6-heteroaryloxy benzimidazoles and azabenzimidazoles as jak2 inhibitors

Abstract

This disclosure provides compounds and compositions thereof that can be used to inhibit 6-heteroaryloxybenzimidazole and azabenzimidazole of JAK2.

Description

prior art

[0001] Janus kinase 2 (JAK2) is a non-receptor tyrosine kinase involved in the JAK-STAT signaling pathway, which plays a role in cellular processes such as immunity, cell division and cell death. Dysfunction of the JAK-STAT pathway is associated with a variety of diseases, including cancer and other proliferative diseases, as well as disorders of the immune system. For example, essentially all BCR-ABL1 negative myeloproliferative neoplasms are associated with mutations that activate JAK2. Specifically, JAK2 V617F is the most common mutation in myeloproliferative neoplasms, occurring in approximately 70% of all patients and up to 95% in patients with plethora vera. (Vainchenker, W., Kralovics, R. Blood 2017, 129(6):667-79). Even less common mutations, such as those in MPL and CALR, have been shown to cause activation of JAK2, thereby initiating and / or driving disease progression. (Vainchenker, W. et al., F1000 Research 2018, 7 (F1000 Faculty Rev): 82). In addition, polymorphisms in JAK2 have been associated with various autoimmune and inflammatory disorders, such as psoriasis and inflammatory bowel disease. (O'Shea, J. J. et al., Ann. Rheum. Dis. 2013 Apr, 72:ii111-ii115). Increased signaling through JAK2 and other members of the JAK family has also been associated with atopic dermatitis. (Rodrigues, M. A. and Torres, T. J. Derm. Treat. 2019, 31(1):33-40).

[0002] JAK (eg, JAK2) inhibitors are classified based on their mode of binding. All currently approved JAK inhibitors are type I inhibitors, which are those inhibitors that bind the ATP binding site in the active conformation of the kinase domain, thereby blocking catalysis (Vainchenker, W. et al.). However, type I inhibitors have been observed to increase phosphorylation of the JAK2 activation loop and may confer acquired resistance in some patients (Meyer S. C., Levine, R. L. Clin. Cancer Res. 2014, 20(8):2051-9 ). Type II inhibitors, on the other hand, bind the ATP binding site in the inactive conformation of the kinase domain and thus avoid the hyperphosphorylation observed with type I inhibitors (Wu, S. C. et al., Cancer Cell 2015 Jul 13, 28(1):29-41). Contents of the invention

[0003] The disclosure provides compounds useful for inhibiting JAK2. In some embodiments, provided compounds are particularly useful in the treatment and / or prevention of diseases, disorders or disorders associated with JAK2.

[0004] In some embodiments, the disclosure provides compounds of Formula I-1: I-1 or a pharmaceutically acceptable salt thereof, wherein rings A, L, W, X, Y, Z, R1, R2 and Ra are as defined herein.

[0005] In some embodiments, the disclosure provides compounds of formula I: I or a pharmaceutically acceptable salt thereof, wherein rings A, L, X, Y, Z, R1, R2 and Ra are as defined herein. Implementation

[0006] [] [Related applications] []

[0007] This application asserts U.S. Application No. 63 / 020,645, filed May 6, 2020, U.S. Application No. 63 / 087,717, filed October 5, 2020, and U.S. Application No. 63 / 087,717, filed December 23, 2020. Priority to and benefit of Application No. 63 / 130,254, the entire contents of each of these US applications are hereby incorporated by reference in their entirety. [ Compounds and Definitions , ] [ , ]

[0008] Compounds of the present invention include those summarized above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75th edition). In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th edition, edited by Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0009] Unless otherwise stated, structures depicted herein are intended to include all stereoisomeric (eg, mirror-isomeric or non-mirromeric) forms of the structures, as well as all geometric or configurational isomeric forms of the structures. For example, consider the R and S configurations of each stereocenter as part of this disclosure. Accordingly, single stereochemical isomers as well as enantiomerically, diastereomerically and geometric (or configurational) mixtures of the provided compounds are within the scope of the present disclosure. For example, in some instances, Table 1 shows one or more stereoisomers of a compound, and unless otherwise indicated, represents each individual stereoisomer and / or as a mixture. Unless otherwise stated, all tautomeric forms of the compounds provided are within the scope of the disclosure.

[0010] Unless otherwise indicated, structures depicted herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having structures of the present invention, including replacement of hydrogen with deuterium or tritium, or replacement of carbon with 13 C or 14 C enriched carbon, are within the scope of the disclosure.

[0011] Aliphatic: The term "aliphatic" means an optionally substituted straight (i.e., unbranched) or branched hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, either fully saturated or containing one or more units of unsaturation. A monocyclic or bicyclic hydrocarbon (also referred to herein as a "carbocycle" or "cycloaliphatic") with multiple units of unsaturation, but which is not aromatic, having a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (eg, C1-6). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (eg, C1-5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (eg, C1-4). In other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C1-3). 2 ). Suitable aliphatic groups include, but are not limited to, substituted or unsubstituted straight or branched chain alkyl, alkenyl, alkynyl, and hybrids thereof. In some embodiments, "aliphatic" refers to a fully saturated or optionally substituted straight (i.e., unbranched) or branched hydrocarbon chain containing one or more units of unsaturation, which is distinct from the rest of the molecule. Some have a single connection point.

[0012] Alkyl: The term "alkyl" when used alone or as part of a larger moiety means having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1 -4, 1-3 or 1-2 carbon atoms (such as C1-12, C1-10, C1-8, C1-6, C1-4, C1-3 or C1-2) optionally substituted straight-chain or branched-chain saturated hydrocarbon groups. Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.

[0013] Carbocyclyl: As used herein, the terms "carbocyclyl", "carbocycle and carbocyclic ring" refer to a saturated or partially unsaturated cyclic aliphatic monocyclic ring having from 3 to 14 members as described herein, Bicyclic or polycyclic ring systems, wherein the aliphatic ring system is optionally substituted as described herein. Carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctyl alkenyl, norbornyl, adamantyl and cyclooctadienyl. In some embodiments, "carbocyclyl" (or "cycloaliphatic") refers to an optionally substituted monocyclic C3-C8 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic. Or an optionally substituted C7-C10 bicyclic hydrocarbon having a single point of attachment to the rest of the molecule. The term "cycloalkyl" refers to an optionally substituted saturated ring system having about 3 to about 10 ring carbon atoms. In some embodiments, cycloalkyl groups have 3-6 carbons. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "cycloalkenyl" refers to an optionally substituted non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and having from about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0014] Alkenyl: The term "alkenyl" when used alone or as part of a larger moiety means having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4 or 2-3 carbon atoms (such as C2-12, C2-10, C2-8, C2-6, C2-4 or C2-3) optionally substituted straight chain Or branched hydrocarbon chain. Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.

[0015] Alkynyl: The term "alkynyl" when used alone or as part of a larger moiety means having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4 or 2-3 carbon atoms (such as C2-12, C2-10, C2-8, C2-6, C2-4 or C2-3) optionally substituted straight chain Or a branched hydrocarbon group. Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0016] Aryl: The term "aryl" refers to monocyclic and bicyclic ring systems having a total of 6 to 14 ring members (eg, C6-14), wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" is used interchangeably with the term "aryl ring". In some embodiments, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, naphthyl, anthracenyl, and the like, which may bear one or more substituents. Unless otherwise specified, "aryl" is a hydrocarbon.

[0017] Heteroaryl: The terms "heteroaryl" and "heteroaryl-" when used alone or as part of a larger moiety (such as "heteroaralkyl" or "heteroaralkoxy") refer to 10 ring atoms (e.g. 5 to 6 membered monocyclic heteroaryl or 9 to 10 membered bicyclic heteroaryl); have 6, 10 or 14 π-electrons shared in a ring array; and other than carbon atoms There are also monocyclic or bicyclic groups having 1 to 5 heteroatoms. Exemplary heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazole Base, isothiazolyl, thiadiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridyl, pteridyl, imidazo[1,2 -a]pyrimidinyl, imidazo[1,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl and benzisoxazolyl. As used herein, the terms "heteroaryl" and "heteroaryl-" also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherein the linking group or The point of attachment is on a heteroaromatic ring (ie, a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuryl, dibenzofuryl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl , benzoxazolyl, quinolinyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinazinyl, carbazolyl, acridinyl, phenazine Base, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-1,4-oxazin-3(4H)-one and benzo And isoxazolyl. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic", any of which terms include the optional replace the ring.

[0018] Heteroatom: The term "heteroatom" as used herein refers to nitrogen, oxygen or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternary ammonium form of basic nitrogen.

[0019] Heterocycle: As used herein, the terms "heterocycle", "heterocyclyl" and "heterocyclic ring" are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 7-membered to 10-membered bicyclic heterocyclic moieties which are saturated or partially unsaturated and which, in addition to carbon atoms, also have one or more (such as one to four) heteroatoms as defined above. The term "nitrogen" when used with reference to a ring atom of a heterocyclic ring includes substituted nitrogens. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl). A heterocycle can be attached to its pendant group at any heteroatom or carbon atom, resulting in a stable structure, and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, hexahydropyridyl, decahydroquinolinyl, oxazolidinyl, hexahydropyrazinyl, dihydropyrazinyl, Oxaalkyl, dioxolanyl, diazolyl, oxazazayl, thiazazayl, morpholinyl and thiomorpholinyl. The heterocyclic group can be monocyclic, bicyclic, tricyclic or polycyclic, preferably monocyclic, bicyclic or tricyclic, more preferably monocyclic or bicyclic. Bicyclic heterocycles also include groups wherein the heterocycle is fused to one or more aryl, heteroaryl, or cycloaliphatic rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl base and tetrahydroquinolinyl. Bicyclic heterocycles may also be spiro ring systems (e.g. 7- to 11-membered spirofused heterocycles which, in addition to carbon atoms, also have one or more heteroatoms as defined above (e.g. one, two, three one or four heteroatoms)).

[0020] Partially unsaturated: As used herein, the term "partially unsaturated" when referring to a ring moiety means a ring moiety that includes at least one double or triple bond between ring atoms. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (eg aryl or heteroaryl) moieties as defined herein.

[0021] Patient or individual: As used herein, the term "patient" or "individual" refers to any living organism to which a provided composition is or can be administered, for example, for experimental, diagnostic, prophylactic, cosmetic and / or therapeutic purposes. body. Typical patients or individuals include animals (eg, mammals such as mice, rats, rabbits, non-human primates and / or humans). In some embodiments, the patient is human. In some embodiments, a patient or individual suffers from or is susceptible to one or more conditions or disorders. In some embodiments, a patient or individual exhibits one or more symptoms of a disorder or disorder. In some embodiments, a patient or individual has been diagnosed with one or more conditions or disorders. In some embodiments, a patient or individual is receiving or has received a therapy for the diagnosis and / or treatment of a disease, disorder or disorder.

[0022] Substituted or optionally substituted: As described herein, compounds of the disclosure may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of a specified moiety are replaced by a suitable substituent. "Substituted" applies to one or more hydrogens that are explicit or implicit from the structure (e.g. means at least ;and means at least ,or ). Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and more than one position in any given structure may be selected from the specified When substituents of a group are substituted, the substituents at each position may be the same or different. Combinations of substituents contemplated by this invention are preferably those combinations of substituents which result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that, when subjected to conditions for one or more of the purposes provided herein, allows its production, detection, and in certain embodiments, its recovery, purification, and use , which does not change substantially. A group described as "substituted" preferably has 1 to 4 substituents, more preferably 1 or 2 substituents. Groups described as "optionally substituted" may be unsubstituted or "substituted" as set forth above.

[0023] Suitable monovalent substituents on substitutable carbon atoms of "optionally substituted" groups are independently halogen; -(CH2)0-4 Ro; -(CH2)0-4 ORo; -O(CH2)0-4 Ro 、-O-(CH2 )0-4 C(O)ORo ;-(CH2 )0-4 CH(ORo )2 ;-(CH2 )0-4 SRo ;-(CH2 )0-4 Ph, which can Substituted by Ro; -(CH2 )0-4 O(CH2 )0-1 Ph, which can be substituted by Ro; -CH=CHPh, which can be substituted by Ro; -(CH2 )0-4 O(CH2 )0- 1-pyridyl, which may be substituted by Ro;-NO2;-CN;-N3;-(CH2)0-4N(Ro)2;-(CH2)0-4N(Ro)C(O)Ro; -N(Ro )C(S)Ro ;-(CH2 )0-4 N(Ro )C(O)NRo 2 ;-N(Ro )C(S)NRo 2 ;-(CH2 )0-4 N( Ro )C(O)ORo ;-N(Ro )N(Ro )C(O)Ro ;-N(Ro )N(Ro )C(O)NRo 2 ;-N(Ro )N(Ro )C( O)ORo ;-(CH2 )0-4 C(O)Ro ;-C(S)Ro ;-(CH2 )0-4 C(O)ORo ;-(CH2 )0-4 C(O)SRo ; -(CH2 )0-4 C(O)OSiRo 3 ;-(CH2 )0-4 OC(O)Ro ;-OC(O)(CH2 )0-4 SRo ;-(CH2 )0-4 SC(O )Ro ;-(CH2 )0-4 C(O)NRo 2 ;-C(S)NRo 2 ;-C(S)SRo ; NRo 2 ;-C(O)N(ORo )Ro ;-C(O)C(O)Ro ;-C(O)CH2 C(O)Ro ;-C(NORo )Ro ;-(CH2 )0- 4 SSRo; [-] (CH2 )0-4 S(O)2 Ro ;-(CH2 )0-4 S(O)2 ORo ;-(CH2 )0-4 OS(O)2 Ro ;-S(O)2 NRo 2 ;-(CH2 )0-4 S(O)Ro ;-N(Ro )S(O)2 NRo 2 ;-N(Ro )S(O)2 Ro ;-N(ORo )Ro ;-C (NH)NRo 2 ;-P(O)2 Ro ;-P(O)Ro 2 ;-OP(O)Ro 2 ;-OP(O)(ORo )2 ;-SiRo 3 ;-(C1-4 straight chain or branched chain alkylene) O-N(Ro )2; or -(C1-4 straight chain or branched chain alkylene)C(O)O-N(Ro )2, wherein each Ro can be as defined below Substituted and independently hydrogen, C1-6 aliphatic, -CH2 Ph, -O(CH2)0-1 Ph, -CH2-(5 to 6 membered heteroaryl ring) or having 0-4 independently 3- to 6-membered saturated, partially unsaturated or aryl rings of heteroatoms selected from nitrogen, oxygen or sulfur, or notwithstanding the above definition, two independent occurrences of Ro formed together with its intermediate atom have 0-4 3 to 12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic rings of heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below. []

[0024] Suitable monovalent substituents on Ro (or a ring formed by two independent occurrences of Ro together with an intermediate atom) are independently halogen, -(CH2)0-2 Rl, -(haloRl), -(CH2)0- 2 OH, -(CH2)0-2 ORl, -(CH2)0-2 CH(ORl)2, -O(halogen Rl), -CN, -N3, -(CH2)0-2 C(O) Rl, -(CH2)0-2 C(O)OH, -(CH2)0-2 C(O)ORl, -(CH2)0-2 SRl, -(CH2)0-2 SH, -(CH2) 0-2 NH2 , -(CH2 )0-2 NHRl , -(CH2 )0-2 NRl 2 , -NO2 , -SiRl 3 , -OSiRl 3 , -C(O)SRl , -(C1-4 straight chain or Branched chain alkylene) C(O)OR1 or -SSR1, wherein each R1 is unsubstituted or substituted with one or more halogens in the case of preceding "halo", and is independently selected from C1- 4 Aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 3- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur . Suitable divalent substituents on saturated carbon atoms of Ro include =O and =S.

[0025] Suitable divalent substituents on saturated carbon atoms of "optionally substituted" groups include the following: =O ("side oxy"), =S, =NNR*2, =NNHC(O)R*, =NNHC (O)OR* , =NNHS(O)2 R* , =NR* , =NOR* , -O(C(R* 2 ))2-3 O- or -S(C(R* 2 ))2 -3 S-, wherein each independently occurring R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an untreated group having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur Substituted 3-6 membered saturated, partially unsaturated or aryl rings. Suitable divalent substituents bonded to an ortho substitutable carbon of an "optionally substituted" group include: -O(CR*2)2-3O-, wherein each independent occurrence of R* is selected from hydrogen, optionally A substituted C1-6 aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, as defined below.

[0026] Suitable substituents on the aliphatic group of R* include halogen, -R1, -(haloR1), -OH, -OR1, -O(haloR1), -CN, -C(O)OH, - C(O)OR1 , -NH2 , -NHR1 , -NR1 2 or -NO2 , wherein each R1 is unsubstituted or substituted with one or more halogens in the case of preceding "halo", and is independently C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or 3- to 6-membered saturated, partially unsaturated or aromatic with 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur base ring. []

[0027] Suitable substituents on substitutable nitrogens of "optionally substituted" groups include -R†, -NR†2, -C(O)R†, -C(O)OR†, -C(O)C( O)R† , -C(O)CH2 C(O)R† , -S(O)2 R† , -S(O)2 NR† 2 , -C(S)NR† 2 , -C(NH )NR†2 or -N(R†)S(O)2 R†; wherein each R† is independently hydrogen, C1-6 aliphatic which may be substituted as defined below or has 0-4 independently Unsubstituted 3- to 6-membered saturated, partially unsaturated or aryl rings of heteroatoms selected from nitrogen, oxygen or sulfur, or notwithstanding the above definition, two independent occurrences of R† are formed together with an intermediate atom Unsubstituted 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic rings having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. []

[0028] Suitable substituents on the aliphatic groups of R† are independently halogen, -R1, -(haloR1), -OH, -OR1, -O(haloR1), -CN, -C(O)OH , -C(O)ORl , -NH2 , -NHRl , -NRl 2 or -NO2 , wherein each Rl is unsubstituted or substituted with one or more halogens in the case of preceding "halogen", and independently C1-4 aliphatic, -CH2 Ph, -O(CH2)0-1 Ph, or 3-6 membered saturated, partially unsaturated with 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur or aryl ring.

[0029] Treatment: As used herein, the term "treat" (and "treatment (or treating)") refers to the partial or complete alleviation, amelioration, alleviation, suppression of one or more symptoms of a particular disease, disorder and / or condition , characteristics and / or etiology, delaying its onset, reducing its severity and / or reducing its incidence. In some embodiments, such treatment may be directed at individuals who exhibit no signs of the relevant disease, disorder, and / or disorder and / or individuals who exhibit only early signs of the disease, disorder, and / or disorder. Alternatively or additionally, such treatment may be directed at individuals exhibiting one or more established signs of the relevant disease, disorder, and / or disorder. In some embodiments, treatment may be directed at individuals who have been diagnosed with the relevant disease, disorder and / or disorder. [ Compound provided , ] [ , ]

[0030] The disclosure provides compounds of formula I-1: I-1 or a pharmaceutically acceptable salt thereof, wherein: W is CRw or N; X is CRx or N; Y is CRy or N; Z is -O- or -NRz-; Rw, Rx and Ry are each independently hydrogen, halogen, -OR3, -N(R3)2, -SR3, optionally substituted C1-6 aliphatic or -CN; Rz is hydrogen or optionally substituted C1-6 aliphatic; R1 is -N(R)2, -N(R)C(O)R', -C(O)N(R)2 or -N(R)C(O)N(R)2; R2 is an optionally substituted C1-6 aliphatic; each R3 is independently hydrogen or optionally substituted C1-6 aliphatic; Ring A is optionally substituted phenyl, optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, having 1-4 An optionally substituted 8-membered to 10-membered bicyclic heteroaryl group independently selected from heteroatoms of nitrogen, oxygen and sulfur, an optionally substituted 3-membered to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, having 1-3 optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic groups with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur or having 1-4 heteroatoms independently selected from nitrogen, oxygen A 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group optionally substituted with heteroatoms of sulfur and sulfur; L is a covalent bond or a divalent C1-3 straight or branched hydrocarbon chain; R is hydrogen, halogen, optionally substituted C1-6 aliphatic, optionally substituted phenyl, optionally substituted 5 members having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur to 6-membered monocyclic heteroaryl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur A substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic group or an optionally substituted 7-10 membered saturated or partially substituted heteroatom having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Unsaturated bicyclic heterocyclyl; Each R is independently hydrogen, optionally substituted C1-6 aliphatic, optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl, or has 1-3 independently selected from nitrogen, oxygen and sulfur heteroatoms optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic groups, or two R when connected to the same nitrogen atom together form 0-2 independently selected from nitrogen 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl optionally substituted with additional heteroatoms of , oxygen and sulfur; and Each R' is independently optionally substituted C1-6 aliphatic or optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl.

[0031] In some embodiments, the disclosure provides a compound of Formula I-1, or a pharmaceutically acceptable salt thereof, wherein: W is CRw or N; X is CRx or N; Y is CRy or N; Z is -O- or -NRz-; Rw, Rx and Ry are each independently hydrogen, halogen, -OR3, -N(R3)2, -SR3, optionally substituted C1-6 aliphatic or -CN; Rz is hydrogen or optionally substituted C1-6 aliphatic; R1 is -N(R)2, -N(R)C(O)R', -C(O)N(R)2 or -N(R)C(O)N(R)2; R2 is an optionally substituted C1-6 aliphatic; each R3 is independently hydrogen or optionally substituted C1-6 aliphatic; Ring A is optionally substituted phenyl, optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, having 1-4 An optionally substituted 8-membered to 10-membered bicyclic heteroaryl group independently selected from heteroatoms of nitrogen, oxygen and sulfur, an optionally substituted 3-membered to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, having 1-3 optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic groups with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur or having 1-4 heteroatoms independently selected from nitrogen, oxygen A 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group optionally substituted with heteroatoms of sulfur and sulfur; L is a covalent bond or a divalent C1-3 straight or branched hydrocarbon chain; R is hydrogen, halogen, optionally substituted C1-6 aliphatic, optionally substituted phenyl, optionally substituted 5 members having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur to 6-membered monocyclic heteroaryl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur A substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic group or an optionally substituted 7-10 membered saturated or partially substituted heteroatom having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Unsaturated bicyclic heterocyclyl; Each R is independently hydrogen, optionally substituted C1-6 aliphatic, optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl, or has 1-3 independently selected from nitrogen, oxygen and sulfur heteroatoms optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic groups, or two R when connected to the same nitrogen atom together form 0-2 independently selected from nitrogen 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl with additional heteroatoms of , oxygen and sulfur; and Each R' is independently optionally substituted C1-6 aliphatic or optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl.

[0032] In some embodiments, the disclosure provides compounds of formula I: I or a pharmaceutically acceptable salt thereof, wherein: X is CRx or N; Y is CRy or N; Z is -O- or -NRz-; Rx and Ry are each independently hydrogen, optionally substituted C1-6 aliphatic or -CN; Rz is hydrogen or optionally substituted C1-6 aliphatic; R1 is -N(R)2, -N(R)C(O)R', -C(O)N(R)2 or -N(R)C(O)N(R)2; R2 is an optionally substituted C1-6 aliphatic; Ring A is optionally substituted phenyl, optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, having 1-4 An optionally substituted 8-membered to 10-membered bicyclic heteroaryl group independently selected from heteroatoms of nitrogen, oxygen and sulfur, an optionally substituted 3-membered to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, having 1-3 optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic groups with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur or having 1-4 heteroatoms independently selected from nitrogen, oxygen A 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group optionally substituted with heteroatoms of sulfur and sulfur; L is a covalent bond or a divalent C1-3 straight or branched hydrocarbon chain; R is hydrogen, halogen, optionally substituted C1-6 aliphatic, optionally substituted phenyl, optionally substituted 5 members having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur to 6-membered monocyclic heteroaryl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur A substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic group or an optionally substituted 7-10 membered saturated or partially substituted heteroatom having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Unsaturated bicyclic heterocyclyl; Each R is independently hydrogen, optionally substituted C1-6 aliphatic, optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl, or has 1-3 independently selected from nitrogen, oxygen and sulfur heteroatoms optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic groups, or two R when connected to the same nitrogen atom together form 0-2 independently selected from nitrogen 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl with additional heteroatoms of , oxygen and sulfur; and Each R' is independently optionally substituted C1-6 aliphatic or optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl.

[0033] In some embodiments, the disclosure provides compounds of formula II: II or a pharmaceutically acceptable salt thereof, wherein rings A, L, Z, R1, R2, Ra, Rx and Ry are as defined above for formula I-1 and are described herein individually and in combination and subcategories. In some embodiments, Rings A, L, Z, R1, R2, Ra, Rx, and Ry are as defined above for Formula I.

[0034] In some embodiments, the disclosure provides compounds of formula III: III or a pharmaceutically acceptable salt thereof, wherein rings A, L, Z, R1, R2, Ra and Ry are as defined above for formula I-1 and are described in classes and subclasses herein, both individually and in combination. in class. In some embodiments, Rings A, L, Z, R1, R2, Ra and Ry are as defined above for Formula I.

[0035] In some embodiments, the disclosure provides compounds of formula IV: IV or a pharmaceutically acceptable salt thereof, wherein rings A, L, Z, R1, R2, Ra and Rx are as defined above for formula I-1 and are described in the classes and subclasses herein, both individually and in combination. in class. In some embodiments, Rings A, L, Z, R1, R2, Ra and Rx are as defined above for Formula I.

[0036] In some embodiments, the disclosure provides compounds of Formula I': I' or a pharmaceutically acceptable salt thereof, wherein rings A, L, Z, R1, R2, Ra, X and Y are as defined above for formula I-1 and are described herein, both individually and in combination and subclasses; and Rb is hydrogen, halogen, -CN, -OR, -SR, -N(R)2 , -NO2 , -C(O)R', -C(O)OR, -C(O)N(R)2 , -OC(O)R', -OC(O)N(R)2 , -OC(O)OR, -OSO2 R, -OSO2 N(R)2 , -N(R)C(O)R' , -N(R)SO2 R', -SO2 R', -SO2 N(R)2, -SO3 R', optionally substituted C1-6 aliphatic, optionally substituted 3-6 member saturated Or partially unsaturated carbocyclic group, optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclic group with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, with 1- An optionally substituted 5-6 membered monocyclic heteroaryl with 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0037] In some embodiments of Formula I', Rings A, L, Z, R1, R2, Ra, X, and Y are as defined above for Formula I, and Rb is as defined above for Formula I'.

[0038] In some embodiments, the disclosure provides compounds of Formula II': II' or a pharmaceutically acceptable salt thereof, wherein rings A, L, Z, R1, R2, Ra, Rx and Ry are as defined above for formula I-1 and Rb is as defined above for formula I', and Described in categories and subcategories herein, both individually and in combination. In some embodiments, Rings A, L, Z, R1, R2, Ra, Rx, and Ry are as defined above for Formula I and Rb is as defined above for Formula I'.

[0039] In some embodiments, the disclosure provides compounds of formula III': III' or a pharmaceutically acceptable salt thereof, wherein rings A, L, Z, R1, R2, Ra and Ry are as defined above for formula I-1 and Rb is as defined above for formula I', and are represented by a single Both ways and combinations are described in the categories and subcategories of this article. In some embodiments, Rings A, L, Z, R1, R2, Ra and Ry are as defined above for Formula I and Rb is as defined above for Formula I'.

[0040] In some embodiments, the disclosure provides compounds of Formula IV': IV' or a pharmaceutically acceptable salt thereof, wherein rings A, L, Z, R1, R2, Ra and Rx are as defined above for formula I-1 and Rb is as defined above for formula I', and are represented by a single Both ways and combinations are described in the categories and subcategories of this article. In some embodiments, Rings A, L, Z, R1, R2, Ra, and Rx are as defined above for Formula I and Rb is as defined above for Formula I'.

[0041] In some embodiments, the disclosure provides compounds of formula I-A: I-A or a pharmaceutically acceptable salt thereof, wherein rings A, L, X, Y, R' and Ra are the classes and subclasses as defined above for formula I-1 and described herein both individually and in combination middle. In some embodiments, Rings A, L, X, Y, R' and Ra are as defined above for Formula I.

[0042] In some embodiments, the disclosure provides compounds of formula II-A: II-A or a pharmaceutically acceptable salt thereof, wherein rings A, L, R', Rx, Ry and Ra are as defined above for formula I-1 and are described in classes and subclasses herein, both individually and in combination middle. In some embodiments, Rings A, L, R', Rx, Ry and Ra are as defined above for Formula I.

[0043] In some embodiments, the disclosure provides compounds of formula III-A: III-A or a pharmaceutically acceptable salt thereof, wherein rings A, L, R', Ry and Ra are as defined above for formula I-1 and are described in classes and subclasses herein both individually and in combination. In some embodiments, Rings A, L, R', Ry and Ra are as defined above for Formula I.

[0044] In some embodiments, the disclosure provides compounds of Formula IV-A: IV-A or a pharmaceutically acceptable salt thereof, wherein rings A, L, R', Rx and Ra are as defined above for formula I-1 and are described in classes and subclasses herein both individually and in combination. In some embodiments, Rings A, L, R', Rx and Ra are as defined above for Formula I.

[0045] In some embodiments, the disclosure provides compounds of formula I-B: I-B or a pharmaceutically acceptable salt thereof, wherein L, X, Y, Z, R1, R2 and Ra are as defined above for formula I-1 and Rb is as defined above for formula I', and are individually and Combining the two methods is described in the categories and subcategories of this article. In some embodiments, L, X, Y, Z, R1, R2, and Ra are as defined above for Formula I and Rb is as defined above for Formula I'.

[0046] In some embodiments, the disclosure provides compounds of Formula II-B: II-B or a pharmaceutically acceptable salt thereof, wherein L, Z, R1, R2, Rx, Ry and Ra are as defined above for formula I-1 and Rb is as defined above for formula I', and are individually and Combining the two methods is described in the categories and subcategories of this article. In some embodiments, L, Z, R1, R2, Rx, Ry, and Ra are as defined above for Formula I and Rb is as defined above for Formula I'.

[0047] In some embodiments, the disclosure provides compounds of formula III-B: III-B or a pharmaceutically acceptable salt thereof, wherein L, Z, R1, R2, Ry and Ra are as defined above for formula I-1 and Rb is as above defined for formula I', and both alone and in combination Each approach is described in the categories and subcategories of this article. In some embodiments, L, Z, R1, R2, Ry and Ra are as defined above for Formula I and Rb is as defined above for Formula I'.

[0048] In some embodiments, the disclosure provides compounds of formula IV-B: IV-B or a pharmaceutically acceptable salt thereof, wherein L, Z, R1, R2, Rx and Ra are as defined above for formula I-1 and Rb is as defined above for formula I', and both alone and in combination Each approach is described in the categories and subcategories of this article. In some embodiments, L, Z, R1, R2, Rx, and Ra are as defined above for Formula I and Rb is as defined above for Formula I'.

[0049] In some embodiments, the disclosure provides compounds of Formula I-C: I-C or a pharmaceutically acceptable salt thereof, wherein L, X, Y, R' and Ra are as defined above for formula I-1 and Rb is as defined above for formula I', and either alone or in combination Methods are described in categories and subcategories in this article. In some embodiments, L, X, Y, R' and Ra are as defined above for Formula I and Rb is as defined above for Formula I'.

[0050] In some embodiments, the disclosure provides compounds of Formula II-C: II-C or a pharmaceutically acceptable salt thereof, wherein L, R', Rx, Ry and Ra are as defined above for formula I-1 and Rb is as defined above for formula I', and either alone or in combination Methods are described in categories and subcategories in this article. In some embodiments, L, R', Rx, Ry and Ra are as defined above for Formula I and Rb is as defined above for Formula I'.

[0051] In some embodiments, the disclosure provides compounds of formula III-C: III-C or a pharmaceutically acceptable salt thereof, wherein L, R', Ry and Ra are as defined above for formula I-1 and Rb is as defined above for formula I', and are described individually and in combination In the categories and subcategories of this article. In some embodiments, L, R', Ry and Ra are as defined above for Formula I and Rb is as defined above for Formula I'.

[0052] In some embodiments, the disclosure provides compounds of formula IV-C: IV-C or a pharmaceutically acceptable salt thereof, wherein L, R', Rx and Ra are as defined above for formula I-1 and Rb is as defined above for formula I', and are described individually and in combination In the categories and subcategories of this article. In some embodiments, L, R', Rx, and Ra are as defined above for Formula I and Rb is as defined above for Formula I'.

[0053] In some embodiments, the disclosure provides compounds of Formula I-D: I-D or a pharmaceutically acceptable salt thereof, wherein L, X, Y, Z, R1, R2 and Ra are as defined above for formula I-1 and Rb is as defined above for formula I', and are individually and Combining the two methods is described in the categories and subcategories of this article. In some embodiments, L, X, Y, Z, R1, R2, and Ra are as defined above for Formula I and Rb is as defined above for Formula I'.

[0054] In some embodiments, the disclosure provides compounds of Formula II-D: II-D or a pharmaceutically acceptable salt thereof, wherein L, Z, Rx, Ry, R1, R2 and Ra are as defined above for formula I-1 and Rb is as defined above for formula I', and are individually and Combining the two methods is described in the categories and subcategories of this article. In some embodiments, L, Z, Rx, Ry, R1, R2, and Ra are as defined above for Formula I and Rb is as defined above for Formula I'.

[0055] In some embodiments, the disclosure provides compounds of formula III-D: III-D or a pharmaceutically acceptable salt thereof, wherein L, Z, Ry, R1, R2 and Ra are as defined above for formula I-1 and Rb is as above defined for formula I', and both alone and in combination Each approach is described in the categories and subcategories of this article. In some embodiments, L, Z, Ry, R1, R2, and Ra are as defined above for Formula I and Rb is as defined above for Formula I'.

[0056] In some embodiments, the disclosure provides compounds of formula IV-D: IV-D or a pharmaceutically acceptable salt thereof, wherein L, Z, Rx, R1, R2 and Ra are as defined above for formula I-1 and Rb is as defined above for formula I', and both alone and in combination Each approach is described in the categories and subcategories of this article. In some embodiments, L, Z, Rx, R1, R2, and Ra are as defined above for Formula I and Rb is as defined above for Formula I'.

[0057] In some embodiments, the disclosure provides compounds of Formulas I-E: I-E or a pharmaceutically acceptable salt thereof, wherein L, X, Y, R' and Ra are as defined above for formula I-1 and Rb is as defined above for formula I', and either alone or in combination Methods are described in categories and subcategories in this article. In some embodiments, L, X, Y, R' and Ra are as defined above for Formula I and Rb is as defined above for Formula I'.

[0058] In some embodiments, the disclosure provides compounds of formula II-E: II-E or a pharmaceutically acceptable salt thereof, wherein L, R', Rx, Ry and Ra are as defined above for formula I-1 and Rb is as defined above for formula I', and either alone or in combination Methods are described in categories and subcategories in this article. In some embodiments, L, R', Rx, Ry and Ra are as defined above for Formula I and Rb is as defined above for Formula I'.

[0059] In some embodiments, the disclosure provides compounds of Formula III-E: III-E or a pharmaceutically acceptable salt thereof, wherein L, R', Ry and Ra are as defined above for formula I-1 and Rb is as defined above for formula I', and are described individually and in combination In the categories and subcategories of this article. In some embodiments, L, R', Ry and Ra are as defined above for Formula I and Rb is as defined above for Formula I'.

[0060] In some embodiments, the disclosure provides compounds of Formula IV-E: IV-E or a pharmaceutically acceptable salt thereof, wherein L, R', Rx and Ra are as defined above for formula I-1 and Rb is as defined above for formula I', and are described individually and in combination In the categories and subcategories of this article. In some embodiments, L, R', Rx, and Ra are as defined above for Formula I and Rb is as defined above for Formula I'.

[0061] In some embodiments of Formula I-1, W is CRw. In some embodiments, W is N.

[0062] In some embodiments of any of Formulas I-1, I, I', I-A, I-B, I-C, I-D, and I-E, X is CRx. In some embodiments, X is N.

[0063] In some embodiments of any of Formulas I-1, I, I', I-A, I-B, I-C, I-D, and I-E, Y is CRy. In some embodiments, Y is N.

[0064] In some embodiments of Formula I-1, W is CRw or N, X is CRx or N, and Y is CRy or N, and no more than one of W, X, and Y is N. In some embodiments of Formula I-1, W is CRw or N, X is CRx or N, and Y is CRy or N, and no more than two of W, X, and Y are N.

[0065] In formula I-1, I, II, III, IV, I', II', III', IV', I-B, II-B, III-B, IV-B, I-D, II-D, III-D and In some embodiments of any of IV-D, Z is -O-. In some embodiments, Z is -NRz-. In some embodiments, Z is -NH-.

[0066] In some embodiments of any one of Formulas I-1, Rw is hydrogen, halogen, optionally substituted C1-6 aliphatic, or -CN. In some embodiments, Rw is hydrogen, optionally substituted C1-6 aliphatic, or -CN. In some embodiments, Rw is hydrogen or methyl. In some embodiments, Rw is hydrogen, methyl, or -CN. In some embodiments, Rw is hydrogen. In some embodiments, Rw is halogen. In some embodiments, Rw is fluorine. In some embodiments, Rw is chlorine. In some embodiments, Rw is bromine. In some embodiments, Rw is iodine. In some embodiments, Rw is -OR3. In some embodiments, Rw is -OR3, wherein R3 is optionally substituted C1-6 aliphatic. In some embodiments, Y is N, W is CRw, and Rw is -OR3, wherein R3 is optionally substituted C1-6 aliphatic. In some embodiments, Rw is -N(R3)2. In some embodiments, Rw is -SR3. In some embodiments, Rw is -SR3, wherein R3 is optionally substituted C1-6 aliphatic. In some embodiments, Y is N, W is CRw, and Rw is -SR3, wherein R3 is optionally substituted C1-6 aliphatic. In some embodiments, Rw is optionally substituted C1-6 aliphatic. In some embodiments, Rw is optionally substituted linear or branched C1-6 aliphatic (ie, optionally substituted acyclic C1-6 aliphatic). In some embodiments, Rw is optionally substituted C1-6 alkyl. In some embodiments, Rw is optionally substituted C1-4 alkyl. In some embodiments, Rw is unsubstituted C1-4 alkyl. In some embodiments, Rw is optionally substituted C1-2 alkyl. In some embodiments, Rw is optionally substituted methyl (eg, methyl optionally substituted with one or more fluorines). In some embodiments, Rw is methyl. In some embodiments, Rw is -CN.

[0067] In formula I-1, I, II, IV, I', II', IV', I-A, II-A, IV-A, I-B, II-B, IV-B, I-C, II-C, IV-C In some embodiments of any of , I-D, II-D, IV-D, I-E, II-E, and IV-E, Rx is hydrogen, halogen, optionally substituted C1-6 aliphatic, or -CN . In some embodiments, Rx is hydrogen, halogen, -OR3, optionally substituted C1-6 aliphatic, or -CN. In some embodiments, Rx is hydrogen, optionally substituted C1-6 aliphatic, or -CN. In some embodiments, Rx is halogen, -OR3, -N(R3)2, -SR3, or -CN. In some embodiments, Rx is halogen, -OR3 or -CN. In some embodiments, Rx is hydrogen or methyl. In some embodiments, Rx is hydrogen, methyl, or -CN. In some embodiments, Rx is hydrogen. In some embodiments, Rx is halogen. In some embodiments, Rx is fluorine. In some embodiments, Rx is chlorine. In some embodiments, Rx is bromine. In some embodiments, Rx is iodine. In some embodiments, Rx is -OR3. In some embodiments, Rx is -OCH3. In some embodiments, Rx is -N(R3)2. In some embodiments, Rx is -SR3. In some embodiments, Rx is optionally substituted C1-6 aliphatic. In some embodiments, Rx is optionally substituted linear or branched C1-6 aliphatic (ie, optionally substituted acyclic C1-6 aliphatic). In some embodiments, Rx is optionally substituted C1-6 alkyl. In some embodiments, Rx is optionally substituted C1-4 alkyl. In some embodiments, Rx is unsubstituted C1-4 alkyl. In some embodiments, Rx is optionally substituted C1-2 alkyl. In some embodiments, Rx is ethyl. In some embodiments, Rx is optionally substituted methyl (eg, methyl optionally substituted with one or more fluorines, eg -CHF 2 ). In some embodiments, Rx is methyl. In some embodiments, Rx is -CN.

[0068] In formula I-1, I, II, III, I', II', III', I-A, II-A, III-A, I-B, II-B, III-B, I-C, II-C, III-C , I-D In some embodiments of any of II-D, III-D, I-E, II-E, and III-E, Ry is hydrogen, halogen, optionally substituted C1-6 aliphatic, or -CN. In some embodiments, Ry is hydrogen, optionally substituted C1-6 aliphatic, or -CN. In some embodiments, Ry is hydrogen or methyl. In some embodiments, Ry is hydrogen, methyl, or -CN. In some embodiments, Ry is hydrogen. In some embodiments, Ry is halogen. In some embodiments, Ry is fluorine. In some embodiments, Ry is chlorine. In some embodiments, Ry is bromine. In some embodiments, Ry is iodine. In some embodiments, Ry is -OR3. In some embodiments, Ry is -OR3, wherein R3 is optionally substituted C1-6 aliphatic. In some embodiments, W is N, Y is CRy, and Ry is -OR3, wherein R3 is optionally substituted C1-6 aliphatic. In some embodiments, Ry is -N(R3)2. In some embodiments, Ry is -SR3. In some embodiments, Ry is -SR3, wherein R3 is optionally substituted C1-6 aliphatic. In some embodiments, W is N, Y is CRy, and Ry is -SR3, wherein R3 is optionally substituted C1-6 aliphatic. In some embodiments, Ry is optionally substituted C1-6 aliphatic. In some embodiments, Ry is an optionally substituted linear or branched C1-6 aliphatic (ie, an optionally substituted acyclic C1-6 aliphatic). In some embodiments, Ry is optionally substituted C1-6 alkyl. In some embodiments, Ry is optionally substituted C1-4 alkyl. In some embodiments, Ry is unsubstituted C1-4 alkyl. In some embodiments, Ry is optionally substituted C1-2 alkyl. In some embodiments, Ry is optionally substituted methyl (eg, optionally substituted with one or more fluorines). In some embodiments, Ry is methyl. In some embodiments, Ry is -CN.

[0069] In formula I-1, I, II, III, IV, I', II', III', IV', I-B, II-B, III-B, IV-B, I-D, II-D, III-D, In some embodiments of any of IV-D, I-E, II-E, III-E, and IV-E, Rz is hydrogen. In some embodiments, Rz is optionally substituted C1-6 aliphatic. In some embodiments, Rz is optionally substituted linear or branched C1-6 aliphatic (ie, optionally substituted acyclic C1-6 aliphatic). In some embodiments, Rz is optionally substituted C1-6 alkyl. In some embodiments, Rz is optionally substituted C1-4 alkyl. In some embodiments, Rz is unsubstituted C1-4 alkyl. In some embodiments, Rz is optionally substituted C1-2 alkyl. In some embodiments, Rz is unsubstituted C1-2 alkyl.

[0070] In formula I-1, I, II, III, IV, I', II', III', IV', I-B, II-B, III-B, IV-B, I-D, II-D, III-D and In some embodiments of any of IV-D, R1 is -N(R)C(O)R' or -C(O)N(R)2. In some embodiments, R1 is -N(R)C(O)R', -C(O)N(R)2 or -N(R)C(O)N(R)2. In some embodiments, R1 is -N(R)C(O)R'. In some embodiments, R1 is -N(H)C(O)R'. In some embodiments, R1 is -N(R)C(O) (optionally substituted C1-6 aliphatic). In some embodiments, R1 is -N(H)C(O) (optionally substituted C1-6 aliphatic). In some embodiments, R1 is -N(R)C(O)R', wherein R' is C1-6 aliphatic optionally substituted with -OC1-6 alkyl or has 1-2 independently selected from A 3- to 7-membered saturated monocyclic heterocyclic group of nitrogen, oxygen and sulfur heteroatoms. In some embodiments, R1 is -N(H)C(O)R', wherein R' is C1-6 aliphatic optionally substituted with -OC1-6 alkyl or has 1-2 independently selected from A 3- to 7-membered saturated monocyclic heterocyclic group of nitrogen, oxygen and sulfur heteroatoms. In some embodiments, R1 is -N(R)C(O)(C1-6 aliphatic). In some embodiments, R1 is -N(H)C(O)(C1-6 aliphatic). In some embodiments, R1 is -N(R)C(O) (straight chain or branched C1-6 aliphatic). In some embodiments, R1 is -N(H)C(O) (straight chain or branched C1-6 aliphatic). In some embodiments, R1 is -N(R)C(O) (optionally substituted C1-6 alkyl). In some embodiments, R1 is -N(H)C(O) (optionally substituted C1-6 alkyl). In some embodiments, R1 is -N(R)C(O)R', wherein R' is optionally -OC1-6 alkyl or has 1-2 heteros independently selected from nitrogen, oxygen and sulfur A C1-6 alkyl group substituted by a 3- to 7-membered saturated monocyclic heterocyclic group. In some embodiments, R1 is -N(H)C(O)R', wherein R' is optionally -OC1-6 alkyl or has 1-2 heteros independently selected from nitrogen, oxygen and sulfur A C1-6 alkyl group substituted by a 3- to 7-membered saturated monocyclic heterocyclic group. In some embodiments, R1 is -N(R)C(O)(C1-6 alkyl). In some embodiments, R1 is -N(H)C(O)(C1-6 alkyl). In some embodiments, R1 is -N(R)C(O) (optionally substituted C1-4 alkyl). In some embodiments, R1 is -N(H)C(O) (optionally substituted C1-4 alkyl). In some embodiments, R1 is -N(R)C(O)R', wherein R' is optionally -OC1-6 alkyl or has 1-2 heteros independently selected from nitrogen, oxygen and sulfur A C1-4 alkyl group substituted by a 3- to 7-membered saturated monocyclic heterocyclic group. In some embodiments, R1 is -N(H)C(O)R', wherein R' is optionally -OC1-6 alkyl or has 1-2 heteros independently selected from nitrogen, oxygen and sulfur A C1-4 alkyl group substituted by a 3- to 7-membered saturated monocyclic heterocyclic group. In some embodiments, R1 is -N(R)C(O)(C1-4 alkyl). In some embodiments, R1 is -N(H)C(O)(C1-4 alkyl). In some embodiments, R1 is -N(R)C(O) (optionally substituted C1-2 alkyl). In some embodiments, R1 is -N(H)C(O) (optionally substituted C1-2 alkyl). In some embodiments, R1 is -N(R)C(O)R', wherein R' is optionally -OC1-6 alkyl or has 1-2 heteros independently selected from nitrogen, oxygen and sulfur A C1-2 alkyl group substituted by a 3- to 7-membered saturated monocyclic heterocyclic group. In some embodiments, R1 is -N(H)C(O)R', wherein R' is optionally -OC1-6 alkyl or has 1-2 heteros independently selected from nitrogen, oxygen and sulfur A C1-2 alkyl group substituted by a 3- to 7-membered saturated monocyclic heterocyclic group. In some embodiments, R1 is -N(R)C(O)(C1-2 alkyl). In some embodiments, R1 is -N(H)C(O)(C1-2 alkyl). In some embodiments, R1 is -N(R)C(O)CH3. In some embodiments, R1 is -N(H)C(O)CH3. In some embodiments, R1 is -N(R)C(O)(optionally substituted C3-7 carbocyclyl). In some embodiments, R1 is -N(H)C(O)(optionally substituted C3-7 carbocyclyl). In some embodiments, R1 is -N(R)C(O) (optionally substituted cyclopropyl). In some embodiments, R1 is -N(H)C(O)(optionally substituted cyclopropyl). In some embodiments, R1 is -N(R)C(O)CH3 or -N(R)C(O)(cyclopropyl). In some embodiments, R1 is -N(H)C(O)CH3 or -N(H)C(O)(cyclopropyl).

[0071] In some embodiments, R1 is -C(O)N(R)2. In some embodiments, R1 is -C(O)N(R)(C1-6 aliphatic). In some embodiments, R1 is -C(O)N(H)(C1-6 aliphatic). In some embodiments, R1 is -C(O)N(R) (straight chain or branched C1-6 aliphatic). In some embodiments, R1 is -C(O)N(H) (straight chain or branched C1-6 aliphatic). In some embodiments, R1 is -C(O)N(R)(C1-6 alkyl). In some embodiments, R1 is -C(O)N(H)(C1-6 alkyl). In some embodiments, R1 is -C(O)N(R)(C1-4 alkyl). In some embodiments, R1 is -C(O)N(H)(C1-4 alkyl). In some embodiments, R1 is -C(O)N(R)(C1-2 alkyl). In some embodiments, R1 is -C(O)N(H)(C1-2 alkyl). In some embodiments, R1 is -C(O)N(R)CH3. In some embodiments, R1 is -C(O)N(H)(R).

[0072] In some embodiments, R1 is -N(R)2. In some embodiments, R1 is -N(H)(R).

[0073] In some embodiments, R1 is -N(R)C(O)N(R)2. In some embodiments, R1 is -N(R)C(O)N(R)2, wherein the two R groups attached to the same nitrogen together form 0-2 groups independently selected from nitrogen, oxygen and sulfur Optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic groups as additional heteroatoms. In some embodiments, R1 is -N(R)C(O)N(R)2, wherein the two R groups attached to the same nitrogen together form 0-2 groups independently selected from nitrogen, oxygen and sulfur 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic groups with additional heteroatoms, which are optionally substituted by one or more halogens, C1-6 alkyl and -O(C1-6 alkyl). In some embodiments, R1 is -N(R)C(O)N(R)2, wherein the two R groups attached to the same nitrogen together form an optionally substituted 3- to 5-membered saturated monocyclic heterocyclic group. In some embodiments, R1 is -N(R)C(O)N(R)2, wherein the two R groups attached to the same nitrogen together form an optionally substituted 4-membered saturated monocyclic heterocyclyl. In some embodiments, R1 is -N(R)C(O)N(R)2, wherein the two R groups attached to the same nitrogen together form a 3- to 5-membered group with 0-1 additional heteroatom Saturated monocyclic heterocyclyl, optionally substituted by one or more halogen, C1-6 alkyl and -O(C1-6 alkyl). In some embodiments, R1 is -N(R)C(O)N(R)2, wherein the two R groups attached to the same nitrogen together form a 4-membered saturated monocyclic ring with 0-1 additional heteroatoms Heterocyclyl, which is optionally substituted by one or more halogen, C1-6 alkyl and -O(C1-6 alkyl). In some embodiments, R1 is -N(H)C(O)N(R)2. In some embodiments, R1 is -N(H)C(O)N(R)2, wherein the two R groups attached to the same nitrogen together form 0-2 groups independently selected from nitrogen, oxygen and sulfur Optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic groups as additional heteroatoms. In some embodiments, R1 is -N(H)C(O)N(R)2, wherein the two R groups attached to the same nitrogen together form 0-2 groups independently selected from nitrogen, oxygen and sulfur 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic groups with additional heteroatoms, which are optionally substituted by one or more halogens, C1-6 alkyl and -O(C1-6 alkyl). In some embodiments, R1 is -N(H)C(O)N(R)2, wherein the two R groups attached to the same nitrogen together form an optionally substituted 3- to 5-membered saturated monocyclic heterocyclic group. In some embodiments, R1 is -N(H)C(O)N(R)2, wherein the two R groups attached to the same nitrogen together form an optionally substituted 4-membered saturated monocyclic heterocyclyl. In some embodiments, R1 is -N(H)C(O)N(R)2, wherein the two R groups attached to the same nitrogen together form a 3- to 5-membered group with 0-1 additional heteroatoms Saturated monocyclic heterocyclyl, optionally substituted by one or more halogen, C1-6 alkyl and -O(C1-6 alkyl). In some embodiments, R1 is -N(H)C(O)N(R)2, wherein the two R groups attached to the same nitrogen together form a 4-membered saturated monocyclic ring with 0-1 additional heteroatoms Heterocyclyl, which is optionally substituted by one or more halogen, C1-6 alkyl and -O(C1-6 alkyl). In some embodiments, R1 is . In some embodiments, R1 is .

[0074] In some embodiments, R1 is selected from: , , or . In some embodiments, R1 is selected from: , , , or . In some embodiments, R1 is selected from: , , , , or . In some embodiments, R1 is selected from: , , , , , , or . In some embodiments, R1 is selected from: , , or . In some embodiments, R1 is selected from: , , , or . In some embodiments, R1 is selected from: , , , , or . In some embodiments, R1 is selected from: , , , , , , or . In some embodiments, R1 is -C(O)N(H)CH3.

[0075] In formula I-1, I, II, III, IV, I', II', III', IV', I-B, II-B, III-B, IV-B, I-D, II-D, III-D and In some embodiments of any of IV-D, R2 is optionally substituted linear or branched C1-6 aliphatic (ie, optionally substituted acyclic C1-6 aliphatic). In some embodiments, R2 is optionally substituted C1-6 alkyl. In some embodiments, R2 is optionally substituted C1-4 alkyl. In some embodiments, R2 is unsubstituted C1-4 alkyl. In some embodiments, R2 is optionally substituted C1-2 alkyl. In some embodiments, R2 is unsubstituted C1-2 alkyl. In some embodiments, R2 is methyl.

[0076] In formula I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, IV-A, I-B, II-B, III-B, Any of IV-B, I-C, II-C, III-C, IV-C, I-D, II-D, III-D, IV-D, I-E, II-E, III-E, and IV-E In some embodiments, each R3 is independently hydrogen or optionally substituted C1-4 aliphatic. In some embodiments, each R3 is independently hydrogen or optionally substituted C1-2 aliphatic. In some embodiments, each R3 is hydrogen. In some embodiments, each R3 is independently an optionally substituted C1-6 aliphatic. In some embodiments, each R3 is independently an optionally substituted linear or branched C1-6 aliphatic (ie, optionally substituted acyclic C1-6 aliphatic). In some embodiments, each R3 is independently an optionally substituted C1-4 aliphatic. In some embodiments, each R3 is independently an optionally substituted linear or branched C1-4 aliphatic (ie, optionally substituted acyclic C1-4 aliphatic). In some embodiments, each R3 is independently an optionally substituted C1-2 aliphatic. In some embodiments, each R3 is methyl. In some embodiments, each R3 is independently hydrogen or C1-6 alkyl. In some embodiments, each R3 is independently hydrogen or C1-4 alkyl. In some embodiments, each R3 is independently hydrogen or C1-2 alkyl.

[0077] In some embodiments of any of Formulas I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, and IV-A, Ring A (i) is optionally substituted on the substitutable carbon atom by one or more groups independently selected from the group consisting of pendant oxygen, halogen, Ro, -CN, -ORo, -SRo, -N(Ro) 2. -NO2 , -C(O)Ro , -C(O)ORo , -C(O)NRo 2 , -OC(O)Ro , -OC(O)NRo 2 , -OC(O)ORo , - OS(O)2 Ro , -OS(O)2 NRo 2 , -N(Ro )C(O)Ro , -N(Ro )S(O)2 Ro , -S(O)2 Ro , and (ii ) is optionally substituted on the substitutable nitrogen atom by one or more groups selected from the group consisting of -R†, -NR† 2 , -C(O)R†, -C(O)OR†, -S( O)2 R† , -S(O)2 NR† 2 and -S(O)2 ORo . In some embodiments, Ring A(i) is optionally substituted on a substitutable carbon atom with one or more groups independently selected from the group consisting of pendant oxy, halogen, Ro, -CN, -ORo, -SRo , -N(Ro )2 , -NO2 , -C(O)Ro , -C(O)ORo , -C(O)NRo 2 , -OC(O)Ro , -OC(O)NRo 2 , -OC (O)ORo , -OS(O)2 Ro , -OS(O)2 NRo 2 , -N(Ro )C(O)Ro , -N(Ro )S(O)2 Ro , -S(O) 2 Ro , -SO2 NRo 2 and -S(O)2 ORo , and (ii) optionally substituted on the substitutable nitrogen atom with one or more groups selected from the group consisting of -R†, -NR†2, -C(O)R† , -C(O)OR† , -S(O)2 R† and -S(O)2 NR† 2 . In some embodiments, Ring A is (i) optionally substituted on a substitutable carbon atom with one or more groups independently selected from pendant oxy, halogen, and Ro, and (ii) on a substitutable nitrogen atom Optionally substituted with one or more groups selected from -R†.

[0078] In some embodiments, Ring A is optionally substituted with one or more Rb (i.e., other than -L-Ra), wherein Rb is as defined above in Formula I' and described herein in the classes and subgroups in class. In some embodiments, Ring A is substituted with zero, one, two, three, four, or five Rb, as valency permits.

[0079] In some embodiments, Ring A is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, having 1-4 independently An optionally substituted 8-membered to 10-membered bicyclic heteroaryl group of heteroatoms selected from nitrogen, oxygen and sulfur, an optionally substituted 3-membered to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, having 1- An optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 3 heteroatoms independently selected from nitrogen, oxygen and sulfur or having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur An optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl of heteroatoms.

[0080] In some embodiments, Ring A is optionally substituted phenyl. In some embodiments, Ring A is not optionally substituted phenyl.

[0081] In some embodiments, Ring A is an optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted isoxazolyl or pyrazolyl. In some embodiments, Ring A is an optionally substituted isoxazolyl, pyrazolyl, or thiazolyl. In some embodiments, Ring A is optionally substituted isoxazolyl, pyrazolyl, imidazolyl, or thiazolyl. In some embodiments, Ring A is an optionally substituted 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted pyridyl, pyridinonyl, or pyrazinonyl.

[0082] In some embodiments, Ring A is an optionally substituted 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 8-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0083] In some embodiments, Ring A is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A is an optionally substituted 3-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A is an optionally substituted 4 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A is an optionally substituted 5-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A is an optionally substituted 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A is optionally substituted cyclohexyl. In some embodiments, Ring A is an optionally substituted 7-membered saturated or partially unsaturated monocyclic carbocyclyl.

[0084] In some embodiments, Ring A is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 3-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 4 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0085] In some embodiments, Ring A is an optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 7-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 9 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted tetrahydrobenzo[d]thiazolyl, tetrahydropyrazol[1,5-a]pyridinyl, isoindolinonyl, indolinonyl or tetrahydroimidazo[1,2-a]pyridyl. In some embodiments, Ring A is an optionally substituted 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted tetrahydroisoquinolinyl.

[0086] In formula I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, IV-A, I-B, II-B, III-B, Any of IV-B, I-C, II-C, III-C, IV-C, I-D, II-D, III-D, IV-D, I-E, II-E, III-E, and IV-E In some embodiments, L is a covalent bond. In some embodiments, L is a divalent C1-3 linear or branched hydrocarbon chain. In some embodiments, L is a divalent C1-2 linear or branched hydrocarbon chain. In some embodiments, L is methylene (-CH2-). In some embodiments, L is -CH2CH2-. In some embodiments, L is -CH2CH2CH2-. In some embodiments, L is a covalent bond or -CH2-.

[0087] In formula I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, IV-A, I-B, II-B, III-B, Any of IV-B, I-C, II-C, III-C, IV-C, I-D, II-D, III-D, IV-D, I-E, II-E, III-E, and IV-E In some embodiments, R is halogen, optionally substituted C1-6 aliphatic, optionally substituted phenyl, optionally substituted with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur Substituted 5- to 6-membered monocyclic heteroaryl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic groups, having 1-3 heterocyclic groups independently selected from nitrogen, oxygen and sulfur Optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group of atoms or optionally substituted 7- to 10-membered heteroatoms having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Member saturated or partially unsaturated bicyclic heterocyclyl.

[0088] In some embodiments, R is halogen, optionally substituted C1-4 alkyl, optionally substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur Group, optionally substituted 3- to 6-membered saturated monocyclic carbocyclic group, optionally substituted 3- to 6-membered saturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur Heterocyclyl or an optionally substituted 7-membered saturated spirocyclic bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0089] In some embodiments, R is C1-4 alkyl, 3-6 membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, or having 1-2 independently A 7- to 8-membered saturated spirocyclic bicyclic heterocyclic group which is a heteroatom selected from nitrogen, oxygen and sulfur.

[0090] In some embodiments, Ra is hydrogen. In some embodiments, Ra is not hydrogen.

[0091] In some embodiments, Ra is halogen. In some embodiments, Ra is fluorine, chlorine, bromine or iodine. In some embodiments, Ra is fluorine. In some embodiments, Ra is chlorine. In some embodiments, Ra is not halogen. In some embodiments, Ra is not fluorine. In some embodiments, Ra is other than chlorine.

[0092] In some embodiments, Ra is optionally substituted C1-6 aliphatic. In some embodiments, Ra is optionally substituted linear or branched C1-6 aliphatic (ie, optionally substituted acyclic C1-6 aliphatic). In some embodiments, Ra is C1-6 aliphatic optionally substituted with one or more pendant oxy groups, halogen, -CN, or -O(C1-6 alkyl). In some embodiments, Ra is C1-6 aliphatic optionally substituted with one or more pendant oxy groups, halogen, -CN, -OH, or -O(C1-6 alkyl). In some embodiments, Ra is C1-6 aliphatic optionally substituted with one or more pendant oxy groups, halogen, -CN, or -OCH3. In some embodiments, Ra is C1-6 aliphatic optionally substituted with one or more pendant oxy groups, halogen, -CN, -OH, or -OCH3. In some embodiments, Ra is optionally substituted C1-6 alkyl. In some embodiments, Ra is C1-6 alkyl. In some embodiments, Ra is C1-6 alkyl optionally substituted with one or more pendant oxy groups, halogen, -CN, or -OCH3. In some embodiments, Ra is C1-6 alkyl optionally substituted with one or more pendant oxy groups, halogen, -CN, -OH, or -O(C1-6 alkyl) (eg, -OCH3). In some embodiments, Ra is optionally substituted C1-4 alkyl. In some embodiments, Ra is C1-4 alkyl. In some embodiments, Ra is C1-4 alkyl optionally substituted with one or more pendant oxy groups, halogen, -CN, or -OCH3. In some embodiments, Ra is C1-4 alkyl optionally substituted with one or more pendant oxy groups, halogen, -CN, -OH, or -O(C1-6 alkyl) (eg, -OCH3). In some embodiments, Ra is optionally substituted C1 alkyl (eg, methyl). In some embodiments, Ra is methyl, -CF3 or -CH2OCH3. In some embodiments, Ra is methyl, -CF3, -CH2OCH3, or -CH2CN. In some embodiments, Ra is optionally substituted C2 alkyl. In some embodiments, Ra is -CH2CH2OCH3, -CH2CH2OH, or -C(O)CH3. In some embodiments, Ra is -CH2CH2OCH3, -CH2CH2OH, -C(O)CH3-CH2CH2F, -CH2CHF2, or -CH2CH2CN. In some embodiments, Ra is optionally substituted C3 alkyl. In some embodiments, Ra is isopropyl or -C(CH3)2CN. In some embodiments, Ra is isopropyl, -C(CH3)2CN, or -CH2CH(OH)CH3. In some embodiments, Ra is optionally substituted C4 alkyl. In some embodiments, Ra is t-butyl. In some embodiments, Ra is tert-butyl or -CH2CH(CH3)CH2OH. In some embodiments, Ra is not -CF3.

[0093] In some embodiments, Ra is optionally substituted phenyl.

[0094] In some embodiments, Ra is an optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ra is an optionally substituted 5 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally via one or more C1-6 alkyl groups (e.g., methane base) substitution. In some embodiments, R is optionally substituted imidazolyl, pyrazolyl, or oxazolyl. In some embodiments, R is imidazolyl, pyrazolyl or oxazolyl optionally substituted with one or more C1-6 alkyl (eg methyl). In some embodiments, Ra is optionally substituted with , , or . In some embodiments, Ra is , , or . In some embodiments, Ra is an optionally substituted 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0095] In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R is 3-7 membered saturated optionally substituted with one or more -(C1-6 alkylene)OH, -CN, -OH, or -O(C1-6 alkyl) or Partially unsaturated monocyclic carbocyclyl. In some embodiments, Ra is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl optionally substituted with one or more -CH2OH, -CN, -OH or -OCH3. In some embodiments, Ra is optionally substituted C3-6 cycloalkyl. In some embodiments, Ra is C3-6 cycloalkyl optionally substituted with one or more -(C1-6 alkylene)OH, -CN, -OH, or -O(C1-6 alkyl). In some embodiments, Ra is C3-6 cycloalkyl optionally substituted with one or more -CH2OH, -CN, -OH or -OCH3. In some embodiments, Ra is optionally substituted C3 cycloalkyl. In some embodiments, Ra is or . In some embodiments, Ra is optionally substituted C4 cycloalkyl. In some embodiments, Ra is , , , or . In some embodiments, Ra is , , , , or . In some embodiments, Ra is optionally substituted C5 cycloalkyl. In some embodiments, Ra is . In some embodiments, Ra is optionally substituted C6 cycloalkyl. In some embodiments, Ra is .

[0096] In some embodiments, Ra is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally via one or more Pendant oxy, C1-4 alkyl, -C(O)(C1-4 alkyl) or -O(C1-4 alkyl) substitution. In some embodiments, R is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally via one or more Pendant oxy, C1-4 alkyl optionally substituted by one or more halogens, -C(O)(C1-4 alkyl) or -O(C1-4 alkyl). In some embodiments, R is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally via one or more Oxygen, halogen, -C(O)(C1-4 alkyl), -O(C1-4 alkyl), or C1 optionally substituted by one or more halogen and -O(C1-4 alkyl) -4 Alkyl substitution. In some embodiments, R is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally via one or more Pendant oxy, C1-2 alkyl, -C(O)CH3 or -OCH3 substitution. In some embodiments, R is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally via one or more Pendant oxy group, optionally substituted by one or more fluorine-substituted C1-2 alkyl groups, -C(O)CH3 or -OCH3. In some embodiments, R is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally via one or more Pendant oxy, fluorine, -C(O)CH3, -OCH3 or C1-2 alkyl optionally substituted with one or more fluorine and -OCH3. In some embodiments, Ra is an optionally substituted 3-6 membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 3-6 membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally via one or more pendant oxy, C1-4 alkyl, -C(O)(C1-4 alkyl) or -O(C1-4 alkyl) substitution. In some embodiments, R is a 3-6 membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally via one or more pendant oxy, Optionally substituted with one or more halogen-substituted C1-4 alkyl, -C(O)(C1-4 alkyl) or -O(C1-4 alkyl). In some embodiments, R is a 3-6 membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally via one or more pendant oxy, Halogen, -C(O)(C1-4 alkyl), -O(C1-4 alkyl), or C1-4 alkyl optionally substituted with one or more halogen and -O(C1-4 alkyl) replace. In some embodiments, R is a 3-6 membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally via one or more pendant oxy, C1-2 alkyl, -C(O)CH3 or -OCH3 substitution. In some embodiments, R is a 3-6 membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally via one or more pendant oxy, Optionally substituted with one or more fluorine-substituted C1-2 alkyl, -C(O)CH3 or -OCH3. In some embodiments, R is a 3-6 membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally via one or more pendant oxy, Fluorine, -C(O)CH3, -OCH3 or C1-2 alkyl optionally substituted with one or more fluorine and -OCH3. In some embodiments, Ra is a 3-6 membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ra is a 3-6 membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ra is an optionally substituted 3 membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ra is an optionally substituted 3 membered saturated monocyclic heterocyclyl having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ra is an optionally substituted 4 membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ra is an optionally substituted 4 membered saturated monocyclic heterocyclyl having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ra is optionally substituted azetidinyl or oxetanyl. In some embodiments, Ra is , or . In some embodiments, Ra is an optionally substituted 5 membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ra is a 5-membered saturated monocyclic heterocyclyl having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted pyrrolidinyl or tetrahydrofuranyl. In some embodiments, Ra is , or . In some embodiments, Ra is , , , or . In some embodiments, Ra is , , , , , , , or . In some embodiments, Ra is an optionally substituted 6 membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ra is an optionally substituted 6 membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted hexahydropyrazinyl, morpholinyl, tetrahydropyranyl, or 1,4-dioxanyl. In some embodiments, R is optionally substituted hexahydropyridyl, hexahydropyrazinyl, morpholinyl, tetrahydropyranyl, or 1,4-dioxanyl. In some embodiments, Ra is , , , , or . In some embodiments, Ra is , , , , , , , or . In some embodiments, Ra is , , , , , , , , or . In some embodiments, Ra is not . In some embodiments, Ra is not .

[0097] In some embodiments, Ra is an optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally modified by one or more- C(O)(C1-4 alkyl) substitution. In some embodiments, R is a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally modified by one or more- C(O)CH3 substitution. In some embodiments, Ra is an optionally substituted 7-10 membered saturated spirocyclic bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ra is an optionally substituted 7-8 membered saturated spirocyclic bicyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ra is a 7-8 membered saturated spirocyclic bicyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ra is a 7-10 membered saturated spirocyclic bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally via one or more -C( O) (C1-4 alkyl) substitution. In some embodiments, Ra is a 7-10 membered saturated spirocyclic bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally via one or more -C( O) CH3 substitution. In some embodiments, Ra is an optionally substituted 7 membered saturated spirobicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ra is an optionally substituted 7 membered saturated spirobicyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ra is optionally substituted 2-oxaspiro[3.3]heptyl or 2-azaspiro[3.3]heptyl. In some embodiments, R is optionally substituted 2-oxaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, or 4-oxaspiro[2.4]heptyl. In some embodiments, Ra is or . In some embodiments, Ra is , or .

[0098] In some embodiments, Ra is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0099] In some embodiments, Ra is not fluorine, chlorine, bromine, -CF3, or . In some embodiments, Ra is not chlorine, bromine, or .

[0100] In formula I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, IV-A, I-B, II-B, III-B, Any of IV-B, I-C, II-C, III-C, IV-C, I-D, II-D, III-D, IV-D, I-E, II-E, III-E, and IV-E In some embodiments, Be-Ra (that is, L is a covalent bond). In some embodiments, is -(C1-3 alkylene)-Ra (that is, L is a C1-3 straight or branched hydrocarbon chain). In some embodiments, It is -(C1-2 alkylene)-Ra (that is, L is a C1-2 straight or branched hydrocarbon chain). In some embodiments, It is -CH2 -Ra (that is, L is a C1 hydrocarbon chain). In some embodiments, It is -CH2 CH2 -Ra (that is, L is a C2 straight chain hydrocarbon chain). In some embodiments, It is -CH2 CH2 CH2 -Ra (that is, L is a C3 straight chain hydrocarbon chain).

[0101] In formula I', II', III', IV', I-B, II-B, III-B, IV-B, I-C, II-C, III-C, IV-C, I-D, II-D, III- In some embodiments of any of D, IV-D, I-E, II-E, III-E, and IV-E, R can occur up to five times, and each independently is halogen, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O) R', -OC(O)N(R)2, -OC(O)OR, -OSO2 R, -OSO2 N(R)2, -N(R)C(O)R', -N(R) SO2 R', -SO2 R', -SO2 N(R)2, -SO3 R', optionally substituted C1-6 aliphatic, optionally substituted 3-6 membered saturated or partially unsaturated carbocycle group, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, having 1-4 heteroatoms independently selected from Optionally substituted 5- to 6-membered monocyclic heteroaryls of heteroatoms of nitrogen, oxygen and sulfur. In some embodiments, each occurrence of Rb is independently hydrogen, halogen, optionally substituted C1-4 alkyl, optionally substituted C3-4 cycloalkyl, with 1-3 independently selected 3- to 5-membered saturated or partially unsaturated monocyclic heterocyclic groups optionally substituted with heteroatoms from nitrogen, oxygen and sulfur or optionally having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur In the case of a substituted 5-membered monocyclic heteroaryl. In some embodiments, Rb is halogen, optionally substituted C1-4 alkyl, or optionally substituted C3-4 cycloalkyl. In some embodiments, Rb is optionally substituted C1-4 alkyl or optionally substituted C3-4 cycloalkyl. In some embodiments, Rb is C3-4 cycloalkyl or C1-4 alkyl optionally substituted with one or more fluorines.

[0102] In some embodiments, Rb is hydrogen.

[0103] In some embodiments, Rb is halogen. In some embodiments, Rb is fluorine, chlorine, bromine or iodine. In some embodiments, Rb is fluorine. In some embodiments, Rb is chlorine. In some embodiments, Rb is not halogen. In some embodiments, Rb is not fluorine. In some embodiments, Rb is not chlorine.

[0104] In some embodiments, Rb is -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R )2 , -OC(O)R', -OC(O)N(R)2 , -OC(O)OR, -OSO2 R, -OSO2 N(R)2 , -N(R)C(O) R', -N(R)SO2 R', -SO2 R, -SO2 N(R)2, or -SO3 R'. In some embodiments, Rb is -CN, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2 R, -OSO2 N(R)2, -N(R)C(O)R', -N(R)SO2 R', -SO2 R, -SO2 N(R)2 or -SO3 R'. In some embodiments, Rb is not -OR. In some embodiments, Rb is not , or .

[0105] In some embodiments, Rb is optionally substituted C1-6 aliphatic. In some embodiments, Rb is optionally substituted linear or branched C1-6 aliphatic (ie, optionally substituted acyclic C1-6 aliphatic). In some embodiments, Rb is optionally substituted C1-6 alkyl. In some embodiments, Rb is optionally substituted C1-4 alkyl. In some embodiments, Rb is C1-4 alkyl optionally substituted with one or more halogens. In some embodiments, Rb is C1-4 alkyl optionally substituted by one or more of halogen and -CN. In some embodiments, Rb is methyl. In some embodiments, Rb is -CF3. In some embodiments, Rb is t-butyl. In some embodiments, Rb is -CF2CF3. In some embodiments, Rb is -C(CH3)2CN.

[0106] In some embodiments, Rb is an optionally substituted 3-6 membered saturated or partially unsaturated carbocyclyl. In some embodiments, Rb is optionally substituted C3-6 cycloalkyl. In some embodiments, Rb is cyclopropyl. In some embodiments, Rb is cyclobutyl.

[0107] In some embodiments, Rb is an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rb is an optionally substituted 3-6 membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rb is an optionally substituted 3-5 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rb is azetidinyl.

[0108] In some embodiments, Rb is an optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rb is an optionally substituted 5 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rb is pyrazolyl.

[0109] In some embodiments, Rb is not fluoro, chloro, bromo, -OR or -CF3. In some embodiments, Rb is not fluorine, chlorine, bromine, -CF3, , or . In some embodiments, Rb is not chloro, bromo, or -OR. In some embodiments, Rb is not chlorine, bromine, , or .

[0110] In some embodiments of any of Formulas I, II, III, IV, I-A, II-A, III-A, and IV-A, optionally substituted for .

[0111] In some embodiments, optionally replaced by is an optionally substituted group selected from: , , , , , , , , , , , , , , , , and .

[0112] In some embodiments, optionally replaced by is an optionally substituted group selected from: . In some embodiments, optionally replaced by is an optionally substituted group selected from: or . In some embodiments, optionally replaced by is an optionally substituted group selected from: , or . In some embodiments, optionally replaced by is an optionally substituted group selected from: , , or . In some embodiments, optionally replaced by is an optionally substituted group selected from: , , , or . In some embodiments, optionally replaced by is an optionally substituted group selected from: , , , or . In some embodiments, optionally replaced by is an optionally substituted group selected from: . In some embodiments, optionally replaced by is an optionally substituted group selected from: , , , or . In some embodiments, optionally replaced by as the case may be substituted .

[0113] In some embodiments, selected from: , , , , , , , , , , , , , , , and . []

[0114] In some embodiments, for: . In some embodiments, for: , or . In some embodiments, for: , , or . In some embodiments, for: , , , or . In some embodiments, for: , , , , or . In some embodiments, for: , , , or . In some embodiments, for: . In some embodiments, for: , or . In some embodiments, for: .

[0115] In some embodiments, for: , , , , , , , , , , , , , , , , , , , , , , or .

[0116] In some embodiments, for: , , , , or . In some embodiments, for: , or . In some embodiments, for: , , or . In some embodiments, for: , , , or . In some embodiments, for: , , , , or . In some embodiments, for: , , , , or . In some embodiments, for: . In some embodiments, for: , , or . In some embodiments, for: .

[0117] In some embodiments, selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0118] In some embodiments, for: , , , , , , , or . In some embodiments, for: , , , , , , , , or . In some embodiments, for: , , , , , , , , , , , or . In some embodiments, for: , , , , , , , , , , , , , , , , , , , , , , , , or . In some embodiments, for: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or . In some embodiments, for: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or . In some embodiments, for: , , , , , , , , , , , , , , , , , , , , , , , , , , or . In some embodiments, for: , , , , , , , , , , , , , , , , , , , , , , , , , , , or . In some embodiments, for: . In some embodiments, for: , , , , , or . In some embodiments, for: .

[0119] In some embodiments, Not for: , , , , , , or . In some embodiments, Not for: , , , or .

[0120] In formula I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, IV-A, I-B, II-B, III-B, Any of IV-B, I-C, II-C, III-C, IV-C, I-D, II-D, III-D, IV-D, I-E, II-E, III-E, and IV-E In some embodiments, each R is independently hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, each R is independently hydrogen or optionally substituted C1-6 alkyl. In some embodiments, each R is independently hydrogen or C1-6 alkyl. In some embodiments, each R is independently hydrogen or optionally substituted C1-4 alkyl. In some embodiments, each R is independently hydrogen or C1-4 alkyl. In some embodiments, each R is independently hydrogen or methyl.

[0121] In some embodiments, R is hydrogen.

[0122] In some embodiments, R is optionally substituted C1-6 aliphatic. In some embodiments, R is an optionally substituted linear or branched C1-6 aliphatic (ie, an optionally substituted acyclic C1-6 aliphatic). In some embodiments, R is optionally substituted C1-6 alkyl. In some embodiments, R is optionally substituted C1-4 alkyl. In some embodiments, R is unsubstituted C1-4 alkyl. In some embodiments, R is optionally substituted C1-2 alkyl. In some embodiments, R is unsubstituted C1-2 alkyl. In some embodiments, R is methyl.

[0123] In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl.

[0124] In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0125] In some embodiments, two R's, when attached to the same nitrogen atom, together form a 3- to 7-membered saturated or partially unsaturated monocyclic heteroatom having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. Ring base. In some embodiments, two R groups, when attached to the same nitrogen, together form a 3- to 7-membered saturated or partially unsaturated monocyclic heteroatom having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. Cyclic group, which is optionally substituted by one or more halogen, C1-6 alkyl and -O(C1-6 alkyl). In some embodiments, two R groups when attached to the same nitrogen form an optionally substituted 3-5 membered saturated monocyclic heterocyclyl having 0-1 additional heteroatoms. In some embodiments, two R groups when attached to the same nitrogen form an optionally substituted 4 membered saturated monocyclic heterocyclyl having 0-1 additional heteroatoms. In some embodiments, two R groups when attached to the same nitrogen form a 3- to 5-membered saturated monocyclic heterocyclyl with 0-1 additional heteroatoms, optionally modified by one or more halogens, C1 -6 alkyl and -O(C1-6 alkyl) substitution. In some embodiments, two R groups when attached to the same nitrogen form a 4-membered saturated monocyclic heterocyclyl with 0-1 additional heteroatoms, optionally via one or more halogen, C1-6 alkane group and -O(C1-6 alkyl) substitution.

[0126] In formula I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, IV-A, I-B, II-B, III-B, Any of IV-B, I-C, II-C, III-C, IV-C, I-D, II-D, III-D, IV-D, I-E, II-E, III-E, and IV-E In some embodiments, each R' is independently optionally substituted C1-6 alkyl or optionally substituted C3-6 cycloalkyl. In some embodiments, each R' is independently optionally substituted C1-2 alkyl or optionally substituted C3-4 cycloalkyl. In some embodiments, each R' is independently methyl or optionally substituted C3 cycloalkyl. In some embodiments, each R' is independently C1-2 alkyl or C3-4 cycloalkyl. In some embodiments, each R' is independently methyl or cyclopropyl. In some embodiments, each R' is independently methyl, or . In some embodiments, each R' is independently methyl, -CH2 CH2 OCH3, or . In some embodiments, each R' is independently methyl, -CH2 CH2 OCH3, , , or .

[0127] In some embodiments, R' is optionally substituted C1-6 aliphatic. In some embodiments, R' is optionally substituted linear or branched C1-6 aliphatic (ie, optionally substituted acyclic C1-6 aliphatic). In some embodiments, R' is optionally substituted C1-6 alkyl. In some embodiments, R' is optionally substituted with -OC1-6 alkyl or a 3- to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur C1-6 alkyl. In some embodiments, R' is optionally substituted C1-4 alkyl. In some embodiments, R' is optionally substituted with -OC1-6 alkyl or a 3- to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur C1-4 alkyl. In some embodiments, R' is unsubstituted C1-4 alkyl. In some embodiments, R' is optionally substituted C1-2 alkyl. In some embodiments, R' is optionally substituted with -OC1-6 alkyl or a 3- to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur C1-2 alkyl. In some embodiments, R' is unsubstituted C1-2 alkyl. In some embodiments, R' is methyl. In some embodiments, R' is -CH2CH2OCH3. In some embodiments, R' is a 3-7 membered saturated monocyclic heterocyclyl optionally having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., morpholinyl or tetrahydropyridine C1-2 alkyl substituted with pyryl).

[0128] In some embodiments, R' is optionally substituted C1-6 aliphatic or optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl. In some embodiments, R' is a 3-7 membered saturated or partially unsaturated carbocyclyl optionally substituted with one or more halogens. In some embodiments, R' is optionally substituted C3-6 cycloalkyl. In some embodiments, R' is C3-6 cycloalkyl optionally substituted with one or more halogen. In some embodiments, R' is optionally substituted C3 cycloalkyl. In some embodiments, R' is . In some embodiments, R' is .

[0129] In some embodiments of any of Formulas I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, and IV-A, The compound is not:

[0130] In some embodiments of any of Formulas I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, and IV-A, The compound is not:

[0131] In some embodiments of any of Formulas I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, and IV-A, The compound is not:

[0132] In some embodiments of any of Formulas I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, and IV-A, When R1 is -N(H)C(O)R' and R' is optionally substituted C1-6 aliphatic (such as optionally substituted C1-6 alkyl, such as optionally substituted C1-2 Alkyl), then ring A is not phenyl.

[0133] In some embodiments of any of Formulas I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, and IV-A, When R1 is -N(H)C(O)R' and R' is methyl, ring A is not phenyl.

[0134] In some embodiments of any of Formulas I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, and IV-A, When R1 is -N(H)C(O)R', R' is optionally substituted C1-6 aliphatic (such as optionally substituted C1-6 alkyl, such as optionally substituted C1-2 Alkyl) and ring A is phenyl, then Ra is not fluorine.

[0135] In some embodiments of any of Formulas I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, and IV-A, When R1 is -N(H)C(O)R', R' is optionally substituted C1-6 aliphatic (such as optionally substituted C1-6 alkyl, such as optionally substituted C1-2 Alkyl) and ring A is phenyl, then Ra is not -CF3 or optionally substituted hexahydropyrazinyl.

[0136] In some embodiments of any of Formulas I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, and IV-A, When R1 is -N(H)C(O)R', R' is optionally substituted C1-6 aliphatic (such as optionally substituted C1-6 alkyl, such as optionally substituted C1-2 Alkyl) and ring A is phenyl, then Ra is not -CF3 or .

[0137] In some embodiments of any of Formulas I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, and IV-A, When R1 is -N(H)C(O)R', R' is optionally substituted C1-6 aliphatic (such as optionally substituted C1-6 alkyl, such as optionally substituted C1-2 alkyl) and ring A is phenyl, then Rb is not -CF3 or .

[0138] In some embodiments of any of Formulas I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, and IV-A, When R1 is -C(O)NH(R) and R is optionally substituted C1-6 aliphatic (such as optionally substituted C1-6 alkyl, such as optionally substituted C1-2 alkyl, For example, when methyl), ring A is not phenyl.

[0139] In some embodiments of any of Formulas I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, and IV-A, When R1 is -C(O)NH(R), R is optionally substituted C1-6 aliphatic (such as optionally substituted C1-6 alkyl, such as optionally substituted C1-2 alkyl, For example, methyl) and ring A is phenyl, then neither Ra nor Rb is chlorine or bromine.

[0140] In some embodiments of any of Formulas I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, and IV-A, When R1 is -C(O)NH(R), R is optionally substituted C1-6 aliphatic (such as optionally substituted C1-6 alkyl, such as optionally substituted C1-2 alkyl, For example methyl) and ring A is phenyl, then R is not chlorine or bromine.

[0141] In some embodiments of any of Formulas I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, and IV-A, When R1 is -C(O)NH(R), R is optionally substituted C1-6 aliphatic (such as optionally substituted C1-6 alkyl, such as optionally substituted C1-2 alkyl, For example, methyl) and ring A is phenyl, then Ra is not .

[0142] In some embodiments of any of Formulas I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, and IV-A, When R1 is -C(O)NH(R), R is optionally substituted C1-6 aliphatic (such as optionally substituted C1-6 alkyl, such as optionally substituted C1-2 alkyl, For example, methyl) and ring A is phenyl, then Rb is not -OR.

[0143] In some embodiments of any of Formulas I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, and IV-A, When R1 is -C(O)NH(R), R is optionally substituted C1-6 aliphatic (such as optionally substituted C1-6 alkyl, such as optionally substituted C1-2 alkyl, For example, methyl) and ring A is phenyl, then Rb is not , or .

[0144] In some embodiments of any of Formulas I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, and IV-A, When ring A is phenyl, R1 is -NHC(O)R' or -NH2, R2 is -CH3, X is CH, and R' is optionally substituted C1-2 aliphatic, then Ra and Rb are not for fluorine or .

[0145] In some embodiments of any of Formulas I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, and IV-A, When ring A is phenyl, R1 is -NHC(O)CH3, R2 is -CH3, and X is N, then Ra and Rb are not fluorine or .

[0146] In some embodiments of any of Formulas I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, and IV-A, When ring A is phenyl, R1 is -NHC(O)CH3, R2 is -CH3, and X is CCH3, then Ra and Rb are not .

[0147] In some embodiments of any of Formulas I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, and IV-A, When ring A is phenyl, R1 is -C(O)NHCH3, R2 is C1-2 alkyl, and X is CH, then Ra and Rb are not halogen.

[0148] In some embodiments, the disclosure provides compounds selected from Table 1: [I-1] [I-2] [I-3] [I-4] [I-5] [I-6] [I-7] [I-8] [I-9] [I-10] [I-11] [I-12] [I-12-i] [I-12-ii] [I-13] [I-14] [I-15] [I-16] [I-17] [I-18] [I-19'] [I-19] [I-23] [I-20'] [I-20] [I-24] [I-21'] [I-21] [I-25] [I-22'] [I-22] [I-26] [I-27] [I-28] [I-29] [I-30] [I-31] [I-32] [I-33] [I-34] [I-35] [I-36] [I-36-i] [I-36-ii] [I-37] [I-38] [I-39] [I-40] [I-41] [I-42] [I-43] [I-44] [I-45] [I-45-i] [I-45-ii] [I-46] [I-47] [I-48] [I-49] [I-50] [I-50-i] [I-50-ii] [I-51] [I-52] [I-53] [I-54] [I-55] [I-56] [I-57] [I-58] [I-58-i] [I-58-ii] [I-59'] [I-59-i] [I-59-ii] [I-60-i] [I-60-ii] [I-61] [I-62] [I-63] [I-64] [I-65] [I-66] [I-66-i] [I-66-ii] [I-67] [I-67-i] [I-67-ii] [I-68] [I-68-i] [I-68-ii] [I-69] [I-70] [I-71] [I-72] [I-73] [I-74] [I-75] [I-75-i] [I-75-ii] [I-76] [I-76-i] [I-76-ii] [I-77] [I-77-i] [I-77-ii] [I-78] [I-78-i] [I-78-ii] [I-79-i] [I-79-ii] [I-80] [I-81] [I-82] [I-83] [I-84] [I-85] [I-86] [I-87] [I-87-i] [I-87-ii] [I-88] [I-89] [I-90] [I-91] [I-92] [I-93] [I-94] [I-95] [I-96] [I-97] [I-98] [I-99] [I-100] [I-101] [I-102] [I-103] [I-104] [I-105'] [I-105] [I-106] [I-107] [I-108'] [I-108] [I-109'] [I-109] [I-110] [I-111] [I-112] [I-112-i] [I-112-ii] [I-113] [I-114] [I-115'] [I-115] [I-116] [I-117] [I-117-i] [I-117-ii] [I-118'] [I-118] [I-119] [I-120'] [I-120] [I-121] [I-122'] [I-122] [I-123] [I-124'] [I-124] [I-125] [I-126'] [I-126] [I-127] [I-128] [I-128-i] [I-128-ii] [I-129] [I-129-i] [I-129-ii] [I-130] [I-131] [I-132] [I-133'] [I-133] [I-134] [I-135] [I-135-i] [I-135-ii] [I-136] [I-137] [I-138'] [I-138] [I-139] [I-140] [I-141'] [I-141] [I-142] [I-143'] [I-143] [I-144] [] [I-145'] [I-145] [I-146] [I-147'] [I-147] [I-148] [I-148-i] [I-148-ii] [I-149] [I-150'] [I-150] [I-151'] [I-151] [I-152] [I-153'] [I-153] [I-154'] [I-154] [I-155'] [I-155] [I-156] [I-157'] [I-157] [I-158] [I-159] [I-160'] [I-160] [I-161] [I-162] [I-162-i] [I-162-ii] [I-162-iii] [I-162-iv] [I-163] [I-163-i] [I-163-ii] [I-164] [I-165'] [I-165] [I-166] [I-167'] [I-167] [I-168] [I-169] [I-169-i] [I-169-ii] [I-170'] [I-170] [I-171] [I-172] [I-172-i] [I-172-ii] [I-173'] [I-173] [I-174] [I-175] [I-175-i] [I-175-ii] [I-176] [I-176-i] [I-176-ii] [I-177'] [I-177] [I-178] [I-179'] [I-179] [I-180] [I-181'] [I-181] [I-182] [I-183'] [I-183] [I-184] [I-185'] [I-185] [I-186] [I-187] [I-187-i] [I-187-ii] [I-188] [I-189] [I-189-i] [I-189-ii] [I-190] [I-190-i] [I-190-ii] [I-191] [I-192] [I-193] [I-194] [I-195] [I-195-i] [I-195-ii] [I-196] [I-197] [I-198] [I-198-i] [I-198-ii] [I-199] [I-200] [I-201] [I-202] [I-203] [I-204] [I-205] [I-206] [I-207] [I-208] [I-209] [I-210] [I-211] [I-212] [I-212-i] [I-212-ii] [I-213] [I-214] [I-215] [I-216] [] or a pharmaceutically acceptable salt thereof.

[0149] In some embodiments, the present disclosure encompasses the recognition that provided compounds exhibit certain desirable properties, for example, compared to other known compounds. For example, in some embodiments, provided compounds are more potent than other known compounds in one or more biochemical or cellular assays, such as the JAK2 binding assay or the SET2-pSTAT5 cellular assay described herein, and and / or have one or more other properties that make it more suitable for drug development, such as selectivity over other kinases and / or better ADME (absorption, distribution, metabolism and excretion) properties, including (but not limited to) more Good permeability, cytotoxicity, hepatocyte stability, solubility and / or plasma protein binding profile (eg based on assays described in the Examples that follow). In some embodiments, provided compounds exhibit certain desirable properties in one or more assays described herein, for example, compared to other known compounds. Without wishing to be bound by any particular theory, this disclosure encompasses the recognition that 6-heteroaryloxybenzimidazoles and azabenzimidazoles, such as the compounds described herein, are more effective than the corresponding 5-heteroaryloxybenzoimidazoles. Imidazoles and azabenzimidazoles exhibit certain more desirable properties (such as better properties in one or more of the assays set forth herein).

[0150] In some embodiments, provided compounds are provided and / or utilized in salt form (eg, a pharmaceutically acceptable salt form). Unless otherwise indicated, reference to a compound provided herein should be understood to include reference to its salt. Pharmaceutically acceptable salt forms are known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977).

[0151] It is to be understood that throughout this disclosure, unless otherwise indicated, references to compounds of Formula I-1 are intended to also include Formulas I, I', II', III', IV', II, III, IV, I-A , II-A, III-A, IV-A, I-B, II-B, III-B, IV-B, I-C, II-C, III-C, IV-C, I-D, II-D, III-D , IV-D, I-E, II-E, III-E and IV-E, and the compound classes of these formulas disclosed herein. [ Preparation of provided compounds , ] [ , ]

[0152] In some embodiments, provided compounds (e.g., compounds of formula I-1, wherein Z is -NH-) are prepared according to the following schemes: wherein rings A, L, W, X, Y, R1, R2 and Ra are as defined above for formula I-1. Thus, in some embodiments, intermediate A.2 is prepared by a procedure comprising contacting intermediate A.1 with thiophosgene in the presence of a suitable base such as NaHCO3 or triethylamine. In some embodiments, compound A-1 is prepared by a process comprising: making intermediate A.2 and intermediate A.3-1 in a suitable coupling agent (such as 1-ethyl-3-(3-di Methylaminopropyl) carbodiimide hydrochloride or N,N'-diisopropylcarbodiimide) in the presence of contact.

[0153] In some embodiments, provided compounds (e.g., compounds of Formula I, wherein Z is -NH-) are prepared according to the following schemes: wherein rings A, L, X, Y, R1, R2 and Ra are as defined above for formula I. Thus, in some embodiments, intermediate A.2 is prepared by a procedure comprising contacting intermediate A.1 with thiophosgene in the presence of a suitable base such as NaHCO3 or triethylamine. In some embodiments, compound A is prepared by a process comprising: making intermediate A.2 and intermediate A.3 in a suitable coupling agent (such as 1-ethyl-3-(3-dimethylamino Propyl) carbodiimide hydrochloride or N,N'-diisopropylcarbodiimide) in the presence of contact.

[0154] In some embodiments, provided compounds (e.g., compounds of formula I-1, wherein Z is -O-) are prepared according to the following schemes: wherein LG is a suitable leaving group (eg halogen, eg chlorine) and rings A, L, W, X, Y, R1, R2 and Ra are as defined above for formula I-1. Accordingly, in some embodiments, compound B-1 is prepared by a procedure comprising contacting intermediate B.1-1 with intermediate B.2 in the presence of a suitable base (eg, K2CO3).

[0155] In some embodiments, provided compounds (e.g., compounds of formula I-1, wherein Z is -O-) are prepared according to the following schemes: wherein LG is a suitable leaving group (eg halogen, eg chlorine) and rings A, L, X, Y, R1, R2 and Ra are as defined above for formula I. Accordingly, in some embodiments, compound B is prepared by a procedure comprising contacting intermediate B.1 with intermediate B.2 in the presence of a suitable base (eg, K2CO3).

[0156] In some embodiments, provided compounds are obtained by processes comprising the purification methods described in the Examples section. In some of these embodiments, the compound is the first eluting isomer. In some of these embodiments, the compound is the second eluting isomer. In some embodiments, the compound is the 3rd eluting isomer. In some embodiments, the compound is the 4th eluting isomer. In some embodiments, the compound is the 5th, 6th, 7th, 8th or later eluting isomer. [ combination , ] [ , ]

[0157] The disclosure also provides compositions comprising a compound provided herein and one or more other components. In some embodiments, provided compositions comprise and / or deliver compounds described herein (e.g., Formula I-1, I, II, III, IV, I', II', III', IV', I-A, II-A, III-A, IV-A, I-B, II-B, III-B, IV-B, I-C, II-C, III-C, IV-C, I-D, II-D, III-D, Compounds of IV-D, I-E, II-E, III-E and IV-E).

[0158] In some embodiments, provided compositions are pharmaceutical compositions comprising and / or delivering compounds provided herein (e.g., Formula I-1, I, II, III, IV, I', II', III' , IV', I-A, II-A, III-A, IV-A, I-B, II-B, III-B, IV-B, I-C, II-C, III-C, IV-C, I-D, II- D, III-D, IV-D, I-E, II-E, III-E and IV-E) and further comprising a pharmaceutically acceptable carrier. Pharmaceutical compositions generally contain an active agent (eg, a compound described herein) in an amount effective to achieve the desired therapeutic effect while avoiding or minimizing undesirable side effects. In some embodiments, provided pharmaceutical compositions comprise the compounds described herein and one or more fillers, disintegrants, lubricants, glidants, anti-adhesives and / or antistatic agents, and the like. The provided pharmaceutical compositions may be in a variety of forms, including oral dosage forms, topical creams, topical patches, iontophoretic forms, suppositories, nasal sprays and / or inhalers, eye drops, intraocular injection forms, depot forms, forms and injectable and infusible solutions. Methods of preparing pharmaceutical compositions are well known in the art.

[0159] In some embodiments, provided compounds are formulated in unit dosage form for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically discrete unit of active agent, such as a compound described herein, for administration to a subject. Typically, each such unit contains a predetermined amount of active agent. In some embodiments, unit dosage forms contain an entire single dose. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is required or expected to be required to achieve the desired effect. The unit dosage form can be, for example, a liquid pharmaceutical composition containing a predetermined amount of one or more active agents, a solid pharmaceutical composition (such as a tablet, capsule, or the like) containing a predetermined amount of one or more active agents, a predetermined amount of Sustained release formulations of one or more active agents or drug delivery devices containing predetermined amounts of one or more active agents, etc.

[0160] The provided compositions can be administered using any amount and any route of administration effective to treat or lessen the severity of any disease or condition described herein. [ use , ] [ , ]

[0161] The disclosure provides uses of the compounds and compositions described herein. In some embodiments, provided compounds and compositions are used in medicine (eg, as therapy). In some embodiments, provided compounds and compositions are useful in research, for example, as analytical tools and / or control compounds in biological assays.

[0162] In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to an individual in need thereof. In some embodiments, the disclosure provides methods of administering provided compounds or compositions to an individual suffering from or susceptible to a disease, disorder, or condition associated with JAK2.

[0163] In some embodiments, provided compounds are useful as JAK2 inhibitors. In some embodiments, provided compounds are useful as type II JAK2 inhibitors. In some embodiments, the present disclosure provides methods of inhibiting JAK2 in a subject comprising administering a provided compound or composition. In some embodiments, the present disclosure provides methods of inhibiting JAK2 in a biological sample comprising contacting the sample with a provided compound or composition.

[0164] JAKs (e.g. JAK2) are associated with various diseases, disorders and disorders such as myeloproliferative neoplasms (Vainchenker, W. et al., F1000 Research 2018, 7 (F1000 Faculty Rev): 82), atopic dermatitis (Rodrigues, M. A. and Torres, T. J. Derm. Treat. 2019, 31(1), 33-40.) and Acute Respiratory Syndrome, Hyperinflammation and / or Cytokine Storm Syndrome (The Lancet . doi:10.1016 / S0140-6736(20) 30628-0). Accordingly, in some embodiments, the present disclosure provides methods of treating a JAK2-associated disease, disorder or condition in an individual in need thereof comprising administering to the individual a provided compound or composition. In some embodiments, the disease, disorder or condition is associated with overexpression of JAK2.

[0165] In some embodiments, the disclosure provides methods of treating cancer comprising administering to a subject in need thereof a provided compound or composition. In some embodiments, the present disclosure provides methods of treating proliferative diseases comprising administering to a subject in need thereof a provided compound or composition.

[0166] In some embodiments, the disclosure provides methods of treating hematological malignancies comprising administering to a subject in need thereof a provided compound or composition. In some embodiments, the hematological malignancy is leukemia (e.g., chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, or acute monocytic leukemia). leukemia). In some embodiments, the hematological malignancy is lymphoma (eg, Burkitt's lymphoma, Hodgkin's lymphoma, or non-Hodgkin's lymphoma). In some embodiments, the non-Hodgkin's lymphoma is B-cell lymphoma. In some embodiments, the non-Hodgkin's lymphoma is NK / T cell lymphoma (eg, cutaneous T cell lymphoma). In some embodiments, the hematological malignancy is myeloma (eg, multiple myeloma). In some embodiments, the hematological malignancy is a myeloproliferative neoplasm (eg, plethora vera, essential thrombocytopenia, or myelofibrosis). In some embodiments, the hematological malignancy is myelodysplastic syndrome.

[0167] In some embodiments, the present disclosure provides for the treatment of inflammatory diseases, disorders or conditions (such as acute respiratory syndrome, hyperinflammation, and / or cytokine storm syndrome (including those associated with COVID-19) or atopic dermatitis), comprising administering a provided compound or composition to a subject in need thereof.

[0168] In some embodiments, provided compounds or compositions are administered as part of a combination therapy. As used herein, the term "combination therapy" refers to those situations in which an individual is simultaneously exposed to two or more therapeutic or prophylactic regimens (eg, two or more therapeutic or prophylactic agents). In some embodiments, the two or more regimens can be administered simultaneously; in some embodiments, the regimens can be administered sequentially (e.g., all "doses" of the first regimen are administered before any dose of the second regimen is administered). previously administered); in some embodiments, the agents are administered in an overlapping dosing schedule. In some embodiments, "administration" of a combination therapy can involve administering one or more agents or modalities to an individual receiving the other agents or modalities in combination. For clarity, combination therapy does not require that the individual agents be administered together in a single composition (or even must be administered simultaneously), but in some embodiments, two or more agents, or active portions thereof, may be administered together in a combined composition.

[0169] For example, in some embodiments, a provided compound or composition is administered to patients who are receiving or have received one or more additional therapies, such as anticancer therapy and / or address one or more side effects of such anticancer therapy. therapy, or otherwise provide palliative care). Exemplary additional therapies include, but are not limited to, BCL2 inhibitors (e.g., venetoclax), HDAC inhibitors (e.g., vorinostat), BET inhibitors (e.g., mivebresib) ), proteasome inhibitors (such as bortezomib), LSD1 inhibitors (such as IMG-7289), and CXCR2 inhibitors. A useful combination of JAK2 inhibitors with BCL2, HDAC, BET and proteasome inhibitors has been demonstrated in cells derived from patients with cutaneous T-cell lymphoma (Yumeen, S. et al., Blood Adv. 2020, 4(10) , 2213-2226). Combination of JAK2 Inhibitor and LSD1 Inhibitor Shows Promising Efficacy in Mouse Model of Myeloproliferative Neoplasms (Jutzi, J.S. et al., HemaSphere 2018, 2(3), dx.doi.org / 10.1097 / HS9.0000000000000054) . CXCR2 activity has been shown to regulate signaling pathways involved in tumor growth, angiogenesis and / or metastasis, including the JAK-STAT3 pathway (Jaffer, T., Ma, D. Transl. Cancer Res. 2016, 5(Suppl 4), S616 -S628). [ Exemplary embodiment , ] [ , ]

[0170] The following numbered examples, although non-limiting, illustrate certain aspects of the disclosure: A1. A compound of formula I-1 or a pharmaceutically acceptable salt thereof, I-1 in: W is CRw or N; X is CRx or N; Y is CRy or N; Z is -O- or -NRz-; Rw, Rx and Ry are each independently hydrogen, halogen, -OR3, -N(R3)2, -SR3, optionally substituted C1-6 aliphatic or -CN; Rz is hydrogen or optionally substituted C1-6 aliphatic; R1 is -N(R)2, -N(R)C(O)R', -C(O)N(R)2 or -N(R)C(O)N(R)2; R2 is an optionally substituted C1-6 aliphatic; R3 is hydrogen or optionally substituted C1-6 aliphatic; Ring A is optionally substituted phenyl, optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, having 1-4 An optionally substituted 8-membered to 10-membered bicyclic heteroaryl group independently selected from heteroatoms of nitrogen, oxygen and sulfur, an optionally substituted 3-membered to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, having 1-3 optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic groups with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur or having 1-4 heteroatoms independently selected from nitrogen, oxygen A 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group optionally substituted with heteroatoms of sulfur and sulfur; L is a covalent bond or a divalent C1-3 straight or branched hydrocarbon chain; R is hydrogen, halogen, optionally substituted C1-6 aliphatic, optionally substituted phenyl, optionally substituted 5 members having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur to 6-membered monocyclic heteroaryl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur A substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic group or an optionally substituted 7-10 membered saturated or partially substituted heteroatom having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Unsaturated bicyclic heterocyclyl; Each R is independently hydrogen, optionally substituted C1-6 aliphatic, optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl, or has 1-3 independently selected from nitrogen, oxygen and sulfur heteroatoms optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic groups, or two R when connected to the same nitrogen atom together form 0-2 independently selected from nitrogen 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl optionally substituted with additional heteroatoms of , oxygen and sulfur; and Each R' is independently optionally substituted C1-6 aliphatic or optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl. A2. the compound as embodiment A1, wherein: W is CRw or N; X is CRx or N; Y is CRy or N; Z is -O- or -NRz-; Rw, Rx and Ry are each independently hydrogen, halogen, -OR3, -N(R3)2, -SR3, optionally substituted C1-6 aliphatic or -CN; Rz is hydrogen or optionally substituted C1-6 aliphatic; R1 is -N(R)2, -N(R)C(O)R', -C(O)N(R)2 or -N(R)C(O)N(R)2; R2 is an optionally substituted C1-6 aliphatic; R3 is hydrogen or optionally substituted C1-6 aliphatic; Ring A is optionally substituted phenyl, optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, having 1-4 An optionally substituted 8-membered to 10-membered bicyclic heteroaryl group independently selected from heteroatoms of nitrogen, oxygen and sulfur, an optionally substituted 3-membered to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, having 1-3 optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic groups with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur or having 1-4 heteroatoms independently selected from nitrogen, oxygen A 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group optionally substituted with heteroatoms of sulfur and sulfur; L is a covalent bond or a divalent C1-3 straight or branched hydrocarbon chain; R is hydrogen, halogen, optionally substituted C1-6 aliphatic, optionally substituted phenyl, optionally substituted 5 members having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur to 6-membered monocyclic heteroaryl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur A substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic group or an optionally substituted 7-10 membered saturated or partially substituted heteroatom having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Unsaturated bicyclic heterocyclyl; Each R is independently hydrogen, optionally substituted C1-6 aliphatic, optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl, or has 1-3 independently selected from nitrogen, oxygen and sulfur heteroatoms optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic groups, or two R when connected to the same nitrogen atom together form 0-2 independently selected from nitrogen 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl with additional heteroatoms of , oxygen and sulfur; and Each R' is independently optionally substituted C1-6 aliphatic or optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl. A3. the compound as embodiment A1 or A2, wherein: W is CH; X is CRx or N; Y is CRy or N; Z is -O- or -NRz-; Rx and Ry are each independently hydrogen, optionally substituted C1-6 aliphatic or -CN; Rz is hydrogen or optionally substituted C1-6 aliphatic; R1 is -N(R)2, -N(R)C(O)R', -C(O)N(R)2 or -N(R)C(O)N(R)2; R2 is an optionally substituted C1-6 aliphatic; Ring A is optionally substituted phenyl, optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, having 1-4 An optionally substituted 8-membered to 10-membered bicyclic heteroaryl group independently selected from heteroatoms of nitrogen, oxygen and sulfur, an optionally substituted 3-membered to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, having 1-3 optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic groups with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur or having 1-4 heteroatoms independently selected from nitrogen, oxygen A 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group optionally substituted with heteroatoms of sulfur and sulfur; L is a covalent bond or a divalent C1-3 straight or branched hydrocarbon chain; R is hydrogen, halogen, optionally substituted C1-6 aliphatic, optionally substituted phenyl, optionally substituted 5 members having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur to 6-membered monocyclic heteroaryl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur A substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic group or an optionally substituted 7-10 membered saturated or partially substituted heteroatom having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Unsaturated bicyclic heterocyclyl; Each R is independently hydrogen, optionally substituted C1-6 aliphatic, optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl, or has 1-3 independently selected from nitrogen, oxygen and sulfur heteroatoms optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic groups, or two R when connected to the same nitrogen atom together form 0-2 independently selected from nitrogen 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl with additional heteroatoms of , oxygen and sulfur; and Each R' is independently optionally substituted C1-6 aliphatic or optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl. A4. The compound of any one of the preceding embodiments, wherein the compound is not: . A5. The compound of any one of the preceding embodiments, wherein ring A is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur radical, optionally substituted 8- to 10-membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3- to 7-membered saturated or partially unsaturated Monocyclic carbocyclyl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur or having 1-4 An optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl of heteroatoms independently selected from nitrogen, oxygen and sulfur. A5. The compound of any one of the preceding embodiments, wherein ring A is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur base. A6. The compound of any one of the preceding embodiments, wherein R is halogen, optionally substituted C1-4 alkyl, optionally having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Substituted 5-membered monocyclic heteroaryl, optionally substituted 3-6 membered saturated monocyclic carbocyclyl, optionally substituted with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur A 3-6 membered saturated monocyclic heterocyclic group or an optionally substituted 7-membered saturated spirocyclic bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. A7. The compound of any one of the preceding embodiments, wherein: for ;and Rb is hydrogen, halogen, -CN, -OR, -SR, -N(R)2 , -NO2 , -C(O)R', -C(O)OR, -C(O)N(R)2 , -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2 R, -OSO2 N(R)2, -N(R)C(O)R' , -N(R)SO2 R', -SO2 R', -SO2 N(R)2, -SO3 R', optionally substituted C1-6 aliphatic, optionally substituted 3-6 member saturated Or partially unsaturated carbocyclic group, optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclic group with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, with 1- An optionally substituted 5-6 membered monocyclic heteroaryl with 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. A8. the compound as embodiment A7, wherein for: , , , , , , , , , , , , , , , , , , , , or . A9. The compound of embodiment A7 or A8, wherein Rb is halogen, optionally substituted C1-4 alkyl or optionally substituted C3-4 cycloalkyl. A10. The compound of any one of the preceding embodiments, wherein R1 is -N(R)2. A11. The compound as in embodiment A10, wherein R1 is -N(H)(R). A12. The compound of any one of embodiments A1 to A9, wherein R1 is -N(R)C(O)R'. A13. The compound as in embodiment A12, wherein R1 is -N(H)C(O)R'. A14. The compound as in embodiment A13, wherein R1 is -N(H)C(O)CH3. A15. The compound of any one of embodiments A1 to A9, wherein R1 is -C(O)N(R)2. A16. The compound as in embodiment A15, wherein R1 is -C(O)N(H)CH3. A17. The compound of any one of embodiments A1 to A9, wherein R1 is -N(R)C(O)N(R)2. A18. The compound as in embodiment A17, wherein R1 is -N(H)C(O)N(R)2. A19. The compound of any one of the preceding embodiments, wherein R2 is C1-4 alkyl. A20. The compound of any one of the preceding embodiments, wherein X is CRx. A21. The compound of embodiment A20, wherein Rx is hydrogen, halogen, -OR3, optionally substituted C1-6 aliphatic or -CN. A22. the compound as embodiment A21, wherein Rx is hydrogen. A23. The compound of any one of embodiments A1 to A19, wherein X is N. A24. The compound of any one of the preceding embodiments, wherein Y is CRy. A25. the compound as embodiment A24, wherein Ry is hydrogen. A26. The compound of any one of embodiments A1 to A23, wherein Y is N. A27. The compound according to any one of the preceding embodiments, wherein Z is -NRz-. A28. The compound as in embodiment 27, wherein Rz is hydrogen. A29. The compound of any one of embodiments A1 to A26, wherein Z is -O-. A30. The compound of any one of the preceding embodiments, wherein the compound is a compound of formula I-A: I-A or a pharmaceutically acceptable salt thereof. A31. The compound of any one of the preceding embodiments, wherein the compound is a compound of formula I-B: I-B or a pharmaceutically acceptable salt thereof. A32. The compound of any one of the preceding embodiments, wherein the compound is a compound of formula I-C: I-C or a pharmaceutically acceptable salt thereof. A33. The compound of any one of the preceding embodiments, wherein the compound is a compound of formula I-D: I-D or a pharmaceutically acceptable salt thereof. A34. The compound of any one of the preceding embodiments, wherein the compound is a compound of formula I-E: I-E or a pharmaceutically acceptable salt thereof. A35. The compound as in embodiment 1, wherein the compound is the compound in Table 1. A36. A pharmaceutical composition comprising the compound of any one of the foregoing embodiments or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A37. A method of inhibiting JAK2 in an individual comprising administering a compound according to any one of embodiments A1 to A35 or a composition according to embodiment A36. A38. A method of treating a disease, disorder or disorder associated with JAK2, comprising administering a compound according to any one of Embodiments A1 to A35 or a composition according to Embodiment A36 to an individual in need thereof. A39. A method of treating cancer, comprising administering a compound according to any one of Embodiments A1 to A35 or a composition according to Embodiment A36 to an individual in need thereof. A40. A method of treating hematologic malignancies, comprising administering a compound according to any one of Embodiments A1 to A35 or a composition according to Embodiment A36 to an individual in need thereof. A41. The method according to embodiment A40, wherein the hematological malignancy is leukemia or lymphoma. A42. A method of treating myeloproliferative neoplasms, comprising administering a compound according to any one of embodiments A1 to A35 or a composition according to embodiment A36 to an individual in need. A43. The method according to embodiment A42, wherein the myeloproliferative neoplasm is plethora vera, essential thrombocytopenia or myelofibrosis. B1. A compound of formula I-1 or a pharmaceutically acceptable salt thereof, I-1 in: W is CRw or N; X is CRx or N; Y is CRy or N; Z is -O- or -NRz-; Rw, Rx and Ry are each independently hydrogen, halogen, -OR3, -N(R3)2, -SR3, optionally substituted C1-6 aliphatic or -CN; Rz is hydrogen or optionally substituted C1-6 aliphatic; R1 is -N(R)2, -N(R)C(O)R', -C(O)N(R)2 or -N(R)C(O)N(R)2; R2 is an optionally substituted C1-6 aliphatic; R3 is hydrogen or optionally substituted C1-6 aliphatic; Ring A is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur An optionally substituted 8-membered to 10-membered bicyclic heteroaryl group, an optionally substituted 3-membered to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, having 1-3 independently selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic groups optionally substituted with nitrogen, oxygen and sulfur heteroatoms or optionally having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic groups; L is a covalent bond or a divalent C1-3 straight or branched hydrocarbon chain; R is hydrogen, halogen, optionally substituted C1-6 aliphatic, optionally substituted phenyl, optionally substituted 5 members having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur to 6-membered monocyclic heteroaryl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur A substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic group or an optionally substituted 7-10 membered saturated or partially substituted heteroatom having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Unsaturated bicyclic heterocyclyl; Each R is independently hydrogen, optionally substituted C1-6 aliphatic, optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl, or has 1-3 independently selected from nitrogen, oxygen and sulfur heteroatoms optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic groups, or two R when connected to the same nitrogen atom together form 0-2 independently selected from nitrogen 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl optionally substituted with additional heteroatoms of , oxygen and sulfur; and Each R' is independently optionally substituted C1-6 aliphatic or optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl. B2. The compound of embodiment B1, wherein ring A is an optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. B3. The compound of embodiment B1, wherein ring A is an optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. B4. The compound according to embodiment B1, wherein ring A is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl. B5. The compound of embodiment B1, wherein ring A is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur base. B6. The compound of embodiment B1, wherein ring A is an optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur . B7. The compound of any one of the preceding embodiments, wherein R is halogen, optionally substituted C1-4 alkyl, optionally having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Substituted 5-membered monocyclic heteroaryl, optionally substituted 3-6 membered saturated monocyclic carbocyclyl, optionally substituted with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur A 3-6 membered saturated monocyclic heterocyclic group or an optionally substituted 7-membered saturated spirocyclic bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. B8. The compound of any one of the preceding embodiments, wherein R is C1-4 optionally substituted by one or more side oxygen groups, halogen, -CN, -OH or -O(C1-6 alkyl) alkyl. B9. The compound of any one of embodiments B1 to B7, wherein R is optionally modified by one or more -(C1-6 alkylene)OH, -CN, -OH or -O(C1-6 alkane group) substituted 3 to 6 membered saturated monocyclic carbocyclic group. B10. The compound of any one of embodiments B1 to B7, wherein R is a 3-6 membered saturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Optionally through one or more side oxygen, halogen, -C(O)(C1-4 alkyl), -O(C1-4 alkyl) or optionally through one or more halogen and -O(C1- 4 alkyl) substituted C1-4 alkyl substituted. B11. The compound of any one of embodiments B1 to B7, wherein R is an optionally substituted 7-8 membered saturated spirocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur Bicyclic heterocyclyl. B12. The compound of any one of the preceding embodiments, wherein R is C1-4 alkyl, 3-6 membered saturated monocyclic heteroatoms with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur A cyclic group or a 7- to 8-membered saturated spirocyclic bicyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. B13. The compound of any one of the preceding embodiments, wherein: for ;and Rb is hydrogen, halogen, -CN, -OR, -SR, -N(R)2 , -NO2 , -C(O)R', -C(O)OR, -C(O)N(R)2 , -OC(O)R', -OC(O)N(R)2 , -OC(O)OR, -OSO2 R, -OSO2 N(R)2 , -N(R)C(O)R' , -N(R)SO2 R', -SO2 R', -SO2 N(R)2, -SO3 R', optionally substituted C1-6 aliphatic, optionally substituted 3-6 member saturated Or partially unsaturated carbocyclic group, optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclic group with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, with 1- An optionally substituted 5-6 membered monocyclic heteroaryl with 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. B14. the compound as embodiment B13, wherein for: , , , , , , , , , , , , , , or . B15. The compound of embodiment B13 or B14, wherein for: or . B16. The compound of any one of embodiments B13 to B15, wherein Rb is hydrogen, halogen, optionally substituted C1-4 alkyl, optionally substituted C3-4 cycloalkyl, having 1-3 An optionally substituted 3-membered to 5-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 heteroatom independently selected from nitrogen, oxygen and sulfur or having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Heteroatom optionally substituted 5 membered monocyclic heteroaryl. B17. The compound of any one of embodiments B13 to B16, wherein Rb is halogen, optionally substituted C1-4 alkyl or optionally substituted C3-4 cycloalkyl. B18. The compound of any one of embodiments B13 to B16, wherein Rb is C3-4 cycloalkyl or C1-4 alkyl optionally substituted with one or more fluorines. B19. The compound of any one of the preceding embodiments, wherein the compound is a compound of formula I-B: I-B or a pharmaceutically acceptable salt thereof. B20. The compound of any one of the preceding embodiments, wherein the compound is a compound of formula I-C: I-C or a pharmaceutically acceptable salt thereof. B21. The compound of any one of the preceding embodiments, wherein the compound is a compound of formula I-D: I-D or a pharmaceutically acceptable salt thereof. B22. The compound of any one of the preceding embodiments, wherein the compound is a compound of formula I-E: I-E or a pharmaceutically acceptable salt thereof. B23. A compound of formula I-1 or a pharmaceutically acceptable salt thereof, I-1 in: W is CRw or N; X is CRx or N; Y is CRy or N; Z is -O- or -NRz-; Rw, Rx and Ry are each independently hydrogen, halogen, -OR3, -N(R3)2, -SR3, optionally substituted C1-6 aliphatic or -CN; Rz is hydrogen or optionally substituted C1-6 aliphatic; R1 is -N(R)2, -N(R)C(O)R', -C(O)N(R)2 or -N(R)C(O)N(R)2; R2 is an optionally substituted C1-6 aliphatic; R3 is hydrogen or optionally substituted C1-6 aliphatic; Ring A is optionally substituted phenyl; L is a covalent bond or a divalent C1-3 straight or branched hydrocarbon chain; R is hydrogen, halogen, optionally substituted C1-6 aliphatic, optionally substituted phenyl, optionally substituted 5 members having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur to 6-membered monocyclic heteroaryl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur A substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic group or an optionally substituted 7-10 membered saturated or partially substituted heteroatom having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Unsaturated bicyclic heterocyclyl; Each R is independently hydrogen, optionally substituted C1-6 aliphatic, optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl, or has 1-3 independently selected from nitrogen, oxygen and sulfur heteroatoms optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic groups, or two R when connected to the same nitrogen atom together form 0-2 independently selected from nitrogen 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl optionally substituted with additional heteroatoms of , oxygen and sulfur; and Each R' is independently optionally substituted C1-6 aliphatic or optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl. B22. The compound as embodiment B21, wherein the compound is not: . B24. the compound as embodiment B22 or B23, wherein: (i) If R1 is -NHC(O)R' or -NH2, R2 is -CH3, X is CH, and R' is an optionally substituted C1-2 aliphatic, then Ra and Rb are not fluorine or ; (ii) If R1 is -NHC(O)CH3, R2 is -CH3, and X is N, then Ra and Rb are not fluorine or ; (iii) If R1 is -NHC(O)CH3, R2 is -CH3, and X is CCH3, then Ra and Rb are not ;and (iv) If R1 is -C(O)NHCH3, R2 is C1-2 alkyl, and X is CH, then Ra and Rb are not halogen. B25. The compound of any one of embodiments B22 to B24, wherein R is halogen, optionally substituted C1-4 alkyl, 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Optionally substituted 5-membered monocyclic heteroaryl, optionally substituted 3-6 membered saturated monocyclic carbocyclyl, optionally having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur A substituted 3- to 6-membered saturated monocyclic heterocyclyl or an optionally substituted 7-membered saturated spirobicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. B26. The compound of any one of embodiments B22 to B25, wherein R is optionally substituted by one or more pendant oxygen groups, halogen, -CN, -OH or -O(C1-6 alkyl) -4 alkyl. B27. The compound of any one of embodiments B22 to B25, wherein R is a 5-membered monocyclic heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is optionally modified by one or multiple C1-6 alkyl substitutions. B28. The compound of any one of embodiments B22 to B25, wherein R is a 3-7 membered saturated or partially unsaturated monocyclic heteroatom having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur Cyclic group, which optionally passes through one or more side oxygen groups, halogen, -C (O) (C1-4 alkyl), -O (C1-4 alkyl), or optionally passes one or more halogens and - O(C1-4 alkyl) substituted C1-4 alkyl substituted. B29. The compound of any one of embodiments B22 to B28, wherein: for ;and Rb is hydrogen, halogen, -CN, -OR, -SR, -N(R)2 , -NO2 , -C(O)R', -C(O)OR, -C(O)N(R)2 , -OC(O)R', -OC(O)N(R)2 , -OC(O)OR, -OSO2 R, -OSO2 N(R)2 , -N(R)C(O)R' , -N(R)SO2 R', -SO2 R', -SO2 N(R)2, -SO3 R', optionally substituted C1-6 aliphatic, optionally substituted 3-6 member saturated Or partially unsaturated carbocyclic group, optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclic group with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, with 1- An optionally substituted 5-6 membered monocyclic heteroaryl with 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. B30. The compound of any one of embodiments B22 to B29, wherein for: , , , , or . B31. The compound of embodiment B29 or B30, wherein Rb is halogen, optionally substituted C1-4 alkyl or optionally substituted C3-4 cycloalkyl. B32. The compound of any one of the preceding embodiments, wherein L is a covalent bond or -CH2-. B33. The compound according to any one of the preceding embodiments, wherein R1 is -N(R)2. B34. The compound of any one of embodiments B1 to B32, wherein R1 is -N(H)(R). B35. The compound of any one of embodiments B1 to B32, wherein R1 is -N(R)C(O)R'. B36. The compound of any one of embodiments B1 to B32, wherein R1 is -N(H)C(O)R'. B37. The compound of any one of embodiments B1 to B32, wherein R1 is -N(H)C(O) (optionally substituted C1-4 alkyl). B38. The compound of any one of embodiments B1 to B32, wherein R1 is -N(H)C(O)CH3 or -N(H)C(O)(cyclopropyl). B39. The compound of any one of embodiments B1 to B32, wherein R1 is -C(O)N(R)2. B40. The compound of any one of embodiments B1 to B32, wherein R1 is -C(O)N(H)CH3. B41. The compound of any one of embodiments B1 to B32, wherein R1 is -N(R)C(O)N(R)2. B42. The compound of any one of embodiments B1 to B32, wherein R1 is -N(H)C(O)N(R)2. B43. The compound of any one of embodiments B1 to B32, wherein R1 is -N(R)C(O)N(R)2, wherein the two R groups connected to the same nitrogen form together a group having O- 3- to 5-membered saturated monocyclic heterocyclyl with 1 additional heteroatom optionally substituted with one or more halogen, C1-6 alkyl and -O(C1-6 alkyl). B44. The compound according to any one of the preceding embodiments, wherein R2 is C1-4 alkyl. B45. The compound of any one of the preceding embodiments, wherein R2 is methyl. B46. The compound of any one of the preceding embodiments, wherein X is CRx. B47. The compound of embodiment B46, wherein Rx is hydrogen, halogen, -OR3, optionally substituted C1-6 aliphatic or -CN. B48. The compound as in embodiment B46, wherein Rx is halogen, -OR3 or -CN. B49. The compound as in embodiment B46, wherein Rx is halogen, -OR3, -N(R3)2, -SR3 or -CN. B50. The compound of any one of embodiments B1 to B45, wherein X is N. B51. The compound of any one of the preceding embodiments, wherein Y is CRy. B52. the compound as embodiment B51, wherein Ry is hydrogen. B53. The compound of any one of embodiments B1 to B50, wherein Y is N. B54. The compound of any one of the preceding embodiments, wherein W is CRw. B55. the compound as embodiment B54, wherein Rw is hydrogen. B56. The compound of any one of embodiments B1 to B53, wherein W is N. B57. The compound of any one of the preceding embodiments, wherein Z is -NRz-. B58. the compound as embodiment B57, wherein Rz is hydrogen. B59. The compound of any one of embodiments B1 to B56, wherein Z is -O-. B60. The compound of any one of the preceding embodiments, wherein each R is independently hydrogen, optionally substituted C1-6 aliphatic, optionally substituted 3-7 membered saturated or partially unsaturated carbon A cyclic group or an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or two Rs connected to the same The nitrogen atoms are taken together to form a 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur. B61. A compound according to any one of the preceding embodiments, wherein each R is independently hydrogen or optionally substituted C1-6 aliphatic. B62. A compound according to any one of the preceding embodiments, wherein each R' is independently optionally substituted C1-2 alkyl or optionally substituted C3-4 cycloalkyl. B63. The compound of any one of the preceding embodiments, wherein: W is CH; Rx and Ry are each independently hydrogen, optionally substituted C1-6 aliphatic or -CN; Each R is independently hydrogen, optionally substituted C1-6 aliphatic, optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl, or has 1-3 independently selected from nitrogen, oxygen and sulfur heteroatoms optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic groups, or two R when connected to the same nitrogen atom together form 0-2 independently selected from nitrogen 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic groups with additional heteroatoms of , oxygen and sulfur. B64. The compound of any one of the preceding embodiments, wherein the compound is a compound of formula I-A: I-A or a pharmaceutically acceptable salt thereof. B65. A compound selected from Table 1 or a pharmaceutically acceptable salt thereof. B66. A pharmaceutical composition comprising the compound of any one of the foregoing embodiments or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. B67. A method of inhibiting JAK2 in an individual comprising administering a compound according to any one of embodiments B1 to B63 or a composition according to embodiment B64. B68. The method of embodiment B67, wherein the administered compound or composition is characterized in that it is a type II JAK2 inhibitor. B69. A method of treating a disease, disorder or disorder associated with JAK2, comprising administering a compound according to any one of Embodiments B1 to B65 or a composition according to Embodiment B66 to an individual in need thereof. B70. A method of treating cancer, comprising administering a compound according to any one of Embodiments B1 to B65 or a composition according to Embodiment B66 to an individual in need thereof. B71. A method of treating hematological malignancies, comprising administering the compound according to any one of embodiments B1 to B65 or the composition according to embodiment B66 to an individual in need. B72. The method of embodiment B71, wherein the hematologic malignancy is leukemia or lymphoma. B73. A method of treating myeloproliferative neoplasms, comprising administering the compound of any one of embodiments B1 to B65 or the composition of embodiment B66 to an individual in need. B74. The method of embodiment B73, wherein the myeloproliferative neoplasm is plethora vera, essential thrombocytopenia or myelofibrosis. [example] []

[0171] As illustrated in the Examples below, in certain illustrative examples, compounds were prepared according to the following general procedures. It should be understood that although the general methods illustrate the synthesis of certain compounds of the present disclosure, the following general methods and others known to those skilled in the art can be applied to all compounds and their respective subclasses as described herein and types. [ Preparation of intermediates , ] [ , ] [intermediate] [Int-1] [Preparation]: N-(4-hydroxypyridin-2-yl)acetamide []

[0172] [compound] [Int-1]. [2] [The synthesis]. To a solution of benzyl alcohol (17.05 g, 157.69 mmol, 1.0 equiv) in THF (250 mL) was added sodium hydride (12.61 g, 315.38 mmol, 2.0 equiv) in small portions at 0 °C. The mixture was stirred for 1 h, and 2-chloro-4-nitropyridine ( [Int-1]. [1] , 25 g, 157.69 mmol, 1.0 equiv). The reaction mixture was stirred at 0 °C for 2 h. It was poured onto ice, stirred and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 10% ethyl acetate in hexane as eluent) to give [Int-1]. [2] . MS (ES): m / z 220.13 [M+H]+.

[0173] [compound] [Int-1]. [3] [The synthesis]. The compound was bubbled through with argon for 10 min [Int-1]. A solution of [2] (20 g, 91.05 mmol, 1.0 equiv) in THF (200 mL) was degassed. Add 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (4.34 g, 9.105 mmol, 0.1 equivalent) and ginseng(dibenzylideneacetone)dipalladium ( 4.17 g, 4.55 mmol, 0.05 eq), and degas again for 5 min. A solution of lithium bis(trimethylsilyl)amide (1 M in THF, 182 mL, 182.1 mmol, 2.0 equiv) was added to the mixture, and it was stirred at 60 °C for 1 h. The reaction mixture was cooled to room temperature, poured on ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3% methanol in dichloromethane as eluent) to give [Int-1]. [3]. MS (ES): m / z 201.2 [M+H]+. []

[0174] [compound] [Int-1]. [4] [The synthesis]. compound at room temperature [Int-1]. [3] To a solution of (11.2 g, 55.93 mmol, 1.0 eq) in dichloromethane (110 mL) and pyridine (6.3 mL, 78.30 mmol, 1.4 eq) was slowly added acetic anhydride (6.34 mL, 67.11 mmol, 1.2 eq ) and stirred for 1 h. The reaction mixture was poured onto ice, stirred and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 1% methanol in dichloromethane as eluent) to give [Int-1]. [4]. MS (ES): m / z 243.21 [M+H]+. []

[0175] [compound] [Int-1] [The synthesis]. will be loaded with compound [Int-1]. A round bottom flask of [4] (6.1 g, 25.18 mmol, 1.0 equiv), 10% palladium on carbon (2 g), and methanol (60 mL) was evacuated and purged with hydrogen three times. The reaction mixture was stirred at room temperature under 1 atm of hydrogen for 1 h. The flask was evacuated and purged with nitrogen before being left open to air. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (CombiFlash®, 5% methanol in dichloromethane as eluent) to give [Int-1]. MS (ES): m / z 153.2 [M+H]+. [intermediate] [Int-2] [Preparation]: N-(4-(4-amino-3-(methylamino)phenoxy)pyridin-2-yl)acetamide []

[0176] [compound] [Int-2]. [2] [The synthesis]. To 2,4-difluoro-1-nitrobenzene ( [Int-2]. [1,] To a solution of 1.0 g, 6.29 mmol, 1.0 equiv) in THF (10 mL) was added dropwise a solution of methylamine (33% in ethanol, 1.18 mL, 12.58 mmol, 2.0 equiv). The reaction mixture was stirred at room temperature for 2 h. It was poured onto ice and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give [Int-2]. [2] . MS (ES): m / z 171.2 [M+H]+. []

[0177] [compound] [Int-2]. [3] [The synthesis]. Will [Int-2]. [2] (0.170 g, 0.99 mmol, 1.0 eq), A mixture of [Int-1] (0.152 g, 0.99 mmol, 1.0 eq) and potassium carbonate (0.273 g, 1.98 mmol, 2.0 eq) in N-methyl-2-pyrrolidone (1.7 mL) was prepared under nitrogen at Stir at 130°C for 12 h. Allow to cool to room temperature, pour onto ice and extract three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2.5% methanol in dichloromethane as eluent) to give [Int-2]. [3]. MS (ES): m / z 303.3 [M+H]+. []

[0178] [compound] [Int-2] [The synthesis]. will be filled with [Int-2]. A round bottom flask of [3] (0.180 g, 0.59 mmol, 1.0 equiv), 10% palladium on carbon (0.1 g), and methanol (2 mL) was evacuated and purged with hydrogen. The reaction mixture was stirred at room temperature under 1 atm of hydrogen for 2 h. The flask was evacuated and purged with nitrogen before being left open to air. The mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (CombiFlash®, 5% methanol in dichloromethane as eluent) to give [Int-2]. MS (ES): m / z 273.3 [M+H]+. [intermediate] [Int-3] [Preparation]: N-(4-(4-amino-2-methyl-3-(methylamino)phenoxy)pyridin-2-yl)acetamide

[0179] [compound] [Int-3]. [2] [The synthesis]. [Int-3.2] is derived from 1,3-difluoro-2-methyl-4-nitrobenzene ( [Int-3]. [1] ) follow the compound The procedure described in the synthesis of [Int-2.2] was prepared. MS (ES): m / z 185.2 [M+H]+. []

[0180] [compound] [Int-3]. [3] [The synthesis]. [Int-3.3] is derived from [Int-3]. [2] follow compound The procedure described in the synthesis of [Int-2.3] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.5% methanol in dichloromethane as eluent). MS (ES): m / z 317.03 [M+H]+. []

[0181] [compound] [Int-3] [The synthesis]. [Int-3] is from [Int-3]. [3] follow compound The procedure described in the synthesis of [Int-2] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 5% methanol in dichloromethane as eluent). MS (ES): m / z 287.3 [M+H]+. [intermediate] [Int-4] [Preparation]: N-(4-(4-amino-2-cyano-3-(methylamino)phenoxy)pyridin-2-yl)acetamide

[0182] [compound] [Int-4]. [2] [Synthesis:] 2,6-difluorobenzonitrile ( [Int-4]. [1] , 5.0 g, 35.94 mmol, 1.0 eq) in concentrated sulfuric acid (15 mL) was slowly added concentrated nitric acid (6 mL). The reaction mixture was stirred at room temperature for 15 min. Pour it over crushed ice. The precipitate was collected by filtration, rinsed with a small amount of water and air-dried to obtain [Int-4]. [2] . MS (ES): m / z 185.1 [M+H]+. []

[0183] [compound] [Int-4]. [3] [The synthesis]. at 0°C to [Int-4]. [2] To a solution of (2.6 g, 14.12 mmol, 1.0 equiv) in THF (25 mL) was added a solution of methylamine (40% in water, 2.19 mL, 28.24 mmol, 2.0 equiv) dropwise. The reaction mixture was stirred at room temperature for 2 h. It was poured on ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 6% ethyl acetate in hexane as eluent) to give [Int-4]. [3]. MS (ES): m / z 196.2 [M+H]+. []

[0184] [compound] [Int-4]. [4] [The synthesis]. [Int-4.4] is derived from [Int-4.3] follow compound The procedure described in the synthesis of [Int-2.3] was prepared. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2.5% methanol in dichloromethane as eluent). MS (ES): m / z 328.3 [M+H]+. []

[0185] [compound] [Int-4] [The synthesis]. compound [Int-4]. [4] (0.860 g, 2.63 mmol, 1.0 equiv), ammonium chloride (1.406 g, 26.3 mmol, 10 equiv), iron powder (1.472, 26.3 mmol, 10 equiv) in ethanol (9 mL) and water (3 mL ) was stirred at 80 °C for 3 h under nitrogen. The mixture was filtered through a pad of Celite®. The filtrate was poured on ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol in dichloromethane as eluent) to give [Int-4]. MS (ES): m / z 298.3 [M+H]+. [intermediate] [Int-5] [Preparation]: N-(4-((5-amino-6-(methylamino)pyridin-2-yl)oxy)pyridin-2-yl)acetamide

[0186] [compound] [Int-5]. [2] [The synthesis]. To 2,6-dichloro-3-nitropyridine ( [Int-5]. [1], 5.0 g, 25.91 mmol, 1.0 eq) in ethanol (30 mL) was added dropwise with methylamine solution (33% in ethanol, 4.9 mL, 51.82 mmol, 2.0 eq) followed by sodium carbonate (4.10 g, 38.7 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 16 h. It was poured on ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain [Int-5]. [2] . MS (ES): m / z 188.5 [M+H]+. []

[0187] [compound] [Int-5]. [3] [The synthesis]. Will [Int-5]. [2] (0.500 g, 2.67 mmol, 1.0 eq), A mixture of [Int-1] (0.405 g, 2.67 mmol, 1.0 eq) and sodium carbonate (0.311 g, 2.93 mmol, 1.1 eq) in DMF (5 mL) was stirred at 90°C for 12 h under nitrogen. Allow to cool to room temperature, pour on ice-water and extract with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 25% ethyl acetate in hexane as eluent) to give [1] . [3]. MS (ES): m / z 304.3 [M+H]+. []

[0188] [compound] [Int-5] [The synthesis]. [Int-5] is from [Int-5]. [3] follow compound The procedure described in the synthesis of [Int-2] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 5% methanol in dichloromethane as eluent). MS (ES): m / z 274.3 [M+H]+. [ Compound preparation , ] [ , ]

[0189] [example] [1] [:] N-(4-((2-((5-(tert-butyl)isoxazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazole-6- base)oxy)pyridin-2-yl)acetamide

[0190] [compound] [1.2] [The synthesis]. at 0°C to [1] . [1] To a solution of (0.8 g, 5.71 mmol, 1.0 equiv) and triethylamine (2.38 mL, 17.13 mmol, 3.0 equiv) in THF (8 mL) was added dropwise thiophosgene (0.52 mL, 6.85 mmol, 1.2 equivalent). The reaction mixture was stirred at 0 °C for 30 min. It was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 10% ethyl acetate in hexane as eluent) to give [1] . [2] . MS (ES): m / z 183.2 [M+H]+. []

[0191] [compound] [I-1] [The synthesis]. Towards [Int-2] (0.100 g, 0.37 mmol, 1.0 equiv) and [1.2] To a solution of (0.087 g, 0.47 mmol, 1.3 equiv) in THF (2 mL) was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.141 g, 0.74 mmol, 2.0 equiv). The reaction mixture was stirred at 50 °C for 4 h. Allow to cool to room temperature, pour on ice-water and extract with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 4% methanol in dichloromethane as eluent) to give [I-1]. MS (ES): m / z: 421.6 [M+H]+ ;1 H NMR (DMSO-d6, 400 M Hz): δ 10.14 (bs, 2H), 8.15-8.14 (d,J = 5.6 Hz, 1H ), 7.65 (s, 1H), 7.42-7.40 (d,J = 8.4 Hz, 1H), 7.13 (s, 1H), 6.86-6.84 (d,J = 8.0 Hz, 1H), 6.63-6.62 (d, J = 3.6 Hz, 1H), 3.56 (s, 3H), 2.06 (s, 3H), 1.34 (s, 9H). [example] [2] [:] N-(4-((2-((5-(tert-butyl)isoxazol-3-yl)amino)-1,7-dimethyl-1H-benzo[d]imidazole -6-yl)oxy)pyridin-2-yl)acetamide

[0192] [I-2] [The synthesis]. Towards [Int-3] (0.150 g, 0.52 mmol, 1.0 equiv) and [1] . To a solution of [2] (0.124 g, 0.68 mmol, 1.3 equiv) in THF (3 mL) was added N,N'-diisopropylcarbodiimide (0.087 mL, 1.04 mmol, 2.0 equiv). The reaction mixture was stirred at 70 °C for 5 h. Allow to cool to room temperature, pour on ice-water and extract with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 8% methanol in dichloromethane as eluent) to give [I-2]. MS (ES): m / z: 435.1[M+H]+ ;1 H NMR (DMSO-d6, 400 MHz): δ 10.50 (s, 1H), 10.10 (s, 1H), 8.14-8.13 (d, J = 5.2 Hz, 1H), 7.58 (s, 1H), 7.31-7.29 (d, J = 8.4 Hz, 1H), 6.84-6.80 (t, 1H), 6.73 (bs, 1H), 6.55 (bs, 1H ), 3.77 (s, 3H), 2.39 (s, 3H), 2.02 (s, 3H), 1.30 (s, 9H). [example] [3] [:] N-(4-((2-((5-(tert-butyl)isoxazol-3-yl)amino)-7-cyano-1-methyl-1H-benzo[d ]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0193] [compound] [I-3] [The synthesis]. compound [I-3] Derived from [Int-4] and [1.2] Follow Compound The procedure described in the synthesis of [I-2] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 5% methanol in dichloromethane as eluent). MS (ES): m / z: 446.45 [M+H]+ ;1 H NMR (DMSO-d6, 400 MHz): δ 10.24 (s, 1H), 8.22-8.21 (d,J = 5.6 Hz, 1H) , 7.70 (bs, 2H), 7.01 (s, 1H), 6.69 (bs, 2H), 3.95 (bs, 3H), 3.78 (bs, 1H), 2.07-2.06 (d, 3H), 1.27 (s, 9H ). [example] [4] [:] N-(4-((2-((4-chloro-3-(trifluoromethyl)phenyl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl )oxy)pyridin-2-yl)acetamide

[0194] [compound] [4]. [2] [The synthesis]. compound [4.2] Derived from 4-chloro-3-(trifluoromethyl)aniline ( [4.1] ) follow the compound The procedure described in the synthesis of [1.2] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 8% ethyl acetate in hexane as eluent). MS (ES): m / z 238.5 [M+H]+. []

[0195] [I-4] [The synthesis]. compound [I-4] Derived from [4.2] and [Int-2] follow compound The procedure described in the synthesis of [I-1] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 5% methanol in dichloromethane as eluent). MS (ES): m / z: 476.6 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 9.49 (s, 1H), 8.41 (s, 1H) , 8.33-8.31 (d, J = 8.8 Hz, 1H), 8.16-8.14 (d, J = 5.6 Hz, 1H), 7.70-7.65 (m, 2H), 7.49-7.47 (d, J = 8.8 Hz, 1H ), 7.29 (s, 1H), 6.90-6.88 (d,J = 8.4 Hz, 1H), 6.63-6.61 (t,J = 3.6 Hz, 1H), 3.77 (s, 3H), 2.03 (s, 3H) . [example] [5] [:] N-(4-((2-((4-chloro-3-(trifluoromethyl)phenyl)amino)-1,7-dimethyl-1H-benzo[d]imidazole- 6-yl)oxy)pyridin-2-yl)acetamide

[0196] [compound] [I-5] [The synthesis]. compound [I-5] is from [Int-3] and [4.2] Following compounds The procedure described in the synthesis of [I-2] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4% methanol in dichloromethane as eluent). MS (ES): m / z: 490.71 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 9.43 (s, 1H), 8.35 (s, 1H) , 8.26-8.24 (d,J = 8.4 Hz, 1H), 8.14-8.13 (d,J = 5.6 Hz, 1H), 7.68-7.66 (d,J = 8.8 Hz, 1H), 7.59 (s, 1H), 7.34-7.32 (d,J = 8.4 Hz, 1H), 6.85-6.83 (d,J = 7.6 Hz, 1H), 6.55-6.54 (d,J = 4 Hz, 1H), 3.97 (s, 3H), 2.50 (s, 3H), 2.02 (s, 3H). [example] [6] [:] N-(4-((2-((2,4-difluorophenyl)amino)-1,7-dimethyl-1H-benzo[d]imidazol-6-yl)oxy )pyridin-2-yl)acetamide

[0197] [compound] [6]. [2] [The synthesis]. compound [6.2] is derived from 2,4-difluoroaniline ( [6.1] ) follow the compound The procedure described in the synthesis of [1.2] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 10% ethyl acetate in hexane as eluent). MS (ES): m / z 172.2 [M+H]+. []

[0198] [compound] [I-6] [The synthesis]. compound [I-6] Derived from [Int-3] and [6.2] Following compounds The procedure described in the synthesis of [I-2] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2% methanol in dichloromethane as eluent). MS (ES): m / z: 424.0 [M+H]+ ;1 H NMR (DMSO-d6, 400 MHz): δ 10.53 (s, 1H), 8.68 (s, 1H), 8.18-8.16 (d, J = 5.2 Hz, 1H), 7.86 (s, 1H), 7.63 (s, 1H), 7.37 (bs, 1H), 7.23 (s, 1H), 7.14 (s, 1H), 6.84-6.82 (d, J = 7.6 Hz, 1H), 6.57 (bs, 1H), 3.94 (s, 3H), 2.46 (s, 3H), 2.07 (s, 3H). [example] [7] [:] N-(4-((2-((3-(3-methoxyazetidin-1-yl)-5-(trifluoromethyl)phenyl)amino)-1-methyl Base-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0199] [compound] [7]. [2] [The synthesis]. 3-Bromo-5-(trifluoromethyl)aniline ( [7]. [1] , 0.7 g, 2.92 mmol, 1.0 equiv), 3-methoxyazetidine hydrochloride (0.72 g, 5.83 mmol, 2.0 equiv), cesium carbonate (2.37 g, 7.3 mmol, 2.5 equiv) The mixture in 1,4-dioxane (20 mL) was degassed. Add BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (0.363 g, 0.584 mmol, 0.2 equiv) and Pd2 (dba)3 (0.267 g, 0.292 mmol, 0.1 equiv ), and degas for 5 min. The reaction mixture was stirred at 110 °C for 5 h under argon. Allow to cool to room temperature and filter through a pad of Celite®. The filtrate was poured on water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 10%-15% ethyl acetate in hexane as eluent) to give [7]. [2] . MS (ES): m / z 247.2 [M+H]+.

[0200] [compound] [7]. [3] [The synthesis]. compound [7.3] Department of [7.2] Following compounds The procedure described in the synthesis of [1.2] was prepared. MS (ES): m / z 289.3 [M+H]+. []

[0201] [I-7] [The synthesis]. compound [I-7] is from [7.3] and [Int-2] follow compound The procedure described in the synthesis of [I-2] was prepared. The product was purified by trituration with methanol and dried under vacuum. MS (ES): m / z: 527.49 [M-H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 9.16 (s, 1H), 8.15-8.14 (d,J = 5.6 Hz, 1H), 7.68 (s, 1H), 7.65 (s, 1H), 7.46-7.44 (d,J = 8.4 Hz, 1H), 7.26-7.22 (m, 2H), 6.87-6.85 (d,J = 8.0 Hz, 1H), 6.62-6.61 (t, 1H), 6.30 (s, 1H), 4.36 (bs, 1H), 4.15-4.11 (t, 2H), 3.69 (s, 5H), 3.27 (s, 3H), 1.99 (s, 3H). [example] [8] [:] N-(4-((2-((4-(2-cyanopropan-2-yl)phenyl)amino)-1-methyl-1H-benzo[d]imidazole-6- base)oxy)pyridin-2-yl)acetamide []

[0202] [compound] [8] . [2] [The synthesis]. compound [8.2] is derived from 2-(4-aminophenyl)-2-methylpropionitrile ( [8.1] ) follow the compound The procedure described in the synthesis of [1.2] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 8% ethyl acetate in hexane as eluent). MS (ES): m / z 203.2 [M+H]+. []

[0203] [I-8] [The synthesis]. compound [I-8] Derived from [8.2] and [Int-2] follow compound The procedure described in the synthesis of [I-1] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 10% methanol in dichloromethane as eluent). MS (ES): m / z: 441.29[M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 9.12 (s, 1H), 8.15-8.14 (d, J = 5.2 Hz, 1H), 7.67 (s, 1H), 7.91-7.89 (d, J = 8 Hz, 1H), 7.65 (s, 1H), 7.49-7.47 (m, 2H), 7.43-7.41 (d ,J = 8 Hz, 1H ), 7.24 (s, 1H), 6.87-6.85 (d,J = 8 Hz, 1H), 6.62 (bs, 1H), 3.70 (s, 3H), 2.03 (s, 3H) , 1.69 (s, 6H). [example] [9] [:] N-(4-((1-methyl-2-((4-((1-methyl-1H-imidazol-5-yl)methyl)-3-(trifluoromethyl)phenyl )amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0204] [compound] [9] . [3] [The synthesis]. 5-iodo-1-methyl-1H-imidazole ( [9] . [2,] 1.9 g, 9.13 mmol, 1.0 equiv) in THF (20 mL) was added n-butyllithium (2.5 M in hexane, 7.3 mL, 18.26 mmol, 2.0 equiv) dropwise. To the reaction mixture was added 4-nitro-2-(trifluoromethyl)benzaldehyde ( [9] . [1,] 2.00 g, 9.13 mmol, 1.0 equiv) in THF (5 mL), and stirred at -78°C for 10 min. It was poured on saturated ammonium chloride solution, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 4% methanol in dichloromethane as eluent) to give [9] . [3]. MS (ES): m / z 302.2 [M+H]+.

[0205] [compound] [9] . [4] [The synthesis]. To the compound [9] . [3] To a solution of (0.460 g, 1.53 mmol, 1.0 equiv) in THF (10 mL) was added phosphorus tribromide (0.44 mL, 4.59 mmol, 3.0 equiv), and the reaction mixture was stirred at 80°C for 2 h . It was poured on ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 1% methanol in dichloromethane as eluent) to give [9] . [4]. MS (ES): m / z 286.2 [M+H]+.

[0206] [compound] [9] . [5] [The synthesis]. compound [9] . [4] (0.210 g, 0.736 mmol, 1.0 equiv) and 10% palladium on carbon (0.1 g) in methanol (10 mL) was stirred under 1 atm of hydrogen at room temperature for 2 h. The mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (CombiFlash®, 3% methanol in dichloromethane as eluent) to give [9] . [5]. MS (ES): m / z 256.3 [M+H]+. []

[0207] [compound] [9] . [6] [The synthesis]. compound [9.6] is from [9.4] Following compounds The procedure described in the synthesis of [1.2] was prepared. MS (ES): m / z 298.3 [M+H]+.

[0208] [I-9] [The synthesis]. compound [I-9] Derived from [9.6] and [Int-2] follow compound The procedure described in the synthesis of [I-1] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol in dichloromethane as eluent). MS (ES): m / z: 534.15 [M-H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 9.32 (s, 1H), 8.32 (s, 1H), 8.15 -8.08 (m, 2H), 7.65 (s, 1H), 7.46-7.42 (d, J = 8.4 Hz, 1H), 7.26 (s, 1H), 7.12 (s, 1H), 7.01-6.99 (m, 1H ), 6.87-6.82 (m, 2H), 6.62-6.61 (m, 1H), 4.14 (s, 2H), 3.70 (s, 3H), 3.51 (s, 3H), 1.99 (s, 3H). [example]

[10] [:] N-(4-((2-((4-((1H-pyrazol-4-yl)methyl)-3-(trifluoromethyl)phenyl)amino)-1-methyl -1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0209] [compound]

[10] . [2] [The synthesis]. To 4-iodo-1H-pyrazole (

[10] . [1], 5.0 g, 25.78 mmol, 1.0 equiv) in DMF (50 mL) was added sodium hydride (1.48 g, 30.93 mmol, 1.2 equiv) in small portions. After the addition, the mixture was stirred for 15 min before adding 4-methoxybenzyl chloride (4.85 g, 30.93 mmol, 1.2 equiv) and stirring at room temperature for 2 h. It was poured on ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 6% ethyl acetate in hexane as eluent) to give

[10] . [2] . MS (ES): m / z 315.13 [M+H]+.

[0210] [compound]

[10] . [4] [The synthesis]. at -10°C to

[10] . [2] To a solution of (2.06 g, 6.37 mmol, 1.0 equiv) in THF (20 mL) was added a solution of isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 12.25 mL, 15.92 mmol, 2.5 equiv. ). The reaction mixture was stirred at -10 °C for 30 min, and 4-nitro-2-(trifluoromethyl)benzaldehyde (

[10] . [3] , 1.12 g, 5.09 mmol, 0.8 eq) in THF (10 mL) and stirred for 5 min. It was poured onto ice, stirred and acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 25% ethyl acetate in hexane as eluent) to give

[10] . [4]. MS (ES): m / z 408.4 [M+H]+. []

[0211] [compound]

[10] . [5] [The synthesis]. at 0°C to

[10] . [4] To a solution of (0.700 g, 1.72 mmol, 1.0 equiv) in dichloromethane (10 mL) and trifluoroacetic acid (7 mL) was added triethylsilane (3.5 mL). Allow to warm to 50 °C and stir for 1 h. It was carefully poured onto cold saturated sodium bicarbonate solution, stirred and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 15% ethyl acetate in hexane as eluent) to give

[10] . [5]. MS (ES): m / z 392.4 [M+H]+. []

[0212] [compound]

[10] . [6] [The synthesis]. compound [10.6] is from [10.5] Follow Compound The procedure described in the synthesis of [9.5] was prepared. MS (ES): m / z 362.4 [M+H]+.

[0213] [compound]

[10] . [7] [The synthesis]. compound [10.7] is from [10.6] Follow Compound The procedure described in the synthesis of [1.2] was prepared. MS (ES): m / z 404.4 [M+H]+.

[0214] [compound]

[10] . [8] [The synthesis]. compound [10.8] is from [10.7] and [Int-2] follow compound The procedure described in the synthesis of [I-1] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.6% methanol in dichloromethane as eluent). MS (ES): m / z 626.6 [M+H]+. []

[0215] [I-10] [The synthesis]. Will

[10] . [8] A mixture of (0.162 g, 0.258 mmol, 1.0 equiv) and palladium hydroxide (0.200 g) in ethanol (8 mL) and cyclohexene (4 mL) was stirred at 80°C for 16 h. The reaction mixture was filtered through a pad of Celite® and rinsed with ethanol. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol in dichloromethane as eluent) to give [I-10]. MS (ES): m / z: 522.7 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 9.28 (s, 1H), 8.24 (s, 1H) , 8.15-8.14 (d,J = 5.6 Hz, 1H), 7.65 (s, 1H), 7.45-7.39 (m, 4H), 7.26 (s, 1H), 7.06 (bs, 2H), 6.87-6.81 (m , 1H), 6.62-6.61 (d,J = 3.6 Hz, 1H), 3.90 (bs, 2H), 3.70 (s, 3H), 2.02 (s, 3H). [example]

[11] [:] N -(4-((2-((3-methoxy-4-(methoxymethyl)-5-(trifluoromethyl)phenyl)amino)-1-methyl- 1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0216] [compound]

[11] . [2] [The synthesis]. 4-nitro-2-(trifluoromethyl)benzoic acid (

[11] . [1], 10 g, 42.53 mmol, 1.0 equiv) in THF (200 mL) was added in portions with sodium borohydride (4.84 g, 127.59 mmol, 3.0 equiv), followed by the slow addition of three Boron fluoride diethyl ether (15.7 mL, 127.59 mmol, 3.0 equiv). The reaction mixture was stirred at room temperature for 16 h. It was poured on ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 9% ethyl acetate in hexane as eluent) to give [11.2]. MS (ES): m / z 222.1 [M+H]+. []

[0217] [compound]

[11] . [3] [The synthesis]. Towards

[11] . [2] To a solution of (9.0 g, 40.7 mmol, 1.0 equivalent) in dichloromethane (90 mL), add silver oxide (47 g, 203.5 mmol, 5.0 equivalent), water (9 mL), and then add iodomethane ( 25 mL, 407 mmol, 10 equiv). The reaction mixture was stirred at room temperature in the dark for 16 h. The reaction mixture was filtered through a pad of Celite®, and the filtrate was poured on ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 4% ethyl acetate in hexane as eluent) to give

[11] . [3]. MS (ES): m / z 236.2 [M+H]+.

[0218] [compound]

[11] . [4] [The synthesis]. Towards

[11] . [3] To a solution of (4.6 g, 19.56 mmol, 1.0 equivalent) in sulfuric acid (46 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (5.59 g, 19.56 mmol, 1.0 equivalent). The reaction mixture was stirred at room temperature for 16 h. Pour it over ice-water and stir. The precipitate was collected by filtration, rinsed with water and dried under vacuum. MS (ES): m / z 315.1 [M+H]+. []

[0219] [compound]

[11] . [5] [The synthesis]. Towards

[11] . [4] To a solution of (1.5 g, 4.78 mmol, 1.0 equiv) in 1,4-dioxane (12 mL) and water (12 mL) was added potassium hydroxide (0.602 g, 10.75 mmol, 2.25 equiv). The reaction mixture was degassed by bubbling argon for 10 min. Add 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.052 g, 0.123 mmol, 0.18 equivalents) and ginseng (dibenzylideneacetone) dipalladium (0 ) (0.131 g, 0.143 mmol, 0.03 eq), degas again for 5 min. The reaction mixture was stirred at 80 °C under argon for 1 h. Allow to cool to room temperature and filter through a pad of Celite®. The filtrate was poured on water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 9% ethyl acetate in hexane as eluent) to give

[11] . [5]. MS (ES): m / z 252.2 [M+H]+. []

[0220] [compound]

[11] . [6] [The synthesis]. Towards

[11] . [5] To a mixture of (0.45 g, 1.79 mmol, 1.0 equiv) and potassium carbonate (0.494 g, 3.58 mmol, 2.0 equiv) in DMF (4 mL) was added iodomethane (0.381 g, 2.68 mmol, 1.5 equiv). The reaction mixture was stirred at 70 °C under argon for 1 h. It was poured on ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 5% ethyl acetate in hexane as eluent) to give

[11] . [6]. MS (ES): m / z 266.2 [M+H]+.

[0221] [compound]

[11] . [7] [The synthesis]. compound [11.7] is from [11.6] Following compounds The procedure described in the synthesis of [9.5] was prepared. MS (ES): m / z 236.3 [M+H]+.

[0222] [compound]

[11] . [8] [The synthesis]. at 0°C to

[11] . [7] To a solution of (0.120 g, 0.510 mmol, 1.0 eq) in dichloromethane (3 mL) was added a solution of sodium bicarbonate (0.214 g, 2.55 mmol, 5.0 eq) in water (1 mL), and then Thiophosgene (0.146 g, 1.27 mmol, 2.5 equiv) was added. The reaction mixture was stirred at room temperature for 1 h. It was poured on ice-water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain

[11] . [8] . MS (ES): m / z 278.3 [M+H]+.

[0223] [I-11] [The synthesis]. compound [I-11] Derived from [11.8] and [Int-2] follow compound The procedure described in the synthesis of [I-1] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.7% methanol in dichloromethane as eluent). MS (ES): m / z: 516.5 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 9.41 (s, 1H), 8.16-8.15 (d, J = 5.6 Hz, 1H), 8.01 (s, 1H), 7.65 (s, 1H), 7.48-7.46 (d, J = 8.4 Hz, 1H), 7.29 (s, 1H), 7.07 (s, 1H), 6.89-6.81 (m, 1H), 6.63-6.62 (d, J = 3.6 Hz, 1H), 4.43 (s, 2H), 3.90 (s, 3H), 3.72 (s, 3H), 3.28 (s, 3H) , 2.02 (s, 3H). [example]

[12] [:] (R )-N -(4-((1-methyl-2-((3-(1-methyl-5-oxopyrrolidin-3-yl)-5-(trifluoromethyl Base) phenyl) amino) -1H-benzo [d] imidazol-6-yl) oxy) pyridin-2-yl) acetamide [and] (S )-N-(4-((1-methyl-2-((3-(1-methyl-5-oxopyrrolidin-3-yl)-5-(trifluoromethyl Base) phenyl) amino) -1H-benzo [d] imidazol-6-yl) oxy) pyridin-2-yl) acetamide

[0224] [compound]

[12] . [2] [The synthesis]. 3-(trifluoromethyl)benzaldehyde (

[12] . [1,] 10 g, 57.43 mmol, 1.0 eq) in a mixture of concentrated sulfuric acid (98%, 20 mL) was slowly added nitric acid (2.5 mL). The reaction mixture was stirred at 50 °C for 8 h. It was poured on crushed ice, stirred and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 10% ethyl acetate in hexane as eluent) to give

[12] . [2] . MS (ES): m / z 220.2 [M+H]+. []

[0225] [compound]

[12] . [3] [The synthesis]. To a solution of ethyl diethylphosphinoacetate (4.74 g, 22.59 mmol, 1.1 eq) in THF (50 mL) was added sodium hydride (1.18 g, 24.64 mmol, 1.2 eq) at 0 °C and stirred for 30 min . Add to the solution

[12] . [2] (4.5 g, 20.54 mmol, 1.2 equiv), and the mixture was stirred at room temperature for 3 h. It was poured into ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 20% ethyl acetate in hexane as eluent) to give

[12] . [3]. MS (ES): m / z 290.2 [M+H]+. []

[0226] [compound] [(±)-12]. [4] [The synthesis]. compound

[12] . [3] A solution of (4.0 g, 13.83 mmol, 1.0 equiv) and tetramethylguanidine (0.6 mL) in nitromethane (40 mL) was stirred at 80°C for 2 h. It was poured into ice-water, stirred and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 12% ethyl acetate in hexane as eluent) to give [(±)-12]. [4]. MS (ES): m / z 351.3 [M+H]+.

[0227] [compound] [(±)-12]. [5] [The synthesis]. at 0°C to [(±)-12]. [4] To a solution of (1.1 g, 3.14 mmol, 1.0 equiv) in isopropanol (60 mL) and 1 N aqueous hydrochloric acid (30 mL) was added zinc dust (3.9 g, 61.23 mmol, 19.5 equiv) in portions . After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 h. It was poured slowly into stirring saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 10% methanol in dichloromethane as eluent) to give the amine, which was dissolved in ethanol (20 mL) and triethylamine added (2 mL) and heated to reflux for 16 h. The reaction mixture was poured into ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 4.1% methanol in dichloromethane as eluent) to give [(±)-12]. [5]. MS (ES): m / z 245.2 [M+H]+.

[0228] [compound] [(±)-12]. [6] [The synthesis]. Towards

[12] . [5] To a solution of (0.4 g, 1.64 mmol, 1.0 eq) in acetic acid (5 mL) was added phthalic anhydride (0.485 g, 3.28 mmol, 2.0 eq) and stirred at 80°C for 4 h. It was poured into ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 10% methanol in dichloromethane as eluent) to give [(±)-12]. [6]. MS (ES): m / z 375.3 [M+H]+.

[0229] [compound] [(±)-12]. [7] [The synthesis]. Will [(±)-12]. [6] (0.271 g, 0.723 mmol, 1.0 equiv) and potassium carbonate (0.209 g, 1.51 mmol, 2.1 equiv) in DMF (3 mL) was stirred for 15 min and iodomethane (0.123 g, 0.867 mmol, 1.2 equivalent). The reaction mixture was stirred at 85 °C for 3 h. It was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 4.7% methanol in dichloromethane as eluent) to give [(±)-12]. [7]. MS (ES): m / z 389.4 [M+H]+.

[0230] [compound] [(±)-12]. [8] [The synthesis]. Towards [(±)-12]. To a solution of [7] (0.190 g, 0.489 mmol, 1.0 equiv) in methanol (10 mL) was added hydrazine (99%, 1 mL), and the mixture was heated to reflux for 2 h. It was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain [(±)-12]. [8] . MS (ES): m / z 259.2 [M+H]+.

[0231] [compound] [(±)-12]. [9] [The synthesis]. compound [(±)-12.9] is derived from compound [(±)-12.8] follow The procedure described in the synthesis of [11.8] was prepared. MS (ES): m / z 301.3 [M+H]+.

[0232] [compound] [(±)-I-12] [The synthesis]. compound [(±)-I-12] is from [(±)-12.9] and [Int-2] follow compound The procedure described in the synthesis of [I-1] was prepared. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 4.8% methanol in dichloromethane as eluent). MS (ES): m / z 539.5 [M+H]+.

[0233] [I-12-a] [and] [I-12-b]. In HPLC (CHIRALPAK IH (250 mm × 21 mm, 5 µm); mobile phase: (A) 0.1% diethylamine / n-hexane (B) 0.1% diethylamine / isopropanol: acetonitrile (70: 30); Flow rate: 20 mL / min) separation on The enantiomer of [(±)-I-12] obtained the first elution fraction ( [I-12-a] ) and the second elution fraction ( [I-12-b]). (*Absolute stereochemistry not determined.)

[0234] [I-12-a] [:] MS (ES): m / z: 539.8 [M+H]+ ;1 H NMR (DMSO-d6, 400 MHz): δ 10.50 (s, 1H), 9.37 (s, 1H), 8.34 (s , 1H), 8.16-8.14 (d,J = 5.6 Hz, 1H), 8.01 (s, 1H), 7.65 (s, 1H), 7.48-7.46 (d,J = 8.4 Hz, 1H), 7.29 (s, 1H), 7.25 (s, 1H), 6.89-6.87 (m, 1H), 6.63-6.62 (m, 1H), 3.82-3.80 (m, 1H), 3.72 (s, 3H), 3.69-3.65 (m, 1H), 3.40-3.35 (m, 1H), 2.81 (s, 3H), 2.79-2.72 (m, 1H), 2.42-2.33 (m, 1H), 2.02 (s, 3H).

[0235] [I-12-b] :MS (ES):m / z: 539.4 [M+H]+ ;1 H NMR (DMSO-d6, 400 MHz): δ 10.50 (s, 1H), 9.37 (s, 1H ), 8.34 (s, 1H), 8.16-8.14 (d,J = 5.6 Hz, 1H), 8.01 (s, 1H), 7.65 (s, 1H), 7.48-7.46 (d,J = 8.4 Hz, 1H) , 7.29 (s, 1H), 7.25 (s, 1H), 6.89-6.86 (m, 1H), 6.63-6.61 (m, 1H), 3.82-3.80 (m, 1H), 3.72 (s, 3H), 3.69 -3.65 (m, 1H), 3.40-3.35 (m, 1H), 2.81 (s, 3H), 2.79-2.72 (m, 1H), 2.42-2.33 (m, 1H), 2.02 (s, 3H). [example]

[13] [:] N-(4-((1-methyl-2-((6-morpholinopyridin-2-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy) Pyridin-2-yl)acetamide

[0236] [compound]

[13] . [2] [The synthesis]. 6-bromopyridin-2-amine (

[13] . [1] , 1.5 g, 8.67 mmol, 1.0 eq) and morpholine (7.47 mL, 86.7 mmol, 10 eq) were stirred at 150°C for 4 h. Allow to cool to room temperature, pour on ice-water and extract with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 40% ethyl acetate in hexane as eluent) to give

[13] . [2] . MS (ES): m / z 180.3 [M+H]+. []

[0237] [compound]

[13] . [3] [The synthesis]. compound [13.3] is from [13.2] Following compounds The procedure described in the synthesis of [1.2] was prepared. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 15% ethyl acetate in hexane as eluent). MS (ES): m / z 222.3 [M+H]+. []

[0238] [I-13] [The synthesis]. compound [I-12] Derived from [13.3] and [Int-2] follow compound The procedure described in the synthesis of [I-1] was prepared. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 8% methanol in dichloromethane as eluent). MS (ES): m / z: 460.45 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 9.13 (s, 1H), 8.15-8.14 (d, J = 5.6 Hz, 1H), 7.65 (s, 1H), 7.57-7.46 (m, 3H), 7.29 (s, 1H), 6.90-6.88 (d, J = 8.4 Hz, 1H), 6.63-6.62 (d ,J = 3.6 Hz, 1H), 6.40-6.38 (d,J = 8 Hz, 1H), 3.69 (bs, 8H), 3.55 (s, 3H), 2.02 (s, 3H). [example]

[14] [:] N -(4-((2-((4-((4-ethylhexahydropyrazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)amino)- 1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

[0239] [compound]

[14] . [2] [The synthesis]. To a solution of benzyl alcohol (17.05 g, 157.69 mmol, 1.0 equiv) in THF (250 mL) was added sodium hydride (12.61 g, 315.38 mmol, 2 equiv) at 0 °C and stirred for 1 h. Add 2-chloro-4-nitropyridine (

[14] . [1] , 25 g, 157.69 mmol, 1.0 equiv), and the reaction mixture was stirred at 0°C for 2 h. It was poured on ice, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 10% ethyl acetate in hexane as eluent) to give [1] . [1] . MS (ES): m / z 220.13 [M+H]+.

[0240] [compound]

[14] . [3] [The synthesis]. [] by bubbling argon for 10 min

[14] . A solution of [2] (20 g, 91.05 mmol, 1.0 equiv) in THF (200 mL) was degassed. Add 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (4.34 g, 9.105 mmol, 0.1 equivalent) and ginseng (dibenzylideneacetone) dipalladium (0) (4.17 g, 4.55 mmol, 0.05 equivalent), and degassed for 5 min. To the mixture was added lithium bis(trimethylsilyl)amide solution (1 M in THF, 182 mL, 182.1 mmol, 2.0 equiv), and the reaction mixture was stirred at 60 °C under argon for 1 h. Allow to cool to room temperature, pour on ice-water and extract with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3% methanol in dichloromethane as eluent) to give

[14] . [3]. MS (ES): m / z 201.2 [M+H]+. []

[0241] [compound]

[14] . [4] [The synthesis]. at room temperature to

[14] . [3] To a solution of (0.8 g, 4.0 mmol, 1.0 equiv) in dichloromethane (10 mL) was added triethylamine (1.67 mL, 12.0 mmol, 3.0 equiv), followed by cyclopropylcarbonyl chloride (0.49 g , 4.8 mmol, 1.2 eq) and stirred for 1 h. It was poured onto ice, stirred and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 1.2% methanol in dichloromethane as eluent) to give

[14] . [4]. MS (ES): m / z 269.3 [M+H]+. []

[0242] [compound]

[14] . [5] [The synthesis]. compound [14.5] is from [14.4] follow The procedure described in the synthesis of [Int-1] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 5% methanol in dichloromethane as eluent). MS (ES): m / z 179.2 [M+H]+.

[0243] [compound]

[14] . [7] [The synthesis]. To 4-amino-2-(trifluoromethyl)benzoic acid (

[14] . [6] , 10 g, 48.75 mmol, 1.0 equiv) in DMF (30 mL) was added O-(benzotriazol-1-yl)-N,N,N',N'- Tetramethyluronium (18.4 g, 58.5 mmol, 1.2 equiv). The reaction mixture was stirred for 30 min, and 1-ethylhexahydropyrazine (6.67, 58.5 mmol, 1.2 equiv) was added followed by N,N [-] Diisopropylethylamine (24 mL, 146.25 mmol, 3.0 equiv). It was stirred at room temperature for 3 h. It was poured on ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 1.5% methanol in dichloromethane as eluent) to give

[14] . [7]. MS (ES): m / z 302.3 [M+H]+.

[0244] [compound]

[14] . [8] [The synthesis]. at 0°C to

[14] . [7] To a solution of (2 g, 6.64 mmol, 1.0 equiv) in THF (20 mL) was added a solution of lithium aluminum hydride (1 M in THF, 19.9 mL, 19.92 mmol, 3.0 equiv). The reaction mixture was heated to reflux for 3 h. Allow to cool to room temperature, pour carefully on ice-water and extract with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain

[14] . [8] . MS (ES): m / z 288.3 [M+H]+. []

[0245] [compound]

[14] . [9] [The synthesis]. compound [14.9] is from [14.8] Following compound The procedure described in the synthesis of [1.2] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol in dichloromethane as eluent). MS (ES): m / z 330.3 [M+H]+. []

[0246] [compound]

[14] .

[11] [The synthesis]. To 2,4-difluoro-1-nitrobenzene (

[14] .

[10] , 1.0 g, 6.29 mmol, 1.0 equiv) in THF (10 mL) was added dropwise a solution of methylamine (33% in ethanol, 1.18 mL, 12.58 mmol, 2.0 equiv). The reaction mixture was stirred at room temperature for 2 h. It was poured on ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain

[14] .

[11] . MS (ES): m / z 171.2 [M+H]+. []

[0247] [compound]

[14] .

[12] [The synthesis]. compound [14.12] Derived from [14.11] and [14.5] Following compound The procedure described in the synthesis of [Int-2.3] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.5% methanol in dichloromethane as eluent). MS (ES): m / z 329.3 [M+H]+. []

[0248] [compound]

[14] .

[13] [The synthesis]. compound [14.13] is from [14.12] Following compounds The procedure described in the synthesis of [Int-2] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 5% methanol in dichloromethane as eluent). MS (ES): m / z 299.3 [M+H]+. []

[0249] [I-14] [The synthesis]. compound [I-14] Derived from [14.9] and [14.13] Following compounds The procedure described in the synthesis of [I-2] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 10% methanol in dichloromethane as eluent). MS (ES): m / z: 594.30 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.79 (s, 1H), 9.31 (s, 1H), 8.24 (s, 1H) , 8.19-8.15 (m, 2H), 7.68-7.66 (d,J = 8.4 Hz, 1H), 7.62 (s, 1H), 7.45-7.43 (d,J = 7.6 Hz, 1H), 7.26 (s, 1H ), 6.87-6.85 (d,J = 10.4 Hz, 1H), 6.66-6.65 (d,J = 3.2 Hz, 1H), 3.70 (s, 3H), 3.55 (s, 2H), 2.33 (bs, 10H) , 1.95 (bs, 1H), 1.01-0.97 (t, 3H), 0.75 (bs, 4H). [example]

[15] [:] 4-((2-((4-((4-ethylhexahydropyrazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)amino)-1-methyl Base-1H-benzo[d]imidazol-6-yl)oxy)-N-methylpyridinamide

[0250] [compound]

[15] . [2] [The synthesis]. compound in a microwave reactor

[15] . [1] A mixture of (0.5 g, 2.93 mmol, 1.0 equiv) and 1 M hydrochloric acid (5 mL) was stirred at 150°C for 2 h. It was poured on saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3% methanol in dichloromethane as eluent) to give

[15] . [2] . MS (ES): m / z 153.2 [M+H]+. []

[0251] [compound]

[15] . [3] [The synthesis]. compound [15.3] is from [Int-2.2] and [15.2] Following compounds The procedure described in the synthesis of [Int-2.3] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.0% methanol in dichloromethane as eluent). MS (ES): m / z 303.3 [M+H]+. []

[0252] [compound]

[15] . [4] [The synthesis]. compound [15.4] is from [15.3] Following compounds The procedure described in the synthesis of [Int-2] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 5% methanol in dichloromethane as eluent). MS (ES): m / z 273.3 [M+H]+.

[0253] [I-15] [The synthesis]. compound [I-15] Department of [15.4] and [14.9] Following compound The procedure described in the synthesis of [I-2] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 10% methanol in dichloromethane as eluent). MS (ES): m / z: 568.9 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 9.35 (s, 1H), 8.80-8.78 (d,J = 4.8 Hz, 1H) , 8.50-8.49 (d,J = 5.6 Hz, 1H), 8.25 (s, 1H), 8.21-8.19 (d,J = 8.0 Hz, 1H), 7.69-7.67 (d,J = 8.4 Hz, 1H), 7.50-7.48 (d,J = 8.4 Hz, 1H), 7.37-7.36 (d,J = 2.4 Hz, 1H), 7.33 (s, 1H), 7.17-7.15 (m, 1H), 6.93-6.90 (t, J = 8.4 Hz, 1H), 3.71 (s, 3H), 3.55 (s, 2H), 2.76 (s, 3H), 2.42 (bs, 6H), 2.33 (bs, 4H), 1.01-0.97 (t, 3H ). [example]

[16] [:] 4-((2-((5-(tert-butyl)isoxazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy base)-N-methylpyridinamide

[0254] [I-16] [The synthesis]. compound [I-16] is derived from the compound [15.4] and compounds [1.2] Follow Compound The procedure described in the synthesis of [I-2] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3% methanol in dichloromethane as eluent). MS (ES): m / z: 421.46 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 8.49-8.48 (d, 2H), 7.46 (bs, 2H), 7.17-7.11 ( m, 2H), 6.89-6.87 (d, J = 7.2 Hz, 1H), 3.56 (bs, 3H), 2.84 (s, 3H), 1.35 (s, 9H). [example]

[17] [:] N-(4-((2-((3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)amino)-1-methyl-1H-benzo [d] imidazol-6-yl) oxy) pyridin-2-yl) acetamide

[0255] [compound]

[17] . [2] [The synthesis]. compound [17.2] Derived from [17.1] Follow Compound The procedure described in the synthesis of [1.2] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 12% ethyl acetate in hexane as eluent). MS (ES): m / z 196.3 [M+H]+. []

[0256] [I-17] [The synthesis]. compound [I-17] Derived from [17.2] and [Int-2] follow compound The procedure described in the synthesis of [I-1] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3% methanol in dichloromethane as eluent). MS (ES): m / z: 434.4 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.56-10.50 (m, 2H), 8.18-8.16 (d,J = 5.6 Hz, 1H), 7.67 (s, 1H), 7.35-7.16 (m, 2H), 6.84-6.78 (t,J = 7.6 Hz, 1H), 6.64 (bs, 1H), 5.92 (s, 1H), 3.61 (bs , 3H), 3.42 (s, 3H), 2.04 (s, 3H), 1.27 (s, 9H). [example]

[18] [:] N-(4-((2-((3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)amino)-1,7-dimethyl-1H -Benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0257] [I-18] [The synthesis]. compound [I-18] Derived from [17.2] and [Int-3] follow compound The procedure described in the synthesis of [I-2] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3% methanol in dichloromethane as eluent). MS (ES): m / z: 448.4 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.53-10.48 (t, 1H), 8.76 (s, 1H), 8.15-8.12 ( m, 1H), 7.58 (s, 1H), 7.07-7.05 (d, J = 8.0 Hz, 1H), 6.78-6.74 (t, 1H), 6.56-6.55 (d, J = 5.6 Hz, 1H), 6.07 (s, 1H), 3.72 (s, 3H), 3.61 (bs, 3H), 2.37 (s, 3H), 2.03 (s, 3H), 1.26 (s, 9H). [example]

[19] [:] (S )-N-(4-((2-((3-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-5-yl)amino)- 1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0258] [compound]

[19] . [1] [The synthesis]. A round bottom flask equipped with a Dean-Stark apparatus and a condenser was charged with 5-(t-butyl)-1H-pyrazol-3-amine (

[17] . [1] , 5.0 g, 35.92 mmol, 1.0 equiv), 2,5-hexanedione (4.09 g, 35.92 mmol, 1.0 equiv), toluene (100 mL) and a few drops of acetic acid (catalytic). The reaction mixture was heated to reflux for 3 hours. Allow to cool to room temperature and concentrate under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 12% ethyl acetate in hexane as eluent) to give

[19] . [1] . MS (ES): m / z 218.3 [M+H]+.

[0259] [compound]

[19] . [3] [and] [19.4] [The synthesis]. Will

[19] . [1] (2.5 g, 11.50 mmol, 1.0 equiv),

[19] . [2] A mixture of (1.91 g, 11.50 mmol, 1.0 eq) and cesium carbonate (7.49 g, 23 mmol, 2.0 eq) in DMF (15 mL) was stirred at 70°C for 12 h under nitrogen. It was poured into ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2% ethyl acetate in hexane as eluent) to give

[19] . [3]. MS (ES): m / z 287.4 [M+H]+ and

[19] . [4]. MS (ES): m / z 248.3 [M+H]+.

[0260] [compound]

[19] . [5] [Synthesis] by microwave reactor

[19] . [3] A solution of (0.100 g, 0.347 mmol, 1.0 eq) and hydroxylamine hydrochloride (0.239 g, 3.47 mmol, 10 eq) in ethanol-water (2 / 1, v / v, 3 mL) was stirred at 120°C 1 h. It was poured into ice-water, and the pH was adjusted to about 10 by adding 2 N aqueous sodium hydroxide solution. The mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give

[19] . [5]. MS (ES): m / z 210.3 [M+H]+.

[0261] [compound]

[19] . [6] [The synthesis]. compound [19.6] is from [19.5] Following compounds The procedure described in the synthesis of [1.2] was prepared. MS (ES): m / z 252.3 [M+H]+.

[0262] [I-19] [The synthesis]. compound [I-19] Derived from [19.6] and [Int-2] follow compound The procedure described in the synthesis of [I-2] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 1.4% methanol in dichloromethane as eluent). MS (ES): m / z: 490.85 [M+H]+ ,1 H NMR (CDCl3 , 400 M Hz): δ 8.14-8.12 (d,J = 5.6 Hz, 1H), 7.99 (bs, 1H), 7.82 (bs, 1H), 7.17-7.15 (d, J = 7.6 Hz, 1H), 6.86-6.84 (d, J = 8.0 Hz, 1H), 6.64 (bs, 1H), 5.27 (bs, 1H), 4.39 (bs, 1H), 4.25 (bs, 1H), 4.14 (bs, 2H), 4.02 (bs, 1H), 3.49 (s, 3H), 2.54 (bs, 2H), 2.20 (s, 3H), 1.35 ( s, 9H). [example]

[20] [:] (S )-N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)- 1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0263] [compound]

[20] . [1] [The synthesis]. compound [20.1] Derived from compound [19.4] Following compounds The procedure described in the synthesis of [19.5] was prepared. MS (ES): m / z 210.3 [M+H]+.

[0264] [compound]

[20] . Synthesis of [2]. compound [20.2] Derived from compound [20.1] follow The procedure described in the synthesis of [11.8] was prepared. The crude product was used without further purification. MS (ES): m / z 252.3 [M+H]+.

[0265] [compound] [I-20] [The synthesis]. compound [I-20] from [20.2] and [Int-2] follow compound The procedure described in the synthesis of [I-1] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 1.5% methanol in dichloromethane as eluent). MS (ES): m / z: 490.25 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 9.51 (s, 1H), 8.14-8.13 (d, J = 6.0 Hz, 1H), 7.64 (s, 1H), 7.36-7.34 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 7.08-7.06 (d, J = 8 Hz, 1H), 6.81-6.79 (m, 1H), 6.61-6.60 (d, J = 3.6 Hz, 1H), 5.22 (bs, 1H), 4.08-4.07 (m, 2H), 3.99-3.95 (m, 1H), 3.85- 3.82 (m, 2H), 3.62 (s, 3H), 2.24 (bs, 1H), 2.02 (s, 3H), 1.39 (s, 9H). [example] [twenty one] [:] (S )-N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)- 7-cyano-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0266] [I-21] [The synthesis]. compound [I-21] Department of [20.2] and [Int-4] follow compound The procedure described in the synthesis of [I-1] was prepared. The product was purified by preparative HPLC. MS (ES): m / z: 515.8 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.60 (s, 1H), 9.88 (s, 1H), 8.22-8.20 (d, J = 5.6 Hz, 1H), 7.68 (s, 1H), 7.65 (s, 1H), 7.02-7.00 (d, J = 8.4 Hz, 1H), 6.70-6.68 (m, 1H), 6.51 (s, 1H ), 5.25 (bs, 1H), 4.10-4.07 (m, 2H), 3.91 (s, 3H), 3.87-3.81 (m, 2H), 2.37-2.34 (m, 1H), 2.24-2.20 (m, 1H ), 2.04 (s, 3H), 1.39 (s, 9H). [example] [twenty two] [:] (S )-N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)- 3-Methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)pyridin-2-yl)acetamide

[0267] [I-22] [The synthesis]. compound [I-22] Derived from [20.2] and [Int-5] follow compound The procedure described in the synthesis of [I-1] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.2% methanol in dichloromethane as eluent). MS (ES): m / z: 491.45 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.54 (s, 1H), 9.81 (s, 1H), 8.19-8.18 (d, J = 5.6 Hz, 1H), 7.79-7.77 (d,J = 8 Hz, 1H), 7.75 (s, 1H), 6.84-6.82 (d,J = 8 Hz, 1H), 6.71-6.70 (d,J = 4 Hz, 1H), 6.56 (s, 1H), 5.24 (bs, 1H), 4.08 (bs, 2H), 3.87-3.81 (m, 2H), 3.59 (s, 3H), 2.33 (bs, 1H) , 2.25-2.22 (m, 1H), 2.04 (s, 3H), 1.39 (s, 9H). [example] [twenty three] [:] (R )-N -(4-((2-((3-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-5-yl)amino)- 1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0268] [compound] [twenty three] . [2] [and] [twenty three] . [3] [The synthesis]. compound [23.2] and [23.3] Derived from compound [19.1] and [23.1] Following compounds [19.3] and The procedure described in the synthesis of [19.4] was prepared. The isomers were separated by flash column chromatography on silica gel (CombiFlash®, 2% ethyl acetate in hexane as eluent) to give [twenty three] . [2] . MS (ES): m / z 287.4 [M+H]+ and [twenty three] . [3]. MS (ES): m / z 248.3 [M+H]+.

[0269] [I-23] [The synthesis]. compound [I-23] Derived from [23.2] Following compounds [I-19] was prepared according to the procedures described in each step of the synthesis. The product was purified by flash column chromatography on silica gel (CombiFlash®, 1.5% methanol in dichloromethane as eluent). MS (ES): m / z: 490.80 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.58 (s, 1H), 10.51 (s, 1H), 8.16-8.15 (d, J = 5.2 Hz, 1H), 7.65 (bs, 1H), 7.17-7.15 (d, J = 8.4 Hz, 1H), 7.07 (s, 1H), 6.80-6.78 (d, J = 8.0 Hz, 1H), 6.63 (bs, 1H), 5.21 (bs, 1H), 4.01-3.99 (m, 2H), 3.83-3.77 (m, 2H), 3.65 (bs, 1H), 3.39 (s, 3H), 2.22-2.20 ( m, 2H), 2.03 (s, 3H), 1.26 (s, 9H). [example] [twenty four] [:] (R )-N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)- 1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0270] [compound] [I-24] [The synthesis]. compound [I-24] Derived from [23.3] Following compounds [I-20] was prepared according to the procedures described in each step of the synthesis. The product was purified by flash column chromatography on silica gel (CombiFlash®, 1.5% methanol in dichloromethane as eluent). MS (ES): m / z: 490.37 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 9.56 (s, 1H), 8.16-8.14 (d, J = 5.6 Hz, 1H), 7.65 (s, 1H), 7.38-7.36 (d, J = 8.4 Hz, 1H), 7.19 (s, 1H), 7.10-7.04 (d, J = 8 Hz, 1H), 6.84-6.82 (m, 1H), 6.62-6.61 (d, J = 3.6 Hz, 1H), 5.24 (bs, 1H), 4.10-4.07 (m, 2H), 4.01-3.96 (m, 1H), 3.89- 3.83 (m, 2H), 3.63 (s, 3H), 2.24 (bs, 1H), 2.03 (s, 3H), 1.39 (s, 9H). [example]

[25] [:] (R )-N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)- 7-cyano-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0271] [compound] [I-25] [The synthesis]. compound [I-25] Derived from [Int-4] and [24.2] Following compounds The procedure described in the synthesis of [I-1] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 1.8% methanol in dichloromethane as eluent). MS (ES): m / z: 515.36 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.60 (s, 1H), 9.88 (s, 1H), 8.22-8.20 (d, J = 5.6 Hz, 1H), 7.68 (s, 1H), 7.66 (s, 1H), 7.02-7.00 (d, J = 8.4 Hz, 1H), 6.70-6.68 (m, 1H), 6.51 (s, 1H ), 5.25 (bs, 1H), 4.10-4.07 (m, 2H), 3.91 (s, 3H), 3.88-3.84 (m, 2H), 2.37-2.34 (m, 1H), 2.23-2.22 (m, 1H ), 2.04 (s, 3H), 1.39 (s, 9H). [example]

[26] [:] (R )-N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)- 3-Methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)pyridin-2-yl)acetamide

[0272] [compound] [I-26] [The synthesis]. compound [I-26] Derived from [Int-5] and [24.2] follow The procedure described in the synthesis of [I-1] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.1% methanol in dichloromethane as eluent). MS (ES): m / z: 491.40 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.54 (s, 1H), 9.81 (s, 1H), 8.19-8.18 (d, J = 5.6 Hz, 1H), 7.79-7.77 (d,J = 8 Hz, 1H), 7.75 (s, 1H), 6.84-6.82 (d,J = 8 Hz, 1H), 6.71-6.70 (d,J = 4 Hz, 1H), 6.56 (s, 1H), 5.24 (bs, 1H), 4.08 (bs, 2H), 3.85-3.81 (m, 2H), 3.59 (s, 3H), 2.33 (bs, 1H) , 2.25-2.20 (m, 1H), 2.04 (s, 3H), 1.39 (s, 9H). [example]

[27] [:] N-(4-((2-((5-(tert-butyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl)amino )-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0273] [compound]

[27] . [2] [The synthesis]. To tetrahydro-2H-pyran-4-ol (

[27] . [1] , [4] .0 g, 39.16 mmol, 1.0 equiv) in dichloromethane (40 mL) and triethylamine (13.64 mL, 97.9 mmol, 2.5 equiv) was slowly added methanesulfonyl chloride (3.61 mL, 46.99 mmol, 1.2 equiv). The reaction mixture was allowed to warm to room temperature and stirred for 6 h. It was poured on ice-water, stirred and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 20% ethyl acetate in hexane as eluent) to give

[27] . [2] . MS (ES): m / z 181.2 [M+H]+.

[0274] [compound]

[27] . [3] [and]

[27] . [4] [The synthesis]. compound [27.3] and [27.4] from [27.2] and [19.1] Following compounds [19.3] and The procedure described in the synthesis of [19.4] was prepared. The isomers were separated by flash column chromatography on silica gel (CombiFlash®, 8%-12% ethyl acetate in hexane as eluent) to obtain

[27] . [3]. MS (ES): m / z 302.4 [M+H]+ and

[27] . [4]. MS (ES): m / z 302.3 [M+H]+.

[0275] [compound] [I-27] [The synthesis]. compound [I-27] is derived from the compound [27.4] follow [I-20] was prepared according to the procedures described in each step of the synthesis. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.5% methanol in dichloromethane as eluent). MS (ES): m / z: 503.85 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 9.48 (s, 1H), 8.16-8.14 (d, J = 5.6 Hz, 1H), 7.65 (s, 1H), 7.37-7.35 (d, J = 8.4 Hz, 1H), 7.17 (s, 1H), 6.82-6.80 (d, J = 8.4 Hz, 1H), 6.62-6.61 (d,J = 3.6 Hz, 1H), 6.51 (s, 1H), 4.50 (bs, 1H), 3.98-3.96 (m, 2H), 3.64 (s, 3H), 3.59-3.53 (m, 2H), 2.21-2.16 (m, 2H), 2.04 (s, 3H), 1.79-1.76 (m, 2H), 1.40 (s, 9H). [example]

[28] [:] N-(4-((2-((5-(tert-butyl)-1-(((1s ,3s )-3-hydroxycyclobutyl)methyl)-1H-pyrazole-3 -yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0276] [compound]

[28] . [2] [The synthesis]. at 0°C to

[28] . [4] To a solution of (5 g, 39.02 mmol, 1.0 equiv) in methanol (25 mL) was added sodium borohydride (2.21 g, 58.53 mmol, 1.5 equiv) in small portions. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. It was poured on ice-water, stirred and the pH was adjusted to 4-5 by adding 1 N hydrochloric acid. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain

[28] . [2] . The crude product was used in the next step without further purification. MS (ES): m / z 131.2 [M+H]+.

[0277] [compound]

[28] . [3] [The synthesis]. Towards

[28] . [2] To a solution of (3.6 g, 27.66 mmol, 1.0 equiv) in dichloromethane (36 mL) was added imidazole (2.82 g, 41.49 mmol, 1.5 equiv), followed by addition of tertiary butyldimethylsilyl chloride ( 6.22 g, 41.49 mmol, 1.5 eq) and stirred at room temperature for 12 h. It was poured on saturated sodium bicarbonate solution, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 10% ethyl acetate in hexane as eluent) to give

[28] . [3] [. ] 1 H NMR (CDCl3 , 400 MHz): δ 4.19-4.14 (m, 1H), 3.69 (s, 3H), 2.57-2.46 (m, 3H), 2.25-2.17 (m, 2H), 0.89 (s, 9H), 0.05 (s, 6H).

[0278] [compound]

[28] . [4] [The synthesis]. at 0°C to

[28] . [3] To a solution of (4.1 g, 16.78 mmol, 1.0 equiv) in ether (40 mL) was added a solution of lithium aluminum hydride (1 M in THF, 20.1 mL, 20.13 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, water (4 mL) and 15% sodium hydroxide (12 mL) were added and stirred for 30 min. The reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 30% ethyl acetate in hexane as eluent) to give

[28] . [4]. 1 H NMR (CDCl3 , 400 MHz): δ 4.22-4.15 (m, 1H),3.66-3.62 (m, 2H), 2.41-2.35 (m, 2H), 2.15-2.11 (m, 1H), 2.02-1.94 (m, 1H), 1.73-1.66 (m, 2H), 0.91 (s, 9H), 0.06 (s, 6H).

[0279] [compound]

[28] . [5] [The synthesis]. at 0°C to

[28] . [4] To a solution of (2.3 g, 10.63 mmol, 1.0 eq) in dichloromethane (25 mL) was added triethylamine (4.44 mL, 31.89 mmol, 3.0 eq) followed by methanesulfonyl chloride (2.45 mL, 31.89 mmol, 3.0 equivalents), and stirred at room temperature for 3 h. It was poured onto ice, stirred and extracted with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate solution, then brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 12% ethyl acetate in hexane as eluent) to give

[28] . [5]. 1 H NMR (CDCl3 , 400 MHz): δ 4.24-4.16 (m, 3H), 3.03 (s, 3H), 2.45-2.39 (m, 1H), 2.20-2.14 (m, 1H), 1.78-1.69 (m , 3H), 0.89 (s, 9H), 0.05 (s, 6H). []

[0280] [compound]

[28] . [6] [and]

[28] . [7] [The synthesis]. Towards

[19] . [1] (2.0 g, 9.20 mmol, 1.0 equiv) and

[28] . [5] To a solution of (3.25 g, 11.04 mmol, 1.2 equiv) in DMF (7 mL) was added cesium carbonate (5.98 g, 18.40 mmol, 2.0 equiv), and the reaction mixture was stirred at 80°C for 16 h. It was poured on ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 6%-8% ethyl acetate in hexane as eluent) to give

[28] . [6]. MS (ES): m / z 416.7 [M+H]+ and

[28] . [7] (0.500 g, yield: 13.07%). MS (ES): m / z 416.6 [M+H]+.

[0281] [compound]

[28] . [8] [The synthesis]. in a microwave reactor

[28] . [7] A solution of (0.500 g, 1.2 mmol, 1.0 eq) and hydroxylamine hydrochloride (0.828 g, 12 mmol, 10 eq) in ethanol:water (2:1, 10 mL) was stirred at 120°C for 1 h. It was poured on ice-water, neutralized by 2 N sodium hydroxide and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a chiral mixture, which was separated by preparative HPLC to obtain

[28] . [8] . MS (ES): m / z 224.3 [M+H]+ and

[28] . [9] . MS (ES): m / z 224.2 [M+H]+.

[0282] [compound]

[28] . [9] [The synthesis]. compound [28.9] from [28.8] follow The procedure described in the synthesis of [1.2] was prepared. The crude product was used in the next step without purification. MS (ES): m / z 266.4 [M+H]+.

[0283] [I-28] [The synthesis]. compound [I-28] is derived from the compound [28.9] follow [I-1] was prepared according to the procedures described in each step of the synthesis. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.5% methanol in dichloromethane as eluent). MS (ES): m / z: 504.9 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 9.39 (s, 1H), 8.14-8.13 (d, J = 5.2 Hz, 1H), 7.64 (s, 1H), 7.35-7.33 (d, J = 8.4 Hz, 1H), 7.16 (s, 1H), 6.81-6.78 (d, J = 8.4 Hz, 1H), 6.61-6.60 (d,J = 4 Hz, 1H), 6.50 (s, 1H), 5.02-5.01 (d,J = 6.4 Hz, 1H), 4.08-4.07 (d,J = 5.2 Hz, 2H), 3.93 -3.91 (m, 1H), 3.62 (s, 3H), 2.32-2.29 (m, 3H), 2.02 (s, 3H), 1.70-1.68 (m, 2H), 1.37 (s, 9H). [example]

[29] [:] N-(4-((2-((5-(tert-butyl)-1-((1r ,3r )-3-hydroxycyclobutyl)-1H-pyrazol-3-yl)amine Base)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0284] [compound]

[29] . [2] [Synthesis] [] at 0°C to

[29] . [1] To a solution of (3.0 g, 16.83 mmol, 1.0 equivalent) in dichloromethane (30 mL) and triethylamine (3.0 mL, 21.87 mmol, 1.3 equivalent) was added methanesulfonyl chloride (1.7 mL, 21.87 mmol , 1.3 equivalent). The reaction mixture was allowed to warm to room temperature and stirred for 12 h. It was poured on ice-water, stirred and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 20% ethyl acetate in hexane as eluent) to give

[29] . [2] . MS (ES): m / z 257.3 [M+H]+.

[0285] [compound]

[29] . [3] [,]

[29] . [4] [,]

[29] . [5] [and]

[29] . [6] [The synthesis]. compound

[29] . [3] [,]

[29] . [4] [,]

[29] . [5] and

[29] . [6] Derived from the compound [19.1] and [29.2] Following compounds [19.3] and The procedure described in the synthesis of [19.4] was prepared. The isomers were separated by flash column chromatography on silica gel (CombiFlash®, 8%-12% ethyl acetate in hexane as eluent). MS (ES): m / z 378.5 [M+H]+.

[0286] [compound]

[29] . [9] [The synthesis]. compound [29.9] from [29.5] Following compounds [I-20] was prepared according to the procedures described in each step of the synthesis. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.2% methanol in dichloromethane as eluent). MS (ES): m / z 580.7 [M+H]+. []

[0287] [I-29] [The synthesis]. compound

[29] . A mixture of [9] (0.070 g, 0.120 mmol, 1.0 equiv) and 20% palladium hydroxide on carbon (0.150 g) in methanol (5 mL) was stirred under 1 atm of hydrogen at room temperature for 12 h. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (CombiFlash®, 5% methanol in dichloromethane as eluent) to give [I-29]. MS (ES): m / z: 490.51 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 9.53 (s, 1H), 8.16-8.14 (d, J = 5.2 Hz, 1H), 7.65 (s, 1H), 7.38-7.36 (d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 6.83-6.81 (d, J = 7.6 Hz, 1H), 6.62-6.61 (d,J = 3.6 Hz, 1H), 6.50 (s, 1H), 5.19-5.18 (m, 2H), 4.46 (bs, 1H), 3.64 (s, 3H), 2.74 (bs, 2H) , 2.33 (bs, 2H), 2.03 (s, 3H), 1.36 (s, 9H). [example]

[30] [:] N-(4-((2-((5-(tert-butyl)-1-((1s ,3s )-3-hydroxycyclobutyl)-1H-pyrazol-3-yl)amine Base)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0288] [compound] [I-30] [The synthesis]. compound [I-30] from [29.6] with It was prepared in the same manner as in the synthesis of [I-29]. The product was purified by flash column chromatography on silica gel (CombiFlash®, 5% methanol in dichloromethane as eluent). MS (ES): m / z: 490.46 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 9.53 (s, 1H), 8.15-8.13 (d, J = 5.6 Hz, 1H), 7.64 (s, 1H), 7.36-7.34 (d, J = 8.4 Hz, 1H), 7.17 (s, 1H), 6.82-6.80 (d, J = 7.6 Hz, 1H), 6.61-6.60 (d,J = 3.6 Hz, 1H), 6.48 (s, 1H), 5.20-5.19 (m, 2H), 4.03-4.01 (m, 1H), 3.63 (s, 3H), 3.50-3.48 ( m, 2H), 2.62 (bs, 2H), 2.02 (s, 3H), 1.35 (s, 9H). [example]

[31] [:] N -(4-((2-((5-(tert-butyl)-1-(oxetan-3-ylmethyl)-1H-pyrazol-3-yl)amino) -1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0289] [compound]

[31] . [2] [and]

[31] . [3] [The synthesis]. at 0°C to

[31] . [1] To a solution of (0.4 g, 2.65 mmol, 1.0 equiv) in DMF (5 mL) was added sodium hydride (0.165 g, 3.45 mmol, 1.3 equiv) and stirred for 30 min. Add to this solution

[17] . [1] (0.0.368 g, 2.65 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 16 h. It was poured on ice, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain

[31] . [2] . MS (ES): m / z 210.3 [M+H]+ and

[31] . [3]. MS (ES): m / z 210.3 [M+H]+.

[0290] compound

[31] . [4] [The synthesis]. compound [31.4] from [31.2] follow The procedure described in the synthesis of [11.8] was prepared. MS (ES): m / z 252.3 [M+H]+.

[0291] [I-31] [The synthesis]. compound [31.4] from [31.4] and [Int-2] follow compound The procedure described in the synthesis of [I-1] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3%-4% methanol in dichloromethane as eluent). MS (ES): m / z 489.8 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 9.41 (s, 1H), 8.15-8.13 (d, J = 5.6 Hz, 1H), 7.64 (s, 1H), 7.36-7.34 (d,J = 8.4 Hz, 1H), 7.17 (s, 1H), 6.82-6.80 (d,J = 7.6 Hz, 1H ), 6.60 (s, 1H), 6.48 (s, 1H), 4.71-4.67 (m, 2H), 4.56-4.54 (m, 2H), 4.42-4.40 (m, 2H), 3.60 (bs, 3H), 3.50-3.47 (m, 1H), 2.02 (s, 3H), 1.37 (s, 9H). [example]

[32] [:] N -(4-((2-((5-(tert-butyl)-1-(oxetan-3-ylmethyl)-1H-pyrazol-3-yl)amino) -7-cyano-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0292] [I-32] [The synthesis]. compound [I-32] Derived from [31.4] and [Int-4] follow compound The procedure described in the synthesis of [I-1] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.0% methanol in dichloromethane as eluent). MS (ES): m / z: 515.15 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.61 (s, 1H), 9.79 (s, 1H), 8.22 (bs, 1H) , 7.68-7.58 (m, 2H), 7.04 (bs, 1H), 6.70 (bs, 1H), 6.51-6.48 (m, 1H), 4.69 (bs, 2H), 4.54 (bs, 2H), 4.29 (bs , 2H), 3.90 (s, 3H), 3.77 (s, 1H), 2.04 (s, 3H), 1.38 (s, 9H). [example]

[33] [:] N -(4-((1-methyl-2-((1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)-1H - Pyrazol-3-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0293] [compound]

[33] . [1] [The synthesis]. To a solution of 1,1,1-triethoxyethane (20 g, 123.28 mmol, 1.0 equiv) and pyridine (21 mL, 258.8 mmol, 2.1 equiv) in dichloromethane (200 mL) at 0°C Trifluoroacetic anhydride (52 g, 246.57 mmol, 2.0 equiv) was added to . The reaction solution was allowed to warm to room temperature and stirred for 16 h. It was poured on saturated sodium bicarbonate solution, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain

[33] . [1] . MS (ES): m / z 213.2 [M+H]+.

[0294] [compound]

[33] . [2] [The synthesis]. at 0°C to

[33] . [1] To a solution of (14.2 g, 66.93 mmol, 1.0 equiv) in acetonitrile (150 mL) was added an aqueous ammonia solution (28 mL). The reaction mixture was allowed to warm to room temperature and stirred for 24 h. It was poured on ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude, which was triturated with n-pentane to obtain

[33] . [2] . MS (ES): m / z 184.2 [M+H]+. []

[0295] [compound]

[33] . [3] [The synthesis]. Towards

[33] . [2] To a solution of (7.0 g, 38.22 mmol, 1.0 equiv) in ethanol (70 mL) was added triethylamine (5.3 mL, 38.22 mmol, 1.0 equiv), followed by addition of hydrazine hydrochloride (2.61 g, 38.22 mmol , 1.0 equivalent). The reaction mixture was heated to reflux for 12 h. It was poured on ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 30% ethyl acetate in hexane as eluent) to give

[33] . [3]. MS (ES): m / z 152.1 [M+H]+. []

[0296] [compound]

[33] . [4] [and]

[33] . [5] [The synthesis]. To a solution of 4-(bromomethyl)tetrahydro-2H-pyran (0.7 g, 4.63 mmol, 1.0 equiv) in DMF (8 mL) was added sodium hydride (0.288 g, 6.019 mmol, 1.3 equivalent) and stirred for 30 min. Add to this solution

[33] . [3] (0.829 g, 4.63 mmol, 1.0 equiv). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. It was poured on ice, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain

[33] . [4]. MS (ES): m / z 250.4 [M+H]+ and

[33] . [5]. MS (ES): m / z 250.4 [M+H]+.

[0297] [compound]

[33] . [6] [The synthesis]. compound [33.6] from [33.4] follow The procedure described in the synthesis of [11.8] was prepared. The crude product was used without further purification. MS (ES): m / z 292.3 [M+H]+. []

[0298] [I-33] [The synthesis]. compound [I-33] Department of [33.6] and [Int-2] follow The procedure described in the synthesis of [I-1] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 10% methanol in dichloromethane as eluent). MS (ES): m / z: 530.49 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 10.07 (s, 1H), 8.15-8.13 (d, J = 6.0 Hz, 1H), 7.64 (s, 1H), 7.43-7.41 (d, J = 8.4 Hz, 1H), 7.32 (s, 1H), 7.23 (s, 1H), 6.85-6.83 (d, J = 6.8 Hz, 1H), 6.61-6.60 (d,J = 3.2 Hz, 1H), 4.04-4.02 (m, 2H), 3.87-3.84 (m, 2H), 3.67 (s, 3H), 2.20 (bs, 1H), 2.02 (s, 3H), 1.56 (bs, 1H), 1.48-1.45 (m, 2H), 1.35-1.23 (m, 3H). [example]

[34] [:] N -(4-((7-cyano-1-methyl-2-((1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethane Base)-1H-pyrazol-3-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0299] [I-34] [The synthesis]. compound [I-34] Derived from [33.6] and [Int-4] follow The procedure described in the synthesis of [I-1] was prepared. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 1.8% methanol in dichloromethane as eluent). MS (ES): m / z: 555.42 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.61 (s, 1H), 10.41 (s, 1H), 8.22-8.21 (d, J = 5.6 Hz, 1H), 7.75-7.73 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.30 (s, 1H), 7.07-7.05 (d, J = 8.4 Hz, 1H), 6.71-6.70 (d,J = 4 Hz, 1H), 4.06-4.04 (m, 2H), 3.94 (s, 3H), 3.87-3.85 (m, 2H), 3.27-3.24 (m, 2H), 2.20 ( bs, 1H), 2.04 (s, 3H), 1.48-1.45 (m, 2H), 1.35-1.27 (m, 2H). [example]

[35] [:] N -(4-((2-((1-(((1s ,4s )-4-hydroxycyclohexyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3- Base) amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0300] [compound]

[35] . [2] [The synthesis]. Towards

[35] . [1] To a solution of (5.0 g, 34.68 mmol, 1.0 equivalent) and triethylamine (10.6 mL, 76.29 mmol, 2.2 equivalent) in DMF (30 mL) was added tertiary butyldimethylsilyl chloride (11.5 g , 76.29 mmol, 2.2 equivalents), and stirred at room temperature for 2 h. It was poured on ice-water, acidified to pH = 4 with 1 M hydrochloric acid, and extracted with ether. The organic layer was separated, washed with brine and concentrated under reduced pressure to obtain crude product. The crude product was dissolved in a mixture of methanol and THF (1:1, 20 mL), and 5 M aqueous sodium hydroxide (10 mL) was added at room temperature. The mixture was stirred for 3 h and concentrated to half volume. It was acidified to pH = 4 with 2 M hydrochloric acid and extracted with diethyl ether. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain

[35] . [2] . MS (ES): m / z 259.4 [M+H]+.

[0301] [compound]

[35] . [3] [The synthesis]. at 0°C to

[35] . [2] To a solution of (3.0 g, 11.61 mmol, 1.0 equiv) in THF (30 mL) was added lithium aluminum hydride solution (1 M in THF, 23.2 mL, 23.2 mmol, 2.0 equiv). The reaction mixture was allowed to warm to room temperature and stirred for 3 h. It was carefully poured onto ice-water, neutralized with 1 M hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain

[35] . [3]. MS (ES): m / z 245.5 [M+H]+. []

[0302] [compound]

[35] . [4] [The synthesis]. at 0°C to

[35] . [3] To a solution of (1.7 g, 6.95 mmol, 1.0 equiv) and triethylamine (1.25 mL, 9.035 mmol, 1.3 equiv) in dichloromethane (25 mL) was added methanesulfonyl chloride (1.6 mL, 20.85 mmol , 1.3 equivalent). The reaction solution was allowed to warm to room temperature and stirred for 12 h. It was poured onto ice, stirred and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 5% ethyl acetate in hexane as eluent) to give

[35] . [4]. MS (ES): m / z 323.5 [M+H]+. []

[0303] [compound]

[35] . [5] [and]

[35] . [6] [The synthesis]. at 0°C to

[33] . [3] To a solution of (0.6 g, 3.97 mmol, 1.0 eq) in DMF (8 mL) was added sodium hydride (0.247 g, 5.161 mmol, 1.3 eq) and stirred for 30 min. Add to the mix

[35] . [4] (1.28 g, 3.97 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 16 h. It was poured on ice, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain

[35] . [5]. MS (ES): m / z 378.5 [M+H]+ and

[35] . [6]. MS (ES): m / z 378.5 [M+H]+.

[0304] [compound]

[35] . [7] [The synthesis]. compound [35.7] from [35.5] follow The procedure described in the synthesis of [11.8] was prepared. The crude product was used in the next step without further purification. MS (ES): m / z 420.5 [M+H]+.

[0305] [compound]

[35] . [8] [The synthesis]. compound [35.8] from [35.5] and [Int-2] follow The procedure described in the synthesis of [I-1] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2% methanol in dichloromethane as eluent). MS (ES): m / z 658.8 [M+H]+. []

[0306] [I-35] [The synthesis]. Towards

[35] . To a solution of [8] (0.062 g, 0.094 mmol, 1.0 equiv) in THF (2 mL) was added tetrabutylammonium fluoride solution (1 M in THF, 5 mL). The reaction mixture was stirred at 50 °C for 3 h. Allow to cool to room temperature, pour on ice-water and extract with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 5% methanol in dichloromethane as eluent) to give [I-35]. MS (ES): m / z: 544.57 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 10.06 (s, 1H), 8.15-8.13 (d, J = 5.6 Hz, 1H), 7.64 (s, 1H), 7.43-7.41 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 7.23 (s, 1H), 6.85-6.83 (d, J = 7.2 Hz, 1H), 6.62-6.60 (d,J = 5.2 Hz, 1H), 4.57-4.56 (d, 1H), 4.02-3.95 (m, 2H), 3.67 (s, 3H), 3.03 (bs, 1H), 2.02 (s, 3H), 1.85-1.82 (m, 2H), 1.55 (bs, 2H), 1.34-1.30 (m, 1H), 1.30 (bs, 2H), 1.11-1.03 (m, 2H) . [example]

[36] [:] (S )-N-(4-((1-methyl-2-((1-((tetrahydro-2H-pyran-3-yl)methyl)-5-(trifluoromethyl )-1H-pyrazol-3-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide [and] (R )-N-(4-((1-methyl-2-((1-((tetrahydro-2H-pyran-3-yl)methyl)-5-(trifluoromethyl )-1H-pyrazol-3-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0307] [compound] [(±)-36]. [2] [and] [(±)-36]. [3] [The synthesis]. at 0°C to

[33] . [3] To a solution of (0.5 g, 3.31 mmol, 1.0 eq) in DMF (8 mL) was added sodium hydride (0.206 g, 4.303 mmol, 1.3 eq) and stirred for 30 min. To the mixture was added 3-(bromomethyl)tetrahydro-2H-pyran ( [(±)-36]. [1] , 0.592 g, 3.31 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 16 h. It was poured on ice, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain [(±)-36]. [2] . MS (ES): m / z 250.3 [M+H]+ and [(±)-36]. [3]. MS (ES): m / z 250.3 [M+H]+.

[0308] [compound] [(±)-36]. [4] [The synthesis]. compound [(±)-36]. [4] Derived from [(±)-36]. [2] follow as The procedure described in the synthesis of [11.8] was prepared. The crude product was used in the next step without further purification. MS (ES): m / z 292.3 [M+H]+. []

[0309] compound [(±)-I-36] [The synthesis]. compound [(±)-I-36] Derived from [(±)-36]. [4] and [Int-2] follow The procedure described in the synthesis of [I-1] was prepared. MS (ES): m / z 530.5 [M+H]+. []

[0310] [I-36-a] [and] [I-36-b]. Separation on SFC (column: CHIRALCEL OJ-H (250 mm × 4.6 mm, 5 µm); eluent: 0.1% DEA in methanol; flow rate: 4 mL / min) The enantiomer of [(±)-I-36] obtained the first elution fraction ( [I-36-a] ) and the second elution fraction ( [I-36-b]). (*Absolute stereochemistry not determined.)

[0311] [I-36-a.] MS (ES): m / z: 530.44 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 10.06 (s, 1H ), 8.15-8.13 (d,J = 6 Hz, 1H), 7.64 (s, 1H), 7.43-7.41 (m, 1H), 7.32 (s, 1H), 7.23 (s, 1H), 6.86-6.83 ( d,J = 10.4 Hz, 1H ), 6.62-6.60 (d,J = 6.4 Hz, 1H), 4.07-4.01 (m, 2H), 3.71 (bs, 1H), 3.67 (s, 3H), 3.27-3.23 (m, 2H), 2.19 (bs, 1H), 2.02 (s, 3H), 1.69-1.60 (m, 3H), 1.49 (bs, 1H), 1.34-1.23 (m, 1H).

[0312] [I-36-b.] MS (ES): m / z: 530.49 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 10.08 (s, 1H ), 8.16-8.14 (d,J = 6 Hz, 1H), 7.65 (s, 1H), 7.44-7.42 (d,J = 8.4 Hz, 1H), 7.33 (s, 1H), 7.23 (s, 1H) , 6.86-6.84 (d,J = 8.4 Hz, 1H ), 6.62-6.61 (d,J = 5.6 Hz, 1H), 4.11-4.00 (m, 2H), 3.71 (bs, 1H), 3.68 (s, 3H ), 3.28-3.23 (m, 2H), 2.20 (bs, 1H), 2.03 (s, 3H), 1.70-1.61 (m, 3H), 1.50 (bs, 1H), 1.34-1.24 (m, 1H). [example]

[37] [:] N -(4-((2-((1-(2-oxaspiro[3.3]hept-6-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl) Amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0313] [compound]

[37] . [2] [The synthesis]. at 0°C to

[37] . [1] To a solution of (0.600 g, 5.35 mmol, 1.0 equiv) in methanol (10 mL) was added sodium borohydride (0.203 g, 5.35 mmol, 1.0 equiv) in small portions. The reaction mixture was stirred at 0 °C for 2 h. It was poured on ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain

[37] . [2] . MS (ES): m / z 115.2 [M+H]+.

[0314] [compound]

[37] . [3] [The synthesis]. at 0°C to

[37] . [2] To a solution of (0.540 g, 4.73 mmol, 1.0 eq) and triethylamine (1.64 mL, 11.82 mmol, 2.5 eq) in dichloromethane (10 mL) was added methanesulfonyl chloride (0.71 mL, 9.46 mmol , 2.0 equivalent). The reaction mixture was stirred at room temperature for 12 h. It was poured on ice-water, stirred and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 40% ethyl acetate in hexane as eluent) to give

[37] . [3]. MS (ES): m / z 193.2 [M+H]+. []

[0315] [compound]

[37] . [4] [and]

[37] . [5] [The synthesis]. Towards

[37] . [3] (0.4 g, 2.08 mmol, 1.0 equiv) and

[33] . [3] To a solution of (0.314 g, 2.08 mmol, 1.0 equiv) in DMF (7 mL) was added cesium carbonate (1.352 g, 4.16 mmol, 2.0 equiv), and the reaction mixture was stirred at 80°C for 5 h. It was poured on ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain

[37] . [4]. MS (ES): m / z 248.2 [M+H]+ and

[37] . [5]. MS (ES): m / z 248.3 [M+H]+.

[0316] [compound]

[37] . [6] [The synthesis]. compound [37.6] from [37.4] follow The procedure described in the synthesis of [11.8] was prepared. The crude product was used in the next step without further purification. MS (ES): m / z 290.2 [M+H]+.

[0317] [I-37] [The synthesis]. compound [I-37] Department of [37.6] follow The procedure described in the synthesis of [I-1] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 1.5% methanol in dichloromethane as eluent). MS (ES): m / z: 527.8 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 10.10 (s, 1H), 8.15-8.13 (d, J = 6.0 Hz, 1H), 7.64 (s, 1H), 7.42-7.40 (d, J = 8.4 Hz, 1H), 7.32 (s, 1H), 7.23-7.22 (d, J = 1.6 Hz, 1H), 6.85-6.83 (m, 1H), 6.62-6.60 (m, 1H), 4.70 (s, 2H), 4.58 (s, 2H), 3.67 (s, 3H), 3.41-3.39 (m, 1H), 2.80- 2.78 (m, 4H), 2.02 (s, 3H). [example]

[38] [:] N -(4-((2-((1-(((1r ,4r )-4-hydroxycyclohexyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3- Base) amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide []

[0318] [compound]

[38] . [2] [The synthesis]. Towards

[38] . [1] To a solution of (5.0 g, 29.03 mmol, 1.0 equivalent) and imidazole (5.0 g, 72.57 mmol, 1.2 equivalent) in DMF (25 mL) was added tertiary butyldimethylsilyl chloride (5.2 g, 34.83 mmol, 1.2 equivalents), and stirred at room temperature for 16 h. It was poured on saturated sodium bicarbonate solution, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 10% ethyl acetate in hexane as eluent) to give

[38] . [2] . MS (ES): m / z 287.5 [M+H]+.

[0319] [compound]

[38] . [3] [The synthesis]. at 0°C to

[38] . [2] To a solution of (4.2 g, 14.66 mmol, 1.0 equiv) in ether (42 mL) was added a solution of lithium aluminum hydride (1 M in THF, 16.1 mL, 16.12 mmol, 1.1 equiv). The reaction mixture was allowed to warm to room temperature and stirred for 4 h. It was carefully poured onto ice, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain

[38] . [3]. MS (ES): m / z 245.5 [M+H]+. []

[0320] [compound]

[38] . [4] [The synthesis]. compound [38.4] from [38.3] follow The procedure described in the synthesis of [35.4] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 12% ethyl acetate in hexane as eluent). MS (ES): m / z 323.5 [M+H]+. []

[0321] [compound]

[38] . [5] [and]

[38] . [6] [The synthesis]. compound [38.5] and [38.6] from [38.4] and 33.3 follow [35.5] and [35.6] was prepared by the procedure described in the synthesis of [35.6]. The isomers were separated by preparative HPLC to obtain

[38] . [5]. MS (ES): m / z 378.5 [M+H]+ and

[38] . [6]. MS (ES): m / z 378.5 [M+H]+.

[0322] [compound]

[38] . [7] [The synthesis]. compound

[38] . [7] Derived from [38.5] follow The procedure described in the synthesis of [11.8] was prepared. The crude product was used in the next step without further purification. MS (ES): m / z 420.5 [M+H]+. []

[0323] [compound]

[38] . [8] [The synthesis]. compound [38.8] from [38.7] and [Int-2] follow The procedure described in the synthesis of [I-2] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2% methanol in dichloromethane as eluent). MS (ES): m / z 658.8 [M+H]+. []

[0324] [compound] [I-38] [The synthesis]. compound [I-38] Follows from 38.8 The procedure described in the synthesis of [I-35] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 5% methanol in dichloromethane as eluent). MS (ES): m / z: 544.49 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 10.05 (s, 1H), 8.15-8.13 (d, J = 5.6 Hz, 1H), 7.64 (s, 1H), 7.43-7.41 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 7.22 (s, 1H), 6.85-6.83 (d, J = 7.2 Hz, 1H), 6.62-6.60 (d,J = 5.2 Hz, 1H), 4.56-4.55 (d, 1H), 4.04-4.02 (m, 2H), 3.67 (s, 3H), 2.02 (s, 3H), 1.85-1.82 (m, 2H), 1.55 (bs, 2H), 1.34-1.30 (m, 1H), 1.30 (bs, 2H), 1.11-1.03 (m, 2H). [example]

[39] [:] N -(4-((2-((1-(2-Acetyl-2-azaspiro[3.3]hept-6-yl)-5-(trifluoromethyl)-1H-pyridine Azol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0325] [compound]

[39] . [2] [The synthesis]. at 0°C to

[39] . [1] To a solution of (2.0 g, 9.47 mmol, 1.0 equiv) in methanol (20 mL) was added sodium borohydride (1.439 g, 37.88 mmol, 4.0 equiv) in small portions. The reaction mixture was stirred at 0 °C for 2 h. It was poured on ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain

[39] . [2] . MS (ES): m / z 214.3 [M+H]+.

[0326] [compound]

[39] . [3] [The synthesis]. at 0°C to

[39] . [2] To a solution of (1.6 g, 7.5 mmol, 1.0 eq) and triethylamine (1.35 mL, 9.75 mmol, 1.3 eq) in dichloromethane (20 mL) was added methanesulfonyl chloride (0.75 mL, 9.75 mmol , 1.3 equivalent). The reaction mixture was stirred at room temperature for 12 h. It was poured on ice-water, stirred and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give

[39] . [3]. MS (ES): m / z 292.3 [M+H]+. []

[0327] [compound]

[39] . [4] [and]

[39] . [5] [The synthesis]. compound [39.4] and [39.5] from [39.3] and [17.1] follow [37.4] and [37.5] was prepared using the procedure described in the synthesis of [37.5]. The isomers were separated by preparative HPLC to obtain

[39] . [4] ,MS (ES):m / z 347.3 [M+H]+ and

[39] . [5] , MS (ES): m / z 347.3 [M+H]+.

[0328] [compound]

[39] . [6] [The synthesis]. compound [39.6] from [39.4] follow The procedure described in the synthesis of [11.8] was prepared. The crude product was used in the next step without further purification. MS (ES): m / z 389.4 [M+H]+.

[0329] [compound]

[39] . [7] [The synthesis]. compound [39.7] from [39.6] follow The procedure described in the synthesis of [I-2] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 1.5% methanol in dichloromethane as eluent). MS (ES): m / z: 627.6 [M+H]+.

[0330] [compound]

[39] . [8] [The synthesis]. at 0°C to

[39] . To a solution of [7] (0.110 g, 0.175 mmol, 1.0 equiv) in dichloromethane (5 mL) was added trifluoroacetic acid (0.199 g, 1.75 mmol, 10.0 equiv). The reaction mixture was stirred at room temperature for 2 h. It was poured onto ice-cold saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain

[39] . [8] . MS (ES): m / z 526.5 [M+H]+.

[0331] [I-39] [The synthesis]. at 0°C to

[39] . [8] Acetic anhydride (0.014 g, 0.140 mmol , 1.0 equivalent). The reaction mixture was stirred for 15 min. It was poured on ice-water, stirred and extracted with dichloromethane. This was further purified by flash column chromatography on silica gel (CombiFlash®, 0.5% methanol in dichloromethane as eluent) to give [I-39]. MS (ES): m / z: 569.5 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.50 (s, 1H), 10.14 (s, 1H), 8.15-8.14 (d, J = 5.6 Hz, 1H), 7.64-7.40 (m, 2H), 7.32 (s, 1H), 7.23 (s, 1H), 6.86-6.83 (d, J = 8.8 Hz, 1H), 6.62-6.61 (d ,J = 4.4 Hz, 1H), 4.94-4.85 (m, 1H), 4.25 (s, 1H), 4.14 (s, 1H), 4.05-3.97 (m, 1H), 3.87 (s, 1H), 3.67 ( s, 3H), 2.82 (s, 3H), 2.74 (bs, 1H), 2.02 (s, 3H), 1.75-1.74 (m, 3H). [example]

[40] [:] N -(4-((2-((4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)amino )-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0332] [compound]

[40] . [2] [The synthesis]. at -78°C to

[40] . [1] Add lithium bis(trimethylsilyl)amide (1 M in THF, 219 mL, 219.7 mmol, 2.2 equiv). The reaction mixture was stirred at room temperature for 16 h. It was poured on ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 10% ethyl acetate in hexane as eluent) to give

[40] . [2] . MS (ES): m / z 129.2 [M+H]+. []

[0333] [compound]

[40] . [3] [The synthesis]. To a solution of diisopropylamine (4.88 g, 48.37 mmol, 1.0 equiv) in THF (100 mL) was slowly added a solution of n-butyllithium (2.5 M in hexane, 24.2 mL, 60.46 mmol, 1.25 equiv). The reaction mixture was stirred for 5 min before adding acetonitrile (2.5 mL, 48.37 mmol, 1.0 equiv). The reaction mixture was stirred for 10 min, and to it was added compound in THF (30 mL)

[40] . [3] (6.20 g, 48.37 mmol, 1.0 equiv). The reaction mixture was stirred at 5 °C for 6 h. It was poured on cold saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 20% ethyl acetate in hexane as eluent) to give

[40] . [3]. MS (ES): m / z 170.2 [M+H]+. []

[0334] [compound]

[40] . [4] [The synthesis]. Towards

[40] . [3] To a solution of (3.9 g, 23.05 mmol, 1.0 equiv) in ethanol (40 mL) was added hydrazine hydrochloride (2.35 g, 34.57 mmol, 1.5 equiv), followed by potassium carbonate (4.77 g, 34.57 mmol, 1.5 equiv). The reaction mixture was heated to reflux for 16 h. It was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3%-4% methanol in dichloromethane as eluent) to give

[40] . [4]. MS (ES): m / z 184.26 [M+H]+. []

[0335] [compound]

[40] . [5] [The synthesis]. Towards

[40] . To a solution of [4] (1.1 g, 6.0 mmol, 1.0 equiv) in THF (20 mL) was added thionyl chloride (2.15 mL, 30 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature for 2 h. It was poured on saturated sodium bicarbonate solution, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2% methanol in dichloromethane as eluent) to give

[40] . [5]. MS (ES): m / z 166.24 [M+H]+. []

[0336] [compound]

[40] . [6] [The synthesis]. compound [40.6] from [40.5] follow The procedure described in the synthesis of [1.2] was prepared. The crude product was used in the next step without further purification. MS (ES): m / z 208.3 [M+H]+. []

[0337] [compound] [I-40] [The synthesis]. compound [I-40] from [40.6] follow The procedure described in the synthesis of [I-1] was prepared. The product was purified by preparative HPLC. MS (ES): m / z: 446.41 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 9.48 (s, 1H), 8.15-8.14 (d, J = 5.6 Hz, 1H), 7.65 (s, 1H), 7.38-7.36 (d, J = 8 Hz, 1H), 7.16 (s, 1H), 6.82-6.80 (d, J = 7.6 Hz, 1H), 6.61-6.56 (m, 2H), 3.94 (bs, 2H), 3.62 (s, 3H), 2.03 (s, 6H), 1.68 (s, 3H), 1.25 (bs, 4H). [example]

[41] [:] N -(4-((7-cyano-2-((4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2 -yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0338] [I-41] [The synthesis]. compound [I-41] Department of [40.6] and [Int-4] follow The procedure described in the synthesis of [I-1] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 5%-7% methanol in dichloromethane as eluent). MS (ES): m / z: 470.83 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.59 (s, 1H), 9.85 (s, 1H), 8.22-8.20 (d, J = 5.6 Hz, 1H), 7.68 (bs, 2H), 7.03-7.01 (d, J = 8.4 Hz, 1H), 6.69 (bs, 1H), 6.55 (s, 1H), 4.02-3.90 (m, 4H ), 2.04 (s, 6H), 1.67 (bs, 2H), 1.30 (bs, 6H). [example]

[42] [:] N -(4-((2-((4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)amino )-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)pyridin-2-yl)acetamide

[0339] [I-42] [The synthesis]. compound [I-42] Department of [40.6] and [Int-5] follows The procedure described in the synthesis of [I-1] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 5%-6% methanol in dichloromethane as eluent). MS (ES): m / z: 447.45 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.53 (s, 1H), 9.79 (s, 1H), 8.19-8.17 (d, J = 5.6 Hz, 1H), 7.81-7.75 (m, 2H), 6.84-6.82 (d, J = 8 Hz, 1H), 6.71-6.70 (t, 1H), 6.58 (s, 1H), 5.76 (s , 1H), 3.95-3.93 (m, 2H), 3.58 (s, 3H), 2.04 (bs, 4H), 1.67 (bs, 2H), 1.30 (bs, 6H). [example]

[43] [:] N-(4-((2-((5,5-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-1,7 -Dimethyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0340] [compound]

[43] . [2] [The synthesis]. To 3,3-dimethylcyclohexan-1-one (

[43] . [1] To a solution of , 6.0 g, 47.54 mmol, 1.0 eq) in ethanol (60 mL) was added thiourea (10.86 g, 142 mmol, 3.0 eq) followed by iodine (12.02 g, 47.54 mmol, 1.0 eq) . The reaction mixture was heated to reflux for 8 h. It was poured on ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 25% ethyl acetate in hexane as eluent) to give

[43] . [2] . MS (ES): m / z 183.3 [M+H]+. []

[0341] [compound]

[43] . [3] [The synthesis]. Towards

[43] . [2] To a solution of (0.200 g, 1.1 mmol, 1.0 equiv) in acetonitrile (4 mL) was added thiocarbonyldiimidazole (0.214, 1.208 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the precipitated solid was filtered off and dried sufficiently to obtain

[43] . [3]. MS (ES): m / z 293.4 [M+H]+. []

[0342] [I-43] [The synthesis]. Towards

[43] . [3] (0.100 g, 0.349 mmol, 1.0 equiv) and To a solution of [Int-3] (0.122 g, 0.417 mmol, 1.2 equiv) in DMF (2 mL) was added N,N-diisopropylethylamine (0.2 mL, 1.047 mmol, 3.0 equiv). The reaction mixture was stirred at 70 °C for 6 h. Allow to cool to room temperature, pour on ice-water and extract with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 5% methanol in dichloromethane as eluent) to give [I-43]. MS (ES): m / z: 477.81 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 11.83 (s, 1H), 10.47 (s, 1H), 8.13-8.11 (d, J = 5.2 Hz, 1H), 7.59 (s, 1H), 7.28 (s, 1H), 6.79 (s, 1H), 6.53 (s, 1H), 3.87 (s, 3H), 2.43-2.42 (m, 2H ), 2.27 (s, 3H), 2.03-2.02 (d, 3H), 1.55 (bs, 2H), 1.00 (s, 6H), 0.99-0.84 (m, 2H). [example]

[44] [:] N-(4-((2-((6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-1,7 -Dimethyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0343] [compound]

[44] . [2] [The synthesis]. compound [44.2] is derived from 4,4-dimethylcyclohex-1-one ( [44.1] ) follow [43.2] was prepared by the procedure described in the synthesis of [43.2]. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 30% ethyl acetate in hexane as eluent). MS (ES): m / z 183.3 [M+H]+. []

[0344] [compound]

[44] . [3] [The synthesis]. compound [44.3] from [44.2] follow The procedure described in the synthesis of [43.3] was prepared. The crude product was used in the next step without further purification. MS (ES): m / z 293.4 [M+H]+. []

[0345] [I-44] [The synthesis]. Will

[44] . [3] (0.100 g, 0.349 mmol, 1.0 equiv), [Int-3] (0.113 g, 0.384 mmol, 1.1 equiv) and N,N-diisopropylethylamine (0.2 mL, 1.047 mmol, 3.0 equiv) in DMF (2 mL) were dissolved under nitrogen at 70 Stir at ℃ for 12 h. Allow to cool to room temperature, pour on ice-water and extract with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain [I-44]. MS (ES): m / z: 477.81 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 11.88 (s, 1H), 10.49 (s, 1H), 8.14-8.13 (d, J = 5.6 Hz, 1H), 7.60 (s, 1H), 7.28 (s, 1H), 6.81-6.79 (d, J = 8.4 Hz, 1H), 6.55-6.53 (m, 1H), 3.88 (s, 3H ), 2.43 (bs, 4H), 2.34 (s, 3H), 2.03 (s, 3H), 1.58-1.55 (m, 2H), 1.01 (s, 6H). [example]

[45] [:] (R )-N-(4-((1-methyl-2-((2-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyridin-6-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide [and] (S )-N-(4-((1-methyl-2-((2-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyridin-6-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0346] [compound]

[45] . [2] [The synthesis]. Towards

[45] . [1] To a solution of (8.0 g, 36.36 mmol, 1.0 equiv) in ethanol (50 mL) was added 1-chloropropan-2-one (5.05 g, 54.54 mmol, 1.5 equiv). The reaction mixture was heated to reflux for 24 h. It was concentrated under reduced pressure. The residue was taken up in water and basified to pH 8 with saturated sodium carbonate solution. The aqueous solution was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 50% ethyl acetate in hexane as eluent) to give

[45] . [2] . MS (ES): m / z 259.2 [M+H]+. []

[0347] [compound]

[45] . [3] [The synthesis]. Towards

[45] . [2] To a solution of (4.8 g, 18.16 mmol, 1.0 eq) in acetonitrile (100 mL) was added (diacetyloxy iodide) benzene (11.69 g, 36.32 mmol, 2.0 eq), cesium fluoride (11.04 g , 72.64 mmol, 4.0 equiv), then added trifluoromethyltrimethylsilane (10.314 g, 72.64 mmol, 4.0 equiv) and stirred at room temperature for 4 h. It was filtered through a bed of Celite® and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 12% ethyl acetate in hexane as eluent) to give

[45] . [3]. MS (ES): m / z 327.2 [M+H]+. []

[0348] [compound]

[45] . [4] [The synthesis]. By bubbling argon gas through for 10 min

[45] . [3] (1.7 g, 5.21 mmol, 1.0 equiv), diphenylformimine (1.037 g, 5.73 mmol, 1.1 equiv) and cesium carbonate (3.39 g, 10.42 mmol, 2.0 equiv) in DMF (20 mL) The mixture is degassed. Add 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.090 g, 0.156 mmol, 0.03 equivalent) and ginseng (dibenzylideneacetone) dipalladium (0, 0.071 g , 0.078 mmol, 0.015 equiv), and degassed for 5 min. The reaction mixture was stirred at 80 °C for 4 h. Allow to cool to room temperature and filter through a pad of Celite®. The filtrate was poured on water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 15% ethyl acetate in hexane as eluent) to give

[45] . [4]. MS (ES): m / z 380.4 [M+H]+. []

[0349] [compound]

[45] . [5] [The synthesis]. Towards

[45] . [4] To a solution of (1.62 g, 4.27 mmol, 1.0 equiv) in THF (16 mL) was added 1 N hydrochloric acid (16 mL, 10v), and stirred at room temperature for 30 min. It was poured on ice-water, stirred and extracted with ethyl acetate. The aqueous layer was separated, neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain

[45] . [5]. MS (ES): m / z 216.2 [M+H]+.

[0350] [compound] [45.6] [The synthesis. ] will compound [45.5] (0.500 g, 2.32 mmol, 1.0 eq), a mixture of 10% palladium on carbon (0.500 g) in methanol (10 mL) was stirred under 280 psi of hydrogen at 90 °C for 12 h. After the reaction was complete, the reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to obtain [45.6]. MS (ES): m / z 220.2 [M+H]+.

[0351] [compound] [(±)-45]. [7] [The synthesis]. compound [(±)-45]. [7] Derived from [45.6] follow The procedure described in the synthesis of [11.8] was prepared. The crude product was used in the next step without further purification. MS (ES): m / z 262.3 [M+H]+.

[0352] [compound] [(±)-I-45] [The synthesis]. compound [(±)-I-45] is from [(±)-45]. [6] follow The procedure described in the synthesis of [I-1] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol in dichloromethane as eluent) to obtain . MS (ES): m / z: 500.5 [M+H]+. []

[0353] [I-45-a] [and] [I-45-b]. Separation by SFC (CHIRALPAK AD-H (250 mm × 4.6 mm, 5 µm), eluent: 0.1% DEA in MEOH; flow rate: 4 mL / min) The enantiomer of [I-45] obtained the first elution fraction ( [I-45-a] ) and the second elution fraction ( [I-45-b]). (*Absolute stereochemistry not determined.)

[0354] [I-45-a] :MS (ES):m / z: 500.8 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.47 (s, 1H), 8.13-8.12 (d ,J = 5.6 Hz, 1H), 7.62 (s, 1H), 7.29-7.27 (d,J = 8.4 Hz, 1H), 7.11 (s, 1H), 6.90-6.88 (d,J = 6.4 Hz, 1H) , 6.78-6.75 (m, 1H), 6.59-6.58 (m, 1H), 4.43 (bs, 1H), 4.37-4.33 (m, 1H), 4.06-3.97 (m, 2H), 3.51 (s, 3H) , 2.99-2.85 (m, 2H), 2.22 (bs, 3H), 2.15-2.10 (m, 1H), 2.02 (s, 3H).

[0355] [I-45-b] :MS (ES):m / z: 500.77 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.46 (s, 1H), 8.13-8.12 (d ,J = 5.6 Hz, 1H), 7.62 (s, 1H), 7.29-7.27 (d,J = 8.4 Hz, 1H), 7.11 (s, 1H), 6.89-6.88 (d,J = 6.4 Hz, 1H) , 6.78-6.76 (m, 1H), 6.59-6.58 (m, 1H), 4.43 (bs, 1H), 4.37-4.33 (m, 1H), 4.04-3.97 (m, 2H), 3.51 (s, 3H) , 2.99-2.89 (m, 2H), 2.22 (bs, 3H), 2.13-2.12 (m, 1H), 2.02 (s, 3H). [example]

[46] [:] N -(4-((2-((2-Acetyl-5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)amino) -1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0356] [compound]

[46] . [2] [Synthesis] at 0°C to

[46] . [1] To a solution of (5.0 g, 35.94 mmol, 1.0 equiv) in concentrated sulfuric acid (20 mL) was added potassium nitrate (4.17 g, 41.35 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature for 3 h. It was poured on crushed ice, neutralized by aqueous ammonium hydroxide, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3%-4% methanol in dichloromethane as eluent) to give

[46] . [2] . MS (ES): m / z 179.2 [M+H]+. []

[0357] [compound]

[46] . [3] [The synthesis]. at 0°C to

[46] . [2] To a solution of (1.3 g, 7.30 mmol, 1.0 equiv) in trifluoromethanesulfonic acid (2.5 mL) was added N-iodo-succinimide (1.97 g, 8.76 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 3 h. It was poured on cold saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3% methanol in dichloromethane as eluent) to give

[46] . [3]. MS (ES): m / z 305.1 [M+H]+. []

[0358] [compound]

[46] . [4] [The synthesis]. at 0°C to

[46] . [3] To a solution of (0.9 g, 2.96 mmol, 1.0 equiv) in THF (20 mL) was added triethylamine (1.23 mL, 8.88 mmol, 3.0 equiv), followed by addition of acetyl chloride (0.25 mL, 3.55 mmol, 1.2 equivalents), and stirred at room temperature for 4 h. Allow to cool to room temperature, pour on water, stir and extract with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 60% ethyl acetate in hexane as eluent) to give

[46] . [4]. MS (ES): m / z 347.12 [M+H]+. []

[0359] [compound]

[46] . [5] [The synthesis]. by microwave reactor [46.4] (0.350 g, 1.01 mmol, 1.0 equiv), copper(II) chloride (0.027 g, 0.202 mmol, 0.2 equiv), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.582 g, 3.03 mmol, 3.0 equiv) in N,N-dimethylformamide (10 mL) was heated at 120 °C for 2 h. The reaction mixture was transferred to saturated sodium bicarbonate solution, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 30% ethyl acetate in hexane as eluent). MS (ES): m / z 289.23 [M+H]+.

[0360] [compound]

[46] . [6] [The synthesis]. compound

[46] . A mixture of [5] (0.155 g, 0.537 mmol, 1.0 equiv) and 10% palladium on carbon (0.050 g) in ethanol (10 mL) was evacuated and purged with hydrogen three times. The reaction mixture was stirred at room temperature under 1 atm of hydrogen for 2 h. The mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (CombiFlash®, 5% methanol in dichloromethane as eluent) to give

[46] . [6]. MS (ES): m / z 259.24 [M+H]+. []

[0361] [compound]

[46] . [7] [The synthesis]. compound [46.7] from [46.6] follow The procedure described in the synthesis of [11.8] was prepared. The crude product was used in the next step without further purification. MS (ES): m / z 301.3 [M+H]+.

[0362] [I-46] [The synthesis]. compound [I-46] Department of [46.7] follow The procedure described in the synthesis of [I-1] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 5% methanol in dichloromethane as eluent). MS (ES): m / z: 539.57 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 9.29 (s, 1H), 8.16 (bs, 2H) , 8.10 (s, 1H), 7.66 (s, 1H), 7.50-7.48 (d,J = 7.6 Hz, 1H), 7.27 (s, 1H), 6.89-6.87 (d,J = 8 Hz, 1H), 6.63 (s, 1H), 4.77-4.70 (m, 2H), 3.71 (bs, 5H), 2.96 (bs, 1H), 2.83 (bs, 1H), 2.14-2.11 (d, 3H), 2.00 (s, 3H). [example]

[47] [:] N -(4-((2-((1-(2-methoxyethyl)-3,3-dimethyl-2-oxo-4-(trifluoromethyl)indole Lin-6-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0363] [compound]

[47] . [2] [The synthesis]. at 0°C to

[47] . [1] To a solution of (10 g, 4.90 mmol, 1.0 equiv) in sulfuric acid (10 mL) was added a solution of N-iodosuccinimide (1.32 g, 5.88 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 12 h. It was poured carefully on ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain

[47] . [2] . MS (ES): m / z 332.2 [M+H]+. []

[0364] [compound]

[47] . [3] [The synthesis]. Dimethyl oxalate (4.27 g, 36.25 mmol, 1.0 equiv) was added to a solution of sodium methoxide in methanol (21%) (9.3 mL, 36.25 mmol, 1.0 equiv) at room temperature and stirred for 1.5 h. Add to the mix

[47] . [2] A solution of (12 g, 36.25 mmol, 1.0 eq) in methanol (10 mL) was stirred at room temperature for 12 h. It was added to ice-cold 2.5 M hydrochloric acid until the pH was 4-5, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 10% ethyl acetate in hexane as eluent) to give

[47] . [3]. MS (ES): m / z 418.2 [M+H]+.

[0365] [compound]

[47] . [4] [The synthesis]. at room temperature to

[47] . [3] To a solution of (10 g, 23.98 mmol, 1.0 equiv) in acetic acid (20 mL) was added perchloric acid (10 mL). The mixture was heated at 80 °C for 1 h. Allow to cool to room temperature and add 30% hydrogen peroxide solution (59 mL, 527 mmol, 22 equiv). The reaction mixture was stirred at 60 °C for 5 h. It was poured on saturated aqueous sodium sulfite, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine and 2 N sodium hydroxide solution. The aqueous layer was acidified to pH 3 with concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water and dried under vacuum to give [47.4]. MS (ES): m / z 376.1 [M+H]+. []

[0366] [compound]

[47] . [5] [The synthesis]. Towards

[47] . [4] To a solution of (2.5 g, 6.67 mmol, 1.0 equiv) in methanol (25 mL) was added oxalyl chloride (3.75 mL, 43.7 mmol, 6.5 equiv). The reaction mixture was stirred at 70 °C for 4 h. It was poured on saturated sodium bicarbonate solution, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 20% ethyl acetate in hexane as eluent) to give

[47] . [5]. MS (ES): m / z 390.1 [M+H]+. []

[0367] [compound]

[47] . [6] [The synthesis]. at 0°C to

[47] . [5] To a solution of (2.0 g, 5.14 mmol, 1.0 equiv) in methanol (20 mL) was added a commercially available 15% titanium(III) chloride solution (9.8 g, 63.73 mmol, 12.4 equiv). The reaction mixture was stirred at room temperature for 12 h. It was poured on ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 10% ethyl acetate in hexane as eluent) to give

[47] . [6]. MS (ES): m / z 328.2 [M+H]+. []

[0368] [compound]

[47] . [7] [The synthesis]. at 0°C to

[47] . [6] To a solution of (1.4 g, 4.28 mmol, 1.0 eq) in THF (15 mL) was added potassium tert-butoxide (2.39 g, 21.4 mmol, 5.0 eq) followed by copper(I)bromide dimethyl Disulfide complex (0.087 g, 0.428 mmol, 0.1 equiv). Iodomethane (1.27 g, 8.98 mmol, 2.1 equiv) was added slowly at 0 °C. The reaction mixture was stirred at room temperature for 3 h. It was poured on ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 8% ethyl acetate in hexane as eluent) to give

[47] . [7]. MS (ES): m / z 356.1 [M+H]+. []

[0369] [compound]

[47] . [8] [The synthesis]. Towards

[47] . [7] (0.5 g, 1.41 mmol, 1.0 equiv) and methanesulfonic acid 2 [-] To a solution of methoxyethyl ester (0.260 g, 1.69 mmol, 1.2 eq) in DMF (5 mL) was added cesium carbonate (1.14 g, 3.52 mmol, 2.5 eq), and the reaction mixture was heated at 80°C Stir for 16 h. It was poured on ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 5%-8% ethyl acetate in hexane as eluent) to give

[47] . [8] . MS (ES): m / z 414.5 [M+H]+. []

[0370] [compound]

[47] . [9] [The synthesis]. Towards

[47] . [8] To a solution of (0.370 g, 0.895 mmol, 1.0 equiv.) in dimethyloxide (4 mL), add L-proline (0.020 g, 0.179 mmol, 0.2 equiv.), copper iodide (0.068 g, 0.358 mmol, 0.4 equiv) and potassium carbonate (0.432 g, 3.13 mmol, 3.5 equiv), and then ammonium hydroxide solution (0.13 mL) was added. The reaction mixture was stirred at 90 °C for 16 h. Allow to cool to room temperature, pour on water and extract with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 25% ethyl acetate in hexane as eluent) to give

[47] . [9] . MS (ES): m / z 303.3 [M+H]+.

[0371] [compound]

[47] .

[10] [The synthesis]. compound [47.10] from [47.9] follow The procedure described in the synthesis of [11.8] was prepared. The crude product was used in the next step without further purification. MS (ES): m / z 345.4 [M+H]+.

[0372] [I-47] [The synthesis]. compound [I-47] Derived from [47.10] and [Int-2] follow The procedure described in the synthesis of [I-1] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3%-5% methanol in dichloromethane as eluent). MS (ES): m / z: 583.9 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 9.42 (s, 1H), 8.16-8.15 (d, J = 6.0 Hz, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.65 (s, 1H), 7.45-7.43 (d, J = 8.4 Hz, 1H), 7.28 (s, 1H), 6.89-6.87 (d,J = 7.2 Hz, 1H), 6.63-6.62 (d,J = 3.6 Hz, 1H), 3.90-3.89 (m, 2H), 3.72 (s, 3H), 3.65-3.62 (m, 2H), 3.24 (s, 3H), 2.03 (s, 3H), 1.36 (s, 6H). [example]

[48] [:] N -(4-((2-((1-(2-hydroxyethyl)-3,3-dimethyl-2-oxo-4-(trifluoromethyl)indoline- 6-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0373] [compound] [48.2] [The synthesis. ] at 0°C to [48.1] (1.0 g, 6.57 mmol, 1.0 equiv) and triethylamine (2.74 mL, 19.71 mmol, 3.0 equiv) in dichloromethane (10 mL) was added methanesulfonyl chloride (0.76 mL, 9.85 mmol , 1.5 equivalents). The reaction mixture was stirred at room temperature for 3 h. It was poured on ice-water, stirred and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain [48.2]. MS (ES): m / z 231.3 [M+H]+.

[0374] [compound] [48.3] [The synthesis. ] compound [48.3] from [48.1] and [47.7] follow [47.8] was prepared by the procedure described in the synthesis of [47.8]. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 10%-12% ethyl acetate in hexane as eluent). MS (ES): m / z 490.3 [M+H]+.

[0375] [compound] [48.4] [The synthesis]. compound [48.4] from [48.3] follow [47.9] was prepared using the procedure described in the synthesis of [47.9]. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 20%-22% ethyl acetate in hexane as eluent). MS (ES): m / z 379.4 [M+H]+.

[0376] [compound] [48.5] [The synthesis. ] compound [48.5] from [48.4] follow The procedure described in the synthesis of [11.8] was prepared. The crude product was used in the next step without further purification. MS (ES): m / z 421.5 [M+H]+.

[0377] [compound] [48.6] [The synthesis. ] compound [48.6] from [48.5] follow The procedure described in the synthesis of [I-1] was prepared. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3%-4% methanol in dichloromethane as eluent). MS (ES): m / z: 659.6 [M+H]+.

[0378] [compound] [I-48] [The synthesis]. to the compound at 0°C To a solution of [48.6] (0.100 g, 0.151 mmol, 1.0 equiv) in dichloromethane (5 mL) was added trifluoromethanesulfonic acid (0.5 mL). The reaction mixture was stirred at 0 °C for 30 min. It was poured on saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by trituration with methanol to obtain [I-48]. MS (ES): m / z: 569.9 [M+H]+ ,1 H NMR (DMSO-d6, 400 MHz): δ 10.50 (s, 1H), 9.42 (s, 1H), 8.16-8.15 (d, J = 5.6 Hz, 1H), 8.03 (s, 1H), 7.92 (s, 1H), 7.65 (s, 1H), 7.47-7.45 (d, J = 8.4 Hz, 1H), 7.29 (s, 1H), 6.89-6.87 (d,J = 8.4 Hz, 1H), 6.64-6.63 (d,J = 3.6 Hz, 1H), 4.99-4.97 (m, 1H), 3.79-3.78 (m, 2H), 3.72 (s, 3H), 3.70-3.67 (m, 2H), 2.02 (s, 3H), 1.37 (s, 6H). [example]

[49] [:] N -(4-((1-methyl-2-((1,1,2-trimethyl-3-oxo-7-(trifluoromethyl)isoindoline-5- Base) amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0379] [compound]

[49] . [2] [The synthesis]. Towards

[49] . [1] To a solution of (1.0 g, 4.90 mmol, 1.0 eq) in 0.2 M aqueous acetic acid (20 mL) was added nitric acid (2.08 mL, 49 mmol, 10 eq), bromine (0.86 g, 5.39 mmol, 1.1 eq) , after which 2.5 M aqueous silver nitrate solution (2.5 mL, 6....

Claims

1. A compound of formula I-1 or a pharmaceutically acceptable salt thereof, 1. Among them: W is CRw or N; X is CRx or N; Y is CRy or N; Z is -O- or -NRz-; Rw, Rx, and Ry are each independently hydrogen, halogen, -OR3, -N(R3)2, -SR3, substituted C1-6 aliphatic, or -CN; Rz is hydrogen or substituted C1-6 aliphatic; R1 is -N(R)2, -N(R)C(O)R', -C(O)N(R)2, or -N(R)C(O)N(R)2; R2 is substituted C1-6 aliphatic; R3 is hydrogen or substituted C1-6 aliphatic; ring A has 1-4 A 5- to 6-membered monocyclic heteroaryl group having one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted; an 8- to 10-membered bicyclic heteroaryl group having one to four heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group having one to three heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted; or a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having one to four heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted; L is a covalent bond or a divalent C1- 3. Straight-chain or branched hydrocarbon chain; Ra is hydrogen, halogen, C1-6 aliphatic, substituted phenyl, substituted 5-6 substituted monocyclic heteroaryl with 1-4 independently selected heteroatoms of nitrogen, oxygen, and sulfur, substituted 3-7 substituted saturated or partially unsaturated monocyclic carbocyclic group, substituted 3-3 substituted saturated or partially unsaturated monocyclic heterocyclic group with 1-3 independently selected heteroatoms of nitrogen, oxygen, and sulfur, or substituted 7-10 substituted bicyclic heterocyclic group with 1-4 independently selected heteroatoms of nitrogen, oxygen, and sulfur; each R Independently, it is hydrogen, a C1-6 aliphatic group as appropriate, a 3- to 7-member saturated or partially unsaturated carbocyclic group as appropriate, or a 3- to 7-member saturated or partially unsaturated monocyclic heterocyclic group as appropriate, having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two Rs together, when attached to the same nitrogen atom, form a 3- to 7-member saturated or partially unsaturated monocyclic heterocyclic group as appropriate, having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R' is independently a C1-6 aliphatic group as appropriate, or a 3- to 7-member saturated or partially unsaturated carbocyclic group as appropriate.

2. The compound of claim 1 or its pharmaceutically acceptable salt, wherein ring A is a 5- to 6-membered monocyclic heteroaryl group having 1 to 4 independently selected heteroatoms chosen from nitrogen, oxygen and sulfur, which may be substituted.

3. The compound of claim 1 or its pharmaceutically acceptable salt, wherein ring A is an 8- to 10-membered bicyclic heteroaryl group having 1 to 4 independently selected heteroatoms chosen from nitrogen, oxygen and sulfur, which may be substituted.

4. The compound of claim 1 or its pharmaceutically acceptable salt, wherein ring A is, where appropriate, a substituted 3- to 7-member saturated or partially unsaturated monocyclic carbocyclic group.

5. The compound of claim 1 or its pharmaceutically acceptable salt, wherein ring A is a substituted 3- to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 independently selected heteroatoms from nitrogen, oxygen and sulfur.

6. The compound of claim 1 or its pharmaceutically acceptable salt, wherein ring A is a 7- to 10-member saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 independently selected heteroatoms selected from nitrogen, oxygen and sulfur, which may be substituted.

7. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Ra is a halogen, a C1-4 alkyl group which is substituted as appropriate, a 5-membered monocyclic heteroaryl group which is substituted as appropriate and has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 6-membered saturated monocyclic carbocyclic group which is substituted as appropriate and has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 7-membered saturated spirocyclic bicyclic heterocyclic group which is substituted as appropriate and has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

8. The compound of claim 7 or its pharmaceutically acceptable salt, wherein Ra is a C1-4 alkyl group substituted with one or more side oxygen, halogen, -CN, -OH or -O (C1-6 alkyl) as appropriate.

9. The compound of claim 7 or its pharmaceutically acceptable salt, wherein Ra is a 3- to 6-member saturated monocyclic carbocyclic group substituted with one or more -(C1-6 alkyl)OH, -CN, -OH or -O(C1-6 alkyl) as appropriate.

10. The compound of claim 7 or its pharmaceutically acceptable salt, wherein Ra is a 3- to 6-membered saturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which, as appropriate, is substituted with one or more side oxygen groups, halogens, -C(O)(C1-4 alkyl), -O(C1-4 alkyl), or, as appropriate, C1-4 alkyl groups substituted with one or more halogens and -O(C1-4 alkyl).

11. The compound of claim 7 or its pharmaceutically acceptable salt, wherein Ra is a substituted 7-membered saturated spirocyclic bicyclic heterocyclic group having 1-2 independently selected heteroatoms from nitrogen, oxygen and sulfur.

12. The compound of claim 7 or its pharmaceutically acceptable salt, wherein Ra is a C1-4 alkyl group, a 3- to 6-membered saturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 7-membered saturated spirocyclic bicyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: Rb is hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)SO2R', -SO2R', -SO2N(R)2, -SO3R', C1-6 aliphatic groups as appropriate, 3- to 6-member saturated or partially unsaturated carbocyclic groups as appropriate, 3- to 6-member saturated or partially unsaturated monocyclic heterocyclic groups as appropriate with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5- to 6-member monocyclic heteroaryl groups as appropriate with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

14. The compound of claim 13 or its pharmaceutically acceptable salt, wherein: , , , , , 14.、、、、or 15. The compound of claim 14 or its pharmaceutically acceptable salt, wherein: or.

16. A compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein Rb is hydrogen, halogen, a C1-4 alkyl group which is substituted as appropriate, a C3-4 cycloalkyl group which is substituted as appropriate, a 3- to 5-member saturated or partially unsaturated monocyclic heterocyclic group which is substituted as appropriate and has 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 5-member monocyclic heteroaryl group which is substituted as appropriate and has 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein Rb is, where appropriate, a C3-4 cycloalkyl or C1-4 alkyl group substituted with one or more fluorine molecules.

18. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L is a covalent bond or -CH2-.

19. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is -N(H)C(O)R'.

20. A compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein R1 is -N(H)C(O) (substituted C1-4 alkyl group, as appropriate).

21. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein R1 is -N(H)C(O)CH3 or -N(H)C(O) (cyclopropyl).

22. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is -C(O)N(H)CH3.

23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is -N(H)C(O)N(R)2.

24. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is a C1-4 alkyl group.

25. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein R2 is a methyl group.

26. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is CRx.

27. A compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein Rx is hydrogen, halogen, -OR3, or, where applicable, a substituted C1-6 aliphatic or -CN.

28. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is N.

29. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is CRy.

30. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein Ry is hydrogen.

31. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is N.

32. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein W is CRw.

33. The compound of claim 32 or its pharmaceutically acceptable salt, wherein Rw is hydrogen.

34. The compound of claim 1 or its pharmaceutically acceptable salt, wherein W is N.

35. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is -NRz-.

36. The compound of claim 35 or its pharmaceutically acceptable salt, wherein Rz is hydrogen.

37. The compound of claim 1 or its pharmaceutically acceptable salt, wherein Z is -O-.

38. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R is independently hydrogen or, where appropriate, a substituted C1-6 aliphatic compound.

39. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R' is independently a substituted C1-2 alkyl or a substituted C3-4 cycloalkyl, as appropriate.

40. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: W is CH; Rx and Ry are each independently hydrogen, or C1-6 aliphatic or -CN substituted as appropriate; and each R is independently hydrogen, or C1-6 aliphatic substituted as appropriate, or a 3- to 7-member saturated or partially unsaturated carbocyclic group substituted as appropriate, or a 3- to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or two Rs together form a 3- to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 0-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur when attached to the same nitrogen atom.

41. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula IA:

41. Or its medically acceptable salt.

42. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula IB:

42. Or a medically acceptable salt thereof.

43. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula IC:

43. Or a medically acceptable salt thereof.

44. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula ID:

44. Or a medically acceptable salt thereof.

45. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula IE:

45. Or a medically acceptable salt thereof.

46. ​​The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following:

46. ​​Or a medically acceptable salt thereof.

47. A pharmaceutical composition comprising a compound of any one of claims 1 to 46 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

48. Use of a compound of any one of claims 1 to 46 or a pharmaceutically acceptable salt thereof or a composition of claim 47 for the preparation of a medicament for inhibiting JAK2 to treat a disease, condition or ailment, wherein the disease, condition or ailment is cancer.

49. Use of any compound of claims 1 to 46 or a pharmaceutically acceptable salt thereof or a composition of claim 47 for the preparation of a medicament for inhibiting JAK2 to treat a disease, condition or ailment, wherein the disease, condition or ailment is a hematologic malignancy.

50. As requested in claim 49, wherein the hematologic malignancy is leukemia or lymphoma.

51. Use of a compound of any one of claims 1 to 46 or a pharmaceutically acceptable salt thereof or a composition of claim 47 for the preparation of a medicament for inhibiting JAK2 to treat a disease, condition or ailment, wherein the disease, condition or ailment is myeloproliferative neoplasm.

52. As claimed in claim 51, wherein the myeloproliferative neoplasm is true polycythemia, primary thrombocytopenia, or myelofibrosis.