Covalent inhibitors of JAK2 JH2 domain

Abstract

Disclosed herein are compounds that are selective inhibitors of JAK2, which target Cys675 in the JH2 domain. Also disclosed herein are pharmaceutical compositions and kits comprising the compounds, and methods of using the compounds in the treatment of proliferative disorders, particularly myeloproliferative neoplasms.

Description

[0001]STDU2-43279.601 COVALENT INHIBITORS OF JAK2 JH2 DOMAIN CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No.63 / 664,256, filed on June 26, 2024, the disclosure of which is incorporated 5 herein by reference in its entirety. FIELD Provided herein are compounds that are selective inhibitors of JAK2, which target Cys675 in the JH2 domain. Also disclosed herein are pharmaceutical compositions and kits comprising the compounds, and methods of using the compounds in the treatment of 10 proliferative disorders, particularly myeloproliferative neoplasms. BACKGROUND Janus kinase 2 (JAK2) is a non-receptor tyrosine kinase. Activation of the JAK2- STAT pathway upon cytokine receptor binding mediates innate immunity, adaptive immunity, and hematopoiesis. The JAK2 V617F mutation has been implicated in 15 myeloproliferative neoplasms (MPNs), which are chronic blood cancer characterized by an excessive production of mature blood cells of the myeloid lineage. Although JAK2 inhibitors have been developed and are in clinical use, many suffer from on-target and off-target adverse effects which have limited their utility. For example, on-target toxicities include anemia, thrombocytopenia, and immunosuppression. 20 SUMMARY Disclosed herein is a series of JAK2 selective inhibitors. The compounds disclosed herein target Cys675 in the JH2 domain of JAK2. In one aspect, disclosed herein is a compound of formula (I): (I) 25 or a pharmaceutically , : 1 STDU2-43279.601 R1is selected from -CONRaRb, –(CH2)mNRcRd, -(CH2)nORe, -(CH2)pNRfZRg, - NRh(CH2)qNRiRj, -(CH2)r-heterocyclyl, and -(CH2)s-heteroaryl; m, n, p, q, r, and s are each independently 0, 1, or 2; Z is -C(O)- or –S(O)2-; 5 A is aryl or heteroaryl; X is selected from a bond, heterocyclyl, and aryl; R2is a warhead moiety; R3is selected from hydrogen and C1-C4alkyl; R4is selected from hydrogen and -O-C1-C4 alkyl; and 10 Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, and Rjare each independently selected from hydrogen and C1-C4 alkyl, wherein Raand Rb, or Rcand Rd, or Riand Rj, together with the nitrogen atom to which they are attached, are optionally taken together to form a monocyclic heterocyclyl; wherein each aryl, heteroaryl, and heterocyclyl is independently unsubstituted or 15 substituted with 1 or 2 substituents independently selected from C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo, oxo, C1-C4 haloalkyl, C1-C4 haloalkoxy, -COOH, cyano, and nitro. In some embodiments, the compound of formula (I) is a compound of formula (Ia): Ia) or a pharmaceutically 20 R1is selected from -CONRaRb, –(CH2)mNRcRd, -(CH2)nORe, -(CH2)pNRfZRg, - NRh(CH2)qNRiRj, -(CH2)r-heterocyclyl, and -(CH2)s-heteroaryl; m, n, p, q, r, and s are each independently 0, 1, or 2; Z is -C(O)- or –S(O)2-; A is aryl or heteroaryl; 25 X is selected from a bond, heterocyclyl, and aryl; R2is a warhead moiety; R3is selected from hydrogen and C1-C4alkyl; and 2 STDU2-43279.601 Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, and Rjare each independently selected from hydrogen and C1-C4alkyl, wherein Raand Rb, or Rcand Rd, or Riand Rj, together with the nitrogen atom to which they are attached, are optionally taken together to form a monocyclic heterocyclyl; 5 wherein each aryl, heteroaryl, and heterocyclyl is independently unsubstituted or substituted with 1 or 2 substituents independently selected from C1-C4alkyl, hydroxy, C1-C4alkoxy, halo, oxo, C1-C4 haloalkyl, C1-C4 haloalkoxy, -COOH, cyano, and nitro. In some embodiments, R1is -CONRaRb. In some embodiments, Rais hydrogen and Rbis C1-C4 alkyl. 10 In some embodiments, R1is -CH2NRcRd. In some embodiments, Rcand Rdare each independently selected from C1-C4 alkyl. In some embodiments, R1is selected from -CONHCH3 and -CH2N(CH3)2. In some embodiments, Rcand Rdare taken together with the nitrogen atom to which they are attached to form a six-membered heterocyclyl. In some embodiments, Rcand Rd, 15 together with the nitrogen atom to which they are attached to form a morpholino group. In some embodiments, A is selected from phenyl, naphthyl, and a monocyclic heteroaryl having 1 or 2 nitrogen atoms, each of which is independently unsubstituted or substituted with 1 substituent selected from hydroxy and C1-C4 alkoxy. In some embodiments, A is selected from phenyl, naphthyl, and pyridyl, each of which is 20 independently unsubstituted or substituted with 1 methoxy group. In some embodiments, X is a bond. In some embodiments, X is a monocyclic or bicyclic heterocyclyl having 1 nitrogen atom. In some embodiments, X is selected from azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyridinyl, dihydropyrrolyl, morpholinyl, and 8-azabicyclo[3.2.1]octenyl. 25 In some embodiments, X is aryl. In some embodiments, X is phenyl. In some embodiments, X is unsubstituted or substituted with 1 substituent selected from hydroxy, methoxy, fluoro, -COOH, cyano, and nitro. In some embodiments, R2is selected from -C(O)CH=CH2, -C(O)CF=CH2, - NHC(O)CH=CH2, -NHC(O)CF=CH2, -NHC(O)C≡CCH3, -C(O)C≡CCH3, -C(O)C≡CH, -30 C(O)C(=CH2)F, -C(O)CH=CH-CH2N(CH3)2, -NHC(O)CH=CH-CH2N(CH3)2, C(O)CF=CH- m - C(O)CH=CH2, -NHC(O)CH=CH2, -NHC(O)C≡CCH3, -C(O)C≡CCH3, -C(O)C≡CH,- C(O)C(=CH2)F, and -C(O)CH=CH-CH2N(CH3)2. In some embodiments, the compound is selected from: 3 STDU2-43279.601 O 5 4 STDU2-43279.601 F N HNO NH 5 5 STDU2-43279.601 6 STDU2-43279.601 of. a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a 5 pharmaceutically acceptable carrier. In another aspect, disclosed herein is a method of treating a proliferative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of formula (I), or a pharmaceutically acceptable salt thereof. 10 In some embodiments, the proliferative disease is a cancer. In some embodiments, the cancer is associated with JAK2. In some embodiments, the cancer is associated with a V617F mutation in JAK2. In some embodiments, the cancer is a myeloproliferative neoplasm. In some embodiments, the myeloproliferative neoplasm is chronic myelogenous leukemia, polycythemia vera, primary myelofibrosis, essential thrombocythemia, chronic neutrophilic 15 leukemia, or chronic eosinophilic leukemia. In another aspect, disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament. In another aspect, disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a proliferative disease. In some 20 embodiments, the proliferative disease is a cancer. In some embodiments, the cancer is associated with JAK2. In some embodiments, the cancer is associated with a V617F mutation in JAK2. In some embodiments, the cancer is a myeloproliferative neoplasm. In some embodiments, the myeloproliferative neoplasm is chronic myelogenous leukemia, 7 STDU2-43279.601 polycythemia vera, primary myelofibrosis, essential thrombocythemia, chronic neutrophilic leukemia, or chronic eosinophilic leukemia. In another aspect, disclosed herein is a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof. 5 DETAILED DESCRIPTION Disclosed herein are compounds that are selective inhibitors of JAK2. The compounds specifically target, and covalently modify, Cys675 in the JH2 domain of JAK2. Also disclosed herein are pharmaceutical compositions and kits comprising the compounds, and methods of using the compounds in the treatment of proliferative disorders, 10 particularly myeloproliferative neoplasms Definitions Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. For example, any nomenclatures used in connection with, and 15 techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization described herein are those that are well known and commonly used in the art. The meaning and scope of the terms should be clear; in the event, however of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required 20 by context, singular terms shall include pluralities and plural terms shall include the singular. As used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise. As used herein, the term “and / or” includes any and all combinations of listed items, including any of the listed items individually. For example, “A, B, and / or C” encompasses A, 25 B, C, AB, AC, BC, and ABC, each of which is to be considered separately described by the statement “A, B, and / or C.” For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6- 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the 30 number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated. Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in 8 STDU2-43279.601 accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Sorrell, Organic Chemistry, 2ndedition, 5 University Science Books, Sausalito, 2006; Smith, March’s Advanced Organic Chemistry: Reactions, Mechanism, and Structure, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Larock, Comprehensive Organic Transformations, 3rdEdition, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are 10 incorporated herein by reference. As used herein, the term “alkyl” refers to a radical of a straight or branched saturated hydrocarbon chain. The alkyl chain can include, e.g., from 1 to 24 carbon atoms (C1-C24 alkyl), 1 to 16 carbon atoms (C1-C16 alkyl), 1 to 14 carbon atoms (C1-C14 alkyl), 1 to 12 carbon atoms (C1-C12 alkyl), 1 to 10 carbon atoms (C1-C10 alkyl), 1 to 8 carbon atoms (C1-C8 15 alkyl), 1 to 6 carbon atoms (C1-C6 alkyl), 1 to 4 carbon atoms (C1-C4 alkyl), 1 to 3 carbon atoms (C1-C3 alkyl), or 1 to 2 carbon atoms (C1-C2 alkyl). Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso- butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. 20 As used herein, the term “alkenyl” refers to a radical of a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond and no triple bonds. The double bond(s) may be located at any position(s) with the hydrocarbon chain. The alkenyl chain can include, e.g., from 2 to 24 carbon atoms (C2-C24alkenyl), 2 to 16 carbon atoms (C2-C16 alkenyl), 2 to 14 carbon atoms (C2-C14 alkenyl), 2 to 12 carbon atoms (C2-C12 25 alkenyl), 2 to 10 carbon atoms (C2-C10alkenyl), 2 to 8 carbon atoms (C2-C8alkenyl), 2 to 6 carbon atoms (C2-C6 alkenyl), 2 to 4 carbon atoms (C2-C4 alkenyl), 2 to 3 carbon atoms (C2- C3 alkenyl), or 2 carbon atoms (C2 alkenyl). Representative examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, butadienyl, 2- methyl-2-propenyl, 3-butenyl, pentenyl, pentadienyl, hexenyl, heptenyl, octenyl, octatrienyl, 30 and the like. As used herein, the term “alkynyl” means a radical of a straight or branched hydrocarbon chain containing at least one carbon-carbon triple bond. The alkynyl chain can include, e.g., from 2 to 24 carbon atoms (C2-C24 alkynyl), 2 to 16 carbon atoms (C2-C16 alkynyl), 2 to 14 carbon atoms (C2-C14alkynyl), 2 to 12 carbon atoms (C2-C12alkynyl), 2 to 9 STDU2-43279.601 10 carbon atoms (C2-C10alkynyl), 2 to 8 carbon atoms (C2-C8alkynyl), 2 to 6 carbon atoms (C2-C6alkynyl), 2 to 4 carbon atoms (C2-C4alkynyl), 2 to 3 carbon atoms (C2-C3alkynyl), or 2 carbon atoms (C2 alkynyl). The triple bond(s) may be located at any position(s) with the hydrocarbon chain. Representative examples of alkynyl include, but are not limited to, 5 ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and the like. As used herein, the term “alkoxy” refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy. 10 As used herein, the term “amino” refers to a group -NR2, wherein each R is independently selected from hydrogen and alkyl (e.g., C1-C4 alkyl). A group -NH(alkyl) may be referred to herein as “alkylamino” and a group -N(alkyl)2 may be referred to herein as “dialkylamino.” As used herein, the term “aryl” refers to a radical of a monocyclic, bicyclic, or 15 tricyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms (“C6-C14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6aryl,” i.e., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl,” e.g., naphthyl such as 1- naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon 20 atoms (“C14 aryl,” e.g., anthracenyl and phenanthrenyl). As used herein, the term “cycloalkyl” refers to a radical of a saturated carbocyclic ring system containing three to ten carbon atoms and zero heteroatoms. The cycloalkyl may be monocyclic, bicyclic, bridged, fused, or spirocyclic. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 25 cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl, and bicyclo[5.2.0]nonanyl. As used herein, the term “cyano” refers to a -CN group. As used herein, the term “halogen” or “halo” refers to F, Cl, Br, or I. As used herein, the term “haloalkyl” refers to an alkyl group, as defined herein, in 30 which at least one hydrogen atom (e.g., one, two, three, four, five, six, seven or eight hydrogen atoms) is replaced with a halogen. In some embodiments, each hydrogen atom of the alkyl group is replaced with a halogen (“perhaloalkyl”). Representative examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2- fluoroethyl, 2,2,2-trifluoroethyl, and 3,3,3-trifluoropropyl. 10 STDU2-43279.601 As used herein, the term “haloalkoxy” refers to a haloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of haloalkoxy include, but are not limited to, difluoromethoxy, trifluoromethoxy, and 2,2,2- trifluoroethoxy. 5 As used herein, the term “heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a 10 carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring 15 system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl 20 groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one 25 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, 30 and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6- 11 STDU2-43279.601 bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. As used herein, the term “heterocyclyl” refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein 5 each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be 10 saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl 15 groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described as, e.g., a 3-7-membered heterocyclyl, wherein the term “membered” refers to the non-hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, within the moiety. 20 Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 25 pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without 30 limitation, piperidinyl (e.g., 2,2,6,6-tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, pyridinonyl (e.g., 1-methylpyridin-2-onyl), and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, pyridazinonyl (2-methylpyridazin-3-onyl), pyrimidinonyl (e.g., 1- methylpyrimidin-2-onyl, 3-methylpyrimidin-4-onyl), dithianyl, dioxanyl. Exemplary 6- 12 STDU2-43279.601 membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and 5 thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclyl ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 5-membered heterocyclyl groups fused to a heterocyclyl ring (also referred to herein as a 5,5-bicyclic heterocyclyl ring) include, without limitation, 10 octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), and the like. Exemplary 6- membered heterocyclyl groups fused to a heterocyclyl ring (also referred to as a 4,6- membered heterocyclyl ring) include, without limitation, diazaspirononanyl (e.g., 2,7- diazaspiro[3.5]nonanyl). Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclyl ring) include, without limitation, 15 tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,7-bicyclic heterocyclyl ring) include, without limitation, azabicyclooctanyl (e.g., (1,5)-8- azabicyclo[3.2.1]octanyl). Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,8-bicyclic heterocyclyl ring) include, without limitation, 20 azabicyclononanyl (e.g., 9-azabicyclo[3.3.1]nonanyl). As used herein, the term “hydroxy” or “hydroxyl” refers to an -OH group. As used herein, the term “nitro” refers to an -NO2 group. As used herein, the term “warhead moiety” refers to a reactive group capable of forming a covalent bond with a cysteine residue on a protein (e.g., a cysteine residue of25 JAK2, such as Cys675). The reactive group may be, for example, -C(O)CH=CH2, - C(O)CF=CH2, -NHC(O)CH=CH2, -NHC(O)CF=CH2, -NHC(O)C≡CCH3, -C(O)C≡CCH3, - C(O)C≡CH, -C(O)C(=CH2)F, -C(O)CH=CH-CH2N(CH3)2, -NHC(O)CH=CH-CH2N(CH3)2, - C(O)CF=CH-CH2N(CH3)2, or -NHC(O)CF=CH-CH2N(CH3)2. When a group or moiety can be substituted, the term “substituted” indicates that one 30 or more (e.g., 1, 2, 3, 4, 5, or 6; in some embodiments 1, 2, or 3; and in other embodiments 1 or 2) hydrogens on the group indicated in the expression using “substituted” can be replaced with a selection of recited indicated groups or with a suitable substituent group known to those of skill in the art (e.g., one or more of the groups recited below), provided that the designated atom’s normal valence is not exceeded. Substituent groups include, but are not 13 STDU2-43279.601 limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkenyl, guanidino, halo, haloalkyl, haloalkoxy, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, phosphate, phosphonate, sulfonic acid, thiol, thione, or combinations thereof. 5 As used herein, in chemical structures the indication: represents a point of attachment of one mo o another moiety (e.g., a substituent group to the rest of the compound). For compounds described herein, groups and substituents thereof may be selected in 10 accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. When substituent groups are specified by their conventional chemical formulae, written from left to right, such indication also encompass substituent groups resulting from 15 writing the structure from right to left. For example, if a bivalent group is shown as -CH2O-, such indication also encompasses -OCH2-; similarly, -OC(O)NH- also encompasses - NHC(O)O-. When linker moieties are shown, the linkers can be attached to other moieties of the compound in either direction. The terms “administer,” “administering,” or “administration,” as used herein refer to 20 implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound or a pharmaceutical composition. As used herein, the terms “condition,” “disease,” and “disorder” are used interchangeably. An “effective amount” of a compound or composition refers to an amount sufficient 25 to elicit a desired biological response (e.g., treating a condition). As will be appreciated by those skilled in the art, the effective amount of a compound may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatment. For example, in 30 treating cancer, an effective amount of a compound or composition may reduce tumor burden or stop the growth or spread of a tumor. A “therapeutically effective amount” of a compound or composition is an amount sufficient to provide a therapeutic benefit in the treatment of a condition, or to delay or 14 STDU2-43279.601 minimize one or more symptoms associated with the condition. In some embodiments, a therapeutically effective amount is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, 5 alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent. A “subject” to which administration is contemplated includes, but is not limited to, a 10 human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) and / or other non-human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, 15 and / or turkeys). As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or condition, or one or more signs or symptoms thereof. In some embodiments, “treatment,” “treat,” and “treating” require that signs or symptoms of the disease disorder or condition have developed 20 or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. 25 Compounds Disclosed herein are compounds of formula (I): (I) 15 STDU2-43279.601 and pharmaceutically acceptable salts thereof, wherein: R1is selected from -CONRaRb, –(CH2)mNRcRd, -(CH2)nORe, -(CH2)pNRfZRg, - NRh(CH2)qNRiRj, -(CH2)r-heterocyclyl, and -(CH2)s-heteroaryl; m, n, p, q, r, and s are each independently 0, 1, or 2; 5 Z is -C(O)- or –S(O)2-; A is aryl or heteroaryl; X is selected from a bond, heterocyclyl, and aryl; R2is a warhead moiety; R3is selected from hydrogen and C1-C4 alkyl; 10 R4is selected from hydrogen and -O-C1-C4alkyl; and Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, and Rjare each independently selected from hydrogen and C1-C4 alkyl, wherein Raand Rb, or Rcand Rd, or Riand Rj, together with the nitrogen atom to which they are attached, are optionally taken together to form a monocyclic heterocyclyl; 15 wherein each aryl, heteroaryl, and heterocyclyl is independently unsubstituted or substituted with 1 or 2 substituents independently selected from C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo, oxo, C1-C4haloalkyl, C1-C4haloalkoxy, -COOH, cyano, and nitro. In some embodiments, the compound of formula (I) is a compound of formula (Ia): Ia) 20 and pharmaceutically R1is selected from -CONRaRb, –(CH2)mNRcRd, -(CH2)nORe, -(CH2)pNRfZRg, - NRh(CH2)qNRiRj, -(CH2)r-heterocyclyl, and -(CH2)s-heteroaryl; m, n, p, q, r, and s are each independently 0, 1, or 2; Z is -C(O)- or –S(O)2-; 25 A is aryl or heteroaryl; X is selected from a bond, heterocyclyl, and aryl; R2is a warhead moiety; R3is selected from hydrogen and C1-C4 alkyl; and 16 STDU2-43279.601 Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, and Rjare each independently selected from hydrogen and C1-C4alkyl, wherein Raand Rb, or Rcand Rd, or Riand Rj, together with the nitrogen atom to which they are attached, are optionally taken together to form a monocyclic heterocyclyl; 5 wherein each aryl, heteroaryl, and heterocyclyl is independently unsubstituted or substituted with 1 or 2 substituents independently selected from C1-C4alkyl, hydroxy, C1-C4alkoxy, halo, oxo, C1-C4 haloalkyl, C1-C4 haloalkoxy, -COOH, cyano, and nitro. In some embodiments, R1is -CONRaRb. In some embodiments, Rais hydrogen and Rbis C1-C4 alkyl. In some embodiments, Rais hydrogen and Rbis methyl. 10 In some embodiments, R1is -CH2NRcRd. In some embodiments, Rcand Rdare each independently selected from C1-C4 alkyl. In some embodiments, Rcand Rdare each methyl. In some embodiments, R1is -CONRaRbor -CH2NRcRd, wherein Ra, Rb, Rc, and Rdare each independently selected from hydrogen and methyl. In some embodiments, R1is selected from -CONHCH3 and -CH2N(CH3)2. 15 In some embodiments, R1is –(CH2)mNRcRd, m is 0 or 1, and Rcand Rdare taken together with the nitrogen atom to which they are attached to form a six-membered heterocyclyl that is optionally substituted with one C1-C4alkyl group. In some embodiments, Rcand Rdare taken together with the nitrogen atom to which they are attached to form a six- membered heterocyclyl selected from morpholino and 4-methylpiperazin-1-yl. 20 In some embodiments, R1is -NRh(CH2)qNRiRj, q is 1 or 2. In some embodiments, Rhis C1-C4alkyl. In some embodiments, Riand Rjare each independently selected from C1-C4alkyl. In some embodiments, R1is -NCH3(CH2)2N(CH3)2. In some embodiments, A is selected from phenyl, naphthyl, and a monocyclic heteroaryl having 1 or 2 nitrogen atoms, each of which is independently unsubstituted or 25 substituted with 1 or 2 substituents independently selected from C1-C4alkyl, hydroxy, C1-C4alkoxy, halo, C1-C4 haloalkyl, C1-C4 haloalkoxy, -COOH, cyano, and nitro. In some embodiments, A is selected from phenyl, naphthyl, and a monocyclic heteroaryl having 1 or 2 nitrogen atoms, each of which is independently unsubstituted or substituted with 1 substituent selected from hydroxy and C1-C4 alkoxy. In some embodiments, A is selected from phenyl, 30 naphthyl, and pyridyl, each of which is independently unsubstituted or substituted with 1 substituent selected from C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo, C1-C4 haloalkyl, C1-C4 haloalkoxy, -COOH, cyano, and nitro. In some embodiments, A is selected from phenyl, naphthyl, and pyridyl, each of which is independently unsubstituted or substituted with 1 methoxy group. 17 STDU2-43279.601 In some embodiments, A is selected from: d . I In some embodiments, X is a monocyclic or bicyclic heterocyclyl having 1 nitrogen 5 atom. In some embodiments, X is a monocyclic or bicyclic heterocyclyl having 1 nitrogen atom, which is unsubstituted or substituted with 1 or 2 substituents independently selected from C1-C4alkyl, hydroxy, C1-C4alkoxy, halo, C1-C4haloalkyl, C1-C4haloalkoxy, -COOH, cyano, and nitro. In some embodiments, X is a monocyclic or bicyclic heterocyclyl having 1 nitrogen atom, which is unsubstituted or substituted with 1 substituent selected from hydroxy, 10 methoxy, fluoro, -COOH, cyano, and nitro. In some embodiments, X is a monocyclic or bicyclic heterocyclyl having 1 nitrogen atom, which is unsubstituted or substituted with 1 substituent selected from hydroxy, methoxy, fluoro, -COOH, and cyano. In some embodiments, X is selected from azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyridinyl, dihydropyrrolyl, morpholinyl, and 8-azabicyclo[3.2.1]octenyl, each of which is 15 independently unsubstituted or substituted with 1 substituent selected from hydroxy, methoxy, fluoro, -COOH, cyano, and nitro. In some embodiments, X is selected from azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyridinyl, dihydropyrrolyl, morpholinyl, and 8-azabicyclo[3.2.1]octenyl, each of which is independently unsubstituted or substituted with 1 substituent selected from hydroxy, methoxy, fluoro, -COOH, and cyano. 20 In some embodiments, X is aryl. In some embodiments, X is aryl, which is unsubstituted or substituted with 1 or 2 substituents independently selected from C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo, C1-C4 haloalkyl, C1-C4 haloalkoxy, -COOH, cyano, and nitro. In some embodiments, X is aryl, which is unsubstituted or substituted with 1 substituent selected from hydroxy, methoxy, fluoro, -COOH, cyano, and nitro. In some embodiments, X25 is aryl, which is unsubstituted or substituted with 1 substituent selected from hydroxy, - COOH, cyano, and nitro. In some embodiments, X is phenyl. In some embodiments, X is phenyl, which is unsubstituted or substituted with 1 or 2 substituents independently selected from C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo, C1-C4 haloalkyl, C1-C4 haloalkoxy, -COOH, cyano, and nitro. In some embodiments, X is phenyl, which is unsubstituted or substituted 30 with 1 substituent selected from hydroxy, methoxy, fluoro, -COOH, cyano, and nitro. In some embodiments, X is phenyl, which is unsubstituted or substituted with 1 substituent selected from hydroxy, -COOH, cyano, and nitro. 18 STDU2-43279.601 In some embodiments, the group -X-R2is selected from: 5 H- m - 10 15 19 STDU2-43279.601 , . 5 l. In some embodiments, R3is methyl. In some embodiments, R4is hydrogen. In some embodiments, R4is -O-C1-C4alkyl. In some embodiments, R4is -O-methyl (i.e., methoxy). In some embodiments, the compound of formula (I) is selected from: 10 20 STDU2-43279.601 O 5 21 STDU2-43279.601 F 22 STDU2-43279.601 of. 5 23 STDU2-43279.601 5 24 STDU2-43279.601 25 STDU2-43279.601 26 STDU2-43279.601 , Certain compounds described herein may have at least one asymmetric center. Additional asymmetric centers may be present depending upon the nature of the various 5 substituents on the molecule. Compounds with asymmetric centers give rise to enantiomers (optical isomers), diastereomers (configurational isomers) or both, and it is intended that all of the possible enantiomers and diastereomers, in mixtures and as pure or partially purified compounds, are included within the scope of this disclosure. The independent syntheses of the enantiomerically or diastereomerically enriched 10 compounds, or their chromatographic separations, may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the X-ray crystallography of crystalline products or crystalline intermediates that are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. 15 If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction 20 is often the formation of salts using an enantiomerically pure acid or base. The diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis 25 using optically pure starting materials or reagents of known configuration by methods well known in the art. Compounds may also possess tautomeric forms, and all tautomers also constitute embodiments of the disclosure. 27 STDU2-43279.601 The present disclosure also includes an isotopically-labeled compound, which is identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the 5 compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to2H,3H,13C,14C,15N,18O,17O,31P,32P,35S, 18F, and36Cl, respectively. Substitution with heavier isotopes such as deuterium (2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in 10 some circumstances. The compound may incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors. Suitable positron-emitting isotopes that can be incorporated in compounds of formula (I) are11C,13N,15O, and18F. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by 15 processes analogous to those described in the accompanying Examples using appropriate isotopically-labeled reagent in place of non-isotopically-labeled reagent. Compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure encompass both solvated and unsolvated forms. In one embodiment, the 20 compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form. a. Methods of Synthesis Compounds disclosed herein can be prepared by a variety of methods, including those 25 illustrated in the Examples. Compounds and intermediates may be isolated and purified by methods well-known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by 30 recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for instance in “Vogel's Textbook of Practical Organic Chemistry,” 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM202JE, England. 28 STDU2-43279.601 Reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Reactions can be worked up in a conventional manner, e.g., by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not 5 limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. Standard experimentation, including appropriate manipulation of the reaction 10 conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the disclosure. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in 15 the art; examples of which can be found in PGM Wuts and TW Greene, in Greene's book titled Protective Groups in Organic Synthesis (4thed.), John Wiley & Sons, NY (2006). When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by 20 resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization, or enzymatic resolution). Similarly, when a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the procedures described herein using a pure geometric 25 isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation. The synthetic schemes and specific examples as described are illustrative and are not to be read as limiting the scope of the disclosure or the claims. Alternatives, modifications, and equivalents of the synthetic methods and specific examples are contemplated. 30 b. Pharmaceutically Acceptable Salts The disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio and 29 STDU2-43279.601 effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compound with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like 5 hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, 10 formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric, and the like. Amino groups of the compounds may also be quaternized with alkyl chlorides, bromides 15 and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like. Basic addition salts may be prepared during the final isolation and purification of the disclosed compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, 20 calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine 25 and N,N’-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like. Pharmaceutical Compositions The disclosed compounds may be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which may be a human or non- 30 human). The pharmaceutical compositions may include a “therapeutically effective amount” or a “prophylactically effective amount” of the agent. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the composition may be 30 STDU2-43279.601 determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of a compound of the disclosure are outweighed by the 5 therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease or condition, the prophylactically effective amount will be less than the therapeutically effective amount. 10 The pharmaceutical compositions may include pharmaceutically acceptable carriers. The term “pharmaceutically acceptable carrier,” as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, 15 but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol; esters such 20 as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, 25 flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. Thus, the compounds and their pharmaceutically acceptable salts may be formulated for administration by, for example, solid dosing, eye drop, in a topical oil-based formulation, injection, inhalation (either through the mouth or the nose), implants, or oral, buccal, 30 parenteral, or rectal administration. Techniques and formulations may generally be found in “Remington’s Pharmaceutical Sciences,” (Meade Publishing Co., Easton, Pa.). Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage. 31 STDU2-43279.601 The route by which the disclosed compounds are administered and the form of the composition will dictate the type of carrier to be used. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral) or topical administration (e.g., dermal, pulmonary, nasal, 5 aural, ocular, liposome delivery systems, or iontophoresis). Carriers for systemic administration typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others. All carriers are optional in the compositions. 10 Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol. The amount of diluent(s) in a systemic or topical composition is typically about 50 to about 90% by weight of the composition. Suitable lubricants include silica, talc, stearic acid and its magnesium salts and 15 calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma. The amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10% by weight of the composition. Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; 20 starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically about 5 to about 50% by weight of the composition. Suitable disintegrants include agar, alginic acid and the sodium salt thereof, 25 effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10% by weight of the composition. Suitable colorants include a colorant such as an FD&C dye. When used, the amount of colorant in a systemic or topical composition is typically about 0.005 to about 0.1% by 30 weight of the composition. Suitable flavors include menthol, peppermint, and fruit flavors. The amount of flavor(s), when used, in a systemic or topical composition is typically about 0.1 to about 1.0%. 32 STDU2-43279.601 Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s), when used, in a systemic or topical composition is typically about 0.001 to about 1% by weight of the composition. Suitable antioxidants include butylated hydroxyanisole (“BHA”), butylated 5 hydroxytoluene (“BHT”), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically about 0.1 to about 5% by weight of the composition. Suitable preservatives include benzalkonium chloride, methyl paraben, and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about 0.01 to about 5% by weight of the composition. 10 Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5% by weight of the composition. Suitable solvents include water, isotonic saline, ethyl oleate, glycerin, hydroxylated castor oils, alcohols such as ethanol, and phosphate buffer solutions. The amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100% by 15 weight of the composition. Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically about 1 to about 8% by weight of the composition. Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and 20 the TWEENS from Atlas Powder Company of Wilmington, Delaware. Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp.587-592; Remington’s Pharmaceutical Sciences, 15th Ed.1975, pp.335-337; and McCutcheon’s Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp.236-239. The amount of surfactant(s) in the systemic or topical composition is typically about 0.1% to 25 about 5% by weight of the composition. Although the amounts of components in the systemic compositions may vary depending on the type of systemic composition prepared, in general, systemic compositions include 0.01% to 50% by weight of an active compound and 50% to 99.99% by weight of one or more carriers. Compositions for parenteral administration typically include 0.1% to 30 10% by weight of actives and 90% to 99.9% by weight of a carrier including a diluent and a solvent. Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount, usually at least about 5% by weight, and more 33 STDU2-43279.601 particularly from about 25% to about 50% by weight of actives. The oral dosage compositions include about 50% to about 95% by weight of carriers, and more particularly, from about 50% to about 75% by weight. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, 5 or multiple-compressed. Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific 10 lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination thereof. Capsules (including implants, time release and sustained release formulations) 15 typically include an active compound (e.g., a compound of formula (I)), and a carrier including one or more diluents disclosed above in a capsule comprising gelatin. Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics. Implants can be of the biodegradable or the non-biodegradable type. 20 The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this disclosure. Solid compositions may be coated by conventional methods, typically with pH or time-dependent coatings, such that a disclosed compound is released in the gastrointestinal 25 tract in the vicinity of the desired application, or at various points and times to extend the desired action. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Evonik Industries of Essen, Germany), waxes and shellac. 30 Compositions for oral administration can have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically include a disclosed compound 34 STDU2-43279.601 and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners. Other compositions useful for attaining systemic delivery of the subject compounds 5 include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants. 10 The disclosed compounds can be topically administered. Topical compositions that can be applied locally to the skin may be in any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. Topical compositions include: a disclosed compound (e.g., a compound of formula (I)), or a pharmaceutically acceptable salt thereof), 15 and a carrier. The carrier of the topical composition preferably aids penetration of the compounds into the skin. The carrier may further include one or more optional components. The amount of the carrier employed in conjunction with a disclosed compound is sufficient to provide a practical quantity of composition for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods 20 of this disclosure are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976). A carrier may include a single ingredient or a combination of two or more ingredients. In the topical compositions, the carrier includes a topical carrier. Suitable topical carriers 25 include one or more ingredients selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more 30 particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols. The carrier of a topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional. 35 STDU2-43279.601 Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl 5 sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and 10 polydimethylsiloxane. The amount of emollient(s) in a skin-based topical composition is typically about 5% to about 95% by weight of the composition. Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant(s) in a topical composition is typically about 0% to about 95% by weight of the composition. 15 Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically about 0% to about 95% by weight of the 20 composition. Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant(s) in a topical composition is typically 0% to 95% by weight of the composition. 25 The amount of thickener(s) in a topical composition is typically about 0% to about 95% by weight of the composition. Suitable powders include beta-cyclodextrins, hydroxypropyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified 30 magnesium aluminum silicate, organically-modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in a topical composition is typically 0% to 95% by weight of the composition. 36 STDU2-43279.601 The amount of fragrance in a topical composition is typically about 0% to about 0.5%, particularly, about 0.001% to about 0.1% by weight of the composition. Suitable pH adjusting additives include HCl or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition. 5 Methods of Use The compounds disclosed herein can covalently modify the JH2 domain of JAK2. Accordingly, the compounds and pharmaceutical compositions disclosed herein can be used for treatment of proliferative diseases such as cancer, and particularly cancers associated with the V617F domain of JAK2. 10 Accordingly, disclosed herein is a method of treating a proliferative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the proliferative disease is a cancer. In some embodiments, the cancer is associated with JAK2. In some embodiments, the cancer is associated with a 15 V617F mutation in JAK2. In some embodiments, the cancer is a myeloproliferative neoplasm. In some embodiments, the myeloproliferative neoplasm is chronic myelogenous leukemia, polycythemia vera, primary myelofibrosis, essential thrombocythemia, chronic neutrophilic leukemia, or chronic eosinophilic leukemia. i. Dosages 20 It will be appreciated that appropriate dosages of the compounds, and compositions comprising the compounds, can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments described herein. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular 25 compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and / or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient. The amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local 30 concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects. Administration in vivo can be effected in one dose, continuously or intermittently (e.g. in divided doses at appropriate intervals) throughout the course of treatment. Methods of 37 STDU2-43279.601 determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the 5 treating physician. ii. Combination Therapies A compound or composition described herein may be used in combination with other known therapies. Administered “in combination,” as used herein, means that two (or more) different treatments are delivered to the subject during the course of the subject’s affliction 10 with the disorder, e.g., the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons. In some embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent 15 delivery.” In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were 20 administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. In some embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an 25 effect of the first treatment delivered is still detectable when the second is delivered. A compound or composition described herein and the at least one additional therapeutic agent can be administered simultaneously, in the same or in separate compositions, or sequentially. For sequential administration, the compound described herein can be administered first, and the additional agent can be administered subsequently, or the 30 order of administration can be reversed. In some embodiments, a compound or composition described herein is administered in combination with at least one of chemotherapy, surgery, radiation therapy, hormone therapy, immunotherapy, cryotherapy, T cell transfer therapy, and thermotherapy, or any combination thereof. In some embodiments a compound or composition described herein is 38 STDU2-43279.601 administered in combination with two or more of chemotherapy, surgery, radiation therapy, hormone therapy, immunotherapy, cryotherapy, T cell transfer therapy, and thermotherapy. For example, in some embodiments, a compound or composition described herein is administered in combination with an immunotherapy, such as an immune checkpoint 5 inhibitor. In some embodiments, a compound or composition described herein is administered in combination with a T cell transfer therapy, such as CAR T-cell therapy. In some embodiments, a compound or composition described herein is used in combination with chemotherapy. In some embodiments, a compound or composition described herein is used in combination with a chemotherapeutic agent identified on the “A to 10 Z List of Cancer Drugs” published by the National Cancer Institute. In some embodiments, the chemotherapeutic agent is selected from arsenic trioxide, azacitidine, cedazuridine, cyclophosphamide, cytarabine, dasatinib, daunorubicin, decitabine, doxorubicin, fedratinib, imatinib, ivosidenib, momelotinib, nilotinib, pacritinib , pemigatinib, ropeginteferon Alfa-2b- njft, and ruxolitinib. 15 Kits For use in the therapeutic applications described herein, kits and articles of manufacture are also provided, which include a compound or pharmaceutical composition described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical comosition comprising a compound of formula (I), or a 20 pharmaceutically acceptable salt thereof ). In some embodiments, such kits comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from a variety of materials 25 such as glass or plastic. The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products include those found in, e.g., U.S. Patent Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, 30 vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. For example, in some embodiments the container(s) includes a compound of formula (I), or a pharmaceutically acceptable salt thereof, optionally in a composition or in combination with another agent as 39 STDU2-43279.601 disclosed herein. The container(s) optionally have a sterile access port (e.g., the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein. 5 For example, a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and / or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and / or tube labels listing contents 10 and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a 15 package insert. In addition, a label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates directions for use of the contents, such as in methods described herein. In certain embodiments, the pharmaceutical composition is presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack, for example, contains metal 20 or plastic foil, such as a blister pack. Or, the pack or dispenser device is accompanied by instructions for administration. Or, the pack or dispenser is accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for 25 example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In some embodiments, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Examples 30 Abbreviations used in the Examples include the following: ACN is acetonitrile; BINAP is 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Boc2O is di-tert-butyl dicarbonate; DCM is dichloromethane; DMF is N,N-dimethylformamide; DMSO is dimethylsulfoxide; dppf is 1,1′-bis(diphenylphosphino)ferrocene; EtOAc is ethyl acetate; LCMS is liquid 40 STDU2-43279.601 chromatography mass spectrometry; NaOAc is sodium acetate; NMR is nuclear magnetic resonance; TEA is triethylamine; TFA is trifluoroacetic acid; and THF is tetrahydrofuran. Example 1 Compound Syntheses 5 Compound 1 of 4- amino-N-methyl-benzamide (10 g, 66.59 mmol, 1 eq) in THF (150 mL) was added diphenoxymethylenecyanamide (23.80 g, 99.88 mmol, 1.5 eq). The mixture was stirred at 80°C 10 for 12 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O 20 mL and extracted with EtOAc 60 mL (20 mL× 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~72% Ethyl acetate / Petroleum ether 41 STDU2-43279.601 gradient @ 100 mL / min) to give phenyl N'-cyano-N-(4- (methylcarbamoyl)phenyl)carbamimidate (14.75 g, 50.12 mmol, 75.27% yield) as a pink solid. 4-((5-amino-1H-1,2,4-triazol-3-yl)amino)-N-methylbenzamide. To a solution of phenyl N'-cyano-N-(4-(methylcarbamoyl)phenyl)carbamimidate (14.75 g, 50.12 mmol, 1 eq) 5 in THF (150 mL) was added N2H4.H2O (4.86 g, 95.22 mmol, 4.71 mL, 98% purity, 1.9 eq) at 0°C. The mixture was stirred at 70°C for 3 hr. LCMS showed desired compound formed. The mixture was filtered and concentrated under reduced pressure to give intermediate A 4-[(5- amino-1H-1,2,4-triazol-3-yl)amino]-N-methyl-benzamide (6 g, crude) as a white solid.1H NMR (400 MHz, METHANOL-d4) δ 7.71 (br d, J = 8.5 Hz, 2H), 7.45 (br d, J = 8.6 Hz, 2H), 10 2.89 (s, 3H). N-(5-nitronaphthalen-2-yl)-1,1-diphenylmethanimine. A mixture of diphenylmethanimine (1.08 g, 5.95 mmol, 998.60 μL, 1.5 eq), 6-bromo-1-nitro-naphthalene (1 g, 3.97 mmol, 1 eq), t-BuONa (762.51 mg, 7.93 mmol, 2 eq), BINAP (494.06 mg, 793.45 μmol, 0.2 eq) and Pd2(dba)3 (363.29 mg, 396.72 μmol, 0.1 eq) in toluene (20 mL) was degassed and 15 purged with N2 for 3 times, and then the mixture was stirred at 80°C for 12 hr under N2 atmosphere. LCMS showed desired compound formed. The residue was diluted with H2O 20 mL and extracted with EtOAc 60 mL (20 mL × 3). The combined organic layers were washed with brine 60 mL (20 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g 20 Silica Flash Column, Eluent of 0~3% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give N-(5-nitronaphthalen-2-yl)-1,1-diphenylmethanimine (620 mg) as a yellow oil. MS (ESI): m / z = 353.2 [M+H]+. 5-nitronaphthalen-2-amine. To a solution of N-(5-nitronaphthalen-2-yl)-1,1- diphenylmethanimine (620 mg, 1.76 mmol, 1 eq) in MeOH (15 mL) was added NH2OH.HCl 25 (281.21 mg, 4.05 mmol, 2.3 eq) and NaOAc (433.00 mg, 5.28 mmol, 3 eq). The mixture was stirred at 60°C for 2 hr. LCMS showed desired compound formed. The residue was diluted with H2O 10 mL and extracted with EtOAc 30 mL (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent30 of 0~7% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give 5-nitronaphthalen-2- amine (277 mg, 1.43 mmol, 81.15% yield, 97% purity) as a brown solid.1H NMR (400 MHz, CHLOROFORM-d) δ 7.52 - 7.45 (m, 3H), 7.45 - 7.39 (m, 2H), 7.38 - 7.32 (m, 1H). phenyl (5-nitronaphthalen-2-yl)carbamate. To a solution of 5-nitronaphthalen-2- amine (277 mg, 1.47 mmol, 1 eq) in THF (3 mL) and H2O (1.5 mL) was added NaHCO342 STDU2-43279.601 (123.66 mg, 1.47 mmol, 1 eq) and phenyl carbonochloridate (253.51 mg, 1.62 mmol, 203.13 μL, 1.1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound formed. The residue was diluted with H2O 5 mL and extracted with EtOAc 15 mL (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced 5 pressure to give phenyl (5-nitronaphthalen-2-yl)carbamate (416 mg, crude) as a yellow solid. 5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-N-(5-nitronaphthalen-2-yl)-1H- 1,2,4-triazole-1-carboxamide. A mixture of phenyl (5-nitronaphthalen-2-yl)carbamate (416 mg, 1.35 mmol, 1 eq), TEA (136.54 mg, 1.35 mmol, 187.82 μL, 1 eq) in dioxane (5 mL) was stirred at 90°C for 5 min to get mixture 1. Meantime, a mixture of 4-[(5-amino-1H-1,2,4- 10 triazol-3-yl)amino]-N-methyl-benzamide (313.38 mg, 1.35 mmol, 1 eq), TEA (136.54 mg, 1.35 mmol, 187.82 μL, 1 eq) in dioxane (5 mL) was stirred at 80°C for 5 min to get mixture 2. Then mixture 2 was added to mixture 1, the reaction was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110°C for 12 hr under N2 atmosphere. LCMS showed desired compound formed. The residue was diluted with H2O 15 mL and extracted with EtOAc 15 30 mL (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C1875×30mm×3 μm;mobile phase: [H2O(0.1% TFA)-ACN];gradient:30%-60% B over 8.0 min) to give 5-amino-3-[4- (methylcarbamoyl)anilino]-N-(5-nitro-2-naphthyl)-1,2,4-triazole-1-carboxamide (50 mg) as a 20 yellow solid. 5-amino-N-(5-aminonaphthalen-2-yl)-3-((4-(methylcarbamoyl)phenyl)amino)-1H- 1,2,4-triazole-1-carboxamide. A mixture of 5-amino-3-[4-(methylcarbamoyl)anilino]-N-(5- nitro-2-naphthyl)-1,2,4-triazole-1-carboxamide (80 mg, 179.20 μmol, 1 eq) , Pd / C (40 mg, 10% purity) in THF (2 mL) was degassed and purged with H2 for 3 times, and then the mixture 25 was stirred at 25°C for 12 hr under H2(15psi). LCMS showed desired compound formed. The mixture was filtered and concentrated under reduced pressure to give 5-amino-N-(5-amino-2- naphthyl)-3-[4-(methylcarbamoyl)anilino]-1,2,4-triazole-1-carboxamide (70 mg, crude) as a brown solid. MS (ESI): m / z = 417.3 [M+H]+. N-(5-acrylamidonaphthalen-2-yl)-5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-30 1H-1,2,4-triazole-1-carboxamide. To a solution of 5-amino-N-(5-amino-2-naphthyl)-3-[4- (methylcarbamoyl)anilino]-1,2,4-triazole-1-carboxamide (70 mg, 168.09 μmol, 1 eq) in DCM (1.5 mL) was added TEA (51.03 mg, 504.28 μmol, 70.19 μL, 3 eq) and prop-2-enoyl chloride (15.21 mg, 168.09 μmol, 13.66 μL, 1 eq) at 0°C. The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced 43 STDU2-43279.601 pressure to remove solvent. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 75×30mm×3 μm;mobile phase: [H2O(0.1% TFA)- ACN];gradient:15%-50% B over 8.0 min) to give N-(5-acrylamidonaphthalen-2-yl)-5-amino- 3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (1.91 mg) as a 5 brown solid.1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 9.91 - 9.76 (m, 1H), 9.53 (s, 1H), 8.29 (d, J = 1.8 Hz, 1H), 8.21 (br d, J = 4.5 Hz, 1H), 8.09 (d, J = 9.1 Hz, 1H), 7.87 (dd, J = 1.9, 9.2 Hz, 1H), 7.82 - 7.70 (m, 5H), 7.56 - 7.40 (m, 3H), 6.79 - 6.64 (m, 1H), 6.39 - 6.23 (m, 1H), 5.89 - 5.71 (m, 1H), 2.77 (d, J = 4.5 Hz, 3H). MS (ESI): m / z = 471.3 [M+H]+. 10 Compound 2 5-a (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5- amino-N-(5-amino-2-naphthyl)-3-[4-(methylcarbamoyl)anilino]-1,2,4-triazole-1- 15 carboxamide (40 mg, 88.32 μmol, 1 eq, HCl) in THF (1 mL) / H2O (1 mL) was added NaHCO3 (22.26 mg, 264.96 μmol, 3 eq) and but-2-ynoyl chloride (9.96 mg, 97.15 μmol, 1.1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 100×30mm×5μm;mobile20 phase: [H2O(0.1% TFA)-ACN];gradient:20%-50% B over 8.0 min) to give 5-amino-N-[5-(but- 2-ynoylamino)-2-naphthyl]-3-[4-(methylcarbamoyl)anilino]-1,2,4-triazole-1-carboxamide (13.7 mg, 98.52% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 9.85 (s, 1H), 9.54 (s, 1H), 8.28 (s, 1H), 8.22 (q, J = 4.0 Hz, 1H), 8.00 (d, J = 9.1 Hz, 1H), 7.86 (dd, J = 1.6, 9.2 Hz, 1H), 7.81 - 7.73 (m, 5H), 7.56 - 7.42 (m, 4H), 2.77 (d, J = 4.4 Hz, 3H), 25 2.09 (s, 3H). 44 STDU2-43279.601 Compound 3 tert-butyl (6-aminonaphthalen-2-yl)carbamate. To a solution of naphthalene-2,6- diamine (850 mg, 5.37 mmol, 1 eq) in toluene (20 mL) was added Boc2O (1.17 g, 5.37 mmol, 5 1.23 mL, 1 eq). The mixture was stirred at 110°C for 12 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~15% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give tert-butyl (6- aminonaphthalen-2-yl)carbamate (780 mg, 54.96% yield, 97.79% purity) as a white solid. MS 10 (ESI): m / z = 259.2[M+H]+. tert-butyl phenyl naphthalene-2,6-diyldicarbamate. To a solution of tert-butyl (6- aminonaphthalen-2-yl)carbamate (300 mg, 1.16 mmol, 1 eq) in THF (4 mL) / H2O (2 mL) was added phenyl carbonochloridate (200.02 mg, 1.28 mmol, 160.27 μL, 1.1 eq) and NaHCO3(117.08 mg, 1.39 mmol, 1.2 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired 15 compound was detected. The residue was diluted with H2O 3 mL and extracted with EtOAc (3 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl phenyl naphthalene-2,6-diyldicarbamate (400 mg, crude) as a yellow solid. 45 STDU2-43279.601 tert-butyl (6-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1- carboxamido)naphthalen-2-yl)carbamate. A mixture of tert-butyl phenyl naphthalene-2,6- diyldicarbamate (400 mg, 1.06 mmol, 1 eq) and TEA (106.96 mg, 1.06 mmol, 147.13 μL, 1 eq) in dioxane (5 mL) was stirred at 90°C for 10 min to get mixture 1. Meantime, a mixture 4- 5 [(5-amino-1H-1,2,4-triazol-3-yl)amino]-N-methyl-benzamide (245.49 mg, 1.06 mmol, 1 eq) and TEA (106.96 mg, 1.06 mmol, 147.13 μL, 1 eq) in dioxane (5 mL) was stirred at 90°C for 10 min to get mixture 2. Then mixture 2 was added to mixture 1 and the reaction was degassed and purged with N2for 3 times, and then the mixture was stirred at 110°C for 12 hr under N2atmosphere. LCMS showed desired compound was detected. The reaction mixture was filtrated 10 and then concentrated under reduced pressure to remove the solvent. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 10:1) to give tert-butyl (6-(5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)naphthalen-2- yl)carbamate (160 mg, 22.86% yield, 78% purity) as a white solid. MS (ESI): m / z = 517.4 [M+H]+. 15 5-amino-N-(6-aminonaphthalen-2-yl)-3-((4-(methylcarbamoyl)phenyl)amino)-1H- 1,2,4-triazole-1-carboxamide. tert-butyl (6-(5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)naphthalen-2- yl)carbamate (160 mg, 309.75 μmol, 1 eq) in HCl / EtOAc (4 mL, 4 M) was stirred at 25°C for 2 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated20 under reduced pressure to remove solvent to give 5-amino-N-(6-aminonaphthalen-2-yl)-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (140 mg, crude, HCl) as a white solid. N-(6-acrylamidonaphthalen-2-yl)-5-amino-3-((4-(methylcarbamoyl)phenyl)amino)- 1H-1,2,4-triazole-1-carboxamide. To a solution of 5-amino-N-(6-aminonaphthalen-2-yl)-3- 25 ((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (140 mg, 309.12 μmol, 1 eq, HCl) in THF (2 mL) / H2O (1 mL) was added NaHCO3 (77.90 mg, 927.37 μmol, 3 eq) and prop-2-enoyl chloride (27.98 mg, 309.12 μmol, 25.11 μL, 1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by 30 prep-HPLC (TFA condition; column: Phenomenex luna C18100×40mm×3 μm;mobile phase: [H2O(0.1% TFA)-ACN]; gradient:25%-55% B over 10.0 min) to give N-(6- acrylamidonaphthalen-2-yl)-5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4- triazole-1-carboxamide (69.27 mg, 47.01% yield, 98.7% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 10.36 (s, 1H), 9.78 (s, 1H), 9.53 (s, 1H), 8.42 - 8.36 (m, 1H), 8.26 - 8.16 46 STDU2-43279.601 (m, 2H), 7.89 - 7.82 (m, 2H), 7.81 - 7.72 (m, 5H), 7.65 (dd, J = 2.0, 8.9 Hz, 1H), 7.44 (br s, 2H), 6.56 - 6.45 (m, 1H), 6.31 (dd, J = 1.9, 16.9 Hz, 1H), 5.83 - 5.75 (m, 1H), 2.77 (d, J = 4.5 Hz, 3H). MS (ESI): m / z = 471.3 [M+H]+. 5 Compound 4 of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate (1 g, 3.23 mmol, 1 eq), 4-bromoaniline (556.33 mg, 3.23 mmol, 1 eq), K2CO3 10 (893.93 mg, 6.47 mmol, 2 eq), Pd(dppf)Cl2(236.64 mg, 323.41 μmol, 0.1 eq) in dioxane (12 mL) / H2O (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2atmosphere. TLC indicated the reaction was completed and one new spot formed. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of15 0~16% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give tert-butyl 5-(4- aminophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (370 mg, 1.20 mmol, 37.11% yield, 89% purity) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ 7.20 (br d, J = 8.1 47 STDU2-43279.601 Hz, 2H), 6.68 (dd, J = 2.9, 8.4 Hz, 2H), 6.07 (br s, 1H), 4.23 (br s, 2H), 3.53 (br t, J = 5.6 Hz, 2H), 2.29 (br s, 2H), 1.50 (s, 9H). tert-butyl 5-(4-((phenoxycarbonyl)amino)phenyl)-3,6-dihydropyridine-1(2H)- carboxylate. To a solution of tert-butyl 5-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- 5 carboxylate (270 mg, 984.12 μmol, 1 eq) and phenyl carbonochloridate (169.49 mg, 1.08 mmol, 135.81 μL, 1.1 eq) in THF (4 mL) / H2O (2 mL) was added NaHCO3(99.21 mg, 1.18 mmol, 1.2 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound was detected. The residue was diluted with H2O 5 mL and extracted with EtOAc (5 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 5-(4- 10 ((phenoxycarbonyl)amino)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (390 mg, crude) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) δ 7.36 - 7.33 (m, 2H), 7.29 (t, J = 8.7 Hz, 3H), 7.16 - 7.10 (m, 3H), 6.76 (d, J = 8.3 Hz, 1H), 4.18 (br s, 2H), 3.68 (t, J = 6.4 Hz, 1H), 3.48 (t, J = 5.7 Hz, 2H), 2.24 (br d, J = 3.6 Hz, 2H), 1.79 (td, J = 3.3, 6.4 Hz, 1H), 1.43 (s, 9H). tert-butyl 5-(4-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-15 1-carboxamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate. A mixture of tert-butyl 5-(4- ((phenoxycarbonyl)amino)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (390 mg, 988.69 μmol, 2 eq) and TEA (50.02 mg, 494.34 μmol, 68.81 μL, 1 eq) in dioxane (5 mL) was stirred at 90°C for 10 min to get mixture 1. Meantime, a mixture of 4-((5-amino-1H-1,2,4-triazol-3- yl)amino)-N-methylbenzamide (114.81 mg, 494.34 μmol, 1 eq) and TEA (50.02 mg, 494.34 20 μmol, 68.81 μL, 1 eq) in dioxane (5 mL) was stirred at 90°C for 10 min to get mixture 2. Then mixture 2 was added to mixture 1 and the reaction was degassed and purged with N2for 3 times, and then the mixture was stirred at 110°C for 12 hr under N2 atmosphere. LCMS showed desired compound was detected. The reaction mixture was filtrated under reduced pressure to give tert-butyl 5-(4-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1- 25 carboxamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (290 mg, 86% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.50 (s, 1H), 8.23 - 8.17 (m, 1H), 7.80 - 7.64 (m, 6H), 7.47 - 7.37 (m, 4H), 6.32 - 6.27 (m, 1H), 4.22 (br d, J = 1.5 Hz, 2H), 3.47 (br t, J = 5.4 Hz, 2H), 2.76 (d, J = 4.4 Hz, 3H), 2.26 (br d, J = 3.6 Hz, 2H), 1.44 (s, 9H). MS (ESI): m / z = 533.4 [M+H]+. 30 5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-N-(4-(1,2,5,6-tetrahydropyridin-3- yl)phenyl)-1H-1,2,4-triazole-1-carboxamide. Tert-butyl 5-(4-(5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (100 mg, 187.76 μmol, 1 eq) in HCl / EtOAc (3 mL, 4 M) was stirred at 25°C for 1 hr. LCMS showed desired compound was detected. The reaction 48 STDU2-43279.601 mixture was concentrated under reduced pressure to give 5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-N-(4-(1,2,5,6-tetrahydropyridin-3-yl)phenyl)-1H-1,2,4- triazole-1-carboxamide (88 mg, crude, HCl) as a white solid. N-(4-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)phenyl)-5-amino-3-((4- 5 (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5- amino-3-((4-(methylcarbamoyl)phenyl)amino)-N-(4-(1,2,5,6-tetrahydropyridin-3-yl)phenyl)- 1H-1,2,4-triazole-1-carboxamide (88 mg, 187.66 μmol, 1 eq, HCl) in DCM (3 mL) / DMF (0.2 mL) was added TEA (56.97 mg, 562.97 μmol, 78.36 μL, 3 eq) and prop-2-enoyl chloride (16.98 mg, 187.66 μmol, 15.25 μL, 1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed 10 desired compound was detected. The reaction mixture was filtered to give a solution. The residue was purified by prep-HPLC (TFA condition;Column: Phenomenex Luna C18 100×30mm×5μm;Mobile phase: A: H2O(0.1% TFA);B: ACN; Gradient: B from 25.00% to 55.00% in 9.00min; Flow rate: 60.00ml / min) to give N-(4-(1-acryloyl-1,2,5,6- tetrahydropyridin-3-yl)phenyl)-5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4- 15 triazole-1-carboxamide (19 mg, 38.78 μmol, 20.66% yield, 99.29% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 9.50 (s, 1H), 8.20 (br d, J = 4.5 Hz, 1H), 7.81 - 7.65 (m, 6H), 7.55 - 7.36 (m, 4H), 7.05 - 6.84 (m, 1H), 6.40 - 6.27 (m, 1H), 6.15 (br d, J = 17.1 Hz, 1H), 5.74 - 5.68 (m, 1H), 4.49 - 4.40 (m, 2H), 3.72 - 3.66 (m, 2H), 2.76 (d, J = 4.4 Hz, 3H), 2.37 - 2.24 (m, 2H). MS (ESI): m / z = 487.3 [M+H]+. 20 49 STDU2-43279.601 Compound 5A and Compound 5B tert-butyl 3-(4-aminophenyl)piperidine-1-carboxylate. A mixture of Pd / C (100 mg, 10% purity) in EtOH (3 mL) was degassed and purged with N2, and then tert-butyl 5-(4- 5 aminophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 728.98 μmol, 1 eq) was added. The mixture was stirred at 25°C for 2 hr under H2atmosphere (15Psi). LCMS showed desired compound was detected. The reaction mixture was filtrated and then concentrated under reduced pressure to give tert-butyl 3-(4-aminophenyl)piperidine-1-carboxylate (180 mg, crude) as a purple solid. 10 tert-butyl 3-(4-((phenoxycarbonyl)amino)phenyl)piperidine-1-carboxylate. To a solution of tert-butyl 3-(4-aminophenyl)piperidine-1-carboxylate (180 mg, 651.29 μmol, 1 eq) in THF (2 mL) / H2O (1 mL) was added phenyl carbonochloridate (112.17 mg, 716.42 μmol, 89.88 μL, 1.1 eq) and NaHCO3(65.66 mg, 781.55 μmol, 1.2 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound was detected. The residue was diluted with 15 H2O mL and extracted with EtOAc (3 mL × 2), dried over Na2SO4, filtered and concentrated 50 STDU2-43279.601 under reduced pressure to give tert-butyl 3-(4-((phenoxycarbonyl)amino)phenyl)piperidine-1- carboxylate (250 mg, crude) as a purple solid. tert-butyl 3-(4-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole- 1-carboxamido)phenyl)piperidine-1-carboxylate. A mixture of tert-butyl 3-(4- 5 ((phenoxycarbonyl)amino)phenyl)piperidine-1-carboxylate (250 mg, 630.55 μmol, 2 eq) and TEA (31.90 mg, 315.28 μmol, 43.88 μL, 1 eq) in dioxane (5 mL) was stirred at 90°C for 10 min to get mixture 1. Meantime, a mixture of 4-((5-amino-1H-1,2,4-triazol-3-yl)amino)-N- methylbenzamide (73.22 mg, 315.28 μmol, 1 eq) and TEA (31.90 mg, 315.28 μmol, 43.88 μL, 1 eq) in dioxane (5 mL) was stirred at 90°C for 10 min to get mixture 2. Then mixture 2 was 10 added to mixture 1 and the reaction was degassed and purged with N2for 3 times, and then the mixture was stirred at 110°C for 12 hr under N2 atmosphere. LCMS showed desired compound was detected. The reaction mixture was filtrated and the filter cake was concentrated under reduced pressure to give tert-butyl 3-(4-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H- 1,2,4-triazole-1-carboxamido)phenyl)piperidine-1-carboxylate (100 mg, crude) as a white 15 solid. 5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-N-(4-(piperidin-3-yl)phenyl)-1H- 1,2,4-triazole-1-carboxamide. Tert-butyl 3-(4-(5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)phenyl)piperidine-1- carboxylate (100 mg, 187.05 μmol, 1 eq) in HCl / EtOAc (3 mL, 4 M) was stirred at 25°C for 2 20 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to give 5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-N-(4- (piperidin-3-yl)phenyl)-1H-1,2,4-triazole-1-carboxamide (88 mg, crude, HCl) as a white solid. N-(4-(1-acryloylpiperidin-3-yl)phenyl)-5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5-25 amino-3-((4-(methylcarbamoyl)phenyl)amino)-N-(4-(piperidin-3-yl)phenyl)-1H-1,2,4- triazole-1-carboxamide (88 mg, 186.85 μmol, 1 eq, HCl) in DCM (3 mL) / DMF (0.2 mL) was added TEA (56.72 mg, 560.56 μmol, 78.02 μL, 3 eq) and prop-2-enoyl chloride (16.91 mg, 186.85 μmol, 15.18 μL, 1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure. The 30 residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 100×30mm×5μm;mobile phase: [H2O(0.1% TFA)-ACN]; gradient:30%-50% B over 9.0 min) to give desired compound (18 mg, purity 98.45%) as a white solid, which was further separated by SFC (condition: column: ChiralPak IH, 250×30mm, 10μm; mobile phase: [CO2- MeOH(0.1%NH3H2O)]; B%:50%, isocratic elution mode) to give isomer 1 as Compound 5A 51 STDU2-43279.601 (7.65 mg, 14.97 μmol, 8.01% yield, 95.58% purity, retention time=1.772) as a white solid and isomer 2 as Compound 5B (8.95 mg, 17.27 μmol, 9.24% yield, 94.26% purity, retention time=2.137) as a white solid. Compound 5A:1H NMR (400 MHz, DMSO-d6) δ 9.61 - 9.42 (m, 2H), 8.20 (br d, J = 5 4.6 Hz, 1H), 7.82 - 7.67 (m, 4H), 7.62 (br d, J = 8.4 Hz, 2H), 7.39 (br s, 2H), 7.35 - 7.28 (m, 2H), 6.86 (dd, J = 10.6, 16.9 Hz, 1H), 6.17 - 6.04 (m, 1H), 5.74 - 5.61 (m, 1H), 4.56 - 4.41 (m, 1H), 4.16 - 4.00 (m, 1H), 3.23 - 3.04 (m, 2H), 2.77 (d, J = 4.4 Hz, 3H), 2.66 (br d, J = 13.8 Hz, 1H), 2.01 - 1.89 (m, 1H), 1.85 - 1.67 (m, 2H), 1.55 - 1.40 (m, 1H). MS (ESI): m / z = 489.4 [M+H]+. 10 Compound 5B:1H NMR (400 MHz, DMSO-d6) δ 9.61 - 9.44 (m, 2H), 8.20 (br d, J = 4.4 Hz, 1H), 7.81 - 7.68 (m, 4H), 7.62 (br d, J = 8.5 Hz, 2H), 7.44 - 7.27 (m, 4H), 6.85 (dd, J = 10.6, 16.7 Hz, 1H), 6.17 - 6.04 (m, 1H), 5.75 - 5.61 (m, 1H), 4.55 - 4.43 (m, 1H), 4.16 - 3.98 (m, 1H), 3.24 - 3.06 (m, 2H), 2.77 (d, J = 4.5 Hz, 3H), 2.69 - 2.62 (m, 1H), 1.98 - 1.88 (m, 1H), 1.84 - 1.66 (m, 2H), 1.56 - 1.39 (m, 1H). MS (ESI): m / z = 489.4 [M+H]+. 15 Compound 6 a solution of tert-butyl 3-(4-aminophenyl)azetidine-1-carboxylate (200 mg, 805.41 μmol, 1 eq) 20 in THF (3 mL) and H2O (1.5 mL) was added NaHCO3 (81.19 mg, 966.49 μmol, 1.2 eq) and phenyl carbonochloridate (138.71 mg, 885.95 μmol, 111.15 μL, 1.1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound formed. The residue was diluted with H2O 5 mL and extracted with EtOAc 15 mL (5 mL × 3). The combined organic layers were 52 STDU2-43279.601 dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 3-[4- (phenoxycarbonylamino)phenyl]azetidine-1-carboxylate (330 mg, crude) as a white solid. tert-butyl 3-(4-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole- 1-carboxamido)phenyl)azetidine-1-carboxylate. A mixture of tert-butyl 3-[4- 5 (phenoxycarbonylamino)phenyl]azetidine-1-carboxylate (330 mg, 895.70 μmol, 1 eq), TEA (90.64 mg, 895.70 μmol, 124.67 μL, 1 eq) in dioxane (3 mL) was stirred at 90°C for 5 min. A mixture of 4-[(5-amino-1H-1,2,4-triazol-3-yl)amino]-N-methyl-benzamide (208.02 mg, 895.70 μmol, 1 eq), TEA (90.64 mg, 895.70 μmol, 124.67 μL, 1 eq) in dioxane (3 mL) was stirred at 90°C for 5 min. Then mixture 2 was added to mixture 1, the reaction was degassed 10 and purged with N2for 3 times, and then the mixture was stirred at 110°C for 12 hr under N2atmosphere. LCMS showed desired compound formed. The residue was diluted with H2O 5 mL and extracted with EtOAc 15 mL (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~75% Ethyl15 acetate / Petroleum ether gradient @ 80 mL / min) to give tert-butyl 3-[4-[[5-amino-3-[4- (methylcarbamoyl)anilino]-1,2,4-triazole-1-carbonyl]amino]phenyl]azetidine-1-carboxylate (250 mg, 467.87 μmol, 52.23% yield, 94.8% purity) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.49 (s, 1H), 8.24 - 8.16 (m, 1H), 7.85 - 7.69 (m, 4H), 7.66 (d, J = 8.6 Hz, 2H), 7.45 - 7.29 (m, 4H), 4.35 - 4.16 (m, 2H), 3.90 - 3.75 (m, 3H), 2.82 - 2.73 (m, 3H), 20 1.41 (s, 9H). MS (ESI): m / z = 407.2 [M+H]+. 5-amino-N-(4-(azetidin-3-yl)phenyl)-3-((4-(methylcarbamoyl)phenyl)amino)-1H- 1,2,4-triazole-1-carboxamide. To a solution of tert-butyl 3-[4-[[5-amino-3-[4- (methylcarbamoyl)anilino]-1,2,4-triazole-1-carbonyl]amino]phenyl]azetidine-1-carboxylate (100 mg, 197.41 μmol, 1 eq) in DCM (2 mL) was added TFA (0.2 mL). The mixture was stirred 25 at 25°C for 1 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure to give 5-amino-N-[4-(azetidin-3-yl)phenyl]-3-[4- (methylcarbamoyl)anilino]-1,2,4-triazole-1-carboxamide (120 mg, crude, TFA) as a yellow oil. N-(4-(1-acryloylazetidin-3-yl)phenyl)-5-amino-3-((4-30 (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5- amino-N-[4-(azetidin-3-yl)phenyl]-3-[4-(methylcarbamoyl)anilino]-1,2,4-triazole-1- carboxamide (120 mg, 230.56 μmol, 1 eq, TFA) in THF (2 mL) and H2O (1 mL) was added NaHCO3 (58.11 mg, 691.69 μmol, 3 eq) and prop-2-enoyl chloride (22.95 mg, 253.62 μmol, 20.61 μL, 1.1 eq) at 0°C. The mixture was stirred at 0°C for 1 hr. LCMS showed desired 53 STDU2-43279.601 compound formed. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 100×30mm×5μm;mobile phase: [H2O(0.1% TFA)-ACN];gradient:15%-45% B over 8.0 min) to give N-(4-(1-acryloylazetidin-3-yl)phenyl)-5-amino-3-((4- 5 (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (57.72 mg, 124.59 μmol, 54.04% yield, 99.4% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 9.50 (s, 1H), 8.20 (br d, J = 4.5 Hz, 1H), 7.82 - 7.62 (m, 6H), 7.39 (br d, J = 8.5 Hz, 4H), 6.37 (dd, J = 10.3, 17.0 Hz, 1H), 6.14 (dd, J = 2.2, 16.9 Hz, 1H), 5.77 - 5.65 (m, 1H), 4.63 (t, J = 8.4 Hz, 1H), 4.41 - 4.29 (m, 1H), 4.22 (dd, J = 5.8, 8.3 Hz, 1H), 3.97 - 3.90 (m, 2H), 2.76 (d, J 10 = 4.4 Hz, 3H). MS (ESI): m / z = 461.3 [M+H]+. Compound 7 f 4-15 bromoaniline (1 g, 5.81 mmol, 1 eq), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-2,5-dihydropyrrole-1-carboxylate (2.06 g, 6.98 mmol, 1.2 eq), K2CO3(1.61 g, 11.63 mmol, 2 eq), Pd(dppf)Cl2 (425.35 mg, 581.32 μmol, 0.1 eq) in dioxane (12 mL) and H2O (3 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2 atmosphere. LCMS showed desired compound formed. The residue was diluted with 20 H2O 10 mL and extracted with EtOAc 30 mL (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~10% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert-butyl 3-(4- aminophenyl)-2,5-dihydropyrrole-1-carboxylate (770 mg, 2.87 mmol, 49.35% yield, 97% 25 purity) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ 7.20 (d, J = 8.5 Hz, 2H), 54 STDU2-43279.601 6.67 (d, J = 8.4 Hz, 2H), 6.01 - 5.86 (m, 1H), 4.51 - 4.38 (m, 2H), 4.32 - 4.20 (m, 2H), 1.51 (d, J = 5.6 Hz, 9H). MS (ESI): m / z = 205.2 [M+H]+. tert-butyl 3-(4-((phenoxycarbonyl)amino)phenyl)-2,5-dihydro-1H-pyrrole-1- carboxylate. To a solution of tert-butyl 3-(4-aminophenyl)-2,5-dihydropyrrole-1-carboxylate 5 (500 mg, 1.92 mmol, 1 eq) in THF (10 mL) and H2O (5 mL) was added NaHCO3 (193.62 mg, 2.30 mmol, 1.2 eq). Then phenyl carbonochloridate (330.78 mg, 2.11 mmol, 265.05 μL, 1.1 eq) was added at 0°C. The mixture was stirred at 0 C for 1 hr. LCMS showed desired compound formed. The residue was diluted with H2O 10 mL and extracted with EtOAc 30 mL (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under10 reduced pressure to give tert-butyl 3-[4-(phenoxycarbonylamino)phenyl]-2,5-dihydropyrrole- 1-carboxylate (700 mg, crude) as a yellow solid. tert-butyl 3-(4-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole- 1-carboxamido)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate. A mixture of tert-butyl 3-[4- (phenoxycarbonylamino)phenyl]-2,5-dihydropyrrole-1-carboxylate (610 mg, 1.60 mmol, 1 15 eq), TEA (162.25 mg, 1.60 mmol, 223.18 μL, 1 eq) in dioxane (10 mL) was stirred at 90°C for 5 min to get mixture 1. Meantime, a mixture of 4-[(5-amino-1H-1,2,4-triazol-3-yl)amino]-N- methyl-benzamide (372.38 mg, 1.60 mmol, 1 eq), TEA (162.25 mg, 1.60 mmol, 223.18 μL, 1 eq) in dioxane (5 mL) was stirred at 90°C for 5 min. Then mixture 2 was added to mixture 1 at 90°C, the reaction was degassed and purged with N2for 3 times, and then stirred at 110°C for 20 12 hr under N2 atmosphere. LCMS showed desired compound formed. The mixture was filtered and concentrated under reduced pressure to give tert-butyl 3-[4-[[5-amino-3-[4- (methylcarbamoyl)anilino]-1,2,4-triazole-1-carbonyl]amino]phenyl]-2,5-dihydropyrrole-1- carboxylate (780 mg, crude) as a white solid. MS (ESI): m / z = 419.3 [M+H]+. 5-amino-N-(4-(2,5-dihydro-1H-pyrrol-3-yl)phenyl)-3-((4- 25 (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. A solution of tert-butyl 3-[4-[[5-amino-3-[4-(methylcarbamoyl)anilino]-1,2,4-triazole-1-carbonyl]amino]phenyl]-2,5- dihydropyrrole-1-carboxylate (200 mg, 385.68 μmol, 1 eq) in HCl / EtOAc (3 mL, 4M) was stirred at 25°C for 1 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure to give 5-amino-N-[4-(2,5-dihydro-1H-pyrrol-3- 30 yl)phenyl]-3-[4-(methylcarbamoyl)anilino]-1,2,4-triazole-1-carboxamide (140 mg, crude, HCl) as a purple solid. N-(4-(1-acryloyl-2,5-dihydro-1H-pyrrol-3-yl)phenyl)-5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5- amino-N-[4-(2,5-dihydro-1H-pyrrol-3-yl)phenyl]-3-[4-(methylcarbamoyl)anilino]-1,2,4- 55 STDU2-43279.601 triazole-1-carboxamide (140 mg, 307.75 μmol, 1 eq, HCl) in THF (2 mL) / H2O (1 mL) was added NaHCO3(77.56 mg, 923.26 μmol, 3 eq). Then prop-2-enoyl chloride (30.64 mg, 338.53 μmol, 27.50 μL, 1.1 eq) was added at 0°C. The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced 5 pressure. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18100×30mm×5μm;mobile phase: [H2O(0.1% TFA)-ACN];B%:0%, isocratic elution mode) to give N-(4-(1-acryloyl-2,5-dihydro-1H-pyrrol-3-yl)phenyl)-5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (26.57 mg, 50.08 μmol, 16.27% yield, 89.05% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 10 9.50 (s, 1H), 8.26 - 8.12 (m, 1H), 7.84 - 7.65 (m, 6H), 7.55 (dd, J = 2.2, 8.7 Hz, 2H), 7.41 (br s, 2H), 6.83 - 6.57 (m, 1H), 6.48 - 6.36 (m, 1H), 6.22 (dd, J = 2.3, 16.8 Hz, 1H), 5.74 (ddd, J = 2.3, 6.0, 10.2 Hz, 1H), 4.79 (br d, J = 2.0 Hz, 1H), 4.56 (br d, J = 2.6 Hz, 2H), 4.34 (br d, J = 2.6 Hz, 1H), 2.76 (d, J = 4.4 Hz, 3H). MS (ESI): m / z = 473.3 [M+H]+. 15 Compound 8 NH2 N NH HN N 250 mg, 10% purity) in THF (10 mL) was added tert-butyl 3-(4-aminophenyl)-2,5-dihydropyrrole- 1-carboxylate (500 mg, 1.92 mmol, 1 eq) under N2 atmosphere. The suspension was degassed 20 and purged with H2for 3 times. The mixture was stirred under H2(15 Psi) at 25 °C for 4 hr. LCMS showed desired compound formed. The mixture was filtered and concentrated under reduced pressure to give tert-butyl 3-(4-aminophenyl)pyrrolidine-1-carboxylate (530 mg, crude) as brown oil. tert-butyl 3-(4-((phenoxycarbonyl)amino)phenyl)pyrrolidine-1-carboxylate. To a 25 solution of tert-butyl 3-(4-aminophenyl)pyrrolidine-1-carboxylate (530 mg, 2.02 mmol, 1 eq) 56 STDU2-43279.601 in THF (10 mL) / H2O (5 mL) was added NaHCO3(203.66 mg, 2.42 mmol, 1.2 eq). Then phenyl carbonochloridate (347.93 mg, 2.22 mmol, 278.79 μL, 1.1 eq) was added at 0°C. The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound formed. The residue was diluted with H2O 5 mL and extracted with EtOAC 15 mL (5 mL × 3). The combined organic layers 5 were dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 3- [4-(phenoxycarbonylamino)phenyl]pyrrolidine-1-carboxylate (660 mg, crude) as a brown solid. tert-butyl 3-(4-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole- 1-carboxamido)phenyl)pyrrolidine-1-carboxylate. A mixture of tert-butyl 3-[4- 10 (phenoxycarbonylamino)phenyl]pyrrolidine-1-carboxylate (660 mg, 1.73 mmol, 1 eq), TEA (174.62 mg, 1.73 mmol, 240.20 μL, 1 eq) in dioxane (10 mL) was stirred at 90°C for 5 min to get mixture 1. Meantime, a mixture of 4-[(5-amino-1H-1,2,4-triazol-3-yl)amino]-N-methyl- benzamide (400.78 mg, 1.73 mmol, 1 eq), TEA (174.62 mg, 1.73 mmol, 240.20 μL, 1 eq) in dioxane (5 mL) was stirred at 90°C for 5 min. Then mixture 2 was added to mixture 1, the 15 reaction was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110°C for 12 hr under N2 atmosphere. LCMS showed desired compound formed. The residue was diluted with H2O 15 mL and extracted with EtOAc 30 mL (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica Flash20 Column, Eluent of 0~30% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert- butyl 3-[4-[[5-amino-3-[4-(methylcarbamoyl)anilino]-1,2,4-triazole-1- carbonyl]amino]phenyl]pyrrolidine-1-carboxylate (400 mg, 683.85 μmol, 39.63% yield, 89% purity) as a yellow solid. MS (ESI): m / z = 421.3 [M+H]+. 5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-N-(4-(pyrrolidin-3-yl)phenyl)-1H-25 1,2,4-triazole-1-carboxamide. A solution of tert-butyl 3-[4-[[5-amino-3-[4- (methylcarbamoyl)anilino]-1,2,4-triazole-1-carbonyl]amino]phenyl]pyrrolidine-1-carboxylate (200 mg, 384.19 μmol, 1 eq) in HCl / EtOAc (3 mL,4M) was stirred at 25°C for 0.5 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure to give 5-amino-3-[4-(methylcarbamoyl)anilino]-N-(4-pyrrolidin-3-ylphenyl)-1,2,4- 30 triazole-1-carboxamide (200 mg, crude, HCl) as a yellow solid. N-(4-(1-acryloylpyrrolidin-3-yl)phenyl)-5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5- amino-3-[4-(methylcarbamoyl)anilino]-N-(4-pyrrolidin-3-ylphenyl)-1,2,4-triazole-1- carboxamide (200 mg, 437.71 μmol, 1 eq, HCl) in THF (2 mL) / H2O (1 mL) was added 57 STDU2-43279.601 NaHCO3(110.31 mg, 1.31 mmol, 3 eq). Then prop-2-enoyl chloride (43.58 mg, 481.48 μmol, 39.12 μL, 1.1 eq) was adde at 0°C. The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (TFA condition; column: 5 Phenomenex Luna C18 100×30mm×5μm;mobile phase: [H2O(0.1% TFA)- ACN];gradient:15%-45% B over 8.0 min) to give N-(4-(1-acryloylpyrrolidin-3-yl)phenyl)-5- amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (96.12 mg, 198.92 μmol, 45.45% yield, 98.20% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 9.49 (s, 1H), 8.20 (br d, J = 4.8 Hz, 1H), 7.80 - 7.68 (m, 4H), 7.62 (dd, J = 3.3, 10 8.4 Hz, 2H), 7.45 - 7.28 (m, 4H), 6.63 (ddd, J = 2.7, 10.3, 16.8 Hz, 1H), 6.16 (ddd, J = 2.4, 4.7, 16.7 Hz, 1H), 5.74 - 5.59 (m, 1H), 3.96 - 3.76 (m, 2H), 3.73 - 3.55 (m, 1H), 3.51 - 3.42 (m, 1H), 3.41 - 3.25 (m, 1H), 2.76 (d, J = 4.4 Hz, 3H), 2.38 - 2.18 (m, 1H), 2.11 - 1.88 (m, 1H). MS (ESI): m / z = 475.3 [M+H]+. 15 Compound 9 dihydro- 1H-pyrrol-3-yl)phenyl)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5-amino-N-[4- (2,5-dihydro-1H-pyrrol-3-yl)phenyl]-3-[4-(methylcarbamoyl)anilino]-1,2,4-triazole-1- 20 carboxamide (50 mg, 109.91 μmol, 1 eq, HCl) in DMF (2 mL) was added DIEA (42.62 mg, 329.73 μmol, 57.43 μL, 3 eq), prop-2-ynoic acid (7.70 mg, 109.91 μmol, 6.77 μL, 1 eq) and HATU (45.97 mg, 120.90 μmol, 1.1 eq). The mixture was stirred at 25°C for 1 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA condition;column: Phenomenex luna 25 C18100 × 40mm × 5 μm;mobile phase: [H2O(0.2% FA)-ACN];gradient:20%-50% B over 8.0 min ) to give 5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-N-(4-(1-propioloyl-2,5- dihydro-1H-pyrrol-3-yl)phenyl)-1H-1,2,4-triazole-1-carboxamide (5.04 mg, 10.71 μmol, 9.75% yield, 100% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.69 (d, J = 4.8 Hz, 1H), 9.51 (s, 1H), 8.21 (br d, J = 4.3 Hz, 1H), 7.82 - 7.69 (m, 6H), 7.54 (br dd, J = 4.1, 8.5 58 STDU2-43279.601 Hz, 2H), 7.47 - 7.32 (m, 2H), 6.41 (br s, 1H), 4.79 (br s, 1H), 4.64 - 4.49 (m, 3H), 4.30 (br s, 1H), 2.77 (d, J = 4.5 Hz, 3H). MS (ESI): m / z = 471.2 [M+H]+. Compound 10 5 f 1- bromo-4-iodo-benzene (5 g, 17.67 mmol, 1 eq) in THF (50 mL) was cooled to -78°C. Then n- BuLi (2.5 M, 7.42 mL, 1.05 eq) was added at N2 atmosphere. After 15 min, tert-butyl 3- oxopiperidine-1-carboxylate (3.52 g, 17.67 mmol, 1 eq) in THF (30 mL) was added. The 10 mixture was stirred at -78°C for 2 hr. LCMS showed desired compound formed. The reaction mixture was quenched by addition NH4Cl solution (20mL), and then diluted with H2O (30 mL) and extracted with EtOAc 120 mL (40 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~7% Ethyl15 acetate / Petroleum ether gradient @ 80 mL / min) to give tert-butyl 3-(4-bromophenyl)-3- hydroxy-piperidine-1-carboxylate (3.3 g, 8.21 mmol, 46.46% yield) as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ 7.52 - 7.49 (m, 1H), 7.49 - 7.47 (m, 1H), 7.42 - 7.40 (m, 1H), 7.39 - 7.37 (m, 1H), 4.01 (s, 2H), 3.59 (t, J = 6.0 Hz, 1H), 3.13 (br d, J = 13.6 Hz, 1H), 2.86 (br t, J = 12.4 Hz, 1H), 2.02 - 1.94 (m, 1H), 1.93 - 1.84 (m, 2H), 1.68 - 1.55 (m, 1H), 1.47 (d, 20 J = 1.9 Hz, 9H). tert-butyl 3-(4-((diphenylmethylene)amino)phenyl)-3-hydroxypiperidine-1- carboxylate. A mixture of tert-butyl 3-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylate 59 STDU2-43279.601 (2 g, 5.61 mmol, 1 eq) , diphenylmethanimine (1.53 g, 8.42 mmol, 1.41 mL, 1.5 eq) , t-BuONa (1.08 g, 11.23 mmol, 2 eq) , BINAP (699.13 mg, 1.12 mmol, 0.2 eq) and Pd2(dba)3(514.08 mg, 561.40 μmol, 0.1 eq) in toluene (20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 4 hr under N2atmosphere. LCMS showed desired 5 compound formed. The residue was diluted with H2O 20 mL and extracted with EtOAc 60 mL (20 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~15% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert-butyl 3-[4-(benzhydrylideneamino)phenyl]-3-hydroxy- 10 piperidine-1-carboxylate (1.89 g, 1.56 mmol, 27.72% yield) as a yellow oil. tert-butyl 3-(4-aminophenyl)-3-hydroxypiperidine-1-carboxylate. To a solution of tert-butyl 3-[4-(benzhydrylideneamino)phenyl]-3-hydroxy-piperidine-1-carboxylate (1.89 g, 4.14 mmol, 1 eq) in MeOH (20 mL) was added NaOAc (1.02 g, 12.42 mmol, 3 eq) and NH2OH.HCl (661.62 mg, 9.52 mmol, 2.3 eq). The mixture was stirred at 60°C for 1 hr. LCMS 15 showed desired compound formed. The residue was diluted with H2O 10 mL and extracted with EtOAc 30 mL (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~16% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give tert-butyl 3-(4-aminophenyl)-3-hydroxy-piperidine-1- 20 carboxylate (720 mg, 2.22 mmol, 53.57% yield) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ 7.32 (d, J = 8.5 Hz, 2H), 6.85 (br d, J = 7.0 Hz, 2H), 4.03 (br d, J = 12.4 Hz, 2H), 3.14 (br d, J = 13.5 Hz, 1H), 2.98 - 2.76 (m, 1H), 2.01 - 1.80 (m, 3H), 1.62 - 1.53 (m, 1H), 1.49 - 1.44 (m, 9H). tert-butyl 3-hydroxy-3-(4-((phenoxycarbonyl)amino)phenyl)piperidine-1-25 carboxylate. To a solution of tert-butyl 3-(4-aminophenyl)-3-hydroxy-piperidine-1- carboxylate (300 mg, 1.03 mmol, 1 eq) in THF (3 mL) / H2O (1 mL) was added NaHCO3 (103.44 mg, 1.23 mmol, 1.2 eq). Then phenyl carbonochloridate (176.72 mg, 1.13 mmol, 141.60 μL, 1.1 eq) was added at 0°C. The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound formed. The residue was diluted with H2O 10 mL and extracted with EtOAc 30 15 mL (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 3-hydroxy-3-[4- (phenoxycarbonylamino)phenyl]piperidine-1-carboxylate (460 mg, crude) as a yellow solid. tert-butyl 3-(4-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole- 1-carboxamido)phenyl)-3-hydroxypiperidine-1-carboxylate. A mixture of tert-butyl 3- 60 STDU2-43279.601 hydroxy-3-[4-(phenoxycarbonylamino)phenyl]piperidine-1-carboxylate (460 mg, 1.12 mmol, 1 eq), TEA (112.85 mg, 1.12 mmol, 155.22 μL, 1 eq) in dioxane (5 mL) was stirred at 90°C for 5 min to get mixture 1. Meantime, a mixture of 4-[(5-amino-1H-1,2,4-triazol-3-yl)amino]- N-methyl-benzamide (259.00 mg, 1.12 mmol, 1 eq), TEA (112.85 mg, 1.12 mmol, 155.22 μL, 5 1 eq) in dioxane (5 mL) was stirred at 90°C for 5 min. Then mixture 2 was added to the mixture 1 at 90°C. The reaction was degassed and purged with N2for 3 times, and then the mixture was stirred at 110°C for 12 hr under N2 atmosphere. LCMS showed desired compound formed. The residue was diluted with H2O 10 mL and extracted with EtOAc 15 mL (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced 10 pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~80% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert-butyl 3-[4-[[5-amino-3-[4-(methylcarbamoyl)anilino]-1,2,4-triazole-1- carbonyl]amino]phenyl]-3-hydroxy-piperidine-1-carboxylate (280 mg, 437.33 μmol, 39.22% yield) as a yellow solid. MS (ESI): m / z = 551.5 [M+H]+15 5-amino-N-(4-(3-hydroxypiperidin-3-yl)phenyl)-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. A solution of tert-butyl 3-[4-[[5-amino-3-[4-(methylcarbamoyl)anilino]-1,2,4-triazole-1-carbonyl]amino]phenyl]-3- hydroxy-piperidine-1-carboxylate (120 mg, 217.94 μmol, 1 eq) in HCl / EtOAc (1.5 mL, 4M) was stirred at 25°C for 1 hr. LCMS showed desired compound formed. The reaction mixture20 was concentrated under reduced pressure to give 5-amino-N-[4-(3-hydroxy-3- piperidyl)phenyl]-3-[4-(methylcarbamoyl)anilino]-1,2,4-triazole-1-carboxamide (100 mg, crude, HCl) as a white solid. N-(4-(1-acryloyl-3-hydroxypiperidin-3-yl)phenyl)-5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5-25 amino-N-[4-(3-hydroxy-3-piperidyl)phenyl]-3-[4-(methylcarbamoyl)anilino]-1,2,4-triazole- 1-carboxamide (100 mg, 205.36 μmol, 1 eq, HCl) in THF (1 mL) / H2O (1 mL) was added NaHCO3 (51.75 mg, 616.08 μmol, 3 eq). Then prop-2-enoyl chloride (20.45 mg, 225.89 μmol, 18.35 μL, 1.1 eq) was added at 0°C. The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound formed. The reaction mixture was dried under N2 flow to the remove the 30 solvent. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18100×30mm×5μm;mobile phase: [H2O(0.1% TFA)-ACN];gradient:15%-45% B over 8.0 min ) to give N-(4-(1-acryloyl-3-hydroxypiperidin-3-yl)phenyl)-5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (55.04 mg, 109.09 μmol, 53.12% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.51 (s, 1H), 61 STDU2-43279.601 8.21 (br d, J = 4.5 Hz, 1H), 7.81 - 7.69 (m, 4H), 7.68 - 7.60 (m, 2H), 7.58 - 7.51 (m, 2H), 7.41 (br s, 2H), 6.91 - 6.70 (m, 1H), 6.15 - 6.00 (m, 1H), 5.70 - 5.56 (m, 1H), 4.46 (br d, J = 12.6 Hz, 1H), 4.11 (br d, J = 13.3 Hz, 1H), 3.74 (br d, J = 14.0 Hz, 1H), 3.42 (d, J = 13.6 Hz, 1H), 3.30 - 3.11 (m, 1H), 2.76 (d, J = 4.4 Hz, 3H), 2.12 - 1.98 (m, 1H), 1.93 - 1.79 (m, 1H), 1.75 (br 5 d, J = 13.1 Hz, 1H), 1.57 - 1.45 (m, 1H). MS (ESI): m / z = 505.2 [M+H]+. Compound 11 of 10 tert-butyl 3-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylate (2 g, 5.61 mmol, 1 eq) in THF (30 mL) was added NaH (336.81 mg, 8.42 mmol, 60% purity, 1.5 eq) at 0°C and stirred for 30 min, and then MeI (3.98 g, 28.07 mmol, 1.75 mL, 5 eq) was added to the mixture. The resulting mixture was stirred at 25°C for 3 hr under N2 atmosphere. TLC indicated the reaction was completed. The residue was diluted with 30 mL NH4Cl solution and extracted with EtOAc 15 (30 mL × 2), The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (40 g Silica Flash Column, Eluent of 0~4% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give tert-butyl 3-(4-bromophenyl)-3-methoxypiperidine-1- carboxylate (1.74 g, 4.59 mmol, 81.77% yield, 97.69% purity) as a white solid.1H NMR (400 20 MHz, CHLOROFORM-d) δ 7.50 (d, J = 8.4 Hz, 2H), 7.30 (br d, J = 8.1 Hz, 2H), 4.09 - 3.77 (m, 2H), 3.42 - 3.19 (m, 1H), 3.10 - 2.85 (m, 4H), 2.09 - 2.03 (m, 1H), 1.83 (br d, J = 10.0 Hz, 2H), 1.66 - 1.59 (m, 1H), 1.48 (s, 9H). tert-butyl 3-(4-((diphenylmethylene)amino)phenyl)-3-methoxypiperidine-1- carboxylate. A mixture of tert-butyl 3-(4-bromophenyl)-3-methoxy-piperidine-1-carboxylate 62 STDU2-43279.601 (1.74 g, 4.70 mmol, 1 eq), diphenylmethanimine (1.02 g, 5.64 mmol, 946.26 μL, 1.2 eq), t- BuONa (903.21 mg, 9.40 mmol, 2 eq), BINAP (585.20 mg, 939.83 μmol, 0.2 eq) and Pd2(dba)3(430.31 mg, 469.91 μmol, 0.1 eq) in toluene (30 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 12 hr under N2atmosphere. LCMS showed 5 desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (40 g Silica Flash Column, Eluent of 0~15% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give tert-butyl 3-(4-((diphenylmethylene)amino)phenyl)-3- methoxypiperidine-1-carboxylate (2.18 g, 3.10 mmol, 66.05% yield, 67% purity) as yellow oil. 101H NMR (400 MHz, CHLOROFORM-d) δ 7.77 (d, J = 7.4 Hz, 2H), 7.53 - 7.47 (m, 1H), 7.46 - 7.40 (m, 2H), 7.27-7.15 (m, 3H), 7.12 (br d, J = 6.8 Hz, 2H), 6.74 (br d, J = 7.1 Hz, 2H), 4.10 - 3.74 (m, 2H), 3.24 (br s, 1H), 3.07 - 2.92 (m, 1H), 2.88 (s, 3H), 2.08 - 1.99 (m, 1H), 1.89 - 1.72 (m, 2H), 1.61 - 1.53 (m, 1H), 1.51 - 1.44 (m, 9H). MS (ESI): m / z = 471.3 [M+H]+. tert-butyl 3-(4-aminophenyl)-3-methoxypiperidine-1-carboxylate. To a solution of 15 tert-butyl 3-(4-((diphenylmethylene)amino)phenyl)-3-methoxypiperidine-1-carboxylate (2.18 g, 4.63 mmol, 1 eq) in MeOH (20 mL) was added NH2OH.HCl (965.72 mg, 13.90 mmol, 3 eq) and NaOAc (874.03 mg, 10.65 mmol, 2.3 eq). The mixture was stirred at 60°C for 3 hr. LCMS showed desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel 20 chromatography (40 g Silica Flash Column, Eluent of 0~12% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give tert-butyl 3-(4-aminophenyl)-3-methoxy-piperidine-1- carboxylate (700 mg, 2.01 mmol, 43.40% yield, 88% purity) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) δ 7.23 (br s, 2H), 6.75 (d, J = 8.4 Hz, 2H), 4.68 - 4.23 (m, 1H), 4.18 - 3.75 (m, 2H), 3.33 - 3.18 (m, 1H), 3.08 - 2.85 (m, 4H), 2.06 (br d, J = 11.9 Hz, 1H), 1.82 (br 25 s, 2H), 1.48 (s, 9H). tert-butyl 3-methoxy-3-(4-((phenoxycarbonyl)amino)phenyl)piperidine-1- carboxylate. To a solution of tert-butyl 3-(4-aminophenyl)-3-methoxy-piperidine-1- carboxylate (300 mg, 979.12 μmol, 1 eq) in THF (4 mL) / H2O (2 mL) was added phenyl carbonochloridate (183.96 mg, 1.17 mmol, 147.40 μL, 1.2 eq) and NaHCO3 (90.48 mg, 1.08 30 mmol, 1.1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound was detected. The residue was diluted with H2O 3 mL and extracted with EtOAc (3 mL × 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 3-methoxy-3-(4-((phenoxycarbonyl)amino)phenyl)piperidine-1- carboxylate (350 mg, crude) as a yellow oil. 63 STDU2-43279.601 tert-butyl 3-(4-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole- 1-carboxamido)phenyl)-3-methoxypiperidine-1-carboxylate. A mixture of 4-[(5-amino-1H- 1,2,4-triazol-3-yl)amino]-N-methyl-benzamide (190.58 mg, 820.62 μmol, 1 eq) and TEA (83.04 mg, 820.62 μmol, 114.22 μL, 1 eq) in dioxane (3 mL) was stirred at 90°C for 10 min to 5 get mixture 1. Meantime, a mixture of tert-butyl 3-methoxy-3-(4- ((phenoxycarbonyl)amino)phenyl)piperidine-1-carboxylate (350 mg, 820.62 μmol, 1 eq) and TEA (83.04 mg, 820.62 μmol, 114.22 μL, 1 eq) in dioxane (3 mL) was stirred at 90°C for 10 min get mixture 2. Then mixture 1was added to mixture 2 at 90 °C and the reaction was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110°C for 12 hr 10 under N2atmosphere. LCMS showed desired compound was detected. The reaction mixture was filtered and the solid was dried under reduced pressure to give tert-butyl 3-[4-[[5-amino- 3-[4-(methylcarbamoyl)anilino]-1,2,4-triazole-1-carbonyl]amino]phenyl]-3-methoxy- piperidine-1-carboxylate (100 mg, crude) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 9.50 (s, 1H), 8.20 (br d, J = 4.5 Hz, 1H), 7.80 - 7.65 (m, 5H), 7.41 (br d, J = 8.8 15 Hz, 4H), 4.12 - 3.95 (m, 2H), 3.91 - 3.77 (m, 1H), 3.17 (d, J = 5.1 Hz, 1H), 2.94 - 2.85 (m, 3H), 2.76 (d, J = 4.4 Hz, 3H), 2.08 - 2.00 (m, 1H), 1.91 - 1.79 (m, 1H), 1.77 - 1.62 (m, 1H), 1.41 (s, 10H). MS (ESI): m / z = 587.3 [M+Na]+. 5-amino-N-(4-(3-methoxypiperidin-3-yl)phenyl)-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. Tert-butyl 3-[4-[[5-20 amino-3-[4-(methylcarbamoyl)anilino]-1,2,4-triazole-1-carbonyl]amino]phenyl]-3-methoxy- piperidine-1-carboxylate (100 mg, 177.11 μmol, 1 eq) in HCl / EtOAc (3 mL, 4 M) was stirred at 25°C for 1 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent to give 5-amino-N-(4-(3- methoxypiperidin-3-yl)phenyl)-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1- 25 carboxamide (80 mg, crude, HCl) as a white solid. N-(4-(1-acryloyl-3-methoxypiperidin-3-yl)phenyl)-5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5- amino-N-(4-(3-methoxypiperidin-3-yl)phenyl)-3-((4-(methylcarbamoyl)phenyl)amino)-1H- 1,2,4-triazole-1-carboxamide (80 mg, 159.69 μmol, 1 eq, HCl) in THF (2 mL) / H2O (1 mL) was 30 added NaHCO3(40.24 mg, 479.06 μmol, 3 eq) and prop-2-enoyl chloride (14.45 mg, 159.69 μmol, 12.97 μL, 1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex luna C18 100×40mm×3 μm;mobile phase: [H2O(0.1% TFA)-ACN]; 64 STDU2-43279.601 gradient:25%-50% B over 8.0 min) to give N-(4-(1-acryloyl-3-methoxypiperidin-3-yl)phenyl)- 5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (28.05 mg, 53.16 μmol, 33.29% yield, 98.27% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.63 (br d, J = 3.3 Hz, 1H), 9.50 (s, 1H), 8.20 (br d, J = 4.4 Hz, 1H), 7.79 - 7.74 (m, 2H), 7.74 5 - 7.67 (m, 4H), 7.52 - 7.33 (m, 4H), 6.86 (td, J = 10.1, 16.6 Hz, 1H), 6.10 (dd, J = 1.1, 16.6 Hz, 1H), 5.66 (br t, J = 9.4 Hz, 1H), 4.56 - 4.39 (m, 1H), 4.11 - 3.92 (m, 1H), 3.31 - 3.12 (m, 2H), 2.87 (br d, J = 6.5 Hz, 3H), 2.76 (br d, J = 4.1 Hz, 4H), 2.25 - 1.87 (m, 2H), 1.82 - 1.47 (m, 2H). MS (ESI): m / z = 519.4 [M+H]+. 10 Compound 12 -1- carboxylate. A mixture of tert-butyl 3-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylate (2.5 g, 7.02 mmol, 1 eq), diphenylmethanimine (1.91 g, 10.53 mmol, 1.77 mL, 1.5 eq), t- 15 BuONa (1.35 g, 14.03 mmol, 2 eq), BINAP (873.91 mg, 1.40 mmol, 0.2 eq) and Pd2(dba)3(642.60 mg, 701.75 μmol, 0.1 eq) in toluene (30 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 12 hr under N2atmosphere. LCMS showed desired compound formed. The residue was diluted with H2O 20 mL and extracted with EtOAc 60 mL (20 mL × 3). The combined organic layers were washed with brine 60 mL (20 mL × 3), 20 dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~15% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert-butyl 3-[4- 65 STDU2-43279.601 (benzhydrylideneamino)phenyl]-3-hydroxy-piperidine-1-carboxylate (1.4 g, 674.59 μmol, 9.61% yield, 22% purity) as a white solid. tert-butyl 3-(4-aminophenyl)-3-hydroxypiperidine-1-carboxylate. To a solution of tert-butyl 3-[4-(benzhydrylideneamino)phenyl]-3-hydroxy-piperidine-1-carboxylate (1.4 g, 5 3.07 mmol, 1 eq) in MeOH (15 mL) was added NaOAc (754.62 mg, 9.20 mmol, 3 eq) and NH2OH.HCl (490.09 mg, 7.05 mmol, 2.3 eq). The mixture was stirred at 60°C for 1 hr. LCMS showed desired compound formed. The residue was diluted with H2O 10 mL and extracted with EtOAc 30 mL (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash 10 silica gel chromatography (20 g Silica Flash Column, Eluent of 0~16% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give tert-butyl 3-(4-aminophenyl)-3-hydroxy-piperidine-1- carboxylate (430 mg, 1.47 mmol, 47.96% yield) as a yellow solid. tert-butyl 3-hydroxy-3-(4-((phenoxycarbonyl)amino)phenyl)piperidine-1- carboxylate. To a solution of tert-butyl 3-(4-aminophenyl)-3-hydroxy-piperidine-1- 15 carboxylate (430 mg, 1.47 mmol, 1 eq) in THF (6 mL) / H2O (2 mL) was added NaHCO3 (148.27 mg, 1.76 mmol, 1.2 eq). Then phenyl carbonochloridate (253.29 mg, 1.62 mmol, 202.96 μL, 1.1 eq) was added at 0°C. The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound formed. The residue was diluted with H2O 10 mL and extracted with EtOAc 15 mL (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered and20 concentrated under reduced pressure to give tert-butyl 3-hydroxy-3-[4- (phenoxycarbonylamino)phenyl]piperidine-1-carboxylate (520 mg, crude) as a yellow solid. tert-butyl 3-(4-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole- 1-carboxamido)phenyl)-3-hydroxypiperidine-1-carboxylate. A mixture of tert-butyl 3- hydroxy-3-[4-(phenoxycarbonylamino)phenyl]piperidine-1-carboxylate (520 mg, 1.26 mmol, 25 1 eq), TEA (127.57 mg, 1.26 mmol, 175.47 μL, 1 eq) in dioxane (6 mL) was stirred at 90 °C for 5 min to get mixture 1. Meantime, a mixture of 4-[(5-amino-1H-1,2,4-triazol-3-yl)amino]- N-methyl-benzamide (292.78 mg, 1.26 mmol, 1 eq), TEA (127.57 mg, 1.26 mmol, 175.47 μL, 1 eq) in dioxane (5 mL) was stirred at 90 °C for 5 min to get mixture 2. Then mixture 2 was added to mixture 1 at 90 °C, the reaction was degassed and purged with N2 for 3 times, and 30 then the mixture was stirred at 110°C for 12 hr under N2atmosphere. LCMS showed desired compound formed. The residue was diluted with H2O 10 mL and extracted with EtOAc 15 mL (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~80% Ethyl acetate / Petroleum ether 66 STDU2-43279.601 gradient @ 80 mL / min) to give tert-butyl 3-[4-[[5-amino-3-[4-(methylcarbamoyl)anilino]- 1,2,4-triazole-1-carbonyl]amino]phenyl]-3-hydroxy-piperidine-1-carboxylate (220 mg, 292.48 μmol, 23.20% yield, 73.2% purity) as a yellow solid. MS (ESI): m / z = 551.5 [M+H]+. tert-butyl 3-(4-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole- 5 1-carboxamido)phenyl)-3-fluoropiperidine-1-carboxylate. To a solution of tert-butyl 3-[4- [[5-amino-3-[4-(methylcarbamoyl)anilino]-1,2,4-triazole-1-carbonyl]amino]phenyl]-3- hydroxy-piperidine-1-carboxylate (338 mg, 613.87 μmol, 1 eq) in DCM (5 mL) was added DAST (148.42 mg, 920.80 μmol, 121.66 μL, 1.5 eq) at 0°C. The mixture was stirred at 0°C for 0.5 hr. LCMS showed desired compound formed. The residue was diluted with NaHCO3 10 solution 5 mL and extracted with DCM 15 mL (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18 100×40mm×5 μm; mobile phase: [H2O(0.2% FA)-ACN]; gradient:40%-70% B over 8.0 min) to give tert-butyl 3-[4-[[5-amino-3-[4-(methylcarbamoyl)anilino]-1,2,4-triazole-1- 15 carbonyl]amino]phenyl]-3-fluoro-piperidine-1-carboxylate (15 mg, 27.14 μmol, 4.42% yield, 100% purity) as a white solid. MS (ESI): m / z = 553.3 [M+H]+5-amino-N-(4-(3-fluoropiperidin-3-yl)phenyl)-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. A solution of tert-butyl 3-[4-[[5-amino-3-[4-(methylcarbamoyl)anilino]-1,2,4-triazole-1-carbonyl]amino]phenyl]-3- 20 fluoro-piperidine-1-carboxylate (25 mg, 45.24 μmol, 1 eq) in HCl / EtOAc (1.5 mL, 4M) was stirred at 25°C for 1 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure to give 5-amino-N-[4-(3-fluoro-3-piperidyl)phenyl]-3-[4- (methylcarbamoyl)anilino]-1,2,4-triazole-1-carboxamide (34 mg, crude, HCl) as a white solid. N-(4-(1-acryloyl-3-fluoropiperidin-3-yl)phenyl)-5-amino-3-((4-25 (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5- amino-N-[4-(3-fluoro-3-piperidyl)phenyl]-3-[4-(methylcarbamoyl)anilino]-1,2,4-triazole-1- carboxamide (33.52 mg, 68.55 μmol, 1 eq, HCl) in THF (1 mL) / H2O (1 mL) was added NaHCO3(17.28 mg, 205.66 μmol, 3 eq) and prop-2-enoyl chloride (6.83 mg, 75.41 μmol, 6.13 μL, 1.1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound formed. 30 The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 100×30mm×5μm;mobile phase: [H2O(0.1% TFA)-ACN];gradient:20%-50% B over 8.0 min) to give N-(4-(1-acryloyl-3-fluoropiperidin-3-yl)phenyl)-5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (9.85 mg, 19.29 μmol, 67 STDU2-43279.601 28.14% yield, 99.20% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.52 (s, 1H), 8.21 (br d, J = 4.5 Hz, 1H), 7.85 - 7.65 (m, 5H), 7.57 - 7.34 (m, 3H), 6.98 - 6.73 (m, 1H), 6.12 (br d, J = 16.6 Hz, 1H), 5.78 - 5.57 (m, 1H), 4.64 - 4.49 (m, 2H), 4.22 - 4.11 (m, 1H), 3.79 - 3.52 (m, 1H), 3.31 - 3.06 (m, 1H), 2.76 (d, J = 4.4 Hz, 3H), 2.33 - 1.95 (m, 2H), 5 1.85 - 1.62 (m, 2H). MS (ESI): m / z = 507.4 [M+H]+. Compound 13 of10 tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1- carboxylate (300 mg, 970.22 μmol, 1 eq), 4-bromoaniline (166.90 mg, 970.22 μmol, 1 eq), K2CO3(268.19 mg, 1.94 mmol, 2 eq), Pd(dppf)Cl2(70.99 mg, 97.02 μmol, 0.1 eq) in dioxane (4 mL) / H2O (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2atmosphere. LCMS showed desired compound was detected. 15 The residue was diluted with H2O 10 mL and extracted with EtOAc (30 mL × 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate=3 / 1) to give tert-butyl 5-(4-aminophenyl)-3,4-dihydropyridine-1(2H)-carboxylate (180 mg, 610.88 μmol, 62.96% yield, 93.11% purity) as a white solid.1H NMR (400 MHz, 20 CHLOROFORM-d) δ 7.21 - 7.13 (m, 3H), 6.84 (d, J = 8.5 Hz, 2H), 3.52 (br d, J = 4.4 Hz, 2H), 2.33 (br t, J = 5.8 Hz, 2H), 1.88 (br s, 2H), 1.45 (s, 9H). MS (ESI): m / z = 275.2 [M+H]+. tert-butyl 5-(4-((phenoxycarbonyl)amino)phenyl)-3,4-dihydropyridine-1(2H)- carboxylate. To a solution of tert-butyl 5-(4-aminophenyl)-3,4-dihydropyridine-1(2H)- carboxylate (180 mg, 656.08 μmol, 1 eq) in THF (2 mL) / H2O (1 mL) was added phenyl 25 carbonochloridate (123.26 mg, 787.29 μmol, 98.77 μL, 1.2 eq) and NaHCO3(60.63 mg, 721.69 68 STDU2-43279.601 μmol, 1.1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound was detected. The residue was diluted with H2O 3 mL and extracted with EtOAc (3 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 5-(4-((phenoxycarbonyl)amino)phenyl)-3,4-dihydropyridine-1(2H)- 5 carboxylate (190 mg, crude) as a yellow solid. tert-butyl 5-(4-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole- 1-carboxamido)phenyl)-3,4-dihydropyridine-1(2H)-carboxylate. A mixture of 4-[(5-amino- 1H-1,2,4-triazol-3-yl)amino]-N-methyl-benzamide (111.86 mg, 481.67 μmol, 1 eq) and TEA (48.74 mg, 481.67 μmol, 67.04 μL, 1 eq) in dioxane (2 mL) was stirred at 90°C for 10 min. 10 Meantime, a mixture of tert-butyl 5-(4-((phenoxycarbonyl)amino)phenyl)-3,4- dihydropyridine-1(2H)-carboxylate (190 mg, 481.67 μmol, 1 eq) and TEA (48.74 mg, 481.67 μmol, 67.04 μL, 1 eq) in dioxane (3 mL) was stirred at 90°C for 10 min. Then mixture 1 was added to mixture 2 at 90°C and the reaction was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110°C for 12 hr under N2 atmosphere. LCMS showed desired 15 compound was detected. The reaction mixture was filtered and the solid was dried under reduced pressure to give tert-butyl 5-(4-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H- 1,2,4-triazole-1-carboxamido)phenyl)-3,4-dihydropyridine-1(2H)-carboxylate (160 mg, crude) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.63 - 9.55 (m, 1H), 9.51 (s, 1H), 8.21 (br d, J = 4.5 Hz, 1H), 7.79 - 7.70 (m, 4H), 7.69 - 7.61 (m, 3H), 7.50 (d, J = 8.6 Hz, 1H), 20 7.40 (br s, 2H), 5.92 (br s, 1H), 3.54 (br s, 2H), 2.77 - 2.74 (m, 3H), 2.40 (br t, J = 5.3 Hz, 2H), 1.94 - 1.84 (m, 2H), 1.48 (s, 9H). 5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-N-(4-(1,4,5,6-tetrahydropyridin-3- yl)phenyl)-1H-1,2,4-triazole-1-carboxamide. Tert-butyl 5-(4-(5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)phenyl)-3,4- 25 dihydropyridine-1(2H)-carboxylate (150 mg, 281.64 μmol, 1 eq) in HCl / EtOAc (3 mL, 4 M) was stirred at 25°C for 15 min. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent to give 5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-N-(4-(1,4,5,6-tetrahydropyridin-3-yl)phenyl)-1H-1,2,4- triazole-1-carboxamide (130 mg, crude, HCl) as a white solid. 30 N-(4-(1-acryloyl-1,4,5,6-tetrahydropyridin-3-yl)phenyl)-5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5- amino-3-((4-(methylcarbamoyl)phenyl)amino)-N-(4-(1,4,5,6-tetrahydropyridin-3-yl)phenyl)- 1H-1,2,4-triazole-1-carboxamide (130 mg, 277.22 μmol, 1 eq, HCl) in THF (3 mL) / H2O (1.5 mL) was added NaHCO3(23.29 mg, 277.22 μmol, 1 eq) and prop-2-enoyl chloride (25.09 mg, 69 STDU2-43279.601 277.22 μmol, 22.52 μL, 1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex luna C18 100×40mm×3 μm;mobile phase: [H2O(0.1% TFA)-ACN]; 5 gradient:15%-45% B over 8.0 min) to give N-(4-(1-acryloyl-1,4,5,6-tetrahydropyridin-3- yl)phenyl)-5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (10 mg, 20.10 μmol, 7.25% yield, 97.79% purity) as a white solid.1H NMR (400 MHz, DMSO- d6) δ 9.61 (br s, 1H), 9.50 (s, 1H), 8.20 (br d, J = 4.5 Hz, 1H), 7.81 - 7.32 (m, 11H), 7.23 - 6.83 (m, 1H), 6.24 (br t, J = 14.3 Hz, 1H), 5.81 (br d, J = 11.8 Hz, 1H), 3.82 - 3.66 (m, 4H), 2.76 10 (d, J = 4.4 Hz, 3H), 1.94 (br d, J = 7.1 Hz, 2H). MS (ESI): m / z = 487.3 [M+H]+. Compound 14 5-amin l-1,4,5,6-15 tetrahydropyridin-3-yl)phenyl)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5-amino- 3-[4-(methylcarbamoyl)anilino]-N-[4-(1,2,3,4-tetrahydropyridin-5-yl)phenyl]-1,2,4-triazole- 1-carboxamide (50 mg, 106.62 μmol, 1 eq, HCl) and prop-2-ynoic acid (7.47 mg, 106.62 μmol, 6.56 μL, 1 eq) in DMF (1 mL) was added DIEA (41.34 mg, 319.87 μmol, 55.72 μL, 3 eq) and HATU (44.60 mg, 117.29 μmol, 1.1 eq). The mixture was stirred at 25°C for 1 hr. LCMS 20 showed desired compound formed. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 100 × 30mm × 5μm; mobile phase: [H2O(0.1% TFA)-ACN]; gradient:20%-50% B over 10.0 min) to give 5-amino-3-((4-(methylcarbamoyl)phenyl)amino)- N-(4-(1-propioloyl-1,4,5,6-tetrahydropyridin-3-yl)phenyl)-1H-1,2,4-triazole-1-carboxamide 25 (5.77 mg, 11.04 μmol, 10.36% yield, 92.74% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.50 (s, 1H), 8.27 - 8.14 (m, 1H), 7.83 - 7.64 (m, 6H), 7.54 (br d, J = 4.3 Hz, 1H), 7.46 (br dd, J = 8.6, 12.8 Hz, 2H), 7.40 (br s, 1H), 4.81 (d, J = 19.5 Hz, 1H), 3.94 - 3.84 (m, 1H), 3.65 (br d, J = 0.8 Hz, 3H), 2.76 (d, J = 4.3 Hz, 3H), 2.05 - 1.86 (m, 2H). MS (ESI): m / z = 485.3 [M+H]+. 30 70 STDU2-43279.601 Compound 15 xirane (2 g, 10.05 mmol, 1 eq) in 2-aminoethanol (10 mL) was stirred at 20°C for 2 hr. TLC indicated 5 2-(4-bromophenyl)oxirane was consumed completely and one new spot formed. The residue was diluted with H2O 20 mL and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-(4-bromophenyl)-2-((2-hydroxyethyl)amino)ethan-1-ol (2.6 g, crude) as a yellow oil. 10 tert-butyl (2-(4-bromophenyl)-2-hydroxyethyl)(2-hydroxyethyl)carbamate. To a solution of 1-(4-bromophenyl)-2-((2-hydroxyethyl)amino)ethan-1-ol (2.6 g, 10.00 mmol, 1 eq) in DCM (30 mL) was added Boc2O (2.62 g, 11.99 mmol, 2.76 mL, 1.2 eq) and TEA (2.02 g, 19.99 mmol, 2.78 mL, 2 eq). The mixture was stirred at 25°C for 12 hr. LCMS showed desired compound was not detected. Boc2O (8.73 g, 39.98 mmol, 9.18 mL, 4 eq) was added, the 15 mixture was stirred at 25°C for 12 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~60% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert-butyl (2-(4-bromophenyl)-2- hydroxyethyl)(2-hydroxyethyl)carbamate (3.6 g, 9.99 mmol, 99.98% yield) as pale yellow 71 STDU2-43279.601 solid.1H NMR (400 MHz, CHLOROFORM-d) δ 7.49 (br d, J = 8.1 Hz, 2H), 7.32 - 7.28 (m, 1H), 3.72 (t, J = 5.0 Hz, 4H), 3.30 (br d, J = 4.5 Hz, 4H), 1.51 (s, 9H). tert-butyl 2-(4-bromophenyl)morpholine-4-carboxylate. To a solution of tert-butyl (2- (4-bromophenyl)-2-hydroxyethyl)(2-hydroxyethyl)carbamate (3.2 g, 8.89 mmol, 1 eq) in THF 5 (80 mL) was added DIAD (2.69 g, 13.32 mmol, 1.78 mL, 1.5 eq), Tributylphosphane (TBP, 2.69 g, 13.32 mmol, 2.26 mL, 1.5 eq). The mixture was stirred at 25°C for 12 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~5% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to 10 give tert-butyl 2-(4-bromophenyl)morpholine-4-carboxylate (750 mg, 2.05 mmol, 33.58% yield, 93.57% purity) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.59 - 7.53 (m, 2H), 7.34 (d, J = 8.4 Hz, 2H), 4.40 (dd, J = 2.6, 10.6 Hz, 1H), 3.98 - 3.74 (m, 3H), 3.59 - 3.50 (m, 1H), 3.05 - 2.88 (m, 1H), 2.67 (br s, 1H), 1.41 (s, 9H). tert-butyl 2-(4-((diphenylmethylene)amino)phenyl)morpholine-4-carboxylate. A 15 mixture of tert-butyl 2-(4-bromophenyl)morpholine-4-carboxylate (1 g, 2.92 mmol, 1 eq), diphenylmethanimine (794.34 mg, 4.38 mmol, 735.50 μL, 1.5 eq), t-BuONa (561.61 mg, 5.84 mmol, 2 eq), BINAP (363.89 mg, 584.41 μmol, 0.2 eq) and Pd2(dba)3(267.58 mg, 292.20 μmol, 0.1 eq) in toluene (20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 12 hr under N2atmosphere. LCMS showed desired compound 20 was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~5% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert-butyl 2-(4- ((diphenylmethylene)amino)phenyl)morpholine-4-carboxylate (1.2 g, 1.22 mmol, 41.76% yield, 45% purity) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.66 - 7.63 (m, 2H), 7.51 25 - 7.44 (m, 4H), 7.34 - 7.30 (m, 3H), 7.16 - 7.13 (m, 3H), 6.67 (d, J = 8.3 Hz, 2H), 4.25 (dd, J = 2.5, 10.5 Hz, 1H), 3.93 - 3.71 (m, 3H), 3.55 - 3.43 (m, 1H), 3.03 - 2.64 (m, 2H), 1.41 (s, 9H). tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate. To a solution of tert-butyl 2- (4-((diphenylmethylene)amino)phenyl)morpholine-4-carboxylate (1.2 g, 2.71 mmol, 1 eq) in MeOH (20 mL) was added NH2OH.HCl (433.39 mg, 6.24 mmol, 2.3 eq) and NaOAc (667.32 30 mg, 8.13 mmol, 3 eq). The mixture was stirred at 60°C for 2 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~30% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert- butyl 2-(4-aminophenyl)morpholine-4-carboxylate (600 mg, 2.15 mmol, 79.23% yield, 72 STDU2-43279.601 99.66% purity) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ 7.17 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 8.4 Hz, 2H), 4.30 (br d, J = 9.5 Hz, 1H), 4.02 - 3.85 (m, 3H), 3.69 - 3.60 (m, 1H), 3.03 (br s, 1H), 2.94 - 2.79 (m, 1H), 1.48 (s, 9H). tert-butyl 2-(4-((phenoxycarbonyl)amino)phenyl)morpholine-4-carboxylate. To a 5 solution of tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (200 mg, 718.53 μmol, 1 eq) in THF (2 mL) / H2O (1 mL) was added NaHCO3(72.43 mg, 862.24 μmol, 1.2 eq) and phenyl carbonochloridate (123.75 mg, 790.38 μmol, 99.16 μL, 1.1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound was detected. The residue was diluted with H2O 3 mL and extracted with EtOAc (3 mL × 2). The combined organic layers were dried over10 Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 2-(4- ((phenoxycarbonyl)amino)phenyl)morpholine-4-carboxylate (280 mg, crude) as a yellow oil. tert-butyl 2-(4-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole- 1-carboxamido)phenyl)morpholine-4-carboxylate. A mixture of 4-[(5-amino-1H-1,2,4- triazol-3-yl)amino]-N-methyl-benzamide (163.20 mg, 702.72 μmol, 1 eq) and TEA (71.11 mg, 15 702.72 μmol, 97.81 μL, 1 eq) in dioxane (3 mL) was stirred at 90°C for 10 min to get mixture 1. Meantime, a mixture of tert-butyl 2-(4-((phenoxycarbonyl)amino)phenyl)morpholine-4- carboxylate (280 mg, 702.72 μmol, 1 eq) and TEA (71.11 mg, 702.72 μmol, 97.81 μL, 1 eq) in dioxane (3 mL) was stirred at 90°C for 10 min to get mixture 2. Then mixture 2 was added to mixture 1 at 90 °C and the reaction was degassed and purged with N2for 3 times, and then the 20 mixture was stirred at 110°C for 12 hr under N2 atmosphere. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 10:1) to give tert-butyl 2-(4-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1- carboxamido)phenyl)morpholine-4-carboxylate (70 mg, 117.41 μmol, 16.71% yield, 90% 25 purity) as a white solid. MS (ESI): m / z = 537.5 [M+H]+. 5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-N-(4-(morpholin-2-yl)phenyl)-1H- 1,2,4-triazole-1-carboxamide. Tert-butyl 2-(4-(5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)phenyl)morpholine-4- carboxylate (70 mg, 130.46 μmol, 1 eq) in HCl / EtOAc (3 mL, 4 M) was stirred at 25°C for 1 30 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent to give 5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-N-(4-(morpholin-2-yl)phenyl)-1H-1,2,4-triazole-1- carboxamide (60 mg, crude, HCl) as a white solid. 73 STDU2-43279.601 N-(4-(4-acryloylmorpholin-2-yl)phenyl)-5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5- amino-3-((4-(methylcarbamoyl)phenyl)amino)-N-(4-(morpholin-2-yl)phenyl)-1H-1,2,4- triazole-1-carboxamide (60 mg, 126.87 μmol, 1 eq, HCl) in THF (2 mL) / H2O (1 mL) was added 5 NaHCO3 (31.97 mg, 380.61 μmol, 3 eq) and prop-2-enoyl chloride (11.48 mg, 126.87 μmol, 10.31 μL, 1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 100×30mm×5μm; mobile phase: [H2O(0.1% TFA)-ACN]; gradient:15%-45% B over 8.0 min10 ) to give N-(4-(4-acryloylmorpholin-2-yl)phenyl)-5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (27.63 mg, 56.33 μmol, 44.40% yield, 99.35% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.50 (s, 1H), 8.20 (br d, J = 4.5 Hz, 1H), 7.81 - 7.65 (m, 6H), 7.49 - 7.35 (m, 4H), 6.98 - 6.79 (m, 1H), 6.17 (br d, J = 16.5 Hz, 1H), 5.72 (br t, J = 9.4 Hz, 1H), 4.48 - 4.37 (m, 2H), 4.03 (br 15 d, J = 11.3 Hz, 2H), 3.65 - 3.51 (m, 1H), 3.36 - 3.07 (m, 1H), 2.76 (m, 4H). MS (ESI): m / z = 491.3 [M+H]+. Compound 16 O NTfH2N B2O O TfO H N Boc 74 STDU2-43279.601 tert-butyl 2-(((trifluoromethyl)sulfonyl)oxy)-8-azabicyclo[3.2.1]oct-2-ene-8- carboxylate. A mixture of tert-butyl 2-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (500 mg, 2.22 mmol, 1 eq) in THF (15 mL) was degassed and purged with N2 for 3 times, was added dropwise LiHMDS (1 M, 4.44 mL, 2 eq) at -60°C and the mixture was stirred at -60°C for 1 5 hr, and then 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl) methanesulfonamide (1.19 g, 3.33 mmol, 1.5 eq) was added to the mixture at -60°C. The mixture was stirred at 0°C for 3 hr under N2 atmosphere. TLC indicated the reaction was completed and one new spot formed. The residue was diluted with NH4Cl solution 20 mL and extracted with EtOAc (20 mL × 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced 10 pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~3% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert-butyl 2-(((trifluoromethyl)sulfonyl)oxy)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (700 mg, 1.96 mmol, 88.26% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 5.85 - 5.71 (m, 1H), 4.26 (br d, J = 4.9 Hz, 1H), 4.16 (br s, 1H), 2.78 - 2.64 (m, 1H), 2.23 - 2.01 (m, 15 4H), 1.69 - 1.58 (m, 1H), 1.39 (s, 9H). tert-butyl 2-(4-aminophenyl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate. A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (429.17 mg, 1.96 mmol, 1 eq), tert- butyl 2-(((trifluoromethyl)sulfonyl)oxy)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (700 mg, 1.96 mmol, 1 eq), K2CO3(541.46 mg, 3.92 mmol, 2 eq) and Pd(dppf)Cl2(143.33 mg, 195.89 20 μmol, 0.1 eq) in dioxane (12 mL) / H2O (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2atmosphere. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~6% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert- 25 butyl 2-(4-aminophenyl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (370 mg, 1.20 mmol, 61.44% yield, 97.72% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.07 (br d, J = 7.3 Hz, 2H), 6.56 (d, J = 8.4 Hz, 2H), 5.93 - 5.78 (m, 1H), 5.65 - 5.50 (m, 1H), 4.59 (br s, 1H), 4.17 (br t, J = 5.3 Hz, 1H), 3.33 (br s, 1H), 2.81 - 2.65 (m, 1H), 2.19 - 1.83 (m, 3H), 1.79 (br t, J = 9.4 Hz, 1H), 1.64 (br d, J = 7.5 Hz, 1H), 1.37 (br d, J = 8.3 Hz, 9H). 30 tert-butyl 2-(4-((phenoxycarbonyl)amino)phenyl)-8-azabicyclo[3.2.1]oct-2-ene-8- carboxylate. To a solution of tert-butyl 2-(4-aminophenyl)-8-azabicyclo[3.2.1]oct-2-ene-8- carboxylate (170 mg, 565.92 μmol, 1 eq) in THF (2 mL) / H2O (1 mL) was added NaHCO3(57.05 mg, 679.11 μmol, 1.2 eq) and phenyl carbonochloridate (106.33 mg, 679.11 μmol, 85.20 μL, 1.2 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound was 75 STDU2-43279.601 detected. The residue was diluted with H2O 3 mL and extracted with EtOAc (4 mL × 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 2-(4-((phenoxycarbonyl)amino)phenyl)-8-azabicyclo[3.2.1]oct-2- ene-8-carboxylate (240 mg, crude) as a yellow solid. 5 tert-butyl 2-(4-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole- 1-carboxamido)phenyl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate. A mixture of 4-[(5- amino-1H-1,2,4-triazol-3-yl)amino]-N-methyl-benzamide (132.55 mg, 570.75 μmol, 1 eq) and TEA (57.75 mg, 570.75 μmol, 79.44 μL, 1 eq) in dioxane (3 mL) was stirred at 90°C for 10 min to get mixture 1. Meantime, a mixture of tert-butyl 2-(4- 10 ((phenoxycarbonyl)amino)phenyl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (240 mg, 570.75 μmol, 1 eq) and TEA (57.75 mg, 570.75 μmol, 79.44 μL, 1 eq) in dioxane (3 mL) was stirred at 90°C for 10 min to get mixture 2. Then mixture 1 was added to mixture 2 at 90°C the reaction was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110°C for 12 hr under N2 atmosphere. LCMS showed desired compound was detected. The 15 reaction mixture was filtered and the solid was dried under reduced pressure to give tert-butyl 2-(4-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1- carboxamido)phenyl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (130 mg, crude) as a white solid. N-(4-(8-azabicyclo[3.2.1]oct-2-en-2-yl)phenyl)-5-amino-3-((4-20 (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. Tert-butyl 2-[4-[[5- amino-3-[4-(methylcarbamoyl)anilino]-1,2,4-triazole-1-carbonyl]amino]phenyl]-8- azabicyclo[3.2.1]oct-2-ene-8-carboxylate (130 mg, 232.71 μmol, 1 eq) in HCl / EtOAc (3 mL, 4 M) was stirred at 25°C for 1 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent to give N-(4-(8-25 azabicyclo[3.2.1]oct-2-en-2-yl)phenyl)-5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H- 1,2,4-triazole-1-carboxamide (115 mg, crude, HCl) as a white solid. N-(4-(8-acryloyl-8-azabicyclo[3.2.1]oct-2-en-2-yl)phenyl)-5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of N-(4- (8-azabicyclo[3.2.1]oct-2-en-2-yl)phenyl)-5-amino-3-((4-(methylcarbamoyl)phenyl)amino)- 30 1H-1,2,4-triazole-1-carboxamide (115 mg, 232.33 μmol, 1 eq, HCl) in THF (3 mL) / H2O (1.5 mL) was added NaHCO3 (58.55 mg, 697.00 μmol, 3 eq) and prop-2-enoyl chloride (21.03 mg, 232.33 μmol, 18.88 μL, 1 eq) .The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (TFA condition;column: Phenomenex 76 STDU2-43279.601 luna C18100×40mm×3 μm;mobile phase: [H2O(0.1% TFA)-ACN]; gradient:25%-55% B over 8.0 min ) to give N-(4-(8-acryloyl-8-azabicyclo[3.2.1]oct-2-en-2-yl)phenyl)-5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (38.17 mg, 74.31 μmol, 31.98% yield, 99.78% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.64 (d, J = 5 4.1 Hz, 1H), 9.51 (s, 1H), 8.21 (br d, J = 4.0 Hz, 1H), 7.81 - 7.62 (m, 6H), 7.52 - 7.35 (m, 4H), 6.78 (dd, J = 10.3, 16.7 Hz, 1H), 6.23 - 6.09 (m, 1H), 5.92 (br d, J = 17.4 Hz, 1H), 5.75 - 5.61 (m, 1H), 5.19 - 5.11 (m, 1H), 4.69 - 4.60 (m, 1H), 2.76 (d, J = 4.4 Hz, 3H), 2.71 - 2.57 (m, 1H), 2.35 - 2.12 (m, 2H), 2.09 - 1.91 (m, 2H), 1.85 - 1.65 (m, 1H). MS (ESI): m / z = 513.3 [M+H]+. 10 Compound 17 5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-N-(4-(1-propioloyl-1,2,5,6- tetrahydropyridin-3-yl)phenyl)-1H-1,2,4-triazole-1-carboxamide -N-[4-(1,2,3,6- 15 tetrahydropyridin-5-yl)phenyl]-1,2,4-triazole-1-carboxamide (150 mg, 319.87 μmol, 1 eq, HCl) in DMF (3 mL) was added HATU (133.79 mg, 351.86 μmol, 1.1 eq) and DIEA (124.02 mg, 959.61 μmol, 167.15 μL, 3 eq), prop-2-ynoic acid (26.89 mg, 383.85 μmol, 23.63 μL, 1.2 eq). The mixture was stirred at 25°C for 12 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was 20 purified by prep-HPLC (TFA condition;column: Phenomenex Luna C18 100×30mm×5μm;mobile phase: [H2O(0.1% TFA)-ACN];gradient:20%-50% B over 8.0 min ) to give 5-amino-3-[4-(methylcarbamoyl)anilino]-N-[4-(1-prop-2-ynoyl-3,6-dihydro-2H- pyridin-5-yl)phenyl]-1,2,4-triazole-1-carboxamide (56.21 mg, 112.55 μmol, 35.18% yield, 97.01% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.50 (s, 1H), 25 8.26 - 8.11 (m, 1H), 7.81 - 7.66 (m, 6H), 7.51 - 7.43 (m, 2H), 7.41 (br s, 2H), 6.34 (br s, 1H), 4.66 - 4.58 (m, 2H), 4.39 (br s, 1H), 3.87 - 3.85 (m, 1H), 3.68 - 3.65 (m, 1H), 2.76 (d, J = 4.5 Hz, 3H), 2.41 - 2.27 (m, 2H). MS (ESI): m / z = 485.4 [M+H]+. 77 STDU2-43279.601 Compound 18 5-amino-N-(4-(1-(but-2-ynoyl)-1,2,5,6-tetrahydropyridin-3-yl)phenyl)-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide 5 N-[4-(1,2,3,6- tetrahydropyridin-5-yl)phenyl]-1,2,4-triazole-1-carboxamide (150 mg, 319.87 μmol, 1 eq, HCl) in THF (2 mL) / H2O (2 mL) was added NaHCO3 (80.61 mg, 959.61 μmol, 3 eq). Then but-2-ynoyl chloride (36.07 mg, 351.86 μmol, 1.1 eq) was added at 0°C. The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound formed. The reaction mixture was10 concentrated under reduced pressure to remove solvent. The residue was purified by prep- HPLC (TFA condition; column: Phenomenex Luna C18 100×30mm×5μm;mobile phase: [H2O(0.1% TFA)-ACN];gradient:25%-55% B over 8.0 min) to give 5-amino-N-[4-(1-but-2- ynoyl-3,6-dihydro-2H-pyridin-5-yl)phenyl]-3-[4-(methylcarbamoyl)anilino]-1,2,4-triazole-1- carboxamide (38.26 mg, 76.38 μmol, 23.88% yield, 99.53% purity) as a white solid.1H NMR 15 (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.51 (s, 1H), 8.21 (br d, J = 4.5 Hz, 1H), 7.81 - 7.65 (m, 6H), 7.46 (d, J = 8.6 Hz, 2H), 7.41 (br s, 2H), 6.33 (br d, J = 4.9 Hz, 1H), 4.58 (br s, 1H), 4.36 (br d, J = 1.8 Hz, 1H), 3.84 (br t, J = 5.8 Hz, 2H), 2.76 (d, J = 4.5 Hz, 3H), 2.40 - 2.23 (m, 2H), 2.06 (d, J = 3.1 Hz, 3H). MS (ESI): m / z = 499.3 [M+H]+. 20 Compound 19 5-amino-N-(4-(1-(2-fluoroacryloyl)-1,2,5,6-tetrahydropyridin-3-yl)phenyl)-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide ]-N-[4-(1,2,3,6- 25 tetrahydropyridin-5-yl)phenyl]-1,2,4-triazole-1-carboxamide (200 mg, 426.50 μmol, 1 eq, HCl) in DMF (4 mL) was added HATU (178.38 mg, 469.14 μmol, 1.1 eq) and DIEA (165.36 78 STDU2-43279.601 mg, 1.28 mmol, 222.86 μL, 3 eq), 2-fluoroprop-2-enoic acid (46.09 mg, 511.79 μmol, 1.2 eq). The mixture was stirred at 25°C for 12 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (TFA condition;column: Phenomenex Luna C18 5 100×30mm×5μm;mobile phase: [H2O(0.1% TFA)-ACN];gradient:20%-50% B over 8.0 min ) to give 5-amino-N-[4-[1-(2-fluoroprop-2-enoyl)-3,6-dihydro-2H-pyridin-5-yl]phenyl]-3-[4- (methylcarbamoyl)anilino]-1,2,4-triazole-1-carboxamide (73.59 mg, 144.93 μmol, 33.98% yield, 99.36% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.51 (s, 1H), 8.21 (br d, J = 4.5 Hz, 1H), 7.85 - 7.63 (m, 6H), 7.52 - 7.35 (m, 4H), 6.34 (br s, 1H), 5.40 10 - 5.28 (m, 1H), 5.19 (br s, 1H), 4.40 (br s, 2H), 3.67 (br t, J = 5.6 Hz, 2H), 2.76 (d, J = 4.4 Hz, 3H), 2.43 - 2.27 (m, 2H). MS (ESI): m / z = 505.3 [M+H]+. Compound 20 (E)-5-amino-N-(4-(1-(4-(dimethylamino)but-2-enoyl)-1,2,5,6-tetrahydropyridin-3- 15 yl)phenyl)-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide NH2NH2 4-(1,2,3,6- tetrahydropyridin-5-yl)phenyl]-1,2,4-triazole-1-carboxamide (100 mg, 213.25 μmol, 1 eq, HCl), (E)-4-bromobut-2-enoyl bromide (58.31 mg, 255.90 μmol, 1.2 eq) in THF (0.7 20 mL) / NMP (2 mL) was added DIEA (82.68 mg, 639.74 μmol, 111.43 μL, 3 eq) and the mixture was stirred at 25°C for 1 hr, and then N-methylmethanamine (2 M, 746.37 μL, 7 eq) was added. The resulting mixture was stirred at 25°C for 1 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 25 100*30mm*5μm;mobile phase: [H2O(0.1% TFA)-ACN]; gradient:15%-45% B over 8.0 min) to give (E)-5-amino-N-(4-(1-(4-(dimethylamino)but-2-enoyl)-1,2,5,6-tetrahydropyridin-3- yl)phenyl)-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (25 mg, 42.37 μmol, 19.87% yield, 92.13% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.65 (s, 1H), 9.52 (s, 1H), 8.21 (br d, J = 4.5 Hz, 1H), 7.80 - 7.76 (m, 2H), 7.75 79 STDU2-43279.601 - 7.68 (m, 4H), 7.50 (br dd, J = 8.6, 18.0 Hz, 2H), 7.41 (br s, 1H), 7.16 - 6.98 (m, 1H), 6.73 - 6.60 (m, 1H), 6.41 - 6.30 (m, 1H), 4.47 (br d, J = 18.0 Hz, 2H), 3.90 (br d, J = 5.1 Hz, 2H), 3.70 (br s, 2H), 2.84 - 2.72 (m, 9H), 2.42 - 2.25 (m, 2H). MS (ESI): m / z = 544.4 [M+H]+. 5 Compound 21 4- (methylaminomethyl)aniline (500 mg, 3.67 mmol, 1 eq) in THF (5 mL) was added Boc2O (961.48mg, 4.41 mmol, 1.01 mL, 1.2 eq) at 0°C. The mixture was stirred at 25°C for 2 hr. 10 LCMS showed desired compound formed. The residue was diluted with H2O 10 mL and extracted with EtOAc 15 mL (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0~5% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert-butyl (4- 15 aminobenzyl)(methyl)carbamate (610 mg, 2.30 mmol, 62.58% yield, 89% purity) as a white solid. tert-butyl (4-(((cyanoimino)(phenoxy)methyl)amino)benzyl)(methyl)carbamate. To a solution of tert-butyl (4-aminobenzyl)(methyl)carbamate (610 mg, 2.58 mmol, 1 eq) in THF (5 mL) was added diphenoxymethylenecyanamide (614.99 mg, 2.58 mmol, 1 eq). The mixture 20 was stirred at 70°C for 12 hr. LCMS showed the desired compound was formed. The residue was diluted with H2O 10 mL and extracted with EtOAc 15 mL (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0~6% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert- 25 butyl 4-(((cyanoimino)(phenoxy)methyl)amino)benzyl)(methyl)carbamate (710 mg, 1.74 mmol, 67.42% yield, 93.25% purity) as a yellow solid.1H NMR (400 MHz, acetone) δ 7.56 80 STDU2-43279.601 (br d, J = 8.0 Hz, 2H), 7.51 - 7.44 (m, 2H), 7.39 - 7.27 (m, 5H), 4.46 (s, 2H), 2.83 (s, 3H), 1.47 (br s, 9H). MS (ESI): m / z = 403.2 [M+Na]+. tert-butyl (4-((5-amino-1H-1,2,4-triazol-3-yl)amino)benzyl)(methyl)carbamate. To a solution of tert-butyl (4-(((cyanoimino)(phenoxy)methyl)amino)benzyl)(methyl)carbamate 5 (710 mg, 1.87 mmol, 1 eq) in THF (10 mL) was added N2H4.H2O (181.13 mg, 3.55 mmol, 175.51 μL, 98% purity, 1.9 eq) at 0°C. The mixture was stirred at 70°C for 3 hr. LCMS showed the desired compound was formed. The reaction mixture was concentrated under reduced pressure to give tert-butyl (4-((5-amino-1H-1,2,4-triazol-3- yl)amino)benzyl)(methyl)carbamate (800 mg, crude) as a white solid which was used directly 10 to next step without further purification. N3-(4-((dimethylamino)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine. A mixture of tert-butyl (4-((5-amino-1H-1,2,4-triazol-3-yl)amino)benzyl)(methyl)carbamate (5 g, 15.70 mmol, 1 eq) in THF (100 mL) was degassed and purged with N2 for 3 times, and then LiAlH4 (LAH, 2.5 M, 12.56 mL, 2 eq) was added at 0°C the mixture was stirred at 70°C for 12 hr under 15 N2 atmosphere. LCMS showed desired compound was detected. The reaction mixture was quenched by addition standard Mg2SO4 solution 1.2 mL at 0°C, then 1.2 g Mg2SO4 was added and the mixture was stirred at 25°C for 10 min, filtered, washed with THF 2L and concentrated under reduced pressure to give N3-[4-[(dimethylamino)methyl]phenyl]-1H-1,2,4-triazole-3,5- diamine (3.2 g, crude) as a yellow solid. 20 tert-butyl 5-(4-(5-amino-3-((4-((dimethylamino)methyl)phenyl)amino)-1H-1,2,4- triazole-1-carboxamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate. A mixture of N3- [4-[(dimethylamino)methyl]phenyl]-1H-1,2,4-triazole-3,5-diamine (200 mg, 861.01 μmol, 1 eq) and TEA (87.13 mg, 861.01 μmol, 119.84 μL, 1 eq) in dioxane (3 mL) was stirred at 90°C for 10 min to get mixture 1. Meantime, a mixture of tert-butyl 5-[4- 25 (phenoxycarbonylamino)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (339.64 mg, 861.01 μmol, 1 eq) and TEA (87.13 mg, 861.01 μmol, 119.84 μL, 1 eq) in dioxane (3 mL) was stirred at 90°C for 10 min to get mixture 2. Then mixture 2 was added to mixture 1 at 90°C and the reaction was degassed and purged with N2for 3 times, and then the mixture was stirred at 110°C for 12 hr under N2 atmosphere. LCMS showed desired compound was detected. The30 reaction mixture was concentrated under reduced pressure. The residue was purified by prep- HPLC (TFA condition; column: Phenomenex Luna C18 100*30mm*5μm;mobile phase: [H2O(0.1% TFA)-ACN];gradient:25%-55% B over 8.0 min) to give tert-butyl 5-(4-(5-amino- 3-((4-((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)phenyl)-3,6- 81 STDU2-43279.601 dihydropyridine-1(2H)-carboxylate (120 mg, 215.31 μmol, 25.01% yield, 95.57% purity) as a white solid. MS (ESI): m / z = 533.5[M+H]+. 5-amino-3-((4-((dimethylamino)methyl)phenyl)amino)-N-(4-(1,2,5,6- tetrahydropyridin-3-yl)phenyl)-1H-1,2,4-triazole-1-carboxamide. Tert-butyl 5-[4-[[5-amino- 5 3-[4-[(dimethylamino)methyl]anilino]-1,2,4-triazole-1-carbonyl]amino]phenyl]-3,6-dihydro- 2H-pyridine-1-carboxylate (120 mg, 225.29 μmol, 1 eq) in HCl / EtOAc (3 mL, 4 M) was stirred at 25°C for 1 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to give 5-amino-3-((4- ((dimethylamino)methyl)phenyl)amino)-N-(4-(1,2,5,6-tetrahydropyridin-3-yl)phenyl)-1H- 10 1,2,4-triazole-1-carboxamide (100 mg, crude, HCl) as a yellow solid. N-(4-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)phenyl)-5-amino-3-((4- ((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5-amino-3-[4-[(dimethylamino)methyl]anilino]-N-[4-(1,2,3,6-tetrahydropyridin-5-yl)phenyl]- 1,2,4-triazole-1-carboxamide (100 mg, 213.23 μmol, 1 eq, HCl) in THF (2 mL) / H2O (1 mL) 15 was added NaHCO3 (17.91 mg, 213.23 μmol, 1 eq) and prop-2-enoyl chloride (19.30 mg, 213.23 μmol, 17.32 μL, 1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 100*30mm*5μm;mobile phase: [H2O(0.1% TFA)-20 ACN];gradient:15%-45% B over 8.0 min) to give N-(4-(1-acryloyl-1,2,5,6-tetrahydropyridin- 3-yl)phenyl)-5-amino-3-((4-((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1- carboxamide (6.94 mg, 13.91 μmol, 6.52% yield, 97.5% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 9.58 - 9.33 (m, 2H), 7.77 (br d, J = 8.5 Hz, 2H), 7.67 (br d, J = 8.0 Hz, 2H), 7.54 - 7.45 (m, 2H), 7.42 - 7.33 (m, 3H), 7.05 - 6.84 (m, 1H), 6.39 - 6.27 (m, 25 1H), 6.15 (br d, J = 16.6 Hz, 1H), 5.72 (br d, J = 10.5 Hz, 1H), 4.50 - 4.37 (m, 2H), 4.25 - 4.14 (m, 2H), 3.74 - 3.66 (m, 2H), 2.74 - 2.67 (m, 6H), 2.36 - 2.27 (m, 2H). MS (ESI): m / z = 487.4[M+H]+. 82 STDU2-43279.601 Compound 22 ure of 2- bromo-5-nitro-pyridine (1.31 g, 6.47 mmol, 2 eq) , tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2- 5 dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1 g, 3.23 mmol, 1 eq), Pd(dppf)Cl2.CH2Cl2(264.11 mg, 323.41 μmol, 0.1 eq) in DME (40 mL) / Na2CO3solution (15 mL, 2M) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 95°C for 12hr under N2atmosphere. LCMS showed desired compound formed. The residue was diluted with H2O 15 mL and extracted with EtOAc 30 mL (10 mL × 3). The combined 10 organic layers were washed with brine 30 mL (10 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~8% Ethyl acetate / Petroleum ether gradient @ 80mL / min) to give tert-butyl 5-nitro-5',6'-dihydro-[2,3'-bipyridine]-1'(2'H)- carboxylate (800 mg, 2.47 mmol, 76.45% yield, 94.36% purity) as a white solid.1H NMR (400 15 MHz, CHLOROFORM-d) δ 9.37 (d, J = 2.3 Hz, 1H), 8.43 (dd, J = 2.6, 8.9 Hz, 1H), 7.56 (br d, J = 7.4 Hz, 1H), 7.03 (br s, 1H), 4.45 (br d, J = 1.9 Hz, 2H), 3.60 (t, J = 5.7 Hz, 2H), 2.44 (br s, 2H), 1.51 (s, 9H). MS (ESI): m / z = 306.1 [M+H]+. tert-butyl 5-amino-5',6'-dihydro-[2,3'-bipyridine]-1'(2'H)-carboxylate. To a solution of tert-butyl 5-(5-nitro-2-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (300 mg, 982.55 20 μmol, 1 eq) in EtOH (4.5 mL) / H2O (1.5 mL) was added Fe (274.35 mg, 4.91 mmol, 5 eq) and 83 STDU2-43279.601 NH4Cl (262.79 mg, 4.91 mmol, 5 eq). The mixture was stirred at 80°C for 0.5 hr .LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O 5 mL and extracted with EtOAc 9 mL (3 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced 5 pressure to give tert-butyl 5-amino-5',6'-dihydro-[2,3'-bipyridine]-1'(2'H)-carboxylate (230 mg, crude) as a yellow oil. MS (ESI): m / z = 276.3 [M+H]+. tert-butyl 5-((phenoxycarbonyl)amino)-5',6'-dihydro-[2,3'-bipyridine]-1'(2'H)- carboxylate. To a solution of tert-butyl 5-(5-amino-2-pyridyl)-3,6-dihydro-2H-pyridine-1- carboxylate (230 mg, 835.31 μmol, 1 eq) in THF (3 mL) was added Pyridine (79.29 mg, 1.00 10 mmol, 80.91 μL, 1.2 eq) and phenyl carbonochloridate (143.86 mg, 918.85 μmol, 115.27 μL, 1.1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound formed. The residue was diluted with H2O 10 mL and extracted with EtOAc 15 mL (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 5-((phenoxycarbonyl)amino)-5',6'-dihydro-[2,3'-bipyridine]-1'(2'H)- 15 carboxylate (280 mg, crude) as a brown solid. tert-butyl 5-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1- carboxamido)-5',6'-dihydro-[2,3'-bipyridine]-1'(2'H)-carboxylate. A mixture of tert-butyl 5- [5-(phenoxycarbonylamino)-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate (150 mg, 379.31 μmol, 1 eq), TEA (38.38 mg, 379.31 μmol, 52.80 μL, 1 eq) in dioxane (1.5 mL) was20 stirred at 90°C for 5min to get mixture 1. Meantime, a mixture of 4-[(5-amino-1H-1,2,4-triazol- 3-yl)amino]-N-methyl-benzamide (88.09 mg, 379.31 μmol, 1 eq), TEA (38.38 mg, 379.31 μmol, 52.80 μL, 1 eq) in dioxane (1 mL) was stirred at 90°C for 5min to get mixture 2. Then mixture 2 was added to mixture 1 at 110°C and the reaction was degassed and purged with N2for 3 times, and then stirred at 110°C for 2 hr under N2 atmosphere. LCMS showed desired 25 compound formed. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 10:1) to give tert-butyl 5-(5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)-5',6'-dihydro-[2,3'- bipyridine]-1'(2'H)-carboxylate (20 mg) as a yellow solid. MS (ESI): m / z = 534.4 [M+H]+. 5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-N-(1',2',5',6'-tetrahydro-[2,3'-30 bipyridin]-5-yl)-1H-1,2,4-triazole-1-carboxamide. A solution of tert-butyl 5-[5-[[5-amino-3- [4-(methylcarbamoyl)anilino]-1,2,4-triazole-1-carbonyl]amino]-2-pyridyl]-3,6-dihydro-2H- pyridine-1-carboxylate (20 mg, 37.48 μmol, 1 eq) in HCl / EtOAc (1.5 mL, 4M) was stirred at 25°C for 0.5 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure to give 5-amino-3-((4-(methylcarbamoyl)phenyl)amino)- 84 STDU2-43279.601 N-(1',2',5',6'-tetrahydro-[2,3'-bipyridin]-5-yl)-1H-1,2,4-triazole-1-carboxamide (20 mg, crude, HCl) as a yellow solid. N-(1'-acryloyl-1',2',5',6'-tetrahydro-[2,3'-bipyridin]-5-yl)-5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5- 5 amino-3-[4-(methylcarbamoyl)anilino]-N-[6-(1,2,3,6-tetrahydropyridin-5-yl)-3-pyridyl]- 1,2,4-triazole-1-carboxamide (20 mg, 42.56 μmol, 1 eq, HCl) in THF (1 mL) / H2O (1 mL) was added NaHCO3 (10.73 mg, 127.68 μmol, 3 eq) and prop-2-enoyl chloride (4.24 mg, 46.82 μmol, 3.80 μL, 1.1 eq) at 0°C. The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure to remove 10 solvent. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18100 × 30mm × 5μm;mobile phase: [H2O(0.1% TFA)-ACN];gradient:15%-45% B over 8.0 min) to give N-(1'-acryloyl-1',2',5',6'-tetrahydro-[2,3'-bipyridin]-5-yl)-5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (10.61 mg, 20.34 μmol, 47.80% yield, 93.47% purity) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.86 15 (s, 1H), 9.52 (s, 1H), 8.84 (br s, 1H), 8.21 (br d, J = 4.8 Hz, 1H), 8.08 (br d, J = 8.5 Hz, 1H), 7.83 - 7.67 (m, 5H), 7.54 - 7.38 (m, 2H), 6.98 - 6.76 (m, 2H), 6.25 - 6.03 (m, 1H), 5.72 (br d, J = 11.1 Hz, 1H), 4.67 - 4.51 (m, 2H), 3.74 - 3.68 (m, 2H), 2.76 (d, J = 4.4 Hz, 3H), 2.40 - 2.32 (m, 2H). MS (ESI): m / z = 488.4 [M+H]+. 20 Compound 23 85 STDU2-43279.601 tert-butyl 5-(2-methoxy-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate. A mixture of 1-bromo-2-methoxy-4-nitro-benzene (1 g, 4.31 mmol, 1 eq), tert-butyl 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.33 g, 4.31 mmol, 1 eq), K2CO3(1.19 g, 8.62 mmol, 2 eq) and Pd(dppf)Cl2(315.35 mg, 430.98 μmol, 0.1 5 eq) in dioxane (12 mL) / H2O (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2atmosphere. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~10% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert- 10 butyl 5-(2-methoxy-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.4 g, 3.96 mmol, 91.91% yield, 94.6% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.82 (dd, J = 2.2, 8.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 6.01 (br s, 1H), 4.14 (br s, 2H), 3.91 (s, 3H), 3.47 (br t, J = 5.5 Hz, 2H), 2.25 (br d, J = 3.4 Hz, 2H), 1.41 (s, 9H). 15 tert-butyl 5-(4-amino-2-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate. To a solution of tert-butyl 5-(2-methoxy-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.4 g, 4.19 mmol, 1 eq) in EtOH (12 mL) / H2O (4 mL) was added Fe (1.17 g, 20.94 mmol, 5 eq) and NH4Cl (1.12 g, 20.94 mmol, 5 eq). The mixture was stirred at 80°C for 2 hr. LCMS showed desired compound was detected. The reaction mixture was filtered and concentrated20 under reduced pressure to give tert-butyl 5-(4-amino-2-methoxy-phenyl)-3,6-dihydro-2H- pyridine-1-carboxylate (1.2 g, crude) as yellow oil. tert-butyl 5-(2-methoxy-4-((phenoxycarbonyl)amino)phenyl)-3,6-dihydropyridine- 1(2H)-carboxylate. To a solution of tert-butyl 5-(4-amino-2-methoxy-phenyl)-3,6-dihydro- 2H-pyridine-1-carboxylate (550 mg, 1.81 mmol, 1 eq) in THF (8 mL) / H2O (4 mL) was added 25 phenyl carbonochloridate (311.19 mg, 1.99 mmol, 249.35 μL, 1.1 eq) and NaHCO3(182.15 mg, 2.17 mmol, 1.2 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound was detected. The residue was diluted with H2O 3 mL and extracted with EtOAc (8 mL × 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 5-(2-methoxy-4-((phenoxycarbonyl)amino)phenyl)-3,6- 30 dihydropyridine-1(2H)-carboxylate (730 mg, crude) as a yellow oil. tert-butyl 5-(4-(5-amino-3-((4-((dimethylamino)methyl)phenyl)amino)-1H-1,2,4- triazole-1-carboxamido)-2-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate. A mixture of tert-butyl 5-[2-methoxy-4-(phenoxycarbonylamino)phenyl]-3,6-dihydro-2H- pyridine-1-carboxylate (365.49 mg, 861.01 μmol, 1 eq) and TEA (87.13 mg, 861.01 μmol, 86 STDU2-43279.601 119.84 μL, 1 eq) in dioxane (3 mL) was stirred at 90°C for 10 min to get mixture 1. Meantime, a mixture of N3-[4-[(dimethylamino)methyl]phenyl]-1H-1,2,4-triazole-3,5-diamine (200 mg, 861.01 μmol, 1 eq) and TEA (87.13 mg, 861.01 μmol, 119.84 μL, 1 eq) in dioxane (3 mL) was stirred at 90°C for 10 min to get mixture 2. Then mixture 2 was added to mixture 1 at 90°C and 5 the reaction was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110°C for 12 hr under N2atmosphere. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (TFA condition;column: Phenomenex luna C18 100×40mm×3 μm;mobile phase: [H2O(0.1% TFA)-ACN];gradient:25%-55% B over 8.0 min ) to give tert-10 butyl 5-(4-(5-amino-3-((4-((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1- carboxamido)-2-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (150 mg, 247.24 μmol, 28.71% yield, 92.74% purity) as a yellow solid. MS (ESI): m / z = 563.5[M+H]+. 5-amino-3-((4-((dimethylamino)methyl)phenyl)amino)-N-(3-methoxy-4-(1,2,5,6- tetrahydropyridin-3-yl)phenyl)-1H-1,2,4-triazole-1-carboxamide. Tert-butyl 5-[4-[[5-amino-15 3-[4-[(dimethylamino)methyl]anilino]-1,2,4-triazole-1-carbonyl]amino]-2-methoxy-phenyl]- 3,6-dihydro-2H-pyridine-1-carboxylate (150 mg, 266.59 μmol, 1 eq) in HCl / EtOAc (3 mL, 4 M) was stirred at 25°C for 1 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to give 5-amino-3-((4- ((dimethylamino)methyl)phenyl)amino)-N-(3-methoxy-4-(1,2,5,6-tetrahydropyridin-3- 20 yl)phenyl)-1H-1,2,4-triazole-1-carboxamide (130 mg, crude, HCl) as a yellow solid. N-(4-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-3-methoxyphenyl)-5-amino-3-((4- ((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5-amino-3-[4-[(dimethylamino)methyl]anilino]-N-[3-methoxy-4-(1,2,3,6-tetrahydropyridin- 5-yl)phenyl]-1,2,4-triazole-1-carboxamide (130 mg, 260.52 μmol, 1 eq, HCl) in THF (2 mL) 25 / H2O (1 mL) was added NaHCO3(65.66 mg, 781.55 μmol, 3 eq) and prop-2-enoyl chloride (23.58 mg, 260.52 μmol, 21.17 μL, 1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex luna C18 100×40mm×3 μm;mobile phase: [H2O(0.1% TFA)-ACN]; 30 gradient:15%-45% B over 8.0 min). The residue was further purified by prep-HPLC (FA condition; column: Phenomenex luna C18100×40mm×5 um;mobile phase: [H2O(0.2% FA)- ACN]; gradient:15%-45% B over 8.0 min) to give N-(4-(1-acryloyl-1,2,5,6-tetrahydropyridin- 3-yl)-3-methoxyphenyl)-5-amino-3-((4-((dimethylamino)methyl)phenyl)amino)-1H-1,2,4- triazole-1-carboxamide (3.1 mg, 5.21 μmol, 2.00% yield, 94.51% purity, FA) as a white solid. 87 STDU2-43279.601 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 9.16 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.46 - 7.42 (m, 1H), 7.38 (br s, 2H), 7.31 (dd, J = 1.8, 8.3 Hz, 1H), 7.19 - 7.13 (m, 3H), 6.94 - 6.74 (m, 1H), 6.13 (br d, J = 16.6 Hz, 1H), 5.89 (br d, J = 1.4 Hz, 1H), 5.71 (dd, J = 2.1, 10.4 Hz, 1H), 4.34 (br d, J = 10.8 Hz, 2H), 3.80 (s, 3H), 3.69 (td, J = 5.4, 10.4 Hz, 2H), 3.31 (s, 2H), 5 2.35 - 2.23 (m, 2H), 2.13 (s, 6H). MS (ESI): m / z = 517.3 [M+H]+. Compound 24 COOMe COOMe O NTfH2 2N BCOOMe O O TfO , ne-10 1,3(2H)-dicarboxylate. To a solution of 1-(tert-butyl) 3-methyl 5-oxopiperidine-1,3- dicarboxylate (1.7 g, 6.61 mmol, 1 eq) in THF (20 mL) was added LiHMDS (1 M, 7.27 mL, 1.1 eq) at -78°C under N2 atmosphere. The mixture was stirred at -78°C for 0.5 hr. Then 1,1,1- trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (2.48 g, 6.94 mmol, 1.05 eq) in THF (20 mL) was added. The mixture was stirred at 25°C for 3 hr. LCMS showed desired 15 compound formed. The reaction mixture was quenched by addition NH4Cl solution (30 ml), and then diluted with H2O (20 mL) and extracted with EtOAc 90 mL (30 mL × 3). The 88 STDU2-43279.601 combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~5% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give 1-(tert-butyl) 3-methyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1,3(2H)- 5 dicarboxylate (590 mg, 1.38 mmol, 20.87% yield, 91% purity) as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ 7.09 (br s, 1H), 4.08 - 3.88 (m, 1H), 3.76 (s, 3H), 3.57 - 3.34 (m, 1H), 3.01 - 2.87 (m, 1H), 2.83 - 2.62 (m, 2H), 1.51 (s, 9H). MS (ESI): m / z = 290.0 [M-Boc+H]+. 1-(tert-butyl) 3-methyl 5-(4-aminophenyl)-3,4-dihydropyridine-1,3(2H)- dicarboxylate. A mixture of 1-(tert-butyl) 3-methyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,4-10 dihydropyridine-1,3(2H)-dicarboxylate (590.00 mg, 1.52 mmol, 1 eq) , 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)aniline (398.40 mg, 1.82 mmol, 1.2 eq), K3PO4 (643.32 mg, 3.03 mmol, 2 eq), [2-(2-aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl- phosphane;methanesulfonate (110.36 mg, 151.54 μmol, 0.1 eq) in THF (20 mL) / H2O (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 70°C for 12 15 hr under N2 atmosphere. LCMS showed desired compound formed. The residue was diluted with H2O 5 mL and extracted with EtOAc 15 mL (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~15% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give 1-(tert-butyl) 3-methyl 20 5-(4-aminophenyl)-3,4-dihydropyridine-1,3(2H)-dicarboxylate (370 mg, 1.01 mmol, 66.48% yield, 90.5% purity) as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ 7.24 - 7.16 (m, 2H), 7.08 (br s, 1H), 6.71 (br d, J = 6.7 Hz, 2H), 4.24 (br d, J = 12.5 Hz, 1H), 3.75 (br d, J = 5.1 Hz, 3H), 3.48 - 3.30 (m, 1H), 2.96 - 2.80 (m, 1H), 2.76 - 2.54 (m, 2H), 1.53 (s, 9H). MS (ESI): m / z = 333.2 [M+H]+. 25 5-(4-aminophenyl)-1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydropyridine-3-carboxylic acid. To a solution of 1-(tert-butyl) 3-methyl 5-(4-aminophenyl)-3,4-dihydropyridine-1,3(2H)- dicarboxylate (370.00 mg, 1.11 mmol, 1 eq) in THF (4 mL) / H2O (4 mL) was added LiOH.H2O (140.13 mg, 3.34 mmol, 3 eq). The mixture was stirred at 80°C for 0.5 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure to 30 remove solvent. The residue was purified by prep-HPLC (FA condition;column: Phenomenex luna C18 100×40mm×5 μm;mobile phase: [H2O(0.2% FA)-ACN];gradient:5%-35% B over 8.0 min) to give 5-(4-aminophenyl)-1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydropyridine-3- carboxylic acid (193 mg, 569.06 μmol, 51.12% yield, 93.87% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.03 (br s, 2H), 6.92 (br s, 1H), 6.52 (br d, J = 8.4 Hz, 2H), 3.90 - 3.71 89 STDU2-43279.601 (m, 1H), 3.56 - 3.33 (m, 2H), 2.85 (br s, 1H), 2.53 (br s, 1H), 1.45 (s, 9H). MS (ESI): m / z = 319.2 [M+H]+. 1-(tert-butoxycarbonyl)-5-(4-((phenoxycarbonyl)amino)phenyl)-1,2,3,4- tetrahydropyridine-3-carboxylic acid. To a solution of 5-(4-aminophenyl)-1-(tert- 5 butoxycarbonyl)-1,2,3,4-tetrahydropyridine-3-carboxylic acid (193 mg, 606.22 μmol, 1 eq) in THF (2 mL) / H2O (2 mL) was added NaHCO3(61.11 mg, 727.46 μmol, 1.2 eq) and phenyl carbonochloridate (104.40 mg, 666.84 μmol, 83.66 μL, 1.1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound formed. The residue was diluted with H2O 5 mL and extracted with EtOAc 15 mL (5 mL × 3). The combined organic layers were dried over10 Na2SO4, filtered and concentrated under reduced pressure to give 1-(tert-butoxycarbonyl)-5- (4-((phenoxycarbonyl)amino)phenyl)-1,2,3,4-tetrahydropyridine-3-carboxylic acid (133 mg, crude) as a white solid. 5-(4-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1- carboxamido)phenyl)-1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydropyridine-3-carboxylic acid. 15 A mixture of 1-(tert-butoxycarbonyl)-5-(4-((phenoxycarbonyl)amino)phenyl)-1,2,3,4- tetrahydropyridine-3-carboxylic acid (133 mg, 303.33 μmol, 1 eq), TEA (30.69 mg, 303.33 μmol, 42.22 μL, 1 eq) in dioxane (1.5 mL) was stirred at 90°C for 5 min to get mixture 1. Meantime, a mixture of 4-[(5-amino-1H-1,2,4-triazol-3-yl)amino]-N-methyl-benzamide (70.44 mg, 303.33 μmol, 1 eq), TEA (30.69 mg, 303.33 μmol, 42.22 μL, 1 eq) in dioxane (1 20 mL) was stirred at 90°C for 5 min to get mixture 2. Then mixture 2 was added to mixture 1 at 90°C, the reaction was degassed and purged with N2for 3 times, and then the mixture was stirred at 110°C for 12 hr under N2 atmosphere. LCMS showed desired compound formed. The residue was diluted with H2O 5 mL and extracted with EtOAc 15 mL (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to25 give a residue. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 8:1) to give 5-(4- (5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)phenyl)- 1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydropyridine-3-carboxylic acid (80 mg) as a yellow solid. MS (ESI): m / z = 577.4 [M+H]+. 5-(4-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-30 carboxamido)phenyl)-1,2,3,4-tetrahydropyridine-3-carboxylic acid. A solution of 5-(4-(5- amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)phenyl)-1- (tert-butoxycarbonyl)-1,2,3,4-tetrahydropyridine-3-carboxylic acid (80 mg, 138.74 μmol, 1 eq) in HCl / EtOAc (1 mL, 4M) was stirred at 25°C for 1 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure to give 5-(4-(5-amino- 90 STDU2-43279.601 3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)phenyl)-1,2,3,4- tetrahydropyridine-3-carboxylic acid (70 mg, crude, HCl) as a green solid. 1-acryloyl-5-(4-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole- 1-carboxamido)phenyl)-1,2,3,4-tetrahydropyridine-3-carboxylic acid. To a solution of 5-[4- 5 [[5-amino-3-[4-(methylcarbamoyl)anilino]-1,2,4-triazole-1-carbonyl]amino]phenyl]-1,2,3,4- tetrahydropyridine-3-carboxylic acid (70 mg, 136.47 μmol, 1 eq, HCl) in THF (1 mL) / H2O (1 mL) was added NaHCO3 (34.39 mg, 409.40 μmol, 3 eq) and prop-2-enoyl chloride (13.59 mg, 150.11 μmol, 12.20 μL, 1.1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure to remove 10 solvent. The residue was purified by prep-HPLC ( neutral condition;column: column: Waters Xbridge Prep OBD C18 150×40mm×10μm;mobile phase: [H2O(10mM NH4HCO3)- ACN];gradient:5%-35% B over 8.0 min) to give 1-acryloyl-5-(4-(5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)phenyl)-1,2,3,4- tetrahydropyridine-3-carboxylic acid (8.76 mg, 16.51 μmol, 12.10% yield, 100% purity) as a 15 white solid.1H NMR (400 MHz, DMSO-d6) δ 9.71 - 9.59 (m, 1H), 9.50 (s, 1H), 8.20 (br d, J = 4.6 Hz, 1H), 7.85 - 7.61 (m, 6H), 7.57 - 7.33 (m, 5H), 7.24 - 6.84 (m, 1H), 6.25 (br d, J = 17.1 Hz, 1H), 5.83 (br d, J = 12.0 Hz, 1H), 4.18 - 3.91 (m, 1H), 3.87 - 3.53 (m, 1H), 3.03 - 2.87 (m, 1H), 2.76 (br d, J = 4.3 Hz, 3H), 2.73 - 2.65 (m, 2H). MS (ESI): m / z = 531.2 [M+H]+. 20 Compound 25 91 STDU2-43279.601 1-(tert-butyl) 2-methyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine- 1,2(2H)-dicarboxylate. To a solution of 1-(tert-butyl) 2-methyl 5-oxopiperidine-1,2- dicarboxylate (4.4 g, 17.10 mmol, 1 eq) in THF (40 mL) was added LiHMDS (1 M, 20.52 mL, 1.2 eq) at -78°C under N2atmosohere. The mixture was stirred at -78°C for 0.5 hr. Then 1,1,1- 5 trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (6.72 g, 18.81 mmol, 1.1 eq) in THF (50 mL) was added. The mixture was stirred at 25°C for 3 hr under N2. LCMS showed desired compound formed. The reaction mixture was quenched by addition NH4Cl solution (50ml), and then diluted with H2O (50 mL) and extracted with EtOAc 120 mL (40 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under 10 reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~3% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give 1-(tert-butyl) 2-methyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6- dihydropyridine-1,2(2H)-dicarboxylate (7.2 g) as a yellow oil. 1-(tert-butyl) 2-methyl 5-(4-nitrophenyl)-3,6-dihydropyridine-1,2(2H)-dicarboxylate. 15 A mixture of 1-(tert-butyl) 2-methyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine- 1,2(2H)-dicarboxylate (5.2 g, 13.36 mmol, 1 eq) , 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2- dioxaborolane (3.33 g, 13.36 mmol, 1 eq) , K3PO4(5.67 g, 26.71 mmol, 2 eq), [2-(2- aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl-phosphane;methanesulfonate (972.66 mg, 1.34 mmol, 0.1 eq) in THF (80 mL) / H2O (20 mL) was degassed and purged with 20 N2 for 3 times, and then the mixture was stirred at 70°C for 12 hr under N2 atmosphere. LCMS showed desired compound formed. The residue was diluted with H2O 20 mL and extracted with EtOAc 90 mL (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~5% Ethyl acetate / Petroleum 25 ether gradient @ 80 mL / min). The residue was purified by prep-HPLC (FA condition;column: Welch Xtimate C18 250×70mm×10μm;mobile phase: [H2O(0.2%FA)-ACN];gradient:42%- 72% B over 20.0 min) and further purified by prep-HPLC (FA condition; column: Phenomenex luna C18100×40mm×5 μm;mobile phase: [H2O(0.2% FA)-ACN];gradient:50%-70% B over 10.0 min) to give 1-(tert-butyl) 2-methyl 5-(4-nitrophenyl)-3,6-dihydropyridine-1,2(2H)- 30 dicarboxylate (613 mg, 1.61 mmol, 12.05% yield, 95.15% purity) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ 8.26 - 8.15 (m, 2H), 7.57 - 7.45 (m, 2H), 6.33 (br s, 1H), 5.18 (br d, J = 6.8 Hz, 1H), 4.67 - 4.41 (m, 1H), 4.22 (br d, J = 17.9 Hz, 1H), 3.73 (d, J = 3.3 Hz, 3H), 2.97 - 2.65 (m, 2H), 1.52 (br d, J = 14.0 Hz, 9H). MS (ESI): m / z = 304.2 [M+H-56]+. 92 STDU2-43279.601 1-(tert-butoxycarbonyl)-5-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine-2-carboxylic acid. To a solution of 1-(tert-butyl) 2-methyl 5-(4-nitrophenyl)-3,6-dihydropyridine-1,2(2H)- dicarboxylate (580 mg, 1.60 mmol, 1 eq) in THF (6 mL) / H2O (6 mL) was added LiOH.H2O (201.48 mg, 4.80 mmol, 3 eq). The mixture was stirred at 80°C for 0.5 hr. LCMS showed 5 desired compound formed. The residue was diluted with H2O 10 mL. The water phase is adjusted to pH about 2. The combined water layers were washed with EtOAc 15 mL (5 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-(tert- butoxycarbonyl)-5-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine-2-carboxylic acid (362 mg, crude) as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ 8.28 - 8.12 (m, 2H), 7.59 - 10 7.44 (m, 2H), 6.41 - 6.25 (m, 1H), 5.27 - 4.98 (m, 1H), 4.68 - 4.40 (m, 1H), 4.32 - 4.04 (m, 1H), 3.00 - 2.86 (m, 1H), 2.82 - 2.64 (m, 1H), 1.58 - 1.46 (m, 9H). MS (ESI): m / z = 249.1 [M+H-56]+. 4'-nitro-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carboxamide. To a solution of 1-tert- butoxycarbonyl-5-(4-nitrophenyl)-3,6-dihydro-2H-pyridine-2-carboxylic acid (360 mg, 1.03 15 mmol, 1 eq) in DMF (10 mL) was added HATU (392.95 mg, 1.03 mmol, 1 eq), DIEA (400.69 mg, 3.10 mmol, 540.01 μL, 3 eq) and NH4Cl (276.39 mg, 5.17 mmol, 5 eq). The mixture was stirred at 25°C for 12 hr. LCMS showed desired compound formed. The residue was diluted with H2O 3 mL and extracted with EtOAc 9 mL (3 mL × 3). The combined organic layers were washed with brine 9 mL (3 mL × 3), dried over Na2SO4, filtered and concentrated under 20 reduced pressure to give 4'-nitro-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carboxamide (265 mg, crude) as a yellow oil. tert-butyl 2-cyano-5-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate. To a solution of tert-butyl 2-carbamoyl-5-(4-nitrophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (265 mg, 762.89 μmol, 1 eq) in DCM (10 mL) was added TEA (154.39 mg, 1.53 mmol, 212.37 25 μL, 2 eq). Then trifluoroacetic anhydride (TFAA, 640.92 mg, 3.05 mmol, 424.17 μL, 4 eq) was added at 0°C. The mixture was stirred at 25°C for 2 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 3:1) to give tert-butyl 2-cyano-5-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (140 mg, 394.47 μmol, 30 51.71% yield, 92.8% purity) as a yellow oil. MS (ESI): m / z = 330.3 [M+H]+. tert-butyl 5-(4-aminophenyl)-2-cyano-3,6-dihydropyridine-1(2H)-carboxylate. To a solution of tert-butyl 2-cyano-5-(4-nitrophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (60 mg, 182.18 μmol, 1 eq) in EtOH (1.5 mL) / H2O (0.5 mL) was added Fe (50.87 mg, 910.89 μmol, 5 eq) and NH4Cl (48.72 mg, 910.89 μmol, 5 eq). The mixture was stirred at 80°C for 0.5 93 STDU2-43279.601 hr. LCMS showed desired compound formed. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was diluted with H2O 5 mL and extracted with EtOAc 9 mL (3 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 5-(4-aminophenyl)-2-cyano-3,6- 5 dihydropyridine-1(2H)-carboxylate (50 mg, crude) as a yellow solid. MS (ESI): m / z = 300.2 [M+H]+. tert-butyl 2-cyano-5-(4-((phenoxycarbonyl)amino)phenyl)-3,6-dihydropyridine- 1(2H)-carboxylate. To a solution of tert-butyl 5-(4-aminophenyl)-2-cyano-3,6-dihydro-2H- pyridine-1-carboxylate (50 mg, 167.02 μmol, 1 eq) in THF (1 mL) / H2O (1 mL) was added 10 NaHCO3(16.84 mg, 200.42 μmol, 1.2 eq) and phenyl carbonochloridate (28.76 mg, 183.72 μmol, 23.05 μL, 1.1 eq) at 0°C. The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound formed. The residue was diluted with H2O 5 mL and extracted with EtOAc 15 mL (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 2-cyano-5-(4-((phenoxycarbonyl)amino)phenyl)-3,6- 15 dihydropyridine-1(2H)-carboxylate (48 mg, crude) as a yellow solid. tert-butyl 5-(4-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole- 1-carboxamido)phenyl)-2-cyano-3,6-dihydropyridine-1(2H)-carboxylate. A mixture of tert- butyl 2-cyano-5-[4-(phenoxycarbonylamino)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (48 mg, 114.43 μmol, 1 eq), TEA (11.58 mg, 114.43 μmol, 15.93 μL, 1 eq) in dioxane (1 mL)20 was stirred at 90°C for 5 min to get mixture 1. Meantime, a mixture of 4-[(5-amino-1H-1,2,4- triazol-3-yl)amino]-N-methyl-benzamide (26.58 mg, 114.43 μmol, 1 eq), TEA (11.58 mg, 114.43 μmol, 15.93 μL, 1 eq) in dioxane (1 mL) was stirred at 90°C for 5 min to get mixture 2. Then mixture 2 was added to mixture 1 at 90°C, the reaction mixture was degassed and purged with N2 for 3 times, and then stirred at 110°C for 2hr under N2 atmosphere. LCMS 25 showed desired compound formed. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 10:1) to give tert-butyl 5-(4-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1- carboxamido)phenyl)-2-cyano-3,6-dihydropyridine-1(2H)-carboxylate (18 mg, crude) as a white solid. 30 5-amino-N-(4-(6-cyano-1,2,5,6-tetrahydropyridin-3-yl)phenyl)-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. A solution of tert-butyl 5-[4-[[5-amino-3-[4-(methylcarbamoyl)anilino]-1,2,4-triazole-1-carbonyl]amino]phenyl]-2- cyano-3,6-dihydro-2H-pyridine-1-carboxylate (16 mg, 28.69 μmol, 1 eq) in HCl / EtOAc (0.5 mL,1 M) was stirred at 25°C for 0.5 hr. LCMS showed desired compound formed. The reaction 94 STDU2-43279.601 mixture was concentrated under reduced pressure to give 5-amino-N-(4-(6-cyano-1,2,5,6- tetrahydropyridin-3-yl)phenyl)-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1- carboxamide (10 mg, crude, HCl) as a yellow solid. N-(4-(1-acryloyl-6-cyano-1,2,5,6-tetrahydropyridin-3-yl)phenyl)-5-amino-3-((4- 5 (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5- amino-N-[4-(2-cyano-1,2,3,6-tetrahydropyridin-5-yl)phenyl]-3-[4- (methylcarbamoyl)anilino]-1,2,4-triazole-1-carboxamide (10 mg, 20.25 μmol, 1 eq, HCl) in DCM (1 mL) was added TEA (6.15 mg, 60.74 μmol, 8.45 μL, 3 eq). Then prop-2-enoyl chloride (2.02 mg, 22.27 μmol, 1.81 μL, 1.1 eq) was added at 0°C. The mixture was stirred at 10 0°C for 0.5 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep- HPLC (FA condition; column: column: Phenomenex luna C18 100×40mm×5 μm; mobile phase: [H2O(0.2% FA)-ACN]; gradient:20%-50% B over 8.0 min) to give N-(4-(1-acryloyl-6- cyano-1,2,5,6-tetrahydropyridin-3-yl)phenyl)-5-amino-3-((4- 15 (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (1.67 mg, 3.20 μmol, 15.79% yield, 97.89% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.50 (s, 1H), 8.24 - 8.12 (m, 1H), 7.81 - 7.70 (m, 5H), 7.59 (br d, J = 8.1 Hz, 2H), 7.41 (br s, 2H), 7.13 - 6.93 (m, 1H), 6.43 - 6.23 (m, 2H), 5.97 - 5.81 (m, 2H), 4.98 - 4.82 (m, 1H), 2.76 (d, J = 4.5 Hz, 3H), 2.70 - 2.60 (m, 3H), 2.37 - 2.28 (m, 1H). MS (ESI): m / z = 512.2 [M+H]+. 20 95 STDU2-43279.601 Compound 26 (4- nitrophenyl)boronic acid (613.39 mg, 3.67 mmol, 1 eq), tert-butyl N-(3- 5 bromophenyl)carbamate (1 g, 3.67 mmol, 1 eq), K2CO3 (1.02 g, 7.35 mmol, 2 eq) and Pd(dppf)Cl2(268.87 mg, 367.46 μmol, 0.1 eq) in dioxane (12 mL) / H2O (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2 atmosphere. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica 10 gel chromatography (20 g Silica Flash Column, Eluent of 0~10% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert-butyl (4'-nitro-[1,1'-biphenyl]-3-yl)carbamate (1.08 g, 3.32 mmol, 90.34% yield, 96.62% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.32 (d, J = 8.8 Hz, 2H), 7.92 (s, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.53 - 7.48 (m, 1H), 7.45 - 7.33 (m, 2H), 1.49 (s, 9H). 15 tert-butyl (4'-amino-[1,1'-biphenyl]-3-yl)carbamate. To a solution of tert-butyl (4'- nitro-[1,1'-biphenyl]-3-yl)carbamate (1.08 g, 3.44 mmol, 1 eq) in EtOH (12 mL) / H2O (4 mL) was added Fe (959.37 mg, 17.18 mmol, 5 eq) and NH4Cl (918.93 mg, 17.18 mmol, 5 eq). The mixture was stirred at 80°C for 2 hr. LCMS showed desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl (4'- 20 amino-[1,1'-biphenyl]-3-yl)carbamate (750 mg, crude) as a yellow oil. 96 STDU2-43279.601 tert-butyl phenyl [1,1'-biphenyl]-3,4'-diyldicarbamate. To a solution of tert-butyl (4'- amino-[1,1'-biphenyl]-3-yl)carbamate (550 mg, 1.93 mmol, 1 eq) in THF (8 mL) / H2O (4 mL) was added NaHCO3 (194.98 mg, 2.32 mmol, 1.2 eq) and phenyl carbonochloridate (333.12 mg, 2.13 mmol, 266.92 μL, 1.1 eq). The mixture was stirred at 0°C for 1hr. LCMS showed 5 desired compound was detected. The residue was diluted with H2O 3 mL and extracted with EtOAc (8 mL × 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl phenyl [1,1'-biphenyl]-3,4'- diyldicarbamate (720 mg, crude) as a yellow oil. tert-butyl (4'-(5-amino-3-((4-((dimethylamino)methyl)phenyl)amino)-1H-1,2,4- 10 triazole-1-carboxamido)-[1,1'-biphenyl]-3-yl)carbamate. A mixture of phenyl tert-butyl phenyl [1,1'-biphenyl]-3,4'-diyldicarbamate (348.24 mg, 861.01 μmol, 1 eq) and TEA (87.13 mg, 861.01 μmol, 119.84 μL, 1 eq) in dioxane (2 mL) was stirred at 90°C for 10 min to get mixture 1. Meantime, a mixture of N3-[4-[(dimethylamino)methyl]phenyl]-1H-1,2,4-triazole- 3,5-diamine (200 mg, 861.01 μmol, 1 eq) and TEA (87.13 mg, 861.01 μmol, 119.84 μL, 1 eq) 15 in dioxane (2 mL) was stirred at 90°C for 10 min to get mixture 2. Then mixture 2 was added to mixture 1 at 90 °C and the reaction was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110°C for 12 hr under N2atmosphere. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (TFA condition; column:20 Phenomenex luna C18 100×40mm×3 μm;mobile phase: [H2O(0.1% TFA)- ACN];gradient:26%-56% B over 8.0 min) to give tert-butyl (4'-(5-amino-3-((4- ((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)-[1,1'-biphenyl]-3- yl)carbamate (110 mg, 197.75 μmol, 22.97% yield, 97.55% purity) as a white solid. MS (ESI): m / z = 543.4[M+H]+. 25 5-amino-N-(3'-amino-[1,1'-biphenyl]-4-yl)-3-((4- ((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. Tert-butyl (4'-(5- amino-3-((4-((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)-[1,1'- biphenyl]-3-yl)carbamate (110 mg, 202.72 μmol, 1 eq) in HCl / EtOAc (3 mL, 4M) was stirred at 25°C for 1 hr. LCMS showed desired compound was detected. The reaction mixture was30 concentrated under reduced pressure to give 5-amino-N-(3'-amino-[1,1'-biphenyl]-4-yl)-3-((4- ((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (95 mg, crude, HCl) as a yellow solid. N-(3'-acrylamido-[1,1'-biphenyl]-4-yl)-5-amino-3-((4- ((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of 97 STDU2-43279.601 5-amino-N-(3'-amino-[1,1'-biphenyl]-4-yl)-3-((4-((dimethylamino)methyl)phenyl)amino)- 1H-1,2,4-triazole-1-carboxamide (95 mg, 198.34 μmol, 1 eq, HCl) in THF (2 mL) / H2O (1 mL) was added NaHCO3 (49.99 mg, 595.02 μmol, 3 eq) and prop-2-enoyl chloride (17.95 mg, 198.34 μmol, 16.11 μL, 1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired 5 compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 100×30mm×5μm;mobile phase: [H2O(0.1% TFA)- ACN];gradient:20%-50% B over 8.0 min) to give N-(3'-acrylamido-[1,1'-biphenyl]-4-yl)-5- amino-3-((4-((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (18.110 mg, 34.20 μmol, 17.24% yield, 93.82% purity) as a white solid.1H NMR (400 MHz, DMSO- d6) δ 10.26 (s, 1H), 9.68 (s, 1H), 9.53 - 9.39 (m, 2H), 8.07 - 8.02 (m, 1H), 7.79 (dd, J = 5.6, 8.6 Hz, 4H), 7.70 - 7.58 (m, 3H), 7.47 - 7.33 (m, 6H), 6.53 - 6.42 (m, 1H), 6.34 - 6.22 (m, 1H), 5.83 - 5.74 (m, 1H), 4.24 - 4.17 (m, 2H), 2.76 - 2.68 (m, 6H). MS (ESI): m / z = 497.4[M+H]+. 15 Compound 27 , . tro- benzoic acid (2 g, 8.13 mmol, 1 eq) , 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.78 g, 8.13 mmol, 1 eq), K2CO3 (2.25 g, 16.26 mmol, 2 eq), Pd(dppf)Cl2 (594.85 mg, 812.96 20 μmol, 0.1 eq) in dioxane (40 mL) / H2O (10 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2 atmosphere. LCMS showed desired 98 STDU2-43279.601 compound formed. The residue was diluted with H2O 20 mL and extracted with EtOAc 60 mL (20 mL × 3). The combined water layers were washed with HCl solution (1M) 20 mL. The combined water layers were washed with EtOAc 60 mL (20 mL × 3) dried over Na2SO4, filtered and concentrated under reduced pressure to give 4'-amino-5-nitro-[1,1'-biphenyl]-3- 5 carboxylic acid (460 mg, crude) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.43 (d, J = 1.5 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 6.72 (d, J = 8.5 Hz, 2H). MS (ESI): m / z = 259.1 [M+H]+. 5-nitro-4'-((phenoxycarbonyl)amino)-[1,1'-biphenyl]-3-carboxylic acid. To a solution of 4'-amino-5-nitro-[1,1'-biphenyl]-3-carboxylic acid (260 mg, 1.01 mmol, 1 eq) in 10 THF (3 mL) / H2O (3 mL) was added NaHCO3(101.50 mg, 1.21 mmol, 1.2 eq) and phenyl carbonochloridate (173.40 mg, 1.11 mmol, 138.95 μL, 1.1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound formed. The residue was diluted with H2O 10 mL and extracted with EtOAc 30 mL (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 5-nitro-4'- 15 ((phenoxycarbonyl)amino)-[1,1'-biphenyl]-3-carboxylic acid (360 mg, crude) as a brown solid. 4'-(5-amino-3-((4-((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1- carboxamido)-5-nitro-[1,1'-biphenyl]-3-carboxylic acid. A mixture of 5-nitro-4'- ((phenoxycarbonyl)amino)-[1,1'-biphenyl]-3-carboxylic acid (360 mg, 951.54 μmol, 1 eq), TEA (96.29 mg, 951.54 μmol, 132.44 μL, 1 eq) in dioxane (3 mL) was stirred at 90°C for 520 min to get mixture 1. Meantime, a mixture of N3-[4-[(dimethylamino)methyl]phenyl]-1H- 1,2,4-triazole-3,5-diamine (221.03 mg, 951.54 μmol, 1 eq), TEA (96.29 mg, 951.54 μmol, 132.44 μL, 1 eq) in dioxane (3 mL) was stirred at 90°C for 5 min to get mixture 2. Then mixture 2 was added to mixture 1 at 110°C, the reaction was degassed and purged with N2for 3 times, and then stirred at 110°C for 12 hr under N2 atmosphere. LCMS showed desired compound 25 formed. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 100 × 30mm × 5μm;mobile phase: [H2O(0.1% TFA)-ACN];gradient:15%-45% B over 8.0 min) to give 4'-(5- amino-3-((4-((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)-5- nitro-[1,1'-biphenyl]-3-carboxylic acid (200 mg, 317.19 μmol, 33.33% yield, TFA) as a yellow 30 solid.1H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 9.59 - 9.41 (m, 2H), 8.76 - 8.54 (m, 3H), 7.98 - 7.87 (m, 3H), 7.79 (br d, J = 8.3 Hz, 2H), 7.50 - 7.41 (m, 2H), 7.37 (br d, J = 8.2 Hz, 2H), 4.26 - 4.12 (m, 2H), 2.72 (br d, J = 4.2 Hz, 6H). 5-amino-4'-(5-amino-3-((4-((dimethylamino)methyl)phenyl)amino)-1H-1,2,4- triazole-1-carboxamido)-[1,1'-biphenyl]-3-carboxylic acid. To a solution of Pd / C (100 mg, 99 STDU2-43279.601 10% purity) in THF (5 mL) was added 4'-(5-amino-3-((4- ((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)-5-nitro-[1,1'- biphenyl]-3-carboxylic acid (200 mg, 387.22 μmol, 1 eq) under N2 atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 Psi) at 5 25°C for 2 hr. LCMS showed desired compound formed. The mixture was filtered and concentrated under reduced pressure to give 5-amino-4'-(5-amino-3-((4- ((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)-[1,1'-biphenyl]-3- carboxylic acid (180 mg, crude) as a yellow oil. MS (ESI): m / z = 487.3 [M+H]+. 5-acrylamido-4'-(5-amino-3-((4-((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-10 triazole-1-carboxamido)-[1,1'-biphenyl]-3-carboxylic acid. To a solution of 5-amino-4'-(5- amino-3-((4-((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)-[1,1'- biphenyl]-3-carboxylic acid (160 mg, 266.42 μmol, 1 eq, TFA) in THF (1.5 mL) / H2O (1.5 mL) was added NaHCO3 (67.14 mg, 799.27 μmol, 3 eq) and prop-2-enoyl chloride (26.52 mg, 293.07 μmol, 23.81 μL, 1.1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired 15 compound formed. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA condition; column: column: Phenomenex Luna C18100 × 30mm × 5μm;mobile phase: [H2O(0.1% TFA)-ACN];gradient:10%-40% B over 8.0 min) to give 5-acrylamido-4'-(5-amino-3-((4-((dimethylamino)methyl)phenyl)amino)-1H-1,2,4- triazole-1-carboxamido)-[1,1'-biphenyl]-3-carboxylic acid (7.48 mg, 11.09 μmol, 4.16% yield, 20 97.05% purity, TFA) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.71 (s, 1H), 9.47 (s, 2H), 8.37 - 8.16 (m, 2H), 7.91 (s, 1H), 7.81 (dd, J = 8.7, 19.6 Hz, 4H), 7.70 (d, J = 8.6 Hz, 2H), 7.43 (br s, 2H), 7.37 (d, J = 8.6 Hz, 2H), 6.54 - 6.41 (m, 1H), 6.35 - 6.27 (m, 1H), 5.86 - 5.78 (m, 1H), 4.20 (br d, J = 5.1 Hz, 2H), 2.72 (d, J = 4.8 Hz, 6H). MS (ESI): m / z = 541.3 [M+H]+. 25 100 STDU2-43279.601 Compound 28 tro- aniline (2 g, 9.22 mmol, 1 eq) in DCM (30 mL) was added TEA (1.87 g, 18.43 mmol, 2.57 mL, 5 2 eq), Boc2O (2.41 g, 11.06 mmol, 2.54 mL, 1.2 eq) and DMAP (112.59 mg, 921.57 μmol, 0.1 eq). The mixture was stirred at 25°C for 3 hr. TLC indicated the reaction was completed, but the reaction was messy. The reaction was diluted with H2O 20 mL and extracted with DCM 60 mL (20 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica 10 gel chromatography (12 g Silica Flash Column, Eluent of 0~4% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert-butyl (3-bromo-5-nitrophenyl)carbamate (2.3 g, 7.25 mmol, 78.70% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.39 (t, J = 1.9 Hz, 1H), 8.02 (t, J = 1.7 Hz, 1H), 7.94 (t, J = 1.9 Hz, 1H), 1.49 (s, 9H). tert-butyl (4'-amino-5-nitro-[1,1'-biphenyl]-3-yl)carbamate. A mixture of tert-butyl15 (3-bromo-5-nitrophenyl)carbamate (1 g, 3.15 mmol, 1 eq), 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)aniline (690.83 mg, 3.15 mmol, 1 eq), K2CO3(871.59 mg, 6.31 mmol, 2 eq), Pd(dppf)Cl2 (230.72 mg, 315.32 μmol, 0.1 eq) in dioxane (16 mL) / H2O (4 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2atmosphere. LCMS showed desired compound formed. The residue was diluted with 20 H2O 10 mL and extracted with EtOAc 30 mL (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The 101 STDU2-43279.601 residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0~15% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert-butyl (4'-amino-5- nitro-[1,1'-biphenyl]-3-yl)carbamate (750 mg, 2.04 mmol, 64.82% yield, 89.76% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.29 (s, 1H), 8.03 - 7.84 (m, 2H), 5 7.37 (d, J = 8.5 Hz, 2H), 6.67 (d, J = 8.5 Hz, 2H), 5.44 (s, 2H), 1.51 (s, 9H). MS (ESI): m / z = 330.2 [M+H]+. tert-butyl phenyl (5-nitro-[1,1'-biphenyl]-3,4'-diyl)dicarbamate. To a solution of tert- butyl (4'-amino-5-nitro-[1,1'-biphenyl]-3-yl)carbamate (500 mg, 1.52 mmol, 1 eq) in THF (5 mL) / H2O (5 mL) was added NaHCO3 (153.04 mg, 1.82 mmol, 1.2 eq) and phenyl 10 carbonochloridate (261.46 mg, 1.67 mmol, 209.50 μL, 1.1 eq) at 0°C. The mixture was stirred at 0°C for 0.5 hr. LCMS showed desired compound formed. The residue was diluted with H2O 10 mL and extracted with EtOAc 30 mL (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl phenyl (5- nitro-[1,1'-biphenyl]-3,4'-diyl)dicarbamate (560 mg, crude) as a yellow solid. 15 tert-butyl (4'-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1- carboxamido)-5-nitro-[1,1'-biphenyl]-3-yl)carbamate. A mixture of phenyl tert-butyl phenyl (5-nitro-[1,1'-biphenyl]-3,4'-diyl)dicarbamate (560 mg, 1.25 mmol, 1 eq), TEA (126.08 mg, 1.25 mmol, 173.42 μL, 1 eq) in dioxane (6 mL) was stirred at 90°C for 5 min to get mixture 1. Meantime, a mixture of 4-[(5-amino-1H-1,2,4-triazol-3-yl)amino]-N-methyl-benzamide 20 (289.36 mg, 1.25 mmol, 1 eq), TEA (126.08 mg, 1.25 mmol, 173.42 μL, 1 eq) in dioxane (4 mL) was stirred at 90°C for 5 min to get mixture 2. Then mixture 2 was added to mixture 1 at 110°C, the reaction was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110°C for 12 hr under N2atmosphere. LCMS showed desired compound formed. The reaction mixture was filtered and the solid was dried under reduced pressure to give tert-butyl25 (4'-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)-5- nitro-[1,1'-biphenyl]-3-yl)carbamate (480 mg, crude) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 9.77 (s, 1H), 9.52 (s, 1H), 8.43 (s, 1H), 8.21 (br d, J = 4.6 Hz, 1H), 8.13 - 8.05 (m, 2H), 7.86 (d, J = 8.6 Hz, 2H), 7.81 - 7.70 (m, 6H), 7.44 (br s, 2H), 2.77 (d, J = 4.5 Hz, 3H), 1.52 (s, 9H). MS (ESI): m / z = 588.3 [M+H]+. 30 5-amino-N-(3'-amino-5'-nitro-[1,1'-biphenyl]-4-yl)-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. A solution of tert-butyl (4'-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)-5- nitro-[1,1'-biphenyl]-3-yl)carbamate (200 mg, 340.38 μmol, 1 eq) in HCl / EtOAc (4M, 2 mL) was stirred at 25°C for 0.5 hr. LCMS showed desired compound formed. The reaction mixture 102 STDU2-43279.601 was concentrated under reduced pressure to give 5-amino-N-(3'-amino-5'-nitro-[1,1'- biphenyl]-4-yl)-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (200 mg, crude, HCl) as a yellow solid. N-(3'-acrylamido-5'-nitro-[1,1'-biphenyl]-4-yl)-5-amino-3-((4- 5 (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5- amino-N-(3'-amino-5'-nitro-[1,1'-biphenyl]-4-yl)-3-((4-(methylcarbamoyl)phenyl)amino)- 1H-1,2,4-triazole-1-carboxamide (200 mg, 381.73 μmol, 1 eq, HCl) in THF (2 mL) / H2O (2 mL) was added NaHCO3(96.20 mg, 1.15 mmol, 3 eq) and prop-2-enoyl chloride (38.00 mg, 419.90 μmol, 34.12 μL, 1.1 eq) at 0°C. The mixture was stirred at 0°C for 1 hr. LCMS showed 10 desired compound formed. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 100*30mm*5μm; mobile phase: [H2O(0.1% TFA)- ACN];gradient:15%-65% B over 8.0 min ). The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 100 × 30mm × 5μm;mobile phase: [H2O(0.1%15 TFA)-ACN];gradient:25%-55% B over 10.0 min ) to give N-(3'-acrylamido-5'-nitro-[1,1'- biphenyl]-4-yl)-5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1- carboxamide (6.52 mg, 11.74 μmol, 3.08% yield, 97.53% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.78 (s, 1H), 9.53 (s, 1H), 8.66 (t, J = 1.9 Hz, 1H), 8.31 (s, 1H), 8.23 - 8.18 (m, 2H), 7.92 - 7.86 (m, 2H), 7.81 - 7.69 (m, 6H), 7.49 - 7.38 (m, 2H), 6.51 20 - 6.42 (m, 1H), 6.40 - 6.32 (m, 1H), 5.91 - 5.82 (m, 1H), 2.77 (d, J = 4.5 Hz, 3H). MS (ESI): m / z = 542.3 [M+H]+. 103 STDU2-43279.601 Compound 29 mo- benzonitrile (2 g, 10.15 mmol, 1 eq) in DCM (30 mL) was added TEA (2.05 g, 20.30 mmol, 5 2.83 mL, 2 eq), Boc2O (2.66 g, 12.18 mmol, 2.80 mL, 1.2 eq) and DMAP (124.01 mg, 1.02 mmol, 0.1 eq). TLC indicated the reaction was completed, but the reaction was messy. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~4% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert-butyl (3-bromo-5-cyanophenyl)carbamate (2.5 g, 10 7.57 mmol, 74.60% yield, 90% purity) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ 7.84 (s, 1H), 7.66 (s, 1H), 7.43 (t, J = 1.4 Hz, 1H), 6.62 (br s, 1H), 1.53 (s, 9H). tert-butyl (4'-amino-5-cyano-[1,1'-biphenyl]-3-yl)carbamate. A mixture of tert-butyl (3-bromo-5-cyanophenyl)carbamate (1 g, 3.37 mmol, 1 eq) , 4-(4,4,5,5-tetramethyl-1,3,2- 15 dioxaborolan-2-yl)aniline (811.03 mg, 3.70 mmol, 1.1 eq) , K2CO3(930.25 mg, 6.73 mmol, 2 eq), Pd(dppf)Cl2(246.24 mg, 336.53 μmol, 0.1 eq) in dioxane (16 mL) / H2O (4 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2atmosphere. LCMS showed desired compound formed. The residue was diluted with H2O 10 mL and extracted with EtOAC 60 mL (20 mL * 3). The combined organic layers were 20 dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The 104 STDU2-43279.601 residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0~20% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert-butyl (4'-amino-5- cyano-[1,1'-biphenyl]-3-yl)carbamate (900 mg, 2.78 mmol, 82.63% yield, 95.58% purity) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.91 (s, 1H), 7.69 (s, 1H), 7.57 (s, 5 1H), 7.34 (d, J = 8.5 Hz, 2H), 6.65 (d, J = 8.5 Hz, 2H), 5.38 (s, 2H), 1.49 (s, 9H). MS (ESI): m / z = 310.2 [M+H]+. tert-butyl phenyl (5-cyano-[1,1'-biphenyl]-3,4'-diyl)dicarbamate. To a solution of tert- butyl (4'-amino-5-cyano-[1,1'-biphenyl]-3-yl)carbamate (500 mg, 1.62 mmol, 1 eq) in THF (5 mL) / H2O (5 mL) was added NaHCO3 (162.93 mg, 1.94 mmol, 75.47 μL, 1.2 eq) and phenyl 10 carbonochloridate (278.35 mg, 1.78 mmol, 223.04 μL, 1.1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound formed. The residue was diluted with H2O 10 mL and extracted with EtOAc 30 mL (10 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl phenyl (5-cyano- [1,1'-biphenyl]-3,4'-diyl)dicarbamate (636 mg, crude) as a white solid. 15 tert-butyl (4'-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1- carboxamido)-5-cyano-[1,1'-biphenyl]-3-yl)carbamate. A mixture of tert-butyl phenyl (5- cyano-[1,1'-biphenyl]-3,4'-diyl)dicarbamate (230 mg, 535.55 μmol, 1 eq), TEA (54.19 mg, 535.55 μmol, 74.54 μL, 1 eq) in dioxane (2 mL) was stirred at 90°C for 5 min to get mixture 1. Meantime, a mixture of 4-[(5-amino-1H-1,2,4-triazol-3-yl)amino]-N-methyl-benzamide 20 (124.38 mg, 535.55 μmol, 1 eq), TEA (54.19 mg, 535.55 μmol, 74.54 μL, 1 eq) in dioxane (2 mL) was stirred at 90°C for 5 min to get mixture 2. Then mixture 2 was added to mixture 1 at 110°C, the reaction was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110°C for 12 hr under N2atmosphere. LCMS showed desired compound formed. The mixture was filtered and the filter cake was dried to give the desired product tert-butyl (4'-(5-25 amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)-5-cyano- [1,1'-biphenyl]-3-yl)carbamate (180 mg, crude) as a white solid.1H NMR (400 MHz, DMSO- d6) δ 9.85 - 9.65 (m, 2H), 9.52 (s, 1H), 8.21 (br d, J = 4.5 Hz, 1H), 8.05 (s, 1H), 7.82 (br s, 2H), 7.77 (s, 2H), 7.74 - 7.65 (m, 5H), 7.50 (d, J = 8.8 Hz, 1H), 7.43 (br s, 2H), 2.76 (d, J = 4.4 Hz, 3H), 1.50 (s, 9H). 30 5-amino-N-(3'-amino-5'-cyano-[1,1'-biphenyl]-4-yl)-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. A solution of tert-butyl (4'-(5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)-5- cyano-[1,1'-biphenyl]-3-yl)carbamate (180 mg, 317.13 μmol, 1 eq) in DCM (2 mL) was added TFA (921.00 mg, 8.08 mmol, 0.6 mL, 25.47 eq). The reaction was stirred at 25°C for 40 min. 105 STDU2-43279.601 LCMS showed full consumption of starting material and 83.8% of the desired mass peak. The reaction was concentrated under reduced pressure to remove solvent and excess TFA reagent. No purification was performed. The sample was directly used to the next step. The reaction was successful. The crude product 5-amino-N-(3'-amino-5'-cyano-[1,1'-biphenyl]-4-yl)-3-((4- 5 (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (380 mg, 294.06 μmol, 92.73% yield, 45% purity, TFA) was obtained as a white solid and used into the next step without further purification. N-(3'-acrylamido-5'-cyano-[1,1'-biphenyl]-4-yl)-5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a suspension of 5-10 amino-N-(3'-amino-5'-cyano-[1,1'-biphenyl]-4-yl)-3-((4-(methylcarbamoyl)phenyl)amino)- 1H-1,2,4-triazole-1-carboxamide (380 mg, 294.06 μmol, 1 eq, TFA) in THF (3 mL) and H2O (3 mL) was added NaHCO3 (74.11 mg, 882.19 μmol, 3 eq) at 0°C. The mixture was then added acryloyl chloride (31.94 mg, 352.88 μmol, 28.67 μL, 1.2 eq) at 0°C under stirring. The reaction was stirred at 0°C for 1 hr. The reaction was concentrated using a nitrogen flow to remove most 15 of the THF solvent. The residue was purified by prep-HPLC {column: Phenomenex Luna C18 100*30mm*5μm;mobile phase: [H2O(0.1% TFA)- ACN];gradient:25%-55% B over 8.0 min}. The fraction was lyophilized to give N-(3'-acrylamido-5'-cyano-[1,1'-biphenyl]-4-yl)-5-amino- 3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (25.58 mg, 46.35 μmol, 15.76% yield, 94.50% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.58 20 (s, 1H), 9.75 (s, 1H), 9.52 (s, 1H), 8.21 (br d, J = 4.8 Hz, 1H), 8.18 (br d, J = 1.6 Hz, 1H), 8.13 (s, 1H), 7.90 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.80 - 7.71 (m, 6H), 7.43 (br s, 2H), 6.46 (dd, J = 9.9, 16.9 Hz, 1H), 6.34 (dd, J = 1.9, 17.1 Hz, 1H), 5.88 - 5.84 (m, 1H), 2.76 (d, J = 4.5 Hz, 3H). MS (ESI): m / z = 522.3 [M+H]+. 106 STDU2-43279.601 Compound 30 .17 mmol, 1 eq), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.01 g, 9.17 mmol, 1 eq), 5 K2CO3(2.54 g, 18.35 mmol, 2 eq), Pd(dppf)Cl2(671.27 mg, 917.41 μmol, 0.1 eq) in dioxane (20 mL) / H2O (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12hr under N2atmosphere. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~30% Ethyl 10 acetate / Petroleum ether gradient @ 80 mL / min) to give 4'-amino-5-nitro-[1,1'-biphenyl]-3-ol (2 g, 8.62 mmol, 93.97% yield, 99.24% purity) as a yellow solid.1H NMR (400 MHz, DMSO- d6) δ = 10.39 (br s, 1H), 7.76 (t, J = 1.8 Hz, 1H), 7.43 - 7.37 (m, 3H), 7.34 (t, J = 1.8 Hz, 1H), 6.65 (d, J = 8.7 Hz, 2H), 5.40 (s, 2H). MS (ESI): m / z = 231.2[M+H]+. phenyl (3'-hydroxy-5'-nitro-[1,1'-biphenyl]-4-yl)carbamate. To a solution of 4'- 15 amino-5-nitro-[1,1'-biphenyl]-3-ol (1 g, 4.34 mmol, 1 eq) in THF (10 mL) / H2O (5 mL) was added phenyl carbonochloridate (816.11 mg, 5.21 mmol, 653.93 μL, 1.2 eq) and NaHCO3(401.40 mg, 4.78 mmol, 1.1 eq). The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound was detected. The residue was diluted with H2O 10 mL and extracted with EtOAc (20 mL × 2). The combined organic layers were dried over Na2SO4, filtered and concentrated 20 under reduced pressure to give phenyl (3'-hydroxy-5'-nitro-[1,1'-biphenyl]-4-yl)carbamate (1.5 g, crude) as a yellow solid. 5-amino-N-(3'-hydroxy-5'-nitro-[1,1'-biphenyl]-4-yl)-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. A mixture of 4-[(5- amino-1H-1,2,4-triazol-3-yl)amino]-N-methyl-benzamide (994.40 mg, 4.28 mmol, 1 eq) and 25 TEA (433.27 mg, 4.28 mmol, 595.96 μL, 1 eq) in dioxane (20 mL) was stirred at 90°C for 10 107 STDU2-43279.601 min to get mixture 1. Meantime, a mixture of (3'-hydroxy-5'-nitro-[1,1'-biphenyl]-4- yl)carbamate (1.5 g, 4.28 mmol, 1 eq) and TEA (433.27 mg, 4.28 mmol, 595.96 μL, 1 eq) in dioxane (10 mL) was stirred at 90°C for 10 min to get mixture 2. Then mixture 2 was added to mixture 1 at 90°C and the reaction was degassed and purged with N2for 3 times, and then the 5 mixture was stirred at 110°C for 12 hr under N2 atmosphere. LCMS showed desired compound was detected. The reaction mixture was filtered and the solid was dried under reduced pressure to give 5-amino-N-(3'-hydroxy-5'-nitro-[1,1'-biphenyl]-4-yl)-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (1.5 g, crude) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.59 (br s, 1H), 9.75 (s, 1H), 9.52 (s, 1H), 8.21 (br d, 10 J = 4.5 Hz, 1H), 7.93 (t, J = 1.8 Hz, 1H), 7.87 - 7.83 (m, 2H), 7.81 - 7.71 (m, 6H), 7.53 (td, J = 2.0, 16.3 Hz, 2H), 7.44 (br s, 2H), 2.77 (d, J = 4.5 Hz, 3H). MS (ESI): m / z = 489.3[M+H]+. 5-amino-N-(3'-amino-5'-hydroxy-[1,1'-biphenyl]-4-yl)-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5- amino-N-(3'-hydroxy-5'-nitro-[1,1'-biphenyl]-4-yl)-3-((4-(methylcarbamoyl)phenyl)amino)- 15 1H-1,2,4-triazole-1-carboxamide (300 mg, 614.18 μmol, 1 eq) in EtOH (4 mL) / H2O (1 mL) was added Fe (171.49 mg, 3.07 mmol, 5 eq) and NH4Cl (164.27 mg, 3.07 mmol, 5 eq). The mixture was stirred at 80°C for 1 hr. LCMS showed desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to give 5-amino-N-(3'- amino-5'-hydroxy-[1,1'-biphenyl]-4-yl)-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4- 20 triazole-1-carboxamide (170 mg, crude) as a white solid. N-(3'-acrylamido-5'-hydroxy-[1,1'-biphenyl]-4-yl)-5-amino-3-((4- (methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5- amino-N-(3'-amino-5'-hydroxy-[1,1'-biphenyl]-4-yl)-3-((4-(methylcarbamoyl)phenyl)amino)- 1H-1,2,4-triazole-1-carboxamide (170 mg, 370.80 μmol, 1 eq) in THF (3 mL) / H2O (1.5 mL) 25 was added NaHCO3(62.30 mg, 741.59 μmol, 2 eq) and prop-2-enoyl chloride (33.56 mg, 370.80 μmol, 30.13 μL, 1 eq) at 0°C. The mixture was stirred at 0°C for 1 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 100×30mm×5μm;mobile phase: [H2O(0.1% TFA)-ACN];30 gradient:20%-50% B over 8.0 min) to give N-(3'-acrylamido-5'-hydroxy-[1,1'-biphenyl]-4-yl)- 5-amino-3-((4-(methylcarbamoyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (89.48 mg, 173.21 μmol, 46.71% yield, 99.21% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 9.69 (s, 1H), 9.51 (s, 1H), 8.21 (q, J = 4.0 Hz, 1H), 7.82 - 7.69 (m, 6H), 7.59 108 STDU2-43279.601 (d, J = 8.6 Hz, 2H), 7.42 (br s, 2H), 7.37 (s, 1H), 7.27 (s, 1H), 6.76 (s, 1H), 6.52 - 6.40 (m, 1H), 6.32 - 6.21 (m, 1H), 5.80 - 5.69 (m, 1H), 2.76 (d, J = 4.4 Hz, 3H). MS (ESI): m / z = 513.3[M+H]+. Compound 31 5 tetrahydropyridin-3-yl)phenyl)-1H-1,2,4-triazole-1-carboxamide. A mixture of N3-(4- ((dimethylamino)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine (100 mg, 289 μmol, 1.0 eq, TFA salt) and TEA (29.2 mg, 289 μmol, 40.3 μL, 1.0 eq) in Dioxane (2.5 mL) was stirred at10 90 ℃ for 10 min to get mixture 1. Meantime, a mixture of tert-butyl 5-(4- ((phenoxycarbonyl)amino)phenyl)-3,4-dihydropyridine-1(2H)-carboxylate (171 mg, 433 μmol, 1.5 eq) and TEA (29.2 mg, 289 μmol, 40.2 μL, 1.0 eq) in Dioxane (2.5 mL) was stirred at 90 ℃ for 10 min to get mixture 2.Then mixture 2 was added into mixture 1. The mixture was stirred at 110 ℃ overnight. LCMS indicating one major peak with desired mass was 15 formed. The mixture was concentrated to obtain a brown residue. Then purified by prep-HPLC prep-HPLC [SunFire C18 OBD Prep Column, 100Å, 5 μm, 30 mm × 250 mm; A: H2O (0.0375% TFA), B: MeOH (0.0375% TFA); A%: 85%-5%, 40 ml / min, 60 min] and concentrated to obtain a light brown residue. The residue was dissolved into a mixture of 2 ml DCM and 2 ml TFA, then stirred at rt for 1h. LCMS indicating the reaction was completed and desired product 20 formed. The residue was concentrated and then lyophilized to obtain a white powder (177.6 mg, TFA salt). MS: m / z = 433.23 [M+H]+. N-(4-(1-acryloyl-1,4,5,6-tetrahydropyridin-3-yl)phenyl)-5-amino-3-((4- ((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5-amino-3-((4-((dimethylamino)methyl)phenyl)amino)-N-(4-(1,4,5,6-tetrahydropyridin-3- 25 yl)phenyl)-1H-1,2,4-triazole-1-carboxamide (40 mg, 61 μmol, 1.0 eq, 2TFA salt) in DMF (2 mL) at 0 ℃ was added DIEA (39 mg, 0.30 mmol, 53 μL, 5.0 eq,) and acryloyl chloride (6.0 mg, 67 μmol, 0.13 mL, 0.5 molar in DCM, 1.1 eq). The mixture was stirred at rt for 30 min. LCMS indicating some desired product formed. The mixture was purified by prep- HPLC [SunFire C18 OBD Prep Column, 100Å, 5 μm, 30 mm × 250 mm; A: H2O (0.0375%30 TFA), B: MeOH (0.0375% TFA); A%: 99%-10%, 40 ml / min, 60 min] to give N-(4-(1- 109 STDU2-43279.601 acryloyl-1,4,5,6-tetrahydropyridin-3-yl)phenyl)-5-amino-3-((4- ((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (0.6 mg) as a white powder. MS: m / z = 487.23 [M+H]+.1H NMR (500 MHz, DMSO-d6) δ 9.56 – 9.51 (m, 1H), 9.15 (s, 1H), 8.28 (s, 1H), 7.69 – 7.58 (m, 4H), 7.52 – 7.51 (m, 1H), 7.46 – 7.40 (m, 2H), 7.35 5 (s, 2H), 7.16 (d, J = 8.3 Hz, 2H), 6.89 (dd, J = 16.6, 10.4 Hz, 1H), 6.24 (t, J = 17.0 Hz, 1H), 5.81 (d, J = 10.0 Hz, 1H), 3.77 – 3.75 (m, 1H), 3.70– 3.67 (m, 1H), 3.32 (s, 2H), 2.99 – 2.98 (m, 2H), 2.12 (s, 6H), 1.95 – 1.91 (m, 2H). Compound 32 10 ((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. A mixture of N3- (4-((dimethylamino)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine (60 mg, 0.17 mmol, 1.0 eq, TFA salt) and TEA (35 mg, 0.35 mmol, 48 μL, 2 eq) in Dioxane (2.5 mL) was stirred at 90 ℃15 for 10 min to obtain mixture 1. Meantime, a mixture of tert-butyl 3-(4- ((phenoxycarbonyl)amino)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (80 mg, 0.21 mmol, 1.2 eq) and TEA (35 mg, 0.35 mmol, 48 μL, 2.0 eq) in Dioxane (2.5 mL) was stirred at 90 ℃ for 10 min to obtain mixture 2. Then mixture 2 was added into mixture 1. The mixture was stirred at 110 ℃ overnight. LCMS indicating one major peak with desired mass formed. The20 mixture was concentrated to obtain a brown residue. Then purified by prep-HPLC prep- HPLC [SunFire C18 OBD Prep Column, 100Å, 5 μm, 30 mm × 250 mm; A: H2O (0.0375% TFA), B: MeOH (0.0375% TFA); A%: 99%-10%, 40 ml / min, 60 min] and concentrated to obtain a light brown residue. The residue was dissolved into a mixture of 2 ml DCM and 2 ml TFA, then stirred at rt for 1h. LCMS indicating the reaction was completed and desired product 25 formed. The residue was concentrated and then lyophilized to obtain a white powder. (84.6 mg, TFA salt). MS: m / z = 419.23 [M+H]+. N-(4-(1-acryloyl-2,5-dihydro-1H-pyrrol-3-yl)phenyl)-5-amino-3-((4- ((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5-amino-N-(4-(2,5-dihydro-1H-pyrrol-3-yl)phenyl)-3-((4- 30 ((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (40 mg, 62 μmol, 1.0 eq) in DMF (1.5 mL) at 0 ℃ was added DIEA (26 mg, 0.31 mmol, 35 μL, 5.0 eq) and 110 STDU2-43279.601 acryloyl chloride (6.2 mg, 68 μmol, 0.14 mL, 0.5 molar in DCM, 1.1 eq) and the mixture was stirred at rt for 1h. LCMS indicating the reaction worked well and desired product formed. The mixture was purified by prep-HPLC prep-HPLC [SunFire C18 OBD Prep Column, 100Å, 5 μm, 30 mm × 250 mm; A: H2O (0.0375% TFA), B: MeOH (0.0375% TFA); A%: 99%-10%, 5 40 ml / min, 60 min] and lyophilized to obtain a white powder. MS: m / z = 473.28 [M+H]+.1H NMR (500 MHz, DMSO-d6) δ 9.69 (s, 1H), 9.60 (s, 1H), 9.39 (s, 1H), 7.67 (dd, J = 26.2, 8.4 Hz, 4H), 7.48 (dd, J = 8.6, 3.2 Hz, 2H), 7.35 (s, 1H), 7.31 (d, J = 8.5 Hz, 2H), 6.71 – 6.55 (m, 1H), 6.35 (q, J = 2.2 Hz, 1H), 6.16 (dd, J = 16.7, 2.4 Hz, 1H), 5.70 – 5.66 (m, 1H), 4.73 (q, J = 3.2 Hz, 1H), 4.52 – 4.46 (m, 2H), 4.28 (q, J = 3.2 Hz, 1H), 4.12 (d, J = 5.1 Hz, 2H), 2.63 (d, 10 J = 4.9 Hz, 6H). Compound 33 f 4-15 bromoaniline (300 mg, 1.74 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrole-1-carboxylate (541 mg, 1.83 mmol, 1.05 eq), K2CO3 (481 mg, 3.49 mmol, 2.0 eq) and PdCl2(dppf) (128 mg, 174 μmol, 0.1 eq) in Dioxane (4 mL) and Water (0.8 mL) was degassed and the mixture was stirred at 90 ℃ overnight. LCMS indicating desired product formed. The mixture was partitioned into 20 ml EA and 20 ml water, 20 then filtered with celite to remove the insoluble material. The EA layer was dried with anhydrous Na2SO4 and then concentrated to obtain a brown residue. The residue was purified by silica gel chromatography (Combi flash, Hexane: EA=6:1 to 2:1) to obtain a light yellow solid. MS: m / z = 261.17 [M+H]+. Tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-2,3-dihydro-1H-pyrrole-1-25 carboxylate. To a solution of tert-butyl 4-(4-aminophenyl)-2,3-dihydro-1H-pyrrole-1- 111 STDU2-43279.601 carboxylate (200 mg, 768 μmol, 1.0 eq) in a mixture of THF (6 mL) and Water (3 mL) at 0 ℃ was added NaHCO3(77.4 mg, 922 μmol, 1.2 eq) and Phenyl chloroformate (132 mg, 845 μmol, 106 μL, 1.1 eq) and the mixture was stirred at 0℃ for 1h. LCMS indicating desired product formed. The mixture was partitioned into 10 ml water and 20 ml EA, the organic layer was 5 separated and washed with 20 ml brine, then dried with anhydrous Na2SO4, filtered and concentrated, then lyophilized to obtain a white solid. MS: m / z = 281.12 [M-Boc+H]+. 5-amino-N-(4-(4,5-dihydro-1H-pyrrol-3-yl)phenyl)-3-((4- ((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. A mixture of N3- (4-((dimethylamino)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine (100 mg, 289 μmol, 1.0 eq 10 TFA salt) and TEA (58.4 mg, 578 μmol, 80.5 μL, 2.0 eq) in Dioxane (2.5 mL) was stirred at 90 ℃ for 10 min to obtain mixture 1. Meantime, a mixture of tert-butyl 4-(4- ((phenoxycarbonyl)amino)phenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (165 mg, 433 μmol, 1.5 eq) and TEA (58.4 mg, 578 μmol, 80.5 μL, 2.0 eq) in Dioxane (2.5 mL) was stirred at 90 ℃ for 10 min to obtain mixture 2. Then mixture 2 was added into mixture 1. The mixture was 15 stirred at 110 ℃ overnight. LCMS indicating one major peak with desired MS formed. The mixture was concentrated to obtain a brown residue. Then purified by prep-HPLC prep- HPLC [SunFire C18 OBD Prep Column, 100Å, 5 μm, 30 mm × 250 mm; A: H2O (0.0375% TFA), B: MeOH (0.0375% TFA); A%: 99%-10%, 40 ml / min, 60 min] and concentrated to obtain a light brown residue. The residue was dissolved into a mixture of 2 ml DCM and 2 ml 20 TFA, then stirred at rt for 1h. LCMS indicating the reaction was completed and desired product formed. The residue was concentrated and then lyophilized to obtain a white powder. MS: m / z = 419.23 [M+H]+. N-(4-(1-acryloyl-4,5-dihydro-1H-pyrrol-3-yl)phenyl)-5-amino-3-((4- ((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of25 5-amino-N-(4-(4,5-dihydro-1H-pyrrol-3-yl)phenyl)-3-((4- ((dimethylamino)methyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide (16 mg, 25 μmol, 1.0 eq, TFA salt) in DMF (1 mL) at -20 ℃ was added acryloyl chloride (3.4 mg, 37 μmol, 74 μL, 0.5 molar in DMF, 1.5 eq) and the mixture was stirred at -20 ℃ for 5 min. LCMS indicating some reactant was remined and some desired product formed. The mixture was purified by 30 Pre-HPLC [Agilent Pursuit XRs 5 C18150 × 10 mm; A: H2O (0.1% FA), B: ACN (0.1% FA); A%: 95%-5%, 5 ml / min, 30 min] and lyophilized to obtain a white powder. MS: m / z = 473.28 [M+H]+.1H NMR (500 MHz, DMSO-d6) δ 9.53 – 9.52 (m, 1H), 9.33 (s, 1H), 7.67 (d, J = 10.0 Hz, 2H), 7.58 (d, J = 10.0 Hz, 2H), 7.52 – 7.46 (m, 1H), 7.44 – 7.41 (m, 2H), 7.33 (brs, 2H), 7.26 (d, J = 8.2 Hz, 2H), 6.99 – 6.92 (m, 1H), 6.22 – 6.15 (m, 1H), 5.73 – 5.69 (m, 1H), 4.09 – 112 STDU2-43279.601 4.06 (m, 1H), 3.96 (brs, 2H), 3.89 – 3.85 (m, 1H), 3.02 – 2.99 (m, 1H), 2.86 – 2.82 (m, 1H), 2.53 (brs, 6H). Compound 34 5 f 4- (morpholinomethyl)aniline (1 g, 5 mmol, 1.0 eq) in Isopropanol (10 mL) was added diphenyl cyanocarbonimidate (1.5 g, 6.3 mmol, 1.0 eq) and the mixture was stirred at 80 °C for 12 hours. LCMS showed desired compound formed. The reaction mixture was concentrated under 10 reduced pressure. The residue was diluted with H2O 20 mL and extracted with EtOAc 60 mL (20 mL× 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0-40% Ethyl acetate / Hexane gradient @ 100 mL / min) to give phenyl N'-cyano-N-(4-(morpholinomethyl)phenyl)carbamimidate (1.34 15 g) as a tan powder. MS: m / z = 337.27 [M+H]+. N3-(4-(morpholinomethyl)phenyl)-1H-1,2,4-triazole-3,5-diamine. To a solution of phenyl N'-cyano-N-(4-(morpholinomethyl)phenyl)carbamimidate (700 mg, 2.08 mmol, 1.0 eq) in THF (6.5 mL) was added hydrazine hydrate (198 mg, 3.95 mmol, 192 μL, 1.9 eq) at 0°C and the mixture was stirred at 60 °C for 2 hours. LCMS showed desired compound formed. 20 The mixture was filtered and the solid was dried under reduced pressure to give intermediate N3-(4-(morpholinomethyl)phenyl)-1H-1,2,4-triazole-3,5-diamine (519.90 mg) as a yellow powder. MS: m / z = 275.22 [M+H]+. tert-butyl 5-(4-(5-amino-3-((4-(morpholinomethyl)phenyl)amino)-1H-1,2,4-triazole- 1-carboxamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate. A mixture of tert-butyl 5-(4- 25 ((phenoxycarbonyl)amino)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (59 mg, 0.15 113 STDU2-43279.601 mmol, 1.0 eq) and TEA (15 mg, 0.15 mmol, 21 μL, 1.0 eq) in 1,4-Dioxane (2 mL) was stirred at 90 °C for 10 min. At the same time, a separate mixture of N3-(4-(morpholinomethyl)phenyl)- 1H-1,2,4-triazole-3,5-diamine (41 mg, 0.15 mmol, 1.0 eq) and TEA (15 mg, 0.15 mmol, 21 μL, 1.0 eq) in 1,4-Dioxane (2 mL) was stirred at 90 °C for 10 min. Mixture 1 was added to 5 mixture 2 at 90 °C and the reaction was degassed and purged with N2 for 3 times. Then, the mixture was stirred at 110 °C for 12 hours under N2atmosphere. LCMS showed desired compound was detected. The reaction mixture was filtered and the solid was dried under reduced pressure to give crude intermediate tert-butyl 5-(4-(5-amino-3-((4- (morpholinomethyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)phenyl)-3,6- 10 dihydropyridine-1(2H)-carboxylate (20.2 mg) that was used in the next step directly. MS: m / z = 575.19 [M+H]+. 5-amino-3-((4-(morpholinomethyl)phenyl)amino)-N-(4-(1,2,5,6-tetrahydropyridin- 3-yl)phenyl)-1H-1,2,4-triazole-1-carboxamide. A solution of tert-butyl 5-(4-(5-amino-3-((4- (morpholinomethyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamido)phenyl)-3,6- 15 dihydropyridine-1(2H)-carboxylate (20.2 mg, 35.1 μmol, 1.0 eq) in a mixture of DCM and TFA was stirred at 25 °C for 15 min. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to yield 5-amino-3-((4- (morpholinomethyl)phenyl)amino)-N-(4-(1,2,5,6-tetrahydropyridin-3-yl)phenyl)-1H-1,2,4- triazole-1-carboxamide (17.76 mg, TFA salt) as a white solid. MS: m / z = 475.18 [M+H]+.20 N-(4-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)phenyl)-5-amino-3-((4- (morpholinomethyl)phenyl)amino)-1H-1,2,4-triazole-1-carboxamide. To a solution of 5- amino-3-((4-(morpholinomethyl)phenyl)amino)-N-(4-(1,2,5,6-tetrahydropyridin-3- yl)phenyl)-1H-1,2,4-triazole-1-carboxamide (17.76 mg, 34.75 μmol, 1.0 eq) in THF (2 mL) / Water (1 mL) was added sodium bicarbonate (8.76 mg, 104.3 μmol, 3.0 eq) and acryloyl 25 chloride (3.46 mg, 38.23 μmol, 3.1 μL, 1.1 eq). The mixture was stirred at 0 °C for 1 hour. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by prep-HPLC [SunFire C18 OBD Prep Column, 100Å, 5 μm, 30 mm × 250 mm; A: H2O (0.0375% TFA), B: MeOH (0.0375% TFA); A%: 85%-5%, 40 ml / min, 60 min] to give N-(4-(1-acryloyl-1,2,5,6-tetrahydropyridin-30 3-yl)phenyl)-5-amino-3-((4-(morpholinomethyl)phenyl)amino)-1H-1,2,4-triazole-1- carboxamide (5.94 mg, TFA salt) as a white solid. MS: m / z = 529.24 [M+H]+.1H NMR (500 MHz, DMSO-d6) δ 9.79 (s, 1H), 9.63 (s, 1H), 9.48 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.71 – 7.65 (m, 2H), 7.54 – 7.47 (m, 2H), 7.44 – 7.36 (m, 4H), 7.03 – 6.89 (m, 1H), 6.39 – 6.30 (m, 1H), 6.19 – 6.14 (m, 1H), 5.74 – 5.71 (m, 1H), 4.49 – 4.41 (m, 2H), 4.28 (d, J = 4.1 Hz, 2H), 114 STDU2-43279.601 4.01 – 3.94 (m, 2H), 3.77 – 3.64 (m, 2H), 3.27 (d, J = 12.3 Hz, 2H), 3.10 – 3.07 (m, 2H), 2.39 – 2.26 (m, 2H). Biological Assays 5 Intact mass spectrum testing. Buffer condition: 200 mM NaCl, 20 mM Tris-HCl, pH 8.5, 200 μM TCEP, 1% DMSO (from the compound).1:10 protein / test compound ratio (protein conc @1.0uM) mixture was incubated for 1-hour at room temperature, then the mixture was quenched with 0.2% formic acid. The quenched assay plates were analyzed with an Agilent RapidFire 360 system 10 connected to an Agilent 6545 Q-TOF mass spectrometer equipped with an AJS source. 10 mL of sample volume was loaded onto a C4 based cartridge (Agilent, Column A) with loading buffer (ddH2O with 0.09% (vol / vol) formic acid and 0.01% (vol / vol) trifluoroacetic acid; 1.25 ml / min) for 6 seconds before being eluted directly into the mass spectrometer in elution buffer (80% acetonitrile with 0.09% (vol / vol) formic acid and 0.01% (vol / vol) trifluoroacetic acid; 15 0.5 ml / min) for 7 seconds. The cartridge was re-equilibrated with loading buffer for 1 second before collection of the next sample. The Q-TOF was operated in TOF-only positive ionization mode set to the following parameters: Gas Temp = 350 C, Drying Gas = 7 l / min, Nebulizer = 50 psi, Sheath Gas Temp = 400 C, Sheath Gas Flow = 12 l / min, VCap = 4000 V, Nozzle Voltage = 1000V, Fragmentor = 125 V, Skimmer = 65 V and Oct 1 RF Vpp = 750V. Raw MS 20 data files were deconvoluted and analyzed using the Agilent MassHunter Bioconfirm software package to identify both parent protein and expected compound adduct mass signatures. The results are shown in Tabel 1. Table 1. Mass spectra result of the compounds incubated with JAK2 JH2 Compound Covalent Label rate Compound Covalent Label rate 115 STDU2-43279.601 11 ++ 28 + 12 ++ 29 + +++ re ers to cova ent a e rate o 75% 5 JAK2 JH2 domain binding activity by KdELECT assay. The binding activity of the compounds to JAK2 JH2 domain was evaluated by the KdELECT assay at Eurofins DiscoverX Corporation. The JAK2 JH2 domain tagged T7 phage strains were prepared in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage and incubated with shaking at 32°C until lysis. The lysates were centrifuged and filtered to remove 10 cell debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove 15 unbound ligand and to reduce non-specific binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 111X stocks in 100% DMSO. Kds were determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements are distributed 20 by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. All reactions performed in polypropylene 384-well plate. Each was a final volume of 0.02 ml. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1x PBS, 0.05% Tween 20). The beads were then re-suspended 25 in elution buffer (1x PBS, 0.05% Tween 20, 0.5 µM nonbiotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR. Binding constants (Kds) were calculated with a standard dose-response curve using the Hill equation: Response = Background + (Signal-Background) / [1+(KdHill Slope / DoseHill Slope). The 30 Hill Slope was set to -1. Curves were fitted using a non-linear least square fit with the Levenberg-Marquardt algorithm. The data of some compounds are shown in Tabel 2. 116 STDU2-43279.601 Table 2. JAK2 JH2 binding constants (Kds) of some selected compounds Compound Kd Compound Kd 1 * 13 ** *** refers to Kd of ≤100 nM 5 STAT3 Reporter Assay. Human erythroleukemia cell line (HEL92.1.7) was obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA). Cells were cultured in RPMI 1640 supplemented with 10% heat-inactivated FBS, 100 units / mL penicillin, 100 µg / mL streptomycin, and 0.25 µg / mL amphotericin B. Cells were incubated at 37°C with 5% 10 CO2in a humidified atmosphere. Mycoplasma testing was performed monthly using the MycoAlert mycoplasma detection kit (Lonza, Basel, Switzerland) and all lines were negative. STAT3 luciferase reporter lentivirus (BPS Bioscience, San Diego, CA, USA) was used to transduce HEL92.1.7 cells cultured as described above, and transductants were selected by growth in 1 µg / mL puromycin (Gibco Invitrogen Corp., Grand Island, NY, USA) added 15 directly to the culture medium. Briefly, cells were seeded in 384-well plates (Corning, Corning, NY, USA, cat. no. 3570) and incubated overnight. Subsequently, the cells were treated with the indicated concentrations of compounds. After indicated treatment period, the plates were subjected to Bright-Glo Luciferase Assay System (Promega, Madison, WI, USA) as described in the manufacturer's manual. The reporter assays were performed in biological triplicate. IC5020 values were determined using a non-linear regression curve fit in GraphPad PRISM 10.3.0. Table 3. STAT3 reporter assay IC50 of some selected compounds Compound IC50 Compound IC50 117 STDU2-43279.601 12●27●13●●●31●●● 5 Cell Viability Assay (CellTiter-Glo Assay). Cell viability was evaluated using the CellTiter-Glo assay (Promega). Briefly, HEL92.1.7 cells were seeded in 384-well plates and incubated overnight. Subsequently, the cells were treated with the indicated concentrations of compounds. After 72 h, the plates were subjected to CellTiter-Glo as described in the manufacturer's manual. The proliferation assays were performed in biological triplicate. IC5010 values were determined using a non-linear regression curve fit in GraphPad PRISM 10.3.0. Table 4. Cell Viability Assay IC50 of some selected compounds Compound IC50 Compound IC50 4♢♢ ♢♢♢ ♢♢ refers to IC50 of > 5 μM to ≤ 10 μM 15 ♢♢♢ refers to IC50 of ≤5 μM 118

Claims

STDU2-43279.601 CLAIMS 1. A compound of formula (I): (I) 5 or a pharmaceutically : R1is selected from -CONRaRb, –(CH2)mNRcRd, -(CH2)nORe, -(CH2)pNRfZRg, - NRh(CH2)qNRiRj, -(CH2)r-heterocyclyl, and -(CH2)s-heteroaryl; m, n, p, q, r, and s are each independently 0, 1, or 2; Z is -C(O)- or –S(O)2-; 10 A is aryl or heteroaryl; X is selected from a bond, heterocyclyl, and aryl; R2is a warhead moiety; R3is selected from hydrogen and C1-C4 alkyl; R4is selected from hydrogen and -O-C1-C4alkyl; and 15 Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, and Rjare each independently selected from hydrogen and C1-C4 alkyl, wherein Raand Rb, or Rcand Rd, or Riand Rj, together with the nitrogen atom to which they are attached, are optionally taken together to form a monocyclic heterocyclyl; wherein each aryl, heteroaryl, and heterocyclyl is independently unsubstituted or 20 substituted with 1 or 2 substituents independently selected from C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo, oxo, C1-C4haloalkyl, C1-C4haloalkoxy, -COOH, cyano, and nitro.

2. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (Ia): 119STDU2-43279.601 Ia) or a pharmaceutically R1is selected from -CONRaRb, –(CH2)mNRcRd, -(CH2)nORe, -(CH2)pNRfZRg, - NRh(CH2)qNRiRj, -(CH2)r-heterocyclyl, and -(CH2)s-heteroaryl; 5 m, n, p, q, r, and s are each independently 0, 1, or 2; Z is -C(O)- or –S(O)2-; A is aryl or heteroaryl; X is selected from a bond, heterocyclyl, and aryl; R2is a warhead moiety; 10 R3is selected from hydrogen and C1-C4alkyl; and Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, and Rjare each independently selected from hydrogen and C1-C4alkyl, wherein Raand Rb, or Rcand Rd, or Riand Rj, together with the nitrogen atom to which they are attached, are optionally taken together to form a monocyclic heterocyclyl; 15 wherein each aryl, heteroaryl, and heterocyclyl is independently unsubstituted or substituted with 1 or 2 substituents independently selected from C1-C4alkyl, hydroxy, C1-C4alkoxy, halo, oxo, C1-C4 haloalkyl, C1-C4 haloalkoxy, -COOH, cyano, and nitro.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein 20 R1is -CONRaRb.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein Rais hydrogen and Rbis C1-C4alkyl. 25 5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1is -CH2NRcRd. 120STDU2-43279.601 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein Rcand Rdare each independently selected from C1-C4alkyl.

7. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein 5 R1is selected from -CONHCH3 and -CH2N(CH3)2.

8. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein Rcand Rdare taken together with the nitrogen atom to which they are attached to form a six- membered heterocyclyl. 10 9. The compound of claim 8, wherein Rcand Rd, together with the nitrogen atom to which they are attached to form a morpholino group.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt 15 thereof, wherein A is selected from phenyl, naphthyl, and a monocyclic heteroaryl having 1 or 2 nitrogen atoms, each of which is independently unsubstituted or substituted with 1 substituent selected from hydroxy and C1-C4alkoxy.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein A 20 is selected from phenyl, naphthyl, and pyridyl, each of which is independently unsubstituted or substituted with 1 methoxy group.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein X is a bond. 25 13. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein X is a monocyclic or bicyclic heterocyclyl having 1 nitrogen atom.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein X 30 is selected from azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyridinyl, dihydropyrrolyl, morpholinyl, and 8-azabicyclo[3.2.1]octenyl.

15. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein X is aryl. 121STDU2-43279.601 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein X is phenyl. 5 17. The compound of any one of claims 13-16, or a pharmaceutically acceptable salt thereof, wherein X is unsubstituted or substituted with 1 substituent selected from hydroxy, methoxy, fluoro, -COOH, cyano, and nitro.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt10 thereof, wherein R2is selected from -C(O)CH=CH2, -C(O)CF=CH2, -NHC(O)CH=CH2, - NHC(O)C≡CCH3, -NHC(O)CF=CH2, -C(O)C≡CCH3, -C(O)C≡CH, -C(O)C(=CH2)F, - C(O)CH=CH-CH2N(CH3)2, -NHC(O)CH=CH-CH2N(CH3)2, -C(O)CF=CH-CH2N(CH3)2, and -NHC(O)CF=CH-CH2N(CH3)2. 15 19. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R2is selected from -C(O)CH=CH2, -NHC(O)CH=CH2, -NHC(O)C≡CCH3, - C(O)C≡CCH3, -C(O)C≡CH,-C(O)C(=CH2)F, and -C(O)CH=CH-CH2N(CH3)2.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt 20 thereof, wherein R3is hydrogen.

21. The compound of claim 1, wherein the compound is selected from:122STDU2-43279.601 O 5123STDU2-43279.601 5124STDU2-43279.601 eof.

522. A pharmaceutical composition comprising a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

23. A method of treating a proliferative disease in a subject in need thereof, comprising 10 administering to the subject a therapeutically effective amount of a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof.

24. The method of claim 23, wherein the proliferative disease is a cancer. 125STDU2-43279.601 25. The method of claim 24, wherein the cancer is associated with JAK2.

26. The method of claim 25, wherein the cancer is associated with a V617F mutation in JAK2. 5 27. The method of claim 25, wherein the cancer is a myeloproliferative neoplasm.

28. The method of claim 27, wherein the myeloproliferative neoplasm is chronic myelogenous leukemia, polycythemia vera, primary myelofibrosis, essential 10 thrombocythemia, chronic neutrophilic leukemia, or chronic eosinophilic leukemia.

29. A compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, for use as a medicament. 15 30. A compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, for use in treating a proliferative disease.

31. The compound of claim 30, wherein the proliferative disease is a cancer. 20 32. The compound of claim 31, wherein the cancer is associated with JAK2.

33. The compound of claim 32, wherein the cancer is associated with a V617F mutation in JAK2. 25 34. The compound of claim 32, wherein the cancer is a myeloproliferative neoplasm.

35. The compound of claim 34, wherein the myeloproliferative neoplasm is chronic myelogenous leukemia, polycythemia vera, primary myelofibrosis, essential thrombocythemia, chronic neutrophilic leukemia, or chronic eosinophilic leukemia. 30 36. A kit comprising a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof. 126

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