Fused azines as KCC2 potentiators and uses thereof

Abstract

The present disclosure provides compounds, compositions, and methods for treating or preventing neurological disorders in a patient. The disclosed methods include administration to a subject suffering from a neurological disorder of a compound disclosed herein. Formula (I)

Description

[0001] PATENT

[0002] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0003] KCC2 POTENTIATORS AND USES THEREOF

[0004] BACKGROUND OF THE INVENTION

[0005] Potassium chloride cotransporter-2 (KCC2) has been linked to neurological disorder, psychiatric disorders, and central nervous system injuries, and has been linked to neurological functions such as sensory, motor, cognitive, and / or developmental functions in the affected individual. These disorders often result in profound and irreversible neurological effects that pose severe challenges to an afflicted patient’s everyday life. Few therapeutics have been studied or utilized to treat these neurological disorders, which causes severe challenges and suffering for these patients. Additionally, the few that have been studied or utilized are not adequately sufficient to reduce the individual’s suffering or improve recovery from these neurological disorders. Accordingly, there is a need for novel therapeutic agents for the treatment of neurological disorders.

[0006] SUMMARY OF THE INVENTION

[0007] The present disclosure provides compounds, compositions, and methods for treating or preventing neurological disorders in a patient. The disclosed methods include administration to a subject suffering from a neurological disorder of a compound disclosed herein. The disclosure further provides pharmaceutical compositions containing one of the compounds described herein. The disclosure further provides compounds and pharmaceutical compositions for use as a medicament. The disclosure further provides compounds and pharmaceutical compositions for use in the treatment or prevention of neurological disorders.

[0008] In the first aspect, the disclosure provides a compound of Formula (I):

[0009] Formula (I), or a pharmaceutically acceptable salt thereof, wherein A is N or CR4;

[0010] R1is H or F;

[0011] R2is H or F;

[0012] R3is H, or Ci-C4alkyl;

[0013] R4is H or F; PATENT

[0014] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0015] R1ais H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, or OR5;

[0016] R2ais H, halogen, optionally substituted Ci-Ce alkyl, or optionally substituted C3-C12 cycloalkyl;

[0017] R3ais H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C3-C12 cycloalkyl, or

[0018] OR5;

[0019] R4ais H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C3-C12 heterocycle, or optionally substituted C3-C12 cycloalkyl;

[0020] R5ais H, optionally substituted C1-6 alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, or OR5;

[0021] R8is H, optionally substituted Ci-Ce alkyl, optionally substituted C3-C12 cycloalkyl, or CF3; each R9is independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C3- C12 cycloalkyl, or CF3; each R5is, independently, H, optionally substituted Ci-Ce alkyl; and wherein , then R1aand R5aare both not Cl.

[0022] In some embodiments, R1is H.

[0023] In some embodiments, R1is F.

[0024] In some embodiments, R2is H.

[0025] In some embodiments, R2is F.

[0026] In some embodiments, R3is an optionally substituted Ci-Ce alkyl, e.g., CH3.

[0027] In some embodiments, A is N.

[0028] In some embodiments, A is CR4, e.g., CH, or CF.

[0029] In some embodiments, R4is H.

[0030] In some embodiments, R4is F.

[0031] In some embodiments, R1ais optionally substituted Ci-Ce alkyl, e.g., CH3, CF3, or CHF2.

[0032] In some embodiments, R1ais optionally substituted C3-C12 cycloalkyl, e.g.,

[0033] In some embodiments, R1ais halogen, e.g., Cl.

[0034] In some embodiments, R1ais OR5, e.g., OCH3.

[0035] In some embodiments, R3ais an optionally substituted Ci-Ce alkyl, e.g., CH3, CF3, or CHF2.

[0036] In some embodiments, R3ais OR5, e.g., OCH3.

[0037] In some embodiments, R4ais an optionally substituted Ci-Ce alkyl, e.

[0038] In some embodiments, R5ais optionally substituted Ci-Ce alkyl, e.g.,

[0039] In some embodiments, R5ais optionally substituted C3-C12 cycloalkyl, In some embodiments, R5ais OR5, e.g., OCH3.

[0040] In some embodiments, R8is optionally substituted Ci-Ce alkyl, PATENT

[0041] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0042] In some embodiments, R8is optionally substituted C3-C12 cycloalkyl, e.g., V

[0043] In some embodiments, R9is halogen, e.g., F or Cl.

[0044] In some embodiments, R9is optionally substituted C1-C6 alkyl, e.g., CH3.

[0045] In some embodiments, the compound of Formula (I) has the structure of Formula (I l-A): or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, the compound of Formula (I) has the structure of Formula (I l-B): or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the compound of Formula (I) has the structure of Formula (I l-C): or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments, the compound of Formula (I) has the structure of Formula (I l-D): or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-A): or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, the compound of Formula (I) has the structure of Formula (I I l-B): or a pharmaceutically acceptable salt thereof. PATENT

[0051] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0052] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-C): or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-D): or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-E): or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-F): or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-G): (lll-G), or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-H): (lll-H), or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-l): or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-J): PATENT

[0060] ATTORNEY-DOCKET NO.: 51478-031 WO3 or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-K): or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-L): (lll-L), or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-M): or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-N): or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-O): or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-P): or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-Q): PATENT

[0068] ATTORNEY-DOCKET NO.: 51478-031 WO3 or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-R): or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-S): or a pharmaceutically acceptable salt thereof.

[0071] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-T): or a pharmaceutically acceptable salt thereof.

[0072] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-U): or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-V): or a pharmaceutically acceptable salt thereof.

[0074] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-W): (lll-W), or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-X): PATENT

[0076] ATTORNEY-DOCKET NO.: 51478-031 WO3 or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-Y): or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the compound of Formula (I) has the structure of Formula (lll-Z): or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, the compound of Formula (I) has the structure of Formula (IV-A): or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, the compound of Formula (I) has the structure of Formula (IV-B): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) has the structure of Formula (IV-C): or a pharmaceutically acceptable salt thereof.

[0081] In some embodiments, the compound of Formula (I) has the structure of Formula (IV-D): PATENT

[0082] ATTORNEY-DOCKET NO.: 51478-031 WO3 or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, the compound of Formula (I) has the structure of Formula (IV-E): or a pharmaceutically acceptable salt thereof.

[0084] In some embodiments, the compound of Formula (I) has the structure of Formula (IV-F): or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, the compound of Formula (I) has the structure of Formula (IV-G): or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the compound of Formula (I) has the structure of Formula (IV-H): or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the compound of Formula (I) has the structure of Formula (I V-l) : or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the compound of Formula (I) has the structure of Formula (IV-J): or a pharmaceutically acceptable salt thereof. PATENT

[0089] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0090] In some embodiments, the compound of Formula (IV-J) has the structure of Formula (IV-J-1): or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the compound of Formula (IV-J) has the structure of Formula (IV-J-2): or a pharmaceutically acceptable salt thereof. PATENT

[0092] ATTORNEY-DOCKET NO.: 51478-031 WO3 PATENT

[0093] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0094] In another aspect, the present disclosure provides a compound of Table 1 or a pharmaceutically acceptable salt thereof.

[0095] Table 1 PATENT

[0096] ATTORNEY-DOCKET NO.: 51478-031 WO3 PATENT

[0097] ATTORNEY-DOCKET NO.: 51478-031 WO3 PATENT

[0098] ATTORNEY-DOCKET NO.: 51478-031 WO3 PATENT

[0099] ATTORNEY-DOCKET NO.: 51478-031 WO3 PATENT

[0100] ATTORNEY-DOCKET NO.: 51478-031 WO3 PATENT

[0101] ATTORNEY-DOCKET NO.: 51478-031 WO3 PATENT

[0102] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0103] In some embodiments, the compound is one of the compounds 1-41 of Table 1 , or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the compound is one of the compounds 1 -74 of Table 1 , or a pharmaceutically acceptable salt thereof.

[0105] In another aspect, the disclosure provides a pharmaceutical composition including a compound described herein (e.g., any one of the compounds of Formulas (I), (ll-A) to (ll-D), (lll-A) to (IV-J), (IV-J-1) to (IV-J-2), and Table 1), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0106] In another aspect, the disclosure provides a compound described herein (e.g., any one of the compounds of Formulas (I), (ll-A) to (ll-D), (lll-A) to (IV-J), (IV-J-1) to (IV-J-2), and Table 1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including said compound or salt thereof and a pharmaceutically acceptable excipient, for use as a medicament.

[0107] In another aspect, the disclosure provides a method for treating or preventing a neurological disorder, which includes administering to a subject in need thereof a therapeutically effective amount of a compound described herein (e.g., any one of the compounds of Formulas (I), (ll-A) to (ll-D), (III- A) to (IV-J), (IV-J-1) to (IV-J-2), and Table 1), or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure provides a method for treating a neurological disorder, which includes administering to a subject in need thereof a therapeutically effective amount of a compound described herein (e.g., any one of the compounds of Formulas (I), (ll-A) to (ll-D), (lll-A) to (IV-J), (IV-J-1) to (IV- J-2), and Table 1), or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, the neurological disorder is a neurotraumatic disorder, a neurodevelopmental disorder, a neurodegenerative disorder, neurological pain, epilepsy, or an affective disorder.

[0109] In some embodiments, the neurological disorder is dementia.

[0110] In some embodiments, the dementia is Lewy body dementia.

[0111] In some embodiments, the neurological disorder is dementia induced psychosis.

[0112] In some embodiments, the neurological disorder is epilepsy.

[0113] In some embodiments, the epilepsy is refractory epilepsy, developmental and epileptic encephalopathies, Lennox-Gastaut syndrome, neurotrauma associated epilepsy (ischemia, stroke, traumatic brain injury), status epilepticus, tumor associated epilepsy, or hypoxic-ischemic encephalopathy.

[0114] In some embodiments, the neurological disorder is a spinal cord injury, traumatic brain injury, stroke, peripheral nerve injury, ischemia, myelopathy, hypoxic-ischemic encephalopathy, tumor- associated epilepsy, spasticity, neurological pain, neurotraumatic injury, neurodegenerative disease, or peripheral neuropathy.

[0115] In some embodiments, the neurotraumatic injury is traumatic brain injury, stroke, nerve injury or spinal cord injury.

[0116] In some embodiments, the neurodegenerative disorder is multiple sclerosis, amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, Lewy body dementia, or frontotemporal dementia. PATENT

[0117] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0118] In some embodiments, the neurological pain is a neuropathic pain, inflammation, chronic pain, inflammatory pain, arthritic pain, diabetic pain, post-operative pain, lower back pain, central pain, fibromyalgia or neuralgia.

[0119] In some embodiments, the neurodevelopmental disorder is autism spectrum disorder, Rett Syndrome, Tuberous Sclerosis Complex (TSC), Fragile X syndrome, Angelman syndrome, Down syndrome, Dravet syndrome, CKDL5 Deficiency syndrome, SYNGAP1 , 22q11 .2 microdeletion syndrome, or cerebral palsy.

[0120] In some embodiments, the affective disorder is schizophrenia, bipolar disorder, general anxiety disorder, social anxiety disorder, attention-deficit / hyperactivity disorder, or major depressive disorder.

[0121] DEFINITIONS

[0122] To facilitate the understanding of the present disclosure, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the disclosure. Terms such as “a,” “an,” and “the” are not intended to refer to only a singular entity but include the general class of which a specific example may be used for illustration. The terms “comprising” and “including” may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps. The terminology herein is used to describe specific embodiments of the disclosure, but their usage does not limit the disclosure, except as outlined in the claims.

[0123] As used herein, the term “about” is used to indicate that a value includes the standard deviation of error for the method being employed to determine the value. In certain embodiments, the term “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of a stated value, unless otherwise stated or otherwise evident from the context (e.g., where such number would exceed 100% of a possible value).

[0124] As used herein, any values provided in a range of values include both the upper and lower bounds, and any values contained within the upper and lower bounds.

[0125] As used herein, the terms “administer” and “administering” are used to indicate the process of providing a therapeutic, pharmaceutical, housing compartment, medication, or the like thereof to a subject. In some embodiments, a pharmaceutical is provided via oral administration.

[0126] As used herein, the terms “improve” and “improving,” in reference to recovery from a disease or condition, e.g., a neurological disorder, refer to an enhancement of recovery in one or more parameters measuring or quantifying the severity of the neurological disorder relative to the recovery in these parameters in or prior to treatment with the compounds or compositions described herein. Alternatively, improvement may be measured with respect to a reference subject having the same diagnosis as the subject but that did not receive treatment with a compound or composition of the disclosure. For neurological disorders, such parameters may include motor and sensory function in a subject. Methods for assessing motor and sensory function in a subject suffering from a neurological disorder are known in the art and are further described herein. PATENT

[0127] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0128] The phrase “increasing Cl efflux,” as used herein, refers to increasing the level of Cl efflux. Cl efflux may be determined using methods known in the art, e.g., fluorometric assessment in NG-108 cells using the Cl-sensitive indicator Chlomeleon described in Gagnon et al. Nature Medicine, 2013, 19, 1524-1528, or by measuring the reversal potential of the GABAA receptor in neuronal ex vivo slices, or Rhubidium flux in xenopus oocytes.

[0129] As used herein, the term “level” refers to a change in the measure of a compound, metabolite, or enzyme activity, or property thereof, as compared to a reference. The reference can be any useful reference, as defined herein. By a “decreased level” or an “increased level” of a compound or enzyme activity is meant a decrease or increase in level, as compared to a reference (e.g., a decrease or an increase by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more; a decrease or an increase of more than about 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200%, as compared to a reference; a decrease or an increase by about 0.01 -fold, about 0.01 -fold, about 0.02-fold, about 0.1 -fold, about 0.3-fold, about 0.5-fold, about 0.8-fold, about 0.9-fold, or less; or an increase by more than about 1 .1 -fold , about 1 .2- fold, about 1 .3-fold, about 1 .4-fold , about 1 .5-fold, about 1 .8-fold, about 2.0-fold, about 3.0-fold, about 3.5-fold, about 4.5- fold, about 5.0-fold, about 10-fold, about 15-fold, about 20-fold, about 30-fold, about 40-fold, about 50- fold, about 100-fold, or more). A level of a compound may be expressed in mass / vol (e.g., g / dl, mg / ml, pg / ml, ng / ml), concentration or molarity (e.g., M, mM, pM, nM, pM), or percentage relative to total compound in a sample, or by any other suitable units of measure as described by the disclosure. For example, “increasing levels of KCC2 activity” may be considered a subset of the phrase “potentiating KCC2 activity,” when describing an increase in activity of the potassium chloride cotransporter-2, KCC2, in comparison to a reference level.

[0130] As used herein, the term “neurological disorder” refers to any damage or dysfunction of one or more nerves in a subject. A neurological disorder may include any damage or dysfunction that prevents and / or inhibits one or more electrical and / or chemical transmissions of a sensory and / or motor function signal. A neurological disorder may include any damage or dysfunction that results in a transmission of one or more electrical and / or chemical transmissions of a nerve cell uncontrollably by the subject. A neurological disorder may include damage or dysfunction of one or more nerves located within the central nervous system and / or peripheral nervous system of a subject. A neurological disorder may include damage or dysfunction of a somatic, autonomic, and / or enteric nervous system of a subject. A neurological disorder may include damage or dysfunction of an afferent and / or efferent nervous system of a subject. A neurological disorder may include damage or dysfunction of a sympathetic and / or parasympathetic nervous system of a subject. A neurological disorder may include damage of dysfunction of one or more cranial nerves (e.g., the olfactory nerve, optic nerve, oculomotor nerve, trochlear nerve, trigeminal nerve, abducens nerve, facial nerve, vestibulocochlear nerve, glossopharyngeal nerve, vagus nerve, accessory nerve, and / or hypoglossal nerve) of a subject. A neurological disorder may be neuropathic pain which may include inflammation, chronic pain, inflammatory pain, arthritic pain, diabetic pain, post-operative pain, lower PATENT

[0131] ATTORNEY-DOCKET NO.: 51478-031 WO3 back pain, central pain, fibromyalgia or neuralgia. A neurological disorder may be a neurotraumatic disorder, which may include a spinal cord injury, traumatic brain injury, stroke, nerve injury, or peripheral nerve injury. A neurological disorder may be a neurodegenerative disorder (e.g., multiple sclerosis, amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, Lewy body dementia, or frontotemporal dementia). A neurological disorder may be epilepsy which may include refractory epilepsy, developmental and epileptic encephalopathies, Lennox- Gastaut syndrome, neurotrauma associated epilepsy (ischemia, stroke, traumatic brain injury), status epilepticus, tumor associated epilepsy, or hypoxic-ischemic encephalopathy. A neurological disorder may be dementia induced psychosis. A neurological disorder may be a neurodevelopmental disorder, which may include an autism spectrum disorder, Rett syndrome, Tuberous Sclerosis Complex (TSC), Fragile X syndrome, Angelman syndrome, 22q11 .2 microdeletion syndrome, cerebral palsy, Down syndrome, Dravet syndrome, epilepsy (e.g., temporal lobe epilepsy), or sudden unexpected death in epilepsy. A neurological disorder may include an affective disorder, which may include schizophrenia, bipolar-disorder, anxiety disorder, major depressive disorder, attention-deficit / hyperactivity disorder, and the like thereof.

[0132] As used herein, the term “pharmaceutical composition” refers to an active compound, formulated together with one or more pharmaceutically acceptable excipients. In some embodiments, a compound of the disclosure is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions) or tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, or pastes for application to the tongue.

[0133] The term “pharmaceutically acceptable excipient,” as used herein, refers to any inactive ingredient (for example, a vehicle capable of suspending or dissolving the active compound) having the properties of being nontoxic and non-inflammatory in a subject. Typical excipients include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes, emollients, emulsifiers, diluents, film formers or coatings, flavors, fragrances, glidants, lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration. Excipients include, but are not limited to: butylated optionally substituted hydroxytoluene (e.g., BHT), calcium carbonate, calcium phosphate dibasic, calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropyl cellulose, optionally substituted 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, stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those of ordinary skill in the art are familiar with a variety of agents and materials useful as excipients. PATENT

[0134] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0135] As used herein, the term “pharmaceutically acceptable salt” represents those salts of the compounds described that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley- VCH, 2008. These salts may be acid addition salts involving inorganic or organic acids. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable acid. Methods for preparation of the appropriate salts are well-established in the art.

[0136] The phrase “potentiating KCC2 activity,” as used herein, refers to increasing or decreasing the level or activity of the potassium chloride cotransporter-2, KCC2. KCC2 activity may be determined using methods known in the art, e.g., immunoprecipitation, Western blot, qPCR, live cell immunolabeling of cell surface expression as described in Medina et al. eNeuro, 2017, 4, 1 -19, or immunohistochemistry in primary cultures.

[0137] The term “subject,” as used herein, can be a human, non-human primate, or other mammal, such as but not limited to dog, cat, horse, cow, pig, goat, monkey, rat, mouse, and sheep. In preferred embodiments, the subject is a human.

[0138] As used herein, the term “therapeutically effective amount” refers to an amount sufficient to effect beneficial or desired results, such as clinical results, and, as such, a “therapeutically effective amount” depends upon the context in which it is being applied. For example, in the context of administering a compound disclosed herein (e.g., a compounds of any one of Formulas (I), (I l-A) to (I l-D), (II l-A) to (IV-J), (IV-J-1) to (IV-J-2), and other compounds disclosed herein) to treat a neurological disorder, a therapeutically effective amount of a compound is, for example, an amount sufficient to reverse alleviate the neurological disorder.

[0139] As used herein, the terms “treat” and “treating” refer to a therapeutic treatment of a neurological disorder in a subject. The effect of treatment can include reversing, alleviating, reducing severity of, inhibiting the progression of, reducing the likelihood of recurrence of the neurological disorder or one or more symptoms or manifestations of the neurological disorder, stabilizing (i.e., not worsening) the state of the neurological disorder as compared to the state and / or the condition of the disease or disorder in the absence of the therapeutic treatment.

[0140] Chemical Terms

[0141] The terminology employed herein is for the purpose of describing particular embodiments and is not intended to be limiting.

[0142] For any of the following chemical definitions, a number following an atomic symbol indicates that total number of atoms of that element that are present in a particular chemical moiety. As will be understood, other atoms, such as H atoms, or substituent groups, as described herein, may be present, as necessary, to satisfy the valences of the atoms. For example, an unsubstituted C2 alkyl group has the formula -CH2CH3. When used with the groups defined herein, a reference to the PATENT

[0143] ATTORNEY-DOCKET NO.: 51478-031 WO3 number of carbon atoms includes the divalent carbon in acetal and ketal groups but does not include the carbonyl carbon in acyl, ester, carbonate, or carbamate groups. A reference to the number of oxygen, nitrogen, or sulfur atoms in a heteroaryl group only includes those atoms that form a part of a heterocyclic ring.

[0144] Those skilled in the art will appreciate that certain compounds described herein can exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic (e.g., in which one or more atoms has been substituted with a different isotope of the atom, such as hydrogen substituted for deuterium) forms. Unless otherwise indicated or clear from context, a depicted structure can be understood to represent any such isomeric or isotopic form, individually or in combination.

[0145] Compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.

[0146] Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms.

[0147] In some embodiments, one or more compounds depicted herein may exist in different tautomeric forms. As will be clear from context, unless explicitly excluded, references to such compounds encompass all such tautomeric forms. In some embodiments, tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton. In certain embodiments, a tautomeric form may be a prototropic tautomer, which is an isomeric protonation states having the same empirical formula and total charge as a reference form. Examples of moieties with prototropic tautomeric forms are ketone — enol pairs, amide — imidic acid pairs, lactam — lactim pairs, amide — imidic acid pairs, enamine — imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1 H- and 3H-imidazole, 1 H-, 2H- and 4H-1 ,2,4-triazole, 1 H- and 2H-isoindole, and 1 H- and 2H-pyrazole. In some embodiments, tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. In certain embodiments, tautomeric forms result from acetal interconversion.

[0148] In any of the aspects described herein, the compound of Formula (I) may exist in either one of the following tautomeric forms: example, PATENT

[0149] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0150] Compound 1 may exist in either one of the following tautomeric forms:

[0151] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopica lly enriched atoms. Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,170,180,32P,33P,35S,18F,36CI,123l and125l. Isotopically-labeled compounds (e.g., those labeled with3H and14C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e., ,sup.3H) and carbon-14 (i.e.,14C)) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced by2H, D, or3H, or one or more carbon atoms are replaced by13C- or14C-enriched carbon. Positron emitting isotopes such as150,13N,11C, and18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Preparations of isotopically labelled compounds are known to those of skill in the art. For example, isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed for compounds of the present invention described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0152] As is known in the art, many chemical entities can adopt a variety of different solid forms such as, for example, amorphous forms or crystalline forms (e.g., polymorphs, hydrates, solvate). In some embodiments, compounds of the present invention may be utilized in any such form, including in any solid form. In some embodiments, compounds described or depicted herein may be provided or utilized in hydrate or solvate form.

[0153] At various places in the present specification, substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term “Ci-Ce alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and Ce alkyl. Furthermore, where a compound includes a plurality of positions at which substituents are disclosed in groups or in ranges, unless otherwise indicated, the present disclosure is intended to cover individual compounds and groups of compounds (e.g., genera and subgenera) containing each and every individual subcombination of members at each position.

[0154] The term “alkyl,” as used herein, refers to a branched or straight-chain monovalent saturated aliphatic radical containing only C and H when unsubstituted. The monovalency of an alkyl group PATENT

[0155] ATTORNEY-DOCKET NO.: 51478-031 WO3 does not include the optional substituents on the alkyl group. For example, if an alkyl group is attached to a compound, monovalency of the alkyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkyl group. In some embodiments, the alkyl group may contain, e.g., 1-20, 1-18, 1-16, 1-14, 1-12, 1-10, 1-8, 1-6, 1-4, or 1- 2 carbon atoms (e.g., C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, Ci-Cs, Ci-Ce, C1-C4, or Ci-C2). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, and tert-butyl. An alkylene is a divalent alkyl group.

[0156] The term “alkenyl,” as used herein, alone or in combination with other groups, refers to a straight chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 carbon atoms).

[0157] The term “aryl,” as used herein, refers to any monocyclic or fused ring bicyclic or multicyclic system containing only carbon atoms in the ring(s), which has the characteristics of aromaticity in terms of electron distribution throughout the ring system, e.g., phenyl, naphthyl, or phenanthryl. An aryl group may have, e.g., six to sixteen carbons or six to fourteen carbons (e.g., six carbons, ten carbons, thirteen carbons, fourteen carbons, or sixteen carbons). An “arylene” is a divalent aryl group.

[0158] The term “arylalkyl,” as used herein, represents an alkyl group substituted with an aryl group. Unsubstituted arylalkyl groups contain from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as Ci-Ce alkyl Ce-C-io aryl, C1-C10 alkyl Ce-C-io aryl, or C1-C20 alkyl Ce-C-io aryl), such as, benzyl and phenethyl. In some embodiments, the alkyl and the aryl each are further substituted with 1 , 2, 3, or 4 substituent groups, valency permitting, as defined herein for the respective groups.

[0159] The term “carbocycle,” as used herein, refers to a monovalent, saturated (“cycloalkyl”) or unsaturated, non-aromatic cyclic group containing only C and H when unsubstituted. A carbocycle may have, e.g., three to twenty carbons (e.g., a C3-C7, C3-C8, C3-C9, C3-C10, C3-C11, C3-C12, C3-C14, C3-C16, C3-C18, or Cs-C2o carbocycle). Carbocyclyl structures include cycloalkyl groups and unsaturated carbocyclyl radicals.

[0160] The term “cycloalkyl,” as used herein, refers to a monovalent, saturated cyclic group containing only C and H when unsubstituted. A cycloalkyl group may have, e.g., three to twenty carbons (e.g., a C3-C7, Cs-Cs, C3-C9, C3-C10, C3-C11 , C3-C12, C3-C14, C3-C16, C3-C18, or Cs-C2o cycloalkyl). Cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term “cycloalkyl” also includes cyclic groups having a bridged multicyclic structure in which one or more carbons bridges two non-adjacent members of a monocyclic ring, e.g., bicyclo[2.2.1]heptyl and adamantyl. The term “cycloalkyl” also includes bicyclic, tricyclic, and tetracyclic fused ring structures, e.g., decalin and spiro-cyclic compounds.

[0161] The term “halo,” as used herein, refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[0162] The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkyl groups. Examples of heteroalkyl groups are an “alkoxy” which, as PATENT

[0163] ATTORNEY-DOCKET NO.: 51478-031 WO3 used herein, refers alkyl-O- (e.g., methoxy and ethoxy). A heteroalkylene is a divalent heteroalkyl group.

[0164] The term “heteroaryl,” as used herein, refers to an aromatic mono- or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing 1 , 2, or 3 ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazoyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl. A “heteroarylene” is a divalent heteroaryl group.

[0165] The term “heterocycle,” as used herein, represents a monocyclic or fused ring bicyclic or multicyclic system having at least one heteroatom as a ring atom. For example, a heterocycle ring may have, e.g., one to fifteen carbons ring atoms (e.g., a C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, C1-C7, C1- Cs, C1-C9, C1-C10, C1-C11, C1-C12, C1-C13, C1-C14, or C1-C15 heterocycle) and one or more (e.g., one, two, three, four, or five) ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Heterocycle groups may or may not include a ring that is aromatic. An aromatic heterocycle group is referred to as a “heteroaryl” group. In preferred embodiments of the disclosure, a heterocycle group is a 3- to 8-membered ring, a 3- to 6-membered ring, a 4- to 6- membered ring, a 6- to 10-membered ring, a 6- to 12-membered ring, a 5-membered ring, or a 6- membered ring. Exemplary 5-membered heterocycle groups may have zero to two double bonds, and exemplary 6-membered heterocycle groups may have zero to three double bonds. Exemplary 5- membered groups include, for example, optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrolidine, optionally substituted imidazole, optionally substituted thiazole, optionally substituted thiophene, optionally substituted thiolane, optionally substituted furan, optionally substituted tetrahydrofuran, optionally substituted diazole, optionally substituted triazole, optionally substituted tetrazole, optionally substituted oxazole, optionally substituted 1 ,3,4-oxadiazole, optionally substituted 1 ,3,4-thiadiazole, optionally substituted 1 ,2,3,4-oxatriazole, and optionally substituted 1 ,2,3,4-thiatriazole. Exemplary 6-membered heterocycle groups include, for example, optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted 2 / 7- pyran, optionally substituted 4 / 7-pyran, and optionally substituted tetrahydropyran. Exemplary 7- membered heterocycle groups include optionally substituted azepine, optionally substituted 1 ,4- diazepine, optionally substituted thiepine, and optionally substituted 1 ,4-thiazepine.

[0166] The term “hydroxyl,” as used herein, represents an -OH group.

[0167] The term “nitro,” as used herein, represents an -NO2 group.

[0168] The term “optionally substituted X” (e.g., “optionally substituted alkyl”) is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein said alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g., alkyl) per se is optional. As described herein, certain compounds of interest may contain one or more “optionally substituted” moieties. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent, e.g., PATENT

[0169] ATTORNEY-DOCKET NO.: 51478-031 WO3 any of the substituents or groups described herein. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. For example, in the term “optionally substituted Ci-Ce alkyl-C2-Cg heteroaryl,” the alkyl portion, the heteroaryl portion, or both, may be optionally substituted. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds.

[0170] The term “oxo,” as used herein, represents an =O group.

[0171] The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0172] The term “thiol,” as used herein, represents an -SH group.

[0173] Alkyl, carbocycle, cycloalkyl, aryl, and heterocycle groups may be substituted with carbocycle (e.g., cycloalkyl); aryl; heterocycle; halo; ORa, in which Rais H, alkyl, alkenyl, alkynyl, carbocycle (e.g., cycloalkyl), aryl, or heterocycle; SRa, in which Rais as defined herein; CN; NO2; N3; NRbRc, in which each of Rband Rcis, independently, H, alkyl, alkenyl, alkynyl, carbocycle (e.g., cycloalkyl), aryl, or heterocycle; SO2Rd, in which Rdis H, alkyl or aryl; SO2NReRf, in which each of Reand Rfis, independently, H, alkyl, or aryl; SOR9’, in which R9’ is H, alkyl, or aryl; or P(O)(ORh’)2,in which each Rhis, independently, H or alkyl. Aryl, carbocycle (e.g., cycloalkyl), heteroaryl, and heterocycle groups may also be substituted with alkyl, alkenyl, or alkynyl. Alkyl, alkylene, alkenyl, alkynyl, carbocycle (e.g., cycloalkyl), and heterocycle groups may also be substituted with oxo or =NRf, in which is H or alkyl. In some embodiments, a substituent is further substituted as described herein. For example, a Ci alkyl group, i.e., methyl, may be substituted with oxo to form a formyl group and further substituted with OH or NRbRcto form a carboxyl group or an amido group.

[0174] Heteroaryl, alkenyl, alkynyl and arylalkyl groups may be substituted with carbocycle (e.g., cycloalkyl); aryl; heterocycle; halo; ORa, in which Rais H, alkyl, alkenyl, alkynyl, carbocycle (e.g., cycloalkyl), aryl, or heterocycle; SRa, in which Rais as defined herein; CN; NO2; N3; NRbRc, in which each of Rband Rcis, independently, H, alkyl, alkenyl, alkynyl, carbocycle (e.g., cycloalkyl), aryl, or heterocycle; SO2Rd, in which Rdis H, alkyl or aryl; SO2NReRf, in which each of Reand Rfis, independently, H, alkyl, or aryl; SOR9, in which R9is H, alkyl, or aryl; or P(O)(ORh’)2,in which each Rhis, independently, H or alkyl. Aryl, carbocycle (e.g., cycloalkyl), heteroaryl, and heterocycle groups may also be substituted with alkyl, alkenyl, or alkynyl. Alkyl, alkylene, alkenyl, alkynyl, carbocycle (e.g., cycloalkyl), and heterocycle groups may also be substituted with oxo or =NR , in which is H or alkyl. In some embodiments, a substituent is further substituted as described herein. For example, a Ci alkyl group, i.e., methyl, may be substituted with oxo to form a formyl group and further substituted with OH or NRbRcto form a carboxyl group or an amido group.

[0175] For the avoidance of doubt, any and all disclosures of methods of treatment or prevention provided herein should also be read as disclosing the compounds, pharmaceutically acceptable salts PATENT

[0176] ATTORNEY-DOCKET NO.: 51478-031 WO3 thereof, or pharmaceutical compositions comprising the same, for use in the described methods of treatment or prevention.

[0177] DETAILED DESCRIPTION OF THE INVENTION

[0178] Described herein are compounds, compositions, and methods for treating neurological disorders, e.g., neurotraumatic disorders, neurodevelopmental disorders, or affective disorders, in a subject. Without wishing to be bound by theory, the compounds described herein may function as KCC2 potentiators. The compounds described herein are useful for treating neurological disorders, e.g., neurotraumatic disorders, neurodevelopmental disorders, or affective disorders.

[0179] Compounds

[0180] The present disclosure provides compounds and compositions that can be administered to a subject (e.g., a human) in order to treat a neurological disorder (e.g., a neurotraumatic disorder, a neurodevelopmental disorder, or an affective disorder).

[0181] In one aspect, the present disclosure provides a compound of formula (I):

[0182] Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0183] A is N or CR4;

[0184] R1is H or F;

[0185] R2is H or F;

[0186] R3is H, or Ci-C4alkyl;

[0187] R4is H or F;

[0188] R1ais H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, or OR5;

[0189] R2ais H, halogen, optionally substituted Ci-Ce alkyl, or optionally substituted C3-C12 cycloalkyl;

[0190] R3ais H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C3-C12 cycloalkyl, or OR5;

[0191] R4ais H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C3-C12 heterocycle, or optionally substituted C3-C12 cycloalkyl; PATENT

[0192] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0193] R5ais H, optionally substituted C1-6 alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, or OR5;

[0194] R8is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C12 cycloalkyl, or CF3; each R9is, independently, H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C12 cycloalkyl, or CF3; each R5is, independently, H, optionally substituted Ci-Ce alkyl; and wherein , then R1aand R5aare both not Cl.

[0195] In some embodiments, the compound of Formula (I) has the structure of: or a pharmaceutically acceptable salt thereof.

[0196] In some embodiments, the compound of Formula (I) has the structure of: PATENT

[0197] ATTORNEY-DOCKET NO.: 51478-031 WO3 PATENT

[0198] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0199] Pharmaceutical compositions

[0200] A pharmaceutical composition of the disclosure contains one or more of the compounds disclosed herein (e.g., one or more of the compounds of any one of Formulas (I), (ll-A) to (ll-D), (lll-A) to (IV-J), (IV-J-1) to (IV-J-2), and other compounds disclosed herein) as the therapeutic compound. In addition to a therapeutically effective amount of the compound, the pharmaceutical compositions also contain a pharmaceutically acceptable excipient, which can be formulated by methods known to those skilled in the art. The compounds disclosed herein (e.g., any one of the compounds of Formulas (I), (ll-A) to (ll-D), (lll-A) to (IV-J), (IV-J-1) to (IV-J-2), and Table 1 , and other compounds disclosed herein) may also be administered with or without other therapeutics for a particular condition, formulated in the same composition or different compositions for administration via the same or different routes.

[0201] The compounds disclosed herein (e.g., any one of the compounds of Formulas (I), (ll-A) to (II- D), (lll-A) to (IV-J), (IV-J-1) to (IV-J-2), and Table 1), may be used in the form of free base, or in the form of salts or solvates. All forms are within the scope of the disclosure. PATENT

[0202] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0203] Routes of administration of the pharmaceutical compositions (or the compounds of the composition) include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intra-arterial, intracranial, subcutaneous, intracerebroventricular, intraorbital, intraventricular, intrathecal (intraspinal), intraperitoneal, intranasal, inhalation, and topical administration.

[0204] Neurological disorders

[0205] Neurological disorders are disorders that affect the brain, as well as nerves throughout the body and also the spinal cord. Common symptoms of neurological disorders include numbness, tingling, muscle weakness, loss of muscle tone, loss of sensation, disruption or loss of autonomic function, numbness, bowel, or bladder incontinence, paralysis, confusion, pain, altered levels of consciousness, mood disorders, and sexual dysfunction. Certain primary symptoms, such as impaired movement and sensation, can further lead to secondary symptoms including muscle atrophy, loss of voluntary motor control and spasticity at sites of the body innervated by the neurological disorder, pressure (e.g., bed) sores, infections, and respiratory problems. Furthermore, cell death at the neurological disorder may continue long after the initial insult that precipitated the neurological disorder as a result of stress and inflammatory signaling that leads to further ischemia, inflammation, swelling, and disruption of synaptic signaling. Neurological disorder may result in total loss of motor and sensory function distal to the neurological disorder, or incomplete, resulting in partial loss of motor and sensory function.

[0206] Neurological disorders may present as various distinct conditions, depending on the site and severity of the condition. For example, peripheral neurological disorder results from damage to peripheral nerves that extend to the extremities of an individual, leading to numbness and / or loss of sensory function. Proximal neurological disorder results from damage to peripheral and / or central nerves, leading to muscle weakness in the upper part of the legs, buttocks, and / or hips in a subject. Autonomic neurological disorder results from damage and / or dysfunction of autonomic nerves that least to reduced and / or uncontrolled body homeostasis of an individual. Focal neurological disorder and / or polyneurological disorder results from damage to one nerve and / or a plurality of nerves, respectively. Central cord syndrome frequently results from damage to the cervical spinal cord, resulting in weakness in the upper extremities with relative sparing of function in the legs and spared sensation in sacral dermatomes (e.g., urinary sphincter, anal sphincter, and genitalia).

[0207] Neurological disorders include, but are not limited to neurotraumatic disorders such as traumatic brain injury (TBI), stroke, nerve injury or spinal cord injury (SCI). Neurological disorders include, but are not limited to neurodegenerative disorder such as multiple sclerosis, amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, Lewy body dementia, or frontotemporal dementia. Neurological disorders include, but are not limited to neurodevelopmental disorders such as autism spectrum disorder, Rett Syndrome, Tuberous Sclerosis Complex (TSC), Fragile X syndrome, Angelman syndrome, Down syndrome, Dravet syndrome, CKDL5 Deficiency syndrome, SYNGAP1 , 22q11.2 microdeletion syndrome, or cerebral palsy. Neurological disorders include, but are not limited to neurological pain such as neuropathic pain, PATENT

[0208] ATTORNEY-DOCKET NO.: 51478-031 WO3 inflammation, chronic pain, inflammatory pain, arthritic pain, diabetic pain, post-operative pain, lower back pain, central pain, fibromyalgia or neuralgia. Neurological disorders include, but are not limited to affective disorders such as schizophrenia, bipolar disorder, general anxiety disorder, social anxiety disorder, attention-deficit / hyperactivity disorder, or major depressive disorder. Neurological disorders include, but are not limited to dementia, Lewy body dementia, frontotemporal dementia (FTD), or dementia induced psychosis.

[0209] Dementia refers to general mental deterioration due to organic or psychological causes; characterized by disorientation, impaired memory judgment, and intelligence, and shallow, unstable affect. Dementia includes vascular dementia, ischemic vascular dementia (IVD), frontotemporal dementia (FTD), Lewy body dementia, and Alzheimer's dementia.

[0210] Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by progressive neurodegeneration in the frontal and temporal lobes of the cerebral cortex which is characterized by a complex clinical presentation that may include deficits in speech comprehension and production, poor motor planning and coordination, and / or loss of executive function characterized by lack of impulse control and a preference for perseverative behaviors. Histological analyses of post-mortem brain tissue from FTD patients exhibit complex and heterogeneous neuropathological profiles with the common presentation of degeneration of neural tissue in the frontal and temporal lobes of the brain. The clinical manifestation of FTD is complex and heterogeneous, but may present as progressive aphasia, decline in cognition (e.g. reduced working memory and executive function), diminished impulse control, emergence of perseverative behaviors, apraxia, apathy, and / or social withdrawal. Neuronal loss in brains of FTD patients is associated with either one of two distinct neuropathologies: 1) the presence of tau-positive neuronal and glial inclusions; or 2) ubiquitin (ub)- positive and TAR DNA-binding protein 43 (TDP43)-positive, but tau-negative inclusions.

[0211] Neurotraumatic disorders are disorders of the nervous system that result from neurological trauma, such as, e.g., TBI, SCI, PNI, PN, stroke, ischemia, hypoxic-ischemic encephalopathy, tumor- associated epilepsy, and spasticity. In the U.S., roughly 1.7 million people are estimated to suffer TBI every year from causes such as falls, motor vehicle-related incidents, sports injuries, and violence, roughly 52,000 of which succumb to such injuries. Survivors of neurological trauma often face prolonged or indefinite disability.

[0212] TBI (also known as intracranial injury) usually results from an external force suddenly impacting the head of an individual, with the severity of the from mild (e.g., concussion) to severe (e.g., penetrating injury, coma-inducing injury). Sequalae of TBI often includes loss of consciousness, physical, cognitive, social, emotional, and behavioral impairments, but can also be fatal.

[0213] A SCI refers to any insult to any region of the spinal cord, e.g., the cervical vertebrae, the thoracic vertebrae, the lumbar vertebrae, the sacral vertebrae, the sacrum, or the coccyx, that causes a negative effect on the function of the spinal cord, e.g., reduce mobility of feeling in limbs. The severity of a spinal cord injury is measured in levels of the injury’s outcome, e.g., ranging from no effect on mobility, e.g., retained walking capacity, to paraplegia (e.g., paralysis of legs and lower region of body), and tetraplegia (e.g., loss of muscle strength in all four extremities). PATENT

[0214] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0215] PNI refers to any disorder resulting from a nerve injury caused by a traumatic event. Peripheral nerve injury is generally divided into three distinct events, namely, (1) Wallerian degeneration; (2) axon regeneration / growth; and (3) nerve innervation. Types of PNI include, from least severe to most severe: neurapraxia (axon remains intact, but myelin is damaged), axonotmesis (disruption of the axon with maintenance of the epineurium), and neurotmesis (loss of axon continuity / axon transection).

[0216] Stroke is a condition which occurs when the blood supply to a part of the brain is interrupted (i.e., ischemic stroke) by obstruction of a blood vessel by a blood clot, an embolism, systemic hypoperfusion, or cerebral venous sinus thrombosis or when a blood vessel in the brain bursts and releases blood into the spaces surrounding the brain cells (i.e., hemorrhagic stroke) as a result of an intracerebral or a subarachnoid hemorrhage. Stroke poses a substantial public burden as nearly 77.2 million people experienced an ischemic stroke, and 29.1 million people experienced a hemorrhagic stroke in 2019. Depending on the area of the brain affected by the stroke, the symptoms of a stroke may include numbness or weakness, especially on one side of the body corresponding to the contralateral side of the stroke, muscle flaccidity or spasticity, confusion, trouble understanding or producing speech, impaired vision in both eyes, impaired mobility, dizziness, severe headache, or loss of balance or coordination.

[0217] Neurological trauma may also result from progressive neurodegenerative disorders that result in damage to neural tissue of the CNS. Non-limiting examples of neurodegenerative disorders contemplated for treatment using the presently disclosed compositions and methods include, but are not limited to, amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Alzheimer's Disease (AD), and peripheral neuropathy (PN).

[0218] Neurodevelopmental disorders refer to neurological disorders resulting from abnormal development of the nervous system and are characterized by abnormal brain function, including, but not limited to, impairments in emotional regulation, learning and memory, impulse control, and cognition. This class of neurological disorders is characterized by diverse etiologies that may account for the multeity of symptoms and their degree of severity. Generally, neurodevelopmental disorders are caused by disruptions in the neurotypical developmental trajectory of the nervous system, which can produce pathological anatomical architecture and connectivity in the nervous system. Causes of neurodevelopmental disorders may include genetic and metabolic diseases, social isolation, inflammatory and autoimmune disorders, infectious diseases, malnutrition, physical trauma, as well as environmental factors. The present disclosure contemplates treatment of neurodevelopmental disorders such as, e.g., autism spectrum disorders, Rett syndrome, Fragile X syndrome, Angelman syndrome, 22q11.2 microdeletion syndrome, cerebral palsy, Down syndrome, pain (e.g., neuropathic pain, chronic pain, or inflammatory pain), Dravet syndrome, epilepsy (e.g., epilepsy related to one or more KCC2 mutations or epilepsy of infancy with migrating focal seizures (EIMFS) or temporal lobe epilepsy), and sudden unexpected death in epilepsy by administering a composition of the disclosure to the afflicted subject, thereby treating the subject.

[0219] Affective disorders (also known as mood disorders) are a class of neurological conditions characterized by dysregulation of normal affect and mood. Disorders of affect may feature mania or PATENT

[0220] ATTORNEY-DOCKET NO.: 51478-031 WO3 hypomania (e.g., schizophrenia and bipolar disorder), depressed mood (e.g., schizophrenia, bipolar disorder, and MDD), and moods that cycle between mania and depression (e.g., bipolar disorder). Affective disorders that may be treated using the disclosed methods and compositions include schizophrenia, bipolar disorder, and MDD.

[0221] Schizophrenia is a psychiatric disease characterized by recurrent psychosis. Symptoms of schizophrenia may include (1) positive symptoms related to hallucinations and reality distortion; (2) disorganized symptoms characterized by attentional impairment and thought disorder; and (3) negative symptoms such as apathy, anhedonia, avolition and loss of verbal fluency. Dysfunction of the limbic-cortical system may be implicated in all three types of symptoms. Causes of schizophrenia have been attributed to biological sex, genetic mutations, environmental factors, malnutrition during pregnancy, and age of parents, among other factors. Several hypotheses exist as to the etiology of schizophrenia, one being the glutamate hypothesis in which reduced glutamatergic drive to potentiatory interneurons is thought to result in reduced cortical inhibition and altered cortical network dynamics that lead to presentation of clinical symptoms.

[0222] Bipolar disorder is an affective disorder that features recurrent bouts of depression and mania (i.e., abnormally elevated mood) spanning from days to weeks each. Causes of bipolar disorder may be manifold, but genetic and environmental factors have been implicated. Generally, two types of bipolar disorder exist, namely, bipolar I disorder, in which there has been at least one manic episode with or without depressive episodes, and bipolar II disorder, in which there has been at least one hypomanic episode and one major depressive episode.

[0223] MDD is a neurological disorder that is often characterized by the patient having at least two weeks of sustained low mood, low self-esteem, loss of interest in routine activities, hyperalgesia, and low psychomotor activity. Depression in MDD may last for periods of time (weeks, days, months, or years) separated by years or may be continuous. MDD may pose a substantial risk to the afflicted patient as the patient may be at a substantially higher risk for suicide. Etiological causes of the disorder have been attributed to substance abuse, other medical conditions (e.g., neurological disorders, metabolic disorders, gastrointestinal disorders, endocrine disorders, cardiovascular disease, pulmonary disease, cancer, and autoimmune disease), and genetic and environmental factors.

[0224] Dementia refers to general mental deterioration due to organic or psychological causes; characterized by disorientation, impaired memory judgment, and intelligence, and shallow, unstable affect. Dementia includes vascular dementia, ischemic vascular dementia (IVD), frontotemporal dementia (FTD), Lewy body dementia, and Alzheimer's dementia.

[0225] Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by progressive neurodegeneration in the frontal and temporal lobes of the cerebral cortex which is characterized by a complex clinical presentation that may include deficits in speech comprehension and production, poor motor planning and coordination, and / or loss of executive function characterized by lack of impulse control and a preference for perseverative behaviors. Histological analyses of post-mortem brain tissue from FTD patients exhibit complex and heterogeneous neuropathological profiles with the common presentation of degeneration of neural tissue in the frontal and temporal lobes of the PATENT

[0226] ATTORNEY-DOCKET NO.: 51478-031 WO3 brain. The clinical manifestation of FTD is complex and heterogeneous, but may present as progressive aphasia, decline in cognition (e.g. reduced working memory and executive function), diminished impulse control, emergence of perseverative behaviors, apraxia, apathy, and / or social withdrawal. Neuronal loss in brains of FTD patients is associated with either one of two distinct neuropathologies: 1) the presence of tau-positive neuronal and glial inclusions; or 2) ubiquitin (ub)- positive and TAR DNA-binding protein 43 (TDP43)-positive, but tau-negative inclusions.

[0227] A neurological disorder may also be caused by infection, ischemia, and tumors. Owing to the physiological barriers to regeneration in the central nervous system (CNS), neurological disorders have been a notoriously difficult condition to treat, with most treatments being palliative and rehabilitative. Most treatments involve imposing limitations to movement, maintenance of proper blood pressure by frequent repositioning of the subject, and physical and occupation therapy.

[0228] Methods of treating a neurological disorder

[0229] The compounds disclosed herein (e.g., the compounds of Formulas (I), (ll-A) to (I l-D) , (lll-A) to (IV-J), (IV-J-1) to (IV-J-2), and other compounds disclosed herein) are, in general, suitable for use in treating a neurological disorder, or complications resulting therefrom.

[0230] The compounds disclosed herein (e.g., the compounds of Formulas (I), (ll-A) to (I l-D) , (lll-A) to (IV-J), (IV-J-1) to (IV-J-2), and other compounds disclosed herein) are, in general, suitable for use in treating a neurological disorder, e.g., a neurotraumatic, neurodegenerative, neurodevelopmental, neurological pain, epilepsy, and / or affective disorder, or complications resulting therefrom.

[0231] Non-limiting examples of neurotraumatic disorders may include, but are not limited to traumatic brain injury (TBI), stroke, nerve injury or spinal cord injury (SCI). Non-limiting examples of neurodegenerative disorder may include, but are not limited to multiple sclerosis, amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, Lewy body dementia, or frontotemporal dementia. Non-limiting examples of neurodevelopmental disorders may include, but are not limited to autism spectrum disorder, Rett Syndrome, Tuberous Sclerosis Complex (TSC), Fragile X syndrome, Angelman syndrome, Down syndrome, Dravet syndrome, CKDL5 Deficiency syndrome, SYNGAP1 , 22q11.2 microdeletion syndrome, or cerebral palsy. Non-limiting examples of neurological pain may include, but are not limited to neuropathic pain, inflammation, chronic pain, inflammatory pain, arthritic pain, diabetic pain, post-operative pain, lower back pain, central pain, fibromyalgia or neuralgia. Non-limiting examples of affective disorders may include, but are not limited to schizophrenia, bipolar disorder, general anxiety disorder, social anxiety disorder, attention-deficit / hyperactivity disorder, or major depressive disorder. Neurological disorders include, but are not limited to dementia, Lewy body dementia, frontotemporal dementia (FTD), and dementia induced psychosis.

[0232] The dosage of the pharmaceutical compositions of the disclosure depends on factors including, but are not limited to, the route of administration, the severity of the condition to be treated, and physical characteristics, e.g., age, weight, and general health, of the subject. Typically, the amount of a compound disclosed herein (e.g., a compound of any one of Formulas (I), (ll-A) to (I l-D), (lll-A) to (IV-J), (IV-J-1) to (IV-J-2), and other compounds disclosed herein) contained within a single PATENT

[0233] ATTORNEY-DOCKET NO.: 51478-031 WO3 dose may be an amount that effectively imparts the desired therapeutic effect without inducing significant toxicity. The dosage may be adapted by the clinician in accordance with conventional factors such as the extent of the disease and different parameters of the subject.

[0234] The compounds of the disclosure, or pharmaceutical compositions of the disclosure that contain a compound disclosed herein (e.g., a compound of any one of Formulas (I), (ll-A) to (ll-D), (III- A) to (IV-J), (IV-J-1) to (IV-J-2), and other compounds disclosed herein), may be administered to a subject in need thereof one time daily or twice daily. Thus, the compounds and pharmaceutical compositions may be administered QD or BID.

[0235] The following examples are merely illustrative and should not be construed as limiting the scope of this disclosure in any way as many variations and equivalents will become apparent to those skilled in the art upon reading the present disclosure. The contents of all references, patents, and patent applications cited throughout this application are expressly incorporated herein by reference.

[0236] EXAMPLES

[0237] The following examples are put forth so as to provide those of ordinary skill in the art with a description of how the compositions and methods described herein may be used, made, and evaluated, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure.

[0238] Example 1 : Synthesis of 2-{[(5-chloro-3-ethylimidazol-4-yl)methyl]sulfanyl}pyrrolo[2,1- f][1 ,2,4]triazin-4-ol

[0239] To a stirred solution of 2-sulfanylpyrrolo[2,1-f][1 ,2,4]triazin-4-ol (98 mg, 0.586 mmol, 1 equiv) and 4-chloro-5-(chloromethyl)-1 -ethylimidazole (157.42 mg, 0.879 mmol, 1.5 equiv) in DMF (1 mL) was added DIEA (227.28 mg, 1 .758 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1 % TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 2- {[(5-chloro-3-ethylimidazol-4-yl)methyl]sulfanyl}pyrrolo[2,1-f][1 ,2,4]triazin-4-ol (33.1 mg, 19.21% yield) as a white solid. MS (ESI) calcd. For Ci2Hi2CIN5OS:309.05. Found: 310.20 [M+H]+.1H NMR (300 MHz, DMSO-d6) 6 12.12 (s, 1 H), 7.73 (s, 1 H), 7.55 - 7.59 (m, 1 H), 6.86 - 6.91 (m, 1 H), 6.51 - 6.63 (m, 1 H), 4.48 (s, 2H), 4.08 - 4.15 (m, 2H), 1.37-1.42 (m, 3H). PATENT

[0240] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0241] Example 2: Synthesis of 2-{[(5-chloro-3-cyclopropylimidazol-4-yl)methyl] sulfanyl}pyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0242] Step 1. Synthesis of methyl 5-chloro-3-cyclopropylimidazole-4-carboxylate

[0243] ^B(OH)2

[0244] To a solution of methyl 5-chloro-3H-imidazole-4-carboxylate (2 g, 12.456 mmol, 1 equiv) and cyclopropylboron ic acid (3.21 g, 37.368 mmol, 3.00 equiv) in DCE (30 mL) was added Cu(OAc)2 (3.39 g, 18.684 mmol, 1 .50 equiv), Na2COs (5.28 g, 49.824 mmol, 4.00 equiv), 2,2'-Bipyridine (4.86 g, 31 .140 mmol, 2.50 equiv). The resulting mixture was stirred at 70 °C for 2 h under O2. Desired product could be detected by LCMS. The resulting mixture was extracted with EA (3 x 100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (38 %) to afford methyl 5-chloro-3-cyclopropylimidazole-4-carboxylate (480 mg, 19.21 % yield, 93 % purity) as a white solid. MS: mass calcd for C8H9CIN2O2: 200.04 found:201 ,05[M+H]+

[0245] Step 2. Synthesis of (5-chloro-3-cyclopropylimidazol-4-yl)methanol

[0246] To a stirred solution of methyl 5-chloro-3-cyclopropylimidazole-4-carboxylate (300 mg, 1.495 mmol, 1 equiv) in THF (5 mL) were added LAH (68.10 mg, 1 .794 mmol, 1 .2 equiv) in portions at 0 °C. The resulting mixture was stirred at 25 °C for an additional 2 h. Desired product could be detected by LCMS. The reaction was quenched with ice water at 0 °C. The resulting mixture was filtered, the filter cake was washed with ACN (5 mL). The filtrate was concentrated under reduced pressure to afford (5-chloro-3-cyclopropylimidazol-4-yl)methanol (260 mg). The crude product was used in the next step directly without further purification

[0247] Step 3. Synthesis of 4-chloro-5-(chloromethyl)-1 -cyclopropylimidazole

[0248] To a stirred solution of (5-chloro-3-cyclopropylimidazol-4-yl)methanol (260 mg, 1.506 mmol, 1 equiv) in DCM (4 mL) was added SOCI2 (447.97 mg, 3.765 mmol, 2.5 equiv) dropwise at 0 °C. The resulting solution was stirred at room temperature for 2 h. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum to afford 4-chloro-5-(chloromethyl)-1- PATENT

[0249] ATTORNEY-DOCKET NO.: 51478-031 WO3 cyclopropylimidazole (120 mg). The crude product was used in the next step directly without further purification.

[0250] Step 4. Synthesis of 2-{[(5-chloro-3-cyclopropylimidazol-4-yl)methyl] sulfanyl}pyrrolo[2,1- f][1 ,2,4]triazin-4-ol

[0251] To a stirred solution of 4-chloro-5-(chloromethyl)-1 -cyclopropylimidazole (120 mg, 0.628 mmol, 1 equiv) and 2-sulfanylpyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (157.51 mg, 0.942 mmol, 1.5 equiv) in DMF (3 mL) was added DIEA (243.53 mg, 1 .884 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred for an additional 1 h at room temperature. LCMS showed the reaction was completed. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH C18 OE3D Prep Column 5 pm, 30 mm X 150 mm; Mobile Phase A: Water (0.05 % TFA), Mobile Phase E3: ACN; Flow rate: 60 mL / min mL / min; Gradient (E3 %): 20 % E3 to 36 % B in 10 min; Wave Length: 254nm / 220nm nm; RT1 (min): 8.47) to afford 2-{[(5-chloro-3-cyclopropylimidazol-4- yl)methyl]sulfanyl}pyrrolo[2,1 -f][1 ,2,4]triazin-4-ol; trifluoroacetic acid (99.6 mg, 36.39 % yield, 98.7 % purity) as a white solid. LC / MS: mass calcd for C13H12CIN5OS: 321 .05 found:322.00 [M+H]+.1H NMR (300 MHz, DMSO-de) 5: 12.13 (s, 1 H), 7.69 (s, 1 H), 7.55 - 7.56 (m, 1 H), 6.85 - 6.87 (m, 1 H), 6.49 - 6.52 (m, 1 H), 4.53 (s, 2H), 3.37 - 3.45 (m, 1 H), 0.97 - 1 .04 (m, 4H).

[0252] Example 3: Synthesis of 2-{[(3-ethyl-5-fluoroimidazol-4-yl) methyl] sulfanyl} pyrrolo[2,1-f] [1 ,2,4] triazin-4-ol

[0253] Step 1. Synthesis of ethyl 4-fluoro-1 H-imidazole-5-carboxylate

[0254] To a 40 mL microwave tube equipped with a stirring bar were added ethyl 4-amino-1 H- imidazole-5-carboxylate (3.8 g, 24.491 mmol) and 45.6 mL 40% tetrafluoroboric acid solution. Subsequently, NaNO2 (3.72 g, 53.880 mmol) dissolved in 5.6 mL of H2O was added to the above mixture. The resulting solution was stirred at 0 °C for 15 minutes. The reaction solution was spread on a glass plate and irradiated with UV light at 254 nm overnight. The reaction progress was monitored by LCMS, and it showed the reaction was completed. A 5M NaOH aqueous solution was added to the reaction solution at ice cooling temperature. The mixture was extracted with ethyl acetate, followed by washing the organic layer with a saturated sodium chloride solution. The washed organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue PATENT

[0255] ATTORNEY-DOCKET NO.: 51478-031 WO3 obtained was further purified by reverse phase column eluted with ACN and H2O (0.05% NH4HCO3), after concentrated to afford the ethyl 4-fluoro-1 H-imidazole-5-carboxylate (1 .5 g, 38.73% yield) as a yellow solid. LC / MS: MS (ESI) calcd. for C6H7FN2O2: 158.05. Found: 159.10 [M+H]+.

[0256] Step 2. Synthesis of ethyl 3-ethyl-5-fluoroimidazole-4-carboxylate

[0257] To a 40 mL microwave tube equipped with a stirring bar were added ethyl 5-fluoro-3H- imidazole-4-carboxylate (800 mg, 5.059 mmol) and 8 mL DMF. Subsequently, ethyl iodide (1183.56 mg, 7.588 mmol) and K2CO3 (1398.38 mg, 10.118 mmol) were added to the mixture. The resulting solution was stirred at 50°C for 0.5 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The reaction mixture was poured onto cooled water (50 mL) and NH4CI saturated aqueous solution (100 mL), extracted by EA, dried over anhydrous Na2SC>4, filtered and concentrated under vacuum. The residue obtained was further purified by silica gel column eluted with PE / EA (3:1), after concentrated to afford the ethyl 3-ethyl-5-fluoroimidazole-4-carboxylate (750 mg, 79.62% yield) as a yellow oil. LC / MS: MS (ESI) calcd. for C8H11FN2O2: 186.08. Found: 187.20 [M+H]+.

[0258] Step 3. Synthesis of (1-ethyl-4-fluoro-1 H-imidazol-5-yl) methanol

[0259] To a 40 mL tube equipped with a stirring bar were added ethyl 3-ethyl-5-fluoroimidazole-4- carboxylate (750 mg, 4.028 mmol) and 7 mL THF. Subsequently, DIBAL-H (2005.16 mg, 14.098 mmol) was added to the mixture at 0 °C. The resulting solution was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The reaction mixture was poured onto cooled water (50 mL), filtered, concentrated under vacuum, after concentrated to afford the (1-ethyl-4-fluoro-1 H-imidazol-5-yl) methanol (440 mg, 68.2% yield) as a yellow oil. The crude product was used in the next step directly without further purification. LC / MS: MS (ESI) calcd. for C6H9FN20: 144.07. Found: 145.15 [M+H]+.

[0260] Step 4. Synthesis of 5-(chloromethyl)-1-ethyl-4-fluoroimidazole

[0261] To a 40 mL tube equipped with a stirring bar were added (3-ethyl-5-fluoroimidazol-4-yl) methanol (220 mg, 1 .526 mmol) and 3 mL DCM. Subsequently, SOCI2 (453.89 mg, 3.815 mmol) was added to the mixture at 0°C. The resulting solution was stirred at room temperature for 2 h. The PATENT

[0262] ATTORNEY-DOCKET NO.: 51478-031 WO3 reaction progress was monitored by LCMS, and it showed the reaction was completed. The reaction mixture was concentrated under vacuum, after concentrated to afford the 5-(chloromethyl)-1-ethyl-4- fluoroimidazole (230 mg, 83.42% yield) as a yellow oil. LC / MS: MS (ESI) calcd. for C6H8CIFN2: 162.04. Found: 163.05 [M+H]+.

[0263] Step 5. Synthesis of 2-{[(3-ethyl-5-fluoroimidazol-4-yl) methyl] sulfanyl} pyrrolo[2,1-f] [1,2,4] triazin-4-ol

[0264] To a 40 mL tube equipped with a stirring bar were added 5-(chloromethyl)-1-ethyl-4- fluoroimidazole (230 mg, 1.415 mmol) and 3 mL DMF at room temperature. Subsequently, 2-sulfanyl- 3H-pyrrolo[2,1-f][1 ,2,4]triazin-4-one (307.46 mg, 1.840 mmol) and DIEA (548.50 mg, 4.245 mmol) were added to the mixture. The resulting mixture was stirred at room temperature for 0.5 h. The reaction progress was monitored by LCMS. The mixture was further purified by reverse phase column eluted with ACN and H2O (0.05% TFA), after concentrated to afford 2-{[(3-ethyl-5-fluoroimidazol-4-yl) methyl] sulfanyl} pyrrolo[2,1-f] [1 ,2,4] triazin-4-ol (301.6 mg, 72.69% yield) as a white solid. LC / MS: MS (ESI) calcd. for C12H12FN5OS: 293.07. Found: 294.05 [M+H]+.1H NMR (400 MHz, DMSO) 6 (ppm): 12.09 (s, 1 H), 7.48 - 7.60 (m, 1 H), 7.30 - 7.47 (m, 1 H), 6.70 - 6.90 (m, 1 H), 645 - 6 58 (m, 1 H), 4.46 (s, 2H), 3.91 - 4.11 (m, 2H), 1 .35 - 1 .45 (m, 3H).

[0265] Example 4: Synthesis of 2-{[(3-cyclopropyl-5-fluoroimidazol-4-yl)methyl]sulfanyl}pyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0266] Step 1. Synthesis of ethyl 3-cyclopropyl-5-fluoroimidazole-4-carboxylate

[0267] ^B(OH)2

[0268] To a stirred mixture of ethyl 5-fluoro-3H-imidazole-4-carboxylate (1.91 g, 12.079 mmol, 1 equiv) and cyclopropylboronic acid (3.11 g, 36.237 mmol, 3 equiv) in DCE (60 mL) were added CU(OAC)2 (3.29 g, 18.119 mmol, 1.5 equiv), 2,2'-Bipyridine (4.72 g, 30.198 mmol, 2.5 equiv) and Na2CO3 (5.12 g, 48.316 mmol, 4 equiv) in portions at room temperature under air atmosphere. The resulting mixture was stirred at 70 °C for 3 h under air atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with DCE (60 mL) (2x30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 :1) to afford ethyl 3-cyclopropyl-5- PATENT

[0269] ATTORNEY-DOCKET NO.: 51478-031 WO3 fluoroimidazole-4-carboxylate (420 mg, 17.54% yield, 85% purity) as a light brown solid. LC / MS: MS (ESI) calcd. for C9H11FN2O2: 198.08. Found: 199.15 [M+H] +.

[0270] Step 2. Synthesis of (3-cyclopropyl-5-fluoroimidazol-4-yl)methanol

[0271] To a stirred solution of ethyl 3-cyclopropyl-5-fluoroimidazole-4-carboxylate (400 mg, 2.018 mmol, 1 equiv) in THF (5 mL) was added diisobutylaluminum hydride (1 .0 M in THF) (3.1 mL, 1 .5 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h under nitrogen atmosphere. The reaction was quenched by the addition of water (1 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 220 nm. The resulting mixture was concentrated under reduced pressure. This resulted in (3-cyclopropyl-5-fluoroimidazol-4-yl)methanol (220 mg, 69.81 % yield, 98% purity) as a white solid. LC / MS: MS (ESI) calcd. for CyH&FNgO: 156.07. Found: 157.20 [M+H] +.

[0272] Step 3. Synthesis of 5-(chloromethyl)-1-cyclopropyl-4-fluoroimidazole

[0273] To a stirred solution of (3-cyclopropyl-5-fluoroimidazol-4-yl)methanol (200.1 mg, 1 .281 mmol, 1 equiv) in DCM (3 mL) was added SOCI2 (381 .1 mg, 3.204 mmol, 2.50 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS indicating the reaction was completed. Quenched the reaction with cooled water, then extracted with EA(20 ml x 3), the obtained organic layer was collected, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 5-(chloromethyl)-1-cyclopropyl-4-fluoroimidazole (200 mg, 89.39% yield, 80% purity) as a light brown oil. LC / MS: MS (ESI) calcd. for C7H8CIFN2: 174.04. Found: 175.10 [M+H]+. PATENT

[0274] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0275] Step 4. Synthesis of 2-{[(3-cyclopropyl-5-fluoroimidazol-4-yl)methyl]sulfanyl}pyrrolo[2,1 - f][1 ,2,4]triazin-4-ol

[0276] A solution of 5-(chloromethyl)-1-cyclopropyl-4-fluoroimidazole (100.1 mg, 0.573 mmol, 1 equiv) in DMF (2 mL) was treated with 2-sulfanyl-3H-pyrrolo[2,1-f][1 ,2,4]triazin-4-one (95.6 mg, 0.572 mmol, 1 .00 equiv) at 0 °C for 1 min under nitrogen atmosphere followed by the addition of EtsN (174.1 mg, 1 .720 mmol, 3.00 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1 % TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This resulted in 2-{[(3-cyclopropyl-5-fluoroimidazol-4-yl)methyl]sulfanyl}pyrrolo[2,1- f][1 ,2,4]triazin-4-ol (14.7 mg, 8.40 % yield, 95.135 % purity) as a white solid. LC / MS: MS (ESI) calcd. for CI3HI2FN5OS:305.07. Found: 306.00 [M+H]+.1H NMR (300 MHz, DMSO) 6 12.10 (s, 1 H), 7.53 - 7.49 (m, 1 H), 7.41 (d, J = 1 .7 Hz, 1 H), 6.90 - 6.82 (m, 1 H), 6.55 - 6.46 (m, 1 H), 4.51 (s, 2H), 3.38 (s, 1 H), 1.03 - 0.91 (m, 4H).

[0277] Example 5: Synthesis of 2-{[(4-ethyl-1 ,3-thiazol-5-yl)methyl]sulfanyl}pyrrolo[2,1-f][1 ,2,4]triazin- 4-ol

[0278] Step 1. Synthesis of 4-ethyl-1 ,3-thiazole-5-carboxylate

[0279] To a stirred solution of methyl 4-bromo-1 ,3-thiazole-5-carboxylate (300 mg, 1.351 mmol, 1 equiv), Pd(OAc)2 (30.33 mg, 0.135 mmol, 0.1 equiv) and Q-phos (192.04 mg, 0.270 mmol, 0.2 equiv) in THF (3 mL) was added bromo(ethyl)zinc (471 .09 mg, 2.702 mmol, 2 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (2 x 200mL). The combined organic layers were washed with water (1x200 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1 :1) to afford methyl 4-ethyl-1 ,3-thiazole-5-carboxylate (180 mg, 77.82% yield, 92% purity) as a yellow oil. LC / MS: MS (ESI) calcd. for C7H9NO2S: 171 .04, Found: 172.15 [M+H]+. PATENT

[0280] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0281] Step 2. Synthesis of (4-ethyl-1,3-thiazol-5-yl)methanol

[0282] To a stirred solution of methyl 4-ethyl-1 ,3-thiazole-5-carboxylate (180 mg, 1.051 mmol, 1 equiv) in THF (2 mL) was added DIBAL-H (448.57 mg, 3.153 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was monitored by LCMS. The reaction was quenched with ice water at room temperature. The resulting mixture was filtered, the filter cake was washed with water (2x5 mL). The filtrate was concentrated under reduced pressure to afford (4-ethyl-1 ,3-thiazol-5-yl)methanol (120 mg) as a yellow oil. LC / MS: MS (ESI) calcd. for C6H9NOS: 143.04, Found: 144.10 [M+H]+.

[0283] Step 3. Synthesis of 5-(chloromethyl)-4-ethyl-1,3-thiazole

[0284] SOCI DCM

[0285] To a stirred solution of (4-ethyl-1 ,3-thiazol-5-yl)methanol (120 mg, 0.838 mmol, 1 equiv) in DCM (1 mL) was added SOCI2 (299.06 mg, 2.514 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was monitored by TLC. The resulting mixture was concentrated under reduced pressure to afford 5-(chloromethyl)-4-ethyl- 1 ,3-thiazole (100 mg) as a yellow solid. The crude product was used in the next step directly without further purification.

[0286] Step 4. Synthesis of 2-{[(4-ethyl-1,3-thiazol-5-yl)methyl]sulfanyl}pyrrolo[2,1-f][1,2,4]triazin-4-ol

[0287] To a stirred solution of 5-(chloromethyl)-4-ethyl-1 ,3-thiazole (100 mg, 0.619 mmol, 1 equiv) and 2-sulfanylpyrrolo[2,1-f][1 ,2,4]triazin-4-ol (113.77 mg, 0.681 mmol, 1.1 equiv) in DMF (2 mL) was added DIEA (239.86 mg, 1 .857 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was monitored by LCMS. The residue was purified by reverse phase flash (0.05% NH4HCO3) to afford 2-{[(4-ethyl-1 ,3-thiazol-5- yl)methyl]sulfanyl}pyrrolo-[2,1-f][1 ,2,4]triazin-4-ol (17.6 mg, 9.73% yield, 99.4% purity) as a white solid. LC / MS: MS (ESI) calcd. for C12H12N4OS2: 292.05. Found: 293.00 [M+H] +.1H NMR (400 MHz, DMSO-d6) 6 (ppm): 8.86 (s, 1 H), 7.49 - 7.50 (m, 1 H), 6.79 - 6.81 (m, 1 H), 6.47 - 6.48 (m, 1 H), 4.60 (s, 2H), 2.75 - 2.85 (m, 2H), 1 .15 - 1 .28 (m, 3H). PATENT

[0288] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0289] Example 6: 2-{[(2-isopropyl-4-methylpyrazol-3-yl)methyl]sulfanyl}pyrrolo[2,1 -f] [1 ,2,4]triazin-4-ol

[0290] Step 1 . Synthesis of ethyl 2-isopropyl-4-methylpyrazole-3-carboxylate

[0291] To a stirred solution of ethyl 4-methyl-2H-pyrazole-3-carboxylate (1 g, 6.486 mmol, 1 equiv) and CS2CO3 (4.23 g, 12.972 mmol, 2 equiv) in DMF (10 mL) was added 2-iodopropane (2.21 g, 12.972 mmol, 2 equiv) dropwise at room temperature. The resulting mixture was stirred at 60°C for an additional 1 h. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (2 x300mL). The combined organic layers were washed with water (2x300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 :1) to afford ethyl 2-isopropyl-4- methylpyrazole-3-carboxylate (700 mg, 54.99% yield, 95% purity) as a colorless oil and ethyl 1- isopropyl-4-methylpyrazole-3-carboxylate (500 mg, 39.28% yield, 95% purity) as a colorless oil. LC / MS: MS (ESI) calcd. for C10H16N2O2: 196.25, Found: 197.00 [M+H]+.

[0292] Step 2. Synthesis of (2-isopropyl-4-methylpyrazol-3-yl)methanol

[0293] To a stirred solution of ethyl 2-isopropyl-4-methylpyrazole-3-carboxylate (300 mg, 1.529 mmol, 1 equiv) in THF (3 mL) was added DIBAL-H (652.23 mg, 4.587 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was monitored by TLC. The reaction was quenched with ice water at room temperature. The resulting mixture was filtered; the filter cake was washed with ACN (2x5 mL). The filtrate was concentrated under reduced pressure to afford (2-isopropyl-4-methylpyrazol-3-yl)methanol (200 mg) as a colorless oil. LC / MS: MS (ESI) calcd. for C8Hi4N20: 154.21 , Found: 155.00 [M+H]+.

[0294] Step 3. Synthesis of 5-(chloromethyl)-1-isopropyl-4-methylpyrazole

[0295] To a stirred solution of (2-isopropyl-4-methylpyrazol-3-yl)methanol (100 mg, 0.648 mmol, 1 equiv) in DCM (2 mL) was added SOCI2 (231 .42 mg, 1 .944 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was monitored by PATENT

[0296] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0297] TLC. The resulting mixture was concentrated under reduced pressure to afford 5-(chloromethyl)-1- isopropyl-4-methylpyrazole (80 mg) as a yellow oil. The crude product was used in the next step directly without further purification.

[0298] Step 4. Synthesis of 2-{[(2-isopropyl-4-methylpyrazol-3-yl)methyl]sulfanyl}pyrrolo[2,1-f][1 ,2,4]- triazin-4-ol

[0299] To a stirred solution of 5-(chloromethyl)-1-isopropyl-4-methylpyrazole (150 mg, 0.869 mmol, 1 equiv) and 2-sulfanylpyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (159.77 mg, 0.956 mmol, 1.1 equiv) in DMF (2 mL) was added DIEA (336.85 mg, 2.607 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was monitored by LCMS. The crude product was purified by reverse phase flash with the following conditions (0.05% TFA) to afford 2-{[(2- isopropyl-4-methylpyrazol-3-yl)methyl]sulfanyl}pyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (151 .3 mg, 57.41 % yield, 99.7% purity) as a white solid. LC / MS: MS (ESI) calcd. for C14H17N5OS: 303.12. Found: 304.05 [M+H] +.1H NMR (300 MHz, DMSO-d6) 6 (ppm): 12.10 (s, 1 H), 7.52 - 7.59 (m, 1 H), 7.24 (s, 1 H), 6.79 - 6.95 (m, 1 H), 6.55 - 6.70 (m, 1 H), 4.55 - 4.75 (m, 1 H), 4.50 (s, 2H), 2.01 (s, 3H), 1 .20 - 1 .45 (m, 6H).

[0300] Example 7: Synthesis of 2-{[(2,4-dimethylpyridin-3-yl)methyl]sulfanyl}pyrrolo[2,1 -f][1 ,2,4]- triazin-4-ol

[0301] Step 1. Synthesis of (2,4-dimethylpyridin-3-yl) methanol

[0302] To a stirred solution of ethyl 2,4-dimethylpyridine-3-carboxylate (250 mg, 1.395 mmol, 1 equiv) in THF (3 mL) was added DIBAL-H (4.18 mL, 4.185 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred at 25 °C for an additional 2 h. After completion of this reaction, the reaction was quenched with ice water (20 mL). The resulting mixture was filtered; the filter cake was washed with ACN (10 mL). The filtrate was concentrated under reduced pressure, affording the crude product of (2,4-dimethylpyridin-3-yl)methanol (190 mg) as a white solid, which was used directly without any purification. MS: mass calcd for CaHnNO: 137.08 found: 138.10[M+H]+ PATENT

[0303] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0304] Step 2. Synthesis of 3-(chloromethyl)-2,4-dimethylpyridine

[0305] To a solution of (2,4-dimethylpyridin-3-yl)methanol (110 mg, 0.802 mmol, 1 equiv) in DCM (2 mL) was added SOCh (238.47 mg, 2.005 mmol, 2.5 equiv) dropwise at 0 °C. The resulting solution was stirred at room temperature for 2 h. TLC showed the reaction was completed. The resulting mixture was concentrated under vacuum to afford 3-(chloromethyl)-2,4-dimethylpyridine (1 10 mg). The crude product was used in the next step directly without further purification.

[0306] Step 3. Synthesis of 2-{[(2,4-dimethylpyridin-3-yl)methyl]sulfanyl}pyrrolo[2,1 -f][1 ,2,4]triazin-4-ol

[0307] To a stirred solution of 3-(chloromethyl)-2,4-dimethylpyridine (110 mg, 0.707 mmol, 1 equiv) and 2-sulfanylpyrrolo[2,1-f][1 ,2,4]triazin-4-ol (141 .80 mg, 0.848 mmol, 1.2 equiv) in DMF (3 mL) was added DIEA (274.06 mg, 2.121 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred for an additional 1 h at room temperature. LCMS showed the reaction was completed. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.05 % TFA), 5 % to 40 % gradient in 15 min; detector, UV 254 nm to afford 2-{[(2,4-dimethylpyridin-3-yl)methyl]sulfanyl}pyrrolo[2,1-f][1 ,2,4]triazin-4-ol (68.3 mg, 24.14 % yield, 98.6 % purity) as a white solid. LC / MS: mass calcd for C14H14N4OS: 286.09 found:287.05[M+H]+.1H NMR (300 MHz, DMSO-d6) 6: 12.20 (s, 1 H), 8.54 - 8.56 (m, 1 H), 7.63 - 7.72 (m, 1 H), 7.50 - 7.55 (m, 1 H), 6.87 - 6.89 (m, 1 H), 6.51 - 6.54 (m, 1 H), 4.58 (s, 2H), 2.77 (s, 3H), 2.63 (s, 3H).

[0308] Example 8: Synthesis of 2-(((4-methyl-2-(trifluoromethyl) pyridin-3-yl) methyl) thio) pyrrolo[2,1 - f] [1 ,2,4] triazin-4-ol

[0309] To a solution of 3-(chloromethyl)-4-methyl-2-(trifluoromethyl) pyridine (300 mg, 1.431 mmol) in 3 ml of DMF was added 2-mercaptopyrrolo[2,1 -f] [1 ,2,4] triazin-4-ol (358.95 mg, 2.147 mmol), DIEA (554.97 mg, 4.293 mmol) at room temperature. The resulting solution was stirred at room temperature for 0.5 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. PATENT

[0310] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0311] The mixture was further purified by reverse phase column eluted with ACN and H2O (0.05% NH4HCO3), after concentrated to afford 2-(((4-methyl-2-(trifluoromethyl) pyridin-3-yl) methyl) thio) pyrrolo[2,1 -f] [1 ,2,4] triazin-4-ol (300.7 mg, 61 .73% yield) as a white solid. LC / MS: MS (ESI) calcd. for C14H11F3N4OS, 340.06 m / z, found 341.05 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 (ppm): 12.19 (s, 1 H), 8.51 - 8.61 (m, 1 H), 7.67 - 7.81 (m, 1 H), 7.45 - 7.65 (m, 1 H), 6.81 - 6.96 (m,1 H), 6.51 - 6.61 (m,1 H), 4.58 (s, 2H), 2.54 (s, 3H).

[0312] Example 9: Synthesis of 2-({[2-(difluoromethyl)-4-methylpyridin-3-yl]methyl}sulfanyl)pyrrolo-

[0313] [2,1-f][1 ,2,4]triazin-4-ol

[0314] Step 1. Synthesis of ethyl 2-ethenyl-4-methylpyridine-3-carboxylate

[0315] A mixture of ethyl 2-bromo-4-methylpyridine-3-carboxylate (1.2 g, 4.916 mmol, 1 equiv), 2- ethenyl-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (1.51 g, 9.832 mmol, 2 equiv), Pd(dppf)Cl2CH2Cl2 (401.48 mg, 0.492 mmol, 0.1 equiv) and K3PO4 (3.13 g, 14.748 mmol, 3 equiv) in Dioxane (8 mL) and H2O (2 mL) was stirred at 90 °C for 2h under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (2 x 150 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (3:1) to afford ethyl 2-ethenyl-4-methylpyridine-3-carboxylate (780 mg, 82.97% yield, 92% purity) as a white solid. MS (ESI) calcd. For C11H13NO2: 191 .09 m / z, found 192.08 [M+H]+.

[0316] Step 2. Synthesis of ethyl 2-formyl-4-methylpyridine-3-carboxylate

[0317] To a stirred mixture of ethyl 2-ethenyl-4-methylpyridine-3-carboxylate (780 mg, 4.079 mmol, 1 equiv) and Potassium osmate(VI) dihydrate (75.14 mg, 0.204 mmol, 0.05 equiv) in ACN (10 mL) was added NalC (1 .74 g, 8.158 mmol, 2 equiv) in 10 mL H2O dropwise at room temperature under air atmosphere. The resulting mixture was stirred at room temperature for 30 min under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 :1) to afford ethyl 2-formyl-4-methylpyridine-3-carboxylate (430 mg, 54.57% PATENT

[0318] ATTORNEY-DOCKET NO.: 51478-031 WO3 yield, 95% purity) as a light yellow oil. MS (ESI) calcd. For CioHnN03:193.07 m / z, found 194.08 [M+H],

[0319] Step 3. Synthesis of ethyl 2-(difluoromethyl)-4-methylpyridine-3-carboxylate

[0320] To a stirred solution of ethyl 2-formyl-4-methylpyridine-3-carboxylate (400 mg, 2.070 mmol, 1 equiv) in DCM (10 mL) was added Diethylaminosulfur trifluoride (1334.89 mg, 8.280 mmol, 4 equiv) dropwise at 0 °C under air atmosphere. The resulting mixture was stirred at room temperature for 30 min under air atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (2 x 150 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (2:1) to afford ethyl 2-(difluoromethyl)-4-methylpyridine-3- carboxylate (340 mg, 76.31 % yield, 93% purity) as a light yellow oil. MS (ESI) calcd. for CIOHHF2N02:215.08 m / z, found 216.05 [M+H]+.

[0321] Step 4. Synthesis of [2-(difluoromethyl)-4-methylpyridin-3-yl]methanol

[0322] A mixture of ethyl 2-(difluoromethyl)-4-methylpyridine-3-carboxylate (340 mg, 1.580 mmol, 1 equiv) and Lithium aluminum hydriden (71.95 mg, 1.896 mmol, 1.2 equiv) in THF (5 mL) was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of Ns2SO4.10H2O at 0°C. The resulting mixture was stirred at room temperature for 30 min under air atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 :1) to afford [2- (difluoromethyl)-4-methylpyridin-3-yl]methanol (100 mg, 36.55% yield, 95% purity) as a colorless oil. MS (ESI) calcd. for C8H9F2NO: 173.07 m / z, found 174.09 [M+H]+.

[0323] Step 5. Synthesis of 3-(chloromethyl)-2-(difluoromethyl)-4-methylpyridine

[0324] To a stirred solution of [2-(difluoromethyl)-4-methylpyridin-3-yl]methanol (100 mg, 0.577 mmol, 1 equiv) in DCM (5 mL) was added SOCI2(137.40 mg, 1 .154 mmol, 2.00 equiv) dropwise at PATENT

[0325] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0326] 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. This resulted in 3- (chloromethyl)-2-(difluoromethyl)-4-methylpyridine (1 10 mg, 99.41 % yield, 90% purity) as a white solid. MS (ESI) calcd. for C8H8CIF2N: 191.03 m / z, found 192.05 [M+H]+.

[0327] Step 6. Synthesis of 2-({[2-(difluoromethyl)-4-methylpyridin-3-yl]methyl}sulfanyl) pyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0328] A solution of 3-(chloromethyl)-2-(difluoromethyl)-4-methylpyridine (100 mg, 0.522 mmol, 1 equiv), 2-sulfanylpyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (87.26 mg, 0.522 mmol, 1 equiv) and DIEA (168.63 mg, 1 .305 mmol, 2.5 equiv) in DMF (2 mL) was stirred at room temperature for 10 min under air atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1 % TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 2-({[2-(difluoromethyl)-4-methylpyridin-3- yl]methyl}sulfanyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (143.1 mg, 62.84% yield, 99.8% purity) as a white solid. LC / MS (ESI) calcd. for C8H9F2NO: 322.07 m / z, found 323.05 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 6 8.49 (d, J = 4.8 Hz, 1 H), 7.58 (d, J = 1 .8 Hz, 1 H), 7.51 (d, J = 5.1 Hz, 1 H), 7.42 - 7.07 (m, 1 H), 6.94 (t, J = 1 .8, 2.7 Hz, 1 H), 6.56 (d, J = 2.7 Hz, 1 H), 4.63 (s, 2H), 2.56 (s, 3H).

[0329] Example 10: Synthesis of 2-({[4-(difluoromethyl)-2-methylpyridin-3-yl]methyl}sulfanyl)pyrrolo-

[0330] [2,1-f][1 ,2,4]triazin-4-ol

[0331] Step 1. Synthesis of methyl 2-chloro-4-ethenylpyridine-3-carboxylate

[0332] To a stirred solution of methyl 4-bromo-2-chloropyridine-3-carboxylate (2 g, 7.985 mmol, 1 equiv) and 2-ethenyl-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (2.46 g, 15.970 mmol, 2 equiv) in dioxane (20 mL) and H2O (2 mL) was added K2CO3 (2.21 g, 15.970 mmol, 2 equiv) and Pd(dppf)Cl2 (0.58 g, 0.799 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 1 h under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined PATENT

[0333] ATTORNEY-DOCKET NO.: 51478-031 WO3 organic layers were washed with deionized water (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA to afford methyl 2-chloro-4-ethenylpyridine-3- carboxylate (990 mg, 62.74% yield, 91 % purity) as a yellow oil. MS: MS (ESI) calcd. for CgHsCINO : 197.02. Found: 198.10 [M+H] +.

[0334] Step 2. Synthesis of methyl 4-ethenyl-2-methylpyridine-3-carboxylate

[0335] / OH — B OH

[0336] To a stirred solution of methyl 2-chloro-4-ethenylpyridine-3-carboxylate (900 mg, 4.554 mmol,

[0337] 1 equiv) and methylboronic acid (1.09 g, 18.216 mmol, 4 equiv) in Dioxane (10 mL) was added CS2CO3 (2.97 g, 9.108 mmol, 2 equiv), Pd(PPti3)4 (0.53 g, 0.455 mmol, 0.1 equiv) and H2O (1 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110 °C for

[0338] 2 h under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layers were washed with water (3x100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1 :1) to afford methyl 4-ethenyl-2-methylpyridine-3- carboxylate (200 mg, 24.78% yield, 90% purity) as a yellow oil. MS: MS (ESI) calcd. for CIOHHN02:177.08. Found: 178.00 [M+H] +.

[0339] Step 3. Synthesis of methyl 4-formyl-2-methylpyridine-3-carboxylate

[0340] To a stirred solution of methyl 4-ethenyl-2-methylpyridine-3-carboxylate (150 mg, 0.846 mmol, 1 equiv) and Potassium osmate(VI) dihydrate (31.19 mg, 0.085 mmol, 0.1 equiv) in MeCN (1 mL) was added NalC (724.22 mg, 3.384 mmol, 4 equiv) in H2O (1 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 min under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1 :1) to afford methyl 4-formyl-2-methylpyridine-3-carboxylate (110 mg, 72.53% yield, 90% purity) as a yellow oil. MS: MS (ESI) calcd. for CgHgNOs: 179.06. Found: 180.00 [M+H] +. PATENT

[0341] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0342] Step 4. Synthesis of methyl 4-(difluoromethyl)-2-methylpyridine-3-carboxylate

[0343] To a stirred solution of methyl 4-formyl-2-methylpyridine-3-carboxylate (110 mg, 0.614 mmol, 1 equiv) in DCM (1 mL) was added Diethylaminosulfur trifluoride (395.83 mg, 2.456 mmol, 4 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was quenched with ice water at 0 °C. The resulting mixture was extracted with EtOAc (50 mL). The combined organic layers were washed with water (3x10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1 :1) to afford methyl 4-(difluoromethyl)-2-methylpyridine-3-carboxylate (60 mg, 48.58% yield, 90% purity) as a yellow oil. MS: MS (ESI) calcd. for C9H9F2NO2: 201 .06. Found: 201 .95 [M+H] +.

[0344] Step 5. Synthesis of [4-(difluoromethyl)-2-methylpyridin-3-yl]methanol

[0345] To a stirred solution of methyl 4-(difluoromethyl)-2-methylpyridine-3-carboxylate (60 mg, 0.298 mmol, 1 equiv) in THF (1 mL) was added DIBAL-H (106.04 mg, 0.745 mmol, 2.5 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with ice water at 0 °C. The resulting mixture was filtered, the filter cake was washed with water (2x5 mL). The filtrate was concentrated under reduced pressure. This resulted in [4- (difluoromethyl)-2-methylpyridin-3-yl]methanol (50 mg) as a yellow oil. MS: MS (ESI) calcd. for C8H9F2NO: 173.07. Found: 174.15 [M+H] +.

[0346] Step 6. Synthesis of 3-(chloromethyl)-4-(difluoromethyl)-2-methylpyridine

[0347] To a stirred solution of [4-(difluoromethyl)-2-methylpyridin-3-yl]methanol (50 mg, 0.289 mmol, 1 equiv) in DCM (1 mL) was added SOCI2 (68.70 mg, 0.578 mmol, 2 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give 3-(chloromethyl)-4-(difluoromethyl)-2-methylpyridine. The crude PATENT

[0348] ATTORNEY-DOCKET NO.: 51478-031 WO3 product was used in the next step directly without further purification. MS: MS (ESI) calcd. for C8H8CIF2N: 191.03. Found: 192.10 [M+H] +.

[0349] Step 7. Synthesis of 2-({[4-(difluoromethyl)-2-methylpyridin-3-yl]methyl}sulfanyl) pyrrolo [2,1- f] [1 ,2,4]triazi n-4-ol

[0350] A solution of 3-(chloromethyl)-4-(difluoromethyl)-2-methylpyridine (60 mg, 0.313 mmol, 1 equiv), 2-sulfanylpyrrolo[2,1-f][1 ,2,4]triazin-4-ol (104.71 mg, 0.626 mmol, 2 equiv) in DMF (2 mL) was added DIEA (121.42 mg, 0.939 mmol, 3 equiv) at room temperature for 30 min. Desired product could be detected by LCMS. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (0.1% TFA), 10% to 70% gradient in 20 min; detector, UV 254 nm. This resulted in 2-({[4-(difluoromethyl)-2-methylpyridin-3-yl]- methyl}sulfanyl)pyrrolo[2,1-f][1 ,2,4]triazin-4-ol (38.2 mg, 27.96% yield, 97.2% purity) as a white solid. LC / MS: MS (ESI) calcd. for C12H14F2N4OS: 322.07. Found: 323.00 [M+H] +.1H NMR (400 MHz, DMSO-d6) 6 (ppm): 12.14 (s, 1 H), 8.62 - 8.64 (m, 1H), 7.37 - 7.64 (m, 3H), 6.86 - 6.88 (m, 1 H), 6.51 - 6.53 (m, 1 H), 4.59 (s, 2H), 2.69 (s, 3H).

[0351] Example 11 : Synthesis of 2-({[2-(trifluoromethyl)pyridin-3-yl]methyl}sulfanyl)pyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0352] Step 1. Synthesis of [2-(trifluoromethyl)pyridin-3-yl]methanol

[0353] To a stirred solution of 2-(trifluoromethyl)pyridine-3-carboxylic acid (200 mg, 1 .047 mmol, 1 equiv) in THF (3 mL) were added LAH (47.66 mg, 1 .256 mmol, 1 .2 equiv) in portions at 0 °C. The resulting mixture was stirred at 25 °C for an additional 30 min. Desired product could be detected by LCMS. The reaction was quenched with ice water at 0 °C. The resulting mixture was filtered, the filter cake was washed with ACN (5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.05 % TFA), 2 % to 50 % gradient in 10 min; detector, UV 254 nm to afford [2-(trifluoromethyl)pyridin-3-yl]methanol (80 mg, 43.16 % yield, 93 % purity) as a white solid. MS: mass calcd for C / HeFsNO: 177.04 found:178.00[M+H]+ PATENT

[0354] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0355] Step 2. Synthesis of 3-(chloromethyl)-2-(trifluoromethyl)pyridine

[0356] To a stirred solution of [2-(trifluoromethyl)pyridin-3-yl]methanol (80 mg, 0.452 mmol, 1 equiv) in DCM (3 mL) was added SOCI2 (134.32 mg, 1 .130 mmol, 2.5 equiv) dropwise at 0 °C. The resulting solution was stirred at room temperature for 30 min. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum to afford 3-(chloromethyl)-2-(trifluoromethyl)- pyridine (70 mg). The crude product was used in the next step directly without further purification.

[0357] Step 3. Synthesis of 2-({[2-(trifluoromethyl)pyridin-3-yl]methyl}sulfanyl)pyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0358] To a stirred solution of 3-(chloromethyl)-2-(trifluoromethyl)pyridine (70 mg, 0.358 mmol, 1 equiv) and 2-sulfanylpyrrolo[2,1-f][1 ,2,4]triazin-4-ol (71.81 mg, 0.430 mmol, 1.2 equiv) in DMF (2 mL) was added DIEA (138.78 mg, 1.074 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred for an additional 2h at room temperature. LCMS showed the reaction was completed. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.05 % TFA, 5 % to 50 % gradient in 15 min; detector, UV 254 nm to afford 2-({[2-(trifluoromethyl)pyridin-3-yl]methyl}sulfanyl)pyrrolo[2,1-f][1 ,2,4]triazin-4-ol (7.8 mg, 6.68 % yield, 99.0 % purity) as a white solid. LC / MS: mass calcd for C13H9F3N4OS: 326.04 found: 327.00[M+H]+.1H NMR (300 MHz, DMSO-d6) 6: 12.15 (s, 1 H), 8.65 - 8.67 (m, 1 H), 8.27 - 8.30 (m, 1 H), 7.70 - 7.74 (m, 1 H), 7.52 - 7.53 (m, 1 H), 6.84 - 6.86 (m, 1 H), 6.48 - 6.50 (m, 1 H), 4.59 (s, 2H).

[0359] Example 12: Synthesis of 2-({[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]methyl}sulfanyl)- pyrrolo[2,1 -f] [1 ,2,4]triazin-4-ol

[0360] Step 1. Synthesis of 6-methoxy-2-(trifluoromethyl)pyridine-3-carboxylate

[0361] A mixture of methyl 6-chloro-2-(trifluoromethyl)pyridine-3-carboxylate (500 mg, 2.087 mmol, 1 equiv) and MeONa (225.49 mg, 4.174 mmol, 2 equiv) in methanol (10 mL) was stirred at 80 °C for 1 h under air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 :1) to afford methyl 6-methoxy PATENT

[0362] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0363] -2-(trifluoromethyl)pyridine-3-carboxylate (450 mg, 91.69% yield, 90% purity) as a white solid. MS (ESI) calcd. For C9H8F3NO3: 235.06 m / z, found 236.00 [M+H]+.

[0364] Step 2. Synthesis of [6-methoxy-2-(trifluoromethyl)pyridin-3-yl]methanol

[0365] To a stirred solution of methyl 6-methoxy-2-(trifluoromethyl)pyridine-3-carboxylate (300 mg, 1 .276 mmol, 1 equiv) in THF (10 mL) was added DIBAL-H( in hexanes) (1 .53 mL, 1 .530 mmol, 1 .20 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was quenched with N32SO4.10H2O at room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 30 mL). The filtrate was concentrated under reduced pressure. This resulted in [6-methoxy-2-(trifluoro- methyl)pyridin-3-yl]methanol (100 mg, 37.84% yield, 95% purity) as a white solid. The crude product was used in the next step directly without further purification. MS (ESI) calcd. For CsH8F3NO2:207.05 m / z, found 208.05 [M+H]+.

[0366] Step 3. Synthesis of 3-(chloromethyl)-6-methoxy-2-(trifluoromethyl)pyridine

[0367] SOCI DCM

[0368] To a stirred solution of [6-methoxy-2-(trifluoromethyl)pyridin-3-yl]methanol (40 mg, 0.193 mmol, 1 equiv) in DCM (3 mL) was added SOCI2 (45.94 mg, 0.386 mmol, 2 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. This resulted in 3-(chloromethyl)-6-methoxy-2-(trifluoromethyl)pyridine (40 mg, 68.87% yield, 89% purity) as a white solid. The crude product was used in the next step directly without further purification. MS (ESI) calcd. for C8H7CIF3NO:225.02 m / z, found 226.01 [M+H]+.

[0369] Step 4. Synthesis of 2-({[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]methyl}sulfanyl)pyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0370] A mixture of 3-(chloromethyl)-6-methoxy-2-(trifluoromethyl)pyridine (40 mg, 0.177 mmol, 1 equiv), 2-sulfanylpyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (29.64 mg, 0.177 mmol, 1 equiv) and DIEA (57.29 mg, PATENT

[0371] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0372] 0.443 mmol, 2.5 equiv) in DMF (2 mL) was stirred at room temperature for 10 min under air atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1 % TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 2-({[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]methyl}- sulfanyl)pyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (3.6 mg, 4.32% yield, 98.2% purity) as a trifluoroacetate salt and as a white solid. MS (ESI) calcd. for C14H11F3N4O2S: 356.06 m / z, found 356.95 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 6 8.11 (d, J = 8.7 Hz, 1 H), 7.53 (s, 1 H), 7.11 (d, J = 8.7 Hz, 1 H), 6.84 (d, J = 3.0 Hz, 1 H), 6.49 (t, J = 2.7, 4.2 Hz, 1 H), 4.48 (s, 2H), 3.86 (s, 3H).

[0373] Example 13: Synthesis of 2-({[2-(difluoromethyl)pyridin-3-yl]methyl}sulfanyl)pyrrolo[2,1 -f]- [1 ,2,4]triazin-4-ol

[0374] Step 1. Synthesis of methyl 2-(2-ethoxy-1 ,1-difluoro-2-oxoethyl)pyridine-3-carboxylate

[0375] A solution of methyl 2-bromopyridine-3-carboxylate (300 mg, 1 .389 mmol) and ethyl 2,2- difluoro-2-(trimethylsilyl)acetate (545.11 mg, 2.778 mmol) and Cui (317.37 mg, 1.667 mmol) and KF (112.14 mg, 1 .931 mmol) in DMSO (3 mL) was stirred at 80 °C for 1 h under N2 atmosphere. The reaction was monitored by LCMS. After completion of reaction, the reaction was quenched with water. The resulting mixture was extracted with EA (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (5:1) to afford methyl 2-(2-ethoxy-1 ,1-difluoro-2-oxoethyl)pyridine-3-carboxylate (211 mg, 58.62% yield, 93% purity) as a yellow oil. LC / MS: MS (ESI) calcd. for C11H11F2NO4: 259.07. Found: 260.10 [M+H]+.

[0376] Step 2. Synthesis of difluoro[3-(methoxycarbonyl)pyridin-2-yl]acetic acid

[0377] To a stirred solution of methyl 2-(2-ethoxy-1 ,1-difluoro-2-oxoethyl)pyridine-3-carboxylate (211 mg, 0.814 mmol, 1 equiv) in MeOH (3 mL) and H2O (1 mL) was added Na2COs (345.10 mg, 3.256 mmol, 4 equiv) , The resulting mixture was stirred at room temperature for 1 h. After completion of reaction, the reaction was quenched with water. The mixture / residue was acidified to pH 3 with 1 M HCI. The resulting mixture was extracted with EA (50 mL x 3), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in difluoro[3- PATENT

[0378] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0379] (methoxycarbonyl)pyridin -2-yl]acetic acid (156 mg) as an off-white solid. LC / MS: MS (ESI) calcd. for C9H7F2NO4: 231.03. Found: 232.00 [M+H]+.

[0380] Step 3. Synthesis of methyl 2-(difluoromethyl)pyridine-3-carboxylate

[0381] A solution of difluoro[3-(methoxycarbonyl)pyridin-2-yl]acetic acid (156 mg, 0.675 mmol, 1 equiv) and KF (235.25 mg, 4.050 mmol, 6 equiv) in DMF (8 mL) was stirred at 140 °C for 1 h under N2 atmosphere. The reaction was monitored by LCMS. After completion of reaction, the reaction was quenched with ice water. The resulting mixture was extracted with EA (30 mL x 3), dried over anhydrous Na2SC>4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (3:1) to afford methyl 2- (difluoromethyl)pyridine-3-carboxylate (70 mg, 55.42% yield, 93% purity) as a yellow oil. LC / MS: MS (ESI) calcd. for C8H7F2NO2: 187.04. Found: 188.05 [M+H]+.

[0382] Step 4. Synthesis of [2-(difluoromethyl)pyridin-3-yl]methanol

[0383] To a stirred solution of methyl 2-(difluoromethyl)pyridine-3-carboxylate (60 mg, 0.321 mmol) in THF (2 mL) was added LAH (18.25 mg, 0.482 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. After completion of reaction, the reaction was poured into ice water. The resulting mixture was extracted with EA (30 mL x 3), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (1 :1) to afford [2- (difluoromethyl)pyridin-3-yl]methanol (39 mg, 76.44% yield, 93% purity) as a yellow solid. LC / MS: MS (ESI) calcd. for C7H7F2NO: 159.05. Found: 160.00 [M+H]+.

[0384] Step 5. Synthesis of 3-(chloromethyl)-2-(difluoromethyl)pyridine

[0385] To a stirred solution of [2-(difluoromethyl)pyridin-3-yl]methanol (39 mg, 0.245 mmol, 1 equiv) in DCM (1 mL) was added SOCI2 (72.88 mg, 0.613 mmol, 2.5 equiv) at 0 °C. The mixture was stirred for 2 h at room temperature. The reaction was monitored by TLC. After completion of reaction, the PATENT

[0386] ATTORNEY-DOCKET NO.: 51478-031 WO3 resulting mixture was concentrated under reduced pressure. This resulted in 3-(chloromethyl)-2- (difluoromethyl)pyridine (40 mg) as a yellow solid.

[0387] Step 6. Synthesis of 2-({[2-(difluoromethyl)pyridin-3-yl]methyl}sulfanyl)pyrrolo[2,1- f][1 ,2,4]triazin-4-ol

[0388] To a stirred solution of 3-(chloromethyl)-2-(difluoromethyl)pyridine (50 mg, 0.282 mmol) and 2-sulfanylpyrrolo[2,1-f][1 ,2,4]triazin-4-ol (47.07 mg, 0.282 mmol,) in DMF (2 mL) was added DIEA (109.17 mg, 0.846 mmol) at 0 °C. The reaction was stirred for 2 h at room temperature. The reaction was monitored by LCMS. After completion of reaction, the mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water (0.05% TFA) in ACN, 10% to 50% gradient in 15 min; detector, UV 254 nm. After lyophilized, it provided 2-({[2-(difluoromethyl)pyridin-3-yl]methyl}sulfanyl)pyrrolo[2,1-f][1 ,2,4]triazin-4-ol (15.9 mg, 13.37% yield, 99.3% purity) as a trifluoroacetate salt and as a white solid. LC / MS: MS (ESI) calcd. for C13H10F2N4OS: 308.05. Found: 309.00 [M+H] +.1H NMR (400 MHz, DMSO-d6) 6 (ppm): 12.13 (s, 1 H), 8.59 - 8.61 (m, 1 H), 8.13 - 8.15 (m, 1 H), 7.56 - 7.59 (m, 1 H), 7.53 - 7.54 (m, 1 H), 7.18 - 7.44 (m, 1 H), 6.84 - 6.86 (m, 1 H), 6.49 - 6.50 (m, 1 H), 4.60 (s, 2H).

[0389] Example 14: Synthesis of 2-{[(2-methoxypyridin-3-yl)methyl]sulfanyl}pyrrolo[2,1-f][1,2,4]triazin- 4-ol

[0390] Step 1. Synthesis of (2-methoxypyridin-3-yl)methanol

[0391] A solution of methyl 2-methoxypyridine-3-carboxylate (500 mg, 2.991 mmol, 1 equiv) in THF (3 mL) was added DIBAL-H (1276.19 mg, 8.973 mmol, 3 equiv) at 0°C.The resulting mixture was stirred at room temperature for 1 h. Desired product could be detected by LCMS. The reaction was quenched with ice water at room temperature. Filtered, the filter cake was washed with ACN (3 x 3 ml). The filtrate was concentrated under reduced pressure to afford (2-methoxypyridin-3-yl)methanol (250 mg) as a yellow oil. The crude product was used in the next step directly without further purification. MS: MS (ESI) calcd. for C7H9NO2:139.06, Found:140.05 [M+H]+. PATENT

[0392] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0393] Step 2. Synthesis of 3-(chloromethyl)-2-methoxypyridine

[0394] SOCI DCM

[0395] To a solution of (2-methoxypyridin-3-yl)methanol (250 mg, 1.797 mmol, 1 equiv) in DCM (3 mL) was added SOCh (641 .16 mg, 5.391 mmol, 3 equiv) at 0°C. The resulting mixture was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The mixture was concentrated under reduced pressure to afford 3- (chloromethyl)-2-methoxypyridine (100 mg) as a yellow oil. The crude product was used in the next step directly without further purification. MS: MS (ESI) calcd. for CyHsCINC 57.03, Found:158.00 [M+H]+.

[0396] Step 3. Synthesis of 2-{[(2-methoxypyridin-3-yl)methyl]sulfanyl}pyrrolo[2,1-f][1 ,2,4]triazin-4-ol

[0397] To a solution of 3-(chloromethyl)-2-methoxypyridine (100 mg, 0.635 mmol, 1 equiv) and 2- sulfanylpyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (106.09 mg, 0.635 mmol, 1 equiv) in DMF (2 mL) was added DIEA (246.03 mg, 1 .905 mmol, 3 equiv). The resulting mixture was stirred at room temperature for 1 h. Desired product could be detected by LCMS. The residue was purified by reversed-phase flash chromatography with the following conditions: (column, C18 silica gel; mobile phase, MeCN in Water (0.1 % TFA), 2% to 50% gradient in 20 min; detector, UV 254 nm) to afford 2-{[(2-methoxypyridin-3- yl)methyl]sulfanyl}pyrrolo[2, 1 -f][1 ,2,4]triazin-4-ol (104.4 mg, 57.06% yield, 99.9% purity) as a trifluoroacetate salt and as a white solid. LC / MS MS: MS (ESI) calcd. for Ci3Hi2N4O2S:288.07, Found: 289.05 [M+H]+.1H NMR (300 MHz, DMSO-c / 6) 6 (ppm):12.04 (m, 1 H), 8.11 - 8.14 (m, 1 H), 7.80 - 7.87 (m, 1 H), 7.65 - 7.68 (m, 1 H), 6.91 - 6.99 (m, 1 H), 6.83 - 6.85 (m, 1 H), 6.45 - 6.52 (m, 1 H), 4.30 (s, 2H), 3.90 (s, 3H).

[0398] Example 15: Synthesis of 2-{[(4-methoxy-2-methylpyridin-3-yl) methyl] sulfanyl}pyrrolo[2,1-f] [1 ,2,4] triazin-4-ol

[0399] Step 1. Synthesis of methyl 4-methoxy-2-methylpyridine-3-carboxylate

[0400] To a solution of methyl 4-chloro-2-methylpyridine-3-carboxylate (200 mg, 1.078 mmol, 1 equiv) in MeOH (2 mL) was added MeONa (69.85 mg, 1.294 mmol, 1.2 equiv). The resulting mixture PATENT

[0401] ATTORNEY-DOCKET NO.: 51478-031 WO3 was stirred at 80 °C for 1 h. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3 x 10mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1 :1) to afford methyl 4-methoxy-2-methylpyridine-3- carboxylate (103 mg, 52.76% yield, 85% purity) as a white oil. MS: MS (ESI) calcd. for C9H11 NO3: 181.07, Found: 182.05 [M+H]+.

[0402] Step 2. Synthesis of (4-methoxy-2-methylpyridin-3-yl) methanol

[0403] To a solution of methyl 4-methoxy-2-methylpyridine-3-carboxylate (103 mg, 0.568 mmol, 1 equiv) in THF (2 mL) was added DIBAL-H (242.54 mg, 1 .704 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The reaction was quenched with ice water at room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc (3x30 mL). The filtrate was extracted with EtOAc (3 x 20mL), dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure to afford (4-methoxy-2- methylpyridin-3-yl) methanol (70 mg) as a white oil. MS: MS (ESI) calcd. for C8H11NO2: 153.08, Found: 154.05 [M+H]+.

[0404] Step 3. Synthesis of 3-(chloromethyl)-4-methoxy-2-methylpyridine

[0405] To a solution of (4-methoxy-2-methylpyridin-3-yl) methanol (70 mg, 0.457 mmol, 1 equiv) in DCM (2 mL) was added SOCI2 (163.09 mg, 1.371 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The mixture was concentrated under reduced pressure to afford crude compound 3-(chloromethyl)-4-methoxy-2-methylpyridine (69 mg) as a yellow oil. MS: MS (ESI) calcd. for C8HioCINO:171.05, Found: 172.05 [M+H]+. PATENT

[0406] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0407] Step 4. Synthesis of 2-{[(4-methoxy-2-methylpyridin-3-yl) methyl] sulfanyl}pyrrolo[2,1-f] [1 ,2,4] triazin-4-ol

[0408] To a solution of (4-methoxy-2-methylpyridin-3-yl) methanol (69 mg, 0.450 mmol, 1 equiv) in DMF(2 mL)was added 2-sulfanylpyrrolo[2,1-f] [1 ,2,4] triazin-4-ol (75.31 mg, 0.450 mmol, 1 equiv), DIEA (174.66 mg, 1 .350 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 2% to 50% gradient in 20 min; detector, UV 254 nm to afford 2-{[(4-methoxy-2-methylpyridin-3-yl) methyl] sulfanyl} pyrrolo[2,1 -f] [1 ,2,4] triazin-4-ol (63.7 mg, 46.10% yield) as a white solid. LC / MS: MS (ESI) calcd. for C14H14N4O2S: 302.08. Found: 302.95 [M+H] +.1H NMR (300 MHz, DMSO-c / 6>) 6 (ppm):12.14 (m, 1 H), 8.60 - 8.71 (m, 1 H), 7.49 - 7.61 (m, 2H), 6.80 - 6.89 (m, 1 H), 6.41 - 6.52 (m, 1 H), 4.49 (s, 2H), 4.07 (s, 3H), 2.71 (s, 3H).

[0409] Example 16: Synthesis of 2-{[(4-cyclopropyl-2-methylpyridin-3-yl)methyl]sulfanyl}pyrrolo[2,1 - f] [1 ,2,4]triazi n-4-ol

[0410] Step 1 Synthesis of methyl 4-cyclopropyl-2-methylpyridine-3-carboxylate

[0411] A solution of methyl 4-chloro-2-methylpyridine-3-carboxylate (300 mg, 1 .616 mmol), cyclopropylboron ic acid (277.68 mg, 3.232 mmol), Pd(OAc)2 (54.43 mg, 0.242 mmol), di(1 - adamantyl)-N-butylphosphine (115.90 mg, 0.323 mmol) and CS2CO3 (1316.55 mg, 4.040 mmol) in dioxane (5 mL) and H2O (1 mL) was stirred at 100 °C for 2 h under N2 atmosphere. The reaction was monitored by LCMS. After completion of reaction, the mixture was poured into ice water. The resulting mixture was extracted with EA (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (4:1) to afford methyl 4-cyclopropyl-2-methylpyridine-3-carboxylate (240 mg, 77.65% yield, 94% purity) as a colorless oil. LC / MS: MS (ESI) calcd. for C11H13NO2: 191.09. Found: 192.10 [M+H] +. PATENT

[0412] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0413] Step 2. Synthesis of (4-cyclopropyl-2-methylpyridin-3-yl)methanol

[0414] To a stirred solution of methyl 4-cyclopropyl-2-methylpyridine-3-carboxylate (240 mg, 1.255 mmol,) in THF (2 mL) was added Diisobutylaluminum hydride(20% in hexanes) (3.92 mL, 3.137 mmol) at 0 °C. The reaction was stirred for 1 h. The reaction was monitored by LCMS. After completion of reaction, the reaction was poured into ice water (20 mL). The resulting mixture was filtered, the filter cake was washed with water. The filtrate was concentrated under reduced pressure. This resulted in (4-cyclopropyl-2-methylpyridin-3-yl)methanol (200 mg) as a white solid. LC / MS: MS (ESI) calcd. for CioH NO: 163.10. Found: 164.20 [M+H] +.

[0415] Step 3. Synthesis of 3-(chloromethyl)-4-cyclopropyl-2-methylpyridine

[0416] To a stirred solution of (4-cyclopropyl-2-methylpyridin-3-yl)methanol (92 mg, 0.564 mmol) in DCM (2 mL) was added SOCI2 (167.63 mg, 1 .410 mmol) at 0 °C. The reaction was stirred for 1 h. The reaction was monitored by TLC. After completion of reaction, the resulting mixture was concentrated under reduced pressure. This resulted in 3-(chloromethyl)-4-cyclopropyl-2- methylpyridine (100 mg) as a yellow solid.

[0417] Step 4. Synthesis of 2-{[(4-cyclopropyl-2-methylpyridin-3-yl)methyl]sulfanyl}pyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0418] To a stirred solution of 3-(chloromethyl)-4-cyclopropyl-2-methylpyridine (100 mg, 0.550 mmol,) and 2-sulfanylpyrrolo[2,1-f][1 ,2,4]triazin-4-ol (92.03 mg, 0.550 mmol) in DMF (3 mL) was added DIEA (213.44 mg, 1 .650 mmol) at 0 °C. The reaction was stirred for 1 h at room temperature. The reaction was monitored by LCMS. After completion of reaction, the mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water (0.05% TFA) in ACN, 10% to 50% gradient in 20 min; detector, UV 254 nm. After PATENT

[0419] ATTORNEY-DOCKET NO.: 51478-031 WO3 lyophilized, it provided 2-{[(4-cyclopropyl-2-methylpyridin-3-yl)methyl]sulfanyl}pyrrolo[2,1 - f][1 ,2,4]triazin-4-ol (99.2 mg, 42.26% yield, 99.9% purity) as a trifluoroacetate salt and as a white solid. LC / MS: MS (ESI) calcd. for CI6HI6N4OS: 312.10. Found: 313.10 [M+H] +.1H NMR (400 MHz, DMSO-d6) 6 (ppm): 12.20 (s, 1 H), 8.49 - 8.51 (m, 1 H),7.57 (s, 1 H), 7.21 - 7.23 (m, 1 H), 6.88 - 6.89 (m, 1 H), 6.52 - 6.54 (m, 1 H), 4.72 (s, 2H), 2.77 (s, 3H), 2.33 - 2.42 (m, 1 H), 1 .25 - 1 .29 (m, 2H), 1 .01 - 1.04 (m, 2H).

[0420] Example 17: Synthesis of 2-{[(4-ethyl-2-methylpyridin-3-yl) methyl] sulfanyl} pyrrolo[2,1 -f]

[0421] [1 ,2,4] triazin-4-ol

[0422] Step 1. Synthesis of methyl 4-ethenyl-2-methylpyridine-3-carboxylate

[0423] To a solution of methyl 4-chloro-2-methylpyridine-3-carboxylate (500 mg, 2.694 mmol, 1 equiv) in dioxane (5 mL) was added 2-ethenyl-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (829.80 mg, 5.388 mmol, 2 equiv), Pd(dppf)Cl2 (197.11 mg, 0.269 mmol, 0.1 equiv), CS2CO3 <1755.40 mg, 5.388 mmol, 2 equiv) and H2O (1 mL) at room temperature. The resulting mixture was stirred at 110 °C for 2 h under nitrogen atmosphere. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The resulting mixture was extracted with EtOAc (3 x 20mL). The combined organic layers were washed with brine (3x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1 :1) to afford methyl 4-ethenyl-2-methylpyridine-3-carboxylate (280 mg, 58.66% yield, 90% purity) as a white solid. MS: MS (ESI) calcd. for CIQHHNO2:177.08, Found: 178.00 [M+H]+.

[0424] Step 2. Synthesis of methyl 4-ethyl-2-methylpyridine-3-carboxylate

[0425] A solution of methyl 4-ethenyl-2-methylpyridine-3-carboxylate (280 mg, 1.580 mmol, 1 equiv), in MeOH (3 mL) was added Pd / C (168.16 mg, 1.580 mmol, 1 equiv). The resulting mixture was stirred at room temperature for 1 h under hydrogen atmosphere. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The resulting mixture was filtered, the filter cake was washed with EtOAc (2x30 mL). The filtrate was concentrated under reduced pressure to afford methyl 4-ethyl-2-methylpyridine-3-carboxylate (200 mg, 70.63% yield, 90% purity) as a white solid. MS: MS (ESI) calcd. for C10H13NO2: 179.09, Found: 180.05 [M+H]+. PATENT

[0426] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0427] Step 3. Synthesis of (4-ethyl-2-methylpyridin-3-yl) methanol

[0428] To a solution of methyl 4-ethyl-2-methylpyridine-3-carboxylate (150 mg, 0.837 mmol, 1 equiv) in THF (2 mL) was added DIBAL-H (357.10 mg, 2.511 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The reaction was quenched with ice water at room temperature. The resulting mixture was filtered, the filter cake was washed with water (2x5 mL). The filtrate was concentrated under reduced pressure to afford (4-ethyl-2-methylpyridin-3-yl) methanol (110 mg) as a white solid. MS: MS (ESI) calcd. for C9HI3NO:151 .10, Found: 152.10 [M+H]+.

[0429] Step 4. Synthesis of 3-(chloromethyl)-4-ethyl-2-methylpyridine

[0430] To a solution of (4-ethyl-2-methylpyridin-3-yl)methanol (110 mg, 0.727 mmol, 1 equiv) in DCM (2 mL) was added SOCh (259.62 mg, 2.181 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The mixture was concentrated under reduced pressure to afford 3- (chloromethyl)-4-ethyl-2-methylpyridine (100 mg) as a yellow oil. LC / MS: MS (ESI) calcd. for C9H12CIN: 169.07. Found: 170.07 [M+H] +.

[0431] Step 5. Synthesis of 2-{[(4-ethyl-2-methylpyridin-3-yl) methyl] sulfanyl} pyrrolo[2,1-f] [1,2,4] triazin-4-ol

[0432] To a solution of 3-(chloromethyl)-4-ethyl-2-methylpyridine (100 mg, 0.766 mmol, 1 equiv) in DMF (2 mL) was added 2-sulfanylpyrrolo[2,1-f] [1 ,2,4] triazin-4-ol (128.11 mg, 0.766 mmol, 1 equiv), DIEA (198.08 mg, 1 .532 mmol, 2 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 2% to PATENT

[0433] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0434] 30% gradient in 20 min; detector, UV 254 nm to afford 2-{[(4-ethyl-2-methylpyridin-3-yl) methyl] sulfanyl} pyrrolo[2, 1 -f] [1 ,2,4] triazin-4-ol (111 .8 mg, 48.57% yield, 99.5% purity) as a trifluoroacetate salt and as a white solid. LC / MS: MS (ESI) calcd. for C15H16N4OS: 300.10. Found: 301.05 [M+H] +.1H NMR (400 MHz, DMSO-c / 6) 6 (ppm):12.20 (s, 1 H), 8.52 - 8.63 (m, 1 H), 7.60 - 7.61 (m, 1 H), 7.50 - 7.51 (m, 1 H), 6.81 - 6.90 (m, 1 H), 6.51 - 6.52 (m, 1 H), 4.58 (s, 2H), 2.98 - 3.00 (m, 2H), 2.76 (s, 3H), 1 .20 - 1.25 (m, 3H).

[0435] Example 18: Synthesis of 2-{[(4-methylpyridin-3-yl) methyl] sulfanyl}pyrrolo[2,1-f][1 ,2,4]triazin- 4-ol

[0436] Step 1. Synthesis of (4-methylpyridin-3-yl) methanol

[0437] To a solution of methyl 4-methylpyridine-3-carboxylate (400 mg, 2.646 mmol, 1 equiv) in THF (4 mL) was added DIBAL-H (1129.01 mg, 7.938 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The reaction was quenched with ice water at room temperature. The resulting mixture was filtered, the filter cake was washed with water (2x5 mL). The filtrate was concentrated under reduced pressure to afford (4- methylpyridin-3-yl) methanol (170 mg) as a white solid. MS: MS (ESI) calcd. for C HgNCLl 23.07, Found: 124.01 [M+H]+.

[0438] Step 2. Synthesis of 3-(chloromethyl)-4-methylpyridine

[0439] To a solution of (4-methylpyridin-3-yl) methanol (170 mg, 1.380 mmol, 1 equiv) in DCM (2 mL) was added SOCI2 (492.63 mg, 4.140 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The mixture was concentrated under reduced pressure to afford 3-(chloromethyl)-4- methylpyridine (150 mg) as a white solid. The crude product was used in the next step directly without further purification. MS: MS (ESI) calcd. for C / HsCIN: 141.03, Found: 142.00 [M+H]+. PATENT

[0440] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0441] Step 3. Synthesis of 2-{[(4-methylpyridin-3-yl) methyl] sulfanyl}pyrrolo[2,1-f][1 ,2,4]triazin-4-ol

[0442] To a solution of 3-(chloromethyl)-4-methylpyridine (100 mg, 0.706 mmol, 1 equiv) and 2- sulfanylpyrrolo[2,1 -f] [1 ,2,4] triazin-4-ol (118.07 mg, 0.706 mmol, 1 equiv) in DMF (2 mL), was added DIEA (273.83 mg, 2.118 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 2% to 30% gradient to afford 2-{[(4-methylpyridin-3-yl) methyl] sulfanyl}pyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (81 .6 mg, 29.91 % yield, 97.7% purity) as a trifluoroacetate salt and as a white solid. LC / MS: MS (ESI) calcd. for C13H12N4OS: 272.07. Found: 273.10 [M+H] +.1H NMR (300 MHz, DMSO-cfe) 6 (ppm):12.13 (s, 1 H), 8.50 - 8.60 (m, 1 H), 8.36 - 8.41 (m, 1 H), 7.50 - 7.77 (m, 2H), 6.81 - 6.83 (m, 1 H), 6.41 - 4.51 (m, 1 H), 4.52 (s, 2H), 2.76 (s, 3H).

[0443] Example 19: Synthesis of 2-{[(2-methylpyridin-3-yl)methyl]sulfanyl}pyrrolo[2,1-f][1 ,2,4]triazin-4- ol

[0444] Step 1. Synthesis of (2-methylpyridin-3-yl)methanol

[0445] To a solution of methyl 2-methylnicotinate (200 mg, 1.323 mmol, 1 equiv) in THF (2 ml) was added DIBAL-H (564.50 mg, 3.969 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. Desired product could be detected by LCMS. The reaction was quenched by the addition of ice water at room temperature. The resulting mixture was filtered, the filter cake was washed with water (2x5 mL). The filtrate was concentrated under reduced pressure to afford (2- methylpyridin-3-yl)methanol (120 mg) as a yellow oil. MS: MS (ESI) calcd. for C / HgNO: 123.07, Found: 124.05 [M+H]+.

[0446] Step 2. Synthesis of 3-(chloromethyl)-2-methylpyridine

[0447] SOCI DCM

[0448] To a solution of (2-methylpyridin-3-yl)methanol (120 mg, 0.974 mmol, 1 equiv) in DCM (2 mL) was added SOCI2 (347.74 mg, 2.922 mmol, 3 equiv) at 0°C. The resulting mixture was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS, and it showed the reaction PATENT

[0449] ATTORNEY-DOCKET NO.: 51478-031 WO3 was completed. The mixture was concentrated under reduced pressure to afford crude compound 3- (chloromethyl)-2-methylpyridine (100 mg) as a yellow oil. MS: MS (ESI) calcd. for C7HsCIN:141 .03, Found:142.05 [M+H]+.

[0450] Step 3. Synthesis of 2-{[(2-methylpyridin-3-yl)methyl]sulfanyl}pyrrolo[2,1-f][1 ,2,4]triazin-4-ol

[0451] To a solution of 3-(chloromethyl)-2-methylpyridine (100 mg, 0.706 mmol, 1 equiv) in DMF (2 mL) was added 2-sulfanylpyrrolo[2,1-f][1 ,2,4]triazin-4-ol (118.07 mg, 0.706 mmol, 1 equiv), DIEA (273.83 mg, 2.118 mmol, 3 equiv). The resulting mixture was stirred at room temperature for 1 h. The residue was purified by reversed-phase flash chromatography with the following conditions: (column, C18 silica gel; mobile phase, MeCN in Water (0.1 % TFA), 2% to 50% gradient in 15 min; detector, UV 254 nm.) to afford 2-{[(2-methylpyridin-3-yl)methyl]sulfanyl}pyrrolo[2,1-f][1 ,2,4]triazin-4-ol (35.4 mg, 12.97% yield, 95.0% purity) as a trifluoroacetate salt and as a yellow oil. LC / MS MS: MS (ESI) calcd. for Ci3Hi2N4OS:272.07, Found: 273.05 [M+H]+.1H NMR (400 MHz, DMSO-c / 6) 6 (ppm):12.18 (s, 1 H), 8.91 (s, 1 H), 8.52 - 8.60 (m, 1 H), 7.71 - 7.75 (m, 1 H), 7.51 - 7.60 (m, 1 H), 6.80 - 6.81 (m, 1 H), 6.49 - 6.51 (m, 1 H), 4.54 (s, 2H). 2.81 (s, 3H).

[0452] Example 20: Synthesis of 2-{[(2,4,6-trimethylpyridin-3-yl)methyl]sulfanyl}pyrrolo[2,1 - f] [1 ,2,4]triazi n-4-ol

[0453] Step 1. Synthesis of ethyl 2,4,6-trimethylpyridine-3-carboxylate

[0454] To a solution of ethyl 4,6-dichloro-2-methylpyridine-3-carboxylate (500 mg, 2.136 mmol, 1 equiv) in dioxane (5 mL) was added trimethyl-1 ,3,5,2,4,6-trioxatriborinane (536.27 mg, 4.272 mmol, 2 equiv), Pd(dppf)Cl2 (156.29 mg, 0.214 mmol, 0.1 equiv), CS2CO3 (1391.91 mg, 4.272 mmol, 2 equiv) and H2O (1 mL). The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The resulting mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (3x50mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 :1) to PATENT

[0455] ATTORNEY-DOCKET NO.: 51478-031 WO3 afford ethyl 2,4,6-trimethylpyridine-3-carboxylate (300 mg, 72.68% yield) as a white solid. MS: MS (ESI) calcd. for CiiHi5N02:193.11 , Found:194.10 [M+H]+.

[0456] Step 2. Synthesis of (2,4,6-trimethylpyridin-3-yl) methanol

[0457] To a solution of ethyl 2,4,6-trimethylpyridine-3-carboxylate (300 mg, 1.552 mmol, 1 equiv) in THF (3 mL) was added DIBAL-H (662.37 mg, 4.656 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The reaction was quenched with cooling water at 0 °C, filtered, the filter cake was washed with ACN (3 x 3 ml). The filtrate was concentrated under reduced pressure to afford (2,4,6-trimethylpyridin-3-yl) methanol (150mg) as a yellow oil. The crude product was used in the next step directly without further purification. MS: MS (ESI) calcd. for C&HnNO : 151.10, Found:152.10 [M+H]+.

[0458] Step 3. Synthesis of 3-(chloromethyl)-2,4,6-trimethylpyridine

[0459] To a solution of (2,4,6-trimethylpyridin-3-yl) methanol (150 mg, 0.992 mmol, 1 equiv) in DCM (3 mL) was added SOCh (354.03 mg, 2.976 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The mixture was concentrated under reduced pressure to afford 3-(chloro- methyl)-2,4,6-trimethylpyridine (150 mg) as a yellow oil. The crude product was used in the next step directly without further purification. MS: MS (ESI) calcd. for CgHi2CIN:169.07, Found: 170.05 [M+H]+.

[0460] Step 4. Synthesis of 2-{[(2,4,6-trimethylpyridin-3-yl)methyl]sulfanyl}pyrrolo[2,1 -f][1 ,2,4]triazin-

[0461] 4-ol

[0462] To a solution of 3-(chloromethyl)-2,4,6-trimethylpyridine (150 mg, 0.884 mmol, 1 equiv) and 2- sulfanylpyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (147.82 mg, 0.884 mmol, 1 equiv) in DMF (3 mL) was added DIEA (342.83 mg, 2.652 mmol, 3 equiv). The resulting mixture was stirred at room temperature for 1 h. The residue was purified by reversed-phase flash chromatography with the following conditions: PATENT

[0463] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0464] (column, C18 silica gel; mobile phase, MeCN in Water (0.1 % TFA), 2% to 50% gradient in 20 min; detector, UV 254 nm) to afford 2-{[(2,4,6-trimethylpyridin-3-yl)methyl]sulfanyl}pyrrolo[2,1-f][1 ,2,4]- triazin-4-ol (166.3 mg, 45.39% yield, 99.5% purity) as a trifluoroacetate salt and as a white solid.

[0465] LC / MS: MS (ESI) calcd. for Ci3HioF3N5OS:300.10. Found:301.05 [M+H] +.1H NMR (300 MHz, DMSO-C / 6) 6 (ppm):12.18 (s, 1 H), 7.50 - 7.60 (m, 2H), 6.85 - 6.90 (m, 1 H), 6.50 - 6.52 (m, 1 H), 4.55 (s, 2H), 2.74 (s, 3H), 2.49 - 2.51 (m, 6H).

[0466] Example 21 : Synthesis of 2-{[(2-cyclopropyl-4-methylpyridin-3-yl)methyl]sulfanyl}pyrrolo[2,1 - f] [1 ,2,4]triazi n-4-ol

[0467] Step 1. Synthesis of ethyl 2-cyclopropyl-4-methylpyridine-3-carboxylate

[0468] A solution of ethyl 2-bromo-4-methylpyridine-3-carboxylate (200 mg, 0.819 mmol), cyclopropylboron ic acid (140.77 mg, 1.638 mmol), Pd(OAc)2 (27.59 mg, 0.123 mmol), di(1 - adamantyl)-N-butylphosphine (58.76 mg, 0.164 mmol) and CS2CO3(667.42 mg, 2.047 mmol) in dioxane (5 mL) and H2O (1 mL) was stirred at 110 °C for 2 h under N2 atmosphere. The reaction was monitored by LCMS. After completion of reaction, the reaction was poured into water (30 mL). The resulting mixture was extracted with EA (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (5:1) to afford ethyl 2-cyclopropyl-4-methylpyridine-3-carboxylate (90 mg, 53.51 % yield, 94% purity) as a colorless oil. LC / MS: MS (ESI) calcd. for C12H15NO2: 205.11 . Found: 206.10 [M+H] +.

[0469] Step 2. Synthesis of (2-cyclopropyl-4-methylpyridin-3-yl)methanol

[0470] To a stirred solution of ethyl 2-cyclopropyl-4-methylpyridine-3-carboxylate (95 mg, 0.463 mmol) in THF (0.5 mL) was added Diisobutylaluminum hydride (20% in hexanes) (0.78 mL) at 0 °C. The reaction was stirred for 1 h. The reaction was monitored by TLC and LCMS. After completion of reaction, the reaction was poured into water (20 mL). The resulting mixture was filtered, the filter cake was washed with water. The filtrate was extracted with EA (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in (2-cyclopropyl-4-methylpyridin-3-yl)methanol (64 mg) as a yellow solid. LC / MS: MS (ESI) calcd. for CioH NO: 163.10. Found: 164.20 [M+H] +. PATENT

[0471] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0472] Step 3. Synthesis of 3-(chloromethyl)-2-cyclopropyl-4-methylpyridine

[0473] To a stirred solution of (2-cyclopropyl-4-methylpyridin-3-yl)methanol (64 mg, 0.392 mmol) in DCM (1 .5 mL) was added SOCI2 (116.61 mg, 0.980 mmol) at 0 °C. The reaction was stirred for 1 h. The reaction was monitored by TLC. After completion of reaction, the resulting mixture was concentrated under reduced pressure. This resulted in 3-(chloromethyl)-2-cyclopropyl-4- methylpyridine (65 mg) as a yellow solid.

[0474] Step 4. Synthesis of 2-{[(2-cyclopropyl-4-methylpyridin-3-yl)methyl]sulfanyl}pyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0475] To a stirred solution of 3-(chloromethyl)-2-cyclopropyl-4-methylpyridine (65 mg, 0.358 mmol) and 2-sulfanylpyrrolo[2, 1 -f][1 ,2,4]triazin-4-ol (59.82 mg, 0.358 mmol) in DMF (2 mL) was added DIEA (138.74 mg, 1 .074 mmol) at 0 °C. The reaction was stirred at 25 °C for 1 h. The reaction was monitored by LCMS. After completion of reaction, the mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water (0.05% TFA) in ACN, 10% to 50% gradient in 15 min; detector, UV 254 nm. After lyophilized, it provided 2- {[(2-cyclopropyl-4-methylpyridin-3-yl)methyl]sulfanyl}pyrrolo[2,1-f][1 ,2,4]triazin-4-ol (61 .8 mg, 40.50% yield, 99.7% purity) as a trifluoroacetate salt and as a white solid. LC / MS: MS (ESI) calcd. for C16H16N4OS: 312.10. Found: 313.10 [M+H] +.1H NMR (400 MHz, DMSO-d6) 6 (ppm): 12.18 (s, 1 H), 8.32 - 8.34 (m, 1 H),7.57 - 7.58 (m, 1 H), 7.32 (s, 1 H), 6.87 - 6.89 (m, 1 H), 6.51 - 6.53 (m, 1 H), 4.67 (s, 2H), 2.68 (s, 3H), 2.41 - 2.46 (m, 1 H), 1 .05 - 1 .06 (m, 4H).

[0476] PATENT

[0477] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0478] Example 22: Synthesis of 2-{[(4-methoxypyridazin-3-yl)methyl]sulfanyl}pyrrolo[2,1- f][1 ,2,4]triazin-4-ol

[0479] Step 1. Synthesis of (4-methoxypyridazin-3-yl)methanol

[0480] To a stirred solution of 3-chloro-4-methoxypyridazine (300 mg, 2.075 mmol, 1 equiv) and (tributylstannyl)methanol (1332.70 mg, 4.150 mmol, 2 equiv) in THF (5 mL) was added XPhos Pd G2 (163.29 mg, 0.208 mmol, 0.1 equiv) in portions at 25 °C under N2 atmosphere. The resulting mixture was stirred at 130 °C for an additional 2 h. Desired product could be detected by LCMS. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.05 % NH4HCO3), 2 % to 50 % gradient in 20 min; detector, UV 254 nm to afford (4-methoxypyridazin-3-yl)methanol (90 mg, 30.95 % yield, 93 % purity) as a yellow solid.

[0481] LC / MS: mass calcd for C6H8N2O2, 140.06 m / z, found 141.05 [M+H]+.

[0482] Step 2. Synthesis of (3-(chloromethyl)-4-methoxypyridazine

[0483] A solution of (4-methoxypyridazin-3-yl)methanol (90 mg, 0.642 mmol, 1 equiv) in DCM (2 mL) was added SOCh (190.99 mg, 1.605 mmol, 2.5 equiv) dropwise at 0 °C. After stirring for 2 h at room temperature. TLC showed the starting material was consumed completely. The filtrate was concentrated under reduced pressure. After concentrated to afford the crude product (3-(chloro- methyl)-4-methoxypyridazine (80 mg)), The crude product was used in the next step directly without further purification.

[0484] Step 3. Synthesis of 2-{[(4-methoxypyridazin-3-yl)methyl]sulfanyl}pyrrolo[2,1-f][1,2,4]triazin-4- ol

[0485] To a stirred solution of 3-(chloromethyl)-4-methoxypyridazine (80 mg, 0.504 mmol, 1 equiv) and 2-sulfanylpyrrolo[2,1-f][1 ,2,4]triazin-4-ol (101.21 mg, 0.605 mmol, 1.2 equiv) in DMF (2 mL) was added DIEA (112.60 mg, 0.870 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred for PATENT

[0486] ATTORNEY-DOCKET NO.: 51478-031 WO3 an additional 1 h at room temperature. LCMS showed the reaction was completed. The mixture was acidified to pH 5 ~ 6 with 3M TFA. The precipitated solids were collected by filtration and washed with water (5 mL). The resulting mixture was concentrated under reduced pressure to afford 2-{[(4- methoxypyridazin-3-yl)methyl]sulfanyl}pyrrolo[2,1-f][1 ,2,4]triazin-4-ol (87.2 mg, 59.75 % yield, 99.9 % purity) as a white solid. LC / MS: mass calcd for C12H11 N5O2S: 289.06, found: 290.05[M+H]+.1H NMR (300 MHz, DMSO-de) 6: 12.15 (s, 1 H), 8.98 - 9.00 (m, 1 H), 7.53 - 7.55 (m, 1 H), 7.30 - 7.32 (m, 1 H), 6.85 - 6.87 (m, 1 H), 6.48 - 6.51 (m, 1 H), 4.66 (s, 2H), 3.94 (s, 3H).

[0487] Example 23: Synthesis of 2-{[(6-methoxypyridazin-3-yl)methyl]sulfanyl}pyrrolo[2,1-f][1,2,4]- triazin-4-ol

[0488] Step 1. Synthesis of (6-methoxypyridazin-3-yl)methanol

[0489] To a stirred solution of ethyl 6-methoxypyridazine-3-carboxylate (500 mg, 2.745 mmol, 1 equiv) in THF (2 mL) was added Diisobutylaluminum hydride(20% in hexanes) (975.84 mg, 6.863 mmol, 2.5 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was quenched by the addition of ice water (2 mL) at 0 °C. The resulting mixture was filtered, the filter cake was washed with water (3x3 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford (6- methoxypyridazin-3-yl)methanol (350 mg, 91 .00% yield ) as a yellow oil. LC / MS: mass calcd for C6H8N2O2, 140.06, found: 141.00 [M+H]+.

[0490] Step 2. Synthesis of 3-chloro-6-methoxypyridazine

[0491] To a stirred solution of (6-methoxypyridazin-3-yl)methanol (272 mg, 1.941 mmol, 1 equiv) in DCM (3 mL) was added SOCI2 (461 .78 mg, 3.882 mmol, 2 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was washed with 3x3 mL of DCM (3 mL). The resulting mixture was concentrated under reduced pressure. The crude product mixture was used in the next step directly without further purification. LC / MS: mass calcd for C6H7CIN2O, 158.02, found: 158.95 [M+H]+. PATENT

[0492] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0493] Step 3. Synthesis of 2-{[(6-methoxypyridazin-3-yl)methyl]sulfanyl}pyrrolo[2,1 -f][1 ,2,4]triazin-4- ol

[0494] To a stirred solution of 3-chloro-6-methoxypyridazine (100 mg, 0.692 mmol, 1 equiv) and 2- sulfanylpyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (173.48 mg, 1 .038 mmol, 1.5 equiv) in DMF (2 mL) was added DIEA (268.22 mg, 2.076 mmol, 3 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.05% TFA), 10% to 50% gradient in 20 min; detector, UV 254 nm to afford 2- {[(6-methoxypyridazin-3-yl)methyl]sulfanyl}pyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (90.0 mg, 32.26% yield ) as a trifluoroacetate salt and as an off-white solid. LC / MS: mass calcd for C12H11N5O2S, 289.06, found: 289.95 [M+H]+. 1 H NMR (300 MHz, DMSO-c / 6) 6 12.14 (s, 1 H), 7.80 (m, 1 H), 7.55 (m, 1 H), 7.22 (m, 1 H), 6.86 (m, 1 H), 6.49 (m, 1 H), 4.61 (s, 2H), 4.01 (s, 3H).

[0495] Example 24: Synthesis of 2-{[(6-methoxy-4-methylpyridazin-3-yl)methyl]sulfanyl}pyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0496] _Step 1. Synthesis of (6-methoxy-4-methylpyridazin-3-yl)methanol

[0497] A solution of (6-chloro-4-methylpyridazin-3-yl)methanol (100.1 mg, 0.631 mmol, 1 equiv) and MeONa (85.3 mg, 1 .579 mmol, 2.50 equiv) in methanol (3 mL) was stirred at 80°C for 1 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1x60 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in (6-methoxy-4-methylpyridazin-3-yl)methanol (120 mg, 50% purity) as a brown oil. LC / MS: MS (ESI) calcd. for C7H10N2O2: 154.07. Found: 155.15 [M+H] +.

[0498] Step 2. Synthesis of 3-(chloromethyl)-6-methoxy-4-methylpyridazine

[0499] A solution of (6-methoxy-4-methylpyridazin-3-yl)methanol (120 mg, 0.389 mmol, 1 equiv, 50%) in DCM (3.00 mL) was added SOCI2 (1 16.67 mg, 0.980 mmol, 2.52 equiv) dropwise at room temperature for 10 mins under nitrogen atmosphere. The reaction was monitored by LCMS. The PATENT

[0500] ATTORNEY-DOCKET NO.: 51478-031 WO3 resulting mixture was concentrated under reduced pressure. The residue was dissolved in DCM (6 mL). The resulting mixture was concentrated under reduced pressure. This resulted in 3-(chloro- methyl)-6-methoxy-4-methylpyridazine (140 mg, 45% purity) as a brown oil. LC / MS: MS (ESI) calcd. for C7H9CIN2O: 172.04. Found: 173.10 [M+H] +.

[0501] Step 3. Synthesis of 2-{[(6-methoxy-4-methylpyridazin-3-yl)methyl]sulfanyl}pyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0502] A solution of 3-(chloromethyl)-6-methoxy-4-methylpyridazine (120.1 mg, 0.313 mmol, 1 equiv, 45%) in DMF (3 mL) was treated with 2-sulfanylpyrrolo[2,1-f][1 ,2,4]triazin-4-ol (52.4 mg, 0.313 mmol, 1 .00 equiv) at 0°C for 1 min under nitrogen atmosphere followed by the addition of DIEA (101 .6 mg, 0.786 mmol, 2.51 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for 10 mins under nitrogen atmosphere. The reaction was monitored by LCMS. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1 % TFA), 20% to 40% gradient in 15 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This resulted in 2-{[(6-methoxy-4-methyl- pyridazin-3-yl)methyl]sulfanyl}pyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (12.5 mg, 9.57% yield, 97.0% purity) as a trifluoroacetate salt and a white solid. LC / MS: MS (ESI) calcd. for C13H13N5O2S: 303.08. Found: 304.00 [M+H] +.1H NMR (400 MHz, DMSO-d6) 6 (ppm) 12.16 (s, 1 H), 7.62 - 7.51 (m, 1 H), 7.11 (s, 1 H), 6.94 - 6.82 (m, 1 H), 6.54 - 6.47 (m, 1 H), 4.65 (s, 2H), 3.98 (s, 3H), 2.39 (s, 3H).

[0503] Example 25: Synthesis of 2-{[(4,6-dimethoxypyridazin-3-yl)methyl]sulfanyl}pyrrolo[2,1 -f][1 ,2,4]- triazin-4-ol

[0504] Step 1 Synthesis of methyl 4,6-dimethoxypyridazine-3-carboxylate

[0505] To a stirred solution of methyl 4,6-dichloropyridazine-3-carboxylate (1 g, 4.831 mmol, 1 equiv) in MeOH (10 mL) was added MeONa (0.52 g, 9.662 mmol, 2 equiv) in portions at 0°C.The resulting mixture was stirred at 80°C for an additional 1 h. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (2 x 300mL). The combined organic layers were washed with water (1x200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 :1) to PATENT

[0506] ATTORNEY-DOCKET NO.: 51478-031 WO3 afford methyl 4,6-dimethoxypyridazine-3-carboxylate (600 mg, 62.67% yield, 92% purity) as a white solid. LC / MS: MS (ESI) calcd. for C8H10N2O4: 198.06, Found: 199.05 [M+H]+.

[0507] Step 2. Synthesis of (4,6-dimethoxypyridazin-3-yl)methanol

[0508] To a stirred solution of methyl 4,6-dimethoxypyridazine-3-carboxylate (150 mg, 0.757 mmol, 1 equiv) and THF (1 mL) in MeOH (1 mL) was added NaBF (37.22 mg, 0.984 mmol, 1.3 equiv) in portions at 0°C. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was monitored by LCMS. The reaction was quenched with ice water at room temperature. The aqueous layer was extracted with EtOAc (2x50 mL). The residue was purified by silica gel column chromatography, eluted with PE I EA (1 :1) to afford (4,6-dimethoxypyridazin-3-yl)methanol (70 mg, 54.35% yield, 92% purity) as a colorless oil. LC / MS: MS (ESI) calcd. for C7H10N2O3: 170.07, Found: 171 .10 [M+H]+.

[0509] Step 3. Synthesis of 3-(chloromethyl)-4,6-dimethoxypyridazine

[0510] To a stirred solution of (4,6-dimethoxypyridazin-3-yl)methanol (70 mg, 0.411 mmol, 1 equiv) in DCM (1 mL) was added SOCI2 (146.81 mg, 1.233 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for an additional 0.5h. The reaction was monitored by TLC. The resulting mixture was concentrated under reduced pressure to afford 3-(chloromethyl)-4,6- dimethoxy-pyridazine (60 mg) as a yellow solid. The crude product was used in the next step directly without further purification.

[0511] Step 4. Synthesis of 2-{[(4,6-dimethoxypyridazin-3-yl)methyl]sulfanyl}pyrrolo[2,1- f][1 ,2,4]triazin-4-ol

[0512] To a stirred solution of 3-(chloromethyl)-4,6-dimethoxypyridazine (60 mg, 0.318 mmol, 1 equiv) and 2-sulfanylpyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (53.19 mg, 0.318 mmol, 1 equiv) in DMF (2 mL) was added DIEA (123.35 mg, 0.954 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred PATENT

[0513] ATTORNEY-DOCKET NO.: 51478-031 WO3 at room temperature for an additional 1 h. The reaction was monitored by LCMS. The residue was purified by trituration with ACN (20mL). The precipitated solids were collected by filtration and washed with ACN (3x3 mL). This resulted in 2-{[(4,6-dimethoxypyridazin-3-yl)methyl]sulfanyl}pyrrolo[2,1-f]- [1 ,2,4]triazin-4-ol (98.2 mg, 96.67% yield, 97.6% purity) as a white solid. LC / MS: MS (ESI) calcd. for C13H13N5O3S: 319.07. Found: 320.05 [M+H] +.1H NMR (300 MHz, DMSO-d6) 6 (ppm): 12.13 (s, 1 H), 7.52- 7.59 (m, 1 H), 6.86 - 6.94 (m, 1 H), 6.79 (s, 1 H), 6.45 - 6.52 (m, 1 H), 4.55 (s, 2H), 3.99 (s, 3H), 3.91 (s, 3H).

[0514] Example 26: Synthesis of 2-({[6-(2H3)methoxy-4-methylpyridazin-3-yl]methyl}sulfanyl)- pyrrolo[2,1 -f] [1 ,2,4]triazin-4-ol

[0515] Step 1. Synthesis of (6-chloro-4-methylpyridazin-3-yl)methanol

[0516] A solution of methyl 6-chloro-4-methylpyridazine-3-carboxylate (900 mg, 4.823 mmol, 1 equiv) in THF (5 mL) and methanol (5 mL) was treated at 0 °C for 10 min under nitrogen atmosphere followed by the addition of NaBH4 (456.2 mg, 12.059 mmol, 2.50 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for 15 min under nitrogen atmosphere. The reaction was quenched with water at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 :1) to afford (6- chloro-4-methylpyridazin-3-yl)methanol (490 mg, 64.06 % yield, 75 % purity) as a white solid. LC / MS: MS (ESI) calcd. for C6H7CIN2O: 158.02. Found: 159.20 [M+H]+.

[0517] Step 2. Synthesis of [6-(2H3)methoxy-4-methylpyridazin-3-yl]methanol

[0518] To a stirred mixture of (6-chloro-4-methylpyridazin-3-yl)methanol (200.1 mg, 1.262 mmol, 1 equiv), Methanol-d (227.99 mg, 6.323 mmol, 5.01 equiv) and K3PO4 (669.56 mg, 3.155 mmol, 2.50 equiv) in dioxane (5.32 mL) were added FBuBrettPhos Pd G3 (161 .71 mg, 0.189 mmol, 0.15 equiv) and FBuBrettPhos (135.46 mg, 0.252 mmol, 0.20 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 15 min under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1 % TFA), 30 % to 50 % gradient in 20 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This resulted in [6-(2H3)methoxy-4- methylpyridazin-3-yl]methanol (1 10 mg, 55.46 % yield, 90 % purity) as a white solid. LC / MS: MS (ESI) calcd. for C7H7D3N2O2: 157.09. Found: 158.20 [M+H]+. PATENT

[0519] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0520] Step 3. Synthesis of 3-(chloromethyl)-6-(2H3)methoxy-4-methylpyridazine

[0521] To a stirred solution of [6-(2H3)methoxy-4-methylpyridazin-3-yl]methanol (100.1 mg, 0.637 mmol, 1 equiv) in DCM (5 mL) was added SOCI2 (189.39 mg, 1 .593 mmol, 2.50 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS indicating the reaction was completed. Quenched the reaction with cooled water, then extracted with EA (20 ml x 3), the obtained organic layer was collected, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (10:1) to afford 3-(chloromethyl)-6-(2H3)methoxy-4-methylpyridazine (110 mg, 98.35% yield, 70% purity) as a brown oil. LC / MS: MS (ESI) calcd. for C7H6D3CIN2O: 175.06. Found: 176.10 [M+H]+.

[0522] Step 4. Synthesis of 2-({[6-(2H3)methoxy-4-methylpyridazin-3-yl]methyl}sulfanyl)pyrrolo[2,1 - f] [1 ,2,4]triazi n-4-ol

[0523] A solution of 3-(chloromethyl)-6-(2H3)methoxy-4-methylpyridazine (110.1 mg, 0.439 mmol, 1 equiv, 70%) in DMF (3 mL) was treated with 2-sulfanylpyrrolo[2,1-f][1 ,2,4]triazin-4-ol (73.4 mg, 0.439 mmol, 1 .00 equiv) at 0 °C for 5 min under nitrogen atmosphere followed by the addition of DIEA (141 .8 mg, 1 .097 mmol, 2.50 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1 % TFA), 10% to 50% gradient in 15 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This resulted in 2-({[6-(2H3)methoxy-4-methylpyridazin-3-yl]- methyl}sulfanyl)pyrrolo[2,1-f][1 ,2,4]triazin-4-ol (35.8 mg, 26.63 % yield, 99.421 % purity) as a white solid. LC / MS: MS (ESI) calcd. for Ci3HioD3N502S:306.10. Found: 307.05 [M+H]+.1H NMR (400 MHz, DMSO) 6 12.17 (s, 1 H), 7.57 - 7.51 (m, 1 H), 7.11 (s, 1 H), 6.90 - 6.84 (m, 1 H), 6.53 - 6.47 (m, 1 H), 4.65 (s, 2H), 2.39 (s, 3H). PATENT

[0524] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0525] Example 27: Synthesis of 2-{[(4-cyclopropyl-6-methoxypyridazin-3-yl)methyl]sulfanyl}- pyrrolo[2,1 -f] [1 ,2,4]triazin-4-ol

[0526] Step 1. Synthesis of 3-chloro-4-cyclopropyl-6-methoxypyridazine

[0527] To the solution of 3,6-dichloro-4-cyclopropylpyridazine (1 g, 5.290 mmol, 1 equiv) in MeOH (10 mL) was added MeONa (0.86 g, 15.870 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred at 80 °C for 1 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (5 x40 mL). The combined organic layers were washed with brine (5x40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 :1) to afford 3- chloro-4-cyclopropyl-6-methoxypyridazine (and its isomer 6-chloro-4-cyclopropyl-3-methoxy- pyridazine) (800 mg, 81 .92% yield, 85% purity) as a white solid. MS: MS (ESI) calcd. for C8H9CIN2O: 184.04, Found: 185.05 [M+H]+.

[0528] Step 2. Synthesis of 4-cyclopropyl-3-ethenyl-6-methoxypyridazine

[0529] To a solution of 3-chloro-4-cyclopropyl-6-methoxypyridazine (and its isomer 6-chloro-4- cyclopropyl-3-methoxypyridazine) (800 mg, 4.333 mmol, 1 equiv) in dioxane (5 mL) was added 2- ethenyl-4,4,5-trimethyl-1 ,3,2-dioxaborolane (909.91 mg, 6.500 mmol, 1.5 equiv), Pd(dppf)Cl2 (317.07 mg, 0.433 mmol, 0.1 equiv), K2CO3 (1197.75 mg, 8.666 mmol, 2 equiv) and H2O (1 mL). The resulting mixture was stirred at 90 °C for 2 h under nitrogen atmosphere. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The resulting mixture was extracted with EtOAc (3 x 40mL). The combined organic layers were washed with brine (3x40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1 :1) to afford 4-cyclopropyl-3- ethenyl-6-methoxypyridazine (and its isomer 4-cyclopropyl-3-methoxy-6-vinylpyridazine) (500 mg, 65.48% yield, 85% purity) as a white solid. MS: MS (ESI) calcd. for C10H12N2O: 176.09, Found: 176.95 [M+H]+. PATENT

[0530] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0531] Step 3. Synthesis of 4-cyclopropyl-6-methoxypyridazine-3-carbaldehyde

[0532] To a stirred solution of 4-cyclopropyl-3-ethenyl-6-methoxypyridazine (and its isomer 4- cyclopropyl-3-methoxy-6-vinylpyridazine) (500 mg, 2.837 mmol, 1 equiv) and Potassium osmate(VI) dihydrate (104.54 mg, 0.284 mmol, 0.1 equiv) in ACN (5 ml) were added NalO4(1517.22 mg, 7.093 mmol, 2.5 equiv) and H2O (3 mL, 2.837 mmol, 1 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The resulting mixture was extracted with EtOAc (2 x 100mL). The combined organic layers were washed with brine (1x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 :1) to afford 4-cyclopropyl-6- methoxypyridazine-3-carbaldehyde (and its isomer 5-cyclopropyl-6-methoxypyridazine-3- carbaldehyde) (240 mg, 47.47% yield, 90% purity) as a white solid. MS: MS (ESI) calcd. for C9Hi2N2O2:178.07, Found: 179.05 [M+H]+.

[0533] Step 4. Synthesis of (4-cyclopropyl-6-methoxypyridazin-3-yl) methanol

[0534] To a solution of 4-cyclopropyl-6-methoxypyridazine-3-carbaldehyde (and its isomer 5- cyclopropyl-6-methoxypyridazine-3-carbaldehyde) (240 mg, 1.347 mmol, 1 equiv) in THF (3 mL) was added NaBH4(76.43 mg, 2.021 mmol, 1 .5 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The reaction was quenched with MeOH at room temperature. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water(10 mmol / L NH4HCO4), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 2% B to 20 % B in 11 min; Wave Length: 254nm / 220nm nm; RT1 (min): 10.35) to afford (4-cyclopropyl-6-methoxypyridazin-3-yl) methanol (60 mg, 24.72% yield, 90% purity) as a white solid. MS: MS (ESI) calcd. for CgHi2N2O2:180.09, Found: 181.10 [M+H]+. PATENT

[0535] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0536] Step 5. Synthesis of 3-(chloromethyl)-4-cyclopropyl-6-methoxypyridazine

[0537] To a solution of (4-cyclopropyl-6-methoxypyridazin-3-yl)methanol (60 mg, 0.333 mmol, 1 equiv) in DCM (2 mL) was added SOCI2 (118.82 mg, 0.999 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The mixture was concentrated under reduced pressure to afford 3-(chloro-methyl)-4-cyclopropyl-6-methoxypyridazine (60 mg) as a yellow oil. The crude product was used for the next step. MS (ESI) calcd. for C9H11CIN2O: 196.06. Found: 197.05 [M+H]+.

[0538] Step 6. Synthesis of 2-{[(4-cyclopropyl-6-methoxypyridazin-3-yl)methyl]sulfanyl}pyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0539] To a solution of 3-(chloromethyl)-4-cyclopropyl-6-methoxypyridazine (60 mg, 0.302 mmol, 1 equiv) in DMF (2 mL) was added 2-sulfanylpyrrolo[2,1-f][1 ,2,4]triazin-4-ol (50.50 mg, 0.302 mmol, 1 equiv), DIEA (117.11 mg, 0.906 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The residue was purified by reversed-phase flash chromatography with the following conditions:( column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 2% to 50% gradient in 20 min; detector, UV 254 nm) to afford 2-{[(4-cyclopropyl-6-methoxypyridazin- 3-yl)methyl]-sulfanyl}pyrrolo[2,1-f][1 ,2,4]triazin-4-ol (10.7 mg, 10.76% yield, 95.3% purity) as a trifluoroacetate salt and as an off-white solid. LC / MS: MS (ESI) calcd. for C14H14N4O2S: 329.09. Found: 330.00 [M+H]+.1H NMR (300 MHz, DMSO-c / 6>) 6 (ppm):12.14 (s, 1 H), 7.49 - 7.61 (m, 1 H), 6.80 - 6.89 (m, 1 H), 6.70 - 6.79 (m, 1 H), 6.41 - 6.51 (m, 1 H), 4.80 (s, 2H), 3.96 (s, 3H). 2.05 - 2.21(m, 1 H), 1.05 - 1.13 (m, 2H), 0.81 - 0.91 (m, 2H). PATENT

[0540] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0541] Example 28: Synthesis of 2-(((5-methoxy-3-methylpyridazin-4-yl)methyl)thio)pyrrolo[2,1 -f]- [1 ,2,4]triazin-4-ol

[0542] Step 1 . Synthesis of 4-(hydroxymethyl)-5-methoxy-2-(oxan-2-yl)pyridazin-3-one

[0543] To a stirred solution of 4-chloro-5-methoxy-2-(oxan-2-yl)pyridazin-3-one (1.1 g, 4.496 mmol, 1 equiv) and (Tributylstannyl)methanol (4.33 g, 13.488 mmol, 3 equiv) and XPhos Pd G2 (0.53 g, 0.674 mmol, 0.15 equiv) in dioxane (10 mL) was at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 130 °C for 2 h under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1 :1) to afford 4-(hydroxymethyl)-5-methoxy-2-(oxan-2-yl)pyridazin-3-one (570 mg, 52.77% yield ) as a yellow oil. LC / MS: MS (ESI) calcd. for CnHi6N2O4:240.1 1 . Found: 241.00 [M+H]+.

[0544] Step 2. Synthesis of [5-methoxy-2-(oxan-2-yl)-3-oxopyridazin-4-yl]methyl acetate

[0545] To a stirred solution of 4-(hydroxymethyl)-5-methoxy-2-(oxan-2-yl)pyridazin-3-one (570 mg, 2.372 mmol, 1 equiv) and EtsN (720.22 mg, 7.116 mmol, 3 equiv) in DCM (5 mL) was added acetyl chloride (279.35 mg, 3.558 mmol, 1 .5 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 0.5 h under nitrogen atmosphere. The reaction was quenched with ice water at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1 :1) to afford [5-methoxy-2-(oxan-2-yl)-3-oxopyridazin-4-yl]methyl acetate (420 mg, 62.71 % yield ) as a yellow oil. LC / MS: mass calcd for Ci3HiaN2O5:282.12, found: 283.00[M+H]+.

[0546] Step 3. Synthesis of (3-chloro-5-methoxypyridazin-4-yl)methyl acetate

[0547] To a stirred solution of [5-methoxy-2-(oxan-2-yl)-3-oxopyridazin-4-yl]methyl acetate (414 mg, 1 .467 mmol, 1 equiv) in phosphoryl trichloride (4 mL) was at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 1 h under nitrogen atmosphere. The reaction was quenched PATENT

[0548] ATTORNEY-DOCKET NO.: 51478-031 WO3 by the addition of ice water ( 10 mL) at 0 °C. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1 % NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford (3-chloro-5-methoxy- pyridazin-4-yl)methyl acetate (220 mg, 69.25% yield ) as a white solid. LC / MS: mass calcd for C8H9CIN2O3: 216.03, found: 217.15[M+ H]+.

[0549] Step 4. Synthesis of (5-methoxy-3-methylpyridazin-4-yl)methanol

[0550] To a stirred solution of (3-chloro-5-methoxypyridazin-4-yl)methyl acetate (167 mg, 0.771 mmol, 1 equiv), methylboronic acid (184.59 mg, 3.084 mmol, 4 equiv), Pd(PPti3)4 (178.18 mg, 0.154 mmol, 0.2 equiv) and Na2COs (204.27 mg, 1.927 mmol, 2.5 equiv) in Dioxane (1.8 mL) and H2O (0.2 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110 °C for 2 h under nitrogen atmosphere. The reaction was quenched with ice water at 0 °C. The resulting mixture was filtered, the filter cake was washed with DCM (3x5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.05 % NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford (5-methoxy-3-methylpyridazin-4-yl)methanol (97 mg, 81 .61 % yield ) as a white solid. LC / MS: MS (ESI) calcd. For C7H10N2O2: 154.07. Found: 155.05 [M+H]+.

[0551] Step 5. Synthesis of 4-(chloromethyl)-5-methoxy-3-methylpyridazine

[0552] To a stirred solution of (5-methoxy-3-methylpyridazin-4-yl)methanol (90 mg, 0.584 mmol, 1 equiv) in DCM (2 mL) was added SOCI2 (173.61 mg, 1 .460 mmol, 2.5 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was washed with DCM (2 mL). The resulting mixture was concentrated under vacuum. The crude product mixture was used in the next step directly without further purification. LC / MS: MS (ESI) calcd. For C7H9CIN2O: 172.04. Found: 173.00 [M+H]+. PATENT

[0553] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0554] Step 6. Synthesis of 2-(((5-methoxy-3-methylpyridazin-4-yl)methyl)thio)pyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0555] To a stirred solution of 4-(chloromethyl)-5-methoxy-3-methylpyridazine (100 mg, 0.579 mmol, 1 equiv) and 2-sulfanylpyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (96.86 mg, 0.579 mmol, 1 equiv) in DMF (1 mL) was added DIEA (224.63 mg, 1 .737 mmol, 3 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1 % TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 2-(((5-methoxy-3-methylpyridazin-4-yl)methyl)thio)pyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (33.5 mg, 19.06% yield ) as a trifluoroacetate salt and as a white solid. LC / MS: MS (ESI) calcd. For C13H13N5O2S: 303.30. Found: 304.05[M+H]+.1H NMR (300 MHz, DMSO-d6) 6 12.15 (s, 1 H), 9.18 (m, 1 H), 7.55 (m, 1 H), 6.88 (m, 1 H), 6.53 (m 1 H), 4.44 (s, 2H), 4.08 (m, 3H), 2.78 (m, 3H).

[0556] Example 29: Synthesis of 2-{[(3,5-dimethylpyridazin-4-yl) methyl] sulfanyl} pyrrolo[2,1-f] [1 ,2,4] triazin-4-ol

[0557] Stepl . Synthesis of ethyl 3,5-dimethylpyridazine-4-carboxylate

[0558] FeSO4»7H2O, TBHP

[0559] To a solution of ethyl 3-methylpyridazine-4-carboxylate (500 mg, 3.01 mmol) in 5 ml 30% aqueous sulfuric acid, FeSO47H2O (837 mg, 3.01 mmol) previously dissolved in 1 .2 ml H2O and 0.5 ml TBHP (6M in nonane) was added to the above mixture. The resulting solution was stirred at 40°C for 16 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The solution was basified with concentrated aqueous ammonia and extracted with DCM. The combined organic extracts were washed with brine (20 ml), dried over Na2SO4and filtered. The solvent was removed in vacuo. The residue was further purified by reverse phase column eluted with ACN and H2O (0.05% NH4HCC>3), after concentrated to afford ethyl 3,5-dimethylpyridazine-4- carboxylate (180 mg, 33.20% yield) as a yellow oil. LC / MS (ESI) calcd. For C9H12N2O3, 180.08 m / z, found 181.05 [M+H]+. PATENT

[0560] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0561] Step 2. Synthesis of (3,5-dimethylpyridazin-4-yl) methanol

[0562] To a solution of ethyl 3,5-dimethylpyridazine-4-carboxylate (100 mg, 0.555 mmol) in the mixture of solvent 0.8 ml of THF and 0.2 ml of CH3OH was added NaBFL (62.98 mg, 1.665 mmol) at 0°C. The resulting mixture was stirred at 40°C for 1 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The reaction was quenched with cooling water at 0 °C, filtered, the filter cake was washed with ACN (3 x 3 ml). The filtrate was concentrated under reduced pressure to afford the crude compound (3,5-dimethylpyridazin-4-yl) methanol (75 mg, 97.8% yield) as a yellow oil. The crude product was used in the next step directly without further purification. MS (ESI) calcd. for C7HioN20, 138.08 m / z, found 139.10 [M+H]+.

[0563] Step 3. Synthesis of 4-(chloromethyl)-3,5-dimethylpyridazine

[0564] To a solution of (3,5-dimethylpyridazin-4-yl) methanol (75 mg, 0.543 mmol) in 1.5 ml of DCM was added SOCh (161 .43 mg, 1 .358 mmol) at 0°C. The resulting mixture was stirred at room temperature for 0.5 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The mixture was concentrated under reduced pressure to afford crude compound 4- (chloromethyl)-3,5-dimethylpyridazine (70 mg, 82.3% yield) as a yellow oil. The crude product was used in the next step directly without further purification. MS (ESI) calcd. for C7H9CIN2, 156.05 m / z, found 157.05 [M+H]+.

[0565] Step 4. Synthesis of 2-{[(3,5-dimethylpyridazin-4-yl) methyl] sulfanyl} pyrrolo[2,1-f] [1,2,4] triazin-4-ol

[0566] To a solution of 4-(chloromethyl)-3,5-dimethylpyridazine (70 mg, 0.447 mmol) in 1 ml of DMF was added 2-sulfanylpyrrolo[2,1-f] [1 ,2,4] triazin-4-ol (97.15 mg, 0.581 mmol), DIEA (173.31 mg, 1 .341 mmol) at room temperature. The resulting solution was stirred at room temperature for 0.5 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The mixture was further purified by reverse phase column eluted with ACN and H2O (0.05% NH4HCO3), after concentrated to afford 2-{[(3,5-dimethylpyridazin-4-yl) methyl] sulfanyl} pyrrolo[2,1-f] [1 ,2,4] PATENT

[0567] ATTORNEY-DOCKET NO.: 51478-031 WO3 triazin-4-ol (26.5 mg, 20.63 yield) as a white solid. LC / MS (ESI) calcd. for C13H13N5OS, 287.08 m / z, found 288.05 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 (ppm): 8.80 - 9.01 (m, 1 H), 7.11 - 7.11 (m, 1 H), 6.28 - 6.42 (m, 1 H), 6.16 - 6.28 (m, 1 H), 5.88 - 6.10 (m, 1 H), 4.32 (s, 2H), 2.71 (s, 3H), 2.38 (s, 3H).

[0568] Example 30: Synthesis of 2-({[5-methyl-3-(trifluoromethyl)pyridazin-4-yl]methyl}sulfanyl)- pyrrolo[2,1 -f] [1 ,2,4]triazin-4-ol

[0569] Step 1. Synthesis of 4-chloro-5-methyl-2-(oxan-2-yl)pyridazin-3-one

[0570] Into a 500 mL vial were added 4,5-dichloro-2-(oxan-2-yl)pyridazin-3-one (15 g, 60.219 mmol), methylboronic acid (3.60 g, 60.219 mmol), CS2CO3 (58.86 g, 180.657 mmol, 3 equiv), Pd(dppf)Cl2 (2.20 g, 3.011 mmol), H2O (18 mL) and dioxane (180 mL) at room temperature under N2. The resulting mixture was stirred at 110°C for an additional 2h. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (2 x 300mL). The combined organic layers were washed with water (1 x 200 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1 :1) to afford 4-chloro-5-methyl-2-(oxan-2-yl)pyridazin-3-one (4.45 g, 32.31 % yield, 93% purity) as a white solid. LC / MS: MS (ESI) calcd. forCioHi3CIN2C>2: 228.07, Found: 229.00 [M+H]+.

[0571] Step 2. Synthesis of 5-methyl-2-(oxan-2-yl)-3-oxopyridazine-4-carboxylic acid

[0572] CO Pd(dppf)CI2, CsCO3dioxane / H2O

[0573] 130 °C, overnight

[0574] To a solution of 4-chloro-5-methyl-2-(oxan-2-yl)pyridazin-3-one (2.9 g, 12.681 mmol) in MeOH (100 mL) was added Pd(dppf)Cl2 (0.93 g, 1.268 mmol) and TEA (6.42 g, 63.405 mmol) in a pressure tank. The mixture was pressurized to 40 atm with carbon monoxide and stirred at 130 °C overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The resulting mixture was concentrated under reduced pressure. This resulted in 5-methyl-2-(oxan-2-yl)-3- oxopyridazine-4-carboxylic acid (2.2 g) as a red oil. LC / MS: MS (ESI) calcd. for C11H14N2O4: 238.10, Found: 239.15 [M+H]+. PATENT

[0575] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0576] Step 3. Synthesis of methyl 5-methyl-2-(oxan-2-yl)-3-oxopyridazine-4-carboxylate

[0577] To a stirred solution of 5-methyl-2-(oxan-2-yl)-3-oxopyridazine-4-carboxylic acid (2 g, 8.395 mmol, 1 equiv) in DMF (20 mL) was added K2CO3 (2320.40 mg, 16.790 mmol, 2 equiv) and CH3I (1429.86 mg, 10.074 mmol, 1 .2 equiv) at 25 °C. The reaction was stirred at 60 °C for 1 h. The reaction was monitored by LCMS. After completion of reaction, the resulting mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water (0.05% NH4HCO3) in ACN, 10% to 50% gradient in 20 min; detector, UV 254 nm. After concentrated, it provided methyl 5-methyl-2-(oxan-2-yl)-3-oxopyridazine-4-carboxylate (2.01 g) as a yellow oil. LC / MS: MS (ESI) calcd. for C12H16N2O4: 252.11 , Found: 252.95 [M+H]+.

[0578] Step 4. Synthesis of methyl 3-bromo-5-methylpyridazine-4-carboxylate

[0579] Into a 40mL vial were added methyl 5-methyl-2-(oxan-2-yl)-3-oxopyridazine-4-carboxylate (2.01 g, 7.968 mmol, 1 equiv), DCM (20 mL) and POBrs (11.42 g, 39.840 mmol, 5 equiv) at room temperature. The resulting mixture was stirred at 70 °C for an additional 2h. The reaction was monitored by LCMS. The reaction was quenched with Water / lce at room temperature. The resulting mixture was extracted with DCM (2 x 100mL). The combined organic layers were washed with water (1x100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash (0.05%TFA) to afford methyl 3- bromo-5-methylpyridazine-4-carboxylate (1.03 g) as a yellow oil. LC / MS: MS (ESI) calcd. for C7H7BrN2O2: 229.97, Found: 232.90 [M+H]+.

[0580] Step 5. Synthesis of methyl 5-methyl-3-(trifluoromethyl)pyridazine-4-carboxylate

[0581] To a stirred solution of methyl 3-bromo-5-methylpyridazine-4-carboxylate (1.03 g, 4.459 mmol) and Cui (425.8 mg, 2.229 mmol) in NMP (15.00 mL) was added methyl 2,2-difluoro-2-sulfo- PATENT

[0582] ATTORNEY-DOCKET NO.: 51478-031 WO3 acetate (4280.64 mg, 22.295 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 85 °C for an additional 2h. After completion of reaction, the reaction was quenched with water (50 mL). The mixture was extracted by EA (3 x 50 mL), dried over anhydrous Na2SC>4. After concentrated, the crude product was purified by reverse phase flash (0.05% TFA) to afford methyl 5-methyl-3-(trifluoromethyl)pyridazine-4-carboxylate (230 mg) as a yellow oil. LC / MS: MS (ESI) calcd. for C8H7F3N2O2: 220.05, Found: 220.95 [M+H]+.

[0583] Step 6. Synthesis of 5-methyl-3-(trifluoromethyl)pyridazine-4-carboxylic acid

[0584] To a stirred solution of methyl 5-methyl-3-(trifluoromethyl)pyridazine-4-carboxylate (230 mg, 1.041 mmol) and MeOH (1 mL) in THF (3 mL) was added LiOH (49.95 mg, 2.082 mmol, 2 equiv) dissolved in H2O (1 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 2h. The reaction was monitored by LCMS. The mixture / residue was acidified to pH 3 with HCI (aq.). The resulting mixture was extracted with EtOAc (2 x 100mL). The combined organic layers were washed with water (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 5-methyl-3-(trifluoromethyl)pyridazine-4-carboxylic acid (170 mg) as a white solid. LC / MS: MS (ESI) calcd. for C7H5F3N2O2: 206.03, Found: 206.95 [M+H]+.

[0585] Step 7. Synthesis of [5-methyl-3-(trifluoromethyl)pyridazin-4-yl]methanol

[0586] Into an 8mL vial were added 5-methyl-3-(trifluoromethyl)pyridazine-4-carboxylic acid (170 mg, 0.825 mmol), DMAP (251.63 mg, 2.063 mmol), Tf-DMAP (833.45 mg, 2.063 mmol) , 4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolane (316.81 mg, 2.475 mmol) and DCM (4 mL) at room temperature. The resulting mixture was stirred at room temperature for an additional 2h. The reaction was monitored by LCMS. After completion of reaction, the reaction was quenched with water. The mixture was purified by reverse phase flash (0.05% NH4HCO3) to afford [5-methyl-3-(trifluoromethyl)pyridazin-4-yl]- methanol (124 mg) as a brown solid. LC / MS: MS (ESI) calcd. for C7H7F3N2O: 192.05, Found: 192.95 [M+H]+. PATENT

[0587] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0588] Step 8. Synthesis of 4-(chloromethyl)-5-methyl-3-(trifluoromethyl)pyridazine

[0589] To a stirred solution of [5-methyl-3-(trifluoromethyl)pyridazin-4-yl]methanol (60 mg, 0.313 mmol,) in DCM (1 .5 mL) was added thionyl chloride (73.37 mg, 0.625 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was monitored by TLC. The resulting mixture was concentrated under reduced pressure to afford 4-(chloromethyl)-5- methyl-3-(trifluoromethyl)pyridazine (60 mg) as a yellow oil.

[0590] Step 9. Synthesis of 2-({[5-methyl-3-(trifluoromethyl)pyridazin-4-yl]methyl}sulfanyl)pyrrolo[2,1 - f][1 ,2,4]triazin-4-ol

[0591] To a stirred solution of 4-(chloromethyl)-5-methyl-3-(trifluoromethyl)pyridazine (60 mg, 0.285 mmol) and 2-sulfanylpyrrolo[2,1-f][1 ,2,4]triazin-4-ol (47.64 mg, 0.285 mmol) in DMF (1.5 mL) was added DIEA (110.48 mg, 0.855 mmol) at room temperature. The reaction was stirred for 2 h. The reaction was monitored by LCMS. After completion of reaction, the mixture was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water (0.05% TFA) in ACN, 20% to 50% gradient in 20 min; detector, UV 254 nm. After lyophilized, it provided 2-({[5-methyl-3-(trifluoromethyl)pyridazin-4-yl]methyl}sulfanyl)pyrrolo[2,1-f][1 ,2,4]triazin-4-ol (6.9 mg, 7.10% yield, 99.4% purity) as an off-white solid. LC / MS: MS (ESI) calcd. for C13H10F3N5OS: 341.06. Found: 342.00 [M+H] +.1H NMR (400 MHz, DMSO-d6) 6 (ppm): 12.24 (s, 1 H), 9.43 (s, 1 H), 7.75 (s, 1 H), 6.89 - 6.90 (m, 1 H), 6.52 - 6.54 (m, 1 H), 4.55 - 4.59 (m, 2H), 2.51 (s, 3H).

[0592] PATENT

[0593] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0594] Example 31 : Synthesis of 2-{[(5-chloro-3-ethylimidazol-4-yl)methyl]sulfanyl}-5-fluoropyrrolo- [2,1-f][1 ,2,4]triazin-4-ol

[0595] Step 1. Synthesis of ethyl 1-amino-3-fluoropyrrole-2-carboxylate

[0596] A solution of ethyl 3-fluoro-1 H-pyrrole-2-carboxylate (1 g, 6.364 mmol, 1 equiv) in DMF (20 mL) was treated with NaH (0.18 g, 7.637 mmol, 1 .2 equiv) at 0°C for 30 min under nitrogen atmosphere followed by the addition of amino diphenylphosphinate (2.23 g, 9.546 mmol, 1.5 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 30 min. The reaction was monitored by LCMS. The resulting mixture was extracted with EA (2 x 300 mL). The combined organic layers were washed with water (1x300 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (3:1) to afford ethyl 1 -amino-3-fluoropyrrole-2- carboxylate (650 mg, 59.33% yield, 95% purity) as a colorless oil. LC / MS: MS (ESI) calcd. for C7H9FN2O2: 172.06, Found: 173.05 [M+H]+.

[0597] Step 2. Synthesis of ethyl 3-fluoro-1-{[(phenylformamido)methanethioyl]amino}pyrrole-2- carboxylate

[0598] A solution of ethyl 1-amino-3-fluoropyrrole-2-carboxylate (300 mg, 1.743 mmol, 1 equiv) and benzoyl isothiocyanate (284.37 mg, 1 .743 mmol, 1 equiv) in THF (1 mL) was stirred at 80 °C for 30 min. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to afford ethyl 3-fluoro-1-{[(phenylformamido)methanethioyl]amino}pyrrole-2-carboxylate (500 mg) as a yellow solid. LC / MS: MS (ESI) calcd. for C15H14FN3O3S: 335.07, Found: 336.05 [M+H]+. PATENT

[0599] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0600] Step 3. Synthesis of 5-fluoro-2-sulfanylpyrrolo[2,1-f][1 ,2,4]triazin-4-ol

[0601] Into a 40mL vial were added ethyl 3-fluoro-1-{[(phenylformamido)methanethioyl]amino}pyrrole -2-carboxylate (500 mg, 1.491 mmol, 1 equiv) and NaOH (238.54 mg, 5.964 mmol, 4 equiv) at room temperature. The resulting mixture was stirred at 85 °C for an additional 30 min. The reaction was monitored by LCMS. The mixture was allowed to cool down to 0 °C.The mixture was acidified to pH 2 with cone. HCI. The precipitated solids were collected by filtration and washed with water (2x2 mL) to afford 5-fluoro-2-sulfanylpyrrolo[2,1-f][1 ,2,4]triazin-4-ol (200 mg) as a white solid. LC / MS: MS (ESI) ealed. for C6H4FN3OS: 185.01 , Found: 186.05 [M+H]+.

[0602] Step 4. Synthesis of 2-{[(5-chloro-3-ethylimidazol-4-yl)methyl]sulfanyl}-5-fluoropyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0603] To a stirred solution of 5-fluoro-2-sulfanylpyrrolo[2,1-f][1 ,2,4]triazin-4-ol (100 mg, 0.540 mmol, 1 equiv) and 4-chloro-5-(chloromethyl)-1 -ethylimidazole (96.68 mg, 0.540 mmol, 1 equiv) in DMF (2 mL) was added DIEA (209.39 mg, 1 .620 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was monitored by LCMS. The residue was purified by reverse phase flash with the following conditions (0.05% TFA) to afford 2-{[(5-chloro- 3-ethylimidazol-4-yl)methyl]sulfanyl}-5-fluoropyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (48.2 mg, 20.20% yield, 99.7% purity) as a trifluoroacetate salt and as white solid. LC / MS: MS (ESI) ealed. for C12H11CIFN5OS: 327.04. Found: 328.00 [M+H] +.1H NMR (300 MHz, DMSO-d6) 6 (ppm): 12.13 (s, 1 H), 7.76 (s, 1 H), 7.40 - 7.52 (m, 1 H), 6.35 -6.45(m, 1 H), 4.46 (s, 2H), 3.95 - 4.20 (m, 2H), 1.21 - 1 .45 (m, 3H). PATENT

[0604] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0605] Example 32: Synthesis of 2-{[(5-chloro-3-ethylimidazol-4-yl)methyl]sulfanyl}-6-fluoropyrrolo-

[0606] [2,1-f][1 ,2,4]triazin-4-ol

[0607] Step 1. Synthesis of methyl 1-amino-4-fluoropyrrole-2 -carboxylate

[0608] A solution of methyl 4-fluoro-1 H-pyrrole-2-carboxylate (1 g, 6.987 mmol, 1 equiv) in DMF (10 mL) was treated with NaH (201 .22 mg, 8.384 mmol, 1 .2 equiv) at 0 °C for 0.5 h under nitrogen atmosphere followed by the addition of amino diphenylphosphinate (2444.23 mg, 10.480 mmol, 1.5 equiv)in DMF (10 mL) dropwise at 0 °C.The resulting mixture was stirred at room temperature for an additional 0.5h.The reaction was monitored by LCMS. The reaction was quenched by the addition of ice water at room temperature. The aqueous layer was extracted with EtOAc (2x300 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 :1) to afford methyl 1 -amino- 4-fluoropyrrole-2-carboxylate (800 mg, 72.40% yield, 90% purity) as a white solid. LC / MS: MS (ESI) calcd. for C6H7FN2O2: 158.05, Found: 159.05 [M+H]+.

[0609] Step 2. Synthesis of methyl 4-fluoro-1-{[(phenylformamido)methanethioyl]amino}pyrrole-2- carboxylate

[0610] A solution of methyl 1-amino-4-fluoropyrrole-2-carboxylate (400 mg, 2.530 mmol, 1 equiv) and benzoyl isothiocyanate (412.79 mg, 2.530 mmol, 1 equiv) in THF (4 mL) was stirred at 80 °C for 0.5 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to afford methyl 4-fluoro-1-{[(phenylformamido)methanethioyl]amino}pyrrole-2-carboxylate (600 mg) as a yellow solid. The crude product was used in the next step directly without further purification. LC / MS: MS (ESI) calcd. for C14H12FN3O3S: 321.06, Found: 322.05 [M+H]+. PATENT

[0611] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0612] Step 3. Synthesis of 6-fluoro-2-sulfanylpyrrolo[2,1-f][1,2,4]triazin-4-ol

[0613] Into a 30mL vial were added methyl 4-fluoro-1-{[(phenylformamido)methanethioyl]amino} pyrrole-2-carboxylate (600 mg, 1 .867 mmol, 1 equiv) and NaOH (298.74 mg, 7.468 mmol, 4 equiv) at 85 °C. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The mixture was acidified to pH 2 with HCI (aq.). The precipitated solids were collected by filtration and washed with H2O (2x5 mL). This resulted in 6-fluoro-2-sulfanylpyrrolo[2,1-f][1 ,2,4]- triazin-4-ol (240 mg) as a white solid. MS: MS (ESI) calcd. for C6H4FN3OS: 185.01 , Found: 186.05 [M+H]+.

[0614] Step 4. Synthesis of 2-{[(5-chloro-3-ethylimidazol-4-yl)methyl]sulfanyl}-6-fluoropyrrolo[2,1-

[0615] To a stirred solution of 6-fluoro-2-sulfanylpyrrolo[2,1-f][1 ,2,4]triazin-4-ol (100 mg, 0.540 mmol, 1 equiv) and 4-chloro-5-(chloromethyl)-1 -ethylimidazole (96.68 mg, 0.540 mmol, 1 equiv) in DMF (2 mL) was added DIEA (209.39 mg, 1 .620 mmol, 3 equiv) dropwise at 0°C.The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was monitored by LCMS. The residue was purified by reverse phase flash (0.05% TFA) to afford 2-{[(5-chloro-3-ethylimidazol-4-yl)methyl]- sulfanyl}-6-fluoropyrrolo[2,1-f][1 ,2,4]triazin-4-ol (60.6 mg, 25.40% yield, 99.2% purity) as a trifluoroacetate salt and a white solid. LC / MS: MS (ESI) calcd. for C12H11CIFN5OS: 327.04. Found: 328.00 [M+H] +.1H NMR (300 MHz, DMSO-d6) 6 (ppm): 12.37 (s, 1 H), 7.60 - 7.79 (m, 2H), 6.77 -6.83(m, 1 H), 4.46 (s, 2H), 3.95 - 4.18 (m, 2H), 1.21 - 1.43 (m, 3H). PATENT

[0616] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0617] Example 33: Synthesis of 2-{[(2,4-dimethylpyridin-3-yl)methyl]sulfanyl}-6-fluoropyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0618] Synthesis of 2-{[(2,4-dimethylpyridin-3-yl)methyl]sulfanyl}-6-fluoropyrrolo[2,1 -f] [1 ,2,4]triazin-4- ol

[0619] To a stirred solution of 3-(chloromethyl)-2,4-dimethylpyridine (100 mg, 0.643 mmol) and 6- fluoro-2-sulfanylpyrrolo[2,1-f][1 ,2,4]triazin-4-ol (118.99 mg, 0.643 mmol) in DMF (3 mL) was added DIEA (249.14 mg, 1 .929 mmol) at 0 °C. The reaction was stirred for 1 h. The reaction was monitored by LCMS. After completion of reaction, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water (0.05% TFA) in ACN, 20% to 50% gradient in 20 min; detector, UV 254 nm. After lyophilized, it provided 2- {[(2,4-dimethylpyridin-3-yl)methyl]sulfanyl}-6-fluoropyrrolo[2,1-f][1 ,2,4]triazin-4-ol (67.9 mg, 25.26% yield, 99.6% purity) as a trifluoroacetate salt and as a white solid. LC / MS: MS (ESI) calcd. for C14H13FN4OS: 304.08. Found: 305.05 [M+H] +.1H NMR (400 MHz, DMSO-d6) 6 (ppm): 12.44 (s, 1 H), 8.53 - 8.54 (m, 1 H),7.67 - 7.68 (m, 1 H), 7.62 - 7.63 (m, 1 H), 6.76 - 6.77 (m, 1 H), 4.56 (s, 2H), 2.75 (s, 3H), 2.60 (s, 3H).

[0620] Example 34: Synthesis of 2-({[2-(difluoromethyl)-4-methylpyridin-3-yl]methyl}sulfanyl)-6- fluoropyrrolo[2,1 -f] [1 ,2,4]triazin-4-ol

[0621] Synthesis of 2-({[2-(difluoromethyl)-4-methylpyridin-3-yl]methyl}sulfanyl)-6-fluoropyrrolo[2,1- f][1 ,2,4]triazin-4-ol

[0622] To a stirred solution of 3-(chloromethyl)-2-(difluoromethyl)-4-methylpyridine (100 mg, 0.418 mmol) and 6-fluoro-2-sulfanylpyrrolo[2,1-f][1 ,2,4]triazin-4-ol (77.32 mg, 0.418 mmol,) in DMF (2 mL) was added DIEA (161 .89 mg, 1 .254 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. After completion of reaction, the mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water (0.05% TFA) in ACN, 20% to 50% gradient in 15 min; detector, UV 254 nm. After lyophilized, it provided 2-({[2-(difluoromethyl)-4-methylpyridin-3-yl]methyl}sulfanyl)-6- PATENT

[0623] ATTORNEY-DOCKET NO.: 51478-031 WO3 fluoropyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (47.0 mg, 33.08% yield, 99.6% purity) as a white solid. LC / MS: MS (ESI) calcd. for C14H11F3N4OS: 340.06. Found: 341 .05 [M+H] +.1H NMR (400 MHz, DMSO-d6) 6 (ppm): 12.39 (s, 1 H), 8.50 - 8.51 (m, 1 H), 7.68 - 7.70 (m, 1 H), 7.49 - 7.51 (m, 1 H), 7.09 - 7.36 (m, 1 H), 6.76 - 6.77 (m, 1 H), 4.60 (s, 2H), 2.51 (s, 3H).

[0624] Example 35: Synthesis of 2-{[(5-chloro-3-ethylimidazol-4-yl)methyl]sulfanyl}-7-fluoropyrrolo- [2,1-f][1 ,2,4]triazin-4-ol

[0625] Step 1. Synthesis of 2,4-dichloro-7-fluoropyrrolo[2,1-f][1,2,4]triazine

[0626] A solution of 2,4-dichloropyrrolo[2,1-f][1 ,2,4]triazine (1 g, 5.319 mmol, 1 equiv) and 4- (chloromethyl)-1-fluoro-1 ,4-diazabicyclo[2.2.2]octane-1 ,4-diium; bis(tetrafluoroboranuide) (2.83 g, 7.979 mmol, 1 .5 equiv) in ACN (40 mL) was stirred at 80 °C for 4 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (10:1) to afford 2,4-dichloro-7-fluoropyrrolo[2,1- f][1 ,2,4]triazine (600 mg, 54.76% yield, 50% purity) as a yellow green solid. LC / MS: MS (ESI) calcd. for C6H2CI2FN3: 204.96, Found: 205.95 [M+H]+.

[0627] Step 2. Synthesis of 2-chloro-7-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazine

[0628] To a stirred solution of 2,4-dichloro-7-fluoropyrrolo[2,1 -f][1 ,2,4]triazine (570 mg, 2.767 mmol, 1 equiv) in THF (6 mL) was added MeONa (194.33 mg, 3.597 mmol, 1 .3 equiv) in portions at 0 °C. The resulting mixture was stirred at 50 °C for 2 h. The reaction was monitored by LCMS. The reaction was quenched with water at room temperature. The aqueous layer was extracted with EtOAc (2x200 mL). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 2-chloro-7-fluoro-4-methoxypyrrolo[2,1-f]- [1 ,2,4]triazine (300 mg, 53.78% yield, 70% purity) as a yellow solid. LC / MS: MS (ESI) calcd. for C7H5CIFN3O: 201.01 , Found: 201.95 [M+H]+.

[0629] Step 3. Synthesis of 7-fluoro-2-sulfanylpyrrolo[2,1-f][1,2,4]triazin-4-ol PATENT

[0630] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0631] A solution of 2-chloro-7-fluoro-4-methoxypyrrolo[2,1 -f][1 ,2,4]triazine (160 mg, 0.794 mmol, 1 equiv) and Sodium Hydrosulfide (222.47 mg, 3.970 mmol, 5 equiv) in DMF (3 mL) was stirred at 120 °C for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered. The filtrate was used in the next step directly without further purification. MS: MS (ESI) calcd. for C6H4FN3OS: 185.01 , Found: 186.05 [M+H]+.

[0632] Step 4. Synthesis of 2-{[(5-chloro-3-ethylimidazol-4-yl)methyl]sulfanyl}-7-fluoropyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0633] To a stirred solution of 7-fluoro-2-sulfanylpyrrolo[2,1-f][1 ,2,4]triazin-4-ol (100 mg, 0.540 mmol, 1 equiv) and 4-chloro-5-(chloromethyl)-1 -ethylimidazole (116.02 mg, 0.648 mmol, 1.2 equiv) in DMF (2 mL) was added DIEA (209.39 mg, 1 .620 mmol, 3 equiv) dropwise at 0 °C .The resulting mixture was stirred at room temperature for 1 h. The residue was purified by reverse phase flash with the following conditions (0.05% TFA) .The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH C18 Column, 19*250 mm, 5pm; Mobile Phase A: Water(0.1 % FA), Mobile Phase B: ACN; Flow rate: 25 mL / min mL / min; Gradient (B%): 24% B to 37% B inl Omin; Wave Length: 254nm nm; RT1 (min): 8.9, 9.5(min): ) to afford 2-{[(5-chloro-3-ethylimidazol-4-yl)methyl]- sulfanyl}-7-fluoropyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (5.8 mg, 3.28% yield, 98.1 % purity) as a white solid. LC / MS: MS (ESI) calcd. for C12H11CIFN5OS: 327.04. Found: 328.00 [M+H] +.1H NMR (400 MHz, DMSO-d6) 6 (ppm): 12.20 (s, 1 H), 7.73 (s, 1 H), 6.80 - 6.91 (m, 1 H), 6.20 -6.41 (m, 1 H), 4.49 (s, 2H), 3.95 - 4.18 (m, 2H), 1.31 - 1.45 (m, 3H).

[0634] Example 36: Synthesis of 2-({[2-(difluoromethyl)-4-methylpyridin-3-yl]methyl}sulfanyl)-7- fluoropyrrolo[2,1 -f] [1 ,2,4]triazin-4-ol

[0635] Step 1. Synthesis of 7-fluoro-4-methoxy-2-{[(4-methoxyphenyl)methyl]sulfanyl}pyrrolo[2,1 - f][1 ,2,4]triazine t

[0636] Into a 40mL vial were added 2-chloro-7-fluoro-4-methoxypyrrolo[2,1-f][1 ,2,4]triazine (500 mg, 2.480 mmol, 1 equiv), PMBSH (382.53 mg, 2.480 mmol, 1 equiv), CS2CO3 (1616.25 mg, 4.960 mmol, 2 equiv), t-BubrettPhos Pd G3 (211.93 mg, 0.248 mmol, 0.1 equiv), t-BubrettPhos (240.44 mg, 0.496 mmol, 0.2 equiv) and dioxane (6 mL) at room temperature under N2. The resulting mixture was stirred PATENT

[0637] ATTORNEY-DOCKET NO.: 51478-031 WO3 at 100 °C for an additional 2 h. The reaction was monitored by LCMS. The resulting mixture was extracted with EA (2 x 100mL). The combined organic layers were washed with brine (1x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (0.05% TFA) to afford 7-fluoro-4-methoxy-2-{[(4-methoxyphenyl)methyl]sulfanyl}pyrrolo[2,1-f][1 ,2,4]triazine (720 mg, 90.90% yield, 90% purity) as a white solid. LC / MS: MS (ESI) calcd. for C15H14FN3O2S: 319.08, Found: 319.95 [M+H]+.

[0638] Step 2. Synthesis of 7-fluoro-4-methoxypyrrolo[2,1 -f][1 ,2,4]triazine-2-thiol

[0639] Into a 40mL vial were added 7-fluoro-4-methoxy-2-{[(4-methoxyphenyl)methyl]sulfanyl}- pyrrolo[2,1 -f][1 ,2,4]triazine (370 mg, 1.159 mmol, 1 equiv) and the mixture of TFA (5 mL) and MSOH (1 mL) at room temperature. The resulting mixture was stirred at 50 °C for an additional 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The reaction was quenched with water at room temperature. The precipitated solids were collected by filtration and washed with water (2x5 mL). This resulted in 7-fluoro-4-methoxypyrrolo[2,1-f][1 ,2,4]- triazine-2-thiol (280 mg) as a brown solid. LC / MS: MS (ESI) calcd. for C7H6FN3OS: 199.02 Found: 200.10 [M+H]+.

[0640] Step 3. Synthesis of 2-(difluoromethyl)-3-[({7-fluoro-4-methoxypyrrolo[2,1-f][1 ,2,4]triazin-2- yl}sulfanyl)methyl]-4-methylpyridine

[0641] To a stirred solution of 7-fluoro-4-methoxypyrrolo[2,1-f][1 ,2,4]triazine-2-thiol (70 mg, 0.351 mmol, 1 equiv) and 3-(chloromethyl)-2-(difluoromethyl)-4-methylpyridine (67.33 mg, 0.351 mmol, 1 equiv) in DMF (2 mL) was added DIEA (136.25 mg, 1 .053 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was monitored by LCMS. The residue was purified by reverse phase flash with the following conditions (0.05% TFA) to afford 2-(difluoromethyl)-3-[({7-fluoro-4-methoxypyrrolo[2,1-f][1 ,2,4]triazin-2-yl}sulfanyl)methyl]-4- methylpyridine (70 mg, 56.22% yield, 95% purity) as a white solid. LC / MS: MS (ESI) calcd. for C15H13F3N4OS: 354.08. Found: 355.05 [M+H] +. PATENT

[0642] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0643] Step 4. Synthesis of 2-({[2-(difluoromethyl)-4-methylpyridin-3-yl]methyl}sulfanyl)-7- fluoropyrrolo[2,1 -f] [1 ,2,4]triazin-4-ol

[0644] A solution of 2-(difluoromethyl)-3-[({7-fluoro-4-methoxypyrrolo[2,1 -f][1 ,2,4]triazin-2- yl}sulfanyl)methyl]-4-methylpyridine (70 mg, 0.198 mmol, 1 equiv), LiCI (58.62 mg, 1.386 mmol, 7 equiv) and TsOH (238.12 mg, 1.386 mmol, 7 equiv) in DMF (3 mL) was stirred at 120 °C for 2 h. The reaction was monitored by LCMS. The crude product was purified by reverse phase flash with the following conditions (0.05%TFA) to afford 2-({[2-(difluoromethyl)-4-methylpyridin-3-yl]methyl}sulfanyl)- 7-fluoropyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (33.3 mg, 37.10% yield, 97.9% purity) as a trifluoroacetate salt and as a white solid. LC / MS: MS (ESI) calcd. for C14H11F3N4OS: 340.06. Found: 341.00 [M+H] +.1H NMR (300 MHz, DMSO-d6) 6 (ppm): 12.20 (s, 1 H), 8.45 - 8.55 (m, 1 H), 7.43 - 7.53 (m, 1 H), 7.01 - 7.41 (m, 1 H), 6.81 - 6.91 (m, 1 H), 6.20 - 6.31 (m, 1 H), 4.60 (s, 2H), 2.51 (s, 3H).

[0645] Example 37: Synthesis of 2-{[(2,4-dimethylpyridin-3-yl)methyl]sulfanyl}-7-fluoropyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0646] Step 1. Synthesis of 3-[({7-fluoro-4-methoxypyrrolo[2,1 -f][1 ,2,4]triazin-2-yl}sulfanyl)methyl]-2,4- dimethylpyridine

[0647] To a stirred solution of 3-(chloromethyl)-2,4-dimethylpyridine (50 mg, 0.321 mmol, 1 equiv) and 7-fluoro-4-methoxypyrrolo[2,1-f][1 ,2,4]triazine-2-thiol (64.00 mg, 0.321 mmol, 1 equiv) in DMF (1 mL) was added DIEA (124.57 mg, 0.963 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was monitored by LCMS. The crude product was purified by reverse phase flash with the following conditions (0.05% TFA) to afford 3-[({7- fluoro-4-methoxypyrrolo[2,1 -f][1 ,2,4]triazin-2-yl}sulfanyl)methyl]-2,4-dimethylpyridine (60 mg, 58.66% yield, 95% purity) as a white solid. LC / MS: MS (ESI) calcd. for C15H15FN4OS: 318.10, Found: 319.10 [M+H]+. PATENT

[0648] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0649] Step 2. Synthesis of 2-{[(2,4-dimethylpyridin-3-yl)methyl]sulfanyl}-7-fluoropyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0650] A solution of 3-[({7-fluoro-4-methoxypyrrolo[2,1-f][1 ,2,4]triazin-2-yl}sulfanyl)methyl]-2,4- dimethylpyridine (60 mg, 0.188 mmol, 1 equiv), LiCI (55.92 mg, 1.316 mmol, 7 equiv) and TsOH (227.17 mg, 1 .316 mmol, 7 equiv) in DMF (3 mL) was stirred at 120 °C for 2 h. The reaction was monitored by LCMS. The residue was purified by reverse phase flash with the following conditions (0.05% TFA) to afford 2-{[(2,4-dimethylpyridin-3-yl)methyl]sulfanyl}-7-fluoropyrrolo[2,1-f][1 ,2,4]triazin- 4-ol (14.5 mg, 18.39% yield, 98.1% purity) as a trifluoroacetate salt and as a white solid. LC / MS: MS (ESI) calcd. for C14H13FN4OS: 304.08. Found: 305.05 [M+H] +.1H NMR (300 MHz, DMSO-d6) 6 (ppm): 8.52- 8.59 (m, 1 H), 7.65 - 7.74 (m, 1 H), 6.81 - 6.91 (m, 1 H), 6.22 - 6.32 (m, 1 H), 4.60 (s, 2H), 2.79 (s, 3H), 2.65 (s, 3H).

[0651] Example 38: Synthesis of 2-({[4-methyl-2-(trifluoromethyl)pyridin-3-yl]methyl}sulfanyl)- pyrazolo[3,2-f][1,2,4]triazin-4-ol

[0652] Step 1. Synthesis of methyl 2-aminopyrazole-3-carboxylate

[0653] To a stirred mixture of methyl 2H-pyrazole-3-carboxylate (2 g, 15.859 mmol, 1 .00 equiv) in N,N-dimethylacetamide (15 mL) was added NaH (0.76 g, 19.031 mmol, 1.2 equiv, 60%) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 30 min under nitrogen atmosphere. To the above mixture was added amino diphenylphosphinate (5.55 g, 23.788 mmol, 1 .5 equiv) in N,N-dimethylacetamide (15 mL) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for an additional 1 h. Desired product could be detected by LCMS. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1 % TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford methyl 2-aminopyrazole-3-carboxylate (588 mg, 26.27% yield, 90.1% purity) as a white solid. MS: MS (ESI) calcd. For C5H7N302: 141.05, Found: 142.10 [M+H]+. PATENT

[0654] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0655] Step 2. Synthesis of methyl 2-{[(phenylformamido)methanethioyl]amino}pyrazole-3- carboxylate

[0656] To a stirred solution of methyl 2-aminopyrazole-3-carboxylate (580 mg, 4.110 mmol, 1 equiv) in THF (5 mL) was added benzoyl isothiocyanate (670.66 mg, 4.1 10 mmol, 1 equiv) in portions at room temperature under air atmosphere. The resulting mixture was stirred at room temperature for 16 h. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was used in the next step directly without further purification. MS: MS (ESI) calcd. for C13H12N4O3S: 304.06, Found: 305.10 [M+H]+.

[0657] Step 3. Synthesis of 2-sulfanylpyrazolo[3,2-f][1 ,2,4]triazin-4-ol

[0658] To a stirred mixture of NaOH (2M in H2O, 4 equiv) was added methyl 2-{[(phenylformamido)- methanethioyl]amino}pyrazole-3-carboxylate (580 mg, 1 .906 mmol, 1 equiv) in portions at room temperature. The final reaction mixture was stirred at 85 °C for 1 .5 h. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was acidified to pH 2 with HCI (aq.). The precipitated solids were collected by filtration and washed with H2O (2x5 mL). This resulted in 2- sulfanylpyrazolo[3,2-f][1 ,2,4]triazin-4-ol (250 mg) as a white solid. MS: MS (ESI) calcd. for C5H4N40S: 168.01 , Found: 169.00 [M+H]+.

[0659] Step 4. Synthesis of 2-({[4-methyl-2-(trifluoromethyl)pyridin-3-yl]methyl}sulfanyl)pyrazolo[3,2- f] [1 ,2,4]triazi n-4-ol

[0660] To a stirred solution of 3-(chloromethyl)-4-methyl-2-(trifluoromethyl)pyridine (50 mg, 0.239 mmol, 1.00 equiv) and 2-sulfanylpyrazolo[3,2-f][1 ,2,4]triazin-4-ol (48.14 mg, 0.287 mmol, 1 .2 equiv) in PATENT

[0661] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0662] DMF (1 mL) was added DIEA (77.08 mg, 0.597 mmol, 2.5 equiv) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 min under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.05% TFA), 10% to 30% gradient in 10 min; detector, UV 254 nm to afford 2-({[4-methyl-2-(trifluoromethyl)pyridin-3-yl]methyl}sulfanyl)pyrazolo[3,2-f]- [1 ,2,4]triazin-4-ol (15.3 mg, 18.79% yield, 99.6% purity) as a white solid. LC / MS: MS (ESI) calcd. for C13H10F3N5OS: 341.06, Found: 341 ,95[M+H]+.1H NMR (300 MHz, DMSO-d6) 6 (ppm): 12.92 (s, 1 H), 8.51 - 8.65 (m, 1 H), 7.78 - 7.89 (m, 1 H), 7.61 - 7.71 (m, 1 H), 7.01 - 7.09 (m, 1 H), 4.62 (s, 2H), 2.56 (s, 3H).

[0663] Example 39: Synthesis of 2-({[4-cyclopropyl-2-(trifluoromethyl)pyridin-3- yl]methyl)sulfanyl)pyrazolo[3,2-f][1 ,2,4]triazin-4-ol

[0664] Step 1. Synthesis of methyl 4-cyclopropyl-2-(trifluoromethyl)pyridine-3-carboxylate

[0665] Into a 40mL vial were added methyl 4-chloro-2-(trifluoromethyl)pyridine-3-carboxylate (1 g, 4.174 mmol, 1 equiv), cyclopropylboronic acid (0.72 g, 8.348 mmol, 2 equiv), Pd(OAc)2 (0.09 g, 0.417 mmol, 0.1 equiv), CS2CO3 (3.40 g, 10.435 mmol, 2.5 equiv), di(1-adamantyl)-N-butylphosphine (0.30 g, 0.835 mmol, 0.2 equiv) ,1 ,4-dioxane (10 mL) and H2O (2 mL) at room temperature under N2. The resulting mixture was stirred at 100°C for an additional 2h. The reaction was monitored by LCMS. The reaction was quenched by the addition of sat. NH4CI (aq.) (200mL) at room temperature. The aqueous layer was extracted with EtOAc (2x200 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1 :1) to afford methyl 4-cyclopropyl-2-(trifluoromethyl)pyridine-3-carboxylate (800 mg, 78.17% yield, 90% purity) as a yellow oil. MS: MS (ESI) calcd. for C11H10F3NO2: 245.07, Found: 246.10 [M+H]+.

[0666] Step 2. Synthesis of [4-cyclopropyl-2-(trifluoromethyl)pyridin-3-yl]methanol

[0667] To a stirred solution of methyl 4-cyclopropyl-2-(trifluoromethyl)pyridine-3-carboxylate (800 mg, 3.263 mmol, 1 equiv) in THF (8 mL) was added DIBAL-H (1392.05 mg, 9.789 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was monitored by LCMS. The reaction was quenched with ice water at room temperature. The resulting mixture was filtered, the filter cake was washed with MeCN (2x5 mL). The filtrate was PATENT

[0668] ATTORNEY-DOCKET NO.: 51478-031 WO3 concentrated under reduced pressure to afford [4-cyclopropyl-2-(trifluoromethyl)pyridin-3-yl]methanol (600 mg) as a white solid. MS: MS (ESI) calcd. for C10H10F3NO: 217.07, Found: 218.05 [M+H]+.

[0669] Step 3. Synthesis of 3-(chloromethyl)-4-cyclopropyl-2-(trifluoromethyl)pyridine

[0670] To a stirred solution of [4-cyclopropyl-2-(trifluoromethyl)pyridin-3-yl]methanol (600 mg, 2.763 mmol, 1 equiv) in DCM (6 mL) was added SOCI2 (985.90 mg, 8.289 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was monitored by TLC. The resulting mixture was concentrated under reduced pressure to afford 3- (chloromethyl)-4-cyclopropyl-2-(trifluoromethyl)pyridine (550 mg) as a yellow oil.

[0671] Step 4. Synthesis of 2-({[4-cyclopropyl-2-(trifluoromethyl)pyridin-3-yl]methyl}sulfanyl)pyrazolo-

[0672] [3,2-f][1 ,2,4]triazin-4-ol

[0673] To a stirred solution of 2-sulfanylpyrazolo[3,2-f][1 ,2,4]triazin-4-ol (60 mg, 0.357 mmol, 1 equiv) and 3-(chloromethyl)-4-cyclopropyl-2-(trifluoromethyl)pyridine (84.07 mg, 0.357 mmol, 1 equiv) in DMF (2 mL) was added DIEA (138.34 mg, 1.071 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was monitored by LCMS. The crude product was purified by reverse phase flash with the following conditions (0.05% TFA) to afford 2-({[4-cyclopropyl-2-(trifluoromethyl)pyridin-3-yl]methyl}sulfanyl)pyrazolo[3,2-f][1 ,2,4]triazin-4-ol (36.1 mg, 21.02% yield, 98.5% purity) as a trifluoroacetate salt and as a white solid. LC / MS: MS (ESI) calcd. for C15H12F3N5OS: 367.07. Found: 368.05 [M+H] +.1H NMR (300 MHz, DMSO-d6) 6 (ppm): 8.50 - 8.61 (m, 1 H), 7.77 - 7.82 (m, 1 H), 7.25 - 7.35(m, 1 H), 6.99 - 7.09 (m, 1 H), 4.81 (s, 2H), 2.18 - 2.31 (m, 1 H), 1 .09 - 1 .32 (m, 2H), 0.81 - 1 .02 (m, 2H). PATENT

[0674] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0675] Example 40&41 : Synthesis of 2-{[(1S)-1-(2-methylpyridin-3-yl)ethyl]sulfanyl}pyrrolo[2,1-f]- [1 ,2,4]triazin-4-ol and 2-{[( 1 R)-1 -(2-methylpyridin-3-yl)ethyl]sulfanyl}pyrrolo[2,1 -f] [1 ,2,4]triazin- 4-ol

[0676] Step 1. Synthesis of 1-(2-methylpyridin-3-yl)ethanol

[0677] To a stirred solution of 2-methylpyridine-3-carbaldehyde (700 mg, 5.778 mmol, 1 equiv) in THF (10 mL) was added bromo(methyl)magnesium (10.5 mL, 7.51 1 mmol, 1.3 equiv) dropwise at 0 °C under N2. The resulting mixture was stirred at room temperature for 1 h. Desired product could be detected by LCMS. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 1-(2-methylpyridin-3-yl)ethanol (380 mg, 47.94% yield, 93% purity) as a yellow solid. MS: MS (ESI) calcd. for CsHnNO: 137.08. Found: 138.15 [M+H]+.

[0678] Step 2. Synthesis of 1-(2-methylpyridin-3-yl)ethyl methanesulfonate

[0679] To a stirred solution of 1-(2-methylpyridin-3-yl)ethanol (360 mg, 2.624 mmol, 1 equiv) in DCM (4 mL) was added methanesulfonic anhydride (685.68 mg, 3.936 mmol, 1.5 equiv) and TEA (663.89 mg, 6.560 mmol, 2.5 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h. Desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with deionized water (3 x 20 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 1-(2-methylpyridin-3-yl)ethyl methanesulfonate (230 mg) as a yellow oil. MS: MS (ESI) calcd. for C9H13NO3S: 215.06. Found: 216.10 [M+H]+.

[0680] Step 3. Synthesis of 2-{[1-(2-methylpyridin-3-yl)ethyl]sulfanyl}pyrrolo[2,1-f][1 ,2,4]triazin-4-ol

[0681] To a stirred solution of 1-(2-methylpyridin-3-yl)ethyl methanesulfonate (220 mg, 1.022 mmol, 1 equiv) in DMF (3 mL) was added 2-sulfanylpyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (256.30 mg, 1.533 mmol, 1 .5 equiv) and CS2CO3 (998.93 mg, 3.066 mmol, 3 equiv) in portions at 0 °C under air atmosphere. PATENT

[0682] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0683] The resulting mixture was stirred at room temperature for 1 h under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with deionized water (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 70% gradient in 20 min; detector, UV 254 nm. This resulted in 2-{[1-(2-methylpyridin-3-yl)ethyl]sulfanyl}pyrrolo[2,1-f][1 ,2,4]triazin-4-ol (120 mg, 41.01 % yield, 97% purity) as a yellow solid. MS: MS (ESI) calcd. for C14H14N4OS: 286.09. Found: 287.05 [M+H]+.

[0684] Step 4. Synthesis of 2-{[(1S)-1-(2-methylpyridin-3-yl)ethyl]sulfanyl}pyrrolo[2,1-f][1 ,2,4]triazin-4- ol and 2-{[(1 R)-1 -(2-methylpyridin-3-yl)ethyl]sulfanyl}pyrrolo[2,1 -f] [1 ,2,4]triazin-4-ol

[0685] The 2-{[1-(2-methylpyridin-3-yl)ethyl]sulfanyl}pyrrolo[2,1-f][1 ,2,4]triazin-4-ol (120 mg) was purified by SFC with the following conditions (Column: CHIRALPAK IG 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient (B%): isocratic 15; Wave Length: 220 / 254 nm; Sample Solvent: EtOH--HPLC; Injection Volume: 0.5 mL; Number Of Runs: 18) to afford 2-{[(1 S)-1-(2-methylpyridin-3-yl)ethyl]sulfanyl}pyrrolo[2,1- f][1 ,2,4]triazin-4-ol (35.8 mg, 21.34% yield, 99.5% purity, RT1 (min): 21.424) as a white solid. Stereochemistry arbitrarily assigned. LC / MS: MS (ESI) calcd. for C14H14N4OS: 286.09. Found: 287.05 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 (ppm): 12.08 (s, 1 H), 8.35 - 8.36 (m, 1 H), 7.94 - 7.96 (m, 1 H), 7.48 - 7.49 (m, 1 H), 7.27 - 7.30 (m, 1 H), 6.82 - 6.84 (m, 1 H), 6.47 - 6.49 (m, 1 H), 5.10 - 5.15 (m, 1 H), 2.67 (s, 3H), 1.69 - 1.71 (m, 3H). And 2-{[(1 R)-1-(2-methylpyridin-3-yl)ethyl]sulfanyl}pyrrolo[2,1 - f][1 ,2,4]triazin-4-ol (37.6 mg, 31.33% yield, 99.5% purity; RT2(min): 25.864) as a white solid. . Stereochemistry arbitrarily assigned. LC / MS: MS (ESI) calcd. for C14H14N4OS: 286.09. Found: 287.05 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 (ppm): 12.07 (s, 1 H), 8.33 - 8.34 (m, 1 H), 7.89 - 7.91 (m, 1 H), 7.48 - 7.49 (m, 1 H), 7.23 - 7.26 (m, 1 H), 6.82 - 6.84 (m, 1 H), 6.47 - 6.49 (m, 1 H), 5.10 - 5.15 (m, 1 H), 2.65 (s, 3H), 1.69 - 1.71 (m, 3H).

[0686] Example 42: 2-(((4-cyclopropylpyridazin-3-yl)methyl)thio)pyrrolo[2,1 -f][1 ,2,4]triazin-4-ol

[0687] Step 1. Synthesis of 4-chloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one

[0688] To a stirred solution of 4-chloropyridazin-3(2H)-one (10 g, 76.611 mmol, 1 equiv) and DHP (25.78 g, 306.444 mmol, 4 equiv) in THF (200 mL) was added TsOH (1.32 g, 7.661 mmol, 0.1 equiv) PATENT

[0689] ATTORNEY-DOCKET NO.: 51478-031 WO3 at room temperature. The resulting mixture was stirred at 70 °C for 16 h. The reaction was monitored by LCMS. The reaction was poured into water at room temperature. The resulting mixture was extracted with EtOAc (3 x 1000 mL), the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford 4- chloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (16 g, 97.30% yield, 91 % purity) as a white solid. LC / MS: MS (ESI) calcd. for C9H11CIN2O2: 214.05, Found: 215.05 [M+H]+.

[0690] Step 2. Synthesis of 4-cyclopropyl-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one

[0691] To a stirred solution of 4-chloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (15.5 g, 72.211 mmol, 1 equiv) and cyclopropylboronic acid (6513.03 mg, 75.822 mmol, 1.05 equiv) in dioxane (280 mL) and H2O (70 mL) were added Pd(Amphos)2Cl2 (5113.09 mg, 7.221 mmol, 0.1 equiv) and Na2CO3 (15306.91 mg, 144.422 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90°C for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 1000 mL), the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 :1) to afford 4-cyclopropyl-2-(tetrahydro-2H-pyran-2- yl)pyridazin-3(2H)-one (15.5 g, 94.5 % yield, 94% purity) as a white solid. MS: MS (ESI) calcd. for C12H16N2O2: 220.12, Found:221.15 [M+H]+.

[0692] Step 3. Synthesis of 3-chloro-4-cyclopropylpyridazine

[0693] To a stirred solution of 4-cyclopropyl-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (15.5 g, 70.368 mmol, 1 equiv) in MeCN (100 mL) was added POCh (174.01 mg, 1.135 mmol, 5 equiv) at 0 °C under N2 atmosphere. The resulting mixture was stirred at 85°C for 2 h under N2 atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The mixture was neutralized to pH = 8 with saturated NaHCCh (aq.). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile PATENT

[0694] ATTORNEY-DOCKET NO.: 51478-031 WO3 phase, MeCN in water (0.1% TFA), 2% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in 3-chloro-4-cyclopropylpyridazine (9.1 g, 83.65% yield, 90% purity) as a purple liquid. MS: MS (ESI) calcd. for CyHyCIN2: 154.03, Found: 155.05 [M+H]+.

[0695] Step 4. Synthesis of (4-cyclopropylpyridazin-3-yl)methanol ,

[0696] A solution of 3-chloro-4-cyclopropylpyridazine (8.5 g, 54.981 mmol, 1 equiv), (tributylstannyl)methanol (52.96 g, 164.943 mmol, 3 equiv) and XPhos Pd G2 (4.33 g, 5.498 mmol, 0.1 equiv) in dioxane (200 mL) was stirred at 110 °C for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with sat. NF CI (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 800 mL), the combined organic layers were washed with brine (800 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 5% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in (4- cyclopropylpyridazin-3-yl)methanol (1 .8 g, 21 .80% yield, 93% purity) as a white solid. MS: MS (ESI) calcd. for C8HION20:150.08, Found: 151.10 [M+H]+.

[0697] Step 5. Synthesis of 3-(chloromethyl)-4-cyclopropylpyridazine ,

[0698] A solution of (4-cyclopropylpyridazin-3-yl)methanol (800 mg, 5.327 mmol, 1 equiv) and SOCh (1267.38 mg, 10.654 mmol, 2 equiv) in DCM (10 mL) was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The mixture was concentrated under reduced pressure. This resulted in 3-(chloromethyl)-4-cyclopropylpyridazine (500 mg, crude) as a white solid. MS: MS (ESI) calcd. for C8H9CIN2: 168.05, Found: 169.05 [M+H]+. PATENT

[0699] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0700] Step 6. Synthesis of 2-(((4-cyclopropylpyridazin-3-yl)methyl)thio)pyrrolo[2,1-f][1 ,2,4]triazin-4-ol

[0701] To a stirred solution of 3-(chloromethyl)-4-cyclopropylpyridazine (80 mg, 0.474 mmol, 1 equiv) and 2-sulfanylpyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (95.19 mg, 0.569 mmol, 1 .2 equiv) in DMF (2 mL) was added DIEA (183.96 mg, 1.422 mmol, 3 equiv) dropwise at 0°C . The resulting mixture was stirred at room temperature for additional 2 h. The reaction was monitored by LCMS. The mixture was acidified to pH=2 with TFA. The residue was purified by reverse phase flash with the following conditions (0.05% TFA) to afford 2-(((4-cyclopropylpyridazin-3-yl)methyl)thio)pyrrolo[2,1 - f|[1 ,2,4]triazin-4-ol as a trifluoroacetate salt and as a white solid (5.5 mg, 2.80%y ield , 99.8%purity). LC / MS: MS (ESI) calcd. for C14H13N5OS: 299.08. Found: 300.05 [M+H]+.1H NMR (300 MHz, DMSO- cfe) 6 (ppm): 9.15 - 9.22 (m, 1 H), 7.62 - 7.78 (m, 1 H), 7.41 - 7.51 (m, 1 H), 6.85 - 6.92 (m, 1 H), 6.42 - 6.55 (m, 1 H), 4.55 - 4.65 (m, 2H), 2.31 - 2.42 (m, 1 H), 1.30 - 1.41 (m, 2H), 1.05 - 1.13 (m, 2H).

[0702] Example 43: 2-(((4-cyclopropylpyridazin-3-yl)methyl)thio)-7-fluoropyrrolo[2,1 -f| [1 ,2,4]triazin-4- ol

[0703] Step 1. Synthesis of 2-(((4-cyclopropylpyridazin-3-yl) methyl) thio)-7-fluoro-4- methoxypyrrolo[2,1-f] [1 ,2,4] triazine

[0704] To a mixture of 3-(chloromethyl)-4-cyclopropylpyridazine (100 mg, 0.593 mmol, 1 equiv) and 7-fluoro-4-methoxypyrrolo[2,1-f] [1 ,2,4] triazine-2-thiol (118.14 mg, 0.593 mmol, 1 equiv) in DMF (3 mL) was added DIEA (153.30 mg, 1 .186 mmol, 2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3x70 mL). The combined organic layers were washed with water (3x60 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 :4) to afford 2-(((4-cyclopropylpyridazin-3-yl) methyl) thio)-7-fluoro-4- methoxypyrrolo[2,1-f] [1 ,2,4] triazine (130 mg, 66.15% yield, 97.4% purity) as a yellow solid. LC / MS: MS (ESI) calcd. for C15H14FN5OS: 331.09. Found: 332.10 [M+H] +. PATENT

[0705] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0706] Step 2. Synthesis of 2-(((4-cyclopropylpyridazin-3-yl) methyl) thio)-7-fluoropyrrolo[2,1-f] [1 ,2,4] triazin-4-ol

[0707] To a mixture of 2-(((4-cyclopropylpyridazin-3-yl) methyl) thio)-7-fluoro-4-methoxypyrrolo[2,1-f] [1 ,2,4] triazine (100 mg, 0.302 mmol, 1 equiv) in DCM (2 mL) was added BBrs (529.21 mg, 2.114 mmol, 7 equiv) in portions at -78°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was quenched with MeOH at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1 % TFA), 10% to 50% gradient in 10 min; detector, UV 254nm. This resulted in 2-(((4-cyclopropylpyridazin-3-yl) methyl) thio)-7-fluoropyrrolo[2,1-f] [1 ,2,4] triazin-4-ol; (20.0 mg, 15.36% yield, 96.2% purity) as a trifluoroacetate salt and a red solid. LC / MS: MS (ESI) calcd. for C14H12FN5OS: 317.07. Found: 318.05 [M+H] +.1H NMR (300 MHz, DMSO-cfe) 6 (ppm): 12.24 (s, 1 H), 9.01 - 9.03 (m, 1 H), 7.30 - 7.35 (m, 1 H), 6.84 - 6.87 (m, 1 H), 6.22 - 6.23 (m, 1 H), 4.93 - 4.95 (m, 2H), 2.14 - 2.17 (m, 1 H), 1.06 - 1.15 (m, 2H), 0.84 - 0.95 (m, 2H).

[0708] Example 44, example 45: (S)-2-((1-(4-cyclopropylpyridazin-3-yl)ethyl)thio)pyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol ; ( / ?)-2-((1-(4-cyclopropylpyridazin-3-yl)ethyl)thio)pyrrolo[2,1 -f|[1 ,2,4]triazin-4- ol

[0709] Step 1. Synthesis of 4-cyclopropyl-3-vinylpyridazine 100 C, 2 h

[0710] To a solution of 3-chloro-4-cyclopropylpyridazine (4.3 g, 27.922 mmol) in dioxane (60 mL) were added 4,4,5,5-tetramethyl-2-vinyl-1 ,3,2-dioxaborolane (8.59 g, 55.844 mmol), K2CO3 (9.633 g, 69.805 mmol), H2O (15 mL) and Pd(dppf)Cl2 (3.066 g, 4.188 mmol) at room temperature. The resulting mixture was stirred at 100°C for 2 h under N2. The reaction was monitored by LCMS. After completion of reaction, the reaction mixture was quenched by addition of water (300 mL). The aqueous layer was extracted with EA (3 x 300 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford 4-cyclopropyl-3-vinylpyridazine (2.4 g, 58.85% yield, 96% purity) as a yellow solid. LC / MS: MS (ESI) calcd. for C9HioN2: 146.08. Found: 147.05 [M+H]+. PATENT

[0711] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0712] Step 2. Synthesis of 4-cyclopropylpyridazine-3-carbaldehyde r ,

[0713] To a stirred solution of 4-cyclopropyl-3-vinylpyridazine (600 mg, 4.104 mmol) in THF (10 mL) were added potassium osmate(VI) dihydrate (75.61 mg, 0.205 mmol) and NalC (2633.52 mg, 12.312 mmol) in H2O (10 mL) in portions at 0°C. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. After completion of reaction, the resulting mixture was filtered, the filter cake was washed with water (5 mL). The filtrate was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water (0.05% NH4HCO3) in ACN, 10% to 30% gradient in 20 min; detector, UV 254 nm. After concentrated, the crude (300 mg) was purified by silica gel column chromatography, eluted with PE / EA (1 / 2) to afford 4-cyclopropylpyridazine-3-carbaldehyde (200 mg, 32.89% yield, 93% purity) as a yellow solid. LC / MS: MS (ESI) calcd. for C8H8N2O: 148.06. Found: 149.15[M+H]+.

[0714] Step 3. Synthesis of 1-(4-cyclopropylpyridazin-3-yl)ethan-1-ol ,

[0715] To a stirred solution of 4-cyclopropylpyridazine-3-carbaldehyde (150 mg, 1 .012 mmol) in tetrahydrofuran (5 mL) was added methylmagnesium bromide (1 ,4M in THF) (2.17 mL, 3.036 mmol) dropwise at 0 °C. The reaction was stirred at 0°C for 1 h. The reaction was monitored by LCMS. After completion of reaction, the reaction was quenched with ice water / sat. NH4CI (20 mL). The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 1-(4-cyclopropylpyridazin-3-yl)ethan-1-ol (152 mg, crude) as a yellow solid. LC / MS: MS (ESI) calcd. for C9Hi2N20: 164.09. Found: 165.00 [M+H]+.

[0716] Step 4. Synthesis of 3-(1-chloroethyl)-4-cyclopropylpyridazine

[0717] To a stirred solution of 1 -(4-cyclopropylpyridazin-3-yl)ethan-1-ol (152 mg, 0.926 mmol) in DCM (3 mL) was added SOCI2 (275.29 mg, 2.315 mmol) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC. After completion of reaction, the resulting mixture was concentrated under reduced pressure. This resulted in 3-(1- chloroethyl)-4-cyclopropylpyridazine (155 mg, crude) as a yellow solid. PATENT

[0718] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0719] Step 5. Synthesis of 2-((1-(4-cyclopropylpyridazin-3-yl)ethyl)thio)pyrrolo[2,1-f][1 ,2,4]triazin-4-ol

[0720] To a stirred solution of 3-(1-chloroethyl)-4-cyclopropylpyridazine (155 mg, 0.849 mmol) and 2-mercaptopyrrolo[2,1-f][1 ,2,4]triazin-4-ol (141.88 mg, 0.849 mmol) in DMF (4 mL) was added DIEA (329.04 mg, 2.547 mmol) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. After completion of reaction, the mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water (0.05% TFA) in ACN, 10% to 50% gradient in 20 min; detector, UV 254 nm to afford 2- ((1-(4-cyclopropylpyridazin-3-yl)ethyl)thio)pyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (103 mg, 38.73% yield, 95.4% purity) as a white solid. LC / MS: MS (ESI) calcd. for C15H15N5OS: 313.10. Found: 313.95 [M+H]+.

[0721] Step 6. Synthesis of (S)-2-((1-(4-cyclopropylpyridazin-3-yl)ethyl)thio)pyrrolo[2,1-f][1 ,2,4]triazin-

[0722] 4-ol and (R)-2-((1 -(4-cyclopropylpyridazin-3-yl)ethyl)thio)pyrrolo[2,1 -f] [1 ,2,4]triazin-4-ol

[0723] The racemic product (2-((1-(4-cyclopropylpyridazin-3-yl)ethyl)thio)pyrrolo[2,1-f][1 ,2,4]triazin- 4-ol (100 mg ) ) was purified by Prep-SFC with the following conditions: Column: CHIRALPAK ID, 5 pm, 250 mm x 20 mm; Mobile Phase A: Hex (with 0.5% NH3 (2 M in MeOH)), Mobile Phase B: EtOH: DCM=1 : 1 ; Flow rate: 20 mL / min; Gradient (B%): isocratic 40% B; Wave Length: 220 / 254 nm;

[0724] To afford (S)-2-((1-(4-cyclopropylpyridazin-3-yl)ethyl)thio)pyrrolo[2,1-f][1 ,2,4]triazin-4-ol (15.4 mg, 15.40% yield, 99.6% purity) as an off-white solid. RT1 (min): 8.08; Stereochemistry arbitrarily assigned.

[0725] LC / MS: MS (ESI) calcd. for C15H15N5OS: 313.10. Found: 314.05 [M+H]+.

[0726] 1H NMR (400 MHz, DMSO-d6) 6 (ppm): 12.13 (s, 1 H), 8.98 - 8.99 (m, 1 H), 7.52 - 7.53 (m, 1 H), 7.24 - 7.25 (m, 1 H), 6.85 - 6.86 (m, 1 H), 6.49 - 6.50 (m, 1 H), 5.65 - 5.71 (m, 1 H), 2.16 - 2.22 (m, 1 H), 1.84 - 1.86 (m, 3H), 1.13 - 1.19 (m, 2H), 0.84 - 0.97 (m, 1 H), 0.79 - 0.83 (m, 1 H).

[0727] To afford (R)-2-((1-(4-cyclopropylpyridazin-3-yl)ethyl)thio)pyrrolo[2,1-f][1 ,2,4]triazin-4-ol (18.0 mg, 18.00% yield, 99.7% purity) as an off-white solid. RT2(min): 10.06; Stereochemistry arbitrarily assigned

[0728] LC / MS: MS (ESI) calcd. for C15H15N5OS: 313.10. Found: 314.05 [M+H]+.

[0729] 1H NMR (400 MHz, DMSO-d6) 6 (ppm): 12.13 (s, 1 H), 8.98 - 8.99 (m, 1 H), 7.52 - 7.53 (m, 1 H), 7.24 - 7.25 (m, 1 H), 6.85 - 6.86 (m, 1 H), 6.49 - 6.50 (m, 1 H), 5.65 - 5.71 (m, 1 H), 2.16 - 2.22 (m, 1 H), 1.84 - 1.86 (m, 3H), 1.13 - 1.19 (m, 2H), 0.84 - 0.97 (m, 1 H), 0.79 - 0.83 (m, 1 H). PATENT

[0730] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0731] Example 46 and 47: (S)-2-((1-(4-cyclopropylpyridazin-3-yl)propyl)thio)pyrrolo[2,1 - f] [1 ,2,4]triazin-4-ol and (R)-2-((1 -(4-cyclopropylpyridazin-3-yl)propyl)thio)pyrrolo[2,1 - f] [1 ,2,4]triazi n-4-ol

[0732] Step 1. Synthesis of 1-(4-cyclopropylpyridazin-3-yl)propan-1-ol

[0733] To a stirred solution of 4-cyclopropylpyridazine-3-carbaldehyde (180 mg, 1 .215 mmol, 1 equiv) in THF (2 mL) was added ethylmagnesium bromide (1 M in THF) (3.6 mL, 3.645 mmol, 3 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. After the reaction was completed, the reaction was quenched by the addition of sat. NF CI (aq.) at 0°C. The resulting mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 1-(4-cyclopropylpyridazin-3-yl)propan-1-ol (170 mg, crude) as a yellow oil. LC / MS: MS (ESI) calcd. For C10H14N2O: 178.11 . Found: 179.15[M+H]+.

[0734] Step 2. Synthesis of 3-(1-chloropropyl)-4-cyclopropylpyridazine

[0735] To a stirred solution of 1 -(4-cyclopropylpyridazin-3-yl)propan-1-ol (170 mg, 0.954 mmol, 1 equiv) in DCM (2 mL) was added SOCI2 (283.66 mg, 2.385 mmol, 2.5 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was monitored by TLC. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. This resulted in 3-(1-chloropropyl)-4- cyclopropylpyridazine (165 mg, crude) as a yellow solid.

[0736] PATENT

[0737] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0738] Step 3.Synthesis of 2-((1 -(4-cyclopropylpyridazin-3-yl)propyl)thio)pyrrolo[2,1 -f] [1 ,2,4]triazin- 4-ol

[0739] To a stirred solution of 3-(1-chloropropyl)-4-cyclopropylpyridazine (165 mg, 0.839 mmol, 1 equiv) and 2-mercaptopyrrolo[2,1-f][1 ,2,4]triazin-4-ol (168.31 mg, 1.007 mmol, 1.2 equiv) in DMF (2 mL) was added DIEA (325.29 mg, 2.517 mmol, 3 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 50°C for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. After the reaction was completed, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 5% to 70% gradient in 15 min; detector, UV 254 nm to afford 2-((1-(4-cyclopropylpyridazin-3-yl)propyl)thio)pyrrolo[2,1-f][1 ,2,4]triazin-4-ol (45 mg, 16.38% yield, 98% purity) as a yellow solid. LC / MS: MS (ESI) calcd. for C16H17N5OS: 327.12. Found: 328.15 [M+H]+.

[0740] Step 4.Synthesis of (S)-2-((1 -(4-cyclopropylpyridazin-3-yl)propyl)thio)pyrrolo[2,1 -f][1 ,2,4]triazin- 4-ol and (R)-2-((1 -(4-cyclopropylpyridazin-3-yl)propyl)thio)pyrrolo[2,1 -f][1 ,2,4]triazin-4-ol

[0741] The racemic mixture of (2-((1-(4-cyclopropylpyridazin-3-yl)propyl)thio)pyrrolo[2,1- f][1 ,2,4]triazin-4-ol (45 mg, 0.137 mmol, 1 equiv) was purified by Chiral-SFC with the following conditions (Column: CHIRALPAK AD-H, 5 pm, 250 mm x 20 mm; Mobile Phase A: MeOH; Flow rate: 20 mL / min; Gradient (B%): isocratic % B; Wave Length: 220 / 254 nm; Sample Solvent: EtOH; Injection Volume: 2.0 mL.

[0742] To afford (S)-2-((1-(4-cyclopropylpyridazin-3-yl)propyl)thio)pyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (10.1 mg, 16.65% yield, 98.7% purity) as a trifluoroacetate slat and a white solid. RT1 (min): 10.52; Stereochemistry arbitrarily assigned.

[0743] LC / MS: MS (ESI) calcd. for C16H17N5OS: 327.12. Found: 328.15 [M+H]+.

[0744] 1H NMR (300 MHz, DMSO-d6) 6 (ppm): 12.10 (s, 1 H), 8.95 - 8.97 (m, 1 H), 7.48 - 7.50 (m, 1 H), 7.22 - 7.24 (m, 1 H), 6.83 - 6.85 (m, 1 H), 6.47 - 6.50 (m, 1 H), 5.57 - 5.61 (m, 1 H), 2.16 - 2.34 (m, 3H), 1 .10 - 1 .24 (m, 2H), 0.82 - 0.99 (m, 4H), 0.75 - 0.79 (m, 1 H).

[0745] And to afford (R)-2-((1-(4-cyclopropylpyridazin-3-yl)propyl)thio)pyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (10.1 mg, 16.65% yield, 98.7% purity) as a trifluoroacetate slat and a white solid. RT1 (min): 5.69; Stereochemistry arbitrarily assigned. PATENT

[0746] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0747] LC / MS: MS (ESI) calcd. for C16H17N5OS: 327.12. Found: 328.15[M+H]+.

[0748] Example 48: (R)-2-((1 -(4-methylpyridin-3-yl)ethyl)thio)pyrrolo[2,1 -f|[1 ,2,4]triazin-4-ol Step 1. Synthesis of (S)-3-(1-chloroethyl)-4-methylpyridine

[0749] To a stirred solution of (R)-1-(4-methylpyridin-3-yl)ethan-1-ol (110 mg, 0.802 mmol, 1 equiv) in DCM (2 mL) was added SOCI2 (238.47 mg, 2.005 mmol, 2.5 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. This resulted in (S)-3-(1-chloroethyl)-4-methylpyridine (100 mg, crude) as a yellow oil. LC / MS: MS (ESI) calcd. for CsHioCIN: 155.05. Found: 156.20 [M+H]+.

[0750] Step 2. Synthesis of ( / ?)-2-((1-(4-methylpyridin-3-yl)ethyl)thio)pyrrolo[2,1-f][1 ,2,4]triazin-4-ol

[0751] To a stirred solution of (S)-3-(1-chloroethyl)-4-methylpyridine (100 mg, 0.643 mmol, 1 equiv) and 2-mercaptopyrrolo[2,1-f][1 ,2,4]triazin-4-ol (161.14 mg, 0.965 mmol, 1.5 equiv) in DMF (3 mL) was added DIEA (249.14 mg, 1 .929 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The reaction was quenched by the addition of sat. NH4CI (aq.) (2 mL) at 0°C. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 70% gradient in 20 min; detector, UV 254 nm. This resulted in (R)-2-((1-(4-methylpyridin-3-yl)ethyl)thio)pyrrolo[2,1- f][1 ,2,4]triazin-4-ol (77.3 mg, 42.01 % yield, 98.2% purity) as a white solid. LC / MS: MS (ESI) calcd. for C14H14N4OS: 286.09. Found: 287.05 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 (ppm): 10.34 (s, 1 H), 8.66 - 8.68 (m, 1 H), 8.30 - 8.32 (m, 1 H), 7.44 (s, 1 H), 7.19 - 7.24 (m, 1 H), 6.76 - 6.77 (m, 1 H), 6.44 - 6.46 (m, 1 H), 5.1 1 - 5.17 (m, 1 H), 2.47 - 2.50 (m, 3H), 1 .73 - 1 .75 (m, 3H).

[0752] Example 49: (S)-2-(( 1 -(4-methylpyridin-3-yl)ethyl)thio)pyrrolo[2,1 -f][1 ,2,4]triazin-4-ol

[0753] Step 1. Synthesis of (R)-3-(1-chloroethyl)-4-methylpyridine

[0754] To a stirred solution of (S)-1-(4-methylpyridin-3-yl)ethan-1-ol (400 mg, 2.916 mmol, 1 equiv) in DCM (5 mL) was added SOCI2 (867.17 mg, 7.290 mmol, 2.5 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 h. The reaction progress was monitored by PATENT

[0755] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0756] LCMS, and it showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. This resulted in (R)-3-(1-chloroethyl)-4-methylpyridine (350 mg) as a yellow solid. LC / MS: MS (ESI) calcd. for CsHioCIN: 155.05. Found: 156.20 [M+H]+.

[0757] Step 2. Synthesis of (S)-2-((1-(4-methylpyridin-3-yl)ethyl)thio)pyrrolo[2,1-f][1 ,2,4]triazin-4-ol

[0758] To a stirred solution of (R)-3-(1-chloroethyl)-4-methylpyridine (150 mg, 0.964 mmol, 1 equiv) and 2-mercaptopyrrolo[2,1-f][1 ,2,4]triazin-4-ol (241.71 mg, 1.446 mmol, 1.5 equiv) in DMF (3 mL) was added DIEA (373.71 mg, 2.892 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 h. Desired product could be detected by LCMS, and it showed the reaction was completed. The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 80% gradient in 20 min; detector, UV 254 nm. This resulted in (S)-2-((1-(4-methylpyridin-3- yl)ethyl)thio)pyrrolo[2, 1 -f][1 ,2,4]triazin-4-ol (103.7 mg, 37.57% yield, 99.5% purity) as a white solid. LC / MS: MS (ESI) calcd. for C14H14N4OS: 286.09. Found: 287.05 [M+H]+.1H NMR (400 MHz, DMSO- d6) 6 (ppm): 12.09 (s, 1 H), 8.67 (s, 1 H), 8.31 - 8.32 (m, 1 H), 7.49 (s, 1 H), 7.20 - 7.21 (m, 1 H), 6.83 - 6.84 (m, 1 H), 6.48 (s, 1 H), 5.14 - 5.15 (m, 1 H), 2.47 - 2.50 (m, 3H), 1.74 - 1.76 (m, 3H).

[0759] Example 50: 2-(((4-cyclopropyl-2,6-dimethylpyrimidin-5-yl)methyl)thio)pyrrolo[2,1 - f] [1 ,2,4]triazi n-4-ol

[0760] Step 1. Synthesis of 4-chloro-2,6-dimethylpyrimidine-5-carbaldehyde

[0761] B HO OH ,

[0762] To a solution of 4,6-dichloro-2-methylpyrimidine-5-carbaldehyde (1 g, 5.235 mmol, 1 equiv), Pd(dppf)Cl2CH2Cl2 (427.54 mg, 0.524 mmol, 0.1 equiv), K3PO4 (2222.55 mg, 10.470 mmol, 2 equiv) in Dioxane (8 mL) was added methylboronic acid (313.39 mg, 5.235 mmol, 1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:7) to afford 4-chloro-2,6- dimethylpyrimidine-5-carbaldehyde (120 mg, 13.44% yield) as a white solid. LC / MS: MS (ESI) calcd. for C7H7CIN2O: 170.02. Found: 171 .20 [M+H1+. PATENT

[0763] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0764] Step 2. Synthesis of 4-cyclopropyl-2,6-dimethylpyrimidine-5-carbaldehyde .

[0765] To a stirred solution of 4-chloro-2,6-dimethylpyrimidine-5-carbaldehyde (100 mg, 0.586 mmol, 1 equiv), cyclopropylboronic acid (151.06 mg, 1.758 mmol, 3 equiv), Pd(dppf)Cl2CH2Cl2 (47.87 mg, 0.059 mmol, 0.1 equiv), K3PO4 (248.85 mg, 1.172 mmol, 2 equiv) in Dioxane (5 mL) was added H2O (1 mL) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 2h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 4-cyclopropyl-2,6-dimethylpyrimidine-5- carbaldehyde (70 mg, 67.77% yield, 91% purity) as a white solid. LC / MS: MS (ESI) calcd. for C10H12N2O: 176.09. Found: 177.10 [M+H]+.

[0766] Step 3. Synthesis of (4-cyclopropyl-2,6-dimethylpyrimidin-5-yl) methanol ,

[0767] To a stirred solution of 4-cyclopropyl-2,6-dimethylpyrimidine-5-carbaldehyde (50 mg, 0.284 mmol, 1 equiv) in methanol (0.02 mL) was added NaBH4 (15.03 mg, 0.398 mmol, 1 .40 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was quenched with water at 0°C. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LC / MS: MS (ESI) calcd. for C10H14N2O: 178.11. Found: 179.10 [M+H] +.

[0768] Step 4. Synthesis of 5-(chloromethyl)-4-cyclopropyl-2,6-dimethylpyrimidine 0 C - rt, 1 h

[0769] To a stirred solution of (4-cyclopropyl-2,6-dimethylpyrimidin-5-yl) methanol (50 mg, 0.281 mmol, 1 equiv) in DCM (2 mL) was added SOCI2 (166.86 mg, 1 .405 mmol, 5 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 min under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LC / MS: MS (ESI) calcd. for C10H13CIN2: 196.08. Found: 197.10 [M+H]+. PATENT

[0770] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0771] Step 5. Synthesis of 2-{[(4-cyclopropyl-2,6-dimethylpyrimidin-5-yl) methyl] sulfanyl} pyrrolo[2,1-f] [1 ,2,4] triazin-4-ol

[0772] To a stirred solution of 5-(chloromethyl)-4-cyclopropyl-2,6-dimethylpyrimidine (50 mg, 0.254 mmol, 1 equiv),2-sulfanylpyrrolo[2,1 -f] [1 ,2,4] triazin-4-ol (42.50 mg, 0.254 mmol, 1 equiv) in DMF (3 mL) was added DIEA (65.71 mg, 0.508 mmol, 2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1 % TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The crude product (60mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 12% B to 32% B in 10 min; Wave Length: 254nm / 220nm nm; RT1 (min): 10.52) to afford 2-{[(4-cyclopropyl-2,6-dimethylpyrimidin-5-yl) methyl] sulfanyl} pyrrolo[2,1-f] [1 ,2,4] triazin-4-ol; trifluoroacetic acid (5.1 mg, 4.54% yield, 95.5% purity) as a white solid. LC / MS: MS (ESI) calcd. for C16H17N5OS: 327.12. Found: 328.05 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 6 (ppm): 11 .42 - 11 .43 (m, 1 H), 7.56 - 7.58 (m, 1 H), 6.88 - 6.90 (m, 1 H), 6.53 - 6.55 (m, 1 H), 4.61 (s, 2H), 2.56 - 2.74 (m, 4H), 2.35 - 2.41 (m, 3H), 1 .05 - 1 .07 (m, 4H).

[0773] Example 51 : 2-(((3-chloropyridin-2-yl)methyl)thio)pyrrolo[2,1 -f][1 ,2,4]triazin-4-ol

[0774] Stepl . Synthesis of 3-chloro-2-(chloromethyl)pyridine

[0775] 0 "C - rt, 1 h

[0776] To a stirred solution of (3-chloropyridin-2-yl)methanol (100 mg, 0.697 mmol, 1 equiv) in DCM (2 mL) was added SOCI2 (207.15 mg, 1.742 mmol, 2.5 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. This resulted in 3-chloro-2-(chloromethyl)pyridine (89 mg, crude) as a yellow oil. LC / MS: MS (ESI) calcd. for CeHsChN: 160.98. Found: 162.15 [M+H]+. PATENT

[0777] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0778] Step 2. Synthesis of 2-(((3-chloropyridin-2-yl)methyl)thio)pyrrolo[2,1-f][1,2,4]triazin-4-ol

[0779] To a stirred solution of 3-chloro-2-(chloromethyl)pyridine (89 mg, 0.549 mmol, 1 equiv) and 2-mercaptopyrrolo[2,1-f][1 ,2,4]triazin-4-ol (137.77 mg, 0.824 mmol, 1.5 equiv) in DMF (2 mL) was added DIEA (213.01 mg, 1.647 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 70% gradient in 20 min; detector, UV 254 nm. This resulted in 2-(((3-chloropyridin-2- yl)methyl)thio)pyrrolo[2, 1 -f][1 ,2,4]triazin-4-ol (63.6 mg, 39.55% yield, 99.7% purity) as a white solid. LC / MS: MS (ESI) calcd. for C12H9CIN4OS: 292.02. Found: 293.00 [M+H]+.1H NMR (300 MHz, DMSO-d6) 6 (ppm): 12.14 (s, 1 H), 8.49 - 8.51 (m, 1 H), 7.97 - 7.99 (m, 1 H), 7.52 (s, 1 H), 7.38 - 7.42 (m, 1 H), 6.85 - 6.86 (m, 1 H), 6.49 (s, 1 H), 4.68 (s, 2H).

[0780] Example 52: 2-(((4-cyclopropyl-2-methylpyridin-3-yl)methyl)thio)-7-fluoropyrrolo[2,1 - f] [1 ,2,4]triazi n-4-ol

[0781] Step 1. Synthesis of 2-(((4-cyclopropyl-2-methylpyridin-3-yl)methyl)thio)-7-fluoro-4- methoxypyrrolo[2,1 -f] [1 ,2,4]triazine

[0782] To a solution of 3-(chloromethyl)-4-cyclopropyl-2-methylpyridine (90 mg, 0.495 mmol) in 2 ml of DMF were added 7-fluoro-4-methoxypyrrolo[2,1-f][1 ,2,4]triazine-2-thiol (118.43 mg, 0.594 mmol) and DIEA (192.10 mg, 1 ,485 mmol) at room temperature. The resulting mixture was stirred at room temperature for 0.5h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The mixture was further purified by reverse phase column eluted with CAN and H2O (0.05% TFA), after concentrated to afford 2-(((4-cyclopropyl-2-methylpyridin-3-yl)methyl)thio)-7-fluoro- 4-methoxypyrrolo[2,1-f][1 ,2,4]triazine (75 mg, 43.95% yield) as a yellow oil. PATENT

[0783] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0784] Step 2. Synthesis of 2-(((4-cyclopropyl-2-methylpyridin-3-yl)methyl)thio)-7-fluoropyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0785] To a solution of 2-(((4-cyclopropyl-2-methylpyridin-3-yl)methyl)thio)-7-fluoro-4- methoxypyrrolo[2,1-f][1 ,2,4]triazine (75 mg, 0.218 mmol) in 1 ml of DMF were added LiCI (64.62 mg, 1.526 mmol), P-toluenesulfonic acid (262.49 mg, 1.526 mmol) at room temperature. The resulting mixture was stirred at 120°C for 1 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. After cooled to room temperature, the mixture was further purified by reverse phase column eluted with ACN and H2O (0.05% NH4HCO3), after concentrated to afford 2- (((4-cyclopropyl-2-methylpyridin-3-yl)methyl)thio)-7-fluoropyrrolo[2,1-f][1 ,2,4]triazin-4-ol (13.6 mg, 18.90% yield) as a white solid. MS (ESI) calcd. for C16H15FN4OS, 330.10 m / z, found 331 .10 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 (ppm): 8.20 - 8.30 (m, 1 H), 6.80 - 6.90 (m, 2H), 6.10 - 6.20 (m, 1 H), 4.61 (s, 2H), 2.58 (s, 3H), 2.10 - 2.20 (m, 1 H), 0.90 - 1.10 (m, 2H), 0.70 - 0.80 (m, 2H)

[0786] Example 53: 2-(((5-cyclopropylpyrimidin-4-yl)methyl)thio)pyrrolo[2,1 -f] [1 ,2,4]triazin-4-ol Step 1. Synthesis of 5-cyclopropyl-4-methylpyrimidine

[0787] Y

[0788] C.i HO'8'OH v . Pd(OAc -)2, Cataxium A, CSJ : -COJ, dioxan N >e- / H- ->0

[0789] ,

[0790] 100 "C, 2 h

[0791] A solution of 5-chloro-4-methylpyrimidine (300 mg, 2.334 mmol), cyclopropylboronic acid (300.68 mg, 3.501 mmol), Pd(OAc)2 (52.39 mg, 0.233 mmol), di(1 -adamantyl)-N-butylphosphine (167.34 mg, 0.467 mmol), CS2CO3 (1900.78 mg, 5.835 mmol) and H2O (1.6 mL) in dioxane (8 mL) was stirred at 100°C for 2 h under N2 atmosphere. The reaction was monitored by LCMS. After completion of reaction, the reaction was quenched with water / sat. NH4CI (50 mL). The mixture was extracted with EtOAc (2 x 50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE: EA (1 :4) to afford 5-cyclopropyl-4-methylpyrimidine (210 mg, 67.07% yield, 92% purity) as a yellow solid. MS: MS (ESI) calcd. for CsHioN2: 134.08. Found: 135.05 [M+H] +. PATENT

[0792] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0793] Step 2. Synthesis of 4-(bromomethyl)-5-cyclopropylpyrimidine ,

[0794] To a stirred solution of 5-cyclopropyl-4-methylpyrimidine (160 mg, 1.192 mmol) in AcOH (4 mL) was added Br2 (228.67 mg, 1 .430 mmol) at 0°C. The resulting mixture was stirred at 80°C for 1 h. The reaction was monitored by LCMS. After completion of reaction, the reaction was poured into ice water (30 mL). The resulting mixture was extracted with EA (30 m x 3). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE: EA (1 :1) to afford 4-(bromomethyl)-5-cyclopropylpyrimidine (90 mg, 35.42% yield, 92% purity) as a light yellow solid. MS: MS (ESI) calcd. for CsH&BrNg: 211 .99. Found: 213.05 [M+H]+.

[0795] Step 3. Synthesis of 2-(((5-cyclopropylpyrimidin-4-yl)methyl)thio)pyrrolo[2,1-f][1,2,4]triazin-4-ol

[0796] To a stirred solution of 4-(bromomethyl)-5-cyclopropylpyrimidine (80 mg, 0.375 mmol) and 2-mercaptopyrrolo[2,1-f][1 ,2,4]triazin-4-ol (75.33 mg, 0.450 mmol) in DMF (2 mL) was added DIEA (145.58 mg, 1 .125 mmol) at 0 °C. The reaction was stirred at room temperature for 1 h. The reaction was monitored by LCMS. After completion of reaction, the reaction was quenched with ice water at room temperature, the mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water (0.05% TFA) in ACN, 10% to 50% gradient in 20 min; detector, UV 254 nm. After lyophilized, it provided 2-(((5- cyclopropylpyrimidin-4-yl)methyl)thio)pyrrolo[2,1-f][1 ,2,4]triazin-4-ol (27.0 mg, 17.40% yield, 98.6% purity) as a trifluoro acetate salt and a white solid. LC / MS: MS (ESI) calcd. for C14H13N5OS: 299.08. Found: 300.10 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 (ppm): 12.17 (s, 1 H), 8.95 (s, 1 H), 8.47 (s, 1 H), 7.47 - 7.49 (m, 1 H), 6.84 - 6.86 (m, 1 H), 6.47 - 6.49 (m, 1 H), 4.75 (s, 2H), 2.09 - 2.15 (m, 1 H), 1.07 - 1.27 (m, 2H), 0.87 - 0.96 (m, 2H). PATENT

[0797] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0798] Example 54: 2-(((4-cyclopropyl-2,6-dimethylpyridin-3-yl)methyl)thio)pyrrolo[2,1 -f|[1 ,2,4]triazin- 4-ol

[0799] Step 1. Synthesis of ethyl 4-chloro-2,6-dimethylpyridine-3-carboxylate

[0800] B HO OH ,

[0801] To a stirred mixture of ethyl 4,6-dichloro-2-methylpyridine-3-carboxylate (3 g, 12.816 mmol, 1 equiv), Pd(dppf)Cl2 (938.42 mg, 1 .282 mmol, 0.1 equiv) and CH3B(OH)2 (767.17 mg, 12.816 mmol, 1 equiv) in dioxane (5 mL) and H2O (1 mL) was added K2CO3 (1 .46 mL, 25.632 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (200mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1 % TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in ethyl 4-chloro-2,6-dimethylpyridine-3-carboxylate (1.5 g, 54.78% yield, 99% purity) as a black oil. LC / MS: MS (ESI) calcd. for C10H12NCIO2: 213.06. Found: 214.05[M+H]+.

[0802] Step 2. Synthesis of ethyl 4-cyclopropyl-2,6-dimethylpyridine-3-carboxylate

[0803] N 100 ’C, 2 h

[0804] To a stirred mixture of ethyl 4-chloro-2,6-dimethylpyridine-3-carboxylate (1.4 g, 6.552 mmol, 1 equiv), Pd(OAc)2 (147.11 mg, 0.655 mmol, 0.1 equiv), CataxiumA (470.97 mg, 1.310 mmol, 0.2 equiv), CS2CO3 (4269.84 mg, 13.104 mmol, 2 equiv) and cyclopropylboronic acid (1688.57 mg, 19.656 mmol, 3 equiv) in dioxane (20 mL) was added H2O (2 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1 % TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in ethyl 4-cyclopropyl-2,6-dimethylpyridine-3-carboxylate (890 mg, 61.94% yield, 97% purity) as a yellow solid. LC / MS: MS (ESI) calcd. for C13H17NO2: 219.13. Found: 220.20[M+H]+. PATENT

[0805] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0806] Step 3. Synthesis of (4-cyclopropyl-2,6-dimethylpyridin-3-yl)methanol 0 ”C - rt, 1 h

[0807] To a stirred solution of ethyl 4-cyclopropyl-2,6-dimethylpyridine-3-carboxylate (650 mg, 2.964 mmol, 1 equiv) in THF (3 mL) was added DIBAL-H (1.0 M in hexanes) (7.4 mL, 7.410 mmol, 2.5 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of water (5 mL) at 0°C. The resulting mixture was filtered, the filter cake was washed with ACN (3 x 20 mL). The filtrate was concentrated under reduced pressure. This resulted in (4-cyclopropyl-2,6-dimethylpyridin-3-yl)methanol (400 mg, crude) as a yellow solid. The crude product was used in the next step directly without further purification. LC / MS: MS (ESI) calcd. for CuHisNO: 177.12. Found: 178.10[M+H]+.

[0808] Step 4. Synthesis of 3-(chloromethyl)-4-cyclopropyl-2,6-dimethylpyridine

[0809] To a stirred solution of (4-cyclopropyl-2,6-dimethylpyridin-3-yl)methanol (300 mg, 1.693 mmol, 1 equiv) in DCM (5 mL) was added SOCh (503.37 mg, 4.232 mmol, 2.5 equiv) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This resulted in 3-(chloromethyl)-4-cyclopropyl-2,6-dimethylpyridine (280 mg, crude) as a white solid. The crude product was used in the next step directly without further purification. LC / MS: MS (ESI) calcd. for C11H14CIN: 195.08. Found: 196.10[M+H]+.

[0810] Step 5. Synthesis of 2-(((4-cyclopropyl-2,6-dimethylpyridin-3-yl)methyl)thio)pyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0811] To a stirred solution of 3-(chloromethyl)-4-cyclopropyl-2,6-dimethylpyridine (180 mg, 0.920 mmol, 1 equiv), 2-mercaptopyrrolo[2,1-f][1 ,2,4]triazin-4-ol (153.79 mg, 0.920 mmol, 1 equiv) in DMF (4 mL) was added DIEA (237.77 mg, 1 .840 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen PATENT

[0812] ATTORNEY-DOCKET NO.: 51478-031 WO3 atmosphere. The reaction was monitored by LCMS. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1 % TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 2-(((4-cyclopropyl- 2,6-dimethylpyridin-3-yl)methyl)thio)pyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (147.3 mg, 36.36% yield, 97.4% purity) as a trifluoroacetate salt and as a white solid. LC / MS: MS (ESI) calcd. for C17H18N4OS: 326.12. Found: 327.05[M+H]+.1H NMR (400 MHz, DMSO-cfe) 6 (ppm): 12.20 (s, 1 H), 7.56 - 7.57 (m, 1 H), 7.20 - 7.21 (m, 1 H), 6.88 - 6.89 (m, 1 H), 6.52 - 6.54 (m, 1 H), 4.70 (s, 2H), 2.78 (s, 3H), 2.57 (s, 3H), 2.37 - 2.41 (m, 1 H), 1 .27 - 1 .32 (m, 2H), 1 .04 - 1 .07 (m, 2H).

[0813] Example 55: 2-(((4-methyl-6-(trifluoromethyl)pyridazin-3-yl)methyl)thio)pyrrolo[2,1 - f] [1 ,2,4]triazi n-4-ol

[0814] Step 1. Synthesis of 3-chloro-6-iodo-4-methylpyridazine i Cl Pyridine, Tf2O, Nal, TfOH, ACN r r _

[0815] O N n' O 'C - rt, 1 h

[0816] To a stirred solution of 6-chloro-5-methylpyridazin-3(2H)-one (2 g, 13.835 mmol, 1 equiv) and pyridine (1313.26 mg, 16.602 mmol, 1.2 equiv) in ACN (20 mL) was added Tf2O (4293.62 mg, 15.219 mmol, 1 .1 equiv) at 0°C. The resulting mixture was stirred at room temperature for 0.5 h. To the above mixture was added Nal (6221 .40 mg, 41 .505 mmol, 3.0 equiv) and TfOH (2283.85 mg, 15.219 mmol, 1 .1 equiv) at 0°C. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was monitored by LCMS. The reaction was quenched with ice water at room temperature. The resulting mixture was extracted with EtOAc (2 x 400 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford 3-chloro-6-iodo-4-methylpyridazine (3 g, 85.22% yield, 95% purity) as a yellow solid. LC / MS: MS (ESI) calcd. for C5H4CIIN2: 253.91 , Found: 254.95 [M+H]+.

[0817] Step 2. Synthesis of 3-chloro-4-methyl-6-(trifluoromethyl)pyridazine

[0818] To a stirred solution of 3-chloro-6-iodo-4-methylpyridazine (1 .5 g, 5.895 mmol, 1 equiv) and methyl 2,2-difluoro-2-sulfoacetate (1698.69 mg, 8.842 mmol, 1.5 equiv) in DMF (15 mL) was added Cui (1684.01 mg, 8.842 mmol, 1 .5 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 85°C for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with ice water at room temperature. The resulting mixture was extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with PATENT

[0819] ATTORNEY-DOCKET NO.: 51478-031 WO3 brine (300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford 3-chloro-4-methyl-6-(trifluoromethyl)pyridazine (330 mg, 28.48% yield, 92% purity) as a yellow oil. LC / MS: MS (ESI) calcd. for C6H4CIF3N2: 196.00, Found: 197.05 [M+H]+.

[0820] Step 3. Synthesis of (4-methyl-6-(trifluoromethyl)pyridazin-3-yl)methanol

[0821] Xphos Rd G?, dioxane / L / xn. , f jf - r" OH

[0822] FsiC N110 'C, 2 h F3C^^N

[0823] To a stirred solution of 3-chloro-4-methyl-6-(trifluoromethyl)pyridazine (300 mg, 1.526 mmol, 1 equiv) and Xphos-Pd-G2 (120.09 mg, 0.153 mmol, 0.1 equiv) in dioxane (3 mL) was added (tributylstannyl)methanol (1470.20 mg, 4.578 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110°C for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The residue was purified by reverse phase flash with the following conditions (0.05% TFA) to afford (4-methyl-6-(trifluoromethyl)pyridazin-3-yl)methanol (35 mg, 11.93% yield, 92% purity) as a colorless oil. LC / MS: MS (ESI) calcd. for C7H7F3N2O: 192.05. Found: 193.10 [M+H]+.

[0824] Step 4. Synthesis of 3-(chloromethyl)-4-methyl-6-(trifluoromethyl)pyridazine

[0825] To a stirred solution of (4-methyl-6-(trifluoromethyl)pyridazin-3-yl)methanol (35 mg, 0.182 mmol, 1 equiv) in DCM (1 mL) was added SOCI2 (65.01 mg, 0.546 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. The resulting mixture was concentrated under reduced pressure to afford 3-(chloromethyl)-4-methyl- 6-(trifluoromethyl)pyridazine (30 mg, crude) as a yellow solid.

[0826] Step 5. Synthesis of 2-(((4-methyl-6-(trifluoromethyl)pyridazin-3-yl)methyl)thio)pyrrolo[2,1- f][1 ,2,4]triazin-4-ol

[0827] To a stirred solution of 3-(chloromethyl)-4-methyl-6-(trifluoromethyl)pyridazine (30 mg, 0.142 mmol, 1 equiv) and 2-mercaptopyrrolo[2,1-f][1 ,2,4]triazin-4-ol (26.20 mg, 0.156 mmol, 1 .1 equiv) in PATENT

[0828] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0829] DMF (1 mL) was added DIEA (55.24 mg, 0.426 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The residue was purified by reverse phase flash with the following conditions (0.05% NH4HCO3) to afford 2-(((4- methyl-6-(trifluoromethyl)pyridazin-3-yl)methyl)thio)pyrrolo[2,1-f][1 ,2,4]triazin-4-ol (12.0 mg, 24.68% yield, 97.8% purity) as a white solid. LC / MS: MS (ESI) calcd. for C13H10F3N5OS: 341 .06. Found: 342.05 [M+H]+.1H NMR (300 MHz, DMSO-d6) 6 (ppm): 8.08 (s, 1 H), 7.11 - 7.19 (m, 1 H), 6.35 - 6.42 (m, 1 H), 6.20 - 6.28 (m, 1 H), 3.60 - 3.65 (m, 2H), 2.57 - 2.62 (m, 3H).

[0830] Example 56: 2-(((4-cyclopropyl-2-(difluoromethyl)pyridin-3-yl)methyl)thio)pyrrolo[2,1 - f] [1 ,2,4]triazi n-4-ol

[0831] Step 1. Synthesis of methyl 4-chloro-2-(1,1-difluoro-2-methoxy-2-oxoethyl)nicotinate

[0832] To a stirred solution of methyl 2-bromo-4-chloronicotinate (2 g, 7.985 mmol, 1 equiv) and methyl 2,2-difluoro-2-(trimethylsilyl)acetate (2.91 g, 15.970 mmol, 2 equiv) in DMSO (20 mL) were added Cui (1 .82 g, 9.582 mmol, 1 .2 equiv) and KF (0.65 g, 11 .179 mmol, 1 .4 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 70°C for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with MeCN (3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 10% to 70% gradient in 20 min; detector, UV 254 nm to afford methyl 4-chloro-2-(1 ,1-difluoro-2-methoxy-2-oxoethyl)nicotinate (1.9 g, 85.10% yield, 91% purity) as a light yellow solid. LC / MS: MS (ESI) calcd. for CI0H8CIF2NO4: 279.01 . Found: 280.20 [M+H]+.

[0833] Step 2. Synthesis of 2-(4-chloro-3-(methoxycarbonyl)pyridin-2-yl)-2,2-difluoroacetic acid

[0834] To a stirred solution of methyl 4-chloro-2-(1 ,1-difluoro-2-methoxy-2-oxoethyl)nicotinate (1.9 g, 6.795 mmol, 1 equiv) in H2O (10 mL) and MeOH (20 mL) was added Na2CO8(2.16 g, 20.385 mmol, 3 equiv) at room temperature under air atmosphere. The resulting mixture was stirred at room temperature for 2 h under air atmosphere. The reaction was monitored by LCMS. The residue was dissolved in H2O (20 mL). The residue was acidified to pH = 2 with HCI (2 M in H2O). The resulting PATENT

[0835] ATTORNEY-DOCKET NO.: 51478-031 WO3 mixture was extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 2-(4-chloro-3-(methoxycarbonyl)pyridin-2-yl)-2,2-difluoroacetic acid (1 .6 g, 88.66% yield, 99% purity) as a white solid. LC / MS: MS (ESI) calcd. for C9H6CIF2NO4: 265.00. Found: 266.05[M+H]+.

[0836] Step 3. Synthesis of methyl 4-chloro-2-(difluoromethyl)nicotinate

[0837] To a stirred solution of 2-(4-chloro-3-(methoxycarbonyl)pyridin-2-yl)-2,2-difluoroacetic acid (1.5 g, 5.648 mmol, 1 equiv) in DMF (15 mL) was added KF (0.66 g, 11 .296 mmol, 2 equiv) at room temperature under air atmosphere. The resulting mixture was stirred at 140°C for 1 h under air atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with MeCN (3 x 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1 % TFA), 10% to 70% gradient in 20 min; detector, UV 254 nm to afford methyl 4-chloro-2- (difluoromethyl)nicotinate (900 mg, 71.92% yield, 91 % purity) as a white solid. LC / MS: MS (ESI) calcd. for C8H6CIF2NO2: 221 .01 . Found: 222.10[M+H]+.

[0838] Step 4. Synthesis of methyl 4-cyclopropyl-2-(difluoromethyl)nicotinate

[0839] To a stirred mixture of methyl 4-chloro-2-(difluoromethyl)nicotinate (850 mg, 3.836 mmol, 1 equiv) and cyclopropylboronic acid (494.26 mg, 5.754 mmol, 1 .5 equiv) in dioxane (10 mL) and H2O (2 mL) were added Pd(OAc)2 (172.24 mg, 0.767 mmol, 0.2 equiv), di(1-adamantyl)-N-butylphosphine (137.54 mg, 0.384 mmol, 0.1 equiv) and CS2CO3 (3749.44 mg, 11 .508 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The residue was dissolved in water (100 mL). The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1 % TFA), 10% to 70% gradient in 20 min; PATENT

[0840] ATTORNEY-DOCKET NO.: 51478-031 WO3 detector, UV 254 nm to afford methyl 4-cyclopropyl-2-(difluoromethyl)nicotinate (550 mg, 63.11 % yield, 90% purity) as a white solid. LC / MS: MS (ESI) calcd. for C11H11F2NO2: 227.08. Found: 228.20[M+H]+.

[0841] Step 5. Synthesis of (4-cyclopropyl-2-(difluoromethyl)pyridin-3-yl)methanol

[0842] To a stirred solution of methyl 4-cyclopropyl-2-(difluoromethyl)nicotinate (500 mg, 2.201 mmol, 1 equiv) in THF (10 mL) was added Lithium aluminum hydride (100.22 mg, 2.641 mmol, 1.2 equiv) in portions at 0 °C under air atmosphere. The resulting mixture was stirred at room temperature for 1 h under air atmosphere. The reaction was monitored by LCMS. The reaction was quenched with ice water (10 mL) at 0°C. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1 % TFA), 10% to 70% gradient in 15 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This resulted in (4-cyclopropyl-2- (difluoromethyl)pyridin-3-yl)methanol (320 mg, 73.00% yield, 91 % purity) as a white solid. LC / MS: MS (ESI) calcd. for C10H11F2NO: 199.08. Found: 200.20 [M+H]+.

[0843] Step 6. Synthesis 3-(chloromethyl)-4-cyclopropyl-2-(difluoromethyl)pyridine

[0844] To a stirred solution of (4-cyclopropyl-2-(difluoromethyl)pyridin-3-yl)methanol (120 mg, 0.602 mmol, 1 equiv) in DCM (2 mL) was added SOCI2 (88.64 mg, 0.903 mmol, 1 .5 equiv) dropwise at 0°C under N2 atmosphere. The resulting mixture was stirred at room temperature for 1 h under N2 atmosphere. The reaction was monitored by LCMS. After completion of the reaction, the resulting mixture was concentrated under reduced pressure to obtain the crude 3-(chloromethyl)-4- cyclopropyl-2-(difluoromethyl)pyridine (100 mg, 76.27% yield, 91 % purity) as a light brown oil, which was used directly in the next step. LC / MS: MS (ESI) calcd. for C10H10CIF2N: 217.05. Found: 218.10 [M+H]+. PATENT

[0845] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0846] Step 7. Synthesis of 2-(((4-cyclopropyl-2-(difluoromethyl)pyridin-3-yl)methyl)thio)pyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0847] To a stirred solution of 3-(chloromethyl)-4-cyclopropyl-2-(difluoromethyl)pyridine (90 mg, 0.414 mmol, 1 equiv) and 2-mercaptopyrrolo[2,1-f][1 ,2,4]triazin-4-ol (103.7 mg, 0.620 mmol, 1.50 equiv) in DMF (3 mL) was added DIEA (160.3 mg, 1.240 mmol, 3.00 equiv) dropwise at 0°C under air atmosphere. The resulting mixture was stirred at room temperature for 1 h under N2 atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1 % TFA), 10% to 50% gradient in 15 min; detector, UV 254 nm to afford 2-(((4-cyclopropyl-2-(difluoromethyl)pyridin-3- yl)methyl)thio)pyrrolo[2, 1 -f][1 ,2,4]triazin-4-ol (21.9 mg, 15.20% yield, 99.902% purity) as a white solid. LC / MS: MS (ESI) calcd. for C16H14F2N4OS: 348.09. Found: 349.05[M+H]+.1H NMR (400 MHz, DMSO) 6 (ppm) 12.13 (s, 1 H), 8.51 - 8.45 (m, 1 H), 7.62 - 7.56 (m, 1 H), 7.37 - 7.04 (m, 2H), 6.91 - 6.85 (m, 1 H), 6.55 - 6.49 (m, 1 H), 4.77 (s, 2H), 2.29 - 2.17 (m, 1 H), 1.17 - 1.08 (m, 2H), 0.92 - 0.84 (m, 2H).

[0848] Example 57: 2-(((4-cyclopropyl-2-(difluoromethyl)pyridin-3-yl)methyl)thio)pyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0849] Step 1. Synthesis of methyl 2,3,5-trimethylisonicotinate 100 C, 2 h

[0850] To a stirred solution of methyl 2,3,5-trichloroisonicotinate (500 mg, 2.079 mmol, 1 equiv) and 2,4,6-trimethyl-1 ,3,5,2,4,6-trioxatriborinane (783.06 mg, 6.237 mmol, 3 equiv) in dioxane (5 mL) and H2O (1 mL) were added Pd(dppf)Cl2 (152.15 mg, 0.208 mmol, 0.1 equiv) and CS2CO3 (2032.47 mg, 6.237 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with dioxane (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1 % TFA), 10% to 50% gradient in 20 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This resulted PATENT

[0851] ATTORNEY-DOCKET NO.: 51478-031 WO3 in methyl 2,3,5-trimethylisonicotinate (210 mg, 56.35% yield, 90% purity) as a light brown oil. LC / MS: MS (ESI) calcd. for C10H13NO2: 179.09. Found: 180.20 [M+H]+.

[0852] Step 2. Synthesis of (2,3,5-trimethylpyridin-4-yl)methanol

[0853] To a stirred solution of methyl 2,3,5-trimethylisonicotinate (190 mg, 1.060 mmol, 1 equiv) in THF (4 mL) was added Lithium aluminum hydride (48.28 mg, 1.272 mmol, 1.2 equiv) in portions at 0 °C under air atmosphere. The resulting mixture was stirred at 0°C for 1 h under air atmosphere. The reaction was monitored by LCMS. The reaction was poured into ice water (10 mL) at 0 °C. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1 % TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford (2,3,5-trimethylpyridin-4-yl)methanol (75 mg, 46.79% yield, 90% purity)) as an off-white solid. LC / MS: MS (ESI) calcd. for C9H13NO: 151 .10. Found: 152.20 [M+H]+.

[0854] Step 3. Synthesis of 4-(chloromethyl)-2,3,5-trimethylpyridine rt, 1 h

[0855] To a stirred solution of (2,3,5-trimethylpyridin-4-yl)methanol (75 mg, 0.496 mmol, 1 equiv) in DCM (3 mL) was added SOCI2 (88.51 mg, 0.744 mmol, 1 .5 equiv) dropwise at 0°C under N2 atmosphere. The resulting mixture was stirred at room temperature for 1 h under N2 atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford 4-(chloromethyl)-2,3,5-trimethylpyridine (70 mg, 83.19% yield, 91 % purity) as a light brown oil. LC / MS: MS (ESI) calcd. for C9Hi2CIN: 169.07. Found: 170.10[M+H]+.

[0856] Step 4. Synthesis of 2-(((2,3,5-trimethylpyridin-4-yl)methyl)thio)pyrrolo[2,1-f][1 ,2,4]triazin-4-ol

[0857] To a stirred solution of 4-(chloromethyl)-2,3,5-trimethylpyridine (60 mg, 0.354 mmol, 1 equiv) and 2-mercaptopyrrolo[2,1-f][1 ,2,4]triazin-4-ol (88.7 mg, 0.531 mmol, 1 .50 equiv) in DMF (3 mL) was PATENT

[0858] ATTORNEY-DOCKET NO.: 51478-031 WO3 added DIEA (137.1 mg, 1 .061 mmol, 3.00 equiv) dropwise at 0°C under N2 atmosphere. The resulting mixture was stirred at room temperature for 1 h under N2 atmosphere. The reaction was monitored by LCMS. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1 % TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This resulted in 2-(((2,3,5-trimethylpyridin-4-yl)methyl)thio)pyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (50.6 mg, 34.52% yield, 97.407% purity) as a trifluoroacetate salt and as a white solid. LC / MS: MS (ESI) calcd. for C15H16N4OS: 300.10. Found: 301.10[M+H]+.1H NMR (400 MHz, DMSO-c / 6) 6 (ppm) 12.23 (s, 1 H), 8.48 (s, 1 H), 7.59 - 7.52 (m, 1 H), 6.92 - 6.86 (m, 1 H), 6.56 - 6.50 (m, 1 H), 4.61 (s, 3H), 2.61 (s, 3H), 2.52 - 2.48 (m, 2H), 2.45 (s, 3H).

[0859] Example 58: 2-(((3-(trifluoromethyl)pyridin-2-yl)methyl)thio)pyrrolo[2,1 -f|[1 ,2,4]triazin-4-ol Step 1. Synthesis of (3-(trifluoromethyl)pyridin-2-yl)methanol

[0860] CF3O

[0861] 1 JI Tf-DMAP, DMAP, HBPin, DCM

[0862] OOH- ». v rt, 1 h

[0863] To a stirred solution of 3-(trifluoromethyl)picolinic acid (500 mg, 2.616 mmol, 1 equiv) and N,N-dimethyl-1-trifluoromethanesulfonyl-1 lambda4-pyridin-4-amine; trifluoromethanesulfonic acid (2651.04 mg, 6.540 mmol, 2.5 equiv) in DCM (5 mL) were added 4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane (1004.51 mg, 7.848 mmol, 3 equiv) and N,N-dimethylpyridin-4-amine (799.09 mg, 6.540 mmol, 2.5 equiv) at 0°C. The resulting mixture was stirred at room temperature for 1 h. Desired product could be detected by LCMS. The reaction was quenched with ice water at room temperature. The resulting mixture was extracted with CH2CI2 (2 x 100 mL), the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford (3-(trifluoromethyl)pyridin-2-yl)methanol (150 mg, 32.37% yield) as a white solid. LC / MSM: S (ESI) calcd. for C7H6F3NO:177.04, Found:178.10[M+H]+.

[0864] Step 2. Synthesis of 2-(chloromethyl)-3-(trifluoromethyl rt, 1 h

[0865] To a stirred solution of (3-(trifluoromethyl)pyridin-2-yl)methanol (150 mg, 0.847 mmol, 1 equiv) in DCM (2 mL) was added SOCI2 (302.23 mg, 2.541 mmol, 3 equiv) at 0°C. The resulting mixture was stirred at room temperature for 1 h. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure to afford 2-(chloromethyl)-3- (trifluoromethyl)pyridine (130 mg, crude) as a yellow solid. The crude product (130 mg, crude) was used in the next step directly without further purification. LC / MS: MS (ESI) calcd. for C7H5CIF3N:195.01 , Found:196.10 [M+H]+. PATENT

[0866] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0867] Step 3. Synthesis of 2-(((3-(trifluoromethyl)pyridin-2-yl)methyl)thio)pyrrolo[2,1-f][1 ,2,4]triazin-4- ol

[0868] To a stirred solution of 2-(chloromethyl)-3-(trifluoromethyl)pyridine (130 mg, 0.665 mmol, 1 equiv) and 2-mercaptopyrrolo[2,1-f][1 ,2,4]triazin-4-ol (166.70 mg, 0.998 mmol, 1.5 equiv) in DMF (2 mL) was added DIEA (257.74 mg, 1 .995 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Desired product could be detected by LCMS. The reaction was quenched with ice water at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.05% TFA), 2% to 50% gradient in 20 min; detector, UV 254 nm to afford 2-(((3-(trifluoromethyl)pyridin-2-yl)methyl)thio)pyrrolo[2,1-f][1 ,2,4]triazin-4-ol, 2,2,2-trifluoroacetic acid (77.2 mg, 35.59% yield) as a white solid. LC / MS: MS (ESI) calcd. for Ci3H9F3N4OS:326.04, Found:327.05 [M+H]+.1H NMR (300 MHz, DMSO-c / 6) 6 (ppm):12.17 (s, 1 H), 8.79 - 8.88 (m, 1 H), 8.28 - 8.31 (m, 1 H), 7.59 - 7.67 (m, 1 H), 7.47 - 7.58 (m, 1 H), 6.82 - 6.91 (m, 1 H), 6.47 - 6.50 (m, 1 H), 4.76 (s, 2H).

[0869] Example 59: 2-(((3-ethylpyridin-2-yl)methyl)thio)pyrrolo[2,1 -f|[1 ,2,4]triazin-4-ol Step 1. Synthesis of methyl 3-vinylpicolinate

[0870] To a solution of methyl 3-bromopicolinate (1 g, 4.629 mmol, 1 equiv) and 4, 4,5,5- tetramethyl-2-vinyl-1 ,3,2-dioxaborolane (1.069 g, 6.943 mmol, 1.5 equiv) in dioxane (10 mL) and H2O (1 mL) were added Pd(dppf)Cl2 (0.34 g, 0.463 mmol, 0.1 equiv) and CS2CO3 (3.02 g, 9.258 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 85 °C for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. After the reaction was completed, the reaction was quenched by the addition of sat. NH CI (aq.) at 0°C. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in methyl 3-vinylpicolinate (600 mg, 79.44% yield, 94.2% purity) as a yellow oil. LC / MS: MS (ESI) calcd. For C9H9N02: 163.06. Found: 164.10[M+H]+. PATENT

[0871] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0872] Step 2. Synthesis of methyl 3-ethylpicolinate

[0873] To a solution of methyl 3-vinylpicolinate (600 mg, 2.297mmol, 1 equiv) in MeOH (10 mL) was added Pd / C (10%, 240 mg) under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 1 h under hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad and concentrated under reduced pressure. This resulted in methyl 3-ethylpicolinate (510 mg, crude) as a yellow oil. LC / MS: MS (ESI) calcd. For CgHnN02: 165.08. Found: 166.05[M+H]+.

[0874] Step 3. Synthesis of 3-ethylpyridin-2-yl)methanol 0 C - rt, 1 h

[0875] To a solution of methyl 3-ethylpicolinate (510 mg, 3.090 mmol, 1 equiv) in 6 ml of THF was added DIE3AL-H (9.2 mL, 9.272 mmol, 3.0 equiv) (1 M in hexanes) at 0°C. The resulting mixture was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The reaction was quenched by the addition of ice / water at 0°C. The resulting mixture was stirred at room temperature for 30 min under air atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 50 mL). The filtrate was concentrated under reduced pressure to afford (3-ethylpyridin-2-yl)methanol (300 mg, crude) as a white solid. LC / MS: MS (ESI) calcd. For CsHnNO: 137.08. Found: 138.05 [M+H]+.

[0876] Step 4. Synthesis of 2-(chloromethyl)-3-ethylpyridine

[0877] 0 C - it, 1 h

[0878] To a solution of (3-ethylpyridin-2-yl)methanol (300 mg, 1.818 mmol, 1 equiv) in DCM (2 mL) was added SOCL (536.3 mg, 4.545 mmol, 2.5 equiv) at 0°C. The resulting mixture was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS. The mixture was concentrated under reduced pressure to afford 2-(chloromethyl)-3-ethylpyridine (300 mg, crude) as a yellow oil. The crude product was used in the next step directly without further purification. LC / MS: MS (ESI) calcd. for CsHioCIN, 155.05 m / z, found 156.00 [M+H]+. PATENT

[0879] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0880] Step 5. Synthesis of 2-(((3-ethylpyridin-2-yl)methyl)thio)pyrrolo[2,1-f][1 ,2,4]triazin-4-ol

[0881] To a solution of 2-(chloromethyl)-3-ethylpyridine (150 mg, 0.967 mmol, 1 equiv) in DMF (2 mL) were added 2-mercaptopyrrolo[2,1-f][1 ,2,4]triazin-4-ol (242.4 mg, 1.452 mmol, 1.5 equiv) and DIEA (311 .8 mg, 2.417 mmol, 2.5 equiv) at room temperature. The resulting solution was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The mixture was further purified by reverse phase column eluted with ACN and H2O (0.05% TFA), after concentrated to afford 2-(((3-ethylpyridin-2-yl)methyl)thio)pyrrolo[2,1- f][1 ,2,4]triazin-4-ol (54.2 mg, 19.6% yield, 98.605% purity) as a trifluoroacetate salt and as a white solid. LC / MS: MS (ESI) calcd. for C14H14N4OS, 286.09 m / z, found 287.05[M+H]+.1H NMR (400 MHz, DMSO-C / 6) 6 (ppm): 12.20 (s, 1 H), 8.46 - 8.47 (m, 1 H), 7.86 - 7.88 (m, 1 H), 7.53 - 7.54 (m, 1 H), 7.46 - 7.47 (m, 1 H), 6.85 - 6.88 (m, 1 H), 6.48 - 6.50 (m, 1 H), 4.65 (s, 2H), 2.78 - 2.84 (m, 2H), 1 .22 -1 .26 (m, 3H).

[0882] Example 60: 2-(((4-ethyl-2-methylpyridin-3-yl)methyl)thio)-7-fluoropyrrolo[2,1 -f] [1 ,2,4]triazin-4- ol

[0883] Step 1. Synthesis of methyl 2-methyl-4-vinylnicotinate

[0884] F ,

[0885] To a mixture of methyl 4-chloro-2-methylnicotinate (6 g, 32.326 mmol, 1 equiv) and ethenyltrifluoro-lambda4-borane potassium (12.99 g, 96.978 mmol, 3 equiv) in DMSO (60 mL) and H2O (12 mL) were added Pd(dppf)Cl2 (2.37 g, 3.233 mmol, 0.1 equiv) and K2CO3 (13.40 g, 96.978 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 85°C for overnight under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford methyl 2-methyl-4-vinylnicotinate (3.8 g, 66.34% yield, 95% purity) as a white solid. LC / MS: MS (ESI) calcd. for C10H11NO2: 177.08, Found: 178.15 [M+H]+. PATENT

[0886] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0887] Step 2. Synthesis of methyl 4-ethyl-2-methylnicotinate

[0888] To a solution of methyl 2-methyl-4-vinylnicotinate (3.7 g, 20.880 mmol, 1 equiv) in MeOH (40 mL) was added Pd / C (3.71 g, 34.870 mmol, 1 .67 equiv, 10%, w / w) at room temperature under hydrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 15 mL). The filtrate was concentrated under reduced pressure to afford methyl 4-ethyl-2- methylnicotinate (3.5 g, crude) as a colorless liquid. LC / MS: MS (ESI) calcd. for C10H13NO2: 179.09, Found: 180.15 [M+H]+.

[0889] Step 3. Synthesis of (4-ethyl-2-methylpyridin-3-yl)methanol ,

[0890] To a stirred solution of methyl 4-ethyl-2-methylnicotinate (3.5 g, 19.529 mmol, 1 equiv) in THF (35 mL) was added DIBAL-H (1 M in hexanes) (58.6 mL, 58.587 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The reaction was quenched with ice water at room temperature. The resulting mixture was filtered, the filter cake was washed with MeCN (3 x 10 mL). The filtrate was concentrated under reduced pressure to afford (4-ethyl-2-methylpyridin-3-yl)methanol (3.1 g, crude) as a yellow solid. LC / MS: MS (ESI) calcd. for C9Hi3NO: 151.10. Found: 152.15[M+H]+.

[0891] Step 4. Synthesis of 3-(chloromethyl)-4-ethyl-2-methylpyridine

[0892] SOCIZ. DCM 1 r OH - £ £ .Cl

[0893] 0 "C - rt, 1 hN

[0894] To a stirred solution of (4-ethyl-2-methylpyridin-3-yl)methanol (3.1 g, 20.501 mmol, 1 equiv) in DCM (30 mL) was added SOCh (7.32 g, 61 .503 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to afford 3-(chloromethyl)-4-ethyl-2- methylpyridine (3.1 g, crude) as a yellow solid. LC / MS: MS (ESI) calcd. for C9H12CIN: 169.07. Found: 170.10 [M+H]+. PATENT

[0895] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0896] Step 5. Synthesis of 2-(((4-ethyl-2-methylpyridin-3-yl)methyl)thio)-7-fluoro-4- methoxypyrrolo[2,1 -f] [1 ,2,4]triazine

[0897] To a stirred solution of 3-(chloromethyl)-4-ethyl-2-methylpyridine (3.1 g, 18.273 mmol, 1 equiv) and 7-fluoro-4-methoxypyrrolo[2,1-f][1 ,2,4]triazine-2-thiol (4.00 g, 20.100 mmol, 1.1 equiv) in DMF (31 mL) was added DIEA (7.09 g, 54.819 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The residue was purified by reverse phase flash with the following conditions (0.05% TFA) to afford 2-(((4-ethyl- 2-methylpyridin-3-yl)methyl)thio)-7-fluoro-4-methoxypyrrolo[2,1-f][1 ,2,4]triazine (4 g, 65.86% yield, 95% purity) as a white solid. LC / MS: MS (ESI) calcd. for C16H17FN4OS: 332.1 1 . Found: 333.10 [M+H]+.

[0898] Step 6. Synthesis of 2-(((4-ethyl-2-methylpyridin-3-yl)methyl)thio)-7-fluoropyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0899] A solution of 2-(((4-ethyl-2-methylpyridin-3-yl)methyl)thio)-7-fluoro-4-methoxypyrrolo[2,1- f][1 ,2,4]triazine (4 g, 12.034 mmol, 1 equiv), LiCI (2.55 g, 60.170 mmol, 5 equiv) and TsOH (10.36 g, 60.170 mmol, 5 equiv) in DMF (40 mL) was stirred at 120°C for 1 h. The reaction was monitored by LCMS. The resulting mixture was purified by reverse phase flash with the following conditions (0.05% NH4HCO3) to afford 2-(((4-ethyl-2-methylpyridin-3-yl)methyl)thio)-7-fluoropyrrolo[2,1- f][1 ,2,4]triazin-4-ol (2.3404 g, 44.98% yield, 99.1 % purity) as a trifluoroacetate salt and as an off- white solid. LC / MS: MS (ESI) calcd. for C15H15FN4OS: 318.10. Found: 319.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) 6 (ppm): 11.96 (s, 1 H), 8.28 - 8.30 (m, 1 H), 7.1 1 - 7.13 (m, 1 H), 6.82 - 6.84 (m, 1 H), 6.24 - 6.33 (m, 1 H), 4.44 - 4.49 (m, 2H), 2.72 - 2.79 (m, 2H), 2.58 (s, 3H), 1 .18 - 1 .22 (m, 3H). PATENT

[0900] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0901] Example 61 : 2-(((4-chloro-2-methylpyridin-3-yl)methyl)thio)-7-fluoropyrrolo[2,1 -f][1 ,2,4]triazin-4- ol

[0902] Step 1. Synthesis of 2-(((4-chloro-2-methylpyridin-3-yl)methyl)thio)-7-fluoro-4- methoxypyrrolo[2,1 -f] [1 ,2,4]triazine

[0903] To a solution of 4-chloro-3-(chloromethyl)-2-methylpyridine (108 mg, 0.613 mmol, 1 equiv) in 2 ml of DMF were added 7-fluoro-4-methoxypyrrolo[2,1 -f][1 ,2,4]triazine-2-thiol (146.65 mg, 0.736 mmol, 1 .2 equiv) and DIEA (237.88 mg, 1 .839 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at room temperature, for 1 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The resulting mixture was quenched with saturated ammonium chloride aqueous solution and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford 2-(((4-chloro-2-methylpyridin-3-yl)methyl)thio)-7- fluoro-4-methoxypyrrolo[2,1 -f][1 ,2,4]triazine (100 mg, 48% yield) as a white solid. LC / MS: MS (ESI) calcd. For C14H12CIFN4OS: 338.79, found: 339.00[M+H]+.

[0904] Step 2. Synthesis of 2-(((4-chloro-2-methylpyridin-3-yl)methyl)thio)-7-fluoropyrrolo[2,1- f] [1 ,2,4]triazi n-4-ol

[0905] To a solution of 2-(((4-chloro-2-methylpyridin-3-yl)methyl)thio)-7-fluoro-4- methoxypyrrolo[2,1-f][1 ,2,4]triazine (100 mg, 0.295 mmol, 1 equiv) in 2 ml of DMF were added LiCI (62.56 mg, 1 .475 mmol, 5 equiv) and PTSA (254.14 mg, 1 .475 mmol, 5 equiv) at room temperature. The resulting mixture was stirred at 110°C for 0.5 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. After cooled to room temperature, the residue was further purified by reverse phase column eluted with ACN and H2O (0.05% NH4HCO3), 5% to 95% gradient in 30 min; after concentrated to afford 2-(((4-chloro-2-methylpyridin-3-yl)methyl)thio)-7- fluoropyrrolo[2,1 -f][1 ,2,4]triazin-4-ol (27.1 mg, 28.27% yield) as a white solid. LC / MS: MS (ESI) calcd. For C13H10CIFN4OS: 324.76, found: 325.00 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 (ppm): 12.32 (brs, 1 H), 8.31 - 8.42 (m, 1 H), 7.42 - 7.51 (m, 1 H), 6.82 - 6.85 (m, 1 H), 6.24 - 6.26 (m, 1 H), 4.54 (s, 2H), 2.82 (s, 3H). PATENT

[0906] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0907] Example 62: 2-(((2,4-diethylpyridin-3-yl)methyl)thio)pyrrolo[2,1 -f| [1 ,2,4]triazin-4-ol

[0908] Step 1. Synthesis of methyl 2,4-divinylnicotinate ,

[0909] To a mixture of methyl 2,4-dichloronicotinate (3 g, 14.562 mmol, 1 equiv) in 1 ,4-dioxane (40 mL) and H2O (8 mL) were added 4,4,5,5-tetramethyl-2-vinyl-1 ,3,2-dioxaborolane (13.46 g, 87.372 mmol, 6 equiv), Pd(dppf)Cl2 (1 .06 g, 1 .456 mmol, 0.1 equiv) and CS2CO3 (14.23 g, 43.686 mmol, 3 equiv) at 25°C under N2 atmosphere. The resulting mixture was stirred at 100°C overnight. Desired product could be detected by LCMS. The reaction was quenched with sat. NH4CI (aq.) at 0°C. The resulting mixture was extracted with EA (3 x 80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.05 % TFA), 5% to 50% gradient in 10 min; detector, UV 254 nm to afford methyl 2,4-divinylnicotinate (1 g, 36.29 % yield, 93 % purity) as a yellow oil. LC / MS (ESI) calcd. For C11H11NO2: 189.08, found: 190.10[M+H]+.

[0910] Step 2. Synthesis of methyl 2,4-diethylnicotinate

[0911] To a solution of methyl 2,4-divinylnicotinate (1 g, 5.285 mmol, 1 equiv) in methanol (15 mL) was added Pd / C (10%, 800 mg) under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 1 h under hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad and concentrated under reduced pressure. Desired product could be detected by LCMS. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in H2O (0.05% TFA), 20% to 70% gradient in 15 min; detector, UV 254 nm to afford methyl 2,4-diethylnicotinate (630 mg, 61 .69% yield, 93% purity) as a white solid. LC / MS (ESI) calcd. For C11H15NO2: 193.11 , found: 194.10[M+H]+.

[0912] Step 3. Synthesis of (2,4-diethylpyridin-3-yl)methanol ,

[0913] To a stirred solution of methyl 2,4-diethylnicotinate (630 mg, 3.260 mmol, 1 equiv) in THF (10 mL) was added LAH (148.46 mg, 3.912 mmol, 1.2 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for 1 h. Desired product could be detected by LCMS. The PATENT

[0914] ATTORNEY-DOCKET NO.: 51478-031 WO3 reaction was quenched with ice water at 0°C. The resulting mixture was filtered, the filter cake was washed with ACN (10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.05% TFA), 2% to 20% gradient in 10 min; detector, UV 254 nm to afford (2,4-diethylpyridin-3-yl)methanol (510 mg, 94.68% yield, 90% purity). LC / MS (ESI) calcd. For CioHi5NO: 165.12, found: 166.20[M+H]+.

[0915] Step 4. Synthesis of 3-(chloromethyl)-2,4-diethylpyridine 0 C - rt, 1 h

[0916] To a stirred solution of (2,4-diethylpyridin-3-yl)methanol (100 mg, 0.605 mmol, 1 equiv) in DCM (3 mL) was added SOCI2 (179.98 mg, 1.512 mmol, 2.5 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was monitored by TLC. The resulting mixture was concentrated under vacuum. The crude product (3-(chloromethyl)-2,4- diethylpyridine (90 mg, crude)) was used in the next step directly without further purification.

[0917] Step 5. Synthesis of 2-(((2,4-diethylpyridin-3-yl)methyl)thio)pyrrolo[2,1-f][1,2,4]triazin-4-ol

[0918] To a stirred solution of 3-(chloromethyl)-2,4-diethylpyridine (100 mg, 0.544 mmol, 1 equiv) and 3-(chloromethyl)-2,4-diethylpyridine (100 mg, 0.544 mmol, 1 equiv) in DMF (2 mL) was added DIEA (211 .10 mg, 1 .632 mmol, 3 equiv) at 0°C. The resulting mixture was stirred at room temperature for additional 1 h. Desired product could be detected by LCMS. The reaction was quenched with sat. NH4CI (aq.) at 0°C. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.05 % TFA), 20% to 50% gradient in 10 min; detector, UV 254 nm to afford 2-(((2,4-diethylpyridin- 3-yl)methyl)thio)pyrrolo[2,1-f][1 ,2,4]triazin-4-ol (90.0 mg, 38.59% yield, 98.8% purity) as a trifluoroacetate salt and as a white solid. LC / MS: mass calcd for C16H18N4OS: 314.12, found: 315.10[M+H]+.1H NMR (300 MHz, DMSO-d6) 6: 12.20 (s, 1H), 8.60 - 8.62 (m, 1 H), 7.56 - 7.63 (m, 2H), 6.88 - 6.90 (m, 1 H), 6.52 - 6.54 (m, 1 H), 4.59 (s, 2H), 2.90 - 3.11 (m, 4H), 1 .24 - 1 .32 (m, 6H). PATENT

[0919] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0920] Example 63: 2-(((2,4-diethylpyridin-3-yl)methyl)thio)-7-fluoropyrrolo[2,1 -f] [1 ,2,4]triazin-4-ol

[0921] Step 1. Synthesis of 2-(((2,4-diethylpyridin-3-yl)methyl)thio)-7-fluoro-4-methoxypyrrolo[2,1- f][1 ,2,4]triazine

[0922] To a stirred solution of 3-(chloromethyl)-2,4-diethylpyridine (100 mg, 0.544 mmol, 1 equiv) and 7-fluoro-4-methoxypyrrolo[2,1-f][1 ,2,4]triazine-2-thiol (130.14 mg, 0.653 mmol, 1.2 equiv) in DMF (2 mL) was added DIEA (211 .10 mg, 1 .632 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for additional 1 h. Desired product could be detected by LCMS. The reaction was quenched with sat. NH4CI(aq.) at 0°C. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in H2O (0.05% TFA), 30% to 70% gradient in 10 min; detector, UV 254 nm to afford 2-(((2,4- diethylpyridin-3-yl)methyl)thio)-7-fluoro-4-methoxypyrrolo[2,1-f][1 ,2,4]triazine (60 mg, 31.81% yield, 93% purity) as a white solid. LC / MS: MS (ESI) calcd. for C17H19FN4OS: 346.13, found: 347.10[M+H]+.

[0923] Step 2. Synthesis of 2-(((2,4-diethylpyridin-3-yl)methyl)thio)-7-fluoropyrrolo[2,1-f][1 ,2,4]triazin- 4-ol

[0924] To a stirred solution of 2-(((2,4-diethylpyridin-3-yl)methyl)thio)-7-fluoro-4-methoxypyrrolo[2,1- f][1 ,2,4]triazine (60 mg, 0.173 mmol, 1 equiv) in DCM (2 mL) was added BBrs (1 .73 mL, 1 .730 mmol, 10 equiv) dropwise at -78°C under N2 atmosphere. The resulting mixture was stirred at 50°C for additional 4 h. Desired product could be detected by LCMS. The reaction was quenched with ice water at 0°C. The mixture was basified to pH= 7 with sat. Na2CO3 (aq.). The resulting mixture was extracted with DCM (3 x 15 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.05 % TFA), 5% to 50% gradient in 10 min; detector, UV 254 nm to afford 2-(((2,4-diethylpyridin-3- yl)methyl)thio)-7-fluoropyrrolo[2,1-f][1 ,2,4]triazin-4-ol (13.0 mg, 16.81 % yield, 99.0% purity) as a white solid. LC / MS: MS (ESI) calcd. for C16H17FN4OS: 332.11 , found: 333.05[M+H]+.1H NMR (300 MHz, DMSO-de) 5: 12.25 (s, 1 H), 8.58 - 8.60 (m, 1 H), 7.57 - 7.59 (m, 1 H), 6.84 - 6.87 (m, 1 H), 6.25 - 6.28 (m, 1 H), 4.60 (s, 2H), 2.89 - 3.10 (m, 4H), 1 .23 - 1 .34 (m, 6H). PATENT

[0925] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0926] Example 64: 2-(((2,4-diethylpyridin-3-yl)methyl)thio)pyrazolo[5,1 -f|[1 ,2,4]triazin-4-ol

[0927] Step 1. Synthesis of 2-(((2,4-diethylpyridin-3-yl)methyl)thio)pyrazolo[5,1-f][1 ,2,4]triazin-4-ol

[0928] To a stirred solution of 3-(chloromethyl)-2,4-diethylpyridine (60 mg, 0.327 mmol, 1 equiv) and 2-sulfanylpyrazolo[3,2-f][1 ,2,4]triazin-4-ol (65.92 mg, 0.392 mmol, 1.2 equiv) in DMF (2 mL) was added DIEA (126.66 mg, 0.981 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred for additional 1 h at room temperature. LCMS showed the reaction was completed. The reaction was quenched with NH4CI at 0 °C. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH C18 OBD Prep Column 5 pm, 30 mm X 150 mm; Mobile Phase A: water(0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 4% B to 21 % B in 9 min; Wave Length: 254nm / 220nm nm; RT1 (min): 8.4) to afford 2-(((2,4-diethylpyridin-3- yl)methyl)thio)pyrazolo[5,1-f][1 ,2,4]triazin-4-ol (17.1 mg, 12.19% yield, 96.1 % purity) as a trifluoroacetate salt and as a white solid. LC / MS: mass calcd for C15H17N5OS: 315.12, found: 316.05[M+H]+.1H NMR (300 MHz, DMSO-d6) 6: 8.61 - 8.59 (m, 1 H), 7.83 - 7.82 (m, 1 H), 7.57 - 7.59 (m, 1 H), 7.03 - 7.04 (m, 1 H), 4.62 (s, 2H), 2.91 - 3.11 (m, 4H), 1 .23 - 1 .32 (m, 6H).

[0929] Example 65: 2-((( 1 ,4-diethyl-1 H-pyrazol-3-yl)methyl)thio)pyrrolo[2,1 -f| [1 ,2,4]triazin-4-ol Step 1. Synthesis of methyl 4-bromo-1-ethyl-1 H-pyrazole-3-carboxylate and methyl 4-bromo- 1 -ethyl-1 H-pyrazole-5-carboxylate

[0930] To a stirred mixture of methyl 4-bromo-1 H-pyrazole-3-carboxylate (2 g, 9.756 mmol, 1 equiv) and K2CO3 (4.04 g, 29.268 mmol, 3 equiv) in DMF (20 mL) was added ethyl iodide (3.04 g, 19.512 mmol, 2 equiv) dropwise at 0°C. The resulting mixture was stirred at 50°C for 2 h. The reaction was monitored by LCMS. After completion of reaction, the mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of sat. NH4CI (aq.) at 0°C, extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2 / 1) to afford methyl 4-bromo-1 -ethyl-1 H-pyrazole-3-carboxylate (800 mg, 35.19% yield, 95% purity) as a yellow oil. LC / MS: MS (ESI) calcd. for C7H9BrN2O2: 231 .98, 233.98. Found: 232.85, 234.85 [M+H]+. PATENT

[0931] ATTORNEY-DOCKET NO.: 51478-031 WO3

[0932] And methyl 4-bromo-1-ethyl-1 H-pyrazole-5-carboxylate (500 mg, 43.98% yield, 90% purity) as a yellow oil. LC / MS: MS (ESI) calcd. for C?H9BrN2O2: 231 .98, 233.98. Found: 232.85, 234.85 [M+H]+.

[0933] Step 2. Synthesis of methyl 1-ethyl-4-vinyl-1 H-pyrazole-3-carboxylate 100 C , 2 h

[0934] To a stirred mixture of methyl 4-bromo-1-ethyl-1 H-pyrazole-3-carboxylate (800 mg, 3.433 mmol, 1 equiv) and Pd(dppf)Cl2 (0.50 g, 0.687 mmol, 0.2 equiv) in dioxane (8 mL) and H2O (2 mL) were added 4,4,5,5-tetramethyl-2-vinyl-1 ,3,2-dioxaborolane (1.06 g, 6.866 mmol, 2 equiv) and CS2CO3 (3.36 g, 10.299 mmol, 3 equiv) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 2 h under nitrogen atmosphere....

Claims

PATENTATTORNEY-DOCKET NO.: 51478-031 WO3CLAIMS1 . A compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof, whereinA is N or CR4;R1is H or F;R2is H or F;R3is H, or Ci-C4alkyl;R4is H or F;R1ais H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, or OR5;R2ais H, halogen, optionally substituted Ci-Ce alkyl, or optionally substituted C3-C12 cycloalkyl;R3ais H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C3-C12 cycloalkyl or OR5;R4ais H, halogen, optionally substituted Ci-Ce alkyl optionally substituted C3-C12 heterocycle or optionally substituted C3-C12 cycloalkyl;R5ais H, optionally substituted C1-6 alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, or OR5;R8is H, optionally substituted Ci-Ce alkyl, optionally substituted C3-C12 cycloalkyl, or CF3; each R9is independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C3-C12 cycloalkyl, or CF3; each R5is, independently, H, or optionally substituted Ci-Ce alkyl; and whereinthen R1aand R5aare both not Cl.

2. The compound of claim 1 , wherein R1is H.PATENTATTORNEY-DOCKET NO.: 51478-031 WO33. The compound of claim 1 , wherein R1is F.

4. The compound of any one of claims 1 -3, wherein R2is H.

5. The compound of any one of claims 1-3, wherein R2is F.

6. The compound of any one of claims 1-5, wherein A is N.

7. The compound of any one of claims 1-5, wherein A is CR4.

8. The compound of claim 7, wherein R4is H.

9. The compound of claim 7, wherein R4is F.

10. The compound of claim 1 , wherein the compound of Formula (I) has the structure:

12. The compound of claim 1 , wherein the compound of Formula (I) has the structure:PATENTATTORNEY-DOCKET NO.: 51478-031 WO314. The compound of any one of claims 1-13, whereinThe compound of claim 14, whereinPATENTATTORNEY-DOCKET NO.: 51478-031 WO316. The compound of claim 14, wherein, ,17. The compound of claim 14, wherein18. The compound of claim 14, wherein19. The compound of claim 14, whereinPATENTATTORNEY-DOCKET NO.: 51478-031 WO3The compound of claim 14, wherein22. The compound of claim 14, whereinThe compound of claim 14, wherein24. The compound of claim 14, wherein25. The compound of any one of claims 1 to 24, wherein R3is C1-C4 alkyl.

26. The compound of claim 25, wherein the C1-C4 alkyl is Me.

27. The compound of claim 1 , wherein the compound of Formula (I) has the structure:PATENTATTORNEY-DOCKET NO.: 51478-031 WO3pharmaceutically acceptable salt thereof.

28. The compound of claim 1 , wherein the compound of Formula (I) has the structure:

29. The compound of claim 1 , wherein the compound of Formula (I) has the structure:pharmaceutically acceptable salt thereof.PATENTATTORNEY-DOCKET NO.: 51478-031 WO330. The compound of claim 1 , wherein the compound of Formula (I) has the structure:31 . The compound of claim 1 , wherein the compound of Formula (I) has the structure:, .

32. The compound of claim 1 , wherein the compound of Formula (I) has the structure:(lll-Z), or a pharmaceutically acceptable salt thereof.

33. The compound of claim 1 , wherein the compound of Formula (I) has the structure:pharmaceutically acceptable salt thereof.

34. The compound of claim 1 , wherein the compound of Formula (I) has the structure:PATENTATTORNEY-DOCKET NO.: 51478-031 WO336. The compound of claim 1 , wherein the compound of Formula (I) has the structure:pharmaceutically acceptable salt thereof.

37. The compound of any one of claims 1 , 27, 30, and 36, wherein R1ais optionally substituted Ci-C6alkyl.

38. The compound of claim 37, wherein the optionally substituted Ci-Ce alkyl is Me, CF3, or CHF2.

39. The compound of any one of claims 1 , 27, 30, and 36, wherein R1ais OR5.

40. The compound of claim 39, wherein OR5is OCH3.41 . The compound of any one of claims 1 , 27, 30, and 36, wherein R1ais optionally substitutedC3-C12 cycloalkyl.

42. The compound of claim 41 , wherein the optionally substituted C3-C12 cycloalkyl is.

43. The compound of any one of claims 1 , 27-29, 33, and 36, wherein R3ais optionally substituted Ci-Ce alkyl.

44. The compound of claim 43, wherein the optionally substituted Ci-Ce alkyl is Me, CF3, or CHF2.

45. The compound of any one of claims 1 , 27-29, 33, and 36, wherein R3ais OR5.

46. The compound of claim 45, wherein OR5is OCH3.PATENTATTORNEY-DOCKET NO.: 51478-031 WO347. The compound of any one of claims 1 , 27-30, 33, and 35-36, wherein R5ais optionally substituted Ci-Ce alkyl.

48. The compound of claim 47, wherein the optionally substituted Ci-Ce alkyl is Me, CF3, or CHF2.

49. The compound of any one of claims 1 , 27-30, 33, and 35-36, wherein R5ais OR5.

50. The compound of claim 49, wherein OR5is OCH3.51 . The compound of any one of claims 1 , 27-30, 33, and 35-36, wherein R5ais optionally substituted C3-C12 cycloalkyl.

52. The compound of claim 1 , wherein the compound of Formula (I) has the structure:

53. The compound of claim 1 , wherein the compound of Formula (I) has the structure:

54. The compound of claim 1 , wherein the compound of Formula (I) has the structure:PATENTATTORNEY-DOCKET NO.: 51478-031 WO355. The compound of claim 1 , wherein the compound of Formula (I) has the structure:or a pharmaceutically acceptable salt thereof.

56. The compound of any one of claims 1 , 52, and 54-55, wherein R8is optionally substituted Ci- Ce alkyl.

57. The compound of claim 56, wherein the optionally substituted Ci-Ce alkyl is CH2CH3, or58. The compound of any one of claims 1 , 52, and 54-55, wherein R8is optionally substituted C3- C12 cycloalkyl.

59. The compound of claim 58, wherein the optionally substituted C3-C12 cycloalkyl is V60. The compound of any one of claims 1 and 52-59, wherein R9is optionally substituted Ci-Ce alkyl.61 . The compound of claim 60, wherein the optionally substituted Ci-Ce alkyl is CH3, or CH2CH3.

62. The compound of any one of claims 1 and 52-59, wherein R9is halogen.

63. The compound of claim 62, wherein the halogen is Cl.

64. The compound of claim 62, wherein the halogen is F.

65. The compound of claim 1 , wherein the compound has the structure of any of compounds 1 -74 in Table 1.

66. A pharmaceutical composition comprising a compound of any one of claims 1 to 65 and a pharmaceutically acceptable excipient.

67. A compound of any one of claims 1 to 65, or a pharmaceutical composition of claim 66 for use as a medicament.PATENTATTORNEY-DOCKET NO.: 51478-031 WO368. A method of treating or preventing neurological pain in a subject in need thereof, the method including administering to the subject an effective amount of a compound of any one of claims 1 to 65, or a pharmaceutical composition of claim 66.

69. A method of claim of claim 68, wherein the neurological pain is neuropathic pain, inflammation, chronic pain, inflammatory pain, arthritic pain, diabetic pain, post-operative pain, lower back pain, central pain, fibromyalgia or neuralgia.

70. A method of treating epilepsy in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 65, or a pharmaceutical composition of claim 66.71 . The method of claim 70, wherein the epilepsy is refractory epilepsy, developmental and epileptic encephalopathies, Lennox-Gastaut syndrome, neurotrauma associated epilepsy (ischemia, stroke, traumatic brain injury), status epilepticus, tumor associated epilepsy, or hypoxic-ischemic encephalopathy.

72. A method of treating neurodevelopmental disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 65, or a pharmaceutical composition of claim 66.

73. The method of claim 72, wherein the neurodevelopmental disorder is autism spectrum disorder, Rett Syndrome, Tuberous Sclerosis Complex (TSC), Fragile X syndrome, Angelman syndrome, Down syndrome, Dravet syndrome, CKDL5 Deficiency syndrome, SYNGAP1 , 22q11 .2 microdeletion syndrome, or cerebral palsy.

74. A method of treating neurotraumatic injury in a subject in need thereof, the method including administering to the subject an effective amount of a compound of any one of claims 1 to 65, or a pharmaceutical composition of claim 66.

75. The method of claim 73, wherein the neurotraumatic injury is traumatic brain injury, stroke, nerve injury or spinal cord injury.

76. A method of treating neurodegenerative disorder in a subject in need thereof, the method including administering to the subject an effective amount of a compound of any one of claims 1 to 65, or a pharmaceutical composition of claim 66.

77. The method of claim 76, wherein the neurodegenerative disorder is multiple sclerosis, amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, Lewy body dementia, or frontotemporal dementia.PATENTATTORNEY-DOCKET NO.: 51478-031 WO378. A method of treating affective disorders in a subject in need thereof, the method including administering to the subject an effective amount of a compound of any one of claims 1 to 65, or a pharmaceutical composition of claim 66.

79. The method of claim 78, wherein the affective disorder is schizophrenia, bipolar disorder, general anxiety disorder, social anxiety disorder, attention-deficit / hyperactivity disorder, or major depressive disorder.

80. A method of treating dementia in a subject in need thereof, the method including administering to the subject an effective amount of a compound of any one of claims 1 to 65, or a pharmaceutical composition of claim 66.81 . The method of claim 80, wherein the dementia is frontotemporal dementia or Lewy body dementia.

82. A method of treating dementia-induced psychosis in a subject in need thereof, the method including administering to the subject an effective amount of a compound of any one of claims 1 to 65, or a pharmaceutical composition of claim 66.

83. A method for potentiating KCC2 activity, clustering, dimerization or membrane expression in a cell or subject, the method comprising contacting the cell with, or administering to the subject, an effective amount of a compound of any one of claims 1 to 65, or a pharmaceutical composition of claim 66.

84. A method for increasing Cl efflux or potentiating KCC2 activity in a cell or subject, the method comprising contacting the cell with, or administering to the subject, an effective amount of a compound of any one of claims 1 to 65, or a pharmaceutical composition of claim 66.

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