tert-butyl(dimethyl)silyl)oxy-2-ethyl-phenyl) -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (150 mg, 295.3 μmol) and 4-aminoadamantan-1-ol (49.4 mg, 295.3 μmol) in N,N-dimethylacetamide (2 mL) was added N-ethyl-N-isopropyl-propan- 2-amine (114.5 mg, 886.0 μmol). After stirring for 2 hours at 110 °C, the resulting mixture was cooled to room temperature and purified by reverse phase chromatography (acetonitrile/water, 100%) to afford the titled compound as a white solid. Yield: 130 mg, 68%. LCMS (ESI) m/z = 638.0 (M+H). Step 2: N'-(4-(tert-butyl(dimethyl)silyl)oxy-2-ethyl-phenyl)-4-((5-h ydroxy-2-adamantyl)amino)- pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-(4-(tert-butyl(dimethyl)silyl)oxy-2-ethyl-phenyl) -4-((5-hydroxy-2- adamantyl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamidine (200 mg, 313.1 μmol) in methanol (3 mL) was added N,N-diethylethanamine (95.1 mg, 939.4 μmol), followed by addition of 5% palladium on active carbon (30 mg) under nitrogen atmosphere. After stirring for 4 hours at 20 °C under hydrogen atmosphere, the resulting mixture was filtered through a celite pad and washed with methanol. The filtrate was concentrated under reduced pressure to afford the titled compound as a yellow solid. Yield: 160 mg, 91%. LCMS (ESI) m/z = 560.0 (M+H). Step 3: N'-(2-ethyl-4-hydroxy-phenyl)-4-((5-hydroxy-2-adamantyl)amin o)pyrrolo[1,2-b]- pyridazine-3-carboxamidine To a solution of N'-(4-(tert-butyl(dimethyl)silyl)oxy-2-ethyl-phenyl)-4-((5-h ydroxy-2- adamantyl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamidine (140 mg, 250.1 umol) in N,N- dimethylformamide (3 mL) was added cesium fluoride (114 mg, 750.3 umol). After stirring for 4 hours at 20 °C, the resulting mixture was filtered through a celite pad. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-(2-ethyl-4-hydroxy-phenyl)-4-((5-hydroxy-2-adamantyl)amin o)pyrrolo-[1,2- b]pyridazine-3-carboxamidine as a light yellow solid. Yield: 37.6 mg, 33%. LCMS (ESI) m/z = 446.4 (M+H). ¹ H-NMR (DMSO-d6, 300 MHz) δ 12.70 (d, 1H, J=8.0 Hz), 8.91 (s, 1H), 8.19 (s, 1H), 7.62 (s, 1H), 6.64-6.70 (m, 3H), 6.55-6.60 (m, 2H), 5.82 (s, 2H), 4.49 (s, 1H), 4.29-4.34 (m, 1H), 2.39 (q, 2H , J = 7.5 Hz), 2.14-2.21 (m, 2H), 1.76-1.94 (m, 5H), 1.57-1.70 (m, 4H), 1.27-1.38 (m, 2H), 1.04 (t, 3H, J=7.5 Hz). EXAMPLE 10B Synthesis of N'-(2-chloro-5-fluoro-phenyl)-4-[(5-hydroxy-2-adamantyl)amin o]-6-(1H-pyrazol-4- yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: 6-bromo-N'-(2-chloro-5-fluoro-phenyl)-4-[(5-hydroxy-2-adaman tyl)amino]pyrrolo[1,2-b]- pyridazine-3-carboxamidine To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (130 mg, 49.8 μmol) and 4-aminoadamantan-1-ol (81.1 mg, 74.6 μmol) in N,N- dimethylacetamide (2 mL) was added N-ethyl-N-isopropyl-propan-2-amine (125.4 mg, 970.2 μmol). After stirring for 2 hours at 80 °C, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as an off-white solid. Yield: 130 mg, 72%. LCMS (ESI) m/z = 533.8 (M+H) Step 2: N'-(2-chloro-5-fluoro-phenyl)-4-[(5-hydroxy-2-adamantyl)amin o]-6-(1-tetrahydropyran- 2-ylpyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a mixture of 6-bromo-N'-(2-chloro-5-fluoro-phenyl)-4-[(5-hydroxy-2-adaman tyl)amino]- pyrrolo[1,2-b]pyridazine-3-carboxamidine (130 mg, 244.0 μmol) and 1-tetrahydropyran-2-yl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (101.8 mg, 366.0 μmol) in 1,4-dioxane (2 mL) and water (0.4 mL) were added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (15.9 mg, 24.4 μmol) and potassium phosphate (155.4 mg, 731.9 μmol). The resulting mixture was stirred for 2 hours at 90 °C under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a yellow solid. Yield: 100 mg, 62%. LCMS (ESI) m/z = 604.2 (M+H). Step 3: N'-(2-chloro-5-fluoro-phenyl)-4-[(5-hydroxy-2-adamantyl)amin o]-6-(1H-pyrazol-4-yl)- pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of N'-(2-chloro-5-fluoro-phenyl)-4-[(5-hydroxy-2-adamantyl)amin o]-6-(1- tetrahydropyran-2-ylpyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3- carboxamidine (90 mg, 168.6 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.5 mL) at 0 °C. After stirring for 1 hour at 25 °C, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-(2-chloro-5-fluoro-phenyl)-4-[(5-hydroxy-2-adamantyl)amin o]-6-(1H- pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as an off-white solid. Yield: 15 mg, 19%. LCMS (ESI) m/z = 520.4 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 12.83 (s, 1H), 11.74 (d, 1H, J=7.5 Hz), 8.20 (s, 1H), 8.03-8.13 (m, 1H), 7.78-7.96 (m, 2H), 7.43-7.54 (m, 1H), 6.82-6.95 (m, 3H), 6.45 (s, 2H), 4.49 (s, 1H), 4.40 (d, 1H, J=7.5 Hz), 2.15-2.24 (m, 2H), 1.79-2.03 (m, 5H), 1.57- 1.71 (m, 4H), 1.27-1.38 (m, 2H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -114.58 (s, 1F). EXAMPLE 10C Synthesis of N'-(2-chloro-4-hydroxy-phenyl)-4-[(5-hydroxy-2-adamantyl)ami no]-6-(1H-pyrazol- 4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: N'-[4-[tert-butyl(dimethyl)silyl] oxy-2-chloro-phenyl]-4-[(5-hydroxy-2-adamantyl) amino]-6-(1-tetrahydropyran-2-ylpyrazol-4-yl) pyrrolo[1,2-b] pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-phenyl ]-4-[(5-hydroxy-2- adamantyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine (90 mg, 139.5 μmol) in 1,4-dioxane (3 mL) and water (0.6 mL) were added 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazole (77.6 mg, 279 μmol), potassium phosphate (88.8 mg, 418.5 μmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (9.1 mg, 14 μmol). The resulting mixture was stirred for 2 hours at 100 °C under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the titled compound as a yellow solid. Yield: 60 mg, 54%. LCMS (ESI) m/z = 716.2 (M+H). Step 2: N'-(2-chloro-4-hydroxy-phenyl)-4-[(5-hydroxy-2-adamantyl)ami no]-6-(1H-pyrazol-4-yl)- pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-phenyl]-4-[(5- hydroxy-2- adamantyl) amino]-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)pyrrolo[1,2-b]p yridazine-3- carboxamidine (55 mg, 76.8 μmol) in 1,4-dioxane (2 mL) was added 2 mL of 1N hydrochloric acid aqueous solution. After stirring for 3 hours at 25 °C, the reaction mixture was adjusted to pH=8 with saturated aqueous solution of sodium bicarbonate, then dilute with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-(2-chloro-4- hydroxy-phenyl)-4-[(5-hydroxy-2-adamantyl)amino]-6-(1H-pyraz ol-4-yl)pyrrolo[1,2- b]pyridazine-3-carboxamidine as a light-yellow solid. Yield: 4.1 mg, 10%. LCMS (ESI) m/z = 518.4 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.84 (s, 1H), 12.19-12.23 (m, 1H), 9.43 (s, 1H), 8.00-8.17 (m, 2H), 7.75-7.95 (m, 2H), 6.80-6.87 (m, 3H), 6.70-6.74 (m, 1H), 6.11 (s, 2H), 4.50 (s, 1H), 4.34-4.40 (m, 1H), 2.16-2.25 (m, 2H), 1.86-1.98 (m, 5H), 1.62-1.68 (m, 4H), 1.30-1.35 (m, 2H). EXAMPLE 10D Synthesis of (Z)-4-(((1R,2s,3S,5s,7s)-5-hydroxyadamantan-2-yl)amino)-6-(1 -methyl-1H-pyrazol- 4-yl)-N'-phenylpyrrolo[1,2-b]pyridazine-3-carboximidamide Step 1: 6-bromo-4-chloro-N'-phenyl-pyrrolo[1,2-b]pyridazine-3-carbox amidine Aniline (67.8 mg, 728 umol, 66 uL) and 6-bromo-4-chloro-pyrrolo[1,2-b]pyridazine-3- carboxamide (0.1 g, 364 umol) were suspended in toluene (3 mL) in an oven-dried screw cap vial equipped with a stir bar. The mixture was stirred at 0 °C while trimethylaluminum (2 M, 544 uL) was added dropwise via syringe. After 5 min the mixture was warmed to room temperature and then heated to 110 °C in a heating block. After 2.5 h the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 1M aqueous Rochelle salt (x1), saturated aqueous sodium bicarbonate (x1), and brine (x1). The organic phase was dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purification via silica gel chromatography (0 to 65 % ethyl acetate in heptanes) afforded the titled compound as a yellow solid. Yield: 70.1 mg, 55 %. Step 2: 6-bromo-4-[(5-hydroxy-2-adamantyl)amino]-N'-phenyl-pyrrolo[1 ,2-b]pyridazine-3- carboxamidine

4-Aminoadamantan-l-ol (48.7 mg, 239.4 umol) and 6-bromo-4-chloro-N'-phenyl-pyrrolo[l,2- b]pyridazine-3-carboxamidine (0.070 g, 191.5 umol) were dissolved in DMF (3 mL) in an oven- dried screw cap vial equipped with a stir bar. Diisopropylamine (74.2 mg, 574.7 umol, 100 uL) was added and the mixture stirred at 95 °C in a heating block for 1 hour and then cooled to room temperature. Cold water was added and the solids filtered, washed with water, and dried under vacuum to afford the titled compound as a tan solid. Yield: 95 mg, 98 %. LCMS (ESI) m/z = 482.1 (M+H).

Step 3: (Z)-4-(((lR,2s,3S,5s,7s)-5-hydroxyadamantan-2-yl)amino)-6-(l -methyl-lH-pyrazol-4-yl)-

N'-phenylpyrrololL2-b1pyridazine-3-carboximidamide

A bottle of anhydrous 1,4 dioxane was purged with nitrogen gas for 30 min. l-methyl-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (49.3 mg, 237.3 umol), 6-bromo-4-[(5-hydroxy-2- adamantyl)amino]-N'-phenyl-pyrrolo[l,2-b]pyridazine-3-carbox amidine (0.03 g, 79.1 umol), and Pd(dtbpf)C12 (2.5 mg, 3.9 umol) were dissolved in aqueous potassium phosphate (1 M, 237 uL) and 1,4 dioxane (1.2 mL) in an oven-dried screw cap vial equipped with a stir bar. The mixture was purged with argon gas for 2 min and then sealed and heated to 80 °C for 90 min. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and 1 : 1 brine:water and extracted with ethyl acetate (x3). The solids were filtered and the filtrate dried over magnesium sulfate, filtered, and solvent removed in vacuo. This residue was combined with the solids isolated via filtration and taken up in DMSO. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded (Z)-4-(((lR,2s,3S,5s,7s)-5-hydroxyadamantan-2- yl)amino)-6-(l-methyl-lH-pyrazol-4-yl)-N'-phenylpyrrolo[l,2- b]-pyridazine-3-carboximidamide as a tan solid. Yield: 10 mg, 26 %. LCMS (ESI) m/z = 483.4 (M+H). 'H NMR (DMSO-d ₆ , 300 MHz) 8 12.26 (br d, 1H, J=8.4 Hz), 8.20 (s, 1H), 8.04 (s, 1H), 7.88 (s, 1H), 7.78 (s, 1H), 7.35 (t, 2H, J=7.7 Hz), 7.04 (t, 1H, J=7.3 Hz), 6.93 (d, 2H, J=7.7 Hz), 6.83 (s, 1H), 6.15 (br s, 2H), 4.51 (br s, 1H), 4.41 (br d, 1H, J=7.7 Hz), 3.87 (s, 3H), 2.19 (br s, 2H), 1.8-2.0 (m, 4H), 1.6-1.7 (m, 4H), 1.37 (br d, 2H, J=12.8 Hz). EXAMPLE 10E Synthesis of N'-(4-aminophenyl)-4-((5-hydroxy-2-adamantyl)amino)-6-(6-met hoxy-3- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: N, N-bis((4-methoxyphenyl)methyl)-4-nitro-aniline To a solution of 1-fluoro-4-nitro-benzene (3.00 g, 21.26 mmol) and 1-(4-methoxyphenyl)-N-[(4- methoxyphenyl)methyl]methanamine (6.57 g, 25.51 mmol) in DMF (20.0 mL) was added N-ethyl- N-isopropyl-propan-2-amine (6.87 g, 53.15 mmol, 9.26 mL). After stirring for 24 hours at 120 °C, the reaction mixture was cooled to room temperature, diluted with brine and extracted with ethyl acetate (x2). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a yellow solid. Yield: 3.50 g, 44%. LCMS (ESI) m/z = 379.1 (M+H). Step 2: N ¹ , N ¹ -bis((4-methoxyphenyl)methyl)benzene-1,4-diamine To a solution of N, N-bis((4-methoxyphenyl)methyl)-4-nitro-aniline (5.50 g, 14.53 mmol) in a mixture of ethanol (20.0 mL), tetrahydrofuran (20.0 mL) and water (20.0 mL) were added iron (4.06 g, 72.67 mmol) and ammonium chloride (7.77 g, 145.34 mmol). After stirring for 2 hours at 80 °C, the reaction mixture was cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate (x2). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a brown oil. Yield: 3.50 g, 69%. LCMS (ESI) m/z = 349.1 (M+H). Step 3: N'-(4-(bis(4-methoxybenzyl)amino)phenyl)-6-bromo-4-chloropyr rolo[1,2-b]pyridazine-3- carboximidamide To a suspension of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (300 mg, 1.10 mmol) in toluene (5 mL) was added N ¹ , N ¹ -bis((4-methoxyphenyl)methyl)benzene-1,4-diamine (402.7 mg, 1.16 mmol). The resulting mixture was cooled to 0 °C, then trimethylaluminium (238.1 mg, 3.30 mmol) was added dropwise via syringe and stirred for 5 minutes at 0 °C under nitrogen atmosphere. After heating to 110 °C for 16 hours, the reaction mixture was cooled to room temperature, diluted with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (x3). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a light yellow solid. Yield: 147 mg, 22%. LCMS (ESI) m/z = 606.1 (M+H). Step 4: N'-(4-(bis((4-methoxyphenyl)methyl)amino)phenyl)-6-bromo-4-( (5-hydroxy-2- adamantyl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of N'-(4-(bis(4-methoxybenzyl)amino)phenyl)-6-bromo-4-chloropyr rolo[1,2- b]pyridazine-3-carboximidamide (250 mg, 423.1 μmol) and 4-aminoadamantan-1-ol (88.5 mg, 528.9 μmol) in N,N-dimethylacetamide (3 mL) was added N-ethyl-N-isopropyl-propan-2-amine (164.0 mg, 1.27 mmol). After stirring for 2 hours at 100 °C, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a yellow solid. Yield: 250 mg, 82%. LCMS (ESI) m/z = 735.3 (M+H). Step 5: N'-(4-(bis((4-methoxyphenyl)methyl)amino)phenyl)-4-((5-hydro xy-2-adamantyl)amino)- 6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamid ine To a mixture of N'-(4-(bis((4-methoxyphenyl)methyl)amino)phenyl)-6-bromo-4-( (5-hydroxy-2- adamantyl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamidine (250 mg, 339.8 μmol) and (6- methoxy-3-pyridyl)boronic acid (78 mg, 509.7 μmol) in 1,4-dioxane (2 mL) and water (0.4 mL) were added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (22.2 mg, 34.0 μmol) and potassium phosphate (306.2 mg, 1.02 mmol). The resulting mixture was stirred for 2 hours at 100 °C under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a yellow solid. Yield: 150 mg, 57%. LCMS (ESI) m/z = 764.9 (M+H). Step 6: N'-(4-aminophenyl)-4-((5-hydroxy-2-adamantyl)amino)-6-(6-met hoxy-3-pyridyl)pyrrolo- [1,2-b]pyridazine-3-carboxamidine N'-(4-(Bis((4-methoxyphenyl)methyl)amino)phenyl)-4-((5-hydro xy-2-adamantyl)amino)-6-(6- methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (130 mg, 155.3 μmol) was dissolved in trifluoroacetic acid (2 mL) and stirred for 0.5 hour at 50 °C. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-(4-aminophenyl)-4-((5-hydroxy-2-adamantyl)amino)-6-(6-met hoxy-3- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as a yellow solid. Yield: 27.7 mg, 26%. LCMS (ESI) m/z = 524.1 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.72 (d, 1H, J=8.1 Hz), 8.60 (d, 1H, J=2.1 Hz), 8.20 (s, 1H), 8.03-8.17 (m, 2H), 7.03 (d, 1H, J=1.6 Hz), 6.88 (d, 1H, J=8.7 Hz), 6.53- 6.68 (m, 4H), 6.00 (s, 2H), 4.79 (s, 2H), 4.42-4.50 (m, 2H), 3.88 (s, 3H), 2.15-2.23 (m, 2H), 1.85- 2.04 (m, 5H), 1.61-1.71 (m, 4H), 1.31-1.41 (m, 2H). EXAMPLE 10F Synthesis of ((Z)-N'-(2-ethyl-4-hydroxyphenyl)-4-(((1R,2r,3S,5s,7s)-5-hyd roxyadamantan-2- yl)amino)-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine- 3-carboximidamide Step 1: (Z)-6-bromo-N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylphen yl)-4-chloropyrrolo[1,2-b]- pyridazine-3-carboximidamide 4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-aniline (200.0 mg, 795.4 umol) and 6-bromo-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamide (0.2 g, 728.5 umol) were suspended in toluene (5 mL) in an oven-dried screw cap vial equipped with a stir bar. The mixture was stirred at 0 °C while trimethylaluminum (2 M, 1.09 mL) was added dropwise via syringe. After 5 min the mixture was warmed to room temperature and then heated to 110 °C in a heating block. After 20 h the reaction mixture was cooled to room temperature, diluted with ethyl acetate and water and extracted with ethyl acetate (x3) and washed with brine. The organic extracts were dried over magnesium sulfate, filtered, and the solvent removed in vacuo. Purification via silica gel chromatography (0 to 65 % ethyl acetate in heptanes) afforded the titled compound. Yield: 341 mg, 61 % yield, 66 % purity. LCMS (ESI) m/z = 509.7 (M+H) Step 2: (Z)-6-bromo-N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylphen yl)-4-(((1R,2s,3S,5s,7s)-5- hydroxyadamantan-2-yl)amino)pyrrolo[1,2-b]pyridazine-3-carbo ximidamide 4-aminoadamantan-1-ol (0.0242 g, 144.7 umol, S01) and 6-bromo-N'-[4-[tert-butyl- (dimethyl)silyl]oxy-2-ethyl-phenyl]-4-chloro-pyrrolo[1,2-b]p yridazine-3-carboxamidine (0.073 g, 94.86 umol) were dissolved in DMF (1.5 mL) in an oven-dried screw cap vial equipped with a stir bar. Diisopropylethylamine (36.7 mg, 284.5 umol, 49.5 uL) was added and the mixture stirred at room temperature for 2 min and then heated to 90°C in a heating block for 19 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with a 1:1 brine:water solution (x2) and 100 % brine (x1). The organic phase was dried over magnesium sulfate, filtered, and solvent removed in vacuo to afford the titled compound as a yellow solid. Yield: 48.5 mg, 81 %. LCMS (ESI) m/z = 638.6, 640.6 (M+H). Step 3: (Z)-N'-(2-ethyl-4-hydroxyphenyl)-4-(((1R,2s,3S,5s,7s)-5-hydr oxy adamantan-2- yl)amino)-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine- 3-carboximidamide (6-methoxy-3-pyridyl)boronic acid (0.024 g, 149.07 umol) and 6-bromo-N'-[4-[tert- butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-[(5-hydroxy-2-ada mantyl)amino]pyrrolo[1,2-b]- pyridazine-3-carboxamidine (0.031 g, 48.54 umol) were dissolved in DMF (1.5 mL) and aqueous potassium phosphate (1 M, 0.220 mL) in an oven-dried screw cap vial equipped with a stir bar. The mixture was purged with nitrogen for 5 min. Dichloro[1,1'-bis(di-t- butylphosphino)ferrocene]palladium(II) (0.003 g, 48.54 umol) was added, and the mixture purged with nitrogen for an additional 2 min. The vial was sealed and heated at 100 °C in a heating block for 30 min, then cooled to room temperature. The mixture was diluted with ethyl acetate, and washed with a 1:1 brine:water solution (x2) and 100 % brine (x1). The organic phase was dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded (Z)-N'-(4-((tert- butyldimethylsilyl)oxy)-2-ethylphenyl)-4-(((1R,2s,3S,5s,7s)- 5-hydroxyadamantan-2-yl)amino)-6- (6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboximid amide as a tan solid. Yield: 15.6 mg, 58 %. LCMS (ES) m/z = 553.28 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.70 (br d, 1H, J=8.1 Hz), 8.93 (br s, 1H), 8.61 (d, 1H, J=2.4 Hz), 8.2-8.3 (m, 1H), 8.1-8.2 (m, 2H), 7.04 (s, 1H), 6.89 (d, 1H, J=8.6 Hz), 6.67 (s, 1H), 6.60 (s, 2H), 5.86 (br s, 2H), 4.48 (br s, 2H), 3.89 (s, 3H), 2.3- 2.5 (m, 2H), 2.2-2.3 (m, 2H), 1.9-2.1 (m, 3H), 1.83 (br d, 2H, J=12.1 Hz), 1.6-1.7 (m, 4H), 1.34 (br d, 2H, J=12.5 Hz), 1.06 (t, 3H, J=7.5 Hz). EXAMPLE 10G Synthesis of N'-(2-chloro-4-hydroxy-phenyl)-4-[(5-hydroxy-2-adamantyl)ami no]-6-(6-methoxy- 3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-phenyl ]-4-[(5-hydroxy-2- adamantyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-phenyl ]-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (0.25 g, 486.1 μmol) and 4-aminoadamantan-1-ol (97.6 mg, 583.3 μmol) in N,N-dimethylacetamide (3 mL) was added N-ethyl-N-isopropyl-propan-2- amine (189 mg, 1.5 mmol). After stirring for 2 hours at 90 °C, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a light-yellow solid. Yield: 0.20 g, 63 %. LCMS (ESI) m/z = 646.0 (M+H). Step 2: N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-phenyl]-4-[(5- hydroxy-2-adamantyl)amino]- 6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamid ine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-phenyl ]-4-[(5-hydroxy-2- adamantyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine (80 mg, 124.0 μmol) in 1,4-dixoane (2 mL) and water (0.2 mL) were added 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (35 mg, 148.8 μmol), potassium phosphate (79 mg, 372 μmol) and 1,1'-bis (di-t- butylphosphino)ferrocene palladium dichloride (8.1 mg, 12.4 μmol). The resulting mixture was stirred for 2 hours at 90 °C under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the titled compound as a yellow solid. Yield: 70 mg, 83 %. LCMS (ESI) m/z = 673.2 (M+H). Step 3: N'-(2-chloro-4-hydroxy-phenyl)-4-[(5-hydroxy-2-adamantyl)ami no]-6-(6-methoxy-3- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-phenyl]-4-[(5- hydroxy-2- adamantyl) amino]-6-(6-methoxy-3-pyridyl) pyrrolo[1,2-b] pyridazine-3-carboxamidine (70 mg, 104.0 μmol) in DMF (2 mL) was added cesium fluoride (47.4 mg, 312 μmol). After stirring for 2 hours at 25 °C, the reaction mixture was filtered and the filtrate purified via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) to afford N'-(2-chloro-4-hydroxy-phenyl)-4-[(5-hydroxy-2-adamantyl)ami no]-6-(6-methoxy-3- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as a light-yellow solid. Yield: 17.7 mg, 30%. LCMS (ESI) m/z = 559.5 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.61 (d, 1H, J=2.4 Hz), 8.06-8.22 (m, 3H), 7.04 (s, 1H), 6.81-6.91 (m, 3H), 6.73-6.74 (m, 1H), 4.46-4.50 (m, 1H), 3.89 (s, 3H), 2.01-2.30 (m, 2H), 1.80-1.97 (m, 5H), 1.50-1.70 (m, 4H), 1.20-1.40 (m, 2H). EXAMPLE 10H Synthesis of N'-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-4-[(5-hydroxy-2-adama ntyl)amino]-6-(6- methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: 6-bromo-N'-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-4-[(5-hydroxy -2-adamantyl)amino]- pyrrolo[1,2-b]pyridazine-3-carboxamidine To a mixture of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-5-fluor o-phenyl]-4- chloropyrrolo[1,2-b]pyridazine-3-carboxamidine (140 mg, 266.2 umol) in DMA (2 mL) were added 4-aminoadamantan-1-ol (89.0 mg, 532.4 umol) and DIEA (103.0 mg, 798.6 μmol, 131.7 μL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90°C for 3 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column (ethyl acetate, 100%) afforded the titled compound. Yield: 130 mg, 90%. LCMS (ESI) m/z = 542.2 (M+H). Step 2: N'-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-4-[(5-hydroxy-2-adama ntyl)amino]-6-(6- methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-4-[(5-hydroxy -2- adamantyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine (130 mg, 239.7 umol) and 2- methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrid ine (112.7 mg, 479.3 umol) in dioxane (1.2 mL) and water (0.3 mL) were added tripotassium phosphate (216.0 mg, 719.0 umol) and Pd(dtbpf)Cl2 (15.6 mg, 24.0 umol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90°C for 2 h, cooled to room temperature, and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonia) afforded N'-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-4-[(5-hydroxy-2-adama ntyl)amino]- 6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamid ine as a light-yellow solid. Yield: 12 mg, 8.8%. LCMS (ESI) m/z = 571.3 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.50 (d, 1H, J=8.0 Hz), 9.25 (brs, 1H), 8.61 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 8.07-8.10 (m, 1H), 7.04 (s, 1H), 6.89 (d, 1H, J=8.4 Hz), 6.82 (d, 1H, J=9.6 Hz), 6.55 (d, 1H, J=12.0 Hz), 6.07 (brs, 2H), 4.48 (s, 1H), 3.89 (s, 3H), 2.38 (q, 2H, J=7.6 Hz), 2.19-2.22 (m, 2H), 1.92-2.00 (m, 3H), 1.78-1.82 (m, 2H), 1.60-1.70 (m, 4H), 1.35-1.40 (m, 2H), 1.00-1.07 (m, 3H). EXAMPLE 10I Synthesis of N'-(2-chloro-5-fluoro-4-hydroxyphenyl)-4-((5-hydroxyadamanta n-2-yl)amino)-6-(6- methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboximidami de Step 1: 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-5-fluo ro-phenyl]-4-[(5-hydroxy-2- adamantyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine and 6-bromo-N'-(2-chloro-5-fluoro-4-hydroxyphenyl)-4-((5-hydroxy adamantan-2-yl)amino) pyrrolo- [1,2-b]pyridazine-3-carboximidamide To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-5-fluo ro-phenyl]-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (110 mg, 206.7 μmol) in N,N-dimethylacetamide (5 mL) were added 4-aminoadamantan-1-ol (51.8 mg, 310.0 μmol) and N,N-diisopropylethylamine (80.1 mg, 619.9 μmol). After stirring for 3 hours at 90 °C, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with brine (x3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a mixture of the titled compounds as a yellow solid. Yield: 100 mg (2/3 = 51:39). LCMS (ESI) m/z = 662.4 and 550.3 (M+H). Step 2: N'-(2-chloro-5-fluoro-4-hydroxyphenyl)-4-((5-hydroxyadamanta n-2-yl)amino)-6-(6- methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboximidami de To a solution of the mixture of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-5-fluo ro- phenyl]-4-[(5-hydroxy-2-adamantyl)amino]pyrrolo[1,2-b]pyrida zine-3-carboxamidine and 6- bromo-N'-(2-chloro-5-fluoro-4-hydroxyphenyl)-4-((5-hydroxyad amantan-2-yl)amino)pyrrolo- [1,2-b]pyridazine-3-carboximidamide (80 mg, 145.8 μmol) in 1,4-dioxane (5 mL) and water (1 mL) were added 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyr idine (51.4 mg, 218.7 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (9.5 mg, 14.6 μmol) and potassium phosphate (61.9 mg, 291.5 μmol). The resulting mixture was stirred for 2 hours at 90 °C under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered through a celite pad and the filtrate concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) give N'-(2-chloro-5-fluoro-4-hydroxy-phenyl)-4-[(5-hydroxy-2-adam antyl)amino]-6- (6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidin e as a yellow solid. Yield: 21.4 mg, 25%. LCMS (ESI) m/z = 577.4 (M+H). ¹ H NMR (400 MHz, DMSO-d6) δ 12.13 (d, 1H, J=8.0 Hz), 9.84 (s, 1H), 8.60 (d, 1H, J=2.0 Hz), 8.23 (s, 1H), 8.15 (d, 1H, J=2.0 Hz), 8.05-8.10 (m, 1H), 7.03 (d, 2H, J=8.8 Hz), 6.80-6.90 (m, 2H), 6.35 (s, 2H), 4.40-4.50 (m, 2H), 3.88 (s, 3H), 2.17-2.23 (m, 2H), 1.85-2.00 (m, 5H), 1.62-1.67 (m, 4H), 1.25-1.37 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -136.09 (s, 1F). EXAMPLE 11 COMPOUNDS OF FORMULA (I) WHEREIN X IS NH, B IS SUBSTITUTED PIPERIDINE EXAMPLE 11A Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-3-pyridyl)-4-[(1- prop-2-enoyl-3- piperidyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: tert-butyl 3-[[6-bromo-3-[(Z)-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-et hyl-phenyl]- carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]piperidine- 1-carboxylate To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (400 mg, 787.5 umol) in DMA (20 mL) were added tert-butyl 3-aminopiperidine-1-carboxylate (315.4 mg, 1.58 mmol) and DIEA (304.8 mg, 2.36 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90°C for 2 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via silica gel column (petroleum ether / ethyl acetate, 5:1) afforded the titled compound. Yield: 210 mg, 40%. LCMS (ESI) m/z = 673.3 (M+H). Step 2: tert-butyl 3-[[3-[(Z)-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phen yl]carbamimidoyl]- 6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]pi peridine-1-carboxylate To a solution of tert-butyl 3-[[6-bromo-3-[(Z)-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-et hyl- phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]pipe ridine-1-carboxylate (220 mg, 327.5 umol) and 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyr idine (115.5 mg, 491.3 umol) in dioxane (16 mL) and water (4 mL) were added tripotassium phosphate (208.6 mg, 982.5 umol) and Pd(dtbpf)Cl ₂ (21.4 mg, 32.8 umol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90°C for 2 h, cooled to room temperature, and concentrated under reduced pressure. Purification via silica gel column (petroleum ether / ethyl acetate, 2:1) afforded the titled compound. Yield: 135 mg, 59%. LCMS (ESI) m/z = 700.4 (M+H). Step 3: N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-6-(6-me thoxy-3-pyridyl)-4-(3- piperidylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of tert-butyl 3-[[3-[(Z)-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phen yl]- carbamimidoyl]-6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazi n-4-yl]amino]piperidine-1- carboxylate (135 mg, 192.9 umol) in DCM (6 mL) was added trifluoroacetic acid (2 mL). After stirring for 1 h at room temperature, the mixture was concentrated under vacuum to afford the titled compound, which was used in the next step directly without further purification. LCMS (ESI) m/z = 600.2 (M+H) Step 4: N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-3-pyridyl)-4-[(1- prop-2-enoyl-3-piperidyl)- amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine A solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-6-(6-me thoxy-3-pyridyl)-4-(3- piperidylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidine (120 mg, 200.4 umol) in DMF (2 mL) was added prop-2-enoyl chloride (18.2 mg, 200.4 umol) at 0 °C. The resulting mixture was stirred for 1 h at room temperature. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-(2-ethyl-4-hydroxy-phenyl)- 6-(6-methoxy-3-pyridyl)-4-[(1-prop-2-enoyl-3-piperidyl)amino ]pyrrolo[1,2-b]pyridazine-3- carboxamidine as a white solid. Yield: 16.7 mg, 15 %. LCMS (ESI) m/z = 540.2 (M+H). ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.50-8.57 (m, 1H), 8.05-8.14 (m, 2H), 7.96 (s, 1H), 7.16-7.43 (m, 1H), 6.88 (d, 1H, J=8.4 Hz), 6.66-6.80 (m, 3H), 5.99-6.44 (m, 1H), 5.38-5.73 (m, 1H), 4.55-4.70 (m, 4H), 4.40-4.55 (m, 2H), 3.97 (s, 3H), 3.86-3.95 (m, 1H), 3.40-3.50 (m, 2H), 2.50-2.58 (m, 2H), 2.17- 2.30 (m, 1H), 1.80-2.00 (m, 2H), 1.61-1.70 (m, 1H), 1.10-1.21 (m, 3H). EXAMPLE 11B Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-3-pyridyl)-4-[(1- prop-2-enoyl-4- piperidyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: tert-butyl 4-[[6-bromo-3-[(Z)-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-et hyl-phenyl]- carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]piperidine- 1-carboxylate To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (200 mg, 393.8 umol) in DMA (10 mL) were added tert-butyl 4-aminopiperidine-1-carboxylate (157.7 mg, 787.5 umol) and DIEA (152.4 mg, 1.18 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90°C for 2 h, cooled to room temperature, diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via silica gel column (petroleum ether / ethyl acetate, 5:1) afforded the titled compound. Yield: 130 mg, 49%. LCMS (ESI) m/z = 673.3 (M+H). Step 2: tert-butyl 4-[[3-[(Z)-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phen yl]carbamimidoyl]- 6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]pi peridine-1-carboxylate tert-butyl 4-[[6-bromo-3-[(Z)-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-et hyl- phenyl]carbamimidoyl]-pyrrolo[1,2-b]pyridazin-4-yl]amino]pip eridine-1-carboxylate (230 mg, 342.4 umol) and 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyr idine (120.74 mg, 513.59 umol) in 1,4-dioxane (16 mL) and water (4 mL) were added tripotassium phosphate (218.0 mg, 1.03 mmol) and Pd(dtbpf)Cl ₂ (22.3 mg, 34.2 umol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90°C for 2 h, cooled to room temperature, and concentrated under reduced pressure. Purification via silica gel column (petroleum ether / ethyl acetate, 5:1) afforded the titled compound. Yield: 150 mg, 62%. LCMS (ESI) m/z = 700.4 (M+H). Step 3: N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-6-(6-me thoxy-3-pyridyl)-4-(4- piperidylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of tert-butyl 4-[[3-[(Z)-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl- phenyl]carbamimidoyl]-6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b]p yridazin-4-yl]amino]piperidine- 1-carboxylate (150 mg, 214.3 umol) in DCM (6 mL) was added trifluoroacetic acid (2 mL). After stirring for 1 h at room temperature, the resulting mixture was concentrated under vacuum to afford the titled compound, which was used in the next step directly without further purification. LCMS (ESI) m/z = 600.2 (M+H) Step 4: N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-3-pyridyl)-4-[(1- prop-2-enoyl-4-piperidyl)- amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine A solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-6-(6-me thoxy-3-pyridyl)-4-(4- piperidylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidine (90 mg, 150.3 umol) in DMF (2 mL) was added prop-2-enoyl chloride (13.6 mg, 150.3 umol) at 0 °C. The resulting mixture was stirred for 1 h at room temperature. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate) afforded N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-3- pyridyl)-4-[(1-prop-2-enoyl-4-piperidyl)amino]pyrrolo[1,2-b] pyridazine-3-carboxamidine as a white solid. Yield: 12.6 mg, 15 %. LCMS (ESI) m/z = 540.2 (M+H). ¹ H NMR (CD ₃ OD, 400 MHz) δ 8.51 (s, 1H), 8.15 (s, 1H), 8.04-8.07 (m, 1H), 7.95 (s, 1H), 7.20 (s, 1H), 6.88 (d, 1H, J=8.8 Hz), 6.66-6.82 (m, 4H), 6.18-6.22 (m, 1H), 5.72-5.76 (m, 1H), 4.61-4.73 (m, 4H), 4.08-4.15 (m, 1H), 3.90-4.02 (m, 4H), 3.60-3.70 (m, 1H), 3.50-3.60 (m, 1H), 2.52 (q, 2H, J=7.6 Hz), 2.19-2.30 (m, 2H), 1.70-1.80 (m, 2H), 1.17 (t, 3H, J=7.6 Hz). EXAMPLE 11C Synthesis of N'-(2-chloro-4-hydroxy-phenyl)-4-[[1-(6-cyanopyridazin-3-yl) -3,3-dimethyl-4- piperidyl] amino]-6-(4-pyridyl) pyrrolo[1,2-b] pyridazine-3-carboxamidine Step 1: 6-bromo-N'-(2-chloro-4-hydroxy-phenyl)-4-[[1-(6-cyanopyridaz in-3-yl)-3,3-dimethyl-4- piperidyl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl] oxy-2-chloro-phenyl]-4-chloro- pyrrolo[1,2-b] pyridazine-3-carboxamidine (100 mg, 194.4 μmol) and 6-(4-amino-3,3-dimethyl-1- piperidyl) pyridazine-3-carbonitrile (90 mg, 389 μmol) in N, N-dimethylacetamide (3 mL) was added N, N-diisopropylethylamine (75.4 mg, 583.3 μmol). After stirring for 3 hours at 80 °C, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (15 mL) and washed with water (x2) and brine (x3). The organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the titled compound as a brown solid. Yield: 95 mg, 41 %. LCMS (ESI) m/z = 596.0 (M+H). Step 2: N'-(2-chloro-4-hydroxy-phenyl)-4-[[1-(6-cyanopyridazin-3-yl) -3,3-dimethyl-4-piperidyl] amino]-6-(4-pyridyl) pyrrolo[1,2-b] pyridazine-3-carboxamidine To a solution of 6-bromo-N'-(2-chloro-4-hydroxy-phenyl)-4-[[1-(6-cyanopyridaz in-3-yl)-3,3- dimethyl-4-piperidyl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine (85 mg, 71.4 μmol) in 1,4- dioxane (5 mL) and water (0.5 mL) were added 4-pyridylboronic acid (13.2 mg, 107.2 μmol), potassium phosphate (15.2 mg, 72 μmol) and 1,1'-bis(di-t-butylphosphino)ferrocene palladium dichloride (46.5 mg, 71.4 μmol). The resulting mixture stirred for 2 hours at 90 °C under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via prep-TLC (ethanol, 100%) provided N'- (2-chloro-4-hydroxy-phenyl)-4-[[1-(6-cyanopyridazin-3-yl)-3, 3-dimethyl-4-piperidyl]amino]-6- (4-pyridyl)pyrrolo [1,2-b] pyridazine-3-carboxamidine as a yellow solid. Yield: 3 mg, 5 %. LCMS (ESI) m/z = 593.6 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.40-12.44 (m, 1H), 9.44 (s, 1H), 8.57 (d, 2H, J=5.7 Hz), 8.43 (s, 1H), 8.28 (s, 1H), 7.80-7.88 (m, 3H), 7.40-7.48 (m, 2H), 6.80-6.84 (m, 2H), 6.67-6.71 (m, 1H), 6.24 (s, 2H), 4.43-4.45 (m, 2H), 4.07-4.12 (m, 1H), 3.57-3.70 (m, 1H), 3.35-3.45 (m, 1H), 2.13-2.17 (m, 1H), 1.72-1.76 (m, 1H), 1.07 (s, 3H), 0.89 (s, 3H). EXAMPLE 12 COMPOUNDS OF FORMULA (I) WHEREIN X IS NH, B IS FURAN

Compounds 12A-12D were prepared according to the methods described in the previous examples and synthetic schemes from the correspondingly appropriate starting materials. Structure, name and analytical characterization of these compounds are presented below. EXAMPLE 13 COMPOUNDS OF FORMULA (I) WHEREIN X IS NH, B IS FURANONE EXAMPLE 13A Synthesis of (Z)-N'-(2-ethyl-4-hydroxy-phenyl)-4-[[(3S)-5-oxotetrahydrofu ran-3-yl]amino]-6- phenyl-pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: (S, Z)-6-bromo-N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylpheny l)-4-((5-oxotetrahydro- furan-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboximidamide To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl] oxy-2-ethyl-phenyl]-4-chloro- pyrrolo[1,2-b] pyridazine-3-carboxamidine (200 mg, 393.8 umol) and (4S)-4- aminotetrahydrofuran-2-one (79.6 mg, 787.5 umol) in N,N-dimethylacetamide (6 mL) were added sodium iodide (59.0 mg, 393.8 umol) and N,N-diisopropylethylamine (254.5 mg, 1.97 mmol). After irradiating for an hour at 130 °C in a microwave reactor, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a light yellow solid. Yield: 100 mg, 40%. LCMS (ESI) m/z = 573.5 (M+H). Step 2: (S, Z)-N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylphenyl)-4-((5 -oxotetrahydrofuran-3-yl)- amino)-6-phenylpyrrolo[1,2-b]pyridazine-3-carboximidamide To a mixture of (S, Z)-6-bromo-N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylpheny l)-4-((5- oxotetrahydrofuran-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-car boximidamide (100 mg, 174.7 umol) and phenylboronic acid (31.9 mg, 262.0 umol) in 1,4-dioxane (1 mL) and water (0.1 mL) were added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (11.4 mg, 17.5 umol) and potassium phosphate (111.2 mg, 524.0 umol) at room temperature. The reaction mixture was stirred for 2 hours at 100 °C under nitrogen atmosphere, cooled to room temperature, and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the titled compound as a white solid. Yield: 60 mg, 59%. LCMS (ESI) m/z = 570.4 (M+H). Step 3: (Z)-N'-(2-ethyl-4-hydroxy-phenyl)-4-[[(3S)-5-oxotetrahydrofu ran-3-yl]amino]-6-phenyl- pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of (S, Z)-N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylphenyl)-4-((5 - oxotetrahydrofuran-3-yl)amino)-6-phenylpyrrolo[1,2-b]pyridaz ine-3-carboximidamide (55 mg, 96.5 umol) in N,N-dimethylformamide (1 mL) was added cesium fluoride (73.3 mg, 482.7 umol) at 0 °C. After stirring for 1 hour at room temperature, the resulting mixture was filtered. Purification via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate) afforded (Z)-N'-(2-ethyl-4-hydroxy-phenyl)-4-[[(3S)-5-oxotetrahydrofu ran-3-yl]amino]-6- phenyl-pyrrolo[1,2-b]pyridazine-3-carboxamidine as a light yellow solid. Yield: 16.5 mg, 37%. LCMS (ESI) m/z = 456.4 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.85 (d, 1H, J=5.2 Hz), 8.97 (s, 1H), 8.20-8.28 (m, 2H), 7.81-7.88 (m, 2H), 7.41 (t, 2H, J=7.6 Hz), 7.22-7.30 (m, 2H), 6.55-6.70 (m, 3H), 6.01 (s, 2H), 5.34 (s, 1H), 4.68-4.74 (m, 1H), 4.22-4.29 (m, 1H), 3.19-3.27 (m, 2H), 2.30- 2.48 (m, 2H), 1.05 (t, 3H, J=7.2 Hz). EXAMPLES 13B - 13F Compounds 13A - 13D were prepared according to the methods described in the previous example and synthetic schemes from the correspondingly appropriate starting materials. Structure, name and analytical characterization of these compounds are presented below.

EXAMPLE 14 COMPOUNDS OF FORMULA (I) WHEREIN X IS NH, B IS AZABICYCLOOCTANE Synthesis of 4-((8-azabicyclo[3.2.1]octan-3-yl)amino)-N'-(2-chloro-4-hydr oxyphenyl)-6-(1- methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboximid amide Step 1: tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate To a solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (500 mg, 2.22 mmol) in methanol (35 mL) were added ammonium acetate (3.42 g, 44.39 mmol) and sodium cyanoborohydride (1.39 g, 22.19 mmol). After stirring for 2 hours at 70 °C, the reaction mixture was concentrated under reduced pressure. The residue was diluted with 0.5 M aqueous solution of sodium hydroxide and extracted with dichloromethane (x3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the titled compound as a yellow oil. Yield: 350 mg, 70%. LCMS (ESI) m/z = 227.2 (M+H). Step 2: tert-butyl-3-((6-bromo-3-(N'-(4-((tert-butyldimethylsilyl)ox y)-2-chlorophenyl) carbamimidoyl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-8-azabicyc lo[3.2.1]octane-8-carboxylate To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-phenyl ]-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (140 mg, 272.21 μmol) inN,N-dimethylacetamide (5 mL) were added tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (92.4 mg, 408.3 μmol) and N,N-diisopropylethylamine (105.5 mg, 816.6 μmol). After stirring for 2 hours at 90 °C, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the titled compound as a yellow solid. Yield: 100 mg, 51%. LCMS (ESI) m/z = 703.5 (M+H). Step 3: tert-butyl-3-((3-(N'-(4-((tert-butyldimethylsilyl)oxy)-2-chl orophenyl)carbamimidoyl)-6- (1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino )-8-azabicyclo[3.2.1]octane-8- carboxylate To a solution of tert-butyl-3-((6-bromo-3-(N'-(4-((tert-butyldimethylsilyl)ox y)-2- chlorophenyl)carbamimidoyl)pyrrolo[1,2-b]pyridazin-4-yl)amin o)-8-azabicyclo[3.2.1]octane-8- carboxylate (100 mg, 142.0 μmol) in 1,4-dioxane (5 mL) and water (1 mL) were added 1-methyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (44.3 mg, 213.0 μmol), 1,1'-bis (di-t- butylphosphino)ferrocene palladium dichloride (9.3 mg, 14.2 μmol) and potassium phosphate (60.3 mg, 284.0 μmol). The resulting mixture was purged stirred for 1 hour at 100 °C under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered through a celite pad. The filtrate was concentrated under reduced pressure and purified by reverse phase chromatography (acetonitrile/water) to afford the titled compound as a yellow solid. Yield: 70 mg, 63%. LCMS (ESI) m/z = 705.6 (M+H). Step 4: 4-((8-azabicyclo[3.2.1]octan-3-yl)amino)-N'-(4-((tert-butyld imethylsilyl)oxy)-2- chlorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyri dazine-3-carboximidamide To a solution of tert-butyl-3-((3-(N'-(4-((tert-butyldimethylsilyl)oxy)-2-chl orophenyl)- carbamimidoyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyr idazin-4-yl)amino)-8-azabicyclo- [3.2.1]octane-8-carboxylate (70 mg, 99.4 μmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (0.9 mL). After stirring for 1 hour at room temperature, the reaction mixture was concentrated under reduced pressure to afford the titled compound as a brown solid, which was used for next step directly without further purification. Yield: 50 mg, 83%. LCMS (ESI) m/z = 605.6 (M+H). Step 5: 4-((8-azabicyclo[3.2.1]octan-3-yl)amino)-N'-(2-chloro-4-hydr oxyphenyl)-6-(1-methyl- 1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboximidamide To a solution of 4-((8-azabicyclo[3.2.1]octan-3-yl)amino)-N'-(4-((tert-butyld imethylsilyl)oxy)-2- chlorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyri dazine-3-carboximidamide (50 mg, 82.8 μmol) in N,N-dimethylformamide (2 mL) was added cesium fluoride (37.7 mg, 248.3 μmol). After stirring for 3 hours at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-((8- azabicyclo[3.2.1]octan-3-yl)amino)-N'-(2-chloro-4-hydroxyphe nyl)-6-(1-methyl-1H-pyrazol-4- yl)-pyrrolo[1,2-b]pyridazine-3-carboximidamide as a yellow solid. Yield: 10.5 mg, 21%. LCMS (ESI) m/z = 491.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.35 (d, 1H, J=7.2 Hz), 8.32 (s, 2H, HCO-), 8.18 (s, 1H), 8.02 (s, 1H), 7.88 (s, 1H), 7.77 (s, 1H), 6.73-6.88 (m, 4H), 6.15 (s, 2H), 4.55 (d, 1H, J=4.4 Hz), 3.85 (s, 3H), 3.72-3.76 (m, 2H), 2.35-2.41 (m, 2H), 2.00-2.10 (m, 2H), 1.91- 1.97 (m, 2H), 1.65-1.80 (m, 2H). EXAMPLE14B Synthesis of N'-(2-chloro-4-hydroxyphenyl)-4-(((1R,3s,5S)-8-(2-cyanoethyl )-8- azabicyclo[3.2.1]octan-3-yl)amino)-6-(1-methyl-1H-pyrazol-4- yl)pyrrolo[1,2-b]pyridazine-3- carboximidamide Step 1: tert-butyl ((1R,3s,5S)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)c arbamate To a solution of tert-butyl N-[(1R,3s, 5S)-8-azabicyclo[3.2.1]octan-3-yl]carbamate (1.00 g, 4.42 mmol) in ethanol (10 mL) were added 3-bromopropanenitrile (710.4 mg, 5.30 mmol) and 1,8- Diazabicyclo[5.4.0]undec-7-ene (1.01 g, 6.63 mmol). After stirring for 5 hours at 25 °C, the resulting mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (methanol/dichloromethane) afforded the titled compound as a yellow solid. Yield: 1.1 g, 89%. LCMS (ESI) m/z = 280.3 (M+H). Step 2: 3-((1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]octan-8-yl)propanen itrile To a solution of tert-butyl ((1R,3s,5S)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)c arbamate (1.0 g, 3.58 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2.0 mL). After stirring for 1 hour at 25 °C, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, basified to pH=9 with 1N sodium hydroxide and then extracted with dichloromethane (x8). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound as yellow oil. Yield: 620 mg, 97%. ¹ H NMR (DMSO-d6, 400 MHz) δ 3.58-3.36 (m, 3H), 3.29-3.08 (m, 2H), 2.65-2.50 (m, 2H), 1.95-1.71 (m, 2H), 1.69-1.40 (m, 5H), 1.31-1.12 (m, 1H). Step 3: 6-bromo-N'-(2-chloro-4-hydroxyphenyl)-4-(((1R,3s,5S)-8-(2-cy anoethyl)-8-azabicyclo- [3.2.1]octan-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboximi damide To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-phenyl ]-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (120 mg, 233.3 μmol) in N,N-dimethylacetamide (2 mL) were added 3-((1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]octan-8-yl)propanen itrile (62.7 mg, 350.0 μmol) and N,N-diisopropylethylamine (90.5 mg, 700.0 μmol). The reaction mixture was stirred for 2 hours at 100 °C and then cooled to room temperature. Cesium fluoride (106.3 mg, 700.0 μmol) was added to the mixture and stirred for a further 15 hours at room temperature. The resulting mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the titled compound as a light yellow solid. Yield: 60 mg, 47%. LCMS (ESI) m/z = 542.1 (M+H). Step 4: N'-(2-chloro-4-hydroxyphenyl)-4-(((1R,3s,5S)-8-(2-cyanoethyl )-8-azabicyclo[3.2.1]octan- 3-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyrida zine-3-carboximidamide To a solution of 6-bromo-N'-(2-chloro-4-hydroxyphenyl)-4-(((1R,3s,5S)-8-(2-cy anoethyl)-8- azabicyclo[3.2.1]octan-3-yl)amino)pyrrolo[1,2-b]pyridazine-3 -carboximidamide (50 mg, 92.1 μmol) in 1,4-dixaone (3 mL) and water (0.6 mL) were added 1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyrazole (28.8 mg, 138.2 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (6 mg, 9.2 μmol) and potassium phosphate (39.1 mg, 184.2 μmol). The resulting mixture was stirred for 1 hour at 100 °C under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.05% ammonia) afforded N'-(2-chloro-4-hydroxyphenyl)-4-(((1R,3s,5S)-8-(2- cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-6-(1-methyl -1H-pyrazol-4-yl)pyrrolo[1,2- b]pyridazine-3-carboximidamide as an off-white solid. Yield: 9.5 mg, 18%. LCMS (ESI) m/z = 544.5 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 8.12 (s, 1H), 8.00 (s, 1H), 7.88 (d, 1H, J=1.6 Hz), 7.73 (s, 1H), 6.82-6.91 (m, 3H), 6.59-6.73 (m, 1H), 4.30-4.45 (m, 1H), 3.87 (s, 3H), 3.28-3.32 (m, 2H), 2.56-2.63 (m, 4H), 1.83-2.00 (m, 4H), 1.70-1.80 (m, 2H), 1.55-1.65 (m, 2H). EXAMPLE14C Synthesis of 2-((1R,3s,5S)-3-((3-(N'-(2-chloro-4-hydroxyphenyl)carbamimid oyl)-6-(1-methyl- 1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-8-azabic yclo[3.2.1]octan-8-yl)acetic acid To a solution of methyl 2-[(1R,3s,5S)-3-[[3-[N'-(2-chloro-4-hydroxy-phenyl)carbamimi doyl]-6- (1-methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]amino]-8- azabicyclo[3.2.1]octan-8-yl]acetate (136 mg, 241.5 μmol) in tetrahydrofuran (5 mL) was added a solution of lithium hydroxide (17.4 mg, 724.6 μmol) in water (2.5 mL). After stirring for 15 hours at room temperature, the reaction mixture was adjusted to pH = 3 with 3N hydrochloric acid and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 2-((1R,3s,5S)-3-((3-(N'-(2-chloro-4-hydroxyphenyl)carbamimid oyl)-6-(1-methyl-1H- pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-8-azabicycl o[3.2.1]octan-8-yl)acetic acid as a yellow solid. Yield: 38.5 mg, 29%. LCMS (ESI) m/z = 549.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 8.19 (s, 1H), 7.94-8.12 (m, 3H), 7.79 (s, 1H), 6.88-7.14 (m, 3H), 6.80 (d, 1H, J=8.0 Hz), 4.47 (s, 1H), 3.93 (s, 2H), 3.87 (s, 3H), 3.50-3.61 (m, 2H), 1.95-2.25 (m, 8H). EXAMPLE14D Synthesis of methyl 2-((1R,3s,5S)-3-((3-(N'-(2-chloro-4-hydroxyphenyl)carbamimid oyl)-6-(1- methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-8 -azabicyclo[3.2.1]octan-8- yl)acetate Step 1: methyl 2-((1R,3s,5S)-3-((tert-butoxycarbonyl)amino)-8-azabicyclo[3. 2.1]octan-8-yl)- acetate To a solution of tert-butyl N-[(1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl]carbamate (1.0 g, 4.42 mmol) in methanol (10 mL) were added methyl 2-bromoacetate (0.81 g, 5.30 mmol) and 1,8- diazabicyclo[5.4.0]undec-7-ene (1.01 g, 6.63 mmol). After stirring for 5 hours at room temperature, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (methanol/dichloromethane) afforded the titled compound as a light yellow solid. Yield: 1.0 g, 76%. LCMS (ESI) m/z = 299.3 (M+H). Step 2: methyl 2-((1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]octan-8-yl)acetate To a solution of methyl methyl 2-((1R,3s,5S)-3-((tert-butoxycarbonyl)amino)-8-azabicyclo- [3.2.1]octan-8-yl)acetate (1.0 g, 3.35 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (4.5 mL). After stirring for an hour at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and basified to pH=9 with 1N sodium hydroxide and extracted with dichloromethane (x3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound as a yellow oil. Yield: 600 mg, 90%. LCMS (ESI) m/z = 199.3 (M+H). Step 3: methyl 2-((1R,3s,5S)-3-((6-bromo-3-((Z)-N'-(2-chloro-4-hydroxypheny l)carbamimidoyl) pyrrolo[1,2-b]pyridazin-4-yl)amino)-8-azabicyclo[3.2.1]octan -8-yl)acetate To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-phenyl ]-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (400 mg, 777.7 μmol) in N,N-dimethylacetamide (10 mL) were added methyl 2-((1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]octan-8-yl)acetate (231.3 mg, 1.17 mmol) and N,N-diisopropylethylamine (301.5 mg, 2.33 mmol). After stirring for 2 hours at 90 °C, the reaction mixture was cooled to room temperature, diluted with ethyl acetate washed with brine (x3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded methyl 2- [(1R,3s,5S)-3-[[6-bromo-3-[N'-[4-[tert-butyl(dimethyl)silyl] oxy-2-chloro-phenyl]- carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]-8-azabicyc lo[3.2.1]octan-8-yl]acetate as a yellow solid. Yield: 230 mg, 30%. LCMS (ESI) m/z = 675.5 (M+H). Step 4: methyl 2-((1R,3s,5S)-3-((3-(N'-(2-chloro-4-hydroxyphenyl)carbamimid oyl)-6-(1-methyl- 1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-8-azabic yclo[3.2.1]octan-8-yl)acetate To a solution of methyl 2-((1R,3s,5S)-3-((6-bromo-3-((Z)-N'-(2-chloro-4-hydroxypheny l)- carbamimidoyl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-8-azabicyc lo[3.2.1]octan-8-yl)acetate (120 mg, 213.6 μmol) in 1,4-dioxane (5 mL) and water (1 mL) were added 1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (66.7 mg, 320.4 μmol), 1,1'-bis (di-t- butylphosphino)ferrocene palladium dichloride (13.9 mg, 21.4 μmol) and potassium phosphate (90.7 mg, 427.2 μmol). The resulting mixture was stirred for 1 hour at 100 °C under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure and purified via reverse phase HPLC (acetonitrile/water buffered with 10mmol/L ammonium bicarbonate and 0.1% ammonia) to afford methyl 2-((1R,3s,5S)-3-((3-(N'-(2-chloro-4-hydroxyphenyl)carbamimid oyl)-6-(1-methyl-1H- pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-8-azabicycl o[3.2.1]octan-8-yl)acetate as a yellow solid. Yield: 42.8 mg, 35%. LCMS (ESI) m/z = 563.5 (M+H). ¹ H NMR (400 MHz DMSO- d6) δ 11.59 (d, 1H, J=8.4 Hz), 9.47 (s, 1H), 8.13 (s, 1H), 8.00 (s, 1H), 7.88 (d, 1H, J=1.6 Hz), 7.74 (d, 1H, J=0.4 Hz), 6.83-6.90 (m, 3H), 6.71-6.74 (m, 1H), 6.21 (s, 2H), 4.40 (d, 1H, J = 5.2 Hz), 3.87 (s, 3H), 3.61 (s, 3H), 3.30-3.27 (m, 2H), 3.23 (s, 2H), 1.90-2.00 (m, 4H), 1.70-1.80 (m, 2H), 1.55-1.65 (m, 2H). EXAMPLES 14E - 14J Compounds 14E - 14J were prepared according to the methods described in the previous examples and synthetic schemes from the correspondingly appropriate starting materials. Structure, name and analytical characterization of these compounds are presented below.

EXAMPLE 15 COMPOUNDS OF FORMULA (I) WHEREIN X IS NH, B IS PYRROLIDINONE EXAMPLES 15A and 15B Compounds 15A and 15B were prepared according to the methods described in the previous examples and synthetic schemes from the correspondingly appropriate starting materials. Structure, name and analytical characterization of these compounds are presented below. EXAMPLE 16

COMPOUNDS OF FORMULA (I) WHEREIN

X IS NH, B IS PIPERIDINE

EXAMPLES 16A -16D

Compounds 16A - and 16D were prepared according to the methods described in the previous examples and synthetic schemes from the correspondingly appropriate starting materials. Structure, name and analytical characterization of these compounds are presented below.

EXAMPLE 16 Human JAK1, JAK2, JAK3 and TYK2 Biochemical Inhibition Assays The compounds described herein were tested for the ability to inhibit activity of human JAK1, JAK2, JAK3, and TYK2 which was achieved using TR-FRET assays. Briefly, the Kinases (JAK1, JAK2, JAK3 and TYK2) were incubated with a series of concentrations of the test compound for 30 min at RT. ATP solution was added to start the reaction, and incubated for 80 min at RT. The reaction was stopped by adding detection buffer and incubated for a further 60 min at RT. The samples were analyzed using Envision to calculate % inhibition at each of the series of concentrations of the test compound. The IC50 value of the compounds for each of the kinases were calculated using XLFit software, and the values presented in the following table (“na” = not available). To this end, activity EC50 values are noted in the following table according to the following indicators: “*” means > 10 nM; “**” means > 30 nM; “***” means > 300 nM; “+” means < 1 nM; “++” means 1 nM up to, but not including, 10nM; “+++” means 10 nM up to, but not including, 100 nM; and “++++” means 100 nM up to 300nM.

EXAMPLE 17 Synthesis of N'-(2-chloro-5-fluoro-phenyl)-4-[[3-[2- (dimethylamino)ethyl]cyclopentyl]amino]pyrrolo[1,2-b]pyridaz ine- 3-carboxamidine formic acid salt (compound 17) Step 1: Synthesis of 3-azidocyclopentanone To a solution of acetic acid (21.94 g, 365.41 mmol) in dichloromethane (400 mL) was added azido(trimethyl)silane (42.10 g, 365.41 mmol) and the mixture was stirred at room temperature for 20 minutes. Then cyclopent-2-en-1-one (10.00 g, 121.80 mmol) was added, followed by addition of triethylamine (2.47 g, 24.36 mmol). After stirring at 25°C for 15 hours, the reaction mixture was quenched with aqueous solution of sodium bicarbonate and extracted with ethyl acetate twice. The combined organic layers were washed with brine (x3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light yellow liquid, which was used for next step without further purification. Yield: 7.50 g, 49%. Step 2: Synthesis of tert-butyl N-(3-oxocyclopentyl)carbamate To a solution of 3-azidocyclopentanone (7.50 g, 59.94 mmol) in ethanol (75 mL) was added 10% palladium on carbon (0.75 g) under nitrogen atmosphere. The resulting mixture was purged with hydrogen gas and stirred at room temperature for 3 hours under hydrogen atmosphere (1.5 atm). The reaction mixture was filtered through Celite pad and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), then di-tert-butyl pyrocarbonate (19.62 g, 89.91 mmol) and triethylamine (18.20 g, 179.82 mmol) were added. After stirring at 25 °C for 3 hours, the reaction mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as an off-white solid. Yield: 2.40 g, 18%. ¹ H NMR (Chloroform-d, 400 MHz) δ 4.61 (s, 1H), 2.57-2.66 (m, 1H), 2.30-2.42 (m, 2H), 2.06-2.27 (m, 2H), 2.04 (s, 1H), 1.78-1.90 (m, 1H), 1.45 (s, 9H). Step 3: Synthesis of ethyl -2-[3-(tert-butoxycarbonylamino)cyclopentylidene]acetate To a solution of ethyl 2-diethoxyphosphorylacetate (3.88 g, 17.32 mmol) in tetrahydrofuran (25.0 mL) was added potassium bis(trimethylsilyl)azanide (1 M in tetrahydrofuran, 17.32 mL, 17.32 mmol) dropwise at 0 °C under nitrogen atmosphere. After stirring at 0 °C for an hour, a solution of tert-butyl N-(3-oxocyclopentyl)carbamate (2.30 g, 11.54 mmol) in tetrahydrofuran (25 mL) was added dropwise. After stirring at 25 °C for 15 hours, the reaction mixture was quenched with saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate twice. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light yellow oil. Yield: 2.60 g, 83%. ¹ H NMR (Chloroform-d, 400 MHz) δ 5.76-5.83 (m, 1H), 4.39-4.63 (m, 1H), 4.14 (q, 2H, J=6.8 Hz), 3.95-4.09 (m, 1H), 3.06-3.31 (m, 1H), 2.69-3.02 (m, 1H), 2.24-2.65 (m, 2H), 1.96-2.13 (m, 1H), 1.53-1.73 (m, 1H), 1.44 (s, 9H), 1.23-1.31 (t, 3H, J=6.8 Hz). Step 4: Synthesis of ethyl 2-[ 3-(tert-butoxycarbonylamino)cyclopentyl]acetate To a solution of ethyl -2-[3-(tert-butoxycarbonylamino)cyclopentylidene]acetate (1.50 g, 5.57 mmol) in ethanol (30 mL) was added palladium on carbon (0.34 g, 10%). The reaction mixture was purged with hydrogen gas and stirred at 25 °C for 15 hours under hydrogen atmosphere (1.5 atm), and then filtered through Celite pad. The filtrate was concentrated under reduced pressure to afford the title compound as a colorless oil. Yield: 1.07 g, 70%. Step 5: Synthesis of tert-butyl N-[3-(2-hydroxyethyl)cyclopentyl]carbamate To a solution of ethyl 2-[3-(tert-butoxycarbonylamino)cyclopentyl]acetate (1.00 g, 3.69 mmol) in tetrahydrofuran (35 mL) was added lithium aluminum hydride (0.28 g, 7.38 mmol) under nitrogen atmosphere. After stirring at 0 °C for 2 hours, the reaction mixture was quenched with sodium sulfate decahydrate (1.00 g) and then filtered through Celite pad. The filter cake was washed with ethyl acetate (x3). The combined organic layers were concentrated under reduced pressure to afford the title compound as a colorless oil. Yield: 0.71 g, 84%. Step 6: Synthesis of 2-[3-(tert-butoxycarbonylamino)cyclopentyl]ethyl methanesulfonate To a solution of tert-butyl N-[3-(2-hydroxyethyl)cyclopentyl]carbamate (1.10 g, 4.80 mmol) in dichloromethane (15.0 mL) were added methanesulfonyl chloride (824 mg, 7.20 mmol) and triethylamine (1.46 g, 14.39 mmol) under nitrogen atmosphere. After stirring at 25 °C for 15 hours, the reaction mixture was diluted with dichloromethane and filtered through Celite pad. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a light yellow oil. Yield: 1.27 g, 86%. Step 7: Synthesis of tert-butyl N-[3-(2-iodoethyl)cyclopentyl]carbamate To a solution of 2-[3-(tert-butoxycarbonylamino)cyclopentyl]ethyl methanesulfonate (1.27 g, 4.13 mmol) in acetonitrile (50 mL) was added sodium iodide (2.48 g, 16.53 mmol) under nitrogen atmosphere. After stirring at 80 °C for 2 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford the title compound as a light yellow oil. Yield: 1.15 g, 82%. Step 8: Synthesis of tert-butyl N-[3-[2-(dimethylamino)ethyl]cyclopentyl]carbamate To a solution of tert-butyl N-[3-(2-iodoethyl)cyclopentyl]carbamate (650 mg, 1.92 mmol) in methanol (15.0 mL) was added dimethylamine (129.84 mg, 2.88 mmol). After stirring at 80 °C for 2 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford the title compound as a light yellow oil, which was used for next step without further purification. Yield: 450mg (crude). Step 9: Synthesis of 3-[2-(dimethylamino)ethyl]cyclopentanamine hydrochloric acid salt To a solution of tert-butyl N-[3-[2-(dimethylamino)ethyl]cyclopentyl]carbamate (300 mg, 1.17 mmol) in ethyl acetate (1.0 mL) was added 2 N hydrogen chloride in ethyl acetate (3 mL, 6.00 mmol,) dropwise. After stirring at 25 °C for 2 hours, the reaction mixture was concentrated under reduced pressure to afford the title compound as a light yellow solid, which was used for next step without further purification. Yield: 0.20 g (crude). Step 10: Synthesis of 6-bromo-N'-(2-chloro-5-fluoro-phenyl)-4- [2- (dimethylamino)ethyl]cyclopentyl]amino]pyrrolo[1,2-b]pyridaz ine-3-carboxamidine To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (100 mg, 248.7 μmol) and 3-[2-(dimethylamino)ethyl]cyclopentanamine hydrochloric acid salt (230 mg, 1.19 mmol) in tert-amyl alcohol (5.0 mL) was added N,N- diisopropylethylamine (160.7 mg, 1.24 mmol). After stirring at 100 °C for 2 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification via prep-TLC (ethanol) afforded the title compound as a brown solid. Yield: 41 mg, 32%. LCMS (ESI) m/z: 523.1 (M+H). Step 11: N'-(2-chloro-5-fluoro-phenyl)-4- [2-(dimethylamino)ethyl]cyclopentyl]amino] pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt To a solution of 6-bromo-N'-(2-chloro-5-fluoro-phenyl)-4-[[3-[2- (dimethylamino)ethyl]cyclopentyl]amino]pyrrolo[1,2-b]pyridaz ine-3-carboxamidine (36 mg, 69.0 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.5 mL) were added 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (17.52 mg, 69.0 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (5 mg, 6.9 μmol) and potassium phosphate (29 mg, 138.0 μmol) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded N'-(2-chloro-5-fluoro-phenyl)-4-[[3-[2- (dimethylamino)ethyl]cyclopentyl]amino]pyrrolo[1,2-b]pyridaz ine-3-carboxamidine formic acid salt as a brown solid. Yield: 1.9 mg, 5%. LCMS (ESI) m/z: 443.3 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.45-11.48 (m, 1H), 8.29 (s, 1H), 8.18 (s, 1H, HCOOH), 7.64-7.66 (m, 1H), 7.46- 7.52 (m, 1H), 6.83-6.94 (m, 3H), 6.65-6.68 (m, 1H), 6.50 (s, 2H), 4.59-4.63 (m, 1H), 2.12-2.24 (m, 2H), 2.14 (s, 6H), 1.94-2.05 (m, 1H), 1.80-1.95 (m, 2H), 1,50-1.65 (m, 2H), 1.38-1.47 (m, 2H), 1.10-1.25 (m, 2H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -114.53 (s, 1F). EXAMPLE 18 Synthesis of N'-(2-chloro-5-fluoro-phenyl)-4-[[cis-3- [(dimethylamino)methyl]cyclopentyl]amino]pyrrolo[1,2-b]pyrid azine- 3-carboxamidine formic acid salt Step 1: Synthesis of 3-azabicyclo[2.2.1]heptan-2-one To a solution of 3-azabicyclo[2.2.1]hept-5-en-2-one (5.00 g, 45.82 mmol) in methanol (200 mL) purged with nitrogen was added 10% palladium on carbon (1.95 g, 1.83 mmol). The reaction mixture was purged with hydrogen gas and stirred at 25 °C for 2 hours under hydrogen atmosphere (1.5 atm). Then the reaction mixture was filtered through Celite pad and washed with methanol (x3). The filtrate was concentrated under reduced pressure to afford the title compound as a light yellow oil, which was used for next step without further purification. Yield: 4.70 g (crude). Step 2: Synthesis of tert-butyl 2-oxo-3-azabicyclo[2.2.1]heptane-3-carboxylate To a solution of 3-azabicyclo[2.2.1]heptan-2-one (4.80 g, 43.19 mmol) and 4- dimethylaminopyridine (2.90 g, 23.75 mmol) in dichloromethane (363 mL) was added di-tert- butyl dicarbonate (18.85 g, 86.38 mmol) under nitrogen atmosphere. After stirring at 25 °C for 18 hours, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a white solid. Yield: 2.00 g, 21%. LCMS (ESI) m/z: 156.3 (M+H- ^t Bu). Step 3: Synthesis of cis-tert-butyl N-[3-(hydroxymethyl)cyclopentyl]carbamate To a solution of tert-butyl 2-oxo-3-azabicyclo[2.2.1]heptane-3-carboxylate (1.90 g, 8.99 mmol) in methanol (25.0 mL) was added sodium borohydride (680 mg, 17.99 mmol) at 0 °C. After stirred at 0 °C for an hour, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a white solid. Yield: 1.80 g, 92%. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 6.74 (d, 1H, J=7.6 Hz), 4.44-4.47 (m, 1H), 3.65-3.71 (m, 1H), 3.24-3.27 (m, 2H), 1.95-1.98 (m, 1H), 1.86-1.95 (m, 2H), 1.67-1.73 (m, 1H), 1.50-1.56 (m, 1H), 1.35 (s, 9H), 1.26-1.35 (m, 1H), 0.98- 1.05 (m, 1H). Step 4: Synthesis of [cis-3-(tert-butoxycarbonylamino)cyclopentyl]methyl methanesulfonate To a solution of cis-tert-butyl N-[3-(hydroxymethyl)cyclopentyl]carbamate (500 mg, 2.32 mmol) and triethylamine (705.03 mg, 6.97 mmol) in dichloromethane (10 mL) was added methanesulfonyl chloride (399.06 mg, 3.48 mmol) dropwise at room temperature. After stirring for at 25 °C 15 hours, the reaction mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure afforded the title compound as a light yellow solid. Yield: 500 mg, 73%. ¹ H NMR (Chloroform-d, 400 MHz) δ 4.51 (s, 1H), 4.15 (d, 2H, J = 6.4 Hz), 3.96 (s, 1H), 3.01 (s, 3H), 2.20-2.43 (m, 2H), 1.93-2.07 (m, 1H), 1.75-1.89 (m, 1H), 1.44-1.58 (m, 2H), 1.44 (s, 9H), 1.11-1.20 (m, 1H). Step 5: Synthesis of cis-tert-butyl N-[3-(iodomethyl)cyclopentyl]carbamate To a solution of [cis-3-(tert-butoxycarbonylamino)cyclopentyl]methyl methanesulfonate (400 mg, 1.36 mmol) in acetonitrile (8.0 mL) was added sodium iodide (818 mg, 5.45 mmol) at room temperature. After stirring at 80 °C for 3 hours, the reaction mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a light yellow oil. Yield: 410 mg, 92%. ¹ H NMR (Chloroform-d, 400 MHz) δ 4.51 (s, 1H), 3.98 (s, 1H), 3.17-3.29 (m, 2H), 2.26-2.33 (m, 1H), 2.09-2.24 (m, 1H), 1.97-2.07 (m, 1H), 1.79-1.89 (m, 1H), 1.33-1.56 (m, 2H), 1.44 (s, 9H), 1.01-1.22 (m, 1H). Step 6: Synthesis of cis-tert-butyl N-[3-[(dimethylamino)methyl]cyclopentyl]carbamate To a solution of cis-tert-butyl N-[3-(iodomethyl)cyclopentyl]carbamate (410 mg, 1.26 mmol) in methanol (8.0 mL) was added dimethylamine (1.96 mL, 10.09 mmol, 30% aqueous solution) at room temperature. After stirring at 80 °C for 2 hours, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (methanol/dichloromethane) afforded the title compound as an off-white solid. Yield: 0.28 g, 91%. ¹ H NMR (DMSO-d6, 400 MHz) δ 6.92 (d, 1H, J=7.2 Hz), 3.72-3.82 (m, 1H), 3.04 (d, 2H, J=7.2 Hz), 2.75 (s, 6H), 2.02-2.27 (m, 2H), 1.66-1.85 (m, 2H), 1.41-1.52 (m, 1H), 1.38 (s, 9H), 1.26-1.36 (m, 1H), 1.00-1.12 (m, 1H). Step 7: Synthesis of cis-3-[(dimethylamino)methyl]cyclopentanamine trifluoroacetic acid salt To a solution of cis-tert-butyl N-[3-[(dimethylamino)methyl]cyclopentyl]carbamate (200 mg, 825.2 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (1.0 mL). After stirred at 25 °C for 0.5 hour, the reaction mixture was concentrated under reduced pressure to afford the title compound, which was used next step without further purification. Yield: 0.30 g (crude). Step 8: Synthesis of 6-bromo-N'-(2-chloro-5-fluoro-phenyl)-4- 3- [(dimethylamino)methyl]cyclopentyl]amino]pyrrolo[1,2-b]pyrid azine-3-carboxamidine To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (100 mg, 248.7 μmol) and cis-3-[(dimethylamino)methyl]cyclopentanamine trifluoroacetic acid salt (319 mg, 1.24 mmol) in N,N-dimethylacetamide (3.0 mL) was added N,N-diisopropylethylamine (161 mg, 1.24 mmol). After stirring at 100 °C for an hour, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (methanol) afforded the title compound as a yellow oil. Yield: 86 mg.24%. LCMS (ESI) m/z: 509.0 (M+H). Step 9: Synthesis of N'-(2-chloro-5-fluoro-phenyl)-4-[[cis-3- [(dimethylamino)methyl]cyclopentyl] amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt To a solution of 6-bromo-N'-(2-chloro-5-fluoro-phenyl)-4-[[cis-3- [(dimethylamino)methyl]cyclopentyl]amino]pyrrolo[1,2-b]pyrid azine-3-carboxamidine (66 mg, 42.9 μmol) in a solution of 1,4-dioxane (2.0 mL) and water (0.2 mL) were added 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (22 mg, 85.8 μmol), potassium phosphate (27 mg, 128.7 μmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (3 mg, 4.3 μmol) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded N'-(2-chloro-5-fluoro-phenyl)-4-[[cis-3- [(dimethylamino)methyl]cyclopentyl]amino]pyrrolo[1,2-b]pyrid azine-3-carboxamidine formic acid salt as a brown solid. LCMS (ESI) m/z: 429.3 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.45-11.48 (m, 1H), 8.19 (s, 1H), 8.17 (s, 1H, HCOOH), 7.64-7.66 (m, 1H),7.46-7.52 (m, 1H), 6.83-6.94 (m, 3H), 6.65-6.68 (m, 1H), 6.50 (s, 2H), 4.59-4.63 (m, 1H), 2.20-2.35 (m, 4H), 2.17 (s, 6H), 1.94-2.05 (m, 1H), 1.65-1.85 (m, 2H), 1.27-1.42 (m, 2H). ¹⁹ F NMR (DMSO-d ₆ , 300 MHz) δ -114.59 (s, 1F). EXAMPLE 19 Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluorophen yl)-6-(4-methoxy-2- methylphenyl)pyrrolo[1,2-b]pyridazine-3-carboximidamide To a solution of tert-butyl [trans-4-[[3-[N'-(2-chloro-5-fluorophenyl)carbamimidoyl]-6-( 4- methoxy-2-methylphenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cy clohexyl]carbamate (1.60 g, 2.58 mmol) in dichloromethane (8.0 mL) was added trifluoroacetic acid (2.0 mL). After stirring at 25 °C for 16 hours, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluorophen yl)-6- (4-methoxy-2-methylphenyl)pyrrolo[1,2-b]pyridazine-3-carboxi midamide as an off-white solid. Yield: 562.1 mg, 41%. LCMS (ESI) m/z: 521.2 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.33 (d, 1H, J=7.2 Hz), 8.20 (s, 1H), 7.81 (d, 1H, J=1.8 Hz), 7.46-7.52 (m, 1H), 7.39 (d, 1H, J=8.4 Hz), 6.83-6.92 (m, 5H), 6.54 (s, 2H), 4.04-4.11 (m, 1H), 3.78 (s, 3H), 2.51-2.60 (m, 1H), 2.44 (s, 3H), 2.07-2.13 (m, 2H), 1.72-1.81 (m, 2H), 1.15-1.42 (m, 4H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -114.40 (s, 1F). EXAMPLE 20 Synthesis of N'-(2-chloro-6-fluoro-4-hydroxy-phenyl)-4-[[(1R,5S)-8-(2-cya noethyl)-8- azabicyclo[3.2.1]octan-3-yl]amino]-6-(4-methoxy-2-methyl-phe nyl) pyrrolo[1,2-b]pyridazine-3-carboxamidine

Step 1: Synthesis of 2-chloro-6-fluoro-4-iodoaniline To a solution of 2-chloro-6-fluoro-aniline (3.00 g, 20.61 mmol) in N,N-dimethylformamide (30.0 mL) was added N-iodosuccinimide (6.96 g, 30.91 mmol). After stirring at 25 °C for 10 hours, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography fethyl acetate/petroleum ether) afforded the title compound as a light yellow solid. Yield: 3.20 g, 57%. LCMS (ESI) m/z: 271.8 (M+H). Step 2: Synthesis of 4-benzyloxy-2-chloro-6-fluoroaniline To a solution of 2-chloro-6-fluoro-4-iodoaniline (2.70 g, 9.95 mmol) in toluene (40.0 mL) were added phenylmethanol (3.23 g, 29.84 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (235 mg, 994.6 μmol), cuprous iodide (379 mg, 1.99 mmol) and cesium carbonate (6.48 g, 19.89 mmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 15 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a brown oil. Yield: 2.20 g, 59%, 68% purity. LCMS (ESI) m/z: 251.9 (M+H). Step 3: Synthesis of N'-(4-benzyloxy-2-chloro-6-fluoro-phenyl)-6-bromo-4-chloro-p yrrolo[1,2- b]pyridazine-3-carboxamidine and 6-bromo-4-chloro-N'-(2-chloro-6-fluoro-4-hydroxy- phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-4-chloro-pyrrolo[1,2-b]pyridazine-3-carbonitrile (200 mg, 780.0 μmol) in toluene (5.0 mL) was added 4-benzyloxy-2-chloro-6-fluoroaniline (196 mg, 780.0 μmol). The resulting mixture was cooled to 0 °C with ice bath and purged with nitrogen gas. Then trimethylaluminium (1.2 mL, 2.40 mmol, 2 M in toluene) was added slowly. The reaction mixture was stirred at 25 °C for 30 minutes and then heated at 100 °C for 4 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous solution of ammonium chloride and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded two fractions: the title compound as a yellow solid. Yield: 50 mg, 12%. LCMS (ESI) m/z: 509.2 (M+H). Step 4: Synthesis of 6-bromo-N'-(2-chloro-6-fluoro-4-hydroxy-phenyl)-4-[[(1R,5S)- 8-(2- cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl]amino]pyrrolo[1,2- b]pyridazine-3-carboxamidine To a solution of 6-bromo-4-chloro-N'-(2-chloro-6-fluoro-4-hydroxy-phenyl)pyrr olo[1,2- b]pyridazine-3-carboxamidine (110 mg, 263.1 μmol) in N,N-dimethylacetamide (3.0 mL) were added 3-[(1R,5S)-3-amino-8-azabicyclo[3.2.1]octan-8-yl]propanenitr ile (70 mg, 394.7 μmol) and N,N-diisopropylethylamine (102 mg, 789.4 μmol). After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 110 mg, 74%. LCMS (ESI) m/z: 562.3 (M+H). Step 5: Synthesis of N'-(2-chloro-6-fluoro-4-hydroxy-phenyl)-4-[[(1R,5S)-8-(2-cya noethyl)-8- azabicyclo[3.2.1]octan-3-yl]amino]-6-(4-methoxy-2-methyl-phe nyl)pyrrolo[1,2-b]pyridazine-3- carboxamidine To a solution of 6-bromo-N'-(2-chloro-6-fluoro-4-hydroxy-phenyl)-4-[[(1R,5S)- 8-(2-cyanoethyl)- 8-azabicyclo[3.2.1]octan-3-yl]amino]pyrrolo[1,2-b]pyridazine -3-carboxamidine (100 mg, 178.3 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.4 mL) were added (4-methoxy-2- methyl-phenyl)boronic acid (44 mg, 267.5 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene- palladium dichloride (12 mg, 17.8 μmol) and potassium phosphate (75 mg, 356.6 μmol). The resulting mixture was purged with nitrogen gas and stirred at 90 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-(2-chloro-6- fluoro-4-hydroxy-phenyl)-4-[[(1R,5S)-8-(2-cyanoethyl)-8-azab icyclo[3.2.1]octan-3-yl]amino]-6- (4-methoxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine as a light yellow solid. Yield: 23.2 mg, 21%. LCMS (ESI) m/z: 602.5 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.41 (d, 1H, J=8.0 Hz), 9.77 (brs, 1H), 8.16 (s, 1H), 7.82 (d, 1H, J=1.6 Hz), 7.40 (d, 1H, J=8.4 Hz), 6.82-6.92 (m, 3H), 6.73 (s, 1H), 6.60-6.63 (m, 1H), 6.42 (s, 2H), 4.35-4.45 (m, 1H), 3.78 (s, 3H), 3.30-3.34 (m, 2H), 2.52-2.65 (m, 4H), 2.46 (s, 3H), 1.82-2.03 (m, 4H), 1.57-1.71 (m, 4H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -119.01 (s, 1F). EXAMPLE21 Synthesis of 4-[[(1R, 3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(6-chloro- 2,3-difluoro- phenyl)-6-(4-methoxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazin e-3-carboxamidine

Step 1: Synthesis of tert-butyl N-(6-chloro-2,3-difluoro-phenyl)carbamate To a solution of 6-chloro-2,3-difluoro-benzoic acid (1.50 g, 7.79 mmol) in tert-butanol (30.0 mL) were added triethylamine (2.36 g, 23.37 mmol) and diphenyl azidophosphate (3.22 g, 11.69 mmol). The reaction mixture was stirred at 25 °C for 5 minutes and then heated at 90 °C for 15 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as an off-white solid. Yield: 650 mg, 31%. LCMS (ESI) m/z: 262.0 (M-H). ¹ H NMR (DMSO-d6, 400 MHz) δ 9.07 (s, 1H), 7.38-7.47 (m, 1H), 7.34-7.42 (m, 1H), 1.41 (s, 9H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -138.18 (s, 1F), -138.24 (s, 1F). Step 2: Synthesis of 6-chloro-2,3-difluoroaniline To a solution of tert-butyl N-(6-chloro-2,3-difluoro-phenyl)carbamate (500 mg, 1.90 mmol) in dichloromethane (15.0 mL) was added trifluoroacetic acid (3.0 mL). After stirred at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and adjusted to pH=9 with 1N aqueous solution of sodium hydroxide and extracted with dichloromethane (x3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 220 mg, 70%. LCMS (ESI) m/z: 164.2 (M+H). Step 3: Synthesis of 6-bromo-4-chloro-N'-(6-chloro-2,3-difluoro-phenyl)pyrrolo[1, 2- b]pyridazine-3-carboxamidine To a solution of 6-bromo-4-chloro-pyrrolo[1,2-b]pyridazine-3-carbonitrile (250 mg, 974.7 μmol) in toluene (5.0 mL) was added 6-chloro-2,3-difluoroaniline (239 mg, 1.46 mmol). The resulting mixture was cooled to 0 °C with ice bath and purged with nitrogen gas. Then trimethylaluminium (1.5 mL, 3.00 mmol, 2 M in toluene) was added slowly. The reaction mixture was stirred at 25°C for 30 minutes and at 100 °C for 4 hours. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous solution of ammonium chloride and extracted with ethyl acetate (x3). The combined organic layers were washed with brined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a brown yellow solid. Yield: 100 mg, 24%. LCMS (ESI) m/z: 420.8 (M+H). Step 4: Synthesis of 4-[[(1R, 3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bromo-N'-(6 - chloro-2,3-difluoro-phenyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine To a solution of 6-bromo-4-chloro-N'-(6-chloro-2,3-difluoro-phenyl)pyrrolo[1, 2-b]pyridazine-3- carboxamidine (90 mg, 214.2 μmol) in N,N-dimethylacetamide (3.0 mL) were added (1R, 3S)- 1,2,2-trimethylcyclopentane-1,3-diamine (45 mg, 321.4 μmol) and N,N-diisopropylethylamine (83 mg, 642.8 μmol). After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a brown oil. Yield: 120 mg, 84%, 79% purity. LCMS (ESI) m/z: 527.3 (M+H). Step 5: Synthesis of 4-[[(1R, 3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(6-chloro- 2,3- difluoro-phenyl)-6-(4-methoxy-2-methyl-phenyl)pyrrolo[1,2-b] pyridazine-3-carboxamidine To a solution of 4-[[(1R, 3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bromo-N'-(6 -chloro- 2,3-difluoro-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (100 mg, 190.2 μmol) in N,N- dimethylformamide (2.0 mL) and water (0.4 mL) were added (4-methoxy-2-methyl- phenyl)boronic acid (47 mg, 285.3 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene-palladium dichloride (12 mg, 19.0 μmol) and potassium phosphate (80 mg, 380.4 μmol). The resulting mixture was purged with nitrogen gas and stirred at 90 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[[(1R, 3S)-3- amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(6-chloro-2,3-di fluoro-phenyl)-6-(4-methoxy-2- methyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as a yellow solid. Yield: 16.9 mg, 15%. LCMS (ESI) m/z: 567.5 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.33 (s, 1H), 8.21 (s, 1H), 7.81 (d, 1H, J=1.6 Hz), 7.37 (d, 1H, J=8.4 Hz), 7.28-7.32 (m, 1H), 7.04-7.12 (m, 1H), 6.82- 6.91 (m, 3H), 6.65 (s, 2H), 4.42-4.52 (m, 1H), 3.77 (s, 3H), 2.43 (s, 3H), 2.19-2.32 (m, 1H), 1.54- 1.75 (m, 3H), 1.02 (s, 3H), 0.80-0.84 (m, 6H). ¹⁹ F NMR (DMSO, 376 MHz) δ -139.01 (s, 1F), - 145.09 (s, 1F). EXAMPLE 22 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-6-(2-amino-4-methyl-pyrim idin-5-yl)-N'-(2- chloro-5-fluoro-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamid ine Step 1: Synthesis of tert-butyl N-[trans-4-[[6-(2-amino-4-methyl-pyrimidin-5-yl)-3-[N'-(2- chloro-5-fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin -4- yl]amino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (80 mg, 138 μmol) and (2-amino-4-methyl-pyrimidin-5-yl)boronic acid (42 mg, 275 μmol) in N,N- dimethylformamide (3 mL) and water (0.3 mL) were added tetrakis(triphenylphosphine)palladium (16 mg, 14 μmol) and sodium carbonate (44 mg, 414 μmol). The mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (methanol/dichloromethane) afforded the title compound as a yellow oil. Yield: 80 mg, 76%. LCMS (ESI) m/z: 608.2 (M+H). Step 2: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-6-(2-amino-4-methyl-pyrim idin-5-yl)- N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b]pyridazine-3-carb oxamidine To a solution of tert-butyl N-[trans-4-[[6-(2-amino-4-methyl-pyrimidin-5-yl)-3-[N'-(2-ch loro-5- fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]ami no]cyclohexyl]carbamate (60 mg, 99 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[trans-(4-aminocyclohexyl)amino]-6-(2-amino-4- methyl-pyrimidin-5-yl)-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[ 1,2-b]pyridazine-3-carboxamidine as a white solid. Yield: 9.7 mg, 19%. LCMS (ESI) m/z: 508.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.32 (s, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 7.86 (d, 1H, J=1.6 Hz), 7.47-7.51 (m, 1H), 6.86- 6.93 (m, 3H), 6.44-6.62 (m, 4H), 4.05-4.13 (m, 1H), 2.51-2.68 (m, 1H), 2.44 (s, 3H), 2.09-2.12 (m, 2H), 1.76-1.79 (m, 2H), 1.26-1.38 (m, 4H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -114.39 (s, 1F). EXAMPLE23 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(2- cyclopropyl-4-methoxy-phenyl)pyrrolo[1,2-b]pyridazine-3-carb oxamidine

Step 1: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- (2-cyclopropyl-4-methoxy-phenyl)pyrrolo[1,2-b]pyridazin-4-yl ]amino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (120 mg, 207 μmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) were added (2-cyclopropyl-4- methoxy-phenyl)boronic acid (120 mg, 621 μmol), tetrakis(triphenylphosphine)palladium (32 mg, 21 μmol) and sodium carbonate (44 mg, 414 μmol). The resulting mixture was purge with nitrogen gas and stirred at 85 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a light yellow solid. Yield: 50 mg, 38%. LCMS (ESI) m/z: 647.1 (M+H). Step 2: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(2- cyclopropyl-4-methoxy-phenyl)pyrrolo[1,2-b]pyridazine-3-carb oxamidine To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-(2- cyclopropyl-4-methoxy-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]am ino]cyclohexyl]carbamate (50 mg, 77 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5- fluoro-phenyl)-6-(2-cyclopropyl-4-methoxy-phenyl)pyrrolo[1,2 -b]pyridazine-3-carboxamidine as a yellow solid. Yield: 6.1 mg, 14%. LCMS (ESI) m/z: 547.2 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.35 (brs, 1H), 8.19 (s, 1H), 7.83 (d, 1H, J=1.6 Hz), 7.44-7.50 (m, 1H), 7.36 (d, 1H, J=8.4 Hz), 6.98 (d, 1H, J=1.6 Hz), 6.79-6.93 (m, 3H), 6.51-6.61 (m, 3H), 4.04-4.11 (m, 1H), 3.76 (s, 3H), 2.08-2.24 (m, 3H), 1.75-1.83 (m, 2H), 1.31-1.45 (m, 3H), 1.12-1.27 (m, 2H), 0.85-0.98 (m, 3H), 0.71-0.80 (m, 2H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -114.40 (s, 1F). EXAMPLE 24 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(6-methoxy-4- methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- (6-methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]a mino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (90 mg, 155 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (52 mg, 311 μmol) in N,N- dimethylformamide (3 mL) and water (0.3 mL) were added tetrakis(triphenylphosphine)palladium (11 mg, 9 μmol) and potassium phosphate (99 mg, 466 μmol). The mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a light yellow soild. Yield: 80 mg, 78%. LCMS (ESI) m/z: 622.4 (M+H). Step 2: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclohexyl]carbamate (70 mg, 112 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5- fluoro-phenyl)-6-(6-methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b ]pyridazine-3-carboxamidine as a white solid. Yield: 32.1 mg, 53%. LCMS (ESI) m/z: 522.2 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.53 (d, 1H, J=7.2 Hz), 8.26 (s, 1H), 8.22 (s, 1H), 7.91 (d, 1H, J=1.6 Hz), 7.48-7.51 (m, 1H), 6.96 (d, 1H, J=2.0 Hz), 6.85-6.92 (m, 2H), 6.79 (s, 1H), 6.56 (s, 2H), 4.02-4.18 (m, 1H), 3.87 (s, 3H), 2.51-2.67 (m, 1H), 2.43 (s, 3H), 2.07-2.17 (m, 2H), 1.75-1.83 (m, 2H), 1.21-1.41 (m, 4H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.38 (s, 1F). EXAMPLE 25 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(6-methoxy-2- methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- (6-methoxy-2-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]a mino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (120 mg, 206.9 μmol) in N,N-dimethylformamide (3.0 mL) and water (0.6 mL) were added (6-methoxy-2- methyl-3-pyridyl)boronic acid (52 mg, 310.4 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene- palladium dichloride (13 mg, 20.7 μmol) and potassium phosphate (88 mg, 413.8 μmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 110 mg, 85%. LCMS (ESI) m/z: 622.5 (M+H). Step 2: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(6- methoxy-2-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-(6- methoxy-2-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclohexyl]carbamate (100 mg, 160.7 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (1.0 mL). After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6- (6-methoxy-2-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-car boxamidine as a yellow solid. Yield: 37.8 mg, 44%. LCMS (ESI) m/z: 522.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.35 (d, 1H, J=7.2 Hz), 8.21 (s, 1H), 7.89 (d, 1H, J=1.6 Hz), 7.80 (d, 1H, J=8.4 Hz), 7.47-7.51 (m, 1H), 6.85-6.97 (m, 3H), 6.73 (d, 1H, J=8.4 Hz), 6.56 (s, 2H), 4.05-4.14 (m, 1H), 3.87 (s, 3H), 2.55-2.68 (m, 4H), 2.07-2.16 (m, 2H), 1.77-1.81 (m, 2H), 1.21-1.42 (m, 4H). ¹⁹ F NMR (DMSO, 376 MHz) δ -114.38 (s, 1F). EXAMPLE 26 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(2-cyano-3- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine

Step 1: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- (2-cyano-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cycloh exyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (100 mg, 172 μmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-ca rbonitrile (40 mg, 173 μmol) and potassium phosphate (73 mg, 344 μmol) in N,N-dimethylformamide (2 mL) and water (0.5 mL) was added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (11 mg, 17 μmol). The mixture was purged with nitrogen gas and stirred at 90 °C for 1 hour under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 75 mg, 72%. LCMS (ESI) m/z: 603.4 (M+H). Step 2: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(2- cyano-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-(2- cyano-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohexy l]carbamate (70 mg, 116 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)- 6-(2-cyano-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidin e as an off-white solid. Yield: 16.6 mg, 28%. LCMS (ESI) m/z: 503.0 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.56 (d, 1H, J=6.9 Hz), 8.65-8.67 (m, 1H), 8.39-8.49 (m, 1H), 8.36-8.39 (m, 2H), 7.79-7.82 (m, 1H), 7.52- 7.77 (m, 1H), 7.50 (s, 1H), 6.85-6.93 (m, 2H), 6.62 (s, 2H), 4.02-4.16 (m, 1H), 2.54-2.71 (m, 1H), 2.12-2.18 (m, 2H), 1.75-1.88 (m, 2H), 1.30-1.47 (m, 4H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ - 114.33 (s, 1F). EXAMPLE 27 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(3-ethyl-4- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- (3-ethyl-4-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cycloh exyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (120 mg, 207 μmol), 3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrid ine (58 mg, 248 μmol) and potassium phosphate (88 mg, 414 μmol) in N,N-dimethylformamide (2 mL) and water (0.5 mL) was added 1,1'-bis (di-t-butylphosphino)ferrocene-palladium dichloride (14 mg, 21 μmol). The mixture was purged with nitrogen gas and stirred at 90 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 70 mg, 55%. LCMS (ESI) m/z: 606.4 (M+H). Step 2: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(3- ethyl-4-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-(3- ethyl-4-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohexy l]carbamate (70 mg, 115.49 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5- fluoro-phenyl)-6-(3-ethyl-4-pyridyl)pyrrolo[1,2-b]pyridazine -3-carboxamidine as a gray solid. Yield: 10.5 mg, 17%. LCMS (ESI) m/z: 506.2 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.46 (d, 1H, J=6.9 Hz), 8.51(s, 1H), 8.41-8.46 (m, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.47-7.52 (m, 2H), 7.04 (d, 1H, J=1.5 Hz), 6.85-6.91(m, 2H), 6.60 (s, 2H), 4.03-4.18 (m, 1H), 2.89 (q, 2H, J=7.5 Hz), 2.69-2.81 (m, 1H), 2.08-2.22 (m, 2H), 1.80-1.96 (m, 2H), 1.37-1.43 (m, 4H), 1.20-1.29 (m, 3H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -114.36 (s,1F). EXAMPLE 28 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(3-methoxy-4- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- (3-methoxy-4-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (100 mg, 172 μmol) and 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyr idine (41 mg, 173 μmol) and potassium phosphate (74 mg, 345 μmol) in N,N-dimethylformamide (2 mL) and water (0.5 mL) was added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (11 mg, 17 μmol). The mixture was purged with nitrogen gas and stirred at 90 °C for 1 hour under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 70 mg, 66%. LCMS (ESI) m/z: 608.4 (M+H). Step 2: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(3- methoxy-4-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-(3- methoxy-4-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohe xyl]carbamate (65 mg, 106 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)- 6-(3-methoxy-4-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamid ine as an off-white solid. Yield: 14.5 mg, 25%. LCMS (ESI) m/z: 508.1 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.46 (d, 1H, J=7.8 Hz), 8.45 (s, 1H), 8.14-8.32 (m, 3H), 7.80 (d, 1H, J=5.1 Hz), 7.46-7.55 (m, 1H), 7.44 (d, 1H, J=1.8 Hz), 6.82-6.95 (m, 2H), 6.57 (s, 2H), 4.11-4.19 (m, 1H), 4.05 (s, 3H), 2.57-2.65 (m, 1H), 2.10-2.20 (m, 2H), 1.75-1.90 (m, 2H), 1.24-1.50 (m, 4H). EXAMPLE 29 Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(2-methoxy-5- methyl-4-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of 4-iodo-2-methoxy-5-methyl-pyridine To a solution of 2-fluoro-4-iodo-5-methyl-pyridine (3.00 g, 12.66 mmol) in methanol (20.0 mL) was added sodium methanolate (2.05 g, 37.97 mmol). The resulting mixture was stirred at 70 °C for 15 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with water and washed with ethyl acetate (x3). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 1.50 g, 47%. LCMS (ESI) m/z: 250.1 (M+H). Step 2: Synthesis of 2-methoxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)pyridine To a solution of 4-iodo-2-methoxy-5-methyl-pyridine (1.00 g, 4.02 mmol) in N,N- dimethylformamide (10.0 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.04 g, 8.03 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (328 mg, 401.5 μmol) and potassium acetate (788 mg, 8.03 mmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 4 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light yellow solid. Yield: 1.60 g, 57%, 36% purity. LCMS (ESI) m/z: 250.0 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.00 (s, 1H), 6.90 (s, 1H), 3.81 (s, 3H), 2.31 (s, 3H), 1.31 (s, 12H). Step 3: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- (2-methoxy-5-methyl-4-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]a mino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (120 mg, 206.9 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.4 mL) were added 2-methoxy-5-methyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (103 mg, 413.9 μmol), 1,1'-bis (di-t- butylphosphino)ferrocene-palladium dichloride (13 mg, 20.7 μmol) and potassium phosphate (88 mg, 413.9 μmol). The resulting mixture was purged with nitrogen gas and stirred for at 100 °C 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 75 mg, 58%. LCMS (ESI) m/z = 622.2 (M+H). Step 4: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(2- methoxy-5-methyl-4-pyridyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-(2- methoxy-5-methyl-4-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclohexyl]carbamate (60 mg, 96.4 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (0.8 mL). After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6- (2-methoxy-5-methyl-4-pyridyl)pyrrolo[1,2-b]pyridazine-3-car boxamidine as an off-white solid. Yield: 12.9 mg, 24%. LCMS (ESI) m/z: 522.5 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.44 (brs, 1H), 8.24 (s, 1H), 8.08 (s, 1H), 8.05 (s, 1H), 7.47-7.51 (m, 1H), 7.10 (s, 1H), 7.00 (s, 1H), 6.86-6.92 (m, 2H), 6.58 (s, 2H), 4.11-4.16 (m, 1H), 3.86 (s, 3H), 2.58-2.66 (m, 1H), 2.41 (s, 3H), 2.07-2.13 (m, 2H), 1.77-1.80 (m, 2H), 1.21-1.44 (m, 4H). ¹⁹ F NMR (DMSO, 376 MHz) δ -114.37 (s, 1F). EXAMPLE 30 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[5- (difluoromethyl)-2-methyl-phenyl]pyrrolo[1,2-b]pyridazine-3- carboxamidine Step 1: Synthesis of 2-bromo-4-(difluoromethyl)-1-methyl-benzene To a solution of 3-bromo-4-methyl-benzaldehyde (2.00 g, 10.0 mmol) in dichloroethane (20 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (11.12 g, 50.2 mmol). After stirring at 70 °C for 15 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light yellow oil. Yield: 1.96 g, 88%. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.77 (t, 1H, J=1.2 Hz), 7.50 (d, 2H, J=1.2 Hz), 7.00 (t, 1H, J=55.8 Hz), 2.39 (t, 3H, J=1.5 Hz). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -109.67 (s, 2F). Step 2: Synthesis of 2-[5-(difluoromethyl)-2-methyl-phenyl]-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane To a solution of 2-bromo-4-(difluoromethyl)-1-methyl-benzene (1.00 g, 4.5 mmol) in N,N- dimethylformamide (5 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.30 g, 9.0 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (374 mg, 452 μmol) and potassium acetate (888 mg, 9.0 mmol). The resulting mixture was purge with nitrogen gas and stirred at 85 °C for 15 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (crude) as a black solid. Yield: 3.50 g, 58%. Step 3: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- [5-(difluoromethyl)-2-methyl-phenyl]pyrrolo[1,2-b]pyridazin- 4-yl]amino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (120 mg, 207 μmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) were added 2-[5-(difluoromethyl)- 2-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (167 mg, 621 μmol), 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (14 mg, 21 μmol) and potassium phosphate (88 mg, 414 μmol). The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile /water) afforded the title compound as a light yellow solid. Yield: 90 mg, 68%. LCMS (ESI) m/z: 641.1 (M+H). Step 4: Synthesis of 4- 4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phenyl)-6-[5- (difluoromethyl)-2-methyl-phenyl]pyrrolo[1,2-b]pyridazine-3- carboxamidine To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-[5- (difluoromethyl)-2-methyl-phenyl]pyrrolo[1,2-b]pyridazin-4-y l]amino]cyclohexyl]carbamate (80 mg, 124.78 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.4 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'- (2-chloro-5-fluoro-phenyl)-6-[5-(difluoromethyl)-2-methyl-ph enyl]pyrrolo[1,2-b]pyridazine-3- carboxamidine as a light yellow solid. Yield: 17.7 mg, 26%. LCMS (ESI) m/z 541.4 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.36 (s, 1H), 8.21 (s, 1H), 7.92 (d, 1H, J=1.6 Hz), 7.62 (d, 1H, J=1.6 Hz), 7.41-7.53 (m, 3H), 6.85-7.18 (m, 4H), 6.55 (s, 2H), 4.06-4.17 (m, 1H), 2.52-2.68 (m, 4H), 2.06-2.14 (m, 2H), 1.72-1.82 (m, 2H), 1.18-1.46 (m, 4H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -108.67 (s, 2F), -114.39 (s, 1F). EXAMPLE 31 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[2- (difluoromethyl)pyrimidin-5-yl]pyrrolo[1,2-b]pyridazine-3-ca rboxamidine Step 1: Synthesis of 5-bromopyrimidine-2-carbaldehyde To a solution of ethyl 5-bromopyrimidine-2-carboxylate (2.80 g, 12.12 mmol) in tetrahydrofuran (16.0 mL) was added diisobutylaluminium hydride (13.0 mL, 19.50 mmol, 1.5 M in toluene ) dropwise at -55 °C under nitrogen atmosphere. After stirring at -55 °C for an hour, the reaction mixture was quenched with saturated aqueous solution of ammonium chloride and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a brown solid. Yield: 1.50 g, 66%. LCMS (ESI) m/z: 189.1 (M+H). Step 2: synthesis of 5-bromo-2-(difluoromethyl)pyrimidine To a solution of 5-bromopyrimidine-2-carbaldehyde (300 mg, 1.60 mmol) in dichloromethane (3.0 mL) was added diethylaminosulfur trifluoride (517 mg, 3.21 mmol). After stirring at 25 °C for 2 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a brown oil. Yield: 300 mg, 34% yield, 39% purity. LCMS (ESI) m/z: 209.1 (M+H). Step 3: synthesis of 2-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2- yl)pyrimidine To a solution of 5-bromo-2-(difluoromethyl)pyrimidine (200 mg, 957.0 μmol) in 1,4-dioxane (3.0 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)-1,3,2- dioxaborolane (486 mg, 1.91 mmol), 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (79 mg, 95.7 μmol) and potassium acetate (188 mg, 1.91 mmol). The resulting mixture was purged with nitrogen gas and stirred at 90 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was diluted with ethyl acetate and washed with water and brine. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a brown oil. Yield: 260 mg, 51%, 33% purity. LCMS (ESI) m/z: 175.0 (boric acid+H). Step 4: synthesis of tert-butyl -[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6-[2- (difluoromethyl)pyrimidin-5-yl]pyrrolo[1,2-b]pyridazin-4-yl] amino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (100 mg, 172.5 μmol) in N,N-dimethylformamide (3.0 mL) and water (0.3 mL) were added 2-(difluoromethyl)-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (200 mg, 258.7 μmol), 1,1'-bis (di-t- butylphosphino)ferrocene-palladium dichloride (11 mg, 17.2 μmol) and potassium phosphate (73 mg, 344.9 μmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reversed phase chromatography (acetonitrile/water) afforded the title compound as a brown yellow solid. Yield: 130 mg, 85%. LCMS (ESI) m/z: 629.5 (M+H). Step 5: synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[2- (difluoromethyl)pyrimidin-5-yl]pyrrolo[1,2-b]pyridazine-3-ca rboxamidine To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-[2- (difluoromethyl)pyrimidin-5-yl]pyrrolo[1,2-b]pyridazin-4-yl] amino]cyclohexyl]carbamate (120 mg, 135.5 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (1.0 mL). After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5- fluoro-phenyl)-6-[2-(difluoromethyl)pyrimidin-5-yl]pyrrolo[1 ,2-b]pyridazine-3-carboxamidine as a light pink solid. Yield: 27.3 mg, 36%. LCMS (ESI) m/z: 529.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 9.44 (s, 2H), 8.48 (s, 1H), 8.25 (s, 1H), 7.44-7.52 (m, 2H), 7.00 (t, 1H, J=54.4 Hz), 6.86-6.92 (m, 2H), 6.61 (s, 2H), 4.20-4.30 (m, 1H), 2.61-2.73 (m, 1H), 2.07-2.17 (m, 2H), 1.72-1.87 (m, 2H), 1.30-1.52 (m, 4H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.34 (s, 1F), - 117.72 (s, 2F). EXAMPLE 32 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[4- (difluoromethyl)pyrimidin-5-yl]pyrrolo[1,2-b]pyridazine-3-ca rboxamidine

Step 1: Synthesis of 5-bromo-4-(difluoromethyl)pyrimidine To a solution of 5-bromopyrimidine (200 mg, 1.26 mmol) and bis(difluoromethylsulfinyloxy)zinc (744 mg, 2.52 mmol) in dichloromethane (5 mL) and water (2 mL) was added trifluoroacetic acid (0.1 mL, 1.30 mmol) at room temperature, followed by addition of tert-butylhydroperoxide (70% solution in water, 0.86 mL, 6.29 mmol) slowly with vigorous stirring. After stirring at 25 °C for 24 hours, the reaction mixture was partitioned between dichloromethane and saturated aqueous solution of sodium bicarbonate. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (x3). The combined organic layers were dried with sodium sulfate, filtered and concentrated under reduced pressure. Purification via prep-TLC (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid, which was used for next step without further purification. Yield: 120 mg (crude). LCMS (ESI) m/z: 209.1, 211.1 (M+H). Step 2: Synthesis of trans-tert-butyl N-[4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- [4-(difluoromethyl)pyrimidin-5-yl]pyrrolo[1,2-b]pyridazin-4- yl]amino]cyclohexyl]carbamate To a solution of trans-tert-butyl N-[4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]p yridazin-4- yl]amino]cyclohexyl]carbamate (150 mg, 167.4 μmol) and 5-bromo-4- (difluoromethyl)pyrimidine (120 mg, 574.2 μmol) in N,N-dimethylformamide (5 mL) and water (0.5 mL) were added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (11 mg, 16.8 μmol) and potassium phosphate (107 mg, 502.4 μmol) at room temperature. The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 70 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water, brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via prep-TLC (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 30 mg, 22%. LCMS (ESI) m/z: 629.2 (M+H). Step 3: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[4- (difluoromethyl)pyrimidin-5-yl]pyrrolo[1,2-b]pyridazine-3-ca rboxamidine To a solution of trans-tert-butyl N-[4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6-[4- (difluoromethyl)pyrimidin-5-yl]pyrrolo[1,2-b]pyridazin-4-yl] amino]cyclohexyl]carbamate (30 mg, 47.7 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (2.0 mL) dropwise. After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. The resulting solution was washed with saturated aqueous solution of sodium carbonate, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[4- (difluoromethyl)pyrimidin-5-yl]pyrrolo[1,2-b]pyridazine-3-ca rboxamidine as an off-white solid. Yield: 4.7 mg, 17%. LCMS (ESI) m/z: 529.1 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.52 (d, 1H, J= 6.8 Hz), 9.30 (s, 1H), 9.26 (s, 1H), 8.28 (s, 1H), 8.12 (d, 1H, J=1.7 Hz), 7.48-7.52 (m, 1H), 7.21 (t, 1H, J=52.9 Hz), 7.11 (d, 1H, J=1.6 Hz), 6.86-6.92 (m, 2H), 6.62 (s, 2H), 4.00-4.12 (m, 1H), 2.50-2.70 (m, 1H), 2.10-2.20 (m, 2H), 1.70-1.90 (m, 2H), 1.20-1.50 (m, 4H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -114.34 (s, 1F), -116.88 (s, 2F). EXAMPLE 33 Synthesis of N'-(2-chloro-5-fluorophenyl)-4-[[1-(6-cyanopyridazin-3-yl)pi peridin-4-yl]amino]-6- (1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxi midamide To a solution of 6-bromo-N'-(2-chloro-5-fluorophenyl)-4-[[1-(6-cyanopyridazin -3-yl)piperidin-4- yl]amino]pyrrolo[1,2-b]pyridazine-3-carboximidamide (120 mg, 210.9 μmol), 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (52 mg, 253.1 μmol) and potassium phosphate (134 mg, 632.8 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) was added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (13 mg, 21.1 μmol) at room temperature under argon atmosphere. After stirring at 90 °C for 0.5 hour, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-(2-chloro-5-fluorophenyl)-4-[[1-(6- cyanopyridazin-3-yl)piperidin-4-yl]amino]-6-(1-methyl-1H-pyr azol-4-yl)pyrrolo[1,2- b]pyridazine-3-carboximidamide as a yellow solid. Yield: 32.9 mg, 25%. LCMS (ESI) m/z: 570.1 (M+H). ¹ H-NMR (DMSO-d6, 300 MHz,) δ 11.51 (d, 1H, J=7.5 Hz), 8.20 (s, 1H), 8.07 (s, 1H), 7.94 (s, 1H), 7.84-7.88 (m, 2H), 7.37-7.48 (m, 2H), 7.12 (s, 1H), 6.82- 6.90 (m, 2H), 6.57 (brs, 2H), 4.63-4.67 (m, 1H), 4.15-4.29 (m, 2H), 3.87 (s, 3H), 3.59-3.67 (m, 2H), 2.17-2.21 (m, 2H), 1.58-1.69 (m, 2H). ¹⁹ F NMR (DMSO-d6, 282 MHz,) δ -114.36 (s, 1F). EXAMPLE 34 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(6-methoxy-3- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- (6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (150 mg, 258 μmol) in N,N-dimethylformamide (5 mL) and water (0.5 mL) were added 2-methoxy-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (91 mg, 388 μmol), 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (17 mg, 26 μmol) and potassium phosphate (110 mg, 517 μmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a light yellow solid. Yield: 120 mg, 76%. LCMS (ESI) m/z: 608.1 (M+H). Step 2: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(6- methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-(6- methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohe xyl]carbamate (110 mg, 180 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.6 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)- 6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamid ine as a white solid. Yield: 38.7 mg, 41%. LCMS (ESI) m/z: 508.1 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.32 (d, 1H, J=8.0 Hz), 8.63 (d, 1H, J=2.4 Hz), 8.17-8.19 (m, 2H), 8.10-8.14 (m, 1H), 7.47-7.51 (m, 1H), 7.16 (d, 1H, J=2.0 Hz), 6.81-6.93 (m, 3H), 6.55 (s, 2H), 4.17-4.21 (m, 1H), 3.88 (s, 3H), 2.55-2.65 (m, 1H), 2.13-2.15 (m, 2H), 1.74-1.84 (m, 2H), 1.28-1.42 (m, 4H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -114.38 (s, 1F). EXAMPLE 35 Synthesis of N'-(2-chloro-5-fluoro-phenyl)-4-[[(1S,5R)-8-(2-cyanoethyl)-8 -azabicyclo[3.2.1] octan-3-yl]amino]-6-(4-methoxy-2-methyl-phenyl)pyrrolo[1,2-b ]pyridazine-3-carboxamidine

Step 1: Synthesis of tert-butyl N-[(1R,5S)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3- yl]carbamate To a solution of tert-butyl N-[(1R,5S)-8-azabicyclo[3.2.1]octan-3-yl]carbamate (150 mg, 662.8 μmol) in ethanol (2.0 mL) were added 3-bromopropanenitrile (106 mg, 795.4 μmol) and 1,8- diazabicyclo[5.4.0]undec-7-ene (151 mg, 994.2 μmol). After stirred at 25 °C for 5 hours, the reaction mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a yellow solid. Yield: 160 mg, 86%. LCMS (ESI) m/z: 280.3 (M+H). Step 2: Synthesis of 3-[(1R,5S)-3-amino-8-azabicyclo[3.2.1]octan-8-yl]propanenitr ile To a solution of tert-butyl N-[(1R,5S)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl]ca rbamate (160 mg, 572.7 μmol) in dichloromethane (8.0 mL) was added trifluoroacetic acid (1.6 mL). After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and adjusted to pH=9 with 1N aqueous solution of sodium hydroxide and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 90 mg, 87%. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 3.16-3.20 (m, 2H), 2.71-2.83 (m, 1H), 2.54-2.61 (m, 4H), 1.74-1.81 (m, 2H), 1.41-1.61 (m, 4H), 1.20-1.35 (m, 4H). Step 3: Synthesis of 6-bromo-N'-(2-chloro-5-fluoro-phenyl)-4-[[(1R,5S)-8-(2-cyano ethyl)-8- azabicyclo[3.2.1]octan-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (120 mg, 298.5 μmol) in N,N-dimethylacetamide (3.0 mL) were added 3- [(1R,5S)-3-amino-8-azabicyclo[3.2.1]octan-8-yl]propanenitril e (80 mg, 447.7 μmol) and N,N- diisopropylethylamine (116 mg, 895.4 μmol). After stirring at 100 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 140 mg, 86%. LCMS (ESI) m/z: 544.0 (M+H). Step 4: Synthesis of N'-(2-chloro-5-fluoro-phenyl)-4-[[(1S,5R)-8-(2-cyanoethyl)-8 - azabicyclo[3.2.1]octan-3-yl]amino]-6-(4-methoxy-2-methyl-phe nyl)pyrrolo[1,2-b]pyridazine-3- carboxamidine To a solution of 6-bromo-N'-(2-chloro-5-fluoro-phenyl)-4-[[(1S,5R)-8-(2-cyano ethyl)-8- azabicyclo[3.2.1]octan-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine (100 mg, 183.5 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.4 mL) were added (4-methoxy-2- methyl-phenyl)boronic acid (45 mg, 275.3 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene- palladium dichloride (12 mg, 18.4 μmol) and potassium phosphate (78 mg, 367.1 μmol). The resulting mixture was purged with nitrogen gas and stirred at 90 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-(2-chloro-5- fluoro-phenyl)-4-[[(1S,5R)-8-(2-cyanoethyl)-8-azabicyclo[3.2 .1]octan-3-yl]amino]-6-(4- methoxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxami dine -as an off-white solid. Yield: 27.3 mg, 24%. LCMS (ESI) m/z: 586.4 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.23 (brs, 1H), 8.19 (s, 1H), 7.83 (s, 1H), 7.47-7.51 (m, 1H), 7.40 (d, 1H, J=8.4 Hz), 6.84-6.90 (m, 5H), 6.57 (s, 2H), 4.35-4.45 (m, 1H), 3.78 (s, 3H), 3.31-3.33 (m, 2H), 2.56-2.64 (m, 4H), 2.46 (s, 3H), 1.96-2.04 (m, 2H), 1.88-1.94 (m, 2H), 1.58-1.73 (m, 4H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -114.34 (s, 1F). EXAMPLE 36 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-6-(4-amino-2-methyl-pheny l)-N'-(2-chloro-5- fluoro-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of tert-butyl N-[trans-4-[4-[[4-(tert-butoxycarbonylamino)cyclohexyl]amino ]- 3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b] pyridazin-6-yl]-3-methyl- phenyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (120 mg, 207 μmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) were added tert-butyl N-[2-methyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbam ate (207 mg, 621 μmol), 1,1'- bis(di-t-butylphosphino)ferrocene-palladium dichloride (14 mg, 21 μmol) and potassium phosphate (88 mg, 414 μmol). The resulting mixture was purge with nitrogen gas and stirred at 85 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a light yellow solid. Yield: 100 mg, 64%. LCMS (ESI) m/z: 706.2 (M+H). Step 2: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-6-(4-amino-2-methyl-pheny l)-N'-(2- chloro-5-fluoro-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamid ine To a solution of tert-butyl N-[trans-4-[4-[[4-(tert-butoxycarbonylamino)cyclohexyl]amino ]-3- [N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]py ridazin-6-yl]-3-methyl- phenyl]carbamate (90 mg, 127 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.6 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[trans-(4- aminocyclohexyl)amino]-6-(4-amino-2-methyl-phenyl)-N'-(2-chl oro-5-fluoro- phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as a light yellow solid. Yield: 23 mg, 35%. LCMS (ESI) m/z: 506.2 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.27 (d, 1H, J=7.6 Hz), 8.16 (s, 1H), 7.70 (d, 1H, J=1.6 Hz), 7.47-7.51 (m, 1H), 7.14 (d, 1H, J=8.0 Hz), 6.80-6.93 (m, 3H), 6.45-6.57 (m, 4H), 5.03 (s, 2H), 4.02-4.08 (m, 1H), 2.52-2.58 (m, 1H), 2.32 (s, 3H), 2.08-2.14 (m, 2H), 1.74-1.82 (m, 2H), 1.32-1.42 (m, 2H), 1.18-1.28 (m, 2H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.42 (s, 1F). EXAMPLE 37 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[4- (dimethylamino)-2-methyl-phenyl]pyrrolo[1,2-b]pyridazine-3-c arboxamidine

Step 1: Synthesis of N,N,3-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline To a mixture of 4-bromo-N,N,3-trimethyl-aniline (300 mg, 1.4 mmol) and 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxabor olane (712 mg, 2.8 mmol) and potassium acetate (1.17 g, 2.8 mmol) in N,N-dimethylformamide (2 mL) was added 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride (205 mg, 280 μmol). The resulting mixture was purged with nitrogen gas and stirred at 90 °C for 16 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 150 mg, 40%. LCMS (ESI) m/z: 262.3 (M+H). Step 2: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- [4-(dimethylamino)-2-methyl-phenyl]pyrrolo[1,2-b]pyridazin-4 -yl]amino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (120 mg, 207 μmol), N,N,3-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline (54 mg, 207 μmol) and potassium phosphate (88 mg, 414 μmol) in N,N-dimethylformamide (2 mL) and water (0.5 mL) was added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (14 mg, 21 μmol). The resulting mixture was purged with nitrogen gas and stirred at 90 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/ petroleum ether) afforded the title compound as a yellow oil. Yield: 75 mg, 57%. LCMS (ESI) m/z: 634.4 (M+H). Step 3: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[4- (dimethylamino)-2-methyl-phenyl]pyrrolo[1,2-b]pyridazine-3-c arboxamidine To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-[4- (dimethylamino)-2-methyl-phenyl]pyrrolo[1,2-b]pyridazin-4-yl ]amino]cyclohexyl]carbamate (70 mg, 110 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[4- (dimethylamino)-2-methyl-phenyl]pyrrolo[1,2-b]pyridazine-3-c arboxamidine as an off-white solid. Yield: 6.0 mg, 10%. LCMS (ESI) m/z: 534.2 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.32 (d, 1H, J=8.1 Hz), 8.41 (s, 1H), 8.19 (s, 1H), 7.77 (d, 1H, J=1.8 Hz), 7.45-7.55 (m, 1H), 7.26-7.34 (m, 1H), 6.81-6.94 (m, 3H), 6.60-6.70 (m, 1H), 6.55 (s, 2H), 4.02-4.12 (m, 1H), 2.91 (s, 6H), 2.78-2.86 (m, 1H), 2.42 (s, 3H), 2.09-2.21 (m, 2H), 1.80-1.96 (m, 2H), 1.33-1.47 (m, 4H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -114.40 (s,1F). EXAMPLE 38 Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(4-methoxy-2- prop-1-ynyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine

Step 1: Synthesis of 1-bromo-4-methoxy-2-prop-1-ynyl-benzene To a suspension of cuprous iodide (182 mg, 958.7 μmol) and bis(triphenylphosphine)palladium(II) chloride (112 mg, 159.8 μmol) in toluene (5.0 mL) were added 1-bromo-2-iodo-4-methoxy-benzene (1.00 g, 3.20 mmol), 1-(trimethylsilyl)-1-propyne (359 mg, 3.20 mmol), triethylamine (970 mg, 9.59 mmol) and tetrabutylammonium fluoride (1M in tetrahydrofuran, 3.2 mL, 3.20 mmol). After stirring at 25 °C for 16 hours, the reaction mixture was diluted with ethyl acetate and the solids were filtered out. The filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a brown oil. Yield: 500 mg, 69%. ¹ H NMR (Chloroform-d, 300 MHz) δ 7.43 (d, 1H, J=9.0 Hz), 6.98 (d, 1H, J=3.0 Hz), 6.72 (dd, 1H, J=9.0, 3.0 Hz), 3.79 (s, 3H), 2.14 (s, 3H). Step 2: Synthesis of (4-methoxy-2-prop-1-ynyl-phenyl)boronic acid To a solution of 1-bromo-4-methoxy-2-prop-1-ynyl-benzene (300 mg, 1.33 mmol) in tetrahydrofuran (10.0 mL) was added n-butyl lithium (2.5 M in hexane, 0.6 mL, 1.50 mmol) dropwise at -78 °C under nitrogen atmosphere. After stirring for 30 min at the same temperature, triisopropyl borate (501 mg, 2.67 mmol) was added at -78 °C and the reaction mixture was left to stir gradually warming up to 25°C over 4 hours. The reaction mixture was quenched with 1 N aqueous solution of hydrochloric acid and then extracted with diethyl ether, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification via prep-TLC (ethyl acetate/petroleum ether) afforded the title compound as a brown solid. LCMS (ESI) m/z: 191.2 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.72 (s, 2H), 7.50-7.53 (m, 1H), 6.85-6.91 (m, 2H), 3.76 (s, 3H), 2.05 (s, 3H). Step 3: Synthesis of trans-tert-butyl N-[4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- (4-methoxy-2-prop-1-ynyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl ]amino]cyclohexyl]carbamate To a solution of trans-tert-butyl N-[4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (100 mg, 172.4 μmol) and (4-methoxy-2-prop-1-ynyl-phenyl)boronic acid (65 mg, 344.9 μmol) in N,N- dimethylformamide (5.0 mL) and water (0.5 mL) were added potassium phosphate (73 mg, 344.9 μmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (11 mg, 17.2 μmol) . The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 90 °C for 1 hour, the reaction mixture was cooled to room temperature and diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light yellow solid. Yield: 80 mg, 59%. LCMS (ESI) m/z: 645.1 (M+H). Step 4: Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(4- methoxy-2-prop-1-ynyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carb oxamidine To a solution of trans-tert-butyl N-[4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6-(4- methoxy-2-prop-1-ynyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]am ino]cyclohexyl]carbamate (80 mg, 124.0 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (2.0 mL) dropwise at 0°C. After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane. The resulting solution was washed with saturated aqueous solution of sodium carbonate, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(4-methoxy-2- prop-1-ynyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as a light yellow solid. Yield: 20.6 mg, 29%. LCMS (ESI) m/z: 545.1 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.38-11.40 (m, 1H), 8.19 (s, 1H), 8.04 (d, 1H, J=1.8 Hz), 7.46-7.57 (m, 2H), 7.24 (d, 1H, J=1.5 Hz), 6.97-7.03 (m, 2H), 6.84-6.92 (m, 2H), 6.55 (s, 2H), 4.02-4.09 (m, 1H), 3.82 (s, 3H), 2.56-2.63 (m, 1H), 2.10-2.15 (m, 5H), 1.75-1.88 (m, 2H), 1.10-1.50 (m, 4H). ¹⁹ F NMR (282 MHz, DMSO-d6, ppm) δ -114.38. EXAMPLE 39 Synthesis of methyl 4-[4-[trans-(4-aminocyclohexyl)amino]-3-[N'-(2-chloro-5-fluo ro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl- benzoate Step 1: Synthesis of methyl 4-[trans-4-[[4-(tert-butoxycarbonylamino)cyclohexyl]amino]-3 -[N'- (2-chloro-5-fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyrida zin-6-yl]-3-methyl-benzoate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[(Z)-N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (200 mg, 344 μmol), methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benz oate (95 mg, 344 μmol) and potassium phosphate (147 mg, 690 μmol) in N,N-dimethylformamide (2 mL) and water (0.5 mL) was added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (23 mg, 35 μmol). The resulting mixture was purged with nitrogen gas and stirred at 90 °C for 1 hour under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 160 mg, 71%. LCMS (ESI) m/z: 649.3 (M+H). Step 2: Synthesis of methyl 4-[4-[trans-(4-aminocyclohexyl)amino]-3-[N'-(2-chloro-5-fluo ro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl- benzoate To a solution of methyl 4-[trans-4-[[4-(tert-butoxycarbonylamino)cyclohexyl]amino]-3 -[N'-(2- chloro-5-fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin -6-yl]-3-methyl-benzoate (65 mg, 100 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded methyl 4-[4-[trans-(4- aminocyclohexyl)amino]-3-[(Z)-N'-(2-chloro-5-fluoro-phenyl)c arbamimidoyl]pyrrolo[1,2- b]pyridazin-6-yl]-3-methyl-benzoate as an off-white solid. Yield: 15.9 mg, 27%. LCMS (ESI) m/z: 549.4 (M+H) ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.42 (d, 1H, J=6.0 Hz), 8.24 (s, 1H), 8.01 (s, 1H), 7.88-7.94 (m, 1H), 7.78-7.86 (m, 1H), 7.61-7.71 (m, 1H), 7.44-7.54 (m, 1H), 7.05 (s, 1H), 6.85-6.91 (m, 2H), 6.75 (s, 2H), 4.01-4.11 (m, 1H), 3.87 (s, 3H), 2.50-2.63 (m, 4H), 2.09- 2.17 (m, 2H), 1.71-1.89 (m, 2H), 1.19-1.51 (m, 4H). ¹⁹ F NMR (DMSO-d ₆ , 282 MHz) δ -114.37 (s,1F). EXAMPLE 40 Synthesis of [4-[4-[( trans-4-aminocyclohexyl)amino]-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl- phenyl] acetate

Step 1: Synthesis of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen ol To a solution of 4-bromo-3-methyl-phenol (1.00 g, 5.35 mmol) and 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxabor olane (1.36 g, 5.35 mmol) in 1,4- dioxane (30 mL) were added potassium acetate (1.57 g, 16.04 mmol) and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (218 mg, 267.3 μmol) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 90 °C for 15 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as an off- white solid. Yield: 0.80 g, 63%. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.61 (s, 1H), 7.45-7.49 (m, 1H), 6.57 (s, 2H), 2.38 (s, 3H), 1.27 (s, 12H). Step 2: Synthesis of [3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe nyl] acetate To a solution of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen ol (200 mg, 854.3 μmol) in pyridine (5.0 mL) was added acetyl acetate (130.8 mg, 1.28 mmol) dropwise under nitrogen atmosphere. After stirring at 25 °C for 2 hours, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as an off-white solid. Yield: 120 mg, 50%. 1H NMR (DMSO-d6, 300 MHz) δ 7.64-7.67 (m, 1H), 6.95 (s, 2H), 2.47 (s, 3H), 2.26 (s, 3H), 1.30 (s, 12H). Step 3: Synthesis of [4-[4-[[ trans-4-(tert-butoxycarbonylamino)cyclohexyl]amino]-3-[N'-(2 - chloro-5-fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin -6-yl]-3-methyl-phenyl] acetate To a solution of trans-tert-butyl N-[4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (110 mg, 189.7 μmol) and [3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe nyl] acetate (52 mg, 189.7 μmol) in N,N-dimethylformamide (6.0 mL) and water (0.3 mL) were added potassium phosphate (80 mg, 379.4 μmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (12 mg, 18.9 μmol) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 90 °C for 0.5 hour, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light yellow solid. Yield: 100 mg, 73%. LCMS (ESI) m/z: 649.2 (M+H). Step 4: Synthesis of [4-[4-[( trans-4-aminocyclohexyl)amino]-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl- phenyl] acetate ( To a solution of [4-[4-[[trans-4-(tert-butoxycarbonylamino)cyclohexyl]amino]- 3-[N'-(2-chloro-5- fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3- methyl-phenyl] acetate (90 mg, 138.6 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (2.0 mL) dropwise at 0°C. After stirring at 25 °C for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane. The resulting solution was washed with saturated aqueous solution of sodium carbonate, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded [4-[4-[(trans-4-aminocyclohexyl)amino]-3-[N'-(2-chloro-5-flu oro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl- phenyl] acetate as an off-white solid. Yield: 19.1 mg, 23%. LCMS (ESI) m/z: 549.3 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.32-11.37 (m, 1H), 8.22 (s, 1H), 7.90 (s, 1H), 7.46-7.51 (m, 2H), 6.84-7.08 (m, 5H), 6.65 (s, 2H), 3.95-4.09 (m, 1H), 2.68-2.73 (m, 1H), 2.37 (s, 3H), 2.25 (s, 3H), 2.11-2.15 (m, 2H), 1.77- 1.81 (m, 2H), 1.15-1.44 (m, 4H). ¹⁹ F NMR (DMSO-d ₆ , 282 MHz) δ -114.38 (s, 1F). EXAMPLE 41 Synthesis of 4-[trans-4-[(4-aminocyclohexyl)amino]-3-[N'-(2-chloro-5-fluo ro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl- benzoic acid Step 1: Synthesis of 4-[trans-4-[[4-(tert-butoxycarbonylamino)cyclohexyl]amino]-3 -[N'-(2- chloro-5-fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin -6-yl]-3-methyl-benzoic acid To a solution of methyl 4-[trans-4-[[4-(tert-butoxycarbonylamino)cyclohexyl]amino]-3 -[N'-(2- chloro-5-fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin -6-yl]-3-methyl-benzoate (80 mg, 123 μmol) in methanol (2 mL) was added 1.0 M sodium hydroxide in water (2 mL). The resulting mixture was stirred at 25 °C for 1 hour, then diluted with water, acidified with hydrochloric acid and extracted with ethyl acetate (x3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 62 mg, 83%. LCMS (ESI) m/z = 635.1 (M+H). Step 2: Synthesis of 4-[trans-4-[(4-aminocyclohexyl)amino]-3-[N'-(2-chloro-5-fluo ro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl- benzoic acid To a solution of 4-[trans-4-[[4-(tert-butoxycarbonylamino)cyclohexyl]amino]-3 -[N'-(2-chloro-5- fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3- methyl-benzoic acid (60 mg, 94 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[trans-4-[(4-aminocyclohexyl)amino]-3-[(Z)-N'-(2- chloro-5-fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin -6-yl]-3-methyl-benzoic acid as an off-white solid. Yield: 4.3 mg, 8%. LCMS (ESI) m/z: 535.1 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.44 (d, 1H, J = 8.1 Hz), 8.23 (s, 1H), 7.95 (d, 1H, J = 1.5 Hz), 7.73-7.86 (m, 2H), 7.45- 7.57 (m, 2H), 7.06 (s, 1H), 6.86-6.92 (m, 2H), 6.59 (s, 2H), 4.10-4.30 (m, 1H), 2.90-3.08 (m, 1H), 2.39 (s, 3H), 2.12-2.30 (m, 2H), 1.85-2.10 (m, 4H), 1.34-1.56 (m, 2H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -114.38 (s, 1H). EXAMPLE 42 Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(4-hydroxy-2- methyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of trans-tert-butyl N-[4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- (4-hydroxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclohexyl]carbamate To a solution of trans-tert-butyl N-[4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (120 mg, 206.9 μmol) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen ol (48 mg, 206.9 μmol) in N,N-dimethylformamide (5.0 mL) and water (0.5 mL) were added potassium phosphate (88 mg, 413.8 μmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (14 mg, 20.7 μmol). The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 90 °C for 1 hour, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 100 mg, 57%. LCMS (ESI) m/z: 607.1 (M+H). Step 2: Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(4- hydroxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxami dine To a solution of trans-tert-butyl N-[4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6-(4- hydroxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]c yclohexyl]carbamate (100 mg, 164.7 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (2.0 mL) dropwise at 0°C. After stirring at 25 °C for 2 hours, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in dichloromethane, washed with saturated aqueous solution of sodium carbonate, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 4-[(trans-4- aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phenyl)-6-(4-hy droxy-2-methyl- phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine ) as an off-white solid. Yield: 17.2 mg, 19%. LCMS (ESI) m/z: 507.3 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.32-11.37 (m, 1H), 9.38 (brs, 1H), 8.18 (s, 1H), 7.76 (s, 1H), 7.46-7.51 (m, 1H), 7.25-7.28 (m, 1H), 6.85-6.91 (m, 3H), 6.68-6.74 (m, 2H), 6.65 (s, 2H), 3.95-4.09 (m, 1H), 2.68-2.73 (m, 1H), 2.37 (s, 3H), 2.11-2.15 (m, 2H), 1.81-1.85 (m, 2H), 1.25-1.44 (m, 4H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -114.40 (s, 1F). EXAMPLE 43 Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2,6-dichlorophenyl)-6 -(4-methoxy-2- methyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine

Step 1: Synthesis of 6-bromo-4-chloro-N'-(2,6-dichlorophenyl)pyrrolo[1,2-b]pyrida zine-3- carboxamidine To a mixture of 6-bromo-4-chloro-pyrrolo[1,2-b]pyridazine-3-carbonitrile (200 mg, 779.7 μmol) and 2,6-dichloroaniline (152 mg, 935.7 μmol) in toluene (10 mL) was added 1.2 mL of trimethylalumane (2M in Toluene, 2.40 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature and heated to 50 °C for 16 hours. The reaction mixture was cooled to room temperature and quenched with saturated aqueous solution of ammonium chloride at 0°C. The resulting mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 200 mg, 61%. LCMS (ESI) m/z: 418.9 (M+H). Step 2: Synthesis of trans-tert-butyl N-[4-[[6-bromo-3-[N'-(2,6- dichlorophenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]am ino]cyclohexyl]carbamate To a solution of 6-bromo-4-chloro-N'-(2,6-dichlorophenyl)pyrrolo[1,2-b]pyrida zine-3- carboxamidine (190 mg, 454.0 μmol) and trans-tert-butyl N-(4-aminocyclohexyl)carbamate (117 mg, 544.8 μmol) in N,N-dimethylacetamide (10 mL) was added N,N-diisopropylethylamine (117 mg, 908.0 μmol). After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 180 mg, 66%. LCMS (ESI) m/z: 597.3 (M+H). Step 3: Synthesis of trans-tert-butyl N-[4-[[3-[N'-(2,6-dichlorophenyl)carbamimidoyl]-6-(4- methoxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]c yclohexyl]carbamate To a solution of trans-tert-butyl N-[4-[[6-bromo-3-[N'-(2,6- dichlorophenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]am ino]cyclohexyl]carbamate (120 mg, 201.2 μmol) and 2-(4-methoxy-2-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-diox aborolane (75 mg, 301.8 μmol) in N,N-dimethylformamide (5.0 mL) and water (0.5 mL) were added potassium phosphate (85 mg, 402.4 μmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (13 mg, 20.1 μmol). The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 90 °C for 1 hour, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 100 mg, 77%. LCMS (ESI) m/z: 637.0 (M+H). Step 4: Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2,6-dichlorophenyl)-6 -(4-methoxy- 2-methyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of trans-tert-butyl N-[4-[[3-[N'-(2,6-dichlorophenyl)carbamimidoyl]-6-(4-methoxy - 2-methyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohexy l]carbamate (90 mg, 141.1 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (1.0 mL) dropwise at 0°C. After stirring at 25 °C for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane. The resulting solution was washed with saturated aqueous solution of sodium carbonate, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 4-[(trans-4-aminocyclohexyl)amino]-N'-(2,6-dichlorophenyl)-6 -(4-methoxy-2-methyl- phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as an off-white solid. Yield: 23.3 mg, 30%. LCMS (ESI) m/z: 537.4 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.02-11.06 (m, 1H), 8.17 (s, 1H), 7.82 (s, 1H), 7.38-7.46 (m, 3H), 7.01-7.07 (m, 1H), 6.83-6.90 (m, 3H), 6.43 (s, 2H), 4.02- 4.13 (m, 1H), 3.78 (s, 3H), 2.58-2.60 (m, 1H), 2.44 (s, 3H), 2.11-2.15 (m, 2H), 1.76-1.80 (m, 2H), 1.17-1.41 (m, 4H). EXAMPLE 44 Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2,6-dimethylphenyl)-6 -(4-methoxy-2- methyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine

Step 1: 6-bromo-4-chloro-N'-(2,6-dimethylphenyl)pyrrolo[1,2-b]pyrida zine-3-carboxamidine To a mixture of 6-bromo-4-chloro-pyrrolo[1,2-b]pyridazine-3-carboxamide (200 mg, 728.6 μmol) and 2,6-dimethylaniline (106 mg, 874.3 μmol) in toluene (5.0 mL) was added dropwise 1.1 mL of trimethylalumane (2M in toluene, 2.20 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature and heated to 50 °C for 4 hours. The reaction mixture was cooled to room temperature and quenched with saturated ammonium chloride aqueous solution at 0°C. The resulting mixture was diluted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 180 mg, 65%. LCMS (ESI) m/z: 379.0 (M+H). Step 2: trans-tert-butyl N-[4-[[6-bromo-3-[N'-(2,6-dimethylphenyl)carbamimidoyl]pyrro lo[1,2- b]pyridazin-4-yl]amino]cyclohexyl]carbamate To a solution of 6-bromo-4-chloro-N'-(2,6-dimethylphenyl)pyrrolo[1,2-b]pyrida zine-3- carboxamidine (180 mg, 476.6 μmol) and trans-tert-butyl N-(4-aminocyclohexyl)carbamate (153 mg, 714.9 μmol) in N,N-dimethylacetamide (5.0 mL) was added N,N-diisopropylethylamine (185 mg, 1.43 mmol). After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 170 mg, 64%. LCMS (ESI) m/z: 557.2 (M+H). Step 3: trans-tert-butyl N-[4-[[3-[N'-(2,6-dimethylphenyl)carbamimidoyl]-6-(4-methoxy -2- methyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohexyl] carbamate To a solution of trans-tert-butyl N-[4-[[6-bromo-3-[(Z)-N'-(2,6- dimethylphenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]am ino]cyclohexyl]carbamate (150 mg, 270.0 μmol) and 2-(4-methoxy-2-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-diox aborolane (134 mg, 540.0 μmol) in N,N-dimethylformamide (5.0 mL) and water (0.5 mL) were added potassium phosphate (115 mg, 540.0 μmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (18 mg, 27.0 μmol) at room temperature. The resulting mixture was purged with nitrogen for 5 minutes. After stirring at 80 °C for 1 hour, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water, brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 100 mg, 62%. LCMS (ESI) m/z: 597.3 (M+H). Step 4: 4-[(trans-4-aminocyclohexyl)amino]-N'-(2,6-dimethylphenyl)-6 -(4-methoxy-2-methyl- phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of trans-tert-butyl N-[4-[[3-[N'-(2,6-dimethylphenyl)carbamimidoyl]-6-(4- methoxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]c yclohexyl]carbamate (90 mg, 150.8 μmol) in dichloromethane (2.0 mL) was added dropwise trifluoroacetic acid (1.0 mLl) at 0°C. After stirring at 25 °C for 1 hour, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane. The resulting solution was washed with saturated aqueous solution of sodium carbonate, water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 4-[(trans-4-aminocyclohexyl)amino]-N'-(2,6-dimethylphenyl)-6 -(4-methoxy-2-methyl- phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as an off-white solid. Yield: 15.2 mg, 19%. LCMS (ESI) m/z: 497.2 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.91 (d, 1H, J=7.8 Hz), 8.22 (s, 1H), 7.80 (s, 1H), 7.40 (d, 1H, J=7.8 Hz), 7.04-7.08 (m, 2H), 6.83-6.90 (m, 4H), 5.82 (s, 2H), 4.00-4.12 (m, 1H), 3.78 (s, 3H), 2.50-2.66 (m, 1H), 2.44 (s, 3H), 2.11-2.16 (m, 2H), 2.08 (s, 6H), 1.75-1.80 (m, 2H), 1.18-1.39 (m, 4H). EXAMPLE 45 Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2,6-diethylphenyl)-6- (4-methoxy-2- methylphenyl)pyrrolo[1,2-b]pyridazine-3-carboximidamide Step 1: Synthesis of 6-bromo-4-chloro-N'-(2,6-diethylphenyl)pyrrolo[1,2-b]pyridaz ine-3- carboximidamide To a solution of 6-bromo-4-chloro-pyrrolo[1,2-b]pyridazine-3-carbonitrile (200 mg, 779.7 μmol) and 2,6-diethylaniline (174 mg, 1.17 mmol) in toluene (10.0 mL) was added trimethylalumane (1.2 mL, 2 M in toluene, 2.40 mmol) dropwise under 0°C. The resulting mixture was stirred at 0°C for 0.5 hour, then stirred at 50 °C for 16 hours. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous solution of sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 170 mg, 53%. LCMS (ESI) m/z: 406.9 (M+H). Step 2: Synthesis of tert-butyl [trans-4-[[6-bromo-3-[N'-(2,6- diethylphenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]ami no]cyclohexyl]carbamate To a solution of 6-bromo-4-chloro-N'-(2,6-diethylphenyl)pyrrolo[1,2-b]pyridaz ine-3- carboximidamide (170 mg, 419.0 μmol) and trans-tert-butyl N-(4-aminocyclohexyl)carbamate (134 mg, 628.5 μmol) in N,N-dimethylacetamide (2.0 mL) was added N,N-diisopropylethylamine (162 mg, 1.26 mmol) dropwise. After stirring at 80 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 140 mg, 57%. LCMS (ESI) m/z: 585.2 (M+H). Step 3: Synthesis of tert-butyl [trans-4-[[3-[N'-(2,6-diethylphenyl)carbamimidoyl]-6-(4-meth oxy- 2-methylphenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohexyl ]carbamate To a mixture of tert-butyl [trans-4-[[6-bromo-3-[N'-(2,6- diethylphenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]ami no]cyclohexyl]carbamate (90 mg, 154.2 μmol) and 2-(4-methoxy-2-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-diox aborolane (45 mg, 185.0 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (10 mg, 15.4 μmol) and potassium phosphate (98 mg, 462.6 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was heated at 90 °C for 2 hours. After cooled to room temperature, the reaction mixture was diluted with ethyl acetated and washed with saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 80 mg, 83 %. LCMS (ESI) m/z: 623.4 (M-H). Step 4: Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2,6-diethylphenyl)-6- (4-methoxy- 2-methylphenyl)pyrrolo[1,2-b]pyridazine-3-carboximidamide To a solution of tert-butyl [trans-4-[[3-[N'-(2,6-diethylphenyl)carbamimidoyl]-6-(4-meth oxy-2- methylphenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohexyl]c arbamate (100 mg, 160.0 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (1.0 mL) dropwise. The reaction mixture was stirred at 25 °C for 2 hours then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[(trans-4-aminocyclohexyl)amino]-N'-(2,6-diethylphenyl)-6- (4- methoxy-2-methylphenyl)pyrrolo[1,2-b]pyridazine-3-carboximid amide as a white solid. Yield: 24.7 mg, 29%. LCMS (ESI) m/z: 525.2 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.20 (d, 1H, J=7.8 Hz), 8.23 (s, 1H), 7.80 (s, 1H), 7.39 (d, 1H, J=8.4 Hz), 7.06-7.10 (m, 2H), 6.90-6.98 (m, 1H), 6.83-6.89 (m, 3H), 5.78 (s, 2H), 4.05-4.15 (m, 1H), 3.78 (s, 3H), 2.34-2.49 (m, 8H), 2.11- 2.17 (m, 2H), 1.60-1.78 (m, 2H), 1.24-1.35 (m, 4H), 1.01-1.15 (m, 6H). EXAMPLE 46 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(4-methoxy- 2,6-dimethyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- (4-methoxy-2,6-dimethyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl] amino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (100 mg, 172 μmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) were added (4-methoxy-2,6- dimethyl-phenyl)boronic acid (93 mg, 517 μmol), 1,1'-bis(di-t-butylphosphino)ferrocene- palladium dichloride (11 mg, 17 μmol) and potassium phosphate (74 mg, 345 μmol). The resulting mixture was purge with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow oil. Yield: 60 mg, 55%. LCMS (ESI) m/z: 635.4 (M+H). Step 2: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(4- methoxy-2,6-dimethyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carbo xamidine To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-(4- methoxy-2,6-dimethyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]ami no]cyclohexyl]carbamate (50 mg, 78 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'- (2-chloro-5-fluoro-phenyl)-6-(4-methoxy-2,6-dimethyl-phenyl) pyrrolo[1,2-b]pyridazine-3- carboxamidine as a white solid. Yield: 13.4 mg, 32%. LCMS (ESI) m/z: 535.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.26 (d, 1H, J=8.0 Hz), 8.18 (s, 1H), 7.59 (d, 1H, J=1.6 Hz), 7.45-7.51 (m, 1H), 6.85-6.91 (m, 2H), 6.70 (s, 2H), 6.65 (d, 1H, J=1.6 Hz), 6.53 (s, 2H), 3.99-4.09 (m, 1H), 3.75 (s, 3H), 2.58-2.61 (m, 1H), 2.13 (s, 6H), 2.04-2.12 (m, 2H), 1.71-1.77 (m, 2H), 1.13-1.42 (m, 4H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.42 (s, 1F). EXAMPLE 47 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[6-[2-[2-[2-[2- [2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-4-me thyl-3-pyridyl]pyrrolo[1,2- b]pyridazine-3-carboxamidine formic acid salt

Step 1: Synthesis of 5-bromo-2-[2-[2-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-4-methyl-p yridine To a solution of 5-bromo-2-fluoro-4-methyl-pyridine (500 mg, 2.6 mmol) in N,N- dimethylformamide (5 mL) were added 2,5,8,11,14,17-hexaoxanonadecan-19-ol (1.20 g, 4.0 mmol) and cesium carbonate (2.60 g, 7.8 mmol). The resulting mixture was stirred at 90 °C for 15 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light yellow oil. Yield: 750 mg, 58%. LCMS (ESI) m/z: 468.0 (M+H). Step 2: Synthesis of 2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethox y]ethoxy]-4- methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridi ne To a solution of 5-bromo-2-[2-[2-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-4-methyl-p yridine (200 mg, 428 μmol) in N,N-dimethylformamide (2 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (218 mg, 858 μmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (36 mg, 43 μmol) and potassium acetate (126 mg, 1.3 mmol). The resulting mixture was purged with nitrogen gas and stirred at 90 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with brine (x3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (crude) as a black oil, which was used for next step directly without further purification. Yield: 2.50 g, 91%. LCMS (ESI) m/z: 514.2 (M+H). Step 3: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- [6-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]etho xy]ethoxy]-4-methyl-3- pyridyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohexyl]carbam ate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (80 mg, 138 μmol) in N,N-dimethylformamide (2 mL) and water (0.2 mL) were added 2-[2-[2-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-4-methyl-5 -(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (142 mg, 276 μmol), 1,1'-bis(di-t-butylphosphino)ferrocene- palladium dichloride (9 mg, 14 μmol) and potassium phosphate (89 mg, 414 μmol). The mixture was purged with nitrogen gas, stirred at 80 °C for 2 hours under nitrogen atmosphere and then cooled to room temperature. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow soild. Yield: 80 mg, 45%. LCMS (ESI) m/z: 886.3 (M+H). Step 4: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[6-[2- [2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]eth oxy]-4-methyl-3- pyridyl]pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-[6-[2- [2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]eth oxy]-4-methyl-3- pyridyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohexyl]carbam ate (70 mg, 79 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (1.5 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[6-[2-[2-[2-[2-[2- (2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-4-methy l-3-pyridyl]pyrrolo[1,2- b]pyridazine-3-carboxamidine formic acid salt as a light-yellow solid. Yield: 14.2 mg, 21%. LCMS (ESI) m/z: 786.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.37 (s, 1H), 8.42 (s, 1H), 8.23 (d, 2H, J=6.0 Hz), 7.93 (d, 1H, J=1.6 Hz), 7.47-7.51 (m, 1H), 6.81-6.95 (m, 4H), 6.58 (s, 2H), 4.38-4.40 (m, 2H), 4.09-4.19 (m, 1H), 3.74-3.77 (m, 2H), 3.58-3.60 (m, 2H), 3.50-3.56 (m, 2H), 3.44-3.49 (m, 12H), 3.40-3.42 (m, 4H), 3.23 (s, 3H), 2.80-2.90 (m, 1H), 2.43 (s, 3H), 2.10- 2.18 (m, 2H), 1.84-1.94 (m, 2H), 1.38-1.45 (m, 4H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -114.38 (s, 1F). EXAMPLE 48 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[6-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]-4-methyl-3-pyridyl]pyrrolo[1,2- b]pyridazine-3-carboxamidine formic acid salt Step 1: Synthesis of 5-bromo-2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]-4-methyl-pyr idine To a solution of 5-bromo-2-fluoro-4-methyl-pyridine (2.00 g, 10.5 mmol) in N,N- dimethylformamide (10 mL) were added 2-(2-(2-methoxyethoxy)ethoxy)ethan-1-ol (2.60 g, 15.8 mmol) and cesium carbonate (10.30 g, 15.79 mmol). The resulting mixture was stirred at 90 °C for 15 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light yellow oil. Yield: 3.20 g, 89%. LCMS (ESI) m/z: 334.0 (M+H). Step 2: Synthesis of 2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]-4-methyl-5-(4,4,5,5- tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine) To a solution of 5-bromo-2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]-4-methyl-pyr idine (200 mg, 598 μmol) in N,N-dimethylformamide (5 mL) were 1,1'-bis(diphenylphosphino)ferrocene- palladium(II) dichloride dichloromethane complex (50 mg, 60 μmol), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxabor olane (304 mg, 1.2 mmol) and potassium acetate (176 mg, 1.8 mmol). The mixture was purged with nitrogen gas and stirred at 85 °C for 15 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light yellow oil. Yield: 600 mg, 71%. LCMS (ESI) m/z: 382.1 (M+H). Step 3: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- [6-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]-4-methyl-3-pyridyl] pyrrolo[1,2-b]pyridazin-4- yl]amino]cyclohexyl]carbamate) To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (80 mg, 138 μmol) in N,N-dimethylformamide (2 mL) and water (0.2 mL) were added 2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]-4-methyl-5-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2- yl)pyridine (79 mg, 207 μmol), 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (9 mg, 14 μmol) and potassium phosphate (88 mg, 414 μmol). The mixture was purged with nitrogen gas, stirred at 80 °C for 2 hours under nitrogen atmosphere and then cooled to room temperature. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow soild. Yield : 70 mg, 65%. LCMS (ESI) m/z: 754.3 (M+H). Step 4: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[6-[2- [2-(2-methoxyethoxy)ethoxy]ethoxy]-4-methyl-3-pyridyl]pyrrol o[1,2-b]pyridazine-3- carboxamidine formic acid salt To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-[6-[2- [2-(2-methoxyethoxy)ethoxy]ethoxy]-4-methyl-3-pyridyl]pyrrol o[1,2-b]pyridazin-4- yl]amino]cyclohexyl]carbamate (60 mg, 79 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-[trans-(4- aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phenyl)-6-[6-[2 -[2-(2- methoxyethoxy)ethoxy]ethoxy]-4-methyl-3-pyridyl]pyrrolo[1,2- b]pyridazine-3-carboxamidine formic acid salt as a yellow solid. Yield: 12.9 mg, 22%. LCMS (ESI) m/z: 654.2 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.33-11.40 (m, 1H), 8.40 (s, 1H, HCO ₂ H), 8.22-8.24 (m, 2H), 7.93 (d, 1H, J=1.6 Hz), 7.48-7.50 (m, 1H), 6.86-6.95 (m, 3H), 6.81 (s, 1H), 6.59 (s, 2H), 4.39 (t, 2H, J=4.8 Hz), 4.10-4.20 (m, 1H), 3.75 (t, 2H, J=4.8 Hz), 3.57-3.60 (m, 2H), 3.48-3.55 (m, 4H), 3.42-3.44 (m, 2H), 3.24 (s, 3H), 2.81-2.97 (m, 1H), 2.44 (s, 3H), 2.16-2.19 (m, 2H), 1.92-1.95 (m, 2H), 1.35-1.50 (m, 4H). ¹⁹ F NMR (DMSO-d6, 376 MHz 6) δ -114.37 (s, 1F). EXAMPLE 49 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(2-chloro-4- methoxy-6-methyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxami dine Step 1: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- (2-chloro-4-methoxy-6-methyl-phenyl)pyrrolo[1,2-b]pyridazin- 4-yl]amino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]p yridazin-4- yl]amino]cyclohexyl]carbamate (150 mg, 239 μmol) and 2-bromo-1-chloro-5-methoxy-3-methyl- benzene (68 mg, 287 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (16 mg, 24 μmol) and potassium phosphate (153 mg, 718 μmol) at room temperature. The resulting mixture was purged with nitrogen atmosphere and stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 100 mg, 64%. LCMS (ESI) m/z: 655.1 (M+H). Step 2: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(2- chloro-4-methoxy-6-methyl-phenyl)pyrrolo[1,2-b]pyridazine-3- carboxamidine To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-(2- chloro-4-methoxy-6-methyl-phenyl)pyrrolo[1,2-b]pyridazin-4-y l]amino]cyclohexyl]carbamate (90 mg, 137 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (1.0 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'- (2-chloro-5-fluoro-phenyl)-6-(2-chloro-4-methoxy-6-methyl-ph enyl)pyrrolo[1,2-b]pyridazine-3- carboxamidine as an off-white solid. Yield: 12.1 mg, 15%. LCMS (ESI) m/z: 555.1 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.33 (d, 1H, J=7.5 Hz), 8.21 (s, 1H), 7.68 (d, 1H, J=1.5 Hz), 7.46-7.52 (m, 1H), 7.00 (d, 1H, J=2.7 Hz), 6.82-6.96 (m, 3H), 6.76 (d, 1H, J=1.5 Hz), 6.55 (s, 2H), 3.95-4.04 (m, 1H), 3.80 (s, 3H), 2.58-2.62 (m, 1H), 2.22 (s, 3H), 2.08-2.12 (m, 2H), 1.75- 1.79 (m, 2H), 1.13-1.45 (m, 4H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -114.40 (s, 1F). EXAMPLE 50 Synthesis of 4-[[(cis)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-ph enyl)-6-(3-isopropyl- 1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine

Step 1: Synthesis of 4-bromo-3-isopropyl-1-tetrahydropyran-2-yl-pyrazole A mixture of 4-bromo-3-isopropyl-1H-pyrazole (700 mg, 3.70 mmol), DHP (934 mg, 11.11 mmol) and trifluoroacetic acid (42 mg, 370.3 μmol) was stirred at 60 °C for 15 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturation aqueous solution of sodium bicarbonate, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 950 mg, 69%, 74% purity. LCMS (ESI) m/z: 273.0 (M+H). Step 2: Synthesis of 3-isopropyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1, 3,2- dioxaborolan-2-yl)pyrazole To a solution of 4-bromo-3-isopropyl-1-tetrahydropyran-2-yl-pyrazole (500 mg, 1.83 mmol) in N,N-dimethylformamide (20.0 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.16 g, 4.58 mmol), 1,1'-bis (di-t- butylphosphino)ferrocene-palladium dichloride (119 mg, 183.0 μmol) and potassium acetate (359 mg, 3.66 mmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 4 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a brown oil. Yield: 80 mg, 13%. LCMS (ESI) m/z: 321.2 (M+H). Step 3: Synthesis of tert-butyl N-[(cis)-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-(3- isopropyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)pyrrolo[1,2-b] pyridazin-4- yl]amino]cyclopentyl]carbamate To a solution of tert-butyl N-[(cis)-3-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (105 mg, 185.6 μmol) in N,N-dimethylformamide (3.0 mL) and water (0.3 mL) were added 3-isopropyl-1- tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol an-2-yl)pyrazole (71 mg, 222.7 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene-palladium dichloride (12 mg, 18.6 μmol) and potassium phosphate (78 mg, 371.1 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a brown solid. Yield: 90 mg, 29%, 41% purity. LCMS (ESI) m/z: 679.2 (M+H). Step 4: Synthesis of 4-[[(cis)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-ph enyl)-6-(3- isopropyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxa midine To a solution of tert-butyl N-[(cis)-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-(3- isopropyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)pyrrolo[1,2-b] pyridazin-4- yl]amino]cyclopentyl]carbamate (80 mg, 48.3 μmol) in dichloromethane (4.0 mL) were added trifluoroacetic acid (3.0 mL). After stirring at 25 °C for 3 hours, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[[(cis)-3- aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-phenyl)-6-(3-i sopropyl-1H-pyrazol-4- yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as a yellow solid. Yield: 11.2 mg, 44%. LCMS (ESI) m/z: 495.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.37 (s, 1H), 8.17 (s, 1H), 7.73-7.82 (m, 2H), 7.47-7.51 (m, 1H), 6.84-6.95 (m, 3H), 6.51 (s, 2H), 4.57-4.66 (m, 1H), 3.28-3.30 (m, 1H), 2.40-2.56 (m, 1H), 2.05-2.15 (m, 1H), 1.70-1.95 (m, 2H), 1.32-1.50 (m, 2H), 1.22-1.30 (m, 6H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.48 (s, 1F). EXAMPLE 51 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(4-methyl- 1,3-benzodioxol-5-yl)pyrrolo[1,2-b]pyridazine-3-carboxamidin e Step 1: Synthesis of 5-bromo-4-methylbenzo[d][1,3]dioxole) To a solution of 5-bromo-1,3-benzodioxole-4-carbaldehyde (500 mg, 2.2 mmol) in toluene (5 mL) were added potassium hydroxide (370 mg, 6.6 mmol) and hydrazine hydrate (2.0 g, 6.6 mmol). After stirring at 145 °C for 2 hours, the reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 280 mg, 59%. ¹ H NMR (Chloroform- d, 300 MHz) δ 6.94 (d, 1H, J=8.4 Hz), 6.50 (d, 1H, J=8.4 Hz), 5.90 (s, 2H), 2.19 (s, 3H). Step 2: Synthesis of 4,4,5,5-tetramethyl-2-(4-methylbenzo[d][1,3]dioxol-5-yl)-1,3 ,2- dioxaborolane ) To a mixture of 5-bromo-4-methylbenzo[d][1,3]dioxole (250 mg, 1.1 mmol), 4,4,5,5-tetramethyl- 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxab orolane (590 mg, 2.3 mmol) and potassium acetate (968 mg, 2.3 mmol) in N,N-dimethylformamide (3 mL) was added 1,1'- bis(diphenylphosphino)ferrocene-palladium(II) dichloride (85 mg, 116 μmol). The mixture was purged with nitrogen gas and stirred at 85 °C for 15 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 200 mg, 65%. LCMS (ESI) m/z: 263.2 (M+H). Step 3: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- (4-methyl-1,3-benzodioxol-5-yl)pyrrolo[1,2-b]pyridazin-4-yl] amino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (100 mg, 172 μmol), 4,4,5,5-tetramethyl-2-(4-methylbenzo[d][1,3]dioxol-5-yl)-1,3 ,2-dioxaborolane (55 mg, 207 μmol) and potassium phosphate (73.21 mg, 344.89 μmol) in N,N-dimethylformamide (2 mL) and water (0.2 mL) was added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (11 mg, 17 μmol). The mixture was purged with nitrogen gas and stirred at 90 °C for an hour. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 70 mg, 63%. LCMS (ESI) m/z: 635.4 (M+H). Step 4: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(4- methyl-1,3-benzodioxol-5-yl)pyrrolo[1,2-b]pyridazine-3-carbo xamidine To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-(4- methyl-1,3-benzodioxol-5-yl)pyrrolo[1,2-b]pyridazin-4-yl]ami no]cyclohexyl]carbamate (260 mg, 204 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'- (2-chloro-5-fluoro-phenyl)-6-(4-methyl-1,3-benzodioxol-5-yl) pyrrolo[1,2-b]pyridazine-3- carboxamidine as an off-white solid. Yield: 7.4 mg, 13%. LCMS (ESI) m/z: 535.2 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.36 (d, 1H, J=7.5 Hz), 8.20 (s, 1H), 7.81 (d, 1H, J=1.8 Hz), 7.48-7.51 (m, 1H), 6.82-6.99 (m, 5H), 6.55 (s, 2H), 6.04 (s, 2H), 4.03-4.15 (m, 1H), 2.72-2.76 (m, 1H), 2.30 (s, 3H), 2.07-2.13 (m, 2H), 1.75-1.93 (s, 2H), 1.25-1.50 (m, 4H). ¹⁹ F NMR (DMSO-d ₆ , 282 MHz) δ -114.39 (s, 1F). EXAMPLE 52 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[6-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]-4-methyl-3-pyridyl]pyrro lo[1,2-b]pyridazine-3- carboxamidine Step 1: Synthesis of 5-bromo-2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]-4- methyl- pyridine) To a solution of 5-bromo-2-fluoro-4-methyl-pyridine (3.00 g, 15.7 mmol) in N,N- dimethylformamide (20 mL) were added 2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethanol (4.90 g, 23.6 mmol) and cesium carbonate (15.40 g, 47.3 mmol). The mixture was stirred at 90 °C for 15 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with brine (x3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light yellow oil. Yield: 4.70 g, 77%. LCMS (ESI) m/z: 379.9 (M+H). Step 2: Synthesis of 2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]-4-methyl-5 -(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine To a mixture of 5-bromo-2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]-4- methyl-pyridine (1.00 g, 2.6 mmol) in N,N-dimethylformamide (10 mL) were added 1,1'- bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane-complex (219 mg, 264 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)-1,3,2- dioxaborolane (1.30 g, 5.3 mmol) and potassium acetate (778 mg, 7.9 mmol). The mixture was purged with nitrogen gas, stirred at 90 °C for 3 hours under nitrogen atmosphere and then cooled to room temperature. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a brown oil. Yield: 900 mg, 77%. LCMS (ESI) m/z: 426.3 (M+H). Step 3: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- [6-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]-4-methyl- 3-pyridyl]pyrrolo[1,2- b]pyridazin-4-yl]amino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (600 mg, 1.0 mmol) in N,N-dimethylformamide (6 mL) and water (0.6 mL) were added 2-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]-4-methyl-5-(4,4,5,5-tetr amethyl-1,3,2-dioxaborolan-2- yl)pyridine (880 mg, 2.1 mmol), 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (67 mg, 103 μmol) and potassium phosphate (659 mg, 3.1 mmol). The resulting mixture was purged with nitrogen gas, stirred at 80 °C for 2 hours under nitrogen atmosphere and then cooled to room temperature. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow soild. Yield: 600 mg, 70%. LCMS (ESI) m/z: 798.1 (M+H). Step 4: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[6-[2- [2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]-4-methyl-3-pyri dyl]pyrrolo[1,2-b]pyridazine-3- carboxamidine To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-[6-[2- [2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]-4-methyl-3-pyri dyl]pyrrolo[1,2-b]pyridazin-4- yl]amino]cyclohexyl]carbamate (600 mg, 751 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[6-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]-4-methyl-3-pyridyl]pyrro lo[1,2-b]pyridazine-3- carboxamidine as a grey solid. Yield: 271.7 mg, 50%. LCMS (ESI) m/z: 698.4 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.36 (d, 1H, J=8.4 Hz), 8.21-8.24 (m, 2H), 7.91 (d, 1H, J=1.6 Hz), 7.47-7.51 (m, 1H), 6.97 (d, 1H, J=1.6 Hz), 6.86-6.91 (m, 2H), 6.80 (s, 1H), 6.56 (s, 2H), 4.38- 4.40 (m, 2H), 4.05-4.15 (m, 1H), 3.74-3.76 (m, 2H), 3.58-3.60 (m, 2H), 3.50-3.55 (m, 8H), 3.41- 3.43 (m, 2H), 3.23 (s, 3H), 2.52-2.67 (m, 1H), 2.43 (s, 3H), 2.06-2.16 (m, 2H), 1.71-1.85 (m, 2H), 1.20-1.43 (m, 4H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ-114.38 (s, 1F). EXAMPLE 53 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(6-methyl- 1,3-benzodioxol-5-yl)pyrrolo[1,2-b]pyridazine-3-carboxamidin e Step 1: Synthesis of 5-bromo-6-methylbenzo[d][1,3]dioxole To a solution of 6-bromo-1,3-benzodioxole-5-carbaldehyde (200 mg, 873 μmol) in diethylene glycol (2 mL) were added potassium hydroxide (147 mg, 2.6 mmol) and hydrazine hydrate (779 mg, 2.6 mmol) and stirred at 145 °C for 2 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 150 mg, 79%. ¹ H NMR (Chloroform-d, 300 MHz) δ 6.96 (s, 1H), 6.69 (s, 1H), 5.91 (s, 2H), 2.27 (s, 3H). Step 2: Synthesis of 4,4,5,5-tetramethyl-2-(6-methylbenzo[d][1,3]dioxol-5-yl)-1,3 ,2- dioxaborolane To a mixture of 5-bromo-6-methylbenzo[d][1,3]dioxole (200 mg, 930 μmol), 4,4,5,5-tetramethyl- 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxab orolane (473 mg, 1.9 mmol) and potassium acetate (775 mg, 1.9 mmol) in N,N-dimethylformamide (2 mL) was added 1,1'- bis(diphenylphosphino)ferrocene-palladium(II) dichloride (68 mg, 93μmol). The mixture was purged with nitrogen gas and stirred at 85 °C for 15 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 150 mg, 61%. LCMS (ESI) m/z: 263.2 (M+H). Step 3: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- (6-methyl-1,3-benzodioxol-5-yl)pyrrolo[1,2-b]pyridazin-4-yl] amino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (100 mg, 172 μmol), 4,4,5,5-tetramethyl-2-(6-methylbenzo[d][1,3]dioxol-5-yl)-1,3 ,2-dioxaborolane (55 mg, 207 μmol) and potassium phosphate (74 mg, 345 μmol) in N,N-dimethylformamide (2 mL) and water (0.2 mL) was added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (11 mg, 17 μmol). The mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 150 mg, 68%. LCMS (ESI) m/z: 635.4 (M+H). Step 4: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(6- methyl-1,3-benzodioxol-5-yl)pyrrolo[1,2-b]pyridazine-3-carbo xamidine To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-(6- methyl-1,3-benzodioxol-5-yl)pyrrolo[1,2-b]pyridazin-4-yl]ami no]cyclohexyl]carbamate (130 mg, 204 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'- (2-chloro-5-fluoro-phenyl)-6-(6-methyl-1,3-benzodioxol-5-yl) pyrrolo[1,2-b]pyridazine-3- carboxamidine as an off-white solid. Yield: 7.9 mg, 7%. LCMS (ESI) m/z: 535.2 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.34 (d, 1H, J=7.8 Hz), 8.19 (s, 1H), 7.82 (d, 1H, J=1.8 Hz), 7.46-7.51 (m, 1H), 7.05 (s, 1H), 6.84-6.90 (m, 4H), 6.54 (s, 2H), 6.00 (s, 2H), 4.05-4.17 (m, 1H), 2.58-2.72 (m, 1H), 2.37 (s, 3H), 2.06-2.22 (m, 2H), 1.75-1.90 (m, 2H), 1.23-1.43 (m, 4H). ¹⁹ F NMR (DMSO-d ₆ , 282 MHz) δ -114.39 (s, 1F). EXAMPLE 54 Synthesis of N'-(2-chloro-5-fluoro-phenyl)-6-(4-methoxy-2-methyl-phenyl)- 4-[[trans-4- (pentylamino)cyclohexyl]amino]pyrrolo[1,2-b]pyridazine-3-car boxamidine To a solution of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(4- methoxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxami dine (140 mg, 268.7 μmol) and pentanal (16 mg, 188.1 μmol) in dichloromethane (10 mL) was added sodium triacetoxyborohydride (85 mg, 403.0 μmol) in portions under nitrogen atmosphere. After stirring at 25 °C for 16 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded N'-(2-chloro-5-fluoro-phenyl)-6- (4-methoxy-2-methyl-phenyl)-4-[[trans-4-(pentylamino)cyclohe xyl]amino]pyrrolo[1,2- b]pyridazine-3-carboxamidine as a light yellow solid. Yield: 36.2 mg, 22%. LCMS (ESI) m/z: 591.2 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.38 (d, 1H, J=6.3 Hz), 8.22 (s, 1H), 7.81 (d, 1H, J=1.4 Hz), 7.41-7.51 (m, 1H), 7.35-7.39 (m, 1H), 6.82-6.92 (m, 5H), 6.56 (s, 2H), 4.05-4.15 (m, 1H), 3.77 (s, 3H), 2.40-2.51 (m, 5H), 2.28-2.38 (m, 1H), 2.11-2.16 (m, 2H), 1.85-1.90 (m, 2H), 1.30-1.40 (m, 4H), 1.15-1.27 (m, 7H), 0.85 (t, 3H, J=6.8 Hz). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.40 (s, 1F). EXAMPLE 55 Synthesis of N-[(trans)-4-[[3-[N'-(2-chloro-5-fluorophenyl)carbamimidoyl] -6-(4-methoxy-2- methylphenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohexyl]- 2,2,2-trifluoro-N- methylacetamide Step 1: synthesis of tert-butyl N-trans-[4-[(2,2,2-trifluoroacetyl)amino]cyclohexyl]carbamat e To a solution of tert-butyl N-trans-(4-aminocyclohexyl)carbamate (1.00 g, 4.67 mmol) in methanol (5.0 mL) was added methyl trifluoroacetate (1.20 g, 9.33 mmol). After stirring at 25 °C for 4 hours, the reaction mixture was diluted with diethyl ether and washed with water. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a grey solid. Yield: 700 mg, 48%. LCMS (ESI) m/z: 255.2 (M-56+H). Step 2: synthesis of tert-butyl N-trans-[4-[methyl-(2,2,2-trifluoroacetyl) amino]cyclohexyl]carbamate To a solution of tert-butyl N-trans-[4-[(2,2,2-trifluoroacetyl)amino]cyclohexyl]carbamat e (600 mg, 1.93 mmol) in N,N-dimethylacetamide (7.0 mL) was added sodium hydride (93 mg, 2.32 mmol, 60% purity) under nitrogen atmosphere. After stirring at 25 °C for 20 minutes, iodomethane (329 mg, 2.32 mmol) was added dropwise under nitrogen atmosphere. After stirring at 25 °C for 3 hours, the reaction mixture was quenched with water and extracted with ethyl acetate (x3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a yellow solid. Yield: 500 mg, 79%. LCMS (ESI) m/z: 269.2 (M-56+H). Step 3: synthesis of N-trans-(4-aminocyclohexyl)-2,2,2-trifluoro-N-methyl-acetami de hydrochloric acid salt A mixture of tert-butyl N-trans-[4-[methyl-(2,2,2-trifluoroacetyl)amino]cyclohexyl]c arbamate (480 mg, 1.48 mmol) and solution of 4 M hydrogen chloride in 1,4-dioxane (5 mL) was stirred at 25 °C for an hour. The reaction mixture was concentrated under reduced pressure to afford the title compound as a yellow solid, which was used for next step directly without further purification. Yield: 350 mg. LCMS (ESI) m/z: 225.2 (M+H). Step 4: synthesis of N-trans-[4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]-2,2,2-trifluoro-N- methyl-acetamide To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (250 mg, 621.8 μmol) in N,N-dimethylacetamide (3.0 mL) were added N-trans- (4-aminocyclohexyl)-2,2,2-trifluoro-N-methyl-acetamide hydrochloric acid salt (210 mg, 808.4 μmol) and N,N-diisopropylethylamine (241 mg, 1.87 mmol). After stirring at 100 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 210 mg, 57%. LCMS (ESI) m/z: 591.3 (M+H). Step 5: synthesis of N-trans-[4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-(4-methoxy- 2-methyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohexy l]-2,2,2-trifluoro-N-methyl- acetamide To a solution of N-trans-[4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]-2,2,2-trifluoro-N- methyl-acetamide (200 mg, 339.1 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added (4-methoxy-2-methyl-phenyl)boronic acid (84 mg, 508.6 μmol), 1,1'-bis (di-t- butylphosphino)ferrocene-palladium dichloride (22 mg, 33.9 μmol) and potassium phosphate (144 mg, 678.2 μmol). The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded N-trans-[4-[[3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]-6-(4-methoxy-2-methyl-phenyl)pyrrolo[1 ,2-b]pyridazin-4- yl]amino]cyclohexyl]-2,2,2-trifluoro-N-methyl-acetamide as a yellow solid. Yield: 190 mg, 88%. 50 mg was re-purified via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N-trans-[4-[[3-[(Z)-N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]-6-(4-methoxy-2-methyl-phenyl)pyrrolo[1 ,2-b]pyridazin-4- yl]amino]cyclohexyl]-2,2,2-trifluoro-N-methyl-acetamide as a yellow solid. Yield: 15.4 mg. LCMS (ESI) m/z: 631.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.37 (d, 1H, J=6.0 Hz), 8.21 (s, 1H), 7.81 (d, 1H, J=1.6 Hz), 7.48-7.53 (m, 1H), 7.38-7.41 (m, 1H), 7.01-7.04 (m, 1H), 6.83- 6.93 (m, 4H), 6.57 (s, 2H), 4.13-4.25 (m, 1.4H), 3.78 (s, 3H), 3.64-3.74 (m, 0.6H), 2.97-3.06 (m, 3H), 2.44 (s, 3H), 2.20-2.30 (m, 2H), 1.88-2.12 (m, 2H), 1.61-1.73 (m, 2H), 1.42-1.55 (m, 2H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -67.84 (s, 1.2F), -68.73 (s, 1.8F), -114.39 (s, 1F). EXAMPLE 56 Synthesis of N'-trans-(2-chloro-5-fluoro-phenyl)-6-(4-methoxy-2-methyl-ph enyl)-4-[[4- (methylamino)cyclohexyl]amino]pyrrolo[1,2-b]pyridazine-3-car boxamidine To a suspension of N-trans-[4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-(4-methoxy- 2-methyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohexy l]-2,2,2-trifluoro-N-methyl- acetamide (120 mg, 190.2 μmol) in methanol (6.0 mL) was added 1 N aqueous solution of sodium hydroxide (3.0 mL, 3.00 mmol). After stirring at 50 °C for 5 hours, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-trans-(2- chloro-5-fluoro-phenyl)-6-(4-methoxy-2-methyl-phenyl)-4-[[4- (methylamino)cyclohexyl]amino]pyrrolo[1,2-b]pyridazine-3-car boxamidine as a light yellow solid. Yield: 21.9 mg, 21%. LCMS (ESI) m/z: 535.4 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.36 (d, 1H, J=7.6 Hz), 8.20 (s, 1H), 7.81 (d, 1H, J=1.6 Hz), 7.47-7.51 (m, 1H), 7.40 (d, 1H, J=8.4 Hz), 6.83-6.95 (m, 5H), 6.54 (s, 2H), 4.05-4.18 (m, 1H), 3.77 (s, 3H), 2.44 (s, 3H), 2.21- 2.35 (m, 4H), 2.07-2.16 (m, 2H), 1.83-1.96 (m, 2H), 1.33-1.41 (m, 2H), 1.15-1.25 (m, 2H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.40 (s, 1F). EXAMPLE 57 Synthesis of N'-(2-chloro-5-fluoro-phenyl)-6-(4-methoxy-2-methyl-phenyl)- 4-[(1-propylsulfonyl- 4-piperidyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of tert-butyl N-(1-propylsulfonyl-4-piperidyl)carbamate To a solution of tert-butyl N-(4-piperidyl)carbamate (200 mg, 998 μmol) in dichloromethane (5 mL) were added propane-1-sulfonyl chloride (214 mg, 1.5 mmol) and triethylamine (303 mg, 3.0 mmol). After stirring at room temperature for 2 hours, the reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate twice. The combined organic layers were washed with water twice and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a white solid. Yield: 300 mg, 93%. ¹ H NMR (DMSO-d6, 300 MHz) δ 6.91 (d, 1H, J=7.8 Hz), 3.46-3.60 (m, 2H), 3.38-3.42 (m, 1H), 2.93-3.03 (m, 2H), 2.81-2.85 (m, 2H), 1.59- 1.83 (m, 6H), 1.39 (s, 9H), 0.93-1.10 (m, 3H). Step 2: Synthesis of 1-propylsulfonylpiperidin-4-amine To a solution of tert-butyl N-(1-propylsulfonyl-4-piperidyl)carbamate (300 mg, 979 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. The residue was diluted with dichloromethane and water, then basified with an aqueous solution of sodium hydroxide and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a yellow solid, which was used for next step directly without further purification. Yield: 200 mg, 94%. ¹ H NMR (DMSO-d6, 300 MHz) δ 8.02 (s, 2H), 3.57- 3.67 (m, 2H), 3.10-3.16 (m, 1H), 2.95-3.07 (m, 2H), 2.83-2.88 (m, 2H), 1.89-2.01 (m, 2H), 1.60- 1.77 (m, 2H), 1.41-1.60 (m, 2H), 0.98 (t, 3H, J=7.5 Hz). Step 3: Synthesis of 6-bromo-N'-(2-chloro-5-fluoro-phenyl)-4-[(1-propylsulfonyl-4 - piperidyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (100 mg, 248 μmol) in N,N-dimethylacetamide (3 mL) were added 1- propylsulfonylpiperidin-4-amine (103 mg, 498 μmol) and N-ethyl-N-isopropyl-propan-2-amine (96 mg, 746 μmol). The resulting mixture was stirred at 100 °C for 2 hours and then cooled to room temperature. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a white solid. Yield : 120 mg, 78%. LCMS (ESI) m/z: 573.0 (M+H). Step 4: Synthesis of N'-(2-chloro-5-fluoro-phenyl)-6-(4-methoxy-2-methyl-phenyl)- 4-[(1- propylsulfonyl-4-piperidyl)amino]pyrrolo[1,2-b]pyridazine-3- carboxamidine To a solution of 6-bromo-N'-(2-chloro-5-fluoro-phenyl)-4-[(1-propylsulfonyl-4 - piperidyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine (100 mg, 174 μmol) and (4-methoxy- 2-methyl-phenyl)boronic acid (58 mg, 349 μmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (11 mg, 17 μmol) and potassium phosphate (111 mg, 524 μmol). The resulting mixture was purged with nitrogen gas, stirred at 90 °C for 2 hours under nitrogen atmosphere and then cooled to room temperature. Purification via reverse phase column chromatography (acetonitrile/water) afforded crude product. Further purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded N'-(2-chloro-5-fluoro-phenyl)-6- (4-methoxy-2-methyl-phenyl)-4-[(1-propylsulfonyl-4-piperidyl )amino]pyrrolo[1,2-b]pyridazine- 3-carboxamidine as a light yellow solid. Yield: 45.2 mg, 40%. LCMS (ESI) m/z: 613.4 (M+H). 1H NMR (DMSO-d6, 400 MHz) δ 11.58-11.65 (m, 1H), 8.24 (s, 1H), 7.82 (d, 1H, J=1.6 Hz), 7.49-7.52 (m, 1H), 7.39-7.41 (m, 1H), 6.99 (s, 1H), 6.82-6.93 (m, 4H), 6.60 (s, 2H), 4.42-4.51 (m, 1H), 3.77 (s, 3H), 3.35-3.39 (m, 2H), 3.17-3.23 (m, 2H), 2.86-2.89 (m, 2H), 2.43 (s, 3H), 2.07-2.13 (m, 2H), 1.60-1.67 (m, 4H), 0.94 (t, 3H, J=7.4 Hz). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ - 114.31 (s, 1F). EXAMPLE 58 Synthesis of N'-(2-chloro-5-fluoro-phenyl)-6-(4-methoxy-2-methyl-phenyl)- 4-[(1-methyl-4- piperidyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of 6-bromo-N'-(2-chloro-5-fluoro-phenyl)-4-[(1-methyl-4- piperidyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (120 mg, 298 μmol) in N,N-dimethylacetamide (3 mL) were added 1- methylpiperidin-4-amine (52 mg, 448 μmol) and N,N-diisopropylethylamine (116 mg, 896 μmol). The resulting mixture was stirred at 85 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a light yellow solid. Yield: 130 mg, 91%. LCMS (ESI) m/z: 481.1 (M+H). Step 2: Synthesis of N'-(2-chloro-5-fluoro-phenyl)-6-(4-methoxy-2-methyl-phenyl)- 4-[(1-methyl- 4-piperidyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-(2-chloro-5-fluoro-phenyl)-4-[(1-methyl-4- piperidyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine (120 mg, 250 μmol) in N,N- dimethylformamide (3 mL) and water (0.3 mL) were added (4-methoxy-2-methyl-phenyl)boronic acid (62 mg, 375 μmol), 1,1'-Bis (di-t-butylphosphino)ferrocene-palladium dichloride (16 mg, 25 μmol) and potassium phosphate (106 mg, 500 μmol). The resulting mixture was purge with nitrogen gas and stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded N'-(2-chloro-5-fluoro-phenyl)-6-(4- methoxy-2-methyl-phenyl)-4-[(1-methyl-4-piperidyl)amino]pyrr olo[1,2-b]pyridazine-3- carboxamidine as a white solid. Yield: 17.2 mg, 13%. LCMS (ESI) m/z: 521.2 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.49 (d, 1H, J=6.8 Hz), 8.21 (s, 1H), 7.81 (d, 1H, J=1.6 Hz), 7.50-7.55 (m, 1H), 7.39 (d, 1H, J=8.4 Hz), 6.81-6.93 (m, 5H), 6.55 (s, 2H), 4.19-4.26 (m, 1H), 3.77 (s, 3H), 2.55-2.63 (m, 2H), 2.42 (s, 3H), 2.16-2.22 (m, 2H), 2.12 (s, 3H), 1.98-2.08 (m, 2H), 1.52-1.64 (m, 2H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -114.48 (s, 1F). EXAMPLE 59 Synthesis of 4-[(cis-4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluorophenyl )-6-(4-methoxy-2- methylphenyl)pyrrolo[1,2-b]pyridazine-3-carboximidamide

Step 1: Synthesis of tert-butyl [cis-4-[[6-bromo-3-[N'-(2-chloro-5- fluorophenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclohexyl]carbamate To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluorophenyl)pyrrolo[1,2-b]p yridazine-3- carboximidamide (200 mg, 497.4 μmol) and tert-butyl (cis-4-aminocyclohexyl)carbamate (127 mg, 596.9 μmol) in N,N-dimethylacetamide (2.0 mL) was added N,N-diisopropylethylamine (192 mg, 1.49 mmol) dropwise. After stirring at 80 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 170 mg, 58%. LCMS (ESI) m/z: 581.1 (M+H). Step 2: Synthesis of tert-butyl [cis-4-[[3-[N'-(2-chloro-5-fluorophenyl)carbamimidoyl]-6-(4- methoxy-2-methylphenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cy clohexyl]carbamate To a mixture of tert-butyl [cis-4-[[6-bromo-3-[N'-(2-chloro-5- fluorophenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclohexyl]carbamate (150 mg, 258.6 μmol) and 2-(4-methoxy-2-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-diox aborolane (77 mg, 310.4 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (16 mg, 25.8 μmol) and potassium phosphate (164 mg, 776.0 μmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 1 hour. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 130 mg, 80%. LCMS (ESI) m/z: 621.2 (M+H). Step 3: 4-[(cis-4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluorophenyl )-6-(4-methoxy-2- methylphenyl)pyrrolo[1,2-b]pyridazine-3-carboximidamide To a solution of tert-butyl [cis-4-[[3-[N'-(2-chloro-5-fluorophenyl)carbamimidoyl]-6-(4- methoxy-2-methylphenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cy clohexyl]carbamate (100 mg, 160.9 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (1.0 mL). After stirring at 25 °C for 16 hours, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 4-[(cis-4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluorophenyl )-6-(4- methoxy-2-methylphenyl)pyrrolo[1,2-b]pyridazine-3-carboximid amide as an off-white solid. Yield: 26.2 mg, 29%. LCMS (ESI) m/z = 521.2 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.59 (d, 1H, J=7.5 Hz), 8.22 (s, 1H), 7.79 (s, 1H), 7.46-7.52 (m, 1H), 7.38 (d, 1H, J=8.4 Hz), 6.80- 6.94 (m, 5H), 6.47 (s, 2H), 4.30-4.40 (m, 1H), 3.77 (s, 3H), 2.67-2.74 (m, 1H), 2.42 (s, 3H), 1.78- 1.95 (m, 2H), 1.62-1.75 (m, 2H), 1.47-1.61 (m, 3H), 1.25-1.40 (m, 3H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -114.56 (s, 1F). EXAMPLE 60 Synthesis of N'-(2-chloro-5-fluoro-phenyl)-6-(4-methoxy-2-methyl-phenyl)- 4-[cis-[4- (propylsulfonylamino)cyclohexyl]amino]pyrrolo[1,2-b]pyridazi ne-3-carboxamidine

Step 1: Synthesis of tert-butyl N-[cis-4-(propylsulfonylamino)cyclohexyl]carbamate To a solution of tert-butyl N-(cis-4-aminocyclohexyl)carbamate (200 mg, 933 μmol) in dichloromethane (5 mL) were added propane-1-sulfonyl chloride (200 mg, 1.4 mmol) and triethylamine (283 mg, 2.8 mmol). After stirring at room temperature for 2 hours, the reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate twice. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a white solid. Yield: 250 mg, 79%. ¹ H NMR (DMSO-d6, 400 MHz) δ 6.90 (d, 1H, J=6.0 Hz), 6.71 (d, 1H, J=6.4 Hz), 3.25-3.31 (m, 1H), 3.16-3.24 (m, 1H), 2.91-3.01 (m, 2H), 1.45-1.77 (m, 8H), 1.39 (s, 9H), 1.14-1.27 (m, 2H), 0.97 (t, 3H, J=7.2 Hz). Step 2: Synthesis of N-(cis-4-aminocyclohexyl)propane-1-sulfonamide To a solution of tert-butyl N-[cis-4-(propylsulfonylamino)cyclohexyl]carbamate (250 mg, 780 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. The residue was diluted with water, basified with an aqueous solution of sodium hydroxide and extracted with dichloromethane twice. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a light yellow solid. Yield: 120 mg, 66%. ¹ H NMR (300 MHz, DMSO-d6) δ 6.90 (s, 1H), 3.15-3.25 (m, 1H), 2.89-3.00 (m, 2H), 2.72-2.82 (m, 1H), 1.60- 1.76 (m, 2H), 1.38-1.54 (m, 6H), 1.18-2.30 (m, 2H), 0.97 (t, 3H, J=7.5 Hz). Step 3: Synthesis of 6-bromo-N'-(2-chloro-5-fluoro-phenyl)-4-[cis-[4- (propylsulfonylamino)cyclohexyl]amino]pyrrolo[1,2-b]pyridazi ne-3-carboxamidine To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (100 mg, 248 μmol) in N,N-dimethylacetamide (3 mL) were added N-(cis-4- aminocyclohexyl)propane-1-sulfonamide (110 mg, 497 μmol) and N,N-diisopropylethylamine (96 mg, 746 μmol). The resulting mixture was stirred at 85 °C for 2 hours and then cooled to room temperature. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow soild. Yield : 150 mg, 92%. LCMS (ESI) m/z: 585.0 (M+H). Step 4: Synthesis of N'-(2-chloro-5-fluoro-phenyl)-6-(4-methoxy-2-methyl-phenyl)- 4-[cis-[4- (propylsulfonylamino)cyclohexyl]amino]pyrrolo[1,2-b]pyridazi ne-3-carboxamidine To a solution of 6-bromo-N'-(2-chloro-5-fluoro-phenyl)-4-[cis-[4- (propylsulfonylamino)cyclohexyl]amino]pyrrolo[1,2-b]pyridazi ne-3-carboxamidine (120 mg, 204 μmol) and (4-methoxy-2-methyl-phenyl)boronic acid (102 mg, 614 μmol) in N,N- dimethylformamide (3 mL) and water (0.3 mL) were added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (13 mg, 20 μmol) and potassium phosphate (130 mg, 614 μmol). The mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded a crude product. Further purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded N'-(2-chloro-5-fluoro-phenyl)-6-(4-methoxy-2-methyl-phenyl)- 4-[cis-[4- (propylsulfonylamino)cyclohexyl]amino]pyrrolo[1,2-b]pyridazi ne-3-carboxamidine as a white solid. Yield: 7.0 mg, 5%. LCMS (ESI) m/z = 627.1 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.51 (d, 1H, J=7.6 Hz), 8.22 (s, 1H), 7.80 (d, 1H, J=1.6 Hz), 7.47-7.51 (m, 1H), 7.38 (d, 1H, J=8.4 Hz), 7.04 (d, 1H, J=6.0 Hz), 6.81-6.96 (m, 5H), 6.47 (s, 2H), 4.26-4.36 (m, 1H), 3.77 (s, 3H), 3.28-3.30 (m, 1H), 2.90-2.94 (m, 2H), 2.42 (s, 3H), 1.80-1.88 (m, 4H), 1.65-1.71 (m, 2H), 1.54-1.63 (m, 4H), 0.93 (t, 3H, J=7.2 Hz). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -114.58 (s, 1F). EXAMPLE 61 Synthesis of N'-(2-chloro-5-fluoro-phenyl)-6-(4-methoxy-2-methyl-phenyl)- 4-(4- piperidylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidine

Step 1: Synthesis of tert-butyl 4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]pipe ridine-1-carboxylate To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (120 mg, 298 μmol) in N,N-dimethylacetamide (3 mL) were added tert-butyl 4- aminopiperidine-1-carboxylate (90 mg, 448 μmol) and N,N-diisopropylethylamine (116 mg, 896 μmol). The resulting mixture was stirred at 85 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 130 mg, 77%. LCMS (ESI) m/z: 567.2 (M+H). Step 2: Synthesis of tert-butyl 4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6-(4- methoxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]p iperidine-1-carboxylate To a solution of tert-butyl 4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]pipe ridine-1-carboxylate (120 mg, 212 μmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) were added (4-methoxy-2- methyl-phenyl)boronic acid (53 mg, 318 μmol), 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (14 mg, 21 μmol) and potassium phosphate (90 mg, 424 μmol). The resulting mixture was purge with nitrogen gas and stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a light yellow solid. Yield: 80 mg, 62%. LCMS (ESI) m/z: 607.3 (M+H). Step 3: Synthesis of N'-(2-chloro-5-fluoro-phenyl)-6-(4-methoxy-2-methyl-phenyl)- 4-(4- piperidylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of tert-butyl 4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6-(4-meth oxy-2- methyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]piperidine- 1-carboxylate (70 mg, 115 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.4 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded N'-(2-chloro-5-fluoro-phenyl)-6-(4-methoxy-2- methyl-phenyl)-4-(4-piperidylamino)pyrrolo[1,2-b]pyridazine- 3-carboxamidine as a light yellow solid. Yield: 23.3 mg, 39%. LCMS (ESI) m/z: 507.1 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.44 (d, 1H, J=7.2 Hz), 8.21 (s, 1H), 7.81 (d, 1H, J=1.6 Hz), 7.48-7.52 (m, 1H), 7.39 (d, 1H, J=8.4 Hz), 6.83-6.94 (m, 5H), 6.54 (s, 2H), 4.23-4.29 (m, 1H), 3.77 (s, 3H), 2.87-2.95 (m, 2H), 2.57-2.68 (m, 2H), 2.43 (s, 3H), 1.96-2.04 (m, 2H), 1.40-1.52 (m, 2H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.44 (s, 1F). EXAMPLE 62 Synthesis of N'-(2-chloro-5-fluoro-phenyl)-6-(4,5-dimethoxy-2-methyl-phen yl)-4-(4- piperidylmethylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidin e

Step 1: Synthesis of 1-bromo-4,5-dimethoxy-2-methylbenzene To a solution of 2-bromo-4,5-dimethoxy-benzaldehyde (1.00 g, 4.0 mmol) in diethylene glycol (2 mL) were added potassium hydroxide (686 mg, 12 mmol) and hydrazine hydrate (612 mg, 12 mmol). After stirring at 145 °C for 2 hours, the reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afforded the title compound as a white solid. Yield: 700 mg, 74%. ¹ H NMR (Chloroform-d, 300 MHz) δ 6.96 (s, 1H), 6.69 (s, 1H), 3.80 (d, 6H, J=1.5 Hz), 2.28 (s, 3H). Step 2: Synthesis of 2-(4,5-dimethoxy-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-d ioxaborolane To a mixture of 1-bromo-4,5-dimethoxy-2-methylbenzene (680 mg, 2.9 mmol), 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (1.49 g, 5.9 mmol) and potassium acetate (2.45 g, 5.9 mmol) in N,N-dimethylformamide (5 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (215 mg, 294 mol). The resulting mixture was purged with nitrogen gas and stirred at 90 °C for an hour. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 490 mg, 59%. LCMS (ESI) m/z: 279.2 (M+H). Step 3: Synthesis of tert-butyl 4-[[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]meth yl]piperidine-1-carboxylate To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (150 mg, 373 μmol) and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (120 mg, 560 μmol) in N,N-dimethylacetamide (2 mL) was added N,N-diisopropylethylamine (144 mg, 1.1 mmol). The mixture was stirred at 90 °C for 2hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 150 mg, 69%. LCMS (ESI) m/z: 581.3 (M+H). Step 4: Synthesis of tert-butyl 4-[[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6-(4,5- dimethoxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino ]methyl]piperidine-1-carboxylate To a solution of tert-butyl 4-[[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]meth yl]piperidine-1-carboxylate (130 mg, 224 μmol), 2-(4,5-dimethoxy-2-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (75 mg, 269 μmol) and potassium phosphate (95.17 mg, 448.36 μmol) in N,N-dimethylformamide (2 mL) and water (0.2 mL) was added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (15 mg, 22 μmol). The mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purified via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 100 mg, 53%. LCMS (ESI) m/z: 651.4 (M+H). Step 5: Synthesis of N'-(2-chloro-5-fluoro-phenyl)-6-(4,5-dimethoxy-2-methyl-phen yl)-4-(4- piperidylmethylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidin e To a solution of tert-butyl 4-[[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6-(4,5- dimethoxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino ]methyl]piperidine-1-carboxylate (80 mg, 122 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded N'-(2-chloro-5-fluoro-phenyl)-6- (4,5-dimethoxy-2-methyl-phenyl)-4-(4-piperidylmethylamino)py rrolo[1,2-b]pyridazine-3- carboxamidine as an off-white solid. Yield: 14.7 mg, 20%. LCMS (ESI) m/z: 551.2 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.36 (s, 1H), 8.21 (s, 1H), 7.84 (d, 1H, J=1.5 Hz), 7.46-7.51 (m, 1H), 6.97-7.05 (m, 2H), 6.83-6.94 (m, 3H), 6.58 (s, 2H), 3.75-3.78 (m, 6H), 3.65 (d, 2H, J=6.0 Hz), 2.86-2.98 (m, 2H), 2.35-2.42 (m, 5H), 1.71-1.81 (m, 3H), 1.08-1.22 (m, 3H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -114.44 (s, 1F). EXAMPLE 63 Synthesis of 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-ethyl-5-fluoro-pheny l)-6-(5-methoxy-2- methyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of cis-tert-butyl N-[3-[[3-[N'-(2-ethyl-5-fluoro-phenyl)carbamimidoyl]-6-(5- methoxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]c yclopentyl]carbamate To a solution of cis-tert-butyl N-[3-[[6-bromo-3-[N'-(2-ethyl-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (120 mg, 214.5 μmol) and (5-methoxy-2-methyl-phenyl)boronic acid (53 mg, 321.7 μmol) in N,N- dimethylformamide (5.0 mL) and water (0.5 mL) were added potassium phosphate (91 mg, 429.0 μmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (14 mg, 21.4 μmol) at room temperature. The resulting mixture was purged with nitrogen for 5 minutes. After stirring at 80 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as yellow solid. Yield: 90 mg, 69%. LCMS (ESI) m/z: 601.2 (M+H). Step 2: Synthesis of 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-ethyl-5-fluoro-pheny l)-6-(5- methoxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxami dine To a solution of cis-tert-butyl N-[3-[[3-[N'-(2-ethyl-5-fluoro-phenyl)carbamimidoyl]-6-(5- methoxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]c yclopentyl]carbamate (80 mg, 133.2 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (1.0 mL) dropwise at 0°C. After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with saturated aqueous solution of sodium carbonate, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-ethyl-5- fluoro-phenyl)-6-(5-methoxy-2-methyl-phenyl)pyrrolo[1,2-b]py ridazine-3-carboxamidine as a light yellow solid. Yield: 23.6 mg, 35%. LCMS (ESI) m/z: 501.2 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ11.87 (brs, 1H), 8.24 (s, 1H), 7.87 (d, 1H, J=1.5 Hz), 7.18-7.27 (m, 2H), 7.00-7.05 (m, 2H), 6.75-6.82 (m, 2H), 6.60-6.66 (m, 1H), 6.15 (s, 2H), 4.62-4.64 (m, 1H), 3.78 (s, 3H), 3.25-3.32 (m, 1H), 2.27-2.50 (m, 6H), 2.04-2.16 (m, 1H), 1.64-1.89 (m, 2H), 1.23-1.45 (m, 2H), 1.10 (t, 3H, J=7.5 Hz). ¹⁹ F NMR (DMSO-d ₆ , 282 MHz) δ -116.67 (s, 1F). EXAMPLE 64 Synthesis of 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-ethyl-5-fluoro-pheny l)-6-(4-methoxy-2- methyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine

Step 1: Synthesis of cis-tert-butyl N-[3-[[6-bromo-3-[N'-(2-ethyl-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate To a solution of 6-bromo-4-chloro-N'-(2-ethyl-5-fluoro-phenyl)pyrrolo[1,2-b]p yridazine-3- carboxamidine (200 mg, 505.5 μmol) and cis-tert-butyl N-[3-aminocyclopentyl]carbamate (101 mg, 505.5 μmol) in N,N-dimethylacetamide (3.0 mL) was added N,N-diisopropylethylamine (196 mg, 1.52 mmol). After stirring at 80 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 180 mg, 63%. LCMS (ESI) m/z: 559.1 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.85-11.89 (m, 1H), 8.24 (s, 1H), 7.84 (s, 1H), 7.22-7.27 (m, 1H), 7.04 (s, 1H), 6.91-6.94 (m, 1H), 6.76-6.84 (m, 1H), 6.60-6.66 (m, 1H), 6.21 (s, 2H), 4.48-4.53 (m, 1H), 3.83-3.87 (m, 1H), 2.38-2.48 (m, 3H), 2.03-2.13 (m, 1H), 1.84-1.97 (m, 1H), 1.38-1.65 (m, 3H), 1.34 (s, 9H), 1.10 (t, 3H, J=7.5 Hz). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -116.67 (s, 1F). Step 2: Synthesis of cis-tert-butyl N-[3-[[3-[N'-(2-ethyl-5-fluoro-phenyl)carbamimidoyl]-6-(4- methoxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]c yclopentyl]carbamate To a solution of cis-tert-butyl N-[3-[[6-bromo-3-[N'-(2-ethyl-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (120 mg, 214.5 μmol) and (4-methoxy-2-methyl-phenyl)boronic acid (71 mg, 429.0 μmol) in N,N- dimethylformamide (5.0 mL) and water (0.5 mL) were added 1,1'-bis (di-t- butylphosphino)ferrocene palladium dichloride (140 mg, 214.5 μmol) and potassium phosphate (46 mg, 214.5 μmol). The resulting mixture was purged with nitrogen for 5 minutes. After stirring at 80 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 90 mg, 69%. LCMS (ESI) m/z: 601.2 (M+H). Step 3: Synthesis of 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-ethyl-5-fluoro-pheny l)-6-(4- methoxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxami dine To a solution of cis-tert-butyl N-[3-[[3-[N'-(2-ethyl-5-fluoro-phenyl)carbamimidoyl]-6-(4- methoxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]c yclopentyl]carbamate (80 mg, 133.2 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (1.0 mL) dropwise at 0°C. After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. The resulting solution was washed with saturated aqueous solution of sodium carbonate, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-ethyl-5-fluoro-pheny l)-6-(4-methoxy-2- methyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as a light yellow solid. Yield: 25.9 mg, 38%. LCMS (ESI) m/z: 501.2 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.82 (d, 1H, J=4.2 Hz), 8.22 (s, 1H), 7.78 (d, 1H, J=1.8 Hz), 7.37-7.40 (m, 1H), 7.21-7.27 (m, 1H), 6.96 (d, 1H, J=1.5 Hz), 6.75-6.88 (m, 3H), 6.60-6.66 (m, 1H), 6.13 (s, 2H), 4.50-4.70 (m, 1H), 3.77 (s, 3H), 3.25-3.32 (m, 1H), 2.33-2.53 (m, 6H), 2.03-2.13 (m, 1H), 1.65-1.87 (m, 3H), 1.23-1.41 (m, 2H), 1.10 (t, 3H, J=7.5 Hz). ¹⁹ F NMR (282 MHz, DMSO-d6) δ -116.68 (s, 1F). EXAMPLE 65 Synthesis of 4-[[cis-3-aminocyclopentyl]amino]-6-(4,5-dimethoxy-2-methyl- phenyl)-N'-(2-ethyl- 5-fluoro-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt Step 1: Synthesis of tert-butyl N-[cis-3-[[6-(4,5-dimethoxy-2-methyl-phenyl)-3-[N'-(2-ethyl- 5- fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]ami no]cyclopentyl]carbamate To a solution of tert-butyl N-[cis-3-[[6-bromo-3-[N'-(2-ethyl-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (90 mg, 160 μmol), 2-(4,5-dimethoxy-2-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (54 mg, 193 μmol) and potassium phosphate (69 mg, 322 μmol) in N,N-dimethylformamide (2 mL) and water (0.2 mL) was added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (11 mg, 16 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 90 mg, 70%. LCMS (ESI) m/z: 631.5 (M+H). Step 2: Synthesis of 4-[[cis-3-aminocyclopentyl]amino]-6-(4,5-dimethoxy-2-methyl- phenyl)-N'- (2-ethyl-5-fluoro-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxam idine formic acid salt To a solution of tert-butyl N-[cis-3-[[6-(4,5-dimethoxy-2-methyl-phenyl)-3-[N'-(2-ethyl- 5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (85 mg, 134.76 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1.48 g, 12.98 mmol, 1 mL). After stirring at room temperature for an hour, the reaction mixture was filtered through a celite pad and washed with ethyl acetate and methanol. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-[[cis-3-aminocyclopentyl]amino]-6-(4,5-dimethoxy-2-methyl- phenyl)-N'- (2-ethyl-5-fluoro-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxam idine formic acid salt as an off- white solid. Yield: 5.6 mg, 7%. LCMS (ESI) m/z: 531.2 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.88 (brs, 1H), 8.36 (s, 1H), 8.24 (s, 1H), 7.83 (s, 1H), 7.22-7.27 (m, 1H), 6.98-7.02 (m, 2H), 6.89 (s, 1H), 6.79-6.83 (m, 1H), 6.62-6.67 (m, 1H), 6.18 (s, 2H), 4.61-4.71 (m, 1H), 3.77-3.79 (m, 6H), 3.11-3.21 (m, 1H), 2.44-2.49 (m, 2H), 2.38 (s, 3H), 1.85-2.20 (m, 3H), 1.34-1.78 (m, 3H), 1.11 (t, 3H, J=7.5 Hz). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -116.66 (s, 1F). EXAMPLE 66 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[5- (hydroxymethyl)-2-methyl-phenyl]pyrrolo[1,2-b]pyridazine-3-c arboxamidine Step 1: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- [5-(hydroxymethyl)-2-methyl-phenyl]pyrrolo[1,2-b]pyridazin-4 -yl]amino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (120 mg, 207 μmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) were added [5-(hydroxymethyl)-2- methyl-phenyl]boronic acid (52 mg, 310 μmol), 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (14 mg, 21 μmol) and potassium phosphate (88 mg, 414 μmol). The resulting mixture was purge with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a light yellow solid. Yield: 100 mg, 76%. LCMS (ESI) m/z: 621.2 (M+H). Step 2: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[5- (hydroxymethyl)-2-methyl-phenyl]pyrrolo[1,2-b]pyridazine-3-c arboxamidine To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-[5- (hydroxymethyl)-2-methyl-phenyl]pyrrolo[1,2-b]pyridazin-4-yl ]amino]cyclohexyl]carbamate (90 mg, 145 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.4 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'- (2-chloro-5-fluoro-phenyl)-6-[5-(hydroxymethyl)-2-methyl-phe nyl]pyrrolo[1,2-b]pyridazine-3- carboxamidine as a white solid. Yield: 29.7 mg, 38%. LCMS (ESI) m/z: 521.1 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.36 (s, 1H), 8.21 (s, 1H), 7.85 (d, 1H, J=1.6 Hz), 7.46-7.52 (m, 1H), 7.40 (d, 1H, J=1.6 Hz), 7.25 (d, 1H, J=7.6 Hz), 7.14-7.20 (m, 1H), 6.83-6.96 (m, 3H), 6.56 (s, 2H), 5.15 (s, 1H), 4.51 (s, 2H), 4.05-4.15 (m, 1H), 2.60-2.64 (m, 1H), 2.44 (s, 3H), 2.10-2.18 (m, 2H), 1.78-1.84 (m, 2H), 1.20-1.45 (m, 4H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.39 (s, 1F). EXAMPLE 67 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[5- (methanesulfonamidomethyl)-2-methyl-phenyl]pyrrolo[1,2-b]pyr idazine-3-carboxamidine formic acid salt Step 1: Synthesis of N-[(3-bromo-4-methyl-phenyl)methyl]methanesulfonamide To a solution of (3-bromo-4-methyl-phenyl)methanamine (1.00 g, 5.0 mmol) and triethylamine (1.01 g, 10.0 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (687 mg, 6.0 mmol) dropwise at 0 °C. After stirring at room temperature for 2 hours, the reaction mixture was diluted dichloromethane and washed with a saturated aqueous solution of sodium carbonate, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (eluent: ethyl acetate/petroleum ether) afforded the title compound as an off-white solid. Yield: 0.80 g, 58%. ¹ H NMR (DMSO-d6, 300 MHz) δ 7.52-7.66 (m, 2H), 7.33 (d, 1H, J=7.9 Hz), 7.20-7.30 (m, 1H), 4.12 (d, 2H, J=6.3 Hz), 2.87 (s, 3H), 2.33 (s, 3H). Step 2: Synthesis of N-[[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]methyl]methanesulfonamide To a solution of N-[(3-bromo-4-methyl-phenyl)methyl]methanesulfonamide (300 mg, 1.1 mmol) in N,N-dimethylformamide (5 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (548 mg, 2.2 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (90 mg, 108 μmol) and potassium acetate (212 mg, 2.2 mmol). The resulting mixture was purge with nitrogen gas and stirred at 85 °C for 15 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a black oil. Yield: 800 mg, 69%. LCMS (ESI) m/z: 348.1 (M+Na). Step 3: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- [5-(methanesulfonamidomethyl)-2-methyl-phenyl]pyrrolo[1,2-b] pyridazin-4- yl]amino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (120 mg, 207 μmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) were added N-[[4-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]m ethanesulfonamide (202 mg, 621 μmol), 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (14 mg, 21 μmol) and potassium phosphate (88 mg, 414 μmol). The resulting mixture was purge with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a black solid. Yield: 200 mg, 67%. LCMS (ESI) m/z: 698.4 (M+H). Step 4: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[5- (methanesulfonamidomethyl)-2-methyl-phenyl]pyrrolo[1,2-b]pyr idazine-3-carboxamidine formic acid salt To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-[5- (methanesulfonamidomethyl)-2-methyl-phenyl]pyrrolo[1,2-b]pyr idazin-4- yl]amino]cyclohexyl]carbamate (190 mg, 130 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.4 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5- fluoro-phenyl)-6-[5-(methanesulfonamidomethyl)-2-methyl-phen yl]pyrrolo[1,2-b]pyridazine-3- carboxamidine formic acid salt as a yellow solid. Yield: 14.0 mg, 16%. LCMS (ESI) m/z: 598.1 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.40 (s, 1H), 8.32 (d, 1H, J=6.4 Hz), 8.24 (s, 1H), 7.89 (d, 1H, J=1.6 Hz), 7.60-7.65 (m, 1H), 7.44-7.54 (m, 2H), 7.29 (d, 1H, J=7.6 Hz), 7.18-7.24 (m, 1H), 6.84-6.96 (m, 3H), 6.59 (s, 2H), 4.18 (d, 2H, J=3.6 Hz), 4.08-4.14 (m, 1H), 3.00-3.04 (m, 1H), 2.87 (s, 3H), 2.45 (s, 3H), 2.17-2.23 (m, 2H), 1.93-2.01 (m, 2H), 1.38-1.58 (m, 4H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.37 (s, 1F). EXAMPLE 68 Synthesis of N-[[3-[4-[trans-(4-aminocyclohexyl)amino]-3-[N'-(2-chloro-5- fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-4-methyl- phenyl]methyl]acetamide Step 1: Synthesis of N-[(3-bromo-4-methyl-phenyl)methyl]acetamide To a solution of (3-bromo-4-methyl-phenyl)methanamine (600 mg, 3.0 mmol) and triethylamine (607 mg, 6.0 mmol) in dichloromethane (5 mL) was added acetyl chloride (283 mg, 3.6 mmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a white solid. Yield: 500 mg, 69%. LCMS (ESI) m/z: 244.1 (M+H). Step 2: Synthesis of N-[[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]methyl]acetamide To a solution of N-[(3-bromo-4-methyl-phenyl)methyl]acetamide (300 mg, 1.2 mmol) in N,N- dimethylformamide (5 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (629 mg, 2.5 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (103 mg, 124 μmol) and potassium acetate (244 mg, 2.5 mmol). The resulting mixture was purge with nitrogen gas and stirred at 85 °C for 4 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a black solid. Yield: 500 mg, 92%. LCMS (ESI) m/z: 290.2 (M+H). Step 3: Synthesis of tert-butyl N-[trans-4-[[6-[5-(acetamidomethyl)-2-methyl-phenyl]-3-[N'-( 2- chloro-5-fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin -4- yl]amino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (120 mg, 207 μmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) were added N-[[4-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]a cetamide (90 mg, 310 μmol), 1,1'- bis(di-t-butylphosphino)ferrocene-palladium dichloride (14 mg, 21 μmol) and potassium phosphate (88 mg, 414 μmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a brown solid. Yield: 60 mg, 44%. LCMS (ESI) m/z: 662.5 (M+H). Step 4: Synthesis of N-[[3-[4-[trans-(4-aminocyclohexyl)amino]-3-[N'-(2-chloro-5- fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-4-methyl- phenyl]methyl]acetamide To a solution of tert-butyl N-[trans-4-[[6-[5-(acetamidomethyl)-2-methyl-phenyl]-3-[N'-( 2- chloro-5-fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin -4- yl]amino]cyclohexyl]carbamate (60 mg, 90 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded N-[[3-[4- [trans-(4-aminocyclohexyl)amino]-3-[N'-(2-chloro-5-fluoro-ph enyl)carbamimidoyl]pyrrolo[1,2- b]pyridazin-6-yl]-4-methyl-phenyl]methyl]acetamide as a white solid. Yield: 18.9 mg, 36%. LCMS (ESI) m/z: 562.2 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.38 (d, 1H, J=7.2 Hz), 8.36 (t, 1H, J= 5.6 Hz), 8.23 (s, 1H), 7.87 (d, 1H, J=1.6 Hz), 7.47-7.51 (m, 1H), 7.37 (d, 1H, J=2.0 Hz), 7.25 (d, 1H, J=7.6 Hz), 7.08-7.14 (m, 1H), 6.84-6.96 (m, 3H), 6.58 (s, 2H), 4.27 (d, 2H, J=5.6 Hz), 4.08-4.14 (m, 1H), 2.72-2.82 (m, 1H), 2.44 (s, 3H), 2.12-2.22 (m, 2H), 1.82-1.92 (m, 5H), 1.28-1.45 (m, 4H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -114.38 (s, 1F). EXAMPLE 69 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-ethyl-5-fluoro-phen yl)-6-[5- (hydroxymethyl)-2-methyl-phenyl]pyrrolo[1,2-b]pyridazine-3-c arboxamidine

Step 1: Synthesis of 6-bromo-4-chloro-N'-(2-ethyl-5-fluoro-phenyl)pyrrolo[1,2-b]p yridazine-3- carboxamidine To a mixture of 6-bromo-4-chloro-pyrrolo[1,2-b]pyridazine-3-carbonitrile (200 mg, 779.7 μmol) and 2-ethyl-5-fluoro-aniline (162 mg, 1.17 mmol) in toluene (10.0 mL) was added trimethylalumane (1.2 mL, 2 M in toluene, 2.4 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 minutes and stirred at 50 °C for 6 hours. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous solution of sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 200 mg, 64%. LCMS (ESI) m/z: 396.9 (M+1). Step 2: Synthesis of tert-butyl [trans-4-[[6-bromo-3-[N'-(2-ethyl-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate To a solution of 6-bromo-4-chloro-N'-(2-ethyl-5-fluoro-phenyl)pyrrolo[1,2-b]p yridazine-3- carboxamidine (180 mg, 454.9 μmol) and tert-butyl (trans-4-aminocyclohexyl)carbamate (146 mg, 682.4 μmol) in N,N-dimethylacetamide (3.0 mL) was added N,N-diisopropylethylamine (176 mg, 1.36 mmol) dropwise. The resulting mixture was stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 150 mg, 57%. LCMS (ESI) m/z: 575.1 (M+H). Step 3: Synthesis of tert-butyl [trans-4-[[3-[N'-(2-ethyl-5-fluoro-phenyl)carbamimidoyl]-6-[ 5- (hydroxymethyl)-2-methyl-phenyl]pyrrolo[1,2-b]pyridazin-4-yl ]amino]cyclohexyl]carbamate To a mixture of tert-butyl [trans-4-[[6-bromo-3-[N'-(2-ethyl-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (135 mg, 235.4 μmol) and [5-(hydroxymethyl)-2-methyl-phenyl]boronic acid (58 mg, 353.1 μmol) in N,N- dimethylformamide (2.0 mL) and water (0.2 mL) were added potassium phosphate (149 mg, 706.1 μmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (7 mg, 11.7 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 70 °C for 2 hours. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 100 mg, 69%. LCMS (ESI) m/z: 615.2 (M+H). Step 4: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-ethyl-5-fluoro-phen yl)-6-[5- (hydroxymethyl)-2-methyl-phenyl]pyrrolo[1,2-b]pyridazine-3-c arboxamidine To a solution of tert-butyl [trans-4-[[3-[N'-(2-ethyl-5-fluoro-phenyl)carbamimidoyl]-6-[ 5- (hydroxymethyl)-2-methyl-phenyl]pyrrolo[1,2-b]pyridazin-4-yl ]amino]cyclohexyl]carbamate (90 mg, 146.4 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (1.0 mL) dropwise. The reaction mixture was stirred at 25 °C for 16 hours and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-ethyl-5- fluoro-phenyl)-6-[5-(hydroxymethyl)-2-methyl-phenyl]pyrrolo[ 1,2-b]pyridazine-3- carboxamidine as an off-white solid. Yield: 33.4 mg, 44%. LCMS (ESI) m/z: 515.3 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.75 (d, 1H, J=7.5 Hz), 8.25 (s, 1H), 7.84 (s, 1H), 7.41 (s, 1H), 7.21-7.30 (m, 3H), 6.92 (s, 1H), 6.76-6.83 (m, 1H), 6.60-6.66 (m, 1H), 6.19 (s, 2H), 5.16 (brs, 1H), 4.52 (s, 2H), 4.02-4.10 (m, 1H), 2.54-2.62 (m, 1H), 2.46-2.50 (m, 4H), 2.12-2.20 (m, 2H), 1.75-1.85 (m, 2H), 1.15-1.44 (m, 4H), 1.04-1.13 (m, 3H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ - 116.61 (s, 1F). EXAMPLE 70 Synthesis of methyl 2-[4-[4-[trans-(4-aminocyclohexyl)amino]-3-[N'-(2-chloro-5-f luoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl- phenoxy]acetate formic acid salt

Step 1: Synthesis of [4-(2-methoxy-2-oxo-ethoxy)-2-methyl-phenyl]boronic acid To a solution of (4-hydroxy-2-methyl-phenyl)boronic acid (100 mg, 658.1 μmol) in N,N- dimethylformamide (1.0 mL) were added methyl 2-bromoacetate (151 mg, 987.1 μmol) and potassium carbonate (136 mg, 987.1 μmol). After stirring at 25 °C for 5 hours, the reaction mixture was diluted with dichloromethane and washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a light yellow oil. Yield: 300 mg, 61%, 30% purity. LCMS (ESI) m/z: 242.2 (M+H ₂ O) Step 2: Synthesis of methyl 2-[4-[4-[[trans-4-(tert-butoxycarbonylamino)cyclohexyl]amino ]-3- [N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]py ridazin-6-yl]-3-methyl- phenoxy]acetate To a solution of tert-butyl N-trans-[4-[[6-bromo-3-[(Z)-N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (100 mg, 172.5 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added [4-(2-methoxy-2- oxo-ethoxy)-2-methyl-phenyl]boronic acid (58 mg, 258.7 μmol), 1,1'-bis (di-t- butylphosphino)ferrocene-palladium dichloride (11 mg, 17.2 μmol) and sodium bicarbonate (29 mg, 344.9 μmol). The reaction mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered, and the filtrate diluted with water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a brown yellow solid. Yield: 100 mg, 85%. LCMS (ESI) m/z: 679.5 (M+H). Step 3: Synthesis of methyl 2-[4-[4-[trans-(4-aminocyclohexyl)amino]-3-[N'-(2-chloro-5-f luoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl- phenoxy]acetate formic acid salt To a solution of methyl 2-[4-[4-[[trans-4-(tert-butoxycarbonylamino)cyclohexyl]amino ]-3-[N'- (2-chloro-5-fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyrida zin-6-yl]-3-methyl- phenoxy]acetate (90 mg, 132.5 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (1.0 mL). After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and adjusted to pH=8 with aqueous solution of ammonium hydroxide (13% w/w) and then extracted with dichloromethane (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1% formic acid) afforded methyl 2-[4-[4-[trans-(4-aminocyclohexyl)amino]-3- [N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]py ridazin-6-yl]-3-methyl- phenoxy]acetate formic acid salt as a yellow solid. Yield: 28.5 mg, 33%. LCMS (ESI) m/z: 579.1 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.36 (s, 1H), 8.39 (s, 1H), 8.21 (s, 1H), 7.84 (d, 1H, J=1.6 Hz), 7.47-7.51 (m, 1H), 7.40 (d, 1H, J=8.4 Hz), 6.81-6.92 (m, 5H), 6.57 (s, 2H), 4.82 (s, 2H), 4.07-4.15 (m, 1H), 3.72 (s, 3H), 2.90-2.99 (m, 1H), 2.43 (s, 3H), 2.15-2.22 (m, 2H), 1.90- 1.99 (m, 2H), 1.35-1.55 (m, 4H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.38 (s, 1F). EXAMPLE 71 Synthesis of methyl 2-[4-[4-[trans-(4-aminocyclohexyl)amino]-3-[N'-(2-chloro-5-f luoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-2-methoxy -5-methyl-phenoxy]acetate

Step 1: Synthesis of 4-bromo-2-methoxy-5-methylphenol To a solution of 2-bromo-5-hydroxy-4-methoxy-benzaldehyde (1.00 g, 4.3 mmol) in diethylene glycol (20 mL) were added potassium hydroxide (729 mg, 13 mmol) and hydrazine hydrate (3.86 g, 13 mmol). After stirring at 145 °C for 2 hours, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 650 mg, 69%. ¹ H NMR (Chloroform-d, 300 MHz) δ 6.85 (s, 1H), 6.64 (s, 1H), 3.70 (s, 3H), 2.13 (s, 3H). Step 2: Synthesis of methyl 2-(4-bromo-2-methoxy-5-methylphenoxy)acetate To a solution of 4-bromo-2-methoxy-5-methylphenol (592 mg, 2.7 mmol) in acetonitrile (2 mL) were added methyl 2-bromoacetate (500 mg, 3.2 mmol) and potassium carbonate (753 mg, 5.4 mmol). The resulting mixture was stirred at 60 °C for 15 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 500 mg, 48%. LCMS (ESI) m/z: 289.1 (M+H). Step 3: Synthesis of methyl 2-[2-methoxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro lan-2- yl)phenoxy]acetate To a mixture of methyl 2-(4-bromo-2-methoxy-5-methylphenoxy)acetate (480 mg, 1.6 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)-1,3,2-dioxaborolane (843 mg, 3.3 mmol) and potassium acetate (1.38 g, 3.3 mmol) in N,N-dimethylformamide (4 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (121 mg, 166 μmol). The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 15 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 360 mg, 64%. LCMS (ESI) m/z: 337.1 (M+H). Step 4: Synthesis of methyl 2-[4-[trans-4-[[4-(tert-butoxycarbonylamino)cyclohexyl]amino ]-3- [N'-(2-chloro-5-fluoro To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (100 mg, 172 μmol), methyl 2-[2-methoxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro lan-2- yl)phenoxy]acetate (70 mg, 207 μmol) and potassium phosphate (73 mg, 345 μmol) in N,N- dimethylformamide (2 mL) and water (0.2 mL) was added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (11 mg, 17 μmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) to afford the title compound as a yellow oil. Yield: 80 mg, 57%. LCMS (ESI) m/z: 709.5 (M+H). Step 5: Synthesis of methyl 2-[4-[4-[trans-(4-aminocyclohexyl)amino]-3-[N'-(2-chloro-5-f luoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-2-methoxy -5-methyl-phenoxy]acetate To a solution of methyl 2-[4-[trans-4-[[4-(tert-butoxycarbonylamino)cyclohexyl]amino ]-3-[N'- (2-chloro-5-fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyrida zin-6-yl]-2-methoxy-5-methyl- phenoxy]acetate (70 mg, 98 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded methyl 2-[4-[4-[trans-(4- aminocyclohexyl)amino]-3-[N'-(2-chloro-5-fluoro-phenyl)carba mimidoyl]pyrrolo[1,2- b]pyridazin-6-yl]-2-methoxy-5-methyl-phenoxy]acetate as a yellow solid. Yield: 12 mg, 19%. LCMS (ESI) m/z: 609.1 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.36 (d, 1H, J=5.7 Hz), 8.21 (s, 1H), 7.89 (d, 1H, J=1.5 Hz), 7.44-7.54 (m, 1H), 7.06 (s, 1H), 6.84-6.96 (m, 4H), 6.56 (s, 2H), 4.79 (s, 2H), 4.05-4.19 (m, 1H), 3.82 (s, 3H), 3.71 (s, 3H), 2.86-2.96 (m, 1H), 2.37 (s, 3H), 2.09- 2.18 (m, 2H), 1.82-1.98 (m, 2H), 1.30-1.57 (m, 4H), 1.23 (s, 2H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -114.38 (s, 1F). EXAMPLE 72 Synthesis of N-[2-[4-[4-[trans-(4-aminocyclohexyl)amino]-3-[N'-(2-chloro- 5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl- phenoxy]ethyl]acetamide Step 1: Synthesis of tert-butyl N-(2-hydroxyethyl)carbamate To a solution of 2-aminoethanol (1.00 g, 16.37 mmol) in dichloromethane (20.0 mL) was added di-tert-butyl dicarbonate (3.57 g, 16.37 mmol) at 0°C. After stirring at 25 °C for 16 hours, the reaction mixture was diluted with chloroform, washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a colorless oil, which was used next step without further purification. Yield: 1.50 g. ¹ H-NMR (Chloroform-d, 400 MHz,) δ 4.99 (s, 1H), 3.72 (t, 2H, J=10.0 Hz), 3.30 (t, 2H, J=10.0 Hz), 2.59-2.26 (m, 1H), 1.47 (s, 9H). Step 2: Synthesis of 2-(4-bromo-3-methyl-phenoxy)ethanamine To a solution of 4-bromo-3-methyl-phenol (600 mg, 3.21 mmol), tert-butyl N-(2- hydroxyethyl)carbamate (568.8 mg, 3.53 mmol) and triphenylphosphane (1.01 g, 3.85 mmol) in tetrahydrofuran (8.0 mL) was added a solution of diisopropyl azodicarboxylate (778.4 mg, 3.85 mmol) in tetrahydrofuran (2.0 mL) dropwise at room temperature under nitrogen atmosphere. After stirring at 25 °C for 24 hours, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The resulting mixture was washed with 2N aqueous solution of sodium hydroxide and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded 1.10 g of tert-butyl [2-(4-bromo-3- methylphenoxy)ethyl]carbamate, which was dissolved in a solution of dichloromethane (3 mL) and methanol (0.5 mL), followed by addition of 4 M solution of hydrogen chloride in dioxane (5.0 mL, 109.71 mmol). After stirring at 25 °C for 3 hours, the reaction mixture was concentrated under reduced pressure to a the title compound, which was used next step without further purification. Yield: 850 mg. LCMS (ESI) m/z: 230.0 (M+H). Step 3: Synthesis of N-[2-(4-bromo-3-methyl-phenoxy)ethyl]acetamide To a mixture of 2-(4-bromo-3-methyl-phenoxy)ethanamine (300 mg, 1.30 mmol) and triethylamine (395 mg, 3.91 mmol) in dichloromethane (5.0 mL) were added acetic anhydride (199 mg, 1.96 mmol) at room temperature. After stirring at 25 °C for 16 hours, the reaction mixture was diluted with ethyl acetated and washed with saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 150 mg, 42%. LCMS (ESI) m/z: 271.9 (M+H). Step 4: Synthesis of tert-butyl [trans-4-[[6-(4-(2-acetamidoethoxy)-2-methylphenyl]-3-[N'-(2 - chloro-5-fluorophenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin- 4-yl]amino]cyclohexyl]carbamate To a mixture of tert-butyl [trans-4-[[3-[N'-(2-chloro-5-fluorophenyl)carbamimidoyl]-6-( 4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin- 4-yl]amino]cyclohexyl]carbamate (200 mg, 319.0 μmol) and N-[2-(4-bromo-3-methyl-phenoxy)ethyl]acetamide (120 mg, 440.9 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added potassium phosphate (203 mg, 957.0 μmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (20 mg, 31.9 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was heated at 70 °C for 2 hours. After cooled to room temperature, the reaction mixture was diluted with ethyl acetated and washed with brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 100 mg, 45%. LCMS (ESI) m/z: 692.2 (M+H). Step 5: Synthesis of N-[2-[4-[4-[trans-(4-aminocyclohexyl)amino]-3-[N'-(2-chloro- 5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl- phenoxy]ethyl]acetamide To a solution of tert-butyl [trans-4-[[6-(4-(2-acetamidoethoxy)-2-methylphenyl]-3-[N'-(2 -chloro- 5-fluorophenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]am ino]cyclohexyl]carbamate (90 mg, 130.0 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (1.0 mL) dropwise. The reaction mixture was stirred for at 25 °C an hour and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded N-[2-[4-[4-[trans-(4-aminocyclohexyl)amino]-3-[N'- (2-chloro-5-fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyrida zin-6-yl]-3-methyl- phenoxy]ethyl]acetamide as an off-white solid. Yield: 22.1 mg, 28%. LCMS (ESI) m/z: 592.2 (M+H). ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ 11.33 (d, 1H, J=7.2 Hz), 8.20 (s, 1H), 8.10-8.13 (m, 1H), 7.81-7.83 (m, 1H), 7.46-7.51 (m, 1H), 7.37-7.41 (m, 1H), 6.84-6.90 (m, 5H), 6.55 (brs, 2H), 3.98-4.12 (m, 3H), 3.40-3.44 (m, 2H), 2.55-2.65 (m, 1H), 2.44 (s, 3H), 2.05-2.14 (m, 2H), 1.75- 1.85 (m, 5H), 1.15-1.44 (m, 4H). ¹⁹ F NMR (DMSO-d ₆ , 282 MHz) δ -114.04 (s, 1F). EXAMPLE 73 Synthesis of 1-[4-[4-[trans-(4-aminocyclohexyl)amino]-3-[N'-(2-chloro-5-f luoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl- phenyl]-3-methyl-urea Step 1: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- [2-methyl-4-(methylcarbamoylamino)phenyl]pyrrolo[1,2-b]pyrid azin-4- yl]amino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (100 mg, 172 μmol) and 1-methyl-3-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol an-2-yl)phenyl]urea (100 mg, 344 μmol) and potassium phosphate (73 mg, 344 μmol) in N,N-dimethylformamide (2 mL) and water (0.2 mL) was added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (11 mg, 17 μmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 60 mg, 53%. LCMS (ESI) m/z: 663.2 (M+H). Step 2: Synthesis of 1-[4-[4-[trans-(4-aminocyclohexyl)amino]-3-[N'-(2-chloro-5-f luoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl- phenyl]-3-methyl-urea To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-[2- methyl-4-(methylcarbamoylamino)phenyl]pyrrolo[1,2-b]pyridazi n-4- yl]amino]cyclohexyl]carbamate (60 mg, 90 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 1-[4-[4-[trans- (4-aminocyclohexyl)amino]-3-[N'-(2-chloro-5-fluoro-phenyl)ca rbamimidoyl]pyrrolo[1,2- b]pyridazin-6-yl]-3-methyl-phenyl]-3-methyl-urea as an off-white solid. Yield: 25 mg, 49%. LCMS (ESI) m/z: 563.2 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.32 (d, 1H, J=6.8 Hz), 8.52 (s, 1H), 8.19 (s, 1H), 7.80 (d, 1H, J=2.0 Hz), 7.47-7.51 (m, 1H), 7.26-7.32 (m, 3H), 6.82-6.92 (m, 3H), 6.54 (s, 2H), 6.05 (d, 1H, J=5.2 Hz), 4.04-4.14 (m, 1H), 2.65 (d, 3H, J=6.8 Hz), 2.55-2.57 (m, 1H), 2.41 (s, 3H), 2.09-2.15 (m, 2H), 1.76-1.82 (d, 2H), 1.32-1.46 (m, 2H), 1.14-1.31 (m, 2H).19F NMR (DMSO-d6, 376 MHz) δ -114.40 (s, 1F). EXAMPLE 74 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[4-ethyl-6-[2- [2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]-3-pyr idyl]pyrrolo[1,2-b]pyridazine-3-

Step 1: Synthesis of 5-bromo-4-ethyl-pyridin-2-amine) To a solution of 4-ethylpyridin-2-amine (1.00 g, 8.2 mmol) in acetonitrile (15 mL) were added ammonium acetate (1.26 g, 16.4 mmol) and N-bromosuccinimide (1.60 g, 9.0 mmol). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light yellow solid. Yield: 1.20 g, 73%. LCMS (ESI) m/z: 201.0 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.92 (s, 1H), 6.41 (d, 1H, J=0.8 Hz), 6.06 (s, 2H), 2.48-2.54 (m, 2H), 1.10-1.16 (m, 3H). Step 2: Synthesis of 5-bromo-4-ethyl-2-fluoro-pyridine) 5-bromo-4-ethyl-pyridin-2-amine (1.60 g, 8.0 mmol) was dissolved in hydrogen fluoride-pyridine (70% HF) (7.89 g, 79.6 mmol) at -10 °C. Sodium nitrite (878 mg, 12.7 mmol) was added in portions with inner temperature below 0 °C. After stirring at 0 °C for 2 hours and then room temperature for 2 hours, the reaction mixture was diluted with water and extracted with dichloromethane (x3). The combined organic layers were washed with an aqueous solution of potassium carbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light yellow oil. Yield: 1.30 g, 72%. LCMS (ESI) m/z: 204.1 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 8.37 (d, 1H, J=0.8 Hz), 7.23-7.30 (m, 1H), 2.68-2.78 (m, 2H), 1.19 (t, 3H, J=7.6 Hz). ¹⁹ F NMR (DMSO- d ₆ , 376 MHz) δ -71.84 (s, 1F). Step 3: Synthesis of 5-bromo-4-ethyl-2-[2-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]pyridine) To a solution of 5-bromo-4-ethyl-2-fluoro-pyridine (600 mg, 2.9 mmol) in N,N- dimethylformamide (6 mL) was added sodium hydride (294 mg, 7.4 mmol, 60%) at 0 °C. After stirring at 0 °C for an hour, 2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethanol (1.11 g, 4.4 mmol) was added. After stirring at room temperature for 15 hours, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a light yellow oil. Yield: 770 mg, 60%. LCMS (ESI) m/z: 458.3 (M+Na). Step 4: Synthesis of 4-ethyl-2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy] ethoxy]-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine) To a solution of 5-bromo-4-ethyl-2-[2-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]pyridine (400 mg, 916 μmol) in N,N- dimethylacetamide (4 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (466 mg, 1.8 mmol), 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (60 mg, 92 μmol) and potassium acetate (180 mg, 1.8 mmol). The resulting mixture was purge with nitrogen gas and stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) to afford the title compound as a grey solid. Yield: 400 mg, 90%. LCMS (ESI) m/z: 484.4 (M+H). Step 5: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- [4-ethyl-6-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy ]ethoxy]-3-pyridyl]pyrrolo[1,2- b]pyridazin-4-yl]amino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (120 mg, 207 μmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) were added 4-ethyl-2-[2-[2-[2-[2- (2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]-5-(4,4,5,5-tet ramethyl-1,3,2-dioxaborolan-2- yl)pyridine (150 mg, 310 μmol), 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (14 mg, 21 μmol) and potassium phosphate (88 mg, 414 μmol). The resulting mixture was purge with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a brown solid. Yield: 110 mg, 56%. LCMS (ESI) m/z: 856.6 (M+H). Step 6: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[4- ethyl-6-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]et hoxy]-3-pyridyl]pyrrolo[1,2- b]pyridazine-3-carboxamidine To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-[4- ethyl-6-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]et hoxy]-3-pyridyl]pyrrolo[1,2- b]pyridazin-4-yl]amino]cyclohexyl]carbamate (100 mg, 116 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.4 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[4-ethyl-6-[2-[2- [2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]-3-pyridy l]pyrrolo[1,2-b]pyridazine-3- carboxamidine as a light brown solid. Yield: 20.1 mg, 23%. LCMS (ESI) m/z: 778.5 (M+Na). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.37 (d, 1H, J=7.6 Hz), 8.22 (s, 1H), 8.17 (s, 1H), 7.85 (d, 1H, J=1.6 Hz), 7.47-7.51 (m, 1H), 6.84-6.94 (m, 3H), 6.80 (s, 1H), 6.57 (s, 2H), 4.37-4.44 (m, 2H), 4.05-4.15 (m, 1H), 3.73-3.80 (m, 2H), 3.43-3.60 (m, 14H), 3.36-3.42 (m, 2H), 3.23 (s, 3H), 2.77 (q, 2H, J=7.6 Hz), 2.53-2.63 (m, 1H), 2.07-2.15 (m, 2H), 1.74-1.82 (m, 2H), 1.28-1.44 (m, 2H), 1.16-1.25 (m, 2H), 1.16 (t, 3H, J=7.6 Hz). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.38 (s, 1H). EXAMPLE 75 Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(5-ethyl-2- hydroxy-4-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine

Step 1: Synthesis of 5-ethyl-2-methoxy-pyridine To a solution of 5-bromo-2-methoxy-pyridine (10.00 g, 53.19 mmol) and triethylborane (5.73 g, 58.47 mmol) in 1,4-dioxane (60 mL) and water (20 mL) were added potassium carbonate (14.70 g, 106.52 mmol) and bis(triphenylphosphine)palladium(II) dichloride (1.87 g, 2.66 mmol). The resulting mixture was purged with nitrogen gas and stirred at 100 °C for 24 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 3.90 g, 51%. LCMS (ESI) m/z: 138.1 (M+H). Step 2: Synthesis of 5-ethyl-2-methoxy-4-pyridylboronic acid A solution of 5-ethyl-2-methoxy-pyridine (1.00 g, 7.30 mmol) in tetrahydrofuran (15 mL) was dried by 4 Å molecular sieve for 24 hours, and then 5.0 mL of lithium diisopropylamide (2 M in tetrahydrofuran, 11.0 mmol) was added dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 30 minutes, then a solution of triisopropyl borate (0.56 g, 2.95 mmol) in tetrahydrofuran (2.0 mL) was added dropwise at -78 °C. After stirred at -78 °C for 1 hour, the reaction mixture was slowly warmed to room temperature, and then stirred at room temperature for 2 hours. The reaction mixture was quenched with 6 N hydrochloric acid aqueous solution and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a white solid. Yield: 534 mg, 41%. LCMS (ESI) m/z: 182.1 (M+H). Step 3: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- (5-ethyl-2-methoxy-4-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]am ino]cyclohexyl]carbamate To a solution of tert-butyl N-[(trans)-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (200 mg, 344.9 μmol) and 5-ethyl-2-methoxy-4-pyridylboronic acid (125 mg, 690.6 μmol) in N,N- dimethylformamide (2.0 mL) and water (0.2 mL) were added 1,1'-bis (di-t- butylphosphino)ferrocene-palladium dichloride (22 mg, 34.5 μmol) and potassium phosphate (220 mg, 1.03 mmol). The suspension was degassed and purged with nitrogen three times. After stirring at 80 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 254 mg, 85%. LCMS (ESI) m/z: 636.3 (M+H). Step 4: Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(5- ethyl-2-hydroxy-4-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxa midine Tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-(5-ethyl-2-methoxy- 4-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohexyl]carb amate (130 mg, 204.4 μmol) was dissolved in 6 N aqueous solution of hydrochloric acid (10.0 mL) and then stirred at 90 °C for 16 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[(trans-4- aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phenyl)-6-(5-et hyl-2-hydroxy-4- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as a light-yellow solid. Yield: 26.0 mg, 24%. LCMS (ESI) m/z: 522.1 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.32 (d, 1H, J=6.3 Hz), 8.41 (d, 1H, J=1.2 Hz), 8.17 (s, 1H), 7.91 (d, 1H, J=2.4 Hz), 7.40-7.55 (m, 2H), 7.13 (d, 1H, J=2.1 Hz), 6.80-6.95 (m, 2H), 6.53 (s, 2H), 4.10-4.20 (m, 1H), 2.67-2.72 (m, 1H), 2.40-2.50 (m, 2H), 2.05-2.18 (m, 2H), 1.75-1.84 (m, 2H), 1.20-1.50 (m, 4H), 1.00-1.21 (m, 4H). ¹⁹ F NMR (DMSO- d6, 282 MHz) δ -114.26 (s, 1F). EXAMPLE 76 Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(5-ethyl-2- methoxy-4-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt The mixture of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-(5- ethyl-2-methoxy-4-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino ]cyclohexyl]carbamate (94 mg, 147.8 μmol) in 2 N aqueous solution of hydrochloric acid (1.0 mL) was stirred at 50°C for 2 hours. After cooling down to room temperature, the resulting mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1% formic acid) afforded 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-5- fluoro-phenyl)-6-(5-ethyl-2-methoxy-4-pyridyl)pyrrolo[1,2-b] pyridazine-3-carboxamidine formic acid salt as a light yellow solid. Yield: 18.2 mg, 21%. LCMS (ESI) m/z: 536.1 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.41 (d, 1H, J=6.6 Hz), 8.43 (brs, 1H), 8.25-8.30 (m, 2H), 8.06 (d, 1H, J=2.1 Hz), 7.93 (d, 1H, J=2.1 Hz), 7.50-7.60 (m, 1H), 7.47 (d, 1H, J=1.8 Hz), 6.85-6.94 (m, 2H), 6.58 (brs, 2H), 4.10-4.21 (m, 1H), 4.00 (s, 3H), 2.90-3.01 (m, 1H), 2.55-2.65 (m, 2H), 2.15-2.28 (m, 2H), 1.94-2.05 (m, 2H), 1.35-1.65 (m, 4H), 1.24 (t, 3H, J=7.5 Hz). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -114.39 (s, 1F). EXAMPLE 77 Synthesis of 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-phen yl)-6-(4-ethyl-6- methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine

Step 1: Synthesis of tert-butyl N-[cis-3-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (1.00 g, 2.5 mmol) in N,N-dimethylacetamide (10 mL) were added tert-butyl N- [cis-3-aminocyclopentyl]carbamate (598 mg, 3.0 mmol) and N,N-diisopropylethylamine (965 mg, 7.5 mmol). After stirring at 100 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure afforded the title compound as a light yellow solid. Yield: 1.20 g, 85%. LCMS (ESI) m/z: 567.3 (M+H). Step 2: Synthesis of tert-butyl N-[cis-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- (4- ethyl-6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino ]cyclopentyl]carbamate To a solution of tert-butyl N-[cis-3-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (120 mg, 212 μmol) in N,N-dimethylformamide (1 mL) and water (0.1 mL) were added 4-ethyl-2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (112 mg, 424 μmol), 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (14 mg, 21 μmol) and potassium phosphate (135 mg, 636 μmol). The resulting mixture was purged with nitrogen gas, stirred at 70 °C for 2 hours and then cooled to room temperature. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a light-yellow solid. Yield: 100 mg, 72%. LCMS (ESI) m/z: 622.4 (M+H). Step 3: Synthesis of 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-phen yl)-6-(4- ethyl-6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxa midine To a solution of tert-butyl N-[cis-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- (4-ethyl- 6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclo pentyl]carbamate (100 mg, 160 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-chloro-5- fluoro-phenyl)-6-(4-ethyl-6-methoxy-3-pyridyl)pyrrolo[1,2-b] pyridazine-3-carboxamidine as a white solid. Yield: 34.1 mg, 39%. LCMS (ESI) m/z: 522.4 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.47 (s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 7.83 (d, 1H, J=1.6 Hz), 7.48-7.52 (m, 1H), 7.01 (d, 1H, J=2.0 Hz), 6.87-6.92 (m, 2H), 6.78 (s, 1H), 6.54 (s, 2H), 4.58-4.64 (m, 1H), 3.87 (s, 3H), 3.27-3.31 (m, 1H), 2.74-2.79 (m, 2H), 2.36-2.42 (m, 1H), 2.06-2.12 (m, 1H), 1.73-1.85 (m, 2H), 1.34-1.45 (m, 2H), 1.14 (t, 3H, J=7.5 Hz). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ-114.47 (s, 1F). EXAMPLE 78 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(2-ethyl-4,5- dihydroxy-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt Step 1: Synthesis of 1-(2-bromo-4,5-dimethoxy-phenyl)ethanol To a solution of methylmagnesium bromide (3 M in ethyl ether, 1.5 mL) in ethyl ether (5 mL) was added a solution of 2-bromo-4,5-dimethoxy-benzaldehyde (1.00 g, 4.1 mmol) in ethyl ether (15 mL) dropwise at 0 °C under nitrogen atmosphere. After stirring at 0 °C for 5 hours, the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride and then extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a colorless oil. Yield: 700 mg, 69%. ¹ H NMR (Chloroform-d, 300 MHz) δ 7.11 (s, 1H), 6.96 (s, 1H), 5.17 (q, 1H, J=6.3 Hz), 3.85-3.87 (m, 6H), 1.45 (d, 3H, J=6.3 Hz). Step 2: Synthesis of 1-bromo-2-ethyl-4,5-dimethoxybenzene To a solution of 1-(2-bromo-4,5-dimethoxy-phenyl)ethanol (650 mg, 2.5 mmol) in dichloromethane (10 mL) were added triethylsilane (1.45 g, 12.4 mmol) and trifluoroacetic acid (1.42 g, 12.4 mmol). After stirring at room temperature for 4 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afforded the title compound as a white solid. Yield: 420 mg, 68%. ¹ H NMR (Chloroform-d, 300 MHz) δ 7.02 (s, 1H), 6.76 (s, 1H), 3.85-3.88 (m, 6H), 2.67-2.75 (m, 2H), 1.24 (t, 3H, J=7.5 Hz). Step 3: Synthesis of 4-bromo-5-ethylbenzene-1,2-diol To a solution of 1-bromo-2-ethyl-4,5-dimethoxybenzene (200 mg, 816 μmol) in dichloromethane (3 mL) was added boron tribromide (817 mg, 3.2 mmol) dropwise at 0 °C under nitrogen atmosphere. After stirring at room temperature for 16 hours, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 130 mg, 73%. ¹ H NMR (Chloroform-d, 300 MHz) δ 7.07 (s, 1H), 6.78 (s, 1H), 5.21 (s, 2H), 2.65 (q, 2H, J=7.5 Hz), 1.20 (t, 3H, J=7.5 Hz). Step 4: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- (2-ethyl-4,5-dihydroxy-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]a mino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]p yridazin-4- yl]amino]cyclohexyl]carbamate (100 mg, 159 μmol), 4-bromo-5-ethylbenzene-1,2-diol (35 mg, 159 μmol) and potassium phosphate (68 mg, 319 μmol) in N,N-dimethylformamide (2 mL) and water (0.2 mL) was added 1,1'-bis(di-t-butylphosphino)ferrocene palladium dichloride (11 mg, 16 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 55 mg, 54%. LCMS (ESI) m/z: 659.2 (M+Na). Step 5: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(2- ethyl-4,5-dihydroxy-phenyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine formic acid salt To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-(2- ethyl-4,5-dihydroxy-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclohexyl]carbamate (50 mg, 78 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(2-ethyl-4,5- dihydroxy-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt as an off-white solid. Yield: 5.8 mg, 12%. LCMS (ESI) m/z: 537.1 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.34 (d, 1H, J=7.8 Hz), 8.41 (s, 1H), 8.19 (s, 1H), 7.67 (d, 1H, J=1.5 Hz), 7.45-7.53 (m, 1H), 6.84-6.94 (m, 2H), 6.75-6.82 (m, 1H), 6.68 (s, 1H), 6.56 (s, 2H), 4.03-4.13 (m, 1H), 2.88-2.96 (m, 1H), 2.57-2.65 (m, 2H), 2.12-2.22 (m, 2H), 1.82-2.02 (m, 2H), 1.32-1.51 (m, 4H), 1.06-1.21 (m, 3H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -114.39 (s, 1F). EXAMPLE 79 Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(2-ethyl-5- fluoro-4-hydroxy-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxami dine

Step 1: Synthesis of trans-tert-butyl N-[4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]p yridazin-4- yl]amino]cyclohexyl]carbamate To a solution of trans-tert-butyl N-[4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (200 mg, 344.9 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)-1,3,2- dioxaborolane (175 mg, 689.8 μmol) in N,N-dimethylacetamide (10.0 mL) were added potassium acetate (102 mg, 1.03 mmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (238 mg, 34.5 μmol) at room temperature. The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 70 °C for 15 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a brown oil. Yield: 150 mg, 36%. LCMS (ESI) m/z: 627.2 (M+H). Step 2: Synthesis of trans-tert-butyl N-[4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- (2-ethyl-5-fluoro-4-hydroxy-phenyl)pyrrolo[1,2-b]pyridazin-4 -yl]amino]cyclohexyl]carbamate To a solution of trans-tert-butyl N-[4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]p yridazin-4- yl]amino]cyclohexyl]carbamate (130 mg, 107.8 μmol) and 4-bromo-5-ethyl-2-fluoro-phenol (47 mg, 215.6 μmol) in N,N-dimethylformamide (5.0 mL) and water (0.5 mL) were added potassium phosphate (69 mg, 323.5 μmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (7 mg, 10.8 μmol) at room temperature. The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 80 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via prep-TLC (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 42 mg, 60%. LCMS (ESI) m/z: 639.1 (M+H). Step 3: Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(2- ethyl-5-fluoro-4-hydroxy-phenyl)pyrrolo[1,2-b]pyridazine-3-c arboxamidine To a solution of trans-tert-butyl N-[4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6-(2- ethyl-5-fluoro-4-hydroxy-phenyl)pyrrolo[1,2-b]pyridazin-4-yl ]amino]cyclohexyl]carbamate (42 mg, 65.7 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (1.0 mL) dropwise at 0°C. After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. The resulting solution was washed with saturated sodium carbonate aqueous solution, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-(2-ethyl-5-fluoro- 4-hydroxy-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as a brown solid. Yield: 8.7 mg, 22%. LCMS (ESI) m/z: 539.4 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.33 (d, 1H, J=7.5 Hz), 8.22 (s, 1H), 7.76 (s, 1H), 7.46-7.52 (m, 1H), 7.17 (d, 1H, J=12.3 Hz), 6.83-6.91 (m, 4H), 6.54 (s, 2H), 4.00-4.20 (m, 1H), 2.62-2.73 (m, 3H), 2.07-2.14 (m, 2H), 1.76-1.82 (m, 2H), 1.15- 1.44 (m, 9H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -114.40 (s, 1F), -140.41 (s, 1F). EXAMPLE 80 Synthesis of 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-phen yl)-6-(5-fluoro-4- hydroxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxami dine formic acid salt

Step 1: Synthesis of 1-bromo-5-fluoro-4-[(4-methoxyphenyl)methoxy]-2-methyl-benze ne To a solution of 4-bromo-2-fluoro-5-methyl-phenol (1.00 g, 4.9 mmol) in acetonitrile (8 mL) were added 1-(chloromethyl)-4-methoxy-benzene (1.20 g, 7.3 mmol) and potassium carbonate (2.00 g, 14.6 mmol). After stirring at room temperature for 15 hours, the reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a white solid. Yield: 1.0 g , 63%. ¹ H NMR (DMSO-d6, 400 MHz) δ 7.50 (d, 1H, J=10.8 Hz), 7.36-7.43 (m, 2H), 7.33 (d, 1H, J=8.8 Hz), 6.92-7.00 (m, 2H), 5.08 (s, 2H), 3.76 (s, 3H), 2.30 (s, 3H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -135.92 (s, 1F). Step 2: Synthesis of 2-[5-fluoro-4-[(4-methoxyphenyl)methoxy]-2-methyl-phenyl]-4, 4,5,5- tetramethyl-1,3,2-dioxaborolane To a solution of 1-bromo-5-fluoro-4-[(4-methoxyphenyl)methoxy]-2-methyl-benze ne (500 mg, 1.5 mmol) in 1,4-dioxane (5 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (781 mg, 3.1 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (127 mg, 153 μmol) and potassium acetate (452 mg, 4.6 mmol). The mixture was purged with nitrogen gas and stirred at 80 °C for 15 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afford the title compound as an off-white solid. Yield: 500 mg, 86%. ¹ H NMR (DMSO-d6, 300 MHz) δ 7.34-7.44 (m, 2H), 7.28 (d, 1H, J=12 Hz), 7.10 (d, 1H, J=8.1 Hz), 6.91-7.01 (m, 2H), 5.11 (s, 2H), 3.77 (s, 3H), 2.43 (s, 3H), 1.28 (s, 12H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -141.24 (s, 1F). Step 3: Synthesis of tert-butyl N-[(cis-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6 -[5- fluoro-4-[(4-methoxyphenyl)methoxy]-2-methyl-phenyl]pyrrolo[ 1,2-b]pyridazin-4- yl]amino]cyclopentyl]carbamate To a solution of tert-butyl N-[cis-3-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (100 mg, 176 μmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) were added 2-[5-fluoro-4-[(4- methoxyphenyl)methoxy]-2-methyl-phenyl]-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (131 mg, 353 μmol), 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (12 mg, 18 μmol) and potassium phosphate (112 mg, 530 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 90 mg, 59%. LCMS (ESI) m/z: 731.5 (M+H). Step 4: Synthesis of 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-phen yl)-6-(5- fluoro-4-hydroxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazine-3- carboxamidine formic acid salt Tert-Butyl N-[cis-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- [5-fluoro-4-[(4- methoxyphenyl)methoxy]-2-methyl-phenyl]pyrrolo[1,2-b]pyridaz in-4- yl]amino]cyclopentyl]carbamate (80 mg, 109 μmol) was dissolved in trifluoroacetic acid (2 mL) and stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-chloro-5- fluoro-phenyl)-6-(5-fluoro-4-hydroxy-2-methyl-phenyl)pyrrolo [1,2-b]pyridazine-3- carboxamidine formic acid salt as a white solid. Yield: 20.1 mg, 32%. LCMS (ESI) m/z: 511.1 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.47 (s, 1H), 8.39 (s, 1H), 8.20 (s, 1H), 7.83 (d, 1H, J=1.6 Hz), 7.48-7.52 (m, 1H), 7.26 (d, 1H, J=12.4 Hz), 7.02 (d, 1H, J=1.6 Hz), 6.88-6.92 (m, 3H), 6.55 (s, 2H), 4.62-4.72 (m, 1H), 3.39-3.50 (m, 2H), 2.52-2.56 (m, 2H), 2.34 (s, 3H), 2.09-2.14 (m, 1H), 1.90-2.02 (m, 1H), 1.69-1.80 (m, 1H), 1.53-1.60 (m, 1H), 1.42-1.52 (m, 1H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.45 (s, 1F), -140.59 (s, 1F). EXAMPLE 81 Synthesis of 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-phen yl)-6-[4- (hydroxymethyl)-2-methyl-phenyl]pyrrolo[1,2-b]pyridazine-3-c arboxamidine

Step 1: Synthesis of tert-butyl N-[cis-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- [4- (hydroxymethyl)-2-methyl-phenyl]pyrrolo[1,2-b]pyridazin-4-yl ]amino]cyclopentyl]carbamate To a solution of tert-butyl N-[cis-3-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (150 mg, 265 μmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) were added [4-(hydroxymethyl)-2- methyl-phenyl]boronic acid (66 mg, 398 μmol), 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (18 mg, 27 μmol) and potassium phosphate (113 mg, 530 μmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a light yellow oil. Yield: 70 mg, 44%. LCMS (ESI) m/z: 607.1 (M+H). Step 2: Synthesis of 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-phen yl)-6-[4- (hydroxymethyl)-2-methyl-phenyl]pyrrolo[1,2-b]pyridazine-3-c arboxamidine To a solution of tert-butyl N-[cis-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- [4- (hydroxymethyl)-2-methyl-phenyl]pyrrolo[1,2-b]pyridazin-4-yl ]amino]cyclopentyl]carbamate (70 mg, 115 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[[cis-3-aminocyclopentyl]amino]-N'- (2-chloro-5-fluoro-phenyl)-6-[4-(hydroxymethyl)-2-methyl-phe nyl]pyrrolo[1,2-b]pyridazine-3- carboxamidine as a white solid. Yield: 13.3 mg, 23%. LCMS (ESI) m/z: 507.3 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.48 (s, 1H), 8.22 (s, 1H), 7.84-7.86 (m, 1H), 7.40-7.52 (m, 2H), 7.18- 7.24 (m, 2H), 7.02-7.06 (m, 1H), 6.82-6.92 (m, 2H), 6.46-6.60 (m, 2H), 5.14 (t, 1H, J=5.6 Hz), 4.64-4.68 (m, 1H), 4.51 (d, 2H, J=5.6 Hz), 3.27-3.32 (m, 1H), 2.42-2.48 (m, 4H), 2.07-2.18 (m, 1H), 1.88-1.98 (m, 1H), 1.72-1.82 (m, 1H), 1.40-1.58 (m, 2H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -114.47 (s, 1F). EXAMPLE 82 Synthesis of 1-[4-[4-[[(1R, 3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-3-[N'-(2-chlo ro-5- fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-5- methyl-2-pyridyl]-3-(2-hydroxy-2- methyl-propyl)urea Step 1: Synthesis of phenyl N-(4-bromo-5-methyl-2-pyridyl)carbamate To a solution of 4-bromo-5-methyl-pyridin-2-amine (1.00 g, 5.35 mmol) in dichloromethane (20.0 mL) were added pyridine (634 mg, 8.02 mmol) and phenyl carbonochloridate (1.00 g, 6.42 mmol) dropwise at 0 °C. After stirring at 25 °C for 15 hours, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a light yellow solid. Yield: 1.53 g, 93%. LCMS (ESI) m/z: 306.9 (M+H). Step 2: Synthesis of 1-(4-bromo-5-methylpyridin-2-yl)-3-(2-hydroxy-2-methylpropyl )urea To a solution of phenyl N-(4-bromo-5-methyl-2-pyridyl)carbamate (1.53 g, 4.98 mmol) in N,N- dimethylformamide (15.0 mL) were added triethylamine (1.51 g, 14.94 mmol) and 1-amino-2- methyl-propan-2-ol (1.33 g, 14.94 mmol). After stirring at 50 °C for 3 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved with ethyl acetate and washed with saturated aqueous solution of potassium carbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light yellow solid. Yield: 1.30 g, 86%. LCMS (ESI) m/z: 302.2 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 9.23 (s, 1H), 8.09 (s, 1H), 7.83 (s, 1H), 7.62 (s, 1H), 3.08 (d, 2H, J=5.6 Hz), 2.22 (s, 3H), 1.08 (s, 6H). Step 3: Synthesis of 1-(2-hydroxy-2-methyl-propyl)-3-[5-methyl-4-(4,4,5,5-tetrame thyl-1,3,2- dioxaborolan-2-yl)-2-pyridyl]urea To a solution of 1-(4-bromo-5-methyl-2-pyridyl)-3-(2-hydroxy-2-methyl-propyl) urea (500 mg, 1.65 mmol) in N,N-dimethylformamide (6.0 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (840 mg, 3.31 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (136 mg, 165.5 μmol) and potassium acetate (325 mg, 3.31 mmol). The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 16 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a brown solid. Yield: 450 mg, 62%, 80% purity. LCMS (ESI) m/z: 350.1 (M+H). Step 4: Synthesis of 4-[[(1R, 3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bromo-N'-(2 - chloro-5-fluoro-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamid ine To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (250 mg, 621.8 μmol) in N,N-dimethylacetamide (3.0 mL) were added (1R, 3S)- 1,2,2-trimethylcyclopentane-1,3-diamine (132 mg, 932.7 μmol) and N,N-diisopropylethylamine (241 mg, 1.87 mmol). After stirring at 90 °C for 2 hours, the reaction was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 240 mg, 76%. LCMS (ESI) m/z: 509.3 (M+H). Step 5: Synthesis of 1-[4-[4-[[(1R, 3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-3-[N'-(2- chloro-5-fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin -6-yl]-5-methyl-2-pyridyl]-3-(2- hydroxy-2-methyl-propyl)urea To a solution of 4-[[(1R, 3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bromo-N'-(2 -chloro- 5-fluoro-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (120 mg, 236.3 μmol) in N,N- dimethylformamide (5.0 mL) and water (0.5 mL) were added 1-(2-hydroxy-2-methyl-propyl)-3- [5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- pyridyl]urea (247 mg, 708.9 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene-palladium dichloride (15 mg, 23.6 μmol) and potassium phosphate (100 mg, 472.6 μmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 1-[4-[4-[[(1R, 3S)-3-amino-2,2,3- trimethyl-cyclopentyl]amino]-3-[N'-(2-chloro-5-fluoro-phenyl )carbamimidoyl]pyrrolo[1,2- b]pyridazin-6-yl]-5-methyl-2-pyridyl]-3-(2-hydroxy-2-methyl- propyl)urea as a pink solid. Yield: 39.6 mg, 24%. LCMS (ESI) m/z: 650.5 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.59 (brs, 1H), 9.20 (s, 1H), 8.42 (s, 1H), 8.26 (s, 1H), 8.07 (s, 1H), 7.97 (d, 1H, J=1.6 Hz), 7.45-7.49 (m, 2H), 7.05 (d, 1H, J=1.6 Hz), 6.85-6.90 (m, 2H), 6.46 (s, 2H), 4.45-4.56 (m, 2H), 3.15 (d, 2H, J=6.0 Hz), 2.38 (s, 3H), 2.24-2.35 (m, 1H), 1.55-1.75 (m, 3H), 1.02-1.11 (m, 9H), 0.87 (s, 6H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.67 (s, 1F). EXAMPLE 83 Synthesis of 1-[5-[4-[[(1R, 3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-3-[N'-(2-chlo ro-5- fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-4- methyl-2-pyridyl]-3-[(1- hydroxycyclopropyl)methyl]urea Step 1: Synthesis of 1-(5-bromo-4-methyl-2-pyridyl)-3-[(1-hydroxycyclopropyl)meth yl]urea To a solution of phenyl N-(5-bromo-4-methyl-2-pyridyl)carbamate (700 mg, 2.28 mmol) in N,N- dimethylformamide (7.0 mL) were added triethylamine (692 mg, 6.84 mmol) and 1- (aminomethyl)cyclopropanol (595 mg, 6.84 mmol). After stirring at 50 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a white solid. Yield: 590 mg, 86%. LCMS (ESI) m/z: 299.9 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 9.20 (s, 1H), 8.25 (s, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 5.40 (s, 1H), 3.24 (d, 2H, J=5.6 Hz), 2.29 (s, 3H), 0.52-0.60 (m, 2H), 0.45-0.52 (m, 2H). Step 2: Synthesis of 1-[(1-hydroxycyclopropyl)methyl]-3-[4-methyl-5-(4,4,5,5-tetr amethyl-1,3,2- dioxaborolan-2-yl)-2-pyridyl]urea To a solution of 1-(5-bromo-4-methyl-2-pyridyl)-3-[(1-hydroxycyclopropyl)meth yl]urea (500 mg, 1.67 mmol) in N,N-dimethylformamide (24.0 mL) were added 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxabor olane (846 mg, 3.33 mmol), 1,1'-bis (di-t-butylphosphino)ferrocene-palladium dichloride (108 mg, 166.6 μmol) and potassium acetate (327 mg, 3.33 mmol). The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 4 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered and the filtrate was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 400 mg, 50%, 73% purity. LCMS (ESI) m/z: 348.1 (M+H). Step 3: Synthesis of 1-[5-[4-[[(1R, 3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-3-[N'-(2- chloro-5-fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin -6-yl]-4-methyl-2-pyridyl]-3-[(1- hydroxycyclopropyl)methyl]urea To a solution of 4-[[(1R, 3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bromo-N'-(2 -chloro- 5-fluoro-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (100 mg, 196.9 μmol) in N,N- dimethylformamide (3.0 mL) and water (0.3 mL) were added 1-[(1-hydroxycyclopropyl)methyl]- 3-[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 2-pyridyl]urea (205 mg, 590.7 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene-palladium dichloride (13 mg, 19.7 μmol) and potassium phosphate (84 mg, 393.8 μmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 1-[5-[4-[[(1R, 3S)-3-amino-2,2,3-trimethyl- cyclopentyl]amino]-3-[N'-(2-chloro-5-fluoro-phenyl)carbamimi doyl]pyrrolo[1,2-b]pyridazin-6- yl]-4-methyl-2-pyridyl]-3-[(1-hydroxycyclopropyl)methyl]urea as a white solid. Yield: 6.5 mg, 4%. LCMS (ESI) m/z: 648.5 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.49 (s, 1H), 9.17 (s, 1H), 8.21-8.26 (m, 3H), 7.90 (d, 1H, J=1.6 Hz), 7.45-7.49 (m, 1H), 7.34 (s, 1H), 6.98 (d, 1H, J=2.0 Hz), 6.82-6.92 (m, 2H), 6.44 (s, 2H), 5.42 (s, 1H), 4.44-4.52 (m, 1H), 3.20-3.30 (m, 2H), 2.41 (s, 3H), 2.23-2.32 (m, 1H), 1.52-1.71 (m, 3H), 1.05 (s, 3H), 0.87 (s, 6H), 0.56-0.62 (m, 2H), 0.47-0.54 (m, 2H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -114.69 (s, 1F). EXAMPLE 84 Synthesis of 1-[4-[4-[[cis-3-aminocyclopentyl]amino]-3-[N'-(2-chloro-5-fl uoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl- phenyl]-3-(2-hydroxy-2-methyl- propyl)urea Step 1: Synthesis of tert-butyl N-[cis-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- [4- [(2-hydroxy-2-methyl-propyl)carbamoylamino]-2-methyl-phenyl] pyrrolo[1,2-b]pyridazin-4- yl]amino]cyclopentyl]carbamate To a solution of tert-butyl N-[cis-3-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (120 mg, 212 μmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) were added 1-(2-hydroxy-2- methyl-propyl)-3-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-diox aborolan-2-yl)phenyl]urea (111 mg, 318 μmol), 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (14 mg, 21 μmol) and potassium phosphate (90 mg, 424 μmol). The resulting mixture was purge with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a brown solid. Yield: 120 mg, 80%. LCMS (ESI) m/z: 707.0 (M+H). Step 2: Synthesis of 1-[4-[4-[[cis-3-aminocyclopentyl]amino]-3-[N'-(2-chloro-5-fl uoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl- phenyl]-3-(2-hydroxy-2-methyl- propyl)urea To a solution of tert-butyl N-[cis-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- [4-[(2- hydroxy-2-methyl-propyl)carbamoylamino]-2-methyl-phenyl]pyrr olo[1,2-b]pyridazin-4- yl]amino]cyclopentyl]carbamate (120 mg, 169 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.4 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 1-[4-[4-[[cis-3- aminocyclopentyl]amino]-3-[N'-(2-chloro-5-fluoro-phenyl)carb amimidoyl]pyrrolo[1,2- b]pyridazin-6-yl]-3-methyl-phenyl]-3-(2-hydroxy-2-methyl-pro pyl)urea as a white solid. Yield: 33.1 mg, 31%. LCMS (ESI) m/z: 607.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.42 (s, 1H), 8.59 (s, 1H), 8.19 (s, 1H), 7.78 (d, 1H, J=1.6 Hz), 7.47-7.51 (m, 1H), 7.24-7.36 (m, 3H), 7.00 (d, 1H, J=1.6 Hz), 6.86-6.91 (m, 2H), 6.52 (s, 2H), 6.15 (t, 1H, J=5.6 Hz), 4.58-4.69 (m, 1H), 4.53 (s, 1H), 3.28-3.30 (m, 1H), 3.05 (d, 2H, J=5.6 Hz), 2.37-2.43 (m, 4H), 2.07-2.17 (m, 1H), 1.85-1.93 (m, 1H), 1.72-1.80 (m, 1H), 1.35-1.52 (m, 2H), 1.10 (s, 6H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ - 114.47 (s, 1F). EXAMPLE 85 Synthesis of 1-[4-[trans-4-[(4-aminocyclohexyl)amino]-3-[N'-(2-chloro-5-f luoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl- phenyl]-3-(3-hydroxy-3-methyl- butyl)urea Step 1: Synthesis of 1-(3-hydroxy-3-methyl-butyl)-3-[3-methyl-4-(4,4,5,5-tetramet hyl-1,3,2- dioxaborolan-2-yl)phenyl]urea To a solution of phenyl N-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]carbamate (0.40 g, 1.13 mmol) in N,N-dimethylformamide (8 mL) were added triethylamine (344 mg, 3.4 mmol) and 4-amino-2-methyl-butan-2-ol (350 mg, 3.4 mmol). After stirring at 50 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with a saturated aqueous solution of sodium carbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) to afford the title compound as a light orange solid. Yield: 0.40 g, 93%. LCMS (ESI) m/z: 363.2 (M+H).1H NMR (DMSO-d ₆ , 300 MHz) δ 8.54 (s, 1H), 7.48 (d, 1H, J=8.1 Hz), 7.14-7.26 (m, 2H), 6.11 (t, 1H, J=5.4 Hz), 4.32 (s, 1H), 3.07-3.21 (m, 2H), 2.38 (s, 3H), 1.48-1.59 (m, 2H), 1.27 (s, 12H), 1.11 (s, 6H). Step 2: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-[4- [(3-hydroxy-3-methyl-butyl)carbamoylamino]-2-methyl-phenyl]p yrrolo[1,2-b]pyridazin-4- yl]amino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (120 mg, 207 μmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) were added 1-(3-hydroxy-3- methyl-butyl)-3-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxa borolan-2-yl)phenyl]urea (112 mg, 310 μmol), 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (14 mg, 21 μmol) and potassium phosphate (88 mg, 414 μmol). The resulting mixture was purge with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a light yellow solid. Yield: 140 mg, 92%. LCMS (ESI) m/z: 735.0 (M+H). Step 3: Synthesis of 1-[4-[trans-4-[(4-aminocyclohexyl)amino]-3-[N'-(2-chloro-5-f luoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl- phenyl]-3-(3-hydroxy-3-methyl- butyl)urea To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-[4-[(3- hydroxy-3-methyl-butyl)carbamoylamino]-2-methyl-phenyl]pyrro lo[1,2-b]pyridazin-4- yl]amino]cyclohexyl]carbamate (120 mg, 163 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.4 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 1-[4-[trans-4- [(4-aminocyclohexyl)amino]-3-[N'-(2-chloro-5-fluoro-phenyl)c arbamimidoyl]pyrrolo[1,2- b]pyridazin-6-yl]-3-methyl-phenyl]-3-(3-hydroxy-3-methyl-but yl)urea as a light yellow solid. Yield: 28.1 mg, 27%. LCMS (ESI) m/z: 635.5 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.32 (d, 1H, J= 7.6 Hz), 8.53 (s, 1H), 8.19 (s, 1H), 7.81 (d, 1H, J=1.6 Hz), 7.47-7.51 (m, 1H), 7.28- 7.36 (m, 3H), 6.84-6.94 (m, 3H), 6.54 (s, 2H), 6.13 (t, 1H, J=5.6 Hz), 4.36 (brs, 1H), 4.08-4.12 (m, 1H), 3.14-3.24 (m, 3H), 2.54-2.67 (m, 2H), 2.41 (s, 3H), 2.10-2.16 (m, 2H), 1.74-1.84 (m, 2H), 1.52-1.62 (m, 2H), 1.19–1.41 (m, 4H), 1.13 (s, 6H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ - 114.40 (s, 1F). EXAMPLE 86 Synthesis of 1-[4-[4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino] -3-[N'-(2-chloro-5- fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3, 5-dimethyl-phenyl]-3-(2-hydroxy- 2-methyl-propyl)urea To a solution of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-(2-chloro- 5-fluoro-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (50 mg, 98 μmol) in N,N- dimethylformamide (1 mL) and water (0.1 mL) were added 1-[3,5-dimethyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2-hydroxy-2-m ethyl-propyl)urea (54 mg, 148 μmol), 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (7 mg, 10 μmol) and potassium phosphate (42 mg, 197 μmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 15 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 1-[4-[4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino] -3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3,5-dimet hyl-phenyl]-3-(2-hydroxy-2- methyl-propyl)urea as a white solid. Yield: 7.3 mg, 11%. LCMS (ESI) m/z: 663.2 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.39 (brs, 1H), 8.51 (s, 1H), 8.20 (s, 1H), 7.57 (d, 1H, J=1.6 Hz), 7.44-7.50 (m, 1H), 7.15 (s, 2H), 6.82-6.90 (m, 2H), 6.67 (s, 1H), 6.43 (s, 2H), 6.14 (t, 1H, J=5.6 Hz), 4.55 (s, 1H), 4.39-4.45 (m, 1H), 3.04 (d, 2H, J=5.6 Hz), 2.18-2.27 (m, 1H), 2.10 (s, 6H), 1.54-1.63 (m, 3H), 1.18-1.28 (m, 1H), 1.09 (s, 6H), 0.99 (s, 3H), 0.84 (s, 3H), 0.81 (s, 3H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.72 (s, 1F). EXAMPLE 87 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-4-h ydroxy-phenyl)-6-(6- methoxy-2,4-dimethyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-ca rboxamidine Step 1: Synthesis of 3-bromo-6-methoxy-2,4-dimethyl-pyridine A mixture of 3-bromo-6-chloro-2,4-dimethyl-pyridine (900 mg, 4.08 mmol) and sodium methanolate in methanol (9.0 mL, 30% w/w in methanol) was stirred at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a light yellow oil. Yield: 830 mg, 94%. LCMS (ESI) m/z: 215.9 (M+H). Step 2: Synthesis of 6-methoxy-2,4-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxabor olan-2- yl)pyridine To a solution of 3-bromo-6-methoxy-2,4-dimethyl-pyridine (400 mg, 1.85 mmol) in N,N- dimethylformamide (5.0 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (940 mg, 3.70 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (153 mg, 185.1 μmol) and potassium acetate (363 mg, 3.70 mmol). The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 16 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a white solid. Yield: 350 mg, 71%. LCMS (ESI) m/z: 264.1 (M+H). Step 3: Synthesis of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-5-fluo ro-phenyl]-4- chloro-pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-4-chloro-pyrrolo[1,2-b]pyridazine-3-carbonitrile (450 mg, 1.75 mmol) in toluene (5.0 mL) were added 4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-5-fluoro-aniline (484 mg, 1.75 mmol) and trimethylaluminium (2.6 mL, 5.20 mmol, 2 M in toluene) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 30 minutes and then heated at 100 °C for 4 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was quenched with saturation solution of ammonium chloride and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a brown solid. Yield: 690 mg, 64%, 86% purity. LCMS (ESI) m/z: 532.8 (M+H). Step 4: Synthesis of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro-4-hydroxy- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-5-fluo ro-phenyl]-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (150 mg, 281.8 μmol) in N,N-dimethylacetamide (3.0 mL) were added tert-butyl N-(4-aminocyclohexyl)carbamate (75 mg, 352.2 μmol) and N,N- diisopropylethylamine (109 mg, 845.4 μmol). After stirring at 100 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 120 mg, 71%. LCMS (ESI) m/z: 597.3 (M+H). Step 5: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-4-hydroxy- phenyl)carbamimidoyl]-6-(6-methoxy-2,4-dimethyl-3-pyridyl)py rrolo[1,2-b]pyridazin-4- yl]amino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro-4-hydroxy- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (90 mg, 151.0 μmol) in N,N-dimethylformamide (3.0 mL) and water (0.3 mL) were added 6-methoxy-2,4- dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyri dine (60 mg, 226.6 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene-palladium dichloride (10 mg, 15.1 μmol) and sodium carbonate (32 mg, 302.0 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 60 mg, 39%, 65% purity. LCMS (ESI) m/z: 652.2 (M+H). Step 6: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-4-h ydroxy- phenyl)-6-(6-methoxy-2,4-dimethyl-3-pyridyl)pyrrolo[1,2-b]py ridazine-3-carboxamidine To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-4-hydroxy- phenyl)carbamimidoyl]-6-(6-methoxy-2,4-dimethyl-3-pyridyl)py rrolo[1,2-b]pyridazin-4- yl]amino]cyclohexyl]carbamate (50 mg, 76.7 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.4 mL). After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[trans-(4- aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-4-hydroxy-pheny l)-6-(6-methoxy-2,4-dimethyl- 3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as an off-white solid. Yield: 10.9 mg, 24%. LCMS (ESI) m/z: 552.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.59 (d, 1H, J=8.0 Hz), 8.18 (s, 1H), 7.66 (d, 1H, J=1.6 Hz), 7.02 (d, 1H, J=8.8 Hz), 6.83 (d, 1H, J=12.0 Hz), 6.72 (d, 1H, J=1.6 Hz), 6.62 (s, 1H), 6.40 (s, 2H), 3.95-4.01 (m, 1H), 3.84 (s, 3H), 2.56-2.64 (m, 1H), 2.29 (s, 3H), 2.01-2.15 (m.5H), 1.72-1.82 (m, 2H), 1.15-1.40 (m, 4H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -135.97 (s, 1F). EXAMPLE 88 Synthesis of 4-[[(cis)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-4- hydroxy-phenyl)-6-(6- methoxy-2,4-dimethyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-ca rboxamidine formic acid salt

Step 1: Synthesis of tert-butyl N-[(cis)-3-[[6-bromo-3-[N'-(2-chloro-5-fluoro-4-hydroxy- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-5-fluo ro-phenyl]-4- chloro-pyrrolo[1,2-b]pyridazine-3-carboxamidine (180 mg, 338.2 μmol) in N,N- dimethylacetamide (4.0 mL) were added tert-butyl N-[(cis)-3-aminocyclopentyl]carbamate (81 mg, 405.8 μmol) and N,N-diisopropylethylamine (131 mg, 1.01 mmol). The resulting mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded two fractions: the title compound as a yellow solid. Yield: 120 mg, 61%. LCMS (ESI) m/z: 583.1 (M+H). And tert-butyl N-[(cis)-3-[[6-bromo-3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy -2-chloro-5-fluoro- phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate as a light yellow solid. Yield: 70 mg, 29%. LCMS (ESI) m/z: 697.1 (M+H). Step 2: Synthesis of tert-butyl N-[(cis)-3-[[3-[N'-(2-chloro-5-fluoro-4-hydroxy- phenyl)carbamimidoyl]-6-(6-methoxy-2,4-dimethyl-3-pyridyl)py rrolo[1,2-b]pyridazin-4- yl]amino]cyclopentyl]carbamate To a solution of tert-butyl N-[(cis)-3-[[6-bromo-3-[N'-(2-chloro-5-fluoro-4-hydroxy- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (100 mg, 171.8 μmol) in N,N-dimethylformamide (3.0 mL) and water (0.3 mL) were added 6-methoxy- 2,4-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (135 mg, 515.6 μmol), 1,1'- bis (di-t-butylphosphino)ferrocene-palladium dichloride (11 mg, 17.2 μmol) and sodium carbonate (36 mg, 343.7 μmol). The resulting mixture was purged with nitrogen gas and stirred at 90 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a brown solid. Yield: 46 mg, 19%, 46% purity. LCMS (ESI) m/z: 638.1 (M+H). Step 3: Synthesis of 4-[[(cis)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-4- hydroxy- phenyl)-6-(6-methoxy-2,4-dimethyl-3-pyridyl)pyrrolo[1,2-b]py ridazine-3-carboxamidine formic acid salt To a solution of tert-butyl N-[(cis)-3-[[3-[N'-(2-chloro-5-fluoro-4-hydroxy- phenyl)carbamimidoyl]-6-(6-methoxy-2,4-dimethyl-3-pyridyl)py rrolo[1,2-b]pyridazin-4- yl]amino]cyclopentyl]carbamate (75 mg, 54.0 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.4 mL). The resulting mixture was stirred at 25 °C for an hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1%FA) afforded 4-[[(cis)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-4- hydroxy-phenyl)-6-(6-methoxy-2,4-dimethyl-3-pyridyl)pyrrolo[ 1,2-b]pyridazine-3- carboxamidine formic acid salt as a light yellow solid. Yield: 2.5 mg, 7%. LCMS (ESI) m/z: 538.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.77 (brs, 1H), 8.35 (s, 1H), 8.20 (s, 1H), 7.67 (d, 1H, J=1.6 Hz), 7.06 (d, 1H, J=8.8 Hz), 6.81-6.92 (m, 2H), 6.62 (s, 1H), 6.43 (brs, 2H), 4.50- 4.62 (m, 1H), 3.84 (s, 3H), 3.48-3.51 (m, 1H), 2.52-2.54 (m.1H), 2.28 (s, 3H), 2.02-2.17 (m, 4H), 1.91-2.01 (m, 1H), 1.70-1.80 (m, 1H), 1.56-1.65 (m, 1H), 1.42-1.55 (m, 1H). ¹⁹ F NMR (DMSO- d6, 376 MHz) δ -136.03 (s, 1F). EXAMPLE 89 Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[6-(2- hydroxy-1,1-dimethyl-ethyl)-3-pyridyl]pyrrolo[1,2-b]pyridazi ne-3-carboxamidine

Step 1: Synthesis of ethyl 2-(5-bromo-2-pyridyl)-2-methyl-propanoate To a solution of ethyl 2-methylpropanoate (2.64 g, 22.7 mmol) in tetrahydrofuran (20 mL) was added lithium diisopropylamide (2.0 M in tetrahydrofuran, 11.4 mL) at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 0.5 hour, then 5-bromo-2-fluoro- pyridine (2.00 g, 11.4 mmol) was added. After stirring at -78 °C for 0.5 hour and then at room temperature for 2 hours, the reaction mixture was quenched with a saturation solution of ammonium chloride and extracted with ethyl acetate three times. The combined organic layers were washed with brine, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 2.50 g, 81%. LCMS (ESI) m/z: 274.1 (M+H). Step 2: Synthesis of 2-(5-bromo-2-pyridyl)-2-methyl-propan-1-ol To a solution of ethyl 2-(5-bromo-2-pyridyl)-2-methyl-propanoate (2.00 g, 6.3 mmol) in dichloromethane (10 mL) was added diisobutyl aluminium hydride (1 M in toluene, 13.9 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 3 hours, then methanol (30 mL) was added dropwise and stirred further 20 minutes. The solid was filtered out and the filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 700 mg, 44%. LCMS (ESI) m/z: 230.1 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.61-8.62 (m, 1H), 7.91-7.94 (m, 1H), 7.36-7.38 (m, 1H), 4.66 (t, 1H, J=5.4 Hz), 3.52 (d, 2H, J=5.4 Hz), 1.22 (s, 6H). Step 3: Synthesis of 2-methyl-2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 2- pyridyl]propan-1-ol To a solution of 2-(5-bromo-2-pyridyl)-2-methyl-propan-1-ol (700 mg, 3.0 mmol) and 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (1.55 g, 6.0 mmol) in N,N-dimethylformamide (10 mL) were added potassium acetate (597 mg, 6.0 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (223 mg, 304 μmol) at room temperature. The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 2 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a black solid. Yield: 480 mg, 53%. Step 4: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-[6- (2-hydroxy-1,1-dimethyl-ethyl)-3-pyridyl]pyrrolo[1,2-b]pyrid azin-4- yl]amino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (120 mg, 207 μmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) were added 2-methyl-2-[5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]propan-1-ol (86 mg, 310 μmol), 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (14 mg, 21 μmol) and potassium phosphate (88 mg, 414 μmol). The resulting mixture was purge with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a brown solid. Yield: 120 mg, 77%. LCMS (ESI) m/z: 650.5 (M+H). Step 5: Synthesis of 4-[trans-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phe nyl)-6-[6-(2- hydroxy-1,1-dimethyl-ethyl)-3-pyridyl]pyrrolo[1,2-b]pyridazi ne-3-carboxamidine To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-[6-(2- hydroxy-1,1-dimethyl-ethyl)-3-pyridyl]pyrrolo[1,2-b]pyridazi n-4- yl]amino]cyclohexyl]carbamate (100 mg, 153 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[trans-(4- aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-phenyl)-6-[6-(2 -hydroxy-1,1-dimethyl-ethyl)-3- pyridyl]pyrrolo[1,2-b]pyridazine-3-carboxamidine as a white solid. Yield: 23.6 mg, 28%. LCMS (ESI) m/z: 550.1 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.38 (s, 1H), 8.96 (d, 1H, J=2.4 Hz), 8.21-8.24 (m, 2H), 8.04-8.10 (m, 1H), 7.47-7.52 (m, 1H), 7.41-7.44 (m, 1H), 7.21 (d, 1H, J=1.6 Hz), 6.84-6.95 (m, 2H), 6.59 (s, 2H), 4.68 (t, 1H, J=5.2 Hz), 4.15-4.27 (m, 1H), 3.57 (d, 2H, J=5.2 Hz), 2.75-2.81 (m, 1H), 2.10-2.16 (m, 2H), 1.81-1.91 (m, 2H), 1.32-1.52 (m, 4H), 1.28 (s, 6H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -114.36 (s, 1F). EXAMPLE90 Synthesis of N'-(2-chloro-5-fluorophenyl)-6-(6-methoxypyridin-3-yl)-4-[[t rans-4- (propylamino)cyclohexyl]amino]pyrrolo[1,2-b]pyridazine-3-car boximidamide formic acid salt To a solution of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluorophen yl)-6-(6- methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboximidami de (60 mg, 118.1 μmol) and propanal (4 mg, 82.6 μmol) in 1,4-dioxane (2.0 mL) was added sodium triacetoxyborohydride (22 mg, 103.7 μmol) in portions under nitrogen atmosphere. After stirring at 25 °C for 16 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % formic acid) afforded N'-(2-chloro-5-fluorophenyl)-6-(6-methoxypyridin-3-yl)-4-[[t rans-4- (propylamino)cyclohexyl]amino]pyrrolo[1,2-b]pyridazine-3-car boximidamide formic acid salt as an off-white solid. Yield: 5.3 mg, 7%. LCMS (ESI) m/z: 550.2 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.37 (d, 1H, J=6.9 Hz), 8.64 (s, 1H), 8.39 (s, 1H), 8.17-8.23 (m, 2H), 8.10-8.14 (m, 1H), 7.47-7.53 (m, 1H), 7.17-7.19 (m, 1H), 6.83-6.96 (m, 3H), 6.58 (brs, 2H), 4.13-4.27 (m, 1H), 3.88 (s, 3H), 2.61-2.70 (m, 3H), 2.10-2.22 (m, 2H), 1.88-1.96 (m, 2H), 1.30-1.55 (m, 6H), 0.86 (t, 3H, J=7.5 Hz). EXAMPLE 91 Synthesis of 5-[4-[trans-(4-aminocyclohexyl)amino]-3-[N'-(2-chloro-5-fluo ro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-N-[2-(2-m ethoxyethoxy)ethyl]-4-methyl- pyridine-2-carboxamide formic acid salt Step 1: Synthesis of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-[6- [2-(2-methoxyethoxy)ethylcarbamoyl]-4-methyl-3-pyridyl]pyrro lo[1,2-b]pyridazin-4- yl]amino]cyclohexyl]carbamate To a solution of tert-butyl N-[trans-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (120 mg, 207 μmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) were added N-[2-(2- methoxyethoxy)ethyl]-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-d ioxaborolan-2-yl)pyridine-2- carboxamide (113 mg, 310 μmol), 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (14 mg, 21 μmol) and potassium phosphate (88 mg, 414 μmol). The resulting mixture was purge with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a brown solid. Yield: 80 mg, 53%. LCMS (ESI) m/z: 737.5 (M+H). Step 2: Synthesis of 5-[4-[trans-(4-aminocyclohexyl)amino]-3-[N'-(2-chloro-5-fluo ro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-N-[2-(2-m ethoxyethoxy)ethyl]-4-methyl- pyridine-2-carboxamide formic acid salt To a solution of tert-butyl N-[trans-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-[6-[2- (2-methoxyethoxy)ethylcarbamoyl]-4-methyl-3-pyridyl]pyrrolo[ 1,2-b]pyridazin-4- yl]amino]cyclohexyl]carbamate (70 mg, 95 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.4 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 5-[4-[trans-(4-aminocyclohexyl)amino]-3-[N'-(2-chloro- 5-fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]- N-[2-(2-methoxyethoxy)ethyl]-4- methyl-pyridine-2-carboxamide formic acid salt as a white solid. Yield: 17.4 mg, 26%. LCMS (ESI) m/z: 637.5 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.48 (s, 1H), 8.76 (s, 1H), 8.67 (t, 1H, J=5.6 Hz), 8.40 (s, 1H), 8.26 (s, 1H), 8.14 (d, 1H, J=1.6 Hz), 8.01 (s, 1H), 7.47-7.53 (m, 1H), 7.12 (d, 1H, J=1.6 Hz), 6.85-6.96 (m, 2H), 6.63 (s, 2H), 4.16-4.20 (m, 1H), 3.53-3.61 (m, 4H), 3.42- 3.52 (m, 4H), 3.26 (s, 3H), 2.85-2.93 (m, 1H), 2.61 (s, 3H), 2.15-2.23 (m, 2H), 1.86-1.96 (m, 2H), 1.36-1.52 (m, 4H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.35 (s, 1F). EXAMPLE 92 Synthesis of 5-[4-[[cis-3-aminocyclopentyl]amino]-3-[N'-(2-chloro-5-fluor o- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-N-[2-(2-m ethoxyethoxy)ethyl]-4-methyl- pyridine-2-carboxamide formic acid salt Step 1: Synthesis of tert-butyl N-[cis-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- [6- [2-(2-methoxyethoxy)ethylcarbamoyl]-4-methyl-3-pyridyl]pyrro lo[1,2-b]pyridazin-4- yl]amino]cyclopentyl]carbamate To a solution of tert-butyl N-[cis-3-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (100 mg, 176 μmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) were added N-[2-(2- methoxyethoxy)ethyl]-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-d ioxaborolan-2-yl)pyridine-2- carboxamide (129 mg, 353 μmol), 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (12 mg, 17 μmol) and potassium phosphate (112 mg, 530 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow soild. Yield: 54 mg, 34%. LCMS (ESI) m/z: 723.2 (M+H). Step 2: Synthesis of 5-[4-[[cis-3-aminocyclopentyl]amino]-3-[N'-(2-chloro-5-fluor o- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-N-[2-(2-m ethoxyethoxy)ethyl]-4-methyl- pyridine-2-carboxamide formic acid salt To a solution of tert-butyl N-[cis-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- [6-[2-(2- methoxyethoxy)ethylcarbamoyl]-4-methyl-3-pyridyl]pyrrolo[1,2 -b]pyridazin-4- yl]amino]cyclopentyl]carbamate (80 mg, 110 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 5-[4-[[cis-3-aminocyclopentyl]amino]-3-[N'-(2-chloro- 5-fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]- N-[2-(2-methoxyethoxy)ethyl]-4- methyl-pyridine-2-carboxamide formic acid salt as a light-yellow solid. Yield: 11.1 mg, 14%. LCMS (ESI) m/z = 623.5 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.60 (s, 1H), 8.74 (s, 1H), 8.61-8.71 (m, 1H), 8.40 (s, 1H), 8.23-8.32 (m, 1H), 8.11 (s, 1H), 7.99 (s, 1), 7.50-7.53 (m, 1H), 7.28 (s, 1H), 6.88-6.94 (m, 2H), 6.63 (s, 2H), 4.66-4.76 (m, 1H), 3.52-3.58 (m, 9H), 3.26 (s, 3H), 2.55-2.67 (m, 4H), 2.11-2.21 (m, 1H), 1.98-2.06 (m, 1H), 1.71-1.85 (m, 1H), 1.63-1.70 (m, 1H), 1.45-1.53 (m, 1H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -114.40 (s, 1F). EXAMPLE 93 Synthesis of 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-phen yl)-6-[6-[2-(2- methoxyethoxy)ethoxy]-4-methyl-3-pyridyl]pyrrolo[1,2-b]pyrid azine-3-carboxamidine

Step 1: Synthesis of 5-bromo-2-[2-(2-methoxyethoxy)ethoxy]-4-methyl-pyridine To a solution of 2-(2-methoxyethoxy)ethanol (949 mg, 7.9 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (358 mg, 8.9 mmol, 60% purity) at 0 °C. The resulting mixture was stirred at 0 °C for an hour, then 5-bromo-2-fluoro-4-methyl-pyridine (1.00 g, 5.26 mmol) was added. After stirring at 25 °C for 2 hours, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purified by silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 1.2 g, 78%. LCMS (ESI) m/z: 291.9 (M+H). Step 2: Synthesis of 2-[2-(2-methoxyethoxy)ethoxy]-4-methyl-5-(4,4,5,5-tetramethy l-1,3,2- dioxaborolan-2-yl)pyridine To a mixture of 5-bromo-2-[2-(2-methoxyethoxy)ethoxy]-4-methyl-pyridine (600 mg, 2.0 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)-1,3,2-dioxaborolane (630 mg, 2.4 mmol) and potassium acetate (1.72 g, 4.1 mmol) in N,N-dimethylformamide (5 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (302 mg, 413 μmol). The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 2 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 400 mg, 57%. LCMS (ESI) m/z: 338.2 (M+H). Step 3: Synthesis of tert-butyl N-[cis-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- [6- [2-(2-methoxyethoxy)ethoxy]-4-methyl-3-pyridyl]pyrrolo[1,2-b ]pyridazin-4- yl]amino]cyclopentyl]carbamate To a solution of tert-butyl N-[cis-3-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (100 mg, 176 μmol), 2-[2-(2-methoxyethoxy)ethoxy]-4-methyl-5-(4,4,5,5-tetramethy l-1,3,2-dioxaborolan-2- yl)pyridine (119 mg, 353 μmol) and potassium phosphate (75 mg, 353 μmol) in N,N- dimethylformamide (2 mL) and water (0.2 mL) was added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (12 mg, 18 μmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 65 mg, 52%. LCMS (ESI) m/z: 696.5 (M+H). Step 4: Synthesis of 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-phen yl)-6-[6-[2- (2-methoxyethoxy)ethoxy]-4-methyl-3-pyridyl]pyrrolo[1,2-b]py ridazine-3-carboxamidine To a solution of tert-butyl N-[cis-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- [6-[2-(2- methoxyethoxy)ethoxy]-4-methyl-3-pyridyl]pyrrolo[1,2-b]pyrid azin-4- yl]amino]cyclopentyl]carbamate (60 mg, 86 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-phen yl)-6-[6-[2-(2- methoxyethoxy)ethoxy]-4-methyl-3-pyridyl]pyrrolo[1,2-b]pyrid azine-3-carboxamidine as a brown solid. Yield: 25 mg, 39%. LCMS (ESI) m/z = 596.2 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.42-11.48 (m, 1H), 8.21-8.22 (m, 2H), 7.89 (d, 1H, J=1.8 Hz), 7.40-7.56 (m, 1H), 7.06 (d, 1H, J=1.8 Hz), 6.81-6.91 (m, 2H), 6.79 (s, 1H), 6.52 (s, 2H), 4.58-4.68 (m, 1H), 4.38 (t, 2H, J=4.8 Hz), 3.74 (t, 2H, J=4.8 Hz), 3.56-3.40 (m, 2H), 3.44-3.48 (m, 2H), 3.24-3.30 (m, 4H), 2.42 (s, 3H), 2.34-2.38 (m, 1H), 2.03-2.15 (m, 1H), 1.60-1.92 (m, 3H), 1.23-1.45 (m, 2H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -114.48 (s, 1F). EXAMPLE 94 Synthesis of 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-phen yl)-6-[6-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]-4-methyl-3-pyridyl]pyrro lo[1,2-b]pyridazine-3- carboxamidine

Step 1: Synthesis of tert-butyl N-[cis-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- [6- [2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]-4-methyl-3-p yridyl]pyrrolo[1,2-b]pyridazin- 4-yl]amino]cyclopentyl]carbamate To a solution of tert-butyl N-[cis-3-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (80 mg, 141 μmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) were added 2-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]-4-methyl-5-(4,4,5,5-tetr amethyl-1,3,2-dioxaborolan-2- yl)pyridine (120 mg, 282 μmol), 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (9 mg, 14 μmol) and potassium phosphate (90 mg, 424 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a brown soild. Yield : 100 mg, 87%. LCMS (ESI) m/z: 784.5 (M+H). Step 2: Synthesis of 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-phen yl)-6-[6-[2- [2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]-4-methyl-3-pyri dyl]pyrrolo[1,2-b]pyridazine-3- carboxamidine To a solution of tert-butyl N-[cis-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- [6-[2-[2- [2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]-4-methyl-3-pyridyl ]pyrrolo[1,2-b]pyridazin-4- yl]amino]cyclopentyl]carbamate (90 mg, 114 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-phen yl)-6-[6-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]-4-methyl-3-pyridyl]pyrro lo[1,2-b]pyridazine-3- carboxamidine as a black solid. Yield: 27.1 mg, 34%. LCMS (ESI) m/z: 684.5 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.46 (brs, 1H), 8.21-8.23 (m, 2H), 7.89 (d, 1H, J=2.0 Hz), 7.51-7.58 (m, 1H), 7.06 (d, 1H, J=2.0 Hz), 6.87-6.91 (m, 2H), 6.79 (s, 1H), 6.53 (s, 2H), 4.61-4.65 (m, 1H), 4.36-4.40 (m, 2H), 3.74-3.76 (m, 2H), 3.56-3.60 (m, 2H), 3.49-3.55 (m, 8H), 3.41-3.43 (m, 2H), 3.26-3.31 (m, 1H), 3.23 (s, 3H), 2.42 (s, 3H), 2.37-2.41 (m, 1H), 2.03-2.12 (m, 1H), 1.73-1.83 (m, 3H), 1.26-1.44 (m, 2H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.47 (s, 1F). EXAMPLE 95 Synthesis of 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-ethyl-4-hydroxy-phen yl)-6-(6-methoxy- 2,4-dimethyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamid ine Step 1: Synthesis of tert-butyl N-[cis-3-[[6-bromo-3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2 -ethyl- phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (400 mg, 787.5 μmol) and tert-butyl N-[cis-3- aminocyclopentyl]carbamate (236 mg, 1.18 mmol) in N,N-dimethylacetamide (3.0 mL) was added N,N-diisopropylethylamine (305 mg, 2.36 mmol) dropwise. The reaction was stirred at 90 °C for 2 hours and cooled to room temperature. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 320 mg, 60%. LCMS (ESI) m/z: 673.1 (M+H). Step 2: Synthesis of tert-butyl N-[cis-3-[[3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl- phenyl]carbamimidoyl]-6-(6-methoxy-2,4-dimethyl-3-pyridyl)py rrolo[1,2-b]pyridazin-4- yl]amino]cyclopentyl]carbamate To a mixture of tert-butyl N-[cis-3-[[6-bromo-3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2 -ethyl- phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (120 mg, 178.6 μmol) and 6-methoxy-2,4-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxabor olan-2- yl)pyridine (56 mg, 214.3 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added sodium carbonate (42 mg, 400.0 μmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (11 mg, 17.8 μmol) at room temperature under argon atmosphere. The resulting mixture was heated at 80 °C for 2 hours. After cooled to room temperature, the reaction mixture was diluted with ethyl acetated and washed with brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 80 mg, 61%. LCMS (ESI) m/z: 728.3 (M+H). Step 3: Synthesis of tert-butyl N-[cis-3-[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-6- (6- methoxy-2,4-dimethyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl] amino]cyclopentyl]carbamate To a solution of tert-butyl N-[cis-3-[[3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl- phenyl]carbamimidoyl]-6-(6-methoxy-2,4-dimethyl-3-pyridyl)py rrolo[1,2-b]pyridazin-4- yl]amino]cyclopentyl]carbamate (65 mg, 89.2 μmol) in N,N-dimethylformamide (3.0 mL) was added cesium fluoride (40 mg, 267.8 μmol). The reaction mixture was stirred at 25 °C for 5 hours. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 50 mg, 91%. LCMS (ESI) m/z: 614.2 (M+H). Step 4: Synthesis of 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-ethyl-4-hydroxy-phen yl)-6-(6- methoxy-2,4-dimethyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-ca rboxamidine To a solution of tert-butyl N-[cis-3-[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-6- (6- methoxy-2,4-dimethyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl] amino]cyclopentyl]carbamate (50 mg, 81.4 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (1.0 mL) dropwise. The reaction mixture was stirred at 25 °C for 16 hours and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 4-[[cis-3-aminocyclopentyl]amino]-N'-(2-ethyl-4- hydroxy-phenyl)-6-(6-methoxy-2,4-dimethyl-3-pyridyl)pyrrolo[ 1,2-b]pyridazine-3- carboxamidine as a white solid. Yield: 2.1 mg, 4%. LCMS (ESI) m/z: 514.2 (M+H). ¹ H-NMR (DMSO-d6, 300 MHz) δ 8.95 (s, 1H), 8.22 (s, 1H), 7.65 (s, 1H), 6.84 (s, 1H), 6.61-6.68 (m, 3H), 6.59-6.61 (m, 1H), 4.50-4.57 (m, 1H), 3.84 (s, 3H), 3.31-3.33 (m, 1H), 2.41-2.43 (m, 2H), 2.29 (s, 3H), 2.02-2.12 (m, 4H), 1.84-1.97 (m, 1H), 1.30-1.68 (m, 3H), 1.08 (t, 3H, J=7.5 Hz). EXAMPLE 96 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine To a mixture of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine (800 mg, 1.43 mmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (478 mg, 2.86 mmol) in N,N-dimethylformamide (5.0 mL) and water (0.5 mL) were added potassium phosphate (912 mg, 4.3 mmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (93 mg, 143.2 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 hours. After cooled to room temperature, the reaction mixture was diluted with ethyl acetated and washed with saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine as an off-white solid. Yield: 437.9 mg, 61%. LCMS (ESI) m/z: 487.3 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 12.54 (d, 1H, J=5.1 Hz), 8.95 (s, 1H), 8.24-8.25 (m, 2H), 7.91 (s, 1H), 7.05 (s, 1H), 6.78 (s, 1H), 6.54-6.68 (m, 3H), 5.93 (brs, 2H), 4.97-5.00 (m, 1H), 3.91-3.97 (m, 1H), 3.87 (s, 3H), 3.68-3.81 (m, 3H), 2.32-2.49 (m, 6H), 1.85-1.93 (m, 1H), 1.00-1.07 (m, 3H) .EXAMPLE 97 Synthesis of N'-(2-chloro-5-fluoro-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine To a solution of 6-bromo-N'-(2-chloro-5-fluoro-phenyl)-4-[[(3S)-tetrahydrofur an-3- yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine (120 mg, 265 μmol) in N,N- dimethylformamide (3 mL) and water (0.3 mL) were added (6-methoxy-4-methyl-3- pyridyl)boronic acid (89 mg, 530 μmol), 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (18 mg, 27 μmol) and sodium carbonate (56 mg, 530 μmol). The resulting mixture was purge with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded N'-(2-chloro-5-fluoro-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine as a white solid. Yield: 40 mg, 30%. LCMS (ESI) m/z: 495.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.59 (d, 1H, J=7.2 Hz), 8.26 (d, 2H, J=4.8 Hz), 7.94 (d, 1H, J=1.6 Hz), 7.47-7.52 (m, 1H), 7.09 (d, 1H, J=1.6 Hz), 6.84-6.95 (m, 2H), 6.79 (d, 1H, J=0.8 Hz), 6.61 (s, 2H), 4.96-5.05 (m, 1H), 3.94-3.98 (m, 1H), 3.86 (s, 3H), 3.71-3.81 (m, 3H), 2.33-2.46 (m, 4H), 1.89-1.97 (m, 1H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.40 (s, 1F). EXAMPLE 98 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4-(4- piperidylmethylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidin e

Step 1: Synthesis of tert-butyl 4-[[[6-bromo-3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl - phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]meth yl]piperidine-1-carboxylate To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (150 mg, 295.3 μmol) and tert-butyl 4- (aminomethyl)piperidine-1-carboxylate (94 mg, 442.9 μmol) in N,N-dimethylacetamide (2.0 mL) was added N,N-diisopropylethylamine (114 mg, 885.9 μmol) dropwise. The reaction mixture was stirred at 80 °C for 2 hours and cooled to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 130 mg, 64%. LCMS (ESI) m/z: 685.1 (M+H). Step 2: Synthesis of tert-butyl 4-[[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amin o]methyl]piperidine-1- carboxylate To a mixture of tert-butyl 4-[[[6-bromo-3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl - phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]meth yl]piperidine-1-carboxylate (110 mg, 160.4 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (53 mg, 320.8 μmol) in N,N- dimethylformamide (2.0 mL) and water (0.2 mL) were added potassium phosphate (102 mg, 481.2 μmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (10 mg, 16.0 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was heated at 100 °C for 2 hours. After cooled to room temperature, the reaction mixture was diluted with ethyl acetated and washed with saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 80 mg, 81 %. LCMS (ESI) m/z: 614.2 (M+H). Step3: Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4-(4- piperidylmethylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidin e To a solution of tert-butyl 4-[[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-6-(6-met hoxy- 4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]methyl ]piperidine-1-carboxylate (70 mg, 114.0 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (1.0 mL) dropwise. The reaction mixture was stirred at 25 °C for an hour and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4- methyl-3-pyridyl)-4-(4-piperidylmethylamino)pyrrolo[1,2-b]py ridazine-3-carboxamidine as a yellow solid. Yield: 35.2 mg, 57%. LCMS (ESI) m/z: 514.2 (M+H). ¹ H-NMR (DMSO-d6, 300 MHz) δ 12.20 (s, 1H), 8.94 (s, 1H), 8.21-8.23 (m, 2H), 7.87-7.88 (m, 1H), 7.04-7.05 (m, 1H), 6.78 (s, 1H), 6.55-6.68 (m, 3H), 5.89 (brs, 2H), 3.86 (s, 3H), 3.65-3.68 (m, 2H), 2.86-2.92 (m, 2H), 2.28-2.46 (m, 7H), 1.69-1.73 (m, 3H), 1.04-1.20 (m, 6H). EXAMPLE 99 Synthesis of N'-(2-chloro-5-fluoro-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4-(4- piperidylmethylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidin e

Step 1: Synthesis of tert-butyl 4-[[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]meth yl]piperidine-1-carboxylate To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (180 mg, 447 μmol) in N,N-dimethylacetamide (2 mL) were added tert-butyl 4- (aminomethyl)piperidine-1-carboxylate (96 mg, 447 μmol) and N,N-diisopropylethylamine (173 mg, 1.3 mmol). After stirring at 80 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light-yellow solid. Yield: 200 mg, 74%. LCMS (ESI) m/z: 581.1 (M+H). Step 2: Synthesis of tert-butyl 4-[[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amin o]methyl]piperidine-1- carboxylate To a solution of tert-butyl 4-[[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]meth yl]piperidine-1-carboxylate (80 mg, 138 μmol) in N,N-dimethylformamide (2 mL) and water (0.2 mL) were added (6-methoxy-4- methyl-3-pyridyl)boronic acid (46 mg, 276 μmol), 1,1'-bis(di-t-butylphosphino)ferrocene- palladium dichloride (9 mg, 13 μmol) and potassium phosphate (88 mg, 413 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a light-yellow solid. Yield: 70 mg, 81%. LCMS (ESI) m/z: 622.2 (M+H). Step 3: Synthesis of N'-(2-chloro-5-fluoro-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4-(4- piperidylmethylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidin e To a solution tert-butyl 4-[[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6-(6-met hoxy-4- methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]methyl]p iperidine-1-carboxylate (60 mg, 96 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded N'-(2-chloro-5-fluoro-phenyl)-6-(6-methoxy-4- methyl-3-pyridyl)-4-(4-piperidylmethylamino)pyrrolo[1,2-b]py ridazine-3-carboxamidine as a white solid. Yield: 16.3 g, 32%. LCMS (ESI) m/z: 522.1 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.37 (s, 1H), 8.22-8.24 (m, 2H), 7.90 (d, 1H, J=1.6 Hz), 7.48-7.51 (m, 1H), 7.08 (d, 1H, J=1.6 Hz), 6.85-6.91 (m, 2H), 6.78 (s, 1H), 6.59 (s, 2H), 3.86 (s, 3H), 3.64-3.70 (m, 2H), 2.86-2.92 (m, 2H), 2.31-2.43 (m, 5H), 1.67-1.77 (m, 3H), 1.07-1.17 (m, 2H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.46 (s, 1F). EXAMPLE 100 Synthesis of 4-[[(1R, 3S)-3-aminocyclopentyl]amino]-6-cyclohexyl-N'-(2-ethyl-4-hyd roxy- phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt

Step 1: Synthesis of tert-butyl N-[(1S,3R)-3-[[6-bromo-3-[N'-[4-[tert-butyl(dimethyl)silyl]o xy-2- ethyl-phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclopentyl]carbamate To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (200 mg, 394.5 μmol) and tert-butyl N-[(1S,3R)-3- aminocyclopentyl]carbamate (103 mg, 512.0 μmol) in N,N-dimethylacetamide (2.0 mL) was added N,N-diisopropylethylamine (102 mg, 787.5 μmol). After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 258 mg, 93%. LCMS (ESI) m/z: 673.2 (M+H). Step 2: Synthesis of tert-butyl N-[(1S,3R)-3-[[3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-eth yl- phenyl]carbamimidoyl]-6-(cyclohexen-1-yl)pyrrolo[1,2-b]pyrid azin-4- yl]amino]cyclopentyl]carbamate To a solution of tert-butyl N-[(1S,3R)-3-[[6-bromo-3-[N'-[4-[tert-butyl(dimethyl)silyl]o xy-2- ethyl-phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclopentyl]carbamate (220 mg, 328.2 μmol) and cyclohexen-1-ylboronic acid (165 mg, 1.31 mmol) in N,N- dimethylformamide (2.0 mL) and water (0.2 mL) were added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (21 mg, 32.2 μmol) and sodium carbonate (104 mg, 981.1 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours. After cooling to room temperature and diluted with ethyl acetate. The resulting mixture was washed water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 213 mg, 92%. LCMS (ESI) m/z: 673.6 (M+H). Step 3: Synthesis of tert-butyl N-[(1S,3R)-3-[[3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-eth yl- phenyl]carbamimidoyl]-6-cyclohexyl-pyrrolo[1,2-b]pyridazin-4 -yl]amino]cyclopentyl]carbamate To a solution of tert-butyl N-[(1S,3R)-3-[[3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-eth yl- phenyl]carbamimidoyl]-6-(cyclohexen-1-yl)pyrrolo[1,2-b]pyrid azin-4- yl]amino]cyclopentyl]carbamate (220 mg, 326.6 μmol) in methanol (4.0 mL) was added 5% rhodium on alumina (300 mg) under nitrogen atmosphere. The mixture was purged with hydrogen gans and stirred at room temperature for 15 hours under hydrogen atmosphere (1.5 atm). The reaction mixture was filtered through Celite pad and washed with methanol. The filtrate was concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 173 mg, 75%. LCMS (ESI) m/z: 675.6 (M+H). Step 4: Synthesis of tert-butyl N-[(1S,3R)-3-[[6-cyclohexyl-3-[N'-(2-ethyl-4-hydroxy- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate To a solution of tert-butyl N-[(1S,3R)-3-[[3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-eth yl- phenyl]carbamimidoyl]-6-cyclohexyl-pyrrolo[1,2-b]pyridazin-4 -yl]amino]cyclopentyl]carbamate (162 mg, 240.0 μmol) in N,N-dimethylformamide (3.0 mL) was added cesium fluoride (110 mg, 723.7 μmol). After stirring at room temperature for 4 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 84 mg, 57%. LCMS (ESI) m/z: 561.3 (M+H). Step 5: Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-6-cyclohexyl-N'-(2-eth yl-4- hydroxy-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt To a solution of tert-butyl N-[(1S,3R)-3-[[6-cyclohexyl-3-[N'-(2-ethyl-4-hydroxy- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (74 mg, 132.0 μmol) in 6 N aqueous solution of hydrochloric acid (3.0 mL) was stirred at 50 °C for 2 hours and then cooled to room temperature. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1% formic acid) afforded 4-[[(1R,3S)-3-aminocyclopentyl]amino]-6-cyclohexyl- N'-(2-ethyl-4-hydroxy-phenyl)pyrrolo[1,2-b]pyridazine-3-carb oxamidine formic acid salt as an off-white solid. Yield: 11.4 mg, 17%. LCMS (ESI) m/z: 461.4 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 8.36 (s, 1H), 8.12 (s, 1H), 7.48 (d, 1H, J=1.2 Hz), 6.50-6.80 (m, 4H), 4.50-4.66 (m, 1H), 3.45-3.55 (m, 1H), 2.55-2.65 (m, 2H), 2.35-2.45 (m, 2H), 2.10-2.20 (m, 1H), 1.90-2.07 (m, 3H), 1.55-1.85 (m, 5H), 1.35-1.50 (m, 5H), 1.20-1.30 (m, 1H), 1.00-1.15 (m, 3H). EXAMPLE 101 Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro- phenyl)-6- cyclohexyl-pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of tert-butyl N-[(1S,3R)-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl ]-6- (cyclohexen-1-yl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclopen tyl]carbamate To a solution of tert-butyl N-[(1S,3R)-3-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (300 mg, 530.0 μmol) and cyclohexen-1-ylboronic acid (134 mg, 1.06 mmol) in N,N-dimethylformamide (6.0 mL) and water (0.6 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (35 mg, 53.8 μmol) and potassium phosphate (338 mg, 1.59 mmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light yellow solid. Yield: 291 mg, 89%. LCMS (ESI) m/z: 589.0 (M+H). Step 2: Synthesis of tert-butyl N-[(1S,3R)-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl ]-6- cyclohexyl-pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclopentyl]ca rbamate To a solution of tert-butyl N-[(1S,3R)-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl ]-6- (cyclohexen-1-yl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclopen tyl]carbamate (231 mg, 407.4 μmol) in methanol (20 mL) was added rhodium on alumina (150 mg, 5%). After stirring at 25 °C for 15 hours under hydrogen atomsphere (1.5 atm), the reaction mixture was filtered through Celite pad and washed with methanol. The filtrate was concentrated under reduced pressure to afford the title compound as a light-yellow solid. Yield: 189 mg, 79%. LCMS (ESI) m/z: 569.2 (M+H). Step 3: Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro- phenyl)-6- cyclohexyl-pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of tert-butyl N-[(1S,3R)-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl ]-6- cyclohexyl-pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclopentyl]ca rbamate (172 mg, 302.8 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (5.0 mL). After stirring at 25 °C for an hour, the resulting mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro- phenyl)-6- cyclohexyl-pyrrolo[1,2-b]pyridazine-3-carboxamidine as a white solid. Yield: 22.4 mg, 16%. LCMS (ESI) m/z: 469.4 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.30 (brs, 1H), 8.10 (s, 1H), 7.45-7.50 (m, 2H), 6.80-6.95 (m, 2H), 6.74 (d, 1H, J=1.5 Hz), 6.45 (brs, 2H), 4.50-4.60 (m, 1H), 2.60-2.75 (m, 1H), 2.35-2.45 (m, 2H), 1.90-2.10 (m, 3H), 1.65-1.90 (m, 5H), 1.15-1.50 (m, 9H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -114.51 (s, 1F). EXAMPLE 102 Synthesis of 4-[(cis-3-aminocyclobutyl)amino]-N'-(2-ethyl-4-hydroxyphenyl )-6-(6-methoxy-4- methylpyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboximidamid e

Step 1: Synthesis of tert-butyl [cis-3-[[6-bromo-3-[N'-[4-[(tert-butyldimethylsilyl)oxy]-2- ethylphenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino ]cyclobutyl]carbamate To a solution of 6-bromo-N'-[4-[(tert-butyldimethylsilyl)oxy]-2-ethylphenyl]- 4- chloropyrrolo[1,2-b]pyridazine-3-carboximidamide (150 mg, 295.3 μmol) and tert-butyl (cis-3- aminocyclobutyl)carbamate (82 mg, 442.9 μmol) in N,N-dimethylacetamide (2.0 mL) was added N,N-diisopropylethylamine (114 mg, 885.9 μmol) dropwise. After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 150 mg, 77%. LCMS (ESI) m/z: 659.0 (M+H). Step 2: Synthesis of tert-butyl [cis-3-[[3-[N'-(2-ethyl-4-hydroxyphenyl)carbamimidoyl]-6-(6- methoxy-4-methylpyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]am ino]cyclobutyl]carbamate To a mixture of tert-butyl [cis-3-[[6-bromo-3-[N'-[4-[(tert-butyldimethylsilyl)oxy]-2- ethylphenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino ]cyclobutyl]carbamate (135 mg, 205.2 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (102 mg, 615.7 μmol) in N,N- dimethylformamide (2.0 mL) and water (0.2 mL) were added potassium phosphate (131 mg, 615.7 μmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (14 mg, 20.5 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 hours. After cooled to room temperature, the reaction mixture was diluted with ethyl acetated and washed with saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 100 mg, 83%. LCMS (ESI) m/z: 586.2 (M+H). Step 3: Synthesis of 4-[(cis-3-aminocyclobutyl)amino]-N'-(2-ethyl-4-hydroxyphenyl )-6-(6- methoxy-4-methylpyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carb oximidamide To a solution of tert-butyl [cis-3-[[3-[N'-(2-ethyl-4-hydroxyphenyl)carbamimidoyl]-6-(6- methoxy-4-methylpyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]am ino]cyclobutyl]carbamate (90 mg, 153.66 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (1.0 mL) dropwise. The reaction mixture was stirred at 25 °C for 1 hour and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded the title compound-[(cis-3-aminocyclobutyl)amino]- N'-(2-ethyl-4-hydroxyphenyl)-6-(6-methoxy-4-methylpyridin-3- yl)pyrrolo[1,2-b]pyridazine-3- carboximidamide as a yellow solid. Yield: 25.0 mg, 33%. LCMS (ESI) m/z: 486.4 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.29 (d, 1H, J=5.4 Hz), 8.96 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H), 7.87 (s, 1H), 7.03-7.09 (m, 1H), 6.78 (s, 1H), 6.74 (s, 1H), 6.58-6.69 (m, 3H), 5.92 (s, 2H), 4.20- 4.35 (m, 1H), 3.87 (s, 3H), 3.09-3.17 (m, 1H), 2.68-2.80 (m, 2H), 2.40-2.50 (m, 5H), 1.60-1.74 (m, 2H), 1.07 (t, 3H, J=7.5 Hz). EXAMPLE 103 Synthesis of 4-[cis-(3-aminocyclobutyl)amino]-N'-(2-chloro-5-fluoro-pheny l)-6-(6-methoxy-4- methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of tert-butyl N-[cis-3-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl obutyl]carbamate To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (200 mg, 497 μmol) in N,N-dimethylacetamide (2.5 mL) were added tert-butyl cis-N-(3-aminocyclobutyl)carbamate (120 mg, 646 μmol) and N,N-diisopropylethylamine (193 mg, 1.5 mmol). After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 200 mg, 69%. LCMS (ESI) m/z: 553.0 (M+H). Step 2: Synthesis of tert-butyl N-[cis-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- (6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclobutyl]carbamate To a solution of tert-butyl N-[cis-3-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl obutyl]carbamate (200 mg, 362 μmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) were added (6-methoxy-4-methyl- 3-pyridyl)boronic acid (121 mg, 724 μmol), 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (24 mg, 36 μmol) and sodium carbonate (115 mg, 1.0 mmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduce pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a light-yellow soild. Yield: 140 mg, 63%. LCMS (ESI) m/z: 594.2 (M+H). Step 3: Synthesis of 4-[cis-(3-aminocyclobutyl)amino]-N'-(2-chloro-5-fluoro-pheny l)-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine To a solution of tert-butyl N-[cis-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- (6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclobutyl]carbamate (120 mg, 202 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[cis-(3-aminocyclobutyl)amino]-N'-(2- chloro-5-fluoro-phenyl)-6-(6-methoxy-4-methyl-3-pyridyl)pyrr olo[1,2-b]pyridazine-3- carboxamidine as a white solid. Yield: 55.7 mg, 54%. LCMS (ESI) m/z: 494.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.43 (d, 1H, J=6.4 Hz), 8.21-8.25 (m, 2H), 7.89 (d, 1H, J=1.6 Hz), 7.49-7.53 (m, 1H), 7.06 (d, 1H, J=2.0 Hz), 6.86-6.94 (m, 2H), 6.78 (s, 1H), 6.60 (s, 2H), 4.23- 4.33 (m, 1H), 3.86 (s, 3H), 3.07-3.15 (m, 1H), 2.58-2.77 (m, 2H), 2.43 (s, 3H), 1.92 (s, 2H), 1.62- 1.73 (m, 2H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.39 (s, 1F). EXAMPLE 104 Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-ethyl-5-fluoro-4 -hydroxy-phenyl)-6- (5-fluoro-4-hydroxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazine -3-carboxamidine Step 1: Synthesis of tert-butyl N-[(1S,3R)-3-[[6-bromo-3-[N'-[4-[tert-butyl(dimethyl)silyl]o xy-2- ethyl-5-fluoro-phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin- 4-yl]amino]cyclopentyl]carbamate To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-5-fluor o-phenyl]-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (300 mg, 570 μmol) and tert-butyl N-[(1S,3R)-3- aminocyclopentyl]carbamate (171 mg, 855 μmol) in N,N-dimethylacetamide (2 mL) was added N,N-diisopropylethylamine (221 mg, 1.7 mmol). After stirring at 85 °C for 2 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow soild. Yield: 200 mg, 49%. LCMS (ESI) m/z: 691.0 (M+H). Step 2: Synthesis of tert-butyl N-[(1S,3R)-3-[[3-[N'-(2-ethyl-5-fluoro-4-hydroxy- phenyl)carbamimidoyl]-6-[5-fluoro-4-[(4-methoxyphenyl)methox y]-2-methyl- phenyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclopentyl]carbam ate To a solution of tert-butyl N-[(1S,3R)-3-[[6-bromo-3-[N'-[4-[tert-butyl(dimethyl)silyl]o xy-2- ethyl-5-fluoro-phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin- 4-yl]amino]cyclopentyl]carbamate (180 mg, 260 μmol) and 2-[5-fluoro-4-[(4-methoxyphenyl)methoxy]-2-methyl-phenyl]-4, 4,5,5- tetramethyl-1,3,2-dioxaborolane (145 mg, 391 μmol) in N,N-dimethylformamide (2 mL) and water (0.2 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (17 mg, 26 μmol) and sodium carbonate (83 mg, 782 μmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow soild. Yield: 90 mg, 46%. LCMS (ESI) m/z: 741.1 (M+H). Step 3: Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-ethyl-5-fluoro-4 -hydroxy- phenyl)-6-(5-fluoro-4-hydroxy-2-methyl-phenyl)pyrrolo[1,2-b] pyridazine-3-carboxamidine Tert-Butyl N-[(1S,3R)-3-[[3-[N'-(2-ethyl-5-fluoro-4-hydroxy-phenyl)carb amimidoyl]-6-[5- fluoro-4-[(4-methoxyphenyl)methoxy]-2-methyl-phenyl]pyrrolo[ 1,2-b]pyridazin-4- yl]amino]cyclopentyl]carbamate (30 mg, 40 μmol) was dissolved in trifluoroacetic acid (1 mL) and stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[[(1R,3S)-3- aminocyclopentyl]amino]-N'-(2-ethyl-5-fluoro-4-hydroxy-pheny l)-6-(5-fluoro-4-hydroxy-2- methyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as an off-white solid. Yield: 5.7 mg, 26%. LCMS (ESI) m/z: 521.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.10 (s, 1H), 8.19 (s, 1H), 7.79 (d, 1H, J=2.0 Hz), 7.25 (d, 1H, J=12.4 Hz), 6.96 (d, 1H, J=2.0 Hz), 6.80-6.86 (m, 2H), 6.57 (d, 1H, J=12.0 Hz), 6.04 (s, 2H), 4.59-4.65 (m, 1H), 3.25-3.29 (m, 1H), 2.36-2.43 (m, 3H), 2.33 (s, 3H), 2.04-2.11 (m, 1H), 1.80-1.85 (m, 1H), 1.65-1.71 (m, 1H), 1.33-1.42 (m, 1H), 1.23- 1.30 (m, 1H), 1.07 (t, 3H, J=7.6 Hz). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -138.86 (s, 1F), -140.58 (s, 1F). EXAMPLE 105 Synthesis of N'-(2-chloro-5-fluoro-phenyl)-4-[[1-(2-cyanoethyl)-4-piperid yl]amino]-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine

Step 1: Synthesis of tert-butyl N-[1-(2-cyanoethyl)-4-piperidyl]carbamate To a solution of tert-butyl N-(4-piperidyl)carbamate (300 mg, 1.5 mmol) in ethanol (4 mL) were added 3-bromopropanenitrile (241 mg, 1.8 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (342 mg, 2.2 mmol). After stirring at room temperature for 5 hours, the reaction mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a white solid. Yield: 270 mg, 71%. ¹ H NMR (DMSO-d6, 400 MHz) δ 6.77 (d, 1H, J=8.0 Hz), 3.12-3.26 (m, 1H), 2.73-2.83 (m, 2H), 2.57-2.67 (m, 2H), 2.51-2.55 (m, 2H), 1.92- 2.00 (m, 2H), 1.62-1.70 (m, 2H), 1.37 (s, 9H), 1.27-1.35 (m, 2H). Step 2: Synthesis of 3-(4-amino-1-piperidyl)propanenitrile To a solution of tert-butyl N-[1-(2-cyanoethyl)-4-piperidyl]carbamate (260 mg, 1.0 mmol) in dichloromethane (3 mL) were added trifluoroacetic acid (0.6 mL). The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was diluted with water, basified with an aqueous solution of sodium hydroxide and extracted with dichloromethane twice. The combined organic layers were washed with brine was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a light yellow oil. Yield: 120 mg, 76%. Step 3: Synthesis of 6-bromo-N'-(2-chloro-5-fluoro-phenyl)-4-[[1-(2-cyanoethyl)-4 - piperidyl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (150 mg, 373 μmol) in N,N-dimethylacetamide (3 mL) were added 3-(4-amino-1- piperidyl)propanenitrile (86 mg, 560 μmol) and N,N-diisopropylethylamine (145 mg, 1.1 mmol). After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature, then diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a light yellow solid. Yield: 200 mg, 69%. LCMS (ESI) m/z: 520.3 (M+H). Step 4: Synthesis of N'-(2-chloro-5-fluoro-phenyl)-4-[[1-(2-cyanoethyl)-4-piperid yl]amino]-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine To a solution of 6-bromo-N'-(2-chloro-5-fluoro-phenyl)-4-[[1-(2-cyanoethyl)-4 - piperidyl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine (125 mg, 241 μmol) in N,N- dimethylformamide (3 mL) and water (0.3 mL) were added (6-methoxy-4-methyl-3- pyridyl)boronic acid (81 mg, 482 μmol), 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (16 mg, 24 μmol) and sodium carbonate (52 mg, 482 μmol). The resulting mixture was purge with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded N'-(2-chloro-5-fluoro-phenyl)-4-[[1-(2-cyanoethyl)-4- piperidyl]amino]-6-(6-methoxy-4-methyl-3-pyridyl)pyrrolo[1,2 -b]pyridazine-3-carboxamidine as a light yellow solid. Yield: 19.7 mg, 14%. LCMS (ESI) m/z: 561.1 (M+H). ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 11.55 (s, 1H), 8.25 (d, 2H, J=3.6 Hz), 7.92 (d, 1H, J=1.6 Hz), 7.48-7.52 (m 1H), 7.01 (d, 1H, J=1.6 Hz), 6.84-6.96 (m, 2H), 6.79 (s, 1H), 6.58 (s, 2H), 4.27-4.31 (m, 1H), 3.87 (s, 3H), 2.69-2.73 (m, 2H), 2.58-2.68 (m, 2H), 2.55-2.57 (m, 2H), 2.43 (s, 3H), 2.30-2.40 (m, 2H), 2.01-2.09 (m, 2H), 1.55-1.64 (m, 2H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -114.42 (s, 1F). EXAMPLE 106 Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2,6-dichlorophenyl )-6-methyl- pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt Step 1: Synthesis of tert-butyl [(1S,3R)-3-[[6-bromo-3-[N'-(2,6- dichlorophenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]am ino]cyclopentyl]carbamate To a solution of 6-bromo-4-chloro-N'-(2,6-dichlorophenyl)pyrrolo[1,2-b]pyrida zine-3- carboxamidine (200 mg, 477.8 μmol) and tert-butyl [(1S,3R)-3-aminocyclopentyl]carbamate (143 mg, 716.8 μmol) in N,N-dimethylacetamide (2.0 mL) was added N,N-diisopropylethylamine (185 mg, 1.43 mmol). After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 200 mg, 71%. LCMS (ESI) m/z: 582.9 [M+H]. Step 2: Synthesis of tert-butyl [(1S,3R)-3-[[3-[N'-(2,6-dichlorophenyl)carbamimidoyl]-6- methylpyrrolo[1,2-b]pyridazin-4-yl]amino]cyclopentyl]carbama te To a solution of tert-butyl [(1S,3R)-3-[[6-bromo-3-[N'-(2,6- dichlorophenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]am ino]cyclopentyl]carbamate (160 mg, 274.7 μmol) and methylboronic acid (82 mg, 1.37 mmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added XPhos Pd G3 (23 mg, 27.4 μmol) and potassium carbonate (113 mg, 824.2 μmol). The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 60 °C for 3 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 130 mg, 80%. LCMS (ESI) m/z: 517.1 (M+H). Step 3: Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2,6-dichlorophenyl )-6-methyl- pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt To a solution of tert-butyl [(1S,3R)-3-[[3-[N'-(2,6-dichlorophenyl)carbamimidoyl]-6- methylpyrrolo[1,2-b]pyridazin-4-yl]amino]cyclopentyl]carbama te (120 mg, 231.9 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (2.0 mL) . After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % formic acid) afforded 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2,6-dichlorophenyl )-6-methyl- pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt as an off-white solid. Yield: 53.8 mg, 49%. LCMS (ESI) m/z: 417.0 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.04 (d, 1H, J=5.7 Hz), 8.35 (s, 1H), 8.08 (s, 1H), 7.50 (s, 1H), 7.43-7.47 (m, 2H), 7.00-7.08 (m, 1H), 6.77 (s, 1H), 6.42 (brs, 2H), 4.50-4.60 (m, 1H), 3.45-3.55 (m, 1H), 2.53-2.60 (m, 1H), 2.25 (s, 3H), 2.08-2.18 (m, 1H), 1.93-2.05 (m, 1H), 1.55-1.76 (m, 2H), 1.40-1.52 (m, 1H). EXAMPLE 107 Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro- phenyl)-6-methyl- pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of tert-butyl [(1S,3R)-3-[[3-[N'-(2-chloro-5-fluorophenyl)carbamimidoyl]-6 - methylpyrrolo[1,2-b]pyridazin-4-yl]amino]cyclopentyl]carbama te To a mixture of tert-butyl [(1S,3R)-3-[[6-bromo-3-[N'-(2-chloro-5- fluorophenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclopentyl]carbamate (120 mg, 212.0 μmol) and methylboronic acid (253 mg, 4.24 mmol) in 1,4-dioxane (2.0 mL) and water (0.2 mL) were added potassium carbonate (87.9 mg, 636.1 μmol) and XPhos Pd G3 (17.9 mg, 21.2 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 3 hours. After cooled to room temperature, the reaction mixture was diluted with ethyl acetated and washed with saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 70 mg, 60%. LCMS (ESI) m/z: 501.1 (M+H). Step 2: Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro- phenyl)-6- methyl-pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of tert-butyl [(1S,3R)-3-[[3-[N'-(2-chloro-5-fluorophenyl)carbamimidoyl]-6 - methylpyrrolo[1,2-b]pyridazin-4-yl]amino]cyclopentyl]carbama te (70 mg, 139.7 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (1.0 mL). After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro- phenyl)-6- methyl-pyrrolo[1,2-b]pyridazine-3-carboxamidine as an off-white solid. Yield: 25.0 mg, 43%. LCMS (ESI) m/z: 401.0 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.28 (s, 1H), 8.10 (s, 1H), 7.44-7.50 (m, 2H), 6.83-6.90 (m, 2H), 6.71 (s, 1H), 6.45 (brs, 2H), 4.48-4.57 (m, 1H), 3.20-3.30 (m, 1H), 2.30-2.39 (m, 1H), 2.24 (s, 3H), 2.00-2.10 (m, 1H), 1.65-1.85 (m, 1H), 1.26-1.41 (m, 2H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -114.51 (s, 1F). EXAMPLE 108 Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro- phenyl)-6-methyl- pyrrolo[1,2-b]pyridazine-3-carboxamidine

Step 1: Synthesis of tert-butyl [(1S,3R)-3-[[3-[N'-(2-chloro-5-fluorophenyl)carbamimidoyl]-6 - methylpyrrolo[1,2-b]pyridazin-4-yl]amino]cyclopentyl]carbama te To a mixture of tert-butyl [(1S,3R)-3-[[6-bromo-3-[N'-(2-chloro-5- fluorophenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclopentyl]carbamate (120 mg, 212.0 μmol) and methylboronic acid (253 mg, 4.24 mmol) in 1,4-dioxane (2.0 mL) and water (0.2 mL) were added potassium carbonate (87.9 mg, 636.1 μmol) and XPhos Pd G3 (17.9 mg, 21.2 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 3 hours. After cooled to room temperature, the reaction mixture was diluted with ethyl acetated and washed with saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 70 mg, 60%. LCMS (ESI) m/z: 501.1 (M+H). Step 2: Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro- phenyl)-6- methyl-pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of tert-butyl [(1S,3R)-3-[[3-[N'-(2-chloro-5-fluorophenyl)carbamimidoyl]-6 - methylpyrrolo[1,2-b]pyridazin-4-yl]amino]cyclopentyl]carbama te (70 mg, 139.7 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (1.0 mL). After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro- phenyl)-6- methyl-pyrrolo[1,2-b]pyridazine-3-carboxamidine as an off-white solid. Yield: 25.0 mg, 43%. LCMS (ESI) m/z: 401.0 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.28 (s, 1H), 8.10 (s, 1H), 7.44-7.50 (m, 2H), 6.83-6.90 (m, 2H), 6.71 (s, 1H), 6.45 (brs, 2H), 4.48-4.57 (m, 1H), 3.20-3.30 (m, 1H), 2.30-2.39 (m, 1H), 2.24 (s, 3H), 2.00-2.10 (m, 1H), 1.65-1.85 (m, 1H), 1.26-1.41 (m, 2H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.51 (s, 1F). EXAMPLE 109 Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro- phenyl)-6-(3,5- dimethyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxam idine formic acid salt Step 1: Synthesis of tert-butyl N-[(1S,3R)-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl ]-6- (3,5-dimethyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)pyrrolo[1, 2-b]pyridazin-4- yl]amino]cyclopentyl]carbamate To a solution of tert-butyl N-[(1S,3R)-3-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (150 mg, 265 μmol) and 3,5-dimethyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyrazole (122 mg, 397 μmol) in N,N-dimethylformamide (2 mL) and water (0.2 mL) were added tetrakis(triphenylphosphine)palladium (41 mg, 26 μmol) and potassium phosphate (169 mg, 795 μmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow soild. Yield: 60 mg, 33%. LCMS (ESI) m/z: 665.1 (M+H). Step 2: Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro- phenyl)-6- (3,5-dimethyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-car boxamidine formic acid salt Tert-Butyl N-[(1S,3R)-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl ]-6-(3,5-dimethyl-1- tetrahydropyran-2-yl-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4- yl]amino]cyclopentyl]carbamate (40 mg, 60 μmol) was dissolved in 6.0 N hydrochloric acid (1 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-[[(1R,3S)-3- aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-phenyl)-6-(3,5 -dimethyl-1H-pyrazol-4- yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt as a light-yellow solid. Yield: 6.3 mg, 11%. LCMS (ESI) m/z: 481.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.40 (s, 1H), 8.36 (s, 1H), 8.19 (s, 1H), 7.72 (d, 1H, J=1.6 Hz), 7.49-7.52 (m, 1H), 6.86-6.92 (m, 3H), 6.55 (s, 2H), 4.62-4.70 (m, 1H), 3.42-3.47 (m,1H), 2.53-2.56 (m, 1H), 2.30 (s, 6H), 2.08-2.20 (m, 1H), 1.95- 2.04 (m, 1H), 1.75-1.82 (m, 1H), 1.46-1.63 (m, 2H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.46 (s, 1F). EXAMPLE 110 Synthesis of N'-(2-chloro-5-fluoro-phenyl)-6-methyl-4-[[(1R,3S)cis-3- (propylamino)cyclopentyl]amino]pyrrolo[1,2-b]pyridazine-3-ca rboxamidine To a solution of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro- phenyl)-6- methyl-pyrrolo[1,2-b]pyridazine-3-carboxamidine (90 mg, 224.5 μmol) and propanal (78 mg, 1.35 mmol) in methanol (2.0 mL) was added sodium triacetoxyborohydride (142 mg, 673.5 μmol). After stirring at 25 °C for 2 hours, the reaction mixture was diluted with ethyl acetated and washed with saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded N'-(2-chloro-5-fluoro-phenyl)-6-methyl-4-[[(1R,3S)-3- (propylamino)cyclopentyl]amino]pyrrolo[1,2-b]pyridazine-3-ca rboxamidine as an off-white solid. Yield: 14.1 mg, 14%. LCMS (ESI) m/z: 443.1 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.26 (d, 1H, J=6.4 Hz), 8.10 (s, 1H), 7.45-7.50 (m, 2H), 6.81-6.90 (m, 2H), 6.73 (s, 1H), 6.44 (brs, 2H), 4.52-4.60 (m, 1H), 3.00-3.09 (m, 1H), 2.29-2.43 (m, 3H), 2.24 (s, 3H), 1.99-2.10 (m, 1H), 1.80-1.88 (m, 1H), 1.65-1.75 (m, 1H), 1.32-1.50 (m, 2H), 1.20-1.31 (m, 2H), 0.77 (t, 3H, J=7.2 Hz). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -114.65 (s, 1F). EXAMPLE 111 Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro- phenyl)-6-(5- hydroxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxami dine Step 1: Synthesis of 2-bromo-4-(methoxymethoxy)-1-methyl-benzene To a solution of 3-bromo-4-methyl-phenol (1.20 g, 6.42 mmol) and N,N-diisopropylethylamine (1.66 g, 12.83 mmol) in dichloromethane (24.0 mL) was added bromo(methoxy)methane (1.20 g, 9.62 mmol) dropwise at 0 °C. After stirring at 25 °C for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous solution of sodium carbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light yellow oil. Yield: 1.22 g, 82%. ¹ H NMR (DMSO-d6, 300 MHz) δ 7.18-7.31 (m, 2H), 6.93- 6.98 (m, 1H), 5.17 (s, 2H), 3.31 (s, 3H), 2.27 (s, 3H). Step 2: Synthesis of 2-[5-(methoxymethoxy)-2-methyl-phenyl]-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane To a solution of 2-bromo-4-(methoxymethoxy)-1-methyl-benzene (500 mg, 2.16 mmol) in 1,4- dioxane (10.0 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2- yl)-1,3,2-dioxaborolane (1.10 g, 4.33 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (176 mg, 216.3 μmol) and potassium acetate (530 mg, 5.41 mmol). The mixture was purged with nitrogen gas and stirred at 90 °C for 15 hours under nitrogen atmosphere. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light yellow oil. Yield: 0.75 g, 87 %. ¹ H NMR (DMSO-d6, 300 MHz) δ 7.24 (s, 1H), 7.07-7.11 (m, 1H), 6.97-7.01 (m, 1H), 5.13 (s, 2H), 3.35 (s, 3H), 2.38 (s, 3H), 1.29 (s, 12H). Step 3: Synthesis of tert-butyl [(1S,3R)-3-[[3-[N'-(2-chloro-5-fluorophenyl)carbamimidoyl]-6 -[5- (methoxymethoxy)-2-methylphenyl]pyrrolo[1,2-b]pyridazin-4-yl ]amino]cyclopentyl]carbamate To a solution of tert-butyl [(1S,3R)-3-[[6-bromo-3-[N'-(2-chloro-5- fluorophenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclopentyl]carbamate (150 mg, 265.0 μmol) and 2-[5-(methoxymethoxy)-2-methyl-phenyl]-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane (155 mg, 795.2 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added sodium carbonate (84.2 mg, 795.2 μmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (17 mg, 26.5 μmol). The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 70 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 130 mg, 76%. LCMS (ESI) m/z: 637.1 (M+H). Step 4: Synthesis of Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro- phenyl)-6-(5-hydroxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazin e-3-carboxamidine To a mixture of tert-butyl [(1S,3R)-3-[[3-[N'-(2-chloro-5-fluorophenyl)carbamimidoyl]-6 -[5- (methoxymethoxy)-2-methylphenyl]pyrrolo[1,2-b]pyridazin-4-yl ]amino]cyclopentyl]carbamate (100 mg, 156.9 μmol) in tetrahydrofuran (3.0 mL) and methanol (0.1 mL) was added 3N aqueous solution of hydrochloric acid (1.0 mL). After stirring at 50 °C for 16 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5- fluoro-phenyl)-6-(5-hydroxy-2-methyl-phenyl)pyrrolo[1,2-b]py ridazine-3-carboxamidine as an off-white solid. Yield: 23.8 mg, 30%. LCMS (ESI) m/z: 493.0 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.46 (s, 1H), 9.20 (s, 1H), 8.20 (s, 1H), 7.79 (s, 1H), 7.47-7.51 (m, 1H), 7.06 (d, 1H, J=8.4 Hz), 6.98 (s, 1H), 6.85-6.92 (m, 3H), 6.61-6.64 (m, 1H), 6.51 (s, 2H), 4.57-4.67 (m, 1H), 3.25-3.33 (m, 1H), 2.30-2.42 (m, 4H), 2.03-2.12 (m, 1H), 1.60-1.85 (m, 4H), 1.31-1.43 (m, 2H). 1 ⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -114.48 (s, 1F). EXAMPLE 112 Synthesis of N'-(2-chloro-5-fluoro-phenyl)-4-[[(1R, 3S)-3-(ethylamino)-2,2,3-trimethyl- cyclopentyl]amino]-6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyri dazine-3-carboxamidine Step 1: Synthesis of 4-[[(1R, 3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2-chloro- 5- fluoro-phenyl)-6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazi ne-3-carboxamidine To a solution of 4-[[(1R, 3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bromo-N'-(2 -chloro- 5-fluoro-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (200 mg, 393.8 μmol) in N,N- dimethylformamide (4.0 mL) and water (0.4 mL) were added (6-methoxy-3-pyridyl)boronic acid (120 mg, 787.7 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene-palladium dichloride (25 mg, 39.4 μmol) and potassium phosphate (167 mg, 787.7 μmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered, and the filtrate diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 150 mg, 71%. LCMS (ESI) m/z: 536.1 (M+H). Step 2: Synthesis of N'-(2-chloro-5-fluoro-phenyl)-4-[[(1R, 3S)-3-(ethylamino)-2,2,3-trimethyl- cyclopentyl]amino]-6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyri dazine-3-carboxamidine To a solution of 4-[[(1R, 3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2-chloro- 5-fluoro- phenyl)-6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-ca rboxamidine (130 mg, 242.5 μmol) in 1,2-dichloroethane (5.0 mL) were added acetaldehyde (10 mg, 242.5 μmol) and sodium triacetoxyborohydride (103 mg, 485.0 μmol). After stirring at 25 °C for 2 hours, the reaction mixture was quenched with water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC ((acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-(2-chloro-5- fluoro-phenyl)-4-[[(1R, 3S)-3-(ethylamino)-2,2,3-trimethyl-cyclopentyl]amino]-6-(6-m ethoxy-3- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as a light yellow solid. Yield: 36.8 mg, 25%. LCMS (ESI) m/z: 564.5 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.35 (brs, 1H), 8.61 (d, 1H, J=2.4 Hz,), 8.14-8.23 (m, 2H), 8.07-8.11 (m, 1H), 7.45-7.51 (m, 1H), 7.15 (s, 1H), 6.82-6.93 (m, 3H), 6.44 (s, 2H), 4.49-4.58 (m, 1H), 3.88 (s, 3H), 2.52-2.55 (m, 1H), 2.28-2.47 (m, 2H), 1.67- 1.81 (m, 1H), 1.51-1.67 (m, 2H), 1.11 (s, 3H), 0.87-0.96 (m, 6H), 0.78-0.86 (m, 3H). ¹⁹ F NMR (DMSO, 376 MHz) δ -114.77 (s, 1F). EXAMPLE 113 Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -chloro-6-fluoro- phenyl)-6-(6-methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyrida zine-3-carboxamidine To a mixture of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-(2-chloro- 6-fluoro-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (100 mg, 196.9 μmol) and (6- methoxy-4-methyl-3-pyridyl)boronic acid (65 mg, 393.8 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added potassium phosphate (125 mg, 590.7 μmol) and 1,1'-bis (di- t-butylphosphino)ferrocene palladium dichloride (12 mg, 19.6 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 70 °C for 2 hours. After cooled to room temperature, the reaction mixture was diluted with ethyl acetated and washed with brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 4-[[(1R,3S)-3-amino-2,2,3- trimethyl-cyclopentyl]amino]-N'-(2-chloro-6-fluoro-phenyl)-6 -(6-methoxy-4-methyl-3- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as an off-white solid. Yield: 32.1 mg, 29%. LCMS (ESI) m/z: 550.2 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.57 (s, 1H), 8.24 (s, 2H), 7.91 (s, 1H), 7.28-7.32 (m, 1H), 7.15-7.25 (m, 1H), 6.99-7.08 (m, 2H), 6.79 (s, 1H), 6.51 (s, 2H), 4.42-4.52 (m, 1H), 3.87 (s, 3H), 2.42 (s, 3H), 2.27-2.35 (m, 1H), 1.44-1.72 (m, 3H), 1.07 (s, 3H), 0.85 (s, 6H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -120.69 (s, 1F). EXAMPLE 114 Synthesis of 4-[(cis-3-aminocyclopentyl)amino]-N'-(2-chloro-5-fluoro-phen yl)-6-(3-methyl-1H- pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of 3-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan- 2-yl)pyrazole To a mixture of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole (200 mg, 961.2 μmol) and 3,4-dihydro-2H-pyran (121 mg, 1.4 mmol, in tetrahydrofuran (2.0 mL) was added trifluoroacetic acid (10 mg, 96.1 μmol) at room temperature. After heated at 80 °C for 16 hours, the reaction mixture was cooled to room temperature and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a white solid. Yield: 210 mg, 74%. LCMS (ESI) m/z: 292.9 (M+H). Step 2: Synthesis of tert-butyl [cis-3-[[3-[N'-(2-chloro-5-fluorophenyl)carbamimidoyl]-6-[3- methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]pyrrolo[ 1,2-b]pyridazin-4- yl]amino]cyclopentyl]carbamate To a mixture of tert-butyl [cis-3-[[6-bromo-3-[N'-(2-chloro-5- fluorophenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclopentyl]carbamate (100 mg, 176.7 μmol) and 3-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan- 2-yl)pyrazole (103 mg, 353.4 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added sodium carbonate (56 mg, 530.1 μmol) and tetrakis(triphenylphosphine)palladium (20 mg, 17.6 μmol) at room temperature under nitrogen atmosphere. After stirring at 70 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetated and washed with brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as an off-white solid. Yield: 60 mg, 52%. LCMS (ESI) m/z: 651.2 (M+H). Step 3: Synthesis of 4-[(cis-3-aminocyclopentyl)amino]-N'-(2-chloro-5-fluoro-phen yl)-6-(3- methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamid ine To a solution of tert-butyl [cis-3-[[3-[N'-(2-chloro-5-fluorophenyl)carbamimidoyl]-6-[3- methyl- 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]pyrrolo[1,2-b]p yridazin-4- yl]amino]cyclopentyl]carbamate (50 mg, 76.7 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (1.0 mL) dropwise. The reaction mixture was stirred at 25 °C for 16 hours and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 4-[(cis-3- aminocyclopentyl)amino]-N'-(2-chloro-5-fluoro-phenyl)-6-(3-m ethyl-1H-pyrazol-4- yl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as an off-white solid. Yield: 5.2 mg, 13 %. LCMS (ESI) m/z: 467.1 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.36 (brs, 1H), 8.16 (s, 1H), 7.79- 7.87 (m, 2H), 7.46-7.52 (m, 1H), 7.00 (s, 1H), 6.79-6.91 (m, 2H), 6.52 (s, 2H), 4.55-4.69 (m, 1H), 3.40-3.47 (m, 1H), 2.35-2.46 (m, 4H), 2.04-2.17 (m, 1H), 1.68-1.96 (m, 2H), 1.34-1.58 (m, 2H). EXAMPLE 115 Synthesis of N'-(2-chloro-5-fluoro-phenyl)-6-(6-methoxy-3-pyridyl)-4-[[(1 R, 3S)-3- (propylamino)cyclopentyl]amino]pyrrolo[1,2-b]pyridazine-3-ca rboxamidine Step 1: Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro- phenyl)-6-(6- methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of tert-butyl N-[(1S,3R)-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl ]-6-(6- methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclope ntyl]carbamate (200 mg, 336.7 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (1.0 mL). After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and adjusted to pH=9 with 1N aqueous solution of sodium hydroxide, extracted with dichloromethane three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a light yellow solid. Yield: 150 mg, 90%. LCMS (ESI) m/z: 494.3 (M+H). Step 2: Synthesis of N'-(2-chloro-5-fluoro-phenyl)-6-(6-methoxy-3-pyridyl)-4-[[(1 R,3S)-3- (propylamino)cyclopentyl]amino]pyrrolo[1,2-b]pyridazine-3-ca rboxamidine To a solution of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro- phenyl)-6-(6- methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (100 mg, 202.4 μmol) in 1,2- dichloroethane (5.0 mL) were added propanal (12 mg, 202.4 μmol) and sodium triacetoxyborohydride (86 mg, 404.9 μmol). After stirring at 25 °C for 2 hours, the reaction mixture was quenched with water and extracted with dichloromethane three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-(2-chloro-5- fluoro-phenyl)-6-(6-methoxy-3-pyridyl)-4-[[(1R,3S)-3- (propylamino)cyclopentyl]amino]pyrrolo[1,2-b]pyridazine-3-ca rboxamidine as a white solid. Yield: 11.3 mg, 10%. LCMS (ESI) m/z: 537.0 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.41 (s, 1H), 8.65 (s, 1H), 8.12-8.18 (m, 3H), 7.46-7.50 (m, 1H), 7.28 (d, 1H, J=2.0 Hz), 6.82-6.92 (m, 3H), 6.50 (s, 2H), 4.65-4.75 (m, 1H), 3.88 (s, 3H), 3.10-3.14 (m, 1H), 2.33-2.46 (m, 3H), 2.05- 2.18 (m, 1H), 1.80-1.88 (m, 1H), 1.68-1.78 (m, 1H), 1.36-1.57 (m, 2H), 1.21-1.34 (m, 2H), 0.77 (t, 3H, J=7.6 Hz). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.60 (s, 1F). EXAMPLE 116 Synthesis of 4-[[(1R, 3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-phenyl)- 6-(6- methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt Step 1: Synthesis of tert-butyl N-[(1R, 3S)-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]- 6-(6-methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cy clopentyl]carbamate To a solution of tert-butyl N-[(1R, 3S)-3-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (250 mg, 441.8 μmol) in N,N-dimethylformamide (6.0 mL) and water (0.6 mL) were added (6-methoxy-3- pyridyl)boronic acid (135 mg, 883.6 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene-palladium dichloride (29 mg, 44.2 μmol) and potassium phosphate (188 mg, 883.6 μmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered through a celite pad. The filtrate was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 230 mg, 87%. LCMS (ESI) m/z: 594.1 (M+H). Step 2: Synthesis of 4-[[(1R, 3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-phenyl)- 6-(6- methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt To a solution of tert-butyl N-[(1R, 3S)-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6-(6- methoxy-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclope ntyl]carbamate (200 mg, 336.7 μmol) in dichloromethane (5.0 mL) were added trifluoroacetic acid (1.0 mL). After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and adjusted to pH=9 with 1N aqueous solution of sodium hydroxide and extracted with dichloromethane three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1% formic acid) afforded 4-[[(1R, 3S)-3- aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-phenyl)-6-(6-m ethoxy-3-pyridyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine formic acid salt as a light yellow solid. Yield: 11.9 mg, 6%. LCMS (ESI) m/z: 494.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.49 (s, 1H), 8.68 (d, 1H, J=2.4 Hz), 8.39 (s, 1H), 8.12-8.23 (m, 3H), 7.48-7.52 (m, 1H), 7.31 (d, 1H, J=1.6 Hz), 6.86-6.93 (m, 3H), 6.58 (s, 2H), 4.68-4.78 (m, 1H), 3.88 (s, 3H), 3.50-3.60 (m, 1H), 2.54-2.64 (m, 1H), 2.11-2.23 (m, 1H), 1.97-2.08 (m, 1H), 1.70-1.82 (m, 1H), 1.60-1.68 (m, 1H), 1.42-1.57 (m, 1H). 1 ⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -114.44 (s, 1F). EXAMPLE 117 Synthesis of N'-(2-chloro-6-fluoro-phenyl)-6-methyl-4-[[(1R,3S)-3- (propylamino)cyclopentyl]amino]pyrrolo[1,2-b]pyridazine-3-ca rboxamidine To a solution of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-6-fluoro- phenyl)-6- methyl-pyrrolo[1,2-b]pyridazine-3-carboxamidine (48 mg, 120 μmol) in methanol (2.0 mL) was added propanal (5 mg, 86 μmol). After stirring at room temperature for 20 min, sodium cyanoboranuide (15 mg, 240.2 μmol) was added. After stirring at room temperature for an hour, the resulting mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-(2-chloro-6-fluoro-phenyl)-6-methyl-4-[[(1R,3S)-3- (propylamino)cyclopentyl]amino]pyrrolo[1,2-b]pyridazine-3-ca rboxamidine as an off-white solid. Yield: 10.7 mg, 21%. LCMS (ESI) m/z: 443.1 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.22 (d, 1H, J=7.2 Hz), 8.09 (s, 1H), 7.47 (s, 1H), 7.30 (d, 1H, J=8.1 Hz), 7.14-7.21 (m, 1H), 7.00-7.08 (m, 1H), 6.74 (s, 1H), 6.43 (brs, 2H), 4.50-4.60 (m, 1H), 3.04-3.15 (m, 1H), 2.30-2.40 (m, 3H), 2.24 (s, 3H), 1.95-2.10 (m, 1H), 1.65-1.90 (m, 2H), 1.30-1.55 (m, 2H), 1.17-1.30 (m, 2H), 0.76 (t, 3H, J=7.2 Hz). ¹⁹ F NMR (DMSO-d ₆ , 282 MHz) δ -120.37 (s, 1F). EXAMPLE 118 Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2,6-dichlorophenyl)-6 -methylpyrrolo[1,2- b]pyridazine-3-carboximidamide Step 1: Synthesis of tert-butyl [trans-4-[[3-[N'-(2,6-dichlorophenyl)carbamimidoyl]-6- methylpyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohexyl]carbamat e To a mixture of tert-butyl [trans-4-[[6-bromo-3-[N'-(2,6- dichlorophenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]am ino]cyclohexyl]carbamate (160 mg, 268.3 μmol) and methylboronic acid (160 mg, 2.68 mmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added XPhos Pd G3 (22 mg, 26.8 μmol) and potassium carbonate (111 mg, 804.9 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was heated at 60 °C for 3 hours and 70°C for 1 hour. After cooled to room temperature, the reaction mixture was diluted with ethyl acetated and washed with saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as an off-white solid. Yield: 140 mg, 98%. LCMS (ESI) m/z: 531.1 (M+H). Step 2: Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2,6-dichlorophenyl)-6 - methylpyrrolo[1,2-b]pyridazine-3-carboximidamide To a solution of tert-butyl [trans-4-[[3-[N'-(2,6-dichlorophenyl)carbamimidoyl]-6- methylpyrrolo[1,2-b]pyridazin-4-yl]amino]cyclohexyl]carbamat e (120 mg, 225.7 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (1.0 mL) dropwise. The reaction mixture was stirred at 25 °C for an hour and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 4-[(trans-4-aminocyclohexyl)amino]-N'-(2,6-dichlorophenyl)-6 - methylpyrrolo[1,2-b]pyridazine-3-carboximidamide as an off-white solid. Yield: 54.7 mg, 54%. LCMS (ESI) m/z: 431.0 (M+H). ¹ H-NMR (DMSO-d ₆ , 400 MHz,) δ 10.93 (d, 1H, J=8.0 Hz), 8.08 (s, 1H), 7.42-7.66 (m, 4H), 7.01-7.06 (m, 1H), 6.61 (s, 1H), 6.42 (s, 2H), 4.00-4.07 (m, 1H), 2.97- 3.03 (m, 1H), 2.25 (s, 3H), 2.13-2.20 (m, 2H), 1.93-1.99 (m, 2H), 1.31-1.57 (m, 4H). EXAMPLE 119 Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-6-fluoro- phenyl)-6-methyl- pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of tert-butyl N-[(1S,3R)-3-[[6-bromo-3-[N'-(2-chloro-6-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate To a mixture of 6-bromo-4-chloro-N'-(2-chloro-6-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (400 mg, 995.1 μmol) and tert-butyl N-[(1S,3R)-3-aminocyclopentyl]carbamate (299 mg, 1.50 mmol) in N,N-dimethylacetamide (4.0 mL) was added N,N-diisopropylethylamine (257 mg, 2.0 mmol). After stirring at 90°C for 2 hours, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 506 mg, 84%. LCMS (ESI) m/z: 566.8 (M+H). Step 2: Synthesis of tert-butyl N-[(1S,3R)-3-[[3-[N'-(2-chloro-6-fluoro-phenyl)carbamimidoyl ]-6- methyl-pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclopentyl]carbam ate and tert-butyl N-[(1S,3R)-3-[[3-[N'-(2-chloro-6-fluoro-phenyl)carbamimidoyl ]pyrrolo[1,2- b]pyridazin-4-yl]amino]cyclopentyl]carbamate (the title compoundB) To a mixture of tert-butyl N-[(1S,3R)-3-[[6-bromo-3-[N'-(2-chloro-6-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (200 mg, 353.4 μmol) and methylboronic acid (212 mg, 3.54 mmol) in N,N-dimethylformamide (3.0 mL) and water (0.3 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (23 mg, 35.3 μmol) and potassium phosphate (225 mg, 1.06 mmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded two fractions: The title compoundA as a yellow solid. Yield: 140 mg, 48%. LCMS (ESI) m/z: 501.4 (M+H). The title compound B as a yellow solid. Yield: 40 mg, 15%. LCMS (ESI) m/z: 487.2 (M+H). Step 3: Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-6-fluoro- phenyl)-6- methyl-pyrrolo[1,2-b]pyridazine-3-carboxamidine To a mixture of tert-butyl N-[(1S,3R)-3-[[3-[N'-(2-chloro-6-fluoro-phenyl)carbamimidoyl ]-6- methyl-pyrrolo[1,2-b]pyridazin-4-yl]amino]cyclopentyl]carbam ate (3A, 120 mg, 240.1 μmol) in 2 N hydrochloric acid aqueous solution (5.0 mL) was stirred at 50°C for 2 hours and cooled to room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[[(1R,3S)-3- aminocyclopentyl]amino]-N'-(2-chloro-6-fluoro-phenyl)-6-meth yl-pyrrolo[1,2-b]pyridazine-3- carboxamidine as a white solid. Yield: 17.5 mg, 18%. LCMS (ESI) m/z: 401.0 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.22 (brs, 1H), 8.08 (s, 1H), 7.47 (s, 1H), 7.29-7.32 (m, 1H), 7.16-7.21 (m, 1H), 7.01-7.07 (m, 1H), 6.72 (s, 1H), 6.45 (brs, 2H), 4.45-4.55 (m, 1H), 3.20-3.30 (m, 1H), 2.30-2.40 (m, 1H), 2.24 (s, 3H), 2.00-2.10 (m, 1H), 1.78-1.86 (m, 1H), 1.65-1.73 (m, 1H), 1.32- 1.43 (m, 1H), 1.20-1.31 (m, 1H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -120.34 (s, 1F). Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-6-fluoro- phenyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine To a mixture of tert-butyl N-[(1S,3R)-3-[[3-[N'-(2-chloro-6-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (3B, 40 mg, 82.1 μmol) in 2 N hydrochloric acid aqueous solution (1.0 mL) was stirred at 50°C for 2 hours and cooled to room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[[(1R,3S)-3- aminocyclopentyl]amino]-N'-(2-chloro-6-fluoro-phenyl)pyrrolo [1,2-b]pyridazine-3- carboxamidine as a white solid. Yield: 16.1 mg, 49%. LCMS (ESI) m/z: 387.0 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.38 (s, 1H), 8.16 (s, 1H), 7.64-7.66 (m, 1H), 7.31 (d, 1H, J=8.0 Hz), 7.16-7.22 (m, 1H), 7.02-7.08 (m, 1H), 6.89-7.91 (m, 1H), 6.65-6.67 (m, 1H), 6.49 (brs, 2H), 4.50- 4.60 (m, 1H), 3.20-3.30 (m, 1H), 2.30-2.40 (m, 1H), 1.65-2.10 (m, 5H), 1.30-1.41 (m, 1H), 1.27- 1.30 (m, 1H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -120.34 (s, 1F). EXAMPLE 120 Synthesis of 5-[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-4-[[(3S)-t etrahydrofuran-3- yl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-4-methyl-pyridine-2-c arboxylic acid

Step 1: Synthesis of methyl 5-bromo-4-methyl-pyridine-2-carboxylate To a solution of 5-bromo-4-methyl-pyridine-2-carboxylic acid (1.70 g, 7.87 mmol) in methanol (20.0 mL) was added thionyl chloride (3.74 g, 31.48 mmol) at -10 °C. The resulting mixture was stirred at 70 °C for 2 hours. After cooling to room temperature, the reaction mixture was quenched with aqueous solution of sodium carbonate and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a white solid. Yield: 1.50 g, 82%. LCMS (ESI) m/z: 232.1 (M+H). Step 2: Synthesis of methyl 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyri dine-2- carboxylate To a solution of methyl 5-bromo-4-methyl-pyridine-2-carboxylate (500 mg, 2.17 mmol) in N,N- dimethylformamide (10.0 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.10 g, 4.35 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (180 mg, 217.3 μmol) and potassium acetate (427 mg, 4.35 mmol). The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 5 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a brown solid. Yield: 500 mg, 83%. LCMS (ESI) m/z: 278.0 (M+H). Step 3: Synthesis of 6-bromo-N'-(2-chloro-5-fluoro-phenyl)-4-[[(3S)-tetrahydrofur an-3- yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (180 mg, 447.7 μmol) in N,N-dimethylacetamide (5.0 mL) were added (3S)- tetrahydrofuran-3-amine hydrochloric acid salt (83 mg, 671.6 μmol) and N,N- diisopropylethylamine (174 mg, 1.34 mmol). The resulting mixture was stirred at 90 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 180 mg, 88%. LCMS (ESI) m/z: 453.9 (M+H). Step 4: Synthesis of methyl 5-[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-4-m ethyl-pyridine-2-carboxylate To a solution of 6-bromo-N'-(2-chloro-5-fluoro-phenyl)-4-[[(3S)-tetrahydrofur an-3- yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine (160 mg, 353.4 μmol) in N,N- dimethylformamide (5.0 mL) and water (0.5 mL) were added methyl 4-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate (245 mg, 883.6 μmol), 1,1'-bis (di-t- butylphosphino)ferrocene-palladium dichloride (23 mg, 35.3 μmol) and potassium phosphate (150 mg, 706.8 μmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a gray solid. Yield: 160 mg, 55%, 64% purity. LCMS (ESI) m/z: 523.4 (M+H). Step 5: Synthesis of 5-[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-4-m ethyl-pyridine-2-carboxylic acid To a suspension of methyl 5-[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-4-m ethyl-pyridine-2-carboxylate (140 mg, 171.3 μmol) in methanol (10.0 mL) was added 2 N aqueous solution of sodium hydroxide (3.0 mL). After stirring at 25 °C for 2 hours, the reaction mixture was adjusted to pH=6 with 2N aqueous solution of hydrochloric acid and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 5-[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-4-m ethyl-pyridine-2-carboxylic acid as a yellow solid. Yield: 29.9 mg, 33%. LCMS (ESI) m/z: 509.2 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.66 (d, 1H, J=7.2 Hz), 8.80 (s, 1H), 8.29 (s, 1H), 8.12 (d, 1H, J=1.6 Hz), 7.98 (s, 1H), 7.48-7.52 (m, 1H), 7.24 (d, 1H, J=2.0 Hz), 6.84-6.95 (m, 2H), 6.62 (s, 2H), 4.99-5.06 (m, 1H), 3.93-3.99 (m, 1H), 3.72-3.87 (m, 3H), 2.58 (s, 3H), 2.32-2.46 (m, 1H), 1.91-1.98 (m, 1H). 1 ⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -114.39 (s, 1F). EXAMPLE 121 Synthesis of N'-(4-hydroxy-2-methyl-phenyl)-6-(6-methoxy-4-methyl-3-pyrid yl)-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine Step 1: Synthesis of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-methyl-phenyl ]-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-methyl-phenyl ]-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (200 mg, 404 μmol) and (3S)-tetrahydrofuran-3-amine HCl salt (108 mg, 810 μmol, S14) in N,N-dimethylacetamide (2 mL) was added N,N- diisopropylethylamine (157 mg, 1.2 mmol). After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 100 mg, 43%. LCMS (ESI) m/z: 546.1 (M+H). Step 2: Synthesis of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-methyl-phenyl]-6-(6-m ethoxy-4- methyl-3-pyridyl)-4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrrol o[1,2-b]pyridazine-3- carboxamidine To a solution of 6-bromo-N'-[4-[ tert-butyl(dimethyl)silyl]oxy-2-methyl-phenyl]-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine (90 mg, 165 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (55 mg, 330 μmol) in N,N-dimethylformamide (1 mL) and water (0.1 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (11 mg, 16 μmol) and potassium carbonate (69 mg, 496 μmol). The resulting mixture was purged with nitrogen gas, stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 80 mg, 80%. LCMS (ESI) m/z: 587.1 (M+H). Step 3: Synthesis of N'-(4-hydroxy-2-methyl-phenyl)-6-(6-methoxy-4-methyl-3-pyrid yl)-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine To a solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-methyl-phenyl]-6-(6-m ethoxy-4-methyl-3- pyridyl)-4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]p yridazine-3-carboxamidine (70 mg, 119 μmol) in N,N-dimethylformamide (1 mL) was added cesium fluoride (36 mg, 238 μmol). After stirring at room temperature for 2 hours, the resulting mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded N'-(4-hydroxy-2-methyl- phenyl)-6-(6-methoxy-4-methyl-3-pyridyl)-4-[[(3S)-tetrahydro furan-3-yl]amino]pyrrolo[1,2- b]pyridazine-3-carboxamidine as a white solid. Yield: 19.1 mg, 34%. LCMS (ESI) m/z: 473.3 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.48 (d, 1H, J=7.2 Hz), 8.92 (s, 1H), 8.23-8.25 (m, 2H), 7.90 (d, 1H, J=2.0 Hz), 7.05 (d, 1H, J=2.0 Hz), 6.78 (s, 1H), 6.56-6.66 (m, 3H), 5.94 (s, 2H), 4.95-5.01 (m, 1H), 3.92-3.94 (m, 1H), 3.86 (s, 3H), 3.70-3.84 (m, 3H), 2.43 (s, 3H), 2.32-2.42 (m, 1H), 2.04 (s, 3H), 1.88-1.94 (m, 1H). EXAMPLE 122 Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-6-(4-ethyl-6-methoxy-3 -pyridyl)-N'-(4- hydroxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxami dine Step 1: Synthesis of tert-butyl N-[(1S,3R)-3-[[6-bromo-3-[N'-(4-hydroxy-2-methyl- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate To a mixture of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-methyl-phenyl ]-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (250 mg, 506.2 μmol) and tert-butyl N-[(1S,3R)-3- aminocyclopentyl]carbamate (132 mg, 658.0 μmol) in N,N-dimethylacetamide (2.0 mL) was added N,N-diisopropylethylamine (131 mg, 1.01 mmol). After stirring at 90 °C for 5 hours, the resulting mixture was cooled to room temperature and then cesium fluoride (154 mg, 1.01 mmol) was added. After stirring overnight at room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 248 mg, 88%. LCMS (ESI) m/z: 543.3 (M+H). Step 2: Synthesis of tert-butyl N-[(1S,3R)-3-[[6-(4-ethyl-6-methoxy-3-pyridyl)-3-[N'-(4-hydr oxy- 2-methyl-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]a mino]cyclopentyl]carbamate To a solution of tert-butyl N-[(1S,3R)-3-[[6-bromo-3-[N'-(4-hydroxy-2-methyl- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (200 mg, 368.0 μmol) and 4-ethyl-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyridine (291 mg, 1.10 mmol) in N,N-dimethylformamide (3.0 mL) and water (0.3 mL) were added 1,1'-bis(di- t-butylphosphino)ferrocene-palladium dichloride (24 mg, 36.8 μmol) and potassium phosphate (234 mg, 1.10 mmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 91 mg, 40%. LCMS (ESI) m/z: 600.3 (M+H). Step 3: Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-6-(4-ethyl-6-methoxy-3 -pyridyl)- N'-(4-hydroxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazine-3-car boxamidine A mixture of tert-butyl N-[(1S,3R)-3-[[6-(4-ethyl-6-methoxy-3-pyridyl)-3-[N'-(4-hydr oxy-2- methyl-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]ami no]cyclopentyl]carbamate (76 mg, 126.7 μmol) in 2 N hydrochloric acid aqueous solution (3.0 mL) was stirred at 50 °C for 2 hours and then cooled to room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[[(1R,3S)-3- aminocyclopentyl]amino]-6-(4-ethyl-6-methoxy-3-pyridyl)-N'-( 4-hydroxy-2-methyl- phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as an off-white solid. Yield: 11.5 mg, 18%. LCMS (ESI) m/z: 500.1 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 12.30 (brs, 1H), 8.92 (s, 1H), 8.18 (s, 1H), 8.17 (s, 1H), 7.80 (d, 1H, J=1.5 Hz), 6.96 (d, 1H, J=1.5 Hz), 6.77 (s, 1H), 6.55-6.70 (m, 3H), 5.88 (brs, 2H), 4.44 (t, J=7.6 Hz, 1H), 3.87 (s, 3H), 3.20-3.30 (m, 1H), 2.76 (q, J=10, 2H), 2.30-2.40 (m, 1H), 2.00-2.10 (m, 4H), 1.67-1.87 (m, 2H), 1.25-1.45 (m, 2H), 1.09-1.20 (t, J=10 Hz, 3H). EXAMPLE 123 Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-(4- ethyl-6-methoxy-3- pyridyl)-N'-(4-hydroxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridaz ine-3-carboxamidine Step 1: Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-[4- [tert-butyl(dimethyl)silyl]oxy-2-methyl-phenyl]pyrrolo[1,2-b ]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-methyl-phenyl ]-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (200 mg, 404 μmol) in N,N-dimethylacetamide (2 mL) were added (1S,3R)-1,2,2-trimethylcyclopentane-1,3-diamine (86 mg, 607 μmol) and N,N- diisopropylethylamine (52 mg, 404 μmol). After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 110 mg, 45%. LCMS (ESI) m/z: 601.4 (M+H). Step 2: Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-(4- ethyl-6- methoxy-3-pyridyl)-N'-(4-hydroxy-2-methyl-phenyl)pyrrolo[1,2 -b]pyridazine-3-carboxamidine To a solution of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-[4-[tert- butyl(dimethyl)silyl]oxy-2-methyl-phenyl]pyrrolo[1,2-b]pyrid azine-3-carboxamidine (90 mg, 150 μmol) and 4-ethyl-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyridine (79 mg, 300 μmol) in N,N-dimethylformamide (1 mL) and water (0.1 mL) were added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (10 mg, 15 μmol) and sodium carbonate (48 mg, 450 μmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded a crude product. Then further purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-(4- ethyl-6- methoxy-3-pyridyl)-N'-(4-hydroxy-2-methyl-phenyl)pyrrolo[1,2 -b]pyridazine-3-carboxamidine as an off-white solid. Yield: 6.8 mg, 8%. LCMS (ESI) m/z: 542.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.30 (s, 1H), 8.89 (s, 1H), 8.17-8.22 (m, 2H), 7.81 (d, 1H, J=1.6 Hz), 6.89 (d, 1H, J=1.6 Hz), 6.78 (s, 1H), 6.56-6.65 (m, 3H), 5.84 (s, 2H), 4.40-4.56 (m, 1H), 3.87 (s, 3H), 2.76 (q, J=7.6 Hz, 2H), 2.25-2.33 (m, 1H), 2.03 (s, 3H), 1.14-1.83 (m, 5H), 1.10-1.21 (t, J=7.6 Hz, 3H), 1.02 (s, 3H), 0.85 (s, 3H), 0.82 (s, 3H). EXAMPLE 124 Synthesis of 4-[[(1R, 3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-phenyl)- 6-[1- (difluoromethyl)pyrazol-4-yl]pyrrolo[1,2-b]pyridazine-3-carb oxamidine Step 1: Synthesis of tert-butyl N-[(1S,3R)-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl ]-6- [1-(difluoromethyl)pyrazol-4-yl]pyrrolo[1,2-b]pyridazin-4-yl ]amino]cyclopentyl]carbamate To a solution of tert-butyl N-[(1S,3R)-3-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (200 mg, 353 μmol) and 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)pyrazole (259 mg, 1.0 mmol) in N,N-dimethylformamide (5 mL) and water (0.5 mL) were added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (23 mg, 35 μmol) and potassium carbonate (98 mg, 709 μmol) at room temperature. The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a white solid. Yield: 160 mg, 75%. LCMS (ESI) m/z: 603.1 (M+H). Step 2: Synthesis of 4-[[(1S,3R)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro- phenyl)-6-[1- (difluoromethyl)pyrazol-4-yl]pyrrolo[1,2-b]pyridazine-3-carb oxamidine To a solution of tert-butyl N-[(1S,3R)-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl ]-6-[1- (difluoromethyl)pyrazol-4-yl]pyrrolo[1,2-b]pyridazin-4-yl]am ino]cyclopentyl]carbamate (140 mg, 232 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at room temperature. After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[[(1S,3R)-3- aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-phenyl)-6-[1-( difluoromethyl)pyrazol-4- yl]pyrrolo[1,2-b]pyridazine-3-carboxamidine as a yellow solid. Yield: 36.8 mg, 31%. LCMS (ESI) m/z: 503.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.41 (s, 1H), 8.68 (s, 1H), 8.25 (s, 1H), 8.17 (s, 1H), 8.06 (d, 1H, J=1.6 Hz), 7.84 (t, 1H, J=59.6 Hz), 7.47-7.51 (m, 1H), 7.21 (d, 1H, J=2.0 Hz), 6.82-6.94 (m, 2H), 6.51 (s, 2H), 4.62-4.66 (m, 1H), 3.28-3.32 (m, 1H), 2.42-2.48 (m, 1H), 2.08- 2.18 (m, 1H), 1.80-1.96 (m, 2H), 1.68-1.78 (m,1H), 1.38-1.48 (m, 1H), 1.26-1.36 (m, 1H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -93.57 (s, 2F), -114.48 (s, 1F). EXAMPLE 125 Synthesis of 4-[cis-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-pheny l)-6-(6-methoxy-4- methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of tert-butyl N-[cis-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- (6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclohexyl]carbamate To a solution of tert-butyl N-[cis-4-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl ohexyl]carbamate (220 mg, 379 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (254 mg, 1.5 mmol) in N,N- dimethylformamide (3 mL) and water (0.3 mL) were added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (74 mg, 113 μmol) and potassium carbonate (105 mg, 760 μmol) at room temperature. The resulting mixture was purged with nitrogen gas and stirred at 80 °C for an hour under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 170 mg, 72%. LCMS (ESI) m/z: 622.4 (M+H). Step 2: Synthesis of 4-[cis-(4-aminocyclohexyl)amino]-N'-(2-chloro-5-fluoro-pheny l)-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine To a solution of tert-butyl N-[cis-4-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6- (6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclohexyl]carbamate (150 mg, 241 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[cis-(4-aminocyclohexyl)amino]-N'-(2-chloro-5- fluoro-phenyl)-6-(6-methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b ]pyridazine-3-carboxamidine as a white solid. Yield: 40.3 mg, 31%. LCMS (ESI) m/z: 522.3 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.63 (d, 1H, J=8.0 Hz), 8.24 (d, 2H, J= 2.8 Hz), 7.89 (d, 1H, J=2.0 Hz), 7.47-7.51 (m, 1H), 7.01 (d, 1H, J=2.0 Hz), 6.84-6.97 (m, 2H), 6.78 (s, 1H), 6.49 (s, 2H), 4.36-4.42 (m, 1H), 3.87 (s, 3H), 2.68-2.74 (m, 1H), 2.41 (s, 3H), 1.80-1.90 (m, 2H), 1.67-1.77 (m, 2H), 1.56-1.65 (m, 2H), 1.29-1.44 (m, 3H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -114.54 (s, 1F). EXAMPLE 126 Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluorop henyl)-6-[2- [(dimethylamino)methyl]phenyl]pyrrolo[1,2-b]pyridazine-3-car boximidamide formic acid salt Step 1: Synthesis of tert-butyl N-[(1S,3R)-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl ]-6- [2-[(dimethylamino)methyl]phenyl]pyrrolo[1,2-b]pyridazin-4-y l]amino]cyclopentyl]carbamate To a solution of tert-butyl N-[(1S,3R)-3-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (200 mg, 353.4 μmol) and [2-[(dimethylamino)methyl]phenyl]boronic acid (190 mg, 1.11 mmol) in N,N- dimethylformamide (3.0 mL) and water (0.3 mL) were added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (23 mg, 35.3 μmol) and potassium phosphate (226 mg, 1.10 mmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a black solid. Yield: 135 mg, 42%. LCMS (ESI) m/z: 620.3 (M+H). Step 2: Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluorop henyl)-6-[2- [(dimethylamino)methyl]phenyl]pyrrolo[1,2-b]pyridazine-3-car boximidamide formic acid salt A mixture of tert-butyl N-[(1S,3R)-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl ]-6-[2- [(dimethylamino)methyl]phenyl]pyrrolo[1,2-b]pyridazin-4-yl]a mino]cyclopentyl]carbamate (135 mg, 217.7 μmol) in 2 N hydrochloric acid aqueous solution (5.0 mL) was stirred at 50 °C for 2 hours and then cooled to room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1% formic acid) afforded 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro- 5-fluorophenyl)-6-[2-[(dimethylamino)methyl]phenyl]pyrrolo[1 ,2-b]pyridazine-3- carboximidamide formic acid salt as an off-white solid. Yield: 33.8 mg, 27%. LCMS (ESI) m/z: 521.1 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.51 (d, 1H, J=5.2 Hz), 8.31 (s, 3H), 8.23 (s, 1H), 8.02 (d, 1H, J=1.2 Hz), 7.50-7.60 (m, 2H), 7.43-7.48 (m, 1H), 7.26-7.38 (m, 2H), 7.25 (s, 1H), 6.87-6.93 (m, 2H), 6.59 (s, 2H), 4.65-4.75 (m, 1H), 3.40-3.58 (m, 3H) 2.50-2.60 (m, 1H), 2.16-2.20 (m, 7H), 1.97-2.08 (s, 1H), 1.65-1.85 (m, 2H), 1.50-1.65 (m, 1H). ¹⁹ F NMR (DMSO- d6, 376 MHz) δ -114.43 (s, 1F). EXAMPLE 127 Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro- phenyl)-6-[3- (hydroxymethyl)-4-pyridyl]pyrrolo[1,2-b]pyridazine-3-carboxa midine

Step 1: Synthesis of (4-bromo-3-pyridyl)methoxy-tert-butyl-dimethyl-silane To a solution of (4-bromo-3-pyridyl)methanol (800 mg, 4.2 mmol) and tert-butyl-chloro- dimethyl-silane (1.28 g, 8.5 mmol) in N,N-dimethylformamide (5 mL) was added imidazole (869 mg, 13 mmol). After stirring at room temperature for 16 hours, the reaction mixture was poured into water and extracted with ethyl acetate for three times. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a yellow solid. Yield: 1.0 g, 77%. LCMS (ESI) m/z: 301.9 (M+H). Step 2: Synthesis of tert-butyl-dimethyl-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro lan-2-yl)-3- pyridyl]methoxy]silane To a mixture of (4-bromo-3-pyridyl)methoxy-tert-butyl-dimethyl-silane (200 mg, 661 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)-1,3,2-dioxaborolane (336 mg, 1.3 mmol) and potassium acetate (551 mg, 1.3 mmol) in 1,4-dioxane (2 mL) was added 1,1'- bis(diphenylphosphino)ferrocene-palladium(II) dichloride (48 mg, 66 μmol). The resulting mixture was purged with nitrogen gas and stirred at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate for three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 130 mg, 56%. Step 3: Synthesis of tert-butyl N-[(1S,3R)-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl ]-6- [3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-pyridyl]pyrrolo[ 1,2-b]pyridazin-4- yl]amino]cyclopentyl]carbamate To a solution of tert-butyl N-[(1S,3R)-3-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (120 mg, 212 μmol), tert-butyl-dimethyl-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro lan-2-yl)-3- pyridyl]methoxy]silane (148 mg, 424 μmol) and potassium phosphate (90 mg, 424 μmol) in N,N- dimethylformamide (2 mL) and water (0.2 mL) was added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (14 mg, 21 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 80 mg, 53%. LCMS (ESI) m/z: 708.2 (M+H). Step 4: Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro- phenyl)-6-[3- (hydroxymethyl)-4-pyridyl]pyrrolo[1,2-b]pyridazine-3-carboxa midine Tert-Butyl N-[(1S,3R)-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl ]-6-[3-[[tert- butyl(dimethyl)silyl]oxymethyl]-4-pyridyl]pyrrolo[1,2-b]pyri dazin-4- yl]amino]cyclopentyl]carbamate (70 mg, 98.82 μmol) was dissolved in trifluoroacetic acid (2 mL) and stirred at 80 °C for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[[(1R,3S)-3- aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro-phenyl)-6-[3-( hydroxymethyl)-4- pyridyl]pyrrolo[1,2-b]pyridazine-3-carboxamidine as a light yellow solid. Yield: 6.9 mg, 14%. LCMS (ESI) m/z: 494.0 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz,) δ 11.60 (s, 1H), 8.64 (s, 1H), 8.52 (d, 1H, J=5.2 Hz), 8.21-8.27 (m, 2H), 7.65 (d, 1H, J=5.2 Hz), 7.50-7.52 (m, 1H), 7.43 (d, 1H, J=2.0 Hz), 6.85-6.96 (m, 2H), 6.58 (s, 2H), 5.50 (t, 1H, J=5.2 Hz), 4.61-4.71 (m, 3H), 3.39- 3.47 (m, 1H), 2.45-2.49 (m, 1H), 2.11-2.21 (m, 1H), 1.91-1.97 (m, 1H), 1.72-1.80 (m, 1H), 1.41- 1.62 (m, 2H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -114.41 (s,1F). EXAMPLE 128 Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro- phenyl)-6-[2- (hydroxymethyl)phenyl]pyrrolo[1,2-b]pyridazine-3-carboxamidi ne

Step 1: Synthesis of tert-butyl N-[(1S,3R)-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl ]-6- [2-(hydroxymethyl)phenyl]pyrrolo[1,2-b]pyridazin-4-yl]amino] cyclopentyl]carbamate To a solution of tert-butyl N-[(1S,3R)-3-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (100 mg, 176 μmol) and [2-(hydroxymethyl)phenyl]boronic acid (54 mg, 353 μmol) in N,N- dimethylformamide (1 mL) and water (0.1 mL) were added potassium phosphate (112 mg, 530 μmol) and 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (12 mg, 18 μmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 80 mg, 75%. LCMS (ESI) m/z: 593.2 (M+H). Step 2: Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-chloro-5-fluoro- phenyl)-6-[2- (hydroxymethyl)phenyl]pyrrolo[1,2-b]pyridazine-3-carboxamidi ne To a solution of tert-butyl N-[(1S,3R)-3-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl ]-6-[2- (hydroxymethyl)phenyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cyc lopentyl]carbamate (70 mg, 118 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2- chloro-5-fluoro-phenyl)-6-[2-(hydroxymethyl)phenyl]pyrrolo[1 ,2-b]pyridazine-3-carboxamidine as a white solid. Yield: 30.6 mg, 52%. LCMS (ESI) m/z: 493.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.47 (s, 1H), 8.21 (s, 1H), 7.95 (d, 1H, J=1.6 Hz), 7.48-7.54 (m, 3H), 7.31-7.35 (m, 2H), 7.18 (d, 1H, J=2.0 Hz), 6.85-6.91 (m, 2H), 6.52 (s, 2H), 5.26 (t, 1H, J=5.2 Hz), 4.55-4.65 (m, 3H), 3.25-3.28 (m, 1H), 2.38-2.41 (m, 1H), 2.07-2.13 (m, 1H), 1.61-1.83 (m, 4H), 1.33-1.43 (m, 2H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.48 (s, 1F). EXAMPLE 129 Synthesis of N'-(2-chloro-5-fluoro-4-hydroxy-phenyl)-6-[2-[(dimethylamino )methyl]phenyl]-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine Step 1: Synthesis of 6-bromo-N'-(2-chloro-5-fluoro-4-hydroxy-phenyl)-4-[[(3S)-tet rahydrofuran- 3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-chloro-5-fluo ro-phenyl]-4- chloro-pyrrolo[1,2-b]pyridazine-3-carboxamidine (351 mg, 659.4 μmol) and (3S)- tetrahydrofuran-3-amine hydrochloric acid salt (98 mg, 791 μmol) in N,N-dimethylacetamide (4.0 mL) was added N,N-diisopropylethylamine (256 mg, 1.98 mmol). After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature and then cesium fluoride (200 mg, 1.32 mmol) was added. After stirring at 25 °C for 15 hours, the reaction mixture was diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 298 mg, 90%. LCMS (ESI) m/z: 469.9 (M+H). Step 2: Synthesis of N'-(2-chloro-5-fluoro-4-hydroxy-phenyl)-6-[2- [(dimethylamino)methyl]phenyl]-4-[[(3S)-tetrahydrofuran-3-yl ]amino]pyrrolo[1,2-b]pyridazine- 3-carboxamidine To a solution of 6-bromo-N'-(2-chloro-5-fluoro-4-hydroxy-phenyl)-4-[[(3S)-tet rahydrofuran-3- yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine (161 mg, 343.5 μmol) and [2- [(dimethylamino)methyl]phenyl]boronic acid (246 mg, 1.37 mmol) in N,N-dimethylformamide (3.0 mL) and water (0.3 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (22 mg, 34.4 μmol) and potassium carbonate (142 mg, 1.03 mmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-(2-chloro-5-fluoro-4-hydroxy-phenyl)- 6-[2-[(dimethylamino)methyl]phenyl]-4-[[(3S)-tetrahydrofuran -3-yl]amino]pyrrolo[1,2- b]pyridazine-3-carboxamidine as a grey solid. Yield: 42.1 mg, 22%. LCMS (ESI) m/z: 523.3 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.86 (d, 1H, J=6.9 Hz), 9.82 (s, 1H), 8.22 (s, 1H), 8.02 (d, 1H, J=1.5 Hz), 7.54-7.57 (m, 1H), 7.24-7.44 (m, 4H), 7.04 (d, 1H, J=9.0 Hz), 6.85 (d, 1H, J=12.0 Hz), 6.44 (brs, 2H), 4.95-5.02 (m, 1H), 3.90-4.00 (m, 1H), 3.65-3.85 (m, 3H), 3.46 (s, 2H), 2.30-2.40 (m, 1H), 2.20 (s, 6H), 1.85-2.00 (m, 1H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ - 135.94 (s, 1F). EXAMPLE 130 Synthesis of 1-[4-[4-[[(1R, 3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-3-[N'-(2-chlo ro-5- fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3- ethyl-phenyl]-3-(2-hydroxy-2- methyl-propyl)urea

Step 1: Synthesis of phenyl N-(4-bromo-3-ethyl-phenyl)carbamate To a solution of 4-bromo-3-ethyl-aniline (1.00 g, 5.00 mmol) in dichloromethane (20.0 mL) were added pyridine (593 mg, 7.50 mmol) and phenyl carbonochloridate (939 mg, 6.00 mmol) dropwise at 0 °C. After stirring at 0 °C for 2 hours, the reaction mixture was diluted with dichloromethane and washed with aqueous solution of sodium carbonate, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a light brown solid. Yield: 1.66 g, 99%. LCMS (ESI) m/z: 319.9 (M+H). Step 2: Synthesis of 1-(4-bromo-3-ethyl-phenyl)-3-(2-hydroxy-2-methyl-propyl)urea To a solution of phenyl N-(4-bromo-3-ethyl-phenyl)carbamate (1.66 g, 5.18 mmol) in N,N- dimethylformamide (10.0 mL) were added triethylamine (1.57 g, 15.55 mmol) and 1-amino-2- methyl-propan-2-ol (1.39 g, 15.55 mmol). After stirring at 50 °C for 2 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with saturated aqueous solution of sodium carbonate, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as an off-white solid. Yield: 1.20 g, 73%. LCMS (ESI) m/z: 314.9 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.70 (s, 1H), 7.33-7.40 (m, 2H), 7.15-7.20 (m, 1H), 6.15 (t, 1H, J=5.6 Hz), 4.53 (s, 1H), 3.02 (d, 2H, J=5.6 Hz), 2.61 (q, 2H, J=7.6 Hz), 1.14 (t, 3H, J=7.6 Hz), 1.08 (s, 6H). Step 3: Synthesis of 1-[3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ph enyl]-3-(2- hydroxy-2-methyl-propyl)urea To a solution of 1-(4-bromo-3-ethyl-phenyl)-3-(2-hydroxy-2-methyl-propyl)urea (490 mg, 1.55 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)-1,3,2- dioxaborolane (790 mg, 3.11 mmol) in N,N-dimethylformamide (5.0 mL) were added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (114 mg, 155.8 μmol) and potassium acetate (305 mg, 3.11 mmol). The resulting mixture was stirred at 85 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate three times. The combined orange layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (petroleum ether/ethyl acetate) afforded the title compound as a yellow solid. Yield: 400 mg, 71%. LCMS (ESI) m/z: 363.1 (M+H). Step 4: Synthesis of 4-[[(1R, 3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bromo-N'-(2 - chloro-5-fluoro-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamid ine To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (250 mg, 621.8 μmol) in N,N-dimethylacetamide (3.0 mL) were added (1R, 3S)- 1,2,2-trimethylcyclopentane-1,3-diamine (133 mg, 932.7 μmol) and N,N-diisopropylethylamine (241 mg, 1.87 mmol). The resulting mixture was stirred at 90 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 240 mg, 76%. LCMS (ESI) m/z: 509.3 (M+H). Step 5: Synthesis of 1-[4-[4-[[(1R, 3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-3-[N'-(2- chloro-5-fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin -6-yl]-3-ethyl-phenyl]-3-(2- hydroxy-2-methyl-propyl)urea To a solution of 4-[[(1R, 3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bromo-N'-(2 -chloro- 5-fluoro-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (100 mg, 196.9 μmol) in N,N- dimethylformamide (4.0 mL) and water (0.4 mL) were added 1-[3-ethyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl]-3-(2-hydroxy-2-methyl-propyl )urea (178 mg, 492.3 μmol), 1,1'- bis (di-t-butylphosphino)ferrocene-palladium dichloride (13 mg, 19.7 μmol) and potassium carbonate (54 mg, 393.8 μmol). The resulting mixture was purged with nitrogen gas and stirred at 75 °C for 4 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 1-[4-[4-[[(1R, 3S)-3-amino-2,2,3- trimethyl-cyclopentyl]amino]-3-[N'-(2-chloro-5-fluoro-phenyl )carbamimidoyl]pyrrolo[1,2- b]pyridazin-6-yl]-3-ethyl-phenyl]-3-(2-hydroxy-2-methyl-prop yl)urea as an off-white solid. Yield: 25.1 mg, 19%. LCMS (ESI) m/z = 663.1 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.46 (s, 1H), 8.65 (s, 1H), 8.21 (s, 1H), 7.73 (d, 1H, J=1.6 Hz), 7.45-7.49 (m, 1H), 7.21-7.36 (m, 3H), 6.82-6.92 (m, 3H), 6.43 (s, 2H), 6.16 (t, 1H, J=5.6 Hz), 4.55 (s, 1H), 4.43-4.51 (m, 1H), 3.05 (d, 2H, J=5.6 Hz), 2.70-2.80 (m, 2H), 2.20-2.29 (m, 1H), 1.55-1.70 (m, 5H), 1.17 (t, 3H, J=7.6 Hz), 1.10 (s, 6H), 1.02 (s, 3H), 0.83-0.85 (m, 6H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.71 (s, 1F). EXAMPLE 131 Synthesis of 1-[4-[4-[[(1R, 3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-3-[N'-(2-chlo ro-5- fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3- ethyl-phenyl]-3-(2-hydroxy-1,1- dimethyl-ethyl)urea Step 1: Synthesis of 1-(4-bromo-3-ethyl-phenyl)-3-(2-hydroxy-1,1-dimethyl-ethyl)u rea To a solution of phenyl N-(4-bromo-3-ethyl-phenyl)carbamate (1.50 g, 4.68 mmol) in N,N- dimethylformamide (10.0 mL) were added triethylamine (1.42 g, 14.05 mmol) and 2-amino-2- methyl-propan-1-ol (1.25 g, 14.05 mmol). After stirring at 50 °C for 2 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with dichloromethane and washed with saturated aqueous solution of sodium carbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a white solid. Yield: 1.10 g, 74%. LCMS (ESI) m/z: 315.0 (M+H). Step 2: Synthesis of 1-[3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ph enyl]-3-(2- hydroxy-1,1-dimethyl-ethyl)urea To a solution of 1-(4-bromo-3-ethyl-phenyl)-3-(2-hydroxy-1,1-dimethyl-ethyl)u rea (430 mg, 1.36 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)-1,3,2- dioxaborolane (693 mg, 2.73 mmol) in N,N-dimethylformamide (5.0 mL) were added 1,1'- bis(diphenylphosphino)ferrocene-palladium(II) dichloride (100 mg, 136.7 μmol) and potassium acetate (268 mg, 2.73 mmol). The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 16 hours under nitrogen atmosphere. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water. The combined orange layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (petroleum ether/ethyl acetate) afforded the title compound as a yellow solid. Yield: 330 mg, 66%. LCMS (ESI) m/z: 363.1 (M+H). Step 3: Synthesis of 1-[4-[4-[[(1R, 3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-3-[N'-(2- chloro-5-fluoro-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin -6-yl]-3-ethyl-phenyl]-3-(2- hydroxy-1,1-dimethyl-ethyl)urea To a solution of 4-[[(1R, 3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bromo-N'-(2 -chloro- 5-fluoro-phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (100 mg, 196.9 μmol) in N,N- dimethylformamide (4.0 mL) and water (0.4 mL) were added 1-[3-ethyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl]-3-(2-hydroxy-1,1-dimethyl-et hyl)urea (178 mg, 492.3 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene-palladium dichloride (12 mg, 19.7 μmol) and potassium carbonate (54 mg, 393.8 μmol). The resulting mixture was purged with nitrogen gas and stirred at 75 °C for 4 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 1-[4-[4-[[(1R, 3S)-3-amino-2,2,3- trimethyl-cyclopentyl]amino]-3-[N'-(2-chloro-5-fluoro-phenyl )carbamimidoyl]pyrrolo[1,2- b]pyridazin-6-yl]-3-ethyl-phenyl]-3-(2-hydroxy-1,1-dimethyl- ethyl)urea as a white solid. Yield: 14.4 mg, 11%. LCMS (ESI) m/z: 663.1 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.46 (s, 1H), 8.52 (s, 1H), 8.21 (s, 1H), 7.72 (d, 1H, J=1.6 Hz), 7.45-7.49 (m, 1H), 7.35 (d, 1H, J=2.0 Hz), 7.20-7.28 (m, 2H), 6.82-6.92 (m, 3H), 6.43 (s, 2H), 5.95 (s, 1H), 5.01 (t, 1H, J=4.8 Hz), 4.41-4.49 (m, 1H), 3.30-3.40 (m, 2H), 2.70-2.80 (m, 2H), 2.20-2.31 (m, 1H), 1.50-1.73 (m, 5H), 1.24 (s, 6H), 1.17 (t, 3H, J=7.6 Hz), 1.02 (s, 3H), 0.83-0.85 (m, 6H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ - 114.71 (s, 1F). EXAMPLE 132 Synthesis of 6-[2-(aminomethyl)phenyl]-N'-(2-ethyl-4-hydroxy-phenyl)-4-[[ (3S)-tetrahydrofuran- 3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of tert-butyl N-[[2-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-4-[[(3 S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazin-6-yl]phen yl]methyl]carbamate To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine (120 mg, 214 μmol) in N,N-dimethylformamide (2 mL) and water (0.2 mL) were added tert-butyl N-[[2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate (143 mg, 429 μmol), 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (14 mg, 21 μmol) and potassium phosphate (137 mg, 644 μmol). The resulting mixture was purged with nitrogen gas, stirred at 90 °C for 2 hours and then cooled to room temperature. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 80 mg, 63%. LCMS (ESI) m/z: 571.1 (M+H). Step 2: Synthesis of 6-[2-(aminomethyl)phenyl]-N'-(2-ethyl-4-hydroxy-phenyl)-4-[[ (3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine To a solution of tert-butyl N-[[2-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-4-[[(3 S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazin-6-yl]phen yl]methyl]carbamate (70 mg, 122 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.5 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 6-[2-(aminomethyl)phenyl]-N'-(2-ethyl-4-hydroxy- phenyl)-4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]py ridazine-3-carboxamidine as a white solid. Yield: 17.9 mg, 30%. LCMS (ESI) m/z: 471.1 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.52 (d, 1H, J=7.2 Hz), 8.94 (s, 1H), 8.24 (s, 1H), 7.97 (d, 1H, J=1.6 Hz), 7.46-7.54 (m, 2H), 7.28-7.31 (m, 2H), 7.16 (d, 1H, J=2.0 Hz), 6.59-6.67 (m, 3H), 5.92 (s, 2H), 4.97 (d, 1H, J=6.0 Hz), 3.93-3.97 (m, 1H), 3.86 (s, 2H), 3.69-3.81 (m, 3H), 2.32-2.45 (m, 3H), 2.08-2.18 (m, 1H), 1.88-1.95 (m, 1H), 1.07 (t, 3H, J=7.6 Hz). EXAMPLE 133 Synthesis of 4-[(trans-3-aminocyclobutyl)amino]-N'-(2-ethyl-4-hydroxy-phe nyl)-6-(6-methoxy- 4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine

Step 1: Synthesis of tert-butyl N-[trans-3-[[6-bromo-3-[N'-[4-[1,1- dimethylethyl(dimethyl)silyl]oxy-2-ethyl-phenyl]carbamimidoy l]pyrrolo[1,2-b]pyridazin-4- yl]amino]cyclobutyl]carbamate To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (400 mg, 787.5 μmol) and tert-butyl (trans-3- aminocyclobutyl)carbamate (440 mg, 2.36 mmol) in N,N-dimethylacetamide (4.0 mL) was added N,N-diisopropylethylamine (509 mg, 3.94 mmol). After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 310 mg, 53%. LCMS (ESI) m/z: 659.2 (M+H). Step 2: Synthesis of tert-butyl N-[trans-3-[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]- 6- (6-methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]a mino]cyclobutyl]carbamate To a solution of tert-butyl N-[trans-3-[[6-bromo-3-[N'-[4-[1,1-dimethylethyl(dimethyl)si lyl]oxy- 2-ethyl-phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]am ino]cyclobutyl]carbamate (310 mg, 471.3 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (236 mg, 1.41 mmol) in N,N- dimethylformamide (5.0 mL) and water (0.5 mL) were added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (31 mg, 47.1 μmol) and potassium carbonate (195 mg, 1.41 mmol). The resulting mixture was purged with nitrogen gas. After stirring at 80 °C for 4 hours, the reaction mixture was cooled to room temperature, and then cesium fluoride (143 mg, 942.7 μmol) was added. After stirring at 25 °C for 2 hours, the reaction mixture was diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 200 mg, 60%. LCMS (ESI) m/z: 584.3 (M-H). Step 3: Synthesis of 4-[(trans-3-aminocyclobutyl)amino]-N'-(2-ethyl-4-hydroxy-phe nyl)-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine To a solution of tert-butyl N-[trans-3-[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]- 6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclobutyl]carbamate (180 mg, 307.0 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (3.0 mL). After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[(trans-3-aminocyclobutyl)amino]-N'-(2-ethyl-4-hydroxy-phe nyl)-6- (6-methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-car boxamidine as an off-white solid. Yield: 63.5 mg, 42%. LCMS (ESI) m/z: 486.1 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 12.48 (d, 1H, J=5.7 Hz), 8.95 (brs, 1H), 8.22 (s, 2H), 7.87 (d, 1H, J=1.8 Hz), 6.87 (s, 1H), 6.78 (s, 1H), 6.57-6.69 (m, 3H), 5.91 (s, 2H), 4.65-4.75 (m, 1H), 3.87 (s, 3H), 3.45-3.60 (m, 1H), 2.40-2.50 (m, 5H), 2.15-2.30 (m, 4H), 1.09 (t, 3H, J=7.5 Hz). EXAMPLE 134 Synthesis of 4-[(3-aminocycloheptyl)amino]-N'-(2-ethyl-4-hydroxy-phenyl)- 6-(6-methoxy-4- methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine

Step 1: Synthesis of tert-butyl N-(3-oxocycloheptyl)carbamate To a solution of cyclohept-2-en-1-one (6.00 g, 54.47 mmol) and tert-butyl carbamate (6.38 g, 54.47 mmol) in dichloromethane (240.0 mL) was added bismuth nitrate (10.76 g, 27.23 mmol) in portions. After stirring at 20 °C for 24 hours, the reaction mixture was diluted with dichloromethane and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light yellow solid. Yield: 9.00 g, 61%. ¹ H NMR (Chloroform-d, 400 MHz) δ 4.58 (s, 1H), 3.91 (s, 1H), 2.78- 2.86 (m, 1H), 2.43-2.65 (m, 3H), 1.91-2.00 (m, 1H), 1.79-1.89 (m, 1H), 1.60-1.77 (m, 4H), 1.43 (s, 9H). Step 2: Synthesis of tert-butyl N-(3-aminocycloheptyl)carbamate To a solution of tert-butyl N-(3-oxocycloheptyl)carbamate (1.00 g, 4.40 mmol) in methanol (20.0 mL) were added ammonium formate (8.32 g, 131.98 mmol) and acetic acid (264 mg, 4.40 mmol). After stirring at 25 °C for 2 hours, sodium cyanoborohydride (553 mg, 8.80 mmol) was added. After stirring at 25 °C for another 2 hours, the reaction mixture was quenched with saturated aqueous solution of ammonium chloride and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a brown solid. Yield: 900 mg, crude. LCMS (ESI) m/z: 229.3 (M+H). Step 3: Synthesis of tert-butyl N-[3-[[6-bromo-3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-eth yl- phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl oheptyl]carbamate To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (200 mg, 393.7 μmol) in N,N-dimethylacetamide (10.0 mL) were added tert-butyl N-(3-aminocycloheptyl)carbamate (180 mg, 787.5 μmol) and N,N-diisopropylethylamine (152 mg, 1.18 mmol). The resulting mixture was stirred at 90 °C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a brown solid. Yield: 250 mg, 77%. LCMS (ESI) m/z: 701.0 (M+H). Step 4: Synthesis of tert-butyl N-[3-[[3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl- phenyl]carbamimidoyl]-6-(6-methoxy-4-methyl-3-pyridyl)pyrrol o[1,2-b]pyridazin-4- yl]amino]cycloheptyl]carbamate To a solution of tert-butyl N-[3-[[6-bromo-3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-eth yl- phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl oheptyl]carbamate (220 mg, 314.4 μmol) in N,N-dimethylformamide (5.0 mL) and water (0.5 mL) were added (6-methoxy-4- methyl-3-pyridyl)boronic acid (105 mg, 628.7 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene- palladium dichloride (20 mg, 31.4 μmol) and potassium phosphate (133 mg, 628.7 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 120 mg, 51%. LCMS (ESI) m/z: 742.6 (M+H). Step 5: Synthesis of tert-butyl N-[3-[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amin o]cycloheptyl]carbamate To a solution of tert-butyl N-[3-[[3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl- phenyl]carbamimidoyl]-6-(6-methoxy-4-methyl-3-pyridyl)pyrrol o[1,2-b]pyridazin-4- yl]amino]cycloheptyl]carbamate (120 mg, 161.7 μmol) in N,N-dimethylformamide (4.0 mL) was added cesium fluoride (73 mg, 485.1 μmol). After stirring at 25 °C for 2 hours, the reaction mixture was diluted with ethyl acetate and washed with water. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a brown solid. Yield: 110 mg, 92%, 85% purity. LCMS (ESI) m/z: 628.2 (M+H). Step 6: Synthesis of 4-[(3-aminocycloheptyl)amino]-N'-(2-ethyl-4-hydroxy-phenyl)- 6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine To a solution of tert-butyl N-[3-[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amin o]cycloheptyl]carbamate (120 mg, 191.1 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (1.0 mL). After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1% formic acid) and re- purified via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[(3-aminocycloheptyl)amino]-N'-(2-ethyl-4-hydroxy- phenyl)-6-(6-methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyrida zine-3-carboxamidine as a white solid. Yield: 21.4 mg, 20%. LCMS (ESI) m/z: 528.1 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.25-12.35 (m, 1H), 8.97 (brs, 1H), 8.25 (s, 1H), 8.21 (s, 1H), 7.86-7.89 (m, 1H), 6.75-7.16 (m, 2H), 6.56-6.71 (m, 3H), 5.87 (d, 2H, J=8.0 Hz), 4.30-4.60 (m, 1H), 3.87 (s, 3H), 2.99-3.08 (m, 1H), 2.38-2.48 (m, 5H), 2.01-2.20 (m, 2H), 1.85-2.00 (m, 2H), 1.42-1.81 (m, 6H), 1.25-1.40 (m, 2H), 1.06-1.11 (m, 3H). EXAMPLE 135 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4- (tetrahydropyran-4-ylamino)pyrrolo[1,2-b]pyridazine-3-carbox amidine Step 1: Synthesis of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4- (tetrahydropyran-4-ylamino)pyrrolo[1,2-b]pyridazine-3-carbox amidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (200 mg, 393.8 μmol) and tetrahydropyran-4-amine hydrochloric acid salt (119 mg, 1.18 mmol) in N,N-dimethylacetamide (2.0 mL) was added N,N- diisopropylethylamine (254 mg, 1.97 mmol). After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield:160 mg, 70%. LCMS (ESI) m/z: 574.3 (M+H). Step 2: Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4- (tetrahydropyran-4-ylamino)pyrrolo[1,2-b]pyridazine-3-carbox amidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4- (tetrahydropyran-4-ylamino)pyrrolo[1,2-b]pyridazine-3-carbox amidine (150 mg, 262.0 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (131 mg, 785.9 μmol) in N,N- dimethylformamide (3.0 mL) and water (0.3 mL) were added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (17 mg, 26.2 μmol) and potassium carbonate (109 mg, 785.9 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours. After cooling to room temperature, cesium fluoride (80 mg, 524 μmol) was added. After stirring at 25°C for 2 hours, the reaction mixture was diluted with ethyl acetate and the solids were filtered out. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1% formic acid) afforded N'-(2-ethyl-4-hydroxy-phenyl)-6-(6- methoxy-4-methyl-3-pyridyl)-4-(tetrahydropyran-4-ylamino)pyr rolo[1,2-b]pyridazine-3- carboxamidine as a yellow solid. Yield: 45.8 mg, 35%. LCMS (ESI) m/z: 501.1 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.47 (s, 1H), 8.96 (s, 1H), 8.23-8.25 (m, 2H), 7.89 (d, 1H, J=1.5 Hz), 7.02 (d, 1H, J=1.5 Hz), 6.78 (s, 1H), 6.55-6.70 (m, 3H), 5.94 (brs, 2H), 4.40-4.51 (m, 1H), 3.86 (s, 3H), 3.73-3.85 (m, 2H), 3.50-3.65 (m, 2H), 2.40-2.50 (m, 5H), 2.00-2.12 (m, 2H), 1.40- 1.55 (m, 2H), 1.02-1.10 (m, 3H). EXAMPLE 136 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4-(oxetan-3- ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidine

Step 1: Synthesis of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-(oxetan-3- ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (200 mg, 393 μmol) and oxetan-3-amine (35 mg, 473 μmol) in N,N-dimethylacetamide (2 mL) was added N,N-diisopropylethylamine (102 mg, 788 μmol). After stirring at 90°C for 2 hours, the reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 150 mg, 69%. LCMS (ESI) m/z: 546.0 (M+H). Step 2: Synthesis of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-6-(6-me thoxy-4-methyl- 3-pyridyl)-4-(oxetan-3-ylamino)pyrrolo[1,2-b]pyridazine-3-ca rboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-(oxetan-3- ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidine (140 mg, 257 μmol), (6-methoxy-4-methyl-3- pyridyl)boronic acid (64 mg, 385 μmol) and potassium phosphate (109 mg, 514.18 μmol) in N,N- dimethylformamide (5 mL) and water (0.5 mL) was added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (17 mg, 25 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purified via silica gel column chromatography (ethyl acetate/ petroleum ether) afforded the title compound as a yellow oil. Yield: 90 mg, 59%. LCMS (ESI) m/z: 587.3 (M+H). Step 3: Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4-(oxetan- 3-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-6-(6-me thoxy-4-methyl-3- pyridyl)-4-(oxetan-3-ylamino)pyrrolo[1,2-b]pyridazine-3-carb oxamidine (80 mg, 136 μmol) in N,N-dimethylformamide (2 mL) was added cesium fluoride (207 mg, 1.3 mmol). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4- methyl-3-pyridyl)-4-(oxetan-3-ylamino)pyrrolo[1,2-b]pyridazi ne-3-carboxamidine as an off- white solid. Yield: 27.5 mg, 41%. LCMS (ESI) m/z: 473.0 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.98 (d, 1H, J=5.6 Hz), 8.97 (s, 1H), 8.22-8.28 (m, 2H), 7.92 (d, 1H, J=2.0 Hz), 6.76- 6.84 (m, 2H), 6.65-6.73 (m, 2H), 6.60-6.62 (m, 1H), 6.03 (s, 2H), 5.37-5.42 (m, 1H), 5.02 (t, 2H, J=6.4 Hz), 4.39-4.45 (m, 2H), 3.87 (s, 3H), 2.40-2.48 (m, 5H), 1.11 (t, 3H, J=7.6 Hz). EXAMPLE 137 Synthesis of N'-(2-chloro-5-fluorophenyl)-6-(6-methoxy-4-methylpyridin-3- yl)-4-[[[1-(2,2,2- trifluoroethyl)piperidin-4-yl]methyl]amino]pyrrolo[1,2-b]pyr idazine-3-carboximidamide

Step 1: Synthesis of tert-butyl N-[[1-(2,2,2-trifluoroethyl)-4-piperidyl]methyl]carbamate To a solution of tert-butyl N-(4-piperidylmethyl)carbamate (1.00 g, 4.67 mmol) and 1,1,1- trifluoro-2-iodo-ethane (1.08 g, 5.13 mmol) in N,N-dimethylformamide (5.0 mL) was added potassium carbonate (1.93 g, 14.00 mmol). After stirring at 90 °C for 7 hours, the reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate and concentrated under vacuum. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a colorless oil. Yield: 0.80 g, 57%. LCMS (ESI) m/z: 296.9 (M+H). Step 2: Synthesis of [1-(2,2,2-trifluoroethyl)-4-piperidyl]methanamine trifluoroacetic acid salt To a solution of tert-butyl N-[[1-(2,2,2-trifluoroethyl)-4-piperidyl]methyl]carbamate (0.80 g, 2.70 mmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (1.0 mL) dropwise. The reaction mixture was stirred at 25 °C for an hour and concentrated under reduced pressure to give the title compound as a yellow oil. Yield: 0.60 g, 71%. LCMS (ESI) m/z: 197.0 (M+H). Step 3: Synthesis of 6-bromo-N'-(2-chloro-5-fluorophenyl)-4-[[[1-(2,2,2-trifluoro ethyl)piperidin- 4-yl]methyl]amino]pyrrolo[1,2-b]pyridazine-3-carboximidamide To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (200 mg, 497.4 μmol) and [1-(2,2,2-trifluoroethyl)-4-piperidyl]methanamine trifluoroacetic acid salt (195 mg, 629.2 μmol) in N,N-dimethylacetamide (4.0 mL) were added N,N-diisopropylethylamine (321.4 mg, 2.49 mmol) dropwise and sodium iodide (223 mg, 1.49 mmol). The reaction was stirred at 90 °C for 3 hours and then cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 160 mg, 57%. LCMS (ESI) m/z: 563.1 (M+H). Step 4: Synthesis of N'-(2-chloro-5-fluorophenyl)-6-(6-methoxy-4-methylpyridin-3- yl)-4-[[[1- (2,2,2-trifluoroethyl)piperidin-4-yl]methyl]amino]pyrrolo[1, 2-b]pyridazine-3-carboximidamide To a solution of 6-bromo-N'-(2-chloro-5-fluorophenyl)-4-[[[1-(2,2,2-trifluoro ethyl)piperidin-4- yl]methyl]amino]pyrrolo[1,2-b]pyridazine-3-carboximidamide (160 mg, 284.8 μmol) and (6- methoxy-4-methyl-3-pyridyl)boronic acid (95 mg, 569.6 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (18 mg, 28.4 μmol) and potassium carbonate (118 mg, 854.4 μmol). The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 70 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded N'-(2-chloro-5- fluorophenyl)-6-(6-methoxy-4-methylpyridin-3-yl)-4-[[[1-(2,2 ,2-trifluoroethyl)piperidin-4- yl]methyl]amino]pyrrolo[1,2-b]pyridazine-3-carboximidamide as an off-white solid. Yield: 81.3 mg, 46%. LCMS (ESI) m/z: 602.2 (M-H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.39 (s, 1H), 8.24 (s, 1H), 8.23 (s, 1H), 7.91 (s, 1H), 7.47-7.51 (m, 1H), 7.09 (s, 1H), 6.83-6.93 (m, 2H), 6.78 (s, 1H), 6.59 (s, 2H), 3.87 (s, 3H), 3.71 (t, 2H, J=5.6 Hz), 3.08 (q, 2H, J=10.4 Hz), 2.86-2.89 (m, 2H), 2.41 (s, 3H), 2.22-2.28 (m, 2H), 1.60-1.77 (m, 3H), 1.21-1.33 (m, 2H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -68.07 (s, 3F), -114.46 (s, 1F). EXAMPLE 138 Synthesis of N'-(2-chloro-5-fluorophenyl)-4-[[[1-(cyclopropylmethyl)piper idin-4- yl]methyl]amino]-6-(6-methoxy-4-methylpyridin-3-yl)pyrrolo[1 ,2-b]pyridazine-3- carboximidamide

Step 1: Synthesis of tert-butyl N-[[1-(cyclopropylmethyl)-4-piperidyl]methyl]carbamate To a solution of tert-butyl N-(4-piperidylmethyl)carbamate (1.00 g, 4.67 mmol), bromomethylcyclopropane (629 mg, 4.67 mmol) in N,N-dimethylformamide (5.0 mL) was added potassium carbonate (1.93 g, 14.00 mmol). After stirring at 90 °C for 7 hours, the reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a colorless oil. Yield: 600 mg, 47 %. LCMS (ESI) m/z: 269.0 (M+H). Step 2: Synthesis of [1-(cyclopropylmethyl)-4-piperidyl]methanamine hydrochloric acid salt The solution of tert-butyl N-[[1-(cyclopropylmethyl)-4-piperidyl]methyl]carbamate (700 mg, 2.61 mmol) in 4 M hydrogen chloride in 1,4-dioxane (5.0 mL) was stirred at 25 °C for 5 hours. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow solid. Yield: 300 mg, 56%. LCMS (ESI, pos. ion) m/z: 169.0 (M+H). Step 3: Synthesis of 6-bromo-N'-(2-chloro-5-fluorophenyl)-4-[[[1-(cyclopropylmeth yl)piperidin- 4-yl]methyl]amino]pyrrolo[1,2-b]pyridazine-3-carboximidamide To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (150 mg, 373.0 μmol) and [1-(cyclopropylmethyl)-4-piperidyl]methanamine hydrochloric acid salt (229 mg, 1.12 mmol) in N,N-dimethylformamide (2.0 mL) was added N,N- diisopropylethylamine (241 mg, 1.87 mmol) dropwise. After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 110 mg, 55%. LCMS (ESI) m/z: 535.0 (M+H). Step 4: Synthesis of N'-(2-chloro-5-fluorophenyl)-4-[[[1-(cyclopropylmethyl)piper idin-4- yl]methyl]amino]-6-(6-methoxy-4-methylpyridin-3-yl)pyrrolo[1 ,2-b]pyridazine-3- carboximidamide To a mixture of 6-bromo-N'-(2-chloro-5-fluorophenyl)-4-[[[1-(cyclopropylmeth yl)piperidin-4- yl]methyl]amino]pyrrolo[1,2-b]pyridazine-3-carboximidamide (130 mg, 243.5 μmol) and (6- methoxy-4-methyl-3-pyridyl)boronic acid (81 mg, 487.0 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (15 mg, 24.3 μmol) and potassium carbonate (100 mg, 730.5 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 70 °C for 2 hours. After cooled to room temperature, the reaction mixture was diluted with ethyl acetated and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded N'-(2-chloro-5- fluorophenyl)-4-[[[1-(cyclopropylmethyl)piperidin-4-yl]methy l]amino]-6-(6-methoxy-4- methylpyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboximidamid e as an off-white solid. Yield: 30.9 mg, 21%. LCMS (ESI) m/z: 574.3 (M-H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.37 (s, 1H), 8.24 (s, 1H), 8.22 (s, 1H), 7.89 (s, 1H), 7.47-7.51 (m, 1H), 7.08 (s, 1H), 6.84-6.91 (m, 2H), 6.78 (s, 1H), 6.59 (s, 2H), 3.87 (s, 3H), 3.70 (t, 2H, J=6.0 Hz), 2.90-2.93 (m, 2H), 2.41 (s, 3H), 2.06- 2.12 (m, 2H), 1.75-1.85 (m, 4H), 1.60-1.69 (m, 1H), 1.26-1.33 (m, 2H), 0.75-0.78 (m, 1H), 0.38- 0.44 (m, 2H), 0.01-0.05 (m, 2H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.47 (s, 1F). EXAMPLE 139 Synthesis of N'-(2-chloro-5-fluoro-phenyl)-4-[[(2,2-dimethyl-4-piperidyl) methyl]amino]-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine

Step 1: Synthesis of tert-butyl 4-cyano-2,2-dimethylpiperidine-1-carboxylate To a solution of 1-(isocyanomethylsulfonyl)-4-methyl-benzene (472.42 mg, 2.42 mmol) in 1,2- dimethoxyethane (2 mL) was added potassium 2-methylpropan-2-olate (370 mg, 3.3 mmol), followed by addition of tert-butyl 2,2-dimethyl-4-oxo-piperidine-1-carboxylate (500 mg, 2.2 mmol). After stirring at 40 °C for 16 hours, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 310 mg, 59%. Step 2: Synthesis of tert-butyl 4-(aminomethyl)-2,2-dimethylpiperidine-1-carboxylate To a solution of tert-butyl 4-cyano-2,2-dimethylpiperidine-1-carboxylate (310 mg, 1.3 mmol) in tetrahydrofuran (2 mL) was added lithium aluminum hydride (197 mg, 5.2 mmol) at 0 °C. After stirring at 25 °C for 4 hours, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afforded the title compound as a yellow oil. Yield: 220 mg, 69%.1H NMR (Chloroform-d, 400 MHz) δ 3.66- 3.76 (m, 1H), 3.12-3.22 (m, 1H), 2.57 (d, 2H, J=6.8 Hz), 1.76-1.88 (m, 1H), 1.61-1.73 (m, 1H), 1.51 (s, 3H), 1.47 (s, 9H), 1.22-1.34 (m, 5H), 1.08-1.18 (m, 1H). Step 3: Synthesis of tert-butyl 4-[[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]meth yl]-2,2-dimethyl-piperidine-1- carboxylate To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (150 mg, 373 μmol) and tert-butyl 4-(aminomethyl)-2,2-dimethylpiperidine-1- carboxylate (117 mg, 485 μmol) in N,N-dimethylacetamide (5 mL) was added N,N- diisopropylethylamine (97 mg, 746 μmol). After stirring at 70 °C for 16 hours, the reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 160 mg, 70 %. LCMS (ESI) m/z: 608.9 (M+H). Step 4: Synthesis of tert-butyl 4-[[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amin o]methyl]-2,2-dimethyl- piperidine-1-carboxylate To a solution of tert-butyl 4-[[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]meth yl]-2,2-dimethyl-piperidine-1- carboxylate (150 mg, 246 μmol), (6-methoxy-4-methyl-3-pyridyl)boronic acid (50 mg, 296 μmol) and potassium phosphate (157 mg, 740 μmol) in N,N-dimethylformamide (2 mL) and water (0.2 mL) was added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (32 mg, 49 μmol). The resulting mixture was purged with nitrogen gas and stirred at 90 °C for 2 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 80 mg, 50%. LCMS (ESI) m/z 650.1 (M+H). Step 5: Synthesis of N'-(2-chloro-5-fluoro-phenyl)-4-[[(2,2-dimethyl-4-piperidyl) methyl]amino]- 6-(6-methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-c arboxamidine To a solution of tert-butyl 4-[[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6-(6-met hoxy-4- methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]methyl]- 2,2-dimethyl-piperidine-1- carboxylate (70 mg, 107 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded N'-(2-chloro-5-fluoro-phenyl)-4- [[(2,2-dimethyl-4-piperidyl)methyl]amino]-6-(6-methoxy-4-met hyl-3-pyridyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine as a yellow solid. Yield: 48.3 mg, 80%. LCMS (ESI) m/z: 550.1 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.52 (d, 1H, J=5.2 Hz), 8.25 (d, 2H, J=2.4 Hz), 7.90 (s, 1H), 7.47-7.54 (m, 1H), 7.10 (d, 1H, J=2.0 Hz), 6.85-6.94 (m, 2H), 6.78 (s, 1H), 6.60 (s, 2H), 3.86 (s, 3H), 3.59-3.74 (m, 2H), 2.75-2.92 (m, 2H), 2.41 (s, 3H), 1.92-2.08 (m, 1H), 1.73-1.81 (m, 2H), 1.02-1.24 (m, 5H), 0.94 (s, 3H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.58 (s, 1F). EXAMPLE 140 Synthesis of N'-(2-chloro-5-fluoro-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4-[[1-methyl-1-(4- piperidyl)ethyl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidi ne Step 1: Synthesis of tert-butyl 4-[1-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]-1-m ethyl-ethyl]piperidine-1- carboxylate To a solution of 6-bromo-4-chloro-N'-(2-chloro-5-fluoro-phenyl)pyrrolo[1,2-b] pyridazine-3- carboxamidine (150 mg, 373 μmol) in N,N-dimethylacetamide (1.5 mL) were added tert-butyl 4- (1-amino-1-methyl-ethyl)piperidine-1-carboxylate (271 mg, 1.1 mmol) and N,N- diisopropylethylamine (145 mg, 1.1 mmol). After stirring at 120 °C for 2 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 150 mg, 65%. LCMS (ESI) m/z: 609.3 (M+H). Step 2: Synthesis of tert-butyl 4-[1-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amin o]-1-methyl-ethyl]piperidine-1- carboxylate To a solution of tert-butyl 4-[1-[[6-bromo-3-[N'-(2-chloro-5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]-1-m ethyl-ethyl]piperidine-1- carboxylate (140 mg, 230 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (39 mg, 230 μmol) in N,N-dimethylformamide (2 mL) and water (0.2 mL) were added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (150 mg, 230 μmol) and potassium phosphate (49 mg, 230 μmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 120 mg, 79%. LCMS (ESI) m/z: 651.1 (M+H). Step 3: Synthesis of N'-(2-chloro-5-fluoro-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4-[[1- methyl-1-(4-piperidyl)ethyl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine To a solution of tert-butyl 4-[1-[[3-[N'-(2-chloro-5-fluoro-phenyl)carbamimidoyl]-6-(6-m ethoxy- 4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]-1-met hyl-ethyl]piperidine-1-carboxylate (110 mg, 169 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded N'-(2-chloro-5-fluoro-phenyl)-6- (6-methoxy-4-methyl-3-pyridyl)-4-[[1-methyl-1-(4-piperidyl)e thyl]amino]pyrrolo[1,2- b]pyridazine-3-carboxamidine as a white solid. Yield: 15.5 mg, 16%. LCMS (ESI) m/z: 550.4 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.73 (s, 1H), 8.22 (d, 2H, J=2.4 Hz), 7.91 (d, 1H, J=1.6 Hz), 7.47-7.51 (m, 1H), 7.03 (d, 1H, J=2.0 Hz), 6.87-6.91 (m, 2H), 6.80 (s, 1H), 6.52 (s, 2H), 3.87 (s, 3H), 2.82-2.96 (m, 2H), 2.44 (s, 3H), 2.17-2.24 (m, 2H), 2.04-2.11 (m, 1H), 1.64- 1.72 (m, 2H), 1.45 (s, 6H), 1.13-1.20 (m, 2H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -114.67 (s, 1F). EXAMPLE 141 Synthesis of 4-[[(1R)-2,2-dimethylcyclopentyl]amino]-N'-(2-ethyl-4-hydrox y-phenyl)-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine and 4-[[(1S)-2,2-dimethylcyclopentyl]amino]-N'-(2-ethyl-4-hydrox y-phenyl)-6-(6-methoxy-4- methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[(2,2- dimethylcyclopentyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxa midine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (300 mg, 590.6 μmol) and 2,2- dimethylcyclopentanamine (133 mg, 1.18 mmol) in N,N-dimethylacetamide (2.0 mL) were added N,N-diisopropylethylamine (229 mg, 1.77 mmol) dropwise and sodium iodide (44 mg, 295.3 μmol). After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetated. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 220 mg, 63%. LCMS (ESI) m/z: 586.2 (M+H). Step 2: Synthesis of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-[(2,2 - dimethylcyclopentyl)amino]-6-(6-methoxy-4-methyl-3-pyridyl)p yrrolo[1,2-b]pyridazine-3- carboxamidine To a mixture of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[(2,2- dimethylcyclopentyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxa midine (200 mg, 342.0 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (85 mg, 513.1 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (22 mg, 34.2 μmol) and potassium phosphate (217 mg, 1.03 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was heated at 80 °C for 2 hr. After cooled to room temperature, the reaction mixture was diluted with ethyl acetated and washed with saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 130 mg, 24%. LCMS (ESI) m/z: 627.4 (M+H). Step 3: Synthesis of 4-[[(1R)-2,2-dimethylcyclopentyl]amino]-N'-(2-ethyl-4-hydrox y-phenyl)-6- (6-methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-car boxamidine and 4-[[(1S)-2,2- dimethylcyclopentyl]amino]-N'-(2-ethyl-4-hydroxy-phenyl)-6-( 6-methoxy-4-methyl-3- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-[(2,2 - dimethylcyclopentyl)amino]-6-(6-methoxy-4-methyl-3-pyridyl)p yrrolo[1,2-b]pyridazine-3- carboxamidine (130 mg, 207.37 μmol) in N,N-dimethylformamide (3.0 mL) was added cesium fluoride (94.50 mg, 622.10 μmol). The reaction mixture was stirred at 25 °C for 2 hours. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) followed with prep-chiral-HPLC (ethanol/n-hexane buffered with 0.5% 2M ammonia methanol) afforded two fractions: Fraction 1: 4-[[(1R)-2,2-dimethylcyclopentyl]amino]-N'-(2-ethyl-4-hydrox y-phenyl)-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine as an off-white solid. Yield: 14.0 mg, 12%. LCMS (ESI) m/z: 513.4 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.49 (d, 1H, J=8.4 Hz), 8.92 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H), 7.85 (s, 1H), 7.06 (s, 1H), 6.78 (s, 1H), 6.65-6.67 (m, 1H), 6.58-6.60 (m, 2H), 5.84 (s, 2H), 4.22-4.28 (m, 1H), 3.87 (s, 3H), 2.38-2.49 (m, 6H), 1.49-1.74 (m, 5H), 1.06-1.10 (m, 6H), 0.94 (s, 3H). Fraction 2: 4-[[(1S)-2,2-dimethylcyclopentyl]amino]-N'-(2-ethyl-4-hydrox y-phenyl)-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine as an off-white solid. Yield: 12.5 mg, 11%. LCMS (ESI) m/z: 513.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.49 (d, 1H, J=8.4 Hz), 8.92 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H), 7.85 (s, 1H), 7.06 (s, 1H), 6.78 (s, 1H), 6.65-6.67 (m, 1H), 6.58-6.60 (m, 2H), 5.84 (s, 2H), 4.23-4.27 (m, 1H), 3.87 (s, 3H), 2.29-2.45 (m, 6H), 1.54-1.74 (m, 5H), 1.01-1.10 (m, 6H), 0.94 (s, 3H). EXAMPLE 142 Synthesis of 4-[(1-acetyl-4-piperidyl)amino]-N'-(2-ethyl-4-hydroxy-phenyl )-6-(6-methoxy-4- methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of tert-butyl N-(1-acetyl-4-piperidyl)carbamate To a solution of tert-butyl N-(4-piperidyl)carbamate (400 mg, 2.00 mmol) and triethylamine (606 mg, 5.99 mmol) in dichloromethane (3.0 mL) was added acetyl chloride (235 mg, 3.00 mmol) dropwise. The reaction mixture was stirred at 25 °C for an hour, poured into water and extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate and concentrated under reduced pressure afforded the title compound as a yellow oil. Yield: 350 mg, 72%. LCMS (ESI) m/z: 241.0 (M-H). Step 2: Synthesis of 1-(4-amino-1-piperidyl)ethanone hydrochloric acid salt The solution of tert-butyl N-(1-acetyl-4-piperidyl)carbamate (350 mg, 1.44 mmol) in 4 M hydrogen chloride in dioxane (3.0 mL) was stirred at 25 °C for an hour. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow solid. Yield: 250 mg, 96%. LCMS (ESI) m/z: 143.0 (M+H). Step 3: Synthesis of 4-[(1-acetyl-4-piperidyl)amino]-6-bromo-N'-[4-[tert- butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]pyrrolo[1,2-b]pyrida zine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (150 mg, 295.3 μmol) and 1-(4-amino-1- piperidyl)ethanone hydrochloric acid salt (83 mg, 590.6 μmol) in n-butanol (1.0 mL) were added N,N-diisopropylethylamine (114.5 mg, 885.9 μmol) dropwise and sodium iodide (132.8 mg, 885.9 μmol). The reaction mixture was stirred at 110 °C for 8 hours. After cooled to room temperature, the reaction mixture was diluted with ethyl acetated and washed with saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 130 mg, 71%. LCMS (ESI) m/z: 615.3 (M+H). Step 4: Synthesis of 4-[(1-acetyl-4-piperidyl)amino]-N'-(2-ethyl-4-hydroxy-phenyl )-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine To a mixture of 4-[(1-acetyl-4-piperidyl)amino]-6-bromo-N'-[4-[tert-butyl(di methyl)silyl]oxy-2- ethyl-phenyl]pyrrolo[1,2-b]pyridazine-3-carboxamidine (115 mg, 187.4 μmol) and (6-methoxy- 4-methyl-3-pyridyl)boronic acid (93 mg, 562.2 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (12 mg, 18.7 μmol) and potassium phosphate (119 mg, 562.2 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 95 °C for 2 hours. After cooled to room temperature, the reaction mixture was diluted with ethyl acetated and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 4-[(1-acetyl-4- piperidyl)amino]-N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy- 4-methyl-3-pyridyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine as an off-white solid. Yield: 48.1 mg, 45%. LCMS (ESI) m/z: 542.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.51 (d, 1H, J=8.0 Hz), 8.96 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 7.90 (s, 1H), 7.06 (s, 1H), 6.79 (s, 1H), 6.67 (s, 1H), 6.56-6.63 (m, 2H), 5.94 (s, 2H), 4.48-4.53 (m, 1H), 3.94-3.98 (m, 1H), 3.87 (s, 3H), 3.62-3.68 (m, 1H), 3.32-3.40 (m, 1H), 3.09-3.16 (m, 1H), 2.37-2.48 (m, 5H), 2.02-2.10 (m, 2H), 1.98 (s, 3H), 1,41-1.55 (m, 1H), 1.32- 1.40 (m, 1H), 1.05 (t, 3H, J=7.6 Hz). EXAMPLE 143 Synthesis of 4-[[1-(cyclopropanecarbonyl)-4-piperidyl]amino]-N'-(2-ethyl- 4-hydroxy-phenyl)-6- (6-methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-car boxamidine Step 1: Synthesis of tert-butyl N-[1-(cyclopropanecarbonyl)-4-piperidyl]carbamate To a solution of tert-butyl N-(4-piperidyl)carbamate (400 mg, 2.00 mmol) and triethylamine (606 mg, 5.99 mmol) in dichloromethane (10.0 mL) was added cyclopropanecarbonyl chloride (250 mg, 2.40 mmol) dropwise at 0°C under nitrogen atmosphere. After stirring at 25 °C for an hour, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 1N aqueous solution of hydrochloric acid, saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a yellow oil, which was used for next step without further purification. Yield: 320 mg, 59%. ¹ H NMR (DMSO-d6, 400 MHz) δ 6.87 (d, 1H, J=8.0 Hz), 4.12-4.21 (m, 2H), 3.45-3.53 (m, 1H), 3.10-3.16 (m, 1H), 2.64-2.69 (m, 1H), 1.92- 1.98 (m, 1H), 1.66-1.80 (m, 2H), 1.38 (s, 9H), 0.97-1.30 (m, 3H), 0.65-0.70 (m, 4H). Step 2: Synthesis of (4-amino-1-piperidyl)-cyclopropyl-methanone trifluoroacetic acid salt To a solution of tert-butyl N-[1-(cyclopropanecarbonyl)-4-piperidyl]carbamate (320 mg, 1.19 mmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (2.0 mL) dropwise. After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane and concentrated under reduced pressure to give the title compound as a yellow oil, which was used next step without further purification. Yield: 300 mg, 89%. LCMS (ESI) m/z: 169.0 (M+H). Step 3: Synthesis of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[1- (cyclopropanecarbonyl)-4-piperidyl]amino]pyrrolo[1,2-b]pyrid azine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (150 mg, 295.3 μmol) and (4-amino-1-piperidyl)- cyclopropyl-methanone trifluoroacetic acid salt (250 mg, 885.9 μmol) in N,N-dimethylacetamide (2.0 mL) were added N,N-diisopropylethylamine (190 mg, 1.48 mmol) and sodium iodide (132 mg, 885.9 μmol). After stirring at 90 °C for 3 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 120 mg, 63%. LCMS (ESI) m/z: 639.3 (M+H). Step 4: Synthesis of 4-[[1-(cyclopropanecarbonyl)-4-piperidyl]amino]-N'-(2-ethyl- 4-hydroxy- phenyl)-6-(6-methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyrida zine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[1- (cyclopropanecarbonyl)-4-piperidyl]amino]pyrrolo[1,2-b]pyrid azine-3-carboxamidine (110 mg, 171.9 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (57 mg, 343.9 μmol) in N,N- dimethylformamide (2.0 mL) and water (0.2 mL) were added 1,1'-bis (di-t- butylphosphino)ferrocene palladium dichloride (11 mg, 17.2 μmol) and potassium carbonate (71 mg, 515.8 μmol). The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 80 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solids were filtered out and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 4-[[1-(cyclopropanecarbonyl)-4- piperidyl]amino]-N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy- 4-methyl-3-pyridyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine as an off-white solid. Yield: 19.9 mg, 20%. LCMS (ESI) m/z: 568.4 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.52 (d, 1H, J=8.0 Hz), 8.95 (s, 1H), 8.27 (s, 1H), 8.25 (s, 1H), 7.90 (s, 1H), 7.07 (s, 1H), 6.79 (s, 1H), 6.58-6.68 (m, 3H), 5.94 (s, 2H), 4.50- 4.60 (m, 1H), 3.90-4.05 (m, 2H), 3.86 (s, 3H), 3.48-3.60 (m, 1H), 3.14-3.22 (m, 1H), 2.36-2.44 (m, 5H), 1.90-2.20 (m, 3H), 1.30-1.55 (m, 2H), 1.05 (t, 3H, J=7.6 Hz), 0.60-0.68 (m, 4H). EXAMPLE 144 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4-[(1-methyl-4- piperidyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt Step 1: Synthesis of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[(1-methyl- 4-piperidyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (200 mg, 393 μmol) and 1-methylpiperidin-4-amine (68 mg, 595 μmol) in N,N-dimethylacetamide (3 mL) was added N,N-diisopropylethylamine (1 mL) at room temperature. After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature and then concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 200 mg, 86%. LCMS (ESI) m/z: 587.0 (M+H). Step 2: Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4-[(1- methyl-4-piperidyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxam idine formic acid salt To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[(1-methyl-4- piperidyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine (180 mg, 307 μmol) and (6-methoxy- 4-methylpyridin-3-yl)boronic acid (103 mg, 616 μmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (21 mg, 31 μmol) and potassium carbonate (85 mg, 615 μmol) at room temperature. The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4-[(1-methyl-4- piperidyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt as a yellow solid. Yield: 20.5 mg, 11%. LCMS (ESI) m/z: 514.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.41 (s, 1H), 8.22-8.24 (m, 2H), 8.19 (s, 1H), 7.88 (d, 1H, J=1.6 Hz), 6.97 (d, 1H, J=2.0 Hz), 6.78 (s, 1H), 6.56-6.71 (m, 3H), 5.94 (s, 2H), 4.25-4.29 (m, 1H), 3.86 (s, 3H), 2.58-2.66 (m, 2H), 2.41- 2.49 (m, 5H), 2.28-2.38 (m, 2H), 2.16 (s, 3H), 2.01-2.09 (m, 2H), 1.55-1.64 (m, 2H), 1.09 (t, 3H, J=7.6 Hz). EXAMPLE 145 Synthesis of 4-[[[(1R,2R)-1-(cyclopropanecarbonyl)pyrrolidin-2-yl]methyl] amino]-N'-(2-ethyl-4- hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine Step 1: Synthesis of tert-butyl N-[[(R)-1-(cyclopropanecarbonyl)pyrrolidin-2- yl]methyl]carbamate To a solution of tert-butyl N-[[(R)-pyrrolidin-2-yl]methyl]carbamate (300 mg, 1.50 mmol) and triethylamine (455 mg, 4.49 mmol) in dichloromethane (10.0 mL) was added cyclopropanecarbonyl chloride (235 mg, 2.25 mmol). After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure to afford the title compound as a white solid, which was used for next step directly without further purification. Yield: 350 mg. LCMS (ESI) m/z: 269.0 (M+H). Step 2: Synthesis of [(R)-2-(aminomethyl)pyrrolidin-1-yl]-cyclopropyl-methanone To a solution of tert-butyl N-[[(R)-1-(cyclopropanecarbonyl)pyrrolidin-2-yl]methyl]carba mate (330 mg, 1.23 mmol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (3.0 mL). After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and adjusted to pH=9 with 1N aqueous solution of sodium hydroxide and extracted with dichloromethane three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 180 mg, 87%. LCMS (ESI) m/z: 169.0 (M+H) Step 3: Synthesis of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[[(R)-1- (cyclopropanecarbonyl)pyrrolidin-2-yl]methyl]amino]pyrrolo[1 ,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (150 mg, 295.3 μmol) in N,N-dimethylacetamide (5.0 mL) were added [(1R,2R)-2-(aminomethyl)pyrrolidin-1-yl]-cyclopropyl-methano ne (75 mg, 443.0 μmol) and N,N-diisopropylethylamine (115 mg, 886.0 μmol). The resulting mixture was stirred at 85 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 160 mg, 84%. LCMS (ESI) m/z: 641.5 (M+H). Step 4: Synthesis of 4-[[[(R)-1-(cyclopropanecarbonyl)pyrrolidin-2-yl]methyl]amin o]-N'-[4-[1,1- dimethylethyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-6-(6-methox y-4-methyl-3-pyridyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[[(R)-1- (cyclopropanecarbonyl)pyrrolidin-2-yl]methyl]amino]pyrrolo[1 ,2-b]pyridazine-3-carboxamidine (150 mg, 234.4 μmol) in N,N-dimethylformamide (5.0 mL) and water (0.5 mL) were added (6- methoxy-4-methyl-3-pyridyl)boronic acid (98 mg, 586.2 μmol), 1,1'-bis (di-t- butylphosphino)ferrocene-palladium dichloride (15 mg, 23.5 μmol) and potassium phosphate (100 mg, 469.0 μmol). The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a brown solid, which was used for next step directly without further purification. Yield: 160 mg. LCMS (ESI) m/z: 682.6 (M+H). Step 5: Synthesis of 4-[[[(R)-1-(cyclopropanecarbonyl)pyrrolidin-2-yl]methyl]amin o]-N'-(2- ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridyl)pyrr olo[1,2-b]pyridazine-3- carboxamidine To a solution of 4-[[[(R)-1-(cyclopropanecarbonyl)pyrrolidin-2-yl]methyl]amin o]-N'-[4-[1,1- dimethylethyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-6-(6-methox y-4-methyl-3-pyridyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine (150 mg, 220.0 μmol) in N,N-dimethylformamide (5.0 mL) was added caesium fluoride (100 mg, 659.9 μmol). After stirring at 25 °C for 2 hours, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[[[(R)-1-(cyclopropanecarbonyl)pyrrolidin-2- yl]methyl]amino]-N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy- 4-methyl-3-pyridyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine as a yellow solid. Yield: 13.9 mg, 10%. LCMS (ESI) m/z: 568.1 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.30 (s, 1H), 8.94 (s, 1H), 8.22-8.24 (m, 2H), 7.86 (s, 1H), 7.53 (s, 1H), 6.55-6.81 (m, 4H), 5.91 (s, 2H), 4.00-4.50 (m, 2H), 3.86 (s, 3H), 3.50-3.70 (m, 3H), 2.33-2.45 (m, 5H), 1.76-2.02 (m.4H), 1.60-1.70 (m, 1H), 1.03-1.21 (m.3H), 0.60-0.80 (m, 4H). EXAMPLE 146 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4-[[[(R)- pyrrolidin-2-yl]methyl]amino]pyrrolo[1,2-b]pyridazine-3-carb oxamidine

Step 1: Synthesis of tert-butyl (R)-2-[[[6-bromo-3-[N'-[4-[1,1-dimethylethyl(dimethyl)silyl] oxy- 2-ethyl-phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]am ino]methyl]pyrrolidine-1- carboxylate To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (6.00 g, 11.81 mmol) and tert-butyl (1R,2R)-2- (aminomethyl)pyrrolidine-1-carboxylate (7.10 g, 35.44 mmol) in N,N-dimethylacetamide (50 mL) was added N,N-diisopropylethylamine (7.63 g, 59.06 mmol). After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrated was concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. LCMS (ESI) m/z: 673.3 (M+H). Step 2: Synthesis of tert-butyl (R)-2-[[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-6-(6 - methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amin o]methyl]pyrrolidine-1- carboxylate To a solution of tert-butyl (R)-2-[[[6-bromo-3-[N'-[4-[1,1-dimethylethyl(dimethyl)silyl] oxy-2- ethyl-phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amin o]methyl]pyrrolidine-1- carboxylate (10.00 g, 10.87 mmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (3.63 g, 21.73 mmol) in N,N-dimethylformamide (100 mL) and water (10 mL) were added 1,1'-bis (di-t- butylphosphino)ferrocene palladium dichloride (708 mg, 1.09 mmol) and potassium phosphate (6.92 g, 32.60 mmol). The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 80 °C for 2 hours, the reaction mixture was cooled to room temperature and then cesium fluoride (4.95 g, 32.60 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrated was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. LCMS (ESI) m/z: 600.5 (M+H). Step 3: Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4-[[[(R)- pyrrolidin-2-yl]methyl]amino]pyrrolo[1,2-b]pyridazine-3-carb oxamidine To a solution of tert-butyl (R)-2-[[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-6-(6 - methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amin o]methyl]pyrrolidine-1- carboxylate (7.80 g, 13.01 mmol) in dichloromethane (70 mL) was added trifluoroacetic acid (50 mL) dropwise at 0°C. After stirring at 25°C for an hour, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The resulting mixture was washed with saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with acetonitrile three times to afford N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3- pyridyl)-4-[[[(R)-pyrrolidin-2-yl]methyl]amino]pyrrolo[1,2-b ]pyridazine-3-carboxamidine as an off-white solid. Yield: 4.57 g, 68%. LCMS (ESI) m/z: 500.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz,) δ 12.20 (br s, 1H), 8.94 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H), 7.86 (d, 1H, J=1.6 Hz), 7.08 (d, 1H, J=1.6 Hz), 6.77 (s, 1H), 6.57-6.65 (m, 3H), 5.82 (br s, 2H), 3.86 (s, 3H), 3.68-3.82 (m, 2H), 3.30-3.50 (m, 1H), 2.65-2.75 (m, 2H), 2.40-2.50 (m, 5H), 1.70-1.85 (m, 1H), 1.40-1.69 (m, 3H), 1.06 (t, 3H, J=7.6 Hz). EXAMPLE 147 Synthesis of 4-[[[(S)-1-(cyclopropanecarbonyl)pyrrolidin-2-yl]methyl]amin o]-N'-(2-ethyl-4- hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine

Step 1: Synthesis of tert-butyl N-[[(S)-1-(cyclopropanecarbonyl)pyrrolidin-2- yl]methyl]carbamate To a solution of tert-butyl N-[[(S)-pyrrolidin-2-yl]methyl]carbamate (300 mg, 1.5 mmol) in dichloromethane (5 mL) was added triethylamine (455 mg, 4.5 mmol), followed by addition of cyclopropanecarbonyl chloride (188 mg, 1.8 mmol). After stirring at room temperature for an hour, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 340 mg, 85%. Step 2: Synthesis of [(S)-2-(aminomethyl)pyrrolidin-1-yl]-cyclopropyl-methanone To a solution of tert-butyl N-[[(S)-1-(cyclopropanecarbonyl)pyrrolidin-2-yl]methyl]carba mate (340 mg, 1.3 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and dichloromethane and then basified with 2N aqueous solution of sodium hydroxide. The aqueous phase was extracted with dichloromethane twice. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 190 mg, 89%. LCMS (ESI) m/z: 169.2 (M+H). Step 3: Synthesis of 6-bromo-4-[[[(S)-1-(cyclopropanecarbonyl)pyrrolidin-2-yl]met hyl]amino]- N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]pyrrolo[ 1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (120 mg, 236 μmol) and [(2S)-2- (aminomethyl)pyrrolidin-1-yl]-cyclopropyl-methanone (48 mg, 284 μmol) in N,N- dimethylacetamide (2 mL) was added N,N-diisopropylethylamine (92 mg, 709 μmol). After stirring at 85 °C for 2 hours, the reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 120 mg, 80%. LCMS (ESI) m/z: 641.0 (M+H). Step 4: Synthesis of 4-[[[(S)-1-(cyclopropanecarbonyl)pyrrolidin-2-yl]methyl]amin o]-N'-(2- ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridyl)pyrr olo[1,2-b]pyridazine-3- carboxamidine To a solution of 6-bromo-4-[[[(S)-1-(cyclopropanecarbonyl)pyrrolidin-2-yl]met hyl]amino]-N'-[4- [tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]pyrrolo[1,2-b] pyridazine-3-carboxamidine (110 mg, 172 μmol), (6-methoxy-4-methyl-3-pyridyl)boronic acid (35 mg, 207 μmol) and potassium phosphate (73 mg, 344 μmol) in water (0.2 mL) and N,N-dimethylformamide (2 mL) was added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (22 mg, 34 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 4-[[[(S)-1-(cyclopropanecarbonyl)pyrrolidin-2-yl]methyl]amin o]-N'- (2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridyl)p yrrolo[1,2-b]pyridazine-3- carboxamidine as a yellow solid. Yield: 41.8 mg, 41%. LCMS (ESI) m/z: 568.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.29-12.33 (m, 1H), 8.98 (s, 1H), 8.21-8.27 (m, 2H), 7.86-7.90 (m, 1H), 7.54 (s, 1H), 6.78 (d, 1H, J=4.4 Hz), 6.58-6.70 (m, 3H), 5.92 (s, 2H), 4.16-4.26 (m, 2H), 3.86 (s, 3H), 3.50-3.70 (m, 3H), 2.34-2.46 (m, 5H), 1.77-2.03 (m, 4H), 1.58-1.66 (m, 1H), 1.08 (t, 3H, J=7.6 Hz), 0.55-0.81 (m, 4H). EXAMPLE 148 Synthesis of (S)-N'-(2-ethyl-4-hydroxyphenyl)-6-(6-methoxy-4-methylpyridi n-3-yl)-4- [(pyrrolidin-2-ylmethyl)amino]pyrrolo[1,2-b]pyridazine-3-car boximidamide formic acid salt Step 1: Synthesis of tert-butyl (S)-2-[[[6-bromo-3-[N'-[4-[(tert-butyldimethylsilyl)oxy]-2- ethylphenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino ]methyl]pyrrolidine-1- carboxylate To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (300 mg, 590.6 μmol) and tert-butyl (S)-2- (aminomethyl)pyrrolidine-1-carboxylate (355 mg, 1.77 mmol) in N,N-dimethylacetamide (4.0 mL) was added N,N-diisopropylethylamine (229 mg, 1.77 mmol). After stirring at 85 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 190 mg, 48%. LCMS (ESI) m/z: 673.4 (M+H). Step 2: Synthesis of tert-butyl (S)-2-[[[3-[N'-(2-ethyl-4-hydroxyphenyl)carbamimidoyl]-6-(6- methoxy-4-methylpyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]am ino]methyl]pyrrolidine-1- carboxylate To a solution of tert-butyl (S)-2-[[[6-bromo-3-[N'-[4-[(tert-butyldimethylsilyl)oxy]-2- ethylphenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino ]methyl]pyrrolidine-1- carboxylate (170 mg, 253.1 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (127 mg, 759.2 μmol) in N,N-dimethylformamide (4.0 mL) and water (0.4 mL) were added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (17 mg, 25.3 μmol) and potassium phosphate (161 mg, 759.2 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 4 hours. After cooling to room temperature, cesium fluoride (77 mg, 506.2 μmol) was added. After stirring for at 25°C or 2 hours, the reaction mixture was diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 120 mg, 68%. LCMS (ESI) m/z: 600.4 (M+H). Step 3: Synthesis of (S)-N'-(2-ethyl-4-hydroxyphenyl)-6-(6-methoxy-4-methylpyridi n-3-yl)-4- [(pyrrolidin-2-ylmethyl)amino]pyrrolo[1,2-b]pyridazine-3-car boximidamide formic acid salt To a solution of tert-butyl (S)-2-[[[3-[N'-(2-ethyl-4-hydroxyphenyl)carbamimidoyl]-6-(6- methoxy-4-methylpyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]am ino]methyl]pyrrolidine-1- carboxylate (110 mg, 183.4 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (2.0 mL). After stirring at 25°C for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded (S)-N'-(2-ethyl-4-hydroxyphenyl)-6-(6- methoxy-4-methylpyridin-3-yl)-4-[(pyrrolidin-2-ylmethyl)amin o]pyrrolo[1,2-b]pyridazine-3- carboximidamide formic acid salt as a white solid. Yield: 17.2 mg, 10%. LCMS (ESI) m/z: 500.1 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.20-8.30 (m, 3H), 7.87 (d, 1H, J=1.5 Hz), 7.08 (d, 1H, J=1.5 Hz), 6.78 (s, 1H), 6.55-6.70 (m, 3H), 3.89 (s, 3H), 3.70-3.85 (m, 2H), 3.35-3.45 (m, 2H), 2.75-2.85 (m, 2H), 2.40-2.50 (m, 4H), 1.78-1.90 (m, 1H), 1.45-1.75 (m, 3H), 1.00-1.10 (m, 3H). EXAMPLE 149 Synthesis of (S)-N'-(2-chlorophenyl)-6-(6-methoxy-4-methylpyridin-3-yl)-4 -[[pyrrolidin-2- ylmethyl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine

Step 1: Synthesis of tert-butyl (S)-2-[[[6-bromo-3-[N'-(2- chlorophenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amin o]methyl]pyrrolidine-1- carboxylate To a solution of 6-bromo-4-chloro-N'-(2-chlorophenyl)pyrrolo[1,2-b]pyridazine -3-carboxamidine (240 mg, 624.9 μmol) and tert-butyl (S)-2-(aminomethyl)pyrrolidine-1-carboxylate (376 mg, 1.87 mmol) in N,N-dimethylacetamide (5.0 mL) was added N,N-diisopropylethylamine (404 mg, 3.12 mmol). After stirring at 85 °C for 2 hours, the reaction mixture was cooled room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a white solid. Yield: 280 mg, 79%. LCMS (ESI) m/z: 549.2 (M+H). Step 2: Synthesis of tert-butyl (S)-2-[[[3-[N'-(2-chlorophenyl)carbamimidoyl]-6-(6-methoxy-4 - methylpyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]amino]methyl ]pyrrolidine-1-carboxylate To a solution of tert-butyl (S)-2-[[[6-bromo-3-[N'-(2-chlorophenyl)carbamimidoyl]pyrrolo [1,2- b]pyridazin-4-yl]amino]methyl]pyrrolidine-1-carboxylate (150 mg, 273.8 μmol) and (6-methoxy- 4-methyl-3-pyridyl)boronic acid (137 mg, 821.4 μmol) in N,N-dimethylformamide (3.0 mL) and water (0.3 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (18 mg, 27.4 μmol) and potassium phosphate (174 mg, 821.4 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 150 mg, 86%. LCMS (ESI) m/z: 590.3 (M+H). Step 3: Synthesis of (S)-N'-(2-chlorophenyl)-6-(6-methoxy-4-methylpyridin-3-yl)-4 -[[pyrrolidin- 2-ylmethyl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of tert-butyl (S)-2-[[[3-[N'-(2-chlorophenyl)carbamimidoyl]-6-(6-methoxy-4 - methylpyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl]amino]methyl ]pyrrolidine-1-carboxylate (150 mg, 254.2 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (3.0 mL). After stirring at 25 °C for an hour, the resulting mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded (S)-N'-(2-chlorophenyl)-6-(6- methoxy-4-methylpyridin-3-yl)-4-[[pyrrolidin-2-ylmethyl]amin o]pyrrolo[1,2-b]pyridazine-3- carboxamidine as an off-white solid. Yield: 47.1 mg, 37%. LCMS (ESI) m/z: 490.1 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.49 (s, 1H), 8.25 (s, 1H), 8.21 (s, 1H), 7.88 (d, 1H, J=1.5 Hz), 7.44-7.48 (m, 1H), 7.26-7.31 (m, 1H), 7.00-7.11 (m, 3H), 6.77 (d, 1H, J=4.8 Hz), 6.25-6.40 (m, 2H), 3.65-3.90 (m, 5H), 3.20-3.30 (m, 1H), 2.72 (t, 2H, J=6.0 Hz), 2.41-2.49 (m, 1H), 2.33 (s, 3H), 1.70-1.81 (m, 1H), 1.40-1.70 (m, 3H). EXAMPLE 150 Synthesis of N'-(2-chlorophenyl)-6-(6-methoxy-4-methyl-3-pyridyl)-4-[[[(R )-pyrrolidin-2- yl]methyl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine

Step 1: Synthesis of tert-butyl (R)-2-[[[6-bromo-3-[N'-(2-chlorophenyl)carbamimidoyl] pyrrolo[1,2-b]pyridazin-4-yl]amino]methyl]pyrrolidine-1-carb oxylate To a solution of 6-bromo-4-chloro-N'-(2-chlorophenyl)pyrrolo[1,2-b]pyridazine -3-carboxamidine (150 mg, 390 μmol) in N,N-dimethylacetamide (1 mL) were added tert-butyl (R)-2- (aminomethyl)pyrrolidine-1-carboxylate (117 mg, 585 μmol) and N,N-diisopropylethylamine (152 mg, 1.2 mmol). After stirring at 85 °C for 2 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow soild. Yield: 150 mg, 68%. LCMS (ESI) m/z: 547.2 (M+H). Step 2: Synthesis of tert-butyl (R)-2-[[[3-[N'-(2-chlorophenyl)carbamimidoyl]-6-(6-methoxy-4 - methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]methyl]p yrrolidine-1-carboxylate To a solution of tert-butyl (R)-2-[[[6-bromo-3-[N'-(2-chlorophenyl)carbamimidoyl]pyrrolo [1,2- b]pyridazin-4-yl]amino]methyl]pyrrolidine-1-carboxylate (140 mg, 255 μmol) and (6-methoxy-4- methyl-3-pyridyl)boronic acid (85 mg, 511 μmol) in N,N-dimethylformamide (2 mL) and water (0.2 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (17 mg, 26 μmol) and potassium phosphate (163 mg, 766 μmol). The resulting mixture was purged with nitrogen gas, stirred at 80 °C for 2 hours under nitrogen atmosphere and then cooled to room temperature. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 100 mg, 65%. LCMS (ESI) m/z: 590.0 (M+H). Step 3: Synthesis of N'-(2-chlorophenyl)-6-(6-methoxy-4-methyl-3-pyridyl)-4-[[[(R )-pyrrolidin- 2-yl]methyl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of tert-butyl (R)-2-[[[3-[N'-(2-chlorophenyl)carbamimidoyl]-6-(6-methoxy-4 - methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]methyl]p yrrolidine-1-carboxylate (100 mg, 169 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded N'-(2-chlorophenyl)-6-(6-methoxy-4- methyl-3-pyridyl)-4-[[[(R)-pyrrolidin-2-yl]methyl]amino]pyrr olo[1,2-b]pyridazine-3- carboxamidine as a white solid. Yield: 52.4 mg, 61%. LCMS (ESI) m/z: 490.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.48 (s, 1H), 8.21-8.25 (m, 2H), 7.88 (d, 1H, J=1.6 Hz), 7.45-7.47 (m, 1H), 7.26-7.30 (m, 1H), 7.11 (d, 1H, J=2.0 Hz), 7.01-7.05 (m, 2H), 6.77 (s, 1H), 6.28 (s, 2H), 3.86 (s, 3H), 3.78-3.86 (m, 1H), 3.70-3.73 (m, 1H), 3.34-3.37 (m, 1H), 2.67-2.74 (m, 2H), 2.41 (s, 3H), 1.77-1.80 (m, 1H), 1.48-1.64 (m, 3H). EXAMPLE 151 Synthesis of 1-[4-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-4-[[(3S )-tetrahydrofuran-3- yl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl-phenyl]-3-(2 -hydroxy-2-methyl-propyl)urea Step 1: Synthesis of phenyl N-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]carbamate To a solution of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anil ine (480 mg, 2.06 mmol) in dichloromethane (10.0 mL) were added pyridine (195 mg, 2.47 mmol) and phenyl carbonochloridate (355 mg, 2.26 mmol) dropwise at 0 °C under nitrogen atmosphere. After stirring at 25 °C for 2 hours, the reaction mixture was diluted with dichloromethane and washed with saturated aqueous solution of sodium carbonate and brine. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a yellow oil. Yield: 740 mg, 99%. LCMS (ESI) m/z: 354.2 (M+H). Step 2: Synthesis of 1-(2-hydroxy-2-methyl-propyl)-3-[3-methyl-4-(4,4,5,5-tetrame thyl-1,3,2- dioxaborolan-2-yl)phenyl]urea To a solution of phenyl N-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]carbamate (740 mg, 2.10 mmol) in N,N-dimethylformamide (10.0 mL) were added triethylamine (636 mg, 6.29 mmol) and 1-amino-2-methyl-propan-2-ol (560 mg, 6.29 mmol). After stirring at 50 °C for 4 hours under nitrogen atmosphere, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous solution of sodium carbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as an off-white solid. Yield: 580 mg, 79%. LCMS (ESI) m/z: 349.3 (M+H). Step 3: Synthesis of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (2.00 g, 3.94 mmol) in N,N-dimethylacetamide (20.0 mL) were added (3S)-tetrahydrofuran-3-amine hydrochloric acid salt (730 mg, 5.91 mmol) and N,N-diisopropylethylamine (1.53 g, 11.81 mmol). The resulting mixture was stirred at 90 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 2.00 g, 90%. LCMS (ESI) m/z: 558.4 (M+H). Step 4: Synthesis of 1-[4-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-4-[[(3S )- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-3-m ethyl-phenyl]-3-(2-hydroxy-2- methyl-propyl)urea To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine (120 mg, 214.8 μmol) in N,N-dimethylformamide (3.0 mL) and water (0.3 mL) were added 1-(2-hydroxy-2-methyl- propyl)-3-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)phenyl]urea (112 mg, 322.2 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene-palladium dichloride (14 mg, 21.5 μmol) and potassium phosphate (91 mg, 429.6 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 1-[4-[3-[N'-(2-ethyl-4-hydroxy- phenyl)carbamimidoyl]-4-[[(3S)-tetrahydrofuran-3-yl]amino]py rrolo[1,2-b]pyridazin-6-yl]-3- methyl-phenyl]-3-(2-hydroxy-2-methyl-propyl)urea as a yellow solid. Yield: 27.9 mg, 21%. LCMS (ESI) m/z: 586.1 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.48 (s, 1H), 8.94 (s, 1H), 8.61 (s, 1H), 8.22 (s, 1H), 7.82 (s, 1H), 7.28-7.37 (m, 3H), 6.98 (s, 1H), 6.58-6.70 (m, 3H), 6.15 (t, 1H, J=5.6 Hz), 5.88-5.92 (m, 2H), 4.90-5.02 (m, 1H), 4.54 (s, 1H), 3.90-3.96 (m, 1H), 3.70- 3.87 (m, 3H), 3.05 (d, 2H, J=5.6 Hz), 2.31-2.46 (m, 6H), 1.85-1.96 (m, 1H), 1.03-1.14 (m, 9H). EXAMPLE 152 Synthesis of 6-(2-cyclopropyl-4-methoxy-phenyl)-N'-(2-ethyl-4-hydroxy-phe nyl)-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine formic acid salt Step 1: Synthesis of 6-(2-cyclopropyl-4-methoxy-phenyl)-N'-[4-[tert-butyl(dimethy l)silyl]oxy-2- ethyl-phenyl]-4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1, 2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine (100 mg, 179 μmol) and (2-cyclopropyl-4-methoxy-phenyl)boronic acid (103 mg, 537 μmol) in 1,4-dioxane (2 mL) and water (0.2 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (12 mg, 18 μmol) and cesium carbonate (175 mg, 537 μmol). The mixture was purged with nitrogen gas and stirred at 90 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water three times and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a brown solid. Yield: 60 mg, 27%. LCMS (ESI) m/z: 626.5 (M+H). Step 2: Synthesis of 6-(2-cyclopropyl-4-methoxy-phenyl)-N'-(2-ethyl-4-hydroxy-phe nyl)-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine formic acid salt To a solution of 6-(2-cyclopropyl-4-methoxy-phenyl)-N'-[4-[tert-butyl(dimethy l)silyl]oxy-2- ethyl-phenyl]-4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1, 2-b]pyridazine-3-carboxamidine (50 mg, 79 μmol) in N,N-dimethylformamide (2 mL) was added cesium fluoride (36 mg, 239 μmol). The resulting mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 6-(2-cyclopropyl-4-methoxy-phenyl)-N'-(2-ethyl-4-hydroxy-phe nyl)-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine formic acid salt as an off-white solid. Yield: 6.7 mg, 14%. LCMS (ESI) m/z: 512.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.49 (s, 1H), 8.95 (brs, 1H), 8.22 (s, 1H), 8.19 (s, 1H), 7.86 (d, 1H, J=1.6 Hz), 7.39 (d, 1H, J=8.4 Hz), 7.04 (d, 1H, J=2.0 Hz), 6.79-6.82 (m, 1H), 6.55-6.67 (m, 4H), 5.92 (brs, 2H), 4.94- 4.98 (m, 1H), 3.91-3.94 (m, 1H), 3.76-3.81 (m, 5H), 3.69-3.71 (m, 1H), 2.33-2.44 (m, 3H), 2.14- 2.19 (m, 1H), 1.88-1.96 (m, 1H), 1.07 (t, 3H, J=7.6 Hz), 0.90-0.94 (m, 2H), 0.74-0.76 (m, 2H). EXAMPLE 153 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-[6-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]-4-methyl-3-pyridyl]-4-[[ (3S)-tetrahydrofuran-3- yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt

To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine (120 mg, 214 μmol) and 2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]-4-methyl-5 -(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (183 mg, 430 μmol) in N,N-dimethylformamide (1 mL) and water (0.1 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (14 mg, 21 μmol) and potassium phosphate (137 mg, 644 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded N'-(2-ethyl-4- hydroxy-phenyl)-6-[6-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy ]ethoxy]-4-methyl-3-pyridyl]-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine formic acid salt as a yellow solid. Yield: 68.1 mg, 44%. LCMS (ESI) m/z: 663.2 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.49 (brs, 1H), 8.97 (brs, 1H), 8.24 (s, 2H), 8.17 (s, 1H, HCOOH), 7.91 (d, 1H, J=1.6 Hz), 7.06 (d, 1H, J=2.0 Hz), 6.79 (s, 1H), 6.59-6.68 (m, 3H), 5.95 (brs, 2H), 4.94-5.02 (m, 1H), 4.38-4.40 (m, 2H), 3.92-3.96 (m, 1H), 3.71-3.81 (m, 4H), 3.67-3.69 (m, 1H), 3.58-3.62 (m, 2H), 3.50-3.57 (m, 8H), 3.41-3.43 (m, 2H), 3.23 (s, 3H), 2.33-2.44 (m, 6H), 1.86-1.94 (m, 1H), 1.07 (t, 3H, J=7.6 Hz). EXAMPLE 154 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-[2-methyl-5-(trifluoromethyl sulfonyl)phenyl]-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine Step 1: Synthesis of 4,4,5,5-tetramethyl-2-[2-methyl-5-(trifluoromethylsulfonyl)p henyl]-1,3,2- dioxaborolane To a solution of 2-bromo-1-methyl-4-(trifluoromethylsulfonyl)benzene (300 mg, 990 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)-1,3,2-dioxaborolane (503 mg, 2 mmol) in 1,4-dioxane (3 mL) were added potassium acetate (825 mg, 2.0 mmol) and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II) dichloride (73 mg, 99 μmol) at room temperature. The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 15 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow oil. Yield: 200 mg, 58%. Step 2: Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-[2-methyl-5- (trifluoromethylsulfonyl)phenyl]-4-[[(3S)-tetrahydrofuran-3- yl]amino]pyrrolo[1,2-b]pyridazine- 3-carboxamidine To a solution of 6-bromo-N'-[4-[1,1-dimethylethyl(dimethyl)silyl]oxy-2-ethyl- phenyl]-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine (100 mg, 179 μmol) and 4,4,5,5-tetramethyl-2-[2-methyl-5-(trifluoromethylsulfonyl)p henyl]-1,3,2-dioxaborolane (75 mg, 214 μmol) in N,N-dimethylformamide (2 mL) and water (0.2 mL) were added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (26 mg, 36 μmol) and potassium phosphate (114 mg, 537 μmol). The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 2 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded N'-(2-ethyl-4- hydroxy-phenyl)-6-[2-methyl-5-(trifluoromethylsulfonyl)pheny l]-4-[[(3S)-tetrahydrofuran-3- yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine as a yellow solid. Yield: 63.3 mg, 60%. LCMS (ESI) m/z: 588.0 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 12.63 (d, 1H, J=7.2 Hz), 8.96 (s, 1H), 8.29 (s, 1H), 8.01-8.11 (m, 2H), 7.96-8.00 (m, 1H), 7.81 (d, 1H, J=8.1 Hz), 7.14 (d, 1H, J=1.8 Hz), 6.56-6.68 (m, 3H), 5.96 (s, 2H), 4.96-5.06 (m, 1H), 3.91-3.97 (m, 1H), 3.65-3.89 (m, 3H), 2.65 (s, 3H), 2.28-2.48 (m, 3H), 1.87-1.97 (m, 1H), 1.08 (t, 3H, J=7.5 Hz). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -78.45 (s, 3F). EXAMPLE 155 Synthesis of N'-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl -3-pyridyl)-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine formic acid salt Step 1: Synthesis of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-5-fluor o-phenyl]-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-5-fluor o-phenyl]-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (260 mg, 494.4 μmol) and (3S)-tetrahydrofuran-3- amine hydrochloric acid salt (92 mg, 741.6 μmol) in N,N-dimethylacetamide (4.0 mL) was added N,N-diisopropylethylamine (128 mg, 988.8 μmol). After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 150 mg, 52 %. LCMS (ESI) m/z: 578.2 (M+H). Step 2: Synthesis of N'-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl -3-pyridyl)- 4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine -3-carboxamidine formic acid salt To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-5-fluor o-phenyl]-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine (180 mg, 312.2 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (157 mg, 936.6 μmol) in N,N-dimethylacetamide (3.0 mL) and water (0.3 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (20 mg, 31.2 μmol) and potassium carbonate (129 mg, 936.6 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours. After cooling to room temperature, cesium fluoride (95 mg, 624.4 μmol) was added. After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate and the solids were filtered out. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1% formic acid) afforded N'-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-6-(6-methoxy- 4-methyl-3-pyridyl)-4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrr olo[1,2-b]pyridazine-3- carboxamidine formic acid salt as a yellow solid. Yield: 76.9 mg, 45%. LCMS (ESI) m/z: 505.3 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.32 (brs, 1H), 9.35 (brs, 1H), 8.15-8.25 (m, 2H), 8.14 (s, 1H, HCOOH), 7.93 (s, 1H), 7.10 (s, 1H), 6.78-6.84 (m, 2H), 6.64 (brs, 1H), 6.14 (brs, 2H), 4.85-4.94 (m, 1H), 3.88-3.97 (m, 1H), 3.65-3.85 (m, 6H), 2.33-2.50 (m, 6H), 1.85-1.96 (m, 1H), 1.08 (t, 3H, J=7.5 Hz).19F NMR (DMSO-d6, 282 MHz) δ -138.83 (s, 1F). EXAMPLE 156 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(2-methylsulfanylphenyl)-4-[ [(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine Step 1: Synthesis of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-6-(2-me thylsulfanyl phenyl)-4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]py ridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine (120 mg, 214 μmol), (2- methylsulfanylphenyl)boronic acid (108 mg, 644 μmol) and potassium phosphate (91 mg, 429 μmol) in water (0.2 mL) and N,N-dimethylformamide (2 mL) was added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (14 mg, 21 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 1 hour. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 80 mg, 61%. LCMS (ESI) m/z: 602.2 (M+H). Step 2: Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(2-methylsulfanylphenyl)-4-[ [(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine To a solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-6-(2-me thylsulfanylphenyl)- 4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine -3-carboxamidine (70 mg, 116 μmol) in N,N-dimethylformamide (3 mL) was added cesium fluoride (177 mg, 1.2 mmol). The resulting mixture was stirred at 80 °C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded N'-(2-ethyl-4-hydroxy-phenyl)-6-(2-methylsulfanylphenyl)-4-[ [(3S)-tetrahydrofuran-3- yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine as a yellow solid. Yield: 23.6 mg, 39%. LCMS (ESI) m/z: 488.0 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 12.56 (d, 1H, J=7.2 Hz), 8.94 (s, 1H), 8.25 (s, 1H), 7.90 (d, 1H, J=1.8 Hz), 7.47 (d, 1H, J=7.5 Hz), 7.28-7.38 (m, 2H), 7.16-7.26 (m, 1H), 7.12 (s, 1H), 6.53-6.72 (m, 3H), 5.93 (s, 2H), 4.91-4.97 (m, 1H), 3.90-4.00 (m, 1H), 3.68-3.87 (m, 3H), 2.38-2.46 (m, 6H), 1.84-1.98 (m, 1H), 1.07 (t, 3H, J=7.5 Hz). EXAMPLE 157 Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-ethyl-4-hydroxy- phenyl)-6-(2- methylsulfanylphenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidin e

Step 1: Synthesis of tert-butyl N-[(1S,3R)-3-[[6-bromo-3-[N'-[4-[tert-butyl(dimethyl)silyl]o xy-2- ethyl-phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclopentyl]carbamate To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (200 mg, 394 μmol) and tert-butyl N-[(1S,3R)-3- aminocyclopentyl]carbamate (103 mg, 512 μmol) in N,N-dimethylacetamide (2 mL) was added N,N-diisopropylethylamine (102 mg, 788 μmol). After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield:258 mg, 94%. LCMS (ESI) m/z: 673.2 (M+H). Step 2: Synthesis of tert-butyl N-[(1S,3R)-3-[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl ]- 6-(2-methylsulfanylphenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino ]cyclopentyl]carbamate To a solution of tert-butyl N-[(1S,3R)-3-[[6-bromo-3-[N'-[4-[tert-butyl(dimethyl)silyl]o xy-2- ethyl-phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclopentyl]carbamate (150 mg, 223 μmol) and (2-methylsulfanylphenyl)boronic acid (113 mg, 670 μmol) in N,N- dimethylformamide (3 mL) and water (0.3 mL) were added potassium carbonate (93 mg, 670 μmol) and 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (15 mg, 22 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours. After cooling to room temperature, cesium fluoride (69 mg, 447 μmol) was added. After stirring at room temperature for 2 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 110 mg, 77%. LCMS (ESI) m/z: 601.3 (M+H). Step 3: Synthesis of 4-[[(1R,3S)-3-aminocyclopentyl]amino]-N'-(2-ethyl-4-hydroxy- phenyl)-6- (2-methylsulfanylphenyl)pyrrolo[1,2-b]pyridazine-3-carboxami dine To a solution of tert-butyl N-[(1S,3R)-3-[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl ]-6-(2- methylsulfanylphenyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]cycl opentyl]carbamate (110 mg, 183 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL). After stirring at room temperature for an hour, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 4-[[(1R,3S)-3- aminocyclopentyl]amino]-N'-(2-ethyl-4-hydroxy-phenyl)-6-(2-m ethylsulfanylphenyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine as an off-white solid. Yield: 77.8 mg, 84%. LCMS (ESI) m/z: 501.1 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.39 (brs, 1H), 8.94 (s, 1H), 8.21 (s, 1H), 7.86 (d, 1H, J=1.8 Hz), 7.45 (d, 1H, J=7.2 Hz), 7.25-7.37 (m, 2H), 7.15-7.25 (m, 1H), 7.10 (d, 1H, J=1.8 Hz), 6.55-6.70 (m, 3H), 5.88 (brs, 2H), 4.50-4.65 (m, 1H), 3.20-3.30 (m, 1H), 2.30-2.48 (m, 6H), 2.04-2.14 (m, 1H), 1.65-1.90 (m, 2H), 1.20-1.45 (m, 2H), 1.08 (t, 3H, J=7.5 Hz). EXAMPLE 158 Synthesis of N'-(2-ethylphenyl)-6-(2-methylsulfanylphenyl)-4-[[(3S)-tetra hydrofuran-3- yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of 6-bromo-4-chloro-N'-(2-ethylphenyl)pyrrolo[1,2-b]pyridazine- 3- carboxamidine To a solution of 6-bromo-4-chloro-pyrrolo[1,2-b]pyridazine-3-carbonitrile (500 mg, 1.95 mmol) and 2-ethylaniline (472 mg, 3.90 mmol) in toluene (5.0 mL) was added trimethylalumane (11.7 mL, 23.4 mmol, 2 M in toluene) dropwise at 0°C under nitrogen atmosphere. The reaction mixture was stirred at 0°C for 30 minutes and then stirred at 50 °C for 16 hours. After cooled to room temperature, the reaction mixture was quenched with saturated aqueous solution of ammonium chloride and extracted with ethyl acetate three times. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 600 mg, 81%. LCMS (ESI) m/z: 378.9 (M+H). Step 2: Synthesis of 6-bromo-N'-(2-ethylphenyl)-4-[[(3S)-tetrahydrofuran-3- yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-4-chloro-N'-(2-ethylphenyl)pyrrolo[1,2-b]pyridazine- 3-carboxamidine (150 mg, 397.1 μmol) and (3S)-tetrahydrofuran-3-amine hydrochloric acid salt (73 mg, 595.7 μmol) in N,N-dimethylacetamide (2.0 mL) was added N,N-diisopropylethylamine (154 mg, 1.19 mmol) dropwise. After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 140 mg, 82%. LCMS (ESI) m/z: 429.9 (M+H). Step 3: Synthesis of N'-(2-ethylphenyl)-6-(2-methylsulfanylphenyl)-4-[[(3S)-tetra hydrofuran-3- yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine To a mixture of 6-bromo-N'-(2-ethylphenyl)-4-[[(3S)-tetrahydrofuran-3-yl]ami no]pyrrolo[1,2- b]pyridazine-3-carboxamidine (125 mg, 291.8 μmol) and (2-methylsulfanylphenyl)boronic acid (147 mg, 875.5 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added 1,1'- bis (di-t-butylphosphino)ferrocene palladium dichloride (19 mg, 29.1 μmol) and potassium carbonate (121 mg, 875.5 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was heated at 70 °C for 2 hours. After cooled to room temperature, the reaction mixture was diluted with ethyl acetated and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded N'-(2-ethylphenyl)-6-(2-methylsulfanylphenyl)-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine as an off-white solid. Yield: 67.7 mg, 48%. LCMS (ESI) m/z: 472.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.29 (d, 1H, J=7.2 Hz), 8.28 (s, 1H), 7.92 (s, 1H), 7.46-7.49 (m, 1H), 7.31-7.34 (m, 2H), 7.13- 7.26 (m, 4H), 6.98-7.03 (m, 1H), 6.81-6.83 (m, 1H), 6.02 (s, 2H), 4.90-4.93 (m, 1H), 3.92-3.95 (m, 1H), 3.70-3.86 (m, 3H), 2.45-2.53 (m, 2H), 2.44 (s, 3H), 2.30-2.41 (m, 1H), 1.85-1.93 (m, 1H), 1.11 (t, 3H, J=7.6 Hz). EXAMPLE 159 Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -ethylphenyl)-6-(2- methylsulfanylphenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidin e Step 1: Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-(2- ethylphenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-4-chloro-N'-(2-ethylphenyl)pyrrolo[1,2-b]pyridazine- 3-carboxamidine (200 mg, 529.5 μmol) and (1S,3R)-1,2,2-trimethylcyclopentane-1,3-diamine (150 mg, 1.06 mmol) in N,N-dimethylacetamide (2.0 mL) was added N,N-diisopropylethylamine (205 mg, 1.59 mmol) dropwise. After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 160 mg, 62%. LCMS (ESI) m/z: 483.2 (M+H). Step 2: Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -ethylphenyl)- 6-(2-methylsulfanylphenyl)pyrrolo[1,2-b]pyridazine-3-carboxa midine To a mixture of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-(2- ethylphenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (150 mg, 310.2 μmol) and (2- methylsulfanylphenyl)boronic acid (156 mg, 930.8 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (20 mg, 31.0 μmol) and potassium carbonate (128 mg, 930.8 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 70 °C for 2 hours. After cooled to room temperature, the reaction mixture was diluted with ethyl acetated and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 4-[[(1R,3S)-3- amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2-ethylphenyl)- 6-(2- methylsulfanylphenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidin e as an off-white solid. Yield: 67.3 mg, 40%. LCMS (ESI) m/z: 527.1 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.10 (s, 1H), 8.24 (s, 1H), 7.87 (s, 1H), 7.45 (d, 1H, J=7.6 Hz), 7.29-7.38 (m, 2H), 7.13-7.25 (m, 4H), 6.95- 7.01 (m, 1H), 6.80-6.83 (m, 1H), 5.91 (s, 2H), 4.45-4.53 (m, 1H), 2.43-2.48 (m, 5H), 2.21-2.35 (m, 1H), 1.38-1.70 (m, 5H), 1.10 (t, 3H, J=7.6 Hz), 1.03 (s, 3H), 0.83-0.84 (m, 6H). EXAMPLE 160 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(5-fluoro-4-hydroxy-2-methyl -phenyl)-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine formic acid salt To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine (150 mg, 268.5 μmol) and 2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)phenol (271 mg, 1.07 mmol) in N,N-dimethylformamide (7.0 mL) and water (0.7 mL) were added sodium carbonate (57 mg, 537.1 μmol) and 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (18 mg, 26.9 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours. After cooling to room temperature, cesium fluoride (81 mg, 537.1 μmol) was added. After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1% formic acid) afforded N'-(2-ethyl-4-hydroxy-phenyl)-6-(5-fluoro-4-hydroxy-2-methyl - phenyl)-4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]py ridazine-3-carboxamidine formic acid salt as a yellow solid. Yield: 25.4 mg, 17%. LCMS (ESI) m/z: 490.3 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.51 (brs, 1H), 9.76 (s, 1H), 9.00 (brs, 1H), 8.18 (s, 1H), 8.14 (s, 1H, HCOOH), 7.86 (s, 1H), 7.28 (d, 1H, J=12.4 Hz), 7.04 (s, 1H), 6.86 (d, 1H, J=9.2 Hz), 6.55-6.85 (m, 3H), 5.93 (brs, 1H), 4.90-5.00 (m, 1H), 3.92-3.96 (m, 1H), 3.67-3.90 (m, 3H), 2.32-2.49 (m, 6H), 1.88-1.98 (m, 1H), 1.05-1.15 (m, 3H). ¹⁹ F NMR (DMSO-d6, 282 MHz) δ -140.57 (s, 1F). EXAMPLE 161 Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -ethylphenyl)-6-(5- fluoro-4-hydroxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazine-3- carboxamidine Step 1: Synthesis of 1-benzyloxy-4-bromo-2-fluoro-5-methyl-benzene A suspension of 4-bromo-2-fluoro-5-methyl-phenol (1.00 g, 4.88 mmol), bromomethylbenzene (1.25 g, 7.32 mmol) and potassium carbonate (674 mg, 4.88 mmol) in acetonitrile (10.0 mL) was stirred at 25 °C for 2 hours. The resulting solution was concentrated under reduce pressure. The residue was diluted with ethyl acetated and washed with water and brine. The organic layers were combined, washed with brine, dried and concentrated under reduced pressure to give the title compound as a colorless oil, which was used for next step directly without further purification. Yield: 1.20 g, 83%. LCMS (ESI) m/z: 295.0 (M+H). Step 2: Synthesis of 2-(4-benzyloxy-5-fluoro-2-methyl-phenyl)-4,4,5,5-tetramethyl -1,3,2- dioxaborolane To a solution of 1-benzyloxy-4-bromo-2-fluoro-5-methyl-benzene (600 mg, 2.03 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)-1,3,2-dioxaborolane (1.03 g, 4.07 mmol) in 1,4-dioxane (5.0 mL) were added potassium acetate (598 mg, 6.10 mmol) and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride (149 mg, 203.2 μmol). The suspension was degassed under reduced pressure and purged with nitrogen three times. After stirring at 85 °C for 15 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetated and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded the title compound as a yellow solid. Yield: 400 mg, 57%. LCMS (ESI) m/z: 343.0 (M+H). Step 3: Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-(4- benzyloxy-5- fluoro-2-methyl-phenyl)-N'-(2-ethylphenyl)pyrrolo[1,2-b]pyri dazine-3-carboxamidine To a mixture of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-bro mo-N'-(2- ethylphenyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine (145 mg, 299.9 μmol) and 2-(4- benzyloxy-5-fluoro-2-methyl-phenyl)-4,4,5,5-tetramethyl-1,3, 2-dioxaborolane (102 mg, 299.9 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added 1,1'-bis (di-t- butylphosphino)ferrocene palladium dichloride (19 mg, 29.9 μmol) and sodium carbonate (95.3 mg, 899.7 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was heated at 70 °C for 2 hours. After cooled to room temperature, the reaction mixture was diluted with ethyl acetated and washed with saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 50 mg, 26%. LCMS (ESI) m/z: 619.4 (M+H). Step 4: Synthesis of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-N'-(2 -ethylphenyl)- 6-(5-fluoro-4-hydroxy-2-methyl-phenyl)pyrrolo[1,2-b]pyridazi ne-3-carboxamidine To a solution of 4-[[(1R,3S)-3-amino-2,2,3-trimethyl-cyclopentyl]amino]-6-(4- benzyloxy-5- fluoro-2-methyl-phenyl)-N'-(2-ethylphenyl)pyrrolo[1,2-b]pyri dazine-3-carboxamidine (40 mg, 64.6 μmol) in methanol (4.0 mL) was added 5% palladium on carbon (15 mg) under nitrogen atmosphere. After stirred at 25 °C for 16 hours under hydrogen atmosphere (1.5 atm.), the reaction mixture was filtered through Celite pad. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 4-[[(1R,3S)-3-amino-2,2,3-trimethyl- cyclopentyl]amino]-N'-(2-ethylphenyl)-6-(5-fluoro-4-hydroxy- 2-methyl-phenyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine as an off-white solid. Yield: 5.5 mg, 15 %. LCMS (ESI) m/z: 529.4 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.05 (brs, 1H), 9.80 (brs, 1H), 8.21 (s, 1H), 7.81 (d, 1H, J=1.6 Hz), 7.21-7.25 (m, 2H), 7.14-7.19 (m, 1H), 6.97-7.01 (m, 1H), 6.79-6.89 (m, 3H), 5.89 (s, 2H), 4.47 (t, 1H, J=8.0 Hz), 2.48-2.53 (m, 2H), 2.20-2.35 (m, 4H), 1.45-1.65 (m, 3H), 1.08 (t, 3H, J=7.6 Hz), 1.03 (s, 3H), 0.82-0.84 (m, 6H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ - 140.41 (s, 1F). EXAMPLE 162 Synthesis of 6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-N'-(2-ethyl-4-hydroxy- phenyl)-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine Step 1: Synthesis of 1-benzyloxy-4-bromo-5-ethyl-2-fluoro-benzene To a solution of 4-bromo-5-ethyl-2-fluoro-phenol (440 mg, 2.01 mmol) in N,N- dimethylformamide (5.0 mL) was added bromomethylbenzene (412 mg, 2.41 mmol) and potassium carbonate (555 mg, 4.02 mmol). After stirring at 25 °C for 15 hours, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 600 mg, 96%. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.50 (d, 1H, J=10.8 Hz), 7.33-7.50 (m, 5H), 7.28 (d, 1H, J=9.2 Hz), 5.18 (s, 2H), 2.64 (q, 2H, J=7.6 Hz), 1.13 (t, 3H, J=7.6 Hz). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -135.74 (s, 1F). Step 2: Synthesis of 2-(4-benzyloxy-2-ethyl-5-fluoro-phenyl)-4,4,5,5-tetramethyl- 1,3,2- dioxaborolane To a solution of 1-benzyloxy-4-bromo-5-ethyl-2-fluoro-benzene (550 mg, 1.78 mmol) in 1,4- dioxane (11.0 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2- yl)-1,3,2-dioxaborolane (903 mg, 3.56 mmol), 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride (130 mg, 177.9 μmol) and potassium acetate (436 mg, 4.45 mmol). The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 15 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered and the filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as an off-white solid. Yield: 560 mg, 88%. ¹ H NMR (CD ₃ OD-d ₄ , 400 MHz) δ 7.24-7.49 (m, 6H), 6.93 (d, 1H, J=8.0 Hz), 5.15 (s, 2H), 2.84 (q, 2H, J=7.6 Hz), 1.33 (s, 12H), 1.08-1.23 (m, 3H). ¹⁹ F NMR (CD3OD-d4, 376 MHz) δ -138.69 (s, 1F). Step 3: Synthesis of 6-(4-benzyloxy-2-ethyl-5-fluoro-phenyl)-N'-[4-[tert- butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-[[(3S)-tetrahydro furan-3-yl]amino]pyrrolo[1,2- b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[1,1-dimethylethyl(dimethyl)silyl]oxy-2-ethyl- phenyl]-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine (200 mg, 358.0 μmol) in N,N-dimethylformamide (5.0 mL) and water (0.5 mL) were added 2-(4-benzyloxy-2-ethyl-5- fluoro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (255 mg, 716.1 μmol)， 1,1'-bis (di-t- butylphosphino)ferrocene-palladium dichloride (23 mg, 35.8 μmol) and sodium carbonate (76 mg, 716.1 μmol). The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered and the filtrate was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 170 mg, 64%. LCMS (ESI) m/z: 708.6 (M+H). Step 4: Synthesis of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-6-(2-et hyl-5-fluoro-4- hydroxy-phenyl)-4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[ 1,2-b]pyridazine-3-carboxamidine To a solution of 6-(4-benzyloxy-2-ethyl-5-fluoro-phenyl)-N'-[4-[tert-butyl(di methyl)silyl]oxy-2- ethyl-phenyl]-4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1, 2-b]pyridazine-3-carboxamidine (150 mg, 211.8 μmol) in methanol (5.0 mL) was added 10% palladium on carbon (16 mg). The resulting mixture was purged with hydrogen gas and stirred at 25 °C for 2 hours under hydrogen atmosphere (3 atm.). The reaction mixture was filtered through Celite pad and the filtrate was concentrated under reduced pressure to afford the title compound as a yellow solid. Yield: 130 mg, 82%. LCMS (ESI) m/z: 618.1 (M+H). Step 5: Synthesis of 6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-N'-(2-ethyl-4-hydroxy- phenyl)-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine To a solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-6-(2-et hyl-5-fluoro-4- hydroxy-phenyl)-4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[ 1,2-b]pyridazine-3-carboxamidine (110 mg, 148.7 μmol) in N,N-dimethylformamide (5.0 mL) was added cesium fluoride (68 mg, 446.3 μmol). After stirring at 25 °C for 2 hours, the reaction mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-N'-(2-ethyl-4- hydroxy-phenyl)-4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[ 1,2-b]pyridazine-3-carboxamidine as a yellow solid. Yield: 23.3 mg, 30%. LCMS (ESI) m/z: 504.1 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.50 (s, 1H), 9.77 (s, 1H), 8.95 (s, 1H), 8.23 (s, 1H), 7.76 (d, 1H, J=1.6 Hz), 7.19 (d, 1H, J=2.4 Hz), 6.85-6.95 (m, 2H), 6.55-6.70 (m, 3H), 5.92 (s, 2H), 4.95-5.00 (m, 1H), 3.90- 3.94 (m, 1H), 3.72-3.84 (m, 2H), 3.67-3.71 (m, 1H), 2.64-2.74 (m, 2H), 2.29-2.45 (m, 3H), 1.86- 1.96 (m, 1H), 1.12 (t, 3H, J=7.6 Hz), 1.07 (t, 3H, J=7.6 Hz). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ - 140.60 (s, 1F). EXAMPLE 163 Synthesis of N',6-bis(2-ethyl-5-fluoro-4-hydroxy-phenyl)-4-[[(3S)-tetrahy drofuran-3- yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine

Step 1: Synthesis of 6-(4-benzyloxy-2-ethyl-5-fluoro-phenyl)-N'-(2-ethyl-5-fluoro -4-hydroxy- phenyl)-4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]py ridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-5-fluor o-phenyl]-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine (140 mg, 242 μmol) and 2-(4-benzyloxy-2-ethyl-5-fluoro-phenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (87 mg, 243 μmol) in N,N-dimethylformamide (2 mL) and water (0.2 mL) were added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (158 mg, 242 μmol) and potassium carbonate (34 mg, 243 μmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 4 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 70 mg, 44%. LCMS (ESI) m/z: 612.2 (M+H). Step 2: Synthesis of N',6-bis(2-ethyl-5-fluoro-4-hydroxy-phenyl)-4-[[(3S)-tetrahy drofuran-3- yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine To solution of 6-(4-benzyloxy-2-ethyl-5-fluoro-phenyl)-N'-(2-ethyl-5-fluoro -4-hydroxy-phenyl)- 4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine -3-carboxamidine (60 mg, 98 μmol) in methanol (2 mL) was added 10% palladium on carbon (31 mg, 294 μmol) under nitrogen atmosphere. The resulting mixture was purged with hydrogen gas and stirred at room temperature for 3 hours under hydrogen atmosphere (1 atm). The reaction mixture was filtered through a celite pad and washed with methanol. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded N',6-bis(2-ethyl-5-fluoro-4-hydroxy-phenyl)-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine as a white solid. Yield: 4.6 mg, 9%. LCMS (ESI) m/z: 522.3 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.28 (d, 1H, J=7.2 Hz), 9.78 (s, 1H), 9.28 (s, 1H), 8.24 (s, 1H), 7.77 (s, 1H), 7.19 (d, 1H, J=12.4 Hz), 6.87-6.93 (m, 2H), 6.81 (d, 1H, J=9.6 Hz), 6.57 (d, 1H, J=12.4 Hz), 6.11 (s, 2H), 4.94-4.98 (m, 1H), 3.90-3.93 (m, 1H), 3.76-3.82 (m, 2H), 3.68-3.70 (m, 1H), 2.66-2.72 (m, 2H), 2.32-2.41 (m, 3H), 1.88-1.91 (m, 1H), 1.08-1.14 (m, 3H), 1.05 (t, 3H, J=7.6 Hz). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -138.85 (s, 1F), -140.59 (s, 1F). EXAMPLE 164 Synthesis of 1-[4-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-4-[[(3S )-tetrahydrofuran-3- yl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl-phenyl]-3-(2 -methoxyethyl)urea formic acid salt Step 1: Synthesis of 1-[4-[3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl- phenyl]carbamimidoyl]-4-[[(3S)-tetrahydrofuran-3-yl]amino]py rrolo[1,2-b]pyridazin-6-yl]-3- methyl-phenyl]-3-(2-methoxyethyl)urea To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine (200 mg, 358 μmol) and 1-(2-methoxyethyl)-3-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]urea (239 mg, 716 μmol) in N,N-dimethylformamide (2 mL) and water (0.2 mL) were added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (23 mg, 35 μmol) and sodium carbonate (114 mg, 1.1 mmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a light-yellow solid. Yield: 110 mg, 44%. LCMS (ESI) m/z: 686.2 (M+H). Step 2: Synthesis of 1-[4-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-4-[[(3S )- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-3-m ethyl-phenyl]-3-(2- methoxyethyl)urea formic acid salt To a solution of 1-[4-[3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl ]carbamimidoyl]-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazin-6- yl]-3-methyl-phenyl]-3-(2- methoxyethyl)urea (100 mg, 145 μmol) in N,N-dimethylformamide (1.5 mL) was added cesium fluoride (66 mg, 437 μmol). After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 1-[4-[3-[N'-(2-ethyl-4-hydroxy- phenyl)carbamimidoyl]-4-[[(3S)-tetrahydrofuran-3-yl]amino]py rrolo[1,2-b]pyridazin-6-yl]-3- methyl-phenyl]-3-(2-methoxyethyl)urea formic acid salt as a light-yellow solid. Yield: 44.9 mg, 49%. LCMS (ESI) m/z: 572.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.44 (brs, 1H), 8.97 (brs, 1H), 8.51 (s, 1H), 8.21 (s, 1H), 8.15 (s, 1H, HCOOH), 7.81 (d, 1H, J=1.6 Hz), 7.27-7.37 (m, 3H), 6.99 (d, 1H, J=2.0 Hz), 6.58-6.68 (m, 3H), 6.20 (t, 1H, J=5.6 Hz), 5.94 (s, 2H), 4.94-4.98 (m, 1H), 3.92-3.96 (m, 1H), 3.69-3.83 (m, 3H), 3.37-3.41 (m, 2H), 3.22-3.29 (m, 5H), 2.32-2.45 (m, 6H), 1.90-1.93 (m, 1H), 1.07 (t, 3H, J=7.6 Hz). EXAMPLE 165 Synthesis of 1-[4-[4-[[(1R,3S)-3-aminocyclopentyl]amino]-3-[N'-(2-chloro- 5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl- phenyl]-3-(2-methoxyethyl)urea Step 1: Synthesis of tert-butyl [(1S,3R)-3-[[3-[N'-(2-chloro-5-fluorophenyl)carbamimidoyl]-6 -[4- [3-(2-methoxyethyl)ureido]-2-methylphenyl]pyrrolo[1,2-b]pyri dazin-4- yl]amino]cyclopentyl]carbamate To a mixture of tert-butyl [(1S,3R)-3-[[6-bromo-3-[N'-(2-chloro-5- fluorophenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclopentyl]carbamate (300 mg, 530.1 μmol) and 1-(2-methoxyethyl)-3-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan- 2-yl)phenyl]urea (177 mg, 530.1 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (34 mg, 53.0 μmol) and potassium carbonate (219 mg, 1.59 mmol) at room temperature under nitrogen atmosphere. After stirring at 70 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetated and washed with saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 300 mg, 81%. LCMS (ESI) m/z: 693.2 (M+H). Step 2: Synthesis of 1-[4-[4-[[(1R,3S)-3-aminocyclopentyl]amino]-3-[N'-(2-chloro- 5-fluoro- phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl- phenyl]-3-(2-methoxyethyl)urea To a solution of tert-butyl [(1S,3R)-3-[[3-[N'-(2-chloro-5-fluorophenyl)carbamimidoyl]-6 -[4-[3- (2-methoxyethyl)ureido]-2-methylphenyl]pyrrolo[1,2-b]pyridaz in-4- yl]amino]cyclopentyl]carbamate (300 mg, 432.7 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (2.0 mL). After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 1-[4-[4- [[(1R,3S)-3-aminocyclopentyl]amino]-3-[N'-(2-chloro-5-fluoro - phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl- phenyl]-3-(2-methoxyethyl)urea as an off-white solid. Yield: 70.8 mg, 27%. LCMS (ESI) m/z: 593.3 (M+H). ¹ H NMR (DMSO- d6, 400 MHz) δ 11.42 (s, 1H), 8.55 (s, 1H), 8.19 (s, 1H), 7.79 (d, 1H, J=1.6 Hz), 7.47-7.51 (m, 1H), 7.27-7.35 (m, 3H), 6.98 (s, 1H), 6.84-6.91 (m, 2H), 6.50 (s, 2H), 6.24 (s, 1H), 4.57-4.63 (m, 1H), 3.38-3.41 (m, 2H), 3.23-3.31 (m, 6H), 2.30-2.46 (m, 4H), 2.00-2.10 (m, 1H), 1.68-1.85 (m, 2H), 1.30-1.46 (m, 2H). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -114.49 (s, 1F). EXAMPLE 166 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4- (tetrahydrothiophen-3-ylamino)pyrrolo[1,2-b]pyridazine-3-car boxamidine Step 1: Synthesis of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4- (tetrahydrothiophen-3-ylamino)pyrrolo[1,2-b]pyridazine-3-car boxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (300 mg, 590.6 μmol) and tetrahydrothiophen-3-amine hydrochloric acid salt (123 mg, 885.9 μmol) in N,N-dimethylacetamide (5.0 mL) was added N,N- diisopropylethylamine (229 mg, 1.77 mmol). After stirring at 90 °C for 1 hour, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 185 mg, 54%. LCMS (ESI) m/z: 576.1 (M+H). Step 2: Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4- (tetrahydrothiophen-3-ylamino)pyrrolo[1,2-b]pyridazine-3-car boxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4- (tetrahydrothiophen-3-ylamino)pyrrolo[1,2-b]pyridazine-3-car boxamidine (220 mg, 382.8 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (127 mg, 765.6 μmol) in N,N- dimethylformamide (3.0 mL) and water (0.3 mL) were added potassium phosphate (243 mg, 1.15 mmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (24 mg, 38.2 μmol). The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 80 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4- (tetrahydrothiophen-3-ylamino)pyrrolo[1,2-b]pyridazine-3-car boxamidine as an off-white solid. Yield: 77.8 mg, 40%. LCMS (ESI) m/z: 503.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.58 (d, 1H, J=7.6 Hz), 8.93 (s, 1H), 8.25 (s, 2H), 7.91 (s, 1H), 7.11 (s, 1H), 6.78 (s, 1H), 6.67 (s, 1H), 6.56-6.63 (m, 2H), 5.90 (s, 2H), 5.15-5.22 (m, 1H), 3.86 (s, 3H), 3.22-3.26 (m, 1H), 2.90-2.96 (m, 1H), 2.78-2.86 (m, 2H), 2.36-2.49 (m, 5H), 2.07-2.21 (m, 2H), 1.07 (t, 3H, J=7.6 Hz). EXAMPLE 167 Synthesis of N'-[4-hydroxy-2-(1-methylethyl)phenyl]-6-(6-methoxy-4-methyl -3-pyridyl)-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine To a solution of 6-bromo-4-chloro-pyrrolo[1,2-b]pyridazine-3-carbonitrile (350 mg, 1.3 mmol) in toluene (5 mL) was added 4-[tert-butyl(dimethyl)silyl]oxy-2-isopropyl-aniline (471 mg, 1.8 mmol), followed by the addition of trimethylaluminium (2 M in toluene, 2.0 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 5 minutes and then at room temperature for 15 minutes, then heated to 50 °C for 15 hours. After cooling to room temperature, the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate three times. The combined organic layers were washed with brine twice, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light-yellow solid. Yield: 450 mg, 60%. LCMS (ESI) m/z: 523.2 (M+H). Step 2: Synthesis of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-(1-methylethy l)phenyl]-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-isopropyl-phe nyl]-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (300 mg, 574 μmol) in N,N-dimethylacetamide (2 mL) were added (3S)-tetrahydrofuran-3-amine HCl salt (107 mg, 862 μmol) and N,N- diisopropylethylamine (223 mg, 1.7 mmol). After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with water three times and brine three times, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light-yellow solid. Yield: 200 mg, 58%. LCMS (ESI) m/z: 574.0 (M+H). Step 3: Synthesis of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-(1-methylethyl)phenyl ]-6-(6-methoxy- 4-methyl-3-pyridyl)-4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrr olo[1,2-b]pyridazine-3- carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-(1-methylethy l)phenyl]-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine (180 mg, 314 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (105 mg, 628 μmol) in N,N-dimethylformamide (2 mL) and water (0.2 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (21 mg, 31 μmol) and potassium phosphate (200 mg, 943 μmol). The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light yellow solid. Yield: 110 mg, 55%. LCMS (ESI) m/z: 615.5 (M+H). Step 4: Synthesis of N'-[4-hydroxy-2-(1-methylethyl)phenyl]-6-(6-methoxy-4-methyl -3-pyridyl)- 4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine -3-carboxamidine To a solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-(1-methylethyl)phenyl ]-6-(6-methoxy-4- methyl-3-pyridyl)-4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrrol o[1,2-b]pyridazine-3- carboxamidine (100 mg, 162 μmol) in N,N-dimethylformamide (2 mL) was added cesium fluoride (74 mg, 488 μmol). The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded N'-[4-hydroxy-2-(1- methylethyl)phenyl]-6-(6-methoxy-4-methyl-3-pyridyl)-4-[[(3S )-tetrahydrofuran-3- yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine as a light-yellow solid. Yield: 69 mg, 83%. LCMS (ESI) m/z: 501.4 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.54 (s, 1H), 8.96 (s, 1H), 8.24-8.26 (m, 2H), 7.90 (d, 1H, J=1.6 Hz), 7.06 (d, 1H, J=2.0 Hz), 6.78 (s, 1H), 6.71 (s, 1H), 6.56-6.62 (m, 2H), 5.94 (s, 2H), 4.96-5.02 (m, 1H), 3.93-3.96 (m, 1H), 3.86 (s, 3H), 3.75-3.80 (m, 2H), 3.67-3.70 (m, 1H), 2.97-3.04 (m, 1H), 2.43 (s, 3H), 2.33-2.42 (m, 1H), 1.86-1.93 (m, 1H), 1.10 (d, 6H, J=6.8 Hz). EXAMPLE 168 Synthesis of N'-(2-cyclopropyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3- pyridyl)-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine Step 1: Synthesis of 4-benzyloxy-2-bromo-1-nitro-benzene To a mixture of 3-bromo-4-nitro-phenol (2.00 g, 9.17 mmol) and potassium carbonate (2.54 g, 18.35 mmol) in acetonitrile (40.0 mL) was added bromomethylbenzene (2.04 g, 11.93 mmol) at 0 °C. After stirring at 25 °C for 15 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water twice and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light yellow solid. Yield: 2.60 g, 91%. ¹ H NMR (DMSO-d6, 400 MHz) δ 8.08 (d, 1H, J=9.2 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.34-7.49 (m, 5H), 7.22 (dd, 1H, J=9.2, 2.8 Hz), 5.26 (s, 2H). Step 2: Synthesis of 4-benzyloxy-2-cyclopropyl-1-nitro-benzene To a solution of 4-benzyloxy-2-bromo-1-nitro-benzene (2.60 g, 8.44 mmol) in 1,4-dioxane (50.0 mL) were added cyclopropylboronic acid (3.62 g, 42.19 mmol), [1,1'- bis(diphenylphosphino)ferrocene] palladium(II) dichloride (617 mg, 843.8 μmol) and potassium phosphate (5.37 g, 25.31 mmol). The resulting mixture was purged with nitrogen gas and stirred at 100 °C for 5 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 2.00 g, 88%. LCMS (ESI) m/z: 270.0 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 7.94 (d, 1H, J=9.2 Hz), 7.32- 7.50 (m, 5H), 6.97-7.04 (m, 1H), 6.75 (d, 1H, J=2.8 Hz), 5.22 (s, 2H), 2.32-2.44 (m, 1H), 0.93- 1.05 (m, 2H), 0.72-0.85 (m, 2H). Step 3: Synthesis of 4-benzyloxy-2-cyclopropyl-aniline To a solution 4-benzyloxy-2-cyclopropyl-1-nitro-benzene (1.90 g, 7.06 mmol) in ethanol (50.0 mL) and water (10.0 mL) were added zinc powder (4.15 g, 63.50 mmol) and ammonia hydrochloride (5.66 g, 105.83 mmol) at room temperature. After stirring at 25 °C for 3 hours, the reaction mixture was filtrated and the filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a black oil. Yield: 1.30 g, 77%. LCMS (ESI) m/z: 240.1 (M+H). Step 4: Synthesis of N'-(4-benzyloxy-2-cyclopropyl-phenyl)-6-bromo-4-chloro-pyrro lo[1,2- b]pyridazine-3-carboxamidine To a solution of 6-bromo-4-chloro-pyrrolo[1,2-b]pyridazine-3-carbonitrile (300 mg, 1.17 mmol) and 4-benzyloxy-2-cyclopropyl-aniline (420 mg, 1.75 mmol) in toluene (3.0 mL) was added trimethylalumane (1.8 mL, 2 M in toluene, 3.60 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature and then heated to 70 °C for 15 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and saturated aqueous solution of ammonium chloride/sodium bicarbonate (1:1 v/v). The aqueous phase was extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification via reverse column chromatography (acetonitrile/water) afforded the title compound as a brown solid. Yield: 220 mg, 33%. LCMS (ESI) m/z: 497.2 (M+H). Step 5: Synthesis of 6-bromo-4-chloro-N'-(2-cyclopropyl-4-hydroxy-phenyl)pyrrolo[ 1,2- b]pyridazine-3-carboxamidine To a solution of N'-(4-benzyloxy-2-cyclopropyl-phenyl)-6-bromo-4-chloro-pyrro lo[1,2- b]pyridazine-3-carboxamidine (220 mg, 390.48 μmol) in dichloromethane (5.0 mL) was added boron tribromide (2.0 mL, 1 M in dichloromethane, 2.00 mmol) at 0°C under nitrogen atmosphere. After stirring at 0 °C for an hour, the reaction mixture was quenched with methanol at 0°C and further stirred at 0°C for an hour. The resulting mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a brown solid. Yield: 110 mg, 53%. LCMS (ESI) m/z: 407.1 (M+H). Step 6: Synthesis of 6-bromo-N'-(2-cyclopropyl-4-hydroxy-phenyl)-4-[[(3S)-tetrahy drofuran-3- yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-4-chloro-N'-(2-cyclopropyl-4-hydroxy-phenyl)pyrrolo[ 1,2- b]pyridazine-3-carboxamidine (90 mg, 170.8 μmol) and (3S)-tetrahydrofuran-3-amine hydrochloric acid salt (32 mg, 256.2 μmol) in N,N-dimethylacetamide (2.0 mL) was added N,N- diisopropylethylamine (66 mg, 512.5 μmol). After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 46 mg, 39%, 67% purity. LCMS (ESI) m/z: 458.3 (M+H). Step 7: Synthesis of N'-(2-cyclopropyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3- pyridyl)-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine To a solution of 6-bromo-N'-(2-cyclopropyl-4-hydroxy-phenyl)-4-[[(3S)-tetrahy drofuran-3- yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine (40 mg, 58.7 μmol) and (6-methoxy-4- methyl-3-pyridyl)boronic acid (20 mg, 117.5 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (4 mg, 5.9 μmol) and potassium phosphate (25 mg, 117.5 μmol). The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 90 °C for an hour, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via prep-TLC (ethyl acetate/petroleum ether) afforded N'-(2-cyclopropyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3- pyridyl)-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine as a yellow solid. Yield: 12.6 mg, 41%. LCMS (ESI) m/z: 499.4 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.62 (d, 1H, J=6.8 Hz), 8.93 (s, 1H), 8.25 (s, 2H), 7.90 (d, 1H, J=2.0 Hz), 7.04 (d, 1H, J=1.6 Hz), 6.78 (s, 1H), 6.61-6.64 (m, 1H), 6.52-6.56 (m, 1H), 6.25 (d, 1H, J=2.8 Hz), 5.98 (s, 2H), 4.90-5.00 (m, 1H), 3.93-3.97 (m, 1H), 3.86 (s, 3H), 3.65-3.80 (m, 3H), 2.43 (s, 3H), 2.30-2.41(m, 1H), 1.80- 1.92 (m, 2H), 0.78-0.86 (m, 2H), 0.50-0.60 (m, 2H). EXAMPLE 169 Synthesis of 4-[[(3R)-1,1-dioxothiolan-3-yl]amino]-N'-(2-ethyl-4-hydroxy- phenyl)-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine formic acid salt Step 1: Synthesis of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[(3R)-1,1- dioxothiolan-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxami dine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (300 mg, 590.6 μmol) and (3R)-1,1-dioxothiolan-3- amine hydrochloric acid salt (428 mg, 2.36 mmol) in N,N-dimethylacetamide (4.0 mL) was added N,N-diisopropylethylamine (382 mg, 2.95 mmol). After stirring at 80 °C for 2 hours, the reaction mixture was cooled to room temperature, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 300 mg, 84%. LCMS (ESI) m/z: 608.1 (M+H). Step 2: Synthesis of 4-[[(3R)-1,1-dioxothiolan-3-yl]amino]-N'-(2-ethyl-4-hydroxy- phenyl)-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine formic acid salt To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[(3R)-1,1- dioxothiolan-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxami dine (280 mg, 461.6 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (231 mg, 1.38 mmol) in N,N-dimethylformamide (3.0 mL) and water (0.3 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (30 mg, 46.2 μmol) and potassium carbonate (191 mg, 1.38 mmol). The resulting mixture was purged with nitrogen gas and stirred at 90 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1% formic acid) afforded 4-[[(3R)-1,1-dioxothiolan-3-yl]amino]-N'-(2-ethyl-4-hydroxy- phenyl)-6-(6-methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyrida zine-3-carboxamidine formic acid salt as a yellow solid. Yield: 83.6 mg, 32%. LCMS (ESI) m/z: 535.4 (M+H). ¹ H NMR (DMSO- d6, 300 MHz) δ 12.85 (brs, 1H), 8.28 (d, 2H, J=1.8 Hz), 8.17 (s, 1H), 7.95 (d, 1H, J=1.5 Hz), 7.07 (d, 1H, J=1.5 Hz,), 6.79 (s, 1H), 6.55-6.70 (m, 3H), 6.10 (brs, 2H), 5.20-5.30 (m, 1H), 3.87 (s, 3H), 3.70-3.80 (m, 1H), 3.15-3.35 (m, 2H), 3.00-3.10 (m, 1H), 2.60-2.72 (m, 1H), 2.35-2.50 (m, 6H), 2.08-2.20 (m, 1H), 1.02-1.08 (m, 3H). EXAMPLE 170 Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chlorophenyl)-6-[4- methoxy-2- (trifluoromethyl)phenyl]pyrrolo[1,2-b]pyridazine-3-carboximi damide formic acid salt

Step 1: Synthesis of tert-butyl [trans-4-[[6-bromo-3-[N'-(2- chlorophenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amin o]cyclohexyl]carbamate To a solution of 6-bromo-4-chloro-N'-(2-chlorophenyl)pyrrolo[1,2-b]pyridazine -3- carboximidamide (300 mg, 781.1 μmol) and tert-butyl (trans-4-aminocyclohexyl)carbamate (251 mg, 1.17 mmol) in N,N-dimethylacetamide (3.0 mL) was added N,N-diisopropylethylamine (302 mg, 2.34 mmol) dropwise. The reaction was stirred at 90 °C for 2 hours and cooled to room temperature. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 360 mg, 82%. LCMS (ESI) m/z: 561.0 (M+H). Step 2: Synthesis of tert-butyl [trans-4-[[3-[N'-(2-chlorophenyl)carbamimidoyl]-6-[4-methoxy -2- (trifluoromethyl)phenyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]c yclohexyl]carbamate To a mixture of tert-butyl [trans-4-[[6-bromo-3-[N'-(2-chlorophenyl)carbamimidoyl]pyrro lo[1,2- b]pyridazin-4-yl]amino]cyclohexyl]carbamate (300 mg, 533.9 μmol) and [4-methoxy-2- (trifluoromethyl)phenyl]boronic acid (176 mg, 800.8 μmol) in N,N-dimethylformamide (3.0 mL) and water (0.3 mL) were added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (34 mg, 53.3 μmol) and potassium carbonate (221 mg, 1.60 mmol) at room temperature under nitrogen atmosphere. After stirring at 75 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetated and washed with saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 220 mg, 62%. LCMS (ESI) m/z: 657.2 (M+H). Step 3: Synthesis of 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chlorophenyl)-6-[4- methoxy-2- (trifluoromethyl)phenyl]pyrrolo[1,2-b]pyridazine-3-carboximi damide formic acid salt To a solution of tert-butyl [trans-4-[[3-[N'-(2-chlorophenyl)carbamimidoyl]-6-[4-methoxy -2- (trifluoromethyl)phenyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]c yclohexyl]carbamate (170 mg, 258.7 μmol) in tetrahydrofuran (5.0 mL) was added 2N hydrochloric acid (1.0 mL in water). After stirring at 50 °C for an hour, the reaction mixture was concentrated under reduced pressure. The resulting mixture was diluted with ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 4-[(trans-4-aminocyclohexyl)amino]-N'-(2-chlorophenyl)-6-[4- methoxy-2- (trifluoromethyl)phenyl]pyrrolo[1,2-b]pyridazine-3-carboximi damide formic acid salt as an off- white solid. Yield: 125.9 mg, 80%. LCMS (ESI) m/z: 557.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.68 (d, 1H, J=6.4 Hz), 8.45 (s, 1H), 8.22-8.24 (m, 2H), 8.00-8.02 (m, 1H), 7.46-7.49 (m, 1H), 7.27-7.40 (m, 4H), 7.02-7.06 (m, 2H), 6.39 (s, 2H), 4.15-4.22 (m, 1H), 4.03 (s, 3H), 2.89-2.98 (m 1H), 2.18-2.26 (m, 2H), 1.97-2.03 (m, 2H), 1.39-1.65 (m, 4H). ¹⁹ F NMR (DMSO- d ₆ , 376 MHz) δ -60.60 (s, 3F). EXAMPLE 171 Synthesis of trans-N'-(2-ethyl-4-hydroxy-phenyl)-4-[(4-hydroxycyclohexyl) amino]-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine formic acid salt Step 1: Synthesis of trans-6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-p henyl]-4-[(4- hydroxycyclohexyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxami dine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (300 mg, 590.6 μmol) and trans-4-aminocyclohexanol (204 mg, 1.77 mmol) in N,N-dimethylacetamide (4.0 mL) was added N,N-diisopropylethylamine (382 mg, 2.95 mmol). After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 300 mg, 85%. LCMS (ESI) m/z: 586.3 (M+H). Step 2: Synthesis of trans-N'-(2-ethyl-4-hydroxy-phenyl)-4-[(4-hydroxycyclohexyl) amino]-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine formic acid salt To a solution of trans-6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-p henyl]-4-[(4- hydroxycyclohexyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxami dine (280 mg, 477.3 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (239 mg, 1.43 mmol) in N,N-dimethylformamide (3.0 mL) and water (0.3 mL) were added 1,1'-dis(di-t-butylphosphino)ferrocene-palladium dichloride (31 mg, 47.7 μmol) and potassium carbonate (198 mg, 1.43 mmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours. After cooling to room temperature and diluted with ethyl acetate, the resulting mixture was washed with water and brine, anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1% formic acid) afforded trans-N'-(2- ethyl-4-hydroxy-phenyl)-4-[(4-hydroxycyclohexyl)amino]-6-(6- methoxy-4-methyl-3- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt as a yellow solid. Yield: 65.7 mg, 24%. LCMS (ESI) m/z: 515.1 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.12 (brs, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 8.16 (s, 1H), 7.89 (d, 1H, J=1.5 Hz), 6.98 (s, 1H), 6.79 (s, 1H), 6.50- 6.75 (m, 3H), 5.90 (brs, 1H), 4.10-4.20 (m, 1H), 3.87 (s, 3H), 3.40-3.50 (m, 1H), 2.30-2.50 (m, 5H), 2.05-2.15 (m, 2H), 1.75-1.85 (m, 2H), 1.25-1.45 (m, 4H), 1.08 (t, 3H, J=7.5 Hz). EXAMPLE 172 Synthesis of N'-(2-ethyl-4-hydroxyphenyl)-6-(3-methylpyridin-2-yl)-4-[(te trahydrofuran-3- yl)amino]pyrrolo[1,2-b]pyridazine-3-carboximidamide Step 1: Synthesis of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-[[(3S )- tetrahydrofuran-3-yl]amino]-6-(4,4,5,5-tetramethyl-1,3,2-dio xaborolan-2-yl)pyrrolo[1,2- b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine (1.30 g, 2.33 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)-1,3,2-dioxaborolane (1.77 g, 6.98 mmol) in 1,4-dioxane (7.0 mL) were added 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride (170 mg, 232.7 μmol) and potassium acetate (685 mg, 6.98 mmol). The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 85 °C for 16 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 900 mg, 63%. LCMS (ESI) m/z: 606.2 (M+H). Step 2: Synthesis of N'-(2-ethyl-4-hydroxyphenyl)-6-(3-methylpyridin-2-yl)-4-[(te trahydrofuran- 3-yl)amino]pyrrolo[1,2-b]pyridazine-3-carboximidamide To a solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-[[(3R )-tetrahydrofuran-3- yl]amino]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyr rolo[1,2-b]pyridazine-3- carboxamidine (200 mg, 330.2 μmol) and 2-bromo-3-methylpyridine (140 mg, 495.3 μmol) in N,N-dimethylformamide (10.0 mL) and water (1.0 mL) were added 1,1'-bis (di-t- butylphosphino)ferrocene palladium dichloride (21.5 mg, 33.0 μmol) and potassium phosphate (210 mg, 990.6 μmol). The suspension was degassed under reduced pressure and purged with nitrogen three times. After stirring at 85 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrated was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded N'-(2-ethyl-4-hydroxyphenyl)-6- (3-methylpyridin-2-yl)-4-[(tetrahydrofuran-3-yl)amino]pyrrol o[1,2-b]pyridazine-3- carboximidamide as a white solid. Yield: 29.1 mg, 14%. LCMS (ESI) m/z: 457.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.61 (s, 1H), 8.96 (s, 1H), 8.47-8.49 (m, 1H), 8.26 (s, 1H), 8.09 (s, 1H), 7.67-7.69 (m, 1H), 7.37 (s, 1H), 7.18-7.22 (m, 1H), 6.68 (s, 1H), 6.57-6.64 (m, 2H), 5.94 (s, 2H), 4.96-4.98 (m, 1H), 3.93-3.96 (m, 1H), 3.71-3.87 (m, 3H), 2.56 (s, 3H), 2.32-2.50 (m, 3H), 1.88-1.94 (m, 1H), 1.08 (t, 3H, J=7.6 Hz). EXAMPLE 173 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-[6-[2-[2-[2-[2-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]etho xy]-4-methyl-3-pyridyl]-4- [[[(R)-pyrrolidin-2-yl]methyl]amino]pyrrolo[1,2-b]pyridazine -3-carboxamidine Step 1: Synthesis of 5-bromo-2-[2-[2-[2-[2-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]etho xy]-4-methyl-pyridine To a solution of sodium hydride (94 mg, 3.90 mmol, 60%) in tetrahydrofuran (10.0 mL) was added 2-[2-[2-[2-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]etha nol (1.00 g, 2.6 mmol) at 0 °C. After stirring for 10 min at 0 °C, 5-bromo-2-fluoro-4-methyl-pyridine (494 mg, 2.60 mmol) was added. After stirring at room temperature for 5 hours, the reaction mixture was quenched with saturated aqueous solution of ammonium chloride. The resulting mixture was diluted ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a light-yellow oil. Yield: 1.25 g, 81%. LCMS (ESI) m/z: 554.2 (M+H). Step 2: Synthesis of 2-[2-[2-[2-[2-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]etho xy]-4-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine To a solution of 5-bromo-2-[2-[2-[2-[2-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]etho xy]-4-methyl-pyridine (1.00 g, 1.80 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)-1,3,2- dioxaborolane (1.83 g, 7.21 mmol) in 1,4-dioxane (5.0 mL) were added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (132 mg, 180.4 μmol) and potassium acetate (531 mg, 5.41 mmol). The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (methanol/dichloromethane) afforded the title compound as a brown oil. Yield: 493 mg, 39%. LCMS (ESI) m/z: 602.3 (M+H). Step 3: Synthesis of tert-butyl-(R)-2-[[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamim idoyl]-6-[6-[2- [2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]etho xy]ethoxy]ethoxy]ethoxy]-4- methyl-3-pyridyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]methyl]p yrrolidine-1-carboxylate To a solution of tert-butyl-(R)-2-[[[6-bromo-3-[N'-[4-[1,1-dimethylethyl(dime thyl)silyl]oxy-2- ethyl-phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amin o]methyl]pyrrolidine-1- carboxylate (370 mg, 550.8 μmol) and 2-[2-[2-[2-[2-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]etho xy]-4-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (497 mg, 826.2 μmol) in N,N-dimethylformamide (5.0 mL) and water (0.5 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (36 mg, 55.1 μmol) and potassium phosphate (351 mg, 1.65 mmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, filtered and the filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (methanol/dichloromethane) afforded the title compound as a brown oil. Yield: 490 mg, 85%. LCMS (ESI) m/z: 974.4 (M+Na). Step 4: Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-[6-[2-[2-[2-[2-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]etho xy]-4-methyl-3-pyridyl]-4- [[[(R)-pyrrolidin-2-yl]methyl]amino]pyrrolo[1,2-b]pyridazine -3-carboxamidine To a solution of tert-butyl-(R)-2-[[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamim idoyl]-6-[6-[2-[2- [2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethoxy]-4-methyl- 3-pyridyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]methyl]pyrrolid ine-1-carboxylate (250 mg, 262.6 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (3.0 mL). After stirring at room temperature for an hour, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-(2-ethyl-4-hydroxy-phenyl)-6- [6-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethox y]ethoxy]ethoxy]ethoxy]ethoxy]- 4-methyl-3-pyridyl]-4-[[[(R)-pyrrolidin-2-yl]methyl]amino]py rrolo[1,2-b]pyridazine-3- carboxamidine as a yellow oil. Yield: 53.7 mg, 24%. LCMS (ESI) m/z: 852.5 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.20 (brs, 1H), 8.92 (m, 1H), 8.20-8.22 (m, 2H), 7.87 (s, 1H), 7.08 (s, 1H), 6.79 (s, 1H), 6.50-6.70 (m, 3H), 5.90 (brs, 2H), 4.35-4.41 (m, 2H), 3.65-3.85 (m, 4H), 3.45- 3.60 (m, 26H), 3.40-3.45 (m, 3H), 3.23 (s, 3H), 2.65-2.80 (m, 2H), 2.35-2.45 (m, 5H), 1.70-1.80 (m, 1H), 1.35-1.65 (m, 3H), 1.07 (t, 3H, J=7.5 Hz). EXAMPLE 174 Synthesis of 1-[5-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-4-[[[(R )-pyrrolidin-2- yl]methyl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-4-methyl-2-pyr idyl]-3-(2-hydroxy-2-methyl- propyl)urea

Step 1: Synthesis of phenyl N-(5-bromo-4-methyl-2-pyridyl)carbamate To a solution of 5-bromo-4-methyl-pyridin-2-amine (1.00 g, 5.35 mmol) in dichloromethane (20.0 mL) were added pyridine (634 mg, 8.02 mmol) and phenyl carbonochloridate (1.00 g, 6.42 mmol) dropwise at 0 °C under nitrogen atmosphere. After stirring at 25 °C for 2 hours, the reaction mixture was diluted with dichloromethane and washed with saturated aqueous solution of sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white solid. Yield: 2.10 g, 97%, 76% purity. LCMS (ESI) m/z: 306.8 (M+H). Step 2: Synthesis of 1-(5-bromo-4-methyl-2-pyridyl)-3-(2-hydroxy-2-methyl-propyl) urea To a solution of phenyl N-(5-bromo-4-methyl-2-pyridyl)carbamate (2.10 g, 5.20 mmol) in N,N- dimethylformamide (21.0 mL) were added triethylamine (1.57 g, 15.54 mmol) and 1-amino-2- methyl-propan-2-ol (1.85 g, 20.79 mmol). After stirring at 50 °C for 4 hours under nitrogen atmosphere, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with saturated aqueous solution of sodium carbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light yellow solid. Yield: 680 mg, 43%. LCMS (ESI) m/z: 301.9 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 9.23 (s, 1H), 8.23 (s, 1H), 7.57 (s, 2H), 4.52 (s, 1H), 3.08 (d, 2H, J=5.6 Hz), 2.29 (s, 3H), 1.08 (s, 6H). Step 3: Synthesis of 1-(2-hydroxy-2-methyl-propyl)-3-[4-methyl-5-(4,4,5,5-tetrame thyl-1,3,2- dioxaborolan-2-yl)-2-pyridyl]urea To a solution of 1-(5-bromo-4-methyl-2-pyridyl)-3-(2-hydroxy-2-methyl-propyl) urea (1.00 g, 3.31 mmol) in N,N-dimethylformamide (10.0 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.68 g, 6.62 mmol), palladium (II) acetate (37 mg, 165.4 μmol), tricyclohexyl phosphine (93 mg, 330.9 μmol) and potassium acetate (650 mg, 6.6 mmol). The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 5 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered and the filtrate was washed water and brine. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (methanol/dichloromethane) afforded the title compound as a brown oil. Yield: 880 mg, 76%. LCMS (ESI) m/z: 350.1 (M+H). Step 4: Synthesis of tert-butyl (R)-2-[[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-6-[6 - [(2-hydroxy-2-methyl-propyl)carbamoylamino]-4-methyl-3-pyrid yl]pyrrolo[1,2-b]pyridazin-4- yl]amino]methyl]pyrrolidine-1-carboxylate To a solution of 1,1-dimethylethyl (R)-2-[[[6-bromo-3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2- ethyl-phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amin o]methyl]pyrrolidine-1- carboxylate (200 mg, 297.7 μmol) in N,N-dimethylformamide (5.0 mL) and water (0.5 mL) were added 1-(2-hydroxy-2-methyl-propyl)-3-[4-methyl-5-(4,4,5,5-tetrame thyl-1,3,2-dioxaborolan-2- yl)-2-pyridyl]urea (208 mg, 595.5 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene-palladium dichloride (19 mg, 29.7 μmol) and potassium phosphate (126 mg, 595.5 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered and the filtrate was washed with water and brine. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a brown yellow solid. Yield: 170 mg, 81%. LCMS (ESI) m/z: 700.6 (M+H). Step 5: Synthesis of 1-[5-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-4-[[[(R )-pyrrolidin- 2-yl]methyl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-4-methyl-2-p yridyl]-3-(2-hydroxy-2-methyl- propyl)urea To a solution of tert-butyl (R)-2-[[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-6-[6 -[(2- hydroxy-2-methyl-propyl)carbamoylamino]-4-methyl-3-pyridyl]p yrrolo[1,2-b]pyridazin-4- yl]amino]methyl]pyrrolidine-1-carboxylate (150 mg, 214.3 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (1.5 mL). After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 1-[5-[3-[N'-(2- ethyl-4-hydroxy-phenyl)carbamimidoyl]-4-[[[(R)-pyrrolidin-2- yl]methyl]amino]pyrrolo[1,2- b]pyridazin-6-yl]-4-methyl-2-pyridyl]-3-(2-hydroxy-2-methyl- propyl)urea as a yellow solid. Yield: 63.7 mg, 47%. LCMS (ESI) m/z: 600.5 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.11 (s, 1H), 9.20 (s, 1H), 8.92 (s, 1H), 8.20-8.26 (m, 3H), 7.87 (d, 1H, J=1.6 Hz), 7.31 (s, 1H), 7.09 (d, 1H, J=2.0 Hz), 6.56-6.67 (m, 3H), 5.85 (brs, 2H), 4.53 (s, 1H), 3.64-3.86 (m, 2H), 3.23-3.32 (m, 1H), 3.14 (d, 2H, J=5.6 Hz), 2.68-2.76 (m, 2H), 2.35-2.48 (m, 5H), 1.71-1.85 (m, 1H), 1.44- 1.69 (m, 3H), 1.01-1.11 (m, 9H). EXAMPLE 175 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(4-methoxy-2,6-dimethyl-phen yl)-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine To a solution of 6-bromo-N'-[4-[1,1-dimethylethyl(dimethyl)silyl]oxy-2-ethyl- phenyl]-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine (250 mg, 447.5 μmol) and (4-methoxy-2,6-dimethyl-phenyl)boronic acid (161 mg, 895.1 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added potassium phosphate (285 mg, 1.34 mmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (29 mg, 44.7 μmol). The suspension was degassed under reduced pressure and purged with nitrogen three times. After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded N'-(2-ethyl-4-hydroxy-phenyl)-6- (4-methoxy-2,6-dimethyl-phenyl)-4-[[(3S)-tetrahydrofuran-3-y l]amino]pyrrolo[1,2-b]pyridazine- 3-carboxamidine as an off-white solid. Yield: 80.1 mg, 35%. LCMS (ESI) m/z: 500.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.45 (d, 1H, J=7.2 Hz), 8.95 (s, 1H), 8.22 (s, 1H), 7.58 (s, 1H), 6.66-6.75 (m, 4H), 6.56-6.62 (m, 2H), 5.91 (s, 2H), 4.85-4.95 (m, 1H), 3.86-3.92 (m, 1H), 3.70- 3.81 (m, 5H), 3.67-3.69 (m, 1H), 2.35-2.48 (m, 2H), 2.25-2.33 (m, 1H), 2.12 (s, 6H), 1.85-1.93 (m, 1H), 1.07 (t, 3H, J=7.6 Hz). EXAMPLE 176 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(4-methoxy-2,6-dimethyl-phen yl)-4-[[[(R)- pyrrolidin-2-yl]methyl]amino]pyrrolo[1,2-b]pyridazine-3-carb oxamidine Step 1: Synthesis of tert-butyl-(R)-2-[[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamim idoyl]-6-(4- methoxy-2,6-dimethyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]ami no]methyl]pyrrolidine-1- carboxylate To a solution of tert-butyl-(R)-2-[[[6-bromo-3-[N'-[4-[1,1-dimethylethyl(dime thyl)silyl]oxy-2- ethyl-phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amin o]methyl]pyrrolidine-1- carboxylate (250 mg, 372.2 μmol) and (4-methoxy-2,6-dimethyl-phenyl)boronic acid (201 mg, 1.12 mmol) in N,N-dimethylformamide (4.0 mL) and water (0.4 mL) were added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (24 mg, 37.2 μmol) and potassium phosphate (237 mg, 1.12 mmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 210 mg, 79%. LCMS (ESI) m/z: 613.2 (M+H). Step 2: Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(4-methoxy-2,6-dimethyl-phen yl)-4-[[[(R)- pyrrolidin-2-yl]methyl]amino]pyrrolo[1,2-b]pyridazine-3-carb oxamidine To a solution of tert-butyl-(R)-2-[[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamim idoyl]-6-(4- methoxy-2,6-dimethyl-phenyl)pyrrolo[1,2-b]pyridazin-4-yl]ami no]methyl]pyrrolidine-1- carboxylate (190 mg, 310.1 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (3.0 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-(2-ethyl-4-hydroxy-phenyl)-6- (4-methoxy-2,6-dimethyl-phenyl)-4-[[[(R)-pyrrolidin-2-yl]met hyl]amino]pyrrolo[1,2- b]pyridazine-3-carboxamidine as an off-white solid. Yield: 62.9 mg, 39%. LCMS (ESI) m/z: 513.1 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.06 (brs, 1H), 8.93 (s, 1H), 8.18 (s, 1H), 7.54 (d, 1H, J=1.8 Hz), 6.58-6.77 (m, 6H), 5.70 (brs, 1H), 3.55-3.80 (m, 5H), 3.20-3.30 (m, 1H), 2.60- 2.75 (m, 2H), 2.35-2.45 (m, 2H), 2.11 (s, 6H), 1.70-1.80 (m, 1H), 1.35-1.65 (m, 3H), 1.07 (t, 3H, J=7.5 Hz). EXAMPLE 177 Synthesis of 1-(2-cyanoethyl)-3-[5-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carba mimidoyl]-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-4-m ethyl-2-pyridyl]urea To a solution of 6-bromo-N'-[4-[1,1-dimethylethyl(dimethyl)silyl]oxy-2-ethyl- phenyl]-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine (170 mg, 304.3 μmol) in N,N-dimethylformamide (5.0 mL) and water (0.5 mL) were added 1-(2-cyanoethyl)-3-[4-methyl- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]ur ea (180 mg, 456.5 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene-palladium dichloride (20 mg, 30.4 μmol) and potassium phosphate (129 mg, 608.6 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered and the filtrate was washed with water and brine. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 1-(2-cyanoethyl)- 3-[5-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-4-[[(3S )-tetrahydrofuran-3- yl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-4-methyl-2-pyridyl]ur ea as a yellow solid. Yield: 68.0 mg, 38%. LCMS (ESI) m/z: 568.3 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.55 (d, 1H, J=7.2 Hz), 9.38 (s, 1H), 8.96 (s, 1H), 8.52 (brs, 1H), 8.31 (s, 1H), 8.25 (s, 1H), 7.93 (d, 1H, J=1.6 Hz), 7.28 (s, 1H), 7.08 (d, 1H, J=1.6 Hz), 6.67 (s, 1H), 6.57-6.64 (m, 2H), 5.93 (s, 2H), 4.97-5.03 (m, 1H), 3.93-3.97 (m, 1H), 3.74-3.83 (m, 2H), 3.69-3.73 (m, 1H), 3.43-3.51 (m 2H), 2.75 (t, 2H, J=6.4 Hz), 2.31-2.47 (m, 6H), 1.86-1.96 (m, 1H), 1.07 (t, 3H, J=7.6 Hz). EXAMPLE 178 Synthesis of 1-(2-cyanoethyl)-3-[5-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carba mimidoyl]-4-[[[(R)- pyrrolidin-2-yl]methyl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-4 -methyl-2-pyridyl]urea Step 1: Synthesis of tert-butyl (R)-2-[[[6-[6-(2-cyanoethylcarbamoylamino)-4-methyl-3-pyridy l]- 3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]pyrrolo[1,2-b] pyridazin-4- yl]amino]methyl]pyrrolidine-1-carboxylate To a solution of tert-butyl (R)-2-[[[6-bromo-3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-e thyl- phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]meth yl]pyrrolidine-1-carboxylate (250 mg, 372.2 μmol) in N,N-dimethylformamide (6.0 mL) and water (0.6 mL) were added 1-(2- cyanoethyl)-3-[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxabo rolan-2-yl)-2-pyridyl]urea (219 mg, 558.2 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene-palladium dichloride (24 mg, 37.2 μmol) and potassium phosphate (158 mg, 744.3 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered and the filtrate was washed with water and brine. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 200 mg, 78%. LCMS (ESI) m/z: 681.6 (M+H). Step 2: Synthesis of 1-(2-cyanoethyl)-3-[5-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carba mimidoyl]-4- [[[(R)-pyrrolidin-2-yl]methyl]amino]pyrrolo[1,2-b]pyridazin- 6-yl]-4-methyl-2-pyridyl]urea To a solution of tert-butyl (R)-2-[[[6-[6-(2-cyanoethylcarbamoylamino)-4-methyl-3-pyridy l]-3- [N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]pyrrolo[1,2-b]py ridazin-4- yl]amino]methyl]pyrrolidine-1-carboxylate (180 mg, 264.4 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (1.5 mL). After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 1-(2-cyanoethyl)- 3-[5-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-4-[[[(R )-pyrrolidin-2- yl]methyl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-4-methyl-2-pyr idyl]urea as a light yellow solid. Yield: 53.4 mg, 33%. LCMS (ESI) m/z: 581.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.13 (s, 1H), 9.37 (s, 1H), 8.93 (s, 1H), 8.52 (brs, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 7.88 (d, 1H, J=1.6 Hz), 7.27 (s, 1H), 7.10 (d, 1H, J=1.6 Hz), 6.67 (s, 1H), 6.56-6.66 (m, 2H), 5.82 (brs, 2H), 3.68- 3.83 (m, 2H), 3.41-3.51 (m, 2H), 3.28-3.40 (m, 1H), 2.63-2.77 (m 4H), 2.37-2.48 (m, 5H), 1.72- 1.85 (m, 1H), 1.39-1.69 (m, 3H), 1.071 (t, 3H, J=7.6 Hz). EXAMPLE 179 Synthesis of N-[2-[4-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-4-[[ (3S)-tetrahydrofuran- 3-yl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl-phenoxy]et hyl]acetamide formic acid salt To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine (300 mg, 537 μmol) and N-[2-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y l)phenoxy]ethyl]acetamide (514 mg, 1.6 mmol) in N,N-dimethylformamide (6 mL) and water (0.6 mL) were added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (35 mg, 54 μmol) and potassium phosphate (228 mg, 1.1 mmol) at room temperature. The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. N-[2-[4-[3-[N'-(2-ethyl-4-hydroxy- phenyl)carbamimidoyl]-4-[[(3S)-tetrahydrofuran-3-yl]amino]py rrolo[1,2-b]pyridazin-6-yl]-3- methyl-phenoxy]ethyl]acetamide formic acid salt as a yellow solid. Yield: 67.2 mg, 20%. LCMS (ESI) m/z: 557.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.40 (brs, 1H), 9.08 (brs, 1H), 8.22 (s, 1H), 8.17 (s, 1H), 8.12 (t, 1H, J=5.6 Hz), 7.82 (d, 1H, J=1.6 Hz), 7.41 (d, 1H, J=8.4 Hz), 6.99 (d, 1H, J=2.0 Hz), 6.89 (s, 1H), 6.82-6.85 (m, 1H), 6.56-6.71 (m, 3H), 5.97 (s, 2H), 4.95-4.99 (m, 1H), 3.90-4.00 (m, 3H), 3.67-3.86 (m, 3H), 3.38-3.46 (m, 2H), 2.31-2.47 (m, 6H), 1.88-1.97 (m, 1H), 1.84 (s, 3H), 1.07 (t, 3H, J=7.6 Hz). EXAMPLE 180 Synthesis of N-[2-[4-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-4-[[ [(R)-pyrrolidin-2- yl]methyl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-3-methyl-pheno xy]ethyl]acetamide Step 1: Synthesis of tert-butyl (R)-2-[[[6-[4-(2-acetamidoethoxy)-2-methyl-phenyl]-3-[N'-(2- ethyl-4-hydroxy-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin -4-yl]amino]methyl]pyrrolidine- 1-carboxylate To a solution of tert-butyl (R)-2-[[[6-bromo-3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-e thyl- phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]meth yl]pyrrolidine-1-carboxylate (250 mg, 372 μmol) and N-[2-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy]ethyl]acetamide (237 mg, 744 μmol) in N,N-dimethylformamide (6 mL) and water (0.6 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (24 mg, 37 μmol) and potassium carbonate (103 mg, 744 μmol) at room temperature. The resulting mixture was purged with nitrogen gas and stirred at 70 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow solid. Yield: 150 mg, 60%. LCMS (ESI) m/z: 670.2 (M+H). Step 2: Synthesis of N-[2-[4-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-4-[[ [(R)- pyrrolidin-2-yl]methyl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-3 -methyl-phenoxy]ethyl]acetamide To a solution of tert-butyl (R)-2-[[[6-[4-(2-acetamidoethoxy)-2-methyl-phenyl]-3-[N'-(2- ethyl-4- hydroxy-phenyl)carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]am ino]methyl]pyrrolidine-1- carboxylate (130 mg, 194 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (3 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded N-[2-[4-[3-[N'-(2-ethyl-4- hydroxy-phenyl)carbamimidoyl]-4-[[[(R)-pyrrolidin-2-yl]methy l]amino]pyrrolo[1,2-b]pyridazin- 6-yl]-3-methyl-phenoxy]ethyl]acetamide as a white solid. Yield: 63.7 mg, 56%. LCMS (ESI) m/z: 570.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 8.95 (brs, 1H), 8.20 (s, 1H), 8.13 (t, 1H, J=5.6 Hz), 7.79 (d, 1H, J=1.6 Hz), 7.39 (d, 1H, J=8.4 Hz), 7.01 (d, 1H, J=2.0 Hz), 6.79-6.92 (m, 2H), 6.56-6.69 (m, 3H), 5.92 (brs, 1H), 4.00 (t, 2H, J=5.6 Hz), 3.80-3.88 (m, 1H), 3.70-3.78 (m, 1H), 3.35-3.45 (m, 3H), 2.71-2.85 (m, 2H), 2.38-2.48 (m, 5H), 1.75-1.85 (m, 4H), 1.43-1.72 (m, 3H), 1.08 (t, 3H, J=7.6 Hz). EXAMPLE181 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(2-fluoro-3-pyridyl)-4-[[(R) -pyrrolidin-2- ylmethyl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of tert-butyl-(R)-2-[[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamim idoyl]-6-(2- fluoro-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]methyl]p yrrolidine-1-carboxylate To a solution of tert-butyl-(R)-2-[[[6-bromo-3-[N'-[4-[tert-butyl(dimethyl)si lyl]oxy-2-ethyl- phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]meth yl]pyrrolidine-1-carboxylate (250 mg, 372.2 μmol) and (2-fluoro-3-pyridyl)boronic acid (157 mg, 1.12 mmol) in N,N- dimethylformamide (4.0 mL) and water (0.4 mL) were added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (24 mg, 37.2 μmol) and sodium carbonate (118 mg, 1.12 mmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours. After cooling to room temperature, cesium fluoride (113 mg, 744.3 μmol) was added. After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 170 mg, 78%. LCMS (ESI) m/z: 574.3 (M+H). Step 2: Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(2-fluoro-3-pyridyl)-4-[[(R) -pyrrolidin-2- ylmethyl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of tert-butyl-(R)-2-[[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamim idoyl]-6-(2-fluoro- 3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]methyl]pyrrolid ine-1-carboxylate (150 mg, 261.5 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (2.0 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-(2-ethyl-4-hydroxy-phenyl)-6-(2-fluoro-3-pyridyl)- 4-[[(R)-pyrrolidin-2-ylmethyl]amino]pyrrolo[1,2-b]pyridazine -3-carboxamidine as an off-white solid. Yield: 58.4 mg, 47%. LCMS (ESI) m/z: 474.1 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.23 (brs, 1H), 8.93 (s, 1H), 8.47-8.53 (m, 1H), 8.23-8.26 (m, 1H), 8.05-8.15 (m, 2H), 7.38-7.50 (m, 2H), 6.55-6.67 (m, 3H), 5.94 (brs, 1H), 3.70-3.87 (m, 2H), 3.20-3.30 (m, 1H), 2.71-2.76 (m, 2H), 2.40-2.45 (m, 2H), 1.75-1.85 (m, 1H), 1.40-1.70 (m, 3H), 1.01-1.08 (m, 3H). EXAMPLE182 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4-(2- oxaspiro[3.3]heptan-6-ylamino)pyrrolo[1,2-b]pyridazine-3-car boxamidine Step 1: Synthesis of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-(2- oxaspiro[3.3]heptan-6-ylamino)pyrrolo[1,2-b]pyridazine-3-car boxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (300 mg, 590.6 μmol) and 2-oxaspiro[3.3]heptan-6- amine hydrochloric acid salt (132 mg, 885.9 μmol) in N,N-dimethylacetamide (5.0 mL) was added N,N-diisopropylethylamine (229 mg, 1.77 mmol) dropwise. After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 250 mg, 72%. LCMS (ESI) m/z: 586.0 (M+H). Step 2: Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4-(2- oxaspiro[3.3]heptan-6-ylamino)pyrrolo[1,2-b]pyridazine-3-car boxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-(2- oxaspiro[3.3]heptan-6-ylamino)pyrrolo[1,2-b]pyridazine-3-car boxamidine (225 mg, 384.8 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (128 mg, 769.7 μmol) in N,N- dimethylformamide (2.0 mL) and water (0.2 mL) were added potassium phosphate (245 mg, 1.15 mmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (25 mg, 38.4 μmol). The suspension was degassed under reduced pressure and purged with nitrogen three times. After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solids were filtered out and the filter was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded N'-(2-ethyl-4-hydroxy-phenyl)-6- (6-methoxy-4-methyl-3-pyridyl)-4-(2-oxaspiro[3.3]heptan-6-yl amino)pyrrolo[1,2-b]pyridazine-3- carboxamidine as an off-white solid. Yield: 65.6 mg, 32%. LCMS (ESI) m/z: 513.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.46 (d, 1H, J=6.4 Hz), 8.96 (s, 1H), 8.24 (s, 1H), 8.22 (s, 1H), 7.87 (s, 1H), 6.97 (s, 1H), 6.78 (s, 1H), 6.57-6.63 (m, 3H), 5.93 (s, 2H), 4.54-4.63 (m, 3H), 4.48 (s, 2H), 3.85 (s, 3H), 2.80-2.86 (m, 2H), 2.32-2.45 (m, 5H), 2.07-2.13 (m, 2H), 1.07 (t, 3H, J=7.6 Hz). EXAMPLE183 Synthesis of (R)-2-(3-(N'-(2-ethyl-4-hydroxyphenyl)carbamimidoyl)-4-((pyr rolidin-2- ylmethyl)amino)pyrrolo[1,2-b]pyridazin-6-yl)pyridine 1-oxide hydrate Step 1: Synthesis of tert-butyl (R)-2-[[[3-[N'-[4-[1,1-dimethylethyl(dimethyl)silyl]oxy-2-et hyl- phenyl]carbamimidoyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboro lan-2-yl)pyrrolo[1,2-b]pyridazin- 4-yl]amino]methyl]pyrrolidine-1-carboxylate To a solution of tert-butyl (R)-2-[[[6-bromo-3-[N'-[4-[1,1-dimethylethyl(dimethyl)silyl] oxy-2- ethyl-phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amin o]methyl]pyrrolidine-1- carboxylate (300 mg, 446.6 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (340 mg, 1.34 mmol) in 1,4-dioxane (10 mL) were added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (33 mg, 44.7 μmol) and potassium acetate (131 mg, 1.34 mmol). The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 100 °C for 2 hours, the reaction was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over hydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via prep-TLC (ethyl acetate/petroleum ether) afforded the title compound as a brown oil, which was used next step without further purification. Yield: 150 mg, 39%. LCMS (ESI) m/z: 719.7 (M+H). Step 2: Synthesis of tert-butyl (R)-2-[[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-6-(1 - oxidopyridin-1-ium-2-yl)pyrrolo[1,2-b]pyridazin-4-yl]amino]m ethyl]pyrrolidine-1-carboxylate To a solution of tert-butyl (R)-2-[[[3-[N'-[4-[1,1-dimethylethyl(dimethyl)silyl]oxy-2-et hyl- phenyl]carbamimidoyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboro lan-2-yl)pyrrolo[1,2-b]pyridazin- 4-yl]amino]methyl]pyrrolidine-1-carboxylate (120 mg, 166.9 μmol) and 2-bromo-1-oxido- pyridin-1-ium hydrochloric acid salt (176 mg, 834.7 μmol) in N,N-dimethylformamide (3.0 mL) and water (0.3 mL) were added tetrakis(triphenylphosphine)palladium (58 mg, 50.1 μmol) and potassium carbonate (69 mg, 500.8 μmol). The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 100 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via prep-TLC (ethyl acetate/petroleum ether) afforded the title compound as a brown solid. Yield: 48 mg, 39%. LCMS (ESI) m/z: 572.5 (M+H). Step 3: Synthesis of (R)-2-(3-(N'-(2-ethyl-4-hydroxyphenyl)carbamimidoyl)-4-((pyr rolidin-2- ylmethyl)amino)pyrrolo[1,2-b]pyridazin-6-yl)pyridine 1-oxide hydrate To a solution of tert-butyl (R)-2-[[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-6-(1 - oxidopyridin-1-ium-2-yl)pyrrolo[1,2-b]pyridazin-4-yl]amino]m ethyl]pyrrolidine-1-carboxylate (48 mg, 66.3 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (3.0 mL) dropwise at 0°C. After stirring at 25 °C for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous solution of sodium carbonate and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded (R)-2-(3-(N'-(2-ethyl-4-hydroxyphenyl)carbamimidoyl)-4-((pyr rolidin-2- ylmethyl)amino)pyrrolo[1,2-b]pyridazin-6-yl)pyridine 1-oxide hydrate as a yellow solid. Yield: 9.1 mg, 28%. LCMS (ESI) m/z: 472.5 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 10.95 (s, 1H), 9.88 (s, 1H), 9.58 (s, 1H), 9.12-9.20 (m, 1H), 9.00 (d, 1H, J=1.6 Hz), 8.83-8.90 (m, 1H), 8.66 (s, 1H), 8.38 (d, 1H, J=6.0 Hz), 8.13 (d, 1H, J=1.6 Hz), 8.05 (s, 1H), 7.99 (d, 1H, J=1.6 Hz), 7.75 (s, 1H), 7.42-7.50 (m, 1H), 7.30-7.38 (m, 2H), 6.77-6.83 (m, 2H), 3.90-4.00 (m, 1H), 3.75-3.85 (m, 1H), 3.20-3.30 (m, 2H), 2.50-2.60 (m, 3H), 2.15-2.25 (m, 1H), 1.85-2.00 (m, 2H), 1.65-1.75 (m, 1H), 1.17 (t, 3H, J=7.6 Hz). EXAMPLE184 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4-(oxetan-3- ylmethylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-(oxetan-3- ylmethylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (300 mg, 590.6 μmol) and oxetan-3-ylmethanamine (102 mg, 1.18 mmol) in N,N-dimethylacetamide (2.0 mL) was added N,N-diisopropylethylamine (229 mg, 1.77 mmol) dropwise. After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 320 mg, 96%. LCMS (ESI) m/z: 558.1 (M+H). Step 2: Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4-(oxetan- 3-ylmethylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-(oxetan-3- ylmethylamino)pyrrolo[1,2-b]pyridazine-3-carboxamidine (300 mg, 537.0 μmol) in N,N- dimethylformamide (3.0 mL) and water (0.3 mL) were added (6-methoxy-4-methyl-3- pyridyl)boronic acid (179 mg, 1.07 mmol), potassium phosphate (342 mg, 1.61 mmol) and 1,1'- bis (di-t-butylphosphino)ferrocene palladium dichloride (35 mg, 53.7 μmol). The resulting mixture was purged with nitrogen gas and stirred at 90 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4- (oxetan-3-ylmethylamino)pyrrolo[1,2-b]pyridazine-3-carboxami dine as an off-white solid. Yield: 62.5 mg, 23%. LCMS (ESI) m/z = 487.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.26 (t, 1H, J=4.8 Hz), 8.96 (s, 1H), 8.26 (s, 1H), 8.23 (s, 1H), 7.89 (s, 1H), 7.16 (s, 1H), 6.79 (s, 1H), 6.67 (s, 1H), 6.56-6.62 (m, 2H), 5.92 (s, 2H), 4.60-4.64 (m, 2H), 4.40 (t, 2H, J=6.0 Hz), 4.11-4.14 (m, 2H), 3.87 (s, 3H), 3.25-3.34 (m, 1H), 2.33-2.42 (m, 5H), 1.08 (t, 3H, J=7.6 Hz). EXAMPLE185 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(4-methyl-3-pyridyl)-4-[[[(R )-pyrrolidin-2- yl]methyl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine Step 1: Synthesis of tert-butyl-(R)-2-[[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamim idoyl]-6-(4- methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]methyl]p yrrolidine-1-carboxylate To a solution of tert-butyl-(R)-2-[[[6-bromo-3-[N'-[4-[1,1-dimethylethyl(dime thyl)silyl]oxy-2- ethyl-phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amin o]methyl]pyrrolidine-1- carboxylate (250 mg, 372.2 μmol) and (4-methyl-3-pyridyl)boronic acid (153 mg, 1.12 mmol) in N,N-dimethylformamide (3.0 mL) and water (0.3 mL) were added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (24 mg, 37.2 μmol) and sodium carbonate (118 mg, 1.12 mmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours. After cooling to room temperature, cesium fluoride (113 mg, 744.3 μmol) was added. After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate, filtered and the filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (methanol/dichloromethane) afforded the title compound as a brown solid. Yield: 180 mg, 83%. LCMS (ESI) m/z: 570.6 (M+H). Step 2: Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(4-methyl-3-pyridyl)-4-[[[(R )-pyrrolidin-2- yl]methyl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of tert-butyl-(R)-2-[[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamim idoyl]-6-(4- methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amino]methyl]p yrrolidine-1-carboxylate (160 mg, 280.8 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (0.3 mL). After stirring at room temperature for an hour, the reaction mixture was filtered concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-(2-ethyl-4-hydroxy-phenyl)-6-(4- methyl-3-pyridyl)-4-[[[(R)-pyrrolidin-2-yl]methyl]amino]pyrr olo[1,2-b]pyridazine-3- carboxamidine as an off-white solid. Yield: 65.0 mg, 49%. LCMS (ESI) m/z: 470.4 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.17 (brs, 1H), 8.93 (s, 1H), 8.67 (s, 1H), 8.36 (d, 1H, J=4.8 Hz), 8.23 (s, 1H), 7.96 (d, 1H, J=1.8 Hz), 7.31 (d, 1H, J=5.1 Hz), 7.17 (d, 1H, J=1.8 Hz), 6.55-6.67 (m, 3H), 5.85 (brs, 2H), 3.68-3.84 (m, 2H), 3.25-3.30 (m, 1H), 2.64-2.76 (m, 2H), 2.41-2.49 (m, 5H), 1.70-1.82 (m, 1H), 1.40-1.68 (m, 3H), 1.07 (t, 3H, J=7.5 Hz). EXAMPLE186 Synthesis of 6-[4-[(S)-3-aminopyrrolidin-1-yl]pyridin-3-yl]-N'-(2-ethyl-4 -hydroxyphenyl)-4- [[(S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3- carboximidamide

Step 1: Synthesis of tert-butyl (S)-[1-(3-bromopyridin-4-yl)pyrrolidin-3-yl]carbamate To a solution of 3-bromo-4-fluoro-pyridine (1.00 g, 5.68 mmol) and tert-butyl (S)-pyrrolidin-3- ylcarbamate (1.59 g, 8.52 mmol) in N,N-dimethylacetamide (5.0 mL) was added N,N- diisopropylethylamine (2.20 g, 17.05 mmol) dropwise. After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as an off-white solid. Yield: 1.40 g, 71%. LCMS (ESI) m/z: 343.9 (M+H). Step 2: Synthesis of tert-butyl [(S)-1-[3-[3-[N'-(2-ethyl-4-hydroxyphenyl)carbamimidoyl]-4- [[(S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazin-6-y l]pyridin-4-yl]pyrrolidin-3- yl]carbamate To a mixture of N'-[4-[(tert-butyldimethylsilyl)oxy]-2-ethylphenyl]-4-[[(3S) -tetrahydrofuran-3- yl]amino]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyr rolo[1,2-b]pyridazine-3- carboximidamide (350 mg, 577.8 μmol) and tert-butyl (S)-[1-(3-bromopyridin-4-yl)pyrrolidin-3- yl]carbamate (296 mg, 866.8 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (37 mg, 57.7 μmol) and potassium phosphate (368 mg, 1.73 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 hours. After cooled to room temperature, the reaction mixture was diluted with ethyl acetated and washed with saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 300 mg, 49%. LCMS (ESI) m/z: 627.2 (M+H). Step 3: Synthesis of 6-[4-[(S)-3-aminopyrrolidin-1-yl]pyridin-3-yl]-N'-(2-ethyl-4 - hydroxyphenyl)-4-[[(S)-tetrahydrofuran-3-yl]amino]pyrrolo[1, 2-b]pyridazine-3-carboximidamide To a solution of tert-butyl [(S)-1-[3-[3-[N'-(2-ethyl-4-hydroxyphenyl)carbamimidoyl]-4-[ [(S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazin-6-yl]pyri din-4-yl]pyrrolidin-3-yl]carbamate (270 mg, 258.4 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (2.0 mL) . After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 6-[4-[(S)-3-aminopyrrolidin-1-yl]pyridin-3-yl]-N'-(2- ethyl-4-hydroxyphenyl)-4-[[(S)-tetrahydrofuran-3-yl]amino]py rrolo[1,2-b]pyridazine-3- carboximidamide as an off-white solid. Yield: 11.4 mg, 3%. LCMS (ESI) m/z: 527.1 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.49 (d, 1H, J=7.2 Hz), 9.00 (brs, 1H), 8.24 (s, 1H), 8.09 (d, 2H, J=4.4 Hz), 7.75 (s, 1H), 6.91 (s, 1H), 6.55-6.70 (m, 4H), 5.93 (s, 2H), 4.85-4.95 (m, 1H), 3.85- 3.92 (m, 1H), 3.66-3.82 (m, 3H), 3.05-3.40 (m, 4H), 2.68-2.74 (m, 1H), 2.33-2.43 (m, 2H), 2.28- 2.32 (m, 1H), 1.83-1.95 (m, 2H), 1.52-1.60 (m, 1H), 1.07 (t, 3H, J=7.6 Hz). EXAMPLE187 Synthesis of 6-[4-(3-aminoazetidin-1-yl)-3-pyridyl]-N'-(2-ethyl-4-hydroxy -phenyl)-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine

Step 1: Synthesis of tert-butyl N-[1-(3-bromo-4-pyridyl)azetidin-3-yl]carbamate To a solution of 3-bromo-4-fluoro-pyridine (1.00 g, 5.6 mmol) and tert-butyl N-(azetidin-3- yl)carbamate HCl salt (1.42 g, 6.8 mmol) in N,N-dimethylacetamide (10 mL) was added N,N- diisopropylethylamine (2.20 g, 17 mmol). The resulting mixture was stirred at 100 °C overnight and then cooled to room temperature. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as an off-white solid. Yield: 1.54 g, 79%. LCMS (ESI) m/z: 328.1 (M+1). Step 2: Synthesis of tert-butyl N-[1-[3-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazin-6- yl]-4-pyridyl]azetidin-3- yl]carbamate To a solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-[[(3S )-tetrahydrofuran-3- yl]amino]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyr rolo[1,2-b]pyridazine-3- carboxamidine (270 mg, 445 μmol) and tert-butyl N-[1-(3-bromo-4-pyridyl)azetidin-3- yl]carbamate (219 mg, 668 μmol) in water (2 mL) and N,N-dimethylformamide (10 mL) were added sodium carbonate (142 mg, 1.3 mmol) and 1,1'-bis(di-t-butylphosphino)ferrocene- palladium dichloride (56 mg, 89 μmol) at room temperature. The resulting mixture was purged with nitrogen gas, stirred at 80 °C for 2 hours and then cooled to room temperature. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 190 mg, 67%. LCMS (ESI) m/z: 613.3 (M+1). Step 3: Synthesis of 6-[4-(3-aminoazetidin-1-yl)-3-pyridyl]-N'-(2-ethyl-4-hydroxy -phenyl)-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine To a solution of tert-butyl N-[1-[3-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-4-[[ (3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-4-p yridyl]azetidin-3-yl]carbamate (170 mg, 277 μmol) in methanol (20 mL) was added 4 M hydrogen chloride in 1,4-dixoane (0.7 mL, 2.8 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 hours and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 6-[4-(3-aminoazetidin-1-yl)-3-pyridyl]-N'-(2-ethyl-4-hydroxy -phenyl)-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine as an off-white solid. Yield: 69.8 mg, 46%. LCMS (ESI) m/z: 513.1 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.52 (d, 1H, J=7.2 Hz), 8.94 (s, 1H), 7.95-8.30 (m, 3H), 7.75 (d, 1H, J=1.6 Hz), 6.92 (s, 1H), 6.35- 6.71 (m, 4H), 5.92 (s, 2H), 4.92-4.96 (m, 1H), 3.65-3.95 (m, 7H), 3.10-3.25 (m, 2H), 2.30-2.49 (m, 4H), 1.84-1.92 (m, 1H), 1.07 (t, 3H, J=7.6 Hz). EXAMPLE188 Synthesis of 6-[4-(4-amino-1-piperidyl)-3-pyridyl]-N'-(2-ethyl-4-hydroxy- phenyl)-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine

Step 1: Synthesis of tert-butyl N-[1-(3-bromo-4-pyridyl)-4-piperidyl]carbamate To a solution of 3-bromo-4-chloro-pyridine (1.00 g, 5.20 mmol) and tert-butyl N-(4- piperidyl)carbamate (1.56 g, 7.79 mmol) in N,N-dimethylacetamide (4.0 mL) was added N,N- diisopropylethylamine (2.01 g, 15.59 mmol) dropwise. After stirring at 120 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as an off-white solid. Yield: 750 mg, 40%. LCMS (ESI) m/z: 357.9 (M+H). Step 2: Synthesis of tert-butyl N-[1-[3-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazin-6- yl]-4-pyridyl]-4- piperidyl]carbamate To a solution of N'-[4-[(tert-butyldimethylsilyl)oxy]-2-ethyl-phenyl]-4-[[(3S )-tetrahydrofuran-3- yl]amino]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyr rolo[1,2-b]pyridazine-3- carboxamidine (300 mg, 495.3 μmol) and tert-butyl N-[1-(3-bromo-4-pyridyl)-4- piperidyl]carbamate (264 mg, 743.0 μmol) in N,N-dimethylformamide (5.0 mL) and water (0.5 mL) were added 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (32 mg, 49.5 μmol) and potassium phosphate (315 mg, 1.49 mmol). The suspension degassed under reduced and purged with nitrogen three times. After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a brown oil. Yield: 370 mg, 89 %. LCMS (ESI) m/z: 641.3 (M+H). Step 3: Synthesis of 6-[4-(4-amino-1-piperidyl)-3-pyridyl]-N'-(2-ethyl-4-hydroxy- phenyl)-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine To a solution of tert-butyl N-[1-[3-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-4-[[ (3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-4-p yridyl]-4-piperidyl]carbamate (350 mg, 546.2 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (4.0 mL). After stirring at 25 °C for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 6-[4-(4-amino-1-piperidyl)-3-pyridyl]-N'-(2-ethyl-4- hydroxy-phenyl)-4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[ 1,2-b]pyridazine-3-carboxamidine as an off-white solid. Yield: 11.4 mg, 3%. LCMS (ESI) m/z: 541.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.58 (d, 1H, J=6.8 Hz), 8.55 (s, 1H), 8.40 (s, 1H), 8.27-8.30 (m, 2H), 8.11 (s, 1H), 7.24 (s, 1H), 7.00-7.02 (m, 1H), 6.59-6.68 (m, 3H), 5.94 (s, 2H), 4.95-5.00 (m, 1H), 3.95-4.00 (m, 1H), 3.69-3.82 (m, 3H), 3.28-3.32 (m, 2H), 2.85-2.96 (m, 1H), 2.60-2.67 (m, 2H), 2.35-2.45 (m, 3H), 1.78-1.96 (m, 3H), 1.45-1.55 (m, 2H), 1.07 (t, 3H, J=7.6 Hz). EXAMPLE189 Synthesis of 6-[4-[(R)-3-aminopyrrolidin-1-yl]pyridin-3-yl]-N'-(2-ethyl-4 -hydroxyphenyl)-4- [[(S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3- carboximidamide

Step 1: Synthesis of tert-butyl (R)-[1-(3-bromopyridin-4-yl)pyrrolidin-3-yl]carbamate To a solution of 3-bromo-4-fluoro-pyridine (2.00 g, 11.36 mmol) and tert-butyl N-[(3R)- pyrrolidin-3-yl]carbamate (3.17 g, 17.05 mmol) in N,N-dimethylacetamide (30.0 mL) was added N,N-diisopropylethylamine (4.41 g, 34.09 mmol). After stirring for 2 hours at 120 °C, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a brown oil. Yield: 3.00 g, 77%. LCMS (ESI) m/z: 342.1 (M+H). Step 2: Synthesis of tert-butyl [(R)-1-[3-[3-[N'-(2-ethyl-4-hydroxyphenyl)carbamimidoyl]-4- [[(S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazin-6-y l]pyridin-4-yl]pyrrolidin-3- yl]carbamate To a solution of (S)-N'-[4-[(tert-butyldimethylsilyl)oxy]-2-ethylphenyl]-4-[( tetrahydrofuran-3- yl)amino]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyr rolo[1,2-b]pyridazine-3- carboximidamide (200 mg, 330.2 μmol) and tert-butyl (R)-[1-(3-bromopyridin-4-yl)pyrrolidin-3- yl]carbamate (113 mg, 330.2 μmol) in N,N-dimethylformamide (3.0 mL) and water (0.3 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (50 mg, 33.0 μmol) and sodium carbonate (105 mg, 990.7 μmol). The resulting mixture was purged with nitrogen gas and stirred at 90 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a brown solid. Yield: 150 mg, 71%. LCMS (ESI) m/z: 627.6 (M+H). Step 3: Synthesis of 6-[4-[(R)-3-aminopyrrolidin-1-yl]pyridin-3-yl]-N'-(2-ethyl-4 - hydroxyphenyl)-4-[[(S)-tetrahydrofuran-3-yl]amino]pyrrolo[1, 2-b]pyridazine-3-carboximidamide To a solution of tert-butyl [(R)-1-[3-[3-[N'-(2-ethyl-4-hydroxyphenyl)carbamimidoyl]-4-[ [(S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazin-6-yl]pyri din-4-yl]pyrrolidin-3-yl]carbamate (130 mg, 207.0 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (5.0 mL). After stirring at room temperature for an hour, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 6-[4-[(R)-3- aminopyrrolidin-1-yl]pyridin-3-yl]-N'-(2-ethyl-4-hydroxyphen yl)-4-[[(S)-tetrahydrofuran-3- yl]amino]pyrrolo[1,2-b]pyridazine-3-carboximidamide as a white solid. Yield: 48.5 mg, 45%. LCMS (ESI) m/z: 527.2 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 12.48 (d, 1H, J=7.2 Hz), 8.95 (s, 1H), 8.23 (s, 1H), 8.00-8.15 (m, 2H), 7.75 (d, 1H, J=1.5 Hz), 6.91 (d, 1H, J=1.5 Hz), 6.56- 6.67 (m, 4H), 5.92 (s, 2H), 4.85-4.95 (m, 1H), 3.85-3.95 (m, 1H), 3.65-3.82 (m, 3H), 3.35-3.45 (m, 1H), 3.05-3.25 (m, 3H), 2.65-2.75 (m, 1H), 2.30-2.45 (m, 3H), 1.45-1.95 (m, 5H), 1.07 (t, 3H, J=7.5 Hz). EXAMPLE 190 Synthesis of 6-[2-[3-(dimethylamino)propyl]phenyl]-N'-(2-ethyl-4-hydroxy- phenyl)-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine Step 1: Synthesis of 1-bromo-2-(3-bromopropyl)benzene To a solution of 3-(2-bromophenyl)propan-1-ol (4.80 g, 22.32 mmol) in dichloromethane (55.0 mL) were added triphenylphosphine (8.78 g, 33.47 mmol) and carbon tetrabromide (11.10 g, 33.47 mmol) at 0 °C. After stirring at 25 °C for 2 hours, the reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 5.00 g, 80%. LCMS (ESI) m/s: 279.3 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.51-7.64 (m, 1H), 7.26-7.41 (m, 2H), 7.09-7.23 (m, 1H), 3.49-3.60 (m, 2H), 2.76-2.87 (m, 2H), 2.00-2.15 (m, 2H). Step 2: Synthesis of 3-(2-bromophenyl)-N,N-dimethyl-propan-1-amine To a solution of 2 M dimethylamine in tetrahydrofuran (30 mL) was added 1-bromo-2-(3- bromopropyl)benzene (3.00 g, 10.79 mmol). After stirring at 25 °C for 2 hours, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 1.40 g, 53%. LCMS (ESI) m/z: 244.2 (M+H). Step 3: Synthesis of 6-[2-[3-(dimethylamino)propyl]phenyl]-N'-(2-ethyl-4-hydroxy- phenyl)-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine To a solution of N'-[4-(tert-butyldimethylsilyl)oxy-2-ethyl-phenyl]-4-[[(3S)- tetrahydrofuran-3- yl]amino]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyr rolo[1,2-b]pyridazine-3- carboxamidine (260 mg, 429.3 μmol) in N,N-dimethylformamide (8.0 mL) and water (0.8 mL) were added 3-(2-bromophenyl)-N,N-dimethyl-propan-1-amine (156 mg, 643.9 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene-palladium dichloride (28 mg, 42.9 μmol) and potassium phosphate (182 mg, 858.5 μmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered and the filtrate was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded 6-[2-[3- (dimethylamino)propyl]phenyl]-N'-(2-ethyl-4-hydroxy-phenyl)- 4-[[(3S)-tetrahydrofuran-3- yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine as a light yellow solid. Yield: 15.5 mg, 6%. LCMS (ESI) m/z: 527.5 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.53 (d, 1H, J=7.2 Hz), 8.95 (s, 1H), 8.24 (s, 1H), 7.80 (d, 1H, J=2.0 Hz), 7.38-7.41 (m, 1H), 7.20-7.35 (m, 3H), 6.97 (d, 1H, J=1.6 Hz), 6.67 (d, 1H, J=2.4 Hz), 6.54-6.65 (m, 2H), 5.93 (s, 2H), 4.92-4.97 (m, 1H), 3.88-3.97 (m, 1H), 3.66-3.85 (m, 3H), 2.73-2.80 (m, 2H), 2.29-2.46 (m, 3H), 2.19 (t, 2H, J=7.2 Hz), 2.06 (s, 6H), 1.84-1.97 (m, 1H), 1.55-1.71 (m, 2H), 1.07 (t, 3H, J=7.6 Hz). EXAMPLE 191 Synthesis of 6-[2-[3-(dimethylamino)propyl]-6-methyl-phenyl]-N'-(2-ethyl- 4-hydroxy-phenyl)-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine formic acid salt Step 1: Synthesis of 3-(2-bromo-3-methylphenyl)-N,N-dimethylprop-2-en-1-amine To a suspension of (2-(2-(dimethylamino)ethyl)triphenylphosphonium bromide (1.50 g, 3.6 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M in hexane, 1.5 mL, 3.7 mmol) dropwise at -78 °C. The mixture was stirred at -78 °C for 30 minutes, then a solution of 2- bromo-3-methylbenzaldehyde (480 mg, 2.4 mmol) in tetrahydrofuran (2 mL) was added dropwise. After stirring at -78 °C for 2 hours, the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride and then extracted with ethyl acetate three times. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 590 mg, 63%. LCMS (ESI) m/z: 254.1 (M+H). Step 2: Synthesis of 3-(2-bromo-3-methylphenyl)-N,N-dimethylpropan-1-amine To a solution of 3-(2-bromo-3-methylphenyl)-N,N-dimethylprop-2-en-1-amine (580 mg, 2.2 mmol) in methanol (20 mL) was added 5% rhodium on alumina (47 mg) at room temperature under nitrogen atmosphere. The resulting mixture was purged with hydrogen gas and stirred at room temperature for 2 hours under hydrogen atmosphere (1.5 atm.). The reaction mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 140 mg, 15%. LCMS (ESI) m/z: 258.1 (M+H). Step 3: Synthesis of 6-[2-[3-(dimethylamino)propyl]-6-methyl-phenyl]-N'-(2-ethyl- 4-hydroxy- phenyl)-4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]py ridazine-3-carboxamidine formic acid salt To a solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-[[(3S )-tetrahydrofuran-3- yl]amino]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyr rolo[1,2-b]pyridazine-3- carboxamidine (200 mg, 330 μmol) and 3-(2-bromo-3-methylphenyl)-N,N-dimethylpropan-1- amine (127 mg, 495 μmol) in N,N-dimethylformamide (15 mL) and water (3 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (22 mg, 33 μmol) and potassium phosphate (210 mg, 990 μmol) at room temperature. The resulting mixture was purged with nitrogen gas, stirred at 80 °C for 2 hours and then cooled to room temperature. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 6-[2-[3- (dimethylamino)propyl]-6-methyl-phenyl]-N'-(2-ethyl-4-hydrox y-phenyl)-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine formic acid salt as a yellow solid. Yield: 115.1 mg, 58%. LCMS (ESI) m/z: 541.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 10.94 (s, 1H), 9.37 (s, 1H), 8.03-8.20 (m, 2H), 7.69 (d, 1H, J=1.6 Hz), 7.14-7.29 (m, 3H), 6.92 (s, 2H), 6.60-6.81 (m, 2H), 4.69-4.73 (m, 1H), 3.79-3.94 (m, 2H), 3.70-3.78 (m, 2H), 2.82- 2.94 (m, 2H), 2.65 (s, 6H), 2.41-2.49 (m, 4H), 2.24-2.38 (m, 1H), 2.07 (s, 3H), 1.92-2.02 (m, 1H), 1.72-1.82 (m, 2H), 1.10 (t, 3H, J=7.6 Hz). EXAMPLE 192 Synthesis of 6-[4-[3-(dimethylamino)propyl]-3-pyridyl]-N'-(2-ethyl-4-hydr oxy-phenyl)-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine

Step 1: Synthesis of ethyl 3-(3-bromo-4-pyridyl)prop-2-enoate To a solution of 3-bromopyridine-4-carbaldehyde (5.00 g, 26.9 mmol) in dichloromethane (100 mL) was added (2-ethoxy-2-oxoethylidene)triphenylphosphorane (14.05 g, 40.3 mmol). After stirring at room temperature for 5 hours, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as an off-white solid. Yield: 6.50 g, 95%. LCMS (ESI) m/z: 255.9 (M+H). Step 2: Synthesis of ethyl 3-(3-bromo-4-pyridyl)propanoate To a solution of ethyl 3-(3-bromo-4-pyridyl)prop-2-enoate (6.00 g, 23.4 mmol) in toluene (180 mL) was added 4-methylbenzenesulfonohydrazide (12.24 g, 35.1 mmol). After stirring at reflux for 15 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium carbonate, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light yellow oil. Yield: 5.00 g, 83%. ¹ H NMR (DMSO-d6, 400 MHz) δ 8.65-8.70 (m, 1H), 8.45 (d, 1H, J=5.2 Hz), 7.36-7.42 (m, 1H), 4.06 (q, 2H, J=7.2 Hz), 2.95 (t, 2H, J=7.6 Hz), 2.64-2.72 (m, 2H), 1.16 (t, 3H, J=7.2 Hz). Step 3: Synthesis of 3-(3-bromo-4-pyridyl)propan-1-ol To a solution of ethyl 3-(3-bromo-4-pyridyl)propanoate (5.00 g, 19.3 mmol) in dichloromethane (32 mL) was added diisobutylaluminium hydride (1 M in dichloromethane, 38.7 mL) at 0 ℃. After stirring at room temperature, the reaction mixture was quenched with sodium sulfate decahydrate and stirred for 2 hours, then filtered and washed with ethyl acetate. The combined filtrates were concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afford the title compound as a colorless oil. Yield: 3.20 g, 72%. LCMS (ESI) m/z: 218.1 (M+H). Step 4: Synthesis of 3-bromo-4-(3-bromopropyl)pyridine To a solution of 3-(3-bromo-4-pyridyl)propan-1-ol (1.95 g, 9.0 mmol) in dichloromethane (50 mL) was added triphenylphosphine (3.55 g, 13.5 mmol) at room temperature, followed by addition of carbon tetrabromide (4.49 g, 13.5 mmol) at 0 °C. After stirring at room temperature for 0.5 hour, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a light-yellow oil. Yield: 2.10 g, 72%. LCMS (ESI) m/z: 280.0 (M+H). ¹ H NMR (DMSO-d6, 300 MHz): δ 8.67 (s, 1H), 8.46 (d, 1H, J=5.1 Hz), 7.40 (d, 1H, J=5.1 Hz), 3.58 (t, 2H, J=6.6 Hz), 2.72-2.91 (m, 2H), 2.03-2.17 (m, 2H). Step 5: Synthesis of 3-(3-bromo-4-pyridyl)-N,N-dimethyl-propan-1-amine 3-Bromo-4-(3-bromopropyl)pyridine (2.10 g, 7.5 mmol) was dissolved in dimethylamine (2 M in tetrahydrofuran, 15 mL) and stirred at 50 °C for 1 hour in a sealed tube. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a red solid. Yield: 1.20 g, 60%. LCMS (ESI) m/z: 244.9 (M+H). ¹ H-NMR (DMSO-d6, 300 MHz) δ 8.71 (s, 1H), 8.50 (d, 1H, J=5.1 Hz), 7.47 (d, 1H, J=5.1 Hz), 3.04-3.16 (m, 2H), 2.68-2.82 (m, 8H), 1.88-2.04 (m, 2H). Step 6: Synthesis of 6-[4-[3-(dimethylamino)propyl]-3-pyridyl]-N'-(2-ethyl-4-hydr oxy-phenyl)-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine To a solution of N'-[4-[1,1-dimethylethyl(dimethyl)silyl]oxy-2-ethyl-phenyl]- 4-[[(3S)- tetrahydrofuran-3-yl]amino]-6-(4,4,5,5-tetramethyl-1,3,2-dio xaborolan-2-yl)pyrrolo[1,2- b]pyridazine-3-carboxamidine (280 mg, 462 μmol) and 3-(3-bromo-4-pyridyl)-N,N-dimethyl- propan-1-amine (169 mg, 694 μmol) in N,N-dimethylformamide (4 mL) and water (0.4 mL) were added tetrakis(triphenylphosphine)palladium (141 mg, 92 μmol) and sodium carbonate (98 mg, 924 μmol). The resulting mixture was purged with nitrogen gas and stirred at 90 °C for 2 hours. After cooling to room temperature, cesium fluoride (140 mg, 924 μmol) was added to the mixture and stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded 160 mg of a crude product. Further purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 6-[4-[3-(dimethylamino)propyl]-3-pyridyl]-N'-(2-ethyl-4-hydr oxy-phenyl)-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine as a yellow solid. Yield: 56.5 mg, 23%. LCMS (ESI) m/z: 528.4 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.59 (d, 1H, J=7.2 Hz), 8.95 (s, 1H), 8.59 (s, 1H), 8.41 (d, 1H, J=5.2 Hz), 8.27 (s, 1H), 7.93 (d, 1H, J=1.6 Hz), 7.35 (d, 1H, J=5.2 Hz), 7.07 (d, 1H, J=1.6 Hz), 6.67 (d, 1H, J=2.4 Hz), 6.55-6.65 (m, 2H), 5.95 (s, 2H), 4.93-5.02 (m, 1H), 3.91-3.97 (m, 1H), 3.72-3.85 (m, 2H), 3.69-3.71 (m, 1H), 2.78-2.86 (m, 2H), 2.32-2.43 (m, 3H), 2.19 (t, 2H, J=7.2 Hz), 2.05 (s, 6H), 1.85-1.97 (m, 1H), 1.62-1.72 (m, 2H), 1.07 (t, 3H, J = 7.6 Hz). EXAMPLE 193 Synthesis of 6-[2-[4-(dimethylamino)butyl]phenyl]-N'-(2-ethyl-4-hydroxy-p henyl)-4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine Step 1: Synthesis of 1-bromo-2-but-3-enyl-benzene To a solution of 1-bromo-2-(bromomethyl)benzene (2.00 g, 8.0 mmol) in tetrahydrofuran (100 mL) was added allylmagnesium bromide (1.0 M in ether, 8.8 mL, 8.8 mmol) dropwise at 0 °C. After stirring at room temperature for 15 hours, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a colorless oil. Yield: 1.35 g, 76%. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.55-7.59 (m, 1H), 7.26-7.40 (m, 2H), 7.11-7.17 (m, 1H), 5.83-8.89 (m, 1H), 4.91- 5.10 (m, 2H), 2.69-2.88 (m, 2H), 2.29-2.33 (m, 2H). Step 2: Synthesis of 4-(2-bromophenyl)butan-1-ol To a solution of 1-bromo-2-but-3-enyl-benzene (1.25 g, 5.9 mmol) in tetrahydrofuran (20 mL) was added borane-tetrahydrofuran (1.0 M in tetrahydrofuran, 11.8 mL, 11.8 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 3 hours, then methanol (5 mL) was added, followed by addition of hydrogen peroxide (603 mg, 5.9 mmol, 30%). After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate and washed with water twice and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 1.04 g, 73%. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.52-7.61 (m, 1H), 7.27-7.38 (m, 2H), 7.07-7.20 (m, 1H), 4.41 (t, 1H, J=5.2 Hz), 3.39-3.45 (m, 2H), 2.62-2.74 (m, 2H), 1.52-1.66 (m, 2H), 1.39-1.51 (m, 2H). Step 3: Synthesis of 4-(2-bromophenyl)butyl methanesulfonate To a solution of 4-(2-bromophenyl)butan-1-ol (940 mg, 4.1 mmol) and triethylamine (1.25 g, 12.3 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (940 mg, 8.2 mmol) dropwise at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane and washed with a saturated aqueous solution of sodium bicarbonate twice, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 950 mg, 72%. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.56-7.61 (m, 1H), 7.30-7.39 (m, 2H), 7.12-7.19 (m, 1H), 4.24 (t, 2H, J=6.0 Hz), 3.17 (s, 3H), 2.67-2.79 (m, 2H), 1.58-1.80 (m, 4H). Step 4: Synthesis of 4-(2-bromophenyl)-N,N-dimethyl-butan-1-amine 4-(2-Bromophenyl)butyl methanesulfonate (950 mg, 3.1 mmol) was dissolved in N- methylmethanamine (2.0 M in tetrahydrofuran, 20 mL) and then stirred at 70 °C for 15 hours in a sealed tube. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (methanol/dichloromethane) afforded the title compound as a yellow oil. Yield: 450 mg, 54%. ¹ H NMR (DMSO-d6, 400 MHz) δ 7.55-7.59 (m, 1H), 7.28-7.37 (m, 2H), 7.11-7.17 (m, 1H), 2.65-2.73 (m, 2H), 2.17-2.24 (m, 2H), 2.09 (s, 6H), 1.50-1.62 (m, 2H), 1.39-1.49 (m, 2H). Step 5: Synthesis of 6-[2-[4-(dimethylamino)butyl]phenyl]-N'-(2-ethyl-4-hydroxy-p henyl)-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine To a solution of N'-[4-[1,1-dimethylethyl(dimethyl)silyl]oxy-2-ethyl-phenyl]- 4-[[(3S)- tetrahydrofuran-3-yl]amino]-6-(4,4,5,5-tetramethyl-1,3,2-dio xaborolan-2-yl)pyrrolo[1,2- b]pyridazine-3-carboxamidine (280 mg, 462.31 μmol) and 4-(2-bromophenyl)-N,N-dimethyl- butan-1-amine (177 mg, 693 μmol) in water (2 mL) and N,N-dimethylformamide (10 mL) were added tetrakis(triphenylphosphine)palladium (107 mg, 92 μmol) and sodium carbonate (147 mg, 1.4 mmol). The resulting mixture was purged with nitrogen gas, stirred at 85 °C for 2 hours and then cooled to room temperature. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 6-[2-[4- (dimethylamino)butyl]phenyl]-N'-(2-ethyl-4-hydroxy-phenyl)-4 -[[(3S)-tetrahydrofuran-3- yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine as an off-white solid. Yield: 81.8 mg, 33%. LCMS (ESI) m/z: 541.3 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.54 (d, 1H, J=6.8 Hz), 8.95 (s, 1H), 8.25 (s, 1H), 7.79 (d, 1H, J=1.6 Hz), 7.35-7.48 (m, 1H), 7.16-7.34 (m, 3H), 6.96 (d, 1H, J=1.6 Hz), 6.66-6.70 (m, 1H), 6.53-6.65 (m, 2H), 5.93 (s, 2H), 4.91-4.99 (m, 1H), 3.90-3.94 (m, 1H), 3.68-3.86 (m, 3H), 2.73-2.84 (m, 2H), 2.27-2.46 (m, 3H), 2.11 (t, 2H, J=7.2 Hz), 2.04 (s, 6H), 1.89-1.93 (m, 1H), 1.44-1.58 (m, 2H), 1.33-1.41 (m, 2H), 1.07 (t, 3H, J=7.6 Hz). EXAMPLE 194 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-4-[[(1-methylazetidin-3-yl)met hyl]amino]-6-(4- methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt

Step 1: Synthesis of tert-butyl N-[(1-methylazetidin-3-yl)methyl]carbamate To a solution of tert-butyl N-(azetidin-3-ylmethyl)carbamate hydrochloric acid salt (1.00 g, 4.5 mmol) in methanol (30 mL) was added formaldehyde (1.82 g, 22.4 mmol, 37%), followed by addition of sodium cyanoborohydride (847 mg, 13.5 mmol) at 0 °C. After stirring at room temperature for 15 hours, the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride and then extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography afforded the title compound as a yellow oil. Yield: 660 mg, 70%. ¹ H NMR (DMSO-d6, 400 MHz): δ (ppm) 7.10 (t, 1H, J=6.0 Hz), 3.93-4.07 (m, 2H), 3.74-3.83 (m, 2H), 3.11-3.19 (m, 2H), 2.78-2.90 (m, 1H), 2.78 (s, 3H), 1.39 (s, 9H). Step 2: Synthesis of (1-methylazetidin-3-yl)methanamine hydrochloric acid salt To a solution of tert-butyl N-[(1-methylazetidin-3-yl)methyl]carbamate (660 mg, 3.3 mmol) in ethyl acetate (20 mL) was added 2 M hydrogen chloride in ethyl acetate (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours and then filtered. The solid was collected and dried in air to afford the title compound as a white solid. Yield: 400 mg, 63%. ¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.37 (brs, 3H), 3.96-4.18 (m, 3H), 3.79-3.90 (m, 1H), 3.17-3.29 (m, 1H), 2.97-3.13 (m, 2H), 2.77 (s, 3H). Step 3: Synthesis of 6-bromo-N'-(2-ethyl-4-hydroxy-phenyl)-4-[[(1-methylazetidin- 3- yl)methyl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (350 mg, 689 μmol) and (1-methylazetidin-3- yl)methanamine hydrochloric acid salt (377 mg, 2.8 mmol) in N,N-dimethylacetamide (10 mL) was added N,N-diisopropylethylamine (445 mg, 3.4 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 15 hours and then cooled to room temperature. Purification via reverse phase column chromatography (methanol/water) afforded the title compound as a yellow solid. Yield: 140 mg, 43%. LCMS (ESI) m/z: 457.2 (M+H). Step 4: Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-4-[[(1-methylazetidin-3-yl)met hyl]amino]-6- (4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt To a solution of 6-bromo-N'-(2-ethyl-4-hydroxy-phenyl)-4-[[(1-methylazetidin- 3- yl)methyl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine (140 mg, 306 μmol) and (4-methyl- 3-pyridyl)boronic acid (63 mg, 459 μmol) in N,N-dimethylformamide (10 mL) and water (2 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (20 mg, 30 μmol) and potassium phosphate (195 mg, 918 μmol) at room temperature. The resulting mixture was purged with nitrogen gas, stirred at 80 °C for 2 hours and then cooled to room temperature. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded N'-(2- ethyl-4-hydroxy-phenyl)-4-[[(1-methylazetidin-3-yl)methyl]am ino]-6-(4-methyl-3- pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt as a white solid. Yield: 28.7 mg, 17%. LCMS (ESI) m/z: 470.4 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.98 (brs, 1H), 8.62 (s, 1H), 8.35-8.43 (m, 3H), 8.09 (d, 1H, J=1.6 Hz), 7.85 (s, 1H), 7.51 (d, 1H, J=1.2 Hz), 7.34 (d, 1H, J=4.8 Hz), 7.16 (d, 1H, J=8.4 Hz), 6.92 (d, 1H, J=2.4 Hz), 6.79-6.85 (m, 1H), 3.60-3.87 (m, 3H), 3.30-3.42 (m, 1H), 2.68-2.80 (m, 1H), 2.40-2.49 (m, 6H), 2.30 (s, 3H), 2.15-2.21 (m, 1H), 1.19 (t, 3H, J=7.6 Hz). EXAMPLE 195 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(4-methyl-3-pyridyl)-4-[(1-m ethylsulfonyl-4- piperidyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine

Step 1: Synthesis of tert-butyl N-(1-methylsulfonyl-4-piperidyl)carbamate To a solution of tert-butyl N-(4-piperidyl)carbamate (3.00 g, 15.0 mmol) and triethylamine (3.04 g, 30.00 mmol) in dichloromethane (40.0 mL) was added methanesulfonyl chloride (2.57 g, 22.50 mmol) dropwise. After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a red solid. Yield: 4.00 g, 96%. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 6.93 (d, 1H, J=7.8 Hz), 3.40- 3.55 (m, 1H), 3.30-3.40 (m, 2H), 2.85 (s, 3H), 2.70-2.80 (m, 2H), 1.75-1.85 (m, 2H), 1.39 (s, 11H). Step 2: Synthesis of 1-methylsulfonylpiperidin-4-amine trifluoroacetic acid salt To a solution of tert-butyl N-(1-methylsulfonyl-4-piperidyl)carbamate (1.00 g, 3.59 mmol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (10.0 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 389 mg, 48%. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 3.30- 3.50 (m, 2H), 2.81 (s, 3H), 2.62-2.78 (m, 3H), 1.69-1.81 (m, 2H), 1.19-1.33 (m, 2H). ¹⁹ F NMR (DMSO, 282 MHz) δ -74.25 (s, 3F). Step 3: 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[(1-methylsulfonyl-4- piperidyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (250 mg, 492.2 μmol) and 1-methylsulfonylpiperidin- 4-amine trifluoroacetic acid salt (263 mg, 1.17 mmol) in N,N-dimethylacetamide (4.0 mL) was added N,N-diisopropylethylamine (636 mg, 4.92 mmol). After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 240 mg, 75%. LCMS (ESI) m/z: 651.2 (M+H). Step 4: N'-(2-ethyl-4-hydroxy-phenyl)-6-(4-methyl-3-pyridyl)-4-[(1-m ethylsulfonyl-4- piperidyl)amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[(1- methylsulfonyl-4-piperidyl)amino]pyrrolo[1,2-b]pyridazine-3- carboxamidine (220 mg, 338.6 μmol) and (4-methyl-3-pyridyl)boronic acid (139 mg, 1.02 mmol) in N,N-dimethylformamide (4.2 mL) and water (0.4 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (22 mg, 33.9 μmol) and potassium phosphate (216 mg, 1.02 mmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours. After cooling to room temperature, cesium fluoride (103 mg, 677.2 μmol) was added. After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate, filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1% ammonia) afforded N'-(2-ethyl-4- hydroxy-phenyl)-6-(4-methyl-3-pyridyl)-4-[(1-methylsulfonyl- 4-piperidyl)amino]pyrrolo[1,2- b]pyridazine-3-carboxamidine as an off-white solid. Yield: 72.2 mg, 38%. LCMS (ESI) m/z: 548.4 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 12.68 (d, 1H, J=8.1 Hz), 8.98 (s, 1H), 8.69 (s, 1H), 8.37 (d, 1H, J=4.8 Hz), 8.28 (s, 1H), 8.00 (d, 1H, J=1.5 Hz), 7.33 (d, 1H, J=4.8 Hz), 7.12 (d, 1H, J=1.5 Hz), 6.51-6.68 (m, 3H), 6.00 (brs, 2H), 4.40-4.50 (m, 1H), 3.28-3.35 (m, 2H), 3.14 (t, 2H, J=9.0 Hz), 2.75 (s, 3H), 2.35-2.50 (m, 5H), 2.10-2.20 (m, 2H), 1.50-1.67 (m, 2H), 1.08 (t, 3H, J=7.5 Hz). EXAMPLE 196 Synthesis of 4-[[[(6R)-5-azaspiro[2.4]heptan-6-yl]methyl]amino]-N'-(2-eth yl-4-hydroxy-phenyl)- 6-(6-methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-c arboxamidine

Step 1: Synthesis of tert-butyl (6R)-6-(hydroxymethyl)-5-azaspiro[2.4]heptane-5-carboxylate To a solution of (6R)-5-(1,1-dimethylethoxycarbonyl)-5-azaspiro[2.4]heptane-6 -carboxylic acid (800 mg, 3.32 mmol) in tetrahydrofuran (4.0 mL) was added borane-tetrahydrofuran complex (1M in tetrahydrofuran, 6.6 mL, 6.6 mmol) dropwise at 0 °C under nitrogen atmosphere. After stirring at room temperature for 16 hours, the reaction mixture was quenched with methanol, stirred for 20 minutes and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as an off-white solid, which was used for next step without further purification. Yield: 460 mg (crude). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 4.70-4.75 (m, 1H), 3.76-3.80 (m, 1H), 3.53-3.58 (m, 1H), 3.29-3.33 (m, 1H), 2.92-2.97 (m, 1H), 1.97-2.04 (m, 1H), 1.59-1.69 (m, 1H), 1.35-1.41 (m, 10H), 0.48-0.61 (m, 4H). Step 2: Synthesis of tert-butyl (6R)-6-(methylsulfonyloxymethyl)-5-azaspiro[2.4]heptane-5- carboxylate To a solution of tert-butyl (6R)-6-(hydroxymethyl)-5-azaspiro[2.4]heptane-5-carboxylate (510 mg, 2.2 mmol) and trimethylamine (681 mg, 6.7 mmol) in dichloromethane (10 mL) was added methanesulfonyl chloride (387 mg, 3.4 mmol) at 0 °C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduce pressure. The residue was dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 650 mg, 66%. ¹ H NMR (DMSO-d6, 400 MHz) δ 4.14-4.28 (m, 2H), 4.01-4.11 (m, 1H), 3.12-3.24 (m, 4H), 2.95-3.03 (m, 1H), 2.10-2.24 (m, 1H), 1.51-1.61 (m, 1H), 1.41 (s, 9H), 0.46-0.68 (m, 4H). Step 3: Synthesis of tert-butyl (6R)-6-(azidomethyl)-5-azaspiro[2.4]heptane-5-carboxylate To a solution of tert-butyl (6R)-6-(methylsulfonyloxymethyl)-5-azaspiro[2.4]heptane-5- carboxylate (3， 650 mg, 2.1 mmol) in N,N-dimethylformamide (10 mL) was added sodium azide (139 mg, 2.1 mmol) at room temperature. After stirring at 80 °C for 15 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (ethyl acetate/petroleum ether) afforded the title compound as a yellow oil. Yield: 310 mg, 46%.1H NMR (DMSO-d ₆ , 400 MHz) δ 3.92-4.05 (m, 1H), 3.48-3.66 (m, 1H), 3.27-3.43 (m, 2H), 3.00-3.12 (m, 1H), 2.04-2.20 (m, 1H), 1.49-1.60 (m, 1H), 1.41 (s, 9H), 0.49-0.68 (m, 4H). Step 4: Synthesis of tert-butyl (6R)-6-(aminomethyl)-5-azaspiro[2.4]heptane-5-carboxylate To a solution of tert-butyl (6R)-6-(azidomethyl)-5-azaspiro[2.4]heptane-5-carboxylate (310 mg, 1.2 mmol) in methanol (10.0 mL) was added 10% palladium on carbon (13 mg) under nitrogen atmosphere. The resulting mixture was purged with hydrogen gas and stirred at room temperature for 2 hours under hydrogen atmosphere (1 atm.). The reaction mixture was filtered through Celite pad. The filtrate was concentrated under reduced pressure to afford the title compound as a yellow oil, which was used for next step without further purification. Yield: 110 mg (crude). ¹ H NMR (DMSO-d6, 400 MHz) δ 3.63-3.77 (m, 1H), 3.28-3.35 (m, 1H), 2.90-3.30 (m, 1H), 2.73- 2.83 (m, 1H), 2.52-2.63 (m, 1H), 1.95-2.04 (m, 1H), 1.55-1.70 (m, 1H), 1.39 (s, 9H), 0.45-0.62 (m, 4H). Step 5: Synthesis of tert-butyl (6R)-6-[[[6-bromo-3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2- ethyl- phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]meth yl]-5-azaspiro[2.4]heptane-5- carboxylate To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (210 mg, 413 μmol) and tert-butyl (6R)-6- (aminomethyl)-5-azaspiro[2.4]heptane-5-carboxylate (94 mg, 413 μmol) in N,N- dimethylacetamide (3 mL) was added N,N-diisopropylethylamine (160 mg, 1.2 mmol) at room temperature. After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. Purification via reverse phase column chromatography (methanol/water) afforded the title compound as a yellow solid. Yield: 210 mg, 73%. LCMS (ESI) m/z: 699.3 (M+H). Step 6: Synthesis of tert-butyl (6R)-6-[[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-6-( 6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amin o]methyl]-5- azaspiro[2.4]heptane-5-carboxylate To a solution of tert-butyl (6R)-6-[[[6-bromo-3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2- ethyl- phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]amino]meth yl]-5-azaspiro[2.4]heptane-5- carboxylate (190 mg, 272 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (91 mg, 545 μmol) in water (0.4 mL) and N,N-dimethylformamide (2 mL) were added 1,1'- bis(diphenylphosphino)ferrocene-palladium(II) dichloride (35 mg, 54 μmol) and potassium phosphate (173 mg, 817 μmol) at room temperature. The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 5 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 120 mg, 67%. LCMS (ESI) m/z: 626.0 (M+H). Step 7: Synthesis of 4-[[[(6R)-5-azaspiro[2.4]heptan-6-yl]methyl]amino]-N'-(2-eth yl-4-hydroxy- phenyl)-6-(6-methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyrida zine-3-carboxamidine To a solution of tert-butyl (6R)-6-[[[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-6-( 6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]amin o]methyl]-5- azaspiro[2.4]heptane-5-carboxylate (120 mg, 192 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (2.0 mL). The resulting was stirred at room temperature for 2 hours and then concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded 4-[[[(6R)-5- azaspiro[2.4]heptan-6-yl]methyl]amino]-N'-(2-ethyl-4-hydroxy -phenyl)-6-(6-methoxy-4-methyl- 3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carboxamidine as a pink solid. Yield: 35.3 mg, 34%. LCMS (ESI) m/z: 526.2 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.11 (brs, 1H), 8.91 (s, 1H), 8.20-8.26 (m, 2H), 7.86 (d, 1H, J=1.6 Hz), 7.08 (d, 1H, J=1.6 Hz), 6.77 (s, 1H), 6.52-6.70 (m, 3H), 5.88 (brs, 2H), 3.83-3.93 (m, 4H), 3.72-3.82 (m, 1H), 3.46-3.56 (m, 1H), 2.64-2.73 (m, 2H), 2.35-2.48 (m, 5H), 1.55-1.75 (m, 2H), 1.06 (t, 3H, J=7.6 Hz), 0.37-0.48 (m, 4H). EXAMPLE 197 Synthesis of N'-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl -3-pyridyl)-4- [[[(2R)-pyrrolidin-2-yl]methyl]amino]pyrrolo[1,2-b]pyridazin e-3-carboxamidine Step 1: Synthesis of tert-butyl (R)-2-[[[6-bromo-3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-e thyl- 5-fluoro-phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]a mino]methyl]pyrrolidine-1- carboxylate To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-5-fluor o-phenyl]-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (1.00 g, 1.9 mmol) and tert-butyl (R)-2- (aminomethyl)pyrrolidine-1-carboxylate (419 mg, 2.1 mmol) in N,N-dimethylacetamide (15 mL) was added N,N-diisopropylethylamine (737 mg, 5.7 mmol). The resulting mixture was stirred at 90 °C for 2 hours and then cooled to room temperature. Purification via reverse phase column chromatography (methanol/water) afforded the title compound as a yellow solid. Yield: 1.15 g, 86%. LCMS (ESI) m/z: 691.6 (M+H). Step 2: Synthesis of tert-butyl (R)-2-[[[3-[N'-(2-ethyl-5-fluoro-4-hydroxy- phenyl)carbamimidoyl]-6-(6-methoxy-4-methyl-3-pyridyl)pyrrol o[1,2-b]pyridazin-4- yl]amino]methyl]pyrrolidine-1-carboxylate To a solution of tert-butyl (R)-2-[[[6-bromo-3-[N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-e thyl-5- fluoro-phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin-4-yl]ami no]methyl]pyrrolidine-1- carboxylate (300 mg, 435 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (109 mg, 653 μmol) in N,N-dimethylformamide (6 mL) and water (2 mL) were added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (29 mg, 44 μmol) and potassium phosphate (277 mg, 1.3 mmol). The resulting mixture was purged with nitrogen gas, stirred at 80 °C for 2 hours and then cooled to room temperature. Purification via reverse phase column chromatography (methanol/water) afforded the title compound as a yellow solid. Yield: 200 mg, 69%. LCMS (ESI) m/z: 618.3 (M+H). Step 3: Synthesis of N'-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl -3-pyridyl)- 4-[[[(R)-pyrrolidin-2-yl]methyl]amino]pyrrolo[1,2-b]pyridazi ne-3-carboxamidine To a solution of tert-butyl (R)-2-[[[3-[N'-(2-ethyl-5-fluoro-4-hydroxy-phenyl)carbamimid oyl]-6- (6-methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazin-4-yl]a mino]methyl]pyrrolidine-1- carboxylate (200 mg, 323 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded N'-(2-ethyl-5-fluoro-4-hydroxy- phenyl)-6-(6-methoxy-4-methyl-3-pyridyl)-4-[[[(R)-pyrrolidin -2-yl]methyl]amino]pyrrolo[1,2- b]pyridazine-3-carboxamidine as a yellow solid. Yield: 65.3 mg, 38%. LCMS (ESI) m/z: 518.1 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.92 (brs, 1H), 9.26 (brs, 1H), 8.21 (s, 1H), 8.23 (s, 1H), 7.87 (d, 1H, J=2.0 Hz), 7.08 (d, 1H, J=2.0 Hz), 6.73-6.84 (m, 2H), 6.56 (d, 1H, J=12.4 Hz), 5.94 (brs, 2H), 3.86 (s, 3H), 3.79-3.83 (m, 1H), 3.71-3.75 (m, 1H), 3.20-3.30 (m, 1H), 2.71-2.79 (m, 2H), 2.36-2.46 (m, 5H), 1.75-1.85 (m, 1H), 1.54-1.69 (m, 2H), 1.42-1.52 (m, 1H), 1.06 (t, 3H, J=7.6 Hz). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -138.96 (s, 1F). EXAMPLE 198 Synthesis of 5-[3-[N'-(2-ethyl-5-fluoro-4-hydroxy-phenyl)carbamimidoyl]-4 -[[[(R)-pyrrolidin-2- yl]methyl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-N-(2-methoxyet hyl)-4-methyl-pyridine-2- carboxamide Step 1: Synthesis of tert-butyl (R)-2-[[[3-[N'-(2-ethyl-5-fluoro-4-hydroxy- phenyl)carbamimidoyl]-6-[6-(2-methoxyethylcarbamoyl)-3-pyrid yl]pyrrolo[1,2-b]pyridazin-4- yl]amino]methyl]pyrrolidine-1-carboxylate To a solution of tert-butyl (R)-2-[[[6-bromo-3-[N'-[4-[1,1-dimethylethyl(dimethyl)silyl] oxy-2- ethyl-5-fluoro-phenyl]carbamimidoyl]pyrrolo[1,2-b]pyridazin- 4-yl]amino]methyl]pyrrolidine-1- carboxylate (300 mg, 435 μmol) and N-(2-methoxyethyl)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine-2-carboxamide (140 mg, 435 μmol) in N,N-dimethylformamide (10 mL) and water (2 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (56 mg, 87 μmol) and potassium phosphate (277 mg, 1.3 mmol). The resulting mixture was purged with nitrogen gas, stirred at 85 °C for 2 hours and then cooled to room temperature. Purification via reverse phase column chromatography (methanol/water) afforded the title compound as a yellow solid. Yield: 250 mg, 60%. LCMS (ESI) m/z: 618.3 (M-56+H). Step 2: Synthesis of 5-[3-[N'-(2-ethyl-5-fluoro-4-hydroxy-phenyl)carbamimidoyl]-4 -[[[(R)- pyrrolidin-2-yl]methyl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-N -(2-methoxyethyl)-4-methyl- pyridine-2-carboxamide To a solution of tert-butyl (R)-2-[[[3-[N'-(2-ethyl-5-fluoro-4-hydroxy-phenyl)carbamimid oyl]-6- [6-(2-methoxyethylcarbamoyl)-3-pyridyl]pyrrolo[1,2-b]pyridaz in-4- yl]amino]methyl]pyrrolidine-1-carboxylate (250 mg, 259 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 5-[3-[N'-(2-ethyl-5-fluoro-4-hydroxy-phenyl)carbamimidoyl]-4 -[[[(R)-pyrrolidin-2- yl]methyl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-N-(2-methoxyet hyl)-4-methyl-pyridine-2- carboxamide as a yellow solid. Yield: 61.7 mg, 40%. LCMS (ESI) m/z: 589.1 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.99 (brs, 1H), 9.25 (brs, 1H), 8.73 (s, 1H), 8.63 (s, 1H), 8.27 (s, 1H), 8.06 (d, 1H, J=1.6 Hz), 7.97 (s, 1H), 7.24 (d, 1H, J=2.0 Hz), 6.79-6.85 (m, 1H), 6.54-6.62 (m, 1H), 6.14 (brs, 2H), 3.70-3.83 (m, 2H), 3.45-3.55 (m, 4H), 3.24-3.32 (m, 4H), 2.68-2.78 (m, 2H), 2.54-2.64 (m, 4H), 2.35-2.45 (m, 2H), 1.76-1.82 (m, 1H), 1.55-1.67 (m, 2H), 1.41-1.51 (m, 1H), 1.06 (t, 3H, J=7.6 Hz). ¹⁹ F NMR (DMSO-d6, 376 MHz) δ -138.95 (s, 1F). EXAMPLE 199 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4-[[(3- methyloxetan-3-yl)methyl]amino]pyrrolo[1,2-b]pyridazine-3-ca rboxamidine Step 1: Synthesis of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[(3- methyloxetan-3-yl)methyl]amino]pyrrolo[1,2-b]pyridazine-3-ca rboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (250 mg, 492 μmol) and (3-methyloxetan-3- yl)methanamine (75 mg, 738 μmol) in N,N-dimethylacetamide (4 mL) was added N,N- diisopropylethylamine (127 mg, 984 μmol). The resulting mixture was stirred at 85 °C for 2 hours and then cooled to room temperature. Purification via reverse phase column chromatography (methanol/water) afforded the title compound as an off white solid. Yield: 200 mg, 68%. LCMS (ESI) m/z: 574.3 (M+H). Step 2: Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl-3-pyridy l)-4-[[(3- methyloxetan-3-yl)methyl]amino]pyrrolo[1,2-b]pyridazine-3-ca rboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[(3- methyloxetan-3-yl)methyl]amino]pyrrolo[1,2-b]pyridazine-3-ca rboxamidine (180 mg, 314 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (79 mg, 472 μmol) in N,N-dimethylformamide (4 mL) and water (0.4 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (21 mg, 31 μmol) and potassium phosphate (133 mg, 629 μmol) at room temperature. The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded N'-(2-ethyl-4-hydroxy-phenyl)-6-(6-methoxy-4- methyl-3-pyridyl)-4-[[(3-methyloxetan-3-yl)methyl]amino]pyrr olo[1,2-b]pyridazine-3- carboxamidine as an off-white solid. Yield : 48.2 mg, 30%. LCMS (ESI) m/z: 501.1 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.42 (s, 1H), 8.92 (s, 1H), 8.23-8.26 (m, 2H), 7.89 (d, 1H, J=1.8 Hz), 7.19 (d, 1H, J=1.8 Hz), 6.78 (s, 1H), 6.66 (s, 1H), 6.58 (s, 2H), 5.88 (s, 2H), 4.47 (d, 2H, J=5.7 Hz), 4.20 (d, 2H, J=5.7 Hz), 4.07-4.12 (m, 2H), 3.86 (s, 3H), 2.42 (s, 3H), 2.31-2.41 (m, 2H), 1.33 (s, 3H), 1.05 (t, 3H, J=7.5 Hz). EXAMPLE 200 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-4-[[[3-(hydroxymethyl)oxetan-3 -yl]methyl]amino]- 6-(6-methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-c arboxamidine formic acid salt Step 1: Synthesis of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[[3- (hydroxymethyl)oxetan-3-yl]methyl]amino]pyrrolo[1,2-b]pyrida zine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (300 mg, 590.6 μmol) and [3-(aminomethyl)oxetan-3- yl]methanol (207 mg, 1.77 mmol) in N,N-dimethylacetamide (2.0 mL) was added N,N- diisopropylethylamine (382 mg, 2.95 mmol). After stirring at 85 °C for 3 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 210 mg, 60%. LCMS (ESI) m/z: 590.3 (M+H). Step 2: Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-4-[[[3-(hydroxymethyl)oxetan-3 - yl]methyl]amino]-6-(6-methoxy-4-methyl-3-pyridyl)pyrrolo[1,2 -b]pyridazine-3-carboxamidine formic acid salt To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[[3- (hydroxymethyl)oxetan-3-yl]methyl]amino]pyrrolo[1,2-b]pyrida zine-3-carboxamidine (190 mg, 322.8 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (108 mg, 645.6 μmol) in N,N- dimethylformamide (2.0 mL) and water (0.2 mL) were added 1,1'-bis (di-t- butylphosphino)ferrocene palladium dichloride (21 mg, 32.3 μmol) and potassium phosphate (206 mg, 968.4 μmol). The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 80 °C for 2 hours, the reaction mixture was cooled to room temperature and then cesium fluoride (98 mg, 645.6 μmol) was added. The reaction mixture was stirred for 2 hours at room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrated was concentrated under reduced pressure. Purification via prep-TLC (ethyl acetate/petroleum ether) to give 160 mg crude product, which was re-purified via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded N'-(2-ethyl-4-hydroxy-phenyl)-4-[[[3- (hydroxymethyl)oxetan-3-yl]methyl]amino]-6-(6-methoxy-4-meth yl-3-pyridyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine formic acid salt as an off-white solid. Yield: 79.9 mg, 43.8%. LCMS (ESI) m/z = 517.4 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.31 (brs, 1H), 8.98 (brs, 1H), 8.22-8.24 (m, 2H), 8.15 (s, 1H, HCOOH), 7.89 (d, 1H, J=2.0 Hz), 7.20 (d, 1H, J=1.6 Hz), 6.78 (s, 1H), 6.65-6.68 (m, 3H), 6.00 (brs, 2H), 5.10 (brs, 1H), 4.42 (d, 2H, J=6.0 Hz), 4.25 (d, 2H, J=5.6 Hz), 4.07 (s, 2H), 3.89 (s, 3H), 3.68 (s, 2H), 2.32-2.49 (m, 5H), 1.06 (t, 3H, J=7.6 Hz). EXAMPLE 201 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-4-[[(3-hydroxyoxetan-3-yl)meth yl]amino]-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine

Step 1: Synthesis of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[(3- hydroxyoxetan-3-yl)methyl]amino]pyrrolo[1,2-b]pyridazine-3-c arboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (280 mg, 551 μmol) and 3-(aminomethyl)oxetan-3-ol (85 mg, 827 μmol) in N,N-dimethylacetamide (4 mL) was added N,N-diisopropylethylamine (214 mg, 1.6 mmol) at room temperature. The resulting mixture was stirred at 85 °C for 2 hours and then cooled to room temperature. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 240 mg, 74%. LCMS (ESI) m/z: 576.0 (M+H). Step 2: Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-4-[[(3-hydroxyoxetan-3-yl)meth yl]amino]-6- (6-methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-car boxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[(3- hydroxyoxetan-3-yl)methyl]amino]pyrrolo[1,2-b]pyridazine-3-c arboxamidine (180 mg, 313 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (78 mg, 470 μmol) in N,N- dimethylformamide (4 mL) and water (0.4 mL) were added 1,1'-bis(di-t- butylphosphino)ferrocene-palladium dichloride (41 mg, 63 μmol) and potassium phosphate (133 mg, 626 μmol) at room temperature. The resulting mixture was purged with nitrogen gas, stirred at 80 °C for 2 hours and then cooled to room temperature. Purification via reverse phase column chromatography (acetonitrile/water) afforded a crude product. Then further purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded N'-(2-ethyl-4-hydroxy-phenyl)-4-[[(3-hydroxyoxetan-3- yl)methyl]amino]-6-(6-methoxy-4-methyl-3-pyridyl)pyrrolo[1,2 -b]pyridazine-3-carboxamidine as an off-white solid. Yield: 10.2 mg, 6%. LCMS (ESI) m/z: 503.1 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz): δ 12.09 (s, 1H), 8.88 (s, 1H), 8.26 (s, 1H), 8.21 (s, 1H), 7.88 (d, 1H, J=1.6 Hz), 7.23 (d, 1H, J=2.0 Hz), 6.78 (s, 1H), 6.65 (s, 1H), 6.56 (s, 2H), 6.06 (s, 1H), 5.81 (s, 2H), 4.40-4.49 (m, 4H), 4.16 (d, 2H, J=4.8 Hz), 3.86 (s, 3H), 2.30-2.48 (m, 5H), 1.05 (t, 3H, J=7.5 Hz). EXAMPLE 202 Synthesis of N'-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl -3-pyridyl)-4-[[(3R)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine Step 1: Synthesis of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-5-fluor ophenyl]-4- [[(3R)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-5-fluor ophenyl]-4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (250 mg, 475.3 μmol) and (3R)-tetrahydrofuran-3- amine (62 mg, 713.0 μmol) in N,N-dimethylacetamide (2.0 mL) was added N,N- diisopropylethylamine (184 mg, 1.43 mmol) dropwise. After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 220 mg, 80%. LCMS (ESI) m/z: 578.1 (M+H). Step 2: Synthesis of N'-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-6-(6-methoxy-4-methyl -3-pyridyl)- 4-[[(3R)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine -3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-5-fluor ophenyl]-4-[[(3R)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine (200 mg, 346.8 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (86 mg, 520.3 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added potassium phosphate (220 mg, 1.04 mmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (22 mg, 34.6 μmol). The suspension was degassed under reduced pressure and purged with nitrogen three times. After stirring at 90 °C for 2 hours, the reaction was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded N'-(2-ethyl-5-fluoro-4-hydroxy- phenyl)-6-(6-methoxy-4-methyl-3-pyridyl)-4-[[(3R)-tetrahydro furan-3-yl]amino]pyrrolo[1,2- b]pyridazine-3-carboxamidine as an off-white solid. Yield: 101.4 mg, 57%. LCMS (ESI) m/z: 505.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.30 (d, 1H, J=7.2 Hz), 9.26 (s, 1H), 8.25 (s, 2H), 7.90 (s, 1H), 7.06 (s, 1H), 6.77-6.83 (m, 2H), 6.56-6.59 (m, 1H), 6.11 (s, 2H), 4.92-5.01 (m, 1H), 3.91-3.96 (m, 1H), 3.86 (s, 3H), 3.73-3.82 (m, 2H), 3.68-3.70 (m, 1H), 2.30-2.45 (m, 6H), 1.85-1.95 (m, 1H), 1.06 (t, 3H, J=7.6 Hz). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -138.84 (s, 1F). EXAMPLE 203 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-4-[[(3-fluorooxetan-3-yl)methy l]amino]-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine formic acid salt Step 1: Synthesis of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[(3- fluorooxetan-3-yl)methyl]amino]pyrrolo[1,2-b]pyridazine-3-ca rboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (300 mg, 590.6 μmol) and (3-fluorooxetan-3- yl)methanamine (186 mg, 1.77 mmol) in N,N-dimethylacetamide (2.0 mL) was added N,N- diisopropylethylamine (382 mg, 2.95 mmol). After stirring at 85 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 220.0 mg, 64%. LCMS (ESI) m/z = 578.0 (M+H). Step 2: Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-4-[[(3-fluorooxetan-3-yl)methy l]amino]-6-(6- methoxy-4-methyl-3-pyridyl)pyrrolo[1,2-b]pyridazine-3-carbox amidine formic acid salt To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[(3- fluorooxetan-3-yl)methyl]amino]pyrrolo[1,2-b]pyridazine-3-ca rboxamidine (200 mg, 346.9 μmol) and (6-methoxy-4-methyl-3-pyridyl)boronic acid (116 mg, 693.8 μmol) in N,N- dimethylformamide (5.0 mL) and water (0.5 mL) were added 1,1'-bis (di-t- butylphosphino)ferrocene palladium dichloride (23 mg, 34.7 μmol) and potassium phosphate (221 mg, 1.04 mmol). The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 80 °C for 2 hours, the reaction mixture was cooled to room temperature and then cesium fluoride (105 mg, 693.7 μmol) was added. The reaction mixture was stirred for 2 hours at room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrated was concentrated under reduced pressure. Purification via prep-TLC (ethyl acetate/petroleum ether) afforded 140 mg crude product, which was further purified via reverse phase HPLC (acetonitrile/water buffered with 0.1% formic acid) afforded N'-(2-ethyl-4-hydroxy-phenyl)-4- [[(3-fluorooxetan-3-yl)methyl]amino]-6-(6-methoxy-4-methyl-3 -pyridyl)pyrrolo[1,2- b]pyridazine-3-carboxamidine formic acid salt as a light yellow solid. Yield: 89.4 mg, 46%. LCMS (ESI) m/z = 505.3 (M+H-FA). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.49 (brs, 1H), 8.97 (brs, 1H), 8.25-8.27 (m, 2H), 8.16 (s, 1H, HCOOH), 7.91 (d, 1H, J=1.6 Hz), 7.23 (d, 1H, J=2.0 Hz), 6.78 (s, 1H), 6.66 (d, 1H, J=1.6 Hz), 6.56-6.60 (m, 2H), 5.97 (brs, 2H), 4.57-4.73 (m, 4H), 4.45 (s, 1H), 4.39 (s, 1H), 3.87 (s, 3H), 2.26-2.49 (m, 5H), 1.05 (t, 3H, J=7.6 Hz). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz) δ -152.81 (s, 1F). EXAMPLE 204 Synthesis of 6-[4-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-N'-(2-ethyl- 4-hydroxy-phenyl)-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine

Step 1: Synthesis of 6-(4-chloro-3-pyridyl)-N'-(2-ethyl-4-hydroxy-phenyl)-4-[[(3S )- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-[[(3S)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine (300 mg, 537 μmol) and 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyri dine (258 mg, 1.1 mmol) in water (2 mL) and N,N-dimethylformamide (10 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene- palladium dichloride (70 mg, 107 μmol) and potassium phosphate (342 mg, 1.6 mmol) at room temperature. The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 75 mg, 27%. LCMS (ESI) m/z: 477.3 (M+H). Step 2: Synthesis of 6-[4-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-N'-(2-ethyl- 4-hydroxy- phenyl)-4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]py ridazine-3-carboxamidine To a solution of 6-(4-chloro-3-pyridyl)-N'-(2-ethyl-4-hydroxy-phenyl)-4-[[(3S )-tetrahydrofuran- 3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine (75 mg, 157 μmol) and N,N- dimethylpiperidin-4-amine (81 mg, 629 μmol) in N,N-dimethylacetamide (2 mL) was added N,N-diisopropylethylamine (61 mg, 472 μmol) at room temperature. The resulting mixture was stirred at 145 °C for 15 hours and then cooled to room temperature. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 6-[4-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-N'-(2-ethyl- 4-hydroxy- phenyl)-4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]py ridazine-3-carboxamidine as a brown solid. Yield: 13.6 mg, 15%. LCMS (ESI) m/z: 569.4 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.61 (d, 1H, J=7.2 Hz), 9.03 (s, 1H), 8.55 (s, 1H), 8.33 (d, 1H, J=5.6 Hz), 8.29 (s, 1H), 8.15 (s, 1H), 7.33 (s, 1H), 7.06 (d, 1H, J=5.6 Hz), 6.73 (s, 1H), 6.65-6.68 (m, 2H), 5.99 (s, 2H), 5.01-5.05 (m, 1H), 3.98-4.04 (m, 1H), 3.72-3.91 (m, 3H), 3.30-3.32 (m, 2H), 2.56-2.66 (m, 2H), 2.39-2.52 (m, 3H), 2.15-2.27 (m, 7H), 1.93-2.00 (m, 1H), 1.77-1.85 (m, 2H), 1.45-1.55 (m, 2H), 1.13 (t, 3H, J=7.6 Hz). EXAMPLE 205 Synthesis of 6-[4-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-N'-(2-ethyl- 4-hydroxy-phenyl)-4- [[(3S, 4S)-4-hydroxytetrahydropyran-3-yl]amino]pyrrolo[1,2-b]pyrida zine-3-carboxamidine formic acid salt Step 1: Synthesis of 6-bromo-N'-[4-[1,1-dimethylethyl(dimethyl)silyl]oxy-2-ethyl- phenyl]-4- [[(3S, 4S)-4-hydroxytetrahydropyran-3-yl]amino]pyrrolo[1,2-b]pyrida zine-3-carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (500 mg, 984.4 μmol) in N,N-dimethylacetamide (5.0 mL) were added (3S,4S)-3-aminotetrahydropyran-4-ol (288 mg, 2.46 mmol) and N,N- diisopropylethylamine (382 mg, 2.95 mmol). The resulting mixture was stirred at 85 °C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 470 mg, 81%. LCMS (ESI) m/z: 590.5 (M+H). Step 2: Synthesis of 6-(4-chloro-3-pyridyl)-N'-(2-ethyl-4-hydroxy-phenyl)-4-[[(3S , 4S)-4- hydroxytetrahydropyran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine To a solution of 6-bromo-N'-[4-[1,1-dimethylethyl(dimethyl)silyl]oxy-2-ethyl- phenyl]-4-[[(3S, 4S)-4-hydroxytetrahydropyran-3-yl]amino]pyrrolo[1,2-b]pyrida zine-3-carboxamidine (400 mg, 679.5 μmol) in N,N-dimethylformamide (8.0 mL) and water (0.8 mL) were added 4-chloro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (325 mg, 1.36 mmol), 1,1'-bis (di-t- butylphosphino)ferrocene-palladium dichloride (44 mg, 68.0 μmol) and potassium phosphate (288 mg, 1.36 mmol). The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reation mixture was diluted with ethyl acetate and filtered and the filtrate was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded two fractions: the title compound as a brown oil. Yield: 220 mg, 50%, 78% purity. LCMS (ESI) m/z: 507.1 (M+H). And N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-6-(4-ch loro-3-pyridyl)-4- [[(3S)-4-hydroxytetrahydropyran-3-yl]amino]pyrrolo[1,2-b]pyr idazine-3-carboxamidine as a brown solid. Yield: 170 mg, 40%. LCMS (ESI) m/z: 621.3 (M+H). Step 3: Synthesis of 6-[4-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-N'-(2-ethyl- 4-hydroxy- phenyl)-4-[[(3S, 4S)-4-hydroxytetrahydropyran-3-yl]amino]pyrrolo[1,2-b]pyrida zine-3- carboxamidine formic acid salt To a solution of 6-(4-chloro-3-pyridyl)-N'-(2-ethyl-4-hydroxy-phenyl)-4-[[(3S , 4S)-4- hydroxytetrahydropyran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine (160 mg, 246.2 μmol) in 1-methyl-2-pyrrolidinone (3.0 mL) was added N,N-dimethylpiperidin-4-amine (126 mg, 984.6 μmol). The resulting mixture was stirred at 145 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1% formic acid) afforded 6-[4-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-N'-(2-ethyl- 4-hydroxy- phenyl)-4-[[(3S, 4S)-4-hydroxytetrahydropyran-3-yl]amino]pyrrolo[1,2-b]pyrida zine-3- carboxamidine formic acid salt as a yellow solid. Yield: 9.9 mg, 5%. LCMS (ESI) m/z: 599.7 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.30 (brs, 1H), 8.46 (s, 1H), 8.29 (d, 1H, J=5.6 Hz), 8.15-8.25 (m, 4H), 8.07 (s, 1H), 7.28 (s, 1H), 7.01 (d, 1H, J=5.6 Hz), 6.53-6.73 (m, 3H), 6.90 (brs, 2H), 4.01-4.09 (m, 1H), 3.82-3.86 (m, 3H), 3.28-3.43 (m, 5H), 2.54-2.66 (m, 2H), 2.40-2.47 (m, 2H), 2.32 (s, 6H), 1.88-1.98 (m, 1H), 1.78-1.87 (m, 2H), 1.40-1.63 (m, 3H), 1.08 (t, 3H, J=7.6 Hz). EXAMPLE 206 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-[4-(4-methylpiperazin-1-yl)- 3-pyridyl]-4-[[(3R)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine Step 1: Synthesis of 6-bromo-N'-[4-[1,1-dimethylethyl(dimethyl)silyl]oxy-2-ethyl- phenyl]-4- [[(3R)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine To a solution of 6-bromo-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl] -4-chloro- pyrrolo[1,2-b]pyridazine-3-carboxamidine (500 mg, 984.4 μmol) and (3R)-tetrahydrofuran-3- amine (128 mg, 1.48 mmol) in N,N-dimethylacetamide (3.0 mL) was added N,N- diisopropylethylamine (381 mg, 2.95 mmol) dropwise. The reaction was stirred at 90 °C for 2 hours and cooled to room temperature. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 450 mg, 81 %. LCMS (ESI) m/z: 558.1 (M+H). Step 2: Synthesis of N'-[4-[1,1-dimethylethyl(dimethyl)silyl]oxy-2-ethyl-phenyl]- 4-[[(3R)- tetrahydrofuran-3-yl]amino]-6-(4,4,5,5-tetramethyl-1,3,2-dio xaborolan-2-yl)pyrrolo[1,2- b]pyridazine-3-carboxamidine To a solution of 6-bromo-N'-[4-[1,1-dimethylethyl(dimethyl)silyl]oxy-2-ethyl- phenyl]-4-[[(3R)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine (1.40 g, 2.51 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)-1,3,2-dioxaborolane (1.59 g, 6.27 mmol) in 1,4-dioxane (50.0 mL) were added potassium acetate (738 mg, 7.52 mmol) and [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (183 mg, 250.6 μmol). The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 85 °C for 16 hours, the reaction was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in diluted with ethyl acetate and then washed with water and brine, dried over anhydrous sodium sulfate and filtered and concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 830 mg, 54%. LCMS (ESI) m/z: 606.3 (M+H). Step 3: Synthesis of 1-(3-bromo-4-pyridyl)-4-methyl-piperazine To a solution of 3-bromo-4-fluoro-pyridine (200 mg, 1.14 mmol) and 1-methylpiperazine (170.7 mg, 1.70 mmol) in N,N-dimethylacetamide (3.0 mL) was added N,N-diisopropylethylamine (440.6 mg, 3.41 mmol). After stirring at 120 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification via reverse phase chromatography (acetonitrile/water) afforded the title compound as a yellow oil. Yield: 250 mg, 85%. LCMS (ESI) m/z: 255.8 (M+H). Step 4: Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-[4-(4-methylpiperazin-1-yl)- 3-pyridyl]-4- [[(3R)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine To a solution of 1-(3-bromo-4-pyridyl)-4-methyl-piperazine (120 mg, 468.4 μmol) and N'-[4- [1,1-dimethylethyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-[[(3 R)-tetrahydrofuran-3-yl]amino]-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]p yridazine-3-carboxamidine (189 mg, 312.3 μmol) in N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added potassium phosphate (198 mg, 936.9 μmol) and 1,1'-bis (di-t-butylphosphino)ferrocene palladium dichloride (20 mg, 31.2 μmol). The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 90 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.1 % ammonia) afforded N'-(2-ethyl-4-hydroxy-phenyl)-6-[4-(4-methylpiperazin-1-yl)- 3-pyridyl]-4-[[(3R)- tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3-carbox amidine as a brown solid. Yield: 47.4 mg, 27%. LCMS (ESI) m/z: 541.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.58 (d, 1H, J=7.2 Hz), 8.96 (s, 1H), 8.52 (s, 1H), 8.28-8.30 (m, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 7.27 (s, 1H), 6.99-7.01 (m, 1H), 6.67 (s, 1H), 6.56-6.62 (m, 2H), 5.95 (s, 2H), 4.98-5.02 (m, 1H), 3.95-3.99 (m, 1H), 3.73-3.83 (m, 3H), 2.90-2.98 (m, 4H), 2.34-2.47 (m, 7H), 2.20 (s, 3H), 1.88-1.94 (m, 1H), 1.01-1.08 (m, 3H). EXAMPLE 207 Synthesis of 6-[4-[4-(3,3-difluoroazetidin-1-yl)-1-piperidyl]-3-pyridyl]- N'-(2-ethyl-4-hydroxy- phenyl)-4-[[(3R)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]py ridazine-3-carboxamidine formic acid salt

Step 1: Synthesis of tert-butyl 4-(3,3-difluoroazetidin-1-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (500 mg, 2.5 mmol) in dichloromethane (20 mL) was added 3,3-difluoroazetidine hydrochloric acid salt (234 mg, 1.8 mmol), followed by addition of sodium triacetoxyborohydride (1.60 g, 7.5 mmol) at room temperature. After stirring at room temperature for 4 hours, the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride and then extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 500 mg, 65%. LCMS (ESI, pos. ion) m/z: 277.2 (M+H). Step 2: Synthesis of 4-(3,3-difluoroazetidin-1-yl)piperidine hydrochloric acid salt To a solution of tert-butyl 4-(3,3-difluoroazetidin-1-yl)piperidine-1-carboxylate (500 mg, 1.8 mmol) in ethyl acetate (20 mL) was added 2 M hydrogen chloride in ethyl acetate (9 mL, 18 mmol). The resulting mixture was stirred at room temperature for 2 hours and then filtered. The solid was collected and dried in air to afford the title compound as a white solid. Yield: 450 mg, 94%. ¹ H NMR (DMSO-d6, 400 MHz): δ 8.93 (s, 1H), 4.75 (s, 4H), 3.52-3.66 (m, 1H), 3.37-3.46 (m, 2H), 2.74-2.86 (m, 2H), 2.06-2.14 (m, 2H), 1.75-1.91 (m, 2H). Step 3: Synthesis of 3-bromo-4-[4-(3,3-difluoroazetidin-1-yl)-1-piperidyl]pyridin e To a solution of 4-(3,3-difluoroazetidin-1-yl)piperidine hydrochloric acid salt (400 mg, 1.9 mmol) and 3-bromo-4-fluoro-pyridine (331 mg, 1.9 mmol) in N,N-dimethylacetamide (15 mL) was added N,N-diisopropylethylamine (1.22 g, 9.4 mmol) at room temperature. The resulting mixture was stirred at 120 °C for 2 hours and then cooled to room temperature. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow solid. Yield: 130 mg, 19%. LCMS (ESI) m/z: 332.2 (M+H). Step 4: Synthesis of 6-[4-[4-(3,3-difluoroazetidin-1-yl)-1-piperidyl]-3-pyridyl]- N'-(2-ethyl-4- hydroxy-phenyl)-4-[[(3R)-tetrahydrofuran-3-yl]amino]pyrrolo[ 1,2-b]pyridazine-3-carboxamidine formic acid salt To a solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-[[(3R )-tetrahydrofuran-3- yl]amino]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyr rolo[1,2-b]pyridazine-3- carboxamidine (110 mg, 181 μmol) and 3-bromo-4-[4-(3,3-difluoroazetidin-1-yl)-1- piperidyl]pyridine (60 mg, 181 μmol) in N,N-dimethylformamide (6 mL) and water (1.5 mL) were added tetrakis(triphenylphosphine)palladium (42 mg, 36 μmol) and sodium carbonate (58 mg, 545 μmol) at room temperature. The resulting mixture was purged with nitrogen gas, stirred at 85 °C for 2 hours and then cooled to room temperature. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 6-[4-[4-(3,3-difluoroazetidin-1-yl)- 1-piperidyl]-3-pyridyl]-N'-(2-ethyl-4-hydroxy-phenyl)-4-[[(3 R)-tetrahydrofuran-3- yl]amino]pyrrolo[1,2-b]pyridazine-3-carboxamidine formic acid salt as a white solid. Yield: 8.3 mg, 7%. LCMS (ESI) m/z: 617.3 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.53 (s, 1H), 8.97 (brs, 1H), 8.51 (s, 1H), 8.16-8.31 (m, 3H), 8.10 (d, 1H, J=1.6 Hz), 7.25 (d, 1H, J=2.0 Hz), 7.00 (d, 1H, J=5.6 Hz), 6.52-6.74 (m, 3H), 5.95 (s, 2H), 4.96-5.02 (m, 1H), 3.93-3.99 (m, 1H), 3.73- 3.86 (m, 2H), 3.69-3.73 (m, 1H), 3.51-3.57 (m, 4H), 3.20-3.24 (m, 2H), 2.59-2.65 (m, 2H), 2.34- 2.46 (m, 3H), 2.28-2.32 (m, 1H), 1.88-1.94 (m, 1H), 1.66-1.72 (m, 2H), 1.21-1.37 (m, 2H), 1.07 (t, 3H, J=7.6 Hz). EXAMPLE 208 Synthesis of N'-(2-ethyl-4-hydroxy-phenyl)-6-[4-[(1-methylazetidin-3-yl)m ethoxy]-3-pyridyl]-4- [[(3R)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine formic acid salt To a solution of N'-[4-(tert-butyldimethylsilyl)oxy-2-ethyl-phenyl]-4-[[(3R)- tetrahydrofuran-3- yl]amino]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyr rolo[1,2-b]pyridazine-3- carboxamidine (260 mg, 429.3 μmol) in N,N-dimethylformamide (5.0 mL) and water (0.5 mL) were added 3-bromo-4-[(1-methylazetidin-3-yl)methoxy]pyridine (220 mg, 858.6 μmol), 1,1'-bis (di-t-butylphosphino)ferrocene-palladium dichloride (28 mg, 42.9 μmol) and potassium phosphate (182 mg, 858.6 μmol). The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered and the filtrate was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1% formic acid) afforded N'-(2-ethyl-4-hydroxy-phenyl)-6-[4-[(1-methylazetidin-3- yl)methoxy]-3-pyridyl]-4-[[(3R)-tetrahydrofuran-3-yl]amino]p yrrolo[1,2-b]pyridazine-3- carboxamidine formic acid salt as a yellow solid. Yield: 59.2 mg, 21%. LCMS (ESI) m/z: 542.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.48 (brs, 1H), 8.95 (s, 1H), 8.36 (d, 1H, J=6.0 Hz), 8.21-8.24 (m, 3H), 8.15 (s, 1H), 7.37 (s, 1H), 7.15 (d, 1H, J=6.0 Hz), 6.57-6.68 (m, 3H), 5.00- 5.05 (m, 1H), 4.37 (d, 2H, J=6.8 Hz), 3.91-3.99 (m, 1H), 3.76-3.89 (m, 2H), 3.62-3.74 (m, 3H), 3.38-3.56 (m, 2H), 3.01-3.12 (m, 1H), 2.33-2.49 (m, 6H), 1.84-1.95 (m, 1H), 1.07 (t, 3H, J=7.6 Hz). EXAMPLE 209 Synthesis of 6-[4-[3-(dimethylamino)azetidin-1-yl]-3-pyridyl]-N'-(2-ethyl -4-hydroxy-phenyl)-4- [[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine Step 1: Synthesis of 1-(3-bromo-4-pyridyl)-N,N-dimethyl-azetidin-3-amine To a solution of 3-bromo-4-fluoro-pyridine (500 mg, 2.8 mmol) and N,N-dimethylazetidin-3- amine hydrochloric acid salt (285 mg, 1.6 mmol) in N,N-dimethylacetamide (10 mL) was added N,N-diisopropylethylamine (1.84 g, 14 mmol) at room temperature. The resulting mixture was stirred at 110 °C for 2 hours and then cooled to room temperature. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow oil. Yield: 580 mg, 80%. LCMS (ESI) m/z: 256.1 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.23 (s, 1H), 8.09 (d, 1H, J=5.6 Hz), 6.45 (d, 1H, J=5.6 Hz), 4.19-4.28 (m, 2H), 3.85-3.93 (m, 2H), 3.06-3.14 (m, 1H), 2.10 (s, 6H). Step 3: Synthesis of 6-[4-[3-(dimethylamino)azetidin-1-yl]-3-pyridyl]-N'-(2-ethyl -4-hydroxy- phenyl)-4-[[(3S)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]py ridazine-3-carboxamidine To a solution of N'-[4-[1,1-dimethylethyl(dimethyl)silyl]oxy-2-ethyl-phenyl]- 4-[[(3S)- tetrahydrofuran-3-yl]amino]-6-(4,4,5,5-tetramethyl-1,3,2-dio xaborolan-2-yl)pyrrolo[1,2- b]pyridazine-3-carboxamidine (250 mg, 412 μmol) and 1-(3-bromo-4-pyridyl)-N,N-dimethyl- azetidin-3-amine (212 mg, 826 μmol) in N,N-dimethylformamide (10 mL) and water (2 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (27 mg, 41 μmol) and potassium phosphate (263 mg, 1.2 mmol) at room temperature. The resulting mixture was purged with nitrogen gas, stirred at 85 °C for 2 hours under nitrogen atmosphere and then cooled to room temperature. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 6-[4-[3-(dimethylamino)azetidin-1-yl]-3- pyridyl]-N'-(2-ethyl-4-hydroxy-phenyl)-4-[[(3S)-tetrahydrofu ran-3-yl]amino]pyrrolo[1,2- b]pyridazine-3-carboxamidine as an off-white solid. Yield: 71 mg, 32%. LCMS (ESI) m/z: 541.3 (M+H). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.53 (d, 1H, J=7.2 Hz), 8.95 (s, 1H), 8.24 (s, 1H), 8.14-8.16 (m, 2H), 7.78 (d, 1H, J=1.6 Hz), 6.95 (d, 1H, J=1.6 Hz), 6.67 (d, 1H, J=2.0 Hz), 6.56- 6.62 (m, 2H), 6.49 (d, 1H, J=5.6 Hz), 5.93 (s, 2H), 4.92-4.96 (m, 1H), 3.92-3.96 (m, 1H), 3.67- 3.83 (m, 5H), 3.41-3.47 (m, 2H), 2.95-3.03 (m, 1H), 2.28-2.42 (m, 3H), 2.00 (s, 6H), 1.84-1.95 (m, 1H), 1.07 (t, 3H, J=7.6 Hz). EXAMPLE 210 Synthesis of 6-[4-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-N'-(2-ethyl- 4-hydroxy-phenyl)-4- [[(3R)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine

To a solution of N'-[4-[1,1-dimethylethyl(dimethyl)silyl]oxy-2-ethyl-phenyl]- 4-[[(3R)- tetrahydrofuran-3-yl]amino]-6-(4,4,5,5-tetramethyl-1,3,2-dio xaborolan-2-yl)pyrrolo[1,2- b]pyridazine-3-carboxamidine (200 mg, 330 μmol) and 1-(3-bromo-4-pyridyl)-N,N-dimethyl- piperidin-4-amine (141 mg, 495 μmol) in N,N-dimethylformamide (10 mL) and water (1 mL) were added 1,1'-bis(di-t-butylphosphino)ferrocene-palladium dichloride (22 mg, 33 μmol) and potassium phosphate (210 mg, 990 μmol). The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 6-[4-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-N'-(2-ethyl- 4-hydroxy-phenyl)-4- [[(3R)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine as a white solid. Yield: 29.1 mg, 15%. LCMS (ESI) m/z: 569.2 (M+H). ¹ H NMR (DMSO-d6, 400 MHz): δ 12.56 (d, 1H, J=7.2 Hz), 8.95 (s, 1H), 8.50 (s, 1H), 8.21-8.33 (m, 2H), 8.10 (d, 1H, J=1.7 Hz), 7.27 (d, 1H, J=1.8 Hz), 7.00 (d, 1H, J=5.6 Hz), 6.54-6.71 (m, 3H), 5.94 (s, 2H), 4.92-5.02 (m, 1H), 3.92- 3.98 (m, 1H), 3.69-3.84 (m, 3H), 3.28-3.32 (m, 2H), 2.56-2.60 (m, 2H), 2.33-2.46 (m, 4H), 2.18 (s, 6H), 1.90-1.95 (m, 1H), 1.74-1.80 (m, 2H), 1.38-1.52 (m, 2H), 1.07 (t, 3H, J=7.6 Hz). EXAMPLE 211 Synthesis of 4-[4-(dimethylamino)-1-piperidyl]-5-[3-[N'-(2-ethyl-4-hydrox y- phenyl)carbamimidoyl]-4-[[(3R)-tetrahydrofuran-3-yl]amino]py rrolo[1,2-b]pyridazin-6-yl]-N-(2- methoxyethyl)pyridine-2-carboxamide formic acid salt

Step 1: Synthesis of 5-bromo-4-chloro-N-(2-methoxyethyl)pyridine-2-carboxamide To a solution of 5-bromo-4-chloro-pyridine-2-carboxylic acid (0.90 g, 3.81 mmol) in N,N- dimethylformamide (9.0 mL) were added 2-methoxyethanamine (857 mg, 11.42 mmol) and HATU (2.17 g, 5.71 mmol). After stirring at 25 °C for 3 hours, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solution of sodium carbonate, water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as an off-white solid. Yield: 1.10 g, 98 %. LCMS (ESI) m/z: 294.8 (M+H). Step 2: Synthesis of 5-bromo-4-[4-(dimethylamino)-1-piperidyl]-N-(2-methoxyethyl) pyridine-2- carboxamide To a solution of 5-bromo-4-chloro-N-(2-methoxyethyl)pyridine-2-carboxamide (1.10 g, 3.75 mmol) in N,N-dimethylacetamide (11.0 mL) was added N,N-dimethylpiperidin-4-amine (1.20 g, 9.37 mmol). After stirring at 120 °C for 2 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (methanol/dichloromethane) afforded the title compound as a yellow solid. Yield: 1.05 g, 72%. LCMS (ESI) m/z: 385.0 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 8.65 (s, 1H), 8.56 (s, 1H), 7.60 (s, 1H), 3.57-6.65 (m, 2H), 3.43-3.51 (m, 4H), 3.25 (s, 3H), 2.76-2.86 (m, 2H), 2.25-2.37 (m, 1H), 2.21 (s, 6H), 1.85-1.93 (m, 2H), 1.45- 1.59 (m, 2H). Step 3: Synthesis of 4-[4-(dimethylamino)-1-piperidyl]-5-[3-[N'-(2-ethyl-4-hydrox y- phenyl)carbamimidoyl]-4-[[(3R)-tetrahydrofuran-3-yl]amino]py rrolo[1,2-b]pyridazin-6-yl]-N-(2- methoxyethyl)pyridine-2-carboxamide formic acid salt To a solution of N'-[4-[1,1-dimethylethyl(dimethyl)silyl]oxy-2-ethyl-phenyl]- 4-[[(3R)- tetrahydrofuran-3-yl]amino]-6-(4,4,5,5-tetramethyl-1,3,2-dio xaborolan-2-yl)pyrrolo[1,2- b]pyridazine-3-carboxamidine (150 mg, 247.6 μmol) and 5-bromo-4-[4-(dimethylamino)-1- piperidyl]-N-(2-methoxyethyl)pyridine-2-carboxamide (143 mg, 371.5 μmol) in N,N- dimethylformamide (5.0 mL) and water (0.5 mL) were added 1,1'-bis (di-t- butylphosphino)ferrocene palladium dichloride (16 mg, 24.8 μmol) and potassium phosphate (158 mg, 743.0 μmol). The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 85 °C for 2 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 4-[4-(dimethylamino)-1-piperidyl]- 5-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-4-[[(3R)-t etrahydrofuran-3- yl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-N-(2-methoxyethyl)pyr idine-2-carboxamide formic acid salt as a light yellow solid. Yield: 76.8 mg, 43%. LCMS (ESI) m/z: 668.6 (M-H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.60 (s, 1H), 8.54-8.61 (m, 2H), 8.25 (s, 1H), 8.16-8.19 (m, 2H), 7.66 (s, 1H), 7.31 (s, 1H), 6.57-6.70 (m, 3H), 6.00 (brs, 2H), 4.90-4.96 (m, 1H), 3.90-3.95 (m, 1H), 3.70-3.85 (m, 3H), 3.35-3.50 (m, 6H), 3.28 (s, 3H), 2.60-2.70 (m, 2H), 2.30-2.49 (m, 4H), 2.20- 2.28 (m, 6H), 1.90-1.96 (m, 1H), 1.76-1.88 (m, 2H), 1.40-1.60 (m, 2H), 1.07 (t, 3H, J=7.6 Hz). EXAMPLE 212 Synthesis of N-[1-[3-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-4-[( 3R)-tetrahydrofuran- 3-ylamino]pyrrolo[1,2-b]pyridazin-6-yl]-4-pyridyl]-4-piperid yl]acetamide

Step 1: Synthesis of N-[1-(3-bromo-4-pyridyl)-4-piperidyl]acetamide To a solution of 3-bromo-4-fluoro-pyridine (600 mg, 3.4 mmol) and N-(4- piperidyl)acetamide (727 mg, 5.1 mmol) in N,N-dimethylacetamide (4 mL) was added N,N- diisopropylethylamine (881 mg, 6.8 mmol) at room temperature. The resulting mixture was stirred at 120 °C for 2 hours and then cooled to room temperature. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a light-yellow solid. Yield: 920 mg, 87%. LCMS (ESI) m/z: 298.1 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 8.52 (s, 1H), 8.34 (d, 1H, J=5.4 Hz), 7.89 (d, 1H, J=7.6 Hz), 7.06 (d, 1H, J=5.4 Hz), 3.67-3.81 (m, 1H), 3.43-3.50 (m, 2H), 2.80-2.87 (m, 2H), 1.83-1.89 (m, 2H), 1.81 (s, 3H), 1.48-1.58 (m, 2H). Step 2: Synthesis of N-[1-[3-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-4-[( 3R)- tetrahydrofuran-3-ylamino]pyrrolo[1,2-b]pyridazin-6-yl]-4-py ridyl]-4-piperidyl]acetamide To a solution of N-[1-(3-bromo-4-pyridyl)-4-piperidyl]acetamide (150 mg, 503 μmol) and N'-[4-[1,1-dimethylethyl(dimethyl)silyl]oxy-2-ethyl-phenyl]- 4-[[(3R)-tetrahydrofuran-3- yl]amino]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyr rolo[1,2-b]pyridazine-3- carboxamidine (200 mg, 330 μmol) in N,N-dimethylformamide (4 mL) and water (0.4 mL) were added tetrakis(triphenylphosphine)palladium (101 mg, 87 μmol) and sodium carbonate (70 mg, 660 μmol) at room temperature. The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, cesium fluoride (132 mg, 869 μmol) was added to the mixture and stirred further 1 hour. Purification via reverse phase column chromatography (acetonitrile/water) afforded a crude product. Further purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded N-[1-[3-[3-[N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-4-[( 3R)- tetrahydrofuran-3-ylamino]pyrrolo[1,2-b]pyridazin-6-yl]-4-py ridyl]-4-piperidyl]acetamide as an off-white solid. Yield: 26.9 mg, 14%. LCMS (ESI) m/z: 583.5 (M+H). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.57 (d, 1H, J=7.2 Hz), 8.95 (s, 1H), 8.55 (s, 1H), 8.21-8.33 (m, 2H), 8.12 (d, 1H, J=1.5 Hz), 7.90 (d, 1H, J=7.5 Hz), 7.26 (d, 1H, J=1.8 Hz), 7.02 (d, 1H, J=5.6 Hz), 6.51-6.71 (m, 3H), 5.94 (s, 2H), 4.97-5.03 (m, 1H), 3.92-4.02 (m, 1H), 3.62-3.89 (m, 4H), 3.20-3.30 (m, 2H), 2.62- 2.72 (m, 2H), 2.31-2.44 (m, 3H), 1.89-1.95 (m, 1H), 1.72-1.85 (m, 5H), 1.42-1.52 (m, 2H), 1.07 (t, 3H, J=7.5 Hz). EXAMPLE 213 Synthesis of 6-[4-[4-(dimethylamino)azepan-1-yl]-3-pyridyl]-N'-(2-ethyl-4 -hydroxy-phenyl)-4- [[(3R)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine formic acid salt

Step 1: Synthesis of benzyl 4-(dimethylamino)azepane-1-carboxylate Benzyl 4-oxoazepane-1-carboxylate (1.00 g, 4.0 mmol) was dissolved in 1 mL of dimethylamine (2 M in tetrahydrofuran), then acetic acid (0.2 mL) was added. After stirring at room temperature for 20 min, sodium triacetoxyborohydride (2.57 g, 12.1 mmol) was added in portions. After stirring overnight at room temperature, the reaction mixture was diluted with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate three times. The combined organic layers were washed with brine three times, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow oil. Yield: 700 mg, 62% . LCMS (ESI) m/z: 277.3 (M+H). Step 2: Synthesis of N,N-dimethylazepan-4-amine To a solution of benzyl 4-(dimethylamino)azepane-1-carboxylate (700 mg, 2.5 mmol) in methanol (10 mL) was added 10% palladium on active carbon (135 mg, 127 μmol) under nitrogen atmosphere. The resulting mixture was purged with hydrogen gas and stirred at room temperature for 24 hours under hydrogen atmosphere (1 atm.). The reaction mixture was filtered through a Celite pad and washed with methanol three times. The filtrate was concentrated under reduced pressure to afford the title compound as a yellow oil. Yield: 300 mg, 83%. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 2.81-2.61 (m, 2H), 2.51-2.40 (m, 3H), 2.11 (s, 6H), 1.78-1.66 (m, 2H), 1.66-1.48 (m, 2H), 1.48-1.32 (m, 2H). Step 3: Synthesis of 1-(3-bromo-4-pyridyl)-N,N-dimethyl-azepan-4-amine To a solution of N,N-dimethylazepan-4-amine (300 mg, 2.1 mmol) and 3-bromo-4-fluoro- pyridine (557 mg, 3.2 mmol) in N,N-dimethylacetamide (2 mL) was added N,N- diisopropylethylamine (545 mg, 4.2 mmol) at room temperature. The resulting mixture was stirred at 120 °C for 2 hours and then cooled to room temperature. Purification via reverse phase column chromatography (acetonitrile/water) afforded the title compound as a brown oil. Yield: 360 mg, 49%. LCMS (ESI) m/z: 300.0 (M+H). Step 4: Synthesis of 6-[4-[4-(dimethylamino)azepan-1-yl]-3-pyridyl]-N'-(2-ethyl-4 -hydroxy- phenyl)-4-[[(3R)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]py ridazine-3-carboxamidine formic acid salt To a solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-[[(3R )- tetrahydrofuran-3-yl]amino]-6-(4,4,5,5-tetramethyl-1,3,2-dio xaborolan-2-yl)pyrrolo[1,2- b]pyridazine-3-carboxamidine (300 mg, 495 μmol) and 1-(3-bromo-4-pyridyl)-N,N-dimethyl- azepan-4-amine (222 mg, 743 μmol) in N,N-dimethylformamide (4 mL) and water (0.4 mL) were added 1,1'-bis (di-t-butylphosphino)ferrocene-palladium dichloride (32 mg, 49 μmol) and potassium phosphate (210 mg, 991 μmol) at room temperature. The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, cesium fluoride (298 mg, 1.5 mmol) was added to the mixture and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The combined orange layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (methanol/dichloromethane) afforded a crude product. Further purification via reverse phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded 6-[4-[4-(dimethylamino)azepan-1-yl]-3-pyridyl]-N'-(2-ethyl-4 -hydroxy-phenyl)-4- [[(3R)-tetrahydrofuran-3-yl]amino]pyrrolo [1,2-b]pyridazine-3-carboxamidine formic acid salt as a light-yellow solid. Yield: 15.7 mg, 5%. LCMS (ESI) m/z: 583.6 (M+H). ¹ H NMR (DMSO- d ₆ , 400 MHz) δ 12.45 (brs, 1H), 8.18-8.36 (m, 5H), 7.86 (d, 1H, J=1.6 Hz), 6.91-7.04 (m, 2H), 6.57-6.67 (m, 3H), 5.99 (brs, 2H), 4.89-4.93 (m, 1H), 3.88-3.96 (m, 1H), 3.67-3.85 (m, 3H), 3.28- 3.42 (m, 2H), 3.08-3.24 (m, 2H), 2.70-2.96 (m, 1H), 2.29-2.49 (m, 9H), 1.27-2.10 (m, 7H), 1.08 (t, 3H, J=7.6 Hz). EXAMPLE 214 Synthesis of (Z)-N'-(2-chlorophenyl)-6-(4-methoxy-2-methylphenyl)-4-(((1R ,3S)-3- (propylamino)cyclopentyl)amino)pyrrolo[1,2-b]pyridazine-3-ca rboximidamide and (Z)-N'-(2-chlorophenyl)-4-(((1R,3S)-3-(dipropylamino)cyclope ntyl)amino)-6-(4-methoxy-2- methylphenyl)pyrrolo[1,2-b]pyridazine-3-carboximidamide (Compounds 214A and 214B) To a solution of (Z)-4-(((1R,3S)-3-aminocyclopentyl)amino)-N'-(2-chlorophenyl )-6-(4- methoxy-2-methylphenyl)pyrrolo[1,2-b]pyridazine-3-carboximid amide (30 mg, 61.4 μmol) in dichloromethane (1.0 mL) was added propanal (4.6 mg, 79.8 μmol, 5.7 μL). After stirring for 10 min sodium triacetoxyborohydride (25.8 mg, 123 μmol) was added in portions and the mixture was stirred at rt overnight. The reaction was carefully quenched with sat. aq. NaHCO ₃ and stirred for 10 min. The layers were separated, and the aqueous was extracted with dichloromethane (3 x 2.0 mL). The combined organics were concentrated and purified via reverse-phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) to afford (Z)-N'-(2-chlorophenyl)-6-(4-methoxy-2-methylphenyl)-4-(((1R ,3S)-3- (propylamino)cyclopentyl) amino)pyrrolo[1,2-b]pyridazine-3-carboximidamide as an off-white solid. Yield: 6.4 mg, 17% yield. LCMS (ESI) m/z = 531.5 (M+H). ¹ H NMR (DMSO-d ₆ ,300 MHz) δ 11.66 (brs, 1H), 8.29 (s, 1H), 8.21 (s, 1H, HCOOH), 7.80 (s, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.29 (t, J=7.4 Hz, 1H), 6.99-7.08 (m, 3H), 6.89 (s, 1H), 6.84 (d, J=8.9 Hz, 1H), 6.32 (brs, 2H), 4.60-4.74 (m, 1H), 3.78 (s, 3H), 3.23-3.32 (m, 1H), 2.45-2.56 (m, 2H), 2.44 (s, 3H), 2.04-2.17 (m, 1H), 1.84-1.99 (m, 1H), 1.69-1.85 (m, 1H), 1.45-1.66 (m, 2H), 1.29-1.43 (m, 2H), 0.81 (t, J=7.5 Hz, 3H). And (Z)-N'-(2-chlorophenyl)-4-(((1R,3S)-3-(dipropylamino)cyclope ntyl)amino)-6-(4- methoxy-2-methylphenyl)pyrrolo[1,2-b]pyridazine-3-carboximid amide as an off-white solid. Yield: 3.8 mg, 10%. LCMS (ESI) m/z = 573.5 (M+H). ¹ H NMR (DMSO-d6,300 MHz) δ 11.72 (brs, 1H), 8.21 (s, 1H), 8.19 (s, 1H, HCOOH), 7.79 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.29 (t, J=8.1 Hz, 1H), 7.02-7.08 (m, 2H), 6.99 (s, 1H), 6.88 (s, 1H), 6.83 (d, J=7.4 Hz, 1H), 6.31 (brs, 2H), 4.57-4.71 (m, 1H), 3.78 (s, 3H), 3.14-3.24 (m, 1H), 2.44 (s, 3H), 2.27-2.36 (m, 5H), 1.94-2.09 (m, 1H), 1.65-1.80 (m, 2H), 1.41-1.65 (m, 2H), 1.23-1.33 (m, 4H), 0.74 (t, J=7.2 Hz, 6H). EXAMPLE 215 Synthesis of (Z)-N'-(2-chlorophenyl)-6-(4-methoxy-2-methylphenyl)-4-(((1r ,4r)-4- (propylamino)cyclohexyl)amino)pyrrolo[1,2-b]pyridazine-3-car boximidamide To a solution of (Z)-4-(((1r,4r)-4-aminocyclohexyl)amino)-N'-(2-chlorophenyl) -6-(4- methoxy-2-methylphenyl)pyrrolo[1,2-b]pyridazine-3-carboximid amide (40 mg, 79.5 μmol) in DCM (1.0 mL) was added propanal (6.0 mg, 103 μmol, 7.4 μL) . After stirring for 10 min sodium triacetoxyborohydride (33.4 mg, 159 μmol) was added in portions. The reaction was stirred at rt overnight. The reaction mixture was carefully quenched with sat. aq. NaHCO ₃ and stirred for 10 min. The layers were separated, and the aqueous was extracted 3 times with DCM. Concentrated and purified via reverse-phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) to give (Z)-N'-(2-chlorophenyl)-6-(4-methoxy-2-methylphenyl)-4-(((1r ,4r)-4- (propylamino)cyclohexyl)amino)pyrrolo[1,2-b]pyridazine-3-car boximidamide as a solid. Yield: 15.5 mg, 31%. LCMS (ESI) m/z = 545.4 (M+H). 1H NMR (DMSO-d6,300 MHz) δ 11.59 (brs, 1H), 8.21 (s, 1H), 7.83 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.29 (t, J=7.4 Hz, 1H), 7.02-7.09 (m, 2H), 6.81-6.92 (m, 3H), 6.36 (brs, 2H), 4.10-4.21 (m, 1H), 3.78 (s, 3H), 2.75-2.87 (m, 1H), 2.69 (t, J=7.5 Hz, 2H), 2.45 (s, 3H), 2.14-2.36 (m, 2H), 2.01 (m, 2H), 1.33-1.57 (m, 6H), 0.89 (t, J=7.4 Hz, 3H). EXAMPLE 216 Synthesis of (S,Z)-N'-(2-ethyl-4-hydroxyphenyl)-6-(2-fluoro-6-methylpyrid in-3-yl)-4- ((tetrahydrofuran-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carb oximidamide and (S,Z)-N'-(2-ethyl-4-hydroxyphenyl)-6-(2-methoxy-6-methylpyri din-3-yl)-4-((tetrahydrofuran-3- yl)amino)pyrrolo[1,2-b]pyridazine-3-carboximidamide Compounds 216A and 216B Step 1: (S,Z)-N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylphenyl)-6- (2-fluoro-6-methylpyridin-3- yl)-4-((tetrahydrofuran-3-yl)amino)pyrrolo[1,2-b]pyridazine- 3-carboximidamide (S,Z)-6-bromo-N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylph enyl)-4-((tetrahydrofuran-3- yl)amino)pyrrolo[1,2-b]pyridazine-3-carboximidamide (180 mg, 322 μmol), (2-fluoro-6-methyl- 3-pyridyl)boronic acid (64.9 mg, 419 μmol) and aq. sodium carbonate (2 M, 483.36 μL) were dissolved in 1,4-dioxane (2.0 mL) in a screw capped vial equipped with a stir bar. The mixture was sparged with N ₂ gas for 15 min and tetrakis(triphenylphosphine)palladium (37 mg, 32.2 μmol) was added. The vial was then sealed and heated to 85 °C. After 1h the reaction mixture was cooled to room temperature. The reaction mixture was diluted with ethyl acetate and water. The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 X 2.0 mL). The combined organic material was washed with brine, dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purified on silica gel (0-100% EtOAc in heptane) to give the title compounds as a solid. Yield: 125 mg, 66%. LCMS (ESI) m/z = 589.5 (M+H). Step 2: Synthesis of (S,Z)-N'-(2-ethyl-4-hydroxyphenyl)-6-(2-fluoro-6-methylpyrid in-3-yl)-4- ((tetrahydrofuran-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carb oximidamide and (S,Z)-N'-(2-ethyl-4-hydroxyphenyl)-6-(2-methoxy-6-methylpyri din-3-yl)-4-((tetrahydrofuran-3- yl)amino)pyrrolo[1,2-b]pyridazine-3-carboximidamide The intermediate was dissolved in methanol (2.0 mL) and 4N HCl in 1,4-dioxane (2.0 mL) was added. After stirring for 1 h at rt the mixture was concentrated in vacuo. The residue was diluted with acetonitrile and DMSO. Purification via reverse-phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded: (S,Z)-N'-(2-ethyl-4-hydroxyphenyl)-6-(2-fluoro-6-methylpyrid in-3-yl)-4-((tetrahydrofuran-3- yl)amino)pyrrolo[1,2-b]pyridazine-3-carboximidamide as a solid. Yield: 15.8 mg, 10%. LCMS (ESI) m/z = 475.4 (M+H).1H NMR (DMSO- d ₆ , 300 MHz) δ 12.63 (brs, 1H), 8.97 (brs, 1H), 8.34-8.46 (m, 1H), 8.26 (s, 1H), 8.10 (s, 1H), 7.36 (s, 1H), 7.30 (d, J=7.2 Hz, 1H), 6.67 (s, 1H), 6.56-6.65 (m, 2H), 5.95 (brs, 2H), 4.95-5.09 (m, 1H), 3.99 (dd, J=9.4, 4.9 Hz, 1H), 3.80 (t, J=7.2 Hz, 2H), 3.70 (d, J=8.9 Hz, 1H), 2.35-2.47 (m, 6H), 1.85-1.99 (m, 1H), 1.07 (t, J=7.3 Hz, 3H). and (S,Z)-N'-(2-ethyl-4-hydroxyphenyl)-6-(2-methoxy-6-methylpyri din-3-yl)-4- ((tetrahydrofuran-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carb oximidamide as a solid. Yield: 61 mg, 37%. LCMS (ESI) m/z = 487.4 (M+H).1H NMR (DMSO- d6, 300 MHz) δ 12.53 (brs, 1H), 8.97 (brs, 1H), 8.22 (s, 1H), 8.12-8.18 (m, 2H), 7.37 (s, 1H), 6.93 (d, J=7.5 Hz, 1H), 6.67 (s, 1H), 6.56-6.66 (m, 2H), 5.93 (brs, 2H), 4.96-5.10 (m, 1H), 3.96-4.04 (m, 4H), 3.81 (t, J=6.8 Hz, 2H), 3.71 (d, J=9.6 Hz, 1H), 2.38-2.45 (m, 6H), 1.85-1.98 (m, 1H), 1.07 (t, J=7.5 Hz, 3H). EXAMPLE 218 Synthesis of (Z)-6-(4-((S)-3-(dimethylamino)pyrrolidin-1-yl)pyridin-3-yl) -N'-(2-ethyl-4- hydroxyphenyl)-4-(((S)-tetrahydrofuran-3-yl)amino)pyrrolo[1, 2-b]pyridazine-3-carboximidamide

To a solution of (Z)-6-(4-((S)-3-aminopyrrolidin-1-yl)pyridin-3-yl)-N'-(2-eth yl-4- hydroxyphenyl)-4-(((S)-tetrahydrofuran-3-yl)amino)pyrrolo[1, 2-b]pyridazine-3-carboximidamide (23 mg, 43.7μmol) in dichloromethane (0.5 mL) and DMF (0.25 mL) was added 37% formaldehyde in water (10.6 mg, 131 μmol, 9.8 μL). After stirring at rt for 10 min, sodium triacetoxyborohydride (23.1 mg, 87.4 μmol) was added and the reaction mixture was stirred overnight. The reaction was quenched with aq. sat. NaHCO3 and stirred for 30min. The product was extracted with 10% MeOH in DCM (5 X 2.0 mL) and the combined organics were concentrated in vacuo. Purification via reverse-phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded (Z)-6-(4-((S)-3-(dimethylamino)pyrrolidin-1-yl)pyridin-3-yl) -N'-(2- ethyl-4-hydroxyphenyl)-4-(((S)-tetrahydrofuran-3-yl)amino)py rrolo[1,2-b]pyridazine-3- carboximidamide as a solid. Yield: 5.5 mg, 21%. LCMS (ESI) m/z = 555.5 (M+H). 1H NMR (METHANOL- d ₄ , 300 MHz) δ 8.53 (brs, 1H), 8.10-8.18 (m, 2H), 8.09 (s, 1H), 7.83 (s, 1H), 7.13 (s, 1H), 7.00 (d, J=8.6 Hz, 1H), 6.92 (d, J=6.6 Hz, 1H), 6.84 (s, 1H), 6.76 (d, J=8.4 Hz, 1H), 4.66 (s, 1H), 3.96-4.08 (m, 2H), 3.84-3.95 (m, 2H), 3.35-3.52 (m, 3H), 3.18 (t, J=9.4 Hz, 1H), 2.88 (quin, J=7.6 Hz, 1H), 2.61 (q, J=7.7 Hz, 2H), 2.39-2.53 (m, 1H), 2.27 (s, 6H), 2.07-2.23 (m, 2H), 1.82 (quin, J=9.8 Hz, 1H), 1.24 (t, J=7.5 Hz, 3H). EXAMPLE 219 Synthesis of 2-(4-(4-(((1r,4r)-4-aminocyclohexyl)amino)-3-((Z)-N'-(2-chlo ro-5- fluorophenyl)carbamimidoyl)pyrrolo[1,2-b]pyridazin-6-yl)-3-m ethylphenoxy)acetic acid To a solution of methyl 2-(4-(4-(((1r,4r)-4-aminocyclohexyl)amino)-3-((Z)-N'-(2-chlo ro- 5-fluorophenyl)carbamimidoyl)pyrrolo[1,2-b]pyridazin-6-yl)-3 -methylphenoxy)acetate (14.5 mg, 25.0 μmol) in THF (0.5 mL) and methanol (0.2 mL) was added sodium hydroxide (1.0 M, 75.1 μL) . After stirring at room temperature for 4h the mixture was concentrated to dryness. The solid was dissolved in DMSO and acidified with formic acid. Filtered and purified via HPLC (acetonitrile/water buffered with 0.1 % formic acid) to give 2-(4-(4-(((1r,4r)-4- aminocyclohexyl)amino)-3-((Z)-N'-(2-chloro-5-fluorophenyl)ca rbamimidoyl)pyrrolo[1,2- b]pyridazin-6-yl)-3-methylphenoxy)acetic acid as a white solid. Yield: 10.4 mg, 68%. LCMS (ESI) m/z = 566.0 (M+H). EXAMPLE 220 Synthesis of (Z)-4-((((1S,5S)-3-azabicyclo[3.1.0]hexan-1-yl)methyl)amino) -N'-(2-ethyl-4- hydroxyphenyl)-6-(6-methoxy-4-methylpyridin-3-yl)pyrrolo[1,2 -b]pyridazine-3- carboximidamide To a solution of benzyl (1R,5S)-1-(((3-((Z)-N'-(2-ethyl-4- hydroxyphenyl)carbamimidoyl)-6-(6-methoxy-4-methylpyridin-3- yl)pyrrolo[1,2-b]pyridazin-4- yl)amino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (28 mg, 43.36 μmol) in methanol (1.0 mL) was added 10% Pd/C (4.6 mg, 4.3 μmol) and placed under a balloon of H2. After stirring overnight the reaction was filtered through celite, concentrated, and purified on HPLC (acetonitrile/water buffered with 0.1 % formic acid) to give (Z)-4-((((1S,5S)-3- azabicyclo[3.1.0]hexan-1-yl)methyl)amino)-N'-(2-ethyl-4-hydr oxyphenyl)-6-(6-methoxy-4- methylpyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboximidamid e as a solid. Yield: 5 mg, 19%. LCMS (ESI) m/z = 512.5 (M+H). 1H NMR (DMSO-d6, 300 MHz) δ 12.27 (brs, 1H), 8.19-8.26 (m, 3H), 7.88 (s, 1H), 7.08 (s, 1H), 6.77 (s, 1H), 6.67 (s, 1H), 6.56-6.65 (m, 2H), 5.88 (brs, 1H), 3.86 (s, 3H), 3.65-3.74 (m, 2H), 2.85-2.96 (m, 2H), 2.69-2.82 (m, 2H), 2.38-2.46 (m, 5H), 1.34-1.44 (m, 1H), 1.08 (t, J=7.6 Hz, 3H), 0.55-0.72 (m, 2H). EXAMPLE 221 Synthesis of (Z)-4-((2-azaspiro[3.3]heptan-5-yl)amino)-N'-(2-ethyl-4-hydr oxyphenyl)-6-(6- methoxy-4-methylpyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carb oximidamide Step 1: tert-butyl (Z)-5-((3-(N'-(2-ethyl-4-hydroxyphenyl)carbamimidoyl)-6-(6-m ethoxy-4- methylpyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-2-aza spiro[3.3]heptane-2-carboxylate A solution of tert-butyl 7-[[3-[(Z)-N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl- phenyl]carbamimidoyl]-6-(6-methoxy-4-methyl-3-pyridyl)pyrrol o[1,2-b]pyridazin-4-yl]amino]- 2-azaspiro[3.3]heptane-2-carboxylate (100 mg, 138 μmol) in THF (1.0 mL) was cooled to 0°C and treated with TBAF in THF (1.0 M, 207 μL). The reaction mixture was stirred for 3 hr and diluted with ethyl acetate. The mixture was washed with water and the aqueous was extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried (Na ₂ SO4), filtered, and concentrated under reduced pressure to afford the title compound. Yield 80mg, 95%. LCMS (ESI) m/z = 614.5 (M+H). Step 2: (Z)-4-((2-azaspiro[3.3]heptan-5-yl)amino)-N'-(2-ethyl-4-hydr oxyphenyl)-6-(6-methoxy- 4-methylpyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboximidam ide The intermediate was dissolved in DCM (1.0 mL) and TFA (0.5 mL) was added dropwise. The mixture was stirred for 1h. Concentrated and purified on HPLC (acetonitrile/water buffered with 0.1 % formic acid) to give (Z)-4-((2-azaspiro[3.3]heptan-5-yl)amino)-N'-(2-ethyl- 4-hydroxyphenyl)-6-(6-methoxy-4-methylpyridin-3-yl)pyrrolo[1 ,2-b]pyridazine-3- carboximidamide (22.0 mg, 36.7 μmol, 26.67% yield, 93% purity, S14) as a solid after lyophilization. LCMS (ESI) m/z = 512.4 (M+H). 1H NMR (DMSO-d ₆ , 300 MHz) δ 12.73 (brs, 1H), 8.32 (s, 2H), 8.27 (s, 1H), 7.93 (s, 1H), 7.19 (s, 1H), 6.79 (s, 1H), 6.69 (s, 1H), 6.55-6.68 (m, 2H), 5.98 (brs, 2H), 4.90-5.00 (m, 1H), 3.96-4.06 (m, 2H), 3.87 (s, 3H), 3.67-3.77 (m, 2H), 2.29-2.47 (m, 6H), 2.02-2.13 (m, 2H), 1.55- 1.72 (m, 1H), 1.08 (t, J=7.4 Hz, 3H). EXAMPLE 222 Synthesis of (S,Z)-5-(3-(N'-(2-ethyl-4-hydroxyphenyl)carbamimidoyl)-4-((t etrahydrofuran-3- yl)amino)pyrrolo[1,2-b]pyridazin-6-yl)-4-methylpicolinic acid Methyl (S,Z)-5-(3-(N'-(2-ethyl-4-hydroxyphenyl)carbamimidoyl)-4-((t etrahydrofuran-3- yl)amino)pyrrolo[1,2-b]pyridazin-6-yl)-4-methylpicolinate (23 mg, 44.7 umol) was dissolved in THF (1.0 mL) and methanol (0.1 mL) followed by 1M NaOH (1.0mL). After stirring for 4 h at rt the mixture was concentrated in vacuo. The residue was diluted with acetonitrile and DMSO and acidified with formic acid. Purification via reverse-phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded (S,Z)-5-(3-(N'-(2-ethyl-4-hydroxyphenyl)carbamimidoyl)-4- ((tetrahydrofuran-3-yl)amino)pyrrolo[1,2-b]pyridazin-6-yl)-4 -methylpicolinic acid as a solid. Yield: 5.3 mg, 15% yield. LCMS (ESI) m/z = 501.1 (M+H). 1H NMR (DMSO-d6, 300 MHz) δ 12.59 (d, J=6.8 Hz, 1H), 8.95 (s, 1H), 8.69 (s, 1H), 8.37 (d, J=4.5 Hz, 1H), 8.27 (s, 1H), 8.01 (s, 1H), 7.32 (d, J=5.0 Hz, 1H), 7.15 (s, 1H), 6.67 (s, 1H), 6.56-6.65 (m, 2H), 5.94 (brs, 2H), 4.97-5.06 (m, 1H), 3.95 (dd, J=9.2, 5.2 Hz, 1H), 3.75-3.83 (m, 2H), 3.71 (d, J=8.7 Hz, 1H), 3.33 (s, 3H), 2.34-2.46 (m, 3H), 1.86-1.97 (m, 1H), 1.07 (t, J=7.2 Hz, 3H). EXAMPLE 223 Synthesis of 6-[2-[4-(dimethylamino)-1-piperidyl]phenyl]-N'-(2-ethyl-4-hy droxy-phenyl)-4- [[(3R)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine-3 -carboxamidine (Compound 214A)

Step 1: Synthesis of 1-(2-bromophenyl)-N,N-dimethyl-piperidin-4-amine To a solution of 1-bromo-2-iodo-benzene (1.40 g, 4.9 mmol) in toluene (28 mL) were added N,N-dimethylpiperidin-4-amine (698 mg, 5.4 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct (256 mg, 247 μmol) , (±)-2,2'- bis(diphenylphosphino)-1,1'-binaphthalene (462 mg, 742 μmol) and sodium 2-methylpropan-2- olate (951 mg, 9.9 mmol). The resulting mixture was purged with nitrogen gas and stirred at 80 °C for 15 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel column chromatography (methanol/dichloromethane) and then reverse phase column chromatography (acetonitrile/water) afforded the title compound as a yellow oil. Yield: 150 mg, 11%. LCMS (ESI) m/z: 283.2 (M+H). Step 2: Synthesis of 6-[2-[4-(dimethylamino)-1-piperidyl]phenyl]-N'-(2-ethyl-4-hy droxy-phenyl)- 4-[[(3R)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]pyridazine -3-carboxamidine To a solution of N'-[4-[tert-butyl(dimethyl)silyl]oxy-2-ethyl-phenyl]-4-[[(3R )- tetrahydrofuran-3-yl]amino]-6-(4,4,5,5-tetramethyl-1,3,2-dio xaborolan-2-yl)pyrrolo[1,2- b]pyridazine-3-carboxamidine (180 mg, 297.20 μmol) and 1-(2-bromophenyl)-N,N-dimethyl- piperidin-4-amine (126 mg, 446 μmol) in N,N-dimethylformamide (8 mL) and water (2 mL) were added sodium carbonate (95 mg, 892 μmol) and tetrakis(triphenylphosphine)palladium (69 mg, 60 μmol) at room temperature. The resulting mixture was purged with nitrogen gas and stirred at 85 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification via reverse phase HPLC (acetonitrile/water buffered with 10 mmol/L ammonium bicarbonate and 0.05 % ammonia) afforded 6-[2-[4-(dimethylamino)-1-piperidyl]phenyl]-N'-(2-ethyl-4-hy droxy- phenyl)-4-[[(3R)-tetrahydrofuran-3-yl]amino]pyrrolo[1,2-b]py ridazine-3-carboxamidine as an off-white solid. Yield: 27.7 mg, 16%. LCMS (ESI) m/z: 568.3 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ 12.51 (d, 1H, J=7.2 Hz), 8.96 (brs, 1H), 8.15-8.25 (m, 2H), 7.50-7.56 (m, 1H), 7.32 (d, 1H, J=2.0 Hz), 7.19-7.25 (m, 1H), 7.02-7.16 (m, 2H), 6.67 (s, 1H), 6.57-6.63 (m, 2H), 5.92 (s, 2H), 4.95-5.00 (m, 1H), 3.94-3.98 (m, 1H), 3.75-3.86 (m, 2H), 3.68-3.74 (m, 1H), 3.11-3.19 (m, 2H), 2.52-2.58 (m, 2H), 2.34-2.45 (m, 3H), 2.10-2.22 (m, 7H), 1.90-1.98 (m, 1H), 1.73-1.83 (m, 2H), 1.42-1.55 (m, 2H), 1.07 (t, 3H, J=7.6 Hz). EXAMPLE 223B (Z)-4-(((1r,4r)-4-aminocyclohexyl)amino)-6-(2-chloro-4-metho xyphenyl)-N'-(2- chlorophenyl)pyrrolo[1,2-b]pyridazine-3-carboximidamide Compound 214B was prepared by analogous methods. 1H NMR (300 MHz, METHANOL-d4) δ 8.54 (brs, 1H), 8.15 (s, 1H), 7.87 (s, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.32 (t, J=7.8 Hz, 1H), 7.17 (s, 1H), 7.05-7.13 (m, 3H), 6.98 (d, J=8.5 Hz, 1H), 4.18-4.32 (m, 1H), 3.86 (s, 3H), 3.13-3.25 (m, 1H), 2.38-2.50 (m, 2H), 2.16 (brs, 2H), 1.50-1.74 (m, 4H). LCMS m/z (ES+) (M + H) ⁺ = 523.4 EXAMPLE 223C (Z)-4-(((1r,4r)-4-aminocyclohexyl)amino)-N'-(2-chlorophenyl) -6-(4-methoxy-2- methylphenyl)pyrrolo[1,2-b]pyridazine-3-carboximidamide Compound 214C was prepared by analogous methods. 1H NMR (300 MHz, DMSO-d ₆ ) δ 11.58 (brs, 1H), 8.42 (s, 1H), 7.83 (s, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.29 (t, J=7.4 Hz, 1H), 7.02-7.08 (m, 2H), 6.82-6.91 (m, 3H), 6.36 (br s, 2H), 4.08-4.18 (m, 1H), 3.78 (s, 3H), 2.87-2.95 (m, 1H), 2.45 (s, 3H), 2.18 (br dd, J=6.7, 1.3 Hz, 2H), 1.92 (br s, 2H), 1.37-1.50 (m, 4H). m/z (ES+) (M + H) ⁺ = 503.5 EXAMPLE224 Synthesis of (Z)-4-(((1R,3S)-3-aminocyclopentyl)amino)-N'-(2-chlorophenyl )-6-(6-methoxy-4- methylpyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboximidamid e (Compound 224A) Step 1: tert-butyl ((1S,3R)-3-((3-((Z)-N'-(2-chlorophenyl)carbamimidoyl)-6-(6-m ethoxy-4- methylpyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)cyclop entyl)carbamate tert-butyl ((1S,3R)-3-((6-bromo-3-((Z)-N'-(2-chlorophenyl)carbamimidoyl )pyrrolo[1,2- b]pyridazin-4-yl)amino)cyclopentyl)carbamate (50 mg, 91.3 μmol), (6-methoxy-4-methyl-3- pyridyl)boronic acid (19.8 mg, 119 μmol) and aq. sodium carbonate (2 M, 137 μL) were dissolved in DMF (1.0 mL) in a screw capped vial equipped with a stir bar. The mixture was sparged with N2 gas for 15 min and tetrakis(triphenylphosphine)palladium (10.6 mg, 9.13 μmol) was added. The vial was then sealed and heated to 85 °C. After 1h the reaction mixture was cooled to room temperature. The reaction mixture was diluted with ethyl acetate and water. The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 X 2mL). The combined organic material was washed with brine, dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purified on silica gel (0-100% EtOAc in heptane) to give the title compound as a solid. Yield: 39.1 mg, 73%. LCMS (ESI) m/z = 590.5 (M+H). Step 2: (Z)-4-(((1R,3S)-3-aminocyclopentyl)amino)-N'-(2-chlorophenyl )-6-(6-methoxy-4- methylpyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboximidamid e Tert-butyl ((1S,3R)-3-((3-((Z)-N'-(2-chlorophenyl)carbamimidoyl)-6-(6-m ethoxy-4- methylpyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)cyclop entyl)carbamate (39.1 mg, 66.1 umol) was dissolved in DCM (1.0 mL) and TFA (0.5 mL) was added. After stirring for 1 h at rt the mixture was concentrated in vacuo. The residue was dissolved in DMSO and filtered. Purification via reverse-phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded (Z)-4-(((1R,3S)-3-aminocyclopentyl)amino)-N'-(2-chlorophenyl )-6-(6-methoxy-4- methylpyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboximidamid e as an off-white solid. Yield: 16.1 mg, 47% yield. LCMS (ESI) m/z = 490.4 (M+H). 1H NMR (DMSO-d6, 300 MHz) δ 11.68 (brs, 1H), 8.25 (s, 1H), 8.22 (s, 1H), 7.89 (s, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.29 (t, J=7.3 Hz, 1H), 7.01-7.10 (m, 3H), 6.78 (s, 1H), 6.32 (brs, 2H), 4.59-4.70 (m, 1H), 3.87 (s, 3H), 3.24-3.30 (m, 1H), 2.38-2.48 (m, 4H), 2.04-2.17 (m, 1H), 1.67- 1.92 (m, 2H), 1.29-1.51 (m, 2H).

To a solution of (Z)-4-(((1R,3S)-3-aminocyclopentyl)amino)-N'-(2-chlorophenyl )-6-(4- methoxy-2-methylphenyl)pyrrolo[1,2-b]pyridazine-3-carboximid amide (32 mg, 65.4 μmol) in dichloromethane (0.5 mL) was added N,N-diisopropylethylamine (21.1 mg, 164 μmol, 28.5 μL) followed by methanesulfonyl chloride (8.3 mg, 72.0 μmol, 5.6 μL). The reaction was stirred at rt overnight, concentrated, and diluted with DMSO. Purification via reverse-phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded (Z)-N'-(2-chlorophenyl)-6-(4- methoxy-2-methylphenyl)-4-(((1R,3S)-3-(methylsulfonamido)cyc lopentyl)amino)pyrrolo[1,2- b]pyridazine-3-carboximidamide as an off-white solid. Yield: 26.1 mg, 67% yield. LCMS (ESI) m/z = 569.4 (M+H). 1H NMR (DMSO-d ₆ , 300 MHz) δ 11.65 (d, J=4.9 Hz, 1H), 8.20 (s, 1H), 7.80 (s, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.26-7.34 (m, 1H), 7.20 (d, J=7.2 Hz, 1H), 7.07 (d, J=8.3 Hz, 2H), 7.03 (s, 1H), 6.88 (s, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.33 (br s, 2H), 4.58-4.72 (m, 1H), 3.78 (s,3H), 3.66-3.76 (m, 1H), 2.86 (s, 3H), 2.54-2.64 (m, 1H), 2.44 (s, 3H), 2.07-2.24 (m, 1H), 1.93-2.06 (m, 1H), 1.48-1.76 (m, 3H). EXAMPLE 225B (Z)-N'-(2-chlorophenyl)-6-(4-methoxy-2-methylphenyl)-4-(((1R ,3S)-3- (propylsulfonamido)cyclopentyl)amino)pyrrolo[1,2-b]pyridazin e-3-carboximidamide Compound 225B was prepared by analogous methods 1H NMR (DMSO-d ₆ , 300 MHz) δ 11.65 (brs, 1H), 8.20 (s, 1H), 7.80 (s, 1H), 7.49 (d, J=7.7 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.26-7.37 (m, 1H), 7.23 (d, J=7.2 Hz, 1H), 7.07 (d, J=7.8 Hz, 2H), 7.03 (s, 1H), 6.88 (s, 1H), 6.83 (d, J=8.7 Hz, 1H), 6.34 (brs, 2H), 4.56-4.72 (m, 1H), 3.78 (s, 3H), 3.69-3.77 (m, 1H), 2.87-2.96 (m, 2H), 2.53-2.60 (m, 1H), 2.44 (s, 3H), 2.07-2.20 (m, 1H), 1.92-2.06 (m, 1H), 1.51-1.75 (m, 5H), 0.93 (t, J=7.3 Hz,3H). MS m/z (ES+) (M + H) ⁺ = 597.7 EXAMPLE 225C (Z)-N'-(2-chlorophenyl)-4-(((1R,3S)-3-((4-fluorophenyl)sulfo namido)cyclopentyl)amino)-6-(4- methoxy-2-methylphenyl)pyrrolo[1,2-b]pyridazine-3-carboximid amide Compound 225C was prepared by analogous methods 1H NMR (DMSO-d6, 300 MHz) δ 11.42-11.69 (m, 1H), 8.19 (s, 1H), 7.88 (d, J=7.1 Hz, 1H), 7.79-7.86 (m, 2H), 7.78 (s, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.24-7.43 (m, 4H), 6.96-7.15 (m, 2H), 6.90 (d, J=11.5 Hz, 2H), 6.83 (d, J=8.6 Hz, 1H), 6.33 (brs, 2H), 4.47-4.68 (m, 1H), 3.78 (s, 3H), 3.50-3.65 (m, 1H), 2.40 (s, 3H), 2.16-2.31 (m, 1H), 1.95-2.11 (m, 1H), 1.70-1.85 (m, 1H), 1.34-1.67 (m, 3H). MS m/z (ES+) (M + H) ⁺ = 649.4 EXAMPLE226A Synthesis of (Z)-N'-(2-chlorophenyl)-6-(4-methoxy-2-methylphenyl)-4-(((1r ,4r)-4- (methylsulfonamido)cyclohexyl)amino)pyrrolo[1,2-b]pyridazine -3-carboximidamide (compound 226A) To a solution of (Z)-4-(((1r,4r)-4-aminocyclohexyl)amino)-N'-(2-chlorophenyl) -6-(4- methoxy-2-methylphenyl)pyrrolo[1,2-b]pyridazine-3-carboximid amide (34 mg, 67.6 μmol) in dichloromethane (0.5 mL) was added N,N-diisopropylethylamine (21.8 mg, 169 μmol, 29.4 μL) followed by methanesulfonyl chloride (8.5 mg, 74.4 μmol, 5.8 μL). The reaction was stirred at rt for 1h, concentrated, and diluted with DMSO. Purification via reverse-phase HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded (Z)-N'-(2-chlorophenyl)-6-(4- methoxy-2-methylphenyl)-4-(((1r,4r)-4-(methylsulfonamido)cyc lohexyl)amino)pyrrolo[1,2- b]pyridazine-3-carboximidamide as a solid. Yield: 16.1 mg, 39% yield. LCMS (ESI) m/z = 581.5 (M+H). 1H NMR (DMSO-d ₆ ,300 MHz) δ 11.57 (brs, 1H), 8.21 (s, 1H), 7.81 (s, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 7.30 (t, J=7.5 Hz, 1H), 7.06 (d, J=7.9 Hz, 2H), 7.00 (d, J=7.3 Hz, 1H), 6.89 (s, 2H), 6.85 (d, J=8.4 Hz, 1H), 6.34 (s, 2H), 4.03-4.21 (m, 1H), 3.78 (s, 3H), 3.11-3.22 (m, 1H), 2.91 (s, 3H), 2.45 (s, 3H), 2.07-2.23 (m, 2H), 1.87-2.03 (m, 2H), 1.37-1.57 (m, 4H). EXAMPLE226B ((Z)-N'-(2-chlorophenyl)-6-(4-methoxy-2-methylphenyl)-4-(((1 r,4r)-4- (propylsulfonamido)cyclohexyl)amino)pyrrolo[1,2-b]pyridazine -3-carboximidamide (compound 226B) Compound 226B was prepared by analogous methods 1H NMR (DMSO-d ₆ ,300 MHz) δ 11.57 (brs, 1H), 8.20 (s, 1H), 7.82 (s, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.30 (t, J=7.0 Hz, 1H), 6.98-7.14 (m, 3H), 6.89 (br s, 2H), 6.85 (d, J=8.9 Hz, 1H), 6.35 (br s, 2H), 3.99-4.20 (m, 1H), 3.78 (s, 3H), 3.09-3.22 (m, 1H), 2.90- 3.03 (m, 2H), 2.45 (s, 3H), 2.07-2.22 (m, 2H), 1.84-2.03 (m, 2H), 1.57-1.76 (m, 2H), 1.35-1.56 (m, 4H), 0.96 (t, J=7.4 Hz, 3H). MS m/z (ES+) (M + H) ⁺ = 460.4 EXAMPLE 227A Synthesis of 5-(4-(((1R,3S)-3-aminocyclopentyl)amino)-3-((Z)-N'-(2- chlorophenyl)carbamimidoyl)pyrrolo[1,2-b]pyridazin-6-yl)-4-m ethylpicolinamide (compound 227A) Step 1: tert-butyl ((1S,3R)-3-((6-(6-carbamoyl-4-methylpyridin-3-yl)-3-((Z)-N'- (2- chlorophenyl)carbamimidoyl)pyrrolo[1,2-b]pyridazin-4-yl)amin o)cyclopentyl)carbamate To a solution of 5-(4-(((1R,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)ami no)-3- ((Z)-N'-(2-chlorophenyl)carbamimidoyl)pyrrolo[1,2-b]pyridazi n-6-yl)-4-methylpicolinic acid (50 mg, 49.66 μmol) and HATU (38.0 mg, 99.3 μmol) in DMA (0.5 mL) was added ammonium chloride (8.0 mg, 150 μmol) followed by N,N-diisopropylethylamine (32.1 mg, 248 μmol, 43.3 μL). The reaction mixture was stirred at rt overnight. The mixture was filtered and purified via HPLC (acetonitrile/water buffered with 0.1 % formic acid) to give the title compound. Yield: 19mg, 63%. LCMS (ESI) m/z = 603.4 (M+H). Step 2: 5-(4-(((1R,3S)-3-aminocyclopentyl)amino)-3-((Z)-N'-(2- chlorophenyl)carbamimidoyl)pyrrolo[1,2-b]pyridazin-6-yl)-4-m ethylpicolinamide The intermediate was dissolved in DCM (1.0 mL) and TFA (0.5 mL) and stirred for 1 h. The reaction mixture was concentrated, dissolved in DMSO, and filtered. Purification on HPLC (acetonitrile/water buffered with 0.1 % formic acid) gave 5-(4-(((1R,3S)-3- aminocyclopentyl)amino)-3-((Z)-N'-(2-chlorophenyl)carbamimid oyl)pyrrolo[1,2-b]pyridazin-6- yl)-4-methylpicolinamide as a solid. Yield: 7.4 mg 27% over 2 steps. LCMS (ESI) m/z = 503.3 (M+H). 1H NMR (DMSO-d6, 300 MHz) δ 11.82 (brs, 1H), 8.74 (s, 1H), 8.27 (s, 1H), 8.04-8.14 (m, 2H), 7.99 (s, 1H), 7.64 (brs, 1H), 7.49 (d, J=7.2 Hz, 1H), 7.27-7.35 (m, 1H), 7.25 (s, 1H), 7.02-7.11 (m, 2H), 6.40 (brs, 2H), 4.63-4.79 (m, 1H), 3.42-3.51 (m, 1H), 2.59 (s, 3H), 2.53-2.58 (m, 1H), 2.09-2.23 (m, 1H), 1.90-2.05 (m, 1H), 1.69-1.86 (m,1H), 1.43-1.66 (m, 2H). Eg Structure Name NMR MS (Z)-N'-(2-ethyl-4- ¹ hydroxyphenyl)- H NMR (DMSO-d ₆ , 300 MHz) δ 4-(((3S,4S)-4- 8.66 (s, 1H), 8.38 (d, 1H, J=4.8 Hz), hydroxytetrahydro 8.25 (s, 1H), 8.17 (s, 1H), 8.00 (s, -2H-pyran-3- 1H), 7.33 (d, 1H, J=4.8 Hz), 7.09 (s, 227F yl)amino)-6-(6- 1H), 6.6-6.7 (m, 3H), 5.99 (br s, hoxy-4- 1H), 4.05 517.2 met (br d, 3H, J=11.6 Hz), methylpyridin-3- 3.86 (m, 2H), 3.6-3.8 (m, 3H), 3.2- yl)pyrrolo[1,2- 3.4 (m, 6H), 2.4-2.5 (m, 5H), 1.95 b]pyridazine-3- (m, 1H), 1.51 (m, 1H), 1.08 (t, 3H, carboximidamide J=7.4 Hz) (Z)-N'-(2- ¹ H NMR (DMSO-d6, 300 MHz) δ chlorophenyl)-4- 11.6-12.0 (bs, 1H), 8.27 (s, 1H), (((4- 7.92 (s, 1H), 7.47 (d, 1H, J=8.0 Hz), fluoropiperidin-4- 7.2-7.3 (m, 1H), 7.18 (s, 1H), 7.0- 227G yl)methyl)amino)- 7.1 (m, 1H), 7.0-7.1 (m, 1H), 6.78 6-(6-methoxy-4- (s, 1H), 6.35 (br s, 1H), 6.1-6.6 (m, 522.2 methylpyridin-3- 1H), 4.0-4.3 (m, 1H), 3.87 (s, 1H), yl)pyrrolo[1,2- 2.95 (br d, 1H, J=12.2 Hz), 2.78 (br b]pyridazine-3- t, 1H, J=11.8 Hz), 2.43 (s, 1H), 1.8- carboximidamide 2.0 (m, 1H), 1.6-1.9 (m, 1H) EXAMPLE 228A Synthesis of (Z)-N'-(2-chlorophenyl)-6-(6-methoxy-4-methylpyridin-3-yl)-4 -((1-methyl-5- oxopyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxim idamide Step 1: (Z)-6-bromo-N'-(2-chlorophenyl)-4-((1-methyl-5-oxopyrrolidin -3-yl)amino)pyrrolo[1,2- b]pyridazine-3-carboximidamide To a solution of 6-bromo-4-chloro-N'-(2-chlorophenyl)pyrrolo[1,2-b]pyridazine -3- carboxamidine (100 mg, 260 μmol) and 4-amino-1-methyl-pyrrolidin-2-one hydrochloride (43.1 mg, 286 μmol) in DMA (1.0 mL) was added N,N-diisopropylethylamine (84 mg, 651 μmol, 113 μL). The reaction mixture was heated to 85 °C. After 18 h the mixture was cooled to room temperature. The reaction was diluted with ethyl acetate and washed with water two times, and then once more with brine. The organic phase was dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purification via silica gel chromatography (0 to 100 % ethyl acetate in heptane) afforded the title compound as a light-yellow solid. Yield: 91 mg, 76%. LCMS (ESI) m/z = 464.5 (M+H). Step 2: (Z)-N'-(2-chlorophenyl)-6-(6-methoxy-4-methylpyridin-3-yl)-4 -((1-methyl-5- oxopyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxim idamide (Z)-6-bromo-N'-(2-chlorophenyl)-4-((1-methyl-5-oxopyrrolidin -3-yl)amino)pyrrolo[1,2- b]pyridazine-3-carboximidamide (40 mg, 86.6 μmol), (6-methoxy-4-methyl-3-pyridyl)boronic acid (18.8 mg, 113 μmol) and aq. sodium carbonate (2 M, 130 μL) were dissolved in DMF (1.0 mL) in a screw capped vial equipped with a stir bar. The mixture was sparged with N2 gas and tetrakis(triphenylphosphine)palladium (10 mg, 8.7 μmol) was added. The vial was then sealed and heated to 85 °C. After 1h the reaction mixture was cooled to room temperature. The reaction mixture was diluted with ethyl acetate and water. The layers were separated, and then aqueous phase was extracted with ethyl acetate two times. The combined organic material was washed with brine, dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purification via HPLC (acetonitrile/water buffered with 0.1 % formic acid) afforded (Z)-N'-(2-chlorophenyl)-6- (6-methoxy-4-methylpyridin-3-yl)-4-((1-methyl-5-oxopyrrolidi n-3-yl)amino)pyrrolo[1,2- b]pyridazine-3-carboximidamide as a solid. Yield: 13 mg, 28%. LCMS (ESI) m/z = 504.3 (M+H). ¹ H NMR (DMSO-d6, 300 MHz) δ 11.90 (brs, 1H), 8.28 (s, 1H), 8.26 (s, 1H), 7.95 (s, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.25-7.34 (m, 1H), 7.01-7.10 (m, 3H), 6.79 (s, 1H), 6.47 (brs, 2H), 4.98-5.13 (m, 1H), 3.88-3.94 (m, 1H), 3.87 (s, 3H), 3.33-3.41 (m, 2H), 2.91 (br dd, J=17.1, 7.4 Hz, 1H), 2.71 (s, 3H), 2.45 (s, 3H), 2.27 (d, J=17.2 Hz, 1H). Compounds 228B and 228Cwere prepared according to analogous methods EXAMPLE 229A Synthesis of 5-[3-[(Z)-N'-(2-ethyl-4-hydroxy-phenyl)carbamimidoyl]-4-[[(3 S)-tetrahydrofuran-3- yl]amino]pyrrolo[1,2-b]pyridazin-6-yl]-N-(2-methoxyethyl)-4- methyl-pyridine-2-carboxamide

Step 1: N-(2-methoxyethyl)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dio xaborolan-2- yl)picolinamide A solution of 2-methoxyethanamine (108 mg, 1.4 mmol, 125 μL) and methyl 4-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carb oxylate (200 mg, 0.7 mmol) in DMF (0.5 mL) was heated to 90°C for 16 h. The reaction mixture was cooled to rt and water (1.0 mL) was added. The product was extracted with EtOAc (3 x 1.0 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to afford N-(2- methoxyethyl)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxabor olan-2-yl)pyridine-2-carboxamide. Yield: 168 mg, 73%. LCMS (ESI) m/z = 321.1 (M+H). Step 2: (S,Z)-5-(3-(N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylphen yl)carbamimidoyl)-4- ((tetrahydrofuran-3-yl)amino)pyrrolo[1,2-b]pyridazin-6-yl)-N -(2-methoxyethyl)-4- methylpicolinamide (S,Z)-6-bromo-N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylph enyl)-4-((tetrahydrofuran-3- yl)amino)pyrrolo[1,2-b]pyridazine-3-carboximidamide (120 mg, 215 μmol), N-(2-methoxyethyl)- 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyri dine-2-carboxamide (75.7 mg, 236 μmol) and aq. sodium carbonate (2 M, 322 μL) were dissolved in 1,4-dioxane (2.0 mL) in a screw capped vial equipped with a stir bar. The mixture was sparged with N2 gas for 15 min and tetrakis(triphenylphosphine)palladium (24.8 mg, 21.5 μmol) was added. The vial was then sealed and heated to 85 °C. After 1h the reaction mixture was cooled to room temperature. The reaction mixture was diluted with ethyl acetate and water. The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 X 3.0 mL). The combined organic material was washed with brine, dried over magnesium sulfate, filtered, and solvent removed in vacuo. Purified on silica gel (0-100% EtOAc in heptane) to afford (S,Z)-5-(3-(N'-(4-((tert-butyldimethylsilyl)oxy)-2- ethylphenyl)carbamimidoyl)-4-((tetrahydrofuran-3-yl)amino)py rrolo[1,2-b]pyridazin-6-yl)-N-(2- methoxyethyl)-4-methylpicolinamide as a solid. Yield: 96 mg, 67%. LCMS (ESI) m/z = 672.5 (M+H). Step 3: (S,Z)-5-(3-(N'-(2-ethyl-4-hydroxyphenyl)carbamimidoyl)-4-((t etrahydrofuran-3- yl)amino)pyrrolo[1,2-b]pyridazin-6-yl)-N-(2-methoxyethyl)-4- methylpicolinamide (S,Z)-5-(3-(N'-(4-((tert-butyldimethylsilyl)oxy)-2-ethylphen yl)carbamimidoyl)-4- ((tetrahydrofuran-3-yl)amino)pyrrolo[1,2-b]pyridazin-6-yl)-N -(2-methoxyethyl)-4- methylpicolinamide (96 mg, 143 μmol) was dissolved in methanol (2.0 mL) and 4N HCl in 1,4- dioxane (1.0 mL) was added. After stirring for 3 h at rt the mixture was concentrated in vacuo. The residue was diluted with acetonitrile and DMSO. Purification via reverse-phase (acetonitrile/water buffered with 0.1 % formic acid) afforded 5-[3-[(Z)-N'-(2-ethyl-4-hydroxy- phenyl)carbamimidoyl]-4-[[(3S)-tetrahydrofuran-3-yl]amino]py rrolo[1,2-b]pyridazin-6-yl]-N-(2- methoxyethyl)-4-methyl-pyridine-2-carboxamide as a solid. Yield:46.4 mg, 39%. LCMS (ESI) m/z = 558.4 (M+H). 1H NMR (DMSO- d6, 300 MHz) δ 12.62 (brs, 1H), 8.96 (s, 1H), 8.76 (s, 1H), 8.57-8.68 (m, 1H), 8.29 (s, 1H), 8.11 (s, 1H), 7.98 (s, 1H), 7.22 (s, 1H), 6.68 (s, 1H), 6.55-6.65 (m, 2H), 5.96 (brs, 2H), 4.95-5.09 (m, 1H), 3.96 (dd, J=9.3, 4.8 Hz, 1H), 3.76-3.85 (m, 2H), 3.67-3.74 (m, 1H), 3.50 (s, 4H), 3.29 (s, 3H), 2.60 (s, 3H), 2.34-2.45 (m, 3H), 1.87-2.00 (m, 1H), 1.08 (t, J=7.5 Hz, 3H).

carboximidamide

EXAMPLE 230 Human JAK1, JAK2, JAK3 and TYK2 Biochemical Inhibition Assays Compounds 17-229 were tested for the ability to inhibit activity of human JAK1, JAK2, JAK3 and TYK2, according to the procedure as described in Example 16; IC ₅₀ values are presented in the following table according to the following indicators: The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary, to employ concepts of the various patents, applications and publications to provide yet further embodiments. These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure. All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. This application claims the benefit of priority to U.S. Provisional Application No. 63/117,387, filed November 23, 2020, which application is hereby incorporated by reference in its entirety.