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]STDU2-43395.601 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 / 669,447, filed on July 10, 2024, the disclosure of which is incorporated 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 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 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. 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): or a pharmaceutically R1is selected from C1-C6alkyl, C3-C6cycloalkyl, and heterocyclyl; STDU2-43395.601 Q is N or CH; X1is O, NRa, or a bond; X2is selected from aryl, heterocyclyl, and cycloalkyl; R2is a warhead moiety; R3is selected from hydrogen, alkyl, halo, hydroxy, alkoxy, amino, haloalkyl, haloalkoxy, cyano, and nitro; R4is hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl, or R4is taken together with Q to form a ring; and Rais hydrogen or C1-C4 alkyl; wherein each alkyl, cycloalkyl, aryl, and heterocyclyl is independently unsubstituted or substituted with one or more substituents independently selected from halo, hydroxy, alkoxy, amino, alkyl, haloalkyl, haloalkoxy, cyano, and nitro. In another aspect, disclosed herein is a compound of formula (Ia): or a R1is selected from C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl; Q is N or CH; X1is O, NRa, or a bond; X2is selected from aryl, heterocyclyl, and cycloalkyl; R2is a warhead moiety; R3is selected from hydrogen, alkyl, halo, hydroxy, alkoxy, amino, haloalkyl, haloalkoxy, cyano, and nitro; R4is hydrogen, or R4is taken together with Q to form a ring; and Rais hydrogen or C1-C4alkyl; wherein each alkyl, cycloalkyl, aryl, and heterocyclyl is independently unsubstituted or substituted with one or more substituents independently selected from halo, hydroxy, alkoxy, amino, alkyl, haloalkyl, haloalkoxy, cyano, and nitro. In some embodiments, R1is C3-C6 cycloalkyl. In some embodiments, R1is cyclopropyl. STDU2-43395.601 In some embodiments, Q is N. In some embodiments, X1is O. In some embodiments, X2is aryl. In some embodiments, X2is phenyl. In some embodiments, X2is a monocyclic or bicyclic heterocyclyl having 1 nitrogen atom. In some embodiments, X is selected from piperidinyl, pyrrolidinyl, azetidinyl, 2- azaspiro[3.3]heptan-6-yl, 1-azaspiro[3.3]heptan-6-yl, and 1,2,3,6-tetrahydropyridinyl. In some embodiments, X is selected from piperidinyl, pyrrolidinyl, azetidinyl, and 2- azaspiro[3.3]heptan-6-yl. In some embodiments, X2is C3-C6 cycloalkyl. In some embodiments, X2is cyclobutyl. In some embodiments, X2is unsubstituted or substituted with 1 or 2 substituents independently selected from methyl, methoxy, hydroxy, and halo. In some embodiments, R2is selected from -C(O)CH=CH2, -C(O)CF=CH2, - NHC(O)CH=CH2, -N(CH3)C(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. In some embodiments, R2is selected from -C(O)CH=CH2, -NHC(O)CH=CH2, -C(O)C≡CCH3, -C(O)C≡CH, and -C(O)CF=CH2. In some embodiments, R3is hydrogen or C1-C4alkoxy. In some embodiments, R3is hydrogen. In some embodiments, R4is hydrogen. In some embodiments, R4is C1-C4 alkyl or C3-C6 cycloalkyl. In some embodiments, R4is methyl. In some embodiments, R4is ethyl. In some embodiments, R4is cyclopropyl. In some embodiments, the compound is selected from: STDU2-43395.601 5 STDU2-43395.601 pharmaceutically acceptable salts thereof. a pharmaceutical composition comprising a , acceptable salt thereof, and a 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. 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 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 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 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. STDU2-43395.601 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, 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 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 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, 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 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 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, University Science Books, Sausalito, 2006; Smith, March’s Advanced Organic Chemistry: STDU2-43395.601 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 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-C16alkyl), 1 to 14 carbon atoms (C1-C14alkyl), 1 to 12 carbon atoms (C1-C12 alkyl), 1 to 10 carbon atoms (C1-C10 alkyl), 1 to 8 carbon atoms (C1-C8 alkyl), 1 to 6 carbon atoms (C1-C6alkyl), 1 to 4 carbon atoms (C1-C4alkyl), 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. 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-C24 alkenyl), 2 to 16 carbon atoms (C2-C16alkenyl), 2 to 14 carbon atoms (C2-C14alkenyl), 2 to 12 carbon atoms (C2-C12alkenyl), 2 to 10 carbon atoms (C2-C10 alkenyl), 2 to 8 carbon atoms (C2-C8 alkenyl), 2 to 6 carbon atoms (C2-C6alkenyl), 2 to 4 carbon atoms (C2-C4alkenyl), 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, 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-C24alkynyl), 2 to 16 carbon atoms (C2-C16alkynyl), 2 to 14 carbon atoms (C2-C14 alkynyl), 2 to 12 carbon atoms (C2-C12 alkynyl), 2 to 10 carbon atoms (C2-C10alkynyl), 2 to 8 carbon atoms (C2-C8alkynyl), 2 to 6 carbon atoms (C2-C6 alkynyl), 2 to 4 carbon atoms (C2-C4 alkynyl), 2 to 3 carbon atoms (C2-C3 alkynyl), or 2 carbon atoms (C2alkynyl). 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, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and the like. STDU2-43395.601 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. As used herein, the term “amino” refers to a group -NR2, wherein each R is independently selected from hydrogen and alkyl (e.g., C1-C4alkyl). 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 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 (“C6 aryl,” 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 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, 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 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. 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. STDU2-43395.601 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 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 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 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 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, 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- 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 each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, STDU2-43395.601 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 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 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. 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, 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 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- 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 thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6aryl ring (also referred STDU2-43395.601 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, 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, 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, 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 -NO2group. 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 of JAK2, such as Cys675). The reactive group may be, for example, -C(O)CH=CH2, - C(O)CF=CH2, -NHC(O)CH=CH2, -N(CH3)C(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 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 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. STDU2-43395.601 As used herein, in chemical structures the indication: represents a point of attachment of one 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 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 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 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 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 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 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, STDU2-43395.601 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 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, 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 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. Compounds Disclosed herein are compounds or formula (I): or a pharmaceutically R1is selected from C1-C6alkyl, C3-C6cycloalkyl, and heterocyclyl; Q is N or CH; X1is O, NRa, or a bond; X2is selected from aryl, heterocyclyl, and cycloalkyl; STDU2-43395.601 R2is a warhead moiety; R3is selected from hydrogen, alkyl, halo, hydroxy, alkoxy, amino, haloalkyl, haloalkoxy, cyano, and nitro; R4is hydrogen, C1-C4alkyl, or C3-C6cycloalkyl, or R4is taken together with Q to form a ring; and Rais hydrogen or C1-C4alkyl; wherein each alkyl, cycloalkyl, aryl, and heterocyclyl is independently unsubstituted or substituted with one or more substituents independently selected from halo, hydroxy, alkoxy, amino, alkyl, haloalkyl, haloalkoxy, cyano, and nitro. Also disclosed herein are compounds of formula (Ia): or a pharmaceutically R1is selected from C1-C6alkyl, C3-C6cycloalkyl, and heterocyclyl; Q is N or CH; X1is O, NRa, or a bond; X2is selected from aryl, heterocyclyl, and cycloalkyl; R2is a warhead moiety; R3is selected from hydrogen, alkyl, halo, hydroxy, alkoxy, amino, haloalkyl, haloalkoxy, cyano, and nitro; R4is hydrogen, or R4is taken together with Q to form a ring; and Rais hydrogen or C1-C4 alkyl; wherein each alkyl, cycloalkyl, aryl, and heterocyclyl is independently unsubstituted or substituted with one or more substituents independently selected from halo, hydroxy, alkoxy, amino, alkyl, haloalkyl, haloalkoxy, cyano, and nitro. In some embodiments, R1is C3-C6 cycloalkyl. In some embodiments, R1is cyclopropyl. In some embodiments, Q is N. In some embodiments, Q is CH. In some embodiments, X1is O. In some embodiments, X1is NRa, and Rais selected from hydrogen and methyl. STDU2-43395.601 In some embodiments, X2is selected from phenyl, monocyclic or bicyclic heterocyclyl having 1 nitrogen atom, and C3-C6cycloalkyl. In some embodiments, X2is selected from phenyl, piperidinyl, pyrrolidinyl, azetidinyl, 2-azaspiro[3.3]heptan-6-yl, 1- azaspiro[3.3]heptan-6-yl, 1,2,3,6-tetrahydropyridinyl, and cyclobutyl. In some embodiments, X2is aryl. In some embodiments, X2is phenyl. In some embodiments, X2is a monocyclic or bicyclic heterocyclyl having 1 nitrogen atom. In some embodiments, X2is a 3- to 6-membered monocyclic or bicyclic heterocyclyl having 1 nitrogen atom. In some embodiments, X is selected from piperidinyl, pyrrolidinyl, azetidinyl, 2-azaspiro[3.3]heptan-6-yl, 1-azaspiro[3.3]heptan-6-yl, and 1,2,3,6- tetrahydropyridinyl. In some embodiments, X is selected from piperidinyl, pyrrolidinyl, azetidinyl, and 2-azaspiro[3.3]heptan-6-yl. In some embodiments, X2is C3-C6 cycloalkyl. In some embodiments, X2is cyclobutyl. In some embodiments, X2is unsubstituted or substituted with 1 or 2 substituents independently selected from halo, hydroxy, alkoxy, amino, alkyl, haloalkyl, haloalkoxy, cyano, and nitro. In some embodiments, X2is unsubstituted or substituted with 1 or 2 substituents independently selected from methyl, methoxy, hydroxy, and halo. In some embodiments, X2is unsubstituted or substituted with 1 or 2 substituents independently selected from C1-C4alkyl (e.g., methyl). In some embodiments, X2is unsubstituted. In some embodiments, X2is a group selected from: , STDU2-43395.601 In some embodiments, R2is selected from -C(O)CH=CH2, -C(O)CF=CH2, - NHC(O)CH=CH2, -N(CH3)C(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. In some embodiments, R2is selected from -C(O)CH=CH2, -NHC(O)CH=CH2, -C(O)C≡CCH3, -C(O)C≡CH, and -C(O)CF=CH2. In some embodiments, R2is selected from - C(O)CH=CH2 and -NHC(O)CH=CH2. In some embodiments, R3is hydrogen or C1-C4alkoxy (e.g., methoxy). In some embodiments, R3is hydrogen. In some embodiments, R4is hydrogen, C1-C4alkyl, or C3-C6cycloalkyl. In some embodiments, R4is hydrogen, methyl, ethyl, or cyclopropyl. In some embodiments, R4is hydrogen. In some embodiments, R4is taken together with Q to form a ring. In some embodiments, R4is taken together with Q to form a pyridin-2- one ring. In some embodiments, R4is C1-C4 alkyl or C3-C6 cycloalkyl. In some embodiments, R4is C1-C4 alkyl. In some embodiments, R4is methyl. In some embodiments, R4is ethyl. In some embodiments, R4is C3-C6cycloalkyl. In some embodiments, R4is cyclopropyl. In some embodiments, the compound of formula (I) is selected from: STDU2-43395.601 N pharmaceutically acceptable salts thereof. include: STDU2-43395.601 N O HN O O 8 STDU2-43395.601 O HN pharmaceutically acceptable salts thereof. may have at least one asymmetric center. may depending upon the nature of the various 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 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. 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 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 STDU2-43395.601 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. 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 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 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 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 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 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 STDU2-43395.601 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. 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 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 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 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 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 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. STDU2-43395.601 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 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 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, 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 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, 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 and N,N’-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like. STDU2-43395.601 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- 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 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 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. 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, 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 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, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. STDU2-43395.601 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, 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. 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, 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. 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 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; 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, 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. STDU2-43395.601 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 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%. 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 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. 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 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 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 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 STDU2-43395.601 one or more carriers. Compositions for parenteral administration typically include 0.1% to 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 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, 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 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) 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. 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 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 STDU2-43395.601 methyl cellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Evonik Industries of Essen, Germany), waxes and shellac. 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 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 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. 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), 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 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 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, STDU2-43395.601 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 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. 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 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 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. 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 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. The amount of thickener(s) in a topical composition is typically about 0% to about 95% by weight of the composition. STDU2-43395.601 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 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. 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. 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. 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 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 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 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 STDU2-43395.601 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 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 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 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 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 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 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 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 STDU2-43395.601 compositions, or sequentially. For sequential administration, the compound described herein can be administered first, and the additional agent can be administered subsequently, or the 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 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 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 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. 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 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 such as glass or plastic. STDU2-43395.601 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, 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 disclosed herein. The container(s) optionally have a sterile access port (for example 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. 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 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 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 the 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 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 example, is the labeling approved by the U.S. Food and Drug Administration for STDU2-43395.601 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 Abbreviations used in the Examples include the following: ACN is acetonitrile; DCM is dichloromethane; DIEA is N,N-diisopropylethylamine; DMF is N,N-dimethylformamide; DMSO is dimethylsulfoxide; EtOAc is ethyl acetate; LCMS is liquid chromatography mass spectrometry; NMR is nuclear magnetic resonance; TFA is trifluoroacetic acid; THF is tetrahydrofuran; and TLC is thin layer chromatography. Example 1 Compound Syntheses Compound 1 solution of 3-methoxyaniline (3 g, 24.36 mmol, 2.74 mL, 1 eq) in ACN (10 mL) was added DIEA (6.30 g, 48.72 mmol, 8.49 mL, 2 eq) and methyl 4,6-dichloropyridazine-3-carboxylate (5.04 g, 24.36 mmol, 1 eq). The sealed tube was heated at 90°C for 2 hr under microwave. TLC indicated 3-methoxyaniline was consumed completely. The residue was diluted with H2O 30 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, STDU2-43395.601 Eluent of 0~20% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give methyl 6- chloro-4-((3-methoxyphenyl)amino)pyridazine-3-carboxylate (2.2 g, 7.19 mmol, 29.52% yield, 96% purity) as a brown solid. MS (ESI): m / z = 294.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 7.43 - 7.32 (m, 1H), 7.07 (s, 1H), 6.97 - 6.93 (m, 2H), 6.91 - 6.86 (m, 1H), 3.96 (s, 3H), 3.77 (s, 3H). methyl 6-(cyclopropanecarboxamido)-4-((3-methoxyphenyl)amino)pyridazine-3- carboxylate. A mixture of methyl 6-chloro-4-(3-methoxyanilino)pyridazine-3-carboxylate (1.5 g, 5.11 mmol, 1 eq), cyclopropanecarboxamide (651.96 mg, 7.66 mmol, 1.5 eq) , [2-(2- aminophenyl)phenyl]-methylsulfonyloxy-palladium;cyclopentane;ditert-butyl-[(1S)-1-(2- dicyclohexylphosphanylcyclopentyl)ethyl]phosphane;iron (236.28 mg, 255.36 μmol, 0.05 eq), K3PO4 (2.17 g, 10.21 mmol, 2 eq) in dioxane (20 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. TLC indicated the reaction was completed. The mixture was filtered to obtain a solid. Then washed with water to give methyl 6-(cyclopropanecarboxamido)-4-((3- methoxyphenyl)amino)pyridazine-3-carboxylate (800 mg, crude) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.08 (s, 1H), 7.34 (t, J = 8.1 Hz, 1H), 6.94 - 6.87 (m, 2H), 6.82 (dd, J = 1.9, 8.3 Hz, 1H), 3.94 (s, 3H), 3.76 (s, 3H), 2.09 - 2.01 (m, 1H), 0.88 - 0.76 (m, 4H). MS (ESI): m / z = 343.2 [M+H]+. 6-(cyclopropanecarboxamido)-4-((3-methoxyphenyl)amino)pyridazine-3- carboxamide. A solution of methyl 6-(cyclopropanecarbonylamino)-4-(3- methoxyanilino)pyridazine-3-carboxylate (800 mg, 2.34 mmol, 1 eq) in NH3.THF(10M, 5mL) was stirred at 25°C for 12 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure to give 6-(cyclopropanecarboxamido)-4- ((3-methoxyphenyl)amino)pyridazine-3-carboxamide (640 mg, crude) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.50 (br s, 1H), 8.14 (s, 1H), 7.86 (br s, 1H), 7.33 (t, J = 8.1 Hz, 1H), 6.90 - 6.82 (m, 2H), 6.78 (dd, J = 2.1, 8.3 Hz, 1H), 3.76 (s, 3H), 2.11 - 2.03 (m, 1H), 0.87 - 0.76 (m, 4H). 6-(cyclopropanecarboxamido)-4-((3-hydroxyphenyl)amino)pyridazine-3- carboxamide. To a solution of 6-(cyclopropanecarbonylamino)-4-(3- methoxyanilino)pyridazine-3-carboxamide (640 mg, 1.96 mmol, 1 eq) in DCM (10 mL) was added BBr3 (2 M, 4.89 mL, 5 eq) at 0°C. The mixture was stirred at 25°C for 1 hr. LCMS showed desired compound formed. The mixture is quenched with NH3.H2O 10 mL at 0°C. Then the mixture was filtered to give 6-(cyclopropanecarboxamido)-4-((3- STDU2-43395.601 hydroxyphenyl)amino)pyridazine-3-carboxamide (690 mg, crude) as a green solid. MS (ESI): m / z = 314.2 [M+H]+. 6-(cyclopropanecarboxamido)-4-((3-(3-nitrophenoxy)phenyl)amino)pyridazine-3- carboxamide. To a solution of 6-(cyclopropanecarbonylamino)-4-(3- hydroxyanilino)pyridazine-3-carboxamide (300 mg, 957.52 μmol, 1 eq) and 1-fluoro-3-nitro- benzene (135.11 mg, 957.52 μmol, 101.97 μL, 1 eq) in DMF (10 mL) was added Cs2CO3(1.44 g, 4.40 mmol, 4.6 eq). The mixture was stirred at 120°C for 3 hr. LCMS showed desired compound formed. The residue was diluted with H2O 5 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 reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 1:1) to give 6- (cyclopropanecarboxamido)-4-((3-(3-nitrophenoxy)phenyl)amino)pyridazine-3-carboxamide (67 mg, 137.27 μmol, 14.34% yield, 89% purity) as a white solid. MS (ESI): m / z = 435.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 10.82 (s, 1H), 8.51 (br s, 1H), 8.11 (s, 1H), 8.00 (dd, J = 1.4, 8.1 Hz, 1H), 7.87 (br s, 1H), 7.76 (t, J = 2.2 Hz, 1H), 7.66 (t, J = 8.3 Hz, 1H), 7.57 - 7.47 (m, 2H), 7.18 (br d, J = 7.9 Hz, 1H), 7.10 (s, 1H), 6.98 (dd, J = 1.9, 8.2 Hz, 1H), 2.11 - 2.01 (m, 1H), 0.87 - 0.73 (m, 4H). 4-((3-(3-aminophenoxy)phenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3- carboxamide. To a solution of 6-(cyclopropanecarbonylamino)-4-[3-(3- nitrophenoxy)anilino]pyridazine-3-carboxamide (50 mg, 115.10 μmol, 1 eq) in EtOH (1.5 mL) / H2O (0.5 mL) was added Fe (32.14 mg, 575.50 μmol, 5 eq) and NH4Cl (30.78 mg, 575.50 μmol, 5 eq). The mixture was stirred at 80°C for 1 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 4-((3-(3-aminophenoxy)phenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide (45 mg, crude) as a white solid. MS (ESI): m / z = 405.2 [M+H]+. 4-((3-(3-acrylamidophenoxy)phenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide. To a solution of 4-[3-(3- aminophenoxy)anilino]-6-(cyclopropanecarbonylamino)pyridazine-3-carboxamide (52 mg, 128.58 μmol, 1 eq) in THF (0.5 mL) / H2O (0.5 mL) was added NaHCO3(32.40 mg, 385.74 μmol, 15.01 μL, 3 eq) and prop-2-enoyl chloride (12.80 mg, 141.44 μmol, 11.49 μL, 1.1 eq) at 0°C. The mixture was stirred at 0 °C for 1hr. LCMS showed desired compound formed. STDU2-43395.601 The reaction mixture was concentrated under reduced pressure to remove 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%-50% B over 8.0 min ) to give 4-((3-(3-acrylamidophenoxy)phenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3- carboxamide (28.57 mg, 61.83 μmol, 48.09% yield, 99.22% purity) as a yellow solid. MS (ESI): m / z = 459.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 10.80 (s, 1H), 10.21 (s, 1H), 8.50 (s, 1H), 8.11 (s, 1H), 7.86 (s, 1H), 7.48 - 7.38 (m, 3H), 7.31 (t, J = 8.3 Hz, 1H), 7.14 - 7.05 (m, 1H), 6.96 (t, J = 1.9 Hz, 1H), 6.86 (dd, J = 1.9, 8.3 Hz, 1H), 6.81 - 6.75 (m, 1H), 6.45 - 6.33 (m, 1H), 6.29 - 6.20 (m, 1H), 5.75 (dd, J = 2.1, 10.1 Hz, 1H), 2.13 - 2.01 (m, 1H), 0.88 - 0.78 (m, 4H). Compound 2 3- carboxamide. To a solution of 6-(cyclopropanecarbonylamino)-4-(3- hydroxyanilino)pyridazine-3-carboxamide (350 mg, 1.12 mmol, 1 eq) in DMF (15 mL) was added Cs2CO3(1.53 g, 4.69 mmol, 4.2 eq) and 1-fluoro-4-nitro-benzene (157.62 mg, 1.12 mmol, 118.51 μL, 1 eq). The mixture was stirred at 120°C for 1 hr. LCMS showed desired compound formed. The residue was diluted with H2O 20 mL and extracted with EtOAc 30 mL (10 mL × 3). The combined organic layers were washed with brine 30 mL (10 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give 6- (cyclopropanecarboxamido)-4-((3-(4-nitrophenoxy)phenyl)amino)pyridazine-3-carboxamide (163 mg, crude) as a yellow solid. MS (ESI): m / z = 435.2 [M+H]+.1H NMR (400 MHz, STDU2-43395.601 DMSO-d6) δ 11.31 (s, 1H), 10.80 (s, 1H), 8.51 (br s, 1H), 8.29 - 8.19 (m, 2H), 8.09 (s, 1H), 7.87 (br s, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.25 - 7.15 (m, 4H), 7.09 - 6.98 (m, 1H), 2.14 - 2.03 (m, 1H), 0.89 - 0.77 (m, 4H) 4-((3-(4-aminophenoxy)phenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3- carboxamide. To a solution of 6-(cyclopropanecarbonylamino)-4-[3-(4- nitrophenoxy)anilino]pyridazine-3-carboxamide (163 mg, 375.23 μmol, 1 eq) in EtOH (3 mL) / H2O (1 mL) was added Fe (104.77 mg, 1.88 mmol, 5 eq) and NH4Cl (100.36 mg, 1.88 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 to remove solvent. The residue was diluted with H2O 5 mL and extracted with EtOAc 9 mL (3mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-((3- (4-aminophenoxy)phenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3-carboxamide (160 mg, crude) as brown oil. 4-((3-(4-acrylamidophenoxy)phenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide. To a solution of 4-((3-(4- aminophenoxy)phenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3-carboxamide (50 mg, 123.63 μmol, 1 eq) in THF (0.5 mL) / H2O (0.5 mL) was added NaHCO3(31.16 mg, 370.90 μmol, 14.43 μL, 3 eq) and prop-2-enoyl chloride (12.31 mg, 136.00 μmol, 11.05 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 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%-45% B over 10.0 min) to give 4- ((3-(4-acrylamidophenoxy)phenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3- carboxamide (6.49 mg, 14.03 μmol, 11.34% yield, 99.08% purity) as a yellow solid. MS (ESI): m / z = 459.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 10.74 (s, 1H), 10.17 (s, 1H), 8.48 (s, 1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.68 (d, J = 9.0 Hz, 2H), 7.41 (t, J = 8.1 Hz, 1H), 7.11 - 7.00 (m, 3H), 6.87 (t, J = 2.1 Hz, 1H), 6.82 (dd, J = 1.9, 8.1 Hz, 1H), 6.49 - 6.34 (m, 1H), 6.32 - 6.20 (m, 1H), 5.79 - 5.70 (m, 1H), 2.13 - 2.01 (m, 1H), 0.84 (d, J = 6.0 Hz, 4H). STDU2-43395.601 Compound 3 yl)amino)phenoxy)piperidine-1-carboxylate. A mixture of 6-(cyclopropanecarbonylamino)- 4-(3-hydroxyanilino)pyridazine-3-carboxamide (300 mg, 957.52 μmol, 1 eq), tert-butyl 4- methylsulfonyloxypiperidine-1-carboxylate (401.23 mg, 1.44 mmol, 1.5 eq), Cs2CO3(1.31 g, 4.02 mmol, 4.2 eq) in DMF (15 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 120°C for 12 hr under N2atmosphere. LCMS showed desired compound formed. The residue was diluted with H2O 20 mL and extracted with EtOAc 30 mL (10 mL × 3). The combined 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 0~40% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert-butyl 4-(3-((3- carbamoyl-6-(cyclopropanecarboxamido)pyridazin-4-yl)amino)phenoxy)piperidine-1- carboxylate (180 mg, crude) as a white solid. MS (ESI): m / z = 497.2 [M+H]+. 6-(cyclopropanecarboxamido)-4-((3-(piperidin-4-yloxy)phenyl)amino)pyridazine-3- carboxamide. A solution of tert-butyl 4-(3-((3-carbamoyl-6- (cyclopropanecarboxamido)pyridazin-4-yl)amino)phenoxy)piperidine-1-carboxylate (80 mg, 161.11 μmol, 1 eq) in HCl / EtOAc (4M, 1.5 mL) was stirred at 25 °C for 1hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure to give 6-(cyclopropanecarboxamido)-4-((3-(piperidin-4-yloxy)phenyl)amino)pyridazine-3- carboxamide (50 mg, crude, HCl) as a yellow solid. 4-((3-((1-acryloylpiperidin-4-yl)oxy)phenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide. To a solution of 6- STDU2-43395.601 (cyclopropanecarboxamido)-4-((3-(piperidin-4-yloxy)phenyl)amino)pyridazine-3- carboxamide (50 mg, 115.50 μmol, 1 eq, HCl) in THF (1 mL) / H2O (1 mL) was added NaHCO3 (29.11 mg, 346.50 μmol, 13.48 μL, 3 eq) and prop-2-enoyl chloride (11.50 mg, 127.05 μmol, 10.32 μL, 1.1 eq) at 0°C. The mixture was stirred at 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 (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 4-((3-((1-acryloylpiperidin-4- yl)oxy)phenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3-carboxamide (18.25 mg, 39.71 μmol, 34.38% yield, 98.03% purity) as a yellow solid. MS (ESI): m / z = 451.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 10.75 (s, 1H), 8.49 (br s, 1H), 8.10 (s, 1H), 7.86 (br s, 1H), 7.32 (t, J = 8.1 Hz, 1H), 6.98 (s, 1H), 6.87 - 6.76 (m, 3H), 6.09 (dd, J = 2.4, 16.8 Hz, 1H), 5.74 - 5.61 (m, 1H), 4.66 (tt, J = 3.6, 7.8 Hz, 1H), 3.85 - 3.74 (m, 2H), 3.48 - 3.17 (m, 2H), 2.12 - 2.02 (m, 1H), 2.01 - 1.89 (m, 2H), 1.68 - 1.42 (m, 2H), 0.94 - 0.70 (m, 4H). Compound 4 tert-butyl 3-(3-((3-carbamoyl-6-(cyclopropanecarboxamido)pyridazin-4- yl)amino)phenoxy)piperidine-1-carboxylate. To a solution of 6- (cyclopropanecarbonylamino)-4-(3-hydroxyanilino)pyridazine-3-carboxamide (300 mg, 957.52 μmol, 1 eq) in DMF (20 mL) was added K2CO3 (555.80 mg, 4.02 mmol, 4.2 eq) and tert-butyl 3-methylsulfonyloxypiperidine-1-carboxylate (1.52 g, 5.46 mmol, 5.7 eq). The mixture was stirred at 120°C for 12 hr. LCMS showed desired compound formed. The STDU2-43395.601 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 (4 g Silica Flash Column, Eluent of 0~35% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert-butyl 3-(3-((3-carbamoyl-6- (cyclopropanecarboxamido)pyridazin-4-yl)amino)phenoxy)piperidine-1-carboxylate as a white solid. MS (ESI): m / z = 497.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 10.76 (s, 1H), 8.49 (br s, 1H), 8.12 (s, 1H), 7.86 (br s, 1H), 7.32 (br t, J = 7.9 Hz, 1H), 7.04 - 6.60 (m, 3H), 4.41 (br d, J = 1.1 Hz, 1H), 4.12 - 3.96 (m, 1H), 3.37 - 3.19 (m, 2H), 2.54 (br s, 1H), 2.11 - 1.88 (m, 2H), 1.80 - 1.64 (m, 2H), 1.50 - 1.10 (m, 10H), 0.93 - 0.68 (m, 4H). 6-(cyclopropanecarboxamido)-4-((3-(piperidin-3-yloxy)phenyl)amino)pyridazine-3- carboxamide. A solution of tert-butyl 3-(3-((3-carbamoyl-6- (cyclopropanecarboxamido)pyridazin-4-yl)amino)phenoxy)piperidine-1-carboxylate (100 mg, 201.39 μmol, 1 eq) in HCl / EtOAc (4M, 1.5 mL) was stirred at 25°C for 1 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure to give 6-(cyclopropanecarboxamido)-4-((3-(piperidin-3- yloxy)phenyl)amino)pyridazine-3-carboxamide (80 mg, crude, HCl) as a yellow solid. 4-((3-((1-acryloylpiperidin-3-yl)oxy)phenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide. To a solution of 6- (cyclopropanecarboxamido)-4-((3-(piperidin-3-yloxy)phenyl)amino)pyridazine-3- carboxamide (80 mg, 184.80 μmol, 1 eq, HCl) in THF (0.2 mL) / H2O (0.2 mL) was added NaHCO3 (46.57 mg, 554.40 μmol, 21.57 μL, 3 eq) and prop-2-enoyl chloride (18.40 mg, 203.28 μmol, 16.52 μL, 1.1 eq). The mixture was stirred at 0 °C for 1hr. 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 C18100 × 30mm × 5μm; mobile phase: [H2O(0.1% TFA)-ACN]; gradient:15%-45% B over 8.0 min) to give 4-((3-((1-acryloylpiperidin-3- yl)oxy)phenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3-carboxamide (48.63 mg, 107.29 μmol, 58.06% yield, 99.39% purity) as a yellow solid. MS (ESI): m / z = 451.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.30 (br s, 1H), 10.75 (br d, J = 18.1 Hz, 1H), 8.49 (br s, 1H), 8.08 (s, 1H), 7.88 (br s, 1H), 7.32 (dt, J = 4.6, 7.9 Hz, 1H), 6.97 - 6.84 (m, 2H), 6.83 - 6.74 (m, 1H), 6.60 (br dd, J = 10.4, 16.6 Hz, 1H), 6.18 - 5.93 (m, 1H), 5.76 - 5.42 (m, 1H), 4.51 (br s, 1H), 3.75 - 3.60 (m, 2H), 3.46 - 3.16 (m, 2H), 2.07 - 1.88 (m, 2H), 1.86 - 1.64 (m, 2H), 1.47 (br s, 1H), 0.87 - 0.74 (m, 4H). STDU2-43395.601 Compound 5 yl)amino)phenoxy)pyrrolidine-1-carboxylate. To a solution of 6- (cyclopropanecarbonylamino)-4-(3-hydroxyanilino)pyridazine-3-carboxamide (300 mg, 957.52 μmol, 1 eq) and tert-butyl 3-methylsulfonyloxypyrrolidine-1-carboxylate (279.46 mg, 1.05 mmol, 1.1 eq) in DMF (4 mL) was added K2CO3(397.00 mg, 2.87 mmol, 3 eq). The mixture was stirred at 120°C for 24 hr. LCMS showed desired compound was detected. The residue was diluted with H2O 5 mL and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (20 mL × 2), 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 C18100×30mm×5μm;mobile phase: [H2O(0.1% TFA)-ACN]; gradient:20%-50% B over 8.0 min) to give tert-butyl 3-(3-((3- carbamoyl-6-(cyclopropanecarboxamido)pyridazin-4-yl)amino)phenoxy)pyrrolidine-1- carboxylate (80 mg, 162.48 μmol, 16.97% yield, 98% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 10.74 (s, 1H), 8.49 (br s, 1H), 8.09 (s, 1H), 7.86 (br s, 1H), 7.34 (t, J = 8.0 Hz, 1H), 6.93 - 6.85 (m, 2H), 6.84 - 6.75 (m, 1H), 5.03 (br s, 1H), 3.55 (br d, J = 8.4 Hz, 2H), 3.47 - 3.26 (m, 4H), 2.07 (br d, J = 4.8 Hz, 1H), 1.40 (br d, J = 6.1 Hz, 9H), 0.82 (br d, J = 7.5 Hz, 4H). MS (ESI): m / z = 483.3 [M+H]+. 6-(cyclopropanecarboxamido)-4-((3-(pyrrolidin-3-yloxy)phenyl)amino)pyridazine- 3-carboxamide. Tert-butyl 3-(3-((3-carbamoyl-6-(cyclopropanecarboxamido)pyridazin-4- yl)amino)phenoxy)pyrrolidine-1-carboxylate (80 mg, 165.79 μmol, 1 eq) in HCl / EtOAc (3 mL, 4 M) was stirred at 25°C for 2 hr. LCMS showed desired compound was detected. The reaction mixture was concentrated under reduced pressure to give 6- STDU2-43395.601 (cyclopropanecarboxamido)-4-((3-(pyrrolidin-3-yloxy)phenyl)amino)pyridazine-3- carboxamide (70 mg, crude, HCl) as a yellow solid. 4-((3-((1-acryloylpyrrolidin-3-yl)oxy)phenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide. To a solution of 6- (cyclopropanecarboxamido)-4-((3-(pyrrolidin-3-yloxy)phenyl)amino)pyridazine-3- carboxamide (70 mg, 167.11 μmol, 1 eq, HCl) in THF (2 mL) / H2O (1 mL) was added NaHCO3 (42.12 mg, 501.34 μmol, 19.51 μL, 3 eq) and prop-2-enoyl chloride (15.13 mg, 167.11 μmol, 13.58 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 C18100×30mm×5μm; mobile phase: [H2O(0.1% TFA)-ACN]; gradient:10%-40% B over 8.0 min) to give 4-((3-((1-acryloylpyrrolidin-3- yl)oxy)phenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3-carboxamide (38.24 mg, 86.54 μmol, 51.79% yield, 98.78% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.33 (d, J = 4.3 Hz, 1H), 10.77 (s, 1H), 8.50 (br s, 1H), 8.07 (d, J = 10.0 Hz, 1H), 7.88 (br s, 1H), 7.34 (dt, J = 2.0, 8.1 Hz, 1H), 6.98 - 6.85 (m, 2H), 6.84 - 6.77 (m, 1H), 6.60 (td, J = 9.8, 16.7 Hz, 1H), 6.14 (td, J = 2.0, 16.8 Hz, 1H), 5.66 (ddd, J = 2.3, 10.3, 15.2 Hz, 1H), 5.18 - 5.05 (m, 1H), 3.78 - 3.70 (m, 1H), 3.67 - 3.56 (m, 2H), 3.51 - 3.34 (m, 1H), 2.24 - 2.14 (m, 1H), 2.13 - 2.01 (m, 2H), 0.92 - 0.71 (m, 4H). MS (ESI): m / z = 437.2 [M+H]+. Compound 6 4- yl)amino)phenoxy)azetidine-1-carboxylate. To a solution of 6- (cyclopropanecarbonylamino)-4-(3-hydroxyanilino)pyridazine-3-carboxamide (300 mg, STDU2-43395.601 957.52 μmol, 1 eq) in DMF (10 mL) was added K2CO3(397.00 mg, 2.87 mmol, 3 eq) and tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate (288.75 mg, 1.15 mmol, 1.2 eq). The mixture was stirred at 120°C for 12 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 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 (4 g Silica Flash Column, Eluent of 0~43% Ethyl acetate / Petroleum ether gradient @ 80mL / min) to give tert-butyl 3-(3-((3-carbamoyl-6- (cyclopropanecarboxamido)pyridazin-4-yl)amino)phenoxy)azetidine-1-carboxylate (163 mg, 312.64 μmol, 32.65% yield, 89.86% purity) as a white solid. MS (ESI): m / z = 469.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 10.73 (s, 1H), 8.50 (br s, 1H), 8.11 (s, 1H), 7.86 (br s, 1H), 7.34 (t, J = 8.1 Hz, 1H), 6.90 (br d, J = 8.1 Hz, 1H), 6.81 - 6.75 (m, 1H), 6.71 (dd, J = 2.0, 8.3 Hz, 1H), 5.10 - 4.94 (m, 1H), 4.28 (br d, J = 7.3 Hz, 2H), 3.86 - 3.74 (m, 2H), 2.14 - 2.03 (m, 1H), 1.39 (s, 9H), 0.82 (br d, J = 6.4 Hz, 4H). 4-((3-(azetidin-3-yloxy)phenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3- carboxamide. A solution of tert-butyl 3-(3-((3-carbamoyl-6- (cyclopropanecarboxamido)pyridazin-4-yl)amino)phenoxy)azetidine-1-carboxylate (180 mg, 384.20 μmol, 1 eq) in TFA (0.4 mL) / DCM (2 mL) was stirred at 25°C for 0.5 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure to give 4-((3-(azetidin-3-yloxy)phenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide (180 mg, crude, TFA) as a yellow oil. 4-((3-((1-acryloylazetidin-3-yl)oxy)phenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide. To a solution of 4-((3-(azetidin-3- yloxy)phenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3-carboxamide (70 mg, 145.10 μmol, 1 eq, TFA) in THF (0.5 mL) / H2O (0.5 mL) was added NaHCO3(36.57 mg, 435.31 μmol, 16.94 μL, 3 eq) and prop-2-enoyl chloride (14.45 mg, 159.61 μmol, 12.97 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 solvent. The residue was purified by prep-HPLC (TFA condition;column: Phenomenex Luna C18100 × 30mm × 5μm; mobile phase: [H2O(0.1% TFA)-ACN]; gradient:10%-45% B over 8.0 min ) to give 4-((3-((1-acryloylazetidin-3-yl)oxy)phenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide (22.26 mg, 52.62 μmol, 36.26% yield, 99.85% purity) as a yellow solid. MS (ESI): m / z = 423.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 10.77 (s, 1H), 8.51 (s, 1H), 8.07 (s, 1H), 7.88 (s, 1H), 7.36 (t, J = STDU2-43395.601 8.1 Hz, 1H), 6.92 (dd, J = 1.3, 7.9 Hz, 1H), 6.80 (t, J = 2.1 Hz, 1H), 6.74 (dd, J = 2.0, 8.1 Hz, 1H), 6.38 - 6.25 (m, 1H), 6.17 - 6.06 (m, 1H), 5.73 - 5.62 (m, 1H), 5.12 - 5.03 (m, 1H), 4.65 (br dd, J = 6.4, 9.1 Hz, 1H), 4.38 - 4.34 (m, 2H), 4.17 (br dd, J = 3.3, 9.6 Hz, 1H), 3.88 (br dd, J = 3.4, 11.0 Hz, 1H), 2.08 - 2.05 (m, 1H), 0.93 - 0.71 (m, 4H). Compound 7 yl)amino)phenoxy)-2-azaspiro[3.3]heptane-2-carboxylate. To a solution of 6- (cyclopropanecarbonylamino)-4-(3-hydroxyanilino)pyridazine-3-carboxamide (300 mg, 957.52 μmol, 1 eq) in DMF (10 mL) was added K2CO3 (555.80 mg, 4.02 mmol, 4.2 eq) and tert-butyl 6-methylsulfonyloxy-2-azaspiro[3.3]heptane-2-carboxylate (278.98 mg, 957.52 μmol, 1 eq). The mixture was stirred at 120°C for 12 hr. LCMS showed desired compound formed. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O 5 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 reduced pressure to give tert-butyl 6-(3-((3-carbamoyl-6- (cyclopropanecarboxamido)pyridazin-4-yl)amino)phenoxy)-2-azaspiro[3.3]heptane-2- carboxylate (150 mg, crude) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 10.75 (s, 1H), 8.50 (br s, 1H), 8.10 (s, 1H), 7.86 (br s, 1H), 7.30 (br t, J = 8.1 Hz, 1H), 6.83 (br d, J = 7.8 Hz, 1H), 6.76 (br s, 1H), 6.68 (br d, J = 8.3 Hz, 1H), 4.69 - 4.51 (m, 1H), 3.93 - 3.75 (m, 4H), 2.72 - 2.63 (m, 2H), 2.27 - 2.14 (m, 2H), 2.12 - 2.01 (m, 1H), 1.36 (s, 9H), 0.95 - 0.66 (m, 4H). MS (ESI): m / z = 509.4 [M+H]+. STDU2-43395.601 4-((3-((2-azaspiro[3.3]heptan-6-yl)oxy)phenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide. A solution of tert-butyl 6-(3-((3- carbamoyl-6-(cyclopropanecarboxamido)pyridazin-4-yl)amino)phenoxy)-2- azaspiro[3.3]heptane-2-carboxylate (130 mg, 255.62 μmol, 1 eq) in DCM (2 mL)was added TFA (767.50 mg, 6.73 mmol, 0.5 mL, 26.33 eq). The reaction was stirred at 25°C for 40 min. LCMS showed desired compound formed. The reaction was concentrated under reduced pressure to remove solvent and the excess TFA. The crude product 4-((3-((2- azaspiro[3.3]heptan-6-yl)oxy)phenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3- carboxamide (310 mg, 243.26 μmol, 95.17% yield, 41% purity, TFA) was obtained as a yellow oil which was directly used into the next step without further purification. 4-((3-((2-acryloyl-2-azaspiro[3.3]heptan-6-yl)oxy)phenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide. To a suspension of 4-((3-((2- azaspiro[3.3]heptan-6-yl)oxy)phenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3- carboxamide (310 mg, 243.26 μmol, 1 eq, TFA) in THF (3 mL) and H2O (3 mL) was added NaHCO3 (81.74 mg, 973.06 μmol, 37.86 μL, 4 eq). The mixture was cooled down to 0°C and then added prop-2-enoyl chloride (24.22 mg, 267.59 μmol, 21.74 μL, 1.1 eq) dropwise under stirring. The reaction was stirred at 0°C for 1 hr. LCMS showed desired compound formed. The reaction was concentrated using a nitrogen flow to remove most of THF solvent. The residue was diluted with DMF (4 mL) and was purified by prep-HPLC {column: Phenomenex Luna C18100*30mm*5μm; mobile phase: [H2O(0.1% TFA)-ACN]; gradient:15%-45% B over 8.0 min}. The fraction was lyophilized to give 4-((3-((2-acryloyl- 2-azaspiro[3.3]heptan-6-yl)oxy)phenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3- carboxamide (47.62 mg, 102.01 μmol, 41.94% yield, 99.08% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 10.76 (s, 1H), 8.50 (br s, 1H), 8.07(s, 1H), 7.87 (s, 1H), 7.31 (t, J = 8.1 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.77 (br d, J = 2.1 Hz, 1H), 6.69 (dd, J = 2.0,8.3 Hz, 1H), 6.26 (dd, J = 10.3, 16.9 Hz, 1H), 6.07 (td, J = 2.8, 17.0 Hz, 1H), 5.65 (ddd, J = 2.3, 5.8, 10.2 Hz, 1H), 4.71 - 4.61 (m, 1H), 4.25 (s, 1H), 4.19 (s, 1H), 3.96 (s, 1H), 3.90 - 3.89 (m, 1H), 2.77 - 2.68 (m, 2H), 2.29 - 2.21 (m, 2H), 2.10 - 2.02 (m, 1H), 0.85 - 0.76 (m, 4H). MS (ESI): m / z = 463.3 [M+H]+. STDU2-43395.601 Compound 8 6- yl)oxy)phenyl) 4-((3-(azetidin-3- yloxy)phenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3-carboxamide (25 mg, 1 eq, 52 μmol, TFA salt) in DMF (1 mL) was added propiolic acid (5.4 mg, 4.8 μL, 1.5 eq, 78 μmol), DIEA (33 mg, 45 μL, 5 eq, 0.26 mmol) and HATU (30 mg, 1.5 eq, 78 μmol). The mixture was stirred at rt for 5min. LCMS indicating desired product formed. The mixture was purified by prep-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.1H NMR (500 MHz, DMSO-d6) δ 11.29 (s, 1H), 10.75 (s, 1H), 8.58 – 8.45 (m, 1H), 8.13 (s, 1H), 7.96 – 7.77 (m, 1H), 7.37 (t, J = 8.1 Hz, 1H), 6.94 (dd, J = 7.9, 1.9 Hz, 1H), 6.83 (t, J = 2.2 Hz, 1H), 6.75 (dd, J = 8.2, 2.4 Hz, 1H), 5.12 – 5.09 (m, 1H), 4.64 (ddd, J = 10.0, 6.5, 1.5 Hz, 1H), 4.48 (s, 1H), 4.39 (ddd, J = 11.2, 6.5, 1.6 Hz, 1H), 4.13 (ddd, J = 10.1, 4.0, 1.5 Hz, 1H), 3.89 (ddd, J = 11.1, 4.0, 1.5 Hz, 1H), 2.15 – 2.03 (m, 1H), 0.91 – 0.77 (m, 4H). MS (ESI): m / z = 421.13 [M+H]+. Compound 9 4-((3-( (cyclopropanecarboxamido)pyridazine-3-carboxamide. The solution of 4-((3-(azetidin-3- yloxy)phenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3-carboxamide (25 mg, 1 eq, 52 μmol, TFA salt) in DMF (1 mL) was added but-2-ynoic acid (5.2 mg, 62 μL, 1 molar, 1.2 eq, 62 μmol), DIEA (33 mg, 45 μL, 5 eq, 0.26 mmol) and HATU (30 mg, 1.5 eq, 78 μmol). The mixture was stirred at rt for 5min. LCMS indicating desired product formed. The mixture was purified by prep-HPLC [Agilent Pursuit XRs 5 C18150 × 10 mm; A: H2O (0.1% FA), B: STDU2-43395.601 ACN (0.1% FA); A%: 95%-5%, 5 ml / min, 30 min] and lyophilized to obtain a white powder.1H NMR (500 MHz, DMSO-d6) δ 11.29 (s, 1H), 10.74 (s, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.13 (s, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.36 (t, J = 8.1 Hz, 1H), 6.93 (dd, J = 7.6, 1.9 Hz, 1H), 6.81 (t, J = 2.2 Hz, 1H), 6.74 (dd, J = 8.4, 2.5, 1H), 5.11 – 5.07 (m, 1H), 4.59 (ddd, J = 10.1, 6.4, 1.5 Hz, 1H), 4.34 (ddd, J = 11.0, 6.5, 1.5 Hz, 1H), 4.06 (ddd, J = 10.1, 3.9, 1.4 Hz, 1H), 3.85 (ddd, J = 11.1, 4.0, 1.5 Hz, 1H), 2.10 – 2.07 (m, 1H), 2.01 (s, 3H), 0.89 – 0.78 (m, 4H). MS (ESI): m / z = 435.18 [M+H]+. Compound 10 6- yl)oxy)phenyl)amino)pyridazine-3-carboxamide. The solution of 4-((3-(azetidin-3- yloxy)phenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3-carboxamide (25 mg, 1 eq, 52 μmol, TFA salt) in DMF (1 mL) was added 2-fluoroacrylic acid (5.6 mg, 62 μL, 1 molar, 1.2 eq, 62 μmol), DIEA (33 mg, 45 μL, 5 eq, 0.26 mmol) and HATU (30 mg, 1.5 eq, 78 μmol). The mixture was stirred at rt for 5 min. LCMS indicating desired product formed. The mixture was purified by prep-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.1H NMR (500 MHz, DMSO-d6) δ 11.21 (s, 1H), 10.66 (s, 1H), 8.43 (d, J = 2.3 Hz, 1H), 8.04 (s, 1H), 7.78 (d, J = 2.3 Hz, 1H), 7.29 (t, J = 8.1 Hz, 1H), 6.85 (dd, J = 7.7, 1.9 Hz, 1H), 6.73 (t, J = 2.2 Hz, 1H), 6.66 (dd, J = 7.8, 2.4 Hz, 1H), 5.47 (d, J = 3.6 Hz, 0.5H), 5.37 (d, J = 3.6 Hz, 0.5H), 5.24 (dd, J = 16.5, 3.6 Hz, 1H), 5.04 – 5.00 (m, 1H), 4.75 – 4.71 (m, 1H), 4.38 – 4.34 (m, 1H), 4.24 (d, J = 10.6 Hz, 1H), 3.90 – 3.83 (m, 1H), 2.02 – 1.97 (m, 1H), 0.77 – 0.72 (m, 4H). MS (ESI): m / z = 441.13 [M+H]+. STDU2-43395.601 Compound 11 3- carboxylate. To a solution of methyl 6-(cyclopropanecarboxamido)-4-((3- methoxyphenyl)amino)pyridazine-3-carboxylate (1.2 g, 1 eq, 3.5 mmol) in DCM (15 mL) at 0 ℃ was added BBr3(2.6 g, 11 mL, 1 molar, 3 eq, 11 mmol) and the mixture was stirred at rt for 1h. LCMS indicating the reaction was completed and desired product formed. 10 ml ammonia was added at 0 ℃ and stirred to quench the reaction. Then the mixture was filtered and the filtrate was concentrated. The residue was partitioned into 20 ml EA, then the mixture was filtered to obtain a black residue, dried to obtain the desired product. MS (ESI): m / z = 329.12 [M+H]+. 4-((3-((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)phenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxylic acid. To a solution of methyl 6- (cyclopropanecarboxamido)-4-((3-hydroxyphenyl)amino)pyridazine-3-carboxylate (400 mg, 1 eq, 1.22 mmol) in DMF (2 mL) was added tert-butyl 3-((methylsulfonyl)oxy)azetidine-1- carboxylate (306 mg, 1 eq, 1.22 mmol) and K2CO3 (505 mg, 3 eq, 3.65 mmol). The mixture was stirred at 120 ℃ overnight. LCMS indicating direct formation of the ester hydrolysis product. The mixture was partitioned into 10 ml water and the PH was adjusted to 5 with 2M HCl solution. The mixture was extracted with 15 ml EA for two times. The combined EA was dried with anhydrous Na2SO4 and then concentrated. 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] and lyophilized to obtain the desired product. MS (ESI): m / z = 470.23 [M+H]+. 4-((3-(azetidin-3-yloxy)phenyl)amino)-6-(cyclopropanecarboxamido)-N- methylpyridazine-3-carboxamide. To a solution of 4-((3-((1-(tert-butoxycarbonyl)azetidin-3- STDU2-43395.601 yl)oxy)phenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3-carboxylic acid (15 mg, 1 eq, 32 μmol) in DMF (1.5 mL) was added Methylamine hydrochloride (3.2 mg, 1.5 eq, 48 μmol), DIEA (21 mg, 28 μL, 5 Eq, 0.16 mmol) and HATU (18 mg, 1.5 Eq, 48 μmol), and the mixture was stirred at rt for 5min. LCMS indicating the reaction was completed. The mixture was concentrated and the residue was dissolved into 2 ml DCM and 2 ml TFA, then stirred at rt for 1h. LCMS indicating desired product formed. The mixture was concentrated and lyophilized to obtain the desired product used directly in the next step. MS (ESI): m / z = 383.12 [M+H]+. 4-((3-((1-acryloylazetidin-3-yl)oxy)phenyl)amino)-6-(cyclopropanecarboxamido)-N- methylpyridazine-3-carboxamide. The solution of 4-((3-(azetidin-3-yloxy)phenyl)amino)-6- (cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide (12 mg, 1 eq, 31 μmol) in 0.5 ml DMF was stirred at 0 ℃ for 5 min. Then DIEA (20 mg, 27 μL, 5 eq, 0.16 mmol) and acryloyl chloride (3.4 mg, 38 μL, 1 molar in DCM, 1.2 eq, 38 μmol) was added. The mixture was stirred at 0 ℃ for 30 min. LCMS indicating the reaction was completed and desired product formed. The reaction mixture was purified by prep-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] to obtain the desired product.1H NMR (500 MHz, DMSO-d6) δ 11.25 (s, 1H), 10.68 (s, 1H), 9.09 (q, J = 4.8 Hz, 1H), 8.06 (s, 1H), 7.29 (t, J = 8.1 Hz, 1H), 6.85 (dd, J = 7.8, 1.9 Hz, 1H), 6.73 – 6.72 (m, 1H), 6.67 (dd, J = 8.2, 2.4 Hz, 1H), 6.28 – 6.22 (m, 1H), 6.07– 6.04 (m, 1H), 5.62 (dd, J = 10.3, 2.2 Hz, 1H), 5.07 – 4.95 (m, 1H), 4.59 (dd, J = 10.1, 6.2 Hz, 1H), 4.29 (dd, J = 11.2, 6.6 Hz, 1H), 4.11 (dd, J = 10.2, 3.9 Hz, 1H), 3.82 (dd, J = 11.3, 3.9 Hz, 1H), 2.77 (d, J = 4.8 Hz, 3H), 2.08 – 1.96 (m, 1H), 0.82 – 0.68 (m, 4H). MS (ESI): m / z = 437.18 [M+H]+. Compound 12 ethylpyridazine-3-carboxamide. To a solution of 4-((3-((1-(tert-butoxycarbonyl)azetidin-3- yl)oxy)phenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3-carboxylic acid (15 mg, 1 eq, 32 μmol) in DMF (1.5 mL) was added Ethylamine (2.2 mg, 24 μL, 2 molar in THF, 1.5 eq, 48 μmol), DIEA (21 mg, 28 μL, 5 Eq, 0.16 mmol) and HATU (18 mg, 1.5 Eq, 48 μmol), the STDU2-43395.601 mixture was stirred at rt for 5 min. LCMS indicating desired product formed. The mixture was concentrated, the residue was dissolved into 2 ml DCM and 2 ml TFA, then stirred at rt for 1h. LCMS indicating desired product formed. The mixture was concentrated and lyophilized to obtain the desired product used directly in the next step. MS (ESI): m / z = 397.17 [M+H]+. 4-((3-((1-acryloylazetidin-3-yl)oxy)phenyl)amino)-6-(cyclopropanecarboxamido)-N- ethylpyridazine-3-carboxamide. The solution of 4-((3-(azetidin-3-yloxy)phenyl)amino)-6- (cyclopropanecarboxamido)-N-ethylpyridazine-3-carboxamide (12 mg, 1 eq, 30 μmol) in 0.5 ml DMF was stirred at 0 ℃ for 5 min. Then DIEA (20 mg, 26 μL, 5 Eq, 0.15 mmol) and acryloyl chloride (3.3 mg, 36 μL, 1 molar in DCM, 1.2 Eq, 36 μmol) was added. The mixture was stirred at 0 ℃ for 30 min. LCMS indicating the reaction was completed and desired product formed. The reaction mixture was purified by prep-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] to obtain the desired product.1H NMR (500 MHz, DMSO-d6) δ 11.25 (s, 1H), 10.69 (s, 1H), 9.16 (t, J = 6.1 Hz, 1H), 8.06 (s, 1H), 7.29 (t, J = 8.1 Hz, 1H), 6.85 (dd, J = 8.0, 2.0 Hz, 1H), 6.73 (t, J = 2.3 Hz, 1H), 6.67 (dd, J = 8.2, 2.4 Hz, 1H), 6.25 (dd, J = 17.0, 10.3 Hz, 1H), 6.05 (dd, J = 17.0, 2.2 Hz, 1H), 5.62 (dd, J = 10.4, 2.1 Hz, 1H), 5.02 – 5.00 (m, 1H), 4.59 (ddd, J = 9.9, 6.3, 1.4 Hz, 1H), 4.29 (ddd, J = 11.2, 6.5, 1.5 Hz, 1H), 4.15 – 4.06 (m, 1H), 3.85 – 3.77 (m, 1H), 3.31 – 3.30 (m, 2H), 2.03 – 1.99 (m, 1H), 1.09 (t, J = 7.2 Hz, 3H), 0.80 – 0.70 (m, 4H). MS (ESI): m / z = 451.23 [M+H]+. Compound 13 cyclopropylpyridazine-3-carboxamide. To a solution of 4-((3-((1-(tert- butoxycarbonyl)azetidin-3-yl)oxy)phenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3- carboxylic acid (15 mg, 1 eq, 32 μmol) in DMF (1.5 mL) was added Cyclopropylamine (2.7 mg, 3.3 μL, 1.5 eq, 48 μmol), DIEA (12 mg, 17 μL, 3 eq, 96 μmol) and HATU (18 mg, 1.5 eq, 48 μmol), the mixture was stirred at rt for 5 min. LCMS indicating desired product formed. The mixture was concentrated, the residue was dissolved into 2 ml DCM and 2 ml TFA, then stirred at rt for 1h. LCMS indicating desired product formed. The mixture was concentrated STDU2-43395.601 and lyophilized to obtain the desired product used directly in the next step. MS (ESI): m / z = 409.17 [M+H]+. 4-((3-((1-acryloylazetidin-3-yl)oxy)phenyl)amino)-6-(cyclopropanecarboxamido)-N- cyclopropylpyridazine-3-carboxamide. The solution of 4-((3-(azetidin-3- yloxy)phenyl)amino)-6-(cyclopropanecarboxamido)-N-cyclopropylpyridazine-3- carboxamide (12 mg, 1 eq, 29 μmol) in 0.5 ml DMF was stirred at 0 ℃ for 5 min. Then DIEA (19 mg, 26 μL, 5 eq, 0.15 mmol) and acryloyl chloride (3.2 mg, 35 μL, 1 molar in DCM, 1.2 eq, 35 μmol) was added. The mixture was stirred at 0 ℃ for 30 min. LCMS indicating the reaction was completed and desired product formed. The reaction mixture was purified by prep-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] to obtain the desired product.1H NMR (500 MHz, DMSO- d6) δ 11.28 (s, 1H), 10.69 (s, 1H), 9.13 (d, J = 4.8 Hz, 1H), 8.12 (s, 1H), 7.36 (t, J = 8.1 Hz, 1H), 6.93 (dd, J = 7.8, 2.0 Hz, 1H), 6.80 (t, J = 2.3 Hz, 1H), 6.73 (dd, J = 8.3, 2.5 Hz, 1H), 6.41 – 6.27 (m, 1H), 6.12 (dd, J = 17.0, 2.2 Hz, 1H), 5.68 (dd, J = 10.4, 2.2 Hz, 1H), 5.10 – 5.06 (m, 1H), 4.66 (dd, J = 9.9, 6.5 Hz, 1H), 4.36 (dd, J = 11.1, 6.6 Hz, 1H), 4.17 (dd, J = 10.2, 3.8 Hz, 1H), 3.88 (dd, J = 11.0, 3.9 Hz, 1H), 2.94 – 2.88 (m, 1H), 2.11 – 2.05 (m, 1H), 0.88 – 0.77 (m, 4H), 0.75 – 0.67 (m, 4H). MS (ESI): m / z = 463.28 [M+H]+. Example 2 Biological Assays 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 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; 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 = STDU2-43395.601 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 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 Table 1. Table 1. Mass spectra result of the compounds incubated with JAK2 JH2 Compound Covalent Label rate 1 + + + re ers o cova en a e ra e o ≥ 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% CO2 in 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 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. IC50 values were determined using a non-linear regression curve fit in GraphPad PRISM 10.3.0. STDU2-43395.601 Table 2. STAT3 reporter assay IC50of some selected compounds Compound IC50 Compound IC50 1●●●9●●● ●●● refers to IC50of ≤2 μM 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. IC50values were determined using a non-linear regression curve fit in GraphPad PRISM 10.3.0. Table 3. Cell Viability Assay IC50 of some selected compounds Compound IC50 Compound IC50 1♢♢ ♢♢♢ ♢♢ refers to IC50 of > 5 μM to ≤ 10 μM ♢♢♢ refers to IC50 of ≤5 μM

Claims

1. STDU2-43395.601 CLAIMS 1. A compound of formula (I): or a pharmaceutically 1R is selected from heterocyclyl; Q is N or CH; X1is O, NRa, or a bond; X2is selected from aryl, heterocyclyl, and cycloalkyl; R2is a warhead moiety; R3is selected from hydrogen, alkyl, halo, hydroxy, alkoxy, amino, haloalkyl, haloalkoxy, cyano, and nitro; R4is hydrogen, C1-C4alkyl, or C3-C6cycloalkyl, or R4is taken together with Q to form a ring; and Rais hydrogen or C1-C4alkyl; wherein each alkyl, cycloalkyl, aryl, and heterocyclyl is independently unsubstituted or substituted with one or more substituents independently selected from halo, hydroxy, alkoxy, amino, alkyl, haloalkyl, haloalkoxy, cyano, and nitro.

2. A compound of formula (Ia): or a pharmaceuticallyR1is selected from C1-C6 alkyl, C3-C6 cycloalkyl, and heterocyclyl; Q is N or CH;STDU2-43395.601 X1is O, NRa, or a bond; X2is selected from aryl, heterocyclyl, and cycloalkyl; R2is a warhead moiety; R3is selected from hydrogen, alkyl, halo, hydroxy, alkoxy, amino, haloalkyl, haloalkoxy, cyano, and nitro; R4is hydrogen, or R4is taken together with Q to form a ring; and Rais hydrogen or C1-C4 alkyl; wherein each alkyl, cycloalkyl, aryl, and heterocyclyl is independently unsubstituted or substituted with one or more substituents independently selected from halo, hydroxy, alkoxy, amino, alkyl, haloalkyl, haloalkoxy, cyano, and nitro.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R1is C3-C6 cycloalkyl.

4. The compound of any one of claims 1-3,or a pharmaceutically acceptable salt thereof, wherein R1is cyclopropyl.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein Q is N.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein X1is O.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein X2is aryl.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein X2is phenyl.

9. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein X2is a monocyclic or bicyclic heterocyclyl having 1 nitrogen atom.STDU2-43395.601 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein X is selected from piperidinyl, pyrrolidinyl, azetidinyl, 2-azaspiro[3.3]heptan-6-yl, 1- azaspiro[3.3]heptan-6-yl, and 1,2,3,6-tetrahydropyridinyl.

11. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein X is selected from piperidinyl, pyrrolidinyl, azetidinyl, and 2-azaspiro[3.3]heptan-6-yl.

12. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein X2is C3-C6 cycloalkyl.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein X2is cyclobutyl.

14. The compound of any one of claims 7-13, or a pharmaceutically acceptable salt thereof, wherein X2is unsubstituted or substituted with 1 or 2 substituents independently selected from methyl, methoxy, hydroxy, and halo.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R2is selected from -C(O)CH=CH2, -C(O)CF=CH2, -NHC(O)CH=CH2, - N(CH3)C(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.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R2is selected from -C(O)CH=CH2, -NHC(O)CH=CH2, -C(O)C≡CCH3, - C(O)C≡CH, and -C(O)CF=CH2.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen or C1-C4 alkoxy.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen.STDU2-43395.601 19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen.

20. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R4is C1-C4 alkyl or C3-C6 cycloalkyl.

21. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R4is methyl.

22. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R4is ethyl.

23. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R4is cyclopropyl.

24. The compound of claim 1, wherein the compound is selected from:STDU2-43395.601pharmaceutically acceptable salts thereof.

25. A pharmaceutical composition comprising a compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

26. 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 claims 1-24, or a pharmaceutically acceptable salt thereof.

27. The method of claim 26, wherein the proliferative disease is a cancer.STDU2-43395.601 28. The method of claim 27, wherein the cancer is associated with JAK2.

29. The method of claim 28, wherein the cancer is associated with a V617F mutation in JAK2.

30. The method of claim 29, wherein the cancer is a myeloproliferative neoplasm.

31. The method of claim 30, wherein the myeloproliferative neoplasm is chronic myelogenous leukemia, polycythemia vera, primary myelofibrosis, essential thrombocythemia, chronic neutrophilic leukemia, or chronic eosinophilic leukemia.

32. A compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, for use as a medicament.

33. A compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, for use in treating a proliferative disease.

34. The compound of claim 33, wherein the proliferative disease is a cancer.

35. The compound of claim 34, wherein the cancer is associated with JAK2.

36. The compound of claim 35, wherein the cancer is associated with a V617F mutation in JAK2.

37. The compound of claim 35, wherein the cancer is a myeloproliferative neoplasm.

38. The compound of claim 37, wherein the myeloproliferative neoplasm is chronic myelogenous leukemia, polycythemia vera, primary myelofibrosis, essential thrombocythemia, chronic neutrophilic leukemia, or chronic eosinophilic leukemia.

39. A kit comprising a compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof.

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