Novel pyrrolotriazine derivative and use thereof

Abstract

The present invention relates to a novel pyrrolotriazine derivative, and use thereof as an inhibitor of the activities of YES1 kinase and transcriptional enhanced associated domain (TEAD). The compound of the present invention effectively inhibits the activities of YES1 kinase and TEAD, and thus can be useful for the prevention or treatment of YES1 kinase-related diseases and TEAD-related diseases, particularly solid cancer.

Description

Novel pyrrolotriazine derivatives and uses thereof

[0001] The present invention relates to a novel pyrrolotriazine derivative and its use as an inhibitor of YES1 (YES proto-oncogene 1), a non-receptor protein kinase. More specifically, the present invention relates to its use as an anticancer agent based on inhibition of TEAD activity via a YES1 inhibition mechanism.

[0002]

[0003] Protein kinase is an enzyme that catalyzes the phosphorylation of hydroxyl groups located on tyrosine, serine, and threonine residues of proteins, and plays an important role in growth factor signaling that induces cell growth, differentiation, and proliferation.

[0004] Among protein kinases, tyrosine protein kinases are known to be divided into 58 receptor tyrosine kinases (RTKs) and 32 non-receptor tyrosine kinases (NRTKs). While receptor tyrosine kinases have traditionally been considered primary targets for drug development, non-receptor tyrosine kinases are recently being considered as effective target enzymes for cancer treatment.

[0005] The SRC family of kinases (SFKs) is a non-receptor tyrosine kinase family comprising nine members: SRC, YES, FYN, FGR, LCK, HCK, BLK, LYN, and FRK. Among them, YES1 regulates cancer signaling pathways, is the only SRC kinase family member that exhibits gene amplification in primary tumors of untreated patients, and is known to be overexpressed in cancer to promote cell proliferation, survival, and invasiveness. High levels of YES1 expression are associated with poor prognosis, and its role as a target and prognostic biomarker in cancer has been studied (Garmendia et al., Mol Cancer Ther., 2022, 21, 1371-1380).

[0006] Recently, various reports have investigated the association between YES1 and tumorigenicity. For example, downregulation of YES1 using short hairpin RNA (shRNA) significantly inhibited cell growth in several malignant tumors, including colon carcinoma, rhabdomyosarcoma, and basal-like breast cancer (Sancier et al., PloS One., 2011, 6, e17237; Yeung et al., Oncogene, 2013, 32, 5429-38; Bilalet et al., Genes Cancer, 2010, 1, 1063-73). In addition, some miRNAs have been shown to modulate tumor progression through YES1 regulation (Fang et al., Mol Cancer., 2017, 16, 139).

[0007] Additionally, overexpression of YES1 is known to promote tyrosine phosphorylation of Yes-associated protein (YAP), a mechanism that induces malignant tumors, leading to transcription factor activation through binding to the transcriptional enhanced associated domain (TEAD) via translocation to the nucleus.

[0008] The YAP-TEAD complex induces transcription of genes involved in cell growth, such as connective tissue growth factor (CTGF), and is an important anticancer target that acts at the lowest level of the Hippo pathway. It is overexpressed in various cancers, including prostate, gastric, and rectal cancers. Recently, the Hippo pathway has become a subject of interest in hyperproliferative disorders and diseases, especially in the treatment of cancer (J. Med. Chem. 2018, 61, 12, 5057-5072 (2017)).

[0009]

[0010] The present inventors have conducted research efforts to derive novel compounds having inhibitory properties for YES1 kinase and TEAD, and as a result, have completed the present invention by elucidating that novel pyrrolotriazine derivative compounds can effectively inhibit YES1 kinase and also have excellent inhibitory properties for TEAD.

[0011] The purpose of the present invention is to provide a novel pyrrolotriazine derivative compound having YES1 kinase and TEAD inhibitory activity and a pharmaceutically acceptable salt thereof.

[0012] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating a disease related to YES1 kinase and TEAD, comprising a novel pyrrolotriazine derivative compound, a use of the novel compound for preventing or treating a disease related to YES1 kinase and TEAD, and a method for preventing or treating a disease related to YES1 kinase and TEAD, comprising a step of administering the novel compound to a subject in need thereof.

[0013] However, the purpose of the present invention is not limited to this, and other unmentioned purposes and advantages of the present invention can be understood through the following description and will be more clearly understood through the embodiments of the present invention. Furthermore, the purposes and advantages of the present invention can be readily realized by the means and combinations thereof set forth in the claims.

[0014]

[0015] According to one embodiment of the present invention, a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof is provided.

[0016] [Chemical Formula 1]

[0017]

[0018] In the above chemical formula 1,

[0019] X is C or N,

[0020] Ring B is absent or is (3-10 membered) cycloalkyl or (3-10 membered) heterocyclyl,

[0021] R 1 are each independently hydrogen, halogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-6 Haloalkoxy, (3-10 membered)cycloalkyl, C 1-10 Alkylene-(3-10 membered)cycloalkyl, (3-10 membered)heterocyclyl, C 1-10 Alkylene-(3-10 membered)heterocyclyl, (6-14 membered)aryl, C 1-10 Alkylene-(6-14 membered)aryl, (5-12 membered)heteroaryl, C 1-10 Alkylene-(5-12 membered)heteroaryl, NR a R b , OC 1-10 alkylene-NR a R b , C 1-10 alkylene-O-NR a R b , C(O)-NR a Rb, C 1-10 alkylene-C(O)-NR a R b and C(O)O-NR a R b is one selected from the group consisting of,

[0022] Here, the (3-10 membered) cycloalkyl, (3-10 membered) heterocyclyl, (6-14 membered) aryl and (5-12 membered) heteroaryl are each independently unsubstituted or C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 which may be substituted with any one selected from the group consisting of haloalkyl, NH2, NO2, OH and CN,

[0023] n is an integer from 1 to 4,

[0024] R 2 is hydrogen, halogen, C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 1-5 Haloalkoxy, C(O)-C 1-5 Alkyl, C(O)-C 1-5 Haloalkyl, C(O)OC 1-5 Alkyl, C(O)OC 1-5 Haloalkyl, CC(O)OC 1-5 Alkyl, CC(O)OC 1-5 Haloalkyl, NR c R d , any one selected from the group consisting of O-(6-14 membered) aryl and O-(5-12 membered) heteroaryl,

[0025] The above R c and R d are each independently hydrogen, C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 1-5 Haloalkoxy, C 1-3 Aryl, C 1-3 Heteroaryl, C(O)OC 1-5 Alkyl, C(O)OC 1-5Haloalkyl, C(O)O-(3-10 membered)cycloalkyl, C(O)C 1-3 Aryl, C(O)-(5-12 membered) heteroaryl, and C(0)NHC 1-5 which may be substituted with any one selected from the group consisting of alkyl,

[0026] Here, the (3-10 membered) cycloalkyl and (5-12 membered) heteroaryl are each independently unsubstituted or C 1-6 Alkyl, C 1-6 Alkoxy, halogen and C 1-6 which may be substituted with any one selected from the group consisting of haloalkyl,

[0027] R 3 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NH2, OH, CN, COOH, NO2, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl and C 1-6 Any one selected from the group consisting of alkylamino,

[0028] R 4 is (3-10 membered) cycloalkyl, (3-14 membered) heterocyclyl, (3-14 membered) N-heterocyclyl, (6-14 membered) aryl, (5-12 membered) heteroaryl, C 1-6 Alkylene-(3-10 membered)cycloalkyl, C 1-6 Alkylene-(3-14 membered) heterocyclyl, C 1-6 Alkylene-(3-10 membered) N-heterocyclyl, C 1-6 Alkylene-(6-14 membered) aryl, C 1-6 Alkylene-(5-12 membered) heteroaryl, NR o R p and Any one selected from the group consisting of, wherein the ring A is a (3-10 membered) cycloalkyl or a (3-14 membered) heterocyclyl,

[0029] The above R4 is one or more R 7 can be substituted with , where R7 are each independently halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-10 alkylene-C 1-6 Alkoxy, C 1-10 alkylene-C 1-6 Haloalkoxy, (3-10 membered)cycloalkyl, C 1-10 Alkylene-(3-10 membered)cycloalkyl, (6-14 membered)aryl, C 1-10 Alkylene-(6-14 membered)aryl, (5-12 membered)heteroaryl, C 1-10 Alkylene-(5-12 membered)heteroaryl, NR e R f , C 1-6 Alkyl-NR e R f, C 1-10 alkylene-NR e R f , oxo, C(O)-NR e R f , C 1-10 alkylene-C(O)-NR e R f , C(O)O-NR e R f , CN, OH, NO2, C(O)R e, C(O)OR e , C 1-6 Alkylene-C(O)OR e and C 1-6 alkylene-OH is one selected from the group consisting of,

[0030] R 5 Silver hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NH2, OH, CN, COOH, NO2, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl and C 1-6 Any one selected from the group consisting of alkylamino,

[0031] R6 is NR g R h And,

[0032] R a , R b , R e , R f , R g and R h are each independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Haloalkyl, C(O)OC 1-6 Alkyl and C(O)OC 1-6 Any one selected from the group consisting of haloalkyl,

[0033] R o and R p are each independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, (3-10 membered)cycloalkyl, C 1-10 Alkylene-(3-10 membered)cycloalkyl, (3-10 membered)heterocyclyl and C 1-10 Any one selected from the group consisting of alkylene-(3-10 membered) heterocyclyl,

[0034] The above (3-10 won) cycloalkyl, C 1-10 Alkylene-(3-10 membered)cycloalkyl, (3-10 membered)heterocyclyl or C 1-10 Alkylene-(3-10 membered) heterocyclyl is one or more R 8 can be substituted with , where R 8 are each independently halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NR q R r , C 1-10 alkylene-NR q R r , oxo, C(O)-NR q R r , C 1-10 alkylene-C(O)-NR qR r , C(O)O-NR q R r , CN, OH, NO2, C(O)R q , C(O)OR q, C 1-6 Alkylene-C(O)OR q and C 1-6 Any one selected from the group consisting of alkylene-OH,

[0035] R q and R r are each independently hydrogen, halogen, C 1-6 Alkyl and C 1-6 Any one selected from the group consisting of haloalkyl.

[0036] The compounds disclosed herein have high inhibitory activity against YES1 kinase and transcriptional enhancer associated domain.

[0037] The compounds and pharmaceutical compositions disclosed herein are useful for preventing or treating YES1 kinase-associated diseases or transcriptional enhancer-associated domain-associated diseases by administering the compounds or compositions to a subject.

[0038] The compounds and pharmaceutical compositions disclosed herein are useful for preventing or treating solid tumors by administering the compounds or compositions to a subject.

[0039]

[0040] The pyrrolotriazine derivative compound of the present invention is a novel compound not previously known, which effectively inhibits the activity of YES1 kinase and TEAD, and thus may be useful for the prevention or treatment of YES1 kinase and TEAD-related diseases, particularly solid cancers.

[0041]

[0042] Definition of Terms

[0043] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Furthermore, unless explicitly stated otherwise, numerical values ​​described herein are considered to include the meaning of "about."

[0044] Definitions of residues and substituents used herein are provided below. Unless otherwise specified, each residue has the following definition and is used in the same sense as commonly understood by those skilled in the art.

[0045] The substituents used herein are intended to include both substituted and unsubstituted groups.

[0046] The terms “halo” and “halogen” as used herein refer to bromo, chloro, fluoro or iodo.

[0047] The term "alkyl" as used herein refers to a hydrocarbon group having primary, secondary, tertiary, and / or quaternary carbon atoms, and includes saturated aliphatic groups which may be straight-chain, branched, or cyclic, or combinations thereof. For example, an alkyl group may have 1 to 8 carbon atoms (i.e., C1-C8 alkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable alkyls include methyl (Me, -CH3), ethyl (Et, -C2H5), 1-propyl (n-Pr, -CH2CH2CH3), 2-propyl (i-Pr, -CH(CH3)2), 1-butyl (n-Bu, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, -CH2CH(CH3)2), 2-butyl (s-Bu, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-CH(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3) and octyl (-(CH2)7 C H3) but is not limited to these.

[0048] The term "alkoxy" as used herein means -O-(alkyl) including, but not limited to, -OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4(CH3), -O(CH2)5CH3, and the like, wherein alkyl is as defined above.

[0049] As used herein, the terms "haloalkyl" and "haloalkoxy" refer to alkyl and alkoxy groups, respectively, in which one or more hydrogen atoms are replaced by halogen atoms. For example, haloalkyl includes, but is not limited to, -CF3, -CHF2, -CH2F, -CBr3, -CHBr2, -CH2Br, -CCl3, -CHCl2, -CH2Cl, -CI3, -CHI2, -CH2I, -CH2-CF3, -CH2-CHF3, -CH2-CH2F, -CH2-CBr3, -CH2-CHBr2, -CH2-CH2Br, -CH2-CCl3, -CH2-CHCl2, -CH2-CH2Cl, -CH2-CI3, -CH2-CHI2, -CH2-CH2I and the like. Herein, alkyl and halogen are each as defined above.

[0050] The term "amine" or "amino" as used herein refers to a substituted or unsubstituted amine group represented by the form -NRR', wherein R and R' are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, and heterocyclyl groups.

[0051] The term "amino" also includes the corresponding quaternary ammonium salt of any amino group, e.g., -[N(R1)(Rm)(Rn)] + Examples of amino groups include aminoalkyl groups wherein at least one of R1, Rm, or Rn is an alkyl group. In certain embodiments, R1, Rm, and Rn are selected from hydrogen or alkyl.

[0052] The term “alkylamino” as used herein is a concept that includes mono-alkylamino and di-alkylamino.

[0053] The term "mono-alkylamino" as used herein means -NH(alkyl) including -NHCH3, -NHCH2CH3, -NH(CH2)2CH3, -NH(CH2)3CH3, -NH(CH2)4CH3, -NH(CH2)5CH3 and the like, wherein alkyl is as defined above.

[0054] The term "di-alkylamino" as used herein means -N(alkyl)(alkyl) including -N(CH3)2, -N(CH2CH3)2, -N((CH2)2CH3)2, -N(CH3)(CH2CH3) and the like, wherein each alkyl is independently as defined above.

[0055] The term "cycloalkyl" as used herein means a monocyclic or polycyclic saturated ring having carbon and hydrogen atoms and no carbon-carbon multiple bonds. A cycloalkyl group may have 3 to 10 carbon atoms as a monocyclic, 7 to 12 carbon atoms as a bicyclic, and up to about 20 carbon atoms as a polycyclic. Preferably, the cycloalkyl group may be monocyclic. Examples of cycloalkyl groups include (C3-C 20 )cycloalkyl, or (C3-C 10 ) cycloalkyl, preferably including but not limited to (C3-C7) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl). In addition, the cycloalkyl group may be optionally substituted.

[0056] As used herein, "heterocyclyl (heterocycle)" refers to a monovalent or divalent, saturated or partially saturated non-aromatic ring structure, preferably a 3- to 10-membered ring, more preferably a 3- to 7-membered ring, wherein the ring structure comprises one or more heteroatoms, preferably 1 to 4 heteroatoms, more preferably 1 to 2 heteroatoms. Suitable examples of such heteroatoms include, but are not limited to, oxygen, sulfur and nitrogen. The term "heterocyclyl" also includes polycyclic ring systems having two or more cyclic rings in which at least one carbon is common to two adjacent rings, wherein at least one of the rings is heterocyclic, for example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Bicyclic and polycyclic / heterocyclic ring systems may be fused, bridged, or spiro ring systems.Suitable examples of the above heterocycloalkyl include azetidinyl, dihydropyridyl, dihydroindolyl, tetrahydropyridyl (piperidinyl), tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, indolenyl, piperidinyl, 4-piperidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, 6H-1,2,5-thiadiazinyl, pyranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, Examples include, but are not limited to, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazinyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, quinuclidinyl, morpholinyl, and oxazolidinyl (each of which may be substituted or unsubstituted).

[0057] The term "alkylene" as used herein, unless otherwise specified, may mean an alkylene group having 1 to 20 carbon atoms, 1 to 16 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms or 1 to 4 carbon atoms. The alkylene group may be a straight-chain, branched or cyclic alkylene group, and may be optionally substituted by one or more substituents.

[0058] The term "aryl" as used herein includes substituted or unsubstituted monovalent or divalent aromatic hydrocarbon groups, which are monocyclic, bicyclic, or polycyclic, each atom of the ring being carbon. Preferably, the aryl ring is a 6- to 20-membered ring, a 6- to 14-membered ring, a 6- to 10-membered ring, or preferably a 6-membered ring. An aryl group may be a polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein at least one of the rings is aromatic, for example, the other cyclic ring may be a cycloalkyl, a cycloalkenyl, a cycloalkynyl, an aryl heteroaryl, and / or a heterocyclyl. Examples of aryl groups include, but are not limited to, benzene, naphthalene, phenanthrene, anthracene, indene, indane, phenol, aniline, and the like.

[0059] The term "heteroaryl" as used herein refers to a substituted or unsubstituted monovalent or divalent aromatic group that is monocyclic, bicyclic, or polycyclic and contains one or more heteroatoms in the ring. Examples of suitable heteroatoms that can be contained in the aromatic ring include, but are not limited to, oxygen, sulfur, and nitrogen. In a polycyclic heteroaryl ring system, the ring system has two or more cyclic rings in which at least one carbon is common to two adjacent rings, wherein at least one of the rings is heteroaromatic, for example, the other cyclic ring can be a cycloalkyl, a cycloalkenyl, a cycloalkynyl, an aryl, a heteroaryl, and / or a heterocyclyl. Bicyclic and polycyclic / heteroaryl ring systems can be fused, bridged, or spiro ring systems. Representative heteroaryls include, but are not limited to, triazolyl, tetrazolyl, oxadiazolyl, pyridinyl, furyl, benzofuranyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, isoxazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl, pyrimidyl, oxetanyl, azepinyl, piperazinyl, morpholinyl, dioxanyl, and oxazolyl, each of which may be substituted or unsubstituted.

[0060] The term "substituted" used in the present invention with respect to alkyl, alkoxy, alkoxyalkyl, alkylamino, aryl, heteroaryl, cycloalkyl or heterocyclyl means that one or more hydrogen atoms of alkyl, alkoxy, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, heterocyclyl or cycloalkyl are each independently replaced by a non-hydrogen substituent. Substituents include, but are not limited to, any of the substituents described herein, for example, halogen, hydroxyl, amino, nitroalkyl, alkoxy, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), phosphoryl, phosphate, phosphonate, amido, amidine, imine, cyano, azido, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. Those skilled in the art will appreciate that the substituted moiety on the hydrocarbon chain may itself be substituted, if desired.

[0061] Unless otherwise specified, the point of attachment of a substituent used herein may be from any suitable position on the substituent.

[0062] As used herein, the terms "treat," "treating," "treatment," "improvement," and "improving" refer to any sign of success in treating or ameliorating an injury, pathology, condition, or symptom (e.g., pain), including any objective or subjective parameter, such as ameliorating, remission, reducing symptoms, making the symptom, injury, pathology, or condition more tolerable to the patient, reducing the frequency or duration of the symptom or condition, or, in some circumstances, preventing the onset of the symptom or condition. Treatment or amelioration of symptoms may be based on any objective or subjective parameter, including, for example, the results of a physical examination.

[0063] The term "prevention" as used herein collectively refers to partially or completely delaying or preventing the onset or recurrence of a disease, disorder, or its associated symptoms, preventing the acquisition or reacquisition of a disease or disorder, or reducing the risk of acquiring a disease or disorder. The term "prevention" refers to any action that inhibits or delays the development of cancer using a composition according to one embodiment of the present invention.

[0064] The phrase "pharmaceutically acceptable" as used herein is a term commonly used in the art to indicate that a substance or composition must be chemically and / or toxicologically compatible with the other ingredients making up the formulation and / or the mammal to be treated therewith.

[0065] "Pharmaceutically acceptable salt" or "salt" is used herein to refer to an acid or base addition salt suitable for or compatible with the treatment of a patient. Exemplary inorganic acids that form suitable salts include hydrochloric, hydrobromic, sulfuric, and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphoric acid and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include mono-, di-, and tricarboxylic acids, such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic, and salicylic acids, as well as sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. Mono- or diacid salts may be formed, and such salts may exist in hydrated, solvated, or substantially anhydrous form. In general, acid addition salts of the compounds of the present invention are more soluble in water and various hydrophilic organic solvents, and generally exhibit higher melting points, compared to their free base forms. The selection of suitable salts is well known to those skilled in the art. Other non-pharmaceutically acceptable salts, such as oxalates, may be used, for example, in the isolation of the compounds of the present invention, either for laboratory use or for subsequent conversion into pharmaceutically acceptable acid addition salts. Exemplary inorganic bases that form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Exemplary organic bases that form suitable salts include aliphatic, cycloaliphatic, or aromatic organic amines, such as methylamine, trimethylamine, and picoline, or ammonia. Thus, in some instances, contemplated salts of the present invention include alkyl, dialkyl, trialkyl, or tetra-alkyl ammonium salts.In certain embodiments, contemplated salts of the present invention include, but are not limited to, L-arginine, benentamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.

[0066] The selection of appropriate salt is known to those skilled in the art.

[0067] Pharmaceutically acceptable acid addition salts may also exist as solvates with various solvents, such as water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates may also be prepared. The source of such solvates may be from the solvent of crystallization, inherent in the solvent of crystallization or preparation, or incidental to such solvent.

[0068] The term "IC" used herein 50 " refers to the concentration of an inhibitor or compound that achieves 50% inhibition of the target protein.

[0069] The term "GI" used herein 50 "refers to the concentration of an inhibitor or compound that produces 50% inhibition of maximal inhibition of cell proliferation.

[0070] The terms "subject," "subject," "individual," and "patient" as used herein refer to warm-blooded animals, such as, for example, pigs, cows, chickens, horses, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, monkeys, chimpanzees, and humans.

[0071]

[0072] Pyrrolotriazine derivative compounds

[0073] The present invention provides a novel pyrrolotriazine derivative compound.

[0074] In one embodiment, the present invention relates to a novel pyrrolotriazine derivative compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0075] [Chemical Formula 1]

[0076]

[0077] In the above chemical formula 1,

[0078] X is C or N,

[0079] Ring B is absent or is (3-10 membered) cycloalkyl or (3-10 membered) heterocyclyl,

[0080] R 1 are each independently hydrogen, halogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-6 Haloalkoxy, (3-10 membered)cycloalkyl, C 1-10 Alkylene-(3-10 membered)cycloalkyl, (3-10 membered)heterocyclyl, C 1-10 Alkylene-(3-10 membered)heterocyclyl, (6-14 membered)aryl, C 1-10 Alkylene-(6-14 membered)aryl, (5-12 membered)heteroaryl, C 1-10 Alkylene-(5-12 membered)heteroaryl, NR a R b, OC 1-10 alkylene-NR a R b , C 1-10 alkylene-O-NR a R b , C(O)-NR a R b , C 1-10 alkylene-C(O)-NR a R b and C(O)O-NR a Rb is one selected from the group consisting of,

[0081] Here, the (3-10 membered) cycloalkyl, (3-10 membered) heterocyclyl, (6-14 membered) aryl and (5-12 membered) heteroaryl are each independently unsubstituted or C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 which may be substituted with any one selected from the group consisting of haloalkyl, NH2, NO2, OH and CN,

[0082] n is an integer from 1 to 4,

[0083] R 2 is hydrogen, halogen, C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 1-5 Haloalkoxy, C(O)-C 1-5 Alkyl, C(O)-C 1-5 Haloalkyl, C(O)OC 1-5 Alkyl, C(O)OC 1-5 Haloalkyl, CC(O)OC 1-5 Alkyl, CC(O)OC 1-5 Haloalkyl, NR c R d , any one selected from the group consisting of O-(6-14 membered) aryl and O-(5-12 membered) heteroaryl,

[0084] The above R c and R d are each independently hydrogen, C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 1-5 Haloalkoxy, C 1-3 Aryl, C 1-3 Heteroaryl, C(O)OC 1-5 Alkyl, C(O)OC 1-5 Haloalkyl, C(O)O-(3-10 membered)cycloalkyl, C(O)C 1-3 Aryl, C(O)-(5-12 membered) heteroaryl, and C(0)NHC 1-5which may be substituted with any one selected from the group consisting of alkyl,

[0085] Here, the (3-10 membered) cycloalkyl and (5-12 membered) heteroaryl are each independently unsubstituted or C 1-6 Alkyl, C 1-6 Alkoxy, halogen and C 1-6 which may be substituted with any one selected from the group consisting of haloalkyl,

[0086] R 3 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NH2, OH, CN, COOH, NO2, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl and C 1-6 Any one selected from the group consisting of alkylamino,

[0087] R 4 is (3-10 membered) cycloalkyl, (3-14 membered) heterocyclyl, (3-14 membered) N-heterocyclyl, (6-14 membered) aryl, (5-12 membered) heteroaryl, C 1-6 Alkylene-(3-10 membered)cycloalkyl, C 1-6 Alkylene-(3-14 membered) heterocyclyl, C 1-6 Alkylene-(3-10 membered) N-heterocyclyl, C 1-6 Alkylene-(6-14 membered) aryl, C 1-6 Alkylene-(5-12 membered) heteroaryl, NR o R p and is one selected from the group consisting of,

[0088] Here, the above ring A is (3-10 membered) cycloalkyl or (3-14 membered) heterocyclyl,

[0089] The above R 4 is one or more types of R 7 can be substituted with , where R 7 are each independently halogen, C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-10 alkylene-C 1-6 Alkoxy, C 1-10 alkylene-C 1-6 Haloalkoxy, (3-10 membered)cycloalkyl, C 1-10 Alkylene-(3-10 membered)cycloalkyl, (6-14 membered)aryl, C 1-10 Alkylene-(6-14 membered)aryl, (5-12 membered)heteroaryl, C 1-10 Alkylene-(5-12 membered)heteroaryl, NR e R f , C 1-6 Alkyl-NR e R f, C 1-10 alkylene-NR e R f , oxo, C(O)-NR e R f, C 1-10 alkylene-C(O)-NR e R f , C(O)O-NR e R f , CN, OH, NO2, C(O)R e , C(O)OR e , C 1-6 Alkylene-C(O)OR e and C 1-6 alkylene-OH is one selected from the group consisting of,

[0090] R 5 Silver hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NH2, OH, CN, COOH, NO2, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl and C 1-6 Any one selected from the group consisting of alkylamino,

[0091] R 6 is NR g R h And,

[0092] R a , R b , R e , R f , R g and R h are each independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Haloalkyl, C(O)OC 1-6 Alkyl and C(O)OC 1-6 Any one selected from the group consisting of haloalkyl,

[0093] R o and R p are each independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, (3-10 membered)cycloalkyl, C 1-10 Alkylene-(3-10 membered)cycloalkyl, (3-10 membered)heterocyclyl and C 1-10 Any one selected from the group consisting of alkylene-(3-10 membered) heterocyclyl,

[0094] The above (3-10 won) cycloalkyl, C 1-10 Alkylene-(3-10 membered)cycloalkyl, (3-10 membered)heterocyclyl or C 1-10 Alkylene-(3-10 membered) heterocyclyl is one or more R 8 can be substituted with , where R 8 are each independently halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NR q R r , C 1-10 alkylene-NR q R r , oxo, C(O)-NR q R r , C 1-10 alkylene-C(O)-NR q R r , C(O)O-NR q R r, CN, OH, NO2, C(O)R q , C(O)OR q, C 1-6 Alkylene-C(O)OR q and C 1-6 Any one selected from the group consisting of alkylene-OH,

[0095] R q and R r are each independently hydrogen, halogen, C 1-6 Alkyl and C 1-6 It may be any one selected from the group consisting of haloalkyl.

[0096] In one specific embodiment of the present invention, R 1 Silver hydrogen, halogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-6 Haloalkoxy, NR a R b, OC 1-10 alkylene-NR a R b , C 1-10 alkylene-O-NR a R b , C(O)-NR a R b, C 1-10 alkylene-C(O)-NR a R b and C(O)O-NR a R b is one selected from the group consisting of,

[0097] n is an integer from 1 to 4,

[0098] R 2 is hydrogen, halogen, C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 1-5 Haloalkoxy, NR c R d , any one selected from the group consisting of O-(6-14 membered) aryl and O-(5-12 membered) heteroaryl,

[0099] The above R c and R d are each independently hydrogen, C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 1-5 Haloalkoxy, C(O)OC 1-5 Alkyl, C(O)OC 1-5 which may be substituted with at least one selected from the group consisting of haloalkyl, C(O)O-(3-10 membered)cycloalkyl and C(O)-(5-12 membered)heteroaryl,

[0100] Here, the (3-10 membered) cycloalkyl and (5-12 membered) heteroaryl are each independently unsubstituted or C 1-6 Alkyl or C 1-6 may be substituted with haloalkyl,

[0101] R 3 is hydrogen, halogen, C 1-6 Alkyl and C 1-6 It may be any one selected from the group consisting of haloalkyl.

[0102] In one specific embodiment of the present invention, R 4 is (3-10 membered) cycloalkyl, (3-14 membered) heterocyclyl, (3-14 membered) N-heterocyclyl, (6-14 membered) aryl, (5-12 membered) heteroaryl, C 1-6 Alkylene-(3-10 membered) cycloalkyl, C 1-6 Alkylene-(3-14 membered) heterocyclyl, C 1-6 Alkylene-(3-10 membered) N-heterocyclyl, C 1-6 Alkylene-(6-14 membered) aryl, C 1-6 Alkylene-(5-12 membered) heteroaryl, NR o R p and is one selected from the group consisting of,

[0103] Here, the above ring A is (3-10 membered) cycloalkyl or (3-14 membered) heterocyclyl,

[0104] The above R4 is one or more types of R 7 can be substituted with , where R 7 Silver halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-10 alkylene-C 1-6 Alkoxy, C 1-10 alkylene-C 1-6 Haloalkoxy, (3-10 membered)cycloalkyl, (6-14 membered)aryl, (5-12 membered)heteroaryl, NR e R f , C 1-10 Alkyl-NR e R f , C 1-10 alkylene-NR e R f , oxo, C(O)-NR e R f, C 1-10 alkylene-C(O)-NR e R f , C(O)O-NR e R f , CN, OH, NO2, C(O)R e , C(O)OR e , C 1-6 Alkylene-C(O)OR e and C 1-6 Any one selected from the group consisting of alkylene-OH,

[0105] R o and R p are each independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, (3-10 membered) cycloalkyl, C 1-10 Alkylene-(3-10 membered) cycloalkyl, (3-10 membered) heterocyclyl and C 1-10 Any one selected from the group consisting of alkylene-(3-10 membered) heterocyclyl,

[0106] The above (3-10 won) cycloalkyl, C 1-10 Alkylene-(3-10 membered) cycloalkyl, (3-10 membered) heterocyclyl or C1-10 Alkylene-(3-10 membered) heterocyclyl is one or more R 8 can be substituted with , where R 8 Silver halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NR q R r , C 1-10 alkylene-NR q R r , oxo, C(O)-NR q R r , C 1-10 alkylene-C(O)-NR q R r , C(O)O-NR q R r , CN, OH, NO2, C(O)R q , C(O)OR q, C 1-6 Alkylene-C(O)OR q and C 1-6 Any one selected from the group consisting of alkylene-OH,

[0107] R q and R r are each independently hydrogen, halogen, C 1-6 Alkyl and C 1-6 It may be any one selected from the group consisting of haloalkyl.

[0108] In one specific embodiment of the present invention, R 5 Silver hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NH2, OH, CN, COOH, NO2, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl and C 1-6 Any one selected from the group consisting of alkylamino,

[0109] R 6 is NR g R h And,

[0110] R gand R h are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C(O)C 1-6 It can be any one selected from the group consisting of alkyl.

[0111] In one specific embodiment of the present invention, R 1 Silver hydrogen, halogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy and C 1-6 Any one selected from the group consisting of haloalkoxy,

[0112] R 2 is NR c R d , O-(6-14 membered) aryl or O-(5-12 membered) heteroaryl,

[0113] The above R c and R d are each independently hydrogen, C(O)OC 1-5 Alkyl, C(O)OC 1-5 Haloalkyl, C(O)O-(3-10 membered)cycloalkyl and C(O)-(5-12 membered)heteroaryl,

[0114] Here, the (3-10 membered) cycloalkyl and (5-12 membered) heteroaryl are each independently unsubstituted or C 1-6 Alkyl, C 1-6 Alkoxy, halogen and C 1-6 It may be substituted with any one selected from the group consisting of haloalkyl, R 3 is hydrogen, halogen, C 1-6 Alkyl and C 1-6 Any one selected from the group consisting of haloalkyl,

[0115] R 4is a monocyclic (3-7 membered) cycloalkyl, a monocyclic (3-6 membered) heterocyclyl, a spirocyclic (7-14 membered) heterocyclyl, a fused cyclic (7-14 membered) heterocyclyl, a (6-10 membered) aryl, a (5-10 membered) heteroaryl, C 1-6 Alkylene-(3-10 membered) N-heterocyclyl, NR o R p and is one selected from the group consisting of,

[0116] Here, the above ring A is (3-10 membered) cycloalkyl or (3-14 membered) heterocyclyl,

[0117] The above R 4 is one or more types of R 7 can be substituted with , where R 7 Silver halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-10 alkylene-C 1-6 Alkoxy, (3-10 membered) cycloalkyl, (6-14 membered) aryl, (5-12 membered) heteroaryl, NR e R f , C 1-6 Alkyl-NR e R f , C 1-10 alkylene-NR e R f , oxo, CN, OH, NO2, C(O)OR e , C 1-6 Alkylene-C(O)OR e and C 1-6 Any one selected from the group consisting of alkylene-OH,

[0118] R 5 is hydrogen or halogen,

[0119] R 6 is NR g R h And,

[0120] R e , R f , Rg and R h are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C(O)C 1-6 Any one selected from the group consisting of alkyl

[0121] R o and R p are each independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, (3-10 membered) cycloalkyl, C 1-10 Alkylene-(3-10 membered) cycloalkyl, (3-10 membered) heterocyclyl and C 1-10 Any one selected from the group consisting of alkylene-(3-10 membered) heterocyclyl,

[0122] The above (3-10 won) cycloalkyl, C 1-10 Alkylene-(3-10 membered) cycloalkyl, (3-10 membered) heterocyclyl or C 1-10 Alkylene-(3-10 membered) heterocyclyl is one or more R 8 can be substituted with , where R 8 Silver halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NR q R r , C 1-10 alkylene-NR q R r , oxo, C(O)-NR q R r , C 1-10 alkylene-C(O)-NR q R r , C(O)O-NR q R r , CN, OH, NO2, C(O)R q , C(O)OR q, C 1-6 Alkylene-C(O)OR q and C 1-6 Any one selected from the group consisting of alkylene-OH,

[0123] Rq and R r are each independently hydrogen, halogen, C 1-6 Alkyl and C 1-6 It may be any one selected from the group consisting of haloalkyl.

[0124] In one specific embodiment of the present invention,

[0125] The above ring B is absent or is (3-10 membered) heterocyclyl,

[0126] The above R 1 is hydrogen or methoxy,

[0127] The above R 2 Is , , , , and is one selected from the group consisting of,

[0128] The above R 3 is hydrogen, halogen, C 1-3 Alkyl and C 1-3 It may be any one selected from the group consisting of haloalkyl.

[0129] In one specific embodiment of the present invention, the R 4 Is

[0130] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and It can be any one selected from the group consisting of .

[0131] In one embodiment of the present invention,

[0132] R 5 is hydrogen or halogen,

[0133] R 6 is NR g R h And,

[0134] R g and R h are each independently hydrogen or C 1-6 It could be an alkyl.

[0135] In one specific embodiment of the present invention,

[0136] Above Is , , , , , , and It can be any one selected from the group consisting of .

[0137] In one specific embodiment of the present invention, the representative compound of the chemical formula 1 includes, but is not limited to, a compound selected from the group consisting of compounds 1 to 138 below.

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145] In one embodiment of the present invention, the present invention can provide a pharmaceutical composition for preventing or treating a YES1-associated disease, comprising the above-described pyrrolotriazine derivative compound or a pharmaceutically acceptable salt thereof.

[0146] In one embodiment of the present invention, the present invention can provide a pharmaceutical composition for preventing or treating a Transcriptional Enhanced Associated Domain (TEAD)-related disease, comprising the above-described pyrrolotriazine derivative compound or a pharmaceutically acceptable salt thereof.

[0147] In one embodiment of the present invention, the YES1-associated disease and the transcriptional enhancement-associated domain-associated disease include malignant cells expressing YES1 kinase and hyperproliferative malignant cells whose cell growth is not suppressed by the activity of the transcriptional enhancement-associated domain, such as cancer. In some embodiments, the cancer includes a solid tumor.

[0148] In one embodiment of the present invention, the present invention can provide a pharmaceutical composition for preventing or treating solid cancer, comprising the above-described pyrrolotriazine derivative compound or a pharmaceutically acceptable salt thereof.

[0149] In one embodiment of the present invention, the present invention can provide a pharmaceutical composition for preventing or treating a solid cancer, wherein the solid cancer is any one selected from the group consisting of thyroid cancer, bladder cancer, breast cancer, colon cancer, small intestine cancer, endometrial cancer, cervical cancer, bone cancer, stomach cancer, lymphoma, bronchial cancer, laryngeal cancer, head and neck cancer, liver cancer, prostate cancer, pancreatic cancer, ovarian cancer, esophageal cancer, kidney cancer, lung cancer, oral cancer, brain cancer, brain tumor, glioma, gallbladder cancer, cholangiocarcinoma, skin cancer, skin melanoma, rectal cancer, colon cancer, uterine cancer, uterine sarcoma, and malignant mesothelioma.

[0150] In the present invention, the term "pharmaceutical composition" may refer to a composition comprising a molecule or compound that, when administered to a subject, imparts several beneficial pharmaceutical effects. Such beneficial pharmaceutical effects may include enabling diagnostic determination; improving a disease, symptom, disorder, or condition; reducing or preventing the onset of a disease, symptom, disorder, or condition; and generally combating a disease, symptom, disorder, or condition.

[0151] The above pharmaceutical composition may be formulated as any one preparation selected from the group consisting of tablets, soft or hard capsules, pills, powders, suspensions, syrups, injections, and granules.

[0152] The above pharmaceutical composition may be for oral or parenteral administration.

[0153] The concentration of the active ingredient of the pharmaceutical composition may be 0.00001 to 9 wt% based on the total weight of the composition, for example, 0.00001 wt% or more, 0.0001 wt% or more, 0.001 wt% or more, 0.01 wt% or more, 9 wt% or less, 8 wt% or less, 7 wt% or less, 6 wt% or less, 5 wt% or less, 4 wt% or less, 3 wt% or less, 2 wt% or less, or 1 wt% or less. In one embodiment of the present specification, the concentration of the active ingredient may preferably be 0.0001 to 5 wt%, more preferably 0.001 to 3 wt%.

[0154] The pharmaceutical composition may contain conventional fillers, bulking agents, binders, disintegrants, anticoagulants, lubricants, wetting agents, pH regulators, nutrients, vitamins, electrolytes, alginic acid and its salts, pectic acid and its salts, protective colloids, glycerin, flavorings, emulsifiers, or preservatives. The formulation of the pharmaceutical composition may vary depending on the method of use, and may be formulated using methods well known in the art to which the present invention pertains so as to provide rapid, sustained, or delayed release of the active ingredient after administration to a mammal.

[0155] One embodiment of the present invention provides a method for preventing, improving, or treating a condition of a subject, comprising administering the pharmaceutical composition to the subject. Administration may be by any method known in the art. Administration may be by any route, such as intravenous, intramuscular, oral, transdermal, mucosal, intranasal, intratracheal, or subcutaneous administration, directly into the subject. Administration may be systemic or local.

[0156] The above administration is in an amount of 0.00001 mg to 1,000 mg per day per subject, for example, 0.00001 mg to 500 mg, 0.00001 mg to 100 mg, 0.00001 mg to 50 mg, 0.00001 mg to 25 mg, 1 mg to 1,000 mg, 1 mg to 500 mg, 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 25 mg, 5 mg to 1,000 mg, 5 mg to 500 mg, 5 mg to 100 mg, 5 mg to 50 mg, 5 mg to 25 mg, 10 mg to 1,000 mg, 10 mg to 500 mg, 10 mg to 100 mg, 10 mg to 50 mg, or It may be administered in a dose of 10 mg to 25 mg. However, the dosage may vary depending on factors such as the formulation method, administration method, patient age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and response sensitivity, and a person skilled in the art can appropriately adjust the dosage by considering these factors. The frequency of administration may be once a day or twice or more within the range of clinically acceptable side effects, and the administration site may be administered in one or more sites, and the total number of administration days may be from 1 to 30 days per treatment, daily or at intervals of 2 to 5 days. If necessary, the same treatment may be repeated after an appropriate period. For animals other than humans, the same dosage as for humans per kg may be administered, or the above dosage may be converted into an amount based on the volume ratio (e.g., average value) of the organs (heart, etc.) of the target animal and humans.

[0157]

[0158] For preventive or therapeutic purposes

[0159] The novel pyrrolotriazine derivative compound or a pharmaceutically acceptable salt thereof according to the present invention exhibits a preventive or therapeutic effect on cancer diseases associated with the activity of YES1 kinase and transcriptional enhancer associated domain (TEAD) by inhibiting the activity of these kinases.

[0160] In one embodiment of the present invention, the compound of the present invention can be used for the prevention or treatment of YES1 kinase-associated diseases and transcriptional enhancer-associated domain (TEAD)-associated diseases.

[0161] In one embodiment of the present invention, the YES1-associated disease and the transcriptional enhancement-associated domain-associated disease include malignant cells expressing YES1 kinase and hyperproliferative malignant cells, e.g., cancer, whose cell growth is not suppressed by the activity of the transcriptional enhancement-associated domain.

[0162] In one embodiment of the present invention, the use of a compound according to the present invention or a pharmaceutically acceptable salt thereof for the prevention or treatment of solid cancer is provided. In a specific embodiment, the solid cancer may be, but is not limited to, thyroid cancer, bladder cancer, breast cancer, colon cancer, small intestine cancer, endometrial cancer, cervical cancer, bone cancer, stomach cancer, lymphoma, bronchial cancer, laryngeal cancer, head and neck cancer, liver cancer, prostate cancer, pancreatic cancer, ovarian cancer, esophageal cancer, kidney cancer, lung cancer, oral cancer, brain cancer, brain tumor, glioma, gallbladder cancer, cholangiocarcinoma, skin cancer, skin melanoma, rectal cancer, colon cancer, uterine cancer, uterine sarcoma, and malignant mesothelioma.

[0163]

[0164] Hereinafter, the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples, in accordance with the gist of the present invention.

[0165]

[0166] Intermediate manufacturing example

[0167] Intermediate 1: Preparation of 2-fluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0168] The title compound was prepared by the method shown in the following reaction scheme 1.

[0169] [Reaction Formula 1]

[0170]

[0171] 2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 eq), K2CO3 (3.0 eq), and MeI (2.5 eq) were dissolved in DMF and stirred at 100 °C for 16 h. After cooling the reaction mixture to room temperature, water was added, and the organic matter was extracted with ethyl acetate. After washing the organic layer with brine, the remaining water was removed through Na2SO4, and the organic matter was concentrated. The concentrate was purified through a silica gel column (Petroleum ether / Ethyl acetate (B: 0-5% concentration variation)). The target compound was obtained as a colorless oil and was actually used in the preparation of Example 4 (yield: 76.0%, LCMS: m / z (M+H)+= 266.1).

[0172]

[0173] Intermediate 2: Preparation of 2-methoxy-N,N-di(methyl)-4-[4,4,5,5-tetra(methyl)-1,3,2-dioxaborolan-2-yl]aniline

[0174] The title compound was prepared by the method shown in the following reaction scheme 2.

[0175] [Reaction Formula 2]

[0176]

[0177]

[0178] Step 1: Preparation of 4-bromo-2-methoxy-N,N-dimethylaniline

[0179] 4-Bromo-2-methoxyaniline (1.0 eq) and 37% paraformaldehyde (3.0 eq) were dissolved in methanol, acetic acid (0.1 eq) was added, and the mixture was stirred at room temperature under nitrogen for 2 hours. NaBH3CN (1.5 eq) was added little by little to the reaction mixture, and the mixture was stirred at room temperature for 32 hours. After completion of the reaction, sat. NaHCO3 aqueous solution was added, and the organic matter was extracted with ethyl acetate. The organic layer was washed with brine, and the remaining water was removed with Na2SO4, and the mixture was concentrated. The concentrate was purified through a silica gel column (Petroleum ether / Ethyl acetate (B: 1-5% concentration variation)). The target compound 4-bromo-2-methoxy-N,N-dimethylaniline was obtained as a colorless oil (yield: 79.0%, LCMS: m / z (M+H)+= 229.9).

[0180]

[0181] Step 2: Preparation of 2-methoxy-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0182] 4-Bromo-2-methoxy-N,N-dimethylaniline (1.0 eq) prepared in Step 1 was dissolved in 1,4-dioxane, and then B2pin2 (1.2 eq), Pd(dppf)Cl2 (0.1 eq), and KOAc (2.0 eq) were added, and the mixture was stirred at 100°C for 16 h under nitrogen. After completion of the reaction, the mixture was concentrated under reduced pressure, and the concentrate was purified through a silica gel column (Petroleum ether / Ethyl acetate (B: 1-6% concentration variation)). The target compound was obtained as a yellow oil and was actually used in the preparation of Example 6 (yield: 83.0%, LCMS: m / z (M+H)+= 278.2).

[0183]

[0184] Intermediate 3: Preparation of N,N,4-trimethylpiperidin-4-amine

[0185] The title compound was prepared by the method shown in the following reaction scheme 3.

[0186] [Reaction Formula 3]

[0187]

[0188]

[0189] Step 1: Preparation of tert-butyl 4-(dimethylamino)-4-methylpiperidine-1-carboxylate

[0190] tert-Butyl 4-amino-4-methylpiperidine-1-carboxylate (1.0 eq) and 37% paraformaldehyde (3.0 eq) were dissolved in acetic acid (0.1 eq) and methanol, and stirred for 1 hour. Then, the reaction mixture was cooled to 0°C and NaBH3CN (2.0 eq) was added. The mixture was stirred at room temperature for 15 hours, and after completion of the reaction, sat. NaHCO3 aqueous solution was added and the organic matter was extracted with ethyl acetate. The organic layer was washed with brine, and the remaining water was removed with Na2SO4 and concentrated. The concentrate was purified through a silica gel column (Petroleum ether / Ethyl acetate (B: 60-85% concentration variation)). The target compound tert-butyl 4-(dimethylamino)-4-methylpiperidine-1-carboxylate was obtained as a colorless oil (yield: 32.4%, LCMS: m / z (M+H)+= 243.2).

[0191]

[0192] Step 2: Preparation of N,N,4-trimethylpiperidin-4-amine

[0193] tert-Butyl 4-(dimethylamino)-4-methylpiperidine-1-carboxylate (1.0 eq) prepared in Step 1 was added with HCl (2 M in dioxane) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and obtained as a yellow solid without further purification, which was actually used in the preparation of Example 13 (yield: 100%, LCMS: m / z (M+H)+= 143.3).

[0194]

[0195] In addition, intermediates were prepared in the same manner for Examples 18, 30, and 32.

[0196]

[0197] Example Manufacturing Example

[0198] Example 1: Preparation of tert-butyl(4-(4-amino-7-(4-(dimethylamino)phenyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0199] The title compound was prepared by the method shown in the following reaction scheme 4.

[0200] [Reaction Formula 4]

[0201]

[0202]

[0203] Step 1: Preparation of 7-bromanyl-5-iodanyl-pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0204] 7-Bromannylpyrrolo[2,1-f][1,2,4]triazin-4-amine (1.0 eq) was dissolved in DMF, NIS (1.4 eq) was added, and the mixture was stirred at room temperature for two days. After completion of the reaction, the precipitate was filtered and washed with ACN to obtain the target compound 7-bromannyl-5-iodanyl-pyrrolo[2,1-f][1,2,4]triazin-4-amine as a white solid without further purification (yield: 80.7%, LCMS: m / z (M+H)+= 338.9).

[0205]

[0206] Step 2: Preparation of 1,1-di(methyl)ethylN-[4-(4-azanyl-7-bromanyl-pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxy-phenyl]carbamate

[0207] 7-Bromanyl-5-iodanyl-pyrrolo[2,1-f][1,2,4]triazin-4-amine (1.0 eq) prepared in Step 1, 4-(tert-butoxycarbonylamino)-3-methoxyphenylboronic acid, pinacol ester (1.1 eq) were dissolved in 1,4-dioxane and water (5:1), and Pd(dppf)Cl2 (0.1 eq) and Na2CO3 (2.0 eq) were added. The mixture was stirred at 90°C for 1 h under nitrogen. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the concentrate was purified through a silica gel column (Petroleum ether / Ethyl acetate (B: 15-50% concentration variation)). The target compound 1,1-di(methyl)ethyl N-[4-(4-azanyl-7-bromanyl-pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxy-phenyl]carbamate was obtained as a yellow solid (yield: 74.1%, LCMS: m / z (M+H)+= 434.1).

[0208]

[0209] Step 3: Preparation of tert-butyl(4-(4-amino-7-(4-(dimethylamino)phenyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0210] 1,1-Di(methyl)ethyl N-[4-(4-azanyl-7-bromanyl-pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxy-phenyl]carbamate (1.0 eq), 4-(N,N-dimethylamino)phenylboronic acid, pinacol ester (1.2 eq) prepared in Step 2 were dissolved in 1,4-dioxane and water (5:1), and Pd(dppf)Cl2 (0.1 eq) and K2PO4 (3.0 eq) were added. The mixture was stirred at 100°C for 2 h under nitrogen. After completion of the reaction, water was added to the reaction mixture, and the organic matter was extracted with ethyl acetate. The organic layer was washed with Brine, and the remaining water was removed with Na2SO4 and concentrated. After filtration, the filtrate was concentrated, and the concentrate was purified through a silica gel column (Petroleum ether / Ethyl acetate (1:1)). The target compound, tert-butyl(4-(4-amino-7-(4-(dimethylamino)phenyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate, was obtained as a yellow solid (yield: 28.3%, LCMS: m / z (M+H)+= 475.2).

[0211]

[0212] Examples 2 to 9: Preparation of compounds 2 to 9

[0213] Compounds of Examples 2 to 9 according to the present invention were prepared in a similar manner to Example 1 above.

[0214]

[0215] Example 10: Preparation of tert-butyl(R)-(4-(4-amino-7-(3-(dimethylamino)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0216] The title compound was prepared by the method shown in the following reaction scheme 5.

[0217] [Reaction Formula 5]

[0218]

[0219] Steps 1 and 2 were prepared in the same manner as in Example 1.

[0220]

[0221] Step 3: Preparation of tert-butyl(R)-(4-(4-amino-7-(3-(dimethylamino)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0222] 1,1-Di(methyl)ethyl N-[4-(4-azanyl-7-bromanyl-pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxy-phenyl]carbamate (1.0 eq) prepared in Step 2, (3R)-N,N-dimethylpyrrolidin-3-amine (3.0 eq) were dissolved in ethanol, and then CuI (0.2 eq), K3PO4 (2.0 eq), and N,N'-bis(2-furylmethyl)oxamide (0.2 eq) were added, and the mixture was stirred at 80°C for 24 h under nitrogen. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the concentrate was purified through a silica gel column (Ethyl acetate / Methanol (B: 5-20% concentration variation)). The target compound tert-butyl(R)-(4-(4-amino-7-(3-(dimethylamino)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate was obtained as a yellow solid (yield: 3.35%, LCMS: m / z (M+H)+= 468.3).

[0223]

[0224] Preparation of Examples 11, 13, 17, 19, 21 and 22

[0225] Compounds of Examples 11, 13, 17, 19, 21 and 22 according to the present invention were prepared in a similar manner to Example 10 above.

[0226]

[0227] Example 12: Preparation of tert-butyl(4-(4-amino-7-(4-aminopiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0228] The title compound was prepared by the method shown in the following reaction scheme 6.

[0229] [Reaction Formula 6]

[0230]

[0231]

[0232] Step 1: Preparation of tert-butyl(4-(4-amino-7-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0233] tert-Butyl(4-(4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate (1.0 eq) and benzyl piperidin-4-ylcarbamate (1.0 eq) were dissolved in DMSO, and 2-((2,6-dimethylphenyl)amino)-2-oxoacetic acid (0.2 eq), CuI (0.2 eq), and K3PO4 (2.0 eq) were added. The reaction mixture was stirred at 100°C for 48 h under nitrogen. After completion of the reaction, sat. NaHCO3 aqueous solution was added, and the organic matter was extracted with ethyl acetate. After washing the organic layer with Brine, the remaining water was removed with Na2SO4, and the concentrate was purified through a silica gel column (Ethyl acetate / Methanol (B: 5-20% concentration variation)). The target compound tert-butyl(4-(4-amino-7-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate was obtained as a yellow solid (yield: 13.6%, LCMS: m / z (M+H)+= 588.3).

[0234]

[0235] Step 2: Preparation of tert-butyl(4-(4-amino-7-(4-aminopiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0236] Tert-Butyl(4-(4-amino-7-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate (1.0 eq) prepared in Step 1 was dissolved in THF, and 10% Pd / C was added. The reaction mixture was stirred at 40°C for 2 h under hydrogen (15 psi). The mixture was filtered and concentrated, and purified by prep-HPLC (0.1% FA in water / ACN (B: 5-35% concentration variation)). The target compound tert-butyl(4-(4-amino-7-(4-aminopiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate was obtained as a yellow solid (yield: 39.9%, LCMS: m / z (M+H)+= 454.3).

[0237]

[0238] Example 14: Preparation of tert-butyl(4-(4-amino-7-(4-(diethylamino)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0239] [Reaction Formula 7]

[0240]

[0241] Step 1: Preparation of 5-bromanyl-7-[4-[di(ethyl)amino]-1-piperidyl]pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0242] 5-Bromannyl-7-iodanyl-pyrrolo[2,1-f][1,2,4]triazin-4-amine (1.0 eq), 4-diethylamino-piperidine (1.0 eq), and K3PO4 (2.0 eq) were dissolved in DMSO, and [(2,6-dimethylphenyl)carbamoyl]formic acid (0.2 eq) and CuBr (0.2 eq) were added, and the mixture was stirred at 100°C for 16 h. After completion of the reaction, the reaction mixture was filtered, and DMSO was removed under reduced pressure, and the concentrate was purified through a silica gel column (Ethyl acetate / Methanol (B: 5-50% concentration variation)). The target compound 5-bromanyl-7-[4-[di(ethyl)amino]-1-piperidyl]pyrrolo[2,1-f][1,2,4]triazin-4-amine was obtained as a yellow solid (yield: 30.8%, LCMS: m / z (M+H)+= 367.1).

[0243]

[0244] Step 2: Preparation of tert-butyl(4-(4-amino-7-(4-(diethylamino)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0245] 5-Bromanyl-7-[4-[di(ethyl)amino]-1-piperidyl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (1.0 eq), 4-(tert-butoxycarbonylamino)-3-methoxyphenylboronic acid, pinacol ester (1.0 eq) prepared in Step 1 were dissolved in 1,4-dioxane and water (5:1), and Pd(dppf)Cl2 (0.1 eq) and Na2CO3 (2.0 eq) were added. The mixture was stirred at 90°C for 4 h under nitrogen. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the concentrate was purified by prep-HPLC (0.1% FA in water / ACN (B: 8-45% concentration change)). The target compound tert-butyl(4-(4-amino-7-(4-(diethylamino)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate was obtained as a brown solid (yield: 10.5%, LCMS: m / z (M+H)+= 510.3).

[0246]

[0247] Preparation of Examples 15, 16, 18, 20, 24, 26 to 48 and 50 to 57

[0248] Compounds of Examples 15, 16, 18, 20, 24, 26 to 48 and 50 to 57 according to the present invention were prepared in a similar manner to Example 14.

[0249]

[0250] Example 23: Preparation of tert-butyl(4-(4-amino-7-(1,8-diazaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate (Example 25 was also prepared by the same method)

[0251] The title compound was prepared by the method shown in the following reaction scheme 8.

[0252] [Reaction Formula 8]

[0253]

[0254]

[0255] Step 1: Preparation of tert-butyl 8-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-1,8-diazaspiro[4.5]decane-1-carboxylate

[0256] 5-Bromannyl-7-iodanyl-pyrrolo[2,1-f][1,2,4]triazin-4-amine (1.0 eq), tert-butyl 1,8-diazaspiro[4.5]decane-1-carboxylate (1.0 eq) were dissolved in DMSO, and then 2-((2,6-Dimethylphenyl)amino)-2-oxoacetic Acid (DMPAO) (0.2 eq), CuI (0.2 eq), and K3PO4 (2.0 eq) were added. The reaction mixture was stirred at 105°C for 16 h under nitrogen. After completion of the reaction, the mixture was concentrated under reduced pressure, and the concentrate was purified through a silica gel column (Petroleum ether / Ethyl acetate (B: 5-50% concentration variation)). The target compound tert-butyl 8-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-1,8-diazaspiro[4.5]decane-1-carboxylate was obtained as a yellow solid (yield: 30.0%, LCMS: m / z (M+H)+= 451.2).

[0257]

[0258] Step 2: Preparation of 5-bromo-7-(1,8-diazaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0259]

[0260] The tert-butyl 8-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-1,8-diazaspiro[4.5]decane-1-carboxylate prepared in Step 1 was dissolved in DCM, and then TFA was added (1:1 ratio). The reaction mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to obtain the target compound 5-bromo-7-(1,8-diazaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine as a yellow oil without further purification (LCMS: m / z (M+H)+= 351.2).

[0261]

[0262] Step 3: Preparation of tert-butyl (4-(4-amino-7-(1,8-diazaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0263] 5-Bromo-7-(1,8-diazaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (1.0 eq) and 4-(tert-butoxycarbonylamino)-3-methoxyphenylboronic acid pinacol ester (1.1 eq) prepared in Step 2 were dissolved in 1,4-dioxane and water (5:1), and Pd(dppf)Cl2 (0.1 eq) and Na2CO3 (3.0 eq) were added. The mixture was stirred at 90°C for 4 h under nitrogen. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the concentrate was purified by prep-HPLC (0.1% FA in water / ACN (B: 10-40% concentration variation)). The target compound tert-butyl (4-(4-amino-7-(1,8-diazaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate was obtained as a yellow solid (yield: 24.5%, LCMS: m / z (M+H)+= 494.2).

[0264]

[0265] Preparation of Examples 25, 49, 58, 59, 65, 66, 70, 71, 72, 73, 79 to 87, 89, 90, 91 to 97, 101 to 109 and 135 to 138

[0266] In a similar manner to Example 23, compounds of Examples 25, 49, 58, 59, 65, 66, 70, 71, 72, 73, 79 to 87, 89, 90, 91 to 97, 101 to 109 and 135 to 138 according to the present invention were prepared.

[0267]

[0268] Preparation of Examples 75 and 76

[0269] [Reaction Formula 9]

[0270]

[0271]

[0272] Step 1: Dissolve 7-iodopyrrole[2,1-f][1,2,4]triazin-4-amine (25 g, 96.14 mmol), tert-butyl methyl(piperidin-4-yl)carbamate (1.3 eq), and K3PO4 (1.5 eq) in DMSO, and add 2-((2,6-dimethylphenyl)amino)-2-oxoacetic acid (0.2) and CuBr (0.2 eq). React at 105°C for 16 h. The reaction solution was concentrated under reduced pressure and purified by silica column chromatography (5-60% ethyl acetate in petroleum ether). The target compound tert-butyl (1-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-4-yl)(methyl)carbamate (13.51% yield) was obtained as a yellow solid. LCMS: m / z (M+H) + =374.2.

[0273]

[0274] Step 2: tert-butyl (1-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-4-yl)(methyl)carbamate (1 eq) was dissolved in DMF and AcOH, and NBS (0.8 eq) was added at 0°C. The reaction solution was reacted at room temperature for 2 hours, and then water was added to terminate the reaction. NaHCO3 was added to adjust the pH to 8-9, and the reactant was extracted with ethyl acetate. The organic layer was evaporated under reduced pressure and purified by column chromatography (5-60% ethyl acetate in petroleum ether) to obtain the target product tert-butyl (1-(4-amino-6-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-4-yl)(methyl)carbamate (54.91% yield) as a yellow solid. LCMS: m / z (M+H) + =425.0.

[0275]

[0276] Step 3: tert-Butyl (1-(4-amino-6-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-4-yl)(methyl)carbamate (1 eq), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (50% in THF) (10 eq), Cs2CO3 (3 eq) and XPhos Pd G4 (0.2 eq) were dissolved in dioxane and reacted at 80°C for 1 h. The reaction solution was concentrated under reduced pressure and purified by column chromatography (5-80% ethyl acetate in petroleum ether) to obtain the target product tert-butyl (1-(4-amino-6-methylpyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-4-yl(methyl)carbamate (68.00% yield) as a yellow solid. LCMS: m / z (M+H) + =361.1.

[0277]

[0278] Step 4: tert-Butyl (1-(4-amino-6-methylpyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-4-yl)(methyl)carbamate (1 eq) was dissolved in DMF and NBS (1.1 eq) was added at 0°C. The mixture was reacted at 25°C for 0.5 h and the reaction was terminated by adding sat. aq. NaHCO3 and sat. aq. Na2SO3. After extraction with ethyl acetate, the organic layer was evaporated under reduced pressure and purified by column chromatography (5-100% ethyl acetate in petroleum ether) to obtain the target product tert-butyl (1-(4-amino-5-bromo-6-methylpyrazole[2,1-f][1,2,4]triazin-7-yl)piperidin-4-yl)(methyl)carbamate (91.69% yield) as a yellow solid. LCMS: m / z (M+H) + =439.0.

[0279]

[0280] Step 5: tert-Butyl (1-(4-amino-5-bromo-6-methylpyrazole[2,1-f][1,2,4]triazin-7-yl)piperidin-4-yl)(methyl)carbamate (1 eq) was added HCl (2 M in dioxane, 10 eq) and reacted at 25°C for 16 h. The reactant was evaporated under reduced pressure to obtain the target product, 5-bromo-6-methyl-7-(4-(methylamino)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (98.48% yield) as a yellow solid. LCMS: m / z (M+H) + =339.0.

[0281]

[0282] Step 6: 5-Bromo-6-methyl-7-(4-(methylamino)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (1 eq), tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (1.1 eq), Cs2CO3 (4 eq), and XPhos Pd G4 (0.2 eq) were dissolved in dioxane and water and reacted at 90 °C for 1 h. The reactant was evaporated under reduced pressure and purified by column chromatography (5-50% methanol in ethyl acetate). The target product, tert-butyl (4-(4-amino-6-methyl-7-(4-(methylamino)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]trizin-5-yl)-2-methoxyphenyl)carbamate, was obtained as a yellow solid. LCMS: m / z (M+H) + =482.3.

[0283]

[0284] Step 7: tert-Butyl (4-(4-amino-6-methyl-7-(4-(methylamino)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate (1 eq) and 37% aq. HCHO (10 eq) were dissolved in MeOH, and NaBH3CN (2 eq) was added at 0°C. The reaction mixture was reacted at 25°C for 1 h. After completion of the reaction, the residue was evaporated under reduced pressure and purified by column chromatography (eluent of 40% MeOH / Ethyl acetate) to obtain the target product tert-butyl (4-(4-amino-7-(4-(dimethylamino)piperidin-1-yl)-6-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate (57.26% yield) as a yellow solid. LCMS: m / z (M+H) + =496.3.

[0285]

[0286] Compounds of Examples 60 to 63, 74 and 77 according to the present invention were prepared in a similar manner to Example 76 above.

[0287]

[0288] Preparation of Example 110

[0289]

[0290] [Reaction Formula 10]

[0291]

[0292]

[0293] Step 1: 5-Bromo-7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine (1 eq), tert-butyl ((1R,3S)-3-(aminomethyl)cyclopentyl)carbamate (1.2 eq), and K3PO4 (2 eq) were dissolved in DMSO, and CuBr (0.2 eq) and DMPAO (0.2 eq) were added. The reaction mixture was reacted at 90°C for 16 h. The reaction mixture was evaporated under reduced pressure and purified by column chromatography (Petroleum ether / Ethyl acetate = 1:2) to afford the target product tert-butyl ((1R,3S)-3-(((4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)amino)methyl)cyclopentyl)carbamate (5.36% yield) as a yellow oil. LCMS: m / z (M+H) + = 424.9.

[0294]

[0295] Step 2: tert-Butyl ((1R,3S)-3-(((4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)amino)methyl)cyclopentyl)carbamate (1 eq) was added HCl (2.0 M in ethyl acetate, 10 eq) and reacted at 25°C for 2 h. Evaporation under reduced pressure gave the target product, N7-(((1S,3R)-3-aminocyclopentyl)methyl)-5-bromopyrrolo[2,1-f][1,2,4]triazine-4,7-diamine, as a yellow solid. LCMS: m / z (M+H)+ = 325.0.

[0296]

[0297] Step 3: N7-(((1S,3R)-3-aminocyclopentyl)methyl)-5-bromopyrrolo[2,1-f][1,2,4]triazine-4,7-diamine (1 eq) and K3PO4 (3 eq) were dissolved in dioxane and H2O, and tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (1.2 eq) and Pd(dppf)Cl2 (0.2 eq) were added. The reaction solution was reacted at 90°C for 1 h and evaporated under reduced pressure. Afterwards, the product was purified through column chromatography (Ethyl acetate / Methanol=1:2 to 0:1) to obtain the target product, tert-butyl (4-(4-amino-7-((((1S,3R)-3-aminocyclopentyl)methyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate (18.8% yield) as a yellow solid.

[0298]

[0299] Preparation of Examples 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121 and 122

[0300] Compounds of Examples 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121 and 122 according to the present invention were prepared in a similar manner to Example 110 above.

[0301]

[0302] Preparation of Example 132

[0303]

[0304] [Reaction Formula 11]

[0305]

[0306]

[0307] Step 1: 8-Bromo-6-iodopyrrolo[1,2-a]pyrazin-1-amine (1 eq), tert-butyl piperidin-4-ylcarbamate (1.3 eq), and K3PO4 (2 eq) were dissolved in DMSO, and 2-((2,6-dimethylphenyl)amino)-2-oxoacetic acid (0.2 eq) and CuBr (0.2 eq) were added. The reaction mixture was reacted at 105°C for 32 h. The reaction mixture was evaporated under reduced pressure, and the target product, tert-butyl (1-(1-amino-8-bromopyrrolo[1,2-a]pyrazin-6-yl)piperidin-4-yl)carbamate (14.21 % yield), was obtained as a yellow solid through column chromatography (5-50% ethyl acetate in petroleum ether). LCMS: m / z (M+H) + =410.0.

[0308]

[0309] Step 2: tert-Butyl (1-(1-amino-8-bromopyrrolo[1,2-a]pyrazin-6-yl)piperidin-4-yl)carbamate (1 eq) was dissolved in TFA and DCM and reacted at 25°C for 0.5 h. The reaction mixture was evaporated under reduced pressure to obtain the target product, 6-(4-aminopiperidin-1-yl)-8-bromopyrrolo[1,2-a]pyrazin-1-amine, as a yellow solid. MS: m / z (M+H) + =309.9.

[0310]

[0311] Step 3: 6-(4-Amino-1-piperidyl)-8-bromo-pyrrolo[1,2-a]pyrazin-1-amine, tert-butyl (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (1.2 eq), Pd(dppf)Cl2 (0.1 eq) and K3PO4 (3 eq) were dissolved in dioxane and water and reacted at 90°C for 16 h. The reaction mixture was dried under reduced pressure and purified by column chromatography (5-20% methanol in ethyl acetate) to afford the target product, tert-butyl (4-(1-amino-6-(4-aminopiperidin-1-yl)pyrrolo[1,2-a]pyrazin-8-yl)-2-methoxyphenyl)carbamate (8.24% yield) as a yellow solid. LCMS: m / z (M+H) + =453.3.

[0312]

[0313] Compounds of Examples 133 and 134 according to the present invention were prepared in a similar manner to Example 132 above.

[0314]

[0315] Preparation of Example 98

[0316]

[0317] [Reaction Formula 12]

[0318]

[0319] Step 1: 5-Bromo-7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine (1 eq) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 eq) were dissolved in dioxane and H2O, and K3PO4 (2 eq) and Pd(dppf)Cl2 (0.1 eq) were added. The reaction solution was reacted at 80°C for 2 h. H2O was added to the reaction solution, and the mixture was extracted with EtOAc. The organic layer was evaporated under reduced pressure and purified by column chromatography (Petroleum ether / Ethyl acetate = 1:1 to 0:1) to obtain the target product, (E)-5-bromo-7-(2-ethoxyvinyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, as a yellow solid. LCMS: m / z (M+H) + = 282.9.

[0320]

[0321] Step 2: (E)-5-Bromo-7-(2-ethoxyvinyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (1 eq) was added HCl (2.0 M in 1,4-dioxane, 10 eq) and reacted at 25°C for 5.5 h. The reaction solution was evaporated under reduced pressure to obtain the target product, 2-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)acetaldehyde, as a yellow solid. LCMS: m / z (M+H) + =254.9.

[0322]

[0323] Step 3: 2-(4-Amino-5-bromo-pyrrolo[2,1-f][1,2,4]triazin-7-yl)acetaldehyde (1 eq) and N,N-dimethylpiperidin-4-amine (2 eq) were dissolved in DCM, and NaBH3CN (2 eq) was added at 0°C. The reaction solution was reacted at 25°C for 16 h. Water was added to the reaction mixture, and the mixture was extracted with EtOAc. The organic layer was evaporated under reduced pressure and purified by column chromatography (Ethyl acetate / Methanol = 0:1) to obtain the target product, 5-bromo-7-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (41.01% yield) as a yellow solid. LCMS: m / z (M+H) + =367.0.

[0324]

[0325] Step 4: 5-Bromo-7-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (1 eq) and tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (1.2 eq) were dissolved in dioxane and H2O, and K3PO4 (2 eq) and Pd(dppf)Cl2 (0.2 eq) were added. The reaction solution was reacted at 90°C for 1 h. The reaction solution was evaporated under reduced pressure and purified through column chromatography (Ethyl acetate / Methanol = 0:1) to obtain the target product, ert-butyl (4-(4-amino-7-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate (21.90% yield) as a yellow solid.

[0326]

[0327] Compounds of Examples 64, 67 to 69, 78, 99, 100, and 131 according to the present invention were prepared in a similar manner to Example 98.

[0328]

[0329] Preparation of Example 123

[0330] [Reaction Formula 13]

[0331]

[0332] Step 1: tert-Butyl (1-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-4-yl)carbamate (1 eq) was dissolved in DMF, and NCS (1.5 eq) was added at 0°C. The reaction solution was stirred at 25°C for 3 h. The reaction mixture was added with saturated Na2SO3 solution and saturated NaHCO3 solution, and extracted with EtOAc. After that, the organic layer was evaporated under reduced pressure and purified by column chromatography (Petroleum ether / Ethyl acetate = 1:1) to obtain the target product 1-(4-amino-5-bromo-6-chloropyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-4-yl)carbamate (75.66% yield) as a yellow solid. LCMS: m / z (M+H) + = 445.0.

[0333]

[0334] Step 2: tert-Butyl (1-(4-amino-5-bromo-6-chloropyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-4-yl)carbamate was dissolved in DCM, TFA was added, and the mixture was stirred at 25°C for 1 h. After completion of the reaction, the mixture was evaporated under reduced pressure to obtain the target product, 7-(4-aminopiperidin-1-yl)-5-bromo-6-chloropyrrolo[2,1-f][1,2,4]triazin-4-amine, as a yellow solid. LCMS: m / z (M+H) + =344.9.

[0335]

[0336] Step 3: Dissolve 7-(4-aminopiperidin-1-yl)-5-bromo-6-chloropyrrolo[2,1-f][1,2,4]triazin-4-amine (1 eq) and K3PO4 (3 eq) in dioxane and H2O, and add tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (0.4 eq) and Pd(dppf)Cl2 (0.2 eq). Stir the reaction solution at 80°C for 3 h. After evaporation under reduced pressure, the target product, tert-butyl (4-(4-amino-7-(4-aminopiperidin-1-yl)-6-chloropyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate (3.9% yield), was obtained as a white solid through column chromatography (Petroleum ether / Ethyl acetate = 1:1).

[0337]

[0338] Compound Example 124 according to the present invention was prepared in a similar manner to Example 123 above.

[0339]

[0340] Preparation of Example 127

[0341] [Reaction Formula 14]

[0342]

[0343] Step 1: 6-Fluoro-7-iodo-pyrrolo[2,1-f][1,2,4]triazin-4-amine (1 eq), tert-butyl N-(4-piperidyl)carbamate (1 eq), and K3PO4 (1 eq) were dissolved in DMSO, and 2-((2,6-dimethylphenyl)amino)-2-oxoacetic acid (0.2 eq) and CuBr (0.2 eq) were added. The reaction solution was stirred at 105°C for 16 h. Water was added to the reaction solution, and the mixture was extracted with EtOAc. The organic layer was evaporated under reduced pressure and purified by column chromatography (5-30% ethyl acetate in petroleum ether) to obtain the target product tert-butyl (1-(4-amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-4-yl)carbamate (9.5% yield) as a yellow solid. LCMS: m / z (M+H) + =351.0.

[0344]

[0345] Step 2: tert-butyl (1-(4-amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-4-yl)carbamate (1 eq) was dissolved in AcOH, and NBS (1.1 eq) was added. The reaction solution was stirred at 25°C for 10 min. After completion of the reaction, the pH was adjusted to 7-8 with sat. aq. NaHCO3 solution, and extracted with EtOAc. The organic layer was evaporated under reduced pressure to obtain the target product tert-butyl (1-(4-amino-5-bromo-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-4-yl)carbamate as a yellow solid. LCMS: m / z (M+H) + =438.9.

[0346]

[0347] Step 3: tert-Butyl (1-(4-amino-5-bromo-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-4-yl)carbamate (1 eq) was dissolved in HCl (2 M in EtOAc) and stirred at 25°C for 0.5 h. The reaction solution was evaporated under reduced pressure to obtain the target product, 7-(4-aminopiperidin-1-yl)-5-bromo-6-fluoropyrrolo[2,1-f][1,2,4]triazin-4-amine, as a yellow solid. LCMS: m / z (M+H) + =328.9.

[0348]

[0349] Step 4: 7-(4-Amino-1-piperidyl)-5-bromo-6-fluoro-pyrrolo[2,1-f][1,2,4]triazin-4-amine (1 eq), tert-butyl (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (1.2 eq), Pd(dppf)Cl2 (0.1 eq) and Na2CO3 (3 eq) were dissolved in dioxane and water and stirred at 90°C for 1 h. After evaporation under reduced pressure, the residue was purified by column chromatography (5-20% methanol in ethyl acetate) to obtain the target product tert-butyl N-[4-[4-amino-7-(4-amino-1-piperidyl)-6-fluoro-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxy-phenyl]carbamate (19.15% yield) as a yellow solid. LCMS: m / z (M+H) + =472.1.

[0350]

[0351] Compounds of Examples 128, 129, and 130 according to the present invention were prepared in a similar manner to Example 127 above.

[0352]

[0353] Preparation of Example 125

[0354] [Reaction Formula 15]

[0355]

[0356]

[0357] Step 1: tert-Butyl piperidin-4-ylcarbamate (1.2 eq) and 5-bromo-7-iodo-N,N-bis(4-methoxybenzyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (1 eq) were dissolved in DMSO, and DMPAO (0.2 eq), CuBr (0.2 eq), and K3PO4 (1 eq) were added. The reaction solution was stirred at 105°C for 16 h. After the reaction was completed, water was added and the mixture was extracted with EtOAc. The organic layer was evaporated under reduced pressure and purified by column chromatography (eluent of 20-35% ethyl acetate / petroleum ether) to obtain the target product tert-butyl (1-(4-(bis(4-methoxybenzyl)amino)-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-4-yl)carbamate (40.54% yield) as a yellow solid. LCMS: m / z (M+H) + = 653.1

[0358]

[0359] Step 2: tert-Butyl (1-(4-(bis(4-methoxybenzyl)amino)-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-4-yl)carbamate (1 eq) was dissolved in DMF, and NIS (1 eq) was added at 0 °C. The reaction solution was stirred at 0 °C for 0.5 h. The reaction solution was poured into Na2SO3 solution and extracted with EtOAc. The organic layer was evaporated under reduced pressure and purified by column chromatography (eluent of 35-45% ethyl acetate / petroleum ether) to obtain the target product tert-butyl (1-(4-(bis(4-methoxybenzyl)amino)-5-bromo-6-iodopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-4-yl)carbamate (83.81% yield) as a yellow oil. LCMS: m / z (M+H)+ = 779.0

[0360]

[0361] Step 3: tert-Butyl (1-(4-(bis(4-methoxybenzyl)amino)-5-bromo-6-iodopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-4-yl)carbamate (1 eq) was dissolved in DMF, and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (4 eq) and CuI (1.1 eq) were added. The reaction solution was stirred at 80 °C for 32 h. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with EtOAc. The organic layer was evaporated under reduced pressure and purified by column chromatography (Eluent of 45-70% Ethyl acetate / Petroleum ether) to obtain the target product tert-butyl (1-(4-(bis(4-methoxybenzyl)amino)-5-bromo-6-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-4-yl)carbamate (63.42% yield) as a yellow oil. LCMS: m / z (M+H) + = 721.1

[0362]

[0363] Step 4: tert-Butyl (1-(4-(bis(4-methoxybenzyl)amino)-5-bromo-6-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-4-yl)carbamate (1 eq) was dissolved in TFA and heated at 100 °C for 2 h. The reaction solution was evaporated under reduced pressure to obtain the target product, 7-(4-aminopiperidin-1-yl)-5-bromo-6-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, as a yellow solid. LCMS: m / z (M+H) + = 380.9

[0364]

[0365] Step 5: 7-(4-Aminopiperidin-1-yl)-5-bromo-6-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (1 eq) and tert-butyl (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (1.2 eq) were dissolved in dioxane and H2O, and K3PO4 (1.2 eq) and Pd(dppf)Cl2 (0.2 eq) were added. The reaction solution was stirred at 90 °C for 2 h. After completion of the reaction, the residue was evaporated under reduced pressure and purified through column chromatography (eluent of 80% MeOH / Ethyl acetate) to obtain the target product, tert-butyl (4-(4-amino-7-(4-aminopiperidin-1-yl)-6-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate (12.2% yield) as a white solid.

[0366]

[0367] Compound Example 126 according to the present invention was prepared in a similar manner to Example 125 above.

[0368]

[0369] The chemical structures, compound names, NMR, purity, and yield results of the compounds of Examples 1 to 138 are as follows.

[0370]

[0371] Example 1:

[0372] tert-Butyl(4-(4-amino-7-(4-(dimethylamino)phenyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0373] 1H NMR (400 MHz, DMSO-d6) δ = 8.01 (s, 1H), 7.98 - 7.89 (m, 3H), 7.82 (d, J = 8.6 Hz, 1H), 7.13 (s, 1H), 7.07 - 7.01 (m, 1H), 6.98 (s, 1H), 6.81 (d, J = 8.9 Hz, 2H), 3.87 (s, 3H), 2.96 (s, 6H), 1.48 (s, 9H), LCMS: m / z (M+H) + = 475.2

[0374] Purity: 97.8%, Yield: 28.3%

[0375]

[0376] Example 2:

[0377] tert-Butyl(4-(4-amino-7-(4-(dimethylamino)-2-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0378] 1 H NMR (400 MHz, DMSO-d6) δ = 7.99 (s, 1H), 7.83 - 7.81 (m, 2H), 7.20 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 1.8 Hz, 1H), 7.05 (dd, J = 1.9, 8.1 Hz, 1H), 6.69 (s, 1H), 6.67 (d, J = 2.4 Hz, 1H), 6.63 (dd, J = 2.9, 8.6 Hz, 1H), 3.87 (s, 3H), 2.94 (s, 6H), 2.15 (s, 3H), 1.48 (s, 9H), LCMS: m / z (M+H) + = 489.3.

[0379] Purity: 96.6%, Yield: 4.42%

[0380]

[0381] Example 3:

[0382] tert-Butyl(4-(4-amino-7-(4-(dimethylamino)-3-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0383] 1 H NMR (400 MHz, DMSO-d6) δ = 8.00 (s, 1H), 7.96 (s, 1H), 7.90 - 7.80 (m, 3H), 7.14 (d, J = 1.3 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.07 - 7.01 (m, 2H), 3.87 (s, 3H), 2.68 (s, 6H), 2.32 (s, 3H), 1.48 (s, 9H), LCMS: m / z (M+H) + =489.3.

[0384] Purity: 99.1%, Yield: 10.5%

[0385]

[0386] Example 4:

[0387] tert-Butyl(4-(4-amino-7-(4-(dimethylamino)-3-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0388] 1 H NMR (400 MHz, DMSO-d6) δ = 8.04 - 7.94 (m, 3H), 7.84 (dd, J = 1.9, 8.4 Hz, 2H), 7.16 - 7.10 (m, 2H), 7.07 - 7.00 (m, 2H), 3.87 (s, 3H), 2.85 (s, 6H), 1.48 (s, 9H), LCMS: m / z (M+H) + =493.2.

[0389] Purity: 94.1%, Yield: 9.67%

[0390]

[0391] Example 5:

[0392] tert-Butyl(4-(4-amino-7-(4-(dimethylamino)-3-methoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0393] 1 H NMR (400 MHz, DMSO-d6, HCl salt) δ = 8.88 (s, 1H), 8.47 (br s, 1H), 8.23 ​​- 8.11 (m, 1H), 8.06 (s, 1H), 7.94 - 7.82 (m, 1H), 7.42 - 7.33 (m, 1H), 7.22 (br s, 1H), 7.16 (s, 1H), 7.08 (d, J = 8.1 Hz, 1H), 3.87 (s, 3H), 3.24 (d, J = 5.3 Hz, 6H), 1.48 (s, 9H), LCMS: m / z (M+H) + =476.2.

[0394] Purity: 95.6%, Yield: 18.6%

[0395]

[0396] Example 6:

[0397] tert-Butyl(4-(4-amino-7-(6-(dimethylamino)pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0398] 1 H NMR (400 MHz, DMSO-d6, HCl salt) δ = 8.86 (br s, 1H), 8.23 ​​(s, 1H), 8.07 (s, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.87 - 7.81 (m, 2H), 7.78 (br s, 1H), 7.42 (s, 1H), 7.19 (d, J = 1.6 Hz, 1H), 7.11 (dd, J = 1.6, 8.2 Hz, 1H), 4.02 (s, 3H), 3.88 (s, 3H), 3.12 (s, 6H), 1.48 (s, 9H), LCMS: m / z (M+H) + =505.3.

[0399] Purity: 96.7%, Yield: 25.5%

[0400]

[0401] Example 7:

[0402] tert-Butyl(4-(4-amino-7-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0403] 1 H NMR (400 MHz, DMSO-d6) δ = 8.01 (s, 1H), 7.94 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.56 - 7.50 (m, 2H), 7.13 (d, J = 1.6 Hz, 1H), 7.03 (dd, J) = 1.3, 8.3 Hz, 1H), 6.99 (s, 1H), 6.77 (d, J = 8.9 Hz, 1H), 4.30 - 4.22 (m, 2H), 3.87 (s, 3H), 3.31 - 3.27 (m, 2H), 2.88 (s, 3H), 1.48 (s, 9H), LCMS: m / z (M+H) + = 503.1.

[0404] Purity: 98.2%, Yield: 8.33%

[0405]

[0406] Example 8:

[0407] tert-Butyl(4-(4-amino-7-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0408] 1H NMR (400 MHz, DMSO-d6) δ = 8.02 - 8.00 (m, 2H), 7.90 - 7.80 (m, 3H), 7.26 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H), 7.15 (d, J = 1.2 Hz, 1H), 7.09 - 7.02 (m, 1H), 4.71 (s, 2H), 3.87 (s, 3H), 3.27 (s, 3H), 1.48 (s, 9H), LCMS: m / z (M+H) + = 517.3.

[0409] Purity: 98.2%, Yield: 39.9%

[0410]

[0411] Example 9:

[0412] tert-Butyl(4-(4-amino-7-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0413] 1 H NMR (400 MHz, DMSO-d6) δ = 8.14 (d, J = 1.3 Hz, 1H), 8.07 - 7.96 (m, 3H), 7.84 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.19 (s, 1H), 7.15 (d, J = 1.6 Hz, 1H), 7.06 (dd, J = 1.7, 8.2 Hz, 1H), 3.87 (s, 3H), 3.39 (s, 3H), 1.48 (s, 9H), LCMS: m / z (M+H) + = 503.2.

[0414] Purity: 96.8%, Yield: 41.3%

[0415]

[0416] Example 10:

[0417] tert-Butyl(R)-(4-(4-amino-7-(3-(dimethylamino)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0418] 1 H NMR (400 MHz, DMSO-d6, FA salt) δ = 8.13 (s, 1H), 7.97 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.04 (d, J = 1.8 Hz, 1H), 6.96 (dd, J = 1.8, 8.2 Hz, 1H), 6.13 (s, 1H), 3.84 (s, 3H), 3.55 - 3.38 (m, 5H), 2.38 (s, 6H), 2.19 - 2.11 (m, 1H), 1.96 - 1.83 (m, 1H), 1.46 (s, 9H), LCMS: m / z (M+H) + =468.3.

[0419] Purity: 95.5%, Yield: 3.35%

[0420]

[0421] Example 11:

[0422] tert-Butyl(S)-(4-(4-amino-7-(3-(dimethylamino)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0423] 1H NMR (400 MHz, DMSO-d6, FA salt) δ = 8.13 (s, 1H), 7.99 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.77 (s, 1H), 7.04 (d, J = 1.6 Hz, 1H), 6.97 (dd, J = 1.5, 8.3 Hz, 1H), 6.17 (s, 1H), 3.85 (s, 3H), 3.60 - 3.45 (m, 4H), 3.42 - 3.38 (m, 1H), 2.55 (s, 6H), 2.26 - 2.17 (m, 1H), 2.07 - 1.93 (m, 1H), 1.47 (s, 9H), LCMS: m / z (M+H) + =468.3.

[0424] Purity: 98.3%, Yield: 4.45%

[0425]

[0426] Example 12:

[0427] tert-Butyl(4-(4-amino-7-(4-aminopiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0428] 1 H NMR (400 MHz, DMSO-d6, FA salt) δ = 8.42 (s, 1H), 7.97 (s, 1H), 7.81 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 1.7 Hz, 1H), 6.97 (dd, J = 1.6, 8.2 Hz, 1H), 6.24 (s, 1H), 3.85 (s, 3H), 3.69 - 3.65 (m, 2H), 2.97 - 2.90 (m, 1H), 2.74 (t, J = 10.8 Hz, 2H), 1.89 (dd, J = 1.5, 10.8 Hz, 2H), 1.65 - 1.51 (m, 2H), 1.47 (s, 9H), LCMS: m / z (M+H) + =454.3.

[0429] Purity: 99.9%, Yield: 39.9%

[0430]

[0431] Example 13:

[0432] tert-Butyl(4-(4-amino-7-(4-(dimethylamino)-4-methylpiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0433] 1 H NMR (400 MHz, DMSO-d6, FA salt) δ = 8.42 (s, 1H), 7.97 (s, 1H), 7.81 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 1.7 Hz, 1H), 6.97 (dd, J = 1.6, 8.2 Hz, 1H), 6.24 (s, 1H), 3.85 (s, 3H), 3.69 - 3.65 (m, 2H), 2.97 - 2.90 (m, 1H), 2.74 (t, J = 10.8 Hz, 2H), 1.89 (dd, J = 1.5, 10.8 Hz, 2H), 1.65 - 1.51 (m, 2H), 1.47 (s, 9H), LCMS: m / z (M+H) + =454.3.

[0434] Purity: 90.0%, Yield: 1.13%

[0435]

[0436] Example 14:

[0437] tert-Butyl(4-(4-amino-7-(4-(diethylamino)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0438] 1H NMR (400 MHz, DMSO-d6, FA salt) δ = 7.99 (s, 1H), 7.90 - 7.73 (m, 2H), 7.05 (d, J = 1.5 Hz, 1H), 6.97 (dd, J = 1.4, 8.2 Hz, 1H), 6.23 (s, 1H), 3.85 (s, 3H), 3.77 (d, J = 12.4 Hz, 2H), 2.81 - 2.50 (m, 7H), 1.89 - 1.77 (m, 2H), 1.74 - 1.59 (m, 2H), 1.47 (s, 9H), 1.03 (t, J = 6.8 Hz, 6H), LCMS: m / z (M+H) + =510.3.

[0439] Purity: 92.8%, Yield: 10.5%

[0440]

[0441] Example 15:

[0442] tert-Butyl(4-(4-amino-7-(4-(dimethylamino)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0443] 1 H NMR (400 MHz, DMSO-d6, FA salt) δ = 8.14 (s, 1H), 7.98 (s, 1H), 7.82 (s, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.05 (d, J = 1.5 Hz, 1H), 6.97 (dd, J = 1.5, 8.3 Hz, 1H), 6.26 (s, 1H), 3.85 (s, 3H), 3.80 (br d, J = 11.6 Hz, 2H), 2.96 - 2.85 (m, 1H), 2.70 (br t, J = 11.8 Hz, 2H), 2.56 (br s, 6H), 1.99 (br d, J = 10.3 Hz, 2H), 1.80 - 1.66 (m, 2H), 1.47 (s, 9H), LCMS: m / z (M+H) + =482.3.

[0444] Purity: 100%, Yield: 27.8%

[0445]

[0446] Example 16:

[0447] tert-Butyl(4-(4-amino-7-(4-(tert-butyl)piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0448] 1 H NMR (400 MHz, DMSO-d6) δ = 7.99 (s, 1H), 7.88 - 7.74 (m, 2H), 7.05 (s, 1H), 6.98 (dd, J = 1.3, 8.2 Hz, 1H), 6.28 (s, 1H), 3.85 (s, 3H), 3.20 - 2.81 (m, 8H), 1.47 (s, 9H), 1.20 (s, 9H), LCMS: m / z (M+H) + = 536.3.

[0449] Purity: 98.3%, Yield: 0.42%

[0450]

[0451] Example 17:

[0452] tert-Butyl(4-(4-amino-7-(4-cyclopropylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0453] 1H NMR (40 MHz, DMSO-d6) δ = 7.98 (s, 1H), 7.81 (s, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.05 (s, 1H), 6.97 (d, J = 8.6 Hz, 1H), 6.21 (s, 1H), 3.85 (s, 3H), 3.20 - 3.12 (m, 4H), 2.76 - 2.68 (m, 4H), 1.70 (td, J = 3.3, 6.8 Hz, 1H), 1.47 (s, 9H), 0.47 - 0.43 (m, 2H), 0.36 - 0.32 (m, 2H), LCMS: m / z (M+H) + = 480.2.

[0454] Purity: 87.8%, Yield: 0.68%

[0455]

[0456] Example 18:

[0457] tert-Butyl(4-(4-amino-7-(6-(dimethylamino)-2-azaspiro[3.3]heptan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0458] 1 H NMR (400 MHz, DMSO-d6, FA salt) δ = 8.14 (s, 1H), 7.98 (s, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.69 (s, 1H), 7.03 (d, J = 1.3 Hz, 1H), 6.96 (dd, J = 1.4, 8.3 Hz, 1H), 5.96 (s, 1H), 3.99 (s, 2H), 3.88 (s, 2H), 3.84 (s, 3H), 2.89 - 2.75 (m, 1H), 2.41 - 2.30 (m, 2H), 2.21 (s, 6H), 2.09 (t, J = 9.9 Hz, 2H), 1.47 (s, 9H), LCMS: m / z (M+H) + =494.2.

[0459] Purity: 98.1%, Yield: 22.3%

[0460]

[0461] Example 19:

[0462] tert-Butyl(4-(4-amino-7-(4-((dimethylamino)methyl)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0463] 1 H NMR (400 MHz, DMSO-d6, FA salt) δ = 8.00 (s, 1H), 7.90 - 7.80 (m, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 6.97 (dd, J = 1.7, 8.2 Hz, 1H), 6.23 (s, 1H), 3.85 (s, 3H), 3.69 (d, J = 11.7 Hz, 2H), 2.67 (t, J = 11.2 Hz, 2H), 2.57 - 2.52 (m, 2H), 2.40 (s, 6H), 1.82 - 1.68 (m, 2H), 1.47 (s, 9H), 1.41 - 1.27 (m, 2H), LCMS: m / z (M+H) + =496.3.

[0464] Purity: 93.0%, Yield: 4.11%

[0465]

[0466] Example 20:

[0467] tert-Butyl(4-(4-amino-7-(3-((dimethylamino)methyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0468] 1H NMR (400 MHz, DMSO-d6) δ = 7.97 (s, 1H), 7.78 (d, J = 7.1 Hz, 1H), 7.73 (br s, 1H), 7.05 (s, 1H), 6.97 (d, J = 7.3 Hz, 1H), 6.06 (s, 1H), 3.85 (s, 3H), 3.52 (t, J = 8.1 Hz, 1H), 3.42 - 3.34 (m, 2H), 3.17 - 3.11 (m, 1H), 2.40 - 2.19 (m, 3H), 2.15 (s, 6H), 2.08 - 1.99 (m, 1H), 1.65 - 1.54 (m, 1H), 1.47 (s, 9H), LCMS: m / z (M+H) + =482.2.

[0469] Purity: 95.6%, Yield: 3.73%

[0470]

[0471] Example 21:

[0472] tert-Butyl(4-(4-amino-7-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0473] 1 H NMR (400 MHz, Methanol-d4) δ = 7.94 (d, J = 8.3 Hz, 1H), 7.81 (br s, 1H), 7.10 - 7.06 (m, 1H), 7.05 - 7.01 (m, 1H), 6.29 (s, 1H), 3.93 (s, 3H), 3.48 - 3.36 (m, 4H), 3.22 - 3.14 (m, 4H), 2.55 (s, 3H), 2.04 - 1.98 (m, 4H), 1.56 (s, 9H), LCMS: m / z (M+H) + =494.2.

[0474] Purity: 90.3%, Yield: 0.45%

[0475]

[0476] Example 22:

[0477] tert-Butyl(4-(4-amino-7-(2-methyl-2,8-diazaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0478] 1 H NMR (400 MHz, Methanol-d4) δ = 7.93 (d, J = 8.0 Hz, 1H), 7.79 (br s, 1H), 7.06 (s, 1H), 7.02 (d, J = 8.6 Hz, 1H), 6.29 (s, 1H), 3.92 (s, 3H), 3.26 - 3.16 (m, 4H), 2.74 - 2.65 (m, 2H), 2.59 (s, 2H), 2.41 (s, 3H), 1.92 - 1.75 (m, 6H), 1.54 (s, 9H), LCMS: m / z (M+H) + =508.2.

[0479] Purity: 97.5%, Yield: 1.14%

[0480]

[0481] Example 23:

[0482] tert-Butyl(4-(4-amino-7-(1,8-diazaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0483] 1H NMR (400 MHz, DMSO-d6, FA salt) δ = 8.85 - 8.68 (m, 2H), 8.01 (s, 1H), 7.85 (s, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.05 (d, J = 1.8 Hz, 1H), 6.98 (dd, J = 1.7, 8.2 Hz, 1H), 6.29 (s, 1H), 3.85 (s, 3H), 3.57 - 3.50 (m, 2H), 3.29 - 3.23 (m, 2H), 3.03 (t, J = 9.6 Hz, 2H), 2.06 - 1.87 (m, 8H), 1.47 (s, 9H), LCMS: m / z (M+H) + =494.2.

[0484] Purity: 99.0%, Yield: 24.5%

[0485]

[0486] Example 24:

[0487] tert-Butyl(4-(4-amino-7-(1-methyl-1,8-diazaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0488] 1 H NMR (400 MHz, DMSO-d6, FA salt) δ = 8.21 (s, 1H), 7.98 (s, 1H), 7.85 - 7.75 (m, 2H), 7.05 (d, J = 1.8 Hz, 1H), 6.97 (dd, J = 1.7, 8.2 Hz, 1H), 6.25 (s, 1H), 3.85 (s, 3H), 3.70 (d, J = 11.6 Hz, 2H), 2.79 - 2.66 (m, 4H), 2.29 (s, 3H), 1.84 (dt, J = 3.8, 12.5 Hz, 2H), 1.80 - 1.68 (m, 4H), 1.47 (s, 9H), 1.33 (d, J = 12.3 Hz, 2H), LCMS: m / z (M+H) + =508.3.

[0489] Purity: 97.3%, Yield: 8.59%

[0490]

[0491] Example 25:

[0492] tert-Butyl(4-(4-amino-7-(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0493] 1 H NMR (400 MHz, DMSO-d6, FA salt) δ = 9.04 (br s, 1H), 8.69 (br s, 1H), 8.01 (s, 1H), 7.86 (s, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 6.98 (dd, J = 1.8, 8.1 Hz, 1H), 6.30 (s, 1H), 3.85 (s, 3H), 3.79 - 3.72 (m, 1H), 3.34 - 3.20 (m, 5H), 3.06 - 2.96 (m, 1H), 2.56 - 2.53 (m, 1H), 2.17 - 1.97 (m, 3H), 1.95 - 1.83 (m, 1H), 1.47 (s, 9H), LCMS: m / z (M+H) + =480.3.

[0494] Purity: 99.0%, Yield: 22.6%

[0495]

[0496] Example 26:

[0497] tert-Butyl(4-(4-amino-7-(1-methyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0498] 1H NMR (400 MHz, Methanol-d4) δ = 7.96 (d, J = 8.2 Hz, 1H), 7.84 (s, 1H), 7.08 (s, 1H), 7.04 (dd, J = 1.5, 8.1 Hz, 1H), 6.39 (s, 1H), 3.93 (s, 3H), 3.90 - 3.80 (m, 1H), 3.77 - 3.66 (m, 1H), 3.52 - 3.36 (m, 2H), 3.29 - 3.09 (m, 2H), 3.04 - 2.87 (m, 4H), 2.78 - 2.59 (m, 1H), 2.43 - 1.99 (m, 4H), 1.54 (s, 9H), LCMS: m / z (M+H) + =494.2.

[0499] Purity: 97.2%, Yield: 2.34%

[0500]

[0501] Example 27:

[0502] tert-Butyl(4-(4-amino-7-(2-methyl-3-oxo-2,8-diazaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0503] 1 H NMR (400 MHz, Methanol-d4, HCl salt) δ = 7.98 (d, J = 8.1 Hz, 1H), 7.86 (s, 1H), 7.10 (s, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.43 (s, 1H), 3.93 (s, 3H), 3.46 - 3.39 (m, 2H), 3.37 (s, 2H), 3.36 - 3.32 (m, 2H), 2.86 (s, 3H), 2.39 (s, 2H), 1.92 - 1.78 (m, 4H), 1.54 (s, 9H), LCMS: m / z (M+H) + =522.3.

[0504] Purity: 99.5%, Yield: 6.72%

[0505]

[0506] Example 28:

[0507] tert-Butyl(4-(4-amino-7-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0508] 1 H NMR (400 MHz, Methanol-d4) δ = 8.01 - 7.92 (m, 1H), 7.84 (d, J = 2.2 Hz, 1H), 7.12 - 7.00 (m, 2H), 6.37 (d, J = 2.4 Hz, 1H), 3.93 (d, J = 2.3) Hz, 3H), 3.45 - 3.39 (m, 4H), 3.36 - 3.33 (m, 2H), 2.95 (s, 3H), 2.94 (s, 3H), 2.84 - 2.74 (m, 6H), 1.54 (d, J = 2.3 Hz, 9H), LCMS: m / z (M+H) + =511.3.

[0509] Purity: 94.5%, Yield: 2.72%

[0510]

[0511] Example 29:

[0512] tert-Butyl(4-(4-amino-7-(4-(2-methoxyethyl)piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0513] 1H NMR (400 MHz, DMSO-d6) δ = 7.98 (s, 1H), 7.80 (s, 1H), 7.78 (s, 1H), 7.05 (d, J = 1.5 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.23 (s, 1H), 3.85 (s, 3H), 3.47 (t, J = 5.7 Hz, 2H), 3.25 (s, 3H), 3.23 - 3.17 (m, 4H), 2.65 - 2.57 (m, 4H), 2.56 - 2.50 (m, 2H), 1.47 (s, 9H), LCMS: m / z (M+H) + =498.2.

[0514] Purity: 100%, Yield: 9.38%

[0515]

[0516] Example 30:

[0517] tert-Butyl(4-(4-amino-7-((3S,4R)-4-(dimethylamino)-3-fluoropiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0518] 1 H NMR (400 MHz, DMSO-d6) δ = 7.98 (s, 1H), 7.82 (s, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.05 (d, J = 1.8 Hz, 1H), 6.97 (dd, J = 1.7, 8.2 Hz, 1H), 6.23 (s, 1H), 5.16 - 4.95 (m, 1H), 4.03 - 3.92 (m, 1H), 3.88 - 3.86 (m, 1H), 3.85 (s, 3H), 2.92 (dd, J = 13.2, 38.0 Hz, 1H), 2.72 (t, J = 11.6 Hz, 1H), 2.44 - 2.35 (m, 1H), 2.29 (s, 6H), 2.05 - 1.88 (m, 1H), 1.81 - 1.69 (m, 1H), 1.47 (s, 9H), LCMS: m / z (M+H) + =500.3.

[0519] Purity: 99.2%, Yield: 10.4%

[0520]

[0521] Example 31:

[0522] tert-Butyl(4-(4-amino-7-((3S,4S)-4-(dimethylamino)-3-fluoropiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0523] 1 H NMR (400 MHz, DMSO-d6) δ = 7.98 (s, 1H), 7.84 (s, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.06 (d, J = 1.8 Hz, 1H), 6.98 (dd, J = 1.5, 8.3 Hz, 1H), 6.31 (s, 1H), 4.95 - 4.73 (m, 1H), 4.04 - 3.93 (m, 1H), 3.85 (s, 3H), 3.71 - 3.62 (m, 1H), 2.82 - 2.77 (m, 1H), 2.77 - 2.68 (m, 2H), 2.37 (br s, 6H), 1.94 - 1.82 (m, 1H), 1.74 - 1.62 (m, 1H), 1.47 (s, 9H), LCMS: m / z (M+H) + =500.3.

[0524] Purity: 99.6%, Yield: 2.24%

[0525]

[0526] Example 32:

[0527] tert-Butyl(4-(4-amino-7-((3R,4R)-4-(dimethylamino)-3-fluoropiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0528] 1H NMR (400 MHz, Methanol-d4) δ = 8.52 (br s, 1H), 7.94 (br d, J = 8.1 Hz, 1H), 7.79 (s, 1H), 7.06 (d, J = 1.5 Hz, 1H), 7.02 (dd, J = 1.8, 8.3 Hz, 1H), 6.33 (s, 1H), 5.07 - 4.94 (m, 1H), 4.11 - 4.00 (m, 1H), 3.92 (s, 3H), 3.76 - 3.67 (m, 1H), 2.97 - 2.87 (m, 1H), 2.86 - 2.76 (m, 2H), 2.53 (s, 6H), 2.07 - 1.97 (m, 1H), 1.95 - 1.81 (m, 1H), 1.54 (s, 9H), LCMS: m / z (M+H) + =500.3.

[0529] Purity: 94.6%, Yield: 18.6%

[0530]

[0531] Example 33:

[0532] tert-Butyl(4-(4-amino-7-((3R,4S)-4-(dimethylamino)-3-fluoropiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0533] 1H NMR (400 MHz, DMSO-d6) δ = 9.94 - 9.58 (m, 1H), 7.99 (s, 1H), 7.84 (s, 1H), 7.80 (br d, J = 8.3 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 6.97 (dd, J = 1.8, 8.3 Hz, 1H), 6.28 (s, 1H), 5.48 - 5.10 (m, 1H), 4.21 - 4.02 (m, 1H), 3.97 - 3.88 (m, 1H), 3.85 (s, 3H), 3.12 - 2.91 (m, 2H), 2.90 - 2.69 (m, 6H), 2.17 - 1.94 (m, 3H), 1.47 (s, 11H), LCMS: m / z (M+H) + =500.3.

[0534] Purity: 96.7%, Yield: 12.9%

[0535]

[0536] Example 34:

[0537] tert-Butyl(4-(4-amino-7-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0538] 1 H NMR (400 MHz, Methanol-d4) δ = 7.93 (br d, J = 8.1 Hz, 1H), 7.73 (s, 1H), 7.06 (s, 1H), 7.04 - 6.98 (m, 1H), 6.18 (s, 1H), 3.92 (s, 3H), 3.44 (br d, J = 9.2 Hz, 2H), 3.26 (br d, J = 5.5 Hz, 2H), 2.97 (br d, J = 4.3 Hz, 4H), 2.53 - 2.43 (m, 2H), 2.39 (s, 3H), 1.54 (s, 9H), LCMS: m / z (M+H) + =480.3.

[0539] Purity: 99.5%, Yield: 4.03%

[0540]

[0541] Example 35A:

[0542] tert-Butyl(4-(4-amino-7-((3aR,7aR)-5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0543] 1 H NMR (400 MHz, DMSO-d6) δ = 7.97 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.66 (s, 1H), 7.05 (d, J = 1.2 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 5.99 (s, 1H), 3.85 (s, 3H), 3.58 - 3.51 (m, 2H), 3.51 - 3.43 (m, 1H), 3.39 - 3.35 (m, 1H), 2.38 (br d, J = 8.3 Hz, 3H), 2.34 - 2.28 (m, 1H), 2.24 - 2.17 (m, 1H), 2.15 (s, 3H), 2.13 - 2.07 (m, 1H), 1.75 - 1.65 (m, 1H), 1.62 - 1.52 (m 1H), 1.47 (s, 9H), LCMS: m / z (M+H) + =494.2.

[0544] Purity: 98.6%, Yield: 1.94%

[0545]

[0546] Example 35B:

[0547] tert-Butyl(4-(4-amino-7-((3aS,7aS)-5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0548] 1H NMR (400 MHz, DMSO-d6) δ = 7.98 (s, 1H), 7.77 (br d, J = 8.3 Hz, 1H), 7.66 (s, 1H), 7.05 (d, J = 1.8 Hz, 1H), 6.97 (dd, J = 1.7, 8.2 Hz, 1H), 5.99 (s, 1H), 3.85 (s, 3H), 3.54 (dt, J = 3.4, 6.4 Hz, 2H), 3.50 - 3.44 (m, 1H), 3.39 - 3.34 (m, 1H), 2.43 - 2.34 (m, 3H), 2.33 - 2.27 (m, 1H), 2.24 - 2.17 (m, 1H), 2.15 (s, 3H), 2.12 - 2.06 (m, 1H), 1.77 - 1.64 (m, 1H), 1.63 - 1.53 (m, 1H), 1.47 (s, 9H), LCMS: m / z (M+H) + =494.2.

[0549] Purity: 98.2%, Yield: 1.61%

[0550]

[0551] Example 36:

[0552] tert-Butyl(4-(4-amino-7-(8-methyl-2,8-diazaspiro[4.5]decan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0553] 1H NMR (400 MHz, Methanol-d4) δ = 7.92 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.06 (d, J = 1.6 Hz, 1H), 7.02 (dd, J = 1.8, 8.2 Hz, 1H), 6.11 (s, 1H), 3.92 (s, 3H), 3.55 (t, J = 7.0 Hz, 2H), 3.38 (s, 2H), 2.89 - 2.61 (m, 4H), 2.49 (s, 3H), 1.90 (t, J = 7.0 Hz, 2H), 1.86 - 1.75 (m, 4H), 1.54 (s, 9H), LCMS: m / z (M+H) + =508.3.

[0554] Purity: 95.8%, Yield: 6.83%

[0555]

[0556] Example 37:

[0557] tert-Butyl(4-(4-amino-7-(2-methyl-2,6-diazaspiro[3.4]octan-6-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0558] 1 H NMR (400 MHz, Methanol-d4) δ = 7.92 (d, J = 8.1 Hz, 1H), 7.67 (s, 1H), 7.05 (s, 1H), 7.02 (dd, J = 1.7, 8.2 Hz, 1H), 6.11 (s, 1H), 3.92 (s, 3H), 3.62 (s, 2H), 3.46 (t, J = 7.0 Hz, 2H), 3.42 - 3.34 (m, 4H), 2.40 (s, 3H), 2.20 (t, J = 7.0 Hz, 2H), 1.54 (s, 9H), LCMS: m / z (M+H) + =480.2.

[0559] Purity: 95.6%, Yield: 4.89%

[0560]

[0561] Example 38:

[0562] tert-Butyl(4-(4-amino-7-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0563] 1 H NMR (400 MHz, DMSO-d6, FA salt) δ = 8.01 (s, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.70 (s, 1H), 7.03 (d, J = 1.8 Hz, 1H), 6.96 (dd, J = 1.7, 8.2 Hz, 1H), 5.97 (s, 1H), 3.85 (s, 3H), 3.80 (s, 4H), 3.18 - 2.86 (m, 4H), 2.67 (s, 3H), 2.05 - 1.87 (m, 4H), 1.47 (s, 9H), LCMS: m / z (M+H) + =494.3.

[0564] Purity: 99.0%, Yield: 7.72%

[0565]

[0566] Example 39:

[0567] tert-Butyl(4-(4-amino-7-(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0568] 1H NMR (400 MHz, Methanol-d4) δ = 7.92 (d, J = 8.1 Hz, 1H), 7.65 (s, 1H), 7.05 (d, J = 1.6 Hz, 1H), 7.01 (dd, J = 1.7, 8.1 Hz, 1H), 6.03 (s, 1H), 4.04 (d, J = 7.2 Hz, 2H), 3.97 (d, J = 7.2 Hz, 2H), 3.92 (s, 3H), 2.89 (s, 2H), 2.64 (t, J = 7.0 Hz, 2H), 2.40 (s, 3H), 2.20 (t, J = 7.1 Hz, 2H), 1.54 (s, 9H), LCMS: m / z (M+H) + =480.2.

[0569] Purity: 99.6%, Yield: 4.87%

[0570]

[0571] Example 40:

[0572] tert-Butyl(S)-(4-(4-amino-7-(3-((dimethylamino)methyl)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0573] 1 H NMR (400 MHz, Methanol-d4) δ = 7.94 (d, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.05 (d, J = 1.6 Hz, 1H), 7.02 (dd, J = 1.8, 8.2 Hz, 1H), 6.31 (s, 1H), 3.92 (s, 3H), 3.43 - 3.33 (m, 2H), 3.16 - 2.88 (m, 4H), 2.83 (s, 6H), 2.37 - 2.27 (m, 1H), 1.98 - 1.88 (m, 2H), 1.86 - 1.78 (m, 1H), 1.54 (s, 9H), 1.50 - 1.41 (m, 1H), LCMS: m / z (M+H) + =496.3.

[0574] Purity: 96.91%, Yield: 5.72%

[0575]

[0576] Example 41:

[0577] tert-Butyl(R)-(4-(4-amino-7-(3-((dimethylamino)methyl)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0578] 1 H NMR (400 MHz, Methanol-d4) δ = 7.93 (br d, J = 7.8 Hz, 1H), 7.77 (s, 1H), 7.06 (s, 1H), 7.02 (dd, J = 1.3, 8.4 Hz, 1H), 6.29 (s, 1H), 3.92 (s, 3H), 3.70 - 3.58 (m, 2H), 3.42 - 3.36 (m, 2H), 2.83 - 2.70 (m, 1H), 2.56 - 2.38 (m, 2H), 2.31 (br s, 6H), 2.17 - 2.05 (m, 1H), 1.96 - 1.77 (m, 3H), 1.54 (s, 9H), LCMS: m / z (M+H) + =496.3.

[0579] Purity: 93.8%, Yield: 10.8%

[0580]

[0581] Example 42:

[0582] tert-Butyl(4-(4-amino-7-((1R,5S,6s)-6-(dimethylamino)-3-azabicyclo[3.1.0]hexan-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0583] 1H NMR (400 MHz, Methanol-d4) δ = 7.92 (d, J = 8.2 Hz, 1H), 7.67 (s, 1H), 7.04 (d, J = 1.6 Hz, 1H), 7.00 (dd, J = 1.7, 8.3 Hz, 1H), 6.07 (s, 1H), 3.95 (d, J = 9.2 Hz, 2H), 3.91 (s, 3H), 3.24 (d, J = 9.2 Hz, 2H), 2.45 (s, 6H), 2.10 (s, 1H), 1.77 (s, 2H), 1.54 (s, 9H), LCMS: m / z (M+H) + =480.2.

[0584] Purity: 93.8%, Yield: 13.4%

[0585]

[0586] Example 44:

[0587] tert-Butyl (4-(4-amino-7-(4-(methylamino)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0588] 1 H NMR (400 MHz, DMSO-d6) δ = 8.30 (s, 1H), 7.98 (s, 1H), 7.82 (s, 1H), 7.80 (d,J= 8.2 Hz, 1H), 7.05 (d,J= 1.5 Hz, 1H), 6.97 (dd,J= 1.5, 8.2 Hz, 1H), 6.26 (s, 1H), 3.85 (s, 3H), 3.73 (d,J= 11.2 Hz, 2H), 2.95 - 2.85 (m, 1H), 2.73 (t,J= 11.4 Hz, 2H), 2.47 (s, 3H), 2.07 - 1.99 (m, 2H), 1.69 - 1.56 (m, 2H), 1.47 (s, 9H). LCMS: m / z (M+H) + = 468.2.

[0589] Purity: 99% Yield: 31%

[0590]

[0591] Example 45:

[0592] tert-Butyl (4-(4-amino-7-(4-amino-4-methylpiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0593] 1 H NMR (400 MHz, DMSO-d6) δ = 8.00 (br s, 3H), 7.84 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H), 6.97 (dd, J = 1.6, 8.0 Hz, 1H), 6.30 (s, 1H), 3.85 (s, 3H), 3.56 - 3.48 (m, 2H), 3.05 (t, J = 10.0 Hz, 2H), 2.00 - 1.87 (m, 2H), 1.84 - 1.75 (m, 2H), 1.47 (s, 9H), 1.36 (s, 3H). LCMS: m / z (M+H) + = 468.3.

[0594] Purity: 99% Yield: 17%

[0595]

[0596] Example 46:

[0597] tert-Butyl (4-(4-amino-7-((3S,4R)-4-amino-3-fluoropiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0598] LCMS: m / z (M+H) + =472.2. 1H NMR (400 MHz, METHANOL-d4) δ = 7.94 (d, J = 8.1 Hz, 1H), 7.78 (s, 1H), 7.06 (d, J = 1.4 Hz, 1H), 7.02 (dd, J = 1.6, 8.3 Hz, 1H), 6.31 (s, 1H), 4.99 - 4.91 (m, 1H), 4.14 - 4.02 (m, 1H), 3.92 (s, 3H), 3.85 (d, J = 12.6 Hz, 1H), 3.42 - 3.36 (m, 1H), 3.23 - 3.11 (m, 1H), 2.93 (t, J = 12.0 Hz, 1H), 2.25 - 2.12 (m, 1H), 2.00 - 1.88 (m, 1H), 1.54 (s, 9H).

[0599] Purity: 98% Yield: 14%

[0600]

[0601] Example 48:

[0602] tert-Butyl (4-(4-amino-7-(4-amino-3-methylpiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0603] LCMS: m / z (M+H) + =468.2. 1H NMR (400 MHz, DMSO-d6) δ = 7.99 (s, 1H), 7.94 (br s, 3H), 7.83 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.04 (d, J = 1.8 Hz, 1H), 6.97 (dd, J = 1.7, 8.2 Hz, 1H), 6.27 (s, 1H), 3.85 (s, 3H), 3.78 (d, J = 11.9 Hz, 1H), 3.67 (dd, J = 2.7, 11.8 Hz, 1H), 2.99 - 2.86 (m, 1H), 2.82 - 2.71 (m, 1H), 2.59 - 2.56 (m, 1H), 2.07 - 1.98 (m, 1H), 1.96 - 1.86 (m, 1H), 1.72 (dq, J = 3.4, 12.3 Hz, 1H), 1.47 (s, 9H), 1.00 (d, J = 6.5 Hz, 3H).

[0604] Purity: 99% Yield: 33%

[0605]

[0606] Example 49:

[0607] Tert-butyl (4-(4-amino-7-(4-amino-3,5-dimethylpiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0608] 1 H NMR (400 MHz, METHANOL-d4) δ = 7.93 (d, J = 8.3 Hz, 1H), 7.80 - 7.75 (m, 1H), 7.09 - 7.00 (m, 2H), 6.32 - 6.22 (m, 1H), 3.92 (s, 3H), 3.73 - 3.51 (m, 1H), 3.39 - 3.34 (m, 1H), 3.05 - 2.99 (m, 1H), 2.72 (t,J= 12.0 Hz, 1H), 2.64 - 2.45 (m, 1H), 2.29 - 2.17 (m, 2H), 1.98 - 1.79 (m, 1H), 1.54 (s, 9H), 1.11 - 0.97 (m, 6H).

[0609] Purity: 93% Yield: 18%

[0610]

[0611] Example 51:

[0612] tert-Butyl (4-(4-amino-7-(5-amino-2-azabicyclo[2.2.1]hepten-2-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0613] LCMS: m / z (M+H) + =466.2. 1 H NMR (400 MHz, DMSO-d6) δ = 8.30 (br s, 1H), 7.98 (s, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.69 (s, 1H), 7.04 (d, J = 1.5 Hz, 1H), 6.97 (dd, J = 1.5, 8.3 Hz, 1H), 6.08 (s, 1H), 4.40 (s, 1H), 3.85 (s, 3H), 3.52 (dd, J = 3.7, 9.5 Hz, 1H), 3.17 - 3.13 (m, 1H), 2.98 (d, J = 9.2 Hz, 1H), 2.46 - 2.44 (m, 1H), 2.13 - 2.02 (m, 1H), 1.90 (d, J = 10.5 Hz, 1H), 1.68 - 1.61 (m, 1H), 1.47 (s, 9H), 1.37 - 1.28 (m, 1H).

[0614] Purity: 99% Yield: 5%

[0615]

[0616] Example 52:

[0617] tert-Butyl (4-(4-amino-7-(3-oxo-2,8-diazaspiro[4.5]decane-8-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0618] 1H NMR (400 MHz, DMSO-d6) δ = 7.97 (s, 1H), 7.84 - 7.74 (m, 2H), 7.55 (s, 1H), 7.06 (d, J = 1.6 Hz, 1H), 6.97 (dd, J = 1.6, 8.4 Hz, 1H), 6.24 (s, 1H), 3.85 (s, 3H), 3.27 - 3.17 (m, 2H), 3.15 - 3.04 (m, 4H), 2.12 (s, 2H), 1.80 - 1.65 (m, 4H), 1.47 (s, 9H). LCMS: m / z (M+H) + =508.3.

[0619] Purity: 99% Yield: 16%

[0620]

[0621] Example 53:

[0622] tert-Butyl (4-(4-amino-7-(1-oxo-2,8-diazaspiro[4.5]decane-8-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0623] 1 H NMR (400 MHz, DMSO-d6) δ = 7.97 (s, 1H), 7.82 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H), 7.06 (d, J = 1.2 Hz, 1H), 6.98 (d, J = 8.0) Hz, 1H), 6.25 (s, 1H), 3.85 (s, 3H), 3.71 - 3.60 (m, 2H), 3.20 (t, J = 6.8 Hz, 2H), 2.82 (t, J = 10.6 Hz, 2H), 2.01 (t, J = 6.8 Hz, 2H), 1.93 - 1.84 (m, 2H), 1.52 - 1.35 (m, 11H). LCMS: m / z (M+H) + =508.2.

[0624] Purity: 96% Yield: 6%

[0625]

[0626] Example 54:

[0627] tert-Butyl (4-(4-amino-7-(2-oxo-1,8-diazaspiro[4.5]decane-8-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0628] LCMS: m / z (M+H) + =508.3. 1 H NMR (400 MHz, DMSO-d6) δ = 8.00 (s, 1H), 7.97 (s, 1H), 7.84 - 7.77 (m, 2H), 7.05 (d, J = 1.6 Hz, 1H), 6.97 (dd, J = 1.7, 8.2 Hz, 1H), 6.23 (s, 1H), 3.85 (s, 3H), 3.44 - 3.36 (m, 2H), 3.12 - 3.04 (m, 2H), 2.22 (t, J = 7.9 Hz, 2H), 1.90 (t, J = 7.9 Hz, 2H), 1.83 - 1.66 (m, 4H), 1.47 (s, 9H).

[0629] Purity: 99% Yield: 5%

[0630]

[0631] Example 55:

[0632] tert-Butyl (4-(4-amino-7-(1-oxo-2,7-diazaspiro[3.5]nonane-7-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0633] 1H NMR (400 MHz, DMSO-d6) δ = 7.98 (s, 1H), 7.82 (s, 1H), 7.81 - 7.77 (m, 2H), 7.06 (d, J = 1.6 Hz, 1H), 6.97 (dd, J = 1.6, 8.8 Hz, 1H), 6.25 (s, 1H), 3.85 (s, 3H), 3.57 - 3.45 (m, 2H), 3.10 (s, 2H), 3.00 (t, J = 8.8 Hz, 2H), 2.00 - 1.91 (m, 2H), 1.90 - 1.83 (m, 2H), 1.47 (s, 9H). LCMS: m / z (M+H) + =494.3.

[0634] Purity: 98% Yield: 8%

[0635]

[0636] Example 56:

[0637] tert-Butyl (4-(4-amino-7-(2-oxo-1,7-diazaspiro[3.5]nonane-7-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0638] LCMS: m / z (M+H) + =494.2. 1 H NMR (400 MHz, DMSO-d6) δ = 8.37 (s, 1H), 8.12 - 7.93 (m, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.08 (s, 1H), 7.02 (dd, J = 1.8, 8.2 Hz, 1H), 6.48 (s, 1H), 3.83 (s, 3H), 3.33 - 3.18 (m, 4H), 2.67 (s, 2H), 1.92 - 1.76 (m, 4H), 1.45 (s, 9H).

[0639] Purity: 97% Yield: 12%

[0640]

[0641] Example 58: tert-Butyl(4-(4-amino-7-(4-(methylamino)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0642] 1 H NMR (400 MHz, DMSO-d6) δ = 8.37 (br s, 2H), 7.97 (s, 1H), 7.85 (s, 1H), 7.81 (d,J= 8.3 Hz, 1H), 7.05 (d,J= 1.8 Hz, 1H), 6.98 (dd,J= 1.8, 8.2 Hz, 1H), 6.28 (s, 1H), 3.85 (s, 3H), 3.73 (d,J= 11.5 Hz, 2H), 2.94 - 2.86 (m,J= 5.4 Hz, 2H), 2.75 - 2.65 (m, 2H), 2.60 (t,J= 5.1 Hz, 3H), 1.87 - 1.77 (m, 3H), 1.47 - 1.39 (m, 2H). LCMS: m / z (M+H) + = 482.3.

[0643] Purity 99.2%, Yield: 18%

[0644]

[0645] Example 59: tert-Butyl (4-(4-amino-7-(4-(aminomethyl)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0646] 1H NMR (400 MHz, DMSO-d6) δ = 8.25 (br s, 1H), 7.99 (s, 1H), 7.83 - 7.77 (m, 2H), 7.05 (d,J= 1.8 Hz, 1H), 6.97 (dd,J= 1.7, 8.2 Hz, 1H), 6.25 (s, 1H), 3.85 (s, 3H), 3.72 (d,J= 11.8 Hz, 2H), 2.82 - 2.74 (m, 2H), 2.70 - 2.60 (m, 2H), 1.81 (d,J= 12.0 Hz, 2H), 1.76 - 1.66 (m, 1H), 1.47 (s, 9H), 1.45 - 1.36 (m, 2H). LCMS: m / z (M+H) + = 468.1

[0647] Purity 99.48%, Yield: 14%

[0648]

[0649] Example 60:

[0650] 1-Fluoro-2-methylpropan-2-yl (4-(4-amino-7-(4-aminopiperidin-1-yl-6-methylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0651] 1 H NMR (400 MHz, DMSO-d6) δ = 8.43 (s, 1H), 8.28 (s, 1H), 7.79 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 1.6 Hz, 1H), 6.89 (dd, J = 1.6, 8.0 Hz, 1H), 4.56 (d, J = 47.6 Hz, 2H), 3.82 (s, 3H), 3.41 (t, J = 11.0 Hz, 2H), 3.11 (d, J = 11.6 Hz, 2H), 3.06 - 2.98 (m, 1H), 2.04 (s, 3H), 1.95 - 1.89 (m, 2H), 1.66 - 1.54 (m, 2H), 1.47 (d, J = 2.0 Hz, 6H). LCMS: m / z (M+H) + = 486.1.

[0652] Purity: 98%, Yield: 26%

[0653]

[0654] Example 61:

[0655] 1-Fluoro-2-methylpropan-2-yl (4-(4-amino-6-methyl-7-(4-(methylamino)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0656] 1 H NMR (400 MHz, DMSO-d6) δ = 8.34 (s, 1H), 8.28 (s, 1H), 7.79 (s, 1H), 7.75 (d, J = 8.3 Hz, 1H), 6.98 (d, J = 1.8 Hz, 1H), 6.89 (dd, J = 1.6, 8.1 Hz, 1H), 4.56 (d,J= 47.6 Hz, 2H), 3.82 (s, 3H), 3.40 (t, J = 10.9 Hz, 2H), 3.14 (d, J = 11.9 Hz, 2H), 2.91 - 2.77 (m, 1H), 2.47 (s, 3H), 2.04 (s, 3H), 2.03 - 1.97 (m, 2H), 1.62 - 1.51 (m, 2H), 1.47 (d, J = 2.1 Hz, 6H).

[0657] Purity: 98.87%, Yield: 14.83%

[0658]

[0659] Example 62:

[0660] 1-Fluoro-2-methylpropan-2-yl (4-(4-amino-7-(4-(dimethylamino)piperidin-1-yl)-6-methylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methylmethoxy)carbamate

[0661] 1H NMR (400 MHz, DMSO-d6) δ = 8.27 - 8.25 (m, 2H), 7.79 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 1.6 Hz, 1H), 6.89 (dd, J = 1.6, 8.0 Hz, 1H), 4.55 (d, J = 47.6 Hz, 2H), 3.82 (s, 3H), 3.46 - 3.32 (m, 2H), 3.14 (d, J = 11.6 Hz, 2H), 2.39 - 2.32 (m, 1H), 2.27 (s, 6H), 2.04 (s, 3H), 1.83 (d, J = 10.8 Hz, 2H), 1.61 - 1.49 (m, 2H), 1.47 (d, J = 2.0 Hz, 6H). LCMS: m / z (M+H) + = 514.3.

[0662] Purity: 100%, Yield: 59%

[0663]

[0664] Example 63:

[0665] 1-Fluoro-2-methylpropan-2-yl (4-(4-amino-6-methyl-7-(4-(2-(methylamino)ethyl)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0666] 1H NMR (400 MHz, DMSO-d6) δ = 8.39 (s, 1H), 8.26 (s, 1H), 7.78 (s, 1H), 7.75 (d,J= 8.4 Hz, 1H), 6.98 (d,J= 1.6 Hz, 1H), 6.89 (dd,J= 1.6, 8.0 Hz, 1H), 4.55 (d,J= 47.6 Hz, 2H), 3.82 (s, 3H), 3.43 - 3.35 (m, 2H), 3.07 (d,J= 11.6 Hz, 2H), 2.81 (t,J= 7.2 Hz, 2H), 2.46 (s, 3H), 2.04 (s, 3H), 1.73 (d,J= 11.2 Hz, 2H), 1.61 - 1.50 (m, 3H), 1.47 (d,J= 2.0 Hz, 6H), 1.36 - 1.24 (m, 2H). LCMS: m / z (M+H) + = 528.2.

[0667] Purity: 98.62%, Yield: 48%

[0668]

[0669] Example 64:

[0670] 1-Fluoro-2-methylpropan-2-yl (4-(4-amino-6-methyl-7-(2-(4-(methylamino)piperidin-1-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0671] 1H NMR (400 MHz, DMSO-d6) δ = 8.30 (s, 1H), 8.28 (s, 1H), 7.84 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 1.6 Hz, 1H), 6.89 (dd, J = 1.8, 8.0 Hz, 1H), 4.56 (d, J = 47.6 Hz, 2H), 3.13 - 2.98 (m, 4H), 2.81 - 2.72 (m, 1H), 2.56 - 2.52 (m, 2H), 2.46 (s, 3H), 2.08 (s, 3H), 2.00 (t, J = 11.0 Hz, 2H), 1.94 - 1.90 (m, 2H), 1.47 (d, J = 2.0 Hz, 6H), 1.46 - 1.36 (m, 2H). LCMS: m / z (M+H) + = 528.2.

[0672] Purity: 99%, Yield: 34%

[0673]

[0674] Example 65:

[0675] 1-Fluoro-2-methylpropan-2-yl (4-(4-amino-7-(4-aminopiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0676] 1H NMR (400 MHz, DMSO-d6) δ = 8.41 (s, 1H), 8.25 (s, 1H), 7.82 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 1.6 Hz, 1H), 6.97 (dd, J = 1.6, 8.4 Hz, 1H), 6.25 (s, 1H), 4.55 (d, J = 47.6 Hz, 2H), 3.85 (s, 3H), 3.68 (d, J = 12.0 Hz, 2H), 3.01 - 2.92 (m, 1H), 2.74 (t, J = 10.4) Hz, 2H), 1.98 - 1.85 (m, 2H), 1.65 - 1.54 (m, 2H), 1.47 (d, J = 2.0 Hz, 6H). LCMS: m / z (M+H) + = 472.1.

[0677] Purity: 98%, Yield: 11%.

[0678]

[0679] Example 66:

[0680] 1-Fluoro-2-methylpropan-2-yl (4-(4-amino-7-(4-(2-(methylamino)ethyl)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0681] 1 H NMR (400 MHz, DMSO-d6) δ = 8.24 (s, 1H), 7.80 (s, 1H), 7.73 (d,J= 8.0 Hz, 1H), 7.06 (d,J= 1.2 Hz, 1H), 6.98 (dd,J= 1.6, 8 Hz, 1H), 6.22 (s, 1H), 4.55 (d,J= 47.6 Hz, 2H), 3.85 (s, 3H), 3.67 (d,J= 11.2 Hz, 2H), 2.68 - 2.59 (m, 2H), 2.56 - 2.53 (m, 2H), 2.29 (s, 3H), 1.74 (d,J= 10.4 Hz, 2H), 1.55 - 1.28 (m, 11H). LCMS: m / z (M+H) += 514.3.

[0682] Purity: 96%, Yield: 19%

[0683]

[0684] Example 67:

[0685] 1-Fluoro-2-methylpropan-2-yl (4-(4-amino-7-(2-(4-(methylamino)piperidin-1-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0686] 1 H NMR (400 MHz, DMSO-d6) δ = 8.33 (s, 1H), 8.26 (s, 1H), 7.89 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 6.97 (dd, J = 1.6, 8.0 Hz, 1H), 6.60 (s, 1H), 4.55 (d, J = 47.6 Hz, 2H), 3.85 (s, 3H), 3.07 - 3.02 (m, 2H), 2.99 - 2.91 (m, 2H), 2.66 (d, J = 8.0 Hz, 2H), 2.49 - 2.43 (m, 1H), 2.39 (s, 3H), 2.05 - 1.94 (m, 2H), 1.90 - 1.79 (m, 2H), 1.47 (d, J = 2.0 Hz, 6H), 1.42 - 1.29 (m, 2H). LCMS: m / z (M+H) + = 514.2.

[0687] Purity: 95% Yield 6%.

[0688]

[0689] Example 68:

[0690] 1-Fluoro-2-methylpropan-2-yl (4-(4-amino-7-(2-(4-aminopiperidin-1-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0691] 1H NMR (400 MHz, DMSO-d6) δ = 8.35 (s, 2H), 8.26 (s, 1H), 7.89 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 1.2 Hz, 1H), 7.00 - 6.94 (m, 1H), 6.61 (s, 1H), 4.55 (d, J = 47.6 Hz, 2H), 3.85 (s, 3H), 3.04 (t, J = 7.6 Hz, 2H), 2.95 (d, J = 11.2 Hz, 2H), 2.90 - 2.84 (m, 1H), 2.70 - 2.62 (m, 2H), 2.02 (t, J = 11.4 Hz, 2H), 1.87 - 1.79 (m, 2H), 1.52 - 1.40 (m, 8H). LCMS: m / z (M+H) + = 500.2.

[0692] Purity: 98%. Yield: 7%

[0693]

[0694] Example 69:

[0695] 1-Fluoro-2-methylpropan-2-yl (4-(4-amino-7-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0696] 1H NMR (400 MHz, DMSO-d6) δ = 8.25 (s, 2H), 7.89 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 6.97 (dd, J = 1.6, 8.4 Hz, 1H), 6.60 (s, 1H), 4.55 (d, J = 47.6 Hz, 2H), 3.85 (s, 3H), 3.08 - 2.97 (m, 4H), 2.64 (t, J = 7.8 Hz, 2H), 2.21 (s, 6H), 2.17 - 2.09 (m, 1H), 1.97 (t, J = 11.0 Hz, 2H), 1.78 - 1.70 (m, 2H), 1.47 (d, J = 2.0 Hz, 6H), 1.44 - 1.31 (m, 2H). LCMS: m / z (M+H) + = 528.2.

[0697] Purity: 96% Yield: 7%

[0698]

[0699] Example 70:

[0700] 1-Methylcyclopropyl (7-(4-amino-7-(4-aminopiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)benzo[d][1,3]dioxo-4-yl)carbamate

[0701] 1 H NMR (400 MHz, DMSO-d6) δ = 9.20 (br s, 1H), 8.36 (s, 1H), 7.81 (s, 1H), 7.09 (br d, J = 8.6 Hz, 1H), 6.78 (d, J = 8.6 Hz, 1H), 6.19 (s, 1H), 6.02 (s, 2H), 3.68 - 3.66 (m, 2H), 3.13 - 3.07 (m, 1H), 2.73 (t, J = 11.1 Hz, 2H), 1.96 (d, J = 10.1 Hz, 2H), 1.75 - 1.61 (m, 2H), 1.52 (s, 3H), 0.89 - 0.81 (m, 2H), 0.70 - 0.63 (m, 2H).

[0702] Purity: 99% Yield: 26%

[0703]

[0704] Example 71:

[0705] 1-Methylcyclopropyl (4-(4-amino-7-(4-aminopiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0706] 1 H NMR (400 MHz, DMSO-d6) δ = 8.42 (s, 1H), 8.34 (s, 1H), 7.82 (s, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 6.98 (dd, J = 1.6, 8.4 Hz, 1H), 6.25 (s, 1H), 3.83 (s, 3H), 3.67 (d, J = 12.0 Hz, 2H), 3.00 - 2.93 (m, 1H), 2.74 (t, J = 11.2 Hz, 2H), 1.94 - 1.86 (m, 2H), 1.64 - 1.54 (m, 2H), 1.53 (s, 3H), 0.89 - 0.81 (m, 2H), 0.71 - 0.61 (m, 2H). LCMS: m / z (M+H) + = 452.2.

[0707] Purity 99% Yield: 7%

[0708]

[0709] Example 72:

[0710] 1,1,1-Trifluoro-2-methylpropan-2-yl (4-(4-amino-7-(4-aminopiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0711] 1H NMR (400 MHz, DMSO-d6) δ = 8.73 (br s, 1H), 8.44 (br s, 1H), 7.82 (s, 1H), 7.63 (br s, 1H), 7.08 (d,J= 1.6 Hz, 1H), 6.99 (dd,J= 1.6, 8.2 Hz, 1H), 6.26 (s, 1H), 3.85 (s, 3H), 3.69 (d,J= 11.6 Hz, 2H), 3.06 - 2.96 (m, 1H), 2.74 (t,J= 11.1 Hz, 2H), 1.97 - 1.89 (m, 2H), 1.79 - 1.56 (m, 8H). LCMS: m / z (M+H) + = 508.2.

[0712] Purity: 99% Yield: 20%

[0713]

[0714] Example 73:

[0715] tert-Butyl (7-(4-amino-7-(4-aminopiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)benzo[d][1,3]dioxo-4-yl)carbamate

[0716] 1 H NMR (400 MHz, DMSO-d6) δ = 8.94 (s, 1H), 8.41 (s, 1H), 7.81 (s, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.18 (s, 1H), 6.02 (s, 2H), 3.65 (d, J = 12.0 Hz, 2H), 3.08 - 2.98 (m, 1H), 2.72 (t, J = 10.8 Hz, 2H), 1.97 - 1.89 (m, 2H), 1.68 - 1.58 (m, 2H), 1.46 (s, 9H) LCMS: m / z (M+H) + =468.1.

[0717] Purity: 99% Yield: 34%

[0718]

[0719] Example 74:

[0720] tert-Butyl (4-(4-amino-7-(4-aminopiperidin-1-yl)-6-methylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0721] 1 H NMR (400 MHz, DMSO-d6) δ = 8.01 (s, 1H), 7.84 - 7.77 (m, 2H), 6.96 (d,J= 1.6 Hz, 1H), 6.88 (dd,J= 1.6, 8.2 Hz, 1H), 3.82 (s, 3H), 3.45 - 3.39 (m, 2H), 3.18 - 3.09 (m, 3H), 2.04 (s, 3H), 1.98 - 1.90 (m, 2H), 1.67 - 1.57 (m, 2H), 1.47 (s, 9H). LCMS: m / z (M+H) + = 468.3.

[0722] Purity: 97% Yield: 7%

[0723]

[0724] Example 75:

[0725] tert-Butyl (4-(4-amino-6-methyl-7-(4-(methylamino)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0726] 1H NMR (400 MHz, DMSO-d6) δ = 8.38 (s, 1H), 8.01 (s, 1H), 7.85 - 7.76 (m, 2H), 6.96 (d,J= 1.6 Hz, 1H), 6.88 (dd,J= 1.5, 8.1 Hz, 1H), 3.82 (s, 3H), 3.40 (t,J= 11.1 Hz, 2H), 3.14 (d,J= 11.9 Hz, 2H), 2.90 - 2.80 (m, 1H), 2.47 (s, 3H), 2.04 (s, 3H), 2.03 - 1.99 (m, 2H), 1.64 - 1.50 (m, 2H), 1.47 (s, 9H). LCMS: m / z (M+H) + =482.3.

[0727] Purity: 98% Yield: 33%

[0728]

[0729] Example 76:

[0730] tert-Butyl (4-(4-amino-7-(4-(dimethylamino)piperidin-1-yl)-6-methylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0731] LCMS: m / z (M+H) + =496.3. 1 H NMR (400 MHz, DMSO-d6) δ = 8.21 (s, 1H), 8.00 (s, 1H), 7.83 - 7.77 (m, 2H), 6.97 (d,J= 2 Hz, 1H), 6.88 (dd,J= 1.6, 8 Hz, 1H), 3.82 (s, 3H), 3.40 (t,J= 10.8 Hz, 2H), 3.14 (d,J= 12.0 Hz, 2H), 2.42 - 2.37 (m, 1H), 2.30 (s, 6H), 2.04 (s, 3H), 1.84 (d,J= 10.4 Hz, 2H), 1.62 - 1.51 (m, 2H), 1.47 (s, 9H).

[0732] Purity: 99% Yield: 57%

[0733]

[0734] Example 77:

[0735] tert-Butyl (4-(4-amino-6-methyl-7-(4-(2-(methylamino)ethyl)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0736] 1 H NMR (400 MHz, DMSO-d6) δ = 8.38 (s, 1H), 8.01 (s, 1H), 7.83 - 7.76 (m, 2H), 6.96 (d,J= 1.6 Hz, 1H), 6.88 (dd,J= 1.8, 8 Hz, 1H), 3.82 (s, 3H), 3.43 - 3.33 (m, 2H), 3.11 - 3.03 (m, 2H), 2.83 - 2.77 (m, 2H), 2.46 (s, 3H), 2.04 (s, 3H), 1.76 - 1.68 (m, 2H), 1.55 - 1.47 (m, 12H), 1.38 - 1.19 (m, 2H). LCMS: m / z (M+H) + = 510.4.

[0737] Purity 99% Yield 22%

[0738]

[0739] Example 78:

[0740] tert-Butyl (4-(4-amino-7-(4-aminopiperidin-1-yl)-6-methylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0741] 1H NMR (400 MHz, DMSO-d6) δ = 8.29 (s, 2H), 8.01 (s, 1H), 7.84 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 1.6 Hz, 1H), 6.88 (dd, J = 1.6, 8.0 Hz, 1H), 3.82 (s, 3H), 3.10 - 2.99 (m, 4H), 2.90 - 2.80 (m, 1H), 2.56 - 2.52 (m, 2H), 2.50 (br s, 3H), 2.08 (s, 3H), 2.04 - 1.91 (m, 4H), 1.52 - 1.42 (m, 11H). LCMS: m / z (M+H) + = 510.2.

[0742] Purity: 99% Yield: 45%

[0743]

[0744] Example 79:

[0745] tert-Butyl (4-(4-amino-7-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0746] 1 H NMR (400 MHz, DMSO-d6) δ = 8.17 (s, 1H), 7.99 (s, 1H), 7.82 - 7.78 (m, 2H), 7.05 (d, J = 1.6 Hz, 1H), 6.97 (dd, J = 1.6, 8.4 Hz, 1H), 6.26 (s, 1H), 3.85 (s, 3H), 3.07 - 2.97 (m, 2H), 2.80 (s, 2H), 1.74 - 1.63 (m, 2H), 1.56 - 1.49 (m, 2H), 1.47 (s, 9H), 1.06 (s, 3H). LCMS: m / z (M+H) + = 482.2.

[0747] Purity: 99% Yield: 17%

[0748]

[0749] Example 80:

[0750] tert-Butyl (4-(4-amino-7-(8-amino-5-azaspiro[2.5]octen-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0751] 1 H NMR (400 MHz, DMSO-d6) δ = 8.33 (s, 1H), 7.98 (s, 1H), 7.86 - 7.73 (m, 2H), 7.04 (d, J = 1.6 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.20 (s, 1H), 3.85 (s, 3H), 3.22 - 3.18 (m, 3H), 2.85 (d, J = 11.6 Hz, 1H), 2.75 - 2.73 (m, 1H), 2.08 - 1.89 (m, 1H), 1.76 - 1.61 (m, 1H), 1.47 (s, 9H), 0.70 - 0.56 (m, 2H), 0.44 - 0.29 (m, 2H). LCMS: m / z (M+H) + = 480.2.

[0752] Purity: 99% Yield: 14%

[0753]

[0754] Example 81:

[0755] tert-Butyl (4-(4-amino-7-(4-(1-aminoethyl)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0756] 1H NMR (400 MHz, DMSO-d6) δ = 8.43 (s, 1H), 7.98 (s, 1H), 7.87 - 7.73 (m, 2H), 7.05 (d, J = 1.2 Hz, 1H), 6.97 (dd, J = 1.2, 8.0 Hz, 1H), 6.24 (s, 1H), 3.85 (s, 3H), 3.75 (d, J = 11.2 Hz, 2H), 2.95 - 2.90 (m, 1H), 2.60 (t, J = 10.0 Hz, 2H), 1.84 - 1.77 (m, 1H), 1.76 - 1.69 (m, 1H), 1.47 (s, 12H), 1.11 (d, J = 6.4 Hz, 3H). LCMS: m / z (M+H) + = 482.2.

[0757] Purity 99% Yield 7%

[0758]

[0759] Example 82:

[0760] tert-Butyl (4-(4-amino-7-(4-amino-4-ethylpiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0761] 1 H NMR (400 MHz, DMSO-d6) δ = 8.37 (br s, 1H), 7.98 (s, 1H), 7.84 - 7.75 (m, 2H), 7.05 (s, 1H), 7.01 - 6.93 (m, 1H), 6.26 (s, 1H), 3.85 (s, 3H), 3.32 - 3.17 (m, 4H), 1.80 - 1.65 (m, 4H), 1.59 (q, J = 7.6 Hz, 2H), 1.47 (s, 9H), 0.90 (t, J = 7.2 Hz, 3H). LCMS: m / z (M+H) + = 482.2.

[0762] Purity: 99% Yield: 18%

[0763]

[0764] Example 83:

[0765] tert-Butyl (4-(4-amino-7-(4-amino-4-(trifluoromethyl)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0766] 1 H NMR (400 MHz, DMSO-d6) δ = 8.40 (s, 1H), 7.99 (s, 1H), 7.85 - 7.75 (m, 2H), 7.06 (d,J= 1.5 Hz, 1H), 6.98 (dd,J= 1.6, 8.3 Hz, 1H), 6.28 (s, 1H), 3.85 (s, 3H), 3.59 -3.51 (m, 2H), 3.07 (t,J= 10.7 Hz, 2H), 1.93 - 1.82 (m, 2H), 1.59 (d,J= 12.3 Hz, 2H), 1.47 (s, 9H) LCMS: m / z (M+H) + = 522.2

[0767] Purity: 95% Yield: 10%

[0768]

[0769] Example 84:

[0770] tert-Butyl (4-(4-amino-7-(4-(methylamino)-4-(trifluoromethyl)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0771] 1 H NMR (400 MHz, DMSO-d6) δ = 7.97 (s, 1H), 7.82 (s, 1H), 7.79 (d,J= 8.1 Hz, 1H), 7.07 (d,J= 1.8 Hz, 1H), 6.98 (dd,J= 1.7, 8.2 Hz, 1H), 6.28 (s, 1H), 3.85 (s, 3H), 3.53 (d,J= 11.0 Hz, 2H), 3.05 - 2.90 (m, 2H), 2.34 (s, 3H), 1.91 - 1.74 (m, 4H), 1.47 (s, 9H). LCMS: m / z (M+H)+ = 536.1.

[0772] Purity: 95% Yield: 26%

[0773]

[0774] Example 85:

[0775] tert-Butyl (4-(4-amino-7-((3S,4S)-4-amino-3-(trifluoromethyl)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0776] 1 H NMR (400 MHz, METHANOL-d4) δ = 7.95 (d, J = 8.0 Hz, 1H), 7.81 (s, 1H), 7.09 (s, 1H), 7.05 (d, J = 9.6 Hz, 1H), 6.38 (s, 1H), 3.94 (s, 3H), 3.70 - 3.60 (m, 3H), 3.40 - 3.38 (m, 1H), 3.23 - 3.21 (m, 1H), 2.92 - 2.86 (m, 1H), 2.18 - 2.11 (m, 1H), 1.90 - 1.84 (m, 1H), 1.56 (s, 9H)).

[0777] Purity 94.58% Yield 5%

[0778]

[0779] Example 86:

[0780] tert-Butyl (4-(4-amino-7-((3S,4R)-4-amino-3-(trifluoromethyl)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0781] 1H NMR (400 MHz, METHANOL-d4) δ = 7.93 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.06 (s, 1H), 7.05 - 6.99 (m, 1H), 6.32 (s, 1H), 3.98 (d, J = 10.3 Hz, 1H), 3.92 (s, 3H), 3.70 - 3.65 (m, 1H), 3.13 - 3.08 (m, 1H), 2.90 (dt, J = 2.3, 12.3 Hz, 1H), 2.78 - 2.71 (m, 1H), 2.66 - 2.59 (m, 1H), 2.09 - 2.02 (m, 1H), 1.86 - 1.75 (m, 1H), 1.54 (s, 9H)).

[0782] Purity 99.15% Yield 6%

[0783]

[0784] Example 87:

[0785] tert-Butyl (4-(4-amino-7-((3S,4R)-3-fluoro-4-(methylamino)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0786] 1 H NMR (400 MHz, METHANOL-d4) δ = 7.94 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.05 (s, 1H), 7.02 (d, J = 8.9 Hz, 1H), 6.31 (s, 1H), 5.26 - 5.06 (m, 1H), 4.26 - 4.14 (m, 1H), 4.01 - 3.88 (m, 4H), 3.56 - 3.39 (m, 1H), 3.25 - 3.06 (m, 1H), 2.92 (t, J = 11.6 Hz, 1H), 2.81 (s, 3H), 2.31 - 2.18 (m, 1H), 2.16 - 2.07 (m, 1H), 1.54 (s, 9H).

[0787] Purity: 98% Yield: 40%

[0788]

[0789] Example 89:

[0790] 1-(4-amino-5-(4-((tert-butoxycarbonyl)amino)-3-methoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-4-carboxylic acid

[0791] 1 H NMR (400 MHz, DMSO-d6) δ = 12.15 (br s, 1H), 7.98 (s, 1H), 7.82 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.98 (dd, J = 2.0, 8.0 Hz, 1H), 6.24 (s, 1H), 3.85 (s, 3H), 3.68 - 3.55 (m, 2H), 2.85 - 2.72 (m, 2H), 2.45 - 2.39 (m, 1H), 1.98 - 1.90 (m, 2H), 1.83 - 1.69 (m, 2H), 1.47 (s, 9H). LCMS: m / z (M+H) + = 483.2.

[0792] Purity 99% Yield 26%

[0793]

[0794] Example 90:

[0795] tert-Butyl (4-(4-amino-7-(4-hydroxypiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0796] 1H NMR (400 MHz, DMSO-d6) δ = 7.97 (s, 1H), 7.81 (s, 1H), 7.79 (d,J= 8.3 Hz, 1H), 7.05 (d,J= 1.6 Hz, 1H), 6.97 (dd,J= 1.6, 8.1 Hz, 1H), 6.22 (s, 1H), 4.71 (br s, 1H), 3.85 (s, 3H), 3.70 - 3.60 (m, 1H), 3.57 - 3.46 (m, 2H), 2.84 (t,J= 9.5 Hz, 2H), 1.91 - 1.81 (m, 2H), 1.63 - 1.52 (m, 2H), 1.47 (s, 9H) LCMS: m / z (M+H)+ = 455.2.

[0797] Purity 99% Yield 29%

[0798]

[0799] Example 91:

[0800] tert-Butyl (4-(4-amino-7-(4-amino-3,5-dimethylpiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0801] LCMS: m / z (M+H) + =482.2. 1 H NMR (400 MHz, METHANOL-d4) δ = 7.93 (d, J = 8.3 Hz, 1H), 7.80 - 7.75 (m, 1H), 7.09 - 7.00 (m, 2H), 6.32 - 6.22 (m, 1H), 3.92 (s, 3H), 3.73 - 3.51 (m, 1H), 3.39 - 3.34 (m, 1H), 3.05 - 2.99 (m, 1H), 2.72 (t,J= 12.0 Hz, 1H), 2.64 - 2.45 (m, 1H), 2.29 - 2.17 (m, 2H), 1.98 - 1.79 (m, 1H), 1.54 (s, 9H), 1.11 - 0.97 (m, 6H).

[0802] Purity: 93% Yield: 18%

[0803]

[0804] Example 92:

[0805] tert-Butyl (4-(4-amino-7-(4-(ethylamino)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0806] 1 H NMR (400 MHz, DMSO-d6) δ = 8.34 (br s, 1H), 7.98 (s, 1H), 7.85 - 7.76 (m, 2H), 7.05 (d,J= 1.6 Hz, 1H), 6.97 (dd,J= 1.7, 8.2 Hz, 1H), 6.25 (s, 1H), 3.85 (s, 3H), 3.73 (d,J= 11.9 Hz, 2H), 3.00 - 2.92 (m, 1H), 2.89 - 2.81 (m, 2H), 2.73 (t,J= 11.3 Hz, 2H), 2.06 - 1.98 (m, 2H), 1.70 - 1.56 (m, 2H), 1.47 (s, 9H), 1.15 (t,J= 6.5 Hz, 3H) LCMS: m / z (M+H) + = 482.2

[0807] Purity: 99% Yield: 38%

[0808]

[0809] Example 93:

[0810] tert-Butyl (4-(4-amino-7-(6-amino-3-azabicyclo [3.1.1]hepten-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0811] 1H NMR (400 MHz, DMSO-d6) δ = 8.16 (s, 1H), 8.01 (s, 1H), 7.79 (d,J= 8.4 Hz, 1H), 7.78 (s, 1H), 7.05 (d,J= 1.6 Hz, 1H), 6.98 (dd,J= 1.8, 8.1 Hz, 1H), 6.29 (s, 1H), 3.85 (s, 3H), 3.80 - 3.69 (m, 4H), 3.45 (t,J= 5.6 Hz, 1H), 2.57 - 2.52 (m, 2H), 1.83 (td,J= 5.9, 9.4 Hz, 1H), 1.53 (d,J= 9.3 Hz, 1H), 1.47 (s, 9H) LCMS: m / z (M+H) + = 466.2

[0812] Purity 98% Yield 18%

[0813]

[0814] Example 94:

[0815] tert-Butyl (4-(4-amino-7-(4-amino-3,3-dimethylpiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0816] 1 H NMR (400 MHz, DMSO-d6) δ = 8.01 (s, 1H), 7.88 - 7.82 (m, 4H), 7.79 (d,J= 8.1 Hz, 1H), 7.03 (d,J= 1.8 Hz, 1H), 6.96 (dd,J= 1.7, 8.2 Hz, 1H), 6.24 (s, 1H), 3.85 (s, 3H), 3.75 - 3.67 (m, 1H), 3.12 - 2.99 (m, 1H), 2.80 - 2.69 (m, 1H), 2.64 - 2.53 (m, 2H), 1.93 - 1.83 (m, 2H), 1.47 (s, 9H), 1.10 (s, 3H), 1.06 (s, 3H). LCMS: m / z (M+H) + = 482.3

[0817] Purity 97% Yield 23%

[0818]

[0819] Example 95:

[0820] tert-butyl (4-(4-amino-7-(4-(methylcarbamoyl)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)

[0821] 1 H NMR (400 MHz, DMSO-d6) δ = 7.97 (s, 1H), 7.84 - 7.71 (m, 3H), 7.05 (d,J= 1.6 Hz, 1H), 6.97 (dd,J= 1.7, 8.2 Hz, 1H), 6.24 (s, 1H), 3.85 (s, 3H), 3.71 (d,J= 11.4 Hz, 2H), 2.72 - 2.63 (m, 2H), 2.58 (d,J= 4.5 Hz, 3H), 2.31 - 2.21 (m, 1H), 1.82 - 1.72 (m, 4H), 1.47 (s, 9H). LCMS: m / z (M+H) + = 496.3.

[0822] Purity 99% Yield 6.8%

[0823]

[0824] Example 96:

[0825] tert-Butyl (4-(7-(4-acetamido-4-methylpiperidin-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0826] 1H NMR (400 MHz, DMSO-d6) δ = 7.98 (s, 1H), 7.81 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.97 (dd, J = 1.6, 8.0 Hz, 1H), 6.23 (s, 1H), 3.85 (s, 3H), 3.39 - 3.34 (m, 2H), 2.97 (t, J = 10.0 Hz, 2H), 2.21 (d, J = 12.8 Hz, 2H), 1.82 (s, 3H), 1.70 - 1.58 (m, 2H), 1.50 (s, 9H), 1.33 (s, 3H). LCMS: m / z (M+H) + = 510.2.

[0827] Purity 99% Yield 18%

[0828]

[0829] Example 97:

[0830] tert-Butyl (4-(4-amino-7-(4-carbamoylpiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0831] 1 H NMR (400 MHz, DMSO-d6) δ = 7.97 (s, 1H), 7.85 - 7.75 (m, 2H), 7.29 (s, 1H), 7.06 (s, 1H), 6.97 (d,J= 8.3 Hz, 1H), 6.79 (s, 1H), 6.24 (s, 1H), 3.85 (s, 3H), 3.71 (d,J= 11.3 Hz, 2H), 2.73 - 2.62 (m, 2H), 2.30 - 2.21 (m, 1H), 1.84 - 1.70 (m, 4H), 1.47 (s, 9H). LCMS: m / z (M+H) + = 482.2.

[0832] Purity 97% Yield 8%

[0833]

[0834] Example 98:

[0835] tert-Butyl (4-(4-amino-7-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0836] 1 H NMR (400 MHz, DMSO-d6) δ = 8.25 (s, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H), 7.00 - 6.93 (m, 1H), 6.60 (s, 1H), 3.85 (s, 3H), 3.04 (t, J = 7.2 Hz, 2H), 2.98 (d, J = 11.6 Hz, 2H), 2.66 - 2.59 (m, 2H), 2.19 (s, 6H), 2.14 - 2.04 (m, 1H), 1.96 (t, J = 10.4 Hz, 2H), 1.74 (d, J = 11.6 Hz, 2H), 1.47 (s, 9H), 1.42 - 1.31 (m, 2H). LCMS: m / z (M+H) + = 510.3.

[0837] Purity 96% Yield 22%

[0838]

[0839] Example 99:

[0840] tert-Butyl (4-(4-amino-7-(2-(4-(methylamino)piperidin-1-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0841] 1H NMR (400 MHz, DMSO-d6) δ = 8.30 (s, 1H), 8.00 (s, 1H), 7.89 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H), 6.96 (dd, J = 1.6, 8.0 Hz, 1H), 6.60 (s, 1H), 3.85 (s, 3H), 3.06 - 2.97 (m, 4H), 2.83 - 2.72 (m, 1H), 2.66 (t, J = 7.6 Hz, 2H), 2.47 (s, 3H), 2.00 (t, J = 11.6 Hz, 2H), 1.91 (d, J = 10.4 Hz, 2H), 1.47 (s, 9H), 1.46 - 1.38 (m, 2H). LCMS: m / z (M+H) + = 496.3.

[0842] Purity 97% Yield 18%

[0843]

[0844] Example 100:

[0845] tert-Butyl (4-(4-amino-7-(2-(4-aminopiperidin-1-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0846] 1H NMR (400 MHz, DMSO-d6) δ = 8.26 (s, 1H), 8.00 (s, 1H), 7.89 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H), 6.96 (dd, J = 1.6, 8.0 Hz, 1H), 6.60 (s, 1H), 3.85 (s, 3H), 3.04 (t, J = 7.6 Hz, 2H), 2.96 (d, J = 11.6 Hz, 2H), 2.70 - 2.62 (m, 2H), 2.55 - 2.51 (m, 1H), 2.03 (t, J = 11.6 Hz, 2H), 1.90 - 1.77 (m, 2H), 1.53 - 1.41 (m, 11H). LCMS: m / z (M+H) + = 482.2.

[0847] Purity 98% Yield 5%

[0848]

[0849] Example 101:

[0850] 2-(1-(4-amino-5-(4-((tert-butoxycarbonyl)amino)-3-methoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-4-yl)acetic acid

[0851] 1 H NMR (400 MHz, DMSO-d6) δ = 12.05 (br s, 1H), 7.97 (s, 1H), 7.84 - 7.75 (m, 2H), 7.05 (d, J = 1.6 Hz, 1H), 6.97 (dd, J = 1.6, 8.0 Hz, 1H), 6.23 (s, 1H), 3.85 (s, 3H), 3.67 (d, J = 10.8 Hz, 2H), 2.66 (t, J = 11.2 Hz, 2H), 2.23 (d, J = 6.6 Hz, 2H), 1.87 - 1.75 (m, 3H), 1.47 (s, 9H), 1.43 - 1.33 (m, 2H). LCMS: m / z (M+H) + = 497.2.

[0852] Purity 99% Yield 9%

[0853]

[0854] Example 102:

[0855] tert-Butyl (4-(4-amino-7-(4-(hydroxymethyl)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0856] LCMS: m / z (M+H) + =469.1. 1 H NMR (400 MHz, DMSO-d6) δ = 7.97 (s, 1H), 7.86 - 7.72 (m, 2H), 7.05 (d, J = 1.6 Hz, 1H), 6.97 (dd, J = 1.7, 8.2 Hz, 1H), 6.22 (s, 1H), 4.49 (br s, 1H), 3.85 (s, 3H), 3.70 (d, J = 11.3 Hz, 2H), 3.43 - 3.37 (m, 2H), 2.64 (t, J = 10.9 Hz, 2H), 1.76 (d, J = 11.1 Hz, 2H), 1.58 - 1.50 (m, 1H), 1.47 (s, 9H), 1.41 - 1.28 (m, 2H).

[0857] Purity: 99% Yield: 11%

[0858]

[0859] Example 103:

[0860] tert-Butyl (4-(7-(4-acetamidopiperidin-1-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0861] 1H NMR (400 MHz, CDCL3) δ = 8.18 (m, 1H), 7.88 (s, 1H), 7.12 (s, 1H), 7.04 - 7.02 (d, 1H), 6.94 (s, 1H), 6.15 (s, 1H), 5.40 (d, 1H), 5.53 (s, 2H), 3.96 (m, 1H), 3.91 (s, 3H), 3.74 (d, 2H), 2.90 (m, 2H), 2.13 (m, 3H), 2.01 (s, 3H), 1.74 (m, 3H), 1.54 (s, 9H). LCMS: m / z (M+H) + =496.3.

[0862] Purity: 98% Yield: 33%

[0863]

[0864] Example 104:

[0865] tert-Butyl (4-(4-amino-7-(4-(aminomethyl)-3,3-dimethylpiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0866] LCMS: m / z (M+H) + =496.3.

[0867] 1 H NMR (400 MHz, DMSO-d6) δ = 8.35 (s, 1H), 7.99 (s, 1H), 7.84 - 7.76 (m, 2H), 7.04 (d, J = 1.6 Hz, 1H), 6.96 (dd, J = 1.7, 8.1 Hz, 1H), 6.22 (s, 1H), 3.85 (s, 3H), 3.76 - 3.73 (m, 2H), 3.00 (d, J = 11.7 Hz, 2H), 2.48 - 2.40 (m, 2H), 1.95 - 1.84 (m, 1H), 1.60 - 1.50 (m, 1H), 1.47 (s, 9H), 1.44 - 1.36 (m, 1H), 0.99 (s, 3H), 0.97 (s, 3H).

[0868] Purity 99% Yield 30%

[0869]

[0870] Example 105:

[0871] tert-Butyl (4-(4-amino-7-(4-methyl-4-(methylamino)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0872] LCMS: m / z (M+H) + =482.2.

[0873] 1 H NMR (400 MHz, DMSO-d6) δ = 8.38 (s, 1H), 7.97 (s, 1H), 7.80 (s, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.05 (d, J = 1.5 Hz, 1H), 6.97 (dd, J = 1.5, 8.3 Hz, 1H), 6.25 (s, 1H), 3.85 (s, 3H), 3.38 - 3.30 (m, 2H), 3.13 - 3.05 (m, 2H), 2.30 (s, 3H), 1.79 - 1.71 (m, 2H), 1.70 - 1.62 (m, 2H), 1.47 (s, 9H), 1.16 (s, 3H).

[0874] Purity 99% Yield 6%

[0875]

[0876] Example 106:

[0877] tert-Butyl (4-(4-amino-7-(4-(2-aminopropan-2-yl)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0878] LCMS: m / z (M+H) + =496.4.

[0879] 1H NMR (400 MHz, METHANOL-d4) δ = 8.54 (br s, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.77 (s, 1H), 7.05 (d, J = 1.5 Hz, 1H), 7.02 (dd, J = 1.7, 8.2 Hz, 1H), 6.29 (s, 1H), 3.92 (s, 3H), 3.83 (d, J = 10.9 Hz, 2H), 2.78 - 2.68 (m, 2H), 1.86 - 1.80 (m, 2H), 1.76 - 1.67 (m, 3H), 1.54 (s, 9H), 1.37 (s, 6H).

[0880] Purity: 98% Yield: 3%

[0881]

[0882] Example 107:

[0883] tert-Butyl (4-(4-amino-7-(4-(2-aminoethyl)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0884] LCMS: m / z (M+H) + =482.3.

[0885] 1 H NMR (400 MHz, DMSO-d6) δ = 8.46 - 8.38 (m, 1H), 7.99 (s, 1H), 7.83 - 7.77 (m, 2H), 7.06 (d, J = 1.8 Hz, 1H), 6.98 (dd, J = 1.8, 8.3 Hz, 1H), 6.23 (s, 1H), 3.86 (s, 3H), 3.69 (d, J = 11.4 Hz, 2H), 2.84 - 2.77 (m, 2H), 2.68 - 2.61 (m, 2H), 1.76 (d, J = 11.1 Hz, 2H), 1.53 - 1.50 (m, 2H), 1.48 (s, 9H), 1.40 - 1.34 (m, 3H).

[0886] Purity: 100% Yield: 18%

[0887]

[0888] Example 108:

[0889] tert-Butyl (4-(4-amino-7-(4-(2-(methylamino)ethyl)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0890] LCMS: m / z (M+H) + =496.3.

[0891] 1 H NMR (400 MHz, DMSO-d6) δ = 8.35 (s, 1H), 7.98 (s, 1H), 7.82 - 7.76 (m, 2H), 7.05 (d, J = 1.8 Hz, 1H), 6.97 (dd, J = 1.6, 8.1 Hz, 1H), 6.22 (s, 1H), 3.85 (s, 3H), 3.68 (d, J = 11.6 Hz, 2H), 2.80 - 2.74 (m, 2H), 2.68 - 2.63 (m, 2H), 2.44 (s, 3H), 1.75 (d, J = 11.8 Hz, 2H), 1.56 - 1.47 (m, 11H), 1.41 - 1.32 (m, 3H).

[0892] Purity: 96% Yield: 14%

[0893]

[0894] Example 109:

[0895] tert-Butyl (4-(4-amino-7-(4-(2-(dimethylamino)ethyl)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0896] 1H NMR (400 MHz, DMSO-d6) δ = 7.99 (s, 1H), 7.85 - 7.74 (m, 2H), 7.05 (d, J = 1.8 Hz, 1H), 6.97 (dd, J = 1.8, 8.1 Hz, 1H), 6.23 (s, 1H), 3.85 (s, 3H), 3.69 (d, J = 11.8 Hz, 2H), 3.12 - 2.99 (m, 2H), 2.73 (s, 6H), 2.69 - 2.61 (m, 2H), 1.77 (d, J = 10.9 Hz, 2H), 1.65 - 1.56 (m, 2H), 1.47 (s, 9H), 1.45 - 1.34 (m, 3H). LCMS: m / z (M+H) + =510.3.

[0897] Purity: 98% Yield: 18%

[0898]

[0899] Example 110:

[0900] tert-Butyl (4-(4-amino-7-((((1S,3R)-3-aminocyclopentyl)methyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0901] 1 H NMR (400 MHz, DMSO-d6) δ = 8.40 (br s, 1H), 7.97 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.04 (d, J = 1.6 Hz, 1H), 6.97 (dd, J = 1.6, 8.0 Hz, 1H), 5.97 (s, 1H), 5.61 (br s, 1H), 3.85 (s, 3H), 3.21 - 3.15 (m, 2H), 2.33 - 2.22 (m, 1H), 2.21 - 2.05 (m, 1H), 1.91 - 1.83 (m, 1H), 1.76 - 1.67 (m, 1H), 1.66 - 1.48 (m, 3H), 1.47 (s, 9H), 1.27 - 1.16 (m, 1H). LCMS: m / z (M+H)+ =468.2.

[0902] Purity 98% Yield 18%

[0903]

[0904] Example 111:

[0905] tert-Butyl (4-(4-amino-7-(((1R,3S)-3-(aminomethyl)cyclopentyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0906] 1 H NMR (400 MHz, DMSO-d6) δ = 8.41 (br s, 1H), 7.98 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.04 (d, J = 1.6 Hz, 1H), 6.98 (dd, J = 1.6, 8.0 Hz, 1H), 5.98 (s, 1H), 5.43 (br s, 1H), 3.85 (s, 3H), 3.21 - 3.15 (m, 1H), 2.77 - 2.75 (m, 2H), 2.31 - 2.21 (m, 1H), 2.13 - 2.07 (m, 1H), 2.05 - 1.90 (m, 2H), 1.79 - 1.63 (m, 2H), 1.47 (s, 9H), 1.33 - 1.27 (m, 1H). LCMS: m / z (M+H) + = 468.2.

[0907] Purity 98% Yield 3%

[0908]

[0909] Example 112:

[0910] tert-Butyl (4-(4-amino-7-(((1S,3S)-3-(dimethylamino)cyclopentyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0911] LCMS: m / z (M+H) + =482.3.

[0912] 1 H NMR (400 MHz, DMSO-d6) δ = 7.98 (s, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.72 (s, 1H), 7.05 (d, J = 1.5 Hz, 1H), 6.98 (dd, J = 1.6, 8.2 Hz, 1H), 5.96 (s, 1H), 5.32 (d, J = 7.1 Hz, 1H), 3.92 - 3.86 (m, 1H), 3.85 (s, 3H), 2.69 - 2.61 (m, 1H), 2.18 - 2.08 (m, 7H), 1.93 - 1.84 (m, 1H), 1.83 - 1.77 (m, 2H), 1.65 - 1.53 (m, 1H), 1.47 (s, 9H), 1.43 - 1.34 (m, 1H).

[0913] Purity 99% Yield 20%

[0914]

[0915] Example 113:

[0916] tert-Butyl (4-(4-amino-7-(((1S,3R)-3-aminocyclopentyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0917] 1 H NMR (400 MHz, DMSO-d6) δ = 8.45 (br s, 1H), 7.97 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.04 (d, J = 2.0 Hz, 1H), 6.98 (dd, J = 1.6, 8.0 Hz, 1H), 5.98 (s, 1H), 5.68 (br s, 1H), 3.93 - 3.85 (m, 4H), 3.48 - 3.44 (m, 1H), 2.01 - 1.92 (m, 1H), 1.89 - 1.74 (m, 2H), 1.67 - 1.58 (m, 1H), 1.54 - 1.50 (m, 1H), 1.47 (s, 9H), 1.46 - 1.41 (m, 1H). LCMS: m / z (M+H) +=454.2.

[0918] Purity 90% Yield 0.39%

[0919]

[0920] Example 114:

[0921] tert-Butyl (4-(4-amino-7-(((1R,3S)-3-aminocyclopentyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0922] 1 H NMR (400 MHz, DMSO-d6) δ = 8.05 (s, 1H), 8.00 (s, 1H), 7.97 - 7.84 (m, 4H), 7.64 (br s, 1H), 7.10 (d,J= 1.6 Hz, 1H), 7.04 (dd,J= 1.7, 8.2 Hz, 1H), 6.61 (br s, 1H), 6.29 (s, 1H), 4.03 - 3.95 (m, 1H), 3.86 (s, 3H), 3.57 - 3.48 (m, 1H), 2.08 - 1.90 (m, 2H), 1.85 - 1.69 (m, 2H), 1.63 (td,J= 7.0, 13.7 Hz, 1H), 1.51 - 1.46 (m, 10H) LCMS: m / z (M+H) + = 454.2

[0923] Purity: 99% Yield 60%.

[0924]

[0925] Example 115:

[0926] tert-Butyl (4-(4-amino-7-(((1R,3R)-3-aminocyclopentyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0927] LCMS: m / z (M+H) + =454.2. 1H NMR (400 MHz, DMSO-d6) δ = 8.14 (s, 1H), 8.01 (s, 1H), 7.97 - 7.72 (m, 5H), 7.06 (d, J = 1.8 Hz, 1H), 7.00 (dd, J = 1.8, 8.3 Hz, 1H), 6.07 (s, 1H), 5.99 (br s, 1H), 4.11 - 4.01 (m, 1H), 3.86 (s, 3H), 3.74 - 3.64 (m, 1H), 2.23 - 2.09 (m, 2H), 2.07 - 1.92 (m, 2H), 1.73 - 1.63 (m, 1H), 1.62 - 1.54 (m, 1H), 1.47 (s, 9H).Purity: 99% Yield: 6%

[0928]

[0929] Example 116:

[0930] tert-Butyl (4-(4-amino-7-(((1S,3S)-3-aminocyclopentyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0931] LCMS: m / z (M+H) + =454.2. 1 H NMR (400 MHz, DMSO-d6) δ = 8.05 (s, 1H), 7.95 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.82 (br s, 3H), 7.48 (br s, 1H), 7.09 (d, J = 1.8 Hz, 1H), 7.03 (dd, J = 1.8, 8.1 Hz, 1H), 6.54 (br s, 1H), 6.21 (s, 1H), 4.14 - 4.04 (m, 1H), 3.86 (s, 3H), 3.74 - 3.64 (m, 1H), 2.21 - 2.09 (m, 2H), 2.05 - 1.93 (m, 2H), 1.73 - 1.63 (m, 1H), 1.61 - 1.52 (m, 1H), 1.48 (s, 9H).

[0932] Purity 96% Yield 10%

[0933]

[0934] Example 117:

[0935] tert-Butyl (4-(4-amino-7-((piperidin-4-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0936] 1 H NMR (400 MHz, DMSO-d6) δ = 8.44 (s, 1H), 7.96 (s, 1H), 7.78 (d,J= 8.5 Hz, 1H), 7.72 (s, 1H), 7.04 (s, 1H), 6.98 (dd,J= 1.5, 8.1 Hz, 1H), 5.96 (s, 1H), 5.58 (t,J= 6.4 Hz, 1H), 3.85 (s, 3H), 3.12 - 3.01 (m, 4H), 2.61 - 2.53 (m, 2H), 1.86 - 1.67 (m, 3H), 1.47 (s, 9H), 1.26 - 1.09 (m, 2H) LCMS: m / z (M+H) + = 468.2

[0937] Purity 99% Yield 11%

[0938]

[0939] Example 118:

[0940] tert-Butyl(4-(4-amino-7-(((1s,3s)-3-aminocyclobutyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0941] LCMS: m / z (M+H) + =440.2. 1H NMR (400 MHz, DMSO-d6) δ = 8.12 - 7.95 (m, 5H), 7.87 (d,J= 8.2 Hz, 1H), 7.51 (br s, 1H), 7.08 (s, 1H), 7.03 (d,J= 8.3 Hz, 1H), 6.74 (br s, 1H), 6.18 (s, 1H), 3.89 - 3.80 (m, 4H), 3.45 - 3.41 (m, 1H), 2.80 - 2.70 (m, 2H), 2.17 (q,J= 8.9 Hz, 2H), 1.48 (s, 9H).

[0942] Purity: 99% Yield: 97%

[0943]

[0944] Example 119:

[0945] tert-Butyl (4-(4-amino-7-(((1r,3r)-3-aminocyclobutyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0946] 1 H NMR (400 MHz, DMSO-d6) δ = 8.14 (s, 1H), 7.98 (s, 1H), 7.79 (d,J= 8.3 Hz, 1H), 7.76 (s, 1H), 7.03 (s, 1H), 6.97 (d,J= 8.4 Hz, 1H), 6.07 (d,J= 7.1 Hz, 1H), 5.82 (s, 1H), 4.22 - 4.13 (m, 1H), 3.87 - 3.79 (m, 4H), 2.46 - 2.38 (m, 4H), 1.47 (s, 9H) LCMS: m / z (M+H) + = 440.2

[0947] Purity 94% Yield 5%

[0948]

[0949] Example 120:

[0950] tert-Butyl (4-(4-amino-7-(piperidin-4-ylamino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0951] 1 H NMR (400 MHz, DMSO-d6) δ = 8.65 - 8.55 (m, 1H), 8.42 - 8.29 (m, 1H), 8.04 (s, 1H), 7.90 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 1.2 Hz, 1H), 7.02 (dd, J = 1.6, 8.4 Hz, 1H), 6.34 (br s, 1H), 6.24 (s, 1H), 3.85 (s, 3H), 3.70 - 3.60 (m, 1H), 3.40 - 3.30 (m, 2H), 3.06 - 2.90 (m, 2H), 2.11 - 2.03 (m, 2H), 1.83 - 1.68 (m, 2H), 1.47 (s, 9H). LCMS: m / z (M+H) + = 454.2.

[0952] Purity 100% Yield 21%

[0953]

[0954] Example 121:

[0955] tert-Butyl (4-(4-amino-7-(((1s,4s)-4-aminocyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0956] 1H NMR (400 MHz, DMSO-d6) δ = 8.14 (s, 1H), 8.01 (s, 1H), 7.88 - 7.80 (m, 5H), 7.07 (d, J = 1.6 Hz, 1H), 7.02 (dd, J = 1.6, 8.0 Hz, 1H), 6.21 (s, 1H), 5.80 (br s, 1H), 3.86 (s, 3H), 3.49 - 3.41 (m, 1H), 3.02 - 2.94 (m, 1H), 2.16 - 1.84 (m, 4H), 1.47 (s, 9H), 1.46 - 1.33 (m, 4H). LCMS: m / z (M+H) + = 468.3.

[0957] Purity 98% Yield 26%

[0958]

[0959] Example 122:

[0960] tert-Butyl (4-(4-amino-7-(((1s,4s)-4-aminocyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0961] 1 H NMR (400 MHz, DMSO-d6) δ = 8.13 (s, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.77 (br s, 3H), 7.08 (d, J = 1.6 Hz, 1H), 7.01 (dd, J = 1.6, 8.4 Hz, 1H), 6.18 (s, 1H), 5.45 (br s, 1H), 3.86 (s, 3H), 3.68 - 3.62 (m, 1H), 3.20 - 3.14 (m, 1H), 1.95 - 1.85 (m, 2H), 1.78 - 1.66 (m, 6H), 1.47 (s, 9H). LCMS: m / z (M+H) + = 468.2.

[0962] Purity: 97% Yield: 31%

[0963]

[0964] Example 123:

[0965] tert-Butyl (4-(4-amino-7-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0966] 1 H NMR (400 MHz, DMSO-d6) δ = 8.42 (s, 1H), 8.04 (s, 1H), 7.89 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 1.6 Hz, 1H), 6.94 (dd, J = 1.6, 8.4 Hz, 1H), 3.82 (s, 3H), 3.30 - 3.18 (m, 4H), 3.00 - 2.94 (m, 1H), 1.89 (d, J = 9.2 Hz, 2H), 1.63 - 1.52 (m, 2H), 1.48 (s, 9H) LCMS: m / z (M+H) + = 488.1.

[0967] Purity 99% Yield 4%

[0968]

[0969] Example 124:

[0970] tert-Butyl (4-(4-amino-6-chloro-7-(4-(dimethylamino)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0971] 1H NMR (400 MHz, DMSO-d6) ┙ = 8.04 (s, 1H), 7.89 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 1.6 Hz, 1H), 6.94 (dd, J = 2.0, 8.0 Hz, 1H), 3.82 (s, 3H), 3.36 - 3.24 (m, 4H), 2.34 - 2.24 (m, 1H), 2.22 (s, 6H), 1.81 (d, J = 11.2 Hz, 2H), 1.62 - 1.52 (m, 2H), 1.48 (s, 9H). LCMS: m / z (M+H) + = 516.3.

[0972] Purity: 99% Yield: 21%

[0973]

[0974] Example 125:

[0975] tert-Butyl (4-(4-amino-7-(4-aminopiperidin-1-yl)-6-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0976] 1 H NMR (400 MHz, DMSO-d6) δ = 8.38 (s, 1H), 8.07 (s, 1H), 7.95 (s, 1H), 7.82 (d,J= 8.0 Hz, 1H), 7.02 (d,J= 1.6 Hz, 1H), 6.93 (dd,J= 1.4, 8.2 Hz, 1H), 3.79 (s, 3H), 3.44 - 3.38 (m, 2H), 3.16 - 3.12 (m, 2H), 3.07 - 3.01 (m, 1H), 1.94 - 1.88 (m, 2H), 1.64 - 1.52 (m, 2H), 1.47 (s, 9H). LCMS: m / z (M+H) + = 522.3

[0977] Purity 98% Yield 12%

[0978]

[0979] Example 126:

[0980] tert-Butyl (4-(4-amino-7-(4-aminopiperidin-1-yl)-6-iodopyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0981] 1 H NMR (400 MHz, DMSO-d6) δ = 8.43 (s, 1H), 8.03 (s, 1H), 7.86 - 7.80 (m, 2H), 6.99 (d,J= 1.6 Hz, 1H), 6.90 (dd,J= 1.6, 8.4 Hz, 1H), 3.83 (s, 3H), 3.46 (t,J= 11.2 Hz, 2H), 3.11 (d,J= 11.6 Hz, 2H), 3.06 - 2.95 (m, 1H), 1.93 (d,J= 11.2 Hz, 2H), 1.68 - 1.53 (m, 2H), 1.48 (s, 9H). LCMS: m / z (M+H) + = 580.1

[0982] Purity 99% Yield 11%

[0983]

[0984] Example 127:

[0985] tert-Butyl (4-(4-amino-7-(4-aminopiperidin-1-yl)-6-fluoropyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0986] 1 H NMR (400 MHz, DMSO-d6) δ = 8.42 (s, 1H), 8.04 (s, 1H), 7.94 (s, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.05 (s, 1H), 6.97 (d, J = 7.9 Hz, 1H), 3.83 (s, 3H), 3.44 - 3.38 (m, 2H), 3.12 (t, J = 11.4 Hz, 2H), 3.00 - 2.94 (m, 1H), 1.95 - 1.83 (m, 2H), 1.62 - 1.49 (m, 2H), 1.47 (s, 9H). LCMS: m / z (M+H)+ =472.1.

[0987] Purity 98% Yield 20%

[0988]

[0989] Example 128:

[0990] tert-Butyl (4-(4-amino-7-(4-(dimethylamino)piperidin-1-yl)-6-fluoropyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0991] 1 H NMR (400 MHz, DMSO-d6) δ = 8.19 (s, 1H), 8.03 (s, 1H), 7.93 (s, 1H), 7.84 (d,J= 8.4 Hz, 1H), 7.05 (d,J= 1.2 Hz, 1H), 6.97 (dd,J= 1.6, 8.4 Hz, 1H), 3.83 (s, 3H), 3.46 (d,J= 11.6 Hz, 2H), 3.09 (t,J= 11.6 Hz, 2H), 2.41 - 2.38 (m, 1H), 2.28 (s, 6H), 1.85 (d,J= 11.2 Hz, 2H), 1.63 - 1.53 (m, 2H), 1.47 (s, 9H). LCMS: m / z (M+H) + = 500.2.

[0992] Yield: 53% Purity: 98%

[0993]

[0994] Example 129:

[0995] tert-Butyl (4-(4-amino-6-fluoro-7-(4-(methylamino)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[0996] 1H NMR (400 MHz, DMSO-d6) δ = 8.32 (s, 1H), 8.04 (s, 1H), 7.94 (s, 1H), 7.84 (d,J= 8.4 Hz, 1H), 7.05 (d,J= 1.6 Hz, 1H), 6.97 (dd,J= 1.2, 8.0 Hz, 1H), 3.83 (s, 3H), 3.45 (d,J= 11.6 Hz, 2H), 3.12 (t,J= 11.2 Hz, 2H), 2.95 - 2.85 (m, 1H), 2.48 (s, 3H), 2.05 - 1.99 (m, 2H), 1.67 - 1.53 (m, 2H), 1.47 (s, 9H). LCMS: m / z (M+H) + = 486.2

[0997] Purity 99% Yield 61%

[0998]

[0999] Example 130:

[1000] tert-Butyl (4-(4-amino-6-fluoro-7-(2-(4-(methylamino)piperidin-1-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[1001] 1 H NMR (400 MHz, DMSO-d6) δ = 8.32 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.85 (d,J= 8.0 Hz, 1H), 7.05 (d,J= 1.6 Hz, 1H), 7.01 - 6.95 (m, 1H), 3.83 (s, 3H), 3.06 (t,J= 7.4 Hz, 2H), 2.94 (d,J= 12.0 Hz, 2H), 2.62 (t,J= 7.6 Hz, 2H), 2.53 - 2.51 (m, 1H), 2.40 (s, 3H), 1.99 (t,J= 10.6 Hz, 2H), 1.92 - 1.80 (m, 2H), 1.48 (s, 9H), 1.40 - 1.28 (m, 2H). LCMS: m / z (M+H) + = 514.4

[1002] Purity: 98% Yield: 15%

[1003]

[1004] Example 131:

[1005] tert-Butyl (4-(4-amino-6-fluoro-7-(4-(2-(methylamino)ethyl)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate

[1006] 1 H NMR (400 MHz, DMSO-d6) δ = 8.38 (s, 1H), 8.03 (s, 1H), 7.93 (s, 1H), 7.84 (d,J= 8.2 Hz, 1H), 7.05 (d,J= 1.3 Hz, 1H), 6.97 (d,J= 7.9 Hz, 1H), 3.83 (s, 3H), 3.39 (d,J= 12.0 Hz, 2H), 3.07 (t,J= 11.3 Hz, 2H), 2.74 (t,J= 7.1 Hz, 2H), 2.42 (s, 3H), 1.73 (d,J= 12.0 Hz, 2H), 1.54 - 1.47 (m, 12H), 1.36 - 1.28 (m, 2H).

[1007] Purity: 99% Yield: 19%

[1008]

[1009] Example 132:

[1010] tert-Butyl (4-(1-amino-6-(4-aminopiperidin-1-yl)pyrrolo[1,2-a]pyrazin-8-yl)-2-methoxyphenyl)carbamate

[1011] LCMS: m / z (M+H) + =453.3. 1H NMR (400 MHz, DMSO-d6) δ = 8.33 (br s, 1H), 7.97 (s, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 4.6 Hz, 1H), 7.02 (s, 1H), 7.00 (d, J = 4.8 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.37 (s, 1H), 5.61 (br s, 2H), 3.84 (s, 3H), 3.22 - 3.18 (m, 2H), 3.11 - 3.08 (m, 1H), 2.77 (t, J = 11.3 Hz, 3H), 2.02 - 1.91 (m, 2H), 1.78 - 1.64 (m, 2H), 1.47 (s, 9H).

[1012] Purity: 99% Yield: 8%

[1013]

[1014] Example 133:

[1015] tert-Butyl (4-(1-amino-6-(4-(methylamino)piperidin-1-yl)pyrrolo[1,2-a]pyrazin-8-yl)-2-methoxyphenyl)carbamate

[1016] LCMS: m / z (M+H) + =467.4. 1 H NMR (400 MHz, DMSO-d6) δ = 8.32 (br s, 1H), 7.97 (s, 1H), 7.76 (d,J= 7.8 Hz, 1H), 7.26 (d,J= 4.9 Hz, 1H), 7.03 (d,J= 1.6 Hz, 1H), 6.99 (d,J= 4.9 Hz, 1H), 6.95 (dd,J= 1.5, 8.3 Hz, 1H), 6.37 (s, 1H), 5.60 (br s, 2H), 3.84 (s, 3H), 3.25 - 3.15 (m, 3H), 2.79 - 2.70 (m, 2H), 2.43 (s, 3H), 2.06 - 1.97 (m, 2H), 1.67 - 1.55 (m, 2H), 1.47 (s, 9H).

[1017] Purity: 99% Yield: 14%

[1018]

[1019] Example 134:

[1020] tert-Butyl (4-(1-amino-6-(4-(dimethylamino)piperidin-1-yl)pyrrolo[1,2-a]pyrazin-8-yl)-2-methoxyphenyl)carbamate

[1021] LCMS: m / z (M+H) + =481.3. 1 H NMR (400 MHz, DMSO-d6) δ = 7.97 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 4.9 Hz, 1H), 7.03 (d, J = 1.5 Hz, 1H), 6.98 (d, J = 4.9 Hz, 1H), 6.95 (dd, J = 1.5, 8.1 Hz, 1H), 6.35 (s, 1H), 5.60 (br s, 2H), 3.84 (s, 3H), 3.22 (d, J = 11.6 Hz, 2H), 2.70 (t, J = 11.0 Hz, 2H), 2.37 - 2.29 (m, 1H), 2.25 (s, 6H), 1.91 - 1.83 (m, 2H), 1.65 (dq, J = 3.4, 11.7 Hz, 2H), 1.47 (s, 9H).

[1022] Purity: 99% Yield: 12%

[1023]

[1024] Example 135:

[1025] 7-(4-aminopiperidin-1-yl)-5-(4-phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[1026] 1H NMR (400 MHz, DMSO-d6) δ = 8.41 (s, 1H), 7.82 (s, 1H), 7.48 - 7.38 (m, 4H), 7.20 - 7.14 (m, 1H), 7.13 - 7.06 (m, 4H), 6.22 (s, 1H), 3.69 (br d,J= 11.6 Hz, 2H), 3.07 - 2.98 (m, 1H), 2.81 - 2.68 (m, 2H), 1.93 (d,J= 10.4 Hz, 2H), 1.70 - 1.55 (m, 2H). LCMS: m / z (M+H) + = 401.1

[1027] Purity: 99% Yield: 33%

[1028]

[1029] Example 136:

[1030] 7-(4-(dimethylamino)piperidin-1-yl)-5-(4-phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[1031] 1 H NMR (400 MHz, DMSO-d6) δ = 7.82 (s, 1H), 7.49 - 7.39 (m, 4H), 7.20 - 7.15 (m, 1H), 7.12 - 7.06 (m, 4H), 6.20 (s, 1H), 3.73 (d, J = 11.8 Hz, 2H), 2.71 - 2.64 (m, 2H), 2.29 - 2.24 (m, 1H), 2.22 (s, 6H), 1.91 - 1.78 (m, 2H), 1.66 - 1.50 (m, 2H). LCMS: m / z (M+H) + = 429.2.

[1032] Purity 99% Yield 3%

[1033]

[1034] Example 137:

[1035] N-(4-(4-amino-7-(4-aminopiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)furan-2-carboxamide

[1036] 1 H NMR (400 MHz, DMSO-d6) δ = 9.14 (s, 1H), 8.38 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.93 (s, 1H), 7.83 (s, 1H), 7.33 (d, J = 3.6 Hz, 1H), 7.15 (d, J = 1.6 Hz, 1H), 7.05 (dd, J = 1.6, 8.4 Hz, 1H), 6.73 (dd, J = 1.6, 3.2 Hz, 1H), 6.30 (s, 1H), 3.93 (s, 3H), 3.71 (d, J = 11.6) Hz, 2H), 3.15 - 3.05 (m, 1H), 2.76 (t, J = 11.4 Hz, 2H), 2.01 - 1.91 (m, 2H), 1.75 - 1.60 (m, 2H). LCMS: m / z (M+H) + = 448.1.

[1037] Purity 99% Yield 7%

[1038]

[1039] Example 138:

[1040] N-(4-(4-amino-7-(4-aminopiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)furan-3-carboxamide

[1041] LCMS: m / z (M+H) + =448.2. 1H NMR (400 MHz, DMSO-d6) δ = 9.23 (s, 1H), 8.43 (s, 1H), 8.38 - 8.34 (m, 1H), 7.86 - 7.79 (m, 3H), 7.13 (d, J = 1.7 Hz, 1H), 7.04 (dd, J = 1.7, 8.1 Hz, 1H), 6.99 (d, J = 1.2 Hz, 1H), 6.31 (s, 1H), 3.89 (s, 3H), 3.71 (d, J = 11.7 Hz, 2H), 3.13 - 3.05 (m, 1H), 2.76 (t, J = 10.9 Hz, 2H), 1.98 - 1.92 (m, 2H), 1.72 - 1.62 (m, 2H).

[1042] Purity: 98% Yield: 19%

[1043]

[1044] Experimental Example 1. Evaluation of YES1 kinase activity inhibition by compounds according to the present invention.

[1045] To evaluate the activity inhibition of the compound according to the present invention against YES1 kinase, the ADP glo assay (Promega) was used, and the experiment was performed using the following method with reference to the Promega kinase enzyme system protocol. To conduct the experiment, AF buffers and compound dilution plates are required.

[1046] To make A.4X Reaction Buffer, use 800ul of 5X Reaction Buffer and 200ul of Distilled Water. To make B.4X Kinase Buffer, add 996.6ul of A.4X Reaction Buffer, 2ul of 0.1M DTT, and 3.2ul of 2.5M MnCl2 and mix. To make C.1X Kinase Buffer (containing 5% DMSO) used for compound dilution, add 250ul of B.4X kinase buffer, 700ul of distilled water, and 50ul of DMSO to make DMSO concentration 5%. Then, dilute 10mM compounds 100-fold to make 100uM, and make D.5X inhibitor solution to make compound concentration 5uM. Using a 96-well plate, dilute 5uM compounds 3-fold with C.1X kinase buffer (containing 5% DMSO) to make compound plates of 0.25uM to 5uM and store them at room temperature. E. To make 2.5X ATP / substrate mixture, mix 50ul of B.4X kinase buffer, 50ul of 10uM ATP, and 100ul of substrate. F. To make YES1 kinase enzyme solution, mix 35ul of B.4X kinase buffer, 0.4ul of YES1 enzyme, and 104.6ul of distilled water. Once the diluted compound plates, ATP / substrate mixture, and YES1 kinase solution are all ready, transfer 3ul from the diluted compound plate to each luciferase 96-well white plate.(Since the total volume of the ATP / substrate and YES1 kinase solution reacting with the compound is 15ul, it is diluted 5 times and the final compound concentration is 0.05uM to 1uM.) Then, 6ul of F. YES1 kinase enzyme solution was transferred and mixed by pipetting 10 times, and incubated in a mixer at room temperature for 10 minutes. After that, 6ul of E. 2.5X ATP / substrate mixture was transferred and mixed by pipetting 10 times, and centrifuged at 12,000 rpm for 5 minutes. And incubated in a mixer at room temperature for 40 minutes. After that, 15ul of ADP-glo Reagent dissolved at room temperature was added, pipetted 10 times, and incubated in a mixer at room temperature for 40 minutes. Finally, 30 μl of Kinase Detection Reagent melted at room temperature was added, pipetted 10 times, and incubated in a mixer for 30 minutes at room temperature. Luminescence was measured using a luminescence plate reader. After that, the background value was subtracted from all measured values, and the YES1 kinase activity at 1 nM, 10 nM, and 100 nM of the compound was calculated. The measured values ​​were calculated as a percentage using the average value of the negative control. A graph was drawn with GraphPad Prism, and the enzyme activity was calculated as a % of the YES1 kinase activity inhibition value at 1 nM, 10 nM, and 100 nM of the compound. IC. 50 For values, the Microsoft Excel program was used to obtain them.

[1047] The results of calculating the measured YES1 enzyme inhibition ratio are shown in Table 1 below.

[1048] Example YES1 enzyme, % inhibition YES1 enzyme, IC 501 nM10 nM100 nM11731221283444943129538686414672849833649395710838112144126586137 7931419771567881630361753591839811969862036702167922260872358872450 8225287626306927597428418529284730739432518234377436367837246938448 039578940543426390448096A458092A465277487096517090526090A5329605420 60A554076562368A58A595680A65A744366A831424855978A876180A89193490124 7912159926681A931448944178A9865909971901007088101164010211391032766 1043345105A10637431073852A1083852A1093751A1122960116306311739641192 45512040781215077123A1276788A1287292A1297092A13562871366490137A138A

[1049] (A: IC 50 ≤ 100nM; B: 100nM < IC 50 ≤ 1 uM; C: 1uM < IC 50 ≤ 10 uM; D: 10 uM < IC 50 )

[1050] As confirmed from Table 1, the compounds of the present invention exhibited excellent inhibitory activity against YES1 kinase. In particular, it was confirmed that even when the compounds of the present invention were treated at a low concentration of 10 nM, YES1 kinase could be inhibited at a generally considerably high inhibition ratio, and in the case of compounds 74, 83, 89, 90, 101, 102, 104, 106 to 109, 112, 116 and 119 of the present invention, it was confirmed that YES1 kinase could be inhibited even at a low concentration of 1 nM.

[1051]

[1052] Experimental Example 2. Evaluation of cell growth inhibition of the compound according to the present invention

[1053] The cell line according to the present invention was selected as KYSE-70, an esophageal cancer cell line overexpressing YES1 (amplified). Cell growth inhibition was evaluated as follows.

[1054] KYSE-70 was cultured in RPMI-1640 (Capricorn) supplemented with 10% FBS (Cellgro). 24 hours before compound treatment, 7,500 cells per well of three 96-well F-bottom clear plates (greiner) were seeded in 180 μL of medium. 10 mM compounds were diluted 100-fold in the medium to make 100 μM compounds, which were then placed in 96-well plates and diluted three-fold in the medium to make compound plates with concentrations of 0.046 μM to 100 μM. 20 μL of the compounds in the drug plate were injected into the plates containing the cell lines to make final concentrations of 0.0046 μM to 10 μM. Simultaneously, 50 μL of 33% trichloroacetic acid was injected into one plate and stored at 4 °C for fixation. This was named the D0 plate. For the measurement of living cells, 50 μL of 33% trichloroacetic acid was injected 72 hours after compound treatment and fixed at 4 °C for more than 1 hour. This was named the D3 plate. After washing the D0 plate and D3 plate 5 times with sterile water, 100 μL of 0.04% sulfodamine B solution in 1% acetic acid was added and stained for 1 hour. After staining, the plate was washed 4 times with 1% acetic acid solution and completely dried. Then, sulfodamine B stained in the cell protein was completely dissolved with 10 mM Tris base solution (pH 10.5), and the absorbance was measured at a wavelength of 510 nm using a microplate reader (TECAN, sunrise microplate reader).The analysis was performed using GraphPad Prism, and the average absorbance value of the D0 plate was set to 0%, and the average absorbance value of the negative control of the D3 plate was set to 100% to create a graph and GI. 50 The values ​​were calculated. Each test was repeated twice.

[1055]

[1056] Experimental Example 3. Evaluation of TEAD inhibition of compounds according to the present invention

[1057] To evaluate the inhibitory activity of YES1 overexpressing KYSE-70 on TEAD activity, the following experiments were performed.

[1058] TEAD luciferase reporter lentivirus (BPS Bioscience; TEAD luciferase reporter lentivirus) was co-cultured with KYSE-70 cells for 48 hours, and then 1 ug / ml puromycin (Invitrogen) was added to induce apoptosis only in cells not infected with the virus, thereby constructing a KYSE-70 cell line transfected with the TEAD luciferase reporter. The KYSE-70 TEAD luciferase reporter cell line was cultured in RPMI-1640 (Capricorn) supplemented with 10% FBS (Cellgro). 24 hours before compound treatment, 20,000 cells were seeded in 180 μL of medium in two 96-well F-bottom clear plates (greiner) and two white clear bottom 96-well plates (greiner). 10 mM compound was diluted 100-fold in the medium to make 100 μM compound, placed in a 96-well plate, and diluted 3-fold in the medium to make compound plates of 0.046 μM - 100 μM. 20 μL of the compound in the drug plate was injected into the plate where the cell line was dispensed to make the final concentration 0.0046 μM - 10 μM. TEAD activity was measured by removing 100 μL of medium from each well 24 hours after compound treatment in a white clear bottom 96-well plate and using a one-step TM100 μL of luciferase assay system solution was added, and after 15 minutes of reaction at room temperature, the luminescence intensity was measured using a microplate reader (VICTOR X3, PerkinElmer). Since the TEAD activity value should be normalized with living cells (cell viability), a cell viability assay was also performed. For cell viability measurement, 50 μL of 33% trichloroacetic acid was injected into each well 24 hours after compound treatment in a 96-well F-bottom clear plate and fixed by storing at 4 °C for 1 hour. After that, the plate was washed 5 times with sterile water, and 100 μL of 0.04% sulfodamine B solution in 1% acetic acid was added and stained for 1 hour. After staining, the plate was washed four times with 1% acetic acid solution, completely dried, and sulfodamine B stained on the cell protein was completely dissolved in 10 mM Tris base solution (pH 1.05). The absorbance was measured at a wavelength of 510 nm using a microplate reader (TECAN, sunrise microplate reader). The TEAD activity value and cell viability value were normalized, and a graph was drawn using the GraphPad Prism version 5.0 program, and IC 50 The value was calculated.

[1059] The results for Experimental Examples 2 and 3 are shown in Table 2 below.

[1060] Example KYSE70GI 50 TEAD IC 50<h2 style=";text-align:left;direction:ltr">1CD2DC3DA4CD5BB6CA7CB8DB9CA10CB11BB12BA13AA14BA15AA16CC17CA18BA19AA20BA21BA22BA23AA24BA25BA26CA27CA28CA29DB30AA32N.TNT34N.TNT36BB37BC38AA39AB40CC42AA44AA45AA46BA48AA51BA52BA53AA54AB55AB56AA58BA59BA60AA61AA62AA63AA64AA65BA66AA67BA68AA69AA70BA71AA72BA73AA74AA 75AA76AA77BA78AA79AA80BA81BA82AA83BB85AA87AA89DD90BA91BA92BA93BA94AA95BA96DB97DA98AA99AA100AA101DD102BA103BA104BB105AA106AA107BA108AA109AA110BB111DB112BA116BA117BB119BA120BA121BA123AA124AA125BB126BA127AA128AA129AA130AA131AA132BA133BB134AA135AA136AA137BD138DD<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[1061] <h2 style=";text-align:left;direction:ltr"> (A: GI<h2 style=";text-align:left;direction:ltr"> 50 <h2 style=";text-align:left;direction:ltr"> A: ≤ 100nM; B: 100nM < GI<h2 style=";text-align:left;direction:ltr"> 50 <h2 style=";text-align:left;direction:ltr"> ≤ 1 uM; C: 1 uM < GI<h2 style=";text-align:left;direction:ltr"> 50 <h2 style=";text-align:left;direction:ltr"> ≤ 10 uM; D: 10 uM < GI<h2 style=";text-align:left;direction:ltr"> 50 <h2 style=";text-align:left;direction:ltr"> )<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[1062] <h2 style=";text-align:left;direction:ltr"> (A: IC<h2 style=";text-align:left;direction:ltr"> 50 <h2 style=";text-align:left;direction:ltr"> A: ≤ 100nM; B: 100nM < IC<h2 style=";text-align:left;direction:ltr"> 50 <h2 style=";text-align:left;direction:ltr"> ≤ 1 uM; C: 1 uM < IC<h2 style=";text-align:left;direction:ltr"> 50 <h2 style=";text-align:left;direction:ltr"> ≤ 10 uM; D: 10 uM < IC<h2 style=";text-align:left;direction:ltr"> 50 <h2 style=";text-align:left;direction:ltr"> )<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[1063] <h2 style=";text-align:left;direction:ltr"> NT: not tested<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[1064] As confirmed from Table 2, the compound of the present invention was confirmed to exhibit potent anti-proliferative activity in esophageal cancer cell lines, a type of solid cancer. In addition, it was confirmed to exhibit excellent inhibitory activity against transcriptional enhancer-associated domain (TEAD) in esophageal cancer cell lines.

[1065] From this, it was confirmed that the compound of the present invention has excellent inhibitory activity against YES1 kinase and transcriptional enhancer-associated domain (TEAD), and preventive or therapeutic effect against solid cancer related thereto.

Claims

1. A compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof. [Chemical Formula 1] In the above chemical formula 1, X is C or N, Ring B is absent or is (3-10 membered)cycloalkyl or (3-10 membered)heterocyclyl, R 1 are each independently hydrogen, halogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-6 Haloalkoxy, (3-10 membered)cycloalkyl, C 1-10 Alkylene-(3-10 membered)cycloalkyl, (3-10 membered)heterocyclyl, C 1-10 Alkylene-(3-10 membered)heterocyclyl, (6-14 membered)aryl, C 1-10 Alkylene-(6-14 membered)aryl, (5-12 membered)heteroaryl, C 1-10 Alkylene-(5-12 membered)heteroaryl, NR a R b, OC 1-10 Alkylene-NR a R b , C 1-10 Alkylene-O-NR a R b , C(O)-NR a R b, C 1-10 Alkylene-C(O)-NR a R b and C(O)O-NR a R b is one selected from the group consisting of, Here, the above (3-10 membered) cycloalkyl, (3-10 membered) heterocyclyl, (6-14 membered) aryl and (5-12 membered) heteroaryl are each independently unsubstituted or C 1-6 Alkyl, C 1-6 Alkoxy, Halogen, C 1-6 which may be substituted with any one selected from the group consisting of haloalkyl, NH2, NO2, OH and CN, n is an integer from 1 to 4, R 2 is hydrogen, halogen, C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 1-5 Haloalkoxy, C(O)-C 1-5 Alkyl, C(O)-C 1-5 Haloalkyl, C(O)OC 1-5 Alkyl, C(O)OC 1-5 Haloalkyl, CC(O)OC 1-5 Alkyl, CC(O)OC 1-5 Haloalkyl, NR c R d , any one selected from the group consisting of O-(6-14 membered) aryl and O-(5-12 membered) heteroaryl, Above R c and R d are each independently hydrogen, C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 1-5 Haloalkoxy, C 1-3 Aryl, C 1-3 Heteroaryl, C(O)OC 1-5 Alkyl, C(O)OC 1-5 Haloalkyl, C(O)O-(3-10 membered)cycloalkyl, C(O)C 1-3 Aryl, C(O)-(5-12 membered) heteroaryl and C(0)NHC 1-5 may be substituted with at least one selected from the group consisting of alkyl, Here, the above (3-10 membered) cycloalkyl and (5-12 membered) heteroaryl are each independently unsubstituted or C 1-6 Alkyl, C 1-6 Alkoxy, Halogen and C 1-6 which may be substituted with any one selected from the group consisting of haloalkyl, R 3 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NH2, OH, CN, COOH, NO2, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl and C 1-6 Any one selected from the group consisting of alkylamino, R 4 is (3-10 member) cycloalkyl, (3-14 member) heterocyclyl, (3-14 member) N-heterocyclyl, (6-14 member) aryl, (5-12 member) heteroaryl, C 1-6 Alkylene-(3-10 membered)cycloalkyl, C 1-6 Alkylene-(3-14 membered) heterocyclyl, C 1-6 Alkylene-(3-10 membered) N-heterocyclyl, C 1-6 Alkylene-(6-14 membered) aryl, C 1-6 Alkylene-(5-12 membered) heteroaryl, NR o R p and is one selected from the group consisting of, wherein the above ring A is (3-10 membered) cycloalkyl or (3-14 membered) heterocyclyl, Above R 4 is one or more types of R 7 can be replaced with, Here R 7 are each independently halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-10 Alkylene-C 1-6 Alkoxy, C 1-10 Alkylene-C 1-6 Haloalkoxy, (3-10 membered)cycloalkyl, C 1-10 Alkylene-(3-10 membered)cycloalkyl, (6-14 membered)aryl, C 1-10 Alkylene-(6-14 membered)aryl, (5-12 membered)heteroaryl, C 1-10 Alkylene-(5-12 membered)heteroaryl, NR e R f , C 1-10 Alkyl-NR e R f , C 1-10 Alkylene-NR e R f , oxo, C(O)-NR e R f , C 1-10 Alkylene-C(O)-NR e R f , C(O)O-NR e R f , CN, OH, NO2, C(O)R e , C(O)OR e , C 1-6 Alkylene-C(O)OR e and C 1-6 Any one selected from the group consisting of alkylene-OH, R 5 Silver hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NH2, OH, CN, COOH, NO2, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl and C 1-6 Any one selected from the group consisting of alkylamino, R 6 is NR g R h And, R a , R b , R e , R f , R g and R h are each independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)C 1-6 Alkyl, C(O)C 1-6 Haloalkyl, C(O)OC 1-6 Alkyl and C(O)OC 1-6 Any one selected from the group consisting of haloalkyl, R o and R p are each independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, (3-10 membered)cycloalkyl, C 1-10 Alkylene-(3-10 membered)cycloalkyl, (3-10 membered)heterocyclyl and C 1-10 Any one selected from the group consisting of alkylene-(3-10 membered) heterocyclyl, The above (3-10 won) cycloalkyl, C 1-10 Alkylene-(3-10 membered)cycloalkyl, (3-10 membered)heterocyclyl or C 1-10 Alkylene-(3-10 membered) heterocyclyl is composed of one or more R 8 can be substituted with , where R 8 are each independently halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NR q R r , C 1-10 Alkylene-NR q R r , oxo, C(O)-NR q R r , C 1-10 Alkylene-C(O)-NR q R r , C(O)O-NR q R r , CN, OH, NO2, C(O)R q , C(O)OR q, C 1-6 Alkylene-C(O)OR q and C 1-6 Any one selected from the group consisting of alkylene-OH, R q and R r are each independently hydrogen, halogen, C 1-6 Alkyl and C 1-6 One selected from the group consisting of haloalkyl.

2. In paragraph 1, R 1 Silver hydrogen, halogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 1-6 Haloalkoxy, NR a R b, OC 1-10 Alkylene-NR a R b , C 1-10 Alkylene-O-NR a R b , C(O)-NR a R b, C 1-10 Alkylene-C(O)-NR a R b and C(O)O-NR a R b is one selected from the group consisting of, n is an integer from 1 to 4, R 2 is hydrogen, halogen, C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 1-5 Haloalkoxy, NR c R d , any one selected from the group consisting of O-(6-14 membered) aryl and O-(5-12 membered) heteroaryl, Above R c and R d are each independently hydrogen, C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 1-5 Haloalkoxy, C(O)OC 1-5 Alkyl, C(O)OC 1-5 which may be substituted with at least one selected from the group consisting of haloalkyl, C(O)O-(3-10 membered)cycloalkyl and C(O)-(5-12 membered)heteroaryl, Here, the above (3-10 membered) cycloalkyl and (5-12 membered) heteroaryl are each independently unsubstituted or C 1-6 Alkyl or C 1-6 may be substituted with haloalkyl, R 3 is hydrogen, halogen, C 1-6 Alkyl and C 1-6 A compound represented by the chemical formula 1, wherein the compound is one selected from the group consisting of haloalkyl, or a pharmaceutically acceptable salt thereof.

3. In paragraph 1 or 2, R 4 is (3-10 member) cycloalkyl, (3-14 member) heterocyclyl, (3-14 member) N-heterocyclyl, (6-14 member) aryl, (5-12 member) heteroaryl, C 1-6 Alkylene-(3-10 membered) cycloalkyl, C 1-6 Alkylene-(3-14 membered) heterocyclyl, C 1-6 Alkylene-(3-10 membered) N-heterocyclyl, C 1-6 Alkylene-(6-14 membered) aryl, C 1-6 Alkylene-(5-12 membered) heteroaryl, NR o R p and is one selected from the group consisting of, wherein the above ring A is (3-10 membered) cycloalkyl or (3-14 membered) heterocyclyl, Above R 4 is one or more types of R 7 can be substituted with , where R 7 Silver halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-10 Alkylene-C 1-6 Alkoxy, C 1-10 Alkylene-C 1-6 Haloalkoxy, (3-10 membered)cycloalkyl, (6-14 membered)aryl, (5-12 membered)heteroaryl, NR e R f , C 1-10 Alkylene-NR e R f , C 1-10 Alkylene-NR e R f , oxo, C(O)-NR e R f, C 1-10 Alkylene-C(O)-NR e R f , C(O)O-NR e R f , CN, OH, NO2, C(O)R e, C(O)OR e , C(O)OR e , C 1-6 Alkylene-C(O)OR e and C1 -6 Any one selected from the group consisting of alkylene-OH, R o and R p are each independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, (3-10 membered) cycloalkyl, C 1-10 Alkylene-(3-10 membered) cycloalkyl, (3-10 membered) heterocyclyl and C 1-10 Any one selected from the group consisting of alkylene-(3-10 membered) heterocyclyl, The above (3-10 won) cycloalkyl, C 1-10 Alkylene-(3-10 membered) cycloalkyl, (3-10 membered) heterocyclyl or C 1-10 Alkylene-(3-10 membered) heterocyclyl is composed of one or more R 8 can be substituted with , where R 8 Silver halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NR q R r , C 1-10 Alkylene-NR q R r , oxo, C(O)-NR q R r , C 1-10 Alkylene-C(O)-NR q R r , C(O)O-NR q R r , CN, OH, NO2, C(O)R q , C(O)OR q, C 1-6 Alkylene-C(O)OR q and C 1-6 Any one selected from the group consisting of alkylene-OH, R q and R r are each independently hydrogen, halogen, C 1-6 Alkyl and C 1-6 Any one selected from the group consisting of haloalkyl, A compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof.

4. In any one of paragraphs 1 to 3, R 5 Silver hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NH2, OH, CN, COOH, NO2, C(O)C 1-6 Alkyl, C(O)OC 1-6 Alkyl and C 1-6 Any one selected from the group consisting of alkylamino, R 6 is NR g R h And, R g and R h are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C(O)C 1-6 Any one selected from the group consisting of alkyl, A compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof.

5. In any one of paragraphs 1 to 4, R 1 Silver hydrogen, halogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy and C 1-6 Any one selected from the group consisting of haloalkoxy, R 2 is NR c R d , O-(6-14 membered) aryl or O-(5-12 membered) heteroaryl, Above R c and R d are each independently hydrogen, C(O)OC 1-5 Alkyl, C(O)OC 1-5 Haloalkyl, C(O)O-(3-10 membered)cycloalkyl and C(O)-(5-12 membered)heteroaryl, Here, the above (3-10 membered) cycloalkyl and (5-12 membered) heteroaryl are each independently unsubstituted or C 1-6 Alkyl, C 1-6 Alkoxy, Halogen and C 1-6 which may be substituted with any one selected from the group consisting of haloalkyl, R 3 is hydrogen, halogen, C 1-6 Alkyl and C 1-6 Any one selected from the group consisting of haloalkyl, R 4 is a monocyclic (3-7 membered) cycloalkyl, a monocyclic (3-6 membered) heterocyclyl, a spirocyclic (7-14 membered) heterocyclyl, a fused cyclic (7-14 membered) heterocyclyl, a (6-10 membered) aryl, a (5-10 membered) heteroaryl, C 1-6 Alkylene-(3-10 membered) N-heterocyclyl, NR o R p and is one selected from the group consisting of, wherein the above ring A is (3-10 membered) cycloalkyl or (3-14 membered) heterocyclyl, Above R 4 is one or more types of R 7 can be substituted with , where R 7 Silver halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-10 Alkylene-C 1-6 Alkoxy, (3-10 member) cycloalkyl, (6-14 member) aryl, (5-12 member) heteroaryl, NR e R f , C 1-10 Alkylene-NR e R f , oxo, CN, OH, NO2, C(O)OR e, C 1-6 Alkylene-C(O)OR e and C 1-6 Any one selected from the group consisting of alkylene-OH, R 5 is hydrogen or halogen, R 6 is NR g R h And, R e , R f , R g and R h are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C(O)C 1-6 Any one selected from the group consisting of alkyl, R o and R p are each independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, (3-10 membered) cycloalkyl, C 1-10 Alkylene-(3-10 membered) cycloalkyl, (3-10 membered) heterocyclyl and C 1-10 Any one selected from the group consisting of alkylene-(3-10 membered) heterocyclyl, The above (3-10 won) cycloalkyl, C 1-10 Alkylene-(3-10 membered) cycloalkyl, (3-10 membered) heterocyclyl or C 1-10 Alkylene-(3-10 membered) heterocyclyl is composed of one or more R 8 can be substituted with , where R 8 Silver halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, NR q R r , C 1-10 Alkylene-NR q R r , oxo, C(O)-NR q R r , C 1-10 Alkylene-C(O)-NR q R r , C(O)O-NR q R r , CN, OH, NO2, C(O)R q , C(O)OR q, C 1-6 Alkylene-C(O)OR q and C 1-6 Any one selected from the group consisting of alkylene-OH, R q and R r are each independently hydrogen, halogen, C 1-6 Alkyl and C 1-6 Any one selected from the group consisting of haloalkyl, A compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof.

6. In any one of paragraphs 1 to 5, The above ring B is absent or is (3-10 membered) heterocyclyl, Above R 1 is hydrogen or methoxy, Above R 2 Is , , , , and is one selected from the group consisting of, Above R 3 is hydrogen, halogen, C 1-3 Alkyl and C 1-3 A compound represented by the chemical formula 1, wherein the compound is one selected from the group consisting of haloalkyl, or a pharmaceutically acceptable salt thereof.

7. In any one of paragraphs 1 to 6, Above R 4 Is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and characterized by being one selected from the group consisting of, A compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof.

8. In any one of paragraphs 1 to 7, R 5 is hydrogen or halogen, R 6 is NR g R h And, R g and R h are each independently hydrogen or C 1-6 A compound represented by the chemical formula 1, or a pharmaceutically acceptable salt thereof.

9. In any one of paragraphs 1 to 8, Above Is , , , , , , and Any one selected from the group consisting of, A compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof.

10. A compound selected from the group consisting of compounds 1 to 138 below, or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition for preventing or treating a YES1-associated disease, comprising a compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition for preventing or treating a disease associated with Transcriptional Enhanced Associated Domain (TEAD), comprising a compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition for preventing or treating solid cancer, comprising a compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

14. In paragraph 13, A pharmaceutical composition for the prevention or treatment of a solid cancer, wherein the solid cancer is any one selected from the group consisting of thyroid cancer, bladder cancer, breast cancer, colon cancer, small intestine cancer, endometrial cancer, cervical cancer, bone cancer, stomach cancer, lymphoma, bronchial cancer, laryngeal cancer, head and neck cancer, liver cancer, prostate cancer, pancreatic cancer, ovarian cancer, esophageal cancer, kidney cancer, lung cancer, oral cancer, brain cancer, brain tumor, glioma, gallbladder cancer, cholangiocarcinoma, skin cancer, skin melanoma, rectal cancer, colon cancer, uterine cancer, uterine sarcoma, and malignant mesothelioma.

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